Quinoline compounds as KRAS inhibitors

Abstract

Disclosed are compounds of formula I, methods of using the compounds to inhibit KRAS activity, and pharmaceutical compositions comprising such compounds, which are useful for treating, preventing, or ameliorating diseases or disorders associated with KRAS activity, such as cancer.

Claims

[Claim 1] A compound which is 3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexane-5-yl)-2-((1R,3R,5R)-2-(cyclopropanecarbonyl)-2-azabicyclo[3.1.0]hexane-3-yl)-7-(2,3-dichlorophenyl)-6-fluoro-4-methyl-1H-pyrrolo[3,2-c]quinoline-8-yl)propanenitrile, or a pharmaceutically acceptable salt thereof. [Claim 2] The compound according to claim 1, wherein the compound is 3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexane-5-yl)-2-((1R,3R,5R)-2-(cyclopropanecarbonyl)-2-azabicyclo[3.1.0]hexane-3-yl)-7-(2,3-dichlorophenyl)-6-fluoro-4-methyl-1H-pyrrolo[3,2-c]quinoline-8-yl)propanenitrile. [Claim 3] A pharmaceutically acceptable salt of the compound according to claim 1, which is a pharmaceutically acceptable salt of 3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexane-5-yl)-2-((1R,3R,5R)-2-(cyclopropanecarbonyl)-2-azabicyclo[3.1.0]hexane-3-yl)-7-(2,3-dichlorophenyl)-6-fluoro-4-methyl-1H-pyrrolo[3,2-c]quinoline-8-yl)propanenitrile. [Claim 4] A compound which is methyl(1S,3R,5S)-3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexane-5-yl)-8-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-4-(6-(dimethylcarbamoyl)pyridine-3-yl)-6-fluoro-1H-pyrrolo[3,2-c]quinoline-2-yl)-2-azabicyclo[3.1.0]hexane-2-carboxylate, or a pharmaceutically acceptable salt thereof. [Claim 5] The compound according to claim 4, wherein the compound is methyl(1S,3R,5S)-3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexane-5-yl)-8-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-4-(6-(dimethylcarbamoyl)pyridine-3-yl)-6-fluoro-1H-pyrrolo[3,2-c]quinoline-2-yl)-2-azabicyclo[3.1.0]hexane-2-carboxylate. [Claim 6] A pharmaceutically acceptable salt of the compound according to claim 4, which is a pharmaceutically acceptable salt of methyl(1S,3R,5S)-3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexane-5-yl)-8-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-4-(6-(dimethylcarbamoyl)pyridine-3-yl)-6-fluoro-1H-pyrrolo[3,2-c]quinoline-2-yl)-2-azabicyclo[3.1.0]hexane-2-carboxylate. [Claim 7] A compound which is methyl(1R,3R,5R)-3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexane-5-yl)-8-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-4-(6-(dimethylcarbamoyl)pyridine-3-yl)-6-fluoro-1H-pyrrolo[3,2-c]quinoline-2-yl)-2-azabicyclo[3.1.0]hexane-2-carboxylate, or a pharmaceutically acceptable salt thereof. [Claim 8] The compound according to claim 7, wherein the compound is methyl(1R,3R,5R)-3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexane-5-yl)-8-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-4-(6-(dimethylcarbamoyl)pyridine-3-yl)-6-fluoro-1H-pyrrolo[3,2-c]quinoline-2-yl)-2-azabicyclo[3.1.0]hexane-2-carboxylate. [Claim 9] A pharmaceutically acceptable salt of the compound according to claim 7, which is a pharmaceutically acceptable salt of methyl(1R,3R,5R)-3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexane-5-yl)-8-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-4-(6-(dimethylcarbamoyl)pyridine-3-yl)-6-fluoro-1H-pyrrolo[3,2-c]quinoline-2-yl)-2-azabicyclo[3.1.0]hexane-2-carboxylate. [Claim 10] A compound which is 3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexane-5-yl)-7-(2,3-dichlorophenyl)-6-fluoro-4-(1-hydroxyethyl)-2-((1R,3R,5R)-2-(1-methylcyclopropane-1-carbonyl)-2-azabicyclo[3.1.0]hexane-3-yl)-1H-pyrrolo[3,2-c]quinoline-8-yl)propanenitrile, or a pharmaceutically acceptable salt thereof. [Claim 11] The compound according to claim 10, wherein the compound