Tetrahydroisoquinoline heterobifunctional BCL-XL degrader

Abstract

The present disclosure relates to BCL-X L compounds of formula (I) (e.g., (I-A) (e.g., (I-A-1), (I-A-2), or (I-A-3)), (I-B) (e.g., (I-B-1), (I-B-2), or (I-B-3)), (I-C), (I-D), (I-E) (e.g., (I-E-1), (I-E-2), or (I-E-3)), (I-Ea) (e.g., (I-Ea-1), (I-Ea-2), or (I-Ea-3)), (I-Eb) (e.g., (I-Eb-1), (I-Eb-2), or (I-Eb-3)), (I-F) (e.g., (I-F-1), (I-F-2), or (I-F-3)), (I-G), (I-Ga), (I-H) (e.g., (I-H-1), (I-H-2), or (I-H-3))), or formula (II) (e.g., (II-a)), or pharmaceutically acceptable salts thereof. These compounds are useful, for example, in treating cancer in a subject (e.g., a human). The present disclosure also provides compositions containing the compounds provided herein, as well as methods of using and making the same. TIFF2025517642000966.tif79128

Claims

1. Compound of formula (I): or a pharmaceutically acceptable salt thereof, wherein Ring A is (a) R ａ and R ｂ 1 to 6 substituents independently selected from the group consisting of, each optionally substituted, C ３～１５ cycloalkylene or 3- to 15-membered heterocyclylene, and (b) R ａ and R ｂ Each of which is optionally substituted with 1 to 3 substituents independently selected from the group consisting of phenylene or 5- to 6-membered heteroarylene which may each be optionally substituted selected from the group consisting of R １ is (a) C(O)OH and (b) C(O)NR ｄ R ｅ and (c) C(O)OC １～６ is alkyl, wherein said C １～６ alkyl may be optionally substituted with 1 to 3 R ｃ and is C(O)OC １～６ alkyl selected from the group consisting of Each R ２ 、R ３ 、R ４ 、and R ５ is independently selected from the group consisting of halo, CN, C １～３ alkyl, C １～３ haloalkyl, C １～３ alkoxy, C １～３ haloalkoxy, OH, and NR ｄ R ｅ and is selected from the group consisting of: m2 is 0, 1, or 2, m3 and m4 are independently 0, 1, 2, or 3, m5 is 0, 1, 2, 3, or 4, L is, -(L Ａ ) ｎ１ -, where L Ａ and n1 are defined according to (AA) or (BB), (AA) n1 is an integer from 3 to 15, Each L Ａ is independently selected from the group consisting of L Ａ１ , L Ａ３ , and L Ａ４ , provided that 1 to 3 occurrences of L Ａ are L Ａ４ . (BB) n1 is an integer from 0 to 20, Each L Ａ is independently selected from the group consisting of L Ａ１ and L Ａ３ and is selected from the group consisting of Each L Ａ１ is independently selected from the group consisting of -CH ２ -, -CHR Ｌ -, and -C(R Ｌ ) ２ -. Each L Ａ３ is independently selected from the group consisting of -N(R ｄ )-, -N(R ｂ )-, -O-, -S(O) ０～２ - and C(=O). Each L Ａ４ is, independently, (a) R ａ and R ｂ 1 to 6 substituents independently selected from the group consisting of, each optionally substituted, C ３～１５ cycloalkylene or 3- to 15-membered heterocyclylene, and (b) R ａ and R ｂ Each of 1 to 6 substituents independently selected from the group consisting of and R may be optionally substituted, C ６～１５ arylene or 5- to 15-membered heteroarylene and selected from the group consisting of However, L does not contain any of the bonds N—O, O—O, N—N, N—S(O) ０ , and O—S(O) ０～２ and is to contain none of the bonds In the formula, each R Ｌ is independently selected from the group consisting of halo, cyano, -OH, -C １～６ alkoxy, -C １～６ haloalkoxy, -NR ｄ R ｅ and C(=O)N(R ｆ ) ２ and S(O) ０～２ (C １～６ alkyl), S(O) ０～２ (C １～６ haloalkyl), S(O) １～２ N(R ｆ ) ２ and -R ｂ and optionally substituted C ｃ alkyl with 1 to 6 R １～６ and is selected from the group consisting of: Ring C is selected from the group consisting of c1 is 0, 1, 2, or 3, Each R Ｙ is independently selected from the group consisting of R ａ and R ｂ ​ R ａＮ is H or C alkyl which may optionally be substituted with 1 to 3 R ｃ and which may optionally be substituted with 1 to 3 R １～６ groups Y １ and Y ２ are independently N, CH, or CR Ｙ and yy represents the point of attachment to L, X is CH, C, or N, said is a single bond or a double bond, L Ｃ is selected from the group consisting of a bond, -CH ２ -, -CHR ａ -, -C(R ａ ) ２ -, -N(R ｄ )- and O, provided that when X is N, L Ｃ is other than O Each R ａ is, independently, (a) halo, (b) cyano, (c) -OH, (d) oxo, (e)-C １～６ alkoxy, (f)-C １～６ Haloalkoxy, (g) -NR ｄ R ｅ , (h) C(=O)C １～６ alkyl, (i) C(=O)C １～６ Haloalkyl, (j) C(=O)OH, (k) C(=O)OC １～６ alkyl, (l) C(=O)OC １～６ haloalkyl, (m)C(=O)N(R ｆ ) ２ , (n) S(O) ０～２ (C １～６ alkyl), (o) S(O) ０～２ (C １～６ haloalkyl), (p)S(O) １～２ N(R ｆ ) ２ and (q) 1 to 6 Rs ｃ each of which may optionally be substituted, C １～６ alkyl, C ２～６ alkenyl, or C ２～６ alkynyl selected from the group consisting of Each R ｂ is independently selected from the group consisting of -(L ｂ ), ｂ -R ｂ１ and -R ｂ１ wherein, each b is independently 1, 2, or 3, each -L ｂ is independently selected from the group consisting of -O-, -N(H)-, -N(C １～３ alkyl)-, -S(O) ０～２ -, C(=O), and C １～３ alkylene Each R ｂ１ is independently selected from the group consisting of C ３～１０ cycloalkyl, 4- to 10-membered heterocyclyl, C ６～１０ aryl, and 5- to 10-membered heteroaryl, each of which may be optionally substituted with 1 to 3 R ｇ and may be optionally substituted, Each R ｃ is independently selected from the group consisting of halo, cyano, -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), S(O) ０～２ (C １～６ haloalkyl), and S(O) １～２ N(R ｆ ) ２ ; Each R ｄ and R ｅ is independently selected from the group consisting of 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), S(O) １～２ (C １～６ haloalkyl), S(O) １～２ N(R ｆ ) ２ , and C ｈ alkyl optionally substituted with 1 to 3 R １～６ and is selected from the group consisting of: Each R ｆ is independently selected from the group consisting of H and C ｈ alkyl which may optionally be substituted with 1 to 3 R １～６ groups, Each R ｇ is independently selected from the group consisting of R ｈ , C １～３ alkyl, and C １～３ haloalkyl Each R ｈ is independently selected from the group consisting of halo, cyano, -OH, -C １～６ alkoxy, -C １～６ haloalkoxy, -NH ２ , -N(H)(C １～３ alkyl), and -N(C １～３ alkyl) ２ selected from the group consisting of: said compound or a pharmaceutically acceptable salt thereof.

