HK40083716B - Diacylglycerol kinase modulating compounds - Google Patents

Description

Diacylglycerol kinase-regulating compounds

Cross-reference to related applications

This application claims priority to Japanese Application No. 2019-232938, filed on December 24, 2019, and Japanese Application No. 2020-135810, filed on August 11, 2020, each of which is incorporated herein by reference in its entirety.

Background Technology

Diacylglycerol (DAG) is known as a second messenger in signal transduction molecules and plays an important role in cell proliferation, differentiation, and/or metabolism (Carrasco, S., Merida, I. Trends Biochem. Sci. 2007, 32, 27-36). The intracellular concentration and localization of DAG are tightly controlled, and diacylglycerol kinase (DGK) is one of the enzymes that regulates them. DGK is an enzyme that synthesizes phosphatidic acid (PA) by transferring a phosphoryl group to DAG. Ten human isoenzymes (α, β, γ, δ, ε, ζ, η, θ, ι, κ) are known (Joshi, R.P., Koretzky, G.A. Int. J. Mol. Sci. 2013, 14, 6649-6673). Each isoenzyme is believed to localize and associate with different proteins and/or different cell types. DGK has been reported to be involved in the pathogenesis of a variety of diseases, including cancer, immune diseases, neurodegenerative diseases, and diabetes (Sakane, F. et al. Front. Cell Dev. Biol., 2016, 4, 82).

DGKα is a research target, including for potential cancer treatments. For example, as a result of knockdown induced by RNA interference targeting DGKα, inhibitory activity against glioblastoma cell proliferation has been reported (Dominguez, C.L. et al., Cancer Discov., 2013, 782-797). Inhibitory effects on human colon cancer cell lines in three-dimensional cell cultures have also been reported, and further, DGKα knockdown has been reported to inhibit tumor proliferation in mouse models (Torres-Ayuso, P. et al., Oncotarget, 2014, 5, 9710-9726). Inhibition of DGKα is disclosed in WO 2007/114239. Therefore, compounds with inhibitory activity against DGKα can be used for therapies, such as treating cancers in which DGKα is involved in their proliferation.

In recent years, cancer immunotherapy has attracted attention as a potential cancer treatment. Immune checkpoint inhibitors such as anti-CTLA-4 (cytotoxic T-lymphocyte antigen 4) antibodies, anti-PD-1 (programmed death receptor 1) antibodies, and anti-PD-L1 (programmed death ligand 1) antibodies can be administered, and can enhance the anti-tumor immune response in patients. Some immune checkpoint inhibitors have been approved for use as anti-tumor therapy. However, the anti-tumor effect is often limited to a few patients. In addition, some patients are resistant to inhibitors (Spranger, S., Gajewski, T.F., Nat. Rev. Cancer., 2018, 18, 139-147).

DGKα is expressed on T cells, mediates signaling of the T cell receptor (TCR), and is believed to play a role in T cell activation (Joshi et al., ibid. and Merida, I. et al., Adv. Biol. Regul., 2017, 63, 22-31). DGKα expression may increase when T cells are in an immune-unresponsive condition (such as allergy), and overexpression of DGKα has been reported to induce allergic symptoms (Zha, Y. et al., Nat. Immunol., 2006, 7, 1166-1173). Furthermore, T cell activation has been reported due to knockdown of DGKα in T cells via RNA interference (Avila-Flores, A. et al., Immunol. Cell. Biol., 2017, 95, 549-563). Therefore, compounds with DGKα-controlling activity could be used for the prevention and/or treatment of T cell-related diseases such as immune or inflammatory disorders.

Recently, CAR (chimeric antigen receptor) T-cell therapy has also attracted attention as a promising immunotherapy for cancer. DGKα-deficient CAR T cells have been reported to exhibit high effector function and antitumor activity against solid cancers (Riese, M.J. et al., Cancer Res., 2013, 73, 3566-3577; Jung, I.Y. et al., Cancer Res., 2018, 78, 4692-4703). Therefore, the use of compounds that inhibit DGKα could complement CAR T-cell therapy.

However, there is still a need for DGKα inhibitors, such as those with the desired pharmaceutical and therapeutic properties.

Summary of the Invention

In one embodiment, this disclosure provides a compound of formula (I-1):

Or its pharmaceutically acceptable salt, wherein

^R1 , ^R2 , ^R3 and ^R4 are independently hydrogen atoms, halogen atoms, hydroxyl groups, carboxyl groups, formyl groups, cyano groups, amino groups, nitro groups, nitroso groups, alkoxy carbonyl groups, optionally substituted alkyl groups, optionally substituted alkenyl groups, optionally substituted alkynyl groups, optionally substituted alkylamino groups, optionally substituted aryl groups, optionally substituted heteroaryl groups, optionally substituted acyl groups, optionally substituted carbamoyl groups, optionally substituted acylamino groups, optionally substituted saturated heterocyclic groups or optionally substituted alkyl sulfonylamino groups;

^R5 is a hydrogen atom, an optionally substituted alkyl group, an optionally substituted alkynyl group, or an optionally substituted aryl group; and

^R6 is an optionally substituted alkyl, optionally substituted aryl, optionally substituted heteroaryl, or ^R5 and ^R6 together with the nitrogen atom to which they are bonded can form a nitrogen-containing saturated heterocyclic ring with which the aryl ring is fused, and the fused ring can be substituted.

The prerequisite is that the compound is not

In another embodiment, this disclosure provides a compound of formula (I):

Or its pharmaceutically acceptable salt, wherein

^R1 is hydrogen, _C1-6 alkyl, _C2-6 alkenyl, _C2-6 alkynyl, _C1-6 alkoxy, halogen, _C1-6 haloalkyl, _C1-6 haloalkoxy, or –CN;

^R2 represents hydrogen, _C1-6 alkyl, _C2-6 alkenyl, _C2-6 alkynyl, _C1-6 hydroxyalkyl, _C1-6 aminoalkyl, C1-6 alkoxy, _C2-6 alkoxyalkyl, halogen, _C1-6 haloalkyl, _C1-6 haloalkoxy, -CN, -NO, -NO2, -C(O) _R2a , -C(O ₎ ^OR2a , -OC(O) ^R2a , -C(O)N(R2a)( ^R2b ), -N( ^R2a )C(O) ^R2b , -OC(O)N( ^R2a )( ^R2b ), ^{-N(R2a )} C(O) ^OR2b , ^-C (＝ ^NR2a )N( ^R2b )( ^R2c ), -N( ^R2a )( ^R2b ), -N(R ^2a )N(R ^2b )(R ^2c ), -N(R ^2a )N＝C(R ^2b )(OR ^2c ), -OR ^2a , -SR ^2a , -S(O)R ^2a , -S(O)(NR ^2a )(R ^2b ), -S(NR ^2a )(NR ^2b )(R ^2c ), -S(O) ₂ R ^2a , -S(O) ₂ N(R ^2a )(R ^2b ), -N(R ^2a )S(O) ₂ (R ^2b ), -P(R ^2a )(R ^2b ), -P(O)(R ^2a )(R ^2b ), -P(O)(OR ^2a )(R ^2b ), -P(O)(OR ^2a )(OR ^2b ), C _3-10 cycloalkyl, C _1-6 alkyl-C _3-10 cycloalkyl, C _6-12 aryl, C _1-6 alkyl-C _6-12 aryl, heterocycloalkyl, C _1-6 alkyl-(heterocycloalkyl), heteroaryl or C _1-6 alkyl-(heteroaryl), wherein each alkyl, alkenyl or alkynyl group is independently and optionally substituted with 1 to 3 R ^2d groups, each cycloalkyl group is optionally substituted with 1 to 3 R ^2e groups, each aryl group is optionally substituted with 1 to 3 R ^2f groups, each heterocycloalkyl group is optionally substituted with 1 to 3 R ^2g groups, and each heteroaryl group is optionally substituted with 1 to 3 R ^2h groups;

Each R ^2a , R ^2b and R ^2c is independently hydrogen, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 hydroxyalkyl, C _1-6 aminoalkyl, C _2-6 alkoxyalkyl, C _1-6 haloalkyl, C _3-10 cycloalkyl, C _1-6 alkyl-C _3-10 cycloalkyl, C _6-12 aryl, C _1-6 alkyl-C _6-12 aryl, heterocycloalkyl, C _1-6 alkyl-(heterocycloalkyl), heteroaryl or C _1-6 alkyl-(heteroaryl), wherein the aryl or heteroaryl is optionally substituted by one to three R ^2j ;

Alternatively, ^R2a , ^R2b and ^R2c, when attached to the same atom, can combine with the atom to which they are attached to to form a heterocyclic alkyl group;

Each R ^2d is independently –CN, -C(O)R ^2d1 , -C(O)OR ^2d1 , -OC(O)R ^2d1 , -C(O)N(R ^2d1 )(R ^2d2 ), -N(R ^2d1 )C(O)R ^2d2 , -OC(O)N(R ^2d1 )(R ^2d2 ), -N(R ^2d1 )C(O)OR ^2d2 , -N(R ^2d1 )(R ^2d2 ), =O, -OR ^2d1 , -SR ^2d1 , -S(O)R ^2d1 , -S(O)(NR ^2d1 )(R ^2d2 ), -S(O) ₂ R ^2d1 , -S(O)N(R ^2d1 )(R ^2d2 ), -N(R ^2d1) S(O) ₂ R ^2d2 , C _3-10 cycloalkyl, C _1-6 alkyl-C _3-10 cycloalkyl, C _6-12 aryl, C _1-6 alkyl-C _6-12 aryl, heterocycloalkyl, C _1-6 alkyl-(heterocycloalkyl), heteroaryl or C _1-6 alkyl-(heteroaryl);

Each R ^2d1 and R ^2d2 is independently hydrogen, a C _1-6 alkyl, a C _1-6 hydroxyalkyl, a C _1-6 aminoalkyl, a C _2-6 alkoxyalkyl, or a C _1-6 haloalkyl;

Each of ^R2e , ^R2f , ^R2g and ^R2h is independently hydrogen, _C1-6 alkyl, _C1-6 hydroxyalkyl, _C1-6 aminoalkyl, _C1-6 alkoxy, _C2-6 alkoxyalkyl, halogen, _C1-6 haloalkyl, _C1-6 haloalkoxy, -CN or -OH;

Each R ^2j is independently a _C1-6 alkyl, _C1-6 hydroxyalkyl, _C1-6 aminoalkyl, _C1-6 alkoxy, _C2-6 alkoxyalkyl, halogen, _C1-6 haloalkyl, or _C1-6 haloalkoxy;

^R3 represents hydrogen, _C1-6 alkyl, _C2-6 alkenyl, _C2-6 alkynyl, _C1-6 hydroxyalkyl, _C1-6 aminoalkyl, C1-6 alkoxy, _C2-6 alkoxyalkyl, halogen, _C1-6 haloalkyl, _C1-6 haloalkoxy, -CN, -NO, -NO2, -C(O) _R3a , -C(O ₎ ^OR3a , -OC(O) ^R3a , -C(O)N(R3a)( ^R3b ), -N( ^R3a )C(O) ^R3b , -OC(O)N( ^R3a )( ^R3b ), ^{-N(R3a )} C(O) ^OR3b , ^-C (＝ ^NR3a )N( ^R3b )( ^R3c ), -N( ^R3a )( ^R3b ), -N(R ^3a )N(R ^3b )(R ^3c ), -N(R ^3a )N＝C(R ^3b )(OR ^3c ), -OR ^3a , -SR ^3a , -S(O)R ^3a , -S(O)(NR ^3a )(R ^3b ), -S(NR ^3a )(NR ^3b )(R ^3c ), -S(O) ₂ R ^3a , -S(O) ₂ N(R ^3a )(R ^3b ), -N(R ^3a )S(O) ₂ (R ^3b ), -P(R ^3a )(R ^3b ), -P(O)(R ^3a )(R ^3b ), -P(O)(OR ^3a )(R ^3b ), -P(O)(OR ^3a )(OR ^3b ), C _3-10 cycloalkyl, C _1-6 alkyl-C _3-10 cycloalkyl, C _6-12 aryl, C _1-6 alkyl-C _6-12 aryl, heterocycloalkyl, C _1-6 alkyl-(heterocycloalkyl), heteroaryl or C _1-6 alkyl-(heteroaryl), wherein each alkenyl or ynyl group is independently and optionally substituted with 1 to 3 R ^3d groups, each cycloalkyl group is optionally substituted with 1 to 3 R ^3e groups, each aryl group is optionally substituted with 1 to 3 R ^3f groups, each heterocycloalkyl group is optionally substituted with 1 to 3 R ^3g groups, and each heteroaryl group is optionally substituted with 1 to 3 R ^3h groups;

Each R ^3a , R ^3b and R ^3c is independently hydrogen, C _1-6 alkyl, C _1-6 hydroxyalkyl, C _2-6 alkoxyalkyl, C _1-6 haloalkyl, C _3-10 cycloalkyl, C _1-6 alkyl-C _3-10 cycloalkyl, C _6-12 aryl, C _1-6 alkyl-C _6-12 aryl, heterocycloalkyl or heteroaryl;

Alternatively, ^R3a , ^R3b and ^R3c , when attached to the same atom, can combine with the atom to which they are attached to to form a heterocyclic alkyl group;

Each R ^3d is independently -N(R ^3d1 )(R ^3d2 ), -OR ^3d1 , C _3-10 cycloalkyl, C _1-6 alkyl-C _3-10 cycloalkyl, C _6-12 aryl, C _1-6 alkyl-C _6-12 aryl, heterocycloalkyl, or heteroaryl;

Each R ^3d1 and R ^3d2 is independently hydrogen, C _1-6 alkyl, or –C(O)O-(C _1-6 alkyl);

Each of ^R3e , ^R3f , ^R3g and ^R3h is independently hydrogen, _C1-6 alkyl, _C1-6 alkoxy, halogen, _C1-6 haloalkyl or _C1-6 haloalkoxy;

^R4 is hydrogen, _C1-6 alkyl, _C2-6 alkenyl, _C2-6 alkynyl, _C1-6 alkoxy, halogen, _C1-6 haloalkyl, _C1-6 haloalkoxy, or –CN;

R ⁵ is hydrogen, _C1-6 alkyl, _C2-6 alkenyl, _C2-6 alkynyl, _C1-6 hydroxyalkyl, _C2-6 alkoxyalkyl, _C1-6 haloalkyl, _C3-10 cycloalkyl, _C1-6 alkyl- _C3-10 cycloalkyl, _C6-12 aryl, _C1-6 alkyl- _C6-12 aryl, heterocycloalkyl, _C1-6 alkyl-(heterocycloalkyl), heteroaryl, or _C1-6 alkyl-(heteroaryl), wherein the alkyl group is optionally substituted with R ^5a ;

R ^5a is –OSi(R ^5a1 )(R ^5a2 )(R ^5a3 );

^R5a1 , ^R5a2 , and ^R5a3 are each independently a _C1-6 alkyl group; and

^R6 is a _C1-6 alkyl, _C2-6 alkenyl, _C2-6 alkynyl, _C1-6 haloalkyl, _C6-12 aryl or heteroaryl, wherein each of the aryl or heteroaryl groups is optionally substituted by one to three ^R6a .

Each R ^6a is independently a _C1-6 alkyl, _C2-6 alkenyl, _C2-6 alkynyl, _C1-6 hydroxyalkyl, _C1-6 aminoalkyl, C1-6 alkoxy, _C2-6 alkoxyalkyl, halogen, _C1-6 haloalkyl, _C1-6 haloalkoxy, –CN, -NO ₂ , -C(O)R 6b, _-C (O)OR ^6b , -OC(O)R ^6b , -C(O)N(R ^6b )(R ^6c ), -N(R ^6b )C(O)R ^6c , -C(＝NR ^6b )N(R ^6c )(R ^6d ), -N(R ^6b )(R ^6c ), -OR ^6b , -SR ^6b , -S(O ⁾ R ^6b , -S(O) _2R ^6b -S(NR ^6b )(NR ^6c )R ^6d , -S(O)(NR ^6b )(R ^6c ), -S(O) ₂ N(R ^6b )(R ^6c ), -N(R ^6b )S(O) ₂ (R ^6c ), -P(R ^6b )(R ^6c ), -P(O)(R ^6b )(R ^6c ), -P(O)(OR ^6b )(R ^6c ), -P(O)(OR ^6b )(OR ^6c ), C _3-10 cycloalkyl, C _1-6 alkyl-C _3-10 cycloalkyl, C _6-12 aryl, C _1-6 alkyl-C _6-12 aryl, heterocycloalkyl, C _1-6 alkyl-(heterocycloalkyl), heteroaryl or C _1-6 alkyl-(heteroaryl), wherein the cycloalkyl, aryl, heterocycloalkyl or heteroaryl group is optionally substituted by 1 to 3 R ^6e , the alkyl group is optionally substituted by R ^6f , and the alkynyl group is optionally substituted by 1 to 4 R ^6j ;

Each R ^6b , R ^6c , and R ^6d is independently hydrogen, C _1-6 alkyl, C _1-6 hydroxyalkyl, C _1-6 aminoalkyl, C _2-6 alkoxyalkyl, C _1-6 haloalkyl, C _3-10 cycloalkyl, C _1-6 alkyl-C _3-10 cycloalkyl, C _6-12 aryl, C _1-6 alkyl-C _6-12 aryl, heterocycloalkyl, C _1-6 alkyl-(heterocycloalkyl), heteroaryl, or C _1-6 alkyl-(heteroaryl), wherein the cycloalkyl, aryl, heterocycloalkyl, or heteroaryl is optionally substituted by one to three R ^6k ;

Each R ^6k is independently a _C1-6 alkyl, _C1-6 hydroxyalkyl, _C1-6 aminoalkyl, _C1-6 alkoxy, _C2-6 alkoxyalkyl, _C1-6 haloalkyl, _C1-6 haloalkoxy, _C3-10 cycloalkyl, _C1-6 alkyl- _C3-10 cycloalkyl, heterocycloalkyl, or _C1-6 alkyl-(heterocycloalkyl);

Each R ^6e is independently a _C1-6 alkyl, _C2-6 alkenyl, _C2-6 alkynyl, _C1-6 hydroxyalkyl, _C1-6 aminoalkyl, C1-6 alkoxy, _C2-6 alkoxyalkyl, halogen, _C1-6 haloalkyl, _C1-6 haloalkoxy, –CN, -NO ₂ , -C(O)R ^6e1 , _-C (O)OR ^6e1 , -OC(O)R ^6e1 , -C(O)N(R 6e1)(R ^6e2 ), -N(R ^6e1 )C(O)R ^6e2 , -OC(O)N(R ^6e1 )(R ^6e2 ), -N(R ^6e1 )C(O)OR ^6e2 , -C(＝NR ^6e1 )N(R ^6e2 )( ^{R 6e3 )} , -N(R ^6e1 )(R ^6e2 ), =O, -OR ^6e1 , -SR ^6e1 , -S(O)R ^6e1 , -S(NR ^6e1 )(NR ^6e2 ), -S(O)(NR ^6e1 )(R ^6e2 ) , -S(O) ₂ R ^6e1 , -S(O) ₂ N(R ^6e1 )(R ^6e2 ), -SF ₅ , -N(R ^6e1 )S(O) ₂ (R ^6e2 ), -P(R ^6e1 )(R ^6e2 ), -P(O)(R ^6e1 )(R ^6e2 ), -P(O)(OR ^6e1 )(R ^6e2 ), -P(O)(OR ^6e1 )(OR ^6e2 ), -Si(R ^6e1 )(R ^6e2 )(R ^6e3 )、C _3-10 cycloalkyl, _C1-6 alkyl- _C3-10 cycloalkyl, _C6-12 aryl, _C1-6 alkyl- _C6-12 aryl, heterocycloalkyl, _C1-6 alkyl-heterocycloalkyl, heteroaryl or _C1-6 alkyl-heteroaryl, wherein each of the cycloalkyl, aryl, heterocycloalkyl or heteroaryl is optionally substituted with 1 to 3 ^R6h , and the alkyl group is optionally substituted with 1 to 3 ^R6m ;

Each R ^6e1 , R ^6e2 , and R ^6e3 is independently hydrogen, C _1-6 alkyl, C _1-6 hydroxyalkyl, C _1-6 aminoalkyl, C _1-6 alkoxyalkyl, C _1-6 haloalkyl, C _3-10 cycloalkyl, C _1-6 alkyl-C _3-10 cycloalkyl, C _6-10 aryl, C _1-6 alkyl-C _6-10 aryl, heterocycloalkyl, C _1-6 alkyl-(heterocycloalkyl), heteroaryl, or C _1-6 alkyl-(heteroaryl), wherein the cycloalkyl, aryl, heterocycloalkyl, or heteroaryl is optionally substituted by one to three R ⁶ⁿ ;

Each R ⁶ⁿ is a _C1-6 alkyl, _C2-6 alkenyl, _C2-6 alkynyl, _C1-6 hydroxyalkyl, _C1-6 aminoalkyl, _C1-6 alkoxy, C2-6 alkoxyalkyl, halogen, _C1-6 haloalkyl, _C1-6 haloalkoxy, -CN, -C(O)R ⁶ⁿ¹ , -C(O)OR _6n1 , -OC(O)R ⁶ⁿ¹ , -C(O)N(R ⁶ⁿ¹ )(R ⁶ⁿ² ), -N(R ⁶ⁿ¹ )C(O)R ⁶ⁿ² , -OC(O)N(R ⁶ⁿ¹ )(R ⁶ⁿ² ), -N(R ⁶ⁿ¹ )C ^{(O)OR 6n2 ,} -C(＝NR ⁶ⁿ¹ )N(R ⁶ⁿ² )(R ⁶ⁿ³ ), -N(R ⁶ⁿ¹ )(R ⁶ⁿ² ), =O, –OH, -SR ⁶ⁿ¹ , -S(O)R ⁶ⁿ¹ , -S(NR ⁶ⁿ¹ )(NR ⁶ⁿ² )R ⁶ⁿ³ , -S(O)(NR ⁶ⁿ¹ )(R ⁶ⁿ² ), -S(O) ₂ R ⁶ⁿ¹ , -S(O) ₂ N(R ⁶ⁿ¹ )(R ⁶ⁿ² ) or -N(R ⁶ⁿ¹ )S(O) ₂ (R ⁶ⁿ² );\

Each R ⁶ⁿ¹ , R ⁶ⁿ² , and R ⁶ⁿ³ is independently hydrogen, C _1-6 alkyl, C _1-6 hydroxyalkyl, C _1-6 aminoalkyl, C _2-6 alkoxyalkyl, C _1-6 haloalkyl, C _3-10 cycloalkyl, C _1-6 alkyl-C _{3-10 cycloalkyl, C 6-10 aryl} , C _1-6 alkyl-C _6-10 aryl, heterocycloalkyl, C _1-6 alkyl-(heterocycloalkyl), heteroaryl, or C _1-6 alkyl-(heteroaryl);

Each R ^6h is independently a _C1-6 alkyl, _C2-6 alkenyl, _C2-6 alkynyl, _C1-6 hydroxyalkyl, _C1-6 aminoalkyl, C1-6 alkoxy, _C2-6 alkoxyalkyl, halogen, _C1-6 haloalkyl, _C1-6 haloalkoxy, -CN, -C(O)R ^6h1 , -C(O)OR _6h1 , -OC(O)R ^6h1 , -C(O)N(R ^6h1 )(R ^6h2 ), -N(R ^6h1 )C(O)R ^{6h2, -OC(O)N(R 6h1 )} (R ^6h2 ), -N(R ^6h1 )C(O)OR ^6h2 , -C(＝NR ^6h1 )N(R ^6h2 )(R ^6h3 ), -N(R ^{6h1 )} (R ^6h2 ), =O, –OH, -SR ^6h1 , -S(O)R ^6h1 , -S(NR ^6h1 )(NR ^6h2 )R ^6h3 , -S(O)(NR ^6h1 )(R ^6h2 ), -S(O) _2R ^6h1 , -S(O) _2N (R ^6h1 )(R ^6h2 ), -N(R ^6h1 )S(O) ₂ (R ^6h2 ), C _3-10 cycloalkyl, C _1-6 alkyl-C _3-10 cycloalkyl, heterocycloalkyl or C _1-6 alkyl-(heterocycloalkyl);

Each R ^6h1 , R ^6h2 , and R ^6h3 is independently hydrogen, C _1-6 alkyl, C _1-6 hydroxyalkyl, C _1-6 aminoalkyl, C _2-6 alkoxyalkyl, C _1-6 haloalkyl, C _3-10 cycloalkyl, C _1-6 alkyl-C _3-10 cycloalkyl, C _6-10 aryl, C _1-6 alkyl-C _6-10 aryl, heterocycloalkyl, C _1-6 alkyl-(heterocycloalkyl), heteroaryl, or C _1-6 alkyl-(heteroaryl);

Each R ^6m is independently a halogen, a _C1-6 haloalkyl group, a _C1-6 haloalkoxy group, -CN, -C(O)R ^6m1 , -C(O)OR ^6m1 , -OC(O)R ^6m1 , -C(O)N(R ^6m1 )(R ^6m2 ), -N(R ^6m3 )C(O)R ^6m2 , -OC(O)N(R ^6m1 )(R ^6m2 ), -N(R ^6m1 )C(O)OR ^6m2 , -C(＝NR ^6m3 )N(R ^6m1 )(R ^6m2 ), -N(R ^6m1 )(R ^6m2 ), =O, –OH, -SR ^6m1 , -S(O)R ^6m1 , -S(NR ^6m1 )(NR ^6m2 )R ^6m3 , -S(O)(NR ^6m1 )(R ^6m2 ), -S(O) ₂ R ^6m1 , -S(O) ₂ N(R ^6m1 )(R ^6m2 ) or -N(R ^6m3 )S(O) ₂ (R ^6m2 );

Each R ^6m1 , R ^6m2 and R ^6m3 is independently hydrogen, C _1-6 alkyl, C _1-6 hydroxyalkyl, C _1-6 aminoalkyl, C _2-6 alkoxyalkyl, C _1-6 haloalkyl, C _3-10 cycloalkyl, C _1-6 alkyl-C _3-10 cycloalkyl, C _6-10 aryl, C _1-6 alkyl-C _6-10 aryl, heterocycloalkyl, C _1-6 alkyl-(heterocycloalkyl), heteroaryl or C _1-6 alkyl-(heteroaryl);

R ^6f is –OSi(R ^6f1 )(R ^6f2 )(R ^6f3 );

^R6f1 , ^R6f2 and ^R6f3 are each independently _C1-6 alkyl groups;

Each R ^6j is independently a C _2-6 alkoxyalkyl, halogen, C _1-6 haloalkyl, C _1-6 haloalkoxy, -CN, -C(O)R ^6j1 , -C(O)OR ^6j1 , -OC(O)R ^6j1 , -C(O)N(R ^6j1 )(R ^6j2 ), -N(R ^6j3 )C(O)R ^6j2 , -OC(O)N(R ^6j1 )(R ^6j2 ), -N(R ^6j1 )C(O)OR ^6j2 , -C(＝NR ^6j3 )N(R ^6j1 )(R ^6j2 ), -N(R ^6j1 )(R ^6j2 ), =O, -OR ^6j1 , -SR ^6j1 , -S(O)R ^6j1 , -S(NR ^6j1 ) -S(NR ^6j1 )(NR ^6j2 )R ^6j3 , ^{-S(O)(NR 6j1)(R 6j2 ) ,} -S(O) _2R ^6j1 , -S(O) _2N (R 6j1)(R ^6j2 ), -N(R ^6j1 )S(O) ₂ (R ^6j2 ), ^{-Si(R 6j1 )} (R ^6j2 )(R ^6j3 ), C _3-10 cycloalkyl, C _6-12 aryl, heterocycloalkyl or heteroaryl, wherein the cycloalkyl, aryl, heterocycloalkyl or heteroaryl is optionally substituted by 1 to 3 R ^6p ;

Each R ^6j1 , R ^6j2 , and R ^6j3 is independently hydrogen, C _1-6 alkyl, C _1-6 hydroxyalkyl, C _1-6 aminoalkyl, C _2-6 alkoxyalkyl, C _1-6 haloalkyl, C _3-10 cycloalkyl, C _1-6 alkyl-C _{3-10 cycloalkyl, C 6-10 aryl} , C _1-6 alkyl-C _6-10 aryl, heterocycloalkyl, C _1-6 alkyl-(heterocycloalkyl), heteroaryl, or C _1-6 alkyl-(heteroaryl);

Each R ^6p is independently a _C1-6 alkyl, _C1-6 hydroxyalkyl, _C1-6 aminoalkyl, _C1-6 alkoxy, C2-6 alkoxyalkyl, halogen, _C1-6 haloalkyl, _C1-6 haloalkoxy, -CN, -C(O)R ^6p1 , -C(O)OR ^6p1 , -OC(O)R ^{6p1, -C(O)N(R 6p1} ₎ (R 6p2), -N(R ^6p1 )C(O)R ^6p2 , -OC(O)N(R ^6p1 )(R ^6p2 ), -N(R ^6p1 )C(O)OR ^6p2 , -C(＝NR ^6p3 )N(R ^6p1 )(R ^{6p2 )} , -N(R ^6p1 )(R ^6p2 ), =O, -OH ^, -SR ^6p1 , -S(O)R ^6p1 , -S(NR ^6p1 )(NR ^6p2 )R ^6p3 , -S(O)(NR ^6p1 )(R ^6p2 ) , -S(O) ₂ R ^6p1 , -S(O) ₂ N(R ^6p1 )(R ^6p2 ) or -N(R ^6p1 )S(O) ₂ (R ^6p2 );

Each R ^6p1 , R ^6p2 , and R ^6p3 is independently hydrogen, _C1-6 alkyl, _C1-6 hydroxyalkyl, _C1-6 aminoalkyl, _C2-6 alkoxyalkyl, _C1-6 haloalkyl, C3-10 cycloalkyl, _C1-6 alkyl- _{C3-10 cycloalkyl, C6-10 aryl} , _C1-6 alkyl- _C6-10 aryl, _{heterocycloalkyl} , _C1-6 alkyl-(heterocycloalkyl), heteroaryl, or _C1-6 alkyl-(heteroaryl);

Alternatively, ^R5 and one ^R6a together with the atoms to which they are attached form a heterocyclic alkyl group, optionally substituted by one to three ^R6g ;

Each R ^6g is independently a _C1-6 alkyl, _C2-6 alkenyl, _C2-6 alkynyl, _C1-6 hydroxyalkyl, _C1-6 aminoalkyl, _C2-6 alkoxyalkyl, halogen, _C1-6 haloalkyl, _C1-6 haloalkoxy, or –CN;

R ⁷ is hydrogen, _C1-6 alkyl, _C1-6 hydroxyalkyl, C1-6 aminoalkyl, _C1-6 alkoxy, _C2-6 alkoxyalkyl, _C1-6 alkylthio, halogen, _C1-6 haloalkyl, –CN, –OH, _-NH2 , _C3-10 cycloalkyl, _C1-6 alkyl- _{C3-10 cycloalkyl} , heterocycloalkyl, or _C1-6 alkyl-(heterocycloalkyl);

Each heterocyclic alkyl group is a 3- to 20-membered ring having 1 to 4 heteroatoms, each independently of N, O, or S; and

Each heteroaryl group is a 5- to 18-membered ring having 1 to 4 heteroatoms, each of which is independently N, O, or S;

The prerequisite is that ^R5 and ^R6 are not both _C1-4 alkyl; and when ^R5 is hydrogen, ^R6 is not isopropyl or a phenyl substituted with 2-Me.

In another embodiment, this disclosure provides a pharmaceutical composition comprising a pharmaceutically effective amount of a compound of the disclosure or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient.

In another embodiment, this disclosure provides a method for inhibiting DGKα in a subject of need, the method comprising administering to the subject a therapeutically effective amount of a compound of this disclosure or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of this disclosure.

In another embodiment, this disclosure provides a method for inhibiting DGKα in a subject of need, the method comprising administering to the subject a therapeutically effective amount of a compound of formula (I):

Or its pharmaceutically acceptable salt, wherein

^R1 is hydrogen, _C1-6 alkyl, _C2-6 alkenyl, _C2-6 alkynyl, _C1-6 alkoxy, halogen, _C1-6 haloalkyl, _C1-6 haloalkoxy, or –CN;

^R2 represents hydrogen, _C1-6 alkyl, _C2-6 alkenyl, _C2-6 alkynyl, _C1-6 hydroxyalkyl, _C1-6 aminoalkyl, C1-6 alkoxy, _C2-6 alkoxyalkyl, halogen, _C1-6 haloalkyl, _C1-6 haloalkoxy, -CN, -NO, -NO2, -C(O) _R2a , -C(O ₎ ^OR2a , -OC(O) ^R2a , -C(O)N(R2a)( ^R2b ), -N( ^R2a )C(O) ^R2b , -OC(O)N( ^R2a )( ^R2b ), ^{-N(R2a )} C(O) ^OR2b , ^-C (＝ ^NR2a )N( ^R2b )( ^R2c ), -N( ^R2a )( ^R2b ), -N(R ^2a )N(R ^2b )(R ^2c ), -N(R ^2a )N＝C(R ^2b )(OR ^2c ), -OR ^2a , -SR ^2a , -S(O)R ^2a , -S(O)(NR ^2a )(R ^2b ), -S(NR ^2a )(NR ^2b )(R ^2c ), -S(O) ₂ R ^2a , -S(O) ₂ N(R ^2a )(R ^2b ), -N(R ^2a )S(O) ₂ (R ^2b ), -P(R ^2a )(R ^2b ), -P(O)(R ^2a )(R ^2b ), -P(O)(OR ^2a )(R ^2b ), -P(O)(OR ^2a )(OR ^2b ), C _3-10 cycloalkyl, C _1-6 alkyl-C _3-10 cycloalkyl, C _6-12 aryl, C _1-6 alkyl-C _6-12 aryl, heterocycloalkyl, C _1-6 alkyl-(heterocycloalkyl), heteroaryl or C _1-6 alkyl-(heteroaryl), wherein each alkyl, alkenyl or alkynyl group is independently and optionally substituted with 1 to 3 R ^2d groups, each cycloalkyl group is optionally substituted with 1 to 3 R ^2e groups, each aryl group is optionally substituted with 1 to 3 R ^2f groups, each heterocycloalkyl group is optionally substituted with 1 to 3 R ^2g groups, and each heteroaryl group is optionally substituted with 1 to 3 R ^2h groups;

Each R ^2a , R ^2b and R ^2c is independently hydrogen, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 hydroxyalkyl, C _1-6 aminoalkyl, C _2-6 alkoxyalkyl, C _1-6 haloalkyl, C _3-10 cycloalkyl, C _1-6 alkyl-C _3-10 cycloalkyl, C _6-12 aryl, C _1-6 alkyl-C _6-12 aryl, heterocycloalkyl, C _1-6 alkyl-(heterocycloalkyl), heteroaryl or C _1-6 alkyl-(heteroaryl), wherein the aryl or heteroaryl is optionally substituted by one to three R ^2j ;

Alternatively, ^R2a , ^R2b and ^R2c, when attached to the same atom, can combine with the atom to which they are attached to to form a heterocyclic alkyl group;

Each R ^2d is independently –CN, -C(O)R ^2d1 , -C(O)OR ^2d1 , -OC(O)R ^2d1 , -C(O)N(R ^2d1 )(R ^2d2 ), -N(R ^2d1 )C(O)R ^2d2 , -OC(O)N(R ^2d1 )(R ^2d2 ), -N(R ^2d1 )C(O)OR ^2d2 , -N(R ^2d1 )(R ^2d2 ), =O, -OR ^2d1 , -SR ^2d1 , -S(O)R ^2d1 , -S(O)(NR ^2d1 )(R ^2d2 ), -S(O) ₂ R ^2d1 , -S(O)N(R ^2d1 )(R ^2d2 ), -N(R ^2d1) S(O) ₂ R ^2d2 , C _3-10 cycloalkyl, C _1-6 alkyl-C _3-10 cycloalkyl, C _6-12 aryl, C _1-6 alkyl-C _6-12 aryl, heterocycloalkyl, C _1-6 alkyl-(heterocycloalkyl), heteroaryl or C _1-6 alkyl-(heteroaryl);

Each R ^2d1 and R ^2d2 is independently hydrogen, a C _1-6 alkyl, a C _1-6 hydroxyalkyl, a C _1-6 aminoalkyl, a C _2-6 alkoxyalkyl, or a C _1-6 haloalkyl;

Each of ^R2e , ^R2f , ^R2g and ^R2h is independently hydrogen, _C1-6 alkyl, _C1-6 hydroxyalkyl, _C1-6 aminoalkyl, _C1-6 alkoxy, _C2-6 alkoxyalkyl, halogen, _C1-6 haloalkyl, _C1-6 haloalkoxy, -CN or -OH;

Each R ^2j is independently a _C1-6 alkyl, _C1-6 hydroxyalkyl, _C1-6 aminoalkyl, _C1-6 alkoxy, _C2-6 alkoxyalkyl, halogen, _C1-6 haloalkyl, or _C1-6 haloalkoxy;

^R3 represents hydrogen, _C1-6 alkyl, _C2-6 alkenyl, _C2-6 alkynyl, _C1-6 hydroxyalkyl, _C1-6 aminoalkyl, C1-6 alkoxy, _C2-6 alkoxyalkyl, halogen, _C1-6 haloalkyl, _C1-6 haloalkoxy, -CN, -NO, -NO2, -C(O) _R3a , -C(O ₎ ^OR3a , -OC(O) ^R3a , -C(O)N(R3a)( ^R3b ), -N( ^R3a )C(O) ^R3b , -OC(O)N( ^R3a )( ^R3b ), ^{-N(R3a )} C(O) ^OR3b , ^-C (＝ ^NR3a )N( ^R3b )( ^R3c ), -N( ^R3a )( ^R3b ), -N(R ^3a )N(R ^3b )(R ^3c ), -N(R ^3a )N＝C(R ^3b )(OR ^3c ), -OR ^3a , -SR ^3a , -S(O)R ^3a , -S(O)(NR ^3a )(R ^3b ), -S(NR ^3a )(NR ^3b )(R ^3c ), -S(O) ₂ R ^3a , -S(O) ₂ N(R ^3a )(R ^3b ), -N(R ^3a )S(O) ₂ (R ^3b ), -P(R ^3a )(R ^3b ), -P(O)(R ^3a )(R ^3b ), -P(O)(OR ^3a )(R ^3b ), -P(O)(OR ^3a )(OR ^3b ), C _3-10 cycloalkyl, C _1-6 alkyl-C _3-10 cycloalkyl, C _6-12 aryl, C _1-6 alkyl-C _6-12 aryl, heterocycloalkyl, C _1-6 alkyl-(heterocycloalkyl), heteroaryl or C _1-6 alkyl-(heteroaryl), wherein each alkenyl or ynyl group is independently and optionally substituted with 1 to 3 R ^3d groups, each cycloalkyl group is optionally substituted with 1 to 3 R ^3e groups, each aryl group is optionally substituted with 1 to 3 R ^3f groups, each heterocycloalkyl group is optionally substituted with 1 to 3 R ^3g groups, and each heteroaryl group is optionally substituted with 1 to 3 R ^3h groups;

Each R ^3a , R ^3b and R ^3c is independently hydrogen, C _1-6 alkyl, C _1-6 hydroxyalkyl, C _2-6 alkoxyalkyl, C _1-6 haloalkyl, C _3-10 cycloalkyl, C _1-6 alkyl-C _3-10 cycloalkyl, C _6-12 aryl, C _1-6 alkyl-C _6-12 aryl, heterocycloalkyl or heteroaryl;

Alternatively, ^R3a , ^R3b and ^R3c , when attached to the same atom, can combine with the atom to which they are attached to to form a heterocyclic alkyl group;

Each R ^3d is independently -N(R ^3d1 )(R ^3d2 ), -OR ^3d1 , C _3-10 cycloalkyl, C _1-6 alkyl-C _3-10 cycloalkyl, C _6-12 aryl, C _1-6 alkyl-C _6-12 aryl, heterocycloalkyl, or heteroaryl;

Each R ^3d1 and R ^3d2 is independently hydrogen, C _1-6 alkyl, or –C(O)O-(C _1-6 alkyl);

Each of ^R3e , ^R3f , ^R3g and ^R3h is independently hydrogen, _C1-6 alkyl, _C1-6 alkoxy, halogen, _C1-6 haloalkyl or _C1-6 haloalkoxy;

^R4 is hydrogen, _C1-6 alkyl, _C2-6 alkenyl, _C2-6 alkynyl, _C1-6 alkoxy, halogen, _C1-6 haloalkyl, _C1-6 haloalkoxy, or –CN;

R ⁵ is hydrogen, _C1-6 alkyl, _C2-6 alkenyl, _C2-6 alkynyl, _C1-6 hydroxyalkyl, _C2-6 alkoxyalkyl, _C1-6 haloalkyl, _C3-10 cycloalkyl, _C1-6 alkyl- _C3-10 cycloalkyl, _C6-12 aryl, _C1-6 alkyl- _C6-12 aryl, heterocycloalkyl, _C1-6 alkyl-(heterocycloalkyl), heteroaryl, or _C1-6 alkyl-(heteroaryl), wherein the alkyl group is optionally substituted with R ^5a ;

R ^5a is –OSi(R ^5a1 )(R ^5a2 )(R ^5a3 );

^R5a1 , ^R5a2 , and ^R5a3 are each independently a _C1-6 alkyl group; and

^R6 is a _C1-6 alkyl, _C2-6 alkenyl, _C2-6 alkynyl, _C1-6 haloalkyl, _C6-12 aryl or heteroaryl, wherein each of the aryl or heteroaryl groups is optionally substituted by one to three ^R6a .

Each R ^6a is independently a _C1-6 alkyl, _C2-6 alkenyl, _C2-6 alkynyl, _C1-6 hydroxyalkyl, _C1-6 aminoalkyl, C1-6 alkoxy, _C2-6 alkoxyalkyl, halogen, _C1-6 haloalkyl, _C1-6 haloalkoxy, –CN, -NO ₂ , -C(O)R 6b, _-C (O)OR ^6b , -OC(O)R ^6b , -C(O)N(R ^6b )(R ^6c ), -N(R ^6b )C(O)R ^6c , -C(＝NR ^6b )N(R ^6c )(R ^6d ), -N(R ^6b )(R ^6c ), -OR ^6b , -SR ^6b , -S(O ⁾ R ^6b , -S(O) _2R ^6b -S(NR ^6b )(NR ^6c )R ^6d , -S(O)(NR ^6b )(R ^6c ), -S(O) ₂ N(R ^6b )(R ^6c ), -N(R ^6b )S(O) ₂ (R ^6c ), -P(R ^6b )(R ^6c ), -P(O)(R ^6b )(R ^6c ), -P(O)(OR ^6b )(R ^6c ), -P(O)(OR ^6b )(OR ^6c ), C _3-10 cycloalkyl, C _1-6 alkyl-C _3-10 cycloalkyl, C _6-12 aryl, C _1-6 alkyl-C _6-12 aryl, heterocycloalkyl, C _1-6 alkyl-(heterocycloalkyl), heteroaryl or C _1-6 alkyl-(heteroaryl), wherein the cycloalkyl, aryl, heterocycloalkyl or heteroaryl group is optionally substituted by 1 to 3 R ^6e , the alkyl group is optionally substituted by R ^6f , and the alkynyl group is optionally substituted by 1 to 4 R ^6j ;

Each R ^6b , R ^6c , and R ^6d is independently hydrogen, C _1-6 alkyl, C _1-6 hydroxyalkyl, C _1-6 aminoalkyl, C _2-6 alkoxyalkyl, C _1-6 haloalkyl, C _3-10 cycloalkyl, C _1-6 alkyl-C _3-10 cycloalkyl, C _6-12 aryl, C _1-6 alkyl-C _6-12 aryl, heterocycloalkyl, C _1-6 alkyl-(heterocycloalkyl), heteroaryl, or C _1-6 alkyl-(heteroaryl), wherein the cycloalkyl, aryl, heterocycloalkyl, or heteroaryl is optionally substituted by one to three R ^6k ;

Each R ^6k is independently a _C1-6 alkyl, _C1-6 hydroxyalkyl, _C1-6 aminoalkyl, _C1-6 alkoxy, _C2-6 alkoxyalkyl, _C1-6 haloalkyl, _C1-6 haloalkoxy, _C3-10 cycloalkyl, _C1-6 alkyl- _C3-10 cycloalkyl, heterocycloalkyl, or _C1-6 alkyl-(heterocycloalkyl);

Each R ^6e is independently a _C1-6 alkyl, _C2-6 alkenyl, _C2-6 alkynyl, _C1-6 hydroxyalkyl, _C1-6 aminoalkyl, C1-6 alkoxy, _C2-6 alkoxyalkyl, halogen, _C1-6 haloalkyl, _C1-6 haloalkoxy, –CN, -NO ₂ , -C(O)R ^6e1 , _-C (O)OR ^6e1 , -OC(O)R ^6e1 , -C(O)N(R 6e1)(R ^6e2 ), -N(R ^6e1 )C(O)R ^6e2 , -OC(O)N(R ^6e1 )(R ^6e2 ), -N(R ^6e1 )C(O)OR ^6e2 , -C(＝NR ^6e1 )N(R ^6e2 )( ^{R 6e3 )} , -N(R ^6e1 )(R ^6e2 ), =O, -OR ^6e1 , -SR ^6e1 , -S(O)R ^6e1 , -S(NR ^6e1 )(NR ^6e2 ), -S(O)(NR ^6e1 )(R ^6e2 ) , -S(O) ₂ R ^6e1 , -S(O) ₂ N(R ^6e1 )(R ^6e2 ), -SF ₅ , -N(R ^6e1 )S(O) ₂ (R ^6e2 ), -P(R ^6e1 )(R ^6e2 ), -P(O)(R ^6e1 )(R ^6e2 ), -P(O)(OR ^6e1 )(R ^6e2 ), -P(O)(OR ^6e1 )(OR ^6e2 ), -Si(R ^6e1 )(R ^6e2 )(R ^6e3 )、C _3-10 cycloalkyl, _C1-6 alkyl- _C3-10 cycloalkyl, _C6-12 aryl, _C1-6 alkyl- _C6-12 aryl, heterocycloalkyl, _C1-6 alkyl-heterocycloalkyl, heteroaryl or _C1-6 alkyl-heteroaryl, wherein each of the cycloalkyl, aryl, heterocycloalkyl or heteroaryl is optionally substituted with 1 to 3 ^R6h , and the alkyl group is optionally substituted with 1 to 3 ^R6m ;

Each R ^6e1 , R ^6e2 , and R ^6e3 is independently hydrogen, C _1-6 alkyl, C _1-6 hydroxyalkyl, C _1-6 aminoalkyl, C _1-6 alkoxyalkyl, C _1-6 haloalkyl, C _3-10 cycloalkyl, C _1-6 alkyl-C _3-10 cycloalkyl, C _6-10 aryl, C _1-6 alkyl-C _6-10 aryl, heterocycloalkyl, C _1-6 alkyl-(heterocycloalkyl), heteroaryl, or C _1-6 alkyl-(heteroaryl), wherein the cycloalkyl, aryl, heterocycloalkyl, or heteroaryl is optionally substituted by one to three R ⁶ⁿ ;

Each R ⁶ⁿ is a _C1-6 alkyl, _C2-6 alkenyl, _C2-6 alkynyl, _C1-6 hydroxyalkyl, _C1-6 aminoalkyl, _C1-6 alkoxy, C2-6 alkoxyalkyl, halogen, _C1-6 haloalkyl, _C1-6 haloalkoxy, -CN, -C(O)R ⁶ⁿ¹ , -C(O)OR _6n1 , -OC(O)R ⁶ⁿ¹ , -C(O)N(R ⁶ⁿ¹ )(R ⁶ⁿ² ), -N(R ⁶ⁿ¹ )C(O)R ⁶ⁿ² , -OC(O)N(R ⁶ⁿ¹ )(R ⁶ⁿ² ), -N(R ⁶ⁿ¹ )C ^{(O)OR 6n2 ,} -C(＝NR ⁶ⁿ¹ )N(R ⁶ⁿ² )(R ⁶ⁿ³ ), -N(R ⁶ⁿ¹ )(R ⁶ⁿ² ), =O, –OH, -SR ⁶ⁿ¹ , -S(O)R ⁶ⁿ¹ , -S(NR ⁶ⁿ¹ )(NR ⁶ⁿ² )R ⁶ⁿ³ , -S(O)(NR ⁶ⁿ¹ )(R ⁶ⁿ² ), -S(O) ₂ R ⁶ⁿ¹ , -S(O) ₂ N(R ⁶ⁿ¹ )(R ⁶ⁿ² ) or -N(R ⁶ⁿ¹ )S(O) ₂ (R ⁶ⁿ² );

Each R ⁶ⁿ¹ , R ⁶ⁿ² , and R ⁶ⁿ³ is independently hydrogen, C _1-6 alkyl, C _1-6 hydroxyalkyl, C _1-6 aminoalkyl, C _2-6 alkoxyalkyl, C _1-6 haloalkyl, C _3-10 cycloalkyl, C _1-6 alkyl-C _3-10 cycloalkyl, C _6-10 aryl, C _1-6 alkyl-C _6-10 aryl, heterocycloalkyl, C _1-6 alkyl-(heterocycloalkyl), heteroaryl, or C _1-6 alkyl-(heteroaryl);

Each R ^6h is independently a _C1-6 alkyl, _C2-6 alkenyl, _C2-6 alkynyl, _C1-6 hydroxyalkyl, _C1-6 aminoalkyl, C1-6 alkoxy, _C2-6 alkoxyalkyl, halogen, _C1-6 haloalkyl, _C1-6 haloalkoxy, -CN, -C(O)R ^6h1 , -C(O)OR _6h1 , -OC(O)R ^6h1 , -C(O)N(R ^6h1 )(R ^6h2 ), -N(R ^6h1 )C(O)R ^{6h2, -OC(O)N(R 6h1 )} (R ^6h2 ), -N(R ^6h1 )C(O)OR ^6h2 , -C(＝NR ^6h1 )N(R ^6h2 )(R ^6h3 ), -N(R ^{6h1 )} (R ^6h2 ), =O, –OH, -SR ^6h1 , -S(O)R ^6h1 , -S(NR ^6h1 )(NR ^6h2 )R ^6h3 , -S(O)(NR ^6h1 )(R ^6h2 ), -S(O) _2R ^6h1 , -S(O) _2N (R ^6h1 )(R ^6h2 ), -N(R ^6h1 )S(O) ₂ (R ^6h2 ), C _3-10 cycloalkyl, C _1-6 alkyl-C _3-10 cycloalkyl, heterocycloalkyl or C _1-6 alkyl-(heterocycloalkyl);

Each R ^6h1 , R ^6h2 , and R ^6h3 is independently hydrogen, C _1-6 alkyl, C _1-6 hydroxyalkyl, C _1-6 aminoalkyl, C _2-6 alkoxyalkyl, C _1-6 haloalkyl, C _3-10 cycloalkyl, C _1-6 alkyl-C _3-10 cycloalkyl, C _6-10 aryl, C _1-6 alkyl-C _6-10 aryl, heterocycloalkyl, C _1-6 alkyl-(heterocycloalkyl), heteroaryl, or C _1-6 alkyl-(heteroaryl);

Each R ^6m is independently a halogen, a _C1-6 haloalkyl group, a _C1-6 haloalkoxy group, -CN, -C(O)R ^6m1 , -C(O)OR ^6m1 , -OC(O)R ^6m1 , -C(O)N(R ^6m1 )(R ^6m2 ), -N(R ^6m3 )C(O)R ^6m2 , -OC(O)N(R ^6m1 )(R ^6m2 ), -N(R ^6m1 )C(O)OR ^6m2 , -C(＝NR ^6m3 )N(R ^6m1 )(R ^6m2 ), -N(R ^6m1 )(R ^6m2 ), =O, –OH, -SR ^6m1 , -S(O)R ^6m1 , -S(NR ^6m1 )(NR ^6m2 )R ^6m3 , -S(O)(NR ^6m1 )(R ^6m2 ), -S(O) ₂ R ^6m1 , -S(O) ₂ N(R ^6m1 )(R ^6m2 ) or -N(R ^6m3 )S(O) ₂ (R ^6m2 );

Each R ^6m1 , R ^6m2 and R ^6m3 is independently hydrogen, C _1-6 alkyl, C _1-6 hydroxyalkyl, C _1-6 aminoalkyl, C _2-6 alkoxyalkyl, C _1-6 haloalkyl, C _3-10 cycloalkyl, C _1-6 alkyl-C _3-10 cycloalkyl, C _6-10 aryl, C _1-6 alkyl-C _6-10 aryl, heterocycloalkyl, C _1-6 alkyl-(heterocycloalkyl), heteroaryl or C _1-6 alkyl-(heteroaryl);

R ^6f is –OSi(R ^6f1 )(R ^6f2 )(R ^6f3 );

^R6f1 , ^R6f2 and ^R6f3 are each independently _C1-6 alkyl groups;

Each R ^6j is independently a C _2-6 alkoxyalkyl, halogen, C _1-6 haloalkyl, C _1-6 haloalkoxy, -CN, -C(O)R ^6j1 , -C(O)OR ^6j1 , -OC(O)R ^6j1 , -C(O)N(R ^6j1 )(R ^6j2 ), -N(R ^6j3 )C(O)R ^6j2 , -OC(O)N(R ^6j1 )(R ^6j2 ), -N(R ^6j1 )C(O)OR ^6j2 , -C(＝NR ^6j3 )N(R ^6j1 )(R ^6j2 ), -N(R ^6j1 )(R ^6j2 ), =O, -OR ^6j1 , -SR ^6j1 , -S(O)R ^6j1 , -S(NR ^6j1 ) -S(NR ^6j1 )(NR ^6j2 )R ^6j3 , ^{-S(O)(NR 6j1)(R 6j2 ) ,} -S(O) _2R ^6j1 , -S(O) _2N (R 6j1)(R ^6j2 ), -N(R ^6j1 )S(O) ₂ (R ^6j2 ), ^{-Si(R 6j1 )} (R ^6j2 )(R ^6j3 ), C _3-10 cycloalkyl, C _6-12 aryl, heterocycloalkyl or heteroaryl, wherein the cycloalkyl, aryl, heterocycloalkyl or heteroaryl is optionally substituted by 1 to 3 R ^6p ;

Each R ^6j1 , R ^6j2 , and R ^6j3 is independently hydrogen, _C1-6 alkyl, _C1-6 hydroxyalkyl, _C1-6 aminoalkyl, _C2-6 alkoxyalkyl, _C1-6 haloalkyl, C3-10 cycloalkyl, _C1-6 alkyl- _{C3-10 cycloalkyl, C6-10 aryl} , _C1-6 alkyl- _C6-10 aryl, _{heterocycloalkyl} , _C1-6 alkyl-(heterocycloalkyl), heteroaryl, or _C1-6 alkyl-(heteroaryl);

Each R ^6p is independently a _C1-6 alkyl, _C1-6 hydroxyalkyl, _C1-6 aminoalkyl, _C1-6 alkoxy, C2-6 alkoxyalkyl, halogen, _C1-6 haloalkyl, _C1-6 haloalkoxy, -CN, -C(O)R ^6p1 , -C(O)OR ^6p1 , -OC(O)R ^{6p1, -C(O)N(R 6p1} ₎ (R 6p2), -N(R ^6p1 )C(O)R ^6p2 , -OC(O)N(R ^6p1 )(R ^6p2 ), -N(R ^6p1 )C(O)OR ^6p2 , -C(＝NR ^6p3 )N(R ^6p1 )(R ^{6p2 )} , -N(R ^6p1 )(R ^6p2 ), =O, -OH ^, -SR ^6p1 , -S(O)R ^6p1 , -S(NR ^6p1 )(NR ^6p2 )R ^6p3 , -S(O)(NR ^6p1 )(R ^6p2 ) , -S(O) ₂ R ^6p1 , -S(O) ₂ N(R ^6p1 )(R ^6p2 ) or -N(R ^6p1 )S(O) ₂ (R ^6p2 );

Each R ^6p1 , R ^6p2 , and R ^6p3 is independently hydrogen, _C1-6 alkyl, _C1-6 hydroxyalkyl, _C1-6 aminoalkyl, _C2-6 alkoxyalkyl, _C1-6 haloalkyl, C3-10 cycloalkyl, _C1-6 alkyl- _{C3-10 cycloalkyl, C6-10 aryl} , _C1-6 alkyl- _C6-10 aryl, _{heterocycloalkyl} , _C1-6 alkyl-(heterocycloalkyl), heteroaryl, or _C1-6 alkyl-(heteroaryl);

Alternatively, ^R5 and one ^R6a together with the atoms to which they are attached form a heterocyclic alkyl group, optionally substituted by one to three ^R6g ;

Each R ^6g is independently a _C1-6 alkyl, _C2-6 alkenyl, _C2-6 alkynyl, _C1-6 hydroxyalkyl, _C1-6 aminoalkyl, _C2-6 alkoxyalkyl, halogen, _C1-6 haloalkyl, _C1-6 haloalkoxy, or –CN;

R ⁷ is hydrogen, _C1-6 alkyl, _C1-6 hydroxyalkyl, C1-6 aminoalkyl, _C1-6 alkoxy, _C2-6 alkoxyalkyl, _C1-6 alkylthio, halogen, _C1-6 haloalkyl, –CN, –OH, _-NH2 , _C3-10 cycloalkyl, _C1-6 alkyl- _{C3-10 cycloalkyl} , heterocycloalkyl, or _C1-6 alkyl-(heterocycloalkyl);

Each heterocyclic alkyl group is a 3- to 20-membered ring having 1 to 4 heteroatoms, each independently of N, O, or S; and

Each heteroaryl group is a 5- to 18-membered ring having 1 to 4 heteroatoms, each of which is independently N, O, or S.

In another embodiment, this disclosure provides a method of treating cancer in a subject in need, the method comprising administering to the subject a therapeutically effective amount of a compound of this disclosure or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of this disclosure.

In another embodiment, this disclosure provides a method for treating HIV or hepatitis B virus infection in a subject of need, the method comprising administering to the subject a therapeutically effective amount of a compound of this disclosure or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of this disclosure.

Detailed Implementation

I. Definition

"Alkyl" is a straight-chain or branched saturated monovalent hydrocarbon. For example, an alkyl group can have 1 to 18 carbon atoms (i.e., _C1-18 alkyl), 1 to 8 carbon atoms (i.e., _C1-8 alkyl), 1 to 6 carbon atoms (i.e., _C1-6 alkyl), or 1 to 4 carbon atoms (i.e., _C1-4 alkyl). Examples of alkyl groups include, but are not limited to _, methyl ₍ Me, _-CH3 ), ethyl (Et, _-CH2CH3 ), 1-propyl (n-Pr, _n -propyl, _-CH2CH2CH3 ), 2-propyl (i-Pr, iso-propyl, -CH( _CH3 ) ₂ ), 1-butyl (n-Bu, n-butyl, _{-CH2CH2CH2CH3} ), ₂ -methyl-1-propyl (i-Bu, iso-butyl, -CH2CH( _CH3 ) _{2 )} , ₂ -butyl (s-Bu, sec-butyl, -CH( _CH3 ) _CH2CH3 ), ₂ -methyl- ₂ -propyl (t-Bu, tert-butyl, -C( _CH3 ) ₃ ), 1-pentyl (n-pentyl, -CH2CH2CH2CH2CH3), _{2 -} pentyl (-CH( _CH3 ) _CH2CH3 ), and 2-pentyl (-CH( _CH3 ) _CH2CH3 ) _{. 2} CH ₃ ), 3-pentyl (-CH(CH ₂ CH ₃ ) ₂ ), 2-methyl-2-butyl (-C(CH ₃ ) ₂ CH ₂ CH ₃ ), 3-methyl-2-butyl (-CH(CH ₃ )CH(CH ₃ ) ₂ ), 3-methyl-1-butyl (-CH ₂ CH ₂ CH(CH ₃ ) ₂ ), 2-methyl-1-butyl (-CH ₂ CH(CH ₃ )CH ₂ CH ₃ ), 1-hexyl (-CH ₂ CH ₂ CH ₂ CH ₂ CH ₂ CH ₃ ), 2-hexyl (-CH(CH ₃ )CH ₂ CH ₂ CH ₂ CH ₃ ), 3-hexyl (-CH(CH ₂ CH ₃ )(CH ₂ CH ₂ CH ₃ ) ), 2-methyl-2-pentyl (-C(CH ₃ ) ₂ CH ₂ CH ₂ CH _{3 )} ), 3-methyl-2-pentyl (-CH( _CH3 )CH( _CH3 ) _{CH2CH3 )} , 4-methyl-2-pentyl (-CH( _CH3 ) _CH2CH ( _CH3 ) ₂ ), 3-methyl- _{3-pentyl (-C(CH3)(CH2CH3)2 ) , 2} -methyl-3-pentyl (-CH( _CH2CH3 )CH _{( CH3} ) ₂ ), 2,3-dimethyl-2-butyl (-C( _CH3 ) _2CH ( _CH3 ) ₂ ) and 3,3-dimethyl-2-butyl (-CH( _CH3 )C( _CH3 ) ₃ ). Other alkyl groups include heptyl, octyl, nonyl, decyl, undecyl, dodecyl, pentadecyl, hexadecyl, heptadecanyl and octadecyl.

"Alkylene" refers to a straight-chain or branched saturated aliphatic group, i.e., a divalent hydrocarbon group, having an indicated number of carbon atoms and being attached to at least two other groups. The two parts attached to the alkylene group can be attached to the same atom or different atoms of the alkylene group. For example, a straight-chain alkylene group can be a divalent group -( _CH₂ ) _n- , where n is 1, 2, 3, 4, 5, or 6. Representative alkylene groups include, but are not limited to, methylene, ethylene, propylene, isopropylene, butylene, isobutylene, secondary-butylene, pentylene, and hexylene. Alkylene groups can be substituted or unsubstituted.

"Alkenyl" refers to a straight-chain or branched hydrocarbon having at least two carbon atoms and at least one double bond. Alkenyl groups can include any number of carbon atoms, such as _C2 , _C2-3 , _C2-4 , _C2-5 , _C2-6 , _C2-7 , _C2-8 , _C2-9 , _C2-10 , _C3 , _C3-4 , _C3-5 , _C3-6 , C4, _C4-5 , _C4-6 , _C5 , _C5-6 , and _C6 . Alkenyl groups can have any suitable number of double bonds, including but not limited to one, two, three, four, five _, or more. Examples of alkenyl groups include, but are not limited to, vinyl, propenyl, isopropenyl, 1-butenyl, 2-butenyl, isobutenyl, butadienyl, 1-pentenyl, 2-pentenyl, isopentenyl, 1,3-pentadienyl, 1,4-pentadienyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 1,3-hexadienyl, 1,4-hexadienyl, 1,5-hexadienyl, 2,4-hexadienyl, or 1,3,5-hextrienyl. Alkenyl groups can be substituted or unsubstituted.

"Alynyl" refers to a straight-chain or branched hydrocarbon having at least two carbon atoms and at least one triple bond. Alynyl groups can include any number of carbons, such as _C2 , _C2-3 , _C2-4 , _C2-5 , _C2-6 , _C2-7 , _C2-8 , _C2-9 , _C2-10 , C3, _C3-4 , _C3-5 , _C3-6 , _C4 , _C4-5 , _C4-6 , _C5 , _{C5-6 ,} and _C6 . Examples of alkynyl groups include, but are not limited to, ethynyl, propynyl, 1-butynyl, 2-butynyl, butyrynyl, 1-pentynyl, 2-pentynyl, isopentenynyl, 1,3-pentadiynyl, 1,4-pentadiynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 1,3-hexadiynyl, 1,4-hexadiynyl, 1,5-hexadiynyl, 2,4-hexadiynyl, or 1,3,5-hextriynyl. The alkynyl group can be substituted or unsubstituted.

"Alkoxy" refers to an alkyl group having an oxygen atom attached to the alkyl group at the junction: alkyl-O-. With respect to the alkyl group, the alkoxy group can have any suitable number of carbon atoms, such as _C1-6 . Alkoxy groups include, for example, methoxy, ethoxy, propoxy, isopropoxy, butoxy, 2-butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentoxy, hexoxy, etc. Alkoxy groups can be further substituted by a variety of substituents described herein. Alkoxy groups can be substituted or unsubstituted.

"Alkoxyalkyl" refers to an alkoxy group attached to an alkyl group, which is then attached to the remainder of the compound, making the alkyl group divalent. Alkoxyalkyl groups can have any suitable number of carbons, such as 2 to 6 (C _2-6 alkoxyalkyl), 2 to 5 (C _2-5 alkoxyalkyl), 2 to 4 (C _2-4 alkoxyalkyl), or 2 to 3 (C _2-3 alkoxyalkyl). The number of carbons refers to the total number of carbons in the alkoxy group and the alkyl group. For example, C ₆ alkoxyalkyl means ethoxy (C ₂ alkoxy) attached to butyl (C ₄ alkyl) and n-propoxy (C ₃ alkoxy) attached to isopropyl (C ₃ alkyl). Alkoxy and alkyl groups are defined above, wherein the alkyl group is divalent, and may include, but are not limited to, methoxymethyl (CH ₃ OCH ₂ -), methoxyethyl (CH ₃ OCH ₂ CH ₂ -), etc.

"Aminoalkyl" refers to an amino group attached to an alkyl group, which is then attached to the remainder of the compound, making the alkyl group divalent. The amino group can be an unsubstituted amino group ( _-NH₂ ) or substituted with an alkyl group, such as a monosubstituted amino group (e.g., _-NHCH₃ ) or a disubstituted amino group (e.g., -N( _CH₃ ) _₂ ). An aminoalkyl group can have any suitable number of carbons, such as 1 to 8 (C₁ _-8 aminoalkyl), 1 to 6 (C₁ _- 6 aminoalkyl), 2 to 6 (C₂ _-6 aminoalkyl), 2 to 4 (C₂ _-4 aminoalkyl), or 2 to 3 (C₂ _-3 aminoalkyl). The number of carbons refers to the total number of carbons in the amino group and the alkyl group. For example, a _C₆ aminoalkyl group means -N( _{CH₃ ) ₂ ( C₂} amino) attached to a butyl group ( _C₄ alkyl), and _{–NHCH₂CH₂CH₃} ( _C₃ amino) attached to an isopropyl group ( _C₃ alkyl). Alkyl groups are defined above, wherein the alkyl group is divalent. Aminoalkyl groups may include, but are not limited to, aminomethyl ( _H₂NCH₂- ), methylaminomethyl ( _{CH₃NHCH₂-} ) _{, dimethylaminomethyl ((CH₃)₂NCH₂- ) , dimethylaminoethyl (} ( _{CH₃ ) ₂NCH₂CH₂-} ), _etc.

"Alkoxy-alkoxy" refers to an alkoxy group attached to a second alkoxy group that is attached to the rest of the compound. Alkoxy groups are defined above and may include, but are not limited to, methoxy- _methoxy ( _CH3OCH2O- ), methoxy- _{ethoxy ( CH3OCH2CH2O-} ), etc.

As used herein, the terms “halogen” or “halogen” refer to fluorine (-F), chlorine (-Cl), bromine (-Br), and iodine (-I).

As used herein, “haloalkyl” means an alkyl group as defined herein, wherein one or more hydrogen atoms of the alkyl group are independently substituted by a halogen substituent, which may be the same or different. For example, a _C1-4 haloalkyl group is a _C1-4 alkyl group in which one or more hydrogen atoms of the _C1-4 alkyl group have been substituted by a halogen substituent. Examples of haloalkyl groups include, but are not limited to, fluoromethyl, fluorochloromethyl, difluoromethyl, difluorochloromethyl, trifluoromethyl, 1,1,1-trifluoroethyl, and pentafluoroethyl.

"Haloalkoxy" refers to an alkoxy group in which some or all of its hydrogen atoms are replaced by halogen atoms. For alkyl groups, haloalkoxy groups can have any suitable number of carbon atoms, such as _C1-6 . Alkoxy groups can be substituted with one, two, three, or more halogens. When all hydrogen atoms are replaced by a halogen (e.g., by fluorine), the compound is per-substituted, such as perfluorinated. Haloalkoxy groups include, but are not limited to, trifluoromethoxy, 2,2,2-trifluoroethoxy, perfluoroethoxy, etc.

“Cycloalkyl” refers to all carbocyclic rings (i.e., C3-20 cycloalkyl) having a single saturated or partially unsaturated ring having 3 to 20 cyclic carbon atoms (e.g., 3 to 12 cyclic atoms, such as 3 to 10 cyclic atoms, or 3 to 8 cyclic atoms, or 3 to 6 cyclic atoms, or 3 to 5 cyclic atoms, or ₃ to 4 cyclic atoms). The term “cycloalkyl” also includes all carbocyclic systems of multiple condensed saturated and partially unsaturated rings (e.g., cyclic systems containing 2, 3, or 4 carbon rings). Thus, cycloalkyl includes polycyclic carbocyclic rings, such as bicyclic carbocyclic rings (e.g., bicyclic carbocyclic rings having 6 to 12 cyclic carbon atoms, such as bicyclic [3.1.0]hexane and bicyclic [2.1.1]hexane) and polycyclic carbocyclic rings (e.g., tricyclic and tetracyclic carbocyclic rings having up to 20 cyclic carbon atoms). When valence requirements permit, the rings of a polycyclic fused ring system can be connected to each other through fusion, spirocyclic, and bridging. Non-limiting examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, 1-cyclopent-1-enyl, 1-cyclopent-2-enyl, 1-cyclopent-3-enyl, cyclohexyl, 1-cyclohex-1-enyl, 1-cyclohex-2-enyl, and 1-cyclohex-3-enyl.

"alkyl-cycloalkyl" refers to a group having an alkyl component and a cycloalkyl component, wherein the alkyl component connects the cycloalkyl component to a junction. The alkyl component is as defined above, except that it is at least a divalent alkylene group connected to the cycloalkyl component and the junction. In some cases, the alkyl component may be absent. The alkyl component may include any number of carbons, such as _C1-6 , _C1-2 , _C1-3 , _C1-4 , _C1-5 , _C2-3 , _C2-4 , _C2-5 , _C2-6 , _C3-4 , _C3-5 , _C3-6 , _C4-5 , _C4-6 , and _C5-6 . The cycloalkyl component is as defined herein. Exemplary alkyl-cycloalkyl groups include, but are not limited to, methyl-cyclopropyl, methyl-cyclobutyl, methyl-cyclopentyl, and methyl-cyclohexyl.

As used herein, "heterocyclic group" or "heterocyclic" or "heterocyclic alkyl" refers to a single saturated or partially unsaturated non-aromatic ring or a system of rings having at least one heteroatom (i.e., at least one cyclic heteroatom selected from oxygen, nitrogen, and sulfur), wherein the system of rings comprises at least one non-aromatic ring containing at least one heteroatom. The system of rings may also include other aromatic and non-aromatic rings. Unless otherwise stated, a heterocyclic group has 3 to 20 cyclic atoms, for example 3 to 12 cyclic atoms, such as 3 to 10 cyclic atoms, or 3 to 8 cyclic atoms, or 3 to 6 cyclic atoms, or 3 to 5 cyclic atoms, or 4 to 6 cyclic atoms, or 4 to 5 cyclic atoms. Therefore, the term includes a single saturated or partially unsaturated ring (e.g., a 3-, 4-, 5-, 6-, or 7-membered ring) having one to six cyclic carbon atoms and one to three cyclic heteroatoms independently selected from the group consisting of oxygen, nitrogen, and sulfur. The heteroatoms may optionally be oxidized to form –N(-OH)-, =N(-O-)-, -S(=O)-, or –S(=O) _2- . When valence requirements permit, the rings of a polyfused ring system (e.g., a bicyclic heterocyclic group) can be connected to each other through fusion, spirocyclic, and bridging. Heterocyclic compounds include, but are not limited to, aziridine, imidazoline, morpholine, ethylene oxide (epoxide), oxacyclobutane, thietane, piperazine, piperidine, pyrazolidine, piperidine, pyrrolidine, pyrrolidone, tetrahydrofuran, tetrahydrothiophene, dihydropyridine, tetrahydropyridine, quinone, 2-oxa-6-azaspiro[3.3]hept-6-yl, and 6-oxa-1-azaspiro[3.3]hept-1 -yl, 2-thia-6-azaspiro[3.3]hept-6-yl, 2,6-diazaspiro[3.3]hept-2-yl, 2-azabicyclo[3.1.0]hex-2-yl, 3-azabicyclo[3.1.0]hexyl, 2-azabicyclo[2.1.1]hexyl, 2-azabicyclo[2.2.1]hept-2-yl, 4-azaspiro[2.4]heptyl, 5-azaspiro[2.4]heptyl, etc.

Heterocyclic alkyl rings also include 9- to 15-membered fused-ring heterocyclic alkyl groups having 2, 3, or more rings, wherein at least one ring is an aryl ring and at least one ring is a non-aromatic ring containing at least one heteroatom. Representative fused bicyclic heterocyclic alkyl groups include, but are not limited to, indoline (dihydroindole), isoindoline (dihydroisoindole), indazoline (dihydroindazole), benzo[d]imidazolium, dihydroquinoline, dihydroisoquinoline, dihydrobenzofuran, dihydroisobenzofuran, benzo[d][1,3]dioxacyclopentene, dihydrobenzo[b]dioxin, dihydrobenzo[d]oxazole, dihydrobenzo[b]thiophene, dihydroisobenzo[c]thiophene, dihydrobenzo[d]thiazole, dihydrobenzo[c]isothiazole, and benzo[b][1,4]thiazine, as shown in the following structures:

Fused bicyclic heterocyclic alkyl groups can also be represented by the following structures:

^X1 , ^X2 , ^X3 , and ^X4 are each independently absent, _–CH2- , –NH-, –O-, or –S-, at least one of ^X1 , ^X2 , ^X3 , and ^X4 is –NH-, –O-, or –S-, and the dashed circle represents a saturated or partially unsaturated non-aromatic ring. The fused bicyclic heterocyclic alkyl group is optionally substituted.

"alkyl-heterocyclic alkyl" refers to a group having an alkyl component and a heterocyclic alkyl component, wherein the alkyl component connects the heterocyclic alkyl component to a linking point. The alkyl component is as defined above, except that the alkyl component is at least a divalent alkylene group connected to the heterocyclic alkyl component and the linking point. The alkyl component may include any number of carbons, such as _C0-6 , _C1-2 , _C1-3 , _C1-4 , _C1-5 , _C1-6 , _C2-3 , _C2-4 , _C2-5 , _C2-6 , _C3-4 , _C3-5 , _C3-6 , _C4-5 , _C4-6 , and _C5-6 . In some cases, the alkyl component may be absent. The heterocyclic alkyl component is as defined above. The alkyl-heterocyclic alkyl group may be substituted or unsubstituted.

As used herein, “aryl” refers to a single all-carbon aromatic ring or a condensed all-carbon ring system, wherein at least one ring is aromatic. For example, in some embodiments, the aryl group has 6 to 20 carbon atoms, 6 to 14 carbon atoms, or 6 to 12 carbon atoms. Aryl groups include phenyl groups. Aryl groups also include multiple condensed ring systems (e.g., ring systems comprising 2, 3, or 4 rings) having 9 to 20 carbon atoms (e.g., 9 to 16 carbon atoms), wherein at least one ring is aromatic and another ring may be aromatic or non-aromatic (i.e., a carbon ring). Such multiple condensed ring systems are optionally substituted with one or more (e.g., 1, 2, or 3) oxo groups on any carbon ring portion of the multiple condensed ring system. When valence requirements permit, the rings of a polyfused ring system can be connected to each other by fusion, spirocyclic, and bridging. It should also be understood that when referring to a range of aryl groups (e.g., 6-10 aryl groups), the atomic range is the total number of ring atoms in the aryl group. For example, a 6-membered aryl group would include a phenyl group, and a 10-membered aryl group would include a naphthyl group and a 1,2,3,4-tetrahydronaphthyl group. Non-limiting examples of aryl groups include, but are not limited to, phenyl, indenyl, naphthyl, 1,2,3,4-tetrahydronaphthyl, anthraceneyl, etc.

"alkyl-aryl" refers to a group having an alkyl component and an aryl component, wherein the alkyl component attaches the aryl component to a linking point. The alkyl component is as defined above, except that it is at least a divalent alkylene group attached to the aryl component and the linking point. The alkyl component may include any number of carbons, such as _C0-6 , _C1-2 , _C1-3 , _C1-4 , _C1-5 , _C1-6 , _C2-3 , _C2-4 , _C2-5 , _C2-6 , _C3-4 , _C3-5 , _C3-6 , _C4-5 , _C4-6 , and _C5-6 . In some cases, the alkyl component may be absent. The aryl component is as defined above. Examples of alkyl-aryl groups include, but are not limited to, benzyl and ethylbenzene. Alkyl-aryl groups may be substituted or unsubstituted.

As used herein, "heteroaryl" refers to a single aromatic ring having at least one atom other than carbon, wherein the atom is selected from the group consisting of oxygen, nitrogen, and sulfur; "heteroaryl" also includes multiple condensed ring systems having at least one such aromatic ring, which are further described below. Thus, "heteroaryl" comprises a single aromatic ring with 1 to 6 carbon atoms and 1 to 4 heteroatoms selected from the group consisting of oxygen, nitrogen, and sulfur. Sulfur and nitrogen atoms may also be present in oxidized forms, provided that the ring is aromatic. Exemplary heteroaryl ring systems include, but are not limited to, pyridinyl, pyrimidinyl, oxazolyl, or furanyl. "Heteroaryl" also includes multiple condensation ring systems (e.g., ring systems comprising 2, 3, or 4 rings), wherein the heteroaryl group as defined above condenses with one or more rings to form multiple condensation ring systems, said one or more rings being selected from heteroaryl (to form, for example, 1,8-naphthidyl), heterocyclic (to form, for example, 1,2,3,4-tetrahydro-1,8-naphthidyl), carbocyclic (to form, for example, 5,6,7,8-tetrahydroquinolinyl), and aryl (to form, for example, indazole). Thus, a heteroaryl group (a single aromatic ring or multiple condensation ring systems) has 1-20 carbon atoms and 1-6 heteroatoms within the heteroaryl ring. Such multiple condensation ring systems may optionally be substituted with one or more (e.g., 1, 2, 3, or 4) oxo groups on the carbocyclic or heterocyclic portion of the condensation ring. When valence requirements permit, the rings of a polyfused ring system can be connected to each other by fusion, spirocyclic, and bridging. It should be understood that the individual rings of a multi-ring condensation system can be connected relative to each other in any order. It should be understood that the connection points of a heteroaryl or multi-ring condensation system can be located at any suitable atom (including carbon atoms and heteroatoms (e.g., nitrogen)) of the heteroaryl or multi-ring condensation system. It should also be understood that when referring to an atomic range of heteroaryl (e.g., 5- to 10-membered heteroaryl), the atomic range is the total number of ring atoms of the heteroaryl and includes carbon atoms and heteroatoms. For example, a 5-membered heteroaryl would include a thiazolyl group, and a 10-membered heteroaryl would include a quinolinyl group. Exemplary heteroaryl groups include, but are not limited to, pyridyl, pyrroloyl, pyrazinyl, pyrimidinyl, pyridazinyl, thiophenyl, indolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, furanyl, oxadiazolyl, thiazolyl, quinolinyl, isoquinolinyl, benzothiazolyl, benzooxazolyl, inzolyl, quinoxolinyl, quinazolinyl, 5,6,7,8-tetrahydroisoquinolinyl, benzofuranyl, benzoimidazolyl, thioindyl, pyrrolo[2,3-b]pyridyl, quinazolinyl-4(3H)-one, and triazolyl.

"alkyl-heteroaryl" refers to a group having an alkyl component and a heteroaryl component, wherein the alkyl component connects the heteroaryl component to a linking point. The alkyl component is as defined above, except that it is at least a divalent alkylene group connected to the heteroaryl component and the linking point. The alkyl component may include any number of carbons, such as _C0-6 , _C1-2 , _C1-3 , _C1-4 , _C1-5 , _C1-6 , _C2-3 , _C2-4 , _C2-5 , _C2-6 , _C3-4 , _C3-5 , _C3-6 , _C4-5 , _C4-6 , and _C5-6 . In some cases, the alkyl component may be absent. The heteroaryl component is as defined herein. Alkyl-heteroaryl groups may be substituted or unsubstituted.

"Compounds of this disclosure" includes compounds disclosed herein, such as compounds of formula (I), (I-1), (Ia), (Ia-1), (Ib), (Ic), (IIa), (IIa-1), (IIc), (IIc-1), (IIc-2), (IIc-3), (IIc-4), (IIc-5), (IIc-6), (IIc-7), and (IIc-8), including the compounds of the examples.

As used herein, “composition” is intended to cover products containing a specified amount of a specified ingredient and any product formed directly or indirectly from a combination of the specified amounts of the specified ingredients. “Pharmaceutically acceptable” means that the carrier, diluent, or excipient must be compatible with the other components of the formulation and be harmful to the recipient.

"Effective amount of drug" means the amount of the disclosed compound or combination thereof in the formulation that provides the desired therapeutic or pharmaceutical outcome.

"Pharmaceutical acceptable excipients" include, but are not limited to, any adjuvants, carriers, excipients, glidants, sweeteners, diluents, preservatives, dyes/colorants, flavor enhancers, surfactants, wetting agents, dispersants, suspending agents, stabilizers, isotonic agents, solvents, or emulsifiers that have been approved by the U.S. Food and Drug Administration for acceptable use in humans or livestock.

As used herein, “treatment” or “treat” or “treating” refers to a method for achieving a beneficial or desired outcome. For the purposes of this disclosure, beneficial or desired outcomes include, but are not limited to, the reduction of symptoms and/or the lessening of the severity of symptoms and/or the prevention of the worsening of symptoms associated with a disease or condition. In some embodiments, “treatment” or “treating” includes one or more of the following: a) suppressing a disease or condition (e.g., reducing one or more symptoms caused by a disease or condition, and/or lessening the severity of a disease or condition); b) slowing or preventing the development of one or more symptoms associated with a disease or condition (e.g., stabilizing a disease or condition, delaying the worsening or progression of a disease or condition); and c) alleviating a disease or condition, such as causing the disappearance of clinical symptoms, improving disease status, delaying disease progression, improving quality of life, and/or prolonging survival.

As used herein, "therapeutic effective amount" or "effective amount" means an amount that effectively elicits the desired biological or medical response, including amounts of compounds sufficient to achieve such treatment of a disease when administered to a subject. Effective amounts may vary depending on the compound, the subject's disease and its severity, and factors such as age and weight. Effective amounts may include a range of amounts. As understood in the art, an effective amount may be one or more doses; that is, a single dose or multiple doses may be required to achieve the desired therapeutic endpoint. Effective amounts may be considered in the context of administering one or more therapeutic agents, and a single agent may be considered if, in combination with one or more other agents, a desired or beneficial outcome can be achieved. The appropriate dose of any co-administered compounds may optionally be reduced due to the combined effects of the compounds (e.g., additive or synergistic effects).

"Administration" refers to oral administration to a subject, administration as a suppository, local contact, parenteral administration, intravenous administration, intraperitoneal administration, intramuscular administration, intralesional administration, intranasal or subcutaneous administration, intrathecal administration, or implantation of a slow-release device (e.g., a micro-osmotic pump). Administration can be performed according to a schedule based on the specified administration frequency, dosage, and other factors.

As used herein, “co-administration” means administering a unit dose of the compound disclosed herein before or after administering a unit dose of one or more additional therapeutic agents, for example, administering the compound disclosed herein within seconds, minutes, or hours after administering one or more additional therapeutic agents. For example, in some embodiments, a unit dose of the compound disclosed herein is administered first, followed by a unit dose of one or more additional therapeutic agents within seconds or minutes. Alternatively, in other embodiments, a unit dose of one or more additional therapeutic agents is administered first, followed by a unit dose of the compound disclosed herein within seconds or minutes. In some embodiments, a unit dose of the compound disclosed herein is administered first, followed by a unit dose of one or more additional therapeutic agents after several hours (e.g., 1-12 hours). In other embodiments, a unit dose of one or more additional therapeutic agents is administered first, followed by a unit dose of the compound disclosed herein after several hours (e.g., 1-12 hours). Co-administration of the compound disclosed herein with one or more additional therapeutic agents generally means administering the compound disclosed herein and one or more additional therapeutic agents simultaneously or sequentially, such that a therapeutically effective amount of each agent is present in the patient.

"Subject" refers to an animal, such as a mammal, including but not limited to primates (e.g., humans), cattle, sheep, goats, horses, dogs, cats, rabbits, rats, mice, etc. In some implementations, the subject is a human.

"Disease" or "symptom" refers to the state of being or health status of a patient or subject who can be treated with the compounds, pharmaceutical compositions, or methods provided herein. A disease can be an autoimmune disease, an inflammatory disease, cancer, an infectious disease (e.g., a viral infection), a metabolic disease, a developmental disease, a cardiovascular disease, a liver disease, an intestinal disease, an endocrine disease, a neurological disease, or another disease. In some embodiments, the disease is cancer (e.g., lung cancer, ovarian cancer, osteosarcoma, bladder cancer, cervical cancer, liver cancer, kidney cancer, skin cancer (e.g., Merkel cell carcinoma), testicular cancer, leukemia, lymphoma, head and neck cancer, colorectal cancer, prostate cancer, pancreatic cancer, melanoma, breast cancer, neuroblastoma).

“Cancer” refers to all types of cancer, tumors, or malignant tumors found in mammals, including leukemia, lymphoma, melanoma, neuroendocrine tumors, carcinoma, and sarcoma. Exemplary cancers that can be treated with the compounds, pharmaceutical compositions, or methods provided herein include lymphoma, sarcoma, bladder cancer, bone cancer, brain cancer, cervical cancer, colon cancer, esophageal cancer, gastric cancer, head and neck cancer, kidney cancer, myeloma, thyroid cancer, leukemia, prostate cancer, breast cancer (e.g., triple-negative, ER-positive, ER-negative, chemotherapy-resistant, Herceptin-resistant, HER2-positive, doxorubicin-resistant, tamoxifen-resistant, ductal carcinoma, lobular carcinoma, primary, metastatic), ovarian cancer, pancreatic cancer, liver cancer (e.g., hepatocellular carcinoma), lung cancer (e.g., Non-small cell lung cancer, squamous cell lung cancer, adenocarcinoma, large cell lung cancer, small cell lung cancer, carcinoid, sarcoma, glioblastoma multiforme, glioma, melanoma, prostate cancer, castration-resistant prostate cancer, breast cancer, triple-negative breast cancer, glioblastoma, ovarian cancer, lung cancer, squamous cell carcinoma (e.g., head, neck, or esophagus), colorectal cancer, leukemia, acute myeloid leukemia, lymphoma, B-cell lymphoma, or multiple myeloma.

Additional examples include thyroid cancer, endocrine system cancer, brain cancer, breast cancer, cervical cancer, colon cancer, head and neck cancer, esophageal cancer, liver cancer, kidney cancer, lung cancer, non-small cell lung cancer, melanoma, mesothelioma, ovarian cancer, sarcoma, gastric cancer, uterine cancer or medulloblastoma, Hodgkin's disease, non-Hodgkin's lymphoma, multimorphic myeloma, neuroblastoma, glioma, glioblastoma multiforme, ovarian cancer, rhabdomyosarcoma, essential thrombocytosis, essential macroglobulinemia, primary brain tumors, and other cancers. Malignant pancreatic insulinoma, malignant carcinoid tumor, bladder cancer, pre-malignant skin lesions, testicular cancer, lymphoma, thyroid cancer, neuroblastoma, esophageal cancer, urogenital tract cancer, malignant hypercalcemia, endometrial cancer, adrenocortical carcinoma, endocrine or exocrine pancreatic tumors, medullary thyroid cancer, medullary thyroid carcinoma, melanoma, colorectal cancer, papillary thyroid carcinoma, hepatocellular carcinoma, Paget's disease of the breast, phyllodes tumor, lobular carcinoma, ductal carcinoma, pancreatic astrocytoma, hepatic astrocytoma, or prostate cancer.

"Leukemia" broadly refers to a progressive malignant disease of the blood-forming organs and is usually characterized by the distorted proliferation and development of white blood cells and their precursors in the blood and bone marrow. Leukemia is usually classified clinically based on the following: (1) the duration and characteristics of the disease - acute or chronic; (2) the type of cells involved; myeloid (myelopathic), lymphoid (lymphocytic), or monocytic; and (3) the increase or absence of an abnormal number of cells in the blood - leukemic or non-leukemic (subleukemic). Exemplary leukemias that can be treated with the compounds, pharmaceutical compositions, or methods provided herein include, for example, acute non-lymphocytic leukemia, chronic lymphocytic leukemia, acute myeloid leukemia, chronic myeloid leukemia, acute promyelocytic leukemia, adult T-cell leukemia, non-leukemic leukemia, leukopenic leukemia, basophylic leukemia, stem cell leukemia, bovine leukemia, chronic myeloid leukemia, cutaneous leukemia, stem cell leukemia, eosinophilic leukemia, Gross leukemia, hairy cell leukemia, hemoblastic leukemia, hematopoietic leukemia, histiocytic leukemia, stem cell leukemia, acute monocytic leukemia, and leukemia. Cytopenic leukemia, lymphocytic leukemia, lymphoblastic leukemia, lymphocytic leukemia, lymphogenous leukemia, lymphoid leukemia, lymphosarcoma cell leukemia, mast cell leukemia, megakaryocytic leukemia, small myeloblastic leukemia, monocytic leukemia, myeloblastic leukemia, myeloid leukemia, myelomonocytic leukemia, Naegeli leukemia, plasma cell leukemia, multiple myeloma, plasma cell leukemia, promyelocytic leukemia, Rieder cell leukemia, Schilling's leukemia, stem cell leukemia, subleukemic leukemia, or undifferentiated cell leukemia.

"Sarcoma" generally refers to a tumor composed of materials such as embryonic connective tissue, and is typically composed of closely packed cells embedded in fibrils or homogeneous material. Sarcomas that can be treated with the compounds, pharmaceutical compositions, or methods provided herein include chondrosarcoma, fibrosarcoma, lymphosarcoma, melanosarcoma, myxosarcoma, osteosarcoma, Abemethyst sarcoma, liposarcoma, liposarcoma, soft tissue alveolar sarcoma, ameloblastic sarcoma, botryoid sarcoma, chloroma sarcoma, choriosarcoma, embryonal sarcoma, Wilms' tumor sarcoma, endometrial sarcoma, stromal sarcoma, Ewing sarcoma, fascial sarcoma, fibroblastic sarcoma, and giant cell sarcoma. Sarcoma, granulocytic sarcoma, Hodgkin's sarcoma, idiopathic multiple pigmented hemorrhagic sarcoma of the skin, B-cell immunoblastic sarcoma, lymphoma, T-cell immunoblastic sarcoma, Jensen's sarcoma, Kaposi's sarcoma, Kupffer cell sarcoma, angiosarcoma, leukemic sarcoma, malignant mesenchymal sarcoma, periosteal sarcoma, reticulum cell sarcoma, Rous sarcoma, serous cystic sarcoma, synovial sarcoma, or capillary hemangiosarcoma.

"Melanoma" refers to tumors arising from the melanocyte system of the skin and other organs. Melanomas that can be treated with the compounds, pharmaceutical compositions, or methods provided herein include, for example, acral lentigines melanoma, amelanoma, benign juvenile melanoma, Cloudman's melanoma, S91 melanoma, Harding-Passey melanoma, juvenile melanoma, malignant lentigines melanoma, malignant melanoma, nodular melanoma, subungual melanoma, or superficial diffuse melanoma.

"Cancer" refers to a malignant new growth composed of epithelial cells that tends to infiltrate surrounding tissues and metastasize. Exemplary cancers that can be treated with the compounds, pharmaceutical compositions, or methods provided herein include, for example, medullary thyroid carcinoma, familial medullary thyroid carcinoma, acinar carcinoma, acinous carcinoma, cystic adenoid carcinoma, adenoid cystic carcinoma, adenoma, adrenocortical carcinoma, alveolar carcinoma, alveolar cell carcinoma, basal cell carcinoma, basal cell carcinoma, basal cell-like carcinoma, basal squamous cell carcinoma, bronchioloalveolar carcinoma, bronchiolar carcinoma, bronchial protocarcinoma, gyral carcinoma of the brain, cholangiocarcinoma, choriocarcinoma, colloid carcinoma, comedo carcinoma, uterine endometrial carcinoma, cribriform carcinoma, thoracic carcinoma, skin cancer, and columnar cell carcinoma. (The text lists various carcinoma types, including rcinoma, cylindrical cell carcinoma, ductal carcinoma, dural carcinoma, embryonal carcinoma, brain-like carcinoma, epidermoid carcinoma, epithelial adenoidectomy ... Carcinoma, intraepithelial carcinoma, intraepithelial carcinoma, Krompecher carcinoma, Kulchitzky cell carcinoma, large cell carcinoma, lenticular carcinoma, lipoma-like carcinoma, lobular carcinoma, lymphoepithelial carcinoma, medullary carcinoma, melanoma, soft carcinoma, mucinous carcinoma, mucinous cell carcinoma, mucinous epidermal carcinoma, colloid carcinoma, mucous carcinoma, myxomatous carcinoma, nasopharyngeal carcinoma, oat cell carcinoma, bone carcinoma Carcinoma, bone carcinoma, papillary carcinoma, periportal carcinoma, preinvasive carcinoma, acanthosis nigra, comedo carcinoma, renal cell carcinoma, reserve cell carcinoma, sarcomatoid carcinoma, schneiderian carcinoma, sclerosing carcinoma, scrotal carcinoma, signet ring cell carcinoma, simple carcinoma, small cell carcinoma, potato-shaped carcinoma, spherical cell carcinoma, spindle cell carcinoma, cavernous carcinoma (carcinoma spongiosum), squamous carcinoma, squamous cell carcinoma, truncate carcinoma, angiodilated carcinoma (carcinoma telangiectaticum, carcinoma telangiectodes), transitional cell carcinoma, nodular carcinoma (carcinoma tuberosum), tubular carcinoma, tuberous carcinoma, verrucous carcinoma, or villous carcinoma.

The terms “metastasis,” “metastatic,” and “metastatic cancer” are used interchangeably and refer to the spread of a proliferative disease or disorder (e.g., cancer) from one organ or another non-adjacent organ or body part. Cancer originating at a site of origin, such as the breast, is called the primary tumor, such as primary breast cancer. Some cancer cells in the primary tumor or site of origin acquire the ability to penetrate and infiltrate the surrounding normal tissue in a local area and/or penetrate the walls of the lymphatic or vascular system, thus allowing circulation to other parts and tissues in the body. A second, clinically detectable tumor formed from the cancer cells of the primary tumor is called a metastatic or secondary tumor. When cancer cells metastasize, metastatic tumors and their cells are presumed to resemble those of the original tumor. Therefore, if lung cancer metastasizes to the breast, the secondary tumor at the breast site is composed of abnormal lung cells rather than abnormal breast cells. The secondary tumor in the breast is called metastatic lung cancer. Therefore, the phrase metastatic cancer refers to a disease in which a subject has or has a primary tumor and one or more secondary tumors. The phrase "non-metastatic cancer" or "a subject with a cancer that is not metastatic" refers to a subject who has a primary tumor but no one or more secondary tumors. For example, metastatic lung cancer refers to a subject who has a primary lung tumor or a history of a primary lung tumor and has one or more secondary tumors in a second or more locations (e.g., in the breast).

In the context of a substance or its activity or function relating to a disease (e.g., diabetes, cancer (e.g., prostate cancer, kidney cancer, metastatic cancer, melanoma, castration-resistant prostate cancer, breast cancer, triple-negative breast cancer, glioblastoma, ovarian cancer, lung cancer, squamous cell carcinoma (e.g., head, neck, or esophagus), colorectal cancer, leukemia, acute myeloid leukemia, lymphoma, B-cell lymphoma, or multiple myeloma)), "related" or "associated with" means that the disease (e.g., lung cancer, ovarian cancer, osteosarcoma, bladder cancer, cervical cancer, liver cancer, kidney cancer, skin cancer (e.g., Merkel cell carcinoma)), testicular cancer, leukemia, lymphoma, head and neck cancer, colorectal cancer, prostate cancer, pancreatic cancer, melanoma, breast cancer, neuroblastoma) is caused (in whole or in part) by the substance or its activity or function, or that the symptoms of the disease are caused (in whole or in part) by the substance or its activity or function.

Pharmaceutically acceptable salts, hydrates, solvates, tautomers, polymorphs, and prodrugs of the compounds described herein are also provided. "Pharmaceutically acceptable" or "physiologically acceptable" means compounds, salts, compositions, dosage forms, and other substances that can be used to prepare pharmaceutical compositions suitable for veterinary or human use.

The compounds of this disclosure, as described herein, can be prepared and/or formulated as pharmaceutically acceptable salts or, where appropriate, as free bases. A pharmaceutically acceptable salt is a non-toxic salt of the free base form of a compound that possesses the desired pharmacological activity of a free base. These salts can be derived from inorganic or organic acids or bases. Examples of pharmaceutically acceptable salts of the compounds of formula (I) of this disclosure include inorganic acid salts, such as hydrochlorides, sulfates, carbonates, and phosphates; and organic acid salts, such as fumarates, maleates, methanesulfonates, and p-toluenesulfonates. Additional salts or ammonium salts containing alkaline earth metals (such as sodium, magnesium, etc.), containing organic amines (such as lower alkylamines, lower alcoholamines), or containing basic amino acids (such as lysine, arginine, ornithine) are also included. For example, compounds containing basic nitrogen can be prepared into pharmaceutically acceptable salts by contacting the compound with an inorganic or organic acid. Non-limiting examples of pharmaceutically acceptable salts include sulfates, pyrosulfates, bisulfates, sulfites, phosphates, monohydrogen phosphates, dihydrogen phosphates, metaphosphates, pyrophosphates, chlorides, bromides, iodides, acetates, propionates, decanoates, caprylates, acrylates, formates, isobutyrates, hexanoates, heptanoates, propargylates, oxalates, malonates, succinates, octanoates, sebacic acid salts, fumarates, maleates, etc. Alkyne-1,4-diacidate, hexyne-1,6-diacidate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, phthalate, sulfonate, methanesulfonate, propylsulfonate, benzenesulfonate, xylenesulfonate, naphthalene-1-sulfonate, naphthalene-2-sulfonate, phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate, γ-hydroxybutyrate, glycolate, tartrate, and mandelate. A list of other suitable pharmaceutically acceptable salts can be found in Remington: The Science and Practice of Pharmacy, 21st edition, Lippincott Wiliams and Wilkins, Philadelphia, Pa., 2006.

Examples of pharmaceutically acceptable salts of ^{the compounds disclosed herein also include salts derived from suitable bases such as alkali metals (e.g., sodium, potassium), alkaline earth metals (e.g., magnesium), ammonium, and NX 4+} ₍ where X is a C ₁ -C ₄ alkyl group). Base addition salts, such as sodium or potassium salts, are also included.

Also provided are compounds described herein, or pharmaceutically acceptable salts, isomers, or mixtures thereof, wherein one to n hydrogen atoms attached to a carbon atom may be replaced by a deuterium atom or D, where n is the number of hydrogen atoms in the molecule. As is known in the art, a deuterium atom is a non-radioactive isotope of hydrogen. Such compounds can increase resistance to metabolism and are therefore used to increase the half-life of compounds described herein, or pharmaceutically acceptable salts, isomers, or mixtures thereof, when administered to mammals. See, for example, Foster, “Deuterium Isotope Effects in Studies of Drug Metabolism”, Trends Pharmacol. Sci., 5(12):524-527 (1984). Such compounds are synthesized by methods well known in the art, for example by using starting materials in which one or more hydrogen atoms have been replaced by deuterium.

Examples of isotopes that can be incorporated into the disclosed compounds include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, chlorine, and iodine, such as ^2H , ^3H , ^11C , ^13C , 14C, ^13N , ^15N , ^{15O, 17O , 18O} , ^31P , ^32P , ^35S , ^18F , ^36Cl , ^123I , and ^125I , ^respectively . Substitution with positron-emitting isotopes such as ^11C , ^18F , ^15O , and ^13N can be used in positron emission tomography (PET) studies to examine substrate acceptor occupancy. Isotopically labeled compounds of formulas (I), (I-1), (Ia), (Ia-1), (Ib), (Ic), (IIa), (IIa-1), (IIc), (IIc-1), (IIc-2), (IIc-3), (IIc-4), (IIc-5), (IIc-6), (IIc-7), or (IIc-8) can generally be prepared by conventional techniques known to those skilled in the art or by methods similar to those described in the examples set forth below, using appropriate isotopically labeled reagents instead of previously used unlabeled reagents.

The compounds and their pharmaceutically acceptable salts of the embodiments disclosed herein may contain one or more asymmetric centers, and thus may produce enantiomers, diastereomers, and other stereoisomers that can be defined by absolute stereochemistry as (R)- or (S)- or (D)- or (L)- for amino acids. This disclosure is intended to include all such possible isomers as well as their racemic and optically pure forms. Optically active (+) and (-), (R)- and (S)- or (D)- and (L)- isomers can be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques such as chromatography and fractional crystallization. Conventional techniques for preparing/separating individual enantiomers include chiral synthesis from suitable optically pure precursors or resolution of racemates (or racemates of salts or derivatives) using, for example, chiral high-performance liquid chromatography (HPLC). When the compounds described herein contain alkene double bonds or other geometrically asymmetric centers, and unless otherwise stated, the compounds are intended to include both E and Z geometric isomers. Similarly, all tautomers are also intended to be included. When a compound is represented in its chiral form, it should be understood that the embodiments cover, but are not limited to, specific diastereomers or enantiomerically enriched forms. When chirality is not specified but is present, it should be understood that the embodiments relate to specific diastereomers or enantiomerically enriched forms; or racemic or non-racemic mixtures of such compounds. As used herein, a "non-racemic mixture" is a mixture of stereoisomers in a ratio not equal to 1:1.

A "racemate" is a mixture of enantiomers. The mixture may contain equal or unequal amounts of each enantiomer.

"One stereoisomer" and "multiple stereoisomers" refer to compounds that differ in chirality in one or more stereocenters. Stereoisomers include enantiomers and diastereomers. If a compound has one or more asymmetric centers or has asymmetrically substituted double bonds, the compound may exist in stereoisomeric forms and therefore may be produced as individual stereoisomers or as mixtures. Unless otherwise stated, the description is intended to include individual stereoisomers as well as mixtures. Methods for determining stereoisomers and the separation of stereoisomers are well known in the art (see, for example, Chapter 4 of Advanced Organic Chemistry (4th Edition), J. March, John Wiley and Sons, New York, 1992).

"Tautomers" refer to alternative forms of compounds that differ in the position of the proton (such as enol-ketone and imine-enamine tautomers) or tautomers containing heteroaryl groups connected to both the ring-NH- and ring=N- rings, such as pyrazoles, imidazoles, benzimidazoles, triazoles, and tetraazoles.

Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. Dashes at the beginning or end of chemical groups are for convenience; chemical groups may be depicted without one or more dashes without losing their ordinary meaning. Wavy lines drawn through lines in the structure indicate the attachment points of groups. Dashed lines indicate optional bonds. Directionality is not indicated or implied by the order in which chemical groups are written or the points where they connect to the rest of the molecule unless required by chemistry or structure. For example, the group “ _-SO₂CH₂- ” is equivalent to _{“-CH₂SO₂- ”} and both can be connected in either direction. Similarly, a group such as “arylalkyl” can be attached to the rest of the molecule at the aryl or alkyl portion of the group. Prefixes such _as “ _Cuv ” or ( _Cu - _Cv ) indicate that the following groups have u to v carbon atoms. For example, “C₁ _- 6alkyl” and “ _C₁ - _C₆alkyl ” indicate that the alkyl group has 1 to 6 carbon atoms.

As used herein, "solvent" refers to the result of the interaction between the solvent and the compound. Solvents of salts of the compounds described herein are also provided. Hydrates of the compounds described herein are also provided.

As used in this article, "prodrug" refers to a drug derivative that is converted into the parent drug through some chemical or enzymatic pathways when administered to the human body.

II.Compounds

This disclosure provides compounds of formulas (I), (I-1), (Ia), (Ia-1), (Ib), (Ic), (IIa), (IIa-1), (IIc), (IIc-1), (IIc-2), (IIc-3), (IIc-4), (IIc-5), (IIc-6), (IIc-7) and (IIc-8), as well as their pharmaceutically acceptable salts.

In some embodiments, the compound has the structure of formula (I-1):

Or its pharmaceutically acceptable salt.

In some embodiments, the compound of formula (I-1) or a pharmaceutically acceptable salt thereof is a compound, wherein

^R1 , ^R2 , ^R3 and ^R4 are independently hydrogen atoms, halogen atoms, hydroxyl groups, carboxyl groups, formyl groups, cyano groups, amino groups, nitro groups, nitroso groups, alkoxy carbonyl groups, optionally substituted alkyl groups, optionally substituted alkenyl groups, optionally substituted alkynyl groups, optionally substituted alkylamino groups, optionally substituted aryl groups, optionally substituted heteroaryl groups, optionally substituted acyl groups, optionally substituted carbamoyl groups, optionally substituted acylamino groups, optionally substituted saturated heterocyclic groups or optionally substituted alkyl sulfonylamino groups;

^R5 is a hydrogen atom, an optionally substituted alkyl group, an optionally substituted alkynyl group, or an optionally substituted aryl group; and

^R6 is an optionally substituted alkyl, optionally substituted aryl, optionally substituted heteroaryl, or ^R5 and ^R6 together with the nitrogen atom to which they are bonded can form a nitrogen-containing saturated heterocyclic ring with which the aryl ring is fused, and the fused ring can be substituted.

The prerequisite is that the compound is not

Examples of substituents ^R1 to ^R4 in compounds of formula (I-1) include halogen atoms, such as fluorine, chlorine, bromine, or iodine atoms; hydroxyl; carboxyl; formyl; cyano; amino; nitro; nitroso; optionally substituted alkyl groups (e.g., optionally substituted _C1-6 alkyl groups or optionally substituted aralkyl groups are exemplified). Furthermore, substituents in substituted alkyl groups include hydroxyl, methoxy, dimethylamino, morpholino, 4-methylpiperazin-1-yl, and piperidin-1-yl); optionally substituted alkenyl groups (e.g., optionally substituted _C2-6 alkenyl groups, such as vinyl, allyl, isopropenyl, butenyl, isobutenyl, etc.); optionally substituted alkynyl groups (e.g., optionally substituted _C2-6 alkynyl groups, such as ethynyl, 1-propynyl, and propargyl), and amino, cyclopropyl, hydroxyl, phenyl, etc., are included in the substituents of the substituted alkynyl groups. Furthermore, the amino group can be protected by the following groups: an amino protecting group, an optionally substituted cycloalkyl group (e.g., optionally substituted _C3-7 cycloalkyl groups), an optionally substituted alkoxy group (e.g., optionally substituted _C1-6 alkoxy groups), an optionally substituted alkylamino group (e.g., mono- _C1-6 alkylamino groups, di- _C1-6 alkylamino groups, and hydroxyl, methoxy, etc., are included in the substituents of the substituted alkylamino group), an optionally substituted acylamino group (e.g., optionally substituted _C1-4 aliphatic acylamino or aryl acylamino groups, and including acetylamino, benzoylamino, or pyridylcarbonylamino groups), an alkoxycarbonyl group (e.g., optionally substituted _C1-4 alkoxycarbonyl groups), an optionally substituted acyl group (e.g., alkyl- or aryl-substituted carbonyl groups, and including, for example, acetyl or benzoyl groups), an optionally substituted carbamoyl group (e.g., optionally substituted C1-4 carbamoyl groups), an optionally substituted C1-6 carbamoyl group (e.g., optionally substituted C1-6 ... _1-4 alkylcarbamoyl), optionally substituted urea (e.g., optionally substituted _C1-4 alkylurea), optionally substituted aryl (e.g., optionally substituted phenyl), optionally substituted saturated heterocyclic (e.g., optionally substituted morpholino, 4-methylpiperazin-1-yl, piperidin-1-yl, or pyrrolidinyl), optionally substituted heteroaryl (e.g., optionally substituted pyridinyl, thiophene, or furanyl), optionally substituted thioalkyl (e.g., optionally substituted _C1-4 thioalkyl), optionally substituted alkylsulfonyl (e.g., optionally substituted _C1-4 alkylsulfonyl), optionally substituted alkylsulfonylamino (e.g., optionally substituted _C1-4 alkylsulfonylamino), etc.

Examples of ^R5 in compounds of formula (I-1) include hydrogen atoms, optionally substituted alkyl groups (e.g., optionally substituted _C1-6 alkyl groups are exemplified, and _C3-6 cycloalkyl groups, hydroxyl groups, methoxy groups, phenyl groups, etc., are included as substituents of substituted alkyl groups). Furthermore, the hydroxyl group may be protected by: OH- protecting groups (explained later), optionally substituted alkynyl groups (e.g., optionally substituted _C2-6 alkynyl groups are exemplified), optionally substituted aryl groups (e.g., optionally substituted phenyl groups are exemplified), etc.

Examples of ^R6 in compounds of formula (I-1) include optionally substituted alkyl groups (e.g., optionally substituted _C1-6 alkyl groups are exemplified, and _C3-6 cycloalkyl groups, hydroxyl groups, methoxy groups, etc. are included as substituents of the substituted alkyl groups). Furthermore, the hydroxyl group may be protected by: OH-protecting groups (explained later), optionally substituted alkynyl groups, optionally substituted aryl groups (e.g., phenyl and biphenyl groups are exemplified), and halogen atoms, hydroxyl groups, methoxy groups, cyano groups, nitro groups, _C1-4 alkyl groups, carboxyl groups, carbamoyl groups, amino groups, methoxycarbonyl groups, cyclopropyl groups, formyl groups, fluoromethyl groups, trifluoromethyl groups, hydroxymethyl groups, methoxymethyl groups, acetylamino groups, phenyl groups, 5- or 6-membered saturated or unsaturated heterocyclic groups, etc. Additionally, the hydroxyl group may be protected by: OH-protecting groups (explained later) and optionally substituted heteroaryl groups (e.g., including pyridyl or thiophene groups).

Examples of nitrogen-containing 5- to 8-membered saturated heterocyclic rings formed by the fusion of ^R5 and ^R6a with a nitrogen atom and an aryl ring (e.g., phenyl) in compounds of formula (Ic), (IIc), or (IIc-1) include, for example, 1,2,3,4-tetrahydroquinoline, 3,4-dihydro-2H-1,4-benzoxazine, tetrahydrobenzozazepine, and hexahydrobenzoxacoxine.

In some embodiments, this disclosure provides a compound of formula (I):

Or its pharmaceutically acceptable salt, wherein

^R1 is hydrogen, _C1-6 alkyl, _C2-6 alkenyl, _C2-6 alkynyl, _C1-6 alkoxy, halogen, _C1-6 haloalkyl, _C1-6 haloalkoxy, or –CN;

^R2 represents hydrogen, _C1-6 alkyl, _C2-6 alkenyl, _C2-6 alkynyl, _C1-6 hydroxyalkyl, _C1-6 aminoalkyl, C1-6 alkoxy, _C2-6 alkoxyalkyl, halogen, _C1-6 haloalkyl, _C1-6 haloalkoxy, -CN, -NO, -NO2, -C(O) _R2a , -C(O ₎ ^OR2a , -OC(O) ^R2a , -C(O)N(R2a)( ^R2b ), -N( ^R2a )C(O) ^R2b , -OC(O)N( ^R2a )( ^R2b ), ^{-N(R2a )} C(O) ^OR2b , ^-C (＝ ^NR2a )N( ^R2b )( ^R2c ), -N( ^R2a )( ^R2b ), -N(R ^2a )N(R ^2b )(R ^2c ), -N(R ^2a )N＝C(R ^2b )(OR ^2c ), -OR ^2a , -SR ^2a , -S(O)R ^2a , -S(O)(NR ^2a )(R ^2b ), -S(NR ^2a )(NR ^2b )(R ^2c ), -S(O) ₂ R ^2a , -S(O) ₂ N(R ^2a )(R ^2b ), -N(R ^2a )S(O) ₂ (R ^2b ), -P(R ^2a )(R ^2b ), -P(O)(R ^2a )(R ^2b ), -P(O)(OR ^2a )(R ^2b ), -P(O)(OR ^2a )(OR ^2b ), C _3-10 cycloalkyl, C _1-6 alkyl-C _3-10 cycloalkyl, C _6-12 aryl, C _1-6 alkyl-C _6-12 aryl, heterocycloalkyl, C _1-6 alkyl-(heterocycloalkyl), heteroaryl or C _1-6 alkyl-(heteroaryl), wherein each alkyl, alkenyl or alkynyl group is independently and optionally substituted with 1 to 3 R ^2d groups, each cycloalkyl group is optionally substituted with 1 to 3 R ^2e groups, each aryl group is optionally substituted with 1 to 3 R ^2f groups, each heterocycloalkyl group is optionally substituted with 1 to 3 R ^2g groups, and each heteroaryl group is optionally substituted with 1 to 3 R ^2h groups;

Each R ^2a , R ^2b and R ^2c is independently hydrogen, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 hydroxyalkyl, C _1-6 aminoalkyl, C _2-6 alkoxyalkyl, C _1-6 haloalkyl, C _3-10 cycloalkyl, C _1-6 alkyl-C _3-10 cycloalkyl, C _6-12 aryl, C _1-6 alkyl-C _6-12 aryl, heterocycloalkyl, C _1-6 alkyl-(heterocycloalkyl), heteroaryl or C _1-6 alkyl-(heteroaryl), wherein the aryl or heteroaryl is optionally substituted by one to three R ^2j ;

Alternatively, ^R2a , ^R2b and ^R2c, when attached to the same atom, can combine with the atom to which they are attached to to form a heterocyclic alkyl group;

Each R ^2d is independently –CN, -C(O)R ^2d1 , -C(O)OR ^2d1 , -OC(O)R ^2d1 , -C(O)N(R ^2d1 )(R ^2d2 ), -N(R ^2d1 )C(O)R ^2d2 , -OC(O)N(R ^2d1 )(R ^2d2 ), -N(R ^2d1 )C(O)OR ^2d2 , -N(R ^2d1 )(R ^2d2 ), =O, -OR ^2d1 , -SR ^2d1 , -S(O)R ^2d1 , -S(O)(NR ^2d1 )(R ^2d2 ), -S(O) ₂ R ^2d1 , -S(O)N(R ^2d1 )(R ^2d2 ), -N(R ^2d1) S(O) ₂ R ^2d2 , C _3-10 cycloalkyl, C _1-6 alkyl-C _3-10 cycloalkyl, C _6-12 aryl, C _1-6 alkyl-C _6-12 aryl, heterocycloalkyl, C _1-6 alkyl-(heterocycloalkyl), heteroaryl or C _1-6 alkyl-(heteroaryl);

Each R ^2d1 and R ^2d2 is independently hydrogen, a C _1-6 alkyl, a C _1-6 hydroxyalkyl, a C _1-6 aminoalkyl, a C _2-6 alkoxyalkyl, or a C _1-6 haloalkyl;

Each of ^R2e , ^R2f , ^R2g and ^R2h is independently hydrogen, _C1-6 alkyl, _C1-6 hydroxyalkyl, _C1-6 aminoalkyl, _C1-6 alkoxy, _C2-6 alkoxyalkyl, halogen, _C1-6 haloalkyl, _C1-6 haloalkoxy, -CN or -OH;

Each R ^2j is independently a C _1-6 alkyl, C _1-6 hydroxyalkyl, C _1-6 aminoalkyl, C _1-6 alkoxy, C _2-6 alkoxyalkyl, halogen, C _1-6 haloalkyl, or C _1-6 haloalkoxy;

^R3 represents hydrogen, _C1-6 alkyl, _C2-6 alkenyl, _C2-6 alkynyl, _C1-6 hydroxyalkyl, _C1-6 aminoalkyl, C1-6 alkoxy, _C2-6 alkoxyalkyl, halogen, _C1-6 haloalkyl, _C1-6 haloalkoxy, -CN, -NO, -NO2, -C(O) _R3a , -C(O ₎ ^OR3a , -OC(O) ^R3a , -C(O)N(R3a)( ^R3b ), -N( ^R3a )C(O) ^R3b , -OC(O)N( ^R3a )( ^R3b ), ^{-N(R3a )} C(O) ^OR3b , ^-C (＝ ^NR3a )N( ^R3b )( ^R3c ), -N( ^R3a )( ^R3b ), -N(R ^3a )N(R ^3b )(R ^3c ), -N(R ^3a )N＝C(R ^3b )(OR ^3c ), -OR ^3a , -SR ^3a , -S(O)R ^3a , -S(O)(NR ^3a )(R ^3b ), -S(NR ^3a )(NR ^3b )(R ^3c ), -S(O) ₂ R ^3a , -S(O) ₂ N(R ^3a )(R ^3b ), -N(R ^3a )S(O) ₂ (R ^3b ), -P(R ^3a )(R ^3b ), -P(O)(R ^3a )(R ^3b ), -P(O)(OR ^3a )(R ^3b ), -P(O)(OR ^3a )(OR ^3b ), C _3-10 cycloalkyl, C _1-6 alkyl-C _3-10 cycloalkyl, C _6-12 aryl, C _1-6 alkyl-C _6-12 aryl, heterocycloalkyl, C _1-6 alkyl-(heterocycloalkyl), heteroaryl or C _1-6 alkyl-(heteroaryl), wherein each alkenyl or ynyl group is independently and optionally substituted with 1 to 3 R ^3d groups, each cycloalkyl group is optionally substituted with 1 to 3 R ^3e groups, each aryl group is optionally substituted with 1 to 3 R ^3f groups, each heterocycloalkyl group is optionally substituted with 1 to 3 R ^3g groups, and each heteroaryl group is optionally substituted with 1 to 3 R ^3h groups;

Each R ^3a , R ^3b and R ^3c is independently hydrogen, C _1-6 alkyl, C _1-6 hydroxyalkyl, C _2-6 alkoxyalkyl, C _1-6 haloalkyl, C _3-10 cycloalkyl, C _1-6 alkyl-C _3-10 cycloalkyl, C _6-12 aryl, C _1-6 alkyl-C _6-12 aryl, heterocycloalkyl or heteroaryl;

Alternatively, ^R3a , ^R3b and ^R3c , when attached to the same atom, can combine with the atom to which they are attached to to form a heterocyclic alkyl group;

Each R ^3d is independently -N(R ^3d1 )(R ^3d2 ), -OR ^3d1 , C _3-10 cycloalkyl, C _1-6 alkyl-C _3-10 cycloalkyl, C _6-12 aryl, C _1-6 alkyl-C _6-12 aryl, heterocycloalkyl, or heteroaryl;

Each R ^3d1 and R ^3d2 is independently hydrogen, C _1-6 alkyl, or –C(O)O-(C _1-6 alkyl);

Each of ^R3e , ^R3f , ^R3g and ^R3h is independently hydrogen, _C1-6 alkyl, _C1-6 alkoxy, halogen, _C1-6 haloalkyl or _C1-6 haloalkoxy;

^R4 is hydrogen, _C1-6 alkyl, _C2-6 alkenyl, _C2-6 alkynyl, _C1-6 alkoxy, halogen, _C1-6 haloalkyl, _C1-6 haloalkoxy, or –CN;

R ⁵ is hydrogen, _C1-6 alkyl, _C2-6 alkenyl, _C2-6 alkynyl, _C1-6 hydroxyalkyl, _C2-6 alkoxyalkyl, _C1-6 haloalkyl, _C3-10 cycloalkyl, _C1-6 alkyl- _C3-10 cycloalkyl, _C6-12 aryl, _C1-6 alkyl- _C6-12 aryl, heterocycloalkyl, _C1-6 alkyl-(heterocycloalkyl), heteroaryl, or _C1-6 alkyl-(heteroaryl), wherein the alkyl group is optionally substituted with R ^5a ;

R ^5a is –OSi(R ^5a1 )(R ^5a2 )(R ^5a3 );

^R5a1 , ^R5a2 , and ^R5a3 are each independently a _C1-6 alkyl group; and

^R6 is a _C1-6 alkyl, _C2-6 alkenyl, _C2-6 alkynyl, _C1-6 haloalkyl, _C6-12 aryl or heteroaryl, wherein each of the aryl or heteroaryl groups is optionally substituted by one to three ^R6a .

Each R ^6a is independently a _C1-6 alkyl, _C2-6 alkenyl, _C2-6 alkynyl, _C1-6 hydroxyalkyl, _C1-6 aminoalkyl, C1-6 alkoxy, _C2-6 alkoxyalkyl, halogen, _C1-6 haloalkyl, _C1-6 haloalkoxy, –CN, -NO ₂ , -C(O)R 6b, _-C (O)OR ^6b , -OC(O)R ^6b , -C(O)N(R ^6b )(R ^6c ), -N(R ^6b )C(O)R ^6c , -C(＝NR ^6b )N(R ^6c )(R ^6d ), -N(R ^6b )(R ^6c ), -OR ^6b , -SR ^6b , -S(O ⁾ R ^6b , -S(O) _2R ^6b -S(NR ^6b )(NR ^6c )R ^6d , -S(O)(NR ^6b )(R ^6c ), -S(O) ₂ N(R ^6b )(R ^6c ), -N(R ^6b )S(O) ₂ (R ^6c ), -P(R ^6b )(R ^6c ), -P(O)(R ^6b )(R ^6c ), -P(O)(OR ^6b )(R ^6c ), -P(O)(OR ^6b )(OR ^6c ), C _3-10 cycloalkyl, C _1-6 alkyl-C _3-10 cycloalkyl, C _6-12 aryl, C _1-6 alkyl-C _6-12 aryl, heterocycloalkyl, C _1-6 alkyl-(heterocycloalkyl), heteroaryl or C _1-6 alkyl-(heteroaryl), wherein the cycloalkyl, aryl, heterocycloalkyl or heteroaryl group is optionally substituted by 1 to 3 R ^6e , the alkyl group is optionally substituted by R ^6f , and the alkynyl group is optionally substituted by 1 to 4 R ^6j ;

Each R ^6b , R ^6c , and R ^6d is independently hydrogen, C _1-6 alkyl, C _1-6 hydroxyalkyl, C _1-6 aminoalkyl, C _2-6 alkoxyalkyl, C _1-6 haloalkyl, C _3-10 cycloalkyl, C _1-6 alkyl-C _3-10 cycloalkyl, C _6-12 aryl, C _1-6 alkyl-C _6-12 aryl, heterocycloalkyl, C _1-6 alkyl-(heterocycloalkyl), heteroaryl, or C _1-6 alkyl-(heteroaryl), wherein the cycloalkyl, aryl, heterocycloalkyl, or heteroaryl is optionally substituted by one to three R ^6k ;

Each R ^6k is independently a _C1-6 alkyl, _C1-6 hydroxyalkyl, _C1-6 aminoalkyl, _C1-6 alkoxy, _C2-6 alkoxyalkyl, _C1-6 haloalkyl, _C1-6 haloalkoxy, _C3-10 cycloalkyl, _C1-6 alkyl- _C3-10 cycloalkyl, heterocycloalkyl, or _C1-6 alkyl-(heterocycloalkyl);

Each R ^6e is independently a _C1-6 alkyl, _C2-6 alkenyl, _C2-6 alkynyl, _C1-6 hydroxyalkyl, _C1-6 aminoalkyl, C1-6 alkoxy, _C2-6 alkoxyalkyl, halogen, _C1-6 haloalkyl, _C1-6 haloalkoxy, –CN, -NO ₂ , -C(O)R ^6e1 , _-C (O)OR ^6e1 , -OC(O)R ^6e1 , -C(O)N(R 6e1)(R ^6e2 ), -N(R ^6e1 )C(O)R ^6e2 , -OC(O)N(R ^6e1 )(R ^6e2 ), -N(R ^6e1 )C(O)OR ^6e2 , -C(＝NR ^6e1 )N(R ^6e2 )( ^{R 6e3 )} , -N(R ^6e1 )(R ^6e2 ), =O, -OR ^6e1 , -SR ^6e1 , -S(O)R ^6e1 , -S(NR ^6e1 )(NR ^6e2 ), -S(O)(NR ^6e1 )(R ^6e2 ) , -S(O) ₂ R ^6e1 , -S(O) ₂ N(R ^6e1 )(R ^6e2 ), -SF ₅ , -N(R ^6e1 )S(O) ₂ (R ^6e2 ), -P(R ^6e1 )(R ^6e2 ), -P(O)(R ^6e1 )(R ^6e2 ), -P(O)(OR ^6e1 )(R ^6e2 ), -P(O)(OR ^6e1 )(OR ^6e2 ), -Si(R ^6e1 )(R ^6e2 )(R ^6e3 )、C _3-10 cycloalkyl, _C1-6 alkyl- _C3-10 cycloalkyl, _C6-12 aryl, _C1-6 alkyl- _C6-12 aryl, heterocycloalkyl, _C1-6 alkyl-heterocycloalkyl, heteroaryl or _C1-6 alkyl-heteroaryl, wherein each of the cycloalkyl, aryl, heterocycloalkyl or heteroaryl is optionally substituted with 1 to 3 ^R6h , and the alkyl group is optionally substituted with 1 to 3 ^R6m ;

Each R ^6e1 , R ^6e2 , and R ^6e3 is independently hydrogen, C _1-6 alkyl, C _1-6 hydroxyalkyl, C _1-6 aminoalkyl, C _1-6 alkoxyalkyl, C _1-6 haloalkyl, C _3-10 cycloalkyl, C _1-6 alkyl-C _3-10 cycloalkyl, C _6-10 aryl, C _1-6 alkyl-C _6-10 aryl, heterocycloalkyl, C _1-6 alkyl-(heterocycloalkyl), heteroaryl, or C _1-6 alkyl-(heteroaryl), wherein the cycloalkyl, aryl, heterocycloalkyl, or heteroaryl is optionally substituted by one to three R ⁶ⁿ ;

Each R ⁶ⁿ is a _C1-6 alkyl, _C2-6 alkenyl, _C2-6 alkynyl, _C1-6 hydroxyalkyl, _C1-6 aminoalkyl, _C1-6 alkoxy, C2-6 alkoxyalkyl, halogen, _C1-6 haloalkyl, _C1-6 haloalkoxy, -CN, -C(O)R ⁶ⁿ¹ , -C(O)OR _6n1 , -OC(O)R ⁶ⁿ¹ , -C(O)N(R ⁶ⁿ¹ )(R ⁶ⁿ² ), -N(R ⁶ⁿ¹ )C(O)R ⁶ⁿ² , -OC(O)N(R ⁶ⁿ¹ )(R ⁶ⁿ² ), -N(R ⁶ⁿ¹ )C ^{(O)OR 6n2 ,} -C(＝NR ⁶ⁿ¹ )N(R ⁶ⁿ² )(R ⁶ⁿ³ ), -N(R ⁶ⁿ¹ )(R ⁶ⁿ² ), =O, –OH, -SR ⁶ⁿ¹ , -S(O)R ⁶ⁿ¹ , -S(NR ⁶ⁿ¹ )(NR ⁶ⁿ² )R ⁶ⁿ³ , -S(O)(NR ⁶ⁿ¹ )(R ⁶ⁿ² ), -S(O) ₂ R ⁶ⁿ¹ , -S(O) ₂ N(R ⁶ⁿ¹ )(R ⁶ⁿ² ) or -N(R ⁶ⁿ¹ )S(O) ₂ (R ⁶ⁿ² );

Each R ⁶ⁿ¹ , R ⁶ⁿ² , and R ⁶ⁿ³ is independently hydrogen, C _1-6 alkyl, C _1-6 hydroxyalkyl, C _1-6 aminoalkyl, C _2-6 alkoxyalkyl, C _1-6 haloalkyl, C _3-10 cycloalkyl, C _1-6 alkyl-C _{3-10 cycloalkyl, C 6-10 aryl} , C _1-6 alkyl-C _6-10 aryl, heterocycloalkyl, C _1-6 alkyl-(heterocycloalkyl), heteroaryl, or C _1-6 alkyl-(heteroaryl);

Each R ^6h is independently a _C1-6 alkyl, _C2-6 alkenyl, _C2-6 alkynyl, _C1-6 hydroxyalkyl, _C1-6 aminoalkyl, C1-6 alkoxy, _C2-6 alkoxyalkyl, halogen, _C1-6 haloalkyl, _C1-6 haloalkoxy, -CN, -C(O)R ^6h1 , -C(O)OR _6h1 , -OC(O)R ^6h1 , -C(O)N(R ^6h1 )(R ^6h2 ), -N(R ^6h1 )C(O)R ^{6h2, -OC(O)N(R 6h1 )} (R ^6h2 ), -N(R ^6h1 )C(O)OR ^6h2 , -C(＝NR ^6h1 )N(R ^6h2 )(R ^6h3 ), -N(R ^{6h1 )} (R ^6h2 ), =O, –OH, -SR ^6h1 , -S(O)R ^6h1 , -S(NR ^6h1 )(NR ^6h2 )R ^6h3 , -S(O)(NR ^6h1 )(R ^6h2 ), -S(O) _2R ^6h1 , -S(O) _2N (R ^6h1 )(R ^6h2 ), -N(R ^6h1 )S(O) ₂ (R ^6h2 ), C _3-10 cycloalkyl, C _1-6 alkyl-C _3-10 cycloalkyl, heterocycloalkyl or C _1-6 alkyl-(heterocycloalkyl);

Each R ^6h1 , R ^6h2 and R ^6h3 is independently hydrogen, C _1-6 alkyl, C _1-6 hydroxyalkyl, C _1-6 aminoalkyl, C _2-6 alkoxyalkyl, C _1-6 haloalkyl, C _3-10 cycloalkyl, C _1-6 alkyl-C _3-10 cycloalkyl, C _6-10 aryl, C _1-6 alkyl-C _6-10 aryl, heterocycloalkyl, C _1-6 alkyl-(heterocycloalkyl), heteroaryl or C _1-6 alkyl-(heteroaryl);

Each R ^6m is independently a halogen, a _C1-6 haloalkyl group, a _C1-6 haloalkoxy group, -CN, -C(O)R ^6m1 , -C(O)OR ^6m1 , -OC(O)R ^6m1 , -C(O)N(R ^6m1 )(R ^6m2 ), -N(R ^6m3 )C(O)R ^6m2 , -OC(O)N(R ^6m1 )(R ^6m2 ), -N(R ^6m1 )C(O)OR ^6m2 , -C(＝NR ^6m3 )N(R ^6m1 )(R ^6m2 ), -N(R ^6m1 )(R ^6m2 ), =O, –OH, -SR ^6m1 , -S(O)R ^6m1 , -S(NR ^6m1 )(NR ^6m2 )R ^6m3 , -S(O)(NR ^6m1 )(R ^6m2 ), -S(O) ₂ R ^6m1 , -S(O) ₂ N(R ^6m1 )(R ^6m2 ) or -N(R ^6m3 )S(O) ₂ (R ^6m2 );

Each R ^6m1 , R ^6m2 , and R ^6m3 is independently hydrogen, C _1-6 alkyl, C _1-6 hydroxyalkyl, C _1-6 aminoalkyl, C _2-6 alkoxyalkyl, C _1-6 haloalkyl, C _3-10 cycloalkyl, C _1-6 alkyl-C _3-10 cycloalkyl, C _6-10 aryl, C _1-6 alkyl-C _6-10 aryl, heterocycloalkyl, C _1-6 alkyl-(heterocycloalkyl), heteroaryl, or C _1-6 alkyl-(heteroaryl);

R ^6f is –OSi(R ^6f1 )(R ^6f2 )(R ^6f3 );

^R6f1 , ^R6f2 and ^R6f3 are each independently _C1-6 alkyl groups;

Each R ^6j is independently a C _2-6 alkoxyalkyl, halogen, C _1-6 haloalkyl, C _1-6 haloalkoxy, -CN, -C(O)R ^6j1 , -C(O)OR ^6j1 , -OC(O)R ^6j1 , -C(O)N(R ^6j1 )(R ^6j2 ), -N(R ^6j3 )C(O)R ^6j2 , -OC(O)N(R ^6j1 )(R ^6j2 ), -N(R ^6j1 )C(O)OR ^6j2 , -C(＝NR ^6j3 )N(R ^6j1 )(R ^6j2 ), -N(R ^6j1 )(R ^6j2 ), =O, -OR ^6j1 , -SR ^6j1 , -S(O)R ^6j1 , -S(NR ^6j1 ) -S(NR ^6j1 )(NR ^6j2 )R ^6j3 , ^{-S(O)(NR 6j1)(R 6j2 ) ,} -S(O) _2R ^6j1 , -S(O) _2N (R 6j1)(R ^6j2 ), -N(R ^6j1 )S(O) ₂ (R ^6j2 ), ^{-Si(R 6j1 )} (R ^6j2 )(R ^6j3 ), C _3-10 cycloalkyl, C _6-12 aryl, heterocycloalkyl or heteroaryl, wherein the cycloalkyl, aryl, heterocycloalkyl or heteroaryl is optionally substituted by 1 to 3 R ^6p ;

Each R ^6j1 , R ^6j2 , and R ^6j3 is independently hydrogen, _C1-6 alkyl, _C1-6 hydroxyalkyl, _C1-6 aminoalkyl, _C2-6 alkoxyalkyl, _C1-6 haloalkyl, C3-10 cycloalkyl, _C1-6 alkyl- _{C3-10 cycloalkyl, C6-10 aryl} , _C1-6 alkyl- _C6-10 aryl, _{heterocycloalkyl} , _C1-6 alkyl-(heterocycloalkyl), heteroaryl, or _C1-6 alkyl-(heteroaryl);

Each R ^6p is independently a _C1-6 alkyl, _C1-6 hydroxyalkyl, _C1-6 aminoalkyl, _C1-6 alkoxy, C2-6 alkoxyalkyl, halogen, _C1-6 haloalkyl, _C1-6 haloalkoxy, -CN, -C(O)R ^6p1 , -C(O)OR ^6p1 , -OC(O)R ^{6p1, -C(O)N(R 6p1} ₎ (R 6p2), -N(R ^6p1 )C(O)R ^6p2 , -OC(O)N(R ^6p1 )(R ^6p2 ), -N(R ^6p1 )C(O)OR ^6p2 , -C(＝NR ^6p3 )N(R ^6p1 )(R ^{6p2 )} , -N(R ^6p1 )(R ^6p2 ), =O, -OH ^, -SR ^6p1 , -S(O)R ^6p1 , -S(NR ^6p1 )(NR ^6p2 )R ^6p3 , -S(O)(NR ^6p1 )(R ^6p2 ) , -S(O) ₂ R ^6p1 , -S(O) ₂ N(R ^6p1 )(R ^6p2 ) or -N(R ^6p1 )S(O) ₂ (R ^6p2 );

Each R ^6p1 , R ^6p2 , and R ^6p3 is independently hydrogen, _C1-6 alkyl, _C1-6 hydroxyalkyl, _C1-6 aminoalkyl, _C2-6 alkoxyalkyl, _C1-6 haloalkyl, C3-10 cycloalkyl, _C1-6 alkyl- _{C3-10 cycloalkyl, C6-10 aryl} , _C1-6 alkyl- _C6-10 aryl, _{heterocycloalkyl} , _C1-6 alkyl-(heterocycloalkyl), heteroaryl, or _C1-6 alkyl-(heteroaryl);

Alternatively, ^R5 and one ^R6a together with the atoms to which they are attached form a heterocyclic alkyl group, which may optionally be substituted by one to three ^R6g ;

Each R ^6g is independently a _C1-6 alkyl, _C2-6 alkenyl, _C2-6 alkynyl, _C1-6 hydroxyalkyl, _C1-6 aminoalkyl, _C2-6 alkoxyalkyl, halogen, _C1-6 haloalkyl, _C1-6 haloalkoxy, or –CN;

R ⁷ is hydrogen, _C1-6 alkyl, _C1-6 hydroxyalkyl, C1-6 aminoalkyl, _C1-6 alkoxy, _C2-6 alkoxyalkyl, _C1-6 alkylthio, halogen, _C1-6 haloalkyl, –CN, –OH, _-NH2 , _C3-10 cycloalkyl, _C1-6 alkyl- _{C3-10 cycloalkyl} , heterocycloalkyl, or _C1-6 alkyl-(heterocycloalkyl);

Each heterocyclic alkyl group is a 3- to 20-membered ring having 1 to 4 heteroatoms, each independently of N, O, or S; and

Each heteroaryl group is a 5- to 18-membered ring having 1 to 4 heteroatoms, each of which is independently N, O, or S;

The prerequisite is that ^R5 and ^R6 are not both _C1-4 alkyl; and when ^R5 is hydrogen, ^R6 is not isopropyl or a phenyl substituted with 2-Me.

In some embodiments, this disclosure provides a compound of formula (I):

Or its pharmaceutically acceptable salt, wherein

^R1 is hydrogen, _C1-6 alkyl, _C2-6 alkenyl, _C2-6 alkynyl, _C1-6 alkoxy, halogen, _C1-6 haloalkyl, _C1-6 haloalkoxy, or –CN;

^R2 represents hydrogen, _C1-6 alkyl, _C2-6 alkenyl, _C2-6 alkynyl, _C1-6 hydroxyalkyl, C1-6 alkoxy, _C2-6 alkoxyalkyl, halogen, _C1-6 haloalkyl, _C1-6 haloalkoxy, -CN, -NO, -NO2, -C(O) _R2a , -C( _O ) ^OR2a , -OC(O) ^R2a , -C(O)N(R2a)( ^R2b ), -N( ^R2a )C(O) ^R2b , -OC(O)N( ^R2a )( ^R2b ), -N ^{( R2a} )C(O) ^OR2b , -C(＝ ^NR2a )N( ^R2b )( ^{R2c), -N(R2a)(R2b ) , -OR2a ,} -SR ^2a , -S(O)R ^2a , -S(O) ₂ R ^2a , -S(O) ₂ N(R ^2a )(R ^2b ), -N(R ^2a )S(O) ₂ (R ^2b ), -P(O)(R ^2a )(R ^2b ), -P(O)(OR ^2a )(R ^2b ), -P(O)(OR ^2a )(OR ^2b ), C _3-10 cycloalkyl, C _1-6 alkyl-C _3-10 cycloalkyl, C _6-12 aryl, C _1-6 alkyl-C _6-12 aryl, heterocycloalkyl or heteroaryl, wherein each alkenyl or ynyl group is independently and optionally substituted by 1 to 3 R ^2d groups, each cycloalkyl group is optionally substituted by 1 to 3 R ^2e groups, and each aryl group is optionally substituted by 1 to 3 R 2e groups. The ^2f group is substituted, each heterocyclic alkyl group is optionally substituted by 1 to 3 R ^2g groups, and each heteroaryl group is optionally substituted by 1 to 3 R ^2h groups;

Each R ^2a , R ^2b and R ^2c is independently hydrogen, C _1-6 alkyl, C _1-6 hydroxyalkyl, C _2-6 alkoxyalkyl, C _1-6 haloalkyl, C _3-10 cycloalkyl, C _1-6 alkyl-C _3-10 cycloalkyl, C _6-12 aryl, C _1-6 alkyl-C _6-12 aryl, heterocycloalkyl or heteroaryl;

Alternatively, ^R2a , ^R2b and ^R2c, when attached to the same atom, can combine with the atom to which they are attached to to form a heterocyclic alkyl group;

Each R ^2d is independently -N(R ^2d1 )(R ^2d2 ), -OR ^2d1 , C _3-10 cycloalkyl, C _1-6 alkyl-C _3-10 cycloalkyl, C _6-12 aryl, C _1-6 alkyl-C _6-12 aryl, heterocycloalkyl, or heteroaryl;

Each R ^2d1 and R ^2d2 is independently hydrogen, C _1-6 alkyl, or –C(O)O-(C _1-6 alkyl);

Each of ^R2e , ^R2f , ^R2g and ^R2h is independently hydrogen, _C1-6 alkyl, _C1-6 alkoxy, halogen, _C1-6 haloalkyl or _C1-6 haloalkoxy;

^R3 represents hydrogen, _C1-6 alkyl, _C2-6 alkenyl, _C2-6 alkynyl, _C1-6 hydroxyalkyl, C1-6 alkoxy, _C2-6 alkoxyalkyl, halogen, _C1-6 haloalkyl, _C1-6 haloalkoxy, -CN, -NO, -NO2, -C(O) _R3a , -C( _O ) ^OR3a , -OC(O) ^R3a , -C(O)N( ^R3a )( ^R3b ), -N( ^R3a )C(O) ^R3b , -OC(O)N( ^R3a )( ^R3b ), -N( ^R3a )C(O) ^OR3b , -C(＝ ^NR3a )N( ^R3b )( ^R3c ), ^{-N(R3a )} ( ^R3b ), ^-OR3a , -SR ^3a , -S(O)R ^3a , -S(O) ₂ R ^3a , -S(O) ₂ N(R ^3a )(R ^3b ), -N(R ^3a )S(O) ₂ (R ^3b ), -P(O)(R ^3a )(R ^3b ), -P(O)(OR ^3a )(R ^3b ), -P(O)(OR ^3a )(OR ^3b ), C _3-10 cycloalkyl, C _1-6 alkyl-C _3-10 cycloalkyl, C _6-12 aryl, C _1-6 alkyl-C _6-12 aryl, heterocycloalkyl or heteroaryl, wherein each alkenyl or ynyl group is independently and optionally substituted by 1 to 3 R ^3d groups, each cycloalkyl group is optionally substituted by 1 to 3 R ^3e groups, and each aryl group is optionally substituted by 1 to 3 R 3d groups. The ^3f group is substituted, each heterocyclic alkyl group is optionally substituted by 1 to 3 R ^3g groups, and each heteroaryl group is optionally substituted by 1 to 3 R ^3h groups;

Each R ^3a , R ^3b and R ^3c is independently hydrogen, C _1-6 alkyl, C _1-6 hydroxyalkyl, C _2-6 alkoxyalkyl, C _1-6 haloalkyl, C _3-10 cycloalkyl, C _1-6 alkyl-C _3-10 cycloalkyl, C _6-12 aryl, C _1-6 alkyl-C _6-12 aryl, heterocycloalkyl or heteroaryl;

Alternatively, ^R3a , ^R3b and ^R3c , when attached to the same atom, can combine with the atom to which they are attached to to form a heterocyclic alkyl group;

Each R ^3d is independently -N(R ^3d1 )(R ^3d2 ), -OR ^3d1 , C _3-10 cycloalkyl, C _1-6 alkyl-C _3-10 cycloalkyl, C _6-12 aryl, C _1-6 alkyl-C _6-12 aryl, heterocycloalkyl, or heteroaryl;

Each R ^3d1 and R ^3d2 is independently hydrogen, C _1-6 alkyl, or –C(O)O-(C _1-6 alkyl);

Each of ^R3e , ^R3f , ^R3g and ^R3h is independently hydrogen, _C1-6 alkyl, _C1-6 alkoxy, halogen, _C1-6 haloalkyl or _C1-6 haloalkoxy;

^R4 is hydrogen, _C1-6 alkyl, _C2-6 alkenyl, _C2-6 alkynyl, _C1-6 alkoxy, halogen, _C1-6 haloalkyl, _C1-6 haloalkoxy, or –CN;

R ⁵ is hydrogen, _C1-6 alkyl, _C2-6 alkenyl, _C2-6 alkynyl, _C1-6 hydroxyalkyl, _C2-6 alkoxyalkyl, _C1-6 haloalkyl, _C3-10 cycloalkyl, _C1-6 alkyl- _C3-10 cycloalkyl, _C6-12 aryl, _C1-6 alkyl- _C6-12 aryl, heterocycloalkyl, _C1-6 alkyl-(heterocycloalkyl), heteroaryl, or _C1-6 alkyl-(heteroaryl), wherein the alkyl group is optionally substituted with R ^5a ;

R ^5a is –OSi(R ^5a1 )(R ^5a2 )(R ^5a3 );

^R5a1 , ^R5a2 , and ^R5a3 are each independently a _C1-6 alkyl group; and

^R6 is a _C1-6 alkyl, _C2-6 alkenyl, _C2-6 alkynyl, _C1-6 haloalkyl, _C6-12 aryl or heteroaryl, wherein each of the aryl or heteroaryl groups is optionally substituted by one to three ^R6a .

Each R ^6a is independently a _C1-6 alkyl, _C2-6 alkenyl, _C2-6 alkynyl, _C1-6 hydroxyalkyl, _C1-6 alkoxy, C2-6 alkoxyalkyl, halogen, _C1-6 haloalkyl, _C1-6 haloalkoxy, –CN, -NO ₂ , -C(O)R _6b , -C(O)OR ^6b , -OC(O)R ^6b , -C(O)N(R ^6b )(R ^6c ), -N(R ^6b )C(O)R ^6c , -C(＝NR ^6b )N(R ^6c )(R ^6d ), -N(R ^6b )( ^{R 6c )} , -OR ^6b , -SR ^6b , -S(O)R ^6b , -S(O) _2R ^6b , -S(O) _2N (R ^6b )(R ^6c ), -N(R ^6b )S(O) ₂ (R ^6c ), C _3-10 cycloalkyl, C _6-12 aryl, heterocycloalkyl or heteroaryl, wherein each of the cycloalkyl, aryl, heterocycloalkyl or heteroaryl is optionally substituted by 1 to 3 R ^6e , and the alkyl is optionally substituted by R ^6f ;

Alternatively, ^R5 and one ^R6a together with the atoms to which they are attached form a heterocyclic alkyl group, which may optionally be substituted by one to three ^R6g ;

Each R ^6b , R ^6c and R ^6d is independently hydrogen, C _1-6 alkyl, C _1-6 hydroxyalkyl, C _2-6 alkoxyalkyl, C _1-6 haloalkyl, C _3-10 cycloalkyl, C _1-6 alkyl-C _3-10 cycloalkyl, C _6-12 aryl, C _1-6 alkyl-C _6-12 aryl, heterocycloalkyl or heteroaryl;

Each R ^6e is independently a _C1-6 alkyl, _C2-6 alkenyl, _C2-6 alkynyl, _C1-6 hydroxyalkyl, _C1-6 alkoxy, C2-6 alkoxyalkyl, halogen, _C1-6 haloalkyl, _C1-6 haloalkoxy, –CN, -NO ₂ , -C(O)R _6e1 , -C(O)OR ^6e1 , -OC(O)R ^6e1 , -C(O)N(R ^6e1 )(R ^6e2 ), -N(R ^6e1 )C(O)R ^6e2 , -C(＝NR ^6e1 )N(R ^6e2 )(R ^6e3 ), -N(R ^6e1 )(R ^6e2 ), -OR ^6e1 , -SR ^6e1 , -S(O)R ^6e1 , -S(O ⁾ _2R ^6e1 , -S(O) _2N ( ^R6e1 )(R6e2), -N( ^R6e1 )S(O) ₂ ( ^R6e2 ), ^C3-10 _cycloalkyl , _C6-12 aryl, heterocycloalkyl or heteroaryl, wherein each of the cycloalkyl, aryl, heterocycloalkyl or heteroaryl is optionally substituted by 1 to 3 ^R6h ;

Each of ^R6e1 , ^R6e2 and ^R6e3 is independently hydrogen or _C1-6 alkyl;

R ^6f is –OSi(R ^6f1 )(R ^6f2 )(R ^6f3 );

^R6f1 , ^R6f2 and ^R6f3 are each independently _C1-6 alkyl groups;

Each R ^6g is independently a _C1-6 alkyl, _C2-6 alkenyl, _C2-6 alkynyl, halogen, _C1-6 haloalkyl, _C1-6 haloalkoxy, or –CN;

Each R ^6h is independently a _C1-6 alkyl, _C2-6 alkenyl, _C2-6 alkynyl, _C1-6 alkoxy, halogen, _C1-6 haloalkyl, _C1-6 haloalkoxy, -C(O)R ^6h1 , -C(O)OR ^6h1 , -OC(O)R ^6h1 , -C(O)N(R ^6h1 )(R 6h2), -N(R ^6h1 )C(O)R ^6h2 , -C(＝NR ^6h1 )N(R ^6h2 )(R ^6h3 ), -N(R ^6h1 )(R ^6h2 ), –OH, -SR ^6h1 , -S(O ⁾ R ^6h1 , -S(O) _2R ^6h1 , -S(O) _2N (R ^6h1 )(R ^6h2 ) ) or -N(R ^6h1 )S(O) ₂ (R ^6h2 );

Each of ^R6h1 , ^R6h2 and ^R6h3 is independently hydrogen or _C1-6 alkyl;

^R7 is hydrogen, _C1-6 alkyl, halogen, _C1-6 haloalkyl, –CN, or –OH;

Each heterocyclic alkyl group is a 3- to 10-membered ring having one to four heteroatoms, each independently of N, O, or S; and

Each heteroaryl group is a 5- to 10-membered ring having one to four heteroatoms, each independently of N, O, or S, provided that ^R5 and ^R6 are not simultaneously _C1-4 alkyl groups; and when ^R5 is hydrogen, ^R6 is not isopropyl or a 2-Me-substituted phenyl group.

In some embodiments, the compound of formula (I) or (I-1) or a pharmaceutically acceptable salt thereof is a compound wherein ^R5 is a _C1-6 alkyl, _C2-6 alkenyl, _C2-6 alkynyl, C1-6 hydroxyalkyl, _C2-6 alkoxyalkyl, _C1-6 haloalkyl, _C3-10 cycloalkyl, _C1-6 alkyl- _C3-10 cycloalkyl, _C6-12 aryl, _C1-6 alkyl- _{C6-12 aryl} , heterocycloalkyl, _C1-6 alkyl-(heterocycloalkyl), heteroaryl, or _C1-6 alkyl-(heteroaryl), wherein the alkyl group is optionally substituted with ^R5a ; and ^R6 is a _C6-12 aryl or heteroaryl, wherein each aryl or heteroaryl group is optionally substituted with one to three ^R6a ; or ^R5 and ^R6a together with the atoms to which they are attached form a heterocycloalkyl group, optionally substituted with one to three R6a groups. ^6g replacement.

In some embodiments, a compound of formula (I), (I-1), (Ia), (Ib), (Ic), (IIa), (IIc), (IIc-3), (IIc-4), (IIc-5), (IIc-6), (IIc-7), or (IIc-8), or a pharmaceutically acceptable salt thereof, is a compound wherein ^R1 is hydrogen, a _C1-6 alkyl, a _C1-6 alkoxy, a halogen, a _C1-6 haloalkyl, or –CN. In some embodiments, a compound of formula (I), (I-1), (Ia), (Ib), (Ic), (IIa), (IIc), (IIc-3), (IIc-4), (IIc-5), (IIc-6), (IIc-7), or (IIc-8), or a pharmaceutically acceptable salt thereof, is a compound wherein ^R1 is hydrogen, a _C1-3 alkyl, a _C1-3 alkoxy, or a halogen. In some embodiments, a compound of formula (I), (I-1), (Ia), (Ib), (Ic), (IIa), (IIc), (IIc-3), (IIc-4), (IIc-5), (IIc-6), (IIc-7), or (IIc-8), or a pharmaceutically acceptable salt thereof, is a compound, wherein ^R1 is hydrogen, Me, -OMe, F, or Cl. In some embodiments, a compound of formula (I), (I-1), (Ia), (Ib), (Ic), (IIa), (IIc), (IIc-3), (IIc-4), (IIc-5), (IIc-6), (IIc-7), or (IIc-8), or a pharmaceutically acceptable salt thereof, is a compound, wherein ^R1 is hydrogen or F. In some embodiments, a compound of formula (I), (I-1), (Ia), (Ib), (Ic), (IIa), (IIc), (IIc-3), (IIc-4), (IIc-5), (IIc-6), (IIc-7), or (IIc-8), or a pharmaceutically acceptable salt thereof, is a compound, wherein ^R1 is hydrogen. In some embodiments, a compound of formula (I), (I-1), (Ia), (Ib), (Ic), (IIa), (IIc), (IIc-3), (IIc-4), (IIc-5), (IIc-6), (IIc-7), or (IIc-8), or a pharmaceutically acceptable salt thereof, is a compound, wherein ^R1 is F.

In some embodiments, a compound of formula (I), (I-1), (Ia), (Ia-1), (Ib), (Ic), (IIa), (IIa-1), (IIc), (IIc-1), (IIc-2), (IIc-3), (IIc-4), (IIc-5), (IIc-6), (IIc-7), or (IIc-8), or a pharmaceutically acceptable salt thereof, is a compound wherein ^R2 is hydrogen, _C1-6 alkyl, _C2-6 alkenyl, _C2-6 alkynyl, _C1-6 hydroxyalkyl, _C1-6 alkoxy, _C2-6 alkoxyalkyl, halogen, _C1-6 haloalkyl, _C1-6 haloalkoxy, -CN, -NO, _-NO2 , -C(O) ^R2a , -C(O) ^OR2a , -OC(O) ^R2a , -C(O)N( ^R2a )( ^R2b) -N( ^R2a )C(O) ^R2b , -OC(O)N( ^R2a )( ^R2b ), -N( ^{R2a)C(O)OR2b, -N(R2a ) ( R2b} ), ^-OR2a , -S(O) _2N (R2a)(R2b), ^{-N(R2a )} S(O) ₂ ( ^R2b ), _C3-10 cycloalkyl, _C1-6 alkyl- _C3-10 cycloalkyl, _C6-12 aryl, _C1-6 alkyl- _C6-12 aryl, heterocycloalkyl or heteroaryl, wherein each alkenyl or ynyl group is independently ^and optionally substituted by one to three ^R2d groups, and each aryl group is optionally substituted by one to three ^R2f groups. In some embodiments, the compound of formula (I), (I-1), (Ia), (Ia-1), (Ib), (Ic), (IIa), (IIa-1), (IIc), (IIc-1), (IIc-2), (IIc-3), (IIc-4), (IIc-5), (IIc-6), (IIc-7), or (IIc-8), or a pharmaceutically acceptable salt thereof, is a compound wherein ^R2 is hydrogen, _C1-6 alkyl, _C2-6 alkenyl, _C2-6 alkynyl, _C1-6 hydroxyalkyl, _C1-6 alkoxy, _C2-6 alkoxyalkyl, halogen, _C1-6 haloalkyl, -CN, -NO, _-NO2 , -C(O) ^R2a , -C(O) ^OR2a , -N( ^R2a )C(O) ^R2b , -N( ^R2a )( ^R2b ), ^-OR2a -N( ^R2a )S(O) ₂ ( ^R2b ), _C3-10 cycloalkyl, _C6-10 aryl, heterocycloalkyl or heteroaryl, wherein each alkenyl or alkynyl group is independently and optionally substituted by one to three ^R2d groups, and each aryl group is optionally substituted by one to three ^R2f groups. In some embodiments, the compound of formula (I), (I-1), (Ia), (Ia-1), (Ib), (Ic), (IIa), (IIa-1), (IIc), (IIc-1), (IIc-2), (IIc-3), (IIc-4), (IIc-5), (IIc-6), (IIc-7), or (IIc-8) or a pharmaceutically acceptable salt thereof is a compound, wherein ^R2 is hydrogen, _C1-3 alkyl, _C2-3 alkenyl, _C2-6 alkynyl, _C1-3 hydroxyalkyl, _C1-3 alkoxy, _C2-3 alkoxyalkyl, halogen, _C1-3 haloalkyl, -CN, -NO, _-NO2 , -C(O) ^R2a , -C(O) ^OR2a , -N( ^R2a )C(O) ^R2b , -N( ^R2a )( ^R2b ), -N(R ^2a ) S(O) ₂ ( ^R2b ), _C3-6 cycloalkyl, phenyl, heterocycloalkyl or heteroaryl, wherein each alkenyl or alkynyl group is independently and optionally substituted by one ^R2d group, and each phenyl group is optionally substituted by one ^R2f group. In some embodiments, the compound of formula (I), (I-1), (Ia), (Ia-1), (Ib), (Ic), (IIa), (IIa-1), (IIc), (IIc-1), (IIc-2), (IIc-3), (IIc-4), (IIc-5), (IIc-6), (IIc-7), or (IIc-8), or a pharmaceutically acceptable salt thereof, is a compound wherein ^R2 is hydrogen, _C1-3 alkyl, _C2-3 alkenyl, _C2-6 alkynyl, _C1-3 hydroxyalkyl, _C2-3 alkoxyalkyl, halogen, -CN, -NO, _-NO2 , -C(O) ^R2a , -N( ^R2a )C(O) ^R2b , -N( ^R2a )( ^R2b ), -OR ^2a or a heteroaryl group; and the heteroaryl group is a 5- or 6-membered ring having one to three heteroatoms, each of which is independently N, O or S.

In some embodiments, the compound of formula (I), (I-1), (Ia), (Ia-1), (Ib), (Ic), (IIa), (IIa-1), (IIc), (IIc-1), (IIc-2), (IIc-3), (IIc-4), (IIc-5), (IIc-6), (IIc-7), or (IIc-8) or a pharmaceutically acceptable salt thereof is a compound, wherein each R ^2a and R ^2b is independently hydrogen, a C _1-6 alkyl, a C _1-6 hydroxyalkyl, or a C _2-6 alkoxyalkyl. In some embodiments, the compound of formula (I), (I-1), (Ia), (Ia-1), (Ib), (Ic), (IIa), (IIa-1), (IIc), (IIc-1), (IIc-2), (IIc-3), (IIc-4), (IIc-5), (IIc-6), (IIc-7), or (IIc-8) or a pharmaceutically acceptable salt thereof is a compound, wherein each R ^2a and R ^2b is independently hydrogen, a C _1-3 alkyl, a C _1-3 hydroxyalkyl, or a C _2-3 alkoxyalkyl. In some embodiments, the compound of formula (I), (I-1), (Ia), (Ia-1), (Ib), (Ic), (IIa), (IIa-1), (IIc), (IIc-1), (IIc-2), (IIc-3), (IIc-4), (IIc-5), (IIc-6), (IIc-7), or (IIc-8) or a pharmaceutically acceptable salt thereof is a compound, wherein each R ^2a and R ^2b is independently hydrogen or a _C1-3 alkyl group. In some embodiments, the compound of formula (I), (I-1), (Ia), (Ia-1), (Ib), (Ic), (IIa), (IIa-1), (IIc), (IIc-1), (IIc-2), (IIc-3), (IIc-4), (IIc-5), (IIc-6), (IIc-7), or (IIc-8) or a pharmaceutically acceptable salt thereof is a compound, wherein each R ^2a and R ^2b is independently hydrogen or Me.

In some embodiments, the compound of formula (I), (I-1), (Ia), (Ia-1), (Ib), (Ic), (IIa), (IIa-1), (IIc), (IIc-1), (IIc-2), (IIc-3), (IIc-4), (IIc-5), (IIc-6), (IIc-7), or (IIc-8) or a pharmaceutically acceptable salt thereof is a compound, wherein each R ^2d is independently -N(R ^2d1 )(R ^2d2 ), -OR ^2d1 , _C3-10 cycloalkyl, or _C6-12 aryl. In some embodiments, the compound of formula (I), (I-1), (Ia), (Ia-1), (Ib), (Ic), (IIa), (IIa-1), (IIc), (IIc-1), (IIc-2), (IIc-3), (IIc-4), (IIc-5), (IIc-6), (IIc-7), or (IIc-8) or a pharmaceutically acceptable salt thereof is a compound, wherein each R ^2d is independently -N(R ^2d1 )(R ^2d2 ), -OR ^2d1 , C _3-8 cycloalkyl, or phenyl.

In some embodiments, the compound of formula (I), (I-1), (Ia), (Ia-1), (Ib), (Ic), (IIa), (IIa-1), (IIc), (IIc-1), (IIc-2), (IIc-3), (IIc-4), (IIc-5), (IIc-6), (IIc-7), or (IIc-8) or a pharmaceutically acceptable salt thereof is a compound, wherein each R ^2d1 and R ^2d2 is independently hydrogen, C _1-4 alkyl, or –C(O)O (C _1-4 alkyl). In some embodiments, the compound of formula (I), (I-1), (Ia), (Ia-1), (Ib), (Ic), (IIa), (IIa-1), (IIc), (IIc-1), (IIc-2), (IIc-3), (IIc-4), (IIc-5), (IIc-6), (IIc-7), or (IIc-8) or a pharmaceutically acceptable salt thereof is a compound wherein each R ^2d1 and R ^2d2 is independently hydrogen or –C(O)O (C _1-4 alkyl). In some embodiments, a compound of formula (I), (I-1), (Ia), (Ia-1), (Ib), (Ic), (IIa), (IIa-1), (IIc), (IIc-1), (IIc-2), (IIc-3), (IIc-4), (IIc-5), (IIc-6), (IIc-7), or (IIc-8), or a pharmaceutically acceptable salt thereof, is a compound wherein each R ^2d1 and R ^2d2 is independently hydrogen or –C(O)OtBu. In some embodiments, a compound of formula (I), (I-1), (Ia), (Ia-1), (Ib), or (Ic), or a pharmaceutically acceptable salt thereof, is a compound wherein each R ^2d1 and R ^2d2 is hydrogen.

In some embodiments, the compound of formula (I), (I-1), (Ia), (Ia-1), (Ib), (Ic), (IIa), (IIa-1), (IIc), (IIc-1), (IIc-2), (IIc-3), (IIc-4), (IIc-5), (IIc-6), (IIc-7), or (IIc-8) or a pharmaceutically acceptable salt thereof is a compound, wherein each R ^2f is independently a C _1-6 alkoxy or halogen. In some embodiments, a compound of formula (I), (I-1), (Ia), (Ia-1), (Ib), (Ic), (IIa), (IIa-1), (IIc), (IIc-1), (IIc-2), (IIc-3), (IIc-4), (IIc-5), (IIc-6), (IIc-7), or (IIc-8), or a pharmaceutically acceptable salt thereof, is a compound, wherein each R ^2f is independently a _C1-3 alkoxy or halogen. In some embodiments, a compound of formula (I), (I-1), (Ia), (Ia-1), (Ib), (Ic), (IIa), (IIa-1), (IIc), (IIc-1), (IIc-2), (IIc-3), (IIc-4), (IIc-5), (IIc-6), (IIc-7), or (IIc-8), or a pharmaceutically acceptable salt thereof, is a compound, wherein each R ^2f is independently -OMe or F.

In some embodiments, a compound of formula (I), (I-1), (Ia), (Ia-1), (Ib), (Ic), (IIa), (IIa-1), (IIc), (IIc-1), (IIc-2), (IIc-3), (IIc-4), (IIc-5), (IIc-6), (IIc-7), or (IIc-8), or a pharmaceutically acceptable salt thereof, is a compound wherein ^R2 is hydrogen, _C1-6 alkyl, _C2-6 alkenyl, _C2-6 alkynyl, _C1-6 hydroxyalkyl, _C1-6 alkoxy, _C2-6 alkoxyalkyl, halogen, _C1-6 haloalkyl, _C1-6 haloalkoxy, -CN, -NO, _-NO2 , -C(O) ^R2a , -C(O) ^OR2a , -OC(O) ^R2a , -C(O)N( ^R2a )( ^R2b) -N( ^R2a )C(O) ^R2b , -OC(O)N( ^R2a )( ^R2b ), -N( ^{R2a)C(O)OR2b, -N(R2a ) ( R2b} ), ^-OR2a , -S(O) _2N (R2a)(R2b), -N( ^{R2a )} S(O) ₂ ( ^R2b ), _C3-10 cycloalkyl, _C1-6 ^alkyl - _C3-10 cycloalkyl, _C6-12 aryl, _C1-6 alkyl-C _6-12 aryl, a 3- to 8-membered heterocyclic alkyl ring having 1 to 3 heteroatoms, each independently being N, O, or S, or a 5- to 10-membered heteroaryl ring having 1 to 3 heteroatoms, each independently being N, O, or S, wherein each alkenyl or ynyl group is independently and optionally substituted by 1 to 3 R ^2d groups, and each aryl group is optionally substituted by 1 to 3 R ^2f groups; each R ^2a and R ^2b is independently hydrogen, _C1-6 alkyl, _C1-6 hydroxyalkyl, _C2-6 alkoxyalkyl, or _C1-6 haloalkyl; each R ^2d is independently -N(R ^2d1 )(R ^2d2 ), -OR ^2d1 , _C3-10 cycloalkyl, _C1-6 alkyl- _C3-10 cycloalkyl, _C6-12 aryl, _C1-6 alkyl- _C6-12 aryl; each R ^2d1 and R ^2d2 are independently hydrogen, C _1-6 alkyl or –C(O)O-(C _1-6 alkyl); and each R ^2f is independently hydrogen, C _1-6 alkyl, C _1-6 alkoxy or halogen.

In some embodiments, the compound of formula (I), (I-1), (Ia), (Ia-1), (Ib), (Ic), (IIa), (IIa-1), (IIc), (IIc-1), (IIc-2), (IIc-3), (IIc-4), (IIc-5), (IIc-6), (IIc-7), or (IIc-8), or a pharmaceutically acceptable salt thereof, is a compound wherein ^R2 is hydrogen, _C1-6 alkyl, _C2-6 alkenyl, _C2-6 alkynyl, _C1-6 hydroxyalkyl, _C1-6 alkoxy, _C2-6 alkoxyalkyl, halogen, _C1-6 haloalkyl, -CN, -NO, _-NO2 , -C(O) ^R2a , -C(O) ^OR2a , -N( ^R2a )C(O) ^R2b , -N( ^R2a )( ^R2b ), ^-OR2a -N( ^R2a )S(O) ₂ ( ^R2b ), _C3-10 cycloalkyl, _C6-10 aryl, 5- to 8-membered heterocyclic alkyl ring having one to two heteroatoms, each independently N, O, or S, or 5- to 6-membered heteroaryl ring having one to three heteroatoms, each independently independently N, O, or S, wherein each alkenyl or ynyl group is independently and optionally substituted by one to three ^R2d groups, and each aryl group is optionally substituted by one to three ^R2f groups; each ^R2a and ^R2b is independently hydrogen, _C1-6 alkyl, _C1-6 hydroxyalkyl, or _C2-6 alkoxyalkyl; each ^R2d is independently -N( ^R2d1 )( ^R2d2 ), ^-OR2d1 , _C3-10 cycloalkyl, or _C6-12 aryl; each ^R2d1 and R ^2d2 is independently hydrogen, _C1-4 alkyl or –C(O)O-( _C1-4 alkyl); and each ^R2f is independently _C1-6 alkoxy or halogen.

In some embodiments, the compound of formula (I), (I-1), (Ia), (Ia-1), (Ib), (Ic), (IIa), (IIa-1), (IIc), (IIc-1), (IIc-2), (IIc-3), (IIc-4), (IIc-5), (IIc-6), (IIc-7), or (IIc-8) or a pharmaceutically acceptable salt thereof is a compound, wherein ^R2 is hydrogen, _C1-3 alkyl, _C2-3 alkenyl, _C2-6 alkynyl, _C1-3 hydroxyalkyl, _C1-3 alkoxy, _C2-3 alkoxyalkyl, halogen, _C1-3 haloalkyl, -CN, -NO, _-NO2 , -C(O) ^R2a , -C(O) ^OR2a , -N( ^R2a )C(O) ^R2b , -N( ^R2a )( ^R2b ), -N(R ^2a ) S(O) ₂ ( ^R2b ), _C3-6 cycloalkyl, phenyl, 5- to 6-membered heterocyclic alkyl ring having one or two heteroatoms, each independently N or O, or 5- to 6-membered heteroaryl ring having one or two heteroatoms, each independently N, O, or S, wherein each alkenyl or alkynyl group is independently and optionally substituted by one ^R2d group, and each phenyl group is optionally substituted by one ^R2f group; each ^R2a and ^R2b is independently hydrogen, _C1-3 alkyl, _C1-3 hydroxyalkyl, or _C2-3 alkoxyalkyl; each ^R2d is independently -N( ^R2d1 )( ^R2d2 ), ^-OR2d1 , _C3-8 cycloalkyl, or phenyl; each ^R2d1 and ^R2d2 is independently hydrogen or –C(O)O-( _C1-4 alkyl); and each ^R2f is independently C _1-3 alkoxy or halogen.

In some embodiments, the compound of formula (I), (I-1), (Ia), (Ia-1), (Ib), (Ic), (IIa), (IIa-1), (IIc), (IIc-1), (IIc-2), (IIc-3), (IIc-4), (IIc-5), (IIc-6), (IIc-7), or (IIc-8), or a pharmaceutically acceptable salt thereof, is a compound wherein ^R2 is hydrogen, Me, Et, iPr, -CH= _CH2 , -CH=CHMe, -C(Me)= _CH2 , -CMe=CHMe, -CH=C(Me) ₂ , -CH=CHEt, -C≡CH, -C≡C-Me, -C≡C-Et, -C≡C-tBu, -C≡C- _CH2OH , -C≡C- _CMe2 (OH), -C≡C- _{CH2NH 2.} -C≡C-CH ₂ NHC(O)OtBu, -C≡C-CMe ₂ (SO ₂ Me), -CH ₂ OH, -CH ₂ CH ₂ CH ₂ OH, -CH(OH)CH ₂ CH ₃ , -OMe, -OEt, -OCH ₂ CH＝CH ₂ , -CH ₂ OMe, -CH ₂ NHMe, -CH ₂ NMe ₂ , -CH ₂ CH ₂ COOEt, F, Cl, Br, I, -CF ₃ , -CN, -NO, -NO ₂ , -C(O)H, -COOH, -COOMe, -NHCOMe, -NH ₂ , -NHMe, -NMe ₂ , -NHCH ₂ CH ₂ OH, -NHCH ₂ CH ₂ OMe, -NHSO ₂ Me, -OH, -NH-N=CH-OEt, -NH ₂ -NH ₂ , SMe, _SO2Me , Cyclopropyl,

In some embodiments, the compound of formula (I), (I-1), (Ia), (Ia-1), (Ib), (Ic), (IIa), (IIa-1), (IIc), (IIc-1), (IIc-2), (IIc-3), (IIc-4), (IIc-5), (IIc-6), (IIc-7), or (IIc-8), or a pharmaceutically acceptable salt thereof, is a compound wherein ^R2 is hydrogen, Me, Et, iPr, -CH= _CH2 , -C(Me)= _CH2 , -C≡C- _Me , -C≡C- _tBu , -C≡C-CH2OH, -C≡C- _CH2NH2 , -C≡C- _{CH2NH2NH2NH2NH2NH2NH2NH2NH2NH2OH ,} -CH2OH, -OMe, _-CH2OMe , F, Cl, Br, I, _-CF3 -CN, -NO, _-NO₂ , -C(O ₎ H, -COOH, -COOMe, -NHCOMe, _-NH₂ , _-NHMe , _-NMe₂ , -NHCH₂CH₂OH, _{-NHCH₂CH₂OMe} , _{-NHSO₂Me ,} -OH, cyclopropyl,

In some embodiments, the compound of formula (I), (I-1), (Ia), (Ia-1), (Ib), (Ic), (IIa), (IIa-1), (IIc), (IIc-1), (IIc-2), (IIc-3), (IIc-4), (IIc-5), (IIc-6), (IIc-7), or (IIc-8), or a pharmaceutically acceptable salt thereof, is a compound wherein ^R3 is hydrogen, _C1-6 alkyl, _C2-6 alkenyl, _C2-6 alkynyl, _C1-6 hydroxyalkyl, _C1-6 alkoxy, _C2-6 alkoxyalkyl, halogen, _C1-6 haloalkyl, _C1-6 haloalkoxy, -CN, -NO, _-NO2 , -C(O) ^R3a , -C(O) ^OR3a , -OC(O) ^R3a , -C(O)N( ^R3a )( ^R3b) -N( ^R3a )C(O) ^R3b , -OC(O)N( ^R3a )( ^R3b ), -N( ^{R3a)C(O)OR3b, -N(R3a ) ( R3b} ), ^-OR3a , -S(O) _2N (R3a)( ^R3b ), -N( ^R3a )S(O) ₂ ( ^R3b ), ^C3-10 cycloalkyl, _C1-6 alkyl- _C3-10 cycloalkyl, _C6-12 aryl, _C1-6 alkyl- _{C6-12 aryl} , heterocycloalkyl or heteroaryl, wherein each alkenyl or ynyl group is independently and optionally substituted by one to three ^R3d groups, and each aryl group is optionally substituted by one to three ^R3f groups.

In some embodiments, the compound of formula (I), (I-1), (Ia), (Ia-1), (Ib), (Ic), (IIa), (IIa-1), (IIc), (IIc-1), (IIc-2), (IIc-3), (IIc-4), (IIc-5), (IIc-6), (IIc-7), or (IIc-8), or a pharmaceutically acceptable salt thereof, is a compound wherein ^R3 is hydrogen, _C1-6 alkyl, _C2-6 alkenyl, _C2-6 alkynyl, _C1-6 hydroxyalkyl, _C1-6 alkoxy, _C2-6 alkoxyalkyl, halogen, _C1-6 haloalkyl, _C1-6 haloalkoxy, -CN, -NO, _-NO2 , -C(O) ^R3a , -C(O) ^OR3a , -OC(O) ^R3a , -C(O)N( ^R3a )( ^R3b) -N( ^R3a )C(O) ^R3b , -OC(O)N( ^R3a )( ^R3b ), -N( ^{R3a)C(O)OR3b, -N(R3a ) ( R3b} ), ^-OR3a , -S(O) _2N (R3a)( ^R3b ), -N( ^R3a )S(O) ₂ ( ^R3b ), _C3-10 cycloalkyl, _C1-6 ^alkyl - _C3-10 cycloalkyl, _C6-12 aryl, _C1-6 alkyl-C _6-12 aryl, a 3- to 8-membered heterocyclic alkyl ring having 1 to 3 heteroatoms, each independently of N, O, or S, or a 5- to 10-membered heteroaryl ring having 1 to 3 heteroatoms, each independently of N, O, or S, wherein each alkenyl or ynyl group is independently and optionally substituted by 1 to 3 R ^3d groups, and each aryl group is optionally substituted by 1 to 3 R ^3f groups; each R ^3a and R ^3b is independently hydrogen, _C1-6 alkyl, _C1-6 hydroxyalkyl, or _C2-6 alkoxyalkyl; each R ^3d is independently -N(R ^3d1 )(R ^3d2 ), -OR ^3d1 , _C3-10 cycloalkyl, or _C6-12 aryl; each R ^3d1 and R ^3d2 is independently hydrogen, _C1-4 alkyl, or –C(O)O-( _C1-4 alkyl); and each R ^3f is independently a _C1-6 alkoxy or halogen.

In some embodiments, the compound of formula (I), (I-1), (Ia), (Ia-1), (Ib), (Ic), (IIa), (IIa-1), (IIc), (IIc-1), (IIc-2), (IIc-3), (IIc-4), (IIc-5), (IIc-6), (IIc-7), or (IIc-8), or a pharmaceutically acceptable salt thereof, is a compound wherein ^R3 is hydrogen, _C1-6 alkyl, _C1-6 hydroxyalkyl, _C1-6 alkoxy, _C2-6 alkoxyalkyl, halogen, _C1-6 haloalkyl, -CN, _-NO2 , -C(O) ^OR3a , -C(O)N( ^R3a )( ^R3b ), -N( ^R3a )( ^R3b ), -N( ^R3a )S(O) ₂ ( ^R3b) It may be a 5- or 6-membered heteroaryl ring having one to three heteroatoms, each of which is independently N, O or S; and each R ^3a and R ^3b is independently hydrogen or C _1-6 alkyl. In some embodiments, the compound of formula (I), (I-1), (Ia), (Ia-1), (Ib), (Ic), (IIa), (IIa-1), (IIc), (IIc-1), (IIc-2), (IIc-3), (IIc-4), (IIc-5), (IIc-6), (IIc-7), or (IIc-8), or a pharmaceutically acceptable salt thereof, is a compound wherein ^R3 is hydrogen, _C1-3 alkyl, _C1-3 hydroxyalkyl, _C1-3 alkoxy, _C2-3 alkoxyalkyl, halogen, _C1-3 haloalkyl, -CN, _-NO2 , -C(O) ^OR3a , -C(O)N( ^R3a )( ^R3b ), -N( ^R3a )( ^R3b ), -N( ^R3a )S(O) ₂ ( ^R3b) The compound is a 5- or 6-membered heteroaryl ring having one or two heteroatoms, each being N; and each R ^3a and R ^3b is independently hydrogen or a _C1-3 alkyl group. In some embodiments, the compound of formula (I), (I-1), (Ia), (Ia-1), (Ib), (Ic), (IIa), (IIa-1), (IIc), (IIc-1), (IIc-2), (IIc-3), (IIc-4), (IIc-5), (IIc-6), (IIc-7), or (IIc-8), or a pharmaceutically acceptable salt thereof, is a compound wherein R ³ is hydrogen, Me, Et, -CH ₂ OH, -OMe, -CH ₂ OMe, F, Cl, Br, -CF ₃ , -CN, -NO ₂ , -COOMe, -CONH ₂ , -NH ₂ , -NHSO ₂ Me, or

In some embodiments, the compound of formula (I), (I-1), (Ia), (Ia-1), (Ib), (Ic), (IIa), (IIa-1), (IIc), (IIc-1), (IIc-2), (IIc-3), (IIc-4), (IIc-5), (IIc-6), (IIc- ^{7), or (IIc} -8), or a pharmaceutically acceptable salt thereof, is a compound wherein ^R3 is hydrogen, _C1-6 alkyl, _C1-6 hydroxyalkyl, _C1-6 alkoxy, _C2-6 alkoxyalkyl, _halogen , -CN, -NO2, -C(O)OR3a, -C(O)N( ^R3a )( ^R3b ), -N( ^R3a )( ^R3b ), -N( ^R3a )S(O) ₂ ( ^R3b) It may be a 5- or 6-membered heteroaryl ring having one to three heteroatoms, each of which is independently N, O or S; and each R ^3a and R ^3b is independently hydrogen or C _1-6 alkyl. In some embodiments, the compound of formula (I), (I-1), (Ia), (Ia-1), (Ib), (Ic), (IIa), (IIa-1), (IIc), (IIc-1), (IIc-2), (IIc-3), (IIc-4), (IIc-5), (IIc-6), (IIc-7), or (IIc-8) or a pharmaceutically acceptable salt thereof is a compound wherein ^R3 is hydrogen, _C1-3 alkyl, _C1-3 hydroxyalkyl, _C1-3 alkoxy, _C2-3 alkoxyalkyl, halogen, -CN, _-NO2 , -C(O) ^OR3a , -C(O)N( ^R3a )( ^R3b ), -N( ^R3a )( ^R3b ), -N( ^R3a )S(O) ₂ ( ^R3b ), or heteroaryl. In some embodiments, the compound of formula (I), (I-1), (Ia), (Ia-1), (Ib), (Ic), (IIa), (IIa-1), (IIc), (IIc-1), (IIc-2), (IIc-3), (IIc-4), (IIc-5), (IIc-6), (IIc- ^{7), or (IIc} -8), or a pharmaceutically acceptable salt thereof, is a compound wherein ^R3 is hydrogen, _C1-3 alkyl, _C1-3 hydroxyalkyl, _C1-3 alkoxy, _C2-3 alkoxyalkyl, halogen, -CN, _-NO2 , -C(O)OR3a, -C(O)N( ^R3a )( ^R3b ), -N( ^R3a )( ^R3b ), -N( ^R3a )S(O) ₂ ( ^R3b) It may be a 5- or 6-membered heteroaryl ring having one or two heteroatoms, each being N; and each R ^3a and R ^3b is independently hydrogen or a _C1-3 alkyl group.

In some embodiments, the compound of formula (I), (I-1), (Ia), (Ia-1), (Ib), (Ic), (IIa), (IIa-1), (IIc), (IIc-1), (IIc-2), (IIc-3), (IIc-4), (IIc-5), (IIc-6), (IIc-7), or (IIc-8), or a pharmaceutically acceptable salt thereof, is a compound wherein ^R3 is hydrogen, _C1-3 alkyl, halogen, -CN, or _-NO2 . In some embodiments, the compound of formula (I), (I-1), (Ia), (Ia-1), (Ib), (Ic), (IIa), (IIa-1), (IIc), (IIc-1), (IIc-2), (IIc-3), (IIc-4), (IIc-5), (IIc-6), (IIc-7), or (IIc-8) or a pharmaceutically acceptable salt thereof is a compound, wherein ^R3 is hydrogen, Me, Et, _-CH₂OH , -OMe, _-CH₂OMe , F, Cl, Br, -CN, _-NO₂ , -COOMe, _-CONH₂ , _-NH₂ , _-NHSO₂Me , or

In some embodiments, the compound of formula (I), (I-1), (Ia), (Ia-1), (Ib), (Ic), (IIa), (IIa-1), (IIc), (IIc-1), (IIc-2), (IIc-3), (IIc-4), (IIc-5), (IIc-6), (IIc-7), or (IIc-8), or a pharmaceutically acceptable salt thereof, is a compound wherein ^R2 is hydrogen, _C1-6 alkyl, _C2-6 alkenyl, _C2-6 alkynyl, _C1-6 hydroxyalkyl, _C1-6 alkoxy, _C2-6 alkoxyalkyl, halogen, _C1-6 haloalkyl, -CN, -NO, _-NO2 , -C(O) ^R2a , -C(O) ^OR2a , -N( ^R2a )C(O) ^R2b , -N( ^R2a )( ^R2b ), ^{-OR2a R2a} , _R2b , _C3-10 cycloalkyl, _C6-10 aryl, heterocycloalkyl, ^or heteroaryl, wherein each alkenyl or ynyl group is independently and optionally substituted by one to three ^R2d groups, and each aryl group is optionally substituted by one to three ^R2f groups; each ^R2a and ^R2b is independently hydrogen, _C1-6 alkyl, _C1-6 hydroxyalkyl, or _C2-6 alkoxyalkyl; each ^R2d is independently -N( ^R2d1 )( ^R2d2 ), ^-OR2d1 , _C3-10 cycloalkyl, or _C6-12 aryl; each ^R2f is independently _C1-6 alkoxy or halogen; the heterocycloalkyl group is a 5- to 8-membered ring having one to two heteroatoms, each independently N, O, or S; ^R3 is hydrogen, C _1-6 alkyl, _C2-6 alkenyl, _C2-6 alkynyl, _C1-6 hydroxyalkyl, _C1-6 alkoxy, _C2-6 alkoxyalkyl, halogen, _C1-6 haloalkyl, _C1-6 haloalkoxy, -CN, -NO, -NO2, -C(O) _R3a , -C(O) ^OR3a , -OC(O) ^R3a , -C(O)N( ^R3a )( ^R3b ), -N( ^R3a )C(O) ^R3b , -OC(O)N( ^R3a )( ^R3b ), -N( ^R3a )C(O) ^OR3b , -N( ^R3a )( ^R3b ), ^-OR3a , -S(O) _2N ( ^R3a )( ^R3b ), -N ^{(R3a )} S(O) ₂ (R ^3b ), C _3-10 cycloalkyl, C _1-6 alkyl-C _3-10 cycloalkyl, C _6-12 aryl, C _1-6 alkyl-C _6-12 aryl, heterocycloalkyl or heteroaryl, wherein each alkenyl or ynyl group is optionally substituted by one to three R ^3d groups, and each aryl group is optionally substituted by one to three R ^3f groups; and the heteroaryl group is a 5- or 6-membered ring having one to three heteroatoms, each of which is independently N, O or S.

In some embodiments, the compound of formula (I), (I-1), (Ia), (Ia-1), (Ib), (Ic), (IIa), (IIa-1), (IIc), (IIc-1), (IIc-2), (IIc-3), (IIc-4), (IIc-5), (IIc-6), (IIc-7), or (IIc-8) or a pharmaceutically acceptable salt thereof is a compound, wherein ^R2 is hydrogen, _C1-3 alkyl, _C2-3 alkenyl, _C2-6 alkynyl, _C1-3 hydroxyalkyl, _C1-3 alkoxy, _C2-3 alkoxyalkyl, halogen, _C1-3 haloalkyl, -CN, -NO, _-NO2 , -C(O) ^R2a , -C(O) ^OR2a , -N( ^R2a )C(O) ^R2b , -N( ^R2a )( ^R2b ), -N(R ^2a ) S(O) ₂ ( ^R2b ), _C3-6 cycloalkyl, phenyl, heterocycloalkyl, or heteroaryl, wherein each alkenyl or alkynyl group is independently and optionally substituted by one ^R2d group, and each phenyl group is optionally substituted by one ^R2f group; each ^R2a and ^R2b is independently hydrogen, _C1-3 alkyl, _C1-3 hydroxyalkyl, or _C2-3 alkoxyalkyl; each ^R2d is independently -N( ^R2d1 )( ^R2d2 ), ^-OR2d1 , _C3-8 cycloalkyl, or phenyl; each ^R2f is independently _C1-3 alkoxy or halogen; ^R3 is hydrogen, _C1-3 alkyl, _C1-3 hydroxyalkyl, _C1-3 alkoxy, _C2-3 alkoxyalkyl, halogen, -CN, _-NO2 , -C(O) ^OR3a , -C(O)N( ^R3a) (R ^3b ), -N(R ^3a )(R ^3b ), -N(R ^3a )S(O) ₂ (R ^3b ) or heteroaryl; each R ^3a and R ^3b is independently hydrogen or C _1-3 alkyl; the heterocyclic alkyl is a 5- or 6-membered ring having one or two heteroatoms that are each independently N or O; and the heteroaryl is a 5- or 6-membered ring having one or two heteroatoms that are each independently N, O or S.

In some embodiments, a compound of formula (I), (I-1), (Ia), (Ib), (Ic), (IIa), (IIc), (IIc-3), (IIc-4), (IIc-5), (IIc-6), (IIc-7), or (IIc-8), or a pharmaceutically acceptable salt thereof, is a compound, wherein ^R2 is hydrogen, F, ^or Cl. In some embodiments, a compound of formula (I), (I-1), (Ia), (Ib), (Ic), (IIa), (IIc), (IIc-3), (IIc-4), (IIc-5), (IIc-6), (IIc-7), or (IIc-8), or a pharmaceutically acceptable salt thereof, is a compound, wherein ^R2 is F. In some embodiments, a compound of formula (I), (I-1), (Ia), (Ib), (Ic), (IIa), (IIc), (IIc-3), (IIc-4), (IIc-5), (IIc-6), (IIc-7), or (IIc-8), or a pharmaceutically acceptable salt thereof, is a compound, wherein ^R2 is Cl.

In some embodiments, the compound of formula (I), (I-1), (Ia), (Ia-1), (Ib), (Ic), (IIa), (IIa-1), (IIc), (IIc-1), (IIc-2), (IIc-3), (IIc-4), (IIc-5), (IIc-6), (IIc-7), or (IIc-8), or a pharmaceutically acceptable salt thereof, is a compound wherein ^R2 is hydrogen, Me, Et, iPr, -CH= _CH2 , -C(Me)= _CH2 , -C≡C- _Me , -C≡C- _tBu , -C≡C-CH2OH, -C≡C- _CH2NH2 , -C≡C- _{CH2NH2NH2NH2NH2NH2NH2NH2NH2NH2OH ,} -CH2OH, -OMe, _-CH2OMe , F, Cl, Br, I, _-CF3 -CN, -NO, _-NO₂ , -C(O ₎ H, -COOH, -COOMe, -NHCOMe, _-NH₂ , _-NHMe , _-NMe₂ , -NHCH₂CH₂OH, _{-NHCH₂CH₂OMe} , _{-NHSO₂Me ,} -OH, cyclopropyl,

and

^R3 represents hydrogen, Me, Et, _-CH₂OH , -OMe, _-CH₂OMe , F, Cl, Br, -CN, _-NO₂ , -COOMe, _-CONH₂ , _-NH₂ , _-NHSO₂Me , or

In some embodiments, a compound of formula (I), (I-1), (Ia), (Ib), (Ic), (IIa), (IIc), (IIc-3), (IIc-4), (IIc-5), (IIc-6), (IIc-7), or (IIc-8), or a pharmaceutically acceptable salt thereof, is a compound, wherein ^R3 is hydrogen, F, ^or Cl. In some embodiments, the compound of formula (I), (I-1), (Ia), (Ib), (Ic), (IIa), (IIc), (IIc-3), (IIc-4), (IIc-5), (IIc-6), (IIc-7), or (IIc-8) or a pharmaceutically acceptable salt thereof is a compound, wherein ^R3 is F.

In some embodiments, a compound of formula (I), (I-1), (Ia), (Ib), (Ic), (IIa), (IIc), (IIc-3), (IIc-4), (IIc-5), (IIc-6), (IIc-7), or (IIc-8), or a pharmaceutically acceptable salt thereof, is a compound wherein ^R4 is hydrogen, a _C1-6 alkyl, a _C1-6 alkoxy, a halogen, a _C1-6 haloalkyl, or –CN. In some embodiments, a compound of formula (I), (I-1), (Ia), (Ib), (Ic), (IIa), (IIc), (IIc-3), (IIc-4), (IIc-5), (IIc-6), (IIc-7), or (IIc-8), or a pharmaceutically acceptable salt thereof, is a compound wherein ^R4 is hydrogen, a _C1-6 alkyl, or a halogen. In some embodiments, a compound of formula (I), (I-1), (Ia), (Ib), (Ic), (IIa), (IIc), (IIc-3), (IIc-4), (IIc-5), (IIc-6), (IIc-7), or (IIc-8), or a pharmaceutically acceptable salt thereof, is a compound, wherein ^R4 is hydrogen, a _C1-3 alkyl group, or a halogen. In some embodiments, a compound of formula (I), (I-1), (Ia), (Ib), (Ic), (IIa), (IIc), (IIc-3), (IIc-4), (IIc-5), (IIc-6), (IIc-7), or (IIc-8), or a pharmaceutically acceptable salt thereof, is a compound, wherein ^R4 is hydrogen, Me, F, Cl, or Br. In some embodiments, a compound of formula (I), (I-1), (Ia), (Ib), (Ic), (IIa), (IIc), (IIc-3), (IIc-4), (IIc-5), (IIc-6), (IIc-7), or (IIc-8), or a pharmaceutically acceptable salt thereof, is a compound, wherein ^R4 is hydrogen, ^F , or Cl. In some embodiments, the compound of formula (I), (I-1), (Ia), (Ib), (Ic), (IIa), (IIc), (IIc-3), (IIc-4), (IIc-5), (IIc-6), (IIc-7), or (IIc-8) or a pharmaceutically acceptable salt thereof is a compound, wherein ^R4 is F.

In some embodiments, a compound of formula (I), (Ic), (IIa), (IIc), (IIc-3), (IIc-4), (IIc-5), (IIc-6), (IIc-7), or (IIc-8), or a pharmaceutically acceptable salt thereof, is a compound, wherein ^R1 and ^R2 are each hydrogen. In some embodiments, a compound of formula (I), (Ic), (IIa), (IIc), (IIc-3), (IIc-4), (IIc-5), (IIc-6), (IIc-7), or (IIc-8), or a pharmaceutically acceptable salt thereof, is a compound, wherein ^R1 and ^R3 are each hydrogen. In some embodiments, a compound of formula (I), (Ic), (IIa), (IIc), (IIc-3), (IIc-4), (IIc-5), (IIc-6), (IIc-7), or (IIc-8), or a pharmaceutically acceptable salt thereof, is a compound, wherein ^R1 and ^R4 are each hydrogen. In some embodiments, a compound of formula (I), (Ic), (IIa), (IIc), (IIc-3), (IIc-4), (IIc-5), (IIc-6), (IIc-7), or (IIc-8), or a pharmaceutically acceptable salt thereof, is a compound, wherein ^R2 and ^R3 are each hydrogen. In some embodiments, a compound of formula (I), (Ic), (IIa), (IIc), (IIc-3), (IIc-4), (IIc-5), (IIc-6), (IIc-7), or (IIc-8), or a pharmaceutically acceptable salt thereof, is a compound, wherein ^R2 and ^R4 are each hydrogen. In some embodiments, a compound of formula (I), (Ic), (IIa), (IIc), (IIc-3), (IIc-4), (IIc-5), (IIc-6), (IIc-7), or (IIc-8), or a pharmaceutically acceptable salt thereof, is a compound, wherein ^R3 and ^R4 are each hydrogen.

In some embodiments, a compound of formula (I), (Ic), (IIa), (IIc), (IIc-3), (IIc-4), (IIc-5), (IIc-6), (IIc-7), or (IIc-8), or a pharmaceutically acceptable salt thereof, is a compound, wherein ^R1 , ^R2 , and ^R3 are each hydrogen. In some embodiments, a compound of formula (I), (Ic), (IIa), (IIc), (IIc-3), (IIc-4), (IIc-5), (IIc-6), (IIc-7), or (IIc-8), or a pharmaceutically acceptable salt thereof, is a compound, wherein ^R1 , ^R2 , and ^R4 are each hydrogen. In some embodiments, a compound of formula (I), (Ic), (IIa), (IIc), (IIc-3), (IIc-4), (IIc-5), (IIc-6), (IIc-7), or (IIc-8), or a pharmaceutically acceptable salt thereof, is a compound, wherein ^R1 , ^R3 , and ^R4 are each hydrogen. In some embodiments, a compound of formula (I), (Ic), (IIa), (IIc), (IIc-3), (IIc-4), (IIc-5), (IIc-6), (IIc-7), or (IIc-8), or a pharmaceutically acceptable salt thereof, is a compound, wherein ^R2 , ^R3 , and ^R4 are each hydrogen.

In some embodiments, the compound of formula (I), (Ic), (IIa), (IIc), (IIc-3), (IIc-4), (IIc-5), (IIc-6), (IIc-7), or (IIc-8), or a pharmaceutically acceptable salt thereof, is a compound wherein ^R1 is hydrogen; ^R2 is hydrogen, _C1-3 alkyl, _C2-3 alkenyl, _C2-6 alkynyl, _C1-3 hydroxyalkyl, _C2-3 alkoxyalkyl, halogen, -CN, -NO, _-NO2 , -C(O) ^R2a , -N( ^R2a )C(O) ^R2b , -N( ^R2a )( ^R2b ), ^-OR2a , or a 5- to 6-membered heteroaryl ring having one or two heteroatoms that are each independently N, O, or S; ^R2a and ^R2b are each independently hydrogen or _C1-3 alkyl; ^R3 is hydrogen, C _1-3 alkyl, halogen, -CN or -NO ₂ ; R ⁴ is hydrogen or halogen; and R ⁷ is hydrogen or C _1-3 alkyl.

In some embodiments, the compound of formula (I), (Ic), (IIa), (IIc), (IIc-3), (IIc-4), (IIc-5), (IIc-6), (IIc-7), or (IIc-8), or a pharmaceutically acceptable salt thereof, is a compound wherein ^R1 is hydrogen; ^R2 is hydrogen, _C1-3 alkyl, _C2-3 alkenyl, _C2-6 alkynyl, _C1-3 hydroxyalkyl, _C2-3 alkoxyalkyl, halogen, -CN, -NO, _-NO2 , -C(O) ^R2a , -N( ^R2a )C(O) ^R2b , -N( ^R2a )( ^R2b ), ^-OR2a , or a 5- to 6-membered heteroaryl ring having one or two heteroatoms that are each independently N, O, or S; ^R2a and ^R2b are each independently hydrogen or _C1-3 alkyl; ^R3 is hydrogen, C _1-3 alkyl, halogen, -CN or -NO ₂ ; R ⁴ is hydrogen; and R ⁷ is hydrogen.

In some embodiments, a compound of formula (I), (I-1), (Ia), (Ib), (Ic), (IIa), (IIc), (IIc-3), (IIc-4), (IIc-5), (IIc-6), (IIc-7), or (IIc-8), or a pharmaceutically acceptable salt thereof, is a compound wherein ^R1 is hydrogen; ^R2 is hydrogen, _C1-6 alkyl, _C2-6 alkenyl, _C2-6 alkynyl, _C1-6 hydroxyalkyl, _C1-6 alkoxy, _C2-6 alkoxyalkyl, halogen, _C1-6 haloalkyl, -CN, -NO, _-NO2 , -C(O) ^R2a , -C(O) ^OR2a , -N( ^R2a )C(O) ^R2b , -N( ^R2a )( ^R2b ), ^-OR2a , -N( ^R2a )S(O) ₂ (R ^2b ) _C3-10 cycloalkyl, _C6-10 aryl, heterocycloalkyl, or heteroaryl, wherein each alkenyl or ynyl group is independently and optionally substituted by one to three ^R2d groups, and each aryl group is optionally substituted by one to three ^R2f groups; each ^R2a and ^R2b is independently hydrogen, _C1-6 alkyl, _C1-6 hydroxyalkyl, or _C2-6 alkoxyalkyl; each ^R2d is independently -N( ^R2d1 )( ^R2d2 ), ^-OR2d1 , _C3-10 cycloalkyl, or _C6-12 aryl; each ^R2f is independently _C1-6 alkoxy or halogen; the heterocycloalkyl is a 5- to 8-membered ring having one to two heteroatoms, each independently N, O, or S; ^R3 is hydrogen, _C1-6 alkyl, _C2-6 alkenyl, _C2-6 ynyl, C2-6 alkyl ... _1-6 hydroxyalkyl, _C1-6 alkoxy, _C2-6 alkoxyalkyl, halogen, _C1-6 haloalkyl, _C1-6 haloalkoxy, -CN, -NO, -NO2, -C(O) _R3a , -C(O) ^OR3a , -OC(O) ^R3a , -C(O)N(R3a)( ^R3b ), -N( ^R3a )C(O) ^R3b , -OC(O)N ^{( R3a} )( ^R3b ), -N ^{(R3a )} C(O) ^OR3b , -N( ^R3a )( ^R3b ), ^-OR3a , -S(O) _2N ( ^R3a )( ^R3b ), -N( ^R3a )S(O) ₂ ( ^R3b ), _C3-10 cycloalkyl, C _1-6 alkyl-C _3-10 cycloalkyl, C _6-12 aryl, C _1-6 alkyl-C _6-12 aryl, heterocycloalkyl, or heteroaryl, wherein each alkenyl or ynyl group is independently and optionally substituted with one to three R ^3d groups, and each aryl group is optionally substituted with one to three R ^3f groups; and said heteroaryl is a 5- to 6-membered ring having one to three heteroatoms, each independently N, O, or S; and R ⁴ is hydrogen.

In some embodiments, the compound of formula (I), (I-1), (Ia), (Ib), (Ic), (IIa), (IIc), (IIc-3), (IIc-4), (IIc-5), (IIc-6), (IIc-7), or (IIc-8), or a pharmaceutically acceptable salt thereof, is a compound wherein ^R1 is hydrogen or F; ^R2 is hydrogen, _C1-6 alkyl, _C2-6 alkenyl, _C2-6 alkynyl, _C1-6 hydroxyalkyl, _C2-6 alkoxyalkyl, halogen, -CN, -NO, _-NO2 , -C(O) ^R2a , -N( ^R2a )C(O) ^R2b , -N( ^R2a )( ^R2b ), ^-OR2a , or a 5- to 6-membered heteroaryl ring having one or two heteroatoms, each independently of N, O, or S; ^R2a and R ^2b are each independently hydrogen or _C1-6 alkyl; ^R3 is hydrogen, _C1-6 alkyl, halogen, -CN or _-NO2 ; and ^R4 is hydrogen, F or Cl.

In some embodiments, the compound of formula (I), (I-1), (Ia), (Ib), (Ic), (IIa), (IIc), (IIc-3), (IIc-4), (IIc-5), (IIc-6), (IIc-7), or (IIc-8), or a pharmaceutically acceptable salt thereof, is a compound wherein ^R1 is hydrogen; ^R2 is hydrogen, _C1-6 alkyl, _C2-6 alkenyl, _C2-6 alkynyl, _C1-6 hydroxyalkyl, _C2-6 alkoxyalkyl, halogen, -CN, -NO, _-NO2 , -C(O) ^R2a , -N( ^R2a )C(O) ^R2b , -N( ^R2a )( ^R2b ), ^-OR2a , or a 5- to 6-membered heteroaryl ring having one or two heteroatoms, each independently of N, O, or S; ^R2a and ^R2b are each independently hydrogen or C _1-6 alkyl; ^R3 is hydrogen, _C1-6 alkyl, halogen, -CN or _-NO2 ; and ^R4 is hydrogen.

In some embodiments, the compound of formula (I), (I-1), (Ia), (Ib), (Ic), (IIa), (IIc), (IIc-3), (IIc-4), (IIc-5), (IIc-6), (IIc-7), or (IIc-8), or a pharmaceutically acceptable salt thereof, is a compound wherein ^R1 is hydrogen; ^R2 is hydrogen, _C1-3 alkyl, _C2-3 alkenyl, _C2-6 alkynyl, _C1-3 hydroxyalkyl, _C2-3 alkoxyalkyl, halogen, -CN, -NO, _-NO2 , -C(O) ^R2a , -N( ^R2a )C(O) ^R2b , -N( ^R2a )( ^R2b ), ^-OR2a , or a 5- to 6-membered heteroaryl ring having one or two heteroatoms, each independently of N, O, or S; ^R2a and ^R2b are each independently hydrogen or C _1-3 alkyl; ^R3 is hydrogen, _C1-3 alkyl, halogen, -CN or _-NO2 ; and ^R4 is hydrogen.

In some embodiments, the compound of formula (I), (I-1), (Ia), (Ib), (Ic), (IIa), (IIc), (IIc-3), (IIc-4), (IIc-5), (IIc-6), (IIc-7), or (IIc-8), or a pharmaceutically acceptable salt thereof, is a compound wherein ^R1 is hydrogen; ^R2 is hydrogen, _C1-3 alkyl, _C2-3 alkenyl, _C2-6 alkynyl, _C1-3 hydroxyalkyl, _{C2-3 alkoxyalkyl} , halogen, -CN, -NO, -NO2, -C(O) ^R2a , -N( ^R2a ) ^C (O) ^R2b , -N(R2a)( ^R2b ), ^-OR2a , or heteroaryl; ^R2a and ^R2b are each independently hydrogen or _C1-3 alkyl; ^R3 is hydrogen; R ⁴ is hydrogen; and the heteroaryl group is a 5- or 6-membered ring having one or two heteroatoms that are each independently N, O or S.

In some embodiments, a compound of formula (I), (I-1), (Ia), (Ia-1), (Ib), (IIa), or (IIa-1) or a pharmaceutically acceptable salt thereof is a compound wherein ^R5 is a _C1-6 alkyl, _C2-6 alkenyl, _C2-6 alkynyl, _C1-6 hydroxyalkyl, _C2-6 alkoxyalkyl, _C1-6 haloalkyl, _C3-10 cycloalkyl, _C1-6 alkyl _{-C3-10 cycloalkyl, C6-12 aryl, C1-6 alkyl-C6-12 aryl, C1-6 alkyl-(heterocyclic alkyl) or C1-6 alkyl- ( heteroaryl ) ,} wherein the alkyl group is optionally substituted by ^R5a ; ^R5a is –OSi( ^R5a1 )( ^R5a2 )( ^R5a3 ); ^R5a1 , ^R5a2 , and ^R5a3 are each independently C1-6 alkyl-(heterocyclic alkyl) or C1-6 alkyl-(heteroaryl). _1-4 alkyl; and the heterocyclic alkyl is a 5- to 8-membered ring having one or two heteroatoms, each independently of N, O or S; and the heteroaryl is a 5- to 6-membered ring having one or two heteroatoms, each independently of N, O or S. In some embodiments, a compound of formula (I), (I-1), (Ia), (Ia-1), (Ib), (IIa), or (IIa-1) or a pharmaceutically acceptable salt thereof is a compound wherein ^R5 is a _C1-6 alkyl, _C2-6 alkynyl, _C2-6 alkoxyalkyl, _C1-6 haloalkyl, _C3-10 cycloalkyl, _C1-6 alkyl- _C3-10 cycloalkyl, _C6-12 aryl, _C1-6 alkyl- _C6-12 aryl, or _C1-6 alkyl-(heterocyclic alkyl), wherein the alkyl group is optionally substituted by ^R5a ; ^R5a is –OSi( ^R5a1 )( ^R5a2 )( ^R5a3 ); ^R5a1 , ^R5a2 , and ^R5a3 are each independently C1-4 alkyl, wherein ^R5a1 and R5a3 are _C1-4 alkyl groups. ^5a2 is different; and the heterocyclic alkyl group is a 5- or 6-membered ring having one or two heteroatoms, each of which is independently N or O. In some embodiments, a compound of formula (I), (I-1), (Ia), (Ia-1), (Ib), (IIa), or (IIa-1) or a pharmaceutically acceptable salt thereof is a compound wherein ^R5 is a _C1-6 alkyl, _C2-6 alkynyl, _C2-3 alkoxyalkyl, _C1-3 haloalkyl, _C3-8 cycloalkyl, _C1-3 alkyl- _C3-8 cycloalkyl, phenyl, _C1-3 alkyl-phenyl, or _C1-3 alkyl-(heterocyclic alkyl), wherein the alkyl group is optionally substituted with ^R5a ; ^R5a is –OSi( ^R5a1 )( ^R5a2 )( ^R5a3 ); ^R5a1 , ^R5a2 , and ^R5a3 are each independently Me or tBu, wherein ^R5a1 and ^R5a2 are different; and the heterocyclic alkyl group is a 6-membered ring having one heteroatom N or O. In some embodiments, the compound of formula (I), (I-1), (Ia), (Ia-1), (Ib), (IIa) or (IIa-1) or a pharmaceutically acceptable salt thereof is a compound, wherein ^R5 is Me, Et _, nPr, _nBu , _-CH2CMe3 , _-CH2C≡CMe , _{-CH2CH2C≡CH} , _-CH2CH2OMe , _-CH2CH2OSi (Me _{) 2} (tBu ₎ , _CF3 , _{-CH2CF2H , -CH2CF3 ,}

In some embodiments, a compound of formula (I), (I-1), (Ia), (Ia-1), (Ib), (IIa), or (IIa-1), or a pharmaceutically acceptable salt thereof, is a compound wherein ^R5 is a _C1-6 alkyl, C2-6 alkenyl, _C2-6 alkynyl, C1-6 hydroxyalkyl, _C2-6 alkoxyalkyl, _C1-6 haloalkyl, C1-6 alkyl-C3-10 cycloalkyl, C6-12 aryl, _C1-6 alkyl- _C6-12 aryl, _C1-6 alkyl-(heterocyclic alkyl), or _C1-6 alkyl-(heteroaryl), wherein the alkyl group is optionally substituted with R5a; R5a is –OSi(R5a1)( _R5a2 )(R5a3); R5a1, R5a2, and _{R5a3 are each independently C1-6 alkyl-(heterocyclic alkyl), C2-6 alkyl-C3-10 cycloalkyl} , _C6-12 aryl, _C1-6 alkyl-(heterocyclic alkyl), or C1-6 alkyl-(heteroaryl), wherein the alkyl group is optionally substituted with ^R5a ; ^R5a is –OSi( ^R5a1 )( ^R5a2 )( ^R5a3 ); ^R5a1 , ^R5a2 , and ^R5a3 are each independently C1-6 alkyl-(heterocyclic alkyl), C2-6 alkyl-C3-10 ... _1-4 alkyl; the heterocyclic alkyl is a 5- to 8-membered ring having one or two heteroatoms, each independently of N, O or S; and the heteroaryl is a 5- to 6-membered ring having one or two heteroatoms, each independently of N, O or S. In some embodiments, a compound of formula (I), (I-1), (Ia), (Ia-1), (Ib), (IIa), or (IIa-1) or a pharmaceutically acceptable salt thereof is a compound wherein ^R5 is a _C1-6 alkyl, _C2-6 alkynyl, _C2-6 alkoxyalkyl, _C1-6 alkyl- _C3-10 cycloalkyl, _C6-12 aryl, _C1-6 alkyl- _C6-12 aryl, or _C1-6 alkyl-(heterocyclic alkyl), wherein the alkyl group is optionally substituted by ^R5a ; ^R5a is –OSi( ^R5a1 )( ^R5a2 )( ^R5a3 ); ^R5a1 , ^R5a2 , and ^R5a3 are each independently C1-4 alkyl, wherein ^R5a1 and R5a3 are _C1-4 alkyl groups. ^5a2 is different; and the heterocyclic alkyl group is a 5- or 6-membered ring having one or two heteroatoms, each of which is independently N or O. In some embodiments, a compound of formula (I), (I-1), (Ia), (Ia-1), (Ib), (IIa), or (IIa-1) or a pharmaceutically acceptable salt thereof is a compound wherein ^R5 is a _C1-6 alkyl, _C2-6 alkynyl, _C2-3 alkoxyalkyl, _C1-3 alkyl- _C3-8 cycloalkyl, phenyl, _C1-3 alkyl-phenyl, or _C1-3 alkyl-(heterocyclic alkyl), wherein the alkyl group is optionally substituted with ^R5a ; ^R5a is –OSi( ^R5a1 )( ^R5a2 )( ^R5a3 ); ^R5a1 , ^R5a2 , and ^R5a3 are each independently Me or tBu, wherein ^R5a1 and ^R5a2 are different; and the heterocyclic alkyl group is a 6-membered ring having one heteroatom N or O.

In some embodiments, the compound of formula (I), (I-1), (Ia), (Ia-1), (Ib), (IIa), or (IIa-1), or a pharmaceutically acceptable salt thereof, is a compound wherein ^R5 is Me, Et, _nPr , _nBu , _-CH2CMe3 , _-CH2C≡CMe , _{-CH2CH2C≡CH} , _{-CH2CH2OMe , -CH2CH2OSi} ( _Me ) ₂ (tBu),

In some embodiments, a compound of formula (I), (I-1), (Ia), (Ia-1), (Ib), (IIa), or (IIa-1), or a pharmaceutically acceptable salt thereof, is a compound, wherein ^R5a1 , ^R5a2 , and ^R5a3 are each independently _C1-4 alkyl. In some embodiments, a compound of formula (I), (I-1), (Ia), (Ia-1), or (Ib), or a pharmaceutically acceptable salt thereof, is a compound, wherein ^R5a1 and ^R5a2 are each Me or tBu. In some embodiments, a compound of formula (I), (I-1), (Ia), (Ia-1), (Ib), (IIa), or (IIa-1), or a pharmaceutically acceptable salt thereof, is a compound, wherein ^R5a1 and ^R5a2 are different.

In some embodiments, the compound of formula (I) or (I-1) or a pharmaceutically acceptable salt thereof is a compound, wherein ^R6 is a phenyl, naphthyl, thiophene, thiazolyl, pyridyl, pyrazinyl, pyrimidinyl or dibenzofuranyl, each optionally substituted with one or two ^R6a .

In some embodiments, the compound of formula (I) or (I-1) or a pharmaceutically acceptable salt thereof is a compound, wherein ^R6 is a phenyl group optionally substituted with one or two ^R6a , or a 5- to 6-membered heteroaryl ring having one to three heteroatoms, each independently N, O, or S. In some embodiments, the compound of formula (I) or (I-1) or a pharmaceutically acceptable salt thereof is a compound, wherein ^R6 is a phenyl, thiophene, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, pyrrole, pyrazolyl, pyridinyl, or pyrimidinyl group optionally substituted with one or two ^R6a . In some embodiments, the compound of formula (I) or (I-1) or a pharmaceutically acceptable salt thereof is a compound, wherein ^R6 is a phenyl, thiophene, or pyridinyl group optionally substituted with one or two ^R6a . In some embodiments, the compound of formula (I) or (I-1) or a pharmaceutically acceptable salt thereof is a compound, wherein ^R6 is a phenyl group optionally substituted with one or two R6a.

In some embodiments, the compound of formula (I) or (I-1) or a pharmaceutically acceptable salt thereof is a compound, wherein ^R6 is

In some embodiments, the compound of formula (I) or (I-1) or a pharmaceutically acceptable salt thereof is a compound, wherein ^R6 is

In some embodiments, a compound of formula (I), (IIa), (IIa-1), (IIc), (IIc-1), (IIc-2), (IIc-3), (IIc-4), (IIc-5), (IIc-6), (IIc-7), or (IIc-8), or a pharmaceutically acceptable salt thereof, is a compound wherein ^R7 is hydrogen, Me, _Et , OMe, _-CH₂OH , _-CH₂OMe , _-CH₂NMe₂ , Cl, _CHF₂ , OH, _NH₂ , SMe, or

In some embodiments, the compound of formula (I), (IIa), (IIa-1), (IIc), (IIc-1), (IIc-2), (IIc-3), (IIc-4), (IIc-5), (IIc-6), (IIc-7), or (IIc-8), or a pharmaceutically acceptable salt thereof, is a compound wherein ^R7 is hydrogen, Me, _-CH2OMe , _CHF2 , or _NH2 .

In some embodiments, the compound of formula (I), (IIa), (IIa-1), (IIc), (IIc-1), (IIc-2), (IIc-3), (IIc-4), (IIc-5), (IIc-6), (IIc-7), or (IIc-8), or a pharmaceutically acceptable salt thereof, is a compound wherein ^R7 is hydrogen, Me, Et, _OMe , _-CH₂NMe₂ , Cl, OH, _NH₂ , SMe, or

In some embodiments, a compound of formula (I), (IIa), (IIa-1), (IIc), (IIc-1), (IIc-2), (IIc-3), (IIc-4), (IIc-5), (IIc-6), (IIc-7), or (IIc-8), or a pharmaceutically acceptable salt thereof, is a compound, wherein ^R7 is hydrogen or Me. In some embodiments, a compound of formula (I), (IIa), (IIa-1), (IIc), (IIc-1), or (IIc-2), or a pharmaceutically acceptable salt thereof, is a compound, wherein ^R7 is hydrogen. In some embodiments, a compound of formula (I), (IIa), (IIa-1), (IIc), (IIc-1), (IIc-2), (IIc-3), (IIc-4), (IIc-5), (IIc-6), (IIc-7), or (IIc-8), or a pharmaceutically acceptable salt thereof, is a compound, wherein ^R7 is Me.

In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof is a compound having the structure of formula (I-1):

Or its pharmaceutically acceptable salt.

In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof is a compound having the structure of formula (IIa):

Where n is 0, 1, 2, or 3. In some embodiments, the compound of formula (IIa) or a pharmaceutically acceptable salt thereof is a compound, where n is 0. In some embodiments, the compound of formula (IIa) or a pharmaceutically acceptable salt thereof is a compound, where n is 1. In some embodiments, the compound of formula (IIa) or a pharmaceutically acceptable salt thereof is a compound, where n is 2. In some embodiments, the compound of formula (IIa) or a pharmaceutically acceptable salt thereof is a compound, where n is 3.

In some embodiments, the compound of formula (I) or (I-1) or a pharmaceutically acceptable salt thereof is a compound having the structure of formula (Ia):

Where n is 0, 1, 2, or 3. In some embodiments, the compound of formula (Ia) or a pharmaceutically acceptable salt thereof is a compound, where n is 0. In some embodiments, the compound of formula (Ia) or a pharmaceutically acceptable salt thereof is a compound, where n is 1. In some embodiments, the compound of formula (Ia) or a pharmaceutically acceptable salt thereof is a compound, where n is 2. In some embodiments, the compound of formula (Ia) or a pharmaceutically acceptable salt thereof is a compound, where n is 3.

In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof is a compound having the structure of formula (IIa-1):

In some embodiments, the compound of formula (I), (I-1), or (Ia), or a pharmaceutically acceptable salt thereof, is a compound having the structure of formula (Ia-1):

In some embodiments, the compound of formula (I), (I-1), (Ia), (Ia-1), or (Ic), or a pharmaceutically acceptable salt thereof, is a compound wherein each R ^6a is independently a hydrogen atom, optionally substituted _C1 - _C6 alkyl (e.g., methyl and ethyl), optionally substituted _C2 - _C6 alkenyl, optionally substituted _C2 - _C6 alkynyl (e.g., 1-propynyl; halogen atoms, hydroxyl and methoxy groups are exemplified as substituents for these alkyl, alkenyl and alkynyl groups), optionally substituted _C1 - _C6 alkoxy (halogen atoms are exemplified as substituents), _C3 -C ₆ -cycloalkyl (e.g., cyclopropyl and cyclohexyl), hydroxyl, halogen atom, nitro, cyano, amino, acetylamino, methoxycarbonyl, carboxyl, carbamoyl, formyl, 5- or 6-membered saturated cyclic amino (e.g., morpholino, pyrrolidinyl, piperidinyl), 5- or 6-membered heteroaryl (e.g., furanyl, thiophene, imidazolyl, pyrrolidinyl, pyrazolyl, methylpyrazolyl, pyridinyl, pyrimidinyl, etc.), phenyl, substituted phenyl (examples of substituents include _C1 - _C6 alkyl, _C3 - _C6 cycloalkyl, halogen atom, methoxy, trifluoromethyl, acetylamino, etc.), etc.

In some embodiments, the compound of formula (I), (I-1), (Ia), (Ia-1), (Ic), (IIa), (IIa-1), (IIc), (IIc-1), (IIc-2), (IIc-3), (IIc-4), (IIc-5), (IIc-6), (IIc-7), or (IIc-8) or a pharmaceutically acceptable salt thereof is a compound, wherein each R ^6a is independently _{a C1-6} alkyl, _C2-6 alkynyl, _C1-6 hydroxyalkyl, _C1-6 alkoxy, _C2-6 alkoxyalkyl, _halogen , _C1-6 haloalkyl, C1-6 haloalkoxy, –CN, -NO2, -C(O) ^R6b , -C(O) ^OR6b , -C(O)N( ^R6b )( ^R6c ), -N( ^R6b )( ^R6c ), ^-OR6b , C _3-10 cycloalkyl, _C6-12 aryl, heterocycloalkyl or heteroaryl, wherein each of the cycloalkyl, aryl, heterocycloalkyl or heteroaryl is optionally substituted with one to three ^R6e , and the alkyl group is optionally substituted with ^R6f .

In some embodiments, the compound of formula (I), (I-1), (Ia), (Ia-1), (Ic), (IIa), (IIa-1), (IIc), (IIc-1), (IIc-2), (IIc-3), (IIc-4), (IIc-5), (IIc-6), (IIc-7), or (IIc-8) or a pharmaceutically acceptable salt thereof is a compound, wherein each R ^6a is independently _{a C1-6} alkyl, _C2-6 alkynyl, _C1-6 hydroxyalkyl, _C1-6 alkoxy, _C2-6 alkoxyalkyl, _halogen , _C1-6 haloalkyl, C1-6 haloalkoxy, –CN, -NO2, -C(O) ^R6b , -C(O) ^OR6b , -C(O)N( ^R6b )( ^R6c ), -N( ^R6b )( ^R6c ), ^-OR6b , C _3-10 cycloalkyl, _C6-12 aryl, heterocycloalkyl, or heteroaryl, wherein each of the cycloalkyl, aryl, heterocycloalkyl, or heteroaryl is optionally substituted with one to three ^R6e , and the alkyl group is optionally substituted with ^R6f ; each ^R6b and ^R6c is independently hydrogen or _C1-6 alkyl; each ^R6e is independently _C1-6 alkyl, _C2-6 alkenyl, _C2-6 alkynyl, _C1-6 hydroxyalkyl, _C1-6 alkoxy, _C2-6 alkoxyalkyl, halogen, _C1-6 haloalkyl, -C(O) ^OR6e1 , -OC(O) ^R6e1 , -C(O)N( ^R6e1 )( ^R6e2 ), -N( ^R6e1 )C(O) ^R6e2 , ^-OR6e1 , -S(O) _2N ( ^R6e1) (R ^6e2 ), -N(R ^6e1 )S(O) ₂ (R ^6e2 ); each R ^6e1 and R ^6e2 is independently hydrogen or C _1-6 alkyl; R ^6f is –OSi(R ^6f1 )(R ^6f2 )(R ^6f3 ); and R ^6f1 , R ^6f2 and R ^6f3 are each independently C _1-6 alkyl. In some embodiments, the compound of formula (I), (I-1), (Ia), (Ia-1), (Ic), (IIa), (IIa-1), (IIc), (IIc-1), (IIc-2), (IIc-3), (IIc-4), (IIc-5), (IIc-6), (IIc-7), or (IIc-8) or a pharmaceutically acceptable salt thereof is a compound wherein each R ^6a is independently _{a C1-3} alkyl, _C2-3 alkynyl, _C1-3 hydroxyalkyl, _C1-3 alkoxy, _C2-3 alkoxyalkyl, halogen, _C1-3 haloalkyl, C1-3 haloalkoxy, –CN, _-NO2 , -C(O) ^R6b , -C(O) ^OR6b , -C(O)N( ^R6b )( ^R6c ), -N( ^R6b )( ^R6c ), ^-OR6b , C _3-8 cycloalkyl, phenyl, 5- to 6-membered heterocyclic alkyl ring having one or two heteroatoms, each independently N or O, or 5- to 6-membered heteroaryl ring having one or two heteroatoms, each independently N, O, or S, wherein the cycloalkyl, phenyl, heterocyclic alkyl, or heteroaryl group is optionally substituted with one or two R ^6e , and the alkyl group is optionally substituted with R ^6f ; each R ^6b and R ^6c is independently hydrogen or _C1-3 alkyl; each R ^6e is independently _C1-6 alkyl, _C1-6 hydroxyalkyl, _C1-6 alkoxy, _C2-6 alkoxyalkyl, halogen, _C1-6 haloalkyl, -C(O)OR ^6e1 , -OC(O)R ^6e1 , -N(R ^6e1 )C(O)R ^6e2 , -OR ^6e1 ; each R ^6e1 and R ^6e2 is independently hydrogen or _C1-6 alkyl; ^R6f is –OSi( ^R6f1 )( ^R6f2 )( ^R6f3 ); and ^R6f1 , ^R6f2 and ^R6f3 are each independently Me or tBu.

In some embodiments, the compound of formula (I), (I-1), (Ia), (Ia-1), (Ic), (IIa), (IIa-1), (IIc), (IIc-1), (IIc-2), (IIc-3), (IIc-4), (IIc-5), (IIc-6), (IIc-7), or (IIc-8) or a pharmaceutically acceptable salt thereof is a compound, wherein each R ^6b and R ^6c is independently hydrogen, a _C1-6 alkyl, a _C1-6 hydroxyalkyl, a _C2-6 alkoxyalkyl, a _C1-6 haloalkyl, or a _C3-10 cycloalkyl. In some embodiments, the compound of formula (I), (I-1), (Ia), (Ia-1), (Ic), (IIa), (IIa-1), (IIc), (IIc-1), (IIc-2), (IIc-3), (IIc-4), (IIc-5), (IIc-6), (IIc-7), or (IIc-8) or a pharmaceutically acceptable salt thereof is a compound, wherein each R ^6b and R ^6c is independently hydrogen, a _C1-6 alkyl, or a _C1-6 haloalkyl. In some embodiments, the compound of formula (I), (I-1), (Ia), (Ia-1), (Ic), (IIa), (IIa-1), (IIc), (IIc-1), (IIc-2), (IIc-3), (IIc-4), (IIc-5), (IIc-6), (IIc-7), or (IIc-8) or a pharmaceutically acceptable salt thereof is a compound, wherein each R ^6b and R ^6c is independently hydrogen or a _C1-6 alkyl group. In some embodiments, a compound of formula (I), (I-1), (Ia), (Ia-1), (Ic), (IIa), (IIa-1), (IIc), (IIc-1), (IIc-2), (IIc-3), (IIc-4), (IIc-5), (IIc-6), (IIc-7), or (IIc-8), or a pharmaceutically acceptable salt thereof, is a compound wherein each R ^6b and R ^6c is independently hydrogen or a _C1-3 alkyl group. In some embodiments, a compound of formula (I), (I-1), (Ia), (Ia-1), (Ic), (IIa), (IIa-1), (IIc), (IIc-1), (IIc-2), (IIc-3), (IIc-4), (IIc-5), (IIc-6), (IIc-7), or (IIc-8), or a pharmaceutically acceptable salt thereof, is a compound wherein each R ^6b and R ^6c is independently hydrogen or Me.

In some embodiments, the compound of formula (I), (I-1), (Ia), (Ia-1), (Ic), (IIa), (IIa-1), (IIc), (IIc-1), (IIc-2), (IIc-3), (IIc-4), (IIc-5), (IIc-6), (IIc-7), or (IIc-8) or a pharmaceutically acceptable salt thereof is a compound, wherein each R ^6b , R ^6c , and R ^6d is independently hydrogen, a _C1-6 alkyl, a _C1-6 hydroxyalkyl, a _C2-6 alkoxyalkyl, a _C1-6 haloalkyl, or a _C3-10 cycloalkyl. In some embodiments, the compound of formula (I), (I-1), (Ia), (Ia-1), (Ic), (IIa), (IIa-1), (IIc), (IIc-1), (IIc-2), (IIc-3), (IIc-4), (IIc-5), (IIc-6), (IIc-7), or (IIc-8) or a pharmaceutically acceptable salt thereof is a compound, wherein each R ^6b , R ^6c , and R ^6d is independently hydrogen, a _C1-6 alkyl, or a _C1-6 haloalkyl. In some embodiments, the compound of formula (I), (I-1), (Ia), (Ia-1), (Ic), (IIa), (IIa-1), (IIc), (IIc-1), (IIc-2), (IIc-3), (IIc-4), (IIc-5), (IIc-6), (IIc-7), or (IIc-8) or a pharmaceutically acceptable salt thereof is a compound, wherein each R ^6b , R ^6c , and R ^6d is independently hydrogen or a _C1-6 alkyl group. In some embodiments, the compound of formula (I), (I-1), (Ia), (Ia-1), (Ic), (IIa), (IIa-1), (IIc), (IIc-1), (IIc-2), (IIc-3), (IIc-4), (IIc-5), (IIc-6), (IIc-7), or (IIc-8) or a pharmaceutically acceptable salt thereof is a compound, wherein each R ^6b , R ^6c , and R ^6d is independently hydrogen or a _C1-3 alkyl group. In some embodiments, the compound of formula (I), (I-1), (Ia), (Ia-1), (Ic), (IIa), (IIa-1), (IIc), (IIc-1), (IIc-2), (IIc-3), (IIc-4), (IIc-5), (IIc-6), (IIc-7), or (IIc-8) or a pharmaceutically acceptable salt thereof is a compound, wherein each R ^6b , R ^6c , and R ^6d is independently hydrogen or Me.

In some embodiments, a compound of formula (I), (I-1), (Ia), (Ia-1), (Ib), (Ic), (IIa), (IIa-1), (IIc), (IIc-1), (IIc-2), (IIc-3), (IIc-4), (IIc-5), (IIc-6), (IIc-7), or (IIc-8) or a pharmaceutically acceptable salt thereof is a compound wherein each R ^6e is independently a hydrogen atom, a _C1 - _C6 alkyl (e.g., methyl, ethyl, and tert-butyl), a _C2 - _C6 alkenyl, a _{C2 - C6} alkoxy (e.g., methoxy), _{a C3} - _C6 cycloalkyl, a hydroxyl group, a halogen atom, a nitro group, a cyano group, a carbamoyl group, a formyl group, an acetylamino group, etc.

In some embodiments, the compound of formula (I), (I-1), (Ia), (Ia-1), (Ib), (Ic), (IIa), (IIa-1), (IIc), (IIc-1), (IIc-2), (IIc-3), (IIc-4), (IIc-5), (IIc-6), (IIc-7), or (IIc-8), or a pharmaceutically acceptable salt thereof, is a compound wherein each R ^6e is independently a _C1-6 alkyl, _C2-6 alkenyl, _C2-6 alkynyl, _C1-6 hydroxyalkyl, _C1-6 alkoxy, _C2-6 alkoxyalkyl, halogen, _C1-6 haloalkyl, -C(O)OR ^6e1 , -OC(O)R ^6e1 , -C(O)N(R ^6e1 )(R ^6e2 ), -N(R ^6e1 )C(O)R ^6e2 , -OR ^6e1 -S(O) _2N ( ^R6e1 )( ^R6e2 ), -N( ^R6e1 )S(O) ₂ ( ^R6e2 ); and each ^R6e1 and ^R6e2 is independently hydrogen or _C1-6 alkyl. In some embodiments, the compound of formula (I), (I-1), (Ia), (Ia-1), (Ib), (Ic), (IIa), (IIa-1), (IIc), (IIc-1), (IIc-2), (IIc-3), (IIc-4), (IIc-5), (IIc-6), (IIc-7), or (IIc-8), or a pharmaceutically acceptable salt thereof, is a compound wherein each R ^6e is independently a _C1-6 alkyl, _C1-6 hydroxyalkyl, _C1-6 alkoxy, _C2-6 alkoxyalkyl, halogen, _C1-6 haloalkyl, -C(O)OR ^6e1 , -OC(O)R ^6e1 , -N(R ^6e1 )C(O)R ^6e2 , -OR ^6e1 ; and each R ^6e1 and R ^6e2 is independently hydrogen or a _C1-6 alkyl. In some embodiments, a compound of formula (I), (I-1), (Ia), (Ia-1), (Ib), (Ic), (IIa), (IIa-1), (IIc), (IIc-1), (IIc-2), (IIc-3), (IIc-4), (IIc-5), (IIc-6), (IIc-7), or (IIc-8) or a pharmaceutically acceptable salt thereof is a compound wherein each R ^6e is independently a _C1-6 alkyl, _C1-3 alkoxy, halogen, _C1-6 haloalkyl, -N(R ^6e1 )C(O)R ^6e2 , or -OR ^6e1 ; and each R ^6e1 and R ^6e2 is independently hydrogen or a _C1-3 alkyl.

In some embodiments, the compound of formula (I), (I-1), (Ia), (Ia-1), (Ib), (Ic), (IIa), (IIa-1), (IIc), (IIc-1), (IIc-2), (IIc-3), (IIc-4), (IIc-5), (IIc-6), (IIc-7), or (IIc-8) or a pharmaceutically acceptable salt thereof is a compound, wherein each R ⁶ⁿ is a _C1-6 alkyl, _C1-6 hydroxyalkyl, -C(O)OR ⁶ⁿ¹ , -OC(O)R ⁶ⁿ¹ , -C(O)N(R ⁶ⁿ¹ )(R ⁶ⁿ² ), -N(R ⁶ⁿ¹ )C(O)R ⁶ⁿ² , -OC(O)N(R ⁶ⁿ¹ )(R ⁶ⁿ² ), -N(R ⁶ⁿ¹ )C(O)OR ⁶ⁿ² , =O, or –OH; wherein each R ⁶ⁿ¹ and R ⁶ⁿ² are independently hydrogen, _C1-6 alkyl, or _C1-6 hydroxyalkyl. In some embodiments, the compound of formula (I), (I-1), (Ia), (Ia-1), (Ib), (Ic), (IIa), (IIa-1), (IIc), (IIc-1), (IIc-2), (IIc-3), (IIc-4), (IIc-5), (IIc-6), (IIc-7), or (IIc-8) or a pharmaceutically acceptable salt thereof is a compound, wherein each R ⁶ⁿ is a _C1-6 alkyl, -C(O)OR ⁶ⁿ¹ or -OC(O)R ⁶ⁿ¹ , -C(O)N(R ⁶ⁿ¹ )(R ⁶ⁿ² ), -N(R ⁶ⁿ¹ )C(O)R ⁶ⁿ² , -OC(O)N(R ⁶ⁿ¹ )(R ⁶ⁿ² ), -N(R ⁶ⁿ¹ )C(O)OR ⁶ⁿ² , =O, or –OH; wherein each R ⁶ⁿ¹ and R ⁶ⁿ² is independently hydrogen or _C1-6 alkyl. In some embodiments, the compound of formula (I), (I-1), (Ia), (Ia-1), (Ib), (Ic), (IIa), (IIa-1), (IIc), (IIc-1), (IIc-2), (IIc-3), (IIc-4), (IIc-5), (IIc-6), (IIc-7), or (IIc-8) or a pharmaceutically acceptable salt thereof is a compound wherein each R ⁶ⁿ is independently Me or _CO2 tBu.

In some embodiments, the compound of formula (I), (I-1), (Ia), (Ia-1), (Ib), (Ic), (IIa), (IIa-1), (IIc), (IIc-1), (IIc-2), (IIc-3), (IIc-4), (IIc-5), (IIc-6), (IIc-7), or (IIc-8) or a pharmaceutically acceptable salt thereof is a compound wherein each R ^6h is independently a _C1-6 alkyl, _C1-6 hydroxyalkyl, _C1-6 aminoalkyl, _C1-6 alkoxy, _C2-6 alkoxyalkyl, halogen, _C1-6 haloalkyl, -CN, -C(O)R ^6h1 , -C(O)OR ^6h1 , -OC(O)R ^6h1 , -C(O)N(R ^6h1 )(R ^6h2 ), -N(R ^6h1 )C(O)R ^6h2 -OC(O)N( ^R6h1 )( ^R6h2 ), -N( ^R6h1 )C(O) ^OR6h2 , -N( ^{R6h1)(R6h2 )} , =O, –OH, -SR6h1, -S(O) ^R6h1 , -S(O) ^2R6h1 , -S(O) _{2N (R6h1)(R6h2), -N(R6h1)S(O)2} ^{( R6h2 )} _, ^C3-10 cycloalkyl, _C1-6 alkyl- ^C3-10 cycloalkyl, _{heterocycloalkyl} or _C1-6 alkyl-(heterocycloalkyl); wherein each ^R6h1 and ^R6h2 is independently hydrogen, _{C1-6 alkyl, C1-6 hydroxyalkyl} , C1-6 aminoalkyl, C2-6 alkoxyalkyl, _C3-10 cycloalkyl, C3-10 cycloalkyl, _C1-6 aminoalkyl, C2-6 alkoxyalkyl, _C3-10 cycloalkyl, C1 ... _1-6 haloalkyl, _C3-10 cycloalkyl or _C1-6 alkyl- _C3-10 cycloalkyl. In some embodiments, a compound of formula (I), (I-1), (Ia), (Ia-1), (Ib), (Ic), (IIa), (IIa-1), (IIc), (IIc-1), (IIc-2), (IIc-3), (IIc-4), (IIc-5), (IIc-6), (IIc-7), or (IIc-8) or a pharmaceutically acceptable salt thereof is a compound wherein each R ^6h is independently a _C1-6 alkyl, _C1-6 hydroxyalkyl, _C1-6 aminoalkyl, _C1-6 alkoxy, _C1-6 haloalkyl, -C(O)R ^6h1 , -C(O)OR ^6h1 , -N(R ^6h1 )(R ^6h2 ), =O, or heterocyclic alkyl; wherein each R ^6h1 and R ^6h2 is independently hydrogen, a _C1-6 alkyl, or a _C1-6 hydroxyalkyl. In some embodiments, the compound of formula (I), (I-1), (Ia), (Ia-1), (Ib), (Ic), (IIa), (IIa-1), (IIc), (IIc-1), (IIc-2), (IIc-3), (IIc-4), (IIc-5), (IIc-6), (IIc-7), or (IIc-8) or a pharmaceutically acceptable salt thereof is a compound, wherein each R ^6h is independently Me, -CH ₂ OH, -CH ₂ NHMe, OMe, NH ₂ , CF ₃ , CN, -(CO)Me, -(CO)tBu, -(CO)-CH ₂ OH, CO ₂ Me, CO ₂ tBu, =O, or

In some embodiments, the compound of formula (I), (I-1), (Ia), (Ia-1), (Ib), (Ic), (IIa), (IIa-1), (IIc), (IIc-1), (IIc-2), (IIc-3), (IIc-4), (IIc-5), (IIc-6), (IIc-7), or (IIc-8) or a pharmaceutically acceptable salt thereof is a compound wherein each R ^6m is independently a halogen, a _C1-6 haloalkyl group, -CN, -C(O)R ^6m1 , -C(O)OR ^6m1 , -OC(O)R ^6m1 , -C(O)N(R ^6m1 )(R ^6m2 ), -N(R ^6m3 )C(O)R ^6m2 , -OC(O)N(R ^6m1 )(R ^6m2 ), -N(R ^6m1 )C(O)OR ^6m2 , -C(＝NR ^6m3 )N(R ^6m1 )(R ^6m2 ), -N(R ^6m1 )(R ^6m2 ), =O, –OH, -SR ^6m1 , -S(O)R ^6m1 , -S(O)(NR ^6m1 )(R ^6m2 ), -S(O) ₂ R ^6m1 or -S(O) ₂ N(R ^6m1 )(R ^6m2 ); wherein each R ^6m1 and R ^6m2 is independently hydrogen, C _1-6 alkyl, C _1-6 hydroxyalkyl, C _1-6 haloalkyl, C _3-10 cycloalkyl or heterocycloalkyl. In some embodiments, a compound of formula (I), (I-1), (Ia), (Ia-1), (Ib), (Ic), (IIa), (IIa-1), (IIc), (IIc-1), (IIc-2), (IIc-3), (IIc-4), (IIc-5), (IIc-6), (IIc-7), or (IIc-8) or a pharmaceutically acceptable salt thereof is a compound wherein each R ^6m is independently a _C1-6 haloalkyl, -CN, -C(O)R ^6m1 , -C(O)OR ^6m1 , -C(O)N(R ^6m1 )(R ^6m2 ), -N(R ^6m1 )(R ^6m2 ), =O, –OH, or -S(O) _2R ^6m1 ; wherein each R ^6m1 and R ^6m2 is independently hydrogen, a _C1-6 alkyl, or a heterocyclic alkyl. In some embodiments, the compound of formula (I), (I-1), (Ia), (Ia-1), (Ib), (Ic), (IIa), (IIa-1), (IIc), (IIc-1), (IIc-2), (IIc-3), (IIc-4), (IIc-5), (IIc-6), (IIc-7), or (IIc-8), or a pharmaceutically acceptable salt thereof, is a compound wherein each R ^6m is independently OH, _CF3 , CN, _CO2H , _CONH2 , _NMe2 , _SO2Me , or

In some embodiments, a compound of formula (I), (I-1), (Ia), (Ia-1), (Ib), (Ic), (IIa), (IIa-1), (IIc), (IIc-1), (IIc-2), (IIc-3), (IIc-4), (IIc-5), (IIc-6), (IIc-7), or (IIc-8) or a pharmaceutically acceptable salt thereof is a compound, wherein each R ^6e is independently Me, Et, iPr, tBu, -CH ₂ OH, -C(OH)Me ₂ , -OMe, -OEt, -OCH ₂ CH ₂ CH ₃ , -CH ₂ OMe, -OCH ₂ CH ₂ NMe ₂ , F, Cl, Br, CHF ₂ , -CF ₃ , -CH ₂ CHF ₂ , -CH ₂ CF ₃ , -CF ₂ CH ₃ , -C(CH ₃ ) ₂ CF _3. OCF ₃ , -OCH ₂ CF ₃ , -OCH(CH ₃ )CF ₃ , CN, -C(O)Me, -C(O)tBu, CO ₂ H, CO ₂ Me, CO ₂ tBu, C(O)NH ₂ , =O, OH, NH ₂ , NMe ₂ , -NMeCH ₂ CH ₂ OMe, -NHC(O)Me, -NHC(O)tBu, -NHCO ₂ tBu, SO ₂ Me, SO ₂ Et, SO ₂ (iPr), SO ₂ (iBu), SO ₂ CF ₃ , -CH ₂ SO ₂ Me, SO(N＝H)Me, SO ₂ NH ₂ , SO ₂ NHMe, SO ₂ NMe ₂ , -SO ₂ NHCH ₂ CH ₂ OH, -NHSO ₂ Me, SF ₅ , -POMe ₂ ,

In some embodiments, a compound of formula (I), (I-1), (Ia), (Ia-1), (Ib), (Ic), (IIa), (IIa-1), (IIc), (IIc-1), (IIc-2), (IIc-3), (IIc-4), (IIc-5), (IIc-6), (IIc-7), or (IIc-8) or a pharmaceutically acceptable salt thereof is a compound, wherein each R ^6e is Me, Et, iPr, tBu, -CH ₂ OH, -C(OH)Me ₂ , -OMe, -OEt, -OCH ₂ CH ₂ CH ₃ , -CH ₂ OMe, -OCH ₂ CH ₂ NMe ₂ , F, Cl, Br, CHF ₂ , -CF ₃ , -CH ₂ CHF ₂ , -CH ₂ CF ₃ , -CF ₂ CH ₃ , -C(CH ₃ ) ₂ CF ₃ , OCF ₃ , -OCH ₂ CF ₃ , -OCH(CH ₃ )CF ₃ , CN, -C(O)Me, -C(O)tBu, CO ₂ H, CO ₂ Me, CO ₂ tBu, C(O)NH ₂ , =O, OH, NH ₂ , NMe ₂ , -NMeCH ₂ CH ₂ OMe, -NHC(O)Me, -NHC(O)tBu, -NHCO ₂ tBu, SO ₂ Me, SO ₂ Et, SO ₂ (iPr), SO ₂ (iBu), SO ₂ CF ₃ , -CH ₂ SO ₂ Me, SO(N＝H)Me, SO ₂ NH ₂ , SO ₂ NHMe, SO ₂ NMe ₂ , -SO ₂ NHCH ₂ CH ₂ OH, -NHSO ₂ Me, SF ₅ , -POMe ₂ ,

In some embodiments, the compound of formula (I), (I-1), (Ia), (Ia-1), (Ib), (Ic), (IIa), (IIa-1), (IIc), (IIc-1), (IIc-2), (IIc-3), (IIc-4), (IIc-5), (IIc-6), (IIc-7), or (IIc-8) or a pharmaceutically acceptable salt thereof is a compound, wherein each R ^6e is independently Me, Et, tBu, -OMe, F, Cl, _-CF3 , -NHC(O)Me, or -OH.

In some embodiments, the compound of formula (I), (I-1), (Ia), (Ia-1), (Ib), (Ic), (IIa), (IIa-1), (IIc), (IIc-1), (IIc-2), (IIc-3), (IIc-4), (IIc-5), (IIc-6), (IIc-7), or (IIc-8) or a pharmaceutically acceptable salt thereof is a compound wherein each R ^6e1 , R ^6e2 , and R ^6e3 is independently hydrogen, C _1-6 alkyl, C _1-6 hydroxyalkyl, C _1-6 aminoalkyl, C _1-6 alkoxyalkyl, C _1-6 haloalkyl, C _3-10 cycloalkyl, C _1-6 alkyl- _C 3-10 cycloalkyl, heterocycloalkyl, or C _1-6 alkyl-(heterocycloalkyl), wherein the cycloalkyl or heterocycloalkyl is optionally substituted with one to three R ⁶ⁿ . In some embodiments, the compound of formula (I), (I-1), (Ia), (Ia-1), (Ib), (Ic), (IIa), (IIa-1), (IIc), (IIc-1), (IIc-2), (IIc-3), (IIc-4), (IIc-5), (IIc-6), (IIc-7), or (IIc-8) or a pharmaceutically acceptable salt thereof is a compound wherein each R ^6e1 , R ^6e2 , and R ^6e3 is independently hydrogen, a C _1-6 alkyl, a C _1-6 hydroxyalkyl, a C _1-6 alkoxyalkyl, a C _3-10 cycloalkyl, a C _1-6 alkyl-C _3-10 cycloalkyl, or a heterocyclic alkyl, wherein the cycloalkyl or heterocyclic alkyl is optionally substituted with one to three R ⁶ⁿ .

In some embodiments, the compound of formula (I), (I-1), (Ia), (Ia-1), (Ib), (Ic), (IIa), (IIa-1), (IIc), (IIc-1), (IIc-2), (IIc-3), (IIc-4), (IIc-5), (IIc-6), (IIc-7), or (IIc-8) or a pharmaceutically acceptable salt thereof is a compound, wherein each R ^6j is independently a halogen, a _C1-6 haloalkyl group, -C(O)R ^6j1 , -C(O)OR ^6j1 , -OC(O)R ^6j1 , -C(O)N(R ^6j1 )(R ^6j2 ), -N(R ^6j3 )C(O)R ^6j2 , -OC(O)N(R ^6j1 )(R ^6j2 ), -N(R ^6j1 )C(O)OR ^6j2 -N( ^R6j1 )( ^R6j2 ), =O, ^–OR6j1 , ^-S(O)2R6j1 _, -Si( ^R6j1 )( ^R6j2 )( ^R6j3 ), _C3-10 cycloalkyl, _C6-12 aryl, heterocycloalkyl or heteroaryl, wherein the cycloalkyl, aryl, heterocycloalkyl or heteroaryl is optionally substituted by 1 to 3 ^R6p ; wherein each ^R6j1 , ^R6j2 and ^R6j3 is independently hydrogen or _C1-6 alkyl.

In some embodiments, the compound of formula (I), (I-1), (Ia), (Ia-1), (Ib), (Ic), (IIa), (IIa-1), (IIc), (IIc-1), (IIc-2), (IIc-3), (IIc-4), (IIc-5), (IIc-6), (IIc-7), or (IIc-8) or a pharmaceutically acceptable salt thereof is a compound, wherein each ^R6j is independently OH, _OMe , _CH2OMe , F, CHF2, _CF3 , CN, _NH2 , NH(CO) _CF3 , NH(CO)OtBu, _SO2Me , Si(iPr) ₃ ,

In some embodiments, the compound of formula (I), (I-1), (Ia), (Ia-1), (Ib), (Ic), (IIa), (IIa-1), (IIc), (IIc-1), (IIc-2), (IIc-3), (IIc-4), (IIc-5), (IIc-6), (IIc-7), or (IIc-8) or a pharmaceutically acceptable salt thereof is a compound, wherein each ^R6j is independently OH, OMe, F, _CHF2 , _CF3 , _NH2 , NH(CO)OtBu, _SO2Me , Si(iPr) ₃ ,

In some embodiments, a compound of formula (I), (I-1), (Ia), (Ia-1), (Ib), (Ic), (IIa), (IIa-1), (IIc), (IIc-1), (IIc-2), (IIc-3), (IIc-4), (IIc-5), (IIc-6), (IIc-7), or (IIc-8) or a pharmaceutically acceptable salt thereof is a compound wherein each R ^6p is independently a _C1-6 alkyl, _C1-6 hydroxyalkyl, _C1-6 aminoalkyl, _C1-6 alkoxy, _C2-6 alkoxyalkyl, halogen, _C1-6 haloalkyl, _C1-6 haloalkoxy, -CN, -C(O)R ^6p1 , -C(O)OR ^6p1 , -OC(O)R ^6p1 , -C(O)N(R ^6p1 )(R ^6p2 ), -N(R ^6p1) )C(O)R ^6p2 , -OC(O)N(R ^6p1 )(R ^6p2 ), -N(R ^6p1 )C(O)OR ^6p2 , -C(＝NR ^6p3 )N(R ^6p1 )(R ^6p2 ), -N(R ^6p1 )(R ^6p2 ), ＝O, -OH, -SR ^6p1 , -S(O)R ^6p1 , -S(NR ^6p1 )(NR ^6p2 )R ^6p3 , -S(O)(NR ^6p1 )(R ^6p2 ), -S(O) ₂ R ^6p1 , -S(O) ₂ N(R ^6p1 )(R ^6p2 ) or -N(R ^6p1 ) ^S (O) ₂ (R ^6p2 ); where each ,R ^6p2 and R ^6p3 are independently hydrogen, _C1-6 alkyl, _C1-6 hydroxyalkyl, _C1-6 aminoalkyl, C2-6 alkoxyalkyl, _C1-6 haloalkyl, _C3-10 cycloalkyl, _C1-6 alkyl- _C3-10 cycloalkyl, _C6-10 aryl, _C1-6 alkyl- _C6-10 aryl, _{heterocycloalkyl} , _C1-6 alkyl-(heterocycloalkyl), heteroaryl, or _C1-6 alkyl-(heteroaryl). In some embodiments, the compound of formula (I), (I-1), (Ia), (Ia-1), (Ib), (Ic), (IIa), (IIa-1), (IIc), (IIc-1), (IIc-2), (IIc-3), (IIc-4), (IIc-5), (IIc-6), (IIc-7), or (IIc-8), or a pharmaceutically acceptable salt thereof, is a compound wherein each R ^6p is independently a _C1-6 alkyl, _C1-6 hydroxyalkyl, _C1-6 alkoxy, _C2-6 alkoxyalkyl, halogen, _C1-6 haloalkyl, -CN, -C(O)R ^6p1 , -C(O)OR ^6p1 , -OC(O)R ^6p1 , -C(O)N(R ^6p1 )(R ^6p2 ), -N(R ^6p1 )C(O)R ^6p2 -OC(O)N(R ^6p1 )(R ^6p2 ), -N(R ^6p1 )C(O)OR ^6p2 , -N(R ^6p1 )(R ^6p2 ), =O, -OH, -SR ^6p1 , -S(O)R ^6p1 , -S(O) _2R ^6p1 , -S(O) _2N (R ^6p1 )(R ^6p2 ) or -N(R ^6p1 )S(O) ₂ (R ^6p2 ); wherein each R ^6p1 and R ^6p2 is independently hydrogen or C _1-6 alkyl.

In some embodiments, the compound of formula (I), (I-1), (Ia), (Ia-1), (Ib), (Ic), (IIa), (IIa-1), (IIc), (IIc-1), (IIc-2), (IIc-3), (IIc-4), (IIc-5), (IIc-6), (IIc-7), or (IIc- ₈ ) or a pharmaceutically acceptable salt thereof is a compound, wherein each R ^6p is independently Me, Et, iPr, F, Cl, _CH₂F , _CHF₂ , _CF₃ , _CF₂CH₃ , _CH₂CF₃ , =O _, or OH.

In some embodiments, the compound of formula (I), (I-1), (Ia), (Ia-1), (Ib), (Ic), (IIa), (IIa-1), (IIc), (IIc-1), (IIc-2), (IIc-3), (IIc-4), (IIc-5), (IIc-6), (IIc-7), or (IIc-8) or a pharmaceutically acceptable salt thereof is a compound, wherein each R ^6p is independently Me, Cl, _CF3 , =O, or OH.

In some embodiments, the compound of formula (I), (I-1), (Ia), (Ia-1), (Ib), (Ic), (IIa), (IIa-1), (IIc), (IIc-1), (IIc-2), (IIc-3), (IIc-4), (IIc-5), (IIc-6), (IIc-7), or (IIc-8) or a pharmaceutically acceptable salt thereof is a compound, wherein each R ^6a is independently a compound.

In some embodiments, the compound of formula (I), (I-1), (Ia), (Ia-1), (Ic), (IIa), (IIa-1), (IIc), (IIc-1), (IIc-2), (IIc-3), (IIc-4), (IIc-5), (IIc-6), (IIc-7), or (IIc-8) or a pharmaceutically acceptable salt thereof is a compound, wherein each R ^6a is independently a compound.

In some embodiments, a compound of formula (I), (I-1), (Ia), (Ia-1), (Ic), (IIa), (IIa-1), (IIc), (IIc-1), (IIc-2), (IIc-3), (IIc-4), (IIc-5), (IIc-6), (IIc-7), or (IIc-8) or a pharmaceutically acceptable salt thereof is a compound, wherein each R ^6a is independently Me, Et, -C≡CMe, -OMe, _-CH₂OH , _-CH₂OMe , _-CH₂OSi (Me) _₂ (tBu), F, Cl, Br, _I , -CH₂F, _-CF₃ , _-OCF₃ , -CN, _-NO₂ , -C(O)H, -COOH, -COOMe, _-CONH₂ , _-NH₂ , -OH, cyclopropyl, cyclohexyl, phenyl,

In some embodiments, the compound of formula (I), (I-1), (Ia), (Ia-1), (Ib), (IIa), or (IIa-1), or a pharmaceutically acceptable salt thereof, is a compound wherein ^R5 is a _C1-6 alkyl, _C2-6 alkynyl, _C2-6 alkoxyalkyl, _C1-6 alkyl- _C3-8 cycloalkyl, phenyl, _C1-6 alkyl-phenyl, or _C1-6 alkyl-(heterocyclic alkyl); ^R6 is phenyl, optionally substituted with one or two ^R6a ; each ^R6a is independently a _C1-6 alkyl, _C2-6 alkynyl, _C1-6 hydroxyalkyl, _C1-6 alkoxy, _C2-6 alkoxyalkyl, halogen, _C1-6 haloalkyl, _C1-6 haloalkoxy, –CN, _-NO2 , -C(O) ^R6b , -C(O) ^OR6b -C(O)N( ^R6b )( ^R6c ), -N( ^R6b )( ^R6c ), ^-OR6b or phenyl, wherein the phenyl is optionally substituted with one or two ^R6e ; ^R6b and ^R6c are each independently hydrogen or _C1-6 alkyl; each ^R6e is independently _C1-6 alkyl, halogen, _C1-6 haloalkyl, -N( ^R6e1 )C(O) ^R6e2 or ^-OR6e1 ; each ^R6e1 and ^R6e2 are independently hydrogen or _C1-6 alkyl; and the heterocyclic alkyl is a 5- or 6-membered ring having one heteroatom N or O. In some embodiments, a compound of formula (I), (I-1), (Ia), (Ia-1), (Ib), (IIa), or (IIa-1), or a pharmaceutically acceptable salt thereof, is a compound wherein ^R5 is a _C1-6 alkyl, _C2-6 alkynyl, _C2-3 alkoxyalkyl, _C1-3 alkyl- _C3-8 cycloalkyl, phenyl, _C1-3 alkyl-phenyl, or _C1-3 alkyl-(heterocyclic alkyl); ^R6 is phenyl, optionally substituted with ^R6a ; ^R6a is independently a _C1-3 alkyl, _C2-3 alkynyl, _C1-3 hydroxyalkyl, _C1-3 alkoxy, _C2-3 alkoxyalkyl, halogen, _C1-3 haloalkyl, _C1-3 haloalkoxy, –CN, _-NO2 , -C(O) ^R6b , -C(O) ^OR6b , -C(O)N( ^R6b ) ^R6e can be substituted with R6e, -N( ^R6b )( ^R6c ), -OH, or phenyl, wherein the phenyl is optionally substituted with ^R6e ; ^R6b and ^R6c are each independently hydrogen or _C1-3 alkyl; ^R6e is _C1-6 alkyl, halogen, _C1-3 haloalkyl, -N( ^R6e1 )C(O) ^R6e2 , or ^-OR6e1 ; ^R6e1 and ^R6e2 are independently hydrogen or _C1-3 alkyl; and the heterocyclic alkyl is a 6-membered ring having one heteroatom N or O.

In some embodiments, the compound of formula (I), (I-1), or (Ia), or a pharmaceutically acceptable salt thereof, is a compound having the structure of formula (Ib):

Where m is 0, 1, 2, or 3. In some embodiments, a compound of formula (I), (I-1), or (Ia), or a pharmaceutically acceptable salt thereof, is a compound, where m is 0. In some embodiments, a compound of formula (I), (I-1), or (Ia), or a pharmaceutically acceptable salt thereof, is a compound, where m is 1. In some embodiments, a compound of formula (I), (I-1), or (Ia), or a pharmaceutically acceptable salt thereof, is a compound, where m is 2. In some embodiments, a compound of formula (I), (I-1), or (Ia), or a pharmaceutically acceptable salt thereof, is a compound, where m is 3.

In some embodiments, the compound of formula (I) or (I-1) or a pharmaceutically acceptable salt thereof is a compound, wherein ^R6 is

In some embodiments, the compound of formula (I) or (I-1) or a pharmaceutically acceptable salt thereof is a compound, wherein ^R6 is

In some embodiments, the compound of formula (I) or (I-1) or a pharmaceutically acceptable salt thereof is a compound, wherein ^R6 is

In some embodiments, the compound of formula (I) or (I-1) or a pharmaceutically acceptable salt thereof is a compound wherein ^R5 and ^R6, together with the nitrogen to which they are bound, have the following structure:

In some embodiments, the compound of formula (I) or (I-1) or a pharmaceutically acceptable salt thereof is a compound having the structure of formula (Ic):

Wherein ring A is optionally a 5- to 8-membered heterocyclic alkyl group having one or two additional heteroatoms, each independently of N, O, or S, and optionally ring A is substituted by one or two R ^6g atoms; and n is 0, 1, or 2. In some embodiments, the compound of formula (Ic) or a pharmaceutically acceptable salt thereof is a compound wherein ring A is optionally a 5- to 8-membered heterocyclic alkyl group having one or two additional heteroatoms, each independently of N, O, or S; and n is 0, 1, or 2. In some embodiments, the compound of formula (Ic) or a pharmaceutically acceptable salt thereof is a compound wherein n is 0. In some embodiments, the compound of formula (Ic) or a pharmaceutically acceptable salt thereof is a compound wherein n is 1. In some embodiments, the compound of formula (Ic) or a pharmaceutically acceptable salt thereof is a compound wherein n is 2. In some embodiments, the compound of formula (Ic) or a pharmaceutically acceptable salt thereof is a compound wherein ring A is a 5- to 8-membered heterocyclic alkyl group. In some embodiments, the compound of formula (Ic) or a pharmaceutically acceptable salt thereof is a compound wherein ring A is a 6-membered heterocyclic alkyl group having an additional heteroatom O.

In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof is a compound having the structure of formula (IIc):

Wherein ring A is optionally a 5- to 8-membered heterocyclic alkyl group having one or two additional heteroatoms, each independently of N, O, or S, and optionally ring A is substituted by one or two R ^6g atoms; and n is 0, 1, or 2. In some embodiments, the compound of formula (IIc) or a pharmaceutically acceptable salt thereof is a compound wherein ring A is optionally a 5- to 8-membered heterocyclic alkyl group having one or two additional heteroatoms, each independently of N, O, or S; and n is 0, 1, or 2. In some embodiments, the compound of formula (IIc) or a pharmaceutically acceptable salt thereof is a compound wherein n is 0. In some embodiments, the compound of formula (IIc) or a pharmaceutically acceptable salt thereof is a compound wherein n is 1. In some embodiments, the compound of formula (IIc) or a pharmaceutically acceptable salt thereof is a compound wherein n is 2. In some embodiments, the compound of formula (IIc) or a pharmaceutically acceptable salt thereof is a compound wherein ring A is a 5- to 8-membered heterocyclic alkyl group. In some embodiments, the compound of formula (IIc) or a pharmaceutically acceptable salt thereof is a compound wherein ring A is a 6-membered heterocyclic alkyl group having an additional heteroatom O.

In some embodiments, a compound of formula (Ic), (IIc), (IIc-3), (IIc-4), (IIc-5), (IIc-6), (IIc-7), or (IIc-8), or a pharmaceutically acceptable salt thereof, is a compound, wherein ^R1 is hydrogen or a halogen. In some embodiments, a compound of formula (Ic), (IIc), (IIc-3), (IIc-4), (IIc-5), (IIc-6), (IIc-7), or (IIc-8), or a pharmaceutically acceptable salt thereof, is a compound, wherein ^R1 is hydrogen or F.

In some embodiments, a compound of formula (Ic), (IIc), (IIc-3), (IIc-4), (IIc-5), (IIc-6), (IIc-7), or (IIc-8) ^, or a pharmaceutically acceptable salt thereof, is a compound, wherein ^R4 is hydrogen, _C1-3 alkyl, or halogen.

In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof is a compound having the structure of formula (IIc-1):

Wherein ring A is optionally a 5- to 8-membered heterocyclic alkyl group having one or two additional heteroatoms, each independently of N, O, or S, and optionally ring A is substituted by one or two R ^6g atoms; and n is 0, 1, or 2. In some embodiments, the compound of formula (IIc-1) or a pharmaceutically acceptable salt thereof is a compound wherein ring A is optionally a 5- to 8-membered heterocyclic alkyl group having one or two additional heteroatoms, each independently of N, O, or S; and n is 0, 1, or 2. In some embodiments, the compound of formula (IIc-1) or a pharmaceutically acceptable salt thereof is a compound wherein n is 0. In some embodiments, the compound of formula (IIc-1) or a pharmaceutically acceptable salt thereof is a compound wherein n is 1. In some embodiments, the compound of formula (IIc-1) or a pharmaceutically acceptable salt thereof is a compound wherein n is 2. In some embodiments, the compound of formula (IIc-1) or a pharmaceutically acceptable salt thereof is a compound wherein ring A is a 5- to 8-membered heterocyclic alkyl group. In some embodiments, the compound of formula (IIc-1) or a pharmaceutically acceptable salt thereof is a compound wherein ring A is a 6-membered heterocyclic alkyl group having an additional heteroatom O.

In some embodiments, the compound of formula (Ic), (IIc), or (IIc-1), or a pharmaceutically acceptable salt thereof, is a compound, wherein

Having structure

In some embodiments, a compound of formula (I) or (Ic) or a pharmaceutically acceptable salt thereof is a compound, wherein each R ^6g is independently a _C1-6 alkyl, halogen, _C1-6 haloalkyl, or –CN. In some embodiments, a compound of formula (I) or (Ic) or a pharmaceutically acceptable salt thereof is a compound, wherein each R ^6g is independently a _C1-6 alkyl or halogen. In some embodiments, a compound of formula (I) or (Ic) or a pharmaceutically acceptable salt thereof is a compound, wherein each R ^6g is independently methyl.

In some embodiments, the compound of formula (Ic), (IIc), or (IIc-1), or a pharmaceutically acceptable salt thereof, is a compound, wherein

Having structure

In some embodiments, the compound of formula (Ic), (IIc), or (IIc-1), or a pharmaceutically acceptable salt thereof, is a compound, wherein

Having structure

In some embodiments, the compound of formula (Ic) or a pharmaceutically acceptable salt thereof is a compound, wherein

Having structure

In some embodiments, the compound of formula (Ic), (IIc), or (IIc-1), or a pharmaceutically acceptable salt thereof, is a compound, wherein

In some embodiments, a compound of formula (Ic), (IIc), or (IIc-1), or a pharmaceutically acceptable salt thereof, is a compound having a structure in which

In some embodiments, a compound of formula (Ic), (IIc), or (IIc-1), or a pharmaceutically acceptable salt thereof, is a compound having a structure in which

Having structure

In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof is a compound having the structure of formula (IIc-2):

Where n is 0, 1, or 2.

In some embodiments, the compound of formula (Ic), (IIc), or (IIc-1), or a pharmaceutically acceptable salt thereof, is a compound, wherein

Having structure

In some embodiments, the compounds of formula (I), (IIa), or (IIc), or their pharmaceutically acceptable salts, are compounds having the following structures:

In some embodiments, the compound of formula (IIc) is a compound of formula (IIc-3) or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of formula (IIc) is a compound of formula (IIc-4) or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of formula (IIc) is a compound of formula (IIc-5) or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of formula (IIc) is a compound of formula (IIc-6) or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of formula (IIc) is a compound of formula (IIc-7) or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of formula (IIc) is a compound of formula (IIc-8) or a pharmaceutically acceptable salt thereof.

In some embodiments, a compound of formula (I), (IIa), (IIa-1), (IIc), (IIc-3), (IIc-4), (IIc-5), (IIc-6), (IIc-7), or (IIc-8), or a pharmaceutically acceptable salt thereof, is a compound wherein ^R1 is hydrogen, _C1-3 alkyl, or halogen; ^R2 is hydrogen, _C1-3 alkyl, _C1-3 hydroxyalkyl, _C2-3 alkoxyalkyl, halogen, or -CN; ^R3 is hydrogen, _C1-3 alkyl, or halogen; ^R4 is hydrogen, _C1-3 alkyl, or halogen; each ^R6a is independently _C1-3 alkyl, _C2-3 alkenyl, or _C2-3 alkynyl, wherein the alkynyl is optionally substituted by one to three ^R6j ; each ^R6j is independently _C2-3 alkoxyalkyl, halogen, _C1-3 haloalkyl, _C1-3 haloalkoxy, -CN, C _3-8 cycloalkyl or heterocycloalkyl, wherein the cycloalkyl or heterocycloalkyl is optionally substituted with 1 to 3 R ^6p ; each R ^6p is independently a C _1-3 alkyl, C _1-3 hydroxyalkyl, C _2-3 alkoxyalkyl, halogen, C _1-3 haloalkyl, C _1-3 haloalkoxy, or -CN; and R ⁷ is hydrogen, C _1-3 alkyl, C _2-3 alkoxyalkyl, C _1-3 haloalkyl, or -NH ₂ .

In some embodiments, a compound of formula (I), (IIa), (IIa-1), (IIc), (IIc-3), (IIc-4), (IIc-5), (IIc-6), (IIc-7), or (IIc-8), or a pharmaceutically acceptable salt thereof, is a compound wherein ^R1 is hydrogen, _C1-3 alkyl, or halogen; ^R2 is hydrogen, _C1-3 alkyl, _C1-3 hydroxyalkyl, _C2-3 alkoxyalkyl, halogen, or -CN; ^R3 is hydrogen, _C1-3 alkyl, or halogen; ^R4 is hydrogen, _C1-3 alkyl, or halogen; each ^R6a is independently _C1-3 alkyl, _C2-3 alkenyl, or _C2-3 alkynyl, wherein the alkynyl is optionally substituted by one to three ^R6j ; each ^R6j is independently _C2-3 alkoxyalkyl, halogen, _C1-3 haloalkyl, _C1-3 haloalkoxy, -CN, C _3-8 cycloalkyl or heterocycloalkyl, wherein the cycloalkyl or heterocycloalkyl is optionally substituted with 1 to 3 R ^6p ; each R ^6p is independently a C _1-3 alkyl, C _1-3 hydroxyalkyl, C _2-3 alkoxyalkyl, halogen, C _1-3 haloalkyl, C _1-3 haloalkoxy or -CN; and R ⁷ is hydrogen or C _1-3 alkyl.

In some embodiments, a compound of formula (I), (IIa), (IIa-1), (IIc), (IIc-3), (IIc-4), (IIc-5), (IIc-6), (IIc-7), or (IIc-8), or a pharmaceutically acceptable salt thereof, is a compound wherein ^R1 is hydrogen or F; ^R2 is hydrogen, F, or Cl; ^R3 is hydrogen or F; ^R4 is hydrogen or F; each ^R6a is independently a _C1-3 alkyl, _C2-3 alkenyl, or _C2-3 alkynyl, wherein the alkynyl is optionally substituted by 1 to 3 ^R6j ; each ^R6j is independently a C2-3 alkoxyalkyl, halogen, _C1-3 haloalkyl, C1-3 haloalkoxy, -CN, _C3-8 cycloalkyl, or heterocycloalkyl, wherein the cycloalkyl or heterocycloalkyl is optionally substituted by 1 to 3 R6p; each R6p is independently a C1-3 alkyl, C2-3 alkenyl, _C2-3 alkenyl, -CN, -CN, _C3-8 cycloalkyl, or heterocycloalkyl, wherein the cycloalkyl or heterocycloalkyl is optionally substituted by 1 to 3 ^R6p ; and each ^R6p is independently a _C1-3 alkyl, C2-3 alkenyl, -CN ... _1-3 hydroxyalkyl, _C2-3 alkoxyalkyl, halogen, _C1-3 haloalkyl, _C1-3 haloalkoxy or -CN; and ^R7 is hydrogen or Me.

In some embodiments, the compound of formula (Ic), (IIc), or (IIc-1), or a pharmaceutically acceptable salt thereof, is a compound wherein ^R2 is hydrogen, _C1-3 alkyl, _C1-3 hydroxyalkyl, _C2-3 alkoxyalkyl, halogen, or -CN; ^R3 is hydrogen, _C1-3 alkyl, or halogen; each ^R6a is independently _C1-3 alkyl, _C2-3 alkenyl, or _C2-3 alkynyl, wherein the alkynyl is optionally substituted by 1 to 3 ^R6j ; each ^R6j is independently _C2-3 alkoxyalkyl, halogen, _C1-3 haloalkyl, _C1-3 haloalkoxy, -CN, _C3-8 cycloalkyl, or heterocycloalkyl, wherein the cycloalkyl or heterocycloalkyl is optionally substituted by 1 to 3 ^R6p ; each ^R6p is independently _C1-3 alkyl, _C1-3 hydroxyalkyl, C2-3 alkoxyalkyl, halogen, _C3-8 cycloalkyl, or -CN. _1-3 haloalkyl, _C1-3 haloalkoxy, or -CN; ^R7 is hydrogen or _C1-3 alkyl; and has the following structure

In some embodiments, a compound of formula (Ic), (IIc), (IIc-1), (IIc-2), (IIc-3), (IIc-4), (IIc-5), (IIc-6), (IIc-7), or (IIc-8), or a pharmaceutically acceptable salt thereof, is a compound, wherein ^R2 is hydrogen, a halogen, or -CN. In some embodiments, a compound of formula (Ic), (IIc), (IIc-1), (IIc-2), (IIc-3), (IIc-4), (IIc-5), (IIc-6), (IIc-7), or (IIc-8), or a pharmaceutically acceptable salt thereof, is a compound, wherein ^R2 is hydrogen, F, or Cl.

In some embodiments, the compound of formula (Ic), (IIc), (IIc-1), (IIc-2), (IIc-3), (IIc-4), (IIc-5), (IIc-6), (IIc-7), or (IIc-8) or a pharmaceutically acceptable salt thereof is a compound, wherein ^R3 is hydrogen, F, or Cl.

In some embodiments, a compound of formula (Ic), (IIc), (IIc-1), (IIc-2), (IIc-3), (IIc-4), (IIc-5), (IIc-6), (IIc-7), or (IIc-8), or a pharmaceutically acceptable salt thereof, is a compound wherein each R ^6a is independently a C _2-3 alkynyl or halogen, wherein the alkynyl group is optionally substituted by one to three R ^6j . In some embodiments, a compound of formula (Ic), (IIc), (IIc-1), (IIc-2), (IIc-3), (IIc-4), (IIc-5), (IIc-6), (IIc-7), or (IIc-8), or a pharmaceutically acceptable salt thereof, is a compound wherein each R ^6a is substituted by one to three R 6j.

One R ^6j is replaced.

In some embodiments, a compound of formula (Ic), (IIc), (IIc-1), (IIc-2), (IIc-3), (IIc-4), (IIc-5), (IIc-6), (IIc-7), or (IIc-8) or a pharmaceutically acceptable salt thereof is a compound wherein each R ^6j is independently a C _2-3 alkoxyalkyl, halogen, C _1-3 haloalkyl, -CN, C _3-6 cycloalkyl, or heterocycloalkyl, wherein the cycloalkyl or heterocycloalkyl is optionally substituted with one to three R ^6p , and each heterocycloalkyl is a 3- to 6-membered ring having one to two heteroatoms, each independently of N, O, or S. In some embodiments, a compound of formula (Ic), (IIc), (IIc-1), (IIc-2), (IIc-3), (IIc-4), (IIc-5), (IIc-6), (IIc-7), or (IIc-8) or a pharmaceutically acceptable salt thereof is a compound wherein each R ^6j is independently a halogen, a _C1-3 haloalkyl, a _C3-6 cycloalkyl, or a heterocycloalkyl, wherein the cycloalkyl or heterocycloalkyl is optionally substituted with one to two R ^6p , and each heterocycloalkyl is a 3- to 6-membered ring having one to two heteroatoms, each independently of N, O, or S. In some embodiments, a compound of formula (Ic), (IIc), (IIc-1), (IIc-2), (IIc-3), (IIc-4), (IIc-5), (IIc-6), (IIc-7), or (IIc-8) or a pharmaceutically acceptable salt thereof is a compound wherein each R ^6j is independently a halogen, a _C1-3 haloalkyl, or a _C3-6 cycloalkyl, wherein the cycloalkyl is optionally substituted by an R ^6p . In some embodiments, the compound of formula (Ic), (IIc), (IIc-1), (IIc-2), (IIc-3), (IIc-4), (IIc-5), (IIc-6), (IIc-7), or (IIc-8) or a pharmaceutically acceptable salt thereof is a compound, wherein each R ^6j is independently F, CH ₂ F, CHF ₂ , CF ₃ , CH ₂ CF ₃ , CF ₂ CH ₃ , or cyclopropyl, wherein the cyclopropyl is optionally substituted with an R ^6p .

In some embodiments, a compound of formula (Ic), (IIc), (IIc-1), (IIc-2), (IIc-3), (IIc-4), (IIc-5), (IIc-6), (IIc-7), or (IIc-8), or a pharmaceutically acceptable salt thereof, is a compound wherein each R ^6p is independently a _C1-3 alkyl, _C1-3 hydroxyalkyl, halogen, _C1-3 haloalkyl, or –CN. In some embodiments, a compound of formula (Ic), (IIc), (IIc-1), (IIc-2), (IIc-3), (IIc-4), (IIc-5), (IIc-6), (IIc-7), or (IIc-8), or a pharmaceutically acceptable salt thereof, is a compound wherein each R ^6p is independently Me, Et, _CH₂OH , F, _CH₂F , _{CHF₂ , CF₃} , _CH₂CF₃ , _CF₂CH₃ , or _–CN .

In some embodiments, the compound of formula (Ic), (IIc), or (IIc-1), or a pharmaceutically acceptable salt thereof, is a compound, wherein

Having structure

In some embodiments, a compound of formula (I), (I-1), (Ia), (Ia-1), (Ib), (Ic), (IIa), (IIa-1), (IIc), (IIc-1), (IIc-2), (IIc-2), (IIc-3), (IIc-4), (IIc-5), (IIc-6), (IIc-7), or (IIc-8), or a pharmaceutically acceptable salt thereof, is a compound, wherein the heterocyclic alkyl group is a 5- to 8-membered ring having one to two heteroatoms, each of which is independently N, O, or S. In some embodiments, the compound of formula (I), (I-1), (Ia), (Ia-1), (Ib), (Ic), (IIa), (IIa-1), (IIc), (IIc-1), (IIc-2), (IIc-2), (IIc-3), (IIc-4), (IIc-5), (IIc-6), (IIc-7), or (IIc-8), or a pharmaceutically acceptable salt thereof, is a compound, wherein the heterocyclic alkyl group is a 5- or 6-membered ring having one or two heteroatoms, each of which is independently N or O. In some embodiments, the compound of formula (I), (I-1), (Ia), (Ia-1), (Ib), (Ic), (IIa), (IIa-1), (IIc), (IIc-1), (IIc-2), (IIc-2), (IIc-3), (IIc-4), (IIc-5), (IIc-6), (IIc-7), or (IIc-8), or a pharmaceutically acceptable salt thereof, is a compound, wherein the heterocyclic alkyl group is a 6-membered ring having one heteroatom N or O.

In some embodiments, the compound of formula (I), (I-1), (Ia), (Ia-1), (Ib), (Ic), (IIa), (IIa-1), (IIc), (IIc-1), (IIc-2), (IIc-2), (IIc-3), (IIc-4), (IIc-5), (IIc-6), (IIc-7), or (IIc-8), or a pharmaceutically acceptable salt thereof, is a compound, wherein the heteroaryl group is a 5- or 6-membered ring having one or two heteroatoms, each of which is independently N, O, or S. In some embodiments, the compound of formula (I), (I-1), (Ia), (Ia-1), (Ib), (Ic), (IIa), (IIa-1), (IIc), (IIc-1), (IIc-2), (IIc-3), (IIc-4), (IIc-5), (IIc-6), (IIc-7), or (IIc-8) or a pharmaceutically acceptable salt thereof is a compound, wherein the heteroaryl group is a 6-membered ring having one to two heteroatoms, each of which is N.

In some embodiments, the compound of formula (I), (I-1), (Ia), (Ia-1), (Ib), (Ic), (IIa), (IIa-1), (IIc), (IIc-1)(IIc-2), (IIc-2), (IIc-3), (IIc-4), (IIc-5), (IIc-6), (IIc-7), or (IIc-8), or a pharmaceutically acceptable salt thereof, is a compound, wherein the heterocyclic alkyl group is a 5- or 6-membered ring having one or two heteroatoms, each independently of N or O; and the heteroaryl group is a 5- or 6-membered ring having one or two heteroatoms, each independently of N, O, or S.

In some embodiments, the compounds of formula (I), (I-1), (Ia), (Ia-1), (Ib), (Ic), (IIa), (IIa-1), (IIc), (IIc-1), (IIc-2), (IIc-3), (IIc-4), (IIc-5), (IIc-6), (IIc-7), or (IIc-8), or their pharmaceutically acceptable salts, are compounds having the structure of compounds in Tables 1A, 1B, 1C, 1D, 1E, 1F, 1G, 1H, 1I, 1J, 2A, 2B, 2C, 2D, 2E, 2F, 2G, 2H, 2I, 2J, 2K, 2L, 3A, 3B, 3C, 3D, 3E, 3F, 3G, 3H, 3I, 3J, or 3K. In some embodiments, the compound of formula (I), (I-1), (Ia), (Ia-1), (Ib), (Ic), (IIa), (IIa-1), (IIc), (IIc-1), (IIc-2), (IIc-3), (IIc-4), (IIc-5), (IIc-6), (IIc-7), or (IIc-8), or a pharmaceutically acceptable salt thereof, is a compound having the structure of a compound in Table 3F, Table 3H, Table 3I, Table 3J, or Table 3K.

Table 1A. Compounds

Table 1B. Compounds

Table 1C. Compounds

Table 1D. Compounds

Table 1E. Compounds

Table 1F. Compounds

Table 1G. Compounds

Table 1H. Compounds

Table 1I: Compounds

Table 1J: Compounds

Table 2A: Compounds

Table 2B: Compounds

Table 2C: Compounds

Table 2D: Compounds

Table 2E: Compounds

Table 2F: Compounds

Table 2G: Compounds

Table 2H: Compounds

Table 2I: Compounds

Table 2J: Compounds

Table 2K: Compounds

Table 2L: Compounds

Table 3A: Compounds

Table 3B: Compounds

Table 3C: Compounds

Table 3D: Compounds

Table 3E: Compounds

Table 3F: Compounds

Table 3G: Compounds

Table 3H: Compounds

Table 3I: Compounds

Table 3J: Compounds

Table 3K: Compounds

Table 1A-1. Compounds

The in vivo metabolites of the compounds described herein also fall within the scope of this document, and to some extent, such products are novel and unobservable relative to the prior art. These products can be generated, primarily due to enzymatic processes, such as oxidation, reduction, hydrolysis, amidation, esterification, etc., of the applied compound. Therefore, novel and unobservable compounds produced by methods involving sufficient exposure of the compound to a mammal for a period of time to produce its metabolites are included. Such products are typically identified by the following steps: preparing a radiolabeled (e.g., 14C or 3H) compound; administering a detectable dose (e.g., greater than about 0.5 mg/kg) of the radiolabeled compound parenterally to an animal (e.g., rat, mouse, guinea pig, monkey, or human); allowing sufficient time for metabolism (typically about 30 seconds to about 30 hours); and separating the metabolites from urine, blood, or other biological samples. These products are readily separated because they are labeled (other products are separated using antibodies capable of binding to epitopes that survive in the metabolites). The metabolite structure is determined in a conventional manner (e.g., by MS or NMR analysis). Typically, metabolite analysis is performed in the same manner as routine drug metabolism studies well known to those skilled in the art.

In some embodiments, the compounds of this disclosure exhibit higher selectivity for DGKα than for one or more other DGK isoforms (e.g., β, γ, δ, ε, ζ, η, θ, ι, and/or κ). Selectivity can be measured by relative values in corresponding biochemical assays (e.g., activity against DGK isoforms). In some embodiments, the compounds contain activity against DGKβ, DGKγ, DGKδ, DGKε, DGKζ, DGKη, DGKθ, DGKι, and/or DGKκ, wherein the _IC50 in a biochemical assay is greater than about 30 μM.

In some embodiments, the compounds of this disclosure exhibit selectivity for DGKα that is at least about 1.2 times, about 1.5 times, about 2 times, about 3 times, or about 3 times higher than that for one or more (e.g., 2, 3, 4, 5, 6, 7, 8, or 9 or more) other DGK isoforms (including DGKβ, DGKγ, DGKδ, DGKε, DGKζ, DGKη, DGKθ, DGKι, and/or DGKκ). Approximately 4 times, approximately 5 times, approximately 6 times, approximately 7 times, approximately 8 times, approximately 9 times, approximately 10 times, approximately 15 times, approximately 20 times, approximately 30 times, approximately 40 times, approximately 50 times, approximately 60 times, approximately 70 times, approximately 80 times, approximately 90 times, approximately 100 times, approximately 200 times, approximately 300 times, approximately 400 times, approximately 500 times, approximately 1000 times, approximately 2000 times, approximately 3000 times, approximately 4000 times, approximately 5000 times, or approximately 10000 times or more. In some embodiments, the compound exhibits selectivity for DGKα that is at least about 1.2 times, about 1.5 times, about 2 times, about 3 times, about 4 times, about 5 times, about 6 times, about 7 times, about 8 times, about 9 times, about 10 times, about 15 times, about 20 times, about 30 times, about 40 times, about 50 times, about 60 times, about 70 times, about 80 times, about 90 times, about 100 times, about 200 times, about 300 times, about 400 times, about 500 times, about 1000 times, about 2000 times, about 3000 times, about 4000 times, about 5000 times, or about 10000 times or more than that for DGKβ and/or DGKγ. In some embodiments, the selectivity of the compound for DGKα is at least about 1.2 times, about 1.5 times, about 2 times, about 3 times, about 4 times, about 5 times, about 6 times, about 7 times, about 8 times, about 9 times, about 10 times, about 15 times, about 20 times, about 30 times, about 40 times, about 50 times, about 60 times, about 70 times, about 80 times, about 90 times, about 100 times, about 200 times, about 300 times, about 400 times, about 500 times, about 1000 times, about 2000 times, about 3000 times, about 4000 times, about 5000 times, or about 10000 times or more than that for DGKβ. In some embodiments, the compound exhibits selectivity for DGKα that is at least about 1.2 times, about 1.5 times, about 2 times, about 3 times, about 4 times, about 5 times, about 6 times, about 7 times, about 8 times, about 9 times, about 10 times, about 15 times, about 20 times, about 30 times, about 40 times, about 50 times, about 60 times, about 70 times, about 80 times, about 90 times, about 100 times, about 200 times, about 300 times, about 400 times, about 500 times, about 1000 times, about 2000 times, about 3000 times, about 4000 times, about 5000 times, or about 10000 times or more than that for DGKγ. In some embodiments, the selectivity of the compound for DGKα is at least about 1.2 times, about 1.5 times, about 2 times, about 3 times, about 4 times, about 5 times, about 6 times, about 7 times, about 8 times, about 9 times, about 10 times, about 15 times, about 20 times, about 30 times, about 40 times, about 50 times, about 60 times, about 70 times, about 80 times, about 90 times, about 100 times, about 200 times, about 300 times, about 400 times, about 500 times, about 1000 times, about 2000 times, about 3000 times, about 4000 times, about 5000 times, or about 10000 times or more than that for DGKδ. In some embodiments, the selectivity of the compound for DGKα is at least about 1.2 times, about 1.5 times, about 2 times, about 3 times, about 4 times, about 5 times, about 6 times, about 7 times, about 8 times, about 9 times, about 10 times, about 15 times, about 20 times, about 30 times, about 40 times, about 50 times, about 60 times, about 70 times, about 80 times, about 90 times, about 100 times, about 200 times, about 300 times, about 400 times, about 500 times, about 1000 times, about 2000 times, about 3000 times, about 4000 times, about 5000 times, or about 10000 times or more than that for DGKε. In some embodiments, the selectivity of the compound for DGKα is at least about 1.2 times, about 1.5 times, about 2 times, about 3 times, about 4 times, about 5 times, about 6 times, about 7 times, about 8 times, about 9 times, about 10 times, about 15 times, about 20 times, about 30 times, about 40 times, about 50 times, about 60 times, about 70 times, about 80 times, about 90 times, about 100 times, about 200 times, about 300 times, about 400 times, about 500 times, about 1000 times, about 2000 times, about 3000 times, about 4000 times, about 5000 times, or about 10000 times or more than that for DGKζ. In some embodiments, the selectivity of the compound for DGKα is at least about 1.2 times, about 1.5 times, about 2 times, about 3 times, about 4 times, about 5 times, about 6 times, about 7 times, about 8 times, about 9 times, about 10 times, about 15 times, about 20 times, about 30 times, about 40 times, about 50 times, about 60 times, about 70 times, about 80 times, about 90 times, about 100 times, about 200 times, about 300 times, about 400 times, about 500 times, about 1000 times, about 2000 times, about 3000 times, about 4000 times, about 5000 times, or about 10000 times or more than that for DGKη. In some embodiments, the selectivity of the compound for DGKα is at least about 1.2 times, about 1.5 times, about 2 times, about 3 times, about 4 times, about 5 times, about 6 times, about 7 times, about 8 times, about 9 times, about 10 times, about 15 times, about 20 times, about 30 times, about 40 times, about 50 times, about 60 times, about 70 times, about 80 times, about 90 times, about 100 times, about 200 times, about 300 times, about 400 times, about 500 times, about 1000 times, about 2000 times, about 3000 times, about 4000 times, about 5000 times, or about 10000 times or more than that for DGKθ. In some embodiments, the selectivity of the compound for DGKα is at least about 1.2 times, about 1.5 times, about 2 times, about 3 times, about 4 times, about 5 times, about 6 times, about 7 times, about 8 times, about 9 times, about 10 times, about 15 times, about 20 times, about 30 times, about 40 times, about 50 times, about 60 times, about 70 times, about 80 times, about 90 times, about 100 times, about 200 times, about 300 times, about 400 times, about 500 times, about 1000 times, about 2000 times, about 3000 times, about 4000 times, about 5000 times, or about 10000 times or more than that for DGKα. In some embodiments, the compound exhibits selectivity for DGKα that is at least about 1.2 times, about 1.5 times, about 2 times, about 3 times, about 4 times, about 5 times, about 6 times, about 7 times, about 8 times, about 9 times, about 10 times, about 15 times, about 20 times, about 30 times, about 40 times, about 50 times, about 60 times, about 70 times, about 80 times, about 90 times, about 100 times, about 200 times, about 300 times, about 400 times, about 500 times, about 1000 times, about 2000 times, about 3000 times, about 4000 times, about 5000 times, or about 10000 times or more than that for DGKκ.

III. Pharmaceutical Preparations

In some embodiments, this disclosure provides a pharmaceutical formulation comprising a pharmaceutically effective amount of a compound of the disclosed compound or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient. Pharmaceutical formulations comprising a pharmaceutically effective amount of a compound of formula (I), (I-1), (Ia), (Ia-1), (Ib), (Ic), (IIa), (IIa-1), (IIc), (IIc-1), (IIc-2), (IIc-2), (IIc-3), (IIc-4), (IIc-5), (IIc-6), (IIc-7), or (IIc-8) thereof, or a pharmaceutically acceptable salt thereof, a solvate and/or an ester thereof, and a pharmaceutically acceptable carrier or excipient.

In some embodiments, the pharmaceutical composition further comprises one or more additional therapeutic agents. Any suitable additional therapeutic agent or combination therapy may be used with compounds of formula (I), (I-1), (Ia), (Ia-1), (Ib), (Ic), (IIa), (IIa-1), (IIc), (IIc-1), (IIc-2), (IIc-2), (IIc-3), (IIc-4), (IIc-5), (IIc-6), (IIc-7), or (IIc-8) or their pharmaceutically acceptable salts, such as the pharmaceuticals and therapies described herein.

In some embodiments, the pharmaceutical composition comprises a compound of formula (I), (I-1), (Ia), (Ia-1), (Ib), (Ic), (IIa), (IIa-1), (IIc), (IIc-1), (IIc-2), (IIc-2), (IIc-3), (IIc-4), (IIc-5), (IIc-6), (IIc-7), or (IIc-8) and an adjunct therapeutic agent, wherein the adjunct therapeutic agent is an anticancer agent. In some embodiments, the pharmaceutical composition is a pharmaceutical composition in which the adjunct therapeutic agent is independently an antitumor agent, nivolumab, pembrolizumab, atezolizumab, ipilimumab, chemotherapy, radiotherapy, or resection therapy. In some embodiments, the pharmaceutical composition is a pharmaceutical composition in which the adjunctive therapeutic agent is independently rituximab, doxorubicin, gemcitabine, nivolumab, pembrolizumab, atezolizumab, nivolumab, pembrolizumab, atezolizumab, or ipilimumab. In some embodiments, the pharmaceutical composition is a pharmaceutical composition in which the adjunctive therapeutic agent is a PD-1/PD-L1 inhibitor. In some embodiments, the pharmaceutical composition is a pharmaceutical composition in which the adjunctive therapeutic agent is a vaccine.

In some embodiments, the pharmaceutical composition is a pharmaceutical composition in which the additional therapeutic agent comprises one or more populations of immune cells, such as natural killer (NK) cells, NK-T cells, T cells, cytokine-induced killer (CIK) cells, macrophages (MAC) cells, tumor-infiltrating lymphocytes (TILs), and dendritic cells (DCs).

In some embodiments, the pharmaceutical composition is a pharmaceutical composition in which the additional therapeutic agent comprises one or more chimeric antigen receptors (CARs).

In some embodiments, the pharmaceutical composition is a pharmaceutical composition in which the additional therapeutic agent comprises immunotherapy, immunostimulatory therapy, cytokine therapy, chemokine therapy, cell therapy, gene therapy, or a combination thereof.

In some embodiments, the pharmaceutical composition comprises a compound of formula (I), (I-1), (Ia), (Ia-1), (Ib), (Ic), (IIa), (IIa-1), (IIc), (IIc-1), (IIc-2), (IIc-2), (IIc-3), (IIc-4), (IIc-5), (IIc-6), (IIc-7), or (IIc-8) and an adjunct therapeutic agent, wherein the adjunct therapeutic agent is an agent effective against a viral infection. In some embodiments, the viral infection is HIV. In some embodiments, the viral infection is hepatitis B virus. In some embodiments, the pharmaceutical composition comprises a compound of formula (I), (I-1), (Ia), (Ia-1), (Ib), (Ic), (IIa), (IIa-1), (IIc), (IIc-1), (IIc-2), (IIc-2), (IIc-3), (IIc-4), (IIc-5), (IIc-6), (IIc-7), or (IIc-8) and an adjunct therapeutic agent, wherein the adjunct therapeutic agent comprises a vaccine.

In some implementations, the pharmaceutical composition is used to treat cancer.

In some implementations, the pharmaceutical composition is used to treat HIV or hepatitis B virus infection.

In some embodiments, the compounds disclosed herein are formulated with conventional carriers and excipients, which will be selected according to conventional practice. Tablets may contain excipients, flow aids, fillers, binders, etc. Aqueous formulations may be prepared aseptically and may be isotonic, for example, when intended for delivery via non-oral administration. In some embodiments, the formulation may optionally contain excipients, such as those described in "Handbook of Pharmaceutical Excipients" (1986). Excipients may include, for example, ascorbic acid and other antioxidants, chelating agents such as EDTA, carbohydrates such as dextran, hydroxyalkyl cellulose, hydroxyalkyl methyl cellulose, stearic acid, etc. The pH range of the formulation is from about 3 to about 11, for example from about 7 to about 10.

In some embodiments, the compounds disclosed herein are administered alone. In some embodiments, the compounds disclosed herein are administered as pharmaceutical formulations. In some embodiments, formulations for veterinary and/or human use comprise at least one compound of formula (I), (I-1), (Ia), (Ia-1), (Ib), (Ic), (IIa), (IIa-1), (IIc), (IIc-1), (IIc-2), (IIc-2), (IIc-3), (IIc-4), (IIc-5), (IIc-6), (IIc-7), or (IIc-8), or a pharmaceutically acceptable salt, solvate, and/or ester thereof, together with one or more acceptable carriers and optional other therapeutic ingredients, such as those additional therapeutic ingredients discussed herein. In some embodiments, the carrier is "acceptable," meaning it is compatible with other components of the formulation and physiologically harmless to the recipient.

In some embodiments, the formulations disclosed herein include those suitable for the aforementioned routes of administration. In some embodiments, the formulation is present in a unit dosage form. The formulation can be prepared by methods known in the pharmaceutical field. Techniques and formulations can be found, for example, in "Remington's Pharmaceutical Sciences" (Mack Publishing Co., Easton, PA). Such methods include, for example, the step of associating the active ingredient with a carrier comprising one or more auxiliary ingredients. In some embodiments, the formulation is prepared by associating the active ingredient with a liquid carrier or a finely dispersed solid carrier, or both, and then, in some embodiments, shaping the product.

Formulations suitable for oral administration may be presented as discrete units, such as capsules, pouches, or tablets each containing a predetermined amount of an active ingredient, such as a compound of formula (I), (I-1), (Ia), (Ia-1), (Ib), (Ic), (IIa), (IIa-1), (IIc), (IIc-1), (IIc-2), (IIc-2), (IIc-3), (IIc-4), (IIc-5), (IIc-6), (IIc-7), or (IIc-8) or a pharmaceutically acceptable salt, solvate, and/or ester thereof; present as a powder or granules; present as a solution or suspension in an aqueous or non-aqueous liquid; or present as an oil-in-water or water-in-oil liquid emulsion. In some embodiments, the active ingredient is administered as a pill, saccharin, or paste.

Tablets can be prepared, for example, by compression or molding with one or more excipients. Compressed tablets can be prepared, for example, by compressing a free-flowing form of the active ingredient (such as powder or granules) in a suitable machine, optionally mixed with a binder, lubricant, inert diluent, preservative, surfactant, or dispersant. Molded tablets can be prepared, for example, by molding a mixture of powdered active ingredients moistened with an inert liquid diluent in a suitable machine. Tablets can optionally be coated or indented. In some embodiments, tablets are formulated to provide a slow or controlled release of the active ingredient.

For infections of the eyes or other external tissues such as the mouth and skin, the formulation may be applied as a topical ointment or cream containing, for example, about 0.075 to about 20% w/w (including increments of about 0.1% w/w of the active ingredient in the range of about 0.1% to about 20% (such as about 0.6% w/w, about 0.7% w/w, etc.), such as about 0.2% w/w to about 15% w/w, and such as about 0.5% w/w to about 10% w/w of a compound of formula (I), (I-1), (Ia), (Ia-1), (Ib), (Ic), (IIa), (IIa-1), (IIc), (IIc-1), (IIc-2), (IIc-2), (IIc-3), (IIc-4), (IIc-5), (IIc-6), (IIc-7), or (IIc-8). When formulated into an ointment, compounds of formula (I), (I-1), (Ia), (Ia-1), (Ib), (Ic), (IIa), (IIa-1), (IIc), (IIc-1), (IIc-2), (IIc-2), (IIc-3), (IIc-4), (IIc-5), (IIc-6), (IIc-7), or (IIc-8) may be used with a paraffin or water-miscible ointment base. Alternatively, compounds of formula (I), (I-1), (Ia), (Ia-1), (Ib), (Ic), (IIa), (IIa-1), (IIc), (IIc-1), (IIc-2), (IIc-2), (IIc-3), (IIc-4), (IIc-5), (IIc-6), (IIc-7), or (IIc-8) may be formulated into an oil-in-water emulsion base.

If desired, the aqueous phase of the cream matrix may include, for example, at least 30% w/w of polyols, i.e., alcohols having two or more hydroxyl groups such as propylene glycol, butane-1,3-diol, mannitol, sorbitol, glycerin, and polyethylene glycol (including PEG400), and mixtures thereof. Topical formulations may include, in some embodiments, compounds that enhance the absorption or penetration of the active ingredient through the skin or other affected areas. Examples of such skin penetration enhancers include dimethyl sulfoxide and related analogues.

The oil phase of an emulsion can be composed of known ingredients in a known manner. While this phase may consist only of emulsifiers (or simply emulsifiers), it may include, for example, at least one emulsifier with fats or oils, or with a mixture of both fats and oils. In some embodiments, hydrophilic emulsifiers are included together with lipophilic emulsifiers that act as stabilizers. In some embodiments, the emulsion comprises both oils and fats. Emulsifiers, with or without stabilizers, together constitute a so-called emulsified wax, and the wax, together with the oils and fats, constitutes a so-called emulsified ointment matrix, which forms the oily dispersed phase of the ointment formulation.

Emulsifiers and emulsion stabilizers suitable for formulations include, for example, 60, 80, cetearyl alcohol, benzyl alcohol, myristicin, glyceryl monostearate, and sodium lauryl sulfate.

The appropriate oil or fat is selected for the formulation based on the desired properties. Creams can be non-greasy, non-staining, and washable products with a suitable consistency to prevent leakage from tubes or other containers. Straight-chain or branched monoalkyl or dialkyl esters can be used, such as diisohexyl adipate, isohexadecanoyl stearate, propylene glycol diester of coconut fatty acids, isopropyl myristate, decyl oleate, isopropyl palmitate, butyl stearate, 2-ethylhexyl palmitate, or mixtures of branched esters known as CrodamolCAP. These esters can be used alone or in combination, depending on the desired properties. Alternatively, high-melting-point lipids, such as white soft paraffin and/or liquid paraffin or other mineral oils, can be used.

In some embodiments, the pharmaceutical formulations described herein comprise a combination with one or more pharmaceutically acceptable carriers or excipients and optionally other therapeutic agents. Pharmaceutical formulations containing an active ingredient can be in any form suitable for the intended method of administration. For example, when intended for oral use, they can be prepared as tablets, lozenges, tablets, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, solutions, syrups, or elixirs. Compositions intended for oral use can be prepared according to any method known in the art for manufacturing pharmaceutical compositions, and such compositions may contain one or more pharmaceutical agents, including sweeteners, flavoring agents, coloring agents, and preservatives, to provide a palatable formulation. Tablets containing an active ingredient mixed with non-toxic, pharmaceutically acceptable excipients suitable for manufacturing tablets are acceptable. These excipients can be, for example, inert diluents such as calcium carbonate or sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrants such as corn starch or alginic acid; binders such as starch, gelatin, or gum arabic; and lubricants such as magnesium stearate, stearic acid, or talc. Tablets may be uncoated or coated using known techniques, including microencapsulation, to delay disintegration and adsorption in the gastrointestinal tract, thereby providing sustained action over a longer period. For example, delaying materials such as glyceryl monostearate or glyceryl distearate may be used alone or in combination with waxes.

Formulations intended for oral use may also be provided as hard gelatin capsules in which the active ingredient is mixed with an inert solid diluent (such as calcium phosphate or kaolin) or as soft gelatin capsules in which the active ingredient is mixed with an aqueous or oily medium (such as peanut oil, liquid paraffin, or olive oil).

Aqueous suspensions contain active substances mixed with excipients suitable for manufacturing aqueous suspensions. Such excipients include suspending agents such as sodium carboxymethyl cellulose, methyl cellulose, hydroxypropyl methyl cellulose, sodium alginate, polyvinylpyrrolidone, tragacanth gum, and gum arabic; and dispersing or wetting agents such as naturally occurring phospholipids (e.g., lecithin), condensation products of olefinic oxygen and fatty acids (e.g., polyoxyethylene stearate), condensation products of ethylene oxide and long-chain fatty alcohols (e.g., heptadecanethoxycetyl alcohol), and condensation products of ethylene oxide and esters derived from fatty acids and hexyl anhydrides (e.g., polyoxyethylene sorbitan monooleate). Aqueous suspensions may also contain one or more preservatives, such as ethylparaben or n-propylparaben, one or more colorants, one or more flavoring agents, and one or more sweeteners such as sucrose or saccharin.

Oily suspensions can be prepared by suspending the active ingredients in vegetable oils (such as peanut oil, olive oil, sesame oil, or coconut oil) or mineral oils (such as liquid paraffin). Oral suspensions may contain thickeners such as beeswax, hard paraffin, or cetyl alcohol. Sweeteners (such as those mentioned above) and flavoring agents may be added to provide palatable oral formulations. These compositions may be preserved by adding antioxidants (such as ascorbic acid).

Dispersible powders and granules suitable for preparing aqueous suspensions by adding water provide an active ingredient that can be mixed with a dispersant or wetting agent, a suspending agent, and one or more preservatives. Suitable dispersants or wetting agents and suspending agents are exemplified by those disclosed above. Additional excipients, such as sweeteners, flavoring agents, and coloring agents, may also be present.

Pharmaceutical compositions may also be in the form of oil-in-water emulsions. The oil phase may be vegetable oils (such as olive oil or peanut oil), mineral oils (such as liquid paraffin), or mixtures thereof. Suitable emulsifiers include naturally occurring gums, such as gum arabic and tragacanth; naturally occurring phospholipids, such as soybean lecithin; esters or metaesters derived from fatty acids and hexitan anhydrides, such as sorbitan monooleate; and condensation products of these metaesters with ethylene oxide, such as polyoxyethylene sorbitan monooleate. Emulsions may also contain sweeteners and flavoring agents. Syrups and elixirs may be formulated with sweeteners such as glycerin, sorbitol, or sucrose. Such formulations may also contain modifiers, preservatives, flavoring agents, or coloring agents.

Pharmaceutical compositions may be in the form of sterile injectable or intravenous preparations, such as sterile injectable aqueous or oily suspensions. Such suspensions may be formulated using suitable dispersants or wetting agents and suspending agents already mentioned above, according to known techniques. Sterile injectable or intravenous preparations may also comprise sterile injectable solutions or suspensions in non-toxic, parenteral-acceptable diluents or solvents (such as solutions in 1,3-butanediol), or be prepared as lyophilized powders. Acceptable solvents and media are water, Ringer's solution, and isotonic sodium chloride solution. Furthermore, sterile, non-volatile oils are commonly used as solvents or suspension media. For this purpose, any mild, non-volatile oil may be used, including synthetic monoglycerides or diglycerides. Additionally, fatty acids such as oleic acid may also be used in the preparation of injectable formulations.

The amount of active ingredient that can be combined with a carrier material to produce a single dosage form can vary depending on the host being treated and the specific route of administration. For example, a sustained-release formulation intended for oral administration to humans may contain about 1 mg to about 1000 mg of the active material, compounded with an appropriate and convenient amount of carrier material, which may vary between about 5% to about 95% (weight:weight) of the total composition. Pharmaceutical compositions can be prepared to provide easily measurable dosage amounts. For example, an aqueous solution intended for intravenous infusion may contain about 3 to about 500 μg of the active ingredient per milliliter of solution to allow for the infusion of an appropriate volume at a rate of about 30 mL/hr.

Formulations suitable for topical application to the eyes also include eye drops, wherein the active ingredient is dissolved or suspended in a suitable carrier, particularly in an aqueous solution of the active ingredient. The active ingredient may be present in such formulations at a concentration of about 0.5% to about 20% (such as about 0.5% to about 10%, for example about 1.5% w/w).

Preparations suitable for topical application in the oral cavity include, for example, lozenges containing flavoring active ingredients such as sucrose and gum arabic or tragacanth; tablets containing inert active ingredients such as gelatin and glycerin, or sucrose and gum arabic; and mouthwashes containing active ingredients in a suitable liquid carrier.

Formulations for rectal administration may be provided as suppositories with a suitable matrix, including, for example, cocoa butter or salicylates.

Formulations suitable for intrapulmonary or intranasal administration have particle sizes in the range of from about 0.1 micrometers to about 500 micrometers (such as about 0.5 micrometers, about 1 micrometer, about 30 micrometers, or about 35 micrometers, etc.) and are administered by rapid inhalation through the nasal passage or by inhalation through the mouth to reach the alveolar sacs. Suitable formulations include aqueous or oily solutions of the active ingredient. Formulations suitable for aerosol or dry powder administration can be prepared according to conventional methods and can be delivered together with other therapeutic agents, such as compounds used to date for the treatment of cancers described below.

In some embodiments, the inhalable composition comprises a compound of formula (I), (I-1), (Ia), (Ia-1), (Ib), (Ic), (IIa), (IIa-1), (IIc), (IIc-1), (IIc-2), (IIc-2), (IIc-3), (IIc-4), (IIc-5), (IIc-6), (IIc-7), or (IIc-8), or a pharmaceutically acceptable salt thereof. In some embodiments, the inhalable composition is suitable for treating cancer. In some embodiments, the pharmaceutically acceptable salt is an inorganic acid salt, including hydrochloride, hydrobromide, sulfate, or phosphate. For example, such salts may cause less lung irritation compared to other salts. In some embodiments, the inhalable composition is delivered as an aerosol into the bronchial space, the aerosol comprising particles with a median mass aerodynamic diameter (MMAD) between about 1 μm and about 5 μm. In some embodiments, compounds of formula (I), (I-1), (Ia), (Ia-1), (Ib), (Ic), (IIa), (IIa-1), (IIc), (IIc-1), (IIc-2), (IIc-2), (IIc-3), (IIc-4), (IIc-5), (IIc-6), (IIc-7), or (IIc-8) are formulated for aerosol delivery using a nebulizer, a pressurized metered-dose inhaler (pMDI), or a dry powder inhaler (DPI).

Non-limiting examples of nebulizers include atomizing, jetting, ultrasonic, pressurizing, vibrating perforated plate, or equivalent nebulizers, including those utilizing adaptive aerosol delivery technology (Denyer, J. Aerosol medicine Pulmonary Drug Delivery 2010, 23 Supplement 1, S1-S10). Jet nebulizers use air pressure to break a liquid solution into aerosol droplets. Ultrasonic nebulizers operate by shearing liquid into small aerosol droplets using piezoelectric crystals. Pressurized nebulization systems force a solution under pressure through a small orifice to produce aerosol droplets. Vibrating perforated plate devices utilize rapid vibration to shear a liquid flow into appropriately sized droplets.

In some implementations, a nebulizer is used to deliver a formulation of a compound that can be atomized (I), (I-1), (Ia), (Ia-1), (Ib), (Ic), (IIa), (IIa-1), (IIc), (IIc-1), (IIc-2), (IIc-2), (IIc-3), (IIc-4), (IIc-5), (IIc-6), (IIc-7), or (IIc-8) into the bronchial space as an aerosol containing particles with MMAD primarily between about 1 μm and about 5 μm. For optimal therapeutic efficacy and to avoid upper respiratory tract and systemic side effects, most aerosol particles should not have an MMAD larger than about 5 μm. If the aerosol contains a large number of particles with MMAD larger than about 5 μm, the particles deposit in the upper airways, thereby reducing the amount of drug delivered to the sites of inflammation and bronchoconstriction in the lower respiratory tract. If the MMAD of an aerosol is less than about 1 μm, the particles can remain suspended in inhaled air in some cases and can subsequently be exhaled during exhalation.

When formulated and delivered according to the methods described herein, the aerosol formulation for nebulization delivers a therapeutically effective dose of compounds of formula (I), (I-1), (Ia), (Ia-1), (Ib), (Ic), (IIa), (IIa-1), (IIc), (IIc-1), (IIc-2), (IIc-2), (IIc-3), (IIc-4), (IIc-5), (IIc-6), (IIc-7), or (IIc-8) to a therapeutic target, such as a cancer site. The amount of drug administered can be adjusted to reflect the efficiency of delivering a therapeutically effective dose of compounds of formula (I), (I-1), (Ia), (Ia-1), (Ib), (Ic), (IIa), (IIa-1), (IIc), (IIc-1), (IIc-2), (IIc-2), (IIc-3), (IIc-4), (IIc-5), (IIc-6), (IIc-7), or (IIc-8). In some embodiments, the combination of the aqueous aerosol formulation with an atomizing, spraying, pressurizing, vibrating perforated plate, or ultrasonic nebulizer allows delivery of about 20% to about 90% (such as about 70%) of the administered dose of the compound of formulas (I), (I-1), (Ia), (Ia-1), (Ib), (Ic), (IIa), (IIa-1), (IIc), (IIc-1), (IIc-2), (IIc-2), (IIc-3), (IIc-4), (IIc-5), (IIc-6), (IIc-7), or (IIc-8) (depending on the nebulizer). In some embodiments, about 30% to about 50% of the active compound is delivered. For example, about 70% to about 90% of the active compound may be delivered.

In some embodiments, compounds of formulas (I), (I-1), (Ia), (Ia-1), (Ib), (Ic), (IIa), (IIa-1), (IIc), (IIc-1), (IIc-2), (IIc-2), (IIc-3), (IIc-4), (IIc-5), (IIc-6), (IIc-7), or (IIc-8), or pharmaceutically acceptable salts thereof, are delivered as dry, inhalable powders. The compounds are typically administered intrabronchially as dry powder formulations to efficiently deliver fine particles of the compound into the bronchial space using dry powder or metered-dose inhalers. Compounds of formulas (I), (I-1), (Ia), (Ia-1), (Ib), (Ic), (IIa), (IIa-1), (IIc), (IIc-1), (IIc-2), (IIc-2), (IIc-3), (IIc-4), (IIc-5), (IIc-6), (IIc-7), or (IIc-8) can be processed into MMAD particles primarily between about 1 μm and about 5 μm via DPI delivery, grinding spray drying, critical fluid treatment, or precipitation from solution. Media grinding, jet grinding, and spray drying apparatus and procedures capable of producing MMAD particles between about 1 μm and about 5 μm are well known in the art. In some embodiments, the excipient is added to a compound of formula (I), (I-1), (Ia), (Ia-1), (Ib), (Ic), (IIa), (IIa-1), (IIc), (IIc-1), (IIc-2), (IIc-2), (IIc-3), (IIc-4), (IIc-5), (IIc-6), (IIc-7), or (IIc-8) before processing into particles of the desired size. In some embodiments, the excipient is mixed with particles of the desired size to aid in the dispersion of the drug particles, for example, by using lactose as an excipient.

Particle size determination is performed using devices well known in the art. For example, the Anderson multi-stage cascade impactor or other suitable methods (such as those specifically cited in Chapter 601 of the United States Pharmacopeia) are used as devices for characterizing dosage and aerosols within dry powder inhalers.

In some embodiments, compounds of formula (I), (I-1), (Ia), (Ia-1), (Ib), (Ic), (IIa), (IIa-1), (IIc), (IIc-1), (IIc-2), (IIc-2), (IIc-3), (IIc-4), (IIc-5), (IIc-6), (IIc-7), or (IIc-8) can be delivered as dry powder using devices such as dry powder inhalers or other dry powder dispersing devices. Non-limiting examples of dry powder inhalers and devices include those disclosed in US 5,458,135; US 5,740,794; US 5,775,320; US 5,785,049; US 3,906,950; US 4,013,075; US 4,069,819; US 4,995,385; US 5,522,385; US 4,668,218; US 4,667,668; US 4,805,811 and US 5,388,572. There are two main designs for dry powder inhalers. One design is a metering device in which a reservoir for the medication is located within the device, and the patient adds a dose of medication to the inhalation chamber. The second design is a factory-metering device in which each individual dose is manufactured in a separate container. Both systems rely on formulating the drug into small particles (MMAD) of approximately 1 μm to approximately 5 μm, and often involve co-formulation with larger excipient particles (such as, but not limited to, lactose). The drug powder is placed in the inhalation chamber (dose metered by the device or by a crushing plant), and the patient's inspiratory airflow accelerates the powder out of the device and into the mouth. The non-laminar characteristics of the powder path lead to the breakdown of excipient-drug aggregates, and the mass of the large excipient particles causes them to become lodged in the back of the throat, while the smaller drug particles are deposited deep in the lungs. In some embodiments, a compound of formula (I), (I-1), (Ia), (Ia-1), (Ib), (Ic), (IIa), (IIa-1), (IIc), (IIc-1), (IIc-2), (IIc-2), (IIc-3), (IIc-4), (IIc-5), (IIc-6), (IIc-7), or (IIc-8) or a pharmaceutically acceptable salt thereof is delivered as a dry powder using any type of dry powder inhaler as described herein, wherein the MMAD of the dry powder (excluding any excipients) is primarily in the range of about 1 μm to about 5 μm.

In some embodiments, a metered-dose inhaler is used to deliver compounds of formula (I), (I-1), (Ia), (Ia-1), (Ib), (Ic), (IIa), (IIa-1), (IIc), (IIc-1), (IIc-2), (IIc-2), (IIc-3), (IIc-4), (IIc-5), (IIc-6), (IIc-7), or (IIc-8) as dry powder. Non-limiting examples of metered-dose inhalers and devices include those disclosed in US5,261,538, US5,544,647, US5,622,163, US4,955,371, US3,565,070, US3,361,306, and US6,116,234. In some embodiments, a metered-dose inhaler is used to deliver a compound of formula (I), (I-1), (Ia), (Ia-1), (Ib), (Ic), (IIa), (IIa-1), (IIc), (IIc-1), (IIc-2), (IIc-2), (IIc-3), (IIc-4), (IIc-5), (IIc-6), (IIc-7), or (IIc-8) or a pharmaceutically acceptable salt thereof as a dry powder, wherein the MMAD of the dry powder (excluding any excipients) is primarily in the range of about 1 μm to about 5 μm.

Preparations suitable for vaginal application may be provided in the form of pessaries, tampons, creams, gels, pastes, foams or sprays, and contain, in addition to the active ingredient, a suitable carrier known in the art.

Preparations suitable for parenteral administration include aqueous and non-aqueous sterile injectable solutions that may contain antioxidants, buffers, antibacterial agents, and solutes to make the preparation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions that may contain suspending agents and thickeners.

The formulation is present in single-dose or multi-dose containers, such as sealed ampoules and vials, and can be stored under lyophilized (freeze-dried) conditions, requiring only immediate addition of a sterile liquid carrier, such as water for injection, before use. Temporary injectable solutions and suspensions are prepared from sterile powders, granules, and tablets of the aforementioned types. Single-dose formulations include formulations containing a daily dose or a unit daily sub-dose or a suitable portion thereof of the active ingredient as described above.

It should be understood that, in addition to the ingredients specifically mentioned above, formulations may include other agents conventional in the art related to the type of formulation discussed, such as flavoring agents suitable for oral administration.

Furthermore, a veterinary drug composition comprising at least one active ingredient as defined above and its veterinary drug carrier is provided.

Veterinary drug carriers are materials that can be used to administer compositions and can be solid, liquid, or gaseous materials. They are otherwise inert or acceptable in the veterinary field and compatible with the active ingredient. These veterinary drug compositions can be administered orally, parenterally, or via any other desired route.

The compounds described herein are intended to provide controlled-release pharmaceutical formulations (“controlled-release formulations”) containing one or more compounds as active ingredients, wherein the release of the active ingredient is controlled and modulated to allow administration at a lower frequency or to improve the pharmacokinetic or toxicological characteristics of a given active ingredient.

The effective dose of the active ingredient depends at least on the nature of the condition being treated, its toxicity, the method of delivery, and the pharmaceutical formulation, and can be determined by clinicians using routine dose-escalation studies. This dose is expected to be from about 0.0001 to about 100 mg/kg body weight per day; typically, from about 0.01 to about 10 mg/kg body weight per day; more typically, from about 0.01 to about 5 mg/kg body weight per day; and most typically, from about 0.05 to about 0.5 mg/kg body weight per day. For example, the candidate daily dose range for an adult weighing about 70 kg could be from about 1 mg to about 1000 mg, such as between about 5 mg and about 500 mg, and could be in the form of a single dose or multiple doses.

IV. Route of Administration

One or more of the compounds of formula (I), (I-1), (Ia), (Ia-1), (Ib), (Ic), (IIa), (IIa-1), (IIc), (IIc-1), (IIc-2), (IIc-2), (IIc-3), (IIc-4), (IIc-5), (IIc-6), (IIc-7), or (IIc-8) (referred to herein as the active ingredient) may be administered via any route suitable for the condition to be treated. Suitable routes include oral, rectal, nasal, pulmonary, local (including buccal and sublingual), vaginal, and parenteral (including subcutaneous, intramuscular, intravenous, intradermal, intrathecal, and epidural). It should be understood that the route may be changed depending on, for example, the condition of the recipient. An advantage of the compounds herein is that they are orally bioavailable and can be administered orally.

The compounds disclosed herein (also referred to herein as the active ingredients) can be administered via any route suitable for the condition to be treated. Suitable routes include oral, rectal, nasal, topical (including buccal and sublingual), transdermal, vaginal, and parenteral (including subcutaneous, intramuscular, intravenous, intradermal, intrathecal, and epidural). It should be understood that the route may be changed depending on, for example, the condition of the recipient. An advantage of some of the compounds disclosed herein is that they are orally bioavailable and can be administered orally.

The compounds disclosed herein may be administered to an individual for the desired period of time or duration according to an effective dosing regimen, such as at least about one month, at least about two months, at least about three months, at least about six months, or at least about twelve months or longer. In some embodiments, the compounds are administered on a daily or intermittent schedule throughout the individual's life.

The dosage or frequency of administration of the compounds disclosed herein may be adjusted during treatment based on the judgment of the physician administering the medication.

The compound can be administered to an individual (e.g., a person) in an effective amount. In some embodiments, the compound is administered once daily.

The compound may be administered by any available route and means, such as by oral or parenteral (e.g., intravenous) administration. Therapeutic amounts of the compound may include from about 0.00001 mg/kg body weight per day to about 10 mg/kg body weight per day, such as from about 0.0001 mg/kg body weight per day to about 10 mg/kg body weight per day, or such as from about 0.001 mg/kg body weight per day to about 1 mg/kg body weight per day, or such as from about 0.01 mg/kg body weight per day to about 1 mg/kg body weight per day, or such as from about 0.05 mg/kg body weight per day to about 0.5 mg/kg body weight per day, or such as from about 0.3 mg to about 30 mg per day, or such as from about 30 mg to about 300 mg per day.

The compounds of this disclosure may be combined with one or more additional therapeutic agents at any dose of the disclosed compounds (e.g., about 1 mg to about 1000 mg of the compound). Therapeuticly effective amounts may include about 1 mg/dose to about 1000 mg/dose, such as about 50 mg/dose to about 500 mg/dose, or such as about 100 mg/dose to about 400 mg/dose, or such as about 150 mg/dose to about 350 mg/dose, or such as about 200 mg/dose to about 300 mg/dose. Other therapeutically effective amounts of the compounds of this disclosure are about 100 mg, about 125 mg, about 150 mg, about 175 mg, about 200 mg, about 225 mg, about 250 mg, about 275 mg, about 300 mg, about 325 mg, about 350 mg, about 375 mg, about 400 mg, about 425 mg, about 450 mg, about 475 mg, or about 500 mg per dose. Other therapeutically effective amounts of the disclosed compounds are about 100 mg per dose, or about 125 mg, about 150 mg, about 175 mg, about 200 mg, about 225 mg, about 250 mg, about 275 mg, about 300 mg, about 325 mg, about 350 mg, about 375 mg, about 400 mg, about 425 mg, about 450 mg, or about 500 mg per dose. A single dose may be administered hourly, daily, or weekly. For example, a single dose may be administered every 1 hour, about 2 hours, about 3 hours, about 4 hours, about 6 hours, about 8 hours, about 12 hours, about 16 hours, or about every 24 hours. A single dose may also be administered every 1 day, about 2 days, about 3 days, about 4 days, about 5 days, about 6 days, or about every 7 days. A single dose may also be administered every 1 week, about 2 weeks, about 3 weeks, or about every 4 weeks. In some embodiments, a single dose may be administered about once a week. A single dose can also be administered approximately once a month.

Other therapeutically effective amounts of the disclosed compounds are about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg, or about 100 mg per dose.

The dosage frequency of the disclosed compound can be determined according to the needs of each patient and can be, for example, once daily or twice daily or more. Administration of the compound continues as long as necessary to treat the disease or condition. For example, the compound can be administered to a person with cancer for a period of approximately 20 days to approximately 180 days, or for a period of approximately 20 days to approximately 90 days, or for a period of approximately 30 days to approximately 60 days.

Administration may be intermittent, with the patient receiving a daily dose of the disclosed compound for periods of several days or more, followed by periods of several days or more without receiving the daily dose. For example, the patient may receive a dose of the compound every other day or three times a week. Again, as an example, the patient may receive a daily dose of the compound for a period of approximately 1 day to approximately 14 days, followed by a period of approximately 7 days to approximately 21 days without receiving the compound, and then resume receiving the daily dose of the compound for a subsequent period (e.g., approximately 1 day to approximately 14 days). Depending on clinical need, the patient may be treated with alternating periods of compound administration followed by periods of no administration.

In some embodiments, a pharmaceutical composition is provided comprising a compound of the present disclosure or a pharmaceutically acceptable salt thereof, in combination with one or more (e.g., one, two, three, four, one or two, one to three, or one to four) additional therapeutic agents, and a pharmaceutically acceptable excipient.

In some embodiments, a kit is provided comprising a combination of the compound of the present disclosure or a pharmaceutically acceptable salt thereof with one or more (e.g., one, two, three, four, one or two, one to three, or one to four) additional therapeutic agents.

In some embodiments, the compound of this disclosure or a pharmaceutically acceptable salt thereof is combined with one, two, three, four, or more additional therapeutic agents. In some embodiments, the compound of this disclosure or a pharmaceutically acceptable salt thereof is combined with two additional therapeutic agents. In some embodiments, the compound of this disclosure or a pharmaceutically acceptable salt thereof is combined with three additional therapeutic agents. In some embodiments, the compound of this disclosure or a pharmaceutically acceptable salt thereof is combined with four additional therapeutic agents. The one, two, three, four, or more additional therapeutic agents may be different therapeutic agents selected from the same class of therapeutic agents, and/or they may be selected from different classes of therapeutic agents.

In some embodiments, when the compounds of this disclosure are combined with one or more additional therapeutic agents as described herein, the components of the composition are administered simultaneously or sequentially. When administered sequentially, the combination may be administered in two or more doses.

In some embodiments, the compounds of this disclosure are combined with one or more additional therapeutic agents in a single dosage form for simultaneous administration to a patient, such as as a solid dosage form for oral administration.

In some embodiments, the compounds of this disclosure are administered together with one or more additional therapeutic agents.

To prolong the effect of the compounds disclosed herein, it is generally desirable to slow down the absorption of the compound from subcutaneous or intramuscular injection. This can be achieved by using liquid suspensions of poorly water-soluble crystalline or amorphous materials. The absorption rate of the compound depends on its dissolution rate, and in turn, on the crystal size and crystal form. Alternatively, delayed absorption of the compound in a parenteral administration form can be achieved by dissolving or suspending the compound in an oil medium. Injectable long-acting forms are prepared by forming microcapsule matrices of the compound in biodegradable polymers, such as polylactide-polyglycolic acid. The release rate of the compound can be controlled depending on the ratio of compound to polymer and the properties of the specific polymer used. Examples of other biodegradable polymers include poly(orthoester) and poly(anhydride). Long-acting injectable formulations are also prepared by encapsulating the compound in liposomes or microemulsions that are compatible with body tissues.

V. Combination Therapy

The compounds disclosed herein and the compositions provided herein may also be used in combination with other active therapeutic agents. Depending on the application, these other active therapeutic agents may be anticancer agents or antiviral agents (e.g., anti-HIV agents or anti-hepatitis B virus agents).

A. Combination therapy

1. Cancer

In some embodiments, the compounds described herein are combined with one or more adjunctive therapeutic agents, such as inhibitory immune checkpoint blockers or inhibitors, stimulating immune checkpoint stimulants, agonists or activators, chemotherapeutic agents, anticancer agents, radiotherapy agents, antitumor agents, antiproliferative agents, antiangiogenic agents, anti-inflammatory agents, immunotherapy agents, therapeutic antigen-binding molecules (any form of monospecific and multispecific antibody and fragment thereof, such as including but not limited to BiKEs, TriKEs, scFv, Fab, Fab derivatives), bispecific antibodies, and non-immunoglobulin antibody mimics (such as including but not limited to adnectin, affinity molecules, affilin, af). fimer, affitin, alphabet, anticalin, peptide aptamers, armadillo repeat protein (ARM), atrimer, avimer, engineered ankylosing repeat protein fynomer, knottin, Kunitz domain peptide, monobody, and nanoCLAMP), antibody-drug conjugates (ADCs), antibody-peptide conjugates, oncolytic viruses, gene modifiers or editing agents, cells containing chimeric antigen receptors (CARs) (e.g., including T-cell immunotherapies, NK-cell immunotherapies, or macrophage immunotherapies), cells containing engineered T-cell receptors (TCR-T), or any combination thereof.

Indicative targets

In some embodiments, one or more additional therapeutic agents include, but are not limited to, inhibitors, agonists, antagonists, ligands, modulators, stimulants, blockers, activators, or repressors of targets (e.g., peptides or polynucleotides), including but not limited to: Albsen murine leukemia virus oncogene homolog 1 gene (ABL, such as ABL1), acetyl-CoA carboxylase (such as ACC1/2), activated CDC kinase (ACK, such as ACK1), adenosine deaminase, adenosine receptors (such as A2BR, A2aR, A3aR), adenylate cyclase, ADP-ribosyl cyclase-1, adrenocorticotropic hormone receptor (ACTH), aeromonas lysin, AKT1 gene, Alk-5 protein kinase, alkaline phosphorus Acidase, α1-adrenergic receptor, α2-adrenergic receptor, α-ketoglutarate dehydrogenase (KGDH), aminopeptidase N, AMP-activated protein kinase, anaplastic lymphoma kinase (ALK, such as ALK1), androgen receptor, angiopoietin (such as ligand-1, ligand-2), angiotensinogen (AGT) gene, murine thymoma virus oncogene homolog 1 (AKT) protein kinase (such as AKT1, AKT2, AKT3), apolipoprotein A-I (APOA1) gene, apoptosis-inducing factor, apoptosis proteins (such as 1, 2), apoptosis signal-regulated kinase (ASK, such as ASK1), arginase (I), arginine deiminase, aromatase, steroid homolog 1 (ASTE1). Genes, ataxia-telangiectasia and Rad3-associated (ATR) serine/threonine protein kinases, Aurora protein kinases (such as 1, 2), Axl tyrosine kinase receptors, 4-1BB ligands (CD137L), baculovirus-containing IAP repeat 5 (BIRC5) gene, basigin, B-cell lymphoma 2 (BCL2) gene, Bcl2 binding component 3, Bcl2 protein, BCL2L11 gene, BCR (split cluster region) protein and gene, β-adrenergic receptor, β-catenin, B-lymphocyte antigen CD19, B-lymphocyte antigen CD20, B-lymphocyte adhesion molecules, B-lymphocyte stimulating ligands, bone morphogenetic protein-10 ligands Bone morphogenetic protein-9 ligand regulators, Brachyury protein, Bradykinin receptor, B-Raf proto-oncogene (BRAF), Brc-Abl tyrosine kinase, proteins with bromine-containing and outer (BET) bromine domains (such as BRD2, BRD3, BRD4), Bruton's tyrosine kinase (BTK), calmodulin, calmodulin-dependent protein kinases (CaMK, such as CAMKII), cancer/testis antigen 2, cancer/testis antigen NY-ESO-1, cancer/testis antigen 1B (CTAG1) gene, cannabinoid receptors (such as CB1, CB2), carbonic anhydrase, casein kinases (CK, such as CKI, CKII). Caspases (such as caspase-3, caspase-7, caspase-9), caspase-8 apoptosis-associated cysteine peptidase CASP8-FADD-like regulator, caspase recruitment domain protein-15, cathepsin G, CCR5 gene, CDK activated kinase (CAK), checkpoint kinases (such as CHK1, CHK2), chemokine (C-C motif) receptors (such as CCR2, CCR4, CCR5, CCR8), chemokine (C-X-C motif) receptors (such as CXCR1, CXCR2, CXCR3, and CXCR4), chemokine CC21 ligand, cholecystokinin CCK2 receptor, human chorionic gonadotropin, c-Kit ( Tyrosine-protein kinase Kit or CD117), CISH (cytokine-inducible SH2-containing protein), blocking proteins (such as 6, 18), differentiation clusters (CD) (such as CD4, CD27, CD29, CD30, CD33, CD37, CD40, CD40 ligand receptor, CD40 ligand, CD40LG gene, CD44, CD45, CD47, CD49b, CD51, CD52, CD55, CD58, CD66e (CEACAM6), CD70 gene, CD74, CD79, CD79b, CD79B gene, CD80, CD95, CD99, CD117, CD122, CDw123), CD134, CDw137, CD158a, CD158b1, CD158b2, CD223, CD276 antigens; cluster protein (CLU) gene, cluster protein, c-Met (hepatocyte growth factor receptor (HGFR)), complement C3, connective tissue growth factor, COP9 signaling subunit 5, CSF-1 (colony-stimulating factor 1 receptor), CSF2 gene, CTLA-4 (cytotoxic T lymphocyte protein 4) receptor, C-type lectin domain protein 9A (CLEC9A), cyclin D1, cyclin G1, cyclin-dependent kinases (CDKs, such as CDK1, CDK12, CDK1B, CDK2-9) Cyclooxygenases (such as COX1, COX2), CYP2B1 gene, cysteine palmitoyltransferase (Porcupine), cytochrome P450 11B2, cytochrome P450 17, cytochrome P450 17A1, cytochrome P450 2D6, cytochrome P450 3A4, cytochrome P450 reductase, cytokine signaling 1, cytokine signaling 3, cytoplasmic isocitrate dehydrogenase, cytosine deaminase, cytosine DNA methyltransferase, cytotoxic T lymphocyte protein 4, DDR2 gene, DEAD box helicase 6 (DDX6), death receptor 5 (DR5, TRAILR2), death receptor 4 (DR4, TRAILR) 1) Delta-like protein ligands (such as 3, 4), deoxyribonucleases, deubiquitinases (DUB), Dickkopf-1 ligands, dihydrofolate reductase (DHFR), dihydropyrimidine dehydrogenase, dipeptidyl peptidase IV, discoid domain receptors (DDR, such as DDR1), diacylglycerol kinase ζ (DGKZ), DNA-binding proteins (such as HU-β), DNA-dependent protein kinases, DNA gyrases, DNA methyltransferases, DNA polymerases (such as α), DNA primases, dUTP pyrophosphatase, L-DOPAchrome tautomerase, E3 ubiquitin-protein ligases (such as RNF128, CBL-B), echinoderms, microtubule-like protein 4, EGFR tyrosine kinase Receptors, elastase, elongation factor 1α2, elongation factor 2, endothelial factors, endonucleases, endoplasmic reticulum aminopeptidase (ERAP, such as ERAP1, ERAP2), endoplasmic reticulin, endothelial sialic acid protein, endostatin, endothelial vasoconstrictor peptides (such as ET-A, ET-B), zeste enhancer homolog 2 (EZH2), Ephrin (EPH) tyrosine kinase (such as Epha3, Ephb4), Ephrin B2 ligand, epidermal growth factor, epidermal growth factor receptor (EGFR), epidermal growth factor receptor (EGFR) gene, Epigen, epithelial cell adhesion molecule (EpCAM), Erb-b2 (v-erb-b2 avian erythroblasts) Leukemia virus oncogene homolog 2) Tyrosine kinase receptors, Erb-b3 tyrosine kinase receptors, Erb-b4 tyrosine kinase receptors, E-selectin, estradiol 17β dehydrogenase, estrogen receptors (such as α, β), estrogen-associated receptors, eukaryotic translation initiation factor 5A (EIF5A) gene, export protein 1, extracellular signal-associated kinases (such as 1, 2), extracellular signal-regulated kinases (ERK), hypoxia-inducible factor prolyl hydroxylase (HIF-PH or EGLN), factors (such as Xa, VIIa), farnesoid x receptor (FXR), Fas ligand, fatty acid synthase (FASN), ferritin, FGF-2 ligand, FGF-5 ligand Fibroblast growth factor (FGF, such as FGF1, FGF2, FGF4), fibronectin, focal adhesion kinase (FAK, such as FAK2), folate hydrolase prostate-specific membrane antigen 1 (FOLH1), folate receptor (such as α), folate, folate transporter 1, FYN tyrosine kinase, paired basic amino acid cleaving enzyme (FURIN), β-glucuronidase, galactosyltransferase, galactolectin 3, ganglioside GD2, glucocorticoids, glucocorticoid-induced TNFR-related protein GITR receptor, glutamate carboxypeptidase II, glutaminase, glutathione S-transferase P, glycogen synthase kinase (GSK, such as 3β), phosphatidylinositol proteoglycan 3 (GPC3), Gonadotropin-releasing hormone (GNRH), Granulocyte-macrophage colony-stimulating factor (GM-CSF) receptor, Granulocyte-macrophage colony-stimulating factor (GCSF) ligand, Growth factor receptor-binding protein 2 (GRB2), Grp78 (78kDa glucose-regulated protein), Calcium-binding protein, Molecular chaperone, groEL2 gene, Heme oxygenase 1 (HO1), Heme oxygenase 2 (HO2), Heat shock proteins (such as 27, 70, 90α, β), Heat shock protein gene, Heat-stable enterotoxin receptor, Hedgehog protein, Heparinase, Hepatocyte growth factor, HERV-H LTR-related protein 2, Hexokinase, Histamine H2 receptor, Histone methyl HLA-transferase (DOT1L), histone deacetylases (HDACs, such as 1, 2, 3, 6, 10, 11), histone H1, histone H3, HLA class I antigen (A-2α), HLA class II antigen, HLA class I antigen αG (HLA-G), non-classical HLA, homeobox protein NANOG, HSPB1 gene, human leukocyte antigen (HLA), human papillomavirus (such as E6, E7) protein, hyaluronic acid, hyaluronidase, hypoxia-inducible factor-1α (HIF1α), imprinted maternal transcript (H19) gene, mitogen-activated protein kinase 1 (MAP4K1), tyrosine protein kinase HCK, I-κB kinase (IKK, such as... IL-1α, IL-1β, IL-12, IL-12 gene, IL-15, IL-17, IL-2 gene, IL-2 receptor α subunit, IL-2, IL-3 receptor, IL-4, IL-6, IL-7, IL-8, immunoglobulins (such as G, G1, G2, K, M), immunoglobulin Fc receptor, immunoglobulin γFc receptor (such as I, III, IIIA), indoleamine 2,3-dioxygenase (IDO, such as IDO1 and IDO2), indoleamine pyrrole 2,3-dioxygenase 1 inhibitor, insulin receptor, insulin-like growth factor (such as I, 2), integrin α4/β1, integrin α4/β7, integrin α5/ β1, integrin α-V/β3, integrin α-V/β5, integrin α-V/β6, intercellular adhesion molecule 1 (ICAM-1), interferons (such as α, α2, β, γ), interferon-induced protein 2 (AIM2) not found in melanoma, interferon type I receptor, interleukin 1 ligand, interleukin 13 receptor α2, interleukin 2 ligand, interleukin 1 receptor-associated kinase 4 (IRAK4), interleukin 2, interleukin 29 ligand, interleukin 35 (IL-35), isocitrate dehydrogenases (such as IDH1, IDH2), Janus kinases (JAK, such as JAK1, JAK2), Jun N-terminal kinase, kallikrein-related peptidase 3 (K LK3 gene, killer cell Ig-like receptor, kinase insertion domain receptor (KDR), kinin-like protein KIF11, Kirsten rat sarcoma virus oncogene homolog (KRAS) gene, Kisspeptin (KiSS-1) receptor, KIT gene, v-kit Hardy-Zuckerman 4 feline sarcoma virus oncogene homolog (KIT) tyrosine kinase, lactoferrin, lanosterol-14 demethylase, LDL receptor-associated protein 1, leukocyte immunoglobulin-like receptor subfamily B member 1 (ILT2), leukocyte immunoglobulin-like receptor subfamily B member 2 (ILT4), leukotriene A4 hydrolase, listeriosis. Listeriolysin, L-selectin, luteinizing hormone receptor, lyase, lymphocyte activation gene 3 protein (LAG-3), lymphocyte antigen 75, lymphocyte functional antigen 3 receptor, lymphocyte-specific protein tyrosine kinase (LCK), lymphocyte chemotactic protein, Lyn (Lck/Yes novel) tyrosine kinase, lysine demethylases (such as KDM1, KDM2, KDM4, KDM5, KDM6, A/B/C/D), lysophosphatidyl-1 receptor, lysosome-associated membrane protein family (LAMP) gene, lysyl oxidase homolog 2, lysyl oxidase protein (LOX), 5-lipoxygenase (5-LOX), hematopoietic progenitor cell kinase 1 (HPK1), hepatocyte growth factor receptor (MET) gene, macrophage colony-stimulating factor (MCSF) ligand, macrophage migration inhibitory factor, MAGEC1 gene, MAGEC2 gene, main fornix protein, MAPK activated protein kinases (such as MK2), Mas-associated G protein-coupled receptor, matrix metalloproteinases (MMPs, such as MMP2, MMP9), Mcl-1 differentiation protein, Mdm2 p53 binding protein, Mdm4 protein, Melan-A (MART-1) melanoma antigen, melanocyte protein Pmel 17, melanocyte-stimulating hormone ligand, melanoma antigen family A3 (MAGEA3) gene, melanoma-associated antigens (such as 1, 2) 3, 6), membrane-containing copper amine oxidase, mesothelin, MET tyrosine kinase, pro-metabolic glutamate receptor 1, metalloreductase STEAP1 (prostate six-transmembrane epithelial antigen 1), Metastin, methionine aminopeptidase 2, methyltransferase, mitochondrial 3-ketoyl-CoA thiolase, mitogen-activated protein kinase (MAPK), mitogen-activated protein kinase (MEK, such as MEK1, MEK2), mTOR (mechanical target of rapamycin (serine/threonine kinase)), mTOR complex (such as 1, 2), mucin (such as 1, 5A, 16), mut T homolog (MTH, such as MTH1), Myc proto-oncogene protein, myeloid leukemia 1 (MCL1) Genes, tetradecyl alanine-rich protein kinase C substrate (MARCKS) protein, NAD-ADP ribotransferase, natriuretic peptide receptor C, neurocellular adhesion molecule 1, neurokinin 1 (NK1) receptor, neurokinin receptor, neurocilia protein 2, NFκB activator, NIMA-associated kinase 9 (NEK9), nitric oxide synthase, NK cell receptor, NK3 receptor, NKG2 A B activator of NK receptor, NLRP3 (NACHT LRR PYD domain protein 3) regulator, norepinephrine transporter, Notch (such as Notch-2 receptor, Notch-3 receptor, Notch-4 receptor), nuclear factor erythrocyte 2-related factor 2, nuclear factor (NF)κB, nucleolar protein, nucleolar phosphoprotein, nucleolar phosphoprotein-anaplastic lymphoma kinase (NPM-ALK), 2-ketoglutarate dehydrogenase, 2,5-oligoadenylate synthase, O-methylguanine DNA methyltransferase, opioid receptors (such as delta), ornithine decarboxylase, orotate phosphoribosyltransferase, orphan nucleohormone receptor NR4A1, osteocalcin, osteoclast differentiation factor, osteopontin, OX-40 (tumor necrosis factor receptor superfamily member 4TNFRSF4, or CD134) receptor, P3 protein, p38 kinase, p38 MAP kinase, p53 tumor suppressor protein, parathyroid hormone ligand, peroxisome proliferator-activated receptor (PPAR, such as α, delta) γ), P-glycoproteins (such as 1), phosphatases and tensin homologs (PTEN), phosphatidylinositol 3-kinase (PI3K), phosphoinosyl-3-kinase (PI3K such as α, δ, γ), phosphorylase kinase (PK), PKN3 gene, placental growth factor, platelet-derived growth factor (PDGF, such as α, β), platelet-derived growth factor (PDGF, such as α, β), multiple drug tolerance transporters, Plexin B1, PLK1 gene, polo-like kinase (PLK), polo-like kinase 1, poly(ADP-ribose) polymerase (PARP, such as PARP1, PARP2 and PARP3, PARP7 and mono-PARP), melanin Tumor preferentially expressed antigen (PRAME) gene, isoprenoid-binding protein (PrPB), possible transcription factor PML, progesterone receptor, programmed cell death protein 1 (PD-1), programmed cell death ligand 1 inhibitor (PD-L1), prostate serum acid phosphatase (PSAP) gene, prostaglandin receptor (EP4), prostaglandin E2 synthase, prostate-specific antigen, prostate acid phosphatase, proteasome, protein E7, protein farnesyltransferase, protein kinases (PK, such as A, B, C), protein tyrosine kinase, protein tyrosine phosphatase β, proto-oncogene serine/threonine protein kinase (PIM, such as PIM-1, PIM-2, PIM-3), P-selective Selectives, purine nucleoside phosphorylases, purinergic receptor P2X ligand-gated ion channel 7 (P2X7), pyruvate dehydrogenase (PDH), pyruvate dehydrogenase kinase, pyruvate kinase (PYK), 5-α-reductase, Raf protein kinases (such as 1, B), RAF1 gene, Ras gene, Ras GTPase, RET gene, RET tyrosine kinase receptor, retinoblastoma-associated protein, retinoic acid receptors (such as γ), retinoid X receptors, Rheb (brain-enriched Ras homolog) GTPase, Rho (Ras homolog)-associated protein kinase 2, ribonucleases, ribonucleotide reductases (such as M2 subunit), ribosomal protein S6 kinase, RNA polymerases (such as...) I, II), Ron (Receptor d'Origine Nantais) tyrosine kinase, ROS1 (ROS proto-oncogene 1, receptor tyrosine kinase) gene, Ros1 tyrosine kinase, Runt-related transcription factor 3, γ-secretase, S100 calcium-binding protein A9, Sarco endoplasmic calcium ATPase, mitochondrial-derived second caspase activator (SMAC) protein, secretory coil-associated protein 2, secretory phospholipase A2, semaphorin 4D, serine protease, serine/threonine kinase (STK), serine/threonine protein kinase (TBK, such as TBK1), signal transduction and transcription (STAT) Such as STAT-1, STAT-3, STAT-5), signal transduction lymphocyte activating molecules (SLAM) family members 7, prostatic six-transmembrane epithelial antigen (STEAP) gene, SL cytokine ligands, smoothness (SMO) receptor, sodium iodide cotransporter, sodium phosphate cotransporter 2B, somatostatin receptors (such as 1, 2, 3, 4, 5), sound-sensitive hedgehog protein, non-seven-kinase (SOS) kinase, specific protein 1 (Sp1) transcription factor, sphingomyelin synthase, sphingosine kinase (such as 1, 2), sphingosine 1-phosphate receptor 1, spleen tyrosine kinase (SYK), SRC gene, Src tyrosine kinase, Sta bilin-1 (STAB1), STAT3 gene, steroid sulfatase, interferon gene stimulator (STING) receptor, interferon gene stimulator protein, stromal cell-derived factor 1 ligand, SUMO (small ubiquitin-like modifier), superoxide dismutase, cytokine signaling regulator inhibitor (SOCS), survival threonin, synapticin 3, multiligand glycan 1, synuclein α, T cell surface glycoprotein CD28, TANK-binding kinase (TBK), TATA box-binding protein-associated factor RNA polymerase I subunit B (TAF1B) gene, T cell CD3 glycoprotein ζ chain, T cell differentiation antigen CD6, T cell immunoglobulin and mucin-containing domain protein 3 ( TIM-3), T cell surface glycoprotein CD8, Tec protein tyrosine kinase, Tek tyrosine kinase receptor, telomerase, telomerase reverse transcriptase (TERT) gene, tendon glycoprotein, tripeptide repair exonuclease 1 (TREX1), tripeptide repair exonuclease 2 (TREX2), thrombopoietin receptor, thymidine kinase, thymidine phosphorylase, thymidine synthase, thymosin (such as α1), thyroid hormone receptor, thyroid-stimulating hormone receptor, tissue factor, TNF-associated apoptosis-inducing ligand, TNFR1-associated death domain protein, TNF-associated apoptosis-inducing ligand (TRAIL) receptor, TNFSF11 gene, TNFSF9 gene, Toll-like receptors (TLRs such as 1-13) Topoisomerases (such as I, II, III), transcription factors, transferases, transferrin (TF), transforming growth factor α (TGFα), transforming growth factor β (TGFB) and its isotypes, TGFβ2 ligand, transforming growth factor TGF-β receptor kinase, transglutaminase, translocation-related proteins, transmembrane glycoprotein NMB, Trop-2 calcium signal transduction protein, trophoblast glycoprotein (TPBG) gene, trophoblast glycoprotein, tropomyosin receptor kinase (Trk) receptors (such as TrkA, TrkB, TrkC), tryptophan 2,3-dioxygenase (TDO), tryptophan 5-hydroxylase, tubulin, tumor necrosis factor (TNF, such as α, β), tumor necrosis factor (TNF ... Death factor 13C receptor, tumor progressive locus 2 (TPL2), tumor protein 53 (TP53) gene, tumor suppressor candidate gene 2 (TUSC2) gene, tumor-specific neoantigen, tyrosinase, tyrosine hydroxylase, tyrosine kinase (TK), tyrosine kinase receptor, tyrosine kinase (TIE) receptor with immunoglobulin-like and EGF-like domains, tyrosine protein kinase ABL1 inhibitor, ubiquitin, ubiquitin carboxyl hydrolase isoenzyme L5, ubiquitin thioesterase 14, ubiquitin conjugate E2I (UBE2I, UBC9), ubiquitin-specific processing protein 7 (USP7), urease, urokinase plasminogen activator, uterine globin, capsaicin VR1, vascular cell adhesion protein 1 Vascular endothelial growth factor receptor (VEGFR), T cell activation V domain Ig inhibitor (VISTA), VEGF-1 receptor, VEGF-2 receptor, VEGF-3 receptor, VEGF-A, VEGF-B, vimentin, vitamin D3 receptor, proto-oncogene tyrosine protein kinase, Mer (Mer tyrosine kinase receptor modulator), YAP (Yes-related protein modulator), Wee-1 protein kinase, Werner syndrome RecQ-like helicase (WRN), Wilms tumor antigen 1, Wilms tumor protein, WW domain-containing transcription factor protein 1 (TAZ), X-linked apoptosis protein inhibitor, zinc finger protein transcription factor, or any combination thereof.

Exemplary mechanism of action

In some implementations, one or more adjunctive therapeutic agents may be classified into groups such as the following according to their mechanism of action:

Antimetabolites/anticancer agents, such as pyrimidine analogues fluorouracil, capecitabine, cytarabine, CPX-351 (liposomal cytarabine, daunorubicin) and TAS-118;

α1-adrenergic receptor/α2-adrenergic receptor antagonists, such as phenylbenzamine hydrochloride (injectable, for pheochromocytoma);

androgen receptor antagonists, such as nilumet;

Anti-cadherin antibodies, such as HKT-288;

Antibodies against leucine-rich repeat protein 15 (LRRC15), such as ABBV-085 and ARGX-110;

Angiotensin receptor blockers, nitric oxide donors;

Antisense oligonucleotides, such as AEG35156, IONIS-KRAS-2.5Rx, EZN-3042, RX-0201, IONIS-AR-2.5Rx, BP-100 (prexigebersen), and IONIS-STAT3-2.5Rx;

Anti-angiogenic (ANG)-2 antibodies, such as MEDI3617 and LY3127804;

Anti-ANG-1/ANG-2 antibodies, such as AMG-780;

Anti-CSF1R antibodies, such as emactuzumab, LY3022855, AMG-820, and FPA-008 (cabiralizumab);

Anti-endothelial glycoprotein antibodies, such as TRC105 (carotuximab);

Anti-ERBB antibodies, such as CDX-3379, HLX-02, and seribantumab;

Anti-HER2 antibodies, such as trastuzumab, trastuzumab biosimilars, maggotuximab, MEDI4276, BAT-8001, pertuzumab (Perjeta), RG6264, ZW25 (a bispecific HER2-guided antibody targeting extracellular domains 2 and 4; Cancer Discov. Jan 2019; 9(1):8; PMID:30504239);

Anti-HLA-DR antibodies, such as IMMU-114;

Anti-IL-3 antibodies, such as JNJ-56022473;

Antibodies against TNF receptor superfamily member 18 (TNFRSF18, GITR; NCBI gene ID: 8784), such as MK-4166, MEDI1873, FPA-154, INCAGN-1876, TRX-518, BMS-986156, MK-1248, GWN-323; and those described, for example, in International Patent Publication Nos. WO 2017/096179, WO 2017/096276, WO 2017/096189 and WO 2018/089628;

Anti-EphA3 antibodies, such as KB-004;

Anti-CD37 antibodies, such as otlertuzumab (TRU-016);

Anti-FGFR-3 antibodies, such as LY3076226 and B-701;

Anti-FGFR-2 antibodies, such as GAL-F2;

Anti-C5 antibodies, such as ALXN-1210;

Anti-EpCAM antibodies, such as VB4-845;

Anti-CEA antibodies, such as RG-7813;

CD66C antibodies, such as BAY-1834942 and NEO-201 (CEACAM 5/6);

Anti-GD2 antibodies, such as APN-301;

Anti-interleukin-17 (IL-17) antibodies, such as CJM-112;

Anti-interleukin-1β antibodies, such as konnabi (ACZ885) and VPM087;

Anti-carbonic anhydrase 9 (CA9, CAIX) antibodies, such as TX-250;

Anti-CD38 antibodies, such as isatuximab, MOR-202, and TAK-079;

Anti-CD38 attenukine, such as TAK573;

Anti-mucin 1 (MUC1) antibodies, such as gatipotuzumab and Mab-AR-20.5;

Anti-CD33 antibodies, such as IMGN-779;

Anti-KMA antibodies, such as MDX-1097;

Anti-CD55 antibodies, such as PAT-SC1;

Anti-c-Met antibodies, such as ABBV-399;

Anti-PSMA antibodies, such as ATL-101;

Anti-CD100 antibodies, such as VX-15;

Anti-EPHA3 antibodies, such as fibatuzumab;

Anti-APRIL antibodies, such as BION-1301;

Anti-fibroblast activating protein (FAP)/IL-2R antibodies, such as RG7461;

Anti-fibroblast activating protein (FAP)/TRAIL-R2 antibodies, such as RG7386;

Anti-fucosylation-GM1 antibodies, such as BMS-986012;

Anti-IL-8 (interleukin-8) antibodies, such as HuMax-Inflam;

Antimyosin inhibitors, such as landogrozumab;

Anti-δ-like protein ligand 3 (DDL3) antibodies, such as rovapituzumab tesirine;

Anti-DLL4 (δ-like ligand 4) antibodies, such as demcizumab;

Anti-cluster protein antibodies, such as AB-16B5;

Anti-hepatic glycoprotein A4 (EFNA4) antibodies, such as PF-06647263;

Anti-RANKL antibodies, such as denosumab;

Anti-mesothelin antibodies, such as BMS-986148 and anti-MSLN-MMAE;

Anti-sodium phosphate cotransporter 2B (NaP2B) antibodies, such as lifastuzumab;

Anti-TGFb antibodies, such as SAR439459;

Anti-transforming growth factor-β (TGF-β) antibodies, such as ABBV-151, LY3022859, NIS793, and XOMA 089;

Purine analogues, folic acid antagonists (such as prastriax), cladribine, pentostatin, fludarabine and related inhibitors;

Antiproliferative/antimitotic agents include natural products such as vinca alkaloids (vincrine, vincristine); and microtubule disruptors such as taxanes (paclitaxel, docetaxel), vincristine, nocodaazole, epothilone, vinorelbine, and epipodophyllotoxin (etoposide, teniposide).

DNA damaging agents, such as actinomycin, acridine, busulfan, carboplatin, chlorambucil, cisplatin, cyclophosphamide, daunorubicin, doxorubicin, DEBDOX, epirubicin, ifosfamide, melphalan, nitrogen mustard, mitomycin C, mitoxantrone, nitrosourea, procarbazine, tacrolimus, tebuconazole, teniposide, etoposide, and triethylenethiophosphoramide;

DNA methitylation agents, such as guadecitabine (SGI-110) and ASTX727;

Antibiotics, such as daunorubicin, doxorubicin, idarubicin, anthracycline, mitoxantrone, bleomycin, and procainoxam (photomycin);

Enzymes, such as L-asparaginase, systemically metabolize L-asparagine and deprive cells that do not have the ability to synthesize their own asparagine.

DNAi oligonucleotides targeting Bcl-2, such as PNT2258; agents that activate or reactivate latent human immunodeficiency virus (HIV), such as pabistat and romidesin;

Asparaginase stimulants, such as cristaspase and GRASPA (ERY-001, ERY-ASP), calaspargase pegol, and pegaspargase;

pan-Trk, ROS1 and ALK inhibitors, such as entrectinib and TPX-0005;

Anaplastic lymphoma kinase (ALK) inhibitors, such as alectinib, ceritinib, alecensa (RG7853), and brigatinib;

Antiproliferative/antimitotic alkylating agents, such as nitrogen mustard cyclophosphamide and analogs (e.g., melphalan, chlorambucil, hexamethylpyrimidine, thiotepa), alkylnitrosoureas (e.g., carmustine) and analogs, streptozotocin and triazine (e.g., dacarbazine);

Antiproliferative/antimitotic antimetabolites, such as folic acid analogs (methotrexate);

Platinum coordination complexes (e.g., cisplatin, oxaliplatin, and carboplatin), procarbazine, hydroxyurea, mitotane, and aminoglucopyranoside;

Hormones, hormone analogs (such as estrogens, tamoxifen, goserelin, bicalutamide, and nilutamide), and aromatase inhibitors (such as letrozole and anastrozole);

Antiplatelet agents; anticoagulants, such as heparin, synthetic heparin salts, and other inhibitors of thrombin;

Fibrinolytic agents, such as tissue plasminogen activator, streptokinase, urokinase, aspirin, dipyridamole, ticlopidine, and clopidogrel;

Anti-migration agents; anti-secretion agents (e.g., breveldin);

Immunosuppressants, such as tacrolimus, sirolimus, azathioprine, and mycophenolate mofetil;

Growth factor inhibitors and vascular endothelial growth factor inhibitors;

Fibroblast growth factor inhibitors, such as FPA14;

AMP-activated protein kinase stimulants, such as metformin hydrochloride;

ADP-ribosylcyclase-1 inhibitors, such as daratumumab

Caspase recruitment domain protein-15 stimulators, such as mifamotide (liposomes);

CCR5 chemokine antagonists, such as MK-7690 (vicriviroc);

CDC7 protein kinase inhibitors, such as TAK-931;

Cholesterol side-chain cleaving enzyme inhibitors, such as ODM-209;

Dihydropyrimidine dehydrogenase/orotic phosphoribosyltransferase inhibitors, such as Cefesone (tegafur + gemcitabine + oxazine potassium);

DNA polymerase/ribonucleotide reductase inhibitors, such as clofarabine;

DNA interference oligonucleotides, such as PNT2258 and AZD-9150;

Estrogen receptor modulators, such as bardoxifen;

Estrogen receptor agonists/progesterone receptor antagonists, such as TRI-CYCLEN LO (norethindrone + ethinylestradiol);

HLA class I antigen A-2α modulators, such as FH-MCVA2TCR;

HLA class I antigen A-2α/MART-1 melanoma antigen modulators, such as MART-1F5TCR engineered PBMCs;

Human granulocyte colony-stimulating factor, such as PF-06881894;

GNRH receptor agonists, such as leuprorelin acetate, leuprorelin acetate extended-release reservoir (ATRIGEL), triptorelin dihydroxynaphthyl acetate, and goserelin acetate;

GNRH receptor antagonists, such as elagolix, relugolix, and degarelix;

Endoplasmic protein regulators, such as anlotinib;

H+K+ATPase inhibitors, such as omeprazole and esomeprazole;

ICAM-1/CD55 modifiers, such as cavatak (V-937);

IL-15/IL-12 modulators, such as SAR441000;

Interleukin-23A inhibitors, such as guselkumab;

Lysine-specific histone demethylase 1 inhibitors, such as CC-90011;

IL-12Mrna, such as MEDI1191;

RIG-I modifiers, such as RGT-100;

NOD2 regulators, such as SB-9200 and IR-103.

Progesterone receptor agonists, such as levonorgestrel;

Cereblon protein modulators, such as CC-92480 and CC-90009;

Cereblon protein regulators/DNA-binding protein Ikaros inhibitors/zinc finger binding protein Aiolos inhibitors, such as iberdomide;

Retinoid X receptor modulators, such as retinoic acid and besalodin (oral formulation);

RIP-1 kinase inhibitors, such as GSK-3145095;

Selective estrogen receptor degraders, such as AZD9833;

SUMO inhibitors, such as TAK-981;

Thrombopoietin receptor agonists, such as eltrombopag;

Thyroid hormone receptor agonists, such as levothyroxine sodium;

TNF agonists, such as tasonamin;

Tyrosine phosphatase substrate 1 inhibitors, such as CC-95251;

HER2 inhibitors, such as neratinib and tucatinib (ONT-380);

EGFR/ErbB2/Ephb4 inhibitors, such as tesevatinib;

EGFR/HER2 inhibitors, such as TAK-788;

EGFR family tyrosine kinase receptor inhibitors, such as DZD-9008;

EGFR/ErbB-2 inhibitors, such as valitinib;

Mutant-selective EGFR inhibitors, such as PF-06747775, EGF816 (nazatinib), ASP8273, ACEA-0010, and BI-1482694;

Epha2 inhibitors, such as MM-310;

Polycomb protein (EED) inhibitors, such as MAK683;

DHFR inhibitors/folate transporter 1 regulators/folate receptor antagonists, such as pralatrexate;

DHFR/GAR transformylase/thymidine synthase/transferase inhibitors, such as pemetrexed disodium;

p38 MAP kinase inhibitors, such as ralimetinib;

PRMT inhibitors, such as MS203, PF-06939999, GSK3368715, and GSK3326595;

Sphingosine kinase 2 (SK2) inhibitors, such as opaganib;

Nucleoid erythrocyte 2-related factor 2 stimulators, such as omasorone (RTA-408);

Tropomyosin receptor kinase (TRK) inhibitors, such as LOXO-195 and ONO-7579;

Mucin 1 inhibitors, such as GO-203-2C;

MARCKS protein inhibitors, such as BIO-11006;

Folic acid antagonists, such as arfolitixorin;

Gastrin-3 inhibitors, such as GR-MD-02;

Phosphorylation P68 inhibitors, such as RX-5902;

CD95/TNF modulators, such as ofranergene obadenovec;

Pan-PIM kinase inhibitors, such as INCB-053914;

IL-12 gene stimulators, such as EGEN-001 and tavokinogene telseplasmid;

Inhibitors of heat shock protein HSP90, such as TAS-116 and PEN-866;

VEGF/HGF antagonists, such as MP-0250;

VEGF ligand inhibitors, such as bevacizumab biosimilars;

VEGF receptor antagonists/VEGF ligand inhibitors, such as ramucirumab;

VEGF-1/VEGF-2/VEGF-3 receptor antagonists, such as fruquintinib;

VEGF-1/VEGF-2 receptor modulators, such as HLA-A2402/HLA-A0201 restricted epitope peptide vaccines;

Placental growth factor ligand inhibitors/VEGF-A ligand inhibitors, such as aflibercept;

SYK tyrosine kinase/JAK tyrosine kinase inhibitors, such as ASN-002;

Trk tyrosine kinase receptor inhibitors, such as larotrectinib sulfate;

JAK3/JAK1/TBK1 kinase inhibitors, such as CS-12912;

IL-24 antagonists, such as AD-IL24;

NLRP3 (NACHT LRR PYD domain protein 3) regulators, such as BMS-986299;

RIG-I agonists, such as RGT-100;

Aeromonas hydrolysin stimulants, such as topsalysin;

P-glycoprotein 1 inhibitors, such as HM-30181A;

CSF-1 antagonists, such as ARRY-382 and BLZ-945;

CCR8 inhibitors, such as I-309, SB-649701, HG-1013, and RAP-310;

Anti-mesothelin antibodies, such as SEL-403;

Thymidine kinase stimulants, such as aglatimagene besadenovec;

Polo-like kinase 1 inhibitors, such as PCM-075 and onvansertib;

NAE inhibitors, such as pevonedistat (MLN-4924) and TAS-4464;

Multipath modulators, such as avadomide (CC-122);

Amyloid-binding protein-1 inhibitors/ubiquitin ligase modulators, such as pevonedistat;

FoxM1 inhibitors, such as thiosphingolipids;

UBA1 inhibitors, such as TAK-243;

Src tyrosine kinase inhibitors, such as VAL-201;

VDAC/HK inhibitors, such as VDA-1102;

Elf4a inhibitors, such as rohinitib and eFT226;

TP53 gene stimulators, such as ad-p53;

Retinyl receptor agonists, such as retinoic acid;

Retinyl receptor α (RARα) inhibitors, such as SY-1425;

SIRT3 inhibitors, such as YC8-02;

Inhibitors of stromal cell-derived factor 1 ligands, such as oxidized pegol (NOX-A12);

IL-4 receptor modulators, such as mDNA-55;

Arginase-I stimulants, such as pegzilarginase;

Topoisomerase I inhibitors, such as irinotecan hydrochloride and Onivyde;

Topoisomerase I inhibitors/hypoxia-inducible factor-1α inhibitors, such as PEG-SN38 (firtecan pegol);

Hypoxia-inducible factor-1α inhibitors, such as PT-2977 and PT-2385;

CD122 (IL-2 receptor) agonists, such as proleukin (adelipin, IL-2); pegylated IL-2 (e.g., NKTR-214); modified variants of IL-2 (e.g., THOR-707);

TLR7/TLR8 agonists, such as NKTR-262;

TLR7 agonists, such as DS-0509, GS-9620, LHC-165, and TMX-101 (imiquimod);

p53 tumor suppressor protein stimulants, such as kevetrin;

Mdm4/Mdm2 p53 binding protein inhibitors, such as ALRN-6924;

Inhibitors of kinesin (KSP), such as finanesib (ARRY-520);

CD80-fc fusion protein inhibitors, such as FPT-155;

Menin and mixed lineage leukemia (MLL) inhibitors, such as KO-539;

Hepatic X receptor agonists, such as RGX-104;

IL-10 agonists, such as polyethylene glycolated IL-10 (Pegilodecakin) (AM-0010);

VEGFR/PDGFR inhibitors, such as vorolanib;

IRAK4 inhibitors, such as CA-4948;

Anti-TLR-2 antibodies, such as OPN-305;

Calmodulin regulators, such as CBP-501;

Glucocorticoid receptor antagonists, such as relacorilant (CORT-125134);

Inhibitors of the second mitochondrial-derived activator (SMAC) protein of caspase, such as BI-891065;

Lactoferrin modulators, such as LTX-315;

KIT proto-oncogene receptor tyrosine kinase (KIT) inhibitors, such as PLX-9486;

Platelet-derived growth factor receptor α (PDGFRA)/KIT proto-oncogene receptor tyrosine kinase (KIT) mutant specific antagonists/inhibitors, such as BLU-285 and DCC-2618.

Export protein 1 inhibitors, such as eltanexor;

CHST15 gene inhibitors, such as STNM-01;

Somatostatin receptor antagonists, such as OPS-201;

CEBPA gene stimulants, such as MTL-501;

DKK3 gene regulators, such as MTG-201;

Chemokines (CXCR1/CXCR2) inhibitors, such as SX-682;

p70s6k inhibitors, such as MSC2363318A;

Methionine aminopeptidase 2 (MetAP2) inhibitors, such as M8891 and APL-1202;

Arginine N-methyltransferase 5 inhibitors, such as GSK-3326595;

CD71 modulators, such as CX-2029 (ABBV-2029);

ATM (ataxia-telangiectasia) inhibitors, such as AZD0156 and AZD1390;

CHK1 inhibitors, such as GDC-0575, LY2606368 (prexasertib), SRA737, and RG7741 (CHK1/2);

CXCR4 antagonists, such as BL-8040, LY2510924, burixafor (TG-0054), X4P-002, X4P-001-IO, and burixafor;

EXH2 inhibitors, such as GSK2816126;

KDM1 inhibitors, such as ORY-1001, IMG-7289, INCB-59872, and GSK-2879552;

CXCR2 antagonists, such as AZD-5069;

GM-CSF antibodies, such as lenzilumab;

DNA-dependent protein kinase inhibitors, such as MSC2490484A (nedisertib), VX-984, and AsiDNA (DT-01); protein kinase C (PKC) inhibitors, such as LXS-196 and sotrastaurin.

Selective estrogen receptor downregulators (SERDs), such as fulvestrant RG6046, RG6047, RG6171, ellastrant (RAD-1901), SAR439859 and AZD9496;

Selective estrogen receptor covalent antagonists (SERCAs), such as H3B-6545;

Selective androgen receptor modulators (SARMs), such as GTX-024 and dalotamid;

Transforming growth factor-β (TGF-β) kinase antagonists, such as galonitib, LY3200882; TGF-β inhibitors described in WO 2019/103203;

TGFβ receptor 1 inhibitors, such as PF-06952229;

Bispecific antibodies, such as ABT-165 (DLL4/VEGF), MM-141 (IGF-1/ErbB3), MM-111 (Erb2/Erb3), JNJ-64052781 (CD19/CD3), PRS-343 (CD-137/HER2), AFM26 (BCMA/CD16A), JNJ-61186372 (EGFR/cMET), AMG-211 (CEA/CD3), RG7802 (CEA/CD3), ERY-974 (CD3/GPC3), vancizumab (angiopoietin/VEGF), PF-06671008 (cadherin/CD3), AFM-13 (CD16/CD30), APVO436 (CD123/CD3), fluticizumab (CD123/CD3), and REGN-1979 (CD20/CD3). ), MCLA-117(CD3/CLEC12A), MCLA-128(HER2/HER3), JNJ-0819, JNJ-7564(CD3/heme), AMG-757(D LL3-CD3), MGD-013(PD-1/LAG-3), FS-118(LAG-3/PD-L1), MGD-019(PD-1/CTLA-4), KN-046(PD- 1/CTLA-4), MEDI-5752(CTLA-4/PD-1), RO-7121661(PD-1/TIM-3), XmAb-20717(PD-1/CTLA-4), AK-104(CTLA-4/PD-1), AMG-330(CD33/CD3), AMG-420(BCMA/CD3), BI-836880(VEFG/ANG2), JNJ -63709178(CD123/CD3), MGD-007(CD3/gpA33), MGD-009(CD3/B7H3), AGEN1223, IMCgp100(CD3/ gp100), AGEN-1423, ATOR-1015 (CTLA-4/OX40), LY-3415244 (TIM-3/PDL1), INHIBRX-105 (4-1BB /PDL1), faricimab (VEGF-A/ANG-2), FAP-4-IBBL (4-1BB/FAP), XmAb-13676 (CD3/CD20), TAK-252 (PD-1/OX40L), TG-1801 (CD19/CD47), XmAb-18087 (SSTR2/CD3), caputoxumab (CD3/EpCAM), S AR-156597(IL4/IL13), EMB-01(EGFR/cMET), REGN-4018(MUC16/CD3), REGN-1979(CD20/CD3), R G-7828 (CD20/CD3), CC-93269 (CD3/BCMA), REGN-5458 (CD3/BCMA), navicixizumab (DLL 4/VEGF), GRB-1302(CD3/Erbb2), vanucizumab(VEGF-A/ANG-2), GRB-1342(CD38/CD3), GEM-333 (CD3/CD33), IMM-0306 (CD47/CD20), RG6076, MEDI5752 (PD-1/CTLA-4), LY3164530 (MET/EGFR);

Inhibitors of α-ketoglutarate dehydrogenase (KGDH), such as CPI-613;

XPO1 inhibitors, such as selinexor (KPT-330);

Isocitrate dehydrogenase 2 (IDH2) inhibitors, such as inananib (AG-221);

IDH1 inhibitors, such as AG-120 and AG-881 (IDH1 and IDH2), IDH-305, and BAY-1436032;

IDH1 gene inhibitors, such as evanixib;

Interleukin-3 receptor (IL-3R) modulators, such as SL-401;

Arginine deiminase stimulants, such as pegargiminase (ADI-PEG-20);

Blocking protein-18 inhibitors, such as claudiximab;

β-catenin inhibitors, such as CWP-291;

Chemokine receptor 2 (CCR) inhibitors, such as PF-04136309, CCX-872, and BMS-813160 (CCR2/CCR5);

Thymidylate synthase inhibitors, such as ONX-0801;

ALK/ROS1 inhibitors, such as lolatinib;

End-anchored polymerase inhibitors, such as G007-LK;

Mdm2 p53 binding protein inhibitors, such as CMG-097 and HDM-201; c-PIM inhibitors, such as PIM447;

Sphingosine kinase-2 (SK2) inhibitors, such as (ABC294640);

DNA polymerase inhibitors, such as sapattabine;

Cell cycle/microtubule inhibitors, such as eribulin mesylate;

c-MET inhibitors, such as AMG-337, cevotinib, tevantinib (ARQ-197), carmatinib and terpoxtinib, ABT-700, AG213, AMG-208, JNJ-38877618 (OMO-1), meritinib, and HQP-8361;

c-Met/VEGFR inhibitors, such as BMS-817378 and TAS-115;

c-Met/RON inhibitors, such as BMS-777607;

BCR/ABL inhibitors, such as rebasitinib, axitinib, and panatinib

MNK1/MNK2 inhibitors, such as eFT-508;

Cytochrome P450 11B2/cytochrome P450 17/AKT protein kinase inhibitors, such as LAE-201;

Cytochrome P450 3A4 stimulants, such as mitotane;

Lysine-specific demethylase-1 (LSD1) inhibitors, such as CC-90011;

CSF1R/KIT and FLT3 inhibitors, such as percidatinib (PLX3397);

Flt3 tyrosine kinase/Kit tyrosine kinase inhibitors and PDGF receptor antagonists, such as quizartinib dihydrochloride;

Kinase inhibitors, such as vandetanib;

E-selective protein antagonists, such as GMI-1271;

Differentiation inducers, such as retinoic acid;

Epidermal growth factor receptor (EGFR) inhibitors, such as osimertinib (AZD-9291) and cetuximab;

Topoisomerase inhibitors, such as doxorubicin, doxorubicin, daunorubicin, daunoxicin, DaunoXome, Caelyx, eniposide, epirubicin, etoposide, idarubicin, irinotecan, mitoxantrone, pinaxane, sobuzosen, topotecan, irinotecan, MM-398 (liposomal irinotecan), vorxarosine and GPX-150, doxorubicin, AR-67, marchertinib, AST-2818, avitinib (ACEA-0010), and ilofofen (MGI-114);

Corticosteroids, such as cortisone, dexamethasone, hydrocortisone, methylprednisolone, prednisolone, and prednisolone;

Growth factor signal transduction kinase inhibitors;

Nucleoside analogues, such as DFP-10917;

Axl inhibitors, such as BGB-324 (bemcentinib) and SLC-0211;

Axl/Flt3 inhibitors, such as giretinib;

Inhibitors of bromodomain and terminal outer motif (BET) proteins, including ABBV-744, BRD2 (NCBI gene ID: 6046), BRD3 (NCBI gene ID: 8019), BRD4 (NCBI gene ID: 23476), and bromodomain testis-specific protein (BRDT; NCBI gene ID: 676), such as INCB-054329, INCB057643, TEN-010, AZD-5153, ABT-767, BMS-986158, and CC-90. 010, GSK525762 (molibresib), NHWD-870, ODM-207, GSK-2820151, GSK-1210151A, ZBC246, ZBC260, ZEN3694, FT-1101, RG-6146, CC-90010, CC-95775, mivebresib, BI-894999, PLX-2853, PLX-51107, CPI-0610, GS-5829;

PARP inhibitors, such as olaparib (MK7339), rucaparib, veliparib, tapazoparib, ABT-767, BGB-290, fluzoparib (SHR-3162), niraparib (JNJ-64091742), and bendamustine hydrochloride.

PARP/terminal anchor polymerase inhibitors, such as 2X-121 (e-7499);

IMP-4297, SC-10914, IDX-1197, HWH-340, CK-102, Simmiparib;

Proteasome inhibitors, such as ixazomib, carfilzomib, marizomib, and bortezomib;

Glutamine inhibitors, such as CB-839 (telaglenastat) and bis-2-(5-phenylacetamido-1,3,4-thiadiazol-2-yl)ethyl sulfide (BPTES);

Inhibitors of mitochondrial complex I, such as metformin and phenformin;

Vaccines, such as peptide vaccines TG-01 (RAS), GALE-301, GALE-302, nelipepimut-s, SurVaxM, DSP-7888, TPIV-200, PVX-410, VXL-100, DPX-E7, ISA-101, 6MHP, OSE-2101, galinpepimut-S, SVN53-67/M57-KLH, IMU-131, and peptide subunit vaccines (acute lymphoblastic leukemia, University Children's Hospital Tuebingen); bacterial vector vaccines, such as CRS-207/GVAX, axalimogene. filolisbac (ADXS11-001); adenovirus vector vaccines, such as nadofaragene firadenovec; autologous Gp96 vaccines; dendritic cell vaccines, such as CVactm, tapuldencel-T, eltrapuldencel-T, SL-701, BSK01TM, rocapuldencel-T (AGS-003), DCVAC, CVactm, tapuldencel-T, eltrapuldencel-T, SL-701, BSK01TM, ADXS31-142; autologous dendritic cell vaccine (metastatic melanoma, intradermal/intravenous, Universitatsklinikum Erlangen); oncolytic vaccines, such as talimogene laherparepvec, pexastimogene devacirepvec, GL-ONC1, MG1-MA3, parvovirus H-1, ProstAtak, enadenotucirev, MG1MA3, ASN-002 (TG-1042); therapeutic vaccines, such as CVAC-301, CMP-001, CreaVax-BC, PF-06753512, VBI-1901, TG-4010, ProscaVax ^™ ; tumor cell vaccines, such as (IND-14205), Oncoquest-L vaccine; live attenuated recombinant poliovirus type 1 serotype vaccines, such as PVS-RIPO; Adagloxad Simolenin; MEDI-0457; DPV-001: Tumor-derived autophagosome-rich cancer vaccines; RNA vaccines, such as CV-9209, LV-305; DNA vaccines, such as MEDI-0457, MVI-816, INO-5401; Modified vaccinia virus Ankara vaccines expressing p53, such as MVA-p53; DPX-Survivac; BriaVax ^™ ; GI-6301; GI-6207; GI-4000; IO-103; Neoantigen peptide vaccines, such as AGEN-2017, GEN-010, NeoVax, RG-6180, GEN-009, PGV-001 (TLR-3 agonist), GRANITE-001, NEO-PV-01; Peptide vaccines targeting heat shock proteins, such as PhosphoSynVax ^™ Vitspen (HSPPC-96-C), NANT colorectal cancer vaccine containing aldoxorubicin, autologous tumor cell vaccine + systemic CpG-B + IFN-α (cancer), IO-120 + IO-103 (PD-L1/PD-L2 vaccine), HB-201, HB-202, HB-301, and other vaccines based on [the vaccine name is missing].

TLR-3 agonists/interferon inducers, such as Poly-ICLC (NSC-301463);

STAT-3 inhibitors, such as nababucacin (BBI-608);

ATPase p97 inhibitors, such as CB-5083;

Smooth muscle (SMO) receptor inhibitors, such as sonidegib (formerly known as LDE-225), LEQ506, vismodegib (GDC-0449), BMS-833923, glasdegib (PF-04449913), LY2940680, and itraconazole;

Interferon α ligand modulators, such as interferon α-2b, interferon α-2a biosimilars (Biogenomics), Roferg interferon α-2b (AOP-2014, P-1101, PEG IFNα-2b), Multiferon (Alfanative, Viragen), interferon α1b, Roferon-A (Canferon, Ro-25-3036), interferon α-2a follow-up biologics (Biosidus) (Inmutag, Inter 2A), and interferon α-2b follow-up biologics (Biosi). dus-Bioferon, Citophoron, Ganapar, Beijing Kawin Technology – Kaferon), Alfaferone, pegylated interferon α-1b, pegylated interferon α-2b follow-up biologics (Amega), recombinant human interferon α-1b, recombinant human interferon α-2a, recombinant human interferon α-2b, vetozumab-IFNα2b conjugate, Dynavax (SD-101) and interferon α-n1 (Humoferon, SM-10500, Sumiferon);

Interferon-γ ligand modulators, such as interferon-γ (OH-6000, Oγ100);

IL-6 receptor modulators, such as tocilizumab, AS-101 (CB-06-02, IVX-Q-101);

Heat shock protein inhibitors/IL-6 receptor antagonists, such as sutuximab;

Telomerase regulators, such as tertomotide (GV-1001, HR-2802, Riavax) and imesta (GRN-163, JNJ-63935937);

DNA methyltransferase inhibitors, such as temozolomide (CCRG-81045), decitabine, guarditabine (S-110, SGI-110), KRX-0402, RX-3117, RRx-001 and azacytidine (CC-486).

DNA gyrase inhibitors, such as pisanthocyanin and sobuzosen;

DNA gyrase inhibitors/topoisomerase II inhibitors, such as amrubicin;

Bcl-2 family protein inhibitors, such as ABT-263, venetoclax (ABT-199), ABT-737, RG7601, and AT-101;

Bcl-2/Bcl-XL inhibitors, such as navittoc;

Notch inhibitors, such as LY3039478 (crenigacestat), tarextumab (anti-Notch2/3), and BMS-906024;

Hyaluronidase stimulants, such as PEGPH-20;

Erbb2 tyrosine kinase receptor inhibitors/hyaluronidase stimulants, such as Herceptin Hylecta;

Wnt pathway inhibitors, such as SM-04755, PRI-724, and WNT-974;

Gamma-secretase inhibitors, such as PF-03084014, MK-0752, and RO-4929097;

Grb-2 (growth factor receptor-binding protein-2) inhibitors, such as BP1001;

TRAIL pathway-inducing compounds, such as ONC201 and ABBV-621;

TRAIL modifiers, such as SCB-313;

Follicle adhesion kinase inhibitors, such as VS-4718, defatinib, and GSK2256098;

Hedgehog protein inhibitors, such as saridegib, sonogen (LDE225), and glagib;

Aurora kinase inhibitors, such as alixetine (MLN-8237) and AZD-2811, AMG-900, balazetine, ENMD-2076;

HSPB1 regulators (heat shock protein 27, HSP27), such as brivudine and apatorsen;

ATR inhibitors, such as BAY-937, AZD6738, AZD6783, VX-803, VX-970 (berzortie) and VX-970;

Hsp90 inhibitors, such as AUY922, onalespib (AT13387), SNX-2112, and SNX5422;

Mouse dual microsome (mdm2) oncogene inhibitors, such as DS-3032b, RG7775, AMG-232, HDM201 and idasanutlin (RG7388);

CD137 agonists, such as urelumab, utomilumab (PF-05082566), AGEN2373, ADG-106, and BT-7480;

Sting agonists, such as ADU-S100 (MIW-815), SB-11285, MK-1454, SR-8291, AdVCA0848, GSK-532, SYN-STING, MSA-1, SR-8291, GSK3745417;

FGFR inhibitors, such as FGF-401, INCB-054828, BAY-1163877, AZD4547, JNJ-42756493, LY2874455, and Debio-1347;

Fatty acid synthase (FASN) inhibitors, such as TVB-2640;

Antigen CD19 inhibitors, such as MOR208, MEDI-551, AFM-11, and inebilizumab;

CD44 binders, such as A6;

Inhibitors of protein phosphatase 2A (PP2A), such as LB-100;

CYP17 inhibitors, such as seviteronel (VT-464), ASN-001, ODM-204, CFG920, and abiraterone acetate;

RXR agonists, such as IRX4204;

Hedgehog protein/smoothness (hh/Smo) antagonists, such as taladegib, patidegib, and vismodegib;

Complement C3 modulators, such as Imprime PGG;

IL-15 agonists, such as ALT-803, NKTR-255, interleukin-15/Fc fusion protein, AM-0015, NIZ-985 and hetIL-15;

EZH2 (zeste gene enhancer homolog 2) inhibitors, such as tazemetostat, CPI-1205, GSK-2816126, and PF-06821497;

Oncolytic viruses, such as pelareorep, CG-0070, MV-NIS therapy, HSV-1716, DS-1647, VCN-01, ONCOS-102, TBI-1401, tasadenoturev (DNX-2401), vocimagene amiretrorepvec, RP-1, CVA21, Celyvir, LOAd-703, OBP-301.

DOT1L (histone methyltransferase) inhibitors, such as pinositol (EPZ-5676);

Toxins, such as cholera toxin, ricin, Pseudomonas exotoxin, Bordetella pertussis adenylate cyclase toxin, diphtheria toxin, and caspase activator;

DNA plasmids, such as BC-819;

PLK inhibitors of PLK 1, 2 and 3, such as vorasetib (PLK1);

WEE1 inhibitors, such as AZD-1775 (adavosertib); Rho kinase (ROCK) inhibitors, such as AT13148 and KD025;

Inhibitors of apoptosis protein (IAP), such as ASTX660, debio-1143, pirenapa, APG-1387, and LCL-161;

RNA polymerase inhibitors, such as Rubicatin (PM-1183) and CX-5461;

Microtubule inhibitors, such as PM-184, BAL-101553 (lisavanbulin) and OXI-4503, fluorapacin (AC-0001), plinabulin, and vinblastine;

Toll-like receptor 4 (TLR-4) agonists, such as G100, GSK1795091 and PEPA-10;

Elongation factor 1α2 inhibitors, such as plitidepsin;

Elongation factor 2 inhibitors/interleukin-2 ligands/NAD-ADP ribosyltransferase stimulators, such as denileukin diftitox;

CD95 inhibitors, such as APG-101, APO-010, and asunercept;

WT1 inhibitors, such as DSP-7888;

Inhibitors of splicing factor 3B subunit 1 (SF3B1), such as H3B-8800;

RORγ receptor agonists, such as LYC-55716; and

Microbiome modulators, such as SER-401, EDP-1503, and MRx-0518.

In some embodiments, the compounds described herein are co-administered with one or more adjunctive therapeutic agents, said adjunctive therapeutic agents comprising inhibitors or antagonists of the following substances: myeloid leukemia sequence 1 (MCL1) apoptosis regulator (NCBI gene ID: 4170); mitogen-activated protein kinase 1 (MAP4K1) (also known as hematopoietic progenitor cell kinase 1 (HPK1), NCBI gene ID: 11184); diacylglycerol kinase α (DGKA, DAGK, DAGK1, or DGK-α; NCBI gene ID: 1606); 5'-extracellular nucleotidase (NT5E or CD73; NCBI gene ID: 4907); extracellular nucleotide triphosphate diphosphate hydrolase 1 (ENTPD1 or CD39; NCBI gene ID: 593); transforming growth factor β1 (TGFB1 or TGFβ). ; NCBI gene ID: 7040); Heme oxygenase 1 (HMOX1, HO-1 or HO1; NCBI gene ID: 3162); Heme oxygenase 2 (HMOX2, HO-2 or HO2; NCBI gene ID: 3163); Vascular endothelial growth factor A (VEGFA or VEGF; NCBI gene ID: 7422); erb-b2 receptor tyrosine kinase 2 (ERBB2, HER2, HER2/neu or CD340; NCBI gene ID: 2064), Epidermal growth factor receptor (EGFR, ERBB, ERBB1 or HER1; NCBI gene ID: 1956); ALK receptor tyrosine kinase (ALK, CD246; NCBI gene ID: 238); Poly(ADP-ribose) polymerase 1 (PARP1; NCBI gene ID: 1 42); Poly(ADP-ribose) polymerase 2 (PARP2; NCBI gene ID: 10038); TCDD-inducible poly(ADP-ribose) polymerase (TIPARP, PARP7; NCBI gene ID: 25976); Cyclin-dependent kinase 4 (CDK4; NCBI gene ID: 1019); Cyclin-dependent kinase 6 (CDK6; NCBI gene ID: 1021); TNF receptor superfamily member 14 (TNFRSF14, HVEM, CD270; NCBI gene ID: 8764); T cell immune receptor with Ig and ITIM domains (TIGIT; NCBI gene ID: 201633); X-linked apoptosis inhibitors (XIAP, BIRC4, IAP-3; NCBI gene ID: 331); Baculovirus-containing I AP repeat sequence 2 (BIRC2, cIAP1; NCBI gene ID: 329); baculovirus IAP repeat sequence 3 (BIRC3, cIAP2; NCBI gene ID: 330); baculovirus IAP repeat sequence 5 (BIRC5, survivin; NCBI gene ID: 332); C-C motif chemokine receptor 2 (CCR2, CD192; NCBI gene ID: 729230); C-C motif chemokine receptor 5 (CCR5, CD195; NCBI gene ID: 1234); C-C motif chemokine receptor 8 (CCR8, CDw198; NCBI gene ID: 1237); C-X-C motif chemokine receptor 2 (CXCR2, CD182; NCBI gene ID: 3579); C-X-C motif chemokine receptor 3 (C XCR3, CD182, CD183; NCBI gene ID: 2833); C-X-C motif chemokine receptor 4 (CXCR4, CD184; NCBI gene ID: 7852); arginase (ARG1 (NCBI gene ID: 383), ARG2 (NCBI gene ID: 384)), carbonic anhydrase (CA1 (NCBI gene ID: 759), CA2 (NCBI gene ID: 760), CA3 (NCBI gene ID: 761), CA4 (NCBI gene ID: 762), CA5A (NCBI gene ID: 763), CA5B (NCBI gene ID: 11238), CA6 (NCBI gene ID: 765), CA7 (NCBI gene ID: 766), CA8 (NCBI gene ID: 767), CA9 ( (NCBI gene ID: 768), CA10 (NCBI gene ID: 56934), CA11 (NCBI gene ID: 770), CA12 (NCBI gene ID: 771), CA13 (NCBI gene ID: 377677), CA14 (NCBI gene ID: 23632), prostaglandin-endoperoxidase 1 (PTGS1, COX-1; NCBI gene ID: 5742), prostaglandin-endoperoxidase 2 (PTGS2, COX-2; NCBI gene ID: 5743), secretory phospholipase A2, prostaglandin E synthase (PTGES, PGES; gene ID: 9536), arachidonic acid 5-lipoxygenase (ALOX5, 5-LOX; NCBI gene ID: 240) and/or soluble epoxide hydrolase 2 (EPHX) 2. SEH; NCBI gene ID: 2053); secretory phospholipase A2 (e.g., PLA2G1B (NCBI gene ID: 5319); PLA2G7 (NCBI gene ID: 7941), PLA2G3 (NCBI gene ID: 50487), PLA2G2A (NCBI gene ID: 5320); PLA2G4A (NCBI gene ID: 5321), PLA2G12A (NCBI gene ID: 81579), PLA2G12B (NCBI gene ID: 84647), PLA2G10 (NCBI gene ID: 8399), PLA2G5 (NCBI gene ID: 5322), PLA2G2D (NCBI gene ID: 26279), PLA2G15 (NCBI gene ID: 23659)); indoleamine 2,3-Dioxygenase 1 (IDO1; NCBI gene ID: 3620); Indoleamine 2,3-Dioxygenase 2 (IDO2; NCBI gene ID: 169355); Hypoxia-inducible factor 1 subunit α (HIF1A; NCBI gene ID: 3091); Angiopoietin 1 (ANGPT1; NCBI gene ID: 284); Endothelial TEK tyrosine kinases (TIE-2, TEK, CD202B; NCBI gene ID: 7010); Janus kinase 1 (JAK1; NCBI gene ID: 3716); Catenin β1 (CTNNB1; NCBI gene ID: 1499); Histone deacetylase 9 (HDAC9; NCBI gene ID: 9734), and/or 5'-3' ribonuclease 1 (XRN1; NCBI gene ID: 54464).

TCR signal transduction modulator

In some embodiments, compounds as described herein are combined with one or more agonists or antagonists of T cell receptor (TCR) signaling regulators. T cell activation via the TCR is essential for thymocyte development and effector T cell function. TCR activation promotes a signaling cascade that ultimately determines cell fate by regulating cytokine production, cell survival, proliferation, and differentiation. Examples of TCR signaling regulators include, but are not limited to: CD2 (differentiation cluster 2, LFA-2, T11, LFA-3 receptors), CD3 (differentiation cluster 3), CD4 (differentiation cluster 4), CD8 (differentiation cluster 8), CD28 (differentiation cluster 28), CD45 (PTPRC, B220, GP180), LAT (connector for T cell activation, LAT1), Lck, LFA-1 (ITGB2, CD18, LAD, LCAMB), Src, Zap-70, SLP-76, DGKα, CBL-b, CISH, and HPK1.

Examples of agonists of differentiation cluster 3 (CD3) that can be co-administered include, but are not limited to, MGD015.

In some embodiments, the compounds described herein are combined with one or more blockers or inhibitors of inhibitory immune checkpoint proteins or receptors and/or with one or more stimulators, activators, or agonists of stimulating immune checkpoint proteins or receptors. Blocking or inhibiting inhibitory immune checkpoints can positively modulate T cell or NK cell activation and prevent immune escape of cancer cells within the tumor microenvironment. Activation or stimulation of stimulating immune checkpoints can enhance the efficacy of immune checkpoint inhibitors in cancer therapy. In some embodiments, immune checkpoint proteins or receptors modulate T cell responses (e.g., reviewed in Xu et al., J Exp Clin Cancer Res. (2018) 37:110). In some embodiments, immune checkpoint proteins or receptors modulate NK cell responses (e.g., in Davis et al., Semin Immunol. (2017) 31:64–75 and Chiossone et al., Nat Rev Immunol. (2018) 18(11):671-688).

Examples of immune checkpoint proteins or receptors include, but are not limited to, CD27, CD70; CD40, CD40LG; CD47, CD48 (SLAMF2); 2 containing transmembrane and immunoglobulin domains (TMIGD2, CD28H); CD84 (LY9B, SLAMF5); CD96, CD160, MS4A1 (CD20); CD244 (SLAMF4); CD276 (B7H3); T cell activation inhibitor 1 containing the V-set domain (VTCN1, B7H4); and V-set immunomodulatory receptors (V-set immunomodulatory receptors). VSIR, B7H5, VISTA); Immunoglobulin superfamily member 11 (IGSF11, VSIG3); Natural killer cell cytotoxic receptor 3 ligand 1 (NCR3LG1, B7H6); HERV-H LTR-associated 2 (HHLA2, B7H7); Inducible T cell costimulatory factor (ICOS, CD278); Inducible T cell costimulatory factor ligand (ICOSLG, B7H2); TNF receptor superfamily member 4 (TNFRSF4, OX40); TNF superfamily member 4 (TNFSF4, OX40L) ); TNFRSF8 (CD30), TNFSF8 (CD30L); TNFRSF10A (CD261, DR4, TRAILR1), TNFRSF9 (CD137), TNFSF9 (CD137L); TNFRSF10B (CD262, DR5, TRAILR2), TNFRSF10 (TRAIL); TNFRSF14 (HVEML, CD270), TNFSF14 (HVEML); CD272 (B and T lymphocyte-associated (BTLA)); TNFRSF1 7 (BCMA, CD269), TNFSF13B (BAFF); TNFRSF18 (GITR), TNFSF18 (GITRL); MHC class I peptide-related sequence A (MICA); MHC class I peptide-related sequence B (MICB); CD274 (PDL1, PD-L1); programmed cell death 1 (PDCD1, PD-1, PD-1); cytotoxic T lymphocyte-associated protein 4 (CTLA4, CD152); CD80 (B7-1), CD28; nectin cell adhesion molecule 2 (NECTIN2, CD112); CD226 (DNAM-1); Poliovirus receptor (PVR) cell adhesion molecule (PVR, CD155); Containing PVR-associated immunoglobulin domain (PVRIG, CD112R); T-cell immune receptor with Ig and ITIM domains (TIGIT); Containing T-cell immunoglobulin and mucin domains 4 (TIMD4; TIM4); Hepatitis A virus cell receptor 2 (HAVCR2, TIMD3, TIM-3); Galactagogue 9 (LGALS9); Lymphocyte activity 3 (LAG-3, CD223); SLAM family member 1 (SLAM, CD150); Lymphocyte antigen 9 (LY9, CD229, SLAMF3); SLAM family member 6 (SLAM, CD352); SLAM family member 7 (SLAM, CD319); UL16 binding protein 1 (ULBP1); UL16 binding protein 2 (ULBP2); UL16 binding protein 3 (ULBP3); Retinyl early transcript 1E (RAET1E; ULBP) 4); Early retinoic acid transcript 1G (RAET1G; ULBP5); Early retinoic acid transcript 1L (RAET1L; ULBP6); Lymphocyte activation 3 (CD223); Cytokine immunoglobulin-like receptor (KIR); Cytokine lectin-like receptor C1 (KLRC1, NKG2A, CD159A); Cytokine lectin-like receptor K1 (KLRK1, NKG2D, CD314); Cytokine lectin-like receptor C2 (KLRC2, CD159c, NKG2C); Cytokine lectin-like receptor C3 (KLR... C3, NKG2E); cytotoxic cell lectin-like receptor C4 (KLRC4, NKG2F); cytotoxic cell immunoglobulin-like receptor with two Ig domains and a long cytoplasmic tail 1 (KIR2DL1); cytotoxic cell immunoglobulin-like receptor with two Ig domains and a long cytoplasmic tail 2 (KIR2DL2); cytotoxic cell immunoglobulin-like receptor with two Ig domains and a long cytoplasmic tail 3 (KIR2DL3); cytotoxic cell immunoglobulin-like receptor with three Ig domains and a long cytoplasmic tail 1 (KIR3DL1); cytotoxic cell lectin-like receptor D1 (KLRD1);

In some embodiments, the compounds described herein are combined with one or more blockers or inhibitors of one or more T-cell suppressor immune checkpoint proteins or receptors. Illustrative T-cell suppressor immune checkpoint proteins or receptors include, but are not limited to, CD274 (PDL1, PD-L1); programmed cell death 1 ligand 2 (PDCD1LG2, PD-L2, CD273); programmed cell death 1 (PDCD1, PD1, PD-1); cytotoxic T-lymphocyte-associated protein 4 (CTLA4, CD152); CD276 (B7H3); V-set domain-containing T-cell activation inhibitor 1 (VTCN1, B7H4); V-set immunomodulatory receptors (VSIR, B7H5, VISTA); immunoglobulin superfamily member 11 (IGSF11, VSIG3); TNFRSF14 (HVEM, CD270), TNFSF14 (HVEML); CD272 (B and T lymphocyte-associated (BTLA)). ; Contains PVR-associated immunoglobulin domains (PVRIG, CD112R); T-cell immune receptor with Ig and ITIM domains (TIGIT); Lymphocyte activation 3 (LAG-3, CD223); Hepatitis A virus cell receptor 2 (HAVCR2, TIMD3, TIM-3); Galactoglobulin 9 (LGALS9); Killer cell immunoglobulin-like receptor (KIR); Killer cell immunoglobulin-like receptor with two Ig domains and long cytoplasmic tail 1 (KIR2DL1); Killer cell immunoglobulin-like receptor with two Ig domains and long cytoplasmic tail 2 (KIR2DL2); Killer cell immunoglobulin-like receptor with two Ig domains and long cytoplasmic tail 3 (KIR2DL3); and Killer cell immunoglobulin-like receptor with three Ig domains and long cytoplasmic tail 1 (KIR3DL1). In some embodiments, the compound as described herein is combined with one or more agonists or activators of one or more T-cell-stimulating immune checkpoint proteins or receptors. Examples of T-cell stimulating immune checkpoint proteins or receptors include, but are not limited to, CD27, CD70; CD40, CD40LG; inducible T-cell costimulatory factors (ICOS, CD278); inducible T-cell costimulatory factor ligands (ICOSLG, B7H2); TNF receptor superfamily member 4 (TNFRSF4, OX40); TNF superfamily member 4 (TNFSF4, OX40L); TNFRSF9 (CD137), TNFSF9 (CD137L); TNFRSF18 (GITR), TNFSF18 (GITRL); CD80 (B7-1), CD28; nectin cell adhesion molecule 2 (NECTIN2, CD112); CD226 (DNAM-1); CD244 (2B4, SLAMF4); and poliovirus receptor (PVR) cell adhesion molecule (PVR, CD155). See, for example, Xu et al., J Exp Clin Cancer Res. (2018) 37:110.

In some embodiments, the compounds described herein are combined with one or more blockers or inhibitors of one or more NK cell inhibitory immune checkpoint proteins or receptors. Exemplary NK cell inhibitory immune checkpoint proteins or receptors include, but are not limited to, cytotoxic cell immunoglobulin-like receptors with three Ig domains and a long cytoplasmic tail 1 (KIR, CD158E1); cytotoxic cell immunoglobulin-like receptors with two Ig domains and a long cytoplasmic tail 1 (KIR2DL1); cytotoxic cell immunoglobulin-like receptors with two Ig domains and a long cytoplasmic tail 2 (KIR2DL2); cytotoxic cell immunoglobulin-like receptors with two Ig domains and a long cytoplasmic tail 3 (KIR2DL3); cytotoxic cell immunoglobulin-like receptors with three Ig domains and a long cytoplasmic tail 1 (KIR3DL1); cytotoxic cell lectin-like receptors C1 (KLRC1, NKG2A, CD159A); and cytotoxic cell lectin-like receptors D1 (KLRD1, CD94). In some embodiments, the compounds described herein are combined with one or more agonists or activators of one or more NK cell-stimulating immune checkpoint proteins or receptors. Exemplary NK cell-stimulating immune checkpoint proteins or receptors include, but are not limited to, CD16, CD226 (DNAM-1); CD244 (2B4, SLAMF4); cytotoxic lectin-like receptor K1 (KLRK1, NKG2D, CD314); and SLAM family member 7 (SLAMF7). See, for example, Davis et al., Semin Immunol. (2017) 31:64–75; Fang et al., Semin Immunol. (2017) 31:37-54; and Chiossone et al., Nat Rev Immunol. (2018) 18(11):671-688.

In some embodiments, the compounds described herein are combined with inhibitors of CD47 (IAP, MER6, OA3; NCBI gene ID: 961; UniProt Q08722). Examples of CD47 inhibitors include, but are not limited to, anti-CD47 mAb (Vx-1004), anti-human CD47 mAb (CNTO-7108), CC-90002, CC-90002-ST-001, humanized anti-CD47 antibody (Hu5F9-G4), NI-1701, NI-1801, RCT-1938, ALX-148, TTI-621, RRx-001, DSP-107, VT-1021, TTI-621, TTI-622, and IMM-02SGN-CD47M. Examples of anti-CD47 antibodies include IBI-188, TJC-4, SHR-1603, HLX-24, LQ-001, IMC-002, ZL-1201, IMM-01, B6H12, GenSci-059, TAY-018, PT-240, 1F8-GMCSF, SY-102, and KD-015.

In some implementations, the CD47 inhibitor is a bispecific antibody that targets CD47. Examples of bispecific antibodies targeting CD47 include IBI-322 (CD47/PD-L1), IMM-0306 (CD47/CD20), TJ-L1C4 (CD47/PD-L1), HX-009 (CD47/PD-1), PMC-122 (CD47/PD-L1), PT-217 (CD47/DLL3), IMM-26011 (CD47/FLT3), IMM-0207 (CD47/VEGF), IMM-2902 (CD47/HER2), BH29xx (CD47/PD-L1), IMM-03 (CD47/CD20), IMM-2502 (CD47/PD-L1), HMBD-004B (CD47/BCMA), and HMBD-004A (CD47/CD33).

In some embodiments, the anti-CD47 targeting agent is described in patent publication numbers WO199727873, WO199940940, WO2002092784, WO2005044857, WO2009046541, WO2010070047, WO2011143624, WO2012170250, WO2013109752, WO2013119714, WO2014087248, and WO2015191861. WO2016022971, WO2016023040, WO2016024021, WO2016081423, WO2016109415, WO2016141328, WO201618844 9. WO2017027422, WO2017049251, WO2017053423, WO2017121771, WO2017194634, WO2017196793, WO2017215 585. WO2018075857, WO2018075960, WO2018089508, WO2018095428, WO2018137705, WO2018233575, WO20190 27903, WO2019034895, WO2019042119, WO2019042285, WO2019042470, WO2019086573, WO2019108733, WO201 An anti-CD47 targeting agent as described in WO2019144895, WO2019157843, WO2019179366, WO2019184912, WO2019185717, WO2019201236, WO2019238012, WO2019241732, WO2020019135, WO2020036977, WO2020043188 or WO2020009725.

In some embodiments, one or more immune checkpoint inhibitors include protein (e.g., antibody or fragment thereof or antibody mimic) inhibitors of PD-L1 (CD274), PD-1 (PDCD1), or CTLA4. In some embodiments, one or more immune checkpoint inhibitors include small organic molecule inhibitors of PD-L1 (CD274), PD-1 (PDCD1), or CTLA4.

Examples of CTLA4 inhibitors that can be co-administered include, but are not limited to: ipilimumab, trimemumab, BMS-986218, AGEN1181, AGEN1884, BMS-986249, MK-1308, REGN-4659, ADU-1604, CS-1002, BCD-145, APL-509, JS-007, BA-3071, ONC-392, AGEN-2041, JHL-1155, KN-044, CG-0161, and ATOR-11. 44. PBI-5D3H5, BPI-002, HBM-4003, and multispecific inhibitors FPT-155 (CTLA4/PD-L1/CD28), PF-06936308 (PD-1/CTLA4), MGD-019 (PD-1/CTLA4), KN-046 (PD-1/CTLA4), MEDI-5752 (CTLA4/PD-1), XmAb-20717 (PD-1/CTLA4), and AK-104 (CTLA4/PD-1).

Examples of PD-L1 (CD274) or PD-1 (PDCD1) inhibitors/antibodies that can be co-administered include, but are not limited to: pembrolizumab, nivolumab, cimiprizumab, pildizilzumab, AMG-404, AMP-224, MEDI0680 (AMP-514), spartazolizumab, atezolizumab, avelumab, durvalumab, BMS-936559, CK-301, PF-06801591, BGB-A317 (tislelizumab), GEN-1046 (PD-L1/4-1BB), GLS-010 (WBP-3055), AK- 103(HX-008), AK-105, CS-1003, HLX-10, MGA-012, BI-754091, AGEN-2034, JS-001 (Toripalimab), JNJ-63723283, Genomeamarone (CBT-501), LZM-009, BCD-100, LY-3300054, SHR-1201, SHR-1210 (Camrelizumab), Sym-021, ABBV-181, PD1-PIK, BAT-1306 (MSB0010718C), CX-072, CBT-502, TSR- 042 (dotalipimab), MSB-2311, JTX-4014, BGB-A333, SHR-1316, CS-1001 (WBP-3155, KN-035, IBI-308 (sintilimab), HLX-20, KL-A167, STI-A1014, STI-A1015 (IMC-001), BCD-135, FAZ-053, TQB-2450, MDX1105-01, GS-4224, GS-4416, INCB086550, MAX10181, and the multispecific inhibitor FPT-155 (CTL) A4/PD-L1/CD28), PF-06936308(PD-1/CTLA4), MGD-013(PD-1/LAG-3), RO-7247669(PD-1/LAG-3), FS-118(LAG-3/PD-L1), MGD-019(P D-1/CTLA4), KN-046(PD-1/CTLA4), MEDI-5752(CTLA4/PD-1), RO-7121661(PD-1/TIM-3), XmAb-20717(PD-1/CTLA4), AK-104(CTLA4/P D-1), M7824 (PD-L1/TGFβ-EC domain), CA-170 (PD-L1/VISTA), CDX-527 (CD27/PD-L1), LY-3415244 (TIM-3/PDL1), RG7769 (PD-1/TIM-3), INBRX-105 (4-1BB/PDL1), GNS-1480 (PD-L1/EGFR), RG-7446 (Tecentriq, atezolizumab), ABBV-181, nivolumab (BMS-936558, MDX-1106), pembrolizumab (MK- 3477, SCH-900475, Lambrolizumab (CAS Registry No. 1374853--91--4), Pildilizumab, PF-06801591, BGB-A317 (Tislelizumab), GLS-010 (WBP-3055), AK-103 (HX-008), CS-1003, HLX-10, MGA-012, BI-754091, REGN-2810 (Cimiprizumab), AAGEN-2034, JS-001 (Toripalimab), JNJ-63723283, Genozamab (CB T-501), LZM-009, BCD-100, LY-3300054, SHR-1201, SHR-1210 (Camrelizumab), Sym-021, ABBV-181, AK-105, PD1-PIK, BAT-1306, BMS-936559, Atezolizumab (MPDL3280A), Duvalimumab (MEDI-4736), Averumab, CK-301 (MSB0010718C), MEDI-0680, CX-072, CBT-502, PDR-001 (Spartazumab), PDR001++M SB-2311, JTX-4014, BGB-A333, SHR-1316, CS-1001 (WBP-3155, KN-035, IBI-308 (sintilimab), HLX-20, KL-A167, STI-A1014, STI-A1015 (IMC-001), BCD-135, FAZ-053, TQB-2450 and MDX1105-01; and those described, for example, in International Patent Publication Nos. WO2018195321, WO2020014643, WO2019160882 and WO2018195321.

Examples of PVRIG inhibitors that can be co-administered include, but are not limited to, COM-701.

Examples of TIGIT inhibitors that can be co-administered include, but are not limited to: BMS-986207, RG-6058, AAGEN-1307, and COM-902.

Examples of TIM-3 inhibitors that can be co-administered include, but are not limited to: TSR-022, LY-3321367, MBG-453, INCAGN-2390, RO-7121661 (PD-1/TIM-3), LY-3415244 (TIM-3/PDL1), and RG7769 (PD-1/TIM-3).

Examples of LAG-3 inhibitors that can be co-administered include, but are not limited to: relatlimab (ONO-4482), LAG-525, MK-4280, REGN-3767, INCAGN2385, TSR-033, MGD-013 (PD-1/LAG-3), and FS-118 (LAG-3/PD-L1).

Monoclonal antibodies against killer cell immunoglobulin-like receptors, three Ig domains, and long cytoplasmic tail 1 (KIR3DL1; KIR; NCBI gene ID: 3811), such as lirilumab (IPH-2102) and IPH-4102.

Examples of anti-NKG2a antibodies that can be co-administered include, but are not limited to, monolinzumab.

Examples of anti-VISTA antibodies that can be administered together include, but are not limited to: HMBD-002 and CA-170 (PD-L1/VISTA).

Examples of anti-CD70 antibodies that can be co-administered include, but are not limited to, AMG-172.

Examples of anti-CD20 antibodies that can be administered together include, but are not limited to: obinutuzumab, IGN-002, and PF-05280586.

Examples of anti-ICOS antibodies that can be administered together include, but are not limited to: JTX-2011 and GSK3359609.

Examples of ICOS agonists that can be co-administered include, but are not limited to: ICOS-L.COMP (Gariepy, J. et al., 106th Annual Meeting of the American Association of Immunologists (AAI) (May 9-13, 2019, San Diego), Abstract 71.5).

TNF receptor superfamily (TNFRSF) agonists or activators

In some embodiments, the compound as described herein is combined with an agonist of one or more members of the TNF receptor superfamily (TNFRSF), such agonists being one or more of the following: TNFRSF1A (NCBI gene ID: 7132), TNFRSF1B (NCBI gene ID: 7133), TNFRSF4 (OX40, CD134; NCBI gene ID: 7293), TNFRSF5 (CD40; NCBI gene ID: 958), TNFRSF6 (FAS, NCBI gene ID: 3... 55), TNFRSF7 (CD27, NCBI gene ID: 939), TNFRSF8 (CD30, NCBI gene ID: 943), TNFRSF9 (4-1BB, CD137, NCBI gene ID: 3604), TNFRSF10A (CD261, DR4, TRAILR1, NCBI gene ID: 8797), TNFRSF10B (CD262, DR5, TRAILR2, NCBI gene ID: 8795), TNFRSF10C (CD263, TRAILR3) TNFRSF10D (CD264, TRAILR4, NCBI gene ID: 8793), TNFRSF11A (CD265, RANK, NCBI gene ID: 8792), TNFRSF11B (NCBI gene ID: 4982), TNFRSF12A (CD266, NCBI gene ID: 51330), TNFRSF13B (CD267, NCBI gene ID: 23495), TNFRSF13C (CD268, NCBI gene ID: 8794), ...CD268, NCBI gene ID: 4982), TNFRSF12A (CD266, NCBI gene ID: 51330), TNFRSF13B (CD267, NCBI gene ID: 23495), TNFRSF13C (CD268, NCBI gene ID: 8794), TNFRSF10D (CD264, TRAILR4, NCBI gene ID: 8793), TNFRSF11 TNFRSF16 (NGFR, CD271, NCBI gene ID: 4804), TNFRSF17 (BCMA, CD269, NCBI gene ID: 608), TNFRSF18 (GITR, CD357, NCBI gene ID: 8784), TNFRSF19 (NCBI gene ID: 55504), TNFRSF21 (CD358, DR6, NCBI gene ID: 27242), and TNFRSF25 (DR3, NCBI gene ID: 8718).

Examples of anti-TNFRSF4 (OX40) antibodies that can be administered co-administered include, but are not limited to, MEDI6469, MEDI6383, MEDI0562 (tavorizumab), MOXR0916, PF-04518600, RG-7888, GSK-3174998, INCAGN1949, BMS-986178, GBR-8383, ABBV-368, and those described in WO2016179517, WO2017096179, WO2017096182, WO2017096281, and WO2018089628.

Examples of antibodies against TNF receptor superfamily members 10b (TNFRSF10B, DR5, TRAILR2) that can be co-administered include, but are not limited to, DS-8273, CTB-006, INBRX-109, and GEN-1029.

Examples of anti-TNFRSF5 (CD40) antibodies that can be co-administered include, but are not limited to, RG7876, SEA-CD40, APX-005M, and ABBV-428, ABBV-927, and JNJ-64457107.

In some implementations, the anti-TNFRSF7 (CD27) antibody varigramab (CDX-1127) is co-administered.

Examples of anti-TNFRSF9 (4-1BB, CD137) antibodies that can be administered together include, but are not limited to, urinumab, urinumab (PF-05082566), AGEN2373, and ADG-106.

In some implementations, the anti-TNFRSF17 (BCMA) antibody GSK-2857916 is co-administered.

Examples of anti-TNFRSF18 (GITR) antibodies that can be co-administered include, but are not limited to, MEDI1873, FPA-154, INCAGN-1876, TRX-518, BMS-986156, MK-1248, GWN-323, and those described in WO2017096179, WO2017096276, WO2017096189, and WO2018089628. In some embodiments, antibodies or fragments thereof that co-target TNFRSF4 (OX40) and TNFRSF18 (GITR) are co-administered. Such antibodies are described, for example, in WO2017096179 and WO2018089628.

Examples of anti-TRAILR1 antibodies, anti-TRAILR2 antibodies, anti-TRAILR3 antibodies, and anti-TRAILR4 antibodies that can be administered together include, but are not limited to, ABBV-621.

Bispecific antibodies targeting TNFRSF family members that can be co-administered include, but are not limited to, PRS-343 (CD-137/HER2), AFM26 (BCMA/CD16A), AFM-13 (CD16/CD30), REGN-1979 (CD20/CD3), AMG-420 (BCMA/CD3), INHIBRX-105 (4-1BB/PDL1), FAP-4-IBBL (4-1BB/FAP), XmAb-13676 (CD3/CD20), RG-7828 (CD20/CD3), CC-93269 (CD3/BCMA), REGN-5458 (CD3/BCMA), IMM-0306 (CD47/CD20), and AMG-424 (CD38.CD3).

Adenosine production and signal transduction

In some embodiments, the compounds described herein are combined with agonists or antagonists of A1R, A2AR, A2BR, A3R, CD73, CD39, or CD26.

Examples of adenosine A3 receptor (A3R) agonists include namodenoson (CF102).

Examples of A2aR/A2bR antagonists include AB928.

Examples of anti-CD73 antibodies include MEDI-9447 (olerutumab), CPX-006, IPH-53, BMS-986179, NZV-930, and CPI-006.

Examples of CD73 inhibitors include AB-680, PSB-12379, PSB-12441, PSB-12425, CB-708; and those described in International Patent Publication No. WO19173692.

Examples of CD39/CD73 inhibitors include PBF-1662.

Examples of anti-CD39 antibodies include TTX-030.

Examples of adenosine A2A receptor antagonists include CPI-444, AZD-4635, preladenant, and PBF-509.

Examples of adenosine deaminase inhibitors include pentostatin and cladribine.

c-kit targeted agent

In various implementation schemes, the compounds described herein are combined with inhibitors of c-kit (PBT, SCFR, CD117, MASTC; NCBI gene ID: 3815; Uniprot-P10721).

Examples of c-kit inhibitors include imatinib mesylate, JSP-191, BLU-263, CD117-ADC, AZD3229 (c-kit/PDGFR inhibitor), telatinib (c-kit/PDGF/VEGF2 inhibitor), quizartinib dihydrochloride (FLT3/c-kit), pexidartinib hydrochloride (CSF1R/FLT3/c-kit), avapritinib (PDGFR/c-kit inhibitor), vorolanib (multi-kinase VEGF/PDGFR/c-kit inhibitor), and ripretinib (c-kit/PDGFRα inhibitor).

Examples of c-kit multi-kinase inhibitors include dasatinib, imatinib, nilotinib, sorafenib, lenvatinib mesylate, cabozantinib malate, AL-8326, ZLJ-33, KBP-7018, sunitinib malate, pazopanib derivatives, AGX-73, rebastinib, NMS-088, lucitinib hydrochloride, midotuxinib, sididanib, duvertinib, sitravatinib, tivozanib, masitinib, regorafenib, HQP-1351, cabozantinib, ponatinib, and famitinib L-malate. Examples of anti-c-kit antibodies include CDX-0158, CDX-0159, and FSI-174.

In some implementations, the anti-c-kit targeting agent is described in patent publication numbers WO199203459, WO199221766, WO2004080462, WO2005020921, WO2006009755, WO2007078034, WO2007092403, WO2007127317, WO2008005877, and WO20121. An anti-c-kit targeting agent as described in WO2014100620, WO2014039714, WO2015134536, WO2017167182, WO2018112136, WO2018112140, WO2019155067, WO2020076105 and patent application number PCT/US2019/063091.

SIRPα targeted agent

In various implementation schemes, the compounds described herein are combined with inhibitors of SIRPα (NCBI gene ID: 140885; UniProtP78324).

Examples of SIRPα inhibitors include AL-008, RRx-001, and CTX-5861.

Examples of anti-SIRPα antibodies include FSI-189, ES-004, BI765063, ADU1805, and CC-95251.

In some implementations, the SIRPα target agent is one of the following: WO200140307, WO2002092784, WO2007133811, WO2009046541, WO2010083253, WO2011076781, WO2013056352, WO2015138600, WO2016179399, WO2016205042, WO201717865. 3. A SIRPα targeting agent as described in WO2018026600, WO2018057669, WO2018107058, WO2018190719, WO2018210793, WO2019023347, WO2019042470, WO2019175218, WO2019183266, WO2020013170 or WO2020068752.

Bispecific T cell adaptor

In some embodiments, the compounds described herein are combined with bispecific T-cell adaptors (e.g., without Fc) or anti-CD3 bispecific antibodies (e.g., with Fc). Illustrative anti-CD3 bispecific antibodies or BiTEs that can be co-administered include: AMG-160 (PSMA/CD3), AMG-212 (PSMA/CD3), AMG-330 (CD33/CD3), AMG-420 (BCMA/CD3), AMG-427 (FLT3/CD3), AMG-562 (CD19/CD3), AMG-596 (EGFRvIII/CD3), AMG-673 (CD33/CD3), AMG-701 (BCMA/CD3), AMG-757 (DLL3/CD3), JNJ-6 4052781(CD19/CD3), AMG-211(CEA/CD3), (CD19/CD3), RG7802(CEA/CD3), ERY-974(CD3/GPC3), huGD2-BsAb(CD3/GD2), PF-06671 008 (cadherin/CD3), APVO436 (CD123/CD3), ERY974, flutizumab (CD123/CD3), GEM333 (CD3/CD33), GEMoab (CD3/PSCA), REGN-1979 (CD20/CD3 ), REGN-5678(PSMA/CD28), MCLA-117(CD3/CLEC12A), JNJ-0819, JNJ-7564(CD3/heme), JNJ-63709178(CD123/CD3), MGD-007(CD3/ gpA33), MGD-009(CD3/B7H3), IMCgp100(CD3/gp100), XmAb-14045(CD123/CD3), XmAb-13676(CD3/CD20), XmAb-18087(SSTR2/CD3) Caputuximab (CD3/EpCAM), REGN-4018 (MUC16/CD3), RG6026, RG6076, RG6194, RG-7828 (CD20/CD3), CC-93269 (CD3/BCMA), REGN-5458 (CD3/BCMA), GRB-1302 (CD3/Erbb2), GRB-1342 (CD38/CD3), GEM-333 (CD3/CD33), PF-06863135 (BCMA/CD3), SAR440234 (CD3/CDw123). Depending on the situation, anti-CD3 binding bispecific molecules may or may not have an Fc. Exemplary bispecific T-cell adaptors that can be co-administered target CD3 and tumor-associated antigens as described herein, including, for example, CD19 (e.g., bonatetumab); CD33 (e.g., AMG330); CEA (e.g., MEDI-565); receptor tyrosine kinase-like orphan receptor 1 (ROR1) (Gohil et al., Oncoimmunology. May 17, 2017; 6(7):e1326437); PD-L1 (Horn et al., Oncotarget. August 3, 2017; 8(35):57964-57980); and EGFRvIII (Yang et al., Cancer Lett. September 10, 2017; 403:224-230).

Bispecific and trispecific natural killer (NK) cell adaptors

In some embodiments, the compounds described herein are combined with bispecific NK cell adaptors (BiKE) or trispecific NK cell adaptors (TriKE) (e.g., without Fc) or bispecific antibodies against the following (e.g., with Fc): NK cell activation receptors, such as CD16A, C-type lectin receptors (CD94/NKG2C, NKG2D, NKG2E/H and NKG2F), native cytotoxic receptors (NKp30, NKp44 and NKp46), cytotoxic cell C-type lectin-like receptors (NKp65, NKp80), Fc receptor FcγR (which mediates antibody-dependent cytotoxicity), SLAM family receptors (e.g. 2B4, SLAM6 and SLAM7), cytotoxic cell immunoglobulin-like receptors (KIR) (KIR-2DS and KIR-3DS), DNAM-1 and CD137 (41BB). Exemplary anti-CD16 bispecific antibodies, BiKEs, or TriKEs that can be administered co-administered include AFM26 (BCMA/CD16A) and AFM-13 (CD16/CD30). Depending on the case, anti-CD16 binding bispecific molecules may or may not have an Fc. Exemplary bispecific NK cell adaptors that can be administered co-administered target CD16 and one or more tumor-associated antigens as described herein, including, for example, CD19, CD20, CD22, CD30, CD33, CD123, EGFR, EpCAM, ganglioside GD2, HER2/neu, HLA class II, and FOLR1. BiKEs and TriKEs are described, for example, in the following literature: Felices et al., Methods Mol Biol. (2016) 1441:333–346; Fang et al., Semin Immunol. (2017) 31:37-54.

MCL1 apoptosis regulators and BCL2 family member (MCL1) inhibitors

In some embodiments, compounds as described herein are combined with inhibitors of MCL1 apoptosis regulators (BCL2 family members) (MCL1, TM; EAT; MCL1L; MCL1S; Mcl-1; BCL2L3; MCL1-ES; bcl2-L-3; mcl1/EAT; NCBI gene ID: 4170). Examples of MCL1 inhibitors include AMG-176, AMG-397, S-64315 and AZD-5991, 483-LM, A-1210477, UMI-77, JKY-5-037 and those described in WO2018183418, WO2016033486 and WO2017147410.

Hematopoietic progenitor cell kinase 1 (HPK1) inhibitors

In some embodiments, the compounds described herein are combined with inhibitors of mitogen-activated protein kinase kinase 1 (MAP4K1, HPK1; NCBI gene ID: 11184). Examples of hematopoietic progenitor cell kinase 1 (HPK1) inhibitors include, but are not limited to, those described in WO-2018183956, WO-2018183964, WO-2018167147, WO-2018183964, WO-2016205942, WO-2018049214, WO-2018049200, WO-2018049191, WO-2018102366, WO-2018049152, WO2020092528, WO2020092621, and WO-2016090300.

Inhibitors of apoptosis signal-regulated kinase (ASK)

In some embodiments, the compounds described herein are combined with inhibitors of ASK inhibitors, such as mitogen-activated protein kinase kinase 5 (MAP3K5; ASK1, MAPKKK5, MEKK5; NCBI gene ID: 4217). Examples of ASK1 inhibitors include, but are not limited to, those described in WO 2011/008709 (Gilead Sciences) and WO 2013/112741 (Gilead Sciences).

Bruton's tyrosine kinase (BTK) inhibitors

In some implementations, the compounds described herein are combined with inhibitors of Bruton's tyrosine kinases (BTK, AGMX1, AT, ATK, BPK, IGHD3, IMD1, PSCTK1, XLA; NCBI gene ID: 695). Examples of BTK inhibitors include, but are not limited to: (S)-6-amino-9-(1-(but-2-ynyl)pyrrolidone-3-yl)-7-(4-phenoxyphenyl)-7H-purine-8(9H)-one, acalabrutinib (ACP-196), BGB-3111, CB988, HM71224, ibrutinib (Imbruvica), M-2951 (evobrutinib), M7583, tirabrutinib (ONO-4059), PRN-1008, spetinib (CC-292), TAK-020, vecabrutinib, ARQ-531, SHR-1459, DTRMWXHS-12, TAS-5315, Calquence+AZD6738, Calquence+danvatirsen.

Cyclin-dependent kinase (CDK) inhibitors

In some embodiments, the compounds described herein are combined with inhibitors of the following substances: cyclin-dependent kinase 1 (CDK1, CDC2; CDC28A; p34CDC2; NCBI gene ID: 983); cyclin-dependent kinase 2 (CDK2, CDKN2; p33(CDK2); NCBI gene ID: 1017); cyclin-dependent kinase 3 (CDK3; NCBI gene ID: 1018); cyclin-dependent kinase 4 (CDK4, CMM3; PSK-J3); NCBI gene ID: 1019); Cyclin-dependent kinase 6 (CDK6, MCPH12; PLSTIRE; NCBI gene ID: 1021); Cyclin-dependent kinase 7 (CDK7, CAK; CAK1; HCAK; MO15; STK1; CDKN7; p39MO15; NCBI gene ID: 1022); Cyclin-dependent kinase 9 (CDK9, TAK; C-2k; CTK1; CDC2L4; PITALRE; NCBI gene ID: 1025). Inhibitors of CDK 1, 2, 3, 4, 6, 7 and/or 9 include, but are not limited to: abecilibi, avozidil (HMR-1275, frapindo), AT-7519, dinascilibi, ibrance, FLX-925, LEE001, pebocilli, ribociclib, rigosertib, selinexor, UCN-01, SY1365, CT-7001, SY-1365, G1T38, mircizoli, trilacizoli, PF-06873600, AZD4573 and TG-02.

Discoid domain receptor (DDR) inhibitors

In some embodiments, the compounds described herein are combined with inhibitors of the following substances: discoid domain receptor tyrosine kinase 1 (DDR1, CAK, CD167, DDR, EDDR1, HGK2, MCK10, NEP, NTRK4, PTK3, PTK3A, RTK6, TRKE; NCBI gene ID: 780); and/or discoid domain receptor tyrosine kinase 2 (DDR2, MIG20a, NTRKR3, TKT, TYRO10, WRCN; NCBI gene ID: 4921). Examples of DDR inhibitors include, but are not limited to, dasatinib and those disclosed in WO2014/047624 (Gilead Sciences), US 2009-0142345 (Takeda Pharmaceutical), US2011-0287011 (Oncomed Pharmaceuticals), WO 2013/027802 (Chugai Pharmaceutical) and WO2013/034933 (Imperial Innovations).

Histone deacetylase (HDAC) inhibitors

In some embodiments, the compounds described herein are combined with inhibitors of histone deacetylases, such as histone deacetylase 9 (HDAC9, HD7, HD7b, HD9, HDAC, HDAC7, HDAC7B, HDAC9B, HDAC9FL, HDRP, MITR; gene ID: 9734). Examples of HDAC inhibitors include, but are not limited to: abexinostat, ACY-241, AR-42, BEBT-908, belinostat, CKD-581, CS-055 (HBI-8000), CUDC-907 (fimepinostat), entinostat, givinostat, mocetinostat, panobinostat, pracinostat, quisinostat (JNJ-26481585), remixitana, ricolinostat, SHP-141, valproic acid (VAL-001), vorinostat, tinostamustine, remetinostat, entinostat, romidesin, and tucidinostat.

Indoleamine-pyrrole-2,3-dioxygenase (IDO1) inhibitors

In some embodiments, compounds as described herein are combined with inhibitors of indoleamine 2,3-dioxygenase 1 (IDO1; NCBI gene ID: 3620). Examples of IDO1 inhibitors include, but are not limited to, BLV-0801, icardolstat, F-001287, GBV-1012, GBV-1028, GDC-0919, indomod, NKTR-218, NLG-919-based vaccines, PF-06840003, pyranoquinone derivatives (SN-35837), remixstat, SBLK-200802, BMS-986205, and shIDO-ST, EOS-200271, KHK-2455, and LY-3381916.

Janus kinase (JAK) inhibitors

In some embodiments, the compounds described herein are combined with inhibitors of Janus kinase 1 (JAK1, JAK1A, JAK1B, JTK3; NCBI gene ID: 3716); Janus kinase 2 (JAK2, JTK10, THCYT3; NCBI gene ID: 3717); and/or Janus kinase 3 (JAK3, JAK-3, JAK3_HUMAN, JAKL, L-JAK, LJAK; NCBI gene ID: 3718). Examples of JAK inhibitors include, but are not limited to, AT9283, AZD1480, baricitinib, BMS-911543, fedratinib, filgotinib (GLPG0634), gandotinib (LY2784544), INCB039110 (itacitinib), lestaurtinib, momelotinib (CYT0387), NS-018, pacritinib (SB1518), peficitinib (ASP015K), ruxolitinib, tofacitinib (formerly known as tasocitinib citrate), INCB052793, and XL019.

Matrix metalloproteinase (MMP) inhibitors

In some embodiments, the compounds described herein are combined with inhibitors of matrix metalloproteinases (MMPs), such as inhibitors of the following substances: MMP1 (NCBI gene ID: 4312), MMP2 (NCBI gene ID: 4313), MMP3 (NCBI gene ID: 4314), MMP7 (NCBI gene ID: 4316), MMP8 (NCBI gene ID: 4317), MMP9 (NCBI gene ID: 4318), MMP10 (NCBI gene ID: 4319), MMP11 (NCBI gene ID: 4320), MMP12 (NCBI gene ID: 4321), and MMP13 (NCBI gene ID: 4322). MMP14 (NCBI gene ID: 4323), MMP15 (NCBI gene ID: 4324), MMP16 (NCBI gene ID: 4325), MMP17 (NCBI gene ID: 4326), MMP19 (NCBI gene ID: 4327), MMP20 (NCBI gene ID: 9313), MMP21 (NCBI gene ID: 118856), MMP24 (NCBI gene ID: 10893), MMP25 (NCBI gene ID: 64386), MMP26 (NCBI gene ID: 56547), MMP27 (NCBI gene ID: 64066), and/or MMP28 (NCBI gene ID: 79148). Examples of MMP9 inhibitors include, but are not limited to, marimastastat (BB-2516), simmastastat (Ro 32-3555), GS-5745 (andadecaliximab), and those described in WO 2012/027721 (Gilead Biologics).

RAS and RAS pathway inhibitors

In some embodiments, the compounds described herein are combined with KRAS proto-oncogene GTPase (KRAS; also known as NS; NS3; CFC2; RALD; K-Ras; KRAS1; KRAS2; RASK2; KI-RAS; C-K-RAS; K-RAS2A; K-RAS2B; K-RAS4A; K-RAS4B; c-Ki-ras2; NCBI gene ID: 3845); NRAS proto-oncogene GTPase (NRAS; also known as NS6; CMNS; NCMS; ALPS4; N-ras; NRAS1; NCBI gene ID: 4893); HRas proto-oncogene GTPase (HRAS; also known as CTLO; KRAS; HAMSV; HRAS1; KRAS2; RASH1; RASK2; Ki-Ras; p21ras; C-H-RAS; c-K-ras; H-RASIDX; c-Ki-ras; C-BAS/HAS; C-HA-RAS1; NCBI gene ID: 3265);. Ras inhibitors can inhibit Ras at the polynucleotide (e.g., transcription inhibitors) or peptide (e.g., GTPase inhibitors) level. In some embodiments, the inhibitor targets one or more proteins in the Ras pathway, such as inhibiting one or more of EGFR, Ras, Raf (A-Raf, B-Raf, C-Raf), MEK (MEK1, MEK2), ERK, PI3K, AKT, and mTOR.

In some embodiments, compounds as described herein are combined with inhibitors of KRAS. Examples of KRAS inhibitors include AMG-510, COTI-219, MRTX-1257, ARS-3248, ARS-853, WDB-178, BI-3406, BI-1701963, ARS-1620 (G12C), SML-8-73-1 (G12C), compound 3144 (G12D), Kobe0065/2602 (RasGTP), RT11, MRTX-849 (G12C), and K-Ras(G12D)-selective inhibitory peptides, including KRpep-2(Ac-RRCPLYISYDPVCRR-NH ₂ ) (SEQ ID NO:108) and KRpep-2d(Ac-RRRRCPLYISYDPVCRRRR-NH ₂ ) (SEQ ID NO:109).

In some embodiments, compounds as described herein are combined with KRAS mRNA inhibitors. Exemplary KRAS mRNA inhibitors include anti-KRAS U1 aptamers, AZD-4785, siG12D-LODER ^™ , and siG12D exosomes.

In some implementations, compounds as described herein are combined with MEK inhibitors. Illustrative MEK inhibitors that can be co-administered include bimetinib, cobimetinib, PD-0325901, pimateb, RG-7304, selumetinib, trametinib, and selumetinib.

In some implementations, compounds as described herein are combined with AKT inhibitors. Illustrative AKT inhibitors that can be co-administered include RG7440, MK-2206, ipatrolinib, afucetinib, AZD5363, ARQ-092, capapasetinib, tricelibin, and ABTL-0812 (PI3K/Akt/mTOR).

In some embodiments, compounds as described herein are combined with Raf inhibitors. Illustrative Raf inhibitors that can be co-administered include BGB-283 (Raf/EGFR), HM-95573, LXH-254, LY-3009120, RG7304, TAK-580, dabrafenib, vemurafenib, cannefenib (LGX818), PLX8394, RAF-265 (Raf/VEGFR), and ASN-003 (Raf/PI3K).

In some implementations, compounds as described herein are combined with ERK inhibitors. Illustrative ERK inhibitors that can be co-administered include LTT-462, LY-3214996, MK-8353, ravoxertinib, GDC-0994, and unitinib.

In some embodiments, compounds as described herein are combined with PI3K inhibitors. Illustrative PI3K inhibitors that can be co-administered include edolisiba, abductasiba, bupalisiba, and pictilisib. Illustrative PI3K/mTOR inhibitors that can be co-administered include dactolisiba, omipalisib, voxtalisib, gedatolisib, GSK2141795, and RG6114.

In some implementations, compounds as described herein are combined with mTOR inhibitors. Illustrative mTOR inhibitors that can be co-administered include: salpassetin, vitusertib (AZD2014), ME-344, sirolimus (oral nanoamorphous formulation, cancer), and TYME-88 (mTOR/cytochrome P450 3A4).

In some implementations, Ras-driven cancers with CDKN2A mutations (e.g., NSCLC) can be suppressed by co-administration of the MEK inhibitor selumetinib and the CDK4/6 inhibitor pebocilib. See, for example, Zhou et al., Cancer Lett. 2017 Nov 1; 408:130-137. Furthermore, K-RAS and mutant N-RAS can be reduced by the irreversible ERBB1/2/4 inhibitor lenatatinib. See, for example, Booth et al., Cancer Biol Ther. 2018 Feb 1; 19(2):132-137.

In some implementations, compounds as described herein are combined with inhibitors of RAS. Examples of RAS inhibitors include NEO-100 and regoratinib.

In some embodiments, the compounds described herein are combined with EGFR antagonists such as AMG-595, nexituzumab, ABBV-221, depatuxizumab mafodotin (ABT-414), thromboxane, ABT-806, vevictibi, mutuximab, and RM-1929.

In some embodiments, the compounds described herein are combined with inhibitors of protein tyrosine phosphatase non-receptor type 11 (PTPN11; BPTP3, CFC, JMML, METCDS, NS1, PTP-1D, PTP2C, SH-PTP2, SH-PTP3, SHP2; NCBI gene ID: 5781). Examples of SHP2 inhibitors include TNO155 (SHP-099), RMC-4550, JAB-3068, RMC-4630, SAR442720, and those described in WO2018172984 and WO2017211303.

In some implementations, the compounds described herein are combined with inhibitors of mitogen-activated protein kinase 7 (MAP2K7, JNKK2, MAPKK7, MEK, MEK 7, MKK7, PRKMK7, SAPKK-4, SAPKK4; NCBI gene ID: 5609). Examples of MEK inhibitors include: antroquinol, binimetinib, CK-127, cobimetinib (GDC-0973, XL-518), MT-144, selumetinib (AZD6244), sorafenib, trametinib (GSK1120212), uprosertib + trametinib, PD-0325901, pimasertib, LTT462, AS703988, CC-90003, refamethinib, TAK-733, CI-1040, and RG7421.

Phosphatidylinositol 3-kinase (PI3K) inhibitors

In some embodiments, the compounds described herein are combined with inhibitors of: phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunits, such as phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit α (PIK3CA, CLAPO, CLOVE, CWS5, MCAP, MCM, MCMTC, PI3K, PI3K-α, p110-α; NCBI gene ID: 5290); phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit β (PIK3CB, p110BETA, PI3K PI3K inhibitors include: PI3KBETA, PIK3C1 (NCBI gene ID: 5291); phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit γ (PIK3CG, PI3CG, PI3K, PI3Kγ, PIK3, p110γ, p120-PI3K; gene ID: 5494); and/or phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit δ (PIK3CD, APDS, IMD14, P110DELTA, PI3K, p110D; NCBI gene ID: 5293). In some embodiments, the PI3K inhibitor is a pan-PI3K inhibitor. Examples of PI3K inhibitors include, but are not limited to, ACP-319, AEZA-129, AMG-319, AS252424, AZD8186, BAY10824391, BEZ235, bupalixib (BKM120), BYL719 (abolixib), CH5132799, copanlixib (BAY 80-6946), duvelixib, GDC-0032, and GDC-0077. GDC-0941, GDC-0980, GSK2636771, GSK2269557, Adrenaline INCB50465, IPI-145, IPI-443, IPI-549, KAR4141, LY294002, LY3023414, MLN1117, OXY111A, PA799, PX-866, RG7604, Regoratinib, RP5090, RP65 30. SRX3177, tasselisib, TG100115, TGR-1202 (embralisib), TGX221, WX-037, X-339, X-414, XL147 (SAR245408), XL499, XL756, woumacil, ZSTK474, and the compounds described in WO 2005/113556 (ICOS), WO 2013/052699 (Gilead Calistoga), WO 2013/116562 (Gilead Calistoga), WO 2014/100765 (Gilead Calistoga), WO 2014/100767 (Gilead Calistoga) and WO 2014/201409 (Gilead Sciences).

Mitogen-activated protein kinase (MEK) inhibitors

In some implementations, compounds as described herein are combined with inhibitors of mitogen-activated protein kinase kinase 7 (MAP2K7, JNKK2, MAPKK7, MEK, MEK 7, MKK7, PRKMK7, SAPKK-4, SAPKK4; NCBI gene ID: 5609). Examples of MEK inhibitors include antroquinol, binimetinib, cobimetinib (GDC-0973, XL-518), MT-144, selumetinib (AZD6244), sorafenib, trametinib (GSK1120212), uprosertib + trametinib, PD-0325901, pimastetinib, LTT462, AS703988, CC-90003, and refamethinib.

Spleen tyrosine kinase (SYK) inhibitors

In some embodiments, compounds as described herein are combined with inhibitors of spleen-associated tyrosine kinase (SYK, p72-Syk, gene ID: 6850). Examples of SYK inhibitors include, but are not limited to, 6-(1H-indazole-6-yl)-N-(4-morpholinophenyl)imidazo[1,2-a]pyrazin-8-amine, BAY-61-3606, cerdulatinib (PRT-062607), entospletinib, fostamatinib (R788), HMPL-523, NVP-QAB 205AA, R112, R343, tamatinib (R406), and those described in US 8450321 (Gilead Connecticut) and U.S. 2015/0175616.

Toll-like receptor (TLR) agonists

In some embodiments, the compounds described herein are combined with agonists of toll-like receptors (TLRs), such as agonists of TLR1 (NCBI gene ID: 7096), TLR2 (NCBI gene ID: 7097), TLR3 (NCBI gene ID: 7098), TLR4 (NCBI gene ID: 7099), TLR5 (NCBI gene ID: 7100), TLR6 (NCBI gene ID: 10333), TLR7 (NCBI gene ID: 51284), TLR8 (NCBI gene ID: 51311), TLR9 (NCBI gene ID: 54106), and/or TLR10 (NCBI gene ID: 81793). Examples of TLR7 agonists that can be used in combination include, but are not limited to: DS-0509, GS-9620, LHC-165, TMX-101 (imiquimod), GSK-2245035, remiquimod, DSR-6434, DSP-3025, IMO-4200, MCT-465, MEDI-9197, 3M-051, SB-9922, 3M-052, Limtop, TMX-30X, TMX-202, RG-7863, RG-7795, and US201001433. 01(Gilead Sciences), US20110098248(Gilead Sciences) and US20090047249(Gilead Sciences), US20140045849(Ja nssen), US20140073642(Janssen), WO2014/056953(Janssen), WO2014/076221(Janssen), WO2014/128189(Janssen), US20140350031(Janssen)、WO2014/023813(Janssen)、US20080234251(Array Biopharma)、US20080306050(Array B iopharma), US20100029585 (Ventirx Pharma), US20110092485 (Ventirx Pharma), US20110118235 (Ventirx Pharma) The compounds disclosed in US20120082658 (Ventirx Pharma), US20120219615 (Ventirx Pharma), US20140066432 (Ventirx Pharma), US20140088085 (Ventirx Pharma), US20140275167 (Novira Therapeutics), and US20130251673 (Novira Therapeutics). A co-administerable TLR7/TLR8 agonist is NKTR-262. Examples of TLR8 agonists that can be co-administered include, but are not limited to, E-6887, IMO-4200, IMO-8400, IMO-9200, MCT-465, MEDI-9197, motolimod, remiquimod, GS-9688, VTX-1463, VTX-763, 3M-051, 3M-052, and US20140045849 (Janssen), US20140073642 (Janssen), WO2014/056953 (Janssen), WO2014/076221 (Janssen), WO2014/128189 (Janssen), US20140350031 (Janssen), WO2014/023813 (Janssen), and US20080234251 (Array Biopharma). The compounds disclosed in US20080306050 (Array Biopharma), US20100029585 (Ventirx Pharma), US20110092485 (Ventirx Pharma), US20110118235 (Ventirx Pharma), US20120082658 (Ventirx Pharma), US20120219615 (Ventirx Pharma), US20140066432 (Ventirx Pharma), US20140088085 (Ventirx Pharma), US20140275167 (Novira Therapeutics) and US20130251673 (Novira Therapeutics). Examples of TLR9 agonists that can be used in combination include, but are not limited to, AST-008, CMP-001, IMO-2055, IMO-2125, literimod, MGN-1601, BB-001, BB-006, IMO-3100, IMO-8400, IR-103, IMO-9200, agatolimod, DIMS-9054, DV-1079, DV-1179, AZD-1419, leftolimod (MGN-1703), CYT-003, CYT-003-QbG10, and PUL-042. Examples of TLR3 agonists include rapamod, polyICLC, apoxxim, IPH-33, MCT-465, MCT-475, and ND-1.1.

Examples of TLR8 inhibitors include, but are not limited to, E-6887, IMO-8400, IMO-9200, and VTX-763.

Examples of TLR8 agonists include, but are not limited to, MCT-465, Motomod, GS-9688, and VTX-1463.

Examples of TLR9 inhibitors include, but are not limited to, AST-008, IMO-2055, IMO-2125, lefitolimod, ritomod, MGN-1601, and PUL-042.

Examples of TLR7/TLR8 agonists include NKTR-262, IMO-4200, MEDI-9197 (tetramod), and retinomod.

Examples of TLR agonists include, but are not limited to: Lefetemod, Tilsotolimod, Ratamod, DSP-0509, AL-034, G-100, Cobitolimod, AST-008, Motomod, GSK-1795091, GSK-2245035, VTX-1463, GS-9688, LHC-165, BDB-001, RG-7854, and Tiramide.

In some embodiments, the therapeutic agent is an interferon gene stimulator (STING). In some embodiments, the STING receptor agonist or activator is selected from the group consisting of: ADU-S100 (MIW-815), SB-11285, MK-1454, SR-8291, AdVCA0848, GSK-532, SYN-STING, MSA-1, SR-8291, 5,6-dimethylxanthonone-4-acetic acid (DMXAA), cyclic GAMP (cGAMP), and cyclic diAMP.

Indoleamine-pyrrole-2,3-dioxygenase (IDO1) inhibitors

In some embodiments, compounds as described herein are combined with inhibitors of indoleamine 2,3-dioxygenase 1 (IDO1; NCBI gene ID: 3620). Examples of IDO1 inhibitors include, but are not limited to, BLV-0801, icardolstat, F-001287, GBV-1012, GBV-1028, GDC-0919, indomod, NKTR-218, NLG-919-based vaccines, PF-06840003, pyranoquinone derivatives (SN-35837), remixstat, SBLK-200802, BMS-986205, and shIDO-ST, EOS-200271, KHK-2455, and LY-3381916.

In some embodiments, the therapeutic agent is a small organic compound. In some embodiments, the therapeutic agent is an agonist or activator of a Toll-like receptor (TLR) or an interferon gene stimulator (STING). In some embodiments, the STING receptor agonist or activator is selected from the group consisting of: ADU-S100 (MIW-815), SB-11285, MK-1454, SR-8291, AdVCA0848, GSK-532, SYN-STING, MSA-1, SR-8291, 5,6-dimethylxanthonone-4-acetic acid (DMXAA), cyclic GAMP (cGAMP), and cyclic diAMP.

Tyrosine kinase inhibitors (TKIs)

In some embodiments, the compounds described herein are combined with tyrosine kinase inhibitors (TKIs). TKIs can target receptors for epidermal growth factor (EGFR), as well as receptors for fibroblast growth factor (FGF), platelet-derived growth factor (PDGF), and vascular endothelial growth factor (VEGF). Examples of TKIs include, but are not limited to: axitinib, afatinib, ARQ-087 (derazantinib), asp5878, AZD3759, AZD4547, bosutinib, brigatinib, cabozantinib, sildenafil, clenbuterol, dacomitinib, dasatinib, dovirtinib, E-6201, erdatinib, erlotinib, gefitinib, girritinib (ASP-2215), FP-1039, HM61713, icotinib, imatinib, KX2-391 ( Src), lapatinib, lenvatinib, midotutolin, nintedanib, ODM-203, omatinib, osimertinib (AZD-9291), pazopanib, panatinib, poziotinib, quezatinib, ladotinib, roxitinib, surufatinib (HMPL-012), sunitinib, famitinib L-malate (MAC-4), tevorib, TH-4000, tevorib and MEDI-575 (anti-PDGFR antibody), TAK-659, cabozantinib.

Chemotherapy agents (nursing standard)

In some implementations, the compounds described herein are combined with chemotherapeutic agents or antitumor agents.

As used herein, the terms “chemotherapy agent” or “chemotherapeutic agent” (or “chemotherapy” in the context of treatment with a chemotherapy agent) are intended to cover any non-protein (e.g., non-peptide) compound that can be used to treat cancer. Examples of chemotherapy agents include, but are not limited to: alkylating agents, such as thiotepa and cyclophosphamide alkyl sulfonates, such as busulfan, indomethacin, and piperazine; aziridines, such as benzothiopepa, carboquinone, metopepa, and urotepa; ethylene imines and methyl melamines, including hexamethylmelamine, triethylene melamine, triethylene phosphoramide, triethylene thiophosphamide, and trimemylolomelamine; lactones, such as brassic acid and brassacone; camptothecin, including the synthetic analogue topotecan; bryophyll, callus inhibin; CC-1065, including its synthetic analogues adolexin, callystatin, and bizelexin; nostocins, especially nostocin 1 and nostocin Fibroside 8; Saccharin; Betamethasone, including synthetic analogs KW-2189 and CBI-TMI; eleutherobin; 5-azacytidine; pancratistatin; sarcodictyin; spongistatin; nitrogen mustard, such as chlorambucil, naphthalenemus, cyclophosphamide, glucosamine, levomycin, bendamustine, estradiol, ifosfamide, dichloromethyldiethylamine, dichloromethyldiethylamine hydrochloride, melphalan, neo-embezzin, benzylmustine, prednimustine, trelophosphamide, and uracil mustard; nitrosourea, such as carmustine, chloramphenicol, formustine, Lomustine, nimustine, and ramustine; antibiotics such as endothymic antibiotics (e.g., chachiomycin, especially chachiomycin γII and chachiomycin phiI1), dannimycin (including dannimycin A), bisphosphonates (such as clophosphonates), esparmycin, neo-cancer suppressant chromophores and associated chromophores, endothymic antibiotic chromophores, aclarubicin, actinomycin, autramycin, diazoserine, bleomycin, actinomycin, carabicin, carrninomycin, carzinophilin, chromomycin, daunorubicin, detoxin 6-Diazon-5-oxo-L-leucine, doxorubicin (including morpholino-doxorubicin, cyanomorpholino-doxorubicin, 2-pyrrolo-doxorubicin and deoxydoxorubicin), epirubicin, isopycin, idarubicin, ephedrine, mitomycin (such as mitomycin C), mycophenolic acid, nogamycin, olivomycin, pepromycin, pofibromycin, puromycin, quinamycin, rhodopycin, streptomycin, streptozotocin, tuberculin, ubenmex, fenestrated statin and zolrubicin; antimetabolites, such as methotrexate and 5-fluorouracil (5-FU); folic acid analogs, such as norpterin, methotrexate, pteroxetine and trimethoprim; purine analogs, such as cladribine, pentostatin, fludarabine, 6-mercapto-6-ethylhexyl-2 ... Purines, thioimidine, and thioguanine; pyrimidine analogues, such as ancitabine, azacitidine, 6-azouridine, carmoflurane, cytarabine, dideoxyuridine, deoxyfluorouridine, enoxabin, and fluorouridine; androgens, such as capprotestone, drotaloferrin propionate, cyclothionol, meandrolone, and testrolide; antiadrenergics, such as aminoglutethimide, mitotane, and trilosterone; folic acid supplements, such as folinic acid; radiotherapy agents, such as radium-223; trichothecenes, especially T-2 toxin, verracurin A, roridin A, and anguidine; taxanes, such as abraxane, docetaxel, and cabazitaxel. Cyprodin, BIND-014, Texstatin; Platinum analogs, such as cisplatin and carboplatin, NC-6004 nanoplatinum; acetoglucan lactone; aldehyde phosphoramidide glycoside; aminolevulinic acid; enuramicin; acridine; hestrabucil; bifenthrin; idatraxa; desphosphonamide; colchicine; desaccharin; elformthine; eletyl acetate; epothilone; etogluconate; gallium nitrate; hydroxyurea; lentinan; formyltetrahydrofolate; chlordamine; maytem alkaloids, such as maytem and anthraquinone; mitoxantrone; mitoxantrone; moperadol; diaminonitroacin; pentostatin; methamidophos; pirarubicin; loxoantrone; fluoropyrimidine; leucovorin; podophyllotoxin; 2-ethylhydrazine; propionyl ether Carbazine; Polysaccharide-K (PSK); Razosen; Rhizomycin; Cizonan; Germonylspiramine; Alternaria solanilic acid; Trabectedin, Triaminoquinone; 2,2',2”-Trichlorotrimethylamine; Carbamate; Vinpocetine; Dacarbazine; Mannomustine; Dibromomannitol; Dibromoeugenol; Piperobromide; Gacytosine; Arabinoside (“Ara-C”); Cyclophosphamide; Thiotepa; Chlorbutazone; Gemcitabine 6-thioguanine; Mercaptopurine; Methotrexate; Vincristine; Platinum; Etoposide (VP-16); Ifosfamide; Mitoxantrone; Vincristine; Vinorelbine; Teniposide; Idatraxa; Donomycin; Ampicillin; Xeoloda; Ibandronate; CPT-11; topoisomerase inhibitor RFS 2000; difluoromethylornithine (DFMO); visual pigments such as retinoic acid; capecitabine; NUC-1031; FOLFOX (leucovorin, 5-fluorouracil, oxaliplatin); FOLFIRI (leucovorin, 5-fluorouracil, irinotecan); FOLFOXIRI (leucovorin, 5-fluorouracil, oxaliplatin, irinotecan), FOLFIRINOX (leucovorin, 5-fluorouracil, irinotecan, oxaliplatin), and pharmaceutically acceptable salts, acids, or derivatives of any of the above substances. Such agents can be conjugated to antibodies or any of the targeting agents described herein to form antibody-drug conjugates (ADCs) or targeted drug conjugates.

Anti-hormone agents

The definition of “chemotherapy agents” also includes anti-hormonal agents, such as anti-estrogens and selective estrogen receptor modulators (SERMs), aromatase inhibitors, anti-androgens, and any pharmaceutically acceptable salts, acids, or derivatives of the above substances, which are used to regulate or inhibit the effects of hormones on tumors.

Examples of anti-estrogens and SERMs include, for example, tamoxifen (including NOLVADEXTM), raloxifene, droloxifene, 4-hydroxytamoxifen, trivoxifen, raloxifene hydrochloride, LY117018, onanasone, and toremifene.

Inhibitors of aromatase regulate estrogen production in the adrenal glands. Examples include 4(5)-imidazole, aminoglutethimide, megestrol acetate exemestane, formesterane, fazodazole, vorazole letrozole, and anastrozole.

Examples of anti-androgens include apalutamide, abiraterone, enzalutamide, flutamide, galactone, nilumet, bicalutamide, leuprorelin, goserelin, ODM-201, APC-100, and ODM-204.

Examples of progesterone receptor antagonists include onassidone.

Anti-angiogenic agents

In some embodiments, the compounds described herein are combined with anti-angiogenic agents. Anti-angiogenic agents that can be co-administered include, but are not limited to, retinoic acid and its derivatives, 2-methoxyestradiol, regorafenib, nicopanyl, suramin, squalamine, tissue inhibitors of metalloproteinase-1, tissue inhibitors of metalloproteinase-2, plasminogen activator inhibitor-1, plasminogen activator inhibitor-2, cartilage-derived inhibitors, paclitaxel (nabu-paclitaxel), platelet factor 4, protamine sulfate (herring protamine), sulfated chitin derivatives (prepared from snow crab shells), sulfated polysaccharide-peptide-polysaccharide complex (sp-pg), astrocorticoids, and matrix metabolism modifiers (including proline analogs such as 1-azacyclobutane-2-carboxylic acid (LACA), cis-hydroxyproline, d,I-3,4-dehydroproline, thio- Proline), α,α'-bipyridine, β-aminopropionitrile fumarate, 4-propyl-5-(4-pyridyl)-2(3h)-oxazolone, methotrexate, mitoxantrone, heparin, interferon, 2-macroglobulin-serum, chicken metalloproteinase-3 inhibitor (ChIMP-3), chymotrypsin inhibitor, β-cyclodextrin tetratetrasulfate, epomycin, fumaricin, sodium gold thiomalate, dextropenicillamine, β-1-anticollagenase-serum, α-2-antifibrinolytic enzyme, bifenthrin, chlorbenzalidine disodium, n-2-carboxyphenyl-4-chloroanthrone acid disodium or "CCA", thalidomide, angiotensin-releasing steroids, carboxyaminoimidazole, metalloproteinase inhibitors (such as BB-94), S100A9 inhibitors (such as taquimod). Other anti-angiogenic agents include antibodies, such as monoclonal antibodies against these angiogenic growth factors: β-FGF, α-FGF, FGF-5, VEGF isotype, VEGF-C, HGF/SF, and Ang-1/Ang-2.

Anti-fibrotic agent

In some embodiments, the compounds described herein are combined with antifibrotic agents. Antifibrotic agents that can be co-administered include, but are not limited to, compounds such as β-aminopropionitrile (BAPN), and compounds disclosed in US 4965288 relating to lysyl oxidase inhibitors and their use in treating diseases and conditions associated with abnormal collagen deposition, and in US 4997854 relating to compounds that inhibit LOX to treat various pathological fibrotic states, which are incorporated herein by reference. Further exemplary inhibitors are described in US 4943593 relating to compounds such as 2-isobutyl-3-fluoro-, chloro-, or bromo-allylamine, and in US 5021456, US 5059714, US5120764, US 5182297, US 5252608, and US 2004-0248871 relating to 2-(1-naphthoxymethyl)-3-fluoroallylamine, which are incorporated herein by reference.

Exemplary antifibrotic agents also include primary amines that react with the carbonyl group at the active site of lysyl oxidase, and more specifically, those that, upon binding with the carbonyl group, produce a product stabilized by resonance, such as the following primary amines: ethylenediamine, hydrazine, phenylhydrazine and their derivatives; aminourea and urea derivatives; aminonitriles, such as BAPN or 2-nitroethylamine; unsaturated or saturated haloamines, such as 2-bromoethylamine, 2-chloroethylamine, 2-trifluoroethylamine, 3-bromopropylamine and p-halobenzylamine; and selenocysteine lactone.

Other antifibrotic agents are copper chelators, whether they penetrate cells or not. Exemplary compounds include indirect inhibitors that block aldehyde derivatives derived from the oxidative deamination of lysyl and hydroxylysyl residues by lysyl oxidase. Examples include thiol amines (particularly D-penicillamine) and analogues such as 2-amino-5-mercapto-5-methylhexanoic acid, D-2-amino-3-methyl-3-((2-acetaminoethyl)dithio)butyric acid, p-2-amino-3-methyl-3-((2-aminoethyl)dithio)butyric acid, sodium 4-((p-1-dimethyl-2-amino-2-carboxyethyl)dithio)butane sulfate, 2-acetaminoethyl-2-acetaminoethylthiol sulfate, and sodium 4-mercaptobutanesulfinate trihydrate.

anti-inflammatory agents

In some embodiments, the compounds described herein are combined with anti-inflammatory agents. Examples of anti-inflammatory agents include, but are not limited to, inhibitors of one or more of the following: argininase (ARG1 (NCBI gene ID: 383), ARG2 (NCBI gene ID: 384)), carbonic anhydrase (CA1 (NCBI gene ID: 759), CA2 (NCBI gene ID: 760), CA3 (NCBI gene ID: 761), CA4 (NCBI gene ID: 762), CA5A (NCBI gene ID: 763), CA5B (NCBI gene ID: 11238), CA6 (NCBI gene ID: 765), CA7 (NCBI gene ID: 766), CA8 (NCBI gene ID: 767), CA9 (NCBI gene ID: 768), CA10 (NCBI gene ID: 56934), CA11 (NCBI gene ID: 770), CA... 12 (NCBI gene ID: 771), CA13 (NCBI gene ID: 377677), CA14 (NCBI gene ID: 23632)), prostaglandin-endoperoxidase 1 (PTGS1, COX-1; NCBI gene ID: 5742), prostaglandin-endoperoxidase 2 (PTGS2, COX-2; NCBI gene ID: 5743), secretory phospholipase A2, prostaglandin E synthase (PTGES, PGES; gene ID: 9536), arachidonic acid 5-lipoxygenase (ALOX5, 5-LOX; NCBI gene ID: 240), soluble epoxide hydrolase 2 (EPHX2, SEH; NCBI gene ID: 2053) and/or mitogen-activated protein kinase kinase 8 (MAP3K8, TPL2; NCBI gene ID: 1326). In some implementations, the inhibitor is a dual inhibitor, such as a dual inhibitor of COX-2/COX-1, COX-2/SEH, COX-2/CA, or COX-2/5-LOX.

Examples of prostaglandin-endoperoxidase 1 (PTGS1, COX-1; NCBI gene ID: 5742) inhibitors that can be co-administered include, but are not limited to, monoxazol, GLY-230, and TRK-700.

Examples of prostaglandin-endoperoxidase 2 (PTGS2, COX-2; NCBI gene ID: 5743) inhibitors that can be co-administered include, but are not limited to: diclofenac, meloxicam, parecoxib, etoricoxib, AP-101, celecoxib, AXS-06, diclofenac potassium, DRGT-46, AAT-076, mesosulide, romecoxib, meloxicam, vardicoxib, zaltoprofen, nimesulide, anizafen, alicoxib, cimecoxib, delacoxib, flumicazole, ferocoxib, malvacoxib, NS-398, pamigre, parecoxib, robecoxib, rofecoxib, evodiamine, temoxib, and zaltoprofen. Examples of dual COX1/COX2 inhibitors that can be co-administered include, but are not limited to, HP-5000, lornoxicam, ketorolac tromethamine, bromfenac sodium, ATB-346, and HP-5000. Examples of dual COX-2/carbonic anhydrase (CA) inhibitors that can be co-administered include, but are not limited to, pomacitabine and ericoxib.

Examples of co-administered inhibitors of secretory phospholipase A2 and prostaglandin E synthase (PTGES, PGES; gene ID: 9536) include, but are not limited to, LY3023703, GRC27864, and WO2015158204, WO2013024898, WO2006063466, WO2007059610, WO2007124589, WO2010100249, WO2010034796, WO2010034797, WO2012022793, WO2012076673, WO2012076672, WO2010034798, WO2010034799, WO2012022792, WO2009103778, and WO2011048. 004, WO2012087771, WO2012161965, WO2013118071, WO2013072825, WO2014167444, WO 2009138376, WO2011023812, WO2012110860, WO2013153535, WO2009130242, WO200914 Compounds described in WO2013186692, WO2015059618, WO2016069376, WO2016069374, WO2009117985, WO2009064250, WO2009064251, WO2009082347, WO2009117987 and WO2008071173. Metformin was also found to inhibit the COX2/PGE2/STAT3 axis and could be co-administered. See, for example, Tong et al., Cancer Lett. (2017) 389:23-32; and Liu et al., Oncotarget. (2016) 7(19):28235-46.

Examples of carbonic anhydrase inhibitors that can be co-administered (e.g., one or more of CA1 (NCBI gene ID: 759), CA2 (NCBI gene ID: 760), CA3 (NCBI gene ID: 761), CA4 (NCBI gene ID: 762), CA5A (NCBI gene ID: 763), CA5B (NCBI gene ID: 11238), CA6 (NCBI gene ID: 765), CA7 (NCBI gene ID: 766), CA8 (NCBI gene ID: 767), CA9 (NCBI gene ID: 768), CA10 (NCBI gene ID: 56934), CA11 (NCBI gene ID: 770), CA12 (NCBI gene ID: 771), CA13 (NCBI gene ID: 377677), CA14 (NCBI gene ID: 23632)) include, but are not limited to, acetazolamide, metronidazole, dazolamide, zonisamide, brinzolamide, and dichlorobenzylsulfonamide. Dual COX-2/CA1/CA2 inhibitors that can be used in combination include CG100649.

Examples of arachidonic acid 5-lipoxygenase (ALOX5, 5-LOX; NCBI gene ID: 240) inhibitors that can be co-administered include, but are not limited to, meclofenamic acid sodium and zileuton.

Examples of co-administerable inhibitors of soluble epoxide hydrolase 2 (EPHX2, SEH; NCBI gene ID: 2053) include, but are not limited to, the compounds described in WO2015148954. Co-administerable dual inhibitors of COX-2/SEH include the compounds described in WO2012082647. Co-administerable dual inhibitors of SEH and fatty acid amide hydrolase (FAAH; NCBI gene ID: 2166) include the compounds described in WO2017160861.

Examples of co-administerable inhibitors of mitogen-activated protein kinase kinase 8 (MAP3K8, tumor progression locus-2, TPL2; NCBI gene ID: 1326) include, but are not limited to, GS-4875, GS-5290, BHM-078, and those described in the following literature: WO2006124944, WO2006124692, WO2014064215, WO2018005435; Teli et al., J Enzyme Inhib Med Chem. (2012) 27(4):558-70; Gangwall et al., Curr Top MedChem. (2013) 13(9):1015-35; Wu et al., Bioorg Med Chem Lett. (2009) 19(13):3485-8; Kaila et al., Bioorg Med Chem. (2007) 15(19):6425-42; and Hu et al., Bioorg Med Chem Lett. (2011) 21(16):4758-61.

Tumor oxygenation

In some embodiments, the compounds described herein are combined with agents that promote or increase tumor oxygenation or reoxygenation, or prevent or reduce tumor hypoxia. Exemplary agents that can be co-administered include, for example, hypoxia-inducible factor 1α (HIF-1α) inhibitors, such as PT-2977 and PT-2385; VEGF inhibitors, such as bevacizumab, IMC-3C5, GNR-011, tenibiruzumab, LYN-00101, and ABT-165; and/or oxygen carrier proteins (e.g., heme nitric oxide and/or oxygen-binding protein (HNOX)), such as OMX-302 and HNOX proteins as described in WO 2007/137767, WO 2007/139791, WO 2014/107171, and WO 2016/149562.

Immunotherapy agents

In some embodiments, the compounds described herein are combined with immunotherapeutic agents. Exemplary immunotherapeutic agents that can be co-administered include, but are not limited to, abagovomab, ABP-980, adecatumumab, afutuzumab, alemtuzumab, altumomab, amatuximab, anatumomab, arcitumomab, bavituximab, bectumomab, bevacizumab, bivatuzumab, and blinatumomab. ab), Brentuximab, Cantuzumab, Catumaxomab, CC49, Cetuximab, Citatuzumab, Cixutumab, Clivatuzumab, Conatumumab, Dacetuzumab, Dalotuzumab, Daratumumab, Detumomab, Dinutuximab, Drozitu mab), duligotuzumab, dusigitumab, ecromeximab, elotuzumab, emibetuzumab, ensituximab, ertumaxomab, etaracizumab, farletuzumab, ficlatuzumab, figitumumab, flanvotumab, futuximab, ganituzumab nitumab), gemtuzumab, girentuximab, glembatumumab, ibritumomab, igovomab, imgatuzumab, indatuximab, inotuzumab, intetumumab, ipilimumab (MDX-010, BMS-734016 and MDX-101), iratumumab, labetuzumab, lexamumab ( Lexatumumab, Lintuzumab, Lorvotuzumab, Lucarumumab, Mapatumumab, Matuzumab, Milatuzumab, Minretumomab, Mitumomab, Mogamulizumab, Moxetumomab, Naptumomab, Narnatuzumab, Necitumumab, Nimotuzumab (nimotuzumab), nofetumomab, OBI-833, obinutuzumab, ocaratuzumab, ofatumumab, olaratumab, onartuzumab, oportuzumab, oregovomab, panitumumab, parsatuzumab, pasudotox, patritumab, pemtumomab Pertuzumab, Pintumomab, Pritumumab, Racotumomab, Radretumab, Ramucirumab, Rilotumumab, Rituximab, Robatumumab, Samalizumab, Satumomab, Siboruzumab, Siltuximab, Solitomab, Simituzumab Rituximab, including tartuzumab, tacatuzumab, taplitumomab, tenatumomab, teprotumumab, tigatuzumab, tositumomab, trastuzumab, tucotuzumab, ubilituximab, veltuzumab, vorsetuzumab, votumumab, zalutumumab, and 3F8, is used to treat indolent B-cell cancers, including marginal zone lymphoma, WM, CLL, and small lymphocytic lymphoma. The combination of rituximab and chemotherapy is particularly effective.

The illustrated therapeutic antibodies can be further labeled or combined with radioactive isotope particles such as indium-111, yttrium-90 (90Y-crituzumab), or iodine-131.

In some implementations, the immunotherapeutic agent is an antibody-drug conjugate (ADC). Exemplary ADCs that can be co-administered include, but are not limited to, drug-conjugated antibodies, fragments thereof, or antibody mimics targeting the proteins or antigens listed above and herein. Examples of ADCs that can be used together include, but are not limited to, gemutuzumab, tonutuzumab, trastuzumab, osintutuzumab, glembarumab, arnetuzumab, mivirutuzumab, ditoxizumab, rovapitumab, varadutuzumab, labetuzumab, cetoxizumab, lifatoxizumab, indulutuzumab, polotoxizumab, pinatuzumab, cotoxizumab, indulutuzumab, miratuzumab, rovapitumab, ABBV-399, AGS-16C3F, ASG-22ME, AGS67E, AMG172, AMG575, BAY1129980, BAY1187982, and BAY9. 4-9343, GSK2857916, Humax-TF-ADC, IMGN289, IMGN529, IMGN853, LOP628, PCA062, MDX-1203 (BMS936561), MEDI-547, PF-06263507, PF -06647020, PF-06647263, PF-06664178, RG7450, RG7458, RG7598, SAR566658, SGN-CD19A, SGN-CD33A, SGN-CD70A, SGN-LIV1A and SYD985. ADCs that can be co-administered are described, for example, in Lambert et al., Adv Ther (2017) 34:1015–1035 and de Goeij, Current Opinion in Immunology (2016) 40:14–23.

Exemplary therapeutic agents (e.g., anticancer or antitumor agents) that can be conjugated to drugs, their fragments, or antibody mimics include, but are not limited to, methylreoxetine E (MMAE), methylreoxetine F (MMAF), chachiin, anserine, maytansine, or analogues thereof (e.g., mertansine/emtansine (DM1), ravtansine/soravtansine (D)). M4), anthracyclines (e.g., doxorubicin, daunorubicin, epirubicin, idarubicin), pyrrolobenzodiazepine (PBD) DNA cross-linking agent SC-DR002 (D6.5), pyroximin, microtubule inhibitors (MTI) (e.g., taxane, vinca alkaloids, epothilone), pyrrolobenzodiazepine (PBD) or its dimer, pyroximin (A, B1, B2, C1, C2, D, SA, CC-1065), and other anticancer or antitumor agents described herein.

Cancer gene therapy and cell therapy

In some implementations, compounds as described herein are combined with cancer gene therapy and cell therapy. Cancer gene therapy and cell therapy include inserting normal genes into cancer cells to replace mutated or altered genes; genetic modification to silence mutated genes; genetic methods to directly kill cancer cells; including the infusion of immune cells designed to replace most of the patient's own immune system to enhance the immune response against cancer cells, or to activate the patient's own immune system (T cells or natural killer cells) to kill cancer cells, or to locate and kill cancer cells; and genetic methods to alter cell activity to further modify the endogenous immune response against cancer.

Cell therapy

In some embodiments, compounds as described herein are combined with one or more cell therapies. Illustrative cell therapies include, but are not limited to, co-administration of one or more immune cell populations. In some embodiments, immune cells are natural killer (NK) cells, NK-T cells, T cells, γδT cells, B cells, cytokine-induced killer (CIK) cells, macrophages (MAC), tumor-infiltrating lymphocytes (TILs), granulocytes, innate lymphoid cells, megakaryocytes, monocytes, macrophages, platelets, thymocytes, bone marrow cells, and/or dendritic cells (DCs). In some embodiments, the cell therapy requires T cell therapy, such as co-administration of populations of α/βTCR T cells, γ/δTCR T cells, regulatory T (Treg) cells, and/or TruC ^™ T cells. In some embodiments, the cell therapy requires NK cell therapy, such as co-administration of NK-92 cells. Depending on the circumstances, the cell therapy may require co-administration of cells that are autologous, syngeneic, or allogeneic to the subject.

In some embodiments, cell therapy requires co-administration of immune cells engineered to express a chimeric antigen receptor (CAR) or a T-cell receptor (TCR) TCR. In a particular embodiment, the immune cell population is engineered to express a CAR, wherein the CAR contains a tumor antigen-binding domain. In other embodiments, the immune cell population is engineered to express a T-cell receptor (TCR) engineered to target tumor-derived peptides presented on the surface of tumor cells. In one embodiment, the immune cells engineered to express a chimeric antigen receptor (CAR) or a T-cell receptor (TCR) TCR are T cells. In another embodiment, the immune cells engineered to express a chimeric antigen receptor (CAR) or a T-cell receptor (TCR) TCR are NK cells.

Regarding the structure of the CAR, in some embodiments, the CAR comprises an antigen-binding domain, a transmembrane domain, and an intracellular signaling domain. In some embodiments, the intracellular domain comprises a primary signaling domain, a co-stimulatory domain, or both a primary signaling domain and a co-stimulatory domain. In some embodiments, the primary signaling domain comprises a functional signaling domain of one or more proteins selected from the group consisting of: CD3ζ, CD3γ, CD3δ, CD3ε, common FcRγ (FCERIG), FcRβ (FcεRlb), CD79a, CD79b, FcγRIIa, DAP10 and DAP12 4-1BB/CD137, activated NK cell receptor, immunoglobulin, B7-H3, BAFFR, BLAME (SLAMF8), BTLA, CD100 (SEMA4D), CD103, CD160 (BY55), CD18, CD19, CD19a, CD2, C D247, CD27, CD276 (B7-H3), CD28, CD29, CD3δ, CD3ε, CD3γ, CD30, CD4, CD40, CD49a, CD49D, CD49f, CD69, CD7, CD84, CD8α, CD8β, CD96 (Tactile), CD11a, CD11b, CD11c, CD11d, CDS, CEACAM1, CRTAM, cytokine receptor, DAP-10, DNAM1 (CD226), Fcγ receptor, GADS, GITR, HVEM (LIGHTR), IA4, ICAM-1, ICAM-1, Igα ( CD79a), IL-2Rβ, IL-2Rγ, IL-7Rα, inducible T cell co-stimulatory factor (ICOS), integrin, ITGA4, ITGA4, ITGA6, ITGAD, ITGAE, ITGAL, ITGAM, ITGAX, ITGB2, ITGB7, ITGB1, KIRDS2, LAT, LFA-1, LFA-1, ligands binding to CD83, LIGHT, LIGHT, LTBR, Ly9 (CD229), Ly108, lymphocyte function-associated antigen-1 (LFA-1; CD1-1a/CD18), MHC class 1 molecules, NKG2C, NKG2D. NKp30, NKp44, NKp46, NKp80 (KLRF1), OX-40, PAG/Cbp, programmed cell death-1 (PD-1), PSGL1, SELPLG (CD162), signaling lymphocyte activation molecules (SLAM protein), SLAM (SLAMF1; CD150; IPO-3), SLAMF4 (CD244; 2B4), SLAMF6 (NTB-A, SLAMF7, SLP-76, TNF receptor protein, TNFR2, TNFSF14, Toll ligand receptor, TRANCE/RANKL, VLA1 or VLA-6, or fragments, truncated forms or combinations thereof.

In some implementations, the co-stimulatory domain comprises a functional domain of one or more proteins selected from the group consisting of: CD27, CD28, 4-1BB (CD137), OX40, CD30, CD40, PD-1, ICOS, CD2, CD7, LIGHT, NKG2C, lymphocyte function-associated antigen-1 (LFA-1), MYD88, B7-H3, a ligand that specifically binds to CD83, CDS, ICAM-1, GITR, BAFFR, HVE. M(LIGHTR), SLAMF7, NKp80(KLRFI), CD160, CD19, CD4, CD8α, CD8β, IL2Rβ, IL2Rγ, IL7Rα, ITGA4, VLA1, CD49a, I TGA4, IA4, CD49D, ITGA6, VLA-6, CD49f, ITGAD, ITGAE, CD103, ITGAL, CD1A (NCBI gene ID: 909), CD1B (NCBI gene ID: 9 10) CD1C (NCBI gene ID: 911), CD1D (NCBI gene ID: 912), CD1E (NCBI gene ID: 913), ITGAM, ITGAX, ITGB1, CD29, ITGB2 (CD18, LFA-1), ITGB7, TNFR2, TRANCE/RANKL, DNAM1 (CD226), SLAMF4 (CD244, 2B4), CD84, CD96 (Tactile), CEACA M1, CRTAM, Ly9 (CD229), CD160 (BY55), PSGL1, CD100 (SEMA4D), CD69, SLAMF6 (NTB-A, Ly108), SLAM (SLAMF1, CD 150, IPO-3), BLAME (SLAMF8), SELPLG (CD162), LTBR, LAT, GADS, SLP-76, PAG/Cbp, NKp44, NKp30, NKp46 and NKG2D.

In some implementations, the transmembrane domain comprises a transmembrane domain derived from a protein selected from the group consisting of: the α, β, or ζ chain of the T-cell receptor, CD28, CD3ε, CD3δ, CD3γ, CD45, CD4, CD5, CD7, CD8α, CD8β, CD9, CD11a, CD11b, CD11c, CD11d, CD16, CD18, CD22, CD33, CD37, CD64, CD80, CD86, CD134, CD137, CD154, KIRDS2, OX40, CD2, CD27, ICOS (CD278) ), 4-1BB(CD137), GITR, CD40, BAFFR, HVEM(LIGHTR), SLAMF7, NKp80(KLRF1), CD19, CD19a, IL2Rβ, IL2Rγ, IL7Rα, ITGA1, VLA1, CD49a ,ITGA4,IA4,CD49D,ITGA6,VLA-6,CD49f,ITGAD,CD1A,CD1B,CD1C,CD1D,CD1E,ITGAE,CD103,ITGAL,ITGAM,ITGAX,ITGB1,ITGB2,IT GB7, CD29, ITGB2 (LFA-1, CD18), ITGB7, TNFR2, DNAM1 (CD226), SLAMF4 (CD244, 2B4), CD84, CD96 (TACTILE), CEACAM1, CRTAM, Ly9 (CD 229), CD160(BY55), PSGL1, CD100(SEMA4D), SLAMF6(NTB-A, Ly108), SLAM(SLAMF1, CD150, IPO-3), BLAME(SLAMF8), SELPLG(CD162), LTBR, PAG/Cbp, NKp44, NKp30, NKp46, NKG2D and NKG2C activate NK cell receptors, immunoglobulins, BTLA, CD247, CD276 (B7-H3), CD30, CD84, CDS, cytokine receptors, Fcγ receptors, GADS, ICAM-1, Igα (CD79a), integrin, LAT, ligands that bind to CD83, LIGHT, MHC class 1 molecules, PAG/Cbp, TNFSF14, Toll ligand receptor, TRANCE/RANKL, or fragments, truncated forms or combinations thereof.

In some implementations, the CAR includes a hinge domain. The hinge domain may be derived from proteins selected from the group consisting of: CD2, CD3δ, CD3ε, CD3γ, CD4, CD7, CD8α, CD8β, CD11a (ITGAL), CD11b (ITGAM), CD11c (ITGAX), CD11d (ITGAD), CD18 (ITGB2), CD19 (B4), CD27 (TNFRSF7), CD28, CD28T, CD29 (ITGB1), CD30 (TNFRSF8), CD40 (TNFRSF5), CD48 (SLAMF2), CD49a (ITGA1), CD49d (ITGA4), CD49f (ITGA6), CD66a (CEACAM1), CD66b (CEACAM8), CD66c (… CEACAM6), CD66d (CEACAM3), CD66e (CEACAM5), CD69 (CLEC2), CD79A (B cell antigen receptor complex-associated α chain), CD79B (B cell antigen receptor complex-associated β chain), CD84 (SLAMF5), CD96 (Tactile), CD100 (SEMA4D), CD103 (ITGAE), CD134 (OX40), CD137 (4-1BB), CD150 (SLAMF1), CD158A (KIR2DL1), CD158B1 (KIR2DL2), CD158B2 (KIR2DL3), CD158C (KIR3DP1), CD158D (KIRDL4), CD158F1 (KIR2DL5A), CD 158F2(KIR2DL5B), CD158K(KIR3DL2), CD160(BY55), CD162(SELPLG), CD226(DNAM1), CD229(SLAMF3), CD244(SLAMF4), CD247(CD3-zeta), CD258(LIGHT), CD268(BAFFR), CD2 70(TNFSF14), CD272(BTLA), CD276(B7-H3), CD279(PD-1), CD314(NKG2D), CD319(SLAM F7), CD335(NK-p46), CD336(NK-p44), CD337(NK-p30), CD352(SLAMF6), CD353(SLAMF8) CD355 (CRTAM), CD357 (TNFRSF18), inducible T cell co-stimulatory factor (ICOS), LFA-1 (CD11a/CD18), NKG2C, DAP-10, ICAM-1, NKp80 (KLRF1), IL-2Rβ, IL-2Rγ, IL-7Rα, LFA-1, SLAMF9, LAT, GADS (GrpL), SLP-76 (LCP2), PAG1/CBP, CD83 ligand, Fcγ receptor, MHC class 1 molecules, MHC class 2 molecules, TNF receptor protein, immunoglobulin, cytokine receptor, integrin, activating NK cell receptor or Toll ligand receptor, IgG1, IgG2, IgG3, IgG4, IgA, IgD, IgE, IgM, or fragments or combinations thereof.

In some embodiments, one or more adjunctive therapeutic agents include immunotherapy, immunostimulatory therapy, cytokine therapy, chemokine therapy, cell therapy, gene therapy, and combinations thereof. In some embodiments, immunotherapy includes co-administration of one or more antibodies or their antigen-binding antibody fragments or their antibody-drug conjugates, multispecific molecules targeting CD3, multispecific molecules targeting CD16, or non-immunoglobulin antigen-binding domains, or antibody mimics targeting one or more targets or tumor-associated antigens (TAAs).

In some embodiments, the TCR or CAR antigen-binding domain or the immunotherapeutic agent described herein (e.g., a monospecific or multispecific antibody or its antigen-binding fragment or antibody mimic) binds to a tumor-associated antigen (TAA). In some embodiments, the tumor-associated antigen is selected from the group consisting of: CD19; CD123; CD22; CD30; CD171; CS-1 (also known as CD2 subset 1, CRACC, SLAMF7, CD319, and 19A24); C-type lectin-like molecule-1 (CLL-1 or CLECLI); CD33; epidermal growth factor receptor variant III (EGFRv111); ganglioside G2 (GD2); ganglion Glycoside GD3 (αNeuSAc(2-8)αNeuSAc(2-3)βDGaip(1-4)bDGIcp(1-1)Cer); ganglioside GM3 (αNeuSAc(2-3)βDGalp(1-4)βDGlcp(1-1)Cer); GM-CSF receptor; TNF receptor superfamily member 17 (TNFRSF17, BCMA); B-lymphocyte cell adhesion molecule; Tn antigen ((Tn A) g) or (GaINAcu-Ser/Thr)); prostate-specific membrane antigen (PSMA); receptor tyrosine kinase-like orphan receptor 1 (RORI); tumor-associated glycoprotein 72 (TAG72); CD38; CD44v6; carcinoembryonic antigen (CEA); epithelial cell adhesion molecule (EPCAM); B7H3 (CD276); KIT (CD117); interleukin-13 receptor subunit α-2 (IL-13Ra2 or CD213A2); mesothelin; interleukin-11 receptor α (IL-11Ra); prostate stem cell antigen (PSCA); protease serine 21 (Testisin or PRSS21); vascular endothelial growth factor receptor 2 (VEGFR2); HLA class I antigen A-2α; HLA antigen; Lewis (Y) antigen; CD24; platelet-derived growth factor receptor β (PDGFR-β); stage-specific embryonic antigen-4 (SSEA-4); CD2 0; δ-like 3 (DLL3); folate receptor α; folate receptor β, GDNFα4 receptor, receptor tyrosine protein kinase, ERBB2 (Her2/neu); cell surface-associated mucin 1 (MUC1); APRIL receptor; ADP ribosyl cyclase-1; Ephb4 tyrosine kinase receptor, DCAMKL1 serine-threonine kinase, aspartate β-hydroxylase, epidermal growth factor receptor (EGFR); neural cell adhesion molecule (NCAM); prostate enzyme; prostatic acid phosphatase (PAP); mutant elongation factor 2 (ELF2M); liver ligand B2; fibroblast activation protein α (FAP); insulin-like growth factor 1 receptor (IGF-I receptor), carbonic anhydrase IX (CAIX); proteasome (Macropain) subunit β-type 9 (LMP2); glycoprotein 100 (gp100); composed of split cluster region (BCR) and Abelson murine leukemia virus carcinoma Oncogene fusion protein composed of gene homolog 1 (Abl)(bcr-abl); tyrosinase; liver glycoside A receptor 2 (EphA2); liver glycoside A receptor 3 (EphA3); fucose GM1; sialylated Lewis adhesion molecule (sLe); transglutaminase 5 (TGS5); high molecular weight melanoma-associated antigen (HMWMAA); o-acetyl-GD2 ganglioside (OAcGD2); folate receptor β; tumor endothelial markers TEM1/CD248; Tumor endothelial marker 7 associated (TEM7R); Prostatic six-transmembrane epithelial antigen I (STEAP1); Blocking protein 6 (CLDN6); Thyroid-stimulating hormone receptor (TSHR); G protein-coupled receptor class C5 member D (GPRCSD); IL-15 receptor (IL-15); Chromosome X open reading frame 61 (CXORF61); CD97; CD179a; Anaplastic lymphoma kinase (ALK); Polysialic acid; Placental-specific 1 (PLAC1); GloboH glycoceramide hexasaccharide moiety (GloboH); Breast differentiation antigen (NY-BR-1); Uroplakin 2 (UPK2); Hepatitis A virus cell receptor 1 (HAVCR1); Adrenal receptor β3 (ADRB3); Pantothecin 3 (PANX3); G protein-coupled receptor 20 (GPR20); Lymphocyte antigen 6 complex, gene K9 (LY6K); olfactory receptor 51E2 (ORS IE2); TCRγ alternating reading frame protein (TARP); Wilms tumor protein (WT1); cancer/testis antigen 1 (NY-ESO-1); cancer/testis antigen 2 (LAGE-1a); melanoma-associated antigen 1 (MAGE-A1); melanoma-associated antigen 3 (MAGE-A3); melanoma-associated antigen 4 (MAGE-A4); T cell receptor β2 chain C; located in the chromosomal region ETS translocation variant gene 6 on chromosome 12p (ETV6-AML); spermin 17 (SPA17); X antigen family member 1A (XAGE1); angiopoietin-binding cell surface receptor 2 (Tie 2); melanoma cancer testis antigen-1 (MADCT-1); melanoma cancer testis antigen-2 (MAD-CT-2); Fos-associated antigen 1; tumor protein p53 (p53); p53 mutant; prostein; survivin; Telomerase; prostate cancer tumor antigen-1 (PCTA-1 or galactagogue 8), melanoma antigen recognized by T cell 1 (MelanA or MARTI); rat sarcoma (Ras) mutant; human telomerase reverse transcriptase (hTERT); sarcoma translocation breakpoint; melanoma cell apoptosis inhibitor (ML-IAP); ERG (transmembrane protease, serine 2 (TMPRSS2) ETS fusion gene); N-acetylglucosamine transferase V (NA17); cassette Protein Pax-3 (PAX3); androgen receptor; cyclin A1; cyclin B1; v-myc avian myeloma virus oncogene neuroblastoma-derived homolog (MYCN); Ras homolog family member C (RhoC); tyrosinase-associated protein 2 (TRP-2); cytochrome P450 1B1 (CYP IBI); CCCTC binding factor (zinc finger protein)-like (BORIS or imprinted site regulator sibling factor), and others. T-cell recognized squamous cell carcinoma antigen 3 (SART3); pairing box protein Pax-5 (PAX5); proapocrine-binding protein sp32 (OY-TES I); lymphocyte-specific protein tyrosine kinase (LCK); A kinase anchoring protein 4 (AKAP-4); peptidoglycan recognition protein, synovial sarcoma, X-breakpoint 2 (SSX2); receptor for advanced glycation end products (RAGE-I); renal integrin 1 (RUI); renal integrin 2 (RU2); Bean pod protein; Human papillomavirus E6 (HPV E6); Human papillomavirus E7 (HPV E7); Intestinal carboxylesterase; Mutant heat shock protein 70-2 (muthsp70-2); CD79a; CD79b; CD72; Leukocyte-associated immunoglobulin-like receptor 1 (LAIRI); Fc fragment of IgA receptor (FCAR or CD89); Leukocyte immunoglobulin-like receptor subfamily A member 2 (LILRA2); CD300 The targets include: molecular-like family member f (CD300LF); C-type lectin domain family 12 member A (CLEC12A); bone marrow stromal cell antigen 2 (BST2); EGF-like module 2 containing mucin-like hormone receptor-like receptors (EMR2); lymphocyte antigen 75 (LY75); phosphatidylinositol glycan-2 (GPC2); phosphatidylinositol glycan-3 (GPC3); Fc receptor-like 5 (FCRL5); and immunoglobulin λ-like polypeptide 1 (IGLL1). In some embodiments, the target is an epitope of a tumor-associated antigen presented in the MHC.

In some implementations, the tumor antigen is selected from CD150, 5T4, ActRIIA, B7, TNF receptor superfamily member 17 (TNFRSF17, BCMA), CA-125, CCNA1, CD123, CD126, CD138, CD14, CD148, CD15, CD19, CD20, CD200, CD21, CD22, CD23, CD24, CD25, CD26, CD261, CD262, CD30, CD33, CD362, CD37, CD38, CD4, CD40, CD40L, CD44, CD46, CD5, CD52, CD53, CD54, CD56, CD66a-d, CD74, CD56 ... 8. CD80, CD92, CE7, CS-1, CSPG4, ED-B fibroin, EGFR, EGFRvIII, EGP-2, EGP-4, EPHa2, ErbB2, ErbB3, ErbB4, FBP, HER1-HER2 combination, HER2-HER3 combination, HERV-K, HIV-1 envelope glycoprotein gp120, HIV-1 envelope glycoprotein gp41, HLA-DR, HLA class I antigen αG, HM1.24, K-Ras GTPase, HMW-MAA, Her2, Her2/neu, IGF-1R, IL-11Rα, IL-13R-α2, IL-2, IL-22R-α, IL-6, IL-6R Ia, Ii, L1-CAM, L1 cell adhesion molecule, Lewis Y, Ll-CAM, MAGE A3, MAGE-A1, MART-1, MUC1, NKG2C ligand, NKG2D ligand, NYESO-1, OEPHa2, PIGF, PSCA, PSMA, ROR1, T101, TAC, TAG72, TIM-3, TRAIL-R1, TRAIL-R1(DR4), TRAIL-R2(DR5), VEGF, VEGFR2, WT-I, G protein-coupled receptor, alpha-fetoprotein (AFP), angiogenesis factor, exogenous homologous binding molecule (ExoCBM), oncogene products, antifolate receptor, c-Met, carcinoembryonic antigen (CEA) Cyclin (D1), liver ligand B2, epithelial tumor antigen, estrogen receptor, fetal acetylcholine e receptor, folate-binding protein, gp100, hepatitis B surface antigen, Epstein-Barr nuclear antigen 1, latent membrane protein 1, secretory protein BARF1, P2X7 purine receptor, Syndecan-1, κ chain, κ light chain, kdr, λ chain, activin, melanoma-associated antigen, mesothelin, mouse bimin 2 homolog (MDM2), mucin 16 (MUC16), mutant p53, mutant ras, necrosis antigen, carcinoembryonic antigen, ROR2, progesterone receptor, prostate-specific antigen, tEGFR, tendinin, P2-microgiobuin, Fc receptor-like 5 (FcRL5).

Examples of cell therapies include, but are not limited to: AMG-119, Algenpantucel-L, Sipuleucel-T, (BPX-501)rivogenlecleucel US9089520, WO2016100236, AU-105, ACTR-087, activated allogeneic natural killer cells CNDO-109-AANK, MG-4101, AU-101, BPX-601, FATE-NK100, LFU-835 hematopoietic stem cells, Imilecleucel-T, baltaleucel-T, PNK-007, UCARTCS1, ET-1504, ET-1501, ET-1502, ET-190, CD19-ARTEMIS, ProHema, bone marrow stem cell therapy treated with FT-1050, CD4CARNK-92 cells, SNK-01, NEXI-001, CryoSt im, AlloStim, lentivirally transduced huCART racemic cells, CART-22 cells, EGFRt/19-28z/4-1BBL CAR T cells, autologous 4H11-28z/fIL-12/EFGRt T cells, CCR5-SBC-728-HSPC, CAR4-1BBZ, CH-296, dnTGFbRII-NY-ESOc259T, Ad-RTS-IL-12, IMA-1 01, IMA-201, CARMA-0508, TT-18, CMD-501, CMD-503, CMD-504, CMD-502, CMD-601, CMD-602, CSG-005, LAAP T-cell therapy, PD-1 knockout T-cell therapy (esophageal cancer/NSCLC), anti-MUC1 CAR T-cell therapy (esophageal cancer/NSCLC), anti-MUC1 CAR T-cell therapy + PD-1 knockout T-cell therapy (Esophageal cancer/NSCLC), Anti-KRASG12D mTCR PBL, Anti-CD123 CAR T-cell therapy, Anti-mutated neoantigen TCR T-cell therapy, Dendritic cell vaccine loaded with tumor lysate/MUC1/survivin and PepTivator, Autologous dendritic cell vaccine (metastatic melanoma, intradermal/intravenous), Anti-LeY-scFv-CD28-ζCAR T cells, PRGN-3005, iC9-GD2-CAR-IL-15 T cells, HSC-100, ATL-DC-101, MIDRIX4-LUNG, MIDRIXNEO, FCR-001, PLX stem cell therapy, MDR-101, GeniusVac-Mel4, ilixadencel, Allogeneic mesenchymal stem cell therapy, romyelocel L, CYNK-001, ProTrans, ECT-100, MSCTRAIL, dilanu bicel, FT-516, ASTVAC-2, E-CEL UVEC, CK-0801, depleted allogeneic α/βCD3+ T cells and CD19+ B cells stem cells (hematologic malignancies), TBX-1400, HLCN-061, umbilical cord-derived Hu-PHEC cells (hematologic malignancies/aplastic anemia), AP-011, apceth-201, apceth-301, SENTI-101, stem cell therapy (pancreatic cancer), ICOVIR15-cBiTE, CD33HSC/CD33 CAR-T, PLX-immunization, SUBCUVAX, gene therapy based on CRISPR allogeneic γ-δ T cells (cancer), gene therapy based on ex vivo CRISPR allogeneic healthy donor NK cells (cancer), gene therapy based on ex vivo allogeneic induced pluripotent stem cell-derived NK cells (solid tumors), and anti-CD20 CAR T cell therapy (non-Hodgkin's lymphoma).

Other agents used to target tumors include, but are not limited to :

Alpha fetal proteins, such as ET-1402 and AFP-TCR;

Anthrax toxin receptor 1, such as anti-TEM8 CAR T-cell therapy;

TNF receptor superfamily members 17 (TNFRSF17, BCMA), such as bb-2121 (ide-cel), bb-21217, JCARH125, UCART-BCMA, ET-140, KITE-585, MCM-998, LCAR-B38M, CART-BCMA, SEA-BCMA, BB212, ET-140, P-BCMA-101, AUTO-2 (APRIL-CAR), JNJ-68284528;

Anti-CLL-1 antibodies, such as KITE-796; see, for example, PCT/US2017/025573;

Anti-PD-L1-CAR targeted activation of natural killer cells, such as KD-045;

Anti-PD-L1 t-haNK, such as PD-L1 t-haNK;

Anti-CD45 antibodies, such as 131I-BC8 (lomab-B);

Anti-HER3 antibodies, such as LJM716 and GSK2849330;

Anti-CD52 antibodies, such as alemtuzumab;

APRIL receptor modulators, such as anti-BCMA CAR T-cell therapy and Descartes-011;

ADP-ribosylcyclase-1/APRIL receptor modulators, such as dual anti-BCMA/anti-CD38CAR T-cell therapy; CART-ddBCMA;

B7 homologs 6, such as CAR-NKp30 and CAR-B7H6;

B lymphocyte antigen CD19, such as TBI-1501, CTL-119, CAR-19T cells, liso-cel, JCAR-015 (US7446190), JCAR-014, JCAR-017 (WO2016196388, WO2016033570, WO2015157386), axicabtagene ciloleucel (KTE-C19), KTE-X19, US7741465, US6319494, UCART-19, EBV-CTL, T tisagenlecleucel-T (CTL019). WO2012079000, WO2017049166, T cells expressing CD19CAR-CD28-CD3ζ-EGFRt, CAR T cell therapy with armored CD19/4-1BBL, C-CAR-011, CIK-CAR.CD19, CD19CAR-28-ζ T cells, PCAR-019, MatchCAR, DSCAR-01, IM19 CAR-T, TC-110; Anti-CD19 CAR T cell therapy (B-cell acute lymphoblastic leukemia, Universiti Kebangsaan Malaysia); Anti-CD19 CA R-T cell therapy (acute lymphoblastic leukemia/non-Hodgkin's lymphoma, University Hospital Heidelberg), anti-CD19 CAR T cell therapy (IL-6 expression silencing, cancer, Shanghai Unicar-Therapy Bio-medicine Technology), MB-CART2019.1 (CD19/CD20), GC-197 (CD19/CD7), CLIC-1901, ET-019003, anti-CD19-STAR-T cells, AVA-001, BCMA-CD19 cCAR (CD19/APRIL), ICG-134, ICG-132 (CD19/CD20), CTA-101, WZTL-002, dual anti-CD19/anti-CD20 CAR T cells (chronic lymphocytic leukemia/B-cell lymphoma), HY-001, ET-019002, YTB-323, GC-012 (CD19/APRIL), GC-022 (CD19/CD22), Tn/mem expressing CD19CAR-CD28-CD3ζ-EGFRt; UCAR-011, ICTCAR-014, GC-007F, PTG-01, CC-97540;

Allogeneic anti-CD19 CAR-T cells, such as GC-007G;

Allogeneic T cells expressing CD20 CAR, such as LB-1905;

APRIL receptor modulator; SLAM family member 7 modulator BCMA-CS1 cCAR;

Autologous dendritic cell tumor antigen (ADCTA), such as ADCTA-SSI-G;

B-lymphocyte antigen CD20, such as ACTR707 ATTCK-20 and PBCAR-20A;

B-lymphocyte antigen CD19/B-lymphocyte antigen 22, such as TC-310;

B-lymphocyte antigen 22 cell adhesion, such as UCART-22, JCAR-018WO2016090190;

NY-ESO-1 modifiers, such as GSK-3377794, TBI-1301, and GSK3537142;

Carbonic anhydrases, such as DC-Ad-GMCAIX;

Caspase 9 suicide gene, such as Caspase DLI and BPX-501;

CCR5, such as SB-728;

CCR5 gene inhibitors/TAT gene/TRIM5 gene stimulating factors, such as autologous CD34-positive hematopoietic progenitor cells transduced by lentiviral vector CCR5 shRNA/TRIM5α/TAR decoys;

CDw123, such as MB-102, IM-23, JEZ-567, UCART-123;

CD4, such as ICG-122;

CD5 regulators, such as CD5.28z CAR-T cells;

Anti-CD22, such as anti-CD22 CART;

Anti-CD30, such as TT-11;

CD33, such as CIK-CAR, CD33, CD33CART;

Dual anti-CD33/anti-CLL1, such as LB-1910;

CD38, such as T-007, UCART-38;

CD40 ligands, such as BPX-201 and MEDI5083;

CD56, such as allogeneic CD56-positive and CD3-negative natural killer cells (malignant bone marrow tumors);

CD19/CD7 modulators, such as GC-197;

T-cell antigen CD7 modulators, such as anti-CD7 CAR T-cell therapy (CD7-positive hematologic malignancies);

CD123 modifiers, such as UniCAR02-T-CD123;

Anti-CD276, such as anti-CD276 CART;

CEACAM protein 5 regulators, such as MG7-CART;

Blocking protein 6, such as CSG-002;

Blocking protein 18.2, such as LB-1904;

Chlorine toxins, such as CLTX-CART;

Targeting EBV, such as CMD-003;

MUC16EGFR, such as autologous 4H11-28z/fIL-12/EFGRt T cells;

Endonucleases, such as PGN-514 and PGN-201;

Epstein-Barr virus-specific T lymphocytes, such as TT-10;

Epstein-Barr nuclear antigen 1/latent membrane protein 1/secretory protein BARF1 regulators, such as TT-10X;

Erbb2, such as CST-102, CIDeCAR;

Gangliosides (GD2), such as 4SCAR-GD2;

γδT cells, such as ICS-200;

Folic acid hydrolase 1 (FOLH1, glutamate carboxypeptidase II, PSMA; NCBI gene ID: 2346), such as CIK-CAR.PSMA, CART-PSMA-TGFβRDN, P-PSMA-101;

Phosphatidylinositol proteoglycan-3 (GPC3), such as TT-16 and GLYCAR;

Hemoglobin, such as PGN-236;

Hepatocyte growth factor receptors, such as anti-cMet RNA CAR T;

HLA class I antigen A-2α modulators, such as FH-MCVA2TCR;

HLA class I antigen A-2α/melanoma-associated antigen 4 modulators, such as ADP-A2M4CD8;

HLA antigen modulators, such as FIT-001 and NeoTCR-P1;

Human papillomavirus E7 protein, such as KITE-439. See, for example, PCT/US2015/033129;

ICAM-1 modifiers, such as AIC-100;

Immunoglobulin γFc receptor III, such as ACTR087;

IL-12, such as DC-RTS-IL-12;

IL-12 agonists/mucin 16, such as JCAR-020;

IL-13α2, such as MB-101;

IL-15 receptor agonists, such as PRGN-3006 and ALT-803; interleukin-15/Fc fusion proteins (e.g., XmAb24306); recombinant interleukin-15 (e.g., AM0015 and NIZ-985); pegylated IL-15 (e.g., NKTR-255).

IL-2, such as CST-101;

Interferon-alpha ligands, such as autologous tumor cell vaccines + systemic CpG-B + IFN-α (cancer);

K-Ras GTPases, such as anti-KRAS G12V mTCR cell therapy;

Neural cell adhesion molecules L1 and L1CAM (CD171), such as JCAR-023;

Latent membrane protein 1/latent membrane protein 2, such as autologous dendritic cells transduced with Ad5f35-LMPd1-2;

MART-1 melanoma antigen modulators, such as MART-1F5 TCR-engineered PBMCs;

Melanoma-associated antigen 10, such as MAGE-A10C796T MAGE-A10 TCR;

Melanoma-associated antigen 3/melanoma-associated antigen 6 (MAGE A3/A6), such as KITE-718 (see, for example, PCT/US2013/059608);

Mesothelin, such as CSG-MESO and TC-210;

Mucin 1 modulators, such as ICTCAR-052, Tn MUC-1CAR-T, and ICTCAR-053;

Anti-MICA/MICB, such as CYAD-02;

NKG2D, such as NKR-2;

Ntrkr1 tyrosine kinase receptors, such as JCAR-024;

PRAMET cell receptors, such as BPX-701;

Prostate stem cell antigen modulators, such as MB-105;

Ring island homolog 1 modifiers, such as ATCG-427;

Peptidoglycan recognition protein modulators, such as Tag-7 gene-modified autologous tumor cell vaccines;

PSMA, such as PSMA-CAR T-cell therapy (lentiviral vector, castration-resistant prostate cancer);

SLAM family member 7 modifiers, such as IC9-Luc90-CD828Z;

TGFβ receptor modulators, such as DNR.NPC T cells;

T lymphocytes, such as TT-12;

T-lymphocyte stimulants, such as ATL-001;

TSH receptor modulators, such as ICTCAR-051;

Tumor-infiltrating lymphocytes, such as LN-144 and LN-145; and/or

Wilms tumor proteins, such as JTCR-016 and WT1-CTL.

agonists of FMS-associated receptor tyrosine kinase 3 (FLT3)

In some embodiments, the compounds described herein are combined with agonists of the fms-associated receptor tyrosine kinase 3 (FLT3); FLK2; STK1; CD135; FLK-2; NCBI gene ID: 2322. Examples of FLT3 agonists include CDX-301 and GS-3583.

MCL1 apoptosis regulators and BCL2 family member (MCL1) inhibitors

In some embodiments, compounds as described herein are combined with inhibitors of MCL1 apoptosis regulators (BCL2 family members) (MCL1, TM; EAT; MCL1L; MCL1S; Mcl-1; BCL2L3; MCL1-ES; bcl2-L-3; mcl1/EAT; NCBI gene ID: 4170). Examples of MCL1 inhibitors include AMG-176, AMG-397, S-64315 and AZD-5991, 483-LM, A-1210477, UMI-77, JKY-5-037, and those described in WO2018183418, WO2016033486, WO2019222112 and WO2017147410.

Inhibitors of proteins containing cytokine-inducible SH2 (CISH)

In some embodiments, the compounds described herein are combined with inhibitors of proteins containing cytokine-inducible SH2 (CISH; CIS; G18; SOCS; CIS-1; BACTS2; NCBI gene ID: 1154). Examples of CISH inhibitors include those described in WO2017100861, WO2018075664, and WO2019213610.

Gene editor

In some implementations, compounds as described herein are combined with gene editors. Exemplary gene editing systems that can be co-administered include, but are not limited to, CRISPR/Cas9 systems, zinc finger nuclease systems, TALEN systems, homing endonuclease systems (e.g., ARCUS), and homing wide-range nuclease systems.

Other drugs with unspecified targets

In some embodiments, the compounds described herein are combined with the following substances: human immunoglobulin (10% liquid formulation), Cuvitru (human immunoglobulin (20% solution)), levofolinic acid disodium, IMSA-101, BMS-986288, IMUNO BGC Moreau RJ, R-OKY-034F, GP-2250, AR-23, levofolinic acid calcium, porphyrin sodium, RG6160, ABBV-155, CC-99282, carmustine implantation film with polyphenylprosan 20 carrier (polyphenylprosan 20 with carmustine), Veregen, gadoxetine disodium, gadobutrol, gadoteric acid meglumine, gadoterol, 99mTc-stabi, pomalidomide, pacibanil, or penoxuridine.

2. Human Immunodeficiency Virus (HIV)

In some implementations, the adjunctive therapeutic agent may be an anti-HIV agent. In some cases, the adjunctive therapeutic agent may be an HIV protease inhibitor, an HIV non-nucleoside or non-nucleotide inhibitor of reverse transcriptase, an HIV nucleoside or nucleotide inhibitor of reverse transcriptase, an HIV integrase inhibitor, an HIV non-catalytic site (or allosteric) integrase inhibitor, an HIV entry inhibitor, an HIV maturation inhibitor, an HIV capsid inhibitor, an HIV Tat or Rev inhibitor, an immunomodulator, an immunotherapeutic agent, an antibody-drug conjugate, a gene modifier, or a gene editor (such as CRISPR/Cas9). Zinc finger nucleases, homing nucleases, synthetic nucleases, TALENs, cell therapies (such as chimeric antigen receptor T-cell CAR-T and engineered T-cell receptor TCR-T, autologous T-cell therapy, engineered B cells), latency reversal agents, immunotherapy, phosphatidylinositol 3-kinase (PI3K) inhibitors, HIV antibodies, bispecific antibodies and "antibody-like" therapeutic proteins, HIV p17 matrix protein inhibitors, IL-13 antagonists, peptidyl prolyl cis-trans isomerase A modulators, protein disulfide bond isomerase inhibitors Formulations, complement C5a receptor antagonists, DNA methyltransferase inhibitors, HIV vif gene modulators, Vif dimerization antagonists, HIV-1 viral infection factor inhibitors, HIV-1 Nef modulators, Hck tyrosine kinase modulators, mixed lineage kinase-3 (MLK-3) inhibitors, HIV-1 splicing inhibitors, integrin antagonists, nucleoprotein inhibitors, splicing factor modulators, COMM domain-containing protein 1 modulators, HIV ribonuclease H inhibitors, defensin modulators, CDK-9 inhibitors Drugs, dendritic ICAM-3 grasping non-integrin 1 inhibitors, HIV GAG protein inhibitors, HIV POL protein inhibitors, complement factor H regulators, ubiquitin ligase inhibitors, deoxycytidine kinase inhibitors, cyclin-dependent kinase inhibitors, proprotein convertase PC9 stimulators, ATP-dependent RNA helicase DDX3X inhibitors, reverse transcriptase initiation complex inhibitors, G6PD and NADH oxidase inhibitors, pharmacokinetic enhancers, HIV gene therapy, HIV vaccines, and combinations thereof.

In some implementations, the adjunctive therapeutic agent is selected from the group consisting of: combination drugs for HIV, other drugs for the treatment of HIV, HIV protease inhibitors, HIV reverse transcriptase inhibitors, HIV integrase inhibitors, HIV non-catalytic site (or allosteric) integrase inhibitors, HIV entry (fusion) inhibitors, HIV maturation inhibitors, latency reversal agents, capsid inhibitors, immune-based therapies, PI3K inhibitors, HIV antibodies and bispecific antibodies and "antibody-like" therapeutic proteins, and combinations thereof.

3. Hepatitis B virus

In some embodiments, the compounds of this disclosure or pharmaceutically acceptable salts thereof are combined with one, two, three, four or more adjunctive therapeutic agents selected from HBV combination drugs, HBV vaccines, HBV DNA polymerase inhibitors, immunomodulators, Toll-like receptor (TLR) modulators, interferon alpha receptor ligands, hyaluronidase inhibitors, hepatitis B core antigen (HBcAg) inhibitors, hepatitis B surface antigen (HBsAg) inhibitors, cytotoxic T lymphocyte-associated protein 4 (ipi4) inhibitors, cyclic protein inhibitors, HBV viral entry inhibitors, antisense oligonucleotides targeting viral mRNA, short interfering RNA (siRNA) and ddRNAi, endonuclease modulators, and ribonucleotide reductases. Inhibitors, HBV E antigen inhibitors, covalently closed circular DNA (cccDNA) inhibitors, farnesol X receptor agonists, STING agonists, anti-HBV antibodies, CCR2 chemokine antagonists, thymosin agonists, cytokines, nucleoprotein regulators, retinoic acid-induced gene 1 stimulators, NOD2 stimulators, phosphatidylinositol 3-kinase (PI3K) inhibitors, indoleamine-2,3-dioxygenase (IDO) pathway inhibitors, PD-1 inhibitors, PD-L1 inhibitors, recombinant thymosin α-1, Bruton's tyrosine kinase (BTK) inhibitors, KDM inhibitors, HBV replication inhibitors, arginase inhibitors, gene therapy and cell therapy, gene editors, CAR-T cell therapy, TCR-T cell therapy and other HBV drugs.

In some embodiments, the compounds of this disclosure or pharmaceutically acceptable salts thereof may be used or combined with one or more of the following: chemotherapeutic agents, immunomodulators, immunotherapeutic agents, therapeutic antibodies, therapeutic vaccines, bispecific antibodies and “antibody-like” therapeutic proteins (such as anti-pMHC TCR-like antibodies, Fab derivatives), antibody-drug conjugates (ADCs), gene modifiers or gene editors (such as CRISPR Cas9, zinc finger nucleases, homing endonucleases, homing broad-spectrum nucleases (e.g., ARCUS), synthetic nucleases, TALEN), cell therapies such as CAR-T (chimeric antigen receptor T cells) and TCR-T (engineered T cell receptor) agents or any combination thereof.

In some embodiments, the agents described herein are combined with one, two, three, four or more adjunctive therapeutic agents, such as 3-dioxygenase (IDO) inhibitors, apolipoprotein A1 modulators, arginase inhibitors, B and T lymphocyte attenuator inhibitors, Bruton's tyrosine kinase (BTK) inhibitors, CCR2 chemokine antagonists, CD137 inhibitors, CD160 inhibitors, CD305 inhibitors, CD4 agonists and modulators, compounds targeting hepatitis B core antigen (HBcAg), core protein allosteric modulators, covalently closed circular DNA (cccDNA) inhibitors, cyclophilic protein inhibitors, cytotoxic T lymphocyte-associated protein 4 (ipi4) inhibitors, DNA polymerase inhibitors, endonuclease modulators, epigenetic modifiers, farnesol X receptor (FXR) agonists, HBV D NA polymerase inhibitors, HBV replication inhibitors, HBV RNase inhibitors, HBV viral entry inhibitors, HBx inhibitors, hepatitis B large envelope protein modulators, hepatitis B large envelope protein stimulators, hepatitis B structural protein modulators, hepatitis B surface antigen (HBsAg) inhibitors, hepatitis B surface antigen (HBsAg) secretion or assembly inhibitors, hepatitis B virus e antigen inhibitors, hepatitis B virus replication inhibitors, hepatitis virus structural protein inhibitors, HIV-1 reverse transcriptase inhibitors, hyaluronidase inhibitors, inhibitor of apoptosis protein family (IAP) protein inhibitors, IL-2 agonists, IL-7 agonists, immunomodulators, indoleamine-2 inhibitors, ribonucleotide reductase inhibitors, interleukin-2 ligands, ipi4 inhibitors, lysine demethylase inhibitors, histone demethylase inhibitors, KDM1 inhibitors. KDM5 inhibitors, cytotoxic cell lectin-like receptor subfamily G member 1 inhibitors, lymphocyte activation gene 3 inhibitors, lymphotoxin β receptor activators, Axl modulators, B7-H3 modulators, B7-H4 modulators, CD160 modulators, CD161 modulators, CD27 modulators, CD47 modulators, CD70 modulators, GITR modulators, HEVEM modulators, ICOS modulators, Mer modulators, NKG2A modulators, NKG2D modulators, OX40 modulators, SIRPα modulators, TIGIT modulators, Tim-4 modulators, Tyro modulators, Na+-taurocholate cotransporter (NTCP) inhibitors, natural killer cell receptor 2B4 inhibitors, NOD2 gene stimulators, nucleoprotein inhibitors, nucleoprotein modulators, O X-40 receptor agonists, PD-1 inhibitors, PD-L1 inhibitors, peptidyl prolyl isomerase inhibitors, phosphatidylinositol-3 kinase (PI3K) inhibitors, retinoic acid-induced gene 1 stimulators, reverse transcriptase inhibitors, ribonuclease inhibitors, RNA/DNA polymerase inhibitors, SLC10A1 gene inhibitors, SMAC mimics, Src tyrosine kinase inhibitors, interferon gene stimulating factor (STING) agonists, NOD1 stimulators, T cell surface glycoprotein CD28 inhibitors, T cell surface glycoprotein CD8 regulators, thymosin agonists, thymosin α1 ligands, Tim-3 inhibitors, TLR-3 agonists, TLR-7 agonists, TLR-9 agonists, TLR9 agonists or gene stimulators, toll-like receptor (TLR) regulators, viral ribonucleotide reductase inhibitors, and combinations thereof.

B. Example of combined therapy

1. Cancer

Combination therapy for lymphoma or leukemia

Some chemotherapy agents are used to treat lymphoma or leukemia. These drugs include interleukin, avoxidec, amifotin trihydrate, aminocamptothecin, antitumor ketone A10, antitumor ketone AS2-1, antithymocyte globulin, arsenic trioxide, Bcl-2 family protein inhibitor ABT-263, β-alethine, BMS-345541 bortezomib (PS-341), bryozoxin 1, bulsulfan, campath-1H, carboplatin, carfilzomib, carmustine, caspofungin acetate, CC-5103, chlorambucil, CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone), cisplatin, cladribine, clofarabine, curcumin, CVP (cyclophosphamide, vincristine, and prednisone), cyclophosphamide, cyclosporine, cytarabine, and denileukin. ftitox), dexamethasone, docetaxel, saccharin 10, doxorubicin, doxorubicin hydrochloride, DT-PACE (dexamethasone, thalidomide, cisplatin, doxorubicin, cyclophosphamide, and etoposide), enzatolin, epoetin afa, etoposide, everolimus (RAD001), FCM (fludarabine, cyclophosphamide, and mitoxantrone), FCR (fludarabine, cyclophosphamide, and rituximab), fenivel-Amin, filgrastim, flavopiridol, fludarabine, FR (fludarabine and rituximab), geldmycin (17AAG), hyperCVAD (high fraction cyclophosphamide, vincristine, doxorubicin, dexamethasone, methotrexate, and cytarabine), ICE (isophosphamide, carboplatin, and etoposide), ifosfamide, irinotecan hydrochloride, interferon alpha-2b Ixaspiron, Lenalidomide (CC-5013), Pomalidomide Lymphokine-Activated Killer Cells, MCP (Mitoxantrone, Chloramic Acid Mustard, and Prednisolone), Melphalan, Mesna, Methotrexate, Mitoxantrone Hydrochloride, Motazafen Gadolin, Mycophenolate Motracetate, Nerapine, Obatoclax (GX15-070), Oblimersen, Octreotide Acetate, ω-3 Fatty Acids, Omr-IgG-am (WNIG, Omrix), Oxaliplatin, Paclitaxel, Palbociclib (PD0332991), Pegfilgrastim, PEGylated Liposome Doxorubicin Hydrochloride, Perifosin, Prednisolone, Prednisone, Recombinant FLT3 Ligand, Recombinant Human Thrombopoietin, Recombinant Interferon Alpha, Recombinant Interleukin-11, Recombinant Interleukin-12, Li Rituximab, R-CHOP (rituximab and CHOP), R-CVP (rituximab and CVP), R-FCM (rituximab and FCM), R-ICE (rituximab and ICE), and R MCP (rituximab and MCP), R-roscovitine (seliciclib, CYC202), saxaglastine, sildenafil citrate, simvastatin, sirolimus, styryl sulfone, tacrolimus, spiramycin, tesimirolimus (CCl-779), thalidomide, therapeutic allogeneic lymphocytes, thiotepa, tepifenesin, vincristine, vincristine sulfate, vinorelbine ditartrate, SAHA (sialoyl aminohydroxamic acid or sialoyl, aniline and isohydroxamic acid), vemurafenib venetoc (ABT-199).

One modified approach is radioimmunotherapy, in which monoclonal antibodies are combined with radioactive isotope particles such as indium-111, yttrium-90, and iodine-131. Examples of combination therapies include, but are not limited to, iodine-131 tosimomab, yttrium-90 timimomab, and CHOP.

The above-mentioned therapies can be supplemented or combined with stem cell transplantation or treatment. Treatment procedures include peripheral blood stem cell transplantation, autologous hematopoietic stem cell transplantation, autologous bone marrow transplantation, antibody therapy, biological therapy, enzyme inhibitor therapy, whole-body irradiation, stem cell infusion, bone marrow ablation with stem cell support, ex vivo processed peripheral blood stem cell transplantation, umbilical cord blood transplantation, immunoenzyme technology, low-LET cobalt-60 gamma ray therapy, bleomycin, conventional surgery, radiotherapy, and non-myeloablative allogeneic hematopoietic stem cell transplantation.

Combination therapy for non-Hodgkin's lymphoma

Treatment for non-Hodgkin lymphoma (NHL) (especially those of B-cell origin) includes the use of monoclonal antibodies, standard chemotherapy regimens (e.g., CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone), CVP (cyclophosphamide, vincristine, and prednisone), FCM (fludarabine, cyclophosphamide, and mitoxantrone), MCP (mitoxantrone, chlorambucil, and prednisolone), all optionally including rituximab®, etc.), radioimmunotherapy, and combinations thereof, especially the integration of antibody therapy with chemotherapy.

Examples of unconjugated monoclonal antibodies used to treat NHL/B-cell cancer include rituximab, alemtuzumab, human or humanized anti-CD20 antibodies, lumiliximab, anti-TNF-related apoptosis-inducing ligand (anti-TRAIL), bevacizumab, galiximab, epratuzumab, SGN-40, and anti-CD74.

Examples of experimental antibody agents used to treat NHL/B-cell cancer include ofatumumab, ha20, PRO131921, alemtumab, galiximab, SGN-40, CHIR-12.12, epazolizumab, phenmiclimab, apolizumab, milatuzumab, and bevacizumab.

Examples of standard chemotherapy regimens for NHL/B-cell cancer include CHOP, FCM, CVP, MCP, R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone), R-FCM, R-CVP, and R-MCP.

Examples of radioimmunotherapy for NHL/B-cell cancer include yttrium-90 teimomab and iodine-131 tosimomab.

Combination therapy for mantle cell lymphoma

Therapeutic treatment for mantle cell lymphoma (MCL) includes combination chemotherapy, such as CHOP, hyperCVAD, and FCM. These regimens can also be supplemented with the monoclonal antibody rituximab to form combination therapies R-CHOP, hyperCVAD-R, and R-FCM. Any of the above therapies can be combined with stem cell transplantation or ICE to treat MCL.

Alternative treatments for MCL include immunotherapy. One type of immunotherapy uses monoclonal antibodies such as rituximab. Another uses cancer vaccines, such as GTOP-99, which are based on the genetic makeup of an individual patient's tumor.

A modified approach to treating MCL is radioimmunotherapy, in which monoclonal antibodies are combined with radioactive isotope particles (such as iodine-131 tosimomumab and yttrium-90 timimomumab). In another example, it is used in conjunction with CHOP sequential therapy.

Other treatments for MCL include autologous stem cell transplantation combined with high-dose chemotherapy, administration of proteasome inhibitors such as bortezomib (or PS-341), or administration of anti-angiogenic agents such as thalidomide, especially in combination with rituximab.

Another treatment approach is to administer drugs in combination with other chemotherapy agents that cause the degradation of the Bcl-2 protein and increase the sensitivity of cancer cells to chemotherapy (such as Olimerson).

Another treatment option involves administering mTOR inhibitors, which can lead to inhibition of cell growth or even cell death. Non-limiting examples include sirolimus, tesimolimus (CCI-779), CC-115, CC-223, SF-1126, PQR-309 (bimiralisib), voxtalisib, GSK-2126458, and tesimolimus in combination with or in combination with other chemotherapeutic agents.

Other recent MCL therapies have been disclosed. Examples of such therapies include frappindo, palbociclib (PD0332991), R-roscovetin (celecoxib, CYC202), styryl sulfone, omeprazole (GX15-070), TRAIL, anti-TRAIL death receptor DR4 and DR5 antibodies, tesiromixol (CCl-779), everolimus (RAD001), BMS-345541, curcumin, SAHA, thalidomide, lenalidomide (CC-5013), and gerdemycin (17AAG).

Waldenstrom macroglobulinemia combination therapy

Therapeutic agents used to treat Waldenström macroglobulinemia (WM) include interleukin, alenmab, avoxidec, amifostatin trihydrate, aminocamptothecin, antitumor ketone A10, antitumor ketone AS2-1, antithymocyte globulin, arsenic trioxide, autologous human tumor-derived HSPPC-96, Bcl-2 family protein inhibitor ABT-263, β-aritin, bortezomib bryozoxin 1, buspirone, campathonine-1H, carboplatin, carmustine, caspofungin acetate, CC-5103, cisplatin, clofarabine, and cyclophosphamide. Cyclosporine, Cytarabine, Interleukin-Dennisin, Dexamethasone, Docetaxel, Saccharin 10, Doxorubicin Hydrochloride, DT-PACE, Enzatolin, Epoetin Alfa, Epraziquantel (hLL2-anti-CD22 humanized antibody), Etoposide, Everolimus, Fenivel Aamine, Filgrastim, Fludarabine, Ibrutinib, Isofosphosphatamide, Indium-111 Monoclonal Antibody MN-14, Iodine-131 Tosimomab, Irinotecan Hydrochloride, Ixaspiron, Lymphokine-Activated Killer Cells, Melphalan, Mesna, Methotrexate, Mifepristone Hydrochloride Toxanthraquinone, monoclonal antibodies CD19 (such as tisagenlecleucel-T, CART-19, CTL-019), monoclonal antibodies CD20, motexafen gadolinium, mycophenolate moxolate, nerabine, olimol, octreotide acetate, omega-3 fatty acids, oxaliplatin, paclitaxel, pegfilgrastim, PEGylated liposome doxorubicin hydrochloride, pentostatin, pevesin, prednisone, recombinant flt3 ligand, recombinant human thrombopoietin, recombinant interferon α, recombinant interleukin-11, recombinant interleukin-12, and levofloxacin. Toxicam, Saxaglastine, Sildenafil Citrate, Simvastatin, Sirolimus, Tacrolimus, Tanspiramycin, Thalidomide, Therapeutic Allogeneic Lymphocytes, Thiotepa, Tepififib, Tosimomab, Ulcuplumab, Veltuzumab, Vincristine Sulfate, Vinorelbine Ditartrate, Vorinostat, WT1 126-134 Peptide Vaccine, WT-1 Similar Peptide Vaccine, Yttrium-90 Teimomab, Yttrium-90 Humanized Epatizumab, and any combination thereof.

Examples of treatment procedures for WM include peripheral blood stem cell transplantation, autologous hematopoietic stem cell transplantation, autologous bone marrow transplantation, antibody therapy, biological therapy, enzyme inhibitor therapy, whole-body irradiation, stem cell infusion, bone marrow ablation with stem cell support, peripheral blood stem cell transplantation with in vitro treatment, umbilical cord blood transplantation, immunoenzyme technology, low-LET cobalt-60 gamma ray therapy, bleomycin, conventional surgery, radiotherapy, and non-bone marrow ablation allogeneic hematopoietic stem cell transplantation.

Combination therapy for diffuse large B-cell lymphoma

Therapeutic agents used to treat diffuse large B-cell lymphoma (DLBCL) include cyclophosphamide, doxorubicin, vincristine, prednisone, anti-CD20 monoclonal antibodies, etoposide, bleomycin, many agents listed for WM, and any combination thereof, such as ICE and RICE.

Combination therapy for chronic lymphocytic leukemia

Examples of therapeutic agents used to treat chronic lymphocytic leukemia (CLL) include chlorambucil, cyclophosphamide, fludarabine, pentostatin, cladribine, doxorubicin, vincristine, prednisone, prednisolone, alemtuzumab, many agents listed for WM, and combination chemotherapy and chemoimmunotherapy, including the following common combination regimens: CVP, R-CVP, ICE, R-ICE, FCR, and FR.

Combination therapy for myelofibrosis

Myelofibrosis inhibitors include, but are not limited to, hedgehog inhibitors, histone deacetylase (HDAC) inhibitors, and tyrosine kinase inhibitors. Non-limiting examples of hedgehog inhibitors include saridegib and vismodegib. Examples of HDAC inhibitors include, but are not limited to, pracinostat and panobinostat. Non-limiting examples of tyrosine kinase inhibitors include lentatinib, bosutinib, imatinib, raditinib, and cabozantinib.

Combination therapy for hyperplastic disorders

Gemcitabine, nalbu-paclitaxel, and gemcitabine/nalbu-paclitaxel can be used in combination with JAK inhibitors and/or PI3Kδ inhibitors to treat hyperplastic disorders.

Combination therapy for bladder cancer

Therapeutic agents used to treat bladder cancer include atezolizumab, carboplatin, cisplatin, docetaxel, doxorubicin, fluorouracil (5-FU), gemcitabine, idosfamide, interferon alpha-2b, methotrexate, mitomycin, nalbu-paclitaxel, paclitaxel, pemetrexed, thiotepa, vincristine, and any combination thereof.

Combination therapy for breast cancer

Therapeutic agents used to treat breast cancer include albumin-bound paclitaxel, anastrozole, capecitabine, carboplatin, cisplatin, cyclophosphamide, docetaxel, doxorubicin, epirubicin, everolimus, exemestane, fluorouracil, fulvestrant, gemcitabine, ixaprilone, lapatinib, letrozole, methotrexate, mitoxantrone, paclitaxel, pegylated liposomal doxorubicin, pertuzumab, tamoxifen, toremifene, trastuzumab, vinorelbine, and any combination thereof.

Triple-negative breast cancer combination therapy

Treatment agents used to treat triple-negative breast cancer include cyclophosphamide, docetaxel, doxorubicin, epirubicin, fluorouracil, paclitaxel, and combinations thereof.

Combination therapy for colorectal cancer

Therapeutic agents used to treat colorectal cancer include bevacizumab, capecitabine, cetuximab, fluorouracil, irinotecan, leucovorin, oxaliplatin, panitumumab, aflibercept, and any combination thereof.

Combination therapy for castration-resistant prostate cancer

Treatment agents used to treat castration-resistant prostate cancer include abiraterone, cabazitaxel, docetaxel, enzalutamide, prednisone, ciproxetine-T, and any combination thereof.

Combination therapy for esophageal and esophagogastric junction cancer

Therapeutic agents used to treat esophageal and esophagogastric junction cancers include capecitabine, carboplatin, cisplatin, docetaxel, epirubicin, fluoropyrimidine, fluorouracil, irinotecan, leucovorin, oxaliplatin, paclitaxel, ramucirumab, trastuzumab, and any combination thereof.

Combination therapy for gastric cancer

Therapeutic agents used to treat gastric cancer include capecitabine, carboplatin, cisplatin, docetaxel, epirubicin, fluoropyrimidine, fluorouracil, irinotecan, leucovorin, mitomycin, oxaliplatin, paclitaxel, ramucirumab, trastuzumab, and any combination thereof.

Combination therapy for head and neck cancer

Therapeutic agents used to treat head and neck cancer include afatinib, bleomycin, capecitabine, carboplatin, cetuximab, cisplatin, docetaxel, fluorouracil, gemcitabine, hydroxyurea, methotrexate, nivolumab, paclitaxel, pembrolizumab, vinorelbine, and any combination thereof.

Combination therapy for hepatobiliary duct cancer

Therapeutic agents used to treat hepatobiliary cancer include capecitabine, cisplatin, fluoropyrimidine, 5-fluorouridine, gemcitabine, oxaliplatin, sorafenib, and any combination thereof.

Hepatocellular carcinoma combination therapy

Therapeutic agents used to treat hepatocellular carcinoma include capecitabine, doxorubicin, gemcitabine, sorafenib, and any combination thereof.

Combination therapy for non-small cell lung cancer

Therapeutic agents used to treat non-small cell lung cancer (NSCLC) include afatinib, albumin-bound paclitaxel, alectinib, bevacizumab, cabozantinib, carboplatin, cisplatin, crizotinib, dabrafenib, docetaxel, erlotinib, etoposide, gemcitabine, nivolumab, paclitaxel, pembrolizumab, pemetrexed, ramucirumab, trametinib, trastuzumab, vandetanib, vemurafenib, vinorelbine, vinorelbine, and any combination thereof.

Small cell lung cancer combination therapy

Therapeutic agents used to treat small cell lung cancer (SCLC) include bendamustine, carboplatin, cisplatin, cyclophosphamide, docetaxel, doxorubicin, etoposide, gemcitabine, ipilimumab, irinotecan, nivolumab, paclitaxel, temozolomide, topotecan, vincristine, vinorelbine, and any combination thereof.

Combination therapy for melanoma

Therapeutic agents used to treat melanoma include albumin-bound paclitaxel, carboplatin, cisplatin, cobiemtinib, dabrafenib, dacarbazine, IL-2, imatinib, interferon alpha-2b, ipilimumab, nitrosourea, nivolumab, paclitaxel, pembrolizumab, ipilimumab, temozolomide, trametinib, vemurafenib, vincristine, and any combination thereof.

Combination therapy for ovarian cancer

Therapeutic agents used to treat ovarian cancer include 5-fluorouracil, albumin-bound paclitaxel, hexamethylmelamine, anastrozole, bevacizumab, capecitabine, carboplatin, cisplatin, cyclophosphamide, docetaxel, doxorubicin, etoposide, exemestane, gemcitabine, isophosphamide, irinotecan, letrozole, leuprolide acetate, liposomal doxorubicin, megestrol acetate, melphalan, olaparib, oxaliplatin, paclitaxel, pazopanib, pemetrexed, tamoxifen, topotecan, vinorelbine, and any combination thereof.

Combination therapy for pancreatic cancer

Therapeutic agents used to treat pancreatic cancer include 5-fluorouracil, albumin-bound paclitaxel, capecitabine, cisplatin, docetaxel, erlotinib, fluorouracil, gemcitabine, irinotecan, leucovorin, oxaliplatin, paclitaxel, and any combination thereof.

Combination therapy for renal cell carcinoma

Therapeutic agents used to treat renal cell carcinoma include axitinib, bevacizumab, cabozantinib, erlotinib, everolimus, levantinib, nivolumab, pazopanib, sorafenib, sunitinib, tesimolimus, and any combination thereof.

Fc mutations that prolong serum half-life

In some embodiments, the Fc region or Fc domain of the targeted antibody contains amino acid modifications that promote the extension of the serum half-life of the anti-binding molecule. Mutations that increase the half-life of the antibody have been described. In one embodiment, the Fc region or Fc domain of one or both of the CD3-targeting heavy chain and the HIV antigen-targeting heavy chain contains a methionine-to-tyrosine substitution at position 252 (EU number), a serine-to-threonine substitution at position 254 (EU number), and a threonine-to-glutamic acid substitution at position 256 (EU number). See, for example, U.S. Patent No. 7,658,921. This type of mutant (designated “YTE mutant”) exhibits a fourfold increase in half-life relative to the wild-type form of the same antibody (Dall’Acqua et al., JBiol Chem, 281:23514-24 (2006); Robbie et al., Antimicrob Agents Chemotherap., 57(12):6147-6153 (2013)). In some embodiments, the Fc region or Fc domain of one or both of the CD3-targeting heavy chain and the HIV antigen-targeting heavy chain includes an IgG constant domain comprising one, two, three, or more amino acid substitutions at positions 251-257, 285-290, 308-314, 385-389, and 428-436 (EU number). Alternatively, the M428L and N434S (“LS”) substitutions may increase the pharmacokinetic half-life of the multispecific antigen-binding molecule. In other embodiments, the Fc region or Fc domain of one or both of the CD3-targeting heavy chain and the HIV antigen-targeting heavy chain includes the M428L and N434S substitutions (EU number). In other embodiments, the Fc region or Fc domain of one or both of the CD3-targeting heavy chain and the HIV antigen-targeting heavy chain includes the T250Q and M428L (EU number) mutations. In other embodiments, the Fc region or Fc domain of one or both of the CD3-targeting heavy chain and the HIV antigen-targeting heavy chain contains H433K and N434F (EU number) mutations.

Fc mutations in enhancement effectors

In some embodiments, the Fc region or Fc domain of the antibody includes post-translational modifications and/or amino acid modifications that increase effector activity (e.g., improved FcγIIIa binding and increased antibody-dependent cytotoxicity (ADCC)). In some embodiments, the Fc region or Fc domain of the antibody includes DE modifications (i.e., EU designations S239D and I332E). In some embodiments, the Fc region or Fc domain of the antibody includes DEL modifications (i.e., EU designations S239D, I332E, and A330L). In some embodiments, the Fc region or Fc domain of the antibody includes DEA modifications (i.e., EU designations S239D, I332E, and G236A). In some embodiments, the Fc region or Fc domain of the antibody includes DEAL modifications (i.e., EU designations S239D, I332E, G236A, and A330L). See, for example, U.S. Patent Nos. 7,317,091, 7,662,925, 8,039,592, 8,093,357, 8,093,359, 8,383,109, 8,388,955, 8,735,545, 8,858,937, 8,937,158, 9,040,041, 9,353,187, 10,184,000, and 10,584,176. Additional amino acid modifications that increase effector activity (e.g., improved FcγIIIa binding and increased antibody-dependent cytotoxicity (ADCC)) include, but are not limited to (EU numbers) F243L/R292P/Y300L/V305I/P396L; S298A/E333A/K334A; or L234Y/L235Q/G236W/S239M/H268D/D270E/S298A on the first Fc domain and D270E/K326D/A330M/K334E on the second Fc domain. Amino acid mutations that increase C1q binding and complement-dependent cytotoxicity (CDC) include, but are not limited to (EU numbers) S267E/H268F/S324T or K326W/E333S. Fc region mutations that enhance effector activity are reviewed in, for example, Wang et al., Protein Cell (2018) 9(1):63–73; and Saunders, Front Immunol. (2019) 10:1296.

In other embodiments, the antibody or its antigen-binding fragment has a modified glycosylation, which may be introduced, for example, post-translational or through genetic engineering. In some embodiments, the antibody or its antigen-binding fragment is, for example, defucosylated at the glycosylation sites present in the antibody or its antigen-binding fragment. Most approved monoclonal antibodies are of the IgG1 isotype, in which two N-linked bibranched complex-type oligosaccharides bind to the Fc region. The Fc region exerts the effector function of ADCC through its interaction with leukocyte receptors of the FcγR family. Defucosylated monoclonal antibodies are monoclonal antibodies engineered so that the oligosaccharides in the antibody's Fc region do not contain any fucosylate units.

2. Human Immunodeficiency Virus (HIV)

In some embodiments, the agents described herein are combined with HIV combination drugs. Examples of combination drugs that can be used with the agents disclosed herein include (efavirenz, tenofovir disoproxil fumarate, and emtricitabine); (rilpivirine, tenofovir disoproxil fumarate, and emtricitabine); (erteiravir, cobicistat, tenofovir disoproxil fumarate, and emtricitabine); (tenofovir disoproxil fumarate and emtricitabine; TDF+FTC); (tenofovir alafenamide and emtricitabine); (tenofovir alafenamide, emtricitabine, and rilpivirine); (tenofovir alafenamide, emtricitabine, cobicistat, and erteiravir); dureravir, tenofovir alafenamide semi-fumarate, emtricitabine, and cobicistat. ; Efavirane, lamivudine, and tenofovir disoproxil fumarate; lamivudine and tenofovir disoproxil fumarate; tenofovir and lamivudine; tenofovir alafenamide and emtricitabine; tenofovir alafenamide semifumarate and emtricitabine; tenofovir alafenamide semifumarate, emtricitabine, and rilpivirine; tenofovir alafenamide semifumarate, emtricitabine, cobistat, and aviravir; (zidovudine and lamivudine; AZT+3TC); (abacavir sulfate and lamivudine; ABC+3TC); (lopinavir and ritonavir); (durutexvir, abacavir, and lamivudine); BIKTARVY (bicagvir) +Emtricitabine +Tenofovir Alambutamide), DOVATO, (Abacavir Sulfate, Zidovudine, and Lamivudine; ABC + AZT + 3TC); Atazanavir and Cobistat; Atazanavir Sulfate and Cobistat; Atazanavir Sulfate and Ritonavir; Derreiravir and Cobistat; Durutvir and Rilpivirine; Durutvir and Rilpivirine Hydrochloride; Durutvir, Abacavir Sulfate, and Lamivudine; Lamivudine, Nevirapine, and Zidovudine; Rettagvir and Lamivudine; Doravirine, Lamivudine, and Tenofovir Disoproxil Fumarate; Doravirine, Lamivudine, and Tenofovir Disoproxil Fumarate; Durutvir + Lamivudine, Lamivudine +Abacavir + Zidovudine, Lamivudine + Abacavir, Lamivudine + Tenofovir Disoproxil Fumarate, Lamivudine + Zidovudine + Nevirapine, Lopinavir + Ritonavir, Lopinavir + Ritonavir + Abacavir + Lamivudine, Lopinavir + Ritonavir + Zidovudine + Lamivudine, Tenofovir + Lamivudine and Tenofovir Disoproxil Fumarate + Emtricitabine + Rilpivirine Hydrochloride, Lopinavir, Ritonavir, Zidovudine and Lamivudine; Cabotevir + Rilpivirine; Elsulfavirine (VM-1500; VM-1500A) binds to and activates signal transduction through this kinase.

Examples of other drugs for the treatment of HIV that can be combined with the agents disclosed herein include acetaminophen, arapovir, BanLec, deferiphenone, Gamimune, mitfaline, naltrexone, alpha-1 protease inhibitor (Prolastin), REP 9, RPI-MN, VSSP, H1 virus, SB-728-T, 1,5-dicaffeoylquinic acid, rHIV7-shl-TAR-CCR5RZ, AAV-eCD4-Ig gene therapy, MazF gene therapy, BlockAide, ABX-464, AG-1105, APH-0812, and BIT-22. 5. CYT-107, HGTV-43, HPH-116, HS-10234, IMO-3100, IND-02, MK-1376, MK-2048, MK-4250, MK-8507, MK-8591, NOV-205, PA-1050040 (PA-040), PGN-007, SCY-635, SB-9200, SCB-719, TR-452, TEV-90110, TEV-90112, TEV-90111, TEV-90113, RN-18, Immuglo and VIR-576.

HIV protease inhibitors

In some embodiments, the agents described herein are combined with HIV protease inhibitors. Examples of HIV protease inhibitors that can be combined with the agents disclosed herein include ampravir, atazanavir, becanavir, derreiravir, fossavir, fossavir calcium, indinavir, indinavir sulfate, lopinavir, nelfinavir, nelfinavir mesylate, ritonavir, saquinavir, saquinavir mesylate, telanavir, DG-17, TMB-657 (PPL-100), T-169, BL-008, MK-8122, TMB-607, and TMC-310911.

HIV reverse transcriptase inhibitors

In some embodiments, the agents described herein are combined with non-nucleoside or non-nucleotide inhibitors. Examples of HIV non-nucleoside or non-nucleotide inhibitors of reverse transcriptase that can be combined with the agents disclosed herein include dapiriline, deraviridine, deraviridine mesylate, doravirine, efavirenz, ectrevirine, lentinan, nevirapine, rilpivirine, ACC-007, AIC-292, KM-023, PC-1005, and isavirin (VM-1500).

In some embodiments, the agents described herein are combined with HIV nucleoside or nucleotide inhibitors. Examples of HIV nucleoside or nucleotide inhibitors of reverse transcriptase that can be combined with the agents disclosed herein include adefovir, adefovir dipivoxil, azvudine, emtricitabine, tenofovir, tenofovir alafenamide, tenofovir alafenamide fumarate, tenofovir alafenamide hemifumarate, tenofovir disoproxil fumarate, tenofovir disoproxil fumarate, tenofovir disoproxil fumarate, and VIDEX (didanovine, ddl), abacavir, abacavir sulfate, alovudine, aripipridine, and aritabhide. Sinavudine, Didanoxin, Avtabin, Fertinavir, Fivudinetimate, CMX-157, Dapirilin, Doravirin, Etravirin, OCR-5753, Tenofovir Disoproxil Flavoxate, Fivudinetimate, Lamivudine, Azide, Stavudine, Zacitabine, Zidovudine, Rovafovir-Etalaflavinamide (GS-9131), GS-9148, MK-8504, MK-8591, MK-8583, VM-2500, and KP-1461.

HIV integrase inhibitors

In some embodiments, the agents described herein are combined with HIV integrase inhibitors. Examples of HIV integrase inhibitors that can be combined with the agents disclosed herein include avermectin, curcumin, derivatives of curcumin, chicoric acid, derivatives of chicoric acid, 3,5-dicaffeoylquinic acid, derivatives of 3,5-dicaffeoylquinic acid, ginsenoside tricarboxylic acid, derivatives of ginsenoside tricarboxylic acid, phenethyl caffeate, derivatives of phenethyl caffeate, tyrosine kinase inhibitors, derivatives of tyrosine kinase inhibitors, quercetin, derivatives of quercetin, retegvir, dulutegravir, JTK-351, bicretiravir, and AVX-1. 5567, Cabotevir (long-acting injectable), diketoquinoline-4-1 derivatives, integrase-LEDGF inhibitors, ledgins, M-522, M-532, NSC-310217, NSC-371056, NSC-48240, NSC-642710, NSC-699171, NSC-699172, NSC-699173, NSC-699174, stilbene disulfonic acid, T-169, VM-3500, and Cabotevir.

In some embodiments, the agents described herein are combined with HIV noncatalytic site or allosteric integrase inhibitors (NCINIs). Examples of HIV noncatalytic site or allosteric integrase inhibitors (NCINIs) that can be combined with the agents disclosed herein include CX-05045, CX-05168, and CX-14442.

HIV entry inhibitors

In some embodiments, the agents described herein are combined with HIV entry inhibitors. Examples of HIV entry (fusion) inhibitors that can be combined with the agents disclosed herein include xenicovirol, CCR5 inhibitors, gp41 inhibitors, CD4 attachment inhibitors, gp120 inhibitors, and CXCR4 inhibitors.

In some embodiments, the agents described herein are combined with CCR5 inhibitors. Examples of CCR5 inhibitors that can be combined with the agents disclosed herein include apravirone, vevicvirone, maravirone, cinnickvirone, leronlimab (PRO-140), adatabvir (RAP-101), nifevirone (TD-0232), anti-GP120/CD4 or CCR5 bispecific antibody, B-07, MB-66, peptide C25P, TD-0680, and vMIP (Haimipu).

In some embodiments, the agents described herein are combined with gp41 inhibitors. Examples of gp41 inhibitors that can be combined with the agents disclosed herein include epovitamide, emfuvirtide, BMS-986197, emfuvirtide biomodifiers, emfuvirtide biosimilars, HIV-1 fusion inhibitors (P26-Bapc), ITV-1, ITV-2, ITV-3, ITV-4, PIE-12 trimer, and sifvirtide.

In some embodiments, the agent is combined with a CD4 attachment inhibitor. Examples of CD4 attachment inhibitors that can be combined with the agents of this disclosure include ibalizumab and CADA analogs.

In some embodiments, the agents described herein are combined with gp120 inhibitors. Examples of gp120 inhibitors that can be combined with the agents disclosed herein include Radha-108 (receptor alcohol) 3B3-PE38, BanLec, bentonite-based nanomedicine, Fostersavir tromethamine, IQP-0831, and BMS-663068.

In some embodiments, the agents described herein are combined with CXCR4 inhibitors. Examples of CXCR4 inhibitors that can be combined with the agents disclosed herein include praxavir, ALT-1188, N15 peptide, and vMIP (Haimipu).

In some embodiments, the agents described herein are combined with HIV maturation inhibitors. Examples of HIV maturation inhibitors that can be combined with the agents disclosed herein include BMS-955176, GSK-3640254, and GSK-2838232.

Delayed reversal agent

In some embodiments, the agents described herein are combined with latency reversal agents (LRAs). Examples of latency reversal agents that can be combined with the agents of this disclosure include toll-like receptor (TLR) agonists (including TLR7 agonists, such as GS-9620), histone deacetylase (HDAC) inhibitors, proteasome inhibitors (such as velcade), protein kinase C (PKC) activators, Smyd2 inhibitors, BET-bromodomain 4 (BRD4) inhibitors, iomycin, IAP antagonists (inhibitors of apoptosis proteins, such as APG-1387, LBW-242), and S... MAC mimics (including TL32711, LCL161, GDC-0917, HGS1029, AT-406), PMA, SAHA (aminosuccinate hydroxamic acid or succinyl, aniline, and hydroxamic acid), NIZ-985, IL-15 modulating antibodies (including IL-15, IL-15 fusion proteins, and IL-15 receptor agonists), JQ1, disulfiram, amphotericin B, and ubiquitin inhibitors (such as lagozolar analogs, APH-0812, and GSK-343). Examples of PKC activators include indolelactam, prostratin, phorbolone B, and DAG-lactone.

Histone deacetylase (HDAC) inhibitors

In some embodiments, the agent as described herein is combined with an inhibitor of histone deacetylases, such as histone deacetylase 9 (HDAC9, HD7, HD7b, HD9, HDAC, HDAC7, HDAC7B, HDAC9B, HDAC9FL, HDRP, MITR; gene ID: 9734). Examples of HDAC inhibitors include, but are not limited to, abexinostat, ACY-241, AR-42, BEBT-908, belinostat, CKD-581, CS-055 (HBI-8000), CUDC-907 (fimepinostat), entinostat, givinostat, mocetinostat, panobinostat, pracinostat, quisinostat (JNJ-26481585), remixitana, ricolinostat, romidesin, SHP-141, valproic acid (VAL-001), vorinostat, tinostamustine, remetinostat, and entinostat.

Capsid inhibitors

In some embodiments, the agents described herein are combined with capsid inhibitors. Examples of capsid inhibitors that can be combined with the agents disclosed herein include capsid polymerization inhibitors or capsid-destructive compounds, HIV nucleocapsid p7 (NCp7) inhibitors (such as azodicarbonamide), HIV p24 capsid protein inhibitors, GS-6207, GS-CA1, AVI-621, AVI-101, AVI-201, AVI-301 and the AVI-CAN1-15 series, as well as the compounds described in this patent (GSK WO2019/087016).

Immune checkpoint modulators

In some embodiments, the agent as described herein is combined with one or more blockers or inhibitors of inhibitory immune checkpoint proteins or receptors and/or with one or more stimulators, activators, or agonists of stimulating immune checkpoint proteins or receptors. Blocking or inhibiting inhibitory immune checkpoints can positively modulate T cell or NK cell activation and prevent immune escape by infected cells. Stimulating or activating immune checkpoints can enhance the efficacy of immune checkpoint inhibitors in the treatment of infections. In some embodiments, immune checkpoint proteins or receptors modulate T cell responses (e.g., reviewed in Xu et al., J Exp Clin Cancer Res. (2018) 37:110). In some embodiments, immune checkpoint proteins or receptors modulate NK cell responses (e.g., in Davis et al., Semin Immunol. (2017) 31:64–75 and Chiossone et al., Nat Rev Immunol. (2018) 18(11):671-688).

Examples of immune checkpoint proteins or receptors include, but are not limited to, CD27, CD70; CD40, CD40LG; CD47, CD48 (SLAMF2); 2 containing transmembrane and immunoglobulin domains (TMIGD2, CD28H); CD84 (LY9B, SLAMF5); CD96, CD160, MS4A1 (CD20); CD244 (SLAMF4); CD276 (B7H3); T cell activation inhibitor 1 containing V-set domains (VTCN1, B7H4); V-set immunomodulatory receptors (VSIR, B... 7H5, VISTA); Immunoglobulin superfamily member 11 (IGSF11, VSIG3); Natural killer cell cytotoxic receptor 3 ligand 1 (NCR3LG1, B7H6); HERV-H LTR related 2 (HHLA2, B7H7); Inducible T cell costimulatory factor (ICOS, CD278); Inducible T cell costimulatory factor ligand (ICOSLG, B7H2); TNF receptor superfamily member 4 (TNFRSF4, OX40); TNF superfamily member 4 (TNFSF4, OX40L); TNFRSF8 (CD278, CD ... 30) TNFSF8 (CD30L); TNFRSF10A (CD261, DR4, TRAILR1), TNFRSF9 (CD137), TNFSF9 (CD137L); TNFRSF10B (CD262, DR5, TRAILR2), TNFRSF10 (TRAIL); TNFRSF14 (HVEML, CD270), TNFSF14 (HVEML); CD272 (B and T lymphocyte-associated (BTLA)); TNFRSF17 (BCMA, CD269), TNF SF13B (BAFF); TNFRSF18 (GITR), TNFSF18 (GITRL); MHC class I peptide-associated sequence A (MICA); MHC class I peptide-associated sequence B (MICB); CD274 (CD274, PDL1, PD-L1); programmed cell death 1 (PDCD1, PD1, PD-1); cytotoxic T lymphocyte-associated protein 4 (CTLA4, CD152); CD80 (B7-1), CD28; nectin cell adhesion molecule 2 (NECTIN2, CD112); CD 226 (DNAM-1); Poliovirus receptor (PVR) cell adhesion molecule (PVR, CD155); Contains PVR-associated immunoglobulin domain (PVRIG, CD112R); T cell immune receptor with Ig and ITIM domains (TIGIT); Contains T cell immunoglobulin and mucin domains 4 (TIMD4; TIM4); Hepatitis A virus cell receptor 2 (HAVCR2, TIMD3, TIM3); Galactagogue 9 (LGALS9); Lymphocyte activation 3 (LAG3, CD223); Signal transduction lymphocyte activation SLAM family members 1 (SLAM, CD150); Lymphocyte antigen 9 (LY9, CD229, SLAM); SLAM family member 6 (SLAM, CD352); SLAM family member 7 (SLAM, CD319); UL16 binding protein 1 (ULBP1); UL16 binding protein 2 (ULBP2); UL16 binding protein 3 (ULBP3); retinoic acid early transcript 1E (RAET1E; ULBP4); retinoic acid early transcript 1G (RAET1G; ULBP5); retinoic acid Early transcript 1L (RAET1L; ULBP6); Lymphocyte activation 3 (CD223); Cytokine immunoglobulin-like receptor 1 with three Ig domains and a long cytoplasmic tail (KIR, CD158E1); Cytokine lectin-like receptor C1 (KLRC1, NKG2A, CD159A); Cytokine lectin-like receptor K1 (KLRK1, NKG2D, CD314); Cytokine lectin-like receptor C2 (KLRC2, CD159c, NKG2C); Cytokine lectin-like receptor C3 (KLRC3, NKG2E); Cytokine Lectin-like receptor C4 (KLRC4, NKG2F); cytotoxic immunoglobulin-like receptor with two Ig domains and a long cytoplasmic tail 1 (KIR2DL1); cytotoxic immunoglobulin-like receptor with two Ig domains and a long cytoplasmic tail 2 (KIR2DL2); cytotoxic immunoglobulin-like receptor with two Ig domains and a long cytoplasmic tail 3 (KIR2DL3); cytotoxic immunoglobulin-like receptor with three Ig domains and a long cytoplasmic tail 1 (KIR3DL1); cytotoxic lectin-like receptor D1 (KLRD1); and SLAM family member 7 (SLAMF7).

In some implementations, the agent as described herein is combined with one or more blockers or inhibitors of one or more T-cell inhibitory immune checkpoint proteins or receptors. Exemplary T-cell suppressor immune checkpoint proteins or receptors include, but are not limited to, CD274 (CD274, PDL1, PD-L1); programmed cell death 1 ligand 2 (PDCD1LG2, PD-L2, CD273); programmed cell death 1 (PDCD1, PD1, PD-1); cytotoxic T-lymphocyte-associated protein 4 (CTLA4, CD152); CD276 (B7H3); V-set domain-containing T-cell activation inhibitor 1 (VTCN1, B7H4); V-set immunomodulatory receptors (VSIR, B7H5, VISTA); immunoglobulin superfamily member 11 (IGSF11, VSIG3); TNFRSF14 (HVEM, CD270), TNFSF14 (HVEML); CD272 (B and T lymphocyte-associated (BTLA)); and PVR-associated proteins. Immunoglobulin domains (PVRIG, CD112R); T-cell immune receptors with Ig and ITIM domains (TIGIT); lymphocyte activation 3 (LAG3, CD223); hepatitis A virus cell receptor 2 (HAVCR2, TIMD3, TIM3); galactagogue 9 (LGALS9); cytotoxic cell immunoglobulin-like receptor with three Ig domains and a long cytoplasmic tail 1 (KIR, CD158E1); cytotoxic cell immunoglobulin-like receptor with two Ig domains and a long cytoplasmic tail 1 (KIR2DL1); cytotoxic cell immunoglobulin-like receptor with two Ig domains and a long cytoplasmic tail 2 (KIR2DL2); cytotoxic cell immunoglobulin-like receptor with two Ig domains and a long cytoplasmic tail 3 (KIR2DL3); and cytotoxic cell immunoglobulin-like receptor with three Ig domains and a long cytoplasmic tail 1 (KIR3DL1). In some implementations, the agent as described herein is combined with one or more agonists or activators of one or more T-cell stimulating immune checkpoint proteins or receptors. Examples of T-cell stimulating immune checkpoint proteins or receptors include, but are not limited to, CD27, CD70; CD40, CD40LG; inducible T-cell costimulatory factors (ICOS, CD278); inducible T-cell costimulatory factor ligands (ICOSLG, B7H2); TNF receptor superfamily member 4 (TNFRSF4, OX40); TNF superfamily member 4 (TNFSF4, OX40L); TNFRSF9 (CD137), TNFSF9 (CD137L); TNFRSF18 (GITR), TNFSF18 (GITRL); CD80 (B7-1), CD28; nectin cell adhesion molecule 2 (NECTIN2, CD112); CD226 (DNAM-1); CD244 (2B4, SLAMF4); and poliovirus receptor (PVR) cell adhesion molecule (PVR, CD155). See, for example, Xu et al., J Exp Clin Cancer Res. (2018) 37:110.

In some embodiments, the agents described herein are combined with one or more blockers or inhibitors of one or more NK cell inhibitory immune checkpoint proteins or receptors. Exemplary NK cell inhibitory immune checkpoint proteins or receptors include, but are not limited to, cytotoxic cell immunoglobulin-like receptors with three Ig domains and a long cytoplasmic tail 1 (KIR, CD158E1); cytotoxic cell immunoglobulin-like receptors with two Ig domains and a long cytoplasmic tail 1 (KIR2DL1); cytotoxic cell immunoglobulin-like receptors with two Ig domains and a long cytoplasmic tail 2 (KIR2DL2); cytotoxic cell immunoglobulin-like receptors with two Ig domains and a long cytoplasmic tail 3 (KIR2DL3); cytotoxic cell immunoglobulin-like receptors with three Ig domains and a long cytoplasmic tail 1 (KIR3DL1); cytotoxic cell lectin-like receptors C1 (KLRC1, NKG2A, CD159A); and cytotoxic cell lectin-like receptors D1 (KLRD1, CD94). In some embodiments, the agent as described herein is combined with one or more agonists or activators of one or more NK cell-stimulating immune checkpoint proteins or receptors. Exemplary NK cell-stimulating immune checkpoint proteins or receptors include, but are not limited to, CD16, CD226 (DNAM-1); CD244 (2B4, SLAMF4); cytotoxic lectin-like receptor K1 (KLRK1, NKG2D, CD314); and SLAM family member 7 (SLAMF7). See, for example, Davis et al., Semin Immunol. (2017) 31:64–75; Fang et al., Semin Immunol. (2017) 31:37-54; and Chiossone et al., NatRev Immunol. (2018) 18(11):671-688.

In some embodiments, one or more immune checkpoint inhibitors include protein (e.g., antibody or fragment thereof or antibody mimic) inhibitors of PD-L1 (CD274), PD-1 (PDCD1), or CTLA4. In some embodiments, one or more immune checkpoint inhibitors include small organic molecule inhibitors of PD-L1 (CD274), PD-1 (PDCD1), or CTLA4. In some embodiments, the small molecule inhibitor of CD274 or PDCD1 is selected from the group consisting of GS-4224, GS-4416, INCB086550, and MAX10181. In some embodiments, the small molecule inhibitor of CTLA4 includes BPI-002.

Examples of CTLA4 inhibitors that can be used co-administered include, but are not limited to: ipilimumab, trimemumab, BMS-986218, AGEN1181, AGEN1884, BMS-986249, MK-1308, REGN-4659, ADU-1604, CS-1002, BCD-145, APL-509, JS-007, BA-3071, ONC-392, AGEN-2041, JHL-1155, KN-044, CG-0161, and ATO. R-1144, PBI-5D3H5, BPI-002, and multispecific inhibitors FPT-155 (CTLA4/PD-L1/CD28), PF-06936308 (PD-1/CTLA4), MGD-019 (PD-1/CTLA4), KN-046 (PD-1/CTLA4), MEDI-5752 (CTLA4/PD-1), XmAb-20717 (PD-1/CTLA4), and AK-104 (CTLA4/PD-1).

Examples of PD-L1 (CD274) or PD-1 (PDCD1) inhibitors that can be co-administered include, but are not limited to, pembrolizumab, nivolumab, cimetizumab, pildizumab, AMP-224, MEDI0680 (AMP-514), spartazumab, atezolizumab, avelumab, durvalumab, BMS-936559, CK-301, PF-06801591, BGB-A317 (tislelizumab), GLS-010 (WBP-3055), AK-103 (HX-008), AK-105, CS-1003, HLX-10, MGA-012, and BI-7540. 91. AAGEN-2034, JS-001 (Toripalimab), JNJ-63723283, Genomeamarab (CBT-501), LZM-009, BCD-100, LY-3300054, SHR-1201, SHR-1210 (Camrelizumab), Sym-021, ABBV-181, PD1-PIK, BAT-1306 (MSB0010718C), CX-072, CBT-502, TSR-042 (Dotalimab), MSB-2311, JTX-4014, BGB-A333, SHR-1316, CS-1001 (WBP-315) 5. KN-035, IBI-308 (sintilimab), HLX-20, KL-A167, STI-A1014, STI-A1015 (IMC-001), BCD-135, FAZ-053, TQB-2450, MDX1105-01, GS-4224, GS-4416, INCB086550, MAX10181, and multispecific inhibitors FPT-155 (CTLA4/PD-L1/CD28), PF-06936308 (PD-1/CTLA4), MGD-013 (PD-1/LAG-3), FS-118 (LAG-3/PD-L 1)MGD-019(PD-1/CTLA4), KN-046(PD-1/CTLA4), MEDI-5752(CTLA4/PD-1), RO-7121661(PD-1/TIM-3), XmAb-20717(PD-1/CTLA4), AK-104(CT LA4/PD-1), M7824 (PD-L1/TGFβ-EC domain), CA-170 (PD-L1/VISTA), CDX-527 (CD27/PD-L1), LY-3415244 (TIM3/PDL1) and INBRX-105 (4-1BB/PDL1).

In some implementations, the agents described herein are combined with anti-TIGIT antibodies such as BMS-986207, RG-6058, and AAGEN-1307.

TNF receptor superfamily (TNFRSF) agonists or activators

In some embodiments, the agent as described herein is combined with an agonist of one or more members of the TNF receptor superfamily (TNFRSF), such agonists being one or more of the following: TNFRSF1A (NCBI gene ID: 7132), TNFRSF1B (NCBI gene ID: 7133), TNFRSF4 (OX40, CD134; NCBI gene ID: 7293), TNFRSF5 (CD40; NCBI gene ID: 958), TNFRSF6 (FAS, NCBI gene ID: 35... 5) TNFRSF7 (CD27, NCBI gene ID: 939), TNFRSF8 (CD30, NCBI gene ID: 943), TNFRSF9 (4-1BB, CD137, NCBI gene ID: 3604), TNFRSF10A (CD261, DR4, TRAILR1, NCBI gene ID: 8797), TNFRSF10B (CD262, DR5, TRAILR2, NCBI gene ID: 8795), TNFRSF10C (CD263, TRAILR3, ... TNFRSF10D (CD264, TRAILR4, NCBI gene ID: 8793), TNFRSF11A (CD265, RANK, NCBI gene ID: 8792), TNFRSF11B (NCBI gene ID: 4982), TNFRSF12A (CD266, NCBI gene ID: 51330), TNFRSF13B (CD267, NCBI gene ID: 23495), TNFRSF13C (CD268, NCBI gene ID: 8794), TNFRSF10D (CD264, TRAILR4, NCBI gene ID: 8793), TNFRSF11A (CD265, RANK, NCBI gene ID: 8792), TNFRSF11B (CD266, NCBI gene ID: 4982), TNFRSF12A (CD266, NCBI gene ID: 51330), TNFRSF13B (CD267, NCBI gene ID: 23495), TNFRSF13C (CD268, NCBI gene ID: 8794), TNFRSF10D (CD264, TRAILR4, NCBI gene ID: 8793), TNFRSF11A (CD265, RANK, NCBI gene ID: 8792), TNFRSF11B (CD268, NCBI gene ID: 4982), TNFRSF12A (CD266, NCBI gene ID: 51330), TNFRSF13B (CD267, NCBI gene ID: 23495), TNFRSF13C (CD268, NCBI gene ID: 8794), TNFRSF10D (CD264, TRAILR4, NCBI gene ID: 8793), D: 115650), TNFRSF16 (NGFR, CD271, NCBI gene ID: 4804), TNFRSF17 (BCMA, CD269, NCBI gene ID: 608), TNFRSF18 (GITR, CD357, NCBI gene ID: 8784), TNFRSF19 (NCBI gene ID: 55504), TNFRSF21 (CD358, DR6, NCBI gene ID: 27242) and TNFRSF25 (DR3, NCBI gene ID: 8718).

Examples of anti-TNFRSF4 (OX40) antibodies that can be administered co-administered include, but are not limited to, MEDI6469, MEDI6383, MEDI0562 (tavorizumab), MOXR0916, PF-04518600, RG-7888, GSK-3174998, INCAGN1949, BMS-986178, GBR-8383, ABBV-368, and those described in WO2016179517, WO2017096179, WO2017096182, WO2017096281, and WO2018089628.

Examples of anti-TNFRSF5 (CD40) antibodies that can be administered together include, but are not limited to, RG7876, SEA-CD40, APX-005M, and ABBV-428.

In some implementations, the anti-TNFRSF7 (CD27) antibody varigramab (CDX-1127) is co-administered.

Examples of anti-TNFRSF9 (4-1BB, CD137) antibodies that can be administered together include, but are not limited to, urinumab, urinumab (PF-05082566), AGEN2373, and ADG-106.

Examples of anti-TNFRSF18 (GITR) antibodies that can be co-administered include, but are not limited to, MEDI1873, FPA-154, INCAGN-1876, TRX-518, BMS-986156, MK-1248, GWN-323, and those described in WO2017096179, WO2017096276, WO2017096189, and WO2018089628. In some embodiments, antibodies or fragments thereof that co-target TNFRSF4 (OX40) and TNFRSF18 (GITR) are co-administered. Such antibodies are described, for example, in WO2017096179 and WO2018089628.

Bispecific and trispecific natural killer (NK) cell adaptors

In some embodiments, the agent as described herein is combined with a bispecific NK cell adaptor (BiKE) or a trispecific NK cell adaptor (TriKE) (e.g., without Fc) or a bispecific antibody against (e.g., with Fc) of: NK cell activation receptors, such as CD16A, C-type lectin receptors (CD94/NKG2C, NKG2D, NKG2E/H, and NKG2F), native cytotoxic receptors (NKp30, NKp44, and NKp46), cytotoxic cell C-type lectin-like receptors (NKp65, NKp80), Fc receptor FcγR (which mediates antibody-dependent cytotoxicity), SLAM family receptors (e.g., 2B4, SLAM6, and SLAM7), cytotoxic cell immunoglobulin-like receptors (KIR) (KIR-2DS and KIR-3DS), DNAM-1, and CD137 (41BB). Depending on the application, the anti-CD16 binding bispecific molecule may or may not have an Fc. Exemplary bispecific NK cell adjuvants that can be co-administered target CD16 and one or more HIV-associated antigens as described herein. BiKE and TriKE are described, for example, in the following literature: Felices et al., Methods Mol Biol. (2016) 1441:333–346; Fang et al., Semin Immunol. (2017) 31:37-54. Examples of trispecific NK cell adjuvants (TRiKE) include OXS-3550 and CD16-IL-15-B7H3TriKe.

Indoleamine-pyrrole-2,3-dioxygenase (IDO1) inhibitors

In some implementations, the agent as described herein is combined with an inhibitor of indoleamine 2,3-dioxygenase 1 (IDO1; NCBI gene ID: 3620). Examples of IDO1 inhibitors include, but are not limited to, BLV-0801, icardolstat, F-001287, GBV-1012, GBV-1028, GDC-0919, indomod, NKTR-218, NLG-919-based vaccines, PF-06840003, pyranoquinone derivatives (SN-35837), remixstat, SBLK-200802, BMS-986205, and shIDO-ST, EOS-200271, KHK-2455, and LY-3381916.

Toll-like receptor (TLR) agonists

In some embodiments, the agent as described herein is combined with an agonist of a toll-like receptor (TLR), such as an agonist of TLR1 (NCBI gene ID: 7096), TLR2 (NCBI gene ID: 7097), TLR3 (NCBI gene ID: 7098), TLR4 (NCBI gene ID: 7099), TLR5 (NCBI gene ID: 7100), TLR6 (NCBI gene ID: 10333), TLR7 (NCBI gene ID: 51284), TLR8 (NCBI gene ID: 51311), TLR9 (NCBI gene ID: 54106), and/or TLR10 (NCBI gene ID: 81793). Examples of TLR7 agonists that can be co-administered include, but are not limited to, AL-034, DSP-0509, GS-9620 (Vesamoxetine), LHC-165, TMX-101 (Imiquimod), GSK-2245035, Remiquimod, DSR-6434, DSP-3025, IMO-4200, MCT-465, MEDI-9197, 3M-051, SB-9922, 3M-052, Limtop, TMX-30X, TMX-202, RG-7863, RG-7854, and RG-779. 5, and US20100143301 (Gilead Sciences), US20110098248 (Gilead Sciences), and US20090047249 (Gilead Sciences), US20140045849(Janssen), US20140073642(Janssen), WO2014/056953(Janssen), WO2014/076221(Janssen), WO2014/128 189(Janssen)、US20140350031(Janssen)、WO2014/023813(Janssen)、US20080234251(Array Biopharma)、US200803060 50(Array Biopharma), US20100029585(VentirxPharma), US20110092485(Ventirx Pharma), US20110118235(Ventirx P Compounds disclosed in harma, US20120082658 (Ventirx Pharma), US20120219615 (Ventirx Pharma), US20140066432 (Ventirx Pharma), US20140088085 (Ventirx Pharma), US20140275167 (Novira Therapeutics), and US20130251673 (Novira Therapeutics). TLR7/TLR8 agonists that can be co-administered are NKTR-262, Tramod, and BDB-001. Examples of TLR8 agonists that can be co-administered include, but are not limited to, E-6887, IMO-4200, IMO-8400, IMO-9200, MCT-465, MEDI-9197, motolimod, remiquimod, GS-9688, VTX-1463, VTX-763, 3M-051, 3M-052, and US20140045849 (Janssen), US20140073642 (Janssen), WO2014/056953 (Janssen), WO2014/076221 (Janssen), WO2014/128189 (Janssen), US20140350031 (Janssen), WO2014/023813 (Janssen), and US20080234251 (Array Biopharma). The compounds disclosed in US20080306050 (Array Biopharma), US20100029585 (Ventirx Pharma), US20110092485 (Ventirx Pharma), US20110118235 (Ventirx Pharma), US20120082658 (Ventirx Pharma), US20120219615 (Ventirx Pharma), US20140066432 (Ventirx Pharma), US20140088085 (Ventirx Pharma), US20140275167 (Novira Therapeutics), and US20130251673 (Novira Therapeutics). Examples of TLR9 agonists that can be used in combination include, but are not limited to, AST-008, cobitolimod, CMP-001, IMO-2055, IMO-2125, litenimod, MGN-1601, BB-001, BB-006, IMO-3100, IMO-8400, IR-103, IMO-9200, agatolimod, DIMS-9054, DV-1079, DV-1179, AZD-1419, lefitolimod (MGN-1703), CYT-003, CYT-003-QbG10, tilsotolimod, and PUL-042. Examples of TLR3 agonists include rapamod, polyICLC, apoxxim, IPH-33, MCT-465, MCT-475, and ND-1.1. Examples of TLR4 agonists include G-100 and GSK-1795091.

STING agonists, RIG-I and NOD2 modulators

In some embodiments, the agents described herein are combined with interferon gene stimulators (STING). In some embodiments, the STING receptor agonist or activator is selected from the group consisting of ADU-S100 (MIW-815), SB-11285, MK-1454, SR-8291, AdVCA0848, GSK-532, SYN-STING, MSA-1, SR-8291, 5,6-dimethylxanthonone-4-acetic acid (DMXAA), cyclic GAMP (cGAMP), and cyclic diAMP. In some embodiments, the agents described herein are combined with RIG-1 regulators (such as RGT-100) or NOD2 regulators (such as SB-9200 and IR-103).

LAG-3 and TIM-3 inhibitors

In some implementations, the agents described herein are combined with anti-TIM-3 antibodies such as TSR-022, LY-3321367, MBG-453, and INCAGN-2390.

In some implementations, the antibody or antigen-binding fragment described herein is combined with an anti-LAG-3 (lymphocyte activation) antibody (such as relatlimab (ONO-4482), LAG-525, MK-4280, REGN-3767, INCAGN2385).

Interleukin agonists

In some embodiments, the pharmaceutical agent as described herein is combined with the following substances: interleukin agonists (such as IL-2, IL-7, IL-15, IL-10, IL-12); examples of IL-2 agonists, such as proleukin (aldeleukin, IL-2); pegylated IL-2 (e.g., NKTR-214); modified variants of IL-2 (e.g., THOR-707), bepepedin, AIC-284, ALKS-42. 30. CUI-101, Neo-2/15; Examples of IL-15 agonists include ALT-803, NKTR-255 and hetIL-15, interleukin-15/Fc fusion protein, AM-0015, NIZ-985, SO-C101, IL-15 Synthorin (PEGylated IL-15), P-22339 and IL-15-PD-1 fusion protein N-809; Examples of IL-7 include CYT-107.

Examples of other immunotherapy-based treatments that can be combined with the agents disclosed herein include interferon α; interferon α-2b; interferon α-n3; pegylated interferon α; interferon γ; Flt3 agonist; gepon; nomfullon, pegylated interferon α-2a, pegylated interferon α-2b, RPI-MN.

Phosphatidylinositol 3-kinase (PI3K) inhibitors

In some embodiments, the pharmaceutical agents described herein are combined with PI3K inhibitors. Examples of PI3K inhibitors that can be combined with the pharmaceutical agents disclosed herein include idelalisib, alpelisib, buparlisib, orotic acid (CAI), copanlisib, duvelisib, gedatolisib, neratinib, panulisib, perifoxine, pictilisib, pilaralisib, praquitinib mesylate, regoratinib, regoratinib sodium, sonolisib, and tasellixib. isib), AMG-319, AZD-8186, BAY-1082439, CLR-1401, CLR-457, CUDC-907, DS-7423, EN-3342, GSK-2126458, GSK-2269577, GSK-2636771, INCB-040093 , LY-3023414, MLN-1117, PQR-309, RG-7666, RP-6530, RV-1729, SAR-245409, SAR-260301, SF-1126, TGR-1202, UCB-5857, VS-5584, XL-765 and ZSTK-474.

α-4/β-7 antagonists

In some embodiments, the agents described herein are combined with α-4/β-7 antagonists. Examples of integrin α-4/β-7 antagonists that can be combined with the agents disclosed herein include PTG-100, TRK-170, abrilumab, etrolizumab, carotegrast methyl, and vedolizumab.

HIV-targeted antibody

Examples of HIV antibodies, bispecific antibodies, and “antibody-like” therapeutic proteins that can be combined with the pharmaceutical agents disclosed herein include Fab derivatives, bNAb (broadly neutralizing HIV-1 antibody), TMB-360, and those antibodies targeting HIV gp120 or gp41, HIV-targeting antibody recruitment molecules, anti-CD63 monoclonal antibodies, anti-GB virus C antibodies, anti-GP120/CD4, CCR5 bispecific antibodies, anti-Nef single-domain antibodies, anti-Rev antibodies, camelid-derived anti-CD18 antibodies, camelid-derived anti-ICAM-1 antibodies, DCVax-001, gp140-targeting antibodies, gp41-based HIV therapeutic antibodies, recombinant human mAb (PGT-121), ibalizumab, Immuglo, and MB-66.

Various bNAbs are known in the art and can be used in this invention. Examples include, but are not limited to, U.S. Patent Nos. 8,673,307, 9,493,549, 9,783,594, WO2014/063059, WO2012/158948, WO2015/117008, PCT/US2015/41272, and WO2017/096221, including antibodies 12A12, 12A21, and NIH45-4. 6. bANC131, 8ANC134, IB2530, INC9, 8ANC195, 8ANC196, 10-259, 10-303, 10-410, 10-847, 10-996, 10-1074, 10-1121, 10-1130, 10-1146, 10-1341, 10-1369 and 10-1074GM. Other examples include those described in the following literature: Klein et al., Nature, 492(7427):118-22 (2012); Horwitz et al., Proc Natl AcadSci U S A, 110(41):16538-43 (2013); Scheid et al., Science, 333:1633-1637 (2011); Scheid et al., Nature, 458:636-640 (2009); Eroshkin et al., Nucleic Acids Res., 42(Database issue):Dl 133-9 (2014); Mascola et al., Immunol Rev., 254(l):225-44 (2013), such as 2F5, 4E10, M66.6, CAP206-CH12, 10E81 (all of which bind to gp41 MPER); PG9, PG16, CH01-04 (all of which bind to V1V2-glycans), 2G12 (which binds to the outer domain glycan); b12, HJ16, CH103-106, VRC01-03, VRC-PG04, 04b, VRC-CH30-34, 3BNC62, 3BNC89, 3BNC91, 3BNC95, 3BNC104, 3BNC176 and 8ANC131 (all of which bind to the CD4 binding site).

Further broadly neutralizing antibodies that can be used as a second therapeutic agent in combination therapy are described, for example, in U.S. Patent Nos. 8,673,307, 9,493,549, 9,783,594, and WO 2012/154312, WO2012/158948, WO 2013/086533, WO 2013/142324, WO2014/063059, WO 2014/089152, WO 2015/0 The following references are incorporated herein by reference in their entirety for all purposes: WO 2015/103549, WO 2015/117008, WO 2016/014484, WO 2016/154003, WO 2016/196975, WO 2016/149710, WO 2017/096221, WO 2017/133639, and WO 2017/133640. Other examples include those described in the following literature: Sajadi et al., Cell. (2018) 173(7): 1783-1795; Sajadi et al., J Infect Dis. (2016) 213(1): 156-64; Klein et al., Nature, 492(7427): 118-22 (2012); Horwitz et al., Proc Natl Acad Sci U S A, 110(41): 16538-43 (2013); Scheid et al., Science, 333: 1633-1637 (2011); S Cheid et al., Nature, 458:636-640 (2009); Eroshkin et al., Nucleic Acids Res., 42(Database issue): DL 133-9 (2014); Mascola et al., Immunol Rev., 254(l):225-44 (2013), such as 2F5, 4E10, M66.6, CAP206-CH12, 10E8, 10E8v4, 10E8-5R-100cF, DH511.11P, 7b2 and LN01 (all of which are bound to gp41 MPER).

Other examples of antibodies include bavituximab, UB-421, BF520.1, CH01, CH59, C2F5, C4E10, C2F5+C2G12+C4E10, 3BNC117, 3BNC117-LS, 3BNC60, DH270.1, DH270.6, D1D2, 10-1074-LS, GS-9722, DH411-2, BG18, PGT145, PGT121, PGT-121.60, PGT-121.66, PGT122, PGT-123, PGT-124, PGT-125, PGT-126, PGT-151, PGT -130, PGT-133, PGT-134, PGT-135, PGT-128, PGT-136, PGT-137, PGT-138, PGT-139, MDX010 (Ipilimumab), DH511, DH511-2, N6, N6LS, N49P6, N49P7, N49P7.1, N49P9, N49P11, N60P1.1, N60P25.1, N60P2.1, N60P31.1, N60P22, NIH45-46, PGC14, PGG14, PGT-142, PGT-143, PGT-144, PGDM1400, PGDM12, PGDM21 PCDN-33A, 2Dm2m, 4Dm2m, 6Dm2m, PGDM1400, MDX010 (Ipilimumab), VRC01, VRC-01-LS, A32, 7B2, 10E8, VRC-07-523, VRC07-523LS, VRC24, VRC41.01, 10E8VLS, 3810109, 10E8v4, IMC-HIV, iMabm36, eCD4-Ig, IOMA, CAP256-VRC26.25, DRVIA7, VRC-HIVMAB080-00-AB, VRC-HIVMAB060-00-AB, P2G12, VRC07, 354 BG8, 354BG18, 354BG42, 354BG33, 354BG129, 354BG188, 354BG411, 354BG426, VRC29.03, CAP256, CAP256-VRC26.08, CAP256-VRC26.09, CAP256-VRC26.25, PCT64-24E and VRC38.01, PGT-151, CAP248-2B, 35O22, ACS202, VRC34 and VRC34.01, 10E8, 10E8v4, 10E8-5R-100cF, 4E10, DH511.11P, 2F5, 7b2 and LN01.

Examples of HIV bispecific and trispecific antibodies include MGD014, B12BiTe, TMB-bispecific, SAR-441236, VRC-01/PGDM-1400/10E8v4, 10E8.4/iMab, and 10E8v4/PGT121-VRC01.

Examples of in vivo delivered bNAb include AAV8-VRC07; mRNA encoding the anti-HIV antibody VRC01; and engineered B cells encoding 3BNC117 (Hartweger et al., J. Exp. Med. 2019, 1301).

Pharmacokinetic enhancers

In some embodiments, the pharmaceutical agents described herein are combined with pharmacokinetic enhancers. Examples of pharmacokinetic enhancers that can be combined with the pharmaceutical agents disclosed herein include cobistat and ritonavir.

Additional treatment

Examples of other HIV treatment agents that can be combined with the agents disclosed herein include WO 2004/096286 (Gilead Sciences), WO 2006/015261 (Gilead Sciences), WO 2006/110157 (Gilead Sciences), WO2012/003497 (Gilead Sciences), WO 2012/003498 (Gilead Sciences), WO 2012/145728 (Gilead Sciences), WO 2013/006738 (Gilead Sciences), WO 2013/159064 (Gilead Sciences), WO 2014/100323 (Gilead Sciences), and US 2013/0 Compounds disclosed in WO 2009/062285 (University of Pennsylvania), US 2014/0221378 (Japan Tobacco), US 2014/0221380 (Japan Tobacco), WO 2009/062285 (Boehringer Ingelheim), WO 2010/130034 (Boehringer Ingelheim), WO 2013/006792 (Pharma Resources), US 20140221356 (Gilead Sciences), US 20100143301 (Gilead Sciences), and WO 2013/091096 (Boehringer Ingelheim).

HIV vaccine

In some embodiments, the agents described herein are combined with HIV vaccines. Examples of HIV vaccines that can be combined with the agents disclosed herein include peptide vaccines, recombinant subunit protein vaccines, live vector vaccines, DNA vaccines, CD4-derived peptide vaccines, vaccine combinations, adenovirus vector vaccines (adenovirus vectors, such as Ad5, Ad26, or Ad35), simian adenovirus (chimpanzee, gorilla, rhesus monkey, i.e., rhAd), adeno-associated virus vector vaccines, chimpanzee adenovirus vaccines (e.g., ChAdOX1, ChAd68, ChAd3, ChAd63, ChAd83, ChAd155, ChAd157, Pan5, Pan6, Pan7, Pan9), Coxsackievirus-based vaccines, enterovirus-based vaccines, gorilla adenovirus vaccines, lentiviral vector-based vaccines, arenavirus vaccines (such as LCMV, Pittend), arenavirus-based vaccines with two or three segments, measles virus-based vaccines, flavivirus-based vaccines, and tobacco-based vaccines. Vaccines based on mosaic virus vectors, varicella-zoster virus, human parainfluenza virus 3 (PIV3), poxvirus-based vaccines (modified vaccinia virus Ankara (MVA), orthopox virus-derived NYVAC, and fowlpox virus-derived ALVAC (canarypox virus) strains); fowlpox virus-based vaccines, rhabdovirus-based vaccines such as VSV and Malabar virus; recombinant human CMV (rhCMV)-based vaccines, alphavirus-based vaccines such as Simelik Forest virus, Venezuelan equine encephalitis virus, and Sindbis virus; (see Lauer, Clinical and Vaccine Immunology, 2017, DOI:10.1128/CVI.00298-16); LNP-formulated mRNA-based therapeutic vaccines; LNP-formulated self-replicating RNA/self-amplifying RNA vaccines.

Examples of vaccines include: rgp120 (AIDSVAX), ALVAC HIV (vCP1521)/AIDSVAX B/E (gp120) (RV144), monomeric gp120 HIV-1C subtype vaccine, Remune, ITV-1, Contre Vir, Ad5-ENVA-48, DCVax-001 (CDX-2401), Vacc-4x, Vacc-C5, VAC-3S, multi-level DNA recombinant adenovirus-5 (rAd5), and rAd5gag-po Lenv A/B/C vaccine, Pennvax-G, Pennvax-GP, Pennvax-G/MVA-CMDR, HIV-TriMix-mRNA vaccine, HIV-LAMP-vax, Ad35, Ad35-GRIN, NAcGM3/VSSP ISA-51, poly-ICLC adjuvant vaccines, TatImmune, GTU-multiHIV (FIT-06), gp140[delta]V2.TV1+MF-59, rVSVIN HIV-1 gag vaccine, SeV-Gag vaccine, AT-20, DNK-4, ad35-Grin/ENV, TBC-M4, HIVAX, HIVAX-2, NYVAC-HIV-PT1, NYVAC-HIV-PT4, DNA-HIV-PT123, rAAV1-PG9DP, GOVX-B11, GOVX-B21, TVI-HIV-1, Ad-4 (Ad4-env CladeC+Ad4-mGag), Paxvax, EN41-UGR7 C, EN41-FPA2, PreVaxTat, AE-H, MYM-V101, CombiHIVvac, ADVAX, MYM-V201, MVA-CMDR, DNA-Ad5 gag/pol/nef/nev (HVTN505), MVATG-17401, ETV-01, CDX-1401, rcAD26.MOS1.HIV-Env, Ad26.Mod.HIV vaccine, Ad26.Mod.HIV+MVA mosaic vaccine+gp140, A GS-004, AVX-101, AVX-201, PEP-6409, SAV-001, ThV-01, TL-01, TUTI-16, VGX-3300, IHV-001 and virus-like particle vaccines (such as pseudovirus vaccines), CombiVICHvac, LFn-p24 B/C fusion vaccines, GTU-based DNA vaccines, HIV gag/pol/nef/env DNA vaccines, anti-TAT HIV vaccines, conjugated peptide vaccines, dendritic cell vaccines (such as DermaV) ir), gag-based DNA vaccines, GI-2010, gp41 HIV-1 vaccine, HIV vaccine (PIKA adjuvant), i-key/MHC class II epitope heterozygous peptide vaccine, ITV-2, ITV-3, ITV-4, LIPO-5, multi-stage Env vaccine, MVA vaccine, Pennvax-GP, pp71 defective HCMV vector HIV gag vaccine, rgp160 HIV vaccine, RNActive HIV vaccine, SCB-703, Tat Oyi vaccine, TBC-M 4. UBI HIV gp120, Vacc-4x + Romidesin, variant gp120 peptide vaccine, rAd5gag-pol env A/B/C vaccine, DNA.HTI and MVA.HTI, VRC-HIVDNA016-00-VP + VRC-HIVADV014-00-VP, INO-6145, JNJ-9220, gp145 C.6980; eOD-GT8 60-mer-based vaccine, PD-201401, env(A, B, C, A/E)/g ag(C) DNA vaccine, gp120 (A, B, C, A/E) protein vaccine, PDPHV-201401, Ad4-EnvCN54, EnvSeq-1 Envs HIV-1 vaccine (GLA-SE adjuvant), HIV p24gag original-boost plasmid DNA vaccine, arenavirus vector-based vaccines (Vaxwave, TheraT), MVA-BN HIV-1 vaccine regimen, UBI HIV gp120, mRNA-based prophylactic vaccines, and TBL-1203HI.

Birth control (contraceptive pill) combination therapy

In some embodiments, the agents described herein are combined with contraceptive or sterilization protocols. Therapeutic agents for contraception that can be combined with the agents disclosed herein include cyproterone acetate, desogestrel, dinogest, drospirenone, estradiol valerate, ethinylestradiol, norethindrone, etoposide, levonorgestrel, levonorgestrel, linegestrel, medroxyprogesterone acetate, ethinylestradiol methyl ether, mifepristone, misoprostol, nomenoprogesterone acetate, nomedroxyprogesterone acetate, norethindrone, norgestrel, olmexifen, sigmason acetate, ulipristal acetate, and any combination thereof.

In some embodiments, the pharmaceutical agents disclosed herein or their pharmaceutically acceptable salts are combined with one, two, three, four or more adjunctive therapeutic agents selected from the following: (efavirenz, tenofovir disoproxil fumarate and emtricitabine); (rilpivirine, tenofovir disoproxil fumarate and emtricitabine); (ertirapvir, cobistat, tenofovir disoproxil fumarate and emtricitabine); (tenofovir disoproxil fumarate and emtricitabine; TDF+FTC); (tenofovir alafenamide and emtricitabine); (tenofovir alafenamide, emtricitabine and rilpivirine) Pivirine); (tenofovir alafenamide, emtricitabine, cobistat and ertirapvir); BIKTARVY (bicagvir + emtricitabine + tenofovir alafenamide), adefovir; adefovir dipivoxil; cobistat; emtricitabine; tenofovir; tenofovir disoproxil fumarate; tenofovir disoproxil fumarate; tenofovir alafenamide; tenofovir alafenamide hemifumarate; (durutexvir, abacavir and lamivudine); dulutexvir, abacavir sulfate and lamivudine; retigvir; retigvir and lamivudine; maraviro; enfuvirtide; (lopina) (Rizonavir and ritonavir); (Zidovudine and lamivudine; AZT+3TC); (Abacavir sulfate and lamivudine; ABC+3TC); (Abacavir sulfate, Zidovudine and lamivudine; ABC+AZT+3TC); Rilpivirine; Rilpivirine hydrochloride; Atazanavir sulfate and cobistat; Atazanavir and cobistat; Duriravir and cobistat; Atazanavir; Atazanavir sulfate; Dulutevir; Ertiravir; Ritonavir; Atazanavir sulfate and ritonavir; Duriravir; Lamivudine; Prandine; Fosanavir; Fosanavir calcium efavirenz; Etridiazole Venin; Nefenavir; Nefenavir mesylate; Interferon; Didanoxin; Stavudine; Indinavir; Indinavir sulfate; Tenofovir and Lamivudine; Zidovudine; Nevirapine; Saquinavir; Saquinavir mesylate; Aldehyde; Zacitabine; Telanavir; Ampravir; Delavudine; Delavudine mesylate; Radha-108 (receptor alcohol); Lamivudine and Tenofovir disoproxil fumarate; Efavirex, Lamivudine and Tenofovir disoproxil fumarate; Aziphosphonate; Lamivudine, Nevirapine and Zidovudine; Abacavir; and Abacavir sulfate.

In some embodiments, the pharmaceutical agents or pharmaceutical compositions thereof disclosed herein are combined with HIV nucleoside or nucleotide inhibitors of reverse transcriptase and HIV non-nucleoside inhibitors of reverse transcriptase. In another specific embodiment, the pharmaceutical agents or pharmaceutical compositions thereof disclosed herein are combined with HIV nucleoside or nucleotide inhibitors of reverse transcriptase and HIV protease inhibitory compounds. In further embodiments, the pharmaceutical agents or pharmaceutical compositions thereof disclosed herein are combined with HIV nucleoside or nucleotide inhibitors of reverse transcriptase, HIV non-nucleoside inhibitors of reverse transcriptase, and pharmacokinetic enhancers. In some embodiments, the pharmaceutical agents or pharmaceutical compositions thereof disclosed herein are combined with at least one HIV nucleoside inhibitor of reverse transcriptase, an integrase inhibitor, and a pharmacokinetic enhancer. In some embodiments, the pharmaceutical agents or pharmaceutical compositions thereof disclosed herein are combined with two HIV nucleoside or nucleotide inhibitors of reverse transcriptase.

In some embodiments, the pharmaceutical agents or pharmaceutical compositions disclosed herein are combined with abacavir sulfate, tenofovir, tenofovir disoproxil fumarate, tenofovir disoproxil fumarate, tenofovir disoproxil fumarate, tenofovir alafenamide, or tenofovir alafenamide fumarate.

In some embodiments, the pharmaceutical agents or pharmaceutical compositions disclosed herein are combined with tenofovir, tenofovir disoproxil fumarate, tenofovir disoproxil fumarate, tenofovir alafenamide, or tenofovir alafenamide hemifumarate.

In some embodiments, the pharmaceutical agent or pharmaceutical composition disclosed herein is combined with a first adjunctive therapy and a second adjunctive therapy, the first adjunctive therapy being selected from the group consisting of abacavir sulfate, tenofovir, tenofovir disoproxil fumarate, tenofovir alafenamide, and tenofovir alafenamide hemifumarate, and the second adjunctive therapy being selected from the group consisting of emtricitabine and lamivudine.

In some embodiments, the pharmaceutical agent or pharmaceutical composition disclosed herein is combined with a first adjunctive therapeutic agent and a second adjunctive therapeutic agent, the first adjunctive therapeutic agent being selected from the group consisting of tenofovir, tenofovir disoproxil fumarate, tenofovir disoproxil fumarate, tenofovir alafenamide and tenofovir alafenamide hemifumarate, wherein the second adjunctive therapeutic agent is emtricitabine.

In some embodiments, the pharmaceutical agent or pharmaceutical composition thereof as described herein is combined with a first adjunctive therapeutic agent (contraceptive), the first adjunctive therapeutic agent being selected from the group consisting of: cyproterone acetate, desogestrel, dinogest, drospirenone, estradiol valerate, ethinylestradiol, norethindrone, etoposide, levonorgestrel, levofloxacin, levonorgestrel, linegestrel, medroxyprogesterone acetate, ethinylestradiol methyl ether, mifepristone, misoprostol, normethylenediamine acetate, norethindrone, norgestrel, olmexifen, sigmason acetate, ulipristal acetate, and any combination thereof.

Gene therapy and cell therapy

In some embodiments, the agents described herein are combined with gene therapy or cell therapy regimens. Gene therapy and cell therapy include, but are not limited to, gene modifications that silence genes; gene methods that directly kill infected cells; infusion of immune cells designed to replace a large portion of the patient's own immune system to enhance the immune response to infected cells, or to activate the patient's own immune system to kill infected cells, or to locate and kill infected cells; and gene methods that modify cell activity to further alter the endogenous immune response to infection. Examples of dendritic cell therapy include AGS-004. CCR5 gene editing agents include SB-728T. CCR5 gene inhibitors include Cal-1. In some embodiments, CD4-positive T cells expressing C34-CCR5/C34-CXCR4 are co-administered with one or more multispecific antigen-binding molecules. In some embodiments, the agents described herein are co-administered with AGT-103-transduced autologous T cell therapy or AAV-eCD4-Ig gene therapy.

Gene editor

In some embodiments, the agents described herein are combined with a gene editor (e.g., an HIV-targeted gene editor). In some embodiments, the genome editing system may be selected from the group consisting of: CRISPR/Cas9 complexes, zinc finger nuclease complexes, TALEN complexes, homing endonuclease complexes, and broad-spectrum nuclease complexes. Exemplary HIV-targeted CRISPR/Cas9 systems include, but are not limited to, EBT-101.

CAR-T cell therapy

In some embodiments, the agents described herein may be co-administered with a population of immune effector cells engineered to express a chimeric antigen receptor (CAR), wherein the CAR contains an HIV antigen-binding domain. The HIV antigen includes an HIV envelope protein or a portion thereof, gp120 or a portion thereof, a CD4 binding site on gp120, a CD4-induced binding site on gp120, a N-glycan on gp120, V2 of gp120, and a proximal membrane region on gp41. The immune effector cells are T cells or NK cells. In some embodiments, the T cells are CD4+ T cells, CD8+ T cells, or a combination thereof. The cells may be autologous or allogeneic. Examples of HIV CAR-T include VC-CAR-T, CMV-N6-CART, anti-CD4 CAR-T cell therapy, CD4 CAR+C34-CXCR4+CCR5 ZFN T cells, and autologous hematopoietic stem cells genetically engineered to express CD4 CAR and C46 peptide.

TCR-T cell therapy

In some implementations, the agents described herein are combined with a population of TCR-T cells. The TCR-T cells are engineered to target HIV-derived peptides, such as ImmTAV, present on the surface of virus-infected cells.

B-cell therapy

In some embodiments, the antibody or antigen-binding fragment described herein is combined with a population of B cells that has been genetically modified to express a broadly neutralizing antibody, such as 3BNC117 (Hartweger et al., J. Exp. Med. 2019, 1301; Moffett et al., Sci. Immunol. 4, eaax0644 (2019), May 17, 2019).

3. Hepatitis B virus

Examples of other medications used to treat HBV include alpha-hydroxytophenone, amdoxovir, antroquinonol, beta-hydroxycytosine nucleoside, ARB-199, CCC-0975, ccc-R08, evitabine, ezetimibe, cyclosporine A, gentianin, HH-003, hepalatide, JNJ-56136379, nitrozonide, birenapa, NJK14047, NOV-205 (molixan, BAM-205), oligonucleotides, mirtovalidone, feron, and GST-HG-131. Levamisole, Ka Shu Ning, alloferon, WS-007, Y-101(Ti Fen Tai), rSIFN-co, PEG-IIFNm, KW-3, BP-Inter-014, caryophyllin, HepB-nRNA, cTP-5(r TP-5), HSK-II-2, HEISCO-106-1, HEISCO-106, Hepbarna, IPBB-006IA, Hepuyinfen, DasKloster 0014-01, ISA-204, Jiangantai (Gan xikang), MIV-210, OB-AI-004, PF-06, berberine, DasKloster-0039, hepulantai, IMB-2613, TCM-800B, reduced glutathione, RO-6864018, RG-7834, QL-007 sofosbuvir, ledipasvir, UB-551 and ZH-2N, and US20150210682 (Roche), US 2016/0122344 (Roche), WO2015173164, WO2016023877, US201525205 The compounds disclosed in 7A (Roche), WO16128335A1 (Roche), WO16120186A1 (Roche), US2016237090A (Roche), WO16107833A1 (Roche), WO16107832A1 (Roche), US2016176899A (Roche), WO16102438A1 (Roche), WO16012470A1 (Roche), US2016220586A (Roche) and US2015031687A (Roche).

HBV vaccine

HBV vaccines include both preventative and therapeutic vaccines. Examples of HBV preventative vaccines include Vaxelis, Hexaxim, Heplisav, Mosquirix, DTwP-HBV vaccine, Bio-Hep-B, D/T/P/HBV/M (LBVP-0101; LBVW-0101), DTwP-Hepb-Hib-IPV vaccine, Heberpenta L, DTwP-HepB-Hib, V-419, CVI-HBV-001, Tetrabhay, and the Hepatitis B prophylactic vaccine (Advax Super D). atrol-07, GSK-223192A, ENGERIX recombinant hepatitis B vaccine (intramuscular injection, Kangtai Biological Products), recombinant hepatitis B vaccine (Hansenula polymorpha yeast, intramuscular injection, Hualan Biological Engineering), recombinant hepatitis B surface antigen vaccine, Bimmugen, CARG-101, Eufovac, Eutravac, anrix-DTaP -IPV-Hep B, HBAI-20, Infanrix-DTaP-IPV-Hep B-Hib, Pentabio Vaksin DTP-HB-Hib, Comvac4, Twinrix, Euvax-B, Trit anrix HB, Infanrix Hep B, Comvax, DTP-Hib-HBV vaccine, DTP-HBV vaccine, Yi Tai, Heberbiovac HB, Trivac HB, GerVax, DTwP-Hep B-Hib vaccine, Bilive, Hepavax-Gene, SUPERVAX, Comvac5, Shanvac-B, Hebsulin, Recombivax HB, Revac B mcf, Revac B+, Fendrix, DTwP-HepB-Hib, DNA-001, Shan5, Shan6, rhHBsAG vaccine, HBI pentavalent vaccine, LBVD, Infanrix HeXa, YS-HBV-001 and DTaP-rHB-Hib vaccine.

Examples of therapeutic HBV vaccines include HBsAG-HBIG complex, ARB-1598, Bio-Hep-B, NASVAC, abi-HB (intravenous), ABX-203, Tetrabhay, GX-110E, GS-4774, peptide vaccine (εPA-44), Hepatrol-07, NASVAC (NASTERAP), IMP-321, BEVAC, Revac B mcf, Revac B+, MGN-1333, KW-2, CVI-HBV-002, AltraHepB, VGX-6200, FP-02, FP-02.2 (HepTcell), NU-500, HBVax, im/TriGrid/antigen vaccine, Mega-C D40L-adjuvanted vaccine, HepB-v, RG7944 (INO-1800), recombinant VLP-based therapeutic vaccines (HBV infection, VLP Biotech), AdTG-17909, AdTG-17910, AdTG-18202, ChronVac-B, TG-1050, VVX-001, GSK-3528869A (ChAd155-hli-HBV+MVA-HBV+Hbc-HBs/AS01B-4), VBI-2601, VTP-300 (ChAdOx1-SIi-HBV-CPmut-TPA-Ssh prime and MVA-SIi-HBV-CPmut-TPA-Ssh boost), MVA-BN, and Lm HBV. HBV isovirus vaccines are described, for example, in WO2017076988 and WO2017198726.

HBV DNA polymerase inhibitor

Examples of HBV DNA polymerase inhibitors include adefovir emtricitabine, tenofovir disoproxil fumarate, tenofovir alafenamide, tenofovir, tenofovir disoproxil fumarate, tenofovir alafenamide fumarate, tenofovir alafenamide hemifumarate, tenofovir alafenamide diterpenoid, tenofovir alafenamide diterpenoid, tenofovir octadecyloxyethyl ester, CMX-157, and tenofovir alafenamide (tenofovirexalidex). Besifovir, Entecavir Maleate, Telbivudine Felosivir, Pradefovir, Clavudine, Ribavirin, Lamivudine Azide, Famciclovir, Fusolin, Metacavir, SNC-019754, FMCA, AGX-1009, AR-II-04-26, HIP-1302, Tenofovir Disoproxil Flavoxate, Tenofovir Disoproxil Flavoxate, and HS-10234.

Immunomodulators

Examples of immunomodulators include rapamod, amidoline hydrochloride, ingaron, dermaVir, hydroxychloroquine, prazolam, hydroxyurea, mycophenolate mofetil (MPA) and its ester derivative mycophenolate mofetil (MMF), JNJ-440, WF-10, AB-452, ribavirin, IL-12, INO-9112, polymeric polyethyleneimine (PEI), Gepon, VGV-1, MOR-22, CRV-431, JNJ-0535, TG-1050, ABI-H2158, BMS-936559, GS-9688, RO-7011785, RG-7854, RO-6871765, AIC-649, and IR-103.

Toll-like receptor (TLR) agonists

In some embodiments, the agent as described herein is combined with an agonist of a toll-like receptor (TLR), such as an agonist of TLR1 (NCBI gene ID: 7096), TLR2 (NCBI gene ID: 7097), TLR3 (NCBI gene ID: 7098), TLR4 (NCBI gene ID: 7099), TLR5 (NCBI gene ID: 7100), TLR6 (NCBI gene ID: 10333), TLR7 (NCBI gene ID: 51284), TLR8 (NCBI gene ID: 51311), TLR9 (NCBI gene ID: 54106) and/or TLR10 (NCBI gene ID: 81793), TLR11, TLR12 and TLR13.

Examples of TLR3 modifiers include rapamod, polyICLC, Apoxxim, IPH-33, MCT-465, MCT-475, and ND-1.1.

Examples of TLR4 agonists include G-100 and GSK-1795091.

Examples of TLR7 agonists that can be co-administered include, but are not limited to, AL-034, DSP-0509, GS-9620 (Vesamoxetine), LHC-165, TMX-101 (Imiquimod), GSK-2245035, Remiquimod, DSR-6434, DSP-3025, IMO-4200, MCT-465, MEDI-9197, 3M-051, SB-9922, 3M-052, Limtop, TMX-30X, TMX-202, RG-7863, RG-7854, and RG-779. 5, and US20100143301 (Gilead Sciences), US20110098248 (GileadSciences), and US20090047249 (Gilead Sciences), U S20140045849(Janssen), US20140073642(Janssen), WO2014/056953(Janssen), WO2014/076221(Janssen), WO2014/1281 89(Janssen), US20140350031(Janssen), WO2014/023813(Janssen), US20080234251(Array Biopharma), US2008030605 0(Array Biopharma)、US20100029585(VentirxPharma)、US20110092485(Ventirx Pharma)、US20110118235(Ventirx Ph The compounds disclosed in US20120082658 (Ventirx Pharma), US20120219615 (Ventirx Pharma), US20140066432 (Ventirx Pharma), US20140088085 (Ventirx Pharma), US20140275167 (NoviraTherapeutics), and US20130251673 (NoviraTherapeutics).

The TLR7/TLR8 agonists that can be used together are NKTR-262, Tramod, and BDB-001.

Examples of TLR8 agonists that can be co-administered include, but are not limited to, E-6887, IMO-4200, IMO-8400, IMO-9200, MCT-465, MEDI-9197, motolimod, resqualide, selgantolimod (GS-9688), VTX-1463, VTX-763, 3M-051, 3M-052, ZG-170607, and those listed in US20140045849 (Janssen) and US20140073642 (Janssen). WO2014/056953(Janssen), WO2014/076221(Janssen), WO2014/128189(Janssen), US20140350031(Janssen), WO2014/023813( Janssen), US20080234251 (Array Biopharma), US20080306050 (Array Biopharma), US20100029585 (VentirxPharma), US20110 092485 (Ventirx Pharma), US20110118235 (Ventirx Pharma), US20120082658 (Ventirx Pharma), US20120219615 (Ventirx P harma), US20140066432 (Ventirx Pharma), US20140088085 (Ventirx Pharma), US20140275167 (Novira Therapeutics) and US2013 The compounds disclosed in 0251673 (Novira Therapeutics), US Patent No. 9670205 (Gilead Sciences, Inc.), US 20160289229 (Gilead Sciences, Inc.), WO2017/048727 (Gilead Sciences, Inc.), US 20180065938 (Gilead Sciences, Inc.), and US 20180086755 (Gilead Sciences, Inc.).

Examples of TLR9 agonists that can be used in combination include, but are not limited to, AST-008, cobitolimod, CMP-001, IMO-2055, IMO-2125, litenimod, MGN-1601, BB-001, BB-006, IMO-3100, IMO-8400, IR-103, IMO-9200, agatolimod, DIMS-9054, DV-1079, DV-1179, AZD-1419, lefitolimod (MGN-1703), CYT-003, CYT-003-QbG10, tilsotolimod, and PUL-042.

Examples of TLR7, TLR8, and TLR9 modifiers include WO2017047769 (Teika Seiyaku), WO2015014815 (Janssen), WO2018045150 (Gilead Sciences Inc.), WO2018045144 (Gilead Sciences Inc.), WO2015162075 (Roche), and WO2017034986 (University of Kansas). WO2018095426 (Jiangsu Hengrui Medicine Co Ltd), WO2016091698 (Roche), WO2016075661 (GlaxoSmithKline Biolo gicals), WO2016180743 (Roche), WO2018089695 (Dynavax Technologies), WO2016055553 (Roche), WO2015168279 (Novar tis), WO2016107536 (Medshine Discovery), WO2018086593 (Livo (Shanghai) Pharmaceutical), WO2017106607 (Merck), WO201 7061532(Sumitomo Dainippon Pharma)、WO2016023511(Chia Tai Tianqing Pharmaceutical)、WO2017076346(Chia T ai Tianqing Pharmaceutical)、WO2017046112(Roche)、WO2018078149(Roche)、WO2017040233(3M Co)、WO2016141092 (Gilead Sciences), WO2018049089 (BristolMyers Squibb), WO2015057655 (Eisai Co Ltd), WO2017001307 (Roche), WO2 018005586(BristolMyers Squibb)、WO201704023(3MCo)、WO2017163264(Council of Scientific and Industrial R esearch (India)), WO2018046460 (GlaxoSmithKline Biologicals), WO2018047081 (Novartis), WO2016142250 (Roche), WO 2015168269(Novartis)、WO201804163(Roche)、WO2018038877(3M Co)、WO2015057659(Eisai Co Ltd)、WO2017202704( Roche), WO2018026620 (BristolMyersSquibb), WO2016029077 (Janus Biotherapeutics), WO201803143 (Merck), WO2016 096778 (Roche), WO2017190669 (Shanghai De Novo Pharmatech), US09884866 (University of Minnesota), WO2017219931(Sichuan KelunBiotechBiopharmaceutical), WO2018002319(Janssen Sciences), WO2017216054(Roche Compounds disclosed in WO2017202703 (Roche), WO2017184735 (IFM Therapeutics), WO2017184746 (IFM Therapeutics), WO2015088045 (Takeda Pharmaceutical), WO2017038909 (Takeda Pharmaceutical), WO2015095780 (University of Kansas), and WO2015023958 (University of Kansas).

In some implementations, the agent as described herein is administered in combination with a TLR7, TLR8, or TLR9 agonist.

Interferon α receptor ligand

Examples of interferon α receptor ligands include interferon α-2b (INTRON), pegylated interferon α-2a, pegylated interferon α-1b, interferon α-1b Veldona, Infradure, Roferon-A, YPEG-interferon α-2a (YPEG-rhIFNα-2a), P-1101, Algeron, Alfarona, Ingaron (interferon γ), rSIFN-co (recombinant supercompound interferon), Ypeg interferon α-2b (YPEG-rhIFNα-2b), MOR-22, pegylated interferon α-2b Bioferon, and Novafer. on, Inmutag (Inferon), interferon α-n1, interferon β-1a, Shaferon, interferon α-2b (Axxo), Alfaferone, interferon α-2b (BioGeneric Pharma), interferon-α2 (CJ), Laferonum, VIPEG, BLAUFERON-A, BLAUFERON-B, Intermaxα, Realdiron, Lanstion, Pegaferon, PDferon-B, PDferon-B, interferon α-2b (IFN, Laboratorios Bioprofarm) a) Interferon α 2b, Kalferon, Pegnano, Feronsure, PegiHep, Interferon α2b (Zydus-Cadila), Interferon α2a, Optipeg A, Realfa 2B, Reliferon, Interferon α-2b (Amega), Interferon α-2b (Virchow), Ropeg Interferon α-2b, rHSA-IFNα-2a (recombinant human serum albumin interferon α2a fusion protein), PEG-IFN-α, rHSA-IFNα2b, recombinant human interferon α-(1b, 2a, 2b), pegylated interferon α-2b (Ame (ga), pegylated interferon α-2a, Reaferon-EC, Proquiferon, Uniferon, Urifron, interferon α-2b (Changchun Institute of Biological Products), Anterferon, Shanferon, Layfferon, Shang Sheng LeiTai, INTEFEN, SINOGEN, Fukangtai, Pegstat, rHSA-IFNα-2b, SFR-9216 and Interapo (Interapa).

Hyaluronidase inhibitor

Examples of hyaluronidase inhibitors include astodrimer.

Hepatitis B surface antigen (HBsAg) inhibitors

Examples of HBsAg inhibitors include AK-074, HBF-0259, PBHBV-001, PBHBV-2-15, PBHBV-2-1, REP-9AC, REP-9C, REP-9, REP-2139, REP-2139-Ca, REP-2055, REP-2163, REP-2165, REP-2053, REP-2031, REP-006, and REP-9AC′.

Examples of HBsAg secretion inhibitors include BM601, GST-HG-131, and AB-452.

Cytotoxic T-lymphocyte-associated protein 4 (ipi4) inhibitors

Examples of cytotoxic T-lymphocyte-associated protein 4 (ipi4) inhibitors include AGEN-2041, AGEN-1884, ipilimumab, beracip, PSI-001, PRS-010, Probody monoclonal antibody, tremelimumab, and JHL-1155.

Cyclic protein inhibitors

Examples of cyclic protein inhibitors include CPI-431-32, EDP-494, OCB-030, SCY-635, NVP-015, NVP-018, NVP-019, STG-175, and compounds disclosed in US8513184 (Gilead Sciences), US20140030221 (Gilead Sciences), US20130344030 (Gilead Sciences), and US20130344029 (Gilead Sciences).

HBV virus enters inhibitor

Examples of HBV inhibitors include Myrcludex B.

Antisense oligonucleotides targeting viral mRNA

Examples of antisense oligonucleotides that target viral mRNA include ISIS-HBVRx, IONIS-HBVRx, IONIS-HBV-LRx, IONIS-GSK6-LRx, GSK-3389404, and RG-6004.

Short interfering RNA (siRNA) and ddRNAi

Examples of siRNAs include TKM-HBV (TKM-HepB), ALN-HBV, SR-008, HepB-nRNA, ARC-520, ARC-521, ARB-1740, ARB-1467, AB-729, DCR-HBVS, RG-6084 (PD-L1), RG-6217, ALN-HBV-02, JNJ-3989 (ARO-HBV), STSG-0002, ALG-010133, ALG-ASO, LUNAR-HBV, and DCR-HBVS (DCR-S219).

Examples of DNA-guided RNA interference (ddRNAi) include BB-HB-331.

Endonuclease regulators

Examples of endonuclease regulators include PGN-514.

Ribonucleotide reductase inhibitors

Examples of ribonucleotide reductase inhibitors include Trimidox.

Non-nucleoside reverse transcriptase inhibitors

Examples of non-nucleoside reverse transcriptase inhibitors (NNRTIs) include compounds disclosed in WO2018118826 (Merck), WO2018080903 (Merck), WO2018119013 (Merck), WO2017100108 (Idenix), WO2017027434 (Merck), WO2017007701 (Merck), and WO2008005555 (Gilead).

HBV replication inhibitors

Examples of hepatitis B virus replication inhibitors include GP-31502, isothifluzidine, IQP-HBV, RM-5038, and Xingantie.

Covalently closed circular DNA (cccDNA) inhibitors

Examples of cccDNA inhibitors include BSBI-25, ccc-R08, and CHR-101.

Farnesol X receptor agonists

Examples of farnesoid X receptor agonists include, for example, EYP-001, GS-9674, EDP-305, MET-409, Tropifexor, AKN-083, RDX-023, BWD-100, LMB-763, INV-3, NTX-023-1, EP-024297, and GS-8670.

Add HBV antibody

Examples of HBV antibodies targeting the surface antigen of hepatitis B virus include lenvervimab (GC-1102), XTL-17, XTL-19, KN-003, IV Hepabulin SN, VIR-3434, and fully human monoclonal antibody therapy (hepatitis B virus infection, Humabs BioMed).

Examples of HBV antibodies (including monoclonal and polyclonal antibodies) include Zutectra, Shang Sheng Gan Di, UmanBig (Hepatitis B Hyperimmune), Omri-Hep-B, Nabi-HB, Hepatect CP, HepaGam B, igantibe, Niuliva, CT-P24, Hepatitis B Immunoglobulin (intravenous, pH 4, HBV infection, Shanghai RAAS Blood Products), and Fovepta (BT-088).

Examples of fully human monoclonal antibodies include HBC-34.

Antibodies against HBV viral peptide/major histocompatibility complex (MHC) class I (pMHC) complexes are described, for example, in Sastry et al., J Virol. 2011 Mar; 85(5):1935-42 and WO2011062562.

CCR2 chemokine antagonists

Examples of CCR2 chemokine antagonists include propargite germanium.

thymosin agonists

Examples of thymosin agonists include thymosin alpha 1 and recombinant thymosin alpha 1 (GeneScience).

Cytokines

Examples of cytokines include recombinant IL-7, CYT-107, interleukin-2 (IL-2, Immunex), recombinant human interleukin-2 (Shenzhen Neptunus), IL-15, IL-21, IL-24, and simmoleukin.

Interleukin agonists

In some embodiments, the pharmaceutical agent as described herein is combined with the following substances: interleukin agonists (such as IL-2, IL-7, IL-15, IL-10, IL-12); examples of IL-2 agonists, such as proleukin (aldeleukin, IL-2); pegylated IL-2 (e.g., NKTR-214); modified variants of IL-2 (e.g., THOR-707), bepepedin, AIC-284, ALKS-42. 30. CUI-101, Neo-2/15; Examples of IL-15 agonists include ALT-803, NKTR-255 and hetIL-15, interleukin-15/Fc fusion protein, AM-0015, NIZ-985, SO-C101, IL-15 Synthorin (PEGylated IL-15), P-22339 and IL-15-PD-1 fusion protein N-809; Examples of IL-7 include CYT-107.

Nucleoprotein regulators

Nucleoprotein modulators can be inhibitors of HBV core protein or capsid protein. Examples of nucleoprotein modulators include GS-4882, AB-423, AT-130, ALG-001075, ALG-001024, ALG-000184, EDP-514, GLS4, NVR-1221, NVR-3778, AL-3778, BAY41-4109, mofexidine mesylate, ARB-168786, and ARB-8. 80. ARB-1820, GST-HG-141, JNJ-379, JNJ-632, RG-7907, GST-HG-141, HEC-72702, KL -060332, AB-506, ABI-H0731, ABI-H3733, JNJ-440, ABI-H2158, CB-HBV-001 and DVR-23.

Examples of capsid inhibitors include compounds disclosed in the following patents: US20140275167 (Novira Therapeutics), US20130251673 (Novira Therapeutics), US20140343032 (Roche), WO2014037480 (Roche), US20130267517 (Roche), WO2014131847 (Janssen), WO2014033176 (Janssen), WO2014033170 (Janssen), WO2014033167 (Janssen), WO2015/059212 (Janssen), WO2015118057 (Janssen), WO201501128 1(Janssen)、WO2014184365(Janssen)、WO2014184350(Janssen)、WO2014161888(Janssen n), WO2013096744(Novira), US20150225355(Novira), US20140178337(Novira), US2015 0315159(Novira)、US20150197533(Novira)、US20150274652(Novira)、US20150259324( Novira), US20150132258 (Novira), US9181288 (Novira), WO2014184350 (Janssen), WO201 3144129(Roche)、WO2017198744(Roche)、US 20170334882(Novira)、US 20170334898(R oche), WO2017202798 (Roche), WO2017214395 (Enanta), WO2018001944 (Roche), WO20180 01952(Roche)、WO2018005881(Novira)、WO2018005883(Novira)、WO2018011100(Roche) , WO2018011160(Roche), WO2018011162(Roche), WO2018011163(Roche), WO2018036941(R oche), WO2018043747(Kyoto Univ), US20180065929(Janssen), WO2016168619(IndianaUniversity), WO2016195982(The Penn State Foundation), WO2017001655(Janssen), WO2017048950 (Assembly Biosciences), WO2017048954 (Assembly Biosciences), WO2017048962 (Assembly Biosciences), US20170121328 (Novira), US20170121329 (Novira).

Examples of transcript inhibitors include compounds disclosed in the following patents: WO2017013046 (Roche), WO2017016960 (Roche), WO2017017042 (Roche), WO2017017043 (Roche), WO2017061466 (Toyoma Chemicals), WO2016177655 (Roche), WO2016161268 (Enanta), WO2017001853 (R edex Pharma), WO2017211791 (Roche), WO2017216685 (Novartis), WO2017216686 (Novartis), WO2018019297 (Gi nkgo Pharma), WO2018022282 (Newave Pharma), US20180030053 (Novartis), WO2018045911 (Zhejiang Pharma).

STING agonists, RIG-I and NOD2 modulators

In some embodiments, the agents described herein are combined with interferon gene stimulators (STING). In some embodiments, the STING receptor agonist or activator is selected from the group consisting of ADU-S100 (MIW-815), SB-11285, MK-1454, SR-8291, AdVCA0848, STINGVAX, GSK-532, SYN-STING, MSA-1, SR-8291, 5,6-dimethylxanthonone-4-acetic acid (DMXAA), cyclic GAMP (cGAMP), and cyclic diAMP. In some embodiments, the agents described herein are combined with RIG-I regulators (such as RGT-100) or NOD2 regulators (such as SB-9200 and IR-103).

Examples of STING agonists include compounds disclosed in the following patents: WO 2018065360 ("BiologLife Science Institute Forschungslabor und Biochemica-Vertrieb GmbH, Germany"), WO 2018009466 (Aduro Biotech), WO 2017186711 (InvivoGen), WO 2017161349 (ImmuneSensor), WO 2017106740 (Aduro Biotech), US 20170158724 (G laxo Smithkline), WO2017075477 (Aduro Biotech), US 20170044206 (Merck), WO 2014179760 (University of California), WO2018098203 (Janssen), WO2018118665 (Merck), WO2018118664 (Merck), WO2018100558 (Takeda), WO2018067423 (Merck), WO2018060323 (Boehringer).

Retinyl oxidase-induced gene 1 stimulator

Examples of retinoic acid-induced gene 1 stimulators include sonagivir (SB-9200), SB-40, SB-44, ORI-7246, ORI-9350, ORI-7537, ORI-9020, ORI-9198, ORI-7170, and RGT-100.

NOD2 stimulant

Examples of NOD2 stimulants include sonagivir (SB-9200).

Phosphatidylinositol 3-kinase (PI3K) inhibitors

Examples of PI3K inhibitors include idarucixib, ACP-319, AZD-8186, AZD-8835, bupalixib, CDZ-173, CLR-457, idarucixib, neratinib, regoratinib, regoratinib sodium, EN-3342, TGR-1202, avocadolixib, duvelixib, IPI-549, UCB-5857, tacelilixib, XL-765, glazolixib, ME-401, VS-5584, copanlixib, orotic acid (CAI), perifoxine, RG-7666, GSK-2636771, DS-7423, panulilixib, and GSK. -2269557, GSK-2126458, CUDC-907, PQR-309, INCB-40093, Pilarisib, BAY-1082439, Praquitinib Mesylate, SAR-245409, AMG-319, RP-6530, ZSTK-474, MLN-1117, SF-1126, RV-1729, Sonolisibu, LY-3023414, SAR-260301, TAK-117, HMPL-689, Tenalisib, Voxtalisib, and CLR-1401.

Immune checkpoint modulators

In some embodiments, the agent as described herein is combined with one or more blockers or inhibitors of inhibitory immune checkpoint proteins or receptors and/or with one or more stimulators, activators, or agonists of stimulating immune checkpoint proteins or receptors. Blocking or inhibiting inhibitory immune checkpoints can positively modulate T cell or NK cell activation and prevent immune escape by infected cells. Stimulating or activating immune checkpoints can enhance the efficacy of immune checkpoint inhibitors in the treatment of infections. In some embodiments, immune checkpoint proteins or receptors modulate T cell responses (e.g., reviewed in Xu et al., J Exp Clin Cancer Res. (2018) 37:110). In some embodiments, immune checkpoint proteins or receptors modulate NK cell responses (e.g., in Davis et al., Semin Immunol. (2017) 31:64–75 and Chiossone et al., Nat Rev Immunol. (2018) 18(11):671-688).

Examples of immune checkpoint proteins or receptors include, but are not limited to, CD27, CD70; CD40, CD40LG; CD47, CD48 (SLAMF2); 2 containing transmembrane and immunoglobulin domains (TMIGD2, CD28H); CD84 (LY9B, SLAMF5); CD96, CD160, MS4A1 (CD20); CD244 (SLAMF4); CD276 (B7H3); T cell activation inhibitor 1 containing V-set domains (VTCN1, B7H4); V-set immunomodulatory receptors (VSIR, B... 7H5, VISTA); Immunoglobulin superfamily member 11 (IGSF11, VSIG3); Natural killer cell cytotoxic receptor 3 ligand 1 (NCR3LG1, B7H6); HERV-H LTR related 2 (HHLA2, B7H7); Inducible T cell costimulatory factor (ICOS, CD278); Inducible T cell costimulatory factor ligand (ICOSLG, B7H2); TNF receptor superfamily member 4 (TNFRSF4, OX40); TNF superfamily member 4 (TNFSF4, OX40L); TNFRSF8 (CD278, CD ... 30) TNFSF8 (CD30L); TNFRSF10A (CD261, DR4, TRAILR1), TNFRSF9 (CD137), TNFSF9 (CD137L); TNFRSF10B (CD262, DR5, TRAILR2), TNFRSF10 (TRAIL); TNFRSF14 (HVEML, CD270), TNFSF14 (HVEML); CD272 (B and T lymphocyte-associated (BTLA)); TNFRSF17 (BCMA, CD269), TNF SF13B (BAFF); TNFRSF18 (GITR), TNFSF18 (GITRL); MHC class I peptide-associated sequence A (MICA); MHC class I peptide-associated sequence B (MICB); CD274 (CD274, PDL1, PD-L1); programmed cell death 1 (PDCD1, PD1, PD-1); cytotoxic T lymphocyte-associated protein 4 (CTLA4, CD152); CD80 (B7-1), CD28; nectin cell adhesion molecule 2 (NECTIN2, CD112); CD 226 (DNAM-1); Poliovirus receptor (PVR) cell adhesion molecule (PVR, CD155); Contains PVR-associated immunoglobulin domain (PVRIG, CD112R); T cell immune receptor with Ig and ITIM domains (TIGIT); Contains T cell immunoglobulin and mucin domains 4 (TIMD4; TIM4); Hepatitis A virus cell receptor 2 (HAVCR2, TIMD3, TIM3); Galactagogue 9 (LGALS9); Lymphocyte activation 3 (LAG3, CD223); Signal transduction lymphocyte activation SLAM family members 1 (SLAM, CD150); Lymphocyte antigen 9 (LY9, CD229, SLAM); SLAM family member 6 (SLAM, CD352); SLAM family member 7 (SLAM, CD319); UL16 binding protein 1 (ULBP1); UL16 binding protein 2 (ULBP2); UL16 binding protein 3 (ULBP3); retinoic acid early transcript 1E (RAET1E; ULBP4); retinoic acid early transcript 1G (RAET1G; ULBP5); retinoic acid Early transcript 1L (RAET1L; ULBP6); Lymphocyte activation 3 (CD223); Cytokine immunoglobulin-like receptor 1 with three Ig domains and a long cytoplasmic tail (KIR, CD158E1); Cytokine lectin-like receptor C1 (KLRC1, NKG2A, CD159A); Cytokine lectin-like receptor K1 (KLRK1, NKG2D, CD314); Cytokine lectin-like receptor C2 (KLRC2, CD159c, NKG2C); Cytokine lectin-like receptor C3 (KLRC3, NKG2E); Cytokine Lectin-like receptor C4 (KLRC4, NKG2F); cytotoxic immunoglobulin-like receptor with two Ig domains and a long cytoplasmic tail 1 (KIR2DL1); cytotoxic immunoglobulin-like receptor with two Ig domains and a long cytoplasmic tail 2 (KIR2DL2); cytotoxic immunoglobulin-like receptor with two Ig domains and a long cytoplasmic tail 3 (KIR2DL3); cytotoxic immunoglobulin-like receptor with three Ig domains and a long cytoplasmic tail 1 (KIR3DL1); cytotoxic lectin-like receptor D1 (KLRD1); and SLAM family member 7 (SLAMF7).

In some implementations, the agent as described herein is combined with one or more blockers or inhibitors of one or more T-cell inhibitory immune checkpoint proteins or receptors. Exemplary T-cell suppressor immune checkpoint proteins or receptors include, but are not limited to, CD274 (CD274, PDL1, PD-L1); programmed cell death 1 ligand 2 (PDCD1LG2, PD-L2, CD273); programmed cell death 1 (PDCD1, PD1, PD-1); cytotoxic T-lymphocyte-associated protein 4 (CTLA4, CD152); CD276 (B7H3); V-set domain-containing T-cell activation inhibitor 1 (VTCN1, B7H4); V-set immunomodulatory receptors (VSIR, B7H5, VISTA); immunoglobulin superfamily member 11 (IGSF11, VSIG3); TNFRSF14 (HVEM, CD270), TNFSF14 (HVEML); CD272 (B and T lymphocyte-associated (BTLA)); and PVR-associated proteins. Immunoglobulin domains (PVRIG, CD112R); T-cell immune receptors with Ig and ITIM domains (TIGIT); lymphocyte activation 3 (LAG3, CD223); hepatitis A virus cell receptor 2 (HAVCR2, TIMD3, TIM3); galactagogue 9 (LGALS9); cytotoxic cell immunoglobulin-like receptor with three Ig domains and a long cytoplasmic tail 1 (KIR, CD158E1); cytotoxic cell immunoglobulin-like receptor with two Ig domains and a long cytoplasmic tail 1 (KIR2DL1); cytotoxic cell immunoglobulin-like receptor with two Ig domains and a long cytoplasmic tail 2 (KIR2DL2); cytotoxic cell immunoglobulin-like receptor with two Ig domains and a long cytoplasmic tail 3 (KIR2DL3); and cytotoxic cell immunoglobulin-like receptor with three Ig domains and a long cytoplasmic tail 1 (KIR3DL1). In some implementations, the agent as described herein is combined with one or more agonists or activators of one or more T-cell stimulating immune checkpoint proteins or receptors. Examples of T-cell stimulating immune checkpoint proteins or receptors include, but are not limited to, CD27, CD70; CD40, CD40LG; inducible T-cell costimulatory factors (ICOS, CD278); inducible T-cell costimulatory factor ligands (ICOSLG, B7H2); TNF receptor superfamily member 4 (TNFRSF4, OX40); TNF superfamily member 4 (TNFSF4, OX40L); TNFRSF9 (CD137), TNFSF9 (CD137L); TNFRSF18 (GITR), TNFSF18 (GITRL); CD80 (B7-1), CD28; nectin cell adhesion molecule 2 (NECTIN2, CD112); CD226 (DNAM-1); CD244 (2B4, SLAMF4); and poliovirus receptor (PVR) cell adhesion molecule (PVR, CD155). See, for example, Xu et al., J Exp Clin Cancer Res. (2018) 37:110.

In some embodiments, the agents described herein are combined with one or more blockers or inhibitors of one or more NK cell inhibitory immune checkpoint proteins or receptors. Exemplary NK cell inhibitory immune checkpoint proteins or receptors include, but are not limited to, cytotoxic cell immunoglobulin-like receptors with three Ig domains and a long cytoplasmic tail 1 (KIR, CD158E1); cytotoxic cell immunoglobulin-like receptors with two Ig domains and a long cytoplasmic tail 1 (KIR2DL1); cytotoxic cell immunoglobulin-like receptors with two Ig domains and a long cytoplasmic tail 2 (KIR2DL2); cytotoxic cell immunoglobulin-like receptors with two Ig domains and a long cytoplasmic tail 3 (KIR2DL3); cytotoxic cell immunoglobulin-like receptors with three Ig domains and a long cytoplasmic tail 1 (KIR3DL1); cytotoxic cell lectin-like receptors C1 (KLRC1, NKG2A, CD159A); and cytotoxic cell lectin-like receptors D1 (KLRD1, CD94). In some embodiments, the agent as described herein is combined with one or more agonists or activators of one or more NK cell-stimulating immune checkpoint proteins or receptors. Exemplary NK cell-stimulating immune checkpoint proteins or receptors include, but are not limited to, CD16, CD226 (DNAM-1); CD244 (2B4, SLAMF4); cytotoxic lectin-like receptor K1 (KLRK1, NKG2D, CD314); and SLAM family member 7 (SLAMF7). See, for example, Davis et al., Semin Immunol. (2017) 31:64–75; Fang et al., Semin Immunol. (2017) 31:37-54; and Chiossone et al., NatRev Immunol. (2018) 18(11):671-688.

In some embodiments, one or more immune checkpoint inhibitors include protein (e.g., antibody or fragment thereof or antibody mimic) inhibitors of PD-L1 (CD274), PD-1 (PDCD1), or CTLA4. In some embodiments, one or more immune checkpoint inhibitors include small organic molecule inhibitors of PD-L1 (CD274), PD-1 (PDCD1), or CTLA4. In some embodiments, the small molecule inhibitor of CD274 or PDCD1 is selected from the group consisting of GS-4224, GS-4416, INCB086550, and MAX10181. In some embodiments, the small molecule inhibitor of CTLA4 includes BPI-002.

Examples of CTLA4 inhibitors that can be used co-administered include, but are not limited to: ipilimumab, trimemumab, BMS-986218, AGEN1181, AGEN1884, BMS-986249, MK-1308, REGN-4659, ADU-1604, CS-1002, BCD-145, APL-509, JS-007, BA-3071, ONC-392, AGEN-2041, JHL-1155, KN-044, CG-0161, and ATO. R-1144, PBI-5D3H5, BPI-002, and multispecific inhibitors FPT-155 (CTLA4/PD-L1/CD28), PF-06936308 (PD-1/CTLA4), MGD-019 (PD-1/CTLA4), KN-046 (PD-1/CTLA4), MEDI-5752 (CTLA4/PD-1), XmAb-20717 (PD-1/CTLA4), and AK-104 (CTLA4/PD-1).

Examples of PD-L1 (CD274) or PD-1 (PDCD1) inhibitors that can be co-administered include, but are not limited to, pembrolizumab, nivolumab, cimetizumab, pidilizumab, AMP-224, MEDI0680 (AMP-514), spartazumab, atezolizumab, avelumab, durvalumab, ALN-PDL, BMS-936559, CK-301, PF-06801591, BGB-108, BGB-A317 (tislelizumab), GLS-010 (WBP-3055), AK-103 (HX-008), GB-226, AK-105, CS-1003, HLX-10, MGA-012, BI-754091, PDR-001, AGEN-2034, JS-001 ( Toripalimab), JNJ-63723283, Genomeamarab (CBT-501), LZM-009, BCD-100, LY-3300054, SHR-1201, SHR-1210 (Camrelizumab), Sym-021, ABBV-181, PD1-PIK, BAT-1306, RO-6084 (PD-L1 antisense oligonucleotide), S TI-1110, GX-P2, RG-7446, mDX-400, (MSB0010718C), CX-072, CBT-502, TSR-042 (Dotalimab), MSB-2311, JTX-4014, BGB-A333, SHR-1316, CS-1001 (WBP-3155), MEDI-0680, Envorimab ( The following are listed: envafolimab (KN-035), KD-033, KY-1003, IBI-308 (sintilimab), HLX-20, KL-A167, STI-A1014, STI-A1015 (IMC-001), BCD-135, FAZ-053, TQB-2450, MDX1105-01, MSB-0010718C, GS-4224, GS-4416, INCB086550, MAX10181, and bispecific inhibitors FPT-155 (CTLA4/PD-L1/CD28), PF-06936308 (PD-1/CTLA4), MGD-013 (PD-1/LAG-3), FS-118 (LAG-3/PD-L1), and MGD-019 (P D-1/CTLA4), KN-046 (PD-1/CTLA4), MEDI-5752 (CTLA4/PD-1), RO-7121661 (PD-1/TIM-3), XmAb-20717 (PD-1/CTLA4), AK-104 (CTLA4/PD-1), M7824 (PD-L1/TGFβ-EC domain), CA-170 (PD-L1/VISTA), CDX-527 (CD27/PD-L1), LY-3415244 (TIM3/PDL1), GNS-1480 (epidermal growth factor receptor antagonist; programmed cell death ligand 1 inhibitor), M-7824 (PD-L1/TGF-β bifunctional fusion protein), and INBRX-105 (4-1BB/PDL1).

Examples of PD-1 inhibitors include compounds disclosed in the following patents: WO2017112730 (Incyte Corp), WO2017087777 (Incyte Corp), WO2017017624, WO2014151634 (Bristol Myers Squibb Co), WO201317322 (Bristol Myers Squibb Co), WO2018119286 (Incyte Corp), WO2018119266 (Incyte Corp), WO2018119263 (Incyte Corp), WO2018119236 (Incyte Corp), WO20181192... 21(Incyte Corp), WO2018118848(BristolMyers Squibb Co), WO20161266460(BristolMyers Squibb Co), WO2017087678(BristolMyers Squibb Co), WO20161493 51 (BristolMyers Squibb Co), WO2015033299 (Aurigene Discovery Technologies Ltd), WO2015179615 (Eisai Co Ltd; Eisai Research Institute), WO2017066 227(BristolMyersSquibb Co)、WO2016142886(Aurigene Discovery Technologies Ltd)、WO2016142852(Aurigene Discovery Technologies Ltd)、WO201614283 5 (Aurigene Discovery Technologies Ltd; Individual), WO2016142833 (Aurigene Discovery Technologies Ltd), WO2018085750 (BristolMyers Squibb Co), WO2 015033303 (Aurigene Discovery Technologies Ltd), WO2017205464 (Incyte Corp), WO2016019232 (3M Co; Individual; Texas A&M University System), WO20151 60641 (BristolMyers Squibb Co), WO2017079669 (Incyte Corp), WO2015033301 (Aurigene Discovery Technologies Ltd), WO2015034820 (BristolMyers Squibb Co), WO2018073754 (Aurigene Discovery Technologies Ltd), WO2016077518 (BristolMyers Squibb Co), WO2016057624 (BristolMyers Squibb Co), WO201804478 3(Incyte Corp), WO2016100608(BristolMyersSquibb Co), WO2016100285(BristolMyersSquibb Co), WO2016039749(BristolMyersSquibb Co), WO2015019284(C ambridge Enterprise Ltd), WO2016142894 (Aurigene Discovery Technologies Ltd), WO2015134605 (BristolMyers Squibb Co), WO2018051255 (Aurigene Disco very Technologies Ltd), WO2018051254 (Aurigene Discovery Technologies Ltd), WO2017222976 (Incyte Corp), WO2017070089 (Incyte Corp), WO2018044963 (Br istolMyers Squibb Co), WO2013144704 (Aurigene Discovery Technologies Ltd), WO2018013789 (Incyte Corp), WO2017176608 (BristolMyers SquibbCo), WO201 8009505 (BristolMyers Squibb Co), WO2011161699 (Aurigene Discovery Technologies Ltd), WO2015119944 (Incyte Corp; Merck Sharp & Dohme Corp), WO201719 2961(Incyte Corp), WO2017106634(Incyte Corp), WO2013132317(Aurigene Discovery Technologies Ltd), WO2012168944(Aurigene Discovery TechnologiesL td), WO2015036927 (Aurigene Discovery Technologies Ltd), WO2015044900 (Aurigene Discovery Technologies Ltd), WO2018026971 (Arising International).

In some implementations, the agents described herein are combined with anti-TIGIT antibodies such as BMS-986207, RG-6058, and AAGEN-1307.

TNF receptor superfamily (TNFRSF) agonists or activators

In some embodiments, the agent as described herein is combined with an agonist of one or more members of the TNF receptor superfamily (TNFRSF), such agonists being one or more of the following: TNFRSF1A (NCBI gene ID: 7132), TNFRSF1B (NCBI gene ID: 7133), TNFRSF4 (OX40, CD134; NCBI gene ID: 7293), TNFRSF5 (CD40; NCBI gene ID: 958), TNFRSF6 (FAS, NCBI gene ID: 35... 5) TNFRSF7 (CD27, NCBI gene ID: 939), TNFRSF8 (CD30, NCBI gene ID: 943), TNFRSF9 (4-1BB, CD137, NCBI gene ID: 3604), TNFRSF10A (CD261, DR4, TRAILR1, NCBI gene ID: 8797), TNFRSF10B (CD262, DR5, TRAILR2, NCBI gene ID: 8795), TNFRSF10C (CD263, TRAILR3, ... TNFRSF10D (CD264, TRAILR4, NCBI gene ID: 8793), TNFRSF11A (CD265, RANK, NCBI gene ID: 8792), TNFRSF11B (NCBI gene ID: 4982), TNFRSF12A (CD266, NCBI gene ID: 51330), TNFRSF13B (CD267, NCBI gene ID: 23495), TNFRSF13C (CD268, NCBI gene ID: 8794), TNFRSF10D (CD264, TRAILR4, NCBI gene ID: 8793), TNFRSF11A (CD265, RANK, NCBI gene ID: 8792), TNFRSF11B (CD266, NCBI gene ID: 4982), TNFRSF12A (CD266, NCBI gene ID: 51330), TNFRSF13B (CD267, NCBI gene ID: 23495), TNFRSF13C (CD268, NCBI gene ID: 8794), TNFRSF10D (CD264, TRAILR4, NCBI gene ID: 8793), TNFRSF11A (CD265, RANK, NCBI gene ID: 8792), TNFRSF11B (CD268, NCBI gene ID: 4982), TNFRSF12A (CD266, NCBI gene ID: 51330), TNFRSF13B (CD267, NCBI gene ID: 23495), TNFRSF13C (CD268, NCBI gene ID: 8794), TNFRSF10D (CD264, TRAILR4, NCBI gene ID: 8793), D: 115650), TNFRSF16 (NGFR, CD271, NCBI gene ID: 4804), TNFRSF17 (BCMA, CD269, NCBI gene ID: 608), TNFRSF18 (GITR, CD357, NCBI gene ID: 8784), TNFRSF19 (NCBI gene ID: 55504), TNFRSF21 (CD358, DR6, NCBI gene ID: 27242) and TNFRSF25 (DR3, NCBI gene ID: 8718).

Examples of anti-TNFRSF4 (OX40) antibodies that can be co-administered include, but are not limited to, MEDI6469, MEDI6383, MEDI0562 (tavorizumab), MOXR0916, PF-04518600, RG-7888, GSK-3174998, INCAGN1949, BMS-986178, GBR-8383, ABBV-368, IBI-101, and those described in WO2016179517, WO2017096179, WO2017096182, WO2017096281, and WO2018089628.

Examples of anti-TNFRSF5 (CD40) antibodies that can be administered together include, but are not limited to, RG7876, SEA-CD40, APX-005M, and ABBV-428.

In some implementations, the anti-TNFRSF7 (CD27) antibody varigramab (CDX-1127) is co-administered.

Examples of anti-TNFRSF9 (4-1BB, CD137) antibodies that can be administered together include, but are not limited to, urinumab, urinumab (PF-05082566), AGEN2373, and ADG-106.

Examples of anti-TNFRSF18 (GITR) antibodies that can be co-administered include, but are not limited to, MEDI1873, FPA-154, INCAGN-1876, TRX-518, BMS-986156, MK-1248, GWN-323, and those described in WO2017096179, WO2017096276, WO2017096189, and WO2018089628. In some embodiments, antibodies or fragments thereof that co-target TNFRSF4 (OX40) and TNFRSF18 (GITR) are co-administered. Such antibodies are described, for example, in WO2017096179 and WO2018089628.

Indoleamine-pyrrole-2,3-dioxygenase (IDO1) inhibitors

In some implementations, the agent as described herein is combined with an inhibitor of indoleamine 2,3-dioxygenase 1 (IDO1; NCBI gene ID: 3620). Examples of IDO1 inhibitors include, but are not limited to, BLV-0801, epacadostat, resminostat, F-001287, GBV-1012, GBV-1028, GDC-0919, indoximod, NKTR-218, NLG-919-based vaccines, PF-06840003, pyranoquinone derivatives (SN-35837), SBLK-200802, and BMS-9862. Compounds disclosed in 05 and shIDO-ST, EOS-200271, KHK-2455, LY-3381916, and US20100015178 (Incyte), US2016137652 (Flexus Biosciences, Inc.), WO2014073738 (Flexus Biosciences, Inc.) and WO2015188085 (Flexus Biosciences, Inc.).

LAG-3 and TIM-3 inhibitors

In some implementations, the agents described herein are combined with anti-TIM-3 antibodies (such as TSR-022, LY-3321367, MBG-453, INCAGN-2390).

In some implementations, the antibody or antigen-binding fragment described herein is combined with an anti-LAG-3 (lymphocyte activation) antibody (such as relatlimab (ONO-4482), LAG-525, MK-4280, REGN-3767, INCAGN2385).

Examples of other immunotherapy-based treatments that can be combined with the agents disclosed herein include interferon α; interferon α-2b; interferon α-n3; pegylated interferon α; interferon γ; Flt3 agonist; gepon; nomfullon, pegylated interferon α-2a, pegylated interferon α-2b, RPI-MN.

Inhibitor of Apoptosis (IAP) family of proteins

Examples of IAP inhibitors include APG-1387.

Recombinant thymosin α-1

Examples of recombinant thymosin α-1 include NL-004 and PEGylated thymosin α-1.

Bruton's tyrosine kinase (BTK) inhibitors

Examples of BTK inhibitors include ABBV-105, acalabrutinib (ACP-196), ARQ-531, BMS-986142, dasatinib, ibrutinib, GDC-0853, PRN-1008, SNS-062, ONO-4059, BGB-3111, ML-319, MSC-2364447, RDX-022, X-022, AC-058, RG-7845, spetinib, and TAS-5315. The compounds disclosed in TP-0158, TP-4207, HM-71224, KBP-7536, M-2951, TAK-020, AC-0025, and US20140330015 (Ono Pharmaceutical), US20130079327 (Ono Pharmaceutical), and US20130217880 (Ono Pharmaceutical).

KDM inhibitors

Examples of KDM5 inhibitors include compounds disclosed in WO2016057924 (Genentech/Constellation Pharmaceuticals), US20140275092 (Genentech/Constellation Pharmaceuticals), US20140371195 (Epitherapeutics), US20140371214 (Epitherapeutics), US20160102096 (Epitherapeutics), US20140194469 (Quanticel), US20140171432, US20140213591 (Quanticel), US20160039808 (Quanticel), US20140275084 (Quanticel), and WO2014164708 (Quanticel).

Examples of KDM1 inhibitors include compounds disclosed in US9186337B2 (Oryzon Genomics), GSK-2879552, RG-6016, and ORY-2001.

Arginase inhibitors

Examples of arginase inhibitors include CB-1158, C-201, and Resminostat.

Bispecific and trispecific natural killer (NK) cell adaptors

In some embodiments, the agent as described herein is combined with a bispecific NK cell adaptor (BiKE) or a trispecific NK cell adaptor (TriKE) (e.g., without Fc) or a bispecific antibody against (e.g., with Fc) of: NK cell activation receptors, such as CD16A, C-type lectin receptors (CD94/NKG2C, NKG2D, NKG2E/H, and NKG2F), native cytotoxic receptors (NKp30, NKp44, and NKp46), cytotoxic cell C-type lectin-like receptors (NKp65, NKp80), Fc receptor FcγR (which mediates antibody-dependent cytotoxicity), SLAM family receptors (e.g., 2B4, SLAM6, and SLAM7), cytotoxic cell immunoglobulin-like receptors (KIR) (KIR-2DS and KIR-3DS), DNAM-1, and CD137 (41BB). Depending on the application, the anti-CD16 binding bispecific molecule may or may not have an Fc. Exemplary bispecific NK cell adaptors that can be co-administered target CD16 and one or more HBV-associated antigens as described herein. BiKE and TriKE are described, for example, in the following literature: Felices et al., Methods Mol Biol. (2016) 1441:333–346; Fang et al., Semin Immunol. (2017) 31:37-54.

Long-term treatment

Long-acting entecavir (subcutaneous reservoir), long-acting tenofovir (TFD and TAF) implants (devices) or subcutaneous reservoirs. Examples of long-acting entecavir are described in Exploration of long-acting implant formulations of hepatitis B drug entecavir., Eur J Pharm Sci. 2019 Aug 1; 136:104958.

Gene therapy and cell therapy

In some implementations, the agents described herein are combined with gene therapy or cell therapy regimens. Gene therapy and cell therapy include, but are not limited to, gene modifications that silence genes; gene methods that directly kill infected cells; infusion of immune cells designed to replace most of the patient's own immune system to enhance the immune response to infected cells, or to activate the patient's own immune system to kill infected cells, or to locate and kill infected cells; and gene methods that modify cell activity to further alter the endogenous immune response to infection.

Gene editor

Genome editing systems are selected from the group consisting of: CRISPR/Cas9 systems, zinc finger nuclease systems, TALEN systems, homing endonuclease systems, and large-scale nuclease systems (e.g., ARCUS systems); for example, cccDNA elimination via targeted cleavage and alteration of one or more of the hepatitis B virus (HBV) viral genes. Altering (e.g., knocking out and/or knocking down) PreC, C, X, PreSI, PreS2, S, P, or SP genes means (1) reducing or eliminating expression of PreC, C, X, PreSI, PreS2, S, P, or SP genes; (2) interfering with the function of precore, core, X protein, long surface protein, intermediate surface protein, S protein (also known as HBs antigen and HBsAg), polymerase protein, and/or hepatitis B splicing protein (HBe, HBc, HBx, PreS1, PreS2, S, Pol, and/or HBSP); or (3) reducing or eliminating intracellular, serum, and/or parenchymal levels of HBe, HBc, HBx, LHB, MHB, SHB, Pol, and/or HBSP proteins. Knockdown of one or more of the PreC, C, X, PreSI, PreS2, S, P, and/or SP genes is performed by targeting HBV cccDNA and/or integrating these genes into HBV DNA.

Examples of gene therapy include liver-targeted anti-HBV gene therapy (using ARCUS technology) or gene editing technology using CRISPR/Cas9 or EBT-106 (a CRISPR/CasX nuclease delivered by LNP).

CAR-T cell therapy

CAR-T cell therapy comprises a population of immune effector cells engineered to express a chimeric antigen receptor (CAR), wherein the CAR includes an HBV antigen-binding domain. In some embodiments, the antigen-binding domain is the domain disclosed herein. In some embodiments, the antigen-binding domain differs from the domain disclosed herein. In some embodiments, the antigen is HBsAg (i.e., HBsAg-CART). The immune effector cells are T cells or NK cells. In some embodiments, the T cells are CD4+ T cells, CD8+ T cells, NK cells, or a combination thereof. The cells may be autologous or allogeneic. An example of HBV-targeted CART is described in Cytotherapy. May 2018; 20(5):697-705. doi:10.1016/j.jcyt.2018.02.

TCR-T cell therapy

TCR-T cell therapy involves T cells expressing HBV-specific T cell receptors. TCR-T cells are engineered to target HBV-derived peptides present on the surface of virus-infected cells. An example of an HBV-targeting TCR is found in Wisskirchen, K. et al., T cell receptor grafting allows virological control of hepatitis B virus infection. J Clin Invest. 2019;129(7):2932-2945.

TCR-T cell therapy involves T cells that express HBV surface antigen (HBsAg)-specific TCRs.

TCR-T cell therapy includes TCR-T therapies targeting HBV, such as LTCR-H2-1.

In another specific embodiment, the agents disclosed herein or their pharmaceutically acceptable salts are combined with HBV DNA polymerase inhibitors, one or more additional therapeutic agents selected from the group consisting of: immunomodulators, TLR modulators, HBsAg inhibitors, HBsAg secretion or assembly inhibitors, HBV therapeutic vaccines, HBV antibodies (including HBV antibodies targeting the surface antigen of hepatitis B virus) and bispecific antibodies and "antibody-like" therapeutic proteins (such as Fab derivatives or TCR-like antibodies), cyclic protein inhibitors, retinoic acid-induced gene 1 stimulators, RIG-I-like receptor stimulators, PD-1 inhibitors, PD-L1 inhibitors, arginase inhibitors, PI3K inhibitors, IDO inhibitors and NOD2 stimulators, and one or more additional therapeutic agents selected from the group consisting of: HBV virus entry inhibitors, NTCP inhibitors, HBx inhibitors, cccDNA inhibitors, HBV antibodies targeting the surface antigen of hepatitis B virus, siRNA, miRNA gene therapy agents, sshRNA, KDM5 inhibitors and nucleoprotein modulators (HBV core protein or capsid protein modulators).

In another specific embodiment, the agent as disclosed herein or a pharmaceutically acceptable salt thereof is combined with at least a second additional therapeutic agent selected from the group consisting of: HBV DNA polymerase inhibitors, immunomodulators, TLR modulators, HBsAg inhibitors, HBV therapeutic vaccines, HBV antibodies (including HBV antibodies targeting the surface antigen of hepatitis B virus) and bispecific antibodies and “antibody-like” therapeutic proteins (such as anti-pMHC TCR-like antibodies, Fab derivatives or TCR-like antibodies), cyclic protein inhibitors, retinoic acid-induced gene 1 stimulators, RIG-I-like receptor stimulators, PD-1 inhibitors, PD-L1 inhibitors, arginase inhibitors, PI3K inhibitors, IDO inhibitors and NOD2 stimulators.

In another specific embodiment, the agent disclosed herein or a pharmaceutically acceptable salt thereof is combined with at least a second additional therapeutic agent selected from the group consisting of: HBV DNA polymerase inhibitors, HBV viral entry inhibitors, NTCP inhibitors, HBx inhibitors, cccDNA inhibitors, HBV antibodies targeting the surface antigen of hepatitis B virus, siRNA, miRNA gene therapy agents, sshRNA, KDM5 inhibitors, and nucleoprotein modulators (HBV core protein or capsid protein modulators).

In certain embodiments, the pharmaceutical agents disclosed herein or their pharmaceutically acceptable salts are combined with compounds such as those disclosed in the following documents: U.S. Publication No. 2010/0143301 (Gilead Sciences), U.S. Publication No. 2011/0098248 (Gilead Sciences), U.S. Publication No. 2009/0047249 (Gilead Sciences), U.S. Patent No. 8722054 (Gilead Sciences), and U.S. Publication No. 2014/0045849 (Janss (en), US Publication No. 2014/0073642 (Janssen), WO2014/056953 (Janssen), WO2014/076221 (Janssen), WO2014/128189 (Janssen), US Publication No. 2014/0350031 (Janssen), WO2014/023813 (Janssen), US Publication No. 2008/0234251 (Array Biopharma), US Publication No. 2008/0306050 (Array Biopharma), US Publication No. 2010/0029585 (Ve Ventrix Pharma, US Publication No. 2011/0092485 (Ventirx Pharma), US Publication No. 2011/0118235 (Ventirx Pharma), US Publication No. 2012/0082658 (Ventirx Pharma), US Publication No. 2012/0219615 (Ventirx Pharma), US Publication No. 2014/0066432 (Ventirx Pharma), US Publication No. 2014/0088085 (Ventirx Pharma), US Publication No. 2014/0275167 (Novira Pharma). Herapeutics), US Publication No. 2013/0251673 (Novira Therapeutics), US Patent No. 8513184 (Gilead Sciences), US Publication No. 2014/0030221 (Gilead Sciences), US Publication No. 2013/0344030 (Gilead Sciences), US Publication No. 2013/0344029 (Gilead Sciences), US20140275167 (Novira Therapeutics), US20130251673 (Novira Therapeutics). (a Therapeutics), US Publication No. 2014/0343032 (Roche), WO2014037480 (Roche), US Publication No. 2013/0267517 (Roche), WO2014131847 (Janssen), WO2014033176 (Janssen), WO2014033170 (Janssen), WO2014033167 (Janssen), WO2015/059212 (Janssen), WO2015118057 (Janssen), WO2015011281 (Janssen) , WO2014184365(Janssen), WO2014184350(Janssen), WO2014161888(Janssen), WO2013096744(Novira), US20150225355(Novira), US20140178 337(Novira), US20150315159(Novira), US20150197533(Novira), US20150274652(Novira), US20150259324(Novira), US20150132258(Novira) US9181288 (Novira), WO2014184350 (Janssen), WO2013144129 (Roche), US20100015178 (Incyte), US2016137652 (Flexus Biosciences, Inc.), WO2014073738 (Flexus Biosciences, Inc.), WO2015188085 (Flexus Biosciences, Inc.), US Publication No. 2014/0330015 (OnoPharmaceutical), US Publication No. 2013/0079327 (Ono Pharmaceutical), US Publication No. 2013/0217880 (Ono pharmaceutical), WO2016057924 (Genentech/Constellation Pharmaceuticals), US20140275092 (Genentech/Constellation Pharmaceuticals), US20140371195 (Epitherapeutics) and US20140371214 (Epitherapeutics). US20160102096 (Epitherapeutics), US20140194469 (Quanticel), US20140171432, US20140213591 (Quanticel), US20 160039808 (Quanticel), US20140275084 (Quanticel), WO2014164708 (Quanticel), US9186337B2 (Oryzon Genomics).

In some embodiments, the pharmaceutically acceptable salts of the agents disclosed herein are combined with 5 mg-30 mg of tenofovir alafenamide fumarate, tenofovir alafenamide hemifumarate, or tenofovir alafenamide. In some embodiments, the pharmaceutically acceptable salts of the agents disclosed herein are combined with 5 mg-10 mg, 5 mg-15 mg, 5 mg-20 mg, 5 mg-25 mg, 25 mg-30 mg, 20 mg-30 mg, 15 mg-30 mg, or 10 mg-30 mg of tenofovir alafenamide fumarate, tenofovir alafenamide hemifumarate, or tenofovir alafenamide. In some embodiments, the pharmaceutically acceptable salts of the agents disclosed herein are combined with 10 mg of tenofovir alafenamide fumarate, tenofovir alafenamide hemifumarate, or tenofovir alafenamide. In some embodiments, the pharmaceutical agents disclosed herein or their pharmaceutically acceptable salts are combined with 25 mg of tenofovir alafenamide fumarate, tenofovir alafenamide hemifumarate, or tenofovir alafenamide. Pharmaceutical agents as disclosed herein may be combined with any dosage of the compound (e.g., 50 mg to 500 mg of the compound) with the pharmaceutical agents provided herein, as each combination of dosages is specifically and individually listed.

In some embodiments, the pharmaceutical agent disclosed herein or a pharmaceutically acceptable salt thereof is combined with 100-400 mg of tenofovir disoproxil fumarate, tenofovir disoproxil fumarate, or tenofovir disoproxil fumarate. In some embodiments, the pharmaceutical agents disclosed herein or their pharmaceutically acceptable salts are combined with 100 mg-150 mg, 100 mg-200 mg, 100 mg-250 mg, 100 mg-300 mg, 100 mg-350 mg, 150 mg-200 mg, 150 mg-250 mg, 150 mg-300 mg, 150 mg-350 mg, 150 mg-400 mg, 200 mg-250 mg, 200 mg-300 mg, 200 mg-350 mg, 200 mg-400 mg, 250 mg-350 mg, 250 mg-400 mg, 350 mg-400 mg or 300 mg-400 mg tenofovir disoproxil fumarate, tenofovir disoproxil fumarate or tenofovir disoproxil fumarate. In some embodiments, the pharmaceutical agents disclosed herein or their pharmaceutically acceptable salts are combined with 300 mg of tenofovir disoproxil fumarate, tenofovir disoproxil fumarate, or tenofovir disoproxil fumarate. In some embodiments, the pharmaceutical agents disclosed herein or their pharmaceutically acceptable salts are combined with 250 mg of tenofovir disoproxil fumarate, tenofovir disoproxil fumarate, or tenofovir disoproxil fumarate. In some embodiments, the pharmaceutical agents disclosed herein or their pharmaceutically acceptable salts are combined with 150 mg of tenofovir disoproxil fumarate, tenofovir disoproxil fumarate, or tenofovir disoproxil fumarate. Pharmaceutical agents as disclosed herein may be combined with any dose of the compound (e.g., 50 mg to 500 mg of the compound) with the pharmaceutical agents provided herein, as each combination of doses is specifically and individually listed.

VI. Treatment methods

In some embodiments, this disclosure provides a method for inhibiting DGKα in a subject of need, the method comprising administering to the subject a therapeutically effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure. In some embodiments, this disclosure provides a method for inhibiting DGKα in a subject of need, the method comprising administering to the subject a therapeutically effective amount of a compound of the present disclosure (e.g., a compound of formula (I), (I-1), (Ia), (Ia-1), (Ib), (Ic), (IIa), (IIa-1), (IIc), (IIc-1), (IIc-2), (IIc-2), (IIc-3), (IIc-4), (IIc-5), (IIc-6), (IIc-7), or (IIc-8)) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure.

In some embodiments, this disclosure provides a method for inhibiting DGKα in a subject of need, the method comprising administering to the subject a therapeutically effective amount of a compound of formula (I):

Or its pharmaceutically acceptable salt, wherein

^R1 is hydrogen, _C1-6 alkyl, _C2-6 alkenyl, _C2-6 alkynyl, _C1-6 alkoxy, halogen, _C1-6 haloalkyl, _C1-6 haloalkoxy, or –CN;

^R2 represents hydrogen, _C1-6 alkyl, _C2-6 alkenyl, _C2-6 alkynyl, _C1-6 hydroxyalkyl, _C1-6 aminoalkyl, C1-6 alkoxy, _C2-6 alkoxyalkyl, halogen, _C1-6 haloalkyl, _C1-6 haloalkoxy, -CN, -NO, -NO2, -C(O) _R2a , -C(O ₎ ^OR2a , -OC(O) ^R2a , -C(O)N(R2a)( ^R2b ), -N( ^R2a )C(O) ^R2b , -OC(O)N( ^R2a )( ^R2b ), ^{-N(R2a )} C(O) ^OR2b , ^-C (＝ ^NR2a )N( ^R2b )( ^R2c ), -N( ^R2a )( ^R2b ), -N(R ^2a )N(R ^2b )(R ^2c ), -N(R ^2a )N＝C(R ^2b )(OR ^2c ), -OR ^2a , -SR ^2a , -S(O)R ^2a , -S(O)(NR ^2a )(R ^2b ), -S(NR ^2a )(NR ^2b )(R ^2c ), -S(O) ₂ R ^2a , -S(O) ₂ N(R ^2a )(R ^2b ), -N(R ^2a )S(O) ₂ (R ^2b ), -P(R ^2a )(R ^2b ), -P(O)(R ^2a )(R ^2b ), -P(O)(OR ^2a )(R ^2b ), -P(O)(OR ^2a )(OR ^2b ), C _3-10 cycloalkyl, C _1-6 alkyl-C _3-10 cycloalkyl, C _6-12 aryl, C _1-6 alkyl-C _6-12 aryl, heterocycloalkyl, C _1-6 alkyl-(heterocycloalkyl), heteroaryl or C _1-6 alkyl-(heteroaryl), wherein each alkyl, alkenyl or alkynyl group is independently and optionally substituted with 1 to 3 R ^2d groups, each cycloalkyl group is optionally substituted with 1 to 3 R ^2e groups, each aryl group is optionally substituted with 1 to 3 R ^2f groups, each heterocycloalkyl group is optionally substituted with 1 to 3 R ^2g groups, and each heteroaryl group is optionally substituted with 1 to 3 R ^2h groups;

Each R ^2a , R ^2b and R ^2c is independently hydrogen, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 hydroxyalkyl, C _1-6 aminoalkyl, C _2-6 alkoxyalkyl, C _1-6 haloalkyl, C _3-10 cycloalkyl, C _1-6 alkyl-C _3-10 cycloalkyl, C _6-12 aryl, C _1-6 alkyl-C _6-12 aryl, heterocycloalkyl, C _1-6 alkyl-(heterocycloalkyl), heteroaryl or C _1-6 alkyl-(heteroaryl), wherein the aryl or heteroaryl is optionally substituted by one to three R ^2j ;

Alternatively, ^R2a , ^R2b and ^R2c, when attached to the same atom, can combine with the atom to which they are attached to to form a heterocyclic alkyl group;

Each R ^2d is independently –CN, -C(O)R ^2d1 , -C(O)OR ^2d1 , -OC(O)R ^2d1 , -C(O)N(R ^2d1 )(R ^2d2 ), -N(R ^2d1 )C(O)R ^2d2 , -OC(O)N(R ^2d1 )(R ^2d2 ), -N(R ^2d1 )C(O)OR ^2d2 , -N(R ^2d1 )(R ^2d2 ), =O, -OR ^2d1 , -SR ^2d1 , -S(O)R ^2d1 , -S(O)(NR ^2d1 )(R ^2d2 ), -S(O) ₂ R ^2d1 , -S(O)N(R ^2d1 )(R ^2d2 ), -N(R ^2d1) S(O) ₂ R ^2d2 , C _3-10 cycloalkyl, C _1-6 alkyl-C _3-10 cycloalkyl, C _6-12 aryl, C _1-6 alkyl-C _6-12 aryl, heterocycloalkyl, C _1-6 alkyl-(heterocycloalkyl), heteroaryl or C _1-6 alkyl-(heteroaryl);

Each R ^2d1 and R ^2d2 is independently hydrogen, a C _1-6 alkyl, a C _1-6 hydroxyalkyl, a C _1-6 aminoalkyl, a C _2-6 alkoxyalkyl, or a C _1-6 haloalkyl;

Each of ^R2e , ^R2f , ^R2g and ^R2h is independently hydrogen, _C1-6 alkyl, _C1-6 hydroxyalkyl, _C1-6 aminoalkyl, _C1-6 alkoxy, _C2-6 alkoxyalkyl, halogen, _C1-6 haloalkyl, _C1-6 haloalkoxy, -CN or -OH;

Each R ^2j is independently a C _1-6 alkyl, C _1-6 hydroxyalkyl, C _1-6 aminoalkyl, C _1-6 alkoxy, C _2-6 alkoxyalkyl, halogen, C _1-6 haloalkyl, or C _1-6 haloalkoxy;

^R3 represents hydrogen, _C1-6 alkyl, _C2-6 alkenyl, _C2-6 alkynyl, _C1-6 hydroxyalkyl, _C1-6 aminoalkyl, C1-6 alkoxy, _C2-6 alkoxyalkyl, halogen, _C1-6 haloalkyl, _C1-6 haloalkoxy, -CN, -NO, -NO2, -C(O) _R3a , -C(O ₎ ^OR3a , -OC(O) ^R3a , -C(O)N(R3a)( ^R3b ), -N( ^R3a )C(O) ^R3b , -OC(O)N( ^R3a )( ^R3b ), ^{-N(R3a )} C(O) ^OR3b , ^-C (＝ ^NR3a )N( ^R3b )( ^R3c ), -N( ^R3a )( ^R3b ), -N(R ^3a )N(R ^3b )(R ^3c ), -N(R ^3a )N＝C(R ^3b )(OR ^3c ), -OR ^3a , -SR ^3a , -S(O)R ^3a , -S(O)(NR ^3a )(R ^3b ), -S(NR ^3a )(NR ^3b )(R ^3c ), -S(O) ₂ R ^3a , -S(O) ₂ N(R ^3a )(R ^3b ), -N(R ^3a )S(O) ₂ (R ^3b ), -P(R ^3a )(R ^3b ), -P(O)(R ^3a )(R ^3b ), -P(O)(OR ^3a )(R ^3b ), -P(O)(OR ^3a )(OR ^3b ), C _3-10 cycloalkyl, C _1-6 alkyl-C _3-10 cycloalkyl, C _6-12 aryl, C _1-6 alkyl-C _6-12 aryl, heterocycloalkyl, C _1-6 alkyl-(heterocycloalkyl), heteroaryl or C _1-6 alkyl-(heteroaryl), wherein each alkenyl or ynyl group is independently and optionally substituted with 1 to 3 R ^3d groups, each cycloalkyl group is optionally substituted with 1 to 3 R ^3e groups, each aryl group is optionally substituted with 1 to 3 R ^3f groups, each heterocycloalkyl group is optionally substituted with 1 to 3 R ^3g groups, and each heteroaryl group is optionally substituted with 1 to 3 R ^3h groups;

Each R ^3a , R ^3b and R ^3c is independently hydrogen, C _1-6 alkyl, C _1-6 hydroxyalkyl, C _2-6 alkoxyalkyl, C _1-6 haloalkyl, C _3-10 cycloalkyl, C _1-6 alkyl-C _3-10 cycloalkyl, C _6-12 aryl, C _1-6 alkyl-C _6-12 aryl, heterocycloalkyl or heteroaryl;

Alternatively, ^R3a , ^R3b and ^R3c , when attached to the same atom, can combine with the atom to which they are attached to to form a heterocyclic alkyl group;

Each R ^3d is independently -N(R ^3d1 )(R ^3d2 ), -OR ^3d1 , C _3-10 cycloalkyl, C _1-6 alkyl-C _3-10 cycloalkyl, C _6-12 aryl, C _1-6 alkyl-C _6-12 aryl, heterocycloalkyl, or heteroaryl;

Each R ^3d1 and R ^3d2 is independently hydrogen, C _1-6 alkyl, or –C(O)O-(C _1-6 alkyl);

Each of ^R3e , ^R3f , ^R3g and ^R3h is independently hydrogen, _C1-6 alkyl, _C1-6 alkoxy, halogen, _C1-6 haloalkyl or _C1-6 haloalkoxy;

^R4 is hydrogen, _C1-6 alkyl, _C2-6 alkenyl, _C2-6 alkynyl, _C1-6 alkoxy, halogen, _C1-6 haloalkyl, _C1-6 haloalkoxy, or –CN;

R ⁵ is hydrogen, _C1-6 alkyl, _C2-6 alkenyl, _C2-6 alkynyl, _C1-6 hydroxyalkyl, _C2-6 alkoxyalkyl, _C1-6 haloalkyl, _C3-10 cycloalkyl, _C1-6 alkyl- _C3-10 cycloalkyl, _C6-12 aryl, _C1-6 alkyl- _C6-12 aryl, heterocycloalkyl, _C1-6 alkyl-(heterocycloalkyl), heteroaryl, or _C1-6 alkyl-(heteroaryl), wherein the alkyl group is optionally substituted with R ^5a ;

R ^5a is –OSi(R ^5a1 )(R ^5a2 )(R ^5a3 );

^R5a1 , ^R5a2 , and ^R5a3 are each independently a _C1-6 alkyl group; and

^R6 is a _C1-6 alkyl, _C2-6 alkenyl, _C2-6 alkynyl, _C1-6 haloalkyl, _C6-12 aryl or heteroaryl, wherein each of the aryl or heteroaryl groups is optionally substituted by one to three ^R6a .

Each R ^6a is independently a _C1-6 alkyl, _C2-6 alkenyl, _C2-6 alkynyl, _C1-6 hydroxyalkyl, _C1-6 aminoalkyl, C1-6 alkoxy, _C2-6 alkoxyalkyl, halogen, _C1-6 haloalkyl, _C1-6 haloalkoxy, –CN, -NO ₂ , -C(O)R 6b, _-C (O)OR ^6b , -OC(O)R ^6b , -C(O)N(R ^6b )(R ^6c ), -N(R ^6b )C(O)R ^6c , -C(＝NR ^6b )N(R ^6c )(R ^6d ), -N(R ^6b )(R ^6c ), -OR ^6b , -SR ^6b , -S(O ⁾ R ^6b , -S(O) _2R ^6b -S(NR ^6b )(NR ^6c )R ^6d , -S(O)(NR ^6b )(R ^6c ), -S(O) ₂ N(R ^6b )(R ^6c ), -N(R ^6b )S(O) ₂ (R ^6c ), -P(R ^6b )(R ^6c ), -P(O)(R ^6b )(R ^6c ), -P(O)(OR ^6b )(R ^6c ), -P(O)(OR ^6b )(OR ^6c ), C _3-10 cycloalkyl, C _1-6 alkyl-C _3-10 cycloalkyl, C _6-12 aryl, C _1-6 alkyl-C _6-12 aryl, heterocycloalkyl, C _1-6 alkyl-(heterocycloalkyl), heteroaryl or C _1-6 alkyl-(heteroaryl), wherein the cycloalkyl, aryl, heterocycloalkyl or heteroaryl group is optionally substituted by 1 to 3 R ^6e , the alkyl group is optionally substituted by R ^6f , and the alkynyl group is optionally substituted by 1 to 4 R ^6j ;

Each R ^6b , R ^6c , and R ^6d is independently hydrogen, C _1-6 alkyl, C _1-6 hydroxyalkyl, C _1-6 aminoalkyl, C _2-6 alkoxyalkyl, C _1-6 haloalkyl, C _3-10 cycloalkyl, C _1-6 alkyl-C _3-10 cycloalkyl, C _6-12 aryl, C _1-6 alkyl-C _6-12 aryl, heterocycloalkyl, C _1-6 alkyl-(heterocycloalkyl), heteroaryl, or C _1-6 alkyl-(heteroaryl), wherein the cycloalkyl, aryl, heterocycloalkyl, or heteroaryl is optionally substituted by one to three R ^6k ;

Each R ^6k is independently a _C1-6 alkyl, _C1-6 hydroxyalkyl, _C1-6 aminoalkyl, _C1-6 alkoxy, _C2-6 alkoxyalkyl, _C1-6 haloalkyl, _C1-6 haloalkoxy, _C3-10 cycloalkyl, _C1-6 alkyl- _C3-10 cycloalkyl, heterocycloalkyl, or _C1-6 alkyl-(heterocycloalkyl);

Each R ^6e is independently a _C1-6 alkyl, _C2-6 alkenyl, _C2-6 alkynyl, _C1-6 hydroxyalkyl, _C1-6 aminoalkyl, C1-6 alkoxy, _C2-6 alkoxyalkyl, halogen, _C1-6 haloalkyl, _C1-6 haloalkoxy, –CN, -NO ₂ , -C(O)R ^6e1 , _-C (O)OR ^6e1 , -OC(O)R ^6e1 , -C(O)N(R 6e1)(R ^6e2 ), -N(R ^6e1 )C(O)R ^6e2 , -OC(O)N(R ^6e1 )(R ^6e2 ), -N(R ^6e1 )C(O)OR ^6e2 , -C(＝NR ^6e1 )N(R ^6e2 )( ^{R 6e3 )} , -N(R ^6e1 )(R ^6e2 ), =O, -OR ^6e1 , -SR ^6e1 , -S(O)R ^6e1 , -S(NR ^6e1 )(NR ^6e2 ), -S(O)(NR ^6e1 )(R ^6e2 ) , -S(O) ₂ R ^6e1 , -S(O) ₂ N(R ^6e1 )(R ^6e2 ), -SF ₅ , -N(R ^6e1 )S(O) ₂ (R ^6e2 ), -P(R ^6e1 )(R ^6e2 ), -P(O)(R ^6e1 )(R ^6e2 ), -P(O)(OR ^6e1 )(R ^6e2 ), -P(O)(OR ^6e1 )(OR ^6e2 ), -Si(R ^6e1 )(R ^6e2 )(R ^6e3 )、C _3-10 cycloalkyl, _C1-6 alkyl- _C3-10 cycloalkyl, _C6-12 aryl, _C1-6 alkyl- _C6-12 aryl, heterocycloalkyl, _C1-6 alkyl-heterocycloalkyl, heteroaryl or _C1-6 alkyl-heteroaryl, wherein each of the cycloalkyl, aryl, heterocycloalkyl or heteroaryl is optionally substituted with 1 to 3 ^R6h , and the alkyl group is optionally substituted with 1 to 3 ^R6m ;

Each R ^6e1 , R ^6e2 , and R ^6e3 is independently hydrogen, C _1-6 alkyl, C _1-6 hydroxyalkyl, C _1-6 aminoalkyl, C _1-6 alkoxyalkyl, C _1-6 haloalkyl, C _3-10 cycloalkyl, C _1-6 alkyl-C _3-10 cycloalkyl, C _6-10 aryl, C _1-6 alkyl-C _6-10 aryl, heterocycloalkyl, C _1-6 alkyl-(heterocycloalkyl), heteroaryl, or C _1-6 alkyl-(heteroaryl), wherein the cycloalkyl, aryl, heterocycloalkyl, or heteroaryl is optionally substituted by one to three R ⁶ⁿ ;

Each R ⁶ⁿ is a _C1-6 alkyl, _C2-6 alkenyl, _C2-6 alkynyl, _C1-6 hydroxyalkyl, _C1-6 aminoalkyl, _C1-6 alkoxy, C2-6 alkoxyalkyl, halogen, _C1-6 haloalkyl, _C1-6 haloalkoxy, -CN, -C(O)R ⁶ⁿ¹ , -C(O)OR _6n1 , -OC(O)R ⁶ⁿ¹ , -C(O)N(R ⁶ⁿ¹ )(R ⁶ⁿ² ), -N(R ⁶ⁿ¹ )C(O)R ⁶ⁿ² , -OC(O)N(R ⁶ⁿ¹ )(R ⁶ⁿ² ), -N(R ⁶ⁿ¹ )C ^{(O)OR 6n2 ,} -C(＝NR ⁶ⁿ¹ )N(R ⁶ⁿ² )(R ⁶ⁿ³ ), -N(R ⁶ⁿ¹ )(R ⁶ⁿ² ), =O, –OH, -SR ⁶ⁿ¹ , -S(O)R ⁶ⁿ¹ , -S(NR ⁶ⁿ¹ )(NR ⁶ⁿ² )R ⁶ⁿ³ , -S(O)(NR ⁶ⁿ¹ )(R ⁶ⁿ² ), -S(O) ₂ R ⁶ⁿ¹ , -S(O) ₂ N(R ⁶ⁿ¹ )(R ⁶ⁿ² ) or -N(R ⁶ⁿ¹ )S(O) ₂ (R ⁶ⁿ² );

Each R ⁶ⁿ¹ , R ⁶ⁿ² , and R ⁶ⁿ³ is independently hydrogen, C _1-6 alkyl, C _1-6 hydroxyalkyl, C _1-6 aminoalkyl, C _2-6 alkoxyalkyl, C _1-6 haloalkyl, C _3-10 cycloalkyl, C _1-6 alkyl-C _3-10 cycloalkyl, C _6-10 aryl, C _1-6 alkyl-C _6-10 aryl, heterocycloalkyl, C _1-6 alkyl-(heterocycloalkyl), heteroaryl, or C _1-6 alkyl-(heteroaryl);

Each R ^6h is independently a _C1-6 alkyl, _C2-6 alkenyl, _C2-6 alkynyl, _C1-6 hydroxyalkyl, _C1-6 aminoalkyl, C1-6 alkoxy, _C2-6 alkoxyalkyl, halogen, _C1-6 haloalkyl, _C1-6 haloalkoxy, -CN, -C(O)R ^6h1 , -C(O)OR _6h1 , -OC(O)R ^6h1 , -C(O)N(R ^6h1 )(R ^6h2 ), -N(R ^6h1 )C(O)R ^{6h2, -OC(O)N(R 6h1 )} (R ^6h2 ), -N(R ^6h1 )C(O)OR ^6h2 , -C(＝NR ^6h1 )N(R ^6h2 )(R ^6h3 ), -N(R ^{6h1 )} (R ^6h2 ), =O, –OH, -SR ^6h1 , -S(O)R ^6h1 , -S(NR ^6h1 )(NR ^6h2 )R ^6h3 , -S(O)(NR ^6h1 )(R ^6h2 ), -S(O) _2R ^6h1 , -S(O) _2N (R ^6h1 )(R ^6h2 ), -N(R ^6h1 )S(O) ₂ (R ^6h2 ), C _3-10 cycloalkyl, C _1-6 alkyl-C _3-10 cycloalkyl, heterocycloalkyl or C _1-6 alkyl-(heterocycloalkyl);

Each R ^6h1 , R ^6h2 and R ^6h3 is independently hydrogen, C _1-6 alkyl, C _1-6 hydroxyalkyl, C _1-6 aminoalkyl, C _2-6 alkoxyalkyl, C _1-6 haloalkyl, C _3-10 cycloalkyl, C _1-6 alkyl-C _3-10 cycloalkyl, C _6-10 aryl, C _1-6 alkyl-C _6-10 aryl, heterocycloalkyl, C _1-6 alkyl-(heterocycloalkyl), heteroaryl or C _1-6 alkyl-(heteroaryl);

Each R ^6m is independently a halogen, a _C1-6 haloalkyl group, a _C1-6 haloalkoxy group, -CN, -C(O)R ^6m1 , -C(O)OR ^6m1 , -OC(O)R ^6m1 , -C(O)N(R ^6m1 )(R ^6m2 ), -N(R ^6m3 )C(O)R ^6m2 , -OC(O)N(R ^6m1 )(R ^6m2 ), -N(R ^6m1 )C(O)OR ^6m2 , -C(＝NR ^6m3 )N(R ^6m1 )(R ^6m2 ), -N(R ^6m1 )(R ^6m2 ), =O, –OH, -SR ^6m1 , -S(O)R ^6m1 , -S(NR ^6m1 )(NR ^6m2 )R ^6m3 , -S(O)(NR ^6m1 )(R ^6m2 ), -S(O) ₂ R ^6m1 , -S(O) ₂ N(R ^6m1 )(R ^6m2 ) or -N(R ^6m3 )S(O) ₂ (R ^6m2 );

Each R ^6m1 , R ^6m2 and R ^6m3 is independently hydrogen, C _1-6 alkyl, C _1-6 hydroxyalkyl, C _1-6 aminoalkyl, C _2-6 alkoxyalkyl, C _1-6 haloalkyl, C _3-10 cycloalkyl, C _1-6 alkyl-C _3-10 cycloalkyl, C _6-10 aryl, C _1-6 alkyl-C _6-10 aryl, heterocycloalkyl, C _1-6 alkyl-(heterocycloalkyl), heteroaryl or C _1-6 alkyl-(heteroaryl);

R ^6f is –OSi(R ^6f1 )(R ^6f2 )(R ^6f3 );

^R6f1 , ^R6f2 and ^R6f3 are each independently _C1-6 alkyl groups;

Each R ^6j is independently a C _2-6 alkoxyalkyl, halogen, C _1-6 haloalkyl, C _1-6 haloalkoxy, -CN, -C(O)R ^6j1 , -C(O)OR ^6j1 , -OC(O)R ^6j1 , -C(O)N(R ^6j1 )(R ^6j2 ), -N(R ^6j3 )C(O)R ^6j2 , -OC(O)N(R ^6j1 )(R ^6j2 ), -N(R ^6j1 )C(O)OR ^6j2 , -C(＝NR ^6j3 )N(R ^6j1 )(R ^6j2 ), -N(R ^6j1 )(R ^6j2 ), =O, -OR ^6j1 , -SR ^6j1 , -S(O)R ^6j1 , -S(NR ^6j1 ) -S(NR ^6j1 )(NR ^6j2 )R ^6j3 , ^{-S(O)(NR 6j1)(R 6j2 ) ,} -S(O) _2R ^6j1 , -S(O) _2N (R 6j1)(R ^6j2 ), -N(R ^6j1 )S(O) ₂ (R ^6j2 ), ^{-Si(R 6j1 )} (R ^6j2 )(R ^6j3 ), C _3-10 cycloalkyl, C _6-12 aryl, heterocycloalkyl or heteroaryl, wherein the cycloalkyl, aryl, heterocycloalkyl or heteroaryl is optionally substituted by 1 to 3 R ^6p ;

Each R ^6j1 , R ^6j2 , and R ^6j3 is independently hydrogen, _C1-6 alkyl, _C1-6 hydroxyalkyl, _C1-6 aminoalkyl, _C2-6 alkoxyalkyl, _C1-6 haloalkyl, C3-10 cycloalkyl, _C1-6 alkyl- _{C3-10 cycloalkyl, C6-10 aryl} , _C1-6 alkyl- _C6-10 aryl, _{heterocycloalkyl} , _C1-6 alkyl-(heterocycloalkyl), heteroaryl, or _C1-6 alkyl-(heteroaryl);

Each R ^6p is independently a _C1-6 alkyl, _C1-6 hydroxyalkyl, _C1-6 aminoalkyl, _C1-6 alkoxy, C2-6 alkoxyalkyl, halogen, _C1-6 haloalkyl, _C1-6 haloalkoxy, -CN, -C(O)R ^6p1 , -C(O)OR ^6p1 , -OC(O)R ^{6p1, -C(O)N(R 6p1} ₎ (R 6p2), -N(R ^6p1 )C(O)R ^6p2 , -OC(O)N(R ^6p1 )(R ^6p2 ), -N(R ^6p1 )C(O)OR ^6p2 , -C(＝NR ^6p3 )N(R ^6p1 )(R ^{6p2 )} , -N(R ^6p1 )(R ^6p2 ), =O, -OH ^, -SR ^6p1 , -S(O)R ^6p1 , -S(NR ^6p1 )(NR ^6p2 )R ^6p3 , -S(O)(NR ^6p1 )(R ^6p2 ) , -S(O) ₂ R ^6p1 , -S(O) ₂ N(R ^6p1 )(R ^6p2 ) or -N(R ^6p1 )S(O) ₂ (R ^6p2 );

Each R ^6p1 , R ^6p2 , and R ^6p3 is independently hydrogen, _C1-6 alkyl, _C1-6 hydroxyalkyl, _C1-6 aminoalkyl, _C2-6 alkoxyalkyl, _C1-6 haloalkyl, C3-10 cycloalkyl, _C1-6 alkyl- _{C3-10 cycloalkyl, C6-10 aryl} , _C1-6 alkyl- _C6-10 aryl, _{heterocycloalkyl} , _C1-6 alkyl-(heterocycloalkyl), heteroaryl, or _C1-6 alkyl-(heteroaryl);

Alternatively, ^R5 and one ^R6a together with the atoms to which they are attached form a heterocyclic alkyl group, optionally substituted by one to three ^R6g ;

Each R ^6g is independently a _C1-6 alkyl, _C2-6 alkenyl, _C2-6 alkynyl, _C1-6 hydroxyalkyl, _C1-6 aminoalkyl, _C2-6 alkoxyalkyl, halogen, _C1-6 haloalkyl, _C1-6 haloalkoxy, or –CN;

R ⁷ is hydrogen, _C1-6 alkyl, _C1-6 hydroxyalkyl, C1-6 aminoalkyl, _C1-6 alkoxy, _C2-6 alkoxyalkyl, _C1-6 alkylthio, halogen, _C1-6 haloalkyl, –CN, –OH, _-NH2 , _C3-10 cycloalkyl, _C1-6 alkyl- _{C3-10 cycloalkyl} , heterocycloalkyl, or _C1-6 alkyl-(heterocycloalkyl);

Each heterocyclic alkyl group is a 3- to 20-membered ring having 1 to 4 heteroatoms, each independently of N, O, or S; and

Each heteroaryl group is a 5- to 18-membered ring having 1 to 4 heteroatoms, each of which is independently N, O, or S.

In some embodiments, this disclosure provides a method for inhibiting DGKα in a subject of need, the method comprising administering to the subject a therapeutically effective amount of a compound of formula (I):

Or its pharmaceutically acceptable salt, wherein

^R1 is hydrogen, _C1-6 alkyl, _C2-6 alkenyl, _C2-6 alkynyl, _C1-6 alkoxy, halogen, _C1-6 haloalkyl, _C1-6 haloalkoxy, or –CN;

^R2 represents hydrogen, _C1-6 alkyl, _C2-6 alkenyl, _C2-6 alkynyl, _C1-6 hydroxyalkyl, _C1-6 alkoxy, _C2-6 alkoxyalkyl, halogen, _C1-6 haloalkyl, _C1-6 haloalkoxy, -CN, -NO, _-NO2 , -C(O) ^R2a ,

-C(O)OR ^2a , -OC(O)R ^2a , -C(O)N(R ^2a )(R ^2b ), -N(R ^2a )C(O)R ^2b , -OC(O)N(R ^2a )(R ^2b ),

-N(R ^2a )C(O)OR ^2b , -C(＝NR ^2a )N(R ^2b )(R ^2c ), -N(R ^2a )(R ^2b ) , -OR ^2a , -SR ^2a , -S(O)R ^2a ,

-S(O) ₂ R ^2a , -S(O) ₂ N(R ^2a )(R ^2b ), -N(R ^2a )S(O) ₂ (R ^2b ), -P(O)(R ^2a )(R ^2b ), -P(O)(OR ^2a )(R ^2b ),

-P(O)(OR ^2a )(OR ^2b ), _C3-10 cycloalkyl, _C1-6 alkyl- _C3-10 cycloalkyl, _C6-12 aryl,

_C1-6 alkyl- _C6-12 aryl, heterocyclic alkyl, or heteroaryl, wherein each alkenyl or ynyl group is optionally substituted by one to three ^R2d groups, each cycloalkyl group is optionally substituted by one to three ^R2e groups, each aryl group is optionally substituted by one to three ^R2f groups, each heterocyclic alkyl group is optionally substituted by one to three ^R2g groups, and each heteroaryl group is optionally substituted by one to three ^R2h groups;

Each R ^2a , R ^2b , and R ^2c is independently hydrogen, _C1-6 alkyl, _C1-6 hydroxyalkyl, _C2-6 alkoxyalkyl, _C1-6 haloalkyl, _C3-10 cycloalkyl, _C1-6 alkyl- _C3-10 cycloalkyl, _C6-12 aryl,

_C1-6 alkyl- _C6-12 aryl, heterocyclic alkyl, or heteroaryl;

Alternatively, ^R2a , ^R2b and ^R2c, when attached to the same atom, can combine with the atom to which they are attached to to form a heterocyclic alkyl group;

Each R ^2d is independently -N(R ^2d1 )(R ^2d2 ), -OR ^2d1 , C _3-10 cycloalkyl, C _1-6 alkyl-C _3-10 cycloalkyl, C _6-12 aryl, C _1-6 alkyl-C _6-12 aryl, heterocycloalkyl, or heteroaryl;

Each R ^2d1 and R ^2d2 is independently hydrogen, C _1-6 alkyl, or –C(O)O-(C _1-6 alkyl);

Each of ^R2e , ^R2f , ^R2g and ^R2h is independently hydrogen, _C1-6 alkyl, _C1-6 alkoxy, halogen, _C1-6 haloalkyl or _C1-6 haloalkoxy;

^R3 represents hydrogen, _C1-6 alkyl, _C2-6 alkenyl, _C2-6 alkynyl, _C1-6 hydroxyalkyl, _C1-6 alkoxy, _C2-6 alkoxyalkyl, halogen, _C1-6 haloalkyl, _C1-6 haloalkoxy, -CN, -NO, _-NO2 , -C(O) ^R3a ,

-C(O)OR ^3a , -OC(O)R ^3a , -C(O)N(R ^3a )(R ^3b ), -N(R ^3a )C(O)R ^3b , -OC(O)N(R ^3a )(R ^3b ),

-N(R ^3a )C(O)OR ^3b , -C(=NR ^3a )N(R ^3b )(R ^3c ), -N(R ^3a )(R ^3b ) , -OR ^3a , -SR ^3a , -S(O)R ^3a ,

-S(O) ₂ R ^3a , -S(O) ₂ N(R ^3a )(R ^3b ), -N(R ^3a )S(O) ₂ (R ^3b ), -P(O)(R ^3a )(R ^3b ), -P(O)(OR ^3a )(R ^3b ),

-P(O)(OR ^3a )(OR ^3b ), _C3-10 cycloalkyl, _C1-6 alkyl- _C3-10 cycloalkyl, _C6-12 aryl,

_C1-6 alkyl- _C6-12 aryl, heterocyclic alkyl, or heteroaryl, wherein each alkenyl or ynyl group is optionally substituted by one to three ^R3d groups, each cycloalkyl group is optionally substituted by one to three ^R3e groups, each aryl group is optionally substituted by one to three ^R3f groups, each heterocyclic alkyl group is optionally substituted by one to three ^R3g groups, and each heteroaryl group is optionally substituted by one to three ^R3h groups;

Each of R ^3a , R ^3b , and R ^3c is independently hydrogen, _C1-6 alkyl, _C1-6 hydroxyalkyl, _C2-6 alkoxyalkyl, _C1-6 haloalkyl, _C3-10 cycloalkyl, _C1-6 alkyl- _C3-10 cycloalkyl, _C6-12 aryl,

_C1-6 alkyl- _C6-12 aryl, heterocyclic alkyl, or heteroaryl;

Alternatively, ^R3a , ^R3b and ^R3c , when attached to the same atom, can combine with the atom to which they are attached to to form a heterocyclic alkyl group;

Each R ^3d is independently -N(R ^3d1 )(R ^3d2 ), -OR ^3d1 , C _3-10 cycloalkyl, C _1-6 alkyl-C _3-10 cycloalkyl, C _6-12 aryl, C _1-6 alkyl-C _6-12 aryl, heterocycloalkyl, or heteroaryl;

Each R ^3d1 and R ^3d2 is independently hydrogen, C _1-6 alkyl, or –C(O)O-(C _1-6 alkyl);

Each of ^R3e , ^R3f , ^R3g and ^R3h is independently hydrogen, _C1-6 alkyl, _C1-6 alkoxy, halogen, _C1-6 haloalkyl or _C1-6 haloalkoxy;

^R4 is hydrogen, _C1-6 alkyl, _C2-6 alkenyl, _C2-6 alkynyl, _C1-6 alkoxy, halogen, _C1-6 haloalkyl, _C1-6 haloalkoxy, or –CN;

R ⁵ is hydrogen, _C1-6 alkyl, _C2-6 alkenyl, _C2-6 alkynyl, _C1-6 hydroxyalkyl, _C2-6 alkoxyalkyl, _C1-6 haloalkyl, _C3-10 cycloalkyl, _C1-6 alkyl- _C3-10 cycloalkyl, _C6-12 aryl, _C1-6 alkyl- _C6-12 aryl, heterocycloalkyl, _C1-6 alkyl-(heterocycloalkyl), heteroaryl, or _C1-6 alkyl-(heteroaryl), wherein the alkyl group is optionally substituted with R ^5a ;

R ^5a is –OSi(R ^5a1 )(R ^5a2 )(R ^5a3 );

^R5a1 , ^R5a2 , and ^R5a3 are each independently a _C1-6 alkyl group; and

^R6 is a _C1-6 alkyl, _C2-6 alkenyl, _C2-6 alkynyl, _C1-6 haloalkyl, _C6-12 aryl or heteroaryl, wherein each of the aryl or heteroaryl groups is optionally substituted by one to three ^R6a .

Each R ^6a is independently a _C1-6 alkyl, _C2-6 alkenyl, _C2-6 alkynyl, _C1-6 hydroxyalkyl, _C1-6 alkoxy, _C2-6 alkoxyalkyl, halogen, _C1-6 haloalkyl, _C1-6 haloalkoxy, –CN, _–NO₂ , –C(O)R ^6b ,

-C(O)OR ^6b , -OC(O)R ^6b , -C(O)N(R ^6b )(R ^6c ), -N(R ^6b )C(O)R ^6c , -C(＝NR ^6b )N(R ^6c )(R ^6d ),

-N(R ^6b )(R ^6c ), -OR ^6b , -SR ^6b , -S(O)R ^6b , -S(O) _2R ^6b , -S(O) _2N (R ^6b )(R ^6c ), -N(R ^6b )S(O) ₂ (R ^6c ), C _3-10 cycloalkyl, C _6-12 aryl, heterocycloalkyl or heteroaryl, wherein each of the cycloalkyl, aryl, heterocycloalkyl or heteroaryl is optionally substituted by 1 to 3 R ^6e , and the alkyl is optionally substituted by R ^6f ;

Alternatively, ^R5 and one ^R6a together with the atoms to which they are attached form a heterocyclic alkyl group, which may optionally be substituted by one to three ^R6g ;

Each R ^6b , R ^6c and R ^6d is independently hydrogen, C _1-6 alkyl, C _1-6 hydroxyalkyl, C _2-6 alkoxyalkyl, C _1-6 haloalkyl, C _3-10 cycloalkyl, C _1-6 alkyl-C _3-10 cycloalkyl, C _6-12 aryl, C _1-6 alkyl-C _6-12 aryl, heterocycloalkyl or heteroaryl;

Each R ^6e is independently a _C1-6 alkyl, _C2-6 alkenyl, _C2-6 alkynyl, _C1-6 hydroxyalkyl, _C1-6 alkoxy, _C2-6 alkoxyalkyl, halogen, _C1-6 haloalkyl, _C1-6 haloalkoxy, –CN, _–NO₂ , –C(O)R ^6e₁ ,

-C(O)OR ^6e1 , -OC(O)R ^6e1 , -C(O)N(R ^6e1 )(R ^6e2 ) , -N(R ^6e1 )C(O)R ^6e2 ,

-C(＝NR ^6e1 )N(R ^6e2 )(R ^6e3 ), -N(R ^6e1 )(R ^6e2 ), -OR ^6e1 , -SR ^6e1 , -S(O)R ^6e1 , -S(O) ₂ R ^6e1 ,

-S(O) _2N ( ^R6e1 )( ^R6e2 ), -N( ^R6e1 )S(O) ₂ ( ^R6e2 ), _C3-10 cycloalkyl, _C6-12 aryl, heterocycloalkyl or heteroaryl, wherein each of the cycloalkyl, aryl, heterocycloalkyl or heteroaryl is optionally substituted by 1 to 3 ^R6h ;

Each of ^R6e1 , ^R6e2 and ^R6e3 is independently hydrogen or _C1-6 alkyl;

R ^6f is –OSi(R ^6f1 )(R ^6f2 )(R ^6f3 );

^R6f1 , ^R6f2 and ^R6f3 are each independently _C1-6 alkyl groups;

Each R ^6g is independently a _C1-6 alkyl, _C2-6 alkenyl, _C2-6 alkynyl, halogen, _C1-6 haloalkyl, _C1-6 haloalkoxy, or –CN;

Each R ^6h is independently a _C1-6 alkyl, _C2-6 alkenyl, _C2-6 alkynyl, _C1-6 alkoxy, halogen, _C1-6 haloalkyl, _C1-6 haloalkoxy, -C(O)R ^6h1 , -C(O)OR ^6h1 , -OC(O)R ^6h1 , -C(O)N(R ^6h1 )(R ^6h2 ),

-N(R ^6h1 )C(O)R ^6h2 , -C(＝NR ^6h1 )N(R ^6h2 )(R ^6h3 ) , -N(R ^6h1 )(R ^6h2 ) , –OH, -SR ^6h1 , -S(O)R ^6h1 ,

-S(O) ₂ R ^6h1 , -S(O) ₂ N(R ^6h1 )(R ^6h2 ) or -N(R ^6h1 )S(O) ₂ (R ^6h2 );

Each of ^R6h1 , ^R6h2 and ^R6h3 is independently hydrogen or _C1-6 alkyl;

^R7 is hydrogen, _C1-6 alkyl, halogen, _C1-6 haloalkyl, –CN, or –OH;

Each heterocyclic alkyl group is a 3- to 10-membered ring having one to four heteroatoms, each independently of N, O, or S; and

Each heteroaryl group is a 5- to 10-membered ring having 1 to 4 heteroatoms, each of which is independently N, O, or S.

In some embodiments, the method of inhibiting DGKα in a subject of need comprises administering to the subject a therapeutically effective amount of a compound having the structure of a compound listed in Tables 1A, 1B, 1C, 1D, 1E, 1F, 1G, 1H, 1I, 1J, 2A, 2B, 2C, 2D, 2E, 2F, 2G, 2H, 2I, 2J, 2K, 2L, 3A, 3B, 3C, 3D, 3E, 3F, 3G, 3H, 3I, 3J, or 3K, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof. In some embodiments, the method of inhibiting DGKα in a subject of need comprises administering to the subject a therapeutically effective amount of a compound having the structure of a compound listed in Tables 3F, 3H, 3I, 3J, or 3K, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

In some embodiments, this disclosure provides a method of treating cancer in a subject of need, the method comprising administering to the subject a therapeutically effective amount of a compound of this disclosure or a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof.

In some implementations, the cancer is pancreatic cancer, bladder cancer, colorectal cancer, breast cancer, prostate cancer, kidney cancer, hepatocellular carcinoma, lung cancer, ovarian cancer, cervical cancer, stomach cancer, esophageal cancer, head and neck cancer, melanoma, neuroendocrine carcinoma, CNS cancer, brain cancer, bone cancer, soft tissue sarcoma, non-small cell lung cancer, small cell lung cancer, or colon cancer. In some implementations, the cancer is acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), myelodysplastic syndrome (MDS), myelodysplastic disorder (MPD), chronic myeloid leukemia (CML), multiple myeloma (MM), non-Hodgkin's lymphoma (NHL), mantle cell lymphoma (MCL), follicular lymphoma, Waldenström macroglobulinemia (WM), T-cell lymphoma, B-cell lymphoma, or diffuse large B-cell lymphoma (DLBCL). In some implementations, cancer is brain (glioma), glioblastoma, astrocytoma, multimorphic glioma, Bannayan-Zonana syndrome, Cowden disease, Lhermitte-Duclos disease, breast cancer, colon cancer, head and neck cancer, kidney cancer, lung cancer, liver cancer, melanoma, ovarian cancer, pancreatic cancer, adenocarcinoma, ductal adenocarcinoma, adenosquamous carcinoma, acinar cell carcinoma, glucagonoma, insulinoma, prostate cancer, sarcoma, or thyroid cancer.

In some implementations, the cancer is a solid tumor, a hematologic malignancy, or a metastatic lesion. In some implementations, the solid tumor is a sarcoma, a fibrosarcoma, a carcinoma, or adenocarcinoma. In some implementations, the hematologic malignancy is leukemia, lymphoma, or myeloma.

In some implementation schemes, cancer includes lung cancer, melanoma, kidney cancer, liver cancer, myeloma, prostate cancer, breast cancer, ovarian cancer, colorectal cancer, pancreatic cancer, head and neck cancer, anal cancer, gastroesophageal cancer, mesothelioma, nasopharyngeal carcinoma, thyroid cancer, cervical cancer, epithelial cancer, peritoneal cancer, lymphoproliferative disease, acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), chronic myeloid monocytic leukemia (CMML), and capillary... Leukemia, B-cell lymphoma, diffuse large B-cell lymphoma (DLBCL), activated B-cell-like (ABC) diffuse large B-cell lymphoma, germinal center B-cell (GCB) diffuse large B-cell lymphoma, mantle cell lymphoma, Hodgkin lymphoma, non-Hodgkin lymphoma, relapsed non-Hodgkin lymphoma, refractory non-Hodgkin lymphoma, relapsed follicular non-Hodgkin lymphoma, Burkitt lymphoma, small lymphocytic lymphoma, follicular lymphoma, lymphoplasmacytic lymphoma, or extranodular marginal zone lymphoma.

In some implementations, the cancer is an epithelial tumor (e.g., carcinoma, squamous cell carcinoma, basal cell carcinoma, squamous intraepithelial neoplasia), an adenomatous tumor (e.g., adenocarcinoma, adenoma, adenomyoma), a mesenchymal or soft tissue tumor (e.g., sarcoma, rhabdomyosarcoma, leiomyosarcoma, liposarcoma, fibrosarcoma, dermatofibrosarcoma, neurofibrosarcoma, fibrous histiocytoma, angiosarcoma, angiomyosarcoma, leiomyosarcoma, chondroma, chondrosarcoma, alveolar soft tissue sarcoma, epithelioid angioendothelioma, Spitz tumor, synovial sarcoma), or lymphoma.

In some implementations, cancer is a solid tumor in or originating from a tissue or organ selected from the group consisting of: bone (e.g., ameloma, aneurysmal bone cyst, angiosarcoma, chondroblastoma, chondroma, chondromycinoid fibroma, chondrosarcoma, chordoma, dedifferentiated chondrosarcoma, enchondroma, epithelioid hemangioendothelioma, fibrous dysplasia of bone, giant cell tumor of bone, hemangioma and related lesions, osteoblastoma, osteochondroma, osteosarcoma, osteoid osteoma, osteoma, periosteal chondroma, desmoid tumor, Ewing sarcoma); lips and oral cavity (e.g., odontogenic ameloblastoma). Cell tumors, oral leukoplakia, oral squamous cell carcinoma, primary oral mucosal melanoma); salivary glands (e.g., pleomorphic salivary gland adenoma, salivary gland adenoid cystic carcinoma, salivary gland mucoepidermoid carcinoma, salivary gland Worsham tumor); esophagus (e.g., Barrett's esophagus, developmental dysplasia, and adenocarcinoma); gastrointestinal tract, including the stomach (e.g., gastric adenocarcinoma, primary gastric lymphoma, gastrointestinal stromal tumor (GIST), metastatic deposits, gastric cancer, gastric sarcoma, neuroendocrine carcinoma, primary gastric squamous cell carcinoma, gastric adenoacanthoma), intestine and smooth muscle (e.g., intravenous leiomyoma), colon (e.g., colorectal adenocarcinoma), rectum, anus; pancreas ( For example, serous tumors, including microcystic or large cystic serous cystadenomas, solid serous cystadenomas, Von Hippel-Landau (VHL)-associated serous cystic tumors, serous cystadenomas, mucinous cystic tumors (MCNs), intraductal papillary mucinous tumors (IPMNs), intraductal eosinophilic papillary tumors (IOPNs), intraductal tubular tumors, cystic acinar tumors (including acinar cell cystadenomas and acinar cell cystadenocarcinomas), pancreatic cancer, invasive pancreatic ductal adenocarcinomas (including tubular adenocarcinomas and adenosquamous carcinomas), colloid carcinoma, medullary carcinoma, hepatoid carcinoma, signet ring cell carcinoma, undifferentiated carcinoma, and others. Undifferentiated carcinoma with osteoclast-like giant cells, acinar cell carcinoma, neuroendocrine tumors, neuroendocrine microadenomas, neuroendocrine tumors (NETs), neuroendocrine carcinomas (NECs) (including small cell or large cell NECs), insulinomas, gastrinomas, glucagonomas, serotonin-producing NETs, somatostatinomas, VIPomas, solid pseudopapillary tumors (SPNs), pancreatoblastomas; gallbladder (e.g., gallbladder cancer and extrahepatic and intrahepatic bile duct cancers); neuroendocrine glands (e.g., adrenocortical carcinomas, carcinoid tumors, pheochromocytomas, pituitary adenomas); thyroid glands (e.g., anaplastic (undifferentiated)). Carcinoma, medullary carcinoma, eosinophilic cell tumor, papillary carcinoma, adenocarcinoma); liver (e.g., adenoma, combined hepatocellular and bile duct epithelial carcinoma, fibrous carcinoma, hepatoblastoma, hepatocellular carcinoma, mesenchymal, nested mesenchymal epithelial tumor, undifferentiated carcinoma, hepatocellular carcinoma, intrahepatic bile duct epithelial carcinoma, bile duct cyst adenocarcinoma, epithelioid cell endothelioma, angiosarcoma, embryonal sarcoma, rhabdomyosarcoma, solitary fibroma, teratoma, York's cyst tumor, carcinosarcoma, rod tumor); kidney (e.g., ALK rearranged renal cell carcinoma, chromophobe renal cell carcinoma, clear cell renal cell carcinoma, clear cell sarcoma, metanephrotic adenoma, metanephrotic fibroma, mucinous tubular and spindle-shaped tumors). Renal cell carcinoma, renal adenoma, nephroblastoma (Wilms' tumor), papillary adenoma, papillary renal cell carcinoma, renal eosinophilic cell carcinoma, renal cell carcinoma, succinate dehydrogenase-deficient renal cell carcinoma, collecting duct carcinoma); breast (e.g., invasive ductal carcinoma, including but not limited to acinar cell carcinoma, adenoid cystic carcinoma, apocrine gland carcinoma, cribriform carcinoma, glycogen-rich/clear cell inflammatory carcinoma, lipid-rich carcinoma, medullary carcinoma, metaplastic carcinoma, micropapillary carcinoma, mucinous carcinoma, neuroendocrine carcinoma, eosinophilic cell carcinoma, papillary carcinoma, sebaceous gland carcinoma, secretory breast cancer, tubular carcinoma, lobular carcinoma (including but not limited to pleomorphic carcinoma, signet ring cell carcinoma), peritoneum (e.g. Mesothelioma, primary peritoneal cancer); female sex organ tissues, including the ovary (e.g., choriocarcinoma, epithelial cell carcinoma, germ cell carcinoma, sex cord-stromal tumor), fallopian tube (e.g., serous adenocarcinoma, mucinous adenocarcinoma, endometrioid adenocarcinoma, clear cell adenocarcinoma, transitional cell carcinoma, squamous cell carcinoma, undifferentiated carcinoma, müllerian tumor, adenosarcoma, leiomyosarcoma, teratoma, germ cell carcinoma, choriocarcinoma, trophoblastoma), uterus (e.g., cervical cancer, endometrial polyps, endometrial hyperplasia, intraepithelial carcinoma (EIC), endometrial cancer (e.g., endometrioid carcinoma, serous carcinoma, clear cell carcinoma), and fallopian tube (e.g., endometrioid carcinoma, serous carcinoma, clear cell carcinoma). Cellular carcinoma, mucinous carcinoma, squamous cell carcinoma, transitional carcinoma, small cell carcinoma, undifferentiated carcinoma, mesenchymal tumor), leiomyomas (e.g., endometrial stromal nodules, leiomyosarcoma, endometrial stromal sarcoma (ESS), mesenchymal tumors), mixed epithelial and mesenchymal tumors (e.g., adenofibroma, carcinoma fibroma, adenosarcoma, carcinosarcoma (malignant mixed mesodermal sarcoma - MMMT), endometrial stromal tumors, malignant mixed Miller's tumors of the endometrium, gestational trophoblastic tumors (partial vesicular mass, complete vesicular mass, invasive vesicular mass, placental site tumors)), vulva, vagina; male sex organ tissue, including This includes the prostate, testes (e.g., germ cell tumors, seminoma), penis; bladder (e.g., squamous cell carcinoma, urothelial carcinoma, bladder urothelial carcinoma); brain (e.g., gliomas (e.g., astrocytomas (including non-invasive, low-grade, anaplastic), glioblastomas; oligodendrogliomas, ependymomas), meningiomas, gangliogliomas, schwannomas/neurilemmomas, craniopharyngiomas, chordomas, non-Hodgkin's lymphomas, pituitary adenomas); and eyes (e.g., retinoblastomas, retinoblastomas, corneal opacities). Malignant melanoma of the choroid, iris hamartoma; head and neck (e.g., nasopharyngeal carcinoma, endolymphatic sac tumor (ELST), epidermoid carcinoma, laryngeal carcinoma (including squamous cell carcinoma (SCC) (e.g., glottic carcinoma, supraglottic laryngeal carcinoma, subglottic laryngeal carcinoma, transglottic carcinoma), carcinoma in situ, verrucous hemangioma, spindle cell and basal cell SCC, undifferentiated carcinoma, laryngeal adenocarcinoma, adenoid cystic carcinoma, neuroendocrine carcinoma, laryngeal tumor), head and neck paraganglioma (e.g., carotid body tumor, tympanic cavity tumor, vagus neuroma); thymus (e.g., thymoma); heart (e.g., cardiac myxoma); lung (e.g., small cell carcinoma (SCLC)). Non-small cell lung cancer (NSCLC) (including squamous cell carcinoma (SCC), adenocarcinoma, and large cell carcinoma), carcinoid tumors (typical or atypical), carcinosarcoma, pulmonary blastoma, giant cell carcinoma, spindle cell carcinoma, and pleural pulmonary blastoma; lymphomas (e.g., lymphomas, including Hodgkin's lymphoma, non-Hodgkin's lymphoma, Epstein-Barr virus (EBV)-associated lymphoid hyperplasia, including B-cell lymphoma and T-cell lymphomas (e.g., Burkitt lymphoma, large B-cell lymphoma, diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma, painless B-cell lymphoma, low-grade B-cell lymphoma). Cellular lymphoma, fibrin-associated diffuse large cell lymphoma; primary exudative lymphoma; plasmablastic lymphoma; nasal extranodal NK/T-cell lymphoma; peripheral T-cell lymphoma, cutaneous T-cell lymphoma, angioimmunoblastic T-cell lymphoma; follicular T-cell lymphoma; systemic T-cell lymphoma, lymphangioleiomyomatosis); central nervous system (CNS) (e.g., gliomas, including astrocytic tumors such as pilocytic astrocytoma, hematocytoid astrocytoma, subependymal giant cell astrocytoma, pleomorphic xanthoastrocytoma, diffuse astrocytoma, fibrous astrocytoma). Species include: 1) Fat cell astrocytoma, protoplasmic astrocytoma, anaplastic astrocytoma; 2) Glioblastoma (e.g., giant cell glioblastoma, glioma, glioblastoma multiforme) and gliomatosis; 3) Oligodendroglial tumors (e.g., oligodendroglioma, anaplastic oligodendroglioma); 4) Oligodendroglial tumors (e.g., oligodendroglioma, anaplastic oligodendroglioma); 5) Ependymal tumors (e.g., subependymoma, myxopapillary ependymoma, ependymoma (e.g., cellular, papillary, clear cell, elongated cell type), anaplastic ependymoma; 6) Optic nerve glioma and non-glial tumors. (e.g., choroid plexus tumors, neuronal and mixed neuron-glial tumors, pineal region tumors, embryonal tumors, medulloblastomas, meningeal tumors, primary CNS lymphomas, germ cell tumors, pituitary adenomas, skull and paravertebral nerve tumors, stellate region tumors), neurofibromas, meningiomas, peripheral schwannomas, peripheral neuroblastomas (including but not limited to neuroblastomas, ganglioblastomas, gangliomas), trisomy 19 ependymomas); neuroendocrine tissues (e.g., the paraganglionic system, including adrenal medulla (pheochromocytoma) and extra-adrenal paraganglionic ganglia). Gangliomas; skin (e.g., clear cell hidradenoma, benign fibrous histiocytoma of the skin, cylindrica, hidradenoma, melanoma (including cutaneous melanoma, mucosal melanoma), pilomatoma, Spitz tumor); and soft tissue (e.g., aggressive angiomyxoma, alveolar rhabdomyosarcoma, alveolar soft partial sarcoma, angiofibroma, hemangioma-like fibrous histiocytoma, synovial sarcoma, biphasic synovial sarcoma, clear cell sarcoma, dermatofibrosarcoma protuberans, desmoid fibroma, small round cell tumor, desmoplastic small round cell tumor, fibroelastoma, embryonal rhabdomyosarcoma, Ewing tumor/progenitor). Neuroectodermal tumors (PNET), extraosseous myxoid chondrosarcoma, extraosseous osteosarcoma, paravertebral sarcoma, inflammatory myofibroblastic tumor, liposarcoma, lipoma, chondroid lipoma, liposarcoma/malignant lipoma tumor, liposarcoma, myxoid liposarcoma, fibromyxoid sarcoma, lymphoangioleiomyosarcoma, malignant myoepithelioma, malignant melanoma of the soft tissue portion, myoepithelial carcinoma, myoepithelioma, myxoinflammatory fibroblastic sarcoma, undifferentiated sarcoma, peridermoma, rhabdomyosarcoma, non-rhabdomyosarcoma soft tissue sarcoma (NRSTS), soft tissue leiomyosarcoma, undifferentiated sarcoma, well-differentiated liposarcoma.

In some implementation schemes, the cancer is melanoma, gastric cancer, triple-negative breast cancer (TNBC), non-small cell lung cancer (NSCLC), rectal adenocarcinoma, colorectal cancer, renal cell carcinoma, ovarian cancer, prostate cancer, oral squamous cell carcinoma (SCC), head and neck squamous cell carcinoma (HNSCC), urinary tract epithelial bladder cancer, glioblastoma (GBM), meningioma, adrenal cancer, or endometrial cancer.

In some embodiments, the method further includes administering one or more adjunctive therapeutic agents to the subject. The adjunctive therapeutic agent may include any of the therapeutic agents described above for combination therapy. In some embodiments, the adjunctive therapeutic agent is independently an antitumor agent, nivolumab, pembrolizumab, atezolizumab, ipilimumab, chemotherapy, radiation therapy, or resection therapy. In some embodiments, the adjunctive therapeutic agent is independently rituximab, doxorubicin, gemcitabine, nivolumab, pembrolizumab, atezolizumab, nivolumab, pembrolizumab, atezolizumab, or ipilimumab.

In some embodiments, the method includes one or more additional therapeutic agents, wherein the additional therapeutic agents are PD-1/PD-L1 inhibitors.

In some implementations, the antitumor agent is an antimicrotubule agent, a platinum coordination complex, an alkylating agent, an antibiotic, a topoisomerase II inhibitor, an antimetabolite, a topoisomerase I inhibitor, a hormone or hormone analog, a signal transduction pathway inhibitor, a non-receptor tyrosine kinase angiogenesis agent, an inhibitor, an immunotherapeutic agent, an apoptosis-promoting agent, a cell cycle signaling inhibitor, a proteasome inhibitor, a cancer metabolism inhibitor, an anti-PD-L1 agent, a PD-1 antagonist, an immunomodulator, a STING regulatory compound, a CD39 inhibitor, an A2a and A2a adenosine antagonist, a TLR4 antagonist, an anti-ICOS antibody, or OX40.

In some embodiments, the compound or pharmaceutical composition is administered in combination with one or more additional therapeutic agents, said additional therapeutic agents including activators or agonists of FMS-associated tyrosine kinase 3 (FLT3; CD135) receptors, Toll-like receptors (TLRs), or interferon gene stimulators (STING) receptors.

In some implementations, the TLR agonist or activator is a TLR2 agonist, a TLR3 agonist, a TLR7 agonist, a TLR8 agonist, or a TLR9 agonist.

In some implementations, the STING receptor agonist or activator is ADU-S100 (MIW-815), SB-11285, MK-1454, SR-8291, AdVCA0848, GSK-532, SYN-STING, MSA-1, SR-8291, 5,6-dimethylxanthonone-4-acetic acid (DMXAA), cyclic GAMP (cGAMP), and cyclic diAMP.

In some embodiments, the compound or pharmaceutical composition is co-administered with one or more adjunctive therapeutic agents comprising inhibitors or antagonists of: protein tyrosine phosphatase, non-receptor type 11 (PTPN11 or SHP2), myeloid leukemia sequence 1 (MCL1) apoptosis regulator; mitogen-activated protein kinase kinase 1 (MAP4K1) (also known as hematopoietic progenitor cell kinase 1 (HPK1)), diacylglycerol kinase α (DGKA, DAGK, DAGK1 or DGK-α); 5'-exonuclease (NT5E or CD73); transforming growth factor β1 (TGFB1 or TGF); heme oxygenase 1 (HMOX1, HO-1 or HO1); vascular endothelial growth factor A (VEGFA or VEGF); ERBB2 receptor tyrosine kinase 2 (ERBB2, HER2, HER2/neu, or CD340); epidermal growth factor receptor (EGFR, ERBB, ERBB1, or HER1); ALK receptor tyrosine kinase (ALK, CD246); poly(ADP-ribose) polymerase 1 (PARP1 or PARP); cyclin-dependent kinase 4 (CDK4); cyclin-dependent kinase 6 (CDK6); C-C motif chemokine receptor 8 (CCR8, CDwl98); CD274 molecule (CD274, PDL1, or PD-L1); programmed cell death protein 1 (PDCD1, PD1, or PD-1); and/or cytotoxic T lymphocyte-associated protein 4 (CTLA4, CTLA-4, CD152);

In some implementations, the inhibitor comprises an antigen-binding molecule, an antibody, or an antigen-binding fragment thereof.

In some implementations, the inhibitors of MCL1 are AMG-176, AMG-397, S-64315, AZD-5991, 483-LM, A1210477, UMI-77, or JKY-5-037.

In some implementations, the inhibitors of PTPN11 or SHP2 are TN0155 (SHP-099), RMC-4550, JAB-3068, and RMC-4630.

In some embodiments, the adjunctive therapeutic agent is a chemotherapeutic agent, an antitumor agent, a radiotherapy agent, or a checkpoint target. In some embodiments, one or more antitumor agents or chemotherapeutic agents are nucleoside analogs (e.g., 5-fluorouracil, gemcitabine, cytarabine), taxanes (e.g., paclitaxel, nalbu-paclitaxel, docetaxel, cabazitaxel), platinum coordination complexes (cisplatin, carboplatin, oxaliplatin, nedaplatin, triplatinum tetranitrate, phenanthreneplatin, pyridine, cetaplatin, bicycloplatin, etopoplatin, lobaplatin, miplatin), dihydrofolate reductase (DHFR) inhibitors (e.g., methotrexate, trimetazidine, pemetrexed), topoisomerase inhibitors (e.g., doxorubicin, daunorubicin, actinomycin, eniposide, epirubicin, etoposide, idarubicin, irinotecan, mitoxantrone, pickaxane, sobuzosen, topotecan, irinotecan, etc.). Rinotecan, MM-398 (liposomal irinotecan), vosaroxin and GPX-150, alarobicin, AR-67, marchertinib, AST-2818, avitinib (ACEA-0010), ilofofen (MGI-114)), alkylating agents (e.g., nitrogen mustard gas (e.g., cyclophosphamide, nitrogen mustard, uramustine or uracil nitrogen mustard, melphalan, chlorambucil, ifosfamide, bendamustine, temozolomide, carmustine), nitrosoureas (e.g., carmustine, lomustine, streptozotocin), alkyl sulfonates (e.g., busulfan)) or mixtures thereof.

In some implementations, the checkpoint target is an antagonist anti-PD-1 antibody, an antagonist anti-PD-L1 antibody, an antagonist anti-PD-L2 antibody, an antagonist anti-CTLA-4 antibody, an antagonist anti-TIM-3 antibody, an antagonist anti-LAG-3 antibody, an antagonist anti-CEACAM1 antibody, an agonist anti-GITR antibody, an antagonist anti-TIGIT antibody, an antagonist anti-VISTA antibody, an agonist anti-CD137 antibody, or an agonist anti-OX40 antibody.

In some embodiments, the adjunctive therapeutic agent comprises one or more cell therapies. In some embodiments, the cell therapy comprises one or more of a population of natural killer (NK) cells, NK-T cells, T cells, cytokine-induced killer (CIK) cells, macrophages (MAC) cells, tumor-infiltrating lymphocytes (TILs), and/or dendritic cells (DCs). In some embodiments, the cell therapy requires T cell therapy, such as co-administration of a population of α/βTCR T cells, γ/δTCR T cells, regulatory T (Treg) cells, and/or TruC ^™ T cells. In some embodiments, the cell therapy requires NK cell therapy, such as co-administration of NK-92 cells. Cell therapy may require co-administration of cells that are autologous, syngeneic, or allogeneic to the subject. In some embodiments, one or more immune cell populations comprise one or more chimeric antigen receptors (CARs).

In some implementations, the adjunctive therapeutic agent includes an antibody or its antigen-binding fragment or its antibody-drug conjugate, a CD3-targeting multispecific molecule, a CD16-targeting multispecific molecule, a non-immunoglobulin antigen-binding molecule, or an antibody mimicry protein.

In some embodiments, one or more adjunctive therapeutic agents include immunotherapy, immunostimulatory therapy, cytokine therapy, chemokine therapy, cell therapy, gene therapy, and combinations thereof. In some embodiments, immunotherapy includes co-administration of one or more antibodies or their antigen-binding antibody fragments or their antibody-drug conjugates, multispecific molecules targeting CD3, multispecific molecules targeting CD16, or non-immunoglobulin antigen-binding domains, or antibody mimics targeting one or more targets or tumor-associated antigens (TAAs).

In some embodiments, this disclosure provides a method of treating a subject in need of HIV or hepatitis B virus infection, the method comprising administering to the subject a therapeutically effective amount of a compound of this disclosure or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof. In some embodiments, the compound or pharmaceutical composition is co-administered with one or more additional therapeutic agents. In some embodiments, one or more additional therapeutic agents include a vaccine.

In some embodiments, a method for manufacturing a medicament for treating cancer in a subject in need is characterized by using a compound of the present disclosure or a pharmaceutically acceptable salt thereof.

In some embodiments, a method for manufacturing a medicament for inhibiting cancer metastasis in a subject in need is characterized by using a compound of the present disclosure or a pharmaceutically acceptable salt thereof.

In some embodiments, a method for manufacturing a medicament for treating HIV or hepatitis B virus infection in a subject in need is characterized by using a compound of the present disclosure or a pharmaceutically acceptable salt thereof.

In some embodiments, the use of the compounds disclosed herein or pharmaceutically acceptable salts thereof is for the manufacture of a medicament for treating a subject's cancer.

In some embodiments, the use of the compounds disclosed herein or pharmaceutically acceptable salts thereof is for the manufacture of a medicament for inhibiting cancer metastasis in a subject.

In some embodiments, the use of the compounds disclosed herein or pharmaceutically acceptable salts thereof is for the manufacture of a medicament for treating a subject with HIV or hepatitis B infection.

In some embodiments, the compounds of this disclosure are used as a therapy. In some embodiments, the compounds are used to treat cancer in a subject of need. In some embodiments, the compounds are used to inhibit cancer metastasis in a subject of need. In some embodiments, the compounds are used to treat HIV or hepatitis B virus infection in a subject of need.

VII. Synthesis Method

Abbreviations. Certain abbreviations and acronyms are used to describe experimental details. While those skilled in the art will understand most of these, Table 4 contains a list of many of these abbreviations and acronyms.

Table 4. List of Abbreviations and Acronyms

General Synthesis Program

Compounds of formulas (I), (I-1), (Ia), (Ia-1), (Ib), (Ic), (IIa), (IIa-1), (IIc), (IIc-1), (IIc-2), (IIc-2), (IIc-3), (IIc-4), (IIc-5), (IIc-6), (IIc-7), or (IIc-8) of this disclosure can be prepared, for example, according to the following schemes. During any method used to prepare the subject compounds, it may be necessary and/or desired to protect sensitive or reactive groups on any molecule of interest. This can be achieved by means of conventional protecting groups as described in standard works such as T.W. Greene and P.G.M. Wuts, “Protective Groups in Organic Synthesis,” 4th edition, Wiley, New York, 2006. For example, in some embodiments, protection includes benzyloxycarbonyl or tert-butoxycarbonyl as an amino protecting group and/or tert-butylmethylsilyl as a hydroxyl protecting group. The protecting group can be removed in a convenient subsequent stage using methods known in the art.

Exemplary chemical entities that can be used in the implementation methods will now be described by referring to the general preparation described herein and subsequent specific examples of the illustrative synthetic scheme. Those skilled in the art will recognize that, in order to obtain the various compounds described herein, starting materials may be suitably selected such that a reaction scheme, carried out as appropriate or without protection, will bring the final desired substituent to produce the desired product. Alternatively, it may be necessary or desirable to use a suitable group instead of the final desired substituent, which can be carried out by the reaction scheme and, as appropriate, replaced by the desired substituent. Furthermore, those skilled in the art will recognize that the transformations shown in the following schemes can be performed in any order compatible with the functionality of the particular side groups. Unless otherwise stated, each reaction in the reactions depicted in the general scheme can be operated at a temperature from about 0°C to the reflux temperature of the organic solvent used. Each variable site disclosed in the following scheme is applicable to each functional group of formula (I), (I-1), (Ia), (Ia-1), (Ib), (Ic), (IIa), (IIa-1), (IIc), (IIc-1), (IIc-2), (IIc-2), (IIc-3), (IIc-4), (IIc-5), (IIc-6), (IIc-7), or (IIc-8) provided in this disclosure.

The implementation plan also relates to methods and intermediates that can be used to prepare the subject compound or its pharmaceutically acceptable salts.

General Option 1

Compounds of formula (I), (I-1), (Ia), (Ia-1), (Ib), (Ic), (IIa), (IIa-1), (IIc), (IIc-1), (IIc-2), (IIc-2), (IIc-3), (IIc-4), (IIc-5), (IIc-6), (IIc-7), or (IIc-8) can be prepared according to general synthetic scheme 1, wherein ^R1 , ^R2 , ^R3 , ^R4 , ^R5 , and ^R6 are as described above.

According to general synthetic scheme 1, the compound of formula (1-a) can react with the compound of formula (1-b) in a solvent to produce the compound of formula (1-c). Any suitable non-reactive solvent is expected to be used for this reaction, such as DMF. The reaction can be carried out at a time and temperature suitable for producing the desired amount of compound (1-c) (e.g., at a temperature ranging from room temperature to 100°C and for a time ranging from minutes to hours, e.g., for one hour at room temperature).

Compounds of formula (1-a) are commercially available or readily synthesized by methods known to those skilled in the art (such as those described in J. Med. Chem. 2014, 57, 5141-5156 or similar methods). Compounds of formula (1-b) are commercially available or readily prepared by those skilled in the art according to known methods.

The compound of formula (1-c) can be combined with hydrazine in a suitable solvent (such as an alcohol) to produce the compound of formula (1-d). Suitable solvents may include non-reactive solvents, and the reaction can be carried out at a time and temperature suitable for producing the desired amount of the compound of formula (1-d) (e.g., temperatures ranging from room temperature to 100°C and time ranging from minutes to hours). For example, the reaction can be carried out for one hour in an ethanol solvent at a temperature below 50°C.

The compound of formula (1-d) can be converted into the compound of formula (I), (I-1), (Ia), (Ia-1), (Ib), (Ic), (IIa), (IIa-1), (IIc), (IIc-1), (IIc-2), (IIc-2), (IIc-3), (IIc-4), (IIc-5), (IIc-6), (IIc-7) or (IIc-8) by reacting 1 to 5 molar equivalents of triethyl orthoformate with the compound of formula (1-d). For example, the compound of formula (1-d) can react with triethyl orthoformate at temperatures ranging from room temperature to 120°C (e.g., at 100°C) for several minutes to several days, such as one minute to one hour.

General Option 2

Compounds of formula (I), (I-1), (Ia), (Ia-1), (Ib), (Ic), (IIa), (IIa-1), (IIc), (IIc-1), (IIc-2), (IIc-2), (IIc-3), (IIc-4), (IIc-5), (IIc-6), (IIc-7), or (IIc-8) can also be prepared according to the following general synthetic scheme 2:

^R1 , ^R2 , ^R3 , ^R4 , ^R5 and ^R6 are as described in this paper.

According to general synthetic scheme 2, the compound of formula (2-a) can be combined with hydrazine in a suitable non-reactive solvent (such as an alcohol). The reaction can be carried out at a temperature ranging from room temperature to 100°C for a time sufficient to produce the desired amount of the compound of formula (2-b) (e.g., from several minutes to several hours). For example, the compound of formula (2-b) can be suitably produced for one hour at a temperature between room temperature and 50°C. The compound of formula (2-a) is commercially available or can be readily prepared by those skilled in the art using known methods (such as by reacting the compound of formula (1-a) with a base in a suitable solvent).

The compound of formula (2-b) can be combined with 1 to 5 molar equivalents of triethyl orthoformate under suitable reaction conditions to produce the compound of formula (2-c). For example, the reaction to produce the compound of formula (2-c) can be carried out at temperatures ranging from room temperature to 120°C for several minutes to several days. For example, the desired amount of the compound of formula (2-c) can be produced at a reaction temperature of 100°C for a duration of 1 minute to one hour.

Compounds of formulas (I), (I-1), (Ia), (Ia-1), (Ib), (Ic), (IIa), (IIa-1), (IIc), (IIc-1), (IIc-2), (IIc-2), (IIc-3), (IIc-4), (IIc-5), (IIc-6), (IIc-7), or (IIc-8) can be obtained according to general synthetic scheme 2 by reacting a compound of formula (2-c) with a compound of formula (1-b) in the presence of a base using a dehydrating condensing agent in a solvent in the presence of a base. Any suitable solvent can be used, including solvents that are non-reactive in the reaction. Non-limiting examples of suitable solvents for this reaction include acetonitrile, NMP, DMF, etc. Suitable dehydrating condensing agents are known to those skilled in the art, including, for example, but not limited to, phosphonic dehydrating condensing agents, such as BOP reagents. Exemplary bases suitable for this reaction include, for example, inorganic bases (such as cesium carbonate) or organic amines (such as triethylamine).

The reaction can be carried out, for example, using acetonitrile solvent with 1 to 5 molar equivalents of BroP (bromotris(dimethylamino)phosphonium hexafluorophosphate) reagent as a dehydrating condensing agent and 1 to 5 molar equivalents of DBU as a base, at a temperature between room temperature and 120°C for several minutes to several days (e.g., for 1 minute to 1 hour at 50°C).

Alternatively, the conversion of a compound of formula (2-c) into compounds of formulas (I), (I-1), (Ia), (Ia-1), (Ib), (Ic), (IIa), (IIa-1), (IIc), (IIc-1), (IIc-2), (IIc-2), (IIc-3), (IIc-4), (IIc-5), (IIc-6), (IIc-7), or (IIc-8) can be carried out without the use of a dehydrating condensing agent. For example, a compound of formula (2-c) can be reacted with 1 to 5 molar equivalents of a compound of formula (1-b) in the presence of a strong base. Any non-reactive solvent is contemplated to be suitable for this reaction, such as ether-based solvents or, for example, THF. Non-limiting examples of suitable strong bases include organic bases such as n-BuLi. In some embodiments, 1 to 5 molar equivalents of LDA can be used. The reaction can be carried out at temperatures ranging from -100°C to 0°C for several minutes to several days. For example, the desired amount of compounds of formula (I), (I-1), (Ia), (Ia-1), (Ib), (Ic), (IIa), (IIa-1), (IIc), (IIc-1), (IIc-2), (IIc-2), (IIc-3), (IIc-4), (IIc-5), (IIc-6), (IIc-7), or (IIc-8) can be produced by carrying out the reaction at a temperature of -78°C for 1 to 20 hours.

Furthermore, the compounds of this disclosure having the desired functional group at the desired position can be prepared by a suitable combination of the methods described above or by procedures commonly performed in organic synthesis (e.g., alkylation of amino groups, oxidation of alkyl thio groups to sulfoxide or sulfone groups, conversion of alkoxy to hydroxyl groups, or the reverse conversion thereof).

VIII. Examples

Numerous general references are available that provide commonly known chemical synthetic schemes and conditions that can be used to synthesize the disclosed compounds (see, for example, Smith, March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, 7th edition, Wiley-Interscience, 2013).

The compounds described herein can be purified by any means known in the art, including chromatographic methods such as high-performance liquid chromatography (HPLC), preparative thin-layer chromatography, rapid column chromatography, and ion-exchange chromatography. Any suitable stationary phase can be used, including normal and reversed-phase, as well as ion exchange resins. For example, the disclosed compounds can be purified by silica gel chromatography. See, for example, Introduction to Modern Liquid Chromatography, 2nd edition, edited by L.R. Snyder and J.J. Kirkland, John Wiley and Sons, 1979; and Thin Layer Chromatography, edited by E. Stahl, Springer-Verlag, New York, 1969.

Compounds were characterized using standard instrumental methods. Identification was performed by proton nuclear magnetic resonance spectroscopy ( ^¹H -NMR) and mass spectrometry (MS). ^¹H -NMR was measured at 400 MHz unless otherwise specified. In some cases, depending on the compound and measurement conditions, exchangeable hydrogens may not be clearly observed. The terms br. or broad as used herein refer to a broad signal. Preparative HPLC was performed in gradient mode using a commercially available ODS column with water/methanol (containing formic acid) as the eluent.

The embodiments provided herein describe the synthesis of the compounds disclosed herein and the intermediates used to prepare said compounds. It should be understood that the individual steps described herein can be combined. It should also be understood that individual batches of the compounds can be combined and then proceed to the next synthetic step.

In the following description of embodiments, specific implementations are described. These embodiments are described in sufficient detail to enable those skilled in the art to practice certain embodiments of this disclosure. Other embodiments may be utilized, and logical and other changes may be made without departing from the scope of this disclosure. Therefore, the following description is not intended to limit the scope of this disclosure.

Representative syntheses of the compounds disclosed herein are described in the following schemes and in subsequent specific examples.

A. Intermediate

Intermediate 1.5-chloro-[1,2,4]triazolo[4,3-a]quinazolin

(Step 1) Synthesis of 2-chloroquinazoline-4(1H)-one

1M NaOH solution (50 mL) was added to a stirred solution of 2,4-dichloroquinazoline (5.0 g, 25.12 mmol) in THF (50 mL) at 0 °C, and the mixture was stirred at room temperature for 16 hours. The reaction mixture was acidified to pH ~6 with acetic acid. The resulting solid was filtered and dried under vacuum to give the desired product. LCMS (m/z) 181.08 [M+H]+.

(Step 2) Synthesis of 2-hydrazinoquinazolin-4(1H)-one

Hydrazine hydrate (3.33 g, 66.66 mmol) was added to a stirred solution of 2-chloroquinazoline-4(1H)-one (4.0 g, 22.22 mmol) in EtOH (80 mL) at room temperature, and the mixture was heated to 50 °C for 4 hours. The reaction mixture was diluted with petroleum ether. The resulting solid was filtered and dried under vacuum to give the desired product. LCMS (m/z) 177.13 [M+H]+.

(Step 3) Synthesis of [1,2,4]triazolo[4,3-a]quinazolin-5(4H)-one (intermediate 2)

A mixture of 2-hydrazinoquinazolin-4(1H)-one (4.0 g, 22.22 mmol) and formic acid (80 mL) was heated to 100 °C for 16 hours. The reaction mixture was evaporated under reduced pressure, and the residue was washed with ethanol and n-hexane. The resulting solid was purified by column chromatography (Si column, hexane:AcOEt = 10:0-4:6) to give the desired product. LCMS (m/z) 187.05 [M+H]+.

(Step 4) Synthesis of 5-chloro-[1,2,4]triazolo[4,3-a]quinazoline

A mixture of [1,2,4]triazolo[4,3-a]quinazolin-5(4H)-one (1.0 g, 5.37 mmol) and phosphorus oxychloride (20 mL) was heated to 110 °C for 6 hours. The reaction mixture was evaporated under reduced pressure, and the residue was neutralized at 0 °C with a saturated sodium bicarbonate solution. The resulting solid was filtered and dried under vacuum to give the desired product. LCMS (m/z) 204.93 [M+H]+.

Intermediate 2.[1,2,4]triazolo[4,3-a]quinazolin-5(4H)-one

[1,2,4]triazolo[4,3-a]quinazolin-5(4H)-one (intermediate 2) can be synthesized alternatively via the following route.

(Step 1) Synthesis of 2-chloro-4(3H)-quinazolone

A mixture of 2,4-dichloroquinazoline (5 g, 25.1 mmol) in 2 M NaOH solution (60 mL, 60 mmol) and THF (60 mL) was stirred for 1.5 hours at room temperature. The reaction mixture was cooled and the pH was adjusted to 5 with AcOH. The precipitated solid was collected and washed with water and EtOH to give the desired product. LCMS (m/z) 181.06 [M+H] ⁺ .

(Step 2) Synthesis of 2-chloro-3-((2-(trimethylsilyl)ethoxy)methyl)quinazolin-4(3H)-one

A solution of 2-chloro-4(3H)-quinazolone (3.9 _g , 21.60 mmol), SEM-Cl (4.21 mL, 23.76 mmol), and _K₂CO₃ (3.58 g, 25.9 mmol) in DMF (50 mL) was stirred overnight at room temperature. The reaction mixture was diluted with EtOAc, washed continuously with water and _brine , dried over _Na₂SO₄ , and concentrated under vacuum. The crude product was used in the next step without purification.

(Step 3) Synthesis of 2-hydrazino-3-((2-(trimethylsilyl)ethoxy)methyl)quinazolin-4(3H)-one

A solution of 2-chloro-3-((2-(trimethylsilyl)ethoxy)methyl)quinazolin-4(3H)-one (170 mg, 0.547 mmol) in a mixture of hydrazine hydrate (0.5 mL, 15.93 mmol) and EtOH (2 mL) was stirred for 1.5 hours at room temperature. The reaction mixture was diluted with EtOAc, washed continuously with water and brine, dried over _Na₂SO₄ , and concentrated under vacuum. The crude product was used in the next step without purification. _LCMS (m/z) 307.18 [M+H] ^⁺ .

(Step 4) 4-((2-(trimethylsilyl)ethoxy)methyl)-[1,2,4]triazolo[4,3-a]quinazolin-5 Synthesis of (4H)-ketones

The resulting solution of 2-hydrazino-3-((2-(trimethylsilyl)ethoxy)methyl)quinazolin-4(3H)-one in triethoxymethane (3 mL) was stirred overnight at 100 °C. The reaction mixture was purified by column chromatography (Si column, hexane:AcOEt = 100:0-0:100) to obtain the desired product.

(Step 5) Synthesis of [1,2,4]triazolo[4,3-a]quinazolin-5(4H)-one

A mixture of 4-((2-(trimethylsilyl)ethoxy)methyl)-[1,2,4]triazolo[4,3-a]quinazolin-5(4H)-one (187 mg, 0.591 mmol) and 2,2,2-trifluoroacetic acid (2 mL, 0.591 mmol) was stirred at room temperature for 1 hour. The reaction mixture was concentrated under vacuum. The resulting solid was collected to give the desired product. LCMS (m/z) 187.11 [M+H] ⁺ ; ^1H NMR (400 MHz, DMSO- _d6 ) δ 12.80 (s, 1H), 9.40 (s, 1H), 8.21–8.12 (m, 2H), 7.96–7.85 (m, 1H), 7.57 (ddd, J = 8.1, 7.4, 1.0 Hz, 1H).

Intermediate 3.8-bromo-5-chloro-[1,2,4]triazolo[4,3-a]quinazolin

(Step 1) Synthesis of 7-bromoquinazolin-2,4(1H,3H)-dione

A mixture of 2-amino-4-bromobenzoic acid (20 g, 92.59 mmol) and urea (55.55 g, 925.92 mmol) was heated to 150 °C for 16 hours. The reaction progress was monitored by TLC. After the reaction was complete, the reaction mixture was diluted with ice water and stirred for 30 minutes. The resulting solid was collected, ground with glacial acetic acid, and washed with petroleum ether to give the desired product. LCMS (m/z) 241.06 [M+H]+.

(Step 2) Synthesis of 7-bromo-2,4-difluoroquinazoline

N,N-diisopropylethylamine (19.6 mL, 118.75 mmol) was added to a stirred solution of 7-bromoquinazolin-2,4(1H,3H)-dione (19 g, 79.17 mmol) in phosphorus oxychloride (74 mL, 791.67 mmol) at 0 °C, and the mixture was heated to 110 °C for 16 hours. The reaction progress was monitored by TLC. After the reaction was complete, the reaction mixture was diluted with ice water and stirred for 30 minutes. The resulting solid was collected, washed with cold water, and dried under vacuum to provide the desired product. LCMS (m/z) 277.08 [M+H]+.

(Step 3) Synthesis of 7-bromo-2-chloroquinazoline-4(3H)-one

1M NaOH (191 mL, 191.30 mmol) was added to a stirred solution of 7-bromo-2,4-dichloroquinazoline (22.0 g, 79.71 mmol) in 200 mL of THF at 0 °C, and the mixture was stirred at room temperature for 2 hours. The reaction progress was monitored by TLC. After the reaction was complete, the reaction mixture was acidified to pH ~5 with glacial acetic acid. The resulting solid was filtered and dried under vacuum to give the desired product. LCMS (m/z) 259.17 [M+H]+.

(Step 4) Synthesis of 7-bromo-2-chloro-3-((2-(trimethylsilyl)ethoxy)methyl)quinazolin-4(3H)-one become

Potassium carbonate (8.53 g, 61.82 mmol) and 2-(trimethylsilyl)ethoxymethyl chloride (10.96 mL g, 61.82 mmol) were added to a stirred solution of 7-bromo-2-chloroquinazoline-4(3H)-one (14.5 g, 56.20 mmol) in 150 mL of DMF at 0 °C, and the mixture was stirred at room temperature for 4 hours. The reaction progress was monitored by TLC. After the reaction was complete, the reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed continuously with water and brine, dried over _Na₂SO₄ , filtered _, and evaporated under reduced pressure to give the desired product.

(Step 5) 7-Bromo-2-hydrazino-3-((2-(trimethylsilyl)ethoxy)methyl)-quinazolin-4(3H)-one synthesis

Hydrazine (386 mL, 386.60 mmol, 1.0 M in THF) was added to a stirred solution of 7-bromo-2-chloro-3-((2-(trimethylsilyl)ethoxy)methyl)quinazolin-4(3H)-one (15 g, 38.66 mmol) in EtOH (150 mL) at 0 °C, and the mixture was stirred at room temperature for 2 h. The reaction progress was monitored by TLC. After the reaction was complete, the reaction mixture was diluted with water and extracted with 10% methanol/dichloromethane. The organic layer was washed continuously with water and brine, dried over _Na₂SO₄ , filtered, and evaporated under reduced pressure to give the desired product. _LCMS (m/z) 385.40 [M+H]⁺.

(Step 6) 8-Bromo-4-((2-(trimethylsilyl)ethoxy)methyl)-[1,2,4]triazolo[4,3-a]quinazole Synthesis of lin-5(4H)-one

A mixture of 7-bromo-2-hydrazino-3-((2-(trimethylsilyl)ethoxy)methyl)quinazolin-4(3H)-one (17 g, 44.27 mmol) and triethyl orthoformate (43.74 mL, 265.62 mmol) was heated to 100 °C for 16 hours. The reaction progress was monitored by TLC. After the reaction was complete, the reaction mixture was evaporated under reduced pressure. The resulting residue was ground with diethyl ether to give the desired product. LCMS (m/z) 397.35 [M+H+2, isotopic mass]+.

(Step 7) Synthesis of 8-bromo-[1,2,4]triazolo[4,3-a]quinazolin-5(4H)-one

Trifluoroacetic acid (1.5 mL) was added to a stirred solution of 8-bromo-4-((2-(trimethylsilyl)ethoxy)methyl)-[1,2,4]triazolo[4,3-a]quinazolin-5(4H)-one (1.5 g, 5.1 mmol) in methanol (15 mL) at room temperature, and the mixture was stirred at room temperature for 16 hours. The reaction progress was monitored by TLC. After the reaction was complete, the reaction mixture was evaporated under reduced pressure. The resulting residue was ground with diethyl ether to provide the desired product. LCMS (m/z) 265.27 [M+H]+; ^1H NMR (400 MHz, DMSO- _d6 ) δ＝12.88(br.s,1H),9.41(s,1H),8.55(d,J＝1.5Hz,1H),8.05(d,J＝8.6Hz,1H),7.75(dd,J＝1.6,8.4Hz,1H).

Synthesis of 8-bromo-5-chloro-[1,2,4]triazolo[4,3-a]quinazoline

A mixture of 8-bromo-[1,2,4]triazolo[4,3-a]quinazolin-5(4H)-one (2.0 g, 7.57 mmol) in phosphorus oxychloride (15 mL) was refluxed for 6 hours. The reaction progress was monitored by TLC. After the reaction was complete, the reaction mixture was evaporated under reduced pressure. The residue was dissolved in toluene and evaporated twice to give the desired product: LCMS (m/z) 283.20 [M+H]+.

Intermediate 4.8-nitro-[1,2,4]triazolo[4,3-a]quinazolin-5(4H)-one

(Step 1) Synthesis of 7-nitroquinazolin-2,4(1H,3H)-dione

A mixture of 2-amino-4-nitrobenzoic acid (10 g, 54.94 mmol) and urea (32.96 g, 549.45 mmol) was heated to 150 °C for 16 hours. The reaction progress was monitored by TLC. After the reaction was complete, the reaction mixture was diluted with ice water and stirred for 10 minutes. The resulting solid was collected and ground with glacial acetic acid to obtain the desired product. LCMS (m/z) 208.14 [M+H]+.

