KRas inhibitors
The present invention provides compounds of the formula: wherein A, Z, G, R 1 , R 2 , and R 4 are as described herein, pharmaceutically acceptable salts thereof, and methods of using these compounds and pharmaceutically acceptable salts thereof for treating patients for cancer.
1 . A compound of the formula:
wherein:
A is —C(H)— or —N—;
Z is —C(R 3c )- or —N—;
G is —C(R 3b )- or —N—;
R is H;
R 2 is H, halogen, or methyl;
R 3b , and R 3c are each independently H, halogen, or methyl;
R 4 is a N-linked cyclic amine,
wherein the N-linked cyclic amine is a N-linked:
i. azetidine substituted with R 4a and R 4b ; or
ii. pyrrolidine, piperidine, piperazine, or morpholine, each of which is optionally bridged by a C 1-3 alkylene, and each of which is optionally substituted with one or more halogen; hydroxyl; —NR 6a R 6a ; (1-methylpiperidin-4-yl)oxy; C 1-3 alkoxy optionally substituted with-NR 6a R 6a ; C 1-3 alkyl optionally substituted with one or more halogen, —NR 6a R 6a or hydroxyl; an imidazole optionally substituted with a methyl; a monocyclic ring selected from azetidine, piperidine, piperazine, morpholine, oxazepane, or diazepane; a bicycle selected from hexahydro-1H-furo[3,4-c]pyrrole, octahydropyrrolo[3,4-c]pyrrole, or octahydropyrrolo[1,2-a]pyrazine; or a spirocycle selected from 4,7-diazaspiro[2.5]octane, 2-oxa-7-azaspiro[3.5] nonane, 2,6-diazaspiro[3.4]octane, or 2-azaspiro[3.3]heptane; wherein the monocyclic ring is optionally bridged by a C 1-3 alkylene, and can optionally be substituted with one or more halogen, hydroxyl, -CN, C 1-3 alkoxy, —NR 10 R 10 , cyclopropyl, oxetane, -CO-C 1-3 alkyl, or a C 1-3 alkyl optionally substituted with hydroxyl, C 1-3 alkoxy, —NR 10 R 10 , halogen, or -CF 3 ; and wherein the bicyclo or spirocyclo is each optionally substituted with a methyl or a halogen;
R 4a is NR 4 R 4d , cyclopropyl, azetidine, pyrrolidine, piperidine, piperazine, morpholine or imidazole, wherein the cyclopropyl, azetidine, pyrrolidine, piperidine, piperazine, or morpholine is optionally substituted with halogen, hydroxyl, C 1-3 alkoxy or —NR 6a R 6a ;
R 4b is H, hydroxyl, or C 1-3 alkyl;
R 4c is independently cyclopropyl or oxetane;
R 4a is independently C 1-3 alkyl;
each R 6a is independently H, trideuteromethyl, a C 3-5 cycloalkyl, a N-methyl pyrrolidine, tetrahydrofuran, tetrahydropyran, bicyclo[1.1.1]pentan-1-yl, bicyclo[1.1.1]pentan-1-ol, or a C 1-3 alkyl optionally substituted with one or more deuterium, hydroxyl, methyl, methoxy, halogen, cyclopropyl, oxetane, tetrahydrofuran, tetrahydropyran, —CO-NHMe, or -CO-NH 2 , wherein the C 3-5 cycloalkyl is optionally substituted with one or more hydroxyl or methyl;
R 10 is H or C 1-3 alkyl optionally substituted with one or more deuterium; or a pharmaceutically acceptable salt thereof.
2 . The compound according to claim 1 , wherein R 4 is a N-linked cyclic amine,
wherein the N-linked cyclic amine is a N-linked:
i. azetidine substituted with R 4a and R 4b ; or
ii. pyrrolidine, piperidine, piperazine, or morpholine; each of which is optionally bridged by a C 1-3 alkylene, and each of which is optionally substituted with one or more halogen, hydroxyl, C 1-3 alkoxy, —NR 6a R 6a , azetidine, piperazine, morpholine, a C 1-3 alkyl, or an imidazole optionally substituted with a methyl; wherein the azetidine is optionally substituted with hydroxyl or C 1-3 alkoxy; the piperazine is optionally substituted with a methyl, and the C 1-3 alkyl is optionally substituted with one or more halogen, —NR 6a R 6a or hydroxyl;
R 4a is NR 4c R 4d , cyclopropyl, azetidine, pyrrolidine, piperidine, morpholine or imidazole, wherein the cyclopropyl, azetidine, pyrrolidine, piperidine, or morpholine is optionally substituted with halogen, hydroxyl, C 1-3 alkoxy or —NR 6a R 6a ; and
each R 6a is independently H, trideuteromethyl, a C 3-5 cycloalkyl, tetrahydrofuran, tetrahydropyran, bicyclo[1.1.1]pentan-1-yl, or a C 1-3 alkyl optionally substituted with one or more hydroxyl, methyl, methoxy, halogen, cyclopropyl, oxetane, tetrahydrofuran, tetrahydropyran, -CO-NHMe, or -CO-NH 2 , wherein the C 3-5 cycloalkyl is optionally substituted with one or more hydroxyl or methyl; or a pharmaceutically acceptable salt thereof.
