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):	James F. Blake, Laurence E. Burgess, Mark Joseph Chicarelli, James Gail Christensen, Adam Cook, Jay Bradford Fell, John P. Fischer, Matthew Arnold Marx, Macedonio J. Mejia, Pavel Savechenkov, Guy P. A. Vigers, Christopher Ronald Smith, Martha E. Rodriguez
Assignee:	Array Biopharma Inc , Mirati Therapeutics Inc
Application Number:	US16/191,190
Patent Claims:	1. A compound of formula (II): or a pharmaceutically acceptable salt thereof: wherein: X is selected from the group consisting of a piperazine, a bridged piperazine, a 7-membered spirocyclic ring and a diazepane, wherein X is optionally substituted with one or more R8; Y is a bond, O, S or NR5; R1 is —C(O)C(RA)C(RB)p or —SO2C(RA)C(RB)p; R2 is hydrogen, alkyl, hydroxyalkyl, dihydroxyalkyl, alkylaminylalkyl, dialkylaminylalkyl, —Z—NR5R10, heterocyclyl, heterocyclylalkyl, aryl, heteroaryl, or heteroarylalkyl, wherein each of the Z, heterocyclyl, heterocyclylalkyl, aryl, heteroaryl, and heteroarylalkyl may be optionally substituted with one or more R9; each Z is C1-C4 alkylene; each R3 is independently C1-C3 alkyl, oxo, haloalkyl, hydroxyl or halogen; L is a bond, —C(O)—, or C1-C3 alkylene; R4 is hydrogen, cycloalkyl, heterocyclyl, aryl, aralkyl or heteroaryl, wherein each of the cycloalkyl, heterocyclyl, aryl, aralkyl and heteroaryl may be optionally substituted with one or more R6, R7 or R8; each R5 is independently hydrogen or C1-C3 alkyl; R6 is cycloalkyl, heterocyclyl, heterocyclylalkyl, aryl, or heteroaryl, wherein each of the cycloalkyl, heterocyclyl, aryl, or heteroaryl may be optionally substituted with one or more R7; each R7 is independently halogen, hydroxyl, C1-C6 alkyl, cycloalkyl, alkoxy, haloalkyl, amino, cyano, heteroalkyl, hydroxyalkyl or Q-haloalkyl, wherein Q is O or S; R8 is oxo, C1-C3 alkyl, C2-C4 alkynyl, heteroalkyl, cyano, —C(O)OR5, —C(O)N(R5)2, —N(R5)2, wherein the C1-C3 alkyl may be optionally substituted with cyano, halogen, —OR5, —N(R5)2, or heteroaryl; each R9 is independently hydrogen, oxo, acyl, hydroxyl, hydroxyalkyl, cyano, halogen, C1-C6 alkyl, aralkyl, haloalkyl, heteroalkyl, cycloalkyl, heterocyclyl, heterocyclylalkyl, alkoxy, dialkylaminyl, dialkylamidoalkyl, or dialkylaminylalkyl, wherein the C1-C6 alkyl may be optionally substituted with cycloalkyl; each R10 is independently hydrogen, acyl, C1-C3 alkyl, heteroalkyl or hydroxyalkyl; R11 is haloalkyl; RA is absent, hydrogen, deuterium, cyano, halogen, C1-C-3 alkyl, haloalkyl, heteroalkyl, —C(O)N(R5)2, or hydroxyalkyl; each RB is independently hydrogen, deuterium, cyano, C1-C3 alkyl, hydroxyalkyl, heteroalkyl, C1-C3 alkoxy, halogen, haloalkyl, —ZNR5R11, —C(O)N(R5)2, —NHC(O)C1-C3 alkyl, —CH2NHC(O)C1-C3 alkyl, -CH2N(CH3)C(O)C1-C3 alkyl, heteroaryl, heteroarylalkyl, dialkylaminylalkyl, or heterocyclylalkyl wherein the heterocyclyl portion is substituted with one or more substituents independently selected from halogen, hydroxyl, alkoxy and C1-C3 alkyl, wherein the heteroaryl or the heteroaryl portion of the heteroarylalkyl is optionally substituted with one or more R7; or when is a double bond and p is two, one RB is hydrogen and RA and one RB and the carbon atoms to which they are attached form a 4-8 membered partially saturated cycloalkyl substituted with oxo; m is zero or an integer between 1 and 2; p is one or two; and wherein, when is a triple bond then RA is absent, p equals one and RB is hydroxyalkyl, or when is a double bond then RA is present, RB is present and p equals two, wherein when RA is hydrogen or C1-C3 alkyl, at least one RB is deuterium, cyano, halogen, haloalkyl, hydroxyalkyl, heteroalkyl, heteroaryl, heteroarylalkyl, —ZNR5R11, —C(O)N(R5)2, —NHC(O)C1-C3 alkyl, -CH2NHC(O)C1-C3 alkyl, —NHC(O)C1-C3 alkyl or heterocyclylalkyl, wherein the heterocyclyl portion is substituted with one or more substituents independently selected from halogen, hydroxyl, alkoxy and C1-C3 alkyl; or when each RB is hydrogen, then RA is deuterium, cyano, halogen, haloalkyl, —C(O)N(R5)2, hydroxyalkyl or heteroalkyl. 