Kras g12d inhibitors

Abstract

To provide compounds that inhibit KRas G12D, pharmaceutical compositions comprising the compounds, and methods of use therefor.SOLUTION: Provided is a compound of formula (I), or a pharmaceutically acceptable salt thereof.SELECTED DRAWING: None

Claims

1. A compound of formula (I), 【Chemistry 1】 or a pharma- ceutically acceptable salt thereof, During the ceremony, R １ is hydrogen, hydroxy, halogen, C1-C3 alkyl, C1-C3 cyanoalkyl, C1-C3 hydroxyalkyl, HC(=O)-, -CO ２ R ５ , -CO ２ N (R ５ ) ２ or 5-6 membered heteroaryl; Y is a bond, O, or NR ５ and R ２ is hydrogen, -N(R ５ ) ２ , heterocyclyl, C1-C6 alkyl, -L-heterocyclyl, -L-aryl, -L-heteroaryl, -L-cycloalkyl, -L-N(R ５ ) ２ , -L-NHC(=NH)NH ２ , -LC(O)N(R ５ ) ２ , -L-C1-C6 haloalkyl, -L-OR ５ , -L-(CH ２ OR ５ ) (CH ２ ) ｎ OR ５ , -L-NR ５ C(O)-aryl, -L-COOH, or -LC(=O)OC1-C6 alkyl; -L-NR ５ The heterocyclyl and aryl portions of C(O)-aryl and the heterocyclyl portion of -L-heterocyclyl and the cycloalkyl portion of said -L-cycloalkyl may optionally be represented by one or more R ６ wherein the aryl or heteroaryl of said -L-aryl and said -L-heteroaryl may optionally be substituted with one or more R ７ may be substituted with each L is independently a C1-C4 alkylene optionally substituted with hydroxy, C1-C4 hydroxyalkyl, or heteroaryl; R ３ is aryl or heteroaryl, said aryl or said heteroaryl optionally being selected from one or more R ８ is replaced by R ４ is hydrogen, halogen, or C1-C3 alkyl; Each R ５ are independently hydrogen or C1-C3 alkyl; Each R ６ are independently halogen, hydroxy, C1-C3 hydroxyalkyl, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, cyano, -Q-phenyl, -Q-phenylSO ２ F, -NHC(O)phenyl, -NHC(O)phenylSO ２ F, C1-C3 alkyl substituted pyrazolyl, arC1-C3 alkyl-, tert-butyldimethylsilyloxyCH ２ -, -N(R ５ ) ２ , (C1-C3 alkoxy)C1-C3 alkyl-, (C1-C3 alkyl)C(=O), oxo, (C1-C3 haloalkyl)C(=O)-, -SO ２ F, (C1-C3 alkoxy)C1-C3 alkoxy, -CH ２ O.C. (O) N (R ５ ) ２ , -CH ２ NHC(O)OC1-C6 alkyl, -CH ２ NHC(O)N(R ５ ) ２ , -CH ２ NHC(O)C1-C6 alkyl, -CH ２ (pyrazolyl), -CH ２ N.H.S.O. ２ C1-C6 alkyl, -CH ２ OC(O)heterocyclyl, -OC(O)N(R ５ ) ２ , -OC(O)NH(C1-C3 alkyl)O(C1-C3 alkyl), -OC(O)NH(C1-C3 alkyl)O(C1-C3 alkyl)phenyl(C1-C3 alkyl)N(CH ３ ) ２ , —OC(O)NH(C1-C3 alkyl)O(C1-C3 alkyl)phenyl, or —OC(O)heterocyclyl, —CH ２ Heterocyclyl, in which the phenyl of -NHC(O)phenyl or -OC(O)NH(C1-C3 alkyl)O(C1-C3 alkyl)phenyl is optionally substituted with -C(O)H or OH, and -CH ２ the heterocyclyl of the heterocyclyl is optionally substituted by oxo; Q is a bond or O; Each R ７ are independently halogen, hydroxy, HC(═O)—, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 hydroxyalkyl, or —N(R ５ ) ２ and Each R ８ are independently halogen, cyano, hydroxy, C1-C4 alkyl, -S-C1-C3 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C2-C4 hydroxyalkynyl, C1-C3 cyanoalkyl, triazolyl, C1-C3 haloalkyl, -O-C1-C3 haloalkyl, -S-C1-C3 haloalkyl, C1-C3 alkoxy, hydroxyC1-C3 alkyl, -CH ２ C(=O)N(R ５ ) ２ , -C3-C4 alkynyl (NR ５ ) ２ , -N(R ５ ) ２ , deutero C2-C4 alkynyl, (C1-C3 alkoxy)haloC1-C3 alkyl-, or C3-C6 cycloalkyl, wherein said C3-C6 cycloalkyl is optionally substituted with halogen or C1-C3 alkyl, or a pharma- ceutically acceptable salt thereof.

2. R １ is hydrogen, halogen, hydroxy, C1-C3 alkyl, C1-C3 cyanoalkyl, hydroxyalkyl, HC(=O)-, -CO ２ R ５ or -CO ２ N (R ５ ) ２ 2. The compound or salt of claim 1,

3. R ５ The compound or salt of claim 2, wherein is hydrogen, C1-C3 alkyl, or C1-C3 cyanoalkyl.

4. Y is O and R ２ optionally, one or more R ６ 3. The compound or salt of claim 2, wherein the -R is C1-C6 alkyl or -L-heterocyclyl substituted with.

5. 5. The compound or salt of claim 4, wherein the C1-C6 alkyl is methyl, ethyl, isopropyl, or isobutyl.

6. L is methylene and the heterocyclyl is hexahydro-1H-pyrrolidinyl, hexahydro-3H-pyrrolidin-3-one, hexahydro-1H-pyrrolo[2,1-c][1,4]oxazinyl, octahydroindolizinyl, hexahydropyrrolidine 4(1H)-oxide, azetidinyl, pyrrolidinyl, pyrrolidin-2-one, oxetanyl, piperidinyl, 1-azabicyclo[2.2.1]heptanyl, morpholinyl, oxa-5-azabicyclo[2.2.1]heptan-5-yl, thiopyranyl, 6-oxa- [0010] -Azaspiro[3.4]octanyl, 7-oxa- [0025] -azaspiro[3.5]nonanyl, 2',3'-dihydrospiro[cyclopropane-1,1'-indenyl], (2S)-1-azabicyclo[2.2.1]heptan-2-yl, or tetrahydrofuranyl, each optionally being selected from one or more R ６ 5. The compound or salt of claim 4 , substituted with:

7. 5. The compound or salt of claim 4, wherein L is methylene and the heterocyclyl is hexahydro-1H-pyrrolidinyl.

8. Heterocyclyl is one R ６ hexahydro-1H-pyrrolidinyl substituted with R ６ 8. The compound or salt of claim 7, wherein is halogen, hydroxy, C1-C3 hydroxyalkyl, C1-C3 haloalkyl, C1-C3 alkyl, C1-C3 alkoxy, phenyl, or pyrazolyl.

9. 9. The compound or salt of claim 8, wherein the halogen is fluorine.

10. The heterocyclyl may have two additional R ６ hexahydro-1H-pyrrolidinyl further substituted with a group, ６ 7. The compound or salt of claim 6, wherein the groups are independently C1-C3 alkyl.

11. The heterocyclyl is one R ６ azetidinyl substituted with R ６ The compound or salt of claim 6, wherein is C1-C3 alkyl.

12. The heterocyclyl is one R ６ pyrrolidinyl substituted with R ６ is hydroxyalkyl, haloalkyl, C1-C3 alkyl, alkoxy, araC1-C3 alkyl, -Q-phenyl, and -NHC(O)phenyl, and the aryl portion of said araC1-C3 alkyl or the phenyl portion of said -Q-phenyl and -NHC(O)phenyl each optionally comprises one or more R ６ 7. The compound or salt of claim 6, substituted with:

13. The phenyl group of the -Q-phenyl or the -NHC(O)phenyl is SO ２ 13. The compound or salt of claim 12, which is substituted with F.

14. The heterocyclyl is selected from the group consisting of two R ６ pyrrolidinyl substituted with a group, ６ is C1-C3 alkyl, and the other R ６ The compound or salt of claim 6, wherein is C1-C3 alkoxy or halogen.

15. The heterocyclyl is one R ６ pyrrolidin-2-one substituted with R ６ The compound or salt of claim 6, wherein is C1-C3 alkyl.

16. The heterocyclyl is one R ６ piperidinyl substituted with R ６ is acetyl, (C1-C3 alkoxy)C1-C3 alkoxy, or -C(O)CH ２ 7. The compound or salt of claim 6, wherein:

17. 7. The compound or salt of claim 6, wherein Y is O, L is ethylene or propylene, and the heterocyclyl is morpholinyl or oxa-5-azabicyclo[2.2.1]heptan-5-yl.

18. Y is O and R ２ is -L-heteroaryl, the heteroaryl moiety optionally being selected from one or more R ７ 3. The compound or salt of claim 2, substituted with:

19. L is methylene or ethylene, and said heteroaryl is pyridyl, pyrazolyl, imidazolyl, triazolyl, 4,5,6,7-tetrahydro-1H-indazolyl, benzimidazolyl, imidazo[1,2-a]pyridinyl, or pyrimidinyl, each optionally selected from one or more R ７ 20. The compound or salt of claim 18, substituted with:

20. The heteroaryl is one R ７ pyridyl substituted with R ７ is halogen, C1-C4 alkyl, -N(R ５ ) ２ or C1-C4 alkoxy.

21. The heteroaryl is one R ７ and R is a pyrazolyl substituted with ７ is C1-C4 alkyl or -N(R ５ ) ２ 20. The compound or salt of claim 19,

22. The heteroaryl is one R ７ is imidazolyl substituted with R ７ 20. The compound or salt of claim 19, wherein is C1-C4 alkyl, C1-C4 haloalkyl, or C1-C4 hydroxyalkyl.

23. The heteroaryl is one R ７ is a triazolyl substituted with R ７ The compound or salt of claim 19, wherein is C1-C4 alkyl.

24. Y is O and R ２ is -L-aryl, the aryl moiety optionally being selected from one or more R ７ 3. The compound or salt of claim 2, substituted with:

25. Y is O and R ２ is -L-cycloalkyl, the cycloalkyl moiety optionally being selected from one or more R ７ 3. The compound or salt of claim 2, substituted with:

26. Y is O and R ２ But -L-N(R ５ ) ２ 3. The compound or salt of claim 2, wherein

27. L is ethylene, and each R ５ is an independently selected C1-C3 alkyl.

28. Y is O and R ２ is -L-NC(=NH)-NH ２ 3. The compound or salt of claim 2, wherein

29. 29. The compound or salt of claim 28, wherein L is ethylene or propylene.

30. Y is O and R ２ The compound or salt of claim 2, wherein is -L-C1-C6 haloalkyl.

31. Y is O and R ２ But -L-OR ５ 3. The compound or salt of claim 2, wherein

32. Y is O and R ２ But -L-(CH ２ OR ５ ) (CH ２ ) ｎ OR ５ 3. The compound or salt of claim 2, wherein

33. Y is O and R ２ But -L-NR ５ The compound or salt of claim 2 which is C(O)-aryl.

34. R ３ optionally, one or more R ８ 3. The compound or salt of claim 2, wherein the aryl is substituted with

35. The aryl is phenyl, naphthyl, 1,2,3,4-tetrahydronaphthalenyl, and 2,3-dihydro-1H-indenyl, each of which optionally has one or more R ８ 35. The compound or salt of claim 34, substituted with:

36. R ３ optionally, one or more R ８ 3. The compound or salt of claim 2, wherein the heteroaryl is substituted with

37. The heteroaryl may optionally be one or more R ８ 43. The compound or salt of claim 42, which is isoquinolinyl, indazolyl, or benzo[d][1,3]dioxolyl substituted with.

38. The heteroaryl is one R ８ isoquinolinyl substituted with R ８ is halogen or C2-C4 alkynyl.

39. The heteroaryl is one R ８ Indazolyl substituted with R ８ is C1-C3 alkyl.

40. The heteroaryl is selected from the group consisting of two R ８ benzo[d][1,3]dioxolyl substituted with a group, ８ 38. The compound or salt of claim 37, wherein the groups are independently selected halogen.

41. R ４ The compound or salt of claim 2, wherein is halogen, or C1-C3 alkyl.

42. 42. The compound or salt of claim 41 , wherein the halogen is fluorine.

43. 42. The compound or salt of claim 41, wherein the C1-C3 alkyl is methyl.

44. R １ The compound or salt of claim 1 , wherein is hydrogen.

45. The compound is 【Chemistry 2-1】 【Chemistry 2-2】 【Chemistry 2-3】 【Chemistry 2-4】 【Chemistry 2-5】 【Chemistry 2-6】 【Chemistry 2-7】 【Chemistry 2-8】 【Chemistry 2-9】 【Chemistry 2-10】 【Chemistry 2-11】 【Chemistry 2-12】 【Chemistry 2-13】 【Chemistry 2-14】 【Chemistry 2-15】 【Chemistry 2-16】 【Chemistry 2-17】 【Chemistry 2-18】 【Chemistry 2-19】 【Chemistry 2-20】 【Chemistry 2-21】 【Chemistry 2-22】 【Chemistry 2-23】 【Chemistry 2-24】 【Chemistry 2-25】 【Chemistry 2-26】 【Chemistry 2-27】 【Chemistry 2-28】 【Chemistry 2-29】 【Chemistry 2-30】 【Chemistry 2-31】 【Chemistry 2-32】 【Chemistry 2-33】 【Chemistry 2-34】 【Chemistry 2-35】 【Chemistry 2-36】 【Chemistry 2-37】 【Chemistry 2-38】 and pharma- ceutically acceptable salts thereof.

46. 13. A pharmaceutical composition comprising a therapeutically effective amount of a compound of claim 1 or a pharma- ceutically acceptable salt thereof, and a pharma- ceutically acceptable excipient.

47. A method for inhibiting KRas G12D activity in a cell, comprising contacting the cell in which inhibition of KRas G12D activity is desired with an effective amount of a compound of claim 1 or a pharma- ceutical acceptable salt thereof.

48. 47. A method for inhibiting KRas G12D activity in a cell, comprising contacting said cell in which inhibition of KRas G12D activity is desired with the pharmaceutical composition of claim 46.

49. 13. A method for treating a KRas G12D associated cancer, comprising administering to a patient in need thereof a therapeutically effective amount of the compound of claim 1 or a pharma- ceutically acceptable salt thereof.

50. 47. A method for treating a KRas G12D associated cancer, comprising administering to a patient in need thereof the pharmaceutical composition of claim 46.

51. 51. The method of claim 50, wherein the therapeutically effective amount of the compound is about 0.01 to 100 mg / kg per day.

