KRAS inhibitors

1 . A compound of the formula:

wherein:

R 1 is a group of the formula

R 1a is H or a C 1-3 alkyl;

R 1b is H, C 1-3 alkyl, or cyclopropyl;

n is 0 or 1;

R 1c is a C 1-3 alkyl;

R 2 is H, halogen, or methyl;

R 3 is a group of the formula

Z is —C(R 3c )— or —N—;

R 3a , R 3b , and R 3c are each independently H, halogen, or methyl;

R 4 is a group of the formula selected from

R 5 is —NR 7 R 7a ;

p is 0 or 1;

R 5a and R 6a are each independently a C 1-3 alkyl;

R 6 is a halogen or C 1-3 alkoxy;

R 7 is H or a C 1-3 alkyl; and

R 7a is a C 1-3 alkyl or C 1-3 alkoxy-C 1-3 alkyl;

R 5 and R 5a are each independently a C 1-3 alkyl; or

R 5 and R 5a together with the nitrogen atom to which they are attached form an optionally substituted 4-, 5-, or 6-membered heterocycle optionally containing a further heteroatom selected from N, O, and S, wherein the heterocycle is optionally substituted with a C 1-3 alkyl;

or a pharmaceutically acceptable salt thereof.

2 . The compound according to claim 1 , wherein:

R 1 is a group of the formula

R 1a is H, or a C 1-3 alkyl;

R 1b is H, C 1-3 alkyl, or cyclopropyl;

n is 0, or 1;

R 1c is a C 1-3 alkyl

R 2 is H, halogen, or methyl;

R 3 is a group of the formula

Z is —C(R 3c )— or —N—;

R 3a , R 3b , and R 3c are each independently H, halogen, or methyl;

R 4 is a group of the formula

R 5 is —NR 7 R 7a ;

p is 0 or 1;

R 5a and R 6a are each independently a C 1-3 alkyl;

R 6 is a halogen;

R 7 is H or a C 1-3 alkyl; and

R 7a is a C 1-3 alkyl; or a pharmaceutically acceptable salt thereof.

3 . The compound according to claim 1 , wherein R 3 is a group of the formula

or a pharmaceutically acceptable salt thereof.

4 . The compound according to claim 1 , wherein R 3 is a group of the formula

or a pharmaceutically acceptable salt thereof.

5 . The compound according to claim 1 , wherein R 3 is a group of the formula

or a pharmaceutically acceptable salt thereof.

6 . The compound according to claim 1 , wherein R 3 is a group of the formula selected from

or a pharmaceutically acceptable salt thereof.

7 . The compound according to claim 1 , wherein R 3 is a group of the formula selected from

or a pharmaceutically acceptable salt thereof.

8 . The compound according to claim 1 , wherein R 3 is a group of the formula

or a pharmaceutically acceptable salt thereof.

9 . The compound according to claim 1 , wherein R 2 is F or Cl, or a pharmaceutically acceptable salt thereof.

10 . The compound according to claim 1 , wherein R 1 is

or a pharmaceutically acceptable salt thereof.

11 . The compound according to claim 10 , wherein R 1 is a group of the formula

or a pharmaceutically acceptable salt thereof.

12 . The compound according to claim 1 , wherein R 1a is H, or a pharmaceutically acceptable salt thereof.

13 . The compound according to claim 1 , wherein R 1b is a C 1-3 alkyl, or a pharmaceutically acceptable salt thereof.

14 . The compound according to claim 1 , wherein n is 0, or a pharmaceutically acceptable salt thereof.

15 . The compound according to claim 1 , wherein n is 1 and R 1c is a C 1-3 alkyl, or a pharmaceutically acceptable salt thereof.

16 . The compound according to claim 1 , wherein R 4 is a group of the formula selected from

or a pharmaceutically acceptable salt thereof.

17 . The compound according to claim 1 , wherein R 4 is a group of the formula selected from

or a pharmaceutically acceptable salt thereof.

18 . The compound according to claim 1 , wherein the compound is selected from

or a pharmaceutically acceptable salt thereof.

19 . The compound according to claim 1 , wherein the compound is selected from

or a pharmaceutically acceptable salt thereof.

20 . A pharmaceutical composition comprising a compound according to claim 1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, diluent or excipient.

21 . A method of treating a patient with cancer, comprising administering to a patient in need thereof, an effective amount of a pharmaceutical composition according to claim 20 , wherein the cancer is selected from lung cancer, pancreatic cancer, cervical cancer, esophageal cancer, endometrial cancer, ovarian cancer, cholangiocarcinoma, colorectal cancer, stomach adenocarcinoma, invasive ductal carcinoma, uterine carcinosarcoma, germ cell tumors, bladder cancer, small bowel adenocarcinoma, appendix cancer, and peritoneum cancer.

22 . A method of treating a patient with cancer, comprising administering to a patient in need thereof, an effective amount of a compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein the cancer is selected from lung cancer, pancreatic cancer, cervical cancer, esophageal cancer, endometrial cancer, ovarian cancer, cholangiocarcinoma, colorectal cancer, stomach adenocarcinoma, invasive ductal carcinoma, uterine carcinosarcoma, germ cell tumors, bladder cancer, small bowel adenocarcinoma, appendix cancer, and peritoneum cancer.

23 . The method according to claim 22 , wherein the patient has a cancer that was determined to have one or more cells expressing the KRAS G12V mutant protein prior to administration of the compound or a pharmaceutically acceptable salt thereof.

24 . The method according to claim 22 , wherein one or more cells express KRAS G12V mutant protein.

25 . A method of treating a patient with a cancer that has a KRAS G12V mutation comprising administering to a patient in need thereof an effective amount of a compound according to claim 1 , or a pharmaceutically acceptable salt thereof, and wherein the cancer is selected from lung cancer, pancreatic cancer, cervical cancer, esophageal cancer, endometrial cancer, ovarian cancer, cholangiocarcinoma, colorectal cancer, stomach adenocarcinoma, invasive ductal carcinoma, uterine carcinosarcoma, germ cell tumors, bladder cancer, small bowel adenocarcinoma, appendix cancer, and peritoneum cancer.

26 . The method according to claim 22 , wherein the patient is also administered an effective amount of one or more of a PD-1 inhibitor, a PD-L1 inhibitor, a CDK4/CDK6 inhibitor, an EGFR inhibitor, an ERK inhibitor, an Aurora A inhibitor, a SHP2 inhibitor, a platinum agent, and pemetrexed, or pharmaceutically acceptable salts thereof.