2. The compound of claim 1, wherein R1—X is: wherein the piperazinyl ring is optionally substituted with R8. 3. The compound of claim 2, wherein R1 is —C(O)C(RA)C(RB)p. 4. The compound of claim 3, wherein is a triple bond and RA is absent, p is one and RB is hydroxyalkyl or C1-C3 alkoxy. 5. The compound of claim 3, wherein is a double bond and RA is hydrogen, p is two and at least one RB is independently deuterium, cyano, halogen, haloalkyl, hydroxyalkyl, heteroalkyl, heteroaryl, heteroarylalkyl, —ZNR5R11, —C(O)N(R5)2, —NHC(O)C1-C3 alkyl, —NHC(O)C1-C3 alkyl or heterocyclylalkyl wherein the heterocyclyl portion is substituted with one or more substituents independently selected from halogen, hydroxyl, alkoxy or C1-C3 alkyl. 6. The compound of claim 5, wherein the at least one RB is halogen. 7. The compound of claim 5, wherein the at least one RB is haloalkyl. 8. The compound of claim 5, wherein the at least one RB is —ZNR5R11. 9. The compound of claim 5, wherein the at least one RB is cyano. 10. The compound of claim 5, wherein the at least one RB is hydroxyalkyl. 11. The compound of claim 5, wherein the at least one RB is heteroalkyl. 12. The compound of claim 5, wherein the at least one RB is —C(O)N(R5)2, wherein each R5 is hydrogen. 13. The compound of claim 5, wherein the at least one RB is —C(O)N(R5)2, wherein each R5 is C1-C3 alkyl. 14. The compound of claim 5, wherein the at least one RB is heteroaryl optionally substituted with one or more R7. 15. The compound of claim 5, wherein the at least one RB is heteroarylalkyl optionally substituted with one or more R7. 16. The compound of claim 5, wherein the at least one RB is heterocyclylalkyl substituted with one or more R7. 17. The compound of claim 3, wherein is a double bond and p is two, each RB is hydrogen, and RA is deuterium, cyano, halogen, haloalkyl, heteroalkyl, —C(O)N(R5)2, or hydroxyalkyl. 18. The compound of claim 17, wherein RA is halogen. 19. The compound of claim 17, wherein RA is haloalkyl. 20. The compound of claim 17, wherein RA is cyano. 21. The compound of claim 17, wherein RA is heteroalkyl. 22. The compound of claim 17, wherein RA is —C(O)N(R5)2, wherein each R5 is hydrogen. 23. The compound of claim 17, wherein RA is hydroxyalkyl. 24. The compound of claim 2, wherein is a double bond and p is two, one RB is hydrogen, the second RB is dialkylaminylalkyl, and RA is halogen. 25. The compound of claim 2, wherein is a double bond and p is two, each RB is deuterium, and RA is deuterium. 26. The compound of claim 2, wherein Y is O. 27. The compound of claim 2, wherein R2 is selected from the group consisting of hydroxyalkyl, alkylaminylalkyl, dialkylaminylalkyl, —ZNR5R10, heterocyclyl and heterocyclylalkyl, wherein each of the Z, heterocyclyl or heterocyclylalkyl are independently optionally substituted with R9. 28. The compound of claim 27, wherein R2 is heterocyclylalkyl optionally substituted with one or more R9. 