2. Ring A is a phenylene which may optionally be substituted by 1 to 3 Rs ａ The compound according to claim 1, wherein Ring A is a phenylene which may optionally be substituted by 1 to 3 Rs.

3. When Ring A is wherein aa represents the point of attachment to L or When Ring A is wherein aa represents the point of attachment to L or When Ring A is wherein aa represents the point of attachment to L, The compound according to Claim 1 or 2.

4. Ring A is a 5- to 6-membered heteroarylene optionally substituted with 1 to 3 Rs ａ The compound according to claim 1, wherein Ring A is a 5- to 6-membered heteroarylene optionally substituted with 1 to 3 Rs.

5. One R present on ring A ａ which may optionally be substituted with 1 to 3 Fs is C １～３ an alkyl or One R existing on ring A ａ is methyl or CF ３ and is The compound according to any one of Claims 1 to 4.

6. R １ The compound according to any one of claims 1 to 5, wherein R is C(O)OH.

7. The compound according to any one of Claims 1 to 6, wherein m2 is 0.

8. The compound according to any one of Claims 1 to 7, wherein m3 is 0.

9. The compound according to any one of Claims 1 to 8, wherein m4 is 0.

10. The compound according to any one of Claims 1 to 9, wherein m5 is 0.

11. The compound according to any one of Claims 1 to 6, wherein m2 is 0, m3 is 0, m4 is 0, and m5 is 0.

12. When Ring C is or When Ring C is or When Ring C is The compound according to any one of Claims 1 to 11.

13. The compound according to Claim 12, wherein c1 is 0.

14.

15. R ａＮ is C １～３ alkyl, or R ａＮ is methyl, the compound according to any one of claims 12 or 13.

16. L Ｃ The compound according to any one of claims 12 to 14, wherein L is a bond. The compound according to any one of Claims 12 to 15, wherein X is CH.

17. said moiety is or said moiety is The compound according to any one of Claims 1 to 12.

18.

19. ​ L is -(L Ａ ) ｎ１ -, and L Ａ and n1 are as defined according to (AA), a compound according to any one of claims 1 to 17. ​ The compound according to any one of claims 1 to 18, wherein n1 is an integer from 3 to 5, or n1 is an integer from 5 to 9, or n1 is 6, 7, or 8, or n1 is an integer from 9 to 12.

20. L Ａ has one or two occurrences in L Ａ４ or one occurrence of L Ａ or two occurrences of L Ａ４ or two occurrences of L Ａ in L, a compound according to any one of claims 1 to 19 Ａ４ wherein the one or two occurrences of L are in L

21. Each L Ａ４ is independently (a) 1 to 3 Rs ａ each of which may optionally be substituted, C ３～１０ cycloalkylene or 4- to 10-membered heterocyclylene, and (b) 1 to 3 Rs ａ each of which may optionally be substituted, and phenylene or 5- or 6-membered heteroarylene The compound according to any one of claims 1 to 20, which is selected from the group consisting of

22. L Ａ has 1 to 4 occurrences of L Ａ３ or has 1 to 3 occurrences of L Ａ in L, the compound according to any one of claims 1 to 21 Ａ３ wherein the compound is as defined in any one of claims 1 to 21

23. L Ａ３ 0 to 1 occurrence of which is C(=O), and L Ａ３ each of the remaining occurrences of which is independently selected from the group consisting of -O-, -N(H)-, and -N(C １～３ alkyl)-; a compound according to any one of claims 1 to 22.

24. L Ａ appears two to seven times in L Ａ１ or appears two to five times in L Ａ The compound according to any one of claims 1 to 23, wherein appears two to five times in L Ａ１ ​

25. L Ａ１ appears 0 to 2 times as -CHR Ｌ - or -C(R Ｌ ) ２ -, and each remaining appearance of L Ａ１ is -CH ２ -, a compound according to any one of claims 1 to 24.

26. L Ａ１ each occurrence of which is —CH ２ —, or one occurrence of L Ａ１ is —CHR Ｌ — or —C(R Ｌ ) ２ —, and each remaining occurrence of L Ａ１ is —CH ２ —, a compound according to any one of claims 1 to 25.

27. Each R Ｌ independently is selected from the group consisting of -F and -C optionally substituted with 1 to 3 F １～３ alkyl, and the compound according to any one of claims 1 to 26

28. L is, -(L Ａ ) ｎ１ -, and L Ａ and n1 are defined according to (AA), n1 is an integer from 5 to 9, L Ａ appears one or two times in L Ａ４ and L Ａ appears two to seven times in L Ａ１ and L Ａ One to three occurrences of Ａ３ are in L The compound according to any one of claims 1 to 18.

