KRAS INHIBITORS FOR TREATING DISEASE
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application claims priority under 35 U.S.C. § 119(e) to U. S. Provisional Application Serial No. 63/318,352 filed on March 9, 2022, and U. S. Provisional Application Serial No. 63/359,804 filed on July 9, 2022, the entire disclosures of which are incorporated herein by reference.
TECHNICAL HELD
[0002] The present disclosure relates to diaryl compounds targeting KRAS, pharmaceutical compositions containing the compounds, and methods of using such compounds to treat disease, such as cancer.
BACKGROUND
[0003] Ras is a GTP-binding protein and regulates many important physiologic processes within a cell, such as cell cycle progression, survival, apoptosis, etc. H-Ras, K-Ras, and N- Ras are the main members of Ras superfamily, which are tightly regulated by factors that switch on/off the GTPase activity. Somatic mutations at codons 12, 13 and 61 in the RAS genes are associated with about 16% of all human cancers and KRAS is the most frequently mutated RAS isoform, accounting for 85% of all RAS-related cancers (Prior I. A. et al, A comprehensive survey of Ras mutations in cancer. Cancer Res. 2012, 72, 2457-2467), including 86-96% in pancreatic cancers, 40-50% in colorectal cancers, and 27-39% in lung adenocarcinomas (Kessler D. et al. Drugging an undruggable pocket on KRAS Proc Natl Acad Sci USA. 2019, 116(32): 15823-15829). Mutated RAS is locked in the constitutively activated GTP bound state and facilitates enhanced Ras signaling in cancer cells.
[0004] Direct targeting of mutant KRAS has previously proven challenging because of its high affinity for nucleotide and the lack of tractable binding pockets for small-molecule inhibitors. Recent successful inhibition of the KRAS G12C mutant by covalent chemical modifiers sotorasib and adagrasib (Stower K, KRAS inhibitors at last, Nature Medicine 2020, 26, 1804) in KRAS G12C mutated lung cancer patients has shed lights on targeting KRAS mutants for therapeutic invention. However, inhibitors targeting KRAS mutants without covalent formation at KRAS G12C are still absent. The increased understanding of structural elements of the KRAS switch II pocket made it possible to design KRAS inhibitors selective for different mutant variants. MRTX1133 has been reported as potent and highly selective
noncovalent KRAS G12D inhibitor (Wang X. et al, Identification of MRTX1133, a noncovalent, potent, and selective KRAS
G12D inhibitor, J. Med. Chem.2022, 65: 3123–3133). However, intraperitoneal injection of MRTX1133 was required to achieve sufficient plasma exposure and demonstrate drug efficacy in mice. This suggests MRTX1133 may have poor bioavailability. [0005] Therefore, there is unmet medical need to develop new noncovalent KRAS inhibitors that can selectively target KRAS mutants such as KRAS G12C, KRAS G12D, KRAS G12V, KRAS G12R, KRAS G12S, KRAS G13C, KRAS G13D with good in vivo efficacy, safety, and predicted human oral pharmacokinetic profile for treating patients with KRAS mutant cancers. SUMMARY [0006] In one aspect, the disclosure provides a compound of the formula I, or a pharmaceutically acceptable salt thereof,
[0007] wherein [0008] X is a -O-, -S-, or -NR
4-; [0009] Y is a bond, -O-, -S-, -S(O)-, -S(O)
2-, or –C(O)NR
10-; [0010] Z
1 is N or C(R
5); [0011] Z
2 is N or C(R
6); [0012] Z
3 is N or C(R
7); [0013] Z
4 is N or C(R
8); [0014] Z
5 is N or C(R
9); [0015] provided that at least two of Z
1-Z
5 are N;
[0016] R is independently H, deuterium,C
1-C
6 alkyl,C
2-C
6 alkenyl, C
2-C
6 alkynyl, or ring A, wherein each hydrogen atom in C
1-C
6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl is independently optionally substituted by deuterium, halogen, -R
e, -R
f, C
1-C
6 alkyl, C
1-C
6 haloalkyl, -OR
e, -OC(O)R
e, -OC(O)NR
eR
f, -OS(O)R
e, -OS(O)
2R
e, -OS(O)NR
eR
f, -OS(O)
2NR
eR
f, -SR
e, -S(O)R
e, -S(O)
2R
e, -S(O)NR
eR
f, -S(O)
2NR
eR
f, -NR
eR
f, -NR
eC(O)R
f, -NR
eC(O)OR
f, -NR
eC(O)NR
eR
f, -NR
eS(O)R
f, -NR
eS(O)
2R
f, -NR
eS(O)NR
eR
f, -NR
eS(O)
2NR
eR
f, -C(O)R
e, -C(O)OR
e, -C(O)NR
eR
f, -PR
eR
f, -P(O)R
eR
f, -P(O)
2R
eR
f, -P(O)NR
eR
f, -P(O)
2NR
eR
f, -P(O)OR
e, -P(O)
2OR
e’, -CN, or -NO
2; and when Y is a bond, -O-, –S-, or –S(O)-, then R
1 is ring A; [0017] each R
2 is independently deuterium, halogen, C
1-C
6 alkyl, C
2-C
6 alkenyl, C
2-C
6 alkynyl, C
3-C
6 cycloalkyl, 4- to 10-membered heterocycloalkyl, C
6-C
10 aryl, 5- to 10-membered heteroaryl, -OR
c, -OC(O)R
c, -OC(O)NR
cR
d, -OC(=NR
c)NR
cR
d, -OS(O)R
c, -OS(O)
2R
c, -OS(O)NR
cR
d, -OS(O)
2NR
cR
d, -SR
c, -S(O)R
c, -S(O)
2R
c, -S(O)NR
cR
d, -S(O)
2NR
cR
d, -NR
cR
d, -NR
cC(O)R
d, -N(C(O)R
c)(C(O)R
d), -NR
cC(O)OR
d, -NR
cC(O)NR
cR
d, -NR
cC(=NR
c)NR
cR
d, -NR
cS(O)R
d, -NR
cS(O)
2R
d, -NR
cS(O)NR
cR
d, -NR
cS(O)
2NR
cR
d, -C(O)R
c, -C(O)OR
c, -C(O)NR
cR
d, -C(=NR
c)NR
cR
d, -PR
cR
d, -P(O)R
cR
d, -P(O)
2R
cR
d, -P(O)NR
cR
d, -P(O)
2NR
cR
d, -P(O)OR
c, -P(O)
2OR
c, -CN, or -NO2, or two of R
2 taken together with the atoms to which they are attached form a C
3-C
6 cycloalkyl or a 4- to 10-membered heterocycloalkyl, wherein each hydrogen atom in C
1-C
6 alkyl, C
2-C
6 alkenyl, C
2-C
6 alkynyl, C
3-C
6 cycloalkyl, C
6-C
10 aryl, 5- to 10-membered heteroaryl, and 4- to 10-membered heterocycloalkyl is independently optionally substituted by deuterium, halogen, C
1-C
6 alkyl, C
1-C
6 haloalkyl, -R
e, -R
f, -OR
e, -OC(O)R
e, -OC(O)NR
eR
f, -OS(O)R
e, -OS(O)
2R
e, -OS(O)NR
eR
f, -OS(O)
2NR
eR
f, -SR
e, -S(O)R
e, -S(O)
2R
e, -S(O)NR
eR
f, -S(O)
2NR
eR
f, -NR
eR
f, -NR
eC(O)R
f, -NR
eC(O)OR
f, -NR
eC(O)NR
eR
f, -NR
eS(O)R
f, -NR
eS(O)
2R
f, -NR
eS(O)NR
eR
f, -NR
eS(O)
2NR
eR
f, -C(O)R
e, -C(O)OR
e, -C(O)NR
eR
f, -PR
eR
f, -P(O)R
eR
f, -P(O)
2R
eR
f, -P(O)NR
eR
f, -P(O)
2NR
eR
f, - P(O)OR
e, -P(O)
2OR
e, -CN, or -NO2; [0018] R
3 is -C
1-C
6 alkyl, -C
2-C
6 alkenyl, -C
2-C
6 alkynyl, -C
3-C
6 cycloalkyl, 4- to 10- membered heterocycloalkyl, -C
1-C
6 alkylene-(4- to 10-membered heterocycloalkyl), -C
6-C
10 aryl, -C
1-C
6 alkylene-(C
6-C
10 aryl), 5- to 10-membered heteroaryl, or -C
1-C
6 alkylene-(4- to 10- membered heterocycloalkyl), wherein each hydrogen atom in C
1-C
6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C
3-C
6 cycloalkyl, 4- to 10-membered heterocycloalkyl, -C
1-C
6 alkylene-(4- to 10- membered heterocycloalkyl), C
6-C
10 aryl, -C
1-C
6 alkylene-(C
6-C
10 aryl), 5- to 10-membered heteroaryl, and -C
1-C
6 alkylene-(5- to 10-membered heteroaryl), is independently optionally substituted by deuterium, halogen, -R
e, -R
f, C
1-C
6 alkyl, -C
1-C
6 alkyl-O-C
1-C
6 alkyl, -OC
1-C
6 alkyl-O-C
1-C
6 alkyl, -C
1-C
6 alkyl-O-R
a, C
6-C
10 aryl, -C
1-C
6 alkyl-(C
6-C
10 aryl), haloalkyl,C
3-
C
6 cycloalkyl, 5 to 10 membered heteroaryl, C
1 C
6 alkyl (5 to 10 membered heterocycloalkyl), -OR
e, -OC(O)R
e, -OC(O)NR
eR
f, -OS(O)R
e, -OS(O)
2R
e, -OS(O)NR
eR
f, -OS(O)
2NR
eR
f, -SR
e, -S(O)R
e, -S(O)
2R
e, -S(O)NR
eR
f, -S(O)
2NR
eR
f, -NR
eR
f, -NR
eC(O)R
f, -NR
eC(O)OR
f, -NR
eC(O)NR
eR
f, -NR
eC(=NR
f)NR
eR
f, -NR
eS(O)R
f, -NR
eS(O)
2R
f, -NR
eS(O)NR
eR
f, -NR
eS(O)
2NR
eR
f, -C(O)R
e, -C(O)OR
e, -C(O)NR
eR
f, -PR
eR
f, -P(O)R
eR
f, -P(O)
2R
eR
f, -P(O)NR
eR
f, -P(O)
2NR
eR
f, -P(O)OR
e, -P(O)
2OR
e’, -CN, or -NO
2; [0019] each of R
4 and R
10 is independently H, deuterium, C
1-C
6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C
3-C
6 cycloalkyl, 4- to 10-membered heterocycloalkyl, C
6-C
10 aryl, or 5- to 10- membered heteroaryl, wherein each hydrogen atom in C
1-C
6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C
3-C
6 cycloalkyl, 4- to 10-membered heterocycloalkyl, C
6-C
10 aryl, and 5- to 10- membered heteroaryl is independently optionally substituted by deuterium, halogen, -R
e, -R
f, C
1-C
6 alkyl, C
1-C
6 haloalkyl, -OR
e, -OC(O)R
e, -OC(O)NR
eR
f, -OS(O)R
e, -OS(O)
2R
e, - OS(O)NR
eR
f, -OS(O)
2NR
eR
f, -SR
e, -S(O)R
e, -S(O)
2R
e, -S(O)NR
eR
f, -S(O)
2NR
eR
f, -NR
eR
f, - NR
eC(O)R
f, -NR
eC(O)OR
f, -NR
eC(O)NR
eR
f, -NR
eS(O)R
f, -NR
eS(O)
2R
f, -NR
eS(O)NR
eR
f, - NR
eS(O)
2NR
eR
f, -C(O)R
e, -C(O)OR
e, -C(O)NR
eR
f, -PR
eR
f, -P(O)R
eR
f, -P(O)
2R
eR
f, - P(O)NR
eR
f, -P(O)
2NR
eR
f, -P(O)OR
e, -P(O)
2OR
e’, -CN, or -NO2; or R
1 and R
10 taken together with the atom or atoms to which they are attached combine to form a monocyclic 4- to 10- membered heterocycloalkyl, a fused bicyclic 5- to 10-membered heterocycloalkyl, or a bridged bicyclic 6- to 10-membered heterocycloalkyl, wherein each hydrogen atom in the monocyclic 4- to 10-membered heterocycloalkyl, fused bicyclic 5- to 10-membered heterocycloalkyl, or a bridged bicyclic 6- to 10-membered heterocycloalkyl is independently optionally substituted by deuterium, halogen, C
1-C
6 alkyl, C
1-C
6 haloalkyl, -OH, -OC
1-C
6 alkyl, -OC(O)C
1-C
6 alkyl, -OC(O)N(H or C
1-C
6 alkyl)
2, -OS(O)C
1-C
6 alkyl, -OS(O)
2C
1-C
6 alkyl, -OS(O)N(H or C
1-C
6 alkyl)
2, -OS(O)
2N(H or C
1-C
6 alkyl)
2, -SC
1-C
6 alkyl, -S(O)C
1-C
6 alkyl, -S(O)
2C
1-C
6 alkyl, -S(O)N(H or C
1-C
6 alkyl)
2, -S(O)
2N(H or C
1-C
6 alkyl)
2, -N(H or C
1-C
6 alkyl)
2, -N(C
1- C6 alkyl)C(O)-C
1-C
6 alkyl, -N(C
1-C
6 alkyl)C(O)OC
1-C
6 alkyl, -N(C
1-C
6 alkyl)C(O)N(H or C1- C
6 alkyl)
2, -N(C
1-C
6 alkyl)S(O)C
1-C
6 alkyl, -N(C
1-C
6 alkyl)S(O)
2C
1-C
6 alkyl, -N(C
1-C
6 alkyl)S(O)N(H or C
1-C
6 alkyl)
2, -N(C
1-C
6 alkyl)S(O)
2N(H or C
1-C
6 alkyl)
2, -C(O)C
1-C
6 alkyl, -C(O)OC
1-C
6 alkyl, -C(O)N(H or C
1-C
6 alkyl)
2, -P(H or C
1-C
6 alkyl)
2, -P(O)(H or C
1-C
6 alkyl)
2, -P(O)
2(H or C
1-C
6 alkyl)
2, -P(O)N(H or C
1-C
6 alkyl)
2, -P(O)
2N(H or C
1-C
6 alkyl)
2, -P(O)OC
1-C
6 alkyl, -P(O)
2OC
1-C
6 alkyl, -CN, or -NO2, or two hydrogen atoms on a single carbon atom of the monocyclic 4- to 10-membered heterocycloalkyl, fused bicyclic 5- to 10- membered heterocycloalkyl, or bridged bicyclic 6- to 10-membered heterocycloalkyl combine to form an oxo group or an alkenyl group;
[0020] each of R , R , R , R , and R is independently H, deuterium, halogen, C
1 C
6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C
3-C
6 cycloalkyl, 4- to 10-membered heterocycloalkyl, C
6-C
10 aryl, 5- to 10-membered heteroaryl, -OR
g, -OC(O)R
g, -OC(O)NR
gR
h, -OS(O)R
g, -OS(O)
2R
g, - SR
g, -S(O)R
g, -S(O)
2R
g, -S(O)NR
gR
h, -S(O)
2NR
gR
h, -OS(O)NR
gR
h, -OS(O)
2NR
gR
h, -NR
gR
h, -NR
gC(O)R
h, -NR
gC(O)OR
h, -NR
gC(O)NR
gR
h, -NR
gS(O)R
h, -NR
gS(O)
2R
h, -NR
gS(O)NR
gR
h, -NR
gS(O)
2NR
gR
h, -C(O)R
g, -C(O)OR
g, -C(O)NR
gR
h, -PR
gR
h, -P(O)R
gR
h, -P(O)
2R
gR
h, -P(O)NR
gR
h, -P(O)
2NR
gR
h, -P(O)OR
g, -P(O)
2OR
g, -CN, or -NO2; [0021] ring A is a C
3-C
8 cycloalkyl, 4- to 10-membered heterocycloalkyl, C
6-C
10 aryl, or 5- to 10-membered heteroaryl, wherein each of C
3-C8 cycloalkyl, 4- to 10-membered heterocycloalkyl, C
6-C
10 aryl, or 5- to 10-membered heteroaryl is unsubstituted or substituted with one or more of R
11; [0022] each R
11 is independently deuterium, halogen, C
1-C
6 alkyl, C
2-C
6 alkenyl, C
2-C
6 alkynyl, C
3-C
6 cycloalkyl, 4- to 10-membered heterocycloalkyl, C
6-C
10 aryl, 5- to 10- membered heteroaryl, -OR
a, -OC(O)R
a, -OC(O)NR
aR
b, -OC(=NR
a)NR
aR
b, -OS(O)R
a, -OS(O)
2R
a, -OS(O)NR
aR
b, -OS(O)
2NR
aR
b, -SR
a, -S(O)R
a, -S(O)
2R
a, -S(O)NR
aR
b, -S(O)
2NR
aR
b, -NR
aR
b, -NR
aC(O)R
b, -N(C(O)R
a)(C(O)R
b), -NR
aC(O)OR
b, -NR
aC(O)NR
aR
b, -NR
aC(=NR
a)NR
aR
b, -NR
aS(O)R
b, -NR
aS(O)
2R
b, -NR
aS(O)NR
aR
b, -NR
aS(O)
2NR
aR
b, - C(O)R
a, -C(O)OR
a, -C(O)NR
aR
b, -C(=NR
a)NR
aR
b, -PR
aR
b, -P(O)R
aR
b, -P(O)
2R
aR
b, - P(O)NR
aR
b, -P(O)
2NR
aR
b, -P(O)OR
a, -P(O)
2OR
a, -CN, or -NO
2, or two of R
11 taken together with the atom or atoms to which they are attached or three of R
11 taken together with the atoms to which they are attached, form a C
3-C
6 cycloalkyl or a 4- to 10-membered heterocycloalkyl, wherein each hydrogen atom in C
1-C
6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C
3-C
6 cycloalkyl, C
6-C
10 aryl, 5- to 10-membered heteroaryl, and 4- to 10-membered heterocycloalkyl is independently optionally substituted by deuterium, halogen, -R
e, -R
f, C
1-C
6 alkyl, C
1-C
6 haloalkyl, -OR
e, -OC(O)R
e, -OC(O)NR
eR
f, -OS(O)R
e, -OS(O)
2R
e, -OS(O)NR
eR
f, -OS(O)
2NR
eR
f, -SR
e, -S(O)R
e, -S(O)
2R
e, -S(O)NR
eR
f, -S(O)
2NR
eR
f, -NR
eR
f, -NR
eC(O)R
f, - NR
eC(O)OR
f, -NR
eC(O)NR
eR
f, -NR
eS(O)R
f, -NR
eS(O)
2R
f, -NR
eS(O)NR
eR
f, -NR
eS(O)
2NR
eR
f, -C(O)R
e, -C(O)OR
e, -C(O)NR
eR
f, -PR
eR
f, -P(O)R
eR
f, -P(O)
2R
eR
f, -P(O)NR
eR
f, -P(O)
2NR
eR
f, -P(O)OR
e, -P(O)
2OR
e, -CN, or -NO2, or two of R
11 taken together with the carbon atom to which they are attached form an oxo group or an alkenyl group; [0023] ring B is a C
6-C
10 aryl or 5- to 10-membered heteroaryl; [0024] each R
a, R
b, R
c, R
d, R
e, R
f, R
g, and R
h is independently selected from the group consisting of H, deuterium, C
1-C
6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C
3-C
6 cycloalkyl, 4- to 10-membered heterocycloalkyl, C
6-C
10 aryl, C
1-C
6 alkyl-C
6-C
10 aryl, and 5- to 10-membered heteroaryl; or two of R
a and R
b, or R
c and R
d, or R
e and R
f, or R
g and R
h, taken together with
the atom or atoms to which they are attached, combine to form a C
3 C
6 cycloalkyl, 4 to 10 membered heterocycloalkyl, C
6-C
10 aryl, or 5- to 10-membered heteroaryl, wherein each hydrogen atom in C
1-C
6 alkyl, C
2-C
6 alkenyl, C
2-C
6 alkynyl, C
3-C
6 cycloalkyl, 4- to 10- membered heterocycloalkyl, C
6-C
10 aryl, C
1-C
6 alkyl-C
6-C
10 aryl, and 5- to 10-membered heteroaryl is independently optionally substituted by deuterium, halogen, C
1-C
6 alkyl, C
1-C
6 haloalkyl, -OH, -OC
1-C
6 alkyl, -OC(O)C
1-C
6 alkyl, -OC(O)N(H or C
1-C
6 alkyl)
2, -OS(O)C
1- C6 alkyl, -OS(O)
2C
1-C
6 alkyl, -OS(O)N(H or C
1-C
6 alkyl)
2, -OS(O)
2N(H or C
1-C
6 alkyl)
2, - SC
1-C
6 alkyl, -S(O)C
1-C
6 alkyl, -S(O)
2C
1-C
6 alkyl, -S(O)N(H or C
1-C
6 alkyl)
2, -S(O)
2N(H or C
1-C
6 alkyl)
2, -N(H or C
1-C
6 alkyl)
2, -N(C
1-C
6 alkyl)C(O)-C
1-C
6 alkyl, -N(C
1-C
6 alkyl)C(O)OC
1-C
6 alkyl, -N(C
1-C
6 alkyl)C(O)N(H or C
1-C
6 alkyl)
2, -N(C
1-C
6 alkyl)S(O)C
1- C6 alkyl, -N(C
1-C
6 alkyl)S(O)
2C
1-C
6 alkyl, -N(C
1-C
6 alkyl)S(O)N(H or C
1-C
6 alkyl)
2, -N(C1- C
6 alkyl)S(O)
2N(H or C
1-C
6 alkyl)
2, -C(O)C
1-C
6 alkyl, -C(O)OC
1-C
6 alkyl, -C(O)N(H or C
1- C6 alkyl)
2, -P(H or C
1-C
6 alkyl)
2, -P(O)(H or C
1-C
6 alkyl)
2, -P(O)
2(H or C
1-C
6 alkyl)
2, - P(O)N(H or C
1-C
6 alkyl)
2, -P(O)
2N(H or C
1-C
6 alkyl)
2, -P(O)OC
1-C
6 alkyl, -P(O)
2OC
1-C
6 alkyl, -CN, or -NO2, or -R
e and -R
f taken together with the carbon atom to which they are attached form an oxo groups or a C2-C6 alkenyl; [0025] n is 0, 1, 2, 3, 4, 5, 6, or 7; [0026] p is 0 or 1; and [0027] q is 0, 1, or 2. [0028] and wherein the compound is not of the formula
C
2-C
6 alkynyl, wherein each hydrogen atom in C
1-C
6 alkyl, C
2-C
6 alkenyl, or C
2-C
6 alkynyl is independently optionally substituted by deuterium, halogen, -R
e, -R
f, C
1-C
6 alkyl, C
1-C
6 haloalkyl, -OR
e, -OC(O)R
e, -OC(O)NR
eR
f, -OS(O)R
e, -OS(O)
2R
e, -OS(O)NR
eR
f, -OS(O)
2NR
eR
f, -SR
e, -S(O)R
e, -S(O)
2R
e, -S(O)NR
eR
f, -S(O)
2NR
eR
f, -NR
eR
f, -NR
eC(O)R
f, -NR
eC(O)OR
f, -NR
eC(O)NR
eR
f, -NR
eS(O)R
f, -NR
eS(O)
2R
f, -NR
eS(O)NR
eR
f, - NR
eS(O)
2NR
eR
f, -C(O)R
e, -C(O)OR
e, -C(O)NR
eR
f, -PR
eR
f, -P(O)R
eR
f, -P(O)
2R
eR
f, - P(O)NR
eR
f, -P(O)
2NR
eR
f, -P(O)OR
e, -P(O)
2OR
e’, -CN, or -NO
2. In some embodiments of this aspect, R
1 is ring A, and ring A is a C
3-C8 cycloalkyl, C
6-C
10 aryl, or 5- to 10-membered heteroaryl, wherein each of C
3-C8 cycloalkyl, C
6-C
10 aryl, or 5- to 10-membered heteroaryl is
unsubstituted or substituted with one or more of R . In some embodiments of this aspect, ring A is a 4- to 10-membered heterocycloalkyl that is covalently attached to –Y-, -(CR
aR
b)n-, or
through a carbon atom in the 4- to 10-membered heterocycloalkyl. In s of this aspect, at least one hydrogen atom on ring A, ring B, R
1, or R
3 in the compound of the formula I is substituted by a deuterium. [0030] In one aspect, the disclosure relates to a compound of the formula I, or a pharmaceutically acceptable salt thereof,
[0031] where [0032] X is a -O-, -S-, or -NR
4-; [0033] Y is a bond, -O-, -S-, -S(O)-, -S(O)
2-, or –C(O)NR
10-; [0034] Z
1 is N or C(R
5); [0035] Z
2 is N or C(R
6); [0036] Z
3 is N or C(R
7); [0037] Z
4 is N or C(R
8); [0038] Z
5 is N or C(R
9); [0039] provided that at least two of Z
1-Z
5 are N; [0040] R
1 is independently H, deuterium, C
1-C
6 alkyl, C
2-C
6 alkenyl, C
2-C
6 alkynyl, or ring A, wherein each hydrogen atom in C
1-C
6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl is independently optionally substituted by deuterium, halogen, -R
e, -R
f, C
1-C
6 alkyl, C
1-C
6 haloalkyl, -OR
e, -OC(O)R
e, -OC(O)NR
eR
f, -OS(O)R
e, -OS(O)
2R
e, -OS(O)NR
eR
f, -OS(O)
2NR
eR
f, -SR
e, -S(O)R
e, -S(O)
2R
e, -S(O)NR
eR
f, -S(O)
2NR
eR
f, -NR
eR
f, -NR
eC(O)R
f, -NR
eC(O)OR
f, -NR
eC(O)NR
eR
f, -NR
eS(O)R
f, -NR
eS(O)
2R
f, -NR
eS(O)NR
eR
f, -NR
eS(O)
2NR
eR
f, -C(O)R
e,
C(O)OR , C(O)NR R, PR R, P(O)R R, P(O)
2R R, P(O)NR R, P(O)
2NR R, -P(O)OR
e, -P(O)
2OR
e’, -CN, or -NO2; and when Y is a bond, -O-, –S-, or –S(O)-, then R
1 is ring A; [0041] each R
2 is independently deuterium, halogen, C
1-C
6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C
3-C
6 cycloalkyl, 4- to 10-membered heterocycloalkyl, C
6-C
10 aryl, 5- to 10-membered heteroaryl, -OR
c, -OC(O)R
c, -OC(O)NR
cR
d, -OC(=NR
c)NR
cR
d, -OS(O)R
c, -OS(O)
2R
c, -OS(O)NR
cR
d, -OS(O)
2NR
cR
d, -SR
c, -S(O)R
c, -S(O)
2R
c, -S(O)NR
cR
d, -S(O)
2NR
cR
d, -NR
cR
d, -NR
cC(O)R
d, -N(C(O)R
c)(C(O)R
d), -NR
cC(O)OR
d, -NR
cC(O)NR
cR
d, -NR
cC(=NR
c)NR
cR
d, -NR
cS(O)R
d, -NR
cS(O)
2R
d, -NR
cS(O)NR
cR
d, -NR
cS(O)
2NR
cR
d, -C(O)R
c, -C(O)OR
c, -C(O)NR
cR
d, -C(=NR
c)NR
cR
d, -PR
cR
d, -P(O)R
cR
d, -P(O)
2R
cR
d, -P(O)NR
cR
d, -P(O)
2NR
cR
d, -P(O)OR
c, -P(O)
2OR
c, -CN, or -NO2, or two of R
2 taken together with the atoms to which they are attached form a C
3-C
6 cycloalkyl or a 4- to 10-membered heterocycloalkyl, wherein each hydrogen atom in C
1-C
6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C
3-C
6 cycloalkyl, C
6-C
10 aryl, 5- to 10-membered heteroaryl, and 4- to 10-membered heterocycloalkyl is independently optionally substituted by deuterium, halogen, C
1-C
6 alkyl, C
1-C
6 haloalkyl, -R
e, -R
f, -OR
e, -OC(O)R
e, -OC(O)NR
eR
f, -OS(O)R
e, -OS(O)
2R
e, -OS(O)NR
eR
f, -OS(O)
2NR
eR
f, -SR
e, -S(O)R
e, -S(O)
2R
e, -S(O)NR
eR
f, -S(O)
2NR
eR
f, -NR
eR
f, -NR
eC(O)R
f, -NR
eC(O)OR
f, -NR
eC(O)NR
eR
f, -NR
eS(O)R
f, -NR
eS(O)
2R
f, -NR
eS(O)NR
eR
f, -NR
eS(O)
2NR
eR
f, -C(O)R
e, -C(O)OR
e, -C(O)NR
eR
f, -PR
eR
f, -P(O)R
eR
f, -P(O)
2R
eR
f, -P(O)NR
eR
f, -P(O)
2NR
eR
f, - P(O)OR
e, -P(O)
2OR
e, -CN, or -NO2; [0042] R
3 is -C
1-C
6 alkyl, -C
2-C
6 alkenyl, -C
2-C
6 alkynyl, -C
3-C
6 cycloalkyl, 4- to 10- membered heterocycloalkyl, -C
1-C
6 alkylene-(4- to 10-membered heterocycloalkyl), -C
6-C
10 aryl, -C
1-C
6 alkylene-(C
6-C
10 aryl), 5- to 10-membered heteroaryl, or -C
1-C
6 alkylene-(4- to 10- membered heterocycloalkyl), wherein each hydrogen atom in C
1-C
6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C
3-C
6 cycloalkyl, 4- to 10-membered heterocycloalkyl, -C
1-C
6 alkylene-(4- to 10- membered heterocycloalkyl), C
6-C
10 aryl, -C
1-C
6 alkylene-(C
6-C
10 aryl), 5- to 10-membered heteroaryl, and -C
1-C
6 alkylene-(5- to 10-membered heteroaryl), is independently optionally substituted by deuterium, halogen, -R
e, -R
f, C
1-C
6 alkyl, -C
1-C
6 alkyl-O-C
1-C
6 alkyl, -OC
1-C
6 alkyl-O-C
1-C
6 alkyl, -C
1-C
6 alkyl-O-R
a, C
6-C
10 aryl, -C
1-C
6 alkyl-(C
6-C
10 aryl), haloalkyl, C
3- C6 cycloalkyl, 5- to 10-membered heteroaryl, -C
1-C
6 alkyl-(5- to 10-membered heterocycloalkyl), -OR
e, -OC(O)R
e, -OC(O)NR
eR
f, -OS(O)R
e, -OS(O)
2R
e, -OS(O)NR
eR
f, -OS(O)
2NR
eR
f, -SR
e, -S(O)R
e, -S(O)
2R
e, -S(O)NR
eR
f, -S(O)
2NR
eR
f, -NR
eR
f, -NR
eC(O)R
f, -NR
eC(O)OR
f, -NR
eC(O)NR
eR
f, -NR
eC(=NR
f)NR
eR
f, -NR
eS(O)R
f, -NR
eS(O)
2R
f, -NR
eS(O)NR
eR
f, -NR
eS(O)
2NR
eR
f, -C(O)R
e, -C(O)OR
e, -C(O)NR
eR
f, -PR
eR
f, -P(O)R
eR
f, -P(O)
2R
eR
f, -P(O)NR
eR
f, -P(O)
2NR
eR
f, -P(O)OR
e, -P(O)
2OR
e’, -CN, or -NO2;
[0043] each of R and R is independently H, deuterium, C
1 C
6 alkyl, C
2 C
6 alkenyl, C
2 C
6 alkynyl, C
3-C
6 cycloalkyl, 4- to 10-membered heterocycloalkyl, C
6-C
10 aryl, or 5- to 10- membered heteroaryl, wherein each hydrogen atom in C
1-C
6 alkyl, C
2-C
6 alkenyl, C
2-C
6 alkynyl, C
3-C
6 cycloalkyl, 4- to 10-membered heterocycloalkyl, C
6-C
10 aryl, and 5- to 10- membered heteroaryl is independently optionally substituted by deuterium, halogen, -R
e, -R
f, C
1-C
6 alkyl, C
1-C
6 haloalkyl, -OR
e, -OC(O)R
e, -OC(O)NR
eR
f, -OS(O)R
e, -OS(O)
2R
e, - OS(O)NR
eR
f, -OS(O)
2NR
eR
f, -SR
e, -S(O)R
e, -S(O)
2R
e, -S(O)NR
eR
f, -S(O)
2NR
eR
f, -NR
eR
f, - NR
eC(O)R
f, -NR
eC(O)OR
f, -NR
eC(O)NR
eR
f, -NR
eS(O)R
f, -NR
eS(O)
2R
f, -NR
eS(O)NR
eR
f, - NR
eS(O)
2NR
eR
f, -C(O)R
e, -C(O)OR
e, -C(O)NR
eR
f, -PR
eR
f, -P(O)R
eR
f, -P(O)
2R
eR
f, - P(O)NR
eR
f, -P(O)
2NR
eR
f, -P(O)OR
e, -P(O)
2OR
e’, -CN, or -NO
2; or R
1 and R
10 taken together with the atom or atoms to which they are attached combine to form a monocyclic 4- to 10- membered heterocycloalkyl, a fused bicyclic 5- to 10-membered heterocycloalkyl, or a bridged bicyclic 6- to 10-membered heterocycloalkyl, wherein each hydrogen atom in the monocyclic 4- to 10-membered heterocycloalkyl, fused bicyclic 5- to 10-membered heterocycloalkyl, or a bridged bicyclic 6- to 10-membered heterocycloalkyl is independently optionally substituted by deuterium, halogen, C
1-C
6 alkyl, C
1-C
6 haloalkyl, -OH, -OC
1-C
6 alkyl, -OC(O)C
1-C
6 alkyl, -OC(O)N(H or C
1-C
6 alkyl)
2, -OS(O)C
1-C
6 alkyl, -OS(O)
2C
1-C
6 alkyl, -OS(O)N(H or C
1-C
6 alkyl)
2, -OS(O)
2N(H or C
1-C
6 alkyl)
2, -SC
1-C
6 alkyl, -S(O)C
1-C
6 alkyl, -S(O)
2C
1-C
6 alkyl, -S(O)N(H or C
1-C
6 alkyl)
2, -S(O)
2N(H or C
1-C
6 alkyl)
2, -N(H or C
1-C
6 alkyl)
2, -N(C
1- C6 alkyl)C(O)-C
1-C
6 alkyl, -N(C
1-C
6 alkyl)C(O)OC
1-C
6 alkyl, -N(C
1-C
6 alkyl)C(O)N(H or C1- C
6 alkyl)
2, -N(C
1-C
6 alkyl)S(O)C
1-C
6 alkyl, -N(C
1-C
6 alkyl)S(O)
2C
1-C
6 alkyl, -N(C
1-C
6 alkyl)S(O)N(H or C
1-C
6 alkyl)
2, -N(C
1-C
6 alkyl)S(O)
2N(H or C
1-C
6 alkyl)
2, -C(O)C
1-C
6 alkyl, -C(O)OC
1-C
6 alkyl, -C(O)N(H or C
1-C
6 alkyl)
2, -P(H or C
1-C
6 alkyl)
2, -P(O)(H or C
1-C
6 alkyl)
2, -P(O)
2(H or C
1-C
6 alkyl)
2, -P(O)N(H or C
1-C
6 alkyl)
2, -P(O)
2N(H or C
1-C
6 alkyl)
2, -P(O)OC
1-C
6 alkyl, -P(O)
2OC
1-C
6 alkyl, -CN, or -NO
2, or two hydrogen atoms on a single carbon atom of the monocyclic 4- to 10-membered heterocycloalkyl, fused bicyclic 5- to 10- membered heterocycloalkyl, or bridged bicyclic 6- to 10-membered heterocycloalkyl combine to form an oxo group or an alkenyl group; [0044] each of R
5, R
6, R
7, R
8, and R
9 is independently H, deuterium, halogen, C
1-C
6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C
3-C
6 cycloalkyl, 4- to 10-membered heterocycloalkyl, C
6-C
10 aryl, 5- to 10-membered heteroaryl, -OR
g, -OC(O)R
g, -OC(O)NR
gR
h, -OS(O)R
g, -OS(O)
2R
g, - SR
g, -S(O)R
g, -S(O)
2R
g, -S(O)NR
gR
h, -S(O)
2NR
gR
h, -OS(O)NR
gR
h, -OS(O)
2NR
gR
h, -NR
gR
h, -NR
gC(O)R
h, -NR
gC(O)OR
h, -NR
gC(O)NR
gR
h, -NR
gS(O)R
h, -NR
gS(O)
2R
h, -NR
gS(O)NR
gR
h, -NR
gS(O)
2NR
gR
h, -C(O)R
g, -C(O)OR
g, -C(O)NR
gR
h, -PR
gR
h, -P(O)R
gR
h, -P(O)
2R
gR
h, -P(O)NR
gR
h, -P(O)
2NR
gR
h, -P(O)OR
g, -P(O)
2OR
g, -CN, or -NO2;
[0045] ring A is a C
3 C
8 cycloalkyl, 4 to 10 membered heterocycloalkyl, C
6 C
10 aryl, or 5 to 10-membered heteroaryl, wherein each of C
3-C8 cycloalkyl, 4- to 10-membered heterocycloalkyl, C
6-C
10 aryl, or 5- to 10-membered heteroaryl is unsubstituted or substituted with one or more of R
11, and 4- to 10-membered heterocycloalkyl is an unsubstituted or a substituted ring of the formula
[0046] each R
11 is independently deuterium, halogen, C
1-C
6 alkyl, C
2-C
6 alkenyl, C
2-C
6 alkynyl, C3-C6 cycloalkyl, 4- to 10-membered heterocycloalkyl, C6-C10 aryl, 5- to 10- membered heteroaryl, -OR
a, -OC(O)R
a, -OC(O)NR
aR
b, -OC(=NR
a)NR
aR
b, -OS(O)R
a, -OS(O)
2R
a, -OS(O)NR
aR
b, -OS(O)
2NR
aR
b, -SR
a, -S(O)R
a, -S(O)
2R
a, -S(O)NR
aR
b, -S(O)
2NR
aR
b, -NR
aR
b, -NR
aC(O)R
b, -N(C(O)R
a)(C(O)R
b), -NR
aC(O)OR
b, -NR
aC(O)NR
aR
b, -NR
aC(=NR
a)NR
aR
b, -NR
aS(O)R
b, -NR
aS(O)
2R
b, -NR
aS(O)NR
aR
b, -NR
aS(O)
2NR
aR
b, - C(O)R
a, -C(O)OR
a, -C(O)NR
aR
b, -C(=NR
a)NR
aR
b, -PR
aR
b, -P(O)R
aR
b, -P(O)
2R
aR
b, - P(O)NR
aR
b, -P(O)
2NR
aR
b, -P(O)OR
a, -P(O)
2OR
a, -CN, or -NO2, or two of R
11 taken together with the atom or atoms to which they are attached or three of R
11 taken together with the atoms to which they are attached, form a C3-C6 cycloalkyl or a 4- to 10-membered heterocycloalkyl, wherein each hydrogen atom in C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C
6-C
10 aryl, 5- to 10-membered heteroaryl, and 4- to 10-membered heterocycloalkyl is independently optionally substituted by deuterium, halogen, -R
e, -R
f, C1-C6 alkyl, C1-C6 haloalkyl, -OR
e, -OC(O)R
e, -OC(O)NR
eR
f, -OS(O)R
e, -OS(O)
2R
e, -OS(O)NR
eR
f, -OS(O)
2NR
eR
f, -SR
e, -S(O)R
e, -S(O)
2R
e, -S(O)NR
eR
f, -S(O)
2NR
eR
f, -NR
eR
f, -NR
eC(O)R
f, - NR
eC(O)OR
f, -NR
eC(O)NR
eR
f, -NR
eS(O)R
f, -NR
eS(O)
2R
f, -NR
eS(O)NR
eR
f, -NR
eS(O)
2NR
eR
f, -C(O)R
e, -C(O)OR
e, -C(O)NR
eR
f, -PR
eR
f, -P(O)R
eR
f, -P(O)
2R
eR
f, -P(O)NR
eR
f, -P(O)
2NR
eR
f, -P(O)OR
e, -P(O)
2OR
e, -CN, or -NO
2, or two of R
11 taken together with the carbon atom to which they are attached form an oxo group or an alkenyl group; [0047] ring B is a C
6-C
10 aryl or 5- to 10-membered heteroaryl; [0048] each R
a, R
b, R
c, R
d, R
e, R
f, R
g, and R
h is independently selected from the group consisting of H, deuterium, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 4- to 10-membered heterocycloalkyl, C
6-C
10 aryl, C
1-C
6 alkyl-C
6-C
10 aryl, and 5- to 10-membered heteroaryl; or two of R
a and R
b, or R
c and R
d, or R
e and R
f, or R
g and R
h, taken together with
the atom or atoms to which they are attached, combine to form a C
3 C
6 cycloalkyl, 4 to 10 membered heterocycloalkyl, C
6-C
10 aryl, or 5- to 10-membered heteroaryl, wherein each hydrogen atom in C
1-C
6 alkyl, C
2-C
6 alkenyl, C
2-C
6 alkynyl, C
3-C
6 cycloalkyl, 4- to 10- membered heterocycloalkyl, C
6-C
10 aryl, C
1-C
6 alkyl-C
6-C
10 aryl, and 5- to 10-membered heteroaryl is independently optionally substituted by deuterium, halogen, C
1-C
6 alkyl, C
1-C
6 haloalkyl, -OH, -OC
1-C
6 alkyl, -OC(O)C
1-C
6 alkyl, -OC(O)N(H or C
1-C
6 alkyl)
2, -OS(O)C
1- C6 alkyl, -OS(O)
2C
1-C
6 alkyl, -OS(O)N(H or C
1-C
6 alkyl)
2, -OS(O)
2N(H or C
1-C
6 alkyl)
2, - SC
1-C
6 alkyl, -S(O)C
1-C
6 alkyl, -S(O)
2C
1-C
6 alkyl, -S(O)N(H or C
1-C
6 alkyl)
2, -S(O)
2N(H or C
1-C
6 alkyl)
2, -N(H or C
1-C
6 alkyl)
2, -N(C
1-C
6 alkyl)C(O)-C
1-C
6 alkyl, -N(C
1-C
6 alkyl)C(O)OC
1-C
6 alkyl, -N(C
1-C
6 alkyl)C(O)N(H or C
1-C
6 alkyl)
2, -N(C
1-C
6 alkyl)S(O)C
1- C6 alkyl, -N(C
1-C
6 alkyl)S(O)
2C
1-C
6 alkyl, -N(C
1-C
6 alkyl)S(O)N(H or C
1-C
6 alkyl)
2, -N(C1- C
6 alkyl)S(O)
2N(H or C
1-C
6 alkyl)
2, -C(O)C
1-C
6 alkyl, -C(O)OC
1-C
6 alkyl, -C(O)N(H or C
1- C6 alkyl)
2, -P(H or C
1-C
6 alkyl)
2, -P(O)(H or C
1-C
6 alkyl)
2, -P(O)
2(H or C
1-C
6 alkyl)
2, - P(O)N(H or C
1-C
6 alkyl)
2, -P(O)
2N(H or C
1-C
6 alkyl)
2, -P(O)OC
1-C
6 alkyl, -P(O)
2OC
1-C
6 alkyl, -CN, or -NO2, or -R
e and -R
f taken together with the carbon atom to which they are attached form an oxo groups or an alkenyl; [0049] n is 0, 1, 2, 3, 4, 5, 6, or 7; [0050] p is 0 or 1; and [0051] q is 0, 1, or 2; [0052] and wherein the compound is not of the formula
[0053] In some embodiments of this aspect, R
1 is H, deuterium, C
1-C
6 alkyl, C
2-C
6 alkenyl, or C2-C6 alkynyl, wherein each hydrogen atom in C
1-C
6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl is independently optionally substituted by deuterium, halogen, -R
e, -R
f, C
1-C
6 alkyl, C
1-C
6 haloalkyl, -OR
e, -OC(O)R
e, -OC(O)NR
eR
f, -OS(O)R
e, -OS(O)
2R
e, -OS(O)NR
eR
f, -OS(O)
2NR
eR
f, -SR
e, -S(O)R
e, -S(O)
2R
e, -S(O)NR
eR
f, -S(O)
2NR
eR
f, -NR
eR
f, -NR
eC(O)R
f, -NR
eC(O)OR
f, -NR
eC(O)NR
eR
f, -NR
eS(O)R
f, -NR
eS(O)
2R
f, -NR
eS(O)NR
eR
f, - NR
eS(O)
2NR
eR
f, -C(O)R
e, -C(O)OR
e, -C(O)NR
eR
f, -PR
eR
f, -P(O)R
eR
f, -P(O)
2R
eR
f, - P(O)NR
eR
f, -P(O)
2NR
eR
f, -P(O)OR
e, -P(O)
2OR
e’, -CN, or -NO2. In some embodiments of this aspect, R
1 is ring A, and ring A is a C
3-C8 cycloalkyl, C
6-C
10 aryl, or 5- to 10-membered
heteroaryl, wherein each of C
3-C
8 cycloalkyl, C
6-C
10 aryl, or 5- to 10-membered heteroaryl is unsubstituted or substituted with one or more of R
11. In some embodiments of this aspect, ring A is a 4- to 10-membered heterocycloalkyl that is covalently attached to –Y-, -(CR
aR
b)
n-, or
through a carbon atom in the 4- to 10-membered heterocycloalkyl. In some embodiments of this aspect, at least one hydrogen atom on ring A, ring B, R
1, or R
3 in the compound of the formula I is substituted by a deuterium. [0054] In one aspect, the disclosure relates to a compound of the formula I, or a pharmaceutically acceptable salt thereof,
[0055] wherein [0056] X is a -O-, -S-, or -NR
4-; [0057] Y is a bond, -O-, -S-, -S(O)-, -S(O)2-, or –C(O)NR
10-; [0058] Z
1 is N or C(R
5); [0059] Z
2 is N or C(R
6); [0060] Z
3 is N or C(R
7); [0061] Z
4 is N or C(R
8); [0062] Z
5 is N or C(R
9); [0063] provided that at least two of Z
1-Z
5 are N; [0064] R
1 is independently H, deuterium, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, or ring A, wherein each hydrogen atom in C
1-C
6 alkyl, C
2-C
6 alkenyl, or C
2-C
6 alkynyl is independently optionally substituted by deuterium, halogen, -R
e, -R
f, C1-C6 alkyl, C1-C6 haloalkyl, -OR
e, -OC(O)R
e, -OC(O)NR
eR
f, -OS(O)R
e, -OS(O)
2R
e, -OS(O)NR
eR
f, -OS(O)
2NR
eR
f, -SR
e, -S(O)R
e, -S(O)2R
e, -S(O)NR
eR
f, -S(O)2NR
eR
f, -NR
eR
f, -NR
eC(O)R
f, -NR
eC(O)OR
f,
NR C(O)NR R, NR S(O)R, NR S(O)
2R, NR S(O)NR R, NR S(O)
2NR R, C(O)R , -C(O)OR
e, -C(O)NR
eR
f, -PR
eR
f, -P(O)R
eR
f, -P(O)
2R
eR
f, -P(O)NR
eR
f, -P(O)
2NR
eR
f, -P(O)OR
e, -P(O)
2OR
e’, -CN, or -NO
2; and when Y is a bond, -O-, –S-, or –S(O)-, then R
1 is ring A; [0065] each R
2 is independently deuterium, halogen, C
1-C
6 alkyl, C
2-C
6 alkenyl, C
2-C
6 alkynyl, C
3-C
6 cycloalkyl, 4- to 10-membered heterocycloalkyl, C
6-C
10 aryl, 5- to 10-membered heteroaryl, -OR
c, -OC(O)R
c, -OC(O)NR
cR
d, -OC(=NR
c)NR
cR
d, -OS(O)R
c, -OS(O)
2R
c, -OS(O)NR
cR
d, -OS(O)
2NR
cR
d, -SR
c, -S(O)R
c, -S(O)
2R
c, -S(O)NR
cR
d, -S(O)
2NR
cR
d, -NR
cR
d, -NR
cC(O)R
d, -N(C(O)R
c)(C(O)R
d), -NR
cC(O)OR
d, -NR
cC(O)NR
cR
d, -NR
cC(=NR
c)NR
cR
d, -NR
cS(O)R
d, -NR
cS(O)
2R
d, -NR
cS(O)NR
cR
d, -NR
cS(O)
2NR
cR
d, -C(O)R
c, -C(O)OR
c, -C(O)NR
cR
d, -C(=NR
c)NR
cR
d, -PR
cR
d, -P(O)R
cR
d, -P(O)
2R
cR
d, -P(O)NR
cR
d, -P(O)
2NR
cR
d, -P(O)OR
c, -P(O)
2OR
c, -CN, or -NO
2, or two of R
2 taken together with the atoms to which they are attached form a C
3-C
6 cycloalkyl or a 4- to 10-membered heterocycloalkyl, wherein each hydrogen atom in C
1-C
6 alkyl, C
2-C
6 alkenyl, C
2-C
6 alkynyl, C
3-C
6 cycloalkyl, C
6-C
10 aryl, 5- to 10-membered heteroaryl, and 4- to 10-membered heterocycloalkyl is independently optionally substituted by deuterium, halogen, C
1-C
6 alkyl, C
1-C
6 haloalkyl, -R
e, -R
f, -OR
e, -OC(O)R
e, -OC(O)NR
eR
f, -OS(O)R
e, -OS(O)
2R
e, -OS(O)NR
eR
f, -OS(O)
2NR
eR
f, -SR
e, -S(O)R
e, -S(O)
2R
e, -S(O)NR
eR
f, -S(O)
2NR
eR
f, -NR
eR
f, -NR
eC(O)R
f, -NR
eC(O)OR
f, -NR
eC(O)NR
eR
f, -NR
eS(O)R
f, -NR
eS(O)
2R
f, -NR
eS(O)NR
eR
f, -NR
eS(O)
2NR
eR
f, -C(O)R
e, -C(O)OR
e, -C(O)NR
eR
f, -PR
eR
f, -P(O)R
eR
f, -P(O)
2R
eR
f, -P(O)NR
eR
f, -P(O)
2NR
eR
f, - P(O)OR
e, -P(O)
2OR
e, -CN, or -NO
2; [0066] R
3 is -C
1-C
6 alkyl, -C2-C6 alkenyl, -C2-C6 alkynyl, -C
3-C
6 cycloalkyl, 4- to 10- membered heterocycloalkyl, -C
1-C
6 alkylene-(4- to 10-membered heterocycloalkyl), -C
6-C
10 aryl, -C
1-C
6 alkylene-(C
6-C
10 aryl), 5- to 10-membered heteroaryl, or -C
1-C
6 alkylene-(4- to 10- membered heterocycloalkyl), wherein each hydrogen atom in C
1-C
6 alkyl, C
2-C
6 alkenyl, C
2-C
6 alkynyl, C
3-C
6 cycloalkyl, 4- to 10-membered heterocycloalkyl, -C
1-C
6 alkylene-(4- to 10- membered heterocycloalkyl), C
6-C
10 aryl, -C
1-C
6 alkylene-(C
6-C
10 aryl), 5- to 10-membered heteroaryl, and -C
1-C
6 alkylene-(5- to 10-membered heteroaryl), is independently optionally substituted by deuterium, halogen, -R
e, -R
f, C
1-C
6 alkyl, -C
1-C
6 alkyl-O-C
1-C
6 alkyl, -OC
1-C
6 alkyl-O-C
1-C
6 alkyl, -C
1-C
6 alkyl-O-R
a, C
6-C
10 aryl, -C
1-C
6 alkyl-(C
6-C
10 aryl), haloalkyl, C
3- C6 cycloalkyl, 5- to 10-membered heteroaryl, -C
1-C
6 alkyl-(5- to 10-membered heterocycloalkyl), -OR
e, -OC(O)R
e, -OC(O)NR
eR
f, -OS(O)R
e, -OS(O)
2R
e, -OS(O)NR
eR
f, -OS(O)
2NR
eR
f, -SR
e, -S(O)R
e, -S(O)
2R
e, -S(O)NR
eR
f, -S(O)
2NR
eR
f, -NR
eR
f, -NR
eC(O)R
f, -NR
eC(O)OR
f, -NR
eC(O)NR
eR
f, -NR
eC(=NR
f)NR
eR
f, -NR
eS(O)R
f, -NR
eS(O)
2R
f,
NR S(O)NR R, NR S(O)
2NR R, C(O)R , C(O)OR , C(O)NR R, PR R, P(O)R R, -P(O)
2R
eR
f, -P(O)NR
eR
f, -P(O)
2NR
eR
f, -P(O)OR
e, -P(O)
2OR
e’, -CN, or -NO2; [0067] each of R
4 and R
10 is independently H, deuterium, C
1-C
6 alkyl, C
2-C
6 alkenyl, C
2-C
6 alkynyl, C
3-C
6 cycloalkyl, 4- to 10-membered heterocycloalkyl, C
6-C
10 aryl, or 5- to 10- membered heteroaryl, wherein each hydrogen atom in C
1-C
6 alkyl, C
2-C
6 alkenyl, C
2-C
6 alkynyl, C
3-C
6 cycloalkyl, 4- to 10-membered heterocycloalkyl, C
6-C
10 aryl, and 5- to 10- membered heteroaryl is independently optionally substituted by deuterium, halogen, -R
e, -R
f, C
1-C
6 alkyl, C
1-C
6 haloalkyl, -OR
e, -OC(O)R
e, -OC(O)NR
eR
f, -OS(O)R
e, -OS(O)
2R
e, - OS(O)NR
eR
f, -OS(O)
2NR
eR
f, -SR
e, -S(O)R
e, -S(O)
2R
e, -S(O)NR
eR
f, -S(O)
2NR
eR
f, -NR
eR
f, - NR
eC(O)R
f, -NR
eC(O)OR
f, -NR
eC(O)NR
eR
f, -NR
eS(O)R
f, -NR
eS(O)
2R
f, -NR
eS(O)NR
eR
f, - NR
eS(O)
2NR
eR
f, -C(O)R
e, -C(O)OR
e, -C(O)NR
eR
f, -PR
eR
f, -P(O)R
eR
f, -P(O)
2R
eR
f, - P(O)NR
eR
f, -P(O)
2NR
eR
f, -P(O)OR
e, -P(O)
2OR
e’, -CN, or -NO
2; or R
1 and R
10 taken together with the atom or atoms to which they are attached combine to form a monocyclic 4- to 10- membered heterocycloalkyl, a fused bicyclic 5- to 10-membered heterocycloalkyl, or a bridged bicyclic 6- to 10-membered heterocycloalkyl, wherein each hydrogen atom in the monocyclic 4- to 10-membered heterocycloalkyl, fused bicyclic 5- to 10-membered heterocycloalkyl, or a bridged bicyclic 6- to 10-membered heterocycloalkyl is independently optionally substituted by deuterium, halogen, C
1-C
6 alkyl, C
1-C
6 haloalkyl, -OH, -OC
1-C
6 alkyl, -OC(O)C
1-C
6 alkyl, -OC(O)N(H or C
1-C
6 alkyl)
2, -OS(O)C
1-C
6 alkyl, -OS(O)
2C
1-C
6 alkyl, -OS(O)N(H or C
1-C
6 alkyl)
2, -OS(O)
2N(H or C
1-C
6 alkyl)
2, -SC
1-C
6 alkyl, -S(O)C
1-C
6 alkyl, -S(O)
2C
1-C
6 alkyl, -S(O)N(H or C
1-C
6 alkyl)
2, -S(O)
2N(H or C
1-C
6 alkyl)
2, -N(H or C
1-C
6 alkyl)
2, -N(C
1- C6 alkyl)C(O)-C
1-C
6 alkyl, -N(C
1-C
6 alkyl)C(O)OC
1-C
6 alkyl, -N(C
1-C
6 alkyl)C(O)N(H or C1- C
6 alkyl)
2, -N(C
1-C
6 alkyl)S(O)C
1-C
6 alkyl, -N(C
1-C
6 alkyl)S(O)
2C
1-C
6 alkyl, -N(C
1-C
6 alkyl)S(O)N(H or C
1-C
6 alkyl)
2, -N(C
1-C
6 alkyl)S(O)
2N(H or C
1-C
6 alkyl)
2, -C(O)C
1-C
6 alkyl, -C(O)OC
1-C
6 alkyl, -C(O)N(H or C
1-C
6 alkyl)
2, -P(H or C
1-C
6 alkyl)
2, -P(O)(H or C
1-C
6 alkyl)
2, -P(O)
2(H or C
1-C
6 alkyl)
2, -P(O)N(H or C
1-C
6 alkyl)
2, -P(O)
2N(H or C
1-C
6 alkyl)
2, -P(O)OC
1-C
6 alkyl, -P(O)
2OC
1-C
6 alkyl, -CN, or -NO
2, or two hydrogen atoms on a single carbon atom of the monocyclic 4- to 10-membered heterocycloalkyl, fused bicyclic 5- to 10- membered heterocycloalkyl, or bridged bicyclic 6- to 10-membered heterocycloalkyl combine to form an oxo group or an alkenyl group; [0068] each of R
5, R
6, R
7, R
8, and R
9 is independently H, deuterium, halogen, C
1-C
6 alkyl, C
2-C
6 alkenyl, C
2-C
6 alkynyl, C
3-C
6 cycloalkyl, 4- to 10-membered heterocycloalkyl, C
6-C
10 aryl, 5- to 10-membered heteroaryl, -OR
g, -OC(O)R
g, -OC(O)NR
gR
h, -OS(O)R
g, -OS(O)
2R
g, - SR
g, -S(O)R
g, -S(O)
2R
g, -S(O)NR
gR
h, -S(O)
2NR
gR
h, -OS(O)NR
gR
h, -OS(O)
2NR
gR
h, -NR
gR
h, -NR
gC(O)R
h, -NR
gC(O)OR
h, -NR
gC(O)NR
gR
h, -NR
gS(O)R
h, -NR
gS(O)
2R
h, -NR
gS(O)NR
gR
h,
NR S(O)
2NR R , C(O)R , C(O)OR , C(O)NR R , PR R , P(O)R R , P(O)
2R R , -P(O)NR
gR
h, -P(O)
2NR
gR
h, -P(O)OR
g, -P(O)
2OR
g, -CN, or -NO2; [0069] ring A is a C
3-C
8 cycloalkyl, 4- to 10-membered heterocycloalkyl, C
6-C
10 aryl, or 5- to 10-membered heteroaryl, wherein each of C
3-C8 cycloalkyl, 4- to 10-membered heterocycloalkyl, C
6-C
10 aryl, or 5- to 10-membered heteroaryl is unsubstituted or substituted with one or more of R
11, and 4- to 10-membered heterocycloalkyl is not of the formula
[0070] each R
11 is independently deuterium, halogen, C
1-C
6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C
3-C
6 cycloalkyl, 4- to 10-membered heterocycloalkyl, C
6-C
10 aryl, 5- to 10- membered heteroaryl, -OR
a, -OC(O)R
a, -OC(O)NR
aR
b, -OC(=NR
a)NR
aR
b, -OS(O)R
a, -OS(O)
2R
a, -OS(O)NR
aR
b, -OS(O)
2NR
aR
b, -SR
a, -S(O)R
a, -S(O)
2R
a, -S(O)NR
aR
b, -S(O)
2NR
aR
b, -NR
aR
b, -NR
aC(O)R
b, -N(C(O)R
a)(C(O)R
b), -NR
aC(O)OR
b, -NR
aC(O)NR
aR
b, -NR
aC(=NR
a)NR
aR
b, -NR
aS(O)R
b, -NR
aS(O)
2R
b, -NR
aS(O)NR
aR
b, -NR
aS(O)
2NR
aR
b, - C(O)R
a, -C(O)OR
a, -C(O)NR
aR
b, -C(=NR
a)NR
aR
b, -PR
aR
b, -P(O)R
aR
b, -P(O)
2R
aR
b, - P(O)NR
aR
b, -P(O)
2NR
aR
b, -P(O)OR
a, -P(O)
2OR
a, -CN, or -NO2, or two of R
11 taken together with the atom or atoms to which they are attached or three of R
11 taken together with the atoms to which they are attached, form a C
3-C
6 cycloalkyl or a 4- to 10-membered heterocycloalkyl, wherein each hydrogen atom in C
1-C
6 alkyl, C
2-C
6 alkenyl, C
2-C
6 alkynyl, C
3-C
6 cycloalkyl, C
6-C
10 aryl, 5- to 10-membered heteroaryl, and 4- to 10-membered heterocycloalkyl is independently optionally substituted by deuterium, halogen, -R
e, -R
f, C
1-C
6 alkyl, C
1-C
6 haloalkyl, -OR
e, -OC(O)R
e, -OC(O)NR
eR
f, -OS(O)R
e, -OS(O)
2R
e, -OS(O)NR
eR
f, -OS(O)
2NR
eR
f, -SR
e, -S(O)R
e, -S(O)
2R
e, -S(O)NR
eR
f, -S(O)
2NR
eR
f, -NR
eR
f, -NR
eC(O)R
f, - NR
eC(O)OR
f, -NR
eC(O)NR
eR
f, -NR
eS(O)R
f, -NR
eS(O)
2R
f, -NR
eS(O)NR
eR
f, -NR
eS(O)
2NR
eR
f, -C(O)R
e, -C(O)OR
e, -C(O)NR
eR
f, -PR
eR
f, -P(O)R
eR
f, -P(O)
2R
eR
f, -P(O)NR
eR
f, -P(O)
2NR
eR
f, -P(O)OR
e, -P(O)
2OR
e, -CN, or -NO2, or two of R
11 taken together with the carbon atom to which they are attached form an oxo group or an alkenyl group; [0071] ring B is a C
6-C
10 aryl or 5- to 10-membered heteroaryl;
[0072] each R , R , R , R , R , R, R , and R is independently selected from the group consisting of H, deuterium, C
1-C
6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C
3-C
6 cycloalkyl, 4- to 10-membered heterocycloalkyl, C
6-C
10 aryl, C
1-C
6 alkyl-C
6-C
10 aryl, and 5- to 10-membered heteroaryl; or two of R
a and R
b, or R
c and R
d, or R
e and R
f, or R
g and R
h, taken together with the atom or atoms to which they are attached, combine to form a C
3-C
6 cycloalkyl, 4- to 10- membered heterocycloalkyl, C
6-C
10 aryl, or 5- to 10-membered heteroaryl, wherein each hydrogen atom in C
1-C
6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C
3-C
6 cycloalkyl, 4- to 10- membered heterocycloalkyl, C
6-C
10 aryl, C
1-C
6 alkyl-C
6-C
10 aryl, and 5- to 10-membered heteroaryl is independently optionally substituted by deuterium, halogen, C
1-C
6 alkyl, C
1-C
6 haloalkyl, -OH, -OC
1-C
6 alkyl, -OC(O)C
1-C
6 alkyl, -OC(O)N(H or C
1-C
6 alkyl)
2, -OS(O)C
1- C6 alkyl, -OS(O)
2C
1-C
6 alkyl, -OS(O)N(H or C
1-C
6 alkyl)
2, -OS(O)
2N(H or C
1-C
6 alkyl)
2, - SC
1-C
6 alkyl, -S(O)C
1-C
6 alkyl, -S(O)
2C
1-C
6 alkyl, -S(O)N(H or C
1-C
6 alkyl)
2, -S(O)
2N(H or C
1-C
6 alkyl)
2, -N(H or C
1-C
6 alkyl)
2, -N(C
1-C
6 alkyl)C(O)-C
1-C
6 alkyl, -N(C
1-C
6 alkyl)C(O)OC
1-C
6 alkyl, -N(C
1-C
6 alkyl)C(O)N(H or C
1-C
6 alkyl)
2, -N(C
1-C
6 alkyl)S(O)C
1- C6 alkyl, -N(C
1-C
6 alkyl)S(O)
2C
1-C
6 alkyl, -N(C
1-C
6 alkyl)S(O)N(H or C
1-C
6 alkyl)
2, -N(C1- C6 alkyl)S(O)
2N(H or C
1-C
6 alkyl)
2, -C(O)C
1-C
6 alkyl, -C(O)OC
1-C
6 alkyl, -C(O)N(H or C1- C6 alkyl)
2, -P(H or C
1-C
6 alkyl)
2, -P(O)(H or C
1-C
6 alkyl)
2, -P(O)
2(H or C
1-C
6 alkyl)
2, - P(O)N(H or C
1-C
6 alkyl)
2, -P(O)
2N(H or C
1-C
6 alkyl)
2, -P(O)OC
1-C
6 alkyl, -P(O)
2OC
1-C
6 alkyl, -CN, or -NO
2, or -R
e and -R
f taken together with the carbon atom to which they are attached form an oxo groups or an alkenyl; [0073] n is 0, 1, 2, 3, 4, 5, 6, or 7; [0074] p is 0 or 1; and [0075] q is 0, 1, or 2; [0076] and wherein the compound is not of the formula
. [0077] In some embodiments of this aspect, R
1 is H, deuterium, C
1-C
6 alkyl, C
2-C
6 alkenyl, or C2-C6 alkynyl, wherein each hydrogen atom in C
1-C
6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl is independently optionally substituted by deuterium, halogen, -R
e, -R
f, C
1-C
6 alkyl, C
1-C
6 haloalkyl, -OR
e, -OC(O)R
e, -OC(O)NR
eR
f, -OS(O)R
e, -OS(O)
2R
e, -OS(O)NR
eR
f, -OS(O)
2NR
eR
f, -SR
e, -S(O)R
e, -S(O)
2R
e, -S(O)NR
eR
f, -S(O)
2NR
eR
f, -NR
eR
f, -NR
eC(O)R
f, -NR
eC(O)OR
f, -NR
eC(O)NR
eR
f, -NR
eS(O)R
f, -NR
eS(O)
2R
f, -NR
eS(O)NR
eR
f, - NR
eS(O)
2NR
eR
f, -C(O)R
e, -C(O)OR
e, -C(O)NR
eR
f, -PR
eR
f, -P(O)R
eR
f, -P(O)
2R
eR
f, - P(O)NR
eR
f, -P(O)
2NR
eR
f, -P(O)OR
e, -P(O)
2OR
e’, -CN, or -NO2. In some embodiments of this aspect, R
1 is ring A, and ring A is a C
3-C8 cycloalkyl, C
6-C
10 aryl, or 5- to 10-membered
heteroaryl, wherein each of C
3 C
8 cycloalkyl, C
6 C
10 aryl, or 5 to 10 membered heteroaryl is unsubstituted or substituted with one or more of R
11. In some embodiments of this aspect, ring A is a 4- to 10-membered heterocycloalkyl that is covalently attached to –Y-, -(CR
aR
b)
n-, or
through a carbon atom in the 4- to 10-membered heterocycloalkyl. In some embodiments of this aspect, at least one hydrogen atom on ring A, ring B, R
1, or R
3 in the compound of the formula I is substituted by a deuterium. [0078] In one aspect, the disclosure relates to a compound of the formula I, or a pharmaceutically acceptable salt thereof,
[0079] wherein [0080] X is a -O-, -S-, or -NR
4-; [0081] Y is a bond, -O-, -S-, -S(O)-, -S(O)
2-, or –C(O)NR
10-; [0082] Z
1 is N or C(R
5); [0083] Z
2 is N or C(R
6); [0084] Z
3 is N or C(R
7); [0085] Z
4 is N or C(R
8); [0086] Z
5 is N or C(R
9); [0087] provided that at least two of Z
1-Z
5 are N; [0088] R
1 is independently H, deuterium, C
1-C
6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, or ring A, wherein each hydrogen atom in C
1-C
6 alkyl, C
2-C
6 alkenyl, or C
2-C
6 alkynyl is independently optionally substituted by deuterium, halogen, -R
e, -R
f, C
1-C
6 alkyl, C
1-C
6 haloalkyl, -OR
e, -OC(O)R
e, -OC(O)NR
eR
f, -OS(O)R
e, -OS(O)
2R
e, -OS(O)NR
eR
f, -OS(O)
2NR
eR
f, -SR
e, -S(O)R
e, -S(O)
2R
e, -S(O)NR
eR
f, -S(O)
2NR
eR
f, -NR
eR
f, -NR
eC(O)R
f, -NR
eC(O)OR
f,
NR C(O)NR R, NR S(O)R, NR S(O)
2R, NR S(O)NR R, NR S(O)
2NR R, C(O)R , -C(O)OR
e, -C(O)NR
eR
f, -PR
eR
f, -P(O)R
eR
f, -P(O)
2R
eR
f, -P(O)NR
eR
f, -P(O)
2NR
eR
f, -P(O)OR
e, -P(O)
2OR
e’, -CN, or -NO
2; and when Y is a bond, -O-, –S-, or –S(O)-, then R
1 is ring A; [0089] each R
2 is independently deuterium, halogen, C
1-C
6 alkyl, C
2-C
6 alkenyl, C
2-C
6 alkynyl, C
3-C
6 cycloalkyl, 4- to 10-membered heterocycloalkyl, C
6-C
10 aryl, 5- to 10-membered heteroaryl, -OR
c, -OC(O)R
c, -OC(O)NR
cR
d, -OC(=NR
c)NR
cR
d, -OS(O)R
c, -OS(O)
2R
c, -OS(O)NR
cR
d, -OS(O)
2NR
cR
d, -SR
c, -S(O)R
c, -S(O)
2R
c, -S(O)NR
cR
d, -S(O)
2NR
cR
d, -NR
cR
d, -NR
cC(O)R
d, -N(C(O)R
c)(C(O)R
d), -NR
cC(O)OR
d, -NR
cC(O)NR
cR
d, -NR
cC(=NR
c)NR
cR
d, -NR
cS(O)R
d, -NR
cS(O)
2R
d, -NR
cS(O)NR
cR
d, -NR
cS(O)
2NR
cR
d, -C(O)R
c, -C(O)OR
c, -C(O)NR
cR
d, -C(=NR
c)NR
cR
d, -PR
cR
d, -P(O)R
cR
d, -P(O)
2R
cR
d, -P(O)NR
cR
d, -P(O)
2NR
cR
d, -P(O)OR
c, -P(O)
2OR
c, -CN, or -NO
2, or two of R
2 taken together with the atoms to which they are attached form a C
3-C
6 cycloalkyl or a 4- to 10-membered heterocycloalkyl, wherein each hydrogen atom in C
1-C
6 alkyl, C
2-C
6 alkenyl, C
2-C
6 alkynyl, C
3-C
6 cycloalkyl, C
6-C
10 aryl, 5- to 10-membered heteroaryl, and 4- to 10-membered heterocycloalkyl is independently optionally substituted by deuterium, halogen, C
1-C
6 alkyl, C
1-C
6 haloalkyl, -R
e, -R
f, -OR
e, -OC(O)R
e, -OC(O)NR
eR
f, -OS(O)R
e, -OS(O)
2R
e, -OS(O)NR
eR
f, -OS(O)
2NR
eR
f, -SR
e, -S(O)R
e, -S(O)
2R
e, -S(O)NR
eR
f, -S(O)
2NR
eR
f, -NR
eR
f, -NR
eC(O)R
f, -NR
eC(O)OR
f, -NR
eC(O)NR
eR
f, -NR
eS(O)R
f, -NR
eS(O)
2R
f, -NR
eS(O)NR
eR
f, -NR
eS(O)
2NR
eR
f, -C(O)R
e, -C(O)OR
e, -C(O)NR
eR
f, -PR
eR
f, -P(O)R
eR
f, -P(O)
2R
eR
f, -P(O)NR
eR
f, -P(O)
2NR
eR
f, - P(O)OR
e, -P(O)
2OR
e, -CN, or -NO
2; [0090] R
3 is -C
1-C
6 alkyl, -C2-C6 alkenyl, -C2-C6 alkynyl, -C
3-C
6 cycloalkyl, 4- to 10- membered heterocycloalkyl, -C
1-C
6 alkylene-(4- to 10-membered heterocycloalkyl), -C
6-C
10 aryl, -C
1-C
6 alkylene-(C
6-C
10 aryl), 5- to 10-membered heteroaryl, or -C
1-C
6 alkylene-(4- to 10- membered heterocycloalkyl), wherein each hydrogen atom in C
1-C
6 alkyl, C
2-C
6 alkenyl, C
2-C
6 alkynyl, C
3-C
6 cycloalkyl, 4- to 10-membered heterocycloalkyl, -C
1-C
6 alkylene-(4- to 10- membered heterocycloalkyl), C
6-C
10 aryl, -C
1-C
6 alkylene-(C
6-C
10 aryl), 5- to 10-membered heteroaryl, and -C
1-C
6 alkylene-(5- to 10-membered heteroaryl), is independently optionally substituted by deuterium, halogen, -R
e, -R
f, C
1-C
6 alkyl, -C
1-C
6 alkyl-O-C
1-C
6 alkyl, -OC
1-C
6 alkyl-O-C
1-C
6 alkyl, -C
1-C
6 alkyl-O-R
a, C
6-C
10 aryl, -C
1-C
6 alkyl-(C
6-C
10 aryl), haloalkyl, C
3- C6 cycloalkyl, 5- to 10-membered heteroaryl, -C
1-C
6 alkyl-(5- to 10-membered heterocycloalkyl), -OR
e, -OC(O)R
e, -OC(O)NR
eR
f, -OS(O)R
e, -OS(O)
2R
e, -OS(O)NR
eR
f, -OS(O)
2NR
eR
f, -SR
e, -S(O)R
e, -S(O)
2R
e, -S(O)NR
eR
f, -S(O)
2NR
eR
f, -NR
eR
f, -NR
eC(O)R
f, -NR
eC(O)OR
f, -NR
eC(O)NR
eR
f, -NR
eC(=NR
f)NR
eR
f, -NR
eS(O)R
f, -NR
eS(O)
2R
f,
NR S(O)NR R, NR S(O)
2NR R, C(O)R , C(O)OR , C(O)NR R, PR R, P(O)R R, -P(O)
2R
eR
f, -P(O)NR
eR
f, -P(O)
2NR
eR
f, -P(O)OR
e, -P(O)
2OR
e’, -CN, or -NO2; [0091] each of R
4 and R
10 is independently H, deuterium, C
1-C
6 alkyl, C
2-C
6 alkenyl, C
2-C
6 alkynyl, C
3-C
6 cycloalkyl, 4- to 10-membered heterocycloalkyl, C
6-C
10 aryl, or 5- to 10- membered heteroaryl, wherein each hydrogen atom in C
1-C
6 alkyl, C
2-C
6 alkenyl, C
2-C
6 alkynyl, C
3-C
6 cycloalkyl, 4- to 10-membered heterocycloalkyl, C
6-C
10 aryl, and 5- to 10- membered heteroaryl is independently optionally substituted by deuterium, halogen, -R
e, -R
f, C
1-C
6 alkyl, C
1-C
6 haloalkyl, -OR
e, -OC(O)R
e, -OC(O)NR
eR
f, -OS(O)R
e, -OS(O)
2R
e, - OS(O)NR
eR
f, -OS(O)
2NR
eR
f, -SR
e, -S(O)R
e, -S(O)
2R
e, -S(O)NR
eR
f, -S(O)
2NR
eR
f, -NR
eR
f, - NR
eC(O)R
f, -NR
eC(O)OR
f, -NR
eC(O)NR
eR
f, -NR
eS(O)R
f, -NR
eS(O)
2R
f, -NR
eS(O)NR
eR
f, - NR
eS(O)
2NR
eR
f, -C(O)R
e, -C(O)OR
e, -C(O)NR
eR
f, -PR
eR
f, -P(O)R
eR
f, -P(O)
2R
eR
f, - P(O)NR
eR
f, -P(O)
2NR
eR
f, -P(O)OR
e, -P(O)
2OR
e’, -CN, or -NO
2; or R
1 and R
10 taken together with the atom or atoms to which they are attached combine to form a monocyclic 4- to 10- membered heterocycloalkyl, a fused bicyclic 5- to 10-membered heterocycloalkyl, or a bridged bicyclic 6- to 10-membered heterocycloalkyl, wherein each hydrogen atom in the monocyclic 4- to 10-membered heterocycloalkyl, fused bicyclic 5- to 10-membered heterocycloalkyl, or a bridged bicyclic 6- to 10-membered heterocycloalkyl is independently optionally substituted by deuterium, halogen, C
1-C
6 alkyl, C
1-C
6 haloalkyl, -OH, -OC
1-C
6 alkyl, -OC(O)C
1-C
6 alkyl, -OC(O)N(H or C
1-C
6 alkyl)
2, -OS(O)C
1-C
6 alkyl, -OS(O)
2C
1-C
6 alkyl, -OS(O)N(H or C
1-C
6 alkyl)
2, -OS(O)
2N(H or C
1-C
6 alkyl)
2, -SC
1-C
6 alkyl, -S(O)C
1-C
6 alkyl, -S(O)
2C
1-C
6 alkyl, -S(O)N(H or C
1-C
6 alkyl)
2, -S(O)
2N(H or C
1-C
6 alkyl)
2, -N(H or C
1-C
6 alkyl)
2, -N(C
1- C6 alkyl)C(O)-C
1-C
6 alkyl, -N(C
1-C
6 alkyl)C(O)OC
1-C
6 alkyl, -N(C
1-C
6 alkyl)C(O)N(H or C1- C
6 alkyl)
2, -N(C
1-C
6 alkyl)S(O)C
1-C
6 alkyl, -N(C
1-C
6 alkyl)S(O)
2C
1-C
6 alkyl, -N(C
1-C
6 alkyl)S(O)N(H or C
1-C
6 alkyl)
2, -N(C
1-C
6 alkyl)S(O)
2N(H or C
1-C
6 alkyl)
2, -C(O)C
1-C
6 alkyl, -C(O)OC
1-C
6 alkyl, -C(O)N(H or C
1-C
6 alkyl)
2, -P(H or C
1-C
6 alkyl)
2, -P(O)(H or C
1-C
6 alkyl)
2, -P(O)
2(H or C
1-C
6 alkyl)
2, -P(O)N(H or C
1-C
6 alkyl)
2, -P(O)
2N(H or C
1-C
6 alkyl)
2, -P(O)OC
1-C
6 alkyl, -P(O)
2OC
1-C
6 alkyl, -CN, or -NO
2, or two hydrogen atoms on a single carbon atom of the monocyclic 4- to 10-membered heterocycloalkyl, fused bicyclic 5- to 10- membered heterocycloalkyl, or bridged bicyclic 6- to 10-membered heterocycloalkyl combine to form an oxo group or an alkenyl group; [0092] each of R
5, R
6, R
7, R
8, and R
9 is independently H, deuterium, halogen, C
1-C
6 alkyl, C
2-C
6 alkenyl, C
2-C
6 alkynyl, C
3-C
6 cycloalkyl, 4- to 10-membered heterocycloalkyl, C
6-C
10 aryl, 5- to 10-membered heteroaryl, -OR
g, -OC(O)R
g, -OC(O)NR
gR
h, -OS(O)R
g, -OS(O)
2R
g, - SR
g, -S(O)R
g, -S(O)
2R
g, -S(O)NR
gR
h, -S(O)
2NR
gR
h, -OS(O)NR
gR
h, -OS(O)
2NR
gR
h, -NR
gR
h, -NR
gC(O)R
h, -NR
gC(O)OR
h, -NR
gC(O)NR
gR
h, -NR
gS(O)R
h, -NR
gS(O)
2R
h, -NR
gS(O)NR
gR
h,
NRS(O)
2NRR, C(O)R, C(O)OR, C(O)NRR, PRR, P(O)RR, P(O)
2RR, -P(O)NR
gR
h, -P(O)
2NR
gR
h, -P(O)OR
g, -P(O)
2OR
g, -CN, or -NO2; [0093] ring A is a C
3-C
8 cycloalkyl, 4- to 10-membered heterocycloalkyl, C
6-C
10 aryl, or 5- to 10-membered heteroaryl, wherein each of C
3-C8 cycloalkyl, 4- to 10-membered heterocycloalkyl, C
6-C
10 aryl, or 5- to 10-membered heteroaryl is unsubstituted or substituted with one or more of R
11, and 4- to 10-membered heterocycloalkyl is not of the formula
[0094] each R
11 is independently deuterium, halogen, C
1-C
6 alkyl, C
2-C
6 alkenyl, C
2-C
6 alkynyl, C
3-C
6 cycloalkyl, 4- to 10-membered heterocycloalkyl, C
6-C
10 aryl, 5- to 10- membered heteroaryl, -OR
a, -OC(O)R
a, -OC(O)NR
aR
b, -OC(=NR
a)NR
aR
b, -OS(O)R
a, -OS(O)
2R
a, -OS(O)NR
aR
b, -OS(O)
2NR
aR
b, -SR
a, -S(O)R
a, -S(O)
2R
a, -S(O)NR
aR
b, -S(O)
2NR
aR
b, -NR
aR
b, -NR
aC(O)R
b, -N(C(O)R
a)(C(O)R
b), -NR
aC(O)OR
b, -NR
aC(O)NR
aR
b, -NR
aC(=NR
a)NR
aR
b, -NR
aS(O)R
b, -NR
aS(O)
2R
b, -NR
aS(O)NR
aR
b, -NR
aS(O)
2NR
aR
b, - C(O)R
a, -C(O)OR
a, -C(O)NR
aR
b, -C(=NR
a)NR
aR
b, -PR
aR
b, -P(O)R
aR
b, -P(O)
2R
aR
b, - P(O)NR
aR
b, -P(O)
2NR
aR
b, -P(O)OR
a, -P(O)
2OR
a, -CN, or -NO
2, or two of R
11 taken together with the atom or atoms to which they are attached or three of R
11 taken together with the atoms to which they are attached, form a C
3-C
6 cycloalkyl or a 4- to 10-membered heterocycloalkyl, wherein each hydrogen atom in C
1-C
6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C
3-C
6 cycloalkyl, C
6-C
10 aryl, 5- to 10-membered heteroaryl, and 4- to 10-membered heterocycloalkyl is independently optionally substituted by deuterium, halogen, -R
e, -R
f, C
1-C
6 alkyl, C
1-C
6 haloalkyl, -OR
e, -OC(O)R
e, -OC(O)NR
eR
f, -OS(O)R
e, -OS(O)
2R
e, -OS(O)NR
eR
f, -OS(O)
2NR
eR
f, -SR
e, -S(O)R
e, -S(O)
2R
e, -S(O)NR
eR
f, -S(O)
2NR
eR
f, -NR
eR
f, -NR
eC(O)R
f, - NR
eC(O)OR
f, -NR
eC(O)NR
eR
f, -NR
eS(O)R
f, -NR
eS(O)
2R
f, -NR
eS(O)NR
eR
f, -NR
eS(O)
2NR
eR
f, -C(O)R
e, -C(O)OR
e, -C(O)NR
eR
f, -PR
eR
f, -P(O)R
eR
f, -P(O)
2R
eR
f, -P(O)NR
eR
f, -P(O)
2NR
eR
f, -P(O)OR
e, -P(O)
2OR
e, -CN, or -NO2, or two of R
11 taken together with the carbon atom to which they are attached form an oxo group or an alkenyl group; [0095] ring B is a C
6-C
10 aryl or 5- to 10-membered heteroaryl;
[0096] each R , R , R , R , R , R, R , and R is independently selected from the group consisting of H, deuterium, C
1-C
6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C
3-C
6 cycloalkyl, 4- to 10-membered heterocycloalkyl, C
6-C
10 aryl, C
1-C
6 alkyl-C
6-C
10 aryl, and 5- to 10-membered heteroaryl; or two of R
a and R
b, or R
c and R
d, or R
e and R
f, or R
g and R
h, taken together with the atom or atoms to which they are attached, combine to form a C
3-C
6 cycloalkyl, 4- to 10- membered heterocycloalkyl, C
6-C
10 aryl, or 5- to 10-membered heteroaryl, wherein each hydrogen atom in C
1-C
6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C
3-C
6 cycloalkyl, 4- to 10- membered heterocycloalkyl, C
6-C
10 aryl, C
1-C
6 alkyl-C
6-C
10 aryl, and 5- to 10-membered heteroaryl is independently optionally substituted by deuterium, halogen, C
1-C
6 alkyl, C
1-C
6 haloalkyl, -OH, -OC
1-C
6 alkyl, -OC(O)C
1-C
6 alkyl, -OC(O)N(H or C
1-C
6 alkyl)
2, -OS(O)C
1- C6 alkyl, -OS(O)
2C
1-C
6 alkyl, -OS(O)N(H or C
1-C
6 alkyl)
2, -OS(O)
2N(H or C
1-C
6 alkyl)
2, - SC
1-C
6 alkyl, -S(O)C
1-C
6 alkyl, -S(O)
2C
1-C
6 alkyl, -S(O)N(H or C
1-C
6 alkyl)
2, -S(O)
2N(H or C
1-C
6 alkyl)
2, -N(H or C
1-C
6 alkyl)
2, -N(C
1-C
6 alkyl)C(O)-C
1-C
6 alkyl, -N(C
1-C
6 alkyl)C(O)OC
1-C
6 alkyl, -N(C
1-C
6 alkyl)C(O)N(H or C
1-C
6 alkyl)
2, -N(C
1-C
6 alkyl)S(O)C
1- C6 alkyl, -N(C
1-C
6 alkyl)S(O)
2C
1-C
6 alkyl, -N(C
1-C
6 alkyl)S(O)N(H or C
1-C
6 alkyl)
2, -N(C1- C6 alkyl)S(O)
2N(H or C
1-C
6 alkyl)
2, -C(O)C
1-C
6 alkyl, -C(O)OC
1-C
6 alkyl, -C(O)N(H or C1- C6 alkyl)
2, -P(H or C
1-C
6 alkyl)
2, -P(O)(H or C
1-C
6 alkyl)
2, -P(O)
2(H or C
1-C
6 alkyl)
2, - P(O)N(H or C
1-C
6 alkyl)
2, -P(O)
2N(H or C
1-C
6 alkyl)
2, -P(O)OC
1-C
6 alkyl, -P(O)
2OC
1-C
6 alkyl, -CN, or -NO
2, or -R
e and -R
f taken together with the carbon atom to which they are attached form an oxo groups or an alkenyl; [0097] n is 0, 1, 2, 3, 4, 5, 6, or 7; [0098] p is 0 or 1; and [0099] q is 0, 1, or 2; [0100] and wherein the compound is not of the formula
[0101] In some embodiments of this aspect, R
1 is H, deuterium, C
1-C
6 alkyl, C
2-C
6 alkenyl, or C2-C6 alkynyl, wherein each hydrogen atom in C
1-C
6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl is independently optionally substituted by deuterium, halogen, -R
e, -R
f, C
1-C
6 alkyl, C
1-C
6 haloalkyl, -OR
e, -OC(O)R
e, -OC(O)NR
eR
f, -OS(O)R
e, -OS(O)
2R
e, -OS(O)NR
eR
f, -OS(O)
2NR
eR
f, -SR
e, -S(O)R
e, -S(O)
2R
e, -S(O)NR
eR
f, -S(O)
2NR
eR
f, -NR
eR
f, -NR
eC(O)R
f, -NR
eC(O)OR
f, -NR
eC(O)NR
eR
f, -NR
eS(O)R
f, -NR
eS(O)
2R
f, -NR
eS(O)NR
eR
f, - NR
eS(O)
2NR
eR
f, -C(O)R
e, -C(O)OR
e, -C(O)NR
eR
f, -PR
eR
f, -P(O)R
eR
f, -P(O)
2R
eR
f, - P(O)NR
eR
f, -P(O)
2NR
eR
f, -P(O)OR
e, -P(O)
2OR
e’, -CN, or -NO2. In some embodiments of this aspect, R
1 is ring A, and ring A is a C
3-C8 cycloalkyl, C
6-C
10 aryl, or 5- to 10-membered
heteroaryl, wherein each of C
3 C
8 cycloalkyl, C
6 C
10 aryl, or 5 to 10 membered heteroaryl is unsubstituted or substituted with one or more of R
11. In some embodiments of this aspect, ring A is a 4- to 10-membered heterocycloalkyl that is covalently attached to –Y-, -(CR
aR
b)
n-, or
through a carbon atom in the 4- to 10-membered heterocycloalkyl. In some embodiments of this aspect, at least one hydrogen atom on ring A, ring B, R
1, or R
3 in the compound of the formula I is substituted by a deuterium. [0102] In one aspect, the disclosure relates to a compound of the formula I, or a pharmaceutically acceptable salt thereof,
[0103] wherein [0104] X is a -O-, -S-, or -NR
