OA21708A

OA21708A - Small molecule inhibitors of ubiquitin specific protease 1 (USP1) and uses thereof.

Info

Publication number: OA21708A
Application number: OA1202400181
Authority: OA
Inventors: Jianping Wu; Luoheng Qin; Jinxin Liu; Yingtao Liu
Original assignee: Insilico Medicine Ip Limited
Priority date: 2021-11-12
Filing date: 2022-11-11
Publication date: 2024-12-18

Abstract

The disclosure provides for small molecules inhibitory compounds of ubiquitin specific protease 1 (USP1) and compositions comprising the same. The disclosure further provides methods for targeting ubiquitin specific protease 1 (USP1) and methods of treating diseases or disorders related to USP1, such as cancer. <img file="OA21708A_A0001.tif"/> Formula IIIa

Description

SMALL MOLECULE INHIBITORS OF UBIQUITIN SPECIFIC PROTEASE 1 (USP1) AND USES THEREOF

CROSS REFERENCE TO RELATED APPLICATIONS

10001] This patent application claims the benefit of International Application No. PCT/CN2021/130289, filed November 12, 2021 and International Application No. PCT/CN2022/123806, filed October 8, 2022, each of which is incorporated herein by reference in its entirety.

BACKGROUND

[0001] Ubiquitin spécifie protease 1 (USP1) is a gene that plays a rôle in a DNA damage repair. Compounds and pharmaceutical compositions targeting USP1, and methods of treatment for USPl-related diseases and disorders, like certain cancers, hâve not been widely developed.

Therefore, there remains a need to address methods of treating USPl-related diseases.

SUMMARY

[0002] The présent disclosure addresses the above need and provides additional advantages as well.

[0003] In one aspect, described herein is a compound having the structure of Formula (III), or a sait or solvaté thereof,

Formula (III) wherein,

Z¹ is N, NR¹, O, S, CR¹, or C(R’)₂;

Z² is N, NR², O, CR², C(R²)₂, S(=O)₂, C(=O), or C(=S);

Z³ is N, NR³, CR³, C(R³)₂, S(=O)₂, C(=O), or C(=S);

---is a single bond or a double bond;

each of R¹, R², and R³ is independently selected from hydrogen, halo, -CN, -OR¹¹, -SR¹¹, N(R^I2)2, optionally substituted Ci-6 alkyl, optionally substituted Ci-6 heteroalkyl, optionally substituted C2-6 alkenyl, and optionally substituted C2-6 alkynyl;

each of R⁸ and R⁹ is independently selected from hydrogen, halo, -CN, optionally substituted Ci6 alkyl, optionally substituted Ci-6heteroalkyl, optionally substituted C2-6 alkenyl, and optionally substituted C2-6 alkynyl; or R⁸ and R⁹ taken together form an oxo; or R⁸ and R⁹taken together with the carbon to which they are attached form an optionally substituted 3-6 membered cycloalkyl or heterocycloalkyl;

ring A is phenyl, naphthyl, monocyclic heteroaryl, or bicyclic heteroaryl;

each of R^A is independently selected from halogen, -NO2, oxo, -CN, optionally substituted Ci-6 alkyl, optionally substituted C2-6 alkenyl, optionally substituted C2-6 alkynyl, optionally substituted Ci-6 heteroalkyl, optionally substituted C3-8 cycloalkyl, optionally substituted C2-7 heterocycloalkyl, -OR, -SR, -N(R^l2)(R), -C(O)R¹², -C(O)OR¹², -OC(O)R¹², OC(O)N(R¹²)(R), -C(O)N(R¹²)(R’ '), -N(R¹²)C(O)R¹² -N(R¹²)C(O)ORⁱ², N(R¹²)C(O)N(R¹²)(R), -N(R¹²)2S(O)2(R'²), -S(O)R¹², -S(O)2R¹², and -S(O)₂N(R¹²)(R);

R is hydrogen, optionally substituted Cmalkyl, optionally substituted C2-6 alkenyl, optionally substituted C2-6 alkynyl, optionally substituted Ci-6 heteroalkyl, optionally substituted C3-8 cycloalkyl, optionally substituted C2-7 heterocycloalkyl, optionally substituted phenyl, optionally substituted heteroaryl, optionally substituted -Cm alkylene-C3-8 cycloalkyl, optionally substituted -C1-4 alkylene-C2-7 heterocycloalkyl, optionally substituted -Cm alkylene-phenyl, or optionally substituted -CiMalkylene-heteroaryl;

each of R¹² is independently selected from hydrogen,, -NO2, -CN, Cm alkyl, CMaminoalkyl, Ci6 hydroxyalkyl, Ci-6 haloalkyl, Ci-6 heteroalkyl, C3-6 carbocycle, and 3- to 6-membered heterocycle, wherein the C3-6 carbocycle and 3- to 6-membered heterocycle is optionally substituted with one or more substituents independently selected from halogen, -OH, oxo, amino,-NO2, -CN, Cmalkyl, Cm alkoxy, and Ci-6haloalkyl;

B is 6 membered heteroaryl, phenyl or a phenyl isostere;

R^B1 is halo, -CN, -NO2, optionally substituted Cmalkyl, optionally substituted C2-6 alkenyl, optionally substituted C2-6alkynyl, optionally substituted Ci-6heteroalkyl, -OR, -SR, N(R¹²)(R), -C(O)R¹², -C(O)OR¹², -OC(O)R¹², -OC(O)N(R¹²)(R), -C(O)N(R¹²)(R),N(R¹²)C(O)R¹² -N(Rⁱ²)C(O)OR¹², -N(R¹²)C(O)N(R¹²)(R), -N(R¹²)S(O)₂(R¹²), S(O)R¹², -S(O)2R¹², -S(O)2N(R^I2)(R), optionally substituted C3-8 cycloalkyl, optionally substituted C2-9 heterocycloalkyl, optionally substituted naphthyl, optionally substituted phenyl, optionally substituted monocyclic heteroaryl, or optionally substituted bicyclic heteroaryl;

each R^b is independently halo, -CN, -NO2, optionally substituted Ci-6 alkyl, optionally substituted C2-6 alkenyl, optionally substituted C2-6 alkynyl, optionally substituted Ci-6 heteroalkyl, -OR, -SR, -N(R¹²)(R), -C(O)R¹², -C(O)OR¹², -OC(O)R¹², OC(O)N(R¹²)(R), -C(O)N(R¹²)(R), -N(R¹²)C(O)R¹² -N(R¹²)C(O)OR¹², N(R¹²)C(O)N(R^I2)(R), -N(R¹²)S(O)2(R¹²), -S(O)R¹², -S(O)2R¹², -S(O)2N(R¹²)(R), optionally substituted C3-8 cycloalkyl, optionally substituted C2-9 heterocycloalkyl, optionally substituted naphthyl, optionally substituted phenyl, optionally substituted monocyclic heteroaryl, or optionally substituted bicyclic heteroaryl; or

R^B1 and one of R^B on adjacent atoms are taken together with the atoms to which they are attached to form an optionally substituted phenyl, optionally substituted naphthyl, optionally substituted monocyclic heteroaryl, optionally substituted bicyclic heteroaryl, optionally substituted C3-8 cycloalkyl, or optionally substituted C2-9 heterocycloalkyl; or

R^B1 and one of R^B on the same atom are taken together with the atom to which they are attached to form an optionally substituted C3-8 cycloalkyl or optionally substituted C2-9 heterocycloalkyl; or two of R^b on the same atom are taken together with the atom to which they are attached to form an optionally substituted C3-8 cycloalkyl or optionally substituted C2-9 heterocycloalkyl;

m is 1, 2, 3, or 4;

n is 0, 1, 2, 3 or 4; and p is 0 or 1.

[0004] In some embodiments, the compound has a structure of Formula (Ilia),

Formula (Ilia).

[0005] In some embodiments, compound has a structure of Formula (IIIa-1 ),

Formula (IIIa-l), wherein

Z¹ is N or CR¹; and

Z² is N or CR².

[0006] In some embodiments, the compound has a structure of Formula (IIIa-2),

wherein

Z¹ is NR¹, O, S, or C(R’)₂;

Z² is NR², O, or C(R²)₂;

[0007] In some embodiments, the compound has a structure of Formula (Illb),

wherein

Z¹ is NR¹, O, S, or C(R’)₂;

Z² is NR², O, C(R²)₂, C(=O), S(=O)₂, or C(=S);

Z³ is NR³, O, S, C(R³)₂, C(=O), S(=O)₂, or C(=S).

[0008] In some embodiments, the compound has a structure of Formula (IIIb-1 ),

wherein,

Z² is C(R²)₂, C(=O), or C(=S); and

Z³ is NR³, C(R³)2, C(=O), or C(=S).

[0009] In some embodiments, compound has a structure of Formula (IIIb-2),

R¹

Z² is NR², C(R²)₂, C(=O), or C(=S); and

Z³ is NR³, C(R³)₂, C(=O), or C(=S).

[0010] In some embodiments, the compound has a structure of Formula (IIle),

Formula (IIIc) wherein,

Y¹ isNor CR^Y1;

Y² is N or CR^Y2;

Y³ is N or CR^Y3;

Y⁴ is N or CR^Y4;

each of R^Y1, R^Y2, R^Y3 and R^Y4 is independently selected from hydrogen, halo, -CN, -OR”, -SR¹¹, -N(R¹²)₂, optionally substituted Ci-6alkyl, optionally substituted Ci-6heteroalkyl, optionally substituted C2-6 alkenyl, and optionally substituted C2-6 alkynyl;

Z¹ is N, NR¹, O, S, CR¹, or C(R*)₂;

Z² is N, NR², O, CR², C(R²)₂, S(=O)₂, C(=O), or C(=S);

Z³ is N, NR³, CR³, C(R³)₂, S(=O)₂, C(=O), or C(=S);

---is a single bond or a double bond;

each of R¹, R², and R³ is independently selected from hydrogen, halo, -CN, -OR¹¹, -SR¹¹, N(R¹²)₂, optionally substituted C1-6 alkyl, optionally substituted C1-6 heteroalkyl, optionally substituted C2-6 alkenyl, and optionally substituted C2-6 alkynyl;

each of R⁸ and R⁹ is independently selected from hydrogen, halo, -CN, optionally substituted Ci6 alkyl, optionally substituted Ci-6 heteroalkyl, optionally substituted C2-6 alkenyl, and optionally substituted C2-6 alkynyl; or R⁸ and R⁹ taken together form an oxo; or R⁸ and R⁹taken together with the carbon to which they are attached form an optionally substituted 3-6 membered cycloalkyl or heterocycloalkyl;

ring A is monocyclic heteroaryl or bicyclic heteroaryl;

each of R^Ais independently selected from halogen, -NO2, oxo, -CN, optionally substituted Ci-6 alkyl, optionally substituted C2-6 alkenyl, optionally substituted C2-6 alkynyl, optionally substituted Ci-6 heteroalkyl, optionally substituted C3-8 cycloalkyl, optionally substituted C2-7heterocycloalkyl, -OR, -SR¹¹, -N(R¹²)(Rⁿ), -C(O)R¹², -C(O)OR¹², -OC(O)R¹², OC(O)N(R¹²)(R‘ *), -C(O)N(R¹²)(R‘ ’), -N(R¹²)C(O)R¹², -N(R¹²)C(O)OR¹², N(R¹²)C(O)N(R¹²)(Rⁿ), -N(R¹²)₂S(O)₂(R¹²), -S(O)R¹², -S(O)2R¹², and -S(O)2N(R¹²)(R^H);

R¹¹ is hydrogen, optionally substituted C1-6 alkyl, optionally substituted C2-6 alkenyl, optionally substituted C2-6 alkynyl, optionally substituted Ci-₆ heteroalkyl, optionally substituted C3-8 cycloalkyl, optionally substituted C2-7 heterocycloalkyl, optionally substituted phenyl, optionally substituted heteroaryl, optionally substituted -Cm alkylene-C3-8 cycloalkyl, optionally substituted -Cm alkylene-C2-7 heterocycloalkyl, optionally substituted -Cm alkylene-phenyl, or optionally substituted -CMalkylene-heteroaryl;

each of R¹² is independently selected from hydrogen,-NO2, -CN, Cmalkyl, CMaminoalkyl, Cm hydroxyalkyl, Ci-6haloalkyl, Cmheteroalkyl, C3-6carbocycle, and 3- to 6-membered heterocycle, wherein the C3-6 carbocycle and 3- to 6-membered heterocycle is optionally substituted with one or more substituents independently selected from halogen, -OH, oxo, amino,-NO2, -CN, Cm alkyl, Cm alkoxy, and Ci-6 haloalkyl;

R^b1 is optionally substituted C3-8 cycloalkyl, optionally substituted C2-9 heterocycloalkyl, optionally substituted naphthyl, optionally substituted phenyl, optionally substituted monocyclic heteroaryl, or optionally substituted bicyclic heteroaryl;

m is 1, 2, 3, or 4;

n is 0, 1, 2, 3 or 4; and p is 0 or 1.

[0011] In some embodiments, the compound has a structure of Formula (IIIc-1)

Formula (IIIc-1).

[0012] In some embodiments, the compound has a structure of Formula (Illd),

Formula (Illd).

[0013] In one aspect, described herein is a compound having the structure of Formula (Ilia), or a sait thereof,

wherein,

Z¹ is N, NR¹, O, S, CR¹, or C(R^!)₂;

Z² is N, NR², O, CR², C(R²)₂, S(=O)₂, C(=O), or C(=S);

---is a single bond or a double bond;

each of R¹ and R² is independently selected from hydrogen, halo, -CN, -OR¹¹, -SR¹¹, N(R¹²)₂, optionally substituted Ci-6 alkyl, optionally substituted Ci-6 heteroalkyl, optionally substituted C₂-6 alkenyl, and optionally substituted C₂-6 alkynyl;

each of R⁸ and R⁹ is independently selected from hydrogen, halogen, -CN, optionally substituted Ci-6 alkyl, optionally substituted Ci-6 heteroalkyl, optionally substituted C₂-₆ alkenyl, and optionally substituted C₂-₆ alkynyl; or R⁸ and R⁹ taken together form an oxo; or R⁸ and R⁹ taken together with the carbon to which they are attached form an optionally substituted 3-6 membered cycloalkyl or heterocycloalkyl;

each of R^Ais independently selected from halogen, -NO2, oxo, -CN, optionally substituted Cm alkyl, optionally substituted C2-6 alkenyl, optionally substituted C2-6 alkynyl, optionally substituted Ci-6heteroalkyl, optionally substituted C3-8cycloalkyl, optionally substituted C2-7heterocycloalkyl, -OR”, -SR”, -N(R^l2)(R”), C(O)R¹², -C(O)OR¹², -OC(O)R¹², -OC(O)N(R¹²)(R”), -C(O)N(R¹²)(R”), N(R¹²)C(O)R¹², -N(R¹²)C(O)OR¹², -N(R^I2)C(O)N(R¹²)(R”), -N(R¹²)2S(O)2(R¹²), S(O)R¹², -S(O)2R¹², and -S(O)₂N(R¹²)(R”);

R” is hydrogen, optionally substituted C1-6 alkyl, optionally substituted C2-6 alkenyl, optionally substituted C2-6 alkynyl, optionally substituted Cm heteroalkyl, optionally substituted C3-8 cycloalkyl, optionally substituted C2-7 heterocycloalkyl, optionally substituted phenyl, optionally substituted heteroaryl, optionally substituted -Cm alkylene-C3-8 cycloalkyl, optionally substituted -Cm alkylene-C2-7 heterocycloalkyl, optionally substituted -Cm alkylene-phenyl, or optionally substituted -Cm alkyleneheteroaryl;

each of R¹² is independently selected from hydrogen, -NO2, -CN, Cm alkyl, Cm aminoalkyl, Ci-6 hydroxyalkyl, Ci-6haloalkyl, Ci-6heteroalkyl, C3-6 carbocycle, and 3to 6-membered heterocycle, wherein the C3-6 carbocycle and 3- to 6-membered heterocycle is optionally substituted with one or more substituents independently selected from halogen, -OH, oxo, amino, -NO2, -CN, Cmalkyl, Cm alkoxy, and Cm haloalkyl;

B is 6 membered heteroaryl, phenyl or a phenyl isostere;

R^B1 is halo, -CN, -NO2, optionally substituted Cm alkyl, optionally substituted C2-6 alkenyl, optionally substituted C2-6 alkynyl, optionally substituted Ci-6 heteroalkyl, OR”, -SR”, -N(R¹²)(R”), -C(O)R¹², -C(O)OR¹², -OC(O)R¹², -OC(O)N(R¹²)(R”), C(O)N(R^I2)(R”), -N(R^I2)C(O)R¹² -N(R¹²)C(O)OR¹², -N(R^I2)C(O)N(R¹²)(R”), 21708

N(R¹²)S(O)₂(R¹²), -S(O)R¹², -S(O)2R¹², -S(O)2N(R¹²)(R^h), optionally substituted C3-8 cycloalkyl, optionally substituted C₂-9 heterocycloalkyl, optionally substituted naphthyl, optionally substituted phenyl, optionally substituted monocyclic heteroaryl, or optionally substituted bicyclic heteroaryl;

each R^b is independently halo, -CN, -NO2, optionally substituted C1-6 alkyl, optionally substituted C2-6 alkenyl, optionally substituted C2-6 alkynyl, optionally substituted Cm heteroalkyl, -OR¹¹, -SR¹¹, -N(R¹²)(R^H), -C(O)R¹², -C(O)OR¹², -OC(O)R¹², OC(O)N(R¹²)(R’ ’), -C(O)N(R¹²)(R'¹ ), -N(R¹²)C(O)R¹², -N(R¹²)C(O)OR¹², N(R¹²)C(O)N(R¹²)(R), -N(R¹²)S(O)2(R¹²), -S(O)R¹², -S(O)2R¹², -S(O)2N(R¹²)(R^h), optionally substituted C3-8 cycloalkyl, optionally substituted C₂-9 heterocycloalkyl, optionally substituted naphthyl, optionally substituted phenyl, optionally substituted monocyclic heteroaryl, or optionally substituted bicyclic heteroaryl; or

R^B1 and one of R^B on adjacent atoms are taken together with the atoms to which they are attached to form an optionally substituted phenyl, optionally substituted naphthyl, optionally substituted monocyclic heteroaryl, optionally substituted bicyclic heteroaryl, optionally substituted C3-8 cycloalkyl, or optionally substituted C₂-9 heterocycloalkyl; or

R^B1 and one of R^B on the same atom are taken together with the atom to which they are attached to form an optionally substituted C3-8 cycloalkyl or optionally substituted C₂. 9 heterocycloalkyl; or two of R^b on the same atom are taken together with the atom to which they are attached to form an optionally substituted C3-8 cycloalkyl or optionally substituted C₂-9 heterocycloalkyl;

n is 0, 1, 2, 3 or 4; and p is 1.

[0014] In some embodiments, the compound has a structure of Formula (IIIc’),

wherein,

Y¹ isNor CR^Y1;

Y² is N or CR^Y2;

Y³ is N or CR^Y3;

Y⁴ isNor CR^Y4;

each of R^Y1, R^Y2, R^Y3 and R^Y4 is independently selected from hydrogen, halo, -CN, OR¹¹, -SR¹¹, -N(R¹²)₂, optionally substituted Ci-₆ alkyl, optionally substituted Ci-₆ heteroalkyl, optionally substituted Cm alkenyl, and optionally substituted Cm alkynyl.

[0015] In some embodiments, the compound has a structure of Formula (IIIc-1 ’)

Formula (IIIc-1 ’).

[0016] In some embodiments, the compound has a structure of Formula (Illd’),

Formula (Illd’).

[0017] In one aspect, described herein is a compound having the structure of Formula (VI), or a

wherein, ring C is phenyl or a 6 membered heteroaryl, wherein each of the phenyl or heteroaryl is optionally substituted;

ring D is an aromatic, saturated or partially saturated 6 membered carbocycle or heterocycle, wherein each of the carbocycle or heterocycle is optionally substituted;

each of R⁸ and R⁹ is independently selected from hydrogen, halo, -CN, optionally substituted Ci6 alkyl, optionally substituted Ci-ôheteroalkyl, optionally substituted C2-6alkenyl, and optionally substituted C2-6 alkynyl; or R⁸ and R⁹ taken together form an oxo; or R⁸ and R⁹taken together with the carbon to which they are attached form an optionally substituted 3-6 membered cycloalkyl or heterocycloalkyl;

ring A is phenyl, naphthyl, monocyclic heteroaryl, or bicyclic heteroaryl;

each of R^Ais independently selected from halogen, -NO2, oxo, -CN, optionally substituted Cm alkyl, optionally substituted C2-6alkenyl, optionally substituted C2-6 alkynyl, optionally substituted Ci-ôheteroalkyl, optionally substituted C3-8 cycloalkyl, optionally substituted C2-7 heterocycloalkyl, -OR¹¹, -SR¹¹, -N(R¹²)(Rⁿ), -C(O)R¹², -C(O)OR¹², -OC(O)R¹², OCONCR^XR¹¹), -C(O)N(R¹²)(R¹¹),-N(R¹²)C(O)R¹²,-N(R¹²)C(O)OR¹²,N(R^,2)C(O)N(R¹²XRⁿ), -N(R¹²)2S(O)₂(R¹²), -S(O)R¹², -S(O)₂R¹², and -S(O)2N(R¹²XR^H);

R¹¹ is hydrogen, optionally substituted C1-6 alkyl, optionally substituted C2-6alkenyl, optionally substituted C2-6 alkynyl, optionally substituted Ci-ôheteroalkyl, optionally substituted C3-8 cycloalkyl, optionally substituted C2-7 heterocycloalkyl, optionally substituted phenyl, optionally substituted heteroaryl, optionally substituted -Ci-4alkylene-C₃-8 cycloalkyl, optionally substituted -Ci-4alkylene-C2-7 heterocycloalkyl, optionally substituted -Cm alkylene-phenyl, or optionally substituted -CMalkylene-heteroaryl;

each of R¹² is independently selected from hydrogen,-NO2, -CN, C1-6 alkyl, Ci-6aminoalkyl, C1-6 hydroxyalkyl, Ci-₆haloalkyl, and C3-6 carbocycle, 3- to 6-membered heterocycle, wherein the C3-6 carbocycle and 3- to 6-membered heterocycle is optionally substituted with one or more substituents independently selected from halogen, -OH, oxo, amino, NO2, -CN, C1-6alkyl, Ci-6alkoxy, and Ci-ôhaloalkyl;

R^b is hydrogen, halo, -CN, -NO2, optionally substituted Cm alkyl, optionally substituted C2-6 alkenyl, optionally substituted C2-6 alkynyl, optionally substituted Ci-6heteroalkyl, -OR¹¹, -SR¹¹, -N(R¹²XRⁿ), -C(O)R¹², -C(O)OR¹², -OC(O)R¹², -OC(O)N(R¹²XR^h), C(O)N(R¹²XRⁿ), -N(R¹²)C(O)R¹², -N(R¹²)C(O)OR¹², -N(R¹²)C(O)N(R¹²XR^h), N(R¹²)S(O)2(R¹²),-S(O)R¹², -S(O)2R¹², -S(O)2N(R¹²)(Rⁿ), optionally substituted C3-8 cycloalkyl, optionally substituted C2-9 heterocycloalkyl, optionally substituted naphthyl, optionally substituted phenyl, optionally substituted monocyclic heteroaryl, or optionally substituted bicyclic heteroaryl· or m is 1, 2, 3, or 4; and p is 0 or 1.

[0018] In one aspect, described herein is a pharmaceutical composition comprising a compound described herein or a pharmaceutically acceptable sait or solvaté thereof, and a pharmaceutically acceptable carrier or excipient.

[0019] In one aspect, described herein is a method of modulating ubiquitin spécifie protease 1 (USP1) in a subject, the method comprising administering to a subject a compound described herein, or a pharmaceutically acceptable sait or solvaté thereof, or a pharmaceutical composition of a compound described herein.

[0020] In one aspect, described herein is a method of inhibiting ubiquitin spécifie protease 1 (USP1) in a subject, the method comprising administering to the subject a compound described herein, or a pharmaceutically acceptable sait or solvaté thereof, or a pharmaceutical composition of a compound described herein.

[0021] In one aspect, described herein is a method of inhibiting or reducing DNA repair activity modulated by ubiquitin spécifie protease 1 (USP1) in a subject, the method comprising administering to the subject in need thereof an effective amount of a compound described herein, or a pharmaceutically acceptable sait or solvaté thereof, or a pharmaceutical composition of a compound described herein.

[0022] In one aspect, described herein is a method of treating a disease or disorder associated with ubiquitin spécifie protease 1 (USP1) in a subject, the method comprising administering to the subject a compound described herein, or a pharmaceutically acceptable sait or solvaté thereof, or a pharmaceutical composition of a compound described herein.

[0023] In one aspect, described herein is a method of treating a disease or disorder associated with modulation of ubiquitin spécifie protease 1 (USP1) in a subject, the method comprising administering to the subject a compound described herein, or a pharmaceutically acceptable sait or solvaté thereof, or a pharmaceutical composition of a compound described herein. In some embodiments, the disease or disorder is cancer.

[0024] In one aspect, described herein is a method of treating cancer in a subject, the method comprising administering to the subject in need thereof an effective amount of a compound described herein, or a pharmaceutically acceptable sait or solvaté thereof, or a pharmaceutical composition of a compound described herein. In some embodiments, the cancer is selected from the group consisting of lung cancer, non-small cell lung cancer (NSCLC), colon cancer, bladder cancer, osteosarcoma, ovanan cancer, skin cancer, and breast cancer. In some embodiments, the cancer is ovarian cancer. In some embodiments, the cancer is a breast cancer. In some embodiments, the cancer is a ovarian cancer or breast cancer.

[0025] In some embodiments, the cancer comprises cancer cells with elevated levels of RAD 18. In some embodiments, the cancer is a DNA damage repair pathway déficient cancer. In some embodiments, the cancer is a PARP inhibitor résistant or refractory cancer. In some embodiments, the cancer is a BRCA1 mutant cancer and/or a BRCA2 mutant cancer. In some embodiments, the cancer is a BRAC1-déficient cancer.

INCORPORATION BY REFERENCE

[0026] Ail publications, patents, and patent applications mentioned in this spécification are herein incorporated by reference to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference. To the extent publications and patents or patent applications incorporated by reference contradict the disclosure contained in the spécification, the spécification is intended to supersede and/or take precedence over any such contradictory material.

DETAILED DESCRIPTION

[0027] While various embodiments of the disclosure hâve been shown and described herein, it will be obvious to those skilled in the art that such embodiments are provided by way of example only. Numerous variations, changes, and substitutions can occur to those skilled in the art without departing from the disclosure. It should be understood that vanous alternatives to the embodiments of the disclosure described herein can be employed.

A. Définitions

[0028] Unless defined otherwise, ail technical and scientific terms used herein hâve the same meaning as is commonly understood by one of skill in the art to which this disclosure belongs. Ail patents and publications referred to herein are incorporated by reference.

[0029] Alkyl refers to an optionally substituted straight-chain, or optionally substituted branched-chain saturated hydrocarbon mono-radical, and preferably having from one to fifteen carbon atoms (i.e., C1-C15 alkyl). In certain embodiments, an alkyl comprises one to thirteen carbon atoms (i.e., C1-C13 alkyl). In certain embodiments, an alkyl comprises one to eight carbon atoms (i.e., Ci-Cs alkyl). In other embodiments, an alkyl comprises one to five carbon atoms (i.e., C1-C5 alkyl). In other embodiments, an alkyl comprises one to four carbon atoms (i.e., CiC4 alkyl). In other embodiments, an alkyl comprises one to three carbon atoms (i.e., C1-C3 alkyl). In other embodiments, an alkyl comprises one to two carbon atoms (i.e., C1-C2 alkyl). Whenever it appears herein, a numerical range such as “C1-C3 alkyl” means that the alkyl group consists of 1 carbon atom, 2 carbon atoms, or 3 carbon atoms. In other embodiments, an alkyl comprises one carbon atom (i.e., Ci alkyl). In other embodiments, an alkyl comprises five to fifteen carbon atoms (i.e., C5-C15 alkyl). In other embodiments, an alkyl comprises five to eight carbon atoms (i.e., C5-C8 alkyl). In other embodiments, an alkyl comprises two to five carbon atoms (i.e., C2C5 alkyl). In other embodiments, an alkyl comprises three to five carbon atoms (i.e., C3-C5 alkyl). In certain embodiments, the alkyl group is selected from methyl, ethyl, 1-propyl (npropyl), 1-methylethyl (zso-propyl), 1-butyl (n-butyl), 1-methylpropyl (sec-butyl), 2methylpropyl (zso-butyl), 1,1-dimethylethyl (Zert-butyl), 1-pentyl (w-pentyl). In other embodiments, examples include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, 2methyl-1-propyl, 2-methyl-2-propyl, 2-methyl-1-butyl, 3-methyl-1-butyl, 2-methyl-3-butyl, 2,2dimethyl-1-propyl, 2-methyl-1-pentyl, 3-methyl-1-pentyl, 4-methyl- 1-pentyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 2,2-dimethyl-1-butyl, 3,3-dimethyl-1-butyl, 2-ethyl-lbutyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, isopentyl, neopentyl, tert-amyl, and hexyl, and longer alkyl groups, such as heptyl, octyl, and the like. The alkyl is attached to the rest of the molécule by a single bond. Unless stated otherwise specifically in the spécification, an alkyl group is optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, the alkyl is optionally substituted with oxo, halogen, -CN, -CF3, -OH, OMe, -NH2, -NO2, or -C^CH. In some embodiments, the alkyl is optionally substituted with oxo, halogen, -CN, -CF3, -OH, or -OMe. In some embodiments, the alkyl is optionally substituted with halogen such as F.

[0030] As used herein, Ci-C_x(or Ci-_X) includes Ci-C₂,Ci-C3... Ci-C_x. By way of example only, a group designated as “C1-C4” indicates that there are one to four carbon atoms in the moiety, i.e. groups containing 1 carbon atom, 2 carbon atoms, 3 carbon atoms or 4 carbon atoms. Thus, by way of example only, “C1-C4 alkyl” indicates that there are one to four carbon atoms in the alkyl group, i.e., the alkyl group is selected from among methyl, ethyl, propyl, z.vo-propyl, «-butyl, isobutyl, sec-butyl, and t-butyl. Also, by way of example, C0-C2 alkylene includes a direct bond, CH2-, and -CH2CH2- linkages.

[0031] Alkoxy refers to a radical bonded through an oxygen atom of the formula -O-alkyl, where alkyl is an alkyl chain as defined above. Unless stated otherwise specifically in the spécification, an alkoxy group can be optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, an alkoxy is optionally substituted with oxo, halogen, -CN, CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, an alkoxy is optionally substituted with oxo, halogen, -CN, -CF3, -OH, or -OMe. In some embodiments, the alkoxy is optionally substituted with halogen.

[0032] Alkenyl refers to an optionally substituted straight or branched hydrocarbon chain radical group containing at least one carbon-carbon double bond, and preferably having from two to twelve carbon atoms (Le., C2-C12 alkenyl). In certain embodiments, an alkenyl comprises two to eight carbon atoms (i.e., C2-C8 alkenyl). In certain embodiments, an alkenyl comprises two to six carbon atoms (i.e., Ci-Ce alkenyl). In other embodiments, an alkenyl comprises two to four carbon atoms (Le., C2-C4 alkenyl). The group can be in either the cis or trans configuration about the double bond(s), and should be understood to include both isomers. Examples include, but are not limited to, ethenyl (-CH=CH₂), 1-propenyl (-CH₂CH=CH₂), isopropenyl [-C(CH₃)=CH₂], butenyl, 1,3-butadienyl, and the like. Whenever it appears herein, a numerical range such as “C2C₆ alkenyl” means that the alkenyl group can consist of 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, or 6 carbon atoms. Unless stated otherwise specifically in the spécification, an alkenyl group is optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, an alkenyl is optionally substituted with oxo, halogen, -CN, CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, an alkenyl is optionally substituted with oxo, halogen, -CN, -CF3, -OH, or -OMe. In some embodiments, the alkenyl is optionally substituted with halogen. The alkenyl is attached to the rest of the molécule by a single bond, for example, ethenyl (i.e., vinyl), prop-1-enyl (Le., allyl), but-1-enyl, pent-1-enyl, penta-l,4-dienyl, and the like. Unless stated otherwise specifically in the spécification, an alkenyl group is optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, an alkenyl is optionally substituted with oxo, halogen, -CN, -CF₃, -OH, -OMe, -NH₂, or -NO2. In some embodiments, an alkenyl is optionally substituted with oxo, halogen, -CN, -CF3, -OH, or OMe. In some embodiments, the alkenyl is optionally substituted with halogen.

[0033] Alkynyl refers to an optionally substituted straight or branched hydrocarbon chain radical group containing at least one carbon-carbon triple bond, and preferably having from two to twelve carbon atoms (Le., C₂-Ci₂ alkynyl). In certain embodiments, an alkynyl comprises two to eight carbon atoms (Le., C₂-C₈ alkynyl). In other embodiments, an alkynyl comprises two to six carbon atoms (Le., C₂-C₆ alkynyl). In other embodiments, an alkynyl comprises two to four carbon atoms (i.e., C2-C4 alkynyl). Whenever it appears herein, a numerical range such as “C2-C6 alkynyl” means that the alkynyl group can consist of 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, or 6 carbon atoms. The alkynyl is attached to the rest of the molécule by a single bond, for example, ethynyl, propynyl, butynyl, pentynyl, hexynyl, 2-propynyl, 2butynyl, 1,3-butadiynyl, and the like. Unless stated otherwise specifically in the spécification, an alkynyl group is optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, an alkynyl is optionally substituted with oxo, halogen, -CN, -CF3, -OH, OMe, -NH2, or -NO₂. In some embodiments, an alkynyl is optionally substituted with oxo, halogen, -CN, -CF3, -OH, or -OMe. In some embodiments, the alkynyl is optionally substituted with halogen.

[0034] Alkylene or alkylene chain refers to an optionally substituted straight or branched divalent hydrocarbon chain linking the rest of the molécule to a radical group containing no unsaturation, and preferably having from one to twelve carbon atoms, for example, methylene, ethylene, propylene, π-butylene, and the like. The alkylene chain is attached to the rest of the molécule through a single bond and to the radical group through a single bond. The points of attachaient of the alkylene chain to the rest of the molécule and to the radical group can be through any two carbons within the chain. In certain embodiments, an alkylene comprises one to ten carbon atoms (i.e., Ci-Cs alkylene). In certain embodiments, an alkylene comprises one to eight carbon atoms (i.e., Ci-Cs alkylene). In other embodiments, an alkylene comprises one to five carbon atoms (i.e., C1-C5 alkylene). In other embodiments, an alkylene comprises one to four carbon atoms (i.e., C1-C4 alkylene). In other embodiments, an alkylene comprises one to three carbon atoms (i.e., C1-C3 alkylene). In other embodiments, an alkylene comprises one to two carbon atoms (i.e., C1-C2 alkylene). In other embodiments, an alkylene comprises one carbon atom (i. e., Ci alkylene). In other embodiments, an alkylene comprises five to eight carbon atoms (i.e., C5-C8 alkylene). In other embodiments, an alkylene comprises two to five carbon atoms (i.e., C2-C5 alkylene). In other embodiments, an alkylene comprises three to five carbon atoms (i.e., C3-C5 alkylene). Unless stated otherwise specifically in the spécification, an alkylene group can be optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, an alkylene is optionally substituted with oxo, halogen, -CN, -CF3, -OH, OMe, -NH2, or -NO2. In some embodiments, an alkylene is optionally substituted with oxo, halogen, -CN, -CF3, -OH, or -OMe. In some embodiments, the alkylene is optionally substituted with halogen. In some embodiments, the alkylene is -CH2-, -CH2CH2-, or -CH2CH2CH2-. In some embodiments, the alkylene is -CH2-. In some embodiments, the alkylene is -CH2CH2-. In some embodiments, the alkylene is -CH2CH2CH2-.

[0035] Aryl refers to a radical derived from a hydrocarbon ring System comprising at least one aromatic ring. In some embodiments, an aryl comprises hydrogens and 6 to 30 carbon atoms. The aryl radical can be a monocyclic, bicyclic, tricyclic, or tetracyclic ring System, which can include fused (when fused with a cycloalkyl or heterocycloalkyl ring, the aryl is bonded through an aromatic ring atom) or bridged ring Systems. In some embodiments, the aryl is a 6- to 10membered aryl. In some embodiments, the aryl is a 6-membered aryl. Aryl radicals include, but are not limited to, aryl radicals derived from the hydrocarbon ring Systems of anthrylene, naphthylene, phenanthrylene, anthracene, azulene, benzene, chrysene, fluoranthene, fluorene, indane, indene, naphthalene, phenalene, phenanthrene, pleiadene, pyrene, and triphenylene. In some embodiments, the aryl is phenyl. Unless stated otherwise specifically in the spécification, an aryl can be optionally substituted, for example, with halogen, amino, alkylamino, aminoalkyl, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, heteroalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, -S(O)2NH-Ci-C₆alkyl, and the like. In some embodiments, an aryl is optionally substituted with halogen, methyl, ethyl, -CN, -CF3, -OH, -OMe, -NH2, -NO2, S(O)₂NH₂, -S(O)2NHCH3,-S(O)₂NHCH₂CH3, -S(O)2NHCH(CH3)2,-S(O)₂N(CH3)2, or S(O)2NHC(CH3)3. In some embodiments, an aryl is optionally substituted with halogen, methyl, ethyl, -CN, -CF3, -OH, or -OMe. In some embodiments, the aryl is optionally substituted with halogen. In some embodiments, the aryl is substituted with alkyl, alkenyl, alkynyl, haloalkyl, or heteroalkyl, wherein each alkyl, alkenyl, alkynyl, haloalkyl, heteroalkyl is independently unsubstituted, or substituted with halogen, methyl, ethyl, -CN, -CF3, -OH, -OMe, -NH2, or -NO2. [0036] Aralkyl refers to a radical of the formula -R^c-aryl where R^c is an alkylene chain as defined above, for example, methylene, ethylene, and the like.

[0037] Aralkenyl refers to a radical of the formula -R^d-aryl where R^d is an alkenylene chain as defined above. Aralkynyl refers to a radical of the formula -R^e-aryl, where R^e is an alkynylene chain as defined above.

[0038] “Carbocycle” refers to a saturated, unsaturated or aromatic rings in which each atom of the ring is carbon. Carbocycle can include 3- to 10-membered monocyclic rings and 6- to 12membered bicyclic rings (such as spiro, fused, or bridged rings). Each ring of a bicyclic carbocycle can be selected from saturated, unsaturated, and aromatic rings. An aromatic ring, e.g., phenyl, can be fused to a saturated or unsaturated ring, e.g., cyclohexane, cyclopentane, or cyclohexene. Any combination of saturated, Unsaturated and aromatic bicyclic rings, as valence permits, are included in the définition of carbocyclic. In an exemplary embodiment, an aromatic ring, e.g., phenyl, can be fused to a saturated or unsaturated ring, e.g., cyclohexane, cyclopentane, or cyclohexene. A bicyclic carbocycle includes any combination of saturated, unsaturated and aromatic bicyclic rings, as valence permits. A bicyclic carbocycle includes any combination of ring sizes such as 4-5 fused ring Systems, 5-5 fused ring Systems, 5-6 fused ring Systems, 6-6 fused ring Systems, 5-7 fused ring Systems, 6-5 fused ring Systems, 6-7 fused ring Systems, 5-8 fused ring Systems, and 6-8 fused ring Systems. Exemplary carbocycles include cyclopentyl, cyclohexyl, cyclohexenyl, adamantyl, phenyl, indanyl, and naphthyl. The term “unsaturated carbocycle” refers to carbocycles with at least one degree of unsaturation and excluding aromatic carbocycles. Examples of unsaturated carbocycles include cyclohexadiene, cyclohexene, and cyclopentene. The term “saturated cycloalkyl” as used herein refers to a saturated carbocycle. Exemplary carbocycles include cyclopropyl,cyclopentyl, cyclohexyl, cyclohexenyl, adamantyl, phenyl, indanyl, norborane, and naphthyl. Carbocycles can be optionally substituted by one or more substituents such as those substituents described herein. [0039] Cycloalkyl refers to a stable, partially or fully saturated, monocyclic or polycychc carbocyclic ring, which can include fused (when fused with an aryl or a heteroaryl ring, the cycloalkyl is bonded through a non-aromatic ring atom), bridged, or spiro ring Systems. Représentative cycloalkyls include, but are not limited to, cycloalkyls having from three to fifteen carbon atoms (C3-C15 cycloalkyl), from three to ten carbon atoms (C3-C10 cycloalkyl), from three to eight carbon atoms (C3-C8 cycloalkyl), from three to six carbon atoms (C3-C6 cycloalkyl), from three to five carbon atoms (C3-C5 cycloalkyl), or three to four carbon atoms (C3-C4 cycloalkyl). In some embodiments, the cycloalkyl is a 3- to 6-membered cycloalkyl. In some embodiments, the cycloalkyl is a 5- to 6-membered cycloalkyl. Monocyclic cycloalkyls include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Polycyclic cycloalkyls or carbocycles include, for example, adamantyl, norbomyl, decalinyl, bicyclo[3.3.0]octane, bicyclo[4.3.0]nonane, cis-decalin, trans-decalin, bicyclo[2.1.1]hexane, bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane, bicyclo[3.2.2]nonane, and bicyclo[3.3.2]decane, and 7,7-dimethyl-bicyclo[2.2.1]heptanyl. Partially saturated cycloalkyls include, for example, cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl. Unless stated otherwise specifïcally in the spécification, a cycloalkyl is optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, a cycloalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -CF3, -OH, OMe, -NH2, or -NO2. In some embodiments, a cycloalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -CF3, -OH, or -OMe. In some embodiments, the cycloalkyl is optionally substituted with halogen.

[0040] Cycloalkylalkyl refers to a radical of the formula -R^c-cycloalkyl where R^c is an alkylene chain as described above.

[0041] Cycloalkylalkoxy refers to a radical bonded through an oxygen atom of the formula O-R^c-cycloalkyl where R^c is an alkylene chain as described above.

[0042] Halo or halogen refers to halogen substituents such as bromo, chloro, fluoro and iodo substituents.

[0043] As used herein, the term haloalkyl or “haloalkane” refers to an alkyl radical, as defined above, that is substituted by one or more halogen radicals, for example, trifluoromethyl, dichloromethyl, bromomethyl, 2,2,2-trifluoroethyl, l-fluoromethyl-2-fluoroethyl, and the like. In some embodiments, the alkyl part of the fluoroalkyl radical is optionally further substituted.

Examples of halogen substituted alkanes (“haloalkanes”) include halomethane (e.g., chloromethane, bromomethane, fluoromethane, iodomethane), di-and trihalomethane (e.g., trichloromethane, tribromomethane, trifluoromethane, triiodomethane), 1-haloethane, 2haloethane, 1,2-dihaloethane, 1-halopropane, 2-halopropane, 3-halopropane, 1,2-dihalopropane, 1,3-dihalopropane, 2,3-dihalopropane, 1,2,3-trihalopropane, and any other suitable combinations of alkanes (or substituted alkanes) and halogens (e.g., Cl, Br, F, I, etc.). When an alkyl group is substituted with more than one halogen radicals, each halogen can be independently selected e.g., 1-chloro,2-fluoroethane.

[0044] Fluoroalkyl refers to an alkyl radical, as defined above, that is substituted by one or more fluoro radicals, for example, trifluoromethyl, difluoromethyl, fluoromethyl, 2,2,2-trifluoroethyl, l-fluoromethyl-2-fluoroethyl, and the like.

[0045] “Hydroxyalkyl” refers to an alkyl radical, as defined above, that is substituted by one or more hydroxyls. In some embodiments, the alkyl is substituted with one hydroxyl. In some embodiments, the alkyl is substituted with one, two, or three hydroxyls. Hydroxyalkyl include, for example, hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, or hydroxypentyl. In some embodiments, the hydroxyalkyl is hydroxymethyl.

[0046] “Aminoalkyl” refers to an alkyl radical, as defined above, that is substituted by one or more amines. In some embodiments, the alkyl is substituted with one amine. In some embodiments, the alkyl is substituted with one, two, or three amines. Aminoalkyl include, for example, aminomethyl, aminoethyl, aminopropyl, aminobutyl, or aminopentyl. In some embodiments, the aminoalkyl is aminomethyl.

[0047] The term “heteroalkyl” refers to an alkyl group in which one or more skeletal atoms of the alkyl are selected from an atom other than carbon, e.g., oxygen, nitrogen (e.g., -NH-, N(alkyl)-), sulfur, or combinations thereof. A heteroalkyl is attached to the rest of the molécule at a carbon atom of the heteroalkyl. In one aspect, a heteroalkyl is a Ci-Cô heteroalkyl wherein the heteroalkyl is comprised of 1 to 6 carbon atoms and one or more atoms other than carbon, e.g., oxygen, nitrogen (e.g. -NH-, -N(alkyl)-), sulfur, or combinations thereof wherein the heteroalkyl is attached to the rest of the molécule at a carbon atom of the heteroalkyl. Examples of such heteroalkyl are, for example, -CH2OCH3, -CH2CH2OCH3, -CH2CH2OCH2CH2OCH3, or CH(CH3)OCH3. Unless stated otherwise specifically in the spécification, a heteroalkyl is optionally substituted for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, a heteroalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, a heteroalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -CF3, -OH, or -OMe. In some embodiments, the heteroalkyl is optionally substituted with halogen.

[0048] “Heterocycloalkyl” refers to a stable 3- to 24-membered partially or fully saturated ring radical comprising 2 to 23 carbon atoms and at least one ring heteroatoms. In some embodiments, a heterocycloalkyl contains from one to 8 heteroatoms selected from the group consisting of nitrogen, oxygen, phosphorous, and sulfur. Unless stated otherwise specifically in the spécification, the heterocycloalkyl radical can be a monocyclic, bicyclic, tricyclic, or tetracyclic ring System, which can include fused (when fused with an aryl or a heteroaryl ring, the heterocycloalkyl is bonded through a non-aromatic ring atom) or bridged ring Systems; and the nitrogen, carbon, or sulfur atoms in the heterocycloalkyl radical can be optionally oxidized; the nitrogen atom can be optionally quatemized.

[0049] Représentative heterocycloalkyls include, but are not limited to, heterocycloalkyls having from two to fifteen carbon atoms (C2-C15 heterocycloalkyl), from two to ten carbon atoms (C2C10 heterocycloalkyl), from two to eight carbon atoms (C2-C8 heterocycloalkyl), from two to six carbon atoms (C2-C6 heterocycloalkyl), from two to five carbon atoms (C2-C5 heterocycloalkyl), or two to four carbon atoms (C2-C4 heterocycloalkyl). In some embodiments, the heterocycloalkyl is a 3- to 6-membered heterocycloalkyl. In some embodiments, the heterocycloalkyl is a 5- to 6-membered heterocycloalkyl. Examples of such heterocycloalkyl radicals include, but are not limited to, aziridinyl, azetidinyl, dioxolanyl, thienyl[l,3]dithianyl, decahydroisoquinolyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofiiryl, trithianyl, tetrahydropyranyl, thiomorpholinyl, thiamorpholinyl, 1-oxo-thiomorpholinyl, 1,1-dioxo-thiomorpholinyl, 1,3dihydroisobenzofuran-l-yl, 3-oxo-l,3-dihydroisobenzofuran-l-yl, methyl-2-oxo-l,3-dioxol-4-yl, and 2-oxo-l,3-dioxol-4-yl. The term heterocycloalkyl also includes ail ring forms of the carbohydrates, including but not limited to, the monosaccharides, the disaccharides, and the oligosaccharides. It is understood that when referring to the number of carbon atoms in a heterocycloalkyl, the number of carbon atoms in the heterocycloalkyl is not the same as the total number of atoms (including the heteroatoms) that make up the heterocycloalkyl (i.e. skeletal atoms of the heterocycloalkyl ring). Unless stated otherwise specifically in the spécification, a heterocycloalkyl is optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, a heterocycloalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, a heterocycloalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -CF3, -OH, or OMe. In some embodiments, the heterocycloalkyl is optionally substituted with halogen. [0050] “Heterocycle” or “heterocyclyl” refers to a saturated, unsaturated or aromatic ring comprising one or more ring heteroatoms. Exemplary heteroatoms include N, O, Si, P, B, and S atoms. Heterocycles include e.g., 3- to 10-membered monocyclic rings and 6- to 12-membered bicyclic rings (such as spiro, fused, or bridged rings). Unless stated otherwise specifically in the spécification, the heterocyclyl radical is a monocyclic, bicyclic, tricyclic or tetracyclic ring System, which optionally includes fused, bridged, or spirocyclic ring Systems. The heteroatoms in the heterocyclyl radical are optionally oxidized. One or more nitrogen atoms, if présent, are optionally quatemized. The heterocyclyl radical can be partially or fully saturated. The heterocyclyl is attached to the rest of the molécule through any atom of the ring(s). Examples of such heterocyclyl radicals include, but are not limited to, dioxolanyl, thienylfl ,3]dithianyl, decahydroisoquinolyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuryl, trithianyl, tetrahydropyranyl, thiomorpholinyl, thiamorpholinyl, l-oxo-thiomorpholinyl, and 1,1-dioxo-thiomorpholinyl. Unless stated otherwise specifically in the spécification, the term heterocyclyl is meant to include heterocyclyl radicals as defined above that are optionally substituted by one or more substituents. For example, a heterocyclyl can be optionally substituted by one or more substituents selected from alkyl, alkenyl, alkynyl, halo, fluoroalkyl, oxo, thioxo, cyano, nitro, optionally substituted aryl, optionally substituted aralkyl, optionally substituted aralkenyl, optionally substituted aralkynyl, optionally substituted carbocyclyl, optionally substituted carbocyclylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, -R^b-OR^a, -R^b-OC(O)-R^a, -R^b-OC(O)-OR^a, -R^b-OC(O)-N(R^a)2, -R^b-N(R^a)2, -R^b-C(O)R^a, -R^b-C(O)OR^a, -R^b-C(O)N(R^a)2, R^b-CN, -R^b-O-R^e-C(O)N(R^a)2, -R^b-N(R^a)C(O)OR^a, -R^b-N(R^a)C(O)R^a, -R^b-N(R^a)S(O)tR^a (where t is 1 or 2), -R^b-S(O)tR^a (where t is 1 or 2), -R^b-S(O)tOR^a (where t is 1 or 2) and -R^b-S(O)tN(R^a)₂(where t is 1 or 2), where each R^a is independently hydrogen, alkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), fluoroalkyl, cycloalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), cycloalkylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aralkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heteroaryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), or heteroarylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), each R^b is independently a direct bond or a straight or branched alkylene or alkenylene chain, and R^e is a straight or branched alkylene or alkenylene chain, and where each of the above substituents is unsubstituted unless otherwise indicated.

[0051] “Heteroaryl” or “aromatic heterocycle” refers to a ring System radical comprising carbon atom(s) and one or more ring heteroatoms (e.g., selected from the group consisting of nitrogen, oxygen, phosphorous, Silicon, and sulfur), and at least one aromatic ring. In some embodiments, a heteroaryl is a 5- to 14-membered ring System radical comprising one to thirteen carbon atoms, one to six heteroatoms selected from the group consisting of nitrogen, oxygen, phosphorous, and sulfur. The heteroaryl radical can be a monocyclic, bicyclic, tricyclic, or tetracyclic ring System, which can include fused (when fused with a cycloalkyl or heterocycloalkyl ring, the heteroaryl is bonded through an aromatic ring atom) or bridged ring Systems; and the nitrogen, carbon, or sulfur atoms in the heteroaryl radical can be optionally oxidized; the nitrogen atom can be optionally quatemized. In some embodiments, the heteroaryl is a 5- to 10-membered heteroaryl. In some embodiments, the heteroaryl is a 5- to 6-membered heteroaryl. Examples include, but are not limited to, azepinyl, acridinyl, benzimidazolyl, benzothiazolyl, benzindolyl, benzodioxolyl, benzofuranyl, benzooxazolyl, benzothiazolyl, benzothiadiazolyl, benzo[b][l,4]dioxepinyl, 1,4-benzodioxanyl, benzonaphthofuranyl, benzoxazolyl, benzodioxolyl, benzodioxinyl, benzopyranyl, benzopyranonyl, benzofuranyl, benzofuranonyl, benzothienyl (benzothiophenyl), benzotriazolyl, benzo[4,6]imidazo[l,2-a]pyridinyl, carbazolyl, cinnolinyl, dibenzofuranyl, dibenzothiophenyl, furanyl, furanonyl, isothiazolyl, imidazolyl, indazolyl, indolyl, indazolyl, isoindolyl, indolinyl, isoindolinyl, isoquinolyl, indolizinyl, isoxazolyl, naphthyridinyl, oxadiazolyl, 2-oxoazepinyl, oxazolyl, oxiranyl, 1-oxidopyridinyl, 1-oxidopyrimidinyl, 1-oxidopyrazinyl, 1-oxidopyridazinyl, 1-phenyl-ΙΗ-pyrrolyl, phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl, purinyl, pyrrolyl, pyrazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, quinazolinyl, quinoxalinyl, quinolinyl, quinuclidinyl, isoquinolinyl, tetrahydroquinolinyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl, triazinyl, and thiophenyl (i.e., thienyl). Unless stated otherwise specifically in the spécification, a heteroaryl is optionally substituted, for example, with halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, a heteroaryl is optionally substituted with halogen, methyl, ethyl, -CN, -CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, a heteroaryl is optionally substituted with halogen, methyl, ethyl, -CN, -CF₃, -OH, or -OMe. In some embodiments, the heteroaryl is optionally substituted with halogen.

[0052] The term “substituted” refers to moieties having substituents replacing a hydrogen on one or more carbons or substitutable heteroatoms, e.g., NH, of the structure. It will be understood that “substitution” or “substituted with” includes the implicit proviso that such substitution is in accordance with permitted valence of the substituted atom and the substituent, and that the substitution results in a stable compound, i.e., a compound which does not spontaneously undergo transformation such as by rearrangement, cyclization, élimination, etc. In certain embodiments, substituted refers to moieties having substituents replacing two hydrogen atoms on the same carbon atom, such as substituting the two hydrogen atoms on a single carbon with an oxo, imino or thioxo group. As used herein, the term “substituted” is contemplated to include ail permissible substituents of organic compounds. In a broad aspect, the permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and non-aromatic substituents of organic compounds. The permissible substituents can be one or more and the sarne or different for appropriate organic compounds. For purposes of this disclosure, the heteroatoms such as nitrogen can hâve hydrogen substituents and/or any permissible substituents of organic compounds described herein which satisfy the valences of the heteroatoms.

[0053] In some embodiments, substituents can include any substituents described herein, for example: halogen, hydroxy, oxo (=0), thioxo (=S), cyano (-CN), nitro (-NO2), imino (=N-H), oximo (=N-OH), hydrazino (=N-NH₂), -R^b-OR^a, -R^b-OC(O)-R^a, -R^b-OC(O)-OR^a,

[0054] -R^b-OC(O)-N(R^a)2, -R^b-N(R^a)2, -R^b-C(O)R^a, -R^b-C(O)OR^a, -R^b-C(O)N(R^a)2, -R^b-O-R^c-C( O)N(R^a)2, -R^b-N(R^a)C(O)OR^a, -R^b-N(R^a)C(O)R^a, -R^b-N(R^a)S(O)_tR^a (where t is 1 or

2), -R^b-S(O)tR^a (where t is 1 or 2), -R^b-S(O)tOR^a (where t is 1 or 2), and -R^b-S(O)tN(R^a)2 (where t is 1 or 2); and alkyl, alkenyl, alkynyl, aryl, aralkyl, aralkenyl, aralkynyl, cycloalkyl, cycloalkylalkyl, and heterocycle, any of which can be optionally substituted by alkyl, alkenyl, alkynyl, halogen, haloalkyl, haloalkenyl, haloalkynyl, oxo (=0), thioxo (=S), cyano (-CN), nitro (-NO2), imino (=N-H), oximo (=N-OH), hydrazine (=N-NH2), SF5, -R^b-OR^a, -R^b-OC(O)-R^a, -R^b-OC(O)-OR^a,

[0055] -R^b-OC(O)-N(R^a)2, -R^b-N(R^a)2, -R^b-C(O)R^a, -R^b-C(O)OR^a, -R^b-C(O)N(R^a)2, -R^b-O-R^c-C (O)N(R^a)2, -R^b-N(R^a)C(O)OR^a, -R^b-N(R^a)C(O)R^a, -R^b-N(R^a)S(O)_tR^a (where t is 1 or

2), -R^b-S(O)tR^a (where t is 1 or 2), -R^b-S(O)tOR^a (where t is 1 or 2) and -R^b-S(O)tN(R^a)2 (where t is 1 or 2); wherein each R^a is independently selected from hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, and heterocycle, wherein each R^a, valence permitting, can be optionally substituted with alkyl, alkenyl, alkynyl, halogen, haloalkyl, haloalkenyl, haloalkynyl, oxo (=0), thioxo (=S), cyano (-CN), nitro (-NO2), imino (=N-H), oximo (=N-OH), hydrazine (=NNH2), -R^b-OR^a, -R^b-OC(O)-R^a, -R^b-OC(O)-OR^a, -R^b-OC(O)-N(R^a)2, -R^b-N(R^a)2, -R^b-C(O)R^a, -R ^b-C(O)OR^a, -R^b-C(O)N(R^a)2, -R^b-O-R^c-C(O)N(R^a)2, -R^b-N(R^a)C(O)OR^a, -R^b-N(R^a)C(O)R^a, -R^bN(R^a)S(O)tR^a (where t is 1 or 2), -R^b-S(O)tR^a (where t is 1 or 2), -R^b-S(O)tOR^a (where t is 1 or 2) and -R^b-S(O)tN(R^a)2 (where t is 1 or 2); and wherein each R^b is independently selected from a direct bond or a straight or branched alkylene, alkenylene, or alkynylene chain, and each R^c is a straight or branched alkylene, alkenylene or alkynylene chain.