(Step 2) Synthesis of 2,4-dichloro-7-nitroquinazolino

N,N-diisopropylethylamine (13 mL, 74.64 mmol) was added to a stirred solution of 7-nitroquinazolin-2,4(1H,3H)-dione (10.3 g, 49.76 mmol) in phosphorus oxychloride (48 mL, 497.58 mmol) at 0 °C, and the mixture was heated to 110 °C for 16 hours. The reaction progress was monitored by TLC. After the reaction was complete, the reaction mixture was quenched with crushed ice and stirred for 10 min. The resulting solid was filtered and dried under vacuum to give the desired product. LCMS (m/z) 244.11 [M+H]+.

(Step 3) Synthesis of 2-chloro-7-nitroquinazolin-4(3H)-one

1M NaOH solution (197 mL, 197.53 mmol) was added to a stirred solution of 2,4-dichloro-7-nitroquinazoline (20 g, 82.3 mmol) in THF (5 mL) at 0 °C, and the mixture was stirred at room temperature for 2 hours. The reaction progress was monitored by TLC. After the reaction was complete, the reaction mixture was acidified with acetic acid at 0 °C to pH ~5. The resulting solid was filtered and dried under vacuum to give the desired product. LCMS (m/z) 226.21 [M+H]+.

(Step 4) 2-Chloro-7-nitro-3-((2-(trimethylsilyl)ethoxy)methyl)quinazolin-4(3H)-one synthesis

Potassium carbonate (10.54 g, 76.27 mmol) and 2-(trimethylsilyl)ethoxymethyl chloride (13.52 mL, 76.27 mmol) were added to a stirred solution of 2-chloro-7-nitroquinazolin-4(3H)-one (15.6 g, 69.33 mmol) in DMF (160 mL) at 0 °C, and the mixture was stirred at room temperature for 4 hours. The reaction progress was monitored by TLC. After the reaction was complete, the reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed continuously with water and brine, dried over _Na₂SO₄ , filtered, and evaporated under reduced pressure to give the desired product. _LCMS (m/z) 356.42 [M+H]⁺.

(Step 5) 2-Hydroxy-7-nitro-3-((2-(trimethylsilyl)ethoxy)methyl)-quinazolin-4(3H)-one Synthesis

Hydrazine (281 mL, 281.69 mmol, 1.0 M in THF) was added to a stirred solution of 2-chloro-7-nitro-3-((2-(trimethylsilyl)ethoxy)methyl)quinazolin-4(3H)-one 5 (crude, 10 g, 28.17 mmol) in EtOH (100 mL) at 0 °C, and the mixture was stirred at room temperature for 2 h. The reaction progress was monitored by TLC. After the reaction was complete, the reaction mixture was diluted with water and extracted with 10% methanol/dichloromethane. The organic layer was dried over _Na₂SO₄ , filtered, and evaporated under reduced pressure to give the desired product. _LCMS (m/z) 352.53 [M+H]⁺.

(Step 6) 8-nitro-4-((2-(trimethylsilyl)ethoxy)methyl)-[1,2,4]triazolo[4,3-a]quinoline Synthesis of azoline-5(4H)-one

A mixture of 2-hydrazino-7-nitro-3-((2-(trimethylsilyl)ethoxy)methyl)quinazolin-4(3H)-one (crude, 12.0 g, 34.19 mmol) and triethyl orthoformate (34.15 mL, 205.13 mmol, 6.0 equivalents) was heated to 100 °C for 16 hours. The reaction progress was monitored by TLC. After the reaction was complete, the reaction mixture was evaporated under reduced pressure, and the residue was washed with diethyl ether and dried under vacuum to give the desired product. LCMS (m/z) 362.40 [M+H]+.

(Step 7) Synthesis of 8-nitro-[1,2,4]triazolo[4,3-a]quinazolin-5(4H)-one

Triethylamine (6.09 mL, 43.45 mmol) was added to a stirred solution of 8-nitro-4-((2-(trimethylsilyl)ethoxy)methyl)-[1,2,4]triazolo[4,3-a]quinazolin-5(4H)-one (6.3 g, 24.14 mmol) in MeOH (60 mL) at room temperature, and the mixture was stirred at the same temperature for 16 hours. The reaction progress was monitored by TLC. After the reaction was complete, the reaction mixture was evaporated under reduced pressure. The residue was washed continuously with diethyl ether and n-pentane and dried under vacuum to provide the desired product: LCMS (m/z) 231.9 [M+H]+; ^1H NMR (500MHz, DMSO- _d6 ) δ＝13.10(brs,1H),9.65(s,1H),9.10(d,J＝2.1Hz,1H),8.40-8.36(m,1H),8.31(dd,J＝2.0,9.0Hz,1H).

Intermediate 5,5,8-dichloro-[1,2,4]triazolo[4,3-a]quinazolin

(Step 1) Synthesis of 7-chloroquinazoline-2,4(1H,3H)-dione

A mixture of 2-amino-4-chlorobenzoic acid (10 g, 58.48 mmol) and urea (35.09 g, 584.79 mmol) was stirred at 150 °C for 16 hours. The reaction mixture was diluted with ice-cold water at 100 °C. The resulting solid was filtered, washed with water, and dried under vacuum to give the desired product: LCMS (m/z) 197.13 [M+H]+.

(Step 2) Synthesis of 2,4,7-trichloroquinazoline

N,N-diisopropylethylamine (12.14 mL, 69.64 mmol) was added to a solution of 7-chloroquinazoline-2,4(1H,3H)-dione (9.1 g, 46.43 mmol) in phosphorus oxychloride (43.39 mL, 464.28 mmol) at 0 °C, and the mixture was stirred at 110 °C for 16 hours. The reaction mixture was diluted with ice-cold water, and the resulting solid was filtered, washed with water, and dried under vacuum to give the desired product.

(Step 3) Synthesis of 2,7-dichloroquinazoline-4(3H)-one

A solution of 1M NaOH (103.45 mL, 103.45 mmol) in 100 mL THF was added at 0 °C, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was acidified with acetic acid to pH ~5 at 0 °C. The resulting solid was filtered, washed with water and petroleum ether, and dried under vacuum to give the desired product. LCMS (m/z) 215.09 [M+H]+.

(Step 4) Synthesis of 2,7-dichloro-3-((2-(trimethylsilyl)ethoxy)methyl)quinazolin-4(3H)-one

Potassium carbonate (6.07 g, 44 mmol) and 2-(trimethylsilyl)ethoxymethyl chloride (7.80 mL, 44 mmol) were added to a solution of 2,7-dichloroquinazoline-4(3H)-one (8.6 g, 40 mmol) in DMF (90 mL) at 0 °C, and the mixture was stirred at room temperature for 4 hours. The reaction mixture was diluted with ice water and extracted with ethyl acetate. The organic layer was washed with ice water and brine, dried over anhydrous _Na₂SO₄ , and evaporated under reduced pressure to give the desired product. _LCMS (m/z) 345.33 [M+H]+.

(Step 5) 7-Chloro-2-hydrazino-3-((2-(trimethylsilyl)ethoxy)methyl)-quinazolin-4(3H)-one synthesis

Hydrazine (145 mL, 145.35 mmol, 1.0 M in THF) was added to a solution of 2,7-dichloro-3-((2-(trimethylsilyl)ethoxy)methyl)quinazolin-4(3H)-one (5 g, 14.53 mmol) in EtOH (50 mL) at 0 °C, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted with water and extracted with 10% methanol/dichloromethane. The organic layer was washed with brine, dried over _Na₂SO₄ , filtered, and evaporated under reduced pressure. The residue was washed with diethyl ether to give the desired product. _LCMS (m/z) 341.37 [M+H]⁺.

(Step 6) 8-Chloro-4-((2-(trimethylsilyl)ethoxy)methyl)-[1,2,4]triazolo[4,3-a]quinazole Synthesis of lin-5(4H)-one

A mixture of 7-chloro-2-hydrazino-3-((2-(trimethylsilyl)ethoxy)methyl)quinazolin-4(3H)-one (4.9 g, 14.41 mmol) and triethyl orthoformate (14.39 mL, 86.47 mmol) was stirred at 100 °C for 16 hours. The reaction mixture was diluted with diethyl ether and evaporated under reduced pressure. The residue was dissolved in diethyl ether and evaporated to give the desired product. LCMS (m/z) 351.42 [M+H]+.

(Step 7) Synthesis of 8-chloro-4-(hydroxymethyl)-[1,2,4]triazolo[4,3-a]quinazolin-5(4H)-one

Trifluoroacetic acid (5.72 mL, 74.74 mmol) was added to a solution of 8-chloro-4-((2-(trimethylsilyl)ethoxy)methyl)-[1,2,4]triazolo[4,3-a]quinazolin-5(4H)-one 7 (2.18 g, 6.23 mmol) in dichloromethane (20 mL) at 0 °C, and the mixture was stirred at room temperature for 16 hours. The reaction mixture was evaporated under reduced pressure, and the residue was dissolved in dichloromethane and evaporated. The resulting solid was washed with diethyl ether to give the desired product.

(Step 8) Synthesis of 8-chloro-[1,2,4]triazolo[4,3-a]quinazolin-5(4H)-one

Triethylamine (2.02 mL, 14.4 mmol) was added to a solution of 1.8 g (7.2 mmol) of 8-chloro-4-(hydroxymethyl)-[1,2,4]triazolo[4,3-a]quinazolin-5(4H)-one in 20 mL MeOH at 0 °C, and the mixture was stirred at room temperature for 16 hours. The reaction mixture was evaporated under reduced pressure, and the residue was dissolved in diethyl ether and evaporated. The resulting solid was washed with diethyl ether to give the desired product. LCMS (m/z) 221.21 [M+H]+.

(Step 9) Synthesis of 5,8-dichloro-[1,2,4]triazolo[4,3-a]quinazoline

A solution of 1.2 g (5.45 mmol) of 8-chloro-[1,2,4]triazolo[4,3-a]quinazolin-5(4H)-one in phosphorus oxychloride (15 mL) was stirred at 100 °C for 6 hours. The reaction mixture was evaporated under reduced pressure. The residue was dissolved in toluene and evaporated to give the desired product. LCMS (m/z) 239.17 [M+H]+.

B. Example

Example 1. N-Methyl-N-phenyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine

(Step 1) Synthesis of 2-chloro-N-methyl-N-phenylquinazoline-4-amine

N-methylaniline (59.2 mg, 0.553 mmol) and sodium hydroxide (20 mg, 0.500 mmol) were added to a DMF solution (5 mL) of 2,4-dichloroquinazoline (100 mg, 0.502 mmol), and the mixture was stirred at room temperature for 2 hours. Ethyl acetate and water were added to the reaction solution, and the organic layer was separated. The organic layer was washed with a saturated aqueous solution of ammonium chloride and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane:ethyl acetate = 1:0 to 4:1) to give 2-chloro-N-methyl-N-phenylquinazoline-4-amine: ^¹H -NMR (400MHz, DMSO- _d6 ) δ 7.70–7.65 (m, 2H), 7.53–7.46 (m, 2H), 7.44–7.36 (m, 3H), 7.11 (ddd, J = 8.4, 4.8, 3.5Hz, 1H), 6.83 (dt, J = 8.6, 1.0Hz, 1H), 3.56); LCMS (m/z) 270.13 [M+H] ⁺ .

(Step 2) Synthesis of 2-hydrazino-N-methyl-7-phenylquinazoline-4-amine

An ethanolic solution (3 ml) of 2-chloro-N-methyl-N-phenylquinazoline-4-amine (135 mmol, 0.500 mmol) and hydrazine monohydrate (75 mg, 1.50 mmol) was stirred at 50 °C for one hour. The reaction mixture was cooled to room temperature, ethyl acetate and water were added, and the organic layer was separated. The organic layer was washed with brine and dried over anhydrous magnesium sulfate. Evaporation of the solvent under reduced pressure yielded 2-hydrazino-N-methyl-7-phenylquinazoline-4-amine: ^¹H NMR (400 MHz, methanol- _d⁴ ) δ 8.36 (d, J = 8.3 Hz, 1H), 7.88–7.76 (m, 3H), 7.67 (d, J = 8.4 Hz, 1H), 7.59 (t, J = 7.7 Hz, 1H), 7.41 (t, J = 7.8 Hz, 2H), 7.21 (t, J = 7.4 Hz, 1H), 3.55 (s, 3H); LCMS (m/z) 266.13 [M+H] ^⁺ .

(Step 3) Synthesis of N-methyl-N-phenyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine

A mixture of 2-hydrazino-N-methyl-7-phenylquinazoline-4-amine (78 mg, 0.294 mmol) and triethyl orthoformate (1 ml) was stirred at 50 °C for one hour. The reaction mixture was cooled to room temperature and purified by silica gel column chromatography (chloroform:methanol = 1:0 to 10:1) to give the title compound: ^¹H -NMR 400 MHz, DMSO-d _δ 9.62 (s, 1H), 8.29 (d, J = 8.3 Hz, 1H), 7.77 (ddd, J = 8.4, 6.7, 1.7 Hz, 1H), 7.44–7.21 (m, 7H), 3.32 (s, 3H). LCMS (m/z) 276.1 [M+H] ⁺ .

Example 2. N-(3-chlorophenyl)-N-methyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine

(Step 1) Synthesis of 2-hydrazolyl-quinazolin-4(3H)-one

An ethanol solution (2 ml) of 2-chloroquinazoline-4(3H)-one (50 mg, 0.277 mmol) and hydrazine monohydrate (41.6 mg, 0.831 mmol) was heated to 50 °C and stirred for 1.5 h. The reaction mixture was cooled to room temperature, ethyl acetate and water were added, and the organic layer was separated. The organic layer was washed with brine and dried over anhydrous magnesium sulfate. The solvent was evaporated to obtain 2-hydrazyl-quinazoline-4(3H)-one: ^¹H -NMR (DMSO- _d⁶ ) δ (ppm): 8.08–6.85 (m, 4H); LCMS (m/z) 177.11 [M+H] ^⁺ .

(Step 2) Synthesis of [1,2,4]-triazolo-[4,3-a]quinazolin-5(4H)-one

A mixture of 2-hydrazino-quinazolin-4(3H)-one (1.26 g, 7.15 mmol) and triethyl orthoformate (10 mL) was heated to 80 °C and stirred for 2 hours. The reaction mixture was cooled to room temperature, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography (chloroform:methanol = 1:0 to 20:1) to give [1,2,4]-triazolo-[4,3-a]quinazolin-5(4H)-one: ^¹H -NMR (DMSO- _d⁶ ) δ (ppm): 12.80 (s, 1H), 9.40 (s, 1H), 8.20–8.12 (m, 2H), 7.96–7.85 (m, 1H), 7.57 (ddd, J = 8.1, 7.4, 1.0 Hz, 1H); LCMS (m/z) 187.16 [M+H] ^⁺ .

(Step 3) Synthesis of N-(3-chlorophenyl)-N-methyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine

LDA (0.147 mL, 0.293 mmol) was added to a 2 mL THF solution of [1,2,4]-triazolo-[4,3-a]quinazolin-5(4H)-one (30 mg, 0.147 mmol) at 0 °C and stirred for 30 min. A 31 mL THF solution of 3-chloro-N-methylaniline (alinin) (31.1 mg, 0.22 mmol) was added to this solution and stirred for one hour at room temperature. Ethyl acetate and water were added to the reaction solution and the organic layer was separated. The organic layer was washed with brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by preparative HPLC to give the title compound: ^¹H -NMR (DMSO- _d₆ ) δ (ppm): 9.66 (s, 1H), 8.36–8.28 (m, 1H), 7.82 (ddd, J = 8.5, 6.4, 2.2 Hz, 1H), 7.48 (t, J = 2.1 Hz, 1H), 7.42–7.21 (m, 5H), 3.55 (s, 3H); LCMS (m/z) 310.13 [M+H] ^⁺ .

Example 3. N-Phenyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine

(Step 1) Synthesis of 2-chloro-N-phenylquinazoline-4-amine

Aniline (46.8 mg, 0.502 mmol) and sodium hydroxide (20.1 mg, 0.502 mmol) were added to a solution of 2,4-dichloroquinazoline (100 mg, 0.502 mmol) in DMF (2.5 mL), and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was diluted with water and extracted with AcOEt. The organic layer was concentrated under vacuum. The crude product was used for the next step without further purification. LCMS (m/z) 256.09 [M+H] ⁺ .

(Step 2) Synthesis of N-phenyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine

The resulting mixture of 2-chloro-N-phenylquinazoline-4-amine (70 mg, 0.274 mmol) and formylhydrazine (32.9 mg, 0.548 mmol) in toluene (1.37 mL) was refluxed for 2.5 days. The reaction mixture was diluted with MeOH/AcOEt and concentrated under vacuum. The residue was dissolved in MeOH and evaporated to remove residual solvent. The residue was suspended in MeOH, and the resulting solid was collected and washed to obtain the desired product: ^¹H -NMR (DMSO- _d₆ ) δ 9.80 (s, 1H), 9.53 (s, 1H), 8.67 (dd, J = 8.3, 1.2 Hz, 1H), 8.33 (dd, J = 8.3, 1.1 Hz, 1H), 7.99 (ddd, J = 8.4, 7.2, 1.2 Hz, 1H), 7.94–7.83 (m, 2H), 7.71 (ddd, J = 8.3, 7.2, 1.1 Hz, 1H), 7.49–7.38 (m, 2H), 7.23–7.14 (m, 1H); LCMS (m/z) 262.2 [M+H] ^⁺ .

Example 4. 5-(3,4-dihydroquinoline-1(2H)-yl)-[1,2,4]triazolo[4,3-a]quinazolin

(Step 1) Synthesis of 2-chloro-4-(3,4-dihydroquinolin-1(2H)-yl)quinazolin

Add 1,2,3,4-tetrahydroquinoline (66.9 mg, 0.502 mmol) and sodium hydride (22.1 mg, 0.553 mmol) to a solution of 2,4-dichloroquinazoline (150 mg, 0.615 mmol) in DMF (2.5 mL), and stir the mixture at room temperature for 2 hours. Dilute the reaction mixture with AcOEt, wash continuously with water and brine, and dry over _Na₂SO₄ . Concentrate the organic layer under vacuum. Use the resulting residue for the next step without further purification. _LCMS (m/z) 296.08 [M+H] ^⁺ .

(Step 2) Synthesis of 5-(3,4-dihydroquinoline-1(2H)-yl)-[1,2,4]triazolo[4,3-a]quinazolin

The resulting mixture of 2-chloro-4-(3,4-dihydroquinoline-1(2H)-yl)quinazoline (50 mg, 0.172 mmol) and formylhydrazine (20.3 mg, 0.338 mmol) in toluene (0.84 mL) was refluxed for 2.5 days. The reaction mixture was diluted with MeOH/AcOEt and concentrated under vacuum. The residue was purified by preparative HPLC to provide the desired product: ^¹H -NMR (DMSO- _d₆ ) δ 9.70 (s, ¹H), 8.40–8.29 (m, ¹H), 7.87 (ddd, J = 8.5, 7.3, 1.4 Hz, ¹H), 7.57 (dd, J = 8.3, 1.3 Hz, ¹H), 7.37 (ddd, J = 8.3, 7.2, 1.2 Hz, ¹H), 7.27 (dd, J = 7.4, 1.6 Hz, ¹H), 7.04–6.88 (m, 2H), 6.72 (dd, J = 8.0, 1.2 Hz, ¹H), 3.92 (t, J = 6.5 Hz, 2H), 2.89 (t, J = 6.6 Hz, 2H), 2.12–1.96 (m, 2H). LCMS(m/z)302.2[M+H] ⁺ .

Example 5. N-(4-methoxyphenyl)-N-methyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine

(Step 1) Synthesis of 2-chloro-N-(4-methoxyphenyl)-N-methylquinazoline-4-amine

Add 4-methoxy-N-methylaniline (68.9 mg, 0.502 mmol) and sodium hydroxide (20.1 mg, 0.502 mmol) to a solution of 2,4-dichloroquinazoline (100 mg, 0.502 mmol) in DMF (2.5 mL), and stir the mixture at room temperature for 0.5 h. Dilute the reaction mixture with AcOEt, wash continuously with water and brine, and dry over _Na₂SO₄ . Concentrate the organic layer under vacuum. Use the resulting residue for the next step without further purification. _LCMS (m/z) 300.08 [M+H] ^⁺ .

(Step 2) Synthesis of N-(4-methoxyphenyl)-N-methyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine

The resulting mixture of 2-chloro-N-(4-methoxyphenyl)-N-methylquinazoline-4-amine (71 mg, 0.237 mmol) and formylhydrazine (21.3 mg, 0.355 mmol) in toluene (1.18 mL) was refluxed and stirred for 2 days. The reaction mixture was diluted with MeOH/AcOEt and concentrated under vacuum. The residue was purified by preparative HPLC to provide the desired product: ^¹H -NMR (methanol- _d⁴ ) δ 9.38 (d, J = 2.5 Hz, 1H), 8.10 (t, J = 6.6 Hz, 1H), 7.71 (t, J = 7.6 Hz, 1H), 7.21–7.16 (m, 4H), 6.97 (s, 1H), 6.85–6.72 (m, 1H), 3.82 (s, 3H), 3.60 (d, J = 2.6 Hz, 3H); LCMS (m/z) 306.2 [M+H] ^⁺ .

Example 6. N-(2-fluorophenyl)-N-methyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine

(Step 1) Synthesis of 2-chloro-N-(2-fluorophenyl)-N-methylquinazoline-4-amine

Add 2-fluoro-N-methylaniline (62.9 mg, 0.502 mmol) and sodium hydroxide (20.1 mg, 0.502 mmol) to a suspension of 2,4-dichloroquinazoline (100 mg, 0.502 mmol) in DMF (2.5 mL), and stir the mixture at room temperature for 30 min. Dilute the reaction mixture with AcOEt, wash continuously with water and brine, and dry _{over Na₂SO₄} . Concentrate the organic layer under vacuum. Purify the residue by column chromatography (Si-column, hexane:AcOEt = 10:0–6:4) to obtain the desired product. LCMS (m/z) 288.13 [M+H]+.

(Step 2) Synthesis of N-(2-fluorophenyl)-N-methyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine

A mixture of 2-chloro-N-(2-fluorophenyl)-N-methylquinazolin-4-amine (47 mg, 0.163 mmol) and formylhydrazide (19.62 mg, 0.327 mmol) in toluene (0.82 mL) was refluxed for 2 days. The reaction mixture was diluted with MeOH/AcOEt and concentrated under vacuum. The residue was dissolved in MeOH and evaporated. The residue was purified by preparative HPLC to provide the desired product: ^¹H -NMR (methanol- _d⁴⁻ ) δ 9.46 (s, 1H), 8.21 (d, J = 8.3 Hz, 1H), 7.80 (t, J = 7.8 Hz, 1H), 7.45–7.24 (m, 6H), 3.63 (s, 3H). LCMS (m/z) 294.2 [M+H]⁺.

Example 7. N,N-Dimethyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine

(Step 1) Synthesis of 2-chloro-N,N-dimethylquinazoline-4-amine

Dimethylamine (18.12 mg, 0.402 mmol) and sodium hydroxide (16.08 mg, 0.402 mmol) were added to a suspension of 2,4-dichloroquinazoline (80 mg, 0.402 mmol) in DMF (2.01 mL), and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was diluted with AcOEt and washed continuously with water and brine. The organic layer was concentrated under vacuum to give the desired product, which was used in the next step without further purification. LCMS (m/z) 208.10 [M+H] ⁺ .

(Step 2) Synthesis of N,N-dimethyl-[1,2,4]triazolo[4,3-a]quinazoline-5-amine: A mixture of 2-chloro-N,N-dimethylquinazoline-4-amine (83 mg, 0.4 mmol) and formylhydrazine (48 mg, 0.8 mmol) in toluene (2 mL) was refluxed for 2 days. The reaction mixture was dissolved in MeOH/AcOEt and concentrated under vacuum. The residue was dissolved in MeOH and evaporated. The residue was purified by preparative HPLC to provide the desired product: ^¹H -NMR (methanol- _d⁴ ) δ 9.34 (s, ¹H), 8.31 (dd, J = 8.4, 1.2 Hz, ¹H), 8.19 (dd, J = 8.4, 1.1 Hz, ¹H), 7.92 (ddd, J = 8.4, 7.3, 1.3 Hz, ¹H), 7.65 (ddd, J = 8.4, 7.2, 1.2 Hz, ¹H), 3.40 (s, 6H). LCMS (m/z) 214.1 [M+H]⁺.

Example 8. 7-Methoxy-N-methyl-N-phenyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine

(Step 1) Synthesis of 2-chloro-6-methoxy-N-methyl-N-phenylquinazoline-4-amine

N-methylaniline (46.8 mg, 0.437 mmol) and NaOH (15.62 mg, 0.428 mmol) were added to a suspension of 2,4-dichloro-6-methoxyquinazoline (100 mg, 0.437 mmol) in 2-propanol (2.1 mL), and the mixture was stirred at room temperature for 3 days. The reaction mixture was filtered and washed with 2-propanol to give the desired product. This product was used in the next step without further purification: LCMS (m/z) 309.09 [M+H]+.

(Step 2) Synthesis of 7-methoxy-N-methyl-N-phenyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine

A mixture of 2-chloro-6-methoxy-N-methyl-N-phenylquinazoline-4-amine (70 mg, 0.234 mmol) and formylhydrazine (28.0 mg, 0.467 mmol) in toluene (0.5 mL) was refluxed for 2 days. The reaction mixture was diluted with MeOH/AcOEt and concentrated under vacuum. The residue was dissolved in MeOH and evaporated, and the residue was purified by preparative HPLC to provide the desired product: ^¹H -NMR (methanol-d⁴) δ 9.36 (s, 1H), 8.06 (d, J = 9.1 Hz, 1H), 7.53–7.40 (m, 2H), 7.38–7.27 (m, 4H), 6.74 (d, J = 2.7 Hz, 1H), 3.66 (s, 3H), 3.33 (s, 3H). LCMS (m/z) 306.2 [M+H]⁺.

Example 9. N-(3-methoxyphenyl)-N-methyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine

BOP (143 mg, 0.322 mmol) was added to a mixture of [1,2,4]triazolo[4,3-a]quinazolin-5(4H)-one (50 mg, 0.269 mmol) and DBU (0.061 mL, 0.403 mmol) in NMP (1 mL) at room temperature. The mixture was stirred at room temperature for 10 minutes. Then, 3-methoxy-N-methylaniline (47.9 mg, 0.349 mmol) was added to the mixture at room temperature, and stirring was continued at room temperature for 3 hours, followed by overnight incubation at 55 °C. The reaction mixture was purified by preparative LCMS (acidic conditions) to provide a crude product, which was then purified by column chromatography (Si column, hexane:AcOEt = 100:0-0:100, followed by MeOH) to provide the desired product: ^¹H -NMR (DMSO- _d₆ ) δ 9.62 (s, 1H), 8.32–8.25 (m, 1H), 7.78 (ddd, J = 8.4, 7.2, 1.4 Hz, 1H), 7.37–7.20 (m, 3H), 6.93 (t, J = 2.3 Hz, 1H), 6.82 (m, 2H), 3.71 (s, 3H), 3.54 (s, 3H). LCMS (m/z) 306.1 [M+H]⁺.

Example 10. 9-Fluoro-N-methyl-N-phenyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine

(Step 1) Synthesis of 2-chloro-8-fluoro-N-methyl-N-phenylquinazoline-4-amine

N-methylaniline (59.3 mg, 0.553 mmol) and sodium hydroxide (23 mg, 0.55 mmol) were added to a suspension of 2,4-dichloro-8-fluoroquinazoline (120 mg, 0.553 mmol) in 2-propanol (2.7 mL), and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was filtered and washed with 2-propanol to give the desired product, which was used in the next step without further purification. LCMS (m/z) 288.08 [M+H] ⁺ .

(Step 2) Synthesis of 8-fluoro-2-hydrazino-N-methyl-N-phenylquinazoline-4-amine

A mixture of 2-chloro-8-fluoro-N-methyl-N-phenylquinazoline-4-amine (63 mg, 0.219 mmol) and hydrazine hydrate (54.8 mg, 1.095 mmol) in EtOH (1.1 mL) was stirred at 55 °C for 4 hours. The reaction mixture was concentrated under vacuum. The resulting residue was used in the next step without further purification. LCMS (m/z) 284.18 [M+H] ⁺ .

(Step 3) Synthesis of 9-fluoro-N-methyl-N-phenyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine

A mixture of 8-fluoro-2-hydrazino-N-methyl-N-phenylquinazoline-4-amine (61 mg, crude) and triethoxymethane (17.26 mg, 0.116 mmol) was stirred at 70 °C for 3 hours. A small amount of AcOH was added to the reaction mixture, and the reaction mixture was concentrated under vacuum. The residue was purified by column chromatography (Si column, _CHCl3 :MeOH = 10:0–95:5) to provide the desired product: ^¹H -NMR (methanol- _d4 ) δ 9.25 (t, J = 3.6 Hz, 1H), 7.67–7.56 (m, 1H), 7.42 (t, J = 7.7 Hz, 2H), 7.34–7.28 (m, 3H), 7.16 (dd, J = 7.9, 4.5 Hz, 2H), 3.66 (d, J = 1.9 Hz, 3H). LCMS(m/z)294.1[M+H]+.

Example 11. 8-Chloro-N-methyl-N-phenyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine

(Step 1) Synthesis of 2,7-dichloro-N-methyl-N-phenylquinazoline-4-amine

N-methylaniline (235 mg, 2.197 mmol) and sodium hydroxide (111 mg, 2.78 mmol) were added to a suspension of 2,4,7-trichloroquinazoline (513 mg, 2.197 mmol) in DMF (1.1 mL), and the mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with AcOEt, washed continuously with water and brine, and dried over _Na₂SO₄ . The organic layer was concentrated under vacuum to give the desired product. _LCMS (m/z) 305.1 [M+H] ^⁺ .

(Step 2) Synthesis of 7-chloro-2-hydrazino-N-methyl-N-phenylquinazoline-4-amine

Hydrazine hydrate (0.11 g, 2.2 mmol) was added to a solution of 2,7-dichloro-N-methyl-N-phenylquinazoline- ₄ -amine (572 mg, 2.2 mmol) in EtOH (11 mL), and the mixture was stirred at 50 °C for 2 hours. The reaction mixture was diluted with AcOEt, washed continuously with water and brine, and dried over _Na₂SO₄ . The organic layer was concentrated under vacuum to give the desired product. LCMS (m/z) 300.13 [M+H] ^⁺ .

(Step 3) Synthesis of 8-chloro-N-methyl-N-phenyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine

A mixture of 7-chloro-2-hydrazino-N-methyl-N-phenylquinazoline-4-amine (659 mg, 2.2 mmol) and triethoxymethane (324 mg, 2.2 mmol) was stirred at 100 °C for 1 hour. The reaction mixture was concentrated under vacuum, and the residue was purified by column chromatography (Si column, _CHCl3 :MeOH = 10:0–9:1) to provide the desired product: ^¹H -NMR (methanol- _d4 ) δ 9.45–9.40 (m, 1H), 8.33 (d, J = 2.0 Hz, 1H), 7.49–7.39 (m, 2H), 7.34–7.13 (m, 5H), 3.65 (s, 3H). LCMS (m/z) 310.0 [M+H]+.

Example 12. 9-Methoxy-N-methyl-N-phenyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine

(Step 1) Synthesis of 2-chloro-8-methoxy-N-methyl-N-phenylquinazoline-4-amine

N-methylaniline (46.8 mg, 0.437 mmol) and sodium hydroxide (17.46 mg, 0.437 mmol) were added to a suspension of 2,4-dichloro- ₈ -methoxyquinazoline (100 mg, 0.437 mmol) in DMF (2.2 mL), and the mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with AcOEt, washed continuously with water and brine, and dried over _Na₂SO₄ . The organic layer was concentrated under vacuum to give the desired product, which was used in the next step without further purification. LCMS (m/z) 300.18 [M+H] ^⁺ .

(Step 2) Synthesis of 2-hydrazino-8-methoxy-N-methyl-N-phenylquinazoline-4-amine

Hydrazine hydrate (43.8 mg, 0.874 mmol) was added to a solution of 2-chloro-8-methoxy-N-methyl-N-phenylquinazoline- ₄ -amine (131 mg, crude) in EtOH (2.2 mL), and the mixture was stirred at 50 °C for 2 hours. The reaction mixture was diluted with AcOEt, washed continuously with water and brine, and dried over _Na₂SO₄ . The organic layer was concentrated under vacuum to give the desired product, which was used in the next step without further purification. LCMS (m/z) 296.18 [M+H] ^⁺ .

(Step 3) Synthesis of 9-methoxy-N-methyl-N-phenyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine

A mixture of 2-hydrazino-8-methoxy-N-methyl-N-phenylquinazoline-4-amine (119 mg, crude), triethoxymethane (259 mg, 1.748 mmol), and one drop of acetic acid (12.04 mg, 0.201 mmol) was stirred at 90 °C for 1 hour. The reaction mixture was concentrated under vacuum, and the residue was purified by column chromatography (Si column, _CHCl3 :MeOH = 10:0–9:1 gradient) to provide the desired product: ^¹H -NMR (methanol- _d4 ) δ 9.51 (s, 1H), 7.44–7.16 (m, 6H), 7.08 (t, J = 8.3 Hz, 1H), 6.87 (d, J = 8.4 Hz, 1H), 4.12 (s, 3H), 3.62 (s, 3H). LCMS (m/z) 306.1 [M+H]+.

Example 13. N-(4-fluorophenyl)-N-methyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine

(Step 1) Synthesis of 2-chloro-N-(4-fluorophenyl)-N-methylquinazoline-4-amine

N-methyl-4-fluoroaniline (62.9 mg, 0.502 mmol) and sodium hydroxide (20.1 mg, 0.502 mmol) were added to a suspension of 2,4-dichloroquinazoline (100 mg, 0.502 mmol) in DMF (0.25 mL), and the mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with AcOEt, washed continuously with water and brine, and dried over _Na₂SO₄ . The resulting residue was used in the next step without further purification. _LCMS (m/z) 288.03 [M+H] ^⁺ .

(Step 2) Synthesis of N-(4-fluorophenyl)-2-hydrazino-N-methylquinazoline-4-amine

Hydrazine hydrate (23.66 mg, 0.473 mmol) was added to a solution of 2-chloro-N-(4-fluorophenyl)-N-methylquinazoline- ₄ -amine (68 mg, crude) in EtOH (1.2 mL), and the mixture was stirred at 50 °C for 2 h. The reaction mixture was diluted with AcOEt, washed continuously with water and brine, and dried over _Na₂SO₄ . The organic layer was concentrated under vacuum. The resulting residue was used in the next step without further purification. LCMS (m/z) 284.13 [M+H] ^⁺ .

(Step 3) Synthesis of N-(4-fluorophenyl)-N-methyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine

A mixture of N-(4-fluorophenyl)-2-hydrazino-N-methylquinazoline-4-amine (51 mg, crude), triethoxymethane (175 mg, 1.182 mmol), and acetic acid (12.04 mg, 0.201 mmol) was concentrated under vacuum at 90 °C. The reaction mixture was then purified by column chromatography (Si column, _CHCl3 :MeOH = 10:0–9:1) to provide the desired product: ^¹H -NMR (methanol- _d4 ) δ 9.44 (s, 1H), 8.19 (d, J = 7.9 Hz, 1H), 7.81–7.72 (m, 1H), 7.38–7.31 (m, 3H), 7.27–7.20 (m, 1H), 7.19–7.15 (m, 2H), 3.63 (s, 3H). LCMS(m/z)294.1[M+H]+.

Example 14. 6-Chloro-N-methyl-N-phenyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine

(Step 1) Synthesis of 2,5-dichloro-N-methyl-N-phenylquinazoline-4-amine

N-methylaniline (45.9 mg, 0.428 mmol) and concentrated HCl (37%, 15.62 mg, 0.428 mmol) were added to a suspension of 2,4,5-trichloroquinazoline (100 mg, 0.428 mmol) in 2-propanol (2.1 mL), and the mixture was stirred at room temperature for 1 hour. The precipitate was collected and washed with 2-propanol to give the desired product. LCMS (m/z) 304.08 [M+H]+.

(Step 2) Synthesis of 5-chloro-2-hydrazino-N-methyl-N-phenylquinazoline-4-amine

Hydrazine hydrate (20.08 mg, 0.401 mmol) was added to a solution of 2,5-dichloro-N-methyl-N-phenylquinazoline- ₄ -amine (61 mg, 0.201 mmol) in EtOH (1 mL), and the mixture was stirred at 50 °C for 2 hours. The reaction mixture was diluted with AcOEt, washed continuously with water and brine, and dried over _Na₂SO₄ . The organic layer was concentrated under vacuum to give the desired product. LCMS (m/z) 300.08 [M+H]⁺.

(Step 3) Synthesis of 6-chloro-N-methyl-N-phenyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine

A mixture of 5-chloro-2-hydrazino-N-methyl-N-phenylquinazoline-4-amine (54 mg, crude), triethoxymethane (29.7 mg, 0.201 mmol), and one drop of acetic acid (12.04 mg, 0.201 mmol) was heated to 90 °C for 2 hours. The reaction mixture was concentrated under vacuum, and the residue was purified by column chromatography (Si column, _CHCl3 :MeOH = 10:0–9:1) to provide the desired product: ^¹H -NMR (methanol- _d4 ) δ 9.46 (s, 1H), 8.17 (dd, J = 8.4, 0.9 Hz, 1H), 7.76 (t, J = 8.1 Hz, 1H), 7.40–7.33 (m, 1H), 7.25–7.15 (m, 2H), 7.08 (t, J = 7.4 Hz, 1H), 7.02–6.93 (m, 2H), 3.68 (s, 3H). LCMS (m/z) 310.1 [M+H]+.

Example 15. N-Ethyl-N-phenyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine

(Step 1) Synthesis of 2-chloro-N-ethyl-N-phenylquinazoline-4-amine

To a solution of 2,4-dichloroquinazoline (200 mg, 1.005 mmol) in DMF (5 mL), N-methylaniline (121 mg, 1.005 mmol) and sodium hydroxide (40.2 mg, 1.005 mmol) were added, and the mixture was stirred at room temperature for 3 hours. The mixture was diluted with AcOEt, washed continuously with water and brine, and dried over _Na₂SO₄ . The resulting residue was used in the next step without further purification. _LCMS (m/z) 284.13 [M+H] ^⁺ .

(Step 2) Synthesis of 2-hydrazino-N-ethyl-N-phenylquinazoline-4-amine

Hydrazine hydrate (37 mg, 0.74 mmol) was added to a solution of 2-chloro-N-ethyl-N-phenylquinazoline- ₄ -amine (210 mg, crude) in EtOH (3.7 mL), and the mixture was stirred at 50 °C for 2 hours. The reaction mixture was diluted with AcOEt, washed continuously with water and brine, and dried over _Na₂SO₄ . The organic layer was concentrated under vacuum. The resulting residue was used in the next step without further purification. LCMS (m/z) 280.18 [M+H] ^⁺ .

(Step 3) Synthesis of N-ethyl-N-phenyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine

A mixture of 2-hydrazino-N-ethyl-N-phenylquinazoline-4-amine (185 mg, crude), triethoxymethane (110 mg, 0.740 mmol), and acetic acid (12.04 mg, 0.201 mmol) was heated at 90 °C. The reaction mixture was concentrated under vacuum, and the residue was purified by column chromatography (Si column, _CHCl3 :MeOH = 10:0–9:1) to provide the desired product: ^¹H -NMR ( _CDCl3 ) δ 8.92 (s, ¹H), 7.78 (dd, J = 8.3, 1.1 Hz, ¹H), 7.62 (ddd, J = 8.4, 7.2, 1.3 Hz, ¹H), 7.43–7.32 (m, 2H), 7.32–7.22 (m, 2H), 7.19–7.04 (m, 3H), 4.25 (q, J = 7.0 Hz, 2H), 1.35 (t, J = 7.0 Hz, 3H). LCMS (m/z) 290.2 [M+H]+.

Example 16. N,9-Dimethyl-N-phenyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine

(Step 1) Synthesis of 8-methylquinazoline-2,4(1H,3H)-dione

Acetic acid (0.5 mL) was added to a suspension of 2-amino-3-methylbenzoic acid (500 mg, 3.31 mmol) in water (5 mL), and the suspension was heated to 35 °C. A freshly prepared solution of potassium cyanate (268 mg, 3.31 mmol) in water (0.5 mL) was added dropwise to the suspension over a 1-hour period. The mixture was stirred at 40 °C for 1 hour. NaOH (8 g) was added portion-wise to the reaction mixture while maintaining the internal temperature below 50 °C, and the mixture was further stirred for 2 hours. The precipitate was collected by filtration to obtain the desired product. LCMS (m/z) 177.11 [M+H] ⁺ .

(Step 2) Synthesis of 2,4-dichloro-8-methylquinazoline

A mixture of 8-methylquinazoline-2,4(1H,3H)-dione (120 mg, 0.68 mmol) and phosphorus trichloride (1521 mg, 9.92 mmol) was stirred at 100 °C for 3 hours. The reaction mixture was concentrated under vacuum, and the resulting residue was used in the next step without further purification. LCMS (m/z) 213.10 [M+H] ⁺ .

(Step 3) Synthesis of 2-chloro-N,8-dimethyl-N-phenylquinazoline-4-amine

N-methylaniline (50.3 mg, 0.469 mmol) and sodium hydroxide (18.77 mg, 0.469 mmol) were added to a suspension of 2,4-dichloro- ₈ -methylquinazoline (100 mg, 0.469 mmol) in DMF (2.35 mL), and the mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with AcOEt, washed continuously with water and brine, and dried over _Na₂SO₄ . The organic layer was concentrated under vacuum to give the desired product, which was used in the next step without further purification. LCMS (m/z) 284.8 [M+H] ^⁺ .

(Step 4) Synthesis of 2-hydrazino-N,8-dimethyl-N-phenylquinazoline-4-amine

Hydrazine hydrate (24.35 mg, 0.486 mmol) was added to a solution of 2-chloro-N,8-dimethyl-N-phenylquinazoline- ₄ -amine (69 mg, 0.243 mmol) in EtOH (1.2 mL), and the mixture was stirred at 50 °C for 2 hours. The reaction mixture was diluted with AcOEt, washed continuously with water and brine, and dried over _Na₂SO₄ . The organic layer was concentrated under vacuum to give the desired product. LCMS (m/z) 280.18 [M+H] ^⁺ .

(Step 5) Synthesis of N,9-dimethyl-N-phenyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine

A mixture of 2-hydrazino-N,8-dimethyl-N-phenylquinazoline-4-amine (54 mg, 0.192 mmol) and triethoxymethane (108 mg, 0.729 mmol) was stirred overnight at 90 °C. The reaction mixture was concentrated under vacuum, and the residue was purified by column chromatography (Si-column, _CHCl3 :MeOH = 10:0–9:1) to provide the desired product: ^¹H -NMR (methanol- _d4 ) δ 9.41 (s, 1H), 7.53 (d, J = 7.3 Hz, 1H), 7.39–7.31 (m, 2H), 7.25 (q, J = 8.3, 7.4 Hz, 2H), 7.17 (dd, J = 7.6, 2.0 Hz, 2H), 7.02 (t, J = 7.9 Hz, 1H), 3.62 (d, J = 1.9 Hz, 3H), 2.82 (s, 3H); LCMS (m/z) 290.1 [M+H]+.

Example 17. N-(3-fluorophenyl)-N-methyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine

3-fluoro-N-methylaniline (51.8 mg, 0.414 mmol) was added to a solution of 5-chloro-[1,2,4]triazolo[4,3-a]quinazoline (70 mg, 0.376 mmol), BOP (183 mg, 0.414 mmol), and DBU (0.068 mL, 0.451 mmol) in NMP (2 mL) at room temperature. The mixture was stirred at 55 °C for 4.5 h. The reaction mixture was purified by preparative LCMS to provide the desired product: ^¹H -NMR (DMSO- _d₆ ) δ 9.66 (s, 1H), 8.32 (d, J = 8.2 Hz, 1H), 7.81 (ddd, J = 8.5, 7.0, 1.7 Hz, 1H), 7.44–7.23 (m, 4H), 7.14–7.02 (m, 2H), 3.56 (s, 3H). LCMS(m/z)294.1[M+H]+.

Example 18. 6-Fluoro-N-methyl-N-phenyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine

(Step 1) Synthesis of 2-chloro-5-fluoro-N-methyl-N-phenylquinazoline-4-amine

N-methylaniline (49.4 mg, 0.461 mmol) and one drop of concentrated HCl (37%) were added to a suspension of 2,4-dichloro-5-fluoroquinazoline (100 mg, 0.461 mmol) in 2-propanol (2.3 mL), and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was filtered and washed with 2-propanol to give the desired product. LCMS (m/z) 288.08 [M+H] ⁺ .

(Step 2) Synthesis of 5-fluoro-2-hydrazino-N-methyl-N-phenylquinazoline-4-amine

Hydrazine hydrate (11.22 mg, 0.224 mmol) was added to a solution of 2-chloro-5-fluoro-N-methyl-N-phenylquinazoline- ₄ -amine (43 mg, 0.149 mmol) in ethanol (0.75 mL), and the mixture was stirred at 50 °C for 2 hours. The reaction mixture was diluted with AcOEt, washed continuously with water and brine, and dried over _Na₂SO₄ . The organic layer was concentrated under vacuum to give the desired product, which was used in the next step without further purification. LCMS (m/z) 284.13 [M+H] ^⁺ .

(Step 3) Synthesis of 6-fluoro-N-methyl-N-phenyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine

A mixture of 5-fluoro-2-hydrazino-N-methyl-N-phenylquinazoline-4-amine (39 mg, crude), triethoxymethane (111 mg, 0.747 mmol), and acetic acid (12.04 mg, 0.201 mmol) was incubated at 90 °C for 2 hours. The reaction mixture was concentrated under vacuum, and the residue was purified by column chromatography (Si column, _CHCl3 :MeOH = 10:0–9:1) to provide the desired product: ^¹H -NMR (methanol- _d4 ) δ 9.44 (s, 1H), 8.02 (d, J = 8.3 Hz, 1H), 7.83 (td, J = 8.3, 5.1 Hz, 1H), 7.32–7.23 (m, 2H), 7.21–7.06 (m, 3H), 6.99 (dd, J = 11.6, 8.3 Hz, 1H), 3.64 (s, 3H); LCMS (m/z) 295.1 [M+H]+.

Example 19. N-Methyl-N,8-diphenyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine

A mixture of 8-bromo-N-methyl-N-phenyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine (Example 28) (50 mg, 0.161 mmol), phenylboronic acid (49.2 mg, 0.404 mmol), cesium fluoride (73.6 mg, 0.484 mmol), and bis[di-tert-butyl(4-dimethylaminophenyl)phosphine]palladium (0) (11 mg, 0.016 mmol) in dioxane (0.8 mL) was treated in a microwave reactor at 100 °C for 2 h, and then at 120 °C for 2 h. The reaction mixture was concentrated under vacuum and purified by column chromatography (Si-column, _CHCl3 :MeOH = 10:0–9:1) to provide the desired product: ^¹H -NMR (methanol- _d4 ) δ 9.46 (s, 1H), 8.22 (d, J = 1.8 Hz, 1H), 7.67–7.57 (m, 2H), 7.43–7.36 (m, 5H), 7.33–7.26 (m, 2H), 7.21 (dd, J = 7.5, 1.5 Hz, 2H), 7.12 (d, J = 8.8 Hz, 1H), 3.58 (s, 3H). LCMS (m/z) 352.1 [M+H]+.

Example 20. 8-Methoxy-N-methyl-N-phenyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine

(Step 1) Synthesis of 2-chloro-7-methoxy-N-methyl-N-phenylquinazoline-4-amine

N-methylaniline (46.7 mg, 0.44 mmol) and sodium hydroxide (18.4 mmol, 0.46 mmol) were added to a solution of 2,4-dichloro-7-methoxyquinazoline (100 mg, 0.44 mmol) in DMF (7 mL). The mixture was stirred at room temperature for 1 hour and then at 60 °C for 2 hours. The mixture was diluted with AcOEt, washed continuously with water and brine, and dried over _Na₂SO₄ . The organic layer was concentrated under vacuum to give the desired product. _LCMS (m/z) 300.08 [M+H] ^⁺ .

(Step 2) Synthesis of 2-hydrazino-7-methoxy-N-methyl-N-phenylquinazoline-4-amine

Hydrazine hydrate (17.01 mg, 0.340 mmol) was added to a solution of 2-chloro-7-methoxy-N-methyl-N-phenylquinazoline- ₄ -amine (92 mg, 0.340 mmol) in EtOH (1.7 mL), and the mixture was stirred at 50 °C for 2 hours. The reaction mixture was diluted with AcOEt, washed continuously with water and brine, and dried over _Na₂SO₄ . The organic layer was concentrated under vacuum to give the desired product. LCMS (m/z) 296.18 [M+H] ^⁺ .

(Step 3) Synthesis of 8-methoxy-N-methyl-N-phenyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine

A mixture of 2-hydrazino-7-methoxy-N-methyl-N-phenylquinazoline-4-amine (67 mg, crude), triethoxymethane (201 mg, 1.359 mmol), and acetic acid (12.04 mg, 0.201 mmol) was incubated at 90 °C for 2 hours. The reaction mixture was concentrated under vacuum, and the residue was purified by column chromatography (Si column, _CHCl3 :MeOH = 10:0–9:1) to provide the desired product: ^¹H -NMR (DMSO- _d₆ ) δ 9.62 (s, 1H), 7.80 (d, J = 2.5 Hz, 1H), 7.43–7.33 (m, 2H), 7.31–7.20 (m, 3H), 7.15 (d, J = 9.3 Hz, 1H), 6.81 (dd, J = 9.3, 2.5 Hz, 1H), 3.91 (s, 3H), 3.51 (s, 3H). LCMS (m/z) 306.1 [M+H]+.

Example 21. 7-Fluoro-N-methyl-N-phenyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine

(Step 1) Synthesis of 2-chloro-6-fluoro-N-methyl-N-phenylquinazoline-4-amine

2,4-Dichloro-6-fluoroquinazoline (300 mg, 1.382 mmol) was added to a solution of N-methylaniline (148 mg, 1.382 mmol) and NaH (60.8 mg, _1.521 mmol) in 10 mL of DMF at room temperature, and the mixture was stirred at room temperature for 3.5 hours. The reaction mixture was diluted with EtOAc, washed continuously with water and brine, dried over _Na₂SO₄ , and concentrated under vacuum to obtain the desired product, which was used in the next step without purification. LCMS (m/z) 288.08 [M+H] ^⁺ .

(Step 2) Synthesis of 6-fluoro-2-hydrazino-N-methyl-N-phenylquinazoline-4-amine

Hydrazine hydrate (1 mL, 20.61 mmol) was added to a solution of 2-chloro-6-fluoro-N-methyl-N-phenylquinazoline-4-amine (398 mg, crude) in EtOH (5 mL) at room temperature, and the mixture was stirred overnight at 50 °C. The reaction mixture was cooled to room temperature and filtered to give the desired product, which was used in the next step without purification. LCMS (m/z) 284.13 [M+H] ⁺ .

(Step 3) Synthesis of 7-fluoro-N-methyl-N-phenyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine

A mixture of 6-fluoro-2-hydrazino-N-methyl-N-phenylquinazoline-4-amine (42 mg, crude) and triethoxymethane (3 mL) was stirred at 100 °C for 2 hours. The reaction mixture was cooled to room temperature and filtered to provide the crude product. The crude compound was purified by preparative LCMS to provide the desired product: ^¹H -NMR (DMSO- _d₆₆ ) δ 9.63 (s, 1H), 8.38 (dd, J = 9.2, 4.9 Hz, 1H), 7.75 (ddd, J = 9.2, 8.0, 2.8 Hz, 1H), 7.48–7.38 (m, 2H), 7.38–7.27 (m, 3H), 6.81 (dd, J = 10.5, 2.8 Hz, 1H), 3.54 (s, 3H). LCMS (m/z) 294.2 [M+H]+.

Example 22. N-Methyl-N-(pyridin-2-yl)-[1,2,4]triazolo[4,3-a]quinazolin-5-amine

(Step 1) Synthesis of 2-chloro-N-methyl-N-(pyridin-2-yl)quinazoline-4-amine

60% sodium hydride (0.150 g, 3.77 mmol) was added to a stirred solution of 2,4-dichloroquinazoline (0.5 g, 2.51 mmol) in 10 mL of DMF at 0 °C, and the mixture was stirred at room temperature for 1 hour. Then, N-methylpyridin-2-amine (0.407 g, 3.77 mmol) was added at 0 °C, and the mixture was stirred at room temperature for 1 hour. The reaction progress was monitored by TLC. After the reaction was complete, the reaction mixture was diluted with ice water and extracted twice with ethyl acetate. The combined organic layers were washed with brine, dried over _Na₂SO₄ , filtered _, and evaporated under reduced pressure. The residue was purified by column chromatography (Si column, AcOEt: petroleum ether = 3:7–1:1) to give the desired product.

(Step 2) Synthesis of N-methyl-N-(pyridin-2-yl)-[1,2,4]triazolo[4,3-a]quinazolin-5-amine

Formylhydrazine (0.044 g, 0.74 mmol) was added to a stirred solution of 0.1 g (0.37 mmol) of 2-chloro-N-methyl-N-(pyridin-2-yl)quinazolin-4-amine in toluene (2 mL) at room temperature, and the mixture was heated to 110 °C for 48 hours. The reaction progress was monitored by TLC. After the reaction was complete, the reaction mixture was evaporated under reduced pressure. The residue was purified by preparative HPLC to yield the desired product: ^¹H -NMR (DMSO- _d₆ ) δ 9.73 (s, ¹H), 8.35 (d, J = 8.3 Hz, ¹H), 8.22 (ddd, J = 5.0, 1.9, 0.9 Hz, ¹H), 7.86 (ddd, J = 8.4, 6.9, 1.7 Hz, ¹H), 7.78 (ddd, J = 8.2, 7.2, 2.0 Hz, ¹H), 7.41–7.23 (m, ³H), 7.12 (ddd, J = 7.4, 4.9, 0.9 Hz, ¹H), 3.64 (s, ³H). LCMS (m/z) 277.2 [M+H]+.

Example 23. N-Methyl-N-(pyridin-3-yl)-[1,2,4]triazolo[4,3-a]quinazolin-5-amine

(Step 1) Synthesis of 2-chloro-N-methyl-N-(pyridin-3-yl)quinazoline-4-amine

60% sodium hydride (0.150 g, 3.77 mmol) was added to a stirred solution of 2,4-dichloroquinazoline (0.5 g, 2.51 mmol) in 10 mL of DMF at 0 °C, and the mixture was stirred at room temperature for 1 hour. Then, N-methylpyridin-3-amine (0.407 g, 3.77 mmol) was added at 0 °C, and the mixture was stirred at room temperature for 1 hour. The reaction progress was monitored by TLC. After the reaction was complete, the reaction mixture was diluted with ice water and extracted twice with ethyl acetate. The combined organic layers were washed with brine, dried over _Na₂SO₄ , filtered _, and evaporated under reduced pressure. The residue was purified by column chromatography (Si column, AcOEt: petroleum ether = 3:7–1:1) to give the desired product.

(Step 2) Synthesis of N-methyl-N-(pyridin-3-yl)-[1,2,4]triazolo[4,3-a]quinazolin-5-amine

Formylhydrazine (0.053 g, 0.88 mmol) was added to a stirred solution of 2-chloro-N-methyl-N-(pyridin-3-yl)quinazolin-4-amine (0.120 g, 0.44 mmol) in toluene (4 mL), and the mixture was heated to 120 °C for 48 hours. The reaction progress was monitored by TLC. After the reaction was complete, the reaction mixture was evaporated under reduced pressure. The residue was purified by preparative HPLC to provide the desired product: ^¹H -NMR (DMSO- _d₆ ) δ 9.66 (s, ¹H), 8.51 (d, J = 2.7 Hz, ¹H), 8.42 (dd, J = 4.8, 1.4 Hz, ¹H), 8.37–8.27 (m, ¹H), 7.87–7.71 (m, 2H), 7.42 (ddd, J = 8.2, 4.7, 0.8 Hz, ¹H), 7.33–7.23 (m, 2H), 3.58 (s, 3H). LCMS (m/z) 277.2 [M+H]⁺.

Example 24. N-Methyl-N-(pyridin-4-yl)-[1,2,4]triazolo[4,3-a]quinazolin-5-amine

(Step 1) Synthesis of 2-chloro-N-methyl-N-(pyridin-4-yl)quinazoline-4-amine

Sodium hydroxide (0.1 g, 2.51 mmol) and N-methylpyridin-4-amine (0.271 g, 2.51 mmol) were added to a stirred solution of 2,4-dichloroquinazoline (0.5 g, 2.51 mmol) in DMF (10 mL) at room temperature, and the mixture was stirred at room temperature for 4 hours. The reaction progress was monitored by TLC. After the reaction was complete, the reaction mixture was diluted with ice water and extracted with ethyl acetate. The organic layer was washed with brine, dried over _Na₂SO₄ , filtered _, and evaporated under reduced pressure to give the desired product.

(Step 2) Synthesis of N-methyl-N-(pyridin-4-yl)-[1,2,4]triazolo[4,3-a]quinazolin-5-amine

Formyl hydrazide (0.111 g, 1.85 mmol) was added to a stirred solution of 2-chloro-N-methyl-N-(pyridin-4-yl)quinazolin-4-amine (0.250 g, 0.92 mmol) in toluene (5 mL), and the mixture was heated to 120 °C for 48 hours. The reaction progress was monitored by TLC. After the reaction was complete, the reaction mixture was evaporated under reduced pressure. The residue was purified by preparative HPLC to provide the desired product: ^¹H -NMR (DMSO- _d₆ ) δ 9.80 (s, 1H), 8.57–8.29 (m, 3H), 7.92 (ddd, J = 8.5, 7.2, 1.4 Hz, 1H), 7.55 (dd, J = 8.3, 1.4 Hz, 1H), 7.43 (ddd, J = 8.2, 7.2, 1.1 Hz, 1H), 7.19–6.98 (m, 2H), 3.60 (s, 3H); LCMS (m/z) 277.2 [M+H]+.

Example 25. N-(2-chlorophenyl)-N-methyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine

2-Chloro-N-methylaniline (41.8 mg, 0.295 mmol) was added to a solution of 5-chloro-[1,2,4]triazolo[4,3-a]quinazoline (50 mg, 0.269 mmol), bromotris(dimethylamino)phosphonium hexafluorophosphate (BrOP) (125 mg, 0.322 mmol), and DBU (49.1 mg, 0.322 mmol) in acetonitrile (1 mL). The mixture was stirred overnight at 80 °C. The reaction mixture was concentrated under vacuum, and the residue was purified by column chromatography (Si column, _CHCl3 :MeOH = 100:0–95:5) to provide a crude product. The crude compound was further purified by preparative LCMS to provide the desired product: ^¹H -NMR ( _CDCl₃ ) δ 8.94 (s, ¹H), 7.82 (ddd, J = 8.3, 1.2, 0.6 Hz, ¹H), 7.66 (ddd, J = 8.4, 6.7, 1.8 Hz, ¹H), 7.60–7.52 (m, ¹H), 7.34–7.29 (m, ¹H), 7.26 (td, J = 7.6, 1.7 Hz, ¹H), 7.20–7.10 (m, ³H), 3.59 (s, ³H); LCMS (m/z) 310.2 [M+H]+.

Example 26. N-(2-cyanophenyl)-N-methyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine

2-Cyano-N-methylaniline (56.8 mg, 0.430 mmol) was added to a solution of 5-chloro-[1,2,4]triazolo[4,3-a]quinazoline (80 mg, 0.430 mmol), BrOP (200 mg, 0.516 mmol), and DBU (79 mg, 0.516 mmol) in acetonitrile (2 mL). The mixture was stirred overnight at 80 °C. The reaction mixture was subjected to solid-phase extraction using a Bond Elut SCX box (Agilent) (washing with MeOH followed by elution with NH3 in MeOH), and the collected fraction was concentrated under vacuum. The residue was then purified by preparative LCMS to provide the desired product: ^¹H -NMR ( _CDCl₃ ) δ 9.05 (s, ¹H), 7.92 (d, J = 8.2 Hz, ¹H), 7.81 (dd, J = 7.8, 1.6 Hz, ¹H), 7.72 (ddd, J = 8.4, 5.2, 3.4 Hz, ¹H), 7.54 (td, J = 7.9, 1.7 Hz, ¹H), 7.41 (td, J = 7.7, 1.1 Hz, ¹H), 7.24–7.14 (m, 2H), 7.10 (dd, J = 8.2, 1.1 Hz, ¹H), 3.73 (s, 3H); LCMS (m/z) 301.2 [M+H]+.

Example 27. N-(2-bromophenyl)-N-methyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine

2-Bromo-N-methylaniline (50 mg, 0.269 mmol) was added to a solution of 5-chloro-[1,2,4]triazolo[4,3-a]quinazoline (50 mg, 0.269 mmol), BrOP (125 mg, 0.322 mmol), and DBU (49.1 mg, 0.322 mmol) in acetonitrile (1 mL). The mixture was stirred overnight at 80 °C. The reaction mixture was subjected to solid-phase extraction using a Bond Elut SCX box (Agilent) (washing with MeOH followed by elution with _NH₃ in MeOH), and the collected fraction was concentrated under vacuum. The residue was then purified by preparative LCMS to provide the desired product: ^¹H -NMR ( _CDCl₃ ) δ 9.13 (s, ¹H), 7.97 (d, J = 8.3 Hz, ¹H), 7.79–7.65 (m, 2H), 7.29 (dt, J = 7.6, 1.6 Hz, 2H), 7.23–7.09 (m, 3H), 3.60 (s, 3H); LCMS (m/z) 355.6 [M+H]+.

Example 28. 8-Bromo-N-methyl-N-phenyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine

(Step 1) Synthesis of 7-bromo-2-chloro-N-methyl-N-phenylquinazoline-4-amine

7-Bromo-2,4-dichloroquinazoline (800 mg, 2.88 mmol) was added to a solution of N-methylaniline (0.327 mL, 3.02 mmol) and NaH (121 mg, _3.02 mmol) in DMF (30 mL) at room temperature. The reaction mixture was stirred at room temperature for 5 hours. The mixture was diluted with AcOEt, washed continuously with water and brine, and dried over _Na₂SO₄ . The organic layer was concentrated under vacuum. The resulting residue was used in the next step without further purification. LCMS (m/z) 347.98 [M+H] ^⁺ .

(Step 2) Synthesis of 7-bromo-2-hydrazino-N-methyl-N-phenylquinazoline-4-amine

The resulting 7-bromo-2-chloro-N-methyl-N-phenylquinazoline-4-amine was stirred in EtOH (5 mL) and hydrazine hydrate (2 mL) at 50 °C for 1 hour. The reaction mixture was cooled to room temperature and then diluted with EtOAc. The solution was washed continuously with water and brine, dried over _Na₂SO₄ , and concentrated under vacuum. The crude product was used in the next step without purification. _LCMS (m/z) 344.08 [M+H] ^⁺ .

(Step 3) Synthesis of 8-bromo-N-methyl-N-phenyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine

The resulting 7-bromo-2-hydrazino-N-methyl-N-phenylquinazoline-4-amine in EtOH (20 mL) and triethoxymethane (5 mL) were stirred overnight at 100 °C. The reaction mixture was concentrated under vacuum. The residue was purified by column chromatography (Si column, _CHCl3 :MeOH = 100:0–95:5) to provide the desired product: ^¹H -NMR (methanol- _d4 ) δ 9.29 (d, J = 2.3 Hz, 1H), 8.29 (d, J = 4.8 Hz, 1H), 7.32 (t, J = 7.6 Hz, 2H), 7.24–7.14 (m, 4H), 6.95 (t, J = 8.1 Hz, 1H), 3.51 (d, J = 2.2 Hz, 3H); LCMS (m/z) 355.0 [M+H]+.

Example 29. N,8-Dimethyl-N-phenyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine

(Step 1) Synthesis of 7-methylquinazoline-2,4(1H,3H)-dione

Acetic acid (0.5 mL) was added to a suspension of 2-amino-4-methylbenzoic acid (500 mg, 3.31 mmol) in water (5 mL), and the suspension was heated to 35 °C. A freshly prepared solution of potassium cyanate (268 mg, 3.31 mmol) in water (0.5 mL) was added dropwise to the suspension over a 1-hour period. The mixture was stirred at 40 °C for 1 hour. NaOH (8 g) was added portion-wise to the reaction mixture while maintaining the internal temperature below 50 °C, and the mixture was further stirred for 2 hours. The precipitate was collected by filtration to obtain the desired product. LCMS (m/z) 177.11 [M+H] ⁺ .

(Step 2) Synthesis of 2,4-dichloro-7-methylquinazoline

A mixture of 7-methylquinazoline-2,4(1H,3H)-dione (100 mg, 0.568 mmol) and phosphorus trichloride (435 mg, 2.84 mmol) was heated to 100 °C for 3 hours. The reaction mixture was concentrated under vacuum to give the desired product. LCMS (m/z) 213.05 [M+H] ⁺ .

(Step 3) Synthesis of 2-chloro-N,7-dimethyl-N-phenylquinazoline-4-amine

N-methylaniline (55.3 mg, 0.516 mmol) and sodium hydroxide (18.77 mg, 0.469 mmol) were added to a solution of 2,4-dichloro- ₇ -methylquinazoline (100 mg, 0.47 mmol) in DMF (2.3 mL), and the mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with AcOEt, washed continuously with _H₂O and brine, and dried over _Na₂SO₄ . The organic layer was concentrated under vacuum to give the desired product. LCMS (m/z) 284.8 [M+H] ^⁺ .

(Step 4) Synthesis of 2-hydrazino-N,7-dimethyl-N-phenylquinazoline-4-amine

Hydrazine hydrate (25.05 mg, 0.5 mmol) was added to a solution of 2-chloro-N,7-dimethyl-N-phenylquinazoline- ₄ -amine (71 mg, 0.25 mmol) in EtOH (1.25 mL), and the mixture was stirred at 50 °C for 2 hours. The reaction mixture was diluted with AcOEt, washed continuously with water and brine, and dried over _Na₂SO₄ . The organic layer was concentrated under vacuum to give the desired product. LCMS (m/z) 280.18 [M+H] ^⁺ .

(Step 5) Synthesis of N,8-dimethyl-N-phenyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine

A mixture of 2-hydrazino-N,7-dimethyl-N-phenylquinazoline-4-amine (68 mg, crude), triethoxymethane (111 mg, 0.751 mmol), and one drop of acetic acid (12.04 mg, 0.201 mmol) was heated to 90 °C for 2 hours. The reaction mixture was concentrated under vacuum and purified by preparative HPLC to provide the desired product: ^¹H -NMR (methanol- _d⁴ ) δ 9.39 (s, 1H), 7.99 (d, J = 1.5 Hz, 1H), 7.47–7.39 (m, 2H), 7.34–7.22 (m, 3H), 7.16 (d, J = 8.6 Hz, 1H), 6.99 (dd, J = 8.5, 1.6 Hz, 1H), 3.64 (s, 3H), 2.47 (s, 3H); LCMS (m/z) 290.2 [M+H]+.

Example 30. 8-Cyclopropyl-N-methyl-N-phenyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine

A mixture of 8-bromo-N-methyl- _N -phenyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine (Example 28) (20 mg, 0.056 mmol), _K₃PO₄ (30.0 mg, 0.141 mmol), Pd(OAc) _₂ (2.54 mg, 0.011 mmol), tricyclohexylphosphine (1.583 mg, 5.65 μmol), and cyclopropylboronic acid (12.13 mg, 0.141 mmol) in dioxane/water (0.28 mL) was treated in a microwave reactor at 120 °C for 2 hours. The reaction mixture was purified by column chromatography (Si-column, CHCl3:MeOH = ₁₀ :0–9:1) to provide the desired product: ^¹H -NMR (methanol- _d4 ) δ 9.44 (s, 1H), 7.81 (d, J = 1.9 Hz, 1H), 7.47–7.37 (m, 2H), 7.36–7.20 (m, 3H), 7.10 (dd, J = 8.9, 4.4 Hz, 1H), 6.84 (dt, J = 8.8, 2.1 Hz, 1H), 3.63 (s, 3H), 2.10–1.98 (m, 1H), 1.20–1.06 (m, 2H), 0.87 (dt, J = 7.0, 4.7 Hz, 2H); LCMS (m/z) 316.0 [M+H]+.

Example 31. N-Methyl-N-phenyl-8-(pyridin-4-yl)-[1,2,4]triazolo[4,3-a]quinazolin-5-amine

A mixture of 8-bromo-N-methyl- _N -phenyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine (Example 28) (20 mg, 0.056 mmol), _K₃PO₄ (30.0 mg, 0.141 mmol), Pd(OAc) _₂ (2.54 mg, 0.011 mmol), tricyclohexylphosphine (1.583 mg, 5.65 μmol), and pyridine-4-ylboronic acid (17.35 mg, 0.141 mmol) in dioxane/water (0.28 mL) was treated in a microwave reactor at 120 °C for 2 hours. The reaction mixture was then concentrated under vacuum. The residue was purified by preparative HPLC to provide the desired product: ^¹H -NMR (methanol- _d⁴ ) δ 9.61 (s, 1H), 8.71–8.61 (m, 4H), 7.89–7.83 (m, 2H), 7.60 (dd, J = 8.8, 1.8 Hz, 1H), 7.46 (d, J = 8.2 Hz, 3H), 7.37–7.31 (m, 2H), 3.70 (s, 3H); LCMS (m/z) 353.2 [M+H]+.

Example 32. N-(2-iodophenyl)-N-methyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine

2-Iodo-N-methylaniline (40 mg, 0.172 mmol) was added to a solution of 5-chloro-[1,2,4]triazolo[4,3-a]quinazoline (32 mg, 0.172 mmol), BrOP (73.3 mg, 0.189 mmol), and DBU (28.7 mg, 0.189 mmol) in acetonitrile (1 mL) at room temperature. The mixture was stirred overnight at 80 °C. The reaction mixture was concentrated under vacuum, and the residue was purified by column chromatography (Si column, _CHCl3 :MeOH = 100:0–95:5) to provide a crude product. The crude compound was further purified by preparative LCMS to provide the desired product: ^¹H -NMR (methanol- _d⁴ ) δ 9.44 (s, ¹H), 8.20 (dd, J = 8.4, 1.0 Hz, ¹H), 8.07 (dd, J = 8.0, 1.4 Hz, ¹H), 7.78 (ddd, J = 8.5, 7.2, 1.4 Hz, ¹H), 7.46 (td, J = 7.6, 1.4 Hz, ¹H), 7.33 (dd, J = 7.9, 1.6 Hz, ¹H), 7.25–7.09 (m, ³H), 3.56 (s, ³H); LCMS (m/z) 402.1 [M+H]+.

Example 33. N-Methyl-N-(o-tolyl)-[1,2,4]triazolo[4,3-a]quinazolin-5-amine

N,2-Dimethylaniline (32.5 mg, 0.269 mmol) was added to a solution of 5-chloro-[1,2,4]triazolo[4,3-a]quinazoline (50 mg, 0.269 mmol), BrOP (115 mg, 0.295 mmol), and DBU (45 mg, 0.295 mmol) in acetonitrile (2 mL) at room temperature. The mixture was stirred overnight at 80 °C. The reaction mixture was concentrated under vacuum, and the residue was purified by column chromatography (Si column, _CHCl3 :MeOH = 100:0-95:5) to give the crude product. The crude compound was further purified by preparative LCMS to provide the desired product: ^¹H -NMR (methanol- _d⁴ ) δ 9.40 (s, ¹H), 8.17 (dt, J = 8.3, 0.8 Hz, ¹H), 7.74 (ddd, J = 8.4, 6.8, 1.8 Hz, ¹H), 7.46–7.39 (m, ¹H), 7.39–7.21 (m, 2H), 7.19–7.07 (m, 3H), 3.56 (s, 3H), 2.31 (s, 3H); LCMS (m/z) 290.2 [M+H]+.

Example 34. N-Methyl-N-(m-Tolyl)-[1,2,4]triazolo[4,3-a]quinazolin-5-amine

N,3-dimethylaniline (32.5 mg, 0.269 mmol) was added to a solution of 5-chloro-[1,2,4]triazolo[4,3-a]quinazoline (50 mg, 0.269 mmol), BrOP (115 mg, 0.295 mmol), and DBU (45.0 mg, 0.295 mmol) in acetonitrile (2 mL) at room temperature. The mixture was stirred overnight at 50 °C. The reaction mixture was concentrated under vacuum, and the residue was purified by column chromatography (Si column, _CHCl3 :MeOH = 100:0-95:5) to give the crude product. The crude compound was further purified by preparative LCMS to provide the desired product: ^¹H -NMR (methanol- _d⁴ ) δ 9.43 (s, ¹H), 8.21–8.07 (m, ¹H), 7.75 (ddd, J = 8.5, 7.2, 1.3 Hz, ¹H), 7.37–7.24 (m, 2H), 7.23–7.11 (m, 3H), 7.11–7.03 (m, ¹H), 3.65 (s, 3H), 2.33 (d, J = 0.8 Hz, 3H); LCMS (m/z) 290.2 [M+H]+.

Example 35. 7-Chloro-N-methyl-N-phenyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine

(Step 1) Synthesis of 2,6-dichloro-N-methyl-N-phenylquinazoline-4-amine

2,4,6-trichloroquinazoline (300 mg, 1.285 mmol) was added to a solution of N-methylaniline (138 mg, 1.285 mmol) and NaH (56.5 mg, 1.413 mmol) in 10 mL of DMF at room temperature. The mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with EtOAc, washed continuously with water and brine, dried over _Na₂SO₄ , and concentrated under vacuum to obtain the desired product, which was used in the next step without purification. _LCMS (m/z) 304.03 [M+H]⁺.

(Step 2) Synthesis of 6-chloro-2-hydrazino-N-methyl-N-phenylquinazoline-4-amine

Hydrazine hydrate (2 mL) was added to a solution of 2,6-dichloro-N-methyl-N-phenylquinazoline-4-amine ( ₁₁₇ mg, crude) in EtOH (5 mL) at room temperature. The mixture was stirred at 50 °C for 2 hours. The reaction mixture was cooled to room temperature, diluted with EtOAc, washed continuously with water and brine, dried over _Na₂SO₄ , and concentrated under vacuum. The crude product was used in the next step without purification. LCMS (m/z) 300.08 [M+H]⁺.

(Step 3) Synthesis of 7-chloro-N-methyl-N-phenyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine

A solution of crude 6-chloro-2-hydrazino-N-methyl-N-phenylquinazoline-4-amine in triethoxymethane (5 mL) was stirred overnight at 100 °C. The reaction mixture was concentrated under vacuum, and the residue was purified by column chromatography (Si column, hexane:AcOEt = 100:0-0:100, then MeOH) to give the crude product. The crude compound was further purified by preparative LCMS to give the desired product: ^¹H -NMR (DMSO- _d⁶ ) δ 9.62 (s, 1H), 8.33 (d, J = 8.8 Hz, 1H), 7.87 (dd, J = 8.9, 2.3 Hz, 1H), 7.49–7.28 (m, 5H), 7.10 (d, J = 2.3 Hz, 1H), 3.55 (s, 3H). LCMS (m/z) 310.1 [M+H]+.

Example 36. N,7-Dimethyl-N-phenyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine

(Step 1) Synthesis of 2-chloro-N,6-dimethyl-N-phenylquinazoline-4-amine

2,4-Dichloro-6-methylquinazoline (300 mg, 1.408 mmol) was added to a solution of N-methylaniline (151 mg, 1.408 mmol) and NaH (61.9 mg, 1.549 mmol) in 10 mL of DMF at room temperature. The mixture was stirred at room temperature for 5 hours. The reaction mixture was quenched with water and diluted with AcOEt. The organic layer was washed with brine, dried over _Na₂SO₄ , and concentrated under vacuum to give the desired product. _LCMS (m/z) 284.13 [M+H]⁺.

(Step 2) Synthesis of 2-hydrazino-N,6-dimethyl-N-phenylquinazoline-4-amine

A mixture of 2-chloro-N,6-dimethyl-N-phenylquinazoline-4-amine (123 mg, 0.43 mmol) and hydrazine hydrate (2 mL) in EtOH (5 mL) was stirred overnight at 50 °C. The reaction mixture was cooled to room temperature, diluted with EtOAc, washed continuously with water and brine, dried over _Na₂SO₄ , and concentrated under vacuum to obtain the desired product, which was used in the next step without purification. _LCMS (m/z) 280.18 [M+H]⁺.

(Step 3) Synthesis of N,7-dimethyl-N-phenyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine

A solution of 2-hydrazino-N,6-dimethyl-N-phenylquinazoline-4-amine (89 mg, crude product) and triethoxymethane (5 mL) in EtOH (5 mL) was stirred at 100 °C for 4 hours. The reaction mixture was concentrated under vacuum. The residue was purified by column chromatography (Si column, _CHCl3 :MeOH = 100:0-95:5) to give the crude product. The crude compound was further purified by preparative LCMS to provide the desired product: ^¹H -NMR (DMSO- _d₆ ) δ 9.57 (s, ¹H), 8.18 (d, J = 8.4 Hz, ¹H), 7.61 (ddd, J = 8.4, 1.9, 0.7 Hz, ¹H), 7.45–7.35 (m, 2H), 7.33–7.24 (m, 3H), 7.00–6.94 (m, ¹H), 3.54 (s, 3H), 2.05 (s, 3H); LCMS (m/z) 290.2 [M+H]+.

Example 37. N-Methyl-N-phenyl-8-(prop-1-yn-1-yl)-[1,2,4]triazolo[4,3-a]quinazolin-5- amine

A mixture of 8-bromo-N-methyl-N-phenyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine (Example 28) (30 mg, 0.085 mmol), prop-1-yne (8.48 mg, 0.212 mmol), triethylamine (8.57 mg, 0.085 mmol), Pd(OAc) ₂ (3.80 mg, 0.017 mmol), triphenylphosphine (19.99 mg, 0.076 mmol), and copper iodide (I) (3.23 mg, 0.017 mmol) in dioxane (0.4 mL) was treated in a microwave reactor at 120 °C for 2 hours. The reaction mixture was purified by column chromatography (Si-column, _CHCl3 :MeOH = 10:0–9:1) to provide the desired product: ^¹H -NMR ( _CDCl3 ) δ 8.90 (s, 1H), 7.77 (d, J = 1.5 Hz, 1H), 7.44–7.32 (m, 2H), 7.31–7.22 (m, 1H), 7.23–7.11 (m, 3H), 7.05 (dd, J = 8.7, 1.6 Hz, 1H), 3.67 (s, 3H), 2.08 (s, 3H); LCMS (m/z) 314.2 [M+H]+.

Example 38. 5-(methyl(phenyl)amino)-[1,2,4]triazolo[4,3-a]quinazolin-8-ol

Tribromoborane (0.197 mL, 0.197 mmol) was added to a solution of 8-methoxy-N-methyl-N-phenyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine (Example 20) (20 mg, 0.066 mmol) in 1,2-dichloroethane (1 mL) at room temperature, and the mixture was stirred at 50 °C for 1 hour. The reaction mixture was concentrated under vacuum, and the residue was purified by column chromatography (Si column, _CHCl3 :MeOH = 100:0–90:10) to provide the desired product: ^¹H -NMR (DMSO- _d6 ) δ 9.48 (s, 1H), 7.50 (d, J = 2.4 Hz, 1H), 7.38 (dd, J = 8.5, 7.1 Hz, 2H), 7.28–7.19 (m, 3H), 7.09 (d, J = 9.1 Hz, 1H), 6.62 (dd, J = 9.2, 2.4 Hz, 1H), 3.50 (s, 3H); LCMS (m/z) 292.2 [M+H]+.

Example 39. N-Phenyl-N-propyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine

(Step 1) Synthesis of 2-chloro-N-phenyl-N-propylquinazoline-4-amine

N-propylaniline (0.339 g, 2.51 mmol) was added to a solution of 60% sodium hydride (0.12 g, 3.01 mmol) in 10 mL of DMF at 0 °C, and the mixture was stirred at room temperature for 1 hour. Then, 2,4-dichloroquinazoline (0.5 g, 2.51 mmol) was added at 0 °C, and the mixture was stirred at room temperature for 16 hours. The reaction mixture was diluted with ice water. The resulting solid was filtered and dried under vacuum to give the desired product. LCMS: 298.14 (M+H).

(Step 2) Synthesis of 2-hydrazino-N-phenyl-N-propylquinazoline-4-amine

Hydrazine hydrate (0.067 g, 1.34 mmol) was added to a stirred solution of 2-chloro-N-phenyl-N-propylquinazolin-4-amine (crude, 0.2 g, 0.67 mmol) in EtOH (5 mL) at room temperature, and the mixture was stirred at 50 °C for 16 hours. The reaction mixture was evaporated under reduced pressure to give the desired product. LCMS: 294.09 (M+H).

(Step 3) Synthesis of N-phenyl-N-propyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine

A mixture of 2-hydrazino-N-phenyl-N-propylquinazolin-4-amine (crude, 0.15 g, 0.51 mmol) and triethyl orthoformate (3 mL) was stirred at 80 °C for 3 hours. The reaction mixture was evaporated under reduced pressure, and the residue was purified by preparative HPLC to provide the desired product: ^¹H -NMR (DMSO- _d₆ ) δ 9.60 (s, 1H), 8.27 (dd, J = 8.3, 1.1 Hz, 1H), 7.75 (ddd, J = 8.4, 7.0, 1.6 Hz, 1H), 7.43–7.33 (m, 2H), 7.30–7.14 (m, 5H), 4.13–3.94 (m, 2H), 1.74 (d, J = 7.5 Hz, 2H), 0.95 (t, J = 7.4 Hz, 3H). LCMS(m/z) 304.18[M+H]+.

Example 40. N-Benzyl-N-Phenyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine

LDA (0.1 mL, 0.2 mmol, 2.0 M in THF) was added to a solution of N-benzylaniline (0.018 g, 0.098 mmol) in 1 mL of THF at 0 °C, and the mixture was stirred at room temperature for 1 hour. Then, 5-chloro-[1,2,4]triazolo[4,3-a]quinazoline (0.02 g, 0.098 mmol) was added at 0 °C, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was dried over _Na₂SO₄ , filtered _, and evaporated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with 5% methanol/dichloromethane to provide the desired product: ^¹H -NMR (DMSO- _d₆ ) δ 9.64 (s, 1H), 8.30 (d, J = 8.3 Hz, 1H), 7.55–7.05 (m, 13H), 5.40 (s, 2H); LCMS (m/z) 352.2 [M+H]+.

Example 41. N-(cyclopropylmethyl)-N-phenyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine

(Step 1) Synthesis of N-(cyclopropylmethyl)aniline

Cyclopropaneformaldehyde (3.01 g, 42.95 mmol) and a catalytic amount of acetic acid were added to a solution of aniline (2.0 g, 21.47 mmol) in EtOH (20 mL) at room temperature, and the mixture was stirred at room temperature for 1 hour. Subsequently, sodium triacetoxyborohydride (9.10 g, 42.95 mmol) was added at room temperature, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography, eluting with 10% ethyl acetate/petroleum ether to give the desired product. LCMS: 148.31 (M+H).

(Step 2) Synthesis of N-(cyclopropylmethyl)-N-phenyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine

LDA (0.15 mL, 0.20 mmol, 1.0 M in THF) was added to a solution of N-(cyclopropylmethyl)aniline (crude, 0.014 g, 0.098 mmol) in 1 mL of THF at 0 °C, and the mixture was stirred at room temperature for 0.5 h. Then, 5-chloro-[1,2,4]triazolo[4,3-a]quinazoline (0.02 g, 0.098 mmol) was added at 0 °C. The mixture was stirred at room temperature for 1 h. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was dried over _Na₂SO₄ , filtered _, and evaporated under reduced pressure. The residue was purified by silica gel column chromatography and eluted with 100% ethyl acetate to provide the desired product: ^¹H -NMR (DMSO- _d₆ ) δ 9.60 (s, 1H), 8.28 (dd, J = 8.3, 1.1 Hz, 1H), 7.76 (ddd, J = 8.4, 7.1, 1.4 Hz, 1H), 7.40–7.36 (m, 2H), 7.30–7.17 (m, 5H), 3.96 (d, J = 6.8 Hz, 2H), 1.45–1.31 (m, 1H), 0.44–0.33 (m, 2H), 0.20–0.09 (m, 2H); LCMS (m/z) 316.4 [M+H]+.

Example 42. 4-([1,2,4]triazolo[4,3-a]quinazolin-5-yl)-3,4-dihydro-2H-benzo[b][1, 4] Oxazine

(Step 1) Synthesis of 4-(2-chloroquinazoline-4-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine

3,4-Dihydro-2H-benzo[b][1,4]oxazine (0.339 g, 2.51 mmol) was added to a stirred solution of 60% sodium hydride (0.120 g, 3.01 mmol) in 10 mL of DMF at 0 °C, and the mixture was stirred at room temperature for 2 hours. Then, 2,4-dichloroquinazoline (0.5 g, 2.51 mmol) was added at 0 °C, and the mixture was stirred at room temperature for 8 hours. The reaction mixture was quenched with ice water. The resulting solid was filtered and dried under vacuum to give the desired product. LCMS: 298.11 (M+H).

(Step 2) Synthesis of 4-(2-hydrazinoquinazolin-4-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine

Hydrazine hydrate (0.101 mL, 2.02 mmol) was added to a solution of 4-(2-chloroquinazoline-4-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine (0.3 g, 1.01 mmol) in EtOH (10 mL) at room temperature, and the mixture was stirred at 50 °C for 5 h. The reaction mixture was evaporated under reduced pressure. The residue was washed with n-pentane and diethyl ether to give the desired product. LCMS: 294.18 (M+H).

(Step 3) 4-([1,2,4]triazolo[4,3-a]quinazolin-5-yl)-3,4-dihydro-2H-benzo[b][1,4]ox Synthesis of azines

A mixture of 4-(2-hydrazinoquinazolin-4-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine (crude, 0.2 g, 0.68 mmol) and triethyl orthoformate (0.3 g, 2.05 mmol) was stirred at 90 °C for 2 hours. The reaction mixture was diluted with ethanol, and the resulting solid was collected by filtration to give the crude product. The crude product was purified by preparative HPLC to obtain the desired product: ^¹H -NMR (500MHz, DMSO- _d₆ ) δ 9.74 (s, 1H), 8.41 (dd, J = 8.4, 1.1Hz, 1H), 8.08 (dd, J = 8.3, 1.3Hz, 1H), 7.97 (ddd, J = 8.5, 7.3, 1.4Hz, 1H), 7.56 (ddd, J = 8.3, 7.3, 1.1Hz, 1H), 7.00–6.92 (m, 2H), 6.92–6.84 (m, 1H), 6.71 (ddd, J = 8.4, 5.5, 3.3Hz, 1H), 4.41 (dd, J = 5.2, 3.7Hz, 2H), 4.03 (t, J = 4.5Hz, 2H); LCMS (m/z) 304.2.

Example 43. N,N-Diphenyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine

(Step 1) Synthesis of 2-chloro-N,N-diphenylquinazoline-4-amine

60% sodium hydride (0.241 g, 6.03 mmol) was added to a solution of 2,4-dichloroquinazoline (1.0 g, 5.02 mmol) in DMF (20 mL) at 0 °C, and the mixture was stirred at room temperature for 1 hour. Then, diphenylamine (0.849 g, 5.02 mmol) was added at 0 °C, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted with ice water and extracted twice with ethyl acetate. The combined organic layers were washed with brine, dried over _{anhydrous Na₂SO₄} , filtered, and evaporated under reduced pressure to give the desired product. LCMS: 332.15 (M+H).

(Step 2) Synthesis of 2-hydrazino-N,N-diphenylquinazoline-4-amine

Hydrazine hydrate (0.090 g, 1.8 mmol) was added to a solution of 2-chloro-N,N-diphenylquinazoline-4-amine (0.3 g, 0.90 mmol) in EtOH (10 mL) at room temperature, and the mixture was stirred at 50 °C for 16 hours. The reaction mixture was evaporated under reduced pressure to give the desired product. LCMS: 328.23 (M+H).

(Step 3) Synthesis of N,N-diphenyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine

A mixture of 2-hydrazino-N,N-diphenylquinazoline-4-amine (0.3 g, 0.91 mmol) and triethyl orthoformate (0.407 g, 2.75 mmol) was stirred at 80 °C for 3 hours. The reaction mixture was evaporated under reduced pressure. The residue was purified by preparative HPLC to provide the desired product: ^¹H -NMR (DMSO- _d₆ ) δ 9.72 (s, 1H), 8.37 (dd, J = 8.3, 1.1 Hz, 1H), 7.87 (ddd, J = 8.5, 7.3, 1.3 Hz, 1H), 7.59 (dd, J = 8.5, 1.3 Hz, 1H), 7.48–7.29 (m, 5H), 7.29–7.10 (m, 6H); LCMS (m/z) 338.3 [M+H]+.

Example 44. N-Methyl-N-(thiophen-3-yl)-[1,2,4]triazolo[4,3-a]quinazolin-5-amine

(Step 1) Synthesis of 2-chloro-N-methyl-N-(thiophen-3-yl)quinazoline-4-amine

60% sodium hydride (0.018 g, 0.45 mmol) was added to a stirred solution of N-methylthiophene-3-amine (0.051 g, 0.45 mmol) in DMF (3 mL) at 0 °C, and the mixture was stirred at room temperature for 1 hour. Then, 2,4-dichloroquinazoline (0.09 g, 0.45 mmol) was added at 0 °C, and the mixture was stirred at room temperature for 12 hours. The reaction progress was monitored by TLC. After the reaction was complete, the reaction mixture was diluted with ice water and extracted twice with ethyl acetate. The combined organic layers were washed continuously with water and brine, dried over _{Na₂SO₄ ,} filtered, and evaporated under reduced pressure. The residue was purified by silica gel column chromatography and eluted with 4% methanol/dichloromethane to give the desired product: LCMS (m/z) 276.07 [M+H] ^⁺ .

(Step 2) Synthesis of N-methyl-N-(thiophen-3-yl)-[1,2,4]triazolo[4,3-a]quinazolin-5-amine

Formyl hydrazide (0.013 g, 0.22 mmol) was added to a stirred solution of 2-chloro-N-methyl-N-(thiophen-3-yl)quinazolin-4-amine (0.030 g, 0.11 mmol) in toluene (3 mL) at room temperature, and the mixture was heated to 120 °C for 72 hours. The reaction progress was monitored by TLC. After the reaction was complete, the reaction mixture was evaporated under reduced pressure. The residue was purified by preparative HPLC to provide the desired product: ^¹H -NMR ( _CDCl₃ ) δ 8.93 (s, ¹H), 7.80 (dd, J = 8.4, 1.2 Hz, ¹H), 7.68 (ddd, J = 8.5, 7.3, 1.3 Hz, ¹H), 7.47–7.34 (m, 2H), 7.20 (ddd, J = 8.5, 7.3, 1.2 Hz, 1H), 7.04–6.95 (m, ¹H), 6.85 (dd, J = 3.2, 1.5 Hz, 1H), 3.64 (s, 3H). LCMS (m/z) 282.1 [M+H]+.

Example 45. 8-(furan-2-yl)-N-methyl-N-phenyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine

A mixture of 8-bromo-N-methyl- _N -phenyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine (Example 28) (30 mg, 0.085 mmol), _K₃PO₄ (17.98 mg, 0.085 mmol), Pd(OAc) _₂ (3.80 mg, 0.017 mmol), tricyclohexylphosphine (4.75 mg, 0.017 mmol), and furan-2-ylboronic acid (23.69 mg, 0.212 mmol) in dioxane/water (0.42 mL) was treated at 100 °C for 3 hours. The reaction mixture was then concentrated under vacuum. The residue was purified by column chromatography (Si-column, _CHCl3 :MeOH = 10:0-9:1) to provide the desired product: ^¹H -NMR (methanol- _d4 ) δ 9.32 (s, 1H), 8.06 (s, 1H), 7.97 (s, 1H), 7.49 (s, 1H), 7.30 (t, J = 7.7 Hz, 2H), 7.19 (t, J = 7.5 Hz, 1H), 7.13 (t, J = 7.5 Hz, 3H), 6.94 (d, J = 8.8 Hz, 1H), 6.81 (s, 1H), 3.49 (s, 3H); LCMS (m/z) 342.0.

Example 46. N-Methyl-N-phenyl-8-(1H-pyrazol-4-yl)-[1,2,4]triazolo[4,3-a]quinazolin-5- amine

A mixture of 8-bromo-N-methyl-N-phenyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine (Example 28) (20 mg, 0.056 mmol), _{K₃PO₄ (} 30.0 mg, 0.141 mmol), Pd(OAc) _₂ (2.54 mg, 0.011 mmol), tricyclohexylphosphine (3.17 mg, 0.011 mmol), and (1H-pyrazol-4-yl)boronic acid (15.79 mg, 0.141 mmol) in dioxane/water (0.28 mL) was treated in a microwave reactor at 100 °C for 3 hours. The reaction mixture was purified by column chromatography (Si-column, _CHCl3 :MeOH = 10:0–9:1) to provide the desired product: ^¹H -NMR (methanol- _d4 ) δ 9.50 (s, 1H), 8.37 (s, 1H), 8.18 (s, 2H), 7.48–7.25 (m, 7H), 7.20 (d, J = 8.8 Hz, 1H), 3.64 (s, 3H); LCMS (m/z) 342.2 [M+H]+.

Example 47. N-Methyl-N-phenyl-8-(thiophen-2-yl)-[1,2,4]triazolo[4,3-a]quinazolin-5-amine

A mixture of 8-bromo-N-methyl- _N -phenyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine (Example 28) (20 mg, 0.056 mmol), _K₃PO₄ (23.97 mg, 0.113 mmol), Pd(OAc) _₂ (2.54 mg, 0.011 mmol), tricyclohexylphosphine (3.17 mg, 0.011 mmol), and thiophene-2-ylboronic acid (18.06 mg, 0.141 mmol) in dioxane/water (0.28 mL) was heated at 120 °C for 2 hours. The reaction mixture was then concentrated under vacuum. The residue was purified by column chromatography (Si-column, _CHCl3 :MeOH = 10:0-9:1) to provide the desired product: ^¹H -NMR ( _CDCl3 ) δ 9.00 (s, 1H), 7.92 (d, J = 1.7 Hz, 1H), 7.46 (dd, J = 3.7, 1.1 Hz, 1H), 7.43–7.33 (m, 3H), 7.31–7.27 (m, 1H), 7.24 (s, 1H), 7.21–7.14 (m, 2H), 7.11 (dd, J = 5.1, 3.7 Hz, 1H), 3.65 (s, 3H); LCMS (m/z) 358.2 [M+H]+.

Example 48. 4-([1,2,4]triazolo[4,3-a]quinazolin-5-yl(methyl)amino)phenol

BBr 3 (0.147 mL, 0.147 mmol) was added to a solution of N-(4-methoxyphenyl)-N-methyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine (Example 5) (15 mg, 0.049 mmol) in _1,2 -dichloroethane (1 mL) at room temperature. The mixture was stirred at 50 °C for 1.5 hours. The reaction mixture was concentrated under vacuum, and the residue was purified by preparative LCMS to provide the desired product: ^¹H -NMR (DMSO- _d₆ ) δ 9.64 (s, ¹H), 9.56 (s, ¹H), 8.29–8.21 (m, ¹H), 7.75 (ddd, J = 8.4, 7.1, 1.5 Hz, ¹H), 7.28 (dd, J = 8.4, 1.4 Hz, ¹H), 7.22 (ddd, J = 8.4, 7.1, 1.2 Hz, ¹H), 7.16–7.02 (m, 2H), 6.84–6.71 (m, 2H), 3.46 (s, 3H); LCMS (m/z) 292.2 [M+H]+.

Example 49. 2-([1,2,4]triazolo[4,3-a]quinazolin-5-yl(methyl)amino)phenol

(Step 1) Synthesis of 2-chloro-N-(2-methoxyphenyl)-N-methylquinazoline-4-amine

2-Methoxy-N-methylaniline (68.9 mg, 0.502 mmol) and sodium hydroxide (20.1 mg, 0.502 mmol) were added to a suspension of 2,4-dichloroquinazoline (100 mg, 0.502 mmol) in DMF (2.5 mL), and the mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted with AcOEt, washed continuously with water and brine, and dried over _Na₂SO₄ . The organic layer was concentrated under vacuum to give the desired product, which was used in the next step without further purification. _LCMS : 300.18 (M+H).

(Step 2) Synthesis of N-(2-methoxyphenyl)-N-methyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine

A mixture of 2-chloro-N-(2-methoxyphenyl)-N-methylquinazoline-4-amine (59 mg, crude) and formylhydrazine (23.64 mg, 0.394 mmol) in toluene (1 mL) was refluxed and stirred for 3 days. The reaction mixture was dissolved in MeOH/AcOEt and concentrated under vacuum. The residue was dissolved in MeOH and evaporated, and the residue was purified by preparative HPLC to give the desired product. LCMS: 306.13 (M+H).

(Step 3) Synthesis of 2-([1,2,4]triazolo[4,3-a]quinazolin-5-yl(methyl)amino)phenol

BBr ₃ (0.147 mL, 0.147 mmol) was added to a solution of N-(2-methoxyphenyl)-N-methyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine (15 mg, 0.049 mmol) in 1,2-dichloroethane (1 mL) at room temperature. The mixture was stirred at 50 °C for 1.5 hours. The reaction mixture was concentrated under vacuum, and the residue was purified by preparative LCMS to provide the desired product: ^¹H -NMR (DMSO- _d₆ ) δ 9.91 (s, ¹H), 9.55 (s, ¹H), 8.26 (dd, J = 8.5, 1.1 Hz, ¹H), 7.75 (ddd, J = 8.4, 7.2, 1.4 Hz, ¹H), 7.30 (dd, J = 8.4, 1.3 Hz, ¹H), 7.23–7.11 (m, ³H), 6.96 (dd, J = 8.1, 1.4 Hz, ¹H), 6.82 (td, J = 7.6, 1.4 Hz, ¹H), 3.41 (s, ³H); LCMS (m/z) 292.2 [M+H]+.

Example 50. 3-([1,2,4]triazolo[4,3-a]quinazolin-5-yl(methyl)amino)phenol

BBr 3 (0.098 mL, 0.098 mmol) was added to a solution of N-(3-methoxyphenyl)-N-methyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine (Example 9) (10 mg, 0.033 mmol) in _1,2 -dichloroethane (1 mL) at room temperature. The mixture was stirred at 50 °C for 1.5 hours. The reaction mixture was concentrated under vacuum, and the residue was purified by preparative LCMS to provide the desired product: ^¹H -NMR (methanol- _d⁴ ) δ 9.42 (s, ¹H), 8.16 (dd, J = 8.3, 1.0 Hz, ¹H), 7.75 (ddd, J = 8.5, 7.3, 1.3 Hz, ¹H), 7.46 (dd, J = 8.4, 1.2 Hz, ¹H), 7.27–7.18 (m, 2H), 6.79–6.72 (m, 3H), 6.67 (t, J = 2.2 Hz, 1H), 3.63 (s, 3H); LCMS (m/z) 292.2 [M+H]⁺.

Example 51. N-Butyl-N-phenyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine

LDA (0.24 mL, 0.49 mmol, 2.0 M in THF) was added to a solution of N-butylaniline (0.036 g, 0.24 mmol) in 10 mL of THF at 0 °C, and the mixture was stirred at room temperature for 1 hour. Then, 5-chloro-[1,2,4]triazolo[4,3-a]quinazoline (0.05 g, 0.24 mmol) was added at 0 °C, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was dried over _Na₂SO₄ , _filtered , and evaporated under reduced pressure. The residue was purified by preparative HPLC to provide the desired product: ^¹H -NMR (500MHz, DMSO- _d₆ ) δ 9.61 (s, ¹H), 8.27 (dd, J = 8.3, 1.1Hz, ¹H), 7.75 (ddd, J = 8.4, 6.9, 1.6Hz, ¹H), 7.45–7.34 (m, 2H), 7.30–7.14 (m, 5H), 4.11–4.03 (m, 2H), 1.70 (ddt, J = 9.4, 7.5, 3.6Hz, 2H), 1.38 (h, J = 7.4Hz, 2H), 0.90 (t, J = 7.4Hz, 3H); LCMS (m/z) 318.2 [M+H]+.

Example 52. N-(2-methoxyethyl)-N-phenyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine

(Step 1) Synthesis of N-(2-methoxyethyl)aniline

Potassium carbonate (1.48 g, 10.74 mmol) and 1-bromo-2-methoxyethane (1.18 g, 8.59 mmol) were added to a solution of aniline (1.0 g, 10.74 mmol) in N-methyl- ₂ -pyrrolidone (10 mL) at room temperature, and the mixture was stirred at 80 °C for 5 hours. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was dried over _Na₂SO₄ , filtered, and evaporated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with 20% ethyl acetate/petroleum ether, to give the desired product. LCMS: 152.13 (M+H).

(Step 2) Synthesis of N-(2-methoxyethyl)-N-phenyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine

LDA (0.1 mL, 0.20 mmol, 2.0 M in THF) was added to a solution of N-(2-methoxyethyl)aniline (0.014 g, 0.098 mmol) in THF (1 mL) at room temperature, and the mixture was stirred at room temperature for 10 min. Subsequently, 5-chloro-[1,2,4]triazolo[4,3-a]quinazoline (0.02 g, 0.098 mmol) was added at room temperature, and the mixture was stirred at room temperature for 2 h. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was dried over _Na₂SO₄ , filtered _, and evaporated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with 5% methanol/dichloromethane, to provide the desired product: ^¹H -NMR (500MHz, DMSO- _d₆ ) δ 9.62 (s, 1H), 8.28 (dt, J = 8.3, 0.9Hz, 1H), 7.76 (ddd, J = 8.4, 5.5, 3.0Hz, 1H), 7.42–7.34 (m, 2H), 7.34–7.15 (m, 5H), 4.24 (t, J = 5.9Hz, 2H), 3.69 (t, J = 5.9Hz, 2H), 3.26 (s, 3H); LCMS (m/z) 320.1 [M+H]+.

Example 53. N-(cyclohexylmethyl)-N-phenyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine

(Step 1) Synthesis of N-(cyclohexylmethyl)aniline

Acetic acid (5 mL, 85.9 mmol) was added to a mixture of aniline (2.0 g, 21.47 mmol) and cyclohexaneformaldehyde (2.59 mL, 21.47 mmol) in acetonitrile (20 mL) at 0 °C, and the mixture was stirred at room temperature for 1 hour. Then, sodium triacetoxyborohydride (13.66 g, 64.42 mmol) was added at 0 °C, and the mixture was stirred at room temperature for 3 hours. The reaction mixture was diluted with ice water and extracted with ethyl acetate. The organic layer was washed with brine, dried over _Na₂SO₄ , filtered, and evaporated under reduced pressure. The residue was purified by silica gel chromatography, eluting with 2% ethyl acetate/petroleum ether, to give the desired product. _LCMS : 190.12 (M+H).

(Step 2) Synthesis of 2-chloro-N-(cyclohexylmethyl)-N-phenylquinazoline-4-amine

Sodium hydroxide (0.211 g, 5.28 mmol) was added to a mixture of 2,4-dichloroquinazoline (0.525 g, 2.64 mmol) and N-(cyclohexylmethyl)aniline (0.501 g, 2.64 mmol) in 5 mL of DMF at 0 °C, and the mixture was stirred at room temperature for 72 hours. The reaction mixture was diluted with ice water and extracted with ethyl acetate. The organic layer was washed with brine, dried over _Na₂SO₄ , filtered, and evaporated under reduced pressure. The residue was purified by silica gel chromatography, eluting with 5% ethyl acetate/petroleum ether, to give the desired product. _LCMS : 352.32 (M+H).

(Step 3) Synthesis of N-(cyclohexylmethyl)-2-hydrazino-N-phenylquinazoline-4-amine

Hydrazine hydrate (0.068 g, 1.36 mmol) was added to a stirred solution of 2-chloro-N-(cyclohexylmethyl)-N-phenylquinazoline-4-amine (0.24 g, 0.68 mmol) in EtOH (5 mL) at room temperature, and the mixture was stirred at 50 °C for 16 h. The reaction mixture was evaporated under reduced pressure to give the desired product. LCMS: 348.22 (M+H).

(Step 4) Synthesis of N-(cyclohexylmethyl)-N-phenyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine

A mixture of N-(cyclohexylmethyl)-2-hydrazino-N-phenylquinazoline-4-amine (0.215 g, 0.62 mmol) and triethyl orthoformate (2 mL) was stirred at 100 °C for 16 hours. The reaction mixture was evaporated under reduced pressure, and the residue was purified by preparative HPLC to provide the desired product: ^¹H -NMR (DMSO- _d₆ ) δ 9.62 (s, ¹H), 8.28 (dd, J = 8.4, 1.2 Hz, ¹H), 7.76 (ddd, J = 8.5, 7.2, 1.4 Hz, ¹H), 7.39–7.16 (m, 7H), 3.94 (d, J = 7.2 Hz, 2H), 1.91 (d, J = 12.0 Hz, 1H), 1.80 (d, J = 8.5 Hz, 2H), 1.70–1.57 (m, 3H), 1.13 (q, J = 10.8 Hz, 5H); LCMS (m/z) 358.3 [M+H]+.

Example 54. N-neopentyl-N-phenyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine

(Step 1) Synthesis of N-neopentylaniline

Neopentaldehyde (0.508 g, 5.91 mmol) and acetic acid (1.288 g, 21.48 mmol) were added to a solution of aniline (0.5 g, 5.37 mmol) in acetonitrile (10 mL) at 0 °C, and the mixture was stirred at room temperature for 2 h. Subsequently, sodium triacetoxyborohydride (2.27 g, 10.74 mmol) was added at 0 °C, and the mixture was stirred at room temperature for 2 h. The reaction mixture was diluted with ice water and extracted with ethyl acetate. The organic layer was washed with brine, dried over _Na₂SO₄ , filtered, and evaporated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with 5% ethyl acetate/petroleum ether, to give the desired product. _LCMS : 164.09 (M+H).

(Step 2) Synthesis of N-neopentyl-N-phenyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine

LDA (0.09 mL, 0.18 mmol, 2.0 M in THF) was added to a solution of N-neopentylaniline (0.024 g, 0.15 mmol) in 2 mL of THF at 0 °C, and the mixture was stirred at room temperature for 1 hour. Subsequently, 5-chloro-[1,2,4]triazolo[4,3-a]quinazoline (0.025 g, 0.12 mmol) was added at 0 °C, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was quenched with ice water and extracted twice with ethyl acetate. The combined organic layers were washed continuously with water and brine, dried over _Na₂SO₄ , filtered _, and evaporated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with 4% methanol/dichloromethane to provide the desired product: ^¹H -NMR (DMSO- _d₆ ) δ 9.70 (s, 1H), 8.33 (dd, J = 8.3, 1.1 Hz, 1H), 7.81 (ddd, J = 8.4, 7.2, 1.4 Hz, 1H), 7.51 (dd, J = 8.4, 1.3 Hz, 1H), 7.35–7.24 (m, 3H), 7.19–7.07 (m, 3H), 4.09 (s, 2H), 0.98 (s, 9H); LCMS (m/z) 332.2 [M+H]+.

Example 55. N-(but-2-yn-1-yl)-N-phenyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine

(Step 1) Synthesis of N-(but-2-yn-1-yl)aniline

Potassium carbonate (0.445 g, 3.22 mmol) was added to a solution of aniline (0.3 g, 3.22 mmol) in acetonitrile (10 mL) at room temperature, and the mixture was stirred at room temperature for 10 min. Then, 1-bromobut-2-yne (0.385 g, 2.90 mmol) was added at room temperature, and the mixture was stirred at room temperature for 16 h. The reaction mixture was diluted with cold water and extracted with ethyl acetate. The combined organic layers were washed continuously with water and brine, dried over _Na₂SO₄ , filtered, and evaporated under reduced pressure. The residue was purified by silica gel chromatography, eluting with 30% ethyl acetate/petroleum ether to give the desired product. _LCMS (m/z) 146.09 [M+H] ^⁺ .

(Step 2) Synthesis of N-(but-2-yn-1-yl)-2-chloro-N-phenylquinazoline-4-amine

60% sodium hydride (0.036 g, 0.90 mmol) was added to a solution of N-(but-2-yn-1-yl)aniline (0.131 g, 0.9 mmol) in DMF (5 mL) at 0 °C, and the mixture was stirred at room temperature for 1 hour. Then, 2,4-dichloroquinazoline (0.180 g, 0.90 mmol) was added at room temperature, and the mixture was stirred at 80 °C for 16 hours. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed continuously with water and brine, dried over _Na₂SO₄ , filtered, and evaporated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with 25% ethyl acetate _/ petroleum ether, to give the desired product. LCMS (m/z) 308.23 [M+H] ^⁺ .

(Step 3) Synthesis of N-(but-2-yn-1-yl)-N-phenyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine

At room temperature, formyl hydrazine (0.027 g, 0.46 mmol) was added to a stirred solution of N-(but-2-yn-1-yl)-2-chloro-N-phenylquinazoline-4-amine (0.07 g, 0.23 mmol) in toluene (4 mL), and the mixture was stirred under reflux for 16 hours. The reaction mixture was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography, followed by preparative HPLC purification to provide the desired product: ^¹H -NMR (500MHz, DMSO- _d⁶ ) δ 9.64 (s, ¹H), 8.29 (dd, J = 8.2, 1.1Hz, ¹H), 7.78 (ddd, J = 8.5, 6.9, 1.7Hz, ¹H), 7.44–7.36 (m, 2H), 7.33–7.17 (m, 5H), 4.80 (q, J = 2.3Hz, 2H), 1.71 (t, J = 2.3Hz, 3H). LCMS (m/z) 314.1 [M+H]⁺.

Example 56. N-(but-3-yn-1-yl)-N-phenyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine

(Step 1) Synthesis of N-(but-3-yn-1-yl)aniline

4-Bromobut-1-yne (0.643 g, 4.84 mmol) and potassium carbonate (0.742 g, 5.38 mmol) were added to a stirred solution of aniline (0.5 g, 5.38 mmol) in acetonitrile (5 mL) at room temperature, and the mixture was stirred at room temperature for 16 hours. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with brine, dried over _Na₂SO₄ , filtered, and evaporated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with 10% ethyl acetate/petroleum ether to give the desired product. _LCMS (m/z) 146.09 [M+H] ^⁺ .

(Step 2) Synthesis of N-(but-3-yn-1-yl)-N-phenyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine

LDA (0.09 mL, 0.18 mmol, 2.0 M in THF) was added to a solution of N-(but-3-yn-1-yl)aniline (0.021 g, 0.15 mmol) in 2 mL of THF at 0 °C, and the mixture was stirred at room temperature for 1 hour. Then, 5-chloro-[1,2,4]triazolo[4,3-a]quinazoline (0.025 g, 0.12 mmol) was added at 0 °C, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was quenched with ice water and extracted twice with ethyl acetate. The combined organic layers were washed continuously with water and brine, dried over _Na₂SO₄ , filtered _, and evaporated under reduced pressure. The residue was purified by preparative HPLC to provide the desired product: ^¹H -NMR (DMSO- _d₆ ) δ 9.63 (s, ¹H), 8.29 (d, J = 8.3 Hz, ¹H), 7.77 (ddd, J = 8.5, 6.3, 2.3 Hz, ¹H), 7.44–7.15 (m, 7H), 4.20 (t, J = 7.3 Hz, 2H), 2.91 (t, J = 2.6 Hz, 1H), 2.66 (td, J = 7.5, 2.7 Hz, 2H); LCMS (m/z) 314.2 [M+H]+.

Example 57. N-Methyl-N-(thiophen-2-yl)-[1,2,4]triazolo[4,3-a]quinazolin-5-amine

(Step 1) Synthesis of 2-chloro-N-methyl-N-(thiophen-2-yl)quinazolin-4-amine

60% sodium hydride (0.056 g, 1.40 mmol) was added to a stirred solution of 2,4-dichloroquinazoline (0.280 g, 1.40 mmol) in DMF (4 mL) at 0 °C, and the mixture was stirred at room temperature for 1 hour. Then, N-methylthiophene-2-amine hydrochloride (0.209 g, 1.40 mmol) was added at 0 °C, and the mixture was stirred at room temperature for 16 hours. The reaction progress was monitored by TLC. After the reaction was complete, the reaction mixture was diluted with ice water and extracted twice with ethyl acetate. The combined organic layers were washed continuously with water and brine, dried over _Na₂SO₄ , filtered, and evaporated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with 15% ethyl acetate/petroleum ether to give the desired product. _LCMS (m/z) 276.04 [M+H] ^⁺ .

(Step 2) Synthesis of N-methyl-N-(thiophen-2-yl)-[1,2,4]triazolo[4,3-a]quinazolin-5-amine

Formyl hydrazine (0.026 g, 0.44 mmol) was added to a stirred solution of 2-chloro-N-methyl-N-(thiophen-2-yl)quinazolin-4-amine (0.06 g, 0.22 mmol) in toluene (4 mL) at room temperature, and the mixture was stirred under reflux for 16 hours. The reaction progress was monitored by TLC. After the reaction was complete, the reaction mixture was diluted with MeOH/THF and evaporated under reduced pressure. The residue was diluted with AcOEt and washed with brine, dried over _Na₂SO₄ , filtered _, and evaporated under reduced pressure. The residue was purified by silica gel column chromatography and eluted with 4% methanol/dichloromethane to provide the desired product: ^¹H -NMR (500MHz, DMSO- _d₆ ) δ 9.65 (s, 1H), 8.32 (dd, J = 8.5, 1.2Hz, 1H), 7.83 (ddd, J = 8.5, 7.3, 1.3Hz, 1H), 7.59 (dd, J = 8.4, 1.3Hz, 1H), 7.44–7.27 (m, 2H), 7.03–6.89 (m, 2H), 3.57 (s, 3H); LCMS (m/z) 282.1 [M+H]+.

Example 58. 2-([1,2,4]triazolo[4,3-a]quinazolin-5-yl(methyl)amino)benzoic acid

2-(methylamino)benzoate (0.518 mL, 3.55 mmol) was added to a solution of 5-chloro-[1,2,4]triazolo[4,3-a]quinazoline (600 mg, 3.22 mmol), BrOP (1376 mg, 3.55 mmol), and DBU (589 mg, 3.87 mmol) in acetonitrile (10.0 mL) at room temperature. The mixture was stirred overnight at 80 °C. The reaction mixture was concentrated under vacuum, and the residue was purified by column chromatography (Si column, _CHCl3 :MeOH = 100:0-95:5) to give the crude product. The crude compound was further purified by preparative LCMS to provide the desired product: ^¹H -NMR (DMSO- _d₆ ) δ 11.50 (s, 1H), 9.62 (s, 1H), 8.88 (d, J = 8.3 Hz, 1H), 8.40 (d, J = 8.2 Hz, 1H), 8.35 (d, J = 8.2 Hz, 1H), 8.08 (dd, J = 8.0, 1.6 Hz, 1H), 8.04 (t, J = 7.9 Hz, 1H), 7.81 (q, J = 8.3, 7.9 Hz, 2H), 7.30 (t, J = 7.5 Hz, 1H), 3.90 (s, 3H); LCMS (m/z) 320.2 [M+H]+.

Example 59. N-Methyl-8-nitro-N-phenyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine

(Step 1) Synthesis of 7-nitroquinazolin-2,4(1H,3H)-dione

A mixture of 2-amino-4-nitrobenzoic acid (3.34 g, 18.3 mmol) and urea (3.30 g, 55 mmol) in NMP (10 mL) was stirred at 160 °C for 5.5 h. The reaction mixture was cooled to room temperature and diluted with water. The resulting precipitate was collected and washed with water and EtOH to give the desired product. LCMS (m/z) 206.01 [MH] ⁺ .

(Step 2) Synthesis of 2,4-dichloro-7-nitroquinazolino

A mixture of 7-nitroquinazolin-2,4(1H,3H)-dione (500 mg, 2.414 mmol) and phosphorus trichloride (10 mL, 2.414 mmol) was stirred at 100 °C for 6 hours. The reaction was monitored by LCMS (quenched by MeOH). The reaction mixture was cooled to room temperature and slowly poured onto ice. The resulting solid was collected and dried. The obtained solid was used in the next step without further purification.

(Step 3) Synthesis of 2-chloro-N-methyl-7-nitro-N-phenylquinazoline-4-amine

N-methylaniline (0.659 g, 6.15 mmol) and sodium hydride (0.148 g, 6.15 mmol) were added to a solution of 2,4-dichloro- ₇ -nitroquinazoline (1.5 g, 6.15 mmol) in DMF (30.7 mL), and the mixture was stirred at room temperature for 1 hour. The mixture was diluted with AcOEt, washed continuously with water and brine, and dried over _Na₂SO₄ . The organic layer was concentrated under vacuum. The resulting residue was used in the next step without further purification. LCMS (m/z) 315.03 [M+H] ^⁺ .

(Step 4) Synthesis of 2-hydrazino-N-methyl-7-nitro-N-phenylquinazoline-4-amine

The resulting 2-chloro-N-methyl-7-nitro-N-phenylquinazoline-4-amine (1.2 g, 3.81 mmol) and hydrazine hydrate (0.191 g, 3.81 mmol) in ethanol (19.06 mL) were stirred at room temperature for 1 hour. The mixture was diluted with AcOEt, washed continuously with water and brine, and dried over _Na₂SO₄ . The organic layer was concentrated under vacuum. The resulting residue was used in the next step without further purification. _LCMS (m/z) 311.08 [M+H] ^⁺ .

(Step 5) Synthesis of N-methyl-8-nitro-N-phenyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine

A mixture of 2-hydrazino-N-methyl-7-nitro-N-phenylquinazoline-4-amine (800 mg, 2.58 mmol) and triethoxymethane (10 mL, 2.58 mmol) was stirred overnight at 100 °C. The reaction mixture was then concentrated under vacuum. The residue was purified by column chromatography (Si-column, _CHCl3 :MeOH = 10:0-9:1) to provide the desired product: ^¹H -NMR (DMSO- _d6 ) δ 9.89 (s, 1H), 9.22 (d, J = 2.3 Hz, 1H), 7.99 (dd, J = 9.1, 2.3 Hz, 1H), 7.46 (d, J = 9.1 Hz, 1H), 7.43–7.38 (m, 2H), 7.37–7.32 (m, 2H), 7.32–7.25 (m, 1H), 3.56 (s, 3H); LCMS (m/z) 321.2.

Example 60. N-(2,6-difluorophenyl)-N-methyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine

2,6-Difluoro-N-methylaniline hydrochloride (48.2 mg, 0.269 mmol) was added to a solution of 5-chloro-[1,2,4]triazolo[4,3-a]quinazoline (50 mg, 0.269 mmol), BrOP (115 mg, 0.295 mmol), and DBU (82 mg, 0.537 mmol) in acetonitrile (2 mL). The mixture was stirred at 80 °C for 2 hours. The reaction mixture was subjected to solid-phase extraction using a Bond Elut SCX box (Agilent) (washing with MeOH followed by elution with _NH₃ in MeOH), and the collected fraction was concentrated under vacuum. The residue was then purified by preparative LCMS to provide the desired product: ^¹H -NMR (DMSO- _d₆ ) δ 9.66 (s, ¹H), 8.36 (dt, J = 8.4, 0.8 Hz, ¹H), 7.87 (ddd, J = 8.4, 7.0, 1.6 Hz, ¹H), 7.49 (tt, J = 8.0, 6.4 Hz, ¹H), 7.38–7.24 (m, 4H), 3.49 (s, 3H); LCMS (m/z) 312.1 [M+H]+.

Example 61. 5-(2,3,4,5-tetrahydrobenzo[b]azapyro-1-yl)-[1,2,4]triazolo[4,3-a]quinazole phyto

(Step 1) Synthesis of 1-(2-chloroquinazoline-4-yl)-2,3,4,5-tetrahydro-1H-benzo[b]azapyrrolidone

Sodium hydroxide (0.060 g, 1.5 mmol) was added to a stirred mixture of 2,4-dichloroquinazoline (0.15 g, 0.75 mmol) and 2,3,4,5-tetrahydro-1H-benzo[b]azapyrrolidone (0.11 g, 0.75 mmol) in DMF (10 mL) at room temperature, and the mixture was then stirred at the same temperature for 16 hours. The reaction mixture was diluted with ice water and extracted with ethyl acetate. The organic layer was washed with brine, dried over _Na₂SO₄ , filtered, and evaporated under reduced pressure to give the desired product. _LCMS : 310.13 (M+H).

(Step 2) Synthesis of 1-(2-hydrazinoquinazolin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[b]azapyrrolidone

Hydrazine hydrate (0.032 g, 0.65 mmol) was added to a stirred solution of 1-(2-chloroquinazoline-4-yl)-2,3,4,5-tetrahydro-1H-benzo[b]azapyrrolidone (crude, 0.1 g, 0.32 mmol) in EtOH (10 mL), and the mixture was stirred at 70 °C for 16 h. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed continuously with water and brine, dried over _Na₂SO₄ , filtered, and evaporated under reduced pressure to give the desired product. _LCMS : 306.21 (M+H).

(Step 3) 5-(2,3,4,5-tetrahydrobenzo[b]azaphen-1-yl)-[1,2,4]triazolo[4,3-a]quinazolin Synthesis

A mixture of 1-(2-hydrazinoquinazolin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[b]azapyrrolidone (0.1 g, 0.33 mmol) and triethyl orthoformate (0.145 g, 0.99 mmol) was stirred at 80 °C for 16 hours. The reaction mixture was evaporated under reduced pressure, and the residue was purified by preparative HPLC to provide the desired product: ^¹H -NMR (DMSO- _d₆ ) δ 9.57 (s, ¹H), 8.26 (dd, J = 8.4, 1.1 Hz, ¹H), 7.74 (ddd, J = 8.4, 7.2, 1.3 Hz, ¹H), 7.46 (dd, J = 7.5, 1.5 Hz, ¹H), 7.29–7.03 (m, 3H), 6.89 (ddd, J = 29.0, 8.1, 1.3 Hz, 2H), 4.44–3.57 (m, 2H), 3.01 (t, J = 5.8 Hz, 2H), 1.91–1.59 (m, 4H); LCMS (m/z) 316.2 [M+H]+.

Example 62. 7-Bromo-N-methyl-N-phenyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine

(Step 1) Synthesis of 6-bromo-2-chloro-N-methyl-N-phenylquinazoline-4-amine

6-Bromo-2,4-dichloroquinazoline (100 mg, 0.360 mmol) was added to a solution of N-methylaniline (38.6 mg, 0.360 mmol) and NaH (14.39 mg, _0.360 mmol) in DMF (1.8 mL) at room temperature. The mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with AcOEt, washed continuously with water and brine, and dried over _Na₂SO₄ . The organic layer was concentrated under vacuum. The resulting residue was used in the next step without further purification. LCMS (m/z) 348.27 [M+H] ^⁺ .

(Step 2) Synthesis of 6-bromo-2-hydrazino-N-methyl-N-phenylquinazoline-4-amine

The resulting 6-bromo-2-chloro-N-methyl-N-phenylquinazoline-4-amine (134 mg, 0.384 mmol) and hydrazine hydrate (38.5 mg, 0.769 mmol) in EtOH ( _{3 mL) were stirred at 50 °C for 2 hours. The reaction mixture was cooled to room temperature and then diluted with EtOAc. The solution was washed continuously with water and brine, dried over Na₂SO₄ ,} and concentrated under vacuum. The resulting crude product was used in the next step without purification. LCMS (m/z) 346.10 [M+H] ^⁺ .

(Step 3) Synthesis of 7-bromo-N-methyl-N-phenyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine

The obtained 6-bromo-2-hydrazino-N-methyl-N-phenylquinazoline-4-amine (136 mg, 0.158 mmol) and triethoxymethane (3 mL) were stirred overnight at 100 °C. The reaction mixture was concentrated under vacuum. The residue was purified by column chromatography (Si column, _CHCl3 :MeOH = 100:0–95:5) to provide the desired product: ^¹H -NMR (methanol- _d4 ) δ 9.42 (s, 1H), 8.11 (d, J = 8.8 Hz, 1H), 7.88 (dd, J = 8.8, 2.1 Hz, 1H), 7.53–7.28 (m, 6H), 4.99–4.77 (m, 3H); LCMS (m/z) 354.1 [M+H]+.

Example 63. N-Methyl-N-phenyl-8-(pyridin-3-yl)-[1,2,4]triazolo[4,3-a]quinazolin-5-amine

A mixture of 8-bromo-N-methyl- _N -phenyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine (Example 28) (20 mg, 0.056 mmol), _K₃PO₄ (23.97 mg, 0.113 mmol), Pd(OAc) _₂ (2.54 mg, 0.011 mmol), tricyclohexylphosphine (3.17 mg, 0.011 mmol), and pyridine-3-ylboronic acid (17.35 mg, 0.141 mmol) in dioxane/water (0.28 mL) was heated at 120 °C for 2 hours. The reaction mixture was then concentrated under vacuum. The residue was purified by column chromatography (Si-column, _CHCl3 :MeOH = 10:0-9:1) to provide the desired product: ^¹H -NMR (methanol- _d4 ) δ 9.54 (d, J = 3.5 Hz, 1H), 8.90 (d, J = 2.4 Hz, 1H), 8.61–8.54 (m, 1H), 8.47–8.40 (m, 1H), 8.23–8.14 (m, 1H), 7.58–7.37 (m, 4H), 7.36–7.21 (m, 4H), 3.64 (d, J = 3.3 Hz, 3H); LCMS (m/z) 353.2 [M+H]+.

Example 64. 8-Iodo-N-methyl-N-phenyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine

(Step 1) Synthesis of 8-(hydroxyamino)-N-methyl-N-phenyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine become

A mixture of N-methyl-8-nitro-N-phenyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine (Example 59) (30 mg, 0.094 mmol) and Pd/C (30 mg, 0.282 mmol) in EtOH (3 mL) was stirred at room temperature under a H2 atmosphere for 3 hours. The reaction mixture was filtered through a diatomaceous earth bed and concentrated under vacuum to obtain the desired product.

(Step 2) Synthesis of 8-iodo-N-methyl-N-phenyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine

At room temperature, tert-butyl nitrite (0.041 ml, 0.343 mmol) was added to a solution of 8-(hydroxyamino)-N-methyl-N-phenyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine (25 mg, 0.082 mmol) and diiodomethane (0.033 ml, 0.408 mmol) in THF (1 ml). The mixture was stirred at 60 °C for 2 hours. The reaction mixture was concentrated under vacuum, and the residue was purified by column chromatography (Si column, _CHCl3 :MeOH = 100:0-95:5) to give the crude product. The crude compound was further purified by preparative LCMS to provide the desired product: ^¹H -NMR (methanol- _d⁴ ) δ 9.43 (s, ¹H), 8.64 (d, J = 1.6 Hz, ¹H), 7.49 (dd, J = 8.8, 1.6 Hz, ¹H), 7.46–7.38 (m, 2H), 7.36–7.30 (m, 1H), 7.30–7.23 (m, 2H), 6.97 (d, J = 8.8 Hz, 1H), 3.63 (s, 3H); LCMS (m/z) 401.7 [M+H]+.

Example 65. N-(4-bromophenyl)-N-methyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine

NBS (5.82 mg, 0.033 mmol) was added to a solution of N-methyl-N-phenyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine (Example 1) (30 mg, 0.109 mmol) in DMF (0.55 mL), and the mixture was stirred at 0 °C for 30 min. Then, additional NBS (5.82 mg, 0.033 mmol) was added to the mixture, and the mixture was stirred at 0 °C for 1 h. The reaction mixture was subjected to solid-phase extraction using a Bond Elut SCX box (Agilent) (washing with MeOH followed by elution with _NH₃ in MeOH), and the collected fraction was concentrated under vacuum. The residue was purified by preparative LCMS to provide the desired product: ^¹H -NMR (methanol- _d⁴ ) δ 9.45 (s, ¹H), 8.17 (dd, J = 8.4, 1.0 Hz, ¹H), 7.77 (ddd, J = 8.5, 7.2, 1.4 Hz, ¹H), 7.61–7.50 (m, 2H), 7.37 (dd, J = 8.4, 1.2 Hz, 1H), 7.31–7.16 (m, 3H), 3.63 (s, 3H); LCMS (m/z) 354.3.

Example 66. N-5-methyl-N5-phenyl-[1,2,4]triazolo[4,3-a]quinazolin-5,8-diamine

A mixture of N-methyl-8-nitro-N-phenyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine (Example 59) (429 mg, 1.339 mmol) and Pd/C (20 mg) in ethanol (6.7 mL) was stirred overnight at 60 °C under a H2 atmosphere. Pd/C was removed by filtration, and the filtrate was purified by column chromatography (Si-column, _CHCl3 :MeOH = 10:0-9:1) to provide the desired product: ^¹H -NMR (DMSO- _d6 ) δ 9.28 (s, 1H), 7.41–7.31 (m, 2H), 7.24–7.15 (m, 3H), 7.02 (d, J = 2.2 Hz, 1H), 6.92 (d, J = 9.1 Hz, 1H), 6.41 (s, 2H), 6.35 (dd, J = 9.1, 2.2 Hz, 1H), 3.47 (s, 3H); LCMS (m/z) 291.2 [M+H]+.

Example 67. N,6-Dimethyl-N-phenyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine

(Step 1) Synthesis of 5-methylquinazoline-2,4(1H,3H)-dione

Acetic acid (1 mL) was added to a suspension of 2-amino-6-methylbenzoic acid (1.5 g, 9.92 mmol) in water (10 mL), and the suspension was heated to 35 °C. A freshly prepared potassium cyanate solution (2.012 g, 24.81 mmol) in water (2 mL) was added dropwise to the suspension over a 1-hour period. The mixture was stirred at 40 °C for 1 hour. NaOH (20 g) was added in portions to the reaction mixture while maintaining the internal temperature below 50 °C, and the mixture was further stirred for 2 hours. The precipitate was collected by filtration to obtain the desired product. LCMS (m/z) 177.16 [M+H]+.

(Step 2) Synthesis of 2,4-dichloro-5-methylquinazoline

A solution of 5-methylquinazoline-2,4(1H,3H)-dione (300 mg, 1.703 mmol) in N,N-dimethylaniline (0.5 mL, 1.703 mmol) and _POCl3 (3 mL) was stirred at 110 °C for 3 hours. The reaction mixture was cooled to room temperature, diluted with EtOAc, washed continuously with water and _brine , dried over _Na2SO4 , and concentrated under vacuum. The residue was purified by column chromatography (Si column, hexane:AcOEt = 100:0-80:20) to obtain the desired product.

(Step 3) Synthesis of 2-chloro-N,5-dimethyl-N-phenylquinazoline-4-amine

2,4-Dichloro-5-methylquinazoline (105 mg, 0.493 mmol) was added to a mixture of N-methylaniline (58.1 mg, 0.542 mmol) and sodium hydride (21.68 mg, 0.542 mmol) in DMF (5 mL) at room temperature. The mixture was stirred overnight at room temperature. The reaction mixture was diluted with EtOAc, washed continuously with _NH4Cl (aqueous solution) and brine, dried over _Na2SO4 , and concentrated under vacuum. The residue was purified by column chromatography (Si column, hexane:AcOEt = 100:0-90:10) to give the desired product. _LCMS (m/z) 284.8 [M+H]+.

(Step 4) Synthesis of 2-hydrazino-N,5-dimethyl-N-phenylquinazoline-4-amine

A solution of 2-chloro-N,5-dimethyl-N-phenylquinazoline-4-amine (80 mg, 0.282 mmol) in hydrazine hydrate (1 mL) and EtOH (2 mL) was stirred at 50 °C for 1.5 h. The reaction mixture was diluted with EtOAc, washed continuously with water and brine, dried over _Na₂SO₄ , and concentrated under vacuum. The residue was used in the next step without purification. _LCMS (m/z) 280.23 [M+H]⁺.

(Step 5) Synthesis of N,6-dimethyl-N-phenyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine

A solution of crude 2-hydrazino-N,5-dimethyl-N-phenylquinazoline-4-amine in triethoxymethane (1 mL) was stirred at 100 °C for 3 hours. The reaction mixture was concentrated under vacuum, and the residue was purified by column chromatography (Si column, _CHCl3 :MeOH = 100:0-95:5) to provide the crude product. The crude compound was further purified by preparative LCMS to provide the desired product: ^¹H -NMR (methanol- _d⁴ ) δ 9.45 (s, ¹H), 8.04 (ddd, J = 8.2, 1.3, 0.7 Hz, ¹H), 7.70 (t, J = 7.9 Hz, ¹H), 7.25–7.13 (m, 3H), 7.13–7.03 (m, ¹H), 6.97–6.88 (m, 2H), 3.67 (s, 3H), 2.30 (s, 3H); LCMS (m/z) 290.2 [M+H]+.

Example 68. N-(5-(methyl(phenyl)amino)-[1,2,4]triazolo[4,3-a]quinazolin-8-yl)acetamide

A solution of N5-methyl-N5-phenyl-[1,2,4]triazolo[4,3-a]quinazolin-5,8-diamine (Example 66) (50 mg, 0.172 mmol) and acetyl chloride (0.037 mL, 0.517 mmol) in DMA (1 mL) was stirred at 80 °C for 4 hours. The reaction mixture was purified by column chromatography (Si-column, _CHCl3 :MeOH = 10:0-95:5) and further purified by preparative LCMS to provide the desired product: ^¹H NMR (DMSO- _d6 ) δ 10.61 (s, 1H), 9.53 (s, 1H), 8.50 (d, J = 1.9 Hz, 1H), 7.42 (tt, J = 7.6, 2.1 Hz, 2H), 7.36–7.26 (m, 3H), 7.19–7.05 (m, 2H), 3.56 (s, 3H), 2.11 (s, 3H); LCMS (m/z) 333.2 [M+H]+.

Example 69. N5,N8-Dimethyl-N5-phenyl-[1,2,4]triazolo[4,3-a]quinazolin-5,8-diamine

Formaldehyde (0.021 mL, 0.775 mmol) was added to a solution of N5-methyl-N5-phenyl-[1,2,4]triazolo[4,3-a]quinazolin-5,8-diamine (Example 66) (50 mg, 0.172 mmol) and AcOH (0.039 mL, 0.689 mmol) in _CH3CN (2 mL) at room temperature. The mixture was stirred at room temperature for 30 minutes. Then, _NaCNBH4 (64.9 mg, 1.033 mmol) was added to the mixture at room temperature, and the mixture was stirred overnight at 60 °C. The reaction mixture was subjected to solid-phase extraction (washing with MeOH followed by elution with _NH3 in MeOH) using a Bond Elut SCX box (Agilent), and the collected fraction was concentrated under vacuum. The residue was purified by preparative LCMS to provide the desired product: ^¹H -NMR (DMSO- _d₆ ) δ 9.50 (s, 1H), 7.40–7.30 (m, 2H), 7.23–7.14 (m, 3H), 7.03 (d, J = 2.3 Hz, 1H), 6.98 (q, J = 4.8 Hz, 1H), 6.91 (d, J = 9.2 Hz, 1H), 6.38 (dd, J = 9.3, 2.3 Hz, 1H), 3.47 (s, 3H), 2.81 (d, J = 4.9 Hz, 3H); LCMS (m/z) 305.0 [M+H]+.

Example 70. N-Methyl-N-(p-Tolyl)-[1,2,4]triazolo[4,3-a]quinazolin-5-amine

N,4-dimethylaniline (35.8 mg, 0.295 mmol) was added to a solution of 5-chloro-[1,2,4]triazolo[4,3-a]quinazoline (50 mg, 0.269 mmol), BrOP (115 mg, 0.295 mmol), and DBU (49.1 mg, 0.322 mmol) in acetonitrile (1 mL). The mixture was stirred at 50 °C for 2 hours. The reaction mixture was subjected to solid-phase extraction using a Bond Elut SCX box (Agilent) (washing with MeOH followed by elution with _NH₃ in MeOH), and the collected fraction was concentrated under vacuum. The residue was then purified by preparative LCMS to provide the desired product: ^¹H NMR (DMSO- _d₆ ) δ 9.61 (s, ¹H), 8.34–8.24 (m, ¹H), 7.76 (ddd, J = 8.4, 7.1, 1.5 Hz, ¹H), 7.35–7.14 (m, 6H), 3.50 (s, 3H), 2.30 (s, 3H); LCMS (m/z) 290.2 [M+H]+.

Example 71. N-(4-chlorophenyl)-N-methyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine

4-Chloro-N-methylaniline (41.8 mg, 0.295 mmol) was added to a solution of 5-chloro-[1,2,4]triazolo[4,3-a]quinazoline (50 mg, 0.269 mmol), BrOP (115 mg, 0.295 mmol), and DBU (49.1 mg, 0.322 mmol) in acetonitrile (2 mL). The mixture was stirred at 50 °C for 2 hours. The reaction mixture was subjected to solid-phase extraction using a Bond Elut SCX box (Agilent) (washing with MeOH followed by elution with _NH₃ in MeOH), and the collected fraction was concentrated under vacuum. The mixture was then purified by preparative LCMS to provide the desired product: ^¹H NMR (methanol- _d⁴ ) δ 9.44 (s, ¹H), 8.16 (ddd, J = 8.4, 1.2, 0.5 Hz, ¹H), 7.76 (ddd, J = 8.5, 7.2, 1.4 Hz, ¹H), 7.45–7.38 (m, 2H), 7.36 (ddd, J = 8.5, 1.4, 0.5 Hz, 1H), 7.31–7.17 (m, 3H), 3.63 (s, 3H); LCMS (m/z) 310.0 [M+H]⁺.

Example 72. 8-(furan-3-yl)-N-methyl-N-phenyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine

A mixture of 8-bromo-N-methyl- _N -phenyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine (Example 28) (15 mg, 0.042 mmol), _K₃PO₄ (27.0 mg, 0.127 mmol), Pd(OAc) _₂ (1.901 mg, 8.47 μmol), tricyclohexylphosphine (2.375 mg, 8.47 μmol), and 3-furanylboronic acid (13.68 mg, 0.040 mmol) in dioxane/water (0.21 mL) was heated at 120 °C for 2 hours. The reaction mixture was subjected to solid-phase extraction using a Bond Elut SCX box (Agilent) (washed with MeOH, then eluted with _NH₃ in MeOH), and the collected fraction was concentrated under vacuum. The residue was purified by column chromatography (Si-column, _CHCl3 :MeOH = 10:0-9:1) to provide the desired product: ^¹H -NMR ( _CDCl3 ) δ 9.02 (s, 1H), 7.91–7.83 (m, 2H), 7.54 (t, J = 1.7 Hz, 1H), 7.44–7.32 (m, 2H), 7.35–7.14 (m, 5H), 6.79–6.73 (m, 1H), 3.68 (s, 3H); LCMS (m/z) 342.0 [M+H]+.

Example 73. N-Methyl-N-phenyl-8-(thiophen-3-yl)-[1,2,4]triazolo[4,3-a]quinazolin-5-amine

A mixture of 8-bromo-N-methyl- _N -phenyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine (Example 28) (15 mg, 0.042 mmol), _K₃PO₄ (27.0 mg, 0.127 mmol), Pd(OAc) _₂ (1.901 mg, 8.47 μmol), tricyclohexylphosphine (2.375 mg, 8.47 μmol), and thiophene-3-ylboronic acid (13.55 mg, 0.106 mmol) in dioxane/water (0.21 mL) was heated at 120 °C for 2 hours. The reaction mixture was subjected to solid-phase extraction using a Bond Elut SCX box (Agilent) (washed with MeOH, then eluted with _NH₃ in MeOH), and the collected fraction was concentrated under vacuum. The residue was purified by column chromatography (Si-column, _CHCl3 :MeOH = 10:0-9:1) to provide the desired product: ^¹H -NMR ( _CDCl3 ) δ 9.00 (s, 1H), 7.94 (d, J = 1.6 Hz, 1H), 7.64 (dd, J = 2.9, 1.4 Hz, 1H), 7.48–7.36 (m, 4H), 7.32–7.23 (m, 3H), 7.21–7.16 (m, 2H), 3.67 (s, 3H); LCMS (m/z) 358.1 [M+H]+.

Example 74. N-Methyl-N-phenyl-8-(1H-pyrazol-3-yl)-[1,2,4]triazolo[4,3-a]quinazolin-5- amine

A mixture of 8-bromo-N-methyl-N-phenyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine (Example 28) (15 mg, 0.042 mmol), _{K₃PO₄ (} 27.0 mg, 0.127 mmol), Pd(OAc) _₂ (1.901 mg, 8.47 μmol), tricyclohexylphosphine (2.375 mg, 8.47 μmol), and (1H-pyrazol-3-yl)boronic acid (11.85 mg, 0.106 mmol) in dioxane/water (0.21 mL) was heated at 120 °C for 1 hour. The reaction mixture was subjected to solid-phase extraction using a Bond Elut SCX box (Agilent) (washed with MeOH, then eluted with _NH₃ in MeOH), and the collected fractions were concentrated under vacuum. The residue was purified by column chromatography (Si-column, _CHCl3 :MeOH = 10:0-9:1) to provide the desired product: ^¹H NMR (DMSO- _d6 ) δ 13.21 (s, 1H), 9.74 (s, 1H), 8.63 (d, J = 1.6 Hz, 1H), 7.91–7.85 (m, 1H), 7.66 (dd, J = 8.8, 1.6 Hz, 1H), 7.44–7.35 (m, 2H), 7.37–7.21 (m, 4H), 6.97 (t, J = 2.1 Hz, 1H), 3.55 (s, 3H); LCMS (m/z) 342.0 [M+H]+.

Example 75. N-Methyl-N-phenyl-7-(pyridin-4-yl)-[1,2,4]triazolo[4,3-a]quinazolin-5-amine

A mixture of 7-bromo-N-methyl- _N -phenyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine (Example 62) (15 mg, 0.042 mmol), _K₃PO₄ (27.0 mg, 0.127 mmol), Pd(OAc) _₂ (1.901 mg, 8.47 μmol), tricyclohexylphosphine (2.375 mg, 8.47 μmol), and pyridine-4-ylboronic acid (13.01 mg, 0.106 mmol) in dioxane/water (0.21 mL) was heated at 120 °C for 1 hour. The reaction mixture was subjected to solid-phase extraction using a Bond Elut SCX box (Agilent) (washed with MeOH, then eluted with _NH₃ in MeOH), and the collected fraction was concentrated under vacuum. The residue was purified by column chromatography (Si-column, _CHCl3 :MeOH = 10:0-9:1) to provide the desired product: ^¹H NMR (methanol- _d4 ) δ 9.49 (s, 1H), 8.53–8.47 (m, 2H), 8.32 (d, J = 8.6 Hz, 1H), 8.16 (dd, J = 8.6, 2.0 Hz, 1H), 7.68 (d, J = 1.9 Hz, 1H), 7.60–7.50 (m, 2H), 7.50–7.37 (m, 3H), 7.21–7.13 (m, 2H), 3.72 (s, 3H); LCMS (m/z) 353.2 [M+H]+.

Example 76. N5,N8,N8-trimethyl-N5-phenyl-[1,2,4]triazolo[4,3-a]quinazolin-5,8-diamine

MeI (0.039 mL, 0.620 mmol) was added to a mixture of N5-methyl-N5-phenyl-[1,2,4]triazolo[4,3-a]quinazolin-5,8-diamine (Example 66) (30 mg, 0.103 mmol) and NaH (12.4 mg, 0.310 mmol) in DMF (2 mL) at room temperature. The mixture was stirred at room temperature for 1.5 hours. The reaction mixture was quenched with water. The reaction mixture was subjected to solid-phase extraction using a BondElut SCX box (Agilent) (washing with MeOH followed by elution with _NH3 in MeOH), and the collected fraction was concentrated under vacuum. The residue was purified by preparative LCMS to provide the desired product: ^¹H NMR (methanol- _d⁴ ) δ 9.41 (s, 1H), 7.45–7.36 (m, 2H), 7.31–7.19 (m, 3H), 7.10 (d, J = 2.6 Hz, 1H), 7.07 (d, J = 9.5 Hz, 1H), 6.52 (dd, J = 9.5, 2.6 Hz, 1H), 3.60 (s, 3H), 3.10 (s, 6H); LCMS (m/z) 319.0 [M+H]+.

Example 77. N-(cyclobutylmethyl)-N-phenyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine

(Step 1) Synthesis of N-(cyclobutylmethyl)aniline

N,N-diisopropylethylamine (2.25 mL, 12.90 mmol) was added to a mixture of aniline (0.2 g, 2.15 mmol) and cyclobutene formaldehyde (0.180 g, 2.15 mmol) in MeOH (10 mL) at 0 °C, and the mixture was stirred at room temperature for 1 hour. Then, sodium triacetoxyborohydride (0.338 g, 5.38 mmol) was added at 0 °C, and the mixture was stirred at room temperature for 3 hours. The reaction mixture was diluted with ice water and extracted with ethyl acetate. The organic layer was washed with brine, dried over _Na₂SO₄ , filtered, and evaporated under reduced pressure. The residue was purified by silica gel chromatography, eluting with 10% ethyl acetate/petroleum ether to give the desired product. _LCMS : 162.08 (M+H).

(Step 2) Synthesis of 2-chloro-N-(cyclobutylmethyl)-N-phenylquinazoline-4-amine

Sodium hydroxide (0.036 g, 0.90 mmol) was added to a mixture of 2,4-dichloroquinazoline (0.09 g, 0.45 mmol) and N-(cyclobutylmethyl)aniline (0.073 g, 0.45 mmol) in 2 mL of DMF at 0 °C, and the mixture was stirred at room temperature for 72 hours. The reaction mixture was diluted with ice water and extracted with ethyl acetate. The organic layer was washed with brine, dried over _Na₂SO₄ , filtered, and evaporated under reduced pressure. The residue was purified by silica gel chromatography, eluting with 5% ethyl acetate/petroleum ether, to give the desired product. _LCMS : 324.13 (M+H).

(Step 3) Synthesis of N-(cyclobutylmethyl)-2-hydrazino-N-phenylquinazoline-4-amine

Hydrazine hydrate (0.014 g, 0.28 mmol) was added to a solution of 2-chloro-N-(cyclobutylmethyl)-N-phenylquinazoline-4-amine (0.045 g, 0.14 mmol) in EtOH (2 mL) at room temperature, and the mixture was stirred at 50 °C for 16 hours. The reaction mixture was evaporated under reduced pressure to give the desired product. LCMS: 320.21 (M+H).

(Step 4) Synthesis of N-(cyclobutylmethyl)-N-phenyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine

A mixture of N-(cyclobutylmethyl)-2-hydrazino-N-phenylquinazoline-4-amine (0.045 g, 0.14 mmol) and triethyl orthoformate (1 mL) was stirred at 100 °C for 16 hours. The reaction mixture was evaporated under reduced pressure, and the residue was purified by preparative HPLC to provide the desired product: ^¹H NMR (DMSO- _d₆ ) δ 9.60 (s, ¹H), 8.35–8.23 (m, ¹H), 7.75 (ddd, J = 8.5, 7.1, 1.5 Hz, ¹H), 7.37–7.12 (m, 7H), 4.13 (d, J = 7.2 Hz, 2H), 2.93–2.84 (m, ¹H), 1.96–1.82 (m, 2H), 1.82–1.71 (m, 4H); LCMS (m/z) 330.2 [M+H]+.

Example 78. N-Phenyl-N-((tetrahydro-2H-pyran-4-yl)methyl)-[1,2,4]triazolo[4,3-a]quinazole 5-Lin-amine

(Step 1) Synthesis of N-((tetrahydro-2H-pyran-4-yl)methyl)aniline

Copper acetate (0.595 g, 3.28 mmol) and triethylamine (0.92 mL, 6.55 mmol) were added to a mixture of (tetrahydro-2H-pyran-4-yl)methylamine (0.4 g, 3.28 mmol) and phenylboronic acid (0.754 g, 6.56 mmol) in acetonitrile (10 mL) at room temperature, and the mixture was stirred at 80 °C for 3 h. The reaction mixture was filtered through a diatomaceous earth bed, the filtrate was diluted with water and extracted with ethyl acetate. The organic layer was washed continuously with water and brine, dried over _Na₂SO₄ , filtered, and evaporated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with 25% ethyl acetate/petroleum ether, to give the desired product. _LCMS (m/z) 192.18 [M+H] ^⁺ .

(Step 2) Synthesis of 2-chloro-N-phenyl-N-((tetrahydro-2H-pyran-4-yl)methyl)quinazolin-4-amine

Sodium hydroxide (0.050 g, 1.26 mmol) was added to a solution of N-((tetrahydro-2H-pyran-4-yl)methyl)aniline (0.240 g, 1.26 mmol) in DMF (6 mL) at 0 °C, and the mixture was stirred at room temperature for 1 hour. Then, 2,4-dichloroquinazoline (0.250 g, 1.26 mmol) was added at room temperature, and the mixture was stirred at room temperature for 24 hours, followed by heating to 80 °C for 2 hours. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed continuously with water and brine, dried over _Na₂SO₄ , filtered, and evaporated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with 25% ethyl acetate/petroleum ether, to give the desired product. _LCMS (m/z) 354.18 [M+H] ^⁺ .

(Step 3) N-phenyl-N-((tetrahydro-2H-pyran-4-yl)methyl)-[1,2,4]triazolo[4,3-a]quinazolin- Synthesis of 5-amines

Formyl hydrazine (0.034 g, 0.56 mmol) was added to a stirred solution of 2-chloro-N-phenyl-N-((tetrahydro-2H-pyran-4-yl)methyl)quinazolin-4-amine (0.1 g, 0.28 mmol) in toluene (5 mL) at room temperature, and the mixture was refluxed for 72 hours. The reaction mixture was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography followed by preparative HPLC to provide the desired product: ^¹H NMR (DMSO- _d₆ ) δ 9.64 (s, ¹H), 8.29 (dd, J = 8.3, 1.2 Hz, ¹H), 7.76 (ddd, J = 8.4, 7.2, 1.4 Hz, ¹H), 7.39–7.17 (m, 7H), 3.99 (d, J = 7.2 Hz, 2H), 3.87–3.80 (m, 2H), 3.42–3.32 (m, ¹H), 3.32–3.15 (m, 3H), 2.16 (ddd, J = 12.0, 9.2, 5.5 Hz, 1H), 1.46–1.34 (m, 2H); LCMS (m/z) 360.2 [M+H]+.

Example 79. 5-(3,4,5,6-tetrahydrobenzo[b]acoxine-1(2H)-yl)-[1,2,4]triazolo[4,3-a] Quinazoline

(Step 1) Synthesis of 3,4,5,6-tetrahydrobenzo[b]acoxine-2(1H)-one

Sodium azide (6.5 g, 100 mmol) was added to 4 g, 25 mmol of concentrated HCl (40 mL) at room temperature, and the mixture was stirred at room temperature for 24 hours. The reaction mixture was diluted with water, neutralized with saturated sodium bicarbonate solution, and extracted with ethyl acetate. The organic layer was dried over _Na₂SO₄ , filtered, and evaporated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with 50% ethyl acetate _/ petroleum ether, to give the desired product. LCMS (m/z) 176.13 [M+H] ^⁺ .

(Step 2) Synthesis of 1,2,3,4,5,6-hexahydrobenzo[b]acoxine

LDA (13.7 mL, 13.71 mmol, 1.0 M in THF) was added to a stirred solution of 3,4,5,6-tetrahydrobenzo[b]acoxine-2(1H)-one (1.2 g, 6.85 mmol) in tetrahydrofuran (20 mL), and the mixture was stirred at 70 °C for 16 hours. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was dried over _Na₂SO₄ , filtered, and evaporated under reduced pressure to give the desired product. _LCMS (m/z) 162.06 [M+H] ^⁺ .

(Step 3) 5-(3,4,5,6-tetrahydrobenzo[b]acoxine-1(2H)-yl)-[1,2,4]triazolo[4,3-a]quinoline Synthesis of azoline

LDA (0.17 mL, 0.17 mmol, 1.0 M in THF) was added to a solution of 1,2,3,4,5,6-hexahydrobenzo[b]acoxine (0.024 g, 0.15 mmol) in 10 mL of THF at 0 °C, and the mixture was stirred at room temperature for 1 hour. Then, 5-chloro-[1,2,4]triazolo[4,3-a]quinazoline (0.03 g, 0.15 mmol) was added at 0 _° C, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was dried over _Na₂SO₄ , filtered, and evaporated under reduced pressure. The residue was purified by silica gel column chromatography followed by preparative HPLC to provide the desired product: ^¹H NMR (DMSO-d ₆₎ )δ9.55(s,1H),8.26(dd,J＝8.2,1.3Hz,1H),7.74(ddd,J＝8.4,7.0,1.5Hz,1H),7.46 (dd,J＝7.6,1.7Hz,1H),7.40(td,J＝7.5,1.3Hz,1H),7.28(td,J＝7.6,1.7Hz,1H),7.1 5(ddd,J＝8.4,7.0,1.2Hz,1H),7.09(ddd,J＝8.6,3.3,1.4Hz,2H),4.06–3.93(m,2H) ,2.77(t,J＝5.9Hz,2H),1.73(s,2H),1.61(d,J＝7.0Hz,4H); LCMS(m/z)330.2[M+H]+.

Example 80. N-(2-((tert-butyldimethylsilyl)oxy)ethyl)-N-phenyl-[1,2,4]triazolidine [4,3-a]quinazolin-5-amine

(Step 1) Synthesis of N-(2-((tert-butyldimethylsilyl)oxy)ethyl)aniline

To a solution of 2-(phenylamino)ethane-1-ol (0.2 g, 1.46 mmol) in dichloromethane (10 mL), tert-butyldimethylsilyl chloride (0.219 g, 1.46 mmol) and imidazole (0.099 g, 1.46 mmol) were added, and the mixture was stirred at room temperature for 16 hours. The reaction mixture was diluted with water and extracted with dichloromethane. The organic layer was dried over _Na₂SO₄ , filtered, and evaporated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with 20% ethyl acetate/petroleum ether, to give the desired product. _LCMS : 252.50 (M+H).

(Step 2) N-(2-((tert-butyldimethylsilyl)oxy)ethyl)-N-phenyl-[1,2,4]triazolo[4, Synthesis of 3-a]quinazolin-5-amine

LDA (0.1 mL, 0.2 mmol, 2.0 M in THF) was added to a solution of N-(2-((tert-butyldimethylsilyl)oxy)ethyl)aniline (0.024 g, 0.098 mmol) in 2 mL of THF at 0 °C, and the mixture was stirred at room temperature for 1 hour. Then, 5-chloro-[1,2,4]triazolo[4,3-a]quinazoline (0.02 g, 0.098 mmol) was added at 0 °C, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was dried over _Na₂SO₄ , filtered _, and evaporated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with 3% methanol/dichloromethane to provide the desired product: ^¹H NMR (DMSO- _d₆ ) δ 9.63 (s, 1H), 8.37–8.23 (m, 1H), 7.76 (ddd, J = 8.5, 6.6, 2.1 Hz, 1H), 7.39–7.31 (m, 4H), 7.24–7.14 (m, 3H), 4.21 (t, J = 5.8 Hz, 2H), 3.95 (t, J = 5.8 Hz, 2H), 0.79 (s, 9H), -0.06 (s, 6H); LCMS (m/z) 420.2 [M+H]+.

Example 81. N-methyl-N-(3-(trifluoromethyl)phenyl)-[1,2,4]triazolo[4,3-a]quinazolin-5-amine

LDA (0.22 mL, 0.44 mmol, 1.5 equivalent, 2.0 M in THF) was added to a stirred solution of N-methyl-3-(trifluoromethyl)aniline (0.052 g, 0.29 mmol) in 5 mL of THF at 0 °C, and the mixture was stirred at room temperature for 1 hour. Subsequently, 5-chloro-[1,2,4]triazolo[4,3-a]quinazoline (0.067 g, 0.29 mmol) was added at 0 °C, and the mixture was stirred at room temperature for 1 hour _. The reaction progress was monitored by TLC. After the reaction was complete, the reaction mixture was quenched with saturated _NH₄Cl solution and extracted with ethyl acetate. The organic layer was dried over _Na₂SO₄ , filtered, and evaporated under reduced pressure. The residue was purified by preparative HPLC to provide the desired product: ^¹H NMR (DMSO- _d₆ ) δ 9.68 (s, ¹H), 8.33 (dd, J = 8.3, 1.0 Hz, ¹H), 7.81 (ddd, J = 8.4, 6.3, 2.3 Hz, ¹H), 7.75–7.66 (m, ¹H), 7.65–7.52 (m, 3H), 7.32–7.19 (m, 2H), 3.60 (s, 3H); LCMS (m/z) 344.1 [M+H]+.

Example 82. N-Methyl-N-(3-(trifluoromethoxy)phenyl)-[1,2,4]triazolo[4,3-a]quinazolin-5- amine

(Step 1) Synthesis of N-methyl-3-(trifluoromethoxy)aniline

37% formaldehyde (0.254 g, 8.47 mmol) and sodium methoxide (1.52 g, 28.22 mmol) were added to a stirred solution of 3-(trifluoromethoxy)aniline (1.0 g, 5.64 mmol) in MeOH (10 mL) at 0 °C, and the mixture was stirred at room temperature for 3 h. Then, sodium borohydride (0.214 g, 5.64 mmol) was added at 0 °C, and the mixture was heated to 60 °C for 3 h. The reaction progress was monitored by TLC. After the reaction was complete, the reaction mixture was evaporated under reduced pressure. The residue was diluted with water and extracted with ethyl acetate. The organic layer was washed continuously with water and brine, dried over _Na₂SO₄ , filtered _, and evaporated under reduced pressure. The residue was purified by silica gel column chromatography and eluted with 10% ethyl acetate/petroleum ether to give the desired product. LCMS: 192.11 (M+H).

(Step 2) N-methyl-N-(3-(trifluoromethoxy)phenyl)-[1,2,4]triazolo[4,3-a]quinazolin-5-amine Synthesis

LDA (0.27 mL, 0.54 mmol, 2.0 M in THF) was added to a stirred solution of N-methyl-3-(trifluoromethoxy)aniline (0.188 g, 0.98 mmol) in 10 mL of THF at 0 °C, and the mixture was stirred at room temperature for 1 hour. Subsequently, 5-chloro-[1,2,4]triazolo[4,3-a]quinazoline (0.1 g, 0.49 mmol) was added at 0 °C, and the mixture was stirred at room temperature for 1 hour. The reaction progress was monitored by TLC. After the reaction was complete, the reaction mixture was quenched with saturated _NH₄Cl solution and extracted with ethyl acetate. The organic layer was dried over _Na₂SO₄ , filtered _, and evaporated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with 1% methanol/dichloromethane, and then subjected to preparative HPLC to provide the desired product: ^¹H NMR (DMSO- _d₆ ) δ 9.67 (s, ¹H), 8.32 (d, J = 8.3 Hz, ¹H), 7.81 (ddd, J = 8.4, 5.5, 3.0 Hz, ¹H), 7.50 (t, J = 8.1 Hz, ¹H), 7.40–7.33 (m, 2H), 7.31–7.24 (m, 2H), 7.20 (ddt, J = 8.3, 2.3, 1.1 Hz, ¹H), 3.58 (s, 3H); LCMS (m/z) 360.1 [M+H]+.

Example 83. (3-([1,2,4]triazolo[4,3-a]quinazolin-5-yl(methyl)amino)phenyl)methanol

Tetra-n-butylammonium fluoride (0.041 g, 0.16 mmol) was added to a solution of N-(3-(((tert-butyldimethylsilyl)oxy)methyl)phenyl)-N-methyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine (Example 104) (0.06 g, 0.14 mmol) in 4 mL of THF at 0 °C, and the mixture was stirred at room temperature for 2 hours. The reaction progress was monitored by TLC. After the reaction was complete, the reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed continuously with water and brine, dried over _Na₂SO₄ , filtered _, and evaporated under reduced pressure. The crude compound was purified by silica gel column chromatography, eluted with 4% methanol/dichloromethane, followed by preparative HPLC, yielding the desired product: ^¹H NMR (DMSO- _d₆ ) δ 9.62 (s, 1H), 8.29 (dd, J = 8.5, 1.2 Hz, 1H), 7.77 (ddd, J = 8.5, 7.1, 1.4 Hz, 1H), 7.33–7.18 (m, 5H), 7.14–7.08 (m, 1H), 5.23 (t, J = 5.7 Hz, 1H), 4.46 (d, J = 5.7 Hz, 2H), 3.53 (s, 3H); LCMS (m/z) 306.2 [M+H]+.

Example 84. N-Methyl-N-phenyl-8-(1H-pyrrolo-2-yl)-[1,2,4]triazolo[4,3-a]quinazolin-5- amine

A mixture of 8-bromo-N-methyl-N-phenyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine (Example 28) (15 mg, 0.042 mmol), _{K3PO4 (} 27.0 mg, 0.127 mmol), Pd(OAc) ₂ (1.901 mg, 8.47 μmol), tricyclohexylphosphine (2.375 mg, 8.47 μmol), and tert-butyl 2-(5-(methyl(phenyl)amino)-[1,2,4]triazolo[4,3-a]quinazolin-8-yl)-1H-pyrrole-1-carboxylate (22.34 mg, 0.106 mmol) in dioxane/water (0.21 mL) was heated at 120 °C for 1 hour. The reaction mixture was subjected to solid-phase extraction using a Bond Elut SCX box (Agilent) (washed with MeOH and then eluted with _NH3 in MeOH), and the collected fractions were concentrated under vacuum. The residue was purified by column chromatography (Si-column, _CHCl3 :MeOH = 10:0-9:1) to provide the desired product: ^¹H -NMR (methanol- _d4 ) δ 9.36 (s, 1H), 8.28 (d, J = 1.8 Hz, 1H), 7.48–7.39 (m, 2H), 7.38–7.26 (m, 5H), 7.21 (d, J = 8.9 Hz, 1H), 6.98–6.92 (m, 1H), 6.82 (dd, J = 3.6, 1.4 Hz, 1H), 6.27–6.20 (m, 1H), 3.65 (s, 3H); LCMS (m/z) 341.0 [M+H]+.

Example 85. N-(5-(methyl(phenyl)amino)-[1,2,4]triazolo[4,3-a]quinazolin-8-yl)methanesulfonate amide

A mixture of N5-methyl-N5-phenyl-[1,2,4]triazolo[4,3-a]quinazolin-5,8-diamine (Example 66) (40 mg, 0.138 mmol), triethylamine (0.192 mL, 1.378 mmol), and methanesulfonyl chloride (6 M in 1,2-dichloroethane, 2 mL) was stirred at 70 °C for 4.5 h. The reaction mixture was evaporated under vacuum. The residue was dissolved in DMA (2 mL), and methanesulfonyl chloride (6 M in 1,2-dichloroethane, 2 mL) was added to the solution at room temperature. The mixture was stirred overnight at 110 °C. The reaction mixture was subjected to solid-phase extraction using a Bond Elut SCX box (Agilent) (washed with MeOH, then eluted with _NH3 in MeOH), and the collected fraction was concentrated under vacuum. The residue was purified by preparative LCMS to provide the desired product: ^¹H NMR (DMSO- _d₆ ) δ 10.67 (s, 1H), 9.48 (s, 1H), 7.72 (s, 1H), 7.47–7.33 (m, 2H), 7.27 (dt, J = 8.2, 1.8 Hz, 3H), 7.13 (d, J = 9.1 Hz, 1H), 6.85 (dd, J = 9.1, 2.2 Hz, 1H), 3.51 (s, 3H), 3.19 (s, 3H); LCMS (m/z) 369.3 [M+H]+.

Example 86. N-Methyl-N-phenyl-8-(piperidin-1-yl)-[1,2,4]triazolo[4,3-a]quinazolin-5-amine

A mixture of 8-bromo-N-methyl-N-phenyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine (Example 28) (20 mg, 0.056 mmol), _K₂CO₃ (15.61 mg, 0.113 mmol), Pd(dba) _₃ (0.011 mmol) _, and piperidine (5.77 mg, 0.068 mmol) in DMF (282 μL) was stirred overnight at 100 °C. The reaction mixture was concentrated under vacuum, and the residue was purified by column chromatography (Si column, _CHCl3 :MeOH = 0–20%) to provide the desired product: ^¹H NMR (methanol- _d4 ) δ 9.36 (s, 1H), 7.46–7.32 (m, 2H), 7.33–7.15 (m, 4H), 6.93 (d, J = 9.5 Hz, 1H), 6.58 (dd, J = 9.6, 2.6 Hz, 1H), 3.56 (s, 3H), 3.43 (dd, J = 6.2, 4.0 Hz, 4H), 1.72–1.61 (m, 6H); LCMS (m/z) 359.2 [M+H]+.

Example 87. Methyl 5-(methyl(phenyl)amino)-[1,2,4]triazolo[4,3-a]quinazolin-8-carboxylate

A mixture of 8-bromo-N-methyl-N-phenyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine (Example 28) (10 mg, 0.028 mmol), Mo(CO)6 (7.45 mg, 0.028 mmol), Pd(OAc) ₂ (1.268 mg, 0.0056 mmol), and Pd(dppf) ₂ (0.0056 mmol) in DMA/MeOH (1:1, 0.14 mL) was stirred at 100 °C for 2 hours. The reaction mixture was filtered through a diatomaceous earth bed using MeOH. The filtrate was concentrated under vacuum, and the residue was purified by preparative HPLC to provide the desired product: ^¹H NMR (methanol- _d⁴ ) δ 9.74 (s, ¹H), 8.90 (d, J = 1.6 Hz, ¹H), 7.81 (dd, J = 8.9, 1.6 Hz, ¹H), 7.61–7.50 (m, ³H), 7.47–7.40 (m, ²H), 7.30 (d, J = 8.8 Hz, ¹H), 3.98 (s, ³H), 3.81 (s, ³H); LCMS (m/z) 334.2 [M+H]⁺.

Example 88. N-methyl-N-(3-nitrophenyl)-[1,2,4]triazolo[4,3-a]quinazolin-5-amine

(Step 1) Synthesis of 2-chloro-N-methyl-N-(3-nitrophenyl)quinazolin-4-amine

60% sodium hydride (0.120 g, 3.01 mmol) was added to a stirred solution of N-methyl-3-nitroaniline (0.382 g, 2.51 mmol) in 10 mL of DMF at 0 °C, and the mixture was stirred at room temperature for 1 hour. Then, 2,4-dichloroquinazoline (0.5 g, 2.51 mmol) was added at 0 °C. The mixture was stirred at room temperature for 3 hours. The reaction progress was monitored by TLC. After the reaction was complete, the reaction mixture was diluted with ice water. The resulting solid was filtered and dried under vacuum to give the desired product. LCMS: 315.10 (M+H).

(Step 2) Synthesis of N-methyl-N-(3-nitrophenyl)-[1,2,4]triazolo[4,3-a]quinazolin-5-amine

Formyl hydrazide (0.038 g, 0.63 mmol) was added to a stirred solution of 0.1 g (0.32 mmol) of 2-chloro-N-methyl-N-(3-nitrophenyl)quinazolin-4-amine in 4 mL of toluene at room temperature, and the mixture was heated to 120 °C for 72 hours. The reaction progress was monitored by TLC. After the reaction was complete, the reaction mixture was evaporated under reduced pressure. The residue was washed with diethyl ether and purified by preparative HPLC to obtain the desired product: ^¹H NMR (DMSO- _d₆ ) δ 9.70 (s, ¹H), 8.42–8.33 (m, ¹H), 8.19 (t, J = 2.2 Hz, ¹H), 8.03 (ddd, J = 8.2, 2.3, 1.0 Hz, ¹H), 7.83 (ddd, J = 8.4, 7.1, 1.4 Hz, ¹H), 7.67 (ddd, J = 8.2, 2.2, 1.0 Hz, ¹H), 7.58 (t, J = 8.1 Hz, ¹H), 7.37 (dd, J = 8.3, 1.4 Hz, ¹H), 7.32 (m, ¹H), 3.63 (s, ³H); LCMS (m/z) 321.1 [M+H]+.

Example 89. N-(3-(methoxymethyl)phenyl)-N-methyl-[1,2,4]triazolo[4,3-a]quinazolin-5- amine

A solution of (3-([1,2,4]triazolo[4,3-a]quinazolin-5-yl(methyl)amino)phenyl)methanol (Example 83) (0.03 g, 0.098 mmol) in DMF (2 mL) was added to 60% sodium hydride (0.005 g, 0.12 mmol) at 0 °C, and the mixture was stirred at room temperature for 15 minutes, followed by the addition of iodomethane (0.007 mL, 0.12 mmol) at 0 °C. The mixture was stirred at room temperature for 16 hours. The reaction mixture was diluted with cold water and extracted with ethyl acetate. The organic layer was washed continuously with water and brine, dried over _Na₂SO₄ , filtered _, and evaporated under reduced pressure. The residue was purified by preparative HPLC to provide the desired product: ^¹H -NMR (DMSO- _d₆ ) δ 9.62 (s, 1H), 8.29 (dd, J = 8.3, 1.2 Hz, 1H), 7.77 (ddd, J = 8.5, 7.1, 1.5 Hz, 1H), 7.37 (td, J = 7.2, 1.9 Hz, 1H), 7.31–7.17 (m, 5H), 4.36 (s, 2H), 3.54 (s, 3H), 3.20 (s, 3H); LCMS (m/z) 320.2 [M+H]+.

Example 90. N-(3-(fluoromethyl)phenyl)-N-methyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine

Diethylaminosulfur trifluoride (0.04 mL, 0.33 mmol) was added to a solution of (3-([1,2,4]triazolo[4,3-a]quinazolin-5-yl(methyl)amino)phenyl)methanol (Example 83) (0.05 g, 0.16 mmol) in dichloromethane (4 mL) at -78 °C, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was quenched with a saturated aqueous sodium bicarbonate solution and extracted with dichloromethane. The organic layer was washed continuously with water and brine, dried over _Na₂SO₄ , filtered _, and evaporated under reduced pressure. The residue was purified by preparative HPLC to provide the desired product: ^¹H -NMR (500MHz, DMSO- _d₆ ) δ 9.64 (s, ¹H), 8.30 (dd, J = 8.3, 1.3Hz, ¹H), 7.78 (ddd, J = 8.4, 7.1, 1.5Hz, ¹H), 7.43–7.37 (m, 2H), 7.29 (ddd, J = 8.1, 4.4, 1.7Hz, 3H), 7.25–7.22 (m, ¹H), 5.37 (d, J = 47.5Hz, 2H), 3.55 (s, 3H). LCMS (m/z) 308.1 [M+H]⁺.

Example 91. N-(3-ethylphenyl)-N-methyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine

LDA (0.18 mL, 0.37 mmol, 2.0 M in THF) was added to a stirred solution of 3-ethyl-N-methylaniline (0.066 g, 0.49 mmol) in 3 mL of THF at 0 °C, and the mixture was stirred at room temperature for 1 hour. Then, 5-chloro-[1,2,4]triazolo[4,3-a]quinazoline (0.05 g, 0.24 mmol) was added to the solution at 0 °C, and the mixture was stirred at room temperature for 1 hour. The reaction progress was monitored by TLC. After the reaction was complete, the reaction mixture was diluted with ice water and extracted with ethyl acetate. The organic layer was dried over _Na₂SO₄ , filtered _, and evaporated under reduced pressure. The residue was purified by preparative HPLC to provide the desired product: ^¹H -NMR (DMSO- _d₆ ) δ 9.61 (s, ¹H), 8.43–8.23 (m, ¹H), 7.76 (ddd, J = 8.4, 7.0, 1.6 Hz, ¹H), 7.34–7.16 (m, ³H), 7.15–7.08 (m, ³H), 3.53 (s, ³H), 2.65–2.51 (m, ²H), 1.08 (t, J = 7.6 Hz, ³H). LCMS (m/z) 304.2 [M+H]⁺.

Example 92. 8-(cyclopropylethynyl)-N-methyl-N-phenyl-[1,2,4]triazolo[4,3-a]quinazolin- 5-amine

A mixture of 8-bromo-N-methyl-N-phenyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine (Example 28) (20 mg, 0.056 mmol), prop-1-yne (0.02 mL, 2 mmol, 0.1 M THF solution), triethylamine (22.85 mg, 0.226 mmol), Pd(OAc) ₂ (3.80 mg, 0.017 mmol), triphenylphosphine (19.99 mg, 0.076 mmol), and copper iodide (I) (3.23 mg, 0.017 mmol) in dioxane (0.4 mL) was treated in a microwave reactor at 120 °C for 2 hours. The reaction mixture was purified by column chromatography (Si column, _CHCl3 :MeOH = 10:0-9:1) to provide the desired product: ^¹H -NMR ( _CDCl3 ) δ 8.91 (s, 1H), 7.73 (d, J = 1.5 Hz, 1H), 7.46–7.30 (m, 2H), 7.31–7.22 (m, 1H), 7.22–7.09 (m, 3H), 7.03 (dd, J = 8.7, 1.6 Hz, 1H), 3.67 (s, 3H), 1.44–1.30 (m, 1H), 0.48–0.35 (m, 2H), 0.20–0.10 (m, 2H); LCMS (m/z) 340.3 [M+H]+.

Example 93. 9-Chloro-N-methyl-N-phenyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine

(Step 1) Synthesis of 2,8-dichloro-N-methyl-N-phenylquinazoline-4-amine

N-methylaniline (45.9 mg, 0.428 mmol) and sodium hydroxide (17.13 mg, 0.428 mmol) were added to a solution of 2,4,8-trichloroquinazoline (100 mg, 0.428 mmol) in DMF (2.1 mL), and the mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with AcOEt, washed continuously with water and brine, and dried over _Na₂SO₄ . The organic layer was concentrated under vacuum to give the desired product. _LCMS (m/z) 303.98 [MH] ^⁺ .

(Step 2) Synthesis of 8-chloro-2-hydrazino-N-methyl-N-phenylquinazoline-4-amine

Hydrazine hydrate (20.08 mg, 0.401 mmol) was added to a solution of 2,8-dichloro-N-methyl-N-phenylquinazoline- ₄ -amine (61 mg, 0.201 mmol) in EtOH (1 mL), and the mixture was stirred at 50 °C for 2 hours. The reaction mixture was diluted with AcOEt, washed continuously with water and brine, and dried over _Na₂SO₄ . The organic layer was concentrated under vacuum to give the desired product. LCMS (m/z) 300.13 [M+H] ^⁺ .

(Step 3) Synthesis of 9-chloro-N-methyl-N-phenyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine

A mixture of 8-chloro-2-hydrazino-N-methyl-N-phenylquinazoline-4-amine (53 mg, 0.177 mmol) and triethoxymethane (52 mg, 0.354 mmol) was stirred at 100 °C for 1 hour. The reaction mixture was concentrated under vacuum, and the residue was purified by column chromatography (Si column, _CHCl3 :MeOH = 10:0–9:1), followed by preparative HPLC purification to provide the desired product: ^¹H NMR (methanol- _d4 ) δ 10.02 (s, 1H), 7.89 (d, J = 7.9 Hz, 1H), 7.45 (t, J = 7.6 Hz, 2H), 7.40–7.13 (m, 5H), 3.71 (s, 3H); LCMS (m/z) 310.1 [M+H]+.

Example 94. 5-(methyl(phenyl)amino)-[1,2,4]triazolo[4,3-a]quinazolin-8-carboxynitrile

Zinc cyanide (19.89 mg, 0.169 mmol) and Pd(PPh3)4 (19.57 mg, 0.017 mmol) were added to a solution of 8-bromo-N-methyl-N-phenyl-[1,2,4]triazolo[4,3-a]quinazolin- _5- amine (Example ₂₈ ) (30 mg, 0.085 mmol) in DMF (423 μL), and the mixture was treated in a microwave reactor at 100 °C for 2 h. The reaction mixture was subjected to solid-phase extraction using a BondElut SCX box (Agilent) (washed with MeOH and then eluted with _NH3 in MeOH), and the collected fraction was concentrated under vacuum. The residue was purified by column chromatography (Si-column, _CHCl3 :MeOH = 10:0-9:1) to provide the desired product: ^¹H NMR (methanol- _d4 ) δ 9.45 (s, 1H), 8.65 (d, J = 1.5 Hz, 1H), 7.46–7.29 (m, 7H), 3.65 (s, 3H); LCMS (m/z) 301.2 [M+H]+.

Example 95. N-Methyl-N-phenyl-8-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]quinazolin-5-amine

(Step 1) Synthesis of 7-(trifluoromethyl)quinazolin-2,4(1H,3H)-dione

A mixture of 2-amino-4-chlorobenzoic acid (5 g, 29.1 mmol) and urea (6.13 g, 102 mmol) was stirred overnight at 200 °C. The reaction mixture was cooled to room temperature and diluted with water. The resulting solid was collected and washed with water to give the desired product.

(Step 2) Synthesis of 2,4-dichloro-7-(trifluoromethyl)quinazoline

A mixture of 7-(trifluoromethyl)quinazoline-2,4(1H,3H)-dione (500 mg, 2.17 mmol) and phosphorus trichloride (833 mg, 5.43 mmol) was stirred at 100 °C for 6 hours. The reaction mixture was concentrated under vacuum. Ice water was added to the residue, and the resulting solid was collected and washed with water to give the desired product. The residue was used in the next step without further purification.

(Step 3) Synthesis of 2-chloro-N-methyl-N-phenyl-7-(trifluoromethyl)quinazoline-4-amine

Sodium hydride (11.68 mg, 0.487 mmol) and N-methylaniline (52.2 mg, 0.487 mmol) were added to a solution of _2,4 -dichloro-7-(trifluoromethyl)quinazoline (130 mg, crude) in DMF (2.4 mL), and the mixture was stirred at room temperature for 30 min. The mixture was diluted with AcOEt, washed continuously with water and brine, and dried over _Na₂SO₄ . The organic layer was concentrated under vacuum. The residue was used for the next step without further purification. LCMS (m/z) 338.03 [M+H] ^⁺ .

(Step 4) Synthesis of 2-hydrazino-N-methyl-N-phenyl-7-(trifluoromethyl)quinazoline-4-amine

Hydrazine hydrate (50.7 mg, 1.013 mmol) was added to a solution of 2-chloro-N-methyl-N-phenyl-7-(trifluoromethyl)quinazolin- ₄ -amine (171 mg, crude) in EtOH (2.5 mL), and the mixture was stirred at 50 °C for 2 hours. The reaction mixture was diluted with AcOEt, washed continuously with water and brine, and dried over _Na₂SO₄ . The organic layer was concentrated under vacuum. The residue was used for the next step. LCMS (m/z) 334.13 [M+H] ^⁺ .

(Step 5) Synthesis of N-methyl-N-phenyl-8-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]quinazolin-5-amine become

A mixture of 2-hydrazino-N-methyl-N-phenyl-7-(trifluoromethyl)quinazolin-4-amine (162 mg, crude) and triethoxymethane (224 mg, 1.519 mmol) was stirred at 90 °C for 2 hours. The mixture was concentrated under vacuum. The residue was purified by column chromatography (Si column, _CHCl3 :MeOH = 10:0–9:1) and preparative HPLC to provide the desired product: ^¹H -NMR (methanol- _d4 ) δ 9.70 (s, 1H), 8.75 (dt, J = 1.7, 0.8 Hz, 1H), 7.60–7.47 (m, 4H), 7.46–7.38 (m, 3H), 3.79 (s, 3H); LCMS (m/z) 344.2 [M+H]+.

Example 96. N-Methyl-N-phenyl-8-(prop-1-en-2-yl)-[1,2,4]triazolo[4,3-a]quinazolin-5- amine

A mixture of 8-bromo-N-methyl- _N -phenyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine (Example 28) (25 mg, 0.071 mmol), _K₃PO₄ (17.98 mg, 0.085 mmol), Pd(OAc) _₂ (7.92 mg, 0.035 mmol), tricyclohexylphosphine (19.79 mg, 0.071 mmol), and 4,4,5,5-tetramethyl-2-(prop-1-en-2-yl)-1,3,2-dioxaborhexacyclopentane (11.86 mg, 0.071 mmol) in dioxane/water (0.35 mL) was heated at 67 °C for 1 hour. The reaction mixture was subjected to solid-phase extraction using a Bond Elut SCX box (Agilent) (washed with MeOH, then eluted with _NH₃ in MeOH), and the collected fraction was concentrated under vacuum. The residue was purified by column chromatography (Si-column, _CHCl3 :MeOH = 10:0-9:1) to provide the desired product: ^¹H -NMR (methanol- _d4 ) δ 9.54 (s, 1H), 8.21 (d, J = 1.7 Hz, 1H), 7.50–7.16 (m, 7H), 5.65–5.64 (m, 1H), 5.33–5.32 (m, 1H), 3.65 (s, 3H), 2.20 (dd, J = 1.5, 0.8 Hz, 3H); LCMS (m/z) 316.2 [M+H]+.

Example 97. 8-(2-fluorophenyl)-N-methyl-N-phenyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine

A mixture of 8-bromo-N-methyl- _N -phenyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine (Example 28) (20 mg, 0.056 mmol), _K₃PO₄ (23.97 mg, 0.113 mmol), Pd(OAc) _₂ (2.54 mg, 0.011 mmol), tricyclohexylphosphine (3.17 mg, 0.011 mmol), and (2-fluorophenyl)boronic acid (15.80 mg, 0.113 mmol) in dioxane/water (0.28 mL) was heated at 100 °C for 1 hour. The reaction mixture was subjected to solid-phase extraction using a Bond Elut SCX box (Agilent) (washed with MeOH, then eluted with _NH₃ in MeOH), and the collected fraction was concentrated under vacuum. The residue was purified by column chromatography (Si-column, _CHCl3 :MeOH = 10:0-9:1) to provide the desired product: ^¹H -NMR (methanol- _d4 ) δ 9.49 (s, 1H), 8.31 (q, J = 1.0 Hz, 1H), 7.56 (td, J = 7.8, 1.8 Hz, 1H), 7.49–7.40 (m, 3H), 7.36–7.17 (m, 7H), 3.66 (s, 3H); LCMS (m/z) 370.3 [M+H]+.

Example 98. 8-(4-fluorophenyl)-N-methyl-N-phenyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine

A mixture of 8-bromo-N-methyl- _N -phenyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine (Example 28) (20 mg, 0.056 mmol), _K₃PO₄ (23.97 mg, 0.113 mmol), Pd(OAc) _₂ (2.54 mg, 0.011 mmol), tricyclohexylphosphine (3.17 mg, 0.011 mmol), and (4-fluorophenyl)boronic acid (19.75 mg, 0.141 mmol) in dioxane/water (0.28 mL) was heated at 100 °C for 1 hour. The reaction mixture was subjected to solid-phase extraction using a Bond Elut SCX box (Agilent) (washed with MeOH, then eluted with _NH₃ in MeOH), and the collected fraction was concentrated under vacuum. The residue was purified by column chromatography (Si-column, _CHCl3 :MeOH = 10:0-9:1) to provide the desired product: ^¹H -NMR (methanol- _d4 ) δ 9.54 (s, 1H), 8.38 (d, J = 1.8 Hz, 1H), 7.83–7.73 (m, 2H), 7.49–7.38 (m, 3H), 7.36–7.27 (m, 4H), 7.25–7.17 (m, 2H), 3.66 (s, 3H); LCMS (m/z) 370.3 [M+H]+.

Example 99. 5-(methyl(phenyl)amino)-[1,2,4]triazolo[4,3-a]quinazolin-8-carboxynitrile

A mixture of 7-bromo-N-methyl-N-phenyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine (Example 62) (20 mg, 0.056 mmol), zinc cyanide (13.26 mg, 0.113 mmol), and Pd( _PPh3 ) ₄ (13.05 mg, 0.011 mmol) in dioxane/water (0.35 mL) was heated at 80 °C for 1 hour. The reaction mixture was subjected to solid-phase extraction using a Bond Elut SCX box (Agilent) (washed with MeOH, then eluted with NH3 in MeOH), and the collected fraction was concentrated under vacuum. The residue was purified by column chromatography (Si-column, _CHCl3 :MeOH = 10:0-9:1) to provide the desired product: ^¹H NMR (methanol- _d4 ) δ 9.47 (s, 1H), 8.32 (d, J = 8.6 Hz, 1H), 8.03 (dd, J = 8.6, 1.7 Hz, 1H), 7.55–7.46 (m, 3H), 7.46–7.39 (m, 1H), 7.38–7.32 (m, 2H), 3.68 (s, 3H); LCMS (m/z) 301.2.

Example 100. N-(3-bromophenyl)-N-methyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine

(Step 1) Synthesis of N-(3-bromophenyl)-2-chloro-N-methylquinazoline-4-amine

Sodium hydroxide (0.402 g, 10.05 mmol) was added to a stirred solution of 2,4-dichloroquinazoline (1.0 g, 5.02 mmol) and 3-bromo-N-methylaniline (0.96 mL, 7.54 mmol) in 15 mL of DMF at 0 °C, and the mixture was stirred at room temperature for 5 hours. The reaction progress was monitored by TLC. After the reaction was complete, the reaction mixture was diluted with ice water. The resulting solid was filtered and dried under vacuum. The residue was purified by silica gel column chromatography, eluting with 19% ethyl acetate/petroleum ether to give the desired product. LCMS: 348.34 (M+H).

(Step 2) Synthesis of N-(3-bromophenyl)-N-methyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine

Formyl hydrazine (0.034 g, 0.57 mmol) was added to a stirred solution of N-(3-bromophenyl)-2-chloro-N-methylquinazolin-4-amine (0.1 g, 0.29 mmol) in toluene (3 mL), and the mixture was heated to 120 °C for 78 hours. The reaction progress was monitored by TLC. After the reaction was complete, the reaction mixture was evaporated under reduced pressure. The residue was washed with diethyl ether and purified by preparative HPLC to provide the desired product: ^¹H -NMR (DMSO- _d₆ ) δ 9.65 (s, 1H), 8.32 (dd, J = 8.3, 1.0 Hz, 1H), 7.81 (ddd, J = 8.5, 6.3, 2.3 Hz, 1H), 7.59 (t, J = 1.9 Hz, 1H), 7.42 (dt, J = 7.1, 2.0 Hz, 1H), 7.31 (ddt, J = 8.8, 4.0, 2.4 Hz, 4H), 3.55 (s, 3H); LCMS (m/z) 354.1 [M+H]+.

Example 101. N-(3-iodophenyl)-N-methyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine

LDA (0.36 mL, 0.73 mmol, 2.0 M in THF) was added to a stirred solution of 0.228 g (0.98 mmol) of 3-iodo-N-methylaniline in 5 mL of THF at 0 °C, and the mixture was stirred at room temperature for 1 hour. 5-Chloro-[1,2,4]triazolo[4,3-a]quinazoline (0.1 g, 0.49 mmol) was added at 0 °C, and the mixture was stirred at room temperature for 1 hour. The reaction progress was monitored by TLC. After the reaction was complete, the reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed continuously with water and brine, dried over _Na₂SO₄ , filtered _, and evaporated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with 4% methanol/dichloromethane, followed by preparative HPLC to provide the desired product: ^¹H NMR (DMSO- _d₆ ) δ 9.64 (s, ¹H), 8.31 (d, J = 8.4 Hz, ¹H), 7.81 (ddd, J = 8.5, 5.5, 3.1 Hz, ¹H), 7.72 (t, J = 1.9 Hz, ¹H), 7.59 (dt, J = 7.8, 1.2 Hz, ¹H), 7.30 (dq, J = 4.8, 1.6, 1.1 Hz, 3H), 7.14 (t, J = 8.0 Hz, 1H), 3.53 (s, 3H); LCMS (m/z) 402.0 [M+H]+.

Example 102. N1-([1,2,4]triazolo[4,3-a]quinazolin-5-yl)-N1-methylphenyl-1,3-diamine

Zinc (0.715 g, 10.94 mmol) and NH₄Cl (0.585 g, 10.94 mmol) were added to a stirred solution of N-methyl-N-(3-nitrophenyl)-[1,2,4]triazolo[4,3-a]quinazolin-5-amine (Example ₈₈ ) (0.350 g, 1.09 mmol) in EtOH/water (20 mL, 1:1) at room temperature, and the mixture was stirred at the same temperature for 16 hours. The reaction progress was monitored by TLC. After the reaction was complete, the reaction mixture was filtered through a diatomaceous earth bed and washed with ethyl acetate. The organic layer was dried over _Na₂SO₄ , filtered _, and evaporated under reduced pressure. The residue was purified by silica gel column chromatography and eluted with 5% methanol/dichloromethane to provide the desired product: ^¹H NMR (DMSO- _d₆ ) δ 9.58 (s, 1H), 8.26 (dd, J = 8.3, 1.2 Hz, 1H), 7.77 (ddd, J = 8.4, 7.3, 1.3 Hz, 1H), 7.46 (dd, J = 8.5, 1.3 Hz, 1H), 7.26 (ddd, J = 8.4, 7.2, 1.2 Hz, 1H), 7.11–6.93 (m, 1H), 6.51–6.35 (m, 3H), 5.20 (s, 2H), 3.47 (s, 3H); LCMS (m/z) 291.2 [M+H]+.

Example 103. Methyl 3-([1,2,4]triazolo[4,3-a]quinazolin-5-yl(methyl)amino)benzoate

(Step 1) Synthesis of methyl-3-((tert-butoxycarbonyl)amino)benzoate (2)

Sodium bismuth carbonate (11.11 g, 132.27 mmol) and di-tert-butyl dicarbonate (14.42 g, 66.14 mmol) were added to a stirred solution of methyl-3-aminobenzoate (10 g, 66.14 mmol) in THF/water (60 mL, 5: ₁ ) at room temperature, and the mixture was stirred at room temperature for 16 hours. The reaction progress was monitored by TLC. After the reaction was complete, the reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with brine, dried over _Na₂SO₄ , filtered, and evaporated under reduced pressure. The crude compound was purified by silica gel column chromatography, eluting with 18% ethyl acetate/petroleum ether to give the desired product. LCMS (m/z) 252.11 [M+H]⁺.

(Step 2) Synthesis of methyl 3-((tert-butoxycarbonyl)(methyl)amino)benzoate

60% sodium hydride (1.95 g, 48.96 mmol) and methyl iodide (3.65 mL, 58.76 mmol) were added to a stirred solution of methyl-3-((tert-butoxycarbonyl)amino)benzoate (12.3 g, 48.96 mmol) in DMF (120 mL) at 0 °C, and the mixture was stirred at room temperature for 2 h. The reaction progress was monitored by TLC. After the reaction was complete, the reaction mixture was diluted with ice water and extracted with ethyl acetate. The organic layer was washed with brine, dried over _Na₂SO₄ , filtered, and evaporated under reduced pressure to give the desired product. _LCMS (m/z) 266.21 [M+H]⁺.

(Step 3) Synthesis of methyl 3-(methylamino)benzoate

4N HCl in 15 mL of 1,4-dioxane was added to a stirred solution of methyl 3-((tert-butoxycarbonyl)(methyl)amino)benzoate (2.0 g, 7.55 mmol) in dichloromethane (20 mL) at 0 °C, and the mixture was stirred at room temperature for 2 hours. The reaction progress was monitored by TLC. After the reaction was complete, the reaction mixture was poured into ice water, neutralized with saturated _NaHCO3 solution, and extracted with dichloromethane. The organic layer was washed continuously with water and brine, dried over _Na2SO4 , filtered, and evaporated under reduced pressure to give the desired product. _LCMS (m/z) 166.46 [M+H]+.

(Step 4) Synthesis of methyl 3-((2-chloroquinazoline-4-yl)(methyl)amino)benzoate

60% sodium hydride (0.048 g, 1.21 mmol) was added to a stirred solution of methyl 3-(methylamino)benzoate (crude, 0.249 g, 1.50 mmol) in DMF (6 mL) at 0 °C, and the mixture was stirred at room temperature for 1 hour. Then, 2,4-dichloroquinazoline (0.2 g, 1.0 mmol) was added at 0 °C, and the mixture was stirred at room temperature _for 5 hours. The reaction progress was monitored by TLC. After the reaction was complete, the reaction mixture was diluted with ice water and extracted with ethyl acetate. The organic layer was washed with brine, dried over _Na₂SO₄ , filtered, and evaporated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with 10% ethyl acetate/petroleum ether to provide the desired product. LCMS (m/z) 328.18 [M+H]+.

(Step 5) Synthesis of methyl 3-((2-hydrazinoquinazolin-4-yl)(methyl)amino)benzoate

Hydrazine hydrate (0.006 mL, 0.12 mmol) was added to a stirred solution of methyl 3-((2-chloroquinazoline-4-yl)(methyl)amino)benzoate (0.04 g, 0.12 mmol) in ethanol (2 mL) at room temperature, and the mixture was heated to 50 °C for 4 hours. The reaction progress was monitored by TLC. After the reaction was complete, the reaction mixture was diluted with petroleum ether. The obtained solid was filtered and dried under vacuum to give the desired product. LC-MS: 324.19 (M+H).

(Step 6) Synthesis of methyl 3-([1,2,4]triazolo[4,3-a]quinazolin-5-yl(methyl)amino)benzoate

A mixture of methyl 3-((2-hydrazinoquinazolin-4-yl)(methyl)amino)benzoate (0.035 g, 0.11 mmol) and triethyl orthoformate (2 mL) was heated to 80 °C for 4 hours. The reaction progress was monitored by TLC. After the reaction was complete, the reaction mixture was purified by preparative HPLC to give the desired product: ^¹H NMR (DMSO- _d₆ ) δ 9.65 (s, 1H), 8.31 (dd, J = 8.2, 1.1 Hz, 1H), 7.94–7.66 (m, 3H), 7.70–7.40 (m, 2H), 7.38–7.13 (m, 2H), 3.83 (s, 3H), 3.57 (s, 3H); LCMS (m/z) 334.2 [M+H]⁺.

Example 104. N-(3-(((tert-butyldimethylsilyl)oxy)methyl)phenyl)-N-methyl-[1,2,4]tri Azo[4,3-a]quinazolin-5-amine

(Step 1) Synthesis of 3-(((tert-butyldimethylsilyl)oxy)methyl)aniline

Imidazole (0.828 g, 12.18 mmol) was added to a solution of (3-aminophenyl)methanol (1.0 g, 8.12 mmol) in DMF (10 mL) at 0 °C, and the mixture was stirred at room temperature for 10 min. Then, tert-butyldimethylsilyl chloride (1.34 g, 8.93 mmol) was added at 0 °C, and the mixture was stirred at room temperature for 16 h. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed continuously with water and brine, dried over _Na₂SO₄ , filtered, and evaporated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with 15% ethyl acetate/petroleum ether to give the desired product. _LCMS : 238.57 (M+H).

(Step 2) Synthesis of 3-(((tert-butyldimethylsilyl)oxy)methyl)-N-methylaniline

37% formaldehyde (0.28 mL, 3.16 mmol) and sodium methoxide (0.228 g, 4.22 mmol) were added to a stirred solution of 3-(((tert-butyldimethylsilyl)oxy)methyl)aniline (0.5 g, 2.11 mmol) in MeOH (10 mL) at 0 °C, and the mixture was heated to 50 °C for 4 hours, followed by the addition of sodium borohydride (0.159 g, 4.22 mmol) at room temperature. The mixture was stirred at room temperature for 16 hours _. The reaction progress was monitored by TLC. After the reaction was complete, the reaction mixture was quenched with water and extracted with dichloromethane. The organic layer was washed continuously with water and brine, dried over _Na₂SO₄ , filtered, and evaporated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with 30% ethyl acetate/petroleum ether to give the desired product. LC-MS: 252.72 (M+H).

(Step 3) N-(3-(((tert-butyldimethylsilyl)oxy)methyl)phenyl)-N-methyl-[1,2,4]triazole Synthesis of [4,3-a]quinazolin-5-amine

LDA (0.65 mL, 1.31 mmol, 2.0 M in THF) was added to a stirred solution of 3-(((tert-butyldimethylsilyl)oxy)methyl)-N-methylaniline (0.22 g, 0.88 mmol) in 6 mL of THF at 0 °C, and the mixture was stirred at room temperature for 1 hour. Subsequently, 5-chloro-[1,2,4]triazolo[4,3-a]quinazoline (0.214 g, 1.05 mmol) was added at 0 °C, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was quenched with saturated NH4Cl solution and extracted with ethyl acetate. The organic layer was washed continuously with water and brine, dried over _Na2SO4 , filtered _, and evaporated under reduced pressure. The residue was purified by silica gel column chromatography and eluted with 30% ethyl acetate/petroleum ether to give the desired product: ^¹H NMR (500MHz, DMSO- _d⁶ ) δ 9.66 (d, J = 4.6Hz, 1H), 8.35–8.23 (m, 1H), 7.79 (ddt, J = 8.4, 7.2, 1.3Hz, 1H), 7.36 (dt, J = 24.6, 7.8Hz, 1H), 7.30–7.11 (m, 5H), 4.55 (d, J = 87.9Hz, 2H), 3.54 (d, J = 4.4Hz, 3H), 3.35–3.25 (m, 9H), -0.05 (d, J = 5.8Hz, 6H); LCMS (m/z) 420.2 [M+H]⁺.

Example 105. N-(3-Cyclopropylphenyl)-N-methyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine

Cyclopropylboronic acid (0.060 g, 0.70 mmol) and potassium phosphate (0.222 g, 1.05 mmol) were added to a stirred solution of N-(3-iodophenyl)-N-methyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine (Example 101) (0.140 g, 0.35 mmol) in a mixture of toluene and water (7.5 mL, 4:1) at room temperature. The mixture was then deoxygenated with argon for 10 min. Subsequently, tricyclohexylphosphine (0.019 g, 0.07 mmol) and palladium(II) acetate (0.004 g, 0.02 mmol) were added at room temperature, and the mixture was heated to 100 °C for 16 h. The reaction progress was monitored by TLC. After the reaction was complete, the reaction mixture was filtered through a diatomaceous earth bed and washed with ethyl acetate. The organic layer was washed continuously with water and brine, dried over _{Na₂SO₄ ,} filtered, and evaporated under reduced pressure. The residue was purified by preparative HPLC to provide the desired product: ^¹H NMR (DMSO- _d₆ ) δ 9.60 (s, ¹H), 8.27 (dd, J = 8.2, 1.1 Hz, ¹H), 7.76 (ddd, J = 8.4, 6.8, 1.9 Hz, ¹H), 7.32–7.15 (m, ³H), 7.08–6.84 (m, ³H), 3.52 (s, ³H), 1.96–1.74 (m, ¹H), 1.00–0.79 (m, ²H), 0.71–0.54 (m, ²H); LCMS (m/z) 316.2 [M+H]+.

Example 106. N-([1,1'-diphenyl]-3-yl)-N-methyl-[1,2,4]triazolo[4,3-a]quinazolin-5- amine

A stirred mixture of N-(3-iodophenyl)-N-methyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine (Example 101) (0.02 g, 0.05 mmol), sodium carbonate (0.011 g, 0.11 mmol), and phenylboronic acid (0.008 g, 0.07 mmol) in 1,4-dioxane/water (4 mL, 1:1) was deoxygenated under argon for 10 min. Triphenylphosphine (0.0026 g, 0.009 mmol) and palladium(II) acetate (0.0005 g, 0.002 mmol) were then added at room temperature, and the mixture was heated to 100 °C for 3 h. The reaction progress was monitored by TLC. After the reaction was complete, the reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with brine, dried over _Na₂SO₄ , filtered _, and evaporated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with 10% ethyl acetate/petroleum ether, to provide the desired product: ^¹H NMR (DMSO- _d₆ ) δ 9.62 (s, ¹H), 8.29 (dd, J = 8.4, 1.2 Hz, ¹H), 7.76 (ddd, J = 8.4, 7.2, 1.4 Hz, ¹H), 7.67–7.59 (m, 3H), 7.57 (dt, J = 7.8, 1.3 Hz, 1H), 7.51–7.13 (m, 7H), 3.62 (s, 3H); LCMS (m/z) 352.2 [M+H]+.

Example 107. N-Methyl-N-(3-(pyrrolidone-1-yl)phenyl)-[1,2,4]triazolo[4,3-a]quinazolin- 5-amine

At room temperature, pyrrolidine (0.03 mL, 0.37 mmol) and NatOBu (0.048 g, 0.49 mmol) were added to a stirred solution of N-(3-iodophenyl)-N-methyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine (Example 101) (0.1 g, 0.25 mmol) in 1,4-dioxane (6 mL), and the mixture was deoxygenated with argon for 10 minutes. [2-(dicyclohexylphosphine)-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-diphenyl][2-(2-aminoethyl)phenyl]palladium(II) chloride (BrettphosPd-G1, 0.04 g, 0.05 mmol) and 2-dicyclohexylphosphine-2',6'-diisopropoxybiphenyl (RuPhos, 0.035 g, 0.07 mmol) were added at room temperature, and the mixture was heated to 100 °C for 4 hours. The reaction progress was monitored by TLC. After the reaction was complete, the reaction mixture was filtered through a diatomaceous earth bed and washed with ethyl acetate. The organic layer was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography with elution of 4% methanol/dichloromethane, followed by preparative HPLC to provide the desired product: ^¹H NMR (DMSO- _d₆ ) δ 9.57 (s, ¹H), 8.45–8.12 (m, ¹H), 7.75 (ddd, J = 8.3, 7.2, 1.3 Hz, ¹H), 7.44 (dd, J = 8.4, 1.4 Hz, ¹H), 7.23 (ddd, J = 8.5, 7.1, 1.2 Hz, ¹H), 7.12 (t, J = 7.9 Hz, ¹H), 6.59–6.10 (m, ³H), 3.53 (s, ³H), 3.21–3.00 (m, ⁴H), 2.11–1.78 (m, ⁴H); LCMS (m/z) 345.3 [M+H]⁺.

Example 108. N-Methyl-N-(3-morpholinophenyl)-[1,2,4]triazolo[4,3-a]quinazolin-5-amine

Morpholine (0.032 g, 0.37 mmol) and sodium tert-butoxide (0.048 g, 0.49 mmol) were added to a stirred solution of N-(3-iodophenyl)-N-methyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine (Example 101) (0.1 g, 0.25 mmol) in 1,4-dioxane (6 mL) at room temperature, and the mixture was deoxygenated with argon for 10 minutes. Then, [2-(dicyclohexylphosphine)-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-diphenyl][2-(2-aminoethyl)phenyl]palladium(II) chloride (Brettphos Pd-G1, 0.04 g, 0.05 mmol) and 2-dicyclohexylphosphine-2',6'-diisopropoxydiphenyl (RuPhos, 0.035 g, 0.07 mmol) were added at room temperature. The mixture was heated to 100°C and maintained for 4 hours. The reaction progress was monitored by TLC. After the reaction was complete, the reaction mixture was filtered through a diatomaceous earth bed and washed with ethyl acetate. The organic layer was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography, eluted with 4% methanol/dichloromethane, followed by preparative HPLC, yielding the desired product: ^¹H NMR (DMSO- _d₆ ) δ 9.59 (s, ¹H), 8.26 (dd, J = 8.4, 1.3 Hz, ¹H), 7.76 (ddd, J = 8.5, 7.3, 1.4 Hz, ¹H), 7.34 (dd, J = 8.5, 1.3 Hz, ¹H), 7.27–7.17 (m, 2H), 6.92–6.80 (m, 2H), 6.75–6.61 (m, 1H), 3.73–3.64 (m, 4H), 3.53 (s, 3H), 3.11–2.98 (m, 4H); LCMS (m/z) 361.2 [M+H]+.

Example 109. N-methyl-N-(3-(prop-1-yn-1-yl)phenyl)-[1,2,4]triazolo[4,3-a]quinazolin- 5-amine

Triethylamine (0.01 mL, 0.07 mmol) was added to a stirred solution of N-(3-iodophenyl)-N-methyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine (Example 101) (0.03 g, 0.07 mmol) in 1,4-dioxane (3 mL) at room temperature, and the mixture was deoxygenated with argon for 10 min. Then, palladium(II) acetate (0.003 g, 0.01 mmol), triphenylphosphine (0.018 g, 0.07 mmol), and cuprous iodide (0.003 g, 0.014 mmol) were added at room temperature. The mixture was purged with propyne gas for 10 min and then treated in a microwave reactor at 120 °C for 1 h. The reaction progress was monitored by TLC. After the reaction was complete, the reaction mixture was filtered through a diatomaceous earth bed and washed with ethyl acetate. The organic layer was evaporated under reduced pressure. The residue was purified by preparative HPLC to provide the desired product: ^¹H NMR (DMSO- _d₆ ) δ 9.63 (s, ¹H), 8.42–8.25 (m, ¹H), 7.79 (ddd, J = 8.5, 6.6, 2.0 Hz, ¹H), 7.33–7.23 (m, 6H), 3.53 (s, 3H), 1.99 (s, 3H); LCMS (m/z) 314.2 [M+H]+.

Example 110. N-Methyl-N-phenyl-8-vinyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine

A mixture of 8-bromo-N-methyl-N-phenyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine (Example 28) (50 mg, 0.141 mmol), _K₃PO₄ (47.5 mg, 0.423 mmol), Pd( _PPh₃ ) _₄ (32.6 mg, 0.028 mmol), and _4,4,5,5 -tetramethyl-2-vinyl-1,3,2-dioxaborhecyclopentane (43.5 mg, 0.282 mmol) in BuOH (0.71 mL) was heated to 80 °C for 1 hour. The reaction mixture was subjected to solid-phase extraction using a Bond Elut SCX box (Agilent) (washed with MeOH, then eluted with _NH₃ in MeOH), and the collected fraction was concentrated under vacuum. The residue was purified by column chromatography (Si-column, _CHCl3 :MeOH = 10:0-9:1) to provide the desired product: ^¹H -NMR (methanol- _d4 ) δ 9.43 (s, 1H), 8.13 (d, J = 1.6 Hz, 1H), 7.47–7.37 (m, 2H), 7.37–7.07 (m, 5H), 6.80 (dd, J = 17.6, 10.9 Hz, 1H), 6.06 (d, J = 17.5 Hz, 1H), 5.51 (d, J = 10.9 Hz, 1H), 3.62 (s, 3H); LCMS (m/z) 302.2 [M+H]+.

Example 111. 8-Isopropyl-N-methyl-N-phenyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine

Pd/C (7 mg, 0.066 mmol) was added to a solution of N-methyl-N-phenyl-8-(prop-1-en-2-yl)-[1,2,4]triazolo[4,3-a]quinazolin-5-amine (Example 96) (20 mg, 0.063 mmol) in EtOH (0.32 mL), and the mixture was stirred at room temperature under a H2 atmosphere for 3 hours. After removing Pd/C by filtration, the filtrate was concentrated under vacuum. The residue was purified by column chromatography (Si-column, _CHCl3 :MeOH = 10:0-9:1) to obtain the desired product: ^¹H NMR ( _CDCl3 ) δ 8.94 (s, 1H), 7.58 (d, J = 1.7 Hz, 1H), 7.42–7.32 (m, 2H), 7.33–7.12 (m, 4H), 6.97 (dd, J = 8.9, 1.7 Hz, 1H), 3.66 (s, 3H), 3.01 (m, J = 6.9 Hz, 1H), 1.28 (d, J = 6.9 Hz, 6H); LCMS (m/z) 318.2 [M+H]+.

Example 112. 8-Ethyl-N-methyl-N-phenyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine

Pd/C (7 mg) was added to a solution of N-methyl-N-phenyl-8-vinyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine (Example 110) (20 mg, 0.066 mmol) in EtOH (0.33 mL), and the mixture was stirred at room temperature under H2 atmosphere for 3 hours. After removing Pd/C by filtration, the filtrate was concentrated under vacuum. The residue was purified by column chromatography (Si-column, _CHCl3 :MeOH = 10:0-9:1) to provide the desired product: ^¹H NMR (methanol- _d4 ) δ 9.42 (d, J = 1.9 Hz, 1H), 8.02–7.95 (m, 1H), 7.45–7.36 (m, 2H), 7.35–7.11 (m, 4H), 7.00 (dq, J = 8.6, 1.6 Hz, 1H), 3.66–3.54 (m, 3H), 2.82–2.71 (m, 2H), 1.26 (td, J = 7.7, 0.8 Hz, 3H); LCMS (m/z) 304.2 [M+H]+.

Example 113. N-Methyl-N-phenyl-8-(phenylethynyl)-[1,2,4]triazolo[4,3-a]quinazolin-5- amine

A mixture of 8-bromo-N-methyl-N-phenyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine (Example 28) (15 mg, 0.042 mmol), acetylenylbenzene (6.49 mg, 0.064 mmol), and cuprous iodide (I) (8.07 mg, 0.042 mmol) in acetonitrile (0.21 mL) was heated at 80 °C for 1 hour. The reaction mixture was subjected to solid-phase extraction using a Bond Elut SCX box (Agilent) (washed with MeOH, then eluted with _NH₃ in MeOH), and the collected fraction was concentrated under vacuum. The residue was purified by column chromatography (Si-column, _CHCl3 :MeOH = 0-20%) and preparative HPLC (general conditions) to provide the desired product: ^¹H NMR ( _CDCl3 ) δ 8.94 (s, 1H), 7.91 (dd, J = 1.6, 0.6 Hz, 1H), 7.58–7.49 (m, 2H), 7.45–7.33 (m, 5H), 7.33–7.13 (m, 5H), 3.68 (s, 3H); LCMS (m/z) 376.3 [M+H]+.

Example 114. 8-(2-methoxyphenyl)-N-methyl-N-phenyl-[1,2,4]triazolo[4,3-a]quinazolin- 5-amine

A mixture of 8-bromo-N-methyl-N-phenyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine (Example 28) (20 mg, 0.056 mmol), _{K₃PO₄ (} 36.0 mg, 0.169 mmol), Pd(OAc) _₂ (2.54 mg, 0.011 mmol), tricyclohexylphosphine (3.17 mg, 0.011 mmol), and (2-methoxyphenyl)boronic acid (21.45 mg, 0.141 mmol) in dioxane/water (0.28 mL) was heated at 100 °C for 1 hour. The reaction mixture was subjected to solid-phase extraction using a Bond Elut SCX box (Agilent) (washed with MeOH, then eluted with _NH₃ in MeOH), and the collected fraction was concentrated under vacuum. The residue was purified by column chromatography (Si-column, _CHCl3 :MeOH = 10:0-9:1) to provide the desired product: ^¹H NMR ( _CDCl3 ) δ 8.97 (s, 1H), 8.01 (t, J = 1.0 Hz, 1H), 7.44–7.36 (m, 3H), 7.34–7.20 (m, 6H), 7.09–6.99 (m, 2H), 3.82 (s, 3H), 3.70 (s, 3H); LCMS (m/z) 382.3 [M+H]+.

Example 115. 3-(5-(methyl(phenyl)amino)-[1,2,4]triazolo[4,3-a]quinazolin-8-yl)propyl 2-Alyn-1-ol

(Step 1) N-Methyl-N-phenyl-8-(((tetrahydro-2H-pyran-2-yl)oxy)ethynyl)-[1,2,4]triazole Synthesis of [4,3-a]quinazolin-5-amine

A mixture of 8-bromo-N-methyl-N-phenyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine (Example 28) (15 mg, 0.042 mmol), _PdCl₂ (dppf) (6.20 mg, 8.47 μmol), triethylamine (17.14 mg, 0.169 mmol), 2-(prop-2-yn-1-yloxy)tetrahydro-2H-pyran (17.81 mg, 0.127 mmol), and cuprous iodide (I) (1.613 mg, 8.47 μmol) in DMF (0.21 mL) was treated in a microwave reactor at 80 °C for 2 h. The reaction mixture was purified by column chromatography (Si column, _CHCl₃ :MeOH = 10:0–9:1) to give the desired product. LCMS (m/z) 414.28 [M+H] ^⁺ .

(Step 2) 3-(5-(methyl(phenyl)amino)-[1,2,4]triazolo[4,3-a]quinazolin-8-yl)prop-2-yne Synthesis of 1-ols

A mixture of N-methyl-N-phenyl-8-(((tetrahydro-2H-pyran-2-yl)oxy)ethynyl)-[1,2,4]triazolo[4,3-a]quinazolin-5-amine (12 mg, 0.029 mmol) and 2N HCl aqueous solution (1 mL) was stirred at room temperature for 1 hour. The reaction mixture was neutralized with 2N NaOH aqueous solution and the mixture was concentrated under vacuum. The residue was purified by column chromatography (Si-column, _CHCl3 :MeOH = 10:0-8:2) to provide the desired product: ^¹H NMR ( _CDCl3 ) δ 10.13 (s, 1H), 8.79 (s, 1H), 7.51 (td, J = 10.8, 9.5, 4.3 Hz, 3H), 7.34 (d, J = 7.2 Hz, 2H), 7.12 (d, J = 8.7 Hz, 1H), 6.94 (d, J = 8.7 Hz, 1H), 4.47 (s, 2H), 3.79 (s, 3H); LCMS (m/z) 330.2 [M+H]+.

Example 116. 8-(3-fluorophenyl)-N-methyl-N-phenyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine

A mixture of 8-bromo-N-methyl- _N -phenyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine (Example 28) (20 mg, 0.056 mmol), _K₃PO₄ (23.97 mg, 0.113 mmol), Pd(OAc) _₂ (2.54 mg, 0.011 mmol), tricyclohexylphosphine (3.17 mg, 0.011 mmol), and (4-fluorophenyl)boronic acid (19.75 mg, 0.141 mmol) in dioxane/water (0.28 mL) was heated at 100 °C for 1 hour. The reaction mixture was subjected to solid-phase extraction using a Bond Elut SCX box (Agilent) (washed with MeOH, then eluted with _NH₃ in MeOH), and the collected fraction was concentrated under vacuum. The residue was purified by column chromatography (Si-column, _CHCl3 :MeOH = 10:0-9:1) to provide the desired product: ^¹H NMR ( _CDCl3 ) δ 9.06 (s, 1H), 7.95 (d, J = 1.7 Hz, 1H), 7.48–7.27 (m, 8H), 7.23–7.17 (m, 2H), 7.13 (tdd, J = 8.3, 2.6, 1.1 Hz, 1H), 3.69 (s, 3H); LCMS (m/z) 370.3 [M+H]+.

Example 117. 5-(methyl(phenyl)amino)-[1,2,4]triazolo[4,3-a]quinazolin-8-carboxaldehyde

Osmium oxide (VIII) (8.44 mg, 0.033 mmol) and sodium periodate (42.6 mg, 0.199 mmol) were added to a solution of N-methyl-N-phenyl-8-vinyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine (Example 110) (50 mg, 0.166 mmol) in acetone/water (1:1, 0.83 mL), and the mixture was stirred overnight at room temperature. The reaction mixture was subjected to solid-phase extraction using a BondElut SCX box (Agilent) (washed with MeOH, then eluted with _NH3 in MeOH), and the collected fraction was concentrated under vacuum. The residue was purified by preparative HPLC to provide the desired product: ^¹H NMR (methanol- _d⁴ ) δ 9.49 (s, 1H), 7.44 (td, J = 6.9, 6.5, 1.6 Hz, 2H), 7.37–7.26 (m, 6H), 5.61 (s, 1H), 3.68 (s, 3H); LCMS (m/z) 304.2 [M+H]+.

Example 118. 5-(methyl(phenyl)amino)-[1,2,4]triazolo[4,3-a]quinazolin-8-carboxylic acid

A mixture of 5-(methyl(phenyl)amino)-[1,2,4]triazolo[4,3-a]quinazolin-8-carboxynitrile (Example 94) (50 mg, 0.166 mmol) and sulfuric acid (2 mL, 0.166 mmol) was heated to 80 °C for 5 hours. The reaction mixture was cooled to 0 °C and neutralized with 4N NaOH aqueous solution. The mixture was concentrated under vacuum. DMSO was added to the mixture, and the resulting solid was filtered off. The filtrate was purified by preparative HPLC to provide the desired product: ^¹H NMR (methanol- _d⁴ ) δ 9.52 (s, 1H), 8.65 (s, 1H), 7.68 (d, J = 8.6 Hz, 1H), 7.50–7.27 (m, 6H), 3.69 (s, 3H); LCMS (m/z) 320.2 [M+H]⁺.

Example 119. N-([1,1'-diphenyl]-3-yl)-N-methyl-8-nitro-[1,2,4]triazolo[4,3-a]quinoline Azoline-5-amine

(Step 1) Synthesis of N-(diphenyl-3-yl)-2-chloro-N-methyl-7-nitroquinazolin-4-amine

To a solution of N-methyldiphenyl-4-amine (22.9 mg, 0.125 mmol) in DMF (0.62 mL), 2,4-dichloro-7-nitroquinazoline (30.5 mg, 0.125 mmol) and sodium hydride (3 mg, 0.125 mmol) were added, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with AcOEt, washed continuously with water and brine, and dried over _Na₂SO₄ . The organic layer was concentrated under vacuum. The residue was used in the next step without further purification. _LCMS (m/z) 391.18 [M+H] ^⁺ .

(Step 2) Synthesis of N-(diphenyl-3-yl)-2-hydrazino-N-methyl-7-nitroquinazolin-4-amine

A mixture of N-(diphenyl-3-yl)-2-chloro-N-methyl-7-nitroquinazolin-4-amine (crude, 61 mg, 0.156 mmol) and hydrazine hydrate (15.63 mg, 0.312 mmol) in EtOH (0.78 mL) was stirred at room temperature to 50 °C for 2 hours. The reaction mixture was diluted with AcOEt and washed continuously with water and brine. The organic layer was concentrated under vacuum. The residue was used in the next step without further purification. LCMS (m/z) 387.23 [M+H] ⁺ .

(Step 3) N-([1,1'-diphenyl]-3-yl)-N-methyl-8-nitro-[1,2,4]triazolo[4,3-a]quinazole Synthesis of 5-line-amine

A mixture of N-(diphenyl-3-yl)-2-hydrazino-N-methyl-7-nitroquinazolin-4-amine (crude, 62 mg, 0.160 mmol) and triethoxymethane (71.3 mg, 0.481 mmol) was heated at 95 °C for 1 hour. The reaction mixture was concentrated under vacuum, and the residue was purified by column chromatography (Si-column, _CHCl3 :MeOH = 10:0–9:1) to provide the desired product: ^¹H NMR ( _CDCl3 ) δ 9.08 (s, 1H), 8.66 (d, J = 2.2 Hz, 1H), 7.93 (dd, J = 9.1, 2.2 Hz, 1H), 7.66–7.33 (m, 9H), 7.17 (ddd, J = 7.8, 2.2, 1.1 Hz, 1H), 3.76 (s, 3H); LCMS (m/z) 397.3 [M+H]+.

Example 120. N-(4'-fluoro-[1,1'-diphenyl]-3-yl)-N-methyl-[1,2,4]triazolo[4,3-a]quinoline Azoline-5-amine

A mixture of N-(3-iodophenyl)-N-methyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine (Example 101) (15 mg, 0.037 mmol), (4-fluorophenyl)boric acid (13.08 mg, 0.093 mmol), _K₃PO₄ (23.81 _mg , 0.112 mmol), Pd(OAc) _₂ (1.679 mg, 7.48 μmol), and tricyclohexylphosphine (2.097 mg, 7.48 μmol) in dioxane/water (0.2 mL) was heated at 100 °C for 1 hour. The reaction mixture was subjected to solid-phase extraction using a Bond Elut SCX box (Agilent) (washed with MeOH, then eluted with _NH₃ in MeOH), and the collected fraction was concentrated under vacuum. The residue was purified by column chromatography (Si-column, _CHCl3 :MeOH = 10:0-9:1) to provide the desired product: ^¹H NMR ( _CDCl3 ) δ 8.99 (s, 1H), 7.89–7.80 (m, 1H), 7.67 (ddd, J = 8.4, 7.2, 1.3 Hz, 1H), 7.46–7.40 (m, 5H), 7.32 (dq, J = 1.5, 0.9 Hz, 1H), 7.17–7.08 (m, 4H), 3.73 (s, 3H); LCMS (m/z) 370.3 [M+H]+.

Example 121. N-(3-(furan-2-yl)phenyl)-N-methyl-[1,2,4]triazolo[4,3-a]quinazolin-5- amine

A mixture of N-(3-iodophenyl)-N-methyl-[ _1,2,4 ]triazolo[4,3-a]quinazolin-5-amine (Example 101) (15 mg, 0.037 mmol), _K₃PO₄ (15.87 mg, 0.075 mmol), Pd(OAc) _₂ (1.679 mg, 0.0075 mmol), tricyclohexylphosphine (2.10 mg, 0.0075 mmol), and furan-2-ylboronic acid (6.27 mg, 0.056 mmol) in dioxane/water (0.2 mL) was heated at 100 °C for 1 hour. The reaction mixture was subjected to solid-phase extraction using a Bond Elut SCX box (Agilent) (washed with MeOH, then eluted with _NH₃ in MeOH), and the collected fraction was concentrated under vacuum. The residue was purified by column chromatography (Si-column, _CHCl3 :MeOH = 10:0-9:1) to provide the desired product: ^¹H NMR (CDCl3 ₎ )δ8.96(s,1H),7.89–7.76(m,1H),7.65(ddd,J＝8.4,7.3,1.3Hz,1H),7.60–7.41(m,4H),7.36(t,J＝7.9Hz,1H),7.13(ddd,J＝8.5,7.3,1.2 Hz, 1H), 7.01 (ddd, J＝7.9, 2.2, 1.0Hz, 1H), 6.66 (dd, J＝3.4, 0.8Hz, 1H), 6.47 (dd, J＝3.4, 1.8Hz, 1H), 3.70 (s, 3H); LCMS (m/z) 342.2[M+H]+.

Example 122. 3-([1,2,4]triazolo[4,3-a]quinazolin-5-yl(methyl)amino)benzaldehyde

Manganese oxide (IV) (0.173 g, 1.97 mmol) was added to a stirred solution of (3-([1,2,4]triazolo[4,3-a]quinazolin-5-yl(methyl)amino)phenyl)methanol (Example 83) (0.06 g, 0.19 mmol) in dichloromethane (6 mL), and the mixture was stirred at room temperature for 24 hours. The reaction progress was monitored by TLC. After the reaction was complete, the reaction mixture was filtered through a diatomaceous earth bed. The filtrate was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography, eluting with 4% methanol/dichloromethane to provide the desired product: ^¹H NMR (DMSO- _d₆ ) δ 9.95 (s, ¹H), 9.68 (s, ¹H), 8.41–8.17 (m, ¹H), 7.91–7.71 (m, ³H), 7.69–7.54 (m, ²H), 7.38–7.21 (m, ²H), 3.60 (s, ³H); LCMS (m/z) 304.1 [M+H]+.

Example 123. 7-Ethyl-N-methyl-N-phenyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine

(Step 1) Synthesis of 6-bromoquinazolin-2,4(1H,3H)-dione

A stirred mixture of 2-amino-5-bromobenzoic acid (2.0 g, 9.26 mmol) and urea (5.5 g, 92.59 mmol) was heated to 150 °C for 16 hours. After cooling to room temperature, the reaction mixture was diluted with ice water and stirred for 5 minutes. The resulting solid was filtered and dried under vacuum to give a crude product. The crude compound was ground with glacial acetic acid to give the desired product. LCMS (m/z) 241.07 [M+H]+.

(Step 2) Synthesis of 6-bromo-2,4-difluoroquinazoline

N,N-diisopropylethylamine (1.85 mL, 10.62 mmol) was added to a solution of 6-bromoquinazolin-2,4(1H,3H)-dione (1.7 g, 7.08 mmol) in phosphorus oxychloride (6.62 mL, 70.83 mmol) at 0 °C, and the mixture was stirred at 120 °C for 3 hours. The reaction mixture was diluted with ice water, and the resulting solid was collected. The solid was dissolved in dichloromethane, washed with water and brine, dried over _Na₂SO₄ , filtered, and evaporated under reduced pressure to give the desired product. _LCMS (m/z) 277.15 [M+H]⁺.

(Step 3) Synthesis of 6-bromo-2-chloro-N-methyl-N-phenylquinazoline-4-amine

Sodium hydroxide (0.072 g, 1.81 mmol) was added to a solution of N-methylaniline (0.2 mL, 1.81 mmol) in DMF (10 mL) at 0 °C, and the mixture was stirred at room temperature for 1 hour. Then, 6-bromo-2,4-dichloroquinazoline (0.5 g, 1.81 mmol) was added at ₀ °C. The mixture was then stirred at room temperature for 2 hours. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed continuously with water and brine, dried over _Na₂SO₄ , filtered, and evaporated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with 15% ethyl acetate/petroleum ether, to give the desired product. LCMS (m/z) 348.27 [M+H]⁺.

(Step 4) Synthesis of 6-bromo-2-hydrazino-N-methyl-N-phenylquinazoline-4-amine

Hydrazine hydrate (0.28 mL, 5.74 mmol) was added to a solution of 6-bromo-2-chloro-N-methyl-N-phenylquinazoline-4-amine (1 g, 2.87 mmol) in EtOH (15 mL) at room temperature, and the mixture was stirred at 50 °C for 16 hours. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed continuously with water and brine, dried over _Na₂SO₄ , filtered, and evaporated under reduced pressure to give the desired product. _LCMS (m/z) 346.10 [M+H]⁺.

(Step 5) Synthesis of 7-bromo-N-methyl-N-phenyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine

A mixture of 6-bromo-2-hydrazino-N-methyl-N-phenylquinazoline-4-amine (0.9 g, 2.62 mmol) and triethyl orthoformate (1.3 mL, 7.87 mmol) was heated to 100 °C for 16 hours. The reaction mixture was diluted with diethyl ether and stirred for several minutes. The resulting solid was filtered and dried under vacuum to give a crude product. The crude compound was washed with diethyl ether to give the desired product. LCMS (m/z) 354.13 [M+H]+.

(Step 6) Synthesis of 7-ethyl-N-methyl-N-phenyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine

Ethylboronic acid (0.026 g, 0.35 mmol) and potassium phosphate (0.090 g, 0.42 mmol) were added to a solution of 7-bromo-N-methyl-N-phenyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine (0.05 g, 0.14 mmol) in 1,4-dioxane/water (5 mL, 4:1) at room temperature, and the mixture was deoxygenated with argon for 10 min. Tricyclohexylphosphine (0.04 g, 0.14 mmol) and Pd(OAc) _₂ (0.006 g, 0.03 mmol) were then added at room temperature, and the mixture was treated in a microwave reactor at 110 °C for 2 h. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with water and brine, dried over _Na₂SO₄ , filtered _, and evaporated under reduced pressure to give the crude product. The crude compound was purified by preparative HPLC to provide the desired product: ^¹H NMR (DMSO- _d₆ ) δ 9.57 (s, ¹H), 8.19 (d, J = 8.4 Hz, ¹H), 7.62 (dd, J = 8.5, 1.9 Hz, ¹H), 7.41 (dd, J = 8.4, 7.2 Hz, 2H), 7.36–7.22 (m, 3H), 7.05 (d, J = 1.8 Hz, 1H), 3.55 (s, 3H), 2.38 (q, J = 7.6 Hz, 2H), 0.79 (t, J = 7.6 Hz, 3H). LCMS (m/z) 304.3 [M+H]⁺.

Example 124. N-Methyl-7-nitro-N-phenyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine

(Step 1) Synthesis of 6-nitroquinazolin-2,4(1H,3H)-dione

A mixture of 2-amino-5-nitrobenzoic acid (4.0 g, 21.98 mmol) and urea (13.18 g, 219.78 mmol) was heated to 150 °C for 16 hours. After cooling to room temperature, the reaction mixture was diluted with ice water and stirred for 5 minutes. The resulting solid was filtered and dried under vacuum to give a crude product. The crude compound was ground with glacial acetic acid to provide the desired product. LCMS (m/z) 208.06 [M+H]+.

(Step 2) Synthesis of 2,4-dichloro-6-nitroquinazoline

N,N-diisopropylethylamine (1.89 mL, 10.87 mmol) was added to a solution of 6-nitroquinazolin-2,4(1H,3H)-dione (1.5 g, 7.24 mmol) in phosphorus oxychloride (6.94 mL, 72.46 mmol) at 0 °C, and the mixture was stirred at 120 °C for 16 hours. The reaction mixture was diluted with ice water and extracted with ethyl acetate. The organic layer was washed continuously with water and brine, dried over _Na₂SO₄ , filtered, and evaporated under reduced pressure. The residue was purified by silica gel column chromatography and eluted with 10% ethyl acetate _/ petroleum ether to give the desired product.

(Step 3) Synthesis of 2-chloro-N-methyl-6-nitro-N-phenylquinazoline-4-amine

Sodium hydroxide (0.050 g, 1.23 mmol) was added to a solution of N-methylaniline (0.132 g, 1.23 mmol) in DMF (8 mL) at 0 °C, and the mixture was stirred at room temperature for 1 hour. Then, 2,4-dichloro-6-nitroquinazoline (0.3 g, 1.23 mmol) was added at ₀ °C. The mixture was then stirred at room temperature for 16 hours. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with ice water and brine, dried over _Na₂SO₄ , filtered, and evaporated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with 20% ethyl acetate/petroleum ether to give the desired product. LCMS (m/z) 315.15 [M+H] ^⁺ .

(Step 4) Synthesis of 2-hydrazino-N-methyl-6-nitro-N-phenylquinazoline-4-amine

Hydrazine hydrate (0.12 mL, 2.42 mmol) was added to a solution of 2-chloro-N-methyl-6-nitro-N-phenylquinazoline-4-amine 4 (0.38 g, 1.21 mmol) in EtOH (10 mL) at room temperature, and the mixture was stirred at 50 °C for 16 hours. The reaction mixture was evaporated under reduced pressure to give the desired product. LCMS (m/z) 311.01 [M+H] ⁺ .

(Step 5) Synthesis of N-methyl-7-nitro-N-phenyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine

A mixture of 2-hydrazino-N-methyl-6-nitro-N-phenylquinazoline-4-amine (0.3 g, 0.97 mmol) and triethyl orthoformate (1 mL, 5.80 mmol) was stirred at 100 °C for 16 hours. The reaction mixture was diluted with diethyl ether and stirred for several minutes. The resulting solid was filtered and dried under vacuum to give the crude product. The crude compound was washed with diethyl ether to provide the desired product: ^¹H NMR (DMSO- _d₆₆ ) δ 9.71 (s, 1H), 8.58 (dd, J = 9.1, 2.4 Hz, 1H), 8.50 (d, J = 9.1 Hz, 1H), 8.02 (d, J = 2.4 Hz, 1H), 7.53–7.39 (m, 4H), 7.38–7.29 (m, 1H), 3.59 (s, 3H); LCMS (m/z) 321.1 [M+H]⁺.

Example 125. 5-(methyl(phenyl)amino)-[1,2,4]triazolo[4,3-a]quinazolin-7-carboxamide

(Step 1) Synthesis of 5-(methyl(phenyl)amino)-[1,2,4]triazolo[4,3-a]quinazolin-7-carboxynitrile

Zinc cyanide (0.166 g, 1.42 mmol) and zinc powder (0.055 g, 0.84 mmol) were added to a solution of 7-bromo-N-methyl-N-phenyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine (0.1 g, 0.28 mmol) in DMF (4 mL) at room temperature, and the mixture was deoxygenated with argon for 10 min at room temperature, followed by the addition of tetrakis(triphenylphosphine)palladium(0) (0.065 g, 0.06 mmol). The mixture was then treated in a microwave reactor at 110 °C for 2 h. The reaction mixture was filtered through a diatomaceous earth bed and washed with ethyl acetate. The filtrate was washed continuously with water and brine, dried over _{Na₂SO₄ ,} filtered, and evaporated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with 4% methanol/dichloromethane to give the desired product. LCMS (m/z) 301.31 [M+H] ^⁺ .

(Step 2) Synthesis of 5-(methyl(phenyl)amino)-[1,2,4]triazolo[4,3-a]quinazolin-7-carboxamide

Nickel(ii) hexahydrate (0.031 g, 0.13 mmol) and sodium borohydride (0.177 g, 4.66 mmol) were added to a solution of 5-(methyl(phenyl)amino)-[1,2,4]triazolo[4,3-a]quinazolin-7-carboxynitrile (0.1 g, 0.33 mmol) in MeOH (5 mL) at 0 °C, and the mixture was stirred at room temperature for 48 hours. The reaction mixture was quenched with saturated _NH4Cl solution and extracted with 10% methanol/dichloromethane. The organic layer was washed continuously with water and brine, dried over _Na2SO4 , filtered _, and evaporated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with 4% methanol/dichloromethane, followed by preparative HPLC, yielding the desired product: ^¹H NMR (DMSO- _d₆ ) δ 9.63 (s, 1H), 8.34 (d, J = 8.6 Hz, 1H), 8.18 (dd, J = 8.6, 1.8 Hz, 1H), 7.87 (d, J = 1.9 Hz, 2H), 7.41–7.27 (m, 5H), 7.27–7.18 (m, 1H), 3.55 (s, 3H); LCMS (m/z) 319.3 [M+H]+.

Example 126. N5-([1,1'-diphenyl]-3-yl)-N5-methyl-[1,2,4]triazolo[4,3-a]quinazolin- 5,8-Diamine

Pd/C (6.17 mg) was added to a solution of N-([1,1'-diphenyl]-3-yl)-N-methyl-8-nitro-[1,2,4]triazolo[4,3-a]quinazolin-5-amine (Example 119) (23 mg, 0.058 mmol) in EtOH (0.29 ml), and the mixture was stirred overnight at 70 °C under a H2 atmosphere. After removing Pd/C by filtration, the filtrate was concentrated under vacuum. The residue was purified by preparative HPLC to provide the desired product: ^¹H NMR (methanol- _d⁴ ) δ 9.19 (s, 1H), 7.57–7.47 (m, 5H), 7.43 (ddd, J = 7.7, 6.9, 1.3 Hz, 2H), 7.39–7.31 (m, 1H), 7.22 (ddd, J = 7.8, 2.3, 1.2 Hz, 1H), 7.16–7.05 (m, 2H), 6.44 (dd, J = 9.2, 2.2 Hz, 1H), 3.68 (s, 3H); LCMS (m/z) 367.3 [M+H]+.

Example 127. N-Methyl-N-(3-(pyridin-4-yl)phenyl)-[1,2,4]triazolo[4,3-a]quinazolin-5- amine

A mixture of N-(3-iodophenyl)-N-methyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine (Example 101) (15 mg, 0.037 mmol), pyridin-4-ylboronic acid (4.60 mg, 0.037 mmol ₎ , _K₃PO₄ (7.94 mg, 0.037 mmol), Pd(OAc) _₂ (8.39 mg, 0.037 mmol), and tricyclohexylphosphine (10.48 mg, 0.037 mmol) in dioxane/water (0.2 mL) was heated at 100 °C for 1 hour. The reaction mixture was subjected to solid-phase extraction using a Bond Elut SCX box (Agilent) (washed with MeOH, then eluted with _NH₃ in MeOH), and the collected fraction was concentrated under vacuum. The residue was purified by column chromatography (Si-column, _CHCl3 :MeOH = 10:0-9:1) to provide the desired product: ^¹H NMR ( _CDCl3 ) δ 8.99 (s, 1H), 8.80–8.73 (m, 1H), 8.68–8.58 (m, 2H), 7.91–7.81 (m, 1H), 7.68 (ddd, J = 8.4, 7.3, 1.3 Hz, 1H), 7.57–7.52 (m, 2H), 7.46–7.34 (m, 3H), 7.26 (d, J = 7.7 Hz, 1H), 7.16 (ddd, J = 8.5, 7.3, 1.2 Hz, 1H), 3.74 (s, 3H); LCMS (m/z) 353.3 [M+H]+.

Example 128. N-([1,1'-diphenyl]-3-yl)-8-bromo-N-methyl-[1,2,4]triazolo[4,3-a]quinazole 5-Lin-amine

(Step 1) Synthesis of N-(diphenyl-3-yl)-7-bromo-2-chloro-N-methylquinazoline-4-amine

Add N-methyldiphenyl-4-amine (183 mg, 0.999 mmol) and sodium hydride (23.96 mg, 0.999 mmol) to a solution of 7-bromo-2,4-dichloroquinazoline (291 mg, 1.049 mmol) in DMF ( ₅ mL). Stir the mixture at room temperature for 1 hour. Dilute the reaction mixture with AcOEt, wash continuously with water and brine, and dry over _Na₂SO₄ . Concentrate the organic layer under vacuum. Use the residue for the next step without further purification. LCMS (m/z) 424.13 [M+H] ^⁺ .

(Step 2) Synthesis of N-(diphenyl-3-yl)-7-bromo-2-hydrazino-N-methylquinazoline-4-amine

A mixture of N-(diphenyl-3-yl)-7-bromo-2-chloro-N-methylquinazoline-4-amine (310 mg, crude) and hydrazine hydrate (73.1 mg, 1.460 mmol) in EtOH (3.6 mL) was stirred at 50 °C for 3 hours. The reaction mixture was diluted with AcOEt and washed continuously with water and brine. The organic layer was concentrated under vacuum. The residue was used in the next step without further purification. LCMS (m/z) 420.18 [M+H] ⁺ .

(Step 3) N-([1,1'-diphenyl]-3-yl)-8-bromo-N-methyl-[1,2,4]triazolo[4,3-a]quinazolin- Synthesis of 5-amines

A mixture of N-(diphenyl-3-yl)-7-bromo-2-hydrazino-N-methylquinazoline-4-amine (256 mg, crude) and triethoxymethane (89 mg, 0.603 mmol) was heated to 100 °C for 2 hours. The reaction mixture was then concentrated under vacuum. The residue was purified by column chromatography (Si-column, _CHCl3 :MeOH = 10:0-9:1) to provide the desired product: ^¹H NMR ( _CDCl3 ) δ 8.91 (s, 1H), 7.98 (dd, J = 1.6, 0.7 Hz, 1H), 7.54–7.36 (m, 8H), 7.28–7.24 (m, 2H), 7.14 (ddd, J = 7.8, 2.2, 1.1 Hz, 1H), 3.71 (s, 3H); LCMS (m/z) 432.2/433.2 [M+H]+.

Example 129. 3-([1,2,4]triazolo[4,3-a]quinazolin-5-yl(methyl)amino)benzamide

(Step 1) Synthesis of 3-([1,2,4]triazolo[4,3-a]quinazolin-5-yl(methyl)amino)benzoic acid

Lithium hydroxide monohydrate (0.025 g, 0.58 mmol) was added to a stirred solution of methyl 3-([1,2,4]triazolo[4,3-a]quinazolin-5-yl(methyl)amino)benzoate (Example 103) (0.065 g, 0.19 mmol) in THF/water (4 mL, 1:1) at room temperature, and the mixture was stirred at room temperature for 16 hours. The reaction progress was monitored by TLC. After the reaction was complete, the reaction mixture was evaporated under reduced pressure, and the residue was acidified with dilute HCl and evaporated under reduced pressure. The residue was purified by preparative HPLC to give the desired product. LCMS: 320.19 (M+H).

(Step 2) Synthesis of 3-([1,2,4]triazolo[4,3-a]quinazolin-5-yl(methyl)amino)benzamide

At room temperature, 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,3-a]quinazolin-5-yl(methyl)amino)benzoic acid (0.040 g, 0.12 mmol) and N,N-diisopropylethylamine (0.043 mL, 0.25 mmol) were added to a stirred solution of 3-([1,2,4]triazolo[4,5-b]pyridinium 3-oxyhexafluorophosphate (0.095 g, 0.25 mmol) in DMF (1 mL), followed by the addition of a 7N ammonia solution in methanol (12 mL) at 0 °C. The mixture was stirred at room temperature for 16 hours. The reaction progress was monitored by TLC. After the reaction was complete, the reaction mixture was evaporated under reduced pressure. The residue was purified by preparative HPLC to provide the desired product: ^¹H NMR (DMSO- _d₆ ) δ 9.65 (s, ¹H), 8.47–8.23 (m, ¹H), 7.92 (brs, ¹H), 7.83–7.70 (m, ³H), 7.47–7.44 (m, ²H), 7.38 (brs, ¹H), 7.29–7.19 (m, ²H), 3.57 (s, ³H); LCMS (m/z) 319.3 [M+H]+.

Example 130. (5-(methyl(phenyl)amino)-[1,2,4]triazolo[4,3-a]quinazolin-7-yl)methanol

(Step 1) Synthesis of N-methyl-N-phenyl-7-vinyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine

4,4,5,5-Tetramethyl-2-vinyl-1,3,2-dioxaborhexacyclopentane (0.48 mL, 2.82 mmol) was added to a stirred solution of 7-bromo-N-methyl-N-phenyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine (0.5 g, 1.41 mmol) in n-butanol (10 mL) at room temperature, and the mixture was deoxygenated with argon for 10 min. Potassium tert-butoxide (0.475 g, 4.23 mmol) and tetrakis(triphenylphosphine)palladium(0) (0.325 g, 0.28 mmol) were then added at room temperature. The mixture was then stirred at 80 °C for 2 h. The reaction mixture was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography, eluting with 5% methanol/dichloromethane to give the desired product. LCMS (m/z) 302.21 [M+H] ⁺ .

(Step 2) Synthesis of 5-(methyl(phenyl)amino)-[1,2,4]triazolo[4,3-a]quinazolin-7-carboxaldehyde

Sodium periodate (0.426 g, 1.99 mmol) and potassium osmium tetroxide (VI) dihydrate (0.122 g, 0.33 mmol) were added to a solution of N-methyl-N-phenyl-7-vinyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine (0.5 g, 1.66 mmol) in acetonitrile/water (15 mL, 2:1) at 0 °C, and the mixture was stirred at room temperature for 16 hours. The reaction mixture was evaporated under reduced pressure, and the residue was diluted with water and extracted with ethyl acetate. The organic layer was washed continuously with water and brine, dried over _Na₂SO₄ , filtered, and evaporated under reduced pressure to give the desired product. _LCMS (m/z) 304.12 [M+H] ^⁺ .

(Step 3) Synthesis of (5-(methyl(phenyl)amino)-[1,2,4]triazolo[4,3-a]quinazolin-7-yl)methanol

Sodium borohydride (0.120 g, 3.17 mmol) was added to a stirred solution of 5-(methyl(phenyl)amino)-[1,2,4]triazolo[4,3-a]quinazolin-7-carboxaldehyde (crude, 0.480 g, 1.58 mmol) in MeOH (10 mL) at 0 °C, and the mixture was stirred at room temperature for 3 hours. The reaction mixture was quenched with cold water and extracted with dichloromethane. The organic layer was washed continuously with water and brine, dried over _Na₂SO₄ , filtered _, and evaporated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with 5% methanol/dichloromethane, to provide the desired product: ^¹H NMR (DMSO- _d₆ ) δ 9.58 (s, 1H), 8.24 (d, J = 8.5 Hz, 1H), 7.70 (dd, J = 8.5, 1.8 Hz, 1H), 7.44–7.34 (m, 2H), 7.32–7.17 (m, 4H), 5.13 (t, J = 5.5 Hz, 1H), 4.22 (d, J = 5.5 Hz, 2H), 3.55 (s, 3H); LCMS (m/z) 306.1 [M+H]+.

Example 131. N5-methyl-N5-phenyl-[1,2,4]triazolo[4,3-a]quinazolin-5,7-diamine

Pd/C (0.04 g) was added to a solution of N-methyl-7-nitro-N-phenyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine (Example 124) (0.2 g, 0.62 mmol) in MeOH (10 mL) at room temperature, and the mixture was stirred for 3 hours under a H2 atmosphere. The reaction mixture was filtered through a diatomaceous earth bed and washed with methanol. The filtrate was evaporated under reduced pressure, and the residue was purified by preparative HPLC to provide the desired product: ^¹H NMR (DMSO- _d₆ ) δ 9.44 (s, ¹H), 7.98 (d, J = 8.8 Hz, ¹H), 7.46–7.27 (m, 2H), 7.28–7.11 (m, 3H), 7.01 (dd, J = 8.8, 2.4 Hz, 1H), 6.42 (d, J = 2.4 Hz, 1H), 5.29 (s, 2H), 3.49 (s, 3H); LCMS (m/z) 291.1 [M+H]+.

Example 132. N-(5-(methyl(phenyl)amino)-[1,2,4]triazolo[4,3-a]quinazolin-7-yl)methane sulfonamide

Triethylamine (0.058 mL, 0.41 mmol) and methanesulfonyl chloride (0.032 mL, 0.41 mmol) were added to a stirred solution of N5-methyl-N5-phenyl-[1,2,4]triazolo[4,3-a]quinazoline-5,7-diamine (Example 131) (0.08 g, 0.27 mmol) in 5 mL of THF at 0 °C, and the mixture was stirred at room temperature for 24 hours. The reaction was quenched with water and extracted with ethyl acetate. The organic layer was washed continuously with water and brine, dried over _Na₂SO₄ , filtered _, and evaporated under reduced pressure. The residue was subjected to preparative HPLC to provide the desired product: ^¹H NMR (DMSO- _d₆ ) δ 9.94 (brs, ¹H), 9.57 (s, ¹H), 8.26 (d, J = 8.9 Hz, ¹H), 7.49 (dd, J = 8.9, 2.4 Hz, ¹H), 7.40–7.34 (m, 2H), 7.30 (d, J = 2.4 Hz, 1H), 7.28–7.23 (m, 2H), 7.24–7.19 (m, 1H), 3.52 (s, 3H), 2.50 (s, 3H); LCMS (m/z) 369.1 [M+H]+.