is 3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexane-5-yl)-7-(2,3-dichlorophenyl)-6-fluoro-4-(1-hydroxyethyl)-2-((1R,3R,5R)-2-(1-methylcyclopropane-1-carbonyl)-2-azabicyclo[3.1.0]hexane-3-yl)-1H-pyrrolo[3,2-c]quinoline-8-yl)propanenitrile. [Claim 12] A pharmaceutically acceptable salt of the compound according to claim 10, which is a pharmaceutically acceptable salt of 3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexane-5-yl)-7-(2,3-dichlorophenyl)-6-fluoro-4-(1-hydroxyethyl)-2-((1R,3R,5R)-2-(1-methylcyclopropane-1-carbonyl)-2-azabicyclo[3.1.0]hexane-3-yl)-1H-pyrrolo[3,2-c]quinoline-8-yl)propanenitrile. [Claim 13] A compound which is 3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexane-5-yl)-7-(2,3-dichlorophenyl)-6-fluoro-2-((1R,3R,5R)-2-(1-fluorocyclopropane-1-carbonyl)-2-azabicyclo[3.1.0]hexane-3-yl)-4-(1-hydroxyethyl)-1H-pyrrolo[3,2-c]quinoline-8-yl)propanenitrile, or a pharmaceutically acceptable salt thereof. [Claim 14] The compound according to claim 13, wherein the compound is 3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexane-5-yl)-7-(2,3-dichlorophenyl)-6-fluoro-2-((1R,3R,5R)-2-(1-fluorocyclopropane-1-carbonyl)-2-azabicyclo[3.1.0]hexane-3-yl)-4-(1-hydroxyethyl)-1H-pyrrolo[3,2-c]quinoline-8-yl)propanenitrile. [Claim 15] A pharmaceutically acceptable salt of the compound according to claim 13, which is a pharmaceutically acceptable salt of 3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexane-5-yl)-7-(2,3-dichlorophenyl)-6-fluoro-2-((1R,3R,5R)-2-(1-fluorocyclopropane-1-carbonyl)-2-azabicyclo[3.1.0]hexane-3-yl)-4-(1-hydroxyethyl)-1H-pyrrolo[3,2-c]quinoline-8-yl)propanenitrile. [Claim 16] A compound which is 3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexane-5-yl)-7-(2,3-dichlorophenyl)-6-fluoro-2-((1R,3R,5R)-2-(1-fluorocyclopropane-1-carbonyl)-2-azabicyclo[3.1.0]hexane-3-yl)-4-methyl-1H-pyrrolo[3,2-c]quinoline-8-yl)propanenitrile, or a pharmaceutically acceptable salt thereof. [Claim 17] The compound according to claim 16, wherein the compound is 3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexane-5-yl)-7-(2,3-dichlorophenyl)-6-fluoro-2-((1R,3R,5R)-2-(1-fluorocyclopropane-1-carbonyl)-2-azabicyclo[3.1.0]hexane-3-yl)-4-methyl-1H-pyrrolo[3,2-c]quinoline-8-yl)propanenitrile. [Claim 18] A pharmaceutically acceptable salt of the compound according to claim 16, which is a pharmaceutically acceptable salt of 3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexane-5-yl)-7-(2,3-dichlorophenyl)-6-fluoro-2-((1R,3R,5R)-2-(1-fluorocyclopropane-1-carbonyl)-2-azabicyclo[3.1.0]hexane-3-yl)-4-methyl-1H-pyrrolo[3,2-c]quinoline-8-yl)propanenitrile. [Claim 19] A pharmaceutical composition comprising the compound described in Claim 1 or a pharmaceutically acceptable salt thereof, the compound described in Claim 2 or a pharmaceutically acceptable salt of the compound described in Claim 3, and at least one pharmaceutically acceptable carrier or excipient. [Claim 20] A pharmaceutical composition comprising the compound described in claim 4 or a pharmaceutically acceptable salt thereof, the compound described in claim 5 or a pharmaceutically acceptable salt of the compound described in claim 6, and at least one pharmaceutically acceptable carrier or excipient. [Claim 21] A pharmaceutical composition comprising the compound according to claim 7 or a pharmaceutically acceptable salt thereof, the compound according to claim 8 or a pharmaceutically acceptable salt of the compound according to claim 9, and at least one pharmaceutically acceptable carrier or excipient. [Claim 22] A pharmaceutical composition comprising the compound according to claim 10 or a pharmaceutically acceptable salt thereof, the compound according to claim 11 or a pharmaceutically acceptable salt of the compound according