Spiro dihydropyranopyrimidine KRas inhibitors

Abstract

Provided herein are compounds of Formula (IV-b), or pharmaceutically acceptable salts thereof, which inhibit KRas proteins (e.g., modulate aberrant KRas proteins (e.g., mutated or amplified KRas proteins)). The disclosure also provides compositions containing a compound as provided herein, or a pharmaceutically acceptable salt thereof, as well as methods of using and preparing these compositions. Formula (IV-b).

Claims

1. A compound of formula (IV-b): Or its pharmaceutically acceptable salt, wherein: R 1 It is arbitrarily divided by 1 to 4 R 7 Substituted 4- to 10-membered heterocyclic groups; Each R 7 Independently selected from R a and R b ; X 1 It is CH2; X 2 It is CH2; X 3 It is CHR L R 9 Selected from: H, OH, NR d R e and halogenated groups; b4 is 0; and R 10 Selected from: -Cl, -F, -CN and optionally by 1 to 3 R c Replacement C 1-3 alkyl; R L Selected from C 1-3 Alkyl, -F, CN, and optionally surrounded by 1 to 3 R c Replacement C 1-3 alkyl; Y 2 It is -CH2-; and R 3 It is optionally substituted by one or two substituents, each independently selected from the following. -F, -C 1-3 Alkoxy and -C 1-3 Halogenated alkoxy groups; Each R a Selected independently from: (a) Halogenated group; (b) Cyano group; (c)-OH; (d) Oxide group; (e) -C 1-6 Alkoxy; (f) -C 1-6 Halogenated alkoxy groups; (g) -NR d R e ; (h) C(=O)C 1-6 alkyl; (i) C(=O)C 1-6 Halogenated alkyl groups; (j) C(=O)OH; (k) C(=O)OC 1-6 alkyl; (l) C(=O)OC 1-6 Halogenated alkyl groups; (m) C(=O)N(R f )2; (n) S(O) 0-2 (C 1-6 alkyl); (o) S(O) 0-2 (C 1-6 (halogenated alkyl); (p) S(O) 1-2 N(R f )2; and (q) C 1-6 Alkyl, C 2-6 alkenyl or C 2-6 Alkyne groups, each optionally surrounded by 1 to 6 R groups c replace; Each R b Selected independently from: -(L b ) b -R b1 and -R b1 ,in: b is 1, 2, or 3; Each -L b Independently selected from: -O-, -N(H)-, -N(C)- 1-3 Alkyl)-, -S(O) 0-2 - C (=O) and C 1-3 Alkylene; and Each R b1 Selected independently from: C 3-10 cycloalkyl, 4- to 10-membered heterocyclic groups, C 6-10 aryl and 5 to 10-membered heteroaryl groups, each optionally bounded by 1 to 3 R groups. g replace; Each R c Independently selected from: halogenated group, cyano group, -OH, -C 1-6 Alkoxy, -C 1-6 Haloalkoxy, -NR d R e C(=O)C 1-6 Alkyl, C(=O)C 1-6 Haloalkyl, C(=O)OC 1-6 Alkyl, C(=O)OC 1-6 Haloalkyl, C(=O)OH, C(=O)N(R) f 2. S(O) 0-2 (C 1-6 Alkyl groups), S(O) 0-2 (C 1-6 (Haloalkyl) and S(O) 1-2 N(R f )2; Each R d and R e Independently selected from: H, C(=O)C 1-6 Alkyl, C(=O)C 1-6 Haloalkyl, C(=O)OC 1-6 Alkyl, C(=O)OC 1-6 Haloalkyl, C(=O)N(R) f 2. S(O) 1-2 (C 1-6 Alkyl groups), S(O) 1-2 (C 1-6 Halogenated alkyl groups), S(O) 1-2 N(R f )2 and optionally by 1 to 3 R h Replacement C 1-6 alkyl; Each R f Independently selected from: H and optionally by 1 to 3 R h Replacement C 1-6 alkyl; Each R g Selected independently from: R h C 1-3 Alkyl, C 1-3 Haloalkyl, C 3-5 cycloalkyl groups and 4- to 5-membered heterocyclic groups; and Each R h Independently selected from: halogenated group, cyano group, -OH, -C 1-6 Alkoxy, -C 1-6 Halogenated alkoxy groups, -NH2, -N(H)(C 1-3 alkyl) and -N(C) 1-3 alkyl) 2- .