Example 133. N-(2'-fluoro-[1,1'-diphenyl]-3-yl)-N-methyl-[1,2,4]triazolo[4,3-a]quinoline Azoline-5-amine

A mixture of N-(3-iodophenyl)-N-methyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine (Example 101) (15 mg, 0.037 mmol), K3PO4 (15.87 mg, 0.075 mmol), Pd(OAc) ₂ (1.679 mg, 7.48 μmol), tricyclohexylphosphine (2.097 mg, 7.48 μmol), and (1H-pyrazol-4-yl)boronic acid (6.28 mg, 0.056 mmol) in dioxane/water (0.20 mL) was heated at 100 °C for 1 hour. The reaction mixture was subjected to solid-phase extraction using a Bond Elut SCX box (Agilent) (washed with MeOH, then eluted with _NH3 in MeOH), and the collected fractions were concentrated under vacuum. The residue was purified by column chromatography (Si-column, _CHCl3 :MeOH = 10:0-9:1) to provide the desired product: ^¹H NMR ( _CDCl3 ) δ 8.96 (s, 1H), 7.82 (dd, J = 8.3, 1.1 Hz, 1H), 7.66 (ddd, J = 8.3, 7.3, 1.1 Hz, 1H), 7.46–7.40 (m, 3H), 7.35–7.28 (m, 3H), 7.20–7.08 (m, 4H), 3.72 (s, 3H); LCMS (m/z) 370.3 [M+H]+.

Example 134. N-(4'-methoxy-[1,1'-diphenyl]-3-yl)-N-methyl-[1,2,4]triazolo[4,3- a] Quinazoline-5-amine

A mixture of N-(3-iodophenyl)-N-methyl-[ _1,2,4 ]triazolo[4,3-a]quinazolin-5-amine (Example 101) (15 mg, 0.037 mmol), _K₃PO₄ (15.87 mg, 0.075 mmol), Pd(OAc) _₂ (1.679 mg, 0.0075 mmol), tricyclohexylphosphine (2.097 mg, 0.0075 mmol), and (4-methoxyphenyl)boronic acid (8.52 mg, 0.056 mmol) in dioxane/water (0.2 mL) was heated at 100 °C for 1 hour. The reaction mixture was subjected to solid-phase extraction using a Bond Elut SCX box (Agilent) (washed with MeOH, then eluted with _NH₃ in MeOH), and the collected fraction was concentrated under vacuum. The residue was purified by column chromatography (Si-column, _CHCl3 :MeOH = 10:0-9:1) to provide the desired product: ^¹H NMR ( _CDCl3 ) δ 8.95 (s, 1H), 7.88–7.77 (m, 1H), 7.64 (ddd, J = 8.4, 7.3, 1.3 Hz, 1H), 7.47–7.39 (m, 5H), 7.33 (t, J = 1.9 Hz, 1H), 7.19–7.08 (m, 2H), 7.01–6.85 (m, 2H), 3.83 (s, 3H), 3.72 (s, 3H); LCMS (m/z) 382.3 [M+H]+.

Example 135. N-(3'-methoxy-[1,1'-diphenyl]-3-yl)-N-methyl-[1,2,4]triazolo[4,3- a]quinazolin-5-amine

A mixture of N-(3-iodophenyl)-N-methyl-[ _1,2,4 ]triazolo[4,3-a]quinazolin-5-amine (Example 101) (15 mg, 0.037 mmol), _K₃PO₄ (15.87 mg, 0.075 mmol), Pd(OAc) _₂ (1.679 mg, 0.0075 mmol), tricyclohexylphosphine (2.097 mg, 0.0075 mmol), and pyrimidine-5-ylboronic acid (6.95 mg, 0.056 mmol) in dioxane/water (0.20 mL) was heated at 100 °C for 1 hour. The reaction mixture was subjected to solid-phase extraction using a Bond Elut SCX box (Agilent) (washed with MeOH, then eluted with _NH₃ in MeOH), and the collected fraction was concentrated under vacuum. The residue was purified by column chromatography (Si-column, _CHCl3 :MeOH = 10:0-9:1) to provide the desired product: ^¹H NMR (methanol- _d4) )δ9.40(s,1H),8.13(dd,J＝8.3,1.2Hz,1H),7.72(ddd,J＝8.3,7.2,1.2Hz,1H), 7.58–7.46(m,3H),7.37(dd,J＝8.5,1.4Hz,1H),7.33–7.20(m,2H),7.17(ddd,J＝ 8.5,7.2,1.2Hz,1H),7.07(dt,J＝7.7,1.3Hz,1H),7.01(t,J＝2.1Hz,1H),6.87( ddd,J＝8.2,2.8,1.0Hz,1H),3.78(s,3H),3.70(s,3H); LCMS(m/z)382.3[M+H]+.

Example 136. 7-(methoxymethyl)-N-methyl-N-phenyl-[1,2,4]triazolo[4,3-a]quinazolin-5- amine

60% sodium hydride (0.023 g, 0.59 mmol) was added to a stirred solution of (5-(methyl(phenyl)amino)-[1,2,4]triazolo[4,3-a]quinazolin-7-yl)methanol (Example 130) (0.150 g, 0.49 mmol) in DMF (5 mL) at 0 °C, and the mixture was stirred at room temperature for 10 min. Iodimethane (0.036 mL, 0.59 mmol) was then added at 0 °C, and the mixture was stirred at room temperature for 16 h. The reaction mixture was quenched with cold water and extracted with ethyl acetate. The organic layer was washed continuously with water and brine, dried over _Na₂SO₄ , filtered _, and evaporated under reduced pressure. The residue was purified by preparative HPLC to provide the desired product: ^¹H NMR (DMSO- _d₆ ) δ 9.60 (s, ¹H), 8.27 (d, J = 8.5 Hz, ¹H), 7.69 (dd, J = 8.5, 1.8 Hz, ¹H), 7.42–7.37 (m, 2H), 7.33–7.29 (m, 2H), 7.28–7.24 (m, 1H), 7.20 (d, J = 1.8 Hz, 1H), 4.17 (s, 2H), 3.55 (s, 3H), 2.95 (s, 3H); LCMS (m/z) 320.4 [M+H]+.

Example 137. N-Methyl-N-(3-(pyridin-3-yl)phenyl)-[1,2,4]triazolo[4,3-a]quinazolin-5- amine

A mixture of N-(3-iodophenyl)-N-methyl-[ _1,2,4 ]triazolo[4,3-a]quinazolin-5-amine (Example 101) (15 mg, 0.037 mmol), _K₃PO₄ (15.87 mg, 0.075 mmol), Pd(OAc) _₂ (1.679 mg, 0.0075 mmol), tricyclohexylphosphine (2.097 mg, 0.0075 mmol), and pyrimidine-5-ylboronic acid (6.95 mg, 0.056 mmol) in dioxane/water (0.2 mL) was heated at 100 °C for 1 hour. The reaction mixture was subjected to solid-phase extraction using a Bond Elut SCX box (Agilent) (washed with MeOH, then eluted with NH₃ in MeOH), and the collected fraction was concentrated under vacuum. The residue was purified by column chromatography (Si-column, _CHCl3 :MeOH = 10:0-9:1) to provide the desired product: ^¹H NMR ( _CDCl3 ) δ 8.97 (s, ¹H), 8.70 (dd, J = 2.4, 0.9 Hz, ¹H), 8.58 (dd, J = 4.8, 1.6 Hz, ¹H), 7.84 (dd, J = 8.4, 1.1 Hz, ¹H), 7.77 (ddd, J = 7.9, 2.4, 1.6 Hz, ¹H), 7.67 (ddd, J = 8.4, 7.3, 1.3 Hz, ¹H) ,7.53–7.45(m,2H),7.41(dd,J＝8.4,1.3Hz,1H),7.36–7.31(m,2H),7.22(dt,J＝7.0, 2.2Hz, 1H), 7.15 (ddd, J=8.5, 7.2, 1.2Hz, 1H), 3.73 (s, 3H); LCMS (m/z) 353.3[M+H]+.

Example 138. N-(3-(1H-pyrazol-4-yl)phenyl)-N-methyl-[1,2,4]triazolo[4,3-a]quinazolin- 5-amine

A mixture of N-(3-iodophenyl)-N-methyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine (Example 101) (15 mg, 0.037 mmol), K3PO4 (15.87 mg, 0.075 mmol), Pd(OAc) ₂ (1.679 mg, 0.0075 mmol), tricyclohexylphosphine (2.097 mg, 0.0075 mmol), and (1H-pyrazol-4-yl)boronic acid (6.28 mg, 0.056 mmol) in dioxane/water (0.2 mL) was heated at 100 °C for 1 hour. The reaction mixture was subjected to solid-phase extraction using a Bond Elut SCX box (Agilent) (washed with MeOH, then eluted with _NH3 in MeOH), and the collected fractions were concentrated under vacuum. The residue was purified by column chromatography (Si-column, _CHCl3 :MeOH = 10:0-9:1) to provide the desired product: ^¹H NMR ( _CDCl3 ) δ 8.96 (s, 1H), 7.90–7.74 (m, 3H), 7.65 (ddd, J = 8.4, 7.3, 1.3 Hz, 1H), 7.47–7.41 (m, 2H), 7.39 (dd, J = 7.7, 0.5 Hz, 1H), 7.31 (dd, J = 2.2, 1.5 Hz, 1H), 7.14 (ddd, J = 8.5, 7.3, 1.2 Hz, 1H), 7.03 (ddd, J = 7.7, 2.2, 1.2 Hz, 1H), 3.70 (s, 3H); LCMS (m/z) 342.3 [M+H]+.

Example 139. (5-(methyl(phenyl)amino)-[1,2,4]triazolo[4,3-a]quinazolin-8-yl)methanol

To a solution of 5-(methyl(phenyl)amino)-[1,2,4]triazolo[4,3-a]quinazolin-8-carboxaldehyde (Example 117) (89 mg, 0.293 mmol) in MeOH (1.48 mL), _NaBH₄ (22.20 mg, 0.587 mmol) was added, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was subjected to solid-phase extraction using a Bond Elut SCX box (Agilent) (washing with MeOH followed by elution with _NH₃ in MeOH), and the collected fraction was concentrated under vacuum. The residue was purified by column chromatography (Si-column, _CHCl3 :MeOH = 10:0-9:1) to provide the desired product: ^¹H NMR (methanol- _d4 ) δ 9.44 (s, 1H), 8.14 (d, J = 1.5 Hz, 1H), 7.48–7.36 (m, 2H), 7.36–7.25 (m, 4H), 7.19–7.07 (m, 1H), 4.73 (s, 2H), 3.65 (s, 3H); LCMS (m/z) 306.2 [M+H]+.

Example 140. N-Methyl-N-(3-(1-methyl-1H-pyrazole-4-yl)phenyl)-[1,2,4]triazolo[4,3-a] Quinazoline-5-amine

A mixture of N-(3-iodophenyl)-N-methyl-[ _1,2,4 ]triazolo[4,3-a]quinazolin-5-amine (Example 101) (15 mg, 0.037 mmol), _K3PO4 (15.87 mg, 0.075 mmol), Pd(OAc) ₂ (1.679 mg, 0.0075 mmol), tricyclohexylphosphine (2.097 mg, 0.0075 mmol) and 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborhexacyclopentan-2-yl)-1H-pyrazole (11.67 mg, 0.056 mmol) in dioxane/water (0.20 ml) was heated at 100 °C for 1 hour. The reaction mixture was subjected to solid-phase extraction using a Bond Elut SCX box (Agilent) (washing with MeOH followed by elution with _NH₃ in MeOH), and the collected fractions were concentrated under vacuum. The residue was purified by column chromatography (Si-column, _CHCl₃ :MeOH = 10:0–9:1) to provide the desired product: ^¹H NMR (CDCl₃ ₎ )δ8.95(s,1H),7.81(dd,J＝8.3,1.2Hz,1H),7.69(d,J＝0.8Hz,1H),7.64(ddd,J＝8.4,7.3,1.3Hz,1H),7.56(dd,J＝13.9,0.8Hz,2H), 7.43–7.40(m,2H),7.37–7.36(m,1H),7.25(m,1H),7.01(dt,J=6.8,2.1Hz,1H),3.91(s,3H),3.68(s,3H); LCMS(m/z)356.3[M+H]+.

Example 141. N-methyl-N-(3-(thiophen-3-yl)phenyl)-[1,2,4]triazolo[4,3-a]quinazolin-5- amine

A mixture of N-(3-iodophenyl)-N-methyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine (Example 101) (15 mg, 0.037 mmol), K3PO4 (15.87 mg, 0.075 mmol), tricyclohexylphosphine (2.097 mg, 0.0075 mmol), Pd(OAc) ₂ (1.679 mg, 0.0075 mmol), and thiophene-3-ylboronic acid (7.18 mg, 0.056 mmol) in dioxane/water (0.2 mL) was heated at 100 °C for 1 hour. The reaction mixture was subjected to solid-phase extraction using a Bond Elut SCX box (Agilent) (washed with MeOH, then eluted with _NH3 in MeOH), and the collected fractions were concentrated under vacuum. The residue was purified by column chromatography (Si-column, _CHCl3 :MeOH = 10:0-9:1) to provide the desired product: ^¹H NMR ( _CDCl3 ) δ 8.96 (s, 1H), 7.85–7.79 (m, 1H), 7.64 (ddd, J = 8.4, 7.3, 1.3 Hz, 1H), 7.50 (ddd, J = 7.7, 1.7, 1.0 Hz, 1H), 7.45–7.35 (m, 5H), 7.30 (dd, J = 5.0, 1.3 Hz, 1H), 7.12 (ddd, J = 8.4, 7.3, 1.3 Hz, 1H), 7.07 (ddd, J = 7.9, 2.2, 1.0 Hz, 1H), 3.70 (s, 3H); LCMS (m/z) 358.2 [M+H]+.

Example 142. Methyl 5-(methyl(phenyl)amino)-[1,2,4]triazolo[4,3-a]quinazolin-7-carboxylate

(Step 1) Synthesis of 5-(methyl(phenyl)amino)-[1,2,4]triazolo[4,3-a]quinazolin-7-carboxylic acid

Potassium persulfate (oxone) (0.405 g, 1.32 mmol) was added to a stirred solution of 5-(methyl(phenyl)amino)-[1,2,4]triazolo[4,3-a]quinazolin-7-carboxaldehyde (0.2 g, 0.66 mmol) in DMF (6 mL), and the mixture was stirred at room temperature for 16 hours. The reaction mixture was quenched with cold water and extracted with ethyl acetate. The organic layer was washed continuously with water and brine, dried over _Na₂SO₄ , filtered, and evaporated under reduced pressure. The residue was purified by preparative HPLC to give the desired product. _LC -MS: 320.23 (M+H).

(Step 2) Synthesis of methyl 5-(methyl(phenyl)amino)-[1,2,4]triazolo[4,3-a]quinazolin-7-carboxylate

At room temperature, 4N HCl in MeOH (1 mL) was added to a solution of 5-(methyl(phenyl)amino)-[1,2,4]triazolo[4,3-a]quinazolin-7-carboxylic acid (0.15 g, 0.47 mmol) in MeOH (6 mL), and the mixture was stirred at 80 °C for 3 hours. The reaction mixture was evaporated under reduced pressure, and the residue was passed through preparative HPLC to provide the desired product: ^¹H -NMR (DMSO- _d₆ ) δ 9.65 (s, ¹H), 8.37 (d, J = 8.7 Hz, ¹H), 8.23 (dd, J = 8.7, 1.8 Hz, ¹H), 7.89 (d, J = 1.8 Hz, ¹H), 7.47–7.39 (m, 2H), 7.38–7.28 (m, 3H), 3.71 (s, 3H), 3.57 (s, 3H); LCMS (m/z) 334.3 [M+H]+.

Example 143. 6-Bromo-N-methyl-N-phenyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine

(Step 1) Synthesis of 5-bromoquinazoline-2,4(1H,3H)-dione

A mixture of 2-amino-6-bromobenzoic acid (5 g, 23.14 mmol) and urea (13.88 g, 231.37 mmol) was heated to 150 °C for 16 hours. The reaction mixture was diluted with ice water and stirred for 30 minutes. The resulting solid was collected, ground with glacial acetic acid, washed with water, and dried under vacuum to give the desired product. LCMS (m/z) 241.02 [M+H] ⁺ .

(Step 2) Synthesis of 5-bromo-2,4-difluoroquinazoline

N,N-diisopropylethylamine (3.48 mL, 19.99 mmol) was added to a stirred solution of 5-bromoquinazolin-2,4(1H,3H)-dione (crude, 3.2 g, 13.33 mmol) in phosphorus oxychloride (13 mL, 133.33 mmol) at 0 °C, and the mixture was stirred at 110 °C for 3 hours. The reaction mixture was diluted with ice water and stirred for 30 minutes. The resulting solid was filtered, washed with water, and dried under vacuum to give the desired product. LCMS (m/z) 277.11 [M+H] ⁺ .

(Step 3) Synthesis of 5-bromo-2-chloro-N-methyl-N-phenylquinazoline-4-amine

Sodium hydroxide (0.333 g, 8.33 mmol) was added to a stirred solution of N-methylaniline (0.892 g, 8.33 mmol) in DMF (25 mL) at 0 °C, and the mixture was stirred at room temperature for 1 hour. Then, 5-bromo-2,4-dichloroquinazoline (crude product, 2.3 g, 8.33 mmol) was added at 0 °C. The mixture was then stirred at room temperature for 2 hours. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed continuously with water and brine, dried over _Na₂SO₄ , filtered, and evaporated under reduced pressure to give the desired product. _LCMS (m/z) 348.15 [M+H] ^⁺ .

(Step 4) Synthesis of 5-bromo-2-hydrazino-N-methyl-N-phenylquinazoline-4-amine

Hydrazine hydrate (0.14 mL g, 2.87 mmol) was added to a stirred solution of 5-bromo-2-chloro-N-methyl-N-phenylquinazoline-4-amine (0.5 g, 1.44 mmol) in EtOH (6 mL) at room temperature, and the mixture was stirred at room temperature for 6 hours. The reaction mixture was evaporated under reduced pressure to give the desired product. LCMS (m/z) 344.36 [M+H] ⁺ .

(Step 5) Synthesis of 6-bromo-N-methyl-N-phenyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine

A mixture of 5-bromo-2-hydrazino-N-methyl-N-phenylquinazoline-4-amine (0.5 g, 1.45 mmol) and triethyl orthoformate (1.45 mL, 8.72 mmol) was stirred at 100 °C for 16 hours. The reaction mixture was diluted with diethyl ether and filtered. The filtrate was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography, eluted with 5% methanol/dichloromethane, and further purified by preparative HPLC to provide the desired product: ^¹H -NMR (DMSO- _d₆ ) δ 9.70 (s, 1H), 8.38 (dd, J = 8.3, 1.2 Hz, 1H), 7.75 (t, J = 8.0 Hz, 1H), 7.67 (dd, J = 8.0, 1.2 Hz, 1H), 7.24–7.12 (m, 2H), 7.07–6.91 (m, 3H), 3.51 (s, 3H); LCMS (m/z) 354.27/356.25 [M+H]+.

Example 144. 8-(methoxymethyl)-N-methyl-N-phenyl-[1,2,4]triazolo[4,3-a]quinazolin-5- amine

Iodimethane (8.37 mg, 0.059 mmol) and sodium hydride (1.415 mg, 0.059 mmol) were added to a solution of (5-(methyl(phenyl)amino)-[1,2,4]triazolo[4,3-a]quinazolin-8-yl)methanol (Example 139) (15 mg, 0.049 mmol) in DMF (0.25 mL), and the mixture was stirred at room temperature for 3 hours. The reaction mixture was diluted with AcOEt and washed continuously with water and brine. The organic layer was concentrated under vacuum and purified by preparative HPLC to provide the desired product: ^¹H NMR (methanol- _d⁴ ) δ 9.46 (s, ¹H), 8.16–8.14 (m, ¹H), 7.46–7.40 (m, 2H), 7.35–7.31 (m, ¹H), 7.30–7.26 (m, 3H), 7.17–7.06 (m, ¹H), 4.57 (m, 2H), 3.66 (s, 3H), 3.43 (s, 3H); LCMS (m/z) 320.2 [M+H]+.

Example 145. N-Methyl-N-(3-(pyrimidin-5-yl)phenyl)-[1,2,4]triazolo[4,3-a]quinazolin-5- amine

A mixture of N-(3-iodophenyl)-N-methyl-[ _1,2,4 ]triazolo[4,3-a]quinazolin-5-amine (Example 101) (15 mg, 0.037 mmol), _K₃PO₄ (15.87 mg, 0.075 mmol), Pd(OAc) _₂ (1.679 mg, 0.0075 mmol), tricyclohexylphosphine (2.097 mg, 0.0075 mmol), and pyrimidine-5-ylboronic acid (6.95 mg, 0.056 mmol) in dioxane/water (0.2 mL) was heated at 100 °C for 1 hour. The reaction mixture was subjected to solid-phase extraction using a Bond Elut SCX box (Agilent) (washed with MeOH, then eluted with _NH₃ in MeOH), and the collected fractions were concentrated under vacuum. The residue was purified by column chromatography (Si-column, _CHCl3 :MeOH = 10:0-9:1) to provide the desired product: ^¹H NMR (CDCl3 ₎ )δ8.81(s,1H),7.76–7.68(m,1H),7.66(t,J＝1.9Hz,1H),7.60(ddd,J＝8.4,7.3,1.3Hz,1H),7.49(ddd,J＝7.9,1.9,1.0Hz,1H),7.45–7.34(m,2 H),7.12–7.02(m,2H),6.80(td,J＝2.7,1.5Hz,1H),6.55(ddd,J＝3.9,2.6,1.5Hz,1H),6.30–6.19(m,1H),3.61(s,3H); LCMS(m/z)354.3[M+H]+.

Example 146. N-(3-(1H-pyrrolo-2-yl)phenyl)-N-methyl-[1,2,4]triazolo[4,3-a]quinazolin- 5-amine

A mixture of N-(3-iodophenyl)-N-methyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine (Example 101) (15 mg, 0.037 mmol), K3PO4 (15.87 mg, 0.075 mmol), Pd(OAc) ₂ (1.679 mg, 0.0075 mmol), tricyclohexylphosphine (2.097 mg, 0.0075 mmol), and (1-(tert-butoxycarbonyl)-1H-pyrrole-2-yl)boronic acid (11.83 mg, 0.056 mmol) in dioxane/water (0.2 mL) was treated in a microwave reactor at 100 °C for 1 hour. The reaction mixture was subjected to solid-phase extraction using a Bond Elut SCX box (Agilent) (washed with MeOH, then eluted with _NH3 in MeOH), and the collected fractions were concentrated under vacuum. The residue was purified by column chromatography (Si-column, _CHCl3 :MeOH = 10:0-9:1) to provide the desired product: ^¹H NMR ( _CDCl3 ) δ 10.56 (s, 1H), 8.77 (s, 1H), 7.77 (t, J = 1.9 Hz, 1H), 7.69 (dd, J = 8.3, 1.2 Hz, 1H), 7.59 (ddd, J = 8.4, 7.2, 1.3 Hz, 1H), 7.51 (ddd, J = 7.9, 1.8, 1.1 Hz, 1H), 7.41 (t, J = 7.9 Hz, 1H), 7. 36(dd,J＝8.5,1.2Hz,1H),7.13–7.04(m,2H),6.78(td,J＝2.7,1.5Hz,1H),6.56(ddd,J＝ 3.9, 2.7, 1.4Hz, 1H), 6.21 (dt, J＝3.5, 2.5Hz, 1H), 3.59 (s, 3H); LCMS (m/z) 341.3[M+H]+.

Example 147. 3-([1,2,4]triazolo[4,3-a]quinazolin-5-yl(methyl)amino)benzyl nitrile

A mixture of N-(3-iodophenyl)-N-methyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine (Example 101) (20 mg, 0.050 mmol), zinc (II) cyanide (11.71 mg, 0.100 mmol), and Pd(PPh ₃ ) ₄ (11.52 mg, 0.010 mmol) in DMF (0.25 mL) was treated in a microwave reactor at 80 °C for 1 hour. Zinc (II) cyanide (11.71 mg, 0.100 mmol) and Pd(PPh ₃ ) ₄ (11.52 mg, 0.010 mmol) were then added and treated in a microwave reactor at 80 °C for 1 hour. The reaction mixture was subjected to solid-phase extraction using a Bond Elut SCX box (Agilent) (washed with MeOH, then eluted with NH ₃ in MeOH), and the collected fraction was concentrated under vacuum. The residue was then concentrated under vacuum. The residue was purified by column chromatography (Si-column, _CHCl3 :MeOH = 10:0-9:1) to provide the desired product: ^¹H NMR (methanol- _d4 ) δ 9.50 (s, 1H), 8.23 (dd, J = 8.5, 1.1 Hz, 1H), 7.85–7.75 (m, 1H), 7.77–7.69 (m, 1H), 7.63 (ddd, J = 6.2, 2.5, 1.4 Hz, 1H), 7.60–7.53 (m, 2H), 7.36 (dd, J = 8.5, 1.4 Hz, 1H), 7.28 (ddd, J = 8.4, 7.2, 1.2 Hz, 1H), 3.68 (s, 3H); LCMS (m/z) 301.2/302.2 [M+H]+.

Example 148. N-(2'-methoxy-[1,1'-diphenyl]-3-yl)-N-methyl-[1,2,4]triazolo[4,3- a] Quinazoline-5-amine

A mixture of N-(3-iodophenyl)-N-methyl-[ _1,2,4 ]triazolo[4,3-a]quinazolin-5-amine (Example 101) (15 mg, 0.037 mmol), _K₃PO₄ (15.87 mg, 0.075 mmol), Pd(OAc) _₂ (1.679 mg, 0.0075 mmol), tricyclohexylphosphine (2.097 mg, 0.0075 mmol), and (2-methoxyphenyl)boronic acid (8.52 mg, 0.056 mmol) in dioxane/water (0.2 mL) was heated at 100 °C for 1 hour. The reaction mixture was subjected to solid-phase extraction using a Bond Elut SCX box (Agilent) (washed with MeOH, then eluted with _NH₃ in MeOH), and the collected fraction was concentrated under vacuum. The residue was purified by column chromatography (Si-column, _CHCl3 :MeOH = 10:0-9:1) to provide the desired product: ^¹H NMR (CDCl3 ₎ )δ8.95(d,J＝0.8Hz,1H),7.82(dt,J＝8.0,0.8Hz,1H),7.66(ddd,J＝8.4,7.3,1.3Hz,1H),7.48–7.39(m,3H),7.34–7.27(m,2H),7.21(dd,J＝7. 5,1.8Hz,1H),7.19–7.12(m,2H),6.98(td,J＝7.5,1.1Hz,1H),6.92(dd,J＝8.3,1.1Hz,1H),3.71(s,3H),3.64(s,3H); LCMS(m/z)382.3[M+H]+.

Example 149. tert-Butyl(3-(5-(methyl(phenyl)amino)-[1,2,4]triazolo[4,3-a]quinazolin-8- propyl-2-yn-1-yl)carbamate

A mixture of 8-bromo-N-methyl-N-phenyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine (Example 28) (30 mg, 0.085 mmol), Pd(dppf) _₂Cl (12.39 mg, 0.017 mmol), triethylamine (25.7 mg, 0.254 mmol), tert-butyl propionate (26.3 mg, 0.169 mmol), and cuprous iodide (I) (3.23 mg, 0.017 mmol) in acetonitrile (0.42 mL) was treated in a microwave reactor at 80 °C for 2 hours. The reaction mixture was subjected to solid-phase extraction using a Bond ElutSCX box (Agilent) (washed with MeOH, then eluted with _NH₃ in MeOH), and the collected fractions were concentrated under vacuum. The filtrate was purified by preparative HPLC to provide the desired product: ^¹H NMR (methanol- _d⁴ ) δ 9.40 (s, ¹H), 8.24 (d, J = 1.5 Hz, ¹H), 7.50–7.37 (m, 2H), 7.37–7.30 (m, 1H), 7.30–7.19 (m, 3H), 7.13 (dd, J = 8.7, 1.5 Hz, 1H), 4.08 (s, 2H), 3.64 (s, 3H), 1.45 (s, 9H); LCMS (m/z) 429.4 [M+H]⁺.

Example 150. 8-(3-aminoprop-1-yn-1-yl)-N-methyl-N-phenyl-[1,2,4]triazolo[4,3-a] Quinazoline-5-amine

A mixture of (3-(5-(methyl(phenyl)amino)-[1,2,4]triazolo[4,3-a]quinazolin-8-yl)prop-2-yn-1-yl)carbamate (Example 149) (25 mg, 0.058 mmol) and TFA (5 mL) was stirred at room temperature for 3 hours, then stirred overnight at 50 °C. The reaction mixture was concentrated under vacuum. 4N HCl (5 mL) was added to the residue, and the solution was stirred at room temperature for 3 hours, then stirred overnight at 50 °C. The reaction mixture was concentrated under vacuum. The residue was purified by column chromatography (Si-column, CHCl3:MeOH = ₁₀ :0-9:1) to provide the desired product: ^¹H -NMR (methanol- _d4 ) δ 9.64 (s, 1H), 8.54 (d, J = 1.5 Hz, 1H), 7.58–7.52 (m, 3H), 7.49–7.42 (m, 2H), 7.35 (dd, J = 8.8, 1.5 Hz, 1H), 7.17 (d, J = 8.8 Hz, 1H), 4.12 (s, 2H), 3.80 (s, 3H); LCMS (m/z) 329.2 [M+H]+.

Example 151. N-Methyl-N-(4'-(trifluoromethyl)-[1,1'-diphenyl]-3-yl)-[1,2,4]triazolidine [4,3-a]quinazolin-5-amine

A mixture of N-(3-iodophenyl)-N-methyl-[ _1,2,4 ]triazolo[4,3-a]quinazolin-5-amine (Example 101) (15 mg, 0.037 mmol), _K₃PO₄ (15.87 mg, 0.075 mmol), Pd(OAc) _₂ (1.679 mg, 0.0075 mmol), tricyclohexylphosphine (2.097 mg, 0.0075 mmol), and (4-(trifluoromethyl)phenyl)boronic acid (10.65 mg, 0.056 mmol) in dioxane/water (0.2 mL) was heated at 100 °C for 1 hour. The reaction mixture was subjected to solid-phase extraction using a Bond Elut SCX box (Agilent) (washed with MeOH, then eluted with _NH₃ in MeOH), and the collected fraction was concentrated under vacuum. The residue was purified by column chromatography (Si-column, _CHCl3 :MeOH = 10:0-9:1) to provide the desired product: ^¹H NMR (methanol- _d4 ) δ 9.42 (s, 1H), 8.13 (dd, J = 8.5, 1.2 Hz, 1H), 7.76–7.66 (m, 5H), 7.66–7.58 (m, 2H), 7.53 (t, J = 7.8 Hz, 1H), 7.37 (dd, J = 8.5, 1.3 Hz, 1H), 7.30 (ddd, J = 7.9, 2.2, 1.0 Hz, 1H), 7.17 (ddd, J = 8.5, 7.3, 1.2 Hz, 1H), 3.71 (s, 3H); LCMS (m/z) 420.3 [M+H]+.

Example 152. N-Methyl-N-(4'-methyl-[1,1'-diphenyl]-3-yl)-[1,2,4]triazolo[4,3-a] Quinazoline-5-amine

A mixture of N-(3-iodophenyl)-N-methyl-[ _1,2,4 ]triazolo[4,3-a]quinazolin-5-amine (Example 101) (15 mg, 0.037 mmol), _K₃PO₄ (15.87 mg, 0.075 mmol), Pd(OAc) _₂ (1.679 mg, 0.0075 mmol), tricyclohexylphosphine (2.097 mg, 0.0075 mmol), and p-tolylboronic acid (7.62 mg, 0.056 mmol) in dioxane/water (0.2 mL) was heated to 100 °C for 1 hour. The reaction mixture was subjected to solid-phase extraction using a Bond Elut SCX box (Agilent) (washed with MeOH, then eluted with NH₃ in MeOH), and the collected fraction was concentrated under vacuum. The residue was purified by column chromatography (Si-column, _CHCl3 :MeOH = 10:0-9:1) to provide the desired product: ^¹H NMR (methanol- _d4 ) δ 9.40 (s, 1H), 8.19–8.08 (m, 1H), 7.70 (ddd, J = 8.5, 7.3, 1.3 Hz, 1H), 7.53 (ddd, J = 7.8, 1.8, 1.1 Hz, 1H), 7.50–7.42 (m, 2H), 7.42–7.31 (m, 3H), 7.19–7.16 (m, 3H), 7.15–7.12 (m, 1H), 3.68 (s, 3H), 2.32 (s, 3H); LCMS (m/z) 366.3 [M+H]+.

Example 153. N-(3'-fluoro-[1,1'-diphenyl]-3-yl)-N-methyl-[1,2,4]triazolo[4,3-a]quinoline Azoline-5-amine

A mixture of N-(3-iodophenyl)-N-methyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine (Example 101) (15 mg, 0.037 mmol), _{K₃PO₄ (} 15.87 mg, 0.075 mmol), Pd(OAc) _₂ (1.679 mg, 0.0075 mmol), tricyclohexylphosphine (2.097 mg, 0.0075 mmol), and (4-(trifluoromethyl)phenyl)boronic acid (10.65 mg, 0.056 mmol) in dioxane/water (0.2 mL) was heated at 100 °C for 1 hour. The reaction mixture was subjected to solid-phase extraction using a Bond Elut SCX box (Agilent) (washed with MeOH, then eluted with _NH₃ in MeOH), and the collected fraction was concentrated under vacuum. The residue was purified by column chromatography (Si-column, CHCl3:MeOH = ₁₀ :0-9:1) to provide the desired product: ^¹H -NMR (methanol- _d4 ) δ 9.45 (s, 1H), 8.24 (d, J = 8.6 Hz, 1H), 8.02 (dd, J = 8.6, 2.0 Hz, 1H), 7.58–7.51 (m, 3H), 7.48–7.41 (m, 1H), 7.40–7.31 (m, 3H), 7.06 (tdd, J = 8.5, 2.6, 0.9 Hz, 1H), 6.93 (dt, J = 7.8, 1.2 Hz, 1H), 6.76 (dt, J = 10.3, 2.1 Hz, 1H), 3.71 (s, 3H); LCMS (m/z) 370.3 [M+H]+.

Example 154. N8-(2-methoxyethyl)-N5-methyl-N5-phenyl-[1,2,4]triazolo[4,3-a]quinazole 5,8-Pyrin-5,8-Diamine

To a solution of 8-bromo-N-methyl-N-phenyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine (Example 28) (20 mg, 0.056 mmol) in acetonitrile (0.28 mL) _, 2-methoxyethyl-1-amine (4.24 mg, 0.056 mmol), _K₂CO₃ (7.80 mg, 0.056 mmol), Pd(dba) _₃ (0.056 mmol), and (9,9-dimethyl-9H-xanthon-4,5-diyl)bis(diphenylphosphine) (32.7 mg, 0.056 mmol) were added. The mixture was stirred at 80 °C for 2 hours. The reaction mixture was concentrated under vacuum. The residue was purified by column chromatography (Si-column, _CHCl3 :MeOH = 10:0-85:15) and further purified by preparative HPLC to provide the desired product: ^¹H NMR (methanol- _d4 ) δ 9.32 (s, 1H), 7.49–7.37 (m, 2H), 7.32–7.25 (m, 1H), 7.25–7.19 (m, 2H), 7.04 (t, J = 1.8 Hz, 1H), 7.01–6.89 (m, 1H), 6.40 (ddd, J = 9.3, 2.4, 0.7 Hz, 1H), 3.62–3.57 (m, 5H), 3.41 (t, J = 5.3 Hz, 2H), 3.37 (s, 3H); LCMS (m/z) 349.3 [M+H]+.

Example 155. 3'-([1,2,4]triazolo[4,3-a]quinazolin-5-yl(methyl)amino)-[1,1'-diphenyl ]-4-ol

A mixture of N-(3-iodophenyl)-N-methyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine (Example 101) (15 mg, 0.037 mmol), _K₃PO₄ (15.87 mg, 0.075 mmol), Pd(OAc _{)₂ (} 1.679 mg, 0.0075 mmol), tricyclohexylphosphine (2.097 mg, 0.0075 mmol), and (4-hydroxyphenyl)boronic acid (7.74 mg, 0.056 mmol) in dioxane/water (0.2 mL) was heated at 100 °C for 1 hour. The reaction mixture was subjected to solid-phase extraction using a Bond Elut SCX box (Agilent) (washed with MeOH, then eluted with _NH₃ in MeOH), and the collected fraction was concentrated under vacuum. The residue was purified by column chromatography (Si-column, _CHCl3 :MeOH = 10:0-9:1) to provide the desired product: ^¹H NMR (methanol- _d4 ) δ 9.44 (s, 1H), 8.18 (dd, J = 8.3, 1.1 Hz, 1H), 7.75 (ddd, J = 8.5, 7.3, 1.3 Hz, 1H), 7.52 (ddd, J = 7.8, 1.8, 1.1 Hz, 1H), 7.48–7.43 (m, 3H), 7.41–7.35 (m, 2H), 7.24–7.14 (m, 2H), 6.83–6.80 (m, 2H), 3.71 (s, 3H); LCMS (m/z) 368.3 [M+H]+.

Example 156. N-(4'-chloro-[1,1'-diphenyl]-3-yl)-N-methyl-[1,2,4]triazolo[4,3-a]quinoline Azoline-5-amine

A mixture of N-(3-iodophenyl)-N-methyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine (Example 101) (15 mg, 0.037 mmol), _K₃PO₄ (15.87 mg, 0.075 mmol), Pd(OAc _{)₂ (} 1.679 mg, 0.0075 mmol), tricyclohexylphosphine (2.097 mg, 0.0075 mmol), and (4-chlorophenyl)boronic acid (8.77 mg, 0.056 mmol) in dioxane/water (0.2 mL) was heated at 100 °C for 1 hour. The reaction mixture was subjected to solid-phase extraction using a Bond Elut SCX box (Agilent) (washed with MeOH, then eluted with _NH₃ in MeOH), and the collected fractions were concentrated under vacuum. The residue was purified by column chromatography (Si-column, _CHCl3 :MeOH = 10:0-9:1) to provide the desired product: ^¹H NMR (methanol- _d4 ) δ 9.44 (s, 1H), 8.26–8.08 (m, 1H), 7.75 (ddd, J = 8.5, 7.3, 1.3 Hz, 1H), 7.58 (ddd, J = 7.8, 1.8, 1.1 Hz, 1H), 7.56–7.48 (m, 4H), 7.44–7.34 (m, 3H), 7.28 (ddd, J = 7.9, 2.3, 1.1 Hz, 1H), 7.20 (ddd, J = 8.5, 7.3, 1.1 Hz, 1H), 3.71 (s, 3H); LCMS (m/z) 386.3 [M+H]+.

Example 157. 2-((5-(methyl(phenyl)amino)-[1,2,4]triazolo[4,3-a]quinazolin-8-yl)amino ethanol

To a solution of 8-bromo-N-methyl-N-phenyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine (Example 28) (20 mg, 0.056 mmol) in acetonitrile (0.42 mL), 2-aminoethanol (6.21 mg, 0.102 mmol), _K₂CO₃ (17.56 mg, 0.127 mmol) _, and Pd(dba) _₃ (0.085 mmol) were added. The mixture was stirred at 80 °C for 2 hours. The reaction mixture was concentrated under vacuum. The residue was purified by column chromatography (Si-column, _CHCl3 :MeOH = 10:0-85:15) and further purified by preparative HPLC to provide the desired product: ^¹H NMR (methanol- _d4 ) δ 9.31 (s, 1H), 7.43–7.37 (m, 2H), 7.30–7.25 (m, 1H), 7.25–7.20 (m, 2H), 7.02 (d, J = 2.3 Hz, 1H), 6.90 (d, J = 9.3 Hz, 1H), 6.39 (dd, J = 9.3, 2.3 Hz, 1H), 3.75 (t, J = 5.6 Hz, 2H), 3.59 (s, 3H), 3.37 (d, J = 5.6 Hz, 2H); LCMS (m/z) 335.3 [M+H]+.

Example 158. 3'-([1,2,4]triazolo[4,3-a]quinazolin-5-yl(methyl)amino)-[1,1'-diphenyl [2-ol]

A mixture of N-(3-iodophenyl)-N-methyl-[ _1,2,4 ]triazolo[4,3-a]quinazolin-5-amine (Example 101) (15 mg, 0.037 mmol), _K₃PO₄ (15.87 mg, 0.075 mmol), Pd(OAc) _₂ (1.679 mg, 0.0075 mmol), tricyclohexylphosphine (2.097 mg, 0.0075 mmol), and (2-hydroxyphenyl)boronic acid (7.74 mg, 0.056 mmol) in dioxane/water (0.2 mL) was heated at 100 °C for 1 hour. The reaction mixture was subjected to solid-phase extraction using a Bond Elut SCX box (Agilent) (washed with MeOH, then eluted with _NH₃ in MeOH), and the collected fraction was concentrated under vacuum. The residue was purified by column chromatography (Si-column, _CHCl3 :MeOH = 10:0-9:1) to provide the desired product: ^¹H NMR (methanol- _d4 ) δ 9.39 (s, 1H), 8.12 (dd, J = 8.4, 1.1 Hz, 1H), 7.72 (ddd, J = 8.4, 7.3, 1.3 Hz, 1H), 7.53–7.47 (m, 2H), 7.46–7.38 (m, 2H), 7.25–7.05 (m, 4H), 6.87–6.82 (m, 2H), 3.68 (s, 3H); LCMS (m/z) 368.3 [M+H]+.

Example 159. N-Methyl-N-(3-(1-methyl-1H-pyrazole-5-yl)phenyl)-[1,2,4]triazolo[4,3-a] Quinazoline-5-amine

A mixture of N-(3-iodophenyl)-N-methyl-[ _1,2,4 ]triazolo[4,3-a]quinazolin-5-amine (Example 101) (15 mg, 0.037 mmol), _K3PO4 (15.87 mg, 0.075 mmol), Pd(OAc) ₂ (1.679 mg, 0.0075 mmol), tricyclohexylphosphine (2.097 mg, 0.0075 mmol) and 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborhexacyclopentan-2-yl)-1H-pyrazole (11.67 mg, 0.056 mmol) in dioxane/water (0.2 mL) was heated at 100 °C for 1 hour. The reaction mixture was subjected to solid-phase extraction using a Bond Elut SCX box (Agilent) (washed with MeOH and then eluted with _NH3 in MeOH), and the collected fractions were concentrated under vacuum. The residue was purified by column chromatography (Si-column, _CHCl3 :MeOH = 10:0-9:1) to provide the desired product: ^¹H NMR (methanol- _d4 ) δ 9.44 (s, 1H), 8.24–8.10 (m, 1H), 7.76 (ddd, J = 8.5, 7.3, 1.3 Hz, 1H), 7.59–7.55 (m, 1H), 7.45–7.39 (m, 4H), 7.33 (t, J = 1.9 Hz, 1H), 7.24 (ddd, J = 8.6, 7.3, 1.3 Hz, 1H), 6.32 (d, J = 2.0 Hz, 1H), 3.71 (s, 3H), 3.62 (s, 3H); LCMS (m/z) 356.3 [M+H]+.

Example 160. N-Methyl-N-(2'-methyl-[1,1'-diphenyl]-3-yl)-[1,2,4]triazolo[4,3-a] Quinazoline-5-amine

A mixture of N-(3-iodophenyl)-N-methyl-[ _1,2,4 ]triazolo[4,3-a]quinazolin-5-amine (Example 101) (15 mg, 0.037 mmol), _K₃PO₄ (15.87 mg, 0.075 mmol), Pd(OAc) _₂ (1.679 mg, 0.0075 mmol), tricyclohexylphosphine (2.097 mg, 0.0075 mmol), and o-tolylboronic acid (7.62 mg, 0.056 mmol) in dioxane/water (0.2 mL) was heated at 100 °C for 1 hour. The reaction mixture was subjected to solid-phase extraction using a Bond Elut SCX box (Agilent) (washed with MeOH, then eluted with _NH₃ in MeOH), and the collected fraction was concentrated under vacuum. The residue was purified by column chromatography (Si-column, _CHCl3 :MeOH = 10:0-9:1) to provide the desired product: ^¹H NMR (methanol- _d4) )δ9.40(s,1H),8.23–8.08(m,1H),7.74(ddd,J＝8.5,7.2,1.3Hz,1H),7.51(t,J＝7.8Hz,1H),7.41(dd,J＝8.5,1.1Hz,1H),7.34(ddd,J＝ 8.1, 2.3, 1.1Hz, 1H), 7.27–7.20 (m, 2H), 7.17–7.13 (m, 3H), 7.07 (t, J = 1.9Hz, 2H), 3.68 (s, 3H), 2.02 (s, 3H); LCMS (m/z) 366.3[M+H]+.

Example 161. N-(4'-(tert-butyl)-[1,1'-diphenyl]-3-yl)-N-methyl-[1,2,4]triazolo[4, [3-a]quinazolin-5-amine

A mixture of N-(3-iodophenyl)-N-methyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine (Example 101) (15 mg, 0.037 mmol), _{K₃PO₄ (} 15.87 mg, 0.075 mmol), Pd(OAc) _₂ (1.679 mg, 0.0075 mmol), tricyclohexylphosphine (2.097 mg, 0.0075 mmol), and (4-(tert-butyl)phenyl)boronic acid (9.98 mg, 0.056 mmol) in dioxane/water (0.2 mL) was heated at 100 °C for 1 hour. The reaction mixture was subjected to solid-phase extraction using a Bond Elut SCX box (Agilent) (washed with MeOH, then eluted with _NH₃ in MeOH), and the collected fraction was concentrated under vacuum. The residue was purified by column chromatography (Si-column, _CHCl3 :MeOH = 100:0-85:15) to provide the desired product: ^¹H NMR (methanol- _d4 ) δ 9.43 (s, 1H), 8.23–8.09 (m, 1H), 7.74 (ddd, J = 8.5, 7.3, 1.3 Hz, 1H), 7.58 (ddd, J = 7.8, 1.7, 1.0 Hz, 1H), 7.51 (dd, J = 4.1, 2.1 Hz, 1H), 7.48–7.41 (m, 6H), 7.29–7.11 (m, 2H), 3.71 (s, 3H), 1.32 (s, 9H); LCMS (m/z) 408.3.

Example 162. N-(3'-([1,2,4]triazolo[4,3-a]quinazolin-5-yl(methyl)amino)-[1,1'-di [Phenyl]-4-yl)acetamide

A mixture of N-(3-iodophenyl)-N-methyl-[ _1,2,4 ]triazolo[4,3-a]quinazolin-5-amine (Example 101) (15 mg, 0.037 mmol), _K₃PO₄ (15.87 mg, 0.075 mmol), Pd(OAc) _₂ (1.679 mg, 0.0075 mmol), tricyclohexylphosphine (2.097 mg, 0.0075 mmol), and (4-acetamidophenyl)boronic acid (9.98 mg, 0.056 mmol) in dioxane/water (0.2 mL) was heated at 100 °C for 1 hour. The reaction mixture was subjected to solid-phase extraction using a Bond Elut SCX box (Agilent) (washed with MeOH, then eluted with _NH₃ in MeOH), and the collected fraction was concentrated under vacuum. The residue was purified by column chromatography (Si-column, _CHCl3 :MeOH = 100:0-85:15) to provide the desired product: ^¹H NMR (methanol- _d4 ) δ 9.42 (s, 1H), 8.16 (d, J = 8.3 Hz, 1H), 7.77–7.69 (m, 1H), 7.60–7.55 (m, 3H), 7.50 (ddd, J = 10.8, 5.8, 3.2 Hz, 4H), 7.42 (m, 1H), 7.24–7.13 (m, 2H), 3.71 (s, 3H), 2.12 (s, 3H); LCMS (m/z) 409.3.

Example 163. N5-(4'-fluoro-[1,1'-diphenyl]-3-yl)-N5-methyl-[1,2,4]triazolo[4,3-a] Quinazoline-5,8-diamine

(Step 1) Synthesis of 2-chloro-N-(3-iodophenyl)-N-methyl-7-nitroquinazolin-4-amine

Add 3-iodo-N-methylaniline (382 mg, 1.639 mmol) and sodium hydride (39.3 mg, 1.639 mmol) to a solution of 2-chloro-7-nitroquinazolin-4(3H)-one (400 mg, 1.639 mmol) in DMF (8.2 mL), and stir the mixture at room temperature for 0.5 h. Dilute the reaction mixture with AcOEt and wash continuously with water and brine. Concentrate the organic layer under vacuum. Use the residue for the next step without further purification. LCMS (m/z) 440.99 [M+H] ⁺ .

(Step 2) Synthesis of 2-hydrazino-N-(3-iodophenyl)-N-methyl-7-nitroquinazolin-4-amine

A mixture of 2-chloro-N-(3-iodophenyl)-N-methyl-7-nitroquinazolin-4-amine (crude, 256 mg, 0.581 mmol) and hydrazine hydrate (58.2 mg, 1.162 mmol) in EtOH (2.9 mL) was stirred at 50 °C for 2 hours. The reaction mixture was diluted with AcOEt, washed continuously with water and brine, and dried over _Na₂SO₄ . The organic layer was concentrated under vacuum. The residue was used in the next step without further purification. _LCMS (m/z) 437.03 [M+H] ^⁺ .

(Step 3) Synthesis of N-(3-iodophenyl)-N-methyl-8-nitro-[1,2,4]triazolo[4,3-a]quinazolin-5-amine become

A mixture of 2-hydrazino-N-(3-iodophenyl)-N-methyl-7-nitroquinazolin-4-amine (208 mg, 0.477 mmol) and triethoxymethane (5 mL, 0.477 mmol) was heated to 100 °C overnight. The reaction mixture was concentrated under vacuum. The residue was purified by column chromatography (Si column, _CHCl3 :MeOH = 10:0–9:1) to give the desired product. LCMS (m/z) 447.04 [M+H] ⁺ .

(Step 4) N-(4'-fluoro-[1,1'-diphenyl]-3-yl)-N-methyl-8-nitro-[1,2,4]triazolo[4,3- a) Synthesis of quinazolin-5-amine

A mixture of N-(3-iodophenyl)-N-methyl-8-nitro-[1,2,4]triazolo[4,3-a]quinazolin-5-amine (50 mg, 0.112 mmol), tricyclohexylphosphine (6.28 mg, 0.022 mmol), _K₃PO₄ (47.6 _mg , 0.224 mmol), Pd(OAc) _₂ (5.03 mg, 0.022 mmol), and (4-fluorophenyl)boronic acid (23.52 mg, 0.168 mmol) in dioxane/water (0.56 mL) was stirred at 100 °C for 1 hour. The reaction mixture was subjected to solid-phase extraction using a Bond Elut SCX box (Agilent) (washing with MeOH followed by elution with _NH₃ in MeOH), and the collected fraction was concentrated under vacuum. The filtrate was concentrated under vacuum. The residue was used in the next step without further purification. LCMS(m/z)415.18[M+H] ⁺ .

(Step 5) N5-(4'-fluoro-[1,1'-diphenyl]-3-yl)-N5-methyl-[1,2,4]triazolo[4,3-a]quinazole Synthesis of 5,8-line-2-diamine

A mixture of N-(4'-fluoro-[1,1'-diphenyl]-3-yl)-N-methyl-8-nitro-[1,2,4]triazolo[4,3-a]quinazolin-5-amine (crude, 36 mg) and Pd/C (10 mg) in EtOH (0.43 mL) was stirred overnight at 60 °C under H2 atmosphere. After removing Pd/C by filtration, the filtrate was concentrated under vacuum. The residue was purified by column chromatography (Si-column, _CHCl3 :MeOH = 10:0-85:15) to provide the desired product: ^¹H NMR ( _CDCl3 ) δ 8.81 (s, 1H), 7.52–7.39 (m, 4H), 7.30 (dd, J = 2.5, 1.4 Hz, 1H), 7.17–7.07 (m, 4H), 6.92 (d, J = 2.2 Hz, 1H), 6.36 (dd, J = 9.1, 2.3 Hz, 1H), 4.44 (s, 2H), 3.67 (s, 3H); LCMS (m/z) 385.3.

Example 164. N-Methyl-N-(4'-methyl-[1,1'-diphenyl]-3-yl)-8-nitroso-[1,2,4]triazole [4,3-a]quinazolin-5-amine

Pd/C (6 mg) was added to a solution of N-methyl-N-(4'-methyl-[1,1'-diphenyl]-3-yl)-8-nitro-[1,2,4]triazolo[4,3-a]quinazolin-5-amine (Example 179, Step 1, 41.0 mg, crude product) in EtOH (0.5 mL), and the suspension was stirred overnight at 60 °C under H2 atmosphere. After removing Pd/C by filtration, the filtrate was concentrated under vacuum. The residue was purified by column chromatography (Si-column, _CHCl3 :MeOH = 10:0-85:15) to provide the desired product: ^¹H NMR (methanol- _d4 ) δ 8.05 (s, 1H), 6.21 (dt, J = 7.8, 1.4 Hz, 1H), 6.14 (m, 3H), 5.96–5.90 (m, 3H), 5.86 (ddd, J = 7.7, 2.2, 1.2 Hz, 1H), 5.79 (d, J = 9.3 Hz, 1H), 5.68 (d, J = 2.3 Hz, 1H), 5.09 (dd, J = 9.3, 2.3 Hz, 1H), 2.35 (s, 3H), 1.59 (s, 3H); LCMS (m/z) 395.3.

Example 165. N-(3-cyclohexylphenyl)-N-methyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine

(Step 1) Synthesis of N-(3-cyclohexenylphenyl)-N-methyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine become

A mixture of N-(3-iodophenyl)-N-methyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine (Example 101) (20 mg, 0.050 mmol), tricyclohexylphosphine (2.80 mg, 0.010 mmol), _K₃PO₄ ( _21.16 mg, 0.100 mmol), Pd(OAc) _₂ (2.238 mg, 0.010 mmol), and cyclohex-1-en-1-ylboronic acid (9.42 mg, 0.075 mmol) in dioxane/water (0.25 mL) was treated in a microwave reactor at 100 °C for 1 h. The reaction mixture was subjected to solid-phase extraction using a Bond Elut SCX box (Agilent) (washing with MeOH followed by elution with _NH₃ in MeOH), and the collected fraction was concentrated under vacuum. The residue was used in the next step without further purification. LCMS: 356.18 (M+H).

(Step 2) Synthesis of N-(3-cyclohexylphenyl)-N-methyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine

Pd/C (5 mg) was added to a solution of N-(3-cyclohexenylphenyl)-N-methyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine (crude, 31 mg, 0.087 mmol) in EtOH (0.436 mL), and the mixture was stirred overnight at 50 °C under H2 atmosphere. After removing Pd/C by filtration, the filtrate was concentrated under vacuum. The residue was purified by column chromatography (Si column, _CHCl3 :MeOH = 10:0–9:1) to provide the desired product: ^¹H NMR (methanol- _d4) )δ9.39(s,1H),8.09(ddd,J＝8.4,1.2,0.6Hz,1H),7.69(ddd,J＝8.4,7.2,1.4Hz,1H),7.34(t,J＝7.8Hz,1H),7.21–7.14(m,2H),7.13– 7.07(m,2H),7.04(t,J＝1.9Hz,1H),3.62(s,3H),2.45(tt,J＝8.2,3.6Hz,1H),1.86–1.65(m,6H),1.37–1.28(m,4H); LCMS(m/z)358.3.

Example 166. N-(4'-ethyl-[1,1'-diphenyl]-3-yl)-N-methyl-[1,2,4]triazolo[4,3-a] Quinazoline-5-amine

A mixture of N-(3-iodophenyl)-N-methyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine (Example 101) (20 mg, 0.050 mmol), tricyclohexylphosphine (2.80 mg, 0.010 mmol), _K₃PO₄ (21.16 _mg , 0.100 mmol), Pd(OAc) _₂ (2.238 mg, 0.010 mmol), and (4-ethylphenyl)boronic acid (11.21 mg, 0.075 mmol) in dioxane/water (0.25 mL) was treated in a microwave reactor at 100 °C for 1 hour. The reaction mixture was subjected to solid-phase extraction using a BondElut SCX box (Agilent) (washed with MeOH, then eluted with _NH₃ in MeOH), and the collected fractions were concentrated under vacuum. The residue was purified by column chromatography (Si-column, _CHCl3 :MeOH = 10:0-9:1) to provide the desired product: ^¹H NMR (methanol- _d4 ) δ 9.40 (s, 1H), 8.18–8.05 (m, 1H), 7.70 (ddd, J = 8.4, 7.3, 1.3 Hz, 1H), 7.54 (ddd, J = 7.8, 1.8, 1.1 Hz, 1H), 7.49–7.39 (m, 4H), 7.35 (dd, J = 8.5, 1.3 Hz, 1H), 7.22–7.11 (m, 4H), 3.68 (s, 3H), 2.63 (q, J = 7.6 Hz, 2H), 1.21 (t, J = 7.6 Hz, 3H); LCMS (m/z) 380.3.

Example 167. N5-(4'-methoxy-[1,1'-diphenyl]-3-yl)-N5-methyl-[1,2,4]triazolo[4, [3-a]quinazolin-5,8-diamine

(Step 1) N-(4'-methoxy-[1,1'-diphenyl]-3-yl)-N-methyl-8-nitro-[1,2,4]triazolidine Synthesis of [4,3-a]quinazolin-5-amine

A mixture of N-(3-iodophenyl)-N-methyl-8-nitro-[1,2,4]triazolo[4,3-a]quinazolin-5-amine 6 (40 mg, 0.090 mmol), tricyclohexylphosphine (5.03 mg, 0.018 mmol), _K₃PO₄ ( _38.1 mg, 0.179 mmol), Pd(OAc) _₂ (4.03 mg, 0.018 mmol), and (4-methoxyphenyl)boronic acid (20.43 mg, 0.134 mmol) in dioxane/water (0.45 mL) was treated in a microwave reactor at 100 °C for 1 h. The reaction mixture was subjected to solid-phase extraction using a Bond Elut SCX box (Agilent) (washing with MeOH followed by elution with _NH₃ in MeOH), and the collected fraction was concentrated under vacuum. The residue was used in the next step without further purification. LCMS(m/z)427.18[M+H] ⁺ .

(Step 2) N5-(4'-methoxy-[1,1'-diphenyl]-3-yl)-N5-methyl-[1,2,4]triazolo[4,3-a] Synthesis of quinazolin-5,8-diamine

Pd/C (5 mg) was added to a solution of N-(4'-methoxy-[1,1'-diphenyl]-3-yl)-N-methyl-8-nitro-[1,2,4]triazolo[4,3-a]quinazolin-5-amine (crude, 24 mg) in EtOH (0.28 mL), and the mixture was stirred overnight at 60 °C under H2 atmosphere. After removing Pd/C by filtration, the filtrate was concentrated under vacuum. The residue was purified by column chromatography (Si-column, _CHCl3 :MeOH = 10:0–9:1) to provide the desired product: ^¹H NMR (methanol- _d4 ) δ 9.16 (s, 1H), 8.22 (s, 1H), 7.53–7.38 (m, 4H), 7.13 (ddd, J = 7.8, 2.2, 1.1 Hz, 1H), 7.09–6.97 (m, 2H), 6.97–6.90 (m, 2H), 6.39 (dd, J = 9.2, 2.2 Hz, 1H), 3.80 (s, 3H), 3.63 (s, 3H). LCMS (m/z) 397.3.

Example 168. N-(3'-((8-amino-[1,2,4]triazolo[4,3-a]quinazolin-5-yl)(methyl)amino)- [1,1'-Diphenyl]-4-yl)acetamide

(Step 1) N-(3'-(methyl(8-nitro-[1,2,4]triazolo[4,3-a]quinazolin-5-yl)amino)-[1, Synthesis of 1'-diphenyl]-4-yl)acetamide

A mixture of N-(3-iodophenyl)-N-methyl-8-nitro-[1,2,4]triazolo[4,3-a]quinazolin-5-amine (40 mg, 0.090 mmol), tricyclohexylphosphine (5.03 mg, 0.018 mmol), _K₃PO₄ (38.1 _mg , 0.179 mmol), Pd(OAc) _₂ (4.03 mg, 0.018 mmol), and (4-acetamidophenyl)boronic acid (24.07 mg, 0.134 mmol) in dioxane/water (0.45 mL) was heated to 100 °C for 1 hour. The reaction mixture was subjected to solid-phase extraction using a Bond Elut SCX box (Agilent) (washing with MeOH followed by elution with _NH₃ in MeOH), and the collected fraction was concentrated under vacuum. The residue was used in the next step without further purification. LCMS(m/z)454.19[M+H] ⁺ .

(Step 2) N-(3'-((8-amino-[1,2,4]triazolo[4,3-a]quinazolin-5-yl)(methyl)amino)-[1, Synthesis of 1'-diphenyl]-4-yl)acetamide

Pd/C (5 mg) was added to a solution of N-(3'-(methyl(8-nitro-[1,2,4]triazolo[4,3-a]quinazolin-5-yl)amino)-[1,1'-diphenyl]-4-yl)acetamide (30 mg, crude) in EtOH (0.33 mL), and the mixture was stirred overnight at 50 °C under H2 atmosphere. After removing Pd/C by filtration, the filtrate was concentrated under vacuum. The residue was purified by column chromatography (Si-column, _CHCl3 :MeOH = 10:0-9:1) to provide the desired product: ^¹H NMR (methanol- _d4 ) δ 9.16 (s, 1H), 7.67–7.37 (m, 7H), 7.19–7.13 (m, 1H), 7.07–7.00 (m, 2H), 6.39 (dd, J = 9.2, 2.2 Hz, 1H), 3.64 (s, 3H), 2.13 (s, 3H); LCMS (m/z) 424.3.

Example 169. N5-(3-fluorophenyl)-N5-methyl-[1,2,4]triazolo[4,3-a]quinazolin-5,8-diamine

(Step 1) Synthesis of 2-chloro-N-(3-fluorophenyl)-N-methyl-7-nitroquinazolin-4-amine

Add 3-fluoro-N-methylaniline (51.3 mg, 0.41 mmol) and sodium hydride (9.83 mg, 0.41 mmol) to a solution of 2,4-dichloro-7-nitroquinazoline (100 mg, 0.41 mmol) in DMF (2.1 mL), and stir the mixture at room temperature for 1 hour. Dilute the reaction mixture with AcOEt and wash continuously with water and brine. Concentrate the organic layer under vacuum. Use the residue for the next step without further purification. LCMS (m/z) 332.8 [M+H] ⁺ .

(Step 2) Synthesis of N-(3-fluorophenyl)-2-hydrazino-N-methyl-7-nitroquinazolin-4-amine

Hydrazine hydrate (17.15 mg, 0.343 mmol) was added to a solution of 2-chloro-N-(3-fluorophenyl)-N-methyl-7-nitroquinazolin-4-amine (crude, 114 mg, 0.343 mmol) in EtOH (1.7 mL), and the mixture was stirred at 50 °C for 1 hour. The reaction mixture was diluted with AcOEt and washed continuously with water and brine. The organic layer was concentrated under vacuum. The residue was used for the next step without further purification. LCMS (m/z) 328.9 [M+H] ⁺ .

(Step 3) Synthesis of N-(3-fluorophenyl)-N-methyl-8-nitro-[1,2,4]triazolo[4,3-a]quinazolin-5-amine become

A mixture of N-(3-fluorophenyl)-2-hydrazino-N-methyl-7-nitroquinazolin-4-amine (crude, 101 mg, 0.308 mmol) and triethoxymethane (3 mL, 0.308 mmol) was stirred overnight at 100 °C. The reaction mixture was concentrated under vacuum, and the residue was purified by column chromatography (Si column, _CHCl3 :MeOH = 10:0-85:15) to give the desired product. LCMS (m/z) 339.08 [M+H] ⁺ .

(Step 4) Synthesis of N5-(3-fluorophenyl)-N5-methyl-[1,2,4]triazolo[4,3-a]quinazolin-5,8-diamine become

Pd/C (10 mg) was added to a solution of N-(3-fluorophenyl)-N-methyl-8-nitro-[1,2,4]triazolo[4,3-a]quinazolin-5-amine (66 mg, 0.195 mmol) in EtOH (0.98 mL), and the suspension was stirred overnight at 60 °C under H2 atmosphere. After removing Pd/C by filtration, the filtrate was concentrated under vacuum. The residue was purified by column chromatography (Si-column, _CHCl3 :MeOH = 10:0-85:15) to provide the desired product: ^¹H NMR (methanol- _d4 ) δ 9.15 (d, J = 1.8 Hz, 1H), 7.35 (td, J = 8.2, 6.5 Hz, 1H), 7.08–6.96 (m, 5H), 6.42 (dt, J = 9.4, 2.0 Hz, 1H), 3.56 (d, J = 1.3 Hz, 3H); LCMS (m/z) 309.1.

Example 170. N5-Ethyl-N5-phenyl-[1,2,4]triazolo[4,3-a]quinazolin-5,8-diamine

(Step 1) Synthesis of 2-chloro-N-ethyl-7-nitro-N-phenylquinazoline-4-amine

N-ethylaniline (99 mg, 0.820 mmol) and sodium hydride (19.67 mg, 0.820 mmol) were added to a solution of 2,4-dichloro-7-nitroquinazoline (200 mg, 0.820 mmol) in DMF (4.1 mL), and the mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with AcOEt and washed continuously with water and brine. The organic layer was concentrated under vacuum. The residue was used for the next step without further purification. LCMS (m/z) 329.08 [M+H] ⁺ .

(Step 2) Synthesis of N-ethyl-2-hydrazino-7-nitro-N-phenylquinazoline-4-amine

Hydrazine hydrate (65.1 mg, 1.3 mmol) was added to a solution of 2-chloro-N-ethyl-7-nitro-N-phenylquinazoline- ₄ -amine (crude, 171 mg, 0.52 mmol) in EtOH (2.6 mL), and the mixture was stirred at room temperature for 3 hours. The reaction mixture was diluted with AcOEt, washed continuously with water and brine, and dried over _Na₂SO₄ . The organic layer was concentrated under vacuum. The residue was used in the next step without further purification. LCMS (m/z) 325.08 [M+H] ^⁺ .

(Step 3) Synthesis of N-ethyl-8-nitro-N-phenyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine

A mixture of N-ethyl-2-hydrazino-7-nitro-N-phenylquinazoline-4-amine (147 mg, 0.453 mmol) and triethoxymethane (5 mL, 0.453 mmol) was stirred overnight at 100 °C. The reaction mixture was concentrated under vacuum. The residue was purified by column chromatography (Si column, _CHCl3 :MeOH = 10:0–9:1) to give the desired product. LCMS (m/z) 335.03 [M+H] ⁺ .

(Step 4) Synthesis of N5-ethyl-N5-phenyl-[1,2,4]triazolo[4,3-a]quinazolin-5,8-diamine

Pd/C (15 mg) was added to a solution of N-ethyl-8-nitro-N-phenyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine (102 mg, 0.305 mmol) in EtOH (1.5 mL), and the suspension was stirred overnight at 60 °C under a _H₂ atmosphere. After removing Pd/C by filtration, the filtrate was concentrated under vacuum. The residue was purified by column chromatography (Si-column, _CHCl3 :MeOH = 10:0–9:1) to provide the desired product: ^¹H NMR ( _CDCl3 ) δ 8.78 (s, 1H), 7.35 (t, J = 7.6 Hz, 2H), 7.22 (s, 1H), 7.13 (d, J = 7.6 Hz, 2H), 7.00 (d, J = 9.3 Hz, 1H), 6.89 (s, 1H), 6.36–6.25 (m, 1H), 3.72 (q, J = 7.0 Hz, 2H), 1.31 (t, J = 7.0 Hz, 3H); LCMS (m/z) 305.2.

Example 171. 5-(3,4-dihydroquinoline-1(2H)-yl)-[1,2,4]triazolo[4,3-a]quinazolin-8-amine

(Step 1) Synthesis of 2-chloro-4-(3,4-dihydroquinoline-1(2H)-yl)-7-nitroquinazolinoline

Add 1,2,3,4-tetrahydroquinoline (273 mg, 2.049 mmol) and sodium hydride (49.2 mg, 2.049 mmol) to a solution of 2,4-dichloro-7-nitroquinazoline (500 mg, 2.049 mmol) in DMF (3.1 mL), and stir the mixture at room temperature for 1 hour. Dilute the reaction mixture with AcOEt, wash continuously with water and brine, and dry over _Na₂SO₄ . Concentrate the organic layer under vacuum. Use the residue for the next step without further purification. _LCMS (m/z) 341.03 [M+H] ^⁺ .

(Step 2) Synthesis of 4-(3,4-dihydroquinoline-1(2H)-yl)-2-hydrazyl-7-nitroquinazolinoline

Hydrazine hydrate (136 mg, 2.71 mmol) was added to a solution of 2-chloro-4-(3,4-dihydroquinolin-1(2H)-yl)-7-nitroquinazoline (462 mg, crude) in EtOH (6.8 mL), and the mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with AcOEt and washed continuously with water and brine. The organic layer was concentrated under vacuum. The residue was used for the next step without further purification. LCMS (m/z) 337.08 [M+H] ⁺ .

(Step 3) 5-(3,4-dihydroquinoline-1(2H)-yl)-8-nitro-[1,2,4]triazolo[4,3-a]quinazolino synthesis

A mixture of 4-(3,4-dihydroquinoline-1(2H)-yl)-2-hydrazino-7-nitroquinazoline (387 mg, 1.151 mmol) and triethoxymethane (171 mg, 1.151 mmol) was stirred overnight at 100 °C. The reaction mixture was concentrated under vacuum. The residue was purified by column chromatography (Si-column, _CHCl3 :MeOH = 10:0–9:1). LCMS (m/z) 347.13 [M+H] ⁺ .

(Step 4) Synthesis of 5-(3,4-dihydroquinolin-1(2H)-yl)-[1,2,4]triazolo[4,3-a]quinazolin-8-amine become

A mixture of 5-(3,4-dihydroquinoline-1(2H)-yl)-8-nitro-[1,2,4]triazolo[4,3-a]quinazoline (60 mg, 0.173 mmol) and Pd/C (5 mg) in EtOH (0.87 mL) was stirred overnight at 60 °C under a _H₂ atmosphere. After removing Pd/C by filtration, the filtrate was concentrated under vacuum. The residue was purified by column chromatography (Si-column, _CHCl3 :MeOH = 10:0-9:1) to provide the desired product: ^¹H NMR (methanol- _d4 ) δ 9.14 (s, 1H), 7.17 (d, J = 9.1 Hz, 1H), 7.15–7.11 (m, 1H), 7.01 (d, J = 2.2 Hz, 1H), 6.91–6.82 (m, 2H), 6.55 (dd, J = 7.7, 1.6 Hz, 1H), 6.45 (dd, J = 9.1, 2.2 Hz, 1H), 3.86 (t, J = 6.6 Hz, 2H), 2.81 (t, J = 6.6 Hz, 2H), 2.02 (q, J = 6.6 Hz, 2H); LCMS (m/z) 317.2.

Example 172. 8-Bromo-N-methyl-N-(4'-methyl-[1,1'-diphenyl]-3-yl)-[1,2,4]triazolidine [4,3-a]quinazolin-5-amine

(Step 1) Synthesis of N,4'-dimethyl-[1,1'-diphenyl]-3-amine

Sodium carbonate (1.82 g, 171.7 mmol) and [1,1'-bis(diphenylphosphine)ferrocene]palladium(II) dichloride (0.630 g, 0.86 mmol) were added to a stirred solution of 3-iodo-N-methylaniline (2.0 g, 8.58 mmol) and p-tolylboronic acid (2.33 g, 17.16 mmol) in 1,4-dioxane/water (30 mL, 5:1) at room temperature. The mixture was then heated to 80 °C for 3 hours. The reaction progress was monitored by TLC. After the reaction was complete, the reaction mixture was filtered through a diatomaceous earth bed and washed with ethyl acetate. The organic layer was washed with brine, dried over _Na₂SO₄ , filtered _, and evaporated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with 10% ethyl acetate/petroleum ether to give the desired product.

(Step 2) 8-Bromo-N-methyl-N-(4'-methyl-[1,1'-diphenyl]-3-yl)-[1,2,4]triazolo[4,3- a) Synthesis of quinazolin-5-amine

Triethylamine (0.06 mL, 0.42 mmol) was added to a stirred solution of 8-bromo-5-chloro-[1,2,4]triazolo[4,3-a]quinazoline (0.06 g, 0.21 mmol) and N,4'-dimethyl-[1,1'-diphenyl]-3-amine (0.063 g, 0.32 mmol) in MeOH (4 mL), and the mixture was stirred at room temperature for 16 hours. The reaction progress was monitored by TLC. After the reaction was complete, the reaction mixture was quenched with water and extracted with 10% methanol/dichloromethane. The organic layer was washed with brine, _dried over _Na₂SO₄ , filtered, and evaporated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with 4% methanol/dichloromethane, and further purified by preparative HPLC to provide the desired product: ^¹H NMR (DMSO- _d₆ ) δ 9.63 (s, ¹H), 8.66 (d, J = 2.0 Hz, ¹H), 7.62 (t, J = 1.9 Hz, ¹H), 7.59–7.51 (m, ³H), 7.48–7.40 (m, ²H), 7.32–7.19 (m, ⁴H), 3.59 (s, ³H), 2.32 (s, ³H); LCMS (m/z) 444.28/446.26.

Example 173. 8-Bromo-N-(4'-methoxy-[1,1'-diphenyl]-3-yl)-N-methyl-[1,2,4]triazolidine [4,3-a]quinazolin-5-amine

(Step 1) Synthesis of 3-iodo-N-methylaniline

A 37% formaldehyde solution (5.55 mL, 68.49 mmol) was added to a stirred solution of 10 g (45.66 mmol) in 150 mL of methanol, followed by the addition of sodium methoxide (4.93 g, 91.32 mmol) at room temperature. The mixture was then heated to 60 °C for 3 h. Sodium borohydride (3.45 g, 91.32 mmol) was then added to the solution at room temperature, and the mixture was stirred for 16 h at room temperature. The reaction progress was monitored by TLC. After the reaction was complete, the reaction mixture was diluted with water and extracted with dichloromethane. The organic layer was washed with brine, dried over _Na₂SO₄ , filtered, and evaporated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with 10% ethyl acetate/petroleum ether to give the desired product. _LCMS (m/z) 234.08 [M+H]⁺.

(Step 2) Synthesis of 4'-methoxy-N-methyl-[1,1'-diphenyl]-3-amine

(4-Methoxyphenyl)boronic acid (2.61 g, 17.17 mmol), sodium carbonate (1.82 g, 171.7 mmol), and [1,1'-bis(diphenylphosphine)ferrocene]palladium(II) dichloride (0.630 g, 0.86 mmol) were added to a stirred solution of 3-iodo-N-methylaniline (2 g, 8.58 mmol) in 1,4-dioxane/water (30 mL, 5:1) at room temperature, and the mixture was heated to 80 °C for 3 hours. The reaction progress was monitored by TLC. After the reaction was complete, the reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with brine, dried over _Na₂SO₄ , filtered, and evaporated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with 15% ethyl acetate/petroleum ether to give the desired product. _LCMS (m/z) 214.36 [M+H]+.

(Step 3) 8-Bromo-N-(4'-methoxy-[1,1'-diphenyl]-3-yl)-N-methyl-[1,2,4]triazolo[4, Synthesis of 3-a]quinazolin-5-amine

4'-methoxy-N-methyl-[1,1'-diphenyl]-3-amine (0.039 g, 0.18 mmol) and triethylamine (0.03 mL, 0.21 mmol) were added to a stirred solution of 8-bromo-5-chloro-[1,2,4]triazolo[4,3-a]quinazoline (0.04 g, 0.14 mmol) in MeOH (2 mL), and the mixture was stirred at room temperature for 16 hours. The reaction progress was monitored by TLC. After _the reaction was complete, the reaction mixture was diluted with water and extracted with dichloromethane. The organic layer was washed with brine, dried over _Na₂SO₄ , filtered, and evaporated under reduced pressure. The residue was purified by preparative HPLC to provide the desired product: ^¹H NMR (DMSO- _d₆ ) δ 9.64 (s, ¹H), 8.67 (d, J = 2.0 Hz, ¹H), 7.61–7.56 (m, ³H), 7.56–7.51 (m, ¹H), 7.49–7.38 (m, 2H), 7.23 (dd, J = 8.4, 2.7 Hz, 2H), 7.03–6.91 (m, 2H), 3.77 (s, ³H), 3.59 (d, J = 2.1 Hz, ³H); LCMS (m/z) 460.19/462.20.

Example 174. N-(3'-((8-bromo-[1,2,4]triazolo[4,3-a]quinazolin-5-yl)(methyl)amino)- [1,1'-Diphenyl]-4-yl)acetamide

(Step 1) Synthesis of N-(3'-(methylamino)-[1,1'-diphenyl]-4-yl)acetamide

Sodium carbonate (1.82 g, 171.7 mmol) was added to a stirred solution of 3-iodo-N-methylaniline (2.0 g, 8.58 mmol) and (4-acetamidophenyl)boronic acid (3.07 g, 17.16 mmol) in 1,4-dioxane/water (30 mL, 5:1) at room temperature, and the mixture was degassed with argon for 10 min. Then, [1,1'-bis(diphenylphosphine)ferrocene]palladium(II) dichloride (0.630 g, 0.86 mmol) was added at room temperature, and the mixture was heated to 80 °C for 3 h. The reaction progress was monitored by TLC. After the reaction was complete, the reaction mixture was filtered through a diatomaceous earth bed and washed with ethyl acetate. The organic layer was washed with brine, dried over _Na₂SO₄ , filtered, and evaporated under reduced pressure. The residue was purified by silica gel column chromatography and eluted with 20% ethyl acetate/petroleum ether to give the desired product. _LCMS (m/z) 241.17 [M+H] ^⁺ .

(Step 2) N-(3'-((8-bromo-[1,2,4]triazolo[4,3-a]quinazolin-5-yl)(methyl)amino)-[1, Synthesis of 1'-diphenyl]-4-yl)acetamide

N-(3'-(methylamino)-[1,2,4]triazolo[4,3-a]quinazoline (0.110 g, 0.39 mmol) and triethylamine (0.109 mL, 0.78 mmol) were added to a stirred solution of 8-bromo-5-chloro-[1,2,4]triazolo[4,3-a]quinazoline (0.110 g, 0.39 mmol) in MeOH (6 mL), and the mixture was stirred at room temperature for 16 hours. The reaction progress was monitored by TLC. After the reaction was complete, the reaction mixture was diluted with water and extracted with 10% methanol/dichloromethane. The organic layer was washed with water and _brine , dried over _Na₂SO₄ , filtered, and evaporated under reduced pressure. The residue was purified by preparative HPLC to provide the desired product: ^¹H NMR (DMSO- _d₆ ) δ 10.02 (s, ¹H), 9.64 (s, ¹H), 8.67 (d, J = 2.0 Hz, ¹H), 7.70–7.50 (m, 6H), 7.47–7.39 (m, 2H), 7.24 (dd, J = 8.3, 4.8 Hz, 2H), 3.59 (s, 3H), 2.05 (s, 3H); LCMS (m/z) 486.8/488.8.

Example 175. 8-Chloro-N-(4'-methoxy-[1,1'-diphenyl]-3-yl)-N-methyl-[1,2,4]triazolidine [4,3-a]quinazolin-5-amine

4'-methoxy-N-methyl-[1,1'-diphenyl]-3-amine (0.134 g, 0.63 mmol) and sodium hydroxide (0.34 g, 0.84 mmol) were added to a stirred solution of 5,8-dichloro-[1,2,4]triazolo[4,3-a]quinazoline (0.1 g, 0.42 mmol) in DMF ( ₅ mL), and the mixture was stirred at room temperature for 3 hours. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with brine, dried over _Na₂SO₄ , filtered, and evaporated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with 6% methanol/dichloromethane to provide the desired product: ^¹H NMR (DMSO- _d₆ ) δ 9.63 (s, 1H), 8.53 (t, J = 1.2 Hz, 1H), 7.61–7.57 (m, 3H), 7.54 (dt, J = 8.0, 1.3 Hz, 1H), 7.44 (t, J = 7.8 Hz, 1H), 7.31 (m, 2H), 7.23 (ddd, J = 8.0, 2.2, 1.1 Hz, 1H), 7.01–6.94 (m, 2H), 3.77 (s, 3H), 3.59 (s, 3H); LCMS (m/z) 416.3.

Example 176. 8-Chloro-N-(4'-chloro-[1,1'-diphenyl]-3-yl)-N-methyl-[1,2,4]triazolo[4, [3-a]quinazolin-5-amine

4'-Chloro-N-methyl-[1,1'-diphenyl]-3-amine (0.178 g, 0.82 mmol) and triethylamine (0.18 mL, 1.26 mmol) were added to a stirred solution of 5,8-dichloro-[1,2,4]triazolo[4,3-a]quinazoline (0.150 g, 0.63 mmol) in DMF (10 mL), and the mixture was stirred at room temperature for 16 hours. The reaction mixture was diluted with water and extracted with dichloromethane. The organic layer was washed with brine, dried over _Na₂SO₄ , filtered _, and evaporated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with 6% methanol/dichloromethane, followed by preparative HPLC purification to provide the desired product: ^¹H NMR (DMSO- _d₆ ) δ 9.64 (s, ¹H), 8.54 (t, J = 1.3 Hz, ¹H), 7.74–7.65 (m, ³H), 7.59 (dt, J = 8.0, 1.2 Hz, ¹H), 7.54–7.43 (m, ³H), 7.36–7.24 (m, ³H), 3.59 (s, ³H); LCMS (m/z) 420.2.

Example 177. 8-Bromo-N-ethyl-N-phenyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine

(Step 1) Synthesis of 7-bromo-2-chloro-N-ethyl-N-phenylquinazoline-4-amine

Sodium hydride (25.9 mg, 1.079 mmol) and N-ethylaniline (131 mg, 1.079 mmol) were added to a solution of 7-bromo-2,4-dichloroquinazoline (300 mg, 1.079 mmol) in DMF (5.4 mL), and the mixture was stirred at room temperature for 1 hour. The mixture was diluted with AcOEt and washed continuously with water and brine. The organic layer was concentrated under vacuum. The residue was used for the next step without further purification. LCMS (m/z) 363.7 [M+H] ⁺ .

(Step 2) Synthesis of 7-bromo-N-ethyl-2-hydrazino-N-phenylquinazoline-4-amine

Hydrazine hydrate (64.6 mg, 1.290 mmol) was added to a solution of 7-bromo-2-chloro-N-ethyl-N-phenylquinazoline- ₄ -amine (234 mg, crude) in EtOH (3.2 mL), and the mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with AcOEt, washed continuously with water and brine, and dried over _Na₂SO₄ . The organic layer was concentrated under vacuum. The residue was used in the next step without further purification. LCMS (m/z) 359.8 [M+H] ^⁺ .

(Step 3) Synthesis of 8-bromo-N-ethyl-N-phenyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine

A mixture of 7-bromo-N-ethyl-2-hydrazino-N-phenylquinazoline-4-amine (198 mg, crude) and triethoxymethane (7 mL, 0.553 mmol) was stirred overnight at 100 °C. The reaction mixture was then concentrated under vacuum. The residue was purified by column chromatography (Si-column, _CHCl3 :MeOH = 10:0-85:15) to provide the desired product: ^¹H NMR (methanol- _d4 ) δ 9.38 (s, 1H), 8.37 (d, J = 1.9 Hz, 1H), 7.46–7.40 (m, 2H), 7.37–7.30 (m, 1H), 7.26 (d, J = 1.5 Hz, 3H), 7.02 (d, J = 9.0 Hz, 1H), 4.21 (q, J = 6.9 Hz, 2H), 1.29 (t, J = 6.9 Hz, 3H); LCMS (m/z) 368.0/380.1.

Example 178. N5-(cyclopropylmethyl)-N5-phenyl-[1,2,4]triazolo[4,3-a]quinazolin-5,8-diamine

(Step 1) Synthesis of 2-chloro-N-(cyclopropylmethyl)-7-nitro-N-phenylquinazoline-4-amine

N-(cyclopropylmethyl)aniline (151 mg, 1.024 mmol) and sodium hydride (24.58 mg, 1.024 mmol) were added to a solution of 2,4-dichloro-7-nitroquinazoline (250 mg, 1.024 mmol) in DMF (5.1 mL), and the mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with AcOEt and washed continuously with water and brine. The organic layer was concentrated under vacuum. The residue was used for the next step without further purification. LCMS (m/z) 355.18 [M+H]+.

(Step 2) Synthesis of N-(cyclopropylmethyl)-2-hydrazino-7-nitro-N-phenylquinazoline-4-amine

Hydrazine hydrate (42.6 mg, 0.851 mmol) was added to a solution of 2-chloro-N-(cyclopropylmethyl)-7-nitro-N-phenylquinazoline-4-amine (302 mg, crude) in EtOH (4.3 mL), and the mixture was stirred at 50 °C for 30 min. The reaction mixture was diluted with AcOEt and washed continuously with water and brine. The organic layer was concentrated under vacuum. The residue was used for the next step without further purification. LCMS (m/z) 351.18 [M+H]+.

(Step 3) N-(cyclopropylmethyl)-8-nitro-N-phenyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine synthesis

A mixture of N-(cyclopropylmethyl)-2-hydrazino-7-nitro-N-phenylquinazoline-4-amine (238 mg, crude) and triethoxymethane (7 mL, 0.679 mmol) was stirred at 100 °C for 4 hours. The reaction mixture was concentrated under vacuum and purified by column chromatography (Si column, _CHCl3 :MeOH = 10:0–9:1) to give the desired product. LCMS (m/z) 361.13 [M+H]+.

(Step 4) N5-(cyclopropylmethyl)-N5-phenyl-[1,2,4]triazolo[4,3-a]quinazolin-5,8-diamine

Pd/C (10 mg) was added to a solution of N-(cyclopropylmethyl)-8-nitro-N-phenyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine (212 mg, 0.588 mmol) in EtOH (3.1 mL), and the suspension was stirred overnight at 60 °C under H2 atmosphere. After removing Pd/C by filtration, the filtrate was concentrated under vacuum. The residue was purified by column chromatography (Si-column, _CHCl3 :MeOH = 10:0-85:15) to provide the desired product: ^¹H NMR (methanol- _d4 ) δ 9.23 (m, 1H), 7.45–7.36 (m, 2H), 7.30–7.21 (m, 3H), 7.04–6.91 (m, 2H), 6.42–6.22 (m, 1H), 4.00 (d, J = 6.8 Hz, 2H), 1.29–1.02 (m, 1H), 0.43–0.37 (m, 2H), 0.19–0.10 (m, 2H); LCMS (m/z) 331.1.

Example 179. N5-methyl-N5-(4'-methyl-[1,1'-diphenyl]-3-yl)-[1,2,4]triazolo[4,3- a] Quinazoline-5,8-diamine

(Step 1) N-Methyl-N-(4'-methyl-[1,1'-diphenyl]-3-yl)-8-nitro-[1,2,4]triazolo[4, Synthesis of 3-a]quinazolin-5-amine

A mixture of N-(3-iodophenyl)-N-methyl-8-nitro-[1,2,4]triazolo[4,3-a]quinazolin-5-amine (50 mg, 0.112 mmol), Pd(OAc) _₂ (5.03 mg, 0.022 mmol), _K₃PO₄ (47.6 _mg , 0.224 mmol), tricyclohexylphosphine (6.28 mg, 0.022 mmol), and p-tolylboronic acid (18.28 mg, 0.134 mmol) in dioxane/water (0.56 mL) was heated at 100 °C for 1 hour. The reaction mixture was subjected to solid-phase extraction using a Bond Elut SCX box (Agilent) (washing with MeOH followed by elution with _NH₃ in MeOH), and the collected fraction was concentrated under vacuum. The residue was used for the next step without further purification. LCMS (m/z) 411.1 [M+H] ^⁺ .

(Step 2) N5-methyl-N5-(4'-methyl-[1,1'-diphenyl]-3-yl)-[1,2,4]triazolo[4,3-a]quinoline Synthesis of azoline-5,8-diamine

Pd/C (5 mg) was added to a solution of N-methyl-N-(4'-methyl-[1,1'-diphenyl]-3-yl)-8-nitro-[1,2,4]triazolo[4,3-a]quinazolin-5-amine (45 mg, 0.110 mmol) in EtOH (0.55 mL), and the suspension was heated to 60 °C overnight under H2 atmosphere. After removing Pd/C by filtration, the filtrate was concentrated under vacuum. The residue was purified by column chromatography (Si-column, _CHCl3 :MeOH = 10:0-80:20) to provide the desired product: ^¹H NMR (methanol- _d4 ) δ 9.17 (s, 1H), 7.53–7.47 (m, 1H), 7.44–7.41 (m, 3H), 7.24–7.21 (m, 3H), 7.20–7.14 (m, 1H), 7.09 (d, J = 9.2 Hz, 1H), 7.07 (d, J = 2.2 Hz, 1H), 6.41 (dd, J = 9.2, 2.2 Hz, 1H), 3.65 (s, 3H), 2.35 (s, 3H); LCMS (m/z) 381.2.

Example 180. (5-(ethyl(phenyl)amino)-[1,2,4]triazolo[4,3-a]quinazolin-8-yl)methanol

(Step 1) Synthesis of N-ethyl-N-phenyl-8-vinyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine

A mixture of 8-bromo-N-ethyl- _N -phenyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine (Example 177) (300 mg, 0.815 mmol), _K₃PO₄ (346 mg, 1.629 mmol), Pd(OAc) _₂ (36.6 mg, 0.163 mmol), 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborhexacyclopentane (188 mg, 1.222 mmol), and tricyclohexylphosphine (45.7 mg, 0.163 mmol) in dioxane/water (4.1 mL) was heated to 100 °C for 1 hour. The reaction mixture was concentrated under vacuum. The residue was purified by column chromatography (Si column, _CHCl₃ :MeOH = 10:0–9:1) to give the desired product. LCMS(m/z) 316.08[M+H] ⁺ .

(Step 2) Synthesis of 5-(ethyl(phenyl)amino)-[1,2,4]triazolo[4,3-a]quinazolin-8-carboxaldehyde

Osmium oxide (VIII) (8.1 mg, 0.032 mmol) and sodium periodate (81 mg, 0.317 mmol) were added to a solution of N-ethyl-N-phenyl-8-vinyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine (100 mg, 0.317 mmol) in acetone/water (1:1, 1.6 mL), and the mixture was stirred overnight at room temperature. The reaction mixture was subjected to solid-phase extraction using a Bond Elut SCX box (Agilent) (washing with MeOH followed by elution with _NH₃ in MeOH), and the collected fraction was concentrated under vacuum. The residue was used for the next step without further purification. LCMS (m/z) 318.03 [M+H] ^⁺ .

(Step 3) Synthesis of (5-(ethyl(phenyl)amino)-[1,2,4]triazolo[4,3-a]quinazolin-8-yl)methanol

To a solution of 5-(ethyl(phenyl)amino)-[1,2,4]triazolo[4,3-a]quinazolin-8-carboxaldehyde (98 mg, 0.31 mmol) in MeOH (1.5 mL), _NaBH₄ (12.90 mg, 0.341 mmol) was added, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was then concentrated under vacuum. The residue was purified by column chromatography (Si-column, _CHCl3 :MeOH = 10:0-85:15) to provide the desired product: ^¹H NMR (methanol- _d4 ) δ 9.42 (d, J = 0.9 Hz, 1H), 8.13 (s, 1H), 7.48–7.21 (m, 6H), 7.12 (d, J = 8.7 Hz, 1H), 4.72 (s, 2H), 4.26 (q, J = 7.0 Hz, 2H), 3.35 (s, 1H), 1.36–1.32 (t, J = 7.0 Hz, 3H); LCMS (m/z) 320.1.

Example 181. N-Ethyl-8-(methoxymethyl)-N-phenyl-[1,2,4]triazolo[4,3-a]quinazolin-5- amine

Iodine (24.44 mg, 0.172 mmol) and sodium hydride (4.51 mg, 0.188 mmol) were added to a solution of (5-(ethyl(phenyl)amino)-[1,2,4]triazolo[4,3-a]quinazolin-8-yl)methanol (Example 180) (50 mg, 0.157 mmol) in DMF (0.78 mL), and the mixture was stirred at room temperature for 4 hours. The reaction mixture was then concentrated under vacuum. The residue was purified by column chromatography (Si-column, _CHCl3 :MeOH = 10:0-9:1) to provide the desired product: ^¹H NMR (methanol- _d4 ) δ 9.37 (s, 1H), 8.05–7.89 (m, 1H), 7.45–7.38 (m, 2H), 7.35–7.28 (m, 1H), 7.26–7.19 (m, 2H), 7.09 (d, J = 8.7 Hz, 1H), 7.00 (dd, J = 8.7, 1.7 Hz, 1H), 4.52 (s, 2H), 4.21 (q, J = 7.0 Hz, 2H), 3.42 (s, 3H), 1.29 (t, J = 7.0 Hz, 3H); LCMS (m/z) 334.1.

Example 182. 7,8-Difluoro-N-methyl-N-phenyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine

(Step 1) Synthesis of 6,7-difluoroquinazolin-2,4(1H,3H)-dione

A mixture of 2-amino-4,5-difluorobenzoic acid (1 g, 5.78 mmol) and urea (0.520 g, 8.66 mmol) in NMP (5 mL) was stirred at 150 °C for 15 hours. The reaction mixture was poured onto ice, and the resulting solid was collected. The crude solid was used in the next step without further purification. LCMS (m/z) 199.19 [M+H] ⁺ .

(Step 2) Synthesis of 2,4-dichloro-6,7-difluoroquinazoline

A mixture of 6,7-difluoroquinazoline-2,4(1H,3H)-dione (1.26 g, 6.36 mmol) and phosphorus trichloride (10 mL, 6.36 mmol) was stirred at 110 °C for 2 days. The reaction mixture was slowly poured into ice water. The resulting solid was collected to give the desired product. The crude solid was used in the next step without further purification. LCMS (m/z) 235.09 [M+H] ⁺ .

(Step 3) Synthesis of 2-chloro-6,7-difluoro-N-methyl-N-phenylquinazoline-4-amine

Sodium hydride (46.0 mg, 1.915 mmol) and N-methylaniline (215 mg, 2.011 mmol) were added to the resulting solution of 2,4-dichloro-6,7-difluoroquinazoline (450 mg, 1.915 mmol) in DMF (9.57 mL), and the mixture was stirred at room temperature for 0.5 h. The reaction mixture was diluted with AcOEt, washed continuously with water and brine, and dried over _Na₂SO₄ . The organic layer was concentrated under vacuum. The resulting residue was used in the next step without further purification. _LCMS (m/z) 306.03 [M+H] ^⁺ .

(Step 4) Synthesis of 6,7-difluoro-2-hydrazino-N-methyl-N-phenylquinazoline-4-amine

Hydrazine hydrate (0.035 g, 0.697 mmol) was slowly added to the resulting 2-chloro-6,7-difluoro-N-methyl-N-phenylquinazoline-4-amine (0.71 g, 2.32 mmol) in a stirred solution of ethanol (11.6 mL) at room temperature. After 1 h and 2 h, an additional fraction of hydrazine hydrate (0.035 g × 2, 1.394 mmol) was slowly added to the solution, and stirring was continued for another 1 h. The mixture was diluted with AcOEt, washed continuously with water and brine, and dried over _Na₂SO₄ . The organic layer was concentrated under vacuum. The resulting residue was used in the next step without further purification. _LCMS (m/z) 302.10 [M+H] ^⁺ .

(Step 5) Synthesis of 7,8-difluoro-N-methyl-N-phenyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine

The resulting mixture of 6,7-difluoro-2-hydrazino-N-methyl-N-phenylquinazoline-4-amine (0.65 g, 2.16 mmol) and triethyl orthoformate (7 mL, 2.18 mmol) was heated to 100 °C for 16 hours. The reaction progress was monitored by TLC. After the reaction was complete, the mixture was concentrated under vacuum. The residue was purified by column chromatography (Si-column, _CHCl3 :MeOH = 10:0-9:1) to provide the desired product: ^¹H NMR (methanol- _d4 ) δ 9.37 (s, 1H), 8.27 (dd, J = 10.5, 7.0 Hz, 1H), 7.52–7.45 (m, 2H), 7.43–7.36 (m, 1H), 7.35–7.29 (m, 2H), 7.06 (dd, J = 12.1, 8.2 Hz, 1H), 3.65 (s, 3H); LCMS (m/z) 312.1.

Example 183. N-Methyl-N-(4'-methyl-[1,1'-diphenyl]-3-yl)-8-(prop-1-yn-1-yl)-[1, [2,4]triazolo[4,3-a]quinazolin-5-amine

Triethylamine (0.047 mL, 0.34 mmol) was added to a stirred and degassed solution of 8-bromo-5-chloro-[1,2,4]triazolo[4,3-a]quinazoline (0.150 g, 0.34 mmol) in 1,4-dioxane (6 mL) at room temperature, and the mixture was degassed with argon for 10 min. Then, triphenylphosphine (0.080 g, 0.30 mmol), cuprous iodide (0.013 g, 0.07 mmol), Pd(OAc) _₂ (0.015 g, 0.07 mmol), and 1-propyne (0.13 mL, 1.69 mmol) were added at room temperature, and the mixture was heated to 100 °C in a sealed tube for 4 h. The reaction progress was monitored by TLC. After the reaction was complete, the reaction mixture was filtered through a diatomaceous earth bed and washed with ethyl acetate. The filtrate was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography, eluted with 4% methanol/dichloromethane, and purified by preparative HPLC to provide the desired product: ^¹H NMR (DMSO- _d₆ ) δ 9.63 (s, ¹H), 8.40 (d, J = 1.6 Hz, ¹H), 7.62–7.49 (m, 4H), 7.45 (t, J = 7.8 Hz, 1H), 7.30–7.20 (m, 4H), 7.17 (dd, J = 8.7, 1.6 Hz, 1H), 3.59 (s, 3H), 2.31 (s, 3H), 2.09 (s, 3H); LCMS (m/z) 404.2.

Example 184. N-(4'-methoxy-[1,1'-diphenyl]-3-yl)-N-methyl-8-(prop-1-yn-1-yl)- [1,2,4]triazolo[4,3-a]quinazolin-5-amine

At room temperature, triphenylphosphine (0.051 g, 0.19 mmol), triethylamine (0.03 mL, 0.22 mmol), cuprous iodide (0.008 g, 0.04 mmol), palladium acetate (0.010 g, 0.04 mmol), and 1-propyne (0.13 mL, 2.18 mmol) were added to a stirred and degassed solution of 8-bromo-N-(4'-methoxy-[1,1'-diphenyl]-3-yl) in 1,4-dioxane (10 mL), and the mixture was heated to 100 °C for 6 hours. The reaction progress was monitored by TLC. After the reaction was complete, the reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with brine, dried over _Na₂SO₄ , filtered _, and evaporated under reduced pressure. The residue was purified by preparative HPLC to provide the desired product: ^¹H NMR (DMSO- _d₆ ) δ 9.63 (s, ¹H), 8.40 (d, J = 1.6 Hz, ¹H), 7.62–7.54 (m, ³H), 7.54–7.49 (m, ¹H), 7.43 (t, J = 7.8 Hz, ¹H), 7.27 (d, J = 8.7 Hz, ¹H), 7.22 (ddd, J = 7.8, 2.2, 1.0 Hz, ¹H), 7.17 (dd, J = 8.7, 1.6 Hz, ¹H), 7.01–6.90 (m, ²H), 3.77 (s, ³H), 3.59 (s, ³H), 2.09 (s, ³H); LCMS (m/z) 420.2.

Example 185. 8-Bromo-N-(4'-chloro-[1,1'-diphenyl]-3-yl)-N-methyl-[1,2,4]triazolo[4, [3-a]quinazolin-5-amine

(Step 1) Synthesis of 7-bromoquinazolin-2,4(1H,3H)-dione

A mixture of 2-amino-4-bromobenzoic acid (20.0 g, 92.59 mmol) and urea (55.55 g, 925.92 mmol) was heated to 150 °C for 16 hours. The reaction progress was monitored by TLC. After the reaction was complete, the reaction mixture was diluted with ice water and stirred for 30 minutes. The resulting solid was filtered off and ground with glacial acetic acid. The resulting solid was collected and washed with petroleum ether to give the desired product. LCMS (m/z) 241.06 [M+H] ⁺ .

(Step 2) Synthesis of 7-bromo-2,4-difluoroquinazoline

N,N-diisopropylethylamine (19.6 mL, 118.75 mmol) was added to a stirred solution of 7-bromoquinazoline-2,4(1H,3H)-dione (19.0 g, 79.17 mmol) in phosphorus oxychloride (74 mL, 791.67 mmol) at 0 °C, and the mixture was heated to 110 °C for 16 hours. The reaction progress was monitored by TLC. After the reaction was complete, the reaction mixture was diluted with ice water and stirred for 30 minutes. The resulting solid was collected, washed with cold water, and dried under vacuum to give the desired product. LCMS (m/z) 279.06 [M+H] ⁺ .

(Step 3) Synthesis of 7-bromo-2-chloroquinazoline-4(3H)-one

1M sodium hydroxide (191 mL, 191.30 mmol) was added to a stirred solution of 7-bromo-2,4-dichloroquinazoline (crude product, 22.0 g, 79.71 mmol) in tetrahydrofuran (200 mL) at 0 °C, and the mixture was stirred at room temperature for 2 hours. The reaction progress was monitored by TLC. After the reaction was complete, the reaction mixture was acidified to pH ~5 with glacial acetic acid. The resulting solid was filtered and dried under vacuum to give the desired product. LCMS (m/z) 259.17 [M+H] ⁺ .

(Step 4) Synthesis of 7-bromo-2-chloro-3-((2-(trimethylsilyl)ethoxy)methyl)quinazolin-4(3H)-one become

Potassium carbonate (8.53 g, 61.82 mmol) and 2-(trimethylsilyl)ethoxymethyl chloride (10.96 mL, 61.82 mmol) were added to a stirred solution of 7-bromo-2-chloroquinazoline-4(3H)-one (14.5 g, 56.20 mmol) in N,N-dimethylformamide (150 mL) at 0 °C, and the mixture was stirred at room temperature for 4 hours. The reaction progress was monitored by TLC. After the reaction was complete, the reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with water and brine, dried over _{anhydrous Na₂SO₄} , filtered, and evaporated under reduced pressure to give the desired product.

(Step 5) 7-Bromo-2-hydrazino-3-((2-(trimethylsilyl)ethoxy)methyl)quinazolin-4(3H)-one synthesis

Hydrazine (386 mL, 386.60 mmol, 1.0 M in tetrahydrofuran) was added to a stirred solution of 7-bromo-2-chloro-3-((2-(trimethylsilyl)ethoxy)methyl)quinazolin-4(3H)-one (15.0 g, 38.66 mmol) in 150 mL of ethanol at 0 °C, and the mixture was stirred at room temperature for 2 h. The reaction progress was monitored by TLC. After the reaction was complete, the reaction mixture was diluted with water and extracted with 10% methanol/dichloromethane. The organic layer was washed with water and brine, dried over anhydrous _Na₂SO₄ , filtered, and evaporated under reduced pressure to give the desired product. _LCMS (m/z) 385.44 [M+H] ^⁺ .

(Step 6) 8-Bromo-4-((2-(trimethylsilyl)ethoxy)methyl)-[1,2,4]triazolo[4,3-a]quinazole Synthesis of lin-5(4H)-one (26)

A mixture of 7-bromo-2-hydrazino-3-((2-(trimethylsilyl)ethoxy)methyl)quinazolin-4(3H)-one (crude, 17 g, 44.27 mmol) and triethyl orthoformate (43.74 mL, 265.62 mmol) was heated to 100 °C for 16 hours. The reaction progress was monitored by TLC. After the reaction was complete, the reaction mixture was evaporated under reduced pressure to give the crude compound. The crude compound was ground with diethyl ether and collected to provide the desired product. LCMS (m/z) 397.35 [M+H] ⁺ .

(Step 7) Synthesis of 8-bromo-[1,2,4]triazolo[4,3-a]quinazolin-5(4H)-one

Trifluoroacetic acid (1.5 mL) was added to a stirred solution of 8-bromo-4-((2-(trimethylsilyl)ethoxy)methyl)-[1,2,4]triazolo[4,3-a]quinazolin-5(4H)-one (1.5 g, 5.10 mmol) in methanol (15 mL), and the mixture was stirred at room temperature for 16 hours. The reaction progress was monitored by TLC. After the reaction was complete, the reaction mixture was evaporated under reduced pressure to give the crude compound. The crude compound was ground with diethyl ether and collected to provide the desired product. LCMS (m/z) 265.27 [M+H] ⁺ .

(Step 8) Synthesis of 8-bromo-5-chloro-[1,2,4]triazolo[4,3-a]quinazoline

A mixture of 8-bromo-[1,2,4]triazolo[4,3-a]quinazolin-5(4H)-one (2.0 g, 7.57 mmol) in phosphorus oxychloride (15 mL) was stirred under reflux for 6 hours. The reaction progress was monitored by TLC. After the reaction was complete, the reaction mixture was evaporated under reduced pressure to give the crude product. The crude product was dissolved in toluene and evaporated twice to provide the desired product. LCMS (m/z) 283.20 [M+H] ⁺ .

(Step 9) 8-Bromo-N-(4'-chloro-[1,1'-diphenyl]-3-yl)-N-methyl-[1,2,4]triazolo[4,3-a] Synthesis of quinazoline-5-amine

4'-Chloro-N-methyldiphenyl-3-amine (0.115 g, 0.53 mmol) and potassium carbonate (0.028 g, 0.71 mmol) were added to a stirred solution of 8-bromo-5-chloro-[1,2,4]triazolo[4,3-a]quinazoline (0.1 g, 0.35 mmol) in N,N-dimethylformamide (5 mL), and the mixture was stirred at room temperature for 3 hours. The reaction progress was monitored by TLC. After the reaction was complete, the reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with brine, dried over _{anhydrous Na₂SO₄} , filtered, and evaporated under reduced pressure to give a crude residue. The residue was purified by preparative HPLC to provide the desired product: ^¹H NMR (DMSO- _d₆ ) δ 9.64 (s, ¹H), 8.67 (d, J = 1.9 Hz, ¹H), 7.71–7.65 (m, ³H), 7.59 (dt, J = 7.9, 1.2 Hz, ¹H), 7.51–7.45 (m, ³H), 7.43 (dd, J = 8.9, 1.9 Hz, ¹H), 7.31 (ddd, J = 7.9, 2.3, 1.0 Hz, ¹H), 7.23 (d, J = 8.9 Hz, ¹H), 3.59 (s, ³H); LCMS (m/z) 464.32/466.34.

Example 186. 8-Bromo-N-(4'-(tert-butyl)-[1,1'-diphenyl]-3-yl)-N-methyl-[1,2,4]triazole [4,3-a]quinazolin-5-amine

(Step 1) Synthesis of 4'-(tert-butyl)-N-methyl-[1,1'-diphenyl]-3-amine

To a stirred solution of 3-iodo-N-methylaniline (0.8 g, 3.43 mmol) in 1,4-dioxane/water (20 mL, 3:1), 4-(tert-butyl)phenyl)boronic acid (1.22 g, 6.87 mmol), sodium carbonate (0.728 g, 6.87 mmol), and [1,1'-bis(diphenylphosphine)ferrocene]palladium(II) dichloride (0.250 g, 0.34 mmol) were added, and the mixture was heated to 80 °C for 3 hours. The reaction progress was monitored by TLC. After the reaction was complete, the reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with brine, dried over _Na₂SO₄ , filtered, and evaporated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with 15% ethyl acetate/petroleum ether to give the desired product. _LCMS (m/z) 240.23 [M+H] ^⁺ .

(Step 2) 8-Bromo-N-(4'-(tert-butyl)-[1,1'-diphenyl]-3-yl)-N-methyl-[1,2,4]triazolidine Synthesis of [4,3-a]quinazolin-5-amine

4'-(tert-butyl)-N-methyl-[1,1'-diphenyl]-3-amine (0.635 g, 2.66 mmol) and potassium carbonate (0.489 g, 3.54 mmol) were added to a stirred solution of 8-bromo-5-chloro-[1,2,4]triazolo[4,3-a]quinazoline (0.5 g, 1.77 mmol) in 10 mL of DMF at 0 °C, and the mixture was stirred at room temperature _for 3 h. The reaction progress was monitored by TLC. After the reaction was complete, the reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with brine, dried over _Na₂SO₄ , filtered, and evaporated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with 10% methanol/dichloromethane, followed by preparative HPLC purification to provide the desired product: ^¹H NMR (DMSO- _d₆ ) δ 9.64 (s, 1H), 8.67 (d, J = 2.0 Hz, 1H), 7.61–7.50 (m, 4H), 7.48 (d, J = 7.8 Hz, 1H), 7.44–7.39 (m, 3H), 7.29 (ddd, J = 8.0, 2.2, 1.1 Hz, 1H), 7.22 (d, J = 8.9 Hz, 1H), 3.59 (s, 3H), 1.28 (s, 9H); LCMS (m/z) 486.14/488.14.

Example 187. 8-Chloro-N-methyl-N-(4'-methyl-[1,1'-diphenyl]-3-yl)-[1,2,4]triazolidine [4,3-a]quinazolin-5-amine

Potassium carbonate (0.116 g, 0.84 mmol) was added to a stirred solution of N,4'-dimethyl-[1,1'-diphenyl]-3-amine (0.124 g, 0.63 mmol) in DMF (6 mL) at 0 °C, and the mixture was stirred at room temperature for 10 min. Then, 5,8-dichloro-[1,2,4]triazolo[4,3-a]quinazoline (0.1 g, _0.42 mmol) was added at room temperature, and the mixture was stirred at room temperature for 3 h. The reaction mixture was diluted with ice water and extracted with ethyl acetate. The organic layer was washed continuously with water and brine, dried over _Na₂SO₄ , filtered, and evaporated under reduced pressure. The residue was purified by preparative HPLC to provide the desired product: ^¹H NMR (DMSO- _d₆ ) δ 9.62 (s, ¹H), 8.53 (t, J = 1.2 Hz, ¹H), 7.62 (t, J = 1.9 Hz, ¹H), 7.58–7.51 (m, ³H), 7.45 (t, J = 7.8 Hz, ¹H), 7.31 (d, J = 1.2 Hz, ²H), 7.26 (ddd, J = 8.0, 2.3, 1.0 Hz, ¹H), 7.24–7.18 (m, ²H), 3.59 (s, ³H), 2.32 (s, ³H); LCMS (m/z) 400.2.

Example 188. N-(3'-((8-chloro-[1,2,4]triazolo[4,3-a]quinazolin-5-yl)(methyl)amino)- [1,1'-Diphenyl]-4-yl)acetamide

Sodium hydroxide (0.033 g, 0.84 mmol) was added to a stirred solution of N-(3'-(methylamino)-[1,1'-diphenyl]-4-yl)acetamide (0.151 g, 0.63 mmol) in DMF (5 mL) at 0 °C, and the mixture was stirred at room temperature for 10 min. Then, 5,8-dichloro-[1,2,4]triazolo[4,3-a]quinazoline (0.1 g, 0.42 mmol) was added at room temperature, and the mixture was stirred at room temperature for 3 h. The reaction mixture was diluted with ice water and extracted with ethyl acetate. The organic layer was washed continuously with water and brine, dried over _Na₂SO₄ , filtered _, and evaporated under reduced pressure. The residue was purified by preparative HPLC to provide the desired product: ^¹H NMR (DMSO- _d₆ ) δ 10.02 (s, ¹H), 9.63 (s, ¹H), 8.54 (t, J = 1.2 Hz, ¹H), 7.66–7.54 (m, 6H), 7.45 (t, J = 7.9 Hz, 1H), 7.31 (d, J = 1.2 Hz, 2H), 7.25 (ddd, J = 7.9, 2.2, 1.0 Hz, 1H), 3.59 (s, 3H), 2.04 (s, 3H); LCMS (m/z) 443.4.

Example 189. (5-((3-fluorophenyl)(methyl)amino)-[1,2,4]triazolo[4,3-a]quinazolin-8-yl) methanol

(Step 1) Synthesis of 7-bromo-2-chloro-N-(3-fluorophenyl)-N-methylquinazoline-4-amine

Add 3-fluoro-N-methylaniline (203 mg, 1.619 mmol) and sodium hydride (38.9 mg, 1.619 mmol) to a solution of 7-bromo-2,4-dichloroquinazoline (450 mg, 1.619 mmol) in DMF (8.1 mL), and stir the mixture at room temperature for 1 hour. Dilute the reaction mixture with AcOEt and wash continuously with water and brine. Concentrate the organic layer under vacuum to obtain the desired product, which is used in the next step without further purification. LCMS (m/z) 367.98 [M+H] ⁺ .

(Step 2) Synthesis of 7-bromo-N-(3-fluorophenyl)-2-hydrazino-N-methylquinazoline-4-amine

Hydrazine hydrate (52.8 mg, 1.056 mmol) was added to a solution of 7-bromo-2-chloro-N-(3-fluorophenyl)-N-methylquinazolin-4-amine (387 mg, crude) in EtOH (5.3 mL), and the mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with AcOEt and washed continuously with water and brine. The organic layer was concentrated under vacuum to give the desired product, which was used in the next step without further purification. LCMS (m/z) 363.18 [M+H] ⁺ .

(Step 3) Synthesis of 8-bromo-N-(3-fluorophenyl)-N-methyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine

A mixture of 7-bromo-N-(3-fluorophenyl)-2-hydrazino-N-methylquinazoline-4-amine (300 mg, crude) and triethoxymethane (10 mL, 0.828 mmol) was stirred overnight at 100 °C. The reaction mixture was concentrated under vacuum. The residue was purified by column chromatography (Si column, _CHCl3 :MeOH = 10:0–9:1) to give the desired product. LCMS (m/z) 373.13 [M+H] ⁺ .

(Step 4) N-(3-fluorophenyl)-N-methyl-8-vinyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine synthesis

A mixture of 8-bromo-N-(3-fluorophenyl)-N-methyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine (232 mg, 0.623 mmol), _K₃PO₄ (265 mg, 1.247 mmol), Pd(OAc) _₂ (28.0 mg, 0.125 _mmol ), 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborhexacyclopentane (144 mg, 0.935 mmol), and tricyclohexylphosphine (35.0 mg, 0.125 mmol) was stirred overnight at 100 °C. The reaction mixture was concentrated under vacuum. The residue was purified by column chromatography (Si column, _CHCl₃ :MeOH = 10:0–9:1) to give the desired product. LCMS (m/z) 319.9 [M+H] ^⁺ .

(Step 5) Synthesis of 5-((3-fluorophenyl)(methyl)amino)-[1,2,4]triazolo[4,3-a]quinazolin-8-carboxaldehyde become

Osmium oxide (VIII) (0.2N in BuOH, 0.4 mL, 0.080 mmol) and sodium periodate (103 mg, 0.481 mmol) were added to a solution of N-(3-fluorophenyl)-N-methyl-8-vinyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine (128 mg, 0.401 mmol) in acetone/water (1:1, 2 mL) and the mixture was stirred overnight at room temperature. The reaction mixture was subjected to solid-phase extraction using a BondElut SCX box (Agilent) (washing with MeOH followed by elution with _NH₃ in MeOH), and the collected fraction was concentrated under vacuum. The residue was concentrated under vacuum to give the desired product. LCMS (m/z) 322.08 [M+H] ^⁺ .

(Step 6) (5-((3-fluorophenyl)(methyl)amino)-[1,2,4]triazolo[4,3-a]quinazolin-8-yl)methanol Synthesis

To a solution of 5-((3-fluorophenyl)(methyl)amino)-[1,2,4]triazolo[4,3-a]quinazolin-8-carboxaldehyde (crude, 129 mg, 0.4 mmol) in MeOH (2 mL), NaBH4 (16.65 mg, 0.440 mmol) was added, and the mixture was stirred overnight at room temperature. The reaction mixture was then concentrated under vacuum. The residue was purified by column chromatography (Si-column, _CHCl3 :MeOH = 10:0-9:1) to provide the desired product: ^¹H NMR (methanol- _d4 ) δ 9.48 (s, 1H), 8.18 (s, 1H), 7.48–7.33 (m, 2H), 7.23 (d, J = 8.8 Hz, 1H), 7.19–7.00 (m, 3H), 4.76 (s, 2H), 3.66 (s, 3H); LCMS (m/z) 324.1.

Example 190. 5-((4'-methoxy-[1,1'-diphenyl]-3-yl)(methyl)amino)-[1,2,4]triazolidine [4,3-a]quinazolin-8-carbaldehyde

Sodium periodate (0.235 g, 1.10 mmol) and potassium osmium tetroxide (VI) dihydrate (0.007 g, 0.02 mmol) were added to a stirred solution of N-(4'-methoxy-[1,1'-diphenyl]-3-yl)-N-methyl-8-vinyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine (Example 192) (0.150 g, 0.37 mmol) in THF/water (9 mL, 2:1) at 0 °C, and the mixture was stirred at room temperature for 2 hours. The reaction progress was monitored by TLC. After _the reaction was complete, the reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with brine, dried over _Na₂SO₄ , filtered, and evaporated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with 8% methanol/dichloromethane to provide the desired product: ^¹H NMR (DMSO- _d₆ ) δ 10.05 (s, 1H), 9.78 (s, 1H), 8.81 (d, J = 1.5 Hz, 1H), 7.69 (dd, J = 8.5, 1.5 Hz, 1H), 7.64–7.50 (m, 5H), 7.44 (t, J = 7.9 Hz, 1H), 7.27 (ddd, J = 7.9, 2.3, 1.0 Hz, 1H), 7.01–6.92 (m, 2H), 3.76 (s, 3H), 3.62 (s, 3H); LCMS (m/z) 410.2.

Example 191. N-(4'-(tert-butyl)-[1,1'-diphenyl]-3-yl)-N-methyl-8-(prop-1-yn-1-yl)- [1,2,4]triazolo[4,3-a]quinazolin-5-amine

Triphenylphosphine (0.048 g, 0.18 mmol), triethylamine (0.029 mL, 0.21 mmol), cuprous iodide (0.0078 g, 0.04 mmol), palladium acetate (0.009 g, 0.04 mmol), and 1-propyne (0.06 mL, 1.03 mmol) were added to a degassed solution of 8-bromo-N-(4'-(tert-butyl)-[1,1'-diphenyl]-3-yl)-N-methyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine (Example 186) (0.1 g, 0.21 mmol) in 1,4-dioxane (5 mL) at room temperature. The mixture was then heated to 100 °C for 6 hours. The reaction progress was monitored by TLC. After the reaction was complete, the reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with brine, dried over _{anhydrous Na₂SO₄} , filtered, and evaporated under reduced pressure. The residue was purified by preparative HPLC to provide the desired product: ^¹H NMR (DMSO- _d₆ ) δ 9.63 (s, ¹H), 8.40 (d, J = 1.6 Hz, ¹H), 7.58–7.50 (m, 4H), 7.50–7.37 (m, 3H), 7.33–7.24 (m, 2H), 7.17 (dd, J = 8.7, 1.6 Hz, ¹H), 3.59 (s, 3H), 2.09 (s, 3H), 1.28 (s, 9H); LCMS (m/z) 446.3.

Example 192. N-(4'-methoxy-[1,1'-diphenyl]-3-yl)-N-methyl-8-vinyl-[1,2,4]tri Azo[4,3-a]quinazolin-5-amine

At room temperature, potassium tert-butoxide (0.048 g, 0.43 mmol), tetrakis(triphenylphosphine)palladium(0) (0.025 g, 0.02 mmol), and 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborhexacyclopentane (0.05 g, 0.33 mmol) were added to a stirred solution of 8-bromo-N-(4'-methoxy-[1,1'-diphenyl]-3-yl)-N-methyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine (Example 173) (0.1 g, 0.22 mmol) in tert-butanol (5 mL), and the mixture was heated to 100 °C for 6 hours. The reaction progress was monitored by TLC. After the reaction was complete, the reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with brine, _dried over _Na₂SO₄ , filtered, and evaporated under reduced pressure. The residue was purified by preparative HPLC to provide the desired product: ^¹H NMR (DMSO-d6 ₎ )δ9.62(s,1H),8.39(d,J＝1.7Hz,1H),7.64–7.55(m,3H),7.53(dt,J＝7.9,1.3Hz ,1H),7.43(t,J＝7.8Hz,1H),7.35(dd,J＝8.9,1.7Hz,1H),7.28(d,J＝8.7Hz,1H), 7.25–7.16(m,1H),7.01–6.92(m,2H),6.78(dd,J＝17.6,10.9Hz,1H),6.16(d,J＝ 17.6Hz, 1H), 5.54 (d, J = 11.0Hz, 1H), 3.77 (s, 3H), 3.60 (s, 3H); LCMS (m/z) 408.2.

Example 193. N-(3'-(methyl(8-vinyl-[1,2,4]triazolo[4,3-a]quinazolin-5-yl)amino)- [1,1'-Diphenyl]-4-yl)acetamide

Cesium carbonate (0.267 g, 0.82 mmol) was added to a stirred solution of N-(3'-((8-bromo-[1,2,4]triazolo[4,3-a]quinazolin-5-yl)(methyl)amino)-[1,1'-diphenyl]-4-yl)acetamide (Example 174) (0.2 g, 0.41 mmol) in DMF (6 mL), and the mixture was degassed with argon for 10 min. Then, bis(triphenylphosphine)palladium(II) dichloride (0.029 g, 0.04 mmol) and 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborhexacyclopentane (0.127 g, 0.82 mmol) were added at room temperature. The mixture was heated to 100 °C in a sealed tube for 3 h. The reaction progress was monitored by TLC. After the reaction was complete, the reaction mixture was diluted with water and stirred for several minutes. The resulting solid was filtered and dried under vacuum. The residue was purified by preparative HPLC to provide the desired product: ^¹H NMR (DMSO- _d₆ ) δ 10.02 (s, ¹H), 9.62 (s, ¹H), 8.39 (d, J = 1.7 Hz, ¹H), 7.66–7.59 (m, 5H), 7.55 (dt, J = 8.0, 1.2 Hz, ¹H), 7.44 (t, J = 7.9 Hz, ¹H), 7.35 (dd, J = 8.8, 1.6 Hz, ¹H), 7.28 (d, J = 8.7 Hz, ¹H). Hz,1H),7.23(ddd,J＝8.0,2.2,1.0Hz,1H),6.78(dd,J＝17.6,11.0Hz,1H),6.16(d, J=17.6Hz, 1H), 5.54 (d, J=10.9Hz, 1H), 3.60 (s, 3H), 2.04 (s, 3H); LCMS (m/z) 435.1.

Example 194. N-(4'-(tert-butyl)-[1,1'-diphenyl]-3-yl)-N-methyl-8-vinyl-[1,2,4] Triazolo[4,3-a]quinazolin-5-amine

At room temperature, potassium tert-butoxide (0.046 g, 0.41 mmol), tetrakis(triphenylphosphine)palladium(0) (0.024 g, 0.02 mmol), and 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborhexacyclopentane (0.048 g, 0.31 mmol) were added to a stirred solution of 8-bromo-N-(4'-tert-butyl-[1,1'-diphenyl]-3-yl)-N-methyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine (Example 186) (0.1 g, 0.21 mmol) in tert-butanol (5 mL), and the mixture was heated to 100 °C for 6 hours. The reaction progress was monitored by TLC. After the reaction was complete, the reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with brine, _dried over _Na₂SO₄ , filtered, and evaporated under reduced pressure. The residue was purified by preparative HPLC to provide the desired product: ^¹H NMR (DMSO- _d₆ ) δ 9.62 (s, ¹H), 8.39 (d, J = 1.6 Hz, ¹H), 7.60–7.50 (m, 4H), 7.49–7.39 (m, 3H), 7.34 (dd, J = 8.7, 1.6 Hz, 1H), 7.31–7.24 (m, 2H), 6.78 (dd, J = 17.6, 11.0 Hz, 1H), 6.16 (d, J = 17.6 Hz, 1H), 5.54 (d, J = 11.0 Hz, 1H), 3.60 (s, 3H), 1.28 (s, 9H); LCMS (m/z) 434.3.

Example 195. N-(4'-(tert-butyl)-[1,1'-diphenyl]-3-yl)-8-chloro-N-methyl-[1,2,4]triazole [4,3-a]quinazolin-5-amine

4'-(tert-butyl)-N-methyl-[1,1'-diphenyl]-3-amine (0.150 g, 0.63 mmol) and potassium carbonate (0.115 g, 0.84 mmol) were added to a stirred solution of 5,8-dichloro-[1,2,4]triazolo[4,3-a]quinazoline (0.1 g, 0.42 mmol) in DMF (5 mL) at room temperature, and the mixture was stirred at room temperature for 4 hours. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with brine, dried over _Na₂SO₄ , filtered _, and evaporated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with 8% methanol/dichloromethane, followed by preparative HPLC purification to provide the desired product: ^¹H NMR (DMSO- _d₆ ) δ 9.63 (s, 1H), 8.65–8.42 (m, 1H), 7.60–7.52 (m, 4H), 7.48 (d, J = 8.0 Hz, 1H), 7.43 (dd, J = 8.4, 6.3 Hz, 2H), 7.33–7.25 (m, 3H), 3.59 (s, 3H), 1.28 (s, 9H); LCMS (m/z) 442.2.

Example 196. 8-Ethyl-N-(3-fluorophenyl)-N-methyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine

Osmium oxide (VIII) (0.2N in BuOH, 0.4 mL, 0.080 mmol) and sodium periodate (103 mg, 0.481 mmol) were added to a solution of N-(3-fluorophenyl)-N-methyl-8-vinyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine (128 mg, 0.401 mmol) in acetone/water (1:1, 2 mL), and the mixture was stirred overnight at room temperature. The reaction mixture was subjected to solid-phase extraction using a BondElut SCX box (Agilent) (washing with MeOH followed by elution with _NH3 in MeOH), and the collected fraction was concentrated under vacuum. The residue was concentrated under vacuum and purified by column chromatography (Si column, _CHCl3 :MeOH = 10:0–9:1) to obtain the desired product: ^¹H NMR (methanol- _d4 ) δ 9.46 (s, 1H), 8.09–7.99 (m, 1H), 7.44–7.37 (m, 1H), 7.28–7.22 (m, 1H), 7.12–7.03 (m, 4H), 3.64 (s, 3H), 2.80 (q, J = 7.6 Hz, 2H), 1.30–1.26 (m, 3H). LCMS (m/z) 322.1.

Example 197. (5-(3,4-dihydroquinoline-1(2H)-yl)-[1,2,4]triazolo[4,3-a]quinazolin-8-yl) methanol

(Step 1) 5-(3,4-dihydroquinoline-1(2H)-yl)-8-vinyl-[1,2,4]triazolo[4,3-a]quinazolin Synthesis

A mixture of 8-bromo-5-(3,4-dihydroquinoline-1(2H)-yl)-[1,2,4]triazolo[4,3-a]quinazoline (Example 205) (600 mg, 1.578 mmol), _K₃PO₄ (670 mg, 3.16 mmol), Pd(OAc) _₂ (70.9 mg, 0.316 mmol), _4,4,5,5 -tetramethyl-2-vinyl-1,3,2-dioxaborhexacyclopentane (365 mg, 2.367 mmol), and tricyclohexylphosphine (89 mg, 0.316 mmol) in dioxane/water (7.9 mL) was heated at 100 °C for 1 hour. The reaction mixture was concentrated under vacuum. The residue was purified by column chromatography (Si column, _CHCl₃ :MeOH = 10:0–9:1) to give the desired product. LCMS(m/z)328.13[M+H] ⁺ .

(Step 2) 5-(3,4-dihydroquinoline-1(2H)-yl)-[1,2,4]triazolo[4,3-a]quinazolin-8-carboxaldehyde synthesis

Osmium oxide (VIII) (98 mg, 0.385 mmol) and sodium periodate (823 mg, 3.85 mmol) were added to a solution of 5-(3,4-dihydroquinoline-1(2H)-yl)-8-vinyl-[1,2,4]triazolo[4,3-a]quinazoline (630 mg) in acetone/water (1:1, 9.6 mL), and the mixture was stirred overnight at room temperature. The reaction mixture was concentrated under vacuum to give the desired product as a crude product. The residue was used in the next step without further purification. LCMS (m/z) 330.08 [M+H] ⁺ .

(Step 3) (5-(3,4-dihydroquinoline-1(2H)-yl)-[1,2,4]triazolo[4,3-a]quinazolin-8-yl)methyl Synthesis of alcohols

To a solution of 5-(3,4-dihydroquinoline-1(2H)-yl)-[1,2,4]triazolo[4,3-a]quinazolin-8-carboxaldehyde (crude, 680 mg, 2.065 mmol) in DMF (10 mL), _NaBH₄ (86 mg, 2.271 mmol) was added, and the mixture was stirred overnight at room temperature. The mixture was concentrated under vacuum. The residue was purified by column chromatography (Si-column, _CHCl₃ :MeOH = 10:0-85:15) to provide the desired product: ^¹H NMR (methanol- _d₄) )δ9.50(s,1H),8.19(s,1H),7.59–7.47(m,1H),7.36–7.25(m,2H),7.05(tt,J＝7.5,1.0Hz,1H),6.93(t,J＝7.7Hz,1H),6.68(d,J＝ 8.0Hz, 1H), 4.78 (s, 2H), 4.09–3.95 (m, 2H), 3.61 (q, J = 7.0Hz, 1H), 2.93 (t, J = 6.6Hz, 2H), 2.15 (p, J = 6.7Hz, 2H); LCMS (m/z) 332.1.

Example 198. 5-(methyl(4'-methyl-[1,1'-diphenyl]-3-yl)amino)-[1,2,4]triazolo[4, [3-a] Quinazoline-8-carboxaldehyde

Sodium periodate (0.903 g, 4.22 mmol) and potassium osmium tetroxide (VI) dihydrate (0.026 g, 0.07 mmol) were added to a stirred solution of N-methyl-N-(4'-methyl-[1,1'-diphenyl]-3-yl)-8-vinyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine (Example 204) (0.550 g, 1.40 mmol) in THF/water (15 mL, 2:1) at 0 °C, and the mixture was stirred at room temperature for 16 hours. The reaction progress was monitored by TLC. After the reaction was complete, the reaction mixture was quenched with ice water and stirred for several minutes. The obtained solid was filtered and vacuum dried to provide the desired product: ^¹H NMR (DMSO- _d₆ ) δ 10.04 (s, 1H), 9.77 (s, 1H), 8.81 (d, J = 1.5 Hz, 1H), 7.68 (dd, J = 8.5, 1.5 Hz, 1H), 7.64 (t, J = 2.0 Hz, 1H), 7.56 (dt, J = 8.3, 1.4 Hz, 1H), 7.53 (d, J = 8.3 Hz, 3H), 7.46 (t, J = 7.8 Hz, 1H), 7.32–7.27 (m, 1H), 7.21 (d, J = 7.8 Hz, 2H), 3.62 (s, 3H), 2.31 (s, 3H); LCMS (m/z) 394.4.

Example 199. N-(3'-((8-formyl-[1,2,4]triazolo[4,3-a]quinazolin-5-yl)(methyl)amino (1,1'-diphenyl]-4-yl)acetamide

Sodium periodate (0.118 g, 0.55 mmol) and potassium osmium tetroxide (VI) dihydrate (0.003 g, 0.009 mmol) were added to a stirred solution of N-(3'-(methyl(8-vinyl-[1,2,4]triazolo[4,3-a]quinazolin-5-yl)amino)-[1,1'-diphenyl]-4-yl)acetamide (Example 193) (0.080 g, 0.18 mmol) in THF/water (6 mL, 2:1) at 0 °C, and the mixture was stirred at room temperature for 16 hours. The reaction progress was monitored by TLC. After the reaction was complete, the reaction mixture was diluted with water and stirred for several minutes. The resulting solid was filtered and dried under vacuum. The residue was purified by silica gel column chromatography, eluting with 8% methanol/dichloromethane to provide the desired product: ^¹H NMR (500MHz, DMSO- _d⁶ ) δ 10.05 (s, 1H), 10.01 (s, 1H), 9.78 (s, 1H), 8.81 (d, J = 1.5Hz, 1H), 7.69 (dd, J = 8.5, 1.5Hz, 1H), 7.61–7.52 (m, 7H), 7.45 (t, J = 7.9Hz, 1H), 7.28 (ddd, J = 8.0, 2.2, 1.0Hz, 1H), 3.62 (s, 3H), 2.04 (s, 3H); LCMS (m/z) 437.2.

Example 200. N-(3'-(methyl(8-(prop-1-yn-1-yl)-[1,2,4]triazolo[4,3-a]quinazolin-5- (1,1'-diphenyl)-4-yl)acetamide

Triethylamine (0.057 mL, 0.41 mmol) was added to a stirred and degassed solution of N-(3'-((8-bromo-[1,2,4]triazolo[4,3-a]quinazolin-5-yl)(methyl)amino)-[1,1'-diphenyl]-4-yl)acetamide (Example 174) (0.2 g, 0.41 mmol) in 1,4-dioxane (8 mL), and the mixture was degassed with argon for 10 min. Then, triphenylphosphine (0.097 g, 0.37 mmol), cuprous iodide (0.015 g, 0.08 mmol), palladium acetate (0.018 g, 0.07 mmol), and 1-propyne (0.15 mL, 2.06 mmol) were added at room temperature, and the mixture was heated to 100 °C in a sealed tube for 3 h. The reaction progress was monitored by TLC. After the reaction was complete, the reaction mixture was filtered through a diatomaceous earth bed and washed with ethyl acetate. The filtrate was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography, eluted with 4% methanol/dichloromethane, and purified by preparative HPLC to provide the desired product: ^¹H NMR (DMSO- _d₆ ) δ 10.01 (brs, ¹H), 9.63 (s, ¹H), 8.40 (d, J = 1.6 Hz, ¹H), 7.66–7.52 (m, 6H), 7.44 (t, J = 7.8 Hz, ¹H), 7.27 (d, J = 8.7 Hz, ¹H), 7.23 (ddd, J = 8.1, 2.3, 1.0 Hz, ¹H), 7.18 (dd, J = 8.7, 1.6 Hz, ¹H), 3.58 (s, 3H), 2.09 (s, 3H), 2.04 (s, 3H); LCMS (m/z) 447.2.

Example 201. (5-(methyl(4'-methyl-[1,1'-diphenyl]-3-yl)amino)-[1,2,4]triazolo[4, [3-a]quinazolin-8-yl)methanol

Sodium borohydride (0.071 g, 1.88 mmol) was added to a stirred solution of 5-(methyl(4'-methyl-[1,1'-diphenyl]-3-yl)amino)-[1,2,4]triazolo[4,3-a]quinazolin-8-carboxaldehyde (Example 198) (0.370 g, 0.94 mmol) in 10 mL of THF at 0 °C, and the mixture was stirred at room temperature for 4 hours. The reaction progress was monitored by TLC. After the reaction was complete, the reaction mixture was quenched with ice water and stirred for several minutes. The resulting solid was filtered and dried under vacuum. The residue was purified by preparative HPLC to provide the desired product: ^¹H NMR (DMSO- _d₆ ) δ 9.63 (s, ¹H), 8.21 (d, J = 1.6 Hz, ¹H), 7.60 (t, J = 1.9 Hz, ¹H), 7.58–7.51 (m, ³H), 7.44 (t, J = 7.8 Hz, ¹H), 7.30 (d, J = 8.6 Hz, ¹H), 7.25–7.20 (m, ³H), 7.14 (dd, J = 8.8, 1.5 Hz, ¹H), 5.50 (s, ¹H), 4.60 (s, 2H), 3.60 (s, ³H), 2.31 (s, ³H); LCMS (m/z) 396.4.

Example 202. (5-((4'-methoxy-[1,1'-diphenyl]-3-yl)(methyl)amino)-[1,2,4]triazolidine [4,3-a]quinazolin-8-yl)methanol

Sodium borohydride (0.018 g, 0.49 mmol) was added to a stirred solution of 5-((4'-methoxy-[1,1'-diphenyl]-3-yl)(methyl)amino)-[1,2,4]triazolo[4,3-a]quinazolin-8-carboxaldehyde (Example 190) (0.1 g, 0.24 mmol) in THF/water (5 mL, 1:1) at 0 °C, and the mixture was stirred at room temperature for 2 hours. The reaction progress was monitored by TLC. After the reaction was complete, the reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with brine, dried over _Na₂SO₄ , filtered _, and evaporated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with 8% methanol/dichloromethane to provide the desired product: ^¹H NMR (DMSO- _d₆ ) δ 9.64 (s, 1H), 8.21 (d, J = 1.6 Hz, 1H), 7.64–7.54 (m, 3H), 7.55–7.48 (m, 1H), 7.42 (t, J = 7.8 Hz, 1H), 7.30 (d, J = 8.6 Hz, 1H), 7.25–7.08 (m, 2H), 7.03–6.90 (m, 2H), 5.50 (t, J = 5.6 Hz, 1H), 4.60 (d, J = 5.6 Hz, 2H), 3.77 (s, 3H), 3.59 (s, 3H); LCMS (m/z) 412.5.

Example 203. N-(3'-((8-(hydroxymethyl)-[1,2,4]triazolo[4,3-a]quinazolin-5-yl)(methyl) (amino)-[1,1'-diphenyl]-4-yl)acetamide

Sodium borohydride (0.038 g, 1.01 mmol) was added to a stirred solution of N-(3'-((8-formyl-[1,2,4]triazolo[4,3-a]quinazolin-5-yl)(methyl)amino)-[1,1'-diphenyl]-4-yl)acetamide (Example 199) (0.220 g, 0.50 mmol) in 6 mL of THF at 0 °C, and the mixture was stirred at room temperature for 4 hours. The reaction progress was monitored by TLC. After the reaction was complete, the reaction mixture was diluted with water and stirred for several minutes. The resulting solid was filtered and dried under vacuum. The residue was purified by preparative HPLC to provide the desired product: ^¹H NMR (DMSO- _d₆ ) δ 10.01 (s, ¹H), 9.64 (s, ¹H), 8.21 (d, J = 1.6 Hz, ¹H), 7.65–7.50 (m, 6H), 7.43 (t, J = 7.9 Hz, 1H), 7.30 (d, J = 8.6 Hz, 1H), 7.21 (ddd, J = 7.9, 2.1, 1.0 Hz, 1H), 7.14 (dd, J = 8.7, 1.6 Hz, 1H), 5.49 (t, J = 5.6 Hz, 1H), 4.60 (d, J = 5.6 Hz, 2H), 3.59 (s, 3H), 2.04 (s, 3H); LCMS (m/z) 439.2.

Example 204. N-Methyl-N-(4'-methyl-[1,1'-diphenyl]-3-yl)-8-vinyl-[1,2,4]triazole [4,3-a]quinazolin-5-amine

Potassium tert-butoxide (0.228 g, 2.03 mmol) was added to a stirred solution of 8-bromo-N-methyl-N-(4'-methyl-[1,1'-diphenyl]-3-yl)-[1,2,4]triazolo[4,3-a]quinazolin-5-amine (Example 172) (0.3 g, 0.68 mmol) in tert-butanol (10 mL), and the mixture was degassed with argon for 10 min. Then, tetrakis(triphenylphosphine)palladium(0) (0.156 g, 0.13 mmol) and 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborhecyclopentane (0.208 g, 1.35 mmol) were added at room temperature, and the mixture was heated to 80 °C in a sealed tube for 4 h. The reaction progress was monitored by TLC. After the reaction was complete, the reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with brine, dried over _Na₂SO₄ , filtered _, and evaporated under reduced pressure. The residue was purified by preparative HPLC to provide the desired product: ^¹H NMR (500MHz, DMSO-d6 ₎ )δ9.62(s,1H),8.39(d,J＝1.6Hz,1H),7.62(t,J＝1.9Hz,1H),7.57–7.51(m ,3H),7.45(t,J＝7.8Hz,1H),7.35(dd,J＝8.7,1.7Hz,1H),7.28(d,J＝8.7Hz ,1H),7.26–7.20(m,3H),6.78(dd,J＝17.6,11.0Hz,1H),6.15(d,J＝17.6Hz ,1H),5.54(d,J=11.0Hz,1H),3.60(s,3H),2.31(s,3H); LCMS(m/z)392.3.

Example 205. 8-Bromo-5-(3,4-dihydroquinoline-1(2H)-yl)-[1,2,4]triazolo[4,3-a]quinazolin

(Step 1) Synthesis of 7-bromo-2-chloro-4-(3,4-dihydroquinolin-1(2H)-yl)quinazolin

Add 1,2,3,4-tetrahydroquinoline (0.958 g, 7.20 mmol) and sodium hydride (0.173 g, 7.20 mmol) to a solution of 6-bromo-2,4-dichloroquinazoline (2 g, 7.20 mmol) in DMF (36 mL), and stir the mixture at room temperature for 1 hour. Dilute the reaction mixture with AcOEt, wash continuously with water and brine, and dry over _Na₂SO₄ . Concentrate the organic layer under vacuum. Use the residue for the next step without further purification. _LCMS (m/z) 376.03 [M+H] ^⁺ .

(Step 2) Synthesis of 7-bromo-4-(3,4-dihydroquinolin-1(2H)-yl)-2-hydrazoline

Hydrazine hydrate (0.326 g, 6.51 mmol) was added to a solution of 7-bromo-2-chloro-4-(3,4-dihydroquinolin-1(2H)-yl)quinazoline (1.22 g, 3.26 mmol) in EtOH (16.28 mL), and the mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted with AcOEt and washed continuously with water and brine. The organic layer was concentrated under vacuum. The residue was used for the next step without further purification. LCMS (m/z) 370.08 [M+H]+.

(Step 3) Synthesis of 8-bromo-5-(3,4-dihydroquinolin-1(2H)-yl)-[1,2,4]triazolo[4,3-a]quinazolin become

A mixture of 7-bromo-4-(3,4-dihydroquinolin-1(2H)-yl)-2-hydrazinoquinazoline (crude, 1.1 g, 2.97 mmol) and triethoxymethane (15 mL, 2.97 mmol) was stirred overnight at 100 °C. The reaction mixture was concentrated under vacuum. The residue was purified by column chromatography (Si-column, _CHCl3 :MeOH = 10:0–9:1) to provide the desired product: ^¹H NMR (DMSO- _d6) )δ9.71(s,1H),8.74(d,J＝1.9Hz,1H),7.57(dd,J＝8.8,1.9Hz,1H),7.45(d,J＝8.8Hz,1H),7.27(d,J＝7.1Hz,1H),7.01(td,J＝7.4,1.3Hz,1H), 6.95(td,J＝7.6,1.7Hz,1H),6.78–6.74(m,1H),3.90(t,J＝6.5Hz,2H),2.89(t,J＝6.6Hz,2H),2.08(q,J＝6.6Hz,2H); LCMS(m/z)380.1/382.1.

Example 206. 7-Fluoro-N5-methyl-N5-phenyl-[1,2,4]triazolo[4,3-a]quinazolin-5,8-diamine

(Step 1) 8-Azide-7-fluoro-N-methyl-N-phenyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine synthesis

Sodium azide (20.68 mg, 0.318 mmol) was added to a solution of 7,8-difluoro-N-methyl-N-phenyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine (Example 182) (20 mg, 0.064 mmol) in DMSO (321 μL), and the mixture was heated to 90 °C for 2 hours. The reaction mixture was diluted with AcOEt, washed continuously with water and brine, and dried over _Na₂SO₄ . The organic layer was concentrated under vacuum. The resulting residue was used in the next step without further purification. _LCMS (m/z) 336.14 [M+H] ^⁺ .

(Step 2) Synthesis of 7-fluoro-N5-methyl-N5-phenyl-[1,2,4]triazolo[4,3-a]quinazolin-5,8-diamine

The resulting mixture of 8-azido-7-fluoro-N-methyl-N-phenyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine (80 mg, 0.239 mmol) and Pd/C (10 mg) in ethanol (1.2 mL) was heated to 60 °C under a H2 atmosphere for 2 days. Pd/C was removed by filtration, and the filtrate was concentrated under vacuum. The residue was purified by column chromatography (Si-column, _CHCl3 :MeOH = 0-15%) to provide the desired product: ^¹H NMR (DMSO- _d6 ) δ 9.31 (s, 1H), 7.47–7.36 (m, 2H), 7.31–7.21 (m, 4H), 6.65 (d, J = 13.3 Hz, 1H), 6.58 (s, 2H), 3.48 (s, 3H); LCMS (m/z) 309.1.

Example 207. N5-Ethyl-7-fluoro-N5-phenyl-[1,2,4]triazolo[4,3-a]quinazolin-5,8-diamine

(Step 1) Synthesis of 2-chloro-N-ethyl-6,7-difluoro-N-phenylquinazoline-4-amine

Sodium hydride (0.112 g, 4.68 mmol) and N-methylaniline (0.567 g, 4.68 mmol) were added to a solution of 2,4-dichloro- _6,7 -difluoroquinazoline (1.1 g, 4.68 mmol) in DMF (23.4 mL), and the mixture was stirred at room temperature for 0.5 h. The reaction mixture was diluted with AcOEt, washed continuously with water and brine, and dried over _Na₂SO₄ . The organic layer was concentrated under vacuum. The resulting residue was used in the next step without further purification. LCMS (m/z) 320.14 [M+H] ^⁺ .

(Step 2) Synthesis of N-ethyl-6,7-difluoro-2-hydrazino-N-phenylquinazoline-4-amine

Hydrazine hydrate (0.038 g, 0.760 mmol) was slowly added to a stirred solution of 2-chloro-N-ethyl-6,7-difluoro-N-phenylquinazoline-4-amine (crude, 0.81 g, 2.53 mmol) in ethanol (12.67 mL) at room temperature. After 1 h and 2 h, an additional fraction of hydrazine hydrate (0.038 g × 2, 1.520 mmol) was slowly added to the solution, and stirring was continued for another 1 h. The mixture was diluted with AcOEt, washed continuously with water and brine, and dried over _Na₂SO₄ . The organic layer was concentrated under vacuum. The resulting residue was used for the next step without further purification. _LCMS (m/z) 316.14 [M+H] ^⁺ .

(Step 3) Synthesis of N-ethyl-7,8-difluoro-N-phenyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine

A mixture of N-ethyl-6,7-difluoro-2-hydrazino-N-phenylquinazoline-4-amine (crude, 0.69 g, 2.188 mmol) and triethyl orthoformate (10 mL, 2.188 mmol) was heated to 100 °C for 3 hours. After the reaction was complete, the mixture was concentrated under vacuum. The residue was purified by column chromatography (Si column, _CHCl3 :MeOH = 10:0-9:1) to obtain the desired product. LCMS (m/z) 326.14 [M+H] ⁺ .

(Step 4) 8-Azide-N-ethyl-7-fluoro-N-phenyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine synthesis

Sodium azide (84 mg, 1.291 mmol) was added to a solution of N-ethyl-7,8-difluoro-N-phenyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine (crude, 400 mg, 1.23 mmol) in DMSO (6148 μL), and the mixture was heated to 60 °C for 2 hours. The reaction mixture was diluted with AcOEt, washed continuously with water and brine, and dried over _Na₂SO₄ . The organic layer was concentrated under vacuum. The resulting residue was used in the next step without further purification. _LCMS (m/z) 349.14 [M+H] ^⁺ .

(Step 5) Synthesis of N5-ethyl-7-fluoro-N5-phenyl-[1,2,4]triazolo[4,3-a]quinazolin-5,8-diamine

A mixture of 8-azido-N-ethyl-7-fluoro-N-phenyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine (crude, 0.46 g, 1.321 mmol) and Pd/C (30 mg) in ethanol (6.6 mL) was heated to 60 °C overnight. Pd/C was removed by filtration, and the filtrate was concentrated under vacuum. The residue was purified by column chromatography (Si-column, _CHCl3 :MeOH = 10:0-9:1) to provide the desired product: ^¹H NMR (methanol- _d4 ) δ 9.17 (s, 1H), 7.55–7.43 (m, 2H), 7.41–7.32 (m, 1H), 7.31–7.17 (m, 3H), 6.68 (dd, J = 13.5, 1.3 Hz, 1H), 4.22 (q, J = 6.9 Hz, 2H), 1.33 (t, J = 7.0 Hz, 3H); LCMS (m/z) 323.1.

Example 208. 7-Fluoro-N5-(3-fluorophenyl)-N5-methyl-[1,2,4]triazolo[4,3-a]quinazolin-5,8- diamine

(Step 1) Synthesis of 2-chloro-6,7-difluoro-N-(3-fluorophenyl)-N-methylquinazoline-4-amine

Add 3-fluoro-N-methylaniline (0.559 g, 4.47 mmol) and sodium hydride (0.107 g, 4.47 mmol) to a solution of 2,4-dichloro-6,7-difluoroquinazoline (1.05 g, 4.47 mmol) in DMF (22.3 mL), and stir the mixture at room temperature for 1 hour. Dilute the reaction mixture with AcOEt, then wash continuously with water and brine, and dry over _Na₂SO₄ . Concentrate the organic layer under vacuum. Use the resulting residue for the next step without further purification. _LCMS (m/z) 324.04 [M+H] ^⁺ .

(Step 2) Synthesis of 6,7-difluoro-N-(3-fluorophenyl)-2-hydrazino-N-methylquinazoline-4-amine

Hydrazine hydrate (0.118 g, 2.354 mmol) was slowly added to a stirred solution of 2-chloro-6,7-difluoro-N-(3-fluorophenyl)-N-methylquinazoline-4-amine (crude, 2.54 g, 7.85 mmol) in ethanol (39.2 mL) at room temperature. After 1 h and 2 h, an additional fraction of hydrazine hydrate (0.118 g × 4.708 mmol) was slowly added to the solution, and stirring was continued for another 1 h. The mixture was diluted with AcOEt, washed continuously with water and brine, and dried over _Na₂SO₄ . The organic layer was concentrated under vacuum. The resulting residue was used for the next step without further purification. _LCMS (m/z) 320.14 [M+H] ^⁺ .

(Step 3) 7,8-Difluoro-N-(3-fluorophenyl)-N-methyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine synthesis

A mixture of 6,7-difluoro-N-(3-fluorophenyl)-2-hydrazino-N-methylquinazoline-4-amine (crude, 0.51 g, 1.597 mmol) and triethoxymethane (5 mL, 1.597 mmol) was stirred at 100 °C for 4 hours. The reaction mixture was concentrated under vacuum. The residue was purified by column chromatography (Si column, _CHCl3 :MeOH = 0-15%) to give the desired product. LCMS (m/z) 330.09 [M+H] ⁺ .

(Step 4) 8-Azide-7-fluoro-N-(3-fluorophenyl)-N-methyl-[1,2,4]triazolo[4,3-a]quinazolin- Synthesis of 5-amines

Sodium azide (0.057 g, 0.881 mmol) was added to a solution of 7,8-difluoro-N-(3-fluorophenyl)-N-methyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine (0.29 g, 0.881 mmol) in DMSO (2.94 mL), and the mixture was stirred at 60 °C for 2 h. The reaction mixture was diluted with AcOEt, washed continuously with water and brine, and dried over _Na₂SO₄ . The organic layer was concentrated under vacuum. The resulting residue was _used in the next step without further purification.

(Step 5) 7-Fluoro-N5-(3-Fluorophenyl)-N5-methyl-[1,2,4]triazolo[4,3-a]quinazolin-5,8-diamine Synthesis

Pd/C (30 mg) was added to a solution of 8-azido-7-fluoro-N-(3-fluorophenyl)-N-methyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine (crude, 0.32 g, 0.908 mmol) in ethanol (4.54 mL), and the suspension was stirred at 60 °C under a _H₂ atmosphere for 5 hours. Pd/C was removed by filtration, and the filtrate was concentrated under vacuum. The residue was purified by column chromatography (Si-column, _CHCl3 :MeOH = 10:0–9:1) to provide the desired product: ^¹H NMR (DMSO- _d6 ) δ 9.37 (s, 1H), 7.38 (td, J = 8.2, 6.8 Hz, 1H), 7.28 (d, J = 7.9 Hz, 1H), 7.19 (dt, J = 10.8, 2.3 Hz, 1H), 7.10–6.97 (m, 2H), 6.77 (d, J = 12.9 Hz, 1H), 6.67 (s, 2H), 3.49 (s, 3H); LCMS (m/z) 327.1.

Example 209. (5-((4'-chloro-[1,1'-diphenyl]-3-yl)(methyl)amino)-[1,2,4]triazolo[4, [3-a]quinazolin-8-yl)methanol

Sodium borohydride (0.018 g, 0.48 mmol) was added to a stirred solution of 5-((4'-chloro-[1,1'-diphenyl]-3-yl)(methyl)amino)-[1,2,4]triazolo[4,3-a]quinazolin-8-carboxaldehyde (Example 211) (0.1 g, 0.24 mmol) in tetrahydrofuran (5 mL), and the mixture was stirred at room temperature for 3 hours. The reaction progress was monitored by TLC. After the reaction was complete, the reaction mixture was diluted with water and extracted with 10% methanol/dichloromethane. The organic layer was washed with brine, dried _over anhydrous _Na₂SO₄ , filtered, and evaporated under reduced pressure to give the crude compound. The crude product was purified by preparative HPLC to provide the desired compound: ^¹H NMR (DMSO- _d₆ ) δ 9.64 (s, ¹H), 8.21 (d, J = 1.6 Hz, ¹H), 7.72–7.64 (m, ³H), 7.57 (dt, J = 8.1, 1.3 Hz, ¹H), 7.50–7.43 (m, ³H), 7.32–7.24 (m, ²H), 7.14 (dd, J = 8.6, 1.6 Hz, ¹H), 5.50 (t, J = 5.6 Hz, ¹H), 4.61 (d, J = 5.4 Hz, ²H), 3.60 (s, ³H); LCMS (m/z) 416.4.

Example 210. N-(4'-chloro-[1,1'-diphenyl]-3-yl)-N-methyl-8-vinyl-[1,2,4]triazolidine [4,3-a]quinazolin-5-amine

At room temperature, potassium tert-butoxide (0.096 g, 0.86 mmol), tetrakis(triphenylphosphine)palladium(0) (0.049 g, 0.04 mmol), and 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborhexacyclopentane (0.099 g, 0.65 mmol) were added to a stirred solution of 8-bromo-N-(4'-chloro-[1,1'-diphenyl]-3-yl)-N-methyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine (Example 185) (0.2 g, 0.43 mmol) in tert-butanol (5 mL), and the mixture was heated to 100 °C for 6 hours. The reaction progress was monitored by TLC. After the reaction was complete, the reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with brine, dried over _{anhydrous Na₂SO₄} , filtered, and evaporated under reduced pressure to give a crude residue. The residue was purified by preparative HPLC to provide the desired product: ^¹H NMR (DMSO- _d₆ ) δ 9.63 (s, ¹H), 8.39 (d, J = 1.6 Hz, ¹H), 7.71–7.64 (m, ³H), 7.58 (dt, J = 8.1, 1.3 Hz, ¹H), 7.51–7.44 (m, ³H), 7.35 (dd, J = 8.7, 1.6 Hz, ¹H), 7.32–7.25 (m, ²H), 6.78 (dd, J = 17.6, 10.9 Hz, ¹H), 6.16 (d, J = 17.6 Hz, ¹H), 5.54 (d, J = 10.9 Hz, ¹H), 3.60 (s, ³H); LCMS (m/z) 412.4.

Example 211. 5-((4'-chloro-[1,1'-diphenyl]-3-yl)(methyl)amino)-[1,2,4]triazolo[4, [3-a] Quinazoline-8-carboxaldehyde

Sodium periodate (0.218 g, 1.02 mmol) and potassium osmium tetroxide (VI) dihydrate (0.006 g, 0.02 mmol) were added to a stirred solution of N-(4'-chloro-[1,1'-diphenyl]-3-yl)-N-methyl-8-vinyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine (Example 210) (0.140 g, 0.34 mmol) in a mixture of tetrahydrofuran/water (13 mL, 10:3) at 0 °C, and the mixture was stirred at room temperature for 2 hours. The reaction progress was monitored by TLC. After the reaction was complete, the reaction mixture was diluted with ice water. The resulting solid was filtered and dried under vacuum to give a crude residue. The residue was purified by silica gel column chromatography, eluting with 6% methanol/dichloromethane to provide the desired product: ^¹H NMR (DMSO- _d₆ ) δ 10.05 (s, 1H), 9.79 (s, 1H), 8.81 (d, J = 1.5 Hz, 1H), 7.72–7.64 (m, 4H), 7.62–7.57 (m, 1H), 7.53 (d, J = 8.5 Hz, 1H), 7.49–7.43 (m, 3H), 7.35 (ddd, J = 7.8, 2.1, 1.0 Hz, 1H), 3.62 (s, 3H); LCMS (m/z) 414.4.

Example 212. 5-((4'-(tert-butyl)-[1,1'-diphenyl]-3-yl)(methyl)amino)-[1,2,4]triazole [4,3-a]quinazolin-8-carbaldehyde

Sodium periodate (0.533 g, 2.49 mmol) and potassium osmium tetroxide (VI) dihydrate (0.015 g, 0.04 mmol) were added to a stirred solution of N-(4'-(tert-butyl)-[1,1'-diphenyl]-3-yl)-N-methyl-8-vinyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine (Example 194) (0.360 g, 0.83 mmol) in THF/water (20 mL, 2:1) at 0 °C, and the mixture was stirred at room temperature for 16 hours. The reaction progress was monitored by TLC. After the reaction was complete, the reaction mixture was diluted with ice water. The resulting solid was filtered and dried under vacuum. The crude solid was purified by preparative HPLC to provide the desired product: ^¹H NMR (DMSO- _d₆ ) δ 10.05 (s, 1H), 9.78 (s, 1H), 8.81 (d, J = 1.5 Hz, 1H), 7.68 (dd, J = 8.5, 1.5 Hz, 1H), 7.60 (m, 1H), 7.58–7.51 (m, 4H), 7.49 (m, 1H), 7.43–7.39 (m, 2H), 7.33 (ddd, J = 7.8, 2.2, 1.1 Hz, 1H), 3.63 (s, 3H), 1.27 (s, 9H); LCMS (m/z) 436.3.

Example 213. (5-((4'-(tert-butyl)-[1,1'-diphenyl]-3-yl)(methyl)amino)-[1,2,4]triazole [4,3-a]quinazolin-8-yl)methanol

Sodium borohydride (0.015 g, 0.41 mmol) was added to a stirred solution of 5-((4'-(tert-butyl)-[1,1'-diphenyl]-3-yl)(methyl)amino)-[1,2,4]triazolo[4,3-a]quinazolin-8-carboxaldehyde (Example 212) (0.09 g, 0.21 mmol) in THF/water (5 mL, 1:1) at 0 °C, and the mixture was stirred at room temperature for 4 hours. The reaction progress was monitored by TLC. After the reaction was complete, the reaction mixture was diluted with ice water and extracted with ethyl acetate. The organic layer was washed with brine, dried over _Na₂SO₄ , filtered _, and evaporated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with 4% methanol/dichloromethane to provide the desired product: ^¹H NMR (DMSO- _d₆ ) δ 9.63 (s, 1H), 8.21 (d, J = 1.6 Hz, 1H), 7.61–7.51 (m, 4H), 7.49–7.39 (m, 3H), 7.29 (d, J = 8.6 Hz, 1H), 7.25 (ddd, J = 8.0, 2.3, 1.1 Hz, 1H), 7.14 (d, J = 1.6 Hz, 1H), 5.49 (t, J = 5.6 Hz, 1H), 4.60 (d, J = 5.4 Hz, 2H), 3.60 (s, 3H), 1.28 (s, 9H); LCMS (m/z) 438.5.

Example 214. N-(4'-chloro-[1,1'-diphenyl]-3-yl)-N-methyl-8-(prop-1-yn-1-yl)-[1,2, 4] Triazolo[4,3-a]quinazolin-5-amine

At room temperature, triphenylphosphine (0.051 g, 0.19 mmol), triethylamine (0.03 mL, 0.21 mmol), cuprous iodide (0.008 g, 0.04 mmol), palladium acetate (0.010 g, 0.04 mmol), and 1-propyne (0.13 mL, 2.16 mmol) were added to a stirred and degassed solution of 8-bromo-N-(4'-chloro-[1,1'-diphenyl]-3-yl) in 1,4-dioxane (3 mL), and the mixture was heated to 100 °C for 6 hours. The reaction progress was monitored by TLC. After the reaction was complete, the reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with brine, dried over _Na₂SO₄ , filtered _, and evaporated under reduced pressure. The residue was purified by preparative HPLC to provide the desired product: ^¹H NMR (500MHz, DMSO- _d₆ ) δ 9.64 (s, ¹H), 8.40 (d, J = 1.6 Hz, ¹H), 7.69–7.63 (m, ³H), 7.57 (ddd, J = 7.9, 1.9, 1.1 Hz, ¹H), 7.50–7.44 (m, ³H), 7.31 (ddd, J = 8.0, 2.2, 1.0 Hz, ¹H), 7.27 (d, J = 8.7 Hz, ¹H), 7.18 (dd, J = 8.6, 1.6 Hz, ¹H), 3.59 (s, ³H), 2.09 (s, ³H); LCMS (m/z) 424.4.

Example 215. 8-Bromo-7-fluoro-N-methyl-N-phenyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine

Copper(II) bromide (49.1 mg, 0.220 mmol) and tert-butyronitrile (24.75 mg, 0.240 mmol) were added to a solution of 7-fluoro-N5-methyl-N5-phenyl-[1,2,4]triazolo[4,3-a]quinazolin-5,8-diamine (Example 206) (25 mg, 0.081 mmol) in acetonitrile ( ₁ mL), and the mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted with AcOEt, washed continuously with water and brine, and dried over _Na₂SO₄ . The organic layer was concentrated under vacuum. The resulting residue was purified by column chromatography (Si column, _CHCl₃ :MeOH = 0-15%) to give the crude product. The reaction mixture was purified by solid-phase extraction (washing with MeOH followed by elution with NH₃ in MeOH) using a Bond Elut _SCX box (Agilent), and the collected fractions were concentrated to provide the desired products: ^¹H NMR (methanol- _d⁴⁻ ) δ 9.33 (s, 1H), 8.54 (d, J = 6.0 Hz, 1H), 7.41–7.36 (m, 2H), 7.33–7.27 (m, 1H), 7.25–7.21 (m, 2H), 6.82 (d, J = 10.3 Hz, 1H), 3.55 (s, 3H); LCMS (m/z) 374.1/375.2.

Example 216. 7-Fluoro-5-(7-Fluoro-3,4-dihydroquinoline-1(2H)-yl)-[1,2,4]triazolo[4,3-a]quinoline Azoline-8-amine

(Step 1) Synthesis of methyl 3-(4-fluoro-2-nitrophenyl)acrylate

A mixture of 4-fluoro-2-nitroaniline (200 mg, 1.281 mmol), methyl acrylate (132 mg, 1.537 mmol), tert-butyronitrile (145 mg, 1.409 mmol), and Pd(OAc) _₂ (57.5 mg, 0.256 mmol) in MeOH (6.4 mL) was stirred at 60 °C for 4 hours. The reaction mixture was diluted with AcOEt and washed continuously with water and brine. The organic layer was concentrated under vacuum to give the desired product.

(Step 2) Synthesis of 7-fluoro-3,4-dihydroquinoline-2(1H)-one

A mixture of methyl 3-(4-fluoro-2-nitrophenyl)acrylate (163 mg, 0.724 mmol) and Pd(OAc) _₂ (163 mg, 0.724 mmol) in MeOH (3.6 mL) was stirred overnight at 60 °C. The mixture was concentrated under vacuum. The residue was purified by column chromatography (Si column, hexane:AcOEt = 10:0-9:1) to give the desired product. LCMS (m/z) 166.14 [M+H] ^⁺ .

(Step 3) Synthesis of 7-fluoro-1,2,3,4-tetrahydroquinoline

The mixture of 7-fluoro-3,4-dihydroquinoline-2(1H)-one (97 mg, 0.587 mmol) and _BH3 (12.19 mg, 0.881 mmol) in THF (0.2 M solution) in THF (2.9 mL) was stirred overnight at 50 °C. The reaction mixture was then concentrated under vacuum. The residue was purified by column chromatography (Si-column, hexane:AcOEt = 10:0-9:1) to obtain the desired product: ^¹H NMR (400MHz, _CDCl₃ ) δ 6.85 (ddt, J = 8.4, 6.6, 1.0Hz, 1H), 6.27 (td, J = 8.5, 2.6Hz, 1H), 6.15 (dd, J = 10.8, 2.6Hz, 1H), 3.39–3.20 (m, 2H), 2.70 (t, J = 6.4Hz, 2H), 2.05–1.83 (m, 2H).

(Step 4) Synthesis of 2-chloro-6,7-difluoro-4-(7-fluoro-3,4-dihydroquinolin-1(2H)-yl)quinazolin

To a solution of 2,4-dichloro-6,7-difluoroquinazoline (0.89 g, 3.79 mmol) in DMF (18.93 mL), 7-fluoro-1,2,3,4-tetrahydroquinoline (0.573 g, 3.79 mmol) and sodium hydride (0.091 g, 3.79 mmol) were added, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted with AcOEt and washed continuously with water and brine. The organic layer was concentrated under vacuum. The residue was used for the next step without further purification. LCMS (m/z) 350.14 [M+H] ⁺ .

(Step 5) Synthesis of 6,7-difluoro-4-(7-fluoro-3,4-dihydroquinolin-1(2H)-yl)-2-hydrazoline

Hydrazine hydrate (0.015 g, 0.3 mmol) was slowly added to a solution of 2-chloro-6,7-difluoro-4-(7-fluoro-3,4-dihydroquinolin-1(2H)-yl)quinazoline (0.35 g, crude) in EtOH (5 mL), and the mixture was stirred at room temperature for 30 min. After 0.5 h and 1 h, additional portions of hydrazine hydrate (0.015 g × 2, 0.6 mmol) were slowly added to the solution, and stirring was continued for 1 h. The reaction mixture was diluted with AcOEt and washed continuously with water and brine. The organic layer was concentrated under vacuum. The residue was used for the next step without further purification. LCMS (m/z) 346.14 [M+H] ⁺ .

(Step 6) 7,8-Difluoro-5-(7-fluoro-3,4-dihydroquinolin-1(2H)-yl)-[1,2,4]triazolo[4,3-a]quinoline Synthesis of azoline

A mixture of 6,7-difluoro-4-(7-fluoro-3,4-dihydroquinolin-1(2H)-yl)-2-hydrazinoquinazoline (0.21 g, crude) and triethoxymethane (10 mL, 0.608 mmol) was stirred overnight at 100 °C. The reaction mixture was concentrated under vacuum. The residue was purified by column chromatography (Si column, _CHCl3 :MeOH = 10:0-85:15) to give the desired product. LCMS (m/z) 356.0 [M+H]+.

(Step 7) 8-Azide-7-fluoro-5-(7-fluoro-3,4-dihydroquinoline-1(2H)-yl)-[1,2,4]triazolo[4, Synthesis of 3-a]quinazoline

A mixture of 7,8-difluoro-5-(7-fluoro-3,4-dihydroquinolin-1(2H)-yl)-[1,2,4]triazolo[4,3-a]quinazoline (50 mg, 0.141 mmol) and sodium azide (4.57 mg, 0.07 mmol) in DMSO (0.35 mL) was stirred at 60 °C for 30 min. The mixture was diluted with AcOEt and washed continuously with water and brine. The organic layer was concentrated under vacuum to obtain the desired product, which was used in the next step without further purification. LCMS (m/z) 379.19 [M+H]+.

(Step 8) 7-Fluoro-5-(7-Fluoro-3,4-dihydroquinolino-1(2H)-yl)-[1,2,4]triazolo[4,3-a]quinazole Synthesis of lin-8-amine

A mixture of 8-azido-7-fluoro-5-(7-fluoro-3,4-dihydroquinoline-1(2H)-yl)-[1,2,4]triazolo[4,3-a]quinazoline (12 mg, 0.032 mmol) and Pd/C (3 mg) in EtOH (0.16 mL) was stirred overnight at 60 °C under a _H₂ atmosphere. After removing Pd/C by filtration, the filtrate was concentrated under vacuum. The residue was purified by column chromatography (Si-column, _CHCl3 :MeOH = 10:0-85:15) to provide the desired product: ^¹H NMR (methanol- _d4 ) δ 9.28 (s, 1H), 7.35 (d, J = 7.5 Hz, 1H), 7.23 (ddt, J = 8.4, 6.4, 0.9 Hz, 1H), 7.13 (d, J = 12.3 Hz, 1H), 6.72 (td, J = 8.4, 2.5 Hz, 1H), 6.47–6.37 (m, 1H), 3.95 (t, J = 6.4 Hz, 2H), 2.90 (t, J = 6.6 Hz, 2H), 2.12 (p, J = 6.5 Hz, 2H); LCMS (m/z) 353.3.

Example 217. 5-(3,4-dihydroquinoline-1(2H)-yl)-7-fluoro-[1,2,4]triazolo[4,3-a]quinazolin- 8-amine

(Step 1) Synthesis of 2-chloro-4-(3,4-dihydroquinolin-1(2H)-yl)-6,7-difluoroquinazolin

Add 1,2,3,4-tetrahydroquinoline (0.623 g, 4.68 mmol) and sodium hydride (0.112 g, 4.68 mmol) to a solution of 2,4-dichloro-6,7-difluoroquinazoline (1.1 g, 4.68 mmol) in DMF (23.4 mL), and stir the mixture at room temperature for 1 hour. Dilute the mixture with AcOEt and wash continuously with water and brine. Concentrate the organic layer under vacuum to give the desired product. LCMS (m/z) 332.19 [M+H] ⁺ .

(Step 2) Synthesis of 4-(3,4-dihydroquinoline-1(2H)-yl)-6,7-difluoro-2-hydrazinoline

Hydrazine hydrate (0.017 g, 0.35 mmol) was added to a solution of 2-chloro-4-(3,4-dihydroquinolin-1(2H)-yl)-6,7-difluoroquinazoline (0.35 g, 1.055 mmol) in EtOH (5.28 mL), and the mixture was stirred for 0.5 h. After 0.5 h and 1 h, an additional fraction of hydrazine hydrate (0.017 g x 2, 0.7 mmol) was slowly added to the solution, and stirring was continued for 1 h. The reaction mixture was diluted with AcOEt and washed continuously with water and brine. The organic layer was concentrated under vacuum. The residue was used for the next step without further purification. LCMS (m/z) 328.14 [M+H] ⁺ .

(Step 3) 5-(3,4-dihydroquinoline-1(2H)-yl)-7,8-difluoro-[1,2,4]triazolo[4,3-a]quinazolin Synthesis

A mixture of 4-(3,4-dihydroquinoline-1(2H)-yl)-6,7-difluoro-2-hydrazinoquinazoline (0.21 g, crude) and triethoxymethane (3 mL, 0.642 mmol) was stirred overnight at 100 °C. The reaction mixture was concentrated under vacuum. The residue was purified by column chromatography (Si column, _CHCl3 :MeOH = 10:0-85:15) to give the desired product. LCMS (m/z) 338.18 [M+H] ⁺ .

(Step 4) 8-Azide-5-(3,4-dihydroquinolin-1(2H)-yl)-7-fluoro-[1,2,4]triazolo[4,3-a]quinoline Synthesis of azoline

A mixture of 5-(3,4-dihydroquinoline-1(2H)-yl)-7,8-difluoro-[1,2,4]triazolo[4,3-a]quinazoline (62 mg, 0.184 mmol) and sodium azide (12.55 mg, 0.193 mmol) in DMSO (0.92 mL) was stirred at 60 °C for 1 hour. The reaction mixture was diluted with AcOEt and washed continuously with water and brine. The organic layer was concentrated under vacuum to give the desired product, which was used in the next step without further purification. LCMS (m/z) 361.19 [M+H] ⁺ .

(Step 5) 5-(3,4-dihydroquinoline-1(2H)-yl)-7-fluoro-[1,2,4]triazolo[4,3-a]quinazolin-8-amine Synthesis

A mixture of 8-azido-5-(3,4-dihydroquinolin-1(2H)-yl)-7-fluoro-[1,2,4]triazolo[4,3-a]quinazoline (51 mg, crude) and Pd/C (5 mg) in EtOH (0.71 mL) was stirred overnight at 60 °C under a _H₂ atmosphere. After removing Pd/C by filtration, the filtrate was concentrated under vacuum. The residue was purified by column chromatography (Si-column, _CHCl3 :MeOH = 10:0-85:15) to provide the desired product: ^¹H NMR (methanol- _d4 ) δ 9.23 (s, 1H), 7.34–7.23 (m, 2H), 7.06–6.97 (m, 3H), 6.72–6.65 (m, 1H), 3.98 (t, J = 6.6 Hz, 2H), 2.91 (t, J = 6.6 Hz, 2H), 2.13 (t, J = 6.6 Hz, 2H); LCMS (m/z) 335.2.

Example 218. 8-Fluoro-N-methyl-N-phenyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine

(Step 1) Synthesis of 2-chloro-7-fluoro-N-methyl-N-phenylquinazoline-4-amine

N-methylaniline (49.4 mg, 0.461 mmol) and concentrated HCl (37%, 15.62 mg, 0.428 mmol) were added to a suspension of 2,4-dichloro-7-fluoroquinazoline (100 mg, 0.461 mmol) in 2-propanol (2.3 mL), and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was concentrated under vacuum. The residue was purified by column chromatography (Si column, hexane:AcOEt = 10:0-6:4) to give the desired product: LCMS (m/z) 288.08 [M+H]+.

(Step 2) Synthesis of 7-fluoro-2-hydrazino-N-methyl-N-phenylquinazoline-4-amine

Hydrazine hydrate (21.75 mg, 0.434 mmol) was added to 2-chloro-7-fluoro-N-methyl-N-phenylquinazoline-4-amine (25 mg, 0.087 mmol), and the reaction mixture was stirred at room temperature for 3 hours. The reaction mixture was diluted with AcOEt and washed continuously with water and brine. The organic layer was concentrated under vacuum. The residue was purified by column chromatography (Si-column, _CHCl3 :MeOH = 10:0-9:1) to give the desired product: LCMS (m/z) 284.13 [M+H]+.

(Step 3) Synthesis of 8-fluoro-N-methyl-N-phenyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine

The mixture of 7-fluoro-2-hydrazino-N-methyl-N-phenylquinazoline-4-amine (12 mg, 0.042 mmol) and triethoxymethane (18.83 mg, 0.127 mmol) was heated to 70 °C for 20 min. The reaction mixture was purified directly by column chromatography (Si column, _CHCl3 :MeOH = 10:0–9:1) to provide the desired product: ^¹H NMR (methanol- _d4 ) δ 9.42 (s, 1H), 8.05 (dd, J = 9.1, 2.6 Hz, 1H), 7.44–7.32 (m, 6H), 7.04–6.94 (m, 1H), 3.67 (s, 3H); LCMS (m/z) 294.1.

Example 219. 8-(3,3-dimethylbut-1-yn-1-yl)-N-methyl-N-phenyl-[1,2,4]triazolo[4, [3-a]quinazolin-5-amine

A mixture of 8-bromo-N-methyl-N-phenyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine (Example 28) (20 mg, 0.056 mmol), Pd(dppf) _Cl₂ (8.26 mg, 0.011 mmol), triethylamine (17.14 mg, 0.169 mmol), 3,3-dimethylbut-1-yne (11.60 mg, 0.141 mmol), and cuprous iodide (I) (2.151 mg, 0.011 mmol) in acetonitrile (0.28 mL) was treated in a microwave reactor at 80 °C for 2 h. The reaction mixture was subjected to solid-phase extraction using a Bond Elut SCX box (Agilent) (washed with MeOH, then eluted with _NH₃ in MeOH), and the collected fraction was concentrated under vacuum. The residue was purified by preparative HPLC to provide the desired product: ^¹H NMR (methanol- _d⁴ ) δ 9.57 (s, ¹H), 7.55 (m, 7H), 7.14 (m, ¹H), 3.79 (s, 3H), 3.67 (m, 9H); LCMS (m/z) 356.2.

Example 220. 7-Fluoro-5-((3-fluorophenyl)(methyl)amino)-[1,2,4]triazolo[4,3-a]quinazolin- 8-Formic acid

(Step 1) 8-Bromo-7-fluoro-N-(3-fluorophenyl)-N-methyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine Synthesis

To a solution of 7-fluoro-N5-(3-fluorophenyl)-N5-methyl-[1,2,4]triazolo[4,3-a]quinazoline-5,8-diamine (Example 208) (315 mg, 0.965 mmol) in acetonitrile (4.8 mL), tert-butyronitrile (149 mg, 1.448 mmol) and copper(II) bromide (237 mg, 1.062 mmol) were added, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was filtered and washed continuously with AcOEt and MeOH, and the filtrate was concentrated under vacuum. The residue was diluted with AcOEt and washed continuously with water and brine. The organic layer was concentrated under vacuum. The residue was used in the next step without further purification. LCMS (m/z) 390.09/392.09 [M+H] ⁺ .

(Step 2) 7-Fluoro-N-(3-fluorophenyl)-N-methyl-8-vinyl-[1,2,4]triazolo[4,3-a]quinazolin- Synthesis of 5-amines

A mixture of 8-bromo-7-fluoro-N-(3-fluorophenyl)-N-methyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine (200 mg, crude), _K₃PO₄ (109 mg, 0.513 mmol), Pd(OAc) _₂ (115 mg, 0.513 mmol), _4,4,5,5 -tetramethyl-2-vinyl-1,3,2-dioxaborhexacyclopentane (118 mg, 0.769 mmol), and tricyclohexylphosphine (28.7 mg, 0.103 mmol) in dioxane/water (1:1, 2.3 mL) was stirred at 100 °C for 1.5 h. The mixture was concentrated under vacuum. The residue was purified by column chromatography (Si column, _CHCl₃ :MeOH = 10:0–8:2) to obtain the desired product.

(Step 3) 7-Fluoro-5-((3-fluorophenyl)(methyl)amino)-[1,2,4]triazolo[4,3-a]quinazolin-8-methyl Acid Synthesis

A mixture of 7-fluoro-N-(3-fluorophenyl)-N-methyl-8-vinyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine (50 mg, 0.148 mmol), osmium oxide (VIII) (0.2 M in BuOH, 0.15 mL, 0.030 mmol), and sodium periodate (79 mg, 0.371 mmol) in acetone/water (1:1, 0.74 mL, ratio = 1:1) was stirred overnight at room temperature. The reaction mixture was concentrated under vacuum, and the residue was purified by column chromatography (Si-column, _CHCl3 :MeOH = 10:0–8:2) to provide the desired product: ^¹H NMR (DMSO- _d6 ) δ 9.86 (s, 1H), 8.82 (d, J = 6.2 Hz, 1H), 7.45 (dd, J = 8.3, 6.8 Hz, 1H), 7.40–7.33 (m, 1H), 7.25–7.14 (m, 2H), 6.96 (d, J = 11.7 Hz, 1H), 3.58 (s, 3H); LCMS (m/z) 356.2.

Example 221. 7-Fluoro-N5,N8-Dimethyl-N5-phenyl-[1,2,4]triazolo[4,3-a]quinazoline-5,8- diamine

A vigorously stirred mixture of Example 182 (7.1 mg, 23 μmol) and methylamine solution (9.8 M in methanol, 1.5 mL, 15 mmol) was heated to 110 °C in a microwave reactor. After 30 minutes, the reaction mixture was cooled to room temperature and the solvent was removed under reduced pressure. The residue was purified by reversed-phase preparative HPLC (acetonitrile/water containing 0.1% trifluoroacetic acid) to give the title compound: ^¹H NMR (400 MHz, DMSO- _d₆ ) δ 9.83 (s, 1H), 7.53 (dd, J = 8.3, 6.9 Hz, 2H), 7.48–7.32 (m, 4H), 6.46 (d, J = 14.0 Hz, 1H), 3.61 (s, 3H), 2.91 (d, J = 4.7 Hz, 3H); LCMS (m/z) 323.3.

Example 222. 7-Fluoro-N5,N8,N8-trimethyl-N5-phenyl-[1,2,4]triazolo[4,3-a]quinazoline-5, 8-Diamine

Example 222 was synthesized in a similar manner to Example 221, except that dimethylamine was used instead of methylamine. ^¹H NMR (400 MHz, DMSO- _d⁶ ) δ 9.88 (s, 1H), 7.55 (dd, J = 8.3, 6.9 Hz, 2H), 7.51–7.35 (m, 4H), 6.46 (d, J = 17.0 Hz, 1H), 3.62 (s, 3H), 3.11 (d, J = 2.4 Hz, 6H); LCMS (m/z) 337.3.

Example 223. 7-Fluoro-8-methoxy-N-methyl-N-phenyl-[1,2,4]triazolo[4,3-a]quinazolin-5- amine

Example 223 was synthesized in a manner similar to Example 221, using an ammonia solution (7.0 M in methanol) instead of a methylamine solution (9.8 M in methanol). ^¹H NMR (400 MHz, DMSO- _d⁶ ) δ 9.89 (s, 1H), 8.15 (d, J = 7.7 Hz, 1H), 7.56–7.48 (m, 2H), 7.49–7.34 (m, 3H), 6.70 (d, J = 13.1 Hz, 1H), 4.07 (s, 3H), 3.62 (s, 3H); LCMS (m/z) 324.3.

Example 224. 7-Fluoro-8-methoxy-N-methyl-N-phenyl-[1,2,4]triazolo[4,3-a]quinazolin-5- amine

A sodium hydroxide aqueous solution (2.0 M, 3.0 mL, 6.0 mmol) was added to a vigorously stirred mixture of Example 182 (64.5 mg, 0.207 mmol) in dimethyl sulfoxide (3.0 mL) using a syringe, and the resulting mixture was heated to 90 °C. One hour later, the resulting mixture was cooled to room temperature and purified by reversed-phase preparative HPLC (acetonitrile/water containing 0.1% trifluoroacetic acid) to give the title compound: ^¹H NMR (400MHz, DMSO- _d⁶ ) δ 11.64 (s, 1H), 9.50 (s, 1H), 7.70 (d, J = 7.6Hz, 1H), 7.44 (t, J = 7.7Hz, 2H), 7.38–7.20 (m, 4H), 6.79 (d, J = 12.7Hz, 1H), 6.52 (s, 1H), 3.52 (s, 3H); LCMS (m/z) 310.3.

Example 225. 8-Ethoxy-7-fluoro-N-methyl-N-phenyl-[1,2,4]triazolo[4,3-a]quinazolin-5- amine

Iodoethane (9.1 μL, 110 μmol) was added via syringe to a vigorously stirred mixture of potassium carbonate (15.6 mg, 0.113 mmol) and Example 224 (7.00 mg, 22.6 μmol) in acetone (0.5 mL), and the resulting mixture was heated to 50 °C. After 90 minutes, the reaction mixture was cooled to room temperature, and ethyl acetate (5 mL) and water (5 mL) were added sequentially. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by reversed-phase preparative HPLC (acetonitrile/water containing 0.1% trifluoroacetic acid) to give the title compound: ^¹H NMR (400MHz, DMSO- _d⁶ ) δ 9.72 (s, 1H), 8.04 (d, J = 7.6Hz, 1H), 7.46 (t, J = 7.7Hz, 2H), 7.35 (d, J = 7.9Hz, 3H), 6.76 (d, J = 13.0Hz, 1H), 4.33 (q, J = 7.0Hz, 2H), 3.56 (s, 3H), 1.42 (t, J = 7.0Hz, 3H); LCMS (m/z) 338.3.

Example 226. 8-(allyloxy)-7-fluoro-N-methyl-N-phenyl-[1,2,4]triazolo[4,3-a]quinazole 5-Lin-amine

Example 226 was synthesized in a manner similar to that of Example 225, except that 3-bromoprop-1-ene was used instead of ethyl iodine. ^¹H NMR (400 MHz, DMSO- _d⁶ ) δ 9.80 (s, ¹H), 8.12 (d, J = 7.6 Hz, ¹H), 7.58–7.34 (m, 5H), 6.72 (d, J = 13.0 Hz, ¹H), 6.12 (ddt, J = 17.4, 10.8, 5.6 Hz, 1H), 5.52 (dt, J = 17.3, 1.6 Hz, 1H), 5.38 (dt, J = 10.5, 1.4 Hz, 1H), 4.87 (dt, J = 5.7, 1.4 Hz, 2H), 3.61 (d, J = 9.7 Hz, 3H); LCMS (m/z) 350.3.

Example 227. 8-Chloro-N-(3-(5-cyclopropylpyridin-3-yl)phenyl)-N-methyl-[1,2,4]triazolo[4, [3-a]quinazolin-5-amine

The mixture of Example 308 (9.5 mg, 24.4 μmol), (5-cyclopropyl-3-pyridyl)boric acid (6.05 mg, 37.1 μmol), [1,1'-bis(diphenylphosphine)ferrocene]palladium(II) dichloride (1.73 mg, 2.4 μmol), and an aqueous solution of sodium carbonate (2.0 M, 122 μL, 244 μmol) in 0.5 mL of 1,4-dioxane was heated to 100 °C. After 5 minutes, the resulting mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by reversed-phase preparative HPLC (acetonitrile/water containing 0.1% trifluoroacetic acid) to give the title compound: ^¹H NMR (400 MHz, acetone- _d⁶ ) δ 9.48 (s, 1H), 8.63 (s, 1H), 8.53–8.24 (m, 2H), 7.80 (t, J = 2.1 Hz, 1H), 7.68 (q, J = 4.0, 2.2 Hz, 2H), 7.59 (t, J = 7.8 Hz, 1H), 7.48 (dd, J = 22.1, 8.2 Hz, 2H), 7.36–7.23 (m, 1H), 3.72 (s, 3H), 1.17–1.00 (m, 2H), 0.83 (dt, J = 6.6, 4.3 Hz, 2H); LCMS (m/z) 427.3.

Example 228. 8-Chloro-N-methyl-N-(3-(5-methylpyridin-3-yl)phenyl)-[1,2,4]triazolo[4,3- a] Quinazoline-5-amine

Example 228 was synthesized in a manner similar to that of Example 227 by using 3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborhexacyclopentan-2-yl)pyridine instead of (5-cyclopropyl-3-pyridyl)boronic acid and (2-dicyclohexylphosphine-2',4',6'-triisopropyl-1,1'-diphenyl)[2-(2'-amino-1,1'-diphenyl)]palladium(II) chloride instead of [1,1'-bis(diphenylphosphine)ferrocene]palladium(II) chloride. ¹ H NMR (400MHz, acetone-d ₆ )δ9.46(s,1H),8.66(s,1H),8.48–8.33(m,2H),7.92(s,1H),7.78(t,J＝2.1Hz,1H),7.68(d,J＝7.6Hz,2H),7.56(dd, J＝29.8,8.4Hz,1H),7.44(d,J＝7.3Hz,1H),7.28(dd,J＝8.9,2.2Hz,1H),3.71(s,3H),0.89(s,3H); LCMS(m/z)401.3.

Compound 229-1 was prepared from the corresponding bromide in Example 308 according to the procedure described in the first step of Example 413.

Example 229. 8-Chloro-N-(3-(5-((dimethylamino)methyl)pyrazin-2-yl)phenyl)-N-methyl-[1, [2,4]triazolo[4,3-a]quinazolin-5-amine

Step 1: A vigorously stirred mixture of compound 229-1 (50.0 mg, 11.5 μmol), 5-bromopyrazine-2-carboxaldehyde (258 mg, 1.38 mmol), [2-(2-aminophenyl)phenyl]chloro-palladium, dicyclohexyl-[2-(2,4,6-triisopropylphenyl)phenyl]phosphine, dicyclohexyl-[3-(2,4,6-triisopropylphenyl)phenyl]phosphine (43.0 mg, 27.3 μmol), and an aqueous solution of sodium carbonate (2.0 M, 1.1 mL, 2.3 mmol) in 1,4-dioxane (3.0 mL) was heated to 60 °C. After 90 minutes, the resulting mixture was diluted successively with ethyl acetate (15 mL) and water (15 mL). The organic layer was separated, washed with brine (15 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel rapid column chromatography (0% to 100% methanol in dichloromethane) to give compound 229-2.

Step 2: A dimethylamine solution (2.0 M in tetrahydrofuran, 140 μL, 290 μmol) was added to a vigorously stirred mixture of glacial acetic acid (16.3 μL, 289 μmol), sodium triacetoxyborohydride (61.2 mg, 289 μmol), and compound 229-2 (15.0 mg, 36.1 μmol) in dichloromethane (1.5 mL). The reaction mixture was heated to 40 °C. After 10 minutes, the solvent was removed under reduced pressure. The residue was purified by reversed-phase preparative HPLC (acetonitrile/water containing 0.1% trifluoroacetic acid) to give the title compound: ^¹H NMR (400 MHz, methanol- _d⁴ ) δ 9.55 (s, 1H), 9.37–9.19 (m, 1H), 8.89–8.69 (m, 1H), 8.46 (d, J = 2.0 Hz, 1H), 8.32–8.14 (m, 2H), 7.71 (t, J = 7.9 Hz, 1H), 7.66–7.50 (m, 1H), 7.38 (d, J = 9.1 Hz, 1H), 7.29 (dd, J = 8.9, 2.1 Hz, 1H), 4.61 (s, 2H), 3.81 (s, 3H), 3.01 (s, 6H); LCMS (m/z) 445.2.

Example 230. 8-Chloro-N-methyl-N-(3-(5-(morpholinomethyl)pyrazin-2-yl)phenyl)-[1,2,4]tri Azo[4,3-a]quinazolin-5-amine

Example 230 was synthesized in a manner similar to that of Example 229, except that pure morpholine was used instead of dimethylamine solution. ^¹H NMR (400 MHz, methanol- _d⁴ ) δ 9.57 (s, 1H), 9.37–9.15 (m, 1H), 8.78 (s, 1H), 8.48 (d, J = 2.1 Hz, 1H), 8.35–8.13 (m, 2H), 7.73 (t, J = 7.9 Hz, 1H), 7.59 (d, J = 7.9 Hz, 1H), 7.47–7.22 (m, 2H), 4.60 (s, 2H), 3.95 (s, 2H), 3.83 (s, 3H), 3.41 (s, 2H); LCMS (m/z) 487.3.

Example 231. 2-(5-(3-((8-chloro-[1,2,4]triazolo[4,3-a]quinazolin-5-yl)(methyl)amino) (Phenyl)pyrazin-2-yl)prop-2-ol

Step 1: Magnesium bromo(methyl)magnesium (3.0 M in diethyl ether, 2.9 mL, 8.7 mmol) was added via syringe to a vigorously stirred mixture of methyl 5-chloropyrazine-2-carboxylate (compound 231-1, 500 mg, 2.90 mmol) in tetrahydrofuran (12.1 mL) at 0 °C. After 1 hour, the reaction was quenched with aqueous hydrochloric acid (2.0 M, 18 mL, 36 mmol) and then extracted with ethyl acetate (2 × 30 mL). The organic layers were combined, washed with brine (30 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel rapid column chromatography (0% to 30% ethyl acetate in hexane) to give compound 231-2.

Step 2: 2-(5-chloropyrazin-2-yl)prop-2-ol (24.2 mg, 140 μmol) was added to a vigorously stirred mixture containing compound 229-1 (12.2 mg, 28.9 mmol), [2-(2-aminophenyl)phenyl]chloro-palladium, dicyclohexyl-[2-(2,4,6-triisopropylphenyl)phenyl]phosphine, dicyclohexyl-[3-(2,4,6-triisopropylphenyl)phenyl]phosphine (4.4 mg, 2.8 μmol), and an aqueous solution of sodium carbonate (2.0 M, 70.0 μL, 140 μmol) in 1,4-dioxane (1.0 mL). The reaction mixture was sealed and heated to approximately 60 °C. After 90 minutes, the reaction mixture was heated to 100 °C. After 20 minutes, the reaction mixture was cooled to room temperature and diluted successively with ethyl acetate (15 mL) and water (15 mL). The organic layer was separated, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by reversed-phase preparative HPLC (acetonitrile/water containing 0.1% trifluoroacetic acid) to give the title compound: ^¹H NMR (400 MHz, methanol- _d⁴ ) δ 9.53 (s, 1H), 8.99 (d, J = 34.1 Hz, 1H), 8.45 (s, 1H), 8.15 (s, 1H), 7.74–7.12 (m, 6H), 3.82 (s, 3H), 1.60 (s, 6H); LCMS (m/z) 446.3.

Example 232. 3'-((8-chloro-[1,2,4]triazolo[4,3-a]quinazolin-5-yl)(methyl)amino)-[1, 1'-Diphenyl]-4-carboxylic acid

Example 232 was synthesized in a manner similar to that of Example 227, except that 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborhexacyclopentan-2-yl)benzoic acid was used instead of (5-cyclopropyl-3-pyridyl)boronic acid. ^¹H NMR (400 MHz, methanol- _d⁴ ) δ 9.59 (s, 1H), 8.51 (d, J = 2.3 Hz, 1H), 8.23–8.05 (m, 2H), 7.92–7.79 (m, 2H), 7.79–7.65 (m, 3H), 7.50 (d, J = 7.9 Hz, 1H), 7.39 (dd, J = 9.1, 2.1 Hz, 1H), 7.36–7.28 (m, 1H), 3.87 (s, 3H); LCMS (m/z) 430.3.

Example 233. 2-(3'-((8-chloro-[1,2,4]triazolo[4,3-a]quinazolin-5-yl)(methyl)amino)- [1,1'-Diphenyl]-4-yl)-2-methylpropionic acid

Example 233 was synthesized in a manner similar to that of Example 227, except that 2-(4-boronphenyl)-2-methylpropionic acid was used instead of (5-cyclopropyl-3-pyridyl)boronic acid. ^¹H NMR (400 MHz, methanol- _d⁴ ) δ 9.55 (s, 1H), 8.46 (s, 1H), 7.76 (d, J = 7.6 Hz, 1H), 7.70 (s, 1H), 7.66–7.54 (m, 3H), 7.48 (d, J = 8.2 Hz, 2H), 7.36 (dd, J = 19.1, 5.0 Hz, 3H), 3.83 (s, 3H), 1.59 (s, 6H); LCMS (m/z) 472.4.

Example 234. 2-(3'-((8-chloro-[1,2,4]triazolo[4,3-a]quinazolin-5-yl)(methyl)amino)- [1,1'-Diphenyl]-4-yl)-2-methylpropionamide

Ammonia solution (0.4 M in tetrahydrofuran, 700 μL, 300 μmol) was added to a vigorously stirred mixture of 3-(ethyliminomethyleneamino)-N,N-dimethyl-propyl-1-amine hydrochloride (26.4 mg, 138 μmol), N,N-dimethylpyridin-4-amine (33.7 mg, 275 μmol), and Example 233 (13.0 mg, 27.5 μmol) in dichloromethane (1.3 mL), and the resulting mixture was heated to 40 °C. After 2 hours, the solvent was removed under reduced pressure. The residue was purified by reversed-phase preparative HPLC (acetonitrile/water containing 0.1% trifluoroacetic acid) to give the title compound: ^¹H NMR (400 MHz, methanol- _d⁴ ) δ 9.59 (s, 1H), 8.51 (d, J = 1.8 Hz, 1H), 7.87–7.78 (m, 1H), 7.73 (t, J = 2.0 Hz, 1H), 7.72–7.56 (m, 2H), 7.53–7.42 (m, 3H), 7.38 (dd, J = 9.1, 2.2 Hz, 1H), 7.28 (d, J = 9.2 Hz, 1H), 3.87 (s, 3H), 1.58 (s, 6H); LCMS (m/z) 471.3.

Example 235. 2-(3'-((8-chloro-[1,2,4]triazolo[4,3-a]quinazolin-5-yl)(methyl)amino)- [1,1'-diphenyl]-4-yl)-2-methylpropionitrile

Example 235 was synthesized in a manner similar to that of Example 227, except that [4-(1-cyano-1-methyl-ethyl)phenyl]boronic acid was used instead of (5-cyclopropyl-3-pyridyl)boronic acid. ^¹H NMR (400 MHz, methanol- _d⁴ ) δ 9.60 (s, 1H), 8.52 (d, J = 2.0 Hz, 1H), 7.88–7.80 (m, 1H), 7.80–7.74 (m, 1H), 7.74–7.59 (m, 5H), 7.53–7.44 (m, 1H), 7.44–7.34 (m, 1H), 7.30 (d, J = 9.2 Hz, 1H), 3.88 (s, 3H), 1.76 (s, 6H); LCMS (m/z) 453.3.

Example 236. 8-Chloro-N-(3'-methoxy-4'-(trifluoromethyl)-[1,1'-diphenyl]-3-yl)-N-methyl [1,2,4]triazolo[4,3-a]quinazolin-5-amine

Example 236 was synthesized in a manner similar to that of Example 227, except that [3-methoxy-4-(trifluoromethyl)phenyl]boronic acid was used instead of (5-cyclopropyl-3-pyridyl)boronic acid. ^¹H NMR (400 MHz, methanol- _d⁴ ) δ 9.58 (s, 1H), 8.49 (s, 1H), 7.81 (d, J = 18.6 Hz, 2H), 7.65 (s, 2H), 7.49 (s, 1H), 7.41–7.24 (m, 4H), 3.97 (s, 3H), 3.86 (s, 3H); LCMS (m/z) 484.3.

Example 237. 8-Chloro-N-(3'-fluoro-4'-(trifluoromethyl)-[1,1'-diphenyl]-3-yl)-N-methyl-[1, [2,4]triazolo[4,3-a]quinazolin-5-amine

Example 237 was synthesized in a manner similar to that of Example 227, except that [3-fluoro-4-(trifluoromethyl)phenyl]boronic acid was used instead of (5-cyclopropyl-3-pyridyl)boronic acid. ^¹H NMR (400 MHz, methanol- _d⁴ ) δ 9.61 (s, 1H), 8.52 (d, J = 2.1 Hz, 1H), 7.93–7.83 (m, 2H), 7.79 (t, J = 7.9 Hz, 1H), 7.76–7.49 (m, 4H), 7.39 (dd, J = 8.0, 3.2 Hz, 1H), 7.31 (d, J = 9.1 Hz, 1H), 3.87 (d, J = 4.5 Hz, 3H); LCMS (m/z) 472.3.

Example 238. 8-Chloro-N-(3'-Chloro-4'-(trifluoromethyl)-[1,1'-diphenyl]-3-yl)-N-methyl-[1, [2,4]triazolo[4,3-a]quinazolin-5-amine

Example 238 was synthesized in a manner similar to that of Example 227, except that [3-chloro-4-(trifluoromethyl)phenyl]boronic acid was used instead of (5-cyclopropyl-3-pyridyl)boronic acid. ^¹H NMR (400 MHz, methanol- _d⁴ ) δ 9.61 (s, 1H), 8.52 (d, J = 2.3 Hz, 1H), 7.97–7.81 (m, 4H), 7.73 (dd, J = 20.9, 8.3 Hz, 2H), 7.55 (d, J = 8.2 Hz, 1H), 7.40 (dd, J = 9.2, 2.2 Hz, 1H), 7.36–7.28 (m, 1H), 3.87 (s, 3H); LCMS (m/z) 488.3.

Example 239. N-(3',4'-bis(trifluoromethyl)-[1,1'-diphenyl]-3-yl)-8-chloro-N-methyl-[1,2, 4] Triazolo[4,3-a]quinazolin-5-amine

Example 239 was synthesized in a manner similar to that of Example 227, except that [3,4-bis(trifluoromethyl)phenyl]boronic acid was used instead of (5-cyclopropyl-3-pyridyl)boronic acid. ^¹H NMR (400 MHz, methanol- _d⁴ ) δ 9.50 (s, 1H), 8.41 (d, J = 2.1 Hz, 1H), 8.18 (s, 3H), 7.99 (s, 2H), 7.79 (d, J = 2.1 Hz, 1H), 7.74 (d, J = 7.8 Hz, 1H), 7.63 (t, J = 7.9 Hz, 1H), 7.46–7.37 (m, 1H), 7.29 (dd, J = 9.0, 2.1 Hz, 1H), 3.78 (s, 3H); LCMS (m/z) 522.3.

Example 240. 8-Chloro-N-methyl-N-(3-(6-(2,2,2-trifluoroethoxy)pyridin-3-yl)phenyl)-[1, [2,4]triazolo[4,3-a]quinazolin-5-amine

Sodium hydride (4.3 mg, 190 μmol) was added at 0 °C to a vigorously stirred mixture of 5.00 mg, 12.4 μmol, and 2,2,2-trifluoroethanol (13.3 μL, 185 μmol) in N,N-dimethylformamide (0.5 mL). The reaction mixture was heated to 45 °C. After 50 minutes, the reaction mixture was cooled to room temperature. The mixture was purified by reversed-phase preparative HPLC (acetonitrile/water containing 0.1% trifluoroacetic acid) to give the title compound: ^¹H NMR (400 MHz, methanol- _d⁴ ) δ 9.56 (s, 1H), 8.48 (s, 1H), 8.42 (d, J = 2.5 Hz, 1H), 8.01 (dd, J = 8.6, 2.5 Hz, 1H), 7.77–7.69 (m, 2H), 7.64 (t, J = 7.9 Hz, 1H), 7.43 (d, J = 8.1 Hz, 1H), 7.36–7.30 (m, 2H), 7.00 (d, J = 8.6 Hz, 1H), 3.83 (s, 3H), 1.96 (s, 2H); LCMS (m/z) 485.3.

Example 241. 8-Chloro-N-methyl-N-(3-(6-((1,1,1-trifluoroprop-2-yl)oxy)pyridin-3-yl)benzene (-[1,2,4]triazolo[4,3-a]quinazolin-5-amine)

Example 241 was synthesized in a manner similar to that of Example 240, except that 1,1,1-trifluoroprop-2-ol was used instead of 2,2,2-trifluoroethanol. ¹ H NMR (400MHz, methanol-d ₄ )δ9.48(s,1H),8.39(d,J＝2.2Hz,2H),7.98(dd,J＝8.6,2.6Hz,1H),7.66–7.59(m,2H),7.56(t,J＝8.1Hz,1H),7.41(d,J＝9.0Hz,1H),7.32(d ,J＝8.2Hz,1H),7.26(dd,J＝9.0,2.1Hz,1H),6.95–6.90(m,1H),5.88(p,J＝6.7Hz,1H),3.75(s,3H),1.50(d,J＝6.5Hz,3H); LCMS(m/z)499.3.

Example 242. 4-(3-((8-chloro-[1,2,4]triazolo[4,3-a]quinazolin-5-yl)(methyl)amino)benzene 2-Cyclopropylbut-3-yn-2-ol

2-Cyclopropylbut-3-yn-2-ol (75% purity, 44 μL, 240 μmol) was added to a vigorously stirred mixture of 1-methylpyrrolidone (0.5 mL) from Example 308 (18.5 mg, 47.6 μmol), [1,1'-bis(diphenylphosphine)ferrocene]palladium(II) dichloride (12.2 mg, 16.7 μmol), triethylamine (166 μL, 1.19 mmol), and zinc bromide (53.6 mg, 238 mmol). The reaction mixture was sealed and heated to approximately 110 °C. After 10 minutes, the reaction mixture was cooled to room temperature. The mixture was purified by reversed-phase preparative HPLC (acetonitrile/water containing 0.1% trifluoroacetic acid) to give the title compound: ^¹H NMR (400 MHz, methanol- _d⁴ ) δ 9.49 (s, 1H), 8.40 (s, 1H), 8.09 (s, 1H), 7.50–7.22 (m, 5H), 3.68 (d, J = 6.0 Hz, 3H), 1.98–1.87 (m, 1H), 1.58 (s, 3H), 1.25–1.07 (m, 2H), 0.49 (q, J = 5.5, 4.6 Hz, 2H); LCMS (m/z) 418.1.

Example 243. N-Methyl-N-(naphth-1-yl)-8-nitro-[1,2,4]triazolo[4,3-a]quinazolin-5-amine

Synthesis of 5-chloro-8-nitro-[1,2,4]triazolo[4,3-a]quinazoline (compound 243-2): A mixture of 8-nitro-[1,2,4]triazolo[4,3-a]quinazoline-5(4H)-one (intermediate 4, 1.0 g, 4.33 mmol) and phosphorus trichloride (13.3 g, 86 mmol) was stirred at 100 °C for 6 h. The reaction was monitored by LCMS. The reaction mixture was cooled to room temperature and then evaporated under reduced pressure. The crude product was used in the next step without further purification.

Synthesis of N-methyl-N-(naphthyl-1-yl)-8-nitro-[1,2,4]triazolo[4,3-a]quinazoline-5-amine: N-methylnaphthyl-1-amine (22 mg, 0.14 mmol) and sodium hydride (5.6 mg, 0.14 mmol) were added to a solution of crude 5-chloro-8-nitro-[1,2,4]triazolo[4,3-a]quinazoline (50 mg, 0.20 mmol) in DMF (5 mL) at room temperature. The mixture was stirred for 1 hour. The mixture was diluted with AcOEt, washed continuously with water and brine, and dried over _MgSO4 . The organic layer was concentrated under vacuum. The resulting residue was purified by reversed-phase chromatography (ACN/water 15-95%, 0.1% TFA, 15 min) to obtain the title compound: ^¹H NMR (400 MHz, methanol- _d⁴ ) δ 9.83 (s, 1H), 9.24 (d, J = 2.3 Hz, 1H), 8.24–8.03 (m, 3H), 7.88 (dd, J = 9.3, 2.3 Hz, 1H), 7.77–7.67 (m, 2H), 7.65–7.45 (m, 2H), 7.15 (d, J = 9.3 Hz, 1H), 3.91 (s, 3H); LCMS (m/z) 371.3.

Example 244. N-Methyl-N-(naphth-2-yl)-8-nitro-[1,2,4]triazolo[4,3-a]quinazolin-5-amine

Example 244 was synthesized in a manner similar to that of Example 243, except that N-methylnaphthyl-2-amine was used instead of N-methylnaphthyl-1-amine. ^¹H NMR (400 MHz, chloroform-d) δ 9.34 (s, 1H), 8.94 (d, J = 2.2 Hz, 1H), 8.06 (d, J = 8.7 Hz, 1H), 8.00–7.92 (m, 1H), 7.88 (dd, J = 9.3, 2.1 Hz, 1H), 7.85–7.75 (m, 2H), 7.69–7.57 (m, 2H), 7.47–7.34 (m, 2H), 3.91 (s, 3H); LCMS (m/z) 371.3.

Example 245. N-(2,2-difluoroethyl)-8-nitro-N-phenyl-[1,2,4]triazolo[4,3-a]quinazolin- 5-amine

Example 245 was synthesized in a manner similar to that of Example 243, except that N-(2,2-difluoroethyl)aniline was used instead of N-methylnaphthalene-1-amine. ^¹H NMR (400 MHz, chloroform-d) δ 9.42 (s, 1H), 8.99 (d, J = 2.2 Hz, 1H), 8.06 (d, J = 8.7 Hz, 1H), 8.00–7.93 (m, 1H), 7.88–7.76 (m, 2H), 7.67–7.56 (m, 2H), 7.44 (dd, J = 8.7, 2.2 Hz, 1H), 7.37 (d, J = 9.3 Hz, 1H), 4.0–3.8 (m, 3H); LCMS (m/z) 371.3.

Example 246. N-Methyl-N-(8-nitro-[1,2,4]triazolo[4,3-a]quinazolin-5-yl)benzo[d]thia 2-azole-amine

Example 246 was synthesized in a manner similar to that of Example 243, except that N-methylbenzo[d]thiazol-2-amine was used instead of N-methylnaphthyl-1-amine. ^¹H NMR (400 MHz, chloroform-d) δ 9.42 (s, 1H), 8.99 (d, J = 2.2 Hz, 1H), 8.06 (d, J = 8.7 Hz, 1H), 8.00–7.93 (m, 1H), 7.89–7.75 (m, 1H), 7.69–7.57 (m, 1H), 7.48–7.33 (m, 2H), 3.90 (s, 3H); LCMS (m/z) 378.2.

Example 247. N-Methyl-N-(8-nitro-[1,2,4]triazolo[4,3-a]quinazolin-5-yl)benzo[d]thia 2-azole-amine

Example 247 was synthesized in a manner similar to that of Example 243, except that N,1-dimethyl-1H-indazole-6-amine was used instead of N-methylnaphthyl-1-amine. ^¹H NMR (400 MHz, chloroform-d) δ 7.49 (s, 1H), 7.36 (t, J = 7.9 Hz, 2H), 7.24 (d, J = 7.7 Hz, 1H), 7.20–7.10 (m, 2H), 6.90 (d, J = 8.5 Hz, 1H), 6.64 (t, J = 7.7 Hz, 1H), 3.59 (s, 3H), 2.09–1.97 (m, 3H); LCMS (m/z) 375.2.

Example 248. 1-(5-(methyl(phenyl)amino)-[1,2,4]triazolo[4,3-a]quinazolin-8-yl)propyl 1-Alcohol

The flask was evacuated and filled with nitrogen. After adding THF (6 mL) and 5-(methyl(phenyl)amino)-[1,2,4]triazolo[4,3-a]quinazolin-8-carboxaldehyde (Example 117, 25 mg, 0.082 mmol) as a solution, the mixture was maintained at 0°C in an ice-water bath. Then EtMgBr (1.0 M, 0.082 mmol) was added, and the mixture was further stirred at room temperature for 24 hours, followed by the addition of water and DCM. The organic layer was washed continuously with water and brine. The organic layer was dried over _MgSO4 and evaporated under reduced pressure. The crude product was subjected to reversed-phase chromatography (ACN/water 15%–95% with 0.1% TFA, duration 15 min) to obtain the title compound as a mixture of isomers: ^¹H NMR (400 MHz, methanol- _d⁴ ) δ 9.63 (s, 1H), 8.29 (d, J = 1.6 Hz, 1H), 7.63–7.50 (m, 3H), 7.48–7.41 (m, 2H), 7.29 (dd, J = 8.9, 1.7 Hz, 1H), 7.16 (d, J = 8.8 Hz, 1H), 4.74 (dd, J = 7.3, 5.4 Hz, 1H), 3.81 (s, 3H), 1.88–1.66 (m, 2H), 0.94 (t, J = 7.4 Hz, 3H); LCMS (m/z) 334.3.

Example 249. 7,8-Difluoro-N-(3-fluorophenyl)-N-methyl-[1,2,4]triazolo[4,3-a]quinazolin-5- amine

Synthesis of 2-chloro-6,7-difluoro-N-(3-fluorophenyl)-N-methylquinazoline-4-amine (compound 249-2): 3-fluoro-N-methylaniline (1.76 g, 14 mmol) and sodium hydride (587 mg, 14.7 mmol) were added to a solution of 2,4-dichloro-6,7-difluoroquinazoline (compound 249-1, 3 g, 12.8 mmol) in DMF (20 mL), and the mixture was stirred at room temperature for 1 hour. Water was added to the reaction mixture, and the mixture was filtered. The resulting residue was used in the next step without further purification.

Synthesis of 6,7-difluoro-N-(3-fluorophenyl)-2-hydrazino-N-methylquinazoline-4-amine (compound 249-3): Hydrazine hydrate (0.018 g, 0.23 mmol) was slowly added to a stirred solution of crude 2-chloro-6,7-difluoro-N-(3-fluorophenyl)-N-methylquinazoline-4-amine (compound 249-2, 254 mg, 0.78 mmol) in ethanol (4 mL) at room temperature. The mixture was diluted with DCM, then washed continuously with water and brine and dried over _MgSO4 . The organic layer was concentrated under vacuum. The resulting residue was used in the next step without further purification.

Synthesis of 7,8-difluoro-N-(3-fluorophenyl)-N-methyl-[1,2,4]triazolo[4,3-a]quinazoline-5-amine: A mixture of crude 6,7-difluoro-N-(3-fluorophenyl)-2-hydrazino-N-methylquinazoline-4-amine (compound 249-3) (340 mg, 1.06 mmol) and triethoxymethane (789 mg, 5.32 mmol) was stirred at 100 °C for 4 hours. The reaction mixture was concentrated under vacuum. The residue was purified by reversed-phase chromatography (ACN/water 15%–95% with 0.1% TFA, for 15 min) to yield the title compound: ^¹H NMR (400 MHz, chloroform-d) δ 8.90 (s, 1H), 7.67 (dd, J = 9.3, 6.6 Hz, 1H), 7.40 (td, J = 8.2, 6.3 Hz, 1H), 7.18 (dd, J = 11.2, 8.0 Hz, 1H), 7.06 (td, J = 8.4, 2.2 Hz, 1H), 6.99–6.87 (m, 2H), 3.68 (s, 3H); LCMS (m/z) 330.3.

Example 250. 8-Chloro-7-fluoro-N-(3-fluorophenyl)-N-methyl-[1,2,4]triazolo[4,3-a]quinazolin- 5-amine

Synthesis of 8-azido-7-fluoro-N-(3-fluorophenyl)-N-methyl-[1,2,4]triazolo[4,3-a]quinazoline-5-amine (compound 250-2): Sodium azide (2.5 g, 38.8 mmol) was added to a solution of 7,8-difluoro-N-(3-fluorophenyl)-N-methyl-[1,2,4]triazolo[4,3-a]quinazoline-5-amine (Example 249, 2.4 g, 7.71 mmol) in DMSO (10 mL), and the mixture was stirred at 100 °C for 2 hours. The reaction mixture was diluted with DCM, then washed continuously with water and brine and dried over _MgSO4 . The organic layer was concentrated under vacuum. The resulting residue was used in the next step without further purification.

Synthesis of 7-fluoro-N5-(3-fluorophenyl)-N5-methyl-[1,2,4]triazolo[4,3-a]quinazoline-5,8-diamine (compound 250-3): Pd/C was added to a solution of crude 8-azido-7-fluoro-N-(3-fluorophenyl)-N-methyl-[1,2,4]triazolo[4,3-a]quinazoline-5-amine (2) (0.6 g, 1.7 mmol) in ethanol (5 ml), and the suspension was stirred at room temperature under a hydrogen atmosphere for 5 hours. Pd/C was removed by filtration, and the filtrate was concentrated under vacuum. The crude product was used in the next step.

Synthesis of 8-chloro-7-fluoro-N-(3-fluorophenyl)-N-methyl-[1,2,4]triazolo[4,3-a]quinazoline-5-amine: A solution of sodium nitrite (23.3 mg, 0.33 mmol) in water (2 ml) was added dropwise at 0 °C to a stirred suspension of 7-fluoro-N5-(3-fluorophenyl)-N5-methyl-[1,2,4]triazolo[4,3-a]quinazoline-5,8-diamine (100 mg, 0.306 mmol) in hydrochloric acid (37% w/v, 4 ml). The solution was stirred at 0 °C for 30 min and then added partically to a stirred boiling solution of cuprous chloride (I) (48 mg, 0.33 mmol) in hydrochloric acid (37% w/v, 2 ml). The stirred mixture was boiled further for 15 min and cooled overnight. Water was added and the product was extracted into DCM. The ether extract was washed with water and 10% w/v sodium hydroxide solution, and then dried over _MgSO4 . The solvent was removed under vacuum. The residue was purified by reversed-phase chromatography (ACN/water 15%–95% with 0.1% TFA, for 15 min) to yield the title compound: ^¹H NMR (400 MHz, chloroform-d) δ 9.22 (s, 1H), 8.31 (d, J = 7.7 Hz, 1H), 7.54 (q, J = 7.8 Hz, 1H), 7.24 (t, J = 8.1 Hz, 1H), 7.09 (dd, J = 11.8, 8.7 Hz, 2H), 6.89 (d, J = 10.2 Hz, 1H), 3.77 (d, J = 2.0 Hz, 3H); LCMS (m/z) 346.

Example 251. (7-Fluoro-5-((3-Fluorophenyl)(methyl)amino)-[1,2,4]triazolo[4,3-a]quinazolin- 8-methyl)methanol

60% sodium hydride (24 mg, 0.6 mmol) was added to a solution of methylthiomethyl-p-tolyl sulfone (131 mg, 0.6 mmol) in DMF (5 mL). The resulting mixture was stirred at 0 °C for 1 hour, followed by the addition of 7,8-difluoro-N-(3-fluorophenyl)-N-methyl-[1,2,4]triazolo[4,3-a]quinazoline-5-amine (Example 249, 100 mg, 0.30 mmol). The reaction was then carried out at room temperature for 24 hours and quenched by adding 5 mL of 10% HCl. DCM and water were added to the mixture. The organic phase was then washed with water and brine, dried over _MgSO4 , and concentrated to dryness. The residue was purified by reversed-phase chromatography (ACN/water 15%–95% with 0.1% TFA, for 15 min) to yield the title compound: ^¹H NMR (400 MHz, methanol- _d⁴ ) δ 9.71 (s, 1H), 8.50 (d, J = 6.2 Hz, 1H), 7.72–7.53 (m, 1H), 7.43–7.18 (m, 3H), 6.80 (d, J = 11.5 Hz, 1H), 4.83 (s, 2H), 3.81 (s, 3H); LCMS (m/z) 342.2.

Example 252. 8-Chloro-N-(3-(6-(1,1-difluoroethyl)pyridin-3-yl)phenyl)-N-methyl-[1,2,4] Triazolo[4,3-a]quinazolin-5-amine

Synthesis of N-(3-bromophenyl)-2,7-dichloro-N-methylquinazoline-4-amine (compound 252-2): 3-fluoro-N-methylaniline (837 mg, 4.5 mmol) and sodium hydride (965 mg, 24.1 mmol) were added to a solution of 2,4,7-trichloroquinazoline (1 g, 4.28 mmol) in DMF (20 mL). The mixture was stirred at room temperature for 24 hours. Water was added to the reaction mixture, and the mixture was filtered. The resulting residue was used in the next step without further purification.

Synthesis of N-(3-bromophenyl)-7-chloro-2-hydrazino-N-methylquinazoline-4-amine (compound 252-3): Hydrazine hydrate (2.8 g, 56.4 mmol) was slowly added to crude N-(3-bromophenyl)-2,7-dichloro-N-methylquinazoline-4-amine (252-2) (800 mg, 2.1 mmol) in a stirred solution of ethanol (6 ml) and THF (1 ml). The mixture was stirred at room temperature for 4 hours. The mixture was evaporated, then dissolved in DCM, and washed continuously with water and brine, and dried over _MgSO4 . The organic layer was concentrated under vacuum. The resulting residue was used in the next step without further purification.

Synthesis of N-(3-bromophenyl)-8-chloro-N-methyl-[1,2,4]triazolo[4,3-a]quinazoline-5-amine (compound 252-4): A mixture of crude N-(3-bromophenyl)-7-chloro-2-hydrazyl-N-methylquinazoline-4-amine (252-3) (550 mg, 1.45 mmol) and triethoxymethane (3.2 g, 21 mmol) was stirred at 100 °C for 4 hours. Hexane was added to the reaction mixture to precipitate the crude product, which was used in the next step.

Synthesis of 8-chloro-N-(3-(6-(1,1-difluoroethyl)pyridin-3-yl)phenyl)-N-methyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine: Pd(dppf)Cl₂ (8 mg, 0.01 mmol) and 2 ml of saturated Na₂CO₃ aqueous solution were added to a solution of N-(3-bromophenyl)-8-chloro-N-methyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine (252-4, 20 mg, 0.05 mmol) and 2-(1,1-difluoroethyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborhexacyclopentan- ₂ -yl)pyridine (15 mg, 0.056 mmol) in _1,4 -dioxane ( ₅ ml). The mixture was stirred at 90 °C for 10 min. The residue was purified by reversed-phase chromatography (ACN/water 15%–95% with 0.1% TFA, for 15 min) to yield the title compound: ^¹H NMR (400 MHz, chloroform-d) δ 9.12 (s, 1H), 8.85 (s, 1H), 8.03 (s, 2H), 7.74 (d, J = 24.2 Hz, 3H), 7.64–7.34 (m, 2H), 7.26–7.3 (m, 2H), 3.86 (s, 3H), 2.06 (t, J = 18.1 Hz, 3H); LCMS (m/z) 451.4.

Example 253. 4-(5-(3-((8-chloro-[1,2,4]triazolo[4,3-a]quinazolin-5-yl)(methyl)amino) tert-butyl phenylpyridin-2-yl)piperazine-1-carboxylate

Example 253 was prepared in a similar manner to Example 252. ^¹H NMR (400 MHz, chloroform-d) δ 9.14 (s, 1H), 8.51 (s, 1H), 8.08 (s, 1H), 8.00 (d, J = 9.3 Hz, 1H), 7.61 (d, J = 6.5 Hz, 2H), 7.43 (s, 1H), 7.36 (dt, J = 6.9, 2.2 Hz, 1H), 7.20 (s, 2H), 7.01 (d, J = 9.3 Hz, 1H), 3.75 (d, J = 12.5 Hz, 7H), 3.65 (dd, J = 6.8, 3.6 Hz, 4H), 1.49 (d, J = 20.5 Hz, 9H); LCMS (m/z) 571.3.

Example 254. 8-Chloro-N-methyl-N-(4'-(thiazol-2-yl)-[1,1'-diphenyl]-3-yl)-[1,2,4] Triazolo[4,3-a]quinazolin-5-amine

Example 254 was prepared in a similar manner to Example 252. ^¹H NMR (400 MHz, chloroform-d): δ 9.10 (s, 1H), 8.15–7.92 (m, 4H), 7.78 (d, J = 7.7 Hz, 1H), 7.72–7.60 (m, 3H), 7.57 (s, 1H), 7.44 (d, J = 3.3 Hz, 1H), 7.32 (d, J = 7.7 Hz, 1H), 7.22 (q, J = 9.5 Hz, 3H), 3.86 (s, 3H); LCMS (m/z): 469.3.

Example 255. N-(3-(1H-pyrrolo[3,2-b]pyridin-6-yl)phenyl)-8-chloro-N-methyl-[1,2,4]tri Azo[4,3-a]quinazolin-5-amine

Example 255 was prepared in a similar manner to Example 252. ^¹H NMR (400 MHz, methanol- _d⁴ ) δ 9.56 (s, 1H), 8.87 (d, J = 1.6 Hz, 1H), 8.75 (d, J = 1.3 Hz, 1H), 8.47 (d, J = 2.1 Hz, 1H), 8.17 (d, J = 3.2 Hz, 1H), 7.88 (d, J = 8.2 Hz, 2H), 7.71 (t, J = 7.8 Hz, 1H), 7.52 (d, J = 8.6 Hz, 1H), 7.42 (d, J = 9.0 Hz, 1H), 7.33 (dd, J = 9.0, 2.1 Hz, 1H), 6.90 (d, J = 3.4 Hz, 1H), 3.84 (s, 3H); LCMS (m/z) 426.2.

Example 256. 8-Chloro-N-(3'-methoxy-4'-(4-(oxecyclobutane-3-yl)piperazin-1-yl)-[1,1'- [diphenyl]-3-yl)-N-methyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine

Example 256 was prepared in a manner similar to that of Example 252. ¹ H NMR (400MHz, methanol-d ₄ )δ9.57(s,1H),8.49(d,J＝2.0Hz,1H),7.78(dt,J＝8.0,1.2Hz,1H),7.71( t,J＝2.0Hz,1H),7.63(t,J＝7.9Hz,1H),7.44–7.28(m,3H),7.22(d,J＝7.4 Hz,2H),7.11–7.02(m,1H),4.93(t,J＝7.7Hz,4H),4.50(tt,J＝7.2,5.6Hz , 1H), 3.93 (s, 4H), 3.86 (s, 4H), 3.31 (d, J = 1.5Hz, 3H); LCMS (m/z) 556.4.

Example 257. 8-Chloro-N-(4'-(1,1-difluoroethyl)-[1,1'-diphenyl]-3-yl)-N-methyl-[1,2, 4] Triazolo[4,3-a]quinazolin-5-amine

Example 257 was prepared in a similar manner to Example 252. ^¹H NMR (400 MHz, chloroform-d) δ 9.04 (s, 1H), 8.03 (s, 1H), 7.70 (d, J = 7.8 Hz, 1H), 7.66–7.57 (m, 4H), 7.48 (d, J = 1.9 Hz, 1H), 7.30 (d, J = 1.7 Hz, 2H), 7.21 (s, 2H), 3.83 (s, 3H), 1.97 (d, J = 36.2 Hz, 3H); LCMS (m/z) 450.3.

Example 258. 8-Chloro-N-methyl-N-(3-(6-(piperazin-1-yl)pyridin-3-yl)phenyl)-[1,2,4]triazole [4,3-a]quinazolin-5-amine

TFA (2 ml) was added to a solution of tert-butyl piperazine-1-carboxylate (Example 253, 20 mg, 0.05 mmol) in DCM (5 ml), and the mixture was stirred at room temperature for 2 hours. The residue was evaporated under reduced pressure and then purified by reversed-phase chromatography (ACN/water 15%–95% with 0.1% TFA, for 15 min) to yield the title compound: ^¹H NMR (400 MHz, chloroform-d) δ 9.04 (s, 1H), 8.03 (s, 1H), 7.70 (d, J = 7.8 Hz, 1H), 7.64–7.57 (m, 4H), 7.48 (d, J = 1.9 Hz, 1H), 7.30 (d, J = 1.7 Hz, 1H), 7.21 (s, 2H), 3.83 (s, 3H), 3.13 (s, 8H); LCMS (m/z) 471.3.

Example 259. 2-(5-(3-((8-chloro-[1,2,4]triazolo[4,3-a]quinazolin-5-yl)(methyl)amino) (Phenyl)pyridin-2-yl)prop-2-ol

Example 259 was prepared in a similar manner to Example 252. ^¹H NMR (400 MHz, methanol- _d⁴ ) δ 9.62 (s, 1H), 8.87 (dd, J = 2.3, 0.7 Hz, 1H), 8.59 (dd, J = 8.5, 2.3 Hz, 1H), 8.53 (d, J = 2.0 Hz, 1H), 8.07 (dd, J = 8.5, 0.7 Hz, 1H), 7.96–7.87 (m, 2H), 7.75 (t, J = 8.2 Hz, 1H), 7.64–7.53 (m, 1H), 7.41–7.25 (m, 2H), 3.88 (s, 3H), 1.67 (s, 5H); LCMS (m/z) 445.3.

Example 260. 2-(5-(3-((8-chloro-[1,2,4]triazolo[4,3-a]quinazolin-5-yl)(methyl)amino) (Phenyl)pyridin-2-yl)prop-2-ol

Example 260 was prepared in a manner similar to that of Example 252. ^¹H NMR (400 MHz, methanol- _d⁴ ) δ 9.57 (s, 1H), 8.49 (d, J = 2.0 Hz, 1H), 7.78 (dt, J = 8.0, 1.2 Hz, 1H), 7.71 (t, J = 2.0 Hz, 1H), 7.63 (t, J = 7.9 Hz, 1H), 7.44–7.27 (m, 2H), 7.10–7.03 (m, 1H), 4.93 (t, J = 7.7 Hz, 2H), 4.50 (tt, J = 7.2, 5.6 Hz, 1H), 3.93 (s, 3H); LCMS (m/z) 403.3.

Example 261. 8-Chloro-N-methyl-N-(3-(2-morpholinopyrimidin-5-yl)phenyl)-[1,2,4]triazolo[4, [3-a]quinazolin-5-amine

Example 261 was prepared in a similar manner to Example 252. ^¹H NMR (400 MHz, chloroform-d) δ 9.14 (s, 1H), 8.51 (s, 1H), 8.08 (s, 1H), 8.00 (d, J = 9.3 Hz, 1H), 7.61 (d, J = 6.5 Hz, 2H), 7.43 (s, 1H), 7.36 (dt, J = 6.9, 2.2 Hz, 1H), 7.20 (s, 1H), 7.01 (d, J = 9.3 Hz, 1H), 3.75 (d, J = 12.5 Hz, 7H), 3.65 (dd, J = 6.8, 3.6 Hz, 4H); LCMS (m/z) 473.2.

Example 262. N-(3-bromophenyl)-8-chloro-6-fluoro-N-methyl-[1,2,4]triazolo[4,3-a]quinazolin-5- amine

Synthesis of 7-chloro-5-fluoroquinazoline-2,4(1H,3H)-dione (compound 262-2): KOCN (3.2 g, 39.6 mmol) dissolved in 10 mL of water was added to a solution of 2-amino-4-chloro- ₆ -fluorobenzoic acid (5.0 g, 26.4 mmol) dissolved in acetic acid (20 mL), and the mixture was stirred at room temperature for 5 hours. Another portion of KOCN (640 mg, 7.9 mmol) was added, and the mixture was stirred for another 5 hours. A saturated aqueous solution of NaHCO3 was slowly added to the mixture, and the solid was filtered off.

Synthesis of 2,4,7-trichloro-5-fluoroquinazoline (compound 262-3): A mixture of 7-chloro-5-fluoroquinazoline-2,4(1H,3H)-dione (compound 262-2, 1.3 g, 6.06 mmol), phosphorus trichloride (2.3 g, 15.1 mmol), and DIPEA (2.2 mL, 12.12 mmol) was stirred at 100 °C for 1 h. The reaction was monitored by LCMS. The reaction mixture was cooled to room temperature and evaporated under reduced pressure. The residue was purified by normal-phase chromatography (hexane:EtOAc 1:2). The appropriate fraction was evaporated and used in the next step.

Synthesis of N-(3-bromophenyl)-2,7-dichloro-N-methylquinazoline-4-amine (compound 262-4): A solution of 3-bromo-N-methylaniline (160 mg, 0.86 mmol) and sodium hydride (109 mg, 2.7 mmol) in DMF was stirred at room temperature for 30 minutes. 2,4,7-trichloro-5-fluoroquinazoline (compound 262-3, 173 mg, 0.68 mmol) was added to the mixture, and the mixture was stirred at room temperature for 24 hours. Water and DCM were added to the mixture, and the organic phase was dried over _MgSO4 and evaporated under reduced pressure. The crude product was used in the next step.

Synthesis of N-(3-bromophenyl)-7-chloro-2-hydrazineyl-N-methylquinazoline-4-amine (compound 262-5): Hydrazine hydrate (1 g, 20.2 mmol) was slowly added to crude N-(3-bromophenyl)-2,7-dichloro-N-methylquinazoline-4-amine (compound 262-4) (300 mg, 0.74 mmol) in a stirred solution of 6 mL ethanol and 1 mL THF at room temperature. The mixture was evaporated under reduced pressure and dissolved in DCM, then washed continuously with water and brine and dried over _MgSO₄ . The organic layer was concentrated under vacuum. The resulting residue was used in the next step without further purification.

Synthesis of N-(3-bromophenyl)-8-chloro-N-methyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine: A mixture of crude N-(3-bromophenyl)-7-chloro-2-hydrazino-N-methylquinazolin-4-amine (compound 262-5) (200 mg, 0.5 mmol) and triethoxymethane (1.4 g, 10 mmol) was stirred at 95 °C for 4 hours. The residue was evaporated under reduced pressure and then purified by reversed-phase chromatography (ACN/water 15%–95% with 0.1% TFA, for 15 min) to give the title compound: ^¹H NMR (400 MHz, chloroform-d) δ 8.95 (s, 1H), 7.72 (s, 1H), 7.39–7.32 (m, 1H), 7.24 (d, J = 2.1 Hz, 1H), 7.16 (t, J = 8.0 Hz, 1H), 7.00 (dd, J = 11.0, 1.9 Hz, 1H), 6.96–6.89 (m, 1H), 3.68 (s, 3H); LCMS (m/z) 408.2.

Example 263. N-(4'-(tert-butyl)-[1,1'-diphenyl]-3-yl)-8-chloro-6-fluoro-N-methyl-[1,2,4] Triazolo[4,3-a]quinazolin-5-amine

Example 263 was prepared in a manner similar to Example 252, except that Compound 252-4 was replaced by Compound 252-4 and (4-(tert-butyl)phenyl)boronic acid was replaced by 2-(1,1-difluoroethyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)pyridine, as in Example 262. ^¹H NMR (400 MHz, chloroform-d) δ 9.25 (s, 1H), 8.06 (s, 1H), 7.60–7.52 (m, 1H), 7.48 (d, J = 8.6 Hz, 2H), 7.46–7.38 (m, 3H), 7.35 (t, J = 1.9 Hz, 1H), 7.08–6.97 (m, 2H), 3.84 (s, 3H), 1.37 (s, 9H); LCMS (m/z) 460.4.

Example 264. N-(6-(4-(tert-butyl)phenyl)pyridin-2-yl)-8-chloro-N-methyl-[1,2,4]triazolidine [4,3-a]quinazolin-5-amine

The synthetic route for preparing 6-(4-(tert-butyl)phenyl)-N-methylpyridin-2-amine (compound 264-2) is similar to the synthetic route used to prepare Example 252.

Synthesis of N-(6-(4-(tert-butyl)phenyl)pyridin-2-yl)-8-chloro-N-methyl-[1,2,4]triazolo[4,3-a]quinazoline-5-amine (compound 264-4): 6-(4-(tert-butyl)phenyl)-N-methylpyridin-2-amine (160 mg, 0.86 mmol) and LiHMDS in THF (1 M, 0.3 ml, 0.32 mmol) were added to a solution of 2,4,7-trichloroquinazoline (173 mg, 0.68 mmol) in THF (5 ml) at -20 °C. The mixture was stirred at -20 °C for 2 hours. Water and DCM were added to the mixture, and the organic phase was dried over _MgSO₄ and evaporated under reduced pressure. The solid was used for the next step.

The synthetic routes for preparing compounds 264-5 and the title compound were similar to those described in Example 252. ^¹H NMR (400 MHz, chloroform-d) δ 9.30 (s, 1H), 8.18 (d, J = 1.7 Hz, 1H), 7.82 (t, J = 7.8 Hz, 1H), 7.68 (dd, J = 15.3, 8.0 Hz, 3H), 7.44 (d, J = 8.2 Hz, 2H), 7.24–7.16 (m, 2H), 7.06 (d, J = 7.9 Hz, 1H), 3.88 (s, 3H), 1.35 (s, 9H); LCMS (m/z) 443.4.

Example 265. 6-(3-((8-chloro-[1,2,4]triazolo[4,3-a]quinazolin-5-yl)(methyl)amino)benzene 4-Fluoro-1-methyl-1,3-dihydro-2H-benzo[d]imidazol-2-one

Example 265 was prepared in a manner similar to that of Example 252. ^¹H NMR (400 MHz, methanol- _d⁴ ) δ 9.58 (s, ¹H), 8.50 (d, J = 2.0 Hz, ¹H), 7.76 (ddd, J = 7.9, 1.9, 1.0 Hz, ¹H), 7.71 (t, J = 2.0 Hz, ¹H), 7.64 (t, J = 7.9 Hz, ¹H), 7.46–7.28 (m, 3H), 7.21–7.08 (m, 2H), 3.85 (s, 3H), 3.61–3.54 (m, 3H); LCMS (m/z) 474.4.

Example 266. 6'-(3-((8-chloro-[1,2,4]triazolo[4,3-a]quinazolin-5-yl)(methyl)amino)benzene 2'-spiro[cyclopropane-1,3'-dihydroindole]-2'-one

Example 266 was prepared in a manner similar to that of Example 252. ¹ H NMR (400MHz, methanol-d ₄ )δ9.59(s,1H),8.50(d,J＝2.0Hz,1H),7.78(dt,J＝7.8,1.3Hz,1H),7.71(t,J＝2.0Hz,1H),7.65(t,J＝7.9Hz,1H),7.44(ddd,J＝7.9,2.3,1.0Hz,1H ),7.38(dd,J＝9.1,2.0Hz,1H),7.30(d,J＝9.2Hz,1H),7.27–7.18(m,2H),7.01(d,J＝7.8Hz,1H),3.86(s,3H),1.78–1.53(m,4H); LCMS(m/z)467.2.

Example 267. 3-(3-((8-chloro-[1,2,4]triazolo[4,3-a]quinazolin-5-yl)(methyl)amino)benzene (B,f)dibenzo[b,f][1,4]oxazate-11(10H)-one

Example 267 was prepared in a similar manner to Example 252. ^¹H NMR (400 MHz, methanol- _d⁴ ) δ 9.60 (s, ¹H), 8.52 (d, J = 2.0 Hz, ¹H), 7.98–7.81 (m, ³H), 7.70 (t, J = 7.9 Hz, ¹H), 7.62–7.47 (m, ³H), 7.39 (dd, J = 9.2, 2.0 Hz, ¹H), 7.34–7.27 (m, 2H), 7.24–7.09 (m, ³H), 3.87 (s, ³H); LCMS (m/z) 519.4.

Example 268. 8-Chloro-N-(3-(6-(1,1-difluoroethyl)pyridin-3-yl)phenyl)-6-fluoro-N-methyl-[1, [2,4]triazolo[4,3-a]quinazolin-5-amine

Example 268 was prepared in a similar manner to Example 252. ^¹H NMR (400 MHz, methanol- _d⁴ ) δ 9.60 (s, ¹H), 8.74 (s, ¹H), 8.38 (s, ¹H), 8.12 (dd, J = 8.3, 2.3 Hz, ¹H), 7.77 (d, J = 8.3 Hz, ¹H), 7.72–7.51 (m, 3H), 7.38 (dd, J = 23.4, 9.8 Hz, 2H), 3.86 (s, 3H), 2.17–1.78 (m, 3H); LCMS (m/z) 469.4.

Example 269. 8-Chloro-N-methyl-N-(3-(6-(4-(oxecyclobutane-3-yl)piperazin-1-yl)pyridine-3- (1,2,4)triazolo[4,3-a]quinazolin-5-amine

Sodium triacetoxyborohydride (40 mg, 0.19 mmol) was added to a solution of 8-chloro-N-methyl-N-(3-(6-(piperazin-1-yl)pyridin-3-yl)phenyl)-[1,2,4]triazolo[4,3-a]quinazolin-5-amine (Example 258, 20 mg, 0.04 mmol) and oxetane-3-one (10 mg, 0.15 mmol) in THF (5 ml) at room temperature. The mixture was stirred at room temperature for 1 hour. Water and DCM were added to the mixture, and the organic phase was dried over _MgSO4 and evaporated under reduced pressure. The crude product was purified by reversed-phase chromatography with ACN/water 15-95% and 0.1% TFA for 15 min, providing the title compound: ^¹H NMR (400 MHz, methanol- _d⁴ ) δ 9.59 (s, 1H), 8.58–8.36 (m, 2H), 8.02–7.88 (m, 1H), 7.82–7.56 (m, 3H), 7.48–7.33 (m, 2H), 7.30 (d, J = 9.1 Hz, 1H), 7.07 (d, J = 8.9 Hz, 1H), 4.93 (d, J = 7.7 Hz, 4H), 4.40 (q, J = 6.3 Hz, 1H), 3.86 (s, 3H), 3.30 (s, 8H); LCMS (m/z) 527.3.

Example 270. 1-(4-(5-(3-((8-chloro-[1,2,4]triazolo[4,3-a]quinazolin-5-yl)(methyl)amino (2,2-dimethylprop-1-one)

A solution of 8-chloro-N-methyl-N-(3-(6-(piperazin-1-yl)pyridin-3-yl)phenyl)-[1,2,4]triazolo[4,3-a]quinazolin-5-amine (Example 258, 20 mg, 0.04 mmol) and tervaponic anhydride (10 mg, 0.15 mmol) in pyridine (5 mL) was stirred at room temperature for 24 hours. The reaction mixture was evaporated and then purified by reversed-phase chromatography (ACN/water 15%–95% with 0.1% TFA, duration 15 min) to give the title compound: ^¹H NMR (400 MHz, methanol- _d4) )δ9.61(s,1H),8.52(d,J＝2.1Hz,1H),8.33(d,J＝2.5Hz,1H),8.16(dd,J＝9.3 ,2.5Hz,1H),7.85–7.73(m,2H),7.68(t,J＝7.8Hz,1H),7.53–7.44(m,1H),7.3 7(dd,J＝9.1,2.1Hz,1H),7.30(d,J＝9.1Hz,1H),7.24(d,J＝9.3Hz,1H),3.88( d, J＝10.9Hz, 7H), 3.74 (dd, J＝6.7, 3.9Hz, 4H), 1.34 (s, 9H); LCMS (m/z) 555.4.

Example 271. 1-(4-(5-(3-((8-chloro-[1,2,4]triazolo[4,3-a]quinazolin-5-yl)(methyl)amino (2,2-dimethylprop-1-one)

Example 271 was prepared using a procedure similar to that of Example 270. ¹ H NMR (400MHz, methanol-d ₄ )δ9.60(s,1H),8.51(d,J＝2.0Hz,1H),8.32(d,J＝2.3Hz,1H),8.07(dd,J＝9. 2,2.5Hz,1H),7.84–7.71(m,2H),7.66(t,J＝7.9Hz,1H),7.45(ddd,J＝8.0,2. 2,1.0Hz,1H),7.37(dd,J＝9.1,2.0Hz,1H),7.30(d,J＝9.1Hz,1H),7.16(d,J =9.2Hz,1H),3.86(s,3H),3.76(s,3H),3.74–3.62(m,8H); LCMS(m/z)529.4.

Example 272. 8-Chloro-N-(6-(4-(1,1-difluoroethyl)phenyl)pyridin-2-yl)-N-methyl-[1,2,4] Triazolo[4,3-a]quinazolin-5-amine

Synthesis of N-(6-bromopyridin-2-yl)-2,7-dichloro-N-methylquinazoline-4-amine (compound 272-2): 6-bromo-N-methylpyridin-2-amine (234 mg, 1.25 mmol) and LiHMDS in THF (1.0 M, 1.6 mL, 1.2 mmol) were added to a solution of 2,4,7-trichloroquinazoline (280 mg, 1.2 mmol) at -20 °C in 5 mL of THF. The mixture was stirred at -20 °C for 2 hours. Water and DCM were added to the mixture, and the organic phase was dried over _MgSO₄ and evaporated under reduced pressure. The crude product was used in the next step without further purification.

The synthesis of compounds 272-3 and 272-4 was carried out by a procedure similar to that described in synthesis example 249.

The final step in the synthesis of 8-chloro-N-(6-(4-(1,1-difluoroethyl)phenyl)pyridin-2-yl)-N-methyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine was carried out by a procedure similar to that described in Example 252. ¹ HNMR (400MHz, methanol-d ₄ )δ9.67(s,1H),8.55(s,1H),8.03(t,J＝7.8Hz,1H),7.90(d,J＝8.8Hz,2H),7.62–7.51(m,2H),7.41(d,J＝8 .7Hz, 2H), 7.29 (d, J = 9.0Hz, 1H), 6.87 (t, J = 8.3Hz, 1H), 3.92 (s, 3H), 2.04–1.76 (m, 3H); LCMS (m/z) 451.4.

Example 273. 8-Chloro-N-methyl-N-(6-(2-morpholinopyrimidin-5-yl)pyridin-2-yl)-[1,2,4]triazole [4,3-a]quinazolin-5-amine

Example 273 was synthesized in a manner similar to that described in Example 272. ^¹H NMR (400 MHz, methanol- _d⁴ ) δ 9.68 (s, 1H), 8.77 (s, 2H), 8.57 (d, J = 2.1 Hz, 1H), 7.99 (t, J = 7.9 Hz, 1H), 7.84 (d, J = 7.8 Hz, 1H), 7.50–7.34 (m, 2H), 7.34–7.13 (m, 1H), 3.99–3.68 (m, 11H); LCMS (m/z) 474.4.

Example 274. 8-Chloro-N-methyl-N-(6-(4-(methanesulfonyl)phenyl)pyridin-2-yl)-[1,2,4]tri Azo[4,3-a]quinazolin-5-amine

Example 274 was synthesized in a manner similar to that described in Example 272. ^¹H NMR (400 MHz, methanol- _d⁴ ) δ 9.4 (s, ¹H), 8.5 (s, ¹H), 8.17–6.95 (m, 9H), 3.14 (s, 6H); LCMS (m/z) 465.3.

Example 275. 8-Chloro-N-(6'-(1,1-difluoroethyl)-[2,3'-dipyridin]-6-yl)-N-methyl-[1,2, 4] Triazolo[4,3-a]quinazolin-5-amine

Example 275 was synthesized in a manner similar to that described in Example 272. ^¹H NMR (400 MHz, methanol- _d⁴ ) δ 9.63 (s, ¹H), 8.26 (s, ¹H), 8.08 (s, ¹H), 7.96–7.30 (m, 4H), 7.25–6.74 (m, 3H), 3.31 (s, 3H), 2.24–1.73 (m, 3H); LCMS (m/z) 452.3.

Example 276. 8-Chloro-N-(6-(4-chlorophenyl)pyridin-2-yl)-N-methyl-[1,2,4]triazolo[4,3-a] Quinazoline-5-amine

Example 276 was synthesized in a manner similar to that described in Example 272. ^¹H NMR (400 MHz, methanol- _d⁴ ) δ 9.59 (s, ¹H), 8.27 (s, 2H), 8.02 (s, ¹H), 7.83 (s, ¹H), 7.67–7.01 (m, 6H), 3.90 (s, 3H); LCMS (m/z) 421.3.

Example 277. 8-Chloro-N-methyl-N-(3-(oxetane-3-ylethynyl)phenyl)-[1,2,4]triazole [4,3-a]quinazolin-5-amine

N-(3-bromophenyl)-8-chloro-N-methyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine (Example 308, 50 mg, 0.13 mmol), 3-ethynyloxetane (21 mg, 0.26 mmol), Pd( _PPh3 ) _Cl2 (0.9 mg, 0.0013 mmol), and CuI (1.2 mg, 0.0064 mmol) were added to a vial equipped with a stir bar. Then, DMF (2.0 mL) and DIPEA (0.045 mL, 0.26 mmol) were added to the vial, and the suspension was bubbled under nitrogen for 5 minutes. The reaction was heated to 100 °C for 24 hours, during which time LC/MS indicated incomplete conversion. Additional alkynes, Pd, CuI, and DIPEA were added, and the reaction was heated again for 24 hours. LC/MS indicated near-complete conversion, and the reactants were filtered through a diatomaceous earth stopper and eluted with EtOAc. The filtrate was evaporated to a residue, which was purified by normal-phase rapid chromatography using a 3:1 EtOAc:EtOH mixture in heptane. The crude product was further purified by preparative HPLC to obtain the title compound: ^¹H NMR (400MHz, DMSO- _d⁶ ) δ 9.74 (s, 1H), 8.61 (d, J = 2.1Hz, 1H), 7.51–7.47 (m, 1H), 7.46–7.35 (m, 4H), 7.23 (d, J = 9.0Hz, 1H), 4.77 (dd, J = 8.5, 5.4Hz, 2H), 4.58 (dd, J = 7.1, 5.4Hz, 2H), 4.12 (ddd, J = 15.6, 8.5, 7.1Hz, 1H), 3.57 (s, 3H); LCMS (m/z) 390.1.