to claim 12, and at least one pharmaceutically acceptable carrier or excipient. [Claim 23] A pharmaceutical composition comprising the compound according to claim 13 or a pharmaceutically acceptable salt thereof, the compound according to claim 14 or a pharmaceutically acceptable salt of the compound according to claim 15, and at least one pharmaceutically acceptable carrier or excipient. [Claim 24] A pharmaceutical composition comprising the compound according to claim 16 or a pharmaceutically acceptable salt thereof, the compound according to claim 17 or a pharmaceutically acceptable salt of the compound according to claim 18, and at least one pharmaceutically acceptable carrier or excipient. [Claim 25] A pharmaceutical agent for treating a disease or disorder related to the activity of KRAS, comprising a compound or a pharmaceutically acceptable salt thereof according to any one of claims 1, 4, 7, 10, 13, and 16, a compound according to any one of claims 2, 5, 8, 11, 14, and 17, or a pharmaceutically acceptable salt of a compound according to any one of claims 3, 6, 9, 12, 15, and 18. [Claim 26] A pharmaceutical agent for treating a disease or disorder related to the activity of a G12D mutation in the KRAS protein, comprising the compound or a pharmaceutically acceptable salt thereof according to any one of claims 1, 4, 7, 10, 13, and 16, the compound according to any one of claims 2, 5, 8, 11, 14, and 17, or a pharmaceutically acceptable salt of the compound according to any one of claims 3, 6, 9, 12, 15, and 18. [Claim 27] ​​The pharmaceutical product according to claim 26, wherein the disease or disorder is an immunological or inflammatory disorder. [Claim 28] The pharmaceutical product according to claim 27, wherein the immunological or inflammatory disorder is Ras-associated lymphoproliferative disorder or juvenile myelomonocytic leukemia caused by a somatic mutation of KRAS. [Claim 29] A pharmaceutical agent for treating cancer in a patient, comprising a compound or a pharmaceutically acceptable salt thereof according to any one of claims 1, 4, 7, 10, 13, and 16, a compound according to any one of claims 2, 5, 8, 11, 14, and 17, or a pharmaceutically acceptable salt of a compound according to any one of claims 3, 6, 9, 12, 15, and 18. [Claim 30] The pharmaceutical product according to claim 29, wherein the cancer is selected from carcinoma, hematological carcinoma, sarcoma, and glioblastoma. [Claim 31] The pharmaceutical product according to claim 29, wherein the cancer is a hematological cancer selected from myeloproliferative neoplasm, myelodysplastic syndrome, chronic and juvenile myelomonocytic leukemia, acute myeloid leukemia, acute lymphoblastic leukemia, and multiple myeloma. [Claim 32] The pharmaceutical product according to claim 29, wherein the cancer is a carcinoma selected from carcinomas of the pancreas, colon, lung, bladder, stomach, esophagus, breast, head and neck, cervix, skin, and thyroid. [Claim 33] The pharmaceutical product according to claim 29, wherein the cancer is characterized by a KRAS protein having a G12D mutation. [Claim 34] The pharmaceutical product according to claim 29, wherein the cancer is pancreatic cancer. [Claim 35] The pharmaceutical product according to claim 29, wherein the cancer is pancreatic ductal adenocarcinoma. [Claim 36] The pharmaceutical product according to claim 29, wherein the cancer is colorectal cancer. [Claim 37] The pharmaceutical product according to claim 29, wherein the cancer is a type of colorectal cancer. [Claim 38] The pharmaceutical product according to claim 29, wherein the cancer is lung cancer. [Claim 39] The pharmaceutical product according to claim 29, wherein the cancer is non-small cell lung cancer.

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