29. The compound of claim 28, wherein the heterocyclyl of the heterocyclylalkyl is independently azetidinyl, methylazetidinyl, N-ethylazetidinyl, N-isopropylazetidinyl, N-tert-butylazetidinyl, fluoroazetidinyl, difluoroazetidinyl, cyclopropylazetidinyl, cyclopentylazetidinyl, tetrahydropyranylazetidinyl, tetrahydropyranyl, pyrrolidinyl, methylpyrrolidinyl, dimethylpyrrolidinyl, (N-methyl)-2-methylpyrrolidinyl, (N-methyl)-2-ethylpyrrolidinyl, (N-methyl)-3,3-dimethylpyrrolidinyl, isopropylpyrrolidinyl, N-tert-butylpyrrolidinyl, cycloalkylalkylpyrrolidinyl, hydroxypyrrolindinyl, hydroxyethylpyrrolidinyl, fluoropyrrolidinyl, difluoropyrrolidinyl, (N-methyl)fluoropyrrolidinyl, (N-methyl)difluoropyrrolidinyl, fluoroethylpyrrolidinyl, methoxyethylpyrrolidinyl, (N-methyl)methoxypyrrolidinyl, piperazinyl, dimethylaminylpyrrolidinyl, morpholinyl, methylmorpholinyl, N-ethylmorpholinyl, N-isopropylmorpholinyl, oxetanyl, 1,4-oxazepanyl, piperdinyl, methylpiperidinyl acylpiperdinyl, cyanopiperdinyl, cycloalkylpiperdinyl, halopiperdinyl, dihalopiperdinyl, fluoropiperdinyl, difluoropiperdinyl, alkoxypiperdinyl, pyrrolidonyl, methylpyrrolidonyl, (N-methyl)-2-pyrrolidin-2-one, (N-ethyl)-2-pyrrolidonyl, (N-benzyl)-2-pyrrolidonyl, hydroxy-substituted-(N-methyl)pyrrolidonyl, piperidinonyl, hexahydropyrrolizinyl, thiomorpholinyl-1,1-dioxide, 3-azabicyclo[3.1.0]hexanyl, oxa-5-azabicyclo[2.2.1]heptan-5-yl, or azabicyclo[2.2.1]heptan-2-yl. 30. The compound of claim 29, wherein the (N-methyl)difluoropyrrolidinyl is 3,3-difluoro-1-methylpyrrolidinyl. 31. The compound of claim 29, wherein the heterocyclyl is N-methylpyrrolidinyl. 32. The compound of claim 27, wherein R2 is dialkylaminylalkyl optionally substituted with one or more R9. 33. The compound of claim 2, wherein R4 is aryl optionally substituted with one or more R7. 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 R7. 35. The compound of claim 34, wherein the phenyl and the naphthyl are each optionally substituted with one or more R7 selected from the group consisting of cyano, halogen, hydroxyl, C1-C6 alkyl, hydroxyalkyl, Q-haloalkyl, cycloalkyl, and alkoxy. 36. The compound of claim 35, wherein R7 is selected from the group consisting of chloro, fluoro, bromo, hydroxymethyl, methyl, ethyl, isopropyl, methoxy, trifluoromethyl, hydroxyl, cyclopropyl and cyano. 37. The compound of claim 2, wherein R4 is heteroaryl. 38. The compound of claim 2, wherein R4 is aralkyl optionally substituted with one or more R7. 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 R8 is heteroalkyl, C2-C4 alkynyl, or C1-C3alkyl optionally substituted with halogen, —OR5, cyano or heteroaryl. 42. The compound of claim 41, wherein R8 is C1-C3 alkyl optionally substituted with cyano. 43. The compound of claim 41, wherein R8 is cyanomethyl. 44. The compound of claim 41, wherein X is substituted with one R8. 45. The compound of claim 1, wherein the compound is: 46. The compound of claim 1, wherein the compound is of Formula II-B: where the piperazinyl ring is optionally substituted with R8, and R1, R3, R4, R8, L and m are as defined in claim 1. 47. The compound of claim 46, wherein R1 is —C(O)C(RA)C(RB)p and is a double bond and RA is hydrogen, p is two and at least one RB is independently deuterium, cyano, halogen, haloalkyl, hydroxyalkyl, heteroalkyl, heteroaryl, heteroarylalkyl, —ZNR5R11, —C(O)N(R5)2, —NHC(O)C1-C3 alkyl, —N(CH3)C(O)C1-C3 alkyl or heterocyclylalkyl wherein the heterocyclyl portion is substituted with one or more substituents independently selected from halogen, hydroxyl, alkoxy and C1-C3 alkyl. 