29. L is (i)-(L Ａ３ ) ０～２ -(L Ａ１ ) ０～５ -L Ａ４ -(L Ａ１ ) ０～５ -(L Ａ３ ) １～２ - ｂｂ and (ii)-(L Ａ３ ) ０～２ -(L Ａ１ ) ０～５ -L Ａ４ -(L Ａ１ ) ０～５ -L Ａ４ - ｂｂ and, (iii)-(L Ａ３ ) ０～２ -(L Ａ１ ) ０～５ -L Ａ４ -(L Ａ１ ) ０～５ -L Ａ３ -L Ａ４ - ｂｂ and, (iv)-(L Ａ３ ) ０～１ -(L Ａ１ ) ２～３ -L Ａ３ -L Ａ４ -(L Ａ１ ) ０～５ -(L Ａ３ ) １～２ - ｂｂ and selected from the group consisting of However, L contains 1 to 7 Ls Ａ１ In the formula, bb represents the bonding point to ring C. The compound according to any one of claims 1 to 18.

30. L is -(L Ａ３ ) ０～２ -(L Ａ１ ) ２～９ -(L Ａ３ ) ０～１ -L Ａ４ - ｂｂ wherein bb represents the bonding point to ring C, The compound according to any one of claims 1 to 18.

31. Each L Ａ４ is, independently, (a) 1 to 3 R's ａ each of which may optionally be substituted, C ３～１０ cycloalkylene or 4- to 10-membered heterocyclylene, and (b) 1 to 3 Rs ａ each of which may optionally be substituted, a phenylene or a 5- or 6-membered heteroarylene and The compound according to any one of claims 28 to 30, which is selected from the group consisting of

32. L Ａ１ appears 0 to 1 times as -CHR Ｌ - or -C(R Ｌ ) ２ -, and each remaining occurrence of L Ａ１ is -CH ２ -, the compound according to any one of claims 28 to 31.

33. L Ａ３ has 0 to 1 occurrence of C(=O), and each of the remaining occurrences of L Ａ３ is independently selected from the group consisting of -O-, -N(H)-, and -N(C １～３ alkyl)-, a compound according to any one of claims 28 to 32.

34. L is -(L Ａ３ ) ０～２ -(L Ａ１ ) ０～５ -L Ａ４ -(L Ａ１ ) ０～５ -(L Ａ３ ) １～２ - ｂｂ and provided that L is 1 to 7 Ls Ａ１ is contained, wherein bb represents a bonding point to ring C The compound according to any one of claims 1 to 18.

35. L is -(L Ａ３ ) ０～１ -(L Ａ１ ) ０～５ -L Ａ４ -(L Ａ１ ) ０～５ -(L Ａ３ ) ２ - ｂｂ wherein L is 1 to 5 Ls, provided that Ａ１ it contains, and in the formula, bb represents a bonding point to ring C The compound according to any one of claims 1 to 18 or 34.

36. L is -(L Ａ３ ) ０～１ -(L Ａ１ ) ０～５ -L Ａ４ -(L Ａ１ ) ０～５ -C(=O)-N(R ｄ )- ｂｂ and provided that L is 1 to 5 Ls Ａ１ is contained, where bb represents the bonding point to ring C The compound according to any one of claims 1 to 18 or 34 to 35.

37. L is a divalent group of formula (L-1): wherein a3 is 0 or 1, L Ａ３ is selected from the group consisting of -O-, -N(H)-, and -N(C １～３ alkyl)- a1a and a1b are independently integers from 0 to 5, provided that a1a + a1b is from 1 to 5, L Ａ１ａ and L Ａ１ｂ each independently represents -CH ２ -, -CHR Ｌ -, and -C(R Ｌ ) ２ and is selected from the group consisting of L Ａ４ is (a) 1 to 3 Rs ａ each of which may optionally be substituted, C ３～１０ cycloalkylene or 4- to 10-membered heterocyclylene, and (b) 1 to 3 Rs ａ each of which may optionally be substituted, and phenylene or 5- to 6-membered heteroarylene selected from the group consisting of bb represents the bonding point to ring C, The compound according to any one of claims 34 to 36.

38. The compound according to claim 37, wherein a3 is 1.

39. L Ａ３ The compound according to claim 37 or 38, wherein L is -O-.

40. The compound according to claim 37, wherein a3 is 0.

41. The compound according to any one of claims 37 to 40, wherein a1a + a1b is 3 or 4, or a1a + a1b is 2 or 5.

42. The compound according to any one of claims 38 to 40, wherein a1a + a1b is from 2 to 5.

43. L is -(L Ａ３ ) ０～１ -(L Ａ１ ) ０～５ -L Ａ４ -(L Ａ１ ) ０～５ -L Ａ３ - ｂｂ and provided that L is 2 to 7 Ls Ａ１ is contained, and in the formula, bb represents a bonding point to ring C The compound according to any one of claims 1 to 18 or 34.

44. L is a divalent group of formula (L-2): wherein a3a is 0 or 1, L Ａ３ａ and L Ａ３ｂ are each independently selected from the group consisting of -O-, -N(H)-, and -N(C １～３ alkyl)- a1a and a1b are independently integers from 0 to 5, provided that a1a + a1b is from 2 to 7, L Ａ１ａ and L Ａ１ｂ each independently represents -CH ２ -, -CHR Ｌ -, and -C(R Ｌ ) ２ and is selected from the group consisting of L Ａ４ is (a) 1 to 3 Rs ａ each of which may optionally be substituted, C ３～１０ cycloalkylene or 4- to 10-membered heterocyclylene, and (b) 1 to 3 Rs ａ each of which may optionally be substituted, and phenylene or 5- to 6-membered heteroarylene selected from the group consisting of bb represents the bonding point to ring C, The compound according to claim 34 or 43.

45. The compound according to claim 44, wherein a3a is 1.

46. L Ａ３ａ The compound according to claim 44 or 45, wherein L is -O-.

47. L Ａ３ｂ is -N(H)- or -N(C １～３ alkyl)-, a compound according to any one of claims 44 to 46.

48. L Ａ３ｂ The compound according to any one of claims 44 to 46, wherein L is -O-.

49. The compound according to any one of claims 44 to 48, wherein a1a + a1b is 2, 3, or 4.

50. The compound according to any one of claims 44 to 48, wherein a1a + a1b is 5 or 6.

51. L is -(L Ａ３ ) ０～１ -(L Ａ１ ) ０～５ -L Ａ４ -(L Ａ１ ) ０～５ -L Ａ４ - ｂｂ 、or -(L Ａ３ ) ０～１ -(L Ａ１ ) ０～５ -L Ａ４ -(L Ａ１ ) ０～５ -L Ａ３ -L Ａ４ - ｂｂ wherein L is 2 to 7 Ls, provided that Ａ１ it contains, and in the formula, bb represents a bonding point to ring C The compound according to any one of claims 1 to 18.

52. L is -(L Ａ３ ) ０～１ -(L Ａ１ ) ０～５ -L Ａ４ -(L Ａ１ ) ０～５ -(piperazinylene)- ｂｂ , -(L Ａ３ ) ０～１ -(L Ａ１ ) ０～５ -L Ａ４ -(L Ａ１ ) ０～５ -(piperidinylene)- ｂｂ or -(L Ａ３ ) ０～１ -(L Ａ１ ) ０～５ -L Ａ４ -(L Ａ１ ) ０～５ -C(=O)-(piperazinylene)- ｂｂ and provided that L contains 2 to 5 Ls Ａ１ shall contain In the formula, the piperazinylene and piperidinylene may each be optionally substituted with 1 to 3 Rs ａ and may be optionally substituted In the formula, bb represents the bonding point to ring C. The compound according to claim 51.

53. L is a divalent group of formula (L-3), (L-3a), (L-3b), or (L-4): In the formula, a3 is 0 or 1. L Ａ３ is selected from the group consisting of -O-, -N(H)-, and -N(C １～３ alkyl)- a1a and a1b are independently integers from 0 to 5, provided that a1a + a1b is 2 to 5. L Ａ１ａ and L Ａ１ｂ each independently represents -CH ２ -, -CHR Ｌ -, and -C(R Ｌ ) ２ and is selected from the group consisting of L Ａ４ is (a) 1 to 3 Rs ａ each of which may optionally be substituted, C ３～１０ cycloalkylene or 4- to 10-membered heterocyclylene, and (b) one to three Rs ａ each of which may optionally be substituted, and phenylene or 5- to 6-membered heteroarylene Selected from the group consisting of n2 and n3 are independently 0, 1, or 2. m8 is 0, 1, or 2. L Ａ４ｂ is a 7- to 10-membered bicyclic nitrogen-containing heterocyclylene optionally substituted with 1 to 3 Rs ａ and is bb represents the bonding point to ring C. The compound according to claim 51.

54. The compound according to claim 53, wherein a3 is 1.

55. L Ａ３ The compound according to claim 53 or 54, wherein L is -O-.

56. The compound according to any one of claims 53 to 55, wherein a1a + a1b is 3 or 4.

57. The compound according to any one of claims 53 to 55, wherein a1a + a1b is 2.

58. L Ａ１ａ and L Ａ１ｂ each occurrence of which is —CH ２ —, a compound according to any one of claims 37 to 42, 44 to 50, or 53 to 57.

59. L Ａ１ａ has one occurrence of -CHR Ｌ - or -C(R Ｌ ) ２ -, and each remaining occurrence of L Ａ１ａ is -CH ２} -, and each occurrence of L Ａ１ｂ is -CH ２ -, a compound according to any one of claims 37 to 42, 44 to 50, or 53 to 57.

60. L Ａ１ｂ has one occurrence of -CHR Ｌ - or -C(R Ｌ ) ２ -, and each remaining occurrence of L Ａ１ｂ is -CH ２ -, and each occurrence of L Ａ１ａ is -CH ２ -, a compound according to any one of claims 37 to 42, 44 to 50, or 53 to 57.

61. L Ａ４ is a 4- to 10-membered heterocyclylene optionally substituted with 1 to 3 R ａ and is a compound according to any one of claims 34 to 60.

62. L Ａ４ is a 4- to 10-membered nitrogen-containing heterocyclylene optionally substituted with 1 to 3 Rs ａ The compound according to any one of claims 34 to 60.

63. L Ａ４ is At one or more ring carbon atoms, 1 to 3 Rs ａ each of which may optionally be substituted selected from the group consisting of, wherein cc is the bond to L Ａ１ｂ representing the point of attachment to The compound according to any one of claims 34 to 62.

64. L Ａ４ each R present thereon ａ is, independently, F or C optionally substituted with 1 to 3 Fs １～３ is alkyl, the compound according to claim 62 or 63

65. L Ａ４ is C cycloalkylene optionally substituted with 1 to 3 Rs ａ and is a compound according to any one of claims 34 to 61. ３～１０ ​

66. L Ａ４ is 1,4 - cyclohexylene which may optionally be replaced by 1 to 3 Rs ａ The compound according to any one of claims 34 to 61 or 65, wherein

67. L Ａ４ is phenylene or 5- to 6-membered heteroarylene, each of which may optionally be substituted with 1 to 3 R ａ and the compound according to any one of claims 34 to 60.

68. L Ａ４ is (a) 1 to 3 Rs ａ phenylene which may optionally be substituted, (b) 1 to 3 Rs ａ 1,2-phenylene which may optionally be replaced by, or (c) 1 to 3 Rs ａ 1,4-phenylene which may optionally be replaced by The compound according to any one of claims 35 to 60 or 67, wherein it is

69. L is -(L Ａ３ ) ０～１ -(L Ａ１ ) ２～９ -(L Ａ３ ) ０～１ -(piperazinylene)- ｂｂ In the formula, bb represents the bonding point to ring C. The compound according to any one of claims 1 to 18 or 30.

70. L is a divalent group of formula (L-6): In the formula, L Ａ３ａ is selected from the group consisting of -O-, -N(H)-, and -N(C １～３ alkyl)- a3a is 0 or 1. a1 is an integer from 2 to 11. a3c is 0 or 1. bb represents the bonding point to ring C. The compound according to claim 69.

71. The compound according to claim 70, wherein a3a is 1.

72. L Ａ３ａ The compound according to claim 70 or 71, wherein L is -O-.

73. L Ａ１ appears 0 to 1 times, -CHR Ｌ - or -C(R Ｌ ) ２ -, and each remaining occurrence of L Ａ１ is -CH ２ -, a compound according to any one of claims 70 to 72.

74. L is Selected from the group consisting of, in the formula, bb represents the bonding point to ring C. The compound according to any one of claims 1 to 18 or 34 to 37.

75. L is Selected from the group consisting of, in the formula, bb represents the bonding point to ring C. The compound according to any one of claims 1 to 18 or 34 to 37.

76. L is wherein bb represents the point of attachment to ring C. The compound according to any one of claims 1 to 18, 34 or 43 to 44.

77. L is selected from the group consisting of, wherein bb represents the point of attachment to ring C. The compound according to any one of claims 1 to 18 or 51 to 53.

78. L is selected from the group consisting of, wherein bb represents the point of attachment to ring C. The compound according to any one of claims 1 to 18 or 51 to 53.

79. Said compound of formula (I) is a compound of formula (I-A): or a pharmaceutically acceptable salt thereof, wherein m6 is 0 or 1, a3 is 0 or 1, L Ａ３ is selected from the group consisting of -O-, -N(H)-, and -N(C １～３ alkyl)- a1a and a1b are independently integers from 0 to 5, provided that a1a + a1b is 1 to 5, L Ａ１ａ and L Ａ１ｂ each independently is selected from the group consisting of -CH ２ -, -CHR Ｌ -, and -C(R Ｌ ) ２ -. L Ａ４ is (a) 1 to 3 Rs ａ each of which may optionally be substituted, C ３～１０ cycloalkylene or 4- to 10-membered heterocyclylene, and (b) 1 to 3 Rs ａ each of which may optionally be substituted, and phenylene or 5- to 6-membered heteroarylene selected from the group consisting of, or Said compound of formula (I) is a compound of formula (I-B): or a pharmaceutically acceptable salt thereof, wherein m6 is 0 or 1, a3 is 0 or 1, L Ａ３ is selected from the group consisting of -O-, -N(H)-, and -N(C １～３ alkyl)- a1a and a1b are independently integers from 0 to 5, provided that a1a + a1b is 1 to 5, L Ａ１ａ and L Ａ１ｂ each independently is selected from the group consisting of -CH ２ -, -CHR Ｌ -, and -C(R Ｌ ) ２ - and is selected from the group consisting of L Ａ４ is (a) 1 to 3 Rs ａ each of which may optionally be substituted, C ３～１０ cycloalkylene or 4- to 10-membered heterocyclylene, and (b) 1 to 3 Rs ａ each of which may optionally be substituted, and phenylene or 5- to 6-membered heteroarylene selected from the group consisting of, or Said compound of formula (I) is a compound of formula (I-C) or (I-D): or pharmaceutically acceptable salts thereof, wherein m6 is 0 or 1, a3a is 0 or 1, L Ａ３ａ and L Ａ３ｂ are each independently selected from the group consisting of -O-, -N(H)-, and -N(C １～３ alkyl)- a1a and a1b are independently integers from 0 to 5, provided that a1a + a1b is 2 to 7, L Ａ１ａ and L Ａ１ｂ each independently represents -CH ２ -, -CHR Ｌ -, and -C(R Ｌ ) ２ and is selected from the group consisting of L Ａ４ is (a) 1 to 3 Rs ａ each of which may optionally be substituted, C ３～１０ cycloalkylene or 4- to 10-membered heterocyclylene, and (b) 1 to 3 Rs ａ each of which may optionally be substituted, and phenylene or 5- to 6-membered heteroarylene selected from the group consisting of, or Said compound of formula (I) is a compound of formula (I-E): or a pharmaceutically acceptable salt thereof, wherein m6 is 0 or 1, a3 is 0 or 1, L Ａ３ is selected from the group consisting of -O-, -N(H)-, and -N(C １～３ alkyl)- a1a and a1b are independently integers from 0 to 5, provided that a1a + a1b is 2 to 5, L Ａ１ａ and L Ａ１ｂ each independently is selected from the group consisting of -CH ２ -, -CHR Ｌ -, and -C(R Ｌ ) ２ -. L Ａ４ is (a) 1 to 3 Rs ａ each of which may optionally be substituted, C ３～１０ cycloalkylene or 4- to 10-membered heterocyclylene, and (b) 1 to 3 Rs ａ each of which may optionally be substituted, a phenylene or a 5- or 6-membered heteroarylene and selected from the group consisting of, m8 is 0, 1, or 2, or Said compound of formula (I) is a compound of formula (I-Ea): or a pharmaceutically acceptable salt thereof, wherein m6 is 0 or 1, a3 is 0 or 1, L Ａ３ is selected from the group consisting of -O-, -N(H)-, and -N(C １～３ alkyl)- a1a and a1b are independently integers from 0 to 5, provided that a1a + a1b is 2 to 5, L Ａ１ａ and L Ａ１ｂ each independently represents -CH ２ -, -CHR Ｌ -, and -C(R Ｌ ) ２ - and is selected from the group consisting of L Ａ４ is (a) 1 to 3 Rs ａ each of which may be optionally substituted, C ３～１０ cycloalkylene or 4- to 10-membered heterocyclylene, and (b) 1 to 3 Rs ａ each of which may optionally be substituted, and phenylene or 5- or 6-membered heteroarylene selected from the group consisting of, n2 and n3 are independently 0, 1, or 2, m8 is 0, 1, or 2, or The compound of formula (I) is a compound of formula (I-Eb): or a pharmaceutically acceptable salt thereof, wherein m6 is 0 or 1; a3 is 0 or 1; L Ａ３ is selected from the group consisting of -O-, -N(H)-, and -N(C １～３ alkyl)- a1a and a1b are independently integers from 0 to 5, provided that a1a + a1b is 2 to 5; L Ａ１ａ and L Ａ１ｂ each independently represents -CH ２ -, -CHR Ｌ -, and -C(R Ｌ ) ２ - and is selected from the group consisting of L Ａ４ is (a) 1 to 3 Rs ａ each of which may optionally be substituted, C ３～１０ cycloalkylene or 4- to 10-membered heterocyclylene, and (b) 1 to 3 R's ａ each of which may be optionally substituted, and phenylene or 5- or 6-membered heteroarylene is selected from the group consisting of n2 and n3 are independently 0, 1, or 2; m8 is 0, 1, or 2; or The compound of formula (I) is a compound of formula (I-F): or a pharmaceutically acceptable salt thereof, wherein m6 is 0 or 1; a3 is 0 or 1; L Ａ３ is selected from the group consisting of -O-, -N(H)-, and -N(C １～３ alkyl)- a1a and a1b are independently integers from 0 to 5, provided that a1a + a1b is 2 to 5; L Ａ１ａ and L Ａ１ｂ each independently represents -CH ２ -, -CHR Ｌ -, and -C(R Ｌ ) ２ - and is selected from the group consisting of, and L Ａ４ is (a) 1 to 3 R's ａ each of which may optionally be substituted, C ３～１０ cycloalkylene or 4- to 10-membered heterocyclylene, and (b) 1 to 3 Rs ａ each of which may optionally be substituted, and phenylene or 5- to 6-membered heteroarylene is selected from the group consisting of m8 is 0, 1, or 2; or The compound of formula (I) is a compound of formula (I-G): or a pharmaceutically acceptable salt thereof, wherein m6 is 0 or 1; a3 is 0 or 1; L Ａ３ is selected from the group consisting of -O-, -N(H)-, and -N(C １～３ alkyl)- a1a and a1b are independently integers from 0 to 5, provided that a1a + a1b is 2 to 5; L Ａ１ａ and L Ａ１ｂ each independently is selected from the group consisting of -CH ２ -, -CHR Ｌ -, and -C(R Ｌ ) ２ -; L Ａ４ is (a) 1 to 3 Rs ａ each of which may optionally be substituted, C ３～１０ cycloalkylene or 4- to 10-membered heterocyclylene, and (b) 1 to 3 Rs ａ each of which may be optionally substituted, and phenylene or 5- or 6-membered heteroarylene is selected from the group consisting of m8 is 0, 1, or 2; or The compound of formula (I) is a compound of formula (I-H): or a pharmaceutically acceptable salt thereof, wherein m6 is 0 or 1; a3 is 0 or 1; L Ａ３ is selected from the group consisting of -O-, -N(H)-, and -N(C １～３ alkyl)- a1a and a1b are independently integers from 0 to 5, provided that a1a + a1b is 2 to 5; L Ａ１ａ and L Ａ１ｂ each independently is selected from the group consisting of -CH ２ -, -CHR Ｌ -, and -C(R Ｌ ) ２ -. L Ａ４ is (a) 1 to 3 R's ａ each of which may optionally be substituted, C ３～１０ cycloalkylene or 4- to 10-membered heterocyclylene, and (b) 1 to 3 Rs ａ each of which may optionally be substituted, and phenylene or 5- or 6-membered heteroarylene is selected from the group consisting of m8 is 0, 1, or 2, The compound according to claim 1.

