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.

Claims

1. A compound of formula (II): ##STR01528## or a pharmaceutically acceptable salt thereof: wherein: X is a 4-12 membered saturated or partially saturated monocyclic, bridged or spirocyclic ring, wherein the saturated or partially saturated monocyclic ring is optionally substituted with one or more R.sup.8; Y is a bond, O, S or NR.sup.8; R.sup.1 is --C(O)C(R.sup.A)C(R.sup.B).sub.p or --SO.sub.2C(R.sup.A)C(R.sup.B).sub.p; R.sup.2 is hydrogen, alkyl, hydroxyalkyl, dihydroxyalkyl, alkylaminylalkyl, dialkylaminylalkyl, --Z--NR.sup.5R.sup.10, 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 R.sup.9; each Z is C1-C4 alkylene; each R.sup.3 is independently C1-C3 alkyl, oxo, haloalkyl, hydroxyl or halogen; L is a bond, --C(O)--, or C1-C3 alkylene; R.sup.4 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 R.sup.6, R.sup.7 or R.sup.8; each R.sup.5 is independently hydrogen or C1-C3 alkyl; R.sup.6 is cycloalkyl, heterocyclyl, heterocyclylalkyl, aryl, or heteroaryl, wherein each of the cycloalkyl, heterocyclyl, aryl, or heteroaryl may be optionally substituted with one or more R.sup.7; each R.sup.7 is independently halogen, hydroxyl, C1-C6 alkyl, cycloalkyl, alkoxy, haloalkyl, amino, cyano, heteroalkyl, hydroxyalkyl or Q-haloalkyl, wherein Q is O or S; R.sup.8 is oxo, C1-C3 alkyl, C2-C4 alkynyl, heteroalkyl, cyano, --C(O)OR.sup.5, --C(O)N(R.sup.5).sub.2, --N(R.sup.5).sub.2, wherein the C1-C3 alkyl may be optionally substituted with cyano, halogen, --OR.sup.5, --N(R.sup.5).sub.2, or heteroaryl; each R.sup.9 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 R.sup.10 is independently hydrogen, acyl, C1-C3 alkyl, heteroalkyl or hydroxyalkyl; R.sup.11 is haloalkyl; R.sup.A is absent, hydrogen, deuterium, cyano, halogen, C1-C-3 alkyl, haloalkyl, heteroalkyl, --C(O)N(R.sup.5).sub.2, or hydroxyalkyl; each R.sup.B is independently hydrogen, deuterium, cyano, C1-C3 alkyl, hydroxyalkyl, heteroalkyl, C1-C3 alkoxy, halogen, haloalkyl, --ZNR.sup.5R.sup.11, --C(O)N(R.sup.5).sub.2, --NHC(O)C1-C3 alkyl, --CH.sub.2NHC(O)C1-C3 alkyl, --CH.sub.2N(CH.sub.3)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 R.sup.7; or when is a double bond and p is two, one R.sup.B is hydrogen and R.sup.A and one R.sup.B 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 R.sup.A is absent, p equals one and R.sup.B is hydroxyalkyl, or when is a double bond then R.sup.A is present, R.sup.B is present and p equals two, wherein when R.sup.A is hydrogen or C1-C3 alkyl, at least one R.sup.B is deuterium, cyano, halogen, haloalkyl, hydroxyalkyl, heteroalkyl, heteroaryl, heteroarylalkyl, --ZNR.sup.5R.sup.11, --C(O)N(R.sup.5).sub.2, --NHC(O)C1-C3 alkyl, --CH.sub.2NHC(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 R.sup.B is hydrogen, then R.sup.A is deuterium, cyano, halogen, haloalkyl, --C(O)N(R.sup.5).sub.2, hydroxyalkyl or heteroalkyl.

2. The compound of claim 1, wherein R.sup.1--X is: ##STR01529## wherein the piperazinyl ring is optionally substituted with R.sup.8.

3. The compound of claim 2, wherein R.sup.1 is --C(O)C(R.sup.A) C(R.sup.B).sub.p.

4. The compound of claim 3, wherein is a double bond and p is two, each R.sup.B is hydrogen, and R.sup.A is deuterium, cyano, halogen, haloalkyl, heteroalkyl, --C(O)N(R.sup.5).sub.2, or hydroxyalkyl.

5. The compound of claim 4, wherein R.sup.A is halogen.

6. The compound of claim 2, wherein is a double bond and p is two, one R.sup.B is hydrogen, the second R.sup.B is dialkylaminylalkyl, and R.sup.A is halogen.

7. The compound of claim 2, wherein Y is O.

8. The compound of claim 2, wherein R.sup.2 is selected from the group consisting of hydroxyalkyl, alkylaminylalkyl, dialkylaminylalkyl, --ZNR.sup.5R.sup.10, heterocyclyl and heterocyclylalkyl, wherein each of the Z, heterocyclyl or heterocyclylalkyl are independently optionally substituted with R.sup.9.