4-; [0105] Y is a bond, -O-, -S-, -S(O)-, -S(O)
2-, or –C(O)NR
10-; [0106] Z
1 is N or C(R
5); [0107] Z
2 is N or C(R
6); [0108] Z
3 is N or C(R
7); [0109] Z
4 is N or C(R
8); [0110] Z
5 is N or C(R
9); [0111] provided that at least two of Z
1-Z
5 are N; [0112] R
1 is independently H, deuterium, C
1-C
6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, or ring A, wherein each hydrogen atom in C
1-C
6 alkyl, C
2-C
6 alkenyl, or C
2-C
6 alkynyl is independently optionally substituted by deuterium, halogen, -R
e, -R
f, C
1-C
6 alkyl, C
1-C
6 haloalkyl, -OR
e, -OC(O)R
e, -OC(O)NR
eR
f, -OS(O)R
e, -OS(O)
2R
e, -OS(O)NR
eR
f, -OS(O)
2NR
eR
f, -SR
e, -S(O)R
e, -S(O)
2R
e, -S(O)NR
eR
f, -S(O)
2NR
eR
f, -NR
eR
f, -NR
eC(O)R
f, -NR
eC(O)OR
f,
NR C(O)NR R, NR S(O)R, NR S(O)
2R, NR S(O)NR R, NR S(O)
2NR R, C(O)R , -C(O)OR
e, -C(O)NR
eR
f, -PR
eR
f, -P(O)R
eR
f, -P(O)
2R
eR
f, -P(O)NR
eR
f, -P(O)
2NR
eR
f, -P(O)OR
e, -P(O)
2OR
e’, -CN, or -NO
2; and when Y is a bond, -O-, –S-, or –S(O)-, then R
1 is ring A; [0113] each R
2 is independently deuterium, halogen, C
1-C
6 alkyl, C
2-C
6 alkenyl, C
2-C
6 alkynyl, C
3-C
6 cycloalkyl, 4- to 10-membered heterocycloalkyl, C
6-C
10 aryl, 5- to 10-membered heteroaryl, -OR
c, -OC(O)R
c, -OC(O)NR
cR
d, -OC(=NR
c)NR
cR
d, -OS(O)R
c, -OS(O)
2R
c, -OS(O)NR
cR
d, -OS(O)
2NR
cR
d, -SR
c, -S(O)R
c, -S(O)
2R
c, -S(O)NR
cR
d, -S(O)
2NR
cR
d, -NR
cR
d, -NR
cC(O)R
d, -N(C(O)R
c)(C(O)R
d), -NR
cC(O)OR
d, -NR
cC(O)NR
cR
d, -NR
cC(=NR
c)NR
cR
d, -NR
cS(O)R
d, -NR
cS(O)
2R
d, -NR
cS(O)NR
cR
d, -NR
cS(O)
2NR
cR
d, -C(O)R
c, -C(O)OR
c, -C(O)NR
cR
d, -C(=NR
c)NR
cR
d, -PR
cR
d, -P(O)R
cR
d, -P(O)
2R
cR
d, -P(O)NR
cR
d, -P(O)
2NR
cR
d, -P(O)OR
c, -P(O)
2OR
c, -CN, or -NO
2, or two of R
2 taken together with the atoms to which they are attached form a C
3-C
6 cycloalkyl or a 4- to 10-membered heterocycloalkyl, wherein each hydrogen atom in C
1-C
6 alkyl, C
2-C
6 alkenyl, C
2-C
6 alkynyl, C
3-C
6 cycloalkyl, C
6-C
10 aryl, 5- to 10-membered heteroaryl, and 4- to 10-membered heterocycloalkyl is independently optionally substituted by deuterium, halogen, C
1-C
6 alkyl, C
1-C
6 haloalkyl, -R
e, -R
f, -OR
e, -OC(O)R
e, -OC(O)NR
eR
f, -OS(O)R
e, -OS(O)
2R
e, -OS(O)NR
eR
f, -OS(O)
2NR
eR
f, -SR
e, -S(O)R
e, -S(O)
2R
e, -S(O)NR
eR
f, -S(O)
2NR
eR
f, -NR
eR
f, -NR
eC(O)R
f, -NR
eC(O)OR
f, -NR
eC(O)NR
eR
f, -NR
eS(O)R
f, -NR
eS(O)
2R
f, -NR
eS(O)NR
eR
f, -NR
eS(O)
2NR
eR
f, -C(O)R
e, -C(O)OR
e, -C(O)NR
eR
f, -PR
eR
f, -P(O)R
eR
f, -P(O)
2R
eR
f, -P(O)NR
eR
f, -P(O)
2NR
eR
f, - P(O)OR
e, -P(O)
2OR
e, -CN, or -NO
2; [0114] R
3 is -C
1-C
6 alkyl, -C2-C6 alkenyl, -C2-C6 alkynyl, -C
3-C
6 cycloalkyl, 4- to 10- membered heterocycloalkyl, -C
1-C
6 alkylene-(4- to 10-membered heterocycloalkyl), -C
6-C
10 aryl, -C
1-C
6 alkylene-(C
6-C
10 aryl), 5- to 10-membered heteroaryl, or -C
1-C
6 alkylene-(4- to 10- membered heterocycloalkyl), wherein each hydrogen atom in C
1-C
6 alkyl, C
2-C
6 alkenyl, C
2-C
6 alkynyl, C
3-C
6 cycloalkyl, 4- to 10-membered heterocycloalkyl, -C
1-C
6 alkylene-(4- to 10- membered heterocycloalkyl), C
6-C
10 aryl, -C
1-C
6 alkylene-(C
6-C
10 aryl), 5- to 10-membered heteroaryl, and -C
1-C
6 alkylene-(5- to 10-membered heteroaryl), is independently optionally substituted by deuterium, halogen, -R
e, -R
f, C
1-C
6 alkyl, -C
1-C
6 alkyl-O-C
1-C
6 alkyl, -OC
1-C
6 alkyl-O-C
1-C
6 alkyl, -C
1-C
6 alkyl-O-R
a, C
6-C
10 aryl, -C
1-C
6 alkyl-(C
6-C
10 aryl), haloalkyl, C
3- C6 cycloalkyl, 5- to 10-membered heteroaryl, -C
1-C
6 alkyl-(5- to 10-membered heterocycloalkyl), -OR
e, -OC(O)R
e, -OC(O)NR
eR
f, -OS(O)R
e, -OS(O)
2R
e, -OS(O)NR
eR
f, -OS(O)
2NR
eR
f, -SR
e, -S(O)R
e, -S(O)
2R
e, -S(O)NR
eR
f, -S(O)
2NR
eR
f, -NR
eR
f, -NR
eC(O)R
f, -NR
eC(O)OR
f, -NR
eC(O)NR
eR
f, -NR
eC(=NR
f)NR
eR
f, -NR
eS(O)R
f, -NR
eS(O)
2R
f,
NR S(O)NR R, NR S(O)
2NR R, C(O)R , C(O)OR , C(O)NR R, PR R, P(O)R R, -P(O)
2R
eR
f, -P(O)NR
eR
f, -P(O)
2NR
eR
f, -P(O)OR
e, -P(O)
2OR
e’, -CN, or -NO2; [0115] each of R
4 and R
10 is independently H, deuterium, C
1-C
6 alkyl, C
2-C
6 alkenyl, C
2-C
6 alkynyl, C
3-C
6 cycloalkyl, 4- to 10-membered heterocycloalkyl, C
6-C
10 aryl, or 5- to 10- membered heteroaryl, wherein each hydrogen atom in C
1-C
6 alkyl, C
2-C
6 alkenyl, C
2-C
6 alkynyl, C
3-C
6 cycloalkyl, 4- to 10-membered heterocycloalkyl, C
6-C
10 aryl, and 5- to 10- membered heteroaryl is independently optionally substituted by deuterium, halogen, -R
e, -R
f, C
1-C
6 alkyl, C
1-C
6 haloalkyl, -OR
e, -OC(O)R
e, -OC(O)NR
eR
f, -OS(O)R
e, -OS(O)
2R
e, - OS(O)NR
eR
f, -OS(O)
2NR
eR
f, -SR
e, -S(O)R
e, -S(O)
2R
e, -S(O)NR
eR
f, -S(O)
2NR
eR
f, -NR
eR
f, - NR
eC(O)R
f, -NR
eC(O)OR
f, -NR
eC(O)NR
eR
f, -NR
eS(O)R
f, -NR
eS(O)
2R
f, -NR
eS(O)NR
eR
f, - NR
eS(O)
2NR
eR
f, -C(O)R
e, -C(O)OR
e, -C(O)NR
eR
f, -PR
eR
f, -P(O)R
eR
f, -P(O)
2R
eR
f, - P(O)NR
eR
f, -P(O)
2NR
eR
f, -P(O)OR
e, -P(O)
2OR
e’, -CN, or -NO
2; or R
1 and R
10 taken together with the atom or atoms to which they are attached combine to form a monocyclic 4- to 10- membered heterocycloalkyl, a fused bicyclic 5- to 10-membered heterocycloalkyl, or a bridged bicyclic 6- to 10-membered heterocycloalkyl, wherein each hydrogen atom in the monocyclic 4- to 10-membered heterocycloalkyl, fused bicyclic 5- to 10-membered heterocycloalkyl, or a bridged bicyclic 6- to 10-membered heterocycloalkyl is independently optionally substituted by deuterium, halogen, C
1-C
6 alkyl, C
1-C
6 haloalkyl, -OH, -OC
1-C
6 alkyl, -OC(O)C
1-C
6 alkyl, -OC(O)N(H or C
1-C
6 alkyl)
2, -OS(O)C
1-C
6 alkyl, -OS(O)
2C
1-C
6 alkyl, -OS(O)N(H or C
1-C
6 alkyl)
2, -OS(O)
2N(H or C
1-C
6 alkyl)
2, -SC
1-C
6 alkyl, -S(O)C
1-C
6 alkyl, -S(O)
2C
1-C
6 alkyl, -S(O)N(H or C
1-C
6 alkyl)
2, -S(O)
2N(H or C
1-C
6 alkyl)
2, -N(H or C
1-C
6 alkyl)
2, -N(C
1- C6 alkyl)C(O)-C
1-C
6 alkyl, -N(C
1-C
6 alkyl)C(O)OC
1-C
6 alkyl, -N(C
1-C
6 alkyl)C(O)N(H or C1- C
6 alkyl)
2, -N(C
1-C
6 alkyl)S(O)C
1-C
6 alkyl, -N(C
1-C
6 alkyl)S(O)
2C
1-C
6 alkyl, -N(C
1-C
6 alkyl)S(O)N(H or C
1-C
6 alkyl)
2, -N(C
1-C
6 alkyl)S(O)
2N(H or C
1-C
6 alkyl)
2, -C(O)C
1-C
6 alkyl, -C(O)OC
1-C
6 alkyl, -C(O)N(H or C
1-C
6 alkyl)
2, -P(H or C
1-C
6 alkyl)
2, -P(O)(H or C
1-C
6 alkyl)
2, -P(O)
2(H or C
1-C
6 alkyl)
2, -P(O)N(H or C
1-C
6 alkyl)
2, -P(O)
2N(H or C
1-C
6 alkyl)
2, -P(O)OC
1-C
6 alkyl, -P(O)
2OC
1-C
6 alkyl, -CN, or -NO
2, or two hydrogen atoms on a single carbon atom of the monocyclic 4- to 10-membered heterocycloalkyl, fused bicyclic 5- to 10- membered heterocycloalkyl, or bridged bicyclic 6- to 10-membered heterocycloalkyl combine to form an oxo group or an alkenyl group; [0116] each of R
5, R
6, R
7, R
8, and R
9 is independently H, deuterium, halogen, C
1-C
6 alkyl, C
2-C
6 alkenyl, C
2-C
6 alkynyl, C
3-C
6 cycloalkyl, 4- to 10-membered heterocycloalkyl, C
6-C
10 aryl, 5- to 10-membered heteroaryl, -OR
g, -OC(O)R
g, -OC(O)NR
gR
h, -OS(O)R
g, -OS(O)
2R
g, - SR
g, -S(O)R
g, -S(O)
2R
g, -S(O)NR
gR
h, -S(O)
2NR
gR
h, -OS(O)NR
gR
h, -OS(O)
2NR
gR
h, -NR
gR
h, -NR
gC(O)R
h, -NR
gC(O)OR
h, -NR
gC(O)NR
gR
h, -NR
gS(O)R
h, -NR
gS(O)
2R
h, -NR
gS(O)NR
gR
h,
NRS(O)
2NRR, C(O)R, C(O)OR, C(O)NRR, PRR, P(O)RR, P(O)
2RR, -P(O)NR
gR
h, -P(O)
2NR
gR
h, -P(O)OR
g, -P(O)
2OR
g, -CN, or -NO2; [0117] ring A is a C
3-C
8 cycloalkyl, 4- to 10-membered heterocycloalkyl, C
6-C
10 aryl, or 5- to 10-membered heteroaryl, wherein each of C
3-C8 cycloalkyl, 4- to 10-membered heterocycloalkyl, C
6-C
10 aryl, or 5- to 10-membered heteroaryl is unsubstituted or substituted with one or more of R
11, provided that the 4- to 10-membered heterocycloalkyl is not an unsubstituted or a substituted ring of the formula
[0118] each R
11 is independently deuterium, halogen, C
1-C
6 alkyl, C
2-C
6 alkenyl, C
2-C
6 alkynyl, C
3-C
6 cycloalkyl, 4- to 10-membered heterocycloalkyl, C
6-C
10 aryl, 5- to 10- membered heteroaryl, -OR
a, -OC(O)R
a, -OC(O)NR
aR
b, -OC(=NR
a)NR
aR
b, -OS(O)R
a, -OS(O)
2R
a, -OS(O)NR
aR
b, -OS(O)
2NR
aR
b, -SR
a, -S(O)R
a, -S(O)
2R
a, -S(O)NR
aR
b, -S(O)
2NR
aR
b, -NR
aR
b, -NR
aC(O)R
b, -N(C(O)R
a)(C(O)R
b), -NR
aC(O)OR
b, -NR
aC(O)NR
aR
b, -NR
aC(=NR
a)NR
aR
b, -NR
aS(O)R
b, -NR
aS(O)
2R
b, -NR
aS(O)NR
aR
b, -NR
aS(O)
2NR
aR
b, - C(O)R
a, -C(O)OR
a, -C(O)NR
aR
b, -C(=NR
a)NR
aR
b, -PR
aR
b, -P(O)R
aR
b, -P(O)
2R
aR
b, - P(O)NR
aR
b, -P(O)
2NR
aR
b, -P(O)OR
a, -P(O)
2OR
a, -CN, or -NO2, or two of R
11 taken together with the atom or atoms to which they are attached or three of R
11 taken together with the atoms to which they are attached, form a C
3-C
6 cycloalkyl or a 4- to 10-membered heterocycloalkyl, wherein each hydrogen atom in C
1-C
6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C
3-C
6 cycloalkyl, C
6-C
10 aryl, 5- to 10-membered heteroaryl, and 4- to 10-membered heterocycloalkyl is independently optionally substituted by deuterium, halogen, -R
e, -R
f, C
1-C
6 alkyl, C
1-C
6 haloalkyl, -OR
e, -OC(O)R
e, -OC(O)NR
eR
f, -OS(O)R
e, -OS(O)
2R
e, -OS(O)NR
eR
f, -OS(O)
2NR
eR
f, -SR
e, -S(O)R
e, -S(O)
2R
e, -S(O)NR
eR
f, -S(O)
2NR
eR
f, -NR
eR
f, -NR
eC(O)R
f, - NR
eC(O)OR
f, -NR
eC(O)NR
eR
f, -NR
eS(O)R
f, -NR
eS(O)
2R
f, -NR
eS(O)NR
eR
f, -NR
eS(O)
2NR
eR
f, -C(O)R
e, -C(O)OR
e, -C(O)NR
eR
f, -PR
eR
f, -P(O)R
eR
f, -P(O)
2R
eR
f, -P(O)NR
eR
f, -P(O)
2NR
eR
f, -P(O)OR
e, -P(O)
2OR
e, -CN, or -NO
2, or two of R
11 taken together with the carbon atom to which they are attached form an oxo group or an alkenyl group; [0119] ring B is a C
6-C
10 aryl or 5- to 10-membered heteroaryl; [0120] each R
a, R
b, R
c, R
d, R
e, R
f, R
g, and R
h is independently selected from the group consisting of H, deuterium, C
1-C
6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C
3-C
6 cycloalkyl, 4- to 10-membered heterocycloalkyl, C
6-C
10 aryl, C
1-C
6 alkyl-C
6-C
10 aryl, and 5- to 10-membered heteroaryl; or two of R
a and R
b, or R
c and R
d, or R
e and R
f, or R
g and R
h, taken together with
the atom or atoms to which they are attached, combine to form a C
3 C
6 cycloalkyl, 4 to 10 membered heterocycloalkyl, C
6-C
10 aryl, or 5- to 10-membered heteroaryl, wherein each hydrogen atom in C
1-C
6 alkyl, C
2-C
6 alkenyl, C
2-C
6 alkynyl, C
3-C
6 cycloalkyl, 4- to 10- membered heterocycloalkyl, C
6-C
10 aryl, C
1-C
6 alkyl-C
6-C
10 aryl, and 5- to 10-membered heteroaryl is independently optionally substituted by deuterium, halogen, C
1-C
6 alkyl, C
1-C
6 haloalkyl, -OH, -OC
1-C
6 alkyl, -OC(O)C
1-C
6 alkyl, -OC(O)N(H or C
1-C
6 alkyl)
2, -OS(O)C
1- C6 alkyl, -OS(O)
2C
1-C
6 alkyl, -OS(O)N(H or C
1-C
6 alkyl)
2, -OS(O)
2N(H or C
1-C
6 alkyl)
2, - SC
1-C
6 alkyl, -S(O)C
1-C
6 alkyl, -S(O)
2C
1-C
6 alkyl, -S(O)N(H or C
1-C
6 alkyl)
2, -S(O)
2N(H or C
1-C
6 alkyl)
2, -N(H or C
1-C
6 alkyl)
2, -N(C
1-C
6 alkyl)C(O)-C
1-C
6 alkyl, -N(C
1-C
6 alkyl)C(O)OC
1-C
6 alkyl, -N(C
1-C
6 alkyl)C(O)N(H or C
1-C
6 alkyl)
2, -N(C
1-C
6 alkyl)S(O)C
1- C6 alkyl, -N(C
1-C
6 alkyl)S(O)
2C
1-C
6 alkyl, -N(C
1-C
6 alkyl)S(O)N(H or C
1-C
6 alkyl)
2, -N(C1- C
6 alkyl)S(O)
2N(H or C
1-C
6 alkyl)
2, -C(O)C
1-C
6 alkyl, -C(O)OC
1-C
6 alkyl, -C(O)N(H or C
1- C6 alkyl)
2, -P(H or C
1-C
6 alkyl)
2, -P(O)(H or C
1-C
6 alkyl)
2, -P(O)
2(H or C
1-C
6 alkyl)
2, - P(O)N(H or C
1-C
6 alkyl)
2, -P(O)
2N(H or C
1-C
6 alkyl)
2, -P(O)OC
1-C
6 alkyl, -P(O)
2OC
1-C
6 alkyl, -CN, or -NO2, or -R
e and -R
f taken together with the carbon atom to which they are attached form an oxo groups or an alkenyl; [0121] n is 0, 1, 2, 3, 4, 5, 6, or 7; [0122] p is 0 or 1; and [0123] q is 0, 1, or 2; [0124] and wherein the compound is not of the formula
[0125] In some embodiments of this aspect, R
1 is H, deuterium, C
1-C
6 alkyl, C
2-C
6 alkenyl, or C2-C6 alkynyl, wherein each hydrogen atom in C
1-C
6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl is independently optionally substituted by deuterium, halogen, -R
e, -R
f, C
1-C
6 alkyl, C
1-C
6 haloalkyl, -OR
e, -OC(O)R
e, -OC(O)NR
eR
f, -OS(O)R
e, -OS(O)
2R
e, -OS(O)NR
eR
f, -OS(O)
2NR
eR
f, -SR
e, -S(O)R
e, -S(O)
2R
e, -S(O)NR
eR
f, -S(O)
2NR
eR
f, -NR
eR
f, -NR
eC(O)R
f, -NR
eC(O)OR
f, -NR
eC(O)NR
eR
f, -NR
eS(O)R
f, -NR
eS(O)
2R
f, -NR
eS(O)NR
eR
f, - NR
eS(O)
2NR
eR
f, -C(O)R
e, -C(O)OR
e, -C(O)NR
eR
f, -PR
eR
f, -P(O)R
eR
f, -P(O)
2R
eR
f, - P(O)NR
eR
f, -P(O)
2NR
eR
f, -P(O)OR
e, -P(O)
2OR
e’, -CN, or -NO
2. In some embodiments of this aspect, R
1 is ring A, and ring A is a C
3-C8 cycloalkyl, C
6-C
10 aryl, or 5- to 10-membered heteroaryl, wherein each of C
3-C
8 cycloalkyl, C
6-C
10 aryl, or 5- to 10-membered heteroaryl is unsubstituted or substituted with one or more of R
11. In some embodiments of this aspect, ring A is a 4- to 10-membered heterocycloalkyl that is covalently attached to –Y-, -(CR
aR
b)
n-, or
through a carbon atom in the 4- to 10-membered heterocycloalkyl. In some embodiments of this aspect, at least one hydrogen atom on ring A, ring B, R
1, or R
3 in the compound of the formula I is substituted by a deuterium. [0126] In one aspect, the disclosure relates to a compound of the formula I, or a pharmaceutically acceptable salt thereof,
[0127] wherein [0128] X is a -O-, -S-, or -NR
4-; [0129] Y is a bond, -O-, -S-, -S(O)-, -S(O)
2-, or –C(O)NR
10-; [0130] Z
1 is N or C(R
5); [0131] Z
2 is N or C(R
6); [0132] Z
3 is N or C(R
7); [0133] Z
4 is N or C(R
8); [0134] Z
5 is N or C(R
9); [0135] provided that at least two of Z
1-Z
5 are N; [0136] R
1 is independently H, deuterium, C
1-C
6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, or ring A, wherein each hydrogen atom in C
1-C
6 alkyl, C
2-C
6 alkenyl, or C
2-C
6 alkynyl is independently optionally substituted by deuterium, halogen, -R
e, -R
f, C
1-C
6 alkyl, C
1-C
6 haloalkyl, -OR
e, -OC(O)R
e, -OC(O)NR
eR
f, -OS(O)R
e, -OS(O)
2R
e, -OS(O)NR
eR
f, -OS(O)
2NR
eR
f, -SR
e, -S(O)R
e, -S(O)
2R
e, -S(O)NR
eR
f, -S(O)
2NR
eR
f, -NR
eR
f, -NR
eC(O)R
f, -NR
eC(O)OR
f, -NR
eC(O)NR
eR
f, -NR
eS(O)R
f, -NR
eS(O)
2R
f, -NR
eS(O)NR
eR
f, -NR
eS(O)
2NR
eR
f, -C(O)R
e, -C(O)OR
e, -C(O)NR
eR
f, -PR
eR
f, -P(O)R
eR
f, -P(O)
2R
eR
f, -P(O)NR
eR
f, -P(O)
2NR
eR
f, -P(O)OR
e, -P(O)
2OR
e’, -CN, or -NO2; and when Y is a bond, -O-, –S-, or –S(O)-, then R
1 is ring A; [0137] each R
2 is independently deuterium, halogen, methyl, C
3-C
6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C
3-C
6 cycloalkyl, 4- to 10-membered heterocycloalkyl, C
6-C
10 aryl, 5- to 10- membered heteroaryl, -OR
c, -OC(O)R
c, -OC(O)NR
cR
d, -OC(=NR
c)NR
cR
d, -OS(O)R
c, -OS(O)
2R
c, -OS(O)NR
cR
d, -OS(O)
2NR
cR
d, -SR
c, -S(O)R
c, -S(O)
2R
c, -S(O)NR
cR
d, -S(O)
2NR
cR
d, -NR
cR
d, -NR
cC(O)R
d, -N(C(O)R
c)(C(O)R
d), -NR
cC(O)OR
d, -NR
cC(O)NR
cR
d, -NR
cC(=NR
c)NR
cR
d, -NR
cS(O)R
d, -NR
cS(O)
2R
d, -NR
cS(O)NR
cR
d, -NR
cS(O)
2NR
cR
d, -
C(O)R , C(O)OR , C(O)NR R , C( NR )NR R , PR R , P(O)R R , P(O)
2R R , P(O)NR
cR
d, -P(O)
2NR
cR
d, -P(O)OR
c, -P(O)
2OR
c, -CN, or -NO2, or two of R
2 taken together with the atoms to which they are attached form a C
3-C
6 cycloalkyl or a 4- to 10-membered heterocycloalkyl, wherein each hydrogen atom in C
1-C
6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C
3-C
6 cycloalkyl, C
6-C
10 aryl, 5- to 10-membered heteroaryl, and 4- to 10-membered heterocycloalkyl is independently optionally substituted by deuterium, halogen, C
1-C
6 alkyl, C
1-C
6 haloalkyl, -R
e, -R
f, -OR
e, -OC(O)R
e, -OC(O)NR
eR
f, -OS(O)R
e, -OS(O)
2R
e, -OS(O)NR
eR
f, -OS(O)
2NR
eR
f, -SR
e, -S(O)R
e, -S(O)
2R
e, -S(O)NR
eR
f, -S(O)
2NR
eR
f, -NR
eR
f, -NR
eC(O)R
f, -NR
eC(O)OR
f, -NR
eC(O)NR
eR
f, -NR
eS(O)R
f, -NR
eS(O)
2R
f, -NR
eS(O)NR
eR
f, -NR
eS(O)
2NR
eR
f, -C(O)R
e, -C(O)OR
e, -C(O)NR
eR
f, -PR
eR
f, -P(O)R
eR
f, -P(O)
2R
eR
f, -P(O)NR
eR
f, -P(O)
2NR
eR
f, -P(O)OR
e, -P(O)
2OR
e, -CN, or -NO2; [0138] R
3 is -C
1-C
6 alkyl, -C
2-C
6 alkenyl, -C
2-C
6 alkynyl, -C
3-C
6 cycloalkyl, 4- to 10- membered heterocycloalkyl, -C
1-C
6 alkylene-(4- to 10-membered heterocycloalkyl), -C
6-C
10 aryl, -C
1-C
6 alkylene-(C
6-C
10 aryl), 5- to 10-membered heteroaryl, or -C
1-C
6 alkylene-(4- to 10- membered heterocycloalkyl), wherein each hydrogen atom in C
1-C
6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C
3-C
6 cycloalkyl, 4- to 10-membered heterocycloalkyl, -C
1-C
6 alkylene-(4- to 10- membered heterocycloalkyl), C
6-C
10 aryl, -C
1-C
6 alkylene-(C
6-C
10 aryl), 5- to 10-membered heteroaryl, and -C
1-C
6 alkylene-(5- to 10-membered heteroaryl), is independently optionally substituted by deuterium, halogen, -R
e, -R
f, C
1-C
6 alkyl, -C
1-C
6 alkyl-O-C
1-C
6 alkyl, -OC
1-C
6 alkyl-O-C
1-C
6 alkyl, -C
1-C
6 alkyl-O-R
a, C
6-C
10 aryl, -C
1-C
6 alkyl-(C
6-C
10 aryl), haloalkyl, C
3- C
6 cycloalkyl, 5- to 10-membered heteroaryl, -C
1-C
6 alkyl-(5- to 10-membered heterocycloalkyl), -OR
e, -OC(O)R
e, -OC(O)NR
eR
f, -OS(O)R
e, -OS(O)
2R
e, -OS(O)NR
eR
f, -OS(O)
2NR
eR
f, -SR
e, -S(O)R
e, -S(O)
2R
e, -S(O)NR
eR
f, -S(O)
2NR
eR
f, -NR
eR
f, -NR
eC(O)R
f, -NR
eC(O)OR
f, -NR
eC(O)NR
eR
f, -NR
eC(=NR
f)NR
eR
f, -NR
eS(O)R
f, -NR
eS(O)
2R
f, -NR
eS(O)NR
eR
f, -NR
eS(O)
2NR
eR
f, -C(O)R
e, -C(O)OR
e, -C(O)NR
eR
f, -PR
eR
f, -P(O)R
eR
f, -P(O)
2R
eR
f, -P(O)NR
eR
f, -P(O)
2NR
eR
f, -P(O)OR
e, -P(O)
2OR
e’, -CN, or -NO2; [0139] each of R
4 and R
10 is independently H, deuterium, C
1-C
6 alkyl, C
2-C
6 alkenyl, C
2-C
6 alkynyl, C
3-C
6 cycloalkyl, 4- to 10-membered heterocycloalkyl, C
6-C
10 aryl, or 5- to 10- membered heteroaryl, wherein each hydrogen atom in C
1-C
6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C
3-C
6 cycloalkyl, 4- to 10-membered heterocycloalkyl, C
6-C
10 aryl, and 5- to 10- membered heteroaryl is independently optionally substituted by deuterium, halogen, -R
e, -R
f, C
1-C
6 alkyl, C
1-C
6 haloalkyl, -OR
e, -OC(O)R
e, -OC(O)NR
eR
f, -OS(O)R
e, -OS(O)
2R
e, - OS(O)NR
eR
f, -OS(O)
2NR
eR
f, -SR
e, -S(O)R
e, -S(O)
2R
e, -S(O)NR
eR
f, -S(O)
2NR
eR
f, -NR
eR
f, - NR
eC(O)R
f, -NR
eC(O)OR
f, -NR
eC(O)NR
eR
f, -NR
eS(O)R
f, -NR
eS(O)
2R
f, -NR
eS(O)NR
eR
f, - NR
eS(O)
2NR
eR
f, -C(O)R
e, -C(O)OR
e, -C(O)NR
eR
f, -PR
eR
f, -P(O)R
eR
f, -P(O)
2R
eR
f, -
P(O)NR R, P(O)
2NR R, P(O)OR , P(O)
2OR , CN, or NO
2; or R and R taken together with the atom or atoms to which they are attached combine to form a monocyclic 4- to 10- membered heterocycloalkyl, a fused bicyclic 5- to 10-membered heterocycloalkyl, or a bridged bicyclic 6- to 10-membered heterocycloalkyl, wherein each hydrogen atom in the monocyclic 4- to 10-membered heterocycloalkyl, fused bicyclic 5- to 10-membered heterocycloalkyl, or a bridged bicyclic 6- to 10-membered heterocycloalkyl is independently optionally substituted by deuterium, halogen, C
1-C
6 alkyl, C
1-C
6 haloalkyl, -OH, -OC
1-C
6 alkyl, -OC(O)C
1-C
6 alkyl, -OC(O)N(H or C
1-C
6 alkyl)
2, -OS(O)C
1-C
6 alkyl, -OS(O)
2C
1-C
6 alkyl, -OS(O)N(H or C
1-C
6 alkyl)
2, -OS(O)
2N(H or C
1-C
6 alkyl)
2, -SC
1-C
6 alkyl, -S(O)C
1-C
6 alkyl, -S(O)
2C
1-C
6 alkyl, -S(O)N(H or C
1-C
6 alkyl)
2, -S(O)
2N(H or C
1-C
6 alkyl)
2, -N(H or C
1-C
6 alkyl)
2, -N(C
1- C6 alkyl)C(O)-C
1-C
6 alkyl, -N(C
1-C
6 alkyl)C(O)OC
1-C
6 alkyl, -N(C
1-C
6 alkyl)C(O)N(H or C1- C
6 alkyl)
2, -N(C
1-C
6 alkyl)S(O)C
1-C
6 alkyl, -N(C
1-C
6 alkyl)S(O)
2C
1-C
6 alkyl, -N(C
1-C
6 alkyl)S(O)N(H or C
1-C
6 alkyl)
2, -N(C
1-C
6 alkyl)S(O)
2N(H or C
1-C
6 alkyl)
2, -C(O)C
1-C
6 alkyl, -C(O)OC
1-C
6 alkyl, -C(O)N(H or C
1-C
6 alkyl)
2, -P(H or C
1-C
6 alkyl)
2, -P(O)(H or C
1-C
6 alkyl)
2, -P(O)
2(H or C
1-C
6 alkyl)
2, -P(O)N(H or C
1-C
6 alkyl)
2, -P(O)
2N(H or C
1-C
6 alkyl)
2, -P(O)OC
1-C
6 alkyl, -P(O)
2OC
1-C
6 alkyl, -CN, or -NO2, or two hydrogen atoms on a single carbon atom of the monocyclic 4- to 10-membered heterocycloalkyl, fused bicyclic 5- to 10- membered heterocycloalkyl, or bridged bicyclic 6- to 10-membered heterocycloalkyl combine to form an oxo group or an alkenyl group; [0140] each of R
5, R
6, R
7, R
8, and R
9 is independently H, deuterium, halogen, C
1-C
6 alkyl, C
2-C
6 alkenyl, C
2-C
6 alkynyl, C
3-C
6 cycloalkyl, 4- to 10-membered heterocycloalkyl, C
6-C
10 aryl, 5- to 10-membered heteroaryl, -OR
g, -OC(O)R
g, -OC(O)NR
gR
h, -OS(O)R
g, -OS(O)
2R
g, - SR
g, -S(O)R
g, -S(O)
2R
g, -S(O)NR
gR
h, -S(O)
2NR
gR
h, -OS(O)NR
gR
h, -OS(O)
2NR
gR
h, -NR
gR
h, -NR
gC(O)R
h, -NR
gC(O)OR
h, -NR
gC(O)NR
gR
h, -NR
gS(O)R
h, -NR
gS(O)
2R
h, -NR
gS(O)NR
gR
h, -NR
gS(O)
2NR
gR
h, -C(O)R
g, -C(O)OR
g, -C(O)NR
gR
h, -PR
gR
h, -P(O)R
gR
h, -P(O)
2R
gR
h, -P(O)NR
gR
h, -P(O)
2NR
gR
h, -P(O)OR
g, -P(O)
2OR
g, -CN, or -NO2; [0141] ring A is a C
3-C
8 cycloalkyl, 4- to 10-membered heterocycloalkyl, C
6-C
10 aryl, or 5- to 10-membered heteroaryl, wherein each of C
3-C8 cycloalkyl, 4- to 10-membered heterocycloalkyl, C
6-C
10 aryl, or 5- to 10-membered heteroaryl is unsubstituted or substituted with one or more of R
11, provided that the 4- to 10-membered heterocycloalkyl is not an unsubstituted or a substituted ring of the formula
[0142] each R
11 is independently deuterium, halogen, C
1-C
6 alkyl, C
2-C
6 alkenyl, C
2-C
6 alkynyl, C
3-C
6 cycloalkyl, 4- to 10-membered heterocycloalkyl, C
6-C
10 aryl, 5- to 10- membered heteroaryl, -OR
a, -OC(O)R
a, -OC(O)NR
aR
b, -OC(=NR
a)NR
aR
b, -OS(O)R
a, -OS(O)
2R
a, -OS(O)NR
aR
b, -OS(O)
2NR
aR
b, -SR
a, -S(O)R
a, -S(O)
2R
a, -S(O)NR
aR
b, -S(O)
2NR
aR
b, -NR
aR
b, -NR
aC(O)R
b, -N(C(O)R
a)(C(O)R
b), -NR
aC(O)OR
b, -NR
aC(O)NR
aR
b, -NR
aC(=NR
a)NR
aR
b, -NR
aS(O)R
b, -NR
aS(O)
2R
b, -NR
aS(O)NR
aR
b, -NR
aS(O)
2NR
aR
b, - C(O)R
a, -C(O)OR
a, -C(O)NR
aR
b, -C(=NR
a)NR
aR
b, -PR
aR
b, -P(O)R
aR
b, -P(O)
2R
aR
b, - P(O)NR
aR
b, -P(O)
2NR
aR
b, -P(O)OR
a, -P(O)
2OR
a, -CN, or -NO2, or two of R
11 taken together with the atom or atoms to which they are attached or three of R
11 taken together with the atoms to which they are attached, form a C
3-C
6 cycloalkyl or a 4- to 10-membered heterocycloalkyl, wherein each hydrogen atom in C
1-C
6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C
3-C
6 cycloalkyl, C
6-C
10 aryl, 5- to 10-membered heteroaryl, and 4- to 10-membered heterocycloalkyl is independently optionally substituted by deuterium, halogen, -R
e, -R
f, C
1-C
6 alkyl, C
1-C
6 haloalkyl, -OR
e, -OC(O)R
e, -OC(O)NR
eR
f, -OS(O)R
e, -OS(O)
2R
e, -OS(O)NR
eR
f, -OS(O)
2NR
eR
f, -SR
e, -S(O)R
e, -S(O)
2R
e, -S(O)NR
eR
f, -S(O)
2NR
eR
f, -NR
eR
f, -NR
eC(O)R
f, - NR
eC(O)OR
f, -NR
eC(O)NR
eR
f, -NR
eS(O)R
f, -NR
eS(O)
2R
f, -NR
eS(O)NR
eR
f, -NR
eS(O)
2NR
eR
f, -C(O)R
e, -C(O)OR
e, -C(O)NR
eR
f, -PR
eR
f, -P(O)R
eR
f, -P(O)
2R
eR
f, -P(O)NR
eR
f, -P(O)
2NR
eR
f, -P(O)OR
e, -P(O)
2OR
e, -CN, or -NO
2, or two of R
11 taken together with the carbon atom to which they are attached form an oxo group or an alkenyl group; [0143] ring B is a C
6-C
10 aryl or 5- to 10-membered heteroaryl; [0144] each R
a, R
b, R
c, R
d, R
e, R
f, R
g, and R
h is independently selected from the group consisting of H, deuterium, C
1-C
6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C
3-C
6 cycloalkyl, 4- to 10-membered heterocycloalkyl, C
6-C
10 aryl, C
1-C
6 alkyl-C
6-C
10 aryl, and 5- to 10-membered heteroaryl; or two of R
a and R
b, or R
c and R
d, or R
e and R
f, or R
g and R
h, taken together with
the atom or atoms to which they are attached, combine to form a C
3 C
6 cycloalkyl, 4 to 10 membered heterocycloalkyl, C
6-C
10 aryl, or 5- to 10-membered heteroaryl, wherein each hydrogen atom in C
1-C
6 alkyl, C
2-C
6 alkenyl, C
2-C
6 alkynyl, C
3-C
6 cycloalkyl, 4- to 10- membered heterocycloalkyl, C
6-C
10 aryl, C
1-C
6 alkyl-C
6-C
10 aryl, and 5- to 10-membered heteroaryl is independently optionally substituted by deuterium, halogen, C
1-C
6 alkyl, C
1-C
6 haloalkyl, -OH, -OC
1-C
6 alkyl, -OC(O)C
1-C
6 alkyl, -OC(O)N(H or C
1-C
6 alkyl)
2, -OS(O)C
1- C6 alkyl, -OS(O)
2C
1-C
6 alkyl, -OS(O)N(H or C
1-C
6 alkyl)
2, -OS(O)
2N(H or C
1-C
6 alkyl)
2, - SC
1-C
6 alkyl, -S(O)C
1-C
6 alkyl, -S(O)
2C
1-C
6 alkyl, -S(O)N(H or C
1-C
6 alkyl)
2, -S(O)
2N(H or C
1-C
6 alkyl)
2, -N(H or C
1-C
6 alkyl)
2, -N(C
1-C
6 alkyl)C(O)-C
1-C
6 alkyl, -N(C
1-C
6 alkyl)C(O)OC
1-C
6 alkyl, -N(C
1-C
6 alkyl)C(O)N(H or C
1-C
6 alkyl)
2, -N(C
1-C
6 alkyl)S(O)C
1- C6 alkyl, -N(C
1-C
6 alkyl)S(O)
2C
1-C
6 alkyl, -N(C
1-C
6 alkyl)S(O)N(H or C
1-C
6 alkyl)
2, -N(C1- C
6 alkyl)S(O)
2N(H or C
1-C
6 alkyl)
2, -C(O)C
1-C
6 alkyl, -C(O)OC
1-C
6 alkyl, -C(O)N(H or C
1- C6 alkyl)
2, -P(H or C
1-C
6 alkyl)
2, -P(O)(H or C
1-C
6 alkyl)
2, -P(O)
2(H or C
1-C
6 alkyl)
2, - P(O)N(H or C
1-C
6 alkyl)
2, -P(O)
2N(H or C
1-C
6 alkyl)
2, -P(O)OC
1-C
6 alkyl, -P(O)
2OC
1-C
6 alkyl, -CN, or -NO2, or -R
e and -R
f taken together with the carbon atom to which they are attached form an oxo groups or an alkenyl; [0145] n is 0, 1, 2, 3, 4, 5, 6, or 7; [0146] p is 0 or 1; and [0147] q is 0, 1, or 2; [0148] and wherein the compound is not of the formula
[0149] In some embodiments of this aspect, R
1 is H, deuterium, C
1-C
6 alkyl, C
2-C
6 alkenyl, or C2-C6 alkynyl, wherein each hydrogen atom in C
1-C
6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl is independently optionally substituted by deuterium, halogen, -R
e, -R
f, C
1-C
6 alkyl, C
1-C
6 haloalkyl, -OR
e, -OC(O)R
e, -OC(O)NR
eR
f, -OS(O)R
e, -OS(O)
2R
e, -OS(O)NR
eR
f, -OS(O)
2NR
eR
f, -SR
e, -S(O)R
e, -S(O)
2R
e, -S(O)NR
eR
f, -S(O)
2NR
eR
f, -NR
eR
f, -NR
eC(O)R
f, -NR
eC(O)OR
f, -NR
eC(O)NR
eR
f, -NR
eS(O)R
f, -NR
eS(O)
2R
f, -NR
eS(O)NR
eR
f, - NR
eS(O)
2NR
eR
f, -C(O)R
e, -C(O)OR
e, -C(O)NR
eR
f, -PR
eR
f, -P(O)R
eR
f, -P(O)
2R
eR
f, - P(O)NR
eR
f, -P(O)
2NR
eR
f, -P(O)OR
e, -P(O)
2OR
e’, -CN, or -NO
2. In some embodiments of this aspect, R
1 is ring A, and ring A is a C
3-C8 cycloalkyl, C
6-C
10 aryl, or 5- to 10-membered heteroaryl, wherein each of C
3-C
8 cycloalkyl, C
6-C
10 aryl, or 5- to 10-membered heteroaryl is unsubstituted or substituted with one or more of R
11. In some embodiments of this aspect, ring A is a 4- to 10-membered heterocycloalkyl that is covalently attached to –Y-, -(CR
aR
b)
n-, or
through a carbon atom in the 4- to 10-membered heterocycloalkyl. In some embodiments of this aspect, at least one hydrogen atom on ring A, ring B, R
1, or R
3 in the compound of the formula I is substituted by a deuterium. [0150] In one aspect, the disclosure provides a compound of the formula I, or a pharmaceutically acceptable salt thereof,
[0151] wherein [0152] X is a -O-, -S-, or -NR
4-; [0153] Y is a bond, -O-, -S-, -S(O)-, -S(O)
2-, or –C(O)NR
10-; [0154] Z
1 is N or C(R
5); [0155] Z
2 is N or C(R
6); [0156] Z
3 is N or C(R
7); [0157] Z
4 is N or C(R
8); [0158] Z
5 is N or C(R
9); [0159] provided that at least two of Z
1-Z
5 are N; [0160] R
1 is H, deuterium, C
1-C
6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, or ring A, wherein each hydrogen atom in C
1-C
6 alkyl, C
2-C
6 alkenyl, or C
2-C
6 alkynyl is independently optionally substituted by deuterium, halogen, -R
e, -R
f, C
1-C
6 alkyl, C
1-C
6 haloalkyl, -OR
e, -OC(O)R
e, -OC(O)NR
eR
f, -OS(O)R
e, -OS(O)
2R
e, -OS(O)NR
eR
f, -OS(O)
2NR
eR
f, -SR
e, -S(O)R
e, -S(O)
2R
e, -S(O)NR
eR
f, -S(O)
2NR
eR
f, -NR
eR
f, -NR
eC(O)R
f, -NR
eC(O)OR
f, -NR
eC(O)NR
eR
f, -NR
eS(O)R
f, -NR
eS(O)
2R
f, -NR
eS(O)NR
eR
f, -NR
eS(O)
2NR
eR
f, -C(O)R
e, -C(O)OR
e, -C(O)NR
eR
f, -PR
eR
f, -P(O)R
eR
f, -P(O)
2R
eR
f, -P(O)NR
eR
f, -P(O)
2NR
eR
f, -P(O)OR
e, -P(O)
2OR
e’, -CN, or -NO
2; and when Y is a bond, -O-, –S-, or –S(O)-, then R
1 is ring A; [0161] each R
2 is independently deuterium, halogen, C
1-C
6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C
3-C
6 cycloalkyl, 4- to 10-membered heterocycloalkyl, C
6-C
10 aryl, 5- to 10-membered heteroaryl, -OR
c, -OC(O)R
c, -OC(O)NR
cR
d, -OC(=NR
c)NR
cR
d, -OS(O)R
c, -OS(O)
2R
c, - , -
, -NR
cS(O)R
d, -NR
cS(O)
2R
d, -NR
cS(O)NR
cR
d, -NR
cS(O)
2NR
cR
d, -C(O)R
c, -C(O)OR
c, -C(O)NR
cR
d, -C(=NR
c)NR
cR
d, -PR
cR
d, -P(O)R
cR
d, -P(O)
2R
cR
d, -P(O)NR
cR
d, -P(O)
2NR
cR
d,
P(O)OR , P(O)
2OR , CN, or NO
2, or two of R taken together with the atoms to which they are attached form a C
3-C
6 cycloalkyl or a 4- to 10-membered heterocycloalkyl, wherein each hydrogen atom in C
1-C
6 alkyl, C
2-C
6 alkenyl, C
2-C
6 alkynyl, C
3-C
6 cycloalkyl, C
6-C
10 aryl, 5- to 10-membered heteroaryl, and 4- to 10-membered heterocycloalkyl is independently optionally substituted by deuterium, halogen, C
1-C
6 alkyl, C
1-C
6 haloalkyl, -R
e, -R
f, -OR
e, -OC(O)R
e, -OC(O)NR
eR
f, -OS(O)R
e, -OS(O)
2R
e, -OS(O)NR
eR
f, -OS(O)
2NR
eR
f, -SR
e, -S(O)R
e, -S(O)
2R
e, -S(O)NR
eR
f, -S(O)
2NR
eR
f, -NR
eR
f, -NR
eC(O)R
f, -NR
eC(O)OR
f, -NR
eC(O)NR
eR
f, -NR
eS(O)R
f, -NR
eS(O)
2R
f, -NR
eS(O)NR
eR
f, -NR
eS(O)
2NR
eR
f, -C(O)R
e, -C(O)OR
e, -C(O)NR
eR
f, -PR
eR
f, -P(O)R
eR
f, -P(O)
2R
eR
f, -P(O)NR
eR
f, -P(O)
2NR
eR
f, - P(O)OR
e, -P(O)
2OR
e, -CN, or -NO
2; [0162] R
3 is -C
1-C
6 alkyl, -C2-C6 alkenyl, -C2-C6 alkynyl, -C
3-C
6 cycloalkyl, 4- to 10- membered heterocycloalkyl, -C
1-C
6 alkylene-(4- to 10-membered heterocycloalkyl), -C
6-C
10 aryl, -C
1-C
6 alkylene-(C
6-C
10 aryl), 5- to 10-membered heteroaryl, or -C
1-C
6 alkylene-(4- to 10- membered heterocycloalkyl), wherein each hydrogen atom in C
1-C
6 alkyl, C
2-C
6 alkenyl, C
2-C
6 alkynyl, C
3-C
6 cycloalkyl, 4- to 10-membered heterocycloalkyl, -C
1-C
6 alkylene-(4- to 10- membered heterocycloalkyl), C
6-C
10 aryl, -C
1-C
6 alkylene-(C
6-C
10 aryl), 5- to 10-membered heteroaryl, and -C
1-C
6 alkylene-(5- to 10-membered heteroaryl), is independently optionally substituted by deuterium, halogen, -R
e, -R
f, C
1-C
6 alkyl, -C
1-C
6 alkyl-O-C
1-C
6 alkyl, -OC
1-C
6 alkyl-O-C
1-C
6 alkyl, -C
1-C
6 alkyl-O-R
a, C
6-C
10 aryl, -C
1-C
6 alkyl-(C
6-C
10 aryl), haloalkyl, C
3- C6 cycloalkyl, 5- to 10-membered heteroaryl, -C
1-C
6 alkyl-(5- to 10-membered heterocycloalkyl), -OR
e, -OC(O)R
e, -OC(O)NR
eR
f, -OS(O)R
e, -OS(O)
2R
e, -OS(O)NR
eR
f, -OS(O)
2NR
eR
f, -SR
e, -S(O)R
e, -S(O)
2R
e, -S(O)NR
eR
f, -S(O)
2NR
eR
f, -NR
eR
f, -NR
eC(O)R
f, -NR
eC(O)OR
f, -NR
eC(O)NR
eR
f, -NR
eC(=NR
f)NR
eR
f, -NR
eS(O)R
f, -NR
eS(O)
2R
f, -NR
eS(O)NR
eR
f, -NR
eS(O)
2NR
eR
f, -C(O)R
e, -C(O)OR
e, -C(O)NR
eR
f, -PR
eR
f, -P(O)R
eR
f, -P(O)
2R
eR
f, -P(O)NR
eR
f, -P(O)
2NR
eR
f, -P(O)OR
e, -P(O)
2OR
e’, -CN, or -NO
2; [0163] each of R
4 and R
10 is independently H, deuterium, C
1-C
6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C
3-C
6 cycloalkyl, 4- to 10-membered heterocycloalkyl, C
6-C
10 aryl, or 5- to 10- membered heteroaryl, wherein each hydrogen atom in C
1-C
6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C
3-C
6 cycloalkyl, 4- to 10-membered heterocycloalkyl, C
6-C
10 aryl, and 5- to 10- membered heteroaryl is independently optionally substituted by deuterium, halogen, -R
e, -R
f, C
1-C
6 alkyl, C
1-C
6 haloalkyl, -OR
e, -OC(O)R
e, -OC(O)NR
eR
f, -OS(O)R
e, -OS(O)
2R
e, - OS(O)NR
eR
f, -OS(O)
2NR
eR
f, -SR
e, -S(O)R
e, -S(O)
2R
e, -S(O)NR
eR
f, -S(O)
2NR
eR
f, -NR
eR
f, - NR
eC(O)R
f, -NR
eC(O)OR
f, -NR
eC(O)NR
eR
f, -NR
eS(O)R
f, -NR
eS(O)
2R
f, -NR
eS(O)NR
eR
f, - NR
eS(O)
2NR
eR
f, -C(O)R
e, -C(O)OR
e, -C(O)NR
eR
f, -PR
eR
f, -P(O)R
eR
f, -P(O)
2R
eR
f, - P(O)NR
eR
f, -P(O)
2NR
eR
f, -P(O)OR
e, -P(O)
2OR
e’, -CN, or -NO2; or R
1 and R
10 taken together
with the atom or atoms to which they are attached combine to form a monocyclic 4 to 10 membered heterocycloalkyl, a fused bicyclic 5- to 10-membered heterocycloalkyl, or a bridged bicyclic 6- to 10-membered heterocycloalkyl, wherein each hydrogen atom in the monocyclic 4- to 10-membered heterocycloalkyl, fused bicyclic 5- to 10-membered heterocycloalkyl, or a bridged bicyclic 6- to 10-membered heterocycloalkyl is independently optionally substituted by deuterium, halogen, C
1-C
6 alkyl, C
1-C
6 haloalkyl, -OH, -OC
1-C
6 alkyl, -OC(O)C
1-C
6 alkyl, -OC(O)N(H or C
1-C
6 alkyl)
2, -OS(O)C
1-C
6 alkyl, -OS(O)
2C
1-C
6 alkyl, -OS(O)N(H or C
1-C
6 alkyl)
2, -OS(O)
2N(H or C
1-C
6 alkyl)
2, -SC
1-C
6 alkyl, -S(O)C
1-C
6 alkyl, -S(O)
2C
1-C
6 alkyl, -S(O)N(H or C
1-C
6 alkyl)
2, -S(O)
2N(H or C
1-C
6 alkyl)
2, -N(H or C
1-C
6 alkyl)
2, -N(C1- C
6 alkyl)C(O)-C
1-C
6 alkyl, -N(C
1-C
6 alkyl)C(O)OC
1-C
6 alkyl, -N(C
1-C
6 alkyl)C(O)N(H or C
1- C6 alkyl)
2, -N(C
1-C
6 alkyl)S(O)C
1-C
6 alkyl, -N(C
1-C
6 alkyl)S(O)
2C
1-C
6 alkyl, -N(C
1-C
6 alkyl)S(O)N(H or C
1-C
6 alkyl)
2, -N(C
1-C
6 alkyl)S(O)
2N(H or C
1-C
6 alkyl)
2, -C(O)C
1-C
6 alkyl, -C(O)OC
1-C
6 alkyl, -C(O)N(H or C
1-C
6 alkyl)
2, -P(H or C
1-C
6 alkyl)
2, -P(O)(H or C
1-C
6 alkyl)
2, -P(O)
2(H or C
1-C
6 alkyl)
2, -P(O)N(H or C
1-C
6 alkyl)
2, -P(O)
2N(H or C
1-C
6 alkyl)
2, -P(O)OC
1-C
6 alkyl, -P(O)
2OC
1-C
6 alkyl, -CN, or -NO2, or two hydrogen atoms on a single carbon atom of the monocyclic 4- to 10-membered heterocycloalkyl, fused bicyclic 5- to 10- membered heterocycloalkyl, or bridged bicyclic 6- to 10-membered heterocycloalkyl combine to form an oxo group or an alkenyl group; [0164] each of R
5, R
6, R
7, R
8, and R
9 is independently H, deuterium, halogen, C
1-C
6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C
3-C
6 cycloalkyl, 4- to 10-membered heterocycloalkyl, C
6-C
10 aryl, 5- to 10-membered heteroaryl, -OR
g, -OC(O)R
g, -OC(O)NR
gR
h, -OS(O)R
g, -OS(O)
2R
g, - SR
g, -S(O)R
g, -S(O)
2R
g, -S(O)NR
gR
h, -S(O)
2NR
gR
h, -OS(O)NR
gR
h, -OS(O)
2NR
gR
h, -NR
gR
h, -NR
gC(O)R
h, -NR
gC(O)OR
h, -NR
gC(O)NR
gR
h, -NR
gS(O)R
h, -NR
gS(O)
2R
h, -NR
gS(O)NR
gR
h, -NR
gS(O)
2NR
gR
h, -C(O)R
g, -C(O)OR
g, -C(O)NR
gR
h, -PR
gR
h, -P(O)R
gR
h, -P(O)
2R
gR
h, -P(O)NR
gR
h, -P(O)
2NR
gR
h, -P(O)OR
g, -P(O)
2OR
g, -CN, or -NO
2; [0165] ring A is a C
3-C8 cycloalkyl, 4- to 10-membered heterocycloalkyl, C
6-C
10 aryl, or 5- to 10-membered heteroaryl, wherein each of C
3-C
8 cycloalkyl, 4- to 10-membered heterocycloalkyl, C
6-C
10 aryl, or 5- to 10-membered heteroaryl is unsubstituted or substituted with one or more of R
11, provided that the 4- to 10-membered heterocycloalkyl is not an unsubstituted or a substituted ring of the formula
wherein * is a point
of covalent attachment, [0166] each R
11 is independently deuterium, halogen, C
1-C
6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C
3-C
6 cycloalkyl, 4- to 10-membered heterocycloalkyl, C
6-C
10 aryl, 5- to 10- membered heteroaryl, -OR
a, -OC(O)R
a, -OC(O)NR
aR
b, -OC(=NR
a)NR
aR
b, -OS(O)R
a, -OS(O)
2R
a, -OS(O)NR
aR
b, -OS(O)
2NR
aR
b, -SR
a, -S(O)R
a, -S(O)
2R
a, -S(O)NR
aR
b, -S(O)
2NR
aR
b, -NR
aR
b, -NR
aC(O)R
b, -N(C(O)R
a)(C(O)R
b), -NR
aC(O)OR
b, -NR
aC(O)NR
aR
b, -NR
aC(=NR
a)NR
aR
b, -NR
aS(O)R
b, -NR
aS(O)
2R
b, -NR
aS(O)NR
aR
b, -NR
aS(O)
2NR
aR
b, - C(O)R
a, -C(O)OR
a, -C(O)NR
aR
b, -C(=NR
a)NR
aR
b, -PR
aR
b, -P(O)R
aR
b, -P(O)
2R
aR
b, - P(O)NR
aR
b, -P(O)
2NR
aR
b, -P(O)OR
a, -P(O)
2OR
a, -CN, or -NO2, or two of R
11 taken together with the atom or atoms to which they are attached or three of R
11 taken together with the atoms to which they are attached, form a C
3-C
6 cycloalkyl or a 4- to 10-membered heterocycloalkyl, wherein each hydrogen atom in C
1-C
6 alkyl, C
2-C
6 alkenyl, C
2-C
6 alkynyl, C
3-C
6 cycloalkyl, C
6-C
10 aryl, 5- to 10-membered heteroaryl, and 4- to 10-membered heterocycloalkyl is independently optionally substituted by deuterium, halogen, -R
e, -R
f, C
1-C
6 alkyl, C
1-C
6 haloalkyl, -OR
e, -OC(O)R
e, -OC(O)NR
eR
f, -OS(O)R
e, -OS(O)
2R
e, -OS(O)NR
eR
f, -OS(O)
2NR
eR
f, -SR
e, -S(O)R
e, -S(O)
2R
e, -S(O)NR
eR
f, -S(O)
2NR
eR
f, -NR
eR
f, -NR
eC(O)R
f, - NR
eC(O)OR
f, -NR
eC(O)NR
eR
f, -NR
eS(O)R
f, -NR
eS(O)
2R
f, -NR
eS(O)NR
eR
f, -NR
eS(O)
2NR
eR
f, -C(O)R
e, -C(O)OR
e, -C(O)NR
eR
f, -PR
eR
f, -P(O)R
eR
f, -P(O)
2R
eR
f, -P(O)NR
eR
f, -P(O)
2NR
eR
f, -P(O)OR
e, -P(O)
2OR
e, -CN, or -NO2, or two of R
11 taken together with the carbon atom to which they are attached form an oxo group or an alkenyl group; [0167] ring B is a C
6-C
10 aryl or 5- to 10-membered heteroaryl; [0168] each R
a, R
b, R
c, R
d, R
e, R
f, R
g, and R
h is independently selected from the group consisting of H, deuterium, C
1-C
6 alkyl, C
2-C
6 alkenyl, C
2-C
6 alkynyl, C
3-C
6 cycloalkyl, 4- to 10-membered heterocycloalkyl, C
6-C
10 aryl, C
1-C
6 alkyl-C
6-C
10 aryl, and 5- to 10-membered heteroaryl; or two of R
a and R
b, or R
c and R
d, or R
e and R
f, or R
g and R
h, taken together with the atom or atoms to which they are attached, combine to form a C
3-C
6 cycloalkyl, 4- to 10- membered heterocycloalkyl, C
6-C
10 aryl, or 5- to 10-membered heteroaryl, wherein each hydrogen atom in C
1-C
6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C
3-C
6 cycloalkyl, 4- to 10-
membered heterocycloalkyl, C
6 C
10 aryl, C
1 C
6 alkyl C
6 C
10 aryl, and 5 to 10 membered heteroaryl is independently optionally substituted by deuterium, halogen, C
1-C
6 alkyl, C
1-C
6 haloalkyl, -OH, -OC
1-C
6 alkyl, -OC(O)C
1-C
6 alkyl, -OC(O)N(H or C
1-C
6 alkyl)
2, -OS(O)C
1- C6 alkyl, -OS(O)
2C
1-C
6 alkyl, -OS(O)N(H or C
1-C
6 alkyl)
2, -OS(O)
2N(H or C
1-C
6 alkyl)
2, - SC
1-C
6 alkyl, -S(O)C
1-C
6 alkyl, -S(O)
2C
1-C
6 alkyl, -S(O)N(H or C
1-C
6 alkyl)
2, -S(O)
2N(H or C
1-C
6 alkyl)
2, -N(H or C
1-C
6 alkyl)
2, -N(C
1-C
6 alkyl)C(O)-C
1-C
6 alkyl, -N(C
1-C
6 alkyl)C(O)OC
1-C
6 alkyl, -N(C
1-C
6 alkyl)C(O)N(H or C
1-C
6 alkyl)
2, -N(C
1-C
6 alkyl)S(O)C1- C
6 alkyl, -N(C
1-C
6 alkyl)S(O)
2C
1-C
6 alkyl, -N(C
1-C
6 alkyl)S(O)N(H or C
1-C
6 alkyl)
2, -N(C
1- C6 alkyl)S(O)
2N(H or C
1-C
6 alkyl)
2, -C(O)C
1-C
6 alkyl, -C(O)OC
1-C
6 alkyl, -C(O)N(H or C1- C
6 alkyl)
2, -P(H or C
1-C
6 alkyl)
2, -P(O)(H or C
1-C
6 alkyl)
2, -P(O)
2(H or C
1-C
6 alkyl)
2, - P(O)N(H or C
1-C
6 alkyl)
2, -P(O)
2N(H or C
1-C
6 alkyl)
2, -P(O)OC
1-C
6 alkyl, -P(O)
2OC
1-C
6 alkyl, -CN, or -NO
2, or -R
e and -R
f taken together with the carbon atom to which they are attached form an oxo groups or an alkenyl; [0169] n is 0, 1, 2, 3, 4, 5, 6, or 7, provided that when B is C
6-C
10 aryl, n is 2, 3, 4, 5, 6, or 7, and when B is 5- to 10-membered heteroaryl, n is 1, 2, 3, 4, 5, 6, or 7; [0170] p is 0 or 1; and [0171] q is 0, 1, or 2; [0172] and wherein the compound is not of the formula
[0173] In some embodiments of this aspect, R
1 is H, deuterium, C
1-C
6 alkyl, C2-C6 alkenyl, or C
2-C
6 alkynyl, wherein each hydrogen atom in C
1-C
6 alkyl, C
2-C
6 alkenyl, or C
2-C
6 alkynyl is independently optionally substituted by deuterium, halogen, -R
e, -R
f, C
1-C
6 alkyl, C
1-C
6 haloalkyl, -OR
e, -OC(O)R
e, -OC(O)NR
eR
f, -OS(O)R
e, -OS(O)
2R
e, -OS(O)NR
eR
f,
OS(O)
2NR R, SR , S(O)R , S(O)
2R , S(O)NR R, S(O)
2NR R, NR R, NR C(O)R, -NR
eC(O)OR
f, -NR
eC(O)NR
eR
f, -NR
eS(O)R
f, -NR
eS(O)
2R
f, -NR
eS(O)NR
eR
f, - NR
eS(O)
2NR
eR
f, -C(O)R
e, -C(O)OR
e, -C(O)NR
eR
f, -PR
eR
f, -P(O)R
eR
f, -P(O)
2R
eR
f, - P(O)NR
eR
f, -P(O)
2NR
eR
f, -P(O)OR
e, -P(O)
2OR
e’, -CN, or -NO2. In some embodiments of this aspect, R
1 is ring A, and ring A is a C
3-C
8 cycloalkyl, C
6-C
10 aryl, or 5- to 10-membered heteroaryl, wherein each of C
3-C
8 cycloalkyl, C
6-C
10 aryl, or 5- to 10-membered heteroaryl is unsubstituted or substituted with one or more of R
11. In some embodiments of this aspect, ring A is a 4- to 10-membered heterocycloalkyl that is covalently attached to –Y-, -(CR
aR
b)
n-, or
through a carbon atom in the 4- to 10-membered heterocycloalkyl. In some embodiments of this aspect, at least one hydrogen atom on ring A, ring B, R
1, or R
3 in the compound of the formula I is substituted by a deuterium. [0174] In one aspect, the disclosure provides a compound of the formula I, or a pharmaceutically acceptable salt thereof,
wherein X is a -O-, -S-, or -NR
4-; Y is a bond, -O-, -S-, -S(O)-, -S(O)
2-, or –C(O)NR
10-; Z
1 is N or C(R
5); Z
2 is N or C(R
6); Z
3 is N or C(R
7); Z
4 is N or C(R
8); Z
5 is N or C(R
9); provided that at least two of Z
1-Z
5 are N;
R is H, deuterium, C
1 C
6 alkyl, C
2 C
6 alkenyl, C
2 C
6 alkynyl, or ring A, wherein each hydrogen atom in C
1-C
6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl is independently optionally substituted by deuterium, halogen, -R
e, -R
f, C
1-C
6 alkyl, C
1-C
6 haloalkyl, -OR
e, -OC(O)R
e, -OC(O)NR
eR
f, -OS(O)R
e, -OS(O)
2R
e, -OS(O)NR
eR
f, -OS(O)
2NR
eR
f, -SR
e, -S(O)R
e, -S(O)
2R
e, -S(O)NR
eR
f, -S(O)
2NR
eR
f, -NR
eR
f, -NR
eC(O)R
f, -NR
eC(O)OR
f, -NR
eC(O)NR
eR
f, -NR
eS(O)R
f, -NR
eS(O)
2R
f, -NR
eS(O)NR
eR
f, -NR
eS(O)
2NR
eR
f, -C(O)R
e, -C(O)OR
e, -C(O)NR
eR
f, -PR
eR
f, -P(O)R
eR
f, -P(O)
2R
eR
f, -P(O)NR
eR
f, -P(O)
2NR
eR
f, -P(O)OR
e, -P(O)
2OR
e’, -CN, or -NO
2; and when Y is a bond, -O-, –S-, or –S(O)-, then R
1 is ring A; each R
2 is independently deuterium, halogen, methyl, C
3-C
6 alkyl, C
2-C
6 alkenyl, C
2-C
6 alkynyl, C
3-C
6 cycloalkyl, 4- to 10-membered heterocycloalkyl, C
6-C
10 aryl, 5- to 10- membered heteroaryl, -OR
c, -OC(O)R
c, -OC(O)NR
cR
d, -OC(=NR
c)NR
cR
d, -OS(O)R
c, -OS(O)
2R
c, -OS(O)NR
cR
d, -OS(O)
2NR
cR
d, -SR
c, -S(O)R
c, -S(O)
2R
c, -S(O)NR
cR
d, -S(O)
2NR
cR
d, -NR
cR
d, -NR
cC(O)R
d, -N(C(O)R
c)(C(O)R
d), -NR
cC(O)OR
d, -NR
cC(O)NR
cR
d, -NR
cC(=NR
c)NR
cR
d, -NR
cS(O)R
d, -NR
cS(O)
2R
d, -NR
cS(O)NR
cR
d, -NR
cS(O)
2NR
cR
d, - C(O)R
c, -C(O)OR
c, -C(O)NR
cR
d, -C(=NR
c)NR
cR
d, -PR
cR
d, -P(O)R
cR
d, -P(O)
2R
cR
d, - P(O)NR
cR
d, -P(O)
2NR
cR
d, -P(O)OR
c, -P(O)
2OR
c, -CN, or -NO2, or two of R
2 taken together with the atoms to which they are attached form a C
3-C
6 cycloalkyl or a 4- to 10-membered heterocycloalkyl, wherein each hydrogen atom in C
1-C
6 alkyl, C
2-C
6 alkenyl, C
2-C
6 alkynyl, C
3-C
6 cycloalkyl, C
6-C
10 aryl, 5- to 10-membered heteroaryl, and 4- to 10-membered heterocycloalkyl is independently optionally substituted by deuterium, halogen, C
1-C
6 alkyl, C
1-C
6 haloalkyl, -R
e, -R
f, -OR
e, -OC(O)R
e, -OC(O)NR
eR
f, -OS(O)R
e, -OS(O)
2R
e, -OS(O)NR
eR
f, -OS(O)
2NR
eR
f, -SR
e, -S(O)R
e, -S(O)
2R
e, -S(O)NR
eR
f, -S(O)
2NR
eR
f, -NR
eR
f, -NR
eC(O)R
f, -NR
eC(O)OR
f, -NR
eC(O)NR
eR
f, -NR
eS(O)R
f, -NR
eS(O)
2R
f, -NR
eS(O)NR
eR
f, -NR
eS(O)
2NR
eR
f, -C(O)R
e, -C(O)OR
e, -C(O)NR
eR
f, -PR
eR
f, -P(O)R
eR
f, -P(O)
2R
eR
f, -P(O)NR
eR
f, -P(O)
2NR
eR
f, -P(O)OR
e, -P(O)
2OR
e, -CN, or -NO2; R
3 is -C
1-C
6 alkyl, -C
2-C
6 alkenyl, -C
2-C
6 alkynyl, -C
3-C
6 cycloalkyl, 4- to 10- membered heterocycloalkyl, -C
1-C
6 alkylene-(4- to 10-membered heterocycloalkyl), -C
6-C
10 aryl, -C
1-C
6 alkylene-(C
6-C
10 aryl), 5- to 10-membered heteroaryl, or -C
1-C
6 alkylene-(4- to 10- membered heterocycloalkyl), wherein each hydrogen atom in C
1-C
6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C
3-C
6 cycloalkyl, 4- to 10-membered heterocycloalkyl, -C
1-C
6 alkylene-(4- to 10- membered heterocycloalkyl), C
6-C
10 aryl, -C
1-C
6 alkylene-(C
6-C
10 aryl), 5- to 10-membered heteroaryl, and -C
1-C
6 alkylene-(5- to 10-membered heteroaryl), is independently optionally substituted by deuterium, halogen, -R
e, -R
f, C
1-C
6 alkyl, -C
1-C
6 alkyl-O-C
1-C
6 alkyl, -OC
1-C
6 alkyl-O-C
1-C
6 alkyl, -C
1-C
6 alkyl-O-R
a, C
6-C
10 aryl, -C
1-C
6 alkyl-(C
6-C
10 aryl), haloalkyl, C
3-
C
6 cycloalkyl, 5 to 10 membered heteroaryl, C
1 C
6 alkyl (5 to 10 membered heterocycloalkyl), -OR
e, -OC(O)R
e, -OC(O)NR
eR
f, -OS(O)R
e, -OS(O)
2R
e, -OS(O)NR
eR
f, -OS(O)
2NR
eR
f, -SR
e, -S(O)R
e, -S(O)
2R
e, -S(O)NR
eR
f, -S(O)
2NR
eR
f, -NR
eR
f, -NR
eC(O)R
f, -NR
eC(O)OR
f, -NR
eC(O)NR
eR
f, -NR
eC(=NR
f)NR
eR
f, -NR
eS(O)R
f, -NR
eS(O)
2R
f, -NR
eS(O)NR
eR
f, -NR
eS(O)
2NR
eR
f, -C(O)R
e, -C(O)OR
e, -C(O)NR
eR
f, -PR
eR
f, -P(O)R
eR
f, -P(O)
2R
eR
f, -P(O)NR
eR
f, -P(O)
2NR
eR
f, -P(O)OR
e, -P(O)
2OR
e’, -CN, or -NO
2; each of R
4 and R
10 is independently H, deuterium, C
1-C
6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C
3-C
6 cycloalkyl, 4- to 10-membered heterocycloalkyl, C
6-C
10 aryl, or 5- to 10- membered heteroaryl, wherein each hydrogen atom in C
1-C
6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C
3-C
6 cycloalkyl, 4- to 10-membered heterocycloalkyl, C
6-C
10 aryl, and 5- to 10- membered heteroaryl is independently optionally substituted by deuterium, halogen, -R
e, -R
f, C
1-C
6 alkyl, C
1-C
6 haloalkyl, -OR
e, -OC(O)R
e, -OC(O)NR
eR
f, -OS(O)R
e, -OS(O)
2R
e, - OS(O)NR
eR
f, -OS(O)
2NR
eR
f, -SR
e, -S(O)R
e, -S(O)
2R
e, -S(O)NR
eR
f, -S(O)
2NR
eR
f, -NR
eR
f, - NR
eC(O)R
f, -NR
eC(O)OR
f, -NR
eC(O)NR
eR
f, -NR
eS(O)R
f, -NR
eS(O)
2R
f, -NR
eS(O)NR
eR
f, - NR
eS(O)
2NR
eR
f, -C(O)R
e, -C(O)OR
e, -C(O)NR
eR
f, -PR
eR
f, -P(O)R
eR
f, -P(O)
2R
eR
f, - P(O)NR
eR
f, -P(O)
2NR
eR
f, -P(O)OR
e, -P(O)
2OR
e’, -CN, or -NO2; or R
1 and R
10 taken together with the atom or atoms to which they are attached combine to form a monocyclic 4- to 10- membered heterocycloalkyl, a fused bicyclic 5- to 10-membered heterocycloalkyl, or a bridged bicyclic 6- to 10-membered heterocycloalkyl, wherein each hydrogen atom in the monocyclic 4- to 10-membered heterocycloalkyl, fused bicyclic 5- to 10-membered heterocycloalkyl, or a bridged bicyclic 6- to 10-membered heterocycloalkyl is independently optionally substituted by deuterium, halogen, C
1-C
6 alkyl, C
1-C
6 haloalkyl, -OH, -OC
1-C
6 alkyl, -OC(O)C
1-C
6 alkyl, -OC(O)N(H or C
1-C
6 alkyl)
2, -OS(O)C
1-C
6 alkyl, -OS(O)
2C
1-C
6 alkyl, -OS(O)N(H or C
1-C
6 alkyl)
2, -OS(O)
2N(H or C
1-C
6 alkyl)
2, -SC
1-C
6 alkyl, -S(O)C
1-C
6 alkyl, -S(O)
2C
1-C
6 alkyl, -S(O)N(H or C
1-C
6 alkyl)
2, -S(O)
2N(H or C
1-C
6 alkyl)
2, -N(H or C
1-C
6 alkyl)
2, -N(C
1- C6 alkyl)C(O)-C
1-C
6 alkyl, -N(C
1-C
6 alkyl)C(O)OC
1-C
6 alkyl, -N(C
1-C
6 alkyl)C(O)N(H or C1- C
6 alkyl)
2, -N(C
1-C
6 alkyl)S(O)C
1-C
6 alkyl, -N(C
1-C
6 alkyl)S(O)
2C
1-C
6 alkyl, -N(C
1-C
6 alkyl)S(O)N(H or C
1-C
6 alkyl)
2, -N(C
1-C
6 alkyl)S(O)
2N(H or C
1-C
6 alkyl)
2, -C(O)C
1-C
6 alkyl, -C(O)OC
1-C
6 alkyl, -C(O)N(H or C
1-C
6 alkyl)
2, -P(H or C
1-C
6 alkyl)
2, -P(O)(H or C
1-C
6 alkyl)
2, -P(O)
2(H or C
1-C
6 alkyl)
2, -P(O)N(H or C
1-C
6 alkyl)
2, -P(O)
2N(H or C
1-C
6 alkyl)
2, -P(O)OC
1-C
6 alkyl, -P(O)
2OC
1-C
6 alkyl, -CN, or -NO2, or two hydrogen atoms on a single carbon atom of the monocyclic 4- to 10-membered heterocycloalkyl, fused bicyclic 5- to 10- membered heterocycloalkyl, or bridged bicyclic 6- to 10-membered heterocycloalkyl combine to form an oxo group or an alkenyl group;
each of R , R , R , R , and R is independently H, deuterium, halogen, C
1 C
6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C
3-C
6 cycloalkyl, 4- to 10-membered heterocycloalkyl, C
6-C
10 aryl, 5- to 10-membered heteroaryl, -OR
g, -OC(O)R
g, -OC(O)NR
gR
h, -OS(O)R
g, -OS(O)
2R
g, - SR
g, -S(O)R
g, -S(O)
2R
g, -S(O)NR
gR
h, -S(O)
2NR
gR
h, -OS(O)NR
gR
h, -OS(O)
2NR
gR
h, -NR
gR
h, -NR
gC(O)R
h, -NR
gC(O)OR
h, -NR
gC(O)NR
gR
h, -NR
gS(O)R
h, -NR
gS(O)
2R
h, -NR
gS(O)NR
gR
h, -NR
gS(O)
2NR
gR
h, -C(O)R
g, -C(O)OR
g, -C(O)NR
gR
h, -PR
gR
h, -P(O)R
gR
h, -P(O)
2R
gR
h, -P(O)NR
gR
h, -P(O)
2NR
gR
h, -P(O)OR
g, -P(O)
2OR
g, -CN, or -NO2; ring A is a C
3-C
8 cycloalkyl, 4- to 10-membered heterocycloalkyl, C
6-C
10 aryl, or 5- to 10-membered heteroaryl, wherein each of C
3-C8 cycloalkyl, 4- to 10-membered heterocycloalkyl, C
6-C
10 aryl, or 5- to 10-membered heteroaryl is unsubstituted or substituted with one or more of R
11, provided that the 4- to 10-membered heterocycloalkyl is not an unsubstituted or a substituted ring of the formula
wherein * is a point of covalent attachment, each R
11 is independently deuterium, halogen, C
1-C
6 alkyl, C
2-C
6 alkenyl, C
2-C
6 alkynyl, C
3-C
6 cycloalkyl, 4- to 10-membered heterocycloalkyl, C
6-C
10 aryl, 5- to 10- membered heteroaryl, -OR
a, -OC(O)R
a, -OC(O)NR
aR
b, -OC(=NR
a)NR
aR
b, -OS(O)R
a, -OS(O)
2R
a, -OS(O)NR
aR
b, -OS(O)
2NR
aR
b, -SR
a, -S(O)R
a, -S(O)
2R
a, -S(O)NR
aR
b, -S(O)
2NR
aR
b, -NR
aR
b, -NR
aC(O)R
b, -N(C(O)R
a)(C(O)R
b), -NR
aC(O)OR
b, -NR
aC(O)NR
aR
b, -NR
aC(=NR
a)NR
aR
b, -NR
aS(O)R
b, -NR
aS(O)
2R
b, -NR
aS(O)NR
aR
b, -NR
aS(O)
2NR
aR
b, - C(O)R
a, -C(O)OR
a, -C(O)NR
aR
b, -C(=NR
a)NR
aR
b, -PR
aR
b, -P(O)R
aR
b, -P(O)
2R
aR
b, - P(O)NR
aR
b, -P(O)
2NR
aR
b, -P(O)OR
a, -P(O)
2OR
a, -CN, or -NO
2, or two of R
11 taken together with the atom or atoms to which they are attached or three of R
11 taken together with the atoms to which they are attached, form a C
3-C
6 cycloalkyl or a 4- to 10-membered heterocycloalkyl, wherein each hydrogen atom in C
1-C
6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C
3-C
6 cycloalkyl, C
6-C
10 aryl, 5- to 10-membered heteroaryl, and 4- to 10-membered heterocycloalkyl is independently optionally substituted by deuterium, halogen, -R
e, -R
f, C
1-C
6 alkyl, C
1-C
6 haloalkyl, -OR
e, -OC(O)R
e, -OC(O)NR
eR
f, -OS(O)R
e, -OS(O)
2R
e, -OS(O)NR
eR
f, -OS(O)
2NR
eR
f, -SR
e, -S(O)R
e, -S(O)
2R
e, -S(O)NR
eR
f, -S(O)
2NR
eR
f, -NR
eR
f, -NR
eC(O)R
f, - NR
eC(O)OR
f, -NR
eC(O)NR
eR
f, -NR
eS(O)R
f, -NR
eS(O)
2R
f, -NR
eS(O)NR
eR
f, -NR
eS(O)
2NR
eR
f, -C(O)R
e, -C(O)OR
e, -C(O)NR
eR
f, -PR
eR
f, -P(O)R
eR
f, -P(O)
2R
eR
f,
P(O)NR R, P(O)
2NR R, P(O)OR , P(O)
2OR , CN, or NO
2, or two of R taken together with the carbon atom to which they are attached form an oxo group or an alkenyl group; ring B is a C
6-C
10 aryl or 5- to 10-membered heteroaryl; each R
a, R
b, R
c, R
d, R
e, R
f, R
g, and R
h is independently selected from the group consisting of H, deuterium, C
1-C
6 alkyl, C
2-C
6 alkenyl, C
2-C
6 alkynyl, C
3-C
6 cycloalkyl, 4- to 10-membered heterocycloalkyl, C
6-C
10 aryl, C
1-C
6 alkyl-C
6-C
10 aryl, and 5- to 10-membered heteroaryl; or two of R
a and R
b, or R
c and R
d, or R
e and R
f, or R
g and R
h, taken together with the atom or atoms to which they are attached, combine to form a C
3-C
6 cycloalkyl, 4- to 10- membered heterocycloalkyl, C
6-C
10 aryl, or 5- to 10-membered heteroaryl, wherein each hydrogen atom in C
1-C
6 alkyl, C
2-C
6 alkenyl, C
2-C
6 alkynyl, C
3-C
6 cycloalkyl, 4- to 10- membered heterocycloalkyl, C
6-C
10 aryl, C
1-C
6 alkyl-C
6-C
10 aryl, and 5- to 10-membered heteroaryl is independently optionally substituted by deuterium, halogen, C
1-C
6 alkyl, C
1-C
6 haloalkyl, -OH, -OC
1-C
6 alkyl, -OC(O)C
1-C
6 alkyl, -OC(O)N(H or C
1-C
6 alkyl)
2, -OS(O)C1- C
6 alkyl, -OS(O)
2C
1-C
6 alkyl, -OS(O)N(H or C
1-C
6 alkyl)
2, -OS(O)
2N(H or C
1-C
6 alkyl)
2, - SC
1-C
6 alkyl, -S(O)C
1-C
6 alkyl, -S(O)
2C
1-C
6 alkyl, -S(O)N(H or C
1-C
6 alkyl)
2, -S(O)
2N(H or C
1-C
6 alkyl)
2, -N(H or C
1-C
6 alkyl)
2, -N(C
1-C
6 alkyl)C(O)-C
1-C
6 alkyl, -N(C
1-C
6 alkyl)C(O)OC
1-C
6 alkyl, -N(C
1-C
6 alkyl)C(O)N(H or C
1-C
6 alkyl)
2, -N(C
1-C
6 alkyl)S(O)C1- C6 alkyl, -N(C
1-C
6 alkyl)S(O)
2C
1-C
6 alkyl, -N(C
1-C
6 alkyl)S(O)N(H or C
1-C
6 alkyl)
2, -N(C1- C
6 alkyl)S(O)
2N(H or C
1-C
6 alkyl)
2, -C(O)C
1-C
6 alkyl, -C(O)OC
1-C
6 alkyl, -C(O)N(H or C
1- C6 alkyl)
2, -P(H or C
1-C
6 alkyl)
2, -P(O)(H or C
1-C
6 alkyl)
2, -P(O)
2(H or C
1-C
6 alkyl)
2, - P(O)N(H or C
1-C
6 alkyl)
2, -P(O)
2N(H or C
1-C
6 alkyl)
2, -P(O)OC
1-C
6 alkyl, -P(O)
2OC
1-C
6 alkyl, -CN, or -NO2, or -R
e and -R
f taken together with the carbon atom to which they are attached form an oxo groups or an alkenyl; n is 0, 1, 2, 3, 4, 5, 6, or 7, provided that when B is C
6-C
10 aryl, n is 2, 3, 4, 5, 6, or 7, and when B is 5- to 10-membered heteroaryl, n is 1, 2, 3, 4, 5, 6, or 7; p is 0 or 1; and q is 0, 1, or 2; and wherein the compound is not of the formula
[0175] In some embodiments of this aspect, R
1 is H, deuterium, C
1-C
6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl, wherein each hydrogen atom in C
1-C
6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl is independently optionally substituted by deuterium, halogen, -R
e, -R
f, C
1-C
6 alkyl, C
1-C
6 haloalkyl, -OR
e, -OC(O)R
e, -OC(O)NR
eR
f, -OS(O)R
e, -OS(O)
2R
e, -OS(O)NR
eR
f, -OS(O)
2NR
eR
f, -SR
e, -S(O)R
e, -S(O)
2R
e, -S(O)NR
eR
f, -S(O)
2NR
eR
f, -NR
eR
f, -NR
eC(O)R
f, -NR
eC(O)OR
f, -NR
eC(O)NR
eR
f, -NR
eS(O)R
f, -NR
eS(O)
2R
f, -NR
eS(O)NR
eR
f, - NR
eS(O)
2NR
eR
f, -C(O)R
e, -C(O)OR
e, -C(O)NR
eR
f, -PR
eR
f, -P(O)R
eR
f, -P(O)
2R
eR
f, - P(O)NR
eR
f, -P(O)
2NR
eR
f, -P(O)OR
e, -P(O)
2OR
e’, -CN, or -NO2. In some embodiments of this aspect, R
1 is ring A, and ring A is a C
3-C
8 cycloalkyl, C
6-C
10 aryl, or 5- to 10-membered heteroaryl, wherein each of C
3-C8 cycloalkyl, C
6-C
10 aryl, or 5- to 10-membered heteroaryl is unsubstituted or substituted with one or more of R
11. In some embodiments of this aspect, ring A is a 4- to 10-membered heterocycloalkyl that is covalently attached to –Y-, -(CR
aR
b)n-, or
through a carbon atom in the 4- to 10-membered heterocycloalkyl. In some embodiments of this aspect, at least one hydrogen atom on ring A, ring B, R
1, or R
3 in the compound of the formula I is substituted by a deuterium. [0176] In some embodiments, the disclosure provides a compound of the formula II, or a pharmaceutically acceptable salt thereof,
[0177] wherein R
2, R
3, R
11, R
a, R
b, A, B, X, Y, Z
1, Z
2, Z
3, Z
4, Z
5, m, n, p, and q are as described herein. [0178] In some embodiments, the disclosure provides a compound of the formula III, or a pharmaceutically acceptable salt thereof,
[0179] wherein R
2, R
3, R
11, A, B, X, Z
1, Z
2, Z
3, Z
4, Z
5, m, n, and p are as described herein. [0180] In some embodiments, the disclosure provides a compound of the formula IV, or a pharmaceutically acceptable salt thereof,
IV [0181] wherein R
2, R
11, A, X, Z
1, Z
2, Z
3, Z
4, Z
5, m, and n are as described herein. [0182] In some embodiments, the disclosure provides a compound of the formula V, or a pharmaceutically acceptable salt thereof,
[0183] wherein R
2, R
3, R
11, A, X, Z
1, Z
2, Z
3, Z
4, Z
5, Z
6, Z
7, m, n, and p are as described herein. [0184] In some embodiments, the disclosure provides a compound of the formula VI, or a pharmaceutically acceptable salt thereof,
[0185] wherein R
2, R
11, A, X, Z
1, Z
2, Z
3, Z
4, Z
5, Z
6, Z
7, m, and n are as described herein. [0186] In some embodiments, the disclosure provides a compound of the formula VII, or a pharmaceutically acceptable salt thereof,
VII [0187] wherein R
2, R
3, R
11, R
12, A, X, Z
1, Z
2, Z
3, Z
4, Z
5, m, n, and p are as described herein. [0188] In some embodiments, the disclosure provides a compound of the formula VIII, or a pharmaceutically acceptable salt thereof,
VIII [0189] wherein R
2, R
11, R
12, A, X, Z
1, Z
2, Z
3, Z
4, Z
5, m, and n are as described herein. [0190] In some embodiments, the disclosure provides a compound of the formula IX, or a pharmaceutically acceptable salt thereof,
[0191] wherein R
2, R
3, R
11, R
13, A, X, Z
1, Z
2, Z
3, Z
4, Z
5, m, n, and p are as described herein. [0192] In some embodiments, the disclosure provides a compound of the formula X, or a pharmaceutically acceptable salt thereof,
[0193] wherein R
2, R
11, R
13, A, X, Z
1, Z
2, Z
3, Z
4, Z
5, m, and n are as described herein. [0194] In some embodiments, the disclosure provides a compound of the formula XI, or a pharmaceutically acceptable salt thereof,
[0195] wherein R
1, R
2, R
3, R
10, R
a, R
b, B, X, Z
1, Z
2, Z
3, Z
4, Z
5, n, p, and q are as described herein. [0196] In some embodiments, the disclosure provides a compound of the formula XII, or a pharmaceutically acceptable salt thereof,
[0197] wherein R
2, R
3, R
10, R
11, R
a, R
b, A, B, X, Z
1, Z
2, Z
3, Z
4, Z
5, m, n, p, and q are as described herein. [0198] In some embodiments, the disclosure provides a compound of the formula XIII, or a pharmaceutically acceptable salt thereof,
XIII [0199] wherein R
2, R
3, R
10, R
11, R
a, R
b, A, X, Z
1, Z
2, Z
3, Z
4, Z
5, Z
6, Z
7, m, n, p, and q are as described herein.
[0200] In some embodiments, the disclosure provides a compound of the formula XIV, or a pharmaceutically acceptable salt thereof,
XIV [0201] wherein R
2, R
10, R
11, R
a, R
b, A, X, Z
1, Z
2, Z
3, Z
4, Z
5, Z
6, Z
7, m, n, and q are as described herein. [0202] In some embodiments, the disclosure provides a compound of the formula XV, or a pharmaceutically acceptable salt thereof,
XV
[0203] wherein R, R, R , R , R , R, R, A, X, Z, Z, Z, Z, Z, m, n, p, and q are as described herein. [0204] In some embodiments, the disclosure provides a compound of the formula XVI, or a pharmaceutically acceptable salt thereof,
XVI [0205] wherein R
2, R
10, R
11, R
12, R
a, R
b, A, X, Z
1, Z
2, Z
3, Z
4, Z
5, m, n, and q are as described herein. [0206] In some embodiments, the disclosure provides a compound of the formula XVII, or a pharmaceutically acceptable salt thereof,
[0207] wherein R
2, R
3, R
10, R
11, R
13, R
a, R
b, A, X, Z
1, Z
2, Z
3, Z
4, Z
5, m, n, p, and q are as described herein. [0208] In some embodiments, the disclosure provides a compound of the formula XVIII, or a pharmaceutically acceptable salt thereof,
[0209] wherein R
2, R
10, R
11, R
13, R
a, R
b, A, X, Z
1, Z
2, Z
3, Z
4, Z
5, m, n, and q are as described herein.
[0210] In certain embodiments of the above aspects, the compound of Formula (I) (XXa) is a compound selected from those species described or exemplified in the detailed description below. [0211] In further aspects, the disclosure relates to a pharmaceutical composition comprising at least one compound of Formula (I)-(XXa) or a pharmaceutically acceptable salt thereof. Pharmaceutical compositions according to the disclosure may further comprise a pharmaceutically acceptable excipient. [0212] In further aspects, the disclosure relates to a compound of Formula (I)-(XXa), or a pharmaceutically acceptable salt thereof, for use as a medicament. [0213] In further aspects, the disclosure relates to a method of treating disease, such as cancer comprising administering to a subject in need of such treatment an effective amount of at least one compound of Formula (I)-(XXa), or a pharmaceutically acceptable salt thereof. [0214] In further aspects, the disclosure relates to use of a compound of Formula (I)-(XXa), or a pharmaceutically acceptable salt thereof, in the preparation of a medicament for the treatment of disease, such as cancer, and the use of such compounds and salts for treatment of such diseases. [0215] In further aspects, the disclosure relates to a method of inhibiting a Ras, such as K-Ras, comprising contacting a cell comprising one or more of Ras with an effective amount of at least one compound of Formula (I)-(XXa), or a pharmaceutically acceptable salt thereof, and/or with at least one pharmaceutical composition of the disclosure, wherein the contacting is in vitro, ex vivo, or in vivo. [0216] Additional embodiments, features, and advantages of the disclosure will be apparent from the following detailed description and through practice of the disclosure. The compounds of the present disclosure can be described as embodiments in any of the following enumerated clauses. It will be understood that any of the embodiments described herein can be used in connection with any other embodiments described herein to the extent that the embodiments do not contradict one another. [0217] 1. A compound of the formula I, or a pharmaceutically acceptable salt thereof,
[0218] wherein [0219] X is a -O-, -S-, or -NR
4-; [0220] Y is a bond, -O-, -S-, -S(O)-, -S(O)
2-, or –C(O)NR
10-; [0221] Z
1 is N or C(R
5); [0222] Z
2 is N or C(R
6); [0223] Z
3 is N or C(R
7); [0224] Z
4 is N or C(R
8); [0225] Z
5 is N or C(R
9); [0226] provided that at least two of Z
1-Z
5 are N; [0227] R
1 is H, deuterium, C
1-C
6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, or ring A, wherein each hydrogen atom in C
1-C
6 alkyl, C
2-C
6 alkenyl, or C
2-C
6 alkynyl is independently optionally substituted by deuterium, halogen, -R
e, -R
f, C
1-C
6 alkyl, C
1-C
6 haloalkyl, -OR
e, -OC(O)R
e, -OC(O)NR
eR
f, -OS(O)R
e, -OS(O)
2R
e, -OS(O)NR
eR
f, -OS(O)
2NR
eR
f, -SR
e, -S(O)R
e, -S(O)
2R
e, -S(O)NR
eR
f, -S(O)
2NR
eR
f, -NR
eR
f, -NR
eC(O)R
f, -NR
eC(O)OR
f, -NR
eC(O)NR
eR
f, -NR
eS(O)R
f, -NR
eS(O)
2R
f, -NR
eS(O)NR
eR
f, -NR
eS(O)
2NR
eR
f, -C(O)R
e, -C(O)OR
e, -C(O)NR
eR
f, -PR
eR
f, -P(O)R
eR
f, -P(O)
2R
eR
f, -P(O)NR
eR
f, -P(O)
2NR
eR
f, -P(O)OR
e, -P(O)
2OR
e’, -CN, or -NO
2; and when Y is a bond, -O-, –S-, or –S(O)-, then R
1 is ring A; [0228] each R
2 is independently deuterium, halogen, C2-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C
3-C
6 cycloalkyl, 4- to 10-membered heterocycloalkyl, C
6-C
10 aryl, 5- to 10- membered heteroaryl, -OR
c, -OC(O)R
c, -OC(O)NR
cR
d, -OC(=NR
c)NR
cR
d, -OS(O)R
c, -OS(O)
2R
c, -OS(O)NR
cR
d, -OS(O)
2NR
cR
d, -SR
c, -S(O)R
c, -S(O)
2R
c, -S(O)NR
cR
d, -S(O)
2NR
cR
d, -NR
cR
d, -NR
cC(O)R
d, -N(C(O)R
c)(C(O)R
d), -NR
cC(O)OR
d, -NR
cC(O)NR
cR
d, -NR
cC(=NR
c)NR
cR
d, -NR
cS(O)R
d, -NR
cS(O)
2R
d, -NR
cS(O)NR
cR
d, -NR
cS(O)
2NR
cR
d, - C(O)R
c, -C(O)OR
c, -C(O)NR
cR
d, -C(=NR
c)NR
cR
d, -PR
cR
d, -P(O)R
cR
d, -P(O)
2R
cR
d, -
P(O)NR R , P(O)
2NR R , P(O)OR , P(O)
2OR , CN, or NO
2, or two of R taken together with the atoms to which they are attached form a C
3-C
6 cycloalkyl or a 4- to 10-membered heterocycloalkyl, wherein each hydrogen atom in C
1-C
6 alkyl, C
2-C
6 alkenyl, C
2-C
6 alkynyl, C
3-C
6 cycloalkyl, C
6-C
10 aryl, 5- to 10-membered heteroaryl, and 4- to 10-membered heterocycloalkyl is independently optionally substituted by deuterium, halogen, C
1-C
6 alkyl, C
1-C
6 haloalkyl, -R
e, -R
f, -OR
e, -OC(O)R
e, -OC(O)NR
eR
f, -OS(O)R
e, -OS(O)
2R
e, -OS(O)NR
eR
f, -OS(O)
2NR
eR
f, -SR
e, -S(O)R
e, -S(O)
2R
e, -S(O)NR
eR
f, -S(O)
2NR
eR
f, -NR
eR
f, -NR
eC(O)R
f, -NR
eC(O)OR
f, -NR
eC(O)NR
eR
f, -NR
eS(O)R
f, -NR
eS(O)
2R
f, -NR
eS(O)NR
eR
f, -NR
eS(O)
2NR
eR
f, -C(O)R
e, -C(O)OR
e, -C(O)NR
eR
f, -PR
eR
f, -P(O)R
eR
f, -P(O)
2R
eR
f, -P(O)NR
eR
f, -P(O)
2NR
eR
f, -P(O)OR
e, -P(O)
2OR
e, -CN, or -NO
2; [0229] R
3 is -C
1-C
6 alkyl, -C2-C6 alkenyl, -C2-C6 alkynyl, -C
3-C
6 cycloalkyl, 4- to 10- membered heterocycloalkyl, -C
1-C
6 alkylene-(4- to 10-membered heterocycloalkyl), -C
6-C
10 aryl, -C
1-C
6 alkylene-(C
6-C
10 aryl), 5- to 10-membered heteroaryl, or -C
1-C
6 alkylene-(4- to 10-membered heterocycloalkyl), wherein each hydrogen atom in C
1-C
6 alkyl, C
2-C
6 alkenyl, C2-C6 alkynyl, C
3-C
6 cycloalkyl, 4- to 10-membered heterocycloalkyl, -C
1-C
6 alkylene-(4- to 10-membered heterocycloalkyl), C
6-C
10 aryl, -C
1-C
6 alkylene-(C
6-C
10 aryl), 5- to 10- membered heteroaryl, and -C
1-C
6 alkylene-(5- to 10-membered heteroaryl), is independently optionally substituted by deuterium, halogen, -R
e, -R
f, C
1-C
6 alkyl, -C
1-C
6 alkyl-O-C
1-C
6 alkyl, -OC
1-C
6 alkyl-O-C
1-C
6 alkyl, -C
1-C
6 alkyl-O-R
a, C
6-C
10 aryl, -C
1-C
6 alkyl-(C
6-C
10 aryl), haloalkyl, C
3-C
6 cycloalkyl, 5- to 10-membered heteroaryl, -C
1-C
6 alkyl-(5- to 10-membered heterocycloalkyl), -OR
e, -OC(O)R
e, -OC(O)NR
eR
f, -OS(O)R
e, -OS(O)
2R
e, -OS(O)NR
eR
f, -OS(O)
2NR
eR
f, -SR
e, -S(O)R
e, -S(O)
2R
e, -S(O)NR
eR
f, -S(O)
2NR
eR
f, -NR
eR
f, -NR
eC(O)R
f, -NR
eC(O)OR
f, -NR
eC(O)NR
eR
f, -NR
eC(=NR
f)NR
eR
f, -NR
eS(O)R
f, -NR
eS(O)
2R
f, -NR
eS(O)NR
eR
f, -NR
eS(O)
2NR
eR
f, -C(O)R
e, -C(O)OR
e, -C(O)NR
eR
f, -PR
eR
f, -P(O)R
eR
f, -P(O)
2R
eR
f, -P(O)NR
eR
f, -P(O)
2NR
eR
f, -P(O)OR
e, -P(O)
2OR
e’, -CN, or -NO
2; [0230] each of R
4 and R
10 is independently H, deuterium, C
1-C
6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C
3-C
6 cycloalkyl, 4- to 10-membered heterocycloalkyl, C
6-C
10 aryl, or 5- to 10- membered heteroaryl, wherein each hydrogen atom in C
1-C
6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C
3-C
6 cycloalkyl, 4- to 10-membered heterocycloalkyl, C
6-C
10 aryl, and 5- to 10- membered heteroaryl is independently optionally substituted by deuterium, halogen, -R
e, -R
f, C
1-C
6 alkyl, C
1-C
6 haloalkyl, -OR
e, -OC(O)R
e, -OC(O)NR
eR
f, -OS(O)R
e, -OS(O)
2R
e, - OS(O)NR
eR
f, -OS(O)
2NR
eR
f, -SR
e, -S(O)R
e, -S(O)
2R
e, -S(O)NR
eR
f, -S(O)
2NR
eR
f, -NR
eR
f, - NR
eC(O)R
f, -NR
eC(O)OR
f, -NR
eC(O)NR
eR
f, -NR
eS(O)R
f, -NR
eS(O)
2R
f, -NR
eS(O)NR
eR
f, - NR
eS(O)
2NR
eR
f, -C(O)R
e, -C(O)OR
e, -C(O)NR
eR
f, -PR
eR
f, -P(O)R
eR
f, -P(O)
2R
eR
f, - P(O)NR
eR
f, -P(O)
2NR
eR
f, -P(O)OR
e, -P(O)
2OR
e’, -CN, or -NO2; or R
1 and R
10 taken together
with the atom or atoms to which they are attached combine to form a monocyclic 4 to 10 membered heterocycloalkyl, a fused bicyclic 5- to 10-membered heterocycloalkyl, or a bridged bicyclic 6- to 10-membered heterocycloalkyl, wherein each hydrogen atom in the monocyclic 4- to 10-membered heterocycloalkyl, fused bicyclic 5- to 10-membered heterocycloalkyl, or a bridged bicyclic 6- to 10-membered heterocycloalkyl is independently optionally substituted by deuterium, halogen, C
1-C
6 alkyl, C
1-C
6 haloalkyl, -OH, -OC
1-C
6 alkyl, -OC(O)C
1-C
6 alkyl, -OC(O)N(H or C
1-C
6 alkyl)
2, -OS(O)C
1-C
6 alkyl, -OS(O)
2C
1-C
6 alkyl, -OS(O)N(H or C
1-C
6 alkyl)
2, -OS(O)
2N(H or C
1-C
6 alkyl)
2, -SC
1-C
6 alkyl, -S(O)C
1-C
6 alkyl, -S(O)
2C
1-C
6 alkyl, -S(O)N(H or C
1-C
6 alkyl)
2, -S(O)
2N(H or C
1-C
6 alkyl)
2, -N(H or C
1-C
6 alkyl)
2, -N(C
1-C
6 alkyl)C(O)-C
1-C
6 alkyl, -N(C
1-C
6 alkyl)C(O)OC
1-C
6 alkyl, -N(C
1-C
6 alkyl)C(O)N(H or C
1-C
6 alkyl)
2, -N(C
1-C
6 alkyl)S(O)C
1-C
6 alkyl, -N(C
1-C
6 alkyl)S(O)
2C1- C
6 alkyl, -N(C
1-C
6 alkyl)S(O)N(H or C
1-C
6 alkyl)
2, -N(C
1-C
6 alkyl)S(O)
2N(H or C
1-C
6 alkyl)
2, -C(O)C
1-C
6 alkyl, -C(O)OC
1-C
6 alkyl, -C(O)N(H or C
1-C
6 alkyl)
2, -P(H or C
1-C
6 alkyl)
2, -P(O)(H or C
1-C
6 alkyl)
2, -P(O)
2(H or C
1-C
6 alkyl)
2, -P(O)N(H or C
1-C
6 alkyl)
2, -P(O)
2N(H or C
1-C
6 alkyl)
2, -P(O)OC
1-C
6 alkyl, -P(O)
2OC
1-C
6 alkyl, -CN, or -NO2, or two hydrogen atoms on a single carbon atom of the monocyclic 4- to 10-membered heterocycloalkyl, fused bicyclic 5- to 10-membered heterocycloalkyl, or bridged bicyclic 6- to 10-membered heterocycloalkyl combine to form an oxo group or an alkenyl group; [0231] each of R
5, R
6, R
7, R
8, and R
9 is independently H, deuterium, halogen, C
1-C
6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C
3-C
6 cycloalkyl, 4- to 10-membered heterocycloalkyl, C
6-C
10 aryl, 5- to 10-membered heteroaryl, -OR
g, -OC(O)R
g, -OC(O)NR
gR
h, -OS(O)R
g, -OS(O)
2R
g, -SR
g, -S(O)R
g, -S(O)
2R
g, -S(O)NR
gR
h, -S(O)
2NR
gR
h, -OS(O)NR
gR
h, -OS(O)
2NR
gR
h, -NR
gR
h, -NR
gC(O)R
h, -NR
gC(O)OR
h, -NR
gC(O)NR
gR
h, -NR
gS(O)R
h, -NR
gS(O)
2R
h, -NR
gS(O)NR
gR
h, -NR
gS(O)
2NR
gR
h, -C(O)R
g, -C(O)OR
g, -C(O)NR
gR
h, -PR
gR
h, -P(O)R
gR
h, -P(O)
2R
gR
h, -P(O)NR
gR
h, -P(O)
2NR
gR
h, -P(O)OR
g, -P(O)
2OR
g, -CN, or -NO2; [0232] ring A is a C
3-C
8 cycloalkyl, 4- to 10-membered heterocycloalkyl, C
6-C
10 aryl, or 5- to 10-membered heteroaryl, wherein each of C
3-C8 cycloalkyl, 4- to 10-membered heterocycloalkyl, C
6-C
10 aryl, or 5- to 10-membered heteroaryl is unsubstituted or substituted with one or more of R
11; [0233] each R
11 is independently deuterium, halogen, C
1-C
6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C
3-C
6 cycloalkyl, 4- to 10-membered heterocycloalkyl, C
6-C
10 aryl, 5- to 10- membered heteroaryl, -OR
a, -OC(O)R
a, -OC(O)NR
aR
b, -OC(=NR
a)NR
aR
b, -OS(O)R
a, -OS(O)
2R
a, -OS(O)NR
aR
b, -OS(O)
2NR
aR
b, -SR
a, -S(O)R
a, -S(O)
2R
a, -S(O)NR
aR
b, -S(O)
2NR
aR
b, -NR
aR
b, -NR
aC(O)R
b, -N(C(O)R
a)(C(O)R
b), -NR
aC(O)OR
b, -NR
aC(O)NR
aR
b,
NR C( NR )NR R , NR S(O)R , NR S(O)
2R , NR S(O)NR R , NR S(O)
2NR R , C(O)R
a, -C(O)OR
a, -C(O)NR
aR
b, -C(=NR
a)NR
aR
b, -PR
aR
b, -P(O)R
aR
b, -P(O)
2R
aR
b, - P(O)NR
aR
b, -P(O)
2NR
aR
b, -P(O)OR
a, -P(O)
2OR
a, -CN, or -NO
2, or two of R
11 taken together with the atom or atoms to which they are attached or three of R
11 taken together with the atoms to which they are attached, form a C
3-C
6 cycloalkyl or a 4- to 10-membered heterocycloalkyl, wherein each hydrogen atom in C
1-C
6 alkyl, C
2-C
6 alkenyl, C
2-C
6 alkynyl, C
3-C
6 cycloalkyl, C
6-C
10 aryl, 5- to 10-membered heteroaryl, and 4- to 10-membered heterocycloalkyl is independently optionally substituted by deuterium, halogen, -R
e, -R
f, C
1- C6 alkyl, C
1-C
6 haloalkyl, -OR
e, -OC(O)R
e, -OC(O)NR
eR
f, -OS(O)R
e, -OS(O)
2R
e, -OS(O)NR
eR
f, -OS(O)
2NR
eR
f, -SR
e, -S(O)R
e, -S(O)
2R
e, -S(O)NR
eR
f, -S(O)
2NR
eR
f, -NR
eR
f, -NR
eC(O)R
f, -NR
eC(O)OR
f, -NR
eC(O)NR
eR
f, -NR
eS(O)R
f, -NR
eS(O)
2R
f, -NR
eS(O)NR
eR
f, -NR
eS(O)
2NR
eR
f, -C(O)R
e, -C(O)OR
e, -C(O)NR
eR
f, -PR
eR
f, -P(O)R
eR
f, -P(O)
2R
eR
f, -P(O)NR
eR
f, -P(O)
2NR
eR
f, -P(O)OR
e, -P(O)
2OR
e, -CN, or -NO2, or two of R
11 taken together with the carbon atom to which they are attached form an oxo group or an alkenyl group; [0234] ring B is a C
6-C
10 aryl or 5- to 10-membered heteroaryl; [0235] each R
a, R
b, R
c, R
d, R
e, R
f, R
g, and R
h is independently selected from the group consisting of H, deuterium, C
1-C
6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C
3-C
6 cycloalkyl, 4- to 10-membered heterocycloalkyl, C
6-C
10 aryl, C
1-C
6 alkyl-C
6-C
10 aryl, and 5- to 10-membered heteroaryl; or two of R
a and R
b, or R
c and R
d, or R
e and R
f, or R
g and R
h, taken together with the atom or atoms to which they are attached, combine to form a C
3-C
6 cycloalkyl, 4- to 10- membered heterocycloalkyl, C
6-C
10 aryl, or 5- to 10-membered heteroaryl, wherein each hydrogen atom in C
1-C
6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C
3-C
6 cycloalkyl, 4- to 10- membered heterocycloalkyl, C
6-C
10 aryl, C
1-C
6 alkyl-C
6-C
10 aryl, and 5- to 10-membered heteroaryl is independently optionally substituted by deuterium, halogen, C
1-C
6 alkyl, C
1-C
6 haloalkyl, -OH, -OC
1-C
6 alkyl, -OC(O)C
1-C
6 alkyl, -OC(O)N(H or C
1-C
6 alkyl)
2, -OS(O)C
1- C6 alkyl, -OS(O)
2C
1-C
6 alkyl, -OS(O)N(H or C
1-C
6 alkyl)
2, -OS(O)
2N(H or C
1-C
6 alkyl)
2, - SC
1-C
6 alkyl, -S(O)C
1-C
6 alkyl, -S(O)
2C
1-C
6 alkyl, -S(O)N(H or C
1-C
6 alkyl)
2, -S(O)
2N(H or C
1-C
6 alkyl)
2, -N(H or C
1-C
6 alkyl)
2, -N(C
1-C
6 alkyl)C(O)-C
1-C
6 alkyl, -N(C
1-C
6 alkyl)C(O)OC
1-C
6 alkyl, -N(C
1-C
6 alkyl)C(O)N(H or C
1-C
6 alkyl)
2, -N(C
1-C
6 alkyl)S(O)C1- C6 alkyl, -N(C
1-C
6 alkyl)S(O)
2C
1-C
6 alkyl, -N(C
1-C
6 alkyl)S(O)N(H or C
1-C
6 alkyl)
2, -N(C1- C6 alkyl)S(O)
2N(H or C
1-C
6 alkyl)
2, -C(O)C
1-C
6 alkyl, -C(O)OC
1-C
6 alkyl, -C(O)N(H or C1- C
6 alkyl)
2, -P(H or C
1-C
6 alkyl)
2, -P(O)(H or C
1-C
6 alkyl)
2, -P(O)
2(H or C
1-C
6 alkyl)
2, - P(O)N(H or C
1-C
6 alkyl)
2, -P(O)
2N(H or C
1-C
6 alkyl)
2, -P(O)OC
1-C
6 alkyl, -P(O)
2OC
1-C
6 alkyl, -CN, or -NO
2, or -R
e and -R
f taken together with the carbon atom to which they are attached form an oxo groups or an alkenyl;
[0236] n is 0, 1, 2, 3, 4, 5, 6, or 7, provided that when B is C
6 C
10 aryl, n is 2, 3, 4, 5, 6, or 7, and when B is 5- to 10-membered heteroaryl, n is 1, 2, 3, 4, 5, 6, or 7; [0237] p is 0 or 1; and [0238] q is 0, 1, or 2; [0239] and wherein the compound is not of the formula
[0240] 2. The compound of clause 1, wherein at least one hydrogen atom on ring A, ring B, R
1, or R
3 in the compound of the formula I is substituted by a deuterium. [0241] 3. The compound of clause 1, wherein the compound is of the formula II or III
[0242] or a pharmaceutically acceptable salt thereof. [0243] 4. The compound of any one of clauses 1 to 3, or a pharmaceutically acceptable salt thereof, wherein the compound is of the formula V, VII, or IX
[0244] wherein [0245] Z
6 is N or C(R
14); [0246] Z
7 is N or C(R
15); [0247] R
12 is H, deuterium, C
1-C
6 alkyl, C
2-C
6 alkenyl, C
2-C
6 alkynyl, C
3-C
6 cycloalkyl, 4- to 10-membered heterocycloalkyl, C
6-C
10 aryl, or 5- to 10-membered heteroaryl, wherein each hydrogen atom in C
1-C
6 alkyl, C
2-C
6 alkenyl, C
2-C
6 alkynyl, C
3-C
6 cycloalkyl, 4- to 10- membered heterocycloalkyl, C
6-C
10 aryl, and 5- to 10-membered heteroaryl is independently optionally substituted by deuterium, halogen, -R
e, -R
f, C
1-C
6 alkyl, C
1-C
6 haloalkyl, -OR
e, -OC(O)R
e, -OC(O)NR
eR
f, -OS(O)R
e, -OS(O)
2R
e, -OS(O)NR
eR
f, -OS(O)
2NR
eR
f, -SR
e, -S(O)R
e, -S(O)
2R
e, -S(O)NR
eR
f, -S(O)
2NR
eR
f, -NR
eR
f, -NR
eC(O)R
f, -NR
eC(O)OR
f, -NR
eC(O)NR
eR
f, -NR
eS(O)R
f, -NR
eS(O)
2R
f, -NR
eS(O)NR
eR
f, -NR
eS(O)
2NR
eR
f, -C(O)R
e, -C(O)OR
e, -C(O)NR
eR
f, -PR
eR
f, -P(O)R
eR
f, -P(O)
2R
eR
f, -P(O)NR
eR
f, -P(O)
2NR
eR
f, -P(O)OR
e, -P(O)
2OR
e’, -CN, or -NO
2;
[0248] R is H, deuterium, C
1 C
6 alkyl, C
2 C
6 alkenyl, C
2 C
6 alkynyl, C
3 C
6 cycloalkyl, 4 to 10-membered heterocycloalkyl, C
6-C
10 aryl, or 5- to 10-membered heteroaryl, wherein each hydrogen atom in C
1-C
6 alkyl, C
2-C
6 alkenyl, C
2-C
6 alkynyl, C
3-C
6 cycloalkyl, 4- to 10- membered heterocycloalkyl, C
6-C
10 aryl, and 5- to 10-membered heteroaryl is independently optionally substituted by deuterium, halogen, -R
e, -R
f, C
1-C
6 alkyl, C
1-C
6 haloalkyl, -OR
e, -OC(O)R
e, -OC(O)NR
eR
f, -OS(O)R
e, -OS(O)
2R
e, -OS(O)NR
eR
f, -OS(O)
2NR
eR
f, -SR
e, -S(O)R
e, -S(O)
2R
e, -S(O)NR
eR
f, -S(O)
2NR
eR
f, -NR
eR
f, -NR
eC(O)R
f, -NR
eC(O)OR
f, -NR
eC(O)NR
eR
f, -NR
eS(O)R
f, -NR
eS(O)
2R
f, -NR
eS(O)NR
eR
f, -NR
eS(O)
2NR
eR
f, -C(O)R
e, -C(O)OR
e, -C(O)NR
eR
f, -PR
eR
f, -P(O)R
eR
f, -P(O)
2R
eR
f, -P(O)NR
eR
f, -P(O)
2NR
eR
f, -P(O)OR
e, -P(O)
2OR
e’, -CN, or -NO
2; and [0249] each of R
14 and R
15 is independently H, deuterium, halogen, C
1-C
6 alkyl, C2-C6 alkenyl, C
2-C
6 alkynyl, C
3-C
6 cycloalkyl, 4- to 10-membered heterocycloalkyl, C
6-C
10 aryl, 5- to 10-membered heteroaryl, -OR
g, -OC(O)R
g, -OC(O)NR
gR
h, -OS(O)R
g, -OS(O)
2R
g, -SR
g, -S(O)R
g, -S(O)
2R
g, -S(O)NR
gR
h, -S(O)
2NR
gR
h, -OS(O)NR
gR
h, -OS(O)
2NR
gR
h, -NR
gR
h, -NR
gC(O)R
h, -NR
gC(O)OR
h, -NR
gC(O)NR
gR
h, -NR
gS(O)R
h, -NR
gS(O)
2R
h, - NR
gS(O)NR
gR
h, -NR
gS(O)
2NR
gR
h, -C(O)R
g, -C(O)OR
g, -C(O)NR
gR
h, -PR
gR
h, -P(O)R
gR
h, - P(O)
2R
gR
h, -P(O)NR
gR
h, -P(O)
2NR
gR
h, -P(O)OR
g, -P(O)
2OR
g, -CN, or -NO2. [0250] or a pharmaceutically acceptable salt thereof. [0251] 5. The compound of any one of the preceding clauses, wherein R
1 is ring A, and ring A is a C
3-C8 cycloalkyl, C
6-C
10 aryl, or 5- to 10-membered heteroaryl, or a 4- to 10- membered heterocycloalkyl that is covalently attached to –Y-, -(CR
aR
b)
n-, or
through a carbon atom in the 4- to 10-membered heterocycloalkyl, wherein each of C
3-C8 cycloalkyl, C
6-C
10 aryl, 5- to 10-membered heteroaryl, and 4- to 10- membered heterocycloalkyl is unsubstituted or substituted with one or more of R
11. [0252] 6. The compound of clause 1, wherein R
1 is H, deuterium, C
1-C
6 alkyl, C2-C6 alkenyl, or C
2-C
6 alkynyl, wherein each hydrogen atom in C
1-C
6 alkyl, C
2-C
6 alkenyl, or C
2-C
6 alkynyl is independently optionally substituted by deuterium, halogen, -R
e, -R
f, C
1-C
6 alkyl, C
1-C
6 haloalkyl, -OR
e, -OC(O)R
e, -OC(O)NR
eR
f, -OS(O)R
e, -OS(O)
2R
e, -OS(O)NR
eR
f, -OS(O)
2NR
eR
f, -SR
e, -S(O)R
e, -S(O)
2R
e, -S(O)NR
eR
f, -S(O)
2NR
eR
f, -NR
eR
f, -NR
eC(O)R
f, -NR
eC(O)OR
f, -NR
eC(O)NR
eR
f, -NR
eS(O)R
f, -NR
eS(O)
2R
f, -NR
eS(O)NR
eR
f, - NR
eS(O)
2NR
eR
f, -C(O)R
e, -C(O)OR
e, -C(O)NR
eR
f, -PR
eR
f, -P(O)R
eR
f, -P(O)
2R
eR
f, - P(O)NR
eR
f, -P(O)
2NR
eR
f, -P(O)OR
e, -P(O)
2OR
e’, -CN, or -NO
2.
[0253] 7. The compound of clause 1, wherein the compound is of the formula XI
[0254] or a pharmaceutically acceptable salt thereof. [0255] 8. The compound of any one of clauses 1, 2, or 7, or a pharmaceutically acceptable salt thereof, wherein the compound is of the formula XII, XIII, XV, or XVII
[0256] wherein [0257] Z
6 is N or C(R
14); [0258] Z
7 is N or C(R
15); [0259] R
12 is H, deuterium, C
1-C
6 alkyl, C
2-C
6 alkenyl, C
2-C
6 alkynyl, C
3-C
6 cycloalkyl, 4- to 10-membered heterocycloalkyl, C
6-C
10 aryl, or 5- to 10-membered heteroaryl, wherein each hydrogen atom in C
1-C
6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C
3-C
6 cycloalkyl, 4- to 10- membered heterocycloalkyl, C
6-C
10 aryl, and 5- to 10-membered heteroaryl is independently optionally substituted by deuterium, halogen, -R
e, -R
f, C
1-C
6 alkyl, C
1-C
6 haloalkyl, -OR
e, -OC(O)R
e, -OC(O)NR
eR
f, -OS(O)R
e, -OS(O)
2R
e, -OS(O)NR
eR
f, -OS(O)
2NR
eR
f, -SR
e, -S(O)R
e, -S(O)
2R
e, -S(O)NR
eR
f, -S(O)
2NR
eR
f, -NR
eR
f, -NR
eC(O)R
f, -NR
eC(O)OR
f, -NR
eC(O)NR
eR
f, -NR
eS(O)R
f, -NR
eS(O)
2R
f, -NR
eS(O)NR
eR
f, -NR
eS(O)
2NR
eR
f, -C(O)R
e, -C(O)OR
e, -C(O)NR
eR
f, -PR
eR
f, -P(O)R
eR
f, -P(O)
2R
eR
f, -P(O)NR
eR
f, -P(O)
2NR
eR
f, -P(O)OR
e, -P(O)
2OR
e’, -CN, or -NO
2; [0260] R
13 is H, deuterium, C
1-C
6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C
3-C
6 cycloalkyl, 4- to 10-membered heterocycloalkyl, C
6-C
10 aryl, or 5- to 10-membered heteroaryl, wherein each hydrogen atom in C
1-C
6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C
3-C
6 cycloalkyl, 4- to 10- membered heterocycloalkyl, C
6-C
10 aryl, and 5- to 10-membered heteroaryl is independently optionally substituted by deuterium, halogen, -R
e, -R
f, C
1-C
6 alkyl, C
1-C
6 haloalkyl, -OR
e, -OC(O)R
e, -OC(O)NR
eR
f, -OS(O)R
e, -OS(O)
2R
e, -OS(O)NR
eR
f, -OS(O)
2NR
eR
f, -SR
e, -S(O)R
e, -S(O)
2R
e, -S(O)NR
eR
f, -S(O)
2NR
eR
f, -NR
eR
f, -NR
eC(O)R
f, -NR
eC(O)OR
f, -NR
eC(O)NR
eR
f, -NR
eS(O)R
f, -NR
eS(O)
2R
f, -NR
eS(O)NR
eR
f, -NR
eS(O)
2NR
eR
f, -C(O)R
e,
C(O)OR , C(O)NR R, PR R, P(O)R R, P(O)
2R R, P(O)NR R, P(O)
2NR R, -P(O)OR
e, -P(O)
2OR
e’, -CN, or -NO2; and [0261] each of R
14 and R
15 is independently H, deuterium, halogen, C
1-C
6 alkyl, C
2-C
6 alkenyl, C2-C6 alkynyl, C
3-C
6 cycloalkyl, 4- to 10-membered heterocycloalkyl, C
6-C
10 aryl, 5- to 10-membered heteroaryl, -OR
g, -OC(O)R
g, -OC(O)NR
gR
h, -OS(O)R
g, -OS(O)
2R
g, -SR
g, -S(O)R
g, -S(O)
2R
g, -S(O)NR
gR
h, -S(O)
2NR
gR
h, -OS(O)NR
gR
h, -OS(O)
2NR
gR
h, -NR
gR
h, -NR
gC(O)R
h, -NR
gC(O)OR
h, -NR
gC(O)NR
gR
h, -NR
gS(O)R
h, -NR
gS(O)
2R
h, - NR
gS(O)NR
gR
h, -NR
gS(O)
2NR
gR
h, -C(O)R
g, -C(O)OR
g, -C(O)NR
gR
h, -PR
gR
h, -P(O)R
gR
h, - P(O)
2R
gR
h, -P(O)NR
gR
h, -P(O)
2NR
gR
h, -P(O)OR
g, -P(O)
2OR
g, -CN, or -NO2. [0262] 9. The compound of clause 1 or 2, wherein the compound is of the formula XIX
[0263] or a pharmaceutically acceptable salt thereof. [0264] 10. The compound of any one of the preceding clauses, or a pharmaceutically acceptable salt thereof, wherein R
3, when present, is -C
1-C
6 alkyl, 4- to 10-membered heterocycloalkyl, or -C
1-C
6 alkylene-(4- to 10-membered heterocycloalkyl), wherein each hydrogen atom in -C
1-C
6 alkyl, 4- to 10-membered heterocycloalkyl, or -C
1-C
6 alkylene-(4- to 10-membered heterocycloalkyl), is independently optionally substituted by deuterium, halogen, C
1-C
6 alkyl, -C
1-C
6 alkyl-O-C
1-C
6 alkyl, -OC
1-C
6 alkyl-O-C
1-C
6 alkyl, -C
1-C
6 alkyl- O-R
a, C
6-C
10 aryl, -C
1-C
6 alkyl-(C
6-C
10 aryl), haloalkyl, C
3-C
6 cycloalkyl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocycloalkyl, -C
1-C
6 alkyl-(4- to 10-membered heterocycloalkyl), -OR
e, -OC(O)R
e, -OC(O)NR
eR
f, -OS(O)R
e, -OS(O)
2R
e, -OS(O)NR
eR
f, -OS(O)
2NR
eR
f, -SR
e, -S(O)R
e, -S(O)
2R
e, -S(O)NR
eR
f, -S(O)
2NR
eR
f, -NR
eR
f, -NR
eC(O)R
f, -NR
eC(O)OR
f, -NR
eC(O)NR
eR
f, -NR
eC(=NR
f)NR
eR
f, -NR
eS(O)R
f, -NR
eS(O)
2R
f, -NR
eS(O)NR
eR
f, -NR
eS(O)
2NR
eR
f, -C(O)R
e, -C(O)OR
e, -C(O)NR
eR
f, -PR
eR
f, -P(O)R
eR
f, -P(O)
2R
eR
f, -P(O)NR
eR
f, -P(O)
2NR
eR
f, -P(O)OR
e, -P(O)
2OR
e’, -CN, or -NO2. [0265] 11. The compound of any one of the preceding clauses, or a pharmaceutically acceptable salt thereof, wherein R
3, when present, is –C
1-C
6 alkyl-(4- to 10-membered
heterocycloalkyl), wherein each hydrogen atom in methyl, ethyl, propyl, or C
1 C
6 alkyl (4 to 10-membered heterocycloalkyl), is independently optionally substituted by deuterium, halogen, C
1-C
6 alkyl, -C
1-C
6 alkyl-O-C
1-C
6 alkyl, -OC
1-C
6 alkyl-O-C
1-C
6 alkyl, -C
1-C
6 alkyl- O-R
a, C
6-C
10 aryl, -C
1-C
6 alkyl-(C
6-C
10 aryl), haloalkyl, C
3-C
6 cycloalkyl, 5- to 10-membered heteroaryl, or -C
1-C
6 alkyl-(4- to 10-membered heterocycloalkyl), -OR
e, -OC(O)R
e, -OC(O)NR
eR
f, -OS(O)R
e, -OS(O)
2R
e, -OS(O)NR
eR
f, -OS(O)
2NR
eR
f, -SR
e, -S(O)R
e, -S(O)
2R
e, -S(O)NR
eR
f, -S(O)
2NR
eR
f, -NR
eR
f, -NR
eC(O)R
f, -NR
eC(O)OR
f, -NR
eC(O)NR
eR
f, -NR
eC(=NR
f)NR
eR
f, -NR
eS(O)R
f, -NR
eS(O)
2R
f, -NR
eS(O)NR
eR
f, -NR
eS(O)
2NR
eR
f, -C(O)R
e, -C(O)OR
e, -C(O)NR
eR
f, -PR
eR
f, -P(O)R
eR
f, -P(O)
2R
eR
f, - P(O)NR
eR
f, -P(O)
2NR
eR
f, -P(O)OR
e, -P(O)
2OR
e’, -CN, or -NO
2. [0266] 12. The compound of any one of the preceding clauses, or a pharmaceutically acceptable salt thereof, wherein R
3, when present, is
[0267] wherein each hydrogen atom is independently optionally substituted by deuterium, halogen, C
1-C
6 alkyl, -C
1-C
6 alkyl-O-C
1-C
6 alkyl, -OC
1-C
6 alkyl-O-C
1-C
6 alkyl, C
6-C
10 aryl, -C
1-C
6 alkyl-(C
6-C
10 aryl), haloalkyl, C
3-C
6 cycloalkyl, 5- to 10-membered heteroaryl, -C
1-C
6 alkyl-(5- to 10-membered heterocycloalkyl), -OR
e, -OC(O)R
e, -OC(O)NR
eR
f, -OS(O)R
e, -OS(O)
2R
e, -OS(O)NR
eR
f, -OS(O)
2NR
eR
f, -SR
e, -S(O)R
e, -S(O)
2R
e, -S(O)NR
eR
f, -S(O)
2NR
eR
f, -NR
eR
f, -NR
eC(O)R
f, -NR
eC(O)OR
f, -NR
eC(O)NR
eR
f, -NR
eC(=NR
f)NR
eR
f, -NR
eS(O)R
f, -NR
eS(O)
2R
f, -NR
eS(O)NR
eR
f, -NR
eS(O)
2NR
eR
f, -C(O)R
e, -C(O)OR
e, -C(O)NR
eR
f, -PR
eR
f, -P(O)R
eR
f, -P(O)
2R
eR
f, -P(O)NR
eR
f, -P(O)
2NR
eR
f, -P(O)OR
e, -P(O)
2OR
e’, -CN, or -NO
2, and “
” is a point of covalent attachment. [0268] 13. The compound of any one of the preceding clauses, wherein the compound is of the formula IV, IVa, VI, VIa, VIIIa, VIIIb, Xa, Xb, XIV, XIVa, XVIa, XVIb, XVIIIa, XVIIIb, XX, or XXa
[0269] or a pharmaceutically acceptable salt thereof. [0270] 14. The compound of any one of clauses 1 to 10, or a pharmaceutically acceptable salt thereof, wherein R
3, when present, is 4- to 10-membered heterocycloalkyl, wherein each hydrogen atom in 4- to 10-membered heterocycloalkyl is independently optionally
substituted by deuterium, halogen, C
1 C
6 alkyl, C
1 C
6 alkyl O C
1 C
6 alkyl, OC
1 C
6 alkyl O C
1-C
6 alkyl, -C
1-C
6 alkyl-O-R
a, C
6-C
10 aryl, -C
1-C
6 alkyl-(C
6-C
10 aryl), haloalkyl, C
3-C
6 cycloalkyl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocycloalkyl, -C
1-C
6 alkyl- (4- to 10-membered heterocycloalkyl), -OR
e, -OC(O)R
e, -OC(O)NR
eR
f, -OS(O)R
e, -OS(O)
2R
e, -OS(O)NR
eR
f, -OS(O)
2NR
eR
f, -SR
e, -S(O)R
e, -S(O)
2R
e, -S(O)NR
eR
f, -S(O)
2NR
eR
f, -NR
eR
f, -NR
eC(O)R
f, -NR
eC(O)OR
f, -NR
eC(O)NR
eR
f, -NR
eC(=NR
f)NR
eR
f, -NR
eS(O)R
f, -NR
eS(O)
2R
f, -NR
eS(O)NR
eR
f, -NR
eS(O)
2NR
eR
f, -C(O)R
e, -C(O)OR
e, -C(O)NR
eR
f, -PR
eR
f, -P(O)R
eR
f, -P(O)
2R
eR
f, -P(O)NR
eR
f, -P(O)
2NR
eR
f, -P(O)OR
e, -P(O)
2OR
e’, -CN, or -NO2. [0271] 15. The compound of any one of clauses 1 to 10, or 14, or a pharmaceutically acceptable salt thereof, wherein R
3, when present, is
[0272] wherein “ ” is a point of covalent attachment. [0273] 16. The compound of clause 1 or 2, or a pharmaceutically acceptable salt thereof, wherein Y is a bond. [0274] 17. The compound of clause 1 or 2, or a pharmaceutically acceptable salt thereof, wherein Y is -O-, -S-, or -S(O)- , and R
1 is ring A. [0275] 18. The compound of clause 1 or 2, or a pharmaceutically acceptable salt thereof, wherein Y is -S(O)
2- or –C(O)NR
10-. [0276] 19. The compound of any one of the preceding clauses, or a pharmaceutically acceptable salt thereof, wherein m, when present, is 0, 1, 2, 3, 4, 5, 6, or 7. [0277] 20. The compound of any one of the preceding clauses, or a pharmaceutically acceptable salt thereof, wherein n is 0, 1, 2, or 3. [0278] 21. The compound of any one of the preceding clauses, or a pharmaceutically acceptable salt thereof, wherein each R
11 is independently deuterium, halogen, C
1-C
6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C
3-C
6 cycloalkyl, 4- to 10-membered heterocycloalkyl, C
6-C
10 aryl, 5- to 10-membered heteroaryl, -OR
a, -OC(O)R
a, -OC(O)NR
aR
b, -OS(O)R
a, -OS(O)
2R
a, -OS(O)NR
aR
b, -OS(O)
2NR
aR
b, -SR
a, -S(O)R
a, -S(O)
2R
a, -S(O)NR
aR
b, -S(O)
2NR
aR
b, -NR
aC(O)R
b, -N(C(O)R
a)(C(O)R
b), -NR
aC(O)OR
b, -NR
aC(O)NR
aR
b, -NR
aS(O)R
b, -NR
aS(O)
2R
b, -NR
aS(O)NR
aR
b, -NR
aS(O)
2NR
aR
b, -C(O)R
a, -C(O)OR
a, -C(O)NR
aR
b, - PR
aR
b, -P(O)R
aR
b, -P(O)
2R
aR
b, -P(O)NR
aR
b, -P(O)
2NR
aR
b, -P(O)OR
a, -P(O)
2OR
a, -CN, or - NO2, or two of R
11 taken together with the atom or atoms to which they are attached or three
of R taken together with the atoms to which they are attached, form a C
3 C
6 cycloalkyl or a 4- to 10-membered heterocycloalkyl, wherein each hydrogen atom in C
1-C
6 alkyl, C2-C6 alkenyl, C
2-C
6 alkynyl, C
3-C
6 cycloalkyl, C
6-C
10 aryl, 5- to 10-membered heteroaryl, and 4- to 10-membered heterocycloalkyl is independently optionally substituted by deuterium, halogen, -R
e, -R
f, C
1-C
6 alkyl, C
1-C
6 haloalkyl, -OR
e, -OC(O)R
e, -OC(O)NR
eR
f, -OS(O)R
e, -OS(O)
2R
e, -OS(O)NR
eR
f, -OS(O)
2NR
eR
f, -SR
e, -S(O)R
e, -S(O)
2R
e, -S(O)NR
eR
f, -S(O)
2NR
eR
f, -NR
eC(O)R
f, -NR
eC(O)OR
f, -NR
eC(O)NR
eR
f, -NR
eS(O)R
f, -NR
eS(O)
2R
f, -NR
eS(O)NR
eR
f, -NR
eS(O)
2NR
eR
f, -C(O)R
e, -C(O)OR
e, -C(O)NR
eR
f, -PR
eR
f, -P(O)R
eR
f, -P(O)
2R
eR
f, -P(O)NR
eR
f, -P(O)
2NR
eR
f, -P(O)OR
e, -P(O)
2OR
e, -CN, or -NO2; wherein each R
a, R
b, R
e, and R
f, is independently selected from the group consisting of H, deuterium, C
1- C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C
3-C
6 cycloalkyl, 4- to 10-membered heterocycloalkyl, C
6-C
10 aryl, C
1-C
6 alkyl-C
6-C
10 aryl, and 5- to 10-membered heteroaryl; or two of R
a and R
b, or R
e and R
f, taken together with the atom or atoms to which they are attached, combine to form a C
3-C
6 cycloalkyl, 4- to 10-membered heterocycloalkyl, C
6-C
10 aryl, or 5- to 10-membered heteroaryl, wherein each hydrogen atom in C
1-C
6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C
3-C
6 cycloalkyl, 4- to 10-membered heterocycloalkyl, C
6-C
10 aryl, C
1-C
6 alkyl-C
6-C
10 aryl, and 5- to 10-membered heteroaryl is independently optionally substituted by deuterium, halogen, C
1-C
6 alkyl, C
1-C
6 haloalkyl, -OH, -OC
1-C
6 alkyl, -OC(O)C
1-C
6 alkyl, -OC(O)N(H or C
1-C
6 alkyl)
2, -OS(O)C
1-C
6 alkyl, -OS(O)
2C
1-C
6 alkyl, -OS(O)N(H or C
1-C
6 alkyl)
2, -OS(O)
2N(H or C
1-C
6 alkyl)
2, -SC
1-C
6 alkyl, -S(O)C
1-C
6 alkyl, -S(O)
2C
1-C
6 alkyl, -S(O)N(H or C
1-C
6 alkyl)
2, -S(O)
2N(H or C
1-C
6 alkyl)
2, -N(C
1-C
6 alkyl)C(O)-C
1-C
6 alkyl, -N(C
1-C
6 alkyl)C(O)OC
1-C
6 alkyl, -N(C
1-C
6 alkyl)C(O)N(H or C1- C
6 alkyl)
2, -N(C
1-C
6 alkyl)S(O)C
1-C
6 alkyl, -N(C
1-C
6 alkyl)S(O)
2C
1-C
6 alkyl, -N(C
1-C
6 alkyl)S(O)N(H or C
1-C
6 alkyl)
2, -N(C
1-C
6 alkyl)S(O)
2N(H or C
1-C
6 alkyl)
2, -C(O)C
1-C
6 alkyl, -C(O)OC
1-C
6 alkyl, -C(O)N(H or C
1-C
6 alkyl)
2, -P(H or C
1-C
6 alkyl)
2, -P(O)(H or C
1- C6 alkyl)
2, -P(O)
2(H or C
1-C
6 alkyl)
2, -P(O)N(H or C
1-C
6 alkyl)
2, -P(O)
2N(H or C
1-C
6 alkyl)
2, -P(O)OC
1-C
6 alkyl, -P(O)
2OC
1-C
6 alkyl, -CN, or -NO
2, or two of R
11 taken together with the carbon atom to which they are attached form an oxo group or an alkenyl group. [0279] 22. The compound of any one of the preceding clauses, or a pharmaceutically acceptable salt thereof, wherein ring A is 4- to 10-membered heterocycloalkyl that is unsubstituted or substituted with one or more of R
11, or a 4- to 10-membered heterocycloalkyl that is unsubstituted or substituted with one or more of R
11 and that is
covalently attached to –Y-, -(CR
aR
b)n-, or
through a carbon atom in the 4- to 10-membered heterocycloalkyl. [0280] 23. The compound of any one of the preceding clauses, or a pharmaceutically acceptable salt thereof, wherein ring A is a mono-cyclic 4- to 10-membered heterocycloalkyl, a fused 5- to 10-membered heterocycloalkyl, a bridged bicyclic 6- to 10-membered heterocycloalkyl, or a spiro bicyclic 6- to 10-membered heterocycloalkyl, wherein each of mono-cyclic 4- to 10-membered heterocycloalkyl, a fused 5- to 10-membered heterocycloalkyl, a bridged bicyclic 6- to 10-membered heterocycloalkyl, or a spiro bicyclic 6- to 10-membered heterocycloalkyl is unsubstituted or substituted with one or more of R
11; or a mono-cyclic 4- to 10-membered heterocycloalkyl, a fused 5- to 10-membered heterocycloalkyl, a bridged bicyclic 6- to 10-membered heterocycloalkyl, or a spiro bicyclic 6- to 10-membered heterocycloalkyl, wherein each of mono-cyclic 4- to 10-membered heterocycloalkyl, a fused 5- to 10-membered heterocycloalkyl, a bridged bicyclic 6- to 10- membered heterocycloalkyl, or a spiro bicyclic 6- to 10-membered heterocycloalkyl is unsubstituted or substituted with one or more of R
11 and that is covalently attached to –Y-, -(CR
aR
b)n-, or
through a carbon atom in the mono-cyclic 4- to 10- membered heterocycloalkyl, a fused 5- to 10-membered heterocycloalkyl, a bridged bicyclic 6- to 10-membered heterocycloalkyl, or a spiro bicyclic 6- to 10-membered heterocycloalkyl. [0281] 24. The compound of any one of the preceding clauses, or a pharmaceutically acceptable salt thereof, wherein ring A is a mono-cyclic 4- to 10-membered heterocycloalkyl that is unsubstituted or substituted with one or more of R
11, or a mono-cyclic 4- to 10- membered heterocycloalkyl that is unsubstituted or substituted with one or more of R
11 and that is covalently attached to –Y-, -(CR
aR
b)
n-, or through a carbon atom
in the mono-cyclic 4- to 10-membered heterocycloalkyl. [0282] 25. The compound of any one of clauses 1 to 23, or a pharmaceutically acceptable salt thereof, wherein ring A is a bridged bicyclic 6- to 10-membered heterocycloalkyl that is unsubstituted or substituted with one or more of R
11, or a bridged bicyclic 6- to 10-membered
heterocycloalkyl that is unsubstituted or substituted with one or more of R and that is covalently attached to –Y-, -(CR
aR
b)
n-, or
through a carbon atom in the bridged bicyclic 6- to 10-membered heterocycloalkyl. [0283] 26. The compound of any one of clauses 1 to 23, or a pharmaceutically acceptable salt thereof, wherein ring A is a spiro bicyclic 6- to 10-membered heterocycloalkyl that is unsubstituted or substituted with one or more of R
11, or a spiro bicyclic 6- to 10-membered heterocycloalkyl that is unsubstituted or substituted with one or more of R
11 and that is covalently attached to –Y-, -(CR
aR
b)n-, or
through a carbon atom in the spiro bicyclic 6- to 10-membered heterocycloalkyl. [0284] 27. The compound of any one of clauses 1 to 23, or a pharmaceutically acceptable salt thereof, wherein ring A is of the formula
[0285] wherein each hydrogen is independently optionally substituted by an R
11, and * is a point of covalent attachment to
[0286] 28. The compound of any one of clauses 1 to 23, or a pharmaceutically acceptable salt thereof, wherein ring A is not of the formula
[0287] wherein each hydrogen is independently optionally substituted by an R
11, and * is a point of covalent attachment to
[0288] 29. The compound of any one of clauses 1 to 23, or a pharmaceutically acceptable salt thereof, wherein ring A is
[0289] wherein * is a point of covalent attachment to
, and m is 0, 1, 2, 3, 4, 5, or 6. [0290] 30. The compound of any one of clauses 1 to 23, or a pharmaceutically acceptable salt thereof, wherein ring A is
[0291] wherein * is a point of covalent attachment to , and m is 0, 1, 2,
3, 4, or 5. [0292] 31. The compound of any one of clauses 1 to 23, or a pharmaceutically acceptable salt thereof, wherein ring A is
[0293] wherein * is a point of covalent attachment to
[0294] 32. The compound of any one of clauses 1 to 23, or a pharmaceutically acceptable salt thereof, wherein ring A is not of the formula
[0295] wherein * is a point of covalent attachment to , and m is 0, 1, 2,
3, 4, 5, or 6. [0296] 33. The compound of any one of clauses 1 to 23, or a pharmaceutically acceptable salt thereof, wherein ring A is not of the formula
[0297] wherein * is a point of covalent attachment to
[0298] 34. The compound of any one of clauses 1 to 21, or a pharmaceutically acceptable salt thereof, wherein ring A is an unsubstituted C
6-C
10 aryl or a C
6-C
10 aryl substituted with 1, 2, 3, 4, 5, or 6 of R
11.
[0299] 35. The compound of any one of clauses 1 to 21, or 34, or a pharmaceutically acceptable salt thereof, wherein ring A is a unsubstituted phenyl, unsubstituted naphthyl, phenyl substituted with 1, 2, 3, 4, or 5 of R
11, or naphthyl substituted with 1, 2, 3, 4, 5, or 6 of R
11. [0300] 36. The compound of any one of clauses 1 to 21, 34, or 35, or a pharmaceutically acceptable salt thereof, wherein ring A is a fluoro-phenyl. [0301] 37. The compound of any one of clauses 1 to 21, or 34 to 36, or a pharmaceutically acceptable salt thereof, wherein ring A is of the formula
wherein * is a point of covalent attachment to
[0302] 38. The compound of any one of clauses 1 to 21, or a pharmaceutically acceptable salt thereof, wherein ring A is an substituted 5- to 10-membered heteroaryl or a 5- to 10- membered heteroaryl substituted with 1, 2, 3, 4, or 5 of R
11. [0303] 39. The compound of any one of clauses 1 to 21, or 38, or a pharmaceutically acceptable salt thereof, wherein ring A is
[0304] wherein * is a point of covalent attachment to
, and m is 0, 1, 2, or 3. [0305] 40. The compound of any one of clauses 1 to 21, 38, or 39, or a pharmaceutically acceptable salt thereof, wherein ring A is
[0306] wherein * is a point of covalent attachment to
[0307] 41. The compound of any one of clauses 1 to 21, or a pharmaceutically acceptable salt thereof, wherein ring A is C
3-C8 cycloalkyl unsubstituted or substituted with 1, 2, 3, 4, 5, or 6 of R
11. [0308] 42. The compound of any one of clauses 1 to 21, or 41, or a pharmaceutically acceptable salt thereof, wherein ring A is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl, cycloheptyl, or cyclooctyl, each of which is optionally substituted with 1, 2, 3, 4, 5, or 6 of R
11. [0309] 43. The compound of any one of clauses 1 to 21, 41, or 42, or a pharmaceutically acceptable salt thereof, wherein ring A is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cyclohexenyl, each of which is optionally substituted with 1, 2, 3, 4, 5, or 6 of R
11 selected from the groups consisting of deuterium, fluoro, chloro, bromo, C
1-C
6 alkyl, -OR
a, or C
1-C
6 alkyl-OR
e. [0310] 43a. The compound of any one of clauses 1 to 21, 36, or 37, or a pharmaceutically acceptable salt thereof, wherein ring A is of the formula
[0311] wherein * is a point of covalent attachment to Y or
[0312] 44. The compound of any one of the preceding clauses, or a pharmaceutically acceptable salt thereof, wherein Z
1 is N. [0313] 45. The compound of any one of the preceding clauses, or a pharmaceutically acceptable salt thereof, wherein Z
2 is N. [0314] 46. The compound of any one of the preceding clauses, or a pharmaceutically acceptable salt thereof, wherein Z
3 is CR
7, Z
4 is N, and Z
5 is CR
9. [0315] 47. The compound of any one of clauses 1 to 45, or a pharmaceutically acceptable salt thereof, wherein Z
3 is CR
7, Z
4 is CR
8, and Z
5 is CR
9.
[0316] 48. The compound of any one of clauses 1 to 45, or a pharmaceutically acceptable salt thereof, wherein Z
3 is CR
7, Z
4 is CR
8, and Z
5 is N. [0317] 49. The compound of any one of clauses 1 to 45, or a pharmaceutically acceptable salt thereof, wherein Z
3 is N, Z
4 is N, and Z
5 is CR
9. [0318] 50. The compound of any one of clauses 1 to 45, or a pharmaceutically acceptable salt thereof, wherein Z
3 is N, Z
4 is N, and Z
5 is N. [0319] 51. The compound of any one of clauses 1 to 45, or a pharmaceutically acceptable salt thereof, wherein Z
3 is CR
7, Z
4 is N, and Z
5 is N. [0320] 52. The compound of any one of clauses 1 to 45, or a pharmaceutically acceptable salt thereof, wherein Z
3 is N, Z
4 is CR
8, and Z
5 is N. [0321] 53. The compound of any one of the preceding clauses, or a pharmaceutically acceptable salt thereof, wherein p is 0. [0322] 54. The compound of any one of clauses 1 to 52, or a pharmaceutically acceptable salt thereof, wherein p is 1. [0323] 55. The compound of any one of clauses 1 to 52, or 54, or a pharmaceutically acceptable salt thereof, wherein X is O. [0324] 56. The compound of any one of clauses 1 to 52, or 54, or a pharmaceutically acceptable salt thereof, wherein X is –NR
4-. [0325] 57. The compound of any one of clauses 1 to 52, or 54, or a pharmaceutically acceptable salt thereof, wherein X is -S-. [0326] 58. The compound of any one of the preceding clauses, or a pharmaceutically acceptable salt thereof, wherein each R
2 is independently deuterium, halogen, C
1-C
6 alkyl, C
2-C
6 alkenyl, C
2-C
6 alkynyl, -OR
c, -C(O)R
C, or -NR
cR
d. [0327] 59. The compound of any one of the preceding clauses, or a pharmaceutically acceptable salt thereof, wherein Ring B is
[0328] wherein “
” is a point of covalent attachment. [0329] 60. The compound of any one of the preceding clauses, or a pharmaceutically acceptable salt thereof, wherein R
4, when present, is H or methyl. [0330] 61. The compound of any one of the preceding clauses, or a pharmaceutically acceptable salt thereof, wherein R
5, when present, is H. [0331] 62. The compound of any one of the preceding clauses, or a pharmaceutically acceptable salt thereof, wherein R
6, when present, is H. [0332] 63. The compound of any one of the preceding clauses, or a pharmaceutically acceptable salt thereof, wherein R
7, when present, is H or F.
[0333] 64. The compound of any one of the preceding clauses, or a pharmaceutically acceptable salt thereof, wherein R
8, when present, is H. [0334] 65. The compound of any one of the preceding clauses, or a pharmaceutically acceptable salt thereof, wherein R
9, when present, is H or –OCH3. [0335] 66. The compound of any one of the preceding clauses, or a pharmaceutically acceptable salt thereof, wherein R
10, when present, is H. [0336] 67. The compound of any one of the preceding clauses, or a pharmaceutically acceptable salt thereof, wherein q is 0. [0337] 68. The compound of any one of clauses 1 to 61, or a pharmaceutically acceptable salt thereof, wherein q is 1. [0338] 69, The compound of any one of the preceding clauses, or a pharmaceutically acceptable salt thereof, wherein at least one hydrogen atom on ring A, ring B, R
1, or R
3 in the compound of the formula I is substituted by a deuterium. [0339] 70. The compound of clause 1, or a pharmaceutically acceptable salt thereof, selected from the group consisting of 5-ethynyl-6-fluoro-4-[8-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro- 1H-pyrrolizin-7a(5H)-yl]methoxy}-4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)pyrido[4,3- d]pyrimidin-7-yl]naphthalen-2-ol; [0340] 5-ethynyl-6-fluoro-4-[8-fluoro-2-(4-methylpiperazin-1-yl)-4-(8-oxa-3- azabicyclo[3.2.1]octan-3-yl)pyrido[4,3-d]pyrimidin-7-yl]naphthalen-2-ol; [0341] 5-ethynyl-6-fluoro-4-{8-fluoro-2-[(3R,3aS,6aS)-3-fluoro-1- methylhexahydropyrrolo[3,4-b]pyrrol-5(1H)-yl]-4-(8-oxa-3-azabicyclo[3.2.1]octan-3- yl)pyrido[4,3-d]pyrimidin-7-yl}naphthalen-2-ol; [0342] 5-ethynyl-6-fluoro-4-{8-fluoro-2-[(3aS,6aS)-1-methylhexahydropyrrolo[3,4-b]pyrrol- 5(1H)-yl]-4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)pyrido[4,3-d]pyrimidin-7-yl}naphthalen-2- ol; [0343] 5-ethynyl-6-fluoro-4-{8-fluoro-2-[(3aR,6aS)-5-methylhexahydropyrrolo[3,4-c]pyrrol- 2(1H)-yl]-4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)pyrido[4,3-d]pyrimidin-7-yl}naphthalen-2- ol; [0344] 5-ethynyl-6-fluoro-4-[4-fluoro-6-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl]methoxy}-8-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-2,7-naphthyridin-3- yl]naphthalen-2-ol; [0345] 4-[4-(3-azabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl]methoxy}pyrido[4,3-d]pyrimidin-7-yl]-5-ethynyl-6-fluoronaphthalen-2- ol;
[0346] 4 [4 (2 azatricyclo[3.3.1.1 ]decan 2 yl) 8 fluoro 2 {[(2R,7aS) 2 fluorotetrahydro 1H-pyrrolizin-7a(5H)-yl]methoxy}pyrido[4,3-d]pyrimidin-7-yl]-5-ethynyl-6- fluoronaphthalen-2-ol; [0347] 5-ethynyl-6-fluoro-4-[8-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl]methoxy}-4-(2-oxa-6-azatricyclo[3.3.1.1
3,7]decan-6-yl)pyrido[4,3-d]pyrimidin-7- yl]naphthalen-2-ol; [0348] 5-ethynyl-6-fluoro-4-[8-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl]methoxy}-4-(6-methyl-2,6-diazatricyclo[3.3.1.1
3,7]decan-2-yl)pyrido[4,3- d]pyrimidin-7-yl]naphthalen-2-ol; [0349] 5-ethynyl-6-fluoro-4-[8-fluoro-4-(3-fluorophenyl)-2-{[(2R,7aS)-2-fluorotetrahydro- 1H-pyrrolizin-7a(5H)-yl]methoxy}pyrido[4,3-d]pyrimidin-7-yl]naphthalen-2-ol; [0350] 5-ethynyl-6-fluoro-4-[4-fluoro-8-(3-fluorophenyl)-6-{[(2R,7aS)-2-fluorotetrahydro- 1H-pyrrolizin-7a(5H)-yl]methoxy}-2,7-naphthyridin-3-yl]naphthalen-2-ol; [0351] 5-ethynyl-6-fluoro-4-[8-fluoro-4-(5-fluoropyridin-3-yl)-2-{[(2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}pyrido[4,3-d]pyrimidin-7-yl]naphthalen- 2-ol; [0352] 5-chloro-4-[8-fluoro-4-(3-fluorophenyl)-2-{[(2R,7aS)-2-fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl]methoxy}pyrido[4,3-d]pyrimidin-7-yl]-6-methylnaphthalen-2-ol; [0353] 5-chloro-4-[8-fluoro-4-(3-fluorophenyl)-2-{[(2R,7aS)-2-fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl]methoxy}pyrido[4,3-d]pyrimidin-7-yl]-6-methylquinolin-2-ol; [0354] 4-[4-(3,4-dihydro-1H-pyrrolo[2,1-c][1,4]oxazin-6-yl)-8-fluoro-2-{[(2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}pyrido[4,3-d]pyrimidin-7-yl]-5-ethynyl- 6-fluoronaphthalen-2-ol; [0355] 4-[8-(3,4-dihydro-1H-pyrrolo[2,1-c][1,4]oxazin-6-yl)-4-fluoro-6-{[(2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}-2,7-naphthyridin-3-yl]-5-ethynyl-6- fluoronaphthalen-2-ol; [0356] 4-[4-(3,4-dihydro-1H-pyrrolo[2,1-c][1,4]oxazin-6-yl)-8-fluoro-2-{[(2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}pyrido[4,3-d]pyrimidin-7-yl]-5-ethynyl- 6-fluoroquinolin-2-ol; [0357] 4-[4-(3,4-dihydro-1H-pyrrolo[2,1-c][1,4]oxazin-6-yl)-8-fluoro-2-{[(2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}pyrido[4,3-d]pyrimidin-7-yl]-5-ethynyl- 6-fluoroquinolin-2-amine; [0358] 5-ethynyl-6-fluoro-4-[8-fluoro-4-(7-fluoro-3,4-dihydro-1H-pyrrolo[2,1-c][1,4]oxazin- 6-yl)-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}pyrido[4,3- d]pyrimidin-7-yl]naphthalen-2-ol;
[0359] 5 chloro 4 [4 (3,4 dihydro 1H pyrrolo[2,1 c][1,4]oxazin 6 yl) 8 fluoro 2 {[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}pyrido[4,3-d]pyrimidin-7- yl]-6-methylnaphthalen-2-ol; [0360] 5-ethynyl-6-fluoro-4-[8-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl]methoxy}-4-(1'H,4'H-spiro[cyclopropane-1,3'-pyrrolo[2,1-c][1,4]oxazin]-6'- yl)pyrido[4,3-d]pyrimidin-7-yl]naphthalen-2-ol; [0361] 4-[4-(6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazin-3-yl)-8-fluoro-2-{[(2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}pyrido[4,3-d]pyrimidin-7-yl]-5-ethynyl- 6-fluoronaphthalen-2-ol; [0362] 5-ethynyl-6-fluoro-4-[8-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl]methoxy}-4-(1-methyl-1,4,5,7-tetrahydropyrano[3,4-c]pyrazol-3-yl)pyrido[4,3- d]pyrimidin-7-yl]naphthalen-2-ol; [0363] 4-[4-(3,4-dihydro-1H-pyrrolo[2,1-c][1,4]oxazin-7-yl)-8-fluoro-2-{[(2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}pyrido[4,3-d]pyrimidin-7-yl]-5-ethynyl- 6-fluoronaphthalen-2-ol; [0364] 4-[4-(4,5-dihydro-1H,3H-pyrrolo[2,1-c][1,4]oxazepin-7-yl)-8-fluoro-2-{[(2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}pyrido[4,3-d]pyrimidin-7-yl]-5-ethynyl- 6-fluoronaphthalen-2-ol; [0365] 6-[7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-{[(2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}pyrido[4,3-d]pyrimidin-4-yl]-3,4- dihydropyrrolo[1,2-a]pyrazin-1(2H)-one; [0366] 6-[7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-{[(2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}pyrido[4,3-d]pyrimidin-4-yl]-2-methyl- 3,4-dihydropyrrolo[1,2-a]pyrazin-1(2H)-one; [0367] 6-[7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-{[(2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}pyrido[4,3-d]pyrimidin-4-yl]-3,4- dihydro-1H-pyrrolo[2,1-c][1,4]oxazin-1-one; [0368] 6-[7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-{[(2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}pyrido[4,3-d]pyrimidin-4-yl]-1H- pyrrolo[2,1-c][1,4]oxazin-3(4H)-one; [0369] 6-[7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-{[(2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}pyrido[4,3-d]pyrimidin-4-yl]-1,2- dihydropyrrolo[1,2-a]pyrazin-3(4H)-one;
[0370] 6 [7 (8 ethynyl 7 fluoro 3 hydroxynaphthalen 1 yl) 8 fluoro 2 {[(2R,7aS) 2 fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}pyrido[4,3-d]pyrimidin-4-yl]-2-methyl- 1,2-dihydropyrrolo[1,2-a]pyrazin-3(4H)-one; [0371] 5-ethynyl-6-fluoro-4-[8-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl]methoxy}-4-(5,6,7,8-tetrahydroindolizin-3-yl)pyrido[4,3-d]pyrimidin-7- yl]naphthalen-2-ol; [0372] (8S)-3-[7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-{[(2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}pyrido[4,3-d]pyrimidin-4-yl]-5,6,7,8- tetrahydroindolizin-8-ol; [0373] 4-[4-(4,7-dihydro-5H-furo[2,3-c]pyran-3-yl)-8-fluoro-2-{[(2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}pyrido[4,3-d]pyrimidin-7-yl]-5-ethynyl- 6-fluoronaphthalen-2-ol; [0374] 4-[4-(6,7-dihydro-4H-furo[3,4-c]pyran-1-yl)-8-fluoro-2-{[(2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}pyrido[4,3-d]pyrimidin-7-yl]-5-ethynyl- 6-fluoronaphthalen-2-ol; [0375] 4-[4-(6,7-dihydro-4H-thieno[3,4-c]pyran-1-yl)-8-fluoro-2-{[(2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}pyrido[4,3-d]pyrimidin-7-yl]-5-ethynyl- 6-fluoronaphthalen-2-ol; [0376] 4-[4-(5,6-dihydro-8H-imidazo[5,1-c][1,4]oxazin-3-yl)-8-fluoro-2-{[(2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}pyrido[4,3-d]pyrimidin-7-yl]-5-ethynyl- 6-fluoronaphthalen-2-ol; [0377] 4-[4-(5,6-dihydro-8H-imidazo[2,1-c][1,4]oxazin-3-yl)-8-fluoro-2-{[(2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}pyrido[4,3-d]pyrimidin-7-yl]-5-ethynyl- 6-fluoronaphthalen-2-ol; [0378] 5-ethynyl-6-fluoro-4-(8-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl]methoxy}-4-[1-(8-oxabicyclo[3.2.1]octan-3-yl)-1H-pyrazol-4-yl]pyrido[4,3- d]pyrimidin-7-yl)naphthalen-2-ol; [0379] 5-ethynyl-6-fluoro-4-(8-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl]methoxy}-4-[1-(oxan-4-yl)-1H-pyrazol-4-yl]pyrido[4,3-d]pyrimidin-7- yl)naphthalen-2-ol; [0380] 4-{4-(3,4-dihydro-1H-pyrrolo[2,1-c][1,4]oxazin-6-yl)-8-fluoro-2-[(3R,3aS,6aS)-3- fluoro-1-methylhexahydropyrrolo[3,4-b]pyrrol-5(1H)-yl]pyrido[4,3-d]pyrimidin-7-yl}-5- ethynyl-6-fluoronaphthalen-2-ol;
[0381] 4 {4 (3,4 dihydro 1H pyrrolo[2,1 c][1,4]oxazin 6 yl) 8 fluoro 2 [(3aR,6aS) 5 methylhexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl]pyrido[4,3-d]pyrimidin-7-yl}-5-ethynyl-6- fluoronaphthalen-2-ol; [0382] 4-[4-(3,4-dihydro-1H-pyrrolo[2,1-c][1,4]oxazin-6-yl)-8-fluoro-2-(4-methylpiperazin- 1-yl)pyrido[4,3-d]pyrimidin-7-yl]-5-ethynyl-6-fluoronaphthalen-2-ol; [0383] 4-[4-(cyclopentylsulfanyl)-8-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl]methoxy}pyrido[4,3-d]pyrimidin-7-yl]-5-ethynyl-6-fluoronaphthalen-2-ol; [0384] 4-[4-(cyclopentanesulfonyl)-8-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl]methoxy}pyrido[4,3-d]pyrimidin-7-yl]-5-ethynyl-6-fluoronaphthalen-2-ol; [0385] 4-[4-(cyclobutylsulfanyl)-8-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl]methoxy}pyrido[4,3-d]pyrimidin-7-yl]-5-ethynyl-6-fluoronaphthalen-2-ol; [0386] 4-[4-(cyclobutanesulfonyl)-8-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl]methoxy}pyrido[4,3-d]pyrimidin-7-yl]-5-ethynyl-6-fluoronaphthalen-2-ol; [0387] 4-[4-(cyclopropylsulfanyl)-8-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl]methoxy}pyrido[4,3-d]pyrimidin-7-yl]-5-ethynyl-6-fluoronaphthalen-2-ol; [0388] 4-[4-(cyclopropanesulfonyl)-8-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl]methoxy}pyrido[4,3-d]pyrimidin-7-yl]-5-ethynyl-6-fluoronaphthalen-2-ol; [0389] [7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-{[(2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}pyrido[4,3-d]pyrimidin-4-yl](8-oxa-3- azabicyclo[3.2.1]octan-3-yl)methanone; and [0390] N-{[1-(dimethylamino)cyclobutyl]methyl}-7-(8-ethynyl-7-fluoro-3- hydroxynaphthalen-1-yl)-8-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl]methoxy}pyrido[4,3-d]pyrimidine-4-carboxamide; [0391] 5-ethynyl-1,6-difluoro-4-[8-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl]methoxy}-4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)pyrido[4,3-d]pyrimidin-7- yl]naphthalen-2-ol; [0392] 5-ethynyl-6-fluoro-4-(8-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl]methoxy}-4-[(2R)-2-(methoxymethyl)morpholin-4-yl]pyrido[4,3-d]pyrimidin-7- yl)naphthalen-2-ol; [0393] 5-ethynyl-6-fluoro-4-[8-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl]methoxy}-4-(morpholin-4-yl)pyrido[4,3-d]pyrimidin-7-yl]naphthalen-2-ol; [0394] 5-ethynyl-6-fluoro-4-[8-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl]methoxy}-4-(2-oxa-5-azabicyclo[4.1.0]heptan-5-yl)pyrido[4,3-d]pyrimidin-7- yl]naphthalen-2-ol;
[0395] 4 {2 [(3S) 3 (dimethylamino)pyrrolidin 1 yl] 8 fluoro 4 (morpholin 4 yl)pyrido[4,3 d]pyrimidin-7-yl}-5-ethynyl-6-fluoronaphthalen-2-ol; [0396] 5-ethynyl-6-fluoro-4-[8-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl]methoxy}-4-(6-oxa-3-azabicyclo[3.1.1]heptan-3-yl)pyrido[4,3-d]pyrimidin-7- yl]naphthalen-2-ol; [0397] 4-[7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-{[(2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}pyrido[4,3-d]pyrimidin-4-yl]-1λ
6- thiomorpholine-1,1-dione; [0398] 4-[4-(2,9-dioxa-6-azaspiro[4.5]decan-6-yl)-8-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro- 1H-pyrrolizin-7a(5H)-yl]methoxy}pyrido[4,3-d]pyrimidin-7-yl]-5-ethynyl-6- fluoronaphthalen-2-ol; [0399] 5-ethynyl-6-fluoro-4-(8-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl]methoxy}-4-[(1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl]pyrido[4,3- d]pyrimidin-7-yl)naphthalen-2-ol; [0400] 5-ethynyl-6-fluoro-4-[8-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl]methoxy}-4-(7-oxa-4-azaspiro[2.5]octan-4-yl)pyrido[4,3-d]pyrimidin-7- yl]naphthalen-2-ol; [0401] 5-ethynyl-6-fluoro-4-[8-fluoro-2-({[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl](
2H
2)methyl}oxy)-4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)pyrido[4,3-d]pyrimidin- 7-yl]naphthalen-2-ol; [0402] 5-ethynyl-6-fluoro-4-[8-fluoro-2-({[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl](
2H2)methyl}oxy)-4-(morpholin-4-yl)pyrido[4,3-d]pyrimidin-7-yl]naphthalen-2- ol; [0403] 5-ethynyl-6-fluoro-4-(8-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl]methoxy}-4-[4-(methoxymethyl)-1H-pyrazol-1-yl]pyrido[4,3-d]pyrimidin-7- yl)naphthalen-2-ol; [0404] 5-ethynyl-6-fluoro-4-(8-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl]methoxy}-4-[4-(methoxymethyl)-1H-1,2,3-triazol-1-yl]pyrido[4,3-d]pyrimidin-7- yl)naphthalen-2-ol; [0405] 5-ethynyl-6-fluoro-4-(8-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl]methoxy}-4-[4-(methoxymethyl)-1H-imidazol-1-yl]pyrido[4,3-d]pyrimidin-7- yl)naphthalen-2-ol; [0406] 5-ethynyl-6-fluoro-4-(8-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl]methoxy}-4-[3-(methoxymethyl)-1H-pyrrol-1-yl]pyrido[4,3-d]pyrimidin-7- yl)naphthalen-2-ol;
[0407] 5 ethynyl 6 fluoro 4 (8 fluoro 2 {[(2R,7aS) 2 fluorotetrahydro 1H pyrrolizin 7a(5H)-yl]methoxy}-4-[1-(2-methoxyethyl)-1H-1,2,3-triazol-4-yl]pyrido[4,3-d]pyrimidin-7- yl)naphthalen-2-ol; [0408] 5-ethynyl-6-fluoro-4-(8-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl]methoxy}-4-[1-(2-methoxyethyl)-1H-pyrazol-4-yl]pyrido[4,3-d]pyrimidin-7- yl)naphthalen-2-ol; [0409] 5-ethynyl-6-fluoro-4-(8-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl]methoxy}-4-[1-(2-methoxyethyl)-1H-imidazol-4-yl]pyrido[4,3-d]pyrimidin-7- yl)naphthalen-2-ol; [0410] 5-ethynyl-6-fluoro-4-(8-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl]methoxy}-4-[(2R)-2-hydroxy-2-methylcyclopropyl]pyrido[4,3-d]pyrimidin-7- yl)naphthalen-2-ol; [0411] 5-ethyl-6-fluoro-4-(8-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl]methoxy}-4-[(2R)-2-hydroxy-2-methylcyclopropyl]pyrido[4,3-d]pyrimidin-7- yl)naphthalen-2-ol; [0412] 5-ethynyl-6-fluoro-4-(8-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl]methoxy}-4-[(2R)-2-hydroxy-2-methylcyclobutyl]pyrido[4,3-d]pyrimidin-7- yl)naphthalen-2-ol; [0413] 5-ethyl-6-fluoro-4-(8-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl]methoxy}-4-[(2R)-2-hydroxy-2-methylcyclobutyl]pyrido[4,3-d]pyrimidin-7- yl)naphthalen-2-ol; [0414] 5-ethyl-6-fluoro-4-(8-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl]methoxy}-4-[(3R)-3-hydroxy-3-methylcyclopentyl]pyrido[4,3-d]pyrimidin-7- yl)naphthalen-2-ol; [0415] 5-ethyl-6-fluoro-4-(8-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl]methoxy}-4-[(3R)-3-hydroxy-3-methylcyclohexyl]pyrido[4,3-d]pyrimidin-7- yl)naphthalen-2-ol; [0416] 5-ethyl-6-fluoro-4-(8-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl]methoxy}-4-[(2R)-3-hydroxy-3-methylbutan-2-yl]pyrido[4,3-d]pyrimidin-7- yl)naphthalen-2-ol; [0417] 5-ethyl-6-fluoro-4-[8-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl]methoxy}-4-(2-hydroxy-2-methylpropyl)pyrido[4,3-d]pyrimidin-7-yl]naphthalen-2-ol; [0418] 5-ethyl-6-fluoro-4-[8-fluoro-2-({[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl](
2H
2)methyl}oxy)-4-(2-hydroxy-2-methylpropyl)pyrido[4,3-d]pyrimidin-7-yl]naphthalen- 2-ol;
[0419] 5 chloro 6 fluoro 4 [8 fluoro 2 {[(2R,7aS) 2 fluorotetrahydro 1H pyrrolizin 7a(5H) yl]methoxy}-4-(2-hydroxy-2-methylpropyl)pyrido[4,3-d]pyrimidin-7-yl]naphthalen-2-ol; [0420] 5,6-difluoro-4-[8-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl]methoxy}-4-(2-hydroxy-2-methylpropyl)pyrido[4,3-d]pyrimidin-7-yl]naphthalen-2-ol; [0421] 5-ethyl-6-fluoro-4-[8-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl]methoxy}-4-(2-hydroxy-2-methylpropyl)-5-methoxypyrido[4,3-d]pyrimidin-7- yl]naphthalen-2-ol, [0422] (3R)-1-[7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-{[(2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}-5-methoxypyrido[4,3-d]pyrimidin-4- yl]-3-methylpiperidin-3-ol; [0423] 1-{4-[7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-{[(2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}pyrido[4,3-d]pyrimidin-4-yl]-1,4- diazepan-1-yl}ethan-1-one; [0424] 5-ethynyl-6-fluoro-4-(8-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl]methoxy}-4-methylpyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol; [0425] 4-(4-cyclohexyl-8-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl]methoxy}pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol; and [0426] 4-[4-(cyclohex-1-en-1-yl)-8-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl]methoxy}pyrido[4,3-d]pyrimidin-7-yl]-5-ethynyl-6-fluoronaphthalen-2-ol; [0427] or a pharmaceutically acceptable salt thereof. [0428] 71. The compound of clause 1, selected from the group consisting of 5-ethynyl-6- fluoro-4-[8-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}-4-(8- oxa-3-azabicyclo[3.2.1]octan-3-yl)pyrido[4,3-d]pyrimidin-7-yl]quinolin-2-ol; [0429] 5-ethynyl-4-[8-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl]methoxy}-4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)pyrido[4,3-d]pyrimidin-7-yl]quinolin- 2-ol; [0430] 5-ethynyl-4-[8-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl]methoxy}-4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)pyrido[4,3-d]pyrimidin-7-yl]-6- methylquinolin-2-ol; [0431] 5-chloro-4-[8-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl]methoxy}-4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)pyrido[4,3-d]pyrimidin-7-yl]-6- methylquinolin-2-ol; [0432] 4-[8-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}-4-(8- oxa-3-azabicyclo[3.2.1]octan-3-yl)pyrido[4,3-d]pyrimidin-7-yl]-6-methylquinolin-2-ol;
[0433] 5 chloro 4 [8 fluoro 2 {[(2R,7aS) 2 fluorotetrahydro 1H pyrrolizin 7a(5H) yl]methoxy}-4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)pyrido[4,3-d]pyrimidin-7-yl]-6- methylquinolin-2-amine; [0434] 5-chloro-4-[8-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl]methoxy}-4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)pyrido[4,3-d]pyrimidin-7-yl]-6- methylquinazolin-2-amine; [0435] 8-chloro-1-[8-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl]methoxy}-4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)pyrido[4,3-d]pyrimidin-7-yl]-7- methylisoquinolin-3-amine; [0436] 5-ethynyl-6-fluoro-4-[8-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl]methoxy}-4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)pyrido[4,3-d]pyrimidin-7- yl]quinolin-2-amine; [0437] 8-ethynyl-7-fluoro-1-[8-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl]methoxy}-4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)pyrido[4,3-d]pyrimidin-7- yl]isoquinolin-3-amine; [0438] 5-chloro-4-[8-fluoro-4-(3-fluorophenyl)-2-{[(2R,7aS)-2-fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl]methoxy}pyrido[4,3-d]pyrimidin-7-yl]-6-methylquinolin-2-ol; [0439] 4-[4-(3,4-dihydro-1H-pyrrolo[2,1-c][1,4]oxazin-6-yl)-8-fluoro-2-{[(2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}pyrido[4,3-d]pyrimidin-7-yl]-5-ethynyl- 6-fluoroquinolin-2-ol; [0440] 4-[4-(3,4-dihydro-1H-pyrrolo[2,1-c][1,4]oxazin-6-yl)-8-fluoro-2-{[(2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}pyrido[4,3-d]pyrimidin-7-yl]-5-ethynyl- 6-fluoroquinolin-2-amine; and [0441] 5-chloro-4-[4-(3,4-dihydro-1H-pyrrolo[2,1-c][1,4]oxazin-6-yl)-8-fluoro-2- {[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}pyrido[4,3-d]pyrimidin-7- yl]-6-methylquinolin-2-ol; [0442] or a pharmaceutically acceptable salt thereof. [0443] 72. The compound of clause 1, or a pharmaceutically acceptable salt thereof, selected from the group consisting of 7-(4-ethynyl-5-fluoro-1H-indazol-3-yl)-8-fluoro-2-{[(2R,7aS)- 2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}-4-(8-oxa-3-azabicyclo[3.2.1]octan-3- yl)pyrido[4,3-d]pyrimidine; [0444] 7-(5-chloro-1H-indazol-3-yl)-8-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl]methoxy}-4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)pyrido[4,3- d]pyrimidine;
[0445] 7 (4 chloro 1H indazol 3 yl) 8 fluoro 2 {[(2R,7aS) 2 fluorotetrahydro 1H pyrrolizin-7a(5H)-yl]methoxy}-4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)pyrido[4,3- d]pyrimidine; [0446] 7-(4-chloro-5-methyl-1H-indazol-3-yl)-8-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl]methoxy}-4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)pyrido[4,3- d]pyrimidine; [0447] 7-(4-chloro-5-fluoro-1H-indazol-3-yl)-8-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl]methoxy}-4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)pyrido[4,3- d]pyrimidine; and [0448] 8-fluoro-7-(4-fluoro-1H-indazol-3-yl)-2-{[(2R,7aS)-2-fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl]methoxy}-4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)pyrido[4,3- d]pyrimidine; [0449] or a pharmaceutically acceptable salt thereof. [0450] 73. The compound of clause 1, or a pharmaceutically acceptable salt thereof, selected from the group consisting of 7-(5-chloro-3-methyl-1H-indazol-4-yl)-8-fluoro-2-{[(2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}-4-(8-oxa-3-azabicyclo[3.2.1]octan-3- yl)pyrido[4,3-d]pyrimidine; [0451] 7-(6-chloro-3,5-dimethyl-1H-indazol-4-yl)-8-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro- 1H-pyrrolizin-7a(5H)-yl]methoxy}-4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)pyrido[4,3- d]pyrimidine; and [0452] 6-chloro-4-[8-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl]methoxy}-4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)pyrido[4,3-d]pyrimidin-7-yl]-5-methyl- 1H-indazole-3-carbonitrile; [0453] or a pharmaceutically acceptable salt thereof. [0454] 74. A pharmaceutical composition comprising at least one compound of any one of clauses 1 to 73, or a pharmaceutically acceptable salt thereof, and optionally one or more pharmaceutically acceptable excipients. [0455] 75. A method of treating disease, such as cancer, comprising administering to a subject in need of such treatment an effective amount of a compound of any one of clauses 1 to 73, or a pharmaceutically acceptable salt thereof. [0456] 76. A compound of any one of clauses 1 to 73, or a pharmaceutically acceptable salt thereof, for use in a method of treating cancer in a subject. [0457] 77. A compound of any one of clauses 1 to 73, or a pharmaceutically acceptable salt thereof, for treating cancer in a subject.
[0458] 78. Use of a compound of any one of clauses 1 to 73, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating cancer in a subject. BRIEF DESCRIPTION OF THE DRAWINGS [0459] FIG. 1 is a gel showing the results of a phosphorylation assay where SW620 cells having a KRAS G12V mutation were treated with compound Ex.1 at 3, 10, 30, 100, and 300 nM. pERK IC
50 = 52 nM. [0460] FIG.2 is a gel showing the results of a phosphorylation assay where H229 cells having a KRAS G12F mutation were treated with compound Ex. 1 dosed at 3, 10, 30, 100, and 300 nM. pERK IC50 = 92 nM. [0461] FIG.3 is a gel showing the results of a phosphorylation assay where H358 cells having a KRAS G12C mutation were treated with compound Ex. 1 dosed at 3, 10, 30, 100, and 300 nM. pERK IC
50 = 29 nM. [0462] FIG. 4 is a gel showing the results of a phosphorylation assay where HCT116 cells having a KRAS G13D mutation were treated with compound Ex. 1 dosed at 3, 10, 30, 100, and 300 nM. pERK IC50 = 117 nM. DETAILED DESCRIPTION [0463] Before the present disclosure is further described, it is to be understood that this disclosure is not limited to particular embodiments described, as such may, of course, vary. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to be limiting, since the scope of the present disclosure will be limited only by the appended claims. [0464] For the sake of brevity, the disclosures of the publications cited in this specification, including patents, are herein incorporated by reference. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as is commonly understood by one of ordinary skill in the art to which this disclosure belongs. All patents, applications, published applications and other publications referred to herein are incorporated by reference in their entireties. If a definition set forth in this section is contrary to or otherwise inconsistent with a definition set forth in a patent, application, or other publication that is herein incorporated by reference, the definition set forth in this section prevails over the definition incorporated herein by reference. [0465] As used herein and in the appended claims, the singular forms “a,” “an,” and “the” include plural referents unless the context clearly dictates otherwise. It is further noted that the
claims may be drafted to exclude any optional element. As such, this statement is intended to serve as antecedent basis for use of such exclusive terminology as “solely,” “only” and the like in connection with the recitation of claim elements, or use of a “negative” limitation. [0466] As used herein, the terms “including,” “containing,” and “comprising” are used in their open, non-limiting sense. [0467] To provide a more concise description, some of the quantitative expressions given herein are not qualified with the term “about.” It is understood that, whether the term “about” is used explicitly or not, every quantity given herein is meant to refer to the actual given value, and it is also meant to refer to the approximation to such given value that would reasonably be inferred based on the ordinary skill in the art, including equivalents and approximations due to the experimental and/or measurement conditions for such given value. Whenever a yield is given as a percentage, such yield refers to a mass of the entity for which the yield is given with respect to the maximum amount of the same entity that could be obtained under the particular stoichiometric conditions. Concentrations that are given as percentages refer to mass ratios, unless indicated differently. [0468] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. Although any methods and materials similar or equivalent to those described herein can also be used in the practice or testing of the present disclosure, the preferred methods and materials are now described. All publications mentioned herein are incorporated herein by reference to disclose and describe the methods and/or materials in connection with which the publications are cited. [0469] Except as otherwise noted, the methods and techniques of the present embodiments are generally performed according to conventional methods well known in the art and as described in various general and more specific references that are cited and discussed throughout the present specification. See, e.g., Loudon, Organic Chemistry, Fourth Edition, New York: Oxford University Press, 2002, pp.360-361, 1084-1085; Smith and March, March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, Fifth Edition, Wiley-Interscience, 2001. [0470] Chemical nomenclature for compounds described herein has generally been derived using the commercially-available ACD/Name 2014 (ACD/Labs) or ChemBioDraw Ultra 13.0 (Perkin Elmer). [0471] As used herein and in connection with chemical structures depicting the vaious embodiments described herein, “*”, “**”, and “ ”, each represent a point of covalent attachment of the chemical group or chemical structure in which the identifier is shown to an
adjacent chemical group or chemical structure. For example, in a hypothetical chemical structure A-B, where A and B are joined by a covalent bond, in some embodiments, the portion of A-B defined by the group or chemical structure A can be represented by
,
where each of
, , a d represents a bond to A and the point of covalent bond attachment to B. Alternatively, in some embodiments, the portion of A-B defined by the group or chemical structure B can be represented by
, represents a bond to B and
the point of covalent bond attachment to A. [0472] It is appreciated that certain features of the disclosure, which are, for clarity, described in the context of separate embodiments, may also be provided in combination in a single embodiment. Conversely, various features of the disclosure, which are, for brevity, described in the context of a single embodiment, may also be provided separately or in any suitable subcombination. All combinations of the embodiments pertaining to the chemical groups represented by the variables are specifically embraced by the present disclosure and are disclosed herein just as if each and every combination was individually and explicitly disclosed, to the extent that such combinations embrace compounds that are stable compounds (i.e., compounds that can be isolated, characterized, and tested for biological activity). In addition, all subcombinations of the chemical groups listed in the embodiments describing such variables are also specifically embraced by the present disclosure and are disclosed herein just as if each and every such sub-combination of chemical groups was individually and explicitly disclosed herein. CHEMICAL DEFINITIONS [0473] The term “alkyl” refers to a straight- or branched-chain monovalent hydrocarbon group. The term “alkylene” refers to a straight- or branched-chain divalent hydrocarbon group. In some embodiments, it can be advantageous to limit the number of atoms in an “alkyl” or “alkylene” to a specific range of atoms, such as C
1-C
20 alkyl or C
1-C
20 alkylene, C1-C12 alkyl or C1-C12 alkylene, or C
1-C
6 alkyl or C
1-C
6 alkylene. Examples of alkyl groups include methyl (Me), ethyl (Et), n-propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl (tBu), pentyl, isopentyl, tert-pentyl, hexyl, isohexyl, and groups that in light of the ordinary skill in the art and the teachings provided herein would be considered equivalent to any one of the foregoing examples. Examples of alkylene groups include methylene (-CH2-),
ethylene (( CH
2 )
2), n propylene (( CH
2 )
3), iso propylene (( C(H)(CH
3)CH
2 )), n butylene ((-CH2-)4), and the like. It will be appreciated that an alkyl or alkylene group can be unsubstituted or substituted as described herein. An alkyl or alkylene group can be substituted with any of the substituents in the various embodiments described herein, including one or more of such substituents. [0474] The term “alkenyl” refers to a straight- or branched-chain mono-valent hydrocarbon group having one or more double bonds. In some embodiments, it can be advantageous to limit the number of atoms in an “alkenyl” to a specific range of atoms, such as C
2-C
20 alkenyl, C2-C12 alkenyl, or C2-C6 alkenyl. Examples of alkenyl groups include ethenyl (or vinyl), allyl, and but-3-en-1-yl. Included within this term are cis and trans isomers and mixtures thereof. It will be appreciated that an alkenyl can be unsubstituted or substituted as described herein. An alkenyl group can be substituted with any of the substituents in the various embodiments described herein, including one or more of such substituents. [0475] The term “alkynyl” refers to a straight- or branched-chain monovalent hydrocarbon group having one or more triple bonds. In some embodiments, it can be advantageous to limit the number of atoms in an “alkynyl” to a specific range of atoms, such as C2-C20 alkynyl, C2-C12 alkynyl, or C2-C6 alkynyl. Examples of alkynyl groups include acetylenyl (- C≡CH) and propargyl (-CH2C≡CH), but-3-yn-1,4-diyl (-C≡C-CH2CH2-), and the like. It will be appreciated that an alkynyl group can be unsubstituted or substituted as described herein. An alkynyl group can be substituted with any of the substituents in the various embodiments described herein, including one or more of such substituents. [0476] The term “cycloalkyl” refers to a saturated or partially saturated, monocyclic or polycyclic mono-valent carbocycle. In some embodiments, it can be advantageous to limit the number of atoms in a “cycloalkyl” to a specific range of atoms, such as having 3 to 12 ring atoms. Polycyclic carbocycles include fused, bridged, and spiro polycyclic systems. Illustrative examples of cycloalkyl groups include monovalent radicals of the following entities::
In particular, a cyclopropyl moiety can be depicted by the structural formula
. It will be appreciated that a cycloalkyl group can be unsubstituted or substituted as described herein. A cycloalkyl group can be substituted with any of the substituents in the various embodiments described herein, including one or more of such substituents. [0477] The term “halogen” or “halo” represents chlorine, fluorine, bromine, or iodine. [0478] The term “haloalkyl” refers to an alkyl group with one or more halo substituents. Examples of haloalkyl groups include –CF3, -(CH2)F, -CHF2, -CH2Br, -CH2CF3, and -CH
2CH
2F. The term “aryl” refers to a monovalent all-carbon monocyclic or fused-ring polycyclic group having a completely conjugated pi-electron system. In some embodiments, it can be advantageous to limit the number of atoms in an “aryl” to a specific range of atoms, such as mono-valent all-carbon monocyclic or fused-ring polycyclic groups of 6 to 14 carbon atoms (C
6-C
14 aryl), or monovalent all-carbon monocyclic or fused-ring polycyclic groups of 6 to 10 carbon atoms (C
6-C
10 aryl).Examples, without limitation, of aryl groups are phenyl, naphthalenyl and anthracenyl. It will be appreciated that an aryl group can be unsubstituted or substituted as described herein. An aryl group can be substituted with any of the substituents in the various embodiments described herein, including one or more of such substituents. [0479] The term “heterocycloalkyl” refers to a mono-valent monocyclic or polycyclic ring structure that is saturated or partially saturated having one or more non-carbon ring atoms. . In some embodiments, it can be advantageous to limit the number of atoms in a “heterocycloalkyl” to a specific range of ring atoms, such as from 3 to 12 ring atoms (3- to 12-membered), or 3 to 7 ring atoms (3- to 7-membered), or 3 to 6 ring atoms (3- to 6- membered), or 4 to 6 ring atoms (4- to 6-membered), 5 to 7 ring atoms (5- to 7-membered), or 4 to 10 ring atoms (4- to 10-membered). In some embodiments, it can be advantageous to limit the number and type of ring heteroatoms in “heterocycloalkyl” or to a specific range or type of heteroatoms, such as 1 to 5 ring heteroatoms selected from nitrogen, oxygen, and sulfur. Examples, without limitations, of mono-cyclic heterocycloalkyl groups include tetrahydrofuran, pyrrolidine, and morpholine. Polycyclic ring systems include fused, bridged, and spiro systems. In some embodiments, it can be advantageous to limit the number of atoms in a bicyclic “heterocycloalkyl” to a specific range of ring atoms, such as from 5 to 10 ring atoms (5- to 10-membered), or 6 to 10 ring atoms (6- to 10-membered). The ring structure may optionally contain an oxo group or an imino group on a carbon ring member or up to two oxo groups on sulfur ring members. Examples, without limitations, of fused
bicyclic, bridged bicyclic, and spiro bicyclic heterocycloalkyl groups include pyrrolizine, 2,5-diazabicyclo[2.2.2]octane, and 1-oxaspiro[4.5]decane. Illustrative examples of heterocycloalkyl groups include monovalent radicals of the following entities:
[0480] A three-membered heterocycle may contain at least one heteroatom ring atom, where the heteroatom ring atom is a sulfur, oxygen, or nitrogen. Non-limiting examples of three- membered heterocycle groups include monovalent and divalent radicals of oxirane, azetidine, and thiirane. A four-membered heterocycle may contain at least one heteroatom ring atom, where the heteroatom ring atom is a sulfur, oxygen, or nitrogen. Non-limiting examples of four-membered heterocycle groups include monovalent and divalent radicals of azitidine, oxtenane, and thietane. A five-membered heterocycle can contain up to four heteroatom ring atoms, where (a) at least one ring atom is oxygen and sulfur and zero, one, two, or three ring atoms are nitrogen, or (b) zero ring atoms are oxygen or sulfur and up to four ring atoms are nitrogen. Non-limiting examples of five-membered heterocyle groups include mono-valent and divalent radicals of pyrrolidine, tetrahydrofuran, 2, 5-dihydro-1H- pyrrole, pyrazolidine, thiazolidine, 4,5-dihydro-1H-imidazole, dihydrothiophen-2(3H)-one, tetrahydrothiophene 1,1-dioxide, imidazolidin-2-one, pyrrolidin-2-one, dihydrofuran-2(3H)-one, 1,3-dioxolan-2- one, and oxazolidin-2-one. A six-membered heterocycle can contain up to four heteroatom ring atoms, where (a) at least one ring atom is oxygen and sulfur and zero, one, two, or three ring atoms are nitrogen, or (b) zero ring atoms are oxygen or sulfur and up to four ring atoms are nitrogen. Non-limiting examples of six-membered heterocycle groups include mono- valent or divalent radicals of piperidine, morpholine, 4H-1,4-thiazine, 1,2,3,4- tetrahydropyridine, piperazine, 1,3-oxazinan-2-one, piperazin-2-one, thiomorpholine, and
thiomorpholine 1,1 dioxide. A heterobicycle is a fused bicyclic system comprising one heterocycle ring fused to a cycloalkyl or another heterocycle ring. [0481] In particular, a hexahydro-1H-pyrrolizinyl moiety can be depicted by the structural formula
. [0482] It will be appreciated that a heterocycloalkyl group can be unsubstituted or substituted as described herein. A heterocycloalkyl group can be substituted with any of the substituents in the various embodiments described herein, including one or more of such substituents. [0483] The term “heteroaryl” refers to a mono-valent monocyclic, fused bicyclic, or fused polycyclic aromatic heterocycle (ring structure having ring atoms or members selected from carbon atoms and up to four heteroatoms selected from nitrogen, oxygen, and sulfur) that is fully unsaturated and having from 3 to 12 ring atoms per heterocycle. In some embodiments, it can be advantageous to limit the number of ring atoms in a “heteroaryl” to a specific range of atom members, such as 5- to 10-membered heteroaryl. In some instances, a 5- to 10-membered heteroaryl can be a monocyclic ring or fused bicyclic rings having 5- to 10-ring atoms wherein at least one ring atom is a heteroatom, such as N, O, or S. The ring structure may optionally contain an oxo group or an imino group on a carbon ring member or up to two oxo groups on sulfur ring members. Illustrative examples of 5- to 10-membered heteroaryl groups include monovalent radicals of the following entities:
[0484] In some embodiments, a “monocyclic” heteroaryl can be an aromatic five- or six- membered heterocycle. A five-membered heteroaryl can contain up to four heteroatom ring atoms, where (a) at least one ring atom is oxygen and sulfur and zero, one, two, or three ring atoms are nitrogen, or (b) zero ring atoms are oxygen or sulfur and up to four ring atoms are
nitrogen. Non liniting examples of five membered heteroaryl groups include mono valent radicals of furan, thiophene, pyrrole, oxazole, isoxazole, thiazole, isothiazole, pyrazole, imidazole, oxadiazole, thiadiazole, triazole, or tetrazole. A six-membered heteroaryl can contain up to four heteroatom ring atoms, where (a) at least one ring atom is oxygen and sulfur and zero, one, two, or three ring atoms are nitrogen, or (b) zero ring atoms are oxygen or sulfur and up to four ring atoms are nitrogen. Non-limiting examples of six-membered heteroaryl groups include monovalent radicals of pyridine, pyrazine, pyrimidine, pyridazine, or triazine. A “bicyclic heteroaryl” is a fused bicyclic system comprising one heteroaryl ring fused to a phenyl or another heteroaryl ring. Non-limiting examples of bicyclic heteroaryl groups include monovalent radicals of quinoline, isoquinoline, quinazoline, quinoxaline, 1,5- naphthyridine, 1,8-naphthyridine, isoquinolin-3(2H)-one, thieno[3,2-b]thiophene, 1H- pyrrolo[2,3-b]pyridine, 1H-benzo[d]imidazole, benzo[d]oxazole, and benzo[d]thiazole. [0485] In particular, an isoquinolin-3(2H)-onyl moiety can be depicted by the structural formula
. [0486] It will be appreciated that a heteroaryl group can be unsubstituted or substituted as described herein. A heteroaryl group can be substituted with any of the substituents in the various embodiments described herein, including one or more of such substituents. [0487] It will be appreciated that a heteroaryl or heteroarylene group can be unsubstituted or substituted as described herein. A heteroaryl or heteroarylene group can be substituted with any of the substituents in the various embodiments described herein, including one or more of such substituents. [0488] The term “oxo” represents a carbonyl oxygen. For example, a cyclopentyl substituted with oxo is cyclopentanone. [0489] The term “substituted” means that the specified group or moiety bears one or more substituents. The term “unsubstituted” means that the specified group bears no substituents. Where the term “substituted” is used to describe a structural system, the substitution is meant to occur at any valency-allowed position on the system. In some embodiments, “substituted” means that the specified group or moiety bears one, two, or three substituents. In other embodiments, “substituted” means that the specified group or moiety bears one or two substituents. In still other embodiments, “substituted” means the specified group or moiety bears one substituent.
[0490] Any formula depicted herein is intended to represent a compound of that structural formula as well as certain variations or forms. For example, a formula given herein is intended to include a racemic form, or one or more enantiomeric, diastereomeric, or geometric isomers, or a mixture thereof. Additionally, any formula given herein is intended to refer also to a hydrate, solvate, or polymorph of such a compound, or a mixture thereof. [0491] Any formula given herein is also intended to represent unlabeled forms as well as isotopically labeled forms of the compounds. Isotopically labeled compounds have structures depicted by the formulas given herein except that one or more atoms are replaced by an atom having a selected atomic mass or mass number. Examples of isotopes that can be incorporated into compounds of the disclosure include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine, chlorine, and iodine, such as
2H,
3H,
11C,
13C,
14C,
15N,
18O,
17O,
31P,
32P,
35S,
18F,
36Cl, and
125I, respectively. Such isotopically labelled compounds are useful in metabolic studies (preferably with
14C), reaction kinetic studies (with, for example
2H or
3H), detection or imaging techniques [such as positron emission tomography (PET) or single- photon emission computed tomography (SPECT)] including drug or substrate tissue distribution assays, or in radioactive treatment of patients. Further, substitution with heavier isotopes such as deuterium (i.e.,
2H) may afford certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life or reduced dosage requirements. Isotopically labeled compounds of this disclosure and prodrugs thereof can generally be prepared by carrying out the procedures disclosed in the schemes or in the examples and preparations described below by substituting a readily available isotopically labeled reagent for a non-isotopically labeled reagent. [0492] Certain chemical entities of Formula (I)-(XXa) may be depicted in two or more tautomeric forms. Any and all alternative tautomers are included within the scope of these formulas, and no inference should be made as to whether the chemical entity exists as the tautomeric form in which it is drawn. It will be understood that the chemical entities described herein, and their constituent rings A, B, etc. can exist in different tautomeric forms. It will be readily appreciated by one of skill in the art that because of rapid interconversion, tautomers can generally be considered to be the same chemical compound. Examples of tautomers include but are not limited to enol-keto tautomers, amine-imine tutomers, and the like.
[0493] In particular, a ring option of isoquinolin-3(2H)-oneylene can exist as the following tautomers
[0494] The nomenclature “(ATOM)
i-(ATOM)
j” with j > i, when applied herein to a class of substituents, is meant to refer to embodiments of this disclosure for which each and every one of the number of atom members, from i to j including i and j, is independently realized. By way of example, the term C1-C
3 refers independently to embodiments that have one carbon member (C1), embodiments that have two carbon members (C2), and embodiments that have three carbon members (C
3). [0495] [0496] The disclosure also includes pharmaceutically acceptable salts of the compounds represented by Formula (I)-(XXa), preferably of those described above and of the specific compounds exemplified herein, and pharmaceutical compositions comprising such salts, and methods of using such salts. [0497] A “pharmaceutically acceptable salt” is intended to mean a salt of a free acid or base of a compound represented herein that is non-toxic, biologically tolerable, or otherwise biologically suitable for administration to the subject. See, generally, S.M. Berge, et al., “Pharmaceutical Salts,” J. Pharm. Sci., 1977, 66, 1-19. Preferred pharmaceutically acceptable salts are those that are pharmacologically effective and suitable for contact with the tissues of subjects without undue toxicity, irritation, or allergic response. A compound described herein may possess a sufficiently acidic group, a sufficiently basic group, both types of functional groups, or more than one of each type, and accordingly react with a number of inorganic or organic bases, and inorganic and organic acids, to form a pharmaceutically acceptable salt.
[0498] Examples of pharmaceutically acceptable salts include sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, phosphates, monohydrogen-phosphates, dihydrogenphosphates, metaphosphates, pyrophosphates, chlorides, bromides, iodides, acetates, propionates, decanoates, caprylates, acrylates, formates, isobutyrates, caproates, heptanoates, propiolates, oxalates, malonates, succinates, suberates, sebacates, fumarates, maleates, butyne-1,4-dioates, hexyne-1,6-dioates, benzoates, chlorobenzoates, methylbenzoates, dinitrobenzoates, hydroxybenzoates, methoxybenzoates, phthalates, sulfonates, methylsulfonates, propylsulfonates, besylates, xylenesulfonates, naphthalene-1-sulfonates, naphthalene-2- sulfonates, phenylacetates, phenylpropionates, phenylbutyrates, citrates, lactates, γ- hydroxybutyrates, glycolates, tartrates, and mandelates. Lists of other suitable pharmaceutically acceptable salts are found in Remington's Pharmaceutical Sciences, 17th Edition, Mack Publishing Company, Easton, Pa., 1985. [0499] For a compound of Formula (I)-(XXa) that contains a basic nitrogen, a pharmaceutically acceptable salt may be prepared by any suitable method available in the art, for example, treatment of the free base with an inorganic acid, such as hydrochloric acid, hydrobromic acid, sulfuric acid, sulfamic acid, nitric acid, boric acid, phosphoric acid, and the like, or with an organic acid, such as acetic acid, phenylacetic acid, propionic acid, stearic acid, lactic acid, ascorbic acid, maleic acid, hydroxymaleic acid, isethionic acid, succinic acid, valeric acid, fumaric acid, malonic acid, pyruvic acid, oxalic acid, glycolic acid, salicylic acid, oleic acid, palmitic acid, lauric acid, a pyranosidyl acid, such as glucuronic acid or galacturonic acid, an alpha-hydroxy acid, such as mandelic acid, citric acid, or tartaric acid, an amino acid, such as aspartic acid or glutamic acid, an aromatic acid, such as benzoic acid, 2-acetoxybenzoic acid, naphthoic acid, or cinnamic acid, a sulfonic acid, such as laurylsulfonic acid, p- toluenesulfonic acid, methanesulfonic acid, or ethanesulfonic acid, or any compatible mixture of acids such as those given as examples herein, and any other acid and mixture thereof that are regarded as equivalents or acceptable substitutes in light of the ordinary level of skill in this technology. [0500] The disclosure also relates to pharmaceutically acceptable prodrugs of the compounds of Formula (I)-(XXa), and treatment methods employing such pharmaceutically acceptable prodrugs. The term “prodrug” means a precursor of a designated compound that, following administration to a subject, yields the compound in vivo via a chemical or physiological process such as solvolysis or enzymatic cleavage, or under physiological conditions (e.g., a prodrug on being brought to physiological pH is converted to the compound of Formula (I)-(XXa)). A “pharmaceutically acceptable prodrug” is a prodrug that is non-toxic, biologically tolerable, and otherwise biologically suitable for administration to the subject. Illustrative procedures
for the selection and preparation of suitable prodrug derivatives are described, for example, in “Design of Prodrugs,” ed. H. Bundgaard, Elsevier, 1985. [0501] The present disclosure also relates to pharmaceutically active metabolites of compounds of Formula (I)-(XXa), and uses of such metabolites in the methods of the disclosure. A “pharmaceutically active metabolite” means a pharmacologically active product of metabolism in the body of a compound of Formula (I)-(XXa) or salt thereof. Prodrugs and active metabolites of a compound may be determined using routine techniques known or available in the art. See, e.g., Bertolini et al., J. Med. Chem.1997, 40, 2011-2016; Shan et al., J. Pharm. Sci. 1997, 86 (7), 765-767; Bagshawe, Drug Dev. Res. 1995, 34, 220-230; Bodor, Adv. Drug Res.1984, 13, 255-331; Bundgaard, Design of Prodrugs (Elsevier Press, 1985); and Larsen, Design and Application of Prodrugs, Drug Design and Development (Krogsgaard- Larsen et al., eds., Harwood Academic Publishers, 1991). [0502] As used herein, the term “KRAS inhibitor” includes, but is not limited to, a compound that is capable of inhibiting the protein encoded by the KRAS gene, called K-Ras, that is involved in the RAS/MAPK signaling pathway. The terms KRAS gene, K-Ras, and RAS/MAPK signaling pathway will be known and understood by one of skill in the art. It will be appreciated that KRAS mutations occur in approximately one in seven of all human metastatic cancers, and that those mutations can occur in a variety of locations in the KRAS gene coding sequence. KRAS mutations primarily occur in KRAS codons 12 and 13, and also occur in codons 18, 61, 117, and 146 at low frequencies and have distinct effects on tumor cell signaling based on the codon and missense mutation. Examples of KRAS mutations include, but are not limited to KRAS G12C, KRAS G12D, KRAS G12V, KRAS G12R, KRAS G12S, KRAS G13C, KRAS G13D, KRAS A18D, KRAS Q61H, KRAS K117N, and the like. It will be understood by a person having ordinary skill in the art that reference to a inhibiting of KRAS mutations, such as KRAS G12D refers to inhibiting the protein encoded by the KRAS G12D gene, having a coding sequence (e.g. a guanine to adenine substitution, at position 35 on codon 12 of the KRAS coding sequence) that produces a K-Ras G12D protein, where a glysine at position 12 of the protein sequence is replaced by am aspartic acid. REPRESENTATIVE EMBODIMENTS [0503] In some embodiments, the disclosure provides a compound of the formula I, or a pharmaceutically acceptable salt thereof,
[0504] wherein R
1, R
2, R
3, R
a, R
b, B, X, Y, Z
1, Z
2, Z
3, Z
4, Z
5, n, p, and q are as described herein. [0505] In some embodiments, the disclosure provides a compound of the formula II, or a pharmaceutically acceptable salt thereof,
[0506] wherein R
2, R
3, R
11, R
a, R
b, A, B, X, Y, Z
1, Z
2, Z
3, Z
4, Z
5, m, n, p, and q are as described herein. [0507] In some embodiments, the disclosure provides a compound of the formula III, or a pharmaceutically acceptable salt thereof,
[0508] wherein R
2, R
3, R
11, A, B, X, Z
1, Z
2, Z
3, Z
4, Z
5, m, n, and p are as described herein. [0509] In some embodiments, the disclosure provides a compound of the formula IV, or a pharmaceutically acceptable salt thereof,
IV [0510] wherein R
2, R
11, A, X, Z
1, Z
2, Z
3, Z
4, Z
5, m, and n are as described herein. [0511] In some embodiments, the disclosure provides a compound of the formula IVa, or a pharmaceutically acceptable salt thereof,
IVa [0512] wherein R
2, R
11, A, B, X, Z
1, Z
2, Z
3, Z
4, Z
5, m, and n are as described herein. [0513] In some embodiments, the disclosure provides a compound of the formula V, or a pharmaceutically acceptable salt thereof,
[0514] wherein R
2, R
3, R
11, A, X, Z
1, Z
2, Z
3, Z
4, Z
5, Z
6, Z
7, m, n, and p are as described herein. [0515] In some embodiments, the disclosure provides a compound of the formula VI, or a pharmaceutically acceptable salt thereof,
[0516] wherein R
2, R
11, A, X, Z
1, Z
2, Z
3, Z
4, Z
5, Z
6, Z
7, m, and n are as described herein. [0517] In some embodiments, the disclosure provides a compound of the formula VIa, or a pharmaceutically acceptable salt thereof,
[0518] wherein R
2, R
11, A, X, Z
1, Z
2, Z
3, Z
4, Z
5, Z
6, Z
7, m, and n are as described herein. [0519] In some embodiments, the disclosure provides a compound of the formula VII, or a pharmaceutically acceptable salt thereof,
VII [0520] wherein R
2, R
3, R
11, R
12, A, X, Z
1, Z
2, Z
3, Z
4, Z
5, m, n, and p are as described herein. [0521] In some embodiments, the disclosure provides a compound of the formula VIII, or a pharmaceutically acceptable salt thereof,
VIII [0522] wherein R
2, R
11, R
12, A, X, Z
1, Z
2, Z
3, Z
4, Z
5, m, and n are as described herein. [0523] In some embodiments, the disclosure provides a compound of the formula VIIIa, or a pharmaceutically acceptable salt thereof,
VIIIa [0524] wherein R
2, R
11, R
12, A, X, Z
1, Z
2, Z
3, Z
4, Z
5, m, and n are as described herein. [0525] In some embodiments, the disclosure provides a compound of the formula VIIIb, or a pharmaceutically acceptable salt thereof,
VIIIb [0526] wherein R
2, R
11, R
12, A, X, Z
1, Z
2, Z
3, Z
4, Z
5, m, and n are as described herein. [0527] In some embodiments, the disclosure provides a compound of the formula IX, or a pharmaceutically acceptable salt thereof,
[0528] wherein R
2, R
3, R
11, R
13, A, X, Z
1, Z
2, Z
3, Z
4, Z
5, m, n, and p are as described herein. [0529] In some embodiments, the disclosure provides a compound of the formula X, or a pharmaceutically acceptable salt thereof,
[0530] wherein R
2, R
11, R
13, A, X, Z
1, Z
2, Z
3, Z
4, Z
5, m, and n are as described herein. [0531] In some embodiments, the disclosure provides a compound of the formula Xa, or a pharmaceutically acceptable salt thereof,
[0532] wherein R
2, R
11, R
13, A, X, Z
1, Z
2, Z
3, Z
4, Z
5, m, and n are as described herein. [0533] In some embodiments, the disclosure provides a compound of the formula Xb, or a pharmaceutically acceptable salt thereof,
[0534] wherein R
2, R
11, R
13, A, X, Z
1, Z
2, Z
3, Z
4, Z
5, m, and n are as described herein. [0535] In some embodiments, the disclosure provides a compound of the formula XI, or a pharmaceutically acceptable salt thereof,
[0536] wherein R
1, R
2, R
3, R
10, R
a, R
b, B, X, Z
1, Z
2, Z
3, Z
4, Z
5, n, p, and q are as described herein. [0537] In some embodiments, the disclosure provides a compound of the formula XII, or a pharmaceutically acceptable salt thereof,
[0538] wherein R
2, R
3, R
10, R
11, R
a, R
b, A, B, X, Z
1, Z
2, Z
3, Z
4, Z
5, m, n, p, and q are as described herein. [0539] In some embodiments, the disclosure provides a compound of the formula XIII, or a pharmaceutically acceptable salt thereof,
XIII [0540] wherein R
2, R
3, R
10, R
11, R
a, R
b, A, X, Z
1, Z
2, Z
3, Z
4, Z
5, Z
6, Z
7, m, n, p, and q are as described herein. [0541] In some embodiments, the disclosure provides a compound of the formula XIV, or a pharmaceutically acceptable salt thereof,
XIV [0542] wherein R
2, R
10, R
11, R
a, R
b, A, X, Z
1, Z
2, Z
3, Z
4, Z
5, Z
6, Z
7, m, n, and q are as described herein.
[0543] In some embodiments, the disclosure provides a compound of the formula XIVa, or a pharmaceutically acceptable salt thereof,
XIVa [0544] wherein R
2, R
10, R
11, R
a, R
b, A, X, Z
1, Z
2, Z
3, Z
4, Z
5, Z
6, Z
7, m, n, and q are as described herein. [0545] In some embodiments, the disclosure provides a compound of the formula XV, or a pharmaceutically acceptable salt thereof,
XV
[0546] wherein R, R, R , R , R , R, R, A, X, Z, Z, Z, Z, Z, m, n, p, and q are as described herein. [0547] In some embodiments, the disclosure provides a compound of the formula XVI, or a pharmaceutically acceptable salt thereof,
XVI [0548] wherein R
2, R
10, R
11, R
12, R
a, R
b, A, X, Z
1, Z
2, Z
3, Z
4, Z
5, m, n, and q are as described herein. [0549] In some embodiments, the disclosure provides a compound of the formula XVIa, or a pharmaceutically acceptable salt thereof,
XVIa [0550] wherein R
2, R
10, R
11, R
12, R
a, R
b, A, X, Z
1, Z
2, Z
3, Z
4, Z
5, m, n, and q are as described herein. [0551] In some embodiments, the disclosure provides a compound of the formula XVIb, or a pharmaceutically acceptable salt thereof,
XVIb [0552] wherein R
2, R
10, R
11, R
12, R
a, R
b, A, X, Z
1, Z
2, Z
3, Z
4, Z
5, m, n, and q are as described herein.
[0553] In some embodiments, the disclosure provides a compound of the formula XVII, or a pharmaceutically acceptable salt thereof,
[0554] wherein R
2, R
3, R
10, R
11, R
13, R
a, R
b, A, X, Z
1, Z
2, Z
3, Z
4, Z
5, m, n, p, and q are as described herein. [0555] In some embodiments, the disclosure provides a compound of the formula XVIII, or a pharmaceutically acceptable salt thereof,
[0556] wherein R, R , R , R , R, R, A, X, Z, Z, Z, Z, Z, m, n, and q are as described herein. [0557] In some embodiments, the disclosure provides a compound of the formula XVIIIa, or a pharmaceutically acceptable salt thereof,
XVIIIa [0558] wherein R
2, R
10, R
11, R
13, R
a, R
b, A, X, Z
1, Z
2, Z
3, Z
4, Z
5, m, n, and q are as described herein. [0559] In some embodiments, the disclosure provides a compound of the formula XVIIIb, or a pharmaceutically acceptable salt thereof,
XVIIIb [0560] wherein R
2, R
10, R
11, R
13, R
a, R
b, A, X, Z
1, Z
2, Z
3, Z
4, Z
5, m, n, and q are as described herein. [0561] In some embodiments, the disclosure provides a compound of the formula XIX, or a pharmaceutically acceptable salt thereof,
[0562] wherein R
1, R
2, R
3, R
a, R
b, B, X, Z
1, Z
2, Z
3, Z
4, Z
5, n, p, and q are as described herein. [0563] In some embodiments, the disclosure provides a compound of the formula XX, or a pharmaceutically acceptable salt thereof,
XX [0564] wherein R
1, R
2, R
a, R
b, B, X, Z
1, Z
2, Z
3, Z
4, Z
5, n, p, and q are as described herein. [0565] In some embodiments, the disclosure provides a compound of the formula XXa, or a pharmaceutically acceptable salt thereof,
XXa [0566] wherein R
1, R
2, R
a, R
b, B, X, Z
1, Z
2, Z
3, Z
4, Z
5, n, p, and q are as described herein. [0567] In some embodiments, the compound is not of the formula
[0568] In some embodiments, at least one hydrogen atom on ring A, ring B, R
1, or R
3 in the compound of the formula I is substituted by a deuterium. [0569] In some embodiments, Y is -S(O)
2- or –C(O)NR
10-. In some embodiments, Y is -S(O)
2- . In some embodiments, Y is –C(O)NR
10-. In some embodiments, Y is -S(O)
2- or –C(O)NR
10- , and R
1 is ring A. In some embodiments, Y is -S(O)
2-, and R
1 is ring A. In some embodiments, Y is or –C(O)NR
10-, and R
1 is ring A. In some embodiments, Y is a bond, -O-, –S-, –S(O)-, or –S(O)
2-, then R
1 is ring A. In some embodiments, Y is -O-, -S-, or -S(O)- , and R
1 is ring A. In some embodiments, Y is -O-, and R
1 is ring A. In some embodiments, Y is -S-, and R
1 is ring A. In some embodiments, Y is -S(O)- , and R
1 is ring A. In some embodiments, Y is a bond, and R
1 is ring A. [0570] In some embodiments, ring A is a C
3-C
8 cycloalkyl, 4- to 10-membered heterocycloalkyl, C
6-C
10 aryl, or 5- to 10-membered heteroaryl, wherein each of C
3-C8 cycloalkyl, 4- to 10-membered heterocycloalkyl, C
6-C
10 aryl, or 5- to 10-membered heteroaryl is unsubstituted or substituted with one or more of R
11. In some embodiments, ring A is an unsubstituted C
3-C8 cycloalkyl, or a C
3-C8 cycloalkyl substituted with one or more of R
11. In some embodiments, ring A is an unsubstituted 4- to 10-membered heterocycloalkyl, or a 4- to 10-membered heterocycloalkyl substituted with one or more of R
11. In some embodiments, ring A is an unsubstituted C
6-C
10 aryl, or a C
6-C
10 aryl substituted with one or more of R
11. In some embodiments, ring A is an unsubstituted 5- to 10-membered heteroaryl, or a 5- to 10-
membered heteroaryl substituted with one or more of R . In some embodiments, ring A is a 4- to 10-membered heterocycloalkyl that is unsubstituted or substituted with one or more of R
11 and is covalently attached to –Y-, -(CR
aR
b)n-, or
through a carbon atom in the 4- to 10-membered heterocycloalkyl. [0571] In some embodiments, ring A is a C
3-C8 cycloalkyl, 4- to 10-membered heterocycloalkyl, C
6-C
10 aryl, or 5- to 10-membered heteroaryl, wherein each of C
3-C
8 cycloalkyl, 4- to 10-membered heterocycloalkyl, C
6-C
10 aryl, or 5- to 10-membered heteroaryl is unsubstituted or substituted with 1, 2, 3, 4, 5, or 6 of R
11. In some embodiments, ring A is an unsubstituted C
3-C8 cycloalkyl, or a C
3-C8 cycloalkyl substituted with 1, 2, 3, 4, 5, or 6 of R
11. In some embodiments, ring A is an unsubstituted 4- to 10-membered heterocycloalkyl, or a 4- to 10-membered heterocycloalkyl substituted with 1, 2, 3, 4, 5, or 6 of R
11. In some embodiments, ring A is an unsubstituted C
6-C
10 aryl, or a C
6-C
10 aryl substituted with 1, 2, 3, 4, 5, or 6 of R
11. In some embodiments, ring A is an unsubstituted 5- to 10-membered heteroaryl, or a 5- to 10-membered heteroaryl substituted with 1, 2, 3, 4, 5, or 6 of R
11. In some embodiments, ring A is a 4- to 10-membered heterocycloalkyl that is unsubstituted or is substituted with 1, 2, 3, 4, 5, or 6 of R
11, and is covalently attached to –Y-, -(CR
aR
b)n-, or
through a carbon atom in the 4- to 10-membered heterocycloalkyl. [0572] In some embodiments, ring A is a 4- to 10-membered heterocycloalkyl that is an unsubstituted or a substituted ring of the formula
[0573] In some embodiments, ring A is a 4- to 10-membered heterocycloalkyl that is not an unsubstituted or a substituted ring of the formula
[0574] In some embodiments, ring A is a 4- to 10-membered heterocycloalkyl that is not an unsubstituted or a substituted ring of the formula
wherein * is a
point of covalent attachment, [0575] In some embodiments, A is 4- to 10-membered heterocycloalkylthat is a mono-cyclic 4- to 10-membered heterocycloalkyl, a fused bicyclic 5- to 10-membered heterocycloalkyl, a bridged bicyclic 6- to 10-membered heterocycloalkyl, or a spiro bicyclic 6- to 10-membered heterocycloalkyl. In some embodiments, ring A is a 4- to 10-membered heterocycloalkyl. In some embodiments, ring A is a mono-cyclic 4- to 10-membered heterocycloalkyl. In some embodiments, ring A is a bicyclic 5- to 10-membered heterocycloalkyl. In some embodiments, ring A is a fused bicyclic 5- to 10-membered heterocycloalkyl. In some embodiments, ring A is a bridged bicyclic 6- to 10-membered heterocycloalkyl. In some embodiments, ring A is a spiro bicyclic 6- to 10-membered heterocycloalkyl. [0576] In some embodiments, ring A is
[0577] In some embodiments, Ring A is
wherein * is a point of covalent attachment to
, and m is 0 or one or more. In some embodiments, m is 0, 1, 2, 3, 4, 5, or 6. [0578] In some embodiments, Ring A is
[0579] wherein * is a point of covalent attachment to
, and m is 0, 1, 2, 3, 4, or 5. [0580] In some embodiments, Ring A is not of the formula
[0581] wherein * is a point of covalent attachment to [0582] In some embodiments, Ring A is
[0583] wherein * is a point of covalent attachment to
, and m is 0 or one or more. In some embodiments, m is 0, 1, 2, 3, 4, 5, or 6. [0584] In some embodiments, Ring A is azitidinyl, oxtenanyl, thietanyl, pyrrolidinyl, tetrahydrofuranyl, 2,5-dihydro-1H-pyrrolyl, pyrazolidinyl, thiazolidinyl, 4,5-dihydro-1H- imidazolyl, dihydrothiophen-2(3H)-onyl, tetrahydrothiophenyl 1,1-dioxide, imidazolidin-2- onyl, pyrrolidin-2-onyl, dihydrofuran-2(3H)-onyl, 1,3-dioxolan-2-onyl, oxazolidin-2-onyl, piperidinyl, morpholinyl, 4H-1,4-thiazinyl, 1,2,3,4-tetrahydropyridinyl, piperazinyl, 1,3- oxazinan-2-onyl, piperazin-2-onyl, thiomorpholinyl, thiomorpholinyl 1,1-dioxide, 3,8- diazabycyclo[3.2.1]octanyl, or (1R,5S)-3,8-diazabicyclo[3.2.1]octanyl, wherein each hydrogen atom in azitidinyl, oxtenanyl, thietanyl, pyrrolidinyl, tetrahydrofuranyl, 2,5-dihydro- 1H-pyrrolyl, pyrazolidinyl, thiazolidinyl, 4,5-dihydro-1H-imidazolyl, dihydrothiophen-2(3H)- onyl, tetrahydrothiophenyl 1,1-dioxide, imidazolidin-2-onyl, pyrrolidin-2-onyl, dihydrofuran- 2(3H)-onyl, 1,3-dioxolan-2-onyl, oxazolidin-2-onyl, piperidinyl, morpholinyl, 4H-1,4- thiazinyl, 1,2,3,4-tetrahydropyridinyl, piperazinyl, 1,3-oxazinan-2-onyl, piperazin-2-onyl, thiomorpholinyl, thiomorpholinyl 1,1-dioxide, 3,8-diazabycyclo[3.2.1]octanyl, or (1R,5S)- 3,8-diazabicyclo[3.2.1]octanyl, is independently optionally substituted by an R
11. [0585] In some embodiments, Ring A is
[0586] wherein * is a point of covalent attachment to
[0587] In some embodiments, Ring A is
, o , [0588] wherein * is a point of covalent attachment to
[0589] In some embodiments, Ring A is
[0590] wherein * is a point of covalent attachment to [0591] In some embodiments, Ring A is
[0592] wherein * is a point of covalent attachment to
[0593] In some embodiments, Ring A is not of the formula
[0594] wherein * is a point of covalent attachment to
[0595] In some embodiments, Ring A is an unsubstituted C
6-C
10 aryl or a C
6-C
10 aryl substituted with one or more of R
11. In some embodiments, Ring A is a unsubstituted phenyl, unsubstituted naphthyl, phenyl substituted with 1, 2, 3, 4, or 5 of R
11, or naphthyl substituted with one or more of R
11. In some embodiments, Ring A is a unsubstituted phenyl, unsubstituted naphthyl, phenyl substituted with 1, 2, 3, 4, or 5 of R
11, or naphthyl substituted with 1, 2, 3, 4, 5, or 6 of R
11. [0596] In some embodiments, Ring A is an substituted 5- to 10-membered heteroaryl or a 5- to 10-membered heteroaryl substituted with one or more of R
11. In some embodiments, Ring A is an substituted 5- to 10-membered heteroaryl or a 5- to 10-membered heteroaryl substituted with 1, 2, 3, 4, 5, or 6 of R
11. [0597] In some embodiments, Ring A is of the formula
[0598] wherein * is a point of covalent attachment to , and m is 0, 1, 2, or
3. [0599] In some embodiments, Ring A is of the formula
[0600] wherein * is a point of covalent attachment to
, and m is 0 or one or more. In some embodiments, m is 0, 1, 2, or 3. [0601] In some embodiments, Ring A is of the formula
[0602] wherein * is a point of covalent attachment to
[0603] In some embodiments, Ring A is of the formula
[0604] wherein * is a point of covalent attachment to
. [0605] In some embodiments, Ring A is an unsubstituted C
3-C
8 cycloalkyl or a C
3-C
8 cycloalkyl substituted with one or more of R
11. In some embodiments, Ring A is an unsubstituted C
3-C
8 cycloalkyl or a C
3-C
8 cycloalkyl substituted with 1, 2, 3, 4, 5, or 6 of R
11. In some embodiments, Ring A is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or cyclooctyl, each of which is optionally substituted with 1, 2, 3, 4, 5, or 6 of R
11. In some embodiments, ring A is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, each of which is optionally substituted with 1, 2, 3, 4, 5, or 6 of R
11 independently selected from the group consisting of deuterium, fluoro, chloro, bromo, C
1-C
6 alkyl, -OR
a, or C
1-C
6 alkyl-OR
e. In some embodiments, Ring A is of the formula
[0606] wherein * is a point of covalent attachment to Y or
[0607] In some embodiments, each R
11 is independently deuterium, halogen, C
1-C
6 alkyl, C
2- C6 alkenyl, C2-C6 alkynyl, C
3-C
6 cycloalkyl, 4- to 10-membered heterocycloalkyl, C
6-C
10 aryl, 5- to 10-membered heteroaryl, -OR
a, -OC(O)R
a, -OC(O)NR
aR
b, -OC(=NR
a)NR
aR
b, -OS(O)R
a,
OS(O)
2R , OS(O)NR R , OS(O)
2NR R , SR , S(O)R , S(O)
2R , S(O)NR R , -S(O)
2NR
aR
b, -NR
aR
b, -NR
aC(O)R
b, -N(C(O)R
a)(C(O)R
b), -NR
aC(O)OR
b, -NR
aC(O)NR
aR
b, -NR
aC(=NR
a)NR
aR
b, -NR
aS(O)R
b, -NR
aS(O)
2R
b, -NR
aS(O)NR
aR
b, -NR
aS(O)
2NR
aR
b, - C(O)R
a, -C(O)OR
a, -C(O)NR
aR
b, -C(=NR
a)NR
aR
b, -PR
aR
b, -P(O)R
aR
b, -P(O)
2R
aR
b, - P(O)NR
aR
b, -P(O)
2NR
aR
b, -P(O)OR
a, -P(O)
2OR
a, -CN, or -NO
2, or two of R
11 taken together with the atom or atoms to which they are attached or three of R
11 taken together with the atoms to which they are attached, form a C
3-C
6 cycloalkyl or a 4- to 10-membered heterocycloalkyl, wherein each hydrogen atom in C
1-C
6 alkyl, C
2-C
6 alkenyl, C
2-C
6 alkynyl, C
3-C
6 cycloalkyl, C
6-C
10 aryl, 5- to 10-membered heteroaryl, and 4- to 10-membered heterocycloalkyl is independently optionally substituted by deuterium, halogen, -R
e, -R
f, C
1-C
6 alkyl, C
1-C
6 haloalkyl, -OR
e, -OC(O)R
e, -OC(O)NR
eR
f, -OS(O)R
e, -OS(O)
2R
e, -OS(O)NR
eR
f, -OS(O)
2NR
eR
f, -SR
e, -S(O)R
e, -S(O)
2R
e, -S(O)NR
eR
f, -S(O)
2NR
eR
f, -NR
eR
f, -NR
eC(O)R
f, - NR
eC(O)OR
f, -NR
eC(O)NR
eR
f, -NR
eS(O)R
f, -NR
eS(O)
2R
f, -NR
eS(O)NR
eR
f, -NR
eS(O)
2NR
eR
f, -C(O)R
e, -C(O)OR
e, -C(O)NR
eR
f, -PR
eR
f, -P(O)R
eR
f, -P(O)
2R
eR
f, -P(O)NR
eR
f, -P(O)
2NR
eR
f, -P(O)OR
e, -P(O)
2OR
e, -CN, or -NO2, or two of R
11 taken together with the carbon atom to which they are attached form an oxo group or an alkenyl group. [0608] In some embodiments, each R
11 is independently deuterium, halogen, C
1-C
6 alkyl, C2- C6 alkenyl, C2-C6 alkynyl, C
3-C
6 cycloalkyl, 4- to 10-membered heterocycloalkyl, C
6-C
10 aryl, 5- to 10-membered heteroaryl, -OR
a, -OC(O)R
a, -OC(O)NR
aR
b, -OS(O)R
a, -OS(O)
2R
a, -OS(O)NR
aR
b, -OS(O)
2NR
aR
b, -SR
a, -S(O)R
a, -S(O)
2R
a, -S(O)NR
aR
b, -S(O)
2NR
aR
b, -NR
aC(O)R
b, -N(C(O)R
a)(C(O)R
b), -NR
aC(O)OR
b, -NR
aC(O)NR
aR
b, -NR
aS(O)R
b, -NR
aS(O)
2R
b, -NR
aS(O)NR
aR
b, -NR
aS(O)
2NR
aR
b, -C(O)R
a, -C(O)OR
a, -C(O)NR
aR
b, -PR
aR
b, -P(O)R
aR
b, -P(O)
2R
aR
b, -P(O)NR
aR
b, -P(O)
2NR
aR
b, -P(O)OR
a, -P(O)
2OR
a, -CN, or -NO
2, or two of R
11 taken together with the atom or atoms to which they are attached or three of R
11 taken together with the atoms to which they are attached, form a C
3-C
6 cycloalkyl or a 4- to 10-membered heterocycloalkyl, wherein each hydrogen atom in C
1-C
6 alkyl, C2-C6 alkenyl, C
2-C
6 alkynyl, C
3-C
6 cycloalkyl, C
6-C
10 aryl, 5- to 10-membered heteroaryl, and 4- to 10- membered heterocycloalkyl is independently optionally substituted by deuterium, halogen, - R
e, -R
f, C
1-C
6 alkyl, C
1-C
6 haloalkyl, -OR
e, -OC(O)R
e, -OC(O)NR
eR
f, -OS(O)R
e, -OS(O)
2R
e, -OS(O)NR
eR
f, -OS(O)
2NR
eR
f, -SR
e, -S(O)R
e, -S(O)
2R
e, -S(O)NR
eR
f, -S(O)
2NR
eR
f, -NR
eC(O)R
f, -NR
eC(O)OR
f, -NR
eC(O)NR
eR
f, -NR
eS(O)R
f, -NR
eS(O)
2R
f, -NR
eS(O)NR
eR
f, -NR
eS(O)
2NR
eR
f, -C(O)R
e, -C(O)OR
e, -C(O)NR
eR
f, -PR
eR
f, -P(O)R
eR
f, -P(O)
2R
eR
f, -P(O)NR
eR
f, -P(O)
2NR
eR
f, -P(O)OR
e, -P(O)
2OR
e, -CN, or -NO2; wherein each R
a, R
b, R
e, and R
f, is independently selected from the group consisting of H, deuterium, C
1-C
6 alkyl, C
2-C
6 alkenyl, C2-C6 alkynyl, C
3-C
6 cycloalkyl, 4- to 10-membered heterocycloalkyl, C
6-C
10 aryl, C1-
C
6 alkyl C
6 C
10 aryl, and 5 to 10 membered heteroaryl; or two of R and R , or R and R, taken together with the atom or atoms to which they are attached, combine to form a C
3-C
6 cycloalkyl, 4- to 10-membered heterocycloalkyl, C
6-C
10 aryl, or 5- to 10-membered heteroaryl, wherein each hydrogen atom in C
1-C
6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C
3-C
6 cycloalkyl, 4- to 10-membered heterocycloalkyl, C
6-C
10 aryl, C
1-C
6 alkyl-C
6-C
10 aryl, and 5- to 10- membered heteroaryl is independently optionally substituted by deuterium, halogen, C
1-C
6 alkyl, C
1-C
6 haloalkyl, -OH, -OC
1-C
6 alkyl, -OC(O)C
1-C
6 alkyl, -OC(O)N(H or C
1-C
6 alkyl)
2, -OS(O)C
1-C
6 alkyl, -OS(O)
2C
1-C
6 alkyl, -OS(O)N(H or C
1-C
6 alkyl)
2, -OS(O)
2N(H or C
1-C
6 alkyl)
2, -SC
1-C
6 alkyl, -S(O)C
1-C
6 alkyl, -S(O)
2C
1-C
6 alkyl, -S(O)N(H or C
1-C
6 alkyl)
2, - S(O)
2N(H or C
1-C
6 alkyl)
2, -N(C
1-C
6 alkyl)C(O)-C
1-C
6 alkyl, -N(C
1-C
6 alkyl)C(O)OC
1-C
6 alkyl, -N(C
1-C
6 alkyl)C(O)N(H or C
1-C
6 alkyl)
2, -N(C
1-C
6 alkyl)S(O)C
1-C
6 alkyl, -N(C
1-C
6 alkyl)S(O)
2C
1-C
6 alkyl, -N(C
1-C
6 alkyl)S(O)N(H or C
1-C
6 alkyl)
2, -N(C
1-C
6 alkyl)S(O)
2N(H or C
1-C
6 alkyl)
2, -C(O)C
1-C
6 alkyl, -C(O)OC
1-C
6 alkyl, -C(O)N(H or C
1-C
6 alkyl)
2, -P(H or C
1-C
6 alkyl)
2, -P(O)(H or C
1-C
6 alkyl)
2, -P(O)
2(H or C
1-C
6 alkyl)
2, -P(O)N(H or C
1-C
6 alkyl)
2, -P(O)
2N(H or C
1-C
6 alkyl)
2, -P(O)OC
1-C
6 alkyl, -P(O)
2OC
1-C
6 alkyl, -CN, or -NO2, or two of R
11 taken together with the carbon atom to which they are attached form an oxo group or an alkenyl group. [0609] In some embodiments, each R
11 is independently selected from the group consisting of deuterium, fluoro, chloro, bromo, C
1-C
6 alkyl, -OR
a, or C
1-C
6 alkyl-OR
e. In some embodiments, each R
11 is independently selected from the group consisting of deuterium, fluoro, chloro, bromo, C
1-C
6 alkyl, -OR
a wherein R
a is not H, or C
1-C
6 alkyl-OR
e, wherein R
e is not H. [0610] In some embodiments, m is 0. In some embodiments, m is one or more. In some embodiments, m is 0, 1, 2, 3, 4, 5, 6, 7, or 8. In some embodiments, m is 0, 1, 2, 3, 4, 5, 6, or 7. In some embodiments, m is 0, 1, 2, 3, 4, 5, or 6. In some embodiments, m is 0, 1, 2, 3, 4, or 5. In some embodiments, m is 0, 1, 2, 3, or 4. In some embodiments, m is 0, 1, 2, or 3. In some embodiments, m is 0, 1, or 2. In some embodiments, m is 0 or 1. In some embodiments, m is 1. In some embodiments, m is 2. In some embodiments, m is 3. In some embodiments, m is 4. [0611] In some embodiments, ring B is a C
6-C
10 aryl or 5- to 10-membered heteroaryl, optuionally substituted with one or more R
2, R
12, or R
13. [0612] In some embodiments, Ring B is
[0613] wherein wherein * is a point of covalent attachment to
, n is 0 or one or more. In some embodiments, n is 0, 1, 2, 3, 4, 5, 6, or 7. [0614] In some embodiments, Ring B is
[0615] wherein wherein * is a point of covalent attachment to
n is 0 or one or more. In some embodiments, n is 0, 1, 2, 3, 4, 5, 6, or 7. [0616] In some embodiments, Ring B is
[0617] wherein wherein * is a point of covalent attachment to
, n is 0 or one or more. In some embodiments, n is 0, 1, 2, 3, 4, 5, 6, or 7. [0618] In some embodiments, each R
2 is independently deuterium, halogen, C
1-C
6 alkyl, C2- C
6 alkenyl, C
2-C
6 alkynyl, C
3-C
6 cycloalkyl, 4- to 10-membered heterocycloalkyl, C
6-C
10 aryl,
5 to 10 membered heteroaryl, OR , OC(O)R , OC(O)NR R , OC( NR )NR R , OS(O)R , -OS(O)
2R
c, -OS(O)NR
cR
d, -OS(O)
2NR
cR
d, -SR
c, -S(O)R
c, -S(O)
2R
c, -S(O)NR
cR
d, -S(O)
2NR
cR
d, -NR
cR
d, -NR
cC(O)R
d, -N(C(O)R
c)(C(O)R
d), -NR
cC(O)OR
d, -NR
cC(O)NR
cR
d, -NR
cC(=NR
c)NR
cR
d, -NR
cS(O)R
d, -NR
cS(O)
2R
d, -NR
cS(O)NR
cR
d, -NR
cS(O)
2NR
cR
d, - C(O)R
c, -C(O)OR
c, -C(O)NR
cR
d, -C(=NR
c)NR
cR
d, -PR
cR
d, -P(O)R
cR
d, -P(O)
2R
cR
d, - P(O)NR
cR
d, -P(O)
2NR
cR
d, -P(O)OR
c, -P(O)
2OR
c, -CN, or -NO
2, or two of R
2 taken together with the atoms to which they are attached form a C
3-C
6 cycloalkyl or a 4- to 10-membered heterocycloalkyl, wherein each hydrogen atom in C
1-C
6 alkyl, C
2-C
6 alkenyl, C
2-C
6 alkynyl, C
3-C
6 cycloalkyl, C
6-C
10 aryl, 5- to 10-membered heteroaryl, and 4- to 10-membered heterocycloalkyl is independently optionally substituted by deuterium, halogen, C
1-C
6 alkyl, C
1-C
6 haloalkyl, -R
e, -R
f, -OR
e, -OC(O)R
e, -OC(O)NR
eR
f, -OS(O)R
e, -OS(O)
2R
e, -OS(O)NR
eR
f, -OS(O)
2NR
eR
f, -SR
e, -S(O)R
e, -S(O)
2R
e, -S(O)NR
eR
f, -S(O)
2NR
eR
f, -NR
eR
f, -NR
eC(O)R
f, -NR
eC(O)OR
f, -NR
eC(O)NR
eR
f, -NR
eS(O)R
f, -NR
eS(O)
2R
f, -NR
eS(O)NR
eR
f, -NR
eS(O)
2NR
eR
f, -C(O)R
e, -C(O)OR
e, -C(O)NR
eR
f, -PR
eR
f, -P(O)R
eR
f, -P(O)
2R
eR
f, -P(O)NR
eR
f, -P(O)
2NR
eR
f, -P(O)OR
e, -P(O)
2OR
e, -CN, or -NO2. In some embodiments, each R
2 is independently deuterium, halogen, C
1-C
6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, -OR
c, or - CN. In some embodiments, each R
2, when present, is independently selected from the group consisting of fluoro, chloro, C
1-C
6 alkyl, -OH, and -CN. In some embodiments, each R
2, when present, is independently selected from the group consisting of fluoro, chloro, methyl, ethyl, iso-propyl, -C≡CH, -CN, and -OH. [0619] In some embodiments, R
12 is H, deuterium, C
1-C
6 alkyl, C
2-C
6 alkenyl, C
2-C
6 alkynyl, C
3-C
6 cycloalkyl, 4- to 10-membered heterocycloalkyl, C
6-C
10 aryl, or 5- to 10-membered heteroaryl, wherein each hydrogen atom in C
1-C
6 alkyl, C
2-C
6 alkenyl, C
2-C
6 alkynyl, C
3-C
6 cycloalkyl, 4- to 10-membered heterocycloalkyl, C
6-C
10 aryl, and 5- to 10-membered heteroaryl is independently optionally substituted by deuterium, halogen, -R
e, -R
f, C
1-C
6 alkyl, C
1-C
6 haloalkyl, -OR
e, -OC(O)R
e, -OC(O)NR
eR
f, -OS(O)R
e, -OS(O)
2R
e, -OS(O)NR
eR
f, -OS(O)
2NR
eR
f, -SR
e, -S(O)R
e, -S(O)
2R
e, -S(O)NR
eR
f, -S(O)
2NR
eR
f, -NR
eR
f, -NR
eC(O)R
f, -NR
eC(O)OR
f, -NR
eC(O)NR
eR
f, -NR
eS(O)R
f, -NR
eS(O)
2R
f, -NR
eS(O)NR
eR
f, - NR
eS(O)
2NR
eR
f, -C(O)R
e, -C(O)OR
e, -C(O)NR
eR
f, -PR
eR
f, -P(O)R
eR
f, -P(O)
2R
eR
f, - P(O)NR
eR
f, -P(O)
2NR
eR
f, -P(O)OR
e, -P(O)
2OR
e’, -CN, or -NO2. In some embodiments, R
12 is H, deuterium, or C
1-C
6 alkyl. In some embodiments, R
12 is H, deuterium, or methyl. [0620] In some embodiments, R
13 is H, deuterium, C
1-C
6 alkyl, C
2-C
6 alkenyl, C
2-C
6 alkynyl, C
3-C
6 cycloalkyl, 4- to 10-membered heterocycloalkyl, C
6-C
10 aryl, or 5- to 10-membered heteroaryl, wherein each hydrogen atom in C
1-C
6 alkyl, C
2-C
6 alkenyl, C
2-C
6 alkynyl, C
3-C
6 cycloalkyl, 4- to 10-membered heterocycloalkyl, C
6-C
10 aryl, and 5- to 10-membered
heteroaryl is independently optionally substituted by deuterium, halogen, R , R, C
1 C
6 alkyl, C
1-C
6 haloalkyl, -OR
e, -OC(O)R
e, -OC(O)NR
eR
f, -OS(O)R
e, -OS(O)
2R
e, -OS(O)NR
eR
f, -OS(O)
2NR
eR
f, -SR
e, -S(O)R
e, -S(O)
2R
e, -S(O)NR
eR
f, -S(O)
2NR
eR
f, -NR
eR
f, -NR
eC(O)R
f, -NR
eC(O)OR
f, -NR
eC(O)NR
eR
f, -NR
eS(O)R
f, -NR
eS(O)
2R
f, -NR
eS(O)NR
eR
f, - NR
eS(O)
2NR
eR
f, -C(O)R
e, -C(O)OR
e, -C(O)NR
eR
f, -PR
eR
f, -P(O)R
eR
f, -P(O)
2R
eR
f, - P(O)NR
eR
f, -P(O)
2NR
eR
f, -P(O)OR
e, -P(O)
2OR
e’, -CN, or -NO
2. In some embodiments, R
13 is H, deuterium, or C
1-C
6 alkyl. In some embodiments, R
13 is H, deuterium, or methyl. [0621] In some embodiments, n is 0. In some embodiments, n is one or more. In some embodiments, n is 0, 1, 2, 3, 4, 5, 6, 7, or 8. In some embodiments, n is 0, 1, 2, 3, 4, 5, 6, or 7. In some embodiments, n is 0, 1, 2, 3, 4, 5, or 6. In some embodiments, n is 0, 1, 2, 3, 4, or 5. In some embodiments, n is 0, 1, 2, 3, or 4. In some embodiments, n is 0, 1, 2, or 3. In some embodiments, n is 0, 1, or 2. In some embodiments, n is 0 or 1. In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, n is 3. In some embodiments, n is 4. [0622] In some embodiments, Ring B is
[0623] In some embodiments, q is 0. In some embodiments, q is 1.
[0624] In some embodiments, X is O , S , or NR . In some embodiments, X is O . In some embodiments, -X- is -S-. In some embodiments, -X- is –NR
4-. [0625] In some embodiments, R
4 is H, deuterium, C
1-C
6 alkyl, C
2-C
6 alkenyl, C
2-C
6 alkynyl, C
3-C
6 cycloalkyl, 4- to 10-membered heterocycloalkyl, C
6-C
10 aryl, or 5- to 10-membered heteroaryl, wherein each hydrogen atom in C
1-C
6 alkyl, C
2-C
6 alkenyl, C
2-C
6 alkynyl, C
3-C
6 cycloalkyl, 4- to 10-membered heterocycloalkyl, C
6-C
10 aryl, and 5- to 10-membered heteroaryl is independently optionally substituted by deuterium, halogen, -R
e, -R
f, C
1-C
6 alkyl, C
1-C
6 haloalkyl, -OR
e, -OC(O)R
e, -OC(O)NR
eR
f, -OS(O)R
e, -OS(O)
2R
e, -OS(O)NR
eR
f, -OS(O)
2NR
eR
f, -SR
e, -S(O)R
e, -S(O)
2R
e, -S(O)NR
eR
f, -S(O)
2NR
eR
f, -NR
eR
f, -NR
eC(O)R
f, -NR
eC(O)OR
f, -NR
eC(O)NR
eR
f, -NR
eS(O)R
f, -NR
eS(O)
2R
f, -NR
eS(O)NR
eR
f, - NR
eS(O)
2NR
eR
f, -C(O)R
e, -C(O)OR
e, -C(O)NR
eR
f, -PR
eR
f, -P(O)R
eR
f, -P(O)
2R
eR
f, - P(O)NR
eR
f, -P(O)
2NR
eR
f, -P(O)OR
e, -P(O)
2OR
e’, -CN, or -NO
2. In some embodiments, R
4 is H, deuterium, or C
1-C
6 alkyl. In some embodiments, R
4 is H, deuterium, or methyl. [0626] In some embodiments, R
3 is -C
1-C
6 alkyl, -C
2-C
6 alkenyl, -C
2-C
6 alkynyl, -C
3-C
6 cycloalkyl, 4- to 10-membered heterocycloalkyl, -C
1-C
6 alkylene-(4- to 10-membered heterocycloalkyl), -C
6-C
10 aryl, -C
1-C
6 alkylene-(C
6-C
10 aryl), 5- to 10-membered heteroaryl, or -C
1-C
6 alkylene-(4- to 10-membered heterocycloalkyl), wherein each hydrogen atom in C1- C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C
3-C
6 cycloalkyl, 4- to 10-membered heterocycloalkyl, -C
1-C
6 alkylene-(4- to 10-membered heterocycloalkyl), C
6-C
10 aryl, -C
1-C
6 alkylene-(C
6-C
10 aryl), 5- to 10-membered heteroaryl, and -C
1-C
6 alkylene-(5- to 10-membered heteroaryl), is independently optionally substituted by deuterium, halogen, -R
e, -R
f, C
1-C
6 alkyl, -C
1-C
6 alkyl- O-C
1-C
6 alkyl, -OC
1-C
6 alkyl-O-C
1-C
6 alkyl, -C
1-C
6 alkyl-O-R
a, C
6-C
10 aryl, -C
1-C
6 alkyl-(C6- C
10 aryl), haloalkyl, C
3-C
6 cycloalkyl, 5- to 10-membered heteroaryl, -C
1-C
6 alkyl-(5- to 10- membered heterocycloalkyl), -OR
e, -OC(O)R
e, -OC(O)NR
eR
f, -OS(O)R
e, -OS(O)
2R
e, -OS(O)NR
eR
f, -OS(O)
2NR
eR
f, -SR
e, -S(O)R
e, -S(O)
2R
e, -S(O)NR
eR
f, -S(O)
2NR
eR
f, -NR
eR
f, -NR
eC(O)R
f, -NR
eC(O)OR
f, -NR
eC(O)NR
eR
f, -NR
eC(=NR
f)NR
eR
f, -NR
eS(O)R
f, -NR
eS(O)
2R
f, -NR
eS(O)NR
eR
f, -NR
eS(O)
2NR
eR
f, -C(O)R
e, -C(O)OR
e, -C(O)NR
eR
f, -PR
eR
f, -P(O)R
eR
f, -P(O)
2R
eR
f, -P(O)NR
eR
f, -P(O)
2NR
eR
f, -P(O)OR
e, -P(O)
2OR
e’, -CN, or -NO2. [0627] In some embodiments, R
3 is -C
1-C
6 alkyl, 4- to 10-membered heterocycloalkyl, or -C1- C6 alkylene-(4- to 10-membered heterocycloalkyl), wherein each hydrogen atom in -C
1-C
6 alkyl, 4- to 10-membered heterocycloalkyl, or -C
1-C
6 alkylene-(4- to 10-membered heterocycloalkyl), is independently optionally substituted by deuterium, halogen, C
1-C
6 alkyl, -C
1-C
6 alkyl-O-C
1-C
6 alkyl, -OC
1-C
6 alkyl-O-C
1-C
6 alkyl, -C
1-C
6 alkyl-O-R
a, C
6-C
10 aryl, - C
1-C
6 alkyl-(C
6-C
10 aryl), haloalkyl, C
3-C
6 cycloalkyl, 5- to 10-membered heteroaryl, 4- to 10- membered heterocycloalkyl, -C
1-C
6 alkyl-(4- to 10-membered heterocycloalkyl), -OR
e,
OC(O)R , OC(O)NR R, OS(O)R , OS(O)
2R , OS(O)NR R, OS(O)
2NR R, SR , -S(O)R
e, -S(O)
2R
e, -S(O)NR
eR
f, -S(O)
2NR
eR
f, -NR
eR
f, -NR
eC(O)R
f, -NR
eC(O)OR
f, -NR
eC(O)NR
eR
f, -NR
eC(=NR
f)NR
eR
f, -NR
eS(O)R
f, -NR
eS(O)
2R
f, -NR
eS(O)NR
eR
f, -NR
eS(O)
2NR
eR
f, -C(O)R
e, -C(O)OR
e, -C(O)NR
eR
f, -PR
eR
f, -P(O)R
eR
f, -P(O)
2R
eR
f, - P(O)NR
eR
f, -P(O)
2NR
eR
f, -P(O)OR
e, -P(O)
2OR
e’, -CN, or -NO
2. [0628] In some embodiments, R
3 is 4- to 10-membered heterocycloalkyl, wherein each hydrogen atom in 4- to 10-membered heterocycloalkyl is independently optionally substituted by deuterium, halogen, C
1-C
6 alkyl, -C
1-C
6 alkyl-O-C
1-C
6 alkyl, -OC
1-C
6 alkyl-O-C
1-C
6 alkyl, -C
1-C
6 alkyl-O-R
a, C
6-C
10 aryl, -C
1-C
6 alkyl-(C
6-C
10 aryl), haloalkyl, C
3-C
6 cycloalkyl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocycloalkyl, -C
1-C
6 alkyl-(4- to 10- membered heterocycloalkyl), -OR
e, -OC(O)R
e, -OC(O)NR
eR
f, -OS(O)R
e, -OS(O)
2R
e, -OS(O)NR
eR
f, -OS(O)
2NR
eR
f, -SR
e, -S(O)R
e, -S(O)
2R
e, -S(O)NR
eR
f, -S(O)
2NR
eR
f, -NR
eR
f, -NR
eC(O)R
f, -NR
eC(O)OR
f, -NR
eC(O)NR
eR
f, -NR
eC(=NR
f)NR
eR
f, -NR
eS(O)R
f, -NR
eS(O)
2R
f, -NR
eS(O)NR
eR
f, -NR
eS(O)
2NR
eR
f, -C(O)R
e, -C(O)OR
e, -C(O)NR
eR
f, -PR
eR
f, -P(O)R
eR
f, -P(O)
2R
eR
f, -P(O)NR
eR
f, -P(O)
2NR
eR
f, -P(O)OR
e, -P(O)
2OR
e’, -CN, or -NO2. [0629] In some embodiments, R
3 is
[0630] In some embodiments, R
3 is –C
1-C
6 alkyl-(4- to 10-membered heterocycloalkyl), wherein each hydrogen atom in methyl, ethyl, propyl, or –C
1-C
6 alkyl-(4- to 10-membered heterocycloalkyl), is independently optionally substituted by deuterium, halogen, C
1-C
6 alkyl, -C
1-C
6 alkyl-O-C
1-C
6 alkyl, -OC
1-C
6 alkyl-O-C
1-C
6 alkyl, -C
1-C
6 alkyl-O-R
a, C
6-C
10 aryl, -C
1-C
6 alkyl-(C
6-C
10 aryl), haloalkyl, C
3-C
6 cycloalkyl, 5- to 10-membered heteroaryl, or -C
1-C
6 alkyl-(4- to 10-membered heterocycloalkyl), -OR
e, -OC(O)R
e, -OC(O)NR
eR
f, - OS(O)R
e, -OS(O)
2R
e, -OS(O)NR
eR
f, -OS(O)
2NR
eR
f, -SR
e, -S(O)R
e, -S(O)
2R
e, -S(O)NR
eR
f, -S(O)
2NR
eR
f, -NR
eR
f, -NR
eC(O)R
f, -NR
eC(O)OR
f, -NR
eC(O)NR
eR
f, -NR
eC(=NR
f)NR
eR
f, -NR
eS(O)R
f, -NR
eS(O)
2R
f, -NR
eS(O)NR
eR
f, -NR
eS(O)
2NR
eR
f, -C(O)R
e, -C(O)OR
e, -C(O)NR
eR
f, -PR
eR
f, -P(O)R
eR
f, -P(O)
2R
eR
f, -P(O)NR
eR
f, -P(O)
2NR
eR
f, -P(O)OR
e, -P(O)
2OR
e’, -CN, or -NO2. [0631] In some embodiments, R
3 is of the formula
[0632] wherein each hydrogen atom is independently optionally substituted by deuterium, halogen, C
1-C
6 alkyl, -C
1-C
6 alkyl-O-C
1-C
6 alkyl, -OC
1-C
6 alkyl-O-C
1-C
6 alkyl, C
6-C
10 aryl, -C
1-C
6 alkyl-(C
6-C
10 aryl), haloalkyl, C
3-C
6 cycloalkyl, 5- to 10-membered heteroaryl, -C
1-C
6 alkyl-(5- to 10-membered heterocycloalkyl), -OR
e, -OC(O)R
e, -OC(O)NR
eR
f, -OS(O)R
e, -OS(O)
2R
e, -OS(O)NR
eR
f, -OS(O)
2NR
eR
f, -SR
e, -S(O)R
e, -S(O)
2R
e, -S(O)NR
eR
f, -S(O)
2NR
eR
f, -NR
eR
f, -NR
eC(O)R
f, -NR
eC(O)OR
f, -NR
eC(O)NR
eR
f, -NR
eC(=NR
f)NR
eR
f, -NR
eS(O)R
f, -NR
eS(O)
2R
f, -NR
eS(O)NR
eR
f, -NR
eS(O)
2NR
eR
f, -C(O)R
e, -C(O)OR
e, -C(O)NR
eR
f, -PR
eR
f, -P(O)R
eR
f, -P(O)
2R
eR
f, -P(O)NR
eR
f, -P(O)
2NR
eR
f, -P(O)OR
e, -P(O)
2OR
e’, -CN, or -NO2. [0633] In some embodiments, R
3 is of the formula
, [0634] wherein each hydrogen atom is independently optionally substituted by deuterium, halogen, C
1-C
6 alkyl, -C
1-C
6 alkyl-O-C
1-C
6 alkyl, -OC
1-C
6 alkyl-O-C
1-C
6 alkyl, C
6-C
10 aryl, -C
1-C
6 alkyl-(C
6-C
10 aryl), haloalkyl, C
3-C
6 cycloalkyl, 5- to 10-membered heteroaryl, -C
1-C
6 alkyl-(5- to 10-membered heterocycloalkyl), -OR
e, -OC(O)R
e, -OC(O)NR
eR
f, -OS(O)R
e, -OS(O)
2R
e, -OS(O)NR
eR
f, -OS(O)
2NR
eR
f, -SR
e, -S(O)R
e, -S(O)
2R
e, -S(O)NR
eR
f, -S(O)
2NR
eR
f, -NR
eR
f, -NR
eC(O)R
f, -NR
eC(O)OR
f, -NR
eC(O)NR
eR
f, -NR
eC(=NR
f)NR
eR
f, -NR
eS(O)R
f, -NR
eS(O)
2R
f, -NR
eS(O)NR
eR
f, -NR
eS(O)
2NR
eR
f, -C(O)R
e, -C(O)OR
e, -C(O)NR
eR
f, -PR
eR
f, -P(O)R
eR
f, -P(O)
2R
eR
f, -P(O)NR
eR
f, -P(O)
2NR
eR
f, -P(O)OR
e, -P(O)
2OR
e’, -CN, or -NO2. [0635] In some embodiments, each R
a, R
b, R
c, R
d, R
e, R
f, R
g, and R
h is independently selected from the group consisting of H, deuterium, C
1-C
6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C
3-C
6 cycloalkyl, 4- to 10-membered heterocycloalkyl, C
6-C
10 aryl, C
1-C
6 alkyl-C
6-C
10 aryl, and 5- to 10-membered heteroaryl; or two of R
a and R
b, or R
c and R
d, or R
e and R
f, or R
g and R
h, taken together with the atom or atoms to which they are attached, combine to form a C
3-C
6 cycloalkyl, 4- to 10-membered heterocycloalkyl, C
6-C
10 aryl, or 5- to 10-membered heteroaryl, wherein each hydrogen atom in C
1-C
6 alkyl, C
2-C
6 alkenyl, C
2-C
6 alkynyl, C
3-C
6 cycloalkyl, 4- to 10-membered heterocycloalkyl, C
6-C
10 aryl, C
1-C
6 alkyl-C
6-C
10 aryl, and 5- to 10- membered heteroaryl is independently optionally substituted by deuterium, halogen, C
1-C
6 alkyl, C
1-C
6 haloalkyl, -OH, -OC
1-C
6 alkyl, -OC(O)C
1-C
6 alkyl, -OC(O)N(H or C
1-C
6 alkyl)
2, -OS(O)C
1-C
6 alkyl, -OS(O)
2C
1-C
6 alkyl, -OS(O)N(H or C
1-C
6 alkyl)
2, -OS(O)
2N(H or C
1-C
6 alkyl)
2, -SC
1-C
6 alkyl, -S(O)C
1-C
6 alkyl, -S(O)
2C
1-C
6 alkyl, -S(O)N(H or C
1-C
6 alkyl)
2, - S(O)
2N(H or C
1-C
6 alkyl)
2, -N(H or C
1-C
6 alkyl)
2, -N(C
1-C
6 alkyl)C(O)-C
1-C
6 alkyl, -N(C1-
C
6 alkyl)C(O)OC
1 C
6 alkyl, N(C
1 C
6 alkyl)C(O)N(H or C
1 C
6 alkyl)
2, N(C
1 C
6 alkyl)S(O)C
1-C
6 alkyl, -N(C
1-C
6 alkyl)S(O)
2C
1-C
6 alkyl, -N(C
1-C
6 alkyl)S(O)N(H or C
1-C
6 alkyl)
2, -N(C
1-C
6 alkyl)S(O)
2N(H or C
1-C
6 alkyl)
2, -C(O)C
1-C
6 alkyl, -C(O)OC
1-C
6 alkyl, -C(O)N(H or C
1-C
6 alkyl)
2, -P(H or C
1-C
6 alkyl)
2, -P(O)(H or C
1-C
6 alkyl)
2, -P(O)
2(H or C1- C
6 alkyl)
2, -P(O)N(H or C
1-C
6 alkyl)
2, -P(O)
2N(H or C
1-C
6 alkyl)
2, -P(O)OC
1-C
6 alkyl, -P(O)
2OC
1-C
6 alkyl, -CN, or -NO
2, or R
e and R
f taken together with the carbon atom to which they are attached form an oxo groups or an alkenyl. [0636] In some embodiments, Z
1 is N. In some embodiments, Z
2 is N. In some embodiments, Z
3 is N. In some embodiments, Z
4 is N. In some embodiments, Z
5 is N. In some embodiments, Z
6 is N. In some embodiments, Z
7 is N. In some embodiments, Z
1 is C(R
5). In some embodiments, Z
2 is C(R
6). In some embodiments, Z
3 is C(R
7). In some embodiments, Z
4 is C(R
8). In some embodiments, Z
5 is C(R
9). In some embodiments, Z
6 is C(R
14). In some embodiments, Z
7 is C(R
15). In some embodiments, any of the possible combinations of Z
1-Z
7 can be combined as embodiemnts. In some embodiments, Z
6 is N or C(R
14). In some embodiments, Z
7 is N or C(R
15). In some embodiments, Z
1 is N, and Z
2 is N. In some embodiments, Z
1 is N, Z
2 is N, Z
3 is C(R
7), Z
4 is N, and Z
5 is C(R
9). In some embodiments, Z
1 is N, Z
2 is N, Z
3 is C(R
7), Z
4 is C(R
8), and Z
5 is C(R
9). In some embodiments, Z
1 is N, Z
2 is N, Z
3 is N, Z
4 is N, and Z
5 is C(R
9). In some embodiments, Z
1 is N, Z
2 is N, Z
3 is N, Z
4 is C(R
8), and Z
5 is C(R
9). In some embodiments, Z
1 is N, Z
2 is N, Z
3 is C(R
7), Z
4 is C(R
8), and Z
5 is N. In some embodiments, Z
1 is N, Z
2 is N, Z
3 is C(R
7), Z
4 is N, and Z
5 is N. In some embodiments, Z
1 is N, Z
2 is N, Z
3 is C(R
7), Z
4 is N, and Z
5 is C(R
9). In some embodiments, Z
1 is N, Z
2 is N, Z
3 is N, Z
4 is C(R
8), and Z
5 is C(R
9). In some embodiments, Z
1 is N, Z
2 is N, Z
3 is N, Z
4 is N, and Z
5 is N. [0637] In some embodiments, each of R
5, R
6, R
7, R
8, R
9, R
14, and R
15 is independently H, deuterium, halogen, C
1-C
6 alkyl, C
2-C
6 alkenyl, C
2-C
6 alkynyl, C
3-C
6 cycloalkyl, 4- to 10- membered heterocycloalkyl, C
6-C
10 aryl, 5- to 10-membered heteroaryl, -OR
g, -OC(O)R
g, -OC(O)NR
gR
h, -OS(O)R
g, -OS(O)
2R
g, -SR
g, -S(O)R
g, -S(O)
2R
g, -S(O)NR
gR
h, -S(O)
2NR
gR
h, -OS(O)NR
gR
h, -OS(O)
2NR
gR
h, -NR
gR
h, -NR
gC(O)R
h, -NR
gC(O)OR
h, -NR
gC(O)NR
gR
h, -NR
gS(O)R
h, -NR
gS(O)
2R
h, -NR
gS(O)NR
gR
h, -NR
gS(O)
2NR
gR
h, -C(O)R
g, -C(O)OR
g, -C(O)NR
gR
h, -PR
gR
h, -P(O)R
gR
h, -P(O)
2R
gR
h, -P(O)NR
gR
h, -P(O)
2NR
gR
h, -P(O)OR
g, - P(O)
2OR
g, -CN, or -NO2. [0638] In some embodiments, R
5, when present, is H. In some embodiments, R
6, when present, is H. In some embodiments, R
7, when present, is H or F. In some embodiments, R
8, when present, is H. In some embodiments, R
9, when present, is H or –OCH
3. In some embodiments, R
14, when present, is H. In some embodiments, R
15, when present, is H.
[0639] In some embodiments, R and R , when present, are each independently H, deuterium, methyl, ethyl, or isopropyl. In some embodiments, R
a, when present, is H, deuterium, methyl, ethyl, or isopropyl. In some embodiments, R
b, when present, is H, deuterium, methyl, ethyl, or isopropyl. [0640] Certain embodiments described herein can be represented by the following list of enumerated embodiments: [0641] 1. A compound of the formula I, or a pharmaceutically acceptable salt thereof,
[0642] wherein [0643] X is a -O-, -S-, or -NR
4-; [0644] Y is a bond, -O-, -S-, -S(O)-, -S(O)
2-, or –C(O)NR
10-; [0645] Z
1 is N or C(R
5); [0646] Z
2 is N or C(R
6); [0647] Z
3 is N or C(R
7); [0648] Z
4 is N or C(R
8); [0649] Z
5 is N or C(R
9); [0650] provided that at least two of Z
1-Z
5 are N; [0651] R
1 is independently H, deuterium, C
1-C
6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, or ring A, wherein each hydrogen atom in C
1-C
6 alkyl, C
2-C
6 alkenyl, or C
2-C
6 alkynyl is independently optionally substituted by deuterium, halogen, -R
e, -R
f, C
1-C
6 alkyl, C
1-C
6 haloalkyl, -OR
e, -OC(O)R
e, -OC(O)NR
eR
f, -OS(O)R
e, -OS(O)
2R
e, -OS(O)NR
eR
f, -OS(O)
2NR
eR
f, -SR
e, -S(O)R
e, -S(O)
2R
e, -S(O)NR
eR
f, -S(O)
2NR
eR
f, -NR
eR
f, -NR
eC(O)R
f, -NR
eC(O)OR
f, -NR
eC(O)NR
eR
f, -NR
eS(O)R
f, -NR
eS(O)
2R
f, -NR
eS(O)NR
eR
f, -NR
eS(O)
2NR
eR
f, -C(O)R
e, -C(O)OR
e, -C(O)NR
eR
f, -PR
eR
f, -P(O)R
eR
f, -P(O)
2R
eR
f, -P(O)NR
eR
f, -P(O)
2NR
eR
f,
P(O)OR , P(O)
2OR , CN, or NO
2; and when Y is a bond, O , S , or S(O) , then R is ring A; [0652] each R
2 is independently deuterium, halogen, C
1-C
6 alkyl, C
2-C
6 alkenyl, C
2-C
6 alkynyl, C
3-C
6 cycloalkyl, 4- to 10-membered heterocycloalkyl, C
6-C
10 aryl, 5- to 10-membered heteroaryl, -OR
c, -OC(O)R
c, -OC(O)NR
cR
d, -OC(=NR
c)NR
cR
d, -OS(O)R
c, -OS(O)
2R
c, -OS(O)NR
cR
d, -OS(O)
2NR
cR
d, -SR
c, -S(O)R
c, -S(O)
2R
c, -S(O)NR
cR
d, -S(O)
2NR
cR
d, -NR
cR
d, -NR
cC(O)R
d, -N(C(O)R
c)(C(O)R
d), -NR
cC(O)OR
d, -NR
cC(O)NR
cR
d, -NR
cC(=NR
c)NR
cR
d, -NR
cS(O)R
d, -NR
cS(O)
2R
d, -NR
cS(O)NR
cR
d, -NR
cS(O)
2NR
cR
d, -C(O)R
c, -C(O)OR
c, -C(O)NR
cR
d, -C(=NR
c)NR
cR
d, -PR
cR
d, -P(O)R
cR
d, -P(O)
2R
cR
d, -P(O)NR
cR
d, -P(O)
2NR
cR
d, -P(O)OR
c, -P(O)
2OR
c, -CN, or -NO
2, or two of R
2 taken together with the atoms to which they are attached form a C
3-C
6 cycloalkyl or a 4- to 10-membered heterocycloalkyl, wherein each hydrogen atom in C
1-C
6 alkyl, C
2-C
6 alkenyl, C
2-C
6 alkynyl, C
3-C
6 cycloalkyl, C
6-C
10 aryl, 5- to 10-membered heteroaryl, and 4- to 10-membered heterocycloalkyl is independently optionally substituted by deuterium, halogen, C
1-C
6 alkyl, C
1-C
6 haloalkyl, -R
e, -R
f, -OR
e, -OC(O)R
e, -OC(O)NR
eR
f, -OS(O)R
e, -OS(O)
2R
e, -OS(O)NR
eR
f, -OS(O)
2NR
eR
f, -SR
e, -S(O)R
e, -S(O)
2R
e, -S(O)NR
eR
f, -S(O)
2NR
eR
f, -NR
eR
f, -NR
eC(O)R
f, -NR
eC(O)OR
f, -NR
eC(O)NR
eR
f, -NR
eS(O)R
f, -NR
eS(O)
2R
f, -NR
eS(O)NR
eR
f, -NR
eS(O)
2NR
eR
f, -C(O)R
e, -C(O)OR
e, -C(O)NR
eR
f, -PR
eR
f, -P(O)R
eR
f, -P(O)
2R
eR
f, -P(O)NR
eR
f, -P(O)
2NR
eR
f, - P(O)OR
e, -P(O)
2OR
e, -CN, or -NO
2; [0653] R
3 is -C
1-C
6 alkyl, -C2-C6 alkenyl, -C2-C6 alkynyl, -C
3-C
6 cycloalkyl, 4- to 10- membered heterocycloalkyl, -C
1-C
6 alkylene-(4- to 10-membered heterocycloalkyl), -C
6-C
10 aryl, -C
1-C
6 alkylene-(C
6-C
10 aryl), 5- to 10-membered heteroaryl, or -C
1-C
6 alkylene-(4- to 10- membered heterocycloalkyl), wherein each hydrogen atom in C
1-C
6 alkyl, C
2-C
6 alkenyl, C
2-C
6 alkynyl, C
3-C
6 cycloalkyl, 4- to 10-membered heterocycloalkyl, -C
1-C
6 alkylene-(4- to 10- membered heterocycloalkyl), C
6-C
10 aryl, -C
1-C
6 alkylene-(C
6-C
10 aryl), 5- to 10-membered heteroaryl, and -C
1-C
6 alkylene-(5- to 10-membered heteroaryl), is independently optionally substituted by deuterium, halogen, -R
e, -R
f, C
1-C
6 alkyl, -C
1-C
6 alkyl-O-C
1-C
6 alkyl, -OC
1-C
6 alkyl-O-C
1-C
6 alkyl, -C
1-C
6 alkyl-O-R
a, C
6-C
10 aryl, -C
1-C
6 alkyl-(C
6-C
10 aryl), haloalkyl, C
3- C6 cycloalkyl, 5- to 10-membered heteroaryl, -C
1-C
6 alkyl-(5- to 10-membered heterocycloalkyl), -OR
e, -OC(O)R
e, -OC(O)NR
eR
f, -OS(O)R
e, -OS(O)
2R
e, -OS(O)NR
eR
f, -OS(O)
2NR
eR
f, -SR
e, -S(O)R
e, -S(O)
2R
e, -S(O)NR
eR
f, -S(O)
2NR
eR
f, -NR
eR
f, -NR
eC(O)R
f, -NR
eC(O)OR
f, -NR
eC(O)NR
eR
f, -NR
eC(=NR
f)NR
eR
f, -NR
eS(O)R
f, -NR
eS(O)
2R
f, -NR
eS(O)NR
eR
f, -NR
eS(O)
2NR
eR
f, -C(O)R
e, -C(O)OR
e, -C(O)NR
eR
f, -PR
eR
f, -P(O)R
eR
f, -P(O)
2R
eR
f, -P(O)NR
eR
f, -P(O)
2NR
eR
f, -P(O)OR
e, -P(O)
2OR
e’, -CN, or -NO
2;
[0654] each of R and R is independently H, deuterium, C
1 C
6 alkyl, C
2 C
6 alkenyl, C
2 C
6 alkynyl, C
3-C
6 cycloalkyl, 4- to 10-membered heterocycloalkyl, C
6-C
10 aryl, or 5- to 10- membered heteroaryl, wherein each hydrogen atom in C
1-C
6 alkyl, C
2-C
6 alkenyl, C
2-C
6 alkynyl, C
3-C
6 cycloalkyl, 4- to 10-membered heterocycloalkyl, C
6-C
10 aryl, and 5- to 10- membered heteroaryl is independently optionally substituted by deuterium, halogen, -R
e, -R
f, C
1-C
6 alkyl, C
1-C
6 haloalkyl, -OR
e, -OC(O)R
e, -OC(O)NR
eR
f, -OS(O)R
e, -OS(O)
2R
e, - OS(O)NR
eR
f, -OS(O)
2NR
eR
f, -SR
e, -S(O)R
e, -S(O)
2R
e, -S(O)NR
eR
f, -S(O)
2NR
eR
f, -NR
eR
f, - NR
eC(O)R
f, -NR
eC(O)OR
f, -NR
eC(O)NR
eR
f, -NR
eS(O)R
f, -NR
eS(O)
2R
f, -NR
eS(O)NR
eR
f, - NR
eS(O)
2NR
eR
f, -C(O)R
e, -C(O)OR
e, -C(O)NR
eR
f, -PR
eR
f, -P(O)R
eR
f, -P(O)
2R
eR
f, - P(O)NR
eR
f, -P(O)
2NR
eR
f, -P(O)OR
e, -P(O)
2OR
e’, -CN, or -NO
2; or R
1 and R
10 taken together with the atom or atoms to which they are attached combine to form a monocyclic 4- to 10- membered heterocycloalkyl, a fused bicyclic 5- to 10-membered heterocycloalkyl, or a bridged bicyclic 6- to 10-membered heterocycloalkyl, wherein each hydrogen atom in the monocyclic 4- to 10-membered heterocycloalkyl, fused bicyclic 5- to 10-membered heterocycloalkyl, or a bridged bicyclic 6- to 10-membered heterocycloalkyl is independently optionally substituted by deuterium, halogen, C
1-C
6 alkyl, C
1-C
6 haloalkyl, -OH, -OC
1-C
6 alkyl, -OC(O)C
1-C
6 alkyl, -OC(O)N(H or C
1-C
6 alkyl)
2, -OS(O)C
1-C
6 alkyl, -OS(O)
2C
1-C
6 alkyl, -OS(O)N(H or C
1-C
6 alkyl)
2, -OS(O)
2N(H or C
1-C
6 alkyl)
2, -SC
1-C
6 alkyl, -S(O)C
1-C
6 alkyl, -S(O)
2C
1-C
6 alkyl, -S(O)N(H or C
1-C
6 alkyl)
2, -S(O)
2N(H or C
1-C
6 alkyl)
2, -N(H or C
1-C
6 alkyl)
2, -N(C
1- C6 alkyl)C(O)-C
1-C
6 alkyl, -N(C
1-C
6 alkyl)C(O)OC
1-C
6 alkyl, -N(C
1-C
6 alkyl)C(O)N(H or C1- C
6 alkyl)
2, -N(C
1-C
6 alkyl)S(O)C
1-C
6 alkyl, -N(C
1-C
6 alkyl)S(O)
2C
1-C
6 alkyl, -N(C
1-C
6 alkyl)S(O)N(H or C
1-C
6 alkyl)
2, -N(C
1-C
6 alkyl)S(O)
2N(H or C
1-C
6 alkyl)
2, -C(O)C
1-C
6 alkyl, -C(O)OC
1-C
6 alkyl, -C(O)N(H or C
1-C
6 alkyl)
2, -P(H or C
1-C
6 alkyl)
2, -P(O)(H or C
1-C
6 alkyl)
2, -P(O)
2(H or C
1-C
6 alkyl)
2, -P(O)N(H or C
1-C
6 alkyl)
2, -P(O)
2N(H or C
1-C
6 alkyl)
2, -P(O)OC
1-C
6 alkyl, -P(O)
2OC
1-C
6 alkyl, -CN, or -NO
2, or two hydrogen atoms on a single carbon atom of the monocyclic 4- to 10-membered heterocycloalkyl, fused bicyclic 5- to 10- membered heterocycloalkyl, or bridged bicyclic 6- to 10-membered heterocycloalkyl combine to form an oxo group or an alkenyl group; [0655] each of R
5, R
6, R
7, R
8, and R
9 is independently H, deuterium, halogen, C
1-C
6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C
3-C
6 cycloalkyl, 4- to 10-membered heterocycloalkyl, C
6-C
10 aryl, 5- to 10-membered heteroaryl, -OR
g, -OC(O)R
g, -OC(O)NR
gR
h, -OS(O)R
g, -OS(O)
2R
g, - SR
g, -S(O)R
g, -S(O)
2R
g, -S(O)NR
gR
h, -S(O)
2NR
gR
h, -OS(O)NR
gR
h, -OS(O)
2NR
gR
h, -NR
gR
h, -NR
gC(O)R
h, -NR
gC(O)OR
h, -NR
gC(O)NR
gR
h, -NR
gS(O)R
h, -NR
gS(O)
2R
h, -NR
gS(O)NR
gR
h, -NR
gS(O)
2NR
gR
h, -C(O)R
g, -C(O)OR
g, -C(O)NR
gR
h, -PR
gR
h, -P(O)R
gR
h, -P(O)
2R
gR
h, -P(O)NR
gR
h, -P(O)
2NR
gR
h, -P(O)OR
g, -P(O)
2OR
g, -CN, or -NO2;
[0656] ring A is a C
3 C
8 cycloalkyl, 4 to 10 membered heterocycloalkyl, C
6 C
10 aryl, or 5 to 10-membered heteroaryl, wherein each of C
3-C8 cycloalkyl, 4- to 10-membered heterocycloalkyl, C
6-C
10 aryl, or 5- to 10-membered heteroaryl is unsubstituted or substituted with one or more of R
11, provided that the 4- to 10-membered heterocycloalkyl is not an unsubstituted or a substituted ring of the formula
[0657] each R
11 is independently deuterium, halogen, C
1-C
6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C
3-C
6 cycloalkyl, 4- to 10-membered heterocycloalkyl, C
6-C
10 aryl, 5- to 10- membered heteroaryl, -OR
a, -OC(O)R
a, -OC(O)NR
aR
b, -OC(=NR
a)NR
aR
b, -OS(O)R
a, -OS(O)
2R
a, -OS(O)NR
aR
b, -OS(O)
2NR
aR
b, -SR
a, -S(O)R
a, -S(O)
2R
a, -S(O)NR
aR
b, -S(O)
2NR
aR
b, -NR
aR
b, -NR
aC(O)R
b, -N(C(O)R
a)(C(O)R
b), -NR
aC(O)OR
b, -NR
aC(O)NR
aR
b, -NR
aC(=NR
a)NR
aR
b, -NR
aS(O)R
b, -NR
aS(O)
2R
b, -NR
aS(O)NR
aR
b, -NR
aS(O)
2NR
aR
b, -
C(O)R , C(O)OR , C(O)NR R , C( NR )NR R , PR R , P(O)R R , P(O)
2R R , P(O)NR
aR
b, -P(O)
2NR
aR
b, -P(O)OR
a, -P(O)
2OR
a, -CN, or -NO2, or two of R
11 taken together with the atom or atoms to which they are attached or three of R
11 taken together with the atoms to which they are attached, form a C
3-C
6 cycloalkyl or a 4- to 10-membered heterocycloalkyl, wherein each hydrogen atom in C
1-C
6 alkyl, C
2-C
6 alkenyl, C
2-C
6 alkynyl, C
3-C
6 cycloalkyl, C
6-C
10 aryl, 5- to 10-membered heteroaryl, and 4- to 10-membered heterocycloalkyl is independently optionally substituted by deuterium, halogen, -R
e, -R
f, C
1-C
6 alkyl, C
1-C
6 haloalkyl, -OR
e, -OC(O)R
e, -OC(O)NR
eR
f, -OS(O)R
e, -OS(O)
2R
e, -OS(O)NR
eR
f, -OS(O)
2NR
eR
f, -SR
e, -S(O)R
e, -S(O)
2R
e, -S(O)NR
eR
f, -S(O)
2NR
eR
f, -NR
eR
f, -NR
eC(O)R
f, - NR
eC(O)OR
f, -NR
eC(O)NR
eR
f, -NR
eS(O)R
f, -NR
eS(O)
2R
f, -NR
eS(O)NR
eR
f, -NR
eS(O)
2NR
eR
f, -C(O)R
e, -C(O)OR
e, -C(O)NR
eR
f, -PR
eR
f, -P(O)R
eR
f, -P(O)
2R
eR
f, -P(O)NR
eR
f, -P(O)
2NR
eR
f, -P(O)OR
e, -P(O)
2OR
e, -CN, or -NO
2, or two of R
11 taken together with the carbon atom to which they are attached form an oxo group or an alkenyl group; [0658] ring B is a C
6-C
10 aryl or 5- to 10-membered heteroaryl; [0659] each R
a, R
b, R
c, R
d, R
e, R
f, R
g, and R
h is independently selected from the group consisting of H, deuterium, C
1-C
6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C
3-C
6 cycloalkyl, 4- to 10-membered heterocycloalkyl, C
6-C
10 aryl, C
1-C
6 alkyl-C
6-C
10 aryl, and 5- to 10-membered heteroaryl; or two of R
a and R
b, or R
c and R
d, or R
e and R
f, or R
g and R
h, taken together with the atom or atoms to which they are attached, combine to form a C
3-C
6 cycloalkyl, 4- to 10- membered heterocycloalkyl, C
6-C
10 aryl, or 5- to 10-membered heteroaryl, wherein each hydrogen atom in C
1-C
6 alkyl, C
2-C
6 alkenyl, C
2-C
6 alkynyl, C
3-C
6 cycloalkyl, 4- to 10- membered heterocycloalkyl, C
6-C
10 aryl, C
1-C
6 alkyl-C
6-C
10 aryl, and 5- to 10-membered heteroaryl is independently optionally substituted by deuterium, halogen, C
1-C
6 alkyl, C
1-C
6 haloalkyl, -OH, -OC
1-C
6 alkyl, -OC(O)C
1-C
6 alkyl, -OC(O)N(H or C
1-C
6 alkyl)
2, -OS(O)C1- C
6 alkyl, -OS(O)
2C
1-C
6 alkyl, -OS(O)N(H or C
1-C
6 alkyl)
2, -OS(O)
2N(H or C
1-C
6 alkyl)
2, - SC
1-C
6 alkyl, -S(O)C
1-C
6 alkyl, -S(O)
2C
1-C
6 alkyl, -S(O)N(H or C
1-C
6 alkyl)
2, -S(O)
2N(H or C
1-C
6 alkyl)
2, -N(H or C
1-C
6 alkyl)
2, -N(C
1-C
6 alkyl)C(O)-C
1-C
6 alkyl, -N(C
1-C
6 alkyl)C(O)OC
1-C
6 alkyl, -N(C
1-C
6 alkyl)C(O)N(H or C
1-C
6 alkyl)
2, -N(C
1-C
6 alkyl)S(O)C1- C6 alkyl, -N(C
1-C
6 alkyl)S(O)
2C
1-C
6 alkyl, -N(C
1-C
6 alkyl)S(O)N(H or C
1-C
6 alkyl)
2, -N(C1- C6 alkyl)S(O)
2N(H or C
1-C
6 alkyl)
2, -C(O)C
1-C
6 alkyl, -C(O)OC
1-C
6 alkyl, -C(O)N(H or C1- C6 alkyl)
2, -P(H or C
1-C
6 alkyl)
2, -P(O)(H or C
1-C
6 alkyl)
2, -P(O)
2(H or C
1-C
6 alkyl)
2, - P(O)N(H or C
1-C
6 alkyl)
2, -P(O)
2N(H or C
1-C
6 alkyl)
2, -P(O)OC
1-C
6 alkyl, -P(O)
2OC
1-C
6 alkyl, -CN, or -NO2, or -R
e and -R
f taken together with the carbon atom to which they are attached form an oxo groups or an alkenyl; [0660] n is 0, 1, 2, 3, 4, 5, 6, or 7;
[0661] p is 0 or 1; and [0662] q is 0, 1, or 2; [0663] and wherein the compound is not of the formula
[0664] 2. The compound of embodiment 1, or a pharmaceutically acceptable salt thereof, wherein the compound is of the formula II
[0665] wherein R
2, R
3, R
11, R
a, R
b, A, B, X, Y, Z
1, Z
2, Z
3, Z
4, Z
5, m, n, p, and q are as described herein. [0666] 3. The compound of embodiment 1 or 2, or a pharmaceutically acceptable salt thereof, wherein the compound is of the formula III
[0667] wherein R
2, R
3, R
11, A, B, X, Z
1, Z
2, Z
3, Z
4, Z
5, m, n, and p are as described herein. [0668] 4. The compound of any one of embodiments 1 to 3, or a pharmaceutically acceptable salt thereof, wherein the compound is of the formula IV, or a pharmaceutically acceptable salt thereof,
IV [0669] wherein R
2, R
11, A, X, Z
1, Z
2, Z
3, Z
4, Z
5, m, and n are as described herein. [0670] 5. The compound of any one of embodiments 1 to 3, or a pharmaceutically acceptable salt thereof, wherein the compound is of the formula V
[0671] wherein R
2, R
3, R
11, A, X, Z
1, Z
2, Z
3, Z
4, Z
5, Z
6, Z
7, m, n, and p are as described herein. [0672] 6. The compound of any one of embodiment 1 to 3 or 5, or a pharmaceutically acceptable salt thereof, wherein the compound is of the formula VI
[0673] wherein R
2, R
11, A, X, Z
1, Z
2, Z
3, Z
4, Z
5, Z
6, Z
7, m, and n are as described herein. [0674] 7. The compound of any one of embodiments 1 to 3, or a pharmaceutically acceptable salt thereof, wherein the compound is of the formula VII
VII [0675] wherein R
2, R
3, R
11, R
12, A, X, Z
1, Z
2, Z
3, Z
4, Z
5, m, n, and p are as described herein. [0676] 8. The compound of any one of embodiments 1 to 3 to 7, or a pharmaceutically acceptable salt thereof, wherein the compound is of the formula VIII
VIII [0677] wherein R
2, R
11, R
12, A, X, Z
1, Z
2, Z
3, Z
4, Z
5, m, and n are as described herein. [0678] 9. The compound of any one of embodiments 1 to 3, or a pharmaceutically acceptable salt thereof, wherein the compound is of the formula IX
[0679] wherein R
2, R
3, R
11, R
13, A, X, Z
1, Z
2, Z
3, Z
4, Z
5, m, n, and p are as described herein. [0680] 10. The compound of any one of embodiments 1 to 3 or 9, or a pharmaceutically acceptable salt thereof, wherein the compound is of the formula X
[0681] wherein R
2, R
11, R
13, A, X, Z
1, Z
2, Z
3, Z
4, Z
5, m, and n are as described herein. [0682] 11. The compound of embodiment 1, or a pharmaceutically acceptable salt thereof, wherein the compound is of the formula XI
[0683] wherein R
1, R
2, R
3, R
10, R
a, R
b, B, X, Z
1, Z
2, Z
3, Z
4, Z
5, n, p, and q are as described herein. [0684] 12. The compound of any one of embodiments 1, 2, or 11, or a pharmaceutically acceptable salt thereof, wherein the compound is of the formula XII
[0685] wherein R
2, R
3, R
10, R
11, R
a, R
b, A, B, X, Z
1, Z
2, Z
3, Z
4, Z
5, m, n, p, and q are as described herein. [0686] 13. The compound of any one of embodiments 1, 2, 11, or 12, or a pharmaceutically acceptable salt thereof, wherein the compound is of the formula XIII
XIII [0687] wherein R
2, R
3, R
10, R
11, R
a, R
b, A, X, Z
1, Z
2, Z
3, Z
4, Z
5, Z
6, Z
7, m, n, p, and q are as described herein.
[0688] 14. The compound of any one of embodiments 1, 2, or 11 to 13, or a pharmaceutically acceptable salt thereof, wherein the compound is of the formula XIV
XIV [0689] wherein R
2, R
10, R
11, R
a, R
b, A, X, Z
1, Z
2, Z
3, Z
4, Z
5, Z
6, Z
7, m, n, and q are as described herein. [0690] 15. The compound of any one of embodiments 1, 2, or 11, or a pharmaceutically acceptable salt thereof, wherein the compound is of the formula XV
XV
[0691] wherein R, R, R , R , R , R, R, A, X, Z, Z, Z, Z, Z, m, n, p, and q are as described herein. [0692] 16. The compound of any one of embodiments 1, 2, 11, or 15, or a pharmaceutically acceptable salt thereof, wherein the compound is of the formula XVI,
XVI [0693] wherein R
2, R
10, R
11, R
12, R
a, R
b, A, X, Z
1, Z
2, Z
3, Z
4, Z
5, m, n, and q are as described herein. [0694] 17. The compound of any one of embodiments 1, 2, or 11, or a pharmaceutically acceptable salt thereof, wherein the compound is of the formula XVII
[0695] wherein R
2, R
3, R
10, R
11, R
13, R
a, R
b, A, X, Z
1, Z
2, Z
3, Z
4, Z
5, m, n, p, and q are as described herein. [0696] 18. The compound of any one of embodiments 1, 2, 11, or 17, or a pharmaceutically acceptable salt thereof, wherein the compound is of the formula XVIII
[0697] wherein R
2, R
10, R
11, R
13, R
a, R
b, A, X, Z
1, Z
2, Z
3, Z
4, Z
5, m, n, and q are as described herein.
[0698] 19. The compound of embodiment 1 or 2, or a pharmaceutically acceptable salt thereof, wherein Y is a bond, and R
1 is ring A. [0699] 20. The compound of embodiment 1 or 2, or a pharmaceutically acceptable salt thereof, wherein Y is -O-, -S-, or -S(O)- , and R
1 is ring A. [0700] 21. The compound of embodiment 1 or 2, or a pharmaceutically acceptable salt thereof, wherein Y is -S(O)
2- or –C(O)NR
10-. [0701] 22. The compound of any one of the preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein each R
11 is independently deuterium, halogen, C
1-C
6 alkyl, C
2- C6 alkenyl, C2-C6 alkynyl, C
3-C
6 cycloalkyl, 4- to 10-membered heterocycloalkyl, C
6-C
10 aryl, 5- to 10-membered heteroaryl, -OR
a, -OC(O)R
a, -OC(O)NR
aR
b, -OS(O)R
a, -OS(O)
2R
a, -OS(O)NR
aR
b, -OS(O)
2NR
aR
b, -SR
a, -S(O)R
a, -S(O)
2R
a, -S(O)NR
aR
b, -S(O)
2NR
aR
b, -NR
aC(O)R
b, -N(C(O)R
a)(C(O)R
b), -NR
aC(O)OR
b, -NR
aC(O)NR
aR
b, -NR
aS(O)R
b, -NR
aS(O)
2R
b, -NR
aS(O)NR
aR
b, -NR
aS(O)
2NR
aR
b, -C(O)R
a, -C(O)OR
a, -C(O)NR
aR
b, -PR
aR
b, -P(O)R
aR
b, -P(O)
2R
aR
b, -P(O)NR
aR
b, -P(O)
2NR
aR
b, -P(O)OR
a, -P(O)
2OR
a, -CN, or -NO
2, or two of R
11 taken together with the atom or atoms to which they are attached or three of R
11 taken together with the atoms to which they are attached, form a C
3-C
6 cycloalkyl or a 4- to 10-membered heterocycloalkyl, wherein each hydrogen atom in C
1-C
6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C
3-C
6 cycloalkyl, C
6-C
10 aryl, 5- to 10-membered heteroaryl, and 4- to 10- membered heterocycloalkyl is independently optionally substituted by deuterium, halogen, - R
e, -R
f, C
1-C
6 alkyl, C
1-C
6 haloalkyl, -OR
e, -OC(O)R
e, -OC(O)NR
eR
f, -OS(O)R
e, -OS(O)
2R
e, -OS(O)NR
eR
f, -OS(O)
2NR
eR
f, -SR
e, -S(O)R
e, -S(O)
2R
e, -S(O)NR
eR
f, -S(O)
2NR
eR
f, -NR
eC(O)R
f, -NR
eC(O)OR
f, -NR
eC(O)NR
eR
f, -NR
eS(O)R
f, -NR
eS(O)
2R
f, -NR
eS(O)NR
eR
f, -NR
eS(O)
2NR
eR
f, -C(O)R
e, -C(O)OR
e, -C(O)NR
eR
f, -PR
eR
f, -P(O)R
eR
f, -P(O)
2R
eR
f, -P(O)NR
eR
f, -P(O)
2NR
eR
f, -P(O)OR
e, -P(O)
2OR
e, -CN, or -NO2; wherein each R
a, R
b, R
e, and R
f, is independently selected from the group consisting of H, deuterium, C
1-C
6 alkyl, C
2-C
6 alkenyl, C2-C6 alkynyl, C
3-C
6 cycloalkyl, 4- to 10-membered heterocycloalkyl, C
6-C
10 aryl, C1- C
6 alkyl-C
6-C
10 aryl, and 5- to 10-membered heteroaryl; or two of R
a and R
b, or R
e and R
f, taken together with the atom or atoms to which they are attached, combine to form a C
3-C
6 cycloalkyl, 4- to 10-membered heterocycloalkyl, C
6-C
10 aryl, or 5- to 10-membered heteroaryl, wherein each hydrogen atom in C
1-C
6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C
3-C
6 cycloalkyl, 4- to 10-membered heterocycloalkyl, C
6-C
10 aryl, C
1-C
6 alkyl-C
6-C
10 aryl, and 5- to 10- membered heteroaryl is independently optionally substituted by deuterium, halogen, C
1-C
6 alkyl, C
1-C
6 haloalkyl, -OH, -OC
1-C
6 alkyl, -OC(O)C
1-C
6 alkyl, -OC(O)N(H or C
1-C
6 alkyl)
2, -OS(O)C
1-C
6 alkyl, -OS(O)
2C
1-C
6 alkyl, -OS(O)N(H or C
1-C
6 alkyl)
2, -OS(O)
2N(H or C
1-C
6 alkyl)
2, -SC
1-C
6 alkyl, -S(O)C
1-C
6 alkyl, -S(O)
2C
1-C
6 alkyl, -S(O)N(H or C
1-C
6 alkyl)
2, -
S(O)
2N(H or C
1 C
6 alkyl)
2, N(C
1 C
6 alkyl)C(O) C
1 C
6 alkyl, N(C
1 C
6 alkyl)C(O)OC
1 C
6 alkyl, -N(C
1-C
6 alkyl)C(O)N(H or C
1-C
6 alkyl)
2, -N(C
1-C
6 alkyl)S(O)C
1-C
6 alkyl, -N(C
1-C
6 alkyl)S(O)
2C
1-C
6 alkyl, -N(C
1-C
6 alkyl)S(O)N(H or C
1-C
6 alkyl)
2, -N(C
1-C
6 alkyl)S(O)
2N(H or C
1-C
6 alkyl)
2, -C(O)C
1-C
6 alkyl, -C(O)OC
1-C
6 alkyl, -C(O)N(H or C
1-C
6 alkyl)
2, -P(H or C
1-C
6 alkyl)
2, -P(O)(H or C
1-C
6 alkyl)
2, -P(O)
2(H or C
1-C
6 alkyl)
2, -P(O)N(H or C
1-C
6 alkyl)
2, -P(O)
2N(H or C
1-C
6 alkyl)
2, -P(O)OC
1-C
6 alkyl, -P(O)
2OC
1-C
6 alkyl, -CN, or -NO
2, or two of R
11 taken together with the carbon atom to which they are attached form an oxo group or an alkenyl group. [0702] 23. The compound of any one of the preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein ring A is 4- to 10-membered heterocycloalkyl. [0703] 24. The compound of any one of the preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein ring A is a mono-cyclic 4- to 10-membered heterocycloalkyl, a fused bicyclic 5- to 10-membered heterocycloalkyl, a bridged bicyclic 6- to 10-membered heterocycloalkyl, or a spiro bicyclic 6- to 10-membered heterocycloalkyl. [0704] 25. The compound of any one of the preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein ring A is a mono-cyclic 4- to 10-membered heterocycloalkyl. [0705] 26. The compound of any one of embodiments 1 to 24, or a pharmaceutically acceptable salt thereof, wherein ring A is a bridged bicyclic 6- to 10-membered heterocycloalkyl. [0706] 27. The compound of any one of embodiments 1 to 24, or a pharmaceutically acceptable salt thereof, wherein ring A is
[0707] wherein * is a point of covalent attachment to
, and m is 0, 1, 2, 3, 4, 5, or 6. [0708] 28. The compound of any one of embodiments 1 to 24, or 27, or a pharmaceutically acceptable salt thereof, wherein ring A is
[0709] wherein * is a point of covalent attachment to
and m is 0, 1, 2, 3, 4, or 5. [0710] 29. The compound of any one of embodiments 1 to 24, 27, or 28 or a pharmaceutically acceptable salt thereof, wherein ring A is
[0711] wherein * is a point of covalent attachment to
[0712] 30. The compound of any one of embodiments 1 to 22, or a pharmaceutically acceptable salt thereof, wherein ring A is an unsubstituted C
6-C
10 aryl or a C
6-C
10 aryl substituted with 1, 2, 3, 4, 5, or 6 of R
11. [0713] 31. The compound of any one of embodiments 1 to 22, or 30, or a pharmaceutically acceptable salt thereof, wherein ring A is a unsubstituted phenyl, unsubstituted naphthyl, phenyl substituted with 1, 2, 3, 4, or 5 of R
11, or naphthyl substituted with 1, 2, 3, 4, 5, or 6 of R
11. [0714] 32. The compound of any one of embodiments 1 to 22, or a pharmaceutically acceptable salt thereof, wherein ring A is an substituted 5- to 10-membered heteroaryl or a 5- to 10-membered heteroaryl substituted with 1, 2, 3, 4, 5, or 6 of R
11. [0715] 33. The compound of any one of embodiments 1 to 22, or 32, or a pharmaceutically acceptable salt thereof, wherein ring A is
[0716] wherein * is a point of covalent attachment to
, and m is 0, 1, 2, or 3.
[0717] 34. The compound of any one of embodiments 1 to 22, 32, or 33, or a pharmaceutically acceptable salt thereof, wherein ring A is
[0718] wherein * is a point of covalent attachment to
[0719] 35. The compound of any one of embodiments 1 to 22, or a pharmaceutically acceptable salt thereof, wherein ring A is C
3-C8 cycloalkyl unsubstituted or substituted with 1, 2, 3, 4, 5, or 6 of R
11. [0720] 36. The compound of any one of embodiments 1 to 22, or 35 or a pharmaceutically acceptable salt thereof, wherein ring A is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or cyclooctyl, each of which is optionally substituted with 1, 2, 3, 4, 5, or 6 of R
11. [0721] 37. The compound of any one of the preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein Z
1 is N.
[0722] 38. The compound of any one of the preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein Z
2 is N. [0723] 39. The compound of any one of the preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein Z
3 is CR
7, Z
4 is N, and Z
5 is CR
9. [0724] 40. The compound of any one of embodiments 1 to 36, or a pharmaceutically acceptable salt thereof, wherein Z
3 is CR
7, Z
4 is CR
8, and Z
5 is CR
9. [0725] 41. The compound of any one of embodiments 1 to 36 or a pharmaceutically acceptable salt thereof, wherein Z
3 is CR
7, Z
4 is CR
8, and Z
5 is N. [0726] 42. The compound of any one of embodiments 1 to 36, or a pharmaceutically acceptable salt thereof, wherein Z
3 is N, Z
4 is N, and Z
5 is CR
9. [0727] 43. The compound of any one of embodiments 1 to 36, or a pharmaceutically acceptable salt thereof, wherein Z
3 is N, Z
4 is N, and Z
5 is N. [0728] 44. The compound of any one of embodiments 1 to 36, or a pharmaceutically acceptable salt thereof, wherein Z
3 is CR
7, Z
4 is N, and Z
5 is N. [0729] 45. The compound of any one of embodiments 1 to 36, or a pharmaceutically acceptable salt thereof, wherein Z
3 is N, Z
4 is CR
8, and Z
5 is N. [0730] 46. The compound of any one of the preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein q is 0. [0731] 47. The compound of any one of embodiments 1 to 45, or a pharmaceutically acceptable salt thereof, wherein q is 1. [0732] 48. The compound of any one of embodiments 1 to 45 or 47, or a pharmaceutically acceptable salt thereof, wherein X is O. [0733] 49. The compound of any one of embodiments 1 to 45 or 47, or a pharmaceutically acceptable salt thereof, wherein X is –NR
7-. [0734] 50. The compound of any one of embodiments 1 to 45 or 47, or a pharmaceutically acceptable salt thereof, wherein X is -S-. [0735] 51. The compound of any one of the preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein R
3, when present, is -C
1-C
6 alkyl, 4- to 10-membered heterocycloalkyl, or -C
1-C
6 alkylene-(4- to 10-membered heterocycloalkyl), wherein each hydrogen atom in -C
1-C
6 alkyl, 4- to 10-membered heterocycloalkyl, or -C
1-C
6 alkylene-(4- to 10-membered heterocycloalkyl), is independently optionally substituted by deuterium, halogen, C
1-C
6 alkyl, -C
1-C
6 alkyl-O-C
1-C
6 alkyl, -OC
1-C
6 alkyl-O-C
1-C
6 alkyl, -C
1-C
6 alkyl- O-R
a, C
6-C
10 aryl, -C
1-C
6 alkyl-(C
6-C
10 aryl), haloalkyl, C
3-C
6 cycloalkyl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocycloalkyl, -C
1-C
6 alkyl-(4- to 10-membered heterocycloalkyl), -OR
e, -OC(O)R
e, -OC(O)NR
eR
f, -OS(O)R
e, -OS(O)
2R
e, -OS(O)NR
eR
f,
OS(O)
2NR R, SR , S(O)R , S(O)
2R , S(O)NR R, S(O)
2NR R, NR R, NR C(O)R, -NR
eC(O)OR
f, -NR
eC(O)NR
eR
f, -NR
eC(=NR
f)NR
eR
f, -NR
eS(O)R
f, -NR
eS(O)
2R
f, -NR
eS(O)NR
eR
f, -NR
eS(O)
2NR
eR
f, -C(O)R
e, -C(O)OR
e, -C(O)NR
eR
f, -PR
eR
f, -P(O)R
eR
f, -P(O)
2R
eR
f, -P(O)NR
eR
f, -P(O)
2NR
eR
f, -P(O)OR
e, -P(O)
2OR
e’, -CN, or -NO2. [0736] 52. The compound of any one of the preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein R
3, when present, is 4- to 10-membered heterocycloalkyl, wherein each hydrogen atom in 4- to 10-membered heterocycloalkyl is independently optionally substituted by deuterium, halogen, C
1-C
6 alkyl, -C
1-C
6 alkyl-O-C
1-C
6 alkyl, -OC
1- C6 alkyl-O-C
1-C
6 alkyl, -C
1-C
6 alkyl-O-R
a, C
6-C
10 aryl, -C
1-C
6 alkyl-(C
6-C
10 aryl), haloalkyl, C
3-C
6 cycloalkyl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocycloalkyl, -C
1-C
6 alkyl-(4- to 10-membered heterocycloalkyl), -OR
e, -OC(O)R
e, -OC(O)NR
eR
f, -OS(O)R
e, -OS(O)
2R
e, -OS(O)NR
eR
f, -OS(O)
2NR
eR
f, -SR
e, -S(O)R
e, -S(O)
2R
e, -S(O)NR
eR
f, -S(O)
2NR
eR
f, -NR
eR
f, -NR
eC(O)R
f, -NR
eC(O)OR
f, -NR
eC(O)NR
eR
f, -NR
eC(=NR
f)NR
eR
f, -NR
eS(O)R
f, -NR
eS(O)
2R
f, -NR
eS(O)NR
eR
f, -NR
eS(O)
2NR
eR
f, -C(O)R
e, -C(O)OR
e, -C(O)NR
eR
f, -PR
eR
f, -P(O)R
eR
f, -P(O)
2R
eR
f, -P(O)NR
eR
f, -P(O)
2NR
eR
f, -P(O)OR
e, -P(O)
2OR
e’, -CN, or -NO2. [0737] 53. The compound of any one of the preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein R
3, when present, is
[0738] 54. The compound of any one of embodiments 1 to 51, or a pharmaceutically acceptable salt thereof, wherein R
3, when present, is –C
1-C
6 alkyl-(4- to 10-membered heterocycloalkyl), wherein each hydrogen atom in methyl, ethyl, propyl, or –C
1-C
6 alkyl-(4- to 10-membered heterocycloalkyl), is independently optionally substituted by deuterium, halogen, C
1-C
6 alkyl, -C
1-C
6 alkyl-O-C
1-C
6 alkyl, -OC
1-C
6 alkyl-O-C
1-C
6 alkyl, -C
1-C
6 alkyl- O-R
a, C
6-C
10 aryl, -C
1-C
6 alkyl-(C
6-C
10 aryl), haloalkyl, C
3-C
6 cycloalkyl, 5- to 10-membered heteroaryl, or -C
1-C
6 alkyl-(4- to 10-membered heterocycloalkyl), -OR
e, -OC(O)R
e, -OC(O)NR
eR
f, -OS(O)R
e, -OS(O)
2R
e, -OS(O)NR
eR
f, -OS(O)
2NR
eR
f, -SR
e, -S(O)R
e, -S(O)
2R
e, -S(O)NR
eR
f, -S(O)
2NR
eR
f, -NR
eR
f, -NR
eC(O)R
f, -NR
eC(O)OR
f, -NR
eC(O)NR
eR
f, -NR
eC(=NR
f)NR
eR
f, -NR
eS(O)R
f, -NR
eS(O)
2R
f, -NR
eS(O)NR
eR
f, -NR
eS(O)
2NR
eR
f, -C(O)R
e, -C(O)OR
e, -C(O)NR
eR
f, -PR
eR
f, -P(O)R
eR
f, -P(O)
2R
eR
f, - P(O)NR
eR
f, -P(O)
2NR
eR
f, -P(O)OR
e, -P(O)
2OR
e’, -CN, or -NO
2.
[0739] 55. The compound of any one of embodiments 1 to 51, or a pharmaceutically acceptable salt thereof, wherein R
3, when present, is
[0740] wherein each hydrogen atom is independently optionally substituted by deuterium, halogen, C
1-C
6 alkyl, -C
1-C
6 alkyl-O-C
1-C
6 alkyl, -OC
1-C
6 alkyl-O-C
1-C
6 alkyl, C
6-C
10 aryl, -C
1-C
6 alkyl-(C
6-C
10 aryl), haloalkyl, C
3-C
6 cycloalkyl, 5- to 10-membered heteroaryl, -C
1-C
6 alkyl-(5- to 10-membered heterocycloalkyl), -OR
e, -OC(O)R
e, -OC(O)NR
eR
f, -OS(O)R
e, -OS(O)
2R
e, -OS(O)NR
eR
f, -OS(O)
2NR
eR
f, -SR
e, -S(O)R
e, -S(O)
2R
e, -S(O)NR
eR
f, -S(O)
2NR
eR
f, -NR
eR
f, -NR
eC(O)R
f, -NR
eC(O)OR
f, -NR
eC(O)NR
eR
f, -NR
eC(=NR
f)NR
eR
f, -NR
eS(O)R
f, -NR
eS(O)
2R
f, -NR
eS(O)NR
eR
f, -NR
eS(O)
2NR
eR
f, -C(O)R
e, -C(O)OR
e, -C(O)NR
eR
f, -PR
eR
f, -P(O)R
eR
f, -P(O)
2R
eR
f, -P(O)NR
eR
f, -P(O)
2NR
eR
f, -P(O)OR
e, -P(O)
2OR
e’, -CN, or -NO2. [0741] 56. The compound of any one of the preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein each R
2 is independently deuterium, halogen, C
1-C
6 alkyl, C
2- C6 alkenyl, C2-C6 alkynyl, -OR
c, or -NR
cR
d. [0742] 57. The compound of any one of the preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein Ring B is
[0743] 58. The compound of any one of the preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein R
4, when present, is H or methyl. [0744] 59. The compound of any one of the preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein R
5, when present, is H. [0745] 60. The compound of any one of the preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein R
6, when present, is H. [0746] 61. The compound of any one of the preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein R
7, when present, is H or F. [0747] 62. The compound of any one of the preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein R
8, when present, is H. [0748] 63. The compound of any one of the preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein R
9, when present, is H. [0749] 64. The compound of any one of the preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein R
12, when present, is H or methyl. [0750] 65. The compound of any one of the preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein R
13, when present, is H or methyl. [0751] 66. The compound of any one of the preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein each R
a, when present, is H. [0752] 67. The compound of any one of the preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein each R
b, when present, is H. [0753] 68. The compound of any one of the preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein R
10, when present, is H. [0754] 69. The compound of any one of the preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein m is 0, 1, or 2. [0755] 70. The compound of any one of the preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein n is 0, 1, 2, or 3.
[0756] 71. The compound of any one of the preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein n is 1, 2, or 3. [0757] 72. The compound of any one of the preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein p is 0. [0758] 73. The compound of any one of embodiments 1 to 71, or a pharmaceutically acceptable salt thereof, wherein p is 1. [0759] 74. The compound of any one of the preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein q is 1. [0760] 79. A pharmaceutical composition comprising at least one compound of any one of embodiments 1 to 74, or a pharmaceutically acceptable salt thereof, and optionally one or more pharmaceutically acceptable excipients. [0761] 80. A method of treating disease, such as cancer, comprising administering to a subject in need of such treatment an effective amount of a compound of any one of embodiments 1 to 74, or a pharmaceutically acceptable salt thereof. [0762] 81. A compound of any one of embodiments 1 to 74, or a pharmaceutically acceptable salt thereof, for use in a method of treating cancer in a subject. [0763] 82. A compound of any one of embodiments 1 to 74, or a pharmaceutically acceptable salt thereof, for treating cancer in a subject. [0764] 83. Use of a compound of any one of embodiments 1 to 74, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating cancer in a subject. [0765] In some embodiments, the disclosure provides a compound selected from the group consisting of 5-ethynyl-6-fluoro-4-[8-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl]methoxy}-4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)pyrido[4,3-d]pyrimidin-7- yl]naphthalen-2-ol; [0766] 5-ethynyl-6-fluoro-4-[8-fluoro-2-(4-methylpiperazin-1-yl)-4-(8-oxa-3- azabicyclo[3.2.1]octan-3-yl)pyrido[4,3-d]pyrimidin-7-yl]naphthalen-2-ol; [0767] 5-ethynyl-6-fluoro-4-{8-fluoro-2-[(3R,3aS,6aS)-3-fluoro-1- methylhexahydropyrrolo[3,4-b]pyrrol-5(1H)-yl]-4-(8-oxa-3-azabicyclo[3.2.1]octan-3- yl)pyrido[4,3-d]pyrimidin-7-yl}naphthalen-2-ol; [0768] 5-ethynyl-6-fluoro-4-{8-fluoro-2-[(3aS,6aS)-1-methylhexahydropyrrolo[3,4-b]pyrrol- 5(1H)-yl]-4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)pyrido[4,3-d]pyrimidin-7-yl}naphthalen-2- ol; [0769] 5-ethynyl-6-fluoro-4-{8-fluoro-2-[(3aR,6aS)-5-methylhexahydropyrrolo[3,4-c]pyrrol- 2(1H)-yl]-4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)pyrido[4,3-d]pyrimidin-7-yl}naphthalen-2- ol;
[0770] 5 ethynyl 6 fluoro 4 [4 fluoro 6 {[(2R,7aS) 2 fluorotetrahydro 1H pyrrolizin 7a(5H)-yl]methoxy}-8-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-2,7-naphthyridin-3- yl]naphthalen-2-ol; [0771] 4-[4-(3-azabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl]methoxy}pyrido[4,3-d]pyrimidin-7-yl]-5-ethynyl-6-fluoronaphthalen-2- ol; [0772] 4-[4-(2-azatricyclo[3.3.1.1
3,7]decan-2-yl)-8-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro- 1H-pyrrolizin-7a(5H)-yl]methoxy}pyrido[4,3-d]pyrimidin-7-yl]-5-ethynyl-6- fluoronaphthalen-2-ol; [0773] 5-ethynyl-6-fluoro-4-[8-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl]methoxy}-4-(2-oxa-6-azatricyclo[3.3.1.1
3,7]decan-6-yl)pyrido[4,3-d]pyrimidin-7- yl]naphthalen-2-ol; [0774] 5-ethynyl-6-fluoro-4-[8-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl]methoxy}-4-(6-methyl-2,6-diazatricyclo[3.3.1.1
3,7]decan-2-yl)pyrido[4,3- d]pyrimidin-7-yl]naphthalen-2-ol; [0775] 5-ethynyl-6-fluoro-4-[8-fluoro-4-(3-fluorophenyl)-2-{[(2R,7aS)-2-fluorotetrahydro- 1H-pyrrolizin-7a(5H)-yl]methoxy}pyrido[4,3-d]pyrimidin-7-yl]naphthalen-2-ol; [0776] 5-ethynyl-6-fluoro-4-[4-fluoro-8-(3-fluorophenyl)-6-{[(2R,7aS)-2-fluorotetrahydro- 1H-pyrrolizin-7a(5H)-yl]methoxy}-2,7-naphthyridin-3-yl]naphthalen-2-ol; [0777] 5-ethynyl-6-fluoro-4-[8-fluoro-4-(5-fluoropyridin-3-yl)-2-{[(2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}pyrido[4,3-d]pyrimidin-7-yl]naphthalen- 2-ol; [0778] 5-chloro-4-[8-fluoro-4-(3-fluorophenyl)-2-{[(2R,7aS)-2-fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl]methoxy}pyrido[4,3-d]pyrimidin-7-yl]-6-methylnaphthalen-2-ol; [0779] 5-chloro-4-[8-fluoro-4-(3-fluorophenyl)-2-{[(2R,7aS)-2-fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl]methoxy}pyrido[4,3-d]pyrimidin-7-yl]-6-methylquinolin-2-ol; [0780] 4-[4-(3,4-dihydro-1H-pyrrolo[2,1-c][1,4]oxazin-6-yl)-8-fluoro-2-{[(2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}pyrido[4,3-d]pyrimidin-7-yl]-5-ethynyl- 6-fluoronaphthalen-2-ol; [0781] 4-[8-(3,4-dihydro-1H-pyrrolo[2,1-c][1,4]oxazin-6-yl)-4-fluoro-6-{[(2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}-2,7-naphthyridin-3-yl]-5-ethynyl-6- fluoronaphthalen-2-ol; [0782] 4-[4-(3,4-dihydro-1H-pyrrolo[2,1-c][1,4]oxazin-6-yl)-8-fluoro-2-{[(2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}pyrido[4,3-d]pyrimidin-7-yl]-5-ethynyl- 6-fluoroquinolin-2-ol;
[0783] 4 [4 (3,4 dihydro 1H pyrrolo[2,1 c][1,4]oxazin 6 yl) 8 fluoro 2 {[(2R,7aS) 2 fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}pyrido[4,3-d]pyrimidin-7-yl]-5-ethynyl- 6-fluoroquinolin-2-amine; [0784] 5-ethynyl-6-fluoro-4-[8-fluoro-4-(7-fluoro-3,4-dihydro-1H-pyrrolo[2,1-c][1,4]oxazin- 6-yl)-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}pyrido[4,3- d]pyrimidin-7-yl]naphthalen-2-ol; [0785] 5-chloro-4-[4-(3,4-dihydro-1H-pyrrolo[2,1-c][1,4]oxazin-6-yl)-8-fluoro-2- {[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}pyrido[4,3-d]pyrimidin-7- yl]-6-methylnaphthalen-2-ol; [0786] 5-ethynyl-6-fluoro-4-[8-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl]methoxy}-4-(1'H,4'H-spiro[cyclopropane-1,3'-pyrrolo[2,1-c][1,4]oxazin]-6'- yl)pyrido[4,3-d]pyrimidin-7-yl]naphthalen-2-ol; [0787] 4-[4-(6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazin-3-yl)-8-fluoro-2-{[(2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}pyrido[4,3-d]pyrimidin-7-yl]-5-ethynyl- 6-fluoronaphthalen-2-ol; [0788] 5-ethynyl-6-fluoro-4-[8-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl]methoxy}-4-(1-methyl-1,4,5,7-tetrahydropyrano[3,4-c]pyrazol-3-yl)pyrido[4,3- d]pyrimidin-7-yl]naphthalen-2-ol; [0789] 4-[4-(3,4-dihydro-1H-pyrrolo[2,1-c][1,4]oxazin-7-yl)-8-fluoro-2-{[(2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}pyrido[4,3-d]pyrimidin-7-yl]-5-ethynyl- 6-fluoronaphthalen-2-ol; [0790] 4-[4-(4,5-dihydro-1H,3H-pyrrolo[2,1-c][1,4]oxazepin-7-yl)-8-fluoro-2-{[(2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}pyrido[4,3-d]pyrimidin-7-yl]-5-ethynyl- 6-fluoronaphthalen-2-ol; [0791] 6-[7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-{[(2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}pyrido[4,3-d]pyrimidin-4-yl]-3,4- dihydropyrrolo[1,2-a]pyrazin-1(2H)-one; [0792] 6-[7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-{[(2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}pyrido[4,3-d]pyrimidin-4-yl]-2-methyl- 3,4-dihydropyrrolo[1,2-a]pyrazin-1(2H)-one; [0793] 6-[7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-{[(2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}pyrido[4,3-d]pyrimidin-4-yl]-3,4- dihydro-1H-pyrrolo[2,1-c][1,4]oxazin-1-one;
[0794] 6 [7 (8 ethynyl 7 fluoro 3 hydroxynaphthalen 1 yl) 8 fluoro 2 {[(2R,7aS) 2 fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}pyrido[4,3-d]pyrimidin-4-yl]-1H- pyrrolo[2,1-c][1,4]oxazin-3(4H)-one; [0795] 6-[7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-{[(2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}pyrido[4,3-d]pyrimidin-4-yl]-1,2- dihydropyrrolo[1,2-a]pyrazin-3(4H)-one; [0796] 6-[7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-{[(2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}pyrido[4,3-d]pyrimidin-4-yl]-2-methyl- 1,2-dihydropyrrolo[1,2-a]pyrazin-3(4H)-one; [0797] 5-ethynyl-6-fluoro-4-[8-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl]methoxy}-4-(5,6,7,8-tetrahydroindolizin-3-yl)pyrido[4,3-d]pyrimidin-7- yl]naphthalen-2-ol; [0798] (8S)-3-[7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-{[(2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}pyrido[4,3-d]pyrimidin-4-yl]-5,6,7,8- tetrahydroindolizin-8-ol; [0799] 4-[4-(4,7-dihydro-5H-furo[2,3-c]pyran-3-yl)-8-fluoro-2-{[(2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}pyrido[4,3-d]pyrimidin-7-yl]-5-ethynyl- 6-fluoronaphthalen-2-ol; [0800] 4-[4-(6,7-dihydro-4H-furo[3,4-c]pyran-1-yl)-8-fluoro-2-{[(2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}pyrido[4,3-d]pyrimidin-7-yl]-5-ethynyl- 6-fluoronaphthalen-2-ol; [0801] 4-[4-(6,7-dihydro-4H-thieno[3,4-c]pyran-1-yl)-8-fluoro-2-{[(2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}pyrido[4,3-d]pyrimidin-7-yl]-5-ethynyl- 6-fluoronaphthalen-2-ol; [0802] 4-[4-(5,6-dihydro-8H-imidazo[5,1-c][1,4]oxazin-3-yl)-8-fluoro-2-{[(2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}pyrido[4,3-d]pyrimidin-7-yl]-5-ethynyl- 6-fluoronaphthalen-2-ol; [0803] 4-[4-(5,6-dihydro-8H-imidazo[2,1-c][1,4]oxazin-3-yl)-8-fluoro-2-{[(2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}pyrido[4,3-d]pyrimidin-7-yl]-5-ethynyl- 6-fluoronaphthalen-2-ol; [0804] 5-ethynyl-6-fluoro-4-(8-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl]methoxy}-4-[1-(8-oxabicyclo[3.2.1]octan-3-yl)-1H-pyrazol-4-yl]pyrido[4,3- d]pyrimidin-7-yl)naphthalen-2-ol;
[0805] 5 ethynyl 6 fluoro 4 (8 fluoro 2 {[(2R,7aS) 2 fluorotetrahydro 1H pyrrolizin 7a(5H)-yl]methoxy}-4-[1-(oxan-4-yl)-1H-pyrazol-4-yl]pyrido[4,3-d]pyrimidin-7- yl)naphthalen-2-ol; [0806] 4-{4-(3,4-dihydro-1H-pyrrolo[2,1-c][1,4]oxazin-6-yl)-8-fluoro-2-[(3R,3aS,6aS)-3- fluoro-1-methylhexahydropyrrolo[3,4-b]pyrrol-5(1H)-yl]pyrido[4,3-d]pyrimidin-7-yl}-5- ethynyl-6-fluoronaphthalen-2-ol; [0807] 4-{4-(3,4-dihydro-1H-pyrrolo[2,1-c][1,4]oxazin-6-yl)-8-fluoro-2-[(3aR,6aS)-5- methylhexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl]pyrido[4,3-d]pyrimidin-7-yl}-5-ethynyl-6- fluoronaphthalen-2-ol; [0808] 4-[4-(3,4-dihydro-1H-pyrrolo[2,1-c][1,4]oxazin-6-yl)-8-fluoro-2-(4-methylpiperazin- 1-yl)pyrido[4,3-d]pyrimidin-7-yl]-5-ethynyl-6-fluoronaphthalen-2-ol; [0809] 4-[4-(cyclopentylsulfanyl)-8-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl]methoxy}pyrido[4,3-d]pyrimidin-7-yl]-5-ethynyl-6-fluoronaphthalen-2-ol; [0810] 4-[4-(cyclopentanesulfonyl)-8-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl]methoxy}pyrido[4,3-d]pyrimidin-7-yl]-5-ethynyl-6-fluoronaphthalen-2-ol; [0811] 4-[4-(cyclobutylsulfanyl)-8-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl]methoxy}pyrido[4,3-d]pyrimidin-7-yl]-5-ethynyl-6-fluoronaphthalen-2-ol; [0812] 4-[4-(cyclobutanesulfonyl)-8-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl]methoxy}pyrido[4,3-d]pyrimidin-7-yl]-5-ethynyl-6-fluoronaphthalen-2-ol; [0813] 4-[4-(cyclopropylsulfanyl)-8-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl]methoxy}pyrido[4,3-d]pyrimidin-7-yl]-5-ethynyl-6-fluoronaphthalen-2-ol; [0814] 4-[4-(cyclopropanesulfonyl)-8-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl]methoxy}pyrido[4,3-d]pyrimidin-7-yl]-5-ethynyl-6-fluoronaphthalen-2-ol; [0815] [7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-{[(2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}pyrido[4,3-d]pyrimidin-4-yl](8-oxa-3- azabicyclo[3.2.1]octan-3-yl)methanone; and [0816] N-{[1-(dimethylamino)cyclobutyl]methyl}-7-(8-ethynyl-7-fluoro-3- hydroxynaphthalen-1-yl)-8-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl]methoxy}pyrido[4,3-d]pyrimidine-4-carboxamide; [0817] 5-ethynyl-1,6-difluoro-4-[8-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl]methoxy}-4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)pyrido[4,3-d]pyrimidin-7- yl]naphthalen-2-ol; [0818] 5-ethynyl-6-fluoro-4-(8-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl]methoxy}-4-[(2R)-2-(methoxymethyl)morpholin-4-yl]pyrido[4,3-d]pyrimidin-7- yl)naphthalen-2-ol;
[0819] 5 ethynyl 6 fluoro 4 [8 fluoro 2 {[(2R,7aS) 2 fluorotetrahydro 1H pyrrolizin 7a(5H)-yl]methoxy}-4-(morpholin-4-yl)pyrido[4,3-d]pyrimidin-7-yl]naphthalen-2-ol; [0820] 5-ethynyl-6-fluoro-4-[8-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl]methoxy}-4-(2-oxa-5-azabicyclo[4.1.0]heptan-5-yl)pyrido[4,3-d]pyrimidin-7- yl]naphthalen-2-ol; [0821] 4-{2-[(3S)-3-(dimethylamino)pyrrolidin-1-yl]-8-fluoro-4-(morpholin-4-yl)pyrido[4,3- d]pyrimidin-7-yl}-5-ethynyl-6-fluoronaphthalen-2-ol; [0822] 5-ethynyl-6-fluoro-4-[8-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl]methoxy}-4-(6-oxa-3-azabicyclo[3.1.1]heptan-3-yl)pyrido[4,3-d]pyrimidin-7- yl]naphthalen-2-ol; [0823] 4-[7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-{[(2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}pyrido[4,3-d]pyrimidin-4-yl]-1λ
6- thiomorpholine-1,1-dione; [0824] 4-[4-(2,9-dioxa-6-azaspiro[4.5]decan-6-yl)-8-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro- 1H-pyrrolizin-7a(5H)-yl]methoxy}pyrido[4,3-d]pyrimidin-7-yl]-5-ethynyl-6- fluoronaphthalen-2-ol; [0825] 5-ethynyl-6-fluoro-4-(8-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl]methoxy}-4-[(1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl]pyrido[4,3- d]pyrimidin-7-yl)naphthalen-2-ol; [0826] 5-ethynyl-6-fluoro-4-[8-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl]methoxy}-4-(7-oxa-4-azaspiro[2.5]octan-4-yl)pyrido[4,3-d]pyrimidin-7- yl]naphthalen-2-ol; [0827] 5-ethynyl-6-fluoro-4-[8-fluoro-2-({[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl](
2H2)methyl}oxy)-4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)pyrido[4,3-d]pyrimidin- 7-yl]naphthalen-2-ol; [0828] 5-ethynyl-6-fluoro-4-[8-fluoro-2-({[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl](
2H
2)methyl}oxy)-4-(morpholin-4-yl)pyrido[4,3-d]pyrimidin-7-yl]naphthalen-2- ol; [0829] 5-ethynyl-6-fluoro-4-(8-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl]methoxy}-4-[4-(methoxymethyl)-1H-pyrazol-1-yl]pyrido[4,3-d]pyrimidin-7- yl)naphthalen-2-ol; [0830] 5-ethynyl-6-fluoro-4-(8-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl]methoxy}-4-[4-(methoxymethyl)-1H-1,2,3-triazol-1-yl]pyrido[4,3-d]pyrimidin-7- yl)naphthalen-2-ol;
[0831] 5 ethynyl 6 fluoro 4 (8 fluoro 2 {[(2R,7aS) 2 fluorotetrahydro 1H pyrrolizin 7a(5H)-yl]methoxy}-4-[4-(methoxymethyl)-1H-imidazol-1-yl]pyrido[4,3-d]pyrimidin-7- yl)naphthalen-2-ol; [0832] 5-ethynyl-6-fluoro-4-(8-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl]methoxy}-4-[3-(methoxymethyl)-1H-pyrrol-1-yl]pyrido[4,3-d]pyrimidin-7- yl)naphthalen-2-ol; [0833] 5-ethynyl-6-fluoro-4-(8-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl]methoxy}-4-[1-(2-methoxyethyl)-1H-1,2,3-triazol-4-yl]pyrido[4,3-d]pyrimidin-7- yl)naphthalen-2-ol; [0834] 5-ethynyl-6-fluoro-4-(8-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl]methoxy}-4-[1-(2-methoxyethyl)-1H-pyrazol-4-yl]pyrido[4,3-d]pyrimidin-7- yl)naphthalen-2-ol; [0835] 5-ethynyl-6-fluoro-4-(8-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl]methoxy}-4-[1-(2-methoxyethyl)-1H-imidazol-4-yl]pyrido[4,3-d]pyrimidin-7- yl)naphthalen-2-ol; [0836] 5-ethynyl-6-fluoro-4-(8-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl]methoxy}-4-[(2R)-2-hydroxy-2-methylcyclopropyl]pyrido[4,3-d]pyrimidin-7- yl)naphthalen-2-ol; [0837] 5-ethyl-6-fluoro-4-(8-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl]methoxy}-4-[(2R)-2-hydroxy-2-methylcyclopropyl]pyrido[4,3-d]pyrimidin-7- yl)naphthalen-2-ol; [0838] 5-ethynyl-6-fluoro-4-(8-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl]methoxy}-4-[(2R)-2-hydroxy-2-methylcyclobutyl]pyrido[4,3-d]pyrimidin-7- yl)naphthalen-2-ol; [0839] 5-ethyl-6-fluoro-4-(8-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl]methoxy}-4-[(2R)-2-hydroxy-2-methylcyclobutyl]pyrido[4,3-d]pyrimidin-7- yl)naphthalen-2-ol; [0840] 5-ethyl-6-fluoro-4-(8-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl]methoxy}-4-[(3R)-3-hydroxy-3-methylcyclopentyl]pyrido[4,3-d]pyrimidin-7- yl)naphthalen-2-ol; [0841] 5-ethyl-6-fluoro-4-(8-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl]methoxy}-4-[(3R)-3-hydroxy-3-methylcyclohexyl]pyrido[4,3-d]pyrimidin-7- yl)naphthalen-2-ol;
[0842] 5 ethyl 6 fluoro 4 (8 fluoro 2 {[(2R,7aS) 2 fluorotetrahydro 1H pyrrolizin 7a(5H) yl]methoxy}-4-[(2R)-3-hydroxy-3-methylbutan-2-yl]pyrido[4,3-d]pyrimidin-7- yl)naphthalen-2-ol; [0843] 5-ethyl-6-fluoro-4-[8-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl]methoxy}-4-(2-hydroxy-2-methylpropyl)pyrido[4,3-d]pyrimidin-7-yl]naphthalen-2-ol; [0844] 5-ethyl-6-fluoro-4-[8-fluoro-2-({[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl](
2H2)methyl}oxy)-4-(2-hydroxy-2-methylpropyl)pyrido[4,3-d]pyrimidin-7-yl]naphthalen- 2-ol; [0845] 5-chloro-6-fluoro-4-[8-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl]methoxy}-4-(2-hydroxy-2-methylpropyl)pyrido[4,3-d]pyrimidin-7-yl]naphthalen-2-ol; [0846] 5,6-difluoro-4-[8-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl]methoxy}-4-(2-hydroxy-2-methylpropyl)pyrido[4,3-d]pyrimidin-7-yl]naphthalen-2-ol; [0847] 5-ethyl-6-fluoro-4-[8-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl]methoxy}-4-(2-hydroxy-2-methylpropyl)-5-methoxypyrido[4,3-d]pyrimidin-7- yl]naphthalen-2-ol, [0848] (3R)-1-[7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-{[(2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}-5-methoxypyrido[4,3-d]pyrimidin-4- yl]-3-methylpiperidin-3-ol; [0849] 1-{4-[7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-{[(2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}pyrido[4,3-d]pyrimidin-4-yl]-1,4- diazepan-1-yl}ethan-1-one; [0850] 5-ethynyl-6-fluoro-4-(8-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl]methoxy}-4-methylpyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol; [0851] 4-(4-cyclohexyl-8-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl]methoxy}pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol; and [0852] 4-[4-(cyclohex-1-en-1-yl)-8-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl]methoxy}pyrido[4,3-d]pyrimidin-7-yl]-5-ethynyl-6-fluoronaphthalen-2-ol; [0853] or a pharmaceutically acceptable salt thereof. [0854] In some embodiments, the disclosure provides a compound selected from the group consisting of 5-ethynyl-6-fluoro-4-[8-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl]methoxy}-4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)pyrido[4,3-d]pyrimidin-7- yl]quinolin-2-ol; [0855] 5-ethynyl-4-[8-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl]methoxy}-4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)pyrido[4,3-d]pyrimidin-7-yl]quinolin- 2-ol;
[0856] 5 ethynyl 4 [8 fluoro 2 {[(2R,7aS) 2 fluorotetrahydro 1H pyrrolizin 7a(5H) yl]methoxy}-4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)pyrido[4,3-d]pyrimidin-7-yl]-6- methylquinolin-2-ol; [0857] 5-chloro-4-[8-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl]methoxy}-4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)pyrido[4,3-d]pyrimidin-7-yl]-6- methylquinolin-2-ol; [0858] 4-[8-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}-4-(8- oxa-3-azabicyclo[3.2.1]octan-3-yl)pyrido[4,3-d]pyrimidin-7-yl]-6-methylquinolin-2-ol; [0859] 5-chloro-4-[8-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl]methoxy}-4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)pyrido[4,3-d]pyrimidin-7-yl]-6- methylquinolin-2-amine; [0860] 5-chloro-4-[8-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl]methoxy}-4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)pyrido[4,3-d]pyrimidin-7-yl]-6- methylquinazolin-2-amine; [0861] 8-chloro-1-[8-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl]methoxy}-4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)pyrido[4,3-d]pyrimidin-7-yl]-7- methylisoquinolin-3-amine; [0862] 5-ethynyl-6-fluoro-4-[8-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl]methoxy}-4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)pyrido[4,3-d]pyrimidin-7- yl]quinolin-2-amine; [0863] 8-ethynyl-7-fluoro-1-[8-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl]methoxy}-4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)pyrido[4,3-d]pyrimidin-7- yl]isoquinolin-3-amine; [0864] 5-chloro-4-[8-fluoro-4-(3-fluorophenyl)-2-{[(2R,7aS)-2-fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl]methoxy}pyrido[4,3-d]pyrimidin-7-yl]-6-methylquinolin-2-ol; [0865] 4-[4-(3,4-dihydro-1H-pyrrolo[2,1-c][1,4]oxazin-6-yl)-8-fluoro-2-{[(2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}pyrido[4,3-d]pyrimidin-7-yl]-5-ethynyl- 6-fluoroquinolin-2-ol; [0866] 4-[4-(3,4-dihydro-1H-pyrrolo[2,1-c][1,4]oxazin-6-yl)-8-fluoro-2-{[(2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}pyrido[4,3-d]pyrimidin-7-yl]-5-ethynyl- 6-fluoroquinolin-2-amine; and [0867] 5-chloro-4-[4-(3,4-dihydro-1H-pyrrolo[2,1-c][1,4]oxazin-6-yl)-8-fluoro-2- {[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}pyrido[4,3-d]pyrimidin-7- yl]-6-methylquinolin-2-ol; [0868] or a pharmaceutically acceptable salt thereof.
[0869] In some embodiments, the disclosure provides a compound selected from the group consisting of 7-(4-ethynyl-5-fluoro-1H-indazol-3-yl)-8-fluoro-2-{[(2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}-4-(8-oxa-3-azabicyclo[3.2.1]octan-3- yl)pyrido[4,3-d]pyrimidine; [0870] 7-(5-chloro-1H-indazol-3-yl)-8-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl]methoxy}-4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)pyrido[4,3- d]pyrimidine; [0871] 7-(4-chloro-1H-indazol-3-yl)-8-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl]methoxy}-4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)pyrido[4,3- d]pyrimidine; [0872] 7-(4-chloro-5-methyl-1H-indazol-3-yl)-8-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl]methoxy}-4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)pyrido[4,3- d]pyrimidine; [0873] 7-(4-chloro-5-fluoro-1H-indazol-3-yl)-8-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl]methoxy}-4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)pyrido[4,3- d]pyrimidine; and [0874] 8-fluoro-7-(4-fluoro-1H-indazol-3-yl)-2-{[(2R,7aS)-2-fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl]methoxy}-4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)pyrido[4,3- d]pyrimidine; [0875] or a pharmaceutically acceptable salt thereof. [0876] In some embodiments, the disclosure provides a compound selected from the group consisting of 7-(5-chloro-3-methyl-1H-indazol-4-yl)-8-fluoro-2-{[(2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}-4-(8-oxa-3-azabicyclo[3.2.1]octan-3- yl)pyrido[4,3-d]pyrimidine; [0877] 7-(6-chloro-3,5-dimethyl-1H-indazol-4-yl)-8-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro- 1H-pyrrolizin-7a(5H)-yl]methoxy}-4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)pyrido[4,3- d]pyrimidine; and [0878] 6-chloro-4-[8-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl]methoxy}-4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)pyrido[4,3-d]pyrimidin-7-yl]-5-methyl- 1H-indazole-3-carbonitrile; [0879] or a pharmaceutically acceptable salt thereof. [0880] The following represent illustrative embodiments of compounds of Formula (I):
and pharmaceutically acceptable salts thereof. [0881] Those skilled in the art will recognize that the species listed or illustrated herein are not exhaustive, and that additional species within the scope of these defined terms may also be selected. PHARMACEUTICAL COMPOSITIONS [0882] For treatment purposes, pharmaceutical compositions comprising the compounds described herein may further comprise one or more pharmaceutically-acceptable excipients. A pharmaceutically-acceptable excipient is a substance that is non-toxic and otherwise biologically suitable for administration to a subject. Such excipients facilitate administration
of the compounds described herein and are compatible with the active ingredient. Examples of pharmaceutically-acceptable excipients include stabilizers, lubricants, surfactants, diluents, anti-oxidants, binders, coloring agents, bulking agents, emulsifiers, or taste-modifying agents. In preferred embodiments, pharmaceutical compositions according to the disclosure are sterile compositions. Pharmaceutical compositions may be prepared using compounding techniques known or that become available to those skilled in the art. [0883] Sterile compositions are also contemplated by the disclosure, including compositions that are in accord with national and local regulations governing such compositions. [0884] The pharmaceutical compositions and compounds described herein may be formulated as solutions, emulsions, suspensions, or dispersions in suitable pharmaceutical solvents or carriers, or as pills, tablets, lozenges, suppositories, sachets, dragees, granules, powders, powders for reconstitution, or capsules along with solid carriers according to conventional methods known in the art for preparation of various dosage forms. Pharmaceutical compositions of the disclosure may be administered by a suitable route of delivery, such as oral, parenteral, rectal, nasal, topical, or ocular routes, or by inhalation. Preferably, the compositions are formulated for intravenous or oral administration. [0885] For oral administration, the compounds the disclosure may be provided in a solid form, such as a tablet or capsule, or as a solution, emulsion, or suspension. To prepare the oral compositions, the compounds of the disclosure may be formulated to yield a dosage of, e.g., from about 0.1 mg to 1 g daily, or about 1 mg to 50 mg daily, or about 50 to 250 mg daily, or about 250 mg to 1 g daily. Oral tablets may include the active ingredient(s) mixed with compatible pharmaceutically acceptable excipients such as diluents, disintegrating agents, binding agents, lubricating agents, sweetening agents, flavoring agents, coloring agents and preservative agents. Suitable inert fillers include sodium and calcium carbonate, sodium and calcium phosphate, lactose, starch, sugar, glucose, methyl cellulose, magnesium stearate, mannitol, sorbitol, and the like. Exemplary liquid oral excipients include ethanol, glycerol, water, and the like. Starch, polyvinyl-pyrrolidone (PVP), sodium starch glycolate, microcrystalline cellulose, and alginic acid are exemplary disintegrating agents. Binding agents may include starch and gelatin. The lubricating agent, if present, may be magnesium stearate, stearic acid, or talc. If desired, the tablets may be coated with a material such as glyceryl monostearate or glyceryl distearate to delay absorption in the gastrointestinal tract, or may be coated with an enteric coating. [0886] Capsules for oral administration include hard and soft gelatin capsules. To prepare hard gelatin capsules, active ingredient(s) may be mixed with a solid, semi-solid, or liquid diluent. Soft gelatin capsules may be prepared by mixing the active ingredient with water, an
oil, such as peanut oil or olive oil, liquid paraffin, a mixture of mono and di glycerides of short chain fatty acids, polyethylene glycol 400, or propylene glycol. [0887] Liquids for oral administration may be in the form of suspensions, solutions, emulsions, or syrups, or may be lyophilized or presented as a dry product for reconstitution with water or other suitable vehicle before use. Such liquid compositions may optionally contain: pharmaceutically-acceptable excipients such as suspending agents (for example, sorbitol, methyl cellulose, sodium alginate, gelatin, hydroxyethylcellulose, carboxymethylcellulose, aluminum stearate gel and the like); non-aqueous vehicles, e.g., oil (for example, almond oil or fractionated coconut oil), propylene glycol, ethyl alcohol, or water; preservatives (for example, methyl or propyl p-hydroxybenzoate or sorbic acid); wetting agents such as lecithin; and, if desired, flavoring or coloring agents. [0888] For parenteral use, including intravenous, intramuscular, intraperitoneal, intranasal, or subcutaneous routes, the agents of the disclosure may be provided in sterile aqueous solutions or suspensions, buffered to an appropriate pH and isotonicity or in parenterally acceptable oil. Suitable aqueous vehicles include Ringer's solution and isotonic sodium chloride. Such forms may be presented in unit-dose form such as ampoules or disposable injection devices, in multi- dose forms such as vials from which the appropriate dose may be withdrawn, or in a solid form or pre-concentrate that can be used to prepare an injectable formulation. Illustrative infusion doses range from about 1 to 1000 μg/kg/minute of agent admixed with a pharmaceutical carrier over a period ranging from several minutes to several days. [0889] For nasal, inhaled, or oral administration, the inventive pharmaceutical compositions may be administered using, for example, a spray formulation also containing a suitable carrier. The inventive compositions may be formulated for rectal administration as a suppository. [0890] For topical applications, the compounds of the present disclosure are preferably formulated as creams or ointments or a similar vehicle suitable for topical administration. For topical administration, the inventive compounds may be mixed with a pharmaceutical carrier at a concentration of about 0.1% to about 10% of drug to vehicle. Another mode of administering the agents of the disclosure may utilize a patch formulation to effect transdermal delivery. [0891] As used herein, the terms “treat” or “treatment” encompass both “preventative” and “curative” treatment. “Preventative” treatment is meant to indicate a postponement of development of a disease, a symptom of a disease, or medical condition, suppressing symptoms that may appear, or reducing the risk of developing or recurrence of a disease or symptom. “Curative” treatment includes reducing the severity of or suppressing the worsening of an existing disease, symptom, or condition. Thus, treatment includes ameliorating or preventing
the worsening of existing disease symptoms, preventing additional symptoms from occurring, ameliorating or preventing the underlying systemic causes of symptoms, inhibiting the disorder or disease, e.g., arresting the development of the disorder or disease, relieving the disorder or disease, causing regression of the disorder or disease, relieving a condition caused by the disease or disorder, or stopping the symptoms of the disease or disorder. [0892] The term “subject” refers to a mammalian patient in need of such treatment, such as a human. [0893] Exemplary diseases include cancer, pain, neurological diseases, autoimmune diseases, and inflammation. As used herein, the term “cancer” includes, but is not limited to, ALCL, NSCLC, neuroblastoma, inflammatory myofibroblastic tumor, adult renal cell carcinoma, pediatric renal cell carcinoma, breast cancer, ER
+ breast cancer, colonic adenocarcinoma, glioblastoma, glioblastoma multiforme, anaplastic thyroid cancer, cholangiocarcinoma, ovarian cancer, gastric adenocarcinoma, colorectal cancer, inflammatory myofibroblastic tumor, angiosarcoma, epithelioid hemangioendothelioma, intrahepatic cholangiocarcinoma, thyroid papillary cancer, spitzoid neoplasms, sarcoma, astrocytoma, brain lower grade glioma, secretory breast carcinoma, mammary analogue carcinoma, acute myeloid leukemia, congenital mesoblastic nephroma, congenital fibrosarcomas, Ph-like acute lymphoblastic leukemia, thyroid carcinoma, skin cutaneous melanoma, head and neck squamous cell carcinoma, pediatric glioma CML, prostate cancer, lung squamous carcinoma, ovarian serous cystadenocarcinoma, skin cutaneous melanoma, castrate-resistant prostate cancer, Hodgkin lymphoma, and serous and clear cell endometrial cancer. In some embodiments, cancer includes, lung cancer, colon cancer, breast cancer, prostate cancer, hepatocellular carcinoma, renal cell carcinoma, gastric and esophago-gastric cancers, glioblastoma, head and neck cancers, inflammatory myofibroblastic tumors, and anaplastic large cell lymphoma. Pain includes, for example, pain from any source or etiology, including cancer pain, pain from chemotherapeutic treatment, nerve pain, pain from injury, or other sources. Autoimmune diseases include, for example, rheumatoid arthritis, Sjogren syndrome, Type I diabetes, and lupus. Exemplary neurological diseases include Alzheimer’s Disease, Parkinson’s Disease, Amyotrophic lateral sclerosis, and Huntington’s disease. Exemplary inflammatory diseases include atherosclerosis, allergy, and inflammation from infection or injury. [0894] In one aspect, the compounds and pharmaceutical compositions of the disclosure specifically target Ras, in particular K-Ras. Thus, these compounds and pharmaceutical compositions can be used to prevent, reverse, slow, or inhibit the activity of one or more KRAS mutations, such as KRAS G12C, KRAS G12D, KRAS G12V, KRAS G12R, KRAS G12S,
KRAS G13C, KRAS G13D, KRAS A18D, KRAS Q61H, KRAS K117N, and the like. In preferred embodiments, methods of treating a target cancer are described. [0895] In the inhibitory methods of the disclosure, an “effective amount” means an amount sufficient to inhibit the target protein. Measuring such target modulation may be performed by routine analytical methods such as those described below. Such modulation is useful in a variety of settings, including in vitro assays. In such methods, the cell is preferably a cancer cell with abnormal signaling due to a mutation of KRAS, such as KRAS G12C, KRAS G12D, KRAS G12V, KRAS G12R, KRAS G12S, KRAS G13C, KRAS G13D, KRAS A18D, KRAS Q61H, KRAS K117N, and the like. [0896] In treatment methods according to the disclosure, an “effective amount” means an amount or dose sufficient to generally bring about the desired therapeutic benefit in subjects needing such treatment. Effective amounts or doses of the compounds of the disclosure may be ascertained by routine methods, such as modeling, dose escalation, or clinical trials, taking into account routine factors, e.g., the mode or route of administration or drug delivery, the pharmacokinetics of the agent, the severity and course of the infection, the subject’s health status, condition, and weight, and the judgment of the treating physician. An exemplary dose is in the range of about from about 0.1 mg to 1 g daily, or about 1 mg to 50 mg daily, or about 50 to 250 mg daily, or about 250 mg to 1 g daily. The total dosage may be given in single or divided dosage units (e.g., BID, TID, QID). [0897] Once improvement of the patient’s disease has occurred, the dose may be adjusted for preventative or maintenance treatment. For example, the dosage or the frequency of administration, or both, may be reduced as a function of the symptoms, to a level at which the desired therapeutic or prophylactic effect is maintained. Of course, if symptoms have been alleviated to an appropriate level, treatment may cease. Patients may, however, require intermittent treatment on a long-term basis upon any recurrence of symptoms. Patients may also require chronic treatment on a long-term basis. DRUG COMBINATIONS [0898] The inventive compounds described herein may be used in pharmaceutical compositions or methods in combination with one or more additional active ingredients in the treatment of the diseases and disorders described herein. Further additional active ingredients include other therapeutics or agents that mitigate adverse effects of therapies for the intended disease targets. Such combinations may serve to increase efficacy, ameliorate other disease symptoms, decrease one or more side effects, or decrease the required dose of an inventive
compound. The additional active ingredients may be administered in a separate pharmaceutical composition from a compound of the present disclosure or may be included with a compound of the present disclosure in a single pharmaceutical composition. The additional active ingredients may be administered simultaneously with, prior to, or after administration of a compound of the present disclosure. [0899] Combination agents include additional active ingredients are those that are known or discovered to be effective in treating the diseases and disorders described herein, including those active against another target associated with the disease. For example, compositions and formulations of the disclosure, as well as methods of treatment, can further comprise other drugs or pharmaceuticals, e.g., other active agents useful for treating or palliative for the target diseases or related symptoms or conditions. For cancer indications, additional such agents include, but are not limited to, kinase inhibitors, such as ALK inhibitors (e.g. crizotinib), Raf inhibitors (e.g., vemurafenib), VEGFR inhibitors (e.g., sunitinib), standard chemotherapy agents such as alkylating agents, antimetabolites, anti-tumor antibiotics, topoisomerase inhibitors, platinum drugs, mitotic inhibitors, antibodies, hormone therapies, or corticosteroids. For pain indications, suitable combination agents include anti-inflammatories such as NSAIDs. The pharmaceutical compositions of the disclosure may additional comprise one or more of such active agents, and methods of treatment may additionally comprise administering an effective amount of one or more of such active agents. CHEMICAL SYNTHESIS METHODS [0900] The following examples are offered to illustrate but not to limit the disclosure. One of skill in the art will recognize that the following synthetic reactions and schemes may be modified by choice of suitable starting materials and reagents in order to access other compounds of Formula (I)-(XXa). [0901] Abbreviations: The examples described herein use materials, including but not limited to, those described by the following abbreviations known to those skilled in the art:
[0902] The proposed targets can be prepared via the conventional chemistry or following the general schemes as shown below. [0903] Scheme I
[0904] The general scheme I is used to prepare the products with general structure Ex. I. The bicyclic aryl core I-1-1 and a variety of amines I-2 are either commercially available or prepared via conventional chemistry from commercially available materials. A: under basic condition such as diisopropylethyl amine (DIPEA) in dichloromethane at reduced temperature such as -40 °C, compound I-1-1 and amine I-2 are converted to a product I-3. B: under basic conditions such as diisopropylethylamine in dioxane at elevated temperature such as 80 °C, compound I-3 and an amine or alcohol I-4 are converted to a product I-5. C: under palladium- catalyzed Suzuki coupling condition, compound I-5 and a boronic ester I-6 are converted to a product which is de-protected if required to provide the final product Ex. I.
[0905] Scheme II
[0906] The general scheme II is used to prepare the examples with the general structure Ex. II. The bicyclic aryl core I-1-1 and a variety of boronic acids or esters II-1 are either commercially available or prepared via conventional chemistry from commercially available materials. A: under palladium-catalyzed Suzuki coupling condition, compound I-1-1 and a boronic acid or ester II-1 are converted to a product II-2. B: under basic conditions such as diisopropylethylamine in dioxane at elevated temperature such as 80 °C, compound II-2 and an amine I-4 are converted to a product II-3. C: under palladium-catalyzed Suzuki coupling condition, compound II-3 and a boronic ester I-6 are converted to a product which is then de- protected if required to provide the final product Ex. II. [0907] Scheme III
[0908] The general scheme III is used to prepare the examples with the general structure Ex. III. The bicyclic aryl core I-1-1 and a variety of thiols III-1 are either commercially available
or prepared via conventional chemistry from commercially available materials. A: under basic conditions such as sodium hydride in anhydrous THF at reduced temperature such as 0 °C, compound I-1-1 and a thiol III-1 are converted to a product III-2. B: under basic conditions such as diisopropylethylamine in dioxane at elevated temperature such as 80 °C, compound III-2 and an amine or alcohol I-4 are converted to a product III-3. C: under palladium- catalyzed Suzuki coupling condition, compound III-3 and a boronic ester I-6 are converted to a product III-7. D: the sulfanic compound III-7 is oxidized to a product Ex. III. [0909] Scheme IV
[0910] The general scheme IV is used for the preparations of examples with general structure Ex. IV. The bicyclic aryl ester I-1-2 and a variety of amines or alcohols I-4 are either commercially available or prepared via conventional chemistry from commercially available materials. A: under basic conditions such as diisopropylethylamine in dioxane at elevated temperature such as 80 °C, compound I-1-2 and an amine I-4 are converted to a product IV-2. B: under palladium-catalyzed Suzuki coupling condition, compound IV-2 and a boronic ester I-6 are converted to a product IV-3. C: under basic hydrolysis condition the ester IV-3 is converted to an acid which is further converted to an amide under amide coupling conditions, followed de-protection if required to provide the final product Ex. IV. [0911] Preparation of 1,3,6-trichloro-5-fluoro-2,7-naphthyridine (I-1-2)
[0912] Step 1. To a stirred solution of ethyl 4,6-dichloro-5-fluoronicotinate (1.00 eq.) in DMF (0.5M) are added tert-butyl methyl malonate (1.50 eq.) and Cs2CO3 (2.00 eq.). After stirring for 3 h at 40 °C under nitrogen, water is added and the mixture is extracted with ethyl acetate. The combined organic layers are washed with brine, dried over anhydrous Na2SO4, filtered and concentrated to provide I-1-2-3. [0913] Step 2. A solution of I-1-2-3 (1.00 eq.) in 20% TFA/DCM (0.4 M) is stirred for 2 h at rt. Then the mixture is concentrated to dryness. Water is added to the residue, and the pH of the solution is adjusted pH>7 with Na2CO3 (solid). The mixture is then extracted with ethyl acetate. The organic layer is washed with brine, dried over anhydrous Na2SO4, filtered and concentrated to provide I-1-2-4. [0914] Step 3. A solution of the product of I-1-2-4 (1.0 eq.) in NH3/H2O (25-28%, 0.8 M) is stirred for 12 h at 120 °C in a sealed tube. The mixture is concentrated to provide I-1-2-5. [0915] Step 4. A mixture of I-1-2-5 (1.0 eq.) in phenylphosphonic dichloride (0.6 M) is stirred for 16 h at 130 °C. The mixture is poured slowly into ice water, and the pH of the solution is adjusted pH>7 with NaHCO3 (solid). The mixture is extracted with ethyl acetate. The organic layer is washed with brine, dried over anhydrous Na
2SO
4, filtered and concentrated to give I- 1-2. [0916] Preparation of methyl 2,7-dichloro-8-fluoropyrido[4,3-d]pyrimidine-4-carboxylate (I- 1-3)
[0917] Step 1. To a solution of I-1-1 (1.0 eq.) in 1,4-dioxane (0.14 M) is added a solution of potassium carbonate (2.0 M) in H2O (7 M). The solution is degassed with argon for 10 min and 1-ethoxyvinyltri-n-butyltin (0.95 eq.) and Pd(PPh
3)
2Cl
2 (0.05 eq.) are added. The mixture is heated to 100 °C for 30 min and the solvent is removed in vacuo. The residue is partitioned between DCM and H
2O and the organic layer is separated and concentrated in vacuo.
Purification by column chromatography affords I 131. [0918] Step 2. To a solution of I-1-3-1 (1.0 eq.) in 1,4-dioxane (0.06 M) is added a solution of potassium meta-periodate (2.0 eq.) in H
2O (0.3 M). Potassium permanganate (0.1 eq) is added and the resulting reaction mixture is stirred at rt for 30 min. The reaction mixture is poured into DCM and the organic layer separated. The aqueous is extracted with DCM and the combined organic extracts dried (MgSO
4), filtered and concentrated in vacuo to afford I-1-3. [0919] Preparation of (3R,3aS,6aS)-3-fluoro-1-methyloctahydropyrrolo[3,4-b]pyrrole (I-4-3)
[0920] Step 1. A solution of nBuLi (1.6 N in hexane, 1.2 eq.) is added dropwise to a stirred solution of I-4-3-1 (1.0 eq.) in dry THF and HMPA at -78 °C and the mixture is stirred at -78 °C for 30 minutes. A solution of NaI (0.5 eq.) and t-buthylbromoacetate (3.0 eq.) in THF (1.5 M) was rapidly transferred with a cannula to the reaction flask at -60 °C. The mixture is allowed to warm to -42 °C and stirred for an additional hour and quenched with a 30% aqueous solution of H
3PO
4. The reaction mixture is diluted with water and extracted with EtOAc. The combined extracts are washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue is purified by flash chromatography to obtain I-4-3-2. [0921] Step 2. To a solution of I-4-3-2 (21.6 g, 58.4 mmol) in methanol (0.3 M) were added ammonium acetate (10 eq.), acetic acid (15 eq.), and sodium cyanoborohydride (1.5 eq.). The mixture is heated at 60 °C for 4 h and cooled to ambient temperature. Sodium bicarbonate and water are added. The mixture is extracted with ethyl acetate. The combined organic extracts are washed with brine, dried over magnesium sulfate, filtered and concentrated. The reside is purified by silica gel chromatography to provide I-4-3-3. [0922] Step 3. To a stirred suspension of 60% sodium hydride in mineral oil (1.1 eq.) in tetrahydrofuran (0.2 M) at room temperature is added I-4-3-3 (1.0 g, 9.9 mmol) portion-wise.
The mixture is stirred at room temperature for 2 h followed by addition of iodomethane (1.1 eq.) and stirring for an additional 2 h. The reaction mixture is diluted with dichloromethane, washed with brine and dried over sodium sulfate. After filtration and condensation, the residue is purified by silica gel chromatography to provide I-4-3-4. [0923] Step 4. To a solution of LDA (1.2 eq.) in anhydrous THF (0.1 M) at -80 ºC is added I- 4-3-4 (1.0 eq.) under agitation for 30 min. To the mixture is added a solution of N- fluorobenzenesulfonimide (NFSi, 1.0 eq.) in anhydrous THF (0.05 M) is slowly added. After 1 h at -80 ºC, the reaction is quenched by adding a saturated solution of ammonium chloride. The reaction is allowed to achieve the ambient temperature and then the organic phase is separated, and the aqueous phase is extracted with ethyl acetate. The organic fractions are concentrated, and the residue is purified by silica gel chromatography followed by chiral SCF separation to provide I-4-3-5. [0924] Step 5. To an ice-cooled solution of I-4-3-5 (1.0 eq.) in Et2O is added dropwise a solution of LAH (1M in Et
2O) (1.5 eq.). The mixture is stirred at 0 °C until disappearance of the starting material. The reaction is carefully quenched by sequential addition of water, 15% (w/w) NaOH. Then diethyl ether is added and the suspension is dried with magnesium sulfate. The solids are filtered and wash with diethyl ether. The solvent is removed and the crude material is dissolved in dichlorometane (0.2 M) and cooled to 0 °C. HCl (4M in dioxane) (4 eq.) was added slowly and the reaction is allowed to warm up to rt and stirred for 2-3 h. The mixture of HCl/dioxane is evaporated off under HV and dried under high vacuum to provide I-4-3 as HCl salt. [0925] Preparation of 6-fluoro-2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5- ((triisopropylsilyl)ethynyl)quinoline (I-6-2)
[0926] Step 1. To the solution of I-6-2-1 (1.0 eq.) in MeOH is added a few droplets of sulfuric acid and the mixture is refluxed until reaction completion. After solvent removal and extraction workup with EtOAc, the ester crude product is obtained. This ester is mixed with acetyl
chloride in dichloromethane, followed by addition of Et
3N. The mixture is stirred at room temperature for 30 minutes. After solvent removal and extraction workup with EtOAc, the residue is purified by silica gel column chromatography to afford I-6-2-2. [0927] Step 2. The dry I-6-2-2 (1.0 eq.) is dissolved in THF and cooled down to -78 °C. Potassium bis(trimethylsilyl)amide solution 0.5 M in toluene (3.0 eq.) is added over 5 minutes. The reaction mixture is stirred at 0 °C for 30 minutes and then at room temperature overnight. After quenching with water and extraction workup with EtOAc, the crude product is purified with silica gel column chromatography to afford the I-6-2-3. [0928] Step 3. To I-6-2-3 (1.0 eq.) in a flask is added dropwise at 0 °C POCl3 (10.0 eq.). The resulting mixture is stirred and heated under reflux overnight. Then, the mixture is cooled, concentrated under reduced pressure and co-evaporated twice times with toluene. The residue is then taken up with DCM and washed with cold water. The aqueous layer is extracted with DCM and the combined organic layers are combined and dried over MgSO4, filtered, and concentrated under reduced pressure to give product I-6-2-4. [0929] Step 4. I-6-2-4 (1.0 eq.) is dissolved in anhydrous toluene, a suspension of sodium methoxide (4.0 eq.) in anhydrous toluene is added and the mixture is heated under reflux for 16 h. After cooling to room temperature, the suspension is filtered, the filter cake washed once with toluene, the combined filtrates are evaporated under reduced pressure to dryness. Purification with silica gel chromatography affords the intermediate I-6-2-5. [0930] Step 5. The mixture of I-6-2-5 (1.0 eq.), Pd (PPh3)
2Cl2 (0.02 eq.) and CuI (0.02 eq.) in DMF and Et
3N is degassed with N
2, and ethynyltriisopropylsilane (1.0 eq.) is then added. The mixture is stirred at 40 °C for 16 h. Extraction workup with EtOAc followed by silica gel column chromatography affords intermediate I-6-2-6. [0931] Step 6. The mixture of I-6-2-6 (1.0 eq.), bis(pinacolato)diborane (2.0 eq.), Pd(dppf)Cl
2·CH
2Cl
2 (0.1 eq.), KOAc (3.0 eq.), and dppf (0.2 eq.) in dioxane is degassed with nitrogen, and then stirred at 100 °C for 33 h. Extraction workup with EtOAc, followed by silica gel chromatography affords product I-6-2. [0932] I-6-3—I-6-6 are prepared following similar methods for the preparation of I-6-2 or certain steps for the preparation of I-6-2 from the corresponding commercially available
starting material as shown below:
[0933] Preparation of 5-chloro-6-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)quinolin-2-amine (I-6-7):
[0934] I-6-5-4 is prepared following similar methods of Steps 1, 2 and 3 for the preparation of I-6-2 starting 6-amino-2-chloro-3-methylbenzoic acid. [0935] Step 1. A solution of I-6-5-4 (1.0 eq.), Pd
2(dba)
3 (0.025 eq.), rac-BINAP (0.1 eq.), and sodium tert-butoxide (1.2 eq.) in toluene is stirred at room temperature under N2 for approximately 5 min. Benzophenone imine (1.0 eq.) is added, and the reaction vial is placed in a heating block preheated to 100 °C for three h. The reaction mixture is cooled to room temperature, MTBE is added, and the mixture is filtered through a short plug of Celite and concentrated. The crude residue is dissolved in THF, and 1 M HCl is added. The reaction mixture is stirred overnight and is quenched by addition of saturated aqueous NaHCO3, extracted with EtOAc, dried, and concentrated. The crude residue is purified by silica gel chromatography to afford I-6-7-1. [0936] Step 2. The mixture of I-6-7-1 (1.0 eq.), bis(pinacolato)diborane (2.0 eq.), Pd(dppf)Cl2·CH2Cl2 (0.1 eq.), KOAc (3.0 eq.), and dppf (0.2 eq.) in dioxane is degassed with nitrogen, and then stirred at 100 °C for 33 h. Extraction workup with EtOAc, followed by silica
gel chromatography affords product I 67. [0937] Preparation of 5-chloro-6-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)quinazolin-2-amine (I-6-8)
[0938] Step 1. The mixture of I-6-8-1 (1.0 eq.), thiourea (1.1 eq.) and Et3N (3.0 eq.) in 1- butanol is refluxed for 6 h. After removing solvent, the residue is purified by silica gel chromatography to give I-6-8-2. [0939] Step 2. To I-6-8-2 (1.0 eq.) in a flask is added dropwise at 0 °C POCl3 (10.0 eq.). The resulting mixture is stirred and heated under reflux overnight. Then, the mixture is cooled, concentrated under reduced pressure and co-evaporated twice times with toluene. The residue is then taken up with DCM and washed with cold water. The aqueous layer is extracted with DCM and the combined organic layers are combined and dried over MgSO4, filtered, and concentrated under reduced pressure to give product I-6-8-3. [0940] Step 3. The mixture of I-6-8-3 (1.0 eq.), bis(pinacolato)diborane (2.0 eq.), Pd(dppf)Cl2·CH2Cl2 (0.1 eq.), KOAc (3.0 eq.), and dppf (0.2 eq.) in dioxane is degassed with nitrogen, and then stirred at 100 °C for 33 h. Extraction workup with EtOAc, followed by silica gel chromatography affords product I-6-8. [0941] Preparation of 8-chloro-7-methyl-1-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)isoquinolin-3-amine (I-6-9)
[0942] Step 1. To a solution of NaH (4.0 eq.) in DMSO is added methyl 2-cyanoacetate (4.0 eq.) at 0 °C. The mixture is stirred for 30 min at room temperature and is then added the solution of I-6-9-1 (1.0 eq.) in DMSO dropwise. The mixture is then stirred at 90 °C for 2 h. Water is then added, and the reaction mixture is stirred at 100 °C overnight. After cooling down to 0 °C, 0.1 N HCl is added to quench the reaction. Extraction workup followed by
silica gel chromatography affords the product I 692. [0943] Step 2. To the mixture of I-6-9-2 (1.0 eq.) in dichloromethane is added hydrobromic acid (30% in AcOH) at room temperature. After stirring for 15 min, the reaction mixture is quenched with K2CO3 saturated aqueous solution. The precipitate is collected by filtration and washed with water to afford the product I-6-9-3. [0944] Step 3. The mixture of I-6-9-3 (1.0 eq.), bis(pinacolato)diborane (2.0 eq.), Pd(dppf)Cl2·CH2Cl2 (0.1 eq.), KOAc (3.0 eq.), and dppf (0.2 eq.) in dioxane is degassed with nitrogen, and then stirred at 100 °C for 33 h. Extraction workup with EtOAc, followed by silica gel chromatography affords product I-6-9. [0945] Preparation of 6-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5- ((triisopropylsilyl)ethynyl)quinolin-2-amine (I-6-10)
[0946] I-6-10 is prepared using similar methods as used for I-6-2 and I-6-7. [0947] Preparation of 7-fluoro-1-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-8- ((triisopropylsilyl)ethynyl)isoquinolin-3-amine (I-6-11)
[0948] I-6-11-3 is prepared using similar methods as I-6-9-3. [0949] Step 3. The solution of p-methoxybenzyl alcohol (3.0 eq.) in anhydrous DMF is cooled down to 0 °C, and treated with NaH (60% mineral oil dispersion, 3.0 eq.). After stirring at 0 °C for 30 min, I-6-11-3 (1.0 eq.) in DMF is added dropwise. The mixture is then warmed to room temperature and stirred for 2 h. Saturated aqueous NaHCO3 is used to quench the reaction. Extraction workup followed by silica gel chromatography affords the
title compound I 6114. [0950] Step 5. The mixture of I-6-11-4 (1.0 eq.), Pd (PPh3)
2Cl2 (0.02 eq.) and CuI (0.02 eq.) in DMF and Et
3N is degassed with N
2, and triisopropylsilylacetylene (1.0 eq.) is then added. The mixture is stirred at 40 °C for 16 h. Extraction workup with EtOAc followed by silica gel column chromatography affords intermediate I-6-11-5. [0951] Step 6. I-6-11-5 (1.0 eq.) is dissolved in acetonitrile and then cerium (IV) ammonium nitrate (CAN) (1.0 eq.) dissolved in water is added. The reaction was stirred at rt for 30 min and then 20% MeOH/DCM and water are added. The layers are separated and the aqueous is extracted with 20% MeOH/DCM twice more. The combined organic phases are dried, filtered and evaporated and the crude was purified by silica gel chromatography to afford the title compound I-6-11-6. [0952] Step 7. A mixture of I-6-11-6 (1.0 eq.) and POCl
3 as solvent is heated at 90-95 °C for 2 h. The resulting solution was cooled to rt, and excess POCl3 was removed by high vacuum equipped with a double trap. The residue is purified by silica gel chromatography to afford the title product I-6-11-7. [0953] Step 8. The mixture of I-6-11-7 (1.0 eq.), bis(pinacolato)diborane (2.0 eq.), Pd(dppf)Cl2·CH2Cl2 (0.1 eq.), KOAc (3.0 eq.), and dppf (0.2 eq.) in dioxane is degassed with nitrogen, and then stirred at 100 °C for 33 h. Extraction workup with EtOAc, followed by silica gel chromatography affords product I-6-11. [0954] Preparation of 5-fluoro-1-(tetrahydro-2H-pyran-2-yl)-3-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)-4-((triisopropylsilyl)ethynyl)-1H-indazole (I-6-12)
[0955] Step 1. To the solution of I-6-12-1 (1.0 eq.) and PTSA (0.1 eq.) in dichloromethane is add dihydropyran (1.0 eq.), and the mixture is stirred for 18 h. After removing solvent, the
residue is purified with silica gel chromatography to afford the title compound I 6122. [0956] Step 2. The mixture of I-6-12-2 (1.0 eq.), Pd (PPh3)
2Cl2] (0.02 eq.) and CuI (0.02 eq.) in DMF and Et
3N is degassed with N
2, and triisopropylsilylacetylene (1.0 eq.) is then added. The mixture is stirred at 40 °C for 16 h. Extraction workup with EtOAc followed by silica gel column chromatography affords intermediate I-6-12-3. [0957] Step 3. The mixture of I-6-12-3 (1.0 eq.) and K
2CO
3 (4 eq.) in DMF is cooled down to 0 °C, iodine (2.0 eq.) is added. The reaction mixture is then stirred at 0 °C for 2 h and then at 25 °C for 16 h. The reaction is quenched with sodium thiosulfate aqueous solution. Extraction workup with EtOAc followed by silica gel chromatography afford the title compound I-6-12-4. [0958] Step 4. The mixture of I-6-12-4 (1.0 eq.), bis(pinacolato)diborane (2.0 eq.), Pd(dppf)Cl
2·CH
2Cl
2 (0.1 eq.), KOAc (3.0 eq.), and dppf (0.2 eq.) in dioxane is degassed with nitrogen, and then stirred at 100 °C for 33 h. Extraction workup with EtOAc, followed by silica gel chromatography affords product I-6-12. [0959] I-6-13—I-6-17 are prepared following similar methods for the preparation of I-6-12 or certain steps for the preparation of I-6-12 from the corresponding commercially available starting material as shown below:
[0960] Preparation of 6-chloro-3,5-dimethyl-1-(tetrahydro-2H-pyran-2-yl)-4-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole (I-6-19)
[0961] Step 1. The mixture of I-6-19-1 (1.0 eq.) and K2CO3 (4 eq.) in DMF is cooled down to 0 °C, iodine (2.0 eq.) is added. The reaction mixture is then stirred at 0 °C for 2 h and then at 25 °C for 16 h. The reaction is quenched with sodium thiosulfate aqueous solution. Extraction workup with EtOAc followed by silica gel chromatography afford the title compound I-6-19-2. [0962] Step 2. To the solution of I-6-19-2 (1.0 eq.) and PTSA (0.1 eq.) in dichloromethane is add dihydropyan (1.0 eq.), and the mixture is stirred for 18 h. After removing solvent, the residue is purified with silica gel chromatography to afford the title compound I-6-19-3. [0963] Step 3. A solution of dimethylzinc (2.0 eq., 2M in toluene) is added dropwise to a
mixture of I 6193 (1.0 eq.) and [1,1 bis(diphenylphosphino)ferrocene]dichloropalladium(II) (0.03 eq.) in 1,4-dioxane under argon. The mixture is heated under reflux for 2 h. After cooling, methanol is added, followed by 2 N HCl and dichloromethane. This mixture is stirred for 30 min. The organic layer is collected, washed with saturated aqueous sodium bicarbonate, brine, and dried over MgSO
4. After removing solvent, the residue is purified by chromatography to afford the title compound I-6-19-4. [0964] Step 4. The mixture of I-6-19-4 (1.0 eq.), bis(pinacolato)diborane (2.0 eq.), Pd(dppf)Cl2·CH2Cl2 (0.1 eq.), KOAc (3.0 eq.), and dppf (0.2 eq.) in dioxane is degassed with nitrogen, and then stirred at 100 °C for 33 h. Extraction workup with EtOAc, followed by silica gel chromatography affords product I-6-19. [0965] Preparation of 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydro-1H- pyrrolo[2,1-c][1,4]oxazine (II-1-3)
[0966] Step 1. To a dry flask is added II-1-3-1 (1.0 eq, previously make according to literature preparation) and dichloromethane (0.2 M), and the flask is wrapped in foil and purged with N
2 for 5 min. N-bromosuccimide (1.05 eq) is added in one portion and the reaction was stirred for 1 h at rt. The reaction is washed with H2O, sat. NaCl solution, dried with Na
2SO
4, filtered, concentrated under reduced pressure, and purified by a column chromatography (ethyl acetate/hexanes) to afford II-1-3-2. [0967] Step 2. To a solution of II-1-3-2 (1.0 eq.) in THF (0.2 M) at 0 °C under N
2 is added LiBH4 (3.0 eq.) and MeOH (1 eq.). The mixture is stirred at 0
oC until reaction is complete then quenched with H
2O. The resulting mixture is extracted with EtOAc three times, and the combined extracts are washed with brine and dried over anhydrous Na2SO4. The mixture is concentrated under reduced pressure and purified by flash chromatography (ethyl acetate in hexanes) to afford II-1-3-3. [0968] Step 3. To a solution of II-1-3-3 (1.0 eq.) in DMF (0.05 M) at ambient temperature under N
2 is added pyridine (3.0 eq.), catalytic DMAP (0.05 eq). To this mixture is added MsCl (0.95 eq) dropwise over 4 h. The mixture is then heated 60 °C until reaction is complete then quenched with H
2O. The resulting mixture is extracted with EtOAc three times, and the combined extracts are washed with brine and dried over anhydrous Na2SO4. Mixture is concentrated under reduced pressure and purified by flash chromatography (ethyl
acetate in hexanes) to afford II 134. [0969] Step 4. To a solution of II-1-3-4 (1.0 eq.) and Bis(pinacolato)diboron (1.0 eq.) and KOAc (3 eq.) in DMF (0.2 M) under N
2, is added Pd(dppf)Cl
2 (0.05 eq.). The mixture is degassed and stirred at 90 °C for 3 h, cooled to ambient temperature, and quenched with H
2O. The resulting mixture is extracted with EtOAc three times. The combined extracts are washed with brine and dried over anhydrous Na
2SO
4. Mixture was concentrated under reduced pressure and purified by flash chromatography (ethyl acetate in hexanes) to afford II-1-3. [0970] Preparation of 7-fluoro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydro- 1H-pyrrolo[2,1-c][1,4]oxazine (II-1-4)
[0971] Step 1. To a flask is added II-1-4-1 (1.0 eq), water (0.2 M), catalytic Tetrabutylammonium bromide (0.05) and NaOH (1.0 eq). The reaction is stirred for 5 h at rt. The reaction mixture is extracted with ethyl acetate three times and combined extracts dried with brine and Na
2SO
4, filtered, concentrated under reduced pressure. The crude product is purified by a flash chromatography (ethyl acetate/hexanes) to afford II-1-4-2. [0972] Step 2. To a solution of II-1-4-2 (1.0 eq.) in MeOH and water (0.2 M) is added Ag
2O (2.0 eq.) and. The mixture is stirred at 60-70 °C for 6 h. The resulting mixture is quenched with additional water and extracted with EtOAc three times, and the combined extracts are washed with brine and dried over anhydrous Na2SO4. The mixture is concentrated under reduced pressure and purified by flash chromatography (ethyl acetate in hexanes) to afford II-1-4-3. [0973] II-1-4-3 is converted to II-1-4 in a manner similar to Steps 1 through 4 for II-1-3. [0974] Preparation of 6'-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1'H,4'H-
spiro[cyclopropane 1,3 pyrrolo[2,1 c][1,4]oxazine] (II 15)
[0975] Step 1. To a mixture of II-1-5-1 (1.0 eq), II-1-5-1a (1.0 eq.) and PPh3 (1.0 eq.) in DCM (0.6 M) at 0 °C is added DIAD (1.05 eq.). The reaction mixture is slowly warmed to rt and stirred for 5 h. The reaction is quenched with water and extracted with ethyl acetate three times. Combined extracts are dried with brine and Na
2SO
4, filtered, concentrated under reduced pressure. The crude product is purified by a flash chromatography (ethyl acetate/hexanes) to afford II-1-5-2. [0976] Step 2. To a solution of II-1-5-2 (1.0 eq.) in dichloromethane (0.2 M) under N2 is added N-bromosuccimide (1.05 eq.) in one portion and the reaction is stirred at rt until complete. The reaction is washed with H2O, sat. NaCl solution, dried with Na2SO4, filtered, concentrated under reduced pressure, and purified by a column chromatography (ethyl acetate/hexanes) to afford II-1-5-3. [0977] Step 3. To a solution of II-1-5-3 (1.0 eq.) in THF (0.2 M) at 0 °C under N2 us added LiBH
4 (3.0 eq.) and MeOH (1 eq.). The mixture is stirred at 0 °C until the reaction is complete then quenched with H2O. The resulting mixture is extracted with EtOAc three times, and the combined extracts are washed with brine and dried over anhydrous Na
2SO
4. The mixture is concentrated under reduced pressure and purified by flash chromatography (ethyl acetate in hexanes) to afford II-1-5-4. [0978] Step 4. To a solution of II-1-5-4 (1.0 eq.) in DCM (0.2 M) at 0
oC is added CBr4 (1.1 eq.) and PPh
3 (1.1 eq.). The reaction mixture is slowly warmed to rt and stirred for 6 h. The reaction is quenched with water and extracted with ethyl acetate three times. Combined extracts are dried with brine and Na2SO4, filtered, concentrated under reduced pressure. The crude product is purified by a flash chromatography (ethyl acetate/hexanes) to afford II-1-5- 5. [0979] Step 5. To a solution of II-1-5-5 (1.0 eq.) in DCM (0.2 M) at 0 °C is added TFA (vol. equal to DCM). The mixture is stirred until complete removal of the THP group. Reaction
mixture is concentrated under reduced pressure to afford crude II 156. [0980] Step 6. Crude II-1-5-6 (1.0 eq.) is taken up in DMF (0.1 M) at ambient temperature under N
2 and K
2CO
3 (4.0 eq.) is added. The mixture is then heated at 60 °C until reaction is complete then cooled and quenched with H2O. The resulting mixture is extracted with EtOAc three times, and the combined extracts are washed with brine and dried over anhydrous Na
2SO
4. The mixture is concentrated under reduced pressure and purified by flash chromatography (ethyl acetate in hexanes to afford II-1-5-7. [0981] Step 7. To a solution of II-1-5-7 (1.0 eq.) and Bis(pinacolato)diboron (1.0 eq.) and KOAc (3 eq.) in DMF (0.2 M) under N2, is added Pd(dppf)Cl2 (0.05 eq.). The mixture is degassed and stirred at 90 °C for 3 h, cooled to ambient temperature, and quenched with H2O. The resulting mixture is extracted with EtOAc three times. The combined extracts are washed with brine and dried over anhydrous Na
2SO
4. Mixture was concentrated under reduced pressure and purified by flash chromatography (ethyl acetate in hexanes) to afford II-1-5. [0982] Preparation of 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-6,7-dihydro-4H- pyrazolo[5,1-c][1,4]oxazine (II-1-6)
[0983] II-1-6 is prepared according to step 4 for II-1-3 starting with II-1-6-1. [0984] Preparation of 1-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,4,5,7- tetrahydropyrano[3,4-c]pyrazole (II-1-7)
[0985] Step 1. To a mixture of II-1-7-1 in THF (0.6 M) at 0 °C is added NaH (1.05 eq.). The
reaction mixture is stirred for 20 min 0 C then MeI (1.1 eq.) is added. The mixture is slowly warmed to rt and stirred for 5 h. The reaction is quenched with saturated NH4Cl solution and extracted with ethyl acetate three times. Combined extracts are dried with brine and Na
2SO
4, filtered, concentrated under reduced pressure. The crude product is purified by a flash chromatography (ethyl acetate/hexanes) to afford II-1-7-2. [0986] Step 2. To a solution of II-1-7-2 (1.0 eq.) in THF (0.2 M) at 0 °C under N
2 is added LiBH4 (5.0 eq.) and MeOH (1 eq.). The mixture is stirred at 0 °C until reaction is complete then quenched with H
2O. The resulting mixture is extracted with EtOAc three times, and the combined extracts are washed with brine and dried over anhydrous Na2SO4. The mixture is concentrated under reduced pressure and purified by flash chromatography (ethyl acetate in hexanes) to afford II-1-7-3. [0987] Step 3. To a solution of II-1-7-3 (1.0 eq.) in DMF (0.05 M) at ambient temperature under N2 is added pyridine (3.0 eq.), catalytic DMAP (0.05 eq). To this mixture is added MsCl (0.95 eq). The mixture is then heated 70 °C until reaction is complete then quenched with H2O. The resulting mixture is extracted with EtOAc three times, and the combined extracts are washed with brine and dried over anhydrous Na2SO4. The mixture is concentrated under reduced pressure and purified by flash chromatography (ethyl acetate in hexanes) to afford II-1-7-4. [0988] Step 4. To a solution of II-1-7-4 (1.0 eq.) in dichloromethane (0.2 M) under N
2 is added N-bromosuccimide (1.05 eq.) in one portion and the reaction is stirred at ambient temperature until complete. The reaction is washed with H
2O, sat. NaCl solution, dried with Na2SO4, filtered, concentrated under reduced pressure, and purified by a column chromatography (ethyl acetate/hexanes) to afford II-1-7-5. [0989] II-1-7-5 is converted to II-1-7 according to step 4 for II-1-3. [0990] Preparation of 7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydro-1H-
pyrrolo[2,1 c][1,4]oxazine ( II 18)
[0991] Steps 1 and 2 are performed in a similar manner to steps 1 and 2 for II-1-4 starting with II-1-8-1 to afford II-1-8-3. [0992] Steps 3 through 5 were performed in a similar manner to steps 2 through 4 for II-1-3 starting with II-1-8-3 to afford II-1-8. [0993] Preparation of 7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-4,5-dihydro-1H,3H- pyrrolo[2,1-c][1,4]oxazepine (II-1-9)
[0994] II-1-9 is prepared in a manner similar to II-1-5. [0995] Preparation of 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4- dihydropyrrolo[1,2-a]pyrazin-1(2H)-one (II-1-5)
[0996] Step 1. To a mixture of II-1-10-1 (1.0 eq.) at 0 °C in DMF (0.2 M) is added NaH (1.05 eq.). The reaction mixture is stirred at 0 °C for 20 min then II-1-10-1a (1.0 eq) is added. The reaction mixture is slowly warmed to ambient temperature and stirred for 5 h. The reaction is quenched with water and extracted with ethyl acetate three times. Combined extracts are dried with brine and Na2SO4, filtered, concentrated under reduced pressure. The crude product is purified by a flash chromatography (ethyl acetate/hexanes) to afford II-1-10- 2. [0997] Step 2. To a solution of II-1-10-2 (1.0 eq) in THF:MeOH:H
2O (3:2:1, 0.1 M) is added LiOH (3.0 eq.). The reaction mixture is stirred at ambient temperature until complete. The reaction is acidified to pH 4 with 2M HCl solution and extracted with DCM three times. Combined extracts are dried with Na2SO4, filtered, concentrated under reduced pressure to afford crude II-1-10-3. [0998] Step 3. To a solution of II-1-10-3 (1.0 eq.) in DCM (0.2 M) is added HCl (10 eq., 4 M in dioxane). The mixture is stirred until reaction was complete then concentrated under reduced pressure to afford crude II-1-10-4. [0999] Step 4. To a solution of II-1-10-4 (1.0 eq.) in DCM (0.05 M) is added DIAD (8 eq.) and FDPP (1.5 eq.). The reaction mixture is stirred for 6 h. The reaction is quenched with 1 M Na2CO3 solution (50 eq.) and extracted with ethyl acetate three times. Combined extracts are washed with water, dried with brine and Na
2SO
4, filtered, concentrated under reduced pressure. The crude product is purified by a flash chromatography (ethyl acetate/hexanes) to afford II-1-10-5. [01000] II-1-10-5 is converted to II-1-10 according to step 4 for II-1-3. [01001] Preparation of 2-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4- dihydropyrrolo[1,2-a]pyrazin-1(2H)-one (II-1-11)
[01002] Step 1. To a mixture of II-1-10-5 (1.0 eq.) at 0 °C in DMF (0.2 M) is added NaH (1.05 eq.). The reaction mixture is stirred at 0 °C for 20 min then MeI (1.2 eq.) is added. The reaction mixture was slowly warmed to rt and stirred for 5 h. The reaction is quenched with water and extracted with ethyl acetate three times. Combined extracts are dried with brine and Na2SO4, filtered, concentrated under reduced pressure. The crude product is purified by a flash chromatography (ethyl acetate/hexanes) to afford II-1-11-1. [01003] II-1-11-1 is converted to II-1-11 according to step 4 for II-1-3. [01004] Preparation of 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydro- 1H-pyrrolo[2,1-c][1,4]oxazin-1-one (II-1-12)
[01005] II-1-12 is synthesized according to step 4 for II-1-3 starting with II-1-3-2. [01006] Preparation of 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H- pyrrolo[2,1-c][1,4]oxazin-3(4H)-one (II-1-13)
[01007] Step 1. To a solution of II-1-13-1 (1.0 eq.) in THF (0.2 M) at 0 °C under N
2 is added LiBH4 (3.0 eq.) and MeOH (1 eq.). The mixture is stirred at 0 °C until the reaction is
complete then quenched with H
2O. The resulting mixture is extracted with EtOAc three times, and the combined extracts are washed with brine and dried over anhydrous Na2SO4. The mixture is concentrated under reduced pressure and purified by flash chromatography (ethyl acetate in hexanes) to afford II-1-13-2. [01008] Step 2. To a solution of II-1-13-2 (1.0 eq.) at 0 °C in DCM (0.2 M) is added DIPEA (3.0 eq.) and II-1-13-2a (1.2 eq.). The reaction mixture is stirred at 0
oC until the reaction is complete. The reaction is quenched with water and extracted with ethyl acetate three times. Combined extracts are dried with brine and Na
2SO
4, filtered, concentrated under reduced pressure. The crude product is purified by a flash chromatography (ethyl acetate/hexanes) to afford II-1-13-3. [01009] Step 3. To a solution of II-1-13-3 (1.0 eq.) in DCM (0.2 M) is added HCl (10 eq., 4 M in dioxane). The mixture is stirred until the reaction is complete then concentrated under reduced pressure to afford crude II-1-13-4. [01010] Step 4. II-1-13-4 (1.0 eq.) is resuspended in DMF (0.05 M) and K
2CO
3 (5 eq.) is added. The reaction mixture is stirred for 6 h. The reaction is quenched with water and extracted with ethyl acetate three times. Combined extracts are washed with water, dried with brine and Na2SO4, filtered, concentrated under reduced pressure. The crude product is purified by a flash chromatography (ethyl acetate/hexanes) to afford II-1-13-5. [01011] II-1-13-5 is converted to II-1-13 according to step 4 for II-1-3. [01012] Preparation of 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2- dihydropyrrolo[1,2-a]pyrazin-3(4H)-one (II-1-14)
[01013] Step 1. To a solution of II-1-13-2 (1.0 eq.) in DCM (0.2 M) at 0 °C is added CBr
4 (1.1 eq.) and PPh
3 (1.1 eq.). The reaction mixture is slowly warmed to ambient temperature and stirred for 6 h. The reaction is quenched with water and extracted with ethyl acetate three times. Combined extracts are dried with brine and Na
2SO
4, filtered,
concentrated under reduced pressure. The crude product is purified by a flash chromatography (ethyl acetate/hexanes) to afford II-1-14-1. [01014] Step 2. To a solution of II-1-14-1 (1.0 eq.) in DMF (0.2 M) under N
2 is added NaN3 (3.0 eq.). The mixture is stirred at rt until the reaction is complete then quenched with H
2O. The resulting mixture is extracted with EtOAc three times, and the combined extracts are washed with brine and dried over anhydrous Na
2SO
4. The mixture is concentrated under reduced pressure and purified by flash chromatography (ethyl acetate in hexanes) to afford II-1-14-2. [01015] Step 3. To a solution of II-1-14-2 (1.0 eq.) in THF (0.2 M) under N2 is added PPh
3 (3.0 eq.). The mixture is stirred at rt 4 h then H
2O (10 eq.) is added. The mixture is stirred overnight then quenched with water. The resulting mixture is extracted with EtOAc three times, and the combined extracts are washed with brine and dried over anhydrous Na2SO4. The mixture is concentrated under reduced pressure and purified by flash chromatography (methanol in dichloromethane) to afford II-1-14-3. [01016] Steps 4 through 6 are performed in a manner similar to steps 2 through 4 for II-1-13 starting with II-1-14-3 to afford II-1-14-6. [01017] II-1-14-6 is converted to II-1-13 according to step 4 for II-1-3. [01018] Preparation of 2-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2- dihydropyrrolo[1,2-a]pyrazin-3(4H)-one (II-1-15)
[01019] II-1-15 is prepared according to II-1-11 starting with II-1-14-6. [01020] Preparation of 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6,7,8-
tetrahydroindolizine (II 116)
[01021] Step 1. To a solution of II-1-13-1 (1.0 eq.) in THF:MeOH:H
2O (3:2:1, 0.1 M) is added LiOH (3.0 eq.). The reaction mixture is stirred at ambient temperature until complete. The reaction is acidified to pH 4 with 2 M HCl solution and extracted with DCM three times. Combined extracts are dried with Na2SO4, filtered, concentrated under reduced pressure to afford crude II-1-16-1. [01022] Step 2. To a solution of II-1-16-1 (1.0 eq) and N,O-Dimethylhydroxylamine (1.1 eq.) in DCM (0.05 M) is added DIPEA (8 eq.) and FDPP (1.5 eq.). The reaction mixture is stirred for 6 h. The reaction is quenched with 1 M Na
2CO
3 solution (50 eq) and extracted with ethyl acetate three times. Combined extracts are washed with water, dried with brine and Na
2SO
4, filtered, concentrated under reduced pressure. The crude product is purified by a flash chromatography (ethyl acetate/hexanes) to afford II-1-16-2. [01023] Step 3. To a solution of II-1-16-2 (1.0 eq.) in THF (0.2 M) at -78 °C under N
2 is added II-1-16-2a (1.1 eq.). The mixture is stirred at -78 °C until the reaction is complete then quenched with saturated NH
4Cl solution. The resulting mixture is extracted with EtOAc three times, and the combined extracts are washed with brine and dried over anhydrous Na2SO4. The mixture is concentrated under reduced pressure and purified by flash chromatography (ethyl acetate in hexanes to afford II-1-16-3. [01024] Step 4. To a solution of II-1-16-3 (1.0 eq.) in DCM (0.2 M) is added HCl (10 eq., 4 M in dioxane). The mixture is stirred until the reaction is complete then concentrated under reduced pressure. The crude material is resuspended in EtOAc and washed with
saturated NaHCO
3 solution. The organic layer is separated and washed with brine and dried over anhydrous Na2SO4. The mixture is concentrated under reduced pressure and purified by flash chromatography (ethyl acetate in hexanes) to afford II-1-16-4. [01025] Step 5. To a solution of II-1-16-4 (1.0 eq.) and PPh3 (1.05 eq.) in DCM (0.2 M) at 0 °C is added DIAD (1.05 eq.). The reaction mixture is slowly warmed to ambient temperature and stirred for 5 h. The reaction is quenched with water and extracted with ethyl acetate three times. Combined extracts are dried with brine and Na2SO4, filtered, concentrated under reduced pressure. The crude product is purified by a flash chromatography (ethyl acetate/hexanes) to afford II-1-16-5. [01026] Step 6. To a solution of II-1-16-5 (1.0 eq.) in THF (0.2 M) at 0 °C under N
2 is added LiBH4 (3.0 eq.) and MeOH (1 eq.). The mixture is stirred at 0 °C until the reaction is complete then quenched with H
2O. The resulting mixture is extracted with EtOAc three times, and the combined extracts are washed with brine and dried over anhydrous Na2SO4. The mixture is concentrated under reduced pressure and purified by flash chromatography (ethyl acetate in hexanes) to afford II-1-16-6. [01027] Step 7. To a solution of II-1-16-6 (1.0 eq.) at 0 °C in DCM (0.2 M) is added DIPEA (3.0 eq.) and TosCl (1.2 eq.). The reaction mixture is stirred at 0
oC until the reaction is complete. The reaction is quenched with water and extracted with ethyl acetate three times. Combined extracts are dried with brine and Na
2SO
4, filtered, concentrated under reduced pressure. The crude product is purified by a flash chromatography (ethyl acetate/hexanes) to afford II-1-16-7. [01028] Step 8. To a solution of II-1-16-7 (1.0 eq.) in THF (0.2 M) at 0 °C under N2 is added LAH (3.0 eq.). The mixture is stirred at 0 °C until the reaction is complete then quenched with EtOAc followed by 0.5 M HCl. The resulting mixture is extracted with EtOAc three times, and the combined extracts are washed with brine and dried over anhydrous Na2SO4. The mixture is concentrated under reduced pressure and purified by flash chromatography (ethyl acetate in hexanes) to afford II-1-16-8. [01029] II-1-16-8 is converted to II-1-16 according to step 4 for II-1-3. [01030] Preparation of (S)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6,7,8-
tetrahydroindolizin 8 ol (II 117)
[01031] Step 1. II-1-16-6 is subjected to chiral SFC separation to afford II-1-17-1 and II-1-17-2. [01032] II-1-17-1 is converted to II-1-17 according to step 4 for II-1-3. [01033] Preparation of 2-(4,7-dihydro-5H-furo[2,3-c]pyran-3-yl)-4,4,5,5-tetramethyl- 1,3,2-dioxaborolane (II-1-18)
[01034] Step 1. To a solution of II-1-18-1 (1.0 eq.) in DCM (0.2 M) under an atmosphere of Ar at -78 °C is added TiCl4 (1.5 eq.) and Bu3N (2.0 eq. in DCM). The reaction mixture was stirred at -78 °C for 15 min then II-1-18-1a (1.5 eq) is added. The reaction mixture is stirred at -78 °C for 1 h then quenched with water. The mixture is extracted with ethyl acetate three times. Combined extracts are dried with brine and Na
2SO
4, then concentrated under reduced pressure. The crude product is purified by a flash chromatography (ethyl acetate/hexanes) to afford II-1-18-2. [01035] Step 2. To a solution of II-1-18-2 (1.0 eq.) in THF (0.2 M) at 0 °C under N2 is added LAH (4.0 eq.). The mixture is stirred at 0 °C until the reaction is complete then
quenched with EtOAc followed by 0.5 M HCl. The resulting mixture is extracted with EtOAc three times, and the combined extracts are washed with brine and dried over anhydrous Na
2SO
4. The mixture is concentrated under reduced pressure and purified by flash chromatography (ethyl acetate in hexanes) to afford II-1-18-3. [01036] Step 3. To a solution of oxalyl chloride (10 eq.) and 3 Å MS in DCM (0.2 M) at -78 °C under N
2 is added dropwise a solution of DMSO (20 eq.) in DCM. After 15 min a solution of II-1-18-3 in DCM is slowly added dropwise. After 30 min, Et3N (30 eq.) is added dropwise. The reaction is stirred 30 min at -78 °C then slowly allowed to warm to rt and stirred for 1 h. The reaction is quenched with water and extracted with ethyl acetate three times. Combined extracts are washed with water, dried with brine and Na
2SO
4, filtered, concentrated under reduced pressure. The crude product is purified by a flash chromatography (ethyl acetate/hexanes) to afford II-1-18-4. [01037] Step 4. To a solution of II-1-18-4 (1.0 eq.) in Toluene (0.2 M) a was added TosOH (0.05 eq.). The mixture was heated to reflux and water removed through the use of a Dean-Stark trap until reaction complete. The reaction mixture was cooled and quenched with saturated NaHCO3 solution then extracted with EtOAc three times, and the combined extracts were washed with brine and dried over anhydrous Na2SO4. Mixture was concentrated under reduced pressure and purified by flash chromatography (ethyl acetate in hexanes to afford II-1-18-5. [01038] Step 5. To a solution of II-1-18-5 (1.0 eq) in dichloromethane (0.2 M) under N
2 is added N-bromosuccimide (2.1 eq.) in one portion and the reaction is stirred at ambient temperature until complete. The reaction is washed with H2O, sat. NaCl solution, dried with Na
2SO
4, filtered, concentrated under reduced pressure, and purified by a column chromatography (ethyl acetate/hexanes) to afford II-1-18-6. [01039] Step 6. To a solution of II-1-18-6 (1 eq) in THF at -78 °C under N
2 is added dropwise a solution of n-BuLi (1.05 eq.) in hexanes. After 1 h at -78 °C the reaction is quenched with saturated NH
4Cl solution at -78 °C. The mixture is warmed to rt and extracted with ethyl acetate three times. Combined extracts are dried with brine and Na2SO4, filtered, concentrated under reduced pressure. The crude product is purified by a flash chromatography (ethyl acetate/hexanes) to afford II-1-18-7. [01040] II-1-18-7 is converted to II-1-18 according to step 4 for II-1-3. [01041] Preparation of 2-(6,7-dihydro-4H-furo[3,4-c]pyran-1-yl)-4,4,5,5-tetramethyl-
1,3,2 dioxaborolane (II 119)
[01042] Step 1. To a solution of II-1-19-1 (1.0 eq.) in DCM (0.2 M) under an atmosphere of Ar at -78
oC is added LiHMDS (1.05 eq.). The reaction mixture is stirred at - 78 °C for 30 min then II-1-19-1a (1.5 eq.) is added. The reaction mixture is warmed to 0 °C and stirred until reaction is complete. The mixture is quenched with NH4Cl solution then extracted with ethyl acetate three times. Combined extracts are dried with brine and Na
2SO
4, then concentrated under reduced pressure. The crude product is purified by a flash chromatography (ethyl acetate/hexanes) to afford II-1-19-2. [01043] Step 2. To a solution of II-1-19-2 (1.0 eq.) in THF (0.2 M) at 0 °C under N2 is added TBAF (4.0 eq.). The mixture is stirred at 0 °C until the reaction is complete then quenched with water. The resulting mixture is extracted with EtOAc three times, and the combined extracts are washed with brine and dried over anhydrous Na
2SO
4. The mixture is concentrated under reduced pressure and purified by flash chromatography (ethyl acetate in hexanes to afford II-1-19-3. [01044] Step 3. To a solution of II-1-19-3 (1.0 eq.) in DMF (0.2 M) at 0 °C is added NaH (1.05 eq). The reaction is stirred at 0 °C for 30 min then heated to 60 °C until reaction is complete. The reaction is cooled and quenched with water and extracted with ethyl acetate three times. Combined extracts are washed with water, dried with brine and Na2SO4, filtered, concentrated under reduced pressure. The crude product is purified by a flash chromatography (ethyl acetate/hexanes) to afford II-1-19-4. [01045] Steps 4 through 6 are performed in a manner similar to steps 2 through 4 for II-1-18 to afford II-1-19-7. [01046] Step 7. To a solution of II-1-19-7 (1.0 eq.) in dichloromethane (0.2 M) under N2 is added N-bromosuccimide (1.0 eq.) in one portion and the reaction is stirred at ambient temperature until complete. The reaction is washed with H2O, sat. NaCl solution, dried with Na
2SO
4, filtered, concentrated under reduced pressure, and purified by a column
chromatography (ethyl acetate/hexanes) to afford II 1198 and II 1199. [01047] II-1-19-9 is converted to II-1-19 according to step 4 for II-1-3. [01048] Preparation of 2-(6,7-dihydro-4H-thieno[3,4-c]pyran-1-yl)-4,4,5,5- tetramethyl-1,3,2-dioxaborolane (II-1-20)
[01049] Step 1. To a solution of II-1-19-6 (1.0 eq.) in Toluene (0.1 M) is added Lawesson’s reagent (3 eq.). The reaction is heated to reflux with an open condenser until reaction complete. The reaction mixture is cooled to rt and quenched with a large quantity of saturated NaHCO3 solution. The mixture is stirred vigorously for 1 h then extracted with ethyl acetate three times. Combined extracts are dried with brine and Na
2SO
4, then concentrated under reduced pressure. The crude product is purified by a flash chromatography (ethyl acetate/hexanes) to afford II-1-20-1. [01050] Step 2. To a solution of II-1-20-1 (1.0 eq.) in dichloromethane (0.2 M) under N2 is added N-bromosuccimide (1.0 eq.) in one portion and the reaction is stirred at rt until complete. The reaction is washed with H
2O, sat. NaCl solution, dried with Na
2SO
4, filtered, concentrated under reduced pressure, and purified by a column chromatography (ethyl acetate/hexanes) to afford II-1-20-2 and II-1-20-3. [01051] II-1-20-3 is converted to II-1-20 according to step 4 for II-1-3. [01052] Preparation of 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydro- 8H-imidazo[5,1-c][1,4]oxazine (II-1-21)
[01053] II-1-21 is synthesized according to the procedure of step 4 for II-1-3 starting with II-1-21-1. [01054] Preparation of 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydro-
8H imidazo[2,1 c][1,4]oxazine (II 122)
[01055] II-1-22 is synthesized according to the procedure of step 4 for II-1-3 starting with II-1-22-1. [01056] Preparation of 1-((1R,5S)-8-oxabicyclo[3.2.1]octan-3-yl)-4-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (II-1-23)
[01057] Step 1. To a solution of II-1-23-1 (1.0 eq.) at 0 °C in DCM (0.2 M) is added DIPEA (3.0 eq.) and TosCl (1.2 eq.). The reaction mixture is stirred at 0 °C until the reaction is complete. The reaction is quenched with water and extracted with ethyl acetate three times. Combined extracts are dried with brine and Na
2SO
4, filtered, concentrated under reduced pressure. The crude product is purified by a flash chromatography (ethyl acetate/hexanes) to afford II-1-23-2. [01058] Step 2. To a solution of 4-bromopyrazole (1.0 eq.) at 0 °C in DMF (0.2 M) is added NaH (1.05 eq.). The reaction mixture is stirred at 0 °C for 30 min then II-1-23-2 (1.0 eq) is added. The reaction mixture is heated to 110 °C and stirred for 14 h. The reaction is cooled, quenched with water and extracted with ethyl acetate three times. Combined extracts are dried with brine and Na
2SO
4, filtered, concentrated under reduced pressure. The crude product is purified by a flash chromatography (ethyl acetate/hexanes) to afford II-1-23-3. [01059] II-1-23-3 is converted to II-1-23 according to step 4 for II-1-3. [01060] Preparation of 1-(tetrahydro-2H-pyran-4-yl)-4-(4,4,5,5-tetramethyl-1,3,2-
dioxaborolan 2 yl) 1H pyrazole (II 124)
[01061] II-1-24 is synthesized according to step 4 for II-1-3 starting with II-1-24-1. [01062] General Method A: Preparation of 5-ethynyl-6-fluoro-4-[8-fluoro-2- {[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}-4-(8-oxa-3- azabicyclo[3.2.1]octan-3-yl)pyrido[4,3-d]pyrimidin-7-yl]naphthalen-2-ol (Ex.1)
[01063] Step 1. To a mixture of I-1-1 (457 mg, 1.81 mmol, 1 eq.) and DIPEA (1.57 g, 12.1 mmol, 6.7 eq.) in DCM (5 mL) was added I-2-1 (271 mg, 1.81 mmol, 1 eq., HCl) and
DIPEA (234 mg, 1.81 mmol, 1 eq.) dropwise at 40 C. The resulting mixture was stirred at 40 °C for 1 h. On completion, the reaction mixture was partitioned between DCM (30 mL × 3) and water (50 mL), and the combined organic layers were dried over Na
2SO
4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (SiO
2, PE/EA =1/0 to 1/1) to provide 1-3 (430 mg, 1.31 mmol, 72.17% yield) as a yellow solid. LCMS: m/z 328.5 (M+1)
+. [01064] Step 2. To a mixture of I-3-1 (430 mg, 1.31 mmol, 1 eq.) and I-4-1 (416 mg, 2.61 mmol, 2 eq.) in dioxane (17 mL) was added DIPEA (506 mg, 3.92 mmol, 3 eq.). The resulting mixture was stirred at 80 °C for 40 h. On completion, the mixture was concentrated and the residue was purified by column chromatography (SiO
2, PE/THF=1/0 to 1/2) to provide I-5-1 (490 mg, 1.08 mmol, 83.00% yield) as a brown solid. LCMS: m/z 451.9 (M+1)
+. [01065] Step 3. To a mixture of I-5-1 (450 mg, 0.996 mmol, 1 eq.) and I-6-1 (1.02 g, 1.99 mmol, 2 eq.) in THF (20 mL) was added tripotassium phosphate (1.5 M, 1.49 mL, 3 eq) and [2-(2-aminophenyl)phenyl]palladium(1+);bis(1-adamantyl)-butyl-phosphane; methanesulfonate (72.5 mg, 0.0996 mmol, 0.1 eq.). The resulting mixture was stirred at 60 °C for 2 h. On completion, the mixture was filtered and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, PE/THF=1:0 to 1:1) to give I-7- 1 (725 mg, 0.904 mmol, 90.78% yield) as a brown solid. LCMS: m/z 802.5 (M+1)
+. [01066] Step 4: The mixture of I-7-1 (300 mg, 0.374 mmol, 1 eq.) and CsF (284 mg, 1.87 mmol, 5 eq.) in DMSO (30 mL) was stirred at 23 °C for 0.5 h. On completion, the reaction mixture was partitioned between ethyl acetate (25 mL) and brine (120 mL) and extracted with ethyl acetate (25 mL × 3). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was dissolved in DCM (4.4 mL) and HCl/dioxane (4 M, 1.70 mL, 10 eq.) was added. The resulting mixture was stirred at 23 °C for 1 h. On completion, the mixture was filtered and washed with DCM (5 mL) to provide Ex.1 HCl salt (278.65 mg, 0.463 mmol, 68% yield) as an orange solid. LC-MS: m/z 602.2 (M+1)
+;
1H NMR (400 MHz, DMSO-d6) δ = 9.17 - 9.11 (m, 1H), 7.99 (dd, J = 6.0, 9.2 Hz, 1H), 7.51 - 7.41 (m, 2H), 7.26 (d, J = 2.4 Hz,1H), 5.67 - 5.49 (m, 1H), 4.67 - 4.61 (m, 2H), 4.50 (br s, 3H), 4.45 - 4.38 (m, 1H), 4.00 (d, J = 3.2 Hz, 1H), 3.87 - 3.71 (m, 5H),3.56 (s, 2H), 3.33 - 3.22 (m, 1H), 2.54 (s, 2H), 2.37 - 2.27 (m, 1H), 2.23 - 2.10 (m, 2H), 2.09 - 1.99 (m, 1H), 1.89 - 1.77 (m, 4H). [01067] Ex.1—Ex.29 are prepared using General Method A as shown below in the table with the corresponding starting materials I-1 and I-2, and reagents I-4 and I-6:
[01068] General Method B Preparation of 5-ethynyl-6-fluoro-4-[8-fluoro-4-(3-fluorophenyl)-2-{[(2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}pyrido[4,3-d]pyrimidin-7-yl]naphthalen- 2-ol (Ex.30)
[01069] Step 1. To a solution of I-1-1 (1.0 eq.) and II-1-1 (1.0 eq.) and Cs2CO3 (3 eq.) in DME/H
2O (5:1, 0.2 M) under N
2, is added Pd(dppf)Cl
2 (0.05 eq.). The mixture is degassed and charged with nitrogen for three times, and stirred at 85 °C overnight, cooled to ambient temperature, and quenched with H
2O. The resulting mixture is extracted with EtOAc for
three times. The combined extracts are washed with brine and dried over anhydrous Na
2SO
4. After filtration and condensation, the resulting residue is purified by silica gel chromatography to afford the desired product II-2-1. [01070] II-2-1 is converted into Ex.30 following similar reaction conditions of Step 2—Step 4 in General Method A. [01071] Ex.30—Ex.65 are prepared following the General Method B using the corresponding starting materials I-1 and II-1 and reagents I-4 and I-6 as shown in the table below:
[01072] General Method C
[01073] Ex.65 is prepared with General Method A using III-1-1 to replace amine I- 2-1. To a solution of Ex.65 (1 eq.) in DCM (0.2 M) is added m-chloroperbenzoic acid (2.2 eq.) at 0 °C. The reaction mixture is stirred at ambient temperature for 16 h, quenched with addition of saturated aqueous Na2S2O3, and extracted with DCM. The combined extracts are washed with saturated aqueous NaHCO
3, water and brine, and dried over sodium sulfate.
After filtration and purification, the residue is purified by flash column chromatography to provide Ex.66. [01074] Ex.65—Ex.70 are prepared with General Method C using the corresponding thiol III-1 to replace the amine I-2 as shown below in the Table:
[01075] General Method D
[01076] IV-2-1 is prepared following Step 2 and 3 in General Method A. [01077] To a solution of IV-2-1 (1.0 eq.) in MeOH (0.2 M) is added LiOH (3 eq.) in H
2O (1 M). The mixture is stirred at 60 °C until the hydrolysis reaction is completed. The solution is cooled to ambient temperature, concentrated to remove methanol, acidified by aqueous HCl (1 N) until pH ~4-5, and then extracted with CH2Cl2. The combined extracts are dried over Na2SO4, concentrated, and dried under vacuum to provide IV-3-1. [01078] To a solution of IV-3-1 (1 eq.) in DMF (0.2 M) are added DIPEA (3 eq.) and pentafluorophenyl diphenylphosphinate (FDPP) (1.1 eq.). The solution is stirred at ambient temperature until the amide formation is completed. The mixture is diluted with water and extracted with EtOAc for three times. The combined extracts are washed with water for
three times, aqueous HCl (1 N), saturated aqueous Na
2CO
3 and brine, dried over Na
2SO
4, and concentrated. The resulting residue is purified by a silica gel column to afford IV-4-1. [01079] IV-4-1 is deprotection following Step 4 in General Method A to provide Ex. 71. [01080] Ex.72 is prepared following General method D using the corresponding amine for amide coupling. [01081] Preparation of 5-ethynyl-6-fluoro-4-[8-fluoro-2-(4-methylpiperazin-1-yl)-4- (8-oxa-3-azabicyclo[3.2.1]octan-3-yl)pyrido[4,3-d]pyrimidin-7-yl]naphthalen-2-ol (Ex.2)
[01082] Ex.2 was prepared following General Method A.
1H NMR (400 MHz, CDCl3) δ = 8.78 (s, 1H), 8.41 (s, 1H), 7.53 (dd, J = 5.6, 9.2 Hz, 1H), 7.19 - 7.10 (m, 2H), 7.00 (d, J = 2.4 Hz, 1H), 4.49 (d, J = 3.2 Hz, 2H), 4.36 (d, J = 12.4 Hz, 1H), 4.17 (d, J = 12.8 Hz, 1H), 4.07 (s, 4H), 3.73 - 3.69 (m, 1H), 3.60 (d, J = 11.2 Hz, 1H), 2.83 (s, 1H), 2.74 (t, J = 4.4 Hz, 4H), 2.49 (s, 3H), 2.06 - 1.87 (m, 3H), 1.84 - 1.71 (m, 1H). LCMS: m/z 543.0 (M+1). [01083] Preparation of 5-ethynyl-6-fluoro-4-{8-fluoro-2-[(3aS,6aS)-1- methylhexahydropyrrolo[3,4-b]pyrrol-5(1H)-yl]-4-(8-oxa-3-azabicyclo[3.2.1]octan-3- yl)pyrido[4,3-d]pyrimidin-7-yl}naphthalen-2-ol (Ex.4)
[01084] Ex.4 was prepared following General Method A.
1H NMR (400 MHz, CDCl3) δ = 9.66 (s, 1H), 8.75 (s, 1H), 7.57 - 7.46 (m, 1H), 7.19 - 7.05 (m, 2H), 6.95 (d, J = 2.0 Hz, 1H), 4.49 (s, 2H), 4.44 - 4.16 (m, 2H), 4.09 - 3.88 (m, 2H), 3.75 - 3.51 (m, 4H), 3.18
(t, J 8.4 Hz, 1H), 2.91 (s, 2H), 2.82 (d, J 7.2 Hz, 1H), 2.45 2.31 (m, 4H), 2.18 2.07 (m, 1H), 2.05 - 1.91 (m, 3H), 1.87 - 1.73 (m, 2H). LCMS: m/z 569.1 (M+1). [01085] Preparation of 5-ethynyl-6-fluoro-4-{8-fluoro-2-[(3aR,6aS)-5- methylhexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl]-4-(8-oxa-3-azabicyclo[3.2.1]octan-3- yl)pyrido[4,3-d]pyrimidin-7-yl}naphthalen-2-ol (Ex.5)
[01086] Ex.5 was prepared following General Method A.
1H NMR (400 MHz, CDCl
3) δ = 8.75 (s, 1H), 7.54 (dd, J = 5.6, 9.2 Hz, 1H), 7.15 (t, J = 8.8 Hz, 1H), 7.10 (d, J =
2.4 Hz, 1H), 6.95 (d, J 2.4 Hz, 1H), 4.49 (s, 2H), 4.40 (d, J 12.0 Hz, 1H), 4.20 (d, J 11.2 Hz, 1H), 3.93 (dd, J = 8.0, 12.0 Hz, 2H), 3.78 - 3.54 (m, 4H), 2.99 (s, 2H), 2.83 (s, 1H), 2.71 (d, J = 8.4 Hz, 2H), 2.54 (d, J = 9.6 Hz, 2H), 2.35 (s, 3H), 2.04 - 1.93 (m, 3H), 1.82 (s, 1H). LCMS: m/z 569.1 (M+1). [01087] Preparation of 5-ethynyl-6-fluoro-4-[8-fluoro-4-(3-fluorophenyl)-2- {[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}pyrido[4,3-d]pyrimidin-7- yl]naphthalen-2-ol (30)
[01088] Step 1. To a mixture of 7-chloro-8-fluoro-2-methylsulfanyl-pyrido[4,3- d]pyrimidin-4-ol (600 mg, 2.44 mmol, 1 eq) in POCl
3 (8.25 g, 53.81 mmol, 22.03 eq) was added DIEA (631 mg, 4.88 mmol, 2 eq) dropwise under N2. The mixture was stirred at 90 °C for 5 hours under N2. On completion, the mixture was concentrated in vacuum. To the mixture was added EtOAc (30 mL). The residue was poured into ice (30 g) slowly. The
mixture was extracted with ethyl acetate (50 mL 2). The combined organic phase was dried over anhydrous Na2SO4, filtered and concentrated in vacuum to give 4,7-dichloro-8-fluoro-2- methylsulfanyl-pyrido[4,3-d]pyrimidine (630 mg, 97% yield) as a yellow solid. LCMS: m/z 263.6 (M+1) [01089] Step 2. A mixture of 2-(3-fluorophenyl)-4,4,5,5-tetramethyl-1,3,2- dioxaborolane (324 mg, 1.46 mmol, 1.1 eq), 4,7-dichloro-8-fluoro-2-methylsulfanyl- pyrido[4,3-d]pyrimidine (350 mg, 1.33 mmol, 1 eq), Pd(dppf)Cl2.CH2Cl2 (108 mg, 0.133 mmol, 0.1 eq) and Na
2CO
3 (421 mg, 3.98 mmol, 3 eq) in dioxane (10 mL) and H
2O (1.5 mL) was stirred at 90 °C for 1.5 hours under N2. On completion, the mixture was concentrated in vacuum. The residue was purified by prep-TLC to give 7-chloro-8-fluoro-4-(3- fluorophenyl)-2-methylsulfanyl-pyrido[4,3-d]pyrimidine (250 mg, 58% yield) as a yellow solid. LCMS: m/z 323.6 (M+1). [01090] Step 3. A mixture of 7-chloro-8-fluoro-4-(3-fluorophenyl)-2-methylsulfanyl- pyrido[4,3-d]pyrimidine (200 mg, 0.618 mmol, 1 eq), 2-[2-fluoro-6-(methoxymethoxy)-8- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-naphthyl]ethynyl-triisopropyl-silane (500 mg, 0.976 mmol, 1.58 eq), Cs2CO3 (604 mg, 1.85 mmol, 3 eq) and ditert- butyl(cyclopentyl)phosphane;dichloropalladium;iron (40.3 mg, 0.0618 mmol, 0.1 eq) in dioxane (10 mL) and H2O (1 mL) was stirred at 90 °C for 2 hours under N2. On completion, the mixture was concentrated in vacuum. The residue was purified by prep-TLC to give 2-[2- fluoro-8-[8-fluoro-4-(3-fluorophenyl)-2-methylsulfanyl-pyrido[4,3-d]pyrimidin-7-yl]-6- (methoxymethoxy)-1-naphthyl]ethynyl-triisopropyl-silane (40 mg, 9.6% yield) as a yellow solid. LCMS: m/z 674.3 (M+1). [01091] Step 4. To a mixture of 2-[2-fluoro-8-[8-fluoro-4-(3-fluorophenyl)-2- methylsulfanyl-pyrido[4,3-d]pyrimidin-7-yl]-6-(methoxymethoxy)-1-naphthyl]ethynyl- triisopropyl-silane (40 mg, 0.0594 mmol, 1 eq) in DCM (1 mL) was added m-CPBA (12.1 mg, 0.0594 mmol, 85% purity, 1 eq) at 0 °C. The mixture was stirred at 25 °C for 0.5 hour under N
2. On completion, the mixture was added DCM (10 mL). The organic phase was washed with Na2SO3 (2 mL * 2), dried with anhydrous Na2SO4, filtered and concentrated in vacuum. The residue was purified by prep-TLC to give 2-[2-fluoro-8-[8-fluoro-4-(3- fluorophenyl)-2-methylsulfonyl-pyrido[4,3-d]pyrimidin-7-yl]-6-(methoxymethoxy)-1- naphthyl]ethynyl-triisopropyl-silane (20 mg, 47% yield) as a yellow solid. LCMS: m/z 706.3 (M+1: 706.3) [01092] Step 5. A mixture of 2-[2-fluoro-8-[8-fluoro-4-(3-fluorophenyl)-2- methylsulfonyl-pyrido[4,3-d]pyrimidin-7-yl]-6-(methoxymethoxy)-1-naphthyl]ethynyl- triisopropyl-silane (20 mg, 0.0283 mmol, 1 eq), [(2R,8S)-2-fluoro-1,2,3,5,6,7-
hexahydropyrrolizin 8 yl]methanol (9.02 mg, 0.0567 mmol, 2 eq) and DIEA (11.0 mg, 0.0850 mmol, 3 eq) in dioxane (0.5 mL) was stirred at 100 °C for 12 hours. On completion, the mixture was concentrated in vacuum. The mixture was purified by prep-TLC to give 2- [2-fluoro-8-[8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]-4- (3-fluorophenyl)pyrido[4,3-d]pyrimidin-7-yl]-6-(methoxymethoxy)-1-naphthyl]ethynyl- triisopropyl-silane (12 mg, 54% yield) as a yellow solid. LCMS: m/z 785.4 (M+1). [01093] Step 6. To a mixture of 2-[2-fluoro-8-[8-fluoro-2-[[(2R,8S)-2-fluoro- 1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]-4-(3-fluorophenyl)pyrido[4,3-d]pyrimidin-7- yl]-6-(methoxymethoxy)-1-naphthyl]ethynyl-triisopropyl-silane (15 mg, 0.0191 mmol, 1 eq) in DCM (0.5 mL) was added HCl/dioxane (4 M, 0.05 mL, 10.5 eq) slowly. The mixture was stirred at 25 °C for 0.5 hour. On completion, the mixture was concentrated in vacuum to give 6-fluoro-4-[8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]-4- (3-fluorophenyl)pyrido[4,3-d]pyrimidin-7-yl]-5-(2-triisopropylsilylethynyl)naphthalen-2-ol (12 mg, 0.0162 mmol, 84.8% yield) as a yellow solid. LCMS: m/z 741.3 (M+1). [01094] Step 7. To a mixture of 6-fluoro-4-[8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7- hexahydropyrrolizin-8-yl]methoxy]-4-(3-fluorophenyl)pyrido[4,3-d]pyrimidin-7-yl]-5-(2- triisopropylsilylethynyl)naphthalen-2-ol (12 mg, 0.0162 mmol, 1 eq) in DMSO (0.5 mL) was added CsF (12.3 mg, 0.0809 mmol, 5 eq). The mixture was stirred at 25 °C for 0.5 hour. On completion, the mixture was filtered. The filtrate was purified by prep-HPLC to give Ex.30 (1.22 mg, 12% yield) as a brown solid.
1H NMR (400 MHz, DMSO-d6) δ = 9.08 (s, 1H), 7.97 - 7.87 (m, 1H), 7.80 - 7.70 (m, 3H), 7.63 - 7.53 (m, 1H), 7.48 - 7.39 (m, 1H), 7.37 - 7.30 (m, 1H), 7.20 (s, 1H), 5.42 - 5.20 (m, 1H), 4.36 - 4.20 (m, 2H), 3.95 (s, 1H), 3.16 - 3.10 (m, 2H),
3.05 (s, 1H), 2.89 2.82 (m, 1H), 2.24 2.15 (m, 1H), 2.14 2.04 (m, 2H), 1.91 1.80 (m, 3H). LCMS: m/z 585.1 (M+1). [01095] Preparation of 4-[4-(cyclopentylsulfanyl)-8-fluoro-2-{[(2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}pyrido[4,3-d]pyrimidin-7-yl]-5-ethynyl- 6-fluoronaphthalen-2-ol (65)
[01096] Step 1. To a solution of 2,4,7-trichloro-8-fluoro-pyrido[4,3-d]pyrimidine (500 mg, 1.98 mmol, 1 eq) in DCM (20 mL) was added DIEA (768 mg, 5.94 mmol, 3 eq) and cyclopentanethiol (243 mg, 2.38 mmol, 1.2 eq) at -40 °C. The mixture was stirred at -40 °C for 2 hours followed by addition of H
2O (50 mL) at 25 °C, and then extracted with DCM (30 mL * 3). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography to give 2,7-dichloro-4-cyclopentylsulfanyl-8-fluoro-pyrido[4,3-d]pyrimidine (540 mg, 1.70 mmol, 85.7% yield) as a white solid.
1H NMR (400 MHz, DMSO-d
6) δ = 9.20 (s, 1H), 4.38 - 4.13 (m, 1H), 2.36 - 2.23 (m, 2H), 1.80 - 1.65 (m, 6H). [01097] Ex.30 were then prepared following similar reaction conditions as Step 2-6 in General Method A as a white solid.
1H NMR (400 MHz, CDCl
3) δ = 9.14 (s, 1H), 7.67 (dd, J = 5.6, 9.2 Hz, 1H), 7.22 (t, J = 8.8 Hz, 1H), 7.18 - 7.12 (m, 2H), 5.43 - 5.20 (m, 1H), 4.37 (s,
3H), 3.40 3.15 (m, 3H), 3.07 2.96 (m, 1H), 2.77 (s, 1H), 2.37 2.21 (m, 4H), 2.17 2.10 (m, 1H), 2.00 - 1.95 (m, 2H), 1.85 - 1.73 (m, 7H). LCMS: m/z 591.3 (M+1). [01098] Preparation of 5-ethynyl-1,6-difluoro-4-[8-fluoro-2-{[(2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}-4-(8-oxa-3-azabicyclo[3.2.1]octan-3- yl)pyrido[4,3-d]pyrimidin-7-yl]naphthalen-2-ol (Ex.73)
[01099] Ex.73 was prepared following General Method A.
1H NMR (400 MHz, DMSO-d6 ) δ = 10.68 - 10.51 (m, 1H), 9.06 (s, 1H), 8.19 - 8.10 (m, 1H), 7.66 - 7.57 (m, 1H), 7.37 (d, J = 8.8 Hz, 1H), 5.44 - 5.12 (m, 1H), 4.52 - 4.41 (m, 3H), 4.29 (br d, J = 12.8 Hz, 1H), 4.18 - 4.09 (m, 1H), 4.08 - 3.99 (m, 2H), 3.77 - 3.64 (m, 3H), 3.14 - 3.00 (m, 4H), 2.90 - 2.78 (m, 2H), 2.13 (br s, 1H), 2.01 (br s, 1H), 1.86 - 1.78 (m, 5H). LCMS: m/z 620.1 (M+1). [01100] Preparation of 5-ethynyl-6-fluoro-4-(8-fluoro-2-{[(2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}-4-[(2R)-2-(methoxymethyl)morpholin- 4-yl]pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol (Ex.74)
[01101] Ex.74 was prepared following General Method A.
1H NMR (400 MHz, DMSO-d6 ) δ = 10.18 (br s, 1H), 9.07 (s, 1H), 8.14 (s, 1H), 7.98 (dd, J = 5.9, 9.2 Hz, 1H), 7.46 (t, J = 9.0 Hz, 1H), 7.40 (d, J = 2.5 Hz, 1H), 7.20 (d, J = 2.3 Hz, 1H), 5.44 - 5.14 (m, 1H), 4.53 - 4.39 (m, 1H), 4.35 (br t, J = 12.6 Hz, 1H), 4.16 (dd, J = 7.2, 10.4 Hz, 1H), 4.10 - 3.92 (m, 3H), 3.87 (tdd, J = 2.4, 5.1, 10.3 Hz, 1H), 3.82 - 3.71 (m, 1H), 3.61 - 3.52 (m, 1H),
3.50 3.45 (m, 2H), 3.35 3.27 (m, 4H), 3.17 3.08 (m, 2H), 3.05 (s, 1H), 2.91 2.81 (m, 1H), 2.18 - 1.94 (m, 3H), 1.92 - 1.72 (m, 3H). LCMS: m/z 620.3 (M+1). [01102] Preparation of 5-ethynyl-6-fluoro-4-[8-fluoro-2-{[(2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}-4-(morpholin-4-yl)pyrido[4,3- d]pyrimidin-7-yl]naphthalen-2-ol (Ex.75)
[01103] Ex.75 was prepared following General Method A.
1HNMR (400 MHz, DMSO-d
6) δ = 10.45 - 9.78 (m, 1H), 9.12 - 9.03 (m, 1H), 8.01 - 7.93 (m, 1H), 7.50 - 7.43 (m, 1H), 7.41 - 7.37 (m, 1H), 7.22 - 7.16 (m, 1H), 5.44 - 5.15 (m, 1H), 4.17 - 4.09 (m, 1H), 4.07 - 3.97 (m, 4H), 3.96 - 3.88 (m, 2H), 3.87 - 3.77 (m, 4H), 3.13 - 3.02 (m, 3H), 2.89 - 2.77 (m, 1H), 2.19 - 1.96 (m, 3H), 1.92 - 1.69 (m, 3H). LCMS: m/z 576.0 (M+1). [01104] Preparation of 5-ethynyl-6-fluoro-4-[8-fluoro-2-{[(2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}-4-(2-oxa-5-azabicyclo[4.1.0]heptan-5- yl)pyrido[4,3-d]pyrimidin-7-yl]naphthalen-2-ol (Ex.76)
[01105] Ex.76 was prepared following General Method A.1H NMR (400 MHz, DMSO-d6 ) δ = 10.41 - 10.05 (m, 1H), 9.77 (d, J = 16.0 Hz, 1H), 8.02 - 7.94 (m, 1H), 7.51 - 7.44 (m, 1H), 7.41 (d, J = 2.4 Hz, 1H), 7.25 - 7.09 (m, 1H), 5.70 - 5.41 (m, 1H), 4.69 - 4.53 (m, 2H), 4.25 - 4.16 (m, 1H), 4.14 - 4.05 (m, 1H), 4.05 - 4.00 (m, 1H), 3.98 - 3.96 (m, 1H), 3.95 - 3.93 (m, 1H), 3.93 - 3.89 (m, 2H), 3.57 - 3.48 (m, 2H), 3.47 - 3.43 (m, 1H), 2.56 (br d,
J 4.0 Hz, 1H), 2.54 (br s, 1H), 2.47 (br s, 1H), 2.38 2.26 (m, 1H), 2.24 2.10 (m, 2H), 2.09 - 1.98 (m, 1H), 1.34 - 1.21 (m, 1H), 1.17 - 1.05 (m, 1H). LCMS: m/z 588.1 (M+1). [01106] Preparation of 4-{2-[(3S)-3-(dimethylamino)pyrrolidin-1-yl]-8-fluoro-4- (morpholin-4-yl)pyrido[4,3-d]pyrimidin-7-yl}-5-ethynyl-6-fluoronaphthalen-2-ol (Ex.77)
[01107] Ex.77 was prepared following General Method A.
1H NMR (400 MHz, DMSO-d6 ) δ = 10.11 - 9.92 (m, 1H), 8.92 (d, J = 4.0 Hz, 1H), 7.98 (dd, J = 6.0, 8.0 Hz, 1H), 7.47 (t, J = 8.0 Hz, 1H), 7.39 (d, J = 2.4 Hz, 1H), 7.18 (d, J = 2.4 Hz, 1H), 4.17 - 4.05 (m, 3H), 4.00 (s, 2H), 3.92 - 3.85 (m, 4H), 3.82 (br d, J = 4.4 Hz, 4H), 3.68 (br dd, J = 6.0, 12.0 Hz, 1H), 3.63 - 3.57 (m, 1H), 2.87 (br s, 6H), 2.24 - 2.16 (m, 1H). LCMS: m/z 531.2 (M+1). [01108] Preparation of 5-ethynyl-6-fluoro-4-[8-fluoro-2-{[(2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}-4-(6-oxa-3-azabicyclo[3.1.1]heptan-3- yl)pyrido[4,3-d]pyrimidin-7-yl]naphthalen-2-ol (Ex.78)
[01109] Ex.78 was prepared following General Method A.1H NMR (400 MHz, DMSO-d6 ) δ = 10.16 (br s, 1H), 9.40 - 9.38 (m, 1H), 8.02 - 7.94(m, 1H), 7.50 - 7.42 (m, 1H), 7.41 - 7.36 (m, 1H), 7.16(d, J = 2.4 Hz, 1H), 5.46 - 5.12 (m, 1H), 4.8 - 4.62 (m, 2H), 4.48 - 4.4 (m, 1H), 4.32 - 4.24 (m, 2H), 4.12 (br s, 1H), 4.20 - 3.96 (m, 3H), 3.20 - 3.12 (m, 1H), 3.12 - 3.00 (m, 1H), 3.20 - 2.98 (m, 1H), 3.20 - 2.98 (m, 3H), 2.88 - 2.78 (m, 1H), 2.14 -
2.10 (m, 1H), 2.08 1.96(m, 2H), 1.88 (br s, 1H), 1.92 (br d, J 8.8Hz, 1H), 1.88 1.74 (m, 1H). LCMS: m/z 588.0 (M+1). [01110] Preparation of 4-[7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro- 2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}pyrido[4,3-d]pyrimidin- 4-yl]-1λ
6-thiomorpholine-1,1-dione (Ex.79)
[01111] Ex.79 was prepared following General Method A.1H NMR (400 MHz, DMSO-d6 ) δ = 9.15 - 9.04 (m, 1H), 8.04 - 7.92 (m, 1H), 7.54 - 7.37 (m, 2H), 7.26 - 7.18 (m, 1H), 5.38 - 5.22 (m, 1H), 4.36 - 4.24 (m, 1H), 4.42 - 4.23 (m, 1H), 4.20 - 4.02 (m, 2H), 3.95 - 3.85 (m, 1H), 3.58- 3.52 (m, 4H), 3.19 - 2.92 (m, 7H), 2.88 - 2.79 (m, 1H), 2.72 - 2.63 (m, 1H), 2.03 - 1.75 (m, 4H). LCMS: m/z 624.3 (M+1). [01112] Preparation of 4-[4-(2,9-dioxa-6-azaspiro[4.5]decan-6-yl)-8-fluoro-2- {[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}pyrido[4,3-d]pyrimidin-7- yl]-5-ethynyl-6-fluoronaphthalen-2-ol (Ex.80)
[01113] Ex.80 was prepared following General Method A.
1H NMR (499 MHz, DMSO-d6 ) δ = 10.79 - 10.64 (m, 1H), 10.29 - 10.17 (m, 1H), 9.12 (d, J = 6.0 Hz, 1H), 8.00 (dd, J = 5.9, 9.2 Hz, 1H), 7.56 - 7.36 (m, 3H), 7.24 - 7.15 (m, 1H), 5.60 - 5.27 (m, 2H), 4.69 - 4.59 (m, 2H), 4.24 (br s, 1H), 4.03 (br dd, J = 2.7, 6.6 Hz, 1H), 3.93 - 3.91 (m, 2H), 3.89 -
3.86 (m, 2H), 3.80 3.72 (m, 8H), 3.10 3.06 (m, 2H), 2.75 (s, 2H), 2.19 (br d, J 7.4 Hz, 2H), 2.02 - 1.96 (m, 1H) LCMS: m/z 632.04 (M+1). [01114] Preparation of 5-ethynyl-6-fluoro-4-(8-fluoro-2-{[(2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}-4-[(1R,4R)-2-oxa-5- azabicyclo[2.2.1]heptan-5-yl]pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol (Ex.81)
[01115] Ex.80 was prepared following General Method A.
1H NMR (400 MHz, DMSO-d6 ) δ = 10.41 - 9.96 (m, 1H), 9.12 (d, J = 11.2 Hz, 1H), 7.97 (dd, J = 6.0, 9.2 Hz, 1H), 7.46 (t, J = 9.2 Hz, 1H), 7.39 (d, J = 2.4 Hz, 1H), 7.20 - 7.14 (m, 1H), 5.49 - 5.38 (m, 1H), 5.36 - 5.19 (m, 1H), 4.14 (dd, J = 6.4, 10.4 Hz, 1H), 4.07 - 3.99 (m, 2H), 3.98 - 3.90 (m, 3H), 3.13 - 3.05 (m, 3H), 2.87 - 2.79 (m, 2H), 2.06 - 1.97 (m, 4H), 1.89 - 1.71 (m, 4H). LCMS: m/z 588.2 (M+1). [01116] Preparation of 5-ethynyl-6-fluoro-4-[8-fluoro-2-{[(2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}-4-(7-oxa-4-azaspiro[2.5]octan-4- yl)pyrido[4,3-d]pyrimidin-7-yl]naphthalen-2-ol (Ex.82)
[01117] Ex.82 was prepared following General Method A.1H NMR (400 MHz, DMSO-d6 ) δ = 10.33 - 9.96 (m, 1H), 9.09 (s, 1H), 7.98 (dd, J = 6.0, 9.2 Hz, 1H), 7.47 (t, J = 9.2 Hz, 1H), 7.40 (d, J = 2.4 Hz, 1H), 7.19 (d, J = 2.0 Hz, 1H), 5.43 - 5.18 (m, 1H), 4.38 - 4.25 (m, 1H), 4.18 - 3.98 (m, 4H), 3.96 - 3.84 (m, 2H), 3.83 - 3.76 (m, 1H), 3.71 - 3.57 (m, 1H), 3.15 - 3.06 (m, 2H), 3.03 (s, 1H), 2.88 - 2.80 (m, 1H), 2.13 (s, 1H), 2.10 - 1.95 (m, 2H), 1.91 - 1.72 (m, 3H), 1.25 - 1.17 (m, 1H), 1.12 (d, J = 4.4 Hz, 2H), 0.96 (s, 1H). LCMS: m/z 602.3 (M+1). [01118] Preparation of 1-{4-[7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8- fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}pyrido[4,3-
d]pyrimidin 4 yl] 1,4 diazepan 1 yl}ethan 1 one (Ex.106)
[01119] Step 1. To a solution of 2,2,2-trifluoroethanol (1.19 g, 11.9 mmol, 1.0 eq) in 2-MeTHF (10 mL) was added NaH (713 mg, 17.8 mmol, 60% purity, 1.5 eq) at 0 °C. The mixture was stirred at 25 °C for 2 hr. Then the mixture was added to the solution of 2,4,7- trichloro-8-fluoro-pyrido[4,3-d]pyrimidine (3.00 g, 11.9 mmol, 1.0 eq) in 2-Me-THF (20
mL) at 40 C. The mixture was stirred at 40 C for 1 hr, quenched with sat. NH
4Cl (30 mL) and extracted with ethyl acetate (25 mL × 3). The combined organic phase was dried over anhydrous sodium sulfate, filtered and concentrated. The residue was triturated with PE at 25
oC for 30 min and then filtered, the filter cake was dried in vacuum to give 2,7-dichloro-8- fluoro-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine (2.52 g, 7.51 mmol, 63.2% yield) as an off-white solid.
1H NMR (400 MHz, CDCl
3) δ = 9.18 (s, 1H), 7.37 - 7.36 (m, 1H), 5.09 (q, J = 8.0 Hz, 2H). [01120] Step 2. To a solution of 2,7-dichloro-8-fluoro-4-(2,2,2- trifluoroethoxy)pyrido[4,3-d]pyrimidine (2.30 g, 7.28 mmol, 1.0 eq) in dioxane (20 mL) was added DIEA (1.88 g, 14.6 mmol, 2.54 mL, 2.0 eq) and [(2R,8S)-2-fluoro-1,2,3,5,6,7- hexahydropyrrolizin-8-yl]methanol (1.27 g, 8.01 mmol, 1.1 eq). The mixture was stirred at 40 °C for 12 hr. On completion, the mixture was concentrated and the residue was purified by column chromatography (SiO2, Petroleum ether/Ethyl acetate=1/0 to 0/1) to give 7- chloro-8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]-4- (2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine (2.00 g, 4.56 mmol, 62.6% yield) as a yellow solid.
1H NMR (400 MHz, CDCl3) δ = 8.99 (s, 1H), 5.40 - 5.22 (m, 1H), 5.02 (q, J = 8.0 Hz, 2H), 4.40 - 4.34 (m, 2H), 3.35 - 3.26 (m, 2H), 3.24 - 3.19 (m, 1H), 3.01 (dt, J = 5.6, 9.6 Hz, 1H), 2.26 (dd, J = 10.0, 14.4 Hz, 2H), 2.17 - 2.10 (m, 2H), 2.01 - 1.96 (m, 2H). [01121] Step 3. A mixture of 7-chloro-8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7- hexahydropyrrolizin-8-yl]methoxy]-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine (1.80 g, 4.10 mmol, 1.0 eq), ((2-fluoro-6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)naphthalen-1-yl)ethynyl)triisopropylsilane (3.15 g, 6.15 mmol, 1.5 eq), K
3PO
4 (2.61 g, 12.3 mmol, 3.0 eq), [2-(2-aminophenyl)phenyl]palladium(1+);bis(1- adamantyl)-butyl-phosphane;methanesulfonate (299 mg, 410 umol, 0.1 eq) in dioxane (20 mL) and H
2O (4 mL) was degassed and purged with N
2 for 3 times, and then the mixture was stirred at 80 °C for 2 h under N2 atmosphere in microwave. The mixture was dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether/Ethyl acetate=5/1 to 0/1) to give 2-[2-fluoro-8-[8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8- yl]methoxy]-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidin-7-yl]-6-(methoxymethoxy)-1- naphthyl]ethynyl-triisopropyl-silane (2.31 g, 2.49 mmol, 60.7% yield, 85% purity) as a brown oil.
1H NMR (400 MHz, CDCl
3) δ = 9.24 (s, 1H), 7.80 (dd, J = 6.0, 9.2 Hz, 1H), 7.53 (d, J = 2.4 Hz, 1H), 7.32 (s, 1H), 7.31 - 7.28 (m, 1H), 5.33 - 5.28 (m, 2H), 5.18 - 5.09 (m, 1H), 5.05 - 4.91 (m, 2H), 4.44 - 4.26 (m, 2H), 3.51 (s, 3H), 3.29 - 3.24 (m, 2H), 3.20 - 3.15 (m, 1H), 2.99 (td, J = 4.8, 9.2 Hz, 1H), 2.22 - 2.07 (m, 3H), 1.96 (td, J = 6.0, 11.6 Hz, 3H),
0.87 (d, J 7.6 Hz, 9H), 0.84 (d, J 7.6 Hz, 9H), 0.58 0.49 (m, 3H); LCMS: m/z 789.5 (M+1) [01122] The remaing steps followed similar reaction conditions as Steps 4 in General Method A to give Ex.106 as an off-white solid.
1H NMR (400 MHz, DMSO-d6 ) δ = 10.41 - 9.98 (m, 1H), 9.22 - 8.95 (m, 1H), 7.97 (dd, J = 6.0, 9.2 Hz, 1H), 7.46 (t, J = 8.8 Hz, 1H), 7.39 (d, J = 2.4 Hz, 1H), 7.24 - 7.17 (m, 1H), 5.53 - 5.06 (m, 1H), 4.35 - 4.09 (m, 4H), 4.06 - 3.94 (m, 4H), 3.71 - 3.59 (m, 2H), 3.54 - 3.44 (m, 2H), 3.13 - 3.06 (m, 3H), 2.91 - 2.74 (m, 2H), 2.14 - 2.04 (m, 3H), 1.94 (s, 3H), 1.84 - 1.73 (m, 3H). LCMS: m/z 631.3 (M+1). [01123] Preparation of 4-(4-cyclohexyl-8-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl]methoxy}pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2- ol (Ex.107)
[01124] Step 1. To a solution of 2,4,7-trichloro-8-fluoro-pyrido[4,3-d]pyrimidine (3 g, 11.9 mmol, 1 eq) in THF (30 mL) was added NaH (951 mg, 23.8 mmol, 60% purity, 2 eq) and NaSMe (750 mg, 10.7 mmol, 0.9 eq). The mixture was stirred at - 40 °C for 16 h. On completion, the mixture was quenched by sat.NH4Cl (10 mL) at 0 °C. The mixture was diluted with H2O (100 mL) and extracted with EA ( 80 mL * 3). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (SiO
2, Petroleum ether/Ethyl acetate=1/0 to 0/1) to give 2,7-dichloro-8-fluoro-4-methylsulfanyl-pyrido[4,3-d]pyrimidine (2.05 g, 7.76 mmol, 65% yield) as a white solid. LCMS: m/z 263.9 (M+1). [01125] Step 2. A mixture of 2,7-dichloro-8-fluoro-4-methylsulfanyl-pyrido[4,3- d]pyrimidine (2 g, 7.57 mmol, 1 eq), [(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8- yl]methanol (1.81 g, 11.4 mmol, 1.5 eq), DIEA (1.96 g, 15.2 mmol, 2.64 mL, 2 eq) in dioxane (20 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 80 °C for 1 h under N2 atmosphere. On completion, the reaction mixture was concentrated under reduced pressure to remove solvent. The residue was purified by column chromatography (SiO2, Petroleum ether/Ethyl acetate=1/0 to 0/1) to give 7-chloro-8-fluoro- 2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]-4-methylsulfanyl-
pyrido[4,3 d]pyrimidine (1.64 g, 4.24 mmol, 56% yield) as a white solid. LCMS: m/z 386.8 (M+1). [01126] Step 3. A mixture of 7-chloro-8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7- hexahydropyrrolizin-8-yl]methoxy]-4-methylsulfanyl-pyrido[4,3-d]pyrimidine (1 g, 2.59 mmol, 1 eq) , cyclohexen-1-ylboronic acid (651 mg, 5.17 mmol, 2 eq), Pd(PPh3)4 (299 mg, 0.259 mmol, 0.1 eq), thiophene-2-carbonyloxycopper (49.3 mg, 0.259 mmol, 0.1 eq) in THF (2 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 60 °C for 16 h under N
2 atmosphere. On completion, the reaction mixture was diluted with H
2O (50 mL) and extracted with EA (30 mL * 3). The combined organic layers were dried over Na
2SO
4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether/Ethyl acetate=1/0 to 0/1) to give 7-chloro-4-(cyclohexen-1-yl)-8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin- 8-yl]methoxy]pyrido[4,3-d]pyri midine (700 mg, 1.66 mmol, 64% yield) as a white solid . LCMS: m/z 421.1 (M+1). [01127] Step 4. A mixture of 7-chloro-4-(cyclohexen-1-yl)-8-fluoro-2-[[(2R,8S)-2- fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3-d]pyrimidine (50 mg, 0.119 mmol, 1 eq), 9, 2-[2-fluoro-6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan- 2-yl)-1-naphthyl]ethynyl-triisopropyl-silane (91.3 mg, 0.178 mmol, 1.5 eq), K3PO4 (75.7 mg, 0.356 mmol, 3 eq), [2-(2-aminophenyl)phenyl]palladium(1+);bis(1-adamantyl)-butyl- phosphane;methanesulfonate (8.65 mg, 0.0119 mmol, 0.1 eq) in THF (1 mL) and H2O (0.2 mL) was degassed and purged with N
2 for 3 times, and then the mixture was stirred at 60 °C for 2 h under N2 atmosphere. On completion, the reaction mixture was diluted with H2O (20 mL) and extracted with EA (15 mL * 3). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (SiO
2, Petroleum ether/Ethyl acetate=1/0 to 0/1) to give 2-[8-[4- (cyclohexen-1-yl)-8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8- yl]methoxy]pyrido[4,3-d]pyrimidin-7-yl]-2-fluoro-6-(methoxymethoxy)-1-naphthyl]ethynyl- triisopropyl-silane (66 mg, 0.0856 mmol, 72% yield) as a brown oil. LCMS: m/z 771.4 (M+1). [01128] Step 5. A mixture of 2-[8-[4-(cyclohexen-1-yl)-8-fluoro-2-[[(2R,8S)-2-fluoro- 1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3-d]pyrimidin-7-yl]-2-fluoro-6- (methoxymethoxy)-1-naphthyl]ethynyl-triisopropyl-silane (66 mg, 0.0856 mmol, 1 eq), Pd/C (10 mg, 10% purity) in MeOH (3 mL) was degassed and purged with H2 for 3 times, and
then the mixture was stirred at 25 C for 1 h under H
2 atmosphere. On completion, the mixture was filtrated and the organic layer was concentrated under reduced pressure to remove solvent to give 2-[8-[4-cyclohexyl-8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7- hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3-d]pyrimidin-7-yl]-2-fluoro-6- (methoxymethoxy)-1-naphthyl]ethynyl-triisopropyl-silane (50 mg, 64.7 umol, 76 % yield) as colorless oil. LCMS: m/z 773.3 (M+1). [01129] The final steps were performed following similar reaction conditions as Steps 2-4 in General Method A and purified by preparative HPLC to give Ex.107 (3.08 mg) as a yellow solid TFA salt.
1H NMR (400 MHz, MeOD-d4) δ = 9.49 - 9.42 (m, 1H), 7.92 - 7.86 (m, 1H), 7.39 (d, J = 2.4 Hz, 1H), 7.37 - 7.32 (m,1H), 7.24 (d, J = 2.4 Hz, 1H), 5.72 - 5.52 (m, 1H), 4.82 - 4.78 (m, 2H), 3.98 - 3.91 (m, 2H), 3.90 - 3.82 (m, 1H), 3.20 - 3.14 (m,1H), 2.69 (br s, 1H), 2.65 - 2.54 (m, 1H), 2.55 - 2.44 (m, 1H), 2.43 - 2.33 (m, 2H), 2.30 - 2.14 (m, 2H), 2.07 (br d, J = 10.4 Hz,2H), 2.01 - 1.93 (m, 2H), 1.93 - 1.78 (m, 4H), 1.73 - 1.63 (m, 2H). LCMS: m/z 573.3 (M+1). [01130] Preparation of 4-[4-(cyclohex-1-en-1-yl)-8-fluoro-2-{[(2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}pyrido[4,3-d]pyrimidin-7-yl]-5-ethynyl- 6-fluoronaphthalen-2-ol (Ex.108)
[01131] Step 1. To a solution of 2-[8-[4-(cyclohexen-1-yl)-8-fluoro-2-[[(2R,8S)-2- fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3-d]pyrimidin-7-yl]-2-fluoro- 6-(methoxymethoxy)-1-naphthyl]ethynyl-triisopropyl-silane (30 mg, 0.0389 mmol, 1 eq) in
DCM (1 mL) was added TFA (924 mg, 8.10 mmol, 208 eq). The mixture was stirred at 25 C for 1 h. On completion, the reaction mixture was concentrated under reduced pressure to remove TFA to give 4-[4-(cyclohexen-1-yl)-8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7- hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3-d]pyrimidin-7-yl]-6-fluoro-5-(2- triisopropylsilylethynyl)naphthalen-2-ol (30 mg, 37.1 umol, 95% yield) as a yellow solid. [01132] Step 2. To a solution of 4-[4-(cyclohexen-1-yl)-8-fluoro-2-[[(2R,8S)-2-fluoro- 1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3-d]pyrimidin-7-yl]-6-fluoro-5-(2- triisopropylsilylethynyl)naphthalen-2-ol (30 mg, 0.0413 mmol, 1 eq) in DMSO (0.3 mL) was added CsF (37.61 mg, 248 mmol, 6 eq). The mixture was stirred at 25 °C for 1 h. On completion, the mixture was filtrated to remove CsF. The filtrate was purified by prep-HPLC to give Ex.108 formic acid salt (2.17 mg, 8.53% yield) as a yellow solid.
1H NMR (400 MHz, MeOD-d
4) δ = 9.24 (s, 1H), 7.91 – 7.85 (m, 1H), 7.38 (d, J = 2.4 Hz, 1H), 7.36 – 7.31 (m, 1H), 7.26 -7.22 (m, 1H), 6.54 – 6.46 (m, 1H), 5.47 – 5.30 (m, 1H), 4.61 – 4.56 (m, 1H),
4.55 4.44 (m, 2H), 3.41 (br s, 2H), 2.77 2.64 (m,2H), 2.46 (br d, J 2.8 Hz, 2H), 2.42 2.18 (m, 4H), 2.12 – 2.05 (m, 2H), 2.03 – 1.82 (m, 6H). LCMS: m/z :571.3 (M+1). [01133] Preparation of 5-ethynyl-6-fluoro-4-(8-fluoro-2-{[(2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}-4-methylpyrido[4,3-d]pyrimidin-7- yl)naphthalen-2-ol (Ex.109)
[01134] Step 1. To a solution of 7-chloro-8-fluoro-2-methylsulfanyl-3H-pyrido [4,3- d]pyrimidin-4-one (1.00 g, 4.07 mmol, 1 eq) in Toluene (10 mL) was added POCl3 (1.87 g, 12.2 mmol, 1.14 mL, 3 eq) and DIEA (4.73 g, 36.6 mmol, 6 mL, 9 eq). The mixture was stirred at 110 °C for 2 h. On completion, the reaction mixture was concentrated under reduced pressure to remove POCl
3. The mixture was quenched with saturated NaHCO
3 (30 mL) and extracted with ethyl acetate (10 mL × 3). The combined organic phase was dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by flash silica gel chromatography to provide 4,7-dichloro-8-fluoro-2-methylsulfanyl-pyrido[4,3-
d]pyrimidine (550 mg, 2.08 mmol, 51% yield) as a yellow solid. H NMR (400 MHz, CDCl3) δ = 9.11 (s, 1H), 2.72 (s, 3H). LCMS: m/z :263.9 (M+1) [01135] Step 2. To a solution of 4,7-dichloro-8-fluoro-2-methylsulfanyl-pyrido[4,3- d]pyrimidine (300 mg, 1.14 mmol, 1 eq) in THF (1 mL) was added Pd(dppf)Cl2 (9.14 mg, 0.0125 mmol, 0.011 eq) under N
2 at 0 °C followed by addition of bromo(methyl)magnesium (3 M, 0.454 mL, 1.2 eq). The mixture was stirred at 60 °C for 1 h. On completion, the reaction mixture was quenched by addition of sat. NH4Cl (10 mL) at 25 °C, and then extracted with EA (3 mL * 3). The combined organic layers were washed with Brine (5 mL * 2), dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography to provide 7-chloro-8-fluoro-4-methyl-2- methylsulfanyl-pyrido[4,3-d]pyrimidine (130 mg, 0.533 mmol, 47% yield) as a yellow solid. LCMS: m/z 243.9 (M+1) [01136] Ex.109 was obtained as an orange solid following similar procedures as general method A starting with 7-chloro-8-fluoro-4-methyl-2-methylsulfanyl-pyrido[4,3- d]pyrimidine.
1H NMR (400 MHz, METHANOL-d4 ) δ = 9.41 (s, 1H), 7.93 - 7.82 (m, 1H), 7.38 (d, J = 2.4 Hz, 1H), 7.34 (t, J = 8.8 Hz, 1H), 7.22 (d, J = 2.4 Hz, 1H), 5.74 - 5.49 (m, 1H), 4.08 - 3.92 (m, 3H), 3.55 - 3.44 (m, 2H), 3.26 - 3.19 (m, 1H), 3.12 (s, 3H), 2.73 - 2.59 (m, 2H), 2.53 - 2.44 (m, 1H), 2.42 - 2.33 (m, 2H), 2.30 - 2.13 (m, 2H). LCMS: m/z 505.0 (M+1). [01137] Screen Assays [01138] HTRF KRAS mutation nucleotide exchange assays: [01139] The HTRF KRAS nucleotide exchange assays were performed at Reaction Biology. Briefly, purified GST tagged KRAS G12C, KRAS G12D, KRAS G12V, KRAS G12R, KRAS G12S, KRAS G12D/T35S or KRAS WT proteins were mixed with a-GST Tb antibody in reaction buffer (20 mM Hepes, pH 7.4, 150 mM NaCl, 5 mM MgCl
2, 1 mM DTT, 0.05% BSA, 0.0025% NP40). Serial dilutions of indicated compounds were prepared in DMSO and added to the KRAS /a-GST Tb antibody mixture using acoustic dispenser (ECHO, Beckman). Compounds were incubated with KRAS/a-GST Tb antibody at room temperature for one hour. Purified SOS1 proteins and GTP-DY-647P1 mix was introduced to initiate the exchange reaction. HTRF signals were quantified 20-60 minutes later. The background subtracted signals are converted to % activity relative to DMSO controls. Data is analyzed using GraphPad Prism 4 with “sigmoidal dose-response (variable slope) equation to obtain compound IC50 values.
[01140] Cell proliferation assays: [01141] Method A: Two thousand KRAS mutant cells per well were seeded in 384- well white plate and then treated with indicated compounds for 72 hours at 37 °C and 5% CO2. Cell proliferation was measured using CellTiter-Glo 2.0 luciferase-based ATP detection assay (Promega, Madison, WI) following the manufacturer’s protocol. IC
50 values were determined using Prism software (GraphPad Software, San Diego, CA).
[01142] Method B: Two thousand KRAS mutant cells per well were seeded in 96-well black plate and then treated with indicated compounds for 5 days at 37°C and 5% CO
2. Cell proliferation was measured using CellTiter-Glo 2.0 luciferase-based ATP detection assay (Promega, Madison, WI) following the manufacturer’s protocol. IC
50 values were determined using Prism software (GraphPad Software, San Diego, CA).
[01143] Kinase phosphorylation assays: [01144] Half a million of KRAS mutant cells per well were seeded in 24-well plate for 2 h prior to treatment. Cells were collected after a 4 h treatment and lysed in RIPA buffer
buffer (50 mM Tris, pH 7.4, 150 mM NaCl, 1% NP 40, 0.5% Deoxycholate, 0.1% SDS) supplemented with 10 mM EDTA, 1X Halt protease and phosphatase inhibitors (Thermo Scientific). Protein lysates were resolved on 4–12% Bolt Bis-Tris gels with MES running buffer, transferred to nitrocellulose membrane using Trans-Blot Turbo Transfer System (BioRad, Hercules, CA), and detected with desired antibodies. Antibodies were incubated overnight at 4 °C, washed, incubated with corresponding HRP-conjugated secondary antibodies, and incubated with chemiluminescent substrate for 5 min at room temperature. Chemiluminescent images were acquired with a C-DiGit Imaging System (LI-COR Biosciences, Lincoln, NE). The relative density of the chemiluminescent bands was quantified via Image Studio Digits from LI-COR (LI-COR Biosciences, Lincoln, NE). Results are shown in FIGs 1-4. [01145] Inhibition of phosphorylation of ERK (Thr202/Tyr204) using In-Cell Western [01146] KRAS mutant cells were plated in clear bottom 96 well plates at a density of 50,000-120,000 cells per well. Cells were allowed to attach overnight and then treated with compounds for 3 hours. After treatment, cells were fixed with 10% buffered formalin for 20 minutes at room temperature, washed with PBS, and then permeabilized with ice cold 100% methanol for 10 minutes to overnight at -20°C. Odyssey Blocking Buffer (LiCOR Biosciences: 927-60001) was added to each well for 1 hour at room temperature prior to incubation with primary antibodies overnight at 4°C. The primary antibodies used were as follows: Phospho-ERK (Cell Signaling: CS-9101) diluted to 1:250 and β-actin (Cell Signaling: CS-3700 ) diluted to 1:2000 in Odyssey Blocking Buffer + 0.05% Tween20. Plates were washed 3X with Wash Buffer (PBS+0.1% Tween20) and incubated with secondary antibodies for 2 hours at room temperature. The following secondary antibodies were used: goat anti-rabbit-800 (LI-COR: 926-32211) and goat anti-mouse-680 (LICOR: 926-68070) both diluted to 1:2000 in Odyssey Blocking Buffer + 0.05% Tween20. The plates were washed 3X with Wash Buffer before imaged on LiCOR Odyssey M Imaging System. Phospho-ERK signal was normalized to β-actin signal for each well and the percent of DMSO control values were calculated. IC50 values were calculated using the sigmoidal dose-response (variable slope) equation in GraphPad Prism 4.
[01147] Mouse oral PK evaluation of Ex.1 [01148] Ex.1 was administered to female BALB/c mice via oral gavage at the dose level of 50 mg/kg. Mouse plasma was collected before the dose and at 15 min, 1 h, 2 h, 4 h, and 8 h after the dose. For each time points, blood samples were collected from three mice into tubes containing K2-EDTA, followed by gentle mixing to assure distribution of the anti- coagulant. Immediately after a blood sample was collected and mixed, it was placed on ice. Blood samples were subsequently centrifuged at 4 °C for 10 min at 5,000 rpm. The plasma was harvested into pre-labeled tubes and stored at -80 °C. Frozen plasma samples were shipped to Integrated Analytical Solutions, Inc. for bioanalysis of Ex.1 by LC/MS/MS. Non-compartment analysis method of Phoenix 64 software (Certara, Inc) was used to calculate various pharmacokinetic parameters and the results were summarized in the Table below:
[0007] wherein [0008] X is a -O-, -S-, or -NR4-; [0009] Y is a bond, -O-, -S-, -S(O)-, -S(O)2-, or –C(O)NR10-; [0010] Z1 is N or C(R5); [0011] Z2 is N or C(R6); [0012] Z3 is N or C(R7); [0013] Z4 is N or C(R8); [0014] Z5 is N or C(R9); [0015] provided that at least two of Z1-Z5 are N;
[0016] R is independently H, deuterium,C1-C6 alkyl,C2-C6 alkenyl, C2-C6 alkynyl, or ring A, wherein each hydrogen atom in C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl is independently optionally substituted by deuterium, halogen, -Re, -Rf, C1-C6 alkyl, C1-C6 haloalkyl, -ORe, -OC(O)Re, -OC(O)NReRf, -OS(O)Re, -OS(O)2Re, -OS(O)NReRf, -OS(O)2NReRf, -SRe, -S(O)Re, -S(O)2Re, -S(O)NReRf, -S(O)2NReRf, -NReRf, -NReC(O)Rf, -NReC(O)ORf, -NReC(O)NReRf, -NReS(O)Rf, -NReS(O)2Rf, -NReS(O)NReRf, -NReS(O)2NReRf, -C(O)Re, -C(O)ORe, -C(O)NReRf, -PReRf, -P(O)ReRf, -P(O)2ReRf, -P(O)NReRf, -P(O)2NReRf, -P(O)ORe, -P(O)2ORe’, -CN, or -NO2; and when Y is a bond, -O-, –S-, or –S(O)-, then R1 is ring A; [0017] each R2 is independently deuterium, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 4- to 10-membered heterocycloalkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, -ORc, -OC(O)Rc, -OC(O)NRcRd, -OC(=NRc)NRcRd, -OS(O)Rc, -OS(O)2Rc, -OS(O)NRcRd, -OS(O)2NRcRd, -SRc, -S(O)Rc, -S(O)2Rc, -S(O)NRcRd, -S(O)2NRcRd, -NRcRd, -NRcC(O)Rd, -N(C(O)Rc)(C(O)Rd), -NRcC(O)ORd, -NRcC(O)NRcRd, -NRcC(=NRc)NRcRd, -NRcS(O)Rd, -NRcS(O)2Rd, -NRcS(O)NRcRd, -NRcS(O)2NRcRd, -C(O)Rc, -C(O)ORc, -C(O)NRcRd, -C(=NRc)NRcRd, -PRcRd, -P(O)RcRd, -P(O)2RcRd, -P(O)NRcRd, -P(O)2NRcRd, -P(O)ORc, -P(O)2ORc, -CN, or -NO2, or two of R2 taken together with the atoms to which they are attached form a C3-C6 cycloalkyl or a 4- to 10-membered heterocycloalkyl, wherein each hydrogen atom in C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, and 4- to 10-membered heterocycloalkyl is independently optionally substituted by deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, -Re, -Rf, -ORe, -OC(O)Re, -OC(O)NReRf, -OS(O)Re, -OS(O)2Re, -OS(O)NReRf, -OS(O)2NReRf, -SRe, -S(O)Re, -S(O)2Re, -S(O)NReRf, -S(O)2NReRf, -NReRf, -NReC(O)Rf, -NReC(O)ORf, -NReC(O)NReRf, -NReS(O)Rf, -NReS(O)2Rf, -NReS(O)NReRf, -NReS(O)2NReRf, -C(O)Re, -C(O)ORe, -C(O)NReRf, -PReRf, -P(O)ReRf, -P(O)2ReRf, -P(O)NReRf, -P(O)2NReRf, - P(O)ORe, -P(O)2ORe, -CN, or -NO2; [0018] R3 is -C1-C6 alkyl, -C2-C6 alkenyl, -C2-C6 alkynyl, -C3-C6 cycloalkyl, 4- to 10- membered heterocycloalkyl, -C1-C6 alkylene-(4- to 10-membered heterocycloalkyl), -C6-C10 aryl, -C1-C6 alkylene-(C6-C10 aryl), 5- to 10-membered heteroaryl, or -C1-C6 alkylene-(4- to 10- membered heterocycloalkyl), wherein each hydrogen atom in C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 4- to 10-membered heterocycloalkyl, -C1-C6 alkylene-(4- to 10- membered heterocycloalkyl), C6-C10 aryl, -C1-C6 alkylene-(C6-C10 aryl), 5- to 10-membered heteroaryl, and -C1-C6 alkylene-(5- to 10-membered heteroaryl), is independently optionally substituted by deuterium, halogen, -Re, -Rf, C1-C6 alkyl, -C1-C6 alkyl-O-C1-C6 alkyl, -OC1-C6 alkyl-O-C1-C6 alkyl, -C1-C6 alkyl-O-Ra, C6-C10 aryl, -C1-C6 alkyl-(C6-C10 aryl), haloalkyl,C3-
C6 cycloalkyl, 5 to 10 membered heteroaryl, C1 C6 alkyl (5 to 10 membered heterocycloalkyl), -ORe, -OC(O)Re, -OC(O)NReRf, -OS(O)Re, -OS(O)2Re, -OS(O)NReRf, -OS(O)2NReRf, -SRe, -S(O)Re, -S(O)2Re, -S(O)NReRf, -S(O)2NReRf, -NReRf, -NReC(O)Rf, -NReC(O)ORf, -NReC(O)NReRf, -NReC(=NRf)NReRf, -NReS(O)Rf, -NReS(O)2Rf, -NReS(O)NReRf, -NReS(O)2NReRf, -C(O)Re, -C(O)ORe, -C(O)NReRf, -PReRf, -P(O)ReRf, -P(O)2ReRf, -P(O)NReRf, -P(O)2NReRf, -P(O)ORe, -P(O)2ORe’, -CN, or -NO2; [0019] each of R4 and R10 is independently H, deuterium, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 4- to 10-membered heterocycloalkyl, C6-C10 aryl, or 5- to 10- membered heteroaryl, wherein each hydrogen atom in C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 4- to 10-membered heterocycloalkyl, C6-C10 aryl, and 5- to 10- membered heteroaryl is independently optionally substituted by deuterium, halogen, -Re, -Rf, C1-C6 alkyl, C1-C6 haloalkyl, -ORe, -OC(O)Re, -OC(O)NReRf, -OS(O)Re, -OS(O)2Re, - OS(O)NReRf, -OS(O)2NReRf, -SRe, -S(O)Re, -S(O)2Re, -S(O)NReRf, -S(O)2NReRf, -NReRf, - NReC(O)Rf, -NReC(O)ORf, -NReC(O)NReRf, -NReS(O)Rf, -NReS(O)2Rf, -NReS(O)NReRf, - NReS(O)2NReRf, -C(O)Re, -C(O)ORe, -C(O)NReRf, -PReRf, -P(O)ReRf, -P(O)2ReRf, - P(O)NReRf, -P(O)2NReRf, -P(O)ORe, -P(O)2ORe’, -CN, or -NO2; or R1 and R10 taken together with the atom or atoms to which they are attached combine to form a monocyclic 4- to 10- membered heterocycloalkyl, a fused bicyclic 5- to 10-membered heterocycloalkyl, or a bridged bicyclic 6- to 10-membered heterocycloalkyl, wherein each hydrogen atom in the monocyclic 4- to 10-membered heterocycloalkyl, fused bicyclic 5- to 10-membered heterocycloalkyl, or a bridged bicyclic 6- to 10-membered heterocycloalkyl is independently optionally substituted by deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, -OH, -OC1-C6 alkyl, -OC(O)C1-C6 alkyl, -OC(O)N(H or C1-C6 alkyl)2, -OS(O)C1-C6 alkyl, -OS(O)2C1-C6 alkyl, -OS(O)N(H or C1-C6 alkyl)2, -OS(O)2N(H or C1-C6 alkyl)2, -SC1-C6 alkyl, -S(O)C1-C6 alkyl, -S(O)2C1-C6 alkyl, -S(O)N(H or C1-C6 alkyl)2, -S(O)2N(H or C1-C6 alkyl)2, -N(H or C1-C6 alkyl)2, -N(C1- C6 alkyl)C(O)-C1-C6 alkyl, -N(C1-C6 alkyl)C(O)OC1-C6 alkyl, -N(C1-C6 alkyl)C(O)N(H or C1- C6 alkyl)2, -N(C1-C6 alkyl)S(O)C1-C6 alkyl, -N(C1-C6 alkyl)S(O)2C1-C6 alkyl, -N(C1-C6 alkyl)S(O)N(H or C1-C6 alkyl)2, -N(C1-C6 alkyl)S(O)2N(H or C1-C6 alkyl)2, -C(O)C1-C6 alkyl, -C(O)OC1-C6 alkyl, -C(O)N(H or C1-C6 alkyl)2, -P(H or C1-C6 alkyl)2, -P(O)(H or C1-C6 alkyl)2, -P(O)2(H or C1-C6 alkyl)2, -P(O)N(H or C1-C6 alkyl)2, -P(O)2N(H or C1-C6 alkyl)2, -P(O)OC1-C6 alkyl, -P(O)2OC1-C6 alkyl, -CN, or -NO2, or two hydrogen atoms on a single carbon atom of the monocyclic 4- to 10-membered heterocycloalkyl, fused bicyclic 5- to 10- membered heterocycloalkyl, or bridged bicyclic 6- to 10-membered heterocycloalkyl combine to form an oxo group or an alkenyl group;
[0020] each of R , R , R , R , and R is independently H, deuterium, halogen, C1 C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 4- to 10-membered heterocycloalkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, -ORg, -OC(O)Rg, -OC(O)NRgRh, -OS(O)Rg, -OS(O)2Rg, - SRg, -S(O)Rg, -S(O)2Rg, -S(O)NRgRh, -S(O)2NRgRh, -OS(O)NRgRh, -OS(O)2NRgRh, -NRgRh, -NRgC(O)Rh, -NRgC(O)ORh, -NRgC(O)NRgRh, -NRgS(O)Rh, -NRgS(O)2Rh, -NRgS(O)NRgRh, -NRgS(O)2NRgRh, -C(O)Rg, -C(O)ORg, -C(O)NRgRh, -PRgRh, -P(O)RgRh, -P(O)2RgRh, -P(O)NRgRh, -P(O)2NRgRh, -P(O)ORg, -P(O)2ORg, -CN, or -NO2; [0021] ring A is a C3-C8 cycloalkyl, 4- to 10-membered heterocycloalkyl, C6-C10 aryl, or 5- to 10-membered heteroaryl, wherein each of C3-C8 cycloalkyl, 4- to 10-membered heterocycloalkyl, C6-C10 aryl, or 5- to 10-membered heteroaryl is unsubstituted or substituted with one or more of R11; [0022] each R11 is independently deuterium, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 4- to 10-membered heterocycloalkyl, C6-C10 aryl, 5- to 10- membered heteroaryl, -ORa, -OC(O)Ra, -OC(O)NRaRb, -OC(=NRa)NRaRb, -OS(O)Ra, -OS(O)2Ra, -OS(O)NRaRb, -OS(O)2NRaRb, -SRa, -S(O)Ra, -S(O)2Ra, -S(O)NRaRb, -S(O)2NRaRb, -NRaRb, -NRaC(O)Rb, -N(C(O)Ra)(C(O)Rb), -NRaC(O)ORb, -NRaC(O)NRaRb, -NRaC(=NRa)NRaRb, -NRaS(O)Rb, -NRaS(O)2Rb, -NRaS(O)NRaRb, -NRaS(O)2NRaRb, - C(O)Ra, -C(O)ORa, -C(O)NRaRb, -C(=NRa)NRaRb, -PRaRb, -P(O)RaRb, -P(O)2RaRb, - P(O)NRaRb, -P(O)2NRaRb, -P(O)ORa, -P(O)2ORa, -CN, or -NO2, or two of R11 taken together with the atom or atoms to which they are attached or three of R11 taken together with the atoms to which they are attached, form a C3-C6 cycloalkyl or a 4- to 10-membered heterocycloalkyl, wherein each hydrogen atom in C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, and 4- to 10-membered heterocycloalkyl is independently optionally substituted by deuterium, halogen, -Re, -Rf, C1-C6 alkyl, C1-C6 haloalkyl, -ORe, -OC(O)Re, -OC(O)NReRf, -OS(O)Re, -OS(O)2Re, -OS(O)NReRf, -OS(O)2NReRf, -SRe, -S(O)Re, -S(O)2Re, -S(O)NReRf, -S(O)2NReRf, -NReRf, -NReC(O)Rf, - NReC(O)ORf, -NReC(O)NReRf, -NReS(O)Rf, -NReS(O)2Rf, -NReS(O)NReRf, -NReS(O)2NReRf, -C(O)Re, -C(O)ORe, -C(O)NReRf, -PReRf, -P(O)ReRf, -P(O)2ReRf, -P(O)NReRf, -P(O)2NReRf, -P(O)ORe, -P(O)2ORe, -CN, or -NO2, or two of R11 taken together with the carbon atom to which they are attached form an oxo group or an alkenyl group; [0023] ring B is a C6-C10 aryl or 5- to 10-membered heteroaryl; [0024] each Ra, Rb, Rc, Rd, Re, Rf, Rg, and Rh is independently selected from the group consisting of H, deuterium, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 4- to 10-membered heterocycloalkyl, C6-C10 aryl, C1-C6 alkyl-C6-C10 aryl, and 5- to 10-membered heteroaryl; or two of Ra and Rb, or Rc and Rd, or Re and Rf, or Rg and Rh, taken together with
the atom or atoms to which they are attached, combine to form a C3 C6 cycloalkyl, 4 to 10 membered heterocycloalkyl, C6-C10 aryl, or 5- to 10-membered heteroaryl, wherein each hydrogen atom in C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 4- to 10- membered heterocycloalkyl, C6-C10 aryl, C1-C6 alkyl-C6-C10 aryl, and 5- to 10-membered heteroaryl is independently optionally substituted by deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, -OH, -OC1-C6 alkyl, -OC(O)C1-C6 alkyl, -OC(O)N(H or C1-C6 alkyl)2, -OS(O)C1- C6 alkyl, -OS(O)2C1-C6 alkyl, -OS(O)N(H or C1-C6 alkyl)2, -OS(O)2N(H or C1-C6 alkyl)2, - SC1-C6 alkyl, -S(O)C1-C6 alkyl, -S(O)2C1-C6 alkyl, -S(O)N(H or C1-C6 alkyl)2, -S(O)2N(H or C1-C6 alkyl)2, -N(H or C1-C6 alkyl)2, -N(C1-C6 alkyl)C(O)-C1-C6 alkyl, -N(C1-C6 alkyl)C(O)OC1-C6 alkyl, -N(C1-C6 alkyl)C(O)N(H or C1-C6 alkyl)2, -N(C1-C6 alkyl)S(O)C1- C6 alkyl, -N(C1-C6 alkyl)S(O)2C1-C6 alkyl, -N(C1-C6 alkyl)S(O)N(H or C1-C6 alkyl)2, -N(C1- C6 alkyl)S(O)2N(H or C1-C6 alkyl)2, -C(O)C1-C6 alkyl, -C(O)OC1-C6 alkyl, -C(O)N(H or C1- C6 alkyl)2, -P(H or C1-C6 alkyl)2, -P(O)(H or C1-C6 alkyl)2, -P(O)2(H or C1-C6 alkyl)2, - P(O)N(H or C1-C6 alkyl)2, -P(O)2N(H or C1-C6 alkyl)2, -P(O)OC1-C6 alkyl, -P(O)2OC1-C6 alkyl, -CN, or -NO2, or -Re and -Rf taken together with the carbon atom to which they are attached form an oxo groups or a C2-C6 alkenyl; [0025] n is 0, 1, 2, 3, 4, 5, 6, or 7; [0026] p is 0 or 1; and [0027] q is 0, 1, or 2. [0028] and wherein the compound is not of the formula
[0991] Steps 1 and 2 are performed in a similar manner to steps 1 and 2 for II-1-4 starting with II-1-8-1 to afford II-1-8-3. [0992] Steps 3 through 5 were performed in a similar manner to steps 2 through 4 for II-1-3 starting with II-1-8-3 to afford II-1-8. [0993] Preparation of 7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-4,5-dihydro-1H,3H- pyrrolo[2,1-c][1,4]oxazepine (II-1-9)
[0994] II-1-9 is prepared in a manner similar to II-1-5. [0995] Preparation of 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4- dihydropyrrolo[1,2-a]pyrazin-1(2H)-one (II-1-5)
[0996] Step 1. To a mixture of II-1-10-1 (1.0 eq.) at 0 °C in DMF (0.2 M) is added NaH (1.05 eq.). The reaction mixture is stirred at 0 °C for 20 min then II-1-10-1a (1.0 eq) is added. The reaction mixture is slowly warmed to ambient temperature and stirred for 5 h. The reaction is quenched with water and extracted with ethyl acetate three times. Combined extracts are dried with brine and Na2SO4, filtered, concentrated under reduced pressure. The crude product is purified by a flash chromatography (ethyl acetate/hexanes) to afford II-1-10- 2. [0997] Step 2. To a solution of II-1-10-2 (1.0 eq) in THF:MeOH:H2O (3:2:1, 0.1 M) is added LiOH (3.0 eq.). The reaction mixture is stirred at ambient temperature until complete. The reaction is acidified to pH 4 with 2M HCl solution and extracted with DCM three times. Combined extracts are dried with Na2SO4, filtered, concentrated under reduced pressure to afford crude II-1-10-3. [0998] Step 3. To a solution of II-1-10-3 (1.0 eq.) in DCM (0.2 M) is added HCl (10 eq., 4 M in dioxane). The mixture is stirred until reaction was complete then concentrated under reduced pressure to afford crude II-1-10-4. [0999] Step 4. To a solution of II-1-10-4 (1.0 eq.) in DCM (0.05 M) is added DIAD (8 eq.) and FDPP (1.5 eq.). The reaction mixture is stirred for 6 h. The reaction is quenched with 1 M Na2CO3 solution (50 eq.) and extracted with ethyl acetate three times. Combined extracts are washed with water, dried with brine and Na2SO4, filtered, concentrated under reduced pressure. The crude product is purified by a flash chromatography (ethyl acetate/hexanes) to afford II-1-10-5. [01000] II-1-10-5 is converted to II-1-10 according to step 4 for II-1-3. [01001] Preparation of 2-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4- dihydropyrrolo[1,2-a]pyrazin-1(2H)-one (II-1-11)
[01005] II-1-12 is synthesized according to step 4 for II-1-3 starting with II-1-3-2. [01006] Preparation of 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H- pyrrolo[2,1-c][1,4]oxazin-3(4H)-one (II-1-13)
[01007] Step 1. To a solution of II-1-13-1 (1.0 eq.) in THF (0.2 M) at 0 °C under N2 is added LiBH4 (3.0 eq.) and MeOH (1 eq.). The mixture is stirred at 0 °C until the reaction is
complete then quenched with H2O. The resulting mixture is extracted with EtOAc three times, and the combined extracts are washed with brine and dried over anhydrous Na2SO4. The mixture is concentrated under reduced pressure and purified by flash chromatography (ethyl acetate in hexanes) to afford II-1-13-2. [01008] Step 2. To a solution of II-1-13-2 (1.0 eq.) at 0 °C in DCM (0.2 M) is added DIPEA (3.0 eq.) and II-1-13-2a (1.2 eq.). The reaction mixture is stirred at 0 oC until the reaction is complete. The reaction is quenched with water and extracted with ethyl acetate three times. Combined extracts are dried with brine and Na2SO4, filtered, concentrated under reduced pressure. The crude product is purified by a flash chromatography (ethyl acetate/hexanes) to afford II-1-13-3. [01009] Step 3. To a solution of II-1-13-3 (1.0 eq.) in DCM (0.2 M) is added HCl (10 eq., 4 M in dioxane). The mixture is stirred until the reaction is complete then concentrated under reduced pressure to afford crude II-1-13-4. [01010] Step 4. II-1-13-4 (1.0 eq.) is resuspended in DMF (0.05 M) and K2CO3 (5 eq.) is added. The reaction mixture is stirred for 6 h. The reaction is quenched with water and extracted with ethyl acetate three times. Combined extracts are washed with water, dried with brine and Na2SO4, filtered, concentrated under reduced pressure. The crude product is purified by a flash chromatography (ethyl acetate/hexanes) to afford II-1-13-5. [01011] II-1-13-5 is converted to II-1-13 according to step 4 for II-1-3. [01012] Preparation of 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2- dihydropyrrolo[1,2-a]pyrazin-3(4H)-one (II-1-14)
[01013] Step 1. To a solution of II-1-13-2 (1.0 eq.) in DCM (0.2 M) at 0 °C is added CBr4 (1.1 eq.) and PPh3 (1.1 eq.). The reaction mixture is slowly warmed to ambient temperature and stirred for 6 h. The reaction is quenched with water and extracted with ethyl acetate three times. Combined extracts are dried with brine and Na2SO4, filtered,
concentrated under reduced pressure. The crude product is purified by a flash chromatography (ethyl acetate/hexanes) to afford II-1-14-1. [01014] Step 2. To a solution of II-1-14-1 (1.0 eq.) in DMF (0.2 M) under N2 is added NaN3 (3.0 eq.). The mixture is stirred at rt until the reaction is complete then quenched with H2O. The resulting mixture is extracted with EtOAc three times, and the combined extracts are washed with brine and dried over anhydrous Na2SO4. The mixture is concentrated under reduced pressure and purified by flash chromatography (ethyl acetate in hexanes) to afford II-1-14-2. [01015] Step 3. To a solution of II-1-14-2 (1.0 eq.) in THF (0.2 M) under N2 is added PPh3 (3.0 eq.). The mixture is stirred at rt 4 h then H2O (10 eq.) is added. The mixture is stirred overnight then quenched with water. The resulting mixture is extracted with EtOAc three times, and the combined extracts are washed with brine and dried over anhydrous Na2SO4. The mixture is concentrated under reduced pressure and purified by flash chromatography (methanol in dichloromethane) to afford II-1-14-3. [01016] Steps 4 through 6 are performed in a manner similar to steps 2 through 4 for II-1-13 starting with II-1-14-3 to afford II-1-14-6. [01017] II-1-14-6 is converted to II-1-13 according to step 4 for II-1-3. [01018] Preparation of 2-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2- dihydropyrrolo[1,2-a]pyrazin-3(4H)-one (II-1-15)
[01019] II-1-15 is prepared according to II-1-11 starting with II-1-14-6. [01020] Preparation of 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6,7,8-
[01021] Step 1. To a solution of II-1-13-1 (1.0 eq.) in THF:MeOH:H2O (3:2:1, 0.1 M) is added LiOH (3.0 eq.). The reaction mixture is stirred at ambient temperature until complete. The reaction is acidified to pH 4 with 2 M HCl solution and extracted with DCM three times. Combined extracts are dried with Na2SO4, filtered, concentrated under reduced pressure to afford crude II-1-16-1. [01022] Step 2. To a solution of II-1-16-1 (1.0 eq) and N,O-Dimethylhydroxylamine (1.1 eq.) in DCM (0.05 M) is added DIPEA (8 eq.) and FDPP (1.5 eq.). The reaction mixture is stirred for 6 h. The reaction is quenched with 1 M Na2CO3 solution (50 eq) and extracted with ethyl acetate three times. Combined extracts are washed with water, dried with brine and Na2SO4, filtered, concentrated under reduced pressure. The crude product is purified by a flash chromatography (ethyl acetate/hexanes) to afford II-1-16-2. [01023] Step 3. To a solution of II-1-16-2 (1.0 eq.) in THF (0.2 M) at -78 °C under N2 is added II-1-16-2a (1.1 eq.). The mixture is stirred at -78 °C until the reaction is complete then quenched with saturated NH4Cl solution. The resulting mixture is extracted with EtOAc three times, and the combined extracts are washed with brine and dried over anhydrous Na2SO4. The mixture is concentrated under reduced pressure and purified by flash chromatography (ethyl acetate in hexanes to afford II-1-16-3. [01024] Step 4. To a solution of II-1-16-3 (1.0 eq.) in DCM (0.2 M) is added HCl (10 eq., 4 M in dioxane). The mixture is stirred until the reaction is complete then concentrated under reduced pressure. The crude material is resuspended in EtOAc and washed with
saturated NaHCO3 solution. The organic layer is separated and washed with brine and dried over anhydrous Na2SO4. The mixture is concentrated under reduced pressure and purified by flash chromatography (ethyl acetate in hexanes) to afford II-1-16-4. [01025] Step 5. To a solution of II-1-16-4 (1.0 eq.) and PPh3 (1.05 eq.) in DCM (0.2 M) at 0 °C is added DIAD (1.05 eq.). The reaction mixture is slowly warmed to ambient temperature and stirred for 5 h. The reaction is quenched with water and extracted with ethyl acetate three times. Combined extracts are dried with brine and Na2SO4, filtered, concentrated under reduced pressure. The crude product is purified by a flash chromatography (ethyl acetate/hexanes) to afford II-1-16-5. [01026] Step 6. To a solution of II-1-16-5 (1.0 eq.) in THF (0.2 M) at 0 °C under N2 is added LiBH4 (3.0 eq.) and MeOH (1 eq.). The mixture is stirred at 0 °C until the reaction is complete then quenched with H2O. The resulting mixture is extracted with EtOAc three times, and the combined extracts are washed with brine and dried over anhydrous Na2SO4. The mixture is concentrated under reduced pressure and purified by flash chromatography (ethyl acetate in hexanes) to afford II-1-16-6. [01027] Step 7. To a solution of II-1-16-6 (1.0 eq.) at 0 °C in DCM (0.2 M) is added DIPEA (3.0 eq.) and TosCl (1.2 eq.). The reaction mixture is stirred at 0 oC until the reaction is complete. The reaction is quenched with water and extracted with ethyl acetate three times. Combined extracts are dried with brine and Na2SO4, filtered, concentrated under reduced pressure. The crude product is purified by a flash chromatography (ethyl acetate/hexanes) to afford II-1-16-7. [01028] Step 8. To a solution of II-1-16-7 (1.0 eq.) in THF (0.2 M) at 0 °C under N2 is added LAH (3.0 eq.). The mixture is stirred at 0 °C until the reaction is complete then quenched with EtOAc followed by 0.5 M HCl. The resulting mixture is extracted with EtOAc three times, and the combined extracts are washed with brine and dried over anhydrous Na2SO4. The mixture is concentrated under reduced pressure and purified by flash chromatography (ethyl acetate in hexanes) to afford II-1-16-8. [01029] II-1-16-8 is converted to II-1-16 according to step 4 for II-1-3. [01030] Preparation of (S)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6,7,8-
tetrahydroindolizin 8 ol (II 117)
[01034] Step 1. To a solution of II-1-18-1 (1.0 eq.) in DCM (0.2 M) under an atmosphere of Ar at -78 °C is added TiCl4 (1.5 eq.) and Bu3N (2.0 eq. in DCM). The reaction mixture was stirred at -78 °C for 15 min then II-1-18-1a (1.5 eq) is added. The reaction mixture is stirred at -78 °C for 1 h then quenched with water. The mixture is extracted with ethyl acetate three times. Combined extracts are dried with brine and Na2SO4, then concentrated under reduced pressure. The crude product is purified by a flash chromatography (ethyl acetate/hexanes) to afford II-1-18-2. [01035] Step 2. To a solution of II-1-18-2 (1.0 eq.) in THF (0.2 M) at 0 °C under N2 is added LAH (4.0 eq.). The mixture is stirred at 0 °C until the reaction is complete then
quenched with EtOAc followed by 0.5 M HCl. The resulting mixture is extracted with EtOAc three times, and the combined extracts are washed with brine and dried over anhydrous Na2SO4. The mixture is concentrated under reduced pressure and purified by flash chromatography (ethyl acetate in hexanes) to afford II-1-18-3. [01036] Step 3. To a solution of oxalyl chloride (10 eq.) and 3 Å MS in DCM (0.2 M) at -78 °C under N2 is added dropwise a solution of DMSO (20 eq.) in DCM. After 15 min a solution of II-1-18-3 in DCM is slowly added dropwise. After 30 min, Et3N (30 eq.) is added dropwise. The reaction is stirred 30 min at -78 °C then slowly allowed to warm to rt and stirred for 1 h. The reaction is quenched with water and extracted with ethyl acetate three times. Combined extracts are washed with water, dried with brine and Na2SO4, filtered, concentrated under reduced pressure. The crude product is purified by a flash chromatography (ethyl acetate/hexanes) to afford II-1-18-4. [01037] Step 4. To a solution of II-1-18-4 (1.0 eq.) in Toluene (0.2 M) a was added TosOH (0.05 eq.). The mixture was heated to reflux and water removed through the use of a Dean-Stark trap until reaction complete. The reaction mixture was cooled and quenched with saturated NaHCO3 solution then extracted with EtOAc three times, and the combined extracts were washed with brine and dried over anhydrous Na2SO4. Mixture was concentrated under reduced pressure and purified by flash chromatography (ethyl acetate in hexanes to afford II-1-18-5. [01038] Step 5. To a solution of II-1-18-5 (1.0 eq) in dichloromethane (0.2 M) under N2 is added N-bromosuccimide (2.1 eq.) in one portion and the reaction is stirred at ambient temperature until complete. The reaction is washed with H2O, sat. NaCl solution, dried with Na2SO4, filtered, concentrated under reduced pressure, and purified by a column chromatography (ethyl acetate/hexanes) to afford II-1-18-6. [01039] Step 6. To a solution of II-1-18-6 (1 eq) in THF at -78 °C under N2 is added dropwise a solution of n-BuLi (1.05 eq.) in hexanes. After 1 h at -78 °C the reaction is quenched with saturated NH4Cl solution at -78 °C. The mixture is warmed to rt and extracted with ethyl acetate three times. Combined extracts are dried with brine and Na2SO4, filtered, concentrated under reduced pressure. The crude product is purified by a flash chromatography (ethyl acetate/hexanes) to afford II-1-18-7. [01040] II-1-18-7 is converted to II-1-18 according to step 4 for II-1-3. [01041] Preparation of 2-(6,7-dihydro-4H-furo[3,4-c]pyran-1-yl)-4,4,5,5-tetramethyl-
1,3,2 dioxaborolane (II 119)
[01042] Step 1. To a solution of II-1-19-1 (1.0 eq.) in DCM (0.2 M) under an atmosphere of Ar at -78 oC is added LiHMDS (1.05 eq.). The reaction mixture is stirred at - 78 °C for 30 min then II-1-19-1a (1.5 eq.) is added. The reaction mixture is warmed to 0 °C and stirred until reaction is complete. The mixture is quenched with NH4Cl solution then extracted with ethyl acetate three times. Combined extracts are dried with brine and Na2SO4, then concentrated under reduced pressure. The crude product is purified by a flash chromatography (ethyl acetate/hexanes) to afford II-1-19-2. [01043] Step 2. To a solution of II-1-19-2 (1.0 eq.) in THF (0.2 M) at 0 °C under N2 is added TBAF (4.0 eq.). The mixture is stirred at 0 °C until the reaction is complete then quenched with water. The resulting mixture is extracted with EtOAc three times, and the combined extracts are washed with brine and dried over anhydrous Na2SO4. The mixture is concentrated under reduced pressure and purified by flash chromatography (ethyl acetate in hexanes to afford II-1-19-3. [01044] Step 3. To a solution of II-1-19-3 (1.0 eq.) in DMF (0.2 M) at 0 °C is added NaH (1.05 eq). The reaction is stirred at 0 °C for 30 min then heated to 60 °C until reaction is complete. The reaction is cooled and quenched with water and extracted with ethyl acetate three times. Combined extracts are washed with water, dried with brine and Na2SO4, filtered, concentrated under reduced pressure. The crude product is purified by a flash chromatography (ethyl acetate/hexanes) to afford II-1-19-4. [01045] Steps 4 through 6 are performed in a manner similar to steps 2 through 4 for II-1-18 to afford II-1-19-7. [01046] Step 7. To a solution of II-1-19-7 (1.0 eq.) in dichloromethane (0.2 M) under N2 is added N-bromosuccimide (1.0 eq.) in one portion and the reaction is stirred at ambient temperature until complete. The reaction is washed with H2O, sat. NaCl solution, dried with Na2SO4, filtered, concentrated under reduced pressure, and purified by a column
chromatography (ethyl acetate/hexanes) to afford II 1198 and II 1199. [01047] II-1-19-9 is converted to II-1-19 according to step 4 for II-1-3. [01048] Preparation of 2-(6,7-dihydro-4H-thieno[3,4-c]pyran-1-yl)-4,4,5,5- tetramethyl-1,3,2-dioxaborolane (II-1-20)
[01049] Step 1. To a solution of II-1-19-6 (1.0 eq.) in Toluene (0.1 M) is added Lawesson’s reagent (3 eq.). The reaction is heated to reflux with an open condenser until reaction complete. The reaction mixture is cooled to rt and quenched with a large quantity of saturated NaHCO3 solution. The mixture is stirred vigorously for 1 h then extracted with ethyl acetate three times. Combined extracts are dried with brine and Na2SO4, then concentrated under reduced pressure. The crude product is purified by a flash chromatography (ethyl acetate/hexanes) to afford II-1-20-1. [01050] Step 2. To a solution of II-1-20-1 (1.0 eq.) in dichloromethane (0.2 M) under N2 is added N-bromosuccimide (1.0 eq.) in one portion and the reaction is stirred at rt until complete. The reaction is washed with H2O, sat. NaCl solution, dried with Na2SO4, filtered, concentrated under reduced pressure, and purified by a column chromatography (ethyl acetate/hexanes) to afford II-1-20-2 and II-1-20-3. [01051] II-1-20-3 is converted to II-1-20 according to step 4 for II-1-3. [01052] Preparation of 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydro- 8H-imidazo[5,1-c][1,4]oxazine (II-1-21)
[01053] II-1-21 is synthesized according to the procedure of step 4 for II-1-3 starting with II-1-21-1. [01054] Preparation of 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydro-
8H imidazo[2,1 c][1,4]oxazine (II 122)
[01055] II-1-22 is synthesized according to the procedure of step 4 for II-1-3 starting with II-1-22-1. [01056] Preparation of 1-((1R,5S)-8-oxabicyclo[3.2.1]octan-3-yl)-4-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (II-1-23)
[01057] Step 1. To a solution of II-1-23-1 (1.0 eq.) at 0 °C in DCM (0.2 M) is added DIPEA (3.0 eq.) and TosCl (1.2 eq.). The reaction mixture is stirred at 0 °C until the reaction is complete. The reaction is quenched with water and extracted with ethyl acetate three times. Combined extracts are dried with brine and Na2SO4, filtered, concentrated under reduced pressure. The crude product is purified by a flash chromatography (ethyl acetate/hexanes) to afford II-1-23-2. [01058] Step 2. To a solution of 4-bromopyrazole (1.0 eq.) at 0 °C in DMF (0.2 M) is added NaH (1.05 eq.). The reaction mixture is stirred at 0 °C for 30 min then II-1-23-2 (1.0 eq) is added. The reaction mixture is heated to 110 °C and stirred for 14 h. The reaction is cooled, quenched with water and extracted with ethyl acetate three times. Combined extracts are dried with brine and Na2SO4, filtered, concentrated under reduced pressure. The crude product is purified by a flash chromatography (ethyl acetate/hexanes) to afford II-1-23-3. [01059] II-1-23-3 is converted to II-1-23 according to step 4 for II-1-3. [01060] Preparation of 1-(tetrahydro-2H-pyran-4-yl)-4-(4,4,5,5-tetramethyl-1,3,2-
dioxaborolan 2 yl) 1H pyrazole (II 124)
[01061] II-1-24 is synthesized according to step 4 for II-1-3 starting with II-1-24-1. [01062] General Method A: Preparation of 5-ethynyl-6-fluoro-4-[8-fluoro-2- {[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}-4-(8-oxa-3- azabicyclo[3.2.1]octan-3-yl)pyrido[4,3-d]pyrimidin-7-yl]naphthalen-2-ol (Ex.1)
[01063] Step 1. To a mixture of I-1-1 (457 mg, 1.81 mmol, 1 eq.) and DIPEA (1.57 g, 12.1 mmol, 6.7 eq.) in DCM (5 mL) was added I-2-1 (271 mg, 1.81 mmol, 1 eq., HCl) and
DIPEA (234 mg, 1.81 mmol, 1 eq.) dropwise at 40 C. The resulting mixture was stirred at 40 °C for 1 h. On completion, the reaction mixture was partitioned between DCM (30 mL × 3) and water (50 mL), and the combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, PE/EA =1/0 to 1/1) to provide 1-3 (430 mg, 1.31 mmol, 72.17% yield) as a yellow solid. LCMS: m/z 328.5 (M+1)+. [01064] Step 2. To a mixture of I-3-1 (430 mg, 1.31 mmol, 1 eq.) and I-4-1 (416 mg, 2.61 mmol, 2 eq.) in dioxane (17 mL) was added DIPEA (506 mg, 3.92 mmol, 3 eq.). The resulting mixture was stirred at 80 °C for 40 h. On completion, the mixture was concentrated and the residue was purified by column chromatography (SiO2, PE/THF=1/0 to 1/2) to provide I-5-1 (490 mg, 1.08 mmol, 83.00% yield) as a brown solid. LCMS: m/z 451.9 (M+1)+. [01065] Step 3. To a mixture of I-5-1 (450 mg, 0.996 mmol, 1 eq.) and I-6-1 (1.02 g, 1.99 mmol, 2 eq.) in THF (20 mL) was added tripotassium phosphate (1.5 M, 1.49 mL, 3 eq) and [2-(2-aminophenyl)phenyl]palladium(1+);bis(1-adamantyl)-butyl-phosphane; methanesulfonate (72.5 mg, 0.0996 mmol, 0.1 eq.). The resulting mixture was stirred at 60 °C for 2 h. On completion, the mixture was filtered and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, PE/THF=1:0 to 1:1) to give I-7- 1 (725 mg, 0.904 mmol, 90.78% yield) as a brown solid. LCMS: m/z 802.5 (M+1)+. [01066] Step 4: The mixture of I-7-1 (300 mg, 0.374 mmol, 1 eq.) and CsF (284 mg, 1.87 mmol, 5 eq.) in DMSO (30 mL) was stirred at 23 °C for 0.5 h. On completion, the reaction mixture was partitioned between ethyl acetate (25 mL) and brine (120 mL) and extracted with ethyl acetate (25 mL × 3). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was dissolved in DCM (4.4 mL) and HCl/dioxane (4 M, 1.70 mL, 10 eq.) was added. The resulting mixture was stirred at 23 °C for 1 h. On completion, the mixture was filtered and washed with DCM (5 mL) to provide Ex.1 HCl salt (278.65 mg, 0.463 mmol, 68% yield) as an orange solid. LC-MS: m/z 602.2 (M+1)+; 1H NMR (400 MHz, DMSO-d6) δ = 9.17 - 9.11 (m, 1H), 7.99 (dd, J = 6.0, 9.2 Hz, 1H), 7.51 - 7.41 (m, 2H), 7.26 (d, J = 2.4 Hz,1H), 5.67 - 5.49 (m, 1H), 4.67 - 4.61 (m, 2H), 4.50 (br s, 3H), 4.45 - 4.38 (m, 1H), 4.00 (d, J = 3.2 Hz, 1H), 3.87 - 3.71 (m, 5H),3.56 (s, 2H), 3.33 - 3.22 (m, 1H), 2.54 (s, 2H), 2.37 - 2.27 (m, 1H), 2.23 - 2.10 (m, 2H), 2.09 - 1.99 (m, 1H), 1.89 - 1.77 (m, 4H). [01067] Ex.1—Ex.29 are prepared using General Method A as shown below in the table with the corresponding starting materials I-1 and I-2, and reagents I-4 and I-6:
[01068] General Method B Preparation of 5-ethynyl-6-fluoro-4-[8-fluoro-4-(3-fluorophenyl)-2-{[(2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}pyrido[4,3-d]pyrimidin-7-yl]naphthalen- 2-ol (Ex.30)
[01069] Step 1. To a solution of I-1-1 (1.0 eq.) and II-1-1 (1.0 eq.) and Cs2CO3 (3 eq.) in DME/H2O (5:1, 0.2 M) under N2, is added Pd(dppf)Cl2 (0.05 eq.). The mixture is degassed and charged with nitrogen for three times, and stirred at 85 °C overnight, cooled to ambient temperature, and quenched with H2O. The resulting mixture is extracted with EtOAc for
three times. The combined extracts are washed with brine and dried over anhydrous Na2SO4. After filtration and condensation, the resulting residue is purified by silica gel chromatography to afford the desired product II-2-1. [01070] II-2-1 is converted into Ex.30 following similar reaction conditions of Step 2—Step 4 in General Method A. [01071] Ex.30—Ex.65 are prepared following the General Method B using the corresponding starting materials I-1 and II-1 and reagents I-4 and I-6 as shown in the table below:
[01073] Ex.65 is prepared with General Method A using III-1-1 to replace amine I- 2-1. To a solution of Ex.65 (1 eq.) in DCM (0.2 M) is added m-chloroperbenzoic acid (2.2 eq.) at 0 °C. The reaction mixture is stirred at ambient temperature for 16 h, quenched with addition of saturated aqueous Na2S2O3, and extracted with DCM. The combined extracts are washed with saturated aqueous NaHCO3, water and brine, and dried over sodium sulfate.
[01075] General Method D
[01088] Step 1. To a mixture of 7-chloro-8-fluoro-2-methylsulfanyl-pyrido[4,3- d]pyrimidin-4-ol (600 mg, 2.44 mmol, 1 eq) in POCl3 (8.25 g, 53.81 mmol, 22.03 eq) was added DIEA (631 mg, 4.88 mmol, 2 eq) dropwise under N2. The mixture was stirred at 90 °C for 5 hours under N2. On completion, the mixture was concentrated in vacuum. To the mixture was added EtOAc (30 mL). The residue was poured into ice (30 g) slowly. The
mixture was extracted with ethyl acetate (50 mL 2). The combined organic phase was dried over anhydrous Na2SO4, filtered and concentrated in vacuum to give 4,7-dichloro-8-fluoro-2- methylsulfanyl-pyrido[4,3-d]pyrimidine (630 mg, 97% yield) as a yellow solid. LCMS: m/z 263.6 (M+1) [01089] Step 2. A mixture of 2-(3-fluorophenyl)-4,4,5,5-tetramethyl-1,3,2- dioxaborolane (324 mg, 1.46 mmol, 1.1 eq), 4,7-dichloro-8-fluoro-2-methylsulfanyl- pyrido[4,3-d]pyrimidine (350 mg, 1.33 mmol, 1 eq), Pd(dppf)Cl2.CH2Cl2 (108 mg, 0.133 mmol, 0.1 eq) and Na2CO3 (421 mg, 3.98 mmol, 3 eq) in dioxane (10 mL) and H2O (1.5 mL) was stirred at 90 °C for 1.5 hours under N2. On completion, the mixture was concentrated in vacuum. The residue was purified by prep-TLC to give 7-chloro-8-fluoro-4-(3- fluorophenyl)-2-methylsulfanyl-pyrido[4,3-d]pyrimidine (250 mg, 58% yield) as a yellow solid. LCMS: m/z 323.6 (M+1). [01090] Step 3. A mixture of 7-chloro-8-fluoro-4-(3-fluorophenyl)-2-methylsulfanyl- pyrido[4,3-d]pyrimidine (200 mg, 0.618 mmol, 1 eq), 2-[2-fluoro-6-(methoxymethoxy)-8- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-naphthyl]ethynyl-triisopropyl-silane (500 mg, 0.976 mmol, 1.58 eq), Cs2CO3 (604 mg, 1.85 mmol, 3 eq) and ditert- butyl(cyclopentyl)phosphane;dichloropalladium;iron (40.3 mg, 0.0618 mmol, 0.1 eq) in dioxane (10 mL) and H2O (1 mL) was stirred at 90 °C for 2 hours under N2. On completion, the mixture was concentrated in vacuum. The residue was purified by prep-TLC to give 2-[2- fluoro-8-[8-fluoro-4-(3-fluorophenyl)-2-methylsulfanyl-pyrido[4,3-d]pyrimidin-7-yl]-6- (methoxymethoxy)-1-naphthyl]ethynyl-triisopropyl-silane (40 mg, 9.6% yield) as a yellow solid. LCMS: m/z 674.3 (M+1). [01091] Step 4. To a mixture of 2-[2-fluoro-8-[8-fluoro-4-(3-fluorophenyl)-2- methylsulfanyl-pyrido[4,3-d]pyrimidin-7-yl]-6-(methoxymethoxy)-1-naphthyl]ethynyl- triisopropyl-silane (40 mg, 0.0594 mmol, 1 eq) in DCM (1 mL) was added m-CPBA (12.1 mg, 0.0594 mmol, 85% purity, 1 eq) at 0 °C. The mixture was stirred at 25 °C for 0.5 hour under N2. On completion, the mixture was added DCM (10 mL). The organic phase was washed with Na2SO3 (2 mL * 2), dried with anhydrous Na2SO4, filtered and concentrated in vacuum. The residue was purified by prep-TLC to give 2-[2-fluoro-8-[8-fluoro-4-(3- fluorophenyl)-2-methylsulfonyl-pyrido[4,3-d]pyrimidin-7-yl]-6-(methoxymethoxy)-1- naphthyl]ethynyl-triisopropyl-silane (20 mg, 47% yield) as a yellow solid. LCMS: m/z 706.3 (M+1: 706.3) [01092] Step 5. A mixture of 2-[2-fluoro-8-[8-fluoro-4-(3-fluorophenyl)-2- methylsulfonyl-pyrido[4,3-d]pyrimidin-7-yl]-6-(methoxymethoxy)-1-naphthyl]ethynyl- triisopropyl-silane (20 mg, 0.0283 mmol, 1 eq), [(2R,8S)-2-fluoro-1,2,3,5,6,7-
hexahydropyrrolizin 8 yl]methanol (9.02 mg, 0.0567 mmol, 2 eq) and DIEA (11.0 mg, 0.0850 mmol, 3 eq) in dioxane (0.5 mL) was stirred at 100 °C for 12 hours. On completion, the mixture was concentrated in vacuum. The mixture was purified by prep-TLC to give 2- [2-fluoro-8-[8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]-4- (3-fluorophenyl)pyrido[4,3-d]pyrimidin-7-yl]-6-(methoxymethoxy)-1-naphthyl]ethynyl- triisopropyl-silane (12 mg, 54% yield) as a yellow solid. LCMS: m/z 785.4 (M+1). [01093] Step 6. To a mixture of 2-[2-fluoro-8-[8-fluoro-2-[[(2R,8S)-2-fluoro- 1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]-4-(3-fluorophenyl)pyrido[4,3-d]pyrimidin-7- yl]-6-(methoxymethoxy)-1-naphthyl]ethynyl-triisopropyl-silane (15 mg, 0.0191 mmol, 1 eq) in DCM (0.5 mL) was added HCl/dioxane (4 M, 0.05 mL, 10.5 eq) slowly. The mixture was stirred at 25 °C for 0.5 hour. On completion, the mixture was concentrated in vacuum to give 6-fluoro-4-[8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]-4- (3-fluorophenyl)pyrido[4,3-d]pyrimidin-7-yl]-5-(2-triisopropylsilylethynyl)naphthalen-2-ol (12 mg, 0.0162 mmol, 84.8% yield) as a yellow solid. LCMS: m/z 741.3 (M+1). [01094] Step 7. To a mixture of 6-fluoro-4-[8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7- hexahydropyrrolizin-8-yl]methoxy]-4-(3-fluorophenyl)pyrido[4,3-d]pyrimidin-7-yl]-5-(2- triisopropylsilylethynyl)naphthalen-2-ol (12 mg, 0.0162 mmol, 1 eq) in DMSO (0.5 mL) was added CsF (12.3 mg, 0.0809 mmol, 5 eq). The mixture was stirred at 25 °C for 0.5 hour. On completion, the mixture was filtered. The filtrate was purified by prep-HPLC to give Ex.30 (1.22 mg, 12% yield) as a brown solid.1H NMR (400 MHz, DMSO-d6) δ = 9.08 (s, 1H), 7.97 - 7.87 (m, 1H), 7.80 - 7.70 (m, 3H), 7.63 - 7.53 (m, 1H), 7.48 - 7.39 (m, 1H), 7.37 - 7.30 (m, 1H), 7.20 (s, 1H), 5.42 - 5.20 (m, 1H), 4.36 - 4.20 (m, 2H), 3.95 (s, 1H), 3.16 - 3.10 (m, 2H),
[01096] Step 1. To a solution of 2,4,7-trichloro-8-fluoro-pyrido[4,3-d]pyrimidine (500 mg, 1.98 mmol, 1 eq) in DCM (20 mL) was added DIEA (768 mg, 5.94 mmol, 3 eq) and cyclopentanethiol (243 mg, 2.38 mmol, 1.2 eq) at -40 °C. The mixture was stirred at -40 °C for 2 hours followed by addition of H2O (50 mL) at 25 °C, and then extracted with DCM (30 mL * 3). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography to give 2,7-dichloro-4-cyclopentylsulfanyl-8-fluoro-pyrido[4,3-d]pyrimidine (540 mg, 1.70 mmol, 85.7% yield) as a white solid.1H NMR (400 MHz, DMSO-d6) δ = 9.20 (s, 1H), 4.38 - 4.13 (m, 1H), 2.36 - 2.23 (m, 2H), 1.80 - 1.65 (m, 6H). [01097] Ex.30 were then prepared following similar reaction conditions as Step 2-6 in General Method A as a white solid.1H NMR (400 MHz, CDCl3) δ = 9.14 (s, 1H), 7.67 (dd, J = 5.6, 9.2 Hz, 1H), 7.22 (t, J = 8.8 Hz, 1H), 7.18 - 7.12 (m, 2H), 5.43 - 5.20 (m, 1H), 4.37 (s,
3H), 3.40 3.15 (m, 3H), 3.07 2.96 (m, 1H), 2.77 (s, 1H), 2.37 2.21 (m, 4H), 2.17 2.10 (m, 1H), 2.00 - 1.95 (m, 2H), 1.85 - 1.73 (m, 7H). LCMS: m/z 591.3 (M+1). [01098] Preparation of 5-ethynyl-1,6-difluoro-4-[8-fluoro-2-{[(2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}-4-(8-oxa-3-azabicyclo[3.2.1]octan-3- yl)pyrido[4,3-d]pyrimidin-7-yl]naphthalen-2-ol (Ex.73)
[01099] Ex.73 was prepared following General Method A.1H NMR (400 MHz, DMSO-d6 ) δ = 10.68 - 10.51 (m, 1H), 9.06 (s, 1H), 8.19 - 8.10 (m, 1H), 7.66 - 7.57 (m, 1H), 7.37 (d, J = 8.8 Hz, 1H), 5.44 - 5.12 (m, 1H), 4.52 - 4.41 (m, 3H), 4.29 (br d, J = 12.8 Hz, 1H), 4.18 - 4.09 (m, 1H), 4.08 - 3.99 (m, 2H), 3.77 - 3.64 (m, 3H), 3.14 - 3.00 (m, 4H), 2.90 - 2.78 (m, 2H), 2.13 (br s, 1H), 2.01 (br s, 1H), 1.86 - 1.78 (m, 5H). LCMS: m/z 620.1 (M+1). [01100] Preparation of 5-ethynyl-6-fluoro-4-(8-fluoro-2-{[(2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}-4-[(2R)-2-(methoxymethyl)morpholin- 4-yl]pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol (Ex.74)
[01101] Ex.74 was prepared following General Method A.1H NMR (400 MHz, DMSO-d6 ) δ = 10.18 (br s, 1H), 9.07 (s, 1H), 8.14 (s, 1H), 7.98 (dd, J = 5.9, 9.2 Hz, 1H), 7.46 (t, J = 9.0 Hz, 1H), 7.40 (d, J = 2.5 Hz, 1H), 7.20 (d, J = 2.3 Hz, 1H), 5.44 - 5.14 (m, 1H), 4.53 - 4.39 (m, 1H), 4.35 (br t, J = 12.6 Hz, 1H), 4.16 (dd, J = 7.2, 10.4 Hz, 1H), 4.10 - 3.92 (m, 3H), 3.87 (tdd, J = 2.4, 5.1, 10.3 Hz, 1H), 3.82 - 3.71 (m, 1H), 3.61 - 3.52 (m, 1H),
3.50 3.45 (m, 2H), 3.35 3.27 (m, 4H), 3.17 3.08 (m, 2H), 3.05 (s, 1H), 2.91 2.81 (m, 1H), 2.18 - 1.94 (m, 3H), 1.92 - 1.72 (m, 3H). LCMS: m/z 620.3 (M+1). [01102] Preparation of 5-ethynyl-6-fluoro-4-[8-fluoro-2-{[(2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}-4-(morpholin-4-yl)pyrido[4,3- d]pyrimidin-7-yl]naphthalen-2-ol (Ex.75)
[01103] Ex.75 was prepared following General Method A.1HNMR (400 MHz, DMSO-d6) δ = 10.45 - 9.78 (m, 1H), 9.12 - 9.03 (m, 1H), 8.01 - 7.93 (m, 1H), 7.50 - 7.43 (m, 1H), 7.41 - 7.37 (m, 1H), 7.22 - 7.16 (m, 1H), 5.44 - 5.15 (m, 1H), 4.17 - 4.09 (m, 1H), 4.07 - 3.97 (m, 4H), 3.96 - 3.88 (m, 2H), 3.87 - 3.77 (m, 4H), 3.13 - 3.02 (m, 3H), 2.89 - 2.77 (m, 1H), 2.19 - 1.96 (m, 3H), 1.92 - 1.69 (m, 3H). LCMS: m/z 576.0 (M+1). [01104] Preparation of 5-ethynyl-6-fluoro-4-[8-fluoro-2-{[(2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}-4-(2-oxa-5-azabicyclo[4.1.0]heptan-5- yl)pyrido[4,3-d]pyrimidin-7-yl]naphthalen-2-ol (Ex.76)
[01107] Ex.77 was prepared following General Method A.1H NMR (400 MHz, DMSO-d6 ) δ = 10.11 - 9.92 (m, 1H), 8.92 (d, J = 4.0 Hz, 1H), 7.98 (dd, J = 6.0, 8.0 Hz, 1H), 7.47 (t, J = 8.0 Hz, 1H), 7.39 (d, J = 2.4 Hz, 1H), 7.18 (d, J = 2.4 Hz, 1H), 4.17 - 4.05 (m, 3H), 4.00 (s, 2H), 3.92 - 3.85 (m, 4H), 3.82 (br d, J = 4.4 Hz, 4H), 3.68 (br dd, J = 6.0, 12.0 Hz, 1H), 3.63 - 3.57 (m, 1H), 2.87 (br s, 6H), 2.24 - 2.16 (m, 1H). LCMS: m/z 531.2 (M+1). [01108] Preparation of 5-ethynyl-6-fluoro-4-[8-fluoro-2-{[(2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}-4-(6-oxa-3-azabicyclo[3.1.1]heptan-3- yl)pyrido[4,3-d]pyrimidin-7-yl]naphthalen-2-ol (Ex.78)
[01111] Ex.79 was prepared following General Method A.1H NMR (400 MHz, DMSO-d6 ) δ = 9.15 - 9.04 (m, 1H), 8.04 - 7.92 (m, 1H), 7.54 - 7.37 (m, 2H), 7.26 - 7.18 (m, 1H), 5.38 - 5.22 (m, 1H), 4.36 - 4.24 (m, 1H), 4.42 - 4.23 (m, 1H), 4.20 - 4.02 (m, 2H), 3.95 - 3.85 (m, 1H), 3.58- 3.52 (m, 4H), 3.19 - 2.92 (m, 7H), 2.88 - 2.79 (m, 1H), 2.72 - 2.63 (m, 1H), 2.03 - 1.75 (m, 4H). LCMS: m/z 624.3 (M+1). [01112] Preparation of 4-[4-(2,9-dioxa-6-azaspiro[4.5]decan-6-yl)-8-fluoro-2- {[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}pyrido[4,3-d]pyrimidin-7- yl]-5-ethynyl-6-fluoronaphthalen-2-ol (Ex.80)
[01113] Ex.80 was prepared following General Method A.1H NMR (499 MHz, DMSO-d6 ) δ = 10.79 - 10.64 (m, 1H), 10.29 - 10.17 (m, 1H), 9.12 (d, J = 6.0 Hz, 1H), 8.00 (dd, J = 5.9, 9.2 Hz, 1H), 7.56 - 7.36 (m, 3H), 7.24 - 7.15 (m, 1H), 5.60 - 5.27 (m, 2H), 4.69 - 4.59 (m, 2H), 4.24 (br s, 1H), 4.03 (br dd, J = 2.7, 6.6 Hz, 1H), 3.93 - 3.91 (m, 2H), 3.89 -
3.86 (m, 2H), 3.80 3.72 (m, 8H), 3.10 3.06 (m, 2H), 2.75 (s, 2H), 2.19 (br d, J 7.4 Hz, 2H), 2.02 - 1.96 (m, 1H) LCMS: m/z 632.04 (M+1). [01114] Preparation of 5-ethynyl-6-fluoro-4-(8-fluoro-2-{[(2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}-4-[(1R,4R)-2-oxa-5- azabicyclo[2.2.1]heptan-5-yl]pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol (Ex.81)
[01115] Ex.80 was prepared following General Method A.1H NMR (400 MHz, DMSO-d6 ) δ = 10.41 - 9.96 (m, 1H), 9.12 (d, J = 11.2 Hz, 1H), 7.97 (dd, J = 6.0, 9.2 Hz, 1H), 7.46 (t, J = 9.2 Hz, 1H), 7.39 (d, J = 2.4 Hz, 1H), 7.20 - 7.14 (m, 1H), 5.49 - 5.38 (m, 1H), 5.36 - 5.19 (m, 1H), 4.14 (dd, J = 6.4, 10.4 Hz, 1H), 4.07 - 3.99 (m, 2H), 3.98 - 3.90 (m, 3H), 3.13 - 3.05 (m, 3H), 2.87 - 2.79 (m, 2H), 2.06 - 1.97 (m, 4H), 1.89 - 1.71 (m, 4H). LCMS: m/z 588.2 (M+1). [01116] Preparation of 5-ethynyl-6-fluoro-4-[8-fluoro-2-{[(2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}-4-(7-oxa-4-azaspiro[2.5]octan-4- yl)pyrido[4,3-d]pyrimidin-7-yl]naphthalen-2-ol (Ex.82)
[01134] Step 1. To a solution of 7-chloro-8-fluoro-2-methylsulfanyl-3H-pyrido [4,3- d]pyrimidin-4-one (1.00 g, 4.07 mmol, 1 eq) in Toluene (10 mL) was added POCl3 (1.87 g, 12.2 mmol, 1.14 mL, 3 eq) and DIEA (4.73 g, 36.6 mmol, 6 mL, 9 eq). The mixture was stirred at 110 °C for 2 h. On completion, the reaction mixture was concentrated under reduced pressure to remove POCl3. The mixture was quenched with saturated NaHCO3 (30 mL) and extracted with ethyl acetate (10 mL × 3). The combined organic phase was dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by flash silica gel chromatography to provide 4,7-dichloro-8-fluoro-2-methylsulfanyl-pyrido[4,3-
d]pyrimidine (550 mg, 2.08 mmol, 51% yield) as a yellow solid. H NMR (400 MHz, CDCl3) δ = 9.11 (s, 1H), 2.72 (s, 3H). LCMS: m/z :263.9 (M+1) [01135] Step 2. To a solution of 4,7-dichloro-8-fluoro-2-methylsulfanyl-pyrido[4,3- d]pyrimidine (300 mg, 1.14 mmol, 1 eq) in THF (1 mL) was added Pd(dppf)Cl2 (9.14 mg, 0.0125 mmol, 0.011 eq) under N2 at 0 °C followed by addition of bromo(methyl)magnesium (3 M, 0.454 mL, 1.2 eq). The mixture was stirred at 60 °C for 1 h. On completion, the reaction mixture was quenched by addition of sat. NH4Cl (10 mL) at 25 °C, and then extracted with EA (3 mL * 3). The combined organic layers were washed with Brine (5 mL * 2), dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography to provide 7-chloro-8-fluoro-4-methyl-2- methylsulfanyl-pyrido[4,3-d]pyrimidine (130 mg, 0.533 mmol, 47% yield) as a yellow solid. LCMS: m/z 243.9 (M+1) [01136] Ex.109 was obtained as an orange solid following similar procedures as general method A starting with 7-chloro-8-fluoro-4-methyl-2-methylsulfanyl-pyrido[4,3- d]pyrimidine.1H NMR (400 MHz, METHANOL-d4 ) δ = 9.41 (s, 1H), 7.93 - 7.82 (m, 1H), 7.38 (d, J = 2.4 Hz, 1H), 7.34 (t, J = 8.8 Hz, 1H), 7.22 (d, J = 2.4 Hz, 1H), 5.74 - 5.49 (m, 1H), 4.08 - 3.92 (m, 3H), 3.55 - 3.44 (m, 2H), 3.26 - 3.19 (m, 1H), 3.12 (s, 3H), 2.73 - 2.59 (m, 2H), 2.53 - 2.44 (m, 1H), 2.42 - 2.33 (m, 2H), 2.30 - 2.13 (m, 2H). LCMS: m/z 505.0 (M+1). [01137] Screen Assays [01138] HTRF KRAS mutation nucleotide exchange assays: [01139] The HTRF KRAS nucleotide exchange assays were performed at Reaction Biology. Briefly, purified GST tagged KRAS G12C, KRAS G12D, KRAS G12V, KRAS G12R, KRAS G12S, KRAS G12D/T35S or KRAS WT proteins were mixed with a-GST Tb antibody in reaction buffer (20 mM Hepes, pH 7.4, 150 mM NaCl, 5 mM MgCl2, 1 mM DTT, 0.05% BSA, 0.0025% NP40). Serial dilutions of indicated compounds were prepared in DMSO and added to the KRAS /a-GST Tb antibody mixture using acoustic dispenser (ECHO, Beckman). Compounds were incubated with KRAS/a-GST Tb antibody at room temperature for one hour. Purified SOS1 proteins and GTP-DY-647P1 mix was introduced to initiate the exchange reaction. HTRF signals were quantified 20-60 minutes later. The background subtracted signals are converted to % activity relative to DMSO controls. Data is analyzed using GraphPad Prism 4 with “sigmoidal dose-response (variable slope) equation to obtain compound IC50 values.
wherein X is a -O-, -S-, or -NR4-; Y is a bond, -O-, -S-, -S(O)-, -S(O)2-, or –C(O)NR10-; Z1 is N or C(R5); Z2 is N or C(R6); Z3 is N or C(R7); Z4 is N or C(R8); Z5 is N or C(R9); provided that at least two of Z1-Z5 are N; R1 is H, deuterium, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, or ring A, wherein each hydrogen atom in C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl is independently optionally substituted by deuterium, halogen, -Re, -Rf, C1-C6 alkyl, C1-C6 haloalkyl, -ORe, -OC(O)Re, -OC(O)NReRf, -OS(O)Re, -OS(O)2Re, -OS(O)NReRf, -OS(O)2NReRf, -SRe, -S(O)Re, -S(O)2Re, -S(O)NReRf, -S(O)2NReRf, -NReRf, -NReC(O)Rf, -NReC(O)ORf, -NReC(O)NReRf, -NReS(O)Rf, -NReS(O)2Rf, -NReS(O)NReRf, -NReS(O)2NReRf, -C(O)Re, -C(O)ORe, -C(O)NReRf, -PReRf, -P(O)ReRf, -P(O)2ReRf, -P(O)NReRf, -P(O)2NReRf, -P(O)ORe, -P(O)2ORe’, -CN, or -NO2; and when Y is a bond, -O-, –S-, or –S(O)-, then R1 is ring A; each R2 is independently deuterium, halogen, C2-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3- C6 cycloalkyl, 4- to 10-membered heterocycloalkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, -ORc, -OC(O)Rc, -OC(O)NRcRd, -OC(=NRc)NRcRd, -OS(O)Rc, -OS(O)2Rc, -OS(O)NRcRd, -OS(O)2NRcRd, -SRc, -S(O)Rc, -S(O)2Rc, -S(O)NRcRd, -S(O)2NRcRd, -NRcRd,
NR C(O)R , N(C(O)R )(C(O)R ), NR C(O)OR , NR C(O)NR R , NR C( NR )NR R , -NRcS(O)Rd, -NRcS(O)2Rd, -NRcS(O)NRcRd, -NRcS(O)2NRcRd, -C(O)Rc, -C(O)ORc, -C(O)NRcRd, -C(=NRc)NRcRd, -PRcRd, -P(O)RcRd, -P(O)2RcRd, -P(O)NRcRd, -P(O)2NRcRd, -P(O)ORc, -P(O)2ORc, -CN, or -NO2, or two of R2 taken together with the atoms to which they are attached form a C3-C6 cycloalkyl or a 4- to 10-membered heterocycloalkyl, wherein each hydrogen atom in C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, and 4- to 10-membered heterocycloalkyl is independently optionally substituted by deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, - Re, -Rf, -ORe, -OC(O)Re, -OC(O)NReRf, -OS(O)Re, -OS(O)2Re, -OS(O)NReRf, -OS(O)2NReRf, -SRe, -S(O)Re, -S(O)2Re, -S(O)NReRf, -S(O)2NReRf, -NReRf, -NReC(O)Rf, - NReC(O)ORf, -NReC(O)NReRf, -NReS(O)Rf, -NReS(O)2Rf, -NReS(O)NReRf, -NReS(O)2NReRf, -C(O)Re, -C(O)ORe, -C(O)NReRf, -PReRf, -P(O)ReRf, -P(O)2ReRf, -P(O)NReRf, -P(O)2NReRf, -P(O)ORe, -P(O)2ORe, -CN, or -NO2; R3 is -C1-C6 alkyl, -C2-C6 alkenyl, -C2-C6 alkynyl, -C3-C6 cycloalkyl, 4- to 10-membered heterocycloalkyl, -C1-C6 alkylene-(4- to 10-membered heterocycloalkyl), -C6-C10 aryl, -C1-C6 alkylene-(C6-C10 aryl), 5- to 10-membered heteroaryl, or -C1-C6 alkylene-(4- to 10-membered heterocycloalkyl), wherein each hydrogen atom in C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 4- to 10-membered heterocycloalkyl, -C1-C6 alkylene-(4- to 10-membered heterocycloalkyl), C6-C10 aryl, -C1-C6 alkylene-(C6-C10 aryl), 5- to 10-membered heteroaryl, and -C1-C6 alkylene-(5- to 10-membered heteroaryl), is independently optionally substituted by deuterium, halogen, -Re, -Rf, C1-C6 alkyl, -C1-C6 alkyl-O-C1-C6 alkyl, -OC1-C6 alkyl-O-C1- C6 alkyl, -C1-C6 alkyl-O-Ra, C6-C10 aryl, -C1-C6 alkyl-(C6-C10 aryl), haloalkyl, C3-C6 cycloalkyl, 5- to 10-membered heteroaryl, -C1-C6 alkyl-(5- to 10-membered heterocycloalkyl), -ORe, -OC(O)Re, -OC(O)NReRf, -OS(O)Re, -OS(O)2Re, -OS(O)NReRf, -OS(O)2NReRf, -SRe, -S(O)Re, -S(O)2Re, -S(O)NReRf, -S(O)2NReRf, -NReRf, -NReC(O)Rf, -NReC(O)ORf, -NReC(O)NReRf, -NReC(=NRf)NReRf, -NReS(O)Rf, -NReS(O)2Rf, -NReS(O)NReRf, -NReS(O)2NReRf, -C(O)Re, -C(O)ORe, -C(O)NReRf, -PReRf, -P(O)ReRf, -P(O)2ReRf, -P(O)NReRf, -P(O)2NReRf, -P(O)ORe, -P(O)2ORe’, -CN, or -NO2; each of R4 and R10 is independently H, deuterium, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 4- to 10-membered heterocycloalkyl, C6-C10 aryl, or 5- to 10-membered heteroaryl, wherein each hydrogen atom in C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 4- to 10-membered heterocycloalkyl, C6-C10 aryl, and 5- to 10-membered heteroaryl is independently optionally substituted by deuterium, halogen, -Re, -Rf, C1-C6 alkyl, C1-C6 haloalkyl, -ORe, -OC(O)Re, -OC(O)NReRf, -OS(O)Re, -OS(O)2Re, - OS(O)NReRf, -OS(O)2NReRf, -SRe, -S(O)Re, -S(O)2Re, -S(O)NReRf, -S(O)2NReRf, -NReRf, -
NR C(O)R, NR C(O)OR, NR C(O)NR R, NR S(O)R, NR S(O)2R, NR S(O)NR R, NReS(O)2NReRf, -C(O)Re, -C(O)ORe, -C(O)NReRf, -PReRf, -P(O)ReRf, -P(O)2ReRf, - P(O)NReRf, -P(O)2NReRf, -P(O)ORe, -P(O)2ORe’, -CN, or -NO2; or R1 and R10 taken together with the atom or atoms to which they are attached combine to form a monocyclic 4- to 10- membered heterocycloalkyl, a fused bicyclic 5- to 10-membered heterocycloalkyl, or a bridged bicyclic 6- to 10-membered heterocycloalkyl, wherein each hydrogen atom in the monocyclic 4- to 10-membered heterocycloalkyl, fused bicyclic 5- to 10-membered heterocycloalkyl, or a bridged bicyclic 6- to 10-membered heterocycloalkyl is independently optionally substituted by deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, -OH, -OC1-C6 alkyl, -OC(O)C1-C6 alkyl, -OC(O)N(H or C1-C6 alkyl)2, -OS(O)C1-C6 alkyl, -OS(O)2C1-C6 alkyl, -OS(O)N(H or C1-C6 alkyl)2, -OS(O)2N(H or C1-C6 alkyl)2, -SC1-C6 alkyl, -S(O)C1-C6 alkyl, -S(O)2C1-C6 alkyl, -S(O)N(H or C1-C6 alkyl)2, -S(O)2N(H or C1-C6 alkyl)2, -N(H or C1-C6 alkyl)2, -N(C1-C6 alkyl)C(O)-C1-C6 alkyl, -N(C1-C6 alkyl)C(O)OC1-C6 alkyl, -N(C1-C6 alkyl)C(O)N(H or C1-C6 alkyl)2, -N(C1-C6 alkyl)S(O)C1-C6 alkyl, -N(C1-C6 alkyl)S(O)2C1- C6 alkyl, -N(C1-C6 alkyl)S(O)N(H or C1-C6 alkyl)2, -N(C1-C6 alkyl)S(O)2N(H or C1-C6 alkyl)2, -C(O)C1-C6 alkyl, -C(O)OC1-C6 alkyl, -C(O)N(H or C1-C6 alkyl)2, -P(H or C1-C6 alkyl)2, -P(O)(H or C1-C6 alkyl)2, -P(O)2(H or C1-C6 alkyl)2, -P(O)N(H or C1-C6 alkyl)2, -P(O)2N(H or C1-C6 alkyl)2, -P(O)OC1-C6 alkyl, -P(O)2OC1-C6 alkyl, -CN, or -NO2, or two hydrogen atoms on a single carbon atom of the monocyclic 4- to 10-membered heterocycloalkyl, fused bicyclic 5- to 10-membered heterocycloalkyl, or bridged bicyclic 6- to 10-membered heterocycloalkyl combine to form an oxo group or an alkenyl group; each of R5, R6, R7, R8, and R9 is independently H, deuterium, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 4- to 10-membered heterocycloalkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, -ORg, -OC(O)Rg, -OC(O)NRgRh, -OS(O)Rg, -OS(O)2Rg, -SRg, -S(O)Rg, -S(O)2Rg, -S(O)NRgRh, -S(O)2NRgRh, -OS(O)NRgRh, -OS(O)2NRgRh, -NRgRh, -NRgC(O)Rh, -NRgC(O)ORh, -NRgC(O)NRgRh, -NRgS(O)Rh, -NRgS(O)2Rh, - NRgS(O)NRgRh, -NRgS(O)2NRgRh, -C(O)Rg, -C(O)ORg, -C(O)NRgRh, -PRgRh, -P(O)RgRh, - P(O)2RgRh, -P(O)NRgRh, -P(O)2NRgRh, -P(O)ORg, -P(O)2ORg, -CN, or -NO2; ring A is a C3-C8 cycloalkyl, 4- to 10-membered heterocycloalkyl, C6-C10 aryl, or 5- to 10- membered heteroaryl, wherein each of C3-C8 cycloalkyl, 4- to 10-membered heterocycloalkyl, C6-C10 aryl, or 5- to 10-membered heteroaryl is unsubstituted or substituted with one or more of R11; each R11 is independently deuterium, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3- C6 cycloalkyl, 4- to 10-membered heterocycloalkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, -ORa, -OC(O)Ra, -OC(O)NRaRb, -OC(=NRa)NRaRb, -OS(O)Ra, -OS(O)2Ra,
OS(O)NR R , OS(O)2NR R , SR , S(O)R , S(O)2R , S(O)NR R , S(O)2NR R , NR R , -NRaC(O)Rb, -N(C(O)Ra)(C(O)Rb), -NRaC(O)ORb, -NRaC(O)NRaRb, -NRaC(=NRa)NRaRb, -NRaS(O)Rb, -NRaS(O)2Rb, -NRaS(O)NRaRb, -NRaS(O)2NRaRb, -C(O)Ra, -C(O)ORa, -C(O)NRaRb, -C(=NRa)NRaRb, -PRaRb, -P(O)RaRb, -P(O)2RaRb, -P(O)NRaRb, -P(O)2NRaRb, -P(O)ORa, -P(O)2ORa, -CN, or -NO2, or two of R11 taken together with the atom or atoms to which they are attached or three of R11 taken together with the atoms to which they are attached, form a C3-C6 cycloalkyl or a 4- to 10-membered heterocycloalkyl, wherein each hydrogen atom in C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, and 4- to 10-membered heterocycloalkyl is independently optionally substituted by deuterium, halogen, -Re, -Rf, C1-C6 alkyl, C1-C6 haloalkyl, -ORe, -OC(O)Re, -OC(O)NReRf, -OS(O)Re, -OS(O)2Re, -OS(O)NReRf, -OS(O)2NReRf, -SRe, -S(O)Re, -S(O)2Re, -S(O)NReRf, -S(O)2NReRf, -NReRf, -NReC(O)Rf, -NReC(O)ORf, -NReC(O)NReRf, -NReS(O)Rf, -NReS(O)2Rf, -NReS(O)NReRf, -NReS(O)2NReRf, -C(O)Re, -C(O)ORe, -C(O)NReRf, -PReRf, -P(O)ReRf, -P(O)2ReRf, -P(O)NReRf, -P(O)2NReRf, - P(O)ORe, -P(O)2ORe, -CN, or -NO2, or two of R11 taken together with the carbon atom to which they are attached form an oxo group or an alkenyl group; ring B is a C6-C10 aryl or 5- to 10-membered heteroaryl; each Ra, Rb, Rc, Rd, Re, Rf, Rg, and Rh is independently selected from the group consisting of H, deuterium, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 4- to 10- membered heterocycloalkyl, C6-C10 aryl, C1-C6 alkyl-C6-C10 aryl, and 5- to 10-membered heteroaryl; or two of Ra and Rb, or Rc and Rd, or Re and Rf, or Rg and Rh, taken together with the atom or atoms to which they are attached, combine to form a C3-C6 cycloalkyl, 4- to 10- membered heterocycloalkyl, C6-C10 aryl, or 5- to 10-membered heteroaryl, wherein each hydrogen atom in C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 4- to 10- membered heterocycloalkyl, C6-C10 aryl, C1-C6 alkyl-C6-C10 aryl, and 5- to 10-membered heteroaryl is independently optionally substituted by deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, -OH, -OC1-C6 alkyl, -OC(O)C1-C6 alkyl, -OC(O)N(H or C1-C6 alkyl)2, -OS(O)C1- C6 alkyl, -OS(O)2C1-C6 alkyl, -OS(O)N(H or C1-C6 alkyl)2, -OS(O)2N(H or C1-C6 alkyl)2, - SC1-C6 alkyl, -S(O)C1-C6 alkyl, -S(O)2C1-C6 alkyl, -S(O)N(H or C1-C6 alkyl)2, -S(O)2N(H or C1-C6 alkyl)2, -N(H or C1-C6 alkyl)2, -N(C1-C6 alkyl)C(O)-C1-C6 alkyl, -N(C1-C6 alkyl)C(O)OC1-C6 alkyl, -N(C1-C6 alkyl)C(O)N(H or C1-C6 alkyl)2, -N(C1-C6 alkyl)S(O)C1- C6 alkyl, -N(C1-C6 alkyl)S(O)2C1-C6 alkyl, -N(C1-C6 alkyl)S(O)N(H or C1-C6 alkyl)2, -N(C1- C6 alkyl)S(O)2N(H or C1-C6 alkyl)2, -C(O)C1-C6 alkyl, -C(O)OC1-C6 alkyl, -C(O)N(H or C1- C6 alkyl)2, -P(H or C1-C6 alkyl)2, -P(O)(H or C1-C6 alkyl)2, -P(O)2(H or C1-C6 alkyl)2, - P(O)N(H or C1-C6 alkyl)2, -P(O)2N(H or C1-C6 alkyl)2, -P(O)OC1-C6 alkyl, -P(O)2OC1-C6
alkyl, CN, or NO2, or R and R taken together with the carbon atom to which they are attached form an oxo groups or an alkenyl; n is 0, 1, 2, 3, 4, 5, 6, or 7, provided that when B is C6-C10 aryl, n is 2, 3, 4, 5, 6, or 7, and when B is 5- to 10-membered heteroaryl, n is 1, 2, 3, 4, 5, 6, or 7; p is 0 or 1; and q is 0, 1, or 2; and wherein the compound is not of the formula
through a carbon atom in the 4- to 10-membered heterocycloalkyl, wherein each of C3-C8 cycloalkyl, C6-C10 aryl, 
or a pharmaceutically acceptable salt thereof. 
, wherein each hydrogen atom is independently optionally substituted by deuterium, halogen, C1-C6 alkyl, -C1-C6 alkyl-O-C1-C6 alkyl, -OC1-C6 alkyl-O-C1-C6 alkyl, C6-C10 aryl, -C1-C6 alkyl-(C6-C10 aryl), haloalkyl, C3-C6 cycloalkyl, 5- to 10-membered heteroaryl, -C1-C6 alkyl- (5- to 10-membered heterocycloalkyl), -ORe, -OC(O)Re, -OC(O)NReRf, -OS(O)Re, -OS(O)2Re, -OS(O)NReRf, -OS(O)2NReRf, -SRe, -S(O)Re, -S(O)2Re, -S(O)NReRf, -S(O)2NReRf, -NReRf, -NReC(O)Rf, -NReC(O)ORf, -NReC(O)NReRf, -NReC(=NRf)NReRf, -NReS(O)Rf, -NReS(O)2Rf, -NReS(O)NReRf, -NReS(O)2NReRf, -C(O)Re, -C(O)ORe, -C(O)NReRf, -PReRf, -P(O)ReRf, -P(O)2ReRf, -P(O)NReRf, -P(O)2NReRf, -P(O)ORe, -P(O)2ORe’, -CN, or -NO2, and “
” is a point of covalent attachment. 
wherein “ is a point of covalent attachment. 
through a carbon atom in the 4- to 10-membered heterocycloalkyl. 
through a carbon atom in the mono-cyclic 4- to 10-membered heterocycloalkyl, a fused 5- to 10-membered heterocycloalkyl, a bridged bicyclic 6- to 10-membered heterocycloalkyl, or a spiro bicyclic 6- to 10-membered heterocycloalkyl. 
through a carbon atom in the mono-cyclic 4- to 10-membered heterocycloalkyl. 
through a carbon atom in the bridged bicyclic 6- to 10-membered heterocycloalkyl. 
spiro bicyclic 6- to 10-membered heterocycloalkyl. 
wherein * is a point of covalent attachment to
and m is 0, 1, 2, 3, 4, 5, or 6. 
, , , wherein * is a point of covalent attachment to
, and m is 0, 1, 2, 3, 4, or 5. 
wherein * is a point of covalent attachment to
, , wherein * is a point of covalent attachment to
, and m is 0, 1, 2, 3, 4, 5, or 6. 
wherein * is a point of covalent attachment to
wherein * is a point of covalent attachment to , and m is 0, 1, 2, or 3.
wherein * is a point of covalent attachment to
wherein “ ” is a point of covalent attachment.