2. The compound according to claim 1, wherein R 9 It is NR d R e (e.g., -NH2).

3. The compound according to claim 1 or 2, wherein R L Independently selected from: CH3, CF3, CHF2 and CH2F.

4. The compound according to any one of claims 1 to 3, wherein R L It is CH3.

5. The compound according to any one of claims 1 to 4, wherein the compound is a compound of formula (IV-c): Or its pharmaceutically acceptable salt.

6. The compound according to claim 5, wherein R L It is CH3.

7. The compound according to any one of claims 1 to 6, wherein R 3 It can be optionally replaced by one or two -F. .

8. The compound according to any one of claims 1 to 7, wherein R 3 yes (For example ).

9. The compound according to any one of claims 1 to 7, wherein R 3 yes .

10. The compound according to any one of claims 1 to 6, wherein R 3 yes .

11. The compound according to any one of claims 1 to 10, wherein each R 7 Independently selected from: halogenated group; cyano group; -OH group; oxo group; -C group 1-6 Alkyl group; C(=O)N(R) f )2;R b1 ;-(C 1-3 (alkylene)-R b1 ;-OR b1 ; and optionally by 1 to 3 R c7 Replacement C 1-6 Alkyl groups, wherein: Each R b1 Selected independently from: C 3-6 Cycloalkyl, phenyl, 4- to 6-membered heterocyclic and 5- to 6-membered heteroaryl groups, each optionally bound by 1 to 3 R groups. g (For example, each R) g Independently selected from: halogenated group and C 1-3 Alkyl) substitution; and Each R c7 Independently selected from: halogenated group, cyano group, -OH and -C 1-6 Alkyl group.

12. The compound according to any one of claims 1 to 11, wherein R 1 It is a 7 to 10 (e.g., 7) membered heterocyclic group having a cyclic nitrogen atom, an epoxide atom, and no additional cyclic heteroatoms, wherein the 7 to 10 membered heterocyclic group is optionally surrounded by 1 to 4 (e.g., 1 to 2) R atoms. 7 replace.

13. The compound according to any one of claims 1 to 12, wherein R 1 It is a 7- to 10-membered (e.g., 7) monocyclic heterocyclic group having a cyclic nitrogen atom, an epoxide atom, and no additional cyclic heteroatoms, wherein the 7- to 10-membered monocyclic heterocyclic group is optionally surrounded by 1 to 4 (e.g., 1 to 2) R atoms. 7 replace.

14. The compound according to any one of claims 1 to 13, wherein R 1 It is optionally separated into one or more ring carbon atoms by 1 to 4 R 7 Replacement .

15. The compound according to any one of claims 1 to 14, wherein R 1 yes , where b3 is 1, 2 or 3.

16. The compound according to claim 15, wherein the R appears once. 7 It is R b (For example, R appears once) 7 It is R b1 ).

17. The compound according to claim 15 or 16, wherein R appears once. 7 It is arbitrarily selected by 1 to 3 Rs g Substituted 5- to 6-membered heteroaryl groups.

18. The compound according to any one of claims 1 to 17, wherein R appears once. 7 It is arbitrarily selected by 1 to 3 Rs g Substituted 5-membered heteroaryl group.

19. The compound according to any one of claims 1 to 18, wherein R appears once. 7 Selected from pyrazolyl and oxazolyl groups, each optionally separated by 1 to 2 R groups. g Replace (e.g., R) 7 yes ).

20. The compound according to any one of claims 1 to 19, wherein b3 is 1.

21. The compound according to any one of claims 1 to 15, wherein R 1 yes (For example ), where R 7 It is arbitrarily selected by 1 to 3 Rs g Substituted 5-membered heteroaryl group.

22. The compound according to claim 21, wherein R 7 Selected from pyrazolyl and oxazolyl groups, each optionally separated by 1 to 2 R groups. g replace.

23. The compound according to claim 21 or 22, wherein R 7 It is optional to be 1 to 2 R g Substituted pyrazol group (e.g., R) 7 It is arbitrarily assigned to an R g Replacement ); or R in which 7 It is arbitrarily assigned to an R g Substituted oxazolyl group (e.g., R) 7 It is arbitrarily assigned to an R g Replacement ).

24. The compound according to any one of claims 21 to 23, wherein R 7 yes or .

25. The compound according to any one of claims 1 to 12, wherein R 1 It is a 7- to 10-membered (e.g., 7) bicyclic heterocyclic group having a cyclic nitrogen atom, an epoxide atom, and no additional cyclic heteroatoms, wherein the 7- to 10-membered bicyclic heterocyclic group is optionally surrounded by 1 to 4 (e.g., 1 to 2) R atoms. 7 replace.

26. The compound according to any one of claims 1 to 12 or 25, wherein R 1 It is a 7 to 10 (e.g., 7; e.g., 9) spirocyclic bicyclic heterocyclic group having one cyclic nitrogen atom, one cyclic oxygen atom, and no additional cyclic heteroatoms, wherein the 7 to 10 spirocyclic bicyclic heterocyclic group is optionally surrounded by 1 to 4 (e.g., 1 to 2) R 7 replace.

27. The compound according to any one of claims 1 to 12 or 25 to 26, wherein R 1 yes ,in: Ring A1 is a 4- to 7-membered heterocyclic base ring having an epoxy atom and no additional cyclic heteroatoms; n4 is 0, 1, or 2; and n5 is 0, 1, or 2, provided that n4 + n5 is 0, 1, or 2.

28. The compound according to any one of claims 1 to 12 or 25 to 27, wherein R 1 It is optional to be 1 to 2 R 7 Replacement .

29. The compound according to any one of claims 1 to 12 or 25 to 28, wherein R 1 yes .

30. The compound according to any one of claims 1 to 12 or 25 to 27, wherein R 1 yes or Each of them is arbitrarily assigned to one or two Rs. 7 replace.

31. The compound according to any one of claims 1 to 12, 25 to 27 or 30, wherein R 1 yes (For example or )or (For example or ).

32. The compound according to any one of claims 1 to 30, wherein R 1 It is optional to be 1 to 4 (e.g., 1 to 2) R 7 Replaced 4- to 7-membered heterocyclic groups.

33. The compound according to any one of claims 1 to 32, wherein R 1 It is optional to be 1 to 4 (e.g., 1 to 2) R 7 Substituted 4- to 5-membered heterocyclic groups (e.g., azirrobutyl or pyrrolidinyl).

34. The compound according to any one of claims 1 to 10 or 32 to 33, wherein R 1 It is optional to be 1 to 4 (e.g., 1 to 2) R 7 Substituted 4-membered heterocyclic group.

35. The compound according to any one of claims 1 to 10 or 32 to 34, wherein R 1 It is optional to be 1 to 4 (e.g., 1 to 2) R 7 Replacement .

36. The compound according to any one of claims 1 to 10 or 32 to 35, wherein R 1 Selected from: , , , , , , , , and .

37. The compound according to any one of claims 1 to 10 or 32 to 36, wherein R 1 yes (For example ), (For example )or .

38. The compound according to any one of claims 32 to 37, wherein each R 7 Independently selected from: halogenated group; cyano group; -OH group; oxo group; -C group 1-6 Alkyl group; C(=O)N(R) f )2;R b1 ;-(C 1-3 (alkylene)-R b1 ;-OR b1 ; and optionally by 1 to 3 R c7 Replacement C 1-6 Alkyl groups, wherein: Each R b1 Selected independently from: C 3-6 Cycloalkyl, phenyl, 4- to 6-membered heterocyclic and 5- to 6-membered heteroaryl groups, each optionally bound by 1 to 3 R groups. g (For example, each R) g Independently selected from: halogenated group and C 1-3 Alkyl) substitution; and Each R c7 Independently selected from: halogenated group, cyano group, -OH and -C 1-6 Alkyl group.