[0056] As used in the spécification and daims, the singular form “a”, “an” and “the” includes plural references unless the context clearly dictâtes otherwise.

[0057] The term “sait” or “pharmaceutically acceptable sait” refers to salts derived from a variety of organic and inorganic counter ions well known in the art. Pharmaceutically acceptable acid addition salts can be formed with inorganic acids and organic acids. Inorganic acids from which salts can be derived include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like. Organic acids from which salts can be derived include, for example, acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, and the like. Pharmaceutically acceptable base addition salts can be formed with inorganic and organic bases. Inorganic bases from which salts can be derived include, for example, sodium, potassium, lithium, ammonium, calcium, magnésium, iron, zinc, copper, manganèse, aluminum, and the like. Organic bases from which salts can be derived include, for example, primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, basic ion exchange resins, and the like, specifically such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, and ethanolamine. In some embodiments, the pharmaceutically acceptable base addition sait is chosen from ammonium, potassium, sodium, calcium, and magnésium salts.

[0058] The phrases “parentéral administration” and “administered parenterally” as used herein means modes of administration other than enterai and topical administration, usually by injection, and includes, without limitation, intravenous, intramuscular, intraarterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcuticular, intraarticular, subcapsular, subarachnoid, intraspinal and intrastemal injection and infusion.

[0059] The phrase “pharmaceutically acceptable” is employed herein to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animais without excessive toxicity, irritation, allergie response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.

J0060] The phrase “pharmaceutically acceptable excipient” or “pharmaceutically acceptable carrier” as used herein means a pharmaceutically acceptable material, composition or vehicle, such as a liquid or solid filler, diluent, excipient, solvent or encapsulating material. Each carrier must be “acceptable” in the sense of being compatible with the other ingrédients of the formulation and not injurious to the patient. Some examples of materials which can serve as pharmaceutically acceptable carriers include: (1) sugars, such as lactose, glucose and sucrose; (2) starches, such as corn starch and potato starch; (3) cellulose, and its dérivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; (4) powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients, such as cocoa butter and suppository waxes; (9) oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; (10) glycols, such as propylene glycol; (11) polyols, such as glycerin, sorbitol, mannitol and polyethylene glycol; (12) esters, such as ethyl oleate and ethyl laurate; (13) agar; (14) buffering agents, such as magnésium hydroxide and aluminum hydroxide; (15) alginic acid; (16) pyrogenfree water; (17) isotonie saline; (18) Ringer's solution; (19) ethyl alcohol; (20) phosphate buffer solutions; and (21) other non-toxic compatible substances employed in pharmaceutical formulations.

[0061] In certain embodiments, the term “prevent” or “preventing” as related to a disease or disorder can refer to a compound that, in a statistical sample, reduces the occurrence of the disorder or condition in the treated sample relative to an untreated control sample, or delays the onset or reduces the severity of one or more symptoms of the disorder or condition relative to the untreated control sample.

[0062] The terms “treat,” “treating” or “treatment,” as used herein, can include alleviating, abating or ameliorating a disease or condition symptoms, preventing additional symptoms, ameliorating or preventing the underlying causes of symptoms, inhibiting the disease or condition, e.g., arresting the development of the disease or condition, relieving the disease or condition, causing régression of the disease or condition, relieving a condition caused by the disease or condition, or stopping the symptoms of the disease or condition either prophylactically and/or therapeutically.

[0063] The terms “effective amount” or “therapeutically effective amount,” as used herein, refer to a sufficient amount of a compound disclosed herein being administered which will relieve to some extent one or more of the symptoms of the disease or condition being treated, e.g., cancer or an inflammatory disease. In some embodiments, the resuit is a réduction and/or alleviation of the signs, symptoms, or causes of a disease, or any other desired alteration of a biological System. For example, an “effective amount” for therapeutic uses is the amount of the composition comprising a compound disclosed herein required to provide a clinically significant decrease in disease symptoms. In some embodiments, an appropriate “effective” amount in any individual case is determined using techniques, such as a dose escalation study.

[0064] The term “optional” or “optionally” means that the subsequently described event or circumstance may or may not occur, and that the description includes instances where said event or circumstance occurs and instances in which it does not. For example, “optionally substituted alkyl” means either “alkyl” or “substituted alkyl” as defined above. Further, an optionally substituted group can be un-substituted (e.g., -CH2CH3), fully substituted (e.g., -CF2CF3), monosubstituted (e.g., -CH2CH2F) or substituted at a level anywhere in-between fully substituted and mono-substituted (e.g., -CH2CHF2, -CH2CF3, -CF2CH3, -CFHCHF2, etc.).

[0065] As used herein, the term “subject” can be a vertebrate, such as a mammal, a fish, a bird, a reptile, or an amphibian. Thus, the subject of the herein disclosed methods can be a human, nonhuman primate, horse, pig, rabbit, dog, sheep, goat, cow, cat, guinea pig or rodent. The term does not dénoté a particular âge or sex. Thus, adult and newbom subjects, as well as fetuses, whether male or female, are intended to be covered. In one aspect, the subject is a mammal.

[0066] Ranges provided herein are understood to be shorthand for ail of the values within the range. For example, a range of l to 50 is understood to include any number, combination of numbers, or sub-range from the group consisting of l, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, or 50, as well as ail intervening décimal values between the aforementioned integers such as, for example, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, and 1.9. With respect to sub-ranges, “nested sub-ranges” that extend from either end point of the range are specifically contemplated. For example, a nested sub-range of an exemplary range of 1 to 50 can comprise 1 to 10, 1 to 20, 1 to 30, and 1 to 40 in one direction, or 50 to 40, 50 to 30, 50 to 20, and 50 to 10 in the other direction.

B. Compounds of the disclosure

[0067] In one aspect, the disclosure provides a compound represented by Formula (III), or a pharmaceutically acceptable sait or solvaté thereof:

wherein,

Z¹ is N, NR¹, O, S, CR¹, or C(R’)₂;

Z² is N, NR², O, CR², C(R²)₂, S(=O)₂, C(=O), or C(=S);

Z³ is N, NR³, CR³, C(R³)₂, S(=O)₂, C(=O), or C(=S); ---is a single bond or a double bond;

each of R¹, R², and R³ is independently selected from hydrogen, halo, -CN, -OR¹¹, -SR¹¹, N(R¹²)₂, optionally substituted Ci-6 alkyl, optionally substituted Ci-6 heteroalkyl, optionally substituted C2-6 alkenyl, and optionally substituted C2-6 alkynyl;

each of R⁸ and R⁹ is independently selected from hydrogen, halo, -CN, optionally substituted Ci-6 alkyl, optionally substituted C1-6 heteroalkyl, optionally substituted C2-6 alkenyl, and optionally substituted C2-6 alkynyl; or R⁸ and R⁹ taken together form an oxo; or R⁸ and R⁹ taken together with the carbon to which they are attached form an optionally substituted 3-6 membered cycloalkyl or heterocycloalkyl;

ring A is phenyl, naphthyl, monocyclic heteroaryl, or bicyclic heteroaryl;

each of R^a is independently selected from halogen, -NO2, oxo, CN, optionally substituted Ci-6 alkyl, optionally substituted C2-6 alkenyl, optionally substituted C2-6 alkynyl, optionally substituted C1-6 heteroalkyl, optionally substituted C3-8 cycloalkyl, optionally substituted C2-7 heterocycloalkyl, -OR¹¹, -SR¹¹, -N(R¹²)(R^H), -C(O)R¹², C(O)OR¹², -OC(O)R¹², OC(O)N(Rⁱ²)(R), -C(O)N(R¹²)(R^h), -N(R¹²)C(O)R¹², -N(R¹²)C(O)OR¹², N(R^I2)C(O)N(R¹²)(R), -N(R¹²)2S(O)2(R¹²), -S(O)R¹², -S(O)2R¹², and -S(O)2N(R¹²)(R);

R¹¹ is hydrogen, optionally substituted Ci-6 alkyl, optionally substituted C2-6 alkenyl, optionally substituted C2-6 alkynyl, optionally substituted Cm heteroalkyl, optionally substituted C3-8 cycloalkyl, optionally substituted C2-7 heterocycloalkyl, optionally substituted phenyl, optionally substituted heteroaryl, optionally substituted -Cm alkylene-C3-8 cycloalkyl, optionally substituted -Cm alkylene-C2-7 heterocycloalkyl, optionally substituted -Cm alkylene-phenyl, or optionally substituted -Cm alkylene-heteroaryl;

each of R¹² is independently selected from hydrogen, halogen, -OH, -NO2, CN, Cm alkyl, Cm aminoalkyl, Cm hydroxyalkyl, Cm haloalkyl, Cm heteroalkyl, C3-6 carbocycle, and 3- to 6membered heterocycle, wherein the C3-6 carbocycle and 3- to 6-membered heterocycle is optionally substituted with one or more substituents independently selected from halogen, -OH, oxo, amino, -NO2, CN, Cm alkyl, Cm alkoxy, and Cm haloalkyl;

B is 6 membered heteroaryl, phenyl or a phenyl isostere;

R^B1 is halo, -CN, -NO2, optionally substituted Cm alkyl, optionally substituted C2-6 alkenyl, optionally substituted C2-6 alkynyl, optionally substituted Cm heteroalkyl, -OR¹¹, -SR¹¹, N(R¹²)(R^h), -C(O)R¹², C(O)OR¹², -OC(O)R¹², -OC(O)N(R¹²)(R), -C(O)N(R¹²)(R), N(R¹²)C(O)R¹², -N(R¹²)C(O)ORⁱ², -N(R¹²)C(O)N(R¹²)(R), -N(R¹²)S(O)₂(R¹²), -S(O)R¹², S(O)2R¹², -S(O)2N(R¹²)(R^h), optionally substituted C3-8 cycloalkyl, optionally substituted C2-9 heterocycloalkyl, optionally substituted naphthyl, optionally substituted phenyl, optionally substituted monocyclic heteroaryl, or optionally substituted bicyclic heteroaryl;

each R^b is independently halo, -CN, -NO2, optionally substituted Ci-6 alkyl, optionally substituted C2-6 alkenyl, optionally substituted C2-6 alkynyl, optionally substituted Ci-6 heteroalkyl, -OR¹¹, -SR¹¹, -N(R¹²)(Rⁿ), -C(O)R¹², C(O)OR¹², -OC(O)R¹², -OC(O)N(R¹²)(R^H), C(O)N(R¹²)(R), -N(R¹²)C(O)R¹², -N(R¹²)C(O)OR¹², -N(R¹²)C(O)N(R¹²)(R^h), N(R¹²)S(O)2(R¹²), -S(O)R¹², -S(O)2R¹², -S(O)2N(R¹²)(Rⁿ), optionally substituted C3-8 cycloalkyl, optionally substituted C2-9 heterocycloalkyl, optionally substituted naphthyl, optionally substituted phenyl, optionally substituted monocyclic heteroaryl, or optionally substituted bicyclic heteroaryl; or

m is 0, 1,2, 3, or 4;

n is 0, 1, 2, 3 or 4; and p is 0 or 1.

[0068] In some embodiments of Formula (III), Z¹ is NRⁿ¹ and R^N1 is hydrogen, -CN, optionally substituted Cm alkyl, optionally substituted Ci-6heteroalkyl, optionally substituted C2-6 alkenyl, or optionally substituted C2-6 alkynyl. In some embodiments of Formula (III), Z² is NR^N2 and R^N2is hydrogen, -CN, optionally substituted Cm alkyl, optionally substituted Ci-6 heteroalkyl, optionally substituted C2-6 alkenyl, or optionally substituted C2-6 alkynyl. In some embodiments of Formula (III), Z³ is NR^N3 and R^N3 is hydrogen, -CN, optionally substituted C1-6 alkyl, optionally substituted Ci-6 heteroalkyl, optionally substituted C2-6 alkenyl, or optionally substituted C2-6 alkynyl.

[0069] In some embodiments of Formula (III), each of R¹² is independently selected from hydrogen, -NO2, CN, Ci-6 alkyl, C1-6 aminoalkyl, Ci-6 hydroxyalkyl, Cm haloalkyl, Cm heteroalkyl, C3-6 carbocycle, and 3- to 6-membered heterocycle, wherein the C3-6 carbocycle and

3- to 6-membered heterocycle is optionally substituted with one or more substituents independently selected from halogen, -OH, oxo, amino, -NO2, CN, Ci-6 alkyl, Ci-6 alkoxy, and Ci-6 haloalkyl.

[0070] In some embodiments of Formula (III), each of R⁸ and R⁹ is independently selected from hydrogen, -CN, optionally substituted Ci-6 alkyl, optionally substituted Ci-6 heteroalkyl, optionally substituted C2-6 alkenyl, and optionally substituted C2-6 alkynyl; or R⁸ and R⁹ taken together form an oxo; or R⁸ and R⁹ taken together with the carbon to which they are attached form an optionally substituted 3-6 membered cycloalkyl or heterocycloalkyl

[0071] In some embodiments of Formula (III),

Z¹ is N, NR¹, O, S, CR¹, or C(R’)₂;

Z² is N, NR², O, CR², C(R²)₂, S(=O)₂, C(=O), or C(=S);

Z³ is N, NR³, CR³, C(R³)₂, S(=O)₂, C(=O), or C(=S);

---is a single bond or a double bond;

each of R¹, R², and R³ is independently selected from hydrogen, halo, -CN, -OR¹¹, -SR¹¹, -N(R¹²)₂, optionally substituted C1-6 alkyl, optionally substituted C1-6 heteroalkyl, optionally substituted C2-6 alkenyl, and optionally substituted C2-6 alkynyl, wherein the alkyl, heteroalkyl, alkenyl, or alkynyl is optionally substituted with one or more substituents independently selected from: halogen, amino, oxo, -OH,-NO2, -CN, and C1-3 alkoxyl;

each of R⁸ and R⁹ is independently selected from hydrogen, -CN, optionally substituted C1-6 alkyl, optionally substituted C1-6 heteroalkyl, optionally substituted C2-6 alkenyl, and optionally substituted C2-6 alkynyl; or R⁸ and R⁹ taken together form an oxo; or R⁸ and R⁹ taken together with the carbon to which they are attached form an optionally substituted 3-6 membered cycloalkyl or heterocycloalkyl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl or heterocycloalkyl is optionally substituted with one or more substituents independently selected from: halogen, amino, -OH, -NO2, oxo, -CN, C1.3 alkoxyl, C1-3 alkyl and C1-3 haloalkyl;

ring A is phenyl, naphthyl, monocyclic heteroaryl, or bicyclic heteroaryl;

each of R^a is independently selected from halogen, -NO2, oxo, -CN, optionally substituted C1-6 alkyl, optionally substituted C2-6 alkenyl, optionally substituted C2-6 alkynyl, optionally substituted C1-6 heteroalkyl, optionally substituted C3-8 cycloalkyl, optionally substituted C2-7 heterocycloalkyl, -OR¹¹, -SR¹¹, -N(R¹²)(R^H), C(O)R¹², -C(O)OR¹², -OC(O)R¹², -OC(O)N(R¹²)(R), -C(O)N(R^l2)(Rⁿ), 21708

N(R^I2)C(O)R¹² -N(R¹²)C(O)OR¹², -N(R¹²)C(O)N(R¹²)(R), -N(R^I2)2S(O)2(R¹²),S(O)R¹², -S(O)2R¹², and -S(O)₂N(R¹²)(R), wherein the alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, or heterocycloalkyl is optionally substituted with one or more substituents independently selected from: halogen, -OH, -NO₂, oxo, amino, -CN, Ci-6 alkoxyl, Ci-6 alkyl, Ci-6 haloalkyl, C3-6 carbocycle, and 3- to 6-membered heterocycle, wherein the C3-6 carbocycle and 3- to 6-membered heterocycle is optionally substituted with one or more substituents independently selected from halogen, -OH, amino, -NO2, oxo, -CN, C1-6alkyl, Cm alkoxy, and Cmhaloalkyl;

R¹¹ is hydrogen, optionally substituted Cm alkyl, optionally substituted C₂-6 alkenyl, optionally substituted C₂-6 alkynyl, optionally substituted Cm heteroalkyl, optionally substituted C3-8 cycloalkyl, optionally substituted C₂-7 heterocycloalkyl, optionally substituted phenyl, optionally substituted heteroaryl, optionally substituted -Cm alkylene-C₃-8 cycloalkyl, optionally substituted -CMalkylene-C₂-7 heterocycloalkyl, optionally substituted -CMalkylene-phenyl, or optionally substituted -CMalkyleneheteroaryl, wherein the alkyl, alkenyl, alkynyl, heteroalkyl, alkylene, cycloalkyl, heterocycloalkyl, phenyl, or heteroaryl is optionally substituted with one or more substituents independently selected from: halogen, -OH, amino, -NO₂, oxo, Cm alkoxy, -CN, Cm alkyl, and Cm haloalkyl;

each of R¹² is independently selected from hydrogen, -NO₂, -CN, Cmalkyl, Cm aminoalkyl, Ci-ôhydroxyalkyl, Cm haloalkyl, C1.6 heteroalkyl, C3-6 carbocycle, and 3to 6-membered heterocycle, wherein the C3-6 carbocycle and 3- to 6-membered heterocycle is optionally substituted with one or more substituents independently selected from halogen, -OH, oxo, amino, -NO₂, -CN, Ci-6 alkyl, Cm alkoxy, and Cm haloalkyl;

B is 6 membered heteroaryl, phenyl or a phenyl isostere;

R^B1 is halo, -CN, -NO2, optionally substituted Cmalkyl, optionally substituted C2-6 alkenyl, optionally substituted C2-6alkynyl, optionally substituted Cm heteroalkyl, OR, -SR, -N(R'²)(R), -C(O)R¹², -C(O)OR¹², -OC(O)R¹², -OC(O)N(R¹²)(R), C(O)N(R^I2)(R'’), -N(R¹²)C(O)R¹², -N(R¹²)C(O)ORⁱ², -N(R¹²)C(O)N(R¹²)(R'’), N(R¹²)S(O)2(R¹²),-S(O)R¹², -S(O)2R¹²,-S(O)₂N(R¹²)(R), optionally substituted C3-8 cycloalkyl, optionally substituted C2-9 heterocycloalkyl, optionally substituted naphthyl, optionally substituted phenyl, optionally substituted monocyclic heteroaryl, or optionally substituted bicyclic heteroaryl, wherein each of the alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocycloalkyl, naphthyl, phenyl or heteroaryl is optionally substituted with one or more substituents independently selected from: halogen, -NO2, oxo, -CN, optionally substituted Ci-6 alkyl, optionally substituted C2-6 alkenyl, optionally substituted C2-6 alkynyl, optionally substituted Ci-6heteroalkyl, optionally substituted C3-8cycloalkyl, optionally substituted C2-7 heterocycloalkyl, -OR”, -SR”, -N(R^l2)(R”), C(O)R¹², -C(O)OR¹², -OC(O)R¹², -OC(O)N(R¹²)(R”), -C(O)N(R¹²)(R”),N(R¹²)C(O)R¹² -N(R¹²)C(O)OR¹², -N(R¹²)C(O)N(R¹²)(R”), -N(R¹²)S(O)₂(R¹²), S(O)R¹², -S(O)2R¹², and-S(O)2N(R¹²)(R”), wherein the alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, or heterocycloalkyl is optionally substituted with one or more substituents independently selected from: halogen, -OH, -NO2, amino, -NH(Ci-6 alkyl), -N(Ci-6alkyl)2, oxo, -CN, C1-3 alkoxyl, C1-3 alkyl and Ci-3 haloalkyl;

each R^b is independently halo, -CN, -NO2, optionally substituted C1-6 alkyl, optionally substituted C2-6 alkenyl, optionally substituted C2-6 alkynyl, optionally substituted Cm heteroalkyl, -OR”, -SR¹¹, -N(R¹²)(R”), -C(O)R¹², -C(O)OR¹², -OC(O)R¹², OC(O)N(R¹²)(R”), -C(O)N(R¹²)(R”),-N(R¹²)C(O)R¹²-N(R¹²)C(O)OR¹²,N(R¹²)C(O)N(R¹²)(R”), -N(R¹²)S(O)₂(R¹²), -S(O)R¹², -S(O)2R¹², -S(O)2N(R¹²)(R”), optionally substituted C3-8 cycloalkyl, optionally substituted C2-9 heterocycloalkyl, optionally substituted naphthyl, optionally substituted phenyl, optionally substituted monocyclic heteroaryl, or optionally substituted bicyclic heteroaryl, wherein the each of the alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocycloalkyl, naphthyl, phenyl or heteroaryl is optionally substituted with one or more substituents independently selected from: halogen, -OH, -NO2, amino, oxo, -CN, C1-3 alkoxyl, C1-3 alkyl and C1-3 haloalkyl; or

R^B1 and one of R^B on adjacent atoms are taken together with the atoms to which they are attached to form an optionally substituted phenyl, optionally substituted naphthyl, optionally substituted monocyclic heteroaryl, optionally substituted bicyclic heteroaryl, optionally substituted C3-8 cycloalkyl, or optionally substituted C2-9 heterocycloalkyl, wherein the phenyl, naphthyl, heteroaryl, cycloalkyl, or heterocycloalkyl is optionally substituted with one or more substituents independently selected from: halogen, -OH, amino, -NO2, oxo, Ci-6alkoxy, -CN, Ci-6 alkyl, Ci-6 haloalkyl; or R^Bl and one of R^B on the same atom are taken together with the atom to which they are attached to form an optionally substituted C3-8 cycloalkyl or optionally substituted C29 heterocycloalkyl, wherein the cycloalkyl or heterocycloalkyl is optionally substituted with one or more substituents independently selected from: halogen, -OH, amino, -NO₂, oxo, Ci-6 alkoxy, -CN, Ci-6alkyl, Ci-6 haloalkyl; or two of R^b on the same atom are taken together with the atom to which they are attached to form an optionally substituted C3-8 cycloalkyl or optionally substituted C2-9 heterocycloalkyl, wherein the cycloalkyl or heterocycloalkyl is optionally substituted with one or more substituents independently selected from: halogen, -OH, amino, -NO2, oxo, Ci-6 alkoxy, -CN, Ci-6alkyl, Ci-6haloalkyl;

m is 0, l, 2, 3, or 4;

n is 0, 1, 2, 3 or 4; and p is 0 or 1.

[0072] In some embodiments of Formula (III), Z¹ is NRⁿ¹ and R^N1 is hydrogen, -CN, optionally substituted C1-6 alkyl, optionally substituted Ci-6 heteroalkyl, optionally substituted C2-6 alkenyl, or optionally substituted C2-6 alkynyl. In some embodiments of Formula (III), Z² is NR^N2 and R^N2is hydrogen, -CN, optionally substituted C1-6 alkyl, optionally substituted Ci-6 heteroalkyl, optionally substituted C2-6 alkenyl, or optionally substituted C2-6 alkynyl. In some embodiments of Formula (III), Z³ is NR^N3 and R^N3 is hydrogen, -CN, optionally substituted C1-6 alkyl, optionally substituted Ci-6 heteroalkyl, optionally substituted C2-6 alkenyl, or optionally substituted C2-6 alkynyl.

[0073] In some embodiments, the compound of Formula (III) has a structure of Formula (Ilia):

R⁸ I ^zp R⁹

Formula (Ilia).

[0074] In one aspect, the disclosure provides a compound having the structure of Formula (Ilia), or a sait thereof,

Formula (Ilia) wherein,

Z¹ is N, NR¹, O, S, CR¹, or C(R’)₂;

Z² is N, NR², O, CR², C(R²)₂, S(=O)₂, C(=O), or C(=S);

---is a single bond or a double bond;

each of R¹ and R² is independently selected from hydrogen, halo, -CN, -OR¹¹, -SR¹¹, N(R¹²)₂, optionally substituted Ci-6alkyl, optionally substituted Cm heteroalkyl, optionally substituted C₂-6 alkenyl, and optionally substituted C₂-6 alkynyl;

each of R⁸ and R⁹ is independently selected from hydrogen, halogen, -CN, optionally substituted Cm alkyl, optionally substituted Ci-6heteroalkyl, optionally substituted C₂-6 alkenyl, and optionally substituted C₂-6 alkynyl; or R⁸ and R⁹ taken together form an oxo; or R⁸ and R⁹ taken together with the carbon to which they are attached form an optionally substituted 3-6 membered cycloalkyl or heterocycloalkyl;

each of R^a is independently selected from halogen, -NO₂, oxo, -CN, optionally substituted Cm alkyl, optionally substituted C₂-6 alkenyl, optionally substituted C₂-6 alkynyl, optionally substituted Ci-6 heteroalkyl, optionally substituted C3-8cycloalkyl, optionally substituted C2-7 heterocycloalkyl, -OR¹¹, -SR¹¹, -N(R^I2)(R^H), C(O)R¹², -C(O)OR¹², -OC(O)R¹², -OC(O)N(R¹²)(R^H), -C(O)N(R¹²)(R^H),21708

N(R¹²)C(O)R¹² -N(R¹²)C(O)OR¹², -N(R¹²)C(O)N(R¹²)(R), -N(R¹²)2S(O)2(R¹²), S(O)R¹², -S(O)2R¹², and -S(O)₂N(R^I2)(R^H);

R¹¹ is hydrogen, optionally substituted Ci-6 alkyl, optionally substituted C₂-6 alkenyl, optionally substituted C₂-6 alkynyl, optionally substituted Ci-6 heteroalkyl, optionally substituted C3-8 cycloalkyl, optionally substituted C₂-7 heterocycloalkyl, optionally substituted phenyl, optionally substituted heteroaryl, optionally substituted -Cm alkylene-Cs-8 cycloalkyl, optionally substituted -Ci-4alkylene-C₂-7 heterocycloalkyl, optionally substituted -Ci-4alkylene-phenyl, or optionally substituted -Ci-4alkyleneheteroaryl;

each of R¹² is independently selected from hydrogen, -NO₂, -CN, C1-6 alkyl, C1-6 aminoalkyl, Ci-6 hydroxyalkyl, Ci-6 haloalkyl, Ci-6 heteroalkyl, C3-6 carbocycle, and 3to 6-membered heterocycle, wherein the C3-6 carbocycle and 3- to 6-membered heterocycle is optionally substituted with one or more substituents independently selected from halogen, -OH, oxo, amino,-NO₂, -CN, C1-6 alkyl, Ci-6alkoxy, and Ci-6 haloalkyl;

B is 6 membered heteroaryl, phenyl, cyclohexyl, 6-membered heterocycloalkyl, or a phenyl isostere;

R^B1 is halo, -CN, -NO2, optionally substituted C1-6 alkyl, optionally substituted C2-6 alkenyl, optionally substituted C2-6 alkynyl, optionally substituted C1-6 heteroalkyl, OR¹¹, -SR¹¹, -N(R¹²)(R^h), -C(O)R¹², -C(O)OR¹², -OC(O)R¹², -OC(O)N(R¹²)(Rⁿ), C(O)N(R¹²)(R^H), -N(R¹²)C(O)R¹² -N(R¹²)C(O)OR¹², -N(R¹²)C(O)N(R¹²)(R^h), N(R¹²)S(O)2(R¹²),-S(O)R¹², -S(O)₂R¹², -S(O)2N(R¹²)(R^h), optionally substituted C3-8 cycloalkyl, optionally substituted C2-9 heterocycloalkyl, optionally substituted naphthyl, optionally substituted phenyl, optionally substituted monocyclic heteroaryl, or optionally substituted bicyclic heteroaryl;

each R^b is independently halo, -CN, -NO2, optionally substituted C1-6 alkyl, optionally substituted C2-6 alkenyl, optionally substituted C2-6 alkynyl, optionally substituted Ci-6 heteroalkyl, -OR¹¹, -SR¹¹, -N(R¹²)(R^H), -C(O)R¹², -C(O)OR¹², -OC(O)R¹², OC(O)N(R¹²)(R'’), -C(O)N(R¹²)(R^h), -N(R¹²)C(O)R¹² -N(R^I2)C(O)OR¹², N(R^I2)C(O)N(R¹²)(R' '), -N(R¹²)S(O)2(R¹²), -S(O)R¹², -S(O)2R¹², -S(O)2N(R¹²)(R‘’), optionally substituted C3-8 cycloalkyl, optionally substituted C₂-9 heterocycloalkyl, optionally substituted naphthyl, optionally substituted phenyl, optionally substituted monocyclic heteroaryl, or optionally substituted bicyclic heteroaryl; or

R^Bl and one of R^B on adjacent atoms are taken together with the atoms to which they are attached to form an optionally substituted phenyl, optionally substituted naphthyl, optionally substituted monocyclic heteroaryl, optionally substituted bicyclic heteroaryl, optionally substituted C3-8 cycloalkyl, or optionally substituted C2-9 heterocycloalkyl; or

R^Bl and one of R^B on the same atom are taken together with the atom to which they are attached to form an optionally substituted C3.8 cycloalkyl or optionally substituted C29 heterocycloalkyl; or two of R^b on the same atom are taken together with the atom to which they are attached to form an optionally substituted C3-8 cycloalkyl or optionally substituted C2-9 heterocycloalkyl;

n is 0, 1, 2, 3 or 4; and p is 1.

[0075] In some embodiments, m is 1, 2, or 3.

[0076] In some embodiments, ring B is 6 membered heteroaryl, phenyl, or a phenyl isostere. In some embodiments, ring B is cyclohexyl or 6-membered heterocycloalkyl. In some embodiments, ring B is cyclohexyl. In some embodiments, ring B is 6-membered heterocycloalkyl.

[0077] In some embodiments, each of R¹ and R² is independently selected from hydrogen, -CN, optionally substituted Ci-6 alkyl, optionally substituted Ci-6 heteroalkyl, optionally substituted C26 alkenyl, and optionally substituted C2-6 alkynyl;

[0078] In some embodiments, the compound has a structure of Formula (IIIc’),

Formula (IIIc wherein,

Y¹ isNor CR^Y1;

Y² is N or CR^Y2;

Y³ is N or CR^Y3;

Y⁴ is N or CR^Y4;

each of R^Yl, R^Y2, R^Y3 and R^Y4 is independently selected from hydrogen, halo, -CN, OR¹¹, -SR¹¹, -N(R¹²)₂, optionally substituted Ci-6alkyl, optionally substituted Ci-6heteroalkyl, optionally substituted C₂-6 alkenyl, and optionally substituted C₂-6 alkynyl.

[0079] In some embodiments, the compound has a structure of Formula (IIIc-1 ’)

Formula (IIIc-1 ’).

[0080] In some embodiments, the compound has a structure of Formula (Illd’),

Formula (Illd’).

[0081] In some embodiments of Formula (Ilia), (IIIc’), or (Illd’), each of Ri and R₂ is independently selected from hydrogen, halo, -CN, optionally substituted Ci-6 alkyl, optionally substituted Ci-6 heteroalkyl, optionally substituted C₂-6 alkenyl, and optionally substituted C₂-6 alkynyl. In some embodiments, each of R¹ and R² is independently selected from hydrogen, -CN, optionally substituted Ci^alkyl, optionally substituted Ci-6heteroalkyl, optionally substituted C2. 6 alkenyl, and optionally substituted C2-6 alkynyl. In some embodiments of Formula (Ilia), (IIIc’), or (Illd’), Z¹ is NRⁿ¹ and R^N1 is hydrogen, -CN, optionally substituted Ci-6 alkyl, optionally substituted Ci-6 heteroalkyl, optionally substituted C2-6 alkenyl, or optionally substituted C₂-6 alkynyl. In some embodiments of Formula (Ilia), (IIIc’), or (Illd’), Z² is NR^N2 and R^N2is hydrogen, -CN, optionally substituted Ci-6 alkyl, optionally substituted Ci-6heteroalkyl, optionally substituted C₂-6 alkenyl, or optionally substituted C₂-6 alkynyl.

[0082] In some embodiments, the compound of Formula (Ilia) is represented by Formula (Illa1):

wherein,

Z¹ isNor CR¹; and

Z² is N or CR².

Formula (IIIa-1).

[0085] In some aspects, the compound of Formula (Ilia) is represented by Formula (IIIa-2):

wherein

Z¹ is NR¹, O, S, or C(R*)₂; and

Z²is NR², O, or C(R²).

[0086] In some embodiments of Formula (IIIa-2), Z¹ is NRⁿ¹ and R^N1 is hydrogen, -CN, optionally substituted Ci-6 alkyl, optionally substituted Ci-6heteroalkyl, optionally substituted C₂6 alkenyl, or optionally substituted C₂-6 alkynyl. In some embodiments of Formula (IIIa-2), Z² is NRⁿ² and R^N2is hydrogen, -CN, optionally substituted Ci-6alkyl, optionally substituted Ci-6 heteroalkyl, optionally substituted C₂-6 alkenyl, or optionally substituted C₂-6 alkynyl.

[0088] In some aspects, the compound of Formula (III) is represented by Formula (Illb):

Formula (Illb), wherein,

Z¹ is NR¹, O, S, or C(R')₂;

Z² is NR², O, C(R²)₂, C(=O), S(=O)₂, or C(=S); and

Z³ is NR³, O, S, C(R³)₂, C(=O), S(=O)₂, or C(=S).

[0089] In some embodiments of Formula (Illb), Z¹ is NRⁿ¹ and R^N1 is hydrogen, -CN, optionally substituted Ci-6 alkyl, optionally substituted Ci-6heteroalkyl, optionally substituted C2-6 alkenyl, or optionally substituted C2-6 alkynyl. In some embodiments of Formula (Illb), Z² is NR^N2 and Rⁿ² is hydrogen, -CN, optionally substituted Ci-6 alkyl, optionally substituted Ci-6heteroalkyl, optionally substituted C2-6 alkenyl, or optionally substituted C₂-6 alkynyl. In some embodiments of Formula (Illb), Z³ is NR^N3 and R^N3 is hydrogen, -CN, optionally substituted Ci-6 alkyl, optionally substituted Ci-6 heteroalkyl, optionally substituted C₂-6 alkenyl, or optionally substituted C₂-6 alkynyl.

[0090] In some embodiments, the compound of Formula (Illb) has a structure of Formula (Illb-

Formula (IIIb-1) wherein

Z² is C(R²)₂, C(=O), or C(=S); and

Z³ is NR³, C(R³)₂, C(=O), or C(=S);

[0091] In some embodiments of Formula (IIIb-1), Z³ is NR^N3 and R^N3 is hydrogen, -CN, optionally substituted Cm alkyl, optionally substituted Cm heteroalkyl, optionally substituted C₂. 6 alkenyl, or optionally substituted C₂-6 alkynyl.

[0092] In some embodiments,

[0093] In some embodiments, the compound of Formula (Illb) has a structure of Formula (Illb2):

Formula (IIIb-2) wherein

Z² is NR², C(R²)₂, C(=O), or C(=S); and

Z³ is NR³, C(R³)₂, C(=O), or C(=S).

[0094] In some embodiments of Formula (IIIb-2), Z² is NR^N2 and R^N2is hydrogen, -CN, optionally substituted Ci-6 alkyl, optionally substituted Ci-6 heteroalkyl, optionally substituted C₂. 6 alkenyl, or optionally substituted C₂-6 alkynyl. In some embodiments of Formula (IIIb-2), Z³ is NR^N3 and R^N3 is hydrogen, -CN, optionally substituted Ci-6 alkyl, optionally substituted Ci-6 heteroalkyl, optionally substituted C₂-6 alkenyl, or optionally substituted C₂-6 alkynyl.

[0095] In some embodiments of Formula (III), (Ilia), (IIIa-1), (IIIa-2), (Illb), (IIIb-1), or (IIIb-2),

[0096] In some embodiments of Formula (III), (Ilia), (IIIa-1), (IIIa-2), (Illb), (IIIb-1), or (IIIb-2),

Y²-Y¹

Y¹ isNor CR^Y1;

Y² is N or CR^Y2;

Y³ is N or CR^Y3;

Y⁴ is N or CR^Y4; and each of R^Yl, R^Y2, R^Y3 and R^Y4 is independently selected from hydrogen, halo, -CN, -OR”, -SR”, -N(R^l2)2, optionally substituted Ci-6 alkyl, optionally substituted Ci-6 heteroalkyl, optionally substituted C2-6 alkenyl, and optionally substituted C2-6 alkynyl.

[0097] In some embodiments, the compound of Formula (III) has a structure of Formula (IIIc),

Formula (IIIc) wherein,

Y¹ isNor CR^Y1;

Y² is N or CR^Y2;

Y³ is N or CR^Y3;

Y⁴ is N or CR^Y4;

each of R^Y1, R^Y2, R^Y3 and R^Y4 is independently selected from hydrogen, halo, -CN, OR”, -SR”, -N(R¹²)₂, optionally substituted Ci-6alkyl, optionally substituted C1-6 heteroalkyl, optionally substituted C2-6 alkenyl, and optionally substituted C₂-6 alkynyl;

Z¹ is N, NR¹, O, S, CR¹, or C(R')₂;

Z² is N, NR², O, CR², C(R²)₂, S(=O)₂, C(=O), or C(=S);

Z³ is N, NR³, CR³, C(R³)₂, S(=O)₂, C(=O), or C(=S);

---is a single bond or a double bond;

each of R¹, R², and R³ is independently selected from hydrogen, halo, -CN, -OR¹¹, -SR”, N(R¹²)₂, optionally substituted C1-6 alkyl, optionally substituted Ci-6 heteroalkyl, optionally substituted C₂-6 alkenyl, and optionally substituted C₂-6 alkynyl;

each of R⁸ and R⁹ is independently selected from hydrogen, halo, -CN, optionally substituted Ci-6 alkyl, optionally substituted Ci-6 heteroalkyl, optionally substituted C₂-6 alkenyl, and optionally substituted C₂-6 alkynyl; or R⁸ and R⁹ taken together form an oxo; or R⁸ and R⁹ taken together with the carbon to which they are attached form an optionally substituted 3-6 membered cycloalkyl or heterocycloalkyl;

ring A is monocyclic heteroaryl or bicyclic heteroaryl;

each of R^Ais independently selected from halogen, -NO₂, oxo, -CN, optionally substituted C1-6 alkyl, optionally substituted C₂-6 alkenyl, optionally substituted C₂-6 alkynyl, optionally substituted Ci-6 heteroalkyl, optionally substituted C3-8 cycloalkyl, optionally substituted C2-7 heterocycloalkyl, -OR¹¹, -SR¹¹, -N(R¹²)(R^H), -C(O)R¹², -C(O)OR¹², OC(O)R¹², -OC(O)N(R¹²)(R), -C(O)N(R¹²)(Rⁿ),-N(R¹²)C(O)R¹² -N(R¹²)C(O)OR¹²,NCR^QOjNCR^XR¹¹), -N(R¹²)2S(O)2(R¹²),-S(O)R¹², -S(O)2R¹², and -S^NCR^XR¹¹);

R¹¹ is hydrogen, optionally substituted Ci-6alkyl, optionally substituted C2-6 alkenyl, optionally substituted C2-6 alkynyl, optionally substituted Ci-6 heteroalkyl, optionally substituted C3-8 cycloalkyl, optionally substituted C2-7 heterocycloalkyl, optionally substituted phenyl, optionally substituted heteroaryl, optionally substituted -Cm alkylene-Cs-s cycloalkyl, optionally substituted -Ci-4alkylene-C2-7 heterocycloalkyl, optionally substituted -Cm alkylene-phenyl, or optionally substituted -CMalkylene-heteroaryl;

each of R¹² is independently selected from hydrogen-NO2, -CN, Cm alkyl, C1-6 aminoalkyl, Ci-ôhydroxyalkyl, Ci-6 haloalkyl, Ci.6heteroalkyl, C3-6 carbocycle, and 3- to 6membered heterocycle, wherein the C3-6 carbocycle and 3- to 6-membered heterocycle is optionally substituted with one or more substituents independently selected from halogen, OH, oxo, amino,-NO2, -CN, C1-6alkyl, Ci-6alkoxy, and Ci-6 haloalkyl;

m is 1, 2, 3, or 4;

n is 0, 1, 2, 3 or 4; and p is 0 or 1.

[0098] In some embodiments of Formula (IIIc), Z¹ is NRⁿ¹ and R^N1 is hydrogen, -CN, optionally substituted C1.6 alkyl, optionally substituted C1.6 heteroalkyl, optionally substituted C2-6 alkenyl, or optionally substituted C2-6 alkynyl. In some embodiments of Formula (IIIc), Z² is NRⁿ² and R^N2 is hydrogen, -CN, optionally substituted C1-6 alkyl, optionally substituted Ci-6heteroalkyl, optionally substituted C₂-6 alkenyl, or optionally substituted C2-6 alkynyl. In some embodiments of Formula (IIIc), Z³ is NR^N3 and R^N3 is hydrogen, -CN, optionally substituted C1-6 alkyl, optionally substituted C1.6 heteroalkyl, optionally substituted C2-6 alkenyl, or optionally substituted C2-6 alkynyl.

[0099] In some embodiments, the compound of Formula (III) has a structure of Formula (Illd):

Formula (Illd), wherein each of the functional groups has the same définition as in Formula (III).

[0100] In some embodiments of Formula (III), (Ilia), (IIIa-1), (IIIa-2), (Illb), (IIIb-1), (IIIb-2), (IIIc-Γ), (IIIc’), (Illd’), (IIIc), or (Illd), each of R¹ and R² is independently selected from hydrogen, halo, -CN, optionally substituted Ci-6alkyl, optionally substituted Ci-6heteroalkyl, optionally substituted C2-6 alkenyl, and optionally substituted C2-6 alkynyl. In some embodiments, each of R¹ and R² is independently selected from hydrogen, and C1-6 alkyl.

[0101] In some embodiments of Formula (III), (Ilia), (IIIa-1), (IIIa-2), (Illb), (IIIb-1), (IIIb-2),

In some embodiments of Formula (IIIc-Γ), (IIIc’), or (Illd’),

[0102] In some embodiments, the compound of Formula (IIIc) has a structure of Formula (IIIc-

Formula (IIIc-1 ).

[0103] In some embodiments of Formula (III), (Ilia), (IIIa-I), (IIIa-2), (Illb), (IIIb-1 ), (IIIb-2), (IIIc’), or (IIIc), Y¹ is N. In some embodiments, Y¹ is CR^Y1. In some embodiments, Y² is N. In some embodiments, Y² is CR^Y2. In some embodiments, Y³ is N. In some embodiments, Y³ is CR^Y3. In some embodiments, Y⁴ is N. In some embodiments, Y⁴ is CR^Y4.

[0104] In some embodiments of Formula (III), (Ilia), (IIIa-1), (IIIa-2), (Illb), (IIIb-1), (IIIb-2), (Illd), (IIIc), (IIIc-Γ), (IIIc’), (Illd’), or (IIIc-1), ring A is phenyl. In some embodiments,

. In some embodiments, ring

A is naphthyl. In some embodiments, ring A is 5 or 6 membered monocyclic heteroaryl. In some 5 embodiments, ring A is a 6 membered monocyclic heteroaryl containing 1-3 heteroatoms. In some embodiments, ring A is pyridine, pyrimidine, pyrazine, pyridazine, triazine, imidazole, pyrazole, triazole, oxazole, isoxazole, or thiophene. In some embodiments,

some embodiments,

is

. In some embodiments,

embodiments, ring A is bicyclic heteroaryl. In some embodiments, ring A is fused 5-6, 6-6, or 610 5 bicyclic heteroaryl.

[0105] In some embodiments of Formula (III), (Ilia), (IIIa-1), (IIIa-2), (Illb), (IIIb-1), (IIIb-2), (Illd), (IIIc-Γ), (IIIc’), (Illd’), (IIIc) or (IIIc-1), each R^Ais independently selected from halogen, -NO2, oxo, -CN, optionally substituted Ci-6alkyl, optionally substituted Ci-6heteroalkyl, optionally substituted C3-8 cycloalkyl, optionally substituted C2-7 heterocycloalkyl, -OR¹¹, -SR¹¹, -N(R¹²)(Rⁿ), -C(O)R¹², -C(O)OR¹², -OC(O)R¹², -OC(O)N(R¹²)(R^H), -C(O)N(R¹²)(R^H),N(R¹²)C(O)R¹² -NiR'^CiOjOR^^NCR'^CCOjNCR'^CR¹¹), -N(R¹²)₂S(O)2(R¹²), -S(O)R¹², S(O)2R¹², and -S(O)2N(R¹²)(Rⁿ). In some embodiments of Formula (III), (Ilia), (IIIa-1), (IIIa-2), (Illb), (IIIb-1), (IIIb-2), (Illd), (IIIc-Γ), (IIIc’), (Illd’), (IIIc) or (IIIc-1), each R^Ais independently selected from halogen, -NO2, oxo, -CN, C1-6 alkyl, C1-6 alkoxyl, C1.6 haloalkyl, Ci-6 heteroalkyl, and C3-6 cycloalkyl. In some embodiments, each R^Ais independently selected from halogen, C1-6 alkyl, C1-6 alkoxyl, Ci-6 haloalkyl, and C3-6 cycloalkyl. In some embodiments, each R^Ais independently selected from C1-6 alkyl, Ci-6alkoxyl, Ci-ôhaloalkoxyl, Ci-6 haloalkyl, and C3-6 cycloalkyl. In some embodiments, each R^Ais independently selected from halogen, C1.6 alkyl, Ci-6alkoxyl, and C3-6 cycloalkyl, wherein the alkyl, alkoxyl and cycloalkyl is optionally substituted with one or more halogen (e.g., 1-3 fluorine). In some embodiments, each R^Ais independently selected from methyl, ethyl, propyl, butyl, -O-methyl, -O-ethyl, -O-propyl, -Obutyl, cyclopropyl, CN, OH, -O-CHF2, -O-CH2F, CHF2, CH2F, and CF3. In some embodiments, R^A is halogen. In some embodiments, R^A is -NO2. In some embodiments, R^A is oxo. In some embodiments, R^A is -CN. In some embodiments, R^A is optionally substituted C1-6 alkyl. In some embodiments, R^A is Ci-alkyl. In some embodiments, R^A is C2 alkyl. In some embodiments, R^A is C3 alkyl. In some embodiments, R^A is optionally substituted Cm heteroalkyl. In some embodiments, R^A is C3 heteroalkyl. In some embodiments, R^A is optionally substituted C3-8 cycloalkyl. In some embodiments, R^A is C3 cycloalkyl. In some embodiments, R^A is optionally substituted C2-7 heterocycloalkyl. In some embodiments, R^A is C2 heterocycloalkyl. In some embodiments, R^A is -OR¹¹. In some embodiments, R^A is -SR¹¹. In some embodiments, R^A is N(R¹²)(R^h). In some embodiments, R^A is -C(O)R¹². In some embodiments, R^A is -C(O)OR¹². In some embodiments, R^A is -OC(O)R¹². In some embodiments, R^A is -OC(O)N(R¹²)(Rⁿ). In some embodiments, R^A is -C(O)N(R¹²)(R^H) In some embodiments, R^A is -N(R¹²)C(O)R¹², N(R¹²)C(O)OR¹². In some embodiments, R^A is -N(R¹²)C(O)N(R¹²)(R^H). In some embodiments, R^a is -N(R¹²)2S(O)2(R¹²). In some embodiments, R^A is -S(O)R¹². In some embodiments, R^A is S(O)2R¹². In some embodiments, R^A is -S(O)2N(R¹²)(R^H).

[0106] In some embodiments of Formula (III), (Ilia), (IIIa-1), (IIIa-2), (Illb), (IIIb-1), (IIIb-2), (Illd), (IIIc-1 ’), (IIIc’), (Illd’), (IIIc) or (IIIc-1), R^Ais independently substituted with one or more substituents independently selected from: halogen, -OH,-NO2, amino, -CN, C1-6 alkoxyl, C1-6 alkyl, Ci-6 haloalkyl, C3-6carbocycle, and 3- to 6-membered heterocycle, wherein the C3-6 carbocycle and 3- to 6-membered heterocycle is optionally substituted with one or more substituents independently selected from halogen, -OH, amino, -NO2, oxo, -CN, Cm alkyl, Cm alkoxy, and Ci-6haloalkyl. In some embodiments, each R^A is independently substituted with one or more substituents independently selected from halogen, Cm alkyl, Ci-6 haloalkyl, oxo, C3-6 cycloalkyl, and amino.

[0107] In some embodiments of Formula (III), (Ilia), (IIIa-1), (IIIa-2), (Illb), (IIIb-1), (IIIb-2),

(Illd), (IIIc-1 ’), (IIIc’), (Illd’), (IIIc) or (IIIc-1), is selected from:

. In some embodiments,

is

[0108] In some embodiments of Formula (III), (Ilia), (IIIa-1), (IIIa-2), (Illb), (IIIb-1), (IIIb-2), (Illd), (IIIc-Γ), (IIIc’), (Illd’), (IIIc) or (IIIc-1), p is 1. In some embodiments of Formula (III), (Ilia), (IIIa-1), (IIIa-2), (Illb), (IIIb-1), (IIIb-2), (Illd), (IIIc) or (IIIc-1 ), p is 0.

[0109] In some embodiments of Formula (III), (Ilia), (IIIa-1), (IIIa-2), (Illb), (IIIb-1), (IIIb-2), (Illd), (IIIc-1 ’), (IIIc’), (Illd’), (IIIc) or (IIIc-1), each of R⁸ and R⁹ is independently selected from hydrogen, halo, -CN, optionally substituted Ci-6 alkyl, optionally substituted Ci-6heteroalkyl, optionally substituted C2-6 alkenyl, and optionally substituted C2-6 alkynyl. In some embodiments, each of R⁸ and R⁹ is independently selected from hydrogen, -CN, optionally substituted Ci-6 alkyl, optionally substituted Ci-6 heteroalkyl, optionally substituted C2-6 alkenyl, and optionally substituted C₂-6 alkynyl. In some embodiments, R⁸ and R⁹ are hydrogen. In some embodiments, R⁸ and R⁹ are -CN. In some embodiments, R⁸ and R⁹ are optionally substitute Ci-3 alkyl. In some embodiments, R⁸ and R⁹ taken together form an oxo. In some embodiments, R⁸ and R⁹ taken together with the carbon to which they are attached form an optionally substituted 3-6 membered cycloalkyl or heterocycloalkyl.

[0110] In some embodiments of Formula (III), (Ilia), (IIIa-1), (IIIa-2), (Illb), (IIIb-1), (IIIc-1 ’), (IIIc’), (Illd’), or (IIIb-2), B is a ring. In some embodiments of Formula (III), (Ilia), (IIIa-1), (IIIa-2), (Illb), (IIIc-1 ’), (IIIc’), (Illd’), (IIIb-1), or (IIIb-2), ring B is phenyl or 6 membered heteroaryl. In some embodiments, ring B is phenyl, pyridine, pyrimidine, pyrazine, pyridazine, or triazine. In some embodiments, ring B is cyclohexyl, 6-membered heterocycloalkyl, or a phenyl isostere.

[OUI] In some embodiments of a compound of Formula (III), (Ilia), (IIIa-1), (IIIa-2), (Illb), (IIIb-1), (IIIc-1 ’), (IIIc’), (Illd’), or (IIIb-2), B is a phenyl isostere. In some embodiments, B is cubane. In some embodiments, B is cubane and n is 0, In some embodiments, B is hn < ( ^BJl , s —__। . vZy (~r^b ) .

some embodiments, B is ^{5 5} and n is 0. In some embodiments, ⁿ is = R^B1

[0112] In some embodiments of Formula (III), (Ilia), (IIIa-1), (IIIa-2), (Illb), (IIIb-1), (IIIb-2), (Illd), (IIIc-1 ’), (IIIc’), (Illd’), (IIIc) or (IIIc-1), R^B1 is halo, -CN, -NO2, optionally substituted Ci-6alkyl, optionally substituted C2-6 alkenyl, optionally substituted C2-6 alkynyl, optionally substituted C1-6 heteroalkyl, -OR¹¹, -SR¹¹, -N(R¹²)(R^H), -C(O)R¹², -C(O)OR¹², -OC(O)R¹², OC(O)N(R¹²)(R^h), -C(O)N(R¹²)(R¹¹),-N(Rⁱ²)C(O)R¹²-N(R¹²)C(O)ORⁱ²,N(R¹²)C(O)N(R¹²)(R^h), -N(R¹²)S(O)2(R¹²),-S(O)R¹², -S(O)₂R¹²,-S(O)2N(R¹²)(R¹¹), optionally substituted C3-8 cycloalkyl, optionally substituted C2-9 heterocycloalkyl, optionally substituted phenyl, optionally substituted monocyclic heteroaryl, or optionally substituted bicyclic heteroaryl. In some embodiments, R^B1 is optionally substituted cyclopropane, cyclopentane, cyclohexane, imidazole, pyrazole, pyrrole, benzene, pyridine, or pyrrolidine. In some embodiments, R^B1 is optionally substituted cyclopropane. In some embodiments, R^B1 is optionally substituted cyclopentane. In some embodiments, R^B1 is optionally substituted cyclohexane. In some embodiments, R^B1 is optionally substituted imidazole. In some embodiments, R^B1 is optionally substituted pyrazole. In some embodiments, R^B1 is optionally substituted pyrrole. In some embodiments, R^B1 is optionally substituted benzene. In some embodiments, R^B1 is optionally substituted pyridine. In some embodiments, R^BI is optionally substituted pyrrolidine.