52. The KRas G12D associated cancer is: cardiac: sarcoma (angiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma), myxoma, rhabdomyoma, fibroma, lipoma, and teratoma; Lung: bronchogenic carcinoma (squamous cell, small undifferentiated cell, large undifferentiated cell, adenocarcinoma), alveolar (bronchiolar) carcinoma, bronchial adenoma, sarcoma, lymphoma, chondromatous hamartoma, mesothelioma; Gastrointestinal: Esophagus (squamous cell carcinoma, adenocarcinoma, leiomyoma, lymphoma), stomach (carcinoma, lymphoma, leiomyoma), pancreas (ductal adenocarcinoma, insulinoma, glucagonoma, gastrinoma, carcinoid tumor, VIP-producing tumor), small intestine (adenocarcinoma, lymphoma, carcinoid tumor, Kaposi's sarcoma, leiomyoma, hemangioma, lipoma, neurofibroma, fibroma), large intestine (adenocarcinoma, tubular adenoma, villous adenoma, hamartoma, leiomyoma); genitourinary tract: Kidneys (glandular adenocarcinoma, leiomyoma, hemangioma, lipoma, neurofibroma, fibroma) carcinoma, Wilms' 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, stromal cell carcinoma, fibroma, fibroadenoma, adenomatous tumor, lipoma); liver: hepatocellular carcinoma (hepatocellular carcinoma), cholangiocarcinoma, hepatoblastoma, angiosarcoma, hepatocellular adenoma, hemangioma; biliary tract: gallbladder 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, osteochondroma (osteochondral exostosis), benign chordoma, chondroblastoma, chondromyxofibroma, osteoid osteoma, and giant cell tumor; Nervous system: skull (osteoma, hemangioma, granuloma, xanthomatosis, osteitis deformans), meninges (meningioma, meningeal sarcoma, gliomatosis), brain (astrocytoma, medulloblastoma, glioma, ependymoma, germinoma (pinealoma), glioblastoma multiforme, oligodendroglioma, schwannoma, retinoblastoma, congenital tumors), spinal neurofibroma, meningioma, glioma, sarcoma); Gynecology: uterus (endometrial cancer (serous cystadenocarcinoma, mucinous cystadenocarcinoma, unclassified carcinoma), granular 51. The method of claim 50, wherein the tumor is selected from the group consisting of: theca cell carcinoma, Sertoli-Leydig cell tumor, dysgerminoma, malignant teratoma), vulva (squamous cell carcinoma, carcinoma in situ, adenocarcinoma, melanoma), vagina (clear cell carcinoma, squamous cell carcinoma, botryoid sarcoma (embryonal rhabdomyosarcoma)), fallopian tube (carcinoma); hematology: blood (myeloid leukemia (acute and chronic), acute lymphoblastic leukemia, chronic lymphocytic leukemia, myeloproliferative disorders, multiple myeloma, myelodysplastic syndromes), Hodgkin's disease, non-Hodgkin's lymphoma (malignant lymphoma); skin: malignant melanoma, basal cell carcinoma, squamous cell carcinoma, Kaposi's sarcoma, lenticular dysplastic nevus, lipoma, hemangioma, dermatofibroma, keloid, psoriasis; and adrenal gland: neuroblastoma.

53. 53. The method of claim 52, wherein the cancer is non-small cell lung cancer, small cell lung cancer, colon cancer, rectal cancer, or pancreatic cancer.

54. 11. A method for treating cancer in a patient in need thereof, comprising: (a) determining that the cancer is associated with a KRas G12D mutation (e.g., a KRas G12D-associated cancer); and (b) administering to the patient a therapeutically effective amount of a compound of claim 1.

55. 53. A method for treating cancer in a patient in need thereof, comprising: (a) determining that the cancer is associated with a KRas G12D mutation (e.g., a KRas G12D-associated cancer); and (b) administering to the patient a pharmaceutical composition according to claim 52.

56. 56. The method of claim 55, wherein the administration is via a route selected from the group consisting of parenteral, intraperitoneal, intradermal, intracardiac, intraventricular, intracranial, intracerebrospinal, intrasynovial, intrathecal administration, intramuscular injection, intravitreal injection, intravenous injection, intraarterial injection, oral, buccal, sublingual, transdermal, topical, intratracheal, rectal, subcutaneous, and local administration.

57. 57. The method of claim 56, wherein the administration is via intravenous injection.

58. 57. The method of claim 56, wherein the administration is via intramuscular injection.

59. 57. The method of claim 56, wherein the administration is via intramuscular injection.

60. 57. The method of claim 56, wherein the administering comprises utilizing a delivery device.

61. 57. The method of claim 56, wherein the administration occurs in a hospital.

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