3 . The compound according to claim 1 , wherein R 4 is a N-linked cyclic amine,
wherein the N-linked cyclic amine is a N-linked:
i. azetidine substituted with R 4a and R 4b ; or
ii. pyrrolidine, piperidine, piperazine, or morpholine; each of which is optionally bridged by a C 1-3 alkylene, and each of which is optionally substituted with one or more halogen, hydroxyl, C 1-3 alkoxy, —NR 6a R 6a , azetidine, a C 1-3 alkyl, or an imidazole optionally substituted with a methyl; wherein the azetidine is optionally substituted with hydroxyl or C 1-3 alkoxy; and the C 1-3 alkyl is optionally substituted with halogen-NR 6a R 6a or hydroxyl; and
R 4a is NR 4c R 4d , cyclopropyl, azetidine, pyrrolidine, piperidine, morpholine or imidazole, wherein the cyclopropyl, azetidine, pyrrolidine, piperidine, or morpholine is optionally substituted with halogen, hydroxyl, C 1-3 alkoxy or —NR 6a R 6a ; and each R 6a is independently H, trideuteromethyl, a C 3-5 cycloalkyl or a C 1-3 alkyl optionally substituted with hydroxyl; or a pharmaceutically acceptable salt thereof.
4 . The compound according to claim 1 , wherein R 3b , and R 3c are each independently H or halogen, and R 4 is a N-linked cyclic amine,
wherein the N-linked cyclic amine is a N-linked:
i. azetidine substituted with R 4a and R 4b ; or
ii. pyrrolidine, piperidine, piperazine, or morpholine; each of which is optionally bridged by a C 1-3 alkylene, and each of which is optionally substituted with one or more halogen, hydroxyl, —NR 6a R 6a , imidazole or a C 1-3 alkyl; wherein the imidazole is optionally substituted with a methyl; and the C 1-3 alkyl is optionally substituted with-NR 6a R 6a or hydroxyl;
R 4a is NR 4c R 4d , cyclopropyl, azetidine, pyrrolidine, morpholine, wherein the cyclopropyl, azetidine, pyrrolidine or morpholine is optionally substituted with halogen, or —NR 6a R 6a ;
R 4b is H, or C 1-3 alkyl; and
each R 6a is independently H or C 1-3 alkyl; or a pharmaceutically acceptable salt thereof.
5 . The compound according to claim 1 , wherein G is —N-, or a pharmaceutically acceptable salt thereof.
6 . The compound according to claim 1 , wherein G is —C(R 3b )-, or a pharmaceutically acceptable salt thereof.
7 . The compound according to claim 6 , wherein R 3b is F, or a pharmaceutically acceptable salt thereof.
8 . The compound according to claim 1 , wherein Z is —N-, or a pharmaceutically acceptable salt thereof.
9 . The compound according to claim 1 , wherein Z is —C(R 3c )-, or a pharmaceutically acceptable salt thereof.
10 . The compound according to claim 9 , wherein R 3c is H or F, or a pharmaceutically acceptable salt thereof.
11 . The compound according to claim 1 , wherein R 3b , and R 3c are each independently H or halogen, or a pharmaceutically acceptable salt thereof.
12 . The compound according to claim 1 , wherein A is —N-, or a pharmaceutically acceptable salt thereof.
13 . The compound according to claim 1 , wherein A is —C(H)-, or a pharmaceutically acceptable salt thereof.
14 . The compound according to claim 1 , wherein R 2 is For Cl, or a pharmaceutically acceptable salt thereof.
15 . The compound according to claim 1 , wherein R 2 is F, or a pharmaceutically acceptable salt thereof.
16 . The compound according to claim 1 , wherein R 2 is Cl, or a pharmaceutically acceptable salt thereof.
17 . The compound according to claim 1 , wherein R 4 is selected from:
or a pharmaceutically acceptable salt thereof.
18 . The compound according to claim 1 , wherein R 4 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 . The compound of claim 1 , wherein the compound is selected from:
or a pharmaceutically acceptable salt thereof.
21 . A pharmaceutical composition comprising a compound according to claim 1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, diluent or excipient.
22 . A pharmaceutical composition comprising a compound according to claim 19 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, diluent or excipient.
23 . A pharmaceutical composition comprising a compound according to claim 20 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, diluent or excipient.
24 . A method of treating a patient for cancer, comprising administering to a patient in need thereof, an effective amount of a pharmaceutical composition according to claim 21 , wherein the cancer is selected from lung cancer, pancreatic cancer, cervical cancer, esophageal cancer, endometrial cancer, ovarian cancer, cholangiocarcinoma, and colorectal cancer.
25 . A method of treating a patient for 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, and colorectal cancer.
26 . A method of treating a patient for cancer, comprising administering to a patient in need thereof, an effective amount of a compound according to claim 19 , 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, and colorectal cancer.
27 . A method of treating a patient for cancer, comprising administering to a patient in need thereof, an effective amount of a compound according to claim 20 , 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, and colorectal cancer.
28 . The method according to claim 25 , 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.