[0113] In some embodiments of Formula (III), (Ilia), (IIIa-1), (IIIa-2), (Illb), (IIIb-1), (IIIb-2), (Illd), (IIIc-1 ’), (IIIc’), (Illd’), (IIIc) or (IIIc-1), R^B1 is optionally substituted C3-8 cycloalkyl, optionally substituted C2-9 heterocycloalkyl, optionally substituted naphthyl, optionally substituted phenyl, optionally substituted monocyclic heteroaryl, or optionally substituted bicyclic heteroaryl. In some embodiments, R^B1 is optionally substituted 5 membered monocyclic heteroaryl with 1 to 4 heteroatoms selected from N, O, S and P. In some embodiments, R^B1 is optionally substituted C3-8 cycloalkyl. In some embodiments, R^B1 is C3 cycloalkyl. In some embodiments, R^B1 is C5 cycloalkyl. In some embodiments, R^B1 is Cô cycloalkyl. In some embodiments, R^B1 is optionally substituted phenyl. In some embodiments, R^B1 is optionally substituted C2-9 heterocycloalkyl. In some embodiments, R^B1 is C3 heterocycloalkyl. In some embodiments, R^B1 is C5 heterocycloalkyl. In some embodiments, R^B1 is Ce heterocycloalkyl. In some embodiments, R^B1 is optionally substituted monocyclic heteroaryl. In some embodiments,

R^Bl is optionally substituted bicyclic heteroaryl. In some embodiments, R^Bl is imidazole, pyrazole, triazole, or tetrazole, each of which optionally substituted. In some embodiments, R^Blis imidazole. In some embodiments, R^BI is pyrazole. In some embodiments, R^Bl is triazole. In some embodiments, R^Bl is tetrazole. In some embodiments, R^Bl is optionally substituted fused 56, 6-6 or 6-5 heteroaryl. In some embodiments, R^Bl is optionally substituted with one or more substituents independently selected from halogen, -NO2, oxo, -CN, optionally substituted Ci-6 alkyl, optionally substituted Ci-6 heteroalkyl, optionally substituted C3-8 cycloalkyl, optionally substituted C2-7 heterocycloalkyl, -OR¹¹, -SR¹¹, -N(R¹²)(R^H), -C(O)R¹², -C(O)OR¹², -OC(O)R¹², -OC(O)N(R¹²)(R^h), -C(O)N(R¹²)(R^h), -N(R¹²)C(O)R¹² -N(R¹²)C(O)OR¹², N(R¹²)C(O)N(R¹²)(Rⁿ), -N(R¹²)S(O)2(R¹²),-S(O)R¹², -S(O)2R¹², and-S(O)₂N(R¹²)(Rⁿ), wherein the alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, or heterocycloalkyl is optionally substituted with one or more substituents independently selected from: halogen, -OH, -NO2, amino, oxo, -CN, C1-3 alkoxyl, C1.3 alkyl and C1-3 haloalkyl. In some embodiments, R^B1 is optionally substituted with one or more substituents independently selected from halogen, -OR¹¹, -NO2, oxo, -CN, optionally substituted Ci-6 haloalkyl, optionally substituted Ci-6alkyl, optionally substituted Ci-6aminoalkyl, optionally substituted Ci-6 hydroxyalkyl, optionally substituted Ci-6 heteroalkyl, optionally substituted C3-8 cycloalkyl, and optionally substituted C2-7 heterocycloalkyl. In some embodiments R^B1 is optionally substituted with one or more substituents independently selected from halogen, -OR¹¹, -NO2, oxo, -CN, Ci-3 haloalkyl, C1-3 alkyl, C1-3 aminoalkyl, C1-3 hydroxyalkyl, optionally substituted Cm heteroalkyl (e.g., CH2C(=O)N(CH3)2), optionally substituted C3-6 cycloalkyl, and optionally substituted C2-5 heterocycloalkyl. In some embodiments, R^B1 is optionally substituted with one or more substituents independently selected from halogen, oxo, -CN, C 1.3 haloalkyl, Ci-3 alkyl, Ci-3 aminoalkyl, C 1.3 hydroxyalkyl, C3-6 cycloalkyl, and C2-5 heterocycloalkyl. In some embodiments, R^b1 is optionally substituted with one or more substituents (e.g., 1, 2 or 3) independently selected from C1.3 haloalkyl and C1-3 alkyl. In some embodiments, R^B1 is substituted with halogen. In some embodiments, R^B1 is substituted with -OR¹¹. In some embodiments, R^B1 is substituted with -NO2. In some embodiments, R^B1 is substituted with oxo. In some embodiments, R^B1 is substituted with -CN. In some embodiments, R^B1 is substituted with optionally substituted Cm haloalkyl. In some embodiments, R^B1 is substituted with optionally substituted Ci-6alkyl. In some embodiments, R^B1 is substituted with optionally substituted Cm aminoalkyl.

[0114] In some embodiments of Formula (III), (Ilia), (IIIa-1), (IIIa-2), (Illb), (IIIb-1), (IIIb-2),

(Illd), (IIIc-1 ’), (IIIc’), (Illd’), (IIIc) or (IIIc-1), R^B1 is selected from:

embodiments, R^B1 is embodiments, R^BI is embodiments, R^B1

. In some embodiments, R^B1 is . In some embodiments, R^BI is

[0115] In some embodiments of Formula (III), (Ilia), (IIIa-1 ), (IIIa-2), (Illb), (IIIb-1 ), (IIIb-2), (Illd), (IIIc-l ’), (IIIc’), (Illd’), (IIIc) or (IIIc-1), R^B1 is

chf₂

[0116] In some embodiments of Formula (III), (Ilia), (IIIa-1), (IIIa-2), (Illb), (IIIb-1), (IIIc-1 ’), (IIIc’), (Illd’), or (IIIb-2), R^B1 and one of R^B on the same atom are taken together with the atom to which they are attached to form an optionally substituted C3-8 cycloalkyl or optionally substituted C2-9 heterocycloalkyl. In some embodiments, R^B1 and one of R^Bon adjacent atoms are taken together with the atoms to which they are attached to form an optionally substituted phenyl, optionally substituted naphthyl, optionally substituted monocyclic heteroaryl, optionally substituted bicyclic heteroaryl, optionally substituted C3-8 cycloalkyl, or optionally substituted C2-9 heterocycloalkyl. In some embodiments, R^B1 and one of R^Bon adjacent atoms are taken together with the atoms to which they are attached to form an optionally substituted 5 or 6 membered monocyclic heterocycloalkyl.

[0117] In some embodiments of Formula (III), (Ilia), (IIIa-1), (IIIa-2), (Illb), (IIIb-1), (IIIc-1 ’),

[0118] In some embodiments of Formula (III), (Ilia), (IIIa-1), (IIIa-2), (Illb), (IIIb-1), (IIIc-1 ’), (IIIc’), (Illd’), or (IIIb-2), R^B is halo, -CN, -NO2, optionally substituted C1-6 alkyl, optionally substituted Ci-6 heteroalkyl, optionally substituted C3-8 cycloalkyl, optionally substituted C2-9 heterocycloalkyl, optionally substituted phenyl, optionally substituted monocyclic heteroaryl, or optionally substituted bicyclic heteroaryl. In some embodiments, two of R^Bon the same atom are taken together with the atom to which they are attached to form an optionally substituted C3-6 cycloalkyl or optionally substituted C2-5 heterocycloalkyl.

[0119] In some embodiments of Formula (III), (Ilia), (IIIa-1), (IIIa-2), (Illb), (Illb-1), (IIIb-2), (IIIc-1 ’), (IIIc’), (Illd’), (IIIc) or (IIIc-1), n is 0.

[0120] In some embodiments of a compound of Formula (III), (Ilia), (IIIa-1), (IIIa-2), (Illb), (IIIb-1), (IIIb-2), (Illd), (IIIc-1 ’), (IIIc’), (Illd’), (IIIc), or (IIIc-1), Z¹ is N, NR¹, O, S, CR¹, or C(Rⁱ)2. In some embodiments, Z¹ is N. In some embodiments, Z¹ is NR¹. In some embodiments of a compound of Formula (III), (Ilia), (IIIa-1), (IIIa-2), (Illb), (IIIb-1 ), (IIIb-2), (Illd), (IIIc-1 ’), (IIIc’), (Illd’), (IIIc), or (IIIc-1), Z¹ is N, NRⁿ¹, O, S, CR¹, or C(R')2. In some embodiments, Z¹ is N. In some embodiments, Z¹ is NR^Nl. In some embodiments, Z¹ is O. In some embodiments, Z¹ is S. In some embodiments, Z¹ is CR¹. In some embodiments, Z¹ is CCR¹)?.

[0121] In some embodiments of a compound of Formula (III), (Ilia), (IIIa-1), (IIIa-2), (Illb), (IIIb-1), (IIIb-2), (Illd), (IIIc-1 ’), (IIIc’), (Illd’), (IIIc), or (IIIc-1 ), Z² is N, NR², O, CR², C(R²)2, S(=O)2, C(=O), or C(=S). In some embodiments, Z² is N. In some embodiments, Z² is NR². In some embodiments of a compound of Formula (III), (Ilia), (IIIa-1), (IIIa-2), (Illb), (IIIb-1), (Illb2), (Illd), (IIIc-1 ’), (IIIc’), (Illd’), (IIIc), or (IIIc-1), Z² is N, NR^N2, O, CR², C(R²)2, S(=O)₂, C(=O), or C(=S). In some embodiments, Z² is N. In some embodiments, Z² is NR^N2.In some embodiments, Z² is O. In some embodiments, Z² is CR². In some embodiments, Z² is C(R²)2. In some embodiments, Z² is S(=O)2. In some embodiments, Z² is C(=O). In some embodiments, Z²is C(=S).

[0122] In some embodiments of a compound of Formula (III), (Ilia), (IIIa-1), (IIIa-2), (Illb), (IIIb-1), (IIIb-2), (Illd), (IIIc), or (IIIc-1 ), N, NR³, CR³, C(R³)2, S(=O)2, C(=O), or C(=S). In some embodiments, Z³ is N. In some embodiments, Z³ is NR². In some embodiments of a compound of Formula (III), (Ilia), (IIIa-1), (IIIa-2), (Illb), (IIIb-1), (IIIb-2), (Illd), (IIIc), or (IIIc1 ), N, NR^N3, CR³, C(R³)2, S(=O)₂, C(=O), or C(=S). In some embodiments, Z³ is N. In some embodiments, Z³ is NR^N3. In some embodiments, Z³ is O. In some embodiments, Z³ is S. In some embodiments, Z³ is CR². In some embodiments, Z³ is C(R²)2. In some embodiments, Z³ is S(=O)2. In some embodiments, Z³ is C(=O). In some embodiments, Z³ is C(=S).

[0123] In some embodiments of a compound of Formula (III), (Ilia), (IIIa-1), (IIIa-2), (Illb), (IIIb-1), (IIIb-2), (Illd), (IIIc), (IIIc-Γ), (IIIc’), (Illd’), or (IIIc-1),---is a single bond or double bond. In some embodiments,---is a single bond. In some embodiments,---is a double bond.

[0124] In some embodiments of a compound of Formula (III), (Ilia), (IIIa-1), (IIIa-2), (Illb), (IIIb-1), (IIIb-2), (Illd), (IIIc), (IIIc-1 ’), (IIIc’), (Illd’), or (IIIc-1), each of R¹, R², and R³ is independently selected from hydrogen, halo, -CN, -OR¹¹, -SR¹¹, -N(R¹²)2, optionally substituted Ci-6 alkyl, optionally substituted Ci-6 heteroalkyl, optionally substituted C2-6 alkenyl, and optionally substituted C2-6 alkynyl. In some embodiments, each of R¹,R², and R³ is independently selected from hydrogen, -CN, optionally substituted Ci-6 alkyl, optionally substituted Ci-6 heteroalkyl, optionally substituted C2-6 alkenyl, and optionally substituted C₂-6 alkynyl. In some embodiments, each of R¹ and R² is independently selected from hydrogen, -CN, optionally substituted Ci-6alkyl, optionally substituted Ci-6heteroalkyl, optionally substituted C₂-6 alkenyl, and optionally substituted C₂-6 alkynyl. In some embodiments, R¹ is hydrogen. In some embodiments, R¹ is halo. In some embodiments, R¹ is -CN. In some embodiments, R¹ is -OR¹¹. In some embodiments, R¹ is -SR¹¹. In some embodiments, R¹ is -N(R¹²)2. In some embodiments, R¹ is optionally substituted Ci-6 alkyl. In some embodiments, R¹ is optionally substituted Cm heteroalkyl. In some embodiments, R¹ is optionally substituted C2-6 alkenyl. In some embodiments, R¹ is optionally substituted C2-6 alkynyl. In some embodiments, R¹ is C1-3 alkyl. In some embodiments, R¹ is methyl. In some embodiments, R¹ is ethyl. In some embodiments, R¹ is CD3. In some embodiments, R¹ is C1-3 heteroalkyl. In some embodiments, R¹ is C2-3 alkenyl. In some embodiments, R² is hydrogen. In some embodiments, R² is halo. In some embodiments, R²is -CN. In some embodiments, R² is -OR¹¹. In some embodiments, R² is -SR¹¹. In some embodiments, R² is -N(R¹²)2. In some embodiments, R² is optionally substituted Cm alkyl. In some embodiments, R² is optionally substituted Cm heteroalkyl. In some embodiments, R² is optionally substituted C2-6 alkenyl. In some embodiments, R² is optionally substituted C2-6 alkynyl. In some embodiments, R² is C1.3 alkyl. In some embodiments, R² is methyl. In some embodiments, R² is ethyl. In some embodiments, R² is CD3. In some embodiments, R² is Ci-3 heteroalkyl. In some embodiments, R² is C2-3 alkenyl. In some embodiments, R³ is hydrogen. In some embodiments, R³ is halo. In some embodiments, R³ is -CN. In some embodiments, R³ is OR¹¹. In some embodiments, R³ is -SR¹¹. In some embodiments, R³ is -N(R¹²)2. In some embodiments, R³ is optionally substituted Cm alkyl. In some embodiments, R³ is optionally substituted Cm heteroalkyl. In some embodiments, R³ is optionally substituted C2-6 alkenyl. In some embodiments, R³ is optionally substituted C2-6 alkynyl. In some embodiments, R³ is Ci-3 alkyl. In some embodiments, R³ is methyl. In some embodiments, R³ is ethyl. In some embodiments, R³ is CD3. In some embodiments, R³ is C1-3 heteroalkyl. In some embodiments, R³is C2-3 alkenyl.

[0125] In some embodiments of a compound of Formula (III), (Ilia), (IIIa-1), (IIIa-2), (Illb), (IIIb-1), (IIIb-2), (Illd), (IIIc), (IIIc-1 ’), (IIIc’), (Illd’), or (IIIc-1), each of R^N1, R^N2, and R^N3 is independently selected from hydrogen, -CN, optionally substituted Cm alkyl, optionally substituted Cm heteroalkyl, optionally substituted C2-6 alkenyl, and optionally substituted C2-6 alkynyl. In some embodiments, R^N1 is hydrogen. In some embodiments, R^N1 is -CN. In some embodiments, R^N1 is optionally substituted Cm alkyl. In some embodiments, R^N1 is optionally substituted Cm heteroalkyl. In some embodiments, R^N1 is optionally substituted C2-6 alkenyl. In some embodiments, R^N1 is optionally substituted C2-6 alkynyl. In some embodiments, R^N2 is hydrogen. In some embodiments, R^N2 is -CN. In some embodiments, R^N2 is optionally substituted Ci-6 alkyl. In some embodiments, R^N2 is optionally substituted Ci-6 heteroalkyl. In some embodiments, R^N2 is optionally substituted C2-6 alkenyl. In some embodiments, R^N2 is optionally substituted C2-6 alkynyl. In some embodiments, R^N3 is hydrogen. In some embodiments, R^N3 is -CN. In some embodiments, R^N3 is optionally substituted Ci-6 alkyl. In some embodiments, R^N3 is optionally substituted Ci-6 heteroalkyl. In some embodiments, R^N3 is optionally substituted C2-6 alkenyl. In some embodiments, R^N3 is optionally substituted C2-6 alkynyl.

[0126] In some embodiments of a compound of Formula (III), (Ilia), (IIIa-1), (IIIa-2), (Illb), (IIIb-1), (IIIb-2), (Illd), (IIIc), (IIIc-1 ’), (IIIc’), (Illd’), or (IIIc-1), each of R⁸ and R⁹ is independently selected from hydrogen, halo, -CN, optionally substituted Ci-6 alkyl, optionally substituted C1-6 heteroalkyl, optionally substituted C2-6 alkenyl, and optionally substituted C2-6 alkynyl. In some embodiments, each of R⁸ and R⁹ is independently selected from hydrogen, CN, optionally substituted C1-6alkyl, optionally substituted Ci-6 heteroalkyl, optionally substituted C2-6 alkenyl, and optionally substituted C2-6 alkynyl. In some embodiments, R⁸ is hydrogen. In some embodiments, R⁸ is halo. In some embodiments, R⁸ is -CN. In some embodiments, R⁸ is optionally substituted Ci-6 alkyl. In some embodiments, R⁸ is optionally substituted Ci-6 heteroalkyl. In some embodiments, R⁸ is optionally substituted C2-6 alkenyl. In some embodiments, R⁸ is optionally substituted C2-6 alkynyl. In some embodiments, R⁹ is hydrogen. In some embodiments, R⁹ is halo. In some embodiments, R⁹ is -CN. In some embodiments, R⁹ is optionally substituted C1-6 alkyl. In some embodiments, R⁹ is optionally substituted C1-6 heteroalkyl. In some embodiments, R⁹ is optionally substituted C2-6 alkenyl. In some embodiments, R⁹ is optionally substituted C2-6 alkynyl. In some embodiments, R⁸ and R⁹taken together form an oxo. In some embodiments, R⁸ and R⁹ taken together with the carbon to which they are attached form an optionally substituted 3-6 membered cycloalkyl or heterocycloalkyl.

[0127] In some embodiments of a compound of Formula (III), (Ilia), (IIIa-1), (IIIa-2), (Illb), (IIIb-1), (IIIb-2), (Illd), (IIIc), (IIIc-1 ’), (IIIc’), (Illd’), or (IIIc-1), ring A is phenyl, naphthyl, monocyclic heteroaryl, or bicyclic heteroaryl. In some embodiments, ring A is phenyl. In some embodiments, ring A is naphthyl. In some embodiments, ring A is monocyclic heteroaryl. In some embodiments, ring A is bicyclic heteroaryl.

[0128] In some embodiments of a compound of Formula (III), (Ilia), (IIIa-1), (IIIa-2), (Illb), (IIIb-1), (IIIb-2), (Illd), (IIIc), (IIIc-1 ’), (IIIc’), (Illd’), or (IIIc-1), each of R^A is independently selected from halogen, -NO2, oxo, CN, optionally substituted Ci-6 alkyl, optionally substituted C2-6 alkenyl, optionally substituted C2-6 alkynyl, optionally substituted C1-6 heteroalkyl, optionally substituted C3-8 cycloalkyl, optionally substituted C2-7 heterocycloalkyl, -OR¹¹, -SR”, -N(R^l2)(R), -C(O)R¹², C(O)OR¹², -OC(O)R¹², -OC(O)N(R¹²)(R), -C(O)N(R¹²)(R), N(R^I2)C(O)R¹², -N(R¹²)C(O)OR¹², -N(Rⁱ²)C(O)N(Rⁱ²)(R), -N(R¹²)₂S(O)2(R¹²), -S(O)R¹², S(O)2R¹², and -S(O)2N(R¹²)(R^H). In some embodiments, each R^A is independently selected from Cm alkyl, Cm alkoxyl, Cm haloalkyl, Cm heteroalkyl, and C3-6 cycloalkyl. In some embodiments, R^A is halogen. In some embodiments, R^A is -NO2. In some embodiments, R^A is oxo. In some embodiments, R^A is CN. In some embodiments, R^A is optionally substituted Ci-6 alkyl. In some embodiments, R^A is optionally substituted C1-3 alkyl. In some embodiments, R^A is methyl, ethyl, propyl, zso-propyl, zz-butyl, zso-butyl, sec-butyl, Abutyl, -CF3, -CH2CF3,or CH2CH2F. In some embodiments, R^A is optionally substituted C2-6 alkenyl. In some embodiments, R^A is optionally substituted C2-6 alkynyl. In some embodiments, R^A is optionally substituted Cm heteroalkyl. In some embodiments, R^A is optionally substituted C3-8 cycloalkyl. In some embodiments, R^A is optionally substituted C3-6 cycloalkyl, e.g., cyclopropyl. In some

some embodiments, R^A is optionally substituted C2-7 heterocycloalkyl. In some embodiments, R^Ais optionally substituted C2-5 heterocycloalkyl. In some embodiments, R^A is -OR¹¹. In some embodiments, R^A is -O-C1-3 alkyl. In some embodiments, R^A is -OCH3, -OCH2CH3, -OCFFOMe, -OCH2CH2OH, -OC(CH₃)3, or -OCH2CH2OCH3 In some embodiments, R^A is -OCH3. In some embodiments, R^A is v . In some embodiments, R^A is -SR¹¹. In some embodiments, R^A is -N(R¹²)(R^h). In some embodiments, R^A is -C(O)R¹². In some embodiments, R^A is C(O)OR¹². In some embodiments, R^A is -OC(O)R¹². In some embodiments, R^A is -OC(O)N(R¹²)(R^H). In some embodiments, R^A is -C(O)N(R¹²)(R^H). In some embodiments, R^A is -N(R¹²)C(O)R¹². In some embodiments, R^A is -N(R¹²)C(O)OR¹². In some embodiments, R^A is -N(R¹²)C(O)N(R¹²)(R^H). In some embodiments, R^A is -N(R¹²)2S(O)2(R¹²). In some embodiments, R^A is -S(O)R¹². In some embodiments, R^A is -S(O)2R¹². In some embodiments, R^A is -S(O)2N(R¹²)(R^H).

[0129] In some embodiments of a compound of Formula (III), (Ilia), (IIIa-1), (IlIa-2), (Illb), (IIIb-1), (IIIb-2), (Illd), (IIIc), (IIIc-1 ’), (IIIc’), (Illd’), or (IIIc-1), R¹¹ is hydrogen, optionally substituted Ci-6 alkyl, optionally substituted C2-6 alkenyl, optionally substituted C2-6 alkynyl, optionally substituted Cm heteroalkyl, optionally substituted C3-8 cycloalkyl, optionally substituted C2-7 heterocycloalkyl, optionally substituted phenyl, optionally substituted heteroaryl, optionally substituted -Cm alkylene-C3-8 cycloalkyl, optionally substituted -Cm alkylene-C2-7 heterocycloalkyl, optionally substituted -Cm alkylene-phenyl, or optionally substituted -Cm alkylene-heteroaryl. In some embodiments, R¹¹ is hydrogen. In some embodiments, R¹¹ is optionally substituted Cm alkyl. In some embodiments, R¹¹ is optionally substituted C1.3 alkyl. In some embodiments, R¹¹ is methyl, ethyl, propyl, zso-propyl, zz-butyl, zso-butyl, sec-butyl, tbutyl, -CF3, -CH2CF3,or -CH2CH2F. In some embodiments, R¹¹ is optionally substituted C2-6 alkenyl. In some embodiments, R¹¹ is optionally substituted C2-6 alkynyl. In some embodiments, R¹¹ is optionally substituted Cm heteroalkyl. In some embodiments, R¹¹ is optionally substituted C3-8 cycloalkyl. In some embodiments, R¹¹ is optionally substituted C2-7 heterocycloalkyl. In some embodiments, R¹¹ is optionally substituted phenyl. In some embodiments, R¹¹ is optionally substituted heteroaryl. In some embodiments, R¹¹ is optionally substituted -Cm alkylene-C3-8 cycloalkyl. In some embodiments, R¹¹ is optionally substituted -Cm alkylene-C2-7 heterocycloalkyl. In some embodiments, R¹¹ is optionally substituted -Cm alkylene-phenyl. In some embodiments, R¹¹ is optionally substituted -Cm alkylene-heteroaryl.

[0130] In some embodiments of a compound of Formula (III), (Ilia), (IIIa-1), (IIIa-2), (Illb), (IIIb-1), (IIIb-2), (Illd), (IIIc), (IIIc-1 ’), (IIIc’), (Illd’), or (IIIc-1), each of R^l2is independently selected from hydrogen, halogen, -OH, -NO2, CN, Cm alkyl, Cm aminoalkyl, Cm hydroxyalkyl, Ci-6 haloalkyl, Ci-6 heteroalkyl, C3-6 carbocycle, and 3- to 6-membered heterocycle, wherein the C3-6 carbocycle and 3- to 6-membered heterocycle is optionally substituted with one or more substituents independently selected from halogen, -OH, oxo, amino, -NO2, CN, Cm alkyl, Cm alkoxy, and Cm haloalkyl. In some embodiments, each of R¹² is independently selected from hydrogen, -NO2, CN, Cm alkyl, Cm aminoalkyl, Cm hydroxyalkyl, Cm haloalkyl, Cm heteroalkyl, C3-6 carbocycle, and 3- to 6-membered heterocycle, wherein the C3-6 carbocycle and 3- to 6-membered heterocycle is optionally substituted with one or more substituents independently selected from halogen, -OH, oxo, amino, -NO2, CN, Cm alkyl, Cm alkoxy, and Cm haloalkyl. In some embodiments, R¹² is hydrogen. In some embodiments, R¹² is halogen. In some embodiments, R¹² is -OH. In some embodiments, R¹² is -NO2. In some embodiments, R¹² is CN. In some embodiments, R¹² is Cm alkyl. In some embodiments, R¹² is Cm aminoalkyl. In some embodiments, R¹² is Cm hydroxyalkyl. In some embodiments, R¹² is Cm haloalkyl. In some embodiments, R¹² is Cm heteroalkyl. In some embodiments, R¹² is C3-6 carbocycle. In some embodiments, R¹² is and 3- to 6-membered heterocycle, wherein the C3-6 carbocycle and 3- to 6-membered heterocycle is optionally substituted with one or more substituents independently selected from halogen, -OH, oxo, amino, -NO2, CN, Cm alkyl, Cm alkoxy, and Cm haloalkyl. In some embodiments, the one or more substituents is halogen. In some embodiments, the one or more substituents is -OH. In some embodiments, the one or more substituents is oxo. In some embodiments, the one or more substituents is amino. In some embodiments, the one or more substituents is -NO2. In some embodiments, the one or more substituents is CN. In some embodiments, the one or more substituents is Cm alkyl. In some embodiments, the one or more substituents is Cm alkoxy. In some embodiments, the one or more substituents is Cm haloalkyl.

[0131] In some embodiments of a compound of Formula (III), (Ilia), (IIIa-1), (IIIa-2), (Illb), (IIIb-1), (IIIc-1 ’), (IIIc’), (Illd’), or (IIIb-2), B is a ring. In some embodiments of a compound of Formula (III), (Ilia), (IIIa-1), (IIIa-2), (Illb), (IIIb-1), (IIIc-1 ’), (IIIc’), (Illd’), or (IIIb-2), ring B is 6 membered heteroaryl, phenyl, cyclohexyl, 6-membered heterocycloalkyl, or a phenyl isostere. In some embodiments, ring B is 6 membered heteroaryl, phenyl, or a phenyl isostere. In some embodiments, ring B is 6 membered heteroaryl. In some embodiments, ring B is phenyl. In some embodiments, ring B is phenyl isostere. In some embodiments, the phenyl isostere is . In some embodiments, the phenyl isostere is .

[0132] In some embodiments of a compound of Formula (III), (Ilia), (IIIa-1), (IIIa-2), (Illb), (IIIb-1), (IIIc-Γ), (IIIc’), (Illd’), or (IIIb-2), B is a phenyl isostere. In some embodiments, the phenyl isostere is . In some embodiments, the phenyl isostere is . [_n some embodiments, the phenyl isostere is cubane. In some embodiments, B is cubane. In some embodiments, B is | = R^B1 and n is 0. In some embodiments,

[0133] In some embodiments of a compound of Formula (III), (Ilia), (IIIa-1), (IIIa-2), (Illb), (IIIb-1), (IIIb-2), (IIIc), (IIIc-1 ’), (IIIc’), (Illd’), or (IIIc-1), R^BI is halo, -CN, -NO2, optionally substituted Cm alkyl, optionally substituted C2-6 alkenyl, optionally substituted C2-6 alkynyl, optionally substituted Cm heteroalkyl, -OR¹¹, -SR¹¹, -N(R¹²)(R^H), -C(O)R¹², C(O)OR¹², OC(O)R¹², -OC(O)N(R^I2)(R), -C(O)N(R¹²)(R^h), -N(R¹²)C(O)R¹², -N(R¹²)C(O)OR¹², 21708

N(R^l2)C(O)N(R^l2)(R), -N(R¹²)S(O)2(R¹²), -S(O)R¹², -S(O)2R¹², -S(O)2N(R¹²XR^h), optionally substituted C3-8 cycloalkyl, optionally substituted C2-9 heterocycloalkyl, optionally substituted naphthyl, optionally substituted phenyl, optionally substituted monocyclic heteroaryl, or optionally substituted bicyclic heteroaryl. In some embodiments, R^B1 is halo. In some embodiments, R^B1 is optionally substituted C3-8 cycloalkyl, optionally substituted C₂-9 heterocycloalkyl, optionally substituted naphthyl, optionally substituted phenyl, optionally substituted monocyclic heteroaryl, or optionally substituted bicyclic heteroaryl. In some embodiments, R^B1 is -CN. In some embodiments, R^B1 is -NO2. In some embodiments, R^B1 is optionally substituted Cm alkyl. In some embodiments, R^B1 is optionally substituted C1-3 alkyl. In some embodiments, R^B1 is methyl, ethyl, propyl, wo-propyl, w-butyl, fro-butyl, .sec-butyl, tbutyl, -CF3, -CH2CF3,or -CH₂CH₂F. In some embodiments, R^BI is optionally substituted C2-6 alkenyl. In some embodiments, R^BI is optionally substituted C2-6 alkynyl. In some embodiments, R^bi is optionally substituted Cm heteroalkyl. In some embodiments, R^BI is -OR¹¹. In some embodiments, R^B1 is -SR¹¹. In some embodiments, R^B1 is -N(R¹²)(Rⁿ). In some embodiments, R^B1 is -C(O)R¹². In some embodiments, R^B1 is C(O)OR¹². In some embodiments, R^B1 is OC(O)R¹². In some embodiments, R^B1 is -OC(O)N(R¹²)(Rⁿ). In some embodiments, R^B1 is C(O)N(R¹²)(R^h). In some embodiments, R^B1 is -N(R¹²)C(O)R¹². In some embodiments, R^B1 is N(R¹²)C(O)OR¹². In some embodiments, R^B1 is -N/R'^QOjNfR^XR¹¹). In some embodiments, R^B1 is -N(R¹²)S(O)2(R¹²). In some embodiments, R^B1 is -S(O)R¹². In some embodiments, R^B1 is S(O)₂R¹². In some embodiments, R^B1 is -S(O)2N(R¹²)(R¹¹). In some embodiments, R^B1 is optionally substituted C3-8 cycloalkyl. In some embodiments, R^B1 is optionally substituted C2-9 heterocycloalkyl. In some embodiments, R^B1 is optionally substituted naphthyl. In some embodiments, R^B1 is optionally substituted phenyl. In some embodiments, R^B1 is optionally substituted monocyclic heteroaryl. In some embodiments, the optionally substituted monocyclic heteroaryl is substituted with -CN, optionally substituted Cm alkyl, optionally substituted Cm heteroalkyl, optionally substituted C3-8 cycloalkyl, optionally substituted C2-7 heterocycloalkyl, or -OR¹¹. In some embodiments, R^B1 is optionally substituted 5-6 membered heterocycloalkyl. In some embodiments, R^B1 is optionally substituted bicyclic heteroaryl. In some embodiments, the optionally substituted bicyclic heteroaryl is substituted with -CN, optionally substituted Ci-6 alkyl, optionally substituted Ci-6 heteroalkyl, optionally substituted C3-8 cycloalkyl, optionally substituted C2-7 heterocycloalkyl, or -OR¹¹.

[0134] In some embodiments of a compound of Formula (III), (Ilia), (IIIa-1), (IIIa-2), (Illb), (IIIb-1), (IIIc-1 ’), (IIIc’), (Illd’), or (IIIb-2), each R^B is independently halo, -CN, -NO2, optionally substituted Ci-6 alkyl, optionally substituted C2-6 alkenyl, optionally substituted C2-6 alkynyl, optionally substituted Ci-6 heteroalkyl, -OR¹¹, -SR¹¹, -N(R¹²)(R^H), -C(O)R¹², C(O)OR¹², -OC(O)R¹², -OC(O)N(R^I2)(R), -C(O)N(R¹²)(R^h), -N(R¹²)C(O)R¹², N(R¹²)C(O)OR¹², -N(R¹²)C(O)N(R¹²)(R^h), -N(R¹²)S(O)2(R¹²), -S(O)R¹², -S(O)2R¹², S(O)2N(R¹²)(Rⁿ), optionally substituted C3-8 cycloalkyl, optionally substituted C2-9 heterocycloalkyl, optionally substituted naphthyl, optionally substituted phenyl, optionally substituted monocyclic heteroaryl, or optionally substituted bicyclic heteroaryl. In some embodiments, R^B is halo. In some embodiments, R^B is -CN. In some embodiments, R^B is -NO2. In some embodiments, R^B is optionally substituted Ci-6 alkyl. In some embodiments, R^B is optionally substituted C2-6 alkenyl. In some embodiments, R^B is optionally substituted C2-6 alkynyl. In some embodiments, R^B is optionally substituted Cm heteroalkyl. In some embodiments, R^B is -OR¹¹. In some embodiments, R^B is -SR¹¹. In some embodiments, R^B is N(R¹²)(R^h). In some embodiments, R^B is -C(O)R¹². In some embodiments, R^B is C(O)OR¹². In some embodiments, R^B is -OC(O)R¹². In some embodiments, R^B is -OC(O)N(R¹²)(R^H). In some embodiments, R^B is -C(O)N(R¹²)(Rⁿ). In some embodiments, R^B is -N(R¹²)C(O)R¹². In some embodiments, R^B is -N(R¹²)C(O)OR¹². In some embodiments, R^B is -N(R¹²)C(O)N(R¹²)(R^H). In some embodiments, R^B is -N(R¹²)S(O)2(R¹²). In some embodiments, R^B is -S(O)R¹². In some embodiments, R^B is -S(O)₂R¹². In some embodiments, R^B is -S(O)2N(R¹²)(R^H). In some embodiments, R^B is optionally substituted C3-8 cycloalkyl. In some embodiments, R^B is optionally substituted C2-9 heterocycloalkyl. In some embodiments, R^B is optionally substituted naphthyl. In some embodiments, R^B is optionally substituted phenyl. In some embodiments, R^Bis optionally substituted monocyclic heteroaryl. In some embodiments, R^B is optionally substituted bicyclic heteroaryl. In some embodiments, a substituted bicyclic heteroaryl is substituted with halogen, -OH, -NO2, amino, oxo, -CN, C1-3 alkoxyl, C1-3 alkyl or C1-3 haloalkyl. In some embodiments, a substituted bicyclic heteroaryl is substituted with halogen. In some embodiments, a substituted bicyclic heteroaryl is substituted with -OH. In some embodiments, a substituted bicyclic heteroaryl is substituted with -NO2. In some embodiments, a substituted bicyclic heteroaryl is substituted with amino. In some embodiments, a substituted bicyclic heteroaryl is substituted with oxo. In some embodiments, a substituted bicyclic heteroaryl is substituted with -CN. In some embodiments, a substituted bicyclic heteroaryl is substituted with Ci-3 alkoxyl. In some embodiments, a substituted bicyclic heteroaryl is substituted with Ci-3 alkyl. In some embodiments, a substituted bicyclic heteroaryl is substituted with or Ci-3 haloalkyl.

[0135] In some embodiments of a compound of Formula (III), (Ilia), (IIIa-1), (IIIa-2), (Illb), (IIIb-1), (IIIc-Γ), (IIIc’), (Illd’), or (IIIb-2), R^B1 and one of R^B on adjacent atoms are taken together with the atoms to which they are attached to form an optionally substituted phenyl, optionally substituted naphthyl, optionally substituted monocyclic heteroaryl, optionally substituted bicyclic heteroaryl, optionally substituted C3-8 cycloalkyl, or optionally substituted C2-9 heterocycloalkyl. In some embodiments, R^B1 and one of R^Bon adjacent atoms are taken together with the atoms to which they are attached to form an optionally substituted phenyl. In some embodiments, R^B1 and one of R^B on adjacent atoms are taken together with the atoms to which they are attached to form an optionally substituted naphthyl. In some embodiments, R^B1and one of R^B on adjacent atoms are taken together with the atoms to which they are attached to form an optionally substituted monocyclic heteroaryl. In some embodiments, R^BI and one of R^Bon adjacent atoms are taken together with the atoms to which they are attached to form an optionally substituted bicyclic heteroaryl. In some embodiments, R^B1 and one of R^Bon adjacent atoms are taken together with the atoms to which they are attached to form an optionally substituted C3-8 cycloalkyl. In some embodiments, R^BI and one of R^B on adjacent atoms are taken together with the atoms to which they are attached to form an optionally substituted C2-9 heterocycloalkyl.

[0136] In some embodiments of a compound of Formula (III), (Ilia), (IIIa-1), (IIIa-2), (Illb), (IIIb-1), (IIIc-1 ’), (IIIc’), (Illd’), or (IIIb-2), R^BI and one of R^B on the same atom are taken together with the atom to which they are attached to form an optionally substituted C3-8 cycloalkyl or optionally substituted C2-9 heterocycloalkyl. In some embodiments, R^B1 and one of R^b one the same atom are taken together with the atom to which they are attached to form an optionally substituted C3-8 cycloalkyl. In some embodiments, R^B1 and one of R^B one the same atom are taken together with the atom to which they are attached to form an optionally substituted C2-9 heterocycloalkyl.

[0137] In some embodiments of a compound of Formula (III), (Ilia), (IIIa-1), (IIIa-2), (Illb), (IIIb-1), or (IIIb-2), two of R^B on the same atom are taken together with the atom to which they are attached to form an optionally substituted C3-8 cycloalkyl or optionally substituted C2-9 heterocycloalkyl. In some embodiments, two of R^B on the same atom are taken together with the atom to which they are attached to form an optionally substituted C3-8 cycloalkyl. In some embodiments, two of R^B on the same atom are taken together with the atom to which they are attached to form an optionally substituted C2-9 heterocycloalkyl.

[0138] In some embodiments of a compound of Formula (III), (Ilia), (IIIa-1), (IIIa-2), (Illb), (IIIb-1), (IIIb-2), (Illd), (IIIc), or (IIIc-1), m is 1, 2, 3, or 4. In some embodiments, m is 1. In some embodiments, m is 2. In some embodiments, m is 3. In some embodiments, m is 4.

[0139] In some embodiments of a compound of Formula (III), (Ilia), (IIIa-1), (IIIa-2), (Illb), (IIIb-1), or (IIIb-2), n is 0, 1, 2, 3 or 4. In some embodiments, n is 0. In some embodiments, n is

1. In some embodiments, n is 2. In some embodiments, n is 3. In some embodiments, n is 4. [0140] In some embodiments of a compound of Formula (III), (Ilia), (IIIa-1), (IIIa-2), (Illb), (IIIb-1), (IIIb-2), (Illd), (IIIc), or (IIIc-1 ), p is 0 or 1. In some embodiments, p is 0. In some embodiments, p is 1.

[0141] In some embodiments of a compound of Formula (Ilia), Zi is CR¹; Z2 is CR²; each R¹ and R² is hydrogen; each R⁸ and R⁹ is hydrogen; p is 1 ;

□ A

and each R^A is independently selected from Ci-Cô alkyl, Ci-Cô alkoxyl, Ci-Cô haloalkyl, and C3-6

F

cycloalkyl ; B is cubane; R^B1 is

[0142] In some embodiments of a compound of Formula (Ilia), Zi is CR¹; Z2 is CR²; each of R¹ and R² is hydrogen; each R⁸ and R⁹ is hydrogen;

R^a h

^rA ; and each R^A is independently selected from Ci-Cô alkyl, Ci-Cô alkoxyl, Ci-Cô haloalkyl, and C3-6 cycloalkyl (e.g., cyclopropyl); B is cubane; R^B is 5 membered heteroaryl optionally substituted with one or more substituents selected from Ci-3 haloalkyl and Ci-3 alkyl

is 0. In some embodiments, each R^A is independently OH, C1.3 alkyl, -OCH3, Ci-3 haloalkyl, or C3-C6 cycloalkyl (e.g., cyclopropyl). In some embodiments, each R^A is independently OH, OCH3, Ci-3 alkyl, Ci-3 haloalkyl, or cyclopropyl. In some embodiments, each R^A is independently

Ci-3 alkyl, C1-C3 alkoxyl, C1-3 haloalkyl, or cyclopropyl. In some embodiments, -OCH3 is -OCD3.

[0143] In one aspect, described herein is a compound having the structure of Formula (VI), or a sait or solvaté thereof:

Formula (VI) wherein, ring C is phenyl or a 6 membered heteroaryl, wherein each of the phenyl or heteroaryl is optionally substituted;

each of R⁸ and R⁹ is independently selected from hydrogen, halo, -CN, optionally substituted C1-6 alkyl, optionally substituted Ci-6heteroalkyl, optionally substituted C2-6 alkenyl, and optionally substituted C2-6 alkynyl; or R⁸ and R⁹ taken together form an oxo; or R⁸ and R⁹ taken together with the carbon to which they are attached form an optionally substituted 3-6 membered cycloalkyl or heterocycloalkyl;

ring A is phenyl, naphthyl, monocyclic heteroaryl, or bicyclic heteroaryl;

each of R^a is independently selected from halogen, -NO2, oxo, -CN, optionally substituted C1-6 alkyl, optionally substituted C2-6 alkenyl, optionally substituted C2-6 alkynyl, optionally substituted C1-6 heteroalkyl, optionally substituted C3-8 cycloalkyl, optionally substituted C2-7 heterocycloalkyl, -OR¹¹, -SR¹¹, -N(R¹²)(R^H), -C(O)R¹², -C(O)OR¹², OC(O)R¹², -OC(O)N(R¹²)(R^h), -C(O)N(R¹²)(R^h),-N(R¹²)C(O)R¹² -N(R¹²)C(O)OR¹²,NiR'^QOjNiR¹²)^¹¹), -N(R¹²)2S(O)2(R¹²),-S(O)R¹², -S(O)2R¹², and -S(O)2N(R¹²)(R^H);

R¹¹ is hydrogen, optionally substituted C1-6 alkyl, optionally substituted C2-6 alkenyl, optionally substituted C2-6 alkynyl, optionally substituted Ci-6 heteroalkyl, optionally substituted C3.8 cycloalkyl, optionally substituted C2-7 heterocycloalkyl, optionally substituted phenyl, optionally substituted heteroaryl, optionally substituted -Cm alkylene-C3-8 cycloalkyl, optionally substituted -CMalkylene-C2-7 heterocycloalkyl, optionally substituted -Cm alkylene-phenyl, or optionally substituted -CMalkylene-heteroaryl;

each of R¹² is independently selected from hydrogen, halogen, -OH, -NO2, -CN, C1-6 alkyl, Ci-6 aminoalkyl, Ci-6 hydroxyalkyl, Ci-6 haloalkyl, and C3-6 carbocycle, 3- to 6membered heterocycle, wherein the C3-6 carbocycle and 3- to 6-membered heterocycle is optionally substituted with one or more substituents independently selected from halogen, OH, oxo, amino,-NO2, -CN, Ci-6alkyl, Cm alkoxy, and Ci-6 haloalkyl;

R^b is hydrogen, halo, -CN, -NO2, optionally substituted Cm alkyl, optionally substituted C2-6alkenyl, optionally substituted C2-6 alkynyl, optionally substituted Ci-6heteroalkyl, OR¹¹, -SR¹¹, -N(R¹²)(R”), -C(O)R¹², -C(O)OR¹², -OC(O)R¹², -OC(O)N(R¹²)(R^h), C(O)N(R¹²)(R'’), -N(R¹²)C(O)R¹² -N(R¹²)C(O)OR¹², -N(R¹²)C(O)N(R^,2)(R’ ’), N(R¹²)S(O)2(R¹²), -S(O)R¹², -S(O)2R¹²,-S(O)2N(R¹²)(R^h), optionally substituted C3-8 cycloalkyl, optionally substituted C2-9 heterocycloalkyl, optionally substituted naphthyl, optionally substituted phenyl, optionally substituted monocyclic heteroaryl, or optionally substituted bicyclic heteroaryl· m is 0, 1,2, 3, or 4; and p is 0 or 1.

[0144] In some embodiments of Formula (VI), each of R¹² is independently selected from hydrogen, -NO2, -CN, Cmalkyl, Cm aminoalkyl, Ci-6hydroxyalkyl, Cm haloalkyl, and C3-6 carbocycle, 3- to 6-membered heterocycle, wherein the C3-6 carbocycle and 3- to 6-membered heterocycle is optionally substituted with one or more substituents independently selected from halogen, -OH, oxo, amino,-NO2, -CN, Cmalkyl, Cmalkoxy, and Ci-6haloalkyl.

[0145] In some embodiments of Formula (VI), ring C is phenyl or a 6 membered heteroaryl, wherein each of the phenyl or heteroaryl is optionally substituted with 1, 2, 3, or 4 R^1C, and each R^1C is independently halogen, -CN, -NO2, -OH, -OR^a, -OC(=O)R^a, -OC(=O)OR^b, OC(=O)NR^cR^d, -SH, -SR^a, -S(=O)R^a, -S(=O)2R^a, -S(=O)2NR^cR^d, -NR^cR^d, -NR^bC(=O)NR^cR^d, NR^bC(=O)R^a, -NR^bC(=O)OR^b, -NR^bS(=O)2R^a, -C(=O)R^a, -C(=O)OR^b, -C(=O)NR^eR^d, Ci-6alkyl, Ci-ôhaloalkyl, Ci-ehydroxyalkyl, Ci-6aminoalkyl, Ci-6heteroalkyl, C2-(>alkenyl, C2-C6alkynyl, C38 cycloalkyl, C2-7 heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally and independently substituted with one or more R^lCa;

ring D is an aromatic, saturated or partially saturated 6 membered carbocycle or heterocycle, wherein each of the carbocycle or heterocycle is optionally substituted with 1, 2, 3, 4 or 5, or 6 R^1D, and each R^1D is independently halogen, -CN, -NCh, -OH, -OR^a, -OC(=O)R^a, -OC(=O)OR^b, OC(=O)NR^cR^d, -SH, -SR^a, -S(=O)R^a, -S(=O)2R^a, -S(=O)2NR^cR^d, -NR^cR^d, -NR^bC(=O)NR^cR^d, NR^bC(=O)R^a, -NR^bC(=O)OR^b, -NR^bS(=O)2R^a, -C(=O)R^a, -C(=O)OR^b, -C(=O)NR^cR^d, Ci-6alkyl, Ci-ôhaloalkyl, Ci-ôhydroxyalkyl, Ci-6aminoalkyl, Ci-ôheteroalkyl, C2-6alkenyl, C2-Côalkynyl, C38 cycloalkyl, C2-7 heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally and independently substituted with one or more R^1Da;

each of R⁸ and R⁹ is independently selected from hydrogen, halo, -CN, optionally substituted Ci-6 alkyl, optionally substituted Ci-6heteroalkyl, optionally substituted C2-6 alkenyl, and optionally substituted C2-6 alkynyl; or R⁸ and R⁹ taken together form an oxo; or R⁸ and R⁹taken together with the carbon to which they are attached form an optionally substituted 3-6 membered cycloalkyl or heterocycloalkyl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl or heterocycloalkyl is optionally substituted with one or more substituents independently selected from: halogen, amino, -OH, -NO₂, oxo, -CN, C1-3 alkoxyl, C1-3 alkyl and C1-3 haloalkyl;

each of R^a is independently selected from halogen, -NO2, oxo, -CN, optionally substituted Ci-6alkyl, optionally substituted C2-6 alkenyl, optionally substituted C2-6 alkynyl, optionally substituted C1-6 heteroalkyl, optionally substituted C3-8 cycloalkyl, optionally substituted C2-7 heterocycloalkyl, -OR¹¹, -SR¹¹, -N(R¹²)(R^H), -C(O)R¹², -C(O)OR¹², -OC(O)R¹², OC(O)N(R¹²)(R’’), -C(O)N(Rⁱ²)(R''), -N(R¹²)C(O)R¹² -N(R¹²)C(O)OR¹², N(R^I2)C(O)N(R¹²)(Rⁿ), -N(R¹²)2S(O)₂(R¹²), -S(O)R¹², -S(O)2R¹², and -S(O)2N(R¹²)(R^H), wherein the alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, or heterocycloalkyl is optionally substituted with one or more substituents independently selected from: halogen, -OH, -NO2, oxo, amino, -CN, C1-6alkoxyl, C1-6alkyl, C1-6 haloalkyl, C3-6carbocycle, and 3- to 6-membered heterocycle, wherein the C3-6 carbocycle and 3- to 6-membered heterocycle is optionally substituted with one or more substituents independently selected from halogen, -OH, amino, NO2, oxo, -CN, C1-6alkyl, Ci-6alkoxy, and Ci-6 haloalkyl;

R¹¹ is hydrogen, optionally substituted C1-6 alkyl, optionally substituted C2-6 alkenyl, optionally substituted C2-6 alkynyl, optionally substituted Ci-6heteroalkyl, optionally substituted

C3-8 cycloalkyl, optionally substituted C2-7 heterocycloalkyl, optionally substituted phenyl, optionally substituted heteroaryl, optionally substituted -Cm alkylene-C3-8 cycloalkyl, optionally substituted -CMalkylene-C2-7 heterocycloalkyl, optionally substituted -CMalkylene-phenyl, or optionally substituted -Cm alkylene-heteroaryl, wherein the alkyl, alkenyl, alkynyl, heteroalkyl, alkylene, cycloalkyl, heterocycloalkyl, phenyl, or heteroaryl is optionally substituted with one or more substituents independently selected from: halogen, -OH, amino, -NO2, oxo, Ci-6 alkoxy, -CN, Ci-6 alkyl, Ci-6 haloalkyl;

each of R¹² is independently selected from hydrogen, halogen, -OH, -NO2, -CN, Ci-6 alkyl, Ci-6 aminoalkyl, Ci-6 hydroxyalkyl, Ci-6 haloalkyl, and C3-6 carbocycle, 3- to 6-membered heterocycle, wherein the C3-6 carbocycle and 3- to 6-membered heterocycle is optionally substituted with one or more substituents independently selected from halogen, -OH, oxo, amino, -NO2, -CN, C1-6 alkyl, C1-6 alkoxy, and C1-6 haloalkyl;

R^b is hydrogen, halo, -CN, -NO2, optionally substituted Cm alkyl, optionally substituted C2-6 alkenyl, optionally substituted C2-6 alkynyl, optionally substituted Ci-6heteroalkyl, -OR¹¹, SR¹¹, -N(R¹²)(R^h), -C(O)R¹², -C(O)OR¹², -OC(O)R¹², -OC(O)N(R¹²)(R^h), -C(O)N(R¹²)(R^h),N(R¹²)C(O)R¹² -N(R¹²)C(O)OR¹²,-N(R¹²)C(O)N(R¹²)(R), -N(R¹²)S(O)₂(R¹²), -S(O)R¹², S(O)2R¹², -S(O)2N(R¹²)(R^h), optionally substituted C3-8 cycloalkyl, optionally substituted C2-9 heterocycloalkyl, optionally substituted naphthyl, optionally substituted phenyl, optionally substituted monocyclic heteroaryl, or optionally substituted bicyclic heteroaryl, wherein each of the alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocycloalkyl, naphthyl, phenyl or heteroaryl is optionally substituted with one or more substituents independently selected from: halogen, -NO2, oxo, -CN, optionally substituted Ci-6 alkyl, optionally substituted C2-6 alkenyl, optionally substituted C2-6 alkynyl, optionally substituted Cm heteroalkyl, optionally substituted C3-8 cycloalkyl, optionally substituted C2-7 heterocycloalkyl, OR¹¹, -SR¹¹, -N(R¹²)(R), -C(O)R¹², -C(O)OR¹², -OC(O)R¹², -OC(O)N(R¹²)(R^h), C(O)N(R¹²)(R), -N(R¹²)C(O)R¹² -N(R¹²)C(O)OR¹², -N(R¹²)C(O)N(R¹²)(R^h), N(R¹²)S(O)2(R¹²), -S(O)R¹², -S(û)2R¹², and -S(O)2N(R¹²)(Rⁿ), wherein the alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, or heterocycloalkyl is optionally substituted with one or more substituents independently selected from: halogen, -OH, -NO₂, amino, -NH(C 1-6 alkyl), -N(Cm alkyl)2, oxo, -CN, C1-3 alkoxyl, C1-3 alkyl and C1-3 haloalkyl;

each R^a is independently Ci-Côalkyl, Ci-Côhaloalkyl, Ci-Côhydroxyalkyl, Ci-Côaminoalkyl, Ci-Côheteroalkyl, C2-C6alkenyl, C2-Côalkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, -Ci-Côalkylene-cycloalkyl, -Ci-Côalkylene-heterocycloalkyl, -Ci-Côalkylenearyl, or -Ci-Côalkylene-heteroaryl, wherein each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more oxo, halogen, -CN, -OH, OCi-C₆alkyl, -S(=O)Ci-C₆alkyl, -S(=O)₂Ci-C₆alkyl, -S(=O)₂NH₂, -S(=O)₂NHCi-C₆alkyl, S(=O)2N(Ci-C₆alkyl)₂, -NH₂, -NHCi-C₆alkyl, -N(Ci-C₆alkyl)₂, -NHC(=O)OCi-C₆alkyl, C(=O)Ci-C₆alkyl, -C(=O)OH, -C(=O)OCi-C₆alkyl, -C(=O)NH₂, -C(=O)N(Ci-C₆alkyl)₂, C(=O)NHCi-C6alkyl, Ci-Côalkyl, Ci-Côhaloalkyl, Ci-Côhydroxyalkyl, Ci-Côaminoalkyl, or Ci-Côheteroalkyl;

each R^b is independently hydrogen, Ci-Côalkyl, Ci-Côhaloalkyl, Ci-Côhydroxyalkyl, Ci-Côaminoalkyl, Ci-Côheteroalkyl, C2-Côalkenyl, C2-Côalkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, -Ci-Côalkylene-cycloalkyl, -Ci-Côalkylene-heterocycloalkyl, -Ci-Côalkylenearyl, or -Ci-Côalkylene-heteroaryl; wherein each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more oxo, halogen, -CN, -OH, -OCi-Côalkyl, -S(=O)Ci-C6alkyl, -S(=O)2Ci-C6alkyl, -S(=O)2NH2, S(=O)₂NH Ci-C₆alkyl, -S(=O)₂N(Ci-C6alkyl)₂, -NH₂, -NHCi-C₆alkyl, -N(Ci-C₆alkyl)₂, NHC(=O)OCi-C₆alkyl, -C(=O)Ci-C₆alkyl, -C(=O)OH, -C(=O)OCi-C₆alkyl, -C(=0)NH₂, C(=O)N(Ci-C6alkyl)2, -C(=O)NHCi-C6alkyl, Ci-Côalkyl, Ci-Côhaloalkyl, Ci-Côhydroxyalkyl, Ci-Côaminoalkyl, or Ci-Côheteroalkyl;

each R^c and R^d are independently hydrogen, Ci-Côalkyl, Ci-Côhaloalkyl, Ci-Côhydroxyalkyl, Ci-Côaminoalkyl, Ci-Côheteroalkyl, C2-Côalkenyl, C2-Côalkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, -Ci-Côalkylene-cycloalkyl, -Ci-Côalkylene-heterocycloalkyl, Ci-Côalkylene-aryl, or -Ci-Côalkylene-heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more oxo, halogen, -CN, -OH, -OCi-Côalkyl, -S(=O)Ci-C6alkyl, -S(=O)2Ci-C6alkyl, S(=O)₂NH₂, -S(=O)₂NHCi-C₆alkyl, -S(=O)₂N(Ci-C₆alkyl)₂, -NH₂, -NHCi-C₆alkyl, N(Ci-C₆alkyl)₂, -NHC(=O)OCi-C₆alkyl, -C(=O) Ci-C₆alkyl, -C(=O)OH, -C(=O)OCi-C₆alkyl, C(=O)NH₂, -C(=O)N(Cj-C₆alkyl)₂, -C(=O)NHCi-C₆alkyl, Ci-C₆alkyl, Ci-C₆haloalkyl, Ci-Côhydroxyalkyl, Ci-Côaminoalkyl, or Ci-Côheteroalkyl;

or R^c and R^d are taken together with the atom to which they are attached to form a heterocycloalkyl optionally substituted with one or more oxo, halogen, -CN, -OH, -OCi-Côalkyl, -S(=O)Ci-C₆alkyl, -S(=O)₂Ci-C₆alkyl, -S(=O)₂NH₂, -S(=O)₂NHCi-C₆alkyl, S(=O)2N(Ci-C₆alkyl)₂, -NH₂, -NHCi-C₆alkyl, -N(Ci-C₆alkyl)₂, -NHC(=O)OCi-C₆alkyl, -C(=O)

Ci-C₆alkyl, -C(=O)OH, -C(=O)OCi-C₆alkyl, -C(=O)NH₂, -C(=O)N(Ci-C₆alkyl)₂, C(=O)NHCi-C6alkyl, Ci-Côalkyl, Ci-Côhaloalkyl, Ci-Côhydroxyalkyl, Ci-Ceaminoalkyl, or Ci-Côheteroalkyl;

each R^lCa and R^1Da is independently halogen, -CN, -NO2, -OH, -OR^a, -OC(=O)R^a, OC(=O)OR^b, -OC(=O)NR^cR^d, -SH, -SR^a, -S(=O)R^a, -S(=O)2R^a, -S(=O)2NR^cR^d, -NR^cR^d, NR^bC(=O)NR^cR^d, -NR^bC(=O)R^a, -NR^bC(=O)OR^b, -NR^bS(=O)2R^a, -C(=O)R^a, -C(=O)OR^b, C(=O)NR^cR^d, Ci-Côalkyl, Ci-Côhaloalkyl, Ci-Côhydroxyalkyl, Ci-Côaminoalkyl, Ci-Côheteroalkyl, C2-C6alkenyl, C2-Côalkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; m is 1, 2, 3, or 4; and p is 0 or 1.