80. A compound selected from the group consisting of the compounds in Table C1 or pharmaceutically acceptable salts thereof.

81. Under the conditions described in Example B1, Y ｍｉｎ (6 h) ≥ 70% and / or Y ｍｉｎ (24 h) ≥ 70% is not shown, the compound according to claim 80.

82. A pharmaceutical composition comprising the compound according to any one of claims 1 to 81, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

83. A method for treating cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of the compound according to any one of claims 1 to 81, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 82.

84. The method according to claim 83, comprising administering an additional treatment or therapeutic agent.

85. The method according to claim 84, wherein the additional treatment or therapeutic agent is an ALK inhibitor, a BCL-2 inhibitor, a BCR-Abl inhibitor, a BRAf inhibitor, a CDK2 inhibitor, a CDK4 / 6 inhibitor, a CDK7 inhibitor, a CDK9 inhibitor, an EGFR inhibitor, an anti-EGFR antibody or an anti-EGFR antibody-drug conjugate, an ERK inhibitor, an FGFR1 inhibitor, an FGFR2 inhibitor, an FGFR3 inhibitor, an FGFR4 inhibitor, a HER2 inhibitor, an anti-HER2 antibody or an anti-HER2 antibody-drug conjugate, a JAK inhibitor, a KRas inhibitor, a MEK inhibitor, a MET inhibitor, a PARP inhibitor, an LSD1 inhibitor, a BET inhibitor, a telomerase inhibitor, a TORC1 / 2 inhibitor, chemotherapy, radiotherapy, or a combination thereof.

86. The method according to claim 85, wherein the additional treatment or therapeutic agent is a JAK inhibitor.

87. The method according to claim 86, wherein the JAK inhibitor is fedratinib (e.g., fedratinib dihydrochloride monohydrate), momelotinib (e.g., momelotinib dihydrochloride), pacritinib (e.g., pacritinib citrate), ruxolitinib (e.g., ruxolitinib phosphate), or a combination thereof.

88. The method according to any one of claims 85 to 87, wherein the cancer is breast cancer, colorectal cancer, cholangiocarcinoma, colorectal cancer, gastrointestinal stromal tumor, pancreatic cancer, bladder cancer, kidney cancer, cervical cancer, ovarian cancer, uterine cancer, head and neck cancer, blood cancer, lung cancer, skin cancer, or a combination thereof.