39. The compound according to any one of claims 32 to 38, wherein each R 7 Selected independently from: -F； -Cyano; -OH; -R b1 Wherein R b1 It is optional to be 1 to 2 R g Substituted 5- to 6-membered heteroaryl groups, C can be optionally replaced by 1 to 3 Fs 1-3 alkyl; -OH or C 1-3 alkoxy-substituted C 1-3 Alkyl; and C(=O)N(R f )2。 40. The compound according to claim 38 or 39, wherein at least one R 7 It is a C that is replaced by -OH 1-3 alkyl.

41. The compound according to any one of claims 1 to 10, wherein R 1 yes (For example ), where R 7 Is it -OH or C 1-3 alkoxy-substituted C 1-3 Alkyl (e.g., R) 7 It is a C that is replaced by -OH 1-3 alkyl).

42. The compound according to any one of claims 1 to 10 or 41, wherein R 1 yes (For example ).

43. The compound according to any one of claims 1 to 10, wherein R 1 yes or (For example ), where each R 7 Selected independently from: C can be optionally replaced by 1 to 3 Fs 1-3 Alkyl; and -OH or C 1-3 alkoxy-substituted C 1-3 alkyl.

44. The compound according to any one of claims 1 to 10 or 43, wherein R 1 yes (For example )or (For example ), where R 7a It is a C that is replaced by -OH 1-3 Alkyl groups (e.g., -CH2OH); and R 7b Selected from: C can be optionally replaced by 1 to 3 Fs 1-3 Alkyl (e.g., methyl), and -OH or C 1-3 alkoxy-substituted C 1-3 alkyl.

45. The compound according to any one of claims 1 to 10 or 43 to 44, wherein R 1 yes (For example ).

46. ​​The compound according to any one of claims 1 to 10 or 43 to 44, wherein R 1 yes or (For example ).

47. The compound according to claim 1, wherein the compound is a compound of formula (IV-b4), (IV-b5), or (IV-b8): Or their pharmaceutically acceptable salts, wherein: b4 is 0; Each R 10 Independently selected from: -Cl, -F, -CN, and optionally by 1 to 3 Rs c Replacement C 1-3 alkyl; X 1 It is CH2; X 2 It is CH2; and X 3 It is CHR L .

48. The compound according to claim 1, wherein the compound of formula (IV) is a compound of formula (IV-b6) or (IV-b7): Or their pharmaceutically acceptable salts, wherein: R 7 Is it -OH or C 1-3 alkoxy-substituted C 1-3 alkyl; R 7a It is a C that is replaced by -OH 1-3 Alkyl groups (e.g., -CH2OH); R 7b Selected from: C can be optionally replaced by 1 to 3 Fs 1-3 Alkyl (e.g., methyl), and -OH or C 1-3 alkoxy-substituted C 1-3 alkyl; b4 is 0; Each R 10 Independently selected from: -Cl, -F, -CN, and optionally by 1 to 3 Rs c Replacement C 1-3 alkyl; X 1 It is CH2; X 2 It is CH2; and X 3 It is CHR L .

49. The compound according to claim 47 or 48, wherein R 9 It is NR d R e (e.g., -NH2).

50. The compound according to claim 48 or 49, wherein Part of it is .

51. The compound according to claims 48 to 50, wherein R 7 It is a C that is replaced by -OH 1-3 alkyl.

52. The compound according to any one of claims 48 to 51, wherein R 7 It is -CH2OH.

53. The compound according to claim 48 or 49, wherein Part of it is .

54. The compound according to any one of claims 48 to 49 or 53, wherein R 7a It is -CH2OH.

55. The compound according to any one of claims 48 to 49 or 53 to 54, wherein R 7b C is a C that is optionally replaced by 1 to 3 -F. 1-3 alkyl.

56. The compound according to claim 55, wherein R 7b It is a methyl group.

57. The compound according to any one of claims 47 to 56, wherein X 3 It is CH(CH3).

58. The compound according to any one of claims 47 to 57, wherein R 3 It can be optionally replaced by one or two -F. (For example, R) 3 yes , or ).

59. The compound according to any one of claims 47 to 57, wherein R 3 yes (For example ).

60. The compound according to any one of claims 1 to 59, wherein Part of it is .

61. The compound according to claim 1, wherein the compound of formula (IV-b) is selected from the compound numbers 502, 502a, 502b, 511, 511a, 512, 512a, 512b, 532, 532a, 553, 553a, 554, 554a, 554b, 554c, 555, 555a, 556, 556a, 556b, 560, 560a, 561, 561a, 566, 566a, 566b, 567, 567a, 567b, 568, 568a, 568b, 569, 569a, 570, 570a, 571, 571a, 572, 572a, 573, 573a, 5 75, 575a, 575b, 576, 576a, 576b, 576c, 576d, 577, 577a, 578, 578a, 578b, 58 1. 581a, 582, 582a, 583, 583a, 585, 585a, 585b, 589, 589a, 592, 592a, 595, 5 95a, 595b, 597, 597a, 597b, 598, 598a, 598b, 598c, 599, 599a, 599b, 600, 60 0a, 600b, 601, 601a, 605, 605a, 605b, 605c, 606, 606a, 606b, 607, 607a, 608, 608a, 608b, 609, 609a, 609b, 610, 610a, 610b, 611, 611a, 611b, 612, 612a, 6 12b, 613, 613a, 613b, 613c, 618, 618a, 619, 619a, 620, 620a, 621, 621a, 621 b, 622, 622a, 623, 623a, 624, 624a, 624b, 625, 625a, 626, 626a, 627, 627a, 6 33, 633a, 634, 634a, 635, 635a, 636, 636a, 637, 637a, 637b, 638, 638a, 639, 6 39a, 640, 640a, 640b, 642, 642a, 643, 643a, 643b, 644, 644a, 645, 645a, 645 b, 646, 646a, 647, 647a, 647b, 648, 648a, 648b, 649, 649a, 649b, 650, 650a, 6 50b, 650c, 650d, 651, 651a, 651b, 652, 652a, 652b, 652c, 653, 653a, 653b, 6 54, 654a, 654b, 654c, 654d, 655, 655a, 656, 656a, 657, 657a, 658, 658a, 659,659a, 660, 660a, 660b, 661, 661a, 661b, 662, 662a, 662b, 662c, 662d, 6 65, 665a, 665b, 666, 666a, 667, 667a, 667b, 668, 668a, 668b, 668c, 668d ,669,669a,670,670a,671,671a,671b,672,672a,673,673a,674,674 a, 675, 675a, 676, 676a, 677, 677a, 678, 678a, 679, 679a, 680, 680a, 680 b. 680c, 681, 681a, 682, 682a, 683, 683a, 684, 684a, 685, 685a, 686, 68 6a, 687, 687a, 688, 688a, 689, 689a, 689b, 690, 690a, 691, 691a, 692, 69 2a, 693, 693a, 694, 694a, 695, 695a, 696, 696a, 697, 697a, 698, 698a, 6 99, 699a, 700, 700a, 701, 701a, 702, 702a, 702b, 703, 703a, 704, 704a, 7 05, 705a, 707, 707a, 708, 708a, 709, 709a, 710, 710a, 711, 711a, 712, 7 12a, 713, 713a, 714, 714a, 715, 715a, 716, 716a, 717, 717a, 718, 718a, 7 19, 719a, 720, 720a, 721, 721a, 722, 722a, 723, 723a, 724, 724a, 725, 7 25a, 726, 726a, 727, 727a, 728, 728a, 729, 729a, 729b, 730, 730a, 731, 7 31a, 732, 732a, 733, 733a, 734, 734a, 735, 735a, 736, 736a, 737, 737a, 737b, 738, 738a, 739, 739a, 740, 740a, 741, 741a, 741b, 742, 742a, 743, 743a, 744, 744a, 745, 745a, 745b, 746, 746a, 747, 747a, 747b, 748, 748a, 749, 749a, 750, 750a, 752, 752a, 753, 753a, 754 and 754a or their pharmaceutically acceptable salts.

62. The compound of claim 1, wherein the compound of formula (IV-b) is not one of the compounds numbered R179, R179a, R179b, R179d, R179e and R179f as depicted in Table C1 or a pharmaceutically acceptable salt thereof.

63. A pharmaceutical composition comprising a compound according to any one of claims 1 to 62 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.

64. A method for treating a subject with cancer, the method comprising administering to a subject identified or diagnosed with cancer having a KRas regulation disorder a therapeutically effective amount of any one of claims 1 to 62, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 63.

65. A method for treating a subject's cancer, the method comprising (a) determining that the subject's cancer has a KRas regulation abnormality; and (b) administering to the subject a therapeutically effective amount of a compound according to any one of claims 1 to 62 or a pharmaceutically acceptable salt thereof or a pharmaceutical composition according to claim 63.

66. The method of claim 64 or 65, wherein the KRas regulatory abnormality is a KRas mutation.

67. The method of claim 66, wherein the KRas mutation is a KRas G12A mutation, a KRas G12C mutation, a KRas G12D mutation, a KRas G12R mutation, a KRas G12S mutation, or a KRas G12V mutation.

68. The method of claim 67, wherein the KRas mutation is a KRas G12C mutation, a KRas G12D mutation, or a KRas G12V mutation.

69. The method of claim 65, wherein the step of determining that the cancer of the subject has a KRas regulatory abnormality includes performing a assay to detect the KRas regulatory abnormality (e.g., KRas mutation) in a tumor sample from the subject.

70. The method of claim 69, wherein detecting the KRas regulatory abnormality comprises detecting a KRAS gene with a mutation corresponding to a substitution of glycine 12 in the KRas protein and / or a KRas protein with a substitution of glycine 12.

71. The method according to claim 70, wherein the glycine 12 is substituted with alanine, cysteine, aspartic acid, arginine, serine, or valine.

72. The method according to any one of claims 64 to 71, wherein the cancer is selected from: hematologic cancers, soft tissue cancers, bile duct cancers, bladder cancers, brain cancers, breast cancers, cervical cancers, colorectal cancers, endometrial cancers, esophageal cancers, kidney cancers, liver cancers, lung cancers, mucinous cancers, ovarian cancers, pancreatic cancers, prostate cancers, skin cancers, gastric cancers, testicular cancers, thymic cancers, thyroid cancers, urothelial carcinomas, uterine cancers, and combinations thereof.

73. The method of claim 72, wherein the cancer is selected from: colon cancer, endometrial cancer, lung cancer, pancreatic cancer, and uterine cancer.

74. The method of claim 72, wherein the cancer is selected from: colorectal cancer, endometrial cancer, lung cancer (e.g., NSCLC), ovarian cancer, and pancreatic cancer.

75. The method according to any one of claims 64 to 74, the method comprising administering additional therapy or treatment agent to the subject.

76. The method of claim 75, wherein the additional therapy or therapeutic agent is selected from Ras pathway targeted therapeutic agents, kinase targeted therapeutic agents, mTORC1 inhibitors or degraders, YAP inhibitors or degraders, proteasome inhibitors or degraders, HSP90 inhibitors or degraders, farnesyltransferase inhibitors or degraders, PTEN inhibitors or degraders, signal transduction pathway inhibitors or degraders, checkpoint inhibitors, apoptosis pathway modulators, chemotherapeutic agents, angiogenesis-targeted therapies, immunotargeting agents, radiotherapy, and combinations thereof.

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