[0146] In some embodiments of Formula (VI), ring C is 6 membered heteroaryl and ring D is 6 membered heteroaryl. In some embodiments, ring C is 6 membered heteroaryl and ring D is 6 membered heterocycloalkyl.

[0147] In some embodiments of Formula (VI), each of ring C and ring D is independently optionally substituted with one or more substituents selected from halo, -CN, -OR^a, -SH, -SR^a, NR^cR^d, optionally substituted C1-6alkyl, optionally substituted Ci-6 heteroalkyl, optionally substituted C2-6 alkenyl, and optionally substituted C2-6 alkynyl, and wherein the alkyl, heteroalkyl, alkenyl, or alkynyl is optionally substituted with one or more substituents independently selected from: halogen, amino, oxo, -OH, -NO2, -CN, and Ci-3 alkoxyl.

[0148] In some embodiments of Formula (VI), wherein,

Z¹ is N, NR¹, O, S, CR¹, or C(R')₂;

Z² is N, NR², O, CR², C(R²)₂, S(=O)₂, C(=O), or C(=S);

Z³ is N, NR³, CR³, C(R³)₂, S(=O)₂, C(=O), or C(=S);

is a single bond or a double bond;

R¹¹ is hydrogen, optionally substituted C1-6 alkyl, optionally substituted C2-6 alkenyl, optionally substituted C2-6 alkynyl, optionally substituted C1-6 heteroalkyl, optionally substituted

C3-8 cycloalkyl, optionally substituted C2-7 heterocycloalkyl, optionally substituted phenyl, optionally substituted heteroaryl, optionally substituted -Cm alkylene-C3-8 cycloalkyl, optionally substituted -Cm alkylene-C₂-7 heterocycloalkyl, optionally substituted -Cm alkylene-phenyl, or optionally substituted -Cm alkylene-heteroaryl; and each of R¹² is independently selected from hydrogen, -NO2, CN, Cm alkyl, Cm aminoalkyl, Cm hydroxyalkyl, Cm haloalkyl, Cm heteroalkyl, C3-6 carbocycle, and 3- to 6-membered heterocycle, wherein the C3-6 carbocycle and 3- to 6-membered heterocycle is optionally substituted with one or more substituents independently selected from halogen, -OH, oxo, amino, -NO2, CN, Cm alkyl, Cm alkoxy, and Cm haloalkyl.

wherein,

Z¹ is N, NRⁿ¹, O, S, CR¹, or C(R‘)₂;

Z² is N, NR^N2, O, CR², C(R²)₂, S(=O)₂, C(=O), or C(=S);

Z³ is N, NRⁿ³, CR³, C(R³)₂, S(=O)₂, C(=O), or C(=S);

---is a single bond or a double bond;

each of R¹, R², and R³ is independently selected from hydrogen, halo, -CN, -OR¹¹, -SR¹¹, N(R¹²)₂, optionally substituted Cm alkyl, optionally substituted Cm heteroalkyl, optionally substituted C2-6 alkenyl, and optionally substituted C2-6 alkynyl;

each of Rⁿ¹, Rⁿ², and R^N3 is independently selected from hydrogen, -CN, optionally substituted Cm alkyl, optionally substituted Cm heteroalkyl, optionally substituted C2-6 alkenyl, and optionally substituted C2-6 alkynyl;

R¹¹ is hydrogen, optionally substituted Ci-6 alkyl, optionally substituted C2-6 alkenyl, optionally substituted C2-6 alkynyl, optionally substituted Ci-6 heteroalkyl, optionally substituted C3-8 cycloalkyl, optionally substituted C2-7 heterocycloalkyl, optionally substituted phenyl, optionally substituted heteroaryl, optionally substituted -Cm alkylene-C3-8 cycloalkyl, optionally substituted -Cm alkylene-C2-7 heterocycloalkyl, optionally substituted -Cm alkylene-phenyl, or optionally substituted -Cm alkylene-heteroaryl; and each of R¹²is independently selected from hydrogen, -NO2, CN, Cm alkyl, Cm aminoalkyl, Cm hydroxyalkyl, Cm haloalkyl, Cm heteroalkyl, C3-6 carbocycle, and 3- to 6-membered heterocycle, wherein the C3-6 carbocycle and 3- to 6-membered heterocycle is optionally substituted with one or more substituents independently selected from halogen, -OH, oxo, amino, -NO2, CN, Ci-6 alkyl, Ci-6 alkoxy, and Ci-6 haloalkyl.

[0150] In some embodiments of Formula (VI), each of R¹ and R² is independently selected from hydrogen, -CN, optionally substituted C1-6 alkyl, optionally substituted Ci-6heteroalkyl, optionally substituted C2-6 alkenyl, and optionally substituted C2-6 alkynyl.

^N\ A ^Nv _%/Zn [0151] In some embodiments, is ±- ^HN~~\ ^Χ|Μ~λ <~nh Nf$__N>=⁰ ν£$__ν>=⁰ / y—n y y=N y /—N y y— Λ ν' Ά ζΓ—< \ \ ’Χ Ζ ^Ν VI Ζ^Ο Ν y Ζ Ν V- Ζ~~Ν \=ni χ V · ^Ν X· 'χ,/ ^Ν some embodiments, ± is % ( C ! D [0152] In some embodiments of Formula (VI), A /= N N=x _s Æ n' Z=n y Zn y Zni ^N\ / 10 v A /AÀ° n^L Ao ⁿZC / ^NA A A 9 9 9 h o \ 0 N-Z-^U) ZA > /N U. /N s/ ^N y ^N > X a or z . in some embodiments, /=N N=x y m'Z mX /=° L· ^N. y—N ^N. y-N 5 /V /=n y /=N y f N , or N .In some embodiments, ^c

S^. Ao Ao '^{N N}> ^N > 9 9 /—X / y A Zo >=o 7—N ^N\ /—N ^:n y /=n y or .In =N N=x >=° >=O -N ^N. /-N > Z^N , or a j Ao Az A is HN—x /-NH Ao zA A⁰N ^N _x /—N >=n y Zn y 9 9 y / Xo A-?° j A 9 9 ( G ¹ D ) zr-ZZ 1 V —— \j w. A~n ^r is N. z- ₅ ^{c 1} ü ) zZZ _A_X r Ί V z=o — — Lj. z-N ^N V, ^r is N. . In

In some embodiments,

[0153] In some embodiments of Formula (VI), ring A is phenyl. In some embodiments, ring A is naphthyl. In some embodiments, ring A is 5 or 6 membered monocyclic heteroaryl.

[0155] In some embodiments of Formula (VI), ring A is pyridine, pyrimidine, pyrazine, pyridazine, triazine, imidazole, pyrazole, triazole, oxazole, isoxazole, or thiophene. In some

some embodiments, is . In some embodiments,

[0156] In some embodiments of Formula (VI), ring A is bicyclic heteroaryl. In some embodiments, ring A is fused 5-6, 6-6, or 6-5 bicyclic heteroaryl.

[0157] In some embodiments of Formula (VI), each of R^Ais independently selected from halogen, -NO2, oxo, -CN, optionally substituted C1-6 alkyl, optionally substituted C1-6 heteroalkyl, optionally substituted C3-8 cycloalkyl, optionally substituted C2-7 heterocycloalkyl, -OR¹¹, -SR¹¹, -N(R^,2)(R^H), -C(O)R¹², -C(O)OR¹², -OC(O)R¹², -OC(O)N(R^I2)(R), -C(O)N(R¹²)(R),N(R¹²)C(O)R¹² -N(R^I2)C(O)OR¹²,-N(R'²)C(O)N(Rⁱ²)(R), -N(R¹²)₂S(O)₂(R¹²),-S(O)R¹², S(O)2R¹², and -S(O)2N(R¹²)(R^H). In some embodiments, each R^Ais independently substituted with one or more substituents independently selected from: halogen, -OH, -NO2, amino, -CN, Ciôalkoxyl, C1-6 alkyl, C1-6 haloalkyl, C3-6 carbocycle, and 3- to 6-membered heterocycle, wherein the C3-6 carbocycle and 3- to 6-membered heterocycle is optionally substituted with one or more substituents independently selected from halogen, -OH, amino, -NO2, oxo, -CN, Ci-6alkyl, Ci-6 alkoxy, and Ci-6haloalkyl. In some embodiments of Formula (IVa), (IVa-1), and (IVa-2), each R^a is independently selected from halogen, -NO2, oxo, -CN, C1-6 alkyl, Ci-6alkoxyl, C1-6 haloalkyl, Ci-6heteroalkyl, and C3-6cycloalkyl. In some embodiments, each R^Ais independently selected from halogen, C1-6alkyl, Ci-6alkoxyl, Ci-6 haloalkyl, and C3-6 cycloalkyl. In some embodiments, R^A is halogen. In some embodiments, R^A is -NO2. In some embodiments, R^A is oxo. In some embodiments, R^A is -CN. In some embodiments, R^A is optionally substituted C1-6 alkyl. In some embodiments, R^A is Ci-alkyl. In some embodiments, R^A is C2 alkyl. In some embodiments, R^A is C3 alkyl. In some embodiments, R^A is optionally substituted Ci-6 heteroalkyl. In some embodiments, R^A is C3 heteroalkyl. In some embodiments, R^A is optionally substituted C3-8 cycloalkyl. In some embodiments, R^A is C3 cycloalkyl. In some embodiments, R^A is optionally substituted C2-7 heterocycloalkyl. In some embodiments, R^A is C2 heterocycloalkyl. In some embodiments, R^A is -OR¹¹. In some embodiments, R^A is -SR¹¹. In some embodiments, R^Ais -N(R¹²)(Rⁿ). In some embodiments, R^A is -C(O)R¹². In some embodiments, R^A is -C(O)OR¹². In some embodiments, R^A is -OC(O)R¹². In some embodiments, R^A is -OC(O)N(R¹²)(R^H). In some embodiments, R^A is -C(O)N(R¹²)(R”) In some embodiments, R^A is -N(R¹²)C(O)R¹² N(R¹²)C(O)OR¹². In some embodiments, R^A is -N(R¹²)C(O)N(R¹²)(R^H). In some embodiments, R^a is -N(R¹²)2S(O)2(R¹²). In some embodiments, R^A is -S(O)R¹². In some embodiments, R^A is S(O)2R¹². In some embodiments, R^A is -S(O)2N(R¹²)(R^H). In some embodiments, each R^A is independently OH, C1-3 alkyl, -OCH3, C1-3 haloalkyl, or C3-C6 cycloalkyl (e.g., cyclopropyl). In some embodiments, each R^A is independently OH, -OCH3, C1-3 alkyl, C1-3 haloalkyl, or cyclopropyl. In some embodiments, each R^A is independently C1-3 alkyl, C1-C3 alkoxyl, C1-3 haloalkyl, or cyclopropyl. In some embodiments, each R^A is independently OH, Ci-6 alkoxyl (e.g., -OCH3), Ci-6 alkyl, Ci-6 haloalkyl, or C3-C6 cycloalkyl (e.g., cyclopropyl). In some embodiments, -OCH3 is -OCD3

[0158] In some embodiments of Formula (VI), is selected from:

N

[0159] In some embodiments of Formula (VI), p is 0. In some embodiments, p is 1.

[0160] In some embodiments of Formula (VI), each of R⁸ and R⁹ is independently selected from hydrogen, halo, -CN, optionally substituted Cm alkyl, optionally substituted Ci-6heteroalkyl, optionally substituted C2-6 alkenyl, and optionally substituted C2-6 alkynyl. In some embodiments, each of R⁸ and R⁹ is independently selected from hydrogen, halo, -CN, optionally substituted Ci6alkyl, optionally substituted Ci-6heteroalkyl, optionally substituted C2-6alkenyl, and optionally substituted C2-6 alkynyl. In some embodiments, R⁸ and R⁹ are hydrogen. In some embodiments, R⁸ and R⁹ are -CN. In some embodiments, R⁸ and R⁹ are optionally substitute Ci-3 alkyl.

[0161] In some embodiments of Formula (VI), R⁸ and R⁹ taken together form an oxo.

[0162] In some embodiments of Formula (VI), R⁸ and R⁹ taken together with the carbon to which they are attached form an optionally substituted 3-6 membered cycloalkyl or heterocycloalkyl.

[0163] In some embodiments of Formula (VI), R^B is halo, -CN, -NO2, optionally substituted Cm alkyl, optionally substituted C2-6 alkenyl, optionally substituted C2-6 alkynyl, optionally substituted Cm heteroalkyl, -OR¹¹, -SR¹¹, -N^MR¹¹), -C(O)R¹², -C(O)OR¹², -OC(O)R¹², OC(O)N(R¹²)(R'’), -C(O)N(R^I2)(R''), -N(R¹²)C(O)R¹² -N(R¹²)C(O)OR¹², N(R¹²)C(O)N(R¹²)(R), -N(R¹²)S(O)2(R¹²),-S(O)R¹², -S(O)2R¹²,-S(O)2N(R¹²)(R¹¹), optionally substituted C3-8 cycloalkyl, optionally substituted C2-9 heterocycloalkyl, optionally substituted phenyl, optionally substituted monocyclic heteroaryl, or optionally substituted bicyclic heteroaryl. In some embodiments, R^B is optionally substituted 5 membered monocyclic heteroaryl with 1 to 4 heteroatoms selected from N, O, S and P. In some embodiments, R^B is imidazole, pyrazole, triazole, or tetrazole, each of which optionally substituted. In some embodiments, R^B is optionally substituted fused 5-6, 6-6 or 6-5 heteroaryl. In some embodiments, R^B is optionally substituted C3-8 cycloalkyl. In some embodiments, R^B is C3 cycloalkyl. In some embodiments, R^B is C5 cycloalkyl. In some embodiments, R^B is Cô cycloalkyl. In some embodiments, R^B is optionally substituted phenyl. In some embodiments, R^Bis optionally substituted C2-9 heterocycloalkyl. In some embodiments, R^B is optionally substituted 5-6 membered heterocycloalkyl or heteroaryl. In some embodiments, R^B is C3 heterocycloalkyl. In some embodiments, R^B is C5 heterocycloalkyl. In some embodiments, R^B is Ce heterocycloalkyl. In some embodiments, R^B is optionally substituted monocyclic heteroaryl. In some embodiments, R^B is optionally substituted bicyclic heteroaryl. In some embodiments, R^B is imidazole, pyrazole, triazole, or tetrazole, each of which optionally substituted. In some embodiments, R^B is imidazole. In some embodiments, R^B is pyrazole. In some embodiments, R^Bis triazole. In some embodiments, R^B is tetrazole.

[0164] In some embodiments of Formula (VI), R^B is optionally substituted with one or more substituents independently selected from halogen, -NO2, oxo, -CN, optionally substituted C1-6 alkyl, optionally substituted C1-6 heteroalkyl, optionally substituted C3-8 cycloalkyl, optionally substituted C2-7 heterocycloalkyl, -OR¹¹, -SR¹¹, -N(R¹²)(R), -C(O)R¹², -C(O)OR¹², -OC(O)R¹², -OC(O)N(R¹²)(R' ’), -C(O)N(R^I2)(R‘*), -N(R¹²)C(O)R¹² -N(R¹²)C(O)OR¹², N(R¹²)C(O)N(R¹²)(Rⁿ), -N(R¹²)S(O)2(R¹²), -S(O)R¹², -S(O)2R¹², and-S(O)2N(R¹²)(R^H), wherein the alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, or heterocycloalkyl is optionally substituted with one or more substituents independently selected from: halogen, -OH, -NO2, amino, oxo, -CN, C1-3 alkoxyl, C1.3 alkyl and C1-3 haloalkyl. In some embodiments, R^B is optionally substituted with one or more substituents independently selected from halogen, -OR¹¹, -NO₂, oxo, -CN, optionally substituted Ci-6 haloalkyl, optionally substituted Ci-6 alkyl, optionally substituted Ci-6aminoalkyl, optionally substituted Ci-ôhydroxyalkyl, optionally substituted C1-6 heteroalkyl, optionally substituted C3-8 cycloalkyl, and optionally substituted C2-7 heterocycloalkyl. In some embodiments, R^B is optionally substituted with one or more substituents independently selected from halogen, -OR¹¹, -NO2, oxo, -CN, C1-3 haloalkyl, C1.3 alkyl, C1-3 aminoalkyl, C1-3 hydroxyalkyl, optionally substituted Cm heteroalkyl (e.g., CH2C(=O)N(CH3)2), optionally substituted C3-6 cycloalkyl, and optionally substituted C2-5 heterocycloalkyl.

. In some embodiments, R^B is

In some embodiments, R^B is

[0167] In some embodiments of Formula (VI), ring C is phenyl or a 6 membered heteroaryl, wherein each of the phenyl or heteroaryl is optionally substituted. In some embodiments, ring C is optionally substituted phenyl. In some embodiments, ring C is optionally substituted 6 membered heteroaryl.

[0168] In some embodiments of Formula (VI), ring D is an aromatic, saturated or partially saturated 6 membered carbocycle or heterocycle, wherein each of the carbocycle or heterocycle is optionally substituted. In some embodiments, ring D is an optionally substituted aromatic 6 membered carbocycle. In some embodiments, ring D is an optionally substituted aromatic 6 membered heterocycle. In some embodiments, ring D is an optionally substituted saturated 6 membered carbocycle. In some embodiments, ring D is an optionally substituted saturated 6 membered heterocycle. In some embodiments, ring D is an optionally substituted partially saturated 6 membered carbocycle. In some embodiments, ring D is an optionally substituted partially saturated 6 membered heterocycle.

[0169] In some embodiments of Formula (VI), each of R⁸ and R⁹ is independently selected from hydrogen, halo, -CN, optionally substituted Ci-6 alkyl, optionally substituted Ci-6heteroalkyl, optionally substituted C2-6 alkenyl, and optionally substituted C2-6 alkynyl. In some embodiments of Formula (VI), each of R⁸ and R⁹ is independently selected from hydrogen, -CN, optionally substituted C1-6alkyl, optionally substituted Ci-6 heteroalkyl, optionally substituted C2-6 alkenyl, and optionally substituted C2-6 alkynyl. In some embodiments, R⁸ is hydrogen. In some embodiments, R⁸ is halo. In some embodiments, R⁸ is -CN. In some embodiments, R⁸ is optionally substituted C1-6 alkyl. In some embodiments, R⁸ is optionally substituted C1-6 heteroalkyl. In some embodiments, R⁸ is optionally substituted C2-6 alkenyl. In some embodiments, R⁸ is optionally substituted C2-6 alkynyl. In some embodiments, R⁹ is hydrogen. In some embodiments, R⁹ is halo. In some embodiments, R⁹ is -CN. In some embodiments, R⁹ is optionally substituted C1-6 alkyl. In some embodiments, R⁹ is optionally substituted Ci-6 heteroalkyl. In some embodiments, R⁹ is optionally substituted C2-6 alkenyl. In some embodiments, R⁹ is optionally substituted C2-6 alkynyl. In some embodiments, R⁸ and R⁹ taken together form an oxo. In some embodiments, R⁸ and R⁹ taken together with the carbon to which they are attached form an optionally substituted 3-6 membered cycloalkyl or heterocycloalkyl. [0170] In some embodiments of Formula (VI), ring A is phenyl, naphthyl, monocyclic heteroaryl, or bicyclic heteroaryl. In some embodiments, ring A is phenyl. In some embodiments, ring A is naphthyl. In some embodiments, ring A is monocyclic heteroaryl. In some embodiments, ring A is or bicyclic heteroaryl. In some embodiments, ring A is a 6 membered monocyclic heteroaryl containing 1-3 heteroatoms.

[0171] In some embodiments of Formula (VI), R^A is independently selected from halogen, -NÛ2, oxo, -CN, optionally substituted Ci-6 alkyl, optionally substituted C2-6alkenyl, optionally substituted C2-6 alkynyl, optionally substituted Ci-6 heteroalkyl, optionally substituted C3-8 cycloalkyl, optionally substituted C2-7 heterocycloalkyl, -OR¹¹, -SR¹¹, -N(R¹²)(R^H), C(O)R¹², -C(O)OR¹², -OC(O)R¹², -OC(O)N(R¹²)(R^H), -C(O)N(R¹²)(R^H),-N(R¹²)C(O)R¹² N(R¹²)C(O)OR¹²,-N(R¹²)C(O)N(R¹²)(R), -N(R¹²)2S(O)2(R¹²),-S(O)R¹², -S(O)2R¹², and S(O)2N(R¹²)(R^h). In some embodiments, R^A is halogen. In some embodiments, R^A is -NO2. In some embodiments, R^A is oxo. In some embodiments, R^A is -CN. In some embodiments, R^A is optionally substituted Cm alkyl. In some embodiments, R^A is optionally substituted C1-3 alkyl. In some embodiments, R^A is methyl, ethyl, propyl, zso-propyl, n-butyl, fro-butyl, sec-butyl, Abutyl, -CF₃, -CH2CF₃,or -CH2CH2F. In some embodiments, R^A is optionally substituted C2-6alkenyl. In some embodiments, R^A is optionally substituted C2-6 alkynyl. In some embodiments, R^A is optionally substituted Cm heteroalkyl. In some embodiments, R^A is optionally substituted C3-8 cycloalkyl. In some embodiments, R^A is optionally substituted C3-6 cycloalkyl, e.g., cyclopropyl.

In some embodiments, R^A is

In some embodiments, R^A is optionally substituted C2-7 heterocycloalkyl. In some embodiments, R^A is optionally substituted C2-5 heterocycloalkyl. In some embodiments, R^A is -OR¹¹. In some embodiments, R^A is -O-C1-3 alkyl. In some embodiments, R^A is -OCH3, -OCH2CH3, -OCFbOMe, -OCH2CH2OH, -OC(CH3)3, or -OCH2CH2OCH3 In some embodiments, R^A is -OCH3.. In some embodiments, R^A is V . In some embodiments, R^A is -SR¹¹. In some embodiments, R^A is

-N(R¹²)(R^H). In some embodiments, R^A is -C(O)R¹². In some embodiments, R^A is -C(O)OR¹². In some embodiments, R^A is -OC(O)R¹². In some embodiments, R^A is -OC(O)N(R¹²)(R^H). In some embodiments, R^A is -C(O)N(R^I2)(R¹¹). In some embodiments, R^A is-N(R¹²)C(O)R¹². In some embodiments, R^A is -N(R¹²)C(O)OR¹². In some embodiments, R^A is -N(R¹²)C(O)N(R¹²)(R¹¹). In some embodiments, R^A is -N(R¹²)2S(O)2(R¹²). In some embodiments, R^A is -S(O)R¹². In some embodiments, R^A is -S(O)2R¹². In some embodiments, R^A is -S(O)2N(R¹²)(Rⁿ).

[0172] In some embodiments of Formula (VI), R¹¹ is hydrogen, optionally substituted Cm alkyl, optionally substituted C2-6alkenyl, optionally substituted C2-6 alkynyl, optionally substituted Cm heteroalkyl, optionally substituted C3-8 cycloalkyl, optionally substituted C2-7 heterocycloalkyl, optionally substituted phenyl, optionally substituted heteroaryl, optionally substituted -Cm alkylene-C3-8 cycloalkyl, optionally substituted -Cm alkylene-C2-7 heterocycloalkyl, optionally substituted -CMalkylene-phenyl, or optionally substituted -Cm alkylene-heteroaryl. In some embodiments, R¹¹ is hydrogen. In some embodiments, R¹¹ is optionally substituted Ci-6 alkyl. . In some embodiments, R¹¹ is optionally substituted C1.3 alkyl. In some embodiments, R^A is methyl, ethyl, propyl, zso-propyl, π-butyl, wo-butyl, sec-butyl, ί-butyl, -CF3, -CH2CF3,or -CH2CH2F. In some embodiments, R¹¹ is optionally substituted C2-6 alkenyl. In some embodiments, R¹¹ is optionally substituted C2-6 alkynyl. In some embodiments, R¹¹ is optionally substituted C1-6 heteroalkyl. In some embodiments, R¹¹ is optionally substituted C3-8 cycloalkyl. In some embodiments, R¹¹ is optionally substituted C2-7 heterocycloalkyl. In some embodiments, R¹¹ is optionally substituted phenyl. In some embodiments, R¹¹ is optionally substituted heteroaryl. In some embodiments, R¹¹ is optionally substituted -Ci-4alkylene-C3-8 cycloalkyl. In some embodiments, R¹¹ is optionally substituted -Cm alkylene-C2-7 heterocycloalkyl. In some embodiments, R¹¹ is optionally substituted -CMalkylene-phenyl. In some embodiments, R¹¹ is optionally substituted -Ci-4alkylene-heteroaryl.

[0173] In some embodiments of Formula (VI), each of R¹² is independently selected from hydrogen, halogen, -OH,-NO2, -CN, C1-6 alkyl, Ci-6aminoalkyl, Ci-ôhydroxyalkyl, C1-6 haloalkyl, and C3-6 carbocycle, 3- to 6-membered heterocycle, wherein the C3-6 carbocycle and 3to 6-membered heterocycle is optionally substituted with one or more substituents independently selected from halogen, -OH, oxo, amino, -NO2, -CN, C1-6 alkyl, C1-6 alkoxy, and Ci-6 haloalkyl. In some embodiments of Formula (VI), each of R¹² is independently selected from hydrogen, NO2, -CN, C1-6 alkyl, Ci-6aminoalkyl, Ci-ehydroxyalkyl, Ci-6haloalkyl, and C3-6carbocycle, 3to 6-membered heterocycle, wherein the C3-6 carbocycle and 3- to 6-membered heterocycle is optionally substituted with one or more substituents independently selected from halogen, -OH, oxo, amino, -NO2, -CN, C1-6 alkyl, C1-6alkoxy, and Ci-6haloalkyl. In some embodiments, R¹² is hydrogen. In some embodiments, R¹² is halogen. In some embodiments, R¹² is -OH. In some embodiments, R¹² is-NO2. In some embodiments, R¹² is -CN. In some embodiments, R¹² is Ci-6 alkyl. In some embodiments, R¹² is Ci-6aminoalkyl. In some embodiments, R¹² is C1-6 hydroxyalkyl. In some embodiments, R¹² is Ci-6haloalkyl. In some embodiments, R¹² is and C3-6 carbocycle. In some embodiments, R¹² is 3- to 6-membered heterocycle, wherein the C3-6 carbocycle and 3- to 6-membered heterocycle is optionally substituted with one or more substituents independently selected from halogen, -OH, oxo, amino, -NO2, -CN, Ci-6 alkyl, Ci-6 alkoxy, and Ci-6 haloalkyl. In some embodiments, the one or more substituent is halogen. In some embodiments, the one or more substituent is -OH. In some embodiments, the one or more substituent is oxo. In some embodiments, the one or more substituent is amino. In some embodiments, the one or more substituent is -NO2. In some embodiments, the one or more substituent is -CN. In some embodiments, the one or more substituent is Ci-6 alkyl. In some embodiments, the one or more substituent is Ci-6 alkoxy. In some embodiments, the one or more substituent is Ci-6haloalkyl.

[0174] In some embodiments of Formula (VI), R^B is hydrogen, halo, -CN, -NO2, optionally substituted Ci-6 alkyl, optionally substituted C2-6 alkenyl, optionally substituted C2-6alkynyl, optionally substituted Cm heteroalkyl, -OR¹¹, -SR¹¹, -N(R¹²)(R^H), -C(O)R¹², -C(O)OR¹², OC(O)R¹², -OC(O)N(R¹²)(R^h), -C(O)N(R¹²)(R¹¹),-N(Rⁱ²)C(O)R¹² -N(R¹²)C(O)OR¹²,N(R^I2)C(O)N(R^I2)(R^H), -N(R¹²)S(O)2(R¹²),-S(O)R¹², -S(O)2R¹², -S(O)2N(R¹²)(R”), optionally substituted C3-8 cycloalkyl, optionally substituted C2-9 heterocycloalkyl, optionally substituted naphthyl, optionally substituted phenyl, optionally substituted monocyclic heteroaryl, or optionally substituted bicyclic heteroaryl. In some embodiments, R^B is hydrogen. In some embodiments, R^B is halo. In some embodiments, R^B is -CN. In some embodiments, R^B is -NO2. In some embodiments, R^B is optionally substituted Cm alkyl. In some embodiments, R^B is optionally substituted C2-6 alkenyl. In some embodiments, R^B is optionally substituted C2-6 alkynyl. In some embodiments, R^B is optionally substituted Ci-6heteroalkyl. In some embodiments, R^B is -OR¹¹. In some embodiments, R^B is -SR¹¹. In some embodiments, R^B is N(R¹²)(Rⁿ). In some embodiments, R^B is -C(O)R¹². In some embodiments, R^B is -C(O)OR¹². In some embodiments, R^B is -OC(O)R¹². In some embodiments, R^B is -OC(O)N(R¹²)(R¹¹). In some embodiments, R^B is -C(O)N(R¹²)(R^H). In some embodiments, R^B is-N(R¹²)C(O)R¹². In some embodiments, R^B is -N(R¹²)C(O)OR¹². In some embodiments, R^B is-N(R¹²)C(O)N(R¹²)(R). In some embodiments, R^B is -N(R¹²)S(O)2(R¹²). In some embodiments, R^B is-S(O)R¹². In some embodiments, R^B is -S(O)2R¹². In some embodiments, R^B is -S(O)2N(R¹²)(R^H). In some embodiments, R^B is optionally substituted C3-8 cycloalkyl. In some embodiments, R^B is optionally substituted C2-9 heterocycloalkyl. In some embodiments, R^B is optionally substituted naphthyl. In some embodiments, R^B is optionally substituted phenyl. In some embodiments, R^Bis optionally substituted monocyclic heteroaryl. In some embodiments, R^B is optionally substituted bicyclic heteroaryl.

[0175] In some embodiments of Formula (VI), m is 1, 2, 3, or 4. In some embodiments, m is 1. In some embodiments, m is 2. In some embodiments, m is 3. In some embodiments, m is 4.

[0176] In some embodiments of Formula (VI), p is 0 or 1. In some embodiments, p is 0. In some embodiments, p is 1.

]0177] In some embodiments of a compound of Formula (VI), is /=¾ ^N=\ /^N M h/ ^N ,/ ^N « Q , N , or N. ; each R and R is hydrogen; p is 1 ;

from Ci-Cô alkyl, Ci-Cô alkoxyl, Ci-Cô haloalkyl, and C3-6 cycloalkyl (e.g., cyclopropyl); R^B is 5 membered heteroaryl optionally substituted with one or more substituents selected from Ci-3

«, N^/CF₃

HÏ

Z ). in some embodiments, each R^A is independently OH, Ci-3 alkyl, -OCH3, Ci-3 haloalkyl, or C3-C6 cycloalkyl (e.g., cyclopropyl). In some embodiments, each R^A is independently OH, -OCH3, C1-3 alkyl, C1-3 haloalkyl, or cyclopropyl. In some embodiments, each R^a is independently Ci-3 alkyl, C1-C3 alkoxyl, Ci-3 haloalkyl, or cyclopropyl. In some embodiments, -OCH3 is -OCD3.

[0178] Non-limiting examples of compounds described herein, are compounds presented in Table 1, and pharmaceutically acceptable salts or solvatés thereof.

Table 1 Exemplary Compounds of the Disclosure

[0179] Table 2 présents corresponding biological data for USP1 IC50 (nM) and MDA-MB-436 IC50 (nM) for the compounds presented in Table 1.

Table 2:

Compound No.	USP1 ICso(nM)	MDA- MB-436 ICso(nM)
1	A	A
2	B	C
3	A	B
4	A	A
5	B	C
6	A	A
7	A	A
8	A	A
9	A	A
10	B	C
11	A	A
12	A	A
13	A
14	A	B
15	B	B
16	A	A
17	C	D
18	C	D
19	C	D
20	A	A

22	A	B
23	A	A
24	A	A
25	A	A
27	A	B
32	A	A
33	A	A
34	B	B
35	A	A
36	B	C
37	B	B
38	B	A
39	B

[0180] IC50 (nM): 0<A<50; 50<Β<1,000; l,000<C< 10,000; 10,000<D

[0181] Included in the présent disclosure are salts, particularly pharmaceutically acceptable salts, of the compounds described herein. The compounds of the présent disclosure that possess a sufficiently acidic, a sufficiently basic, or both functional groups, can react with any of a number of inorganic bases, and inorganic and organic acids, to form a sait. Altematively, compounds that are inherently charged, such as those with a quatemary nitrogen, can form a sait with an appropriate counterion, e.g., a halide such as bromide, chloride, or fluoride, particularly bromide. [0182] Chemical entities having carbon-carbon double bonds or carbon-nitrogen double bonds can exist in Z- or E- form (or cis- or trans- form). Furthermore, some Chemical entities can exist in various tautomeric forms. Unless otherwise specified, compounds described herein are intended to include ail Z-, E- and tautomeric forms as well.

[0183] As used herein, “phenyl isostere” refers to a moiety or a functional group that exhibits similar physical, biological and/or Chemical properties as a phenyl group. Exemplary phenyl isosteres include, without limitation, cubane, bicyclo[l.l.l]pentane (BCP), bicyclo[2.2.1]heptane, bicyclo[2.1.1]hexane, bicyclo[2.2.2]octane, adamantane, norbomene, closo-1,2- carborane, closo-1,7- carborane, closo-1,12- carborane, and ethynyl group. In some embodiments, the phenyl isostere is cubane. In some embodiments, the phenyl isostere is an ethynyl group.

[0184] A “tautomer” refers to a molécule wherein a proton shift from one atom of a molécule to another atom of the same molécule is possible. The compounds presented herein, in certain embodiments, exist as tautomers. In circumstances where tautomerization is possible, a Chemical equilibrium of the tautomers will exist. The exact ratio of the tautomers dépends on several factors, including physical State, température, solvent, and pH. Some examples of tautomeric equilibrium include:

[0185] The compounds disclosed herein, in some embodiments, are used in different enriched isotopic forms, e.g., enriched in the content of ²H, ³H, ^HC, ¹³C and/or ¹⁴C. In one particular embodiment, the compound is deuterated in at least one position. Such deuterated forms can be made by the procedure described in U.S. Patent Nos. 5,846,514 and 6,334,997. As described in U.S. Patent Nos. 5,846,514 and 6,334,997, deutération can improve the metabolic stability and or efficacy, thus increasing the duration of action of drugs.

[0186] Unless otherwise stated, compounds described herein may exhibit their natural isotopic abundance, or one or more of the atoms may be artificially enriched in a particular isotope having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number predominantly found in nature. Ail isotopic variations of the compounds of the présent disclosure, whether radioactive or not, are encompassed within the scope of the présent disclosure. For example, the compounds described herein may be artificially enriched in one or more particular isotopes. In some embodiments, the compounds described herein may be artificially enriched in one or more isotopes that are not predominantly found in nature. In some embodiments, the compounds described herein may be artificially enriched in one or more isotopes selected from deuterium (²H), tritium (³H), iodine-125 (¹²⁵I) or carbon-14 (^l4C). In some embodiments, the compounds described herein are artificially enriched in one or more isotopes selected from ²H, C, ¹³C, ^I4C, ¹⁵C, ^l2N, ^l3N, ^l5N, ^l6N, ^l6O, ^l7O, ^l4F, ^l5F, ^l6F, ^l7F, ^l8F, ³³S, ³⁴S, ³⁵S, ³⁶S, ³⁵Cl, ³⁷Cl, ⁷⁹Br, ^8lBr, ^l31I, and ^l25I. In some embodiments, the abundance of the enriched isotopes is independently at least 1%, at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, or 100% by molar. [0187] In some embodiments of a compound disclosed herein, one or more of R¹, R², R³, R⁸, R⁹, R¹¹, R¹², R^Y1, R^Y2, R^Y3, R^Y4, R^a, R^b, R^b1, R^ICa, R^1Da, R^a, R^b, R^c, and/or R^d groups comprise deuterium at a percentage higher than the natural abundance of deuterium.

[0188] In some embodiments of a compound disclosed herein, one or more 'H are replaced with one or more deuteriums in one or more of the following groups R¹, R², R³, R⁸, R⁹, R¹¹, R¹², R^Y1, R^Y2, R^Y3, R^Y4, R^a, R^b, R^b1, R^1Ca, R^1Da, R^a, R^b, R^c, and/or R^d.

[0189] In some embodiments of a compound disclosed herein, the abundance of deuterium in each of R¹, R², R³, R⁸, R⁹, R¹¹, R¹², R^Y1, R^Y2, R^Y3, R^Y4, R^A, R^B, R^B1, R^1Ca, R^IDa, R^a, R^b, R^c, and/or R^d is independently at least 1%, at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, or 100% by molar.

[0190] In some embodiments of a compound disclosed herein, one or more ’H of Ring A, Ring B, Ring C, and/or Ring D are replaced with one or more deuteriums.

[0191] In certain embodiments, the compounds disclosed herein hâve some or ail of the ‘H atoms replaced with ²H atoms. The methods of synthesis for deuterium-containing compounds are known in the art and include, by way of non-limiting example only, the following synthetic methods. Deuterium substituted compounds can be synthesized using various methods such as described in: Dean, Dennis C.; Editor. Recent Advances in the Synthesis and Applications of Radiolabeled Compounds for Drug Discovery and Development. [In: Curr., Pharm. Des., 2000; 6(10)] 2000, 110 pp; George W.; Varma, Rajender S. The Synthesis of Radiolabeled Compounds via Organometallic Intermediates, Tetrahedron, 1989, 45(21), 6601-21; and Evans, E. Anthony. Synthesis of radiolabeled compounds, J. Radioanal. Chem., 1981, 64(1-2), 9-32.

[0192] Deuterated starting materials are readily available and are subjected to the synthetic methods described herein to provide for the synthesis of deuterium-containing compounds. Large numbers of deuterium-containing reagents and building blocks are available commercially from Chemical vendors, such as Aldrich Chemical Co.

[0193] Compounds of the présent disclosure also include crystalline and amorphous forms of those compounds, pharmaceutically acceptable salts, and active métabolites of these compounds having the same type of activity, including, for example, polymorphs, pseudopolymorphs, solvatés, hydrates, unsolvated polymorphs (including anhydrates), conformational polymorphs, and amorphous forms of the compounds, as well as mixtures thereof.

[0194] The compounds described herein can in some cases exist as diastereomers, enantiomers, or other stereoisomeric forms. Where absolute stereochemistry is not specified, the compounds presented herein include ail diastereomeric, enantiomeric, and epimeric forms as well as the appropriate mixtures thereof. Séparation of stereoisomers can be performed by chromatography or by forming diastereomers and separating by recrystallization, or chromatography, or any combination thereof. (Jean Jacques, André Collet, Samuel H. Wilen, “Enantiomers, Racemates and Resolutions”, John Wiley And Sons, Inc., 1981, herein incorporated by reference for this disclosure). Stereoisomers can also be obtained by stereoselective synthesis.

[0195] The methods and compositions described herein include the use of amorphous forms as well as crystalline forms (also known as polymorphs). The compounds described herein can be in the form of pharmaceutically acceptable salts. As well, in some embodiments, active métabolites of these compounds having the same type of activity are included in the scope of the présent disclosure. In addition, the compounds described herein can exist in unsolvated as well as solvated forms with pharmaceutically acceptable solvents such as water, éthanol, and the like. The solvated forms of the compounds presented herein are also considered to be disclosed herein.

[0196] In certain embodiments, compounds or salts of the compounds can be prodrugs, e.g., wherein a hydroxyl in the parent compound is presented as an ester or a carbonate, or carboxylic acid présent in the parent compound is presented as an ester. The term “prodrug” is intended to encompass compounds which, under physiologie conditions, are converted into pharmaceutical agents of the présent disclosure. One method for making a prodrug is to include one or more selected moieties which are hydrolyzed under physiologie conditions to reveal the desired molécule. In other embodiments, the prodrug is converted by an enzymatic activity of the host animal such as spécifie target cells in the host animal. For example, esters or carbonates (e.g., esters or carbonates of alcohols or carboxylic acids and esters of phosphonic acids) are preferred prodrugs of the présent disclosure.

[0197] Prodrug forms of the herein described compounds, wherein the prodrug is metabolized in vivo to produce a compound as set forth herein are included within the scope of the daims. In some cases, some of the herein-described compounds can be a prodrug for another dérivative or active compound.

[0198] Prodrugs are often useful because, in some situations, they can be easier to administer than the parent drug. They may, for instance, be bioavailable by oral administration whereas the parent is not. Prodrugs can help enhance the cell permeability of a compound relative to the parent drug. The prodrug can also hâve improved solubility in pharmaceutical compositions over the parent drug. Prodrugs can be designed as réversible drug dérivatives, for use as modifiers to enhance drug transport to site-specific tissues or to increase drug résidence inside of a cell.

[0199] In some embodiments, the design of a prodrug increases the lipophilicity of the pharmaceutical agent. In some embodiments, the design of a prodrug increases the effective water solubility. See, e.g., Fedorak et al., Am. J. Physiol., 269:G210-218 (1995); McLoed et al., Gastroenterol, 106:405-413 (1994); Hochhaus et al., Biomed. Chrom., 6:283-286 (1992); J. Larsen and H. Bundgaard, Int. J. Pharmaceutics, 37, 87 (1987); J. Larsen et al., Int. J.

Pharmaceutics, 47, 103 (1988); Sinkula et al., J. Pharm. Sci., 64:181-210 (1975); T. Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems, Vol. 14 of the A.C.S. Symposium Sériés; and Edward B. Roche, Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press, 1987, ail incorporated herein for such disclosure). According to another embodiment, the présent disclosure provides methods of producing the above-defined compounds. The compounds can be synthesized using conventional techniques. Advantageously, these compounds are conveniently synthesized from readily available starting materials. [0200] Synthetic chemistry transformations and méthodologies useful in synthesizing the compounds described herein are known in the art and include, for example, those described in R. Larock, Comprehensive Organic Transformations (1989); T. W. Greene and P. G. M.

Wuts, Protective Groups in Organic Synthesis, 2d. Ed. (1991); L. Fieser and M. Fieser, Fieser and Fieser’s Reagents for Organic Synthesis (1994); and L. Paquette, ed., Encyclopedia of Reagents for Organic Synthesis (1995).

C. Pharmaceutical Compositions

[0201] Provided herein, in certain embodiments, are compositions comprising a therapeutically effective amount of any compound or sait of any one of Formulas (III), (Ilia), (IIIa-1), (IIIa-2), (Illb), (IIIb-1), (IIIb-2), (IIIc), (IIIc-1 ) or (VI) (also referred to herein as “a pharmaceutical agent”).

[0202] Pharmaceutical compositions can be formulated using one or more physiologically acceptable carriers including excipients and auxiliaries which facilitate processing of the pharmaceutical agent into préparations which are used pharmaceutically. Proper formulation is dépendent upon the route of administration chosen. A summary of pharmaceutical compositions is found, for example, in Remington: The Science and Practice of Pharmacy, Nineteenth Ed (Easton, Pa., Mack Publishing Company, 1995); Hoover, John E., Remington’s Pharmaceutical Sciences, Mack Publishing Co., Easton, Pennsylvania 1975; Liberman, H.A. and Lachman, L., Eds., Pharmaceutical Dosage Forms, Marcel Decker, New York, N.Y., 1980; and Pharmaceutical Dosage Forms and Drug Delivery Systems, Seventh Ed. (Lippincott Williams & Wilkins, 1999). [0203] The compositions and methods of the présent disclosure can be utilized to treat an individual in need thereof. In certain embodiments, the individual is a mammal such as a human, or a non-human mammal. When administered to an animal, such as a human, the composition or the pharmaceutical agent, is preferably administered as a pharmaceutical composition comprising, for example, a pharmaceutical agent and a pharmaceutically acceptable carrier or excipient. Pharmaceutically acceptable carriers are well known in the art and include, for example, aqueous solutions such as water or physiologically buffered saline or other solvents or vehicles such as glycols, glycerol, oils such as olive oil, or injectable organic esters. In a preferred embodiment, when such pharmaceutical compositions are for human administration, particularly for invasive routes of administration, e.g., routes, such as injection or implantation, that circumvent transport or diffusion through an épithélial barrier, the aqueous solution is pyrogen-free, or substantially pyrogen-free. The excipients can be chosen, for example, to effect delayed release of an agent or to selectively target one or more cells, tissues or organs. The pharmaceutical composition can be in dosage unit form such as tablet, capsule, granule, lyophile for reconstitution, powder, solution, syrup, suppository, injection or the like. The composition can also be présent in a transdermal delivery System, e.g., a skin patch. The composition can also be présent in a solution suitable for topical administration, such as an eye drop.

[0204] A pharmaceutically acceptable excipient can contain physiologically acceptable agents that act, for example, to stabilize, increase solubility or to increase the absorption of a compound such as a pharmaceutical agent. Such physiologically acceptable agents include, for example, carbohydrates, such as glucose, sucrose or dextrans, antioxidants, such as ascorbic acid or glutathione, chelating agents, low molecular weight proteins or other stabilizers or excipients. The choice of a pharmaceutically acceptable excipient, including a physiologically acceptable agent, dépends, for example, on the route of administration of the composition. The préparation or pharmaceutical composition can be a self-emulsifying drug delivery System or a self microemulsifying drug delivery System. The pharmaceutical composition (préparation) also can be a liposome or other polymer matrix, which can hâve incorporated therein, for example, a compound of the disclosure. Liposomes, for example, which comprise phospholipids or other

100 lipids, are nontoxic, physiologically acceptable and metabolizable carriers that are relatively simple to make and administer.

[0205] A pharmaceutical composition (préparation) can be administered to a subject by any of a number of routes of administration including, for example, orally, for example, drenches as in aqueous or non-aqueous solutions or suspensions, tablets, capsules, including sprinkle capsules and gelatin capsules, boluses, powders, granules, pastes for application to the tongue; absorption through the oral mucosa, e.g., sublingually; anally, rectally or vaginally, for example, as a pessary, cream or foam; parenterally, including intramuscularly, intravenously, subcutaneously or intrathecally as, for example, a stérile solution or suspension; nasally; intraperitoneally; subcutaneously; transdermally, for example, as a patch applied to the skin; and topically, for example, as a cream, ointment or spray applied to the skin, or as an eye drop. The compound can also be formulated for inhalation. In certain embodiments, a compound can be simply dissolved or suspended in stérile water.

[0206] A pharmaceutical composition can be a stérile aqueous or non-aqueous solution, suspension or émulsion, e.g., a microemulsion. The excipients described herein are examples and are in no way limiting. An effective amount or therapeutically effective amount refers to an amount of the one or more pharmaceutical agents administered to a subject, either as a single dose or as part of a sériés of doses, which is effective to produce a desired therapeutic effect.

[0207] Subjects can generally be monitored for therapeutic effectiveness using assays and methods suitable for the condition being treated, which assays will be familiar to those having ordinary skill in the art and are described herein. Pharmacokinetics of a pharmaceutical agent, or one or more métabolites thereof, that is administered to a subject can be monitored by determining the level of the pharmaceutical agent or métabolite in a biological fluid, for example, in the blood, blood fraction, e.g., sérum, and/or in the urine, and/or other biological sample or biological tissue from the subject. Any method practiced in the art and described herein to detect the agent can be used to measure the level of the pharmaceutical agent or métabolite during a treatment course.

[0208] The dose of a pharmaceutical agent described herein for treating a disease or disorder can dépend upon the subject’s condition, that is, stage of the disease, severity of symptoms caused by the disease, general health status, as well as âge, gender, and weight, and other factors apparent to a person skilled in the medical art. Pharmaceutical compositions can be administered in a manner appropriate to the disease to be treated as determined by persons skilled in the medical arts. In addition to the factors described herein and above related to use of pharmaceutical agent

101 for treating a disease or disorder, suitable duration and frequency of administration of the pharmaceutical agent can also be determined or adjusted by such factors as the condition of the patient, the type and severity of the patient’s disease, the particular form of the active ingrédient, and the method of administration. Optimal doses of an agent can generally be determined using experimental models and/or clinical trials. The optimal dose can dépend upon the body mass, weight, or blood volume of the subject. The use of the minimum dose that is sufficient to provide effective therapy is usually preferred. Design and execution of pre-clinical and clinical studies for a pharmaceutical agent, including when administered for prophylactic benefit, described herein are well within the skill of a person skilled in the relevant art. When two or more pharmaceutical agents are administered to treat a disease or disorder, the optimal dose of each pharmaceutical agent can be different, such as less than when either agent is administered alone as a single agent therapy. In certain particular embodiments, two pharmaceutical agents in combination can act synergistically or additively, and either agent can be used in a lesser amount than if administered alone. An amount of a pharmaceutical agent that can be administered per day can be, for example, between about 0.01 mg/kg and 100 mg/kg, e.g., between about 0.1 to l mg/kg, between about 1 to 10 mg/kg, between about 10-50 mg/kg, between about 50-100 mg/kg body weight. In other embodiments, the amount of a pharmaceutical agent that can be administered per day is between about 0.01 mg/kg and 1000 mg/kg, between about 100-500 mg/kg, or between about 500-1000 mg/kg body weight. The optimal dose, per day or per course of treatment, can be different for the disease or disorder to be treated and can also vary with the administrative route and therapeutic regimen.

[0209] Pharmaceutical compositions comprising a pharmaceutical agent can be formulated in a manner appropriate for the delivery method by using techniques routinely practiced in the art. The composition can be in the form of a solid, e.g., tablet, capsule, semi-solid, e.g., gel, liquid, or gas, e.g., aérosol. In other embodiments, the pharmaceutical composition is administered as a bolus infusion.

[0210] Pharmaceutical acceptable excipients are well known in the pharmaceutical art and described, for example, in Rowe et al., Handbook of Pharmaceutical Excipients: A Comprehensive Guide to Uses, Properties, and Safety, 5^th Ed., 2006, and in Remington: The Science and Practice of Pharmacy (Gennaro, 21^st Ed. Mack Pub. Co., Easton, PA (2005)). Exemplary pharmaceutically acceptable excipients include stérile saline and phosphate buffered saline at physiological pH. Preservatives, stabilizers, dyes, buffers, and the like can be provided in the pharmaceutical composition. In addition, antioxidants and suspending agents can also be

102 used. In general, the type of excipient is selected based on the mode of administration, as well as the Chemical composition of the active ingredient(s). Alternatively, compositions described herein can be formulated as a lyophilizate. A composition described herein can be lyophilized or otherwise formulated as a lyophilized product using one or more appropriate excipient solutions for solubilizing and/or diluting the pharmaceutical agent(s) of the composition upon administration. In other embodiments, the pharmaceutical agent can be encapsulated within liposomes using technology known and practiced in the art. In certain particular embodiments, a pharmaceutical agent is not formulated within liposomes for application to a stent that is used for treating highly, though not totally, occluded arteries. Pharmaceutical compositions can be formulated for any appropriate manner of administration described herein and, in the art.

[0211] A pharmaceutical composition, e.g., for oral administration or for injection, infusion, subcutaneous delivery, intramuscular delivery, intraperitoneal delivery or other method, can be in the form of a liquid. A liquid pharmaceutical composition can include, for example, one or more of the following: a stérile diluent such as water, saline solution, preferably physiological saline, Ringer’s solution, isotonie sodium chloride, fixed oils that can serve as the solvent or suspending medium, polyethylene glycols, glycerin, propylene glycol or other solvents; antibacterial agents; antioxidants; chelating agents; buffers and agents for the adjustment of tonicity such as sodium chloride or dextrose. A parentéral composition can be enclosed in ampoules, disposable syringes or multiple dose vials made of glass or plastic. The use of physiological saline is preferred, and an injectable pharmaceutical composition is preferably stérile. In another embodiment, for treatment of an ophthalmological condition or disease, a liquid pharmaceutical composition can be applied to the eye in the form of eye drops. A liquid pharmaceutical composition can be delivered orally.

[0212] For oral formulations, at least one of the pharmaceutical agents described herein can be used alone or in combination with appropriate additives to make tablets, powders, granules or capsules, and if desired, with diluents, buffering agents, moistening agents, preservatives, coloring agents, and flavoring agents. The pharmaceutical agents can be formulated with a buffering agent to provide for protection of the compound from low pH of the gastric environment and/or an enteric coating. A pharmaceutical agent included in a pharmaceutical composition can be formulated for oral delivery with a flavoring agent, e.g., in a liquid, solid or semi-solid formulation and/or with an enteric coating.

[0213] A pharmaceutical composition comprising any one of the pharmaceutical agents described herein can be formulated for sustained or slow release, also called timed release or

103 controlled release. Such compositions can generally be prepared using well known technology and administered by, for example, oral, rectal, intradermal, or subcutaneous implantation, or by implantation at the desired target site. Sustained-release formulations can contain the compound dispersed in a carrier matrix and/or contained within a réservoir surrounded by a rate controlling membrane. Excipients for use within such formulations are biocompatible, and can also be biodégradable; preferably the formulation provides a relatively constant level of active component release. The amount of pharmaceutical agent contained within a sustained release formulation dépends upon the site of implantation, the rate and expected duration of release, and the nature of the condition, disease or disorder to be treated or prevented.

[0214] In certain embodiments, the pharmaceutical compositions comprising a pharmaceutical agent are formulated for transdermal, intradermal, or topical administration. The compositions can be administered using a syringe, bandage, transdermal patch, insert, or syringe-like applicator, as a powder/talc or other solid, liquid, spray, aérosol, ointment, foam, cream, gel, paste. This preferably is in the form of a controlled release formulation or sustained release formulation administered topically or injected directly into the skin adjacent to or within the area to be treated, e.g., intradermally or subcutaneously. The active compositions can also be delivered via iontophoresis. Preservatives can be used to prevent the growth of fungi and other microorganisms. Suitable preservatives include, but are not limited to, benzoic acid, butylparaben, ethyl paraben, methyl paraben, propylparaben, sodium benzoate, sodium propionate, benzalkonium chloride, benzéthonium chloride, benzyl alcohol, cetypyridinium chloride, chlorobutanol, phénol, phenylethyl alcohol, thimerosal, and combinations thereof.

[0215] Pharmaceutical compositions comprising a pharmaceutical agent can be formulated as émulsions for topical application. An émulsion contains one liquid distributed in the body of a second liquid. The émulsion can be an oil-in-water émulsion or a water-in-oil émulsion. Either or both of the oil phase and the aqueous phase can contain one or more surfactants, emulsifiers, émulsion stabilizers, buffers, and other excipients. The oil phase can contain other oily pharmaceutically approved excipients. Suitable surfactants include, but are not limited to, anionic surfactants, non-ionic surfactants, cationic surfactants, and amphoteric surfactants. Compositions for topical application can also include at least one suitable suspending agent, antioxidant, chelating agent, emollient, or humectant.

[0216] Ointments and creams may, for example, be formulated with an aqueous or oily base with the addition of suitable thickening and/or gelling agents. Lotions can be formulated with an aqueous or oily base and will in general also contain one or more emulsifying agents, stabilizing

104 agents, dispersing agents, suspending agents, thickening agents, or coloring agents. Liquid sprays can be delivered from pressurized packs, for example, via a specially shaped closure. Oilin-water émulsions can also be used in the compositions, patches, bandages and articles. These Systems are semisolid émulsions, micro-emulsions, or foam émulsion Systems.

[0217] In some embodiments, the pharmaceutical agent described herein can be formulated as in inhalant. Inhaled methods can deliver médication directly to the airway. The pharmaceutical agent can be formulated as aérosols, microspheres, liposomes, or nanoparticles. The pharmaceutical agent can be formulated with solvents, gases, nitrates, or any combinations thereof. Compositions described herein are optionally formulated for delivery as a liquid aérosol or inhalable dry powder. Liquid aérosol formulations are optionally nebulized predominantly into particle sizes that can be delivered to the terminal and respiratory bronchioles. Liquid aérosol and inhalable dry powder formulations are preferably delivered throughout the endobronchial tree to the terminal bronchioles and eventually to the parenchymal tissue.

[0218] Aerosolized formulations described herein are optionally delivered using an aérosol forming device, such as a jet, vibrating porous plate or ultrasonic nebulizer, preferably selected to allow the formation of aérosol particles having with a mass medium average diameter predominantly between 1 to 5 μ. Further, the formulation preferably has balanced osmolarity ionic strength and chloride concentration, and the smallest aerosolizable volume able to deliver effective dose of the pharmaceutical agent. Additionally, the aerosolized formulation preferably does not impair negatively the functionality of the airways and does not cause undesirable side effects.