48. The compound of claim 46, wherein R1 is —C(O)C(RA)C(RB)p and is a double bond, each RB is hydrogen, and RA is deuterium, cyano, halogen, C1-C-3 alkyl, haloalkyl, heteroalkyl, —C(O)N(R5)2, or hydroxyalkyl. 49. A pharmaceutical composition, 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, 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), 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, excipient or diluents, and wherein the cancer is selected from the group consisting of Cardiac: sarcoma (angiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma), myxoma, rhabdomyoma, fibroma, lipoma and teratoma; Lung: bronchogenic carcinoma (squamous cell, undifferentiated small cell, undifferentiated large cell, adenocarcinoma), alveolar (bronchiolar) carcinoma, bronchial adenoma, sarcoma, lymphoma, chondromatous hamartoma, mesothelioma; Gastrointestinal: esophagus (squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma), stomach (carcinoma, lymphoma, leiomyosarcoma), pancreas (ductal adenocarcinoma, insulinoma, glucagonoma, gastrinoma, carcinoid tumors, vipoma), small bowel (adenocarcinoma, lymphoma, carcinoid tumors, Kaposi's sarcoma, leiomyoma, hemangioma, lipoma, neurofibroma, fibroma), large bowel (adenocarcinoma, tubular adenoma, villous adenoma, hamartoma, leiomyoma); Genitourinary tract: kidney (adenocarcinoma, Wilm's tumor (nephroblastoma), lymphoma, leukemia), bladder and urethra (squamous cell carcinoma, transitional cell carcinoma, adenocarcinoma), prostate (adenocarcinoma, sarcoma), testis (seminoma, teratoma, embryonal carcinoma, teratocarcinoma, choriocarcinoma, sarcoma, interstitial cell carcinoma, fibroma, fibroadenoma, adenomatoid tumors, lipoma); Liver: hepatoma (hepatocellular carcinoma), cholangiocarcinoma, hepatoblastoma, angiosarcoma, hepatocellular adenoma, hemangioma; Biliary tract: gall bladder carcinoma, ampullary carcinoma, cholangiocarcinoma; Bone: osteogenic sarcoma (osteosarcoma), fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing's sarcoma, malignant lymphoma (reticulum cell sarcoma), multiple myeloma, malignant giant cell tumor chordoma, osteochronfroma (osteocartilaginous exostoses), benign chondroma, chondroblastoma, chondromyxofibroma, osteoid osteoma and giant cell tumors; Nervous system: skull (osteoma, hemangioma, granuloma, xanthoma, osteitis deformans), meninges (meningioma, meningiosarcoma, gliomatosis), brain (astrocytoma, medulloblastoma, glioma, ependymoma, germinoma (pinealoma), glioblastoma multiform, oligodendroglioma, schwannoma, retinoblastoma, congenital tumors), spinal cord neurofibroma, meningioma, glioma, sarcoma); Gynecological: uterus (endometrial ‘carcinoma (serous cystadenocarcinoma, mucinous cystadenocarcinoma, unclassified carcinoma), granulosa-thecal cell tumors, Sertoli-Leydig cell tumors, dysgerminoma, malignant teratoma), vulva (squamous cell carcinoma, intraepithelial carcinoma, adenocarcinoma, fibrosarcoma, melanoma), vagina (clear cell carcinoma, squamous cell carcinoma, botryoid sarcoma (embryonal rhabdomyosarcoma), fallopian tubes (carcinoma); Hematologic: blood (myeloid leukemia (acute and chronic), acute lymphoblastic leukemia, chronic lymphocytic leukemia, myeloproliferative diseases, multiple myeloma, myelodysplastic syndrome), Hodgkin's disease, non-Hodgkin's lymphoma (malignant lymphoma); Skin: malignant melanoma, basal cell carcinoma, squamous cell carcinoma, Kaposi's sarcoma, moles dysplastic nevi, lipoma, angioma, dermatofibroma, keloids, 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. 57. A compound of the following structure: