Claims for Patent: 10,689,377

Summary for Patent: 10,689,377

Title:	KRas G12C inhibitors
Abstract:	The present invention relates to compounds that inhibit KRas G12C. In particular, the present invention relates to compounds that irreversibly inhibit the activity of KRas G12C, pharmaceutical compositions comprising the compounds and methods of use therefor.
Inventor(s):	Blake James F., Burgess Laurence E., Chicarelli Mark Joseph, Christensen James Gail, Cook Adam, Fell Jay Bradford, Fischer John P., Marx Matthew Arnold, Mejia Macedonio J., Savechenkov Pavel, Vigers Guy P. A., Smith Christopher Ronald, Rodriguez Martha E.
Assignee:
Application Number:	US16191190
Patent Claims:	3. The compound of claim 2 , wherein Ris —C(O)C(R)C(R).4. The compound of claim 3 , wherein is a triple bond and Ris absent claim 3 , p is one and Ris hydroxyalkyl or C1-C3 alkoxy.5. The compound of claim 3 , wherein is a double bond and Ris hydrogen claim 3 , p is two and at least one Ris independently deuterium claim 3 , cyano claim 3 , halogen claim 3 , haloalkyl claim 3 , hydroxyalkyl claim 3 , heteroalkyl claim 3 , heteroaryl claim 3 , heteroarylalkyl claim 3 , —ZNRR claim 3 , —C(O)N(R) claim 3 , —NHC(O)C1-C3 alkyl claim 3 , —NHC(O)C1-C3 alkyl or heterocyclylalkyl wherein the heterocyclyl portion is substituted with one or more substituents independently selected from halogen claim 3 , hydroxyl claim 3 , alkoxy or C1-C3 alkyl.6. The compound of claim 5 , wherein the at least one Ris halogen.7. The compound of claim 5 , wherein the at least one Ris haloalkyl.8. The compound of claim 5 , wherein the at least one Ris —ZNRR.9. The compound of claim 5 , wherein the at least one Ris cyano.10. The compound of claim 5 , wherein the at least one Ris hydroxyalkyl.11. The compound of claim 5 , wherein the at least one Ris heteroalkyl.12. The compound of claim 5 , wherein the at least one Ris —C(O)N(R) claim 5 , wherein each Ris hydrogen.13. The compound of claim 5 , wherein the at least one Ris —C(O)N(R) claim 5 , wherein each Ris C1-C3 alkyl.14. The compound of claim 5 , wherein the at least one Ris heteroaryl optionally substituted with one or more R.15. The compound of claim 5 , wherein the at least one Ris heteroarylalkyl optionally substituted with one or more R.16. The compound of claim 5 , wherein the at least one Ris heterocyclylalkyl substituted with one or more R.17. The compound of claim 3 , wherein is a double bond and p is two claim 3 , each Ris hydrogen claim 3 , and Ris deuterium claim 3 , cyano claim 3 , halogen claim 3 , haloalkyl claim 3 , heteroalkyl claim 3 , —C(O)N(R) claim 3 , or hydroxyalkyl.18. The compound of claim 17 , wherein Ris halogen.19. The compound of claim 17 , wherein Ris haloalkyl.20. The compound of claim 17 , wherein Ris cyano.21. The compound of claim 17 , wherein Ris heteroalkyl.22. The compound of claim 17 , wherein Ris —C(O)N(R) claim 17 , wherein each Ris hydrogen.23. The compound of claim 17 , wherein Ris hydroxyalkyl.24. The compound of claim 2 , wherein is a double bond and p is two claim 2 , one Ris hydrogen claim 2 , the second Ris dialkylaminylalkyl claim 2 , and Ris halogen.25. The compound of claim 2 , wherein is a double bond and p is two claim 2 , each Ris deuterium claim 2 , and Ris deuterium.26. The compound of claim 2 , wherein Y is O.27. The compound of claim 2 , wherein Ris selected from the group consisting of hydroxyalkyl claim 2 , alkylaminylalkyl claim 2 , dialkylaminylalkyl claim 2 , —ZNRR claim 2 , heterocyclyl and heterocyclylalkyl claim 2 , wherein each of the Z