[0219] Aerosolization devices suitable for administration of aérosol formulations described herein include, for example, jet, vibrating porous plate, ultrasonic nebulizers and energized dry powder inhalers, that are able to nebulize the formulation into aérosol particle size predominantly in the size range from 1-5 μ. Predominantly in this application means that at least 70% but preferably more than 90% of ail generated aérosol particles are within 1-5 μ range. A jet nebulizer works by air pressure to break a liquid solution into aérosol droplets. Vibrating porous plate nebulizers work by using a sonie vacuum produced by a rapidly vibrating porous plate to extrude a solvent droplet through a porous plate. An ultrasonic nebulizer works by a piezoelectric crystal that shears a liquid into small aérosol droplets. A variety of suitable devices are available, including, for example, AeroNebTM and AeroDoseTM vibrating porous plate nebulizers (AeroGen, Inc., Sunnyvale, California), Sidestream® nebulizers (Medic-Aid Ltd., West Sussex, England), Pari LC® and Pari LC Star® jet nebulizers (Pari Respiratory

105

Equipment, Inc., Richmond, Virginia), and AerosonicTM (DeVilbiss Medizinische Produkte (Deutschland) GmbH, Heiden, Germany) and UltraAire® (Omron Healthcare, Inc., Vemon Hills, Illinois) ultrasonic nebulizers.

[0220] In some embodiments, the pharmaceutical agent(s) can be formulated with oleaginous bases or ointments to form a semisolid composition with a desired shape. In addition to the pharmaceutical agent, these semisolid compositions can contain dissolved and/or suspended bactericidal agents, preservatives and/or a buffer System. A petrolatum component that can be included can be any paraffm ranging in viscosity from minerai oil that incorporâtes isobutylene, colloïdal silica, or stéarate salts to paraffm waxes. Absorption bases can be used with an oleaginous System. Additives can include cholestérol, lanolin (lanolin dérivatives, beeswax, fatty alcohols, wool wax alcohols, low HLB (hydrophobellipophobe balance) emulsifiers, and assorted ionic and nonionic surfactants, singularly or in combination.

[0221] Controlled or sustained release transdermal or topical formulations can be achieved by the addition of time-release additives, such as polymeric structures, matrices, that are available in the art. For example, the compositions can be administered through use of hot-melt extrusion articles, such as bioadhesive hot-melt extruded film. The formulation can comprise a crosslinked polycarboxylic acid polymer formulation. A cross-linking agent can be présent in an amount that provides adéquate adhesion to allow the System to remain attached to target épithélial or endothélial cell surfaces for a sufficient time to allow the desired release of the compound.

[0222] An insert, transdermal patch, bandage or article can comprise a mixture or coating of polymers that provide release of the pharmaceutical agents at a constant rate over a prolonged period of time. In some embodiments, the article, transdermal patch or insert comprises watersoluble pore forming agents, such as polyethylene glycol (PEG) that can be mixed with water insoluble polymers to increase the durability of the insert and to prolong the release of the active ingrédients.

[0223] Transdermal devices (inserts, patches, bandages) can also comprise a water insoluble polymer. Rate controlling polymers can be useful for administration to sites where pH change can be used to effect release. These rate controlling polymers can be applied using a continuous coating film during the process of spraying and drying with the active compound. In one embodiment, the coating formulation is used to coat pellets comprising the active ingrédients that are compressed to form a solid, biodégradable insert.

106

[0224] A polymer formulation can also be utilized to provide controlled or sustained release. Bioadhesive polymers described in the art can be used. By way of example, a sustained-release gel and the compound can be incorporated in a polymeric matrix, such as a hydrophobie polymer matrix. Examples of a polymeric matrix include a microparticle. The microparticles can be microspheres, and the core can be of a different material than the polymeric shell. Alternatively, the polymer can be cast as a thin slab or film, a powder produced by grinding or other standard techniques, or a gel such as a hydrogel. The polymer can also be in the form of a coating or part of a bandage, stent, cathéter, vascular graft, or other device to facilitate delivery of the pharmaceutical agent. The matrices can be formed by solvent évaporation, spray drying, solvent extraction and other methods known to those skilled in the art.

[0225] Kits with unit doses of one or more of the agents described herein, usually in oral or injectable doses, are provided. Such kits can include a container containing the unit dose, an informational package insert describing the use and attendant benefits of the drugs in treating disease, and optionally an appliance or device for delivery of the composition.

D. Methods of Treatment

[0226] Ubiquitin Spécifie Protease l (USPl) is a member of the ubiquitin-specific processing family of proteases. USPl is a deubiquitinating enzyme (“DUB”) and deubiquitinates its substrates involved in key oncogenic pathways to modulate their functions. Among its rôles, USPl can exhibit DNA-mediated activation at the réplication fork, protects the fork, and promote survival in BRCA 1-déficient cells. As loss of both USPl and BRCA1 leads to réplication fork dégradation, inhibition of USPl can selectively decrease the viability, or kill, tumor cells with defects in BRCA defects without affecting the survival of cells with normal BRCA function.

[0227] In the United States (US), it has been estimated that inherited BRCA1 and BRCA2 mutations are présent in 5-10% of breast cancers and 10-15% of ovarian cancers. Breast cancer is the most common cancer in the world and the most common malignancy in women. BRCA1 and BRCA2 can be detected in at least 5% of unselected breast cancer patients and in approximately 30% of patients with a family history of developing breast or ovarian cancer. At présent, treatment options including chemotherapy and immune checkpoint inhibitors are limited for breast cancer patients with germline BRCA mutations, more aggressive progression and higher risk of récurrence. While PARP inhibitors hâve been approved by the US Food and Drug Administration (FDA) as monotherapies for deleterious/suspected deleterious germline BRCAmutated, HER2-negative breast cancer, in some cases, résistance to the PARP inhibitors can be

107 observed to develop quickly in breast cancer patients. Ovarian cancers represent a heterogenous group of solid tumors. On average, one in five ovarian cancer can be associated with germline mutations. Of those ovarian cancers with germline mutations, 65-85% can be associated with germline BRCA mutations. Similar to the breast cancer setting, while the PARP inhibitors can be the first-line maintenance therapy for patients with BRCA-mutated ovarian cancer, those patients can develop résistance to the PARP inhibitors.

[0228] The compounds described herein can be used as inhibitors of USP1. Such compounds can exhibit BRCAl and/or BRCA2 mutant-selective, anti-proliferative activities. The compounds described herein can be used to treat BRCAl and/or BRCA2 mutant or homologous recombination (HRD) positive cancers. The compounds described herein can exhibit antiproliferative activities in cancer cells with a BRCAl and/or BRCA2 mutation, particularly MDA-MB-436 cells. The compounds described herein may not exhibit similar anti-proliferative activities in cancer cells with wild-type BRCA, particularly SNG-M cells. In some embodiments, the compounds described herein can show selectivity for mutant BRCAl and/or BRCA2 over wild-type BRCA of at least 50-fold, 100-fold, 150-fold, 200-fold, 250-fold, 300-fold, 350-fold, 400-fold, 450-fold, 500-fold, 550-fold, 600-fold, or more.

[0229] The compounds described herein can be used in the préparation of médicaments for the prévention or treatment of diseases or conditions. In some embodiments, the compounds described herein are used in a method of modulating USP1 in a subject. In some embodiments, the compounds described herein are used in a method of inhibiting USP1 in subject. In some embodiments, the compounds described herein are used in a method of inhibiting or reducing DNA repair activity modulated by USP1 in a subject. In some embodiments, the compounds herein are used in a method of treating a disease or disorder associated with USP1 in a subject. In some embodiments, the compounds described herein are used in a method of treating a disease or disorder associated with modulation of USP in a subject. In addition, a method for modulating, inhibiting, or treating any of the diseases or conditions described herein in a subject in need of such treatment, involves administration of pharmaceutical compositions containing at least one compound described herein, or a pharmaceutically acceptable sait, pharmaceutically acceptable prodrug, or pharmaceutically acceptable solvaté thereof, in therapeutically effective amounts to said subject.

[0230] The compositions containing the compound(s) described herein can be administered for prophylactic and/or therapeutic treatments. In therapeutic applications, the compositions are administered to a patient already suffering from a disease or condition, in an amount sufficient to

108 cure or at least partially arrest the symptoms of the disease or condition. Amounts effective for this use will dépend on the severity and course of the disease or condition, previous therapy, the patient's health status, weight, response to the drugs, and the judgment of the treating physician. [0231] In prophylactic applications, compositions containing the compounds described herein are administered to a patient susceptible to or otherwise at risk of a particular disease, disorder or condition. Such an amount is defined to be a prophylactically effective amount or dose. In this use, the précisé amounts also dépend on the patient's State of health, weight, and the like. When used in a patient, effective amounts for this use will dépend on the severity, course of the disease, disorder or condition, previous therapy, the patient's health status and response to the drugs, and the judgment of the treating physician.

[0232] In the case wherein the patient’s condition does not improve, upon the doctor’s discrétion the administration of the compounds can be administered chronically, that is, for an extended period of time, including throughout the duration of the patient’s life in order to ameliorate or otherwise control or limit the symptoms of the patient’s disease or condition.

[0233] Once improvement of the patient's conditions has occurred, a maintenance dose is administered if necessary. Subsequently, the dosage or the frequency of administration, or both, can be reduced, as a function of the symptoms, to a level at which the improved disease, disorder or condition is retained. Patients can, however, require intermittent treatment on a long-term basis upon any récurrence of symptoms.

[0234] The amount of a given agent that will correspond to such an amount will vary depending upon factors such as the particular compound, disease or condition and its severity, the identity (e.g., weight) of the subject or host in need of treatment, but can nevertheless be determined in a manner recognized in the field according to the particular circumstances surrounding the case, including, e.g., the spécifie agent being administered, the route of administration, the condition being treated, and the subject or host being treated. In general, however, doses employed for adult human treatment will typically be in the range of about 0.02 - about 5000 mg per day, in some embodiments, about 1 - about 1500 mg per day. The desired dose can conveniently be presented in a single dose or as divided doses administered simultaneously (or over a short period of time) or at appropriate intervals, for example as two, three, four or more sub-doses per day.

[0235] The pharmaceutical composition described herein can be in unit dosage forms suitable for single administration of précisé dosages. In unit dosage form, the formulation is divided into unit doses containing appropriate quantities of one or more compound. The unit dosage can be in

109 the form of a package containing discrète quantities of the formulation. Non-limiting examples are packaged tablets or capsules, and powders in vials or ampoules. Aqueous suspension compositions can be packaged in single-dose non-recloseable containers. Altematively, multipledose recloseable containers can be used, in which case it is typical to include a preservative in the composition. By way of example only, formulations for parentéral injection can be presented in unit dosage form, which include, but are not limited to ampoules, or in multi-dose containers, with an added preservative.

[0236] Toxicity and therapeutic efficacy of such therapeutic regimens can be determined by standard pharmaceutical procedures in cell cultures or experimental animais, including, but not limited to, the détermination of the LD50 (the dose léthal to 50% of the population) and the ED50 (the dose therapeutically effective in 50% of the population). The dose ratio between the toxic and therapeutic effects is the therapeutic index and it can be expressed as the ratio between LD50 and ED50. Compounds exhibiting high therapeutic indices are preferred. The data obtained from cell culture assays and animal studies can be used in formulating a range of dosage for use in human. The dosage of such compounds lies preferably within a range of circulating concentrations that include the ED50 with minimal toxicity. The dosage can vary within this range depending upon the dosage form employed and the route of administration utilized.

[0237] In one aspect, the disclosure provides a method of modulating USP1 in a subject, comprising administering to the subject a compound described herein, or a pharmaceutically acceptable sait or solvaté thereof.

[0238] In one aspect, the disclosure provides a method of inhibiting USP1 in a subject, comprising administering to the subject a compound described herein, or a pharmaceutically acceptable sait or solvaté thereof.

[0239] In one aspect, the disclosure provides a method of inhibiting or reducing DNA repair activity modulated by USP1 in a subject in need thereof, the method comprising administering a therapeutically effective amount of a compound described herein, or a pharmaceutically acceptable sait or solvaté thereof, or a pharmaceutical composition described herein.

[0240] In one aspect, the disclosure provides a method of treating a disease or disorder associated with USP1 in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound described herein, or a pharmaceutically acceptable sait or solvaté thereof, or a pharmaceutical composition of described herein. In some embodiments, the disease or a disorder is cancer.

110

[0241] In one aspect, the disclosure provides a method of treating a disease or disorder associated with modulation of USPl in a subject, comprising administering to the subject a therapeutically effective amount of a compound described herein, or a pharmaceutically acceptable sait or solvaté thereof, or a pharmaceutical composition of described herein. In some embodiments, the disease or disorder is cancer.

[0242] In one aspect, the disclosure provides a method of treating cancer in a subject, comprising administering to the subject in need thereof an effective amount of a compound described herein, or a pharmaceutically acceptable sait or solvaté thereof, or a pharmaceutical composition of described herein.

[0243] In some embodiments, administration of a compound described herein, or a pharmaceutically acceptable sait or solvaté thereof can further comprise combination with other biologically active ingrédients (e.g., a second therapeutic agent). Other biologically active ingrédients can include a second and different antineoplastic agent or a second agent that targets a USPl independent mechanism of DNA repair. In some embodiments, administration of a compound described herein, or a pharmaceutically acceptable sait or solvaté thereof can further comprise combination with a non-drug therapy. Non-drug therapy can include surgery, radiation treatment, etc. Such combination of the compounds described herein, or pharmaceutically acceptable salts or solvatés thereof, with other biological active ingrédients or non-drug thérapies can enhance the effect of the compounds described herein, or pharmaceutically acceptable salts or solvatés thereof. The compounds described herein can be administered simultaneously or sequentially to other biological active ingrédients, but at least two or more compounds or biologically active ingrédients can be administered during a single cycle or course of therapy. In some embodiments, the second therapeutic agent is a poly ADP-ribose polymerase (PARP) inhibitor. In some embodiments, a USPl inhibitor described herein is administered with two PARP inhibitors. In some embodiments, the PARP inhibitor is olaparib, niraparib, talazoparib, or rucaparib.

[0244] In one aspect, the disclosure provides a method of treating cancer in a subject, comprising administering to the subject in need thereof an amount of a compound described herein, or a pharmaceutically acceptable sait or solvaté thereof, or a pharmaceutical composition of described herein. In some embodiments, the cancer is leukemia, acute myeloid leukemia (AML), chronic myeloid leukemia, acute lymphoblastic leukemia (ALL), non-Hodgkin lymphoma (NHL), Hodgkin lymphoma (HL), or multiple myeloma (MM).

111

[0245] In some embodiments, the cancer is a carcinoma, squamous carcinoma, adenocarcinoma, sarcomata, endométrial cancer, breast cancer, ovarian cancer, cervical cancer, fallopian tube cancer, primary peritoneal cancer, colon cancer, colorectal cancer, squamous cell carcinoma of the anogenital région, melanoma, rénal cell carcinoma, lung cancer, non-small cell lung cancer, squamous cell carcinoma of the lung, stomach cancer, bladder cancer, gall bladder cancer, liver cancer, thyroid cancer, laryngeal cancer, salivary gland cancer, esophageal cancer, head and neck cancer, glioblastoma, glioma, squamous cell carcinoma of the head and neck, prostate cancer, pancreatic cancer, mesothelioma, sarcoma, hematological cancer, leukemia, lymphoma, neuroma, and combinations thereof. In some embodiments, a cancer to be treated by the methods of the présent disclosure include, for example, carcinoma, squamous carcinoma (for example, cervical canal, eyelid, tunica conjunctiva, vagina, lung, oral cavity, skin, urinary bladder, tongue, larynx, and gullet), and adenocarcinoma (for example, prostate, small intestine, endometrium, cervical canal, large intestine, lung, pancréas, gullet, rectum, utérus, stomach, mammary gland, and ovary). In some embodiments, a cancer to be treated by the methods of the présent disclosure further include sarcomata (for example, myogénie sarcoma), leukosis, neuroma, melanoma, and lymphoma. In some embodiments, a cancer to be treated by the methods of the présent disclosure is breast cancer. In some embodiments, a cancer to be treated by the methods of treatment of the présent disclosure is triple négative breast cancer (TNBC). In some embodiments, a cancer to be treated by the methods of treatment of the présent disclosure is ovarian cancer. In some embodiments, a cancer to be treated by the methods of treatment of the présent disclosure is colorectal cancer. In some embodiments, the cancer is a homolgous-recombination déficient cancer. In some embodiments, the cancer comprises cancer cells with a mutation in a gene encoding p53.

[0246] In some embodiments, a patient or population of patients to be treated with a pharmaceutical composition of the présent disclosure hâve a solid tumor. In some embodiments, a solid tumor is a melanoma, rénal cell carcinoma, lung cancer, bladder cancer, breast cancer, cervical cancer, colon cancer, gall bladder cancer, laryngeal cancer, liver cancer, thyroid cancer, stomach cancer, salivary gland cancer, prostate cancer, pancreatic cancer, or Merkel cell carcinoma. In some embodiments, a patient or population of patients to be treated with a pharmaceutical composition of the présent disclosure hâve a hematological cancer. In some embodiments, the patient has a hematological cancer such as Diffuse large B cell lymphoma (“DLBCL”), Hodgkin’s lymphoma (“HL”), Non-Hodgkin’s lymphoma (“NHL”), Follicular lymphoma (“FL”), acute myeloid leukemia (“AML”), or Multiple myeloma (“MM”). In some

112 embodiments, a patient or population of patients to be treated having the cancer selected from the group consisting of ovarian cancer, lung cancer and melanoma.

[0247] Spécifie examples of cancers that can be prevented and/or treated in accordance with présent disclosure include, but are not limited to, the following: rénal cancer, kidney cancer, glioblastoma multiforme, metastatic breast cancer; breast carcinoma; breast sarcoma; neurofibroma; neurofibromatosis; pédiatrie tumors; neuroblastoma; malignant melanoma; carcinomas of the epidermis; leukemias such as but not limited to, acute leukemia, acute lymphocytic leukemia, acute myelocytic leukemias such as myeloblastic, promyelocytic, myelomonocytic, monocytic, erythroleukemia leukemias and myclodysplastic syndrome, chronic leukemias such as but not limited to, chronic myelocytic (granulocytic) leukemia, chronic lymphocytic leukemia, hairy cell leukemia; polycythemia vera; lymphomas such as but not limited to Hodgkin’s disease, non-Hodgkin’s disease; multiple myelomas such as but not limited to smoldering multiple myeloma, nonsecretory myeloma, osteosclerotic myeloma, plasma cell leukemia, solitary plasmacytoma and extramedullary plasmacytoma; Waldenstrom’s macroglobulinemia; monoclonal gammopathy of undetermined significance; benign monoclonal gammopathy; heavy chain disease; bone cancer and connective tissue sarcomas such as but not limited to bone sarcoma, myeloma bone disease, multiple myeloma, cholesteatoma-induced bone osteosarcoma, Paget’s disease of bone, osteosarcoma, chondrosarcoma, Ewing’s sarcoma, malignant giant cell tumor, fibrosarcoma of bone, chordoma, periosteal sarcoma, soft-tissue sarcomas, angiosarcoma (hemangiosarcoma), fibrosarcoma, Kaposi’s sarcoma, leiomyosarcoma, liposarcoma, lymphangio sarcoma, neurilemmoma, rhabdomyosarcoma, and synovial sarcoma; brain tumors such as but not limited to, glioma, astrocytoma, brain stem glioma, ependymoma, oligodendroglioma, nonglial tumor, acoustic neurinoma, craniopharyngioma, medulloblastoma, meningioma, pineocytoma, pineoblastoma, and primary brain lymphoma; breast cancer including but not limited to adenocarcinoma, lobular (small cell) carcinoma, intraductal carcinoma, medullary breast cancer, mucinous breast cancer, tubular breast cancer, papillary breast cancer, Paget’s disease (including juvénile Paget’s disease) and inflammatory breast cancer; adrenal cancer such as but not limited to pheochromocytom and adrenocortical carcinoma; thyroid cancer such as but not limited to papillary or follicular thyroid cancer, medullary thyroid cancer and anaplastic thyroid cancer; pancreatic cancer such as but not limited to, insulinoma, gastrinoma, glucagonoma, vipoma, somatostatin-secreting tumor, and carcinoid or islet cell tumor; pituitary cancers such as but limited to Cushing’s disease, prolactin-secreting tumor, acromegaly, and diabètes insipius; eye cancers such as but not limited to ocular

113 melanoma such as iris melanoma, choroidal melanoma, and cilliary body melanoma, and retinoblastoma; vaginal cancers such as squamous cell carcinoma, adenocarcinoma, and melanoma; vulvar cancer such as squamous cell carcinoma, melanoma, adenocarcinoma, basal cell carcinoma, sarcoma, and Paget’s disease; cervical cancers such as but not limited to, squamous cell carcinoma, and adenocarcinoma; uterine cancers such as but not limited to endométrial carcinoma and uterine sarcoma; ovarian cancers such as but not limited to, ovarian épithélial carcinoma, borderline tumor, germ cell tumor, and stromal tumor; cervical carcinoma; esophageal cancers such as but not limited to, squamous cancer, adenocarcinoma, adenoid cyctic carcinoma, mucoepidermoid carcinoma, adenosquamous carcinoma, sarcoma, melanoma, plasmacytoma, verrucous carcinoma, and oat cell (small cell) carcinoma; stomach cancers such as but not limited to, adenocarcinoma, fungating (polypoid), ulcerating, superficial spreading, diffusely spreading, malignant lymphoma, liposarcoma, fibrosarcoma, and carcinosarcoma; colon cancers; colorectal cancer, KRAS mutated colorectal cancer; colon carcinoma; rectal cancers; liver cancers such as but not limited to hepatocellular carcinoma and hepatoblastoma, gallbladder cancers such as adenocarcinoma; cholangiocarcinomas such as but not limited to pappillary, nodular, and diffuse; lung cancers such as KRAS-mutated non-small cell lung cancer, non-small cell lung cancer, squamous cell carcinoma (epidermoid carcinoma), adenocarcinoma, large-cell carcinoma and small-cell lung cancer; lung carcinoma; testicular cancers such as but not limited to germinal tumor, seminoma, anaplastic, classic (typical), spermatocytic, nonseminoma, embryonal carcinoma, teratoma carcinoma, choriocarcinoma (yolk-sac tumor), prostate cancers such as but not limited to, androgen-independent prostate cancer, androgendependent prostate cancer, adenocarcinoma, leiomyosarcoma, and rhabdomyosarcoma; penal cancers; oral cancers such as but not limited to squamous cell carcinoma; basal cancers; salivary gland cancers such as but not limited to adenocarcinoma, mucoepidermoid carcinoma, and adenoidcystic carcinoma; pharynx cancers such as but not limited to squamous cell cancer, and verrucous; skin cancers such as but not limited to, basal cell carcinoma, squamous cell carcinoma and melanoma, superficial spreading melanoma, nodular melanoma, lentigo malignant melanoma, acrallentiginous melanoma; kidney cancers such as but not limited to rénal cell cancer, adenocarcinoma, hypemephroma, fibrosarcoma, transitional cell cancer (rénal pelvis and/or uterer); rénal carcinoma; Wilms’ tumor; bladder cancers such as but not limited to transitional cell carcinoma, squamous cell cancer, adenocarcinoma, carcinosarcoma. In addition, cancers include myxosarcoma, ostéogénie sarcoma, endotheliosarcoma, lymphangioendotheliosarcoma, mesothelioma, synovioma, hemangioblastoma, épithélial

114 carcinoma, cystadenocarcinoma, bronchogenic carcinoma, sweat gland carcinoma, sebaceous gland carcinoma, papillary carcinoma and papillary adenocarcinomas.

[0248] In one aspect, the disclosure provides a method of treating cancer in a subject, comprising administering to the subject in need thereof an effective amount of a compound described herein, or a pharmaceutically acceptable sait or solvaté thereof, or a pharmaceutical composition of described herein. In some embodiments, the cancer can comprise cancer cells with elevated levels of RAD 18 mRNA expression. In some embodiments, elevated levels of RAD 18 are elevated levels of RAD 18 protein. In some embodiments, RAD 18 levels can be detected using quantitative methods like microarray, RNA-Seq, or reverse transcriptase polymerase chain reaction (RT-PCR). In some embodiments, the levels of RAD 18 in a cancer cell can be detected prior to administration of the compounds described herein. In some embodiments, RAD 18 levels can be detected in a cancer sample obtained from a subject. In some embodiments, if a subject has elevated levels of RAD 18, the subject can be treated with the compounds described herein. In some embodiments, elevated levels of RAD 18 in cancer cells indicate that a subject administered the compounds or pharmaceutical compositions described herein is responsive to treatment using the compounds or pharmaceutical compositions described herein. In some embodiments, the compounds described herein are not administered to a subject with elevated levels of RAD 18.

[0249] In some embodiments, the cancer is a DNA damage repair pathway déficient cancer. In some embodiments, the cancer is a PARP inhibitor résistant or refractory BRCA1 or BRCA2mutant cancer. In some embodiments, the cancer comprises cells with elevated levels of RAD 18, where the elevated levels of RAD 18 are at least as high as the RAD 18 mRNA and/or protein levels in ES2 cells or HEP3B217 cells.

[0250] In some embodiments, the cancer is a BRCA1 mutant cancer and/or a BRCA2 mutant cancer. In some embodiments, the cancer is a BRCA1 or BRCA2 wildtype cancer. In some embodiments, the cancer is a BRCA 1-déficient cancer. In some embodiments, the cancer is a BRCA2-deficient cancer. In some embodiments, the cancer that comprises cancer cells with a mutation in a gene that encodes BRCA1 and/or BRCA2. In some embodiments, the cancer is a BRCA1 mutant cancer and BRCA2 déficient cancer. In some embodiments, the cancer is a BRCA1 déficient cancer and BRCA2 mutant cancer. In some embodiments, the cancer comprises cells with elevated levels of RAD 18, where the elevated levels of RAD 18 are at least as high as the RAD 18 mRNA and/or protein levels in ES2 cells or HEP3B217 cells.

115

EXAMPLES

[0251] The following examples are offered to illustrate, but not to limit the claimed disclosure. The following examples further illustrate the disclosure but, of course, should not be construed as in any way limiting its scope.

[0252] The following synthetic schemes are provided for purposes of illustration, not limitation. The following examples illustrate the various methods of making compounds described herein. It is understood that one skilled in the art may be able to make these compounds by similar methods or by combining other methods known to one skilled in the art. It is also understood that one skilled in the art would be able to make, in a similar manner as described below by using the appropriate starting materials and modifying the synthetic route as needed. In general, starting materials and reagents can be obtained from commercial vendors or synthesized according to sources known to those skilled in the art or prepared as described herein.

[0253] The compounds and salts of Formulas (III), (Ilia), (IIIa-1 ), (IIIa-2), (Illb), (IIIb-1 ), (Illb2), (Illd), (IIIc), (IIIc-1 ) or (VI) can be synthesized according to one or more illustrative schemes herein and/or techniques known in the art. Materials used herein are either commercially available or prepared by synthetic methods generally known in the art. These schemes are not limited to the compounds listed in the examples or by any particular substituents, which are employed for illustrative purposes. Although various steps are described and depicted in the synthesis schemes below, the steps in some cases can be performed in a different order than the order shown below. Numberings or R groups in each scheme do not necessarily correspond to that of the daims or other schemes or tables herein.

Examples A _ Biological Assays

[0254] Example Al: Enzymatic Assay

[0255] Human recombinant USP1/UAF1 expressed in baculovirus infected Sf21 cells were used (R&D, E-568-050). Test compound and/or vehicle was incubated with 2 nM of USP1/UAF1 in modified HEPES buffer pH 8.0 for 15 minutes at RT. The reaction was initiated by addition of 500 nM of Ubiquitin Rhodamine 110 (R&D, U-555-050) for kinetic reading. Slope change of fluorescence intensity was read spectrofluorimetrically at 485 nm / 535 nm. Dose response of test compounds or reference compound ML-323 was analyzed by nonlinear régression of GraphPad prism software. Results of the assay are illustrated in Table 2.

[0256] Example A2: MDA-MB-436 Breast Cancer Cell Culture

116

[0257] MDA-MB-436 cells were grown in Leibovitz's L-15 medium with 10 ug/ml insulin, 16 ug/ml glutathione, 10%FBS. Cells were passaged at subconfluence after trypsinization and maintained in incubators at 37°C in a humidified atmosphère with 5% CO2.

[0258] Example A3: MDA-MB-436 Breast Cancer Cell Prolifération Assay

[0259] Cell prolifération was determined using CellTiter-Glo® Luminescent Cell Viability

Assay (Promega, # G7573). MDA-MB-436 cells were seeded in 384-well plates and allowed to attach for 24 h. Compounds were added into 384-well plate by ECHO, and incubated at 37°C in a humidified atmosphère with 5% CO2. After 7 days, CellTiter-Glo was added into 384 well plates, contents were mixed on an orbital shaker at 400g for 2 min before centrifuging the plate 10 for 2 min at 1000 rpm. After incubation at RT for 30 min, luminescence was read on envision.

Results of the assay are illustrated in Table 2.

Examples B _ Chemical Synthesis

[0260] Example Bl: LCMS Method

[0261] The LCMS methods used in the following synthesis procedures are provided in Table 3.

Table 3: LCMS Method codes (Flow expressed in mL/min; column température (T) in °C; Run time in minutes). _________

Method code	Instrument	Column	Mobile phase	Gradient	Flow Column T	<un time
Method A	Shimadzu: LC- MS2020 SPD-M20A and Alltech 3300ELSD	SunFire Cl 8 5pm 50*4.6mm	A: FA 0.1% in water, B: FA 0.1% inCIfCN	70% A for 0.4 min, to 5% A in 1.6 min, 5% A for 0.6 min	2.0 mL/min 40 °C	2.6 min
Method B	Shimadzu: LC- MS2020 SPD-M20A and Alltech 3300ELSD	SunFire Cl 8 5pm 50*4.6mm	A: FA 0.1% in water, B: FA 0.1% inCHaCN	50% A for 0.4 min, to 5% A in 1.6 min, 5% A for 0.6 min	2.0 mL/min 40 °C	2.6 min

[0262] Example B2: Synthesis of Intermediate A

117

[0263] Synthesis of 4-cyclopropyl-6-methoxypyrimidine

[0264] To a solution of 4-chloro-6-methoxypyrimidine (150.00 g, 1.04 mol) in dioxane (1500 mL) and FLO (300 mL) were added cyclopropylboronic acid (178.27 g, 2.08 mol), K2CO3 (286.82 g, 2.08 mol) and Pd(dppf)Ch (75.92 g, 0.10 mol). The reaction was stirred at 100 °C for 16 h under Ar atmosphère. The mixture was diluted with water (500 mL) and extracted with EtOAc (400 mL x 3). The combined organic layers were washed with brine (500 mL), dried over Na2SÛ4, fdtered and concentrated. The residue was purified by column chromatography on silica gel eluted with ΡΕ/EtOAc = 20/1 to afford desired product (82.10 g, 0.55 mol, 52.88 %) as a yellow oil.

LCMS: Rétention time: 1.157min, (M+H)⁺ =151.1, method A.

[0265] Synthesis of 5-bromo-4-cyclopropyl-6-methoxypyrimidine

[0266] To a solution of 4-cyclopropyl-6-methoxypyrimidine (82.00 g, 546.01 mmol) in EtOH (900 mL) was added Br2 (30.85 mL, 600.61 mmol) at 0 °C. The reaction mixture was stirred at room température for 16 h. The suspension was fdtered and washed with MeOH (200 mL). The solid was dried to afford desired product (99.70 g, 435.22 mmol, 80%) as a white solid.

LCMS: Rétention time: 1.707min, (M+H)⁺ =229.1, method A.

[0267] Synthesis of 4-cycIopropyl-6-methoxy-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2yl)pyrimidine (0268] To a solution of 5-bromo-4-cyclopropyl-6-methoxypyrimidine (50.00 g, 218.26 mmol) in DMSO (500 mL) were added 4,4,5,5-tetramethyl-2-(tetramethyl-l,3,2-dioxaborolan-2-yl)-l,3,2dioxaborolane (110.88 g, 436.53 mmol), KOAc (64.26 g, 654.79 mmol) and Pd(dppf)Cb (15.97 g, 21.83 mmol). The reaction was stirred at 100 °C for 16 h under Ar atmosphère. The mixture was diluted with 600 mL of water and extracted with EtOAc (500 mL x 3). The combined

118 organic layers were washed with brine (200 mL x 3), dried over Na₂SO4. filtered and concentrated under vacuum. The residue was purified by column chromatography on silica gel eluted with PE/EtOAc = 10: l to afford desired product (28.00 g, 101.40 mmol, 46%) as a white solid.

LCMS: Rétention time: 1.627min, (M+H)⁺ =277.2, method A.

Ή NMR (400 MHz, DMSO-î/₆) : δ = 8.59 (s, 1 H), 3.86 (s, 3 H), 2.05- 2.02 (m, 1H), 1.32 (s, 12 H), 1.04-1.00 (m, 4 H).

[0269] Example B3: Synthesis of Intermediate B

Intermediate B

[0270] Synthesis of methyl 4-hydrazineylbenzoate hydrochloride

[0271] To a suspension of methyl 4-aminobenzoate (3.00 g, 19.85 mmol) in water (65 mL) and conc. HCl (25 mL) was added a solution of sodium nitrite (1.51 g, 21.83 mmol) in water (15 mL) dropwise at 0 °C. The mixture was kept at 0 °C for 45 minutes and a solution of SnCl₂ (3.76 g, 19.85 mmol) in conc. HCl (10 mL) was added. Once the addition was completed, the température was allowed to slowly increase until achieving room température. The suspension was filtered and the solid was washed with saturated brine (50 mL) and diethyl ether (50 mL). The solid was dried to give desired product (3.02 g, 18.19 mmol, 92%) as a yellow solid.

[0272] LCMS: Rétention time: 0.827 min, (M+H) ⁺ = 167.1, method A.

[0273] Synthesis of methyl 4-(5-methyI-3-(trifluoromethyl)-lH-pyrazol-l-yl)benzoate

[0274] To a solution of methyl 4-hydrazinylbenzoate hydrochloride (1.98 g, 11.92 mmol) and l,l,l-trifhioropentane-2,4-dione (1.84 g, 11.92 mmol) in HFIP (20 mL) was added TEA (2.41 g, 23.84 mmol) at 0 °C slowly. The mixture was warmed up to room température and stirred for 1 h. The reaction mixture was quenched with water (40 mL) and then extracted with DCM (20 mL x 3). The combined organic layer was washed with brine (50 mL), dried over Na₂SO4, filtered and concentrated to give the crude product. The crude product was purified by Silica gel

119 chromatography (eluting with 15% Ethyl Acetate in petroleum ether) to afford desired product (2.2 g, 7.75 mmol, 65% yield) as a white solid.

[0275] LCMS: Rétention time: 1.887 min, (M+H) ⁺ = 285.0, method A.

[0276] Synthesis of (4-(5-methyl-3-(trifluoromethyl)-lH-pyrazol-l-yl)phenyl)methanol [0277] To a solution of methyl 4-[5-methyl-3-(trifluoromethyl)-lH-pyrazol-l-yl] benzoate (1.70 g, 5.99 mmol) in dry THF (20 mL) was added L1AIH4 (0.41 g, 10.8 mmol) at 0 °C. Then the mixture was warmed up to room température and stirred for 2 h. The resulting mixture was diluted with THF (20 mL) and quenched with water (0.5 mL) at °C. After 0.5 h, NaiSCU was added. Then the suspended solution was stirred about 15 minutes and filtered. The filtrate was concentrated to give a residue. The residue was purified by column chromatography on silica gel (eluting with 30% ethyl acetate in petroleum ether) to afford desired product (0.75 g, 2.93 mmol, 49%) as yellow oil.

LCMS: Rétention time: 1.677 min, (M+H) ⁺ = 257.0, method A.

[0278] Synthesis of l-(4-(chloromethyl)phenyl)-5-methyl-3-(trifluoroniethyl)-lH-pyrazole [0279] To a solution of (4-(5-methyl-3-(trifluoromethyl)-lH-pyrazol-l- yl) phenyl) methanol (0.75 g, 2.93 mmol) in DCE (15 mL) was added in SOCh (1.04 g, 8.78 mmol) in one portion. After the reaction was stirred at 50 °C for 0.5 h. The mixture was cooled to 0 °C and quenched with water (10 mL). The resulting solution was neutralized with saturated NaHCCh solution and extracted with DCM (50 mL x 3). The combined organic layer was dried over anhydrous Na2SÛ4, filtered and concentrated to afford desired product (0.5 g, 1.82 mmol, 62%) as brown oil, which was used for the next step directly.

LCMS: Rétention time: 1.917 min, (M+H) ⁺ = 275.0, method A.

[0280] Example B4: Synthesis of Intermediate C

120

1. HCl, NaNO₂, 0°C, 0.5h

2. SnCI₂, 0 °C, 0.5h

Intermediate C-1

Intermediate C-2

AcONa, AcOH, 120 °C, 1h

Intermediate C-4

Pd(OAc)₂, tri-p-tolylphosphine TEA, DMF.100 °C, 6h

[0281] Synthesis of 4-hydrazineylbenzonitrile hydrochloride

[0282] To a cooled (-5 to 0 °C) and stirred suspension of 4-aminobenzonitrile (10.00 g, 84.65 mmol) in conc. HCl (100 mL) was added dropwise aqueous Sodium nitrite (6.42 g, 93.11 mmol) solution. To this cooled (0 °C) solution, Stannous chloride dihydrate (42.09 g, 186.22 mmol) in concentrated hydrochloric acid was added while stirring and maintaining the température below 0 °C. The resulting solution was further stirred for 30 min. White précipitâtes so formed were collected by filtration, and washed with Et₂O (50 mL) to give desired product (10.00 g, 58.96 mmol, 70%) as a pale yellow solid.

‘H NMR: (400 MHz, DMSO-J₆) δ = 10.55 (s, 2 H), 9.12 (s, 1 H), 7.73 (d, J= 8.8 Hz, 2 H), 7.04 (d, J =8.8 Hz, 2 H)

[0283] Synthesis of 4-(5-methyl-3-(trifluoromethyl)-lH-pyrazol-l-yl)benzonitrile

[0284] A mixture of 4-hydrazinylbenzonitrile hydrochloride (10.00 g, 58.96 mmol), 1,1,1trifluoropentane-2,4-dione (15.035 g, 97.63 mmol), sodium acetate (12.32 g, 150.21 mmol) and acetic acid (100 mL) was stirred for 1 h at 120 °C. After cooling to ambient température, the reaction mixture was concentrated under vacuum and purified by silica gel chromatography (PE/EtOAc from 50/1 to 10/1) to afford desired product (6.90 g, 27.5 mmol, 47%) as a pale yellow solid.

Ή NMR: (400 MHz, DMSO-î/₆) δ = 8.08 - 8.06 (m, 2 H), 7.86 - 7.84 (m, 2 H), 6.84 (s, 1 H), 2.44 (s, 3 H)

[0285] Synthesis of (4-(5-methyl-3-(trifluoromethyl)-lH-pyrazoI-l-yI)phenyl)methanamine

121

[0286] To a mixture of 4-(5-methyl-3-(trifluoromethyl)-lH-pyrazol-l-yl)benzonitrile (500 mg, 1.99 mmol) in MeOH (15 mL) and THF (5 mL) was added ammonium hydroxide (l mL) and then excess amount of moist Raney Ni was added. Under a hydrogen pressure (0.5 Mpa), the mixture was stirred at room température for 2 h. The mixture was filtered and concentrated to give crude product as a yellow oil, which was used in next step directly.

LCMS: Rétention time: 0.813 min, (M+H) + = 256.0, method A.

[0287] Synthesis of 2-chloro-5-iodo-N-(4-(5-methyl-3-(trifluoromethyl)-lH-pyrazoI-lyl)benzyl)pyrimidin-4-amine

[0288] To a solution of 2,4-dichloro-5-iodopyrimidine (547 mg, 1.99 mmol) and (4-(5-methyl-3(trifluoromethyl)-lH-pyrazol-l-yl)phenyl)methanamine (508 mg, 1.99 mmol) in EtOH (5 mL) was added N,N-diisopropylethylamine (0.99 mL, 5.97 mmol) at 0 °C. The mixture was stirred at room température for 16 h. The mixture was diluted with water (20 mL) and extracted with EtOAc (15 mL x 3). The combined organic fractions were washed with brine (20 mL), dried over Na2SÛ4, filtered and concentrated. The residue was purified by pre-TLC (PE/EA = 3/1) to give desired product (600 mg, 1.21 mmol, 61%) as a white solid.

LCMS: Rétention time: 1.853 min, (M+H)⁺ = 494.0, method A.

[0289] Synthesis of methyl (E)-3-(2-chloro-4-((4-(5-methyl-3-(trifluoromethyl)-lH-pyrazoll-yl)benzyl)amino)pyrimidin-5-yl)acrylate

[0290] A mixture of methyl prop-2-enoate (288 mg, 3.34 mmol), 2-chloro-5-iodo-N-(4-(5methyl-3-(trifluoromethyl)-lH-pyrazol-l-yl)benzyl)pyrimidin-4-amine (550 mg, 1.11 mmol), trip-Tolylphosphine (102 mg, 0.33 mmol), Pd(OAc)2 (25 mg, 0.11 mmol) and TEA (0.47 mL, 3.34 mmol) in DMF (10 mL) was stirred at 100 °C for 6 h. LCMS showed desired product was detected. The mixture was diluted with water (20 mL) and extracted with EtOAc (15 mL x 3). The combined organic fractions were washed with brine (20 mL), dried over Na2SÛ4, filtered and concentrated. The residue was purified by column chromatography on silica gel (PE/EA from 10/1 to 3/1) to give desired product (410 mg, 0.91 mmol, 82%) as a yellow solid.

LCMS: Rétention time: 1.784 min, (M+H)⁺ = 452.1, method A.

[0291] Example B5: Synthesis of Intermediate D

Br F

2) NH₄OH, MeOH, rt, 16h Intermediate D

[0292] 4-(4-(trifluoromethyl)-lH-imidazol-2-yI)benzonitrile

122

[0293] To a solution of 3, 3-dibromo-l, 1, 1-trifluoropropan-2-one (12.859 g, 47.66 mmol) in H2O (30 mL) was added NaOAc (7.82 g, 95.33 mmol). The mixture was stirred at 100 °C for Ih and then cooled to room température. A mixture of 4-formylbenzonitrile (6.243 g, 47.66 mmol) in NH4OH (24.48 mL, 190.65 mmol) and MeOH (50 mL) was added and the resulting mixture was stirred at room température for 16 h. The mixture was concentrated to remove MeOH, diluted with water (100 mL) and extracted with EtOAc (150 mL x 3). The combined organic fractions were washed with brine (50mL), dried over Na2SO4, filtered and concentrated. The residue was purified by column chromatography on silica gel (eluting with ΡΕ/EtOAc from 100/0 to 1/1) to afford desired product (10.00 g, 42.16 mmol, 88 %) as a yellow solid.

LCMS: mass calcd. For C11H6F3N3 237.05, m/z found 238.0 (M+H)⁺.

[0294] Example B6: Synthesis of Intermediate E:

^BrH° Br cf3 ^{BH3 Me}2^S °\\ ZZX, DCM, DMP °\\ /Xx 1. NaOAc, H2O, 100°C, 1h —O OH 0°Ctort, 1h—o OH _{rtj 0}.5h — O H 2. MeOH, NH₄OH, rt, 16h

Intermediate E-1 Intermediate E-2

Intermediate E-3

100°C, 3h

H₂SO₄

Dioxane, H₂O

Intermediate E

[0295] Methyl 4-(hydroxymethyl)cubane-l-carboxylate

[0296] To a solution of 4-(methoxycarbonyl)cubane-l-carboxylic acid (1.80 g, 8.73 mmol) in THF (20 mL) was added (methylsulfanyl)methane borane (5.238 mL, 2 mol/L, 10.476 mmol) at 0 °C under Ar. The mixture was stirred at rt for Ih. The mixture was quenched with water (30 mL) at 0 °C and concentrated to removed THF. Then the mixture was extracted with DCM (30 mL x 3) and the combined organic fractions were washed with brine (15 mL), dried over Na₂SO4, filtered and concentrated to give desired product (1.60 g, 8.33 mmol, 95%) as a white solid.

Ή NMR: (400 MHz, DMSO-d₆) δ = 4.53 (t, J= 5.4 Hz, 1 H), 4.04 (t, J =4.8 Hz, 3 H), 3.79 (t, J = 4.8 Hz, 3 H), 3.61 (s, 3 H), 3.51 (d, J =5.6 Hz, 2 H)

[0297] methyl 4-formylcubane-l-carboxylate

[0298] To a solution of methyl 4-(hydroxymethyl)cubane-l-carboxylate (1.68 g, 8.74 mmol) in DCM (30 mL) was added Dess-Martin Periodinane (4.08 g, 9.61 mmol, 1.1 eq.) at rt. The mixture was stirred at rt for 0.5 h. To the mixture was added sat. NaHCCh (15 mL) and Na2SOs solution (15 mL). After stirred for 10 min, the mixture was extracted with DCM (10 mL x 6).

123

The combined organic fractions were dried over Na₂SÛ4, filtered and concentrated to give desired product (l .20 g, 6.31 mmol, 72%) as a white solid.

[0299] 4-(4-(trifluoromethyl)-lH-imidazol-2-yl)cubane-l-carboxamide

[0300] A mixture of 3,3-dibromo-1,1,1 -trifluoropropan-2-one (2.212 g, 8.20 mmol) and sodium acetate (1.04 g, 12.62 mmol) in water (5 mL) was stirred at 100 °C for lh and then cooled to rt. A mixture of methyl 4-formylcubane-l-carboxylate (1.20 g, 6.31 mmol), MeOH (20 mL), and Ammonium hydroxide (10 mL) was added, and the resulting mixture was stirred at 25 °C for 16 h. The reaction mixture was concentrated to give crude product (1.77 g) as a white solid.

LCMS: Rétention time: 0.891 min, (M+H)⁺ = 282.1, method A.

[0301] 4-(4-(trifluoromethyl)-lH-imidazol-2-yl)cubane-l-carboxylic acid

[0302] A solution of 4-(4-(trifluoromethyl)-lH-imidazol-2-yl)cubane-l-carboxamide (1.77 g, 6.30 mmol) in dioxane (10 mL) was added to 3N H₂SÛ4 (6 mL). The mixture was stirred at 100 °C for 3 h. Then the mixture was concentrated and dissolved in water (15 mL). The solution was basified with 2N NaOH until pH = 7. The mixture was concentrated and dissolved in DCM/MeOH (10/1). After stirred for 0.5 h, the suspension was filtered. The filtrate was concentrated to give desired product (1.50 g, 5.32 mmol, yield 84%) as a white solid.

LCMS: Rétention time: 1.350 min, (M+H)⁺ = 283.1, method A.

[0303] Example B7: Synthesis of Intermediate F:

/1 ⁰

N | NIS N 'ηΚ TEA,tris(4-methylphenyl)phosphine, Pd(OAc)_2t

Cl N NH₂ AcOH, 80 °C, 3h Cl n' NH_{2 nM}Finn°r. 4 h

Intermediate F-1

Intermediate F-3

Intermediate F

[0304] 2-chloro-5-iodopyrimidin-4-amine

124

[0305] To a solution of 2-chloropyrimidin-4-amine (8.00 g, 61.75 mmol) in AcOH (80 mL) was added NIS (16.67 g, 74.10 mmol) and the mixture was stirred at 80 °C for 3h. The solution was concentrated under reduced pressure. The residue was partitioned between CH2Q2 (2000 mL) and 5% aqueous Na2S2Û3 (1000 mL). The separated organic layer was washed with brine (1000 mL), dried over Na2SÛ4, filtered and concentrated. The residue was recrystallized from Et2Û (300 mL) to give desired product (6.00 g, 23.49 mmol, 38%) as a white solid.

LCMS: Rétention time: 1.200 min, (M+H) + = 255.8, method A.

[0306] methyl (E)-3-(4-amino-2-chloropyrimidin-5-yl)acrylate

[0307] A mixture of methyl prop-2-enoate (7.40 mL, 82.18 mmol), 2-chloro-5-iodopyrimidin-4amine (3.00 g, 11.74 mmol), tris(4-methylphenyl)phosphine (1.07 g, 3.52 mmol), Pd(OAc)2 (0.26 g, 1.17 mmol) and TEA (4.90 mL, 35.23 mmol) in DMF (30 mL) was stirred at 100 °C for 4 h under Ar. The mixture was diluted with water (20 mL) and extracted with EtOAc (30 mL x 3). The combined organic fractions were washed with brine (20 mL x 3), dried over Na2SO4, filtered and concentrated. The residue was recrystallized with EtOAc/PE (1/2, 50 mL) to give desired product (1.70 g, 7.96 mmol, 68%) as a yellow solid.

LCMS: Rétention time: 1.167 min, (M+H) ⁺ = 214.1, method A.

[0308] methyl (E)-3-(4-amino-4'-cyclopropyl-6’-methoxy-[2,5’-bipyrimidin]-5-yl)acrylate [0309] A mixture of methyl (2E)-3-(4-amino-2-chloropyrimidin-5-yl)prop-2-enoate (500 mg, 2.34 mmol), 4-cyclopropyl-6-methoxy-5-(tetramethyl-l,3,2-dioxaborolan-2-yl)pyrimidine (775 mg, 2.81 mmol), K.2CO3 (647 mg, 4.68 mmol) and Pd(PPh3)4 (541 mg, 0.47 mmol) in dioxane (10 mL) and H2O (1 mL) was stirred at 100 °C under Ar for 4h. The mixture was diluted with water (100 mL) and extracted with EtOAc (80 mL x 5). The combined organic fractions were washed with brine (20 mL x 3), dried over Na2SÛ4, filtered and concentrated. The residue was purified by column chromatography on silica gel eluting with ΡΕ/EtOAc (from 100/1 to 1/1) to give desired product (348 mg, 1.06 mmol, 45%) as a yellow solid.

LCMS: Rétention time: 1.050 min, (M+H) ⁺ = 328.2, method A.

[0310] 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)pyrido[2,3-d]pyrimidin-7(8H)-one

[0311] To a solution of methyl (2E)-3-[4-amino-2-(4-cyclopropyl-6-methoxypyrimidin-5-yl) pyrimidin-5-yl] prop-2-enoate (348 mg, 1.06 mmol) in MeOH (5 mL) was added NaH (55 mg, 1.38 mmol) (60% dispersion in minerai oil) at 0 °C. The mixture was stirred at 70 °C for 1.5 h. The mixture was concentrated and then diluted with water (30 mL), extracted with EtOAc (20 mL x 3). The combined organic fractions were washed with brine (30 mL), dried over Na2SO4, filtered and concentrated. The residue was purified by column chromatography eluted with

125

DCM/MeOH (from 100/1 to 30/1) to give desired product (144 mg, 0.49 mmol, 46%) as a white solid.

LCMS: Rétention time: 1.417 min, (M+H) ⁺ = 296.1, method A.

[0312] Example B8: Synthesis of Intermediate G:

Intermediate D

NaH, DMF

0°C 30min to rt, 16h

Raney Ni, H₂

NH₄OH, THF, MeOH, rt, 2h

Intermediate G

[0313] 4-(l-isopropyl-4-(trifluoromethyI)-lH-imidazol-2-yl)benzonitrile

[0314] To a solution of 4-[4-(trifluoromethyl)-lH-imidazol-2-yl] benzonitrile (3.00 g, 12.65 mmol) in DMF (30 mL) was added NaH (0.36 g, 9.00 mmol, 60% dispersion in minerai oil) at 0 °C. After stirring for 30 min, 2-iodopropane (2.15 g, 12.65 mmol) was added to the mixture. The mixture was stirred at room température for 16 h. Then the mixture was diluted with water (100 mL) at 0 °C and extracted with EtOAc (150mL x 3). The combined organic fractions were washed with brine (50mL) and dried over Na₂SO4, filtered and concentrated. The residue was purified by column chromatography on silica gel (eluting with PE/EtOAc from 100/0 to 6/1) to afford desired product (610 mg, 2.18 mmol, 17%) as a yellow solid.

LCMS: mass calcd. For C14H12F3N3 279.1, m/z found 280.0 (M+H) ⁺.

[0315] (4-(l-isopropyl-4-(trifluoromethyI)-lH-imidazol-2-yl)phenyl)methanamine

[0316] To a mixture of 4-[l-(propan-2-yl)-4-(trifluoromethyl)-lH-imidazol-2-yl]benzonitrile (540 mg, 1.93 mmol) in MeOH (15 mL) and THF (5 mL) was added Ammonium hydroxide (4 mL). Then excess amount of moist Raney Ni was added. Under a hydrogen pressure (0.5 Mpa), the mixture was stirred at room température for 2 h. Then the mixture was filtered and concentrated under vacuum. The residue was purified by column chromatography on silica gel (eluting with DCM/MeOH from 100/0 to 10/1) to give desired product (450 mg, 1.59 mmol, 82%) as a yellow oil.

LCMS: mass calcd. For C14H16F3N3 283.1, m/z found 284.2 (M+H)⁺.

[0317] Example B9: Synthesis of Intermediate H:

_N,, .O BBr, £V^OH + f j⁰J CI'^N^x^^xNH2 DCM, rt, 16h ^{Cl N NH}2 Cs2CO₃, DMF Cl N rt,4h

Intermediate H-1

Intermediate H

126

[0318] 4-amino-2-chloropyrimidin-5-ol

[0319] BBr₃ (3.10 g, 12.53 mmol) was added to the solution of 2-chloro-5-methoxypyrimidin-4amine (1.00 g, 6.25 mmol) in DCM (10 mL) at 0 °C. The mixture was stirred at rt for 16 h. After MeOH (20 mL) was added dropwise at 0 °C, the mixture was concentrated to afford the crude as a black solid without further purification.

LCMS: Rétention time: 1.034 min, (M-H) ’ =144.0, method A.

[0320] 2-chloro-7,8-dihydro-6H-pyrimido[5,4-b][l,4]oxazine

[0321] To a solution of 4-amino-2-chloropyrimidin-5-ol (400 mg, 2.75 mmol) in DMF (10 mL) were added 1,2-dibromoethane (517 mg, 2.75 mmol) and CS2CO3 (2686 mg, 8.24 mmol). The mixture was stirred at rt for 4 h. The mixture was diluted with water (15 mL) and extracted with EtOAc (15 mL x 3). The combined organic phases were washed with brine (15 mL), dried over Na2SÜ4, filtered and concentrated. The residue was purified by column chromatography (eluting with PE/EtOAc from 100/0 to 1/1) to afford desired product (300 mg, 1.75 mmol, 64%) as a white solid.

LCMS: Rétention time: 0.837min, (M+H)⁺ =172.1, method A.

[0322] Example B10: Synthesis of Compound 1

[0323] methyl (E)-3-(4’-cyclopropyl-6'-methoxy-4-((4-(5-methyl-3-(trifluoromethyl)-lHpyrazol-l-yl)benzyl)amino)-[2,5’-bipyrimidin]-5-yl)acrylate

[0324] A mixture of methyl (E)-3-(2-chloro-4-((4-(5-methyl-3-(trifluoromethyl)-lH-pyrazol-lyl)benzyl)amino)pyrimidin-5-yl)acrylate (150 mg, 0.33 mmol), 4-cyclopropyl-6-methoxy-5(tetramethyl-l,3,2-dioxaborolan-2-yl)pyrimidine (138 mg, 0.50 mmol), cataCXium A Pd G3 (48 mg, 0.07 mmol) and K3PO4 (211 mg, 1.00 mmol) in THF (10 mLjÆEO (2 mL) was stirred at 70 °C for 24 h. The mixture was diluted with water (20 mL) and extracted with EtOAc (15 mL x 3).

127

The combined organic fractions were washed with brine (20 mL), dried over Na₂SÛ4, filtered and concentrated. The residue was purified by pre-TLC (PE/EtOAc = 1/1) to give desired product (85 mg, 0.15 mmol, 46%) as a white solid.

LCMS: Rétention time: 1.668 min, (M+H) ⁺ = 566.2, method A.