9. The compound of claim 8, wherein R.sup.2 is heterocyclylalkyl optionally substituted with one or more R.sup.9.

10. The compound of claim 9, 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.

11. The compound of claim 10, wherein the (N-methyl)difluoropyrrolidinyl is 3,3-difluoro-1-methylpyrrolidinyl.

12. The compound of claim 10, wherein the heterocyclyl is N-methylpyrrolidinyl.

13. The compound of claim 8, wherein R.sup.2 is dialkylaminylalkyl optionally substituted with one or more R.sup.9.

14. The compound of claim 2, wherein R.sup.4 is aryl optionally substituted with one or more R.sup.7.

15. The compound of claim 14, wherein the aryl is selected from the group consisting of phenyl and naphthyl optionally substituted with one or more R.sup.7.

16. The compound of claim 15, wherein the phenyl and the naphthyl are each optionally substituted with one or more R.sup.7 selected from the group consisting of cyano, halogen, hydroxyl, C1-C6 alkyl, hydroxyalkyl, Q-haloalkyl, cycloalkyl, and alkoxy.

17. The compound of claim 16, wherein R.sup.7 is selected from the group consisting of chloro, fluoro, bromo, hydroxymethyl, methyl, ethyl, isopropyl, methoxy, trifluoromethyl, hydroxyl, cyclopropyl and cyano.

18. The compound of claim 2, wherein m is zero.

19. The compound of claim 2, wherein L is a bond.

20. The compound of claim 2, wherein R.sup.8 is heteroalkyl, C2-C4 alkynyl, or C1-C3alkyl optionally substituted with halogen, --OR.sup.5, cyano or heteroaryl.

21. The compound of claim 20, wherein R.sup.8 is C1-C3 alkyl optionally substituted with cyano.

22. The compound of claim 20, wherein R.sup.8 is cyanomethyl.

23. The compound of claim 20, wherein X is substituted with one R.sup.8.

24. The compound of claim 1, wherein the compound is: ##STR01530## ##STR01531## ##STR01532## ##STR01533## ##STR01534## ##STR01535## ##STR01536## ##STR01537## ##STR01538## ##STR01539## ##STR01540## ##STR01541## ##STR01542## ##STR01543## ##STR01544## ##STR01545## ##STR01546## ##STR01547## ##STR01548## ##STR01549## ##STR01550## ##STR01551## ##STR01552## ##STR01553## ##STR01554## ##STR01555## ##STR01556## ##STR01557## ##STR01558## ##STR01559## ##STR01560## ##STR01561## ##STR01562## ##STR01563## ##STR01564## ##STR01565## ##STR01566## ##STR01567## ##STR01568## ##STR01569## ##STR01570## ##STR01571## ##STR01572## ##STR01573## ##STR01574## ##STR01575## ##STR01576## ##STR01577## ##STR01578## ##STR01579## ##STR01580## ##STR01581## ##STR01582## ##STR01583## ##STR01584## ##STR01585## ##STR01586## ##STR01587## ##STR01588## ##STR01589## ##STR01590## ##STR01591## ##STR01592## ##STR01593## ##STR01594## ##STR01595## ##STR01596## ##STR01597##

25. The compound of claim 1, wherein the compound is of Formula II-B: ##STR01598## where the piperazinyl ring is optionally substituted with R.sup.8, and R.sup.1, R.sup.3, R.sup.4, R.sup.8, L and m are as defined in claim 1.

26. The compound of claim 25, wherein R.sup.1 is --C(O)C(R.sup.A)C(R.sup.B).sub.p and is a double bond, each R.sup.B is hydrogen, and R.sup.A is deuterium, cyano, halogen, C1-C-3 alkyl, haloalkyl, heteroalkyl, --C(O)N(R.sup.5).sub.2, or hydroxyalkyl.

27. A pharmaceutical composition, comprising a therapeutically effective amount of a compound of Formula (II)according to claim 1, and a pharmaceutically acceptable excipient.

28. 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.

29. 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.

30. The method of claim 29, wherein the therapeutically effective amount of the compound is between about 0.01 to 100 mg/kg per day.

31. The method of claim 30, wherein the therapeutically effective amount of the compound is between about 0.1 to 50 mg/kg per day.

32. The method of claim 29, 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.

33. The method of claim 29, wherein the cancer wherein the cancer is a KRas G12C-associated cancer.

34. The method of claim 29, wherein the cancer is non-small cell lung cancer.

35. The method of claim 34, wherein non-small cell lung cancer is a KRas G12C-associated cancer.

36. A method for treating cancer in a patient in need thereof, the method comprising (a) determining that the cancer is associated with a KRas G12C mutation (e.g., a KRas G12C-associated cancer); and (b) administering to the patient a therapeutically effective amount of a compound of Formula (II) or a pharmaceutically acceptable salt thereof according to claim 1, or a pharmaceutical composition thereof.