Azalactam compounds as HPK1 inhibitors
This invention relates to compounds of general Formula (I) and pharmaceutically acceptable salts thereof, in which R 1 , R 1a , R 2 , R 3 , R 4 , and (R 5 ) a are as defined herein, to pharmaceutical compositions comprising such compounds and pharmaceutically acceptable salts thereof, and to methods of using such compounds, pharmaceutically acceptable salts and compositions for the treatment of abnormal cell growth, including cancer.
1. A compound of Formula I
or a pharmaceutically acceptable salt thereof, wherein:
R 1 is selected from the group consisting of hydrogen, halogen, (C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, halo(C 1 -C 6 )alkoxy, —N(R 6 )(R 7 ), and (C 3 -C 6 )cycloalkyl, wherein said (C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkyl, and (C 3 -C 6 )cycloalkyl are optionally substituted with one to three substituents selected from the group consisting of halogen, hydroxy, cyano, (C 1 -C 6 )alkyl, and (C 1 -C 6 )alkoxy;
R 6 and R 7 are each independently selected from the group consisting of hydrogen and (C 1 -C 6 )alkyl, wherein said (C 1 -C 6 )alkyl is optionally substituted with 1 to 3 substituents selected from the group consisting of halogen, (C 1 -C 6 )alkoxy, cyano, and hydroxy, or R 6 and R 7 taken together with the nitrogen to which they are attached form a (4- to 8-membered)heterocycloalkyl that is optionally substituted with one to three substituents selected from the group consisting of halogen, (C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, and halo(C 1 -C 6 )alkoxy, wherein said (C 1 -C 6 )alkyl, and halo(C 1 -C 6 )alkyl are optionally substituted with one to three substituents selected from the group consisting of halogen, hydroxy, cyano, (C 1 -C 6 )alkyl, and (C 1 -C 6 )alkoxy;
R 1a is selected from the group consisting of hydrogen and halogen;
R 2 is:
i) —(CH 2 ) m N(R 8 )(R 9 ), wherein m is an integer selected from 0, 1, 2, or 3, and R 8 and R 9 are each independently selected from the group consisting of hydrogen and (C 1 -C 6 )alkyl, wherein said (C 1 -C 6 )alkyl is optionally substituted with 1 to 3 substituents selected from the group consisting of halogen, (C 1 -C 6 )alkoxy, cyano, and hydroxy, or R 8 and R 9 taken together with the nitrogen to which they are attached form a (4- to 6-membered)heterocycloalkyl that is optionally substituted with one to three substituents selected from the group consisting of halogen, hydroxy, (C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, and halo(C 1 -C 6 )alkoxy, wherein said (C 1 -C 6 )alkyl and halo(C 1 -C 6 )alkyl are optionally substituted with one to three substituents selected from the group consisting of halogen, hydroxy, cyano, and (C 1 -C 6 )alkoxy;
ii) (C 1 -C 6 )alkyl, wherein said (C 1 -C 6 )alkyl is optionally substituted with 1 to 3 substituents selected from the group consisting of halogen, (C 1 -C 6 )alkoxy, —N(R 6 )(R 7 ), cyano, and hydroxy, wherein R 6 and R 7 are each independently selected from the group consisting of hydrogen and (C 1 -C 6 )alkyl; or
iii) a (4- to 6-membered)heterocycloalkyl, wherein said heterocycloalkyl is optionally substituted with one to three substituents selected from the group consisting of halogen, hydroxy, cyano, (C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, and halo(C 1 -C 6 )alkoxy, wherein said (C 1 -C 6 )alkyl and halo(C 1 -C 6 )alkyl are optionally substituted with one to three substituents selected from the group consisting of halogen, hydroxy, cyano, and (C 1 -C 6 )alkoxy;
R 3 is selected from the group consisting of hydrogen, halogen, hydroxy, (C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, and halo(C 1 -C 6 )alkoxy;
X is carbon or nitrogen;
R 4 is a (4- to 6-membered)heterocycloalkyl or a (5- to 10-membered)heteroaryl, wherein said (4- to 6-membered)heterocycloalkyl and (5- to 10-membered)heteroaryl are optionally substituted with 1 to 3 substituents selected from the group consisting of halogen, cyano, oxo, hydroxy, —N(R 10 )(R 11 ), (C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, halo(C 1 -C 6 )alkoxy, and —(CH 2 ) n (C 3 -C 6 )cycloalkyl, wherein said (C 1 -C 6 )alkyl and halo(C 1 -C 6 )alkyl are optionally substituted with one to three substituents selected from the group consisting of halogen, hydroxy, cyano, and (C 1 -C 6 )alkoxy, and wherein n is an integer selected from 0, 1, or 2; and wherein R 10 and R 11 are each independently selected from the group consisting of hydrogen and (C 1 -C 6 )alkyl, wherein said (C 1 -C 6 )alkyl is optionally substituted with 1 to 3 substituents selected from the group consisting of halogen and hydroxy;
R 5 is selected from the group consisting of hydrogen, halogen, hydroxy, (C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, and halo(C 1 -C 6 )alkoxy; and
a is an integer selected from 0 or 1, provided that when X is nitrogen a is 0.
2. The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1 is —N(R 6 )(R 7 ), and R 6 and R 7 are each independently selected from the group consisting of hydrogen and (C 1 -C 6 )alkyl, wherein said (C 1 -C 6 )alkyl is optionally substituted with 1 to 3 halogen.
3. The compound according to claim 2 , or a pharmaceutically acceptable salt thereof, wherein R 6 and R 7 are each methyl.
4. The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1 is —N(R 6 )(R 7 ) and R 6 and R 7 taken together with the nitrogen to which they are attached form a (4- to 8-membered)heterocycloalkyl that is optionally substituted with one to three substituents selected from the group consisting of halogen, (C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, and halo(C 1 -C 6 )alkoxy.
5. The compound according to claim 4 , or a pharmaceutically acceptable salt thereof, wherein the (4- to 8-membered)heterocycloalkyl is azetidinyl optionally substituted with one to three substituents selected from the group consisting of halogen, (C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, and halo(C 1 -C 6 )alkoxy.
6. The compound according to claim 4 , or a pharmaceutically acceptable salt thereof, wherein the (4- to 8-membered)heterocycloalkyl is pyrrolidinyl optionally substituted with one to three substituents selected from the group consisting of halogen, (C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, and halo(C 1 -C 6 )alkoxy.
7. The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1 is a (C 3 -C 6 )cycloalkyl, wherein said (C 3 -C 6 )cycloalkyl is optionally substituted with one to three substituents selected from the group consisting of halogen, hydroxy, (C 1 -C 6 )alkyl, and (C 1 -C 6 )alkoxy.
8. The compound according to claim 7 , or a pharmaceutically acceptable salt thereof, wherein said (C 3 -C 6 )cycloalkyl is cyclopropyl.
9. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 3 is hydrogen.
10. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 4 is a (5- to 6-membered)heteroaryl optionally substituted with 1 to 3 substituents selected from the group consisting of halogen, cyano, hydroxy, —N(R 10 )(R 11 ), (C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, halo(C 1 -C 6 )alkoxy, and —(CH 2 ) n (C 3 -C 6 )cycloalkyl, wherein n is an integer selected from 0, 1, or 2; and wherein R 10 and R 11 are each independently selected from the group consisting of hydrogen and (C 1 -C 6 )alkyl, wherein said (C 1 -C 6 )alkyl is optionally substituted with 1 to 3 substituents selected from the group consisting of halogen and hydroxy.
11. The compound according to claim 10 , or a pharmaceutically acceptable salt thereof, wherein the (5- to 6-membered)heteroaryl is 1, 2, 3-triazolyl, 1, 2, 4-triazolyl or pyrazolyl.
12. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein X is carbon, a is 1 and R 5 is hydrogen or halogen.
13. The compound according to claim 12 , or a pharmaceutically acceptable salt thereof, wherein R 5 is halogen and the halogen is fluoro.
14. A compound of Formula II
or a pharmaceutically acceptable salt thereof, wherein:
R 1 is selected from the group consisting of hydrogen, halogen, (C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, halo(C 1 -C 6 )alkoxy, —N(R 6 )(R 7 ), and (C 3 -C 6 )cycloalkyl, wherein said (C 3 -C 6 )cycloalkyl is optionally substituted with one to three substituents selected from the group consisting of halogen, hydroxy, (C 1 -C 6 )alkyl, and (C 1 -C 6 )alkoxy;
R 6 and R 7 are each independently selected from the group consisting of hydrogen and (C 1 -C 6 )alkyl, wherein said (C 1 -C 6 )alkyl is optionally substituted with 1 to 3 substituents selected from the group consisting of halogen and hydroxy, or R 6 and R 7 taken together with the nitrogen to which they are attached form a (4- to 8-membered)heterocycloalkyl that is optionally substituted with one to three substituents selected from the group consisting of halogen, (C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, and halo(C 1 -C 6 )alkoxy;
R 2 is:
i) a —(CH 2 ) m N(R 8 )(R 9 ), wherein m is an integer selected from 0, 1, 2, or 3, and R 8 and R 9 are each independently selected from the group consisting of hydrogen and (C 1 -C 6 )alkyl, wherein said (C 1 -C 6 )alkyl is optionally substituted with 1 to 3 substituents selected from the group consisting of halogen and hydroxy, or R 8 and R 9 taken together with the nitrogen to which they are attached form a (4- to 6-membered)heterocycloalkyl that is optionally substituted with one to three substituents selected from the group consisting of halogen, (C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, and halo(C 1 -C 6 )alkoxy; or
ii) a (4- to 6-membered)heterocycloalkyl, wherein said heterocycloalkyl is optionally substituted with one to three substituents selected from the group consisting of halogen, (C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, and halo(C 1 -C 6 )alkoxy;
R 5 is selected from the group consisting of hydrogen, halogen, hydroxy, (C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, and halo(C 1 -C 6 )alkoxy; and
R 12 is selected from the group consisting of (C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkyl, and —(CH 2 ) n (C 3 -C 6 )cycloalkyl, wherein n is an integer 0 or 1.
15. The compound according to claim 14 , or a pharmaceutically acceptable salt thereof, wherein R 1 is —N(R 6 )(R 7 ), and R 6 and R 7 are each independently selected from the group consisting of hydrogen and (C 1 -C 6 )alkyl, wherein said (C 1 -C 6 )alkyl is optionally substituted with 1 to 3 halogen.
16. The compound according to claim 15 , or a pharmaceutically acceptable salt thereof, wherein R 6 and R 7 are each methyl.
17. The compound according to claim 15 , or a pharmaceutically acceptable salt thereof, wherein one of R 6 and R 7 is hydrogen and the other is methyl.
18. The compound according to claim 15 , or a pharmaceutically acceptable salt thereof, wherein one of R 6 and R 7 is methyl and the other is ethyl.
19. The compound according to claim 14 , or a pharmaceutically acceptable salt thereof, wherein R 1 is —N(R 6 )(R 7 ) and R 6 and R 7 taken together with the nitrogen to which they are attached form the (4- to 8-membered)heterocycloalkyl that is optionally substituted with one to three substituents selected from the group consisting of halogen, (C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, and halo(C 1 -C 6 )alkoxy.
20. The compound according to claim 19 , or a pharmaceutically acceptable salt thereof, wherein the (4- to 8-membered)heterocycloalkyl is azetidinyl optionally substituted with one to three substituents selected from the group consisting of halogen, (C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, and halo(C 1 -C 6 )alkoxy.
21. The compound according to claim 19 , or a pharmaceutically acceptable salt thereof, wherein the (4- to 8-membered)heterocycloalkyl is pyrrolidinyl optionally substituted with one to three substituents selected from the group consisting of halogen, (C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, and halo(C 1 -C 6 )alkoxy.
22. A compound of Formula III
or a pharmaceutically acceptable salt thereof, wherein:
R 1 is selected from the group consisting of hydrogen, halogen, (C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, halo(C 1 -C 6 )alkoxy, —N(R 6 )(R 7 ), and (C 3 -C 6 )cycloalkyl, wherein said (C 3 -C 6 )cycloalkyl is optionally substituted with one to three substituents selected from the group consisting of halogen, hydroxy, (C 1 -C 6 )alkyl, and (C 1 -C 6 )alkoxy;
R 6 and R 7 are each independently selected from the group consisting of hydrogen and (C 1 -C 6 )alkyl, wherein said (C 1 -C 6 )alkyl is optionally substituted with 1 to 3 substituents selected from the group consisting of halogen and hydroxy, or R 6 and R 7 taken together with the nitrogen to which they are attached form a (4- to 8-membered)heterocycloalkyl that is optionally substituted with one to three substituents selected from the group consisting of halogen, (C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, and halo(C 1 -C 6 )alkoxy;
R 2 is:
i) a —(CH 2 ) m N(R 8 )(R 9 ), wherein m is an integer selected from 0, 1, 2, or 3, and R 8 and R 9 are each independently selected from the group consisting of hydrogen and (C 1 -C 6 )alkyl, wherein said (C 1 -C 6 )alkyl is optionally substituted with 1 to 3 substituents selected from the group consisting of halogen and hydroxy, or R 8 and R 9 taken together with the nitrogen to which they are attached form a (4- to 6-membered)heterocycloalkyl that is optionally substituted with one to three substituents selected from the group consisting of halogen, (C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, and halo(C 1 -C 6 )alkoxy; or
ii) a (4- to 6-membered)heterocycloalkyl, wherein said heterocycloalkyl is optionally substituted with one to three substituents selected from the group consisting of halogen, (C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, and halo(C 1 -C 6 )alkoxy;
R 5 is selected from the group consisting of hydrogen, halogen, hydroxy, (C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, and halo(C 1 -C 6 )alkoxy; and
R 12 is selected from the group consisting of (C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkyl, and —(CH 2 ) n (C 3 -C 6 )cycloalkyl, wherein n is an integer 0 or 1.
23. The compound according to claim 22 , or a pharmaceutically acceptable salt thereof, wherein R 1 is —N(R 6 )(R 7 ), and R 6 and R 7 are each independently selected from the group consisting of hydrogen and (C 1 -C 6 )alkyl, wherein said (C 1 -C 6 )alkyl is optionally substituted with 1 to 3 halogen.
24. The compound according to claim 22 , or a pharmaceutically acceptable salt thereof, wherein R 1 is —N(R 6 )(R 7 ) and R 6 and R 7 taken together with the nitrogen to which they are attached form the (4- to 8-membered)heterocycloalkyl that is optionally substituted with one to three substituents selected from the group consisting of halogen, (C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, and halo(C 1 -C 6 )alkoxy.
25. The compound of claim 22 , or a pharmaceutically acceptable salt thereof, wherein R 2 is —(CH 2 ) m N(R 8 )(R 9 ), m is 1 and one of R 8 and R 9 is hydrogen and the other is methyl.
26. The compound of claim 22 , or a pharmaceutically acceptable salt thereof, wherein R 12 is (C 1 -C 6 )alkyl selected from the group consisting of ethyl, propyl, isopropyl, butyl, and tert-butyl.
27. The compound of claim 22 , or a pharmaceutically acceptable salt thereof, wherein R 12 is halo(C 1 -C 6 )alkyl selected from the group consisting of fluoromethyl, fluoroethyl, difluoromethyl, difluoroethyl, trifluoromethyl, triflourobutanyl, and trifluoropentanyl.
28. A compound of Formula I
or a pharmaceutically acceptable salt thereof, wherein:
R 1 is selected from the group consisting of hydrogen, halogen, (C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, halo(C 1 -C 6 )alkoxy, —N(R 6 )(R 7 ), and (C 3 -C 6 )cycloalkyl, wherein said (C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkyl, and (C 3 -C 6 )cycloalkyl are optionally substituted with one to three substituents selected from the group consisting of halogen, hydroxy, cyano, (C 1 -C 6 )alkyl, and (C 1 -C 6 )alkoxy;
R 6 and R 7 are each independently selected from the group consisting of hydrogen and (C 1 -C 6 )alkyl, wherein said (C 1 -C 6 )alkyl is optionally substituted with 1 to 3 substituents selected from the group consisting of halogen, (C 1 -C 6 )alkoxy, cyano, and hydroxy, or R 6 and R 7 taken together with the nitrogen to which they are attached form a (4- to 8-membered)heterocycloalkyl that is optionally substituted with one to three substituents selected from the group consisting of halogen, (C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, and halo(C 1 -C 6 )alkoxy, wherein said (C 1 -C 6 )alkyl, and halo(C 1 -C 6 )alkyl are optionally substituted with one to three substituents selected from the group consisting of halogen, hydroxy, cyano, (C 1 -C 6 )alkyl, and (C 1 -C 6 )alkoxy;
R 1a is H;
R 2 is CH 2 N(R 8 )(R 9 ), wherein R 8 and R 9 are each independently selected from the group consisting of hydrogen and (C 1 -C 6 )alkyl, wherein said (C 1 -C 6 )alkyl is optionally substituted with 1 to 3 substituents selected from the group consisting of halogen, (C 1 -C 6 )alkoxy, cyano, and hydroxy, or R 8 and R 9 taken together with the nitrogen to which they are attached form a (4- to 6-membered)heterocycloalkyl that is optionally substituted with one to three substituents selected from the group consisting of halogen, hydroxy, (C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, and halo(C 1 -C 6 )alkoxy, wherein said (C 1 -C 6 )alkyl and halo(C 1 -C 6 )alkyl are optionally substituted with one to three substituents selected from the group consisting of halogen, hydroxy, cyano, and (C 1 -C 6 )alkoxy; and
R 3 is H;
X is carbon;
R 5 is hydrogen;
a is 1; and
R 4 is a (4- to 6-membered)heterocycloalkyl or a (5- to 10-membered)heteroaryl, wherein said (4- to 6-membered)heterocycloalkyl and (5- to 10-membered)heteroaryl are optionally substituted with 1 to 3 substituents selected from the group consisting of halogen, cyano, oxo, hydroxy, —N(R 10 )(R 11 ), (C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, halo(C 1 -C 6 )alkoxy, and —(CH 2 ) n (C 3 -C 6 )cycloalkyl, wherein said (C 1 -C 6 )alkyl and halo(C 1 -C 6 )alkyl are optionally substituted with one to three substituents selected from the group consisting of halogen, hydroxy, cyano, and (C 1 -C 6 )alkoxy, and wherein n is an integer selected from 0, 1, or 2; and wherein R 10 and R 11 are each independently selected from the group consisting of hydrogen and (C 1 -C 6 )alkyl, wherein said (C 1 -C 6 )alkyl is optionally substituted with 1 to 3 substituents selected from the group consisting of halogen and hydroxy.
29. The compound of claim 28 , or a pharmaceutically acceptable salt thereof, wherein:
R 1 is selected from the group consisting of (C 1 -C 4 )alkyl, CF 3 , —N(R 6 )(R 7 ), and (C 3 -C 4 )cycloalkyl, wherein said (C 3 -C 4 )cycloalkyl is optionally substituted with one CH 3 ;
R 6 and R 7 are each independently selected from the group consisting of hydrogen and (C 1 -C 3 )alkyl, or
R 6 and R 7 taken together with the nitrogen to which they are attached form the (4- to 5-membered)heterocycloalkyl that is optionally substituted with one to two CH 3 substituents;
R 2 is CH 2 N(R 8 )(R 9 ), wherein R 8 is hydrogen and R 9 is selected from the group consisting of hydrogen and CH 3 ; and
R 4 is a (5-membered)heterocycloalkyl or a (5-membered)heteroaryl, wherein said (5-membered)heterocycloalkyl is 1,3-oxazolidin-3-yl and said (5-membered)heteroaryl is 1H-pyrazolyl or triazolyl, each optionally substituted with 1 to 2 substituents selected from the group consisting of oxo, (C 1 -C 5 )alkyl, halo(C 1 -C 5 )alkyl, and —CH 2 -cyclopropyl.
30. The compound of claim 28 , or a pharmaceutically acceptable salt thereof, wherein:
R 1 is selected from the group consisting of (C 1 -C 4 )alkyl, CF 3 , —N(R 6 )(R 7 ), and (C 3 -C 4 )cycloalkyl, wherein said (C 3 -C 4 )cycloalkyl is optionally substituted with one CH 3 ;
R 6 and R 7 are each independently selected from the group consisting of hydrogen and (C 1 -C 3 )alkyl, or
R 6 and R 7 taken together with the nitrogen to which they are attached form the (4- to 5-membered)heterocycloalkyl that is optionally substituted with one to two CH 3 substituents;
R 2 is CH 2 N(R 8 )(R 9 ), wherein R 8 is hydrogen and R 9 is selected from the group consisting of hydrogen and CH 3 ; and
R 4 is a (5-membered)heterocycloalkyl or a (5-membered)heteroaryl, wherein said (5-membered)heterocycloalkyl is 2-oxo-1,3-oxazolidin-3-yl, optionally substituted with 1 CH 3 , CH 2 F, CHF 2 , or CF 3 , and said (5-membered)heteroaryl is 1H-pyrazolyl or triazolyl, optionally substituted with 1 to 2 substituents selected from the group consisting of (C 1 -C 5 )alkyl, halo(C 1 -C 5 )alkyl, and —CH 2 -cyclopropyl.
31. The compound of claim 28 , or a pharmaceutically acceptable salt thereof, wherein:
R 1 is selected from the group consisting of —N(R 6 )(R 7 ), and (C 3 -C 4 )cycloalkyl, wherein said (C 3 -C 4 )cycloalkyl is optionally substituted with one CH 3 ;
R 6 and R 7 are each independently selected from the group consisting of hydrogen and (C 1 -C 3 )alkyl, or
R 6 and R 7 taken together with the nitrogen to which they are attached form a (4- to 5-membered)heterocycloalkyl that is optionally substituted with one to two substituents selected from the group consisting of CH 3 , or halo(C 1 )alkyl;
R 2 is —CH 2 N(R 8 )(R 9 ), wherein R 8 and R 9 are each independently selected from the group consisting of hydrogen and CH 3 ; and
R 4 is a (5-membered)heterocycloalkyl or a (5-membered)heteroaryl, wherein said (5-membered)heterocycloalkyl is 2-oxo-1,3-oxazolidin-3-yl, optionally substituted with 1 substituent selected from the group consisting of CH 3 , CHF 2 , and CH 2 F, and said (5-membered)heteroaryl is imidazolyl, 1H-pyrazolyl, thiadiazolyl, or triazolyl, optionally substituted with 1 to 2 substituents independently selected from the group consisting of (C 1 -C 5 )alkyl, halo(C 1 -C 6 )alkyl, and —(C 4 -C 5 )cycloalkyl, wherein said (C 1 -C 5 )alkyl is optionally substituted with one hydroxy.
32. The compound of claim 28 , or a pharmaceutically acceptable salt thereof, wherein:
R 1 is —N(R 6 )(R 7 );
R 6 and R 7 are each independently selected from the group consisting of hydrogen and (C 1 -C 3 )alkyl, or
R 6 and R 7 taken together with the nitrogen to which they are attached form pyrrolidin-1-yl, optionally substituted with 1 to 2 CH 3 ;
R 2 is —CH 2 N(R 8 )(R 9 ), wherein R 8 and R 9 are each independently selected from the group consisting of hydrogen and CH 3 ; and
R 4 is triazol-3-yl, substituted with 1 to 2 substituents independently selected from the group consisting of CH 3 , CH 3 —CH 2 —, and CH 3 —CH 2 —CH 2 —.
33. A compound or pharmaceutically acceptable salt thereof, wherein the compound is selected from the group consisting of
4-[(methylamino)methyl]-6-[methyl(propan-2-yl)amino]-2-[6-(4-propyl-4H-1,2,4-triazol-3-yl)pyridin-2-yl]-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one;
4-[(methylamino)methyl]-6-[(2R)-2-methylpyrrolidin-1-yl]-2-[6-(4-propyl-4H-1,2,4-triazol-3-yl)pyridin-2-yl]-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one;
4-[(methylamino)methyl]-2-[6-(5-methyl-4-propyl-4H-1,2,4-triazol-3-yl)pyridin-2-yl]-6-[(2R)-2-methylpyrrolidin-1-yl]-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one;
4-[(methylamino)methyl]-6-[methyl(propan-2-yl)amino]-2-[6-(5-methyl-4-propyl-4H-1,2,4-triazol-3-yl)pyridin-2-yl]-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one; and
4-(aminomethyl)-2-[6-(4-ethyl-5-methyl-4H-1,2,4-triazol-3-yl)pyridin-2-yl]-6-[(2S)-2-methylpyrrolidin-1-yl]-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one.
34. The compound of claim 33 , or pharmaceutically acceptable salt thereof, wherein the compound is 4-[(methylamino)methyl]-6-[methyl(propan-2-yl)amino]-2-[6-(4-propyl-4H-1,2,4-triazol-3-yl)pyridin-2-yl]-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one.
35. The compound of claim 33 , or pharmaceutically acceptable salt thereof, wherein the compound is 4-[(methylamino)methyl]-6-[(2R)-2-methylpyrrolidin-1-yl]-2-[6-(4-propyl-4H-1,2,4-triazol-3-yl)pyridin-2-yl]-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one.
36. The compound of claim 33 , or pharmaceutically acceptable salt thereof, wherein the compound is 4-[(methylamino)methyl]-2-[6-(5-methyl-4-propyl-4H-1,2,4-triazol-3-yl)pyridin-2-yl]-6-[(2R)-2-methylpyrrolidin-1-yl]-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one.
37. The compound of claim 33 , or pharmaceutically acceptable salt thereof, wherein the compound is 4-[(methylamino)methyl]-6-[methyl(propan-2-yl)amino]-2-[6-(5-methyl-4-propyl-4H-1,2,4-triazol-3-yl)pyridin-2-yl]-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one.
38. The compound of claim 33 , or pharmaceutically acceptable salt thereof, wherein the compound is 4-(aminomethyl)-2-[6-(4-ethyl-5-methyl-4H-1,2,4-triazol-3-yl)pyridin-2-yl]-6-[(2S)-2-methylpyrrolidin-1-yl]-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one.
39. A pharmaceutical composition comprising a compound of claim 1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient.
40. A method for reversing, alleviating, or inhibiting abnormal cell growth in a mammal, comprising administering to the mammal a therapeutically effective amount of a compound of claim 1 , or a pharmaceutically acceptable salt thereof.