claim 2 , heterocyclyl or heterocyclylalkyl are independently optionally substituted with R.28. The compound of claim 27 , wherein Ris heterocyclylalkyl optionally substituted with one or more R.29. The compound of claim 28 , wherein the heterocyclyl of the heterocyclylalkyl is independently azetidinyl claim 28 , methylazetidinyl claim 28 , N-ethylazetidinyl claim 28 , N-isopropylazetidinyl claim 28 , N-tert-butylazetidinyl claim 28 , fluoroazetidinyl claim 28 , difluoroazetidinyl claim 28 , cyclopropylazetidinyl claim 28 , cyclopentylazetidinyl claim 28 , tetrahydropyranylazetidinyl claim 28 , tetrahydropyranyl claim 28 , pyrrolidinyl claim 28 , methylpyrrolidinyl claim 28 , dimethylpyrrolidinyl claim 28 , (N-methyl)-2-methylpyrrolidinyl claim 28 , (N-methyl)-2-ethylpyrrolidinyl claim 28 , (N-methyl)-3 claim 28 ,3-dimethylpyrrolidinyl claim 28 , isopropylpyrrolidinyl claim 28 , N-tert-butylpyrrolidinyl claim 28 , cycloalkylalkylpyrrolidinyl claim 28 , hydroxypyrrolindinyl claim 28 , hydroxyethylpyrrolidinyl claim 28 , fluoropyrrolidinyl claim 28 , difluoropyrrolidinyl claim 28 , (N-methyl)fluoropyrrolidinyl claim 28 , (N-methyl)difluoropyrrolidinyl claim 28 , fluoroethylpyrrolidinyl claim 28 , methoxyethylpyrrolidinyl claim 28 , (N-methyl)methoxypyrrolidinyl claim 28 , piperazinyl claim 28 , dimethylaminylpyrrolidinyl claim 28 , morpholinyl claim 28 , methylmorpholinyl claim 28 , N-ethylmorpholinyl claim 28 , N-isopropylmorpholinyl claim 28 , oxetanyl claim 28 , 1 claim 28 ,4-oxazepanyl claim 28 , piperdinyl claim 28 , methylpiperidinyl acylpiperdinyl claim 28 , cyanopiperdinyl claim 28 , cycloalkylpiperdinyl claim 28 , halopiperdinyl claim 28 , dihalopiperdinyl claim 28 , fluoropiperdinyl claim 28 , difluoropiperdinyl claim 28 , alkoxypiperdinyl claim 28 , pyrrolidonyl claim 28 , methylpyrrolidonyl claim 28 , (N-methyl)-2-pyrrolidin-2-one claim 28 , (N-ethyl)-2-pyrrolidonyl claim 28 , (N-benzyl)-2-pyrrolidonyl claim 28 , hydroxy-substituted-(N-methyl)pyrrolidonyl claim 28 , piperidinonyl claim 28 , hexahydropyrrolizinyl claim 28 , thiomorpholinyl-1 claim 28 ,1-dioxide claim 28 , 3-azabicyclo[3.1.0]hexanyl claim 28 , oxa-5-azabicyclo[2.2.1]heptan-5-yl claim 28 , or azabicyclo[2.2.1]heptan-2-yl.30. The compound of claim 29 , wherein the (N-methyl)difluoropyrrolidinyl is 3 claim 29 ,3-difluoro-1-methylpyrrolidinyl.31. The compound of claim 29 , wherein the heterocyclyl is N-methylpyrrolidinyl.32. The compound of claim 27 , wherein Ris dialkylaminylalkyl optionally substituted with one or more R.33. The compound of claim 2 , wherein Ris aryl optionally substituted with one or more R.34. The compound of claim 33 , wherein the aryl is selected from the group consisting of phenyl and naphthyl optionally substituted with one or more R.35. The compound of claim 34 , wherein the phenyl and the naphthyl are each optionally substituted with one or more Rselected from the group consisting of cyano claim 34 , halogen claim 34 , hydroxyl claim 34 , C1-C6 alkyl claim 34 , hydroxyalkyl claim 34 , Q-haloalkyl claim 34 , cycloalkyl claim 34 , and alkoxy.36. The compound of claim 35 , wherein Ris selected from the group consisting of chloro claim 35 , fluoro claim 35 , bromo claim 35 , hydroxymethyl claim 35 , methyl claim 35 , ethyl claim 35 , isopropyl claim 35 , methoxy claim 35 , trifluoromethyl claim 35 , hydroxyl claim 35 , cyclopropyl and cyano.37. The compound of claim 2 , wherein Ris heteroaryl.38. The compound of claim 2 , wherein Ris aralkyl optionally substituted with one or more R.39. The compound