Example 278. 8-Chloro-N-(4'-(2-(dimethylamino)ethoxy)-[1,1'-diphenyl]-3-yl)-N-methyl [1,2,4]triazolo[4,3-a]quinazolin-5-amine

N-(3-bromophenyl)-8-chloro-N-methyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine (Example 308, 30 mg, 0.077 mmol), N,N-dimethyl-2-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborhexacyclopentan-2-yl)phenoxy]ethylamine (45 mg, 0.15 mmol), and (dtbpf) _PdCl₂ (2.7 mg, 0.004 mmol) were added to a vial equipped with a stir bar. The vial was then rinsed with nitrogen and filled with dioxane (1.0 mL) and a nitrogen-purged 2M _{Na₂CO₃ aqueous} solution (0.2 mL). The reaction was heated to 50 °C and monitored by LC/MS. After completion (approximately 18 hours), the reaction mixture was filtered through a diatomaceous earth stopper and eluted with EtOAc. The filtrate was then evaporated, and the residue was purified by preparative HPLC to give the title compound: ^¹H NMR (400MHz, DMSO- _d⁶ ) δ 9.72 (s, 1H), 9.57 (s, 1H), 8.59 (d, J = 2.1Hz, 1H), 7.67–7.58 (m, 4H), 7.51 (t, J = 7.8Hz, 1H), 7.40–7.29 (m, 2H), 7.28 (d, J = 9.0Hz, 1H), 7.09–7.01 (m, 2H), 4.34 (t, J = 5.0Hz, 2H), 3.64 (s, 3H), 3.52 (q, J = 5.0Hz, 2H), 2.87 (s, 3H), 2.86 (s, 3H); LCMS (m/z) 473.2.

Example 279. 4-((3'-((8-chloro-[1,2,4]triazolo[4,3-a]quinazolin-5-yl)(methyl)amino)- [1,1'-diphenyl]-4-yl)oxy)piperidine-1-carboxylic acid tert-butyl ester

Example 279 was synthesized according to a similar procedure to that described for Example 278. ^¹H NMR (400MHz, DMSO- _d⁶ ) δ 9.76 (s, ¹H), 8.61 (d, J = 2.1 Hz, ¹H), 7.66 (s, ¹H), 7.63 (d, J = 7.9 Hz, ¹H), 7.57 (d, J = 8.8 Hz, 2H), 7.51 (t, J = 7.9 Hz, 1H), 7.39 (dd, J = 9.0, 2.0 Hz, 1H), 7.36–7.30 (m, ¹H), 7. 27(d,J＝9.0Hz,1H),7.03(d,J＝8.8Hz,2H),4.64–4.55(m,1H),3.69–3.60(m,5H),3.2 7–3.12(m,2H),1.98–1.83(m,2H),1.59–1.45(m,2H),1.40(s,9H); LCMS(m/z)585.2.

Example 280. 1-(3'-((8-chloro-[1,2,4]triazolo[4,3-a]quinazolin-5-yl)(methyl)amino)- [1,1'-Diphenyl]-4-yl)imidazolidine-2-one

Example 280 was synthesized according to a procedure similar to that described for Example 278. ^¹H NMR (400MHz, DMSO- _d⁶ ) δ 9.75 (s, 1H), 8.61 (d, J = 2.1Hz, 1H), 7.70 (s, 1H), 7.66 (d, J = 8.0Hz, 1H), 7.61 (s, 4H), 7.51 (t, J = 7.9Hz, 1H), 7.40 (dd, J = 9.0, 2.1Hz, 1H), 7.35–7.30 (m, 1H), 7.28 (d, J = 9.0Hz, 1H), 7.01 (s, 1H), 3.86 (dd, J = 9.3, 6.6Hz, 2H), 3.66 (s, 3H), 3.46–3.36 (m, 2H); LCMS (m/z) 470.1.

Example 281. 1-(3'-((8-chloro-[1,2,4]triazolo[4,3-a]quinazolin-5-yl)(methyl)amino)- [1,1'-Diphenyl]-4-yl)pyrrolidone-2-one

Add 1-(4-bromophenyl)pyrrolidone-2-one (15 mg, 0.064 mmol), bis(pinacol)diboron (20 mg, 0.077 mmol), Pd( _PPh3 ) _Cl2 (4.5 mg, 0.0064 mmol), and KOAc (19 mg, 0.19 mmol) to a microwave-safe reaction flask (0.5–2 mL) equipped with a stir bar. Rinse the flask with nitrogen and add dioxane (1.0 mL). Irradiate the reaction at 120 °C (Biotage Initiator) until complete conversion to the intermediate borate ester is observed by LC/MS (typically 45–90 minutes). Then, N-(3-bromophenyl)-8-chloro-N-methyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine (25 mg, 0.064 mmol) and 0.16 mL _of 2 M _Na₂CO₃ aqueous solution purged with nitrogen were added, and the reaction was heated to 100 °C until complete conversion was observed by LC/MS (usually 15–60 min). The reactants were then filtered through a diatomaceous earth stopper and eluted with EtOAc. The filtrate was evaporated, and the residue was purified by preparative HPLC to provide the title compound: ^¹H NMR (400 MHz, methanol- _d⁴ ) δ 9.56 (s, ¹H), 8.48 (d, J = 2.1 Hz, ¹H), 7.81–7.77 (m, ¹H), 7.73–7.69 (m, 3H), 7.66–7.61 (m, 3H), 7.43–7.39 (m, 1H), 7.36 (dd, J = 9.2, 2.0 Hz, 1H), 7.28 (d, J = 9.2 Hz, 1H), 3.95 (t, J = 7.1 Hz, 2H), 3.84 (s, 3H), 2.61 (t, J = 8.1 Hz, 2H), 2.25–2.14 (m, 2H); LCMS (m/z) 469.1.

Example 282. 8-Chloro-N-methyl-N-(4'-(piperidin-4-yloxy)-[1,1'-diphenyl]-3-yl)-[1, [2,4]triazolo[4,3-a]quinazolin-5-amine

TFA (0.23 mL, 3.0 mmol) was added to a solution of 4-[4-[3-[(8-chloro-[1,2,4]triazolo[4,3-a]quinazolin-5-yl)-methyl-amino]phenyl]phenoxy]piperidine-1-carboxylic acid tert-butyl ester (Example 279, 98 mg, 0.15 mL) in DCM (5 mL). After 3 hours, the reaction was evaporated. The residue was purified by preparative HPLC to give the title compound: ^¹H NMR (400 MHz, DMSO- _d6) )δ9.71(s,1H),8.59(d,J＝2.1Hz,1H),8.43(s,1H),7.64–7.57(m,4H),7.50(t,J ＝7.8Hz,1H),7.36(dd,J＝9.0,2.1Hz,1H),7.34–7.30(m,1H),7.28(d,J＝9.0Hz,1 H),7.10–7.01(m,2H),4.73–4.64(m,1H),3.64(s,3H),3.32–3.18(m,2H),3.15– 3.01(m,2H),2.08(dd,J＝15.3,6.3Hz,2H),1.87–1.73(m,2H); LCMS(m/z)485.2.

Example 283. 3-((3-((8-chloro-[1,2,4]triazolo[4,3-a]quinazolin-5-yl)(methyl)amino)benzene (Alkyl)ethynyl)oxetane-3-ol

Example 283 was synthesized in a manner similar to that described for Example 277. ^¹H NMR (400MHz, DMSO- _d⁶ ) δ 9.75 (s, 1H), 8.62 (d, J = 2.1Hz, 1H), 7.57–7.50 (m, 1H), 7.50–7.38 (m, 4H), 7.23 (d, J = 9.0Hz, 1H), 6.61 (s, 1H), 4.72 (d, J = 6.4Hz, 2H), 4.57 (d, J = 6.4Hz, 2H), 3.58 (s, 3H); LCMS (m/z) 406.1.

Example 284. 1-(4-((3'-((8-chloro-[1,2,4]triazolo[4,3-a]quinazolin-5-yl)(methyl)amino (1,1'-diphenyl]-4-yl)oxy)piperidin-1-yl)ethyl-1-one

A suspension of 8-chloro-N-methyl-N-[3-[4-(4-piperidinyloxy)phenyl]phenyl]-[1,2,4]triazolo[4,3-a]quinazolin-5-amine (Example 282, 10 mg, 0.017 mmol) in DCM (0.75 mL) was treated with acetic anhydride (0.017 mmol) and stirred at ambient temperature. After 2 hours, triethylamine (0.002 mL, 0.017 mmol) was added, and the solution was stirred for another hour, at which point LC/MS indicated complete conversion. The reaction was evaporated, and the residue was purified by preparative HPLC to give the title compound: ^¹H NMR (400 MHz, DMSO-d6 ₎ )δ9.63(s,1H),8.54(d,J＝1.3Hz,1H),7.61–7.51(m,4H),7.44(t,J＝7.8Hz,1H),7.31( s,2H),7.27–7.22(m,1H),7.05–6.99(m,2H),4.68–4.61(m,1H),3.87–3.78(m,1H),3.7 1–3.62(m,1H),3.59(s,3H),3.38–3.33(m,1H),3.28–3.17(m,1H),2.01(s,3H),2.00–1 .91(m,1H),1.93–1.81(m,1H),1.67–1.54(m,1H),1.56–1.42(m,1H); LCMS(m/z)527.2.

Example 285. 8-Chloro-N-methyl-N-(4'-((1-methylpiperidin-4-yl)oxy)-[1,1'-diphenyl]-3- (-[1,2,4]triazolo[4,3-a]quinazolin-5-amine)

A suspension of 8-chloro-N-methyl-N-[3-[4-(4-piperidinyloxy)phenyl]phenyl]-[1,2,4]triazolo[4,3-a]quinazolin-5-amine (Example 282, 15 mg, 0.025 mmol) in DCM (1.0 mL) was treated with formaldehyde (0.005 mL, 0.063 mmol) and stirred at ambient temperature for 5 min. Then, Na(OAc) _₃BH (5.8 mg, 0.028 mmol) was added, and the solution was stirred at ambient temperature for 3 h. The second portion of borohydride was added, and the reaction was stirred again for 45 min until complete conversion was achieved. The reaction was evaporated, and the residue was purified by preparative HPLC to provide the title compound: ^¹H NMR (400 MHz, DMSO-d₆ _). )δ9.70(s,1H),8.58(d,J＝2.0Hz,1H),7.66–7.55(m,4H),7.49(t,J＝7.8Hz,1H),7.39–7. 25(m,3H),7.12–7.00(m,2H),4.81–4.51(m,1H),3.63(s,3H),3.51(d,J＝12.4Hz,1H),3.3 2(d,J＝12.2Hz,1H),3.23–3.02(m,2H),2.82(dd,J＝10.1,4.8Hz,3H),2.26(d,J＝13.5Hz, 1H), 2.07 (d, J＝14.8Hz, 1H), 1.95 (t, J＝13.4Hz, 1H), 1.79–1.64 (m, 1H); LCMS (m/z) 499.2.

Example 286. 8-Chloro-N-(3-(6-fluoropyridin-3-yl)phenyl)-N-methyl-[1,2,4]triazolo[4,3-a] Quinazoline-5-amine

Example 286 was synthesized in a manner similar to that described for Example 278. ^¹H NMR (400MHz, DMSO- _d⁶ ) δ 9.78 (s, 1H), 8.63 (d, J = 2.1Hz, 1H), 8.54 (d, J = 2.6Hz, 1H), 8.28 (td, J = 8.2, 2.7Hz, 1H), 7.86–7.81 (m, 1H), 7.76–7.70 (m, 1H), 7.57 (t, J = 7.9Hz, 1H), 7.46–7.36 (m, 2H), 7.32–7.25 (m, 2H), 3.67 (s, 3H); LCMS (m/z) 405.1.

Example 287. 5-((3-bromophenyl)(methyl)amino)-8-chloro-[1,2,4]triazolo[4,3-a]quinazolin-1 (2H)-ketone

A solution of N-(3-bromophenyl)-7-chloro-2-hydrazino-N-methylquinazoline-4-amine (216 mg, 0.46 mmol) and carbonyl diimidazole (CDI, 89 mg, 0.55 mmol) in THF (4 mL) was stirred at ambient temperature for 90 minutes. The solution was then evaporated, and the resulting residue was purified by rapid chromatography using 10% MeOH/DCM. A portion was further purified by preparative HPLC, providing the title compound: ^¹H NMR (400MHz, DMSO- _d⁶ ) δ 12.17 (s, ¹H), 8.75 (d, J = 2.3Hz, ¹H), 7.63 (s, ¹H), 7.46–7.41 (m, ¹H), 7.36–7.28 (m, 2H), 7.24 (dd, J = 8.9, 2.2Hz, ¹H), 7.10 (d, J = 8.8Hz, ¹H), 3.45 (s, 3H); LCMS (m/z) 406.0/404.0.

Example 288. 5-((4'-(tert-butyl)-[1,1'-diphenyl]-3-yl)(methyl)amino)-8-chloro-[1,2, 4] Triazolo[4,3-a]quinazolin-1(2H)-one

5-(3-bromo-N-methyl-aniline)-8-chloro-2H-[1,2,4]triazolo[4,3-a]quinazolin-1-one (Example 287, 36 mg, 0.079 mmol), 4-tert-butylphenylboronic acid (15 mg, 0.083 mmol), and Pd( _PPh3 ) _Cl2 (5.5 mg, 0.008 mmol) were added to a vial equipped with a stir bar. The vial was then rinsed with nitrogen and filled with 1.0 mL of dioxane and 0.08 mL of _a 2M _Na2CO3 aqueous solution purged with nitrogen. The reaction mixture was heated to 100 °C for 18 hours, at which point LC/MS indicated partial conversion. Additional boric acid, catalyst, and base were added, and the reaction was heated again for 4.5 hours, at which point LC/MS indicated near-complete conversion. The reaction mixture was filtered through a diatomaceous earth stopper and eluted with EtOAc. The filtrate was evaporated, and the residue was purified by preparative HPLC to give the title compound: ^¹H NMR (400 MHz, DMSO- _d⁶ ) δ 12.11 (s, 1H), 8.75 (d, J = 2.0 Hz, 1H), 7.60–7.54 (m, 4H), 7.50–7.42 (m, 3H), 7.29 (dd, J = 7.4, 2.1 Hz, 1H), 7.19–7.10 (m, 2H), 3.52 (s, 3H), 1.29 (s, 9H); LCMS (m/z) 458.2.

Example 289. 8-Chloro-N-methyl-N-(3-(6-(pyrrolidone-1-yl)pyridin-3-yl)phenyl)-[1,2,4]tri Azo[4,3-a]quinazolin-5-amine

A solution of 8-chloro-N-[3-(6-fluoro-3-pyridyl)phenyl]-N-methyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine (Example 286, 16.5 mg, 0.037 mmol) in DMF (0.5 mL) was treated with pyrrolidine (0.005 mL, 0.055 mmol), and the reaction was heated to 80 °C. After 18 hours, LC/MS indicated partial conversion. Pyrrolidine (0.002 mL, 0.028 mmol) was added, and the reaction was heated again for 5 hours. The reaction mixture was then diluted with EtOAc and washed once with saturated brine. The organic phase was then filtered through a diatomaceous earth plug, evaporated, and the residue was purified by preparative HPLC to obtain the title compound: ^¹H NMR (400MHz, DMSO- _d⁶ ) δ 9.74 (s, 1H), 8.60 (d, J = 2.1Hz, 1H), 8.20 (s, 1H), 8.11 (s, 1H), 7.72 (t, J = 2.0Hz, 1H), 7.65 (d, J = 7.9Hz, 1H), 7.52 (t, J = 7.9Hz, 1H), 7.41–7.32 (m, 2H), 7.28 (d, J = 9.0Hz, 1H), 6.92 (s, 1H), 3.65 (s, 3H), 3.54–3.44 (m, 4H), 2.06–1.95 (m, 4H); LCMS (m/z) 456.1.

Example 290. 1-(3'-((8-chloro-[1,2,4]triazolo[4,3-a]quinazolin-5-yl)(methyl)amino)- [1,1'-Diphenyl]-4-yl)-3-methylimidazolidine-2-one

Example 290 was synthesized according to the general approach described for Example 281. ^¹H NMR (400MHz, DMSO- _d⁶ ) δ 9.76 (s, 1H), 8.61 (d, J = 2.1Hz, 1H), 7.70 (t, J = 1.8Hz, 1H), 7.69–7.64 (m, 1H), 7.62 (s, 4H), 7.52 (t, J = 7.9Hz, 1H), 7.40 (dd, J = 9.1, 2.1Hz, 1H), 7.35–7.31 (m, 1H), 7.28 (d, J = 9.0Hz, 1H), 3.85–3.76 (m, 2H), 3.67 (s, 3H), 3.50–3.41 (m, 2H), 2.77 (s, 3H); LCMS (m/z) 484.2.

Example 291. 8-Chloro-N-(3-(6-(4-methoxypiperidin-1-yl)pyridin-3-yl)phenyl)-N-methyl-[1, [2,4]triazolo[4,3-a]quinazolin-5-amine

A solution of 8-chloro-N-[3-(6-fluoro-3-pyridyl)phenyl]-N-methyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine (Example 286, 20 mg, 0.045 mmol) in DMSO (0.75 mL) was treated with _NaHCO3 (19 mg, 0.22 mmol) and 4-methoxy-piperidine (0.009 mL, 0.078 mmol). The reaction was heated at 100 °C for 3.5 h and then at 130 °C for 18 h. The reactants were then filtered and purified by preparative HPLC to give the title compound: ^¹H NMR (400 MHz, DMSO-d6 ₎ )δ9.76(s,1H),8.61(d,J＝2.1Hz,1H),8.36(d,J＝2.6Hz,1H),7.87(d,J＝9.1Hz,1H),7.70–7.66(m, 1H),7.64(d,J＝8.0Hz,1H),7.51(t,J＝7.8Hz,1H),7.39(dd,J＝9.0,2.1Hz,1H),7.32(d,J＝8.9Hz,1H ),7.27(d,J＝9.0Hz,1H),6.97(d,J＝9.0Hz,1H),3.95(dt,J＝13.4,4.8Hz,2H),3.66(s,3H),3.48–3. 38(m,1H),3.27(s,3H),3.25–3.19(m,2H),1.94–1.83(m,2H),1.48–1.36(m,2H); LCMS(m/z)500.2.

Example 292. 5-(3-((8-chloro-[1,2,4]triazolo[4,3-a]quinazolin-5-yl)(methyl)amino)benzene dihydroindole-2-one

Example 292 was synthesized according to the general approach described for Example 278. ^¹H NMR (400MHz, DMSO- _d⁶ ) δ 10.49 (s, 1H), 9.82 (s, 1H), 8.64 (d, J = 2.1 Hz, 1H), 7.69 (t, J = 2.0 Hz, 1H), 7.69–7.63 (m, 1H), 7.57–7.51 (m, 2H), 7.48 (dd, J = 8.1, 1.9 Hz, 1H), 7.44 (dd, J = 9.1, 2.1 Hz, 1H), 7.39–7.34 (m, 1H), 7.25 (d, J = 9.1 Hz, 1H), 6.87 (d, J = 8.1 Hz, 1H), 3.69 (s, 3H), 3.51 (s, 2H); LCMS (m/z) 441.1.

Example 293. (3'-((8-chloro-[1,2,4]triazolo[4,3-a]quinazolin-5-yl)(methyl)amino)-[1, 1'-Diphenyl]-4-yl)tert-butyl carbamate

Example 293 was synthesized according to the general approach described for Example 278. ^¹H NMR (400MHz, DMSO- _d⁶ ) δ 9.78 (s, 1H), 9.46 (s, 1H), 8.62 (d, J = 2.1Hz, 1H), 7.69 (t, J = 2.0Hz, 1H), 7.66 (d, J = 8.0Hz, 1H), 7.59–7.49 (m, 5H), 7.41 (dd, J = 9.0, 2.1Hz, 1H), 7.35–7.30 (m, 1H), 7.27 (d, J = 9.1Hz, 1H), 3.67 (s, 3H), 1.48 (s, 9H); LCMS (m/z) 50 1.2.

Example 294. 1-(3'-((8-chloro-[1,2,4]triazolo[4,3-a]quinazolin-5-yl)(methyl)amino)- [1,1'-diphenyl]-4-yl)piperidin-2-one

Example 294 was synthesized according to the general approach described for Example 281. ^¹H NMR (400MHz, DMSO- _d⁶ ) δ 9.77 (s, ¹H), 8.62 (d, J = 2.1Hz, ¹H), 7.74 (t, J = 2.0Hz, ¹H), 7.72–7.68 (m, ¹H), 7.68–7.63 (m, 2H), 7.56 (t, J = 7.9Hz, ¹H), 7.42–7.37 (m, 2H), 7.37–7.32 (m, 2H), 7.27 (d, J = 9.1Hz, 1H), 3.68 (s, 3H), 3.65–3.59 (m, 2H), 2.43–2.37 (m, 2H), 1.91–1.80 (m, 4H); LCMS (m/z) 483.2.

Example 295. 1-(3'-((8-chloro-[1,2,4]triazolo[4,3-a]quinazolin-5-yl)(methyl)amino)- [1,1'-diphenyl]-4-yl)piperidine 2-(3'-((8-chloro-[1,2,4]triazolo[4,3-a]quinazolin-5-yl)(methyl)amino (1,1'-diphenyl)-[1,1'-diphenyl]-4-yl)isothiazolidinyl 1,1-dioxide

Example 295 was synthesized according to the general approach described for Example 278. ^¹H NMR (400MHz, DMSO- _d⁶ ) δ 9.79 (s, 1H), 8.63 (d, J = 2.1Hz, 1H), 7.73 (t, J = 2.0Hz, 1H), 7.71–7.65 (m, 3H), 7.55 (t, J = 7.9Hz, 1H), 7.42 (dd, J = 9.1, 2.1Hz, 1H), 7.37 (dd, J = 7.6, 2.1Hz, 1H), 7.29–7.23 (m, 3H), 3.77 (t, J = 6.5Hz, 2H), 3.68 (s, 3H), 3.53 (t, J = 7.4Hz, 2H), 2.42 (p, J = 6.9Hz, 2H); LCMS (m/z) 505.1.

Example 296. 3-((3-((8-chloro-[1,2,4]triazolo[4,3-a]quinazolin-5-yl)(methyl)amino)benzene (3-hydroxy-1-methylpyrrolidone)-3-ethynyl-2-one

Example 296 was synthesized according to the general approach described for Example 277. ^¹H NMR (400MHz, DMSO- _d⁶ ) δ 9.74 (s, ¹H), 8.62 (d, J = 2.1 Hz, ¹H), 7.49–7.35 (m, 5H), 7.21 (d, J = 9.0 Hz, ¹H), 3.58 (s, 3H), 3.37–3.26 (m, 2H), 2.77 (s, 3H), 2.43–2.35 (m, ¹H), 2.20–2.10 (m, ¹H); LCMS (m/z) 447.1.

Example 297. 8-Chloro-N-(3-(6-(((2-methoxyethyl)(methyl)amino)pyridin-3-yl)phenyl)-N- Methyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine

Example 297 was synthesized according to the general approach described for Example 291. ^1H NMR (400MHz, DMSO-d6 ₎ )δ9.77(s,1H),8.62(d,J＝2.1Hz,1H),8.30(s,1H),7.91(s,1H),7.68(s,1H), 7.64(d,J＝7.9Hz,1H),7.52(t,J＝7.9Hz,1H),7.39(dd,J＝9.0,2.1Hz,1H),7.33 (d,J＝7.9Hz,1H),7.27(d,J＝9.0Hz,1H),6.84(s,1H),3.74(t,J＝5.7Hz,2H),3 .66 (s, 3H), 3.51 (t, J = 5.6Hz, 2H), 3.24 (s, 3H), 3.08 (s, 3H); LCMS (m/z) 474.2.

Example 298. 1-(3'-((8-chloro-[1,2,4]triazolo[4,3-a]quinazolin-5-yl)(methyl)amino)- [1,1'-diphenyl]-4-yl)azacyclobut-2-one

Example 298 was synthesized according to the general approach described for Example 281. ^¹H NMR (400MHz, DMSO- _d⁶ ) δ 9.78 (s, 1H), 8.62 (d, J = 2.1Hz, 1H), 7.73 (t, J = 2.0Hz, 1H), 7.71–7.64 (m, 3H), 7.53 (t, J = 7.9Hz, 1H), 7.44–7.37 (m, 3H), 7.37–7.33 (m, 1H), 7.27 (d, J = 9.1Hz, 1H), 3.67 (s, 3H), 3.65 (t, J = 4.6Hz, 2H), 3.10 (t, J = 4.5Hz, 2H); LCMS (m/z) 455.1.

Example 299. 5-(3-((8-chloro-[1,2,4]triazolo[4,3-a]quinazolin-5-yl)(methyl)amino)benzene 1-Methyldihydroindol-2-one

Example 299 was synthesized according to the general approach described for Example 278. ^¹H NMR (400MHz, DMSO- _d⁶ ) δ 9.78 (s, ¹H), 8.62 (d, J = 2.1 Hz, ¹H), 7.73 (t, J = 2.0 Hz, ¹H), 7.71–7.64 (m, 3H), 7.53 (t, J = 7.9 Hz, 1H), 7.44–7.37 (m, 3H), 7.37–7.33 (m, 1H), 7.27 (d, J = 9.1 Hz, 1H), 3.67 (s, 3H), 3.65 (t, J = 4.6 Hz, 2H), 3.10 (t, J = 4.5 Hz, 2H); LCMS (m/z) 455.1.

Example 300. 6-(3-((8-chloro-[1,2,4]triazolo[4,3-a]quinazolin-5-yl)(methyl)amino)benzene tert-butyl 2,6-diazaspiro[3.3]heptane-2-carboxylate

Synthesis of N-(3-bromophenyl)-N-methylcarbamate: A solution of 3-bromo-N-methylaniline (500 mg, 2.7 mmol) in toluene (13 mL) was treated with potassium carbonate (743 mg, 5.4 mmol) and benzyl chloroformate (0.66 mL, 4.7 mmol). The reaction was heated to 50 °C and stirred for 16 h. The reaction was then partitioned between EtOAc and water. The aqueous solution was extracted once with EtOAc, and the combined organic matter was washed with brine and dried over _MgSO4 . The organic matter was filtered, evaporated, and the residue was purified by normal-phase rapid chromatography using 30% EtOAc/hexane. ES/MS m/z: 322.0/320.1.

Synthesis of tert-butyl 2,6-diazaspiro[3.3]heptane-2-carboxylate: Tert-butyl 2,6-diazaspiro[3.3]heptane-2-carboxylate (650 mg, 3.3 mmol), RuPhos Pd Gen 4 (93 mg, 0.11 mmol), RuPhos (98 mg, 0.22 mmol), and _Cs₂CO₃ (1780 mg, 5.5 mmol) were added to a vial equipped with a stir bar. The vial was then rinsed with nitrogen and filled with a solution of _N- (3-bromophenyl)-N-methyl-carbamate (700 mg, 2.2 mmol) in tert-amyl alcohol (8 mL). The reaction was heated to 100 °C and maintained for 2.5 h, then filtered through a diatomaceous earth stopper. The product was eluted with EtOAc, and the filtrate was then evaporated. The crude substance was purified by normal-phase rapid chromatography using 50% EtOAc/hexane to obtain the purified product: ^¹H NMR (400MHz, chloroform-d) δ 7.31 (d, J = 3.7Hz, 5H), 7.17 (t, J = 8.0Hz, 1H), 6.63 (dt, J = 8.0, 1.3Hz, 1H), 6.35–6.27 (m, 2H), 5.16 (s, 2H), 4.07 (s, 4H), 3.92 (s, 4H), 3.29 (s, 3H), 1.45 (s, 9H); ES/MS m/z: 438.4.

Synthesis of tert-butyl 6-[3-(methylamino)phenyl]-2,6-diazaspiro[3.3]heptane-2-carboxylate: 10% Pd/C (100 mg) was added to a nitrogen-purged vial and moistened with EtOH (5 mL). Then, tert-butyl 6-[3-[benzyloxycarbonyl(methyl)amino]phenyl]-2,6-diazaspiro[3.3]heptane-2-carboxylate (809 mg, 1.66 mmol) and EtOH (37 mL) were added. The headspace was purged with nitrogen, and then hydrogen was added via a balloon. The mixture was rapidly stirred at ambient temperature for 2 hours, and then the catalyst was filtered off. The product was obtained by evaporating the filtrate: ^¹H NMR (400MHz, DMSO- _d₆ ) δ 6.85 (t, J = 7.9Hz, 1H), 5.91 (ddd, J = 8.0, 2.2, 0.9Hz, 1H), 5.64 (ddd, J = 7.9, 2.2, 0.9Hz, 1H), 5.56 (t, J = 2.1Hz, 1H), 5.42 (q, J = 5.0Hz, 1H), 4.00 (s, 4H), 3.83 (s, 4H), 1.38 (s, 9H); ES/MS m/z: 304.3.

Synthesis of tert-butyl 6-[3-[(2,7-dichloroquinazoline-4-yl)-methyl-amino]phenyl]-2,6-diazaspiro[3.3]heptane-2-carboxylate: A solution of tert-butyl 6-[3-(methylamino)phenyl]-2,6-diazaspiro[3.3]heptane-2-carboxylate (239 mg, 0.79 mmol) and 2,4,7-trichloroquinazoline (184 mg, 0.79 mmol) in DMF (2.0 mL) was treated with DIPEA (0.34 mL, 2.0 mmol) and heated to 50 °C. After ₄₅ min, the reaction was cooled and diluted with water. The mixture was extracted three times with EtOAc, and the combined organic matter was dried over _Na₂SO₄ , filtered, and evaporated. The residue was purified by normal-phase rapid chromatography using 40% EtOAc/hexane, yielding the following products: ^¹H NMR (400 MHz, DMSO- _d⁶ ) δ 7.72 (d, J = 2.2 Hz, 1H), 7.26 (dd, J = 8.8, 7.8 Hz, 1H), 7.19 (dd, J = 9.2, 2.3 Hz, 1H), 6.90 (d, J = 9.2 Hz, 1H), 6.66–6.61 (m, 1H), 6.49–6.43 (m, 2H), 4.00 (s, 4H), 3.91 (s, 4H), 3.51 (s, 3H), 1.37 (s, 9H); ES/MS m/z: 502.2/500.3.

Synthesis of tert-butyl 6-[3-[(7-chloro-2-hydrazolin-4-yl)-methyl-amino]phenyl]-2,6-diazaspiro[3.3]heptane-2-carboxylate: A solution of tert-butyl 6-[3-[(2,7-dichloroquinazolin-4-yl)-methyl-amino]phenyl]-2,6-diazaspiro[3.3]heptane-2-carboxylate (331 mg, 0.63 mmol) in EtOH (14 mL) and THF (6.9 mL) was treated with hydrazine hydrate (0.31 mL, 6.3 mmol). The solution was stirred at ambient temperature for 90 min, then heated to 50 °C for 21 h. The evaporation was distilled off, and the residue was ground with heptane to give the product: ES/MS m/z: 496.4.

Synthesis of tert-butyl 6-[3-[(8-chloro-[1,2,4]triazolo[4,3-a]quinazolin-5-yl)-methyl-amino]phenyl]-2,6-diazaspiro[3.3]heptane-2-carboxylate: tert-butyl 6-[3-[(7-chloro-2-hydrazyl-quinazolin-4-yl)-methyl-amino]phenyl]-2,6-diazaspiro[3.3]heptane-2-carboxylate (312 mg, 0.63 mmol) was suspended in triethyl orthoformate (5.0 mL, 30 mmol) and heated to 100 °C for 1 hour. The evaporator was evaporated. The residue was purified by normal-phase rapid chromatography using 80% (3:1 EtOAc:EtOH)/heptane to provide the product. A small portion was purified by preparative HPLC to obtain the title compound: ^¹H NMR (400MHz, DMSO- _d⁶ ) δ 9.75 (s, 1H), 8.60 (d, J = 2.1Hz, 1H), 7.42 (dd, J = 9.1, 2.1Hz, 1H), 7.28–7.20 (m, 2H), 6.63 (dd, J = 7.8, 2.0Hz, 1H), 6.49–6.38 (m, 2H), 4.00 (s, 4H), 3.90 (s, 4H), 3.58 (s, 3H), 1.37 (s, 9H); LCMS (m/z) 506.2.

Example 301. N-(3-(2,6-diazaspiro[3.3]hept-2-yl)phenyl)-8-chloro-N-methyl-[1,2,4]tri Azo[4,3-a]quinazolin-5-amine

A solution of 6-[3-[(8-chloro-[1,2,4]triazolo[4,3-a]quinazolin-5-yl)-methyl-amino]phenyl]-2,6-diazaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester (Example 300, 80 mg, 0.14 mmol) in DCM (3.0 mL) was treated with 85% aqueous phosphoric acid solution (0.029 mL, 0.43 mmol) and stirred at ambient temperature. After 30 minutes, the reaction was evaporated, and the residue was purified by preparative HPLC, providing the title compound: ^¹H NMR (400MHz, DMSO- _d⁶ ) δ 9.66 (s, ¹H), 8.56 (d, J = 2.1Hz, ¹H), 7.34 (dd, J = 9.0, 2.1Hz, ¹H), 7.27 (d, J = 9.0Hz, ¹H), 7.20 (t, J = 8.0Hz, ¹H), 6.65–6.57 (m, ¹H), 6.43 (t, J = 2.2Hz, ¹H), 6.41–6.37 (m, ¹H), 4.13 (t, J = 6.1Hz, 4H), 3.93 (s, 4H), 3.53 (s, 3H); LCMS (m/z) 406.1.

Example 302. (6-(3-((8-chloro-[1,2,4]triazolo[4,3-a]quinazolin-5-yl)(methyl)amino)benzene (3.3)-2,6-diazaspiro[3.3]hept-2-yl)(cyclopropyl)methyl ketone

A suspension of 8-chloro-N-[3-(2,6-diazaspiro[3.3]hept-2-yl)phenyl]-N-methyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine (Example 301, 13 mg, 0.023 mmol) in DCM (1.0 mL) was treated with cyclopropaneformyl chloride (0.003 mL, 0.028 mmol) and TEA (0.010 mL, 0.068 mmol). The mixture was stirred at ambient temperature for 80 minutes and then evaporated. The residue was purified by preparative HPLC to obtain the title compound: ^¹H NMR (400MHz, DMSO- _d⁶ ) δ 9.74 (s, 1H), 8.60 (d, J = 2.1Hz, 1H), 7.42 (dd, J = 9.0, 2.1Hz, 1H), 7.29–7.20 (m, 2H), 6.63 (d, J = 7.9Hz, 1H), 6.48–6.46 (m, 1H), 6.46–6.42 (m, 1H), 4.41 (s, 2H), 4.01 (s, 2H), 3.98–3.90 (m, 4H), 3.58 (s, 3H), 1.54–1.46 (m, 1H), 0.74–0.63 (m, 4H); LCMS (m/z) 474.2.

Example 303. 8-Chloro-N-(3-(6-(cyclopropylsulfonyl)-2,6-diazaspiro[3.3]hept-2-yl)benzene (N-methyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine)

A suspension of 8-chloro-N-[3-(2,6-diazaspiro[3.3]hept-2-yl)phenyl]-N-methyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine (Example 301, 15 mg, 0.026 mmol) in DCM (1.2 mL) was treated with cyclopropanesulfonyl chloride (0.003 mL, 0.031 mmol) and TEA (0.011 mL, 0.078 mmol). The mixture was stirred at ambient temperature for 90 minutes and then evaporated. The residue was purified by preparative HPLC to obtain the title compound: ^¹H NMR (400MHz, DMSO- _d⁶ ) δ 9.76 (s, ¹H), 8.61 (d, J = 2.1Hz, ¹H), 7.42 (dd, J = 9.0, 2.1Hz, ¹H), 7.28–7.21 (m, 2H), 6.68–6.61 (m, 1H), 6.49–6.46 (m, 1H), 6.46–6.43 (m, 1H), 4.08 (s, 4H), 3.95 (s, 4H), 3.58 (s, 3H), 2.79–2.69 (m, 1H), 1.05–0.98 (m, 2H), 0.96–0.89 (m, 2H); LCMS (m/z) 510.2.

Example 304. 8-Chloro-N-methyl-N-(3-(6-(2,2,2-trifluoroethyl)-2,6-diazaspiro[3.3]hept- 2-yl)phenyl)-[1,2,4]triazolo[4,3-a]quinazolin-5-amine

A solution of 8-chloro-N-[3-(2,6-diazaspiro[3.3]hept-2-yl)phenyl]-N-methyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine (13 mg, 0.022 mmol) in ACN (1.0 mL) was treated with 2,2,2-trifluoroethyltrifluoromethanesulfonate (0.004 mL, 0.026 mmol) and DIPEA (0.011 mL, 0.066 mmol). The mixture was stirred at ambient temperature for 2 hours and then evaporated. The residue was purified by preparative HPLC to obtain the product: ^¹H NMR (400MHz, acetone- _d⁶ ) δ 9.49 (s, 1H), 8.43 (d, J = 2.0 Hz, 1H), 7.45 (d, J = 9.0 Hz, 1H), 7.31 (dd, J = 9.0, 2.1 Hz, 1H), 7.24 (t, J = 8.0 Hz, 1H), 6.68–6.61 (m, 1H), 6.49 (t, J = 2.1 Hz, 1H), 6.47–6.42 (m, 1H), 3.93 (s, 4H), 3.66 (s, 4H), 3.63 (s, 3H), 3.23 (q, J = 9.8 Hz, 2H); LCMS (m/z) 488.1.

Example 305. 8-(but-1-yn-1-yl)-N-methyl-N-phenyl-[1,2,4]triazolo[4,3-a]quinazolin- 5-amine

A vigorously stirred mixture of 8-bromo-N-methyl-N-phenyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine (Example 28, 10.0 mg, 28.2 μmol), but-1-yne (36.7 mg, 678 μmol), triethylamine (100 μL, 717 μmol), cuprous iodide (I) (5.4 mg, 28 μmol), 2-dicyclohexylphosphine-2',4',6'-triisopropyldiphenyl (9.1 mg, 19 μmol), tris(diphenylmethyleneacetone)palladium (0) (5.2 mg, 5.7 μmol), and 1-methylpyrrolidone-2-one (0.5 mL) was heated to 75 °C. Four hours later, the resulting mixture was cooled to room temperature and purified by reversed-phase preparative HPLC (acetonitrile/water containing 0.1% trifluoroacetic acid) to give the title compound: ^¹H NMR (400 MHz, acetone- _d6 ) δ 8.30 (s, 1H), 7.51–7.27 (m, 7H), 7.19 (d, J = 8.5 Hz, 1H), 2.49 (q, J = 7.5 Hz, 2H), 1.22 (t, J = 7.5 Hz, 3H); LCMS (m/z) 328.3.

Example 306. (E)-N-methyl-N-phenyl-8-(prop-1-en-1-yl)-[1,2,4]triazolo[4,3-a]quinazole 5-Lin-amine

A vigorously stirred mixture of 8-bromo-N-methyl-N-phenyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine (Example 28, 10.0 mg, 28.2 μmol), potassium trans-1-propenyltrifluoroborate (16.7 mg, 113 μmol), (2-dicyclohexylphosphine-2',4',6'-triisopropyl-1,1'-diphenyl)[2-(2'-amino-1,1'-diphenyl)]palladium(II) chloride (4.4 mg, 5.7 μmol), and 1,4-dioxane (0.5 mL) was heated to 100 °C. After 10 minutes, the resulting mixture was cooled to room temperature and concentrated under reduced pressure. The residue was subjected to reversed-phase preparative HPLC (acetonitrile/water containing 0.1% trifluoroacetic acid) to obtain the title compound: ^¹H NMR (400 MHz, acetone- _d6 ) δ 9.58 (s, 1H), 8.36 (d, J = 1.7 Hz, 1H), 7.56–7.48 (m, 2H), 7.48–7.38 (m, 3H), 7.32 (dd, J = 8.8, 1.6 Hz, 1H), 7.21 (d, J = 8.8 Hz, 1H), 6.73 (dq, J = 15.6, 6.6 Hz, 1H), 6.57 (dd, J = 15.9, 1.9 Hz, 1H), 3.72 (s, 3H), 1.94 (dd, J = 6.6, 1.6 Hz, 3H); LCMS (m/z) 316.3.

Example 307. 8-Ethynyl-N-methyl-N-phenyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine

Example 307 was synthesized in a manner similar to that of Example 306, except that potassium ethynyltrifluoroborate was used instead of potassium trans-1-propenyltrifluoroborate. ^¹H NMR (400 MHz, acetone- _d⁶ ) δ 9.51 (s, ¹H), 8.42 (s, ¹H), 7.51–7.24 (m, 8H), 4.07 (s, ¹H), 3.65 (s, 3H); LCMS (m/z) 300.3.

Example 308. N-(3-bromophenyl)-8-chloro-N-methyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine

Step 1: Sodium hydride (60% wt dispersion in mineral oil, 382 mg, 9.97 mmol) was added to a vigorously stirred mixture of 2,4,7-trichloroquinazoline (compound 308-1, 1.94 g, 8.31 mmol) and 3-bromo-N-methylaniline (1.11 mL, 8.72 mmol) in N,N-dimethylformamide (30 mL) at 0 °C. After 60 minutes, sodium hydride (60% wt dispersion in mineral oil, 260 mg, 6.79 mmol) was added. After 2 hours, the resulting mixture was poured into a mixture of saturated ammonium chloride aqueous solution (50 mL), brine (5100 mL), and ice (75 g), and the resulting suspension was vigorously vortexed until all the ice melted. The resulting suspension was filtered, and the filter cake was washed successively with ice-cold water (2 × 25 mL) and hexane (25 mL) to give compound 308-2.

Step 2: At room temperature, hydrazine monohydrate (3.22 mL, 66.5 mmol) was added via syringe to a vigorously stirred solution of 308-2 (3.18 g, 8.31 mmol) in ethanol (60 mL) and tetrahydrofuran (40 mL). After 35 minutes, hydrazine monohydrate (6.00 mL, 123 mmol) was added via syringe. After 19 hours, water (100 mL), brine (100 mL), ethyl acetate (150 mL), and tetrahydrofuran (75 mL) were added sequentially. The two-phase mixture was stirred, and the layers were separated. The aqueous layer was extracted with a mixture of ethyl acetate (200 mL) and tetrahydrofuran (100 mL). The combined organic layers were washed with a mixture of water (235 mL) and brine (115 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give compound 308-3.

Step 3: The vigorously stirred mixture of compound 308-3 (3.15 g, 8.31 mmol) and triethyl orthoformate (60 mL) was heated to 120 °C. After 212 minutes, the resulting mixture was heated to 150 °C. After 90 minutes, the resulting mixture was cooled to room temperature and concentrated under reduced pressure until the volume of the resulting suspension was approximately 10 mL. Hexane (70 mL) was added and the resulting coarse material was ground. The resulting suspension was cooled to 0 °C. After 20 minutes, the resulting suspension was filtered, and the filter cake was washed sequentially with a mixture of hexane and diethyl ether (4:1 v:v, 60 mL) and hexane (75 mL), and dried under reduced pressure to give the title compound: ^¹H NMR (400 MHz, DMSO- _d₆ ) δ 9.67 (s, 1H), 8.58 (d, J = 2.1 Hz, 1H), 7.63 (q, J = 1.5 Hz, 1H), 7.48–7.37 (m, 2H), 7.35–7.26 (m, 3H), 3.54 (s, 3H); LCMS (m/z) 388.1.

Example 309. (E)-7-fluoro-N-(3-fluorophenyl)-N-methyl-8-(prop-1-en-1-yl)-[1,2,4]triazolidine [4,3-a]quinazolin-5-amine

Example 309 was synthesized in a manner similar to that of Example 306, except that 8-bromo-7-fluoro-N-(3-fluorophenyl)-N-methyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine (Example 215) was used instead of 8-bromo-N-methyl-N-phenyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine (Example 28) and potassium ethynyltrifluoroborate was used instead of potassium trans-1-propenyltrifluoroborate. ¹ H NMR (400MHz, acetone-d ₆ )δ9.58(s,1H),8.58(d,J＝6.6Hz,1H),7.55(td,J＝8.2,6.5Hz,1H),7.34–7.25(m,2H),7.18(tdd,J＝8.4,2.5,0.9Hz,1H),6.98( d, J＝12.1Hz, 1H), 6.86 (dq, J＝15.9, 6.7Hz, 1H), 6.70–6.56 (m, 1H), 3.70 (s, 3H), 1.99 (dd, J＝6.7, 1.7Hz, 3H); LCMS (m/z) 352.3.

Example 310. (Z)-N-methyl-N-phenyl-8-(prop-1-en-1-yl)-[1,2,4]triazolo[4,3-a]quinazole 5-Lin-amine

Example 310 was synthesized in a manner similar to that of Example 306, except that cis-1-propen-1-ylboronic acid was used instead of potassium trans-1-propenyltrifluoroborate. ¹ H NMR (400MHz, acetone-d ₆ )δ9.56(s,1H),8.24(d,J＝1.5Hz,1H),7.55–7.46(m,2H),7.46–7.36(m,3H),7.30(d,J＝8.7Hz,1H),7.24(dd,J＝8.8,1.6Hz, 1H), 6.56 (dd, J＝11.7, 2.0Hz, 1H), 6.09 (dq, J＝11.7, 7.3Hz, 1H), 3.71 (s, 3H), 1.96 (dd, J＝7.3, 1.9Hz, 3H); LCMS (m/z) 316.3.

Example 311. (E)-8-(but-2-en-2-yl)-N-methyl-N-phenyl-[1,2,4]triazolo[4,3-a]quinazole 5-Lin-amine

Example 311 was synthesized in a manner similar to that of Example 306, except that potassium (2Z)-2-buten-2-yltrifluoroborate was used instead of potassium trans-1-propenyltrifluoroborate. ^¹H NMR (400 MHz, acetone- _d⁶ ) δ 9.67 (s, 1H), 8.35 (d, J = 1.9 Hz, 1H), 7.59–7.49 (m, 2H), 7.48–7.41 (m, 3H), 7.38 (dd, J = 8.9, 1.9 Hz, 1H), 7.22 (d, J = 8.9 Hz, 1H), 6.29 (q, J = 6.9 Hz, 1H), 3.72 (s, 3H), 2.11 (t, J = 1.3 Hz, 3H), 1.86 (dq, J = 6.9, 1.1 Hz, 3H); LCMS (m/z) 330.3.

Example 312. 8-Chloro-N-(4'-isopropyl-[1,1'-diphenyl]-3-yl)-N-methyl-[1,2,4]triazolidine [4,3-a]quinazolin-5-amine

A vigorously stirred mixture of Example 308 (5.0 mg, 13 μmol), (4-isopropylphenyl)boric acid (8.4 mg, 52 μmol), [1,1'-bis(diphenylphosphine)ferrocene]palladium(II) dichloride (1.9 mg, 2.6 μmol), sodium carbonate aqueous solution (2.0 M, 97 μL, 190 μmol), and 1,4-dioxane (0.5 mL) was heated to 100 °C. After 5 minutes, the resulting mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by reversed-phase preparative HPLC (acetonitrile/water containing 0.1% trifluoroacetic acid) to give the title compound: ^¹H NMR (400 MHz, acetone- _d6 ) δ 9.44 (s, 1H), 8.39 (d, J = 2.1 Hz, 1H), 7.66 (t, J = 2.0 Hz, 1H), 7.61 (dt, J = 7.9, 1.4 Hz, 1H), 7.59–7.47 (m, 4H), 7.39–7.29 (m, 3H), 7.26 (dd, J = 9.0, 2.1 Hz, 1H), 3.70 (s, 3H), 3.08–2.75 (m, 1H), 1.26 (d, J = 6.9 Hz, 6H); LCMS (m/z) 428.3.

Example 313. 8-Chloro-N-(4'-cyclopropyl-[1,1'-diphenyl]-3-yl)-N-methyl-[1,2,4]triazolidine [4,3-a]quinazolin-5-amine

Example 313 was synthesized in a manner similar to that of Example 312, except that (4-cyclopropylphenyl)boronic acid was used instead of (4-isopropylphenyl)boronic acid. ^¹H NMR (400MHz, acetone- _d⁶ ) δ 9.49 (s, ¹H), 8.43 (d, J = 2.1 Hz, ¹H), 7.67 (t, J = 2.0 Hz, ¹H), 7.63 (ddd, J = 7.8, 1.8, 1.1 Hz, ¹H), 7.57–7.45 (m, 4H), 7.36 (ddd, J = 7.9, 2.2, 1.1 Hz, ¹H), 7.29 (dd, J = 9.0, 2.1 Hz, ¹H), 7.18–7.06 (m, 2H), 3.72 (s, 3H), 2.03–1.85 (m, 1H), 1.03–0.93 (m, 2H), 0.77–0.64 (m, 2H); LCMS (m/z) 426.3.

Example 314. 8-Chloro-N-(4'-(difluoromethyl)-[1,1'-diphenyl]-3-yl)-N-methyl-[1,2,4]tri Azo[4,3-a]quinazolin-5-amine

Example 314 was synthesized in a manner similar to that of Example 312, except that [4-(difluoromethyl)phenyl]boronic acid was used instead of (4-isopropylphenyl)boronic acid. ^¹H NMR (400 MHz, acetone- _d⁶ ) δ 9.47 (s, 1H), 8.42 (d, J = 2.1 Hz, 1H), 7.83–7.74 (m, 3H), 7.67 (dd, J = 13.3, 7.8 Hz, 3H), 7.58 (t, J = 7.9 Hz, 1H), 7.52 (d, J = 9.0 Hz, 1H), 7.43 (d, J = 8.0 Hz, 1H), 7.29 (dd, J = 9.0, 2.1 Hz, 1H), 6.95 (t, J = 56.1 Hz, 1H), 3.72 (s, 3H); LCMS (m/z) 436.3.

Example 315. 8-Chloro-N-methyl-N-(2',4',6'-trimethyl-[1,1'-diphenyl]-3-yl)-[1,2,4] Triazolo[4,3-a]quinazolin-5-amine

Example 315 was synthesized in a manner similar to that of Example 312, except that (2,4,6-trimethylphenyl)boronic acid was used instead of (4-isopropylphenyl)boronic acid. ^¹H NMR (400 MHz, acetone- _d⁶ ): δ 9.51 (s, 1H), 8.46 (d, J = 2.1 Hz, 1H), 7.64 (t, J = 7.8 Hz, 1H), 7.58–7.47 (m, 2H), 7.39 (dd, J = 9.0, 2.1 Hz, 1H), 7.16 (dt, J = 7.6, 1.3 Hz, 1H), 7.04 (t, J = 1.9 Hz, 1H), 6.88 (s, 2H), 3.73 (s, 3H), 2.25 (s, 3H), 1.89 (s, 6H); LCMS (m/z): 428.3.

Example 316. N-Methyl-8-(2-methylprop-1-en-1-yl)-N-phenyl-[1,2,4]triazolo[4,3-a]quinoline Azoline-5-amine

Example 316 was synthesized in a manner similar to that of Example 306, except that 4,4,5,5-tetramethyl-2-(2-methylprop-1-en-1-yl)-1,3,2-dioxaborane was used instead of potassium trans-1-propenyltrifluoroborate. ¹ H NMR (400MHz, acetone-d ₆ )δ9.56(s,1H),8.17(d,J＝1.6Hz,1H),7.56–7.47(m,2H),7.47–7.37(m,3H),7.26(d,J＝8.7Hz,1H),7.17(dd, J＝8.8,1.6Hz,1H),6.41(s,1H),3.71(s,3H),1.97(d,J＝1.5Hz,3H),1.96(d,J＝1.4Hz,3H); LCMS(m/z)330.3.

Example 317. N-(3-(6-(tert-butyl)pyridin-3-yl)phenyl)-8-chloro-N-methyl-[1,2,4]triazolidine [4,3-a]quinazolin-5-amine

Example 317 was synthesized in a manner similar to that of Example 337, except that 5-bromo-2-tert-butylpyridine was used instead of 2-bromo-5-cyclopropylpyrazine and (2-dicyclohexylphosphine-2',4',6'-triisopropyl-1,1'-diphenyl)[2-(2'-amino-1,1'-diphenyl)]palladium(II) chloride was used instead of [1,1'-bis(diphenylphosphine)ferrocene]palladium(II) chloride. ¹ H NMR (400MHz, acetone-d ₆ )δ9.47(s,1H),8.75(d,J＝2.6Hz,1H),8.42(d,J＝2.2Hz,1H),7.96(dd,J＝8.3,2.6Hz,1H),7.77–7.72(m,1H),7.68–7.63(m,1H),7. 59(t,J＝8.0Hz,1H),7.55–7.47(m,2H),7.47–7.41(m,1H),7.29(dd,J＝8.9,2.2Hz,1H),3.72(s,3H),1.37(s,9H); LCMS(m/z)443.3.

Example 318. N-(3-(5-(tert-butyl)pyridin-2-yl)phenyl)-8-chloro-N-methyl-[1,2,4]triazolidine [4,3-a]quinazolin-5-amine

Example 318 was synthesized in a manner similar to that of Example 337, except that 5-tert-butyl-2-chloro-pyridine was used instead of 2-bromo-5-cyclopropylpyrazine and (2-dicyclohexylphosphine-2',4',6'-triisopropyl-1,1'-diphenyl)[2-(2'-amino-1,1'-diphenyl)]palladium(II) chloride was used instead of [1,1'-bis(diphenylphosphine)ferrocene]palladium(II) dichloride. ¹ H NMR (400MHz, acetone-d ₆ )δ9.51(s,1H),8.75(s,1H),8.44(d,J＝2.3Hz,1H),8.15(t,J＝2.1Hz,1H),8.12(d,J＝8.1Hz,1H),7.94–7.83(m,2H),7.58(t,J＝ 7.8Hz, 1H), 7.50 (d, J = 9.1Hz, 1H), 7.47–7.33 (m, 1H), 7.30 (dd, J = 8.9, 2.2Hz, 1H), 3.74 (s, 3H), 1.39 (s, 9H); LCMS (m/z) 443.3.

Example 319. N-(3-(5-(tert-butyl)pyrimidin-2-yl)phenyl)-8-chloro-N-methyl-[1,2,4]triazolidine [4,3-a]quinazolin-5-amine

Example 319 was synthesized in a manner similar to that of Example 337, except that 2-bromo-5-tert-butylpyrimidine was used instead of 2-bromo-5-cyclopropylpyrazine and (2-dicyclohexylphosphine-2',4',6'-triisopropyl-1,1'-diphenyl)[2-(2'-amino-1,1'-diphenyl)]palladium(II) chloride was used instead of [1,1'-bis(diphenylphosphine)ferrocene]palladium(II) chloride. ^¹H NMR (400MHz, acetone- _d⁶ ) δ 9.46 (s, ¹H), 8.76 (d, J = 5.3 Hz, ¹H), 8.48–8.40 (m, ³H), 7.64–7.41 (m, ⁴H), 7.28 (dd, J = 9.0, 2.1 Hz, ¹H), 3.71 (s, ³H), 1.40 (s, ⁹H); LCMS (m/z) 444.3.

Example 320. N-(3-(2-(tert-butyl)pyrimidin-5-yl)phenyl)-8-chloro-N-methyl-[1,2,4]triazolidine [4,3-a]quinazolin-5-amine

Example 320 was synthesized in a manner similar to that of Example 337, except that 5-bromo-2-tert-butylpyrimidine was used instead of 2-bromo-5-cyclopropylpyrazine and (2-dicyclohexylphosphine-2',4',6'-triisopropyl-1,1'-diphenyl)[2-(2'-amino-1,1'-diphenyl)]palladium(II) chloride was used instead of [1,1'-bis(diphenylphosphine)ferrocene]palladium(II) dichloride. ^¹H NMR (400MHz, acetone- _d⁶ ) δ 9.54 (s, 1H), 8.94 (s, 2H), 8.47 (d, J = 2.2Hz, 1H), 7.84 (t, J = 2.0Hz, 1H), 7.79–7.72 (m, 1H), 7.66 (t, J = 7.8Hz, 1H), 7.58–7.46 (m, 2H), 7.32 (dd, J = 9.0, 2.1Hz, 1H), 3.76 (s, 3H), 1.40 (s, 9H); LCMS (m/z) 444.3.

Example 321. N-(3-(6-(tert-butyl)pyridazin-3-yl)phenyl)-8-chloro-N-methyl-[1,2,4]triazolidine [4,3-a]quinazolin-5-amine

Example 321 was synthesized in a manner similar to that of Example 337, except that 3-bromo-6-tert-butylpyridazine was used instead of 2-bromo-5-cyclopropylpyrazine and (2-dicyclohexylphosphine-2',4',6'-triisopropyl-1,1'-diphenyl)[2-(2'-amino-1,1'-diphenyl)]palladium(II) chloride was used instead of [1,1'-bis(diphenylphosphine)ferrocene]palladium(II) dichloride. ¹ H NMR (400MHz, acetone-d ₆ )δ9.53(s,1H),8.46(d,J＝2.1Hz,1H),8.23(t,J＝2.0Hz,1H),8.22–8.15(m,1H),8.08(d,J＝9.0Hz,1H),7.80(d,J＝9.0Hz ,1H),7.65(t,J＝7.9Hz,1H),7.58–7.51(m,2H),7.31(dd,J＝9.0,2.1Hz,1H),3.76(s,3H),1.47(s,9H); LCMS(m/z)444.3.

Example 322. N-(3-(5-(tert-butyl)pyrazin-2-yl)phenyl)-8-chloro-N-methyl-[1,2,4]triazolidine [4,3-a]quinazolin-5-amine

Example 322 was synthesized in a manner similar to that of Example 337, except that 2-tert-butyl-5-chloro-pyrazine was used instead of 2-bromo-5-cyclopropylpyrazine and (2-dicyclohexylphosphine-2',4',6'-triisopropyl-1,1'-diphenyl)[2-(2'-amino-1,1'-diphenyl)]palladium(II) chloride was used instead of [1,1'-bis(diphenylphosphine)ferrocene]palladium(II) chloride. ¹ H NMR (400MHz, acetone-d ₆ )δ9.50(s,1H),9.06(d,J＝1.6Hz,1H),8.75(d,J＝1.6Hz,1H),8.43(d,J＝2.1Hz,1H),8.15(t,J＝2.0Hz,1H),8.12(dt,J＝7.7,1 .3Hz,1H),7.62(t,J＝7.9Hz,1H),7.55–7.46(m,2H),7.29(dd,J＝9.0,2.1Hz,1H),3.73(s,3H),1.42(s,9H); LCMS(m/z)444.3.

Example 323. (E)-8-(but-1-en-1-yl)-N-methyl-N-phenyl-[1,2,4]triazolo[4,3-a]quinazole 5-Lin-amine

Example 323 was synthesized in a manner similar to that of Example 306, except that [(E)-but-1-enyl]boronic acid was used instead of potassium trans-1-propenyltrifluoroborate. ¹ H NMR (400MHz, acetone-d ₆ )δ9.56(s,1H),8.38(d,J＝1.7Hz,1H),7.58–7.47(m,2H),7.47–7.38(m,3H),7.34(dd,J＝8.8,1.7Hz,1H),7.22(d,J＝8.8Hz,1H),6.7 7(dt,J＝16.0,6.6Hz,1H),6.55(d,J＝15.9Hz,1H),3.71(s,3H),2.31(pd,J＝7.5,1.6Hz,2H),1.10(t,J＝7.4Hz,3H); LCMS (m/z) 330.3.

Example 324. 8-(but-1-yn-1-yl)-7-fluoro-N-(3-fluorophenyl)-N-methyl-[1,2,4]triazolo[4, [3-a]quinazolin-5-amine

Example 324 was synthesized in a manner similar to that of Example 305, except that 8-bromo-7-fluoro-N-(3-fluorophenyl)-N-methyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine was used instead of 8-bromo-N-methyl-N-phenyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine (Example 215). ^¹H NMR (400MHz, acetone- _d⁶ ) δ 9.61 (s, ¹H), 8.49 (d, J = 6.2 Hz, ¹H), 7.55 (td, J = 8.1, 6.5 Hz, ¹H), 7.37–7.26 (m, 2H), 7.22–7.17 (m, 1H), 7.05 (d, J = 10.7 Hz, 1H), 3.71 (s, 3H), 2.56 (q, J = 7.5 Hz, 2H), 1.25 (t, J = 7.5 Hz, 3H); LCMS (m/z) 364.3.

Example 325. 8-(cyclopent-1-en-1-yl)-N-methyl-N-phenyl-[1,2,4]triazolo[4,3-a]quinazole 5-Lin-amine

Example 325 was synthesized in a manner similar to that of Example 306, except that cyclopentyl-1-boronic acid was used instead of potassium trans-1-propenyltrifluoroborate. ^¹H NMR (400 MHz, acetone- _d⁶ ) δ 9.59 (s, 1H), 8.37–8.19 (m, 1H), 7.55–7.45 (m, 2H), 7.45–7.32 (m, 4H), 7.26 (d, J = 8.9 Hz, 1H), 6.75–6.60 (m, 1H), 3.68 (s, 3H), 2.86–2.71 (m, 2H), 2.65–2.48 (m, 2H), 2.15–1.98 (m, 2H); LCMS (m/z) 342.3.

Example 326. 8-(cyclohexyl-1-en-1-yl)-N-methyl-N-phenyl-[1,2,4]triazolo[4,3-a]quinazole 5-Lin-amine

Example 326 was synthesized in a manner similar to that of Example 306, except that cyclohexene-1-ylboronic acid was used instead of potassium trans-1-propenyltrifluoroborate. ¹ H NMR (400MHz, acetone-d ₆ )δ9.65(s,1H),8.32(d,J＝1.9Hz,1H),7.57–7.47(m,2H),7.47–7.40(m,3H),7.40–7.35(m,1H),7.24(d,J＝9.0Hz,1H),6.54(td , J＝4.1, 2.1Hz, 1H), 3.70 (s, 3H), 2.55–2.44 (m, 2H), 2.35–2.23 (m, 2H), 1.88–1.74 (m, 2H), 1.74–1.62 (m, 2H); LCMS (m/z) 356.3.

Example 327. N-Methyl-8-(methylsulfonyl)-N-phenyl-[1,2,4]triazolo[4,3-a]quinazolin-5- amine

A vigorously stirred mixture of 8-bromo-N-methyl-N-phenyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine (Example 28, 10.0 mg, 28.2 μmol), sodium methanesulfonate (28.8 mg, 282 μmol), cuprous iodide (I) (53.8 mg, 282 μmol), and 1-methylpyrrolidone-2-one (0.5 mL) was heated to 140 °C. After 60 minutes, the resulting mixture was cooled to room temperature and purified by reversed-phase preparative HPLC (acetonitrile/water containing 0.1% trifluoroacetic acid) to give the title compound: ^¹H NMR (400 MHz, acetone- _d6 ) δ 9.67 (s, 1H), 8.77 (d, J = 1.7 Hz, 1H), 7.73 (dd, J = 8.7, 1.8 Hz, 1H), 7.62 (d, J = 8.7 Hz, 1H), 7.53–7.43 (m, 2H), 7.43–7.39 (m, 2H), 7.39–7.31 (m, 1H), 3.67 (s, 3H), 3.25 (s, 3H); LCMS (m/z) 354.3.

Example 328. N-(3-bromophenyl)-8-(4-(tert-butyl)-1H-imidazol-1-yl)-N-methyl-[1,2,4]triazole [4,3-a]quinazolin-5-amine

The mixture of Example 308 (10.0 mg, 25.7 μmol), 4-(tert-butyl)-1H-imidazole (9.6 mg, 77 μmol), cuprous iodide (I) (2.5 mg, 13 μmol), potassium carbonate (17.9 mg, 129 μmol), L-proline (3.0 mg, 26 μmol), and dimethyl sulfoxide (0.7 mL) was vigorously stirred and heated to 90 °C. After 30 minutes, the resulting mixture was heated to 120 °C. After 13.5 hours, the resulting mixture was cooled to room temperature and purified by reversed-phase preparative HPLC (acetonitrile/water containing 0.1% trifluoroacetic acid) to give the title compound: ^¹H NMR (400 MHz, acetone- _d6 ) δ 9.49 (s, 1H), 8.74 (d, J = 2.3 Hz, 1H), 8.64 (d, J = 1.5 Hz, 1H), 7.76–7.65 (m, 3H), 7.58 (d, J = 9.1 Hz, 1H), 7.53 (dt, J = 6.8, 1.9 Hz, 1H), 7.48–7.38 (m, 2H), 3.69 (s, 3H), 1.36 (s, 9H); LCMS (m/z) 476.3.

Example 329. 8-Chloro-N-(4',4'-dimethyl-2',3',4',5'-tetrahydro-[1,1'-diphenyl]-3-yl)- N-Methyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine

Example 329 was synthesized in a manner similar to that of Example 312, except that (4,4-dimethylcyclohex-1-en-1-yl)boronic acid was used instead of (4-isopropylphenyl)boronic acid. ¹ H NMR (400MHz, acetone-d ₆ )δ9.53(s,1H),8.46(d,J＝2.1Hz,1H),7.52–7.36(m,4H),7.33(dd,J＝9.0,2.1Hz,1H),7.27(dt,J＝7.3,1.9Hz,1H),6.13(tt, J＝3.9, 1.7Hz, 1H), 3.70 (s, 3H), 2.45–2.33 (m, 2H), 2.01–1.95 (m, 2H), 1.51 (t, J＝6.4Hz, 2H), 0.95 (s, 6H); LCMS (m/z) 476.3.

Example 330. N-(4'-(tert-butyl)-2'-methyl-[1,1'-diphenyl]-3-yl)-8-chloro-N-methyl-[1, [2,4]triazolo[4,3-a]quinazolin-5-amine

Example 330 was synthesized in a manner similar to that of Example 337, except that 4-(tert-butyl)-2-methylphenyltrifluoromethanesulfonate was used instead of 2-bromo-5-cyclopropylpyrazine and (2-dicyclohexylphosphine-2',4',6'-triisopropyl-1,1'-diphenyl)[2-(2'-amino-1,1'-diphenyl)]palladium(II) chloride was used instead of [1,1'-bis(diphenylphosphine)ferrocene]palladium(II) dichloride. ^¹H NMR (400 MHz, acetone- _d6 ) δ 9.41 (s, 1H), 8.38 (s, 1H), 7.61–7.14 (m, 8H), 7.08 (d, J = 7.9 Hz, 1H), 3.67 (s, 3H), 2.81 (s, 3H), 1.31 (s, 9H); LCMS (m/z) 456.4.

Example 331. N-(4'-(tert-butyl)-2'-chloro-[1,1'-diphenyl]-3-yl)-8-chloro-N-methyl-[1,2, 4] Triazolo[4,3-a]quinazolin-5-amine

Example 331 was synthesized in a manner similar to that of Example 337, except that 4-(tert-butyl)-2-chlorophenyltrifluoromethanesulfonate was used instead of 2-bromo-5-cyclopropylpyrazine and (2-dicyclohexylphosphine-2',4',6'-triisopropyl-1,1'-diphenyl)[2-(2'-amino-1,1'-diphenyl)]palladium(II) chloride was used instead of [1,1'-bis(diphenylphosphine)ferrocene]palladium(II) dichloride. ^¹H NMR (400 MHz, acetone- _d6 ) δ 9.43 (s, 1H), 8.39 (d, J = 2.1 Hz, 1H), 7.65–7.40 (m, 6H), 7.40–7.25 (m, 3H), 3.68 (s, 3H), 1.34 (s, 9H); LCMS (m/z) 476.3.

Example 332. 8-Chloro-N-methyl-N-(3-(6-methylpyridin-3-yl)phenyl)-[1,2,4]triazolo[4,3- a] Quinazoline-5-amine

Example 332 was synthesized in a manner similar to that of Example 337, except that 5-bromo-2-methylpyridine was used instead of 2-bromo-5-cyclopropylpyrazine and (2-dicyclohexylphosphine-2',4',6'-triisopropyl-1,1'-diphenyl)[2-(2'-amino-1,1'-diphenyl)]palladium(II) chloride was used instead of [1,1'-bis(diphenylphosphine)ferrocene]palladium(II) chloride. ¹ H NMR (400MHz, acetone-d ₆ )δ9.44(s,1H),8.69(s,1H),8.39(d,J＝2.0Hz,1H),7.92–7.86(m,1H),7.72(s,1H),7.63(d,J＝7.9Hz,1H),7.57(d,J＝ 7.8Hz, 1H), 7.52 (d, J = 9.1Hz, 1H), 7.44–7.36 (m, 1H), 7.35–7.22 (m, 2H), 3.70 (s, 3H), 2.52 (s, 3H); LCMS (m/z) 401.2.

Example 333. 8-Chloro-N-methyl-N-(3-(5-methylpyridin-2-yl)phenyl)-[1,2,4]triazolo[4,3- a] Quinazoline-5-amine

Example 333 was synthesized in a manner similar to that of Example 337, except that 2-bromo-5-methylpyridine was used instead of 2-bromo-5-cyclopropylpyrazine and (2-dicyclohexylphosphine-2',4',6'-triisopropyl-1,1'-diphenyl)[2-(2'-amino-1,1'-diphenyl)]palladium(II) chloride was used instead of [1,1'-bis(diphenylphosphine)ferrocene]palladium(II) chloride. ¹ H NMR (400MHz, acetone-d ₆ )δ9.48(s,1H),8.51(d,J＝2.3Hz,1H),8.42(d,J＝2.1Hz,1H),8.13(d,J＝2.1Hz,1H),8.09(d,J＝8.0Hz,1H),7.84(d,J＝8.1Hz,1H),7.6 8(d,J＝8.0Hz,1H),7.57–7.47(m,2H),7.41(d,J＝7.8Hz,1H),7.28(dd,J＝9.1,2.1Hz,1H),3.72(s,3H),2.37(s,3H); LCMS(m/z)401.2.

Example 334. 8-Chloro-N-methyl-N-(3-(5-methylpyrazin-2-yl)phenyl)-[1,2,4]triazolo[4,3- a] Quinazoline-5-amine

Example 334 was synthesized in a manner similar to that of Example 337, except that 2-bromo-5-methylpyrazine was used instead of 2-bromo-5-cyclopropylpyrazine and (2-dicyclohexylphosphine-2',4',6'-triisopropyl-1,1'-diphenyl)[2-(2'-amino-1,1'-diphenyl)]palladium(II) chloride was used instead of [1,1'-bis(diphenylphosphine)ferrocene]palladium(II) chloride. ^¹H NMR (400MHz, acetone- _d⁶ ) δ 9.48 (s, ¹H), 9.02 (s, ¹H), 8.56 (s, ¹H), 8.42 (d, J = 2.0Hz, ¹H), 8.24–8.07 (m, 2H), 7.70–7.41 (m, 3H), 7.32–7.25 (m, ¹H), 3.72 (s, 3H), 2.56 (s, 3H); LCMS (m/z) 402.2.

Example 335. 8-Chloro-N-(3-(6-cyclopropylpyridin-3-yl)phenyl)-N-methyl-[1,2,4]triazolo[4, [3-a]quinazolin-5-amine

Example 335 was synthesized in a manner similar to that of Example 312, except that 2-cyclopropyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentane-2-yl)pyridine was used instead of (4-isopropylphenyl)boronic acid. ¹ H NMR (400MHz, acetone-d ₆ )δ9.59(s,1H),8.69(d,J＝2.5Hz,1H),8.50(d,J＝2.3Hz,1H),7.97(dd,J＝8.1,2.5Hz,1H),7.84–7.77(m,1H),7.77–7.70(m,1H),7.64(dd ,J＝9.0,6.6Hz,1H),7.56–7.44(m,2H),7.44–7.33(m,2H),3.79(d,J＝2.8Hz,3H),2.27–2.14(m,1H),1.08–0.99(m,4H); LCMS(m/z)427.3.

Example 336. 8-Chloro-N-(3-(5-cyclopropylpyridin-2-yl)phenyl)-N-methyl-[1,2,4]triazolo[4, [3-a]quinazolin-5-amine

Example 336 was synthesized in a manner similar to that of Example 337, except that 2-bromo-5-cyclopropylpyridine was used instead of 2-bromo-5-cyclopropylpyrazine and (2-dicyclohexylphosphine-2',4',6'-triisopropyl-1,1'-diphenyl)[2-(2'-amino-1,1'-diphenyl)]palladium(II) chloride was used instead of [1,1'-bis(diphenylphosphine)ferrocene]palladium(II) chloride. ¹ H NMR (400MHz, acetone-d ₆ )δ9.45(s,1H),8.49(d,J＝2.3Hz,1H),8.39(d,J＝2.3Hz,1H),8.14–8.02(m,2H),7.81(d,J＝8.3Hz,1H),7.59–7.41(m,3H),7.4 2–7.33(m,1H),7.25(d,J=8.9Hz,1H),3.69(s,3H),2.03–1.52(m,1H),1.12–1.00(m,2H),0.84–0.73(m,2H); LCMS(m/z)427.3.

Example 337. 8-Chloro-N-(3-(5-cyclopropylpyrazin-2-yl)phenyl)-N-methyl-[1,2,4]triazolo[4, [3-a]quinazolin-5-amine

Step 1: A vigorously stirred mixture of Example 308 (300 mg, 772 μmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bis(1,3,2-dioxaboranecyclopentane) (216 mg, 849 μmol), [1,1'-bis(diphenylphosphine)ferrocene]palladium(II) dichloride (28.2 mg, 38.6 μmol), potassium acetate (379 mg, 3.86 mmol), and 1,4-dioxacyclohexane (10 mL) was heated to 110 °C. After 20 minutes, the resulting mixture was cooled to room temperature. Silica gel (12 g) and ethyl acetate (75 mL) were added sequentially, and the resulting mixture was concentrated under reduced pressure. The residue was purified by rapid silica gel column chromatography (0 to 15% methanol in dichloromethane) to give compound 337-1.

Step 2: A vigorously stirred mixture of compound 313-1 (60.0 mg, 138 μmol), 2-bromo-5-cyclopropylpyrazine (41.1 mg, 207 μmol), [1,1'-bis(diphenylphosphine)ferrocene]palladium(II) dichloride (10.1 mg, 13.8 μmol), sodium carbonate aqueous solution (2.0 M, 689 μL, 1.38 mmol), and 1,4-dioxane ( ^{0.5 mL) was heated to 120 °C. After 35 minutes, the resulting mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by reversed-phase preparative HPLC (acetonitrile/water containing 0.1% trifluoroacetic acid) to give the title compound: ¹H} NMR (400 MHz, acetone- _d6) )δ9.48(s,1H),8.95(d,J＝1.5Hz,1H),8.62(d,J＝1.5Hz,1H),8.42(d,J＝2.1Hz,1H),8.12(t,J＝2.0Hz,1H),8.10–8.03(m,1H),7.59(t,J＝7.8Hz, 1H),7.51(d,J＝9.0Hz,1H),7.48–7.43(m,1H),7.28(dd,J＝9.0,2.1Hz,1 H),3.72(s,3H),2.29–2.20(m,1H),1.12–1.00(m,4H); LCMS(m/z)428.3.

Example 338. N-(3'-(tert-butyl)-[1,1'-diphenyl]-3-yl)-8-chloro-N-methyl-[1,2,4]triazole [4,3-a]quinazolin-5-amine

Example 338 was synthesized in a manner similar to that of Example 312, except that (3-tert-butylphenyl)boronic acid was used instead of (4-isopropylphenyl)boronic acid. ¹ H NMR (400MHz, acetone-d ₆ )δ9.50(s,1H),8.45(d,J＝2.1Hz,1H),7.71(t,J＝2.1Hz,1H),7.65(dt,J＝8.0,1.3Hz,1H),7.60(t,J＝1.9Hz,1H),7.56(t,J＝7 .9Hz,1H),7.50(d,J＝9.0Hz,1H),7.47–7.34(m,4H),7.32(dd,J＝9.0,2.1Hz,1H),3.74(s,3H),1.33(s,9H); LCMS(m/z)442.3.

Example 339. 8-Chloro-N-(3-(5-(4,5-dihydro-1H-imidazol-2-yl)-6-methoxypyridin-2-yl)benzene (N-methyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine)

Step 1: A stirred mixture of 6-chloro-3-(4,5-dihydro-1H-imidazol-2-yl)-2-methoxypyridine (500 mg, 2.36 mmol), hexamethyldistin (967 mg, 2.95 mmol), [1,1'-bis(diphenylphosphine)ferrocene]palladium(II) dichloride (86.4 mg, 118 μmol), and toluene (10 mL) was heated to 115 °C. After 17 hours, the resulting mixture was cooled to room temperature and purified by silica gel rapid column chromatography (0 to 100% ethyl acetate/hexane) to give compound 339-1.

Step 2: A vigorously stirred mixture of Example 308 (10.0 mg, 25.7 μmol), 339-1 (13.1 mg, 38.6 μmol), [1,1'-bis(diphenylphosphine)ferrocene]palladium(II) dichloride (3.8 mg, 5.2 μmol), cesium fluoride (39.1 mg, 257 μmol), and 1,4-dioxane (1.0 mL) was heated to 105 °C. After 7 minutes, the resulting mixture was heated to 120 °C. After 3 hours, the resulting mixture was cooled to 80 °C. After 13 hours, the resulting mixture was cooled to room temperature and filtered. The filter cake was extracted with dichloromethane, and the combined filtrates were concentrated under reduced pressure. The residue was purified by reversed-phase preparative HPLC (acetonitrile/water containing 0.1% trifluoroacetic acid) to give the title compound: ^¹H NMR (400 MHz, methanol- _d4) )δ9.61(s,1H),8.52(d,J＝2.0Hz,1H),8.40–8.27(m,1H),7.99(d,J＝11.4Hz,1H),7.82(d,J＝8.1Hz,1H),7.75(d,J＝7.9Hz,1H),7.70(d,J＝9. 7Hz,1H),7.60(ddd,J＝7.9,2.2,1.0Hz,1H),7.38–7.33(m,1H),7.33–7.28(m,1H),4.21(s,3H),4.11(s,4H),3.88(s,3H); LCMS(m/z)485.3.

Example 340. 8-Chloro-N-(3-(6-cyclopropylpyridazin-3-yl)phenyl)-N-methyl-[1,2,4]triazolo[4, [3-a]quinazolin-5-amine

Example 340 was synthesized in a manner similar to that of Example 337, except that 3-bromo-6-cyclopropylpyridazine was used instead of 2-bromo-5-cyclopropylpyrazine and (2-dicyclohexylphosphine-2',4',6'-triisopropyl-1,1'-diphenyl)[2-(2'-amino-1,1'-diphenyl)]palladium(II) chloride was used instead of [1,1'-bis(diphenylphosphine)ferrocene]palladium(II) chloride. ¹ H NMR (400MHz, acetone-d ₆ )δ9.48(s,1H),8.42(d,J＝2.2Hz,1H),8.12(d,J＝7.9Hz,1H),7.99(d,J＝8.9Hz,1H),7. 88–6.99(m,6H),3.72(s,3H),2.34–2.17(m,1H),1.33–0.94(m,4H); LCMS(m/z)428.3.

Example 341. 8-Chloro-N-(3-(5-cyclopropyl-1,3,4-oxadiazol-2-yl)phenyl)-N-methyl-[1,2,4] Triazolo[4,3-a]quinazolin-5-amine

Example 341 was synthesized in a manner similar to that of Example 337, except that 2-bromo-5-cyclopropyl-1,3,4-oxadiazole was used instead of 2-bromo-5-cyclopropylpyrazine and (2-dicyclohexylphosphine-2',4',6'-triisopropyl-1,1'-diphenyl)[2-(2'-amino-1,1'-diphenyl)]palladium(II) chloride was used instead of [1,1'-bis(diphenylphosphine)ferrocene]palladium(II) chloride. ¹ H NMR (400MHz, acetone-d ₆ )δ9.49(s,1H),8.43(d,J＝2.0Hz,1H),8.01(d,J＝2.5Hz,1H),7.91(d,J＝7.5Hz,1H),7.60(d,J＝7.8Hz,1H),7.56–7.52(m,1H ),7.51(d,J＝9.0Hz,1H),7.29(dd,J＝9.0,2.1Hz,1H),3.70(s,3H),2.50–2.19(m,1H),1.41–0.79(m,4H); LCMS(m/z)418.2.

Example 342. 8-Chloro-N-(3-(5-cyclopropyl-1,3,4-thiadiazol-2-yl)phenyl)-N-methyl-[1,2,4] Triazolo[4,3-a]quinazolin-5-amine

Example 342 was synthesized in a manner similar to that of Example 337, except that 2-bromo-5-cyclopropyl-1,3,4-thiadiazole was used instead of 2-bromo-5-cyclopropylpyrazine and (2-dicyclohexylphosphine 2',4',6'-triisopropyl-1,1'-diphenyl)[2-(2'-amino-1,1'-diphenyl)]palladium(II) chloride was used instead of [1,1'-bis(diphenylphosphine)ferrocene]palladium(II) dichloride. ¹ H NMR (400MHz, acetone-d ₆ )δ9.60(s,1H),8.52(d,J＝2.1Hz,1H),8.02(t,J＝2.0Hz,1H),7.92(dt,J＝7 .6,1.4Hz,1H),7.64(t,J＝7.8Hz,1H),7.58(ddd,J＝8.1,2.3,1.2Hz,1H),7 .51(d,J＝9.0Hz,1H),7.38(dd,J＝9.0,2.1Hz,1H),3.78(s,3H),2.54(tt,J =8.3,4.9Hz,1H),1.33–1.24(m,2H),1.16–1.07(m,2H); LCMS(m/z)434.2.

Example 343. 8-Chloro-N-methyl-N-(4'-(((methanesulfonyl)methyl)-[1,1'-diphenyl]-3-yl)- [1,2,4]triazolo[4,3-a]quinazolin-5-amine

Example 343 was synthesized in a manner similar to that of Example 337, except that 1-bromo-4-((methylsulfonyl)methyl)benzene was used instead of 2-bromo-5-cyclopropylpyrazine and (2-dicyclohexylphosphine-2',4',6'-triisopropyl-1,1'-diphenyl)[2-(2'-amino-1,1'-diphenyl)]palladium(II) chloride was used instead of [1,1'-bis(diphenylphosphine)ferrocene]palladium(II) chloride. ^¹H NMR (400MHz, acetone- _d⁶ ) δ 9.44 (s, ¹H), 8.39 (d, J = 2.2 Hz, ¹H), 7.77–7.42 (m, 8H), 7.42–7.35 (m, ¹H), 7.26 (dd, J = 8.9, 2.1 Hz, ¹H), 4.43 (s, 2H), 3.70 (s, 3H), 2.88 (s, 3H); LCMS (m/z) 478.2.

Example 344. 5-(3-((8-chloro-[1,2,4]triazolo[4,3-a]quinazolin-5-yl)(methyl)amino)benzene (Isoindoline-1,3-dione)

Example 344 was synthesized in a manner similar to that of Example 312, except that 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)isoindoline-1,3-dione was used instead of (4-isopropylphenyl)boronic acid. ¹ H NMR (400MHz, acetone-d ₆ )δ10.14(s,1H),9.52(s,1H),8.45(d,J＝2.2Hz,1H),8.17–8.10(m,1H),8.10–8.03(m,1H),7.95(t,J＝2.1Hz,1H),7.89(d,J ＝7.9Hz,1H),7.82(d,J＝7.7Hz,1H),7.71–7.59(m,1H),7.59–7.45(m,2H),7.42–7.25(m,1H),3.76(s,3H); LCMS(m/z)455.3.

Example 345. 2-(3'-((8-chloro-[1,2,4]triazolo[4,3-a]quinazolin-5-yl)(methyl)amino)- [1,1'-Diphenyl]-4-yl)prop-2-ol

Example 345 was synthesized in a manner similar to that of Example 312, except that (4-(2-hydroxypropyl-2-yl)phenyl)boronic acid was used instead of (4-isopropylphenyl)boronic acid. ^¹H NMR (400 MHz, methanol- _d⁴ ) δ 9.55 (s, 1H), 8.47 (dd, J = 1.8, 0.7 Hz, 1H), 7.77 (ddd, J = 7.9, 1.8, 1.0 Hz, 1H), 7.70 (t, J = 2.0 Hz, 1H), 7.62 (t, J = 7.9 Hz, 1H), 7.58 (s, 4H), 7.39 (ddd, J = 7.9, 2.3, 1.0 Hz, 1H), 7.37–7.30 (m, 2H), 3.83 (s, 3H), 1.56 (s, 6H); LCMS (m/z) 444.3.

Example 346. tert-butyl-4-(3-((8-chloro-[1,2,4]triazolo[4,3-a]quinazolin-5-yl)(methyl)amino 3,6-dihydropyridine-1(2H)-carboxylate

Example 346 was synthesized in a manner similar to that of Example 312, except that tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate was used instead of (4-isopropylphenyl)boronic acid. ^¹H NMR (400MHz, acetone- _d⁶ ) δ 9.54 (s, ¹H), 8.47 (s, ¹H), 7.56–7.43 (m, ³H), 7.43–7.36 (m, ¹H), 7.36–7.26 (m, ²H), 6.19 (s, ¹H), 4.08–3.93 (m, ²H), 3.70 (s, ³H), 3.63–3.54 (m, ²H), 2.58–2.37 (m, ²H), 1.46 (d, J = 3.1Hz, ⁹H); LCMS (m/z) 491.2.

Example 347. 8-Chloro-N-(2-Chloro-4'-cyclopropyl-[1,1'-diphenyl]-3-yl)-N-methyl-[1,2,4] Triazolo[4,3-a]quinazolin-5-amine

Example 347 was synthesized in a manner similar to Example 312, except that compound 349-3 was used instead of Example 308 and (4-cyclopropylphenyl)boronic acid was used instead of (4-isopropylphenyl)boronic acid. ^¹H NMR (400 MHz, acetone- _d⁶ ) δ 9.55 (s, 1H), 8.51 (d, J = 2.1 Hz, 1H), 7.60–7.48 (m, 3H), 7.48–7.36 (m, 3H), 7.30 (d, J = 9.0 Hz, 1H), 7.22 (d, J = 8.3 Hz, 2H), 3.65 (s, 3H), 2.30–1.80 (m, 1H), 1.18–0.58 (m, 4H); LCMS (m/z) 460.3.

Example 348. 8-Chloro-N-(4-chloro-4'-cyclopropyl-[1,1'-diphenyl]-3-yl)-N-methyl-[1,2,4] Triazolo[4,3-a]quinazolin-5-amine

Example 348 was synthesized in a manner similar to that of Example 312, except that compound 349-2 was used instead of Example 308 and (4-cyclopropylphenyl)boronic acid was used instead of (4-isopropylphenyl)boronic acid. ¹ H NMR (400MHz, acetone-d ₆ )δ9.66(s,1H),8.58(d,J＝2.1Hz,1H),7.89(d,J＝2.1Hz,1H),7.84(dd,J＝8.4,2.2Hz,1H),7.78(d,J＝8.4Hz,1H),7.73–7.50(m,2H),7.46(dd,J＝9 .1,2.0Hz,1H),7.36(d,J＝9.0Hz,1H),7.19–7.11(m,2H),3.73(s,3H),2. 28–1.79(m,1H),1.09–0.95(m,2H),0.80–0.61(m,2H); LCMS(m/z)460.3.

Example 349. 8-Chloro-N-(6-Chloro-4'-cyclopropyl-[1,1'-diphenyl]-3-yl)-N-methyl-[1,2,4] Triazolo[4,3-a]quinazolin-5-amine

Step 1: 2-Chloro-1,3-bis(methoxycarbonyl)guanidine (10.8 mg, 51.5 μmol) was added to a stirred solution of Example 308 (20.0 mg, 51.5 μmol) in acetonitrile (0.8 mL) and chloroform (0.5 mL) at 0 °C. After 5 minutes, the resulting mixture was heated to room temperature. After 25 minutes, hydrogen chloride solution (4.0 M in 1,4-dioxane, 12.9 μL, 52 μmol) was added via syringe. After 95 minutes, the resulting mixture was concentrated under reduced pressure. The residue was purified by reversed-phase preparative HPLC (acetonitrile/water containing 0.1% trifluoroacetic acid) to give compounds 349-1, 349-2, and 349-3.

Step 2: Example 349 was synthesized in a manner similar to Example 312, except that compound 349-1 was used instead of Example 308 and (4-cyclopropylphenyl)boronic acid was used instead of (4-isopropylphenyl)boronic acid. ^¹H NMR (400 MHz, acetone- _d⁶ ) δ 9.50 (s, 1H), 8.45 (d, J = 2.1 Hz, 1H), 7.59 (dd, J = 8.7, 1.5 Hz, 2H), 7.46–7.35 (m, 3H), 7.31–7.23 (m, 2H), 7.18–7.10 (m, 2H), 3.71 (s, 3H), 2.05–1.87 (m, 1H), 1.08–0.94 (m, 2H), 0.76–0.60 (m, 2H); LCMS (m/z) 460.3.

Example 350. 8-Chloro-N-methyl-N-(3-(1,2,3,6-tetrahydropyridin-4-yl)phenyl)-[1,2,4]triazole [4,3-a]quinazolin-5-amine

Trifluoroacetic acid (1.0 mL) was added via syringe to a stirred solution of Example 346 (61.5 mg, 125 μmol) in dichloromethane (2.0 mL) at room temperature. After 20 minutes, the resulting mixture was concentrated under reduced pressure. The residue was purified by reversed-phase preparative HPLC (acetonitrile/water containing 0.1% trifluoroacetic acid) to give the title compound: ^¹H NMR (400 MHz, methanol- _d4) )δ9.57(s,1H),8.49(d,J＝2.0Hz,1H),7.66–7.56(m,2H),7.54(d,J＝2.2Hz,1H),7.43(dt,J＝7.1,2.0Hz,1H),7.32(dd,J＝9.1,2.1Hz,1H),7.23 (d, J＝9.1Hz, 1H), 6.23 (dt, J＝3.9, 2.1Hz, 1H), 3.85 (q, J＝2.8Hz, 2H), 3.79 (s, 3H), 3.47 (t, J＝6.1Hz, 2H), 2.82–2.73 (m, 2H); LCMS (m/z) 391.2.

Example 351. 8-Chloro-N-methyl-N-(3-(1-(methanesulfonyl)-1,2,3,6-tetrahydropyridin-4-yl)benzene (-[1,2,4]triazolo[4,3-a]quinazolin-5-amine)

At room temperature, methanesulfonyl chloride (5.0 μL, 64 μmol) was added via syringe to a stirred mixture of Example 350 (5.0 mg, 13 μmol) and triethylamine (35.7 μL, 256 μmol) in dichloromethane (0.5 mL). After 20 minutes, the resulting mixture was concentrated under reduced pressure. The residue was purified by reversed-phase preparative HPLC (acetonitrile/water containing 0.1% trifluoroacetic acid) to give the title compound: ^¹H NMR (400 MHz, acetone- _d6 ) δ 9.53 (s, 1H), 8.46 (d, J = 2.1 Hz, 1H), 7.57–7.54 (m, 1H), 7.54–7.45 (m, 2H), 7.41 (d, J = 9.0 Hz, 1H), 7.38–7.28 (m, 2H), 6.29–6.20 (m, 1H), 3.91 (q, J = 2.9 Hz, 2H), 3.70 (s, 3H), 3.46 (t, J = 5.7 Hz, 2H), 2.87 (s, 3H), 2.70–2.56 (m, 2H); LCMS (m/z) 469.3.

Example 352. 8-Chloro-N-(3-(1-isopropyl-1,2,3,6-tetrahydropyridin-4-yl)phenyl)-N-methyl-[1, [2,4]triazolo[4,3-a]quinazolin-5-amine

Sodium triacetoxyborohydride (54.0 mg, 256 μmol) was added to a stirred mixture of Example 350 (5.0 mg, 13 μmol), acetone (18.9 μL, 256 μmol), triethylamine (17.8 μL, 128 μmol), and acetic acid (7.3 μL, 128 μmol) in dichloromethane (0.5 mL), and the resulting mixture was heated to 45 °C. After 150 min, the resulting mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by reversed-phase preparative HPLC (acetonitrile/water containing 0.1% trifluoroacetic acid) to give the title compound: ^¹H NMR (400 MHz, methanol- _d4) )δ9.58(s,1H),8.50(d,J＝2.1Hz,1H),7.68–7.57(m,2H),7.54(s,1H),7.46 (d,J＝7.3Hz,1H),7.31(dd,J＝9.1,2.1Hz,1H),7.22(d,J＝9.1Hz,1H),6.28– 6.20(m,1H),3.98–3.89(m,2H),3.80(s,3H),3.77–3.70(m,2H),3.66(hept ,J＝6.9Hz,1H),2.95–2.78(m,2H),1.43(d,J＝6.6Hz,6H); LCMS(m/z)433.2.

Example 353. 8-Chloro-N-methyl-N-(3-(6-(trifluoromethyl)pyridin-3-yl)phenyl)-[1,2,4]triazole [4,3-a]quinazolin-5-amine

Example 353 was synthesized in a manner similar to that of Example 312, except that 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)-2-(trifluoromethyl)pyridine was used instead of (4-isopropylphenyl)boronic acid. ¹ H NMR (400MHz, acetone-d ₆ )δ9.50(s,1H),9.00(d,J＝2.3Hz,1H),8.44(d,J＝2.2Hz,1H),8.32(dd,J＝8.2,2.3Hz,1H),7.95–7.85(m,2H),7.85– 7.73(m,1H),7.66(t,J＝7.9Hz,1H),7.58–7.45(m,2H),7.30(dd,J＝9.0,2.1Hz,1H),3.74(s,3H); LCMS(m/z)455.3.

Example 354. 8-Chloro-N-(3-(6-(difluoromethyl)pyridin-3-yl)phenyl)-N-methyl-[1,2,4]triazole [4,3-a]quinazolin-5-amine

Example 354 was synthesized in a manner similar to that of Example 312, except that 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborhexacyclopentan-2-yl)-2-(difluoromethyl)pyridine was used instead of (4-isopropylphenyl)boronic acid. ^¹H NMR (400 MHz, acetone- _d6 ) δ 9.63 (s, 1H), 8.92 (d, J = 2.2 Hz, 1H), 8.54 (d, J = 2.1 Hz, 1H), 8.26 (dd, J = 8.1, 2.3 Hz, 1H), 7.94 (t, J = 2.0 Hz, 1H), 7.85 (dt, J = 8.0, 1.3 Hz, 1H), 7.78 (d, J = 8.1 Hz, 1H). 7.71(t,J＝7.9Hz,1H),7.59(ddd,J＝8.0,2.2,1.0Hz,1H),7.50(d,J＝9.1Hz,1H),7 .39 (dd, J=9.1, 2.1Hz, 1H), 6.84 (t, J=55.3Hz, 1H), 3.82 (s, 3H); LCMS (m/z) 437.3.

Example 355. 3'-((8-chloro-[1,2,4]triazolo[4,3-a]quinazolin-5-yl)(methyl)amino)-4- (trifluoromethyl)-[1,1'-diphenyl]-2-carboxamide

Example 355 was synthesized in a manner similar to that of Example 312, except that 2-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)-5-(trifluoromethyl)benzyl nitrile was used instead of (4-isopropylphenyl)boronic acid. ^¹H NMR (400 MHz, acetonitrile- _d³ ) δ 9.11 (d, J = 3.7 Hz, 1H), 8.23 (s, 1H), 7.95–7.80 (m, 2H), 7.70–7.41 (m, 4H), 7.43–7.18 (m, 3H), 6.58 (s, 1H), 6.13 (s, 1H), 3.76 (s, 3H); LCMS (m/z) 497.3.

Example 356. 1-(4-(3-((8-chloro-[1,2,4]triazolo[4,3-a]quinazolin-5-yl)(methyl)amino) phenyl)-3,6-dihydropyridine-1(2H)-yl)ethyl-1-one

Acetic anhydride (9.6 μL, 100 μmol) was added via syringe to a stirred mixture of Example 350 (4.0 mg, 10 μmol) and N,N-diisopropylethylamine (28.5 μL, 164 μmol) in dichloromethane (0.5 mL). After 10 minutes, the resulting mixture was concentrated under reduced pressure. The residue was purified by reversed-phase preparative HPLC (acetonitrile/water containing 0.1% trifluoroacetic acid) to give the title compound: ^¹H NMR (400 MHz, acetone- _d6 ) δ 9.57 (s, 1H), 8.49 (d, J = 2.0 Hz, 1H), 7.61–7.43 (m, 3H), 7.43–7.28 (m, 3H), 6.28–6.14 (m, 1H), 4.21–4.08 (m, 2H), 3.72 (s, 3H), 3.72–3.64 (m, 2H), 2.65–2.52 (m, 1H), 2.52–2.38 (m, 1H), 2.16–1.94 (m, 3H); LCMS (m/z) 433.3.

Example 357. 1-(4-(3-((8-chloro-[1,2,4]triazolo[4,3-a]quinazolin-5-yl)(methyl)amino) phenyl)-3,6-dihydropyridine-1(2H)-yl)-2,2-dimethylprop-1-one

At room temperature, pentovalin anhydride (12.6 μL, 62.1 μmol) was added via syringe to a stirred mixture of Example 350 (4.0 mg, 10 μmol) and N,N-diisopropylethylamine (28.5 μL, 164 μmol) in dichloromethane (0.5 mL). After 20 minutes, the resulting mixture was concentrated under reduced pressure. The residue was purified by reversed-phase preparative HPLC (acetonitrile/water containing 0.1% trifluoroacetic acid) to give the title compound: ^¹H NMR (400 MHz, acetone- _d⁶ ) δ 9.54 (s, 1H), 8.47 (d, J = 2.1 Hz, 1H), 7.57–7.44 (m, 3H), 7.41 (d, J = 9.0 Hz, 1H), 7.38–7.29 (m, 2H), 6.25 (tt, J = 3.5, 1.6 Hz, 1H), 4.21 (q, J = 3.0 Hz, 2H), 3.82 (t, J = 5.7 Hz, 2H), 3.71 (s, 3H), 2.54 (dt, J = 7.9, 3.9 Hz, 2H), 1.26 (s, 9H); LCMS (m/z) 475.3.

Example 358. 8-Chloro-N-methyl-N-(3-(1-((1-methylcyclopropyl)sulfonyl)-1,2,3,6-tetrahydropyridine (Pyridine-4-yl)phenyl)-[1,2,4]triazolo[4,3-a]quinazolin-5-amine

1-Methylcyclopropane-1-sulfonyl chloride (16.0 mg, 104 μmol) was added to a stirred mixture of Example 350 (4.0 mg, 10 μmol) and N,N-diisopropylethylamine (28.5 μL, 164 μmol) in dichloromethane (0.5 mL) at room temperature. After 23 minutes, the resulting mixture was heated to 60 °C. After 30 minutes, the resulting mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by reversed-phase preparative HPLC (acetonitrile/water containing 0.1% trifluoroacetic acid) to give the title compound: ^1H NMR (400 MHz, acetone- _d6) )δ9.50(s,1H),8.44(d,J＝2.0Hz,1H),7.57–7.49(m,1H),7.49–7.44(m ,2H),7.42(d,J＝9.0Hz,1H),7.39–7.25(m,2H),6.28–6.16(m,1H),4.04 (q,J＝3.0Hz,2H),3.68(s,3H),3.59(t,J＝5.7Hz,2H),2.66–2.50(m,2H),1.45(s,3H),1.31–1.21(m,2H),0.91–0.75(m,2H); LCMS(m/z)509.3.

Example 359. 8-Chloro-N-methyl-N-(3-(1-((trifluoromethyl)sulfonyl)-1,2,3,6-tetrahydropyridine-4- (1,2,4)triazolo[4,3-a]quinazolin-5-amine

Trifluoromethanesulfonic anhydride (2.6 μL, 15 μmol) was added via syringe to a stirred mixture of Example 350 (4.0 mg, 10 μmol) and N,N-diisopropylethylamine (28.5 μL, 164 μmol) in dichloromethane (0.5 mL) at -78 °C. After 10 minutes, water (0.1 mL) was added, and the resulting mixture was heated to room temperature and concentrated under reduced pressure. The residue was purified by reversed-phase preparative HPLC (acetonitrile/water containing 0.1% trifluoroacetic acid) to give the title compound: ^¹H NMR (400 MHz, acetone- _d6 ) δ 9.46 (s, 1H), 8.41 (d, J = 2.1 Hz, 1H), 7.53 (t, J = 1.6 Hz, 1H), 7.50–7.39 (m, 3H), 7.39–7.30 (m, 1H), 7.27 (dd, J = 9.0, 2.1 Hz, 1H), 6.32–6.16 (m, 1H), 4.28–4.13 (m, 2H), 3.91–3.69 (m, 2H), 3.65 (s, 3H), 2.79–2.61 (m, 2H); LCMS (m/z) 523.2.

Example 360. N-Methyl-8-(methanesulfonyl)-N-phenyl-[1,2,4]triazolo[4,3-a]quinazolin-5- amine

A vigorously stirred mixture of Example 308 (5.0 mg, 13 μmol), (2-cyano-4-(trifluoromethyl)phenyl)boronic acid (4.2 mg, 19 μmol), cesium fluoride (19.5 mg, 129 μmol), [1,1'-bis(diphenylphosphine)ferrocene]palladium(II) dichloride (1.0 mg, 1.4 μmol), and 1,4-dioxane was heated to 100 °C. After 14 minutes, the resulting mixture was heated to 120 °C. After 50 minutes, the resulting mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by reversed-phase preparative HPLC (acetonitrile/water containing 0.1% trifluoroacetic acid) to give the title compound: ^¹H NMR (400 MHz, acetonitrile- _d³ ) δ 9.13 (s, 1H), 8.36–8.17 (m, 2H), 8.17–7.99 (m, 1H), 7.84–7.60 (m, 4H), 7.52 (s, 1H), 7.33 (s, 2H), 3.79 (s, 3H); LCMS (m/z) 479.3.

Example 361. 8-Chloro-N-methyl-N-(4'-(trifluoromethyl)-[1,1'-diphenyl]-3-yl)-[1,2,4]tri Azo[4,3-a]quinazolin-5-amine

Example 361 was synthesized in a manner similar to that of Example 312, except that [4-(trifluoromethyl)phenyl]boronic acid was used instead of (4-isopropylphenyl)boronic acid. ^¹H NMR (400 MHz, acetone- _d⁶ ) δ 9.46 (s, 1H), 8.41 (d, J = 2.3 Hz, 1H), 7.88 (d, J = 8.0 Hz, 2H), 7.84–7.73 (m, 3H), 7.70 (d, J = 7.5 Hz, 1H), 7.59 (t, J = 7.9 Hz, 1H), 7.53 (d, J = 8.9 Hz, 1H), 7.50–7.41 (m, 1H), 7.28 (dd, J = 9.0, 2.2 Hz, 1H), 3.71 (s, 3H); LCMS (m/z) 454.3.

Example 362. 3'-((8-chloro-[1,2,4]triazolo[4,3-a]quinazolin-5-yl)(methyl)amino)-4-cyclo Propyl-[1,1'-diphenyl]-2-carboxynitrile

Example 362 was synthesized in a manner similar to that of Example 312, except that 5-cyclopropyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborhexacyclopentan-2-yl)benzylnitrile was used instead of (4-isopropylphenyl)boronic acid. ¹ H NMR (400MHz, acetonitrile-d ₃ )δ9.11(s,1H),8.19(d,J＝2.1Hz,1H),7.70–7.50(m,4H),7.49–7.43(m,2H),7.40(dt,J＝7.2,2.1Hz,1H),7.35(d,J＝9.1Hz,1H) ,7.27(dd,J＝9.1,2.1Hz,1H),3.73(s,3H),2.07–1.92(m,1H),1.25–0.94(m,2H),0.80(dt,J＝6.8,4.6Hz,2H); LCMS(m/z)451.3.

Example 363. (E)-8-chloro-N-(3-(3,3-dimethylbut-1-en-1-yl)phenyl)-N-methyl-[1,2,4] Triazolo[4,3-a]quinazolin-5-amine

Example 363 was synthesized in a manner similar to that of Example 312, except that [(E)-3,3-dimethylbut-1-enyl]boronic acid was used instead of (4-isopropylphenyl)boronic acid. ^¹H NMR (400 MHz, acetone- _d⁶ ) δ 9.43 (s, 1H), 8.39 (d, J = 2.1 Hz, 1H), 7.50–7.43 (m, 2H), 7.44–7.32 (m, 2H), 7.28 (dd, J = 9.0, 2.1 Hz, 1H), 7.16 (dt, J = 7.4, 1.8 Hz, 1H), 6.42 (d, J = 16.3 Hz, 1H), 6.35 (d, J = 16.3 Hz, 1H), 3.62 (s, 3H), 1.10 (s, 9H); LCMS (m/z) 392.3.

Example 364. 1,8-Dichloro-N-(4'-cyclopropyl-[1,1'-diphenyl]-3-yl)-N-methyl-[1,2,4]tri Azo[4,3-a]quinazolin-5-amine

Step 1: A vigorously stirred mixture of compound 308-3 (1.00 g, 2.64 mmol), carbon disulfide (1.36 mL, 22.7 mmol), and pyridine (13.6 mL, 169 mmol) was heated to 110 °C. After 17 hours, the resulting mixture was poured into a mixture of ice (75 g), water (25 mL), and a saturated aqueous solution of ammonium chloride (40 mL), and the resulting suspension was vortexed until all the ice melted. The resulting suspension was filtered, and the filter cake was washed successively with water (50 mL) and hexane (30 mL), and dried under reduced pressure to give compound 364-1.

Step 2: The stirred mixture of compound 364-1 (98.0 mg, 233 μmol) and phosphorus trichloride (2.3 mL) was heated to 110 °C. After 19 minutes, the resulting mixture was heated to 120 °C. After 17 hours, the resulting mixture was concentrated under reduced pressure. The residue was purified by reversed-phase preparative HPLC (acetonitrile/water containing 0.1% trifluoroacetic acid) to give compound 364-2.

Step 3: A vigorously stirred mixture of compound 364-2 (21.2 mg, 50.1 μmol), (4-cyclopropylphenyl)boronic acid (16.2 mg, 100 μmol), [1,1'-bis(diphenylphosphine)ferrocene]palladium(II) dichloride (3.7 mg, 5.0 μmol), sodium carbonate aqueous solution (2.0 M, 250 μL, 500 μmol), and 1,4-dioxane (0.5 mL) was heated to 90 °C. After 25 minutes, the resulting mixture was cooled to room temperature. Acetic acid (0.4 mL) was added via syringe, and the resulting mixture was concentrated under reduced pressure. The residue was purified by reversed-phase preparative HPLC (acetonitrile/water containing 0.1% trifluoroacetic acid) to give the title compound: ^¹H NMR (400 MHz, acetone- _d⁶ ) δ 8.78 (d, J = 2.1 Hz, 1H), 7.68–7.61 (m, 2H), 7.59 (dt, J = 7.8, 1.3 Hz, 1H), 7.54–7.47 (m, 3H), 7.37–7.31 (m, 2H), 7.18–7.12 (m, 2H), 3.69 (s, 3H), 2.03–1.91 (m, 1H), 1.05–0.93 (m, 2H), 0.78–0.68 (m, 2H); LCMS (m/z) 460.3.

Example 365. 8-Chloro-N-methyl-N-(4'-(1,1,1-trifluoro-2-methylpropyl-2-yl)-[1,1'-diphenyl] [1,2,4]triazolo[4,3-a]quinazolin-5-amine

Example 365 was synthesized in a manner similar to that of Example 312, except that 4,4,5,5-tetramethyl-2-(4-(1,1,1-trifluoro-2-methylpropyl-2-yl)phenyl)-1,3,2-dioxaboranecyclopentane was used instead of (4-isopropylphenyl)boronic acid. ^¹H NMR (400MHz, acetone- _d⁶ ) δ 9.44 (s, ¹H), 8.39 (d, J = 2.1 Hz, ¹H), 7.70 (t, J = 2.0 Hz, ¹H), 7.68–7.48 (m, 5H), 7.38 (ddd, J = 7.9, 2.3, 1.1 Hz, 2H), 7.26 (dd, J = 8.9, 2.1 Hz, 1H), 6.88–6.80 (m, ¹H), 3.69 (s, 3H), 1.62 (s, 6H); LCMS (m/z) 496.3.

Example 366. 8-Chloro-N-(4'-cyclopropyl-[1,1'-diphenyl]-3-yl)-1-methoxy-N-methyl-[1, [2,4]triazolo[4,3-a]quinazolin-5-amine

Step 1: At room temperature, an aqueous solution of sodium hydroxide (2.0 M, 360 μL, 720 μmol) was added via syringe to a stirred solution of compound 364-1 (316 mg, 631 μmol) in ethanol (9.0 mL) and tetrahydrofuran (3.0 mL). After 5 minutes, the resulting mixture was cooled to 0 °C, and iodomethane (78.8 μL, 1.26 mmol) was added via syringe. After 90 minutes, citric acid (200 mg), water (60 mL), ethyl acetate (120 mL), and brine (40 mL) were added sequentially. The resulting two-phase mixture was stirred, and the layers were separated. The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel rapid column chromatography (0 to 100% ethyl acetate in hexane) to give compound 366-1.

Step 2: 3-Chlorobenzoperoxy acid (77 wt%, 6.0 mg, 27 μmol) was added to a stirred solution of compound 366-1 (5.0 mg, 12 μmol) in methanol (1.0 mL) at room temperature. After 25 minutes, 3-chlorobenzoperoxy acid (77 wt%, 8.0 mg, 36 μmol) was added. After 29 minutes, the resulting mixture was heated to 60 °C. After 30 minutes, the resulting mixture was heated to 70 °C. After 80 minutes, the resulting mixture was cooled to room temperature, and triethylamine (16.0 μL, 115 μmol) was added via syringe. After 2 minutes, sodium methoxide solution (25 wt% in methanol, 78.9 μL, 350 μmol) was added via syringe. After 35 minutes, saturated ammonium chloride aqueous solution (1.0 mL) and ethyl acetate (50 mL) were added sequentially. The organic layer was washed sequentially with water (25 mL) and a mixture of water and brine (1:1 v:v, 25 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was dissolved in 1,4-dioxane (0.5 mL), and the mixture was stirred at room temperature. (4-Cyclopropylphenyl)boronic acid (2.8 mg, 17 μmol), [1,1'-bis(diphenylphosphine)ferrocene]palladium(II) dichloride (0.8 mg, 1 μmol), and an aqueous solution of sodium carbonate (2.0 M, 58 μL, 120 μmol) were added sequentially, and the mixture was heated to 100 °C. After 5 minutes, the mixture was cooled to room temperature. Acetic acid (0.1 mL) was added via syringe, and the mixture was concentrated under reduced pressure. The residue was purified by reversed-phase preparative HPLC (acetonitrile/water containing 0.1% trifluoroacetic acid) to give the title compound: ^¹H NMR (400 MHz, acetone- _d6 ) δ 8.33 (d, J = 2.2 Hz, 1H), 7.65–7.42 (m, 6H), 7.31–7.25 (m, 1H), 7.21 (dd, J = 8.9, 2.2 Hz, 1H), 7.19–7.10 (m, 2H), 4.37 (s, 3H), 3.63 (s, 3H), 2.03–1.89 (m, 1H), 1.07–0.89 (m, 2H), 0.74–0.66 (m, 2H); LCMS (m/z) 456.3.

Example 367. 1-Chloro-N5-(4'-cyclopropyl-[1,1'-diphenyl]-3-yl)-N5-methyl-[1,2,4]triazole [4,3-a]quinazolin-5,8-diamine

A stirred mixture of compound 364-2 (20.0 mg, 47.3 μmol), sodium azide (38.3 mg, 589 μmol), and dimethyl sulfoxide (0.7 mL) was heated to 80 °C. After 44 minutes, the resulting mixture was heated to 95 °C. After 30 minutes, the resulting mixture was cooled to room temperature, and acetic acid (33.8 μL, 591 μmol), trimethylphosphine solution (1.0 M in tetrahydrofuran, 615 μL, 620 μmol), and water (0.5 mL) were added sequentially. After 75 minutes, ethyl acetate (30 mL) and saturated sodium bicarbonate aqueous solution (5 mL) were added sequentially. The organic layer was washed sequentially with water (50 mL) and a mixture of water and brine (6:1 v:v, 50 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was dissolved in 1,4-dioxane (1.3 mL), and the resulting mixture was stirred at room temperature. (4-Cyclopropylphenyl)boric acid (15.3 mg, 94.5 μmol), [1,1'-bis(diphenylphosphine)ferrocene]palladium(II) dichloride (2.1 mg, 2.8 μmol), and sodium carbonate aqueous solution (2.0 M, 180 μL, 360 μmol) were added sequentially, and the resulting mixture was heated to 100 °C. After 35 minutes, the mixture was cooled to room temperature. Acetic acid (0.1 mL) was added via syringe, and the mixture was concentrated under reduced pressure. The residue was purified by reversed-phase preparative HPLC (acetonitrile/water containing 0.1% trifluoroacetic acid) to give the title compound: ^¹H NMR (400 MHz, methanol- _d⁴ ) δ 7.92 (d, J = 2.2 Hz, 1H), 7.67 (d, J = 8.1 Hz, 1H), 7.60–7.53 (m, 2H), 7.53–7.25 (m, 3H), 7.15 (d, J = 8.3 Hz, 2H), 7.11 (d, J = 9.4 Hz, 1H), 6.50 (dd, J = 9.3, 2.2 Hz, 1H), 3.76 (s, 3H), 2.00–1.89 (m, 1H), 1.04–0.96 (m, 3H), 0.72 (dt, J = 6.6, 4.5 Hz, 3H); LCMS (m/z) 441.3.

Example 368. 4-(3-((8-chloro-[1,2,4]triazolo[4,3-a]quinazolin-5-yl)(methyl)amino)benzene 1,1,1-trifluoro-2-methylbut-3-yn-2-ol

Step 1: The stirred mixture of Example 308 (38.6 mg, 99.3 μmol), trimethyl((tributyltin)ethynyl)silane (55.5 μL, 149 μmol), and [1,1'-bis(diphenylphosphine)ferrocene]palladium(II) dichloride (7.3 mg, 9.9 μmol) in 1-methylpyrrolidone-2-one (2.0 mL) was heated to 110 °C. After 20 minutes, the resulting mixture was cooled to room temperature, and methanol (2.0 mL) and potassium carbonate (207 mg, 1.49 mmol) were added sequentially. After 20 minutes, the mixture was purified by reversed-phase preparative HPLC (acetonitrile/water containing 0.1% trifluoroacetic acid) to give compound 368-1.

Step 2: At -20°C, a solution of bis(trimethylsilyl)aminolithium (1.0 M in tetrahydrofuran, 150 μL, 150 μmol) was added via syringe to a stirred solution of compound 368-1 (5.0 mg, 15 μmol) in tetrahydrofuran (1.0 mL). After 10 minutes, 1,1,1-trifluoroacetone (26.8 μL, 300 μmol) was added via syringe. After another 10 minutes, trifluoroacetic acid (0.1 mL) was added via syringe, and the resulting mixture was heated to room temperature and concentrated under reduced pressure. The residue was purified by reversed-phase preparative HPLC (acetonitrile/water containing 0.1% trifluoroacetic acid) to give the title compound: ^¹H NMR (400 MHz, acetone- _d6 ) δ 9.46 (s, 1H), 8.42 (d, J = 2.1 Hz, 1H), 7.53–7.43 (m, 3H), 7.43–7.37 (m, 2H), 7.33 (dd, J = 9.0, 2.1 Hz, 1H), 5.96 (br-s, 1H), 3.63 (s, 3H), 1.68 (d, J = 1.0 Hz, 3H); LCMS (m/z) 446.3.

Example 369. 1-((3-((8-chloro-[1,2,4]triazolo[4,3-a]quinazolin-5-yl)(methyl)amino)benzene (Hydroxy)cyclobut-1-ol

Example 369 was synthesized in a manner similar to that of Example 368, except that cyclobutanone was used instead of 1,1,1-trifluoroacetone. ^¹H NMR (400 MHz, acetone- _d⁶ ) δ 9.45 (d, J = 1.8 Hz, 1H), 8.41 (d, J = 2.1 Hz, 1H), 7.52–7.37 (m, 3H), 7.36–7.30 (m, 3H), 3.62 (s, 2H), 2.50–1.69 (m, 8H); LCMS (m/z) 446.3.

Example 370. 1-(3'-((8-chloro-[1,2,4]triazolo[4,3-a]quinazolin-5-yl)(methyl)amino)- [1,1'-Diphenyl]-4-yl)-2,2,2-trifluoroethane-1-ol

Example 370 was synthesized in a manner similar to that of Example 312, except that 2,2,2-trifluoro-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)phenyl)ethyl-1-ol was used instead of (4-isopropylphenyl)boronic acid. ^¹H NMR (400MHz, acetone- _d⁶ ) δ 9.44 (s, 1H), 8.39 (d, J = 2.0 Hz, 1H), 7.75–7.59 (m, 6H), 7.58–7.50 (m, 2H), 7.38 (ddd, J = 7.9, 2.2, 1.1 Hz, 1H), 7.26 (dd, J = 9.0, 2.1 Hz, 1H), 5.92 (br-s, 1H), 5.27 (q, J = 7.2 Hz, 1H), 3.70 (s, 3H); LCMS (m/z) 484.3.

Example 371. 8-Chloro-N-(3-(3-methoxy-3-methylbut-1-yn-1-yl)phenyl)-N-methyl-[1,2, 4] Triazolo[4,3-a]quinazolin-5-amine

Example 371 was synthesized in a manner similar to that of Example 376, except that Example 308 was used instead of compound 364-2 and 3-methoxy-3-methylbut-1-yne was used instead of 2-methylbut-3-yne-2-ol. ^¹H NMR (400 MHz, acetone- _d6 ) δ 9.45 (s, 1H), 8.41 (d, J = 2.1 Hz, 1H), 7.51–7.44 (m, 2H), 7.44–7.29 (m, 4H), 3.62 (s, 3H), 3.34 (s, 3H), 1.47 (s, 6H); LCMS (m/z) 406.2.

Example 372. 4-(3-((8-chloro-[1,2,4]triazolo[4,3-a]quinazolin-5-yl)(methyl)amino)benzene 1,1-Difluoro-2-methylbut-3-yn-2-ol

Example 372 was synthesized in a manner similar to that of Example 376, except that Example 308 was used instead of compound 364-2 and 1,1-difluoro-2-methylbut-3-yn-2-ol was used instead of 2-methylbut-3-yn-2-ol. ^¹H NMR (400 MHz, acetone- _d⁶ ) δ 9.46 (s, 1H), 8.41 (d, J = 2.1 Hz, 1H), 7.50–7.30 (m, 6H), 5.84 (t, J = 56.3 Hz, 1H), 3.62 (s, 3H), 1.54 (t, J = 1.6 Hz, 3H); LCMS (m/z) 428.3.

Example 373. (R)-4-(3-((8-chloro-[1,2,4]triazolo[4,3-a]quinazolin-5-yl)(methyl)amino) (Phenyl)-1-fluoro-2-methylbut-3-yne-2-ol

Step 1: A non-homogeneous mixture of (S)-(2-methylethyleneoxy-2-yl)methyl 4-nitrobenzene ester (4.00 g, 16.9 mmol) and triethylamine trihydrofluoride (6.87 mL, 42.2 mmol) was heated to 80 °C. After the mixture became homogeneous, it was heated to 120 °C. After 90 minutes, the resulting mixture was cooled to room temperature and water was added. The aqueous layer was extracted twice with ethyl acetate. An aqueous solution of sodium bicarbonate (1.0 M) was added to the combined organic layers, and the mixture was stirred vigorously. After 15 minutes, the resulting mixture was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel rapid column chromatography (0 to 20% ethyl acetate in hexane) to give compound 373-1.

Step 2: Triethylsilyl trifluoromethanesulfonate (3.82 mL, 16.9 mmol) was added via syringe to a stirred mixture of compound 373-1 (2.90 g, 11.3 mmol) and 2,6-dimethylpyridine (3.94 mL, 33.8 mmol) in dichloromethane (30 mL) at -78 °C, and the resulting mixture was heated to 0 °C. After 60 minutes, the mixture was heated to room temperature, and the organic layer was washed with an aqueous sodium bicarbonate solution (1.0 M, 50 mL). The aqueous layer was extracted with dichloromethane (20 mL), and the combined organic layers were washed with an aqueous acetic acid solution (20% v, 50 mL) and the aqueous layer was extracted with dichloromethane (10 mL). The combined organic layers were washed with water (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel rapid column chromatography (10% ethyl acetate in hexane) to give compound 373-2.

Step 3: At -78°C, a solution of diisobutylaluminum hydride (1.0 M in hexane, 23.6 mL, 24 mmol) was added dropwise via syringe to a stirred solution of compound 373-2 (3.48 g, 9.37 mmol) in dichloromethane (30 mL) and hexane (10 mL). After 60 minutes, a saturated aqueous solution of sodium potassium tartrate (50 mL) was slowly added, and the resulting mixture was heated to 0°C. After 45 minutes, the resulting suspension was added and filtered. The filter cake was extracted with dichloromethane, and the aqueous layer of the combined filtrate was extracted with dichloromethane. The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel rapid column chromatography (0 to 10% ethyl acetate in hexane) to give compound 373-3.

Step 4: 1,1,1-tris(acetoxy)-1,1-dihydro-1,2-benzyl-3-(1H)-one (1.76 g, 4.16 mmol) was added to a stirred solution of compound 373-3 (840 mg, 3.78 mmol) in dichloromethane (15 mL) at room temperature. After 90 minutes, the resulting mixture was concentrated under reduced pressure, and the residue was ground with hexane (10 mL). The resulting suspension was filtered, and the filter cake was extracted with hexane. The combined filtrates were washed successively with water (10 mL) and an aqueous solution of sodium bicarbonate (1.0 M). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give compound 373-4.

Step 5: A solution of carbon tetrabromide (3.76 g, 11.3 mmol) in toluene (6 mL) was added to a stirred mixture of compound 373-4 (832 mg, 3.78 mmol) and triphenylphosphine (5.94 g, 22.7 mmol) in toluene (30 mL) at room temperature. After 90 minutes, the resulting heterogeneous mixture was filtered, and the filter cake was extracted with hexane. The combined filtrates were concentrated under reduced pressure. The residue was dissolved in hexane, and the resulting mixture was filtered through a silica stopper. The filter cake was extracted with hexane (100 mL), and the combined filtrates were concentrated under reduced pressure. The residue was purified by silica gel rapid column chromatography (hexane) to give compound 373-5.

Step 6: At 0°C, ethyl magnesium bromide solution (3.0 M in diethyl ether, 3.80 mL, 11 mmol) was added dropwise via syringe to a stirred solution of compound 373-5 (1.10 g, 2.92 mmol) in 12 mL of 2-methyltetrahydrofuran. After 2 hours, ammonium chloride aqueous solution (4.0 M, 20 mL) and 2-methyltetrahydrofuran (10 mL) were added sequentially. The resulting two-phase mixture was stirred, and the layers were separated. The aqueous layer was extracted with 2-methyltetrahydrofuran, and the combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel rapid column chromatography (pentane) to give compound 373-6.

Step 7: The vigorously stirred mixture of Example 308 (5.0 mg, 13 μmol), compound 373-6 (8.4 mg, 39 μmol), zinc bromide (II) (14.5 mg, 64.3 μmol), triethylamine (35.9 μL, 257 μmol), and [1,1'-bis(diphenylphosphine)ferrocene]palladium(II) dichloride (2.8 mg, 3.9 μmol) in 1-methylpyrrolidone-2-one (0.9 mL) was heated to 110 °C. After 5 minutes, the resulting mixture was cooled to room temperature, and triethylamine trihydrofluoride (69.2 μL, 425 μmol) was added via syringe. After 20 minutes, boric acid (40.0 mg, 647 μmol) was added. Five minutes later, the resulting mixture was purified by reversed-phase preparative HPLC (acetonitrile/water containing 0.1% trifluoroacetic acid) to give the title compound: ^¹H NMR (400 MHz, acetone- _d6 ) δ 9.45 (s, 1H), 8.41 (d, J = 2.1 Hz, 1H), 7.50–7.39 (m, 3H), 7.34 (tdd, J = 8.9, 4.3, 1.8 Hz, 3H), 4.36 (d, J = 47.6 Hz, 1H), 3.62 (s, 3H), 1.52 (d, J = 2.1 Hz, 3H); LCMS (m/z) 410.3.

Example 374. (S)-4-(3-((8-chloro-[1,2,4]triazolo[4,3-a]quinazolin-5-yl)(methyl)amino) (Phenyl)-1-fluoro-2-methylbut-3-yne-2-ol

Example 374 was synthesized in a manner similar to that of Example 373, except that (R)-(2-methylethyleneoxy-2-yl)methyl 4-nitrobenzene was used instead of (S)-(2-methylethyleneoxy-2-yl)methyl 4-nitrobenzene. ^¹H NMR (400 MHz, acetone- _d⁶ ) δ 9.45 (s, 1H), 8.41 (d, J = 2.0 Hz, 1H), 7.51–7.39 (m, 3H), 7.39–7.29 (m, 3H), 4.36 (d, J = 47.6 Hz, 2H), 3.62 (s, 3H), 1.52 (d, J = 2.1 Hz, 3H); LCMS (m/z) 410.3.

Example 375. 3-((3-((8-chloro-[1,2,4]triazolo[4,3-a]quinazolin-5-yl)(methyl)amino)benzene (Hydroxy)tetrahydrofuran-3-ol

The mixture of 5.0 mg (13 μmol) of Example 308, 3-((trimethylsilyl)ethynyl)tetrahydrofuran-3-ol (10 mg, 54.3 μmol), zinc bromide (II) (14.5 mg, 64.3 μmol), triethylamine (35.9 μL, 257 μmol), cesium fluoride (19.7 mg, 130 μmol), and [1,1'-bis(diphenylphosphine)ferrocene]palladium(II) dichloride (II) (2.8 mg, 3.9 μmol) in 1-methylpyrrolidone-2-one (0.9 mL) was heated to 110 °C. After 5 minutes, the resulting mixture was cooled to room temperature and purified by reversed-phase preparative HPLC (acetonitrile/water containing 0.1% trifluoroacetic acid) to give the title compound: ^¹H NMR (400 MHz, acetone- _d6 ) δ 9.47 (s, 1H), 8.42 (d, J = 2.0 Hz, 1H), 7.49–7.30 (m, 6H), 4.10–3.64 (m, 4H), 3.63 (s, 3H), 2.36–2.16 (m, 2H); LCMS (m/z) 420.3.

Example 376. 4-(3-((1,8-dichloro-[1,2,4]triazolo[4,3-a]quinazolin-5-yl)(methyl)amino (2-methylbut-3-yn-2-ol)

A vigorously stirred mixture of compound 364-2 (10.0 mg, 23.6 μmol), 2-methylbut-3-yn-2-ol (6.9 μL, 71 μmol), zinc bromide (II) (26.6 mg, 118 μmol), triethylamine (65.9 μL, 473 μmol), [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (II) (5.2 mg, 7.1 μmol), and 1-methylpyrrolidone-2-one (0.9 mL) was heated to 110 °C. After 5 minutes, the resulting mixture was cooled to room temperature and purified by reversed-phase preparative HPLC (acetonitrile/water containing 0.1% trifluoroacetic acid) to give the title compound: ^¹H NMR (400 MHz, acetone- _d6 ) δ 8.80 (d, J = 2.1 Hz, 1H), 7.57 (d, J = 8.9 Hz, 1H), 7.46–7.36 (m, 3H), 7.36–7.28 (m, 2H), 3.62 (s, 3H), 1.51 (s, 6H); LCMS (m/z) 426.2.

Example 377. 1,8-Dichloro-N-(3-(5-cyclopropylpyrazin-2-yl)phenyl)-N-methyl-[1,2,4]triazole [4,3-a]quinazolin-5-amine

A vigorously stirred mixture of compound 364-2 (14.0 mg, 33.1 μmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bis(1,3,2-dioxaborane) (10.1 mg, 39.7 μmol), [1,1'-bis(diphenylphosphine)ferrocene]palladium(II) dichloride (3.6 mg, 5.0 μmol), potassium acetate (32.5 mg, 331 mmol), and 1,4-dioxacyclohexane (1.0 mL) was heated to 115 °C. After 10 minutes, the resulting mixture was cooled to room temperature, and 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bis(1,3,2-dioxaborhecyclopentane) (4.2 mg, 17 μmol) and [1,1'-bis(diphenylphosphine)ferrocene]palladium(II) dichloride (1.8 mg, 2.5 μmol) were added sequentially. The resulting mixture was heated to 125 °C. After 47 minutes, the resulting mixture was cooled to room temperature, and 2-bromo-5-cyclopropylpyrazine (32.9 mg, 165 μmol), [1,1'-bis(diphenylphosphine)ferrocene]palladium(II) dichloride (2.4 mg, 3.3 μmol), and an aqueous solution of sodium carbonate (2.0 M, 165 μL, 330 μmol) were added sequentially. The resulting mixture was heated to 110 °C. After 40 minutes, the resulting mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by reversed-phase preparative HPLC (acetonitrile/water containing 0.1% trifluoroacetic acid) to give the title compound: ^¹H NMR (400 MHz, acetone- _d6) )δ8.91(d,J＝1.5Hz,1H),8.79(d,J＝2.0Hz,1H),8.62(d,J＝1.5Hz,1H),8.09(t,J＝2.0Hz,1H),8.07(s,1H),7.63(d,J＝9.0Hz,1H),7.57(t,J＝7. 9Hz, 1H), 7.45 (ddd, J＝8.0, 2.3, 1.0Hz, 1H), 7.35 (dd, J＝9.0, 2.1Hz, 1H), 3.71 (s, 3H), 2.35–1.88 (m, 1H), 1.18–0.99 (m, 4H); LCMS (m/z) 462.3.

Example 378. 1-((3-((8-chloro-[1,2,4]triazolo[4,3-a]quinazolin-5-yl)(methyl)amino)benzene (Hydroxy)-3,3-difluorocyclobut-1-ol

A solution of bis(trimethylsilyl)aminolithium (1.0 M in tetrahydrofuran, 193 μL, 190 μmol) was added via syringe to a stirred solution of 1-ethynyl-3,3-difluorocyclobut-1-ol (8.5 mg, 64 μmol) in tetrahydrofuran (0.5 mL). After 10 minutes, tributyltin chloride (41.9 μL, 154 μmol) was added via syringe. After 1 minute, the resulting mixture was heated to room temperature. After 25 minutes, diethyl ether (30 mL) and saturated ammonium chloride aqueous solution (5 mL) were added sequentially, and the organic layer was washed with water (20 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was dissolved in 1-methylpyrrolidone-2-one (0.9 mL), and the resulting mixture was stirred at room temperature. Example 308 (5.0 mg, 13 μmol) and [1,1'-bis(diphenylphosphine)ferrocene]palladium(II) dichloride (2.8 mg, 3.9 μmol) were added sequentially, and the resulting mixture was heated to 120 °C. After 25 minutes, the mixture was cooled to room temperature and purified by reversed-phase preparative HPLC (acetonitrile/water containing 0.1% trifluoroacetic acid) to give the title compound: ^¹H NMR (400 MHz, acetone- _d6 ) δ 9.46 (s, 1H), 8.42 (s, 1H), 7.52–7.29 (m, 6H), 3.62 (s, 3H), 3.17–3.03 (m, 2H), 3.02–2.69 (m, 2H); LCMS (m/z) 440.1.

Example 379. 8-Chloro-N-(7-cyclopropyldibenzo[b,d]furan-4-yl)-N-methyl-[1,2,4]triazolo [4,3-a]quinazolin-5-amine

Step 1: A vigorously stirred mixture of 4-cyclopropyl-2-fluoro-1-iodobenzene (250 mg, 954 μmol), (3-chloro-2-hydroxyphenyl)boronic acid (164 mg, 954 μmol), tetrakis(triphenylphosphine)palladium (0) (33.1 mg, 28.6 μmol), sodium carbonate aqueous solution (2.0 M, 1.43 mL, 2.9 mmol), and tetrahydrofuran (2.4 mL) was heated to 75 °C. After 16 hours, the resulting mixture was cooled to room temperature, and ethyl acetate (60 mL) and citric acid aqueous solution (10 wt%, 5 mL) were added sequentially. The organic layer was washed with a mixture of water and brine (2:1 v:v, 50 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel rapid column chromatography (0 to 20% ethyl acetate in hexane) to give compound 379-1.

Step 2: The mixture of compound 379-1 (240 mg, 914 μL) and potassium carbonate (158 mg, 1.13 mmol) in N,N-dimethylformamide (5.0 mL) was heated to 100 °C with vigorous stirring. After 69 minutes, the resulting mixture was heated to 140 °C. After 125 minutes, the resulting mixture was cooled to room temperature, and ethyl acetate (20 mL), diethyl ether (100 mL), and a saturated aqueous solution of ammonium chloride (5 mL) were added sequentially. The organic layer was washed with water (2 × 100 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel rapid column chromatography (0 to 5% ethyl acetate in hexane) to give compound 379-2.

Step 3: A vigorously stirred mixture of compound 379-2 (100 mg, 412 μmol), methylamine solution (2.0 M in tetrahydrofuran, 412 μL, 820 μmol), sodium tert-butoxide solution (2.0 M in tetrahydrofuran, 278 μL, 560 μmol), and [(2-di-cyclohexylphosphine-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-diphenyl)-2-(2'-(methylamino)-1,1'-diphenyl)]palladium(II) methanesulfonate (19.0 mg, 20.6 μmol) in tert-butanol (1.0 mL) was heated to 65 °C. After 15 minutes, the resulting mixture was cooled to room temperature, and saturated ammonium chloride aqueous solution (5 mL) and ethyl acetate (60 mL) were added sequentially. The organic layer was washed with a mixture of water and brine (1:1 v:v, 50 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel rapid column chromatography (0 to 20% ethyl acetate in hexane) to give compound 379-3.

Step 4: At 0 °C, a solution of sodium bis(trimethylsilyl)amino (1.0 M in tetrahydrofuran, 62.1 μL, 120 μmol) was added via syringe to a stirred solution of compound 379-3 (27.0 mg, 113 μmol) in N,N-dimethylformamide (0.3 mL). After 5 seconds, a solution of intermediate 5 (13.4 mg, 56.5 μmol) in N,N-dimethylformamide (0.7 mL) and tetrahydrofuran (0.3 mL) was added via syringe. After 1 minute, the resulting mixture was heated to room temperature. After 15 minutes, acetic acid (0.1 mL) was added, and the resulting mixture was concentrated under reduced pressure. The residue was purified by reversed-phase preparative HPLC (acetonitrile/water containing 0.1% trifluoroacetic acid) to give the title compound: ^¹H NMR (400 MHz, acetone- _d6) )δ9.56(s,1H),8.46(d,J＝2.1Hz,1H),8.09–8.05(m,1H),8.03(d,J＝8.1Hz,1H),7.45–7.36(m,3H),7.32(d,J＝1.4Hz,1H),7.24(dd,J＝ 8.1, 1.5Hz, 1H), 7.20 (dd, J = 9.0, 2.1Hz, 1H), 3.80 (s, 3H), 2.18–1.95 (m, 1H), 1.13–1.01 (m, 2H), 0.89–0.76 (m, 2H); LCMS (m/z) 440.2.

Example 380. N-Methyl-8-(methanesulfonyl)-N-phenyl-[1,2,4]triazolo[4,3-a]quinazolin-5- amine

Step 1: A solution of n-butyllithium (2.2 M in heptane, 1.27 mL, 2.8 mmol) was added via syringe to a stirred solution of tert-butyl(2-methylbut-3-yn-2-yl)carbamate (252 mg, 1.38 mmol) in tetrahydrofuran (6.0 mL) at -78 °C for 1 minute, and the resulting mixture was heated to 0 °C. After 15 minutes, tributyltin chloride (747 μL, 2.75 μmol) was added via syringe. After 20 minutes, the resulting mixture was heated to room temperature. After 90 minutes, diethyl ether (50 mL) and a saturated aqueous solution of ammonium chloride (10 mL) were added sequentially. The organic layer was washed sequentially with water (30 mL) and a mixture of water and brine (1:1 v:v, 30 mL), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give compound 380-1.

Step 2: Example 380 was synthesized in a manner similar to that of Example 385, except that compound 380-1 was used instead of compound 385-3. ^¹H NMR (400 MHz, acetone- _d⁶ ) δ 9.45 (s, 1H), 8.40 (d, J = 2.1 Hz, 1H), 7.46 (d, J = 8.9 Hz, 1H), 7.44–7.26 (m, 5H), 3.61 (s, 3H), 1.62 (s, 6H), 1.39 (s, 9H); LCMS (m/z) 491.3.

Example 381. N-Methyl-8-(methanesulfonyl)-N-phenyl-[1,2,4]triazolo[4,3-a]quinazolin-5- amine

Example 381 was synthesized in a manner similar to that of Example 350, except that it began with Example 380. ^¹H NMR (400 MHz, methanol- _d⁴ ) δ 9.57 (s, ¹H), 8.49 (d, J = 2.0 Hz, ¹H), 7.61–7.46 (m, 4H), 7.35 (dd, J = 9.1, 2.0 Hz, 1H), 7.27 (d, J = 9.0 Hz, 1H), 3.74 (s, 3H), 1.71 (s, 6H); LCMS (m/z) 391.2.

Example 382. N-Methyl-8-(methanesulfonyl)-N-phenyl-[1,2,4]triazolo[4,3-a]quinazolin-5- amine

Example 382 was synthesized in a manner similar to that of Example 376, except that Example 308 was used instead of compound 364-2 and 1-methoxy-2-methylbut-3-yn-2-ol was used instead of 2-methylbut-3-yn-2-ol. ^¹H NMR (400 MHz, acetone- _d⁶ ) δ 9.45 (s, 1H), 8.41 (d, J = 2.1 Hz, 1H), 7.45 (d, J = 8.9 Hz, 1H), 7.43–7.36 (m, 2H), 7.36–7.27 (m, 3H), 3.62 (s, 3H), 3.44 (s, 2H), 3.40 (s, 3H), 1.46 (s, 3H); LCMS (m/z) 422.2.

Example 383. N-Methyl-8-(methanesulfonyl)-N-phenyl-[1,2,4]triazolo[4,3-a]quinazolin-5- amine

Step 1: Trifluoromethanesulfonic anhydride (257 μL, 1.53 mmol) was added via syringe to a stirred mixture of 4-(bicyclo[1.1.1]pent-1-yl)phenol (122 mg, 763 μmol) and N,N-diisopropylethylamine (532 μL, 3.05 mmol) in dichloromethane (3.0 mL) over 3 minutes at 0 °C. After 20 minutes, the mixture was purified by silica gel rapid column chromatography (hexane) to give compound 383-1.

Step 2: Example 383 was synthesized in a manner similar to that of Example 337, using compound 383-1 instead of 2-bromo-5-cyclopropylpyrazine. ^¹H NMR (400 MHz, acetone- _d⁶ ): δ 9.43 (s, 1H), 8.38 (d, J = 2.1 Hz, 1H), 7.64 (t, J = 2.0 Hz, 1H), 7.61–7.47 (m, 5H), 7.40–7.31 (m, 1H), 7.31–7.22 (m, 3H), 3.68 (s, 3H), 2.55 (s, 1H), 2.10 (s, 6H); LCMS (m/z): 452.3.

Example 384. N-Methyl-8-(methanesulfonyl)-N-phenyl-[1,2,4]triazolo[4,3-a]quinazolin-5- amine

Step 1: A mixture of 5-bromo-2-iodopyridine (500 mg, 1.76 mmol), tricyclo[1.1.1.0 ^1,3 ]pentane solution (0.77 M in diethyl ether, 4.55 mL, 3.5 mmol), [4,4′-bis(1,1-dimethylethyl)-2,2′-dipyridine-N1,N1′]bis[3,5-difluoro-2-[5-(trifluoromethyl)-2-pyridyl-N]phenyl-C]iridium(III) hexafluorophosphate (49.4 mg, 44.0 μmol), and trimethylacetonitrile (11.7 mL) was degassed by circulating it through three freeze-thaw pumps (under reduced pressure only at -78 °C), placed under an argon atmosphere, and stirred at room temperature. The resulting mixture was irradiated with blue light for 16 hours and concentrated under reduced pressure. The residue was purified by silica gel rapid column chromatography (dichloromethane) to give compound 384-1.

Step 2: At -78°C, a solution of triethylborane (1.0 M in hexane, 80.4 μL, 80 μmol) was added via syringe to a stirred mixture of compound 384-1 (281 mg, 804 μmol) and tributyltinane (237 μL, 884 μmol) in tetrahydrofuran. After 15 minutes, the resulting mixture was heated to room temperature, stirred vigorously, and exposed to air. After 120 minutes, an aqueous solution of sodium thiosulfate (1.0 M, 5 mL), a saturated aqueous solution of sodium bicarbonate (5 mL), and water (30 mL) were added sequentially. The aqueous layer was extracted with diethyl ether (60 mL), and the organic layer was dried over anhydrous magnesium sulfate, filtered, and purified by silica gel rapid column chromatography (0 to 90% dichloromethane/hexane) to obtain compound 384-2.

Step 3: Example 384 was synthesized in a manner similar to Example 337, using compound 384-2 instead of 2-bromo-5-cyclopropylpyrazine. ^¹H NMR (400 MHz, acetone- _d⁶ ) δ 9.46 (s, 1H), 8.71 (dd, J = 2.4, 0.9 Hz, 1H), 8.40 (d, J = 2.1 Hz, 1H), 7.95 (dd, J = 8.1, 2.4 Hz, 1H), 7.71 (t, J = 2.0 Hz, 1H), 7.64 (dt, J = 7.8, 1.4 Hz, 1H), 7.58 (t, J = 7.8 Hz, 1H), 7 .51(d,J＝9.0Hz,1H),7.44(ddd,J＝7.8,2.2,1.2Hz,1H),7.31(dd,J＝8.1,0.9Hz,1H), 7.27 (dd, J=9.0, 2.1Hz, 1H), 3.71 (s, 3H), 2.55 (s, 1H), 2.16 (s, 6H); LCMS (m/z) 453.3.

Example 385. N-Methyl-8-(methanesulfonyl)-N-phenyl-[1,2,4]triazolo[4,3-a]quinazolin-5- amine

Step 1: 3-(((ethylimino)methylene)amino)-N,N-dimethylpropyl-1-amine hydrochloride (573 mg, 2.99 mmol) was added to a stirred solution of bicyclo[1.1.1]pentane-1-carboxylic acid (223 mg, 1.99 mmol) in dichloromethane (2.5 mL) at room temperature. After 5 minutes, 1-hydroxybenzotriazole (53.8 mg, 398 μmol), N,O-dimethylhydroxyamine hydrochloride (389 mg, 3.98 mmol), and N,N-diisopropylethylamine (1.21 mL, 6.97 mmol) were added sequentially. After 63 hours, the mixture was purified by silica gel rapid column chromatography (0 to 65% diethyl ether in hexane) to give compound 385-1.

Step 2: At -78°C, a solution of diisobutylaluminum hydride (1.0 M in dichloromethane, 2.32 mL, 2.3 mmol) was added via syringe to a stirred solution of compound 385-1 (266 mg, 1.72 mmol) in dichloromethane (3.0 mL). After 85 minutes, the resulting mixture was heated to 0°C. After 17 minutes, the mixture was heated to room temperature, and a solution of diisobutylaluminum hydride (1.0 M in dichloromethane, 1.80 mL, 1.8 mmol) was added via syringe. After 273 minutes, the mixture was cooled to 0°C, and water (2.0 mL) and an aqueous solution of hydrogen chloride (2.0 M, 3.0 mL) were added sequentially. The mixture was heated to room temperature, and water (15 mL) was added. The mixture was filtered, and the filter cake was extracted with dichloromethane (25 mL). The combined filtrates were stirred, and the layers were separated. The aqueous layer was extracted with dichloromethane (25 mL), and the combined organic layers were dried over anhydrous magnesium sulfate and filtered. Triphenylphosphine (3.69 g, 14.1 mmol) was added to the filtrate, and the resulting mixture was stirred and cooled to 0 °C. Carbon tetrabromide (2.28 g, 6.87 mmol) was added, and the resulting mixture was heated to room temperature. After 12 hours, the resulting mixture was concentrated to approximately 60 mL under reduced pressure. The mixture was thoroughly ground with a mixture of hexane and diethyl ether (10:1 v:v, 60 mL) and filtered. The filter cake was extracted with hexane (60 mL), and the combined filtrates were concentrated under reduced pressure. The residue was purified by silica gel rapid column chromatography (hexane) to give compound 385-2.

Step 3: Within 1 minute, a solution of n-butyllithium (2.7 M in heptane, 83.5 μL, 230 μmol) was added to a stirred solution of compound 385-2 (7.1 mg, 28.2 μmol) in tetrahydrofuran (3.0 mL) at -78 °C using a syringe. After 60 minutes, the resulting mixture was heated to 0 °C. After 45 minutes, tributyltin chloride (61.2 μL, 225 μmol) was added using a syringe, and the resulting mixture was heated to room temperature. After 45 minutes, diethyl ether (40 mL), hexane (20 mL), and saturated sodium bicarbonate aqueous solution (10 mL) were added sequentially. The organic layer was washed with anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to obtain compound 385-3.

Step 4: The vigorously stirred mixture of Example 308 (5.0 mg, 13 μmol), compound 385-3 (16.0 mg, 41.9 μmol), [1,1'-bis(diphenylphosphine)ferrocene]palladium(II) dichloride (2.8 mg, 3.9 μmol) and 1-methylpyrrolidone-2-one (0.9 mL) was heated to 110 °C. After 12 minutes, the resulting mixture was cooled to room temperature and purified by reversed-phase preparative HPLC (acetonitrile/water containing 0.1% trifluoroacetic acid) to obtain a partially purified product, which was further purified by silica gel rapid column chromatography (0 to 100% ethyl acetate in hexane to dichloromethane containing 0 to 10% methanol) and additionally purified by reversed-phase preparative HPLC (acetonitrile/water containing 0.1% trifluoroacetic acid) to give the title compound: ^¹H NMR (400 MHz, acetone- _d6 ) δ 9.47 (s, 1H), 8.41 (d, J = 2.1 Hz, 1H), 7.46–7.36 (m, 3H), 7.36–7.29 (m, 3H), 3.63 (s, 3H), 2.32 (s, 1H), 2.13 (s, 6H); LCMS (m/z) 400.2.

Example 386. N-(4'-(tert-butyl)-4-fluoro-[1,1'-diphenyl]-3-yl)-8-chloro-N-methyl-[1,2,4] Triazolo[4,3-a]quinazolin-5-amine

The title compound was synthesized according to the general procedure described for Example 409: ^¹H NMR (400 MHz, methanol- _d⁴ ) δ 9.60 (s, 1H), 8.53 (d, J = 1.9 Hz, 1H), 7.81 (ddd, J = 6.9, 3.3, 1.2 Hz, 2H), 7.68–7.28 (m, 7H), 3.81 (s, 3H), 1.35 (s, 9H); LCMS (m/z) 460.4.

Example 387. 8-Chloro-N-(4'-Cyclopropyl-4-fluoro-[1,1'-diphenyl]-3-yl)-N-methyl-[1,2,4] Triazolo[4,3-a]quinazolin-5-amine

The title compound was synthesized according to the general procedure described for Example 409: ^¹H NMR (400 MHz, methanol- _d⁴ ) δ 9.60 (s, 1H), 8.53 (d, J = 1.8 Hz, 1H), 7.86–7.34 (m, 7H), 7.16 (d, J = 8.3 Hz, 2H), 3.81 (s, 3H), 1.94 (tt, J = 8.7, 4.2 Hz, 1H), 1.06–0.91 (m, 2H), 0.72 (dt, J = 6.6, 4.5 Hz, 2H); LCMS (m/z) 444.4.

Example 388. 8-Chloro-N-(4'-(difluoromethyl)-4-fluoro-[1,1'-diphenyl]-3-yl)-N-methyl-[1, [2,4]triazolo[4,3-a]quinazolin-5-amine

The title compound was synthesized according to the general procedure described for Example 409: ^¹H NMR (400 MHz, methanol- _d⁴ ) δ 9.61 (s, 1H), 8.62–8.49 (m, 1H), 7.88 (ddd, J = 10.5, 7.3, 3.1 Hz, 2H), 7.74 (d, J = 7.9 Hz, 2H), 7.63 (d, J = 8.0 Hz, 2H), 7.59–7.38 (m, 3H), 6.82 (t, J = 56.2 Hz, 1H), 3.82 (s, 3H); LCMS (m/z) 454.3.

Example 389. 8-Chloro-N-(3-(6-methoxypyridin-3-yl)phenyl)-N-methyl-[1,2,4]triazolo[4, [3-a]quinazolin-5-amine

The title compound was synthesized according to the general procedure described for Example 409: ^¹H NMR (400 MHz, methanol- _d⁴ ) δ 9.60 (s, 1H), 8.51 (d, J = 2.2 Hz, 1H), 8.38 (d, J = 2.7 Hz, 1H), 8.03–7.92 (m, 1H), 7.88–7.59 (m, 3H), 7.54–7.23 (m, 3H), 6.90 (d, J = 8.8 Hz, 1H), 3.96 (s, 3H), 3.87 (s, 3H); LCMS (m/z) 417.3.

Example 390. 8-Chloro-N-methyl-N-(3-(1-(methanesulfonyl)-1H-pyrazole-4-yl)phenyl)-[1,2, 4] Triazolo[4,3-a]quinazolin-5-amine

The title compound was synthesized according to the general procedure described for Example 409: ^¹H NMR (400 MHz, methanol- _d⁴ ) δ 9.60 (s, 1H), 8.62 (d, J = 0.8 Hz, 1H), 8.50 (d, J = 2.0 Hz, 1H), 8.29 (d, J = 0.8 Hz, 1H), 7.88–7.77 (m, 2H), 7.61 (t, J = 7.9 Hz, 1H), 7.46–7.25 (m, 3H), 3.83 (s, 3H), 3.45 (s, 3H); LCMS (m/z) 454.1.

Example 391. 5-(3-((8-chloro-[1,2,4]triazolo[4,3-a]quinazolin-5-yl)(methyl)amino)benzene 2-pyrimidine-2-carboxynitrile

The title compound was synthesized according to the general procedure described for Example 409: ^¹H NMR (400 MHz, methanol- _d⁴ ) δ 9.60 (s, 1H), 9.22 (s, 2H), 8.58–8.46 (m, 1H), 7.93 (dt, J = 6.8, 1.6 Hz, 2H), 7.75 (t, J = 8.2 Hz, 1H), 7.67–7.51 (m, 1H), 7.44–7.26 (m, 2H), 3.85 (s, 3H); LCMS (m/z) 413.3.

Example 392. 8-Chloro-N-methyl-N-(4'-(methanesulfonyl)-[1,1'-diphenyl]-3-yl)-[1,2,4] Triazolo[4,3-a]quinazolin-5-amine

The title compound was synthesized according to the general procedure described for Example 409: ^¹H NMR (400 MHz, methanol- _d⁴ ) δ 9.60 (s, ¹H), 8.51 (d, J = 2.2 Hz, ¹H), 8.38 (d, J = 2.7 Hz, ¹H), 8.02–7.88 (m, ¹H), 7.85–7.60 (m, 3H), 7.55–7.20 (m, 3H), 6.90 (d, J = 8.7 Hz, 1H), 3.96 (d, J = 3.1 Hz, 3H), 3.87 (s, 3H); LCMS (m/z) 464.3.

Example 393. 8-Chloro-N-(5-(5-cyclopropylpyrazin-2-yl)-2-fluorophenyl)-N-methyl-[1,2,4]triazole [4,3-a]quinazolin-5-amine

The title compound was synthesized according to the general procedure described for Example 413: ^¹H NMR (400 MHz, methanol- _d⁴ ) δ 9.63 (s, 1H), 8.91 (d, J = 1.4 Hz, 1H), 8.66–8.49 (m, 2H), 8.43–8.18 (m, 2H), 7.70–7.31 (m, 3H), 3.83 (s, 3H), 2.22 (ddd, J = 8.0, 5.3, 3.1 Hz, 1H), 1.23–0.99 (m, 4H); LCMS (m/z) 446.3.

Example 394. N-(5-bromo-2-fluorophenyl)-8-chloro-N-methyl-[1,2,4]triazolo[4,3-a]quinazolin-5- amine

The title compound was synthesized according to the general procedure described for Example 409: ^¹H NMR (400MHz, DMSO- _d₆ ) δ 9.67 (s, 1H), 8.60 (d, J = 2.1Hz, 1H), 7.76 (dd, J = 7.4, 2.5Hz, 1H), 7.56 (ddd, J = 8.8, 4.3, 2.5Hz, 1H), 7.48–7.23 (m, 3H), 3.33 (s, 3H); LCMS (m/z) 406.3.

Example 395. N-(3-bromo-2-fluorophenyl)-8-chloro-N-methyl-[1,2,4]triazolo[4,3-a]quinazolin-5- amine

The title compound was synthesized according to the general procedure described for Example 409: ^¹H NMR (400MHz, DMSO- _d₆ ) δ 9.67 (s, 1H), 8.60 (d, J = 2.1Hz, 1H), 7.68 (ddd, J = 8.0, 6.4, 1.6Hz, 1H), 7.49–7.36 (m, 2H), 7.27 (d, J = 8.9Hz, 1H), 7.18 (td, J = 8.0, 1.3Hz, 1H), 3.49 (s, 3H); LCMS (m/z) 406.2.

Example 396. N-(4'-(tert-butyl)-2-fluoro-[1,1'-diphenyl]-3-yl)-8-chloro-N-methyl-[1,2,4] Triazolo[4,3-a]quinazolin-5-amine

The title compound was synthesized according to the general procedure described for Example 409: ^1H NMR (400MHz, methanol- _d4 ) δ 9.55 (s, 1H), 8.49 (s, 1H), 7.87–7.37 (m, 9H), 3.77 (s, 3H), 1.38 (s, 9H); LCMS (m/z) 460.4.

Example 397. 8-Chloro-N-(4'-Cyclopropyl-2-fluoro-[1,1'-diphenyl]-3-yl)-N-methyl-[1,2,4] Triazolo[4,3-a]quinazolin-5-amine

The title compound was synthesized according to the general procedure described for Example 409: ^¹H NMR (400 MHz, methanol- _d⁴ ) δ 9.60 (s, 1H), 8.53 (d, J = 1.8 Hz, 1H), 7.86–7.34 (m, 7H), 7.16 (d, J = 8.3 Hz, 2H), 3.81 (s, 3H), 1.94 (tt, J = 8.7, 4.2 Hz, 1H), 1.06–0.91 (m, 2H), 0.72 (dt, J = 6.6, 4.5 Hz, 2H); LCMS (m/z) 444.4.

Example 398. 8-Chloro-N-(4'-(difluoromethyl)-2-fluoro-[1,1'-diphenyl]-3-yl)-N-methyl-[1, [2,4]triazolo[4,3-a]quinazolin-5-amine

The title compound was synthesized according to the general procedure described for Example 409: ^¹H NMR (400 MHz, methanol- _d⁴ ) δ 9.61 (s, 1H), 8.56 (d, J = 2.1 Hz, 1H), 7.84–7.38 (m, 9H), 6.84 (t, J = 56.1 Hz, 1H), 3.83 (s, 3H); LCMS (m/z) 454.3.

Example 399. 8-Chloro-N-(3-(5-cyclopropylpyrazin-2-yl)-2-fluorophenyl)-N-methyl-[1,2,4]triazole [4,3-a]quinazolin-5-amine

The title compound was synthesized according to the general procedure described for Example 413: ^¹H NMR (400 MHz, methanol- _d⁴ ) δ 9.63 (s, 1H), 8.79 (dd, J = 2.7, 1.5 Hz, 1H), 8.69 (d, J = 1.5 Hz, 1H), 8.57 (d, J = 2.0 Hz, 1H), 8.21–8.03 (m, 1H), 7.64 (td, J = 7.6, 1.8 Hz, 1H), 7.57–7.34 (m, 3H), 3.84 (s, 3H), 2.26 (tt, J = 8.0, 4.9 Hz, 1H), 1.14 (ddt, J = 15.1, 5.0, 2.7 Hz, 4H); LCMS (m/z) 446.3.

Example 400. N-(3-bromo-4-fluorophenyl)-8-chloro-N-methyl-[1,2,4]triazolo[4,3-a]quinazolin-5- amine

The title compound was synthesized according to the general procedure described for Example 409: ^¹H NMR (400 MHz, methanol- _d⁴ ) δ 9.62 (s, ¹H), 8.54 (d, J = 2.1 Hz, ¹H), 7.84 (dd, J = 6.0, 2.6 Hz, ¹H), 7.59–7.37 (m, ³H), 7.30 (d, J = 9.1 Hz, ¹H), 3.78 (s, ³H); LCMS (m/z) 406.2.

Example 401. N-(4'-(tert-butyl)-6-fluoro-[1,1'-diphenyl]-3-yl)-8-chloro-N-methyl-[1,2,4] Triazolo[4,3-a]quinazolin-5-amine

The title compound was synthesized according to the general procedure described for Example 409: ^¹H NMR (400 MHz, methanol- _d⁴ ) δ 9.59 (s, ¹H), 8.52 (d, J = 2.1 Hz, ¹H), 7.70–7.08 (m, 9H), 3.84 (s, 3H), 1.35 (s, 9H); LCMS (m/z) 460.4.

Example 402. 8-Chloro-N-(4'-Cyclopropyl-6-fluoro-[1,1'-diphenyl]-3-yl)-N-methyl-[1,2,4] Triazolo[4,3-a]quinazolin-5-amine

The title compound was synthesized according to the general procedure described for Example 409: ^¹H NMR (400 MHz, methanol- _d⁴ ) δ 9.45 (s, ¹H), 8.37 (d, J = 2.3 Hz, ¹H), 7.84–7.05 (m, 9H), 3.70 (d, J = 3.5 Hz, 3H), 2.04–1.86 (m, ¹H), 1.10–0.66 (m, 4H); LCMS (m/z) 444.4.

Example 403. 8-Chloro-N-(4'-(difluoromethyl)-6-fluoro-[1,1'-diphenyl]-3-yl)-N-methyl-[1, [2,4]triazolo[4,3-a]quinazolin-5-amine

The title compound was synthesized according to the general procedure described for Example 409: ^¹H NMR (400 MHz, methanol- _d⁴ ) δ 9.60 (s, 1H), 8.53 (d, J = 2.0 Hz, 1H), 7.75–7.30 (m, 9H), 6.83 (t, J = 56.1 Hz, 1H), 3.84 (s, 3H); LCMS (m/z) 454.3.

Example 404. 8-Chloro-N-(3-(5-cyclopropylpyrazin-2-yl)-4-fluorophenyl)-N-methyl-[1,2,4]triazole [4,3-a]quinazolin-5-amine

The title compound was synthesized according to the general procedure described for Example 413: ^¹H NMR (400 MHz, methanol- _d⁴ ) δ 9.60 (s, 1H), 8.92 (dd, J = 2.6, 1.5 Hz, 1H), 8.63 (d, J = 1.5 Hz, 1H), 8.52 (d, J = 2.1 Hz, 1H), 8.18–8.02 (m, 1H), 7.61–7.26 (m, 4H), 3.84 (s, 3H), 2.24 (tt, J = 7.9, 5.0 Hz, 1H), 1.14 (tt, J = 7.8, 2.8 Hz, 4H); LCMS (m/z) 446.3.

Example 405. N-(3'-((8-chloro-[1,2,4]triazolo[4,3-a]quinazolin-5-yl)(methyl)amino)- [1,1'-Diphenyl]-4-yl)methanesulfonamide

The title compound was synthesized according to the general procedure described for Example 409: ^¹H NMR (400 MHz, methanol- _d⁴ ) δ 9.58 (s, 1H), 8.50 (d, J = 2.0 Hz, 1H), 7.79 (dt, J = 8.1, 1.2 Hz, 1H), 7.72 (t, J = 1.9 Hz, 1H), 7.71–7.54 (m, 3H), 7.51–7.23 (m, 5H), 3.86 (s, 3H), 3.00 (s, 3H); LCMS (m/z) 479.3.

Example 406. 3'-((8-chloro-[1,2,4]triazolo[4,3-a]quinazolin-5-yl)(methyl)amino)-[1, 1'-Diphenyl]-4-carboxamide

The title compound was synthesized according to the general procedure described for Example 409: ^¹H NMR (400 MHz, methanol- _d⁴ ) δ 9.60 (s, 1H), 8.52 (d, J = 2.0 Hz, 1H), 8.03–7.92 (m, 2H), 7.87 (d, J = 8.0 Hz, 1H), 7.81 (t, J = 1.9 Hz, 1H), 7.71 (dd, J = 17.1, 8.3 Hz, 3H), 7.56–7.48 (m, 1H), 7.39 (dd, J = 9.1, 2.0 Hz, 1H), 7.30 (d, J = 9.1 Hz, 1H), 3.88 (s, 3H); LCMS (m/z) 429.3.

Example 407. 8-Chloro-N-(3-(3,3-dimethylbut-1-yn-1-yl)-2-fluorophenyl)-N-methyl-[1,2, 4] Triazolo[4,3-a]quinazolin-5-amine

The title compound was synthesized according to the general procedure described for Example 421: ^¹H NMR (400 MHz, methanol- _d⁴ ) δ 9.61 (s, 1H), 8.55 (d, J = 2.0 Hz, 1H), 7.64–7.39 (m, 3H), 7.38–7.24 (m, 2H), 3.74 (s, 3H), 1.33 (s, 9H); LCMS (m/z) 408.3.

Example 408. N-(3-bromo-5-fluorophenyl)-8-chloro-N-methyl-[1,2,4]triazolo[4,3-a]quinazolin-5- amine

Step 1: Sodium hydride (60% dispersion in mineral oil, 51 mg, 2.19 mmol, 1.28 equivalents) was added in one portion to a solution of 2,4,7-trichloroquinazoline (400 mg, 1.71 mmol) and 3-bromo-5-fluoro-N-methylaniline (447 mg, 2.19 mmol, 1.28 equivalents) in DMF (5 mL). The ice bath was removed, and the mixture was stirred at room temperature for 2 hours. After completion, the reaction mixture was cooled to 0°C and quenched by the slow addition of a saturated aqueous solution of ammonium chloride. The collected material was collected by filtration and washed with water, hexane, and hexane/ether (2:1) to remove all impurities. The residue was then further dried under high vacuum to provide N-(3-bromo-5-fluorophenyl)-2,7-dichloro-N-methylquinazoline-4-amine.

Step 2: Add hydrazine monohydrate (1.7 mL, 34.3 mmol, 20 equivalences) to a solution of N-(3-bromo-5-fluorophenyl)-2,7-dichloro-N-methylquinazoline-4-amine (1.71 mmol) in THF (15 mL)/ethanol (10 mL), and stir the mixture overnight at room temperature. Afterward, add ethyl acetate and water to the mixture. Extract the aqueous layer with ethyl acetate (X2). Wash the combined organic layers with brine, dry ( _MgSO4 ), and concentrate under vacuum. Add triethyl orthoformate (12 mL, 74.3 mmol, 43.4 equivalences) to the crude product (1.71 mmol), and heat the mixture to 100 °C and stir for 30 minutes. Afterward, cool the reaction mixture to room temperature and concentrate under reduced pressure to a minimum volume (<1 mL). Grind the residue with hexane and sonicate for several minutes. The residue was collected by filtration, washed with hexane:ether (5:1) and dried under high vacuum, providing the title compound: ^¹H NMR (400 MHz, methanol- _d⁴ ) δ 9.64 (s, 1H), 8.55 (d, J = 2.0 Hz, 1H), 7.58–7.46 (m, 3H), 7.37 (t, J = 9.1 Hz, 2H), 3.78 (s, 3H); LCMS (m/z) 406.2.

Example 409. N-(4'-(tert-butyl)-5-fluoro-[1,1'-diphenyl]-3-yl)-8-chloro-N-methyl-[1,2,4] Triazolo[4,3-a]quinazolin-5-amine

N-(3-bromo-5-fluorophenyl)-8-chloro-N-methyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine (Example 408, 25 mg, 61.5 μmol) and (4-tert-butylphenyl)boronic acid (11 mg, 61.5 μmol, 1.0 equivalence) were dissolved in dimethylformamide (1 ml) and water (0.1 ml). Potassium carbonate (21 mg, 154 μmol, 2.5 equivalence) and tetrakis(triphenylphosphine)palladium (0) (14 mg, 12.3 μmol, 20 mol%) were added. The mixture was purged with argon and then heated to 84 °C. After completion, ethyl acetate and water were added to the mixture. The organic layer was concentrated under vacuum. The residue was purified by reversed-phase HPLC (acetonitrile/water containing 0.1% trifluoroacetic acid) to provide the title compound as a single TFA salt: ^¹H NMR (400 MHz, methanol- _d⁴ ) δ 9.50 (s, 1H), 8.41 (d, J = 2.0 Hz, 1H), 7.54–7.43 (m, 5H), 7.45–7.28 (m, 3H), 7.13 (dt, J = 9.5, 2.1 Hz, 1H), 3.75 (s, 3H), 1.35 (s, 9H); LCMS (m/z) 460.4.

Example 410. 8-Chloro-N-(4'-Cyclopropyl-5-fluoro-[1,1'-diphenyl]-3-yl)-N-methyl-[1,2,4] Triazolo[4,3-a]quinazolin-5-amine

The title compound was synthesized according to the general procedure described for Example 409: ^¹H NMR (400 MHz, methanol- _d⁴ ) δ 9.48 (s, 1H), 8.39 (d, J = 2.0 Hz, 1H), 7.47 (dd, J = 14.6, 8.7 Hz, 3H), 7.40–7.25 (m, 3H), 7.19–7.00 (m, 3H), 3.73 (s, 3H), 1.99–1.85 (m, 1H), 1.00 (dd, J = 8.5, 2.1 Hz, 2H), 0.78–0.62 (m, 2H); LCMS (m/z) 444.4.

Example 411. 8-Chloro-N-(4'-(difluoromethyl)-5-fluoro-[1,1'-diphenyl]-3-yl)-N-methyl-[1, [2,4]triazolo[4,3-a]quinazolin-5-amine

The title compound was synthesized according to the general procedure described for Example 409: ^¹H NMR (400 MHz, methanol- _d⁴ ) δ 9.61 (s, 1H), 8.52 (t, J = 1.2 Hz, 1H), 7.74 (d, J = 8.1 Hz, 2H), 7.68–7.55 (m, 4H), 7.50–7.39 (m, 2H), 7.34 (dt, J = 9.1, 2.2 Hz, 1H), 6.82 (t, J = 56.1 Hz, 1H), 3.84 (s, 3H); LCMS (m/z) 454.3.

Example 412. 8-Chloro-N-(3'-Fluoro-4'-(Methylsulfonyl)-[1,1'-diphenyl]-3-yl)-N-methyl- [1,2,4]triazolo[4,3-a]quinazolin-5-amine

The title compound was synthesized according to the general procedure described for Example 409: ^¹H NMR (400 MHz, methanol- _d⁴ ) δ 9.60 (s, 1H), 8.51 (d, J = 2.0 Hz, 1H), 8.01 (t, J = 7.7 Hz, 1H), 7.92–7.81 (m, 2H), 7.79–7.65 (m, 3H), 7.56 (ddd, J = 8.0, 2.2, 1.0 Hz, 1H), 7.38 (dd, J = 9.1, 2.0 Hz, 1H), 7.31 (d, J = 9.1 Hz, 1H), 3.86 (s, 3H), 3.29 (s, 3H); LCMS (m/z) 482.2.

Example 413. 8-Chloro-N-(3-(5-cyclopropylpyrazin-2-yl)-5-fluorophenyl)-N-methyl-[1,2,4]triazole [4,3-a]quinazolin-5-amine

Potassium acetate (72 mg, 738 μmol, 5.0 equivalent) and bis(diphenylphosphine)ferrocene)palladium(II) dichloride (5.4 mg, 7.38 μmol, 5 mol%) were added to a mixture of N-(3-bromo-5-fluorophenyl)-8-chloro-N-methyl-[1,2,4]triazolo[4,3-a]quinazolino-5-amine (Example 408, 60 mg, 148 μmol) and bis(pinacol)diborone (41 mg, 162 μmol, 1.1 equivalence) in 1,4-dioxane (2 ml). The mixture was purged with argon and then heated to 110 °C. After completion, the mixture was cooled to room temperature, silica gel (250 mg) and ethyl acetate were added, and the mixture was concentrated to dryness. The crude product was dried and loaded onto a silica gel column and eluted with 0-20% methanol/dichloromethane to provide a mixture of 8-chloro-N-(3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)phenyl)-N-methyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine and its corresponding boric acid.

To the above mixture (148 μmol) in 1,4-dioxane (1 ml) and water (0.1 ml), 2-bromo-5-cyclopropylpyrazine (44 mg, 221 μmol, 1.5 equivalents), potassium carbonate (72 mg, 516 μmol, 3.5 equivalents), and bis(diphenylphosphine)ferrocene)palladium(II) dichloride (12 mg, 14.8 μmol, 10 mol%) were added. The mixture was purged with argon and then heated to 120 °C. After completion, the mixture was filtered through a short bed, and the vacuum-concentrated filtrate was washed with ethyl acetate. The residue was dissolved in methanol (3 ml) and trifluoroacetic acid (0.2 ml) and purified by reversed-phase HPLC (acetonitrile/water containing 0.1% trifluoroacetic acid) to provide the title compound as a single TFA salt: ^¹H NMR (400 MHz, methanol- _d⁴ ) δ 9.64 (s, 1H), 8.92 (d, J = 1.5 Hz, 1H), 8.60 (d, J = 1.5 Hz, 1H), 8.54 (dd, J = 1.7, 0.7 Hz, 1H), 8.04–7.92 (m, 2H), 7.49–7.24 (m, 3H), 3.86 (s, 3H), 2.23 (tt, J = 8.0, 4.9 Hz, 1H), 1.12 (ddt, J = 14.5, 5.0, 2.7 Hz, 4H); LCMS (m/z) 446.3.

Example 414. 3'-((8-chloro-[1,2,4]triazolo[4,3-a]quinazolin-5-yl)(methyl)amino)-[1, 1'-Diphenyl]-4-sulfonamide

The title compound was synthesized according to the general procedure described for Example 409: ^¹H NMR (400 MHz, methanol- _d⁴ ) δ 9.59 (s, 1H), 8.50 (d, J = 2.0 Hz, 1H), 7.98 (d, J = 8.5 Hz, 2H), 7.93–7.77 (m, 4H), 7.69 (t, J = 7.9 Hz, 1H), 7.50 (ddd, J = 7.9, 2.3, 1.0 Hz, 1H), 7.43–7.27 (m, 2H), 3.86 (s, 3H); LCMS (m/z) 465.3.

Example 415. 8-Chloro-N-(3-(6-(dimethylamino)pyridin-3-yl)phenyl)-N-methyl-[1,2,4]tri Azo[4,3-a]quinazolin-5-amine

The title compound was synthesized according to the general procedure described for Example 409: ^¹H NMR (400 MHz, methanol- _d⁴ ) δ 9.59 (s, 1H), 8.50 (dd, J = 1.9, 0.6 Hz, 1H), 8.27 (dd, J = 9.6, 2.4 Hz, 1H), 8.17 (dd, J = 2.4, 0.7 Hz, 1H), 7.77 (dt, J = 3.2, 1.9 Hz, 2H), 7.67 (t, J = 8.1 Hz, 1H), 7.48 (ddd, J = 7.9, 2.1, 1.1 Hz, 1H), 7.36–7.26 (m, 3H), 3.84 (s, 3H), 3.33 (s, 6H); LCMS (m/z) 430.3.

Example 416. (3'-((8-chloro-[1,2,4]triazolo[4,3-a]quinazolin-5-yl)(methyl)amino)-[1, 1'-Diphenyl]-4-yl)(morpholino)methyl ketone

The title compound was synthesized according to the general procedure described for Example 409: ^¹H NMR (400 MHz, methanol- _d⁴ ) δ 9.59 (s, 1H), 8.51 (d, J = 2.0 Hz, 1H), 7.85 (ddd, J = 7.8, 1.8, 1.0 Hz, 1H), 7.80–7.64 (m, 4H), 7.61–7.45 (m, 3H), 7.38 (dd, J = 9.2, 2.1 Hz, 1H), 7.30 (d, J = 9.1 Hz, 1H), 3.87 (s, 3H), 3.84–3.38 (m, 8H); LCMS (m/z) 499.3.

Example 417. 8-Chloro-5-(5-fluoro-3,4-dihydroquinoline-1(2H)-yl)-[1,2,4]triazolo[4,3-a]quinoline zoline

The title compound was synthesized according to the general procedure described for Example 498: ^¹H NMR (400 MHz, methanol- _d⁴ ) δ 9.66 (s, ¹H), 8.56 (d, J = 2.0 Hz, ¹H), 7.74 (d, J = 9.0 Hz, ¹H), 7.52 (dd, J = 9.0, 2.0 Hz, ¹H), 7.17–6.93 (m, 2H), 6.79 (d, J = 8.1 Hz, 1H), 4.22 (t, J = 6.3 Hz, 2H), 3.01 (t, J = 6.8 Hz, 2H), 2.25 (q, J = 6.5 Hz, 2H); LCMS (m/z) 354.3.

Example 418. 9-Bromo-5-(8-chloro-[1,2,4]triazolo[4,3-a]quinazolin-5-yl)-2,3,4,5-tetrahydro Benzo[b][1,4]oxazine

The title compound was synthesized according to the general procedure described for Example 498: ^¹H NMR (400 MHz, methanol- _d⁴ ) δ 9.61 (s, ¹H), 8.52 (d, J = 2.1 Hz, ¹H), 7.75 (dd, J = 8.0, 1.7 Hz, ¹H), 7.44 (dd, J = 9.1, 2.1 Hz, ¹H), 7.18–6.95 (m, ³H), 4.50–4.29 (m, ²H), 3.37–3.28 (m, ²H), 2.37–2.16 (m, ²H); LCMS (m/z) 430.4.

Example 419. 8-Chloro-5-(1,1a,2,7b-tetrahydro-3H-cyclopropyl[c]quinolin-3-yl)-[1,2,4]triazolidine [4,3-a]quinazolin

The title compound was synthesized according to the general procedure described for Example 498: ^¹H NMR (400 MHz, methanol- _d⁴ ) δ 9.62 (s, ¹H), 8.53 (d, J = 2.0 Hz, ¹H), 7.57 (dd, J = 7.6, 1.5 Hz, ¹H), 7.51 (d, J = 9.0 Hz, ¹H), 7.45 (dd, J = 9.0, 2.0 Hz, ¹H), 7.26 (td, J = 7.5, 1.2 Hz, ¹H), 7.04 (td, J = 7.8, 1.5 Hz, ¹H). 6.84(dd,J＝8.0,1.2Hz,1H), 5.12(dd,J＝12.6,1.7Hz,1H), 3.40(dd,J＝12.7,2.0Hz,1H), 2.32 (q, J＝7.2Hz, 1H), 2.16 (dp, J＝8.1, 1.9Hz, 1H), 1.31–1.13 (m, 2H); LCMS (m/z) 348.3.

Example 420. 8-Chloro-N-(5-fluoro-4'-(methylsulfonyl)-[1,1'-diphenyl]-3-yl)-N-methyl- [1,2,4]triazolo[4,3-a]quinazolin-5-amine

The title compound was synthesized according to the general procedure described for Example 409: ^¹H NMR (400 MHz, methanol- _d⁴ ) δ 9.64 (s, ¹H), 8.55 (d, J = 1.9 Hz, ¹H), 8.05 (d, J = 8.5 Hz, 2H), 7.89 (d, J = 8.6 Hz, 2H), 7.73–7.61 (m, 2H), 7.50–7.36 (m, 3H), 3.87 (s, 3H), 3.16 (s, 3H); LCMS (m/z) 482.3.

Example 421. 4-(3-((8-chloro-[1,2,4]triazolo[4,3-a]quinazolin-5-yl)(methyl)amino)-5- (Fluorophenyl)-2-methylbut-3-yne-2-ol

N-(3-bromo-5-fluorophenyl)-8-chloro-N-methyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine (20 mg, 49.2 μmol) and 2-methylbut-3-yn-2-ol (12 mg, 148 μmol, 3.0 equivalence) were dissolved in N-methyl-2-pyrrolidone (1 ml). Zinc bromide (55 mg, 246 μmol, 5.0 equivalence), (1,1'-bis(diphenylphosphine)ferrocene)palladium(II) dichloride (11 mg, 14.8 μmol, 30 mol%) and triethylamine (0.14 ml, 984 μmol, 20.0 equivalence) were added. The mixture was heated at 110 °C for 10 minutes. After heating, the mixture was cooled to room temperature, and ethyl acetate and water were added to the mixture. The organic layer was concentrated under vacuum. The residue was purified by reversed-phase HPLC (acetonitrile/water containing 0.1% trifluoroacetic acid) to provide the title compound as a single TFA salt: ^¹H NMR (400 MHz, methanol- _d⁴ ) δ 9.63 (s, ¹H), 8.55 (d, J = 2.1 Hz, ¹H), 7.49 (dd, J = 9.1, 2.1 Hz, ¹H), 7.43–7.19 (m, 4H), 3.78 (s, 3H), 1.53 (s, 6H); LCMS (m/z) 410.2.

Example 422. N-(4'-(tert-butyl)-5-fluoro-[1,1'-diphenyl]-3-yl)-7-fluoro-N-methyl-[1,2,4] Triazolo[4,3-a]quinazolin-5-amine

The title compound was synthesized according to the general procedure described for Example 409: ^¹H NMR (400 MHz, methanol- _d⁴ ) δ 9.62 (s, 1H), 8.41 (dd, J = 9.2, 4.7 Hz, 1H), 7.79 (ddd, J = 9.2, 7.5, 2.7 Hz, 1H), 7.64–7.45 (m, 6H), 7.35–7.23 (m, 1H), 7.03 (dd, J = 10.3, 2.7 Hz, 1H), 3.86 (s, 3H), 1.35 (s, 9H); LCMS (m/z) 444.4.

Example 423. N-(4'-cyclopropyl-5-fluoro-[1,1'-diphenyl]-3-yl)-7-fluoro-N-methyl-[1,2,4]tri Azo[4,3-a]quinazolin-5-amine

The title compound was synthesized according to the general procedure described for Example 409: ^¹H NMR (400 MHz, methanol- _d⁴ ) δ 9.62 (s, 1H), 8.42 (dd, J = 9.2, 4.7 Hz, 1H), 7.80 (ddd, J = 9.2, 7.5, 2.7 Hz, 1H), 7.69–7.52 (m, 6H), 7.30 (dd, J = 9.0, 2.1 Hz, 1H), 7.02 (dd, J = 10.3, 2.7 Hz, 1H), 3.85 (s, 3H), 2.02–1.91 (m, 1H), 1.06–0.96 (m, 2H), 0.79–0.68 (m, 2H); LCMS (m/z) 428.3.

Example 424. N-(4'-(tert-butyl)-[1,1'-diphenyl]-3-yl)-7-fluoro-N-methyl-[1,2,4]triazole [4,3-a]quinazolin-5-amine

The title compound was synthesized according to the general procedure described for Example 409: ^¹H NMR (400 MHz, methanol- _d⁴ ) δ 9.60 (s, 1H), 8.40 (dd, J = 9.2, 4.8 Hz, 1H), 7.89–7.82 (m, 1H), 7.80–7.33 (m, 8H), 6.88 (dd, J = 10.6, 2.7 Hz, 1H), 3.88 (s, 3H), 1.35 (s, 9H); LCMS (m/z) 426.3.

Example 425. N-(4'-cyclopropyl-[1,1'-diphenyl]-3-yl)-7-fluoro-N-methyl-[1,2,4]triazolidine [4,3-a]quinazolin-5-amine

The title compound was synthesized according to the general procedure described for Example 409: 1H NMR (400MHz, methanol- _d4 ) δ 9.59 (s, 1H), 8.39 (dd, J = 9.2, 4.7 Hz, 1H), 7.94–7.38 (m, 9H), 6.95–6.83 (m, 1H), 3.87 (s, 3H), 1.99–1.90 (m, 1H), 1.06–0.97 (m, 2H), 0.82–0.67 (m, 2H); LCMS (m/z) 410.4.

Example 426. N-(3-(3,3-dimethylbut-1-yn-1-yl)-5-fluorophenyl)-7-fluoro-N-methyl-[1,2,4] Triazolo[4,3-a]quinazolin-5-amine

The title compound was synthesized according to the general procedure described for Example 421: ^¹H NMR (400 MHz, methanol- _d⁴ ) δ 9.63 (s, 1H), 8.43 (dd, J = 9.3, 4.7 Hz, 1H), 7.83 (ddd, J = 9.2, 7.6, 2.7 Hz, 1H), 7.40–7.15 (m, 3H), 6.96 (dd, J = 10.2, 2.7 Hz, 1H), 3.78 (s, 3H), 1.31 (s, 9H); LCMS (m/z) 392.4.

Example 427. N-(3-(cyclopropylethynyl)-5-fluorophenyl)-7-fluoro-N-methyl-[1,2,4]triazolo[4, [3-a]quinazolin-5-amine

The title compound was synthesized according to the general procedure described for Example 421: ^¹H NMR (400 MHz, methanol- _d⁴ ) δ 9.62 (s, 1H), 8.42 (dd, J = 9.2, 4.7 Hz, 1H), 7.82 (ddd, J = 10.0, 7.6, 2.7 Hz, 1H), 7.34–7.12 (m, 3H), 6.96 (dd, J = 10.2, 2.7 Hz, 1H), 3.76 (s, 3H), 1.58–1.43 (m, 1H), 0.91 (dt, J = 8.2, 3.3 Hz, 2H), 0.85–0.66 (m, 2H); LCMS (m/z) 376.3.

Example 428. N-(3-(3,3-dimethylbut-1-yn-1-yl)phenyl)-7-fluoro-N-methyl-[1,2,4]triazole [4,3-a]quinazolin-5-amine

The title compound was synthesized according to the general procedure described for Example 421: ^¹H NMR (400 MHz, methanol- _d⁴ ) δ 9.60 (s, 1H), 8.41 (dd, J = 9.2, 4.8 Hz, 1H), 7.81 (ddd, J = 9.2, 7.5, 2.7 Hz, 1H), 7.61–7.37 (m, 4H), 6.83 (dd, J = 10.5, 2.7 Hz, 1H), 3.80 (s, 3H), 1.32 (s, 9H); LCMS (m/z) 374.3.

Example 429. N-(3-(cyclopropylethynyl)phenyl)-7-fluoro-N-methyl-[1,2,4]triazolo[4,3-a]quinoline Azoline-5-amine

The title compound was synthesized according to the general procedure described for Example 421: ¹H NMR (400 MHz, methanol- _d⁴ ) δ 9.60 (s, ¹H), 8.41 (dd, J = 9.2, 4.7 Hz, ¹H), 7.86–7.73 (m, ¹H), 7.64–7.32 (m, 4H), 6.81 (dd, J = 10.5, 2.7 Hz, ¹H), 3.79 (s, 3H), 1.48 (ddd, J = 8.2, 5.0, 3.3 Hz, ¹H), 0.97–0.85 (m, 2H), 0.76 (dt, J = 4.9, 3.1 Hz, 2H); LCMS (m/z) 358.3.

Example 430. N-(3-bromo-5-fluorophenyl)-7-fluoro-N-methyl-[1,2,4]triazolo[4,3-a]quinazolin-5- amine

The title compound was synthesized according to the general procedure described for Example 409: ^¹H NMR (400 MHz, methanol- _d⁴ ) δ 9.65 (s, 1H), 8.45 (dd, J = 9.2, 4.7 Hz, 1H), 7.84 (ddd, J = 9.2, 7.6, 2.7 Hz, 1H), 7.56 (dd, J = 7.1, 2.2 Hz, 2H), 7.38 (dt, J = 9.3, 2.2 Hz, 1H), 7.00 (dd, J = 10.0, 2.7 Hz, 1H), 3.78 (s, 3H); LCMS (m/z) 390.2.

Example 431. N-(3-bromophenyl)-7-fluoro-N-methyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine

The title compound was synthesized according to the general procedure described for Example 409: ^¹H NMR (400 MHz, methanol- _d⁴ ) δ 9.63 (s, 1H), 8.43 (dd, J = 9.2, 4.8 Hz, 1H), 7.82 (ddd, J = 9.2, 7.5, 2.7 Hz, 1H), 7.74 (tq, J = 3.1, 1.8 Hz, 2H), 7.60–7.47 (m, 2H), 6.86 (dd, J = 10.3, 2.7 Hz, 1H), 3.80 (s, 3H); LCMS (m/z) 372.2.

Example 432. N-(4'-(tert-butyl)-[1,1'-diphenyl]-3-yl)-8-chloro-7-fluoro-N-methyl-[1,2,4] Triazolo[4,3-a]quinazolin-5-amine

Synthesis of 7-chloro-6-fluoroquinazoline-2,4(1H,3H)-dione: 2-amino-4-chloro-5-fluorobenzoic acid (10 g, 51.7 mmol) was dissolved in AcOH (100 mL) and slowly treated with a solution of potassium cyanate (8.7 g, 103 mmol) in water (100 mL). After stirring at room temperature for 24 hours, water (500 mL) was added. The resulting precipitate was collected by filtration and washed with water. The resulting substance was suspended in MeOH (500 mL) and 3N NaOH (110 mL) was added. The suspension was stirred at room temperature for 12 hours, after which the reaction mixture was adjusted to pH ~3 with 6N HCl. The resulting substance was collected by filtration, washed with water (100 mL), and dried under high vacuum to provide the desired product: MS (m/z) 215.0 [M+H] ⁺ .

Synthesis of 2,4,7-trichloro-6-fluoroquinazoline: Phosphoryl chloride (3.25 mL, 34.9 mmol) was added dropwise to a mixture of 7-chloro-6-fluoroquinazoline-2,4(1H,3H)-dione (1 g, 4.66 mmol) and DIPEA (1.51 mL, 8.68 mmol) at room temperature, and the mixture was stirred for 5 minutes and then heated at 100 °C for 3 hours. The mixture was then carefully poured onto crushed ice and stirred vigorously until a suspension was formed. DCM was added to the mixture and transferred to a separatory funnel. The aqueous layer was extracted with DCM (×2), and the combined organic layers were washed with 10% citric acid solution (aqueous solution), washed with brine, and dried over _Na₂SO₄ . The solvent was removed under _reduced pressure and dried under reduced pressure to provide 2,4,7-trichloro-6-fluoroquinazoline: MS (m/z) 252.4 [M+H] ^⁺ .

Synthesis of N-(3-bromophenyl)-2,7-dichloro-6-fluoro-N-methylquinazoline-4-amine: DIPEA (1.52 mL, 8.55 mmol) was added to a solution of 2,4,7-trichloro-6-fluoroquinazoline (860 mg, 3.42 mmol) and 3-bromo-N-methylaniline (636 mg, 3.42 mmol) in DMF (5.0 mL) at room temperature. The resulting mixture was stirred at room temperature for 2 hours. After completion, the reaction mixture was poured into water and transferred to a separatory funnel and extracted with EA (× ₃ ). The combined organic layers were washed with brine, dried over _Na₂SO₄ , and concentrated under reduced pressure to provide the crude product. The residue was suspended in heptane, filtered, and further dried under vacuum to provide the desired product: MS (m/z) 402.0 [M+H] ^⁺ .

Synthesis of (E)-N-(3-bromophenyl)-7-chloro-6-fluoro-2-hydrazinyl-N-methyl-1,2-dihydroquinazoline-4-amine: Hydrazine (1470 mg, 39.5 mmol) was added to a solution of N-(3-bromophenyl)-2,7-dichloro-6-fluoro-N-methylquinazoline-4-amine (1470 mg, 3.67 mmol) in THF (20 mL) and ethanol (20 mL) at 0 °C. The resulting mixture was stirred at room temperature for 30 min. After completion, the reactants were concentrated under reduced pressure and dried under vacuum to provide the product: MS (m/z) 398.0 [M+H] ⁺ .

Synthesis of N-(3-bromophenyl)-8-chloro-7-fluoro-N-methyl-[1,2,4]triazolo[4,3-a]quinazoline-5-amine: A solution of (E)-N-(3-bromophenyl)-7-chloro-6-fluoro-2-hydrazyl-N-methyl-1,2-dihydroquinazoline-4-amine (1400 mg, 3.53 mmol) and triethyl orthoformate (6.27 g, 42.4 mmol) was heated to 100 °C for 1 hour. After completion, the reactants were cooled to room temperature and concentrated under reduced pressure to provide a crude product. The crude product was ground with heptane. The resulting substance was collected by filtration, washed with heptane:ether (1:1), and dried under vacuum to provide compound 432-1.

Synthesis of N-(4'-(tert-butyl)-[1,1'-diphenyl]-3-yl)-8-chloro-7-fluoro-N-methyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine: To a solution of N-(3-bromophenyl)-8-chloro-7-fluoro-N-methyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine (compound 432-1, 25.0 mg, 0.062 mmol) in dioxane (1.0 mL), 2 M solution of (4-(tert-butyl)phenyl)boronic acid (24.2 mg, 0.14 mmol), tetra(triphenylphosphine)palladium (0) (2.16 mg, 1.9 μmmol) and _Na₂CO₃ (aqueous) (0.154 _mL , 0.307 mmol) was added, and the mixture was purged with nitrogen and heated at 80 °C for 20 min. After completion, the mixture was diluted with EA, filtered, and concentrated under reduced pressure. The crude product was dissolved in DMSO and purified by reversed-phase HPLC, providing the title compound: ^¹H NMR (400 MHz, DMSO- _d⁶ ) δ 9.74 (s, 1H), 8.83 (d, J = 6.6 Hz, 1H), 7.71 (dd, J = 4.3, 2.3 Hz, 2H), 7.59 (dd, J = 8.2, 4.6 Hz, 3H), 7.49–7.36 (m, 3H), 6.99 (d, J = 10.9 Hz, 1H), 3.67 (s, 3H), 1.29 (s, 9H); LCMS (m/z) 460.2.

Example 433. 8-Chloro-7-fluoro-N-[3-[2-fluoro-4-(trifluoromethyl)phenyl]phenyl]-N-methyl-[1,2,4] Triazolo[4,3-a]quinazolin-5-amine

The title compound was prepared starting with N-(3-bromophenyl)-8-chloro-7-fluoro-N-methyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine and 2-[2-fluoro-4-(trifluoromethyl)phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentane, according to the method provided for Synthesis Example 432. ^¹H NMR (400 MHz, DMSO- _d⁶ ) δ 9.72 (s, 1H), 8.83 (d, J = 6.6 Hz, 1H), 7.82–7.71 (m, 2H), 7.69–7.59 (m, 4H), 7.55 (dt, J = 7.7, 1.9 Hz, 1H), 7.03 (d, J = 10.8 Hz, 1H), 3.65 (s, 3H); LCMS (m/z) 490.1.

Example 434. 8-Chloro-7-fluoro-N-methyl-N-[3-[4-(trifluoromethyl)phenyl]phenyl]-[1,2,4]triazole [4,3-a]quinazolin-5-amine

The title compound was prepared starting with N-(3-bromophenyl)-8-chloro-7-fluoro-N-methyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine and (trifluoromethyl)phenyl]boronic acid, according to the method provided for synthesis Example 432. ^¹H NMR (400 MHz, DMSO- _d⁶ ) δ 9.73 (s, 1H), 8.83 (d, J = 6.6 Hz, 1H), 7.97–7.76 (m, 7H), 7.62 (t, J = 7.9 Hz, 1H), 7.53–7.42 (m, 1H), 7.04 (d, J = 10.7 Hz, 1H), 3.67 (s, 3H); LCMS (m/z) 472.1.

Example 435. 8-Chloro-7-fluoro-N-methyl-N-[3-[6-(trifluoromethyl)-3-pyridyl]phenyl]-[1,2,4] Triazolo[4,3-a]quinazolin-5-amine

To a solution of N-(3-bromophenyl)-8-chloro-7-fluoro-N-methyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine (compound 432-1, 25 mg, 0.062 mmol) in dioxane (2 mL), a 2 M solution of [6-(trifluoromethyl)-3-pyridyl]boronic acid (24.6 mg, 0.13 mmol), Pd(dppf) _Cl₂ (2.54 mg, 3.07 μmol), and _Na₂CO₃ (aqueous) (0.154 _mL , 0.307 mmol) was added. The mixture was purged with nitrogen and heated at 80 °C for 20 min. After completion, the mixture was diluted with EA, filtered, and concentrated under reduced pressure. The crude product was dissolved in DMSO and purified by reversed-phase HPLC, providing the title compound: ^¹H NMR (400MHz, DMSO- _d⁶ ) δ 9.74 (s, 1H), 9.08 (d, J = 2.2Hz, 1H), 8.84 (d, J = 6.6Hz, 1H), 8.39 (dd, J = 8.2, 2.2Hz, 1H), 7.98 (d, J = 8.2Hz, 1H), 7.93 (d, J = 1.9Hz, 1H), 7.85 (d, J = 7.7Hz, 1H), 7.65 (t, J = 7.9Hz, 1H), 7.53 (dd, J = 8.1, 2.1Hz, 1H), 7.07 (d, J = 10.7Hz, 1H), 3.67 (s, 3H); LCMS (m/z) 473.1.

Example 436. 8-Chloro-N-[3-(6-cyclopropyl-3-pyridyl)phenyl]-7-fluoro-N-methyl-[1,2,4]triazole [4,3-a]quinazolin-5-amine

The title compound was prepared by starting with N-(3-bromophenyl)-8-chloro-7-fluoro-N-methyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine and (6-cyclopropyl-3-pyridyl)boronic acid, according to the method provided for synthesis Example 435. ¹ H NMR (400MHz, DMSO-d ₆ )δ9.70(s,1H),8.81(d,J＝6.6Hz,1H),8.70(d,J＝2.3Hz,1H),8.00(d,J＝8 .1Hz,1H),7.76(s,1H),7.72(d,J＝7.9Hz,1H),7.58(t,J＝7.8Hz,1H),7.41 (dd, J＝17.8, 7.9Hz, 2H), 7.04 (d, J＝10.7Hz, 1H), 2.14 (dd, J＝8.6, 4.1Hz, 1H), 1.00 (d, J＝8.0Hz, 2H), 0.95 (dd, J＝5.0, 2.5Hz, 2H); LCMS (m/z) 445.1.

Example 437. 3-Chloro-4-[3-[(8-chloro-7-fluoro-[1,2,4]triazolo[4,3-a]quinazolin-5-yl)-methyl [-amino]phenyl]benzyl nitrile

The title compound was prepared starting with N-(3-bromophenyl)-8-chloro-7-fluoro-N-methyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine and (2-chloro-4-cyanophenyl)boronic acid, according to the method provided for synthesis Example 435. ^¹H NMR (400 MHz, DMSO- _d⁶ ) δ 9.72 (s, 1H), 8.83 (d, J = 6.6 Hz, 1H), 8.15 (d, J = 1.6 Hz, 1H), 7.91 (dd, J = 7.9, 1.7 Hz, 1H), 7.76–7.53 (m, 3H), 7.54–7.41 (m, 2H), 7.05 (d, J = 10.7 Hz, 1H), 3.64 (s, 3H); LCMS (m/z) 463.0.

Example 438. N-[3-(6-amino-3-pyridyl)phenyl]-8-chloro-7-fluoro-N-methyl-[1,2,4]triazolidine [4,3-a]quinazolin-5-amine

The title compound was prepared by starting with N-(3-bromophenyl)-8-chloro-7-fluoro-N-methyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine and 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)pyridine-2-amine, according to the method provided for synthesis Example 435. ¹ H NMR (400MHz, DMSO-d ₆ )δ9.68(s,1H),8.80(d,J＝6.6Hz,1H),8.27(d,J＝8.9Hz,2H),7.98(s,2H),7.73(d,J＝2.0Hz,1H),7.65(d,J＝7.8Hz,1 H), 7.55 (t, J＝7.9Hz, 1H), 7.40 (dd, J＝7.9, 2.1Hz, 1H), 7.03 (dd, J＝16.9, 9.9Hz, 2H), 3.62 (s, 3H); LCMS (m/z) 420.1.

Example 439. N-[3-(2-aminopyrimidin-5-yl)phenyl]-8-chloro-7-fluoro-N-methyl-[1,2,4]triazolidine [4,3-a]quinazolin-5-amine

The title compound was prepared by starting with N-(3-bromophenyl)-8-chloro-7-fluoro-N-methyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine and 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)pyrimidine-2-amine, according to the method provided for synthesis Example 435. ¹ H NMR (400MHz, DMSO-d ₆ )δ9.74(s,1H),8.83(d,J＝6.6Hz,1H),8.61(s,2H),7.79–7.63(m,2H),7.53(t,J＝7.9Hz,1 H), 7.44–7.29 (m, 1H), 7.02 (d, J = 10.8Hz, 1H), 6.96 (s, 2H), 3.65 (s, 3H); LCMS (m/z) 421.1.

Example 440. 8-Chloro-7-fluoro-N-methyl-N-[3-(4-propoxyphenyl)phenyl]-[1,2,4]triazolo[4, [3-a]quinazolin-5-amine

The title compound was prepared by starting with N-(3-bromophenyl)-8-chloro-7-fluoro-N-methyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine and (4-propoxyphenyl)boronic acid, according to the method provided for synthesis Example 435. ¹ H NMR (400MHz, DMSO-d ₆ )δ9.71(s,1H),8.81(d,J＝6.6Hz,1H),7.77–7.69(m,2H),7.68–7.63(m,2H),7.57(t,J＝7.8Hz,1H),7.43–7.34(m,3H),7. 02 (d, J = 10.8 Hz, 1H), 4.48 (s, 2H), 3.65 (d, J = 6.5 Hz, 3H), 3.48 (q, J = 7.0 Hz, 2H), 1.15 (t, J = 7.0 Hz, 3H); LCMS (m/z) 462.1.

Example 441. 8-Chloro-7-fluoro-N-methyl-N-[3-[4-(trifluoromethoxy)phenyl]phenyl]-[1,2,4]tri Azo[4,3-a]quinazolin-5-amine

The title compound was prepared starting with N-(3-bromophenyl)-8-chloro-7-fluoro-N-methyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine and [4-(trifluoromethoxy)phenyl]boronic acid, according to the method provided for synthesis Example 435. ^¹H NMR (400 MHz, DMSO- _d⁶ ) δ 9.72 (s, 1H), 8.82 (d, J = 6.6 Hz, 1H), 7.86–7.76 (m, 3H), 7.76–7.70 (m, 1H), 7.58 (q, J = 7.2, 6.5 Hz, 2H), 7.48–7.42 (m, 3H), 7.03 (d, J = 10.7 Hz, 1H), 3.66 (s, 3H); LCMS (m/z) 488.1.

Example 442. 8-Chloro-7-fluoro-N-methyl-N-[3-[6-(2,2,2-trifluoroethoxy)-3-pyridyl]benzene [1,2,4]triazolo[4,3-a]quinazolin-5-amine

The title compound was prepared by starting with N-(3-bromophenyl)-8-chloro-7-fluoro-N-methyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine and [6-(2,2,2-trifluoroethoxy)-3-pyridyl]boronic acid, according to the method provided for synthesis Example 435. ¹ H NMR (400MHz, DMSO-d ₆ )δ9.72(s,1H),8.82(d,J＝6.6Hz,1H),8.51(d,J＝2.6Hz,1H),8.13(dd,J＝8.6,2.6Hz,1H),7.78(d,J＝2.1Hz,1H),7.73(d,J＝7.9Hz, 1H), 7.57 (d, J＝7.9Hz, 1H), 7.48–7.37 (m, 1H), 7.05 (dd, J＝12.0, 9.7Hz, 2H), 5.03 (q, J＝9.1Hz, 2H), 3.65 (s, 3H); LCMS (m/z) 503.1.

Example 443. 8-Chloro-7-fluoro-N-[3-(5-fluoro-6-methoxy-3-pyridyl)phenyl]-N-methyl-[1,2, 4] Triazolo[4,3-a]quinazolin-5-amine

The title compound was prepared by starting with N-(3-bromophenyl)-8-chloro-7-fluoro-N-methyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine and (5-fluoro-6-methoxy-3-pyridyl)boronic acid, according to the method provided for synthesis Example 435. ¹ HNMR (400MHz, DMSO-d ₆ )δ9.75(s,1H),8.84(d,J＝6.6Hz,1H),8.34(d,J＝2.1Hz,1H),8.09(dd,J＝11.9,2.1Hz,1H),7.86–7.76(m,2H),7.58 (t, J＝7.9Hz, 1H), 7.43 (dd, J＝8.0, 2.1Hz, 1H), 7.03 (d, J＝10.7Hz, 1H), 3.97 (s, 3H), 3.66 (s, 3H); LCMS (m/z) 453.1.

Example 444. 8-Chloro-N-[3-(6-ethoxy-3-pyridyl)phenyl]-7-fluoro-N-methyl-[1,2,4]triazole [4,3-a]quinazolin-5-amine

The title compound was prepared by starting with N-(3-bromophenyl)-8-chloro-7-fluoro-N-methyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine and 2-ethoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentane-2-yl)pyridine, according to the method provided for Synthesis Example 435. ¹ H NMR (400MHz, DMSO-d ₆ )δ9.74(s,1H),8.83(d,J＝6.6Hz,1H),8.46(d,J＝2.6Hz,1H),8.01(dd,J＝8.7,2.7Hz,1H),7.79–7.68(m,2H),7.58(t,J＝7.9Hz,1H),7.42(dd, J＝8.0,2.2Hz,1H),7.02(d,J＝10.8Hz,1H),6.86(d,J＝8.6Hz,1H),4.32(q,J＝7.0Hz,2H),3.66(s,3H),1.32(t,J＝7.1Hz,3H); LCMS (m/z) 449.1.

Example 445. 8-Chloro-7-fluoro-N-methyl-N-[3-(4-methylsulfonylphenyl)phenyl]-[1,2,4]triazole [4,3-a]quinazolin-5-amine

The title compound was prepared by starting with N-(3-bromophenyl)-8-chloro-7-fluoro-N-methyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine and (4-methylsulfonylphenyl)boronic acid, according to the method provided for synthesis Example 435. ¹ H NMR (400MHz, DMSO-d ₆ )δ9.74(s,1H),8.83(d,J＝6.6Hz,1H),8.05–7.92(m,4H),7.86(t,J＝2.0Hz,1H),7.81(dt,J＝8.0,1.2Hz,1H),7.63(t, J＝7.9Hz, 1H), 7.50 (ddd, J＝8.0, 2.2, 1.0Hz, 1H), 7.03 (d, J＝10.8Hz, 1H), 3.68 (s, 3H), 3.24 (s, 3H); LCMS (m/z) 482.2.

Example 446. 8-Chloro-N-[3-[6-(difluoromethyl)-3-pyridyl]phenyl]-7-fluoro-N-methyl-[1,2,4] Triazolo[4,3-a]quinazolin-5-amine

Synthesis of 2,7-dichloro-6-fluoro-N-(3-iodophenyl)-N-methylquinazoline-4-amine: DIPEA (1.35 mL, 7.56 mmol) was added to a solution of 2,4,7-trichloro-6-fluoroquinazoline (760 mg, 3.02 mmol) and 3-iodo-N-methylaniline (704 mg, 3.02 mmol) in DMF (5.0 mL) at room temperature. The resulting mixture was stirred at room temperature for 2 hours. After completion, the reaction mixture was poured into water and transferred to a separatory funnel and extracted with EA (× ₃ ). The combined organic layers were washed with brine, dried over _Na₂SO₄ , and concentrated under reduced pressure to provide a crude product. The residue was suspended in heptane, filtered, and further dried under vacuum to provide the desired compound: MS (m/z) 449.0 [M+H] ^⁺ .

Synthesis of (E)-N-(3-iodophenyl)-7-chloro-6-fluoro-2-hydrazinyl-N-methyl-1,2-dihydroquinazoline-4-amine: Hydrazine (503 mg, 15.7 mmol) was added to a solution of 2,7-dichloro-6-fluoro-N-(3-iodophenyl)-N-methylquinazoline-4-amine (653 mg, 1.46 mmol) in THF (10 mL) and ethanol (10 mL) at 0 °C. The resulting mixture was stirred at room temperature for 30 min. After completion, the reactants were concentrated under reduced pressure and dried under vacuum to provide the product: MS (m/z) 444.0 [M+H] ⁺ .

Synthesis of N-(3-iodophenyl)-8-chloro-7-fluoro-N-methyl-[1,2,4]triazolo[4,3-a]quinazoline-5-amine (compound 446-1): A solution of (E)-N-(3-iodophenyl)-7-chloro-6-fluoro-2-hydrazyl-N-methyl-1,2-dihydroquinazoline-4-amine (647 mg, 1.46 mmol) and triethyl orthoformate (2.59 g, 17.5 mmol) was heated to 100 °C for 1 hour. After completion, the reactants were cooled to room temperature and concentrated under reduced pressure to provide a crude product. The crude product was ground with heptane. The resulting material was collected by filtration, washed with heptane:ether (1:1), and dried under vacuum to provide the desired compound: MS (m/z) 454.0 [M+H] ⁺ .

The title compound was prepared by starting with N-(3-iodophenyl)-8-chloro-7-fluoro-N-methyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine and 2-(difluoromethyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)pyridine, according to the method provided for synthesis Example 435. ¹ H NMR (400MHz, DMSO-d ₆ )δ9.74(s,1H),8.99(d,J＝2.2Hz,1H),8.83(d,J＝6.6Hz,1H),8.30(dd,J＝8.2,2.3Hz,1H),7.93–7.86(m,1H),7.83(d,J＝7.7 Hz, 1H), 7.77 (d, J = 8.2 Hz, 1H), 7.63 (t, J = 7.9 Hz, 1H), 7.56–7.43 (m, 1H), 7.17–6.80 (m, 2H), 3.67 (s, 3H); LCMS (m/z) 455.1.

Example 447. 8-Chloro-7-fluoro-N-methyl-N-[3-[2-(1-methylcyclopropyl)ethynyl]phenyl]-[1,2, 4] Triazolo[4,3-a]quinazolin-5-amine

To a solution of N-(3-iodophenyl)-8-chloro-7-fluoro-N-methyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine (compound 446-1, 25 mg, 0.055 mmol) in DMF (2 mL), 1-ethynyl-1-methyl-cyclopropane (5.3 mg, 0.07 mmol), Pd( _PPh3 ) _{2Cl2 (} 1.55 mg, 2.2 μmol), CuI (0.3 mg, 0.03 mmol), and triethylamine (0.7 mL, 5.51 mmol) were added, and the mixture was purged with nitrogen and heated at 84 °C for 10 min. Afterward, the mixture was partitioned between EA (20 mL) and water (20 mL), the organic matter was separated, and the mixture was _dried over _Na2SO4 . The result was concentrated under reduced pressure. The crude product was dissolved in DMSO and purified by reversed-phase HPLC, providing the title compound: ^¹H NMR (400MHz, DMSO- _d⁶ ) δ 9.72 (s, ¹H), 8.83 (d, J = 6.6 Hz, ¹H), 7.46–7.38 (m, 2H), 7.35 (dd, J = 6.9, 1.8 Hz, 2H), 6.97 (d, J = 10.7 Hz, 1H), 3.56 (s, 3H), 1.29 (s, 3H), 0.92 (q, J = 3.9 Hz, 2H), 0.77–0.57 (m, 2H); LCMS (m/z) 406.1.

Example 448. 4-[3-[(8-chloro-7-fluoro-[1,2,4]triazolo[4,3-a]quinazolin-5-yl)-methyl-amino [By]-2-methyl-but-3-yn-2-ol

The title compound was prepared starting with N-(3-iodophenyl)-8-chloro-7-fluoro-N-methyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine (compound 446-1) and 2-methylbut-3-yn-2-ol, according to the method provided for synthesis Example 447. ^¹H NMR (400 MHz, DMSO- _d⁶ ) δ 9.73 (s, 1H), 8.84 (d, J = 6.7 Hz, 1H), 7.51–7.43 (m, 2H), 7.40 (d, J = 7.9 Hz, 2H), 6.97 (dd, J = 10.8, 1.6 Hz, 1H), 3.58 (s, 3H), 1.44 (s, 6H); LCMS (m/z) 410.1.

Example 449. 1-[2-[3-[(8-chloro-7-fluoro-[1,2,4]triazolo[4,3-a]quinazolin-5-yl)-methyl- [Amino]phenyl]ethynyl]cyclopropanol

The title compound was prepared starting with N-(3-iodophenyl)-8-chloro-7-fluoro-N-methyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine (compound 446-1) and 1-ethynylcyclopropanol, according to the method provided for synthesis Example 447. ^¹H NMR (400 MHz, DMSO- _d⁶ ) δ 9.70 (s, 1H), 8.82 (d, J = 6.6 Hz, 1H), 7.50–7.41 (m, 2H), 7.40–7.33 (m, 2H), 6.98 (d, J = 10.7 Hz, 1H), 3.61–3.52 (m, 3H), 0.97 (dd, J = 3.3, 2.1 Hz, 2H), 0.94 (dd, J = 3.2, 2.2 Hz, 2H); LCMS (m/z) 408.1.

Example 450. 8-Chloro-N-[3-(2-cyclopropylethynyl)phenyl]-7-fluoro-N-methyl-[1,2,4]triazolidine [4,3-a]quinazolin-5-amine

The title compound was prepared by starting with N-(3-iodophenyl)-8-chloro-7-fluoro-N-methyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine (compound 446-1) and ethynylcyclopropane, according to the method provided for synthesis Example 447. ¹ H NMR (400MHz, DMSO-d ₆ )δ9.71(s,1H),8.83(d,J＝6.6Hz,1H),7.48–7.39(m,2H),7.39–7.33(m,2H),6.97(d,J＝10.7Hz,1H),3.5 6(s,3H),1.52(tt,J＝8.3,5.0Hz,1H),0.96–0.84(m,2H),0.72(dq,J＝5.0,3.9Hz,2H); LCMS(m/z)392.1.

Example 451. 8-Chloro-N-[3-(5-cyclopropylpyrazin-2-yl)phenyl]-7-fluoro-N-methyl-[1,2,4]triazole [4,3-a]quinazolin-5-amine

The title compound was prepared by starting with N-(3-iodophenyl)-8-chloro-7-fluoro-N-methyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine (compound 446-1) and 2-cyclopropyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentane-2-yl)pyrazine, according to the method provided for synthesis Example 435. ¹ H NMR (400MHz, DMSO-d ₆ )δ9.70(s,1H),9.03(d,J＝1.5Hz,1H),8.81(d,J＝6.6Hz,1H),8.66(d,J＝1.5Hz,1H),8.13–8.05(m,2H),7.60(t,J＝8.1Hz,1H),7.52–7.42( m,1H),7.04(d,J＝10.8Hz,1H),3.64(s,3H),2.24(td,J＝8.2,4.2Hz,1H),1.07(dt,J＝8.0,3.1Hz,2H),1.01–0.93(m,2H); LCMS(m/z)446.1.

Example 452. 8-Chloro-N-ethyl-N-[3-(4-methylsulfonylphenyl)phenyl]-[1,2,4]triazolo[4, [3-a]quinazolin-5-amine

The title compound was prepared by starting with N-(3-bromophenyl)-8-chloro-N-ethyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine and (4-methylsulfonylphenyl)boronic acid, according to the method provided for Synthesis Example 455. ¹ H NMR (400MHz, DMSO-d ₆ )δ9.77(s,1H),8.61(d,J＝2.1Hz,1H),8.01–7.90(m,4H),7.83(t,J＝2.0H z,1H),7.79(dd,J＝7.7,1.3Hz,1H),7.61(t,J＝7.9Hz,1H),7.47(ddd,J＝8. 0, 2.2, 1.0Hz, 1H), 7.38 (dd, J = 9.0, 2.1Hz, 1H), 7.23 (d, J = 9.0Hz, 1H), 4.26 (q, J = 6.9Hz, 2H), 3.24 (s, 3H), 1.29 (t, J = 7.0Hz, 3H); LCMS (m/z) 478.1.

Example 453. 4-[3-[(8-chloro-[1,2,4]triazolo[4,3-a]quinazolin-5-yl)-ethyl-amino]benzene ]-2-methyl-but-3-yn-2-ol

To a solution of N-(3-bromophenyl)-8-chloro-N-ethyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine (compound 455-1, 25 mg, 0.62 mmol) in DMF (2 mL), 2-methylbut-3-yn-2-ol (52 mg, 0.06 mmol), Pd(dppf) _Cl₂ (5.13 mg, 6.2 μmol), zinc dibromide (70 mg, 0.31 mmol), and _Et₃N (0.173 mL, 1.24 mmol) were added. The mixture was purged with nitrogen and heated at 100 °C for 10 min. After completion, the reaction mixture was poured into water and transferred to a separatory funnel and extracted with EA (×3). The combined organic layers were washed with brine, dried over _{Na₂SO₄ ,} and concentrated under reduced pressure to provide the crude product. The crude product was dissolved in DMSO and purified by reversed-phase HPLC, providing the title compound: ^¹H NMR (400MHz, DMSO- _d⁶ ) δ 9.74 (s, 1H), 8.61 (d, J = 2.1Hz, 1H), 7.51–7.41 (m, 3H), 7.37 (t, J = 5.0Hz, 2H), 7.18 (d, J = 9.0Hz, 1H), 4.16 (q, J = 6.9Hz, 2H), 1.43 (s, 6H), 1.23 (t, J = 6.9Hz, 3H); LCMS (m/z) 406.1.

Example 454. 8-Chloro-7-fluoro-N-[3-(5-methoxypyrazin-2-yl)phenyl]-N-methyl-[1,2,4]triazole [4,3-a]quinazolin-5-amine

The title compound was prepared by starting with N-(3-iodophenyl)-8-chloro-7-fluoro-N-methyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine and 2-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentane-2-yl)pyrazine, according to the method provided for Synthesis Example 435. ¹ H NMR (400MHz, DMSO-d ₆ )δ9.72(d,J＝4.7Hz,1H),8.95–8.73(m,2H),8.37(d,J＝1.4Hz,1H),8.13–7.98(m,2H),7.61(t,J =8.0Hz,1H),7.53–7.42(m,1H),7.13–6.91(m,1H),3.95(s,3H),3.66(s,3H); LCMS(m/z)436.1.

Example 455. 8-Chloro-N-[3-[6-(difluoromethyl)-3-pyridyl]phenyl]-N-ethyl-[1,2,4]triazole [4,3-a]quinazolin-5-amine

Synthesis of N-(3-bromophenyl)-2,6,7-trichloro-N-ethyl-quinazoline-4-amine: DIPEA (1.91 mL, 10.7 mmol) was added to a solution of 2,4,7-trichloroquinazoline (1000 mg, 4.28 mmol) and 3-bromo-N-ethylaniline (998 mg, 4.99 mmol) in DMF (5.0 mL) at room temperature. The resulting mixture was stirred at 40 °C for 2 hours. After completion, the reaction mixture was poured into water and transferred to a separatory funnel and extracted with EA (×3). The combined organic layers were washed with brine, _dried over _Na₂SO₄ , and concentrated under reduced pressure to provide the crude product. The crude residue was purified by silica gel column chromatography using a solution of 0–30% EA in hexane as the eluent to provide the desired product: MS (m/z) 398.0 [M+H] ^⁺ .

Synthesis of N-(3-bromophenyl)-7-chloro-N-ethyl-2-hydrazino-quinazolin-4-amine at 0 °C: Hydrazine (412 mg, 12.9 mmol) was added to a solution of N-(3-bromophenyl)-2,7-dichloro-N-ethyl-quinazolin-4-amine (511 mg, 1.29 mmol) in THF (10 mL) and ethanol (10 mL). The resulting mixture was stirred at room temperature for 30 min. After completion, the reaction mixture was poured into water and transferred to a separatory funnel and extracted with DCM (×3). The combined organic layers were washed with brine, _dried over _Na₂SO₄ , and concentrated under reduced pressure to provide the crude product: MS (m/z) 393.0 [M+H] ^⁺ .

Synthesis of N-(3-bromophenyl)-8-chloro-N-ethyl-[1,2,4]triazolo[4,3-a]quinazoline-5-amine (compound 455-1): A solution of N-(3-bromophenyl)-7-chloro-N-ethyl-2-hydrazino-quinazoline-4-amine (450 mg, 1.15 mmol) and triethyl orthoformate (2.04 g, 13.8 mmol) was heated to 100 °C for 1 hour. After completion, the reactants were cooled to room temperature and concentrated under reduced pressure to provide a crude product. The crude product was ground with heptane, and the residue was collected by filtration, washed with heptane:ether (1:1), and dried under vacuum to provide the desired product: MS (m/z) 403.0 [M+H] ⁺ .

To a solution of N-(3-bromophenyl)-8-chloro-N-ethyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine (25 mg, 0.062 mmol) in dioxane (2 mL), a 2 M solution (0.154 mL, 0.307 mmol) of 2-(difluoromethyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborhexacyclopentan-2-yl)pyridine (15.8 mg, 0.06 mmol), Pd(dppf) _Cl₂ (2.57 mg, 3.1 μmol), and _{Na₂CO₃ (} aqueous) was added. The mixture was purged with nitrogen and heated at 80 °C for 20 min. After completion, the mixture was diluted with EA, filtered, and concentrated under reduced pressure. The crude product was dissolved in DMSO and purified by reversed-phase HPLC to provide the title compound: ^1H NMR (400MHz, DMSO-d6 ₎ )δ9.77(s,1H),8.97(d,J＝2.2Hz,1H),8.61(d,J＝2.1Hz,1H),8.28(dd,J＝8.2,2. 3Hz,1H),7.89(d,J＝2.0Hz,1H),7.80(dd,J＝16.7,8.0Hz,2H),7.61(t,J＝7.9Hz,1 H),7.50–7.41(m,1H),7.38(dd,J＝9.0,2.1Hz,1H),7.25(d,J＝9.0Hz,1H),7.00( t, J＝54.9Hz, 1H), 4.27 (q, J＝7.0Hz, 2H), 1.29 (t, J＝6.9Hz, 3H); LCMS (m/z) 451.1.

Example 456. 8-Chloro-7-fluoro-N-methyl-N-phenyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine

The title compound was synthesized according to the general procedure described for Example 11: ^¹H NMR (400MHz, DMSO- _d₆ ) δ 9.60 (s, 1H), 8.75 (d, J = 6.7 Hz, 1H), 7.47–7.41 (m, 2H), 7.38–7.30 (m, 3H), 6.90 (d, J = 10.8 Hz, 1H), 3.54 (s, 3H); LCMS (m/z) 328.1.

Example 457. 5-(4-(tert-butyl)phenyl)-N-(8-chloro-[1,2,4]triazolo[4,3-a]quinazolin-5- 2-N-methylthiazol-2-amine

A 1-molar solution of hexamethyldisilazonium azide in tetrahydrofuran (1.55 mL, 1.55 mmol) was added to a solution of 2,4,7-trichloroquinazoline (124 mg, 0.526 mmol) and 5-bromo-N-methylthiazol-2-amine hydrochloride (130.0 mg, 0.565 mmol) in tetrahydrofuran (5 mL). The reaction was stirred at -20 °C for one hour, and then partitioned between dichloromethane and water. The aqueous phase was extracted into dichloromethane, the combined organics were dried over sodium sulfate, filtered, and concentrated under reduced pressure to provide 186 mg of 5-bromo-N-(2,7-dichloroquinazoline-4-yl)-N-methylthiazol-2-amine, which was then transferred to the next step without further purification. ^1H NMR (400MHz, chloroform-d) δ 8.02 (d, J = 9.1Hz, 1H), 7.95 (d, J = 2.2Hz, 1H), 7.55–7.48 (m, 2H), 4.08 (s, 3H).

To a solution of 5-bromo-N-(2,7-dichloroquinazoline-4-yl)-N-methylthiazol-2-amine (186 mg, 0.477 mmol) in tetrahydrofuran (1.5 mL) and ethanol (0.8 mL), hydrazine hydrate (0.25 mL, 5.14 mmol) was added, and the mixture was stirred for 30 minutes. The reaction mixture was diluted with water and then extracted into dichloromethane. The organic phase was washed with brine, dried over sodium sulfate, and concentrated under reduced pressure to provide crude 5-bromo-N-(7-chloro-2-hydrazylquinazoline-4-yl)-N-methylthiazol-2-amine, which was then transferred to the next step without further purification.

A suspension of crude 5-bromo-N-(7-chloro-2-hydrazyl quinazolin-4-yl)-N-methylthiazolin-2-amine (maximum 0.477 mmol) and triethyl orthoformate (2.00 mL, 12.0 mmol) was stirred at 100 °C for 90 min. The reaction mixture was then cooled to room temperature, and hexane was added to the precipitated solid. The precipitated solid was collected by filtration and hexane grinding. The collected solid was purified by silica gel chromatography (0-100% ethyl acetate:hexane) to provide 5-bromo-N-(8-chloro-[1,2,4]triazolo[4,3-a]quinazolin-5-yl)-N-methylthiazolin-2-amine.

A solution of 5-bromo-N-(8-chloro-[1,2,4]triazolo[4,3-a]quinazolin-5-yl)-N-methylthiazol-2-amine (24.0 mg, 0.0607 mmol), (4-tert-butylphenyl)boronic acid (22.0 mg, 0.124 mmol), and 1,1'-bis(diphenylphosphine)ferrocene (11.0 mg, 0.0153 mmol) in dioxane (1 mL) and saturated sodium carbonate aqueous solution (0.1 mL) was stirred at 90 °C for 18 hours, and then at 120 °C for another 3.5 hours. The reaction mixture was concentrated under reduced pressure, dissolved in N,N-dimethylformamide, filtered through a syringe filter, and purified by preparative HPLC (10-100% acetonitrile in water, 0.1% TFA buffer) to provide the title compound: ^¹H NMR (400MHz, DMSO- _d⁶ ) δ 9.83 (s, 1H), 8.71 (d, J = 2.0Hz, 1H), 7.97 (d, J = 8.9Hz, 1H), 7.80 (s, 1H), 7.66 (dd, J = 8.9, 2.1Hz, 1H), 7.53 (d, J = 8.4Hz, 2H), 7.49–7.41 (m, 2H), 3.80 (s, 3H), 1.30 (s, 9H); LCMS (m/z) 449.3.

Example 458. 2-(4-(tert-butyl)phenyl)-N-(8-chloro-[1,2,4]triazolo[4,3-a]quinazolin-5- 5-N-methylthiazol-5-amine

A 1-molar solution of hexamethyldisilazonide in tetrahydrofuran (0.3 mL, 0.3 mmol) was added to a solution of 2,4,7-trichloroquinazoline (34 mg, 0.114 mmol) and 2-(4-(tert-butyl)phenyl)-N-methylthiazol-5-amine (35.7 mg, 0.145 mmol) in tetrahydrofuran (1 mL) cooled to -20 °C. The reaction was stirred at -20 °C for 30 min, and then partitioned between dichloromethane and water. The aqueous phase was extracted into dichloromethane, the combined organics were dried over sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel chromatography (0-20% ethyl acetate:hexane) to provide 2-(4-(tert-butyl)phenyl)-N-(2,7-dichloroquinazoline-4-yl)-N-methylthiazol-5-amine. ^1H NMR (400MHz, chloroform-d) δ 9.96 (d, J = 9.2Hz, 1H), 8.06–7.98 (m, 2H), 7.85 (d, J = 8.4Hz, 2H), 7.59 (dd, J = 9.2, 2.2Hz, 1H), 7.55 (d, J = 8.5Hz, 2H), 3.37 (s, 3H), 1.41 (s, 9H).

To a solution of 2-(4-(tert-butyl)phenyl)-N-(2,7-dichloroquinazoline-4-yl)-N-methylthiazol-5-amine (28 mg, 0.063 mmol) in tetrahydrofuran (1.6 mL) and ethanol (0.8 mL), hydrazine hydrate (0.05 mL, 1.03 mmol) was added, and the mixture was stirred for 2 hours. Then, additional hydrazine hydrate (0.05 mL, 1.03 mmol) was added, and stirring continued for 18 hours. The reaction mixture was diluted with water and then extracted into dichloromethane. The organic phase was washed with brine, dried over sodium sulfate, and concentrated under reduced pressure to provide crude 2-(4-(tert-butyl)phenyl)-N-(7-chloro-2-hydrazinoquinazoline-4-yl)-N-methylthiazol-5-amine, which was then transferred to the next step without further purification.

A suspension of crude 2-(4-(tert-butyl)phenyl)-N-(7-chloro-2-hydrazinoylquinazolin-4-yl)-N-methylthiazol-5-amine (maximum 0.063 mmol) and triethyl orthoformate (1.00 mL, 6.0 mmol) was stirred at 100 °C for 90 minutes. The reaction mixture was then cooled to room temperature, and hexane was added to the precipitate. The precipitate was collected by filtration and hexane was ground. The crude compound was purified by preparative HPLC (10-100% acetonitrile in water, 0.1% TFA buffer) to provide the following values for the title compound: ^¹H NMR (400MHz, DMSO- _d⁶ ) δ 10.10 (dd, J = 12.2, 7.2Hz, 2H), 9.78 (s, 1H), 8.61 (d, J = 2.1Hz, 1H), 7.90–7.79 (m, 3H), 7.56 (d, J = 8.3Hz, 2H), 3.30 (d, J = 4.9Hz, 3H), 1.35 (s, 9H); LCMS (m/z) 449.3.

Example 459. N-(3-bromophenyl)-7,8-difluoro-N-methyl-[1,2,4]triazolo[4,3-a]quinazolin-5- amine

Step 1: Synthesis of methyl 4,5-difluoro-2-ureo-benzoate: Methyl 2-amino-4,5-difluoro-benzoate (52.2 g, 273 mmol) was dissolved in acetic acid (350 mL) and slowly treated with a solution of potassium cyanate (46.2 g, 547 mmol) in water (150 mL). After stirring at room temperature for 20 hours, and then at 60 °C for 2 hours, 350 mL of water was added to the reaction mixture. The resulting precipitate was collected by filtration and washed with water. The precipitate was used directly in the next step.

Step 2: Synthesis of 6,7-difluoro-1H-quinazolin-2,4-dione: 109 mL of 3N sodium hydroxide aqueous solution was added to a suspension of the above-obtained substance in methanol (500 mL). The suspension was vigorously stirred at room temperature for 20 hours. 165 mL of 2N HCl aqueous solution was slowly added under vigorous stirring to adjust the pH to approximately 3. The solid was collected by filtration and then washed with water (50 mL). The filtrate was concentrated to remove most of the organic solvent. The precipitate was collected by filtration. The two batches were combined and dried on a lyophilizer for 24 hours to provide the desired product: ^¹H NMR (400 MHz, DMSO- _d₆ ) δ 11.48 (s, 1H), 11.27 (s, 1H), 7.84 (dd, J = 10.3, 8.5 Hz, 1H), 7.10 (dd, J = 11.1, 6.6 Hz, 1H).

Step 3: Synthesis of 2,4-dichloro-6,7-difluoro-quinazoline: 9.4 g (47.4 mmol) of 6,7-difluoro-1H-quinazoline-2,4-dione was added to 150 mL of toluene in a 1.0 L double-necked round-bottom flask. The mixture was treated with _POCl₃ (10.2 mL, 10⁹ mmol). The mixture was stirred at room temperature for 10 minutes, then heated to 55 °C. Tripropylamine (19 mL, 99.6 mmol) was added. After stirring at 55 °C for 10 minutes, the mixture was heated at 105 °C for 4 hours. After cooling to room temperature, the solution was slowly poured into 300 mL of water (containing 2 mL of 1N HCl aqueous solution) while stirring, and then diluted with toluene (200 mL). After stirring for 30 minutes, the aqueous layer was removed. The organic layer (with a debris layer) was filtered, and the filter cake was washed with toluene (50 mL) and water (40 mL). Separate the two filtrates. Wash the organic layer with water (200 mL × 2) and brine (200 mL) until pH > 3. Dry it with _MgSO4 and concentrate it to dryness to provide the desired product: ^¹H NMR (400 MHz, chloroform-d) δ 8.05 (dd, J = 9.4, 8.0 Hz, 1H), 7.80 (dd, J = 9.9, 7.2 Hz, 1H).

Step 4: Synthesis of N-(3-bromophenyl)-2-chloro-6,7-difluoro-N-methylquinazoline-4-amine: NaH (60% purity) (547 mg, 13.7 mmol) was added to a solution of 3-bromo-N-methylaniline (1.6 mL, 12.5 mmol) and 2,4-dichloro-6,7-difluoro-quinazoline (2.68 g, 11.4 mmol) in DMF (50 mL) at 0 °C. The reaction mixture was heated to room temperature and stirred for 4 hours. The mixture was quenched with ice-cold saturated aqueous _NH₄Cl solution (40 mL), diluted with EtOAc (150 mL), and washed with water (100 mL). The precipitate formed between the aqueous and organic layers was collected by filtration; this precipitate was the desired product. The organic layer was further washed with brine (50 mL), _dried over _Na₂SO₄ , and concentrated under vacuum. The residue was purified by column chromatography using a 0-35% EtOAc hexane solution to provide the desired product. The two batches of products were combined: [M+H] ⁺ = 384.2.

Step 5: Synthesis of N-(3-bromophenyl)-6,7-difluoro-2-hydrazino-N-methyl-quinazolin-4-amine: The product obtained from Step 4 (1.94 g, 5.0 mmol) was added to EtOH (21 mL) and THF (5 mL). Hydrazine monohydrate (7.5 mL, 150 mmol) was slowly added in portions, and the reaction mixture was stirred overnight at room temperature until the reaction was complete. The reaction mixture was diluted with EtOAc. The solution was washed continuously with water and brine, dried over _Na₂SO₄ , and concentrated under vacuum. The crude product was used in the next step without purification. [M+H] ^⁺ ₌ 380.2.

Step 6: Add triethyl orthoformate (4 mL) to the crude product obtained above. Stir the mixture at 100 °C for 16 hours. Concentrate the mixture under vacuum and add EtOAc (100 mL) to the resulting residue. Wash the solution continuously with water and brine, dry it with _{Na₂SO₄ ,} and concentrate it under vacuum. The crude product was purified by column chromatography using a DCM solution of 0-10% MeOH. The following values are provided for the title compound: ^¹H NMR (400 MHz, methanol- _d⁴ ) δ 9.43 (s, 1H), 8.33 (dd, J = 10.5, 7.0 Hz, 1H), 7.59 (t, J = 2.0 Hz, 1H), 7.55 (m, 1H), 7.39 (t, J = 8.0 Hz, 1H), 7.32 (m, 1H), 7.16 (dd, J = 11.8, 8.1 Hz, 1H), 3.66 (s, 3H); LCMS (m/z) 390.2.

Example 460. N-(4'-(tert-butyl)-[1,1'-diphenyl]-3-yl)-7,8-difluoro-N-methyl-[1,2,4] Triazolo[4,3-a]quinazolin-5-amine

DME (3 mL) and 2 M sodium carbonate aqueous solution (0.26 mL) were added to a mixture of N-(3-bromophenyl)-7,8-difluoro-N-methyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine (Example 459, 100 mg, 0.256 mmol), (4-tert-butylphenyl)boric acid (91 mg, 0.51 mmol), and Pd( _PPh3 ) ₄ (30 mg, 26 μmol). After degassing and refilling with nitrogen several times, the reaction mixture was heated at 80 °C for 6 hours. After cooling to room temperature, water and EtOAc were added. The two layers were separated, and the organic layer was dried and concentrated. The crude product was purified by column chromatography using 60–100% EtOAc in hexane, yielding the desired product: ^¹H NMR (400 MHz, methanol- _d⁴ ) δ 9.36 (s, ¹H), 8.32–8.20 (m, ¹H), 7.64 (dt, J = 7.9, 1.3 Hz, ¹H), 7.59–7.42 (m, 6H), 7.26 (m, 1H), 7.19–7.06 (m, 1H), 3.71 (s, 3H), 1.33 (s, 9H); LCMS (m/z) 444.4.

Example 461. 7,8-Difluoro-N-methyl-N-(4'-(trifluoromethyl)-[1,1'-diphenyl]-3-yl)-[1,2, 4] Triazolo[4,3-a]quinazolin-5-amine

Example 461 was prepared according to the procedure described in Example 460. ^¹H NMR (400 MHz, methanol- _d⁴ ) δ 9.37 (s, 1H), 8.27 (dd, J = 10.2, 7.0 Hz, 1H), 7.79–7.65 (m, 5H), 7.64–7.55 (m, 2H), 7.35 (m, 1H), 7.15 (dd, J = 11.8, 8.1 Hz, 1H), 3.73 (s, 3H); LCMS (m/z) 456.3.

Example 462. N5-(4'-(tert-butyl)-[1,1'-diphenyl]-3-yl)-7-fluoro-N5-methyl-[1,2,4]tri Azo[4,3-a]quinazolin-5,8-diamine

Step 1: Synthesis of 8-azido-N-[3-(4-tert-butylphenyl)phenyl]-7-fluoro-N-methyl-[1,2,4]triazolo[4,3-a]quinazoline-5-amine: A mixture of N-[3-(4-tert-butylphenyl)phenyl]-7,8-difluoro-N-methyl-[1,2,4]triazolo[4,3-a]quinazoline-5-amine (Example 460, 175 g, 0.40 mmol) and sodium azide (129 mg, 1.98 mmol) in DMSO (3 mL) was heated at 90 °C for 4 hours. EtOAc (100 mL) was added to the mixture and the solution was washed with water and brine. The organic layer was dried and concentrated to provide a crude product, which was used directly in the next step. [M+H] ⁺ = 467.1.

Step 2: Synthesis of N5-[3-(4-tert-butylphenyl)phenyl]-7-fluoro-N5-methyl-[1,2,4]triazolo[4,3-a]quinazoline-5,8-diamine: EtOH/EtOAc (3/3 mL) and 10% Pd/C (20 mg) were added to the product of Step 1. The reaction mixture was degassed and refilled several times with hydrogen (gas bag). It was then stirred overnight under hydrogen. Pd/C was filtered off. The filtrate was concentrated and purified by column chromatography using a DCM solution of 5–10% MeOH, providing the title compound: ^¹H NMR (400 MHz, methanol- _d⁴ ) δ 9.09 (s, 1H), 7.59 (dt, J = 7.8, 1.3 Hz, 1H), 7.53–7.47 (m, 3H), 7.46 (d, J = 3.3 Hz, 2H), 7.39 (d, J = 2.0 Hz, 1H), 7.23 (d, J = 7.6 Hz, 1H), 7.19 (m, 1H), 6.74 (dd, J = 13.1, 1.3 Hz, 1H), 3.67 (s, 3H), 1.33 (s, 9H); LCMS (m/z) 441.4.

Example 463. 7-Fluoro-N5-methyl-N5-(4'-(trifluoromethyl)-[1,1'-diphenyl]-3-yl)-[1,2,4] Triazolo[4,3-a]quinazolin-5,8-diamine

Example 463 was prepared starting from Example 461 according to the procedure described in Example 462. ^¹H NMR (400 MHz, methanol- _d⁴ ) δ 9.14 (s, 1H), 7.68 (s, 3H), 7.62 (d, J = 3.7 Hz, 2H), 7.57 (t, J = 7.8 Hz, 1H), 7.47 (t, J = 1.9 Hz, 1H), 7.30 (m, 1H), 7.24 (d, J = 7.7 Hz, 1H), 6.74 (d, J = 13.1 Hz, 1H), 3.69 (s, 3H); LCMS (m/z) 453.3.

Example 464. 7-Fluoro-N5-methyl-N5-(4'-(trifluoromethoxy)-[1,1'-diphenyl]-3-yl)-[1,2, 4] Triazolo[4,3-a]quinazolin-5,8-diamine

Example 464 was prepared starting from Example 465 according to the procedure described in Example 462. ^¹H NMR (400MHz, DMSO- _d⁶ ) δ 9.33 (s, 1H), 7.85–7.72 (m, 2H), 7.63 (t, J = 2.0Hz, 1H), 7.60–7.56 (m, 1H), 7.50 (t, J = 7.8Hz, 1H), 7.45–7.39 (m, 2H), 7.31–7.22 (m, 2H), 6.78 (d, J = 13.1Hz, 1H), 6.58 (s, 2H), 3.55 (s, 3H); LCMS (m/z) 469.3.

Example 465. 7,8-Difluoro-N-methyl-N-(4'-(trifluoromethoxy)-[1,1'-diphenyl]-3-yl)-[1, [2,4]triazolo[4,3-a]quinazolin-5-amine

Example 465 was prepared according to the procedure described in Example 460. ^¹H NMR (400 MHz, chloroform-d) δ 9.99 (s, 1H), 8.65 (m, 1H), 7.76–7.68 (m, 2H), 7.68–7.59 (m, 3H), 7.48 (dd, J = 9.7, 7.7 Hz, 1H), 7.30 (d, J = 8.1 Hz, 2H), 6.97 (dd, J = 11.7, 7.7 Hz, 1H), 3.86 (s, 3H); LCMS (m/z) 472.3.

Example 466. (5-((4'-(tert-butyl)-[1,1'-diphenyl]-3-yl)(methyl)amino)-7-fluoro-[1,2, 4] Triazolo[4,3-a]quinazolin-8-yl)methanol

Step 1: Synthesis of N-(4'-(tert-butyl)-[1,1'-diphenyl]-3-yl)-7-fluoro-N-methyl-8-((methylthio)(toluenesulfonyl)methyl)-[1,2,4]triazolo[4,3-a]quinazolin-5-amine: N-[3-(4-tert-butylphenyl)phenyl]-7,8-difluoro-N-methyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine (Example 460, 167 mg, 0.38 mmol) and 1-methyl-4-methylthioalkylmethylsulfonyl)benzene (163 mg, 0.75 mmol) were dissolved in DMF (6 mL). Sodium hydride (60%, 45 mg, 1.13 mmol) was added. The mixture was stirred at room temperature for 4 hours until complete. The mixture was poured into an ice-cold saturated _NH4Cl solution and diluted with EtOAc (100 mL). The organic layer was washed with brine, dried, and concentrated. The crude residue was purified by column chromatography using 80-100% EtOAc in hexane to obtain the desired product: [M+H] ⁺ = 640.1.

Step 2: Synthesis of 5-((4'-(tert-butyl)-[1,1'-diphenyl]-3-yl)(methyl)amino)-7-fluoro-[1,2,4]triazolo[4,3-a]quinazolin-8-carboxaldehyde: The product from Step 1 above was dissolved in 4 mL of MeOH in a 20 mL reaction tube, and concentrated HCl (12N) (1 mL) was added. The reaction tube was sealed and heated at 90 °C for 18 hours. THF (5 mL) was added and the mixture was concentrated. The addition and evaporation of THF were repeated four times to provide the desired aldehyde: [M+H] ⁺ = 454.4.

Step 3: Synthesis of N-[3-(4-tert-butylphenyl)phenyl]-7,8-difluoro-N-methyl-[1,2,4]triazolo[4,3-a]quinazoline-5-amine: The product obtained in Step 2 above was dissolved in THF (6 mL) and water (0.2 mL). 5 equivalents of _NaBH₄ were added, and the reaction mixture was stirred at room temperature for 4 hours. 5 mL of saturated _NaHCO₃ aqueous solution was added. The reaction mixture was extracted with EtOAc (30 mL) and DCM/EtOH (5/1, 30 mL × 2). The organic layers were combined, dried, and concentrated. The residue was purified by RP-HPLC to provide the desired product: ^¹H NMR (400 MHz, methanol- _d⁴ ) δ 9.60 (s, 1H), 8.42 (d, J = 6.2 Hz, 1H), 7.85–7.79 (m, 1H), 7.71–7.60 (m, 2H), 7.56–7.52 (m, 2H), 7.50–7.46 (m, 2H), 7.39 (m, 1H), 6.81 (d, J = 11.7 Hz, 1H), 4.79 (s, 2H), 3.85 (s, 3H), 1.35 (s, 9H); LCMS (m/z) 456.4.

Example 467. 3-[7-fluoro-5-(3-fluoro-N-methyl-aniline)-[1,2,4]triazolo[4,3-a]quinazolin- 8-yl]prop-1-ol

Step 1: Synthesis of methyl 4-bromo-5-fluoro-2-ureo-benzoate: Methyl 2-amino-4-bromo-5-fluoro-benzoate (20.0 g, 79.0 mmol) was dissolved in acetic acid (200 mL) and slowly treated with a solution of potassium cyanate (13.4 g, 158 mmol) in water (40 mL). After stirring at room temperature for 20 hours, and then at 60 °C for 2 hours, 250 mL of water was added to the reaction mixture. The resulting substance was collected by filtration and washed with water. It was used directly in the next step. [M+H] ⁺ = 290.77.

Step 2: Synthesis of 7-bromo-6-fluoro-1H-quinazolin-2,4-dione: Add 95 mL of 1N sodium hydroxide aqueous solution to the suspension of the product from Step 1 obtained above in methanol (300 mL). Stir the suspension vigorously at room temperature for 16 hours. Slowly add 49 mL of 2N HCl aqueous solution under vigorous stirring to adjust the pH to approximately 3. Collect the substance by filtration and wash with water (50 mL). Concentrate the filtrate to remove most of the organic solvent. Collect the precipitate by filtration. Combine the two batches and dry in a vacuum oven to provide the desired product: ^¹H NMR (400 MHz, DMSO- _d⁶ ) δ 11.51 (s, 1H), 11.25 (s, 1H), 7.77 (d, J = 34.5, 1H), 7.44 (d, J = 5.6 Hz, 1H).

Step 3: Synthesis of 7-bromo-2,4-dichloro-6-fluoro-quinazoline: In a 1-liter double-necked round-bottom flask, 6.4 g (24.7 mmol) of 7-bromo-6-fluoro-1H-quinazoline-2,4-dione was added to toluene (100 mL). The mixture was treated with _POCl₃ (5.3 mL, 56.8 mmol). The mixture was stirred at room temperature for 10 minutes, then heated to 55 °C. Tripropylamine (9.9 mL, 51.9 mmol) was added. After stirring at 55 °C for 10 minutes, the reaction mixture was heated at 105 °C for 5 hours. After cooling to room temperature, the solution was slowly poured into 200 mL of water (containing 2 mL of 1N HCl aqueous solution) while stirring, and then diluted with toluene (200 mL). After stirring for 30 minutes, the aqueous layer was removed. The organic layer (with a debris layer) was filtered, and the filter cake was washed with toluene (50 mL) and water (40 mL). Separate the two filtrates. Wash the organic layer with water (200 mL × 2) and brine (200 mL) until pH > 3. Dry it with _MgSO4 and concentrate it to dryness to provide the desired product: ^¹H NMR (400 MHz, chloroform-d) δ 8.33 (d, J = 6.3 Hz, ¹H), 7.95 (d, J = 7.8 Hz, ¹H).

Step 4: Synthesis of 7-bromo-2-chloro-6-fluoro-N-(3-fluorophenyl)-N-methyl-quinazoline-4-amine: NaH (60% purity) (738 mg, 18.5 mmol) was added to a solution of 3-fluoro-N-methylaniline (1.76 mL, 15.6 mmol) and 7-bromo-2,4-dichloro-6-fluoro-quinazoline (4.2 g, 14.2 mmol) in DMF (78 mL) at 0 °C. The reaction mixture was heated to room temperature and stirred overnight. The mixture was quenched with ice-cold saturated _NH₄Cl aqueous solution (40 mL), diluted with AcOEt (200 mL), and washed with water (100 mL). The organic layer was further washed with brine (50 mL), dried over _Na₂SO₄ , and concentrated under vacuum. The resulting residue was refilled with EtOAc (30 mL), and the resulting precipitate was collected by filtration; this precipitate was the desired product. The filtrate was purified by column chromatography using a 0-40% EtOAc hexane solution to provide the desired product. The two product batches were combined: [M+H] ⁺ = 384.3.

Step 5: Synthesis of 7-bromo-N-(3-fluorophenyl)-6-fluoro-2-hydrazino-N-methyl-quinazolin-4-amine: The product from Step 4 (3.8 g, 5.0 mmol) was added to EtOH (44 mL) and THF (11 mL). Hydrazine monohydrate (7.5 mL) was added slowly in portions, and the reaction mixture was stirred overnight at room temperature until the reaction was complete. The resulting precipitate was collected by filtration, which yielded the desired product based on LC/MS. The filtrate was diluted with EtOAc, washed continuously with water and _brine , dried over _Na₂SO₄ , and concentrated under vacuum. The crude product was combined with the precipitate batch and used for the next step without purification. [M+H] ^⁺ = 380.2.

Step 6: Synthesis of 8-bromo-7-fluoro-N-(3-fluorophenyl)-N-methyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine: Triethyl orthoformate (33 mL) was added to the product obtained from Step 5 above. The reaction mixture was stirred at 100 °C for 16 hours. The reaction mixture was concentrated under vacuum and EtOAc (100 mL) was added to the resulting residue. The solution was washed continuously with water and _brine , dried over _Na₂SO₄ and concentrated under vacuum. The crude product was purified by column chromatography using a 5–10% MeOH solution of DCM to provide the desired product. [M+H] ^⁺ = 390.2.

Step 7: Synthesis of ethyl 3-[7-fluoro-5-(3-fluoro-N-methyl-aniline)-[1,2,4]triazolo[4,3-a]quinazolin-8-yl]propionate: 8-bromo-7-fluoro-N-(3-fluorophenyl)-N-methyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine (90 mg, 0.23 mmol), Pd(dba) _₂ (13 mg, 0.023 mmol), and 1,2,3,4,5-pentaphenyl-1'-(di-tert-butylphosphine)ferrocene (16 mg, 0.023 mmol) were added to a 100 mL flask. The mixture was degassed and refilled with nitrogen several times, followed by the addition of THF (4 mL), and then the addition of bromo-(3-ethoxy-3-oxopropyl)zinc reagent (0.5 M in THF, 0.92 mL). Stir the mixture at room temperature for 15 minutes to allow the reaction to complete. Add 10 mL of saturated _NH₄Cl aqueous solution to quench the reaction. Add 60 mL of EtOAc and 20 mL of water. Separate the two layers. Wash the organic layer with brine, dry, concentrate, and purify the crude product using column chromatography with EtOAc to provide the desired ester: [M+H] ^⁺ = 412.3.