89. The method according to claim 88, wherein the blood cancer is acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), follicular lymphoma (FL), small lymphocytic lymphoma (SLL), essential thrombocythemia, polycythemia vera, myelofibrosis, or a combination thereof.

90. The method according to claim 89, wherein the blood cancer is essential thrombocythemia, polycythemia vera, myelofibrosis, or a combination thereof.

91. The method according to any one of claims 89 to 90, wherein the blood cancer has a JAK2 mutation (e.g., JAK2 V617F).

92. A compound of formula (SI-A): or a salt thereof, wherein in the formula, Each R ２ and R ４ are, independently, halo, CN, C １～３ alkyl, C １～３ haloalkyl, C １～３ alkoxy, C １～３ haloalkoxy, OH, and NR ｄ R ｅ selected from, m2 is 0, 1, or 2; m4 is 0, 1, 2, or 3; m6 is 0 or 1; R ｅ１ is H or C optionally substituted with 1 to 3 -F １～６ alkyl R ｅ２ is H or C optionally substituted with 1 to 3 -F １～６ alkyl a3 is 0 or 1; L Ａ３ is selected from the group consisting of -O-, -N(H)-, and -N(C １～３ alkyl)- L Ａ１ａ and L Ａ１ｂ each independently represents -CH ２ -, -CHR Ｌ -, and -C(R Ｌ ) ２ - and is selected from the group consisting of L Ａ４ is (a) 1 to 3 Rs ａ each of which may optionally be substituted, C ３～１０ cycloalkylene or 4- to 10-membered heterocyclylene, and (b) 1 to 3 Rs ａ each of which may optionally be substituted, and phenylene or 5- or 6-membered heteroarylene selected from the group consisting of a1a and a1b are, independently, integers from 0 to 5, provided that a1a + a1b is from 1 to 5, Each R Ｌ is independently selected from the group consisting of halo, cyano, -OH, -C １～６ alkoxy, -C １～６ haloalkoxy, -NR ｄ R ｅ , C(=O)N(R ｆ ), ２ S(O) ０～２ (C １～６ alkyl), S(O) ０～２ (C １～６ haloalkyl), S(O) １～２ N(R ｆ ), ２ -R ｂ , and C ｃ alkyl optionally substituted with 1 to 6 R １～６ ; Each R ａ is, independently, (a) halo, (b) cyano, (c) -OH, (d) oxo, (e)-C １～６ alkoxy, (f)-C １～６ Haloalkoxy, (g) - NR ｄ R ｅ , (h) C(=O)C １～６ alkyl, (i) C(=O)C １～６ Haloalkyl, (j) C(=O)OH, (k) C(=O)OC １～６ alkyl (l) C(=O)OC １～６ Haloalkyl, (m) C(=O)N(R ｆ ) ２ , (n) S(O) ０～２ (C １～６ alkyl), (o) S(O) ０～２ (C １～６ haloalkyl), (p)S(O) １～２ N(R ｆ ) ２ and (q) 1 to 6 Rs ｃ each of which may optionally be substituted, C １～６ alkyl, C ２～６ alkenyl, or C ２～６ alkynyl is selected from the group consisting of, Each R ｂ is independently selected from the group consisting of -(L ｂ ), ｂ -R ｂ１ and -R ｂ１ wherein each b is, independently, 1, 2, or 3, each - L ｂ is, independently, -O-, -N(H)-, -N(C １～３ alkyl)-, -S(O) ０～２ -, C(=O), and C １～３ selected from the group consisting of alkylene, Each R ｂ１ is independently selected from the group consisting of C ３～１０ cycloalkyl, 4- to 10-membered heterocyclyl, C ６～１０ aryl, and 5- to 10-membered heteroaryl, each of which may be optionally substituted with 1 to 3 R ｇ 's, Each R ｃ is independently selected from the group consisting of halo, cyano, -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), S(O) ０～２ (C １～６ haloalkyl), and S(O) １～２ N(R ｆ ) ２ and is independently selected from the group consisting of: Each R ｄ and R ｅ is independently selected from the group consisting of 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), S(O) １～２ (C １～６ haloalkyl), S(O) １～２ N(R ｆ ) ２ and C ｈ alkyl optionally substituted with 1 to 3 R １～６ s, Each R ｆ is independently selected from the group consisting of H and C ｈ optionally substituted with 1 to 3 R １～６ alkyls Each R ｈ is independently selected from the group consisting of halo, cyano, -OH, -C １～６ alkoxy, -C １～６ haloalkoxy, -NH ２ , -N(H)(C １～３ alkyl), and -N(C １～３ alkyl) ２ selected from the group consisting of the compound or a salt thereof.