[0325] 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-8-(4-(5-methyl-3-(trifluoromethyl)-lH pyrazol-l-yl)benzyl)pyrido[2,3-d]pyrimidin-7(8H)-one

[0326] To a solution of methyl (E)-3-(4'-cyclopropyl-6'-methoxy-4-((4-(5-methyl-3(trifluoromethyl)-lH-pyrazol-l-yl)benzyl)amino)-[2,5'-bipyrimidin]-5-yl)acrylate (85 mg, 0.15 mmol) in MeOH (5 mL) was added NaH (7.80 mg, 60 % dispersion in minerai oil, 0.19 mmol).

The mixture was stirred at 70 °C for 1.5 h. The mixture was concentrated and dissolved in water (15 mL). The solution was extracted with EtOAc (15 mL x 3). The combined organic fractions were washed brine (20 mL), dried over Na₂SC>4, filtered and concentrated. The residue was purified by pre-TLC (PE/EtOAc = 1/1) to give desired product (23.00 mg, 0.043 mmol, 29%). LCMS: Rétention time: 1.763 min, (M+H) ⁺ = 534.2, method A.

Ή NMR: (400 MHz, DMSO-î/₆) δ = 9.29 (s, 1 H), 8.69 (s, 1 H), 8.16 (d, J = 9.6 Hz, 1 H), 7.50 7.43 (m, 4 H), 6.91 (d, J = 9.6 Hz, 1 H), 6.74 (s, 1 H), 5.58 (s, 2 H), 3.83 (s, 3 H), 2.30 (s, 3 H), 1.74 - 1.70 (m, 1 H), 1.02 - 1.00 (m, 2 H), 0.79 - 0.76 (m, 2 H)

[0327] Example Bll: Synthesis of Compound 2

128

HO' _______MsCI_______ pyridine, DCM, rt, 16 h

HCI/MeOH, 100 °C, 16 h

(BPin)_; Pd(dppf)CI₂, KOAc

DMSO, 100 °C, 2 h, Microwave

NaH, DMF, 60 °C, 16h

[0328] 2-methoxyethyl methanesulfonate

[0329] To a mixture of 2-methoxyethan-l-ol (1 g, 13.14 mmol) and pyridine (0.50 mL) in DCM (15 mL) was added MsCI (1.22 mL, 15.77 mmol) at 0 °C. The mixture was stirred at rt for 16h.

The mixture was diluted with water (15 mL) and extracted with DCM (15 mL x 3). The combined organic phases were washed with brine (15 mL), dried over Na₂SÛ4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (ΡΕ/EtOAc = 20/1) to give desired product (1800 mg, 11.67 mmol, 89%) as a colorless oil. Ή NMR (400 MHz, CDC1₃) δ = 4.38 - 4.35 (m, 2 H), 3.68 - 3.65 (m, 2 H), 3.41 (s, 3 H), 3.06 (s, 10 3 H)

[0330] 5-bromo-6-cyclopropylpyrimidin-4-ol

[0331] A solution of 5-bromo-4-cyclopropyl-6-methoxypyrimidine (2.00 g, 8.73 mmol) in HCI/MeOH (3M) (20 mL) was stirred at 100 °C for 16 hours. The mixture was concentrated under reduced pressure. The residue was dissolved in EtOAc (100 mL) and washed with aq.

NaHCOs (20 mL). The organic phases were washed with brine (20 mL), dried over Na₂SÜ4, filtered and concentrated under reduced pressure to give desired product (1250 mg, 5.81 mmol, 67%) as a white solid, which was used in next step directly.

LCMS: Rétention time: 0.831min, (M+H) ⁺ =215.1, method B.

129

[0332] 5-bromo-4-cyclopropyl-6-(2-methoxyethoxy)pyrimidine

[0333] To a solution of 5-bromo-6-cyclopropylpyrimidin-4-ol (1450 mg, 6.74 mmol) in DMF (20 mL) was added NaH (405 mg, 10.11 mmol, 60% dispersion in minerai oil) at 0 °C. The mixture was stirred at rt for 0.5 h. 2-methoxyethyl methanesulfonate (1248 mg, 8.09 mmol) was added to the mixture. The mixture was stirred at 60 °C for 16 hours. The mixture was diluted with water (20 mL) and extracted with EtOAc (20 mL x 3). The combined organic phases were washed with brine (20 mL), dried over Na?SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (PE/EtOAc = 5/1) to give desired product (246 mg, 0.90 mmol, 13%) as a colorless oil.

LCMS: Rétention time: 1.647min, (M+H)⁺ =273.1, method A.

[0334] 4-cyclopropyl-6-(2-methoxyethoxy)-5-(4,4,5,5-tetramethyl-l,3,2-dioxaboroIan-2yl)pyrimidine

[0335] A mixture of 5-bromo-4-cyclopropyl-6-(2-methoxyethoxy)pyrimidine (224 mg, 0.82 mmol), 4,4,5,5-tetramethyl-2-(tetramethyl-l,3,2-dioxaborolan-2-yl)-l,3,2-dioxaborolane (417 mg, 1.64 mmol), Pd(dppf)Ch (60 mg, 0.08 mmol) and KOAc (241 mg, 2.46 mmol) in DMSO (5 mL) was stirred at 100 °C using microwave under Ar for 2 hours. The mixture was diluted with water (10 mL) and extracted with EtOAc (10 mL x 3). The combined organic phases were washed with brine (10 mL), dried over Na₂SO4, filtered and concentrated under reduced pressure. The residue was purified by prep-TLC (PE/EtOAc = 10/1) to give desired product (171 mg, 0.53 mmol, 65%) as a colorless oil.

LCMS: Rétention time: 1.347min, (M+H)⁺ =321.2, method B.

[0336] methyl (E)-3-(4’-cycIopropyl-6’-(2-methoxyethoxy)-4-((4-(5-methyl-3(trifluoromethyl)-lH-pyrazol-l-yl)benzyl)amino)-[2,5’-bipyrimidin]-5-yl)acrylate

[0337] A mixture of methyl (2E)-3-{2-chloro-4-[({4-[5-methyl-3-(trifluoromethyl)-lH-pyrazoll-yl]phenyl}methyl)amino]pyrimidin-5-yl}prop-2-enoate (181 mg, 0.40 mmol), 4-cyclopropyl6-(2-methoxyethoxy)-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyrimidine (154 mg, 0.48 mmol), Pd(PPh₃)4 (93 mg, 0.08 mmol) and K2CO₃ (138 mg, 1.00 mmol) in dioxane (3 mL)/Water (0.40 mL) was stirred at 100 °C for 4.5 h under Ar. The mixture was diluted with water (10 mL) and extracted with EtOAc (10 mL x 3). The combined organic phases were washed with brine (10 mL), dried over Na2SÛ4, filtered and concentrated under reduced pressure. The residue was purified by prep-TLC (PE/EtOAc = 1/1) to give desired product (159 mg, 0.26 mmol, 65%) as a yellow solid.

LCMS: Rétention time: 1.337min, (M+H)⁺ =610.3, method B.

130

[0338] 2-(4-cyclopropyl-6-(2-methoxyethoxy)pyrimidin-5-yl)-8-(4-(5-methyl-3(trifluoromethyl)-lH-pyrazoI-l-yl)benzyl)pyrido[2,3-d]pyrimidin-7(8H)-one

[0339] To a solution of methyl (2E)-3-{2-[4-cyclopropyl-6-(2-methoxyethoxy)pyrimidin-5-yl]4-[({4-[5-methyl-3-(trifluoromethyl)-lH-pyrazol-l-yl]phenyl}methyl)amino]pyrimidin-5yl}prop-2-enoate (139 mg, 0.228 mmol) in MeOH (4 mL) was added NaH (12 mg, 0.30 mmol, 60% dispersion in minerai oil)) at 0 °C. The mixture was stirred at 70 °C for 1.5 h. Then the mixture was diluted with water (10 mL) and extracted with EtOAc (10 mL x 3). The combined organic phases were washed with brine (10 mL), dried over NaiSCL, filtered and concentrated under reduced pressure. The residue was purified by prep-TLC (PE/EtOAc = 1/3) to give desired product (14.26 mg, 0.0247 mmol, 11%).

LCMS: Rétention time: 1.487min, (M+H) ⁺ =578.3, method B.

Ή NMR (400 MHz, DMSO-t/₆) δ 9.30 (s, 1 H), 8.67 (s, 1 H), 8.18 (d, J = 9.6Hz, 1 H), 7.49 7.41 (m, 4 H), 6.91 (d, J= 9.6 Hz, 1 H), 6.73 (s, 1 H), 5.60 (s, 2 H), 4.42 (t, J= 4.6 Hz, 2 H), 3.47 (t, J =4.8 Hz, 2 H), 3.10 (s, 3 H), 2.30 (s, 3 H), 1.75-1.69 (m, 1 H), 1.03-1.00 (m, 2 H), 0.79-0.75 (m, 2 H).

[0340] Example B12: Synthesis of Compound 3 o o

Cl

I

DIPEA

EtOH. rt, 16h

[0341 ] 2-fluoro-4-hydrazineylbenzonitrile

[0342] To a solution of 2, 4-difluorobenzonitrile (5 g, 35.95 mmol) in EtOH (50 mL) was added hydrazine hydrate (2.16 g, 43.13 mmol). The mixture was stirred at 80 °C for 2 h. Then the mixture was diluted with water (200 mL) and extracted with EtOAc (50 mL x 3). The combined organic fractions were washed with brine (30 mL), dried over Na2SÛ4, filtered and concentrated.

131

The residue was purified by column chromatography on silica gel eluting with PE/EtOAc from 100/1 to 5/1 to give desired product (2.50 g, 16.54 mmol, 46%) as a yellow solid.

LCMS: Rétention time: 1.217 min, (M+H) ⁺ = 152.1, method A.

[0343] 2-fluoro-4-(5-methyl-3-(trifluoromethyl)-lH-pyrazol-l-yl)benzonitrile

[0344] To a solution of 2-fluoro-4-hydrazinylbenzonitrile (2.00 g, 13.23 mmol) in HFIP (15 mL) were added 1,1, 1-trifluoropentane-2, 4-dione (2.037 g, 13.23 mmol) and TEA (3.68 mL, 26.47 mmol) at 0 °C under Ar. The mixture was stirred at 0 °C for 2 h. Then the mixture was diluted with water (20 mL) and extracted with EtOAc (20 mL x 3). The combined organic fractions were washed with brine (15 mL), dried over Na₂SO4, filtered and concentrated. The residue was purified by column chromatography on silica gel eluting with PE/EtOAc from 100/1 to 3/1 to give desired product (1.40 g, 5.20 mmol, 39%) as a yellow solid.

LCMS: Rétention time: 1.787 min, (M+H) ⁺ = 270.1, method A.

[0345] (2-fluoro-4-(5-methyl-3-(trifluoromethyl)-lH-pyrazol-l-yl)phenyl)methanamine

To a mixture of 2-fluoro-4-[5-methyl-3-(trifluoromethyl)-lH-pyrazol-l-yl] benzonitrile (500 mg, 1.86 mmol) in MeOH (15 mL) and THF (5 mL) were added Ammonium hydroxide (1 mL) and excess amount of moist Raney Ni. Under a hydrogen pressure (0.5 Mpa), the mixture was stirred at room température for 2 h. Then the mixture was filtered and concentrated to give desired product (500 mg, 1.83 mmol, 98%) as a yellow oil, which was used directly.

LCMS: Rétention time: 0.937 min, (M+H) + = 274.2, method A.

[0346] 2-chloro-N-(2-fluoro-4-(5-methyl-3-(trifluoromethyl)-lH-pyrazol-l-yl)benzyl)-5iodopyrimidin-4-aniine

[0347] To a solution of 2, 4-dichloro-5-iodopyrimidine (511 mg, 1.86 mmol) and (2-fluoro-4-(5methyl-3-(trifluoromethyl)-lH-pyrazol-l-yl)phenyl)methanamine (507 mg, 1.86 mmol) in EtOH (10 mL) was added DIPEA (0.921 mL, 5.57 mmol) at 0 °C. The mixture was stirred at rt for 16 h. Then the mixture was diluted with water (30 mL) and extracted with EtOAc (20 mL x 3). The combined organic fractions were washed with brine (25 mL), dried over Na₂SCU, filtered and concentrated. The residue was purified by column chromatography eluted with PE/EtOAc from 100/1 to 5/1 to give desired product (320 mg, 0.625 mmol, 34%) as a yellow solid.

LCMS: Rétention time:2.000 min, (M+H)⁺ = 511.6, method A.

[0348] methyl (E)-3-(2-chIoro-4-((2-fluoro-4-(5-methyl-3-(trifluoromethyl)-lH-pyrazol-lyl)benzyl)amino)pyrimidin-5-yl)acrylate

[0349] A mixture of methyl prop-2-enoate (338 mg, 3.93 mmol), 2-chloro-N-(2-fluoro-4-(5methyl-3-(trifluoromethyl)-lH-pyrazol-l-yl)benzyl)-5-iodopyrimidin-4-amine (550 mg, 1.075

132 mmol), tri-p-tolylphosphine (120 mg, 0.39 mmol), Pd(OAc)2 (29 mg, 0.13 mmol) and TEA (0.55 mL, 3.93 mmol) in DMF (10 mL) was stirred at 100 °C for 4 h. Then the mixture was cooled, diluted with water (100 mL) and extracted with EtOAc (50 mL x 3). The combined organic fractions were washed with brine (30 mL), dried over Na₂SÛ4, filtered and concentrated. The residue was purified by column chromatography eluted with ΡΕ/EtOAc from 10/1 to 3/1 to give desired product (466 mg, 0.99 mmol, 92%) as a yellow solid.

LCMS: Rétention time: 1.897 min, (M+H)⁺ = 470.0, method A.

[0350] methyl (E)-3-(4'-cyclopropyl-4-((2-fluoro-4-(5-methyl-3-(trifluoromethyl)-lHpyrazoI-l-yl)benzyI)amino)-6'-methoxy-[2,5'-bipyrimidin]-5-yl)acrylate

[0351] A mixture of methyl (E)-3-(2-chloro-4-((2-fluoro-4-(5-methyl-3-(trifluoromethyl)-lHpyrazol-l-yl)benzyl)amino)pyrimidin-5-yl)acrylate (200 mg, 0.43 mmol), 4-cyclopropyl-6methoxy-5-(tetramethyl-l,3,2-dioxaborolan-2-yl)pyrimidine (153 mg, 0.55 mmol), K2CO3 (118 mg, 0.85 mmol) and Pd(PPhs)4 (98 mg, 0.09 mmol) in dioxane (5 mL) and H₂O (0.5 mL) was stirred at 100 °C under Ar for 4 h. Then the mixture was diluted with water (20 mL) and extracted with EtOAc (20 mL x 3). The combined organic fractions were washed with brine (30 mL), dried over Na₂SO4, filtered and concentrated. The residue was purified by prep-TLC (ΡΕ/EtOAc = 1/3) to afford desired product (170 mg, 0.29 mmol, 68%) as a white solid. LCMS: Rétention time: 1.587 min, (M+H) ⁺ = 584.4, method A.

[0352] 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-8-(2-fluoro-4-(5-methyl-3(trifluoromethyl)-lH-pyrazol-l-yl)benzyl)pyrido[2,3-d]pyrimidin-7(8H)-one

[0353] To a solution of methyl (2E)-3-[2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-4-[({2fluoro-4-[5-methyl-3-(trifluoromethyl)-lH-pyrazol-l-yl]phenyl}methyl)amino]pyrimidin-5yl]prop-2-enoate (160 mg, 0.274 mmol) in MeOH (3 mL) was added NaH (14 mg, 0.36 mmol, 60% dispersion in minerai oil). The mixture was stirred at 70 °C for 1.5 h. Then the mixture was concentrated and dissolved in water (15 mL). The solution was extracted with EtOAc (15 mL x 2). The combined organic fractions were washed with brine (30 mL), dried over Na2SÛ4, filtered and concentrated. The residue was purified by prep-TLC (ΡΕ/EtOAc = 1/3) to afford desired product (45.48 mg, 0.0825 mmol, 30%).

LCMS: Rétention time: 1.900min, (M+H) ⁺= 551.7, method A.

*H NMR (400 MHz, DMSO-<7₆) δ = 9.31 (s, 1 H), 8.67 (s, 1 H), 8.19 (d, J = 9.6 Hz, 1 H), 7.56 (d, J =10.4 Hz, 1 H), 7.29 (d,J=8.0 Hz, 1 H), 7.15 (t, J =8.4 Hz, 1 H) 6.92 (d,J=9.6 Hz, 1 H), 6.76 (s, 1 H), 5.59 (s, 2 H), 3.79 (s, 3 H), 2.33 (s, 3 H), 1.73-1.71 (m, 1 H), 1.01 - 0.97 (m, 2 H), 0.75-0.72 (m, 2 H).

133

[0354] Example B13: Synthesis of Compound 4

Pd(OAc)₂, tri-p-tolylphosphine

TEA, DMF,100°C, 6h

Raney Ni, H₂

THF/NH₄OH/MeOH, rt, 2 h

Compound 4

[0355] 3-fluoro-4-(5-methyl-3-(trifluoromethyl)-lH-pyrazol-l-yI)benzonitriIe

[0356] A mixture of 3,4-difluorobenzonitrile (1.7 g, 12.22 mmol), 5-methyl-3-(trifluoromethyl)IH-pyrazole (1.833 g, 12.22 mmol) and K2CO3 (3.38 g , 24.44 mmol) in DMF (20 mL) was stirred at 100 °C under Ar for 16 h. Then the mixture was diluted with water (30 mL) and extracted with EtOAc (40 mL x 3). The combined organic fractions were washed with brine (30 mL), dried over Na₂SO4, filtered and concentrated. The residue was purified by column chromatography on silica gel eluted with ΡΕ/EtOAc = 5/1 to afford desired product (2.26 g, 8.39 mmol, 69 %) as a white solid.

LCMS: Retentiontime: 1.637 min, (M+H) ⁺ =270.1, method A.

[0357] (3-fluoro-4-(5-methyl-3-(trifluoromethyl)-lH-pyrazol-l-yl)phenyl)methanamine [0358] To a mixture of 3-fluoro-4-[5-methyl-3-(trifluoromethyl)-lH-pyrazol-l-yl]benzonitrile (500 mg, 1.86 mmol) in MeOH (15 mL) and THF (5 mL) was added Ammonium hydroxide (3 mL) and then excess amount of moist Raney Ni was added. Under a hydrogen pressure (0.5 Mpa), the mixture was stirred at room température for 2 h. The mixture was filtered, and the filtrate was concentrated to give crude product as a yellow oil, which was used in next step directly.

LCMS: Rétention time: 1.045 min, (M+H) ⁺ = 274.1, method A.

[0359] 2-chloro-N-(3-fluoro-4-(5-methyl-3-(trifluoromethyI)-lH-pyrazol-l-yl)benzyl)-5iodopyrimidin-4-amine

134

[0360] To a solution of 2,4-dichloro-5-iodopyrimidine (511 mg, 1.86 mmol) and(3-fluoro-4-(5methyl-3-(trifluoromethyl)-lH-pyrazol-l-yl)phenyl)methanamine (507 mg, 1.86 mmol) in EtOH (5 mL) was added N,N-diisopropylethylamine (0.921 mL, 5.57 mmol) at 0 °C. The mixture was stirred at rt for 16 h. Then the mixture was concentrated under vacuum, diluted with water (20 mL) and extracted with EtOAc (20 mL x 3). The combined organic fractions were washed with brine (20 mL), dried over Na2SO4, filtered and concentrated under vacuum. The residue was purified by prep-TLC (ΡΕ/EtOAc = 3/1) to give desired product (598 mg, 1.17 mmol, 63 %) as a white solid.

LCMS: Retentiontime:1.817 min, (M+H) ⁺= 512.0, method A.

[0361] methyl (E)-3-(2-chloro-4-((3-fluoro-4-(5-methyl-3-(trifluoromethyl)-lH-pyrazol-lyl)benzyl)amino)pyrimidin-5-yl)acrylate

[0362] A mixture of methylprop-2-enoate (0.32 mL,3.5Immol), 2-chloro-N-({3-fluoro-4-[5methyl-3-(trifluoromethyl)-lH-pyrazol-l-yl]phenyl}methyl)-5-iodopyrimidin-4-amine (598 mg, 1.17 mmol), Tri-p-Tolylphosphine (107 mg, 0.35 mmol), Pd(OAc)2 (26 mg, 0.12 mmol) and TEA (0.49 mL, 3.51 mmol) in DMF (6 mL) was stirred at 100 °C for 6 h. The mixture was diluted with water (15 mL) and extracted with EtOAc (20 mL x 3). The combined organic fractions were washed with brine (20 mL), dried over Na2SÛ4, filtered and concentrated. The residue was purified by column chromatography on silica gel eluting with ΡΕ/EtOAc from 10/1 to 3/1 to give desired product (376 mg, 0.80 mmol, 68 %) as a yellow solid.

LCMS: Retentiontime: 1.927min, (M+H) ⁺ =470.1, method A.

[0363] methyl (E)-3-(4'-cyclopropyl-4-((3-fluoro-4-(5-methyl-3-(trifluoromethyl)-lHpyrazol-l-yl)benzyl)amino)-6'-methoxy-[2,5’-bipyrimidin]-5-yl)acrylate

[0364] A mixture of methyl(2E)-3-{2-chloro-4-[({3-fluoro-4-[5-methyl-3-(trifluoromethyl)-lHpyrazol-l-yl]phenyl}methyl)amino]pyrimidin-5-yl}prop-2-enoate (200 mg, 0.426 mmol), 4cyclopropyl-6-methoxy-5-(tetramethyl-l,3,2-dioxaborolan-2-yl)pyrimidine (153 mg, 0.55 mmol), K2CO3 (118 mg, 0.85 mmol) and Pd(PPh3)4 (98 mg, 0.09 mmol) in dioxane (4 mL) and H2O (0.40 mL) was stirred at 100 °C under Ar for 4 h. Then the mixture was diluted with water (20 mL) and extracted with EtOAc (30 mL x 3). The combined organic fractions were washed with brine (30 mL), dried over Na2SO4, filtered and concentrated under vacuum. The residue was purified by prep-TLC (ΡΕ/EtOAc = 3/2) to give desired product (116 mg, 0.199 mmol, 46 %) as a white solid.

LCMS: Retentiontime: 1.877min, (M+H) ⁺ =584.2, method A.

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[0365] 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-8-(3-fluoro-4-(5-methyI-3(trifluoromethyl)-lH-pyrazol-l-yl)benzyl)pyrido[2,3-d]pyrimidin-7(8H)-one

[0366] To a solution of methyl (2E)-3-[2-(4-cyclopropyl-6-methoxy pyrimidin-5-yl)-4-[({3fluoro-4-[5-methyl-3-(trifluorornethyl)-lH-pyrazol-l-yl]phenyl}methyl) amino] pyrimidin-5-yl] prop-2-enoate (100 mg, 0.171 mmol) in MeOH (10 mL) was added NaH (9 mg, 0.22 mmol, 60 % dispersion in minerai oil). The mixture was stirred at 70 °C for 1.5 h. Then the mixture was concentrated under vacuum and dissolved in water (20 mL). The solution was extracted with EtOAc (20 mL x 3). The combined organic fractions were washed with brine (20 mL), dried over Na2SÜ4, filtered and concentrated. The residue was purified by prep-TLC (ΡΕ/EtOAc = 3/2) to give desired product (34.86 mg, 0.0632 mmol, 37 %).

LCMS: Retentiontime: 1.757 min, (M+H) ⁺ =552.3, method A.

‘HNMR (400MHz, DMSO-î/₆) δ = 9.30 (s, 1 H), 8.69 (s, 1 H), 8.17 (d, J= 9.6 Hz, 1 H), 7.56 (t, J =8.2 Hz, 1 H), 7.44 (dd, J= 1.6 Hz, 11.6 Hz, 1 H), 7.29 (d, J=8.4 Hz, 1 H), 6.91 (d, J =9.2 Hz, 1 H), 6.77 (s, 1 H), 5.58 (s, 2 H), 3.82 (s, 3 H), 2.17 (s, 3 H), 1.78 - 1.71 (m, 1 H), 1.04 - 1.01 (m, 2 H), 0.84 - 0.76 (m, 2 H).

[0367] Example B14: Synthesis of Compound 5

[0368] 5-(5-methyl-3-(trifluoromethyl)-lH-pyrazol-l-yl)picolinonitrile

[0369] To a solution of 5-fluoropyridine-2-carbonitrile (500 mg, 4.10 mmol) in DMF (10 mL) were added 5-methyl-3-(trifluoromethyl)-lH-pyrazole (675 mg, 4.50 mmol) and CS2CO3 (2001 mg, 6.14 mmol). The mixture was stirred at 80 °C for 16 h. Then the mixture was diluted with water (15 mL) and extracted with EtOAc (15 mL x 3). The combined organic phases were

136 washed with brine (15 mL) and dried over Na2SC>4, filtered and concentrated. The residue was purified by column chromatography on silica gel (eluting with ΡΕ/EtOAc = 100/0 to 5/1) to afford desired product (800 mg, 3.17 mmol, 77%) as a white solid.

LCMS: Rétention time: 1.687 min, (M+H)⁺ = 253.2, method A.

[0370] methyl 5-(5-methyI-3-(trifluoromethyl)-lH-pyrazol-l-yl)picolinate

[0371] HCl/dioxane (15 mL, 3 mol/L) was added to the solution of 5-[5-methyl-3(trifluoromethyl)-lH-pyrazol-l-yl] pyridine-2-carbonitrile (790 mg, 3.13 mmol) in MeOH (15 mL). The mixture was stirred at 80 °C for 16 h. Then the mixture was concentrated and purified by column chromatography on silica gel (eluting with ΡΕ/EtOAc = 100/0 to 1/1) to afford desired product (400 mg, 1.40 mmol, 45%) as a yellow oil.

LCMS: Rétention time: 1.587 min, (M+H) ⁺ = 286.2, method A.

[0372] (5-(5-methyl-3-(trifluoromethyl)-lH-pyrazol-l-yl)pyridin-2-yl)methanol

[0373] Lithium aluminum hydride (140 mg, 3.68 mmol) was added to the solution of methyl 5[5-methyl-3-(trifluoromethyl)-lH-pyrazol-l-yl]pyridine-2-carboxylate (350 mg, 1.23 mmol) in THF (10 mL) at 0 °C. The mixture was stirred at 0 °C for 2 h. Then the mixture was quenched by water (10 mL) and 10% NaOH solution (10 mL) at 0 °C. The mixture was filtered and extracted with EtOAc (15 mL x 3). The combined organic phases were washed with brine (15 mL) and dried over Na2SÛ4, filtered and concentrated. The residue was purified by column chromatography on silica gel eluting with PE/EtOAc (100/0 to 5/1) to afford desired product (200 mg, 0.78 mmol, 63%) as a white solid.

LCMS: Rétention time: 1.557 min, (M+H) ⁺ = 258.1, method A.

[0374] 2-(chloromethyl)-5-(5-methyl-3-(trifluoromethyl)-lH-pyrazol-l-yl)pyridine

[0375] To a mixture of {5-[5-methyl-3-(trifluoromethyl)-lH-pyrazol-l-yl] pyridin-2-yl} methanol (117 mg, 0.45 mmol) in DCE (10 mL) was added SOCb (99 pL, 1.36 mmol) in one portion. Then the mixture was stirred at 50 °C for 30 min. The reaction mixture was concentrated under reduced pressure to dryness to afford desired product (100 mg, 0.36 mmol, 80%) as a yellow oil.

LCMS: Rétention time: 1.727 min, (M+H)⁺ = 276.1, method A.

[0376] 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-8-((5-(5-methyI-3-(trifluoromethyI)-lHpyrazol-l-yl)pyridin-2-yl)methyl)pyrido[2,3-d]pyrimidin-7(8H)-one

[0377] To a solution of 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-7H,8H-pyrido[2,3d]pyrimidin-7-one (22 mg, 0.07 mmol) in DMF (2 mL) were added 2-(chloromethyl)-5-[5methyl-3-(trifluoromethyl)-lH-pyrazol-l-yl]pyridine (21 mg, 0.07 mmol) and K2CO3 (21 mg,

137

0.15 mmol). The mixture was stirred at 50 °C for 16 h. Then the mixture was cooled to rt, diluted with water (20 mL) and extracted with EtOAc (15 mL x 3). The combined organic phases were washed with brine (15 mL), dried over Na₂SO4, filtered and concentrated. The residue was purified by prep-TLC (PE/EtOAc = 3/1) to afford desired product (8.78 mg, 0.016 mmol, 22%). LCMS: Rétention time: 1.837min, (M+H) ⁺= 535.2, method A.

Ή NMR (400 MHz, DMSO-/4,) δ = 9.29 (s, 1 H), 8.64 (s, 1 H), 8.60 (d, J= 2.4 Hz, 1 H), 8.19 (d, J= 9.2 Hz,l H), 8.01 (dd, J= 8.4, 2.8 Hz, 1 H), 7.55 (d, J= 8.4 Hz, 1 H), 6.92 (d, 9.6 Hz,

H), 6.79 (s, 1 H), 5.73 (s, 2 H), 3.76 (s, 3 H), 2.32 (s, 3 H), 1.64-1.59 (m, 1 H), 0.95 - 0.91 (m, 2 H), 0.67 - 0.63 (m,2 H).

[0378] Example B15: Synthesis of Compound 6

0°C 30min to rt, 16h Intermediate D

Raney Ni, H₂

NH₄OH, THF, MeOH, rt, 2h

EtOH, DIEA, rt, 16h

Pd(OAc)₂, tri-p-tolylphosphine

TEA, DMF, 100 °C, 4h

Pd(PPh₃)₄, K₂CO₃

Dioxane/H₂O, 100°C, 3h

NaH______

MeOH, 70 °C, 1.5h

[0379] 4-(l-methyl-4-(trifluoromethyl)-lH-imidazol-2-yl)benzonitrile

[0380] To a solution of 4-[4-(trifluoromethyl)-lH-imidazol-2-yl]benzonitrile (5.00 g, 21.08 mmol) in DMF (50 mL) was added NaH (0.61 g, 15.25 mmol, 60% dispersion in minerai oil) at 0 °C. After stirred at 0 °C for 30 min, Mel (1.575 mL, 25.30 mmol) was added. The mixture was stirred at room température for 16 h. Then the mixture was diluted with water (100 mL) at 0 °C and extracted with EtOAc (150 mL x 3). The combined organic phases were washed with brine (50 mL), dried over Na₂SÛ4, filtered and concentrated. The residue was purified by column chromatography on silica gel (eluting with PE/EtOAc from 100/0 to 8/1) to afford desired product (2.59 g, 10.31 mmol, 49%) as a yellow solid.

LCMS: mass calcd. For C12H8F3N3 251.10, m/z found 252.0 (M+H)⁺.

[0381] (4-(l-methyl-4-(trifluoromethyl)-lH-imidazol-2-yl)phenyl)methanamine

138

[0382] To a solution of 2-fluoro-4-[5-methyl-3-(trifluoromethyl)-lH-pyrazol-l-yl]benzonitrile (500 mg, l .99 mmol) in MeOH (l 5 mL) and THF (5 mL) was added Ammonium hydroxide (1 mL) and then excess amount of moist Raney Ni was added. Under a hydrogen pressure (0.5 Mpa), the mixture was stirred at room température for 2 h. The mixture was filtered and concentrated. The residue was purified by column chromatography on silica gel (eluting with DCM/MeOH from 20/1 to 10/1) to afford desired product (372 mg, 1.46 mmol, 73%) as a yellow oil.

LCMS: mass calcd. For C12H12F3N3 255.10, m/z found 256.1 (M+H)⁺.

[0383] 2-chloro-5-iodo-N-(4-(l-methyl-4-(trifluoromethyl)-lH-imidazol-2yl)benzyl)pyrimidin-4-amine

[0384] To a solution of 5-iodo-2, 4-dichloropyrimidine (547 mg, 1.99 mmol) and {4-[5-methyl3-(trifluoromethyl)-lH-pyrazol-l-yl] phenyl} methanamine (372 mg, 1.46 mmol) in EtOH (4 mL) was added N, N-diisopropylethylamine (0.72 mL, 4.37 mmol) at 0 °C. The mixture was stirred at room température for 16 h. Then the mixture was diluted with water (50 mL) and extracted with EtOAc (100 mL x 3). The combined organic phases were washed with brine (20 mL) and dried over Na2SÛ4, filtered and concentrated. The residue was purified by column chromatography on silica gel (eluting with ΡΕ/EtOAc from 100/0 to 4/1) to afford desired product (405 mg, 0.82 mmol, 56%) as a white solid.

LCMS: mass calcd. For C16H12CIF3IN5 493.0, m/z found 493.9 (M+H)⁺.

[0385] methyl (E)-3-(2-chloro-4-((4-(l-methyl-4-(trifluoromethyl)-lH-imidazol-2yl)benzyl)amino)pyrimidin-5-yl)acrylate

[0386] A mixture of methyl prop-2-enoate (0.20 mL, 2.16 mmol), 2-chIoro-5-iodo-N-({4-[5methyl-3-(trifluoromethyl)-lH-pyrazol-l-yl]phenyl}methyl)pyrimidin-4-amine (355 mg, 0.72 mmol), tris(4-methylphenyl)phosphine (66 mg, 0.22 mmol), Pd(OAc)2(16 mg, 0.07 mmol) and triethylamine (0.30 mL, 2.16 mmol) in DMF (7 mL) was stirred at 100 °C for 4 h. Then the mixture was diluted with water (40 mL) and extracted with EtOAc (80 mL x 3). The combined organic phases were washed with brine (20 mL) and dried over Na2SÛ4, filtered and concentrated. The residue was purified by column chromatography on silica gel (eluting with ΡΕ/EtOAc from 100/0 to 3/1) to afford desired product (230 mg, 0.51 mmol, 71%) as a white solid.

LCMS: mass calcd. For C20H17CIF3N5O2 451.1, m/z found 451.8 (M+H)⁺.

[0387] methyl (E)-3-(4’-cyclopropyl-6’-methoxy-4-((4-(l-methyl-4-(trifluoromethyl)-lHimidazol-2-yl)benzyl)amino)-[2,5’-bipyrimidin]-5-yl)acrylate

139

[0388] A mixture of methyl(2E)-3-{2-chloro-4-[({4-[l-methyl-4-(trifluoromethyl)-lH-imidazol2-yl]phenyl}methyl)amino]pyrimidin-5-yl} prop-2-enoate (220 mg, 0.49 mmol), 4-cyclopropyl6-methoxy-5-(tetramethyl-l,3,2-dioxaborolan-2-yl) pyrimidine (175 mg, 0.63 mmol), K2CO3 (135 mg, 0.97 mmol) and Pd(PPh3)4 (113 mg, 0.10 mmol) in dioxane (5 mL) and H2O (0.5 mL) was stirred at 100 °C for 3 h. Then the mixture was diluted with water (40 mL) and extracted with EtOAc (80 mL x 3). The combined organic phases were washed with brine (20 mL) and dried over Na2SÛ4, filtered and concentrated. The residue was purified by prep-TLC (PE/EtOAc = 1/1) to give desired product (100 mg, 0.18 mmol, 36%) as a white solid.

LCMS: mass calcd. For C28H26F3N7O3 565.2, m/z found 564.3 (M-H) '.

[0389] 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-8-(4-(l-methyl-4-(trifluoromethyl)-lHimidazol-2-yl)benzyl)py rido [2,3-d] py rimidin-7(8H)-one

[0390] To a solution of methyl (2E)-3-[2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-4-[({4-[lmethyl-4-(trifluoromethyl)-lH-imidazol-2-yl] phenyl} methyl) amino] pyrimidin-5-yl] prop-2enoate (100 mg, 0.18 mmol) in MeOH (4 mL) was added NaH (9 mg, 0.23 mmol, 60% dispersion in minerai oil). The mixture was stirred at 70 °C for 1.5 h. Then the mixture was diluted with water (30 mL) and extracted with EtOAc (50 mL x 3). The combined organic phases were washed with brine (20 mL) and dried over N328()4, filtered and concentrated. The residue was purified by prep-TLC (PE/EA = 1/1) to give desired product (7.05 mg, 0.013 mmol, 7%). LCMS: mass calcd. For C27H22F3N7O2 533.2, m/z found 533.8 (M+H)⁺.

Ή NMR (400 MHz, DMSO-î/₆) δ = 9.29 (s, 1 H), 8.69 (s, 1 H), 8.16 (d, J = 9.2 Hz, 1 H), 7.91 (s, 1 H), 7.62 (d, J = 8.4 Hz, 2 H), 7.39 (d, J = 8.4 Hz, 2 H), 6.90 (d, J= 9.6 Hz, 1 H), 5.57 (s, 2 H), 3.83 (s, 3 H), 3.74 (s, 3 H), 1.73 - 1.71 (m, 1 H), 1.02 - 1.00 (m, 2 H), 0.78 - 0.75 (m, 2 H).

[0391] Example B16: Synthesis of Compound 7

EtOH, DIEA, rt. 16h

Intermediate A

Pd(PPh₃)₄, K₂CO₃

Dioxane/H₂O, 100°C,3h

[0392] 2-chloro-5-iodo-N-(4-(l-isopropyl-4-(trifIuoromethyl)-lH-imidazol-2yl)benzyl)pyrimidin-4-amine

140

[0393] To a solution of 2, 4-dichloro-5-iodopyrimidine (437 mg, 1.59 mmol) and {4-[5-(propan2-yl)-3-(trifluoromethyl)-lH-pyrazol-l-yl] phenyl} methanamine (450 mg, 1.59 mmol) in EtOH (5 mL) was added N, N-diisopropylethylamine (0.79 mL, 4.77 mmol) at 0 °C. The mixture was stirred at room température for 16 h. Then the mixture was diluted with water (50 mL) and extracted with EtOAc (100 mL x 3). The combined organic fractions were washed with brine (30mL) and dried over Na2SÛ4, filtered and concentrated. The residue was purified by column chromatography on silica gel (eluting with ΡΕ/EtOAc from 100/0 to 4/1) to give desired product (460 mg, 0.88 mmol, 55%) as a white solid.

LCMS: mass calcd. For C18H16CIF3IN5 521.0, m/z found 522.1 (M+H)⁺.

[0394] methyl (E)-3-(2-chloro-4-((4-(l-isopropyl-4-(trifluoromethyl)-lH-imidazol-2yl)benzyl)amino)pyrimidin-5-yl)acrylate

[0395] A mixture of methyl prop-2-enoate (0.24 mL, 2.64 mmol), 2-chloro-5-iodo-N-({4-[5(propan-2-yl)-3-(trifluoromethyl)-lH-pyrazol-l-yl]phenyl}methyl)pyrimidin-4-amine (460 mg, 0.88 mmol), tris(4-methylphenyl)phosphine (80 mg, 0.26 mmol), Pd(OAc)2 (18 mg, 0.08 mmol) and triethylamine (0.37 mL, 2.64 mmol) in DMF (10 mL) was stirred at 100 °C for 4 h. Then the mixture was diluted with water (50 mL) and extracted with EtOAc (100 mL x 3). The combined organic fractions were washed with brine (30 mL), dried over Na2SO4, filtered and concentrated. The residue was purified by column chromatography on silica gel (eluting with ΡΕ/EtOAc from 100/0 to 3/1) to give desired product (350 mg, 0.73 mmol, 83%) as a white solid.

LCMS: mass calcd. For C22H21CIF3N5O2 479.1 m/z found 480.3 (M+H)⁺.

[0396] methyl (E)-3-(4'-cyclopropyl-4-((4-(l-isopropyl-4-(trifluoromethyl)-lH-imidazol-2yl)benzyl)amino)-6'-methoxy-[2,5'-bipyrimidin]-5-yl)acrylate

[0397] A mixture of methyl (2E)-3-{2-chloro-4-[({4-[l-(propan-2-yl)-4-(trifluoromethyl)-lHimidazol-2-yl]phenyl}methyl)amino]pyrimidin-5-yl}prop-2-enoate (300 mg, 0.63 mmol), 4cyclopropyl-6-methoxy-5-(tetramethyl-l,3,2-dioxaborolan-2-yl)pyrimidine (224 mg, 0.81 mmol), K2CO3 (173 mg, 1.25 mmol) and Pd(PPh3)4 (144 mg, 0.13 mmol) in dioxane (6 mL) and H2O (0.5 mL) was stirred at 100 °C under N2 for 3 h. Then the mixture was diluted with water (40 mL) and extracted with EtOAc (70 mL x 3). The combined organic fractions were washed with brine (20 mL), dried over Na2SÛ4, filtered and concentrated. The residue was purified by prep-TLC (ΡΕ/EtOAc = 1/1) to give desired product (110 mg, 0.19 mmol, 30%) as a white solid. LCMS: mass calcd. For C30H30F3N7O3 593.2 m/z found 593.8 (M+H)⁺.

[0398] 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-8-(4-(l-isopropyl-4-(trifhioromethyl)lH-imidazol-2-yl)benzyl)pyrido[2,3-d]pyrimidin-7(8H)-one

141

[0399] To a solution of methyl (2E)-3-[2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-4-[({4-[lmethyl-4-(trifluoromethyl)-lH-imidazol-2-yl] phenyl} methyl) amino] pyrimidin-5-yl] prop-2enoate (100 mg, 0.17 mmol) in MeOH (5 mL) was added NaH (9 mg, 0.22 mmol, 60% dispersion in minerai oil). The mixture was stirred at 70 °C for 1.5 h. Then the mixture was diluted with water (20 mL) and extracted with EtOAc (40 mL x 3). The combined organic fractions were washed with brine (10 mL), dried over Na2SÛ4, filtered and concentrated. The residue was purified by pre-TLC (DCM/MeOH = 40/1) to give desired product (45.36 mg, 0.081 mmol, 48%).

LCMS: mass calcd. For C29H26F3N7O2 561.2 m/z found 562.3 (M+H)⁺.

Ή NMR (400 MHz, DMSO-t/₆) δ = 9.30 (s, 1 H), 8.69 (s, 1 H), 8.19 - 8.14 (m, 2 H), 7.48 (d, J= 8.4 Hz, 2 H), 7.40 (d, J= 8.4 Hz, 2 H), 6.90 (d, J= 9.6 Hz, 1 H), 5.58 (s, 2 H), 4.42 - 4.40 (m, 1 H), 3.82 (s, 3 H), 1.72 - 1.70 (m, 1 H), 1.37 (d, J= 6.8 Hz, 6 H), 1.02 - 0.99 (m, 2 H), 0.75 - 0.73 (m, 2 H).

[0400] Example B17: Synthesis of Compound 8

[0401] (4-(4-(trifluoromethyl)-lH-imidazol-2-yl)cuban-l-yl)methanol

[0402] To a solution of 4-(4-(trifluoromethyl)-lH-imidazol-2-yl)cubane-l-carboxylic acid (8.20 g, 14.53 mmol, 50% purity) in THF (100 mL) was added L1AIH4 (1.65 g, 43.58 mmol) at 0 °C. The mixture was stirred at rt for 2 h. The mixture was quenched with water (3.0 mL), 15wt% NaOH solution (3.0 mL) and water (3.0 mL) at 0 °C. After stirred for 15min, Na2SÛ4 was added. The suspension was filtered and washed with DCM (50 mL). The filtrate was concentrated under vacuum to give crude product (4.38 g, 8.16 mmol, 56% yield, 50% purity) as a yellow oil, which was used for next step directly.

LCMS: Rétention time: 0.987 min, (M+H) ⁺ = 269.2, method A.

[0403] (4-(l-isopropyl-4-(trifluoromethyl)-lH-imidazol-2-yl)cuban-l-yl)methanol

142

[0404] A mixture of (4-(4-(trifluoromethyl)-lH-imidazol-2-yl)cuban-l-yl)methanol (2.20 g, 4.10 mmol, 50% purity), 2-iodopropane (1.743 g, 10.25 mmol) and CS2CO3 (3.34 g, 10.25 mmol) in DMF (20 mL) was stirred at 60 °C for 16 h. The mixture was cooled to rt, diluted with water (20mL) and then extracted with EtOAc (15 mL x 3). The combined organic fractions were washed with brine (20 mL), dried with Na2SC>4, filtered and concentrated. The residue was purified by column chromatography on silica gel (eluting with PE/EA from 10/1 to 1/1) to give desired product (350 mg, 1.13 mmol, 28%) as a brown oil.

LCMS: Rétention time: 1.352 min, (M+H)⁺ = 311.2, method A.

[0405] (4-(l-isopropyI-4-(trifluoromethyl)-lH-imidazol-2-yl)cuban-l-yl)methyl methanesulfonate

[0406] To a solution of (4-(l-isopropyl-4-(trifluoromethyl)-lH-imidazol-2-yl)cuban-lyl)methanol (350 mg, 1.13 mmol) in DCM (10 mL) were added pyridine (1 mL, 12.36 mmol) and MsCl (0.13 mL, 1.69 mmol) at 0 °C. After stirred at 0 °C for 0.5 h, the mixture was stirred at rt for 16 h. The mixture was diluted with water (10 mL) and extracted with DCM (15 mL x 3). The combined organic fractions were washed with brine (15 mL), dried over Na2SO4, filtered and concentrated to give crude product (420 mg, 1.08 mmol, 96%) as a yellow solid, which was used in next step directly without ftirther purification.

LCMS: Rétention time: 1.527 min, (M+H)⁺ = 389.1, method A.

[0407] 2-(4-cycIopropyl-6-methoxypyrimidin-5-yl)-8-((4-(l-isopropyl-4-(trifluoromethyl)lH-imidazol-2-yl)cuban-l-yl)methyl)pyrido[2,3-d]pyrimidin-7(8H)-one

[0408] A mixture of (4-(l-isopropyl-4-(trifluoromethyl)-lH-imidazol-2-yl)cuban-l-yl)methyl methanesulfonate (171 mg, 0.44 mmol) and potassium iodide (37 mg, 0.22 mmol) in DMF (5 mL) was stirred at rt for 0.5 h. 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-7H,8H-pyrido[2,3d]pyrimidin-7-one (130 mg, 0.44 mmol) and K2CO3 (152 mg, 1.10 mmol) were added and the mixture was stirred at 50 °C for 16 h. Then the mixture was cooled to rt, diluted with water (10 mL) and extracted with EtOAc (15 mL x 3). The combined organic fractions were washed with brine (20 mL), dried over Na2SÛ4, filtered and concentrated. The residue was purified by prepTLC (PE/EtOAc = 1/1) to give desired product (28.28 mg, 0.048 mmol, 11%).

LCMS: Rétention time: 1.677 (M+H) ⁺ = 588.2, method A.

'H NMR: (400 MHz, DMSO-d₆) δ = 9.25 (s, 1 H), 8.72 (s, 1 H), 8.10 (d, J= 9.2 Hz, 1 H), 7.96 (s, 1 H), 6.87 (d, J = 9.6 Hz, 1 H), 4.67 (s, 2 H), 4.12 (t, J = 4.8 Hz, 3 H), 4.00 - 3.93 (m, 1 H), 3.90 (t, .7 = 4.8 Hz, 3 H), 3.86 (s, 3 H), 1.67- 1.64 (m, 1 H), 1.35 (d, J= 6.4 Hz, 6 H), 1.11 - 1.07 (m,2H), 0.91 - 0.87 (m, 2 H)

143

[0409] Example B18: Synthesis of Compound 9

Mel, NaH

DMF, rt, 16h

LAH,THF

O°C~rt, 2h

Intermediate E

[0410] methyl 4-(l-methyl-4-(trifluoromethyl)-lH-imidazol-2-yl)cubane-l-carboxylate [0411] To a solution of 4-(4-(trifIuoromethyl)-lH-imidazol-2-yl)cubane-l-carboxylic acid (1.50 g, 5.32 mmol) in DMF (20 mL) was added NaH (0.32 g, 60 % dispersion in minerai oil, 7.97 mmol) at 0 °C. After stirred at 0 °C for 0.5 h, Mel (0.50 mL, 7.97 mmol) was added. The mixture was stirred at rt for 16 h. Then the mixture was quenched with sat. NH4CI solution (20 mL) and extracted with EtOAc (15 mL x 3). The combined organic fractions were washed with brine (20 mL), dried over Na₂SÛ4, filtered and concentrated. The residue was purified by pre-HPLC to give desired product (0.50 g, 1.61 mmol, yield 30%) as a white solid. Prep-HPLC condition: (column: Waters sunfire Cl8 lOum OBD 19 x 250mm); mobile phase: [water (0.1%TFA) ACN]; B%: 5ACN%-95ACN%, 14min).

LCMS: Rétention time: 1.399 min, (M+H) ⁺ = 311.1, method A.

[0412] (4-(l-methyl-4-(trifluoromethyl)-lH-imidazol-2-yl)cuban-l-yl)methanol

[0413] To a solution of methyl 4-(l-methyl-4-(trifluoromethyl)-lH-imidazol-2-yl)cubane-lcarboxylate (500 mg, 1.61 mmol) in THF (20 mL) was added L1AIH4 (130 mg, 3.42 mmol) at 0 °C. The mixture was stirred at rt for 2h. Then the mixture was quenched with water (1 mL) and 15wt% NaOH solution (1 mL) at 0 °C. After stirred for 15 min, Na₂SC>4 was added. The suspension was filtered and washed with DCM (20 mL). The filtrate was concentrated. The residue was purified by column chromatography on silica gel (eluting with ΡΕ/EtOAc from 10/1 to 0/1) to give desired product (300 mg, 1.06 mmol, 66% yield) as a yellow oil.

LCMS: Rétention time: 1.167 min, (M+H) ⁺ = 283.1, method A.

[0414] (4-(l-methyl-4-(trifluoromethyl)-lH-imidazol-2-yl)cubaii-l-yl)methyl methanesulfonate

[0415] To a solution of (4-(l-methyl-4-(trifluoromethyl)-lH-imidazol-2-yl)cuban-l-yl)methanol (100 mg, 0.35 mmol) in DCM (10 mL) were added Pyridine (1.00 mL, 12.36 mmol) and MsCl

144 (0.04 mL, 0.53 mmol) at 0 °C. After stirred at 0 °C for 0.5 h, the mixture was stirred at rt for 16 h. Then the mixture was diluted with water (10 mL) and extracted with DCM (10 mL x 3). The combined organic fractions were washed with brine (10 mL), dried over Na₂SO4, filtered and concentrated to give desired product (150 mg, 0.42 mmol, crude) as a yellow solid, which was used directly.

LCMS: Rétention time: 1.387 min, (M+H) ⁺ = 361.1, method A.

[0416] 2-(4-cyclopropyl-6-methoxypyrimidin-5-yI)-8-((4-(l-methyl-4-(trifluoromethyl)-lHimidazoI-2-yl)cuban-l-yl)methyl)pyrido[2,3-d]pyrimidin-7(8H)-one

[0417] Potassium iodide (13 mg, 0.08 mmol) was added to the solution of (4-(l-methyl-4(trifluoromethyl)-lH-imidazol-2-yl)cuban-l-yl)methyl methanesulfonate (61 mg, 0.17 mmol) in DMF (10 mL) at 0 °C. The mixture was stirred for 0.5 h. Then potassium carbonate (47 mg, 0.34 mmol) and 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)pyrido[2,3-d]pyrimidin-7(8H)-one (50 mg, 0.17 mmol) were added. The mixture was stirred at 50 °C for 16 h. Then the mixture was diluted with water (15 mL) and extracted with EtOAc (15 mL x 3). The combined organic phases were washed with brine (15 mL), dried over Na₂SÛ4, filtered and concentrated. The residue was purified by prep-TLC (DCM/MeOH = 35/1) to give desired product (8.83 mg, 0.016 mmol, 9%). LCMS: Rétention time: 1.527 min, (M+H) ⁺ = 560.2, method A.

Ή NMR (400 MHz, CDCh) δ = 9.00 (s, 1 H), 8.68 (s, 1 H), 7.76 (d, J= 9.2 Hz, 1 H), 7.16 (s, 1 H), 6.86 (d, J= 9.6 Hz, 1 H), 4.84 (s, 2 H), 4.24 - 4.20 (m, 3 H), 3.99 - 3.94 (m, 3 H), 3.92 (s, 3 H), 3.52 (s, 3 H), 1.66-1.61 (m, 1 H), 1.27 - 1.24 (m, 2 H), 0.93 - 0.90 (m 2 H).

[0418] Example B19: Synthesis of Compound 10

145

NaBH(OAc)₃, AcOH

DCE, rt, 16h

Raney Ni, H₂

NH₄OH, THF, MeOH, rt, 2h

EtOH, DIPEA, rt, 16h

Pd(OAc)₂, tri-p-tolylphosphine

TEA,DMF,100 °C, 4h

Pd(PPh₃)₄, K₂CO₃

Dioxane/H₂O, 100°C, 3h

NaH

MeOH, 70 °C, 1.5h

Compound 10

[0419] 4-((3,3-difluoropyrroIidin-l-yl)methyl)benzonitrile

[0420] To a solution of 4-formylbenzonitrile (499 mg, 3.81 mmol) in 1,2-dichloroethane (8 mL) were added 3,3-difluoropyrrolidine hydrochloride (657 mg, 4.58 mmol), sodium triacetoxyborohydride (1205 mg, 5.71 mmol) and acetic acid (0.218 mL, 3.81 mmol). The mixture was stirred at room température for 16 h. Then the mixture was diluted with water (50 mL) and extracted with EtOAc (120 mL x 3). The combined organic fractions were washed with brine (30 mL), dried over Na₂SC>4, filtered and concentrated. The residue was purified by column chromatography on silica gel (eluting with ΡΕ/EtOAc from 100/0 to 4/1) to afford desired product (500 mg, 2.25 mmol, 59 %) as a yellow solid.

LCMS: mass calcd. For C12H12F2N2 222.1, m/z found 223.2 (M+H)⁺.

[0421] (4-((3,3-difluoropyrroIidin-l-yl)methyl)phenyl)methanamine

[0422] To a mixture of 4-[(3,3-difluoropyrrolidin-l-yl)methyl]benzonitrile (500 mg, 2.25 mmol) in MeOH (15 mL) and THF (5 mL) was added Ammonium hydroxide (3 mL) and then excess amount of moist Raney Ni was added. Under a hydrogen pressure (0.5 Mpa), the mixture was stirred at room température for 2 h. Then the mixture was filtered and concentrated. The residue was purified by column chromatography on silica gel (eluting with DCM/MeOH from 100/0 to 10/1) to give desired product (300 mg, 1.33 mmol, 59%) as a yellow oil.

LCMS: mass calcd. For C12H16F2N2 226.1, m/z found 227.1 (M+H)⁺.

[0423] 2-chloro-N-(4-((3,3-difluoropyrrolidin-l-yl)methyl)benzyl)-5-iodopyrimidin-4-amine

146

[0424] To a solution of {4-[(3,3-difluoropyrrolidin-l-yl)methyl]phenyl}methanamine (250 mg, 1.10 mmol) in EtOH (5 mL) were added 2,4-dichloro-5-iodopyrimidine (304 mg, 1.10 mmol) and N,N-diisopropylethylamine (0.55 mL, 3.31 mmol) at 0 °C. The mixture was stirred at room température for 16 h. Then the mixture was diluted with water ( 10 mL) and extracted with EtOAc (15 mL x 3). The combined organic fractions were washed with brine (30 mL), dried over Na₂SO4, filtered and concentrated. The residue was purified by column chromatography on silica gel (eluting with ΡΕ/EtOAc from 100/0 to 1/1) to give desired product (390 mg, 0.84 mmol, 76%) as a yellow solid.

LCMS: mass calcd. For C16H16CIF2IN4 464.0 m/z found 464.7 (M+H)⁺.

[0425] methyl (E)-3-(2-chIoro-4-((4-((3,3-difluoropyrrolidin-lyl)methyl)benzyl)amino)pyrimidin-5-yl)acrylate

[0426] A mixture of methyl prop-2-enoate (1.05 g, 12.19 mmol), 2-chloro-5-iodo-N-({4-[5methyl-3-(trifluoromethyl)-lH-pyrazol-l-yl]phenyl}methyl)pyrimidin-4-amine (1.882 g, 4.05 mmol), tris (4-methylphenyl) phosphine (66.66 mg, 0.22 mmol), Pd(OAc)₂ (16.39 mg, 0.07 mmol) and triethylamine (0.30 mL, 2.19 mmol) in DMF (6 mL) was stirred at 100 °C for 4 h. Then the mixture was cooled to rt, diluted with water (30 mL) and extracted with EtOAc (50 mL x 3). The combined organic fractions were washed with brine (20 mL), dried over Na₂SO4, filtered and concentrated. The residue was purified by column chromatography on silica gel (eluting with ΡΕ/EtOAc from 100/0 to 1/1) to give desired product (810 mg, 1.915 mmol, 47%) as a yellow solid.

LCMS: mass calcd. For C₂oH₂iC1F₂N₄0₂ 422.1 m/z found 422.8 (M+H)⁺.

[0427] methyl (E)-3-(4'-cycIopropyl-4-((4-((3,3-difluoropyrrolidin-lyl)methyl)benzyl)amino)-6'-methoxy-[2,5’-bipyrimidin]-5-yl)acrylate

[0428] A mixture of methyl (2E)-3-{2-chloro-4-[({4-[(3,3-difluoropyrrolidin-l-yl) methyl] phenyl} methyl) amino] pyrimidin-5-yl} prop-2-enoate (220 mg, 0.52 mmol), 4-cyclopropyl-6methoxy-5-(tetramethyl-l,3,2-dioxaborolan-2-yl)pyrimidine (187 mg, 0.68 mmol), K₂CCh (144 mg, 1.04 mmol) and Pd(PPhs)4 (120 mg, 0.10 mmol) in dioxane (8 mL) and H₂O (0.8 mL) was stirred at 100 °C for 3 h. Then the mixture was diluted with water (30 mL) and extracted with EtOAc (50 mL x 3). The combined organic fractions were washed with brine (20 mL), dried over Na₂SÜ4, filtered and concentrated. The residue was purified by prep-TLC (ΡΕ/EtOAc = 1/1) to give desired product (60 mg, 0.11 mmol, 21%) as a white solid.

LCMS: mass calcd. For C₂8H3oF₂Nô03 536.2 m/z found 537.3 (M+H)⁺.

147

[0429] 2-(4-cy clopropyl-6-methoxy py rimidin-5-yl)-8-(4-((3,3-difluoropy rrolidin-1 yl)methyI)benzyl)pyrido[2,3-d]pyrimidin-7(8H)-one

[0430] To a solution of methyl (2E)-3-[2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-4-[({4-[lmethyl-4-(trifluoromethyl)-lH-imidazol-2-yl] phenyl} methyl) amino] pyrimidin-5-yl] prop-2enoate (100 mg, 0.18 mmol) in MeOH (4 mL) was added NaH (9 mg, 0.22 mmol, 60% dispersion in minerai oil). The mixture was stirred at 70 °C for 1.5 h. Then the mixture was diluted with water (20 mL) and extracted with EtOAc (30 mL x 3). The combined organic fractions were washed with brine (20 mL), dried over Na2SO4, filtered and concentrated. The residue was purified by prep-TLC (ΡΕ/EtOAc = 1/1) to give desired product (33.00 mg, 0.065 mmol, 36%).

LCMS: mass calcd. For C27H26F2N6O2 504.21 m/z found 505.3 (M+H)⁺.

’H NMR (400 MHz, DMSO-J₆) δ 9.27 = (s, 1 H), 8.69 (s, 1 H), 8.13 (d, J= 9.6 Hz, 1 H), 7.24 7.19 (m, 4 H), 6.87 (d, J= 9.6 Hz, 1 H), 5.48 (s, 2 H), 3.82 (s, 3 H), 3.54 (s, 2 H), 2.79 (t, J= 13.4 Hz, 2 H), 2.65 - 2.62 (m, 2 H), 2.22 - 2.19 (m, 2 H), 1.69 - 1.67 (m, 1 H), 1.02 - 1.00 (m, 2 H), 0.75 - 0.73 (m, 2 H).

[0431] Example B20: Synthesis of Compound 11

[0432] 2-chloro-N-(4-(5-methyI-3-(trifluoromethyl)-lH-pyrazoI-l-yl)benzyl)-5nitropyrimidin-4-amine

[0433] To a solution of {4-[5-methyl-3-(trifluoromethyl)-lH-pyrazol-l-yl] phenyl} methanamine (500 mg, 1.96 mmol) and 2,4-dichloro-5-nitropyrimidine (495 mg, 2.55 mmol) in EtOH (5 mL) was added N, N-diisopropylethylamine (0.97 mL, 5.88 mmol) at 0 °C. The mixture was stirred at rt for 16 h. Then the mixture was diluted with H2O (20 mL) and extracted with EtOAc (20 mL x 3). The combined organic fractions were washed with brine (20 mL), dried over Na2SO4, filtered and concentrated. The residue was purified by pre-TLC (PE/EA = 2/1) to give

148 desired product (450 mg, 1.09 mmol, 56%) as a yellow solid.

LCMS: Rétention time: 1.896 min, (M+H)⁺ =413.0, method A.

[0434] 4’-cyclopropyl-6'-methoxy-N-(4-(5-methyl-3-(trifluoromethyl)-lH-pyrazol-lyl)benzyI)-5-nitro-[2,5'-bipyrimidin]-4-amine

[0435] A mixture of 2-chloro-N-({4-[5-methyl-3-(trifluoromethyl)-lH-pyrazol-lyl]phenyl}methyl)-5-nitropyrimidin-4-amine (80 mg, 0.194 mmol), 4-cyclopropyl-6-methoxy-5(tetramethyl-l,3,2-dioxaborolan-2-yl)pyrimidine (80 mg, 0.29 mmol), cataCXium A Pd G3 (14 mg, 0.02 mmol) and K3PO4 (123 mg, 0.58 mmol) in THF (9 mL)/Water (1.5 mL) was stirred at 68 °C for 16 h. Then the mixture was cooled to rt, diluted with water (10 mL) and extracted with Ethyl Acetate (15 mL x 3). The organic phase was washed with brine (15 mL), dried with Na2SÛ4, filtered and concentrated to give the crude product. The crude product was purified by prep-TLC (ΡΕ/EtOAc = 3/2) to give the desired product (50 mg, 0.095 mmol, 49%) as a yellow oil.

LCMS: Rétention time: 1.957 min, (M+H)⁺ = 527.2, method A.

[0436] 4’-cyclopropyl-6’-methoxy-N4-(4-(5-methyl-3-(trifluoromethyl)-lH-pyrazol-lyl)benzyl)-[2,5'-bipyrimidine]-4,5-diamine

[0437] To a solution of 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-N-({4-[5-methyl-3(trifluoromethyl)-lH-pyrazol-l-yl] phenyl} methyl)-5-nitropyrimidin-4-amine (50 mg, 0.095 mmol) in EtOHÆhO (5 mL/Ι mL) was added Fe (27 mg, 0.47 mmol) and NH4CI (51 mg, 0.95 mmol). The mixture was stirred at 90 °C for 2 h and then cooled to room température. The reaction mixture was filtered. The filtrate was diluted with water (10 mL) and extracted with ethyl acetate (15 mL) for three times. The combined organic layer was washed with brine (15 mL), dried with Na2SÜ4, filtered and concentrated to give the crude product (40 mg, 0.08 mmol, 84%) as a yellow oil, which was used in next step without further purification.

LCMS: Rétention time: 1.107 min, (M+H)⁺= 497.2, method A.

[0438] 2-(4-cyclopropyl-6-methoxypyrimidin-5-yI)-8-(4-(5-methyl-3-(trifluoromethyl)-lHpyrazol-l-yI)benzyl)pteridin-7(8H)-one

[0439] To a solution of 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-N4-({4-[5-methyl-3(trifluoromethyl)-lH-pyrazol-l-yl] phenyl} methyl) pyrimidine-4,5-diamine (40 mg, 0.08 mmol) in éthanol (10 mL) was added Ethyl 2-oxoacetate (0.02 mL, 0.08 mmol). The mixture was degassed with N2 and stirred at 85 °C for 16 h. Then the reaction mixture was cooled to room température and concentrated to give the solid. Then the solid was dissolved in water (10 mL) and extracted with ethyl acetate (10 mL x 3). The organic layer was washed with brine (10 mL),

149 dried with anhydrous Na₂SC>4, filtered and concentrated to give the crude product. The crude product was purified by prep-TLC (PE/EA = 3/2) to afford the desired product (3.10 mg, 0.0058 mmol, 7%).

LCMS: Rétention time: 1.937 min, (M+H)⁺ = 535.2, method A.

Ή NMR: (400 MHz, DMSO-de) δ = 9.37 (s, 1 H), 8.70 (s, 1 H), 8.48 (s, 1 H), 7.56 - 7.49 (m, 4 H), 6.74 (s, 1 H), 5.50 (s, 2 H), 3.84 (s, 3 H), 2.31 (s, 3 H), 1.79 - 1.73 (m, 1 H), 1.03 - 1.02 (m, 2 H), 0.81 -0.78 (m, 2 H).

[0440] Example B21: Synthesis of Compound 12

Fe,NH₄CI

EtOH/H₂O, 90 °C, 2h

[0441] 2-chloro-N-(4-(l-isopropyl-4-(trifluoromethyl)-lH-imidazol-2-yl)benzyl)-5nitropyrimidin-4-amine

[0442] To a solution of {4-[l-(propan-2-yl)-4-(trifluoromethyl)-lH-imidazol-2-yl] phenyl} methanamine (790 mg, 2.79 mmol) in THF (20 mL) were added TEA (0.78 mL, 5.58 mmol) and 2, 4-dichloro-5-nitropyrimidine (595 mg, 3.07 mmol). The mixture was stirred at room température for 1 h and water (15 mL) was added. Then the resulting mixture was extracted with ethyl acetate (15 mL) for three times. The combined organic layer was washed with brine (30 mL), dried with Na₂SC>4, filtered and concentrated to give the crude product. The crude product was purified by flash chromatograph on silica gel (eluting with PE/EA = 15/1 to 10/1) to afford desired product (500 mg, 1.13 mmol, 40%) as yellow solid.

LCMS: Rétention time: 1.727 min, (M+H) ⁺ = 441.1, method A.

[0443] 4’-cyclopropyl-N-(4-(l-isopropyl-4-(trifluoromethyl)-lH-imidazol-2-yl)benzyl)-6'methoxy-5-nitro-[2,5'-bipyrimidin]-4-amine

[0444] To a solution of 2-chloro-5-nitro-N-({4-[l-(propan-2-yl)-4-(trifluoromethyl)-lHimidazol-2-yl]phenyl}methyl)pyrimidin-4-amine (475 mg, 1.08 mmol), 4-cyclopropyl-6methoxy-5-(tetramethyl-l,3,2-dioxaborolan-2-yl)pyrimidine (329 mg, 1.19 mmol) and K3PO4

150 (337 mg, l .59 mmol) in THF (5 mL) and H2O (0.5 mL) was added cataCXium A Pd G3 (5 mg, 0.01 mmol). The mixture was stirred at 68 °C for 16 h and then cooled to room température. The reaction mixture was diluted with water (15 mL) and extracted with ethyl acetate (15 mL x 3). The organic fractions were washed with brine (20 mL), dried over Na₂S()4, filtered and concentrated to give the crude product. The crude product was purified by prep-TLC (PE/EA = 5/1) to afford desired product (100 mg, 0.18 mmol, 17%) as a yellow oil.

LCMS: Rétention time: 1.917 min, (M+H) ⁺ = 555.2, method A.

[0445] 4’-cyclopropyl-N4-(4-(l-isopropyl-4-(trifluoromethyl)-lH-imidazol-2-yl)benzyl)-6'methoxy-[2,5’-bipyrimidine]-4,5-diamine

[0446] To a solution of 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-5-nitro-N-({4-[5-(propan-2yl)-3-(trifluoromethyl)-lH-pyrazol-l-yl]phenyl}methyl)pyrimidin-4-amine (100 mg, 0.18 mmol) in EtOH (12 mL) and H2O (2 mL) were added Fe (71 mg, 1.26 mmol) and NH4CI (67 mg, 1.26 mmol). The mixture was stirred at 90 °C for 2 h and then cooled to room température. The reaction mixture was concentrated and diluted with water (5 mL), extracted with ethyl acetate (10 mL) for three times. The combined organic layer was washed with brine (20 mL), dried with Na₂SO4, filtered and concentrated to give desired product (80 mg, 0.15 mmol, 83%) as yellow oil.

LCMS: Rétention time: 1.180 min, (M+H) ⁺ = 525.3, method A.

[0447] 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-8-(4-(l-isopropyl-4-(trifluoromethyl)lH-imidazoI-2-yl)benzyl)pteridin-7(8H)-one

[0448] To a solution of 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-N4-({4-[5-(propan-2-yl)-3(trifluoromethyl)-lH-pyrazol-l-yl] phenyl} methyl) pyrimidine-4, 5-diamine (80 mg, 0.15 mmol) in EtOH (10 mL) was added ethyl 2-oxoacetate (0.03 mL, 0.17 mmol, 50 w/w% in toluene). The mixture was degassed with N2 for three times and stirred at 85 °C for 16 h. Then the reaction mixture was cooled to room température and concentrated. The residue was diluted with water (10 mL) and extracted with ethyl acetate (10 mL x 3). The combined organic layer was dried with Na2SÜ4, filtered and concentrated to give the crude product. The crude product was purified by prep-TLC (PE/EtOAc = 2/1) to afford desired product (26.11 mg, 0.046 mmol, 31%).

LCMS: Rétention time: 1.667 min, (M+H) ⁺ = 563.2, method A.

Ή NMR: (400 MHz, DMSO-J₆) δ = 9.38 (s, 1 H), 8.70 (s, 1 H), 8.48 (s, 1 H), 8.17 (s, 1 H), 7.49 (s, 4 H), 5.50 (s, 2 H), 4.42 - 4.39 (m, 1 H), 3.84 (s, 3 H), 1.77 - 1.72 (m, 1 H), 1.38 (d,J= 6.8 Hz, 6 H), 1.03 - 1.01 (m, 2 H), 0.78 - 0.75 (m, 2 H).

151

[0449] Example B22: Synthesis of Compound 13

Intermediate A

Pd(PPh₃)₄, K₂CO₃dioxane/H₂O,100 °C, 3.5h

CPI

THF, rt, 16h

[0450] 4-amino-4’-cyclopropyl-6'-methoxy-[2,5’-bipyrimidine]-5-carbonitrile

[0451] A mixture of 4-amino-2-chloropyrimidine-5-carbonitrile (300 mg, 1.94 mmol), 4cyclopropyl-6-methoxy-5-(tetramethyl-l,3,2-dioxaborolan-2-yl)pyrimidine (697 mg, 2.52 mmol), Pd(PPh3)4 (449 mg, 0.39 mmol) and K2CO3 (537 mg, 3.88 mmol) in dioxane (8 mL)/water (1 mL) was stirred at 100 °C for 3.5 h. Then the mixture was diluted with water (15 mL) and extracted with EtOAc (15 mL x 3). The combined organic fractions were washed with brine (20 mL), dried over Na₂SÛ4, filtered and concentrated. The residue was purified by prepTLC (PE/EA = 2/1) to give desired product (156 mg, 0.58 mmol, 30%) as a white solid.

LCMS: Rétention time: 1.027 min, (M+H)⁺ = 269.2, method A.

[0452] 4’-cyclopropyl-6’-methoxy-4-((4-(5-methyl-3-(trifluoromethyI)-lH-pyrazol-lyl)benzyl)amino)-[2,5’-bipyrimidine]-5-carbonitrile

[0453] To a mixture of 4-amino-2-(4-cyclopropyl-6-methoxypyrimidin-5-yl) pyrimidine-5carbonitrile (156 mg, 0.58 mmol) and K.2CO3 (241 mg, 1.74 mmol) in DMF (5 mL) was added 1[4-(chloromethyl) phenyl]-5-methyl-3-(trifluoromethyl)-lH-pyrazole (208 mg, 0.76 mmol). The mixture was stirred at rt for 16 h. Then the mixture was diluted with water (15 mL) and extracted with EtOAc (15 mL x 3). The combined organic fractions were washed with brine (20 mL X 2), dried over Na₂SÛ4, filtered and concentrated. The residue was purified by prep-TLC (PE/EA = 2/1) to give desired product (90 mg, 0.178 mmol, 30%) as a yellow oil.

LCMS: Rétention time: 1.757 min, (M+H) ⁺ = 507.2, method A.

[0454] 5-(aminomethyl)-4’-cyclopropyl-6'-methoxy-N-(4-(5-methyl-3-(trifluoromethyl)-lHpyrazoI-l-yI)benzyl)-[2,5’-bipyrimidin]-4-amine

[0455] To a mixture of 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-4-[({4-[5-methyl-3(trifluoromethyl)-lH-pyrazol-l-yl]phenyl}methyl)amino]pyrimidine-5-carbonitrile (80 mg, 0.16

152 mmol) in MeOH (3 mL) and THF (0.8 mL) were added Ammonium hydroxide (0.6 mL) and excess amount of moist Raney Ni. The mixture was stirred at room température for 2 h under H2. The mixture was filtered and concentrated to give crude product (60 mg, 0.12 mmol, 75%) as a yellow oil, which was used for next step directly.

LCMS: Rétention time: 1.180 min, (M+H) ⁺ = 511.2, method A.

[0456] 7-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-l-(4-(5-methyl-3-(trifluoromethyl)-lHpyrazol-l-yl)benzyl)-3,4-dihydropyrimido[4,5-d]pyrimidin-2(lH)-one

[0457] To a solution of 5-(aminomethyl)-2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-N-({4-[5methyl-3-(trifluoromethyl)-IH-pyrazol-l-yl] phenyl} methyl) pyrimidin-4-amine (50 mg, 0.10 mmol) in THF (3 mL) was added CDI (18 mg, 0.11 mmol). The mixture was stirred at rt under Ar for 16 h. Then the mixture was concentrated and dissolved in water (10 mL). The solution was extracted with EtOAc (10 mL x 3). The combined organic fractions were washed with brine (20 mL), dried over Na2SÜ4, filtered and concentrated. The residue was purified by prep-TLC (PE/EA = 1/3) to give desired product (14.27 mg, 0.027 mmol, 27 %).

LCMS: Rétention time: 1.780min, (M+H) ⁺= 537.2, method A.

Ή NMR (400 MHz, DMSO-î/₆) δ = 8.63 (s, 1 H), 8.54 (s, 1 H), 7.71 (s, 1 H), 7.49 - 7.41 (m, 4 H), 6.74 (s, 1 H), 5.17 (s, 2 H), 4.52 (s, 2 H), 3.80 (s, 3 H), 2.31 (s, 3 H), 1.63 - 1.60 (m, 1 H), 0.97 - 0.95 (m, 2 H), 0.77 - 0.74 (m, 2 H).

[0458] Example B23: Synthesis of Compound 14

[0459] 2-chloro-5-methoxy-N-(4-(5-methyl-3-(trifluoromethyI)-lH-pyrazoI-l yl)benzyl)pyrimidin-4-amine

[0460] To a mixture of 2,4-dichloro-5-methoxypyrimidine (281 mg, 1.57 mmol) and {4-[5methyl-3-(trifluoromethyl)-lH-pyrazol-l-yl]phenyl}methanamine (400 mg, 1.57 mmol) in EtOH (6 mL) was added DIPEA (0.52 mL, 3.13 mmol) at 0 °C. The resulting mixture was stirred at rt for 16 h. Then the mixture was quenched with H2O (20 mL) and extracted with EtOAc (20 mL x

153

3). The combined organic fractions were washed with brine (15 mL), dried over Na₂SO₄, filtered and concentrated. The residue was purified by column chromatography on silica gel (eluting with DCM/MeOH from lOO/l to 20/1) to give desired product (420 mg, 1.06 mmol, 67%) as a yellow solid.

LCMS: Rétention time: 1.900 min, (M+H) ⁺ = 398.1, method A.

[0461] 2-chloro-4-((4-(5-methyl-3-(trifluoromethyI)-1 H-pyrazol-1 yl)benzyl)amino)pyrimidin-5-ol

[0462] To a solution of 2-chloro-5-methoxy-N-({4-[5-methyl-3-(trifluoromethyl)-lH-pyrazol-lyl] phenyl} methyl)-pyrimidin-4-amine (420 mg, 1.06 mmol) in DCM (15 mL) was added BBr₃(0.197 mL, 2.11 mmol) at 0 °C. The mixture was stirred at rt for 16 h. Then the mixture was quenched with H₂O (20 mL) and extracted with DCM (20 mL x 3). The combined organic fractions were washed with brine (15 mL), dried over Na₂SO₄, filtered and concentrated. The residue was purified by column chromatography on silica gel (eluting with PE/EA from 100/1 to 3/1) to give desired product (278 mg, 0.72 mmol, 68%) as a yellow solid.

LCMS: Rétention time: 1.680 min, (M+H) ⁺ = 384.1, method A.

[0463] ethyl 2-((2-chloro-4-((4-(5-methyl-3-(trifluoromethyl)-lH-pyrazol-lyl)benzyl)amino)pyrimidiii-5-yl)oxy)acetate

[0464] To a mixture of 2-chloro-4-[({4-[5-methyl-3-(trifluoromethyl)-lH-pyrazol-l-yl] phenyl} methyl) amino] pyrimidin-5-ol (450 mg, 1.17 mol) and K₂CO₃ (324 mg, 2.35 mmol) in DMF (8 mL) was added ethyl 2-bromoacetate (294 mg, 1.76 mmol). The mixture was stirred at rt for 16 h. Then the mixture was diluted with water (20 mL) and extracted with EtOAc (20 mL x 3). The combined organic fractions were washed with brine (15 mL), dried over Na₂SO₄, filtered and concentrated. The residue was purified by column chromatography on silica gel (eluting with PE/EA from 100/1 to 3/1) to give desired product (370 mg, 0.79 mmol, 67%) as a yellow solid. LCMS: Rétention time: 1.820 min, (M+H) ⁺ =469.8, method A.

[0465] 2-(4-cydopropyl-6-methoxypyrimidin-5-yI)-8-(4-(5-methyl-3-(trifluoromethyl)-lHpyrazol-l-yl)benzyI)-6H-pyrimido[5,4-b][l,4]oxazin-7(8H)-one

[0466] A mixture of ethyl 2-({2-chloro-4-[({4-[5-methyl-3-(trifluoromethyl)-lH-pyrazol-lyl]phenyl}methyl)amino]pyrimidin-5-yl}oxy)acetate (200 mg, 0.43 mmol), 4-cyclopropyl-6methoxy-5-(tetramethyl-l,3,2-dioxaborolan-2-yl)pyrimidine (153 mg, 0.55 mmol), Pd(PPh₃)4 (98 mg, 0.09 mmol) and K₂CO₃ (118 mg, 0.85 mmol) in dioxane (5 mL) and H₂O (0.50 mL) was stirred at 100 °C under Ar for 4 h. Then the mixture was diluted with water (20 mL) and extracted with EtOAc (20 mL x 3). The combined organic fractions were washed with brine (15

154 mL), dried over Na₂SO4, filtered and concentrated. The residue was purified by prep-TLC (DCM/Me OH = 20/l) to afford desired product (17.14 mg, 0.032 mmol, 7%).

LCMS: Rétention time: 1.900 min, (M+H) ⁺ =537.8, method A.

'HNMR (400 MHz, DMSO-tA) δ 8.64 = (s, 1 H), 8.53 (s, 1 H), 7.51 (s, 4 H), 6.75 (s, 1 H), 5.25 (s, 2 H), 5.05 (s, 2 H), 3.81 (s, 3 H), 2.31 (s, 3 H), 1.70 - 1.66 (m, 1 H), 1.01 - 0.97 (m, 2 H), 0.80 - 0.76 (m, 2 H).

[0467] Example B24: Synthesis of Compound 15

[0468] ethyl (4-(5-methyl-3-(trifluoromethyl)-lH-pyrazol-l-yl)benzyl)glycinate

[0469] To a solution of {4-[5-methyl-3-(trifluoromethyl)-lH-pyrazol-l-yl] phenyl} methanamine (50 mg, 0.20 mmol) in THF (5 mL) were added TEA (0.08 mL, 0.59 mmol) and ethyl-2-bromoacetate (37 mg, 0.22 mmol). The mixture was stirred at room température for 0.5 h. Then the reaction mixture was diluted with ethyl acetate (20 mL) and washed with brine (15 mL). The organic layer was dried with Na₂SO4, filtered and concentrated to give the crude product. The crude product was purified by prep-TLC (PE/EA = 5/1) to afford the desired product (35 mg, 0.10 mmol, 50%) as a yellow oil.

LCMS: Rétention time: 1.297 min, (M+H) ⁺ = 342.1, method A.

[0470] ethyl N-(2-chloro-5-nitropyrimidin-4-yl)-N-(4-(5-methyl-3-(trifluoromethyl)-lHpyrazol-l-yl)benzyl)glycinate

[0471] To a solution of ethyl 2-[({4-[5-methyl-3-(trifluoromethyl)-lH-pyrazol-l-yl] phenyl} methyl) amino] acetate (500 mg, 1.46 mmol) in THF (10 mL) were added TEA (0.41 mL, 2.93 mmol) and 2,4-dichloro-5-nitropyrimidine (312 mg, 1.61 mmol). The mixture was stirred at room température for 2 h. Then the reaction mixture was diluted with water (20 mL) and extracted with Ethyl Acetate (20 mL x 3). The combined organic layer was washed with brine

155 (20 mL), dried with Na₂SO4, filtered and concentrated to give the crude product. The crude product was purified by prep-TLC (PE/EA = 3/2) to afford the desired product (270 mg, 0.54 mmol, 37%) as yellow oil.

LCMS: Rétention time: 1.937 min, (M+H) + = 499.1, method A.

[0472] 2-chloro-8-(4-(5-methyl-3-(trifluoromethyl)-lH-pyrazol-l-yl)benzyl)-7,8dihydropteridin-6(5H)-one

[0473] To a solution of ethyl 2-[(2-chloro-5-nitropyrimidin-4-yl) ({4-[5-methyl-3(trifluoromethyl)-lH-pyrazol-l-yl] phenyl} methyl) amino] acetate (150 mg, 0.30 mmol) in EtOEl (10 mL) and H₂O (2 mL) was added Fe (84 mg, 1.50 mmol) and NH4CI (112 mg, 2.10 mmol). The mixture was stirred at 90 °C for 2 h. Then the reaction mixture was cooled to room température, filtered and concentrated to give a residue. The residue was diluted with water (10 mL) and extracted with Ethyl Acetate (10 mL x 3). The organic phase was washed with brine (10 mL), dried over Na₂SÛ4, filtered and concentrated to give the desired product (110 mg, 0.26 mmol, 86%) as yellow solid.

LCMS: Rétention time: 1.767 min, (M+H) + = 423.1, method A.

[0474] 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-8-(4-(5-methyl-3-(trifluoromethyl)-lHpyrazol-l-yl)benzyl)-7,8-dihydropteridin-6(5H)-one

[0475] To a mixture of 2-chloro-8-({4-[5-methyl-3-(trifluoromethyl)-lH-pyrazol-l-yl] phenyl} methyl)-5,6,7,8-tetrahydropteridin-6-one (40 mg, 0.095 mmol), 4-cyclopropyl-6-methoxy-5(tetramethyl-l,3,2-dioxaborolan-2-yl)pyrimidine (39 mg, 0.14 mmol) and Na₂CO₃ (30 mg, 0.28 mmol) in dioxane (5 mL) and H₂O (1 mL) was added Pd(PPh₃)4 (11 mg, 0.01 mmol) under N₂atmosphère. The mixture was stirred at 100 °C for 2 h and then cooled to room température. The reaction mixture was diluted with water (10 mL) and extracted with Ethyl Acetate (10 mL x 3). The organic phase was washed with brine (10 mL), dried over Na₂SO4, filtered and concentrated to give the crude product. The crude product was purified by prep-TLC (DCM/MeOH = 15/1) to afford the desired product (12.00 mg, 0.022 mmol, 23%).

LCMS: Rétention time: 1.707 min, (M+H) ⁺ = 537.2, method A.

Ή NMR: (400 MHz, DMSO-i/é) δ = 10.89 (s, 1 H), 8.61 (s, 1 H), 7.88 (s, 1 H), 7.53 (s, 4 H), 6.75 (s, 1 H), 4.83 (s, 2 H), 4.15 (s, 2 H), 3.85 (s, 3 H), 2.33 (s, 3 H), 1.83 - 1.74 (m, 1 H), 1.00 0.99 (m, 2 H), 0.85 - 0.83 (m, 2 H)

[0476] Example B25: Synthesis of Compound 16

156

Compound 16

[0477] 2-chloro-8-(4-(5-methyl-3-(trifluoromethyl)-lH-pyrazol-l-yl)benzyl)-7,8-dihydro6H-pyrimido [5,4-b] [ 1,4] oxazine

[0478] To a solution of 2-chloro-6H,7H,8H-pyrimido[5,4-b][l,4]oxazine (100 mg, 0.58 mmol) in DMF (2 mL) were added K2CO3 (242 mg, 1.75 mmol) and l-[4-(chloromethyl)phenyl]-5methyl-3-(trifluoromethyl)-lH-pyrazole (176 mg, 0.64 mmol) at rt. The reaction mixture was stirred at room température for 16 h. Then the mixture was diluted with water (15 mL) and extracted with EtOAc (20 mL x 2). The combined organic layers were washed with brine (20 mL x 2), dried over Na2SO₄, filtered and concentrated under vacuum. The residue was purified by column chromatography on silica gel eluted with PE/EA = 1/2 to afford the desired product (150 mg, 0.37 mmol, 63%) as a white solid.

LCMS: Rétention time: 1.912 min, (M+H) ⁺ = 410.0, method B.

[0479] 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-8-(4-(5-methyl-3-(trifluoromethyl)-lHpy razol-1 -yl)benzy!)-7,8-dihydro-6H-py rimido [5,4-b] [1,4] oxazine

[0480] To a solution of l-[4-({2-chloro-6H,7H,8H-pyrimido[5,4-b][l,4]oxazin-8yl}methyl)phenyl]-5-methyl-3-(trifluoromethyl)-lH-pyrazole (100 mg, 0.244 mmol) in dioxane (2 mL) and H2O (0.4 mL) were added 4-cyclopropyl-6-methoxy-5-(tetramethyl-l,3,2dioxaborolan-2-yl)pyrimidine (81 mg, 0.293 mmol), Na?CO3 (78 mg, 0.722 mmol) and Pd(dppf)Ch (18 mg, 0.024 mmol). The mixture was stirred at 90 °C for 4 h under nitrogen atmosphère. Then the mixture was diluted with water (15 mL) and extracted with EtOAc (20mL x 2). The combined organic layers were washed with brine (50 mL X 2), dried over Na2SO₄, filtered and concentrated under vacuum. The residue was purified by prep-TLC (PE/EA = 1/5) to afford desired product (10.00 mg, 0.019 mmol, 8%).

LCMS: Rétention time: 1.386 min, (M+H)⁺ = 524.0, method B.

Ή NMR (400 MHz, MeOD-Λ) δ = 8.53 (s, 1 H), 7.88 (s, 1 H), 7.54 - 7,44 (m, 4 H), 6.57 (s, 1 H), 4.98 (s, 2 H), 4.30 (t, J= 4.4 Hz, 2 H), 3.92 (s, 3 H), 3.65 (t, J= 4.8 Hz, 2 H), 2.34 (s, 3 H), 1.84 - 1.71 (m, 1 H), 1.10 -1.08 (m, 2 H), 0.90 - 0.86 (m, 2 H).

[0481] Example B26: Synthesis of Compound 17

157

[0482] methyl 2-acetyl-l,2,3,4-tetrahydroisoquinoline-6-carboxylate

[0483] To a solution of methyl l,2,3,4-tetrahydroisoquinoline-6-carboxylate (500 mg, 2.62 mmol) in DCM (15 mL) were added DIPEA (0.95 mL, 5.75 mmol) and acetyl chloride (226 mg, 2.88 mmol). The mixture was stirred at rt for 1 h. Then the mixture was diluted with water (15 mL) and extracted with DCM (15 mL x 3). The organic phases were washed with brine (15 mL), dried over Na2SC>4, filtered and concentrated to give desired product (600 mg, 2.58 mmol, 98% yield) as a colorless oil.

LCMS: Rétention time: 1.276min, (M+H)⁺ = 234.2, method A.

[0484] methyl 2-acetyl-l-oxo-l,2,3,4-tetrahydroisoquinoline-6-carboxylate

[0485] To a solution of methyl 2-acetyl-l,2,3,4-tetrahydroisoquinoline-6-carboxylate (400 mg, 1.71 mmol) in DCM (15 mL) were added 18-crown-6 (36 mg, 0.14 mmol) and KMnCU (542 mg, 3.43 mmol). The mixture was stirred at rt for 2 h. Then the mixture was diluted with water (15 mL) and filtered. The filtrate was extracted with DCM (15 mL x 3). The combined organic phases were washed with brine (15 mL), dried over Na2SÛ4, filtered and concentrated to give desired product (420 mg, 1.70 mmol, 99% yield) as a black oil.

LCMS: Rétention time: 1.180min, (M+H) ⁺ = 248.2, method A.

[0486] methyl l-oxo-l,2,3,4-tetrahydroisoquinoline-6-carboxylate

[0487] Sodium methoxide (263 mg, 4.86 mmol) was added to the solution of methyl 2-acetyl-loxo-l,2,3,4-tetrahydroisoquinoline-6-carboxylate (400 mg, 1.62 mmol) in MeOH (10 mL) at 0

158 °C. The mixture was stirred at rt for 2 h. Then the mixture was diluted with water (15 mL) and extracted with DCM (15 mL x 3). The combined organic phases were washed with brine (15 mL), dried over Na2SÜ4, filtered and concentrated to give desired product (330 mg, 1.60 mmol, 99% yield) as a black oil.

LCMS: Rétention time: 1.157min, (M+H)⁺ = 206.2, method A.

[0488] methyl 2-methyl-l-oxo-l,2,3,4-tetrahydroisoquinoIine-6-carboxylate

[0489] NaH (47 mg, 1.17 mmol, 60% dispersion in minerai oil) was added to the solution of methyl l-oxo-l,2,3,4-tetrahydroisoquinoline-6-carboxylate (200 mg, 0.97 mmol) in THF (5 mL) and DMF (1 mL) at 0 °C. The mixture was stirred at 0 °C for 15 min. Then Methyl lodide (166 mg, 1.17 mmol) was added. After stirred at rt for 2 h, the mixture was diluted with water (15 mL) and extracted with DCM (15 mL x 3). The combined organic phases were washed with brine (15 mL), dried over Na2SÛ4, filtered and concentrated. The residue was purified by reverse column chromatography (H2O/ACN from 100:0 to 4:1) to give desired product (130 mg, 0.59 mmol, 61%) as a white solid.

LCMS: Rétention time: 1.233min, (M+H)⁺ = 220.2, method A.

[0490] 6-(hydroxymethyl)-2-methyl-3,4-dihydroisoquinoIin-l(2H)-one

[0491] LiBH4 (24 mg, 1.09 mmol) was added to the solution of methyl 2-methyl-l-oxo-l,2,3,4tetrahydroisoquinoline-6-carboxylate (120 mg, 0.55 mmol) in THF (6 mL) at 0 °C. The mixture was stirred at rt for 16 h. Then the mixture was diluted with water (15 mL) and extracted with EtOAc (15 mL x 3). The combined organic phases were washed with brine (15 mL) and dried over Na2SO4, filtered and concentrated. The residue was purified by reverse chromatography (H2O/ACN from 100/0 to 3/1) to give desired product (65 mg, 0.34 mmol, 62%) as a white solid. LCMS: Rétention time: 0.828min, (M+H)⁺ = 192.1, method A.

[0492] 6-(chloromethyl)-2-methyl-3,4-dihydroisoquinolin-l(2H)-one

[0493] Sulfurous dichloride (3.00 mL, 41.35 mmol) was added to the solution of 6(hydroxymethyl)-2-methyl-l,2,3,4-tetrahydroisoquinolin-l-one (60 mg, 0.31 mmol) in DCE (5 mL). The mixture was stirred at 50 °C for 30 min. Then the mixture was concentrated to give crude product as a brown oil, which was used for next step directly.

LCMS: Rétention time: 1.273min, (M+H)⁺ = 210.1, method A.

[0494] tert-butyl 2-chloro-6,7-dihydro-8H-pyrimido[5,4-b][l,4]oxazine-8-carboxylate [0495] To a solution of 2-chloro-6H,7H,8H-pyrimido[5,4-b][l,4]oxazine (200 mg, 1.17 mmol) in DMF (4 mL) were added di-tert-butyl dicarbonate (382 mg, 1.75 mmol), TEA (0.32 mL, 2.33 mmol) and DMAP (14 mg, 0.12 mmol). The mixture was stirred at rt for 16 h. Then the mixture

159 was diluted with water (15 mL) and extracted with EtOAc (15 mL x 3). The combined organic phases were washed with brine (15 mL) and dried over Na2SÛ4, filtered and concentrated. The residue was purified by column chromatography on silica gel (eluting with PE/EtOAc from 100/0 to 5/1) to afford desired product (250 mg, 0.92 mmol, 79%) as a white solid.

LCMS: Rétention time: 1.527min, (M+H) ⁺ =272.1, method A.

[0496] tert-butyl 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-6,7-dihydro-8H-pyrimido[5,4b] [l,4]oxazine-8-carboxylate

[0497] To a solution of tert-butyl 2-chloro-6H,7H,8H-pyrimido[5,4-b][l,4]oxazine-8carboxylate (230 mg, 0.85 mmol) in dioxane (5 mL) and water (1 mL) were added 4cyclopropyl-6-methoxy-5-(tetramethyl-l,3,2-dioxaborolan-2-yl)pyrimidine (234 mg, 0.85 mmol), Pd(PPha)4 (98 mg, 0.08 mmol) and Na2CCh (179 mg, 1.69 mmol). The mixture was stirred at 100 °C for 16 h. Then the mixture was cooled to rt, diluted with water (15 mL) and extracted with EtOAc (15 mL x 3). The combined organic phases were washed with brine (15 mL) and dried over Na2SÜ4, filtered and concentrated. The residue was purified by column chromatography on silica gel (eluting with PE/EtOAc from 100/0 to 5/1) to afford desired product (200 mg, 0.52 mmol, 61%) as a white solid.

LCMS: Rétention time: 1.497min, (M+H)⁺ =386.2, method A.

[0498] 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-7,8-dihydro-6H-pyrimido[5,4b][l,4]oxazine

[0499] The solution of tert-butyl 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-6H,7H,8Hpyrimido[5,4-b][l,4]oxazine-8-carboxylate (200 mg, 0.52 mmol) in TFA (3 mL, 40.39 mmol) and DCM (6 mL) was stirred at rt for 2 h. Then the mixture was diluted with DCM (15 mL) and NaHCCh (50 mg) was added. The mixture was stirred for 30 min, filtered and concentrated. The residue was purified by reverse column chromatography (H2O/ACN from 100/0 to 9/1) to afford desired product (100 mg, 0.35 mmol, 67%) as a white solid.

LCMS: Rétention time: 0.760min, (M+H)⁺ =286.2, method A.

[0500] 6-((2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-6,7-dihydro-8H-pyrimido[5,4b][l,4]oxazin-8-yl)methyl)-2-methyl-3,4-dihydroisoquinolin-l(2H)-one

[0501] NaH (60% dispersion in minerai oil) (0.8 mg, 0.02 mmol) was added to the solution of 4cyclopropyl-6-methoxy-5-{6H,7H,8H-pyrimido[5,4-b][l,4]oxazin-2-yl}pyrimidine (50 mg, 0.18 mmol) in DMF (5 mL) at 0 °C. The mixture was stirred for 5 min. Then 6-(chloromethyl)-2methyl-l,2,3,4-tetrahydroisoquinolin-l-one (37 mg, 0.18 mmol) was added. The mixture was stirred at rt for 1 h. Then the mixture was quenched with sat.aq NH4CI (15 mL) and extracted

160 with EtOAc (15 mL x 3). The combined organic phases were washed with brine (15 mL) and dried over Na2SO₄, filtered and concentrated. The residue was purified by prep-TLC (DCM/MeOH = 30/1) to afford desired product (3.00 mg, 0.0066 mmol, 4%).

LCMS: Rétention time: 1.090min, (M+H)⁺ =459.2, method A.

Ή NMR (400 MHz, DMSO-ifc) δ = 8.58 (s, 1 H), 7.95 (s, 1 H), 7.80 (d, ./ = 7.6 Hz, 1 H), 7.23 (d, J= 8.0 Hz, 1 H), 7.16 (s, 1 H), 4.81 (s, 2 H), 4.28 (br s, 2 H), 3.82 (s, 3 H), 3.60 - 3.48 (m, 4 H), 3.00 (s, 3 H), 2.92 (t, J= 6.6 Hz, 2 H), 1.74 - 1.70 (m, 1 H), 0.98 - 0.93 (m, 2 H), 0.80 - 0.74 (m, 2 H).

[0502] Example B27: Synthesis of Compound 18

[0503] 2-chloro-8-(4-fluorobenzyl)-7,8-dihydro-6H-pyrimido[5,4-b][l,4]oxazine

[0504] NaH (28 mg, 60 % dispersion in minerai oil, 0.70 mmol) was added to the solution of 2chloro-6H,7H,8H-pyrimido[5,4-b][l,4]oxazine (100 mg, 0.58 mmol) in DMF (2 mL) at 0 °C under N2. Then 1-(bromomethyl)-4-fluorobenzene (132 mg, 0.70 mmol) was added. The mixture was stirred at rt for 2 h. Then the mixture was quenched with water (15 mL) at 0 °C and extracted with EtOAc (20 mL x 3). The combined organic phases were washed with brine (15 mL) and dried over Na2SO₄, filtered and concentrated. The residue was purified by column chromatography on silica gel (eluting with ΡΕ/EtOAc = 100/0 to 5/1) to afford desired product (120 mg, 0.43 mmol, 74%) as white solid

LCMS: Rétention time: 1.707min, (M+H)⁺ = 280.2, method A.

[0505] 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-8-(4-fluorobenzyl)-7,8-dihydro-6Hpyrimido[5,4-b] [l,4]oxazine

[0506] To a solution of 2-chloro-8-[(4-fluorophenyl)methyl]-6H,7H,8H-pyrimido[5,4b][l,4]oxazine (100 mg, 0.36 mmol) in dioxane (5 mL) and Water (1 mL) were added 4cyclopropyl-6-methoxy-5-(tetramethyl-l,3,2-dioxaborolan-2-yl)pyrimidine (99 mg, 0.36 mmol), Pd(PPhs)₄ (41 mg, 0.04 mmol) and Na2COa (76 mg, 0.72 mmol). The mixture was stirred at 100 °C for 16 h. Then the mixture was diluted with water (15 mL) and extracted with EtOAc (20 mL x 2). The combined organic phases were washed with brine (15 mL) and dried over Na₂SO₄, filtered and concentrated. The residue was purified by prep-TLC(PE/EA = 1/3) to afford desired

161 product (62.00 mg, 0.16 mmol, 44%).

LCMS: Rétention time: 1.327min, (M+H)⁺ = 394.2 method A.

Ή NMR (400 MHz, DMSO-î/₆): δ = 8.59 (s, 1 H), 7.93 (s, 1 H), 7.38 - 7.31 (m, 2 H), 7.20 - 7.12 (m, 2 H), 4.76 (s, 2 H), 4.40 - 4.13 (m, 2 H), 3.84 (s, 3 H), 3.58 - 3.48 (m, 2 H), 1.76 - 1.70 (m, 1 H), 1.01 - 0.97 (m, 2 H), 0.85 - 0.81 (m, 2 H).

[0507] Example B28: Synthesis of Compound 19

[0508] 4-hydroxybut-2-yn-l-yl methanesulfonate

[0509] To an ice-bath cooled solution of but-2-yne-l,4-diol (10.00 g, 116.16 mmol) in anhydrous THF (140 mL) were added methanesulfonyl chloride (13.305 g, 116.16 mmol) and TEA (16.15 mL, 116.73 mmol) at 0 °C. After the addition, the reaction mixture was allowed to warm up to rt and stirred at rt for 16 hrs. Then the mixture was concentrated under reduced pressure to give a residue, which was purified by column chromatography on silica gel eluting with MeOH (from 0% to 5.0%) in DCM to give the title compound (5.40 g, 32.89 mmol, 28% yield) as a yellow oil.

LC-MS(ESI+): m/z 165.1 (M+H)⁺.

[0510] 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-8-(4-hydroxybut-2-yn-l-yl)pyrido[2,3d]pyrimidin-7(8H)-one

[0511] A mixture of 4-hydroxybut-2-yn-l-yl methanesulfonate (361 mg, 2.20 mmol) and potassium iodide (141 mg, 0.85 mmol) in DMF (30 mL) was stirred at rt for 0.5 hr. 2-(4

162 cyclopropyl-6-methoxypyrimidin-5-yl)pyrido[2,3-d]pyrimidin-7(8H)-one (500 mg, 1.69 mmol) and K2CO3 (585 mg, 4.23 mmol) were added to the mixture. The reaction mixture was stirred at 50 °C for 16 hr. After cooling to rt, to the mixture was added H2O (40 mL). After extraction with EtOAc (40 mL x 3), the combined organic layers were washed with brine (100 mL), dried over Na2SÛ4, filtered and concentrated under reduced pressure to give a residue, which was purified by column chromatography on silica gel eluting with ethyl acetate (from 5.0% to 50.0%) in dichloromethane to give the title compound (473 mg, 1.30 mmol, 77% yield).

LC-MS(ESI+): m/z 364.1 (M+H)⁺.

[0512] 4-(2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-7-oxopyrido[2,3-d]pyrimidin-8(7H)yl)but-2-ynal

[0513] To a solution of 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-8-(4-hydroxybut-2-yn-lyl)pyrido[2,3-d]pyrimidin-7(8H)-one (400 mg, 1.10 mmol) in DCM (15 mL) was added DessMartin periodinane (653 mg, 1.54 mmol) at 0 °C. The reaction mixture was stirred at rt for 1 hr. Then the mixture was diluted with DCM (50 mL). The solution was washed with 10% sodium thiosulfate aqueous solution (20 mL) and saturated NaHCCh solution (20 mL). The organic layer was washed with brine (50 mL), dried over Na2SÜ4, filtered and concentrated under reduced pressure to give a residue, which was purified by column chromatography on silica gel eluting with ethyl acetate (from 0% to 10.0%) in petroleum ether to give the title compound (230 mg, 0.64 mmol, 58% yield).

LC-MS(ESI+): m/z 362.0 (M+H)⁺.

[0514] 2-(4-cyclopropyI-6-methoxypyrimidin-5-yl)-8-(3-(4-(trifluoromethyl)-lH-imidazol-2yl)prop-2-yn-l-yI)pyrido[2,3-d]pyrimidin-7(8H)-one

[0515] To a solution of 3,3-dibromo-1,1,1-trifluoropropan-2-one (202 mg, 0.75 mmol) in H2O (1 mL) was added NaOAc (103 mg, 1.25 mmol) at 0 °C. The mixture was stirred at 100 °C for lh. After cooling to rt, a mixture of 4-(2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-7-oxopyrido[2,3d]pyrimidin-8(7H)-yl)but-2-ynal (180 mg, 0.50 mmol) and NH4OH (1 mL) in MeOH (3 mL) was added. The resulting mixture was stirred at rt for 16 hr. Then to the mixture was added water (20 mL). After extraction with EtOAc (20 mL x 3), the combined organic layers were washed with brine (30 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue, which was purified by column chromatography on silica gel eluting with ethyl acetate (from 0% to 40.0%) in petroleum ether to give the title compound (200 mg, 0.43 mmol, 86% yield).

LC-MS(ESI+): m/z 468.0 (M+H)⁺.

163

[0516] 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-8-(3-(l-methyl-4-(trifluoromethyl)-lHimidazol-2-yl)prop-2-yn-l-yl)pyrido[2,3-d]pyrimidin-7(8H)-one

[0517] 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-8-(3-(4-(trifluorornethyl)-lH-imidazol-2yl)prop-2-yn-l-yl)pyrido[2,3-d]pyrimidin-7(8H)-one (180 mg, 0.39 mmol) was dissolved in

DMF (3 mL). CS2CO3 (188 mg, 0.58 mmol) was added to the solution. The mixture was cooled and stirred at 0 °C for 10 minutes. Then CH3I (82 mg, 0.58 mmol) was added. The resulting mixture was stirred at rt for 16 hr. Then to the mixture was added water (20 mL). After extraction with EtOAc (15 mL x 2), the combined organic layers were washed with brine (20 mL), dried over Na2SÛ4, filtered and concentrated under reduced pressure to give a residue, which was purified by pre-HPLC (column: Waters X bridge Cl8 lOum OBD 19*250mm; mobile phase: [0.1%NH4HCO3 in water-CH3CN]; B%: 30%-9 5%, 8.45min) to give the title compound (2.68 mg, 98.63% purity, 0.0056 mmol, 1.4% yield).

LC-MS(ESI+): m/z 482.1 (M+H)⁺.

‘H NMR (400 MHz, DMSO-t/₆) δ = 9.30 (s, 1 H), 8.72 (s, 1 H), 8.16 (d, J= 10 Hz, 1 H), 7.90 (s, 15 1 H), 6.91 (d, J= 9.6 Hz, 1 H), 5.35 (s, 2 H), 3.84 (s, 3 H), 3.59 (s, 3 H), 1.91 - 1.83 (m, 1 H),

1.10 - 1.01 (m, 2 H), 0.90 - 0.79 (m, 2 H).

[0518] Example B29: Synthesis of Compound 20

Compound 20

[0519] 2-chloro-N-(2,4-dimethoxybenzyl)-5-nitropyrimidin-4-amine

164

[0520] To a solution of 2,4-dichloro-5-nitropyrimidine (5.00 g, 25.78 mmol) in THF (50 mL) were added (2,4-dimethoxyphenyl)methanamine (3.59 g, 21.47 mmol) and DIPEA (7.10 mL, 40.84 mmol) at 0 °C. The reaction mixture was stirred at rt for 16 hr. Then to the mixture was added water (50 mL). After extraction with EtOAc (50 mL x 3), the combined organic phases were washed with brine (75 mL), dried over Na₂SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel eluting with 0% to 50% EtOAc in PE to give the title compound (6 g, 18.48 mmol, 86% yield) as a brown solid. LC-MS(ESI+): m/z 325.2 (M+H)⁺.

[0521] 2-chloro-N⁴-[(2,4-dimethoxyphenyl)methyl]pyrimidine-4,5-diamine

[0522] To a solution of 2-chloro-N-(2,4-dimethoxybenzyl)-5-nitropyrimidin-4-amine (6.80 g, 20.94 mmol) in EtOH (40 mL) and H₂O (10 mL) were added Fe (5.85 g, 104.74 mmol) and NH4CI (11.20 g, 209.38 mmol). The reaction mixture was stirred at 90 °C for 2hr. After cooling to rt, the mixture was filtered. To the filtrate was added water (100 mL). After extraction with EtOAc (100 mL x 3), the combined organic phases were washed with brine (100 mL), dried over Na₂SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel eluting with 0% to 50% EtOAc in PE to give the title compound (4 g, 13.57 mmol, 65% yield).

LC-MS(ESI+): m/z 295.1 (M+H)⁺.

[0523] ethyl (E)-2-((2-chloro-4-((2,4-dimethoxybenzyI)ammo)pyrimidin-5-yl)imino)acetate [0524] Ethyl 2-oxoacetate (761 mg, 3.73 mmol, 50 wt% in toluene) was added to the solution of 2-chloro-N⁴-(2,4-dimethoxybenzyl)pyrimidine-4,5-diamine (1.00 g, 3.39 mmol) in EtOH (15 mL). The reaction mixture was stirred at 90 °C for 16 hr. After cooling to rt, to the mixture was added water (20 mL). After extraction with EtOAc (20 mL x 3), the combined organic phases were washed with brine (20 mL), dried over Na₂SÜ4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel eluting with 0% to 10% EtOAc in PE to give the title compound (1 g, 2.64 mmol, 78% yield) as a yellow solid. LC-MS(ESI+): m/z 379.1 (M+H)⁺.

[0525] 2-(4-cyclopropyl-6-methoxypyrimidin-5-yI)-8-(2,4-dimethoxybenzyl)pteridin-7(8H)one

[0526] To a solution of ethyl (E)-2-((2-chloro-4-((2,4-dimethoxybenzyl)amino)pyrimidin-5yl)imino)acetate (700 mg, 1.85 mmol) in dioxane (10 mL) and Water (0.7 mL) were added Pd(PPhs)4 (427 mg, 0.37 mmol), Na₂COa (392 mg, 3.70 mmol) and 4-cyclopropyl-6-methoxy-5(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyrimidine (510 mg, 1.85 mmol). The reaction

165 mixture was stirred at 100 °C for 16 hr. After cooling to rt, to the mixture was added water (20 mL). After extraction with EtOAc (20 mL x 3), the combined organic phases were washed with brine (30 mL), dried over Na₂SÛ4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel eluting with 0% to 50% EtOAc in PE to give the title compound (450 mg, 1.01 mmol, 55% yield) as a white solid.

[0527] LC-MS(ESI+): m/z 447.3 (M+H)⁺.

[0528] 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)pteridin-7(8H)-one

[0529] A solution of 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-8-(2,4dimethoxybenzyl)pteridin-7(8H)-one (600 mg, 1.34 mmol) in concentrated H₂SO4 (8 mL) was stirred at rt for 2 hr. Then the mixture was quenched with ice water (20 mL) and extracted with EtOAc (20 mL x 3). The combined organic phases were washed with brine (30 mL), dried over Na₂SÛ4, filtered and concentrated under reduced pressure. The residue was purified by reverse phase column chromatography eluting with 0% to 20% MeCN in water to give the title compound (200 mg, 0.68 mmol, 51% yield) as a white solid.

LC-MS(ESI+): m/z 297.2 (M+H)⁺.

[0530] 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-8-((4-(l-isopropyl-4-(trifluoromethyl)lH-imidazol-2-yl)cuban-l-yl)methyl)pteridin-7(8H)-one

[0531] Potassium iodide (35 mg, 0.21 mmol) was added to the solution of (4-(l-isopropyl-4(trifluoromethyl)-lH-imidazol-2-yl)cuban-l-yl)methyl methanesulfonate (167 mg, 0.43 mmol) in DMF (10 mL) at 0 °C. The mixture was stirred at 0 °C for 0.5 hr. Then 2-(4-cyclopropyl-6methoxypyrimidin-5-yl)pteridin-7(8H)-one (126 mg, 0.43 mmol) and potassium carbonate (118 mg, 0.85 mmol) was added to the mixture. The resulting mixture was stirred at 50 °C for 16 hr. After cooling to rt, to the mixture was added water (15 mL). After extraction with EtOAc (15 mL x 3), the combined organic phases were washed with brine (15 mL), dried over Na₂SO4, filtered and concentrated under reduced pressure. The residue was purified by prep-TLC (ΡΕ/EtOAc = 1/2) to give the title compound (10.00 mg, 0.017 mmol, 4% yield).

LC-MS(ESI+): m/z 589.2 (M+H)⁺.

’H NMR (400 MHz, DMSO-î/₆) δ 9.34 = (s, 1 H), 8.73 (s, 1 H), 8.46 (s, 1 H), 7.96 (s, 1 H), 4.59 (s, 2 H), 4.17-4.09 (m, 3 H), 4.00-3.89 (m, 4 H), 3.87 (s, 3 H), 1.75 - 1.63 (m, 1 H), 1.36 (d, J = 6.4 Hz, 6 H), 1.15 - 1.07 (m, 2 H), 0.95 - 0.86 (m, 2 H).

[0532] Example B30: Synthesis of Compound 22

166

Compound 22

[0533] 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-8-(4-(5-methyl-3-(trifluoromethyl)-lHpyrazol-l-yl)benzyl)-5,8-dihydropyrido[2,3-d]pyrimidin-7(6H)-one

[0534] A mixture of2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-8-(4-(5-methyl-3(trifluoromethyl)-lH-pyrazol-l-yl)benzyl)pyrido[2,3-d]pyrimidin-7(8H)-one (160 mg, 0.30 mmol) and Pd/C (50 mg, 10%) in EtOH (10 mL) was stirred at 50 °C for 16 hr under H₂. After cooling to rt, the mixture was filtered. The filtrate was concentrated under reduced pressure to give a residue, which was purified by pre-HPLC (column: Welch Ultimate XB-Phenyl lOum 21.2*250mm; mobile phase: [water (0.1%TFA)- ACN]; B%:10%ACN-95%ACN, 14min) to give the title compound (28.84 mg, 0.054 mmol, 18% yield).

LC-MS(ESI+): m/z 536.2 (M+H)⁺.

*H NMR (400 MHz, MeOD-Λ) δ = 8.65 (s, 2 H), 7.56 - 7.38 (m, 4 H), 6.57 (s, 1 H), 5.41 (s, 2 H), 3.92 (s, 3 H), 3.15 (t, J = 7.4 Hz, 2 H), 2.94 (t, J= 7.6 Hz, 2 H), 2.33 (s, 3 H), 1.79 - 1.69 (m, 1 H), 1.17 - 1.10 (m, 2 H), 0.91 - 0.83 (m, 2 H).