of claim 2 , wherein m is zero.40. The compound of claim 2 , wherein L is a bond.41. The compound of claim 2 , wherein Ris heteroalkyl claim 2 , C2-C4 alkynyl claim 2 , or C1-C3alkyl optionally substituted with halogen claim 2 , —OR claim 2 , cyano or heteroaryl.42. The compound of claim 41 , wherein Ris C1-C3 alkyl optionally substituted with cyano.43. The compound of claim 41 , wherein Ris cyanomethyl.44. The compound of claim 41 , wherein X is substituted with one R.47. The compound of claim 46 , wherein Ris —C(O)C(R)C(R)and is a double bond and Ris hydrogen claim 46 , p is two and at least one Ris independently deuterium claim 46 , cyano claim 46 , halogen claim 46 , haloalkyl claim 46 , hydroxyalkyl claim 46 , heteroalkyl claim 46 , heteroaryl claim 46 , heteroarylalkyl claim 46 , —ZNRR claim 46 , —C(O)N(R) claim 46 , —NHC(O)C1-C3 alkyl claim 46 , —N(CH)C(O)C1-C3 alkyl or heterocyclylalkyl wherein the heterocyclyl portion is substituted with one or more substituents independently selected from halogen claim 46 , hydroxyl claim 46 , alkoxy and C1-C3 alkyl.48. The compound of claim 46 , wherein Ris —C(O)C(R)C(R)and is a double bond claim 46 , each Ris hydrogen claim 46 , and Ris deuterium claim 46 , cyano claim 46 , halogen claim 46 , C1-C-3 alkyl claim 46 , haloalkyl claim 46 , heteroalkyl claim 46 , —C(O)N(R) claim 46 , or hydroxyalkyl.49. A pharmaceutical composition claim 1 , comprising a therapeutically effective amount of a compound of Formula (II) according to claim 1 , and a pharmaceutically acceptable excipient.50. A method for inhibiting KRas G12C activity in a cell claim 1 , comprising contacting the cell in which inhibition of KRas G12C activity is desired with an effective amount of a compound of Formula (II) according to claim 1 , pharmaceutically acceptable salts thereof or pharmaceutical compositions containing the compound of Formula (II) claim 1 , or pharmaceutically acceptable salt thereof.51. A method for treating cancer comprising administering to a patient having cancer a therapeutically effective amount of a compound of Formula (II) or a pharmaceutically acceptable salt thereof according to claim 1 , alone or combined with a pharmaceutically acceptable carrier claim 1 , excipient or diluents claim 1 , and wherein the cancer is selected from the group consisting of Cardiac: sarcoma (angiosarcoma claim 1 , fibrosarcoma claim 1 , rhabdomyosarcoma claim 1 , liposarcoma) claim 1 , myxoma claim 1 , rhabdomyoma claim 1 , fibroma claim 1 , lipoma and teratoma; Lung: bronchogenic carcinoma (squamous cell claim 1 , undifferentiated small cell claim 1 , undifferentiated large cell claim 1 , adenocarcinoma) claim 1 , alveolar (bronchiolar) carcinoma claim 1 , bronchial adenoma claim 1 , sarcoma claim 1 , lymphoma claim 1 , chondromatous hamartoma claim 1 , mesothelioma; Gastrointestinal: esophagus (squamous cell carcinoma claim 1 , adenocarcinoma claim 1 , leiomyosarcoma claim 1 , lymphoma) claim 1 , stomach (carcinoma claim 1 , lymphoma claim 1 , leiomyosarcoma) claim 1 , pancreas (ductal adenocarcinoma claim 1 , insulinoma claim 1 , glucagonoma claim 1 , gastrinoma claim 1 , carcinoid tumors claim 1 , vipoma) claim 1 , small bowel (adenocarcinoma claim 1 , lymphoma claim 1 , carcinoid tumors claim 1 , Kaposi's sarcoma claim 1 , leiomyoma claim 1 , hemangioma claim 1 , lipoma claim 1 , neurofibroma claim 1 , fibroma) claim 1 , large bowel (adenocarcinoma claim 1 , tubular adenoma claim 1 , villous adenoma claim 1 , hamartoma claim 1 , leiomyoma); Genitourinary tract: kidney (adenocarcinoma claim 1 , Wilm's tumor (nephroblastoma) claim 1 , lymphoma claim 1 , leukemia) claim 1 , bladder and urethra (squamous cell carcinoma claim 1 , transitional cell carcinoma claim 1 , adenocarcinoma) claim 1 , prostate (adenocarcinoma claim 1 , sarcoma) claim 1 , testis (seminoma claim 1 , teratoma claim 1 , embryonal carcinoma claim 1 , teratocarcinoma claim 1 , choriocarcinoma claim 1 , sarcoma claim 1 , interstitial cell carcinoma claim 1 , fibroma claim 1 , fibroadenoma claim 1 , adenomatoid tumors claim 1 , lipoma); Liver: hepatoma (hepatocellular carcinoma) claim 1 , cholangiocarcinoma claim 1 , hepatoblastoma claim 1 , angiosarcoma claim 1 , hepatocellular adenoma claim 1 , hemangioma; Biliary tract: gall bladder carcinoma claim 1 , ampullary carcinoma claim 1 , cholangiocarcinoma; Bone: osteogenic sarcoma (osteosarcoma) claim 1 , fibrosarcoma claim 1 , malignant fibrous histiocytoma claim 1 , chondrosarcoma claim 1 , Ewing's sarcoma claim 1 , malignant lymphoma (reticulum cell sarcoma) claim 1 , multiple myeloma claim 1 , malignant giant cell tumor chordoma claim 1 , osteochronfroma (osteocartilaginous exostoses) claim 1 , benign chondroma claim 1 , chondroblastoma claim 1 , chondromyxofibroma claim 1 , osteoid osteoma and giant cell tumors; Nervous system: skull (osteoma claim 1 , hemangioma claim 1 , granuloma claim 1 , xanthoma claim 1 , osteitis deformans) claim 1 , meninges (meningioma claim 1 , meningiosarcoma claim 1 , gliomatosis) claim 1 , brain (astrocytoma claim 1 , medulloblastoma claim 1 , glioma claim 1 , ependymoma claim 1 , germinoma (pinealoma) claim 1 , glioblastoma multiform claim 1 , oligodendroglioma claim 1 , schwannoma claim 1 , retinoblastoma claim 1 , congenital tumors) claim 1 , spinal cord neurofibroma claim 1 , meningioma claim 1 , glioma claim 1 , sarcoma); Gynecological: uterus (endometrial ‘carcinoma (serous cystadenocarcinoma claim 1 , mucinous cystadenocarcinoma claim 1 , unclassified carcinoma) claim 1 , granulosa-thecal cell tumors claim 1 , Sertoli-Leydig cell tumors claim 1 , dysgerminoma claim 1 , malignant teratoma) claim 1 , vulva (squamous cell carcinoma claim 1 , intraepithelial carcinoma claim 1 , adenocarcinoma claim 1 , fibrosarcoma claim 1 , melanoma) claim 1 , vagina (clear cell carcinoma claim 1 , squamous cell carcinoma claim 1 , botryoid sarcoma (embryonal rhabdomyosarcoma) claim 1 , fallopian tubes (carcinoma); Hematologic: blood (myeloid leukemia (acute and chronic) claim 1 , acute lymphoblastic leukemia claim 1 , chronic lymphocytic leukemia claim 1 , myeloproliferative diseases claim 1 , multiple myeloma claim 1 , myelodysplastic syndrome) claim 1 , Hodgkin's disease claim 1 , non-Hodgkin's lymphoma (malignant lymphoma); Skin: malignant melanoma claim 1 , basal cell carcinoma claim 1 , squamous cell carcinoma claim 1 , Kaposi's sarcoma claim 1 , moles dysplastic nevi claim 1 , lipoma claim 1 , angioma claim 1 , dermatofibroma claim 1 , keloids claim 1 , psoriasis; and Adrenal glands: neuroblastoma.52. The method of claim 51 , wherein the therapeutically effective amount of the compound is between about 0.01 to 100 mg/kg per day.53. The method of claim 52 , wherein the therapeutically effective amount of the compound is between about 0.1 to 50 mg/kg per day.54. The method of claim 51 , wherein the cancer wherein the cancer is a KRas G12C-associated cancer.55. The method of claim 51 , wherein the cancer is non-small cell lung cancer.56. The method of claim 55 , wherein non-small cell lung cancer is a KRas G12C-associated cancer.