93. A compound of formula (I-E): or a salt thereof, wherein, Each R ２ and R ４ are each independently selected from H, C １～３ alkyl, and halo, a3 is 0 or 1, m2 is 0, 1, or 2, m4 is 0, 1, 2, or 3, m6 is 0 or 1, R ｅ１ is H or C optionally substituted with 1 to 3 -F １～６ alkyl L Ａ３ is selected from the group consisting of -O-, -N(H)-, and -N(C １～３ alkyl)- L Ａ１ａ and L Ａ１ｂ each independently is selected from the group consisting of -CH ２ -, -CHR Ｌ -, and -C(R Ｌ ) ２ -. L Ａ４ is (a) 1 to 3 Rs ａ each of which may optionally be substituted, C ３～１０ cycloalkylene or 4- to 10-membered heterocyclylene, and (b) 1 to 3 Rs ａ each of which may optionally be substituted, and phenylene or 5- or 6-membered heteroarylene is selected from the group consisting of, a1a is an integer from 0 to 5, a1d is an integer from 0 to 4, provided that a1a + a1d is from 1 to 4, Each R Ｌ is independently selected from the group consisting of halo, cyano, -OH, -C １～６ alkoxy, -C １～６ haloalkoxy, -NR ｄ R ｅ , C(=O)N(R ｆ ), ２ S(O) ０～２ (C １～６ alkyl), S(O) ０～２ (C １～６ haloalkyl), S(O) １～２ N(R ｆ ), ２ -R ｂ , and C ｃ alkyl optionally substituted with 1 to 6 R １～６ and is selected from the group consisting of: Each R ａ is independently (a) halo, (b) cyano, (c) -OH, (d) oxo, (e)-C １～６ alkoxy, (f)-C １～６ Haloalkoxy, (g) -NR ｄ R ｅ , (h) C(=O)C １～６ alkyl, (i) C(=O)C １～６ Haloalkyl, (j) C(=O)OH, (k) C(=O)OC １～６ alkyl (l) C(=O)OC １～６ haloalkyl, (m)C(=O)N(R ｆ ) ２ , (n) S(O) ０～２ (C １～６ alkyl), (o) S(O) ０～２ (C １～６ haloalkyl), (p) S(O) １～２ N(R ｆ ) ２ and (q) 1 to 6 Rs ｃ each of which may optionally be substituted, C １～６ alkyl, C ２～６ alkenyl, or C ２～６ alkynyl is selected from the group consisting of, Each R ｂ is independently selected from the group consisting of -(L ｂ ), ｂ -R ｂ１ and -R ｂ１ wherein each b is, independently, 1, 2, or 3, Each -L ｂ is independently selected from the group consisting of -O-, -N(H)-, -N(C １～３ alkyl)-, -S(O) ０～２ -, C(=O), and C １～３ alkylene Each R ｂ１ is independently selected from the group consisting of C ３～１０ cycloalkyl, 4- to 10-membered heterocyclyl, C ６～１０ aryl, and 5- to 10-membered heteroaryl, each of which may be optionally substituted with 1 to 3 R ｇ 's, Each R ｃ is independently selected from the group consisting of halo, cyano, -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), S(O) ０～２ (C １～６ haloalkyl), and S(O) １～２ N(R ｆ ) ２ and is independently selected from the group consisting of: Each R ｄ and R ｅ is independently selected from the group consisting of 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), S(O) １～２ (C １～６ haloalkyl), S(O) １～２ N(R ｆ ), ２ and C ｈ alkyl, optionally substituted with 1 to 3 R １～６ ; Each R ｆ is independently selected from the group consisting of H and C ｈ alkyl which may optionally be substituted with 1 to 3 R １～６ groups, Each R ｇ is independently selected from the group consisting of R ｈ , C １～３ alkyl, and C １～３ haloalkyl Each R ｈ is independently selected from the group consisting of halo, cyano, -OH, -C １～６ alkoxy, -C １～６ haloalkoxy, -NH ２ , -N(H)(C １～３ alkyl), and -N(C １～３ alkyl) ２ selected from the group consisting of the compound or a salt thereof.

94. A compound of any one of formula (I-Ind-1), (I-Ind-2), or (I-Ind-3): or a salt thereof, wherein, Each R Ｙ is independently selected from the group consisting of R ａ and R ｂ and is selected independently from the group consisting of c1 is 0, 1, 2, or 3, n2 and n3 are, independently, 0, 1, or 2, R ａＮ is H or C alkyl which may optionally be substituted with 1 to 3 R ｃ groups １～６ and m8 is from 0 to 4, Each R ａ is independently (a) halo, (b) cyano, (c) -OH, (d) oxo, (e)-C １～６ alkoxy, (f)-C １～６ Haloalkoxy, (g) -NR ｄ R ｅ , (h) C(=O)C １～６ alkyl, (i) C(=O)C １～６ Haloalkyl, (j) C(=O)OH, (k) C(=O)OC １～６ alkyl, (l) C(=O)OC １～６ Haloalkyl, (m)C(=O)N(R ｆ ) ２ , (n) S(O) ０～２ (C １～６ alkyl), (o) S(O) ０～２ (C １～６ haloalkyl), (p)S(O) １～２ N(R ｆ ) ２ and (q) 1 to 6 Rs ｃ each of which may optionally be substituted, C １～６ alkyl, C ２～６ alkenyl, or C ２～６ alkynyl is selected from the group consisting of, Each R ｂ is independently selected from the group consisting of -(L ｂ ), ｂ -R ｂ１ and -R ｂ１ wherein each b is, independently, 1, 2, or 3, each -L ｂ is independently selected from the group consisting of -O-, -N(H)-, -N(C １～３ alkyl)-, -S(O) ０～２ -, C(=O), and C １～３ alkylene Each R ｂ１ is independently selected from the group consisting of C ３～１０ cycloalkyl, 4- to 10-membered heterocyclyl, C ６～１０ aryl, and 5- to 10-membered heteroaryl, each of which may optionally be substituted with 1 to 3 R ｇ and may be optionally substituted, Each R ｃ is independently selected from the group consisting of halo, cyano, -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), S(O) ０～２ (C １～６ haloalkyl), and S(O) １～２ N(R ｆ ) ２ and is independently selected from the group consisting of: Each R ｄ and R ｅ is independently selected from the group consisting of 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), S(O) １～２ (C １～６ haloalkyl), S(O) １～２ N(R ｆ ), ２ and C ｈ alkyl optionally substituted with 1 to 3 R １～６ ; Each R ｆ is independently selected from the group consisting of H and C ｈ optionally substituted with 1 to 3 R １～６ alkyls, Each R ｇ is independently selected from the group consisting of R ｈ , C １～３ alkyl, and C １～３ haloalkyl Each R ｈ is independently selected from the group consisting of halo, cyano, -OH, -C １～６ alkoxy, -C １～６ haloalkoxy, -NH ２ , -N(H)(C １～３ alkyl), and -N(C １～３ alkyl) ２ selected from the group consisting of the compound or a salt thereof.

95. Any one of the compounds, compositions, combinations, pharmaceutical compositions, methods, uses, or processes provided herein.

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