Step 8: Add _LiBH₄ (4 mg, 0.18 mmol) and 0.2 mL MeOH to the ester (36 mg, 0.088 mmol) obtained above in THF (4 mL). Stir the reaction mixture at room temperature for 18 hours until complete. Add 10 mL of saturated _NH₄Cl aqueous solution to quench the reaction. Dilute the mixture with 60 mL EtOAc and wash with water (20 mL). The organic layer was washed with brine, dried, concentrated, and the crude product was purified by RP-HPLC to provide the title compound: ^¹H NMR (400 MHz, methanol- _d⁴ ) δ 9.63 (s, 1H), 8.40–8.28 (m, 1H), 7.68–7.56 (m, 1H), 7.40–7.26 (m, 3H), 6.79 (dd, J = 11.4, 8.6 Hz, 1H), 3.80 (s, 3H), 3.63 (t, J = 6.2 Hz, 2H), 2.98–2.90 (m, 2H), 1.99–1.84 (m, 2H); LCMS (m/z) 370.3.

Example 468. 8-Chloro-N-methyl-N-[3-[4-[2-(trifluoromethyl)oxetane-2-yl]phenyl]benzene [1,2,4]triazolo[4,3-a]quinazolin-5-amine

Step 1: Synthesis of 2-(4-bromophenyl)-2-(trifluoromethyl)oxetane: Trimethylsulfonium iodide (6.45 g, 29.3 mmol) was added to a round-bottom flask containing potassium tert-butoxide (3.30 g, 29.3 mmol) in DMSO (40 mL), and the reaction was stirred at room temperature for 20 minutes. A solution of 4-bromo-trifluoroacetophenone (2.6 g, 9.76 mmol) in DMSO (10 mL) was added dropwise to the reaction mixture, and the resulting solution was stirred overnight at room temperature. The crude reaction mixture was partitioned between diethyl ether and brine. The organic layer was separated, washed once more with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by column chromatography using 0–50% EtOAc in hexane to provide the corresponding trifluoromethyloxetane: ^¹H NMR (400 MHz, chloroform-d) δ 7.60–7.55 (m, 2H), 7.34 (s, 2H), 4.85 (m, 1H), 4.61 (dt, J = 9.2, 6.0 Hz, 1H), 3.28 (m, 1H), 2.89 (m, 1H).

Step 2: Synthesis of (4-(2-(trifluoromethyl)oxetane-2-yl)phenyl)boronic acid: 1.6M butyllithium (3.5mL, 5.58mmol) in hexane was added to the trifluoromethyloxetane (1.5g, 5.07mmol) from Step 1 in THF (15mL) at -78°C. After stirring for one hour, trimethylboronic acid ester (0.87mL, 7.6mmol) was added. After warming to room temperature, THF was removed under vacuum. The residue was dissolved in water and extracted with ether to remove nonpolar impurities. The aqueous layer was acidified and extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride, dried over sodium sulfate, filtered, and concentrated to dryness. The crude product was further purified by column chromatography using 20-80% EtOAc in hexane to provide the desired phenylboronic acid: ^¹H NMR (400 MHz, chloroform-d) δ 8.31 (d, J = 7.7 Hz, 1H), 7.60 (d, J = 7.7 Hz, 1H), 7.48 (d, J = 7.7 Hz, 1H), 4.89 (m, 1H), 4.74–4.56 (m, 1H), 3.35 (m, 1H), 2.99 (dt, J = 19.5, 10.0 Hz, 1H).

N-(3-bromophenyl)-8-chloro-N-methyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine (Example 308, 80 mg, 0.20 mmol), [4-[2-(trifluoromethyl)oxetane-2-yl]phenyl]boronic acid (76 mg, 0.31 mmol), and Pd( _PPh3 ) ₄ (24 mg, 0.02 mmol) were added to dioxane (3 mL), and 2M sodium carbonate aqueous solution (0.2 mL) was added. The mixture was degassed and refilled several times with _N2 . The mixture was heated at 80 °C for 90 minutes. After cooling to room temperature, water and EtOAc were added. The two layers were separated, and the organic layer was washed with brine, dried, and concentrated. The crude substance was purified by column chromatography using 80-100% EtOAc in hexane to obtain the title compound: ^¹H NMR (400MHz, methanol- _d⁴ ) δ 9.44 (s, 1H), 8.32 (d, J = 2.1 Hz, 1H), 7.69–7.59 (m, 4H), 7.58–7.45 (m, 3H), 7.36 (d, J = 9.0 Hz, 1H), 7.32–7.26 (m, 1H), 7.21 (dd, J = 9.0, 2.0 Hz, 1H), 4.81 (m, 1H), 4.61 (dt, J = 9.2, 6.0 Hz, 1H), 3.72 (s, 3H), 3.32–3.24 (m, 1H), 3.05–2.92 (m, 1H); LCMS (m/z) 510.3.

Example 469. 8-Chloro-N-methyl-N-(4'-(1-(trifluoromethyl)cyclopropyl)-[1,1'-diphenyl]-3- (-[1,2,4]triazolo[4,3-a]quinazolin-5-amine)

Example 469 was synthesized using the corresponding boric acid or ester, following the method described for Example 468. ^¹H NMR (400 MHz, methanol- _d⁴ ) δ 9.55 (s, 1H), 8.55–8.43 (m, 1H), 7.77 (dt, J = 8.0, 1.2 Hz, 1H), 7.71 (t, J = 2.0 Hz, 1H), 7.67–7.59 (m, 3H), 7.56 (d, J = 8.2 Hz, 2H), 7.41 (m, 1H), 7.33 (t, J = 1.5 Hz, 2H), 3.83 (s, 3H), 1.39 (d, J = 1.9 Hz, 1H), 1.31 (s, 2H), 1.12–1.10 (m, 1H); LCMS (m/z) 494.3.

Example 470. N-(3-(1-(tert-butyl)-1H-pyrazole-4-yl)phenyl)-8-chloro-N-methyl-[1,2,4]triazole [4,3-a]quinazolin-5-amine

Example 470 was synthesized using the corresponding boric acid or ester, according to the method described for Example 468. ^¹H NMR (400 MHz, methanol- _d⁴ ) δ 9.44 (s, ¹H), 8.32 (d, J = 2.1 Hz, ¹H), 8.16 (s, ¹H), 7.85 (s, ¹H), 7.61–7.53 (m, 2H), 7.47–7.33 (m, 2H), 7.20 (dd, J = 9.0, 2.1 Hz, 1H), 7.14–7.08 (m, ¹H), 3.69 (s, 3H), 1.61 (s, 9H); LCMS (m/z) 432.3.

Example 471. 8-Chloro-N-methyl-N-[3-(3-methyl-3-methylsulfonyl-but-1-ynyl)phenyl]-[1, [2,4]triazolo[4,3-a]quinazolin-5-amine

Synthesis of 3-methyl-3-(methanesulfonyl)but-1-yne

3-Chloro-3-methylbut-1-yne (8.2 mL, 73.1 mmol) was added dropwise to a stirred suspension of sodium methanesulfonate (8.96 g, 83.4 mmol) and cuprous iodide (I) (1.39 g, 7.3 mmol) in DMF (25 mL). The resulting reaction mixture was heated at 40 °C for 20 hours. After cooling to room temperature, the reaction mixture was diluted with EtOAc (300 mL), washed with water (100 mL) and brine (100 mL), dried, and concentrated. The crude product was purified by column chromatography using 10–60% EtOAc in hexane, yielding the desired product: ^¹H NMR (400 MHz, chloroform-d) δ 3.06 (s, 3H), 2.60 (s, 1H), 1.69 (s, 6H).

A mixture of N-(3-bromophenyl)-8-chloro-N-methyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine (Example 308, 30 mg, 0.077 mmol), 3-methyl-3-(methanesulfonyl)but-1-yne (23 mg, 0.154 mmol), DIPEA (27 μL, 0.154 mmol), CuI (3 mg, 0.015 mmol), and PdCl₂( _PPh₃ ) _{₂ (} 5.4 mg, 8 μmol) in DMF (2 mL) was degassed and refilled with nitrogen several times, then heated at 100 °C overnight. The reaction mixture was diluted with EtOAc, washed with water and brine, dried, and concentrated. The crude product was purified by column chromatography using 20-100% (EtOAc/EtOH 3/1) in hexane, yielding the desired product: ^¹H NMR (400MHz, methanol- _d4 ) δ 9.46 (s, 1H), 8.36 (d, J = 2.0Hz, 1H), 7.47 (dt, J = 2.3, 1.0Hz, 1H), 7.45–7.42 (m, 2H), 7.36–7.30 (m, 2H), 7.26 (dd, J = 9.0, 2.0Hz, 1H), 3.64 (s, 3H), 3.11 (s, 3H), 1.71 (s, 6H); LCMS (m/z) 454.1.

Example 472. 8-Chloro-N-(3-(3,3-dimethylbut-1-yn-1-yl)phenyl)-N-methyl-[1,2,4]triazole [4,3-a]quinazolin-5-amine

Example 472 was prepared using Example 308 and the corresponding alkyne according to the method described for Example 471. ^¹H NMR (400 MHz, methanol- _d⁴ ) δ 9.46 (s, 1H), 8.36 (d, J = 2.0 Hz, 1H), 7.37 (d, J = 7.8 Hz, 1H), 7.33 (dt, J = 5.7, 2.1 Hz, 3H), 7.27 (dd, J = 9.0, 2.0 Hz, 1H), 7.19 (m, 1H), 3.64 (s, 3H), 1.31 (s, 9H); LCMS (m/z) 390.3.

Example 473. N-Methyl-8-(3-methyl-3-(methanesulfonyl)but-1-yn-1-yl)-N-(3-(3-methyl- 3-(methylsulfonyl)but-1-yn-1-yl)phenyl)-[1,2,4]triazolo[4,3-a]quinazolin-5-amine

Example 473 was isolated from the Sonogashira reaction described in Example 471 to obtain a separate product. ^¹H NMR (400 MHz, methanol- _d⁴ ) δ 9.69 (s, ¹H), 8.50 (d, J = 1.3 Hz, ¹H), 7.59–7.53 (m, ³H), 7.46 (m, ¹H), 7.40 (m, ¹H), 7.27 (dd, J = 8.9, 2.1 Hz, ¹H), 3.77 (s, ³H), 3.18 (s, ³H), 3.10 (s, ⁶H), 1.80 (s, ⁶H), 1.67 (s, ⁶H); LCMS (m/z) 564.1.

Example 474. N-Methyl-N-(3-(3-methyl-3-(methylsulfonyl)but-1-yn-1-yl)phenyl)-8-(methyl (-[1,2,4]triazolo[4,3-a]quinazolin-5-amine)-[1,2,4]triazolo[4,3-a]quinazolin-5-amine

Example 474 was separated into additional products from the Sonogashira reaction described in Example 471. ^¹H NMR (400 MHz, methanol- _d⁴ ) δ 9.84 (s, ¹H), 8.91 (d, J = 1.8 Hz, ¹H), 7.85 (dd, J = 8.8, 1.7 Hz, ¹H), 7.64–7.50 (m, 4H), 7.48 (dt, J = 7.7, 2.0 Hz, 1H), 3.79 (s, 3H), 3.26 (s, 3H), 3.11 (s, 3H), 1.71 (s, 6H); LCMS (m/z) 498.1.

Example 475. 5-(methyl(4'-(2-(trifluoromethyl)oxetane-2-yl)-[1,1'-diphenyl]-3- (1,2,4)triazolo[4,3-a]quinazolin-8-carboxynitrile

Add 8-chloro-N-methyl-N-[3-[4-[2-(trifluoromethyl)oxetane-2-yl]phenyl]phenyl]-[1,2,4]triazolo[4,3-a]quinazolin-5-amine (Example 468, 18 mg, 0.035 mmol), _K₄Fe (CN) _₆ ·3H₂O (4 mg, 9 μmol), Pd(OAc) _₂ ( ₁ mg, 4 μmol), XPhos (3 mg, 7 μmol), and _K₂CO₃ (1 mg, 9 μmol) to _a THF/water mixture (1 mL/1 mL). Degas the reaction mixture and refill it with nitrogen several times. Heat the mixture at 120 °C for 10 hours. After cooling to room temperature, add water and EtOAc. Separate the two layers, wash the organic layer with brine, dry it, and concentrate it. The crude residue was purified by column chromatography using 50-100% EtOH/EtOAc (1/3) in hexane, yielding the desired product: ^¹H NMR (400MHz, methanol- _d4). )δ9.44(s,1H),8.32(d,J＝2.1Hz,1H),7.69–7.59(m,4H),7.58–7.45(m,3H),7.36(d,J＝9.0Hz,1H),7.32–7.26(m,1H),7.21(dd,J =9.0, 2.0Hz, 1H), 4.81 (m, 1H), 4.61 (dt, J = 9.2, 6.0Hz, 1H), 3.72 (s, 3H), 3.32–3.24 (m, 1H), 3.05–2.92 (m, 1H); LCMS (m/z) 510.3.

Example 476. N-(3'-((8-chloro-[1,2,4]triazolo[4,3-a]quinazolin-5-yl)(methyl)amino)- [1,1'-Diphenyl]-4-yl)terpentylamide

Example 476 was prepared using Example 308 and the corresponding boric acid or ester according to the method described for Example 468. ^¹H NMR (400 MHz, methanol- _d⁴ ) δ 9.58 (s, 1H), 8.50 (d, J = 2.0 Hz, 1H), 7.80 (m, 1H), 7.73 (t, J = 2.0 Hz, 1H), 7.69–7.63 (m, 3H), 7.61–7.57 (m, 2H), 7.44–7.34 (m, 2H), 7.30 (d, J = 9.1 Hz, 1H), 3.86 (s, 3H), 1.32 (s, 9H); LCMS (m/z) 485.4.

Example 477. 4-(3-((8-chloro-[1,2,4]triazolo[4,3-a]quinazolin-5-yl)(methyl)amino)benzene 2-Methylbut-3-yn-2-ol

Example 477 was prepared using the method described for Example 471, with the alkynes from Example 308 and the corresponding alkynes. ^¹H NMR (400 MHz, methanol- _d⁴ ) δ 9.61 (s, 1H), 8.51 (d, J = 2.0 Hz, 1H), 7.57–7.51 (m, 2H), 7.51–7.48 (m, 1H), 7.44 (m, 1H), 7.39 (dd, J = 9.1, 2.0 Hz, 1H), 7.23 (dd, J = 9.1, 1.2 Hz, 1H), 3.78 (s, 3H), 1.54 (s, 6H); LCMS (m/z) 392.2.

Example 478. 8-Chloro-N-(3-((4-chlorophenyl)ethynyl)phenyl)-N-methyl-[1,2,4]triazolo[4, [3-a]quinazolin-5-amine

Example 478 was prepared using the method described for Example 471, with the alkynes from Example 308 and the corresponding alkynes. ^¹H NMR (400 MHz, methanol- _d⁴ ) δ 9.62 (s, 1H), 8.50 (d, J = 2.0 Hz, 1H), 7.65 (d, J = 7.7 Hz, 2H), 7.62–7.55 (m, 2H), 7.47 (d, J = 8.6 Hz, 2H), 7.40–7.35 (m, 2H), 7.24 (d, J = 9.1 Hz, 2H), 3.81 (s, 3H); LCMS (m/z) 444.3.

Example 479. 8-Chloro-N-methyl-N-(3-((1-(trifluoromethyl)cyclopropyl)ethynyl)phenyl)-[1,2,4] Triazolo[4,3-a]quinazolin-5-amine

Example 479 was prepared using the method described for Example 471, with the alkynes from Example 308 and the corresponding alkynes. ^¹H NMR (400 MHz, methanol- _d⁴ ) δ 9.43 (s, 1H), 8.34 (d, J = 1.9 Hz, 1H), 7.42–7.36 (m, 3H), 7.29 (d, J = 9.0 Hz, 1H), 7.23 (m, 2H), 3.65 (s, 3H), 1.43–1.35 (m, 2H), 1.28 (d, J = 3.2 Hz, 2H); LCMS (m/z) 442.3.

Example 480. 4-(3-((8-(3-hydroxy-3-methylbut-1-yn-1-yl)-[1,2,4]triazolo[4,3-a] Quinazolin-5-yl)(methyl)amino)phenyl)-2-methylbut-3-yne-2-ol

Example 480 was prepared using the method described for Example 471, with the alkynes from Example 308 and the corresponding alkynes. ^¹H NMR (400 MHz, methanol- _d⁴ ) δ 9.62 (s, 1H), 8.42 (d, J = 1.5 Hz, 1H), 7.54 (m, 2H), 7.50 (m, 1H), 7.48–7.40 (m, 1H), 7.33 (dd, J = 8.8, 1.5 Hz, 1H), 7.20 (d, J = 8.8 Hz, 1H), 3.79 (s, 3H), 1.59 (s, 6H), 1.54 (s, 6H); LCMS (m/z) 440.3.

Example 481. 1-((3-((8-chloro-[1,2,4]triazolo[4,3-a]quinazolin-5-yl)(methyl)amino)benzene (Hydroxy)cyclopentan-1-ol

Example 481 was prepared using the method described for Example 471, with the alkynes from Example 308 and the corresponding alkynes. ^¹H NMR (400 MHz, methanol- _d⁴ ) δ 9.48 (s, 1H), 8.38 (m, 1H), 7.51–7.32 (m, 4H), 7.32–7.22 (m, 2H), 3.66 (s, 3H), 1.89–1.72 (m, 5H), 1.65 (s, 2H), 1.21 (m, 1H); LCMS (m/z) 418.2.

Example 482. N-(3-((8-chloro-[1,2,4]triazolo[4,3-a]quinazolin-5-yl)(methyl)amino)benzene (Bento) benzamide

Example 482 was prepared according to the method described for Example 483, except that it was prepared by replacing aniline and 3-((tert-butoxycarbonyl)(methyl)amino)benzoic acid with tert-butyl(3-aminophenyl)(methyl)carbamate and benzoic acid. ¹ HNMR (400MHz, DMSO-d ₆ )δ10.39(s,1H),9.77(s,1H),8.63(d,J＝2.1Hz,1H),7.99–7.88(m,3H),7.76(d,J＝8.1Hz,1H),7.65–7.57(m,1H),7.53 (t, J＝7.4Hz, 2H), 7.50–7.39 (m, 2H), 7.30 (d, J＝9.0Hz, 1H), 7.09 (dd, J＝7.8, 2.1Hz, 1H), 3.62 (s, 3H); LCMS (m/z) 429.1.

Example 483. 3-((8-chloro-[1,2,4]triazolo[4,3-a]quinazolin-5-yl)(methyl)amino)-N-benzene Benzylbenzamide

Step 1: N-(3-bromophenyl)-N-methyl-carbamate tert-butyl ester: Triethylamine (12 mL, 86.0 mmol) and 4-dimethylaminopyridine (5.25 g, 4.3 mmol) were added to a solution of 3-bromo-N-methylaniline (4.00 g, 21.5 mmol) and di-tert-butyl decarbonate (5.16 g, 23.6 mmol) in DCM. The reaction mixture was stirred at room temperature for 24 hours, then poured into water and extracted twice with ethyl acetate (approximately 150 mL each time). The organic layers were combined and washed with 0.5 N HCl, then with brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. N-(3-bromophenyl)-N-methyl-carbamate tert-butyl ester was provided by rapid chromatography (eluting with a hexane solution of 0–10% v/v ethyl acetate).

Step 2: 3-[tert-butoxycarbonyl(methyl)amino]benzoic acid: A solution of N-(3-bromophenyl)-N-methylcarbamate tert-butyl ester (1.25 g, 4.37 mmol) in THF (50 mL) was purged with nitrogen for 15 min and cooled to -78 °C, followed by the addition of n-BuLi (3.49 mL, 2.50 M, 8.74 mmol). The reaction mixture was stirred at this temperature for 1 hour, during which carbon dioxide was bubbled through the reaction mixture, and the solution was warmed to room temperature. Once the reaction mixture reached room temperature, the addition of carbon dioxide was stopped and the solution was poured into water. The resulting aqueous mixture was made alkaline by adding 1N NaOH and washed with dichloromethane. The aqueous layer was then acidified to pH 3 with 1N HCl and extracted twice with ethyl acetate (approximately 75 mL each time). The organic layers were combined, washed with brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. 3-[tert-butoxycarbonyl(methyl)amino]benzoic acid was provided by rapid chromatography purification (eluting with hexane solution of 10-100% v/v ethyl acetate).

Step 3: 3-(Methylamino)-N-phenyl-benzamide: HATU (190 mg, 0.500 mmol) and N,N-diisopropylethylamine (131 μL, 0.750 mmol) were added to a solution of 3-[tert-butoxycarbonyl(methyl)amino]benzoic acid (62.8 mg, 0.250 mmol) and aniline (34.2 μL, 0.375 mmol) in DMF (1 mL). The resulting solution was stirred at room temperature for 3.5 h, then poured into water and extracted with ethyl acetate, washed with 1N HCl, then washed twice with water, then washed with brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The crude residue was dissolved in dichloromethane (4 mL), followed by the addition of trifluoroacetic acid (0.5 mL). The resulting solution was stirred for 16 h, then poured into water, extracted with ethyl acetate, washed with saturated sodium bicarbonate solution, then washed with brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. 3-(methylamino)-N-phenyl-benzamide was provided by rapid chromatographic purification (eluting with hexane solution of 0-100% v/v ethyl acetate).

Step 4: N-[3-[(2,7-dichloroquinazoline-4-yl)-methyl-amino]phenyl]benzamide: N,N-diisopropylethylamine (29 μL, 0.166 mmol) was added to a solution of N-[3-(methylamino)phenyl]benzamide (15 mg, 66.3 μmol) and 2,4,7-trichloroquinazoline (23.2 mg, 99.4 μmol) in DMF (0.5 mL). The resulting solution was heated to 40 °C for 1 hour, then poured into water, extracted with ethyl acetate, washed twice with water, then washed with brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. N-[3-[(2,7-dichloroquinazoline-4-yl)-methyl-amino]phenyl]benzamide was purified by rapid chromatography (eluting with a hexane solution of 0-100% v/v ethyl acetate).

Step 5: N-[3-[(8-chloro-[1,2,4]triazolo[4,3-a]quinazolin-5-yl)-methyl-amino]phenyl]benzamide: Add hydrazine hydrate (19.2 μL, 0.395 mmol) to a solution of N-[3-[(2,7-dichloroquinazolin-4-yl)-methyl-amino]phenyl]benzamide (17.6 mg, 39.5 μmol) in ethanol (2.2 mL) and THF (1.2 mL). Stir the resulting solution at 40 °C for 16 hours, then concentrate under reduced pressure. The crude material was then dissolved in triethyl orthoformate (0.66 mL) and heated to 100 °C for 1 hour, then cooled to room temperature and concentrated under reduced pressure. Purified by reversed-phase HPLC, the title compound was given as follows: ^¹H NMR (400MHz, DMSO- _d⁶ ) δ 10.29 (s, 1H), 9.79 (s, 1H), 8.65 (d, J = 2.1Hz, 1H), 8.02 (s, 1H), 7.95 (d, J = 7.3Hz, 1H), 7.74 (d, J = 7.4Hz, 2H), 7.64–7.50 (m, 2H), 7.42 (dd, J = 9.0, 2.1Hz, 1H), 7.36 (t, J = 7.9Hz, 2H), 7.24 (d, J = 9.0Hz, 1H), 7.12 (t, J = 7.3Hz, 1H), 3.68 (s, 3H); LCMS (m/z) 429.1.

Example 484. 8-Chloro-N-(3-(5-(difluoromethyl)furan-2-yl)phenyl)-N-methyl-[1,2,4]triazole [4,3-a]quinazolin-5-amine

N-[3-(5-formyl-2-furanyl)phenyl]-N-methyl-carbamate tert-butyl: Sodium carbonate aqueous solution (9.8 mL, 2N, 19.6 mmol) and XPhos Pd G3 (73.6 mg, 97.8 μmol) were added to a solution of tert-butyl N-(3-bromophenyl)-N-methyl-carbamate (560 mg, 1.96 mmol) and (5-formyl-2-furanyl)boronic acid (411 mg, 2.94 mmol) in 1,4-dioxane (19 mL). The mixture was heated to 100 °C for 1.5 h, then cooled to room temperature, filtered, diluted with ethyl acetate, washed with water, then washed with brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. N-[3-(5-formyl-2-furanyl)phenyl]-N-methyl-carbamate tert-butyl ester was provided by rapid chromatography (eluting with hexane solution of 0-100% v/v ethyl acetate).

3-[5-(difluoromethyl)-2-furanyl]-N-methylaniline: Trifluoroacetic acid (0.5 mL) was added to a solution of N-[3-(5-formyl-2-furanyl)phenyl]-N-methyl-carbamate tert-butyl ester (150 mg, 0.498 mmol) in DCM (4 mL). The resulting solution was stirred at room temperature for 1.5 h, then poured into a saturated aqueous sodium bicarbonate solution, extracted with ethyl acetate, washed with brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The resulting crude product was dissolved in DCM (4 mL), followed by the addition of diethylaminosulfur trifluoride (0.257 mL, 1.95 mmol), and the resulting solution was stirred at room temperature for 24 h, then poured into a saturated aqueous sodium bicarbonate solution, extracted with ethyl acetate, washed with water, then washed with brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. 3-[5-(difluoromethyl)-2-furanyl]-N-methylaniline was provided by rapid chromatography (eluting with hexane solution of 0-100% v/v ethyl acetate).

Example 484 was prepared by the method described in Example 483, except that 3-[5-(difluoromethyl)-2-furanyl]-N-methylaniline was used instead of 3-(methylamino)-N-phenylbenzamide. ^¹H NMR (400 MHz, DMSO- _d⁶ ) δ 9.78 (s, 1H), 8.63 (d, J = 2.0 Hz, 1H), 7.88–7.81 (m, 1H), 7.76 (d, J = 7.8 Hz, 1H), 7.54 (t, J = 7.9 Hz, 1H), 7.42 (dd, J = 9.0, 2.1 Hz, 1H), 7.35 (dd, J = 7.9, 2.1 Hz, 1H), 7.29–6.98 (m, 4H), 3.66 (s, 3H); LCMS (m/z) 426.1.

Example 485. 3-((8-chloro-[1,2,4]triazolo[4,3-a]quinazolin-5-yl)(methyl)amino)-N-methyl β-N-phenylbenzamide

Example 485 was prepared according to the method described for Example 483, except that N-methylaniline was used instead of aniline. ^¹H NMR (400 MHz, DMSO- _d⁶ ) δ 9.76 (s, ¹H), 8.62 (d, J = 2.0 Hz, ¹H), 7.33–7.25 (m, 6H), 7.22–7.13 (m, 4H), 6.85 (d, J = 9.0 Hz, ¹H), 3.40 (s, 3H), 3.34 (s, 3H); LCMS (m/z) 443.1.

Example 486. N-(3-((8-chloro-[1,2,4]triazolo[4,3-a]quinazolin-5-yl)(methyl)amino)benzene )-N-methylbenzamide

N-Methyl-N-[3-(methylamino)phenyl]benzamide: HATU (544 mg, 1.43 mmol) and N,N'-dimethylphenyl-1,3-diamine (0.210 mL, 1.64 mmol) were added to a solution of benzoic acid (100 mg, 0.819 mmol) and N,N'-diisopropylethylamine (0.374 mL, 2.15 mmol) in DMF (2 mL). The reaction mixture was stirred at room temperature for 4 hours, then poured into water and extracted with ethyl acetate, washed with 1N HCl, then washed twice with water, then washed with brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. N-Methyl-N-[3-(methylamino)phenyl]benzamide was given by rapid chromatography (eluting with a hexane solution of 0-100% v/v ethyl acetate).

Example 486 was prepared according to the method described for Example 483, except that N-methyl-N-[3-(methylamino)phenyl]benzamide was used instead of 3-(methylamino)-N-phenylbenzamide. ^¹H NMR (400 MHz, DMSO- _d⁶ ) δ 9.75 (s, 1H), 8.61 (d, J = 2.1 Hz, 1H), 7.37–7.22 (m, 9H), 7.15 (d, J = 8.6 Hz, 1H), 7.07 (dd, J = 7.9, 2.1 Hz, 1H), 6.94 (d, J = 9.0 Hz, 1H), 3.44 (s, 3H), 3.34 (s, 3H); LCMS (m/z) 443.1.

Example 487. 8-Chloro-N-methyl-N-(3-(5-(morpholinomethyl)furan-2-yl)phenyl)-[1,2,4]tri Azo[4,3-a]quinazolin-5-amine

2,7-Dichloro-N-methyl-N-[3-[5-(morpholinomethyl)-2-furanyl]phenyl]quinazolin-4-amine: Sodium triacetoxyborohydride (56.3 mg, 0.265 mmol) was added to a solution of N-[3-(5-formyl-2-furanyl)phenyl]-N-methylcarbamate tert-butyl ester (40 mg, 0.133 mmol), morpholine (23 μL, 0.265 mmol), and acetic acid (38 μL) in 1,2-dichloroethane (1.5 mL). The reaction mixture was stirred at room temperature for 16 hours, then poured into water, extracted with ethyl acetate, washed with brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The resulting crude product was dissolved in DCM (4 mL), followed by the addition of trifluoroacetic acid (0.5 mL). The resulting solution was stirred at room temperature for 30 minutes, then poured into water, extracted with ethyl acetate, washed with brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The resulting crude compound was combined with 2,4,7-trichloroquinazoline (46.6 mg, 0.200 mmol) in DMF (1.5 mL), followed by the addition of N,N-diisopropylethylamine (58 μL, 0.333 mmol). The reaction mixture was heated to 40 °C for 2 hours, then poured into water, extracted with ethyl acetate, washed with water, then with brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. Purification by rapid chromatography (eluting with a hexane solution of 0–100% v/v ethyl acetate) yielded 2,7-dichloro-N-methyl-N-[3-[5-(morpholinomethyl)-2-furanyl]phenyl]quinazoline-4-amine.

Example 487 was prepared according to the method described for Example 483, except that 2,7-dichloro-N-methyl-N-[3-[5-(morpholinomethyl)-2-furanyl]phenyl]quinazolin-4-amine was used instead of N-[3-[(2,7-dichloroquinazolin-4-yl)-methyl-amino]phenyl]benzamide. ¹ H NMR (400MHz, DMSO-d ₆ )δ9.74(s,1H),8.61(d,J＝2.1Hz,1H),7.78–7.73(m,1H),7.70(d,J＝7.9Hz,1H),7.51(t,J＝7.9Hz,1H),7.38(dd,J＝9.0,2.1Hz,1H),7.33 –7.25(m,2H),7.09(d,J＝3.4Hz,1H),6.79(d,J＝3.4Hz,1H),4.47(s,2H),3.96(s,4H),3.62(s,3H),3.37–3.03(m,4H); LCMS(m/z)475.1.

Example 488. [5-[3-[(8-chloro-[1,2,4]triazolo[4,3-a]quinazolin-5-yl)-methyl-amino]benzene] [2-furanyl]methanol

5-[3-[(8-chloro-[1,2,4]triazolo[4,3-a]quinazolin-5-yl)-methyl-amino]phenyl]furan-2-carboxaldehyde: Pd(dppf)Cl₂ (21.3 mg, 25.7 μmol) and an aqueous solution of sodium carbonate (0.643 mL, 2 M, 1.29 mmol) were added to a solution of N-(3-bromophenyl)-8-chloro-N-methyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine (Example 308, 100 mg, 0.257 mmol) and (5-formyl- ₂ -furanyl)boronic acid (39.6 mg, 0.283 mmol) in 1,4-dioxane (1 mL). The resulting solution was heated to 100 °C for 1 hour, then filtered, diluted with ethyl acetate, washed with water, then washed with brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. 5-[3-[(8-chloro-[1,2,4]triazolo[4,3-a]quinazolin-5-yl)-methyl-amino]phenyl]furan-2-carboxaldehyde was purified by rapid chromatography (eluting with hexane solution of 0-100% v/v ethyl acetate).

[5-[3-[(8-chloro-[1,2,4]triazol[4,3-a]quinazolin-5-yl)-methyl-amino]phenyl]-2-furanyl]methanol: Sodium borohydride (5 mg, 0.134 mmol) was added to a solution of 5-[3-[(8-chloro-[1,2,4]triazol[4,3-a]quinazolin-5-yl)-methyl-amino]phenyl]furan-2-carboxaldehyde (45 mg, 0.111 mmol) in ethanol (5 mL) at 0 °C. After 20 minutes at this temperature, the reaction mixture was quenched with water and concentrated under reduced pressure. The resulting crude substance was dissolved in ethyl acetate, washed with water, then washed with brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. Purified by reversed-phase HPLC, the title compound was given as follows: ^¹H NMR (400MHz, DMSO- _d⁶ ) δ 9.76 (s, ¹H), 8.62 (d, J = 2.1Hz, ¹H), 7.72 (t, J = 1.8Hz, ¹H), 7.70–7.65 (m, ¹H), 7.49 (t, J = 7.9Hz, ¹H), 7.42 (dd, J = 9.0, 2.1Hz, ¹H), 7.30–7.22 (m, 2H), 6.94 (d, J = 3.3Hz, 1H), 6.40 (d, J = 3.3Hz, 1H), 4.43 (s, 2H), 3.64 (s, 3H); LCMS (m/z) 406.1.

Example 489. 8-Chloro-N-[3-[5-(methoxymethyl)-2-furanyl]phenyl]-N-methyl-[1,2,4]tri Azo[4,3-a]quinazolin-5-amine

8-Chloro-N-[3-[5-(methoxymethyl)-2-furanyl]phenyl]-N-methyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine: NaH (3.4 mg, 60 wt% in mineral oil, 92.4 μmol) was added to a solution of [5-[3-[(8-chloro-[1,2,4]triazolo[4,3-a]quinazolin-5-yl)-methyl-amino]phenyl]-2-furanyl]methanol (25 mg, 61.6 μmol) and iodomethane (37.5 μL, 0.616 mmol) in DMSO (2 mL) at 0 °C. The reaction mixture was then heated to room temperature and stirred at that temperature for 3 hours. The reaction mixture was then quenched with water, diluted with ethyl acetate, washed with water, then washed with brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The title compound was obtained by reversed-phase HPLC purification: ^¹H NMR (400MHz, DMSO- _d⁶ ) δ 9.76 (s, 1H), 8.62 (d, J = 2.1Hz, 1H), 7.74 (t, J = 1.9Hz, 1H), 7.71–7.66 (m, 1H), 7.49 (t, J = 7.9Hz, 1H), 7.42 (dd, J = 9.0, 2.1Hz, 1H), 7.29–7.23 (m, 2H), 6.98 (d, J = 3.4Hz, 1H), 6.56 (d, J = 3.4Hz, 1H), 4.38 (s, 2H), 3.64 (s, 3H), 3.26 (s, 3H); LCMS (m/z) 420.1.

Example 490. 8-Chloro-N-(6-(6-cyclopropylpyridin-3-yl)pyrazin-2-yl)-N-methyl-[1,2,4]triazole [4,3-a]quinazolin-5-amine

6-(6-Cyclopropyl-3-pyridinyl)-N-methyl-pyrazine-2-amine: Pd(PPh₃)₄ (35.5 mg, 30.7 μmol) and an aqueous solution of sodium carbonate (0.46 mL, 2N, 0.920 mmol) were added to a solution of 6-chloro-N-methyl-pyrazine- _2- amine (57.3 mg, 0.399 mmol) and ( ₆ -cyclopropyl-3-pyridinyl)boronic acid (50 mg, 0.307 mmol) in 1,4-dioxane (2 mL). The resulting solution was heated to 90 °C for 2 hours, then cooled to room temperature, diluted with ethyl acetate, filtered, and concentrated under reduced pressure. 6-(6-Cyclopropyl-3-pyridinyl)-N-methyl-pyrazine-2-amine was purified by rapid chromatography (eluting with a hexane solution of 0–100% v/v ethyl acetate).

Example 490 was prepared according to the method described for Example 483, except that 6-(6-cyclopropyl-3-pyridyl)-N-methyl-pyrazine-2-amine was used instead of 3-(methylamino)-N-phenyl-benzamide. ¹ H NMR (400MHz, DMSO-d ₆ )δ9.86(s,1H),8.96–8.89(m,2H),8.73(d,J＝2.0Hz,1H),8.53(s,1H),8.18(dd,J＝8.3,2.3Hz,1H),7.65(d,J＝8.8Hz,1H) ,7.52(dd,J＝8.8,2.0Hz,1H),7.41(d,J＝8.3Hz,1H),3.77(s,3H),2.22–2.12(m,1H),1.06–0.95(m,4H); LCMS(m/z)429.1.

Example 491. 8-Chloro-N-(6-(6-methoxypyridin-3-yl)pyrazin-2-yl)-N-methyl-[1,2,4]triazole [4,3-a]quinazolin-5-amine

6-(6-methoxypyridin-3-yl)-N-methylpyrazine-2-amine was prepared according to the Suzuki coupling procedure described for Example 490, except that 6-chloro-N-methylpyridin-2-amine and (6-methoxypyridin-3-yl)boronic acid were used. Example 491 was prepared according to the method described for Example 483, except that 6-(6-methoxypyridin-3-yl)-N-methylpyrazine-2-amine was used instead of 3-(methylamino)-N-phenyl-benzamide. ¹ H NMR (400MHz, DMSO-d ₆ )δ9.87(s,1H),8.93(s,1H),8.74(dd,J＝6.1,1.9Hz,2H),8.50(s,1H),8.21(dd,J＝8.7,2.5Hz,1H),7.62(d,J＝8 .8Hz, 1H), 7.52 (dd, J＝8.9, 2.1Hz, 1H), 6.91 (dd, J＝8.7, 0.7Hz, 1H), 3.90 (s, 3H), 3.77 (s, 3H); LCMS (m/z) 419.1.

Example 492. 8-Chloro-N-(2-(6-methoxypyridin-3-yl)pyrimidin-4-yl)-N-methyl-[1,2,4]triazole [4,3-a]quinazolin-5-amine

2-(6-methoxypyridin-3-yl)-N-methylpyrimidin-4-amine was prepared according to the Suzuki coupling procedure described for Example 490, except that 2-chloro-N-methylpyrimidin-4-amine and (6-methoxypyridin-3-yl)boronic acid were used. Example 492 was prepared according to the method described for Example 483, except that 2-(6-methoxypyridin-3-yl)-N-methylpyrimidin-4-amine was used instead of 3-(methylamino)-N-phenyl-benzamide. ¹ H NMR (400MHz, DMSO-d ₆ )δ9.95(s,1H),8.80(d,J＝2.3Hz,1H),8.78(d,J＝2.0Hz,1H),8.52(d,J＝6.0Hz,1H),8.29(dd,J＝8.7,2.4Hz,1H),7.83(d,J＝8.8Hz ,1H),7.60(dd,J＝8.8,2.0Hz,1H),6.99(d,J＝6.0Hz,1H),6.85(dd,J＝8.7,0.7Hz,1H),3.89(s,3H),3.72(s,3H); LCMS (m/z) 419.1.

Example 493. 8-Chloro-N-(6-(6-(6-(difluoromethyl)pyridin-3-yl)pyrazin-2-yl)-N-methyl-[1,2,4] Triazolo[4,3-a]quinazolin-5-amine

6-(6-(difluoromethyl)pyridin-3-yl)-N-methylpyrazine-2-amine was prepared according to the method of Example 490, except that 2-(difluoromethyl)pyridin-3-yl)-N-methylpyrazine-2-amine was used instead of (6-cyclopropyl-3-pyridinyl)boronic acid. Example 493 was prepared according to the method described in Example 483, except that 6-(6-(difluoromethyl)pyridin-3-yl)-N-methylpyrazine-2-amine was used instead of 3-(methylamino)-N-phenylbenzamide. ¹ HNMR (400MHz, DMSO-d ₆ )δ9.87(s,1H),9.18(d,J＝2.1Hz,1H),9.03(s,1H),8.74(d,J＝2.0Hz,1H),8.61(s,1H),8.51(dd,J＝8.2,2.2Hz,1H),7.80( d, J＝8.2Hz, 1H), 7.72 (d, J＝8.9Hz, 1H), 7.53 (dd, J＝8.9, 2.0Hz, 1H), 7.02 (t, J＝54.8Hz, 1H), 3.79 (s, 3H); LCMS (m/z) 439.1.

Example 494. 8-Chloro-N-(2-(6-(difluoromethyl)pyridin-3-yl)pyrimidin-4-yl)-N-methyl-[1,2,4] Triazolo[4,3-a]quinazolin-5-amine

2-(6-(difluoromethyl)pyridin-3-yl)-N-methylpyrimidin-4-amine was prepared according to the method of Example 490, except that 2-(difluoromethyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)pyridine and 2-chloro-N-methylpyrimidin-4-amine were used instead of (6-cyclopropyl-3-pyridinyl)boronic acid and 6-chloro-N-methylpyrazine-2-amine. Example 494 was prepared according to the method described in Example 483, except that 2-(6-(difluoromethyl)pyridin-3-yl)-N-methylpyrimidin-4-amine was used instead of 3-(methylamino)-N-phenylbenzamide. ¹ H NMR (400MHz, DMSO-d ₆ )δ9.95(s,1H),9.22(s,1H),8.79(d,J＝2.0Hz,1H),8.63–8.55(m,2H),7.86(d,J＝8.8Hz,1H),7.7 6(d,J＝8.2Hz,1H),7.61(dd,J＝8.8,2.0Hz,1H),7.16–6.84(m,2H),3.74(s,3H); LCMS(m/z)439.1.

Example 495. 8-Chloro-N-(6-(6-(6-(difluoromethyl)pyridin-3-yl)pyrazin-2-yl)-7-fluoro-N-methyl [1,2,4]triazolo[4,3-a]quinazolin-5-amine

7-Chloro-6-fluoro-1H-quinazoline-2,4-dione: A solution of potassium cyanate (8.74 g, 103 mmol) in water (40 mL) was slowly added to a solution of 2-amino-4-chloro-5-fluorobenzoic acid (10 g, 51.7 mmol) in acetic acid (200 mL). The reaction mixture was stirred at room temperature for 24 hours, then poured into water (500 mL). The precipitate was then collected by filtration and added to MeOH (300 mL), followed by the addition of an aqueous solution of sodium hydroxide (25.8 mL, 4 M, 103 mmol). The resulting mixture was then stirred at room temperature for 16 hours, then acidified to pH 3 with 1 N HCl, and the precipitate was collected by filtration and vacuum dried to provide 7-chloro-6-fluoro-1H-quinazoline-2,4-dione.

2,4,7-Trichloro-6-fluoro-quinazoline: 7-Chloro-6-fluoro-1H-quinazoline-2,4-dione (1 g, 4.66 mmol) was dissolved in _POCl₃ (3.25 mL, 35 mmol), followed by the addition of N,N-diisopropylethylamine (1.51 mL, 8.68 mmol). The resulting solution was heated to 100 °C for 1 hour, and then carefully poured into water (500 mL). The precipitate was collected by filtration, dissolved in dichloromethane, washed with water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The crude product was then further dried under vacuum to provide 2,4,7-trichloro-6-fluoro-quinazoline.

Example 495 was prepared according to the method of Example 483, except that 2,4,7-trichloro-6-fluoro-quinazoline and 6-(6-(difluoromethyl)pyridin-3-yl)-N-methylpyrazine-2-amine were used instead of 2,4,7-trichloroquinazoline and N-[3-(methylamino)phenyl]benzamide. ¹ H NMR (400MHz, DMSO-d ₆ )δ9.86(s,1H),9.19(d,J＝2.1Hz,1H),9.01(s,1H),8.96(d,J＝6.4Hz,1H),8.63(s,1H),8.50(dd,J＝8.2,2.2 Hz, 1H), 7.86 (d, J = 9.7Hz, 1H), 7.80 (d, J = 8.2Hz, 1H), 7.02 (t, J = 54.8Hz, 1H), 3.76 (s, 3H); LCMS (m/z) 457.1.

Example 496. 8-Chloro-N-(2-(6-(difluoromethyl)pyridin-3-yl)pyrimidin-4-yl)-7-fluoro-N-methyl [1,2,4]triazolo[4,3-a]quinazolin-5-amine

Example 496 was prepared according to the method of Example 483, except that 2,4,7-trichloro-6-fluoro-quinazoline and 2-(6-(difluoromethyl)pyridin-3-yl)-N-methylpyrimidin-4-amine were used instead of 2,4,7-trichloroquinazoline and N-[3-(methylamino)phenyl]benzamide. ^¹H NMR (400 MHz, DMSO- _d⁶ ) δ 9.94 (s, 1H), 9.24 (s, 1H), 9.01 (d, J = 6.3 Hz, 1H), 8.63–8.56 (m, 2H), 8.00 (d, J = 9.5 Hz, 1H), 7.76 (d, J = 8.2 Hz, 1H), 7.17–6.85 (m, 2H), 3.71 (s, 3H); LCMS (m/z) 457.1.

Example 497. 7,8-Difluoro-N,1-dimethyl-N-phenyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine

Step 1: Preparation of 6,7-difluoro-2-hydrazino-N-methyl-N-phenylquinazoline-4-amine: A solution of 2-chloro-6,7-difluoro-N-methyl-N-phenylquinazoline-4-amine (174.7 mg, 0.571 mmol) in ethanol (4 mL) and THF (1 mL) was treated with hydrazine hydrate (1092 mg, 38.1 equivalents) at room temperature for 20 hours. The resulting suspension was filtered. The filtrate was collected to obtain 6,7-difluoro-2-hydrazino-N-methyl-N-phenylquinazoline-4-amine. Calculated LCMS-ESI+ (m/z): [M+H]+C ₁₅ H ₁₃ F ₂ N ₅ : 302.11 (M+1), experimental value: 302.20 (M+1).

Step 2: Preparation of 7,8-difluoro-N,1-dimethyl-N-phenyl-[1,2,4]triazolo[4,3-a]quinazoline-5-amine: A solution of 6,7-difluoro-2-hydrazino-N-methyl-N-phenylquinazoline-4-amine (30.0 mg, 0.0996 mmol) in triethyl orthoformate (80.0 mg, 0.498 mmol, 5 equivalents) was stirred and heated at 100 °C for 19 hours. The resulting suspension was filtered. The filtrate was collected to obtain the title compound: ^¹H NMR (400MHz, DMSO- _d₆ ) δ 8.19 (dd, J = 11.5, 7.1Hz, 1H), 7.42 (t, J = 7.7Hz, 2H), 7.29 (dd, J = 7.7, 5.3Hz, 3H), 7.15 (dd, J = 12.0, 8.5Hz, 1H), 3.52 (s, 3H), 2.93 (s, 3H); LCMS (m/z) 326.2.

Example 498. 1-(7-bromo-2-chloro-6-fluoroquinazoline-4-yl)-2,3,4,5-tetrahydro-1H-benzo[b]aza Zhuo

Step 1: Preparation of 1-(7-bromo-2-chloro-6-fluoroquinazoline-4-yl)-2,3,4,5-tetrahydro-1H-benzo[b]azapine: 7-bromo-2,4-dichloro-6-fluoroquinazoline (500 mg, 1.69 mmol) and 2,3,4,5-tetrahydro-1H-1-benzozapine (249 mg, 1.69 mmol, 1 equivalent) were treated at room temperature with sodium hydride (155.4 mg, 4.1 mmol, 2.4 equivalents) in DMF (5 mL) for 3 hours. Water (30 mL) was added to the mixture, followed by extraction with EtOAc (30 mL, × 3). The organic layer was washed with brine (30 mL) and _dried over _Na₂SO₄ . The organic solvent was removed under reduced pressure to give the crude product, which was used in subsequent steps without further purification. Calculated values of LCMS-ESI+(m/z):[M+H]+C ₁₉ H ₁₇ BrFN ₅ : 406.00(M-1+1), 408.00(M+1+1), experimental values: 406.19(M-1+1), 408.14(M+1+1).

Step 2: Preparation of 1-(7-bromo-6-fluoro-2-hydrazineylquinazoline-4-yl)-2,3,4,5-tetrahydro-1H-benzo[b]azapyridine: 1-(7-bromo-2-chloro-6-fluoroquinazoline-4-yl)-2,3,4,5-tetrahydro-1H-benzo[b]azapyridine (506 mg, from Step 1) in ethanol (15 mL) and THF (4 mL) was treated with hydrazine hydrate (1675 mg, 27 equivalences) at 55 °C for 16 h. Water (30 mL) was added to the mixture and the entire mixture was extracted with EtOAc (30 mL, × 3). The organic layer was washed with brine (30 mL) and _dried over _Na₂SO₄ . The organic solvent was removed under reduced pressure to give the crude product. The crude product was purified by preparative reversed-phase high-performance liquid chromatography to obtain the calculated values of 1-(7-bromo-6-fluoro-2-hydrazinoquinazolin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[b]azapyrrolidone: LCMS-ESI+(m/z): [M+H]+C ₁₈ H ₁₇ BrFN ₅ : 402.07(M-1+1), 404.06(M+1+1), and experimental values: 402.23(M-1+1), 404.19(M+1+1).

Step 3: A solution of 8-bromo-7-fluoro-5-(2,3,4,5-tetrahydro-1H-benzo[b]azapyro-1-yl)-[1,2,4]triazolo[4,3-a]quinazoline:1-(7-bromo-6-fluoro-2-hydrazinoquinazoline-4-yl)-2,3,4,5-tetrahydro-1H-benzo[b]azapyroline (from Step 1) in triethyl orthoformate (427 mg, 2.88 mmol, 5 equivalents) was heated at 100 °C for 3 hours. The reaction mixture was purified by preparative reversed-phase high-performance liquid chromatography to obtain the title compound: ^¹H NMR (400 MHz, acetone- _d⁶ ) δ 9.71 (s, ¹H), 8.92 (d, J = 6.1 Hz, ¹H), 7.63 (dd, J = 7.6, 1.6 Hz, ¹H), 7.54 (td, J = 7.5, 1.3 Hz, ¹H), 7.37 (td, J = 7.6, 1.6 Hz, ¹H), 7.23 (dd, J = 7.8, 1.3 Hz, ¹H), 6.60 (d, J = 10.8 Hz, ¹H), 5.37 (s, ¹H), 3.03 (d, J = 5.9 Hz, 3H), 2.44–1.25 (m, 4H); LCMS (m/z) 412.2/414.2.

Example 499. 8-Bromo-1-ethyl-7-fluoro-N-methyl-N-phenyl-[1,2,4]triazolo[4,3-a]quinazolin- 5-amine

Example 499 was synthesized in a manner similar to that of Example 500, except that 1,1,1-trimethoxypropane was used instead of 1,1,1-triethoxyethane. ^¹H NMR (400 MHz, DMSO- _d⁶ ): d 8.30 (d, J = 6.0 Hz, 1H), 7.41 (dd, J = 8.6, 7.0 Hz, 2H), 7.30 (d, J = 7.8 Hz, 3H), 7.04 (d, J = 10.1 Hz, 1H), 3.52 (s, 3H), 3.34 (t, J = 7.3 Hz, 2H), 1.46 (t, J = 7.3 Hz, 3H); LCMS (m/z): 400.3/402.2.

Example 500. 8-Bromo-7-fluoro-N,1-dimethyl-N-phenyl-[1,2,4]triazolo[4,3-a]quinazolin-5- amine

A solution of 7-bromo-6-fluoro-2-hydrazino-N-methyl-N-phenylquinazoline-4-amine (20.0 mg, 0.0552 mmol) in 1,1,1-triethoxyethane (74.1 mg, 0.457 mmol, 8.3 equivalents) was stirred and heated at 100 °C for 1 hour. The resulting suspension was filtered. The filtrate was collected to give the title compound: ^¹H NMR (400 MHz, DMSO- _d⁶ ) δ 8.90 (d, J = 6.0 Hz, 1H), 7.94–7.83 (m, 2H), 7.82–7.70 (m, 3H), 7.63 (d, J = 10.1 Hz, 1H), 4.04 (s, 3H), 3.47 (s, 3H); LCMS (m/z) 386.2/388.1.

Example 501. 8-Bromo-7-fluoro-1-isopropyl-N-methyl-N-phenyl-[1,2,4]triazolo[4,3-a]quinazole 5-Lin-amine

Example 501 was synthesized in a manner similar to that of Example 500, except that 1,1,1-trimethoxy-2-methylpropane was used instead of 1,1,1-triethoxyethane. ^¹H NMR (400 MHz, DMSO- _d⁶ ) δ 8.29 (d, J = 6.0 Hz, 1H), 7.41 (dd, J = 8.4, 7.1 Hz, 2H), 7.36–7.23 (m, 3H), 7.06 (d, J = 10.1 Hz, 1H), 3.82 (p, J = 6.7 Hz, 1H), 3.52 (s, 3H), 1.45 (d, J = 6.6 Hz, 6H); LCMS (m/z) 414.2/416.2.

Example 502. (7-Fluoro-1-methyl-5-(methyl(phenyl)amino)-[1,2,4]triazolo[4,3-a]quinazolin- 8-methyl)methanol

A solution of 7,8-difluoro-N,1-dimethyl-N-phenyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine (Example 497, 15.0 mg, 0.0461 mmol) and 1-methyl-4-(methylthioalkylmethylsulfonyl)benzene (MT sulfone, 20 mg, 0.092 mmol, 2 equivalents) in DMF (2 mL) was treated with sodium hydride (60% in mineral oil, 10 mg) for 1 hour at room temperature. TFA (0.3 mL) was added to the reaction mixture. The reaction mixture was directly injected into a preparative reversed-phase high-performance liquid chromatography (Phenomenex Luna C18 column, 5% to 100% gradient acetonitrile in water containing 0.1% TFA) to give 7-fluoro-N,1-dimethyl-8-((methylthio)(toluenesulfonyl)methyl)-N-phenyl-[1,2,4]triazolo[4,3-a]quinazolin- ₅ - _{amine .} Calculated LCMS-ESI+ (m/z): [M+H] _{+ C26H24FN5O2S2} : 522.14 (M+1), experimental: 522.02 (M+1).

7-Fluoro-N,1-Dimethyl-8-((methylthio)(toluenesulfonyl)methyl)-N-phenyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine was dissolved in MeOH (3 mL) and 12N HCl (1 mL), stirred and heated at 80 °C for 16.5 h. THF (20 mL) was added to the mixture and the solvent was removed under reduced pressure. This was repeated three times to remove MeOH from the system (the aldehyde and its hydrate were observed by LCMS). The residue was dissolved in THF (2 mL) and water (1 mL). Sodium borohydride (excess) was added to the mixture and stirred at room temperature for 10 min. Water (30 mL) was added to the mixture and the entire mixture was extracted with EtOAc (30 mL, × 3). The organic layer was washed with brine (30 mL) and _dried over _Na₂SO₄ . The aqueous layer was concentrated to approximately 2 mL. The aqueous layer was purified by preparative reversed-phase high-performance liquid chromatography to obtain the title compound: ^¹H NMR (400MHz, methanol- _d⁴ ) δ 8.46 (d, J = 6.2 Hz, 1H), 7.65–7.49 (m, 3H), 7.48–7.38 (m, 2H), 6.80 (d, J = 11.8 Hz, 1H), 4.80 (s, 2H), 3.79 (s, 3H), 3.09 (s, 3H); LCMS (m/z) 338.3.

Example 503. 7-Fluoro-N-methyl-N-phenyl-8-(prop-1-yn-1-yl)-[1,2,4]triazolo[4,3-a]quinoline Azoline-5-amine

8-Bromo-7-fluoro-N-methyl-N-phenyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine (20 mg, 0.539 mmol), trimethyl(prop-2-ynyl)silane (12.1 mg, 0.108 mmol, 2 equivalents), DIPEA (13.9 mg, 0.108 mmol, 2 equivalents), CuI (2.1 mg, 0.108 mmol, 0.2 equivalents) and bis(triphenylphosphine)palladium chloride (3.8 mg, 0.0539 mmol, 0.1 equivalents) were heated in DMF (2 mL) under nitrogen atmosphere at 80 °C for 1 hour, at 100 °C for 1 hour, and then at 150 °C for 1 hour. After filtration, the mixture was purified by preparative reversed-phase high-performance liquid chromatography to obtain the title compound: ^¹H NMR (400MHz, methanol- _d⁴ ) δ 9.53 (s, 1H), 8.44 (d, J = 6.2 Hz, 1H), 7.67–7.54 (m, 3H), 7.52–7.38 (m, 2H), 6.68 (d, J = 11.2 Hz, 1H), 3.79 (s, 3H), 2.15 (s, 3H); LCMS (m/z) 332.2.

Example 504. 7-Fluoro-5-(2,3,4,5-tetrahydro-1H-benzo[b]azapyro-1-yl)-[1,2,4]triazolo [4,3-a]quinazolin-8-amine

Step 1: 8-Azide-7-fluoro-5-(2,3,4,5-tetrahydro-1H-benzo[b]azapyro-1-yl)-[1,2,4]triazolo[4,3-a]quinazoline: 8-bromo-7-fluoro-5-(2,3,4,5-tetrahydro-1H-benzo[b]azapyro-1-yl)-[1,2,4]triazolo[4,3-a]quinazoline (Example 498, 30.0 mg, 0.728 mmol) was treated at 100 °C with sodium azide (23.8 mg, 0.366 mmol, 5 equivalents) in DMSO (1 mL) for 60 min. Water (30 mL) was added to the mixture, followed by extraction with EtOAc (30 mL × 3). The organic layer was washed with brine (30 mL) and _dried over _Na₂SO₄ . The organic solvent was removed under reduced pressure to give the crude product. It was used in subsequent steps without further purification. Calculated value of 8-azido-7-fluoro-5-(2,3,4,5-tetrahydro-1H-benzo[b]azapyro-1-yl)-[1,2,4]triazolo[4,3-a]quinazoline: LCMS-ESI+(m/z): [M+H]+C ₁₉ H ₁₅ FN ₈ : 375.14 (M+1), experimental value: 375.02 (M+1).

Step 2: Preparation of 7-fluoro-5-(2,3,4,5-tetrahydro-1H-benzo[b]azapyro-1-yl)-[1,2,4]triazolo[4,3-a]quinazoline-8-amine: 8-azido-7-fluoro-5-(2,3,4,5-tetrahydro-1H-benzo[b]azapyro-1-yl)-[1,2,4]triazolo[4,3-a]quinazoline (35.5 mg, 0.0948 mmol) was treated at room temperature under a hydrogen atmosphere with 10% palladium on carbon (15.2 mg) in THF (2 mL) for 30 minutes. After filtration, the reaction mixture was purified by preparative reversed-phase high-performance liquid chromatography to obtain the title compound: ^¹H NMR (400MHz, methanol- _d⁴ ) δ 9.25 (s, 1H), 7.62–7.42 (m, 2H), 7.39–7.26 (m, 2H), 7.12 (d, J = 7.9Hz, 1H), 6.27 (d, J = 14.1Hz, 1H), 5.44 (s, 1H), 3.13 (s, 0H), 2.95 (s, 2H), 1.97 (d, J = 29.4Hz, 4H), 1.63 (s, 2H); LCMS (m/z) 349.2.

Example 505. 8-Chloro-7-fluoro-5-(2,3,4,5-tetrahydro-1H-benzo[b]azapyro-1-yl)-[1,2,4]tri Azo[4,3-a]quinazolin

7-Fluoro-5-(2,3,4,5-tetrahydro-1H-benzo[b]azapyro-1-yl)-[1,2,4]triazolo[4,3-a]quinazolin-8-amine (Example 504, 15.7 mg, 0.0451 mmol) was dissolved in 12N HCl (1 mL). Sodium nitrite (4.7 mg, 0.0676 mmol, 1.5 equivalent) in water (1 mL) was added to the solution at 0 °C, and the mixture was stirred at the same temperature for 1 hour. A solution of Cu(I)Cl (6.6 mg, 0.0676 mmol, 1.5 equivalent) in 12N HCl (1 mL) was added to the reaction mixture. The reaction temperature was then increased to 100 °C, and the mixture was stirred at the same temperature for 10 minutes. After filtration, the reaction mixture was purified by preparative reversed-phase high-performance liquid chromatography to obtain the title compound: ^¹H NMR (400MHz, methanol- _d⁴ ) δ 9.52 (s, 1H), 8.65 (d, J = 6.6 Hz, 1H), 7.64–7.48 (m, 2H), 7.36 (td, J = 7.6, 1.6 Hz, 1H), 7.15 (dd, J = 7.7, 1.3 Hz, 1H), 6.55 (d, J = 11.3 Hz, 1H), 5.43 (s, 1H), 3.00 (s, 2H), 2.06 (d, J = 19.6 Hz, 4H), 1.68 (s, 1H); LCMS (m/z) 350.4.

Example 506. 8-Bromo-5-(7-Bromo-3,4-dihydroquinoline-1(2H)-yl)-7-fluoro-[1,2,4]triazolo[4, 3-a]quinazoline

The title compound was prepared according to the procedure described for Example 498. ^¹H NMR (400 MHz, methanol- _d⁴ ) δ 9.63 (s, 1H), 8.87 (d, J = 5.9 Hz, 1H), 7.39 (dd, J = 8.1, 1.9 Hz, 1H), 7.33 (dd, J = 8.8, 5.9 Hz, 2H), 7.23 (d, J = 1.9 Hz, 1H), 4.15 (t, J = 6.7 Hz, 2H), 2.93 (t, J = 6.6 Hz, 2H), 2.16 (p, J = 6.7 Hz, 2H); LCMS (m/z) 478.1.

Example 507. 7-Fluoro-8-(prop-1-yn-1-yl)-5-(2,3,4,5-tetrahydro-1H-benzo[b]azapyro-1- (-[1,2,4]triazolo[4,3-a]quinazolin)

8-Bromo-7-fluoro-5-(2,3,4,5-tetrahydro-1H-benzo[b]azapyro-1-yl)-[1,2,4]triazolo[4,3-a]quinazoline (Example 498, 38.2 mg, 0.0929 mmol), trimethyl(prop-2-ynyl)silane (20.9 mg, 0.186 mmol, 2 equivalents), DIPEA (24.0 mg, 0.186 mmol, 2 equivalents), CuI (3.5 mg, 0.186 mmol, 0.2 equivalents) and bis(triphenylphosphine)palladium chloride (6.5 mg, 0.0539 mmol, 0.1 equivalents) were heated in DMF (2 mL) at 100 °C for 15.5 hours under a nitrogen atmosphere. After filtration, the reaction mixture was purified by preparative reversed-phase high-performance liquid chromatography to obtain the title compound: ^¹H NMR (400MHz, methanol- _d⁴ ) δ 9.50 (s, 1H), 8.44 (d, J = 6.3Hz, 1H), 7.63–7.46 (m, 2H), 7.35 (td, J = 7.6, 1.6Hz, 1H), 7.14 (dd, J = 7.9, 1.2Hz, 1H), 6.43 (d, J = 11.5Hz, 1H), 5.43 (br s, 1H), 3.20 (br s, 1H), 2.98 (br s, 2H), 2.15 (s, 3H), 2.07 (br s, 2H), 1.67 (br s, 1H), 1.30 (br d, J = 5.1Hz, 1H); LCMS (m/z) 372.3.

Example 508. 5-(7-(4-(tert-butyl)phenyl)-3,4-dihydroquinoline-1(2H)-yl)-7-fluoro-[1,2,4]tri Azo[4,3-a]quinazolin-8-amine

Example 508 was synthesized in a manner similar to that of Example 510, except that (4-(tert-butyl)phenyl)boronic acid was used instead of p-tolylboronic acid. ^¹H NMR (400 MHz, methanol- _d⁴ ) δ 9.27 (s, 1H), 7.42–7.27 (m, 5H), 7.24 (d, J = 8.4 Hz, 2H), 7.15 (d, J = 12.6 Hz, 1H), 6.92 (s, 1H), 4.06 (t, J = 6.5 Hz, 2H), 2.98 (t, J = 6.5 Hz, 2H), 2.19 (t, J = 6.5 Hz, 2H), 1.30 (s, 9H); LCMS (m/z) 467.4.

Example 509. 5-(7-bromo-3,4-dihydroquinoline-1(2H)-yl)-7-fluoro-[1,2,4]triazolo[4,3-a]quinoline Azoline-8-amine

The title compound was prepared according to the procedure described in Example 504. ^¹H NMR (400 MHz, methanol- _d⁴ ) δ 9.41 (s, 1H), 7.42 (d, J = 7.5 Hz, 1H), 7.34 (dd, J = 8.2, 1.9 Hz, 1H), 7.28 (d, J = 8.2 Hz, 1H), 7.20 (d, J = 1.9 Hz, 1H), 7.10 (d, J = 12.6 Hz, 1H), 4.12 (t, J = 6.6 Hz, 2H), 2.90 (t, J = 6.6 Hz, 2H), 2.13 (p, J = 6.6 Hz, 2H); LCMS (m/z) 413.2/415.2.

Example 510. 7-Fluoro-5-(7-(p-Tolyl)-3,4-Dihydroquinoline-1(2H)-yl)-[1,2,4]triazolidine [4,3-a]quinazolin-8-amine

5-(7-bromo-3,4-dihydroquinoline-1(2H)-yl)-7-fluoro-[1,2,4]triazolo[4,3-a]quinazolin-8-amine (Example 509, 7.2 mg, 0.0174 mmol), p-tolylboronic acid (4.7 mg, 0.0348 mmol, 2 equivalents), tetrakis(triphenylphosphine)palladium(O) (4.0 mg, 0.00348 mmol, 0.2 equivalents) and 2M-Na₂CO₃ (0.5 mL) were heated at 100 °C for 30 min under nitrogen atmosphere in 1,4-dioxane (2 mL). After filtration, the reaction mixture was purified by preparative reversed-phase high-performance liquid chromatography. The product was then further purified by silica gel column chromatography (gradient 0% to 20% MeOH/ _{CH₂Cl₂ )} to give the title compound: ^¹H NMR (400 MHz, methanol- _d₄) )δ9.27(s,1H),7.35(dd,J＝7.8,4.7Hz,2H),7.28(dd,J＝7.8,1.8Hz,1H),7.19(d,J＝8.1Hz,2H),7.15(d,J＝12.7Hz,1H),7.11(d,J＝8 .1Hz, 2H), 6.90 (d, J = 1.7Hz, 1H), 4.06 (t, J = 6.5Hz, 2H), 2.98 (t, J = 6.6Hz, 2H), 2.30 (s, 3H), 2.18 (p, J = 6.6Hz, 2H); LCMS (m/z) 425.3.

Example 511. 5-(7-(4-(tert-butyl)phenyl)-3,4-dihydroquinoline-1(2H)-yl)-8-chloro-7-fluoro-[1, [2,4]triazolo[4,3-a]quinazoline

5-(7-(4-(tert-butyl)phenyl)-3,4-dihydroquinolin-1(2H)-yl)-7-fluoro-[1,2,4]triazolo[4,3-a]quinazolin-8-amine (Example 508, 5.0 mg, 0.0107 mmol) was dissolved in 12N HCl (1 mL). Sodium nitrite (1.1 mg, 0.0161 mmol, 1.5 equivalent) in water (1 mL) was added to the solution at 0 °C, and the mixture was stirred for 30 minutes at the same temperature. A solution of Cu(I)Cl (1.6 mg, 0.0161 mmol, 1.5 equivalent) in 12N HCl (1 mL) was added to the reaction mixture. The reaction temperature was then increased to 100 °C, and the mixture was stirred for 10 minutes at the same temperature. Water (30 mL) was added to the mixture, and the entire mixture was extracted with EtOAc (30 mL, × 3). The organic layer was washed with brine (30 mL) and _dried over _Na₂SO₄ . The organic solvent was removed under reduced pressure to obtain a crude mixture. The crude mixture was purified by preparative reversed-phase high-performance liquid chromatography (RP-HPLC) to obtain the title compound: ^¹H NMR (400 MHz, methanol- _d⁴ ) δ 9.60 (s, 1H), 8.70 (d, J = 6.3 Hz, 1H), 7.64–7.46 (m, 2H), 7.42–7.20 (m, 6H), 4.25 (t, J = 6.8 Hz, 2H), 3.00 (dd, J = 8.1, 4.9 Hz, 2H), 2.20 (q, J = 6.6 Hz, 2H), 1.29 (s, 9H); LCMS (m/z) 486.4.

Example 512. 7-Fluoro-8-(methylthio)-5-(2,3,4,5-tetrahydro-1H-benzo[b]azapyro-1-yl)- [1,2,4]triazolo[4,3-a]quinazolin

8-Bromo-7-fluoro-5-(2,3,4,5-tetrahydro-1H-benzo[b]azapyro-1-yl)-[1,2,4]triazolo[4,3-a]quinazolin (Example 498) and 1-methyl-4-(methylthioalkylmethylsulfonyl)benzene (MT sulfone, 15.7 mg, 0.0728 mmol, 2 equivalents) in DMF (2 mL) were treated with sodium hydride (60% in mineral oil, 10 mg) for 1.5 hours at room temperature. The reaction mixture was directly injected into a preparative reversed-phase high-performance liquid chromatograph to obtain the title compound: ^¹H NMR (400 MHz, methanol- _d⁴ ) δ 9.55 (s, 1H), 7.94 (d, J = 6.8 Hz, 1H), 7.50 (dd, J = 7.6, 1.5 Hz, 1H), 7.37 (td, J = 7.5, 1.3 Hz, 1H), 7.21 (td, J = 7.6, 1.6 Hz, 1H), 6.94 (dd, J = 7.8, 1.2 Hz, 1H), 6.46 (d, J = 12.4 Hz, 1H), 3.04 (t, J = 5.9 Hz, 2H), 2.68 (s, 3H), 2.02–1.71 (m, 4H), 1.28 (d, J = 19.1 Hz, 2H); LCMS (m/z) 380.3.

Example 513. 5-(5-bromo-3,4-dihydroquinoline-1(2H)-yl)-7-fluoro-[1,2,4]triazolo[4,3-a]quinoline Azoline-8-amine

The title compound was prepared according to the procedure described in Example 504. ^¹H NMR (400 MHz, methanol- _d⁴ ) δ 9.38 (s, 1H), 7.44 (dd, J = 7.9, 1.2 Hz, 1H), 7.38 (d, J = 7.5 Hz, 1H), 7.13 (d, J = 12.4 Hz, 1H), 6.97 (t, J = 8.0 Hz, 1H), 6.91 (dd, J = 8.1, 1.2 Hz, 1H), 4.10 (t, J = 6.3 Hz, 2H), 3.02 (t, J = 6.7 Hz, 2H), 2.17 (p, J = 6.6 Hz, 2H); LCMS (m/z) 413.2/415.2.

Example 514. 7-Fluoro-5-(5-(p-Tolyl)-3,4-Dihydroquinoline-1(2H)-yl)-[1,2,4]triazolidine [4,3-a]quinazolin-8-amine

Example 514 was synthesized according to the method of Example 510, except that Example 513 was used instead of Example 509. ^¹H NMR (400MHz, DMSO- _d⁶ ) δ 9.41 (s, 1H), 7.38–7.23 (m, 5H), 7.12–6.98 (m, 2H), 6.91 (dd, J = 7.6, 1.2Hz, 1H), 6.72 (s, 2H), 6.68 (d, J = 8.1Hz, 1H), 3.83 (t, J = 6.7Hz, 2H), 2.74 (t, J = 6.5Hz, 2H), 2.38 (s, 3H), 2.02–1.88 (m, 2H); LCMS (m/z) 425.4.

Example 515. 7-Fluoro-5-(5-(4-fluorophenyl)-3,4-dihydroquinoline-1(2H)-yl)-[1,2,4]triazolidine [4,3-a]quinazolin-8-amine

Example 515 was synthesized according to the method of Example 510, except that (4-fluorophenyl)boronic acid was used instead of Example 509 and p-tolylboronic acid. ^¹H NMR (400 MHz, methanol- _d⁴ ) δ 9.25 (s, 1H), 7.43 (dd, J = 8.7, 5.4 Hz, 2H), 7.33 (d, J = 7.6 Hz, 1H), 7.21 (t, J = 8.8 Hz, 2H), 7.12–6.96 (m, 3H), 6.75 (d, J = 8.6 Hz, 1H), 3.98 (t, J = 6.9 Hz, 3H), 2.80 (t, J = 6.4 Hz, 3H), 2.11–1.97 (m, 4H); LCMS (m/z) 429.3.

Example 516. 7-Fluoro-5-(5-(4-(1-(trifluoromethyl)cyclopropyl)phenyl)-3,4-dihydroquinoline-1(2H)- (-[1,2,4]triazolo[4,3-a]quinazolin-8-amine)

Example 516 was synthesized according to the method of Example 510, except that Example 509 and p-tolylboronic acid were replaced with 4,4,5,5-tetramethyl-2-(4-(1-(trifluoromethyl)cyclopropyl)phenyl)-1,3,2-dioxaborane in place of Example 513. ^¹H NMR (400 MHz, methanol- _d4) )δ9.38(s,1H),7.62(d,J＝8.1Hz,2H),7.45(d,J＝8.2Hz,2H),7.38(d,J＝7.5H z,2H),7.26(dd,J＝7.6,1.4Hz,1H),7.20(t,J＝7.8Hz,1H),7.03(dd,J＝7.9,1. 3Hz,1H),6.96(d,J＝12.8Hz,1H),4.12(t,J＝7.1Hz,2H),2.84(t,J＝6.4Hz,2H ),2.11–1.97(m,2H),1.47–1.37(m,2H),1.22–1.10(m,2H); LCMS(m/z)519.4.

Example 517. 5-(5-(3,3-dimethylbut-1-yn-1-yl)-3,4-dihydroquinoline-1(2H)-yl)-7-fluoro- [1,2,4]triazolo[4,3-a]quinazolin-8-amine

Example 517 was prepared according to the method of Example 522, except that 3,3-dimethylbut-1-yne was used instead of ethynylcyclopropane. ^¹H NMR (400 MHz, methanol- _d⁴ ) δ 9.24 (s, 1H), 7.27 (d, J = 7.5 Hz, 1H), 7.15–7.00 (m, 2H), 6.87 (t, J = 7.9 Hz, 1H), 6.57 (d, J = 8.1 Hz, 1H), 3.97 (s, 2H), 3.02 (t, J = 6.7 Hz, 2H), 2.14 (t, J = 6.5 Hz, 2H), 1.36 (s, 9H); LCMS (m/z) 415.4.

Example 518. (R)-7-fluoro-5-(2-methyl-3,4-dihydroquinoline-1(2H)-yl)-[1,2,4]triazolo[4, [3-a]quinazolin-8-amine

The title compound was prepared according to the procedure described in Example 504. ^¹H NMR (400 MHz, methanol- _d4) )δ9.33(s,1H),7.40(dd,J＝7.6,1.4Hz,1H),7.34(d,J＝7.6Hz,1H),7.26(td,J＝ 7.5,1.2Hz,1H),7.13(td,J＝7.7,1.5Hz,1H),6.96–6.88(m,1H),6.77(d,J＝13. 0Hz,1H),5.00(q,J＝6.5Hz,1H),3.00–2.75(m,2H),2.53(dq,J＝13.3,6.5Hz,1H ), 1.64 (ddt, J＝13.7, 8.5, 5.8Hz, 1H), 1.31 (d, J＝6.5Hz, 3H); LCMS (m/z) 349.2.

Example 519. (R)-8-chloro-7-fluoro-5-(2-methyl-3,4-dihydroquinoline-1(2H)-yl)-[1,2,4]triazole [4,3-a]quinazolin

The title compound was prepared according to the procedure described in Example 505. ^¹H NMR (400 MHz, methanol- _d⁴ ) δ 9.55 (s, ¹H), 8.62 (d, J = 6.3 Hz, ¹H), 7.44 (d, J = 7.5 Hz, ¹H), 7.30 (t, J = 7.5 Hz, ¹H), 7.13 (t, J = 7.9 Hz, ¹H), 7.04 (d, J = 10.3 Hz, ¹H), 6.91 (d, J = 7.8 Hz, ¹H), 5.08 (s, ¹H), 2.99–2.86 (m, ³H), 2.60 (d, J = 6.3 Hz, ¹H), 1.70–1.80 (m, ¹H), 1.38 (d, J = 6.4 Hz, 4H); LCMS (m/z) 368.2.

Example 520. 7-Fluoro-5-(2-methyl-3,4-dihydroquinoline-1(2H)-yl)-[1,2,4]triazolo[4,3-a] Quinazoline-8-amine

The title compound was prepared according to the procedure described in Example 504. LCMS (m/z) 349.3.

Example 521. 8-Chloro-7-fluoro-5-(2-methyl-3,4-dihydroquinoline-1(2H)-yl)-[1,2,4]triazolo [4,3-a]quinazolin

The title compound was prepared according to the procedure described in Example 505. ^¹H NMR (400 MHz, methanol- _d⁴ ) δ 9.57 (s, ¹H), 8.67 (d, J = 6.4 Hz, ¹H), 7.50 (d, J = 7.5 Hz, ¹H), 7.40 (td, J = 7.5, 1.1 Hz, ¹H), 7.19 (td, J = 7.7, 1.4 Hz, ¹H), 7.03 (d, J = 7.9 Hz, ¹H), 6.98 (d, J = 10.5 Hz, ¹H) ),5.17(dt,J＝7.8,6.2Hz,1H),3.01–2.79(m,2H),2.67(ddt,J＝13.3,8.0,5.4Hz, 1H), 1.62 (ddt, J=12.7, 9.6, 6.1Hz, 1H), 1.37 (d, J=6.4Hz, 3H); LCMS (m/z) 368.2.

Example 522. 5-(5-(cyclopropylethynyl)-3,4-dihydroquinoline-1(2H)-yl)-7-fluoro-[1,2,4]tri Azo[4,3-a]quinazolin-8-amine

5-(5-bromo-3,4-dihydroquinoline-1(2H)-yl)-7-fluoro-[1,2,4]triazolo[4,3-a]quinazolin-8-amine (Example 513, 35.0 mg, 0.0847 mmol), ethynylcyclopropane (56.0 mg, 0.847 mmol, 10 equivalents), DIPEA (219.0 mg, 1.69 mmol, 20 equivalents), zinc bromide (191.0 mg, 0.847 mmol, 10 equivalents), and [1,1'-bis(diphenylphosphine)ferrocene]palladium(II) dichloride (6.3 mg, 0.00847 mmol, 0.1 equivalents) were heated in NMP (2 mL) at 100 °C for 30 minutes, at 120 °C for 1 hour, and at 120 °C for 1 hour under a nitrogen atmosphere. After filtration, the reaction mixture was purified by preparative reversed-phase high-performance liquid chromatography to obtain the title compound: ^¹H NMR (400MHz, methanol- _d4) )δ9.37(s,1H),7.37(d,J＝7.5Hz,1H),7.25(dd,J＝7.7,1.1Hz,1H),7.08–6.95(m,2H),6.90(dd,J＝8.1,1.1Hz,1H),4.13(t,J＝6.5Hz,2H),3 .03(t,J＝6.7Hz,2H),2.15(p,J＝6.6Hz,2H),1.56(tt,J＝8.3,5.0Hz,1H),0.95(dt,J＝8.2,3.2Hz,2H),0.86–0.75(m,2H); LCMS(m/z)399.3.

Example 523. 5-(5-(cyclopropylethynyl)-3,4-dihydroquinoline-1(2H)-yl)-7-fluoro-[1,2,4]tri Azo[4,3-a]quinazolin-8-amine

5-(5-(cyclopropylethynyl)-3,4-dihydroquinolin-1(2H)-yl)-7-fluoro-[1,2,4]triazolo[4,3-a]quinazolin-8-amine (Example 522, 6.5 mg, 0.0163 mmol) and copper chloride (I) (2.4 mg, 0.0245 mmol, 1.5 equivalents) were dissolved in acetonitrile (0.5 mL). A solution of tert-butyl nitrite (2.5 mg, 0.0245 mmol, 1.5 equivalents) in acetonitrile (0.5 mL) was added to the mixture. Since the reaction was not completed after 40 minutes at room temperature, additional reagents [copper chloride (I) (4.8 mg, 3.0 equivalents) and tert-butyl nitrite (5.0 mg, 3.0 equivalents)] were added. The reaction mixture was stirred at room temperature for 1 hour and 20 minutes. After filtration, the reaction mixture was purified by preparative reversed-phase high-performance liquid chromatography to obtain the title compound: ^¹H NMR (400 MHz, methanol- _d⁴ ) δ 9.61 (s, 1H), 8.70 (d, J = 6.4 Hz, 1H), 7.40–7.18 (m, 2H), 7.04 (t, J = 7.9 Hz, 1H), 6.93 (dd, J = 8.2, 1.2 Hz, 1H), 4.19 (t, J = 6.7 Hz, 2H), 3.07 (t, J = 6.6 Hz, 2H), 2.18 (quin, J = 6.6 Hz, 2H), 1.57 (tt, J = 8.3, 5.0 Hz, 1H), 1.09–0.90 (m, 2H), 0.89–0.73 (m, 2H); LCMS (m/z) 418.3.

Example 524. 5-(5-cyclopropyl-3,4-dihydroquinoline-1(2H)-yl)-7-fluoro-[1,2,4]triazolo[4,3- a] Quinazoline-8-amine

5-(5-bromo-3,4-dihydroquinoline-1(2H)-yl)-7-fluoro-[1,2,4]triazolo[4,3-a]quinazolin-8-amine (Example 513, 35.0 mg, 0.0847 mmol), cyclopropylboronic acid (43.6 mg, 0.508 mmol, 6 equivalents), diacetoxypalladium (3.8 mg, 0.0169 mmol, 0.2 equivalents), tricyclohexylphosphine (19 mg, 0.0678 mmol, 0.8 equivalents), and dipotassiooxyphosphoryloxypotassium (162 mg, 0.762 mmol, 9 equivalents) were heated at 100 °C for 21 hours under nitrogen atmosphere in 1,4-dioxane (2 mL) and water (0.2 mL). After filtration, the reaction mixture was purified by preparative reversed-phase high-performance liquid chromatography to obtain the title compound: ^¹H NMR (400MHz, methanol- _d⁴ ) δ 9.34 (s, ¹H), 7.35 (d, J = 7.6 Hz, ¹H), 7.05–6.94 (m, 2H), 6.91 (d, J = 12.9 Hz, 1H), 6.80 (dd, J = 7.5, 1.6 Hz, 1H), 4.15 (t, J = 6.4 Hz, 2H), 3.11 (t, J = 6.7 Hz, 2H), 2.18 (p, J = 6.6 Hz, 2H), 2.06 (ddd, J = 13.9, 8.6, 5.4 Hz, 1H), 1.11–0.97 (m, 2H), 0.80–0.63 (m, 2H); LCMS (m/z) 375.2.

Example 525. 8-Chloro-N-methyl-N-(4'-morpholino-[1,1'-diphenyl]-3-yl)-[1,2,4]triazolidine [4,3-a]quinazolin-5-amine

To a solution of N-(3-bromophenyl)-8-chloro-N-methyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine (Example 308, 35.0 mg, 0.090 mmol) in dioxane (1.0 mL), a 2 M aqueous solution of 4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborhexacyclopentan-2-yl)phenyl)morpholine (26.0 mg, 0.09 mmol), Pd(dppf) _Cl₂ (3.72 mg, 4.5 μmmol), and _Na₂CO₃ (47.7 _mg , 0.450 mmol) was added. The mixture was purged with nitrogen and heated at 100 °C for 15 minutes. After completion, the mixture was diluted with EA, filtered, and concentrated under reduced pressure. The crude product was dissolved in DMSO and purified by reversed-phase HPLC, providing the title compound: ^¹H NMR (400 MHz, DMSO- _d⁶ ) δ 9.80 (s, 1H), 8.63 (d, J = 1.9 Hz, 1H), 7.66 (d, J = 8.2 Hz, 2H), 7.55–7.50 (m, 3H), 7.44–7.40 (m, 1H), 7.32 (d, J = 8.4 Hz, 1H), 7.26 (d, J = 9.1 Hz, 1H), 6.99 (d, J = 8.8 Hz, 2H), 3.77–3.70 (m, 4H), 3.68 (s, 3H), 3.18–3.10 (m, 4H); LCMS (m/z) 471.1.

Example 526. 1-(3'-((8-chloro-[1,2,4]triazolo[4,3-a]quinazolin-5-yl)(methyl)amino)- [1,1'-Diphenyl]-4-yl)cyclopropane-1-carboxynitrile

Example 526 was prepared according to the method of Example 525. ^¹H NMR (400MHz, DMSO- _d⁶ ) δ 9.78 (s, 1H), 8.63 (d, J = 1.9 Hz, 1H), 7.76–7.66 (m, 4H), 7.67 (d, J = 8.5 Hz, 3H), 7.56 (t, J = 7.9 Hz, 1H), 7.44–7.35 (m, 5H), 7.26 (d, J = 9.0 Hz, 1H), 3.68 (s, 3H), 1.79 (m, 2H), 1.55–1.50 (m, 2H); LCMS (m/z) 451.1.

Example 527. (1-(3'-((8-chloro-[1,2,4]triazolo[4,3-a]quinazolin-5-yl)(methyl)amino)- [1,1'-diphenyl]-4-yl)cyclopropyl)methanol

Synthesis of (1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)phenyl)cyclopropyl)methanol: (1-(4-bromophenyl)cyclopropyl)methanol (60.0 mg, 0.264 mmol), bis(pinacol)diboron (80.5 mg, 0.317 mmol), PdCl₂( _PPh₃ ) _{₂ (} 9.27 mg, 0.013 mmol), KOAc (77.8 mg, 0.793 mmol), and dioxacyclohexane (1 mL) were added to a microwave-safe vial equipped with a stir bar. The vial was purged with nitrogen, sealed, and the mixture was irradiated at 120 °C for 45 min. The mixture was then diluted with EA, filtered, concentrated under reduced pressure, and used in the next step without further purification. MS (m/z) 297.1 [M+Na] ^⁺ .

Synthesis of (1-(3'-((8-chloro-[1,2,4]triazolo[4,3-a]quinazolin-5-yl)(methyl)amino)-[1,1'-diphenyl]-4-yl)cyclopropyl)methanol: To a solution of N-(3-bromophenyl)-8-chloro-N-methyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine (Example 308, 103 mg, 0.264 mmol) in dioxane (2.6 mL), (1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborhexacyclopentan-2-yl)phenyl)cyclopropyl)methanol (72.4 mg, 0.264 mmol), Pd(dppf) _Cl₂ (10.9 mg, 0.013 mmol) and _Na₂CO₃ were added. ₃ % of a 2M aqueous solution (140 mg, 1.32 mmol) was prepared, and the mixture was purged with nitrogen and then heated at 100 °C for 10 minutes. After completion, the mixture was diluted with EA, filtered, and concentrated under reduced pressure. The crude product was dissolved in DMSO and purified by reversed-phase HPLC, providing the title compound: ^¹H NMR (400MHz, DMSO- _d⁶ ) δ 9.80 (s, ¹H), 8.63 (d, J = 1.9 Hz, ¹H), 7.68 (m, 2H), 7.61–7.50 (m, 4H), 7.45–7.37 (m, 2H), 7.35 (d, J = 8.3 Hz, 2H), 7.24 (d, J = 9.1 Hz, 1H), 3.68 (s, 2H), 3.54 (s, 2H), 0.86 (m, 2H), 0.73 (m, 2H); LCMS (m/z) 456.2.

Example 528. (R)-8-chloro-N-methyl-N-(4'-(3-(trifluoromethyl)morpholino)-[1,1'-diphenyl]-3- (-[1,2,4]triazolo[4,3-a]quinazolin-5-amine)

Synthesis of (R)-4-(4-bromophenyl)-3-(trifluoromethyl)morpholine: A solution of 1,4-dibromobenzene (200 mg, 0.848 mmol), (R)-3-(trifluoromethyl)morpholine hydrochloride (171 mg, 0.890 mmol), sodium tert-butoxide (204 mg, 2.12 mmol), and _Pd₂ (dba) _₃ (38.8 mg, 0.042 mmol) in toluene (1.00 mL) was purged with nitrogen and heated at 90 °C for 30 min. After completion, the reaction mixture was diluted with EA, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel chromatography, eluting with EA in hexane at 0-100%. MS (m/z) 310.1 [M+H] ^⁺ .

Synthesis of (R)-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborhexacyclopentan-2-yl)phenyl)-3-(trifluoromethyl)morpholine: (R)-4-(4-bromophenyl)-3-(trifluoromethyl)morpholine (30.0 mg, 0.097 mmol), bis(pinacol)diboron (29.5 mg, 0.116 mmol), PdCl₂( _PPh₃ ) _{₂ (} 3.40 mg, 0.0048 mmol), KOAc (28.5 mg, 0.290 mmol), and dioxane (1 mL) were charged into a microwave-safe vial equipped with a stir bar. The vial was purged with nitrogen, sealed, and the reaction mixture was irradiated at 120 °C for 45 min. The mixture was then diluted with EA, filtered, concentrated under reduced pressure, and used in the next step without further purification. MS(m/z)358.2[M+H] ⁺ .

Synthesis of (R)-8-chloro-N-methyl-N-(4'-(3-(trifluoromethyl)morpholino)-[1,1'-diphenyl]-3-yl)-[1,2,4]triazolo[4,3-a]quinazolin-5-amine: N-(3-bromophenyl)-8-chloro-N-methyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine (37.6 mg, 0.097 mmol), (R)-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)phenyl)-3-(trifluoromethyl)morpholine (34.6 mg, 0.097 mmol), _PdCl₂ ( _PPh₃ ) _₂ (3.40 mg, 0.0048 mmol), and _Na₂CO₃ were added to a microwave-safe vial. ₃ % 2M aqueous solution (51.3 mg, 0.484 mmol) and dioxane (1.0 mL). The mixture was purged with nitrogen, sealed, and irradiated at 100 °C for 1 hour. After completion, the mixture was diluted with EA, filtered, and concentrated under reduced pressure. The crude product was dissolved in DMSO and purified by reversed-phase HPLC, providing the title compound: ^¹H NMR (400 MHz, DMSO-d6 ₎ )δ9.73(s,1H),8.60(d,J＝1.9Hz,1H),7.67(s,1H),7.62(d,J＝8.6Hz,1H),7.5 5(d,J＝8.7Hz,2H),7.48(t,J＝7.9Hz,1H),7.38(d,J＝9.3Hz,1H),7.29(d,J＝9.0 Hz,2H),7.05(d,J＝8.9Hz,2H),4.85(m,1H),4.16(d,J＝12.5Hz,1H),3.99(s,1H ),3.79(s,1H),3.65(s,3H),3.60–3.52(m,1H),3.33(m,2H); LCMS(m/z)539.2.

Example 529. 7,8-Dichloro-N-methyl-N-(3-(6-(trifluoromethyl)pyridin-3-yl)phenyl)-[1,2,4] Triazolo[4,3-a]quinazolin-5-amine

Synthesis of 7,8-dichloro-N-methyl-N-(3-(6-(trifluoromethyl)pyridin-3-yl)phenyl)-[1,2,4]triazolo[4,3-a]quinazolin-5-amine: The title compound was prepared starting with Example 530 and [6-(trifluoromethyl)-3-pyridinyl]boronic acid, according to the method provided for Synthesis Example 528. ¹ H NMR (400MHz, DMSO-d ₆ )δ9.72(s,1H),9.06(d,J＝2.2Hz,1H),8.82(s,1H),8.37(dd,J＝8.2,2.2Hz,1H),7.98(d,J＝8.2Hz,1H),7.92(d,J＝2.0Hz, 1H), 7.85 (d, J = 7.5Hz, 1H), 7.66 (t, J = 7.9Hz, 1H), 7.55 (dd, J = 7.7, 2.2Hz, 1H), 7.32 (s, 1H), 3.66 (s, 3H); LCMS (m/z) 489.

Example 530. N-(3-bromophenyl)-7,8-dichloro-N-methyl-[1,2,4]triazolo[4,3-a]quinazolin-5- amine

Synthesis of 6,7-dichloroquinazoline-2,4(1H,3H)-dione: A mixture of urea (2.86 g, 47.6 mmol) and 2-amino-4,5-dichlorobenzoic acid (1.00 g, 4.76 mmol) was heated at 160 °C for 18 h. The mixture was cooled to 100 °C, and water was added to suspend the substance, and heating was continued for another 10 min. The resulting mixture was filtered and transferred to a flask. 0.5 N NaOH (aqueous) solution was added until a suspension was formed, and the mixture was heated at 100 °C for 10 min. The reaction was then cooled to room temperature, and the pH was adjusted to pH 2 with concentrated HCl, and the mixture was filtered. The resulting residue was washed with water:MeOH (1:1) (60 mL) and dried under vacuum to provide the product: MS (m/z) 230.9 [M+H] ⁺ .

Synthesis of 2,4,6,7-tetrachloroquinazoline: Phosphoryl chloride (3.84 g, 25.1 mmol) was added dropwise to a mixture of 6,7-dichloroquinazoline-2,4(1H,3H)-dione (467 mg, 1.98 mmol) and DIPEA (538 mg, 4.16 mmol) at room temperature. The mixture was stirred at room temperature for 5 minutes, then heated at 107 °C for 3 hours. The mixture was then carefully poured onto crushed ice and stirred vigorously until a suspension was formed. DCM was added to the mixture and transferred to a separatory funnel. The aqueous layer was extracted with DCM (×2), and the combined organic layers were washed with 10% citric acid solution (aqueous solution), washed with brine, and _dried over _Na₂SO₄ . The solvent was removed under reduced pressure to give the desired intermediate.

Synthesis of N-(3-bromophenyl)-2,6,7-trichloro-N-methylquinazoline-4-amine: NaH (60% dispersion in mineral oil) (148 mg, 3.87 mmol) was added in a single addition to a solution of 2,4,6,7-tetrachloroquinazoline (451 mg, 1.68 mmol) and 3-bromo-N-methylaniline (329 mg, 1.77 mmol) in DMF (4.0 mL) at 0 °C. The cold bath was removed, and the mixture was stirred at room temperature for 2 hours. After completion, the reaction was cooled to 0 °C, and a saturated _NH₄Cl (aqueous) solution was slowly added. The reactants were transferred to a separatory funnel and extracted with EA (×3). The combined organic layers were washed with brine, dried over _{Na₂SO₄ ,} and concentrated under reduced pressure to provide a crude product. This crude product was suspended in heptane, filtered, and further dried under vacuum to provide the indicated intermediate: MS (m/z) 416.1 [M+H] ^⁺ .

Synthesis of (E)-N-(3-bromophenyl)-6,7-dichloro-2-hydrazinyl-N-methyl-1,2-dihydroquinazoline-4-amine: Hydrazine monohydrate (141 mg, 2.81 mmol) was added to a solution of N-(3-bromophenyl)-2,6,7-trichloro-N-methylquinazoline-4-amine (236 mg, 0.565 mmol) in THF (5.60 mL) and ethanol (9.40 mL), and the mixture was stirred at 50 °C for 1 hour. After completion, the reaction was cooled to room temperature, concentrated under reduced pressure, and dried under vacuum to provide the intermediate. MS (m/z) 414.1 [M+H] ⁺ .

Synthesis of N-(3-bromophenyl)-7,8-dichloro-N-methyl-[1,2,4]triazolo[4,3-a]quinazoline-5-amine: A solution of (E)-N-(3-bromophenyl)-6,7-dichloro-2-hydrazyl-N-methyl-1,2-dihydroquinazoline-4-amine (234 mg, 0.566 mmol) and triethyl orthoformate (1.65 g, 11.1 mmol) was heated to 100 °C for 30 minutes. After completion, the reactants were cooled to room temperature and concentrated under reduced pressure to provide a crude product. The crude product was ground with heptane, and the residue was collected by filtration, washed with heptane:ether (3:1), and dried under vacuum to provide a partially purified product. The crude material was dissolved in DMSO and purified by reversed-phase HPLC, providing the title compound: ^¹H NMR (400MHz, DMSO- _d₆ ) δ 9.74 (s, 1H), 8.85 (s, 1H), 7.73 (s, 1H), 7.58 (m, 1H), 7.43 (m, 2H), 7.27 (s, 1H), 3.59 (s, 3H); LCMS (m/z) 422.1.

Example 531. 8-Chloro-N-(4'-(cyclopropylsulfonyl)-[1,1'-diphenyl]-3-yl)-N-methyl-[1,2, 4] Triazolo[4,3-a]quinazolin-5-amine

Example 531 was prepared according to the method of Example 525. ^¹H NMR (400MHz, DMSO- _d⁶ ) δ 9.81 (s, 1H), 8.64 (d, J = 1.9Hz, 1H), 7.94 (m, 4H), 7.87 (s, 1H), 7.80 (d, J = 7.8Hz, 1H), 7.62 (t, J = 7.9Hz, 1H), 7.50 (d, J = 7.7Hz, 1H), 7.42 (dd, J = 9.1, 2.0Hz, 1H), 7.27 (d, J = 9.1Hz, 1H), 3.70 (s, 3H), 2.93–2.85 (m, 1H), 1.13 (d, J = 6.9Hz, 2H), 1.05 (d, J = 10.0Hz, 2H); LCMS (m/z) 490.1.

Example 532. 8-Chloro-N-methyl-N-(4'-((trifluoromethyl)sulfonyl)-[1,1'-diphenyl]-3-yl)- [1,2,4]triazolo[4,3-a]quinazolin-5-amine

Example 532 was prepared according to the method of Example 525. ^¹H NMR (400MHz, DMSO- _d⁶ ) δ 9.80 (d, J = 1.9Hz, 1H), 8.64 (s, 1H), 8.20 (d, J = 8.3Hz, 2H), 8.13 (d, J = 8.4Hz, 2H), 7.95 (s, 1H), 7.84 (d, J = 7.9Hz, 1H), 7.64 (t, J = 7.8Hz, 1H), 7.53 (d, J = 7.8Hz, 1H), 7.41 (d, J = 9.0Hz, 1H), 7.29 (d, J = 9.0Hz, 1H), 3.69 (s, 3H); LCMS (m/z) 518.1.

Example 533. (S)-8-chloro-N-methyl-N-(4'-(3-(trifluoromethyl)morpholino)-[1,1'-diphenyl]-3- (-[1,2,4]triazolo[4,3-a]quinazolin-5-amine)

Synthesis of (S)-8-chloro-N-methyl-N-(4'-(3-(trifluoromethyl)morpholino)-[1,1'-diphenyl]-3-yl)-[1,2,4]triazolo[4,3-a]quinazolin-5-amine: The title compound was prepared according to the method provided for Synthetic Example 528, except that it began with (S)-3-(trifluoromethyl)morpholino. ^¹H NMR (400 MHz, DMSO-d6 ₎ )δ9.76(s,1H),8.61(d,J＝1.6Hz,1H),7.68(s,1H),7.64(d,J＝8.1Hz,1H),7.54(d,J＝8.7Hz, 2H),7.49(t,J＝7.9Hz,1H),7.40(dd,J＝9.2,1.7Hz,1H),7.31–7.24(m,2H),7.06(d,J＝8.8Hz, 2H),4.91–4.79(m,1H),4.17(d,J＝12.6Hz,1H),3.98(d,J＝10.3Hz,1H),3.78(d,J＝14.7Hz,1H ), 3.66 (s, 3H), 3.58 (td, J = 12.9, 12.5, 6.6Hz, 1H), 3.31 (d, J = 16.0Hz, 2H); LCMS (m/z) 540.2.

Example 534. N-(4'-((2-oxa-6-azaspiro[3.3]hept-6-yl)sulfonyl)-[1,1'-diphenyl]- 3-yl)-8-chloro-N-methyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine

Example 534 was prepared according to the method of Example 525. ^¹H NMR (400MHz, DMSO- _d⁶ ) δ 9.65 (s, 1H), 8.56 (d, J = 2.0Hz, 1H), 7.95 (d, J = 8.4Hz, 2H), 7.82 (d, J = 8.4Hz, 2H), 7.79 (s, 1H), 7.69 (d, J = 7.7Hz, 1H), 7.53 (t, J = 7.9Hz, 1H), 7.39 (d, J = 8.9Hz, 1H), 7.33 (s, 2H), 4.44 (s, 4H), 3.90 (s, 4H), 3.61 (s, 3H); LCMS (m/z) 547.1.

Example 535. 3'-((8-chloro-[1,2,4]triazolo[4,3-a]quinazolin-5-yl)(methyl)amino)-N- (1-Methylcyclobutyl)-[1,1'-diphenyl]-4-sulfonamide

Synthesis of 4-bromo-N-(1-methylcyclobutyl)benzenesulfonamide: DIPEA (202 mg, 1.57 mmol) was added to a suspension of 4-bromobenzenesulfonyl chloride (200 mg, 0.783 mmol) and 1-methylcyclobutylamine (80.0 mg, 0.939 mmol) in DCM (3.10 mL) under an inert atmosphere at room temperature. The reaction was stirred for 18 hours and then concentrated under reduced pressure. The crude residue was purified by silica gel chromatography, eluting with 0–25% EA in hexane to provide the desired sulfonamide. MS (m/z) 303.5 [M+H] ⁺ . ^1H NMR (400MHz, chloroform-d) δ 7.75 (d, J = 8.7Hz, 2H), 7.63 (d, J = 8.7Hz, 2H), 2.16 (d, J = 9.4Hz, 2H), 1.92–1.82 (m, 2H), 1.79–1.67 (m, 2H), 1.38 (s, 3H).

Synthesis of N-(1-methylcyclobutyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborhexacyclopentan-2-yl)benzenesulfonamide: A solution of 4-bromo-N-(1-methylcyclobutyl)benzenesulfonamide (52.0 mg, 0.171 mmol), bis(pinacol)diboron (52.1 mg, 0.205 mmol), Pd(dppf) _Cl₂ (2.79 mg, 0.0034 mmol), KOAc (50.3 mg, 0.513 mmol), and dioxane (1.10 mL) was purged with nitrogen and heated at 100 °C for 90 min. After completion, the mixture was diluted with EA, filtered, concentrated under reduced pressure, and used in the next step without further purification. MS (m/z) 352.2 [M+H] ^⁺ .

Synthesis of 3'-((8-chloro-[1,2,4]triazolo[4,3-a]quinazolin-5-yl)(methyl)amino)-N-(1-methylcyclobutyl)-[1,1'-diphenyl]-4-sulfonamide: N-(1-methylcyclobutyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborhexacyclopentan-2-yl)benzenesulfonamide (29.8 mg, 0.085 mmol), Pd(dppf)Cl₂ (3.19 mg, 3.90 μmol), and Na₂CO₃ were added to a solution of N-(3-bromophenyl)-8-chloro-N-methyl-[1,2,4]triazolo[4,3-a]quinazolin- _5- amine (Example 308, 30.0 mg, 0.077 mmol) in dioxane ( _0.7 mL). ₃ % of a 2M aqueous solution (40.9 mg, 0.386 mmol) was used to purge the mixture with nitrogen and heat it at 87°C for 10 minutes. After completion, EA was added, and the mixture was filtered and concentrated under reduced pressure. The crude product was dissolved in DMSO and purified by reversed-phase HPLC, providing the title compound: ^¹H NMR (400MHz, DMSO- _d⁶ ) δ 9.79 (s, 1H), 8.63 (d, J = 2.0Hz, 1H), 7.91 (s, 1H), 7.86 (s, 5H), 7.77 (d, J = 7.9Hz, 1H), 7.58 (t, J = 7.9Hz, 1H), 7.45–7.39 (m, 2H), 7.29 (d, J = 9.0Hz, 1H), 3.68 (s, 3H), 2.18–2.05 (m, 2H), 1.69–1.55 (m, 4H), 1.27 (s, 3H); LCMS (m/z) 533.1.

Example 536. 7,8-Dichloro-N-methyl-N-(4'-(methanesulfonyl)-[1,1'-diphenyl]-3-yl)-[1, [2,4]triazolo[4,3-a]quinazolin-5-amine

Synthesis of 7,8-dichloro-N-methyl-N-(4'-(methanesulfonyl)-[1,1'-diphenyl]-3-yl)-[1,2,4]triazolo[4,3-a]quinazolin-5-amine: The title compound was prepared starting with Example 530 and 4,4,5,5-tetramethyl-2-(4-methylsulfonylphenyl)-1,3,2-dioxaborane according to the method provided for Synthesis Example 528. ¹ H NMR (400MHz, DMSO-d ₆ )δ9.73(s,1H),8.82(s,1H),7.99(d,J＝8.6Hz,2H),7.94(d,J＝8.6Hz,2H),7.87(s,1H),7.82(d,J＝8.0Hz, 1H), 7.65 (t, J＝7.9Hz, 1H), 7.52 (d, J＝6.7Hz, 1H), 7.27 (s, 1H), 3.68 (s, 3H), 3.24 (s, 3H); LCMS (m/z) 498.

Example 537. N-(4'-(2-oxa-6-azaspiro[3.3]hept-6-yl)-[1,1'-diphenyl]-3-yl)-8- Chloro-N-methyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine

Synthesis of N-(4'-(2-oxa-6-azaspiro[3.3]hept-6-yl)-[1,1'-diphenyl]-3-yl)-8-chloro-N-methyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine: The title compound was prepared according to the method provided for Synthesis Example 528, except that it began with 2-oxa-6-azaspiro[3.3]heptane. ¹ H NMR (400MHz, DMSO-d ₆ )δ9.62(s,1H),8.53(d,J＝1.9Hz,1H),7.53–7.44(m,4H),7.39(d,J＝7.8Hz,1H),7.30(d,J＝1.2Hz,2H),7 .19–7.13(m,1H),6.45(dd,J＝9.0,2.3Hz,2H),4.71(s,4H),3.98(s,4H),3.58(s,3H); LCMS(m/z)483.2.

Example 538. 8-Chloro-N-(4'-(isobutylsulfonyl)-[1,1'-diphenyl]-3-yl)-N-methyl-[1,2, 4] Triazolo[4,3-a]quinazolin-5-amine

Synthesis of 8-chloro-N-(4'-(isobutylsulfonyl)-[1,1'-diphenyl]-3-yl)-N-methyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine: The title compound was prepared according to the method provided for synthetic Example 525. ¹ H NMR (400MHz, DMSO-d ₆ )δ9.75(s,1H),8.61(s,1H),7.94(s,4H),7.84(s,1H),7.77(d,J＝4.3Hz,1H),7.61–7.55(m,1H),7.45(d,J＝9.1Hz,1H),7.39( s, 1H), 7.29 (d, J = 9.0Hz, 1H), 3.66 (s, 3H), 3.24 (d, J = 6.5Hz, 2H), 2.04–1.94 (m, 1H), 0.97 (d, J = 6.7Hz, 6H); LCMS (m/z) 506.1.

Example 539. 8-Chloro-N-(4'-(1-((dimethylamino)methyl)cyclopropyl)-[1,1'-diphenyl]-3- (N-methyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine)

Synthesis of 1-(1-(4-bromophenyl)cyclopropyl)-N,N-dimethylmethylamine: A solution of dimethylamine in THF (2 M, 0.938 mmol), glacial acetic acid (56.3 mg, 0.938 mmol), and sodium triacetoxyborohydride (199 mg, 0.938 mmol) were added to a solution of 1-(4-bromophenyl)cyclopropaneformaldehyde (176 mg, 0.782 mmol) in THF (6.0 mL). The mixture was stirred at room temperature for 48 hours, quenched with aqueous sodium bicarbonate solution, and extracted twice with EA. The combined organic layers were dried over _MgSO₄ and concentrated under reduced pressure. The crude product was dissolved in DMSO and purified by reversed-phase HPLC to provide the desired amine. ¹ H NMR (400MHz, DMSO-d ₆ )δ7.55(d,J＝8.4Hz,2H),7.43(d,J＝8.5Hz,2H),3.44(d,J＝5.8Hz,2H),2.68(d,J＝4.8Hz,6H),1.02(m,4H); MS(m/z)254.1[M+H] ⁺ .

Synthesis of 8-chloro-N-(4'-(1-((dimethylamino)methyl)cyclopropyl)-[1,1'-diphenyl]-3-yl)-N-methyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine: The title compound was prepared starting with 1-(1-(4-bromophenyl)cyclopropyl)-N,N-dimethylmethylamine according to the method provided for Synthesis Example 535. ¹ H NMR (400MHz, DMSO-d ₆ )δ9.71(s,1H),8.87(brs,1H),8.59(d,J＝2.1Hz,1H),7.67–7.60(m,4H),7.55(d,J＝7.7Hz,1H),7.50(d,J＝8.4Hz,2H),7.39(d,J＝8.9Hz,1H),7 .33(dd,J＝9.0,1.9Hz,1H),7.26(d,J＝9.0Hz,1H),3.63(s,3H),3.47(d,J＝5.5Hz,2H),2.70(s,3H),2.69(s,3H),1.03(m,4H); LCMS (m/z) 483.1.

Example 540. 8-Chloro-N-(4'-(isopropylsulfonyl)-[1,1'-diphenyl]-3-yl)-N-methyl-[1,2, 4] Triazolo[4,3-a]quinazolin-5-amine

Synthesis of 8-chloro-N-(4'-(isopropylsulfonyl)-[1,1'-diphenyl]-3-yl)-N-methyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine: The title compound was prepared according to the method provided for synthetic Example 525. ¹ H NMR (400MHz, DMSO-d ₆ )δ9.80(s,1H),8.64(d,J＝2.1Hz,1H),7.95(d,J＝8.5Hz,2H),7.92–7.86(m,3H),7.79(d,J＝7.8Hz,1H),7.61(t,J＝7.9Hz,1H),7.48(dd,J＝7.6 ,2.1Hz,1H),7.41(dd,J＝9.0,2.1Hz,1H),7.29(d,J＝9.0Hz,1H),3.69(s,3H),3.44(q,J＝6.8Hz,1H),1.17(d,J＝6.8Hz,6H); LCMS (m/z) 492.1.

Example 541. 8-Chloro-N-methyl-N-(3-(6-(2,2,2-trifluoroethyl)pyridin-3-yl)phenyl)-[1,2, 4] Triazolo[4,3-a]quinazolin-5-amine

Example 541 was prepared according to the method of Example 525. ^¹H NMR (400MHz, DMSO- _d⁶ ) δ 9.77 (s, 1H), 8.84 (d, J = 2.4Hz, 1H), 8.62 (s, 1H), 8.11 (dd, J = 8.1, 2.4Hz, 1H), 7.86–7.82 (m, 1H), 7.78–7.70 (m, 1H), 7.59 (d, J = 9.1Hz, 1H), 7.54 (d, J = 8.1Hz, 1H), 7.46–7.35 (m, 2H), 7.29 (d, J = 9.2Hz, 1H), 3.85 (q, J = 11.4Hz, 2H), 3.67 (s, 3H); LCMS (m/z) 469.1.

Example 542. 3'-((8-chloro-[1,2,4]triazolo[4,3-a]quinazolin-5-yl)(methyl)amino)-N,N- Dimethyl-[1,1'-diphenyl]-4-sulfonamide

Example 542 was prepared according to the method of Example 525. ^¹H NMR (400MHz, DMSO- _d⁶ ) δ 9.78 (s, 1H), 8.63 (d, J = 2.0Hz, 1H), 7.93 (d, J = 8.5Hz, 2H), 7.86 (s, 1H), 7.82–7.75 (m, 3H), 7.60 (t, J = 7.9Hz, 1H), 7.47 (d, J = 9.1Hz, 1H), 7.41 (dd, J = 9.0, 2.0Hz, 1H), 7.29 (d, J = 9.0Hz, 1H), 3.68 (s, 3H), 2.63 (s, 6H); LCMS (m/z) 493.1.

Example 543. 8-Chloro-N-(4'-((cyclopropylmethyl)sulfonyl)-[1,1'-diphenyl]-3-yl)-N-methyl [1,2,4]triazolo[4,3-a]quinazolin-5-amine

Example 543 was prepared according to the method of Example 525. ¹ H NMR (400MHz, DMSO-d ₆ )δ9.76(s,1H),8.62(s,1H),7.94(s,4H),7.86(s,1H),7.77(d,J＝8.1Hz, 1H),7.59(t,J＝7.9Hz,1H),7.45(d,J＝8.1Hz,1H),7.39(d,J＝9.0Hz,1H), 7.30(d,J＝9.1Hz,1H),3.67(s,3H),3.29(d,J＝7.1Hz,2H),0.87–0.80(m, 1H), 0.45 (q, J=6.0, 5.3Hz, 2H), 0.13 (d, J=6.1Hz, 2H); LCMS (m/z) 504.1.

Example 544. 8-Chloro-N-(4'-(ethylsulfonyl)-[1,1'-diphenyl]-3-yl)-N-methyl-[1,2,4] Triazolo[4,3-a]quinazolin-5-amine

Example 544 was prepared according to the method of Example 525. ^¹H NMR (400MHz, DMSO- _d⁶ ) δ 9.73 (s, 1H), 8.83 (d, J = 6.6 Hz, 1H), 7.77–7.71 (m, 2H), 7.69 (d, J = 8.5 Hz, 2H), 7.59 (t, J = 7.8 Hz, 1H), 7.43 (dd, J = 7.2, 2.0 Hz, 1H), 7.39 (d, J = 8.5 Hz, 2H), 7.00 (d, J = 10.9 Hz, 1H), 3.67 (s, 3H), 1.80–1.75 (m, 2H), 1.56–1.50 (m, 2H); LCMS (m/z) 478.1.

Example 545. 8-Chloro-N-methyl-N-(4'-((4-methylpiperazin-1-yl)sulfonyl)-[1,1'-diphenyl]- 3-yl)-[1,2,4]triazolo[4,3-a]quinazolin-5-amine

Example 545 was prepared according to the method of Example 525. ^¹H NMR (400MHz, DMSO-d6 ₎ )δ9.76(s,1H),8.62–8.61(m,1H),7.98(d,J＝8.5Hz,2H),7.83(d,J＝8.3Hz,4H ),7.75(d,J＝7.9Hz,1H),7.61(t,J＝7.9Hz,1H),7.49(d,J＝9.0Hz,1H),7.37(dd ,J＝9.0,2.0Hz,1H),7.29(d,J＝9.0Hz,1H),3.88–3.73(m,2H),3.66(s,3H),3.5 4–3.38(m,2H),3.24–3.08(m,2H),2.79(s,3H),2.50(m,2H); LCMS(m/z)548.1.

Example 546. 1-(3'-((8-chloro-7-fluoro-[1,2,4]triazolo[4,3-a]quinazolin-5-yl)(methyl)amino (1,1'-diphenyl]-4-yl)cyclopropane-1-carboxynitrile

The title compound was prepared according to the procedure described in Example 525. ^¹H NMR (400 MHz, DMSO- _d⁶ ) δ 9.73 (s, 1H), 8.83 (d, J = 6.6 Hz, 1H), 7.77–7.71 (m, 2H), 7.69 (d, J = 8.5 Hz, 2H), 7.59 (t, J = 7.8 Hz, 1H), 7.43 (dd, J = 7.2, 2.0 Hz, 1H), 7.39 (d, J = 8.5 Hz, 2H), 7.00 (d, J = 10.9 Hz, 1H), 3.67 (s, 3H), 1.80–1.75 (m, 2H), 1.56–1.50 (m, 2H); LCMS (m/z) 469.1.

Example 547. 1-(5-(3-((8-chloro-[1,2,4]triazolo[4,3-a]quinazolin-5-yl)(methyl)amino) (Phenyl)pyridin-2-yl)cyclopropane-1-carboxynitrile

Synthesis of 1-(5-(3-((8-chloro-[1,2,4]triazolo[4,3-a]quinazolin-5-yl)(methyl)amino)phenyl)pyridin-2-yl)cyclopropane-1-carboxylonitrile: The title compound was prepared according to the method provided for Synthesis Example 527, except that it began with 1-(5-bromopyridin-2-yl)cyclopropane-1-carboxylonitrile. ¹ H NMR (400MHz, DMSO-d ₆ )δ9.80(s,1H),8.79–8.76(m,1H),8.64(d,J＝1.9Hz,1H),8.12(dd,J＝8.3,2 .3Hz,1H),7.82(s,1H),7.75(d,J＝7.9Hz,1H),7.59(dd,J＝8.0,5.7Hz,2H), 7.46(d,J＝6.3Hz,1H),7.41(dd,J＝9.0,2.0Hz,1H),7.27(d,J＝9.0Hz,1H),3 .68(s,3H),1.86–1.82(m,2H),1.70(q,J＝4.9,4.5Hz,2H); LCMS(m/z)452.1.

Example 548. N-(4'-(1-(aminomethyl)cyclopropyl)-[1,1'-diphenyl]-3-yl)-8-chloro-N-methyl- [1,2,4]triazolo[4,3-a]quinazolin-5-amine

Synthesis of tert-butyl-4-bromophenylethyl carbamate (intermediate 548-1): Triethylamine (161 mg, 1.59 mmol) and di-tert-butyl dicarbonate (347 mg, 1.59 mmol) were added to a solution of 2-(4-bromophenyl)ethylamine (300 mg, 1.33 mmol) in DCM (7.0 mL) at 0 °C. The mixture was gradually heated to room temperature and stirred for 18 hours. The reaction mixture was concentrated under reduced pressure, and the crude product was purified by silica gel chromatography by elution with a hexane solution (0-100%) in EA, providing the intermediate carbamate. MS (m/z) 350.1 [M+Na] ⁺ . ¹ H NMR (400MHz, DMSO-d ₆ )δ7.48–7.40(m,2H),7.26–7.18(m,2H),6.87(t,J＝5.9Hz,1H),3.16(d,J＝6.1Hz,2H),1.32(s,6H),0.83(t,J＝3.1Hz,2H),0.69(q,J＝4.4Hz,2H).

Synthesis of tert-butyl carbamate (intermediate 548-2): tert-butyl-4-bromophenylethyl carbamate (50.0 mg, 0.153 mmol), bis(pinacol)diboron (46.7 mg, 0.184 mmol), PdCl₂(PPh₃) _{₂ (} 11.9 mg, 0.017 mmol), KOAc (45.1 mg, 0.460 mmol), and dioxane (2.0 _mL ) were charged into a microwave-safe vial equipped with a stir bar. The vial was purged with nitrogen, sealed, and the reaction mixture was irradiated at 120 °C for 45 min. The mixture was then diluted with EA, filtered, concentrated under reduced pressure, and used in the next step without further purification. MS(m/z) 396.3 [M+Na] ⁺ .

Synthesis of tert-butyl carbamate (intermediate 548-3): To a solution of N-(3-bromophenyl)-8-chloro-N-methyl-[1,2,4]triazolo[4,3-a]quinazolin-5-yl)(methyl)amino)-[1,1'-diphenyl]-4-yl)cyclopropyl)methyl)carbamate (57.8 mg, 0.155 mmol), Pd(dppf)Cl 2 was added to the solution of N-(3-bromophenyl)-8-chloro-N-methyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine (Example 308, 59.0 mg, 0.152 mmol) in dioxane ( _1.7 mL). (6.28 mg, 7.59 μmol) and a 2 _M solution of _Na₂CO₃ (aqueous) (80.4 mg, 0.759 mmol), the mixture was purged with nitrogen and heated at 100 °C for 20 min. After completion, the mixture was diluted with EA, filtered, and concentrated under reduced pressure. The crude product was purified by silica chromatography, eluting with 0–100% EA in hexane followed by 0–35% MeOH in EA, providing the desired intermediate. MS (m/z) 554.2 [M+H] ^⁺ .

TFA (347 mg, 6.94 mmol) was added to a solution of ((1-(3'-((8-chloro-[1,2,4]triazolo[4,3-a]quinazolin-5-yl)(methyl)amino)-[1,1'-diphenyl]-4-yl)cyclopropyl)methyl)carbamate tert-butyl ester (77.0 mg, 0.139 mmol) in DCM (1.4 mL) at room temperature, and the mixture was stirred for 20 min. Afterward, the reaction mixture was concentrated under reduced pressure, and the crude residue was dissolved in DMSO and purified by reversed-phase HPLC to provide the title compound: ¹ H NMR (400 MHz, DMSO-d ₆ )δ9.73(s,1H),8.60(d,J＝1.9Hz,1H),7.73(brs,2H),7.69–7.62(m,3H),7.62(d,J＝8.3Hz,2H),7.55(t,J＝8.1Hz,1H),7.42(d,J＝8.2Hz,3 H), 7.35 (dd, J＝9.0, 1.9Hz, 1H), 7.25 (d, J＝9.0Hz, 1H), 3.65 (s, 3H), 3.13–3.04 (m, 2H), 1.01 (m, 2H), 0.94–0.88 (m, 2H); LCMS (m/z) 455.2.

Example 549. N-Methyl-8-((methylamino)methyl)-N-phenyl-[1,2,4]triazolo[4,3-a]quinazole 5-Lin-amine

Titanium isopropylidene (IV) (0.39 mL, 1.45 mmol) was added dropwise to a commercially available solution of 2M dimethylamine in methanol (0.14 mL, 1.9 mmol), followed by the addition of aldehyde Example 117 (200 mg, 0.6 mmol). The reaction mixture was stirred at ambient temperature for 4.5 h, after which sodium borohydride (48 mg, 1.3 mmol) was added, and the resulting mixture was stirred for another 1.5 h. The resulting inorganic precipitate was then filtered by quenching the reaction with water, washed with diethyl ether, and the aqueous filtrate was extracted with diethyl ether. The combined ether extracts were dried over _MgSO4 and concentrated under vacuum to give N-methyl-8-((methylamino)methyl)-N-phenyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine: ^¹H NMR (400 MHz, methanol-d+) δ 9.52 (s, 1H), 8.46 (d, J = 1.7 Hz, 1H), 7.62–7.47 (m, 3H), 7.47–7.41 (m, 2H), 7.37 (dd, J = 8.8, 1.7 Hz, 1H), 7.29 (d, J = 8.8 Hz, 1H), 4.38 (s, 2H), 3.80 (s, 3H), 2.79 (s, 3H); LCMS (m/z) 319.2.

Example 550. N-methyl-8-(morpholinomethyl)-N-phenyl-[1,2,4]triazolo[4,3-a]quinazolin-5- amine

The title compound was synthesized according to the general procedure described for Example 549: ^¹H NMR (400 MHz, methanol- _d⁴ ) δ 9.52 (d, J = 3.1 Hz, 1H), 8.48 (d, J = 1.7 Hz, 1H), 7.63–7.49 (m, 3H), 7.49–7.37 (m, 3H), 7.29–7.19 (m, 1H), 4.40 (s, 2H), 3.95–3.85 (m, 3H), 3.81 (d, J = 7.2 Hz, 4H), 3.27–3.13 (m, 4H); LCMS (m/z) 375.1.

Example 551. 8-((dimethylamino)methyl)-N-methyl-N-phenyl-[1,2,4]triazolo[4,3-a]quinoline Azoline-5-amine

The title compound was synthesized according to the general procedure described for Example 549: ^¹H NMR (400 MHz, methanol- _d⁴ ) δ 9.51 (d, J = 1.9 Hz, 1H), 8.46 (dd, J = 24.2, 1.7 Hz, 1H), 7.62–7.50 (m, 3H), 7.49–7.35 (m, 3H), 7.28 (dd, J = 8.8, 5.2 Hz, 1H), 4.43 (d, J = 43.9 Hz, 2H), 3.82 (d, J = 1.8 Hz, 3H), 2.92 (s, 3H); LCMS (m/z) 333.2.

Example 552. 7-Fluoro-N-methyl-N-(4'-(trifluoromethyl)-[1,1'-diphenyl]-3-yl)-8-(4 ...[1,1'-diphenyl]-3-yl)-[1,1'-diphenyl]-3-yl)- (Fluoromethyl)phenoxy)-[1,2,4]triazolo[4,3-a]quinazolin-5-amine

The title compound was isolated from the crude product mixture during the synthesis in Example 465. ^¹H NMR (400 MHz, chloroform-d) δ 9.09 (s, 1H), 7.76–7.59 (m, 9H), 7.53 (t, J = 2.0 Hz, 1H), 7.36 (m, 1H), 7.20 (d, J = 8.5 Hz, 2H), 7.09 (d, J = 11.9 Hz, 1H), 3.78 (s, 3H); LCMS (m/z) 598.4.

Example 553. (E)-N-(5-((3-bromophenyl)(methyl)amino)-7-fluoro-[1,2,4]triazolo[4,3-a]quinoline Ethyl oxazolin-8-yl)formylhydrazide

The title compound was isolated from the crude product mixture during the synthesis of Example 459. ^¹H NMR (400 MHz, DMSO- _d⁶ ) δ 9.59 (s, ¹H), 8.76–8.61 (m, ¹H), 7.89 (d, J = 7.3 Hz, ¹H), 7.51 (t, J = 2.0 Hz, ¹H), 7.41 (m, ¹H), 7.32 (t, J = 8.0 Hz, ¹H), 7.29–7.22 (m, ¹H), 7.14 (s, ¹H), 6.88 (d, J = 13.2 Hz, ¹H), 4.25 (q, J = 7.1 Hz, 2H), 3.52 (s, 3H), 1.34 (t, J = 7.1 Hz, 3H); LCMS (m/z) 458.2.

Example 554. 1-((dimethylamino)methyl)-N-methyl-N-phenyl-[1,2,4]triazolo[4,3-a]quinoline Azoline-5-amine

Synthesis of 2-chloro-N-methyl-N-phenylquinazoline-4-amine (554-2): N-methylaniline (2.58 g, 24.1 mmol) and sodium hydride (965 mg, 24.1 mmol) were added to a solution of 2,4-dichloroquinazoline (intermediate 554-1, 4 g, 20.1 mmol) in DMF (20 mL), and the mixture was stirred at room temperature for 1 hour. Water was added to the reaction mixture, and the resulting mixture was filtered. The resulting residue was used in the next step without further purification.

Synthesis of 2-hydrazino-N-methyl-N-phenylquinazoline-4-amine (554-3): Hydrazine hydrate (817 mg, 16.3 mmol) was slowly added to a stirred solution of crude 2-chloro-N-methyl-N-phenylquinazoline-4-amine (intermediate 554-2, 2.2 g, 8.16 mmol) in a 2:1 solution (10 mL) of ethanol and THF. The mixture was heated at 60 °C for 18 hours. The mixture was diluted with DCM, then washed continuously with water and brine and dried over _MgSO4 . The organic layer was concentrated under vacuum. The resulting residue was used in the next step without further purification.

A solution of 2-chloro-1,1,1-trimethoxyethane (1.7 g, 10.9 mmol) and crude 2-hydrazino-N-methyl-N-phenylquinazoline-4-amine (intermediate 554-3, 20 mg, 0.08 mmol) was stirred at 100 °C for 24 hours. The mixture was concentrated under vacuum, then dissolved in a 2 mL solution of 2N dimethylamine in THF and stirred again at room temperature for 24 hours. The mixture was concentrated under vacuum, and the residue was then purified by reversed-phase chromatography (ACN/water 15%–95% containing 0.1% TFA, for 15 minutes) to yield the title compound: ^¹H NMR (400 MHz, methanol- _d⁴ ) δ 8.08 (d, J = 8.7 Hz, 1H), 7.91 (ddd, J = 8.7, 7.2, 1.5 Hz, 1H), 7.56–7.49 (m, 2H), 7.48–7.40 (m, 2H), 7.40–7.25 (m, 3H), 5.16 (s, 2H), 3.78 (s, 3H), 3.16 (s, 6H); LCMS (m/z) 333.2.

Example 555. 8-Bromo-1-cyclopropyl-7-fluoro-N-methyl-N-phenyl-[1,2,4]triazolo[4,3-a]quinazole 5-Lin-amine

Example 555 was synthesized in a manner similar to Example 500, except that trimethoxymethylcyclopropane was used instead of 1,1,1-triethoxyethane. Calculated values for LCMS-ESI+ (m/z): [M+H]+C ₁₉ H ₁₇ BrFN ₅ : 412.05 (M-1+1), 414.05 (M+1+1); experimental values: 412.22 (M-1+1), 414.17 (M+1+1).

Example 556. 7-Fluoro-N-(3-fluorophenyl)-8-hydrazino-N-methyl-[1,2,4]triazolo[4,3-a]quinazole 5-Lin-amine

Hydrazine hydrate (304 mg, 6 mmol) was slowly added to a stirred solution of crude 7,8-difluoro-N-(3-fluorophenyl)-N-methyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine (Example 249, 20 mg, 0.06 mmol) in a 2:1 solution (5 ml) of ethanol and THF. The mixture was heated at 100 °C for 24 hours. The mixture was diluted with DCM, then washed continuously with water and brine, and dried over _MgSO4 . The mixture was concentrated under vacuum, and the residue was then purified by reversed-phase chromatography (ACN/water 15-95% containing 0.1% TFA, for 15 min) to yield the title compound: ^¹H NMR (400 MHz, methanol- _d⁴ ) δ 9.33 (s, 1H), 7.69 (d, J = 7.5 Hz, 1H), 7.43 (q, J = 7.8 Hz, 1H), 7.06 (tt, J = 8.9, 4.0 Hz, 3H), 6.78 (d, J = 13.6 Hz, 1H), 3.62 (s, 3H); LCMS (m/z) 342.1.

Example 557. 3-(7-fluoro-5-((3-fluorophenyl)(methyl)amino)-[1,2,4]triazolo[4,3-a]quinazole Ethyl lin-8-yl)propionate

The title compound was isolated in step 7 of synthetic example 467. ^¹H NMR (400 MHz, chloroform-d) δ 9.11 (s, 1H), 7.94 (d, J = 6.3 Hz, 1H), 7.39 (m, 1H), 7.04 (m, 1H), 6.98 (m, 1H), 6.94–6.86 (m, 2H), 4.12 (q, J = 7.1 Hz, 2H), 3.66 (s, 3H), 3.11 (t, J = 7.3 Hz, 2H), 2.72 (t, J = 7.3 Hz, 2H), 1.22 (t, J = 7.1 Hz, 3H); LCMS (m/z) 412.3.

Example 558. (3'-((8-chloro-[1,2,4]triazolo[4,3-a]quinazolin-5-yl)(methyl)amino)-[1, 1'-Diphenyl]-4-yl)dimethylphosphine oxide

The title compound was synthesized in a manner similar to that described for Example 337, except that (4-bromophenyl)dimethylphosphine oxide was used instead of 2-bromo-5-cyclopropylpyrazine and (2-dicyclohexylphosphine-2',4',6'-triisopropyl-1,1'-diphenyl)[2-(2'-amino-1,1'-diphenyl)]palladium(II) chloride was used instead of [1,1'-bis(diphenylphosphine)ferrocene]palladium(II) chloride. ¹ H NMR (400MHz, acetone-d ₆ )δ9.47(s,1H),8.42(d,J＝2.1Hz,1H),7.95–7.73(m,5H),7.70(d,J＝7.8Hz,1H),7.59(t,J＝7.8Hz,1H),7.51(d,J＝ 9.0Hz,1H),7.49–7.41(m,1H),7.28(dd,J＝9.0,2.1Hz,1H),3.72(s,3H),1.71(d,J＝13.3Hz,6H); LCMS(m/z)462.2.

Example 559. (3'-((8-chloro-[1,2,4]triazolo[4,3-a]quinazolin-5-yl)(methyl)amino)-[1, 1'-Diphenyl]-4-yl)(imino)(methyl)-16-sulfanone

The title compound was synthesized in a manner similar to that described for Example 337, except that (4-bromophenyl)(imino)(methyl) ^-λ6 -sulfonone was used instead of 2-bromo-5-cyclopropylpyrazine and (2-dicyclohexylphosphine-2',4',6'-triisopropyl-1,1'-diphenyl)[2-(2'-amino-1,1'-diphenyl)]palladium(II) chloride was used instead of [1,1'-bis(diphenylphosphine)ferrocene]palladium(II) chloride. ^¹H NMR (400MHz, acetone- _d⁶ ) δ 9.46 (s, ¹H), 8.41 (d, J = 2.1Hz, ¹H), 8.05–7.97 (m, ³H), 7.86 (d, J = 8.4Hz, ²H), 7.79 (t, J = 2.1Hz, ¹H), 7.71 (d, J = 7.7Hz, ¹H), 7.64–7.44 (m, ³H), 7.28 (dd, J = 8.9, 2.1Hz, ¹H), 3.71 (s, ³H), 3.09 (s, ³H); LCMS (m/z) 463.2.

Example 560. 2-(tert-butyl)-5-(3-((8-chloro-[1,2,4]triazolo[4,3-a]quinazolin-5-yl)(methyl) 1-Oxide of 1-aminophenylpyridine

The title compound was synthesized in a manner similar to that described for Example 337, except that 5-bromo-2-(tert-butyl)pyridine 1-oxide was used instead of 2-bromo-5-cyclopropylpyrazine and (2-dicyclohexylphosphine 2',4',6'-triisopropyl-1,1'-diphenyl)[2-(2'-amino-1,1'-diphenyl)]palladium(II) chloride was used instead of [1,1'-bis(diphenylphosphine)ferrocene]palladium(II) dichloride. ¹ H NMR (400MHz, acetone-d ₆ )δ9.45(s,1H),8.40(d,J＝2.0Hz,1H),8.35(d,J＝1.9Hz,1H),7.82–7.43(m,7 H), 7.27 (dd, J=8.8, 2.0Hz, 1H), 3.71 (s, 3H), 1.50 (s, 9H); LCMS (m/z) 459.3.

Example 561. 5-(tert-butyl)-2-(3-((8-chloro-[1,2,4]triazolo[4,3-a]quinazolin-5-yl)(methyl) 1-Oxide of 1-aminophenylpyridine

3-Chlorobenzoperoxy acid (77 wt%, 109 mg, 485 μmol) was added to a stirred solution of 5-(tert-butyl)-2-chloropyridine (30.0 mg, 177 μmol) in dichloromethane (0.5 mL) at room temperature. After 19 hours, the resulting mixture was purified by silica gel rapid column chromatography (hexane) to give intermediate 561-1.

The title compound was synthesized in a manner similar to that described for Example 337, except that intermediate 561-1 was used instead of 2-bromo-5-cyclopropylpyrazine and (2-dicyclohexylphosphine-2',4',6'-triisopropyl-1,1'-diphenyl)[2-(2'-amino-1,1'-diphenyl)]palladium(II) chloride was used instead of [1,1'-bis(diphenylphosphine)ferrocene]palladium(II) dichloride. ^1H NMR (400MHz, acetone- _d6 ) δ 9.45 (s, 1H), 8.40 (d, J = 2.0 Hz, 1H), 8.22 (d, J = 1.9 Hz, 1H), 7.95 (d, J = 2.1 Hz, 1H), 7.87 (d, J = 7.7 Hz, 1H), 7.59–7.49 (m, 3H), 7.49–7.41 (m, 2H), 7.27 (dd, J = 9.0, 2.1 Hz, 1H), 3.68 (s, 3H), 1.37 (s, 9H); LCMS (m/z) 459.3.

Example 563. 8-Chloro-N-(3-((5-((dimethylamino)methyl)pyrazin-2-yl)oxy)phenyl)-N-methyl [1,2,4]triazolo[4,3-a]quinazolin-5-amine

The title compound was isolated from the crude product mixture in the synthesis of Example 229. ^¹H NMR (400 MHz, methanol- _d⁴ ) δ 9.53 (s, ¹H), 8.58 (d, J = 1.4 Hz, ¹H), 8.45 (d, J = 2.0 Hz, ¹H), 8.20 (s, ¹H), 7.60 (t, J = 8.4 Hz, ¹H), 7.46–7.37 (m, 2H), 7.34 (d, J = 7.8 Hz, 1H), 7.32–7.25 (m, 2H), 4.48 (s, 2H), 3.76 (s, 3H), 2.95 (s, 6H); LCMS (m/z) 461.3.

Example 564. 8-Chloro-N-methyl-N-(3-((5-(morpholinomethyl)pyrazin-2-yl)oxy)phenyl)-[1, [2,4]triazolo[4,3-a]quinazolin-5-amine

The title compound was isolated from the crude product mixture in the synthesis of Example 230. ^¹H NMR (400 MHz, methanol- _d⁴ ) δ 9.56 (s, 1H), 8.60 (d, J = 1.6 Hz, 1H), 8.49 (d, J = 2.1 Hz, 1H), 8.23 (d, J = 1.6 Hz, 1H), 7.63 (t, J = 7.7 Hz, 1H), 7.46–7.31 (m, 5H), 4.51 (s, 2H), 3.94 (s, 4H), 3.79 (s, 3H), 3.38 (m, 4H); LCMS (m/z) 503.3.

Example 565. 3'-((8-chloro-[1,2,4]triazolo[4,3-a]quinazolin-5-yl)(methyl)amino)-5-methyl oxy-4-((tetrahydro-2H-pyran-2-yl)oxy)-[1,1'-diphenyl]-3-carboxynitrile

The title compound was synthesized in a manner similar to that described for Example 252: ^¹H NMR (400 MHz, methanol- _d⁴ ) δ 9.57 (s, 1H), 8.49 (d, J = 2.0 Hz, 1H), 7.78 (dt, J = 8.0, 1.2 Hz, 1H), 7.71 (t, J = 2.0 Hz, 1H), 7.63 (t, J = 7.9 Hz, 1H), 7.44–7.25 (m, 2H), 7.22 (d, J = 7.4 Hz, 2H), 7.12–7.01 (m, 1H), 4.93 (t, J = 7.7 Hz, 2H), 3.93 (s, 3H), 3.86 (s, 3H), 3.35–3.29 (m, 6H); LCMS (m/z) 541.3.

Example 566. 8-Chloro-N-methyl-N-(4'-(pentafluoro-16-thioalkyl)-[1,1'-diphenyl]-3-yl)-[1, [2,4]triazolo[4,3-a]quinazolin-5-amine

The title compound was synthesized in a manner similar to that in Example 312, except that (4-(pentafluoro- ^λ6 -thioalkyl)phenyl)boronic acid was used instead of (4-isopropylphenyl)boronic acid. ^¹H NMR (400 MHz, acetone- _d6 ) δ 9.52 (s, 1H), 8.45 (d, J = 2.3 Hz, 1H), 8.01–7.92 (m, 2H), 7.92–7.81 (m, 3H), 7.75 (d, J = 7.4 Hz, 1H), 7.63 (t, J = 7.8 Hz, 1H), 7.51 (dd, J = 8.5, 3.2 Hz, 2H), 7.38–7.26 (m, 1H), 3.75 (s, 3H); LCMS (m/z) 512.3.

Example 567. N-(3-bromophenyl)-8-chloro-N-methyl-1-(methylthio)-[1,2,4]triazolo[4,3-a] Quinazoline-5-amine

The title compound was prepared as described for intermediate 366-1: ^¹H NMR (400 MHz, acetone- _d⁶ ) δ 8.64 (d, J = 2.0 Hz, 1H), 7.59 (td, J = 1.8, 0.9 Hz, 1H), 7.56 (d, J = 8.9 Hz, 1H), 7.48–7.41 (m, 1H), 7.39 (dd, J = 8.9, 2.0 Hz, 1H), 7.37–7.33 (m, 2H), 3.63 (s, 3H), 2.91 (s, 3H); LCMS (m/z) 434.3.

Example 569. 8-Chloro-N-(4'-cyclopropyl-[1,1'-diphenyl]-3-yl)-N-methyl-1-(methylthio)- [1,2,4]triazolo[4,3-a]quinazolin-5-amine

The title compound was synthesized in a manner similar to that of Example 312, except that (4-cyclopropylphenyl)boronic acid was used instead of (4-isopropylphenyl)boronic acid and intermediate 366-1 was used instead of Example 308. ^¹H NMR (400 MHz, acetone- _d⁶ ) δ 8.62 (d, J = 2.0 Hz, 1H), 7.64–7.54 (m, 3H), 7.54–7.46 (m, 3H), 7.34–7.26 (m, 2H), 7.18–7.11 (m, 2H), 3.68 (s, 3H), 2.90 (s, 3H), 2.02–1.90 (m, 1H), 1.04–0.94 (m, 2H), 0.76–0.65 (m, 2H); LCMS (m/z) 472.3.

Example 570. N-(4'-((2-oxa-6-azaspiro[3.3]hept-6-yl)sulfonyl)-[1,1'-diphenyl]- 3-yl)-8-chloro-N-methyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine

The title compound was synthesized according to the general procedure described for Example 535. ^¹H NMR (400 MHz, DMSO- _d⁶ ) δ 9.65 (s, 1H), 8.56 (d, J = 2.0 Hz, 1H), 7.95 (d, J = 8.4 Hz, 2H), 7.82 (d, J = 8.4 Hz, 2H), 7.79 (s, 1H), 7.69 (d, J = 7.7 Hz, 1H), 7.53 (t, J = 7.9 Hz, 1H), 7.39 (d, J = 8.9 Hz, 1H), 7.33 (s, 2H), 4.44 (s, 4H), 3.90 (s, 4H), 3.61 (s, 3H); LCMS (m/z) 547.1.

Example 571. 1-(4-(5-(3-((8-chloro-[1,2,4]triazolo[4,3-a]quinazolin-5-yl)(methyl)amino 2-yl)pyridin-2-yl)piperazin-1-yl)ethyl-1-one

A solution of 8-chloro-N-methyl-N-(3-(6-(piperazin-1-yl)pyridin-3-yl)phenyl)-[1,2,4]triazolo[4,3-a]quinazolin-5-amine (Example 258, 20 mg, 0.04 mmol), DIPEA (52.2 mg, 0.4 mmol), acetic acid (7 mg, 0.12 mmol), and HATU (32 mg, 0.08 mmol) in DMF (5 mL) was stirred at room temperature for 1 hour. The product was extracted with DCM. The organic layer was evaporated, and the residue was then purified by reversed-phase chromatography (ACN/water 15-95% containing 0.1% TFA, 15 min) to yield the title compound: ^¹H NMR (400 MHz, methanol- _d4 ) δ 9.60 (s, 1H), 8.52 (d, J = 2.1 Hz, 1H), 8.32–8.19 (m, 2H), 7.85–7.63 (m, 3H), 7.59–7.49 (m, 1H), 7.37 (dt, J = 9.1, 1.9 Hz, 2H), 7.29 (d, J = 9.1 Hz, 1H), 3.87 (s, 3H), 3.86–3.73 (m, 8H), 2.18 (s, 3H); LCMS (m/z) 513.4.

Example 572. 1-(4-(5-(3-((8-chloro-[1,2,4]triazolo[4,3-a]quinazolin-5-yl)(methyl)amino (2-yl)phenyl)pyridin-2-yl)piperazin-1-yl)-2-hydroxyethyl-1-one

The title compound was obtained using a procedure similar to that used to prepare Example 571. ^¹H NMR (400 MHz, methanol- _d⁴ ) δ 9.60 (s, 1H), 8.52 (d, J = 2.0 Hz, 1H), 8.32–8.15 (m, 2H), 7.86–7.61 (m, 3H), 7.52 (ddd, J = 8.0, 2.2, 1.0 Hz, 1H), 7.41–7.21 (m, 3H), 4.31 (s, 3H), 3.99–3.56 (m, 11H); LCMS (m/z) 529.5.

Example 573. 8-Chloro-N-methyl-N-(3-(6-(pentafluoro-16-thioalkyl)pyridin-3-yl)phenyl)-[1,2, 4] Triazolo[4,3-a]quinazolin-5-amine

The title compound was synthesized in a manner similar to that in Example 337, except that 5-bromo-2-(pentafluoro- ^λ6 -thioalkyl)pyridine was used instead of 2-bromo-5-cyclopropylpyrazine. ^¹H NMR (400 MHz, acetone- _d6 ) δ 9.46 (s, 1H), 8.85 (d, J = 2.4 Hz, 1H), 8.43–8.36 (m, 2H), 8.00 (d, J = 8.6 Hz, 1H), 7.88 (t, J = 2.0 Hz, 1H), 7.83–7.72 (m, 1H), 7.64 (t, J = 7.8 Hz, 1H), 7.58–7.50 (m, 2H), 7.27 (dd, J = 9.0, 2.1 Hz, 1H), 3.72 (s, 3H); LCMS (m/z) 513.3.

Example 574. 8-Chloro-N5-(4'-Cyclopropyl-[1,1'-Diphenyl]-3-yl)-N5-Methyl-[1,2,4]triazole [4,3-a]quinazolin-1,5-diamine

The title compound was prepared according to the general procedure described for Example 367. ^¹H NMR (400 MHz, methanol- _d⁴ ) δ 8.60 (d, J = 2.0 Hz, 1H), 7.72 (d, J = 8.0 Hz, 1H), 7.65 (d, J = 2.3 Hz, 1H), 7.59 (t, J = 7.9 Hz, 1H), 7.48 (d, J = 8.3 Hz, 2H), 7.41–7.31 (m, 3H), 7.15 (d, J = 8.2 Hz, 2H), 3.81 (s, 3H), 2.01–1.89 (m, 1H), 1.07–0.98 (m, 2H), 0.76–0.65 (m, 2H); LCMS (m/z) 441.3.

Example 575. 6-(3-((8-chloro-[1,2,4]triazolo[4,3-a]quinazolin-5-yl)(methyl)amino)benzene 1-Methoxy-4-(methoxymethyl)-2-methylhexane-5-yne-2,4-diol

The title compound was synthesized in a manner similar to that of Example 376, using Example 308 instead of intermediate 364-2 and 1-methoxy-4-(methoxymethyl)-2-methylhexane-5-yn-2,4-diol instead of 2-methylbut-3-yn-2-ol. ^¹H NMR (400 MHz, acetone- _d6 ) δ 9.45 (s, 1H), 8.40 (d, J = 2.0 Hz, 1H), 7.62–7.19 (m, 6H), 4.10–3.21 (m, 6H), 3.63 (s, 3H), 3.40 (s, 3H), 3.35 (s, 3H), 1.86 (s, 3H); LCMS (m/z) 510.2.

Example 576. 3'-((8-chloro-[1,2,4]triazolo[4,3-a]quinazolin-5-yl)(methyl)amino)-N- (2-Hydroxyethyl)-[1,1'-diphenyl]-4-sulfonamide

The title compound was prepared according to the general procedure described for Example 525. ¹ H NMR (400MHz, DMSO-d ₆ )δ9.78(s,1H),8.62(d,J＝2.0Hz,1H),7.88(d,J＝8.6Hz,2H),7.85(s,3H),7.76(d,J＝7.9Hz,1H),7.66(t,J＝5.9Hz,1H),7.59(t,J＝7.8Hz,1H),7. 44(d,J＝7.9Hz,1H),7.40(dd,J＝9.0,2.0Hz,1H),7.28(d,J＝9.0Hz,1H),3.68(s,3H),3.37(t,J＝6.3Hz,2H),2.81–2.75(m,2H); LCMS(m/z)509.1.

Example 577. 4-(1-(7-fluoro-1-methyl-[1,2,4]triazolo[4,3-a]quinazolin-5-yl)-1,2,3, 4-Tetrahydro-1,7-Naphtho-5-yl)-2-methylbut-3-yn-2-ol

The title compound was synthesized in a manner similar to that in Example 421, except that 5-(5-bromo-3,4-dihydro-1,7-naphthid-1(2H)-yl)-7-fluoro-1-methyl-[1,2,4]triazolo[4,3-a]quinazoline was used instead of N-(3-bromo-5-fluorophenyl)-8-chloro-N-methyl-[1,2,4]triazolo[4,3-a]quinazoline-5-amine. ¹ H NMR (400MHz, DMSO-d ₆ )δ8.44(dd,J＝9.4,4.5Hz,1H),8.24(s,1H),8.12(s,1H),7.94(ddd,J＝9.3,7.9,2.9Hz,1H),7.78(dd,J＝9.3,2.9Hz ,1H),4.04–3.95(m,2H),3.03(s,3H),2.99(t,J＝6.7Hz,2H),2.18–2.00(m,2H),1.53(s,6H); LCMS(m/z)417.7[M+H] ⁺ .

Example 578. 5-(5-((1-(difluoromethyl)cyclopropyl)ethynyl)-3,4-dihydro-1,7-naphthidine-1(2H)- )-7-fluoro-1-methyl-[1,2,4]triazolo[4,3-a]quinazolin

The title compound was synthesized in a manner similar to that of Example 421, except that 5-(5-bromo-3,4-dihydro-1,7-naphthid-1(2H)-yl)-7-fluoro-1-methyl-[1,2,4]triazolo[4,3-a]quinazoline was used instead of N-(3-bromo-5-fluorophenyl)-8-chloro-N-methyl-[1,2,4]triazolo[4,3-a]quinazoline-5-amine and 1-(difluoromethyl)-1-ethynylcyclopropane was used instead of 2-methylbut-3-yn-2-ol. ¹ H NMR (400MHz, DMSO-d ₆ )δ8.44(dd,J＝9.4,4.5Hz,1H),8.26(s,1H),8.12(s,1H),7.94(ddd,J＝9.3,7.9,2.9Hz,1H),7.79(dd,J＝9.3,2.9Hz,1H),5.83(t,J＝55.4 Hz,1H),4.00(t,J＝5.8Hz,4H),3.03(s,3H),2.98(t,J＝6.6Hz,2H),2.17–2.01(m,2H),1.29(dq,J＝7.8,2.7Hz,4H); LCMS(m/z)469.6[M+H] ⁺ .

Example 579. 7-Fluoro-1-methyl-5-(5-(4,4,4-trifluoro-3,3-dimethylbut-1-yn-1-yl)-3,4- Dihydro-1,7-naphthid-1(2H)-yl)-[1,2,4]triazolo[4,3-a]quinazolin

The title compound was synthesized in a manner similar to that of Example 421, except that 5-(5-bromo-3,4-dihydro-1,7-naphthid-1(2H)-yl)-7-fluoro-1-methyl-[1,2,4]triazolo[4,3-a]quinazoline was used instead of N-(3-bromo-5-fluorophenyl)-8-chloro-N-methyl-[1,2,4]triazolo[4,3-a]quinazoline-5-amine and 4,4,4-trifluoro-3,3-dimethylbut-1-yne was used instead of 2-methylbut-3-yne-2-ol. ¹ H NMR (400MHz, DMSO-d ₆ )δ8.45(dd,J＝9.4,4.5Hz,1H),8.29(s,1H),8.16(s,1H),7.96(ddd,J＝9.3,7.9,2.9Hz,1H),7.82(dd,J＝9 .3,2.9Hz,1H),4.05–3.97(m,2H),3.04(s,3H),2.98(t,J＝6.7Hz,2H),2.11(p,J＝6.7Hz,2H),1.57(s,6H). LCMS(m/z)469.6[M+H] ⁺ .

Example 580. 7-Fluoro-1-methyl-5-(5-((1-(trifluoromethyl)cyclopropyl)ethynyl)-3,4-dihydro-1, 7-Naphthid-1(2H)-yl)-[1,2,4]triazolo[4,3-a]quinazolin

The title compound was synthesized in a manner similar to that of Example 421, except that 5-(5-bromo-3,4-dihydro-1,7-naphthid-1(2H)-yl)-7-fluoro-1-methyl-[1,2,4]triazolo[4,3-a]quinazoline was used instead of N-(3-bromo-5-fluorophenyl)-8-chloro-N-methyl-[1,2,4]triazolo[4,3-a]quinazoline-5-amine and 1-ethynyl-1-(trifluoromethyl)cyclopropane was used instead of 2-methylbut-3-yn-2-ol. ¹ H NMR (400MHz, DMSO-d ₆ )δ8.45(dd,J＝9.4,4.5Hz,1H),8.30(s,1H),8.16(s,1H),7.96(ddd,J＝9.4,7.9,2.9Hz,1H),7.81(dd,J＝9.3,2.9Hz,1H) ,4.02(t,J＝5.7Hz,2H),3.04(s,3H),2.98(t,J＝6.7Hz,2H),2.10(p,J＝6.4Hz,2H),1.59–1.51(m,2H),1.51–1.41(m,2H). LCMS(m/z)467.7[M+H] ⁺ .

Example 581. 4-(1-(7-fluoro-[1,2,4]triazolo[4,3-a]quinazolin-5-yl)-1,2,3,4-tetrahydro- 1,7-Naphtho-5-yl)-2-methylbut-3-yn-2-ol

The title compound was synthesized in a manner similar to that in Example 421, except that 5-(5-bromo-3,4-dihydro-1,7-naphthid-1(2H)-yl)-7-fluoro-[1,2,4]triazolo[4,3-a]quinazoline was used instead of N-(3-bromo-5-fluorophenyl)-8-chloro-N-methyl-[1,2,4]triazolo[4,3-a]quinazoline-5-amine. ¹ H NMR (400MHz, DMSO-d ₆ )δ9.91(s,1H),8.57(dd,J＝9.2,4.7Hz,1H),8.28(s,1H),8.22(s,1H),8.04(ddd,J＝9.2,8.2,2.8Hz,1H),7.7 4(dd,J＝9.4,2.8Hz,1H),4.17–3.88(m,2H),3.00(t,J＝6.6Hz,2H),2.09(dd,J＝11.3,5.4Hz,2H),1.54(s,6H). LCMS(m/z)403.6[M+H] ⁺ .

Example 582. 5-(5-((1-(difluoromethyl)cyclopropyl)ethynyl)-3,4-dihydro-1,7-naphthidine-1(2H)- α-7-fluoro-[1,2,4]triazolo[4,3-a]quinazolin

The title compound was synthesized in a manner similar to that of Example 421, except that 5-(5-bromo-3,4-dihydro-1,7-naphthid-1(2H)-yl)-7-fluoro-[1,2,4]triazolo[4,3-a]quinazoline was used instead of N-(3-bromo-5-fluorophenyl)-8-chloro-N-methyl-[1,2,4]triazolo[4,3-a]quinazoline-5-amine and 1-(difluoromethyl)-1-ethynylcyclopropane was used instead of 2-methylbut-3-yn-2-ol. ^¹H NMR (400 MHz, DMSO-d6 ₎ )δ9.87(s,1H),8.55(dd,J＝9.2,4.7Hz,1H),8.26(s,1H),8.17(s,1H),8.01(td,J＝8.7,2.8Hz,1H),7.72(dd,J＝9.4,2.8Hz,1H),5.8 3(t,J＝55.5Hz,1H),4.00(dd,J＝6.7,4.8Hz,2H),2.97(t,J＝6.6Hz,2H),2.18–2.01(m,2H),1.40–1.19(m,4H); LCMS(m/z)435.7[M+H] ⁺ .

Example 583. 7-Fluoro-5-(5-(4,4,4-trifluoro-3,3-dimethylbut-1-yn-1-yl)-3,4-dihydro-1, 7-Naphthid-1(2H)-yl)-[1,2,4]triazolo[4,3-a]quinazolin

The title compound was synthesized in a manner similar to that of Example 584, except that N-(3-bromo-5-fluorophenyl)-8-chloro-N-methyl-[1,2,4]triazolo[4,3-a]quinazoline was used instead of N-(3-bromo-5-fluorophenyl)-8-chloro-N-methyl-[1,2,4]triazolo[4,3-a]quinazoline-5-amine and 4,4,4-trifluoro-3,3-dimethylbut-1-yne was used instead of 2-methylbut-3-yne-2-ol. ¹ H NMR (400MHz, DMSO-d ₆ )δ9.90(s,1H),8.57(dd,J＝9.2,4.6Hz,1H),8.29(s,1H),8.22(s,1H),8.03(td,J＝8.7,2.8Hz,1H),7.76(dd,J＝9.4,2 .8Hz,1H),4.02(dd,J＝6.8,4.6Hz,2H),2.98(t,J＝6.7Hz,2H),2.23–2.01(m,2H),1.57(s,6H); LCMS(m/z)455.6[M+H] ⁺ .

Example 584. 7-Fluoro-5-(5-((1-(trifluoromethyl)cyclopropyl)ethynyl)-3,4-dihydro-1,7-naphthidine-1 (2H)-yl)-[1,2,4]triazolo[4,3-a]quinazolin

The title compound was synthesized in a manner similar to that of Example 585, except that N-(3-bromo-5-fluorophenyl)-8-chloro-N-methyl-[1,2,4]triazolo[4,3-a]quinazoline was used instead of N-(3-bromo-5-fluorophenyl)-8-chloro-N-methyl-[1,2,4]triazolo[4,3-a]quinazoline-5-amine and 1-ethynyl-1-(trifluoromethyl)cyclopropane was used instead of 2-methylbut-3-yn-2-ol. ¹ H NMR (400MHz, DMSO-d ₆ )δ9.89(s,1H),8.56(dd,J＝9.2,4.6Hz,1H),8.29(s,1H),8.21(s,1H),8.02(ddd,J＝9.1,8.2,2.8Hz,1H),7.74(dd,J＝9 .4,2.8Hz,1H),4.09–3.89(m,2H),2.98(t,J＝6.6Hz,2H),2.16–2.01(m,2H),1.63–1.36(m,4H); LCMS(m/z)453.6[M+H] ⁺ .

Example 585. 5-(5-((1-(difluoromethyl)cyclopropyl)ethynyl)-3,4-dihydroquinoline-1(2H)-yl)- 6-Fluoro-1-methyl-[1,2,4]triazolo[4,3-a]quinazolin

The title compound was synthesized in a manner similar to that of Example 421, except that 5-(5-bromo-3,4-dihydroquinoline-1(2H)-yl)-6-fluoro-1-methyl-[1,2,4]triazolo[4,3-a]quinazoline was used instead of N-(3-bromo-5-fluorophenyl)-8-chloro-N-methyl-[1,2,4]triazolo[4,3-a]quinazoline-5-amine and 1-(difluoromethyl)-1-ethynylcyclopropane was used instead of 2-methylbut-3-yn-2-ol. ¹ H NMR (400MHz, DMSO-d ₆ )δ8.18(d,J＝8.6Hz,1H),8.00(td,J＝8.4,5.4Hz,1H),7.37(dd,J＝11.8,8.2Hz,1H),7.14(d,J＝7.5Hz,1H),6.93(t,J＝7.9Hz,1H),6.83(d ,J＝8.2Hz,1H),5.81(t,J＝55.6Hz,1H),4.26-3.96(m,2H),3.0-2.7(m,5H),2.29–1.80(m,2H),1.38–1.14(m,4H); LCMS(m/z)448.3[M+H] ⁺ .

Example 586. 5-(5-((1-(difluoromethyl)cyclopropyl)ethynyl)-3,4-dihydroquinoline-1(2H)-yl)- 7-Fluoro-1-methyl-[1,2,4]triazolo[4,3-a]quinazolin

The title compound was synthesized in a manner similar to that of Example 421, except that 5-(5-bromo-3,4-dihydroquinolin-1(2H)-yl)-7-fluoro-1-methyl-[1,2,4]triazolo[4,3-a]quinazolin was used instead of N-(3-bromo-5-fluorophenyl)-8-chloro-N-methyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine and 1-(difluoromethyl)-1-ethynylcyclopropane was used instead of 2-methylbut-3-yn-2-ol. ¹ H NMR (400MHz, DMSO-d ₆ )δ8.37(dd,J＝9.4,4.6Hz,1H),7.86(td,J＝8.6,2.9Hz,1H),7.42(dd,J＝9.6,2.9Hz,1H),7.16(d,J＝7.5Hz,1H),6.98(t,J＝7.9Hz,1H),6.7 9(d,J＝8.2Hz,1H),5.81(t,J＝55.6Hz,1H),3.96(t,J＝6.2Hz,2H),2.99(d,J＝5.7Hz,5H),2.21–2.00(m,2H),1.26(dt,J＝10.1,2.8Hz,4H). LCMS(m/z)448.3[M+H] ⁺ .

Example 587. N-(3-(5-cyclopropylpyrazin-2-yl)-5-fluorophenyl)-N-(2,2-difluoroethyl)-6-fluoro-1- Methyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine

The title compound was synthesized in a manner similar to that of Example 591, except that N-(3-bromo-5-fluorophenyl)-N-(2,2-difluoroethyl)-6-fluoro-1-methyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine was used instead of N-(3-bromo-5-fluorophenyl)-N-methyl-8-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]quinazolin-5-amine. ¹ H NMR (400MHz, DMSO-d ₆ )δ8.88(d,J＝1.5Hz,1H),8.65(d,J＝1.5Hz,1H),8.18(d,J＝8.6Hz,1H),7.95(td,J＝8.4,5.4Hz,1H),7.76–7.48(m,2H),7.35–6.91(m,2H),6.80– 6.36(m,1H),4.89–4.62(m,2H),3.03(s,3H),2.23(tt,J＝8.1,4.7Hz,1H ),1.18–1.00(m,2H),0.96(dt,J＝4.6,3.0Hz,2H); LCMS(m/z)491.1[M+H] ⁺ .

Example 588. 7-Fluoro-5-(5-((1-methylcyclopropyl)ethynyl)-3,4-dihydro-1,8-naphthidine-1(2H)- (-[1,2,4]triazolo[4,3-a]quinazolin)

Except for replacing 7-bromo-2,4-dichloro-6-fluoroquinazoline with 2,4-dichloro-6-fluoroquinazoline and replacing 2,3,4,5-tetrahydro-1H-benzo[b]azapyridine with 5-bromo-1,2,3,4-tetrahydro-1,8-naphthidine, compound 588-1 (5-(5-bromo-3,4-dihydro-1,8-naphthidine-1(2H)-yl)-7-fluoro-[1,2,4]triazolo[4,3-a]quinazoline) was synthesized in a manner similar to that in Example 498.

The title compound was synthesized in a manner similar to that of Example 421, except that N-(3-bromo-5-fluorophenyl)-8-chloro-N-methyl-[1,2,4]triazolo[4,3-a]quinazoline was used instead of N-(3-bromo-5-fluorophenyl)-8-chloro-N-methyl-[1,2,4]triazolo[4,3-a]quinazoline-5-amine and 1-ethynyl-1-methylcyclopropane was used instead of 2-methylbut-3-yn-2-ol. ¹ H NMR (400MHz, DMSO-d ₆ )δ9.85(s,1H),8.49(dd,J＝9.2,4.6Hz,1H),7.92(ddd,J＝9.2,8.3,2.8Hz,1 H),7.69(d,J＝5.1Hz,1H),7.41(dd,J＝9.5,2.8Hz,1H),6.90(d,J＝5.1Hz,1H ),3.97(dd,J＝6.7,4.6Hz,2H),2.95(d,J＝6.7Hz,2H),2.24–2.11(m,2H),1. 37(s,3H),1.04(q,J＝4.0Hz,2H),0.89–0.78(m,2H); LCMS(m/z)399.1[M+H] ⁺ .

Example 589. N-(3-fluoro-5-((1-(trifluoromethyl)cyclopropyl)ethynyl)phenyl)-N-methyl-8-(trifluoro) methyl)-[1,2,4]triazolo[4,3-a]quinazolin-5-amine

The title compound was synthesized in a manner similar to that of Example 421, except that N-(3-bromo-5-fluorophenyl)-N-methyl-8-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]quinazolin-5-amine was used instead of N-(3-bromo-5-fluorophenyl)-8-chloro-N-methyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine and 1-ethynyl-1-(trifluoromethyl)cyclopropane was used instead of 2-methylbut-3-yn-2-ol. ¹ H NMR (400MHz, DMSO-d ₆ )δ9.92(s,1H),8.98–8.80(m,1H),7.75(dd,J＝8.8,1.7Hz,1H),7.56(d,J＝8.7Hz,1H),7.49– 7.32(m,2H),7.32–7.18(m,1H),3.60(s,3H),1.45(dt,J＝6.8,3.8Hz,2H),1.42–1.28(m,2H). LCMS(m/z)494.1[M+H] ⁺ .

Example 590. N-(3-(5-cyclopropylpyrazin-2-yl)-5-fluorophenyl)-N-methyl-7-(trifluoromethyl)-[1, [2,4]triazolo[4,3-a]quinazolin-5-amine

The title compound was synthesized in a manner similar to that of Example 591, except that 2,4-dichloro-6-(trifluoromethyl)quinazoline was used instead of 2,4-dichloro-7-(trifluoromethyl)quinazoline. ¹ H NMR (400MHz, DMSO-d ₆ )δ9.88(s,1H),8.99(d,J＝1.5Hz,1H),8.67(d,J＝1.5Hz,1H),8.59(d,J＝8.7Hz,1H),8.27(dd,J＝8.8,1.9Hz,1H),7.98(t,J＝1.7Hz,1H),7.91(ddd, J＝9.8,2.4,1.4Hz,1H),7.64–7.47(m,2H),3.71(s,3H),2.25(td,J＝8.1, 4.1Hz,1H),1.14–1.03(m,2H),1.03-0.90(m,2H); LCMS(m/z)480.1[M+H] ⁺ .

Example 591. N-(3-(5-cyclopropylpyrazin-2-yl)-5-fluorophenyl)-N-methyl-8-(trifluoromethyl)-[1, [2,4]triazolo[4,3-a]quinazolin-5-amine

(Step 1) Synthesis of N-(3-bromo-5-fluorophenyl)-2-chloro-N-methyl-7-(trifluoromethyl)quinazoline-4-amine (compound 591-1). Hydrochloric acid (37.0%, 483 mg, 4.90 mmol) was added to a mixture of 3-bromo-5-fluoro-N-methylaniline (0 mL, 4.90 mmol) and 2,4-dichloro-7-(trifluoromethyl)quinazoline (1309 mg, 4.90 mmol) in IPA (7.00 mL). The mixture was stirred at room temperature for 16 hours, after which the solid was filtered and washed with 2 mL of cold IPA. The filtrate was used for the next reaction without further purification. LCMS (m/z) 434.28 [M+H] ⁺ .

(Step 2) Synthesis of N-(3-bromo-5-fluorophenyl)-2-hydrazino-N-methyl-7-(trifluoromethyl)quinazoline-4-amine (compound 591-2). N-(3-bromo-5-fluorophenyl)-2-chloro-N-methyl-7-(trifluoromethyl)quinazoline-4-amine was synthesized in a similar manner to compound 308-3, except that N-(3-bromo-5-fluorophenyl)-2-chloro-N-methyl-7-(trifluoromethyl)quinazoline-4-amine was used instead of N-(3-bromophenyl)-2,7-dichloro-N-methylquinazoline-4-amine (compound 308-2). LCMS (m/z) 430.32.1 [M+H] ⁺ .

(Step 3) Synthesis of N-(3-bromo-5-fluorophenyl)-N-methyl-8-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]quinazoline-5-amine (compound 591-3). Compound 591-3 was synthesized in a similar manner to compound 308-3, except that N-(3-bromo-5-fluorophenyl)-2-hydrazyl-N-methyl-7-(trifluoromethyl)quinazoline-4-amine was used instead of N-(3-bromophenyl)-7-chloro-2-hydrazyl-N-methylquinazoline-4-amine. LCMS (m/z) 440.31 [M+H] ⁺ .

(Step 4) Synthesis of N-(3-(5-cyclopropylpyrazin-2-yl)-5-fluorophenyl)-N-methyl-8-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]quinazolin-5-amine (compound 591-4). Compound 591-4 was synthesized in a manner similar to that of 8-chloro-N-(3-(5-cyclopropylpyrazin-2-yl)phenyl)-7-fluoro-N-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]quinazoline-5-amine, except that N-(3-bromo-5-fluorophenyl)-N-methyl-8-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]quinazoline-5-amine was used instead of 8-chloro-7-fluoro-N-(3-iodophenyl)-N-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]quinazoline-5-amine (Example 595). LCMS (m/z) 480.1 [M+H] ⁺ .

Example 592. 8-Chloro-N-(3-fluoro-5-((1-isopropylcyclopropyl)ethynyl)phenyl)-N-methyl-[1,2, 4] Triazolo[4,3-a]quinazolin-5-amine

The title compound was synthesized according to the procedure described for Example 421.

¹ H NMR (400MHz, DMSO-d ₆ )δ9.84(s,1H),8.50(dd,J＝9.2,4.8Hz,1H),8.06–7.83(m,1H),7.44(dt,J＝10.0,2.2Hz,1H),7.35(t,J＝1.6Hz,1H),7.30(dt,J＝8 .8, 1.9Hz, 1H), 6.93 (dd, J＝10.2, 2.7Hz, 1H), 5.75 (t, J＝55.5Hz, 1H), 4.18 (q, J＝6.9Hz, 2H), 1.35–1.03 (m, 8H); LCMS (m/z) 434.1.

Example 593. N-(3-((1-(difluoromethyl)cyclopropyl)ethynyl)-5-fluorophenyl)-N-ethyl-7-fluoro-[1, [2,4]triazolo[4,3-a]quinazolin-5-amine

The title compound was synthesized according to the procedure described for Example 421.

¹ H NMR (400MHz, DMSO-d ₆ )δ9.81(s,1H),8.48(dd,J＝9.2,4.8Hz,1H),7.91(ddd,J＝9.2,8.1,2.8Hz,1H),7.70–7.50(m,1H),7.42(dt,J＝10.0,2.3Hz,1H),7.33(d,J＝1.7Hz, 1H), 7.28 (dd, J＝9.0, 2.0Hz, 1H), 6.93 (dd, J＝10.2, 2.7Hz, 1H), 5.75 (t, J＝55.5Hz, 1H), 4.17 (d, J＝7.0Hz, 2H), 1.41–0.88 (m, 7H); LCMS (m/z) 440.1.

Example 594. 8-Chloro-N-(3-(5-cyclopropylpyrazin-2-yl)-5-fluorophenyl)-N-(trifluoromethyl)-[1,2, 4] Triazolo[4,3-a]quinazolin-5-amine

Synthesis of 1-fluoro-3-iodo-5-isothiocyanate benzene. A solution of 3-fluoro-5-iodo-aniline (4.0 g, 16.9 mmol) and sodium carbonate (2.68 g, 25.3 mmol) in acetone (100 mL) was stirred in an ice bath under a nitrogen atmosphere. Phosgene (1.94 mL, 25.3 mmol) was added dropwise over 30 minutes. The reaction was stirred in an ice bath for another 30 minutes, then the ice bath was removed and the mixture was heated to room temperature. The reaction was stirred at room temperature for 1.5 hours, and then the reaction solution was concentrated under reduced pressure. The residue was azeotropically reacted with toluene to remove residual phosgene and give the desired product.

Example 594 was synthesized in a manner similar to Example 595, except that 1-fluoro-3-iodo-5-isothiocyanate benzene was used instead of 1-iodo-3-isothiocyanate benzene and 2,4,7-trichloroquinazoline was used instead of 2,4,7-trichloro-6-fluoroquinazoline. ¹ H NMR (400MHz, DMSO-d ₆ )δ9.94(s,1H),9.09(d,J＝1.4Hz,1H),8.79–8.71(m,1H),8.69(d,J＝1.4Hz,1H),8.18–7.94(m,3H), 7.76–7.54(m,2H),2.32–2.18(m,1H),1.11-1.04(m,2H),1.02–0.92(m,2H); LCMS(m/z)500.1[M+H] ⁺ .

Example 595. 8-Chloro-N-(3-(5-cyclopropylpyrazin-2-yl)phenyl)-7-fluoro-N-(trifluoromethyl)-[1,2, 4] Triazolo[4,3-a]quinazolin-5-amine

(Step 1) Synthesis of 2,7-dichloro-6-fluoro-N-(3-iodophenyl)-N-(trifluoromethyl)quinazoline-4-amine (compound 595-1). A mixture of 2,4,7-trichloro-6-fluoro-quinazoline (393 mg, 1.56 mmol), 1-iodo-3-isothiocyanate-benzene (400 mg, 1.53 mmol), and silver fluoride (I) (972 mg, 7.66 mmol) in MeCN (12.0 mL) was vigorously stirred at 70 °C for 30 min. The mixture was poured into 100 mL of DCM, filtered through diatomaceous earth, and concentrated under reduced pressure. The residue was purified by silica gel rapid column chromatography (0% to 75% dichloromethane in hexane) to give compound 595-1. LCMS (m/z) 502.17 [M+H] ⁺ .

(Step 2) Synthesis of 7-chloro-6-fluoro-2-hydrazino-N-(3-iodophenyl)-N-(trifluoromethyl)quinazoline-4-amine (compound 595-2). Hydrazine (50.0%, 0.241 mL, 3.86 mmol) was added to a mixture of 2,7-dichloro-6-fluoro-N-(3-iodophenyl)-N-(trifluoromethyl)quinazoline-4-amine (388 mg, 0.773 mmol) in EtOH (2.61 mL) and THF (1.74 mL). The resulting mixture was vigorously stirred at room temperature for 30 minutes. Water (5 mL), THF (40 mL), and EtOAc (80 mL) were added sequentially. The mixture was washed with a 4:1 water:salt solution (2 × 75 mL), dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was azeotropically reacted with THF:toluene and used in the next step without further purification. LCMS(m/z)498.15[M+H] ⁺ .

(Step 3) Synthesis of 8-chloro-7-fluoro-N-(3-iodophenyl)-N-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]quinazoline-5-amine (compound 595-3). A mixture of N-(3-bromophenyl)-7-chloro-6-fluoro-2-hydrazino-N-(trifluoromethyl)quinazoline-4-amine (385 mg, 0.854 mmol) in diethoxymethoxyethane (6.17 mL, 37.1 mmol) was vigorously stirred at 160 °C for 60 min, cooled to room temperature, and concentrated under reduced pressure. The residue was purified by silica gel rapid column chromatography (0% to 20% EtOAc in DCM solution) to give compound 595-3. LCMS (m/z) 507.90 [M+H] ⁺ .

(Step 4) Synthesis of 8-chloro-N-(3-(5-cyclopropylpyrazin-2-yl)phenyl)-7-fluoro-N-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]quinazoline-5-amine. Tributyl-(5-cyclopropylpyrazin-2-yl)stanane (27.3 mg, 0.0668 mmol) and tetrakis(triphenylphosphine)palladium(0) (6.83 mg, 0.00591 mmol) were added to a solution of 8-chloro-7-fluoro-N-(3-iodophenyl)-N-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]quinazoline-5-amine (30.0 mg, 0.0591 mmol). The reaction mixture was heated to 100 °C for 12 hours. The reaction mixture was cooled to room temperature and diluted successively with ethyl acetate (5 mL) and water (5 mL). The organic layer was separated and concentrated under reduced pressure. The residue was purified by reversed-phase preparative HPLC (acetonitrile/water containing 0.1% trifluoroacetic acid) to obtain the title compound. ¹ H NMR (400MHz, DMSO-d ₆ )δ9.90(s,1H),9.06(d,J＝1.4Hz,1H),8.92(d,J＝6.3Hz,1H),8.67(d,J＝1.4Hz,1H),8.27(d,J＝1.9Hz,1H),8.15(dt,J＝7.9,1.3Hz,1H),7. 98(d,J＝9.5Hz,1H),7.79(dd,J＝7.9,2.1Hz,1H),7.64(t,J＝7.9Hz,1H),2.24(tt,J＝8.1,4.7Hz,1H),1.11-1.04(m,2H),1.04–0.90(m,2H). LCMS(m/z)500.10[M+H] ⁺ .

Example 596. 3-[3-[(8-chloro-[1,2,4]triazolo[4,3-a]quinazolin-5-yl)-methyl-amino]benzene [1,1-Dicyclopropyl-prop-2-yn-1-ol]-1,1-Dicyclopropyl-prop-2-yn-1-ol

1,1-Dicyclopropylprop-2-yn-1-ol (52% purity, 20 μL, 61 μmol) was added to a vigorously stirred mixture of [1,1'-bis(diphenylphosphine)ferrocene]palladium(II) dichloride (4.6 mg, 6.3 μmol), triethylamine (63 μL, 450 μmol), and zinc bromide (20.3 mg, 90.1 μmol) in 1-methylpyrrolidone-2-one (0.5 mL). The reaction mixture was sealed and heated to approximately 110 °C. After 20 minutes, the reaction mixture was cooled to room temperature. The mixture was purified by reversed-phase preparative HPLC (acetonitrile/water containing 0.1% trifluoroacetic acid). Ethyl acetate (10 mL), water (5 mL), and saturated sodium bicarbonate aqueous solution (5 mL) were added sequentially. The organic layer was separated, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to provide the title compound: ^¹H NMR (400 MHz, methanol- _d⁴ ) δ 9.47 (d, J = 1.8 Hz, 1H), 8.38 (d, J = 2.0 Hz, 1H), 7.43–7.37 (m, 1H), 7.37–7.30 (m, 3H), 7.30–7.20 (m, 2H), 3.66 (s, 3H), 1.29–1.21 (m, 2H), 0.71–0.59 (m, 2H), 0.59–0.40 (m, 6H); LCMS (m/z) 444.1.

Example 597. 4-[3-[(8-chloro-[1,2,4]triazolo[4,3-a]quinazolin-5-yl)-methyl-amino]benzene [2-(1-Methylcyclopropyl)but-3-yn-2-ol]

Example 597 was prepared in a manner similar to Example 596, using 2-(1-methylcyclopropyl)but-3-yn-2-ol instead of 1,1-dicyclopropylprop-2-yn-1-ol. ^¹H NMR (400 MHz, methanol- _d⁴ ) δ 9.47 (s, 1H), 8.38 (d, J = 2.0 Hz, 1H), 7.41 (t, J = 7.9 Hz, 1H), 7.35 (dt, J = 3.9, 2.0 Hz, 2H), 7.33 (s, 1H), 7.29–7.23 (m, 2H), 3.66 (s, 3H), 1.54 (s, 3H), 1.20 (s, 3H), 0.95–0.76 (m, 2H), 0.29 (q, J = 2.6 Hz, 2H); LCMS (m/z) 432.2.

Example 598. 4-[3-[(8-chloro-[1,2,4]triazolo[4,3-a]quinazolin-5-yl)-methyl-amino]benzene [2-Cyclobutyl-but-3-yn-2-ol]

Example 598 was prepared in a manner similar to that of Example 596, using 2-cyclobutylbut-3-yn-2-ol instead of 1,1-dicyclopropylprop-2-yn-1-ol. ¹ H NMR (400MHz, chloroform-d) δ8.98(s,1H),8.02(m,1H),7.72–7.65(m,1H),7.53(d,J＝8.8Hz,1H),7.49–7.32(m,2H),7.20(d,J＝11.0Hz,2H),3.77(s,3 H), 2.30 (s, 1H), 2.17–2.08 (m, 1H), 1.83 (s, 1H), 1.66 (q, J = 8.2Hz, 1H), 1.47 (s, 3H), 1.42–1.29 (m, 1H), 1.01–0.88 (m, 2H); LCMS (m/z) 432.2.

Example 599. N-(2,2-difluoroethyl)-7-fluoro-N-(2-fluoro-3-(4,4,4-trifluoro-3,3-dimethylbut-1- (1-yl)phenyl)-[1,2,4]triazolo[4,3-a]quinazolin-5-amine

Synthesis of tert-butyl (3-bromo-2-fluorophenyl)carbamate: 0.0105 mol of 3-bromo-2-fluoroaniline was added to a vial, followed by 0.0210 mol of ditert-butyl dicarbonate, and the mixture was heated to 80 °C with stirring for 7 hours. The reaction mixture was cooled to room temperature, concentrated, and purified by column chromatography (hexane to 15% EtOAc in hexane): MS (m/z) 290.129 [M+H] ⁺ .

Synthesis of tert-butyl (3-bromo-2-fluorophenyl)(2,2-difluoroethyl)carbamate: 0.00276 mol of tert-butyl (3-bromo-2-fluorophenyl)carbamate was added to a vial, dissolved in DMF (9.5 mL), and cooled to 0 °C. Sodium hydride (60%, 0.00551 mol) was added to the solution, and the mixture was stirred for 30 min. 0.00331 mol of 2,2-difluoroethyl trifluoromethanesulfonate was added, and the solution was heated to room temperature and stirred for 1 h. The reaction was quenched with ammonium chloride solution, poured into water, extracted with EtOAc, washed with water, washed with brine, concentrated, and deprotected. MS (m/z) 354.163 [M+H] ⁺ .

Synthesis of 3-bromo-N-(2,2-difluoroethyl)-2-fluoroaniline: 0.00270 mol of tert-butyl (3-bromo-2-fluorophenyl)(2,2-difluoroethyl)carbamate was dissolved in DCM (12 mL), and trifluoroacetic acid (99%, 5 mL) was added. The reaction was stirred at room temperature for 30 min, concentrated, and dissolved in EtOAc. The solution was then washed with saturated sodium bicarbonate solution, washed with brine, dried over _Na₂SO₄ , and concentrated to provide the title aniline. _MS (m/z) 254.242 [M+H] ^⁺ .

Synthesis of N-(3-bromo-2-fluorophenyl)-2-chloro-N-(2,2-difluoroethyl)-6-fluoroquinazoline-4-amine: NaH (60% dispersion in mineral oil) (1.01 mmol) was added in a single addition to a solution of 0.92 mmol of 3-bromo-N-(2,2-difluoroethyl)-2-fluoroaniline in 3.0 mL of DMF at 0 °C. The mixture was stirred at 0 °C for 30 min, followed by a single addition of 1.01 mmol of 2,4-dichloro-6-fluoroquinazoline, and the mixture was heated to room temperature over 16 hours. Afterward, the mixture was cooled to 0 °C and quenched with a few drops of saturated _NH₄Cl solution (aqueous) while stirring until the solid was broken up. The solid was filtered off, washed with a 4:1 mixture of hexane and diethyl ether, dried under vacuum, and used without further purification: MS (m/z) 434.391 [M+H] ^⁺ .

Synthesis of N-(3-bromo-2-fluorophenyl)-N-(2,2-difluoroethyl)-6-fluoro-2-hydrazinoquinazolin-4-amine: Hydrazine monohydrate (7.9 mmol) was added to a solution of N-(3-bromo-2-fluorophenyl)-2-chloro-N-(2,2-difluoroethyl)-6-fluoroquinazolin-4-amine (0.658 mmol) in THF (3.5 mL) and ethanol (3.5 mL), and the mixture was stirred at room temperature for 12 hours. After completion, the reactants were diluted with EA and washed with water, dried over _Na₂SO₄ , and concentrated under reduced pressure to provide the product. _MS (m/z) 430.198 [M+H] ^⁺ .

Synthesis of N-(3-bromo-2-fluorophenyl)-N-(2,2-difluoroethyl)-7-fluoro-[1,2,4]triazolo[4,3-a]quinazoline-5-amine: A solution of N-(3-bromo-2-fluorophenyl)-N-(2,2-difluoroethyl)-6-fluoro-2-hydrazino-quinazoline-4-amine (0.604 mmol) and triethyl orthoformate (22.5 mmol) was heated to 110 °C for 16 hours. After completion, the reactants were cooled to room temperature and concentrated under reduced pressure to provide a crude product. The crude product was ground with heptane, and the solid was collected by filtration, washed with hexane:ethyl ether (4:1), and dried under vacuum to provide the product. MS (m/z) 443.307 [M+H] ⁺ .

Synthesis of N-(2,2-difluoroethyl)-7-fluoro-N-(2-fluoro-3-(4,4,4-trifluoro-3,3-dimethylbut-1-yn-1-yl)phenyl)-[1,2,4]triazolo[4,3-a]quinazolin-5-amine: A solution of N-(3-bromo-2-fluoro-phenyl)-N-(2,2-difluoroethyl)-7-fluoro-[1,2,4]triazolo[4,3-a]quinazolin-5-amine (0.0606 mmol), zinc bromide (0.303 mmol), (1,1'-)bis(diphenylphosphine)ferrocene palladium dichloride(II) (0.00303 mmol) and triethylamine (0.303 mmol) in DMF (0.70 mL) was purged with nitrogen for 5 min. Then, 0.00728 mol of 4,4,4-trifluoro-3,3-dimethyl-but-1-yne was added and the mixture was heated at 100 ° _C for 30 minutes. Afterward, the mixture was cooled to room temperature, and ethyl acetate and saturated _NH₄Cl (aqueous solution) were added to the mixture. The aqueous layer was extracted with EA, and the combined organic layers were dried over _Na₂SO₄ and concentrated under vacuum. The residue was purified by reversed-phase HPLC (acetonitrile/water containing 0.1% trifluoroacetic acid) to provide the title compound as a single TFA salt. ¹ H NMR (400MHz, DMSO-d ₆ )δ9.79(s,1H),8.52(dd,J＝9.2,4.9Hz,1H),7.94(ddd,J＝9.2,8.0,2.8Hz,1H),7.69(td,J＝8.0,1.7Hz,1H),7.57(ddd,J＝8.0,6.4,1.6Hz,1H),7. 34(t,J＝7.9Hz,1H),6.86(dd,J＝10.1,2.7Hz,1H),6.60(tt,J＝55.9,4.2H z,1H),4.48(td,J＝13.8,4.2Hz,2H),1.48(s,6H); MS(m/z)497.969[M+H] ⁺ .

Example 600. N-(2,2-difluoroethyl)-7-fluoro-N-(2-fluoro-3-(4,4,4-trifluoro-3,3-dimethylbut-1- (1-yl)phenyl)-[1,2,4]triazolo[4,3-a]quinazolin-5-amine

Synthesis of N-(3-bromo-2-fluorophenyl)-2-chloro-N-(2,2-difluoroethyl)-6-fluoroquinazoline-4-amine: NaH (60% dispersion in mineral oil) (1.01 mmol) was added in a single addition to a solution of 0.92 mmol of 3-bromo-N-(2,2-difluoroethyl)-2-fluoroaniline in 3.0 mL of DMF at 0 °C. The mixture was stirred at 0 °C for 30 min, followed by a single addition of 1.01 mmol of 2,4-dichloro-6-fluoroquinazoline, and the mixture was heated to room temperature over 16 hours. Afterward, the mixture was cooled to 0 °C and quenched with a few drops of saturated _NH₄Cl solution (aqueous) while stirring until the solid was broken up. The solid was filtered off, washed with a 4:1 mixture of hexane and diethyl ether, dried under vacuum, and used without further purification. MS (m/z) 434.391 [M+H] ^⁺ .

Synthesis of N-(3-bromo-2-fluorophenyl)-N-(2,2-difluoroethyl)-6-fluoro-2-hydrazinoquinazolin-4-amine: Hydrazine monohydrate (7.9 mmol) was added to a solution of N-(3-bromo-2-fluorophenyl)-2-chloro-N-(2,2-difluoroethyl)-6-fluoroquinazolin-4-amine (0.658 mmol) in THF (3.5 mL) and ethanol (3.5 mL), and the mixture was stirred at room temperature for 12 hours. After completion, the reactants were diluted with EA and washed with water, dried over _Na₂SO₄ , and concentrated under reduced pressure to provide the product. _MS (m/z) 430.198 [M+H] ^⁺ .

Synthesis of N-(3-bromo-2-fluorophenyl)-N-(2,2-difluoroethyl)-7-fluoro-1-methyl-[1,2,4]triazolo[4,3-a]quinazoline-5-amine: A solution of N-(3-bromo-2-fluorophenyl)-N-(2,2-difluoroethyl)-6-fluoro-2-hydrazino-quinazoline-4-amine (0.818 mmol) and triethyl orthoacetate (27.5 mmol) was heated to 110 °C for 16 hours. After completion, the reactants were cooled to room temperature and concentrated under reduced pressure to provide a crude product. The crude product was ground with heptane, and the solid was collected by filtration, washed with hexane:ethyl ether (4:1), and dried under vacuum to provide the product. MS (m/z) 457.52 [M+H] ⁺ .

Synthesis of N-(2,2-difluoroethyl)-N-[3-[2-[1-(difluoromethyl)cyclopropyl]ethynyl]-2-fluoro-phenyl]-7-fluoro-1-methyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine: A solution of N-(3-bromo-2-fluoro-phenyl)-N-(2,2-difluoroethyl)-7-fluoro-[1,2,4]triazolo[4,3-a]quinazolin-5-amine (0.0550 mmol), zinc bromide (0.275 mmol), (1,1'-)bis(diphenylphosphine)ferrocene)palladium(II) dichloride (0.00275 mmol) and triethylamine (0.275 mmol) in DMF (0.70 mL) was purged with nitrogen for 5 min. Then 1-(difluoromethyl)-1-ethynyl-cyclopropane (0.00660 mol) was added and the mixture was heated at 100 °C for 30 min. Afterward, the mixture was cooled to room temperature, and ethyl acetate and saturated _NH₄Cl (aqueous solution) were added to the mixture. The aqueous layer was extracted with EA, and _the combined organic layers were dried over _Na₂SO₄ and concentrated under vacuum. The residue was purified by reversed-phase HPLC (acetonitrile/water containing 0.1% trifluoroacetic acid) to provide the title compound as a single TFA salt. ^¹H NMR (400 MHz, DMSO- _d₆) )δ8.40(dd,J＝9.4,4.7Hz,1H),7.87(ddd,J＝9.4,7.7,2.9Hz,1H),7.68(td,J ＝8.0,1.7Hz,1H),7.53(ddd,J＝8.0,6.5,1.6Hz,1H),7.35(t,J＝7.9Hz,1H),6. 98(dd,J＝10.0,2.9Hz,1H),6.76–6.44(m,1H),5.74(t,J＝55.4Hz,1H),4.50(t d,J＝13.9,4.1Hz,2H),3.00(s,3H),1.26–1.15(m,4H); MS(m/z)491.866[M+H] ⁺ .

Example 601. N-(2,2-difluoroethyl)-7-fluoro-N-(3-fluoro-5-(3-methoxy-3-methylbut-1-yne-1- (1,2,4)triazolo[4,3-a]quinazolin-5-amine

The title compound was synthesized according to the procedure described in Example 599.

¹ H NMR (400MHz, DMSO-d ₆ )δ9.80(s,1H),8.50(dd,J＝9.2,4.8Hz,1H),7.91(ddd,J＝9.2,8.1,2.8Hz,1H),7.37–7.31(m,2H),7.25–7.20(m,1H),6.97 (dd,J＝9.9,2.8Hz,1H),6.73–6.39(m,1H),4.58(td,J＝14.3,4.0Hz,2H),3.28(s,3H),1.44(s,6H); MS(m/z)458.175[M+H] ⁺ .

Example 602. N-(2,2-difluoroethyl)-6-fluoro-N-(3-fluoro-5-(3-methoxy-3-methylbut-1-yne-1- (1,2,4)triazolo[4,3-a]quinazolin-5-amine

The title compound was synthesized using triethyl orthoformate instead of triethyl orthoacetate, according to the procedure described in Example 603. ^¹H NMR (400 MHz, DMSO- _d⁶ ) δ 9.82 (d, J = 0.8 Hz, 1H), 8.26 (d, J = 8.3 Hz, 1H), 8.01 (dd, J = 8.6, 5.2 Hz, 1H), 7.26 (dd, J = 11.9, 8.3 Hz, 1H), 7.23–7.14 (m, 2H), 7.05 (d, J = 9.0 Hz, 1H), 6.72–6.36 (m, 1H), 4.73–4.55 (m, 2H), 3.26 (s, 3H), 1.43 (s, 6H); MS (m/z) 458.2 [M+H] ^⁺ .

Example 603. N-(2,2-difluoroethyl)-6-fluoro-N-[3-fluoro-5-(3-methoxy-3-methyl-but-1-ynyl)] [Phenyl]-1-methyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine

Synthesis of N-(3-bromo-5-fluorophenyl)-2-chloro-N-(2,2-difluoroethyl)-5-fluoroquinazoline-4-amine: NaH (60% dispersion in mineral oil) (2.36 mmol) was added in a single addition to a solution of 1.97 mmol of 3-bromo-N-(2,2-difluoroethyl)-5-fluoroaniline in 3.0 mL of DMF at 0 °C. The mixture was stirred at 0 °C for 30 min, followed by a single addition of 1.97 mmol of 2,4-dichloro-5-fluoroquinazoline, and the mixture was heated to room temperature over 16 hours. Afterward, the mixture was cooled to 0 °C and quenched with a few drops of saturated _NH₄Cl solution (aqueous) while stirring until the solid was broken up. The solid was filtered off, washed with a 4:1 mixture of hexane and diethyl ether, dried under vacuum, and used without further purification. MS (m/z) 436.340 [M+H] ^⁺ .

Synthesis of N-(3-bromo-5-fluorophenyl)-N-(2,2-difluoroethyl)-5-fluoro-2-hydrazinoquinazolin-4-amine: Hydrazine monohydrate (15.2 mmol) was added to a solution of N-(3-bromo-2-fluorophenyl)-2-chloro-N-(2,2-difluoroethyl)-5-fluoroquinazolin-4-amine (1.27 mmol) in THF (3.5 mL) and ethanol (3.5 mL), and the mixture was stirred at room temperature for 12 hours. After completion, the reactants were diluted with EA and washed with water, dried over _Na₂SO₄ , and concentrated under reduced pressure to provide the product. _MS (m/z) 433.134 [M+H] ^⁺ .

Synthesis of N-(3-bromo-5-fluorophenyl)-N-(2,2-difluoroethyl)-6-fluoro-1-methyl-[1,2,4]triazolo[4,3-a]quinazoline-5-amine: A solution of N-(3-bromo-5-fluorophenyl)-N-(2,2-difluoroethyl)-5-fluoro-2-hydrazinoquinazoline-4-amine (0.604 mmol) and triethyl orthoacetate (22.5 mmol) was heated to 110 °C for 16 hours. After completion, the reactants were cooled to room temperature and concentrated under reduced pressure to provide a crude product. The crude product was ground with heptane and the solid was collected. MS (m/z) 457.360 [M+H] ⁺ .

Synthesis of N-(2,2-difluoroethyl)-6-fluoro-N-[3-fluoro-5-(3-methoxy-3-methyl-but-1-ynyl)phenyl]-1-methyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine: N-(3-bromo-5-fluorophenyl)-N-(2,2-difluoroethyl)-6-fluoro-1-methyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine (0.00568 mmol), zinc bromide (0.284 mmol), (1,1'-)bis(diphenylphosphine)ferrocene)palladium(II) dichloride (0.00284 mmol) and triethylamine (0.284 mmol) in DMF (0.70 mL) were purged with nitrogen for 5 min. Then, 0.170 mol of 3-methoxy-3-methyl-but-1-yne was added and the mixture was heated at 100 ° _C for 30 min. Afterward, the mixture was cooled to room temperature, and ethyl acetate and saturated _NH₄Cl (aqueous solution) were added to the mixture. The aqueous layer was extracted with EA, and the combined organic layers were dried over _Na₂SO₄ and concentrated under vacuum. The residue was purified by reversed-phase HPLC (acetonitrile/water containing 0.1% trifluoroacetic acid) to provide the title compound as a single TFA salt. ¹ H NMR (400MHz, DMSO-d ₆ )δ8.17(d,J＝8.6Hz,1H),7.98(q,J＝8.3Hz,1H),7.36–7.24(m,1H),7.17(s,1H),7.15–7.09(m,1H),7.05(d,J＝9. 0Hz,1H),6.70–6.35(m,1H),4.65(t,J＝14.1Hz,2H),3.26(s,3H),3.02(s,3H),1.43(s,6H); MS(m/z)472.2[M+H] ⁺ .

Example 604. N-(2,2-difluoroethyl)-7-fluoro-N-(3-fluoro-5-(3-methoxy-3-methylbut-1-yne-1- (1,2,4)triazolo[4,3-a]quinazolin-5-amine

The title compound was synthesized according to the procedure described for Example 600.

¹ H NMR (400MHz, DMSO-d ₆ )δ8.39(dd,J＝9.5,4.6Hz,1H),7.90–7.80(m,1H),7.31(d,J＝7.3Hz,2H),7.25(d,J＝8.8Hz,1H),7.09(dd,J＝9.8,2.9Hz, 1H),6.75–6.37(m,1H),4.60(td,J＝14.5,14.0,3.6Hz,2H),3.28(s,3H),3.02(s,3H),1.44(s,6H); MS(m/z)472.2[M+H] ⁺ .

Example 605. 1-(difluoromethyl)-7-fluoro-5-(5-((1-methylcyclopropyl)ethynyl)-3,4-dihydroquinone (1,2,4)-[1,2,4]triazolo[4,3-a]quinazolino

The title compound was synthesized according to the procedure described for Example 713.

^1H NMR (400MHz, DMSO-d6 ₎ )8.21(dd,J＝9.3,4.5Hz,1H),7.98–7.89(m,1H),7.77(d,J＝51.4Hz,1H),7.42( dd,J＝9.5,2.9Hz,1H),7.09(d,J＝7.5Hz,1H),6.92(t,J＝7.9Hz,1H),6.83(d,J＝8 .1Hz,1H),3.94(d,J＝12.4Hz,2H),2.95(t,J＝6.7Hz,2H),2.08(p,J＝6.7Hz,2H) ,1.37(s,3H),1.00(q,J＝4.0Hz,2H),0.80(q,J＝4.1Hz,2H); MS(m/z)448.2[M+H] ⁺ .

Example 606. N-Ethyl-6,7-difluoro-N-[3-fluoro-5-[2-(1-methylcyclopropyl)ethynyl]phenyl]-[1, [2,4]triazolo[4,3-a]quinazolin-5-amine

Synthesis of 2-chloro-N-ethyl-5,6-difluoro-N-(3-fluoro-5-iodophenyl)quinazoline-4-amine: NaH (60% dispersion in mineral oil) (1.53 mmol) was added in a single addition to a solution of N-ethyl-3-fluoro-5-iodoaniline (1.40 mmol) in DMF (3.0 mL) at 0 °C. The mixture was stirred at 0 °C for 30 min, followed by a single addition of 2,4-dichloro-5,6-difluoroquinazoline (1.28 mmol), and the mixture was heated to room temperature over 16 hours. Afterward, the mixture was cooled to 0 °C and quenched with a few drops of saturated _NH₄Cl solution (aqueous) while stirring until the solid was broken up. The solid was filtered off, washed with a 4:1 mixture of hexane and diethyl ether, dried under vacuum, and used without further purification. MS (m/z) 466.285 [M+H] ^⁺ .

Synthesis of N-ethyl-5,6-difluoro-N-(3-fluoro-5-iodophenyl)-2-hydrazinoquinazolin-4-amine: Hydrazine monohydrate (5.97 mmol) was added to a solution of N-(3-iodo-5-fluorophenyl)-2-chloro-N-ethyl-5,6-difluoroquinazolin-4-amine (0.597 mmol) in THF (3.5 mL) and ethanol (3.5 mL), and the mixture was stirred at room temperature for 12 hours. After completion, the reactants were diluted with EA and washed with water, dried over _Na₂SO₄ , and concentrated under reduced pressure to provide the product. _MS (m/z) 461.688 [M+H] ^⁺ .

Synthesis of N-ethyl-6,7-difluoro-N-(3-fluoro-5-iodo-phenyl)-[1,2,4]triazolo[4,3-a]quinazoline-5-amine: A solution of N-(3-iodo-5-fluorophenyl)-N-ethyl-5,6-difluoro-2-hydrazinoquinazoline-4-amine (0.603 mmol) and triethyl orthoformate (7.24 mmol) was heated to 110 °C for 16 hours. After completion, the reactants were cooled to room temperature and concentrated under reduced pressure to provide a crude product. The crude product was ground with heptane and the solid was collected. MS (m/z) 471.728 [M+H] ⁺ .

Synthesis of N-ethyl-6,7-difluoro-N-[3-fluoro-5-[2-(1-methylcyclopropyl)ethynyl]phenyl]-[1,2,4]triazolo[4,3-a]quinazolin-5-amine: N-(3-iodo-5-fluorophenyl)-N-ethyl-6,7-difluoro-[1,2,4]triazolo[4,3-a]quinazolin-5-amine (0.107 mmol), zinc bromide (0.533 mmol), (1,1'-)bis(diphenylphosphine)ferrocene)palladium(II) dichloride (0.0107 mmol), and triethylamine (2.13 mmol) in DMF (0.70 mL) were purged with nitrogen for 5 min. Then 1-ethynyl-1-methylcyclopropane (0.6398 mol) was added and the mixture was heated at 100 °C for 30 min. After completion, the mixture was cooled to room temperature, and ethyl acetate and saturated _NH₄Cl (aqueous solution) were added to the mixture. The aqueous layer was extracted with EA, and _the combined organic layers were dried over _Na₂SO₄ and concentrated under vacuum. The residue was purified by reversed-phase HPLC (acetonitrile/water containing 0.1% trifluoroacetic acid) to provide the title compound as a single TFA salt. ¹ H NMR (400MHz, DMSO-d ₆ )δ9.78(s,1H),8.33–8.24(m,1H),8.21–8.08(m,1H),7.19(dt,J＝10.6,2.3Hz,1H),7.14(t,J＝1.6Hz,1H),7.03–6.97(m,1H) ,4.19(q,J＝6.9Hz,2H),1.27(s,3H),1.22(t,J＝6.9Hz,3H),0.92(q,J＝4.0Hz,2H),0.72(q,J＝4.1Hz,2H); MS(m/z)422.1[M+H] ⁺ .

Example 607. 4-(3-((6,7-difluoro-[1,2,4]triazolo[4,3-a]quinazolin-5-yl)(ethyl)amino (5-fluorophenyl)-2-methylbut-3-yne-2-ol

The title compound was synthesized according to the procedure described for Example 606.

¹ H NMR (400MHz, DMSO-d ₆ )δ9.79(s,1H),8.34–8.24(m,1H),8.16(q,J＝9.2Hz,1H),7.26–7.19(m,1H),7.18(t,J＝1.6Hz,1H) ,7.04–6.98(m,1H),4.20(q,J＝6.9Hz,2H),1.42(s,6H),1.23(t,J＝6.9Hz,3H); MS(m/z)426.1[M+H] ⁺ .

Example 608. N-Ethyl-6,7-difluoro-N-(3-fluoro-5-((1-(trifluoromethyl)cyclopropyl)ethynyl)benzene (-[1,2,4]triazolo[4,3-a]quinazolin-5-amine)

The title compound was synthesized according to the procedure described for Example 606.

¹ H NMR (400MHz, DMSO-d ₆ )δ9.79(s,1H),8.32–8.26(m,1H),8.21–8.12(m,1H),7.30–7.25(m,2H),7.15–7.09(m,1H),4.20( q,J＝6.9Hz,2H),1.45–1.41(m,2H),1.39–1.34(m,2H),1.23(t,J＝6.9Hz,3H); MS(m/z)476.1[M+H] ⁺ .

Example 609. 8-Chloro-N-(2,2,2-trifluoroethyl)-N-(5-((1-(trifluoromethyl)cyclopropyl)ethynyl) pyridin-3-yl)-[1,2,4]triazolo[4,3-a]quinazolin-5-amine

(Step 1) Synthesis of N-(5-bromopyridin-3-yl)-2,2,2-trifluoroacetamide

A solution of 5-bromopyridine-3-amine (5.00 g, 28.9 mmol) and HOBt hydrate (4.87 g, 31.8 mmol) in DCM (150 mL) was treated with TFA (2.21 mL, 28.9 mmol), followed by DIPEA (5.54 mL, 31.8 mmol) and EDC hydrochloride (6.09 g, 31.8 mmol). The resulting mixture was stirred overnight at room temperature. An aqueous solution of HCl (1 M) was added with stirring, and the resulting suspension was filtered. The filtrate layer was separated, and the organic layer was washed with a saturated aqueous solution of NaHCO3. The organic layer was dried over Na2SO4, filtered, and concentrated under vacuum to provide the desired product, which was used in the next step without further purification. LCMS (m/z) 268.9 [M+H] ⁺ .

(Step 2) Synthesis of 5-bromo-N-(2,2,2-trifluoroethyl)pyridine-3-amine

A solution of N-(5-bromopyridin-3-yl)-2,2,2-trifluoroacetamide (2.17 g, 8.07 mmol) in THF (21 mL) was treated with _BH3 πTHF (20.2 mL, 1.0 M solution in THF, 20.2 mmol) under _N2 . The resulting mixture was stirred under reflux for 3 h. The mixture was then cooled to room temperature and carefully quenched by dropwise addition of MeOH (20 mL). The mixture was then refluxed again for 1 h, cooled to room temperature, and concentrated under vacuum. The residue was purified by silica gel chromatography (0 to 55% EtOAc in hexane solution) to provide the desired product. LCMS (m/z) 255.3 [M+H] ⁺ .

(Step 3) Synthesis of N-(5-bromopyridin-3-yl)-2,7-dichloro-N-(2,2,2-trifluoroethyl)quinazoline-4-amine

A solution of 5-bromo-N-(2,2,2-trifluoroethyl)pyridine-3-amine (353 mg, 1.38 mmol) in DMF (2.0 mL) was treated with NaH (60% dispersion in mineral oil, 63.6 mg, 1.66 mmol). After stirring for 30 min, 2,4,7-trichloroquinazoline (323 mg, 1.38 mmol) was added in a single fraction, and the reaction mixture was heated to room temperature with stirring. After 2 hours, the reaction mixture was carefully diluted with water and extracted with EtOAc. The organic layer was washed twice more with water and then concentrated under vacuum. The residue was purified by silica gel chromatography (0 to 20% EtOAc in hexane solution) to provide the desired product. LCMS (m/z) 251.3 [M+H] ⁺ .

(Step 4) N-(5-bromopyridin-3-yl)-7-chloro-2-hydrazino-N-(2,2,2-trifluoroethyl)quinazolin-4-amine synthesis

A solution of N-(5-bromopyridin-3-yl)-2,7-dichloro-N-(2,2,2-trifluoroethyl)quinazolin-4-amine (279 mg, 617 μmol) in THF (2.0 mL) and EtOH (2.0 mL) was treated with hydrazine (192 μL, 3.09 mmol). The reaction mixture was stirred at room temperature for 1 hour, then diluted with EtOAc and washed with a 4:1 water/salt solution. The organic layer was dried over _MgSO4 , filtered, and concentrated under vacuum. The residue was co-evaporated with PhMe to provide the desired product, which was used in the next step without further purification. LCMS (m/z) 447.4 [M+H] ⁺ .

(Step 5) N-(5-bromopyridin-3-yl)-8-chloro-N-(2,2,2-trifluoroethyl)-[1,2,4]triazolo[4,3-a] Synthesis of quinazoline-5-amine

A suspension of N-(5-bromopyridin-3-yl)-7-chloro-2-hydrazino-N-(2,2,2-trifluoroethyl)quinazolin-4-amine (200 mg, 447 μmol) in triethyl orthoformate (3.23 mL, 19.4 mmol) was stirred at 130 °C for 3 h. The reaction mixture was cooled to room temperature and concentrated under vacuum. The residue was purified by silica gel chromatography (0 to 100% EtOAc in hexane) to provide the desired product. LCMS (m/z) 457.4 [M+H] ⁺ .

(Step 6) 8-Chloro-N-(2,2,2-trifluoroethyl)-N-(5-((1-(trifluoromethyl)cyclopropyl)ethynyl)pyridine- Synthesis of 3-yl)-[1,2,4]triazolo[4,3-a]quinazolin-5-amine

A suspension of N-(5-bromopyridin-3-yl)-8-chloro-N-(2,2,2-trifluoroethyl)-[1,2,4]triazolo[4,3-a]quinazolin-5-amine (30 mg, 66 μmol), zinc bromide (74 mg, 328 μmol), Pd(dppf) _Cl₂ (9.3 mg, 13 μmol), and triethylamine (183 μL, 1.31 mmol) in DMF (2.0 mL) was purged with N₂ for 1 min, and then 1-ethynyl-1-(trifluoromethyl)cyclopropane (13 mg, 98 μmol) was added. The vial was quickly sealed, and the mixture was vigorously stirred at 100 °C for 5 min, then immediately cooled in an ice bath. The reaction mixture was diluted with EtOAc and 4:1 water/saline solution, and then filtered through diatomaceous earth. The filtrate layer was separated, and the organic layer was washed twice with 4:1 water/saline solution, followed by saline solution. The organic layer was then concentrated under vacuum, and the residue was purified by reversed-phase preparative HPLC to provide the desired product: ^¹H NMR (400MHz, DMSO- _d⁶ ) δ 9.82 (s, 1H), 8.68 (d, J = 2.0Hz, 1H), 8.51–8.47 (m, 2H), 7.94 (dd, J = 2.2Hz, 1H), 7.45 (dd, J = 8.9, 2.0Hz, 1H), 7.36 (d, J = 8.9Hz, 1H), 5.14 (q, J = 9.2Hz, 2H), 1.50–1.38 (m, 4H); LCMS (m/z) 511.1 [M+H] ^⁺ .

Example 610. 5-((3-fluoro-5-((1-(trifluoromethyl)cyclopropyl)ethynyl)phenyl)(methyl)amino)- [1,2,4]triazolo[4,3-a]quinazolin-8-carboxynitrile

(Step 1) Synthesis of 4-((3-bromo-5-fluorophenyl)(methyl)amino)-2-chloroquinazoline-7-carboxynitrile

Concentrated HCl (37%, 164 μL, 1.96 mmol) was added to a suspension of 2,4-dichloroquinazoline-7-carboxynitrile (483 mg, 2.17 mmol) and 3-bromo-5-fluoro-N-methylaniline (400 mg, 1.96 mmol) in 2-propanol (3.0 mL), and the mixture was stirred at room temperature for 1 hour. The precipitate was collected and washed with 2-propanol to give the desired product, which was used in the next step without further purification. LCMS (m/z) 391.3 [M+H] ⁺ .

(Step 2) Synthesis of 4-((3-bromo-5-fluorophenyl)(methyl)amino)-2-hydrazinoquinazolin-7-carboxynitrile

Hydrazine hydrate (0.294 mL, 9.24 mmol) was added to a solution of 4-((3-bromo-5-fluorophenyl)(methyl)amino)-2-chloroquinazoline-7-carboxynitrile (181 mg, 0.462 mmol) in THF (3 mL) and EtOH (5 mL), and the mixture was stirred at room temperature for 3 hours. The reaction mixture was diluted with EtOAc, washed continuously with water and brine, and dried over Na2SO4. The organic layer was concentrated under vacuum to give the desired product, which was used in the next step without further purification. LCMS (m/z) 387.3 [M+H] ⁺ .

(Step 3) 5-((3-bromo-5-fluorophenyl)(methyl)amino)-[1,2,4]triazolo[4,3-a]quinazolin-8-methyl Synthesis of nitrile

A mixture of 4-((3-bromo-5-fluorophenyl)(methyl)amino)-2-hydrazinoquinazolin-7-carboxynitrile (179 mg, 0.462 mmol) and triethyl orthoformate (4.0 mL, 24 mmol) was stirred at 120 °C for 1 hour. The reaction mixture was concentrated under vacuum, and the residue was purified by column chromatography (DCM/EtOAc; 0 to 40%) followed by reversed-phase preparative HPLC to provide the desired product. LCMS (m/z) 397.2 [M+H] ⁺ .

(Step 4) 5-((3-fluoro-5-((1-(trifluoromethyl)cyclopropyl)ethynyl)phenyl)(methyl)amino)-[1,2, Synthesis of [4]triazolo[4,3-a]quinazolin-8-carboxynitrile

A suspension of 5-((3-bromo-5-fluorophenyl)(methyl)amino)-[1,2,4]triazolo[4,3-a]quinazolin-8-carboxynitrile (30 mg, 60 μmol), zinc bromide (68 mg, 302 μmol), Pd(dppf) _Cl₂ (8.6 mg, 12 μmol), and triethylamine (169 μL, 1.21 mmol) in NMP (2.0 mL) was purged with N₂ for 1 min, and then 1-ethynyl-1-(trifluoromethyl)cyclopropane (32 mg, 24 μmol) was added. The vial was quickly sealed, and the mixture was vigorously stirred at 100 °C for 20 min, then immediately cooled in an ice bath. The reaction mixture was diluted with water and extracted three times with EtOAc. The combined organic layers were concentrated under vacuum, and the resulting residues were purified by silica gel chromatography (using 0 to 20% of a 4:1 EtOAc/MeOH premixed solution as a polar solvent and DCM as a nonpolar solvent). The fractions containing the product were combined and concentrated under vacuum. The resulting residue was further purified by reversed-phase preparative HPLC to provide the desired product: ^¹H NMR (400MHz, DMSO- _d⁶ ) δ 9.77 (s, ¹H), 9.03 (d, J = 1.5Hz, ¹H), 7.80 (dd, J = 8.6, 1.6Hz, ¹H), 7.48 (d, J = 8.6Hz, ¹H), 7.44 (dt, J = 10.2, 2.3Hz, ¹H), 7.39 (t, J = 1.6Hz, ¹H), 7.30–7.25 (m, ¹H), 3.58 (s, 3H), 1.47–1.33 (m, 4H); LCMS (m/z) 451.1 [M+H] ^⁺ .

Example 611. 5-((3-(3,3-dimethylbut-1-yn-1-yl)-5-fluorophenyl)(methyl)amino)-[1,2, 4] Triazolo[4,3-a]quinazolin-8-carboxynitrile

The title compound was synthesized according to the procedure described for Example 610.

¹ H NMR (400MHz, DMSO-d ₆ )δ9.77(s,1H),9.03(d,J＝1.6Hz,1H),7.81(dd,J＝8.6,1.6Hz,1H),7.48(d,J＝8.6Hz,1H),7.35(dt,J＝10. 1,2.3Hz,1H),7.28(t,J＝1.7Hz,1H),7.18–7.14(m,1H),3.58(s,3H),1.25(s,9H); LCMS(m/z)451.1[M+H] ⁺ .

Example 612. N-(2,2-difluoroethyl)-N-(2-(3,3-dimethylbut-1-yn-1-yl)pyridin-4-yl)-6- Fluoro-1-methyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine

Synthesis of N-(2-bromopyridin-4-yl)-2,2-difluoroacetamide: TEA (8.36 mL, 57.9 mmol) was added dropwise to a solution of 2-bromopyridin-4-amine (9.1 g, 52.6 mmol) in anhydrous THF (20 mL) under argon atmosphere, followed by dropwise addition of 2,2-difluoroacetic anhydride (10.1 g, 57.9 mmol). The solution was stirred at room temperature for 3 hours. The reaction mixture was poured into ice water, alkalized with a saturated aqueous solution _{of NaHCO3} , and then extracted with ethyl acetate. The combined organic phases were dried over _MgSO4 , concentrated, and dried under vacuum to provide the desired compound.

Synthesis of 2-bromo-N-(2,2-difluoroethyl)pyridine-4-amine: A solution of _LiAlH4 in THF (1 M, 52.6 mmol) was added fractionally to a solution of 2,2-difluoroacetic anhydride (12 g, 47.8 mmol) in THF (40 mL) under a nitrogen atmosphere at 0 °C. After 10 minutes at 0 °C, the reaction mixture was allowed to reach room temperature and stirred for 6 hours. The mixture was quenched with water at 0 °C and extracted with ethyl acetate. The aqueous phase was washed with saturated sodium chloride solution, dried over _MgSO4 , and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (hexane:ethyl acetate 3:1) to give 2-bromo-N-(2,2-difluoroethyl)pyridine-4-amine.

Synthesis of N-(2-bromopyridin-4-yl)-2-chloro-N-(2,2-difluoroethyl)-5-fluoroquinazoline-4-amine: 2-bromo-N-(2,2-difluoroethyl)pyridin-4-amine (573 mg, 2.42 mmol) and LiHMDS (1.0 M, 2.53 mL, 1.1 equivalents) in THF were added to a solution of 2,4-dichloro-5-fluoroquinazoline (500 mg, 2.3 mmol) at -20 °C in 5 mL of THF. The mixture was stirred at -20 °C for 2 hours. Water and ethyl acetate were added to the mixture, and the organic phase was dried over _MgSO4 and evaporated under reduced pressure. The crude product was used in the next step without further purification.

Synthesis of N-(2-bromopyridin-4-yl)-N-(2,2-difluoroethyl)-5-fluoro-2-hydrazoylquinazoline-4-amine and N-(2-bromopyridin-4-yl)-N-(2,2-difluoroethyl)-6-fluoro-1-methyl-[1,2,4]triazolo[4,3-a]quinazoline-5-amine: The synthesis of these compounds was carried out using 1,1,1-triethoxyethane instead of triethoxymethane by a procedure similar to that described with respect to synthetic Example 249.

Synthesis of N-(2,2-difluoroethyl)-N-(2-(3,3-dimethylbut-1-yn-1-yl)pyridin-4-yl)-6-fluoro-1-methyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine: N-(2-bromopyridin-4-yl)-N-(2,2-difluoroethyl)-6-fluoro-1-methyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine (19.0 mg, 0.044 mmol) 3,3-Dimethylbut-1-yne (3.9 mg, 0.048 mmol, 1.1 equivalents), TEA (0.1 mL, 0.86 mmol, 20 equivalents), zinc bromide (41.3 mg, 0.2 mmol, 5 equivalents), and [1,1'-bis(diphenylphosphine)ferrocene]palladium(II) dichloride (9.15 mg, 0.013 mmol, 0.3 equivalents) were heated at 100 °C for 10 min in DMF (2 mL). After filtration, the reaction mixture was purified by preparative reversed-phase high-performance liquid chromatography to give N-(2,2-difluoroethyl)-N-(2-(3,3-dimethylbut-1-yne-1-yl)pyridin-4-yl)-6-fluoro-1-methyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine. ¹ H NMR (400MHz, methanol-d ₄ )δ8.30(d,J＝8.6Hz,1H),8.18(d,J＝7.1Hz,1H),8.13–8.00(m,1H),7.37(d,J＝17.8Hz,2H),7.2 4(s,1H),6.33(t,J＝55.1Hz,1H),4.65(d,J＝14.4Hz,1H),3.16–3.05(m,2H),1.38–1.13(m,9H). LCMS(m/z)439.18.

Example 613. N-(2,2-difluoroethyl)-6-fluoro-1-methyl-N-(2-((1-methylcyclopropyl)ethynyl)pyridine (-4-yl)-[1,2,4]triazolo[4,3-a]quinazolin-5-amine

The title compound was prepared according to the method of Example 612, except that 1-ethynyl-1-methylcyclopropane was used instead of 3,3-dimethylbut-1-yne in the coupling reaction with N-(2-bromopyridin-4-yl)-N-(2,2-difluoroethyl)-6-fluoro-1-methyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine. ¹ H NMR (400MHz, methanol-d ₄ )δ8.40(d,J＝8.6Hz,1H),8.26(d,J＝7.0Hz,1H),8.16(td,J＝8.5,5.6Hz,1H),7.53–7.41(m,2H),7.32(d,J＝6.9Hz,1H),6 .42(tt,J＝54.8,3.5Hz,1H),4.73(d,J＝14.8Hz,2H),3.19(s,3H),1.36(s,3H),1.11(q,J＝4.3Hz,2H),0.91–0.83(m,2H). LCMS(m/z)437.16.

Example 614. 4-(4-((2,2-difluoroethyl)(6-fluoro-1-methyl-[1,2,4]triazolo[4,3-a]quinazole) (Lin-5-yl)amino)pyridin-2-yl)-2-methylbut-3-yn-2-ol

The title compound was prepared according to the method of Example 612, except that 2-methylbut-3-yne-2-ol was used instead of 3,3-dimethylbut-1-yne in the coupling reaction with N-(2-bromopyridin-4-yl)-N-(2,2-difluoroethyl)-6-fluoro-1-methyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine. ¹ H NMR (400MHz, methanol-d ₄ )δ8.41(d,J＝8.6Hz,1H),8.33(d,J＝7.0Hz,1H),8.17(td,J＝8.5,5.6Hz,1H),7.54(d,J＝2.6Hz,1H),7.52–7. 42(m,1H),7.37(d,J＝6.7Hz,1H),6.43(tt,J＝54.9,3.5Hz,1H),4.84–4.65(m,2H),3.20(s,3H),1.56(s,6H). LCMS(m/z)441.16.

Example 615. N-(2,2-difluoroethyl)-6-fluoro-1-methyl-N-(2-((1-(trifluoromethyl)cyclopropyl)acetylene) (1,2,4)pyridin-4-yl)-[1,2,4]triazolo[4,3-a]quinazolin-5-amine

The title compound was prepared according to the method of Example 612, except that 1-ethynyl-1-(trifluoromethyl)cyclopropane was used instead of 3,3-dimethylbut-1-yne in the coupling reaction with N-(2-bromopyridin-4-yl)-N-(2,2-difluoroethyl)-6-fluoro-1-methyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine. ¹ H NMR (400MHz, methanol-d ₄ )δ8.39(d,J＝8.6Hz,1H),8.33(d,J＝6.8Hz,1H),8.15(td,J＝8.5,5.5Hz,1H),7.55(d,J＝2.7Hz,1H),7.45(ddd,J＝12.0,8.4 ,0.8Hz,1H),7.35(dd,J＝6.9,2.7Hz,1H),6.42(tt,J＝54.9,3.6Hz,1H),4.82–4.65(m,2H),3.19(s,3H),1.60–1.37(m,4H). LCMS(m/z)491.22.

Example 616. N-(2,2-difluoroethyl)-N-(2-(3,3-dimethylbut-1-yn-1-yl)pyridin-4-yl)-6- Fluoro-[1,2,4]triazolo[4,3-a]quinazolin-5-amine

Synthesis of N-(2-bromopyridin-4-yl)-N-(2,2-difluoroethyl)-6-fluoro-[1,2,4]triazolo[4,3-a]quinazolin-5-amine: The above compound was synthesized by a procedure similar to that described with respect to synthetic example 249.

The title compound was prepared according to the method of Example 612, except that N-(2-bromopyridin-4-yl)-N-(2,2-difluoroethyl)-6-fluoro-[1,2,4]triazolo[4,3-a]quinazolin-5-amine was used instead of N-(2-bromopyridin-4-yl)-N-(2,2-difluoroethyl)-6-fluoro-1-methyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine in the final coupling step. ¹ H NMR (400MHz, methanol-d ₄ )δ9.90(s,1H),8.38(dd,J＝8.4,0.9Hz,1H),8.30(d,J＝7.0Hz,1H),8.18(td,J＝8.4,5.3Hz,1H),7.58–7.42(m,2 H), 7.37 (d, J = 6.7Hz, 1H), 6.44 (tt, J = 54.9, 3.5Hz, 1H), 4.78 (d, J = 14.9Hz, 2H), 1.37 (s, 9H); LCMS (m/z) 425.17.

Example 617. N-(2,2-difluoroethyl)-6-fluoro-N-(2-((1-methylcyclopropyl)ethynyl)pyridine-4- (-[1,2,4]triazolo[4,3-a]quinazolin-5-amine)

The title compound was prepared according to the method of Example 616, except that N-(2-bromopyridin-4-yl)-N-(2,2-difluoroethyl)-6-fluoro-[1,2,4]triazolo[4,3-a]quinazolin-5-amine was used instead of N-(2-bromopyridin-4-yl)-N-(2,2-difluoroethyl)-6-fluoro-1-methyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine in the final coupling step. ¹ H NMR (400MHz, methanol-d ₄ )δ9.88(s,1H),8.37(d,J＝8.4Hz,1H),8.27(d,J＝7.0Hz,1H),8.16(td,J＝8.4,5.3Hz,1H),7.46(ddd,J＝12.1,8.8,1.3Hz,2H ), 7.34 (s, 1H), 6.42 (tt, J = 54.7, 3.4Hz, 1H), 1.36 (s, 3H), 1.11 (q, J = 4.3Hz, 2H), 0.88 (q, J = 4.3Hz, 2H); LCMS (m/z) 423.17.

Example 618. N-(2,2-difluoroethyl)-6-fluoro-N-(2-((1-(trifluoromethyl)cyclopropyl)ethynyl)pyridine (-4-yl)-[1,2,4]triazolo[4,3-a]quinazolin-5-amine

The title compound was prepared according to the method of Example 616, except that N-(2-bromopyridin-4-yl)-N-(2,2-difluoroethyl)-6-fluoro-[1,2,4]triazolo[4,3-a]quinazolin-5-amine was used instead of N-(2-bromopyridin-4-yl)-N-(2,2-difluoroethyl)-6-fluoro-1-methyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine in the final coupling step. ¹ H NMR (400MHz, methanol-d ₄ )δ9.86(s,1H),8.34(t,J＝7.2Hz,2H),8.15(td,J＝8.4,5.2Hz,1H),7.57(d,J＝2.7Hz,1H),7.48–7. 26(m,2H),6.43(tt,J＝55.0,3.6Hz,1H),4.83–4.67(m,2H),1.60–1.38(m,4H); LCMS(m/z)477.15.

Example 619. 4-(4-((2,2-difluoroethyl)(6-fluoro-[1,2,4]triazolo[4,3-a]quinazolin-5-yl) (amino)pyridin-2-yl)-2-methylbut-3-yne-2-ol

The title compound was prepared according to the method of Example 616, except that N-(2-bromopyridin-4-yl)-N-(2,2-difluoroethyl)-6-fluoro-[1,2,4]triazolo[4,3-a]quinazolin-5-amine was used instead of N-(2-bromopyridin-4-yl)-N-(2,2-difluoroethyl)-6-fluoro-1-methyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine in the final coupling step. ¹ H NMR (400MHz, methanol-d ₄ )δ9.87(s,1H),8.34(dd,J＝14.3,7.7Hz,2H),8.15(td,J＝8.4,5.3Hz,1H),7.54(d,J＝2.7Hz,1H),7.50 –7.41(m,1H),7.36(d,J＝5.6Hz,1H),6.63–6.23(m,1H),4.78(s,2H),1.56(s,6H); LCMS(m/z)427.18.

Example 620. 6-Fluoro-N-(3-Fluoro-5-((1-(trifluoromethyl)cyclopropyl)ethynyl)phenyl)-1-methyl-N- (oxetane-3-ylmethyl)-[1,2,4]triazolo[4,3-a]quinazolin-5-amine

The synthesis of N-(3-bromo-5-fluorophenyl)oxetane-3-carboxamide (compound 620-1) was carried out by replacing 2,2-difluoroacetic anhydride with oxetane-3-carboxylic anhydride through a procedure similar to that described in Example 612: Synthesis of Compound 620-1.

The title compound was synthesized using a procedure similar to that described in synthetic example 612. ^¹H NMR (400 MHz, methanol- _d4) )δ8.16(d,J＝8.5Hz,1H),7.92(td,J＝8.4,5.5Hz,1H),7.60(t,J＝6.1Hz,1H), 7.53(dd,J＝7.3,3.4Hz,1H),7.14(dd,J＝11.8,8.3Hz,1H),7.00(d,J＝10.1Hz ,1H),4.79–4.68(m,2H),4.62(t,J＝6.5Hz,2H),4.50(d,J＝6.8Hz,21H),3.68 (dt,J＝13.2,5.3Hz,1H),3.07(s,3H),1.46–1.22(m,4H); LCMS(m/z)514.22.

Example 621. N-(2,2-difluoroethyl)-6-fluoro-N-(5-((1-(trifluoromethyl)cyclopropyl)ethynyl)pyridine (-3-yl)-[1,2,4]triazolo[4,3-a]quinazolin-5-amine

Synthesis of N-(5-bromopyridin-3-yl)-2,2-difluoroacetamide (compound 621-1): Compound 621-1 was synthesized by means of a similar procedure to that described with respect to synthetic example 42-1, using 5-bromopyridin-3-amine instead of 2-bromopyridin-4-amine.

Compounds 621-2, 621-3, 621-4, 621-5, and those of Example 621 were synthesized using a similar procedure to that described with respect to Synthetic Example 616. ^¹H NMR (400 MHz, methanol- _d⁴ ) δ 9.73 (s, 1H), 8.47 (dd, J = 7.9, 2.1 Hz, 2H), 8.26 (d, J = 8.3 Hz, 1H), 8.09 (td, J = 8.4, 5.1 Hz, 1H), 7.92 (t, J = 2.1 Hz, 1H), 7.28 (dd, J = 12.0, 8.2 Hz, 1H), 6.72–6.31 (m, 1H), 4.72 (td, J = 13.6, 4.0 Hz, 2H), 1.52–1.42 (m, 2H), 1.38 (d, J = 19.4 Hz, 2H). LCMS(m/z) 477.25.

Example 622. N-(2,2-difluoroethyl)-7-fluoro-1-methyl-N-(5-((1-(trifluoromethyl)cyclopropyl)acetylene) (1,2,4)pyridin-3-yl)-[1,2,4]triazolo[4,3-a]quinazolin-5-amine

Synthesis of N-(5-bromopyridin-3-yl)-2-chloro-N-(2,2-difluoroethyl)-6-fluoroquinazoline-4-amine (compound 622-1): Compound 622-1 was synthesized by means of a similar procedure to that described with respect to synthetic examples 612-4, using 2,4-dichloro-6-fluoroquinazoline instead of 2,4-dichloro-5-fluoroquinazoline.

Compounds 622-2, 622-3, and those of Example 622 were synthesized using a similar procedure to that described in Synthesis Example 612. ^¹H NMR (400 MHz, methanol- _d⁴ ) δ 8.55–8.31 (m, 2H), 7.91 (t, J = 2.1 Hz, 1H), 7.71 (ddd, J = 9.6, 7.7, 2.9 Hz, 1H), 7.62–7.43 (m, 1H), 7.08 (dd, J = 9.5, 2.9 Hz, 1H), 6.68–6.31 (m, 1H), 4.60 (td, J = 14.2, 4.1 Hz, 2H), 3.08 (s, 3H), 1.56–1.31 (m, 4H); LCMS (m/z) 491.23.

Example 623. 8-Chloro-N-methyl-N-(2-((1-(trifluoromethyl)cyclopropyl)ethynyl)pyridin-4-yl)- [1,2,4]triazolo[4,3-a]quinazolin-5-amine

Compounds 623-1, 623-2, 623-3, and Example 623 were synthesized using a similar procedure to that described with respect to Synthetic Example 616. ^¹H NMR (400 MHz, methanol- _d⁴ ) δ 9.86 (s, 1H), 8.70 (d, J = 1.9 Hz, 1H), 8.34 (d, J = 7.0 Hz, 1H), 7.98 (d, J = 8.8 Hz, 1H), 7.74 (dd, J = 8.8, 1.9 Hz, 1H), 7.56 (d, J = 2.7 Hz, 1H), 7.38–7.28 (m, 1H), 3.78 (d, J = 9.5 Hz, 3H), 1.63–1.51 (m, 2H), 1.46 (dtt, J = 5.7, 2.8, 1.5 Hz, 2H); LCMS (m/z) 443.15.

Example 624. 8-Chloro-N-(2,2-difluoroethyl)-6-fluoro-N-(3-fluoro-5-((1-(trifluoromethyl)cyclopropyl) (ethynyl)phenyl)-[1,2,4]triazolo[4,3-a]quinazolin-5-amine

Compounds 624-1, 624-2, and 624-3 were synthesized using a procedure similar to that described in synthetic example 261.

The title compound was synthesized using a procedure similar to that described with respect to Synthetic Example 612. ^¹H NMR (400 MHz, methanol- _d⁴ ) δ 9.77 (s, ¹H), 8.52 (t, J = 1.4 Hz, ¹H), 7.54 (dd, J = 11.5, 1.9 Hz, ¹H), 7.50–7.12 (m, ³H), 6.47 (tt, J = 55.7, 4.0 Hz, ¹H), 4.73 (td, J = 13.4, 4.0 Hz, 2H), 1.48–1.37 (m, 2H), 1.34–1.22 (m, 2H). LCMS (m/z) 528.2.

Example 625. 8-Chloro-N-methyl-N-(5-((1-(trifluoromethyl)cyclopropyl)ethynyl)pyridin-3-yl)- [1,2,4]triazolo[4,3-a]quinazolin-5-amine

The title compound was synthesized using 5-bromo-N-methylpyridin-3-amine instead of 2-bromo-N-methylpyridin-4-amine via a procedure similar to that described in Example 612 regarding synthesis. ^¹H NMR (400 MHz, methanol- _d⁴ ) δ 9.65 (s, 1H), 8.66 (s, 1H), 8.56 (q, J = 4.4, 3.9 Hz, 2H), 8.09 (d, J = 2.1 Hz, 1H), 7.49 (dd, J = 9.0, 2.1 Hz, 1H), 7.33 (d, J = 9.1 Hz, 1H), 3.80 (s, 3H), 1.53–1.44 (m, 2H), 1.41–1.33 (m, 2H); LCMS (m/z) 443.00.

Example 626. 8-Chloro-6-fluoro-N-(3-fluoro-5-((1-(trifluoromethyl)cyclopropyl)ethynyl)phenyl)-N-methyl [1,2,4]triazolo[4,3-a]quinazolin-5-amine

The title compound was synthesized using 3-bromo-5-fluoro-N-methylaniline instead of 3-bromo-N-(2,2-difluoroethyl)-5-fluoroaniline via a procedure similar to that described in Example 624 regarding synthesis. ^¹H NMR (400 MHz, chloroform-d) δ 8.95 (s, 1H), 7.71 (t, J = 1.6 Hz, 1H), 7.03 (dd, J = 11.0, 1.9 Hz, 1H), 6.99–6.94 (m, 1H), 6.85 (d, J = 1.7 Hz, 1H), 6.70 (dt, J = 9.6, 2.3 Hz, 1H), 3.65 (s, 3H), 1.43–1.33 (m, 2H), 1.31–1.22 (m, 2H); LCMS (m/z) 478.00.

Example 627. 1-[4-[3-[(8-chloro-[1,2,4]triazolo[4,3-a]quinazolin-5-yl)-methyl-amino] [Phenylene]-4,4-dimethylpyrrolidone-2-one

Synthesis of 1-(4-bromophenyl)-4,4-dimethylpyrrolidone-2-one: 4,4-dimethylpyrrolidone-2-one (150 mg, 1.3 mmol), 1-bromo-4-iodobenzene (450 mg, 1.6 mmol), CuI (76 mg, 0.4 mmol), and CsF (503 mg, 3.3 mmol) were added to a vial equipped with a stir bar. The vial was then rinsed with nitrogen and filled with anhydrous EtOAc (5.0 mL) and DMEDA (70 mg, 0.8 mmol). The reaction was stirred at 50 °C for 16 h, at which point LC/MS indicated complete conversion to a bromine and iodine product mixture of approximately 3:1. The reaction mixture was cooled and filtered through diatomaceous earth, eluting with EtOAc. The filtrate was evaporated, and the residue was purified by normal-phase rapid chromatography using 35% EtOAc/hexane to give a substance containing a bromine and iodine product mixture of approximately 3:1.

Synthesis of 4,4-dimethyl-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborhexacyclopentan-2-yl)phenyl)pyrrolidine-2-one: A solution containing a mixture of 1-(4-bromophenyl)-4,4-dimethylpyrrolidine-2-one and 1-(4-iodophenyl)-4,4-dimethylpyrrolidine-2-one (155 mg) in dioxane (7.3 mL) was degassed by a stream of nitrogen. Bis(pinacol)diboron (221 mg, 0.87 mmol), (dppf) _PdCl₂ (41 mg, 0.06 mmol), and KOAc (171 mg, 1.7 mmol) were added. The reaction was stirred at 100 °C for 16 h, during which time LC/MS indicated partial conversion of the bromide. (dppf) _PdCl₂ (41 mg, 0.06 mmol), _B₂pin₂ (221 mg, 0.87 mmol), and KOAc (171 mg, 1.7 mmol) were added, and the reaction was stirred at 80 °C for 24 h. _LC /MS indicated incomplete conversion, so additional (dppf) _PdCl₂ (41 mg, 0.06 mmol), _B₂pin₂ (221 mg, 0.87 mmol), and KOAc (171 mg, 1.7 mmol) were added. The reaction was stirred at 80 °C _for another 60 h. LC/MS indicated complete conversion, and the reaction mixture was filtered through diatomaceous earth and eluted with EtOAc. The filtrate was evaporated and purified by normal-phase rapid chromatography using 60% EtOAc/hexane to provide the product: ES/MS m/z: 316.2.

The title compound was synthesized according to a similar procedure to that described for Example 277. ^¹H NMR (400 MHz, DMSO- _d⁶ ) δ 9.79 (s, ¹H), 8.63 (d, J = 2.1 Hz, ¹H), 7.76–7.63 (m, 6H), 7.55 (t, J = 7.9 Hz, 1H), 7.42 (dd, J = 9.0, 2.1 Hz, 1H), 7.40–7.35 (m, 1H), 7.27 (d, J = 9.1 Hz, 1H), 3.68 (s, 3H), 3.59 (s, 2H), 2.38 (s, 2H), 1.17 (s, 6H); ES/MS m/z: 497.2.

Example 628. (8-chloro-5-((4'-cyclopropyl-[1,1'-diphenyl]-3-yl)(methyl)amino)-[1,2,4] Triazolo[4,3-a]quinazolin-1-yl)methanol

Step 1: A stirred mixture of compound 252-3 (210 mg, 555 μmol) and ethyl fluoroacetate (6.00 mL, 62.1 mmol) was heated to 220 °C in a microwave reactor. After 11 hours, the resulting mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by silica gel rapid column chromatography (0 to 100% ethyl acetate in hexane) to give a mixture of compounds 628-1 and 628-2.

Step 2: A vigorously stirred mixture of 628-1 and 628-2 (30 mg), (4-cyclopropylphenyl)boric acid (13.3 mg, 82.0 μmol), [1,1'-bis(diphenylphosphine)ferrocene]palladium(II) dichloride (5.6 mg, 7.7 μmol), sodium carbonate aqueous solution (2.0 M, 360 μL, 720 μmol), and 1,4-dioxane (1.0 mL) was heated to 100 °C. After 5 minutes, the resulting mixture was cooled to room temperature. Acetic acid (0.1 mL) was added via syringe, and the mixture was concentrated under reduced pressure. The residue was purified by reversed-phase preparative HPLC (acetonitrile/water containing 0.1% trifluoroacetic acid) to give the title compound: ^¹H NMR (400 MHz, acetone-d6) δ 8.63 (d, J = 2.1 Hz, 1H), 7.63 (t, J = 2.0 Hz, 1H), 7.60–7.46 (m, 5H), 7.36–7.26 (m, 2H), 7.15 (d, J = 8.3 Hz, 2H), 5.23 (s, 2H), 3.70 (s, 3H), 2.13–1.88 (m, 1H), 1.09–0.95 (m, 2H), 0.78–0.63 (m, 2H); LCMS (m/z) 456.3.

Example 629. 8-Chloro-N-(3-(5-cyclopropylpyrazin-2-yl)phenyl)-1-(difluoromethyl)-N-methyl-[1, [2,4]triazolo[4,3-a]quinazolin-5-amine

A stirred mixture of compound 252-3 (500 mg, 1.32 mmol) and ethyl difluoroacetate (5.00 mL, 47.5 mmol) was heated to 150 °C in a microwave reactor. After 15 minutes, the resulting mixture was cooled to room temperature. Acetic acid (10 mL) was added, and the mixture was heated to 180 °C in the microwave reactor. After 17.5 minutes, the mixture was cooled to room temperature and poured into an aqueous solution of sodium carbonate (10 g) (50 mL). The aqueous layer was extracted with ethyl acetate (100 mL), and the organic layer was washed with water (50 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel rapid column chromatography (0 to 80% ethyl acetate in hexane) to give compound 629-1.

The title compound was synthesized according to the method of Example 376, except that compound 629-1 was used instead of compound 364-2. ^¹H NMR (400 MHz, acetone-d6) δ 8.92 (d, J = 1.5 Hz, 1H), 8.62 (d, J = 1.5 Hz, 1H), 8.25 (d, J = 2.0 Hz, 1H), 8.14 (t, J = 2.0 Hz, 1H), 8.09 (dt, J = 7.8, 1.3 Hz, 1H), 7.66 (d, J = 9.0 Hz, 1H), 7.60 (dt, J = 7.8, 1.3 Hz, 1H), 7.66 (d, J = 9.0 Hz, 1H), 7.60 (dt, J = 7.8, 1.3 Hz, 1H). ,J＝52.0Hz,1H),7.59(t,J＝7.9Hz,1H),7.49(ddd,J＝8.3,2.4,1.2Hz,1H),7.38(dd,J＝ 9.0, 2.0Hz, 1H), 3.75 (s, 3H), 2.30–2.01 (m, 1H), 1.15–0.99 (m, 4H); LCMS (m/z) 478.3.

Example 630. 8-Chloro-N-(4'-cyclopropyl-[1,1'-diphenyl]-3-yl)-1-(difluoromethyl)-N-methyl [1,2,4]triazolo[4,3-a]quinazolin-5-amine

The title compound was synthesized according to the method of Example 312, except that compound 629-1 and (4-cyclopropylphenyl)boronic acid were used instead of those in Example 308 and (4-isopropylphenyl)boronic acid. ^¹H NMR (400 MHz, acetone-d6) δ 8.24 (d, J = 2.0 Hz, 1H), 7.76–7.45 (m, 6H), 7.61 (t, J = 51.8 Hz, 1H), 7.38 (dd, J = 8.9, 2.0 Hz, 2H), 7.17–7.09 (m, 2H), 3.73 (s, 3H), 2.02–1.88 (m, 1H), 1.06–0.94 (m, 2H), 0.75–0.67 (m, 2H); LCMS (m/z) 476.3.

Example 631. 8-Chloro-N-(4'-cyclopropyl-[1,1'-diphenyl]-3-yl)-1-(difluoromethyl)-N-methyl [1,2,4]triazolo[4,3-a]quinazolin-5-amine

Compound 631-1 was synthesized in a manner similar to that in Example 252, using triethyl orthoacetate instead of triethyl orthoformate.

The title compound was synthesized according to the method of Example 376, except that compound 631-1 was used instead of compound 364-2. ¹ H NMR (400MHz, acetone-d6) δ8.92(d,J＝1.5Hz,1H),8.61(d,J＝1.6Hz,1H),8.21(d ,J＝2.0Hz,1H),8.04–8.00(m,2H),7.62(d,J＝8.9Hz,1H),7.55(t,J＝7.8Hz, 1H),7.39(ddd,J＝8.0,2.3,1.0Hz,1H),7.28(dd,J＝8.9,2.0Hz,1H),3.68(s ,3H),3.05(s,3H),2.29–1.98(m,1H),1.14–1.00(m,4H); LCMS(m/z)442.3.

Example 632. 8-Chloro-N-(4'-cyclopropyl-[1,1'-diphenyl]-3-yl)-N,1-dimethyl-[1,2,4]tri Azo[4,3-a]quinazolin-5-amine

The title compound was synthesized according to the method of Example 312, using (4-cyclopropylphenyl)boronic acid instead of (4-isopropylphenyl)boronic acid and compound 631-1 instead of Example 308. ^¹H NMR (400 MHz, acetone-d6) δ 8.28 (d, J = 2.1 Hz, 1H), 7.66–7.57 (m, 3H), 7.57–7.47 (m, 3H), 7.39–7.31 (m, 2H), 7.19–7.11 (m, 2H), 3.73 (s, 3H), 3.10 (s, 3H), 2.02–1.91 (m, 1H), 1.05–0.95 (m, 2H), 0.77–0.66 (m, 2H); LCMS (m/z) 440.3.

Example 633. (R)-8-chloro-N-methyl-N-(3-(6-((1,1,1-trifluoroprop-2-yl)oxy)pyridin-3-yl) phenyl)-[1,2,4]triazolo[4,3-a]quinazolin-5-amine

The title compound was synthesized according to the method of Example 240, except that (R)-1,1,1-trifluoropropane-2-ol was used instead of (±)-1,1,1-trifluoropropane- ² -ol. NMR (400MHz, acetone-d6) δ9.46 (s, 1H), 8.42 (dd, J = 2.6, 0.7Hz, 1H), 8.41 (d, J = 2.1Hz, 1H),8.05(dd,J＝8.6,2.6Hz,1H),7.72(t,J＝2.0Hz,1H),7.69–7.61(m,1H),7.61– 7.48(m,2H),7.47–7.35(m,1H),7.28(dd,J＝9.0,2.1Hz,1H),6.94(dd,J＝8.6,0.7 Hz, 1H), 6.00–5.87 (m, 1H), 3.70 (s, 3H), 1.51 (d, J = 6.5Hz, 3H); LCMS (m/z) 499.3.

Example 634. N-(3-(5-(bicyclo[1.1.1]pent-1-yl)pyridin-2-yl)phenyl)-8-chloro-N-methyl-[1, [2,4]triazolo[4,3-a]quinazolin-5-amine

The title compound was synthesized according to the method of Example 384, except that 2-chloro-5-iodopyridine was used instead of 5-bromo-2-iodopyridine. ¹ H NMR (400MHz, acetone-d6) δ9.44 (s, 1H), 8.52 (dd, J = 2.3, 0.9Hz, 1H), 8.39 (d, J = 2.1 Hz,1H),8.09(d,J＝2.0Hz,1H),8.08–8.04(m,1H),7.86(dd,J＝8.2,0.9Hz,1H), 7.67(dd,J＝8.2,2.3Hz,1H),7.59–7.47(m,2H),7.40(d,J＝9.0Hz,1H),7.24(d d, J=8.9, 2.1Hz, 1H), 3.69 (s, 3H), 2.59 (s, 1H), 2.17 (s, 6H); LCMS (m/z) 453.3.

Example 635. 8-Chloro-N-methyl-N-(3-(4,4,4-trifluoro-3,3-dimethylbut-1-yn-1-yl)phenyl)- [1,2,4]triazolo[4,3-a]quinazolin-5-amine

The title compound was synthesized according to the method of Example 385, except that 3,3,3-trifluoro-2,2-dimethylpropanal was used instead of bicyclo[1.1.1]pentane-1-carboxaldehyde. ^¹H NMR (400 MHz, acetone-d6) δ 9.47 (s, 1H), 8.42 (d, J = 2.1 Hz, 1H), 7.52 (s, 1H), 7.46 (d, J = 8.9 Hz, 1H), 7.41 (d, J = 7.6 Hz, 1H), 7.40–7.31 (m, 3H), 3.63 (s, 3H), 1.51 (s, 6H); LCMS (m/z) 444.3.

Example 636. 5-(6-fluoro-1-methyl-[1,2,4]triazolo[4,3-a]quinazolin-5-yl)-9-(4,4,4- (trifluoro-3,3-dimethylbut-1-yn-1-yl)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazine

The title compound was synthesized according to the preparation of the core structure described in Example 261, wherein the final coupling reaction was as described in Example 421. ^¹H NMR (400 MHz, methanol- _d⁴ ) δ 8.21 (d, J = 8.6 Hz, 1H), 8.02 (td, J = 8.5, 5.3 Hz, 1H), 7.33 (q, J = 4.3 Hz, 1H), 7.29–7.10 (m, 1H), 6.86–6.71 (m, 2H), 4.44 (b, 2H), 3.39–3.25 (m, 2H), 3.09 (s, 3H), 2.38–2.09 (m, 2H), 1.58 (s, 6H); LCMS (m/z) 484.4.

Example 637. 4-(5-(6-fluoro-1-methyl-[1,2,4]triazolo[4,3-a]quinazolin-5-yl)-2,3,4, 5-Tetrahydrobenzo[b][1,4]oxazapyro-9-yl)-2-methylbut-3-yne-2-ol

The title compound was synthesized according to the preparation of the core structure described in Example 261, wherein the final coupling reaction was as described in Example 421. ^¹H NMR (400 MHz, methanol- _d⁴ ) δ 8.22 (d, J = 8.6 Hz, 1H), 8.02 (q, J = 8.4 Hz, 1H), 7.34 (dd, J = 6.7, 2.7 Hz, 1H), 7.23 (dd, J = 11.5, 8.3 Hz, 1H), 6.85–6.71 (m, 2H), 4.46 (b, 2H), 3.39–3.25 (m, 2H), 3.09 (s, 3H), 2.28 (b, 2H), 1.63 (s, 6H); LCMS (m/z) 432.3.

Example 638. 5-(6-fluoro-1-methyl-[1,2,4]triazolo[4,3-a]quinazolin-5-yl)-9-((1-(tri ... (Fluoromethyl)cyclopropyl)ethynyl)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazine

The title compound was synthesized according to the preparation of the core structure described in Example 261, wherein the final coupling reaction was as described in Example 421. ^¹H NMR (400 MHz, methanol- _d⁴ ) δ 8.22 (d, J = 8.6 Hz, 1H), 8.02 (td, J = 8.5, 5.3 Hz, 1H), 7.35 (dd, J = 5.5, 3.8 Hz, 1H), 7.24 (dd, J = 11.5, 8.3 Hz, 1H), 6.87–6.70 (m, 2H), 4.46 (b, 2H), 3.39–3.25 (m, 2H), 3.09 (s, 3H), 2.28 (d, J = 5.7 Hz, 2H), 1.58–1.26 (m, 4H); LCMS (m/z) 482.3.

Example 639. 9-((1-(difluoromethyl)cyclopropyl)ethynyl)-5-(6-fluoro-1-methyl-[1,2,4]triazole [4,3-a]quinazolin-5-yl)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazine

The title compound was synthesized according to the preparation of the core structure described in Example 261, wherein the final coupling reaction was as described in Example 421. ^¹H NMR (400 MHz, methanol- _d⁴ ) δ 8.20 (d, J = 8.6 Hz, 1H), 8.00 (td, J = 8.4, 5.3 Hz, 1H), 7.33 (dd, J = 6.8, 2.5 Hz, 1H), 7.22 (dd, J = 11.5, 8.3 Hz, 1H), 6.82–6.65 (m, 2H), 5.75 (t, J = 56.7 Hz, 1H), 4.44 (b, 2H), 3.39–3.25 (m, 2H), 3.08 (s, 3H), 2.36–2.16 (m, 2H), 1.39–1.16 (m, 4H); LCMS (m/z) 464.4.

Example 640. 9-(3,3-dimethylbut-1-yn-1-yl)-5-(6-fluoro-1-methyl-[1,2,4]triazolo[4, [3-a]quinazolin-5-yl)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazine

The title compound was synthesized according to the preparation of the core structure described in Example 261, wherein the final coupling reaction was as described in Example 421. ^¹H NMR (400 MHz, methanol- _d⁴ ) δ 8.20 (d, J = 8.6 Hz, 1H), 8.01 (td, J = 8.5, 5.3 Hz, 1H), 7.36–7.16 (m, 2H), 6.83–6.66 (m, 2H), 4.42 (b, 2H), 3.39–3.25 (m, 2H), 3.08 (s, 3H), 2.33–2.19 (m, 2H), 1.38 (s, 9H); LCMS (m/z) 430.3.

Example 641. 9-Fluoro-1-methyl-5-(5-(4,4,4-trifluoro-3,3-dimethylbut-1-yn-1-yl)-3,4- Dihydroquinoline-1(2H)-yl)-[1,2,4]triazolo[4,3-a]quinazolin

The title compound was synthesized according to the preparation of the core structure described in Example 261, wherein the final coupling reaction was as described in Example 421. ^¹H NMR (400 MHz, methanol- _d⁴ ) δ 7.85 (ddd, J = 13.1, 7.4, 2.2 Hz, 1H), 7.60–7.45 (m, 2H), 7.35 (dd, J = 7.6, 1.3 Hz, 1H), 7.04 (t, J = 7.9 Hz, 1H), 6.97 (dd, J = 8.2, 1.2 Hz, 1H), 4.22 (t, J = 6.6 Hz, 2H), 3.12 (t, J = 6.7 Hz, 2H), 2.99 (d, J = 14.2 Hz, 3H), 2.24 (p, J = 6.6 Hz, 2H), 1.59 (s, 6H); LCMS (m/z) 468.4.

Example 642. 4-(1-(9-fluoro-1-methyl-[1,2,4]triazolo[4,3-a]quinazolin-5-yl)-1,2,3, 4-Tetrahydroquinoline-5-yl)-2-methylbut-3-yn-2-ol

The title compound was synthesized according to the preparation of the core structure described in Example 261, wherein the final coupling reaction was as described in Example 421. ^¹H NMR (400 MHz, methanol- _d⁴ ) δ 7.88–7.79 (m, 1H), 7.62–7.45 (m, 2H), 7.33 (d, J = 7.5 Hz, 1H), 7.02 (t, J = 7.9 Hz, 1H), 6.93 (d, J = 8.1 Hz, 1H), 4.22 (t, J = 6.6 Hz, 2H), 3.14 (t, J = 6.6 Hz, 2H), 2.99 (d, J = 14.1 Hz, 3H), 2.23 (p, J = 6.6 Hz, 2H), 1.64 (s, 6H); LCMS (m/z) 416.3.

Example 643. 5-(5-((1-(difluoromethyl)cyclopropyl)ethynyl)-3,4-dihydroquinoline-1(2H)-yl)- 9-Fluoro-1-methyl-[1,2,4]triazolo[4,3-a]quinazolin

The title compound was synthesized according to the preparation of the core structure described in Example 261, wherein the final coupling reaction was as described in Example 421. ¹ H NMR (400MHz, methanol-d ₄ )δ7.85(ddd,J＝13.1,7.1,2.4Hz,1H),7.59–7.43(m,2H),7.33(dd,J＝7.6,1.2Hz,1H),7.02(t,J＝7.9Hz,1H),6.93(dd,J＝8.1,1.2Hz,1H),5.71(t ,J＝56.5Hz,1H),4.22(t,J＝6.6Hz,2H),3.13(t,J＝6.7Hz,2H),2.99(d,J＝14.2Hz,3H),2.23(p,J＝6.6Hz,2H),1.39–1.09(m,4H); LCMS (m/z) 448.4.

Example 644. 5-(5-((1-(difluoromethyl)cyclopropyl)ethynyl)-3,4-dihydroquinoline-1(2H)-yl)- 9-Fluoro-1-methyl-[1,2,4]triazolo[4,3-a]quinazolin

The title compound was synthesized according to the preparation of the core structure described in Example 261, wherein the final coupling reaction was as described in Example 421. ^¹H NMR (400 MHz, methanol- _d⁴ ) δ 7.84 (ddd, J = 13.1, 6.8, 2.7 Hz, 1H), 7.54–7.44 (m, 2H), 7.28 (dd, J = 7.6, 1.2 Hz, 1H), 7.00 (t, J = 7.9 Hz, 1H), 6.89 (dd, J = 8.2, 1.2 Hz, 1H), 4.22 (t, J = 6.6 Hz, 2H), 3.11 (t, J = 6.7 Hz, 2H), 2.99 (d, J = 14.2 Hz, 3H), 2.24 (q, J = 6.6 Hz, 2H), 1.40 (s, 9H); LCMS (m/z) 414.4.

Example 645. 5-(6,7-difluoro-1-methyl-[1,2,4]triazolo[4,3-a]quinazolin-5-yl)-9-(4, 4,4-Trifluoro-3,3-dimethylbut-1-yn-1-yl)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazine

The title compound was synthesized according to the preparation of the core structure described in Example 261, wherein the final coupling reaction was as described in Example 421. ^¹H NMR (400 MHz, methanol- _d⁴ ) δ 8.22 (ddd, J = 9.6, 3.9, 1.9 Hz, 1H), 7.98 (td, J = 9.4, 7.9 Hz, 1H), 7.36 (dd, J = 7.0, 2.3 Hz, 1H), 6.90–6.72 (m, 2H), 4.44 (s, 2H), 3.39–3.25 (m, 2H), 3.08 (s, 3H), 2.36–2.21 (m, 2H), 1.63–1.51 (m, 6H); LCMS (m/z) 502.4.

Example 646. 5-(6,7-difluoro-1-methyl-[1,2,4]triazolo[4,3-a]quinazolin-5-yl)-9-((1- (trifluoromethyl)cyclopropyl)ethynyl)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazine

The title compound was synthesized according to the preparation of the core structure described in Example 261, wherein the final coupling reaction was as described in Example 421. ^¹H NMR (400 MHz, methanol- _d⁴ ) δ 8.22 (ddd, J = 9.5, 3.8, 1.8 Hz, 1H), 8.07–7.86 (m, 1H), 7.38 (dd, J = 6.9, 2.5 Hz, 1H), 6.89–6.72 (m, 2H), 4.45 (s, 2H), 3.39–3.25 (m, 2H), 3.08 (s, 3H), 2.28 (t, J = 5.7 Hz, 2H), 1.55–1.28 (m, 4H); LCMS (m/z) 500.4.

Example 647. 5-(6,7-difluoro-1-methyl-[1,2,4]triazolo[4,3-a]quinazolin-5-yl)-9-((1- (difluoromethyl)cyclopropyl)ethynyl)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazine

The title compound was synthesized according to the preparation of the core structure described in Example 261, wherein the final coupling reaction was as described in Example 421. ^¹H NMR (400 MHz, methanol- _d⁴ ) δ 8.22 (ddd, J = 9.5, 3.9, 1.8 Hz, 1H), 7.98 (td, J = 9.4, 7.9 Hz, 1H), 7.37 (dd, J = 7.4, 2.0 Hz, 1H), 6.88–6.72 (m, 2H), 5.77 (t, J = 56.7 Hz, 1H), 4.45 (s, 2H), 3.39–3.25 (m, 2H), 3.08 (s, 3H), 2.28 (t, J = 5.8 Hz, 2H), 1.39–1.14 (m, 4H); LCMS (m/z) 482.4.

Example 648. 5-(6,7-difluoro-1-methyl-[1,2,4]triazolo[4,3-a]quinazolin-5-yl)-9-(3, 3-Dimethylbut-1-yn-1-yl)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazine

The title compound was synthesized according to the preparation of the core structure described in Example 261, wherein the final coupling reaction was as described in Example 421. ^¹H NMR (400 MHz, methanol- _d⁴ ) δ 8.21 (ddd, J = 9.5, 3.9, 1.8 Hz, 1H), 7.98 (dd, J = 9.4, 7.9 Hz, 1H), 7.31 (dd, J = 7.7, 1.7 Hz, 1H), 6.78 (t, J = 7.8 Hz, 1H), 6.71 (dd, J = 7.9, 1.7 Hz, 1H), 4.41 (s, 2H), 3.39–3.25 (m, 2H), 3.07 (s, 3H), 2.36–2.15 (m, 2H), 1.38 (s, 9H); LCMS (m/z) 448.4.

Example 649. 5-(6,7-difluoro-[1,2,4]triazolo[4,3-a]quinazolin-5-yl)-9-(4,4,4-triazolin-5-yl) Fluoro-3,3-dimethylbut-1-yn-1-yl)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazine

The title compound was synthesized according to the preparation of the core structure described in Example 261, wherein the final coupling reaction was as described in Example 421. ^¹H NMR (400 MHz, methanol- _d⁴ ) δ 9.62 (s, ¹H), 8.20 (ddd, J = 9.4, 4.0, 1.8 Hz, ¹H), 8.02 (td, J = 9.4, 7.6 Hz, ¹H), 7.46–7.30 (m, ¹H), 6.90–6.74 (m, 2H), 4.44 (s, 2H), 3.39–3.24 (m, 2H), 2.28 (t, J = 5.6 Hz, 2H), 1.59 (s, 6H); LCMS (m/z) 488.3.

Example 650. 5-(6,7-difluoro-[1,2,4]triazolo[4,3-a]quinazolin-5-yl)-9-((1-(trifluoromethyl) (cyclopropyl)ethynyl)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazine

The title compound was synthesized according to the preparation of the core structure described in Example 261, wherein the final coupling reaction was as described in Example 421. ^¹H NMR (400 MHz, methanol- _d⁴ ) δ 9.59 (s, ¹H), 8.18 (d, J = 8.9 Hz, ¹H), 8.00 (q, J = 8.9 Hz, ¹H), 7.36 (t, J = 4.7 Hz, ¹H), 6.81 (d, J = 4.7 Hz, 2H), 4.43 (s, 2H), 3.39–3.24 (m, 2H), 2.38–2.14 (m, 2H), 1.54–1.26 (m, 4H); LCMS (m/z) 486.3.

Example 651. 5-(6,7-difluoro-[1,2,4]triazolo[4,3-a]quinazolin-5-yl)-9-(3,3-dimethyl) But-1-yn-1-yl)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazine

The title compound was synthesized according to the preparation of the core structure described in Example 261, wherein the final coupling reaction was as described in Example 421. ^¹H NMR (400 MHz, methanol- _d⁴ ) δ 9.60 (s, ¹H), 8.18 (ddd, J = 9.2, 4.0, 1.8 Hz, ¹H), 8.00 (td, J = 9.4, 7.6 Hz, ¹H), 7.31 (dd, J = 7.6, 1.8 Hz, ¹H), 6.87–6.64 (m, 2H), 4.41 (s, 2H), 3.39–3.24 (m, 2H), 2.34–2.13 (m, 2H), 1.39 (s, 9H); LCMS (m/z) 434.3.

Example 652. 9-Fluoro-5-(5-(4,4,4-trifluoro-3,3-dimethylbut-1-yn-1-yl)-3,4-dihydroquinone (1,2,4)-[1,2,4]triazolo[4,3-a]quinazolino

The title compound was synthesized according to the preparation of the core structure described in Example 261, wherein the final coupling reaction was as described in Example 421. ^¹H NMR (400 MHz, methanol- _d⁴ ) δ 9.47 (d, J = 2.5 Hz, 1H), 7.88 (ddd, J = 11.5, 7.4, 2.0 Hz, 1H), 7.54–7.40 (m, 2H), 7.35 (dd, J = 7.6, 1.2 Hz, 1H), 7.06 (t, J = 7.9 Hz, 1H), 6.98 (dd, J = 8.1, 1.2 Hz, 1H), 4.23 (t, J = 6.6 Hz, 2H), 3.11 (t, J = 6.7 Hz, 2H), 2.24 (p, J = 6.7 Hz, 2H), 1.65–1.53 (m, 6H); LCMS (m/z) 454.4.

Example 653. 4-(1-(9-fluoro-[1,2,4]triazolo[4,3-a]quinazolin-5-yl)-1,2,3,4-tetrahydroquinoline (5-yl)-2-methylbut-3-yn-2-ol

The title compound was synthesized according to the preparation of the core structure described in Example 261, wherein the final coupling reaction was as described in Example 421. ^¹H NMR (400 MHz, methanol- _d⁴ ) δ 9.47 (d, J = 2.5 Hz, 1H), 7.94–7.76 (m, 1H), 7.58–7.40 (m, 2H), 7.34 (d, J = 7.6 Hz, 1H), 7.04 (t, J = 7.9 Hz, 1H), 6.95 (d, J = 8.1 Hz, 1H), 4.23 (t, J = 6.7 Hz, 2H), 3.17–3.09 (m, 2H), 2.23 (t, J = 6.6 Hz, 2H), 1.64 (s, 6H); LCMS (m/z) 402.3.

Example 654. 9-Fluoro-5-(5-((1-(trifluoromethyl)cyclopropyl)ethynyl)-3,4-dihydroquinoline-1(2H)- (-[1,2,4]triazolo[4,3-a]quinazolin)

The title compound was synthesized according to the preparation of the core structure described in Example 261, wherein the final coupling reaction was as described in Example 421. ¹ H NMR (400MHz, methanol-d ₄ )δ9.37(d,J＝3.2Hz,1H),7.83–7.69(m,1H),7.51(d,J＝8.3Hz,1H),7.41(td,J＝8.2,5.0Hz,1H),7.19(dd,J＝7.7,1.1Hz,1H),6.95(t,J ＝7.9Hz,1H),6.84–6.67(m,1H),4.14–4.02(m,2H),3.08(t,J＝6.7Hz,2H),2.21(p,J＝6.6Hz,2H),1.53–1.30(m,4H); LCMS(m/z)452.3.

Example 655. 5-(5-(3,3-dimethylbut-1-yn-1-yl)-3,4-dihydroquinoline-1(2H)-yl)-9-fluoro- [1,2,4]triazolo[4,3-a]quinazolin

The title compound was synthesized according to the preparation of the core structure described in Example 261, wherein the final coupling reaction was as described in Example 421. ^¹H NMR (400 MHz, methanol- _d⁴ ) δ 9.46 (d, J = 2.5 Hz, 1H), 7.87 (ddd, J = 11.5, 7.9, 1.4 Hz, 1H), 7.55–7.38 (m, 2H), 7.29 (dd, J = 7.6, 1.2 Hz, 1H), 7.01 (t, J = 7.9 Hz, 1H), 6.91 (d, J = 8.1 Hz, 1H), 4.23 (t, J = 6.6 Hz, 2H), 3.11 (t, J = 6.7 Hz, 2H), 2.22 (t, J = 6.7 Hz, 2H), 1.40 (s, 9H); LCMS (m/z) 400.5.

Example 656. N-(2,2-difluoroethyl)-6,7-difluoro-1-methyl-N-(3-((1-(trifluoromethyl)cyclopropyl) (ethynyl)phenyl)-[1,2,4]triazolo[4,3-a]quinazolin-5-amine

The title compound was synthesized according to the preparation of the core structure described in Example 261, wherein the final coupling reaction was as described in Example 421. ^¹H NMR (400 MHz, methanol- _d⁴ ) δ 8.26 (ddd, J = 9.4, 3.9, 1.8 Hz, 1H), 8.01 (q, J = 9.1 Hz, 1H), 7.44–7.22 (m, 4H), 6.48 (tt, J = 55.9, 4.1 Hz, 1H), 4.67 (td, J = 13.6, 4.1 Hz, 2H), 3.11 (s, 3H), 1.47–1.20 (m, 4H); LCMS (m/z) 508.3.

Example 657. N-(2,2-difluoroethyl)-6,7-difluoro-1-methyl-N-(3-(4,4,4-trifluoro-3,3-dimethyl) (1,2,4)triazolo[4,3-a]quinazolin-5-amine

The title compound was synthesized according to the preparation of the core structure described in Example 261, wherein the final coupling reaction was as described in Example 421. ^¹H NMR (400 MHz, methanol- _d⁴ ) δ 8.16 (ddd, J = 9.5, 3.9, 1.8 Hz, 1H), 7.88 (td, J = 9.4, 7.8 Hz, 1H), 7.33–7.22 (m, 3H), 7.14 (dt, J = 7.5, 2.2 Hz, 1H), 6.49 (tt, J = 56.1, 4.1 Hz, 1H), 4.59 (td, J = 13.6, 4.1 Hz, 2H), 3.06 (s, 3H), 1.49 (s, 6H); LCMS (m/z) 510.3.

Example 658. N-(2,2-difluoroethyl)-N-(3-(3,3-dimethylbut-1-yn-1-yl)phenyl)-6,7-di Fluoro-1-methyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine

The title compound was synthesized according to the preparation of the core structure described in Example 261, wherein the final coupling reaction was as described in Example 421. ^¹H NMR (400 MHz, methanol- _d⁴ ) δ 8.16 (d, J = 8.7 Hz, 1H), 7.88 (q, J = 9.1 Hz, 1H), 7.29–7.10 (m, 3H), 7.10–6.98 (m, 1H), 6.74–6.26 (m, 1H), 4.76–4.49 (m, 2H), 3.06 (s, 3H), 1.30 (s, 9H); LCMS (m/z) 456.3.

Example 659. N-(2,2-difluoroethyl)-7-fluoro-1-methyl-N-(3-((1-(trifluoromethyl)cyclopropyl)acetylene) (1,2,4)triazolo[4,3-a]quinazolin-5-amine

The title compound was synthesized according to the preparation of the core structure described in Example 261, wherein the final coupling reaction was as described in Example 421. ^¹H NMR (400 MHz, methanol- _d⁴ ) δ 8.26 (ddd, J = 9.4, 3.9, 1.8 Hz, 1H), 8.01 (q, J = 9.1 Hz, 1H), 7.44–7.22 (m, 4H), 6.48 (tt, J = 55.9, 4.1 Hz, 1H), 4.67 (td, J = 13.6, 4.1 Hz, 2H), 3.11 (s, 3H), 1.47–1.20 (m, 4H); LCMS (m/z) 508.3.

Example 660. N-(3-(4,4-difluoro-3,3-dimethylbut-1-yn-1-yl)phenyl)-N-(2,2-difluoroethyl) 6-Fluoro-1-methyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine

The title compound was synthesized according to the preparation of the core structure described in Example 261, wherein the final coupling reaction was as described in Example 421. ^¹H NMR (400 MHz, methanol- _d⁴ ) δ 8.27 (d, J = 8.6 Hz, 1H), 8.06 (td, J = 8.5, 5.3 Hz, 1H), 7.38–7.14 (m, 5H), 6.66–6.23 (m, 1H), 5.74 (t, J = 56.7 Hz, 1H), 4.67 (td, J = 13.5, 4.1 Hz, 2H), 3.12 (s, 3H), 1.33 (t, J = 1.1 Hz, 6H); LCMS (m/z) 474.3.

Example 661. N-(2,2-difluoroethyl)-6-fluoro-1-methyl-N-(3-(4,4,4-trifluoro-3,3-dimethylbut- 1-Alyn-1-yl)phenyl)-[1,2,4]triazolo[4,3-a]quinazolin-5-amine

The title compound was synthesized according to the preparation of the core structure described in Example 261, wherein the final coupling reaction was as described in Example 421. ^¹H NMR (400 MHz, methanol- _d⁴ ) δ 8.27 (d, J = 8.5 Hz, 1H), 8.07 (td, J = 8.4, 5.3 Hz, 1H), 7.44–7.17 (m, 5H), 6.47 (tt, J = 55.9, 4.1 Hz, 1H), 4.68 (td, J = 13.5, 4.1 Hz, 2H), 3.12 (s, 3H), 1.59–1.42 (m, 6H); LCMS (m/z) 492.3.

Example 662. N-(3-(4,4-difluoro-3,3-dimethylbut-1-yn-1-yl)phenyl)-N-(2,2-difluoroethyl) 6-fluoro-[1,2,4]triazolo[4,3-a]quinazolin-5-amine

The title compound was synthesized according to the preparation of the core structure described in Example 261, wherein the final coupling reaction was as described in Example 421. ^¹H NMR (400 MHz, methanol- _d⁴ ) δ 9.68 (s, ¹H), 8.21 (d, J = 8.4 Hz, ¹H), 8.06 (td, J = 8.3, 5.0 Hz, ¹H), 7.44–7.13 (m, 5H), 6.75–6.24 (m, ¹H), 5.75 (t, J = 56.7 Hz, ¹H), 4.68 (td, J = 13.5, 4.1 Hz, 2H), 1.33 (t, J = 1.1 Hz, 6H); LCMS (m/z) 460.3.

Example 663. N-(2,2-difluoroethyl)-6-fluoro-N-(3-(4,4,4-trifluoro-3,3-dimethylbut-1-yne-1- (1,2,4)triazolo[4,3-a]quinazolin-5-amine

The title compound was synthesized according to the preparation of the core structure described in Example 261, wherein the final coupling reaction was as described in Example 421. ^¹H NMR (400 MHz, methanol- _d⁴ ) δ 9.69 (s, ¹H), 8.22 (d, J = 8.3 Hz, ¹H), 8.06 (td, J = 8.3, 5.0 Hz, ¹H), 7.47–7.15 (m, 5H), 6.49 (tt, J = 55.9, 4.1 Hz, 1H), 4.68 (td, J = 13.5, 4.1 Hz, 2H), 1.54–1.42 (m, 6H); LCMS (m/z) 478.3.

Example 664. N-(2,2-difluoroethyl)-6-fluoro-N-(3-((1-(trifluoromethyl)cyclopropyl)ethynyl)benzene (-[1,2,4]triazolo[4,3-a]quinazolin-5-amine)

The title compound was synthesized according to the preparation of the core structure described in Example 261, wherein the final coupling reaction was as described in Example 421. ^¹H NMR (400 MHz, methanol- _d⁴ ) δ 9.68 (s, ¹H), 8.21 (d, J = 8.3 Hz, ¹H), 8.05 (td, J = 8.3, 5.0 Hz, ¹H), 7.47–7.12 (m, 5H), 6.48 (tt, J = 55.9, 4.1 Hz, 1H), 4.67 (td, J = 13.5, 4.1 Hz, 2H), 1.50–1.23 (m, 4H); LCMS (m/z) 476.3.

Example 665. N-(2,2-difluoroethyl)-6-fluoro-N-(3-((1-(difluoromethyl)cyclopropyl)ethynyl)benzene (-[1,2,4]triazolo[4,3-a]quinazolin-5-amine)

The title compound was synthesized according to the preparation of the core structure described in Example 261, wherein the final coupling reaction was as described in Example 421. ^¹H NMR (400 MHz, methanol- _d⁴ ) δ 9.67 (s, ¹H), 8.20 (d, J = 8.4 Hz, ¹H), 8.05 (td, J = 8.4, 5.0 Hz, ¹H), 7.41–7.10 (m, 5H), 6.48 (tt, J = 55.9, 4.1 Hz, ¹H), 5.63 (t, J = 56.5 Hz, 1H), 4.66 (td, J = 13.5, 4.1 Hz, 2H), 1.23–1.03 (m, 4H); LCMS (m/z) 458.3.

Example 666. 5-(7-fluoro-1-methyl-[1,2,4]triazolo[4,3-a]quinazolin-5-yl)-9-((1-(tri ... (Fluoromethyl)cyclopropyl)ethynyl)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazine

The title compound was synthesized according to the preparation of the core structure described in Example 261, wherein the final coupling reaction was as described in Example 421. ^¹H NMR (400 MHz, methanol- _d⁴ ) δ 8.44 (dd, J = 9.4, 4.6 Hz, 1H), 7.78 (ddd, J = 9.9, 7.4, 2.9 Hz, 1H), 7.56 (dd, J = 5.5, 3.9 Hz, 1H), 7.09–6.97 (m, 2H), 6.82 (dd, J = 10.2, 2.8 Hz, 1H), 4.40 (b, 2H), 3.08 (s, 3H), 3.37–3.28 (m, 2H), 2.26 (b, 2H), 1.56–1.25 (m, 4H); LCMS (m/z) 482.4.

Example 667. N-(2,2-difluoroethyl)-7-fluoro-N-(3-fluoro-5-(4,4,4-trifluoro-3,3-dimethylbut-1- (1-yl)phenyl)-[1,2,4]triazolo[4,3-a]quinazolin-5-amine

The title compound was synthesized according to the preparation of the core structure described in Example 261, wherein the final coupling reaction was as described in Example 421. ^¹H NMR (400 MHz, methanol- _d⁴ ) δ 9.56 (s, ¹H), 8.36 (dd, J = 9.2, 4.7 Hz, ¹H), 7.72 (ddd, J = 9.1, 7.7, 2.7 Hz, ¹H), 7.30 (t, J = 1.6 Hz, ¹H), 7.25 (dt, J = 9.7, 2.2 Hz, ¹H), 7.21–7.12 (m, ¹H), 7.03 (dd, J = 9.9, 2.7 Hz, ¹H), 6.75–6.39 (m, ¹H), 4.63–4.52 (m, 2H), 1.52 (s, 6H); LCMS (m/z) 496.3.

Example 668. N-(3-(4,4-difluoro-3,3-dimethylbut-1-yn-1-yl)-5-fluorophenyl)-N-(2,2-di... (Fluoroethyl)-7,9-difluoro-[1,2,4]triazolo[4,3-a]quinazolin-5-amine

The title compound was synthesized according to the preparation of the core structure described in Example 261, wherein the final coupling reaction was as described in Example 421. ^¹H NMR (400 MHz, methanol- _d⁴ ) δ 9.47 (d, J = 2.8 Hz, 1H), 7.98–7.82 (m, 1H), 7.40–7.17 (m, 3H), 6.88 (dt, J = 9.7, 2.0 Hz, 1H), 6.55 (t, J = 56.0 Hz, 1H), 5.78 (t, J = 56.6 Hz, 1H), 4.62 (td, J = 13.5, 4.2 Hz, 2H), 1.36 (d, J = 1.1 Hz, 6H); LCMS (m/z) 496.3.

Example 669. N-(2,2-difluoroethyl)-7,9-difluoro-N-(3-fluoro-5-((1-methylcyclopropyl)ethynyl) phenyl)-[1,2,4]triazolo[4,3-a]quinazolin-5-amine

The title compound was synthesized according to the preparation of the core structure described in Example 261, wherein the final coupling reaction was as described in Example 421. ^¹H NMR (400 MHz, methanol- _d⁴ ) δ 9.36 (d, J = 3.3 Hz, 1H), 7.76 (ddd, J = 11.2, 8.2, 2.6 Hz, 1H), 7.21–7.10 (m, 3H), 6.92 (ddd, J = 9.6, 2.6, 1.6 Hz, 1H), 6.75–6.30 (m, 1H), 4.55 (td, J = 13.7, 4.2 Hz, 2H), 1.32 (s, 3H), 0.97 (q, J = 4.1 Hz, 2H), 0.79–0.65 (m, 2H); LCMS (m/z) 458.3.

Example 670. N-(2,2-difluoroethyl)-7,9-difluoro-N-(3-fluoro-5-((1-(trifluoromethyl)cyclopropyl)ethyl) (alkynyl)phenyl)-[1,2,4]triazolo[4,3-a]quinazolin-5-amine

The title compound was synthesized according to the preparation of the core structure described in Example 261, wherein the final coupling reaction was as described in Example 421. ^¹H NMR (400 MHz, methanol- _d⁴ ) δ 9.37 (d, J = 3.3 Hz, 1H), 7.77 (ddd, J = 11.2, 8.2, 2.6 Hz, 1H), 7.35–7.21 (m, 2H), 7.19 (ddd, J = 8.8, 2.4, 1.3 Hz, 1H), 6.92 (dt, J = 9.6, 2.0 Hz, 1H), 6.56 (tt, J = 56.3, 4.2 Hz, 1H), 4.62–4.52 (m, 2H), 1.49–1.23 (m, 4H); LCMS (m/z) 512.3.

Example 671. N-(2,2-difluoroethyl)-6,7-difluoro-N-(3-(4,4,4-trifluoro-3,3-dimethylbut-1- (1-yl)phenyl)-[1,2,4]triazolo[4,3-a]quinazolin-5-amine

The title compound was synthesized according to the preparation of the core structure described in Example 261, wherein the final coupling reaction was as described in Example 421. ^¹H NMR (400 MHz, methanol- _d⁴ ) δ 9.65 (s, 1H), 8.22 (ddd, J = 9.3, 4.0, 1.8 Hz, 1H), 8.02 (td, J = 9.4, 7.6 Hz, 1H), 7.44–7.32 (m, 3H), 7.27 (td, J = 4.6, 2.3 Hz, 1H), 6.48 (tt, J = 55.9, 4.1 Hz, 1H), 4.66 (td, J = 13.6, 4.1 Hz, 2H), 1.56–1.46 (m, 6H); LCMS (m/z) 496.3.

Example 672. N-(2,2-difluoroethyl)-6-fluoro-N-(3-fluoro-5-(4,4,4-trifluoro-3,3-dimethylbut-1- (1-yl)phenyl)-[1,2,4]triazolo[4,3-a]quinazolin-5-amine

The title compound was synthesized according to the preparation of the core structure described in Example 261, wherein the final coupling reaction was as described in Example 421. ^¹H NMR (400 MHz, methanol- _d⁴ ) δ 9.70 (s, 1H), 8.23 (d, J = 8.4 Hz, 1H), 8.08 (td, J = 8.4, 5.0 Hz, 1H), 7.28 (ddd, J = 11.9, 8.3, 1.0 Hz, 1H), 7.23–7.14 (m, 2H), 7.09 (ddd, J = 8.8, 2.4, 1.2 Hz, 1H), 6.50 (tt, J = 55.9, 4.0 Hz, 1H), 4.69 (td, J = 13.7, 4.1 Hz, 2H), 1.56–1.45 (m, 6H); LCMS (m/z) 496.3.

Example 673. N-(2,2-difluoroethyl)-6,7-difluoro-N-(3-((1-(trifluoromethyl)cyclopropyl)ethynyl) phenyl)-[1,2,4]triazolo[4,3-a]quinazolin-5-amine

The title compound was synthesized according to the preparation of the core structure described in Example 261, wherein the final coupling reaction was as described in Example 421. ^¹H NMR (400 MHz, methanol- _d⁴ ) δ 9.68 (s, 1H), 8.25 (ddd, J = 9.4, 4.0, 1.8 Hz, 1H), 8.05 (td, J = 9.3, 7.6 Hz, 1H), 7.49–7.20 (m, 4H), 6.49 (tt, J = 55.9, 4.1 Hz, 1H), 4.68 (td, J = 13.6, 4.1 Hz, 2H), 1.46–1.31 (m, 2H), 1.29 (dq, J = 3.3, 1.7 Hz, 2H); LCMS (m/z) 494.2.

Example 674. N-(3-(4,4-difluoro-3,3-dimethylbut-1-yn-1-yl)-5-fluorophenyl)-N-(2,2-di... (Fluoroethyl)-6-fluoro-[1,2,4]triazolo[4,3-a]quinazolin-5-amine

The title compound was synthesized according to the preparation of the core structure described in Example 261, wherein the final coupling reaction was as described in Example 421. ¹ H NMR (400MHz, methanol-d ₄ )δ9.70(s,1H),8.23(d,J＝8.4Hz,1H),8.07(td,J＝8.3,5.0Hz,1H),7.28(dd,J＝11.7,8.3Hz,1H),7.21–7.09(m,2H),7.07(ddd,J＝8.9,2.4 ,1.3Hz,1H),6.48(tt,J＝55.9,4.1Hz,1H),5.74(t,J＝56.6Hz,1H),4.68(td,J＝13.6,4.0Hz,2H),1.32(t,J＝1.1Hz,6H); LCMS (m/z) 478.3.

Example 675. N-(2,2-difluoroethyl)-6-fluoro-N-(6-((1-(trifluoromethyl)cyclopropyl)ethynyl)pyridine (azin-2-yl)-[1,2,4]triazolo[4,3-a]quinazolin-5-amine

The title compound was synthesized according to the preparation of the core structure described in Example 261, wherein the final coupling reaction was as described in Example 421. ^¹H NMR (400 MHz, methanol- _d⁴ ) δ 9.77 (s, ¹H), 8.49 (s, ¹H), 8.40 (s, ¹H), 8.29 (d, J = 8.4 Hz, ¹H), 8.09 (td, J = 8.3, 5.2 Hz, ¹H), 7.32 (ddd, J = 12.3, 8.3, 1.0 Hz, ¹H), 6.56 (tt, J = 56.2, 4.1 Hz, ¹H), 4.92–4.79 (m, 2H), 1.56–1.27 (m, 4H); LCMS (m/z) 478.2.

Example 676. N-(2,2-difluoroethyl)-6-fluoro-N-(3-fluoro-5-((1-methylcyclopropyl)ethynyl)benzene (-[1,2,4]triazolo[4,3-a]quinazolin-5-amine)

The title compound was synthesized according to the preparation of the core structure described in Example 261, wherein the final coupling reaction was as described in Example 421. ¹ H NMR (400MHz, methanol-d ₄ )δ9.69(s,1H),8.22(d,J＝8.3Hz,1H),8.07(td,J＝8.3,4.9Hz,1H),7.27(dd,J＝11.8,8.3Hz,1H),7.08(d,J＝9.2Hz,2H),6.99(dd,J＝9.0 ,1.8Hz,1H),6.74–6.24(m,1H),4.67(td,J＝13.5,4.0Hz,2H),1.29(s,3H),0.93(q,J＝4.1Hz,2H),0.76–0.59(m,2H); LCMS(m/z)440.3.

Example 677. 4-(3-((2,2-difluoroethyl)(6-fluoro-[1,2,4]triazolo[4,3-a]quinazolin-5-yl) (amino)-5-fluorophenyl)-2-methylbut-3-yne-2-ol

The title compound was synthesized according to the preparation of the core structure described in Example 261, wherein the final coupling reaction was as described in Example 421. ^¹H NMR (400 MHz, methanol- _d⁴ ) δ 9.67 (s, 1H), 8.21 (d, J = 8.4 Hz, 1H), 8.05 (td, J = 8.3, 5.0 Hz, 1H), 7.25 (dd, J = 11.8, 8.2 Hz, 1H), 7.11 (d, J = 11.1 Hz, 2H), 7.04 (dd, J = 8.9, 1.8 Hz, 1H), 6.49 (t, J = 55.9 Hz, 1H), 4.67 (td, J = 13.6, 4.0 Hz, 2H), 1.51 (s, 6H); LCMS (m/z) 444.2.

Example 678. N-(2,2-difluoroethyl)-6-fluoro-N-(3-fluoro-5-((1-(trifluoromethyl)cyclopropyl)acetylene) (1,2,4)triazolo[4,3-a]quinazolin-5-amine

The title compound was synthesized according to the preparation of the core structure described in Example 261, wherein the final coupling reaction was as described in Example 421. ^¹H NMR (400 MHz, methanol- _d⁴ ) δ 9.69 (s, ¹H), 8.22 (d, J = 8.4 Hz, ¹H), 8.07 (td, J = 8.3, 5.0 Hz, ¹H), 7.27 (dd, J = 11.8, 8.3 Hz, ¹H), 7.21–7.14 (m, 2H), 7.15–7.02 (m, 1H), 6.64–6.22 (m, 1H), 4.68 (td, J = 13.6, 4.0 Hz, 2H), 1.47–1.35 (m, 2H), 1.35–1.14 (m, 2H); LCMS (m/z) 494.3.

Example 679. N-(2,2-difluoroethyl)-N-(3-((1-(difluoromethyl)cyclopropyl)ethynyl)-5-fluorobenzene 6-fluoro-[1,2,4]triazolo[4,3-a]quinazolin-5-amine

The title compound was synthesized according to the preparation of the core structure described in Example 261, wherein the final coupling reaction was as described in Example 421. ¹ H NMR (400MHz, methanol-d ₄ )δ9.70(s,1H),8.23(d,J＝8.4Hz,1H),8.07(td,J＝8.3,5.0Hz,1H),7.27(dd,J＝11.8,8.2Hz,1H),7.15(dd,J＝8.9,2.0Hz,2H),7.07(dt,J＝ 8.6, 1.9Hz, 1H), 6.48 (tt, J = 55.9, 4.0Hz, 1H), 5.63 (t, J = 56.5Hz, 1H), 4.68 (td, J = 13.6, 4.1Hz, 2H), 1.28–1.01 (m, 4H); LCMS (m/z) 476.3.

Example 680. N-(3-(4,4-difluoro-3,3-dimethylbut-1-yn-1-yl)-5-fluorophenyl)-7-fluoro-N-methyl [1,2,4]triazolo[4,3-a]quinazolin-5-amine

The title compound was synthesized according to the preparation of the core structure described in Example 261, wherein the final coupling reaction was as described in Example 421. ^¹H NMR (400 MHz, methanol- _d⁴ ) δ 9.64 (s, ¹H), 8.44 (dd, J = 9.2, 4.7 Hz, ¹H), 7.84 (ddd, J = 9.2, 7.6, 2.7 Hz, ¹H), 7.43–7.22 (m, ³H), 6.97 (dd, J = 10.2, 2.7 Hz, ¹H), 5.78 (t, J = 56.6 Hz, ¹H), 3.78 (s, ³H), 1.36 (d, J = 1.2 Hz, 6H); LCMS (m/z) 428.3.

Example 681. N-(3-(4,4-difluoro-3,3-dimethylbut-1-yn-1-yl)-5-fluorophenyl)-7-fluoro-N-methyl [1,2,4]triazolo[4,3-a]quinazolin-5-amine

The title compound was synthesized according to the preparation of the core structure described in Example 261, wherein the final coupling reaction was as described in Example 421. ^¹H NMR (400 MHz, methanol- _d⁴ ) δ 9.71 (s, 1H), 8.47 (dd, J = 9.2, 4.7 Hz, 1H), 7.86 (ddd, J = 9.3, 7.6, 2.7 Hz, 1H), 7.46–7.23 (m, 3H), 6.95 (dd, J = 10.0, 2.7 Hz, 1H), 6.79–6.35 (m, 1H), 5.78 (t, J = 56.6 Hz, 1H), 4.63 (td, J = 13.4, 4.2 Hz, 2H), 1.36 (d, J = 1.2 Hz, 6H); LCMS (m/z) 478.3.

Example 682. 7-Fluoro-N,1-Dimethyl-N-(6-((1-(trifluoromethyl)cyclopropyl)ethynyl)pyrazine-2- (-[1,2,4]triazolo[4,3-a]quinazolin-5-amine)

The title compound was synthesized according to the preparation of the core structure described in Example 261, wherein the final coupling reaction was as described in Example 421. ^¹H NMR (400 MHz, methanol- _d⁴ ) δ 8.60–8.47 (m, 2H), 8.46 (s, 1H), 7.88 (ddd, J = 9.4, 7.7, 2.9 Hz, 1H), 7.37 (dd, J = 9.1, 2.9 Hz, 1H), 3.84 (s, 3H), 3.14 (s, 3H), 1.57–1.30 (m, 4H); LCMS (m/z) 442.3.

Example 683. 8-Chloro-N-(3-(4,4-difluoro-3,3-dimethylbut-1-yn-1-yl)-5-fluorophenyl)-N- (2,2-Difluoroethyl)-[1,2,4]triazolo[4,3-a]quinazolin-5-amine

The title compound was synthesized according to the preparation of the core structure described in Example 261, wherein the final coupling reaction was as described in Example 421. ^¹H NMR (400 MHz, methanol- _d⁴ ) δ 9.69 (s, ¹H), 8.58 (d, J = 2.1 Hz, ¹H), 7.51 (dd, J = 9.1, 2.1 Hz, ¹H), 7.47–7.19 (m, 4H), 6.52 (tt, J = 56.0, 4.2 Hz, 1H), 5.77 (t, J = 56.6 Hz, 1H), 4.62 (d, J = 4.2 Hz, 2H), 1.35 (t, J = 1.1 Hz, 6H); LCMS (m/z) 494.3.

Example 684. 8-Chloro-N-(2,2-difluoroethyl)-N-(3-fluoro-5-((1-methylcyclopropyl)ethynyl)benzene (-[1,2,4]triazolo[4,3-a]quinazolin-5-amine)

The title compound was synthesized according to the preparation of the core structure described in Example 261, wherein the final coupling reaction was as described in Example 421. ^¹H NMR (400 MHz, methanol- _d⁴ ) δ 9.68 (s, 1H), 8.57 (d, J = 2.0 Hz, 1H), 7.50 (dd, J = 9.1, 2.0 Hz, 1H), 7.43–7.08 (m, 4H), 6.76–6.23 (m, 1H), 4.60 (td, J = 13.4, 4.2 Hz, 2H), 1.32 (s, 3H), 0.97 (q, J = 4.1 Hz, 2H), 0.84–0.61 (m, 2H); LCMS (m/z) 456.3.

Example 685. 8-Chloro-N-(2,2-difluoroethyl)-N-(3-fluoro-5-((1-(trifluoromethyl)cyclopropyl)acetylene) (1,2,4)triazolo[4,3-a]quinazolin-5-amine

The title compound was synthesized according to the preparation of the core structure described in Example 261, wherein the final coupling reaction was as described in Example 421. ^¹H NMR (400 MHz, methanol- _d⁴ ) δ 9.69 (s, ¹H), 8.57 (d, J = 2.0 Hz, ¹H), 7.51 (dd, J = 9.1, 2.1 Hz, ¹H), 7.43–7.22 (m, 4H), 6.74–6.27 (m, ¹H), 4.62 (td, J = 13.4, 4.2 Hz, 2H), 1.52–1.22 (m, 4H); LCMS (m/z) 510.3.

Example 686. 8-Chloro-N-(3-(4,4-difluoro-3,3-dimethylbut-1-yn-1-yl)-5-fluorophenyl)-N-methyl [1,2,4]triazolo[4,3-a]quinazolin-5-amine

The title compound was synthesized according to the preparation of the core structure described in Example 261, wherein the final coupling reaction was as described in Example 421. ^¹H NMR (400 MHz, methanol- _d⁴ ) δ 9.62 (s, ¹H), 8.63–8.38 (m, ¹H), 7.49 (dd, J = 9.2, 2.0 Hz, ¹H), 7.39–7.11 (m, 4H), 5.77 (t, J = 56.6 Hz, ¹H), 3.77 (s, 3H), 1.35 (d, J = 1.2 Hz, 6H); LCMS (m/z) 444.3.

Example 687. 8-Chloro-N-(3-((1-ethylcyclopropyl)ethynyl)-5-fluorophenyl)-N-methyl-[1,2,4] Triazolo[4,3-a]quinazolin-5-amine

The title compound was synthesized according to the preparation of the core structure described in Example 261, wherein the final coupling reaction was as described in Example 421. ^¹H NMR (400 MHz, methanol- _d⁴ ) δ 9.61 (s, ¹H), 8.53 (d, J = 2.0 Hz, ¹H), 7.49 (dd, J = 9.1, 2.1 Hz, ¹H), 7.38–7.11 (m, 4H), 3.76 (s, 3H), 1.45 (q, J = 7.4 Hz, 2H), 1.11 (t, J = 7.3 Hz, 3H), 0.94 (q, J = 4.1 Hz, 2H), 0.79–0.61 (m, 2H); LCMS (m/z) 420.3.

Example 688. 8-Chloro-N-(3-((1-(difluoromethyl)cyclopropyl)ethynyl)-5-fluorophenyl)-N-methyl- [1,2,4]triazolo[4,3-a]quinazolin-5-amine

The title compound was synthesized according to the preparation of the core structure described in Example 261, wherein the final coupling reaction was as described in Example 421. ^¹H NMR (400 MHz, methanol- _d⁴ ) δ 9.62 (s, ¹H), 8.53 (d, J = 2.1 Hz, ¹H), 7.49 (dd, J = 9.1, 2.1 Hz, ¹H), 7.43–7.16 (m, 4H), 5.64 (t, J = 56.4 Hz, 1H), 3.77 (s, 3H), 1.32–1.06 (m, 4H); LCMS (m/z) 442.3.

Example 689. 8-Chloro-N-(3-(3,3-dimethylbut-1-yn-1-yl)-5-fluorophenyl)-N-methyl-[1,2, 4] Triazolo[4,3-a]quinazolin-5-amine

The title compound was synthesized according to the preparation of the core structure described in Example 261, wherein the final coupling reaction was as described in Example 421. ^¹H NMR (400 MHz, methanol- _d⁴ ) δ 9.62 (s, ¹H), 8.54 (d, J = 2.1 Hz, ¹H), 7.49 (dd, J = 9.1, 2.1 Hz, ¹H), 7.44–7.14 (m, 4H), 3.77 (s, 3H), 1.30 (s, 9H); LCMS (m/z) 408.4.

Example 690. N-(2,2-difluoroethyl)-7-fluoro-N-(3-fluoro-5-((1-(trifluoromethyl)cyclopropyl)acetylene) (1,2,4)triazolo[4,3-a]quinazolin-5-amine

The title compound was synthesized according to the preparation of the core structure described in Example 261, wherein the final coupling reaction was as described in Example 421. ^¹H NMR (400 MHz, methanol- _d⁴ ) δ 9.71 (s, 1H), 8.47 (dd, J = 9.2, 4.7 Hz, 1H), 7.86 (ddd, J = 9.2, 7.6, 2.7 Hz, 1H), 7.50–7.22 (m, 3H), 6.95 (dd, J = 10.0, 2.7 Hz, 1H), 6.54 (tt, J = 56.0, 4.2 Hz, 1H), 4.63 (td, J = 13.4, 4.2 Hz, 2H), 1.51–1.25 (m, 4H); LCMS (m/z) 494.3.

Example 691. 7-Fluoro-N-(3-Fluoro-5-((1-(trifluoromethyl)cyclopropyl)ethynyl)phenyl)-N-methyl- [1,2,4]triazolo[4,3-a]quinazolin-5-amine

The title compound was synthesized according to the preparation of the core structure described in Example 261, wherein the final coupling reaction was as described in Example 421. ^¹H NMR (400 MHz, methanol- _d⁴ ) δ 9.65 (s, ¹H), 8.44 (dd, J = 9.2, 4.7 Hz, ¹H), 7.84 (ddd, J = 9.3, 7.6, 2.7 Hz, ¹H), 7.46–7.28 (m, ³H), 6.96 (dd, J = 10.1, 2.7 Hz, ¹H), 3.79 (s, ³H), 1.50–1.24 (m, ⁴H); LCMS (m/z) 444.3.

Example 692. 8-Chloro-N-(3-fluoro-5-((1-(trifluoromethyl)cyclopropyl)ethynyl)phenyl)-N-methyl- [1,2,4]triazolo[4,3-a]quinazolin-5-amine

The title compound was synthesized according to the preparation of the core structure described in Example 261, wherein the final coupling reaction was as described in Example 421. ^¹H NMR (400 MHz, methanol- _d⁴ ) δ 9.63 (s, ¹H), 8.54 (d, J = 2.1 Hz, ¹H), 7.49 (dd, J = 9.1, 2.1 Hz, ¹H), 7.47–7.21 (m, 4H), 3.77 (s, 3H), 1.49–1.40 (m, 2H), 1.32 (dtd, J = 6.0, 3.9, 1.4 Hz, 2H); LCMS (m/z) 460.3.

Example 693. 2-(3'-((8-chloro-[1,2,4]triazolo[4,3-a]quinazolin-5-yl)(methyl)amino)- 5'-Fluoro-[1,1'-diphenyl]-4-yl)isothiazolidinyl 1,1-dioxide

The title compound was synthesized according to the preparation of the core structure described in Example 261, wherein the final coupling reaction was as described in Example 421. ^¹H NMR (400 MHz, methanol- _d⁴ ) δ 9.60 (s, ¹H), 8.51 (t, J = 1.3 Hz, ¹H), 7.70–7.29 (m, 8H), 7.26 (dt, J = 9.1, 2.2 Hz, ¹H), 3.98–3.72 (m, 5H), 3.48 (t, J = 7.4 Hz, 2H), 2.65–2.45 (m, 2H); LCMS (m/z) 523.2.

Example 694. 4-(3-((8-chloro-7-fluoro-[1,2,4]triazolo[4,3-a]quinazolin-5-yl)(methyl)amino (5-fluorophenyl)-2-methylbut-3-yne-2-ol

The title compound was synthesized according to the preparation of the core structure described in Example 261, wherein the final coupling reaction was as described in Example 421. ^¹H NMR (400 MHz, methanol- _d⁴ ) δ 9.57 (s, ¹H), 8.68 (d, J = 6.4 Hz, ¹H), 7.37–7.22 (m, ³H), 7.09 (d, J = 10.5 Hz, ¹H), 3.74 (s, ³H), 1.54 (s, 6H); LCMS (m/z) 428.2.

Example 695. N-(3-bromo-5-fluorophenyl)-8-chloro-7-fluoro-N-methyl-[1,2,4]triazolo[4,3-a]quinazole 5-Lin-amine

The title compound was synthesized according to the preparation of the core structure described in Example 261, wherein the final coupling reaction was as described in Example 421. ^¹H NMR (400 MHz, methanol- _d⁴ ) δ 9.60 (s, ¹H), 8.70 (d, J = 6.4 Hz, ¹H), 7.64–7.30 (m, ³H), 7.12 (d, J = 10.4 Hz, ¹H), 3.76 (s, ³H); LCMS (m/z) 424.2.

Example 696. 5-(8-chloro-[1,2,4]triazolo[4,3-a]quinazolin-5-yl)-9-(3,3-dimethylbut- 1-Alyn-1-yl)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazine

The title compound was synthesized according to the preparation of the core structure described in Example 261, wherein the final coupling reaction was as described in Example 421. ^¹H NMR (400 MHz, methanol- _d⁴ ) δ 9.57 (s, ¹H), 8.48 (d, J = 2.1 Hz, ¹H), 7.42 (ddd, J = 21.0, 8.2, 2.0 Hz, 2H), 7.14 (d, J = 9.1 Hz, ¹H), 7.05–6.89 (m, 2H), 4.36 (b, 2H), 3.37–3.28 (m, 2H), 2.23 (b, 2H), 1.38 (s, 9H); LCMS (m/z) 432.4.

Example 697. 4-(1-(6-fluoro-1-methyl-[1,2,4]triazolo[4,3-a]quinazolin-5-yl)-2,3,4, 5-Tetrahydro-1H-benzo[b]azapyro-6-yl)-2-methylbut-3-yne-2-ol

Synthesis of 6-bromo-1-(2-chloro-5-fluoro-quinazoline-4-yl)-2,3,4,5-tetrahydro-1-benzozazepine: NaH (60% dispersion in mineral oil) (177 mg, 4.61 mmol) was added in a single addition to a solution of 6-bromo-2,3,4,5-tetrahydro-1H-1-benzozazepine (521 mg, 2.3 mmol) in DMA (5.0 mL) at 0 °C. The mixture was stirred at 0 °C for 30 min, followed by a single addition of 2,4-dichloro-5-fluoroquinazoline (500 mg, 2.3 mmol), and the mixture was heated to room temperature over 16 hours. After completion, the mixture was poured into water (50 mL) and extracted with ethyl acetate (2 × 50 mL each time). The organic matter was separated, dried over sodium sulfate, filtered, and concentrated under vacuum. The crude product was purified by silica gel column chromatography using 0-40% ethyl acetate in hexane as the eluent. Combine appropriate fractions and concentrate under vacuum to provide the desired compound. (MS(m/z) 407.2 [M+H] ⁺ )

Synthesis of [4-(6-bromo-2,3,4,5-tetrahydro-1-benzozazaporin-1-yl)-5-fluoro-quinazoline-2-yl]hydrazine: Anhydrous hydrazine (158 mg, 4.92 mmol) was added to a solution of 6-bromo-1-(2-chloro-5-fluoro-quinazoline-4-yl)-2,3,4,5-tetrahydro-1-benzozaporin (200 mg, 0.492 mmol) in THF (10 mL) and ethanol (10 mL), and the mixture was stirred at room temperature for 5 hours. After completion, the reaction mixture was diluted with dichloromethane and washed with water, followed by brine. The resulting organic compound was dried over _Na₂SO₄ , filtered, and concentrated under reduced pressure to provide the desired compound. _MS (m/z) 403.2 [M+H] ^⁺ .

Synthesis of 5-(6-bromo-2,3,4,5-tetrahydro-1-benzozap-1-yl)-6-fluoro-1-methyl-[1,2,4]triazolo[4,3-a]quinazoline: A solution of [4-(6-bromo-2,3,4,5-tetrahydro-1-benzozap-1-yl)-5-fluoro-quinazoline-2-yl]hydrazine (75 mg, 0.186 mmol) and triethyl orthoacetate (0.9 g, 5.62 mmol) was heated to 100 °C for 16 hours. After completion, the reactants were cooled to room temperature and concentrated under reduced pressure to provide a crude product. The crude product was ground with heptane, and the solid was collected by filtration, washed with heptane, and dried under vacuum to provide the desired compound. MS (m/z) 427.2 [M+H] ⁺ .

Synthesis of 4-[1-(6-fluoro-1-methyl-[1,2,4]triazolo[4,3-a]quinazolin-5-yl)-2,3,4,5-tetrahydro-1-benzozazepine-6-yl]-2-methyl-but-3-yn-2-ol: A solution of 5-(6-bromo-2,3,4,5-tetrahydro-1-benzozazepine-1-yl)-6-fluoro-1-methyl-[1,2,4]triazolo[4,3-a]quinazolin (25.9 mg, 0.0606 mmol), zinc bromide (68.3 mg, 0.303 mmol), (1,1'-)bis(diphenylphosphine)ferrocene)palladium(II) dichloride (2.5 mg, 0.00303 mmol) and triethylamine (61 mg, 0.6 mmol) in DMF (2 mL) was purged with nitrogen for 2 min. 2-Methylbut-3-yn-2-ol (10 mg, 0.121 mmol) was then added, and the mixture was heated at 100 ° _C for 2 hours. Afterward, the mixture was cooled to room temperature, and ethyl acetate and saturated _NH₄Cl (aqueous solution) were added. The aqueous layer was extracted with EA, and the combined organic layers were dried over _Na₂SO₄ and concentrated under vacuum. The residue was purified by reversed-phase HPLC (acetonitrile/water containing 0.1% trifluoroacetic acid) to provide the title compound as a single TFA salt. 1H NMR (400MHz, DMSO-d ₆ )δ8.12(d,J＝8.6Hz,1H),7.93(td,J＝8.4,5.3Hz,1H),7.37–7.15(m,2H),6.94(t,J＝7.8Hz,1H),6.74( d,J＝7.9Hz,1H),3.44(d,J＝164.0Hz,6H),2.99(s,3H),1.85(s,2H),1.52(s,6H); MS(m/z)430.2[M+H] ⁺ .

Example 698. (R)-4-(3-((2,2-difluoroethyl)(6-fluoro-1-methyl-[1,2,4]triazolo[4,3-a]quinoline) (Zazoline-5-yl)amino)-5-fluorophenyl)but-3-yne-2-ol

The title compound was prepared according to the general procedure described for Example 704. ¹H NMR (400 MHz, DMSO- _d₆ ) δ 8.16 (d, J = 8.6 Hz, 1H), 8.06–7.79 (m, 1H), 7.29 (dd, J = 12.0, 8.1 Hz, 1H), 7.18–7.04 (m, 2H), 6.99 (d, J = 8.7 Hz, 1H), 6.74–6.32 (m, 1H), 4.70–4.55 (m, 2H), 4.53 (q, J = 6.5 Hz, 1H), 3.01 (s, 3H), 1.33 (d, J = 6.6 Hz, 3H); LCMS (m/z) 444.1.

Example 699. N-(3-(cyclopropylethynyl)-5-fluorophenyl)-N-(2,2-difluoroethyl)-6-fluoro-1-methyl [1,2,4]triazolo[4,3-a]quinazolin-5-amine

The title compound was prepared according to the general procedure described for Example 704. 1H NMR (400MHz, DMSO-d ₆ )δ8.16(d,J＝8.6Hz,1H),7.97(td,J＝8.4,5.3Hz,1H),7.29(dd,J＝12.0,8. 2Hz,1H),7.13–7.06(m,1H),7.03(s,1H),6.95(dd,J＝9.1,1.9Hz,1H),6.7 7–6.11(m,1H),4.74–4.49(m,2H),3.01(s,3H),1.49(ddd,J=13.3,8.6,5. 0Hz, 1H), 0.86 (dt, J = 8.2, 3.3Hz, 2H), 0.79–0.58 (m, 2H); LCMS (m/z) 440.1.

Example 700. 5-(5-(cyclopropylethynyl)-3,4-dihydroquinoline-1(2H)-yl)-7-fluoro-1-methyl-[1, [2,4]triazolo[4,3-a]quinazoline

The title compound was prepared according to the general procedure described for Example 719. ¹H NMR (400 MHz, DMSO-d6 ₎ )δ8.39(dd,J＝9.4,4.6Hz,1H),8.00–7.79(m,1H),7.39(dd,J＝9.6,2.9Hz,1H) ,7.16(d,J＝7.6Hz,1H),6.97(t,J＝7.9Hz,1H),6.79(d,J＝8.1Hz,1H),3.98(t,J ＝6.3Hz,2H),3.01(s,3H),2.96(t,J＝6.7Hz,2H),2.10(q,J＝6.6Hz,2H),1.62( td,J＝8.4,4.3Hz,1H),1.00–0.89(m,2H),0.84–0.73(m,2H); LCMS(m/z)398.1.

Example 701. 6-Fluoro-5-(5-((1-(trifluoromethyl)cyclopropyl)ethynyl)-3,4-dihydroquinoline-1(2H)- (-[1,2,4]triazolo[4,3-a]quinazolin-1-amine)

The title compound was prepared according to the general procedure described for Example 704. ¹H NMR (400 MHz, DMSO- _d₆ ) δ 8.30 (d, J = 8.5 Hz, 1H), 8.09–7.84 (m, 1H), 7.35 (dd, J = 11.9, 8.4 Hz, 2H), 7.20 (dd, J = 7.2, 1.6 Hz, 1H), 7.08–6.82 (m, 2H), 3.87 (s, 2H), 2.92 (s, 2H), 2.08 (s, 2H), 1.66–1.24 (m, 4H); LCMS (m/z) 467.2.

Example 702. 7-Fluoro-1-methyl-5-(5-((1-methylcyclopropyl)ethynyl)-3,4-dihydroquinoline-1 (2H)-yl)-[1,2,4]triazolo[4,3-a]quinazolin

The title compound was prepared according to the general procedure described for Example 719. ¹H NMR (400 MHz, DMSO-d6 ₎ )δ8.38(dd,J＝9.4,4.6Hz,1H),7.87(td,J＝8.7,2.9Hz,1H),7.39(dd,J＝9.6, 2.9Hz,1H),7.14(d,J＝7.5Hz,1H),6.96(t,J＝7.9Hz,1H),6.77(d,J＝8.1Hz,1 H),3.97(t,J＝6.2Hz,2H),3.01(s,3H),2.96(t,J＝6.7Hz,2H),2.10(p,J＝6.5 Hz,2H),1.37(s,3H),1.11–0.94(m,2H),0.91–0.71(m,2H); LCMS(m/z)412.2.

Example 703. 6-Fluoro-1-methyl-5-(5-((1-methylcyclopropyl)ethynyl)-3,4-dihydroquinoline-1 (2H)-yl)-[1,2,4]triazolo[4,3-a]quinazolin

The title compound was prepared according to the general procedure described for Example 719. 1H NMR (400MHz, DMSO-d ₆ )δ8.16(d,J＝8.6Hz,1H),7.99(td,J＝8.4,5.3Hz,1H),7.35(dd,J＝11.8,8.2Hz,1H),7.07(d,J＝7.5Hz,1H),6.89(t,J＝7.9Hz,1H),6.76(d,J＝8. 1Hz,1H),3.87(bs,2H),2.99(s,3H),2.89(bs,2H),2.07(m,2H),1.39–1 .31(m,3H),1.05–0.95(m,2H),0.80(d,J=5.2Hz,2H); LCMS(m/z)412.2.

Example 704. 4-(3-((2,2-difluoroethyl)(6-fluoro-1-methyl-[1,2,4]triazolo[4,3-a]quinazole) (Lin-5-yl)amino)-5-fluorophenyl)-2-methylbut-3-yne-2-ol

Synthesis of N-(3-bromo-5-fluoro-phenyl)-2-chloro-N-(2,2-difluoroethyl)-5-fluoro-quinazoline-4-amine: NaH (60% dispersion in mineral oil) (63 mg, 1.66 mmol) was added in a single addition to a solution of 3-bromo-N-(2,2-difluoroethyl)-5-fluoro-aniline (300 mg, 1.38 mmol) in DMF (2.0 mL) at 0 °C. The mixture was stirred at 0 °C for 30 min, followed by a single addition of 2,4-dichloro-5-fluoro-quinazoline (300 mg, 1.38 mmol), and the mixture was heated to room temperature over 2 hours. After completion, the mixture was poured into water (20 mL) and extracted with ethyl acetate (2 × 20 mL each time). The organic matter was separated, dried over sodium sulfate, filtered, and concentrated under vacuum. The crude product was purified by silica gel column chromatography using 0-40% ethyl acetate in hexane as the eluent. Combine appropriate fractions and concentrate under vacuum to provide the desired compound. (MS(m/z) 435.6 [M+H] ⁺ )

Synthesis of N-(3-bromo-5-fluoro-phenyl)-N-(2,2-difluoroethyl)-5-fluoro-2-hydrazino-quinazoline-4-amine: Anhydrous hydrazine (221 mg, 6.90 mmol) was added to a solution of N-(3-bromo-5-fluoro-phenyl)-2-chloro-N-(2,2-difluoroethyl)-5-fluoro-quinazoline-4-amine (300 mg, 0.69 mmol) in THF (5 mL) and ethanol (5 mL), and the mixture was stirred at room temperature for 5 hours. After completion, the reactants were diluted with dichloromethane and washed with water, followed by brine. The resulting organic compound was dried over _Na₂SO₄ , filtered, and concentrated under reduced pressure to provide the desired compound. _MS (m/z) 431.2 [M+H] ^⁺ .

Synthesis of N-(3-bromo-5-fluoro-phenyl)-N-(2,2-difluoroethyl)-6-fluoro-1-methyl-[1,2,4]triazolo[4,3-a]quinazoline-5-amine: A solution of N-(3-bromo-5-fluoro-phenyl)-N-(2,2-difluoroethyl)-5-fluoro-2-hydrazino-quinazoline-4-amine (106 mg, 0.246 mmol) and triethyl orthoacetate (0.9 g, 5.62 mmol) was heated to 100 °C for 16 hours. After completion, the reactants were cooled to room temperature and concentrated under reduced pressure to provide a crude product. The crude product was ground with heptane, and the solid was collected by filtration, washed with heptane, and dried under vacuum to provide the desired compound. MS (m/z) 455.2 [M+H] ⁺ .

Synthesis of 4-[3-[2,2-difluoroethyl-(6-fluoro-1-methyl-[1,2,4]triazolo[4,3-a]quinazolin-5-yl)amino]-5-fluoro-phenyl]-2-methyl-but-3-yn-2-ol: A solution of N-(3-bromo-5-fluoro-phenyl)-N-(2,2-difluoroethyl)-6-fluoro-1-methyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine (30 mg, 0.066 mmol), zinc bromide (74.4 mg, 0.33 mmol), (1,1'-)bis(diphenylphosphine)ferrocene)palladium(II) dichloride (2.73 mg, 0.00330 mmol) and triethylamine (134 mg, 1.32 mmol) in DMF (2 mL) was purged with nitrogen for 2 min. 2-Methylbut-3-yn-2-ol (16.7 mg, 0.198 mmol) was then added, and the mixture was heated at 100 ° _C for 2 hours. Afterward, the mixture was cooled to room temperature, and ethyl acetate and saturated _NH₄Cl (aqueous solution) were added. The aqueous layer was extracted with EA, and the combined organic layers were dried over _Na₂SO₄ and concentrated under vacuum. The residue was purified by reversed-phase HPLC (acetonitrile/water containing 0.1% trifluoroacetic acid) to provide the title compound as a single TFA salt. 1H NMR (400MHz, DMSO-d ₆ )δ8.17(d,J＝8.5Hz,1H),7.97(td,J＝8.5,5.4Hz,1H),7.29(dd,J＝11.9,8.3Hz,1H),7.10(d,J＝7.6Hz,2H),6.97(d,J＝ 9.0Hz, 1H), 6.53 (tt, J＝55.8, 3.9Hz, 1H), 4.63 (td, J＝14.6, 3.9Hz, 2H), 3.01 (s, 3H), 1.42 (s, 6H); MS (m/z) 458.1 [M+H] ⁺ .

Example 705. 4-(3-((2,2-difluoroethyl)(7-fluoro-1-methyl-[1,2,4]triazolo[4,3-a]quinazole) (Lin-5-yl)amino)-5-fluorophenyl)-2-methylbut-3-yne-2-ol

The title compound was prepared according to the general procedure described for Example 704. ¹H NMR (400 MHz, DMSO- _d₆ ) δ 8.38 (dd, J = 9.4, 4.6 Hz, 1H), 7.84 (td, J = 8.8, 2.9 Hz, 1H), 7.31 (d, J = 10.3 Hz, 1H), 7.23 (s, 1H), 7.15 (d, J = 8.9 Hz, 1H), 7.07 (dd, J = 9.8, 2.9 Hz, 1H), 6.56 (tt, J = 55.7, 4.1 Hz, 1H), 4.58 (td, J = 14.4, 4.0 Hz, 2H), 3.01 (s, 3H), 1.43 (s, 6H); LCMS (m/z) 458.1.

Example 706. N-(2,2-difluoroethyl)-6-fluoro-N-(3-fluoro-5-((1-methylcyclopropyl)ethynyl)benzene 1-Methyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine

The title compound was prepared according to the general procedure described for Example 704. ¹H NMR (400 MHz, DMSO- _d₆ ) δ 8.16 (d, J = 8.6 Hz, 1H), 7.97 (q, J = 8.0 Hz, 1H), 7.29 (dd, J = 12.0, 8.3 Hz, 1H), 7.06 (d, J = 7.1 Hz, 2H), 6.95 (d, J = 9.1 Hz, 1H), 6.74–6.28 (m, 1H), 4.61 (td, J = 14.7, 3.8 Hz, 2H), 3.01 (s, 3H), 1.26 (s, 3H), 0.90 (d, J = 4.6 Hz, 2H), 0.77–0.67 (m, 2H); LCMS (m/z) 454.2.

Example 707. N-(2,2-difluoroethyl)-7-fluoro-N-(3-fluoro-5-((1-methylcyclopropyl)ethynyl)benzene 1-Methyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine

The title compound was prepared according to the general procedure described for Example 704. 1H NMR (400MHz, DMSO-d ₆ )δ8.37(dd,J＝9.4,4.6Hz,1H),7.84(td,J＝8.7,2.8Hz,1H),7.25(d,J＝10.3Hz,1H),7.20(s,1H),7.13(d,J＝9.1Hz,1H),7.07(dd,J＝9.8,2.9H z,1H),6.74–6.27(m,1H),4.57(td,J＝14.4,4.0Hz,2H),3.01(s,3H),1.27(s,3H),1.02–0.90(m,2H),0.73(q,J＝4.1Hz,2H); LCMS(m/z)454.2.

Example 708. N-(2,2-difluoroethyl)-7-fluoro-N-(3-fluoro-5-((1-methylcyclopropyl)ethynyl)benzene 1-Methyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine

The title compound was prepared according to the general procedure described for Example 704. ¹H NMR (400 MHz, DMSO- _d⁶ ) δ 8.17 (d, J = 8.6 Hz, 1H), 7.98 (td, J = 8.3, 5.2 Hz, 1H), 7.30 (dd, J = 12.0, 8.3 Hz, 1H), 7.21 (s, 1H), 7.13 (d, J = 10.7 Hz, 1H), 7.06 (d, J = 8.9 Hz, 1H), 6.80–6.26 (m, 1H), 4.65 (td, J = 14.7, 3.8 Hz, 2H), 3.02 (s, 3H), 1.47 (s, 6H); LCMS (m/z) 510.1.

Example 709. N-(2,2-difluoroethyl)-6-fluoro-N-(3-fluoro-5-((1-(trifluoromethyl)cyclopropyl)acetylene) (1,2,4)triazolo[4,3-a]quinazolin-5-amine

The title compound was prepared according to the general procedure described for Example 704. ¹H NMR (400 MHz, DMSO- _d⁶ ) δ 8.17 (d, J = 8.5 Hz, 1H), 7.97 (q, J = 7.6 Hz, 1H), 7.28 (dd, J = 11.9, 8.3 Hz, 1H), 7.19 (s, 1H), 7.14 (d, J = 10.9 Hz, 1H), 7.07 (d, J = 9.0 Hz, 1H), 6.53 (tt, J = 55.6, 4.0 Hz, 1H), 4.75–4.36 (m, 2H), 3.01 (s, 3H), 1.53–1.15 (m, 4H); LCMS (m/z) 508.1.

Example 710. 4-(1-(6-fluoro-1-methyl-[1,2,4]triazolo[4,3-a]quinazolin-5-yl)-1,2,3, 4-Tetrahydroquinoline-5-yl)-2-methylbut-3-yn-2-ol

The title compound was prepared according to the general procedure described for Example 719. ¹H NMR (400 MHz, DMSO- _d⁶ ) δ 8.17 (d, J = 8.6 Hz, 1H), 7.99 (td, J = 8.4, 5.4 Hz, 1H), 7.35 (dd, J = 11.8, 8.2 Hz, 1H), 7.10 (d, J = 7.5 Hz, 1H), 6.92 (t, J = 7.9 Hz, 1H), 6.79 (d, J = 8.1 Hz, 1H), 3.95 (s, 2H), 3.00 (s, 5H), 2.07 (s, 2H), 1.51 (s, 6H); LCMS (m/z) 416.2.

Example 711. 5-(5-(4,4-difluoro-3,3-dimethylbut-1-yn-1-yl)-3,4-dihydroquinoline-1(2H)- 6-Fluoro-1-methyl-[1,2,4]triazolo[4,3-a]quinazolin

The title compound was prepared according to the general procedure described for Example 719. ¹H NMR (400 MHz, DMSO- _d⁶ ) δ 8.18 (d, J = 8.6 Hz, 1H), 8.01 (td, J = 8.4, 5.3 Hz, 1H), 7.37 (dd, J = 11.8, 8.2 Hz, 1H), 7.14 (d, J = 7.5 Hz, 1H), 6.94 (t, J = 7.9 Hz, 1H), 6.84 (d, J = 8.1 Hz, 1H), 6.09 (t, J = 56.4 Hz, 1H), 4.07 (m, 2H), 3.01 (s, 3H), 2.93 (s, 3H), 2.67 (s, 1H), 1.37 (s, 6H); LCMS (m/z) 450.2.

Example 712. 5-(5-(4,4-difluoro-3,3-dimethylbut-1-yn-1-yl)-3,4-dihydroquinoline-1(2H)- )-7-fluoro-1-methyl-[1,2,4]triazolo[4,3-a]quinazolin

The title compound was prepared according to the general procedure described for Example 719. ¹H NMR (400 MHz, DMSO- _d⁶ ) δ 8.38 (dd, J = 9.4, 4.6 Hz, 1H), 7.87 (ddd, J = 10.5, 7.9, 2.9 Hz, 1H), 7.44 (dd, J = 9.6, 2.9 Hz, 1H), 7.29–7.09 (m, 1H), 6.99 (t, J = 7.9 Hz, 1H), 6.81 (d, J = 8.1 Hz, 1H), 6.09 (t, J = 56.4 Hz, 1H), 3.97 (t, J = 6.2 Hz, 2H), 3.00 (d, J = 6.5 Hz, 5H), 2.16–1.93 (m, 2H), 1.38 (s, 6H); LCMS (m/z) 450.2.

Example 713. 1-(difluoromethyl)-7-fluoro-5-(5-((1-(trifluoromethyl)cyclopropyl)ethynyl)-3,4-di Hydroquinoline-1(2H)-yl)-[1,2,4]triazolo[4,3-a]quinazolin

Synthesis of 5-(5-bromo-3,4-dihydro-2H-quinolin-1-yl)-1-(difluoromethyl)-7-fluoro-[1,2,4]triazolo[4,3-a]quinazoline: 2,2-difluoroacetate (978 mg, 5.62 mmol) was added to [4-(5-bromo-3,4-dihydro-2H-quinolin-1-yl)-6-fluoro-quinazoline-2-yl]hydrazine (170 mg, 0.438 mmol), and the resulting mixture was heated to 50 °C for 10 min. Subsequently, THF (2 mL) was added, and the mixture was heated in a microwave oven to 150 °C for 15 min. The crude mixture was then cooled to room temperature and concentrated under vacuum. The crude product was purified by silica gel column chromatography using 0-70% ethyl acetate in hexane as eluent. Appropriate fractions were combined and concentrated under vacuum to provide the desired compound.

Synthesis of 1-(difluoromethyl)-7-fluoro-5-[5-[2-[1-(trifluoromethyl)cyclopropyl]ethynyl]-3,4-dihydro-2H-quinoline-1-yl]-[1,2,4]triazolo[4,3-a]quinazoline: 5-(5-bromo-3,4-dihydro-2H-quinoline-1-yl)-1-(difluoromethyl)-7-fluoro-[1,2,4]triazolo[4,3-a]quinazoline (30 mg, 0.0669 mmol), zinc bromide (76.4 mg, 0.34 mmol), (1,1'-)bis(diphenylphosphine)ferrocene)palladium(II) dichloride (5.53 mg, 0.00669 mmol) and triethylamine (135 mg, 1.34 mmol) in DMF (2 mL) were purged with nitrogen for 2 min. Then 1-ethynyl-1-(trifluoromethyl)cyclopropane (72 mg, 0.535 mmol) was added and the mixture was heated at 100 °C for 2 hours. The mixture was then cooled to room temperature. Ethyl acetate and saturated _NH₄Cl (aqueous solution) were added to the mixture. The aqueous layer was extracted with ethyl acetate. The combined organic layers were dried over _Na₂SO₄ and concentrated under vacuum. The residue was purified by reversed _- phase HPLC (acetonitrile/water containing 0.1% trifluoroacetic acid) to provide the title compound as a single TFA salt. 1H NMR (400MHz, DMSO-d ₆ )δ8.22(dd,J＝9.4,4.5Hz,1H),8.05–7.62(m,2H),7.48(dd,J＝9.5,2.9Hz,1H),7.17(d,J＝7.3Hz,1H),7.02–6.89(m,2H),3.95( t,J＝6.1Hz,2H),2.98(t,J＝6.7Hz,2H),2.10(p,J＝6.5Hz,2H),1.49(t,J＝3.3Hz,2H),1.43(d,J＝5.1Hz,3H); MS(m/z)502.1[M+H] ⁺ .

Example 714. 4-(6,7-difluoro-[1,2,4]triazolo[4,3-a]quinazolin-5-yl)-8-((1-(trifluoromethyl) (cyclopropyl)ethynyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine

The title compound was prepared according to the general procedure described for Example 724. ¹H NMR (400 MHz, DMSO- _d₆ ) δ 9.79 (s, ¹H), 8.33 (dd, J = 9.5, 4.1 Hz, ¹H), 8.24 (q, J = 9.2 Hz, ¹H), 7.09 (dd, J = 17.8, 7.9 Hz, 2H), 6.73 (t, J = 7.9 Hz, 1H), 4.78–3.82 (m, 4H), 1.50–1.42 (m, 2H), 1.37 (s, 2H); LCMS (m/z) 472.1.

Example 715. 6-Fluoro-1-methyl-5-(5-(4,4,4-trifluoro-3,3-dimethylbut-1-yn-1-yl)-3,4- Dihydroquinoline-1(2H)-yl)-[1,2,4]triazolo[4,3-a]quinazolin

The title compound was prepared according to the general procedure described for Example 719. ¹H NMR (400 MHz, DMSO- _d⁶ ) δ 8.17 (d, J = 8.6 Hz, 1H), 7.99 (td, J = 8.4, 5.3 Hz, 1H), 7.36 (dd, J = 12.0, 8.2 Hz, 1H), 7.14 (d, J = 7.5 Hz, 1H), 6.95 (t, J = 7.9 Hz, 1H), 6.85 (d, J = 8.2 Hz, 1H), 4.01 (m, 2H), 3.00 (s, 3H), 2.90 (m, 2H), 2.08 (m, 2H), 1.55 (s, 6H); LCMS (m/z) 468.2.

Example 716. 6-Fluoro-1-methyl-5-(5-((1-(trifluoromethyl)cyclopropyl)ethynyl)-3,4-dihydroquinone (1,2,4)-[1,2,4]triazolo[4,3-a]quinazolino

The title compound was prepared according to the general procedure described for Example 719. ¹H NMR (400 MHz, DMSO- _d₆ ) δ 8.18 (d, J = 8.6 Hz, 1H), 8.01 (td, J = 8.4, 5.4 Hz, 1H), 7.38 (dd, J = 11.8, 8.2 Hz, 1H), 7.17 (dd, J = 7.6, 1.2 Hz, 1H), 6.96 (t, J = 7.9 Hz, 1H), 6.87 (d, J = 8.1 Hz, 1H), 4.47–3.52 (m, 2H), 3.01 (s, 3H), 2.93 (s, 2H), 2.29–1.68 (m, 2H), 1.53–1.39 (m, 4H); LCMS (m/z) 466.2.

Example 717. 6-Fluoro-1-methyl-5-(5-((1-(trifluoromethyl)cyclopropyl)ethynyl)-3,4-dihydroquinone (1,2,4)-[1,2,4]triazolo[4,3-a]quinazolino

The title compound was prepared according to the general procedure described for Example 722. ¹H NMR (400 MHz, DMSO- _d₆ ) δ 9.79 (s, ¹H), 8.27 (d, J = 8.4 Hz, ¹H), 8.06 (td, J = 8.3, 5.1 Hz, ¹H), 7.45 (dd, J = 12.0, 8.2 Hz, ¹H), 7.10 (dd, J = 7.6, 1.5 Hz, ¹H), 7.03 (dd, J = 8.2, 1.5 Hz, ¹H), 6.71 (t, J = 7.9 Hz, ¹H), 4.44 (s, 2H), 1.50–1.42 (m, 2H), 1.37 (s, 2H); LCMS (m/z) 454.1.

Example 718. 7-Fluoro-1-methyl-5-(5-(4,4,4-trifluoro-3,3-dimethylbut-1-yn-1-yl)-3,4- Dihydroquinoline-1(2H)-yl)-[1,2,4]triazolo[4,3-a]quinazolin

The title compound was prepared according to the general procedure described for Example 719. ¹H NMR (400 MHz, DMSO- _d⁶ ) δ 8.40 (dd, J = 9.4, 4.6 Hz, 1H), 7.89 (ddd, J = 9.3, 7.9, 2.9 Hz, 1H), 7.47 (dd, J = 9.6, 2.9 Hz, 1H), 7.22 (dd, J = 7.6, 1.1 Hz, 1H), 7.02 (t, J = 7.9 Hz, 1H), 6.87 (d, J = 8.2 Hz, 1H), 4.00 (t, J = 6.1 Hz, 2H), 3.01 (d, J = 11.0 Hz, 5H), 2.12 (p, J = 6.5 Hz, 2H), 1.56 (s, 6H); LCMS (m/z) 468.2.

Example 719. 7-Fluoro-1-methyl-5-(5-(4,4,4-trifluoro-3,3-dimethylbut-1-yn-1-yl)-3,4- Dihydroquinoline-1(2H)-yl)-[1,2,4]triazolo[4,3-a]quinazolin

Synthesis of 4-(5-bromo-3,4-dihydroquinoline-1(2H)-yl)-2-chloro-6-fluoroquinazoline (compound 719-1): NaH (60% dispersion in mineral oil) (70 mg, 1.84 mmol) was added in a single addition to a solution of 5-bromo-1,2,3,4-tetrahydroquinoline (195 mg, 0.92 mmol) in DMA (2.0 mL) at 0 °C. The mixture was stirred at 0 °C for 30 min, followed by a single addition of 2,4-dichloro-6-fluoroquinazoline (200 mg, 0.92 mmol). The resulting mixture was heated to room temperature over 16 hours. After completion, the mixture was poured into water (20 mL) and extracted with ethyl acetate (2 × 20 mL each time). The organic matter was separated, dried over sodium sulfate, filtered, and concentrated under vacuum. The crude residue was purified by silica gel column chromatography using 0–40% ethyl acetate in hexane as the eluent. Combine appropriate fractions and concentrate under vacuum to provide the desired compound. (MS(m/z) 393.2 [M+H] ⁺ )

Synthesis of [4-(5-bromo-3,4-dihydro-2H-quinolin-1-yl)-6-fluoro-quinazoline-2-yl]hydrazine (compound 719-2): Anhydrous hydrazine (151 mg, 4.71 mmol) was added to a solution of 4-(5-bromo-3,4-dihydroquinolin-1(2H)-yl)-2-chloro-6-fluoroquinazoline (185 mg, 0.47 mmol) in THF (5 mL) and ethanol (5 mL), and the mixture was stirred at room temperature for 5 hours. After completion, the reaction was diluted with dichloromethane and washed with water, followed by brine. The resulting organic compound was dried over _Na₂SO₄ , filtered, and concentrated under reduced pressure to provide the desired compound. _MS (m/z) 390.4 [M+H] ^⁺ .

Synthesis of 5-(4-bromo-3,4-dihydroquinolin-1(2H)-yl)-7-fluoro-1-methyl-[1,2,4]triazolo[4,3-a]quinazoline (compound 719-3): A solution of [4-(5-bromo-3,4-dihydro-2H-quinolin-1-yl)-6-fluoro-quinazoline-2-yl]hydrazine (400 mg, 1.03 mmol) and triethyl orthoacetate (0.9 g, 5.62 mmol) was heated to 100 °C for 16 hours. The reaction was then cooled to room temperature, and the mixture was concentrated under reduced pressure to provide a crude residue. The residue was ground with heptane, and the solid was collected by filtration, washed with heptane, and dried under vacuum to provide the desired compound. MS (m/z) 412.4, 414.3 [M+H] ⁺ .

Synthesis of 7-fluoro-1-methyl-5-[5-[2-[1-(trifluoromethyl)cyclopropyl]ethynyl]-3,4-dihydro-2H-quinolin-1-yl]-[1,2,4]triazolo[4,3-a]quinazoline: A solution of 5-(5-bromo-3,4-dihydro-2H-quinolin-1-yl)-7-fluoro-1-methyl-[1,2,4]triazolo[4,3-a]quinazoline (26.4 mg, 0.0641 mmol), zinc bromide (72.2 mg, 0.32 mmol), (1,1'-)bis(diphenylphosphine)ferrocene)palladium(II) dichloride (5.3 mg, 0.00641 mmol) and triethylamine (130 mg, 1.28 mmol) in DMF (2 mL) was purged with nitrogen for 2 min. Then, 1-ethynyl-1-(trifluoromethyl)cyclopropane (53 mg, 0.396 mmol) was added and the mixture was heated at 100 °C for 2 hours. The mixture was then cooled to room temperature, and ethyl acetate and saturated _NH₄Cl (aqueous solution) were added. The aqueous layer was extracted with ethyl acetate. _The combined organic layers were dried over _Na₂SO₄ and concentrated under vacuum. The crude residue was purified by reversed-phase HPLC (acetonitrile/water containing 0.1% trifluoroacetic acid) to give the title compound as a single TFA salt. 1HNMR(400MHz,DMSO-d ₆ )δ8.40(dd,J＝9.4,4.6Hz,1H),7.89(ddd,J＝9.3,7.8,2.9Hz,1H),7.45(dd,J＝9.5,2.9Hz,1H),7.22(dd,J＝7.6,1.1Hz,1H),7.02(t,J＝7.9H z,1H),6.87(d,J＝8.1Hz,1H),3.99(t,J＝6.2Hz,2H),3.00(d,J＝10.3Hz,5H),2.11(p,J＝6.5Hz,2H),1.55–1.40(m,4H); MS(m/z)466.2[M+H] ⁺ .

Example 720. 4-(7-fluoro-[1,2,4]triazolo[4,3-a]quinazolin-5-yl)-8-((1-(trifluoromethyl)) Cyclopropyl)ethynyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine

The title compound was synthesized according to the general procedure described for Example 724. ¹H NMR (400 MHz, DMSO- _d₆ ) δ 9.85 (t, J = 2.0 Hz, 1H), 8.54 (dd, J = 9.2, 4.6 Hz, 1H), 8.01 (t, J = 8.8 Hz, 1H), 7.90 (dt, J = 9.5, 2.2 Hz, 1H), 7.13 (dt, J = 7.6, 1.3 Hz, 1H), 7.01 (dt, J = 8.2, 1.6 Hz, 1H), 6.74 (t, J = 7.9 Hz, 1H), 4.51 (t, J = 4.4 Hz, 2H), 4.10 (s, 2H), 1.61–1.42 (m, 2H), 1.42–1.28 (m, 2H); LCMS (m/z) 454.1.

Example 721. 4-(7-fluoro-1-methyl-[1,2,4]triazolo[4,3-a]quinazolin-5-yl)-8-((1-(tri ... (Fluoromethyl)cyclopropyl)ethynyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine

The title compound was synthesized according to the general procedure described for Example 722. ¹H NMR (400 MHz, DMSO- _d₆ ) δ 8.41 (dd, J = 9.2, 4.6 Hz, 1H), 7.99–7.87 (m, 2H), 7.12 (dd, J = 7.6, 1.5 Hz, 1H), 6.92 (dd, J = 8.2, 1.5 Hz, 1H), 6.73 (t, J = 7.9 Hz, 1H), 4.51 (t, J = 4.4 Hz, 2H), 4.08 (d, J = 4.5 Hz, 2H), 3.01 (s, 3H), 1.51–1.39 (m, 2H), 1.38 (d, J = 6.1 Hz, 2H); LCMS (m/z) 468.1.

Example 722. 4-(7-fluoro-1-methyl-[1,2,4]triazolo[4,3-a]quinazolin-5-yl)-8-(4,4,4- (trifluoro-3,3-dimethylbut-1-yn-1-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine

Synthesis of 8-bromo-4-(7-fluoro-1-methyl-[1,2,4]triazolo[4,3-a]quinazolin-5-yl)-2,3-dihydro-1,4-benzoxazine: A solution of [4-(8-bromo-2,3-dihydro-1,4-benzoxazine-4-yl)-6-fluoro-quinazolin-2-yl]hydrazine (350 mg, 0.897 mmol) and triethyl orthoacetate (0.9 g, 5.62 mmol) was heated to 100 °C for 16 hours. The reaction was then cooled to room temperature and concentrated under reduced pressure to provide a crude product. The crude product was ground with heptane, and the solid was collected by filtration, washed with heptane, and dried under vacuum to provide the desired compound. MS (m/z) 414.4, 416.3 [M+H] ⁺ .

Synthesis of 4-(7-fluoro-1-methyl-[1,2,4]triazolo[4,3-a]quinazolin-5-yl)-8-(4,4,4-trifluoro-3,3-dimethyl-but-1-ynyl)-2,3-dihydro-1,4-benzoxazine: A solution of 8-bromo-4-(7-fluoro-1-methyl-[1,2,4]triazolo[4,3-a]quinazolin-5-yl)-2,3-dihydro-1,4-benzoxazine (31.1 mg, 0.0751 mmol), zinc bromide (84.6 mg, 0.376 mmol), (1,1'-)bis(diphenylphosphine)ferrocene)palladium(II) dichloride (6.2 mg, 0.00751 mmol), and triethylamine (152 mg, 1.50 mmol) in DMF (2 mL) was purged with nitrogen for 2 min. Then 4,4,4-trifluoro-3,3-dimethyl-but-1-yne (63 mg, 0.464 mmol) was added and the mixture was heated at 100 ° _C for 2 hours. The mixture was then cooled to room temperature, and ethyl acetate and saturated _NH₄Cl (aqueous solution) were added to the mixture. The aqueous layer was extracted with EA, and the combined organic layers were dried over _Na₂SO₄ and concentrated under vacuum. The residue was purified by reversed-phase HPLC (acetonitrile/water containing 0.1% trifluoroacetic acid) to provide the title compound as a single TFA salt. 1H NMR (400MHz, DMSO-d ₆ )δ8.41(dd,J＝9.3,4.5Hz,1H),7.93(ddd,J＝16.8,8.8,2.9Hz,2H),7.10(dd,J＝7.6,1.5Hz,1H),6.92(dd,J＝8.2,1. 4Hz,1H),6.73(t,J＝7.9Hz,1H),4.52(t,J＝4.4Hz,2H),4.09(s,2H),3.01(s,3H),1.52(s,6H); MS(m/z)470.2[M+H] ⁺ .

Example 723. 4-(4-(7-fluoro-[1,2,4]triazolo[4,3-a]quinazolin-5-yl)-3,4-dihydro-2H-benzene [b][1,4]oxazin-8-yl)-2-methylbut-3-yn-2-ol

The title compound was synthesized according to the general procedure described for Example 724. ¹H NMR (400 MHz, DMSO- _d₆ ) δ 9.80 (s, ¹H), 8.52 (dd, J = 9.1, 4.7 Hz, ¹H), 7.98 (td, J = 8.7, 2.8 Hz, ¹H), 7.86 (dd, J = 9.4, 2.8 Hz, ¹H), 7.04 (dd, J = 7.6, 1.5 Hz, ¹H), 6.97–6.90 (m, ¹H), 6.71 (t, J = 7.9 Hz, ¹H), 4.48 (t, J = 4.5 Hz, 2H), 4.06 (s, 2H), 1.48 (s, 6H); LCMS (m/z) 404.1.

Example 724. 4-(7-fluoro-[1,2,4]triazolo[4,3-a]quinazolin-5-yl)-8-(4,4,4-trifluoro-3, (3-Dimethylbut-1-yn-1-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine

Synthesis of 8-bromo-4-(2-chloro-6-fluoroquinazoline-4-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine: NaH (60% dispersion in mineral oil) (212 mg, 0.55 mmol) was added in a single addition to a solution of 8-bromo-3,4-dihydro-2H-1,4-benzoxazine (569 mg, 0.27 mmol) in DMA (2.0 mL) at 0 °C. The mixture was stirred at 0 °C for 30 min, followed by a single addition of 2,4-dichloro-6-fluoroquinazoline (600 mg, 0.27 mmol), and the mixture was heated to room temperature over 16 hours. After completion, the mixture was poured into water (20 mL) and extracted with ethyl acetate (2 × 20 mL each time). The organic matter was separated, dried over sodium sulfate, filtered, and concentrated under vacuum. The crude product was purified by silica gel column chromatography using 0-40% ethyl acetate in hexane as the eluent. Combine appropriate fractions and concentrate under vacuum to provide the desired compound. MS (m/z) 395.2 [M+H] ⁺ .

Synthesis of [4-(8-bromo-2,3-dihydro-1,4-benzoxazin-4-yl)-6-fluoro-quinazoline-2-yl]hydrazine: Anhydrous hydrazine (642 mg, 20.0 mmol) was added to a solution of 8-bromo-4-(2-chloro-6-fluoroquinazoline-4-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine (790 mg, 2.0 mmol) in THF (10 mL) and ethanol (10 mL), and the mixture was stirred at room temperature for 30 min. After completion, the reactants were diluted with dichloromethane and washed with water, followed by brine. The resulting organic compound was dried over _Na₂SO₄ , filtered, and concentrated under reduced pressure to provide the desired compound. _MS (m/z) 391.5, 393.5 [M+H] ^⁺ .

8-Bromo-4-(7-fluoro-[1,2,4]triazolo[4,3-a]quinazolin-5-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine: A solution of [4-(8-bromo-2,3-dihydro-1,4-benzoxazine-4-yl)-6-fluoro-quinazolin-2-yl]hydrazine (350 mg, 0.897 mmol) and triethyl orthoformate (0.8 g, 5.62 mmol) was heated to 100 °C for 16 hours. After completion, the reactants were cooled to room temperature and concentrated under reduced pressure to provide a crude product. The crude product was ground with heptane, and the solid was collected by filtration, washed with heptane, and dried under vacuum to provide the desired compound. MS (m/z) 399.7, 401.2 [M+H] ⁺ .

Synthesis of 4-(7-fluoro-[1,2,4]triazolo[4,3-a]quinazolin-5-yl)-8-(4,4,4-trifluoro-3,3-dimethylbut-1-yn-1-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine: 8-bromo-4-(7-fluoro-[1,2,4]triazolo[4,3-a]quinazolin-5-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine A solution of [b][1,4]oxazine (30.1 mg, 0.0751 mmol), zinc bromide (84.6 mg, 0.376 mmol), (1,1'-)bis(diphenylphosphine)ferrocene)palladium(II) dichloride (6.2 mg, 0.00751 mmol), and triethylamine (152 mg, 1.50 mmol) in DMF (2 mL) was purged with nitrogen for 2 min. Then, 4,4,4-trifluoro-3,3-dimethyl-but-1-yne (63 mg, 0.464 mmol) was added, and the mixture was heated at 100 °C for 2 h. After completion, the mixture was cooled to room temperature, and ethyl acetate and saturated _NH₄Cl (aqueous solution) were added. The aqueous layer was extracted with EA, and the combined organic layers were dried over _Na₂SO₄ and concentrated under vacuum. The residue was purified by reversed _- phase HPLC (acetonitrile/water containing 0.1% trifluoroacetic acid) to provide the title compound. 1H NMR (400MHz, DMSO-d ₆ )δ9.82(s,1H),8.53(dd,J＝9.2,4.7Hz,1H),7.99(td,J＝8.6,2.7Hz,1H),7.89(dd,J＝9.5,2.8Hz,1H),7.09(dd,J＝7.6,1.5Hz,1H ),6.98(dd,J＝8.3,1.5Hz,1H),6.73(t,J＝7.9Hz,1H),4.54–4.47(m,2H),4.08(t,J＝4.3Hz,2H),1.52(s,6H); MS(m/z)456.1[M+H] ⁺ .

Example 725. 6-Fluoro-5-(5-((1-methylcyclopropyl)ethynyl)-3,4-dihydroquinoline-1(2H)-yl)- [1,2,4]triazolo[4,3-a]quinazolin

The title compound was synthesized according to the general procedure described for Example 730. 1H NMR (400MHz, DMSO-d ₆ )δ9.79(s,1H),8.24(d,J＝8.3Hz,1H),8.01(td,J＝8.3,5.1Hz,1H),7.31(dd,J＝11.9,8.2Hz,1H),7.06(dd,J＝7.5,1.2Hz,1H),6.89(t,J＝7.8Hz,1H) ,6.85–6.77(m,1H),4.13–3.66(m,2H),3.04–2.76(m,2H),2.06(m,2H),1. 36 (s, 3H), 0.98 (q, J = 4.0Hz, 2H), 0.79 (q, J = 4.1Hz, 2H); LCMS (m/z) 398.1.

Example 726. 4-(1-(6-fluoro-[1,2,4]triazolo[4,3-a]quinazolin-5-yl)-1,2,3,4-tetrahydroquinoline (5-yl)-2-methylbut-3-yn-2-ol

The title compound was synthesized according to the general procedure described for Example 730. ¹H NMR (400 MHz, DMSO- _d⁶ ) δ 9.79 (s, ¹H), 8.24 (d, J = 8.3 Hz, ¹H), 8.01 (td, J = 8.3, 5.1 Hz, ¹H), 7.31 (dd, J = 12.0, 8.2 Hz, ¹H), 7.17–7.04 (m, ¹H), 6.98–6.77 (m, 2H), 3.89 (s, 2H), 3.05–2.78 (m, 2H), 2.24–1.95 (m, 2H), 1.51 (s, 6H); LCMS (m/z) 402.1.

Example 727. 6-Fluoro-5-(5-(4,4,4-trifluoro-3,3-dimethylbut-1-yn-1-yl)-3,4-dihydroquinone (1,2,4)-[1,2,4]triazolo[4,3-a]quinazolino

The title compound was synthesized according to the general procedure described for Example 730. ¹H NMR (400 MHz, DMSO- _d⁶ ) δ 9.81 (s, ¹H), 8.25 (d, J = 8.3 Hz, ¹H), 8.03 (td, J = 8.3, 5.1 Hz, ¹H), 7.33 (dd, J = 12.0, 8.2 Hz, ¹H), 7.14 (dd, J = 7.2, 1.5 Hz, ¹H), 7.06–6.82 (m, 2H), 3.9 (m, 2H), 2.92 (tt, J = 15.2, 7.7 Hz, 2H), 2.22–1.79 (m, 2H), 1.55 (s, 6H); LCMS (m/z) 454.2.

Example 728. 6-Fluoro-5-(5-((1-(trifluoromethyl)cyclopropyl)ethynyl)-3,4-dihydroquinoline-1(2H)- (-[1,2,4]triazolo[4,3-a]quinazolin)

The title compound was synthesized according to the general procedure described for Example 730. ¹H NMR (400 MHz, DMSO- _d₆ ) δ 9.80 (s, ¹H), 8.25 (d, J = 8.3 Hz, ¹H), 8.02 (td, J = 8.3, 5.1 Hz, ¹H), 7.32 (dd, J = 12.0, 8.2 Hz, ¹H), 7.14 (dd, J = 7.2, 1.5 Hz, ¹H), 7.01–6.74 (m, 2H), 3.9 (m, 2H), 2.92 (m, 2H), 2.08 (m, 2H), 1.67–1.26 (m, 4H); LCMS (m/z) 452.1.

Example 729. 7-Fluoro-5-(5-(4,4,4-trifluoro-3,3-dimethylbut-1-yn-1-yl)-3,4-dihydroquinone (1,2,4)-[1,2,4]triazolo[4,3-a]quinazolino

The title compound was synthesized according to the general procedure described for Example 730. ¹H NMR (400 MHz, DMSO- _d₆ ) δ 9.84 (s, ¹H), 8.51 (dd, J = 9.2, 4.7 Hz, ¹H), 7.95 (td, J = 8.6, 2.8 Hz, ¹H), 7.39 (dd, J = 9.7, 2.8 Hz, ¹H), 7.20 (dd, J = 7.6, 1.2 Hz, ¹H), 7.01 (t, J = 7.9 Hz, ¹H), 6.92 (dd, J = 8.3, 1.1 Hz, ¹H), 3.98 (t, J = 6.2 Hz, 2H), 2.98 (t, J = 6.7 Hz, 2H), 2.11 (p, J = 6.4 Hz, 2H), 1.55 (s, 6H); LCMS (m/z) 454.2.

Example 730. 7-Fluoro-5-(5-((1-(trifluoromethyl)cyclopropyl)ethynyl)-3,4-dihydroquinoline-1(2H)- (-[1,2,4]triazolo[4,3-a]quinazolin)

5-(5-bromo-3,4-dihydroquinolin-1(2H)-yl)-7-fluoro-[1,2,4]triazolo[4,3-a]quinazoline: A solution of [4-(5-bromo-3,4-dihydro-2H-quinolin-1-yl)-6-fluoro-quinazoline-2-yl]hydrazine (300 mg, 0.77 mmol) and triethyl orthoformate (1.4 g, 9.3 mmol) was heated to 100 °C for 12 hours. After completion, the reactants were cooled to room temperature and concentrated under reduced pressure to provide a crude product. The crude product was ground with heptane, and the solid was collected by filtration, washed with heptane, and dried under vacuum to provide the title compound. MS (m/z) 400.8 [M+H] ⁺ .

Synthesis of 7-fluoro-5-(5-((1-(trifluoromethyl)cyclopropyl)ethynyl)-3,4-dihydroquinoline-1(2H)-yl)-[1,2,4]triazolo[4,3-a]quinazoline: A solution of 5-(3,4-dihydroquinoline-1(2H)-yl)-7-fluoro-1-methyl-[1,2,4]triazolo[4,3-a]quinazoline (30 mg, 0.0753 mmol), zinc bromide (84.8 mg, 0.377 mmol), (1,1'-)bis(diphenylphosphine)ferrocene)palladium(II) dichloride (6.23 mg, 0.00753 mmol) and triethylamine (152 mg, 1.51 mmol) in DMF (2 mL) was purged with nitrogen for 2 min. Then, 1-ethynyl-1-(trifluoromethyl)cyclopropane (80.8 mg, 0.603 mol) was added, and the mixture was heated at 100 ° _C for 10 min. Afterward, the mixture was cooled to room temperature, and ethyl acetate and saturated _NH₄Cl (aqueous solution) were added to the mixture. The aqueous layer was extracted with EA, and the combined organic layers were dried over _Na₂SO₄ and concentrated under vacuum. The residue was purified by reversed-phase HPLC (acetonitrile/water containing 0.1% trifluoroacetic acid) to provide the title compound as a single TFA salt: ^¹H NMR (400 MHz, DMSO-d₆ ₎ )δ9.84(s,1H),8.51(dd,J＝9.2,4.7Hz,1H),8.08–7.79(m,1H),7.37(dd,J＝9 .7,2.8Hz,1H),7.20(dd,J＝7.5,1.2Hz,1H),7.01(t,J＝7.9Hz,1H),6.92(dd, J＝8.2,1.2Hz,1H),3.98(t,J＝6.2Hz,2H),2.98(t,J＝6.7Hz,2H),2.10(p,J＝6 .5Hz, 2H), 1.50 (td, J＝6.2, 2.0Hz, 2H), 1.47–1.33 (m, 2H); LCMS (m/z) 452.1.

Example 731. 7-Fluoro-5-(5-((1-(trifluoromethyl)cyclopropyl)ethynyl)-3,4-dihydroquinoline-1(2H)- (-[1,2,4]triazolo[4,3-a]quinazolin)

The title compound was synthesized according to the general procedure described for Example 453. ¹H NMR (400 MHz, DMSO- _d⁶ ) δ 9.82 (s, ¹H), 8.24 (d, J = 8.3 Hz, ¹H), 8.01 (td, J = 8.3, 5.1 Hz, ¹H), 7.32–7.16 (m, 2H), 7.13 (t, J = 1.7 Hz, 1H), 7.01 (dt, J = 9.1, 1.7 Hz, 1H), 4.21 (q, J = 6.9 Hz, 2H), 1.42–1.06 (m, 6H), 0.90 (q, J = 4.0 Hz, 2H), 0.85–0.63 (m, 2H); LCMS (m/z) 404.1.

Example 732. N-Ethyl-6-fluoro-N-(3-fluoro-5-((1-(trifluoromethyl)cyclopropyl)ethynyl)phenyl)-[1, [2,4]triazolo[4,3-a]quinazolin-5-amine

The title compound was synthesized according to the general procedure described for Example 453. ¹H NMR (400 MHz, DMSO- _d₆ ) δ 9.83 (s, ¹H), 8.24 (d, J = 8.3 Hz, ¹H), 8.01 (td, J = 8.3, 5.1 Hz, ¹H), 7.40–7.20 (m, 3H), 7.14 (dt, J = 9.2, 1.7 Hz, 1H), 4.22 (q, J = 6.9 Hz, 2H), 1.43 (dt, J = 6.5, 3.3 Hz, 2H), 1.38–1.31 (m, 2H), 1.23 (t, J = 6.9 Hz, 3H); LCMS (m/z) 458.1.

Example 733. 6-Fluoro-N-(3-Fluoro-5-(4,4,4-trifluoro-3,3-dimethylbut-1-yn-1-yl)phenyl)-N- Methyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine

The title compound was synthesized according to the general procedure described for Example 453. ¹H NMR (400 MHz, DMSO- _d⁶ ) δ 9.81 (s, ¹H), 8.25 (d, J = 8.3 Hz, ¹H), 8.01 (td, J = 8.3, 5.1 Hz, ¹H), 7.42–7.18 (m, ³H), 7.09 (dt, J = 8.6, 1.9 Hz, ¹H), 3.58 (s, ³H), 1.46 (s, ⁶H); LCMS (m/z) 446.1.

Example 734. 6-Fluoro-N-(3-Fluoro-5-((1-(trifluoromethyl)cyclopropyl)ethynyl)phenyl)-N-methyl- [1,2,4]triazolo[4,3-a]quinazolin-5-amine

The title compound was synthesized according to the general procedure described for Example 453. ¹H NMR (400 MHz, DMSO- _d₆ ) δ 9.83 (s, ¹H), 8.25 (d, J = 8.3 Hz, ¹H), 8.01 (td, J = 8.3, 5.1 Hz, ¹H), 7.36–7.20 (m, 3H), 7.12 (dt, J = 9.0, 1.7 Hz, 1H), 3.58 (s, 3H), 1.43 (dt, J = 6.6, 3.5 Hz, 2H), 1.36 (dt, J = 8.5, 5.7 Hz, 2H); LCMS (m/z) 444.1.

Example 735. 6,7-Difluoro-N-methyl-N-(3-((1-(trifluoromethyl)cyclopropyl)ethynyl)phenyl)-[1, [2,4]triazolo[4,3-a]quinazolin-5-amine

The title compound was synthesized according to the general procedure described for Example 453. ¹H NMR (400 MHz, DMSO- _d₆ ) δ 9.78 (s, ¹H), 8.28 (ddd, J = 9.3, 4.3, 1.4 Hz, ¹H), 8.15 (td, J = 9.6, 7.7 Hz, ¹H), 7.46 (d, J = 1.9 Hz, ¹H), 7.34–7.16 (m, 3H), 3.57 (s, 3H), 1.42 (h, J = 3.3, 2.8 Hz, 2H), 1.41–1.30 (m, 2H); LCMS (m/z) 444.1.

Example 736. 6,7-Difluoro-N-methyl-N-(3-((1-methylcyclopropyl)ethynyl)phenyl)-[1,2,4]tri Azo[4,3-a]quinazolin-5-amine

The title compound was synthesized according to the general procedure described for Example 453. ¹H NMR (400 MHz, DMSO- _d₆ ) δ 9.78 (s, ¹H), 8.37–8.22 (m, ¹H), 8.15 (q, J = 9.2 Hz, ¹H), 7.33 (t, J = 1.9 Hz, ¹H), 7.24 (dd, J = 9.0, 6.6 Hz, ¹H), 7.17 (dd, J = 6.8, 1.8 Hz, 2H), 3.56 (s, 3H), 1.27 (s, 3H), 0.90 (q, J = 3.9 Hz, 2H), 0.76–0.58 (m, 2H); LCMS (m/z) 390.1.

Example 737. N-(3-(3,3-dimethylbut-1-yn-1-yl)phenyl)-6,7-difluoro-N-methyl-[1,2,4] Triazolo[4,3-a]quinazolin-5-amine

The title compound was synthesized according to the general procedure described for Example 453. ¹H NMR (400 MHz, DMSO- _d₆ ) δ 9.77 (s, ¹H), 8.33–8.22 (m, ¹H), 8.15 (q, J = 9.0 Hz, ¹H), 7.34 (t, J = 1.9 Hz, ¹H), 7.23 (t, J = 7.8 Hz, ¹H), 7.16 (ddt, J = 9.3, 8.0, 1.5 Hz, 2H), 3.51 (s, 3H), 1.26 (s, 9H); LCMS (m/z) 392.1.

Example 738. 6,7-Difluoro-N-(3-fluoro-5-((1-(trifluoromethyl)cyclopropyl)ethynyl)phenyl)-N-methyl [1,2,4]triazolo[4,3-a]quinazolin-5-amine

The title compound was synthesized according to the general procedure described for Example 453. ¹H NMR (400 MHz, DMSO- _d₆ ) δ 9.80 (s, ¹H), 8.30 (ddd, J = 9.3, 4.4, 1.4 Hz, ¹H), 8.20–8.10 (m, ¹H), 7.34–7.24 (m, 2H), 7.11 (dt, J = 8.8, 1.8 Hz, ¹H), 3.56 (s, 3H), 1.56–1.21 (m, 4H); LCMS (m/z) 462.1.

Example 739. 6,7-Difluoro-N-(3-fluoro-5-((1-methylcyclopropyl)ethynyl)phenyl)-N-methyl-[1, [2,4]triazolo[4,3-a]quinazolin-5-amine

The title compound was synthesized according to the general procedure described for Example 421. ¹H NMR (400 MHz, DMSO- _d₆ ) δ 9.80 (s, ¹H), 8.30 (ddd, J = 9.2, 4.4, 1.5 Hz, ¹H), 8.18 (td, J = 9.6, 7.7 Hz, ¹H), 7.30–7.12 (m, 2H), 7.10–6.94 (m, ¹H), 3.55 (s, 3H), 1.27 (s, 3H), 0.91 (q, J = 4.0 Hz, 2H), 0.72 (q, J = 4.1 Hz, 2H); LCMS (m/z) 408.1.

Example 740. N-Ethyl-7-fluoro-N-(3-fluoro-5-(4,4,4-trifluoro-3,3-dimethylbut-1-yn-1-yl)benzene (-[1,2,4]triazolo[4,3-a]quinazolin-5-amine)

The title compound was synthesized according to the general procedure described for Example 421. ¹H NMR (400 MHz, DMSO- _d⁶ ) δ 9.82 (s, ¹H), 8.49 (dd, J = 9.2, 4.8 Hz, ¹H), 8.06–7.72 (m, ¹H), 7.45 (dt, J = 10.1, 2.3 Hz, ¹H), 7.39 (d, J = 1.6 Hz, ¹H), 7.35–7.29 (m, ¹H), 6.94 (dd, J = 10.1, 2.8 Hz, ¹H), 4.18 (q, J = 6.9 Hz, 2H), 1.48 (s, 6H), 1.25 (t, J = 6.9 Hz, 3H); LCMS (m/z) 460.2.

Example 741. N-Methyl-7-fluoro-N-(3-fluoro-5-(4,4,4-trifluoro-3,3-dimethylbut-1-yn-1-yl)benzene (-[1,2,4]triazolo[4,3-a]quinazolin-5-amine)

The title compound was synthesized according to the general procedure described for Example 421. ¹H NMR (400 MHz, DMSO- _d₆ ) δ 9.81 (s, ¹H), 8.49 (dd, J = 9.2, 4.8 Hz, ¹H), 7.92 (ddd, J = 9.1, 8.1, 2.8 Hz, ¹H), 7.65–7.33 (m, 2H), 7.34–7.16 (m, ¹H), 7.01 (dd, J = 10.0, 2.8 Hz, ¹H), 3.59 (s, 3H), 1.47 (s, 6H); LCMS (m/z) 446.1.

Example 742. N-Ethyl-7-fluoro-N-(3-fluoro-5-((1-(trifluoromethyl)cyclopropyl)ethynyl)phenyl)-[1, [2,4]triazolo[4,3-a]quinazolin-5-amine

The title compound was synthesized according to the general procedure described for Example 447. 1H NMR (400MHz, DMSO-d ₆ )δ9.88–9.78(m,1H),8.49(dd,J＝9.2,4.8Hz,1H),7.93(td,J＝8.6,2.8Hz ,1H),7.46(dt,J＝9.9,2.0Hz,1H),7.39(d,J＝1.7Hz,1H),7.34(dd,J＝8.9, 2.0Hz, 1H), 6.93 (dd, J＝10.1, 2.8Hz, 1H), 4.18 (q, J＝6.9Hz, 2H), 1.50–1.42 (m, 2H), 1.39 (d, J＝6.0Hz, 2H), 1.25 (t, J＝6.9Hz, 3H); LCMS (m/z) 458.1.

Example 743. N-Ethyl-7-fluoro-N-(3-fluoro-5-((1-methylcyclopropyl)ethynyl)phenyl)-[1,2,4]tri Azo[4,3-a]quinazolin-5-amine

The title compound was synthesized according to the general procedure described for Example 447. ¹H NMR (400 MHz, DMSO- _d₆ ) δ 9.78 (s, ¹H), 8.47 (dd, J = 9.1, 4.8 Hz, ¹H), 7.97–7.81 (m, ¹H), 7.36–7.31 (m, ¹H), 7.24 (d, J = 2.1 Hz, ¹H), 7.18 (d, J = 9.0 Hz, ¹H), 6.92 (dd, J = 10.1, 2.8 Hz, ¹H), 4.15 (q, J = 6.9 Hz, 2H), 1.28 (s, 3H), 1.24 (t, J = 7.0 Hz, 3H), 0.93 (q, J = 4.0 Hz, 2H), 0.74 (q, J = 4.1 Hz, 2H); LCMS (m/z) 404.2.

Example 744. N-Ethyl-7-fluoro-1-methyl-N-[3-[2-(1-methylcyclopropyl)ethynyl]phenyl]-[1,2, 4] Triazolo[4,3-a]quinazolin-5-amine

Synthesis of 2-chloro-N-ethyl-6-fluoro-N-(3-iodophenyl)quinazoline-4-amine: 2,4-dichloro-6-fluoro-quinazoline (700 mg, 3.23 mmol) and N,N-diisopropylamine (1042 mg, 8.06 mmol) were added to a solution of N-ethyl-3-iodoaniline (752 mg, 3.04 mmol) in DMF (5.0 mL) at 0 °C. The mixture was stirred at 40 °C for 2 hours. After stirring, the mixture was poured into water (100 mL) and extracted with ethyl acetate (2 × 50 mL each time). The organic matter was separated, dried over sodium sulfate, filtered, and concentrated under vacuum. The crude product was ground with heptane, and the solid was filtered to provide the desired compound. MS (m/z) 428.6 [M+H] ⁺ .

Synthesis of N-ethyl-6-fluoro-2-hydrazino-N-(3-iodophenyl)quinazoline-4-amine: Anhydrous hydrazine (914 mg, 28.5 mmol) was added to a solution of 2-chloro-N-ethyl-6-fluoro-N-(3-iodophenyl)quinazoline-4-amine (1132 mg, 2.65 mmol) in THF (10 mL) and ethanol (10 mL), and the mixture was stirred at room temperature for 30 minutes. After completion, the reactants were diluted with ethyl acetate and washed with water, dried over _Na₂SO₄ , and concentrated under reduced pressure to provide the desired compound. _MS (m/z) 425.5 [M+H] ^⁺ .

Synthesis of N-ethyl-7-fluoro-N-(3-iodophenyl)-1-methyl-[1,2,4]triazolo[4,3-a]quinazoline-5-amine: A solution of N-ethyl-6-fluoro-2-hydrazino-N-(3-iodophenyl)quinazoline-4-amine (450 mg, 1.06 mmol) and triethyl orthoacetate (1.9 g, 11.7 mmol) was heated to 100 °C for 1 hour. After completion, the reactants were cooled to room temperature and concentrated under reduced pressure to provide a crude product. The crude product was ground with heptane, and the solid was collected by filtration, washed with heptane, and dried under vacuum to provide the desired compound. MS (m/z) 448.2 [M+H] ⁺ .

Synthesis of N-ethyl-7-fluoro-1-methyl-N-[3-[2-(1-methylcyclopropyl)ethynyl]phenyl]-[1,2,4]triazolo[4,3-a]quinazolin-5-amine: 1-ethynyl-1-methyl-cyclopropane (5.6 mg, 0.07 mmol), Pd(PPh3)2Cl2 (1.57 mg, 2.2 μmol), CuI (0.3 mg, 0.002 mmol), and triethylamine (0.2 mL, 1.12 mmol) were added to a solution of N-ethyl-7-fluoro-N-( _3- iodophenyl) _-1 -methyl-[1,2,4] _triazolo [4,3-a]quinazolin-5-amine (25 mg, 0.0559 mmol) in DMF (2 mL). The mixture was purged with nitrogen and heated at 84 °C for 10 min. After completion, the mixture was partitioned between EA (20 mL) and water (20 mL) to separate the organic matter, _which was then dried over _Na₂SO₄ and concentrated under vacuum. The residue was purified by reversed-phase HPLC (acetonitrile/water containing 0.1% trifluoroacetic acid) to provide the title compound as a single TFA salt. 1H NMR (400MHz, DMSO-d ₆ )δ8.37(dd,J＝9.4,4.7Hz,1H),7.83(ddd,J＝10.1,7.7,2.9Hz,1H),7.47–7.33(m,4H),6.90(dd,J＝10.3,2.9Hz,1H),4.18(q,J＝ 6.9Hz,2H),3.00(s,3H),1.28(s,3H),1.24(t,J＝7.0Hz,3H),0.92(q,J＝4.0Hz,2H),0.73(q,J＝4.1Hz,2H); MS(m/z)400.1[M+H] ⁺ .

Example 745. N-Ethyl-7-fluoro-N-(3-((1-methylcyclopropyl)ethynyl)phenyl)-[1,2,4]triazolidine [4,3-a]quinazolin-5-amine

The title compound was synthesized according to the general procedure described for Example 447. ¹H NMR (400 MHz, DMSO- _d₆ ) δ 9.82 (s, ¹H), 8.48 (dd, J = 9.2, 4.9 Hz, ¹H), 7.98–7.85 (m, ¹H), 7.51–7.30 (m, 4H), 6.76 (dd, J = 10.5, 2.8 Hz, ¹H), 4.17 (q, J = 7.0 Hz, 2H), 1.29 (s, 3H), 1.24 (t, J = 6.9 Hz, 3H), 0.93 (q, J = 4.0 Hz, 2H), 0.73 (q, J = 4.0 Hz, 2H); LCMS (m/z) 386.2.

Example 746. N-Ethyl-7-fluoro-N-(3-((1-methylcyclopropyl)ethynyl)phenyl)-[1,2,4]triazolidine [4,3-a]quinazolin-5-amine

The title compound was synthesized according to the general procedure described for Example 447. ¹H NMR (400 MHz, DMSO- _d⁶ ) δ 9.76 (s, ¹H), 8.63 (d, J = 2.1 Hz, ¹H), 7.47 (dd, J = 9.0, 2.1 Hz, ¹H), 7.43–7.36 (m, ¹H), 7.33–7.23 (m, 2H), 7.18 (d, J = 9.1 Hz, ¹H), 4.17 (q, J = 7.0 Hz, 2H), 1.42 (s, 6H), 1.23 (t, J = 6.9 Hz, 3H); LCMS (m/z) 424.1.

Example 747. 2,2,2-Trifluoro-N-[3-[7-fluoro-1-(7-fluoro-1-methyl-[1,2,4]triazolo[4,3-a]] Quinazolin-5-yl]-3,4-dihydro-2H-quinolin-5-yl]-1,1-dimethyl-prop-2-ynyl]acetamide

Step 1: Synthesis of N-[3-[7-fluoro-1-(7-fluoro-1-methyl-[1,2,4]triazolo[4,3-a]quinazolin-5-yl)-3,4-dihydro-2H-quinolin-5-yl]-1,1-dimethyl-prop-2-ynyl] tert-butyl carbamate. 5-(5-bromo-7-fluoro-3,4-dihydro-2H-quinolin-1-yl)-7-fluoro-1-methyl-[1,2,4]triazolo[4,3-a]quinazolin (90 mg, 209 μmol) and N-(1,1-dimethylprop-2-ynyl) tert-butyl carbamate (153 mg, 837 μmol) were dissolved in N-methyl-2-pyrrolidone (2 ml). Add zinc bromide (236 mg, 1050 μmol), (1,1'-bis(diphenylphosphine)ferrocene)palladium(II) dichloride (17 mg, 21 μmol), and triethylamine (0.44 mL, 3140 μmol). Blow the mixture through a bubbling process with _N₂ for 1 minute, then heat at 105 °C for 14 hours. Cool the mixture to room temperature and add ethyl acetate and water. Concentrate the organic layer under vacuum. Use the residue directly in the next step.

Step 2: Synthesis of 2,2,2-trifluoro-N-[3-[7-fluoro-1-(7-fluoro-1-methyl-[1,2,4]triazolo[4,3-a]quinazolin-5-yl)-3,4-dihydro-2H-quinolin-5-yl]-1,1-dimethyl-prop-2-ynyl]acetamide. DCM (4 ml) was added to the crude residue obtained above and cooled to 0 °C. TFA (2 ml) was slowly added. After stirring at room temperature for 1 hour, the reaction mixture was concentrated to dryness by several co-evaporations with DCM. DCM (4 ml) was added to the crude residue, followed by triethylamine (0.23 ml, 1.67 mmol) and acetyl chloride (0.06 ml, 0.84 mmol) at 0 °C. After stirring at room temperature for 1 hour, the reaction was quenched with water (1 ml). The reaction mixture was diluted with EtOAc, washed with water and brine, dried, and concentrated. The crude product was purified by column chromatography using a 0-15% MeOH solution in DCM. Fractions containing the desired product were collected and concentrated. Further purification was performed by reversed-phase HPLC to obtain the desired product. ^¹H NMR (400 MHz, methanol- _d⁴ ) δ 8.48 (m, 1H), 7.85 (m, 1H), 7.47 (m, 1H), 7.03 (m, 1H), 6.73 (m, 1H), 4.14 (m, 2H), 3.11 (s, 3H), 3.07 (m, 2H), 2.21 (m, 2H), 1.79 (s, 6H); LCMS (m/z) 529.4.

Example 748. 7-Fluoro-5-(7-Fluoro-5-(4,4,4-trifluoro-3,3-dimethylbut-1-yn-1-yl)-3,4-di Hydroquinoline-1(2H)-yl)-1-methyl-[1,2,4]triazolo[4,3-a]quinazolin

The title compound was synthesized according to the general procedure described for Example 421. ^¹H NMR (400 MHz, methanol- _d⁴ ) δ 8.52 (dd, J = 9.4, 4.4 Hz, 1H), 7.90 (ddd, J = 9.4, 7.5, 2.8 Hz, 1H), 7.49 (dd, J = 9.3, 2.9 Hz, 1H), 7.11 (dd, J = 8.7, 2.6 Hz, 1H), 6.85 (dd, J = 10.0, 2.5 Hz, 1H), 4.20 (t, J = 6.4 Hz, 2H), 3.13 (s, 3H), 3.12–3.04 (m, 2H), 2.22 (m, 2H), 1.60 (s, 6H); LCMS (m/z) 486.4.

Example 749. 7-Fluoro-5-(7-Fluoro-5-((1-(trifluoromethyl)cyclopropyl)ethynyl)-3,4-dihydroquinoline-1 (2H)-yl)-1-methyl-[1,2,4]triazolo[4,3-a]quinazolin

The title compound was synthesized according to the general procedure described for Example 421. ^¹H NMR (400 MHz, methanol- _d⁴ ) δ 8.52 (dd, J = 9.4, 4.4 Hz, 1H), 7.90 (ddd, J = 9.4, 7.5, 2.9 Hz, 1H), 7.48 (dd, J = 9.3, 2.8 Hz, 1H), 7.11 (dd, J = 8.8, 2.6 Hz, 1H), 6.84 (dd, J = 9.9, 2.5 Hz, 1H), 4.20 (t, J = 6.4 Hz, 2H), 3.13 (s, 3H), 3.11–3.05 (m, 2H), 2.22 (p, J = 6.5 Hz, 2H), 1.54–1.48 (m, 2H), 1.46–1.35 (m, 2H); LCMS (m/z) 484.4.

Example 750. 7-Fluoro-5-(7-Fluoro-5-(4,4,4-trifluoro-3,3-dimethylbut-1-yn-1-yl)-3,4-di Hydroquinoline-1(2H)-yl)-[1,2,4]triazolo[4,3-a]quinazolin

The title compound was synthesized according to the general procedure described for Example 421. ^¹H NMR (400 MHz, methanol- _d⁴ ) δ 9.72 (s, 1H), 8.49 (dd, J = 9.2, 4.6 Hz, 1H), 7.91 (m, 1H), 7.42 (dd, J = 9.4, 2.7 Hz, 1H), 7.11 (dd, J = 8.8, 2.5 Hz, 1H), 6.89 (dd, J = 9.9, 2.5 Hz, 1H), 4.21 (t, J = 6.4 Hz, 2H), 3.08 (t, J = 6.6 Hz, 2H), 2.22 (p, J = 6.5 Hz, 2H), 1.60 (s, 6H); LCMS (m/z) 472.4.

Example 751. 5-(5-(4,4-difluoro-3,3-dimethylbut-1-yn-1-yl)-7-fluoro-3,4-dihydroquinoline-1 (2H)-yl)-7-fluoro-[1,2,4]triazolo[4,3-a]quinazolin

The title compound was synthesized according to the general procedure described for Example 421. ¹H NMR (400 MHz, acetonitrile-d³): δ 9.30 (s, ¹H), 8.26 (dt, J = 8.7, 4.4 Hz, ¹H), 7.82 (m, ¹H), 7.44 (dd, J = 9.5, 2.8 Hz, ¹H), 7.04 (dd, J = 9.0, 2.6 Hz, ¹H), 6.70–6.60 (m, ¹H), 5.87 (t, J = 56.6 Hz, ¹H), 4.10 (t, J = 6.2 Hz, 2H), 3.04 (m, 2H), 2.18 (p, J = 6.5 Hz, 2H), 1.44 (s, 6H); LCMS (m/z): 454.4.

Example 752. N-(2,2-difluoroethyl)-6,7-difluoro-N-(3-fluoro-5-((1-methylcyclopropyl)ethynyl) phenyl)-[1,2,4]triazolo[4,3-a]quinazolin-5-amine

The title compound was synthesized according to the general procedure described for Example 421. ^¹H NMR (400 MHz, methanol- _d⁴ ) δ 9.64 (s, 1H), 8.22 (m, 1H), 8.01 (td, J = 9.4, 7.6 Hz, 1H), 7.08–6.95 (m, 3H), 6.46 (tt, J = 55.9, 4.0 Hz, 1H), 4.64 (td, J = 13.7, 4.0 Hz, 2H), 1.30 (s, 3H), 0.95 (q, J = 4.1 Hz, 2H), 0.74–0.64 (m, 2H); LCMS (m/z) 458.3.

Example 753. N-(2,2-difluoroethyl)-6,7-difluoro-N-(3-fluoro-5-((1-(trifluoromethyl)cyclopropyl)ethyl) (alkynyl)phenyl)-[1,2,4]triazolo[4,3-a]quinazolin-5-amine

The title compound was synthesized according to the general procedure described for Example 276. ^¹H NMR (400 MHz, methanol- _d⁴ ) δ 9.69 (s, ¹H), 8.26 (m, ¹H), 8.06 (td, J = 9.4, 7.6 Hz, ¹H), 7.19 (dd, J = 8.2, 2.0 Hz, 2H), 7.15–7.08 (m, ¹H), 6.49 (tt, J = 55.9, 4.0 Hz, 1H), 4.68 (td, J = 13.7, 4.0 Hz, 2H), 1.44–1.38 (m, 2H), 1.30 (m, 2H); LCMS (m/z) 512.3.

Example 754. N-(3-(4,4-difluoro-3,3-dimethylbut-1-yn-1-yl)-5-fluorophenyl)-N-(2,2-di... (Fluoroethyl)-6,7-difluoro-[1,2,4]triazolo[4,3-a]quinazolin-5-amine

The title compound was synthesized according to the general procedure described for Example 421. ^¹H NMR (400 MHz, methanol- _d⁴ ) δ 9.70 (s, 1H), 8.33–8.21 (m, 1H), 8.07 (q, J = 8.9 Hz, 1H), 7.23–7.13 (m, 2H), 7.09 (dt, J = 9.0, 1.8 Hz, 1H), 6.49 (tt, J = 56.0, 4.0 Hz, 1H), 5.76 (t, J = 56.6 Hz, 1H), 4.68 (td, J = 13.7, 4.0 Hz, 2H), 1.34 (s, 6H); LCMS (m/z) 496.3.

Example 755. N-(2,2-difluoroethyl)-6,7-difluoro-N-(3-fluoro-5-(4,4,4-trifluoro-3,3-dimethyl) But-1-yn-1-yl)phenyl)-[1,2,4]triazolo[4,3-a]quinazolin-5-amine

The title compound was synthesized according to the general procedure described for Example 421. ^¹H NMR (400 MHz, methanol- _d⁴ ) δ 9.70 (s, 1H), 8.27 (m, 1H), 8.07 (td, J = 9.4, 7.6 Hz, 1H), 7.26–7.16 (m, 2H), 7.12 (m, 1H), 6.49 (tt, J = 55.8, 4.0 Hz, 1H), 4.69 (td, J = 13.7, 4.0 Hz, 2H), 1.49 (s, 6H); LCMS (m/z) 514.3.

Example 756. (7-Fluoro-5-(methyl(3-((1-(trifluoromethyl)cyclopropyl)ethynyl)phenyl)amino)-[1, [2,4]triazolo[4,3-a]quinazolin-8-yl)methanol

The title compound was synthesized according to the general procedure described for Example 276. ^¹H NMR (400 MHz, methanol- _d⁴ ) δ 9.69 (s, ¹H), 8.48 (d, J = 6.3 Hz, ¹H), 7.65–7.53 (m, ³H), 7.49 (dt, J = 6.5, 2.4 Hz, ¹H), 6.77 (d, J = 11.6 Hz, ¹H), 4.83 (d, J = 1.0 Hz, 2H), 3.78 (s, ³H), 1.42 (m, 2H), 1.32 (m, 2H); LCMS (m/z) 456.4.

Example 757. 1-((3-((8-chloro-[1,2,4]triazolo[4,3-a]quinazolin-5-yl)(methyl)amino)benzene (Hydroxy)cyclohexane-1-ol

The title compound was synthesized according to the general procedure described for Example 276. ^¹H NMR (400 MHz, methanol- _d⁴ ) δ 9.59 (s, ¹H), 8.51 (d, J = 2.1 Hz, ¹H), 7.60–7.48 (m, 3H), 7.48–7.36 (m, 2H), 7.24 (d, J = 9.1 Hz, 1H), 3.79 (s, 3H), 2.02–1.90 (m, 2H), 1.74 (m, 2H), 1.67–1.55 (m, 5H), 1.37–1.26 (m, 1H); LCMS (m/z) 432.2.

Example 758. 8-Chloro-N-(3-fluoro-5-((1-(trifluoromethyl)cyclopropyl)ethynyl)phenyl)-1-methyl-N- (2,2,2-trifluoroethyl)-[1,2,4]triazolo[4,3-a]quinazolin-5-amine

Step 1: Trifluoroacetic anhydride was added to a solution of 3-fluoro-5-iodo-aniline (2 g, 8.44 mmol) in THF (40 mL) at 0 °C. The reaction mixture was heated to room temperature and stirred for 45 min. The reaction mixture was then quenched with a saturated aqueous solution of _NaHCO3 and extracted with _Et2O . The organic layer was washed with _NaHCO3 , water, and brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The crude material was then dissolved in THF (40 mL), followed by the addition of _BH3 ·THF (16.9 mL, 1 M in THF, 16.9 mmol). The resulting solution was then heated to 65 °C for 16 h and cooled to room temperature. Excess borane was quenched by the addition of MeOH (8 mL), and the reaction mixture was concentrated under reduced pressure. 3-fluoro-5-iodo-N-(2,2,2-trifluoroethyl)aniline was purified by rapid chromatography (eluting with a hexane solution of 0-100% v/v ethyl acetate).

Step 2: Add a solution of 3-fluoro-5-iodo-N-(2,2,2-trifluoroethyl)aniline (370 mg, 1.16 mmol) in DMF (2.5 mL) to a suspension of NaH (71 mg, 1.86 mmol) in DMF (5 mL) at 0 °C. Stir the resulting suspension at room temperature for 30 min, then add a solution of 2,4,7-trichloroquinazoline (487 mg, 2.09 mmol) in DMF (5 mL). The reaction mixture is then heated to room temperature and stirred for another 1.5 h. The reaction mixture is cooled to 0 °C, quenched with water, and extracted with EtOAc. The organic layer is washed with water (2×) and brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. 2,7-Dichloro-N-(3-fluoro-5-iodo-phenyl)-N-(2,2,2-trifluoroethyl)quinazolin-4-amine was provided by rapid chromatography (eluting with hexane solution of 0-100% v/v ethyl acetate).

Step 3: Hydrazine (0.255 mL, 8.14 mmol) was added to a solution of 2,7-dichloro-N-(3-fluoro-5-iodo-phenyl)-N-(2,2,2-trifluoroethyl)quinazolin-4-amine (420 mg, 0.814 mmol) in THF (3 mL) and EtOH (6 mL). The resulting solution was heated to 40 °C for 3 hours and then concentrated under reduced pressure to obtain the desired product, which was used without further purification.

A suspension of 7-chloro-N-(3-fluoro-5-iodo-phenyl)-2-hydrazino-N-(2,2,2-trifluoroethyl)quinazoline-4-amine (200 mg, 0.391 mmol) in triethyl orthoacetate (5 mL) was heated to 120 °C for 2 hours, then cooled to room temperature and concentrated under reduced pressure. 8-chloro-N-(3-fluoro-5-iodo-phenyl)-1-methyl-N-(2,2,2-trifluoroethyl)-[1,2,4]triazolo[4,3-a]quinazoline-5-amine was obtained by rapid chromatography (eluting with hexane solution of 0-100% v/v ethyl acetate).

Step 4: Triethylamine (0.166 mL, 1.19 mmol) was added to a suspension of 8-chloro-N-(3-fluoro-5-iodo-phenyl)-1-methyl-N-(2,2,2-trifluoroethyl)-[1,2,4]triazolo[4,3-a]quinazolin-5-amine (31.8 mg, 0.059 mmol), 1,1'-bis(diphenylphosphine)ferrocene-palladium(II) dichloromethane complex (4.9 mg, 0.006 mmol), and zinc dibromide (67 mg, 0.297 mmol) in DMF (1 mL). The resulting mixture was purged with nitrogen for 5 min, followed by the addition of 1-ethynyl-1-(trifluoromethyl)cyclopropane (0.01 mL, 0.073 mmol). The reaction mixture was then heated to 80 °C for 10 min, cooled to room temperature, and diluted with water and ethyl acetate. The organic layer was then washed twice with water, followed by washing with brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The title compound was obtained by HPLC separation and lyophilization: ¹H NMR (400 MHz, DMSO- _d⁶ ) δ 8.23 (d, J = 1.8 Hz, 1H), 7.55 (dd, J = 8.9, 1.9 Hz, 1H), 7.49 (d, J = 8.9 Hz, 1H), 7.31–7.17 (m, 3H), 5.11 (q, J = 9.2 Hz, 2H), 3.04 (s, 3H), 1.49–1.41 (m, 2H), 1.40–1.33 (m, 2H); LCMS (m/z) 542.

Example 759. 8-Chloro-N-(3-fluoro-5-((1-(trifluoromethyl)cyclopropyl)ethynyl)phenyl)-N-(2,2,2- Trifluoroethyl)-[1,2,4]triazolo[4,3-a]quinazolin-5-amine

The title compound was synthesized according to the procedure described for Example 758, except that triethyl orthoformate was used instead of triethyl orthoacetate in step 3. ¹H NMR (400 MHz, DMSO- _d₆ ) δ 9.82 (s, ¹H), 8.67 (d, J = 2.0 Hz, ¹H), 7.49 (dd, J = 8.9, 2.0 Hz, ¹H), 7.40 (d, J = 8.9 Hz, ¹H), 7.33–7.27 (m, 2H), 7.23 (d, J = 7.9 Hz, 1H), 5.11 (q, J = 9.2 Hz, 2H), 1.47–1.41 (m, 2H), 1.41–1.35 (m, 2H); LCMS (m/z) 528.1.

Example 760. 7-Fluoro-N-(3-Fluoro-5-((1-(trifluoromethyl)cyclopropyl)ethynyl)phenyl)-N-(2,2,2- Trifluoroethyl)-[1,2,4]triazolo[4,3-a]quinazolin-5-amine

The title compound was synthesized according to the procedure described for Example 759, except that 2,4-dichloro-6-fluoroquinazoline was used instead of 2,4,7-trichloroquinazoline in step 2. ¹H NMR (400 MHz, DMSO- _d⁶ ) δ 9.86 (s, 1H), 8.53 (dd, J = 9.2, 4.7 Hz, 1H), 7.94 (td, J = 8.7, 2.8 Hz, 1H), 7.39–7.32 (m, 2H), 7.27 (d, J = 8.9 Hz, 1H), 7.04 (dd, J = 9.7, 2.8 Hz, 1H), 5.11 (q, J = 9.2 Hz, 2H), 1.48–1.34 (m, 4H); LCMS (m/z) 512.1.

Example 761. 7-Fluoro-N-(3-Fluoro-5-((3-methyloxetane-3-yl)ethynyl)phenyl)-N-methyl [1,2,4]triazolo[4,3-a]quinazolin-5-amine

The title compound was synthesized according to the procedure described for Example 426. ¹H NMR (400 MHz, DMSO- _d₆ ) δ 9.88 (s, ¹H), 8.52 (dd, J = 9.2, 4.8 Hz, ¹H), 7.96 (ddd, J = 9.1, 8.0, 2.8 Hz, ¹H), 7.46 (dt, J = 10.0, 2.2 Hz, ¹H), 7.39 (s, ¹H), 7.37–7.29 (m, ¹H), 6.99 (dd, J = 10.1, 2.8 Hz, ¹H), 4.71 (d, J = 5.5 Hz, 2H), 4.41 (d, J = 5.5 Hz, 2H), 3.61 (s, 3H), 1.60 (s, 3H); LCMS (m/z) 406.1.

Example 762. 8-Chloro-N-(2,2,2-trifluoroethyl)-N-(3-((1-(trifluoromethyl)cyclopropyl)ethynyl) phenyl)-[1,2,4]triazolo[4,3-a]quinazolin-5-amine

The title compound was synthesized according to the procedure described for Example 759, except that 3-iodo-N-(2,2,2-trifluoroethyl)aniline was used instead of 3-fluoro-5-iodo-N-(2,2,2-trifluoroethyl)aniline in step 2. ¹H NMR (400 MHz, DMSO- _d⁶ ) δ 9.79 (s, ¹H), 8.65 (d, J = 2.1 Hz, ¹H), 7.49–7.47 (m, ¹H), 7.44 (dd, J = 9.0, 2.1 Hz, ¹H), 7.41–7.28 (m, 4H), 5.08 (q, J = 9.2 Hz, 2H), 1.46–1.40 (m, 2H), 1.39–1.33 (m, 2H); LCMS (m/z) 510.1.

Example 763. 8-Chloro-N-(2,2,2-trifluoroethyl)-N-(3-((1-methylcyclopropyl)ethynyl)phenyl)- [1,2,4]triazolo[4,3-a]quinazolin-5-amine

The title compound was synthesized according to the procedure described for Example 759, except that 1-ethynyl-1-methylcyclopropane was used instead of 1-ethynyl-1-(trifluoromethyl)cyclopropane in step 4. ¹H NMR (400 MHz, DMSO- _d⁶ ) δ 9.78 (s, ¹H), 8.64 (d, J = 2.1 Hz, ¹H), 7.44 (dd, J = 9.0, 2.1 Hz, ¹H), 7.37–7.34 (m, ¹H), 7.34–7.28 (m, 2H), 7.27–7.22 (m, 2H), 5.06 (q, J = 9.2 Hz, 2H), 1.28 (s, 3H), 0.91 (dd, J = 3.9 Hz, 2H), 0.73 (dd, 2H); LCMS (m/z) 456.1.

Example 764. 8-Chloro-N-methyl-N-(6-(4-(1-(trifluoromethyl)cyclopropyl)phenyl)pyrazin-2-yl)- [1,2,4]triazolo[4,3-a]quinazolin-5-amine

Except for using 6-bromo-N-methylpyrazine-2-amine instead of 3-iodo-N-(2,2,2-trifluoroethyl)aniline, N-(6-bromopyrazine-2-yl)-8-chloro-N-methyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine was prepared according to the method for preparing 8-chloro-N-(3-fluoro-5-iodophenyl)-N-(2,2,2-trifluoroethyl)-[1,2,4]triazolo[4,3-a]quinazolin-5-amine as described with respect to Example 759.

Pd(PPh3)4 (4.5 mg, 3.8 μmol) and an aqueous solution of sodium carbonate (0.115 mL, 2N, 230 mmol) were added to a solution of N-(6-bromopyrazin-2-yl)-8-chloro-N-methyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine (30 mg, 77 μmol) and 4,4,5,5-tetramethyl- _2- [4-[ _1- (trifluoromethyl)cyclopropyl]phenyl]-1,3,2-dioxaborane (18.7 mg, 60 μmol) in 1,4-dioxacyclohexane (0.75 mL). The resulting solution was heated to 90 °C for 3 hours, then cooled to room temperature, diluted with ethyl acetate, filtered, and concentrated under reduced pressure. The residue was purified by preparative HPLC and the appropriate fractions were lyophilized to provide the title compound: ¹H NMR (400 MHz, DMSO- _d₆ ) δ 9.86 (s, ¹H), 8.91 (s, ¹H), 8.73 (d, J = 2.1 Hz, ¹H), 8.55 (s, ¹H), 7.91 (d, J = 8.4 Hz, 2H), 7.63 (d, J = 8.8 Hz, 1H), 7.57–7.48 (m, 3H), 3.77 (s, 3H), 1.39–1.32 (m, 2H), 1.20–1.11 (m, 2H); LCMS (m/z) 496.1.

Example 765. 8-Chloro-7-fluoro-N-methyl-N-(6-(6-(2,2,2-trifluoroethoxy)pyridin-3-yl)pyrazine- 2-yl)-[1,2,4]triazolo[4,3-a]quinazolin-5-amine

The title compound was synthesized according to the procedure described for Example 495. ¹H NMR (400 MHz, DMSO- _d₆ ) δ 9.86 (s, ¹H), 8.95 (d, J = 6.4 Hz, ¹H), 8.93 (s, ¹H), 8.79 (d, J = 2.1 Hz, ¹H), 8.54 (s, ¹H), 8.33 (dd, J = 8.7, 2.5 Hz, ¹H), 7.77 (d, J = 9.7 Hz, ¹H), 7.09 (d, J = 8.7 Hz, ¹H), 5.05 (q, J = 9.1 Hz, 2H), 3.74 (s, 3H); LCMS (m/z) 505.1.

Example 766. 8-Chloro-7-fluoro-N-methyl-N-(6-(4-(1-(trifluoromethyl)cyclopropyl)phenyl)pyrazine-2- (-[1,2,4]triazolo[4,3-a]quinazolin-5-amine)

The title compound was synthesized according to the procedure described for Example 495. ¹H NMR (400 MHz, DMSO- _d₆ ) δ 9.85 (s, ¹H), 8.95 (d, J = 6.4 Hz, ¹H), 8.90 (s, ¹H), 8.57 (s, ¹H), 7.91 (d, J = 8.4 Hz, 2H), 7.74 (d, J = 9.7 Hz, 1H), 7.53 (d, J = 8.1 Hz, 2H), 3.74 (s, 3H), 1.40–1.32 (m, 2H), 1.19–1.12 (m, 2H); LCMS (m/z) 514.1.

Example 767. 6,7-Difluoro-1-(methoxymethyl)-5-(5-((1-(trifluoromethyl)cyclopropyl)ethynyl)- 3,4-Dihydroquinoline-1(2H)-yl)-[1,2,4]triazolo[4,3-a]quinazolin

The title compound was synthesized according to the procedure described for Example 522. ^¹H NMR (400 MHz, methanol- _d⁴ ) δ 8.29 (dd, J = 9.3, 3.7 Hz, 1H), 8.06 (q, J = 9.0 Hz, 1H), 7.31 (dd, J = 7.6, 1.2 Hz, 1H), 7.00 (t, J = 7.8 Hz, 1H), 6.96–6.87 (m, 1H), 5.11 (s, 2H), 4.20 (br s, 2H), 3.54 (s, 3H), 3.10 (br s, 2H), 2.21 (br s, 2H), 1.53–1.43 (m, 2H), 1.38 (d, J = 5.8 Hz, 2H); LCMS (m/z) 514.4.

Example 768. 7-Fluoro-5-(6-((1-(trifluoromethyl)cyclopropyl)ethynyl)-2,3,4,5-tetrahydro-1H-benzene [b]azapyro-1-yl)-[1,2,4]triazolo[4,3-a]quinazolin

The title compound was synthesized according to the procedure described for Example 522. ^¹H NMR (400 MHz, methanol- _d⁴ ) δ 9.57 (s, 1H), 8.40 (dd, J = 9.2, 4.8 Hz, 1H), 7.78 (ddd, J = 9.3, 7.4, 2.7 Hz, 1H), 7.63 (dd, J = 7.8, 1.2 Hz, 1H), 7.30 (t, J = 7.9 Hz, 1H), 7.15 (dd, J = 7.9, 1.2 Hz, 1H), 6.56 (dd, J = 10.7, 2.7 Hz, 1H), 5.31 (br s, 1H), 3.53 (br s, 1H), 2.95 (br s, 1H), 2.15 (br s, 3H), 1.94 (br s, 1H), 1.66 (br s, 1H). s, 1H), 1.48 (q, J = 4.2, 3.2Hz, 2H), 1.45–1.33 (m, 2H); LCMS (m/z) 466.4.

Example 769. 6,7-Difluoro-1-methyl-5-(6-((1-(trifluoromethyl)cyclopropyl)ethynyl)-2,3,4,5- Tetrahydro-1H-benzo[b]azapyro-1-yl)-[1,2,4]triazolo[4,3-a]quinazolin

The title compound was synthesized according to the procedure described for Example 522. ^¹H NMR (400 MHz, methanol- _d⁴ ) δ 8.20 (ddd, J = 9.5, 4.0, 1.8 Hz, 1H), 7.96 (td, J = 9.4, 7.9 Hz, 1H), 7.42 (dd, J = 7.8, 1.2 Hz, 1H), 7.01 (t, J = 7.9 Hz, 1H), 6.79 (dd, J = 7.9, 1.2 Hz, 1H), 5.06 (br s, 1H), 3.48 (br s, 2H), 3.10 (br s, 1H), 3.06 (s, 3H), 2.37–1.59 (m, 4H), 1.53–1.45 (m, 2H), 1.41–1.33 (m, 2H); LCMS (m/z) 498.4.

Example 770. 6,7-Difluoro-1-methyl-5-(6-(4,4,4-trifluoro-3,3-dimethylbut-1-yn-1-yl)- 2,3,4,5-Tetrahydro-1H-benzo[b]azapyro-1-yl)-[1,2,4]triazolo[4,3-a]quinazolin

The title compound was synthesized according to the procedure described for Example 522. ^¹H NMR (400 MHz, methanol- _d⁴ ) δ 8.21 (ddd, J = 9.5, 4.0, 1.8 Hz, 1H), 7.96 (td, J = 9.4, 7.9 Hz, 1H), 7.42 (dd, J = 7.8, 1.2 Hz, 1H), 7.02 (t, J = 7.8 Hz, 1H), 6.80 (dd, J = 8.0, 1.1 Hz, 1H), 5.08 (br s, 1H), 3.45 (br s, 2H), 3.10 (br s, 1H), 3.06 (s, 3H), 2.25–1.55 (br s, 4H), 1.58 (s, 6H); LCMS (m/z) 500.4.

Example 771. 5-(5-(4,4-difluoro-3,3-dimethylbut-1-yn-1-yl)-3,4-dihydroquinoline-1(2H)- (1,2,4)-6,7-difluoro-1-methyl-[1,2,4]triazolo[4,3-a]quinazolin

The title compound was synthesized according to the procedure described for Example 522. ^¹H NMR (400 MHz, methanol- _d⁴ ) δ 8.26 (ddd, J = 9.7, 3.9, 1.8 Hz, 1H), 8.11–7.97 (m, 1H), 7.30 (dd, J = 7.7, 1.2 Hz, 1H), 6.98 (t, J = 7.9 Hz, 1H), 6.89 (d, J = 8.1 Hz, 1H), 5.84 (t, J = 56.7 Hz, 1H), 4.08 (br s, 2H), 3.25–2.85 (br s, 2H), 3.08 (s, 3H), 2.20 (br s, 2H), 1.42 (d, J = 1.2 Hz, 6H); LCMS (m/z) 468.3.

Example 772. 5-(5-((1-(1,1-difluoroethyl)cyclopropyl)ethynyl)-3,4-dihydroquinoline-1(2H)- (1,2,4)-6,7-difluoro-1-methyl-[1,2,4]triazolo[4,3-a]quinazolin

The title compound was synthesized according to the procedure described for Example 522. ^¹H NMR (400 MHz, methanol- _d⁴ ) δ 8.32–8.20 (m, 1H), 8.04 (q, J = 9.2 Hz, 1H), 7.29 (dd, J = 7.7, 1.2 Hz, 1H), 6.98 (t, J = 7.9 Hz, 1H), 6.89 (d, J = 8.0 Hz, 1H), 4.19 (br s, 2H), 315–3.00 (br s, 2H), 3.08 (br s, 3H), 2.20 (br s, 2H), 1.97–1.79 (m, 3H), 1.36–1.25 (m, 2H), 1.15 (dq, J = 4.9, 3.3, 2.6 Hz, 2H); LCMS (m/z) 480.3.

Example 773. 6,7-Difluoro-5-(6-((1-(trifluoromethyl)cyclopropyl)ethynyl)-2,3,4,5-tetrahydro- 1H-benzo[b]azapyro-1-yl)-[1,2,4]triazolo[4,3-a]quinazolin

The title compound was synthesized according to the procedure described for Example 522. ^¹H NMR (400 MHz, methanol- _d⁴ ) δ 9.59 (s, 1H), 8.18 (ddd, J = 9.3, 4.1, 1.9 Hz, 1H), 8.07–7.94 (m, 1H), 7.43 (dd, J = 7.8, 1.2 Hz, 1H), 7.03 (t, J = 7.8 Hz, 1H), 6.83 (dd, J = 8.0, 1.2 Hz, 1H), 5.10–4.90 (m, 1H), 3.71–3.35 (m, 2H), 1.94 (d, J = 6.8 Hz, 5H), 1.52–1.45 (m, 2H), 1.38 (s, 2H); LCMS (m/z) 484.3.

Example 774. 6,7-Difluoro-1-methyl-5-(5-((1-(trifluoromethyl)cyclopropyl)ethynyl)-3,4-dihydro Quinoline-1(2H)-yl)-[1,2,4]triazolo[4,3-a]quinazolin

The title compound was synthesized according to the procedure described for Example 522. ^¹H NMR (400 MHz, methanol- _d⁴ ) δ 8.11 (ddd, J = 9.4, 3.9, 1.8 Hz, 1H), 7.84 (td, J = 9.4, 7.8 Hz, 1H), 7.13 (dd, J = 7.7, 1.1 Hz, 1H), 6.88 (t, J = 7.9 Hz, 1H), 6.62 (d, J = 8.1 Hz, 1H), 4.05 (brs, 2H), 3.03 (m, 5H), 2.31–2.02 (brs, 2H), 1.48–1.29 (m, 4H); LCMS (m/z) 484.3.

Example 775. 6,7-Difluoro-5-(6-(4,4,4-trifluoro-3,3-dimethylbut-1-yn-1-yl)-2,3,4,5- Tetrahydro-1H-benzo[b]azapyro-1-yl)-[1,2,4]triazolo[4,3-a]quinazolin

The title compound was synthesized according to the procedure described for Example 522. ^¹H NMR (400 MHz, methanol- _d⁴ ) δ 9.56–9.29 (m, 1H), 8.06 (s, 1H), 7.96–7.69 (m, 1H), 7.33 (d, J = 9.0 Hz, 1H), 6.97 (q, J = 9.9, 8.7 Hz, 1H), 6.76–6.59 (m, 1H), 5.59–5.44 (m, 1H), 4.36 (d, J = 189.5 Hz, 1H), 3.18 (s, 1H), 1.98 (d, J = 72.6 Hz, 5H), 1.65–1.51 (m, 6H); LCMS (m/z) 486.3.

Example 776. 8-Chloro-7-fluoro-1-(methoxymethyl)-5-(5-(4,4,4-trifluoro-3,3-dimethylbut-1- (1-yl)-3,4-dihydroquinoline-1(2H)-yl)-[1,2,4]triazolo[4,3-a]quinazolin

The title compound was synthesized in a manner similar to that of Example 500, except that 1,1,1,2-tetramethoxyethane and [7-chloro-6-fluoro-4-[5-(4,4,4-trifluoro-3,3-dimethyl-but-1-ynyl)-3,4-dihydro-2H-quinolin-1-yl]quinazolin-2-yl]hydrazine were used instead of 1,1,1-triethoxyethane and 7-bromo-6-fluoro-2-hydrazino-N-methyl-N-phenylquinazolin-4-amine. ¹ H NMR (400MHz, methanol-d ₄ )δ8.58(d,J＝6.3Hz,1H),7.45–7.33(m,2H),7.09(t,J＝7.9Hz,1H),6.99(dd,J＝8.2,1.1Hz,1H),5.13(s,2H),4 .21(t,J＝6.5Hz,2H),3.55(s,3H),3.11(t,J＝6.6Hz,2H),2.22(p,J＝6.6Hz,2H),1.58(s,6H); LCMS(m/z)532.4.

Example 777. 5-(5-((1-(1,1-difluoroethyl)cyclopropyl)ethynyl)-3,4-dihydroquinoline 1(2H)- (-6,7-difluoro-[1,2,4]triazolo[4,3-a]quinazolin)

The title compound was synthesized according to the procedure described for Example 522. ¹ H NMR (400MHz, methanol-d ₄ )δ9.46(s,1H),8.10(ddd,J＝9.2,4.0,1.8Hz,1H),7.86(td,J＝9.4,7.6Hz,1H), 7.13(dd,J＝7.7,1.1Hz,1H),6.89(t,J＝7.9Hz,1H),6.68–6.61(m,1H),4.02(br s,2H),3.01(br s,2H),2.16(br s,2H),1.89(t,J＝17.9Hz,3H),1.34–1.21(m,2H),1.12(ddq,J＝4.8,3.1,2.0Hz,2H); LCMS(m/z)466.3.

Example 778. 6,7-Difluoro-1-methyl-5-(5-(4,4,4-trifluoro-3,3-dimethylbut-1-yn-1-yl)- 3,4-Dihydroquinoline-1(2H)-yl)-[1,2,4]triazolo[4,3-a]quinazolin

The title compound was synthesized according to the procedure described for Example 522. ^¹H NMR (400 MHz, methanol- _d⁴ ) δ 8.15 (ddd, J = 9.6, 3.9, 1.9 Hz, 1H), 7.88 (td, J = 9.5, 8.0 Hz, 1H), 7.13 (dd, J = 7.7, 1.1 Hz, 1H), 6.92 (t, J = 7.9 Hz, 1H), 6.71 (d, J = 8.0 Hz, 1H), 4.01 (br s, 2H), 3.03 (br s, 2H), 2.48–1.88 (br s, 2H), 1.57 (s, 6H); LCMS (m/z) 486.3.

Example 779. 6,7-Difluoro-5-(5-(4,4,4-trifluoro-3,3-dimethylbut-1-yn-1-yl)-3,4-dihydro Quinoline-1(2H)-yl)-[1,2,4]triazolo[4,3-a]quinazolin

The title compound was synthesized according to the procedure described for Example 522. ^¹H NMR (400 MHz, methanol- _d⁴ ) δ 9.64 (s, ¹H), 8.24 (ddd, J = 9.3, 4.1, 1.8 Hz, ¹H), 8.08 (td, J = 9.4, 7.6 Hz, ¹H), 7.31 (dd, J = 7.5, 1.3 Hz, ¹H), 7.07–6.89 (m, 2H), 4.18 (br s, 2H), 3.06 (br s, 2H), 2.18 (br s, J = 20.9 Hz, 2H), 1.58 (s, 6H); LCMS (m/z) 472.3.

Example 780. 8-Chloro-7-fluoro-1-methyl-5-(6-(4,4,4-trifluoro-3,3-dimethylbut-1-yn-1-yl)- 2,3,4,5-Tetrahydro-1H-benzo[b]azapyro-1-yl)-[1,2,4]triazolo[4,3-a]quinazolin

The title compound was synthesized in a manner similar to that of Example 500, except that [7-chloro-6-fluoro-4-[6-(4,4,4-trifluoro-3,3-dimethyl-but-1-ynyl)-2,3,4,5-tetrahydro-1-benzozazepine-1-yl]quinazolin-2-yl]hydrazine was used instead of 7-bromo-6-fluoro-2-hydrazino-N-methyl-N-phenylquinazolin-4-amine. ¹ H NMR (400MHz, methanol-d ₄ )δ8.42(d,J＝6.4Hz,1H),7.63(dd,J＝7.9,1.3Hz,1H),7.30(t,J＝7.9Hz,1H),7.10(dd,J＝8.0,1.3Hz,1H),6.77(d,J＝10.8Hz,1H),5.25(br s,1H),3.48(br s,3H),3.07(s,3H),1.94(s,4H),1.58(s,6H); LCMS(m/z)516.4.

Example 781. 8-Chloro-5-(5-(4,4,4-trifluoro-3,3-dimethylbut-1-yn-1-yl)-3,4-dihydroquinone (1,2,4)-[1,2,4]triazolo[4,3-a]quinazolino

The title compound was synthesized according to the procedure described for Example 522. ^¹H NMR (400 MHz, methanol- _d⁴ ) δ 9.64 (s, 1H), 8.54 (d, J = 2.0 Hz, 1H), 7.57 (d, J = 9.0 Hz, 1H), 7.48 (dd, J = 9.0, 2.0 Hz, 1H), 7.36 (dd, J = 7.5, 1.3 Hz, 1H), 7.07 (t, J = 7.8 Hz, 1H), 7.01 (dd, J = 8.2, 1.2 Hz, 1H), 4.22 (t, J = 6.6 Hz, 2H), 3.09 (t, J = 6.7 Hz, 2H), 2.22 (p, J = 6.7 Hz, 2H), 1.58 (s, 6H); LCMS (m/z) 470.4.

Example 782. 8-Chloro-5-(5-(4,4-difluoro-3,3-dimethylbut-1-yn-1-yl)-3,4-dihydroquinoline-1 (2H)-yl)-[1,2,4]triazolo[4,3-a]quinazolin

The title compound was synthesized according to the procedure described for Example 522. ¹ H NMR (400MHz, methanol-d ₄ )δ9.55(s,1H),8.45(d,J＝2.0Hz,1H),7.58(d,J＝9.0Hz,1H),7.41(dd,J＝9. 0,2.0Hz,1H),7.22(dd,J＝7.6,1.1Hz,1H),6.98(t,J＝7.9Hz,1H),6.81(dd, J＝8.2,1.1Hz,1H),5.83(t,J＝56.7Hz,1H),4.10(t,J＝6.5Hz,2H),3.07(t,J =6.7Hz, 2H), 2.19 (p, J = 6.3Hz, 2H), 1.42 (d, J = 1.1Hz, 6H); LCMS (m/z) 452.4.

Example 783. 8-Chloro-7-fluoro-5-(5-(4,4,4-trifluoro-3,3-dimethylbut-1-yn-1-yl)-3,4-di Hydroquinoline-1(2H)-yl)-[1,2,4]triazolo[4,3-a]quinazolin

The title compound was synthesized in a manner similar to that in Example 523, except that 7-fluoro-5-[5-(4,4,4-trifluoro-3,3-dimethyl-but-1-ynyl)-3,4-dihydro-2H-quinolin-1-yl]-[1,2,4]triazolo[4,3-a]quinazolin-8-amine was used instead of 5-(5-(cyclopropylethynyl)-3,4-dihydroquinolin-1(2H)-yl)-7-fluoro-[1,2,4]triazolo[4,3-a]quinazolin-8-amine. ¹ H NMR (400MHz, methanol-d ₄ )δ9.40(s,1H),8.48(d,J＝6.2Hz,1H),7.28(d,J＝9.7Hz,1H),7.24–7.16(m,1H),6.95(t,J＝7.9Hz,1H),6.65(d,J =8.1Hz, 1H), 4.05 (t, J = 6.5Hz, 2H), 3.04 (t, J = 6.7Hz, 2H), 2.18 (t, J = 6.5Hz, 2H), 1.55 (s, 6H); LCMS (m/z) 488.4.

Example 784. 8-Chloro-5-(5-(4,4-difluoro-3,3-dimethylbut-1-yn-1-yl)-3,4-dihydroquinoline-1 (2H)-yl)-7-fluoro-[1,2,4]triazolo[4,3-a]quinazolin

The title compound was synthesized according to the procedure described for Example 522. ^¹H NMR (400 MHz, methanol- _d⁴ ) δ 9.45 (s, 1H), 8.53 (d, J = 6.3 Hz, 1H), 7.28 (d, J = 9.8 Hz, 1H), 7.21 (dd, J = 7.8, 1.1 Hz, 1H), 6.96 (t, J = 7.9 Hz, 1H), 6.68 (d, J = 8.1 Hz, 1H), 5.75 (t, J = 56.8 Hz, 1H), 4.06 (t, J = 6.5 Hz, 2H), 3.06 (t, J = 6.7 Hz, 2H), 2.18 (p, J = 6.6 Hz, 2H), 1.41 (d, J = 1.2 Hz, 6H); LCMS (m/z) 470.3.

Example 785. 8-Chloro-N-(3-(4,4-difluoro-3,3-dimethylbut-1-yn-1-yl)phenyl)-N-methyl- [1,2,4]triazolo[4,3-a]quinazolin-5-amine

The title compound was synthesized according to the procedure described for Example 522. ^¹H NMR (400 MHz, methanol- _d⁴ ) δ 9.60 (s, 1H), 8.53 (d, J = 2.1 Hz, 1H), 7.64–7.48 (m, 3H), 7.43 (ddd, J = 9.1, 5.6, 2.5 Hz, 2H), 7.22 (d, J = 9.2 Hz, 1H), 5.77 (t, J = 56.7 Hz, 1H), 3.79 (s, 3H), 1.36 (d, J = 1.2 Hz, 6H); LCMS (m/z) 426.3.

Example 786. 8-Chloro-7-fluoro-5-(5-((1-(trifluoromethyl)cyclopropyl)ethynyl)-3,4-dihydroquinoline-1 (2H)-yl)-[1,2,4]triazolo[4,3-a]quinazolin

The title compound was synthesized in a manner similar to that in Example 523, except that 5-[5-[2-[1-(trifluoromethyl)cyclopropyl]ethynyl]-3,4-dihydro-2H-quinolin-1-yl]-[1,2,4]triazolo[4,3-a]quinazolin-8-amine was used instead of 5-(5-(cyclopropylethynyl)-3,4-dihydroquinolin-1(2H)-yl)-7-fluoro-[1,2,4]triazolo[4,3-a]quinazolin-8-amine. ¹ H NMR (400MHz, methanol-d ₄ )δ9.67(s,1H),8.73(d,J＝6.3Hz,1H),7.40(d,J＝7.5Hz,1H),7.32(d,J＝10.0Hz,1H),7.10(t,J＝7.9Hz,1H),7.03(d,J＝8.1Hz,1H ), 4.22 (t, J = 6.6Hz, 2H), 3.10 (t, J = 6.6Hz, 2H), 2.21 (p, J = 6.6Hz, 2H), 1.48 (q, J = 5.0, 4.3Hz, 2H), 1.38 (s, 2H); LCMS (m/z) 486.2.

Example 787. 8-Chloro-7-fluoro-5-(5-((1-methylcyclopropyl)ethynyl)-3,4-dihydroquinoline-1(2H)- (-[1,2,4]triazolo[4,3-a]quinazolin)

The title compound was synthesized in a manner similar to that in Example 523, except that 7-fluoro-5-[5-[2-(1-methylcyclopropyl)ethynyl]-3,4-dihydro-2H-quinolin-1-yl]-[1,2,4]triazolo[4,3-a]quinazolin-8-amine was used instead of 5-(5-(cyclopropylethynyl)-3,4-dihydroquinolin-1(2H)-yl)-7-fluoro-[1,2,4]triazolo[4,3-a]quinazolin-8-amine. ¹ H NMR (400MHz, methanol-d ₄ )δ9.61(s,1H),8.70(d,J＝6.3Hz,1H),7.33(dd,J＝7.7,1.1Hz,1H),7.27(d,J＝10.1Hz,1H),7.05(t,J＝7.9Hz,1H),6.93(dd,J＝8.1,1.1Hz,1H) ,4.20(t,J＝6.7Hz,2H),3.07(t,J＝6.6Hz,2H),2.19(p,J＝6.7Hz,2H),1.40(s,3H),1.04(q,J＝4.1Hz,2H),0.84–0.75(m,2H); LCMS(m/z)432.3.

Example 788. N-(3-(cyclopropylethynyl)-5-fluorophenyl)-N-(2,2-difluoroethyl)-6,7-difluoro-1- Methyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine

The title compound was synthesized in a similar manner according to the procedure described for Example 690. ¹H NMR (400 MHz, DMSO- _d₆ ) δ 8.16 (dd, J = 10.0, 4.3 Hz, 1H), 8.10–8.02 (m, 1H), 7.08 (d, J = 16.7 Hz, 2H), 6.95 (d, J = 9.7 Hz, 1H), 6.68–6.35 (m, 1H), 4.61 (td, J = 15.6, 15.0, 3.7 Hz, 2H), 2.99 (d, J = 3.6 Hz, 3H), 1.50 (ddd, J = 13.5, 8.6, 5.3 Hz, 1H), 0.90–0.83 (m, 2H), 0.70 (dt, J = 6.9, 3.4 Hz, 2H); LCMS (m/z) 458.2.

Example 789. 1-(1-(6-fluoro-1-methyl-[1,2,4]triazolo[4,3-a]quinazolin-5-yl)-1,2,3, 4-Tetrahydroquinolino-5-yl)-3-methylpentan-1-yn-3-ol

The title compound was synthesized in a similar manner to the procedure described for Example 719. ¹H NMR (400 MHz, DMSO-d6 ₎ )δ8.18(d,J＝8.6Hz,1H),8.01(td,J＝8.4,5.5Hz,1H),7.37(dd,J＝11.8,8.3H z,1H),7.12(d,J＝7.5Hz,1H),6.93(d,J＝7.8Hz,1H),6.82(d,J＝8.1Hz,1H),4 .09–3.95(m,2H),3.00(s,3H),2.90–2.73(m,2H),2.17–2.00(m,2H),1.69(t t, J＝13.3, 6.2Hz, 3H), 1.47 (s, 3H), 1.04 (t, J＝7.4Hz, 3H); LCMS (m/z) 430.2.

Example 790. 1-(1-(6-fluoro-1-methyl-[1,2,4]triazolo[4,3-a]quinazolin-5-yl)-1,2,3, 4-Tetrahydroquinolino-5-yl)-4-methylpentan-1-yn-3-ol

The title compound was synthesized in a similar manner to the procedure described for Example 719. ¹H NMR (400 MHz, DMSO-d6 ₎ )δ8.18(d,J＝8.6Hz,1H),8.01(td,J＝8.3,5.5Hz,1H),7.38(dd,J＝11.7,8.4Hz,1 H),7.15(d,J＝7.5Hz,1H),6.95(t,J＝7.9Hz,1H),6.84(d,J＝8.2Hz,1H),4.31(d,J ＝5.6Hz,1H),3.99–3.75(m,2H),3.01(s,3H),2.93–2.75(m,2H),2.21–1.98(m,2 H), 1.86 (dq, J=13.1, 6.7Hz, 1H), 1.01 (dd, J=10.8, 6.7Hz, 6H); LCMS (m/z) 430.2.

Example 791. 1-(1-(6-fluoro-1-methyl-[1,2,4]triazolo[4,3-a]quinazolin-5-yl)-1,2,3, 4-Tetrahydroquinoline-5-yl)pent-1-yn-3-ol

The title compound was synthesized in a similar manner to the procedure described for Example 719. ¹H NMR (400 MHz, DMSO-d6 ₎ )δ8.18(d,J＝8.6Hz,1H),8.01(td,J＝8.4,5.5Hz,1H),7.37(dd,J＝11.8,8.3H z,1H),7.14(d,J＝7.5Hz,1H),6.94(d,J＝15.8Hz,1H),6.83(d,J＝7.8Hz,1H), 4.46(t,J＝6.4Hz,1H),4.02–3.85(m,2H),3.00(s,3H),2.89–2.69(m,2H),2. 19–2.02(m,2H),1.75–1.67(m,2H),1.01(t,J=7.4Hz,3H); LCMS(m/z)416.2.

Example 792. 6,7-Difluoro-1-methyl-5-(5-((1-(2,2,2-trifluoroethyl)cyclopropyl)ethynyl)-3, 4-Dihydroquinoline-1(2H)-yl)-[1,2,4]triazolo[4,3-a]quinazolin

The title compound was synthesized in a similar manner according to the procedure described for Example 719. ¹H NMR (400 MHz, DMSO- _d₆ ) δ 8.17 (dd, J = 9.5, 3.8 Hz, 1H), 8.09 (q, J = 9.4 Hz, 1H), 7.06 (d, J = 7.5 Hz, 1H), 6.92 (t, J = 7.9 Hz, 1H), 6.80 (d, J = 8.1 Hz, 1H), 4.00–3.75 (m, 2H), 2.99 (s, 3H), 2.82 (d, J = 19.2 Hz, 2H), 2.62–2.53 (m, 2H), 2.09–1.85 (m, 2H), 1.15–1.04 (m, 4H); LCMS (m/z) 498.2.

Example 793. N-(2,2-difluoroethyl)-N-(3-((1-(1,1-difluoroethyl)cyclopropyl)ethynyl)-5-fluoro phenyl)-6,7-difluoro-1-methyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine

The title compound was synthesized in a similar manner according to the procedure described for Example 690. ¹H NMR (400 MHz, DMSO- _d₆ ) δ 8.17 (dd, J = 9.5, 3.5 Hz, 1H), 8.07 (q, J = 9.4 Hz, 1H), 7.17 (s, 1H), 7.12 (d, J = 10.8 Hz, 1H), 7.06 (d, J = 8.8 Hz, 1H), 6.53 (tt, J = 55.9, 3.8 Hz, 1H), 4.63 (t, J = 16.0 Hz, 2H), 3.00 (s, 3H), 1.79 (t, J = 18.5 Hz, 3H), 1.25–1.08 (m, 4H); LCMS (m/z) 522.1.

Example 794. 6,8-Difluoro-1-methyl-5-(5-((1-methylcyclopropyl)ethynyl)-3,4-dihydroquinoline-1 (2H)-yl)-[1,2,4]triazolo[4,3-a]quinazolin

The title compound was synthesized according to the general procedure described for Example 795, using 1-ethynyl-1-methylcyclopropane instead of 1-ethynyl-1-(trifluoromethyl)cyclopropane. 1H NMR (400MHz, DMSO-d ₆ )δ7.94(d,J＝10.1Hz,1H),7.50(dd,J＝11.8,9.3Hz,1H),7.06(d,J＝7.5Hz,1H),6.89(d,J＝7.8Hz,1H),6.76(d,J＝8.1Hz,1H),4.03–3.72 (m,2H),2.98(s,3H),2.87–2.71(m,2H),2.38–1.96(m,2H),1.36(s,3H),0.98(q,J＝4.0Hz,2H),0.79(q,J＝4.1Hz,2H); LCMS(m/z)430.2.

Example 795. 6,8-Difluoro-1-methyl-5-(5-((1-(trifluoromethyl)cyclopropyl)ethynyl)-3,4-dihydro Quinoline-1(2H)-yl)-[1,2,4]triazolo[4,3-a]quinazolin

Synthesis of 2-amino-4,6-difluorobenzoamide: A solution of 2-amino-4,6-difluorobenzoic acid (1.5 g, 8.66 mmol), triethylamine (3.5 g, 34.7 mmol), EDCI.HCl (3.3 g, 17.3 mmol), and HOBt (2.9 g, 21.7 mmol) in THF (86.0 mL) was stirred at room temperature for 1 h, followed by the addition of _NH₄OH solution (5.6 g, 477 mmol, 61.0 mL), and the mixture was stirred for 16 h. The reaction was quenched with water, extracted with DCM, washed with brine, and concentrated under reduced pressure. The crude product was purified by rapid chromatography using hexane elution (0–100%) with EA, providing the product. MS (m/z) 172.8 [M+H] ^⁺ .

Synthesis of 5,7-difluoroquinazoline-2,4(1H,3H)-dione: DIPEA (924 mg, 7.14 mmol) was added to a solution of 2-amino-4,6-difluorobenzamide (492 mg, 2.86 mmol) in dioxane (1.1 mL) at 0 °C, and the mixture was stirred for 5 min, followed by the addition of triphosgene (1.2 g, 4.08 mmol). The cold bath was removed, and the mixture was heated at 100 °C for 12 h. The mixture was concentrated under reduced pressure, and the product was milled with DCM, filtered, and vacuum dried before use. MS (m/z) 199.2 [M+H] ⁺ .

Synthesis of 2,4-dichloro-5,7-difluoroquinazoline: Phosphoryl chloride (2.1 g, 14.0 mmol) was added dropwise to a mixture of 5,7-difluoroquinazoline-2,4(1H,3H)-dione (236 mg, 1.17 mmol) and DIPEA (317 mg, 2.45 mmol) at room temperature. The mixture was stirred at room temperature for 5 minutes, then heated at 107 °C for ₁ hour. The reaction mixture was then carefully poured onto crushed ice and stirred vigorously until the solid was broken up. The solid was filtered off, washed with water, dissolved in DCM, and dried over _Na₂SO₄ . The mixture was filtered, concentrated under reduced pressure, and used without further purification.

Synthesis of 4-(5-bromo-3,4-dihydroquinoline-1(2H)-yl)-2-chloro-5,7-difluoroquinazoline: NaH (60% dispersion in mineral oil) (58.1 mg, 1.52 mmol) was added in a single addition to a solution of 5-bromo-1,2,3,4-tetrahydroquinoline (247 mg, 1.17 mmol) in DMF (1.0 mL) at 0 °C. The mixture was stirred at 0 °C for 30 min, followed by a single addition of 2,4-dichloro-5,7-difluoroquinazoline (274 mg, 1.17 mmol), and the mixture was heated to room temperature over 16 hours. After completion, the mixture was cooled to 0 °C, quenched with a few drops of saturated _NH₄Cl solution (aqueous), and stirred until the solid was broken up. The solid was filtered off, washed with a 4:1 mixture of hexane and diethyl ether, dried under vacuum, and used without further purification. MS(m/z)410.4[M+H] ⁺ .

Synthesis of (E)-4-(5-bromo-3,4-dihydroquinolin-1(2H)-yl)-5,7-difluoro-2-hydrazinyl-1,2-dihydroquinazoline: Hydrazine monohydrate (644 mg, 20.1 mmol) was added to a solution of 4-(5-bromo-3,4-dihydroquinolin-1(2H)-yl)-2-chloro-5,7-difluoroquinazoline (330 mg, 0.804 mmol) in THF (10.0 mL) and ethanol (5.00 mL), and the mixture was stirred at room temperature for 12 hours. After completion, the reactants were diluted with EA and washed with water, dried over _Na₂SO₄ , and concentrated under reduced pressure to provide the product. _MS (m/z) 406.3 [M+H] ^⁺ .

Synthesis of 5-(5-bromo-3,4-dihydroquinolino-1(2H)-yl)-6,8-difluoro-1-methyl-[1,2,4]triazolo[4,3-a]quinazoline: A solution of (E)-N-(3-bromophenyl)-6,7-dichloro-2-hydrazyl-N-methyl-1,2-dihydroquinazoline-4-amine (124 mg, 0.305 mmol) and triethyl orthoacetate (1.98 g, 12.2 mmol) was heated to 110 °C for 16 hours. After completion, the reactants were cooled to room temperature and concentrated under reduced pressure to provide a crude product. The crude product was ground with heptane, and the solid was collected by filtration, washed with hexane:ether (4:1), and dried under vacuum to provide the desired product. MS (m/z) 430.3 [M+H] ⁺ .

Synthesis of 6,8-difluoro-1-methyl-5-(5-((1-(trifluoromethyl)cyclopropyl)ethynyl)-3,4-dihydroquinoline-1(2H)-yl)-[1,2,4]triazolo[4,3-a]quinazoline: A solution of 5-(5-bromo-3,4-dihydroquinoline-1(2H)-yl)-6,8-difluoro-1-methyl-[1,2,4]triazolo[4,3-a]quinazoline (20.9 mg, 0.0486 mmol), zinc bromide (54.7 mg, 0.243 mmol), (1,1'-)bis(diphenylphosphine)ferrocene)palladium(II) dichloride (1.79 mg, 0.00243 mmol) and triethylamine (98.3 mg, 0.972 mmol) in DMF (0.6 mL) was purged with nitrogen for 5 min. Then, 1-ethynyl-1-(trifluoromethyl)cyclopropane (16.3 mg, 0.121 mol) was added, and the mixture was heated at ₁₀₀ °C for 30 minutes. After completion, the mixture was cooled to room temperature, and ethyl acetate and saturated _NH₄Cl (aqueous solution) were added to the mixture. The aqueous layer was extracted with EA, and the combined organic layers were dried over _Na₂SO₄ and concentrated under vacuum. The residue was purified by reversed-phase HPLC (acetonitrile/water containing 0.1% trifluoroacetic acid) to provide the title compound as a single TFA salt: ¹H NMR (400 MHz, DMSO- _d⁶ ) δ 7.95 (d, J = 10.7 Hz, 1H), 7.55–7.48 (m, 1H), 7.14 (d, J = 7.5 Hz, 1H), 6.95 (t, J = 7.9 Hz, 1H), 6.86 (d, J = 8.2 Hz, 1H), 4.09 (m, 2H), 2.99 (s, 3H), 2.88–2.77 (m, 2H), 2.15–1.96 (m, 2H), 1.52–1.38 (m, 4H); MS (m/z) 484.1 [M+H] ^⁺ .

Example 796. N-(2,2-difluoroethyl)-N-(3-((1-ethylcyclopropyl)ethynyl)-5-fluorophenyl)-6,7- Difluoro-1-methyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine

The title compound was synthesized in a similar manner according to the procedure described for Example 690. ¹H NMR (400 MHz, DMSO- _d₆ ) δ 8.17 (dd, J = 9.5, 3.6 Hz, 1H), 8.11–8.03 (m, 1H), 7.11–7.03 (m, 2H), 6.97 (d, J = 10.9 Hz, 1H), 6.52 (tt, J = 56.0, 3.7 Hz, 1H), 4.68–4.57 (m, 2H), 3.00 (s, 3H), 1.40 (q, J = 7.3 Hz, 2H), 1.02 (t, J = 7.3 Hz, 3H), 0.91–0.87 (m, 2H), 0.74–0.69 (m, 2H); LCMS (m/z) 486.2.

Example 797. 4-(1-(6-fluoro-1-methyl-[1,2,4]triazolo[4,3-a]quinazolin-5-yl)-1,2,3, 4-Tetrahydroquinoline-5-yl)-2,2-dimethylbut-3-ynenitrile

The title compound was synthesized in a similar manner according to the procedure described for Example 719. ¹H NMR (400 MHz, DMSO- _d⁶ ) δ 8.18 (d, J = 8.6 Hz, 1H), 8.01 (td, J = 8.4, 5.5 Hz, 1H), 7.37 (dd, J = 11.6, 8.4 Hz, 1H), 7.19 (d, J = 7.5 Hz, 1H), 6.97 (t, J = 7.9 Hz, 1H), 6.89 (d, J = 8.2 Hz, 1H), 3.90 (m, 2H), 3.00 (s, 3H), 2.98–2.82 (m, 2H), 2.18–2.01 (m, 2H), 1.77 (s, 6H); LCMS (m/z) 425.2.

Example 798. 6,8-Difluoro-5-(5-((1-(trifluoromethyl)cyclopropyl)ethynyl)-3,4-dihydroquinoline-1 (2H)-yl)-[1,2,4]triazolo[4,3-a]quinazolin

(E)-4-(5-bromo-3,4-dihydroquinoline-1(2H)-yl)-5,7-difluoro-2-hydrazinyl-1,2-dihydroquinazolinoline was prepared as described in Example 795.

Synthesis of 5-(5-bromo-3,4-dihydroquinoline-1(2H)-yl)-6,8-difluoro-[1,2,4]triazolo[4,3-a]quinazoline: A solution of (E)-4-(5-bromo-3,4-dihydroquinoline-1(2H)-yl)-5,7-difluoro-2-hydrazyl-1,2-dihydroquinazoline (75.8 mg, 0.197 mmol) and triethyl orthoformate (1.1 g, 7.46 mmol) was heated to 110 °C for 16 hours. After completion, the reactants were cooled to room temperature and concentrated under reduced pressure to provide a crude product. The crude product was ground with heptane, and the solid was collected by filtration, washed with hexane:ethyl ether (4:1), and dried under vacuum. MS (m/z) 416.3 [M+H] ⁺ .

Synthesis of 6,8-difluoro-5-(5-((1-(trifluoromethyl)cyclopropyl)ethynyl)-3,4-dihydroquinoline-1(2H)-yl)-[1,2,4]triazolo[4,3-a]quinazoline: A solution of 5-(5-bromo-3,4-dihydroquinoline-1(2H)-yl)-6,8-difluoro-[1,2,4]triazolo[4,3-a]quinazoline (21.6 mg, 0.0519 mmol), zinc bromide (58.4 mg, 0.259 mmol), (1,1'-)bis(diphenylphosphine)ferrocene)palladium(II) dichloride (3.83 mg, 0.00519 mmol) and triethylamine (105 mg, 1.04 mmol) in DMF (0.60 mL) was purged with nitrogen for 5 min. Then, 1-ethynyl-1-(trifluoromethyl)cyclopropane (23.4 mg, 0.156 mol) was added, and the mixture was heated at ₁₀₀ °C for 30 min. Afterward, the mixture was cooled to room temperature, and ethyl acetate and saturated _NH₄Cl (aqueous solution) were added to the mixture. The aqueous layer was extracted with EA, and the combined organic layers were dried over _Na₂SO₄ and concentrated under vacuum. The residue was purified by reversed-phase HPLC (acetonitrile/water containing 0.1% trifluoroacetic acid) to provide the title compound as a single TFA salt. 1H NMR (400MHz, DMSO-d ₆ )δ9.69(s,1H),8.29(d,J＝10.0Hz,1H),7.48–7.40(m,1H),7.12(dd,J＝7.3,1.2Hz,1H),6.92(dd,J＝14. 2,8.3Hz,2H),3.90(m,2H),2.98–2.82(m,2H),2.13–1.97(m,2H),1.51–1.39(m,4H); LCMS(m/z)470.1.

Example 799. 5-(5-((1-ethylcyclopropyl)ethynyl)-3,4-dihydroquinoline-1(2H)-yl)-6-fluoro-1- Methyl-[1,2,4]triazolo[4,3-a]quinazolin

The title compound was synthesized in a similar manner according to the procedure described for Example 719. ¹H NMR (400 MHz, DMSO- _d₆ ) δ 8.17 (d, J = 8.6 Hz, 1H), 8.01 (dt, J = 8.5, 4.3 Hz, 1H), 7.37 (dd, J = 11.8, 8.3 Hz, 1H), 7.09 (d, J = 7.5 Hz, 1H), 6.90 (t, J = 7.9 Hz, 1H), 6.77 (d, J = 7.9 Hz, 1H), 3.00 (s, 3H), 1.47 (q, J = 7.3 Hz, 2H), 1.11 (t, J = 7.3 Hz, 3H), 0.98–0.93 (m, 2H), 0.80–0.75 (m, 2H); LCMS (m/z) 426.2.

Example 800. 6-Fluoro-5-(5-((1-(fluoromethyl)cyclopropyl)ethynyl)-3,4-dihydroquinoline-1(2H)- 1-methyl-[1,2,4]triazolo[4,3-a]quinazolin

The title compound was synthesized in a similar manner according to the procedure described for Example 719. ¹H NMR (400 MHz, DMSO- _d₆ ) δ 8.18 (d, J = 8.6 Hz, ¹H), 8.04–7.95 (m, ¹H), 7.36 (t, J = 11.9 Hz, ¹H), 7.12 (d, J = 7.3 Hz, ¹H), 6.91 (d, J = 7.7 Hz, ¹H), 6.81 (d, J = 7.8 Hz, ¹H), 4.41 (d, J = 48.5 Hz, 2H), 3.00 (s, 3H), 1.17–1.05 (m, 4H); LCMS (m/z) 430.2.

Example 801. N-(2,2-difluoroethyl)-6,7-difluoro-N-(3-fluoro-5-(4,4,4-trifluoro-3,3-dimethyl) But-1-yn-1-yl)phenyl)-1-methyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine

The title compound was synthesized in a similar manner according to the procedure described for Example 690. ¹H NMR (400 MHz, DMSO- _d₆ ) δ 8.20–8.16 (m, ¹H), 8.08 (q, J = 9.5 Hz, ¹H), 7.23 (s, ¹H), 7.14 (dt, J = 10.7, 2.2 Hz, ¹H), 7.08–7.03 (m, ¹H), 6.53 (tt, J = 55.7, 3.8 Hz, ¹H), 4.64 (td, J = 15.3, 14.9, 3.5 Hz, 2H), 3.00 (s, 3H), 1.48 (s, 6H); LCMS (m/z) 528.1.

Example 802. N-(2,2-difluoroethyl)-6,7-difluoro-N-(3-fluoro-5-((1-(fluoromethyl)cyclopropyl)acetylene) (1,2,4)triazolo[4,3-a]quinazolin-5-amine

The title compound was synthesized in a similar manner according to the procedure described for Example 690. ¹H NMR (400 MHz, DMSO- _d₆ ) δ 8.17 (dd, J = 9.2, 3.7 Hz, 1H), 8.08 (q, J = 9.0 Hz, 1H), 7.11 (d, J = 14.6 Hz, 2H), 6.52 (tt, J = 56.1, 4.2 Hz, 1H), 4.62 (t, J = 15.3 Hz, 2H), 4.33 (d, J = 48.5 Hz, 2H), 3.00 (s, 3H), 1.13–0.99 (m, 4H); LCMS (m/z) 490.1.

Example 803. 4-(3-(cyclopropyl(7-fluoro-[1,2,4]triazolo[4,3-a]quinazolin-5-yl)amino)-5- (Fluorophenyl)-2-methylbut-3-yne-2-ol

Synthesis of 2-(3-bromo-5-fluorophenoxy)-N-cyclopropylacetamide: _3- bromo-4-fluorophenol (3.58 g, 18.7 mol) and 2-chloro-N-cyclopropylacetamide (1.00 g, 7.49 mmol) were added to a stirred solution of _K₂CO₃ (2.59 g, 18.7 mol) in toluene (7.0 mL) at room temperature, and the mixture was heated at 105 °C for 18 hours. After completion, the solvent was removed under reduced pressure, and the mixture was dissolved in DCM, filtered, and concentrated under reduced pressure to provide a crude product, which was used without further purification. MS (m/z) 288.3 [M+H] ^⁺ .

Synthesis of 3-bromo-N-cyclopropyl-5-fluoroaniline: 2-(3-bromo-5-fluorophenoxy)-N-cyclopropylacetamide (2.16 g, 7.50 mmol) was added to a solution of KOH (841 mg, 15.0 mmol) in NMP (9.30 mL) and toluene (37.0 mL), and the mixture was heated at 120 °C for 16 h. The solvent was removed under reduced pressure, and the crude product was purified by rapid chromatography using hexane elution (0-50%) with EA to provide the final product. MS (m/z) 230.4 [M+H] ⁺ .

Synthesis of N-(3-bromo-5-fluorophenyl)-2-chloro-N-cyclopropyl-6-fluoroquinazoline-4-amine: NaH (60% dispersion in mineral oil) (68.9 mg, 1.80 mmol) was added in a single addition to a solution of 3-bromo-N-cyclopropyl-5-fluoroaniline (318 mg, 1.38 mmol) in DMF (2.0 mL) at 0 °C. The mixture was stirred at 0 °C for 30 min, followed by the addition of 2,4-dichloro-6-fluoroquinazoline (300 mg, 1.38 mmol). The cold bath was removed, and the mixture was stirred at room temperature for 2 h. After completion, the reactants were cooled to 0 °C and quenched with a few drops of saturated _NH₄Cl solution (aqueous) and stirred until the solid was broken up. The solid was filtered off, washed with a 4:1 mixture of hexane and diethyl ether, dried under vacuum, and used without further purification. MS (m/z) 410.4 [M+H] ^⁺ .

Synthesis of (E)-N-(3-bromo-5-fluorophenyl)-N-cyclopropyl-6-fluoro-2-hydrazinyl-1,2-dihydroquinazoline-4-amine: Hydrazine monohydrate (833 mg, 26.0 mmol) was added to a solution of N-(3-bromo-5-fluorophenyl)-2-chloro-N-cyclopropyl-6-fluoroquinazoline-4-amine (427 mg, 1.04 mmol) in THF (10.0 mL) and ethanol (5.00 mL), and the mixture was stirred at room temperature for 12 hours. After completion, the reactants were diluted with EA and washed with water, dried over _Na₂SO₄ , and concentrated under reduced pressure to provide the product. _MS (m/z) 406.5 [M+H] ^⁺ .

Synthesis of N-(3-bromo-5-fluorophenyl)-N-cyclopropyl-7-fluoro-[1,2,4]triazolo[4,3-a]quinazoline-5-amine: A solution of (E)-N-(3-bromo-5-fluorophenyl)-N-cyclopropyl-6-fluoro-2-hydrazyl-1,2-dihydroquinazoline-4-amine (232 mg, 0.571 mmol) and triethyl orthoformate (3.39 g, 22.8 mmol) was heated to 110 °C for 16 hours. After completion, the reactants were cooled to room temperature and concentrated under reduced pressure to provide a crude product. The crude product was ground with heptane, and the solid was collected by filtration, washed with hexane:ethyl ether (4:1), and dried under vacuum to provide the desired product. MS (m/z) 416.3 [M+H] ⁺ .

Synthesis of 4-(3-(cyclopropyl(7-fluoro-[1,2,4]triazolo[4,3-a]quinazolin-5-yl)amino)-5-fluorophenyl)-2-methylbut-3-yn-2-ol: A solution of N-(3-bromo-5-fluorophenyl)-N-cyclopropyl-7-fluoro-[1,2,4]triazolo[4,3-a]quinazolin-5-amine (24.5 mg, 0.0589 mmol), zinc bromide (66.3 mg, 0.294 mmol), (1,1'-)bis(diphenylphosphine)ferrocene)palladium(II) dichloride (2.17 mg, 0.00294 mmol) and triethylamine (119 mg, 1.18 mmol) in DMF (0.60 mL) was purged with nitrogen for 5 min. Then 2-methylbut-3-yn-2-ol (14.9 mg, 0.177 mol) was added, and the mixture was heated at 100 °C for 30 min. After completion, the mixture was cooled to room temperature, and ethyl acetate and saturated _NH₄Cl (aqueous solution) were added to the mixture. The organic layer was dried over _Na₂SO₄ and concentrated under vacuum. The residue was purified by reversed _- phase HPLC (acetonitrile/water containing 0.1% trifluoroacetic acid) to provide the title compound as a single TFA salt. 1H NMR (400MHz, DMSO-d ₆ )δ9.87(s,1H),8.53(dd,J＝9.2,4.7Hz,1H),7.97(td,J＝8.6,2.6Hz,1H),7.55(dd,J＝9.7,2.6Hz,1H),7.28(d,J＝12.4Hz,1H),7 .22(s,1H),7.10–7.04(m,1H),3.25(m,1H),1.43(s,6H),1.01(q,J＝6.7Hz,2H),0.86(q,J＝8.4,6.4Hz,2H); MS(m/z)420.1[M+H] ⁺ .

Example 804. 4-(3-(cyclopropyl(7-fluoro-[1,2,4]triazolo[4,3-a]quinazolin-5-yl)amino)-5- (Fluorophenyl)-2-methylbut-3-yne-2-ol

The title compound was synthesized in a manner similar to that used in Example 803. ¹H NMR (400 MHz, DMSO- _d₆ ) δ 9.88 (s, ¹H), 8.56–8.50 (m, ¹H), 7.97 (t, J = 9.9 Hz, ¹H), 7.52 (dd, J = 9.7, 2.3 Hz, ¹H), 7.27 (d, J = 10.7 Hz, ¹H), 7.18 (s, ¹H), 7.09–7.03 (m, ¹H), 3.23 (m, ¹H), 1.27 (s, 3H), 1.00 (q, J = 6.4, 5.8 Hz, 2H), 0.92 (d, J = 2.5 Hz, 2H), 0.87 (m, 2H), 0.73 (q, J = 4.0 Hz, 2H); LCMS (m/z) 416.1.

Example 805. N-(2,2-difluoroethyl)-6,7-difluoro-N-(3-fluoro-5-((1-methylcyclopropyl)ethynyl) phenyl)-1-methyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine

The title compound was synthesized in a manner similar to that used in Example 690. ¹H NMR (400 MHz, DMSO- _d₆ ) δ 8.17 (dd, J = 9.6, 3.5 Hz, 1H), 8.08 (q, J = 9.3 Hz, 1H), 7.08 (m, 2H), 7.00–6.93 (m, 1H), 6.52 (tt, J = 55.9, 3.7 Hz, 1H), 4.67–4.56 (m, 2H), 3.00 (s, 3H), 1.27 (s, 3H), 0.92 (q, J = 4.0 Hz, 2H), 0.73 (q, J = 4.1 Hz, 2H); LCMS (m/z) 472.1.

Example 806. 4-(3-((6,7-difluoro-1-methyl-[1,2,4]triazolo[4,3-a]quinazolin-5-yl)(2, 2-Difluoroethyl)amino)-5-fluorophenyl)-2-methylbut-3-yne-2-ol

The title compound was synthesized in a manner similar to that used in Example 690. ¹H NMR (400 MHz, DMSO- _d₆ ) δ 8.18 (dd, J = 9.3, 3.8 Hz, 1H), 8.08 (q, J = 9.2 Hz, 1H), 7.12 (m, 2H), 6.99 (d, J = 8.8 Hz, 1H), 6.53 (tt, J = 56.0, 3.8 Hz, 1H), 4.64 (t, J = 15.3 Hz, 2H), 3.00 (s, 3H), 1.43 (s, 6H); LCMS (m/z) 476.1.

Example 807. N-(2,2-difluoroethyl)-6,7-difluoro-N-(3-fluoro-5-((1-(trifluoromethyl)cyclopropyl)ethyl) (alkynyl)phenyl)-1-methyl-[1,2,4]triazolo[4,3-a]quinazolin-5-amine

The title compound was synthesized in a manner similar to that used in Example 690. ¹H NMR (400 MHz, DMSO- _d₆ ) δ 8.18 (dd, J = 9.4, 3.6 Hz, 1H), 8.11 (d, J = 9.2 Hz, 1H), 7.23 (s, 1H), 7.17 (d, J = 10.7 Hz, 1H), 7.12–7.08 (m, 1H), 6.53 (tt, J = 55.9, 3.6 Hz, 1H), 4.69–4.59 (m, 2H), 3.01 (s, 3H), 1.46–1.34 (m, 4H); LCMS (m/z) 526.1.

Example 808. 5-(5-((1-ethylcyclopropyl)ethynyl)-3,4-dihydroquinoline-1(2H)-yl)-7-fluoro-1- Methyl-[1,2,4]triazolo[4,3-a]quinazolin

The title compound was synthesized in a manner similar to that used in Example 719. ¹H NMR (400 MHz, DMSO- _d₆ ) δ 8.40 (dd, J = 9.4, 4.5 Hz, 1H), 7.89 (ddd, J = 10.1, 7.9, 2.9 Hz, 1H), 7.41 (dd, J = 9.6, 2.7 Hz, 1H), 7.16 (d, J = 7.5 Hz, 1H), 6.96 (d, J = 7.8 Hz, 1H), 6.79 (d, J = 8.1 Hz, 1H), 4.00 (t, J = 6. 1Hz,2H),3.02(s,3H),2.98(t,J＝6.7Hz,2H),2.11(p,J＝6.0Hz,2H),1.48(q,J＝7.3Hz,2H ), 1.13 (t, J = 7.3Hz, 3H), 0.97 (q, J = 4.0Hz, 2H), 0.80 (q, J = 4.1Hz, 2H); LCMS (m/z) 426.2.

Example 809. 5-(5-(3-cyclopropyl-3-methylbut-1-yn-1-yl)-3,4-dihydroquinoline-1(2H)-yl)- 6,7-Difluoro-1-methyl-[1,2,4]triazolo[4,3-a]quinazolin

The title compound was synthesized in a manner similar to that used in Example 719. ¹H NMR (400 MHz, DMSO- _d⁶ ) δ 8.19–8.14 (m, 1H), 8.12–8.03 (m, 1H), 7.04 (d, J = 7.5 Hz, 1H), 6.90 (d, J = 7.8 Hz, 1H), 6.78 (d, J = 8.4 Hz, 1H), 4.08–3.90 (m, 2H), 2.98 (s, 3H), 2.89–2.80 (m, 2H), 2.19–1.93 (m, 2H), 1.37 (s, 6H), 0.96–0.90 (m, 1H), 0.44 (d, J = 5.1 Hz, 4H); LCMS (m/z) 458.2.

Example 810. 5-(5-((1-ethylcyclopropyl)ethynyl)-3,4-dihydroquinoline-1(2H)-yl)-6,7-di Fluoro-1-methyl-[1,2,4]triazolo[4,3-a]quinazoline

The title compound was synthesized in a manner similar to that used in Example 719. ¹H NMR (400 MHz, DMSO- _d₆ ) δ 8.18–8.07 (m, 2H), 7.08 (d, J = 7.7 Hz, 1H), 6.92 (t, J = 7.8 Hz, 1H), 6.79 (d, J = 8.0 Hz, 1H), 4.27–3.82 (m, 2H), 2.99 (s, 3H), 2.90–2.71 (m, 2H), 2.16–1.89 (m, 2H), 1.51–1.44 (m, 2H), 1.12 (t, J = 7.3 Hz, 3H), 0.96 (q, J = 4.1 Hz, 2H), 0.78 (q, J = 4.1 Hz, 2H); LCMS (m/z) 444.2.

Example 811. 8-Chloro-N-(3-(3-cyclopropyl-3-methylbut-1-yn-1-yl)-5-fluorophenyl)-N-(2,2- (difluoroethyl)-[1,2,4]triazolo[4,3-a]quinazolin-5-amine

The title compound was synthesized in a manner similar to that used in Example 421. ¹H NMR (400 MHz, DMSO- _d⁶ ) δ 9.77 (s, ¹H), 8.65 (s, ¹H), 7.48 (d, J = 9.0 Hz, ¹H), 7.34–7.29 (m, ¹H), 7.24 (m, 2H), 7.08 (d, J = 7.5 Hz, ¹H), 6.70–6.38 (m, ¹H), 4.62–4.50 (m, 2H), 1.27 (s, 6H), 0.90 (s, ¹H), 0.37 (m, 4H); LCMS (m/z) 484.1.

Example 812. 5-(5-((1-ethylcyclopropyl)ethynyl)-3,4-dihydroquinolino-1(2H)-yl)-6-fluoro-[1, [2,4]triazolo[4,3-a]quinazoline

The title compound was synthesized in a manner similar to that used in Example 719. ¹H NMR (400 MHz, DMSO-d6 ₎ )δ9.77(s,1H),8.23(d,J＝8.3Hz,1H),8.04–7.97(m,1H),7.30(dd,J＝11.8,8. 3Hz,1H),7.05(d,J＝7.3Hz,1H),6.88(t,J＝7.9Hz,1H),6.79(d,J＝8.1Hz,1H), 3.78(m,2H),3.04–2.76(m,2H),2.15–1.91(m,2H),1.47(q,J＝7.3Hz,2H),1.1 2(t,J＝7.3Hz,3H),0.96(q,J＝4.0Hz,2H),0.80–0.75(m,2H); LCMS(m/z)412.2.

Example 813. 5-(5-((1-fluoromethylcyclopropyl)ethynyl)-3,4-dihydroquinoline-1(2H)-yl)-6-fluoro- [1,2,4]triazolo[4,3-a]quinazolin

The title compound was synthesized in a manner similar to that used in Example 719. ¹H NMR (400 MHz, DMSO- _d₆ ) δ 9.80 (s, ¹H), 8.24 (d, J = 8.4 Hz, ¹H), 8.05–7.97 (m, ¹H), 7.31 (dd, J = 11.9, 8.3 Hz, ¹H), 7.09 (d, J = 7.4 Hz, ¹H), 6.91 (t, J = 7.9 Hz, ¹H), 6.84 (d, J = 8.0 Hz, ¹H), 4.47 (s, ¹H), 4.35 (s, ¹H), 3.78 (m, 2H), 2.99–2.81 (m, 2H), 2.16–1.95 (m, 2H), 1.16–1.07 (m, 4H); LCMS (m/z) 416.1.

Example 814. N-(3-(3-cyclopropyl-3-methylbut-1-yn-1-yl)-5-fluorophenyl)-N-(2,2-difluoroethyl) α-7-fluoro-[1,2,4]triazolo[4,3-a]quinazolin-5-amine

The title compound was synthesized in a manner similar to that used in Example 690. ¹H NMR (400 MHz, DMSO- _d⁶ ) δ 9.82 (s, ¹H), 8.50 (dd, J = 9.2, 4.8 Hz, ¹H), 7.92 (dd, J = 17.2, 2.7 Hz, ¹H), 7.32–7.25 (m, 2H), 7.13 (d, J = 9.1 Hz, 1H), 6.95 (dd, J = 9.9, 2.7 Hz, 1H), 6.72–6.40 (m, ¹H), 4.63–4.47 (m, 2H), 1.28 (s, 6H), 0.92–0.85 (m, 1H), 0.43–0.31 (m, 4H); LCMS (m/z) 468.2.

Example 815. 4-(3-((2,2-difluoroethyl)(7-fluoro-[1,2,4]triazolo[4,3-a]quinazolin-5-yl) (amino)-5-fluorophenyl)-2,2-dimethylbut-3-ynenitrile

The title compound was synthesized in a manner similar to that used in Example 690. ¹H NMR (400 MHz, DMSO- _d₆ ) δ 9.85–9.75 (s, ¹H), 8.53–8.46 (m, ¹H), 7.91 (t, J = 8.6 Hz, ¹H), 7.40 (d, J = 9.9 Hz, 2H), 7.29 (d, J = 9.4 Hz, 1H), 6.97 (d, J = 9.8 Hz, 1H), 6.57 (t, J = 56.1 Hz, 1H), 4.58 (t, J = 15.0 Hz, 2H), 1.69 (s, 6H); LCMS (m/z) 453.1.

Example 816. 4-(3-((2,2-difluoroethyl)(7-fluoro-[1,2,4]triazolo[4,3-a]quinazolin-5-yl) (amino)-5-fluorophenyl)-2,2-dimethylbut-3-ynenitrile

The title compound was synthesized in a manner similar to that used in Example 690. ¹H NMR (400 MHz, DMSO- _d₆ ) δ 9.82 (s, ¹H), 8.50 (dd, J = 9.2, 4.8 Hz, ¹H), 7.92 (td, J = 8.8, 2.7 Hz, ¹H), 7.36–7.28 (m, 2H), 7.19 (d, J = 8.9 Hz, 1H), 6.96 (dd, J = 9.9, 2.7 Hz, 1H), 6.55 (tt, J = 56.0, 3.9 Hz, 1H), 4.56 (td, J = 14.4, 3.7 Hz, 2H), 4.40 (s, ¹H), 4.27 (s, ¹H), 1.12–1.01 (m, 4H); LCMS (m/z) 458.1.

Example 817. N-(3-((1-ethylcyclopropyl)ethynyl)-5-fluorophenyl)-7-fluoro-N-methyl-[1,2,4]tri Azo[4,3-a]quinazolin-5-amine

The title compound was synthesized in a manner similar to that used in Example 690. ¹H NMR (400 MHz, DMSO- _d₆ ) δ 9.85 (s, ¹H), 8.51 (dd, J = 9.2, 4.8 Hz, ¹H), 7.99–7.90 (m, ¹H), 7.38 (d, J = 10.0 Hz, ¹H), 7.29 (s, ¹H), 7.23 (d, J = 8.3 Hz, ¹H), 6.97 (dd, J = 10.1, 2.7 Hz, ¹H), 3.59 (s, 3H), 1.40 (q, J = 7.3 Hz, 2H), 1.03 (t, J = 7.3 Hz, 3H), 0.90 (q, J = 4.0 Hz, 2H), 0.75–0.71 (m, 2H); LCMS (m/z) 404.1.

Example 818. 8-Chloro-N-(3-(3-cyclopropyl-3-methylbut-1-yn-1-yl)-5-fluorophenyl)-N-methyl- [1,2,4]triazolo[4,3-a]quinazolin-5-amine

The title compound was synthesized in a manner similar to that used in Example 447. ¹H NMR (400 MHz, DMSO- _d⁶ ) δ 9.76 (s, ¹H), 8.64 (d, J = 2.0 Hz, ¹H), 7.51–7.46 (m, ¹H), 7.37–7.27 (m, 2H), 7.23 (s, ¹H), 7.12 (d, J = 8.5 Hz, ¹H), 3.57 (s, 3H), 1.27 (s, 6H), 0.88 (tt, J = 7.8, 5.6 Hz, 1H), 0.39–0.33 (m, 4H); LCMS (m/z) 434.1.

Example 819. 8-Chloro-N-(3-((1-(fluoromethyl)cyclopropyl)ethynyl)phenyl)-N-methyl-[1,2,4]tri Azo[4,3-a]quinazolin-5-amine

The title compound was synthesized in a manner similar to that used in Example 447. ¹H NMR (400 MHz, DMSO- _d₆ ) δ 9.77 (s, ¹H), 8.63 (d, J = 2.0 Hz, ¹H), 7.48–7.33 (m, 5H), 7.21 (d, J = 9.0 Hz, 1H), 4.33 (d, J = 48.5 Hz, 2H), 3.58 (s, 3H), 1.10–1.00 (m, 4H); LCMS (m/z) 406.1.

Example 820. 8-Chloro-N-ethyl-N-(3-((1-ethylcyclopropyl)ethynyl)-5-fluorophenyl)-[1,2,4] Triazolo[4,3-a]quinazolin-5-amine

The title compound was synthesized in a manner similar to that used in Example 447. ¹H NMR (400 MHz, DMSO-d6 ₎ )δ9.79(s,1H),8.64(d,J＝2.0Hz,1H),7.49(dd,J＝9.0,2.1Hz,1H),7.34(dt, J＝10.1,2.1Hz,1H),7.29(d,J＝9.0Hz,1H),7.24(d,J＝1.5Hz,1H),7.22–7.17( m,1H),4.16(q,J＝6.9Hz,2H),1.40(q,J＝7.3Hz,2H),1.23(t,J＝7.0Hz,3H),1 .02(t,J＝7.3Hz,3H),0.91–0.86(m,2H),0.75–0.70(m,2H); LCMS(m/z)434.1.

Example 821. 8-Chloro-N-(cyclopropylmethyl)-N-(3-((1-methylcyclopropyl)ethynyl)phenyl)-[1,2, 4] Triazolo[4,3-a]quinazolin-5-amine

Synthesis of 3-bromo-N-(cyclopropylmethyl)aniline: Sodium triacetoxyborohydride (1.30 g, 6.13 mmol) was added to a solution of cyclopropionaldehyde (204 mg, 2.91 mmol) and 3-bromoaniline (500 mg, 2.91 mmol) in DCM (4.20 mL) at room temperature, and the mixture was stirred for 48 hours. After completion, the reaction was quenched with saturated sodium bismuth carbonate solution (bubbling observed), and the mixture was transferred to a separatory funnel and the aqueous phase was extracted with DCM. The combined organic layers were washed with brine, dried over _Na₂SO₄ , and concentrated under reduced pressure. The crude product was purified by rapid chromatography using hexane solution (0–30%) in EA, providing the product. _MS (m/z) 227.9 [M+H] ^⁺ .

Synthesis of N-(3-bromophenyl)-2,7-dichloro-N-(cyclopropylmethyl)quinazoline-4-amine: The intermediate was prepared using 3-bromo-N-(cyclopropylmethyl)aniline and 2,4,7-trichloroquinazoline in a manner similar to that described in Example 803.

Synthesis of (E)-N-(3-bromophenyl)-7-chloro-N-(cyclopropylmethyl)-2-hydrazinyl-1,2-dihydroquinazoline-4-amine: The intermediate was prepared using N-(3-bromophenyl)-2,7-dichloro-N-(cyclopropylmethyl)quinazoline-4-amine in a manner similar to that described in Example 803.

Synthesis of N-(3-bromophenyl)-8-chloro-N-(cyclopropylmethyl)-[1,2,4]triazolo[4,3-a]quinazoline-5-amine: The intermediate was prepared using (E)-N-(3-bromophenyl)-7-chloro-N-(cyclopropylmethyl)-2-hydrazinyl-1,2-dihydroquinazoline-4-amine in a manner similar to that described in Example 803.

Synthesis of 8-chloro-N-(cyclopropylmethyl)-N-(3-((1-methylcyclopropyl)ethynyl)phenyl)-[1,2,4]triazolo[4,3-a]quinazoline-5-amine: The title compound was synthesized using N-(3-bromophenyl)-8-chloro-N-(cyclopropylmethyl)-[1,2,4]triazolo[4,3-a]quinazoline-5-amine and 1-ethynyl-1-methylcyclopropane, as described in Example 803. 1H NMR (400MHz, DMSO-d ₆ )δ9.70(s,1H),8.59(d,J＝1.9Hz,1H),7.42–7.33(m,3H),7.32–7.27(m,2H),7.22(d,J＝9.0Hz,1H),3.97(d,J＝6.8Hz,2H),1.3 6–1.30(m,1H),1.28(s,3H),0.91(q,J＝3.9Hz,2H),0.72(q,J＝4.1Hz,2H),0.42–0.36(m,2H),0.12(m,2H); MS(m/z)428.1[M+H] ⁺ .

Example 822. 8-Chloro-N-(3-((3,3-difluorocyclobutyl)ethynyl)phenyl)-7-fluoro-N-methyl-[1,2, 4] Triazolo[4,3-a]quinazolin-5-amine

The title compound was synthesized in a manner similar to that used in Example 447. ¹H NMR (400 MHz, DMSO- _d₆ ) δ 9.71 (s, ¹H), 8.83 (d, J = 6.2 Hz, ¹H), 7.50 (s, ¹H), 7.49–7.37 (m, ³H), 6.98 (d, J = 11.1 Hz, ¹H), 3.57 (s, ³H), 3.28–3.20 (m, ¹H), 3.00 (q, J = 9.1 Hz, ¹H), 2.77–2.64 (m, ²H); LCMS (m/z) 442.2.

Example 823. 1-(5-(3-((8-chloro-7-fluoro-[1,2,4]triazolo[4,3-a]quinazolin-5-yl)(methyl) (amino)phenyl)pyridin-2-yl)cyclopropane-1-carboxynitrile

The title compound was synthesized in a manner similar to that used in Example 527. ¹H NMR (400 MHz, DMSO- _d₆ ) δ 9.76 (s, ¹H), 8.85 (d, J = 6.6 Hz, ¹H), 8.81 (dd, J = 2.4, 0.9 Hz, ¹H), 8.14 (dd, J = 8.3, 2.4 Hz, ¹H), 7.87–7.75 (m, 2H), 7.67–7.56 (m, 2H), 7.53–7.45 (m, 1H), 7.02 (d, J = 10.8 Hz, 1H), 3.67 (s, 3H), 1.86–1.82 (m, 2H), 1.73–1.68 (m, 2H); LCMS (m/z) 470.1.

Example 824. 1-(5-(3-((8-chloro-[1,2,4]triazolo[4,3-a]quinazolin-5-yl)(methyl)amino) (Phenyl)pyridin-2-yl)cyclobutane-1-carboxynitrile

The title compound was synthesized in a manner similar to that used in Example 527. ¹H NMR (400 MHz, DMSO-d6 ₎ )δ9.79(s,1H),8.90(d,J＝2.1Hz,1H),8.63(s,1H),8.18–8.14(m,1H),7.84( s,1H),7.77(d,J＝8.0Hz,1H),7.66(d,J＝8.2Hz,1H),7.61(t,J＝7.9Hz,1H),7. 47(d,J＝7.8Hz,1H),7.40(d,J＝10.7Hz,1H),7.29(d,J＝9.0Hz,1H),3.68(s,3H ),2.81–2.68(m,4H),2.35–2.21(m,1H),2.12–2.00(m,1H); LCMS(m/z)466.1.

Example 825. 6-Bromo-1-(6-fluoro-1-methyl-[1,2,4]triazolo[4,3-a]quinazolin-5-yl)-3,5- dihydro-2H-4,1-benzoxazine

Step 1: Preparation of 6-bromo-1-(2-chloro-5-fluoro-quinazoline-4-yl)-3,5-dihydro-2H-4,1-benzoxazolidinium: 6-bromo-1,2,3,5-tetrahydro-4,1-benzoxazolidinium (300 mg, 1.32 mmol) was treated with LHMDS (1.0 M THF solution (Aldrich), 1.45 mL, 1.45 mmol, 1.1 equivalent) in 10 mL of THF at room temperature for 20 minutes. 2,4-Dichloro-5-fluoro-quinazoline (285 mg, 1.32 mmol, 1 equivalent) was added to the reaction mixture, and the mixture was stirred at the same temperature for 1 hour. The mixture was then proceeded to the next step without further treatment.

Step 2: Preparation of [4-(6-bromo-3,5-dihydro-2H-4,1-benzoxazolin-1-yl)-5-fluoro-quinazoline-2-yl]hydrazine: A mixture containing 6-bromo-1-(2-chloro-5-fluoro-quinazoline-4-yl)-3,5-dihydro-2H-4,1-benzoxazolin-2-yl) in ethanol (2 mL) and THF (4 mL) was treated with hydrazine hydrate (1912 mg, 38.2 mmol, 27 equivalences) at 60 °C for 1 h. Water (30 mL) was added to the mixture and the entire mixture was extracted with EtOAc (30 mL, × 3). The organic layer was washed with brine (30 mL) and _dried over _Na₂SO₄ . The organic solvent was removed under reduced pressure to give the crude product. The crude product was purified by preparative reversed-phase high-performance liquid chromatography to obtain [4-(6-bromo-3,5-dihydro-2H-4,1-benzoxazon-1-yl)-5-fluoro-quinazolin-2-yl]hydrazine: LCMS- _ESI +(m/z): [M+H]+ _{C17H15BrFN5O .} The calculated values were 404.04(M-1+1) and 406.04(M+1+1), and the experimental values were 404.29(M-1+1) and 406.20(M+1+1).

Step 3: Preparation of 6-bromo-1-(6-fluoro-1-methyl-[1,2,4]triazolo[4,3-a]quinazolin-5-yl)-3,5-dihydro-2H-4,1-benzoxazolin-2-yl]hydrazine (275 mg, 0.68 mol, from Step 2) in triethyl orthoacetate (552 mg, 3.40 mmol, 5 equivalents) was heated at 120 °C for 16 hours. Hexane (5 mL) was added to the reaction mixture to form a precipitate. The precipitate was collected by filtration through a glass filter, yielding the title compound: ^¹H NMR (400 MHz, methanol- _d⁴ ) δ 8.18–8.09 (m, 1H), 7.94–7.81 (m, 1H), 7.43 (d, J = 8.0 Hz, 1H), 7.09 (dd, J = 12.3, 8.4 Hz, 1H), 6.91 (t, J = 8.1 Hz, 1H), 6.65 (d, J = 7.9 Hz, 1H), 5.20 (br s, 4H), 4.06 (br s, 2H), 3.05 (s, 3H); LCMS-ESI+ (m/z): [M ₊ H] _{+ C¹⁹H¹⁵BrFN₅} Calculated values of O: 428.04(M-1+1), 430.04(M+1+1), experimental values: 428.25(M-1+1), 430.20(M+1+1).

Example 826. 1-(6-fluoro-1-methyl-[1,2,4]triazolo[4,3-a]quinazolin-5-yl)-6-(4,4,4- (trifluoro-3,3-dimethyl-but-1-ynyl)-3,5-dihydro-2H-4,1-benzoxazine

6-Bromo-1-(6-fluoro-1-methyl-[1,2,4]triazolo[4,3-a]quinazolin-5-yl)-3,5-dihydro-2H-4,1-benzoxazazepone (Example 825, 11.1 mg, 0.0258 mmol), 4,4,4-trifluoro-3,3-dimethyl-but-1-yne (21.1 mg, 0.155 mmol, 6 equivalents), DIPEA (33.4 mg, 0.258 mmol, 10 equivalents), zinc bromide (58.1 mg, 0.258 mmol, 10 equivalents), and [1,1'-bis(diphenylphosphine)ferrocene]palladium(II) dichloride (1.91 mg, 0.00258 mmol, 0.1 equivalents) were heated in NMP (0.3 mL) at 120 °C for 40 minutes under a nitrogen atmosphere. After filtration, the reaction mixture was purified by preparative reversed-phase high-performance liquid chromatography (RP-HPLC) to obtain the title compound. ^¹H NMR (400 MHz, methanol- _d⁴ ) δ 8.24 (d, J = 8.6 Hz, 1H), 8.04 (td, J = 8.4, 5.4 Hz, 1H), 7.40 (dd, J = 7.8, 1.1 Hz, 1H), 7.23 (ddd, J = 11.9, 8.3, 0.9 Hz, 1H), 7.07 (t, J = 7.9 Hz, 1H), 6.86 (dd, J = 8.0, 1.1 Hz, 1H), 5.90–5.10 (br s, 4H), 4.15 (s, 2H), 3.09 (s, 3H), 1.58 (s _, 6H); LCMS-ESI+ (m/z): [M+H]+ _{C₂₃H₁₉FN} Calculated value of ₆ : 484.17(M+1), experimental value: 484.31(M+1).

Example 827. 1-(6-fluoro-1-methyl-[1,2,4]triazolo[4,3-a]quinazolin-5-yl)-6-[2-[1- [(trifluoromethyl)cyclopropyl]ethynyl]-3,5-dihydro-2H-4,1-benzoxazine

The title compound was synthesized in a manner similar to that of Example 826, except that 1-ethynyl-1-(trifluoromethyl)cyclopropane was used instead of 4,4,4-trifluoro-3,3-dimethyl-but-1-yne. ¹ H NMR (400MHz, methanol-d ₄ )δ8.24(d,J＝8.6Hz,1H),8.04(td,J＝8.5,5.4Hz,1H),7.40(dd,J＝7.8,1.2Hz,1H ),7.28–7.17(m,1H),7.06(t,J＝7.9Hz,1H),6.86(dd,J＝8.1,1.1Hz,1H),5.40(br s,4H),4.15(br s,2H),3.09(s,3H),1.55–1.43(m,2H),1.42–1.29(m,2H); LCMS-ESI+(m/z):[M+H]+C ₂₅ H ₁₉ F ₄ N ₅ Calculated value of O: 482.15(M+1), experimental value: 482.36(M+1).

Example 828. 6-[2-[1-(1,1-difluoroethyl)cyclopropyl]ethynyl]-1-(6-fluoro-1-methyl-[1,2, 4] Triazolo[4,3-a]quinazolin-5-yl)-3,5-dihydro-2H-4,1-benzoxazolidinium

The title compound was synthesized in a manner similar to that in Example 826, except that 1-(1,1-difluoroethyl)-1-ethynyl-cyclopropane was used instead of 4,4,4-trifluoro-3,3-dimethyl-but-1-yne. ^¹H NMR (400 MHz, methanol- _d⁴ ) δ 8.24 (d, J = 8.6 Hz, 1H), 8.03 (td, J = 8.4, 5.4 Hz, 1H), 7.37 (dd, J = 7.8, 1.2 Hz, 1H), 7.22 (ddd, J = 11.9, 8.4, 0.9 Hz, 1H), 7.04 (t, J = 7.9 Hz, 1H), 6.82 (dd, J = 8.0, 1.1 Hz, 1H), 5.44 (br s, 4H), 4.14 (br s,2H),3.09(s,3H),1.89(t,J＝18.0Hz,3H),1.37–1.28(m,2H),1.17(tq,J＝5.0,3.3,2.4Hz,2H);Calculated value of LCMS-ESI+(m/z):[M+H]+C ₂₆ H ₂₂ F ₃ N ₅ O: 478.18(M+1), Experimental value: 478.38(M+1).

Example 829. 1-(6-fluoro-1-methyl-[1,2,4]triazolo[4,3-a]quinazolin-5-yl)-6-[2-(1-methyl [[ ...]]][[[[[[[[[[[[[[[[[[[[]][[[[[[[[[[[[[[[]][[[[[[[[[[[[]][[[[[[

The title compound was synthesized in a manner similar to that of Example 826, except that 1-ethynyl-1-methyl-cyclopropane was used instead of 4,4,4-trifluoro-3,3-dimethyl-but-1-yne. ¹ H NMR (400MHz, methanol-d ₄ )δ8.23(d,J＝8.6Hz,1H),8.03(td,J＝8.5,5.4Hz,1H),7.31(dd,J＝7.8,1.1Hz,1H), 7.21(dd,J＝11.7,8.3Hz,1H),7.00(t,J＝7.9Hz,1H),6.75(d,J＝7.9Hz,1H),5.46(br s,4H),4.13(br s,2H),3.09(s,3H),1.40(s,3H),1.04(q,J＝4.1Hz,2H),0.87–0.70(m,2H); LCMS-ESI+(m/z):[M+H]+C ₂₅ H ₂₂ FN ₅ Calculated value of O: 428.18(M+1), experimental value: 428.29(M+1).

Example 830. Bioactivity

Measuring DGKα activity

The 10 mM solution of the test compound in DMSO was further diluted with DMSO to 10 concentration levels (0.0001 mM, 0.0003 mM, 0.001 mM, 0.003 mM, 0.01 mM, 0.03 mM, 0.1 mM, 0.3 mM, 1 mM, 3 mM), and each concentration level was diluted 25-fold with assay buffer to obtain a drug solution (4% DMSO solution).

Add the drug solution of each concentration to each well to obtain a final volume of 20 μL. Kinase inhibitory activity was assessed using the QSS Assist ADP-Glo ^™ assay kit (BTN-DGKα; Carna Biosciences, Inc., No. 12-403-20N).

Kinase activity was measured using the ADP-Glo ^™ kinase assay (Promega Corporation). 10 μL of the ADP-Glo ^™ reagent (containing 10 mM Mg) provided in the kit was added to each well and incubated at 25°C for 40 minutes. Then, 20 μL of the kinase assay reagent was added and incubated at 25°C for 40 minutes. The luciferase activity in each well was measured using a microplate reader (EnVision, PerkinElmer, Inc.).

Assessment of inhibitory activity

_IC50 values were calculated by regression analysis of the inhibition rate (%) measured from the luminescence intensity at each concentration and the test compound concentration (logarithmic), where the intensity of the group with added enzyme but no compound was set to 100%, and the intensity of the group with neither enzyme nor compound was set to 0%.

The inhibitory effects of exemplary compounds on DGKα activity are shown in Table 5 below.

Table 5. Activity Data

DGKα biochemical activity assay

Alternatively, human DGKα enzyme activity was monitored in a biochemical assay, with or without the presence of the compound, using micelles containing 18:1 diacylglycerol (DAG), 16:0–18:1 PS (POPS), and octyl glucoside as substrates. DGKα activity results in the conversion of DAG and ATP to phosphatidic acid (PA) and ADP. ADP levels were monitored bioluminescently using the ADP-Glo kinase assay (Promega) and indicated DGKα activity.

Using a Labcyte Echo instrument, 10 nanoliters of various concentrations of test compounds dissolved in DMSO were dispensed into 384-well low-volume unbound service white plates (Corning #3824). Recombinant DGKα (CarnaBiosciences) in assay buffer (5 μL in 50 mM MOPS [3-(N-morpholino)propanesulfonic acid], pH 7.2; 0.0025% Triton X-100; 1 mM dithiothreitol; 5 mM _MgCl₂ , 200 μM ATP) was added to the plates containing the compounds and incubated at 25°C for 15 minutes. Then, a substrate solution diluted in DGKα assay buffer (5 μL in 1.7 mM 1,2-dioleoyl-sn-glycerol [18:1DAG], 13.5 mM 1-palmitoyl-2-oleoyl-sn-glycerol-3-phosphate-L-serine [16:0-18:1PS] (POPS), ₂ μM CaCl2, 100 mM octyl glucoside (OG), 1 mM DTT) (obtained from Carna Biosciences) was added to initiate the reaction. The final concentrations were 1 nM DGKα, 100 μM ATP, 1 μM calcium chloride, 0.85 mM 1,2-dioleoyl-sn-glycerol (18:1DAG), 6.75 mM 1-palmitoyl-2-oleoyl-sn-glycerol-3-phosphate-L-serine (16:0-18:1PS) (POPS), ₁ μM CaCl2, 50 mM octyl glucoside (OG), and 5 mM _MgCl2 . The reaction mixture was incubated at 25 °C for 1 hour. 10 μL of the ADP-Glo reagent (containing 10 mM Mg) provided in the kit was added to each well and incubated at 25 °C for 40 minutes. Then, 20 μL of the kinase assay reagent was added and incubated at 25 °C for 40 minutes. The luciferase activity in each well was measured using a PerkinElmer envision plate reader.

Data were normalized based on maximum inhibition (50 μM kinase inhibitor CU3) and no inhibition (DMSO) control. Least squares curve fitting was performed using a four-parameter variable slope nonlinear regression model. _IC50 was defined as the compound concentration required to inhibit 50% of maximum activity. _IC50 values from multiple experiments were averaged using the geometric mean, and the standard deviation was calculated.

Exemplary biochemical data are shown in Table 6 below.

Table 6. Biochemical Activities of DGKα

Jurkat NFκB luciferase assay

The activity of the compound was tested in a cell-based NFκB reporter assay. Jurkat cells stably expressing a luciferase reporter construct under the transcriptional control of the NFκB reporter element were activated with an anti-CD3 antibody, and luciferase levels were measured using bioluminescent readings. Increased bioluminescence levels indicated enhanced T cell activation following DGKα inhibition by the compound.

Flat-bottom polystyrene plates (384 wells, tissue culture treated) were coated overnight at 4°C with 20 μL/well of phosphate-buffered saline solution supplemented with 5 μg/ml anti-CD3 antibody (clone OKT3, Biolegend). The next day, excess antibody was washed five times with 100 μL/well of assay medium (RPMI supplemented with 10% fetal bovine serum) using a Biotek EL406 instrument, leaving a 20 μL residual volume in each well. Jurkat NFκB luciferase cells (Promega#) were harvested and diluted to 1 million cells/ml in assay medium. Using a Labcyte Echo instrument, 60 nm of assay compounds of various concentrations dissolved in DMSO were dispensed into 384-well V-bottom polypropylene plates (Greiner). Then, using a Biotek MicroFlo instrument, 30 μL of medium containing Jurkat NFκB luciferase cells was dispensed into each well of the compound-containing plate. The culture medium/cell/compound mixture was mixed using a Bravo instrument, and 20 μL/well of the mixture was transferred to an anti-CD3 coated plate. The assay mixture was then incubated at 37°C for 2.5 h, followed by equilibration at 25°C for 30 min. Forty μL of One-Glo Ex (Promega) was then added to the assay mixture, and luciferase activity was read on an Envision plate reader after 7 min.

Bioluminescence data were normalized based on the maximum enhancement (1 μmol compound) and basal activation (DMSO) controls. Least squares curve fitting was performed using a four-parameter variable slope nonlinear regression model. _EC50 was defined as the compound concentration required to produce 50% of the maximum NFκB luciferase signal. _EC50 values from multiple experiments were averaged using the geometric mean, and the standard deviation was calculated.

Exemplary cell data are shown in Table 7 below.

Table 7. DGKα inhibition in Jurkat cells

While the foregoing invention has been described in considerable detail by way of illustration and example for clarity and purpose, those skilled in the art will understand that certain variations and modifications may be practiced within the scope of the appended claims. Furthermore, each reference provided herein is incorporated in its entirety as if it were incorporated individually. In the event of any conflict between this application and the references provided herein, this application shall prevail.

Claims (26)

1. A compound of formula (I), Or its pharmaceutically acceptable salt, wherein ^R1 is hydrogen, _C1-6 alkyl, _C2-6 alkenyl, _C2-6 alkynyl, _C1-6 alkoxy, halogen, _C1-6 haloalkyl, _C1-6 haloalkoxy or -CN; ^R2 is hydrogen, _C1-6 alkyl, _C2-6 alkenyl, _C2-6 alkynyl, _C1-6 alkoxy, _C2-6 alkoxyalkyl, halogen, _C1-6 haloalkyl, _C1-6 haloalkoxy, or -CN; R ³ is hydrogen, _C1-6 alkyl, _C2-6 alkenyl, _C2-6 alkynyl, _C1-6 alkoxy, _C2-6 alkoxyalkyl, halogen, _C1-6 haloalkyl, _C1-6 haloalkoxy, or -CN; ^R4 represents hydrogen, _C1-6 alkyl, _C2-6 alkenyl, _C2-6 alkynyl, _C1-6 alkoxy, halogen, _C1-6 haloalkyl, _C1-6 haloalkoxy or -CN; ^R5 is hydrogen, _C1-6 alkyl, _C2-6 alkenyl, _C2-6 alkynyl, _C1-6 hydroxyalkyl, _C2-6 alkoxyalkyl, _C1-6 haloalkyl, _C3-10 cycloalkyl, _C1-6 alkyl- _C3-10 cycloalkyl, _C6-12 aryl, or _C1-6 alkyl- _C6-12 aryl, wherein the alkyl group is optionally substituted with ^R5a ; R ^5a is -OSi(R ^5a1 )(R ^5a2 )(R ^5a3 ); ^R5a1 , ^R5a2 , and ^R5a3 are each independently a _C1-6 alkyl group; and ^R6 is a phenyl, naphthyl, thienyl, thiazolyl, pyridyl, pyrazinyl, pyrimidinyl, or dibenzofuranyl group, each optionally substituted with one or two ^R6a . Each R ^6a is independently a _C1-6 alkyl, _C2-6 alkenyl, _C2-6 alkynyl, _C1-6 hydroxyalkyl, _C1-6 aminoalkyl, C1-6 alkoxy, _C2-6 alkoxyalkyl, halogen, _C1-6 haloalkyl, _C1-6 haloalkoxy, -CN, -NO2, _C6-12 aryl, _C1-6 alkyl- _C6-12 aryl, or _C1-6 alkyl-(heteroaryl), wherein the aryl group is optionally substituted with 1 _{to 3} R ^6e , the alkyl group is optionally substituted with R ^6f , and the alkynyl group is optionally substituted with 1 to 4 R ^6j ; Each R ^6e is independently a _C1-6 alkyl, _C2-6 alkenyl, _C2-6 alkynyl, _C1-6 hydroxyalkyl, _C1-6 aminoalkyl, C1-6 alkoxy, _C2-6 alkoxyalkyl, halogen, _C1-6 haloalkyl, _C1-6 haloalkoxy, -CN, -NO ₂ , -C(O)R ^6e1 , _-C (O)OR ^6e1 , -OC(O)R ^6e1 , -C(O)N(R 6e1)(R ^6e2 ), -N(R ^6e1 )C(O)R ^6e2 , -OC(O)N(R ^6e1 )(R ^6e2 ), -N(R ^6e1 )C(O)OR ^6e2 , ^{-OR 6e1 ,} -S(O)(NR ^6e1 )(R ^6e2 ) -S(O) _₂R₆e₁ , -S(O) _₂N ( ^R₆e₁ )(R₆e₂), ^-SF₅ , -N( ^R₆e₁ )S(O) _₂ ( ^R₆e₂ ), -P( ^R₆e₁ ) ₍ ^R₆e₂ ), -P(O)( ^R₆e₁ )( ^R₆e₂ ), C₃ _-10 cycloalkyl, C₁ _-6 ^alkyl -C₃ _-10 cycloalkyl, heterocycloalkyl, C₁ _-6 alkyl-heterocycloalkyl, heteroaryl or C₁ _-6 alkyl-heteroaryl, wherein each of the cycloalkyl, heterocycloalkyl or heteroaryl is optionally substituted with 1 to 3 ^R₆h , and the alkyl is optionally substituted with 1 to 3 ^R₆m ; Each R ^6e1 , R ^6e2 , and R ^6e3 is independently hydrogen, C _1-6 alkyl, C _1-6 hydroxyalkyl, C _1-6 aminoalkyl, C _1-6 alkoxyalkyl, C _1-6 haloalkyl, C _3-10 cycloalkyl, C _1-6 alkyl-C _{3-10 cycloalkyl, C 6-10 aryl} , C _1-6 alkyl-C _6-10 aryl, heterocycloalkyl, or C _1-6 alkyl-(heterocycloalkyl), wherein the cycloalkyl, aryl, or heterocycloalkyl is optionally substituted by one to three R ⁶ⁿ ; Each R ⁶ⁿ is a _C1-6 alkyl, _C2-6 alkenyl, _C2-6 alkynyl, _C1-6 hydroxyalkyl, _C1-6 aminoalkyl, _C1-6 alkoxy, C2-6 alkoxyalkyl, halogen, _C1-6 haloalkyl, _C1-6 haloalkoxy, -CN, -C(O)R ⁶ⁿ¹ , -C(O)OR _6n1 , ^-OC (O)R ⁶ⁿ¹ ; Each R ⁶ⁿ¹ is independently hydrogen, C _1-6 alkyl, C _1-6 hydroxyalkyl, C _1-6 aminoalkyl, C _2-6 alkoxyalkyl, or C _1-6 haloalkyl; Each R ^6h is independently a _C1-6 alkyl, _C2-6 alkenyl, _C2-6 alkynyl, _C1-6 hydroxyalkyl, _C1-6 aminoalkyl, _C1-6 alkoxy, _C2-6 alkoxyalkyl, halogen, _C1-6 haloalkyl, _C1-6 haloalkoxy, -CN, =O, heterocyclic alkyl, or _C1-6 alkyl-(heterocyclic alkyl); Each R ^6m is independently a halogen, a C _1-6 haloalkyl, a C _1-6 haloalkoxy, -CN, -C(O)R ^6m1 , -C(O)OR ^6m1 , -OC(O)R ^6m1 , -C(O)N(R ^6m1 )(R ^6m2 ), -S(O) _2R ^6m1 ; Each R ^6m1 , R ^6m2 is independently hydrogen, C _1-6 alkyl, C _1-6 hydroxyalkyl, C _1-6 aminoalkyl, C _2-6 alkoxyalkyl, or C _1-6 haloalkyl; R ^6f is -OSi(R ^6f1 )(R ^6f2 )(R ^6f3 ); ^R6f1 , ^R6f2 and ^R6f3 are each independently _C1-6 alkyl groups; Each R ^6j is independently a C _2-6 alkoxyalkyl, halogen, C _1-6 haloalkyl, C _1-6 haloalkoxy, -N(R ^6j1 )(R ^6j2 ), -OR ^6j1 , C _3-10 cycloalkyl, C _6-12 aryl or heterocycloalkyl, wherein the cycloalkyl, aryl or heterocycloalkyl is optionally substituted by one to three R ^6p ; Each R ^6j1 , R ^6j2 is independently hydrogen, C _1-6 alkyl, C _1-6 hydroxyalkyl, C _1-6 aminoalkyl, C _2-6 alkoxyalkyl, or C _1-6 haloalkyl; Each R ^6p is independently a _C1-6 alkyl, _C1-6 hydroxyalkyl, _C1-6 aminoalkyl, _C1-6 alkoxy, _C2-6 alkoxyalkyl, halogen, _C1-6 haloalkyl, _C1-6 haloalkoxy, -CN, =O, -OH; R ⁷ is hydrogen, _C1-6 alkyl, _C1-6 hydroxyalkyl, C1-6 aminoalkyl, _C1-6 alkoxy, _C2-6 alkoxyalkyl, _C1-6 alkylthio, halogen, _C1-6 haloalkyl, -CN, -OH, _-NH2 , _C3-10 cycloalkyl, _C1-6 alkyl- _{C3-10 cycloalkyl} , heterocycloalkyl, or _C1-6 alkyl-(heterocycloalkyl); Each heterocyclic alkyl group is a 3- to 10-membered ring having one to four heteroatoms, each independently of N, O, or S; and Each heteroaryl group is a 5- to 10-membered ring having one to four heteroatoms, each independently of N, O, or S; and When ^R5 is hydrogen, ^R6 is not a phenyl group substituted with 2-Me. The following compounds are not included: 2. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein... ^R1 is hydrogen, _C1-6 alkyl, _C1-6 alkoxy, halogen, _C1-6 haloalkyl, or -CN; ^R2 is hydrogen, _C1-6 alkyl, _C1-6 alkoxy, halogen, _C1-6 haloalkyl, or -CN; ^R3 is hydrogen, _C1-6 alkyl, _C1-6 alkoxy, halogen, _C1-6 haloalkyl, or -CN; ^R4 is hydrogen, _C1-6 alkyl, _C1-6 alkoxy, halogen, _C1-6 haloalkyl, or -CN; and ^R7 is hydrogen, _C1-6 alkyl, halogen, _C1-6 haloalkyl, -CN, or -OH. 3. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein ^R1 is hydrogen, _C1-3 alkyl, _C1-3 alkoxy, or halogen. 4. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein ^R1 is hydrogen, Me, -OMe, F or Cl. 5. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein ^R1 is hydrogen. 6. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein... ^R2 is hydrogen. 7. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein... ^R3 is hydrogen. 8. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein ^R4 is hydrogen, _C1-6 alkyl, or halogen. 9. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein ^R4 is hydrogen, Me, F, Cl, or Br. 10. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein ^R4 is hydrogen or F. 11. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein... R ⁵ is a _C1-6 alkyl, _C2-6 alkynyl, _C2-3 alkoxyalkyl, _C1-3 haloalkyl, _C3-8 cycloalkyl, _C1-3 alkyl- _C3-8 cycloalkyl, phenyl, or _C1-3 alkyl-phenyl, wherein the alkyl group is optionally substituted with R ^5a ; R ^5a is -OSi(R ^5a1 )(R ^5a2 )(R ^5a3 ); and ^R5a1 , ^R5a2 and ^R5a3 are each independently Me or tBu, where ^R5a1 and ^R5a2 are different. 12. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein... R ⁵ is Me, Et, nPr, nBu, -CH ₂ CMe ₃ , -CH ₂ C≡CMe, -CH ₂ CH ₂ C≡CH, -CH ₂ CH ₂ OMe, -CH ₂ CH ₂ OSi(Me) ₂ (tBu), CF ₃ , -CH ₂ CF ₂ H, -CH ₂ CF ₃ , 13. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein ^R6 is 14. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, having formula (IIa): Where n is 0, 1, or 2. 15. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein each ^R6j is independently OH, OMe, _CH2OMe , F, _CHF2 , _CF3 , _NH2 , 16. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein each ^R6j is independently OH, OMe, F, _CHF2 , _CF3 , _NH2 , 17. A compound having the structure of formula (IIc), or a pharmaceutically acceptable salt thereof: in Having structure ^R1 is hydrogen, _C1-3 alkyl, or halogen; ^R2 is hydrogen, _C1-3 alkyl, or halogen; ^R3 is hydrogen, _C1-3 alkyl, or halogen; ^R4 is hydrogen, _C1-3 alkyl, or halogen; R ⁷ is hydrogen or _C1-3 alkyl; Each R ^6a is independently a _C1-6 alkyl, _C2-6 alkenyl, _C2-6 alkynyl, _C1-6 hydroxyalkyl, _C1-6 aminoalkyl, _C1-6 alkoxy, _C2-6 alkoxyalkyl, halogen, _C1-6 haloalkyl, _C1-6 haloalkoxy, -CN, _-NO2 , _C6-12 aryl, The aryl group is optionally substituted with 1 to 3 R ^6e , the alkyl group is optionally substituted with R ^6f , and the alkynyl group is optionally substituted with 1 to 4 R ^6j ; Each R ^6e is independently a _C1-6 alkyl, _C2-6 alkenyl, _C2-6 alkynyl, _C1-6 hydroxyalkyl, _C1-6 aminoalkyl, _C1-6 alkoxy, _C2-6 alkoxyalkyl, halogen, _C1-6 haloalkyl, _C1-6 haloalkoxy, _C3-10 cycloalkyl, _C1-6 alkyl- _C3-10 cycloalkyl, wherein the cycloalkyl group is optionally substituted with 1 to 3 R6h ^groups . Furthermore, the alkyl group is optionally substituted with one to three R ^6m atoms; Each R ^6h is independently a _C1-6 alkyl, _C2-6 alkenyl, _C2-6 alkynyl, _C1-6 hydroxyalkyl, _C1-6 aminoalkyl, _C1-6 alkoxy, _C2-6 alkoxyalkyl, halogen, _C1-6 haloalkyl, _C1-6 haloalkoxy; Each R ^6m is independently a halogen, a _C1-6 haloalkyl, or a _C1-6 haloalkoxy. R ^6f is -OSi(R ^6f1 )(R ^6f2 )(R ^6f3 ); ^R6f1 , ^R6f2 and ^R6f3 are each independently _C1-6 alkyl groups; Each R ^6j is independently a C _2-6 alkoxyalkyl, halogen, C _1-6 haloalkyl, C _1-6 haloalkoxy, -CN, -OR ^6j1 , or C _3-10 cycloalkyl, wherein the cycloalkyl is optionally substituted by one to three R ^6p ; Each R ^6j1 is independently hydrogen, _C1-6 alkyl, _C1-6 hydroxyalkyl, _C1-6 aminoalkyl, _C2-6 alkoxyalkyl, or _C1-6 haloalkyl; Each R ^6p is independently a _C1-6 alkyl, _C1-6 hydroxyalkyl, _C1-6 aminoalkyl, _C1-6 alkoxy, _C2-6 alkoxyalkyl, halogen, _C1-6 haloalkyl, _C1-6 haloalkoxy, -CN; Each heterocyclic alkyl group is a 3- to 10-membered ring having 1 to 4 heteroatoms, each of which is independently N, O, or S; Each heteroaryl group is a 5- to 10-membered ring having one to four heteroatoms, each independently of N, O, or S; and n is 0, 1, or 2. 18. The compound according to claim 17, wherein... ^R1 is hydrogen or halogen. 19. The compound according to claim 17, wherein... ^R1 is hydrogen or F. 20. The compound according to claim 17, wherein... ^R4 is hydrogen, _C1-3 alkyl, or halogen. 21. The compound according to claim 17, wherein... ^R4 is hydrogen, Me, or F. 22. The compound of claim 17, or a pharmaceutically acceptable salt thereof, wherein... ^R2 is hydrogen or halogen; ^R3 is hydrogen or halogen; Each R ^6a is independently a _C1-3 alkyl, _C2-3 alkenyl, or _C2-3 alkynyl, wherein the alkynyl is optionally substituted by one to three R ^6j ; Each R ^6j is independently a C _2-3 alkoxyalkyl, halogen, C _1-3 haloalkyl, C _1-3 haloalkoxy, -CN, or C _3-8 cycloalkyl, wherein the cycloalkyl is optionally substituted by one to three R ^6p ; Each R ^6p is independently a _C1-3 alkyl, _C1-3 hydroxyalkyl, _C2-3 alkoxyalkyl, halogen, _C1-3 haloalkyl, _C1-3 haloalkoxy, or -CN; R ⁷ is hydrogen or a _C1-3 alkyl group; and Having structure 23. A compound having the structure of formula (IIc), or a pharmaceutically acceptable salt thereof: in Having structure ^R1 is hydrogen, _C1-3 alkyl, or halogen; ^R2 is hydrogen, _C1-3 alkyl, or halogen; ^R3 is hydrogen, _C1-3 alkyl, or halogen; ^R4 is hydrogen, _C1-3 alkyl, or halogen; ^R7 is hydrogen or _C1-3 alkyl. 24. The compound of claim 23, or a pharmaceutically acceptable salt thereof, wherein the compound has the structure 25. The compound of claim 23, or a pharmaceutically acceptable salt thereof, wherein the compound has the structure 26. A pharmaceutical composition comprising a pharmaceutically effective amount of the compound according to any one of claims 1-25, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient.