KRAS G12C inhibitors and methods of using the same
Provided herein are KRAS G12C inhibitors, composition of the same, and methods of using the same. These inhibitors are useful for treating a number of disorders, including pancreatic, colorectal, and lung cancers.
1. A compound having a structure of formula (I)
wherein
E 1 and E 2 are each independently N or CR 1 ;
is a single or double bond as necessary to give every atom its normal valence;
R 1 is independently H, hydroxy, —C 1-6 haloalkyl, —C 1-6 alkoxy, —NH—C 1-6 alkyl, —N(C 1-4 alkyl) 2 , cyano, or halo;
R 2 is halo, —C 1-6 alkyl, —C 1-6 haloalkyl, —N(R 2a ) 2 , —C 2-6 alkenyl, —C 2-6 alkynyl, —C 0-3 alkylene-C 3-14 cycloalkyl, —C 0-3 alkylene-C 2-14 heterocycloalkyl, aryl, heteroaryl, —C 0-3 alkylene-C 6-14 aryl, or —C 0-3 alkylene-C 2-14 heteroaryl, and each R 2a is independently H, —C 1-6 alkyl, —C 1-6 haloalkyl, —C 3-14 cycloalkyl, —C 2-14 heterocycloalkyl, —C 2-6 alkenyl, —C 2-6 alkynyl, aryl, or heteroaryl, or two R 2a substituents, together with the nitrogen atom to which they are attached, form a 3-7-membered ring;
R 3 is halo, —C 1-6 alkyl, C 3-6 cycloalkyl, —C 2-14 heterocycloalkyl, —C 2-6 alkenyl, —C 2-6 alkynyl, aryl, or heteroaryl;
R 4 is
ring A is a saturated monocyclic 4-7 membered ring or a bicyclic, bridged, fused, or spirocyclic 6-11 membered ring, wherein the ring is a carbon ring system comprising 1, 2, 3, or 4 heteroatoms independently selected from O, N, or S;
L is a bond, —C 1-6 alkylene, —O—C 0-6 alkylene, —S—C 0-6 alkylene, or —NH—C 0-6 alkylene, and for —C 2-6 alkylene, —O—C 2-6 alkylene, —S—C 2-6 alkylene, and —NH—C 2-6 alkylene, one carbon atom of the alkylene group can optionally be replaced with O, S, or NH;
R 4a is H, C 1-6 alkyl, C 2-6 alkynyl, C 1-6 alkylene-O—C 1-4 alkyl, C 1-6 alkylene-OH, C 1-6 haloalkyl, cycloalkyl, heterocycloalkyl, C 0-3 alkylene-C 3-14 cycloalkyl, C 0-3 alkylene-C 2-14 heterocycloalkyl, aryl, heteroaryl, C 0-3 alkylene-C 6-14 aryl, or selected from
R 5 and R 6 are each independently H, halo, —C 1-6 alkyl, —C 2-6 alkynyl, —C 1-6 alkylene-O—C 1-4 alkyl, —C 1-6 alkylene-OH, —C 1-6 haloalkyl, —C 1-6 alkyleneamine, —C 0-6 alkylene-amide, —C 0-3 alkylene-C(O)OH, —C 0-3 alkylene-C(O)OC 1-4 alkyl, —C 1-6 alkylene-O-aryl, —C 0-3 alkylene-C(O)C 1-4 alkylene-OH, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, —C 0-3 alkylene-C 3-14 cycloalkyl, —C 0-3 alkylene-C 2-14 heterocycloalkyl, —C 0-3 alkylene-C 6-14 aryl, —C 0-3 alkylene-C 2-14 heteroaryl, or cyano, or R 5 and R 6 , together with the atoms to which they are attached, form a 4-6 membered ring;
R 7 is H or C 1-6 alkyl, or R 7 and R 5 , together with the atoms to which they are attached, form a 4-6 membered ring;
R 8 is H, —C 0-3 alkylene-C 6-14 aryl, —C 0-3 alkylene-C 3-14 heteroaryl, —C 0-3 alkylene-C 3-14 cycloalkyl, —C 0-3 alkylene-C 2-14 heterocycloalkyl, —C 1-6 alkoxy, —O—C 0-3 alkylene-C 6-14 aryl, —O—C 0-3 alkylene-C 3-14 heteroaryl, —O—C 0-3 alkylene-C 3-14 cycloalkyl, —O—C 0-3 alkylene-C 2-14 heterocycloalkyl, —NH—C 1-8 alkyl, —N(C 1-8 alkyl) 2 , —NH—C 0-3 alkylene-C 6-14 aryl, —NH—C 0-3 alkylene-C 2-14 heteroaryl, —NH—C 0-3 alkylene-C 3-14 cycloalkyl, —NH—C 0-3 alkylene-C 2-14 heterocycloalkyl, halo, cyano, or C 1-6 alkylene-amine;
wherein the heteroaryl, spiroheterocycloalkyl and heterocycloalkyl groups of any of the R 2 , R 2a , R 3 , R 4 , R 4a , R 5 , R 6 , R 7 , and R 8 substituents have 1, 2, 3 or 4 heteroatoms independently, selected from O, N, or S, wherein the cycloalkyl, spirocycloalkyl, spiroheterocycloalkyl, and heterocycloalkyl groups may include a C═O group, and further wherein the spiroheterocycloalkyl, and heterocycloalkyl groups may include a S═O or SO 2 ;
wherein the —C 1-6 alkyl, —C 2-6 alkenyl, —C 2-6 alkynyl, and the —OC 1-6 alkyl of any of the R 2 , R 2a , R 3 , R 4 , R 4a , L, R 5 , R 6 , R 7 , and R 8 substituents is unsubstituted or substituted by 1, 2, or 3 R 9 substituents independently selected from OH, —OC 1-6 alkyl, —C 1-6 alkyl-O—C 1-6 alkyl, halo, —O-haloC 1-6 alkyl, —CN, —NR a R b , —NR a R b R c , —OSO 2 R a , —SO 2 R a , —CH 2 CH 2 OCH 3 , —(═O), —C(═O), —C(═O)R a , —OC(═O)R a , —C(═O)OR a , —C(═O)NR a R b , —O—SiR a R b R c , —SiR a R b R c , —O-(3- to 10-membered heterocycloakyl), a 6- to 12-membered aryl or heteroaryl, a 5- to 12-membered spirocycloalkyl or spiroheterocycloalkyl, a 3- to 12-membered cycloalkenyl, a 3- to 12-membered monocyclic or bicyclic cycloalkyl, or a 3- to 12-membered monocyclic or bicyclic heterocycloalkyl group, wherein the heteroaryl, spiroheterocycloalkyl, and heterocycloalkyl groups have 1, 2, 3, or 4 heteroatoms independently selected from O, N, or S, wherein the cycloalkyl, spirocycloalkyl, spiroheterocycloalkyl, and heterocycloalkyl groups may include a C═O group, and further wherein the spiroheterocycloalkyl, and heterocycloalkyl groups may include a S═O or SO 2 ;
wherein the aryl, heteroaryl, cycloalkyl, and heterocycloalkyl group of any of the R 1 , R 2 , R 2a , R 3 , R 4 , R 4a , R 5 , R 6 , R 7 , and R 8 , and R 9 substituents can be unsubstituted or substituted with 1, 2, 3, or 4 R 10 substituents independently selected from OH, halo, —NR c R d , —C 1-6 alkyl, —OC 1-6 alkyl, —C 1-6 alkyl-OH, —C 1-6 alkyl-O—C 1-6 alkyl, C 1-6 haloalkyl, —O-haloC 1-6 alkyl, —SO 2 R c , —CN, —C(═O)NR c R d , —C(═O)R c , —OC(═O)R a , —C(═O)OR c , a 6- to 12-membered aryl or heteroaryl, a 5- to 12-membered spirocycloalkyl or spiroheterocycloalkyl, a 3- to 12-membered cycloalkenyl, a 3- to 12-membered monocyclic or bicyclic cycloalkyl, or a 3- to 12-membered monocyclic or bicyclic heterocycloalkyl group, wherein the heteroaryl, spiroheterocycloalkyl, and heterocycloalkyl groups of R 10 have 1, 2, 3, or 4 heteroatoms independently selected from O, N, or S, wherein the cycloalkyl, spirocycloalkyl, and spiroheterocycloalkyl groups of R 10 or the heterocycloalkyl group of R 10 may include a C═O group, and further wherein the spiroheterocycloalkyl and heterocycloalkyl groups may include a S═O or SO 2 ;
wherein each R a , R b , R c , and R d is independently hydrogen, OH, —C 1-6 alkyl, —CH 2 CH 2 OCH 3 , phenyl, —C 1-6 alkylC(═O)OH, —C 1-6 alkylC(═O)—O—C 1-6 alkyl, —C 1-6 alkyl-3- to 12-membered cycloalkyl, —C 1-6 alkyl-3- to 12-membered heterocycloalkyl, —C 1-6 alkyl-6- to 12-membered heteroaryl, a 6- to 12-membered aryl or heteroaryl, a 3- to 12-membered monocyclic or bicyclic cycloalkyl, or a 3- to 12-membered monocyclic or bicyclic heterocycloalkyl group, wherein the heteroaryl group, heterocycloalkyl group of R a , R b , R c , and R d or the heterocycloalkyl group of the —C 1-6 alkyl-heterocycloalkyl group of R a , R b , R c , and R d has from 1, 2, 3, or 4 heteroatoms independently selected from O, N, or S, wherein the cycloalkyl and heterocycloalkyl groups of R a , R b , R c , and R d and the heterocycloalkyl group of the —C 1-6 alkyl-heterocycloalkyl groups of R a , R b , R c , and R d may include a double bond, and further wherein the cycloalkyl and heterocycloalkyl groups of R a , R b , R c , and R d and the heterocycloalkyl group of the —C 1-6 alkyl-heterocycloalkyl groups of R a , R b , R c , and R d may contain a C═O group; and
the alkyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl groups of R a , R b , R c , and R d or the heterocycloalkyl groups of the —C 1-6 alkyl-heterocycloalkyl groups of R a , R b , R c , and R d can be unsubstituted or substituted with from 1, 2, 3, or 4 R 12 substituents, wherein each R 12 is independently selected from H, OH, halo, —C 1-6 alkyl, N(CH 3 ) 2 , —C 1-6 haloalkyl, C(═O)CH 3 , —C(═O)OCH 3 , or —C 1-6 alkyl-O—C 1-6 alkyl; or
a stereoisomer thereof, an atropisomer thereof, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable salt of the stereoisomer thereof, or a pharmaceutically acceptable salt of the atropisomer thereof.
2. A compound having a structure of formula (Ia)
R 2 is aryl, wherein the aryl is unsubstituted or substituted with 1 to 4 substituents independently selected from halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, —CF 3 , —OCF 3 , —NO 2 , —CN, —NC, —OH, amino, —CO 2 H, —CO 2 C 1 -C 6 alkyl, —OCOC 1 -C 6 alkyl, —SO 2 CH 3 , C 3 -C 10 cycloalkyl, C 3 -C 10 heterocycloalkyl, C 5 -C 10 aryl, and C 5 -C 10 heteroaryl;
R 3 is halo;
R 4 is
R 8 is selected from the group consisting of
a stereoisomer thereof, an atropisomer thereof, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable salt of the stereoisomer thereof, or a pharmaceutically acceptable salt of the atropisomer thereof.
3. The compound of claim 1 wherein R 1 is H.
4. The compound of claim 1 wherein R 2 is an unsubstituted or substituted aryl.
5. The compound of claim 4 wherein R 2 is a substituted aryl.
6. The compound of claim 5 wherein R 2 is a fluorinated phenyl.
7. The compound of claim 5 wherein R 2 is
8. The compound of claim 5 wherein R 2 is
9. The compound of claim 5 wherein R 2 is
10. The compound of claim 5 wherein R 2 is
11. The compound of claim 1 wherein R 3 is halo.
12. The compound of claim 11 wherein R 3 is Cl.
13. The compound of claim 1 wherein R 4 is
14. The compound of claim 13 wherein L is a bond.
15. The compound of claim 14 wherein ring A is a monocyclic 4-7 membered ring.
16. The compound of claim 15 wherein A is an unsubstituted or substituted heterocycle.
17. The compound of claim 1 , wherein R 4 is selected from the group consisting of
18. The compound of claim 17 , wherein R 4 is
19. The compound of claim 17 , wherein R 4 is
20. The compound of claim 1 wherein R 8 is H, —C 1-6 alkyl, —C 0-3 alkylene-C 6-14 aryl, or —C 0-3 alkylene-C 3-14 heteroaryl.
21. The compound of claim 20 wherein R 8 is H.
22. The compound of claim 20 wherein R 8 is —C 6-14 aryl.
23. The compound of claim 20 wherein R 8 is —C 3-14 heteroaryl.
24. The compound of claim 1 , wherein R 8 is selected from the group consisting of i-Pr, t-Bu, phenyl, benzyl, OCH 3 , Cl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,
25. The compound of claim 24 , wherein R 8 is selected from the group consisting of
26. A compound selected from the group consisting of:
or a stereoisomer thereof, an atropisomer thereof, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable salt of the stereoisomer thereof, or a pharmaceutically acceptable salt of the atropisomer thereof.
27. A pharmaceutical composition comprising the compound of claim 1 and a pharmaceutically acceptable excipient.
28. A method of treating lung cancer, pancreatic cancer, or colorectal cancer in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of the compound of claim 1 .
29. The method of claim 28 , wherein the cancer is lung cancer.
30. The method of claim 29 , wherein the cancer is non-small cell lung cancer.
31. The method of claim 28 , wherein the cancer is pancreatic cancer.
32. The method of claim 28 , wherein the cancer is colorectal cancer.
33. A pharmaceutical composition comprising the compound of claim 26 and a pharmaceutically acceptable excipient.
34. A method of treating lung cancer, pancreatic cancer, or colorectal cancer in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of the compound of claim 26 .
35. The method of claim 34 , wherein the cancer is lung cancer.
36. The method of claim 34 , wherein the cancer is non-small cell lung cancer.
37. The method of claim 34 , wherein the cancer is pancreatic cancer.
38. The method of claim 34 , wherein the cancer is colorectal cancer.
39. A pharmaceutical composition comprising the compound of claim 2 and a pharmaceutically acceptable excipient.
40. A method of treating lung cancer, pancreatic cancer, or colorectal cancer in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of the compound of claim 2 .
41. The method of claim 40 , wherein the cancer is lung cancer.
42. The method of claim 40 , wherein the cancer is non-small cell lung cancer.
43. The method of claim 40 , wherein the cancer is pancreatic cancer.
44. The method of claim 40 , wherein the cancer is colorectal cancer.
45. The compound of claim 2 wherein R 2 is a fluorinated phenyl.
46. The compound of claim 2 wherein R 2 is
47. The compound of claim 2 wherein R 2 is
48. The compound of claim 2 wherein R 2 is
49. The compound of claim 2 wherein R 2 is
50. The compound of claim 2 wherein R 3 is F.
51. The compound of claim 2 wherein R 3 is Cl.