[0535] Example B31: Synthesis of Compound 23

2. NHxOH, MeOH, rt, 16h

23.1

[0536] methyl 4-(4-(trifluoromethyl)-lH-imidazol-2-yl)benzoate

167

[0537] To a solution of 3,3-dibromo-l,l,l-trifluoropropan-2-one (41.094 g, 152.29 mmol) in H2O (80 mL) was added NaOAc (24.98 g, 304.52 mmol) at 0 °C. The mixture was stirred at 100 °C for 1 hr and then cooled to rt. A solution of methyl 4-formylbenzoate (20.0 g, 121.83 mmol) and NH4OH (78.21 mL, 609.2 mmol, 30 wt%) in MeOH (250 mL) was added and the resulting mixture was stirred at rt for 16 hr. To the mixture was added water (300 mL). After extraction with EtOAc (300 mL x 3), the combined organic layers were washed with brine (300 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue, which was purified by column chromatography on silica gel eluting with ethyl acetate (from 0% to 20%) in Petroleum ether to give the title compound (24.2 g, 89.6 mmol, 74% yield) as a yellow oil. LC-MS(ESI+): m/z 271.0 (M+H)⁺.

[0538] methyl 4-(l-ethyl-4-(trifluoromethyl)-lH-imidazol-2-yl)benzoate

[0539] To a solution of methyl 4-(4-(trifluoromethyl)-lH-imidazol-2-yl)benzoate (2.00 g, 7.40 mmol) in DMF (30 mL) were added CS2CO3 (3.62 g, 11.11 mmol) and iodoethane (1.73 g, 11.09 mmol) at rt. The reaction mixture was stirred at 60 °C for 16 hr. After cooling to rt, to the mixture was added water (50 mL). After extraction with EtOAc (60 mL x 3), the combined organic layers were washed with brine (100 mL), dried over Na2SÛ4, filtered and concentrated under reduced pressure to give a residue, which was purified by column chromatography on silica gel eluting with ethyl acetate (from 0% to 25%) in petroleum ether to give the title compound (2 g, 6.71 mmol, 91% yield) as a yellow solid.

LC-MS(ESI+): m/z 299.2 (M+H)+.

[0540] (4-(l-ethyl-4-(trifluoromethyl)-lH-imidazol-2-yl)phenyl)methanol

[0541] To a solution of methyl 4-(l-ethyl-4-(trifluoromethyl)-lH-imidazol-2-yl)benzoate (2.00 g, 6.71 mmol) in THF (20 mL) was added L1AIH4 (0.51 g, 13.4 mmol) at 0 °C. The reaction mixture was stirred at 0 °C for 1 hr under N2 atmosphère. Then to the mixture was added water (50 mL). After extraction with EtOAc (50 mL x 3), the combined organic layers were washed with brine (70 mL), dried over Na2SÛ4, filtered and concentrated under reduced pressure to give a residue, which was purified by column chromatography on silica gel eluting with ethyl acetate (from 0% to 35%) in petroleum ether to give the title compound (1 g, 3.70 mmol, 55% yield) as a yellow oil.

LC-MS(ESI+): m/z 271.2 (M+H)⁺.

[0542] 2-(4-(chloromethyl)phenyl)-l-ethyl-4-(trifluoromethyI)-lH-imidazole

[0543] To a solution of (4-(l-ethyl-4-(trifluoromethyl)-lH-imidazol-2-yl)phenyl)methanol (1 g, 3.70 mmol) in DCE (9 mL) was added SOCI2 (3 mL, 41.36 mmol) dropwise at 0 °C. The

168 reaction mixture was stirred at 50 °C for 30 min. After cooling to rt, the mixture was concentrated in vacuo to give the title compound (l g, 3.46 mmol, 94% yield) as a yellow oil. LC-MS(ESI+): m/z 289.1 (M+H)⁺.

[0544] 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-8-(4-(l-ethyl-4-(trifluoromethyl)-lHimidazol-2-yl)benzyl)py rido [2,3-d] pyrimidin-7(8H)-one

[0545] To a solution of 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)pyrido[2,3-d]pyrimidin7(8H)-one (50 mg, 0.17 mmol) in DMF (2 mL) were added 2-(4-(chloromethyl)phenyl)-l-ethyl4-(trifluoromethyl)-lH-imidazole (64 mg, 0.22 mmol) and K2CO3 (117 mg, 0.85 mmol). The reaction mixture was stirred at rt for 16 hr. Then the mixture was quenched with water (10 mL) and extracted with EtOAc (10 mL x 3). The combined organic layers were washed with brine (15 mL), dried over Na2SÜ4, filtered and concentrated under reduced pressure to give a residue, which was purified by prep-TLC (DCM/EtOAc = 2/1) to give the title compound (33.41 mg, 0.061 mmol, 97.99% purity, 35% yield).

LC-MS(ESI+): m/z 548.3 (M+H)⁺.

’H NMR (400 MHz, DMSO-î/₆) δ = 9.29 (s, 1 H), 8.69 (s, 1 H), 8.16 (d, J= 9.6 Hz, 1 H), 8.01 (s, 1 H), 7.54 (d, J= 8.0 Hz, 2 H), 7.40 (d, J = 8.4 Hz, 2 H), 6.91 (d, J= 9.2 Hz, 1 H), 5.57 (s, 2 H), 4.10-3.98 (m, 2 H), 3.82 (s, 3 H), 1.77 -1.67 (m, 1 H), 1.29 (t, J=7.4 Hz, 3 H), 1.05 -0.97 (m, 2 H), 0.81 -0.70 (m, 2 H).

[0546] Example B32: Synthesis of Compound 24

[0547] 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-8-(4-(l-ethyl-4-(trifluoromethyl)-lHimidazol-2-yl)-3-fluorobenzyl)pyrido[2,3-d]pyrimidin-7(8H)-one

Compound 24

[0548] In a similar fashion according to the procedure for Compound 23, Compound 24 was synthesized by replacing methyl 4-formylbenzoate with methyl 3-fluoro-4-formylbenzoate.

[0549] The crude product was purified by prep-TLC (PE/DCM = 1/1) to give the title compound (60.34 mg, 0.11 mmol, 33% yield).

LC-MS(ESH-): m/z 566.2 (M+H)⁺.

1HNMR (400 MHz, DMSO-tZ₆) δ = 9.30 (s, 1 H), 8.70 (s, 1 H), 8.17 (d, J = 9.6 Hz, 1 H), 8.08 (s, 1 H), 7.53 - 7.43 (m, 1 H), 7.35 - 7.20 (m, 2 H), 6.90 (d, J= 9.6 Hz, 1 H), 5.57 (s, 2 H), 3.88 21708

169

3.83 (m, 2 H), 3.82 (s, 3 H), 1.77 - 1.69 (m, 1 H), 1.25 (t, J= 7.2 Hz, 3 H), 1.06 - 0.98 (m, 2 H),

0.82 - 0.73 (m, 2 H).

[0550] Example B33: Synthesis of Compound 25

[0551] 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-8-((4-(l-ethyl-4-(trifluoromethyl)-lHimidazol-2-yl)cuban-l-yl)methyl)pyrido[2,3-d]pyrimidin-7(8H)-one

[0552] In a similar fashion according to the procedure for Compound 9, Compound 25 was synthesized by replacing iodomethane with iodoethane.

The crude product was purified by prep-TLC (DCM/MeOH = 20/1) to give the title compound (18.12 mg, 0.03 mmol, 4% yield).

LC-MS(ESH-): m/z 574.1 (M+H)⁺.

Ή NMR (400 MHz, MeOD-Λ): δ = 9.15 (s, 1 H), 8.64 (s, 1 H), 8.06 (d, J= 9.6 Hz, 1 H), 7.59 (s, 1 H), 6.88 (d, J= 9.6 Hz, 1 H), 4.83 (s, 2 H), 4.27 - 4.18 (m, 3 H), 4.03 - 3.94 (m, 3 H), 3.92 (s, 3 H), 3.91 - 3.82 (m, 2 H), 1.73 - 1.64 (m, 1 H), 1.40 (t, J = 7.2 Hz, 3 H), 1.24-1.14 (m, 2 H), 0.99 - 0.89 (m, 2 H).

[0553] Example B34: Synthesis of Compound 27

[0554] 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-8-((4-(l-methyl-4-(trifluoromethyl)-lHimidazol-2-yl)cuban-l-yl)methyl)pteridin-7(8H)-one

[0555] In a similar fashion according to the procedure for Compound 20, Compound 27 was synthesized by replacing (4-(l-isopropyl-4-(trifluoromethyl)-lH-imidazol-2-yl)cuban-lyl)methyl methanesulfonate with (4-(l-methyl-4-(trifluoromethyl)-lH-imidazol-2-yl)cuban-lyl)methyl methanesulfonate.

170

The crude product was purified by prep-TLC (DCM/EtOAc = 2:1) to give the title compound (55.71 mg, 0.10 mmol, 20% yield).

LC-MS(ESI+): m/z 561.2 (M+H)⁺.

’H NMR: (400 MHz, DMSO-î/₆) δ = 9.34 (s, 1 H), 8.73 (s, 1 H), 8.46 (s, 1 H), 7.73 (s, 1 H), 4.58 (s, 2 H), 4.22 - 4.14 (m, 3 H), 3.96 - 3.88 (m, 3 H), 3.86 (s, 3 H), 3.51 (s, 3 H), 1.75 - 1.63 (m, 1 H), 1.14 - 1.05 (m, 2 H), 0.95 - 0.85 (m, 2 H).

[0556] Example B35: Synthesis of Intermediate 32.2

32.1 32.2

[0557] 4-chloro-6-cyclopropylpyrimidine

[0558] To a solution of 4,6-dichloropyrimidine (30.00 g, 201.38 mmol) in Dioxane (300 mL) and H₂O (60 mL) were added cyclopropylboronic acid (34.60 g, 402.79 mmol), K2CO3 (55.67 g, 402.82 mmol) and Pd(dppf)Cl₂ (14.74 g, 20.14 mmol). The reaction mixture was stirred at 100 °C for 16 hr under Ar atmosphère. After cooling to rt, to the mixture was added H₂O (50 mL). After extraction with EtOAc (100 mL x 3), the combined organic layers were washed with brine (100 mL), dried over Na2SÛ4, filtered and concentrated under reduced pressure to give a residue, which was purified by column chromatography on silica gel eluting with ethyl acetate (from 0% to 5.0%) in petroleum ether to give the title compound (8.00 g, 51.75 mmol, 26% yield) as a yellow oil.

LC-MS(ESI+): m/z 155.1 (M+H)' .

[0559] 4-cyclopropyl-6-(methoxy-d3)pyrimidine

[0560] NaH (4.14 g, 103.5 mmol, 60% dispersion in minerai oil) was added to the solution of 4chloro-6-cyclopropylpyrimidine (8.00 g, 51.75 mmol) in dry THF (50 mL) at 0 °C. The mixture was stirred at 0 °C for 5 min. Then deuterated methanol (3.733 g, 103.49 mmol) was added. The reaction mixture was stirred at rt for 16 hr. Then to the mixture was added saturated NH4CI aqueous solution (70mL). After extraction with EtOAc (100 mL x 3), the combined organic layers were washed with brine (100 mL), dried over Na2SÛ4, filtered and concentrated under reduced pressure to give a residue, which was purified by column chromatography on silica gel eluting with ethyl acetate (from 0% to 5.0%) in petroleum ether to give the title compound (7.00 g, 45.69 mmol, 88% yield) as a yellow oil.

LC-MS(ESI+): m/z 154.1 (M+H)⁺.

171

[0561] Example B36: Synthesis of Compound 32

[0562] 2-(4-cyclopropyl-6-(methoxy-d3)pyrimidin-5-yl)-8-((4-(l-isopropyl-4(trifluoromethyl)-lH-imidazol-2-yl)cuban-l-yl)methyI)pyrido[2,3-d]pyrimidin-7(8H)-one

Compound 32

[0563] In a similar fashion according to the procedure for Compound 8, Compound 32 was synthesized by replacing 4-cyclopropyl-6-methoxypyrimidine with 4-cyclopropyl-6-(methoxydsjpyrimidine.

The crude product was purified with Prep-TLC (DCM/EtOAc = 2/1) to give the title compound (151.30 mg, 0.26 mmol, 39% yield).

LC-MS(ESI+): m/z 591.4 (M+H)⁺.

’H NMR (400 MHz, DMSO-J₆) δ = 9.25 (s, 1 H), 8.72 (s, 1 H), 8.10 (d, J = 9.6 Hz, 1 H), 7.96 (d, J =0.8 Hz, 1 H), 6.87 (d, J= 9.6 Hz, 1 H), 4.67 (s, 2 H), 4.16 - 4.08 (m, 3 H), 4.00 - 3.86 (m, 4 H), 1.71 - 1.61 (m, 1 H), 1.38 (d, J= 6.8 Hz, 6 H), 1.13-1.05 (m, 2 H), 0.94-0.84 (m, 2 H).

[0564] Example B37: Synthesis of Intermediate 33.4

[0565] l-(4-bromophenyl)-5-methyl-3-(trifluoromethyl)-lH-pyrazole

[0566] To a solution of (4-bromophenyl)hydrazine (5.00 g, 26.73 mmol) in HFIP (50 mL) were added l,l,l-trifluoropentane-2,4-dione (4.943 g, 32.08 mmol) and TEA (5.57 mL, 40.26 mmol) at 0 °C. The mixture was stirred at rt for 2hr. Then to the mixture was added water (20 mL).

After extraction with EtOAc (25 mL x 3), the combined organic layers were washed with brine (50 mL), dried over Na2SÜ4, filtered and concentrated under reduced pressure to give a residue,

172 which was purified by column chromatography on silica gel eluting with 0% to 1% EtOAc in PE to give the title compound (7 g, 22.94 mmol, 86% yield) as a colorless oil.

LC-MS(ESI+): m/z 305.0 (M+H)⁺.

[0567] 5-methyl-3-(trifluoromethyl)-l-(4-vinylphenyl)-lH-pyrazole

[0568] A mixture of l-(4-bromophenyl)-5-methyI-3-(trifluoromethyl)-lH-pyrazole (3.50 g, 11.47 mmol), Potassium vinyltrifluoroborate (4.61 g, 34.42 mmol), Pd(dppf)Ch (1.68 g, 2.30 mmol) and K2CO3 (3.17 g, 22.94 mmol) in dioxane (50 mL)/Water (10 mL) was stirred at 100 °C for 4.5 hr. After cooling to rt, to the mixture was added water (50 mL). After extraction with EtOAc (50 mL x 3), the combined organic layers were washed with brine (70 mL), dried over Na₂SÜ4, filtered and concentrated under reduced pressure to give a residue, which was purified by column chromatography on silica gel eluting with 1% to 2.5% EtOAc in PE to give the title compound (2.7 g, 10.70 mmol, 93% yield) as a colorless oil.

LC-MS(ESI+): m/z 253.1 (M+H)⁺.

[0569] l-(4-(l-bromoethyl)phenyl)-5-methyl-3-(trifluoromethyl)-lH-pyrazole

[0570] Into a round-bottom flask containing a magnetic stirring bar were added 5-methyl-3(trifluoromethyl)-l-(4-vinylphenyl)-lH-pyrazole (3.00 g, 11.89 mmol), S1O2 gel (230-400 mesh; 5.95 g) and DCM (50 mL). The mixture was stirred vigorously and PBn (1.129 mL, 11.89 mmol) was added at 0 °C. A deep orange solution was formed. The reaction mixture was stirred at rt for 2 hr. Then 10% NaHCCL aqueous solution (50 mL) was added dropwise to the mixture. The resulting slurry was filtered. The filter cake was washed with DCM (100 mL). The resulting organic solution was evaporated to dryness. The residue was purified by column chromatography on silica gel eluting with 2% to 6% EtOAc in PE to give the title compound (3 g, 9.00 mmol, 76% yield) as a yellow oil.

’H NMR: (400 MHz, CDCI3) δ = 7.56 (d, J= 8.4 Hz, 2 H), 7.43 (d, J= 8.4 Hz, 2 H), 6.46 (s, 1 H), 7.24 (q, J= 6.8 Hz, 1 H), 2.37 (s, 3 H), 2.07 (d, J= 6.8 Hz, 3 H).

[0571] 2-chloro-5-iodo-N-(l-(4-(5-methyl-3-(trifluoromethyl)-lH-pyrazol-lyl)phenyl)ethyl)pyrimidin-4-amine

[0572] To a solution of 2-chloro-5-iodopyrimidin-4-amine (1.50 g, 5.87 mmol) in DMF (20 mL) was added NaH (0.47 g, 11.75 mmol, 60 % dispersion in minerai oil) at 0 °C. The mixture was stirred at 0 °C for 0.5 h. Then 1 -(4-(l-bromoethyl)phenyl)-5-methyl-3-(trifluoromethyl)-lHpyrazole (2.35 g, 7.05 mmol) was added. The reaction mixture was stirred at rt for 1 hr. Then the mixture was quenched with saturated NH4CI aqueous solution (30 mL) at 0 °C and extracted with EtOAc (30 mL x 3). The combined organic layers were washed with brine (45 mL), dried

173 over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel eluting with 3% to 15% EtOAc in PE to give the title compound (2 g, 3.94 mmol, 67% yield).

LC-MS(ESI+): m/z 508.1 (M+H)⁺.

[0573] Example B38: Synthesis of Compound 33 and 34

[0574] (S)-2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-8-(l-(4-(5-methyl-3(trifluoromethyl)-lH-pyrazol-l-yl)phenyl)ethyl)pyrido[2,3-d]pyrimidin-7(8H)-one [0575] (R)-2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-8-(l-(4-(5-methyl-3(trifluoromethyl)-lH-pyrazol-l-yl)phenyl)ethyl)pyrido[2,3-d]pyrimidin-7(8H)-one

Compound 34, Peak 2 Single unknown enantiomer

Compound 33, Peak 1 Single unknown enantiomer

[0576] In a similar fashion according to the procedure for Compound 1, Intermediate 33.5 was synthesized by replacing (Intermediate C-4) 2-chloro-5-iodo-N-(4-(5-methyl-3(trifluoromethyl)-lH-pyrazol-l-yl)benzyl)pyrimidin-4-amine with (Intermediate 33.4) 2-chloro5-iodo-N-(l -(4-(5-methyl-3-(trifluoromethyl)-l H-pyrazol-1 -yl)phenyl)ethyl)pyrimidin-4-amine. [0577] Then 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-8-(l-(4-(5-methyl-3-(trifluoromethyl)lH-pyrazol-l-yl)phenyl)ethyl)pyrido[2,3-d]pyrimidin-7(8H)-one (200 mg, 0.37 mmol) was separated by chiral SFC (column: DAICEL CHIRALPAK OJ (3.0 mm*100 mm,3pm); mobile phase: [MeOH-DEA]; B%: 5%-40%, 2.7; 4.8min)) to afford Compound 33 (57.35 mg, 0.10 mmol) as the first eluting peak and Compound 34 (49.48 mg, 0.09 mmol) as the second eluting peak.

[0578] For Compound 33:

[0579] Ή NMR (400 MHz, Methanol-t/4) δ = 9.13 (s, 1 H), 8.60 (s, 1 H), 8.05 (d, J= 9.6 Hz, 1 H), 7.50 (d, J= 8.4 Hz, 2 H), 7.37 (d, J = 8.4 Hz, 2 H), 7.01 (br s, 1 H), 6.82 (d, J= 8.8 Hz, 1 H), 6.55 (s, 1 H), 3.88 (s, 3 H), 2.29 (s, 3 H), 2.03 (t, J = 7.8 Hz, 3 H), 1.70 (br s, 1 H), 1.15 - 1.08 (m, 2H), 0.95-0.81 (m, 2 H).

[0580] For Compound 34:

‘H NMR (400 MHz, Methanol-i/4) δ = 9.12 (s, 1 H), 8.60 (s, 1 H), 8.04 (d, J= 9.6 Hz, 1 H), 7.49 (d, J= 8.4 Hz, 2 H), 7.36 (d, J= 8.0 Hz, 2 H), 7.00 (br s, 1 H), 6.82 (d, J= 9.2 Hz, 1 H), 6.54 (s, 1 H), 3.88 (s, 3 H), 2.29 (s, 3 H), 2.02 (t, J= 7.4 Hz, 3 H), 1.69 (br s, 1 H), 1.15 - 1.07 (m, 2 H), 0.93 - 0.83 (m, 2 H).

174

[0581] Example B39: Synthesis of Intermediate 35.3

[0582] methyl 4-(4-(trifluoromethyl)-lH-imidazol-2-yl)bicyclo[2.2.2]octane-l-carboxylate [0583] In a similar fashion according to the procedure for Intermediate E-2, Intermediate 35.1 was synthesized by replacing 4-(methoxycarbonyl)cubane-l-carboxylic acid with 4(methoxycarbonyl)bicyclo[2.2.2]octane-l-carboxylic acid.

[0584] 3,3-dibromo-l,l,l-trifluoropropan-2-one (4.18 g, 15.49 mmol), NaOAc (1.69 g, 20.60 mmol) and H₂O (5 mL) were added to a three-necked 250 mL round-bottom flask fitted with a nitrogen inlet, magnetic stir bar and thermometer. The resulting mixture was stirred at 100 °C for 1 hr and then cooled to rt. Subsequently, methyl 4-formylbicyclo[2.2.2]octane-l-carboxylate (4.0 g, crude), NH4OH (10 mL) and MeOH (30 mL) were added. The resulting mixture was stirred at rt for 16 hr. Then the mixture was concentrated. To the residue was added water (40 mL). After extraction with ethyl acetate (50 mL x 3), the combined organic layers were washed with brine (60 mL), dried over Na₂SO4, filtered and concentrated under reduced pressure to give the title compound (6.1 g, crude), which was used directly in the next step.

LC-MS (ESI+): m/z 303.2 (M+H)⁺

[0585] methyl 4-(l-methyl-4-(trifluoromethyl)-lH-imidazol-2-yl)bicyclo[2.2.2]octane-lcarboxylate

[0586] To a mixture of methyl 4-(4-(trifluoromethyl)-lH-imidazol-2-yl)bicyclo[2.2.2]octane-lcarboxylate (6.1 g, crude) and Cs₂COs (7.28 g, 22.34 mmol) in DMF (20 mL) was added CH3I (1.1 mL, 17.67 mmol) at 0 °C. The mixture was warmed up to rt and stirred at rt for 16 hr. Then water (20 mL) was added. The resulting mixture was extracted with ethyl acetate (20 mL x 3). The combined organic layers were washed with brine (20 mL), dried over Na₂SO4, filtered and concentrated under reduced pressure to give the title compound (3.1 g, crude), which was used directly in the next step.

LC-MS (ESI+): m/z 317.2 (M+H)⁺

[0587] Example B40: Synthesis of Compound 35

[0588] 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-8-((4-(l-methyl-4-(trifluoromethyl)-1Himidazol-2-yl)bicyclo[2.2.2]octan-l-yl)methyl)pyrido[2,3-d]pyrimidin-7(8H)-one

175

[0589] In a similar fashion according to the procedure for Compound 9, Compound 35 was synthesized by replacing methyl 4-(l-methyl-4-(trifluoromethyl)-lH-imidazol-2-yl)cubane-lcarboxylate with (Intermediate 35.3) methyl 4-(l-methyl-4-(trifluoromethyl)-lH-imidazol-2yl)bicyclo[2.2.2]octane-l-carboxylate. In the last step, Kl and K2CO3 in DMSO (120 °C, 16h) was used.

[0590] The crude product was purified by pre-TLC (DCM/MeOH=20/l) to give the title compound (17.3 mg, 0.03 mmol, 8% yield).

LC-MS (ESI+): m/z 566.4 (M+H)+.

[0591] 1H NR (400 MHz, DMSO-d6) δ = 9.21 (s, 1 H), 8.72 (s, 1 H), 8.07 (d, J = 9.6 Hz, 1 H), 7.61 (s, 1 H), 6.84 (d, J = 9.6 Hz, 1 H), 4.24 (br. s, 2 H), 3.85 (s, 3 H), 3.71 (s, 3 H), 1.90 - 1.80 (m, 6 H), 1.71 - 1.60 (m, 1 H), 1.56 - 1.47 (m, 6 H), 1.12 - 1.04 (m, 2 H), 0.94 - 0.85 (m, 2 H).

[0592] Example B41: Synthesis of Compound 36

[0593] 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-8-((4-(l-methyl-4-(trifluoromethyl)-lHimidazol-2-yl)bicyclo[2.2.1]heptan-l-yl)methyl)pyrido[2,3-d]pyrimidin-7(8H)-one

[0594] In a similar fashion according to the procedure for Compound 35, Compound 36 was synthesized by replacing 4-(methoxycarbonyl)bicyclo[2.2.2]octane-l-carboxylic acid with 4(methoxycarbonyl)bicyclo[2.2.1 ]heptane-1 -carboxylic acid.

The crude product was purified by prep-TLC (DCM/EtOAc = 1 /1 ) to afford the title compound (29.06 mg, 0.053 mmol, 8% yield).

LC-MS(ESI+): m/z 552.4 (M+H)⁺.

176 ’H NMR (400 MHz, DMSO-î/₆) δ = 9.23 (s, 1 H), 8.70 (s, 1 H), 8.09 (d, J= 9.6 Hz, 1 H), 7.62 (s, 1 H), 6.85 (d, J= 9.6 Hz, 1 H), 4.56 (s, 2 H), 3.82 (s, 3 H), 3.63 (s, 3 H), 1.88 - 1.80 (m, 2 H), 1.74 - 1.60 (m, 7 H), 1.49 - 1.40 (m, 2 H), 1.08 - 1.00 (m, 2 H), 0.90 - 0.81 (m, 2 H).

[0595] Exampie B42: Synthesis of Compound 37

[0596] 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-8-((3-(l-isopropyl-4-(trifluoromethyl)lH-imidazol-2-yl)bicyclo[l.l.l]pentan-l-yl)methyl)pyrido[2,3-d]pyrimidin-7(8H)-one

[0597] In a similar fashion according to the procedure for Compound 9, Compound 37 was synthesized by replacing 4-(methoxycarbonyl)cubane-l-carboxylic acid with 3(methoxycarbonyl)bicyclo[l.l.l]pentane-l-carboxylic acid, and replacing iodomethane with 2iodopropane.

[0598] The crude product was purified by column chromatography on silica gel eluting with ethyl acetate (from 4.8% to 50.0%) in dichloromethane to give the title compound (133.62 mg, 0.24 mmol, 34% yield).

LC-MS(ESI+): m/z 552.4 (M+H)⁺.

Ή NMR (400 MHz, DMSO-J₆) δ = 9.25 (s, 1 H), 8.72 (s, 1 H), 8.11 (d, J= 9.6 Hz, 1 H), 7.85 (s, 1 H), 6.87 (d, J= 9.6 Hz, 1 H), 4.56 - 4.43 (m, 3 H), 3.85 (s, 3 H), 2.03 (s, 6 H), 1.66 - 1.61 (m, 1 H), 1.29 (d,J=6.4 Hz, 6 H), 1.12-1.03 (m, 2 H), 0.94-0.84 (m, 2 H).

[0599] Example B43: Synthesis of Compound 38

[0600] 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-8-(((lr,4r)-4-(l-methyl-4(trifluoromethyl)-lH-imidazol-2-yl)cyclohexyl)methyl)pyrido[2,3-d]pyrimidin-7(8H)-one

Compound 38

177

[0601] In a similar fashion according to the procedure for Compound 35, Compound 38 was synthesized by replacing 4-(methoxycarbonyl)bicyclo[2.2.2]octane-l -carboxylic acid with ( 1 r,4r)-4-(methoxycarbonyl)cyclohexane-1 -carboxylic acid.

The crude product was purified by pre-HPLC (column: Waters Xbridge Cl8 lOum OBD 19*250mm, mobile phase: [water (0.1%NH4HCC>3)- ACN]; B%:30%ACN-95%ACN, 9.95min) to give the title compound (73.99 mg, 0.137 mmol, 16% yield).

LC-MS(ESI+): m/z 540.3 (M+H)⁺.

‘H NMR (400 MHz, DMSO-î/₆) δ = 9.24 (s, 1 H), 8.72 (s, 1 H), 8.09 (d, J= 9.6 Hz, 1 H), 7.62 (s, 1 H), 6.84 (d, J=9.6 Hz, 1 H), 4.24 (d,J=7.2 Hz, 2 H), 3.88 (s, 3 H), 3.61 (s, 3 H), 2.81 2.65 (m, 1 H), 2.02 - 1.89 (m, 1 H), 1.88 - 1.74 (m, 3 H), 1.71 - 1.58 (m, 2 H), 1.44 - 1.30 (m, 2 H), 1.30 - 1.15 (m, 2 H), 1.15 - 1.04 (m, 2 H), 0.97 - 0.87 (m, 2 H).

[0602] Example B44: Synthesis of Compound 39

NaH, CH₃I __ n-BuLi, l₂, THF 'vX

Γ />—cf₃ --------------»- I // ^cf3 ----------------»- I /?—cf₃ ljm # N—7 N—'J

THF, rt, 16h / -78 °C to rt, 16h >

39.1 39.2

Compound 39

[0603] 1 -methyl-4-(trifluoromethyl)-l H-imidazole

[0604] To a stirred solution of 4-(trifluoromethyl)-l H-imidazole (6.78 g, 49.82 mmol) in dry THF (100 mL) was added NaH (2.19 g, 54.75 mmol, 60% dispersion in minerai oil) at 0 °C. The mixture was stirred at 0 °C for 15 min and then CH3I (3.10 mL, 49.80 mmol). The reaction mixture was stirred at 0 °C for 30 min and at rt for another 16 hr. Then the mixture was quenched with saturated ammonium chloride aqueous solution (50 mL) and extracted with EtOAc (100 mL x 3). The combined organic layers were dried over anhydrous Na2SÛ4, filtered and concentrated under reduced pressure. The residue was purified by reversed phase column

178 chromatography (0% to 35% MeCN in H2O) to give the title compound (2.28 g, 15.19 mmol, 31% yield).

’H NMR (400 MHz, CDCI3) δ = 7.46 (s, 1 H), 7.24 (s, 1 H), 3.73 (s, 3 H).

[0605] 2-iodo-l-methyl-4-(trifluoromethyl)-lH-imidazole

[0606] l-methyl-4-(trifluoromethyl)-lH-imidazole (4.2 g, 27.98 mmol) was dissolved in dry THF (50 mL) and cooled to -78 °C. n-BuLi (13.43 mL, 33.58 mmol, 2.5 M solution in Hexanes) was added dropwise in 15 minutes to the solution. The resulting mixture was stirred at -78 °C for 2 h. Subsequently, a solution of I2 (8.52 g, 33.57 mmol) in 15 mL dry THF was added slowly at 78 °C. The reaction mixture was warmed to rt and stirred at rt for 16 hr. Then the mixture was quenched with saturated NH4CI aqueous solution (40 mL) at 0 °C and extracted with EtOAc (70 mL x 3). The combined organic fractions were washed with brine (100 mL), dried over Na2SÜ4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel eluting with 3% to 20% EtOAc in PE to give the title compound (5.10 g, 18.48 mmol, 66% yield).

*H NMR (400 MHz, CDCI3) δ = 7.36 (s, 1 H), 3.67 (s, 3 H).

[0607] tert-butyl 4-((2-(4-cyclopropy 1-6-methoxy py rimidin-5-yl)-7-oxopy rido [2,3d]pyrimidin-8(7H)-yl)methyl)piperidine-l-carboxylate

[0608] A mixture of 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)pyrido[2,3-d]pyrimidin-7(8H)one (470 mg, 1.59 mmol), tert-butyl 4-(iodomethyl)piperidine-l-carboxylate (776 mg, 2.39 mmol) and K.2CO3 (550 mg, 3.98 mmol) in DMF (5 mL) was stirred at 80 °C for 16 hr. After cooling to rt, the mixture was diluted with water (15 mL) and extracted with EtOAc (20 mL x 3). The combined organic fractions were washed with brine (30 mL), dried over Na2SÛ4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel eluting with 1% to 2.5% MeOH in DCM to give the title compound (600 mg, 1.22 mmol, 77% yield) as a yellow oil.

LC-MS(ESI+): m/z 493.3 (M+H)⁺.

[0609] 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-8-(piperidin-4-ylmethyl)pyrido[2,3d] pyrimidin-7(8H)-one

[0610] To tert-butyl 4-((2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-7-oxopyrido[2,3d]pyrimidin-8(7H)-yl)methyl)piperidine-l-carboxylate (400 mg, 0.81 mmol) was added HCl (3 mL, 3 M in MeOH). The mixture was stirred at rt for 3 hr. Then the mixture was concentrated and dissolved in MeOH (30 mL). The pH of the mixture was adjusted to 7~8 by adding NaHCOa powder. After filtration, the filtrate was concentrated under reduced pressure. The residue was

179 purified by reversed phase column chromatography eluting with 0% to 70% MeCN in Η₂Ο to give the title compound (300 mg, 0.76 mmol, 94% yield).

[0611] LC-MS(ESI+): m/z 393.3 (M+H)⁺.

[0612] 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-8-((l-(l-methyl-4-(trifluoromethyl)-lHimidazol-2-yl)piperidin-4-yl)methyl)pyrido[2,3-d]pyrimidin-7(8H)-one

[0613] A mixture of 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-8-(piperidin-4ylmethyl)pyrido[2,3-d]pyrimidin-7(8H)-one (80 mg, 0.20 mmol), 2-iodo-l-methyl-4(trifluoromethyl)imidazole (169 mg, 0.6Immol), Pd(OAc)2 (5 mg, 0.02 mmol), X-Phos (194 mg, 0.41 mmol) and t-BuONa (157 mg, 1.63 mmol) in toluene (3 mL) was stirred at 100 °C for 16 hr. After cooling to rt, the mixture was diluted with water (20 mL) and extracted with EtOAc (20 mL x 3). The combined organic fractions were washed with brine (25 mL), dried over Na₂SO₄, filtered and concentrated under reduced pressure. The residue was purified by pre-TLC (DCM/MeOH = 20/1) to give the title compound (2.70 mg, 0.005 mmol, 2.5% yield).

LC-MS(ESI+): m/z 541.2 (M+H)⁺.

Ή NMR (400 MHz, DMSO-7₆) δ = 9.25 (s, 1 H), 8.72 (s, 1 H), 8.10 (d, J = 9.6 Hz, 1 H), 7.52 (d, 7=1.2 Hz, 1 H), 6.85 (d, 7=9.2 Hz, 1 H), 4.29 (d, 7= 6.8 Hz, 2 H), 3.87 (s, 3 H), 3.47 (s, 3 H), 3.27 - 3.19 (m, 2 H), 2.68 - 2.58 (m, 2 H), 2.06 - 1.97 (m, 1 H), 1.85 - 1.76 (m, 1 H), 1.63 1.55 (m, 2 H), 1.52 - 1.39 (m, 2 H), 1.13 - 1.05 (m, 2 H), 0.96 - 0.89 (m, 2 H).

[0614] It is understood that the examples and embodiments described herein are for illustrative purposes only and that various modifications or changes in light thereof will be suggested to persons skilled in the art and are to be included within the spirit and purview of this application and scope of the appended claims. Ail publications, patents, and patent applications cited herein are hereby incorporated by reference in their entirety for ail purposes.

Claims

1. A compound having the structure of Formula (Ilia), or a pharmaceutically acceptable sait thereof,

wherein,

Z¹ is N, NR¹, O, S, CR¹, or C(R')₂;

Z² is N, NR², O, CR², C(R²)₂, S(=O)₂, C(=O), or C(=S);

---is a single bond or a double bond;

each of R¹ and R² is independently selected from hydrogen, halo, -CN, -OR¹¹, -SR¹¹, N(R¹²)₂, optionally substituted Ci-6 alkyl, optionally substituted Ci-6heteroalkyl, optionally substituted C₂-6 alkenyl, and optionally substituted C₂-6 alkynyl;

each of R⁸ and R⁹ is independently selected from hydrogen, halogen, -CN, optionally substituted Ci-6 alkyl, optionally substituted Ci-6heteroalkyl, optionally substituted C₂-6 alkenyl, and optionally substituted C₂-6 alkynyl; or R⁸ and R⁹ taken together form an oxo; or R⁸ and R⁹ taken together with the carbon to which they are attached form an optionally substituted 3-6 membered cycloalkyl or heterocycloalkyl;

R^a

each of R^Ais independently selected from halogen, -NO₂, oxo, -CN, optionally substituted Ci-6 alkyl, optionally substituted C₂-6 alkenyl, optionally substituted C₂-6

181 alkynyl, optionally substituted Ci-6 heteroalkyl, optionally substituted C3-8 cycloalkyl, optionally substituted C2-7 heterocycloalkyl, -OR¹¹, -SR¹¹, -N(R¹²)(R^H), C(O)R¹², -C(O)OR¹², -OC(O)R¹², -OC(O)N(R¹²)(R^H), -C(O)N(R¹²)(R^H),N(R¹²)C(O)R¹² -N(R¹²)C(O)OR¹², -N(R^,2)C(O)N(R¹²XR^h), -N(R¹²)2S(O)2(R¹²), S(O)R¹², -S(O)2R¹², and -S(O)2N(R¹²)(R^H);

R¹¹ is hydrogen, optionally substituted C1-6 alkyl, optionally substituted C2-6 alkenyl, optionally substituted C2-6 alkynyl, optionally substituted Ci-6 heteroalkyl, optionally substituted C3-8 cycloalkyl, optionally substituted C2-7 heterocycloalkyl, optionally substituted phenyl, optionally substituted heteroaryl, optionally substituted -Cm alkylene-Cs-s cycloalkyl, optionally substituted -Ci-4alkylene-C2-7 heterocycloalkyl, optionally substituted -Cm alkylene-phenyl, or optionally substituted -Cm alkyleneheteroaryl;

each of R¹² is independently selected from hydrogen, -NO2, -CN, C1-6 alkyl, Cm aminoalkyl, Ci-6 hydroxyalkyl, Ci-6haloalkyl, Ci-6heteroalkyl, C3-6carbocycle, and 3to 6-membered heterocycle, wherein the C3-6 carbocycle and 3- to 6-membered heterocycle is optionally substituted with one or more substituents independently selected from halogen, -OH, oxo, amino, -NO2, -CN, Cm alkyl, Cm alkoxy, and Cm haloalkyl;

B is 6 membered heteroaryl, phenyl or a phenyl isostere;

R^B1 is halo, -CN, -NO2, optionally substituted Cm alkyl, optionally substituted C2-6 alkenyl, optionally substituted C2-6alkynyl, optionally substituted Ci-6 heteroalkyl, OR¹¹, -SR¹¹, -N(R¹²)(R^h), -C(O)R¹², -C(O)OR¹², -OC(O)R¹², -OC(O)N(R¹²)(R^h), C(O)N(R¹²)(R^h), -N(R¹²)C(O)R¹² -N(R¹²)C(O)OR¹², -n(r^I2)C(O)N(r^,2xr^h), N(R¹²)S(O)2(R¹²), -S(O)R¹², -S(O)2R¹², -S(O)2N(R¹²)(R), optionally substituted C3-8 cycloalkyl, optionally substituted C2-9 heterocycloalkyl, optionally substituted naphthyl, optionally substituted phenyl, optionally substituted monocyclic heteroaryl, or optionally substituted bicyclic heteroaryl;

each R^b is independently halo, -CN, -NO2, optionally substituted Cmalkyl, optionally substituted C2-6 alkenyl, optionally substituted C2-6 alkynyl, optionally substituted Ci-6 heteroalkyl, -OR¹¹, -SR¹¹, -N(R¹²)(R), -C(O)R¹², -C(O)OR¹², -OC(O)R¹², OC(O)N(R¹²)(R), -C(O)N(R¹²)(Rⁿ), -N(R¹²)C(O)R¹² -N(R¹²)C(O)OR¹²,N(R¹²)C(O)N(R¹²)(R^h), -N(R¹²)S(O)2(R¹²),-S(O)R¹², -SCOXR’VSCOhNCR^XR), optionally substituted C3-8 cycloalkyl, optionally substituted C2-9 heterocycloalkyl,

182 optionally substituted naphthyl, optionally substituted phenyl, optionally substituted monocyclic heteroaryl, or optionally substituted bicyclic heteroaryl; or

R^bi and one of R^B on the same atom are taken together with the atom to which they are attached to form an optionally substituted C3-8 cycloalkyl or optionally substituted C29 heterocycloalkyl; or two of R^b on the same atom are taken together with the atom to which they are attached to form an optionally substituted C3-8 cycloalkyl or optionally substituted C2-9 heterocycloalkyl;

n is 0, 1, 2, 3 or 4; and p is 1.

2. The compound of claim 1, or a pharmaceutically acceptable sait thereof, wherein, Z¹ is N, NR¹, O, S, CR¹, or C(R')₂;

Z² is N, NR², O, CR², C(R²)₂, S(=O)₂, C(=O), or C(=S);

---is a single bond or a double bond;

each of R¹ and R² is independently selected from hydrogen, halo, -CN, -OR¹¹, -SR¹¹, N(R¹²)₂, optionally substituted C1-6 alkyl, optionally substituted C1-6 heteroalkyl, optionally substituted C₂-6 alkenyl, and optionally substituted C2-6 alkynyl, wherein the alkyl, heteroalkyl, alkenyl, or alkynyl is optionally substituted with one or more substituents independently selected from: halogen, amino, oxo, -OH, NO2, -CN, and Ci-3 alkoxyl;

each of R⁸ and R⁹ is independently selected from hydrogen, halo, -CN, optionally substituted C1-6alkyl, optionally substituted Ci-6heteroalkyl, optionally substituted C2-6 alkenyl, and optionally substituted C2-6 alkynyl, or R⁸ and R⁹ taken together form an oxo; or R⁸ and R⁹ taken together with the carbon to which they are attached form an optionally substituted 3-6 membered cycloalkyl or heterocycloalkyl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl or heterocycloalkyl is optionally substituted with one or more substituents independently selected from: halogen, amino, -OH, -NO2, oxo, -CN, C1-3 alkoxyl, C1-3 alkyl and C1-3 haloalkyl;

183 each of R^Ais independently selected from halogen, -NO2, oxo, -CN, optionally substituted Ci-6 alkyl, optionally substituted C2-6 alkenyl, optionally substituted C2-6 alkynyl, optionally substituted Ci-6heteroalkyl, optionally substituted C3-8 cycloalkyl, optionally substituted C2-7 heterocycloalkyl, -OR, -SR, -N(R^l2)(R), C(O)R¹², -C(O)OR¹², -OC(O)R¹², -OC(O)N(R¹²)(R), -C(O)N(R¹²)(R),N(R^,2)C(O)R¹² -N(R¹²)C(O)OR¹², -N(R¹²)C(O)N(R¹²)(R), -N(R¹²)2S(O)₂(R¹²), S(O)R¹², -S(O)2R¹², and -S(O)2N(R¹²)(R), wherein the alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, or heterocycloalkyl is optionally substituted with one or more substituents independently selected from: halogen, -OH, -NO2, oxo, amino, -CN, C1-6 alkoxyl, C1-6 alkyl, C1-6 haloalkyl, C3-6 carbocycle, and 3- to 6-membered heterocycle, wherein the C3-6 carbocycle and 3- to 6-membered heterocycle is optionally substituted with one or more substituents independently selected from halogen, -OH, amino, -NO2, oxo, -CN, C1-6 alkyl, C1-6 alkoxy, and C1-6 haloalkyl;

R is hydrogen, optionally substituted Ci-6alkyl, optionally substituted C2-6 alkenyl, optionally substituted C2-6 alkynyl, optionally substituted C1-6 heteroalkyl, optionally substituted C3-8 cycloalkyl, optionally substituted C2-7 heterocycloalkyl, optionally substituted phenyl, optionally substituted heteroaryl, optionally substituted -Cm alkylene-C3-8 cycloalkyl, optionally substituted -Cm alkylene-C2-7 heterocycloalkyl, optionally substituted -Cm alkylene-phenyl, or optionally substituted -Cm alkyleneheteroaryl, wherein the alkyl, alkenyl, alkynyl, heteroalkyl, alkylene, cycloalkyl, heterocycloalkyl, phenyl, or heteroaryl is optionally substituted with one or more substituents independently selected from: halogen, -OH, amino, -NO2, oxo, Ci-6 alkoxy, -CN, C1-6 alkyl, and C1-6 haloalkyl;

each of R¹² is independently selected from hydrogen,-NO2, -CN, C1-6 alkyl, C1-6 aminoalkyl, Ci-6 hydroxyalkyl, C1.6 haloalkyl, Ci-6 heteroalkyl, C3-6 carbocycle, and 3to 6-membered heterocycle, wherein the C3-6 carbocycle and 3- to 6-membered heterocycle is optionally substituted with one or more substituents independently selected from halogen, -OH, oxo, amino, -NO2, -CN, C1-6 alkyl, C1-6 alkoxy, and C1-6 haloalkyl;

B is 6 membered heteroaryl, phenyl or a phenyl isostere;

184

R^Bl is halo, -CN, -NO2, optionally substituted Cmalkyl, optionally substituted C2-6 alkenyl, optionally substituted C2-6 alkynyl, optionally substituted Cm heteroalkyl, OR, -SR¹¹, -N(R¹²)(R^h), -C(O)R¹², -C(O)OR¹², -OC(O)R¹², -OC(O)N(R¹²)(Rⁿ), C(O)N(R¹²)(R‘ ’), -N(R¹²)C(O)R¹² -N(R¹²)C(O)OR¹², -N(R¹²)C(O)N(R¹²)(R' '), N(R¹²)S(O)2(R¹²),-S(O)R¹², -S(O)2R¹²,-S(O)2N(R¹²)(R¹¹), optionally substituted C3-8 cycloalkyl, optionally substituted C2-9 heterocycloalkyl, optionally substituted naphthyl, optionally substituted phenyl, optionally substituted monocyclic heteroaryl, or optionally substituted bicyclic heteroaryl, wherein each of the alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocycloalkyl, naphthyl, phenyl or heteroaryl is optionally substituted with one or more substituents independently selected from: halogen, -NO2, oxo, -CN, optionally substituted Ci-6 alkyl, optionally substituted C2-6 alkenyl, optionally substituted C2-6 alkynyl, optionally substituted Ci-6heteroalkyl, optionally substituted C3-8 cycloalkyl, optionally substituted C2-7 heterocycloalkyl, -OR¹¹, -SR¹¹, -N(R¹²)(R^H), C(O)R¹², -C(O)OR¹², -OC(O)R¹², -OCON/R^XR¹¹), -C(O)N(R¹²)(R^H),N(R¹²)C(O)R¹² -N(R¹²)C(O)OR¹², -N(R¹²)C(O)N(R¹²)(Rⁿ), -N(R¹²)S(O)₂(R¹²), S(O)R¹², -S(O)2R¹², and -S(O)2N(R¹²)(Rⁿ), wherein the alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, or heterocycloalkyl is optionally substituted with one or more substituents independently selected from: halogen, -OH,-NO2, amino, -NH(Cm alkyl), -N(Cm alkyl)2, oxo, -CN, C1-3 alkoxyl, C1-3 alkyl and C1-3 haloalkyl;

each R^Bis independently halo, -CN, -NO2, optionally substituted Cm alkyl, optionally substituted C2-6 alkenyl, optionally substituted C2-6 alkynyl, optionally substituted Cm heteroalkyl, -OR¹¹, -SR¹¹, -N(R¹²)(R^H), -C(O)R¹², -C(O)OR¹², -OC(O)R¹², OC(O)N(R¹²)(R' '), -CCOjNCR^XR¹ '), -N(R^,2)C(O)R¹². -N(R¹²)C(O)OR¹², N(R¹²)C(O)N(R¹²)(R^1I),-N(R^I2)S(O)2(R¹²),-S(O)R¹², -scoxr'Vscoxncr^xr¹¹), optionally substituted C3-8 cycloalkyl, optionally substituted C2-9 heterocycloalkyl, optionally substituted naphthyl, optionally substituted phenyl, optionally substituted monocyclic heteroaryl, or optionally substituted bicyclic heteroaryl, wherein the each of the alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocycloalkyl, naphthyl, phenyl or heteroaryl is optionally substituted with one or more substituents independently selected from: halogen, -OH, -NO2, amino, oxo, -CN, Ci-3 alkoxyl, Ci-3 alkyl and Ci-3 haloalkyl; or

185

R^Bl and one of R^B on adjacent atoms are taken together with the atoms to which they are attached to form an optionally substituted phenyl, optionally substituted naphthyl, optionally substituted monocyclic heteroaryl, optionally substituted bicyclic heteroaryl, optionally substituted C3-8 cycloalkyl, or optionally substituted C2-9 heterocycloalkyl, wherein the phenyl, naphthyl, heteroaryl, cycloalkyl, or heterocycloalkyl is optionally substituted with one or more substituents independently selected from: halogen, -OH, amino, -NO2, oxo, Ci-6alkoxy, -CN, Ci-6alkyl, Ci-6haloalkyl; or

R^Bl and one of R^B on the same atom are taken together with the atom to which they are attached to form an optionally substituted C3-8 cycloalkyl or optionally substituted C29 heterocycloalkyl, wherein the cycloalkyl or heterocycloalkyl is optionally substituted with one or more substituents independently selected from: halogen, -OH, amino,-NO₂, oxo, Ci-6 alkoxy, -CN, C1-6 alkyl, Ci-6 haloalkyl; or two of R^b on the same atom are taken together with the atom to which they are attached to form an optionally substituted C3-8 cycloalkyl or optionally substituted C₂-9 heterocycloalkyl, wherein the cycloalkyl or heterocycloalkyl is optionally substituted with one or more substituents independently selected from: halogen, -OH, amino, -NO2, oxo, Ci-6 alkoxy, -CN, Ci-6 alkyl, Ci-6 haloalkyl;

n is 0, 1, 2, 3 or 4; and p is 1.

3. The compound of claim 1 or 2, or a pharmaceutically acceptable sait thereof, wherein the compound has a structure of Formula (IIIc’),

wherein,

Y¹ isNor CR^Y1;

Y² is N or CR^Y2;

186

Y³ is N or CR^Y3;

Y⁴ is N or CR^Y4;

each of R^Yl, R^Y2, R^Y3 and R^Y4 is independently selected from hydrogen, halo, -CN, OR¹¹, -SR¹¹, -N(R¹²)₂, optionally substituted Ci-6alkyl, optionally substituted Ci-6 heteroalkyl, optionally substituted C₂-6 alkenyl, and optionally substituted C₂-6 alkynyl.

4. The compound of any one of claims 1 -3, or a pharmaceutically acceptable sait thereof, wherein the compound has a structure of Formula (IIIc-1 ’)

Formula (IIIc-Γ).

5. The compound of claims 1 or 2, or a pharmaceutically acceptable sait thereof, wherein ring B is a phenyl isostere, optionally wherein the phenyl isostere is cubane or the phenyl isostere is ethynyl.

6. The compound of any one of claims 1 to 5, wherein each of R^A is independently selected from halogen, -NO2, oxo, -CN, optionally substituted Cmalkyl, optionally substituted Ci6 heteroalkyl, optionally substituted C3-8 cycloalkyl, optionally substituted C2-7 heterocycloalkyl, -OR¹¹, -SR¹¹, -N(R¹²)(R^H), -C(O)R¹², -C(O)OR¹², -OC(O)R¹², OC(O)N(R^,2)(R’ ’), -CmR’W),-N(R¹²)C(O)R¹² -N(R¹²)C(O)OR¹², N(R¹²)C(O)N(R¹²)(R^h), -N(R¹²)2S(O)₂(R¹²), -S(O)R¹², -S(O)2R¹², and -S(O)2N(R¹²)(R”).

7 The compound of any one of claims 1 to 6, or a pharmaceutically acceptable sait thereof, wherein each of R⁸ and R⁹ is independently selected from hydrogen, -CN, optionally substituted Cmalkyl, optionally substituted Ci-6heteroalkyl, optionally substituted C₂-6 alkenyl, and optionally substituted C₂-6 alkynyl.

8. The compound of claim 7, or a pharmaceutically acceptable sait thereof, wherein each of R⁸ and R⁹ is hydrogen, or wherein R⁸ and R⁹ taken together form an oxo, or wherein R⁸ and R⁹ taken together with the carbon to which they are attached form an optionally substituted 3-6 membered cycloalkyl or heterocycloalkyl;

and/or

187 wherein B is phenyl or 6 membered heteroaryl or wherein ring B is phenyl, pyridine, pyrimidine, pyrazine, pyridazine, or triazine.

9. The compound of any one of claims 1 to 8, or a pharmaceutically acceptable sait thereof, wherein R^B1 is halo, -CN, -NO2, optionally substituted C1-6 alkyl, optionally substituted C2-6 alkenyl, optionally substituted C2-6 alkynyl, optionally substituted Ci-6 heteroalkyl, OR¹¹, -SR¹¹, -N(R¹²)(Rⁿ), -C(O)R¹², -C(O)OR¹², -OC(O)R¹², -OC(O)N(R¹²)(R^h), C(O)N(R¹²)(R^h), -N(R¹²)C(O)R¹² -N(R¹²)C(O)OR¹², -N(R¹²)C(O)N(R¹²)(Rⁿ), N(R¹²)S(O)2(R¹²),-S(O)R¹², -S(O)2R¹²,-S(O)2N(R¹²)(R^u), optionally substituted C3-8 cycloalkyl, optionally substituted C2-9 heterocycloalkyl, optionally substituted phenyl, optionally substituted monocyclic heteroaryl, or optionally substituted bicyclic heteroaryl.

10. The compound of claim 9, or a pharmaceutically acceptable sait thereof, wherein R^B1 is optionally substituted monocyclic 5-6 membered heterocycloalkyl or heteroaryl.

11. The compound of claim 9, or a pharmaceutically acceptable sait thereof, wherein R^B1 is optionally substituted 5 membered monocyclic heteroaryl with 1 to 4 heteroatoms selected from N, O, S and P.

12. The compound of claim 11, or a pharmaceutically acceptable sait thereof, wherein R^B1 is imidazole, pyrazole, triazole, or tetrazole, each of which optionally substituted.

13. The compound of claim 9, or a pharmaceutically acceptable sait thereof, wherein R^B1 is optionally substituted fused 5-6, 6-6 or 6-5 heteroaryl.

14 The compound of any one of claims 1 to 13, or a pharmaceutically acceptable sait thereof, wherein R^B1 is optionally substituted with one or more substituents independently selected from halogen, -NO2, oxo, -CN, optionally substituted C1-6 alkyl, optionally substituted Ci-6 heteroalkyl, optionally substituted C3-8 cycloalkyl, optionally substituted C2-7 heterocycloalkyl, -OR¹¹, -SR¹¹, -N(R¹²)(R^H), -C(O)R¹², -C(O)OR¹², OC(O)R¹², -OC(O)N(R^l2)(Rⁿ), -C(O)N(R¹²)(R^h),-N(R¹²)C(O)R¹² -N(R¹²)C(O)OR¹²,N(Rⁱ²)C(O)N(R¹²)(R^h), -N(R¹²)S(O)2(R¹²),-S(O)R¹², -S(O)2R¹², and-S(O)2N(R¹²)(Rⁿ), wherein the alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, or heterocycloalkyl is optionally substituted with one or more substituents independently selected from: halogen, -OH, -NO₂, amino, oxo, -CN, C1.3 alkoxyl, C1-3 alkyl and C1-3 haloalkyl.

15. The compound of any one of claims 1 to 14, or a pharmaceutically acceptable sait thereof, wherein n is 0.

188

16. The compound of claim l or 2, or a pharmaceutically acceptable sait thereof, wherein Zi is CR¹; Z2 is CR²; each of R¹ and R² is hydrogen; each R⁸ and R⁹ is hydrogen;

selected from Ci-Cô alkyl, Ci-Cô alkoxyl, Ci-Cô haloalkyl, and C3-6 cycloalkyl (e.g., cyclopropyl); B is cubane; R^B1 is 5 membered heteroaryl optionally substituted with one

or more substituents selected from C1-3 haloalkyl and C1-3 alkyl (e.g.,

189

190

18. A pharmaceutical composition comprising a compound of any one of daims 1 to 17, or a pharmaceutically acceptable sait thereof, and a pharmaceutically acceptable carrier or excipient.

19. Use of a compound of any one of daims 1 -17 in the manufacture of a médicament for the treatment of cancer.