Tricyclic quinolone BCL6 difunctional degradation agent

By combining compounds with specific structures with BCL6 protein and CRBN, a ternary complex is formed, which induces the degradation of BCL6 protein, solving the problem of BCL6 overexpression or loss of control and improving the effect of cancer treatment.

CN119317623APending Publication Date: 2025-01-14TREELINE BIOSCIENCES INC
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Patent Information

Application Number
CN202380044857.0
Authority / Receiving Office
CN · China
Patent Type
Applications(China)
Current Assignee / Owner
Priority Date
2023-05-09
Filing Date
2023-06-05
Publication Date
2025-01-14

AI Technical Summary

Technical Problem

The prior art is difficult to effectively induce the degradation of BCL6 protein, resulting in BCL6 overexpression or loss of control in some cancers, affecting the therapeutic effect.

Method used

Compounds with specific structures are provided to form ternary complexes by binding to the BCL6 protein and binding to the ubiquitin E3 ligase CRBN, inducing ubiquitination and proteasome degradation of the BCL6 protein.

Benefits of technology

Effective degradation of BCL6 protein is achieved, potentially improving the therapeutic effect on certain cancers, especially in the case of BCL6 overexpression or loss of control.

✦ Generated by Eureka AI based on patent content.

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Patent Text Reader

Abstract

The present disclosure provides a compound having Formula (I) (e.g., Formula (I-aa) (e.g., Formula (I-aa-1), (I-aa-2), (I-aa-3), (I-aa-4), (I-aa-5), or (I-aa-6)), Formula (I-a) (e.g., Formula (I-a-1), (I-a-2), (I-a-3), (I-a-4), (I-a-5), or (I-a-6), Formula (I-bb) (e.g., Formula (I-bb-1) or (I-bb-2)), or Formula (I-b) (e.g., Formula (I-b-1) or (I-b-2)), or Formula (II), or a pharmaceutically acceptable salt thereof, that induces These compounds are useful, for example, in the treatment of cancer in a subject (e.g., a human). The disclosure also provides compositions containing the compounds provided herein and methods of use and manufacture thereof.
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Claims

1. A compound having formula (I): or a pharmaceutically acceptable salt thereof, wherein: TBM is (T1): X 1 Selected from the group consisting of: N and CR 2 ; X 2 It is CH; Each R 2 are independently selected from the group consisting of: H, halo, cyano, C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Haloalkoxy, -OH, and -NR d R e ; m3 is 0 or 1; X 3 is optionally replaced by 1-3 R c Substituted C 1-3 Alkylene; R 1 Selected from the group consisting of: H and C 3-6 Cycloalkyl; m1 is 2; each A 1 independently CH2, CHR 4 , or CR 4 R 4 ; m2 is 1; A 2 is-O-; One R 3 Selected from the group consisting of: (i) optionally with 1 to 3 R g Substituted C 3-6 Cycloalkyl, and (ii) C optionally substituted with 1 to 3 -F 1-3 Alkyl; and Another R 3 It is H; Each R 4 Independently selected from the group consisting of: H, R a , and R b ; X a selected from the group consisting of: N, CH, and CF; X b Selected from the group consisting of: N and CR x1 ; R 6 and R x1 Each independently selected from the group consisting of: H, halo, C 1-2 Alkyl, C 1-2 Haloalkyl, C 1-2 Alkoxy, CN, and -C≡CH; L is –(L A ) n1 –, where L A and n1 is defined according to (AA) or (BB): (AA) n1 is an integer from 1 to 15; and Each L A Independently selected from the group consisting of: L A1 , L A3 , and L A4 , the condition is 1-3 occurrences of L A YesL A4 ; (BB) n1 is an integer from 0 to 20; and Each L A Independently selected from the group consisting of: L A1 and L A3 ; Each L A1 Independently selected from the group consisting of: -CH2-, -CHR L -, and -C(R L )2-; Each L A3 Independently selected from the group consisting of: -N(R d )-、-N(R b )-、-O-、-S(O) 0-2 -, and C(=O); Each L A4 Independently selected from the group consisting of: (a)C 3-15 Cycloalkylene or 3-15 membered heterocyclylene, each of which is optionally substituted by 1-6 substituents independently selected from the group consisting of: R a and R b ; as well as (b)C 6-15 arylene or 5-15 membered heteroarylene, each of which is optionally substituted by 1-6 substituents independently selected from the group consisting of: R a and R b ; Provided that L does not contain any OO, NO, NN, NS(O)0, or OS(O) 0-2 key; Each R L are 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 optionally 1-6 R c Substituted C 1-6 alkyl; Ring C is selected from the group consisting of: c1 is 0, 1, 2, or 3; Each R Y Independently selected from the group consisting of: R a and R b ; R aN is H or optionally 1-3 R c Substituted C 1-6 alkyl; Y 1 and Y 2 are independently N, CH, or CR Y ; yy represents the point of attachment to L; X is CH, C, or N; is a single bond or a double bond; L C Selected from the group consisting of: bond, -CH2-, -CHR a -、-C(R a )2-、-C(=O)-、-N(R d )-, and O, provided that when X is N, L C is not O; and With further proviso that when ring C is attached to -L via the ring nitrogen C -, X is CH, and L C is the key; Each R a Independently selected from the group consisting of: (a) halogenated; (b) cyano; (c) -OH; (d) oxo; (e) optionally 1 to 6 R c Substituted C 1-6 Alkoxy; (f)-NR d R e ; (g)C(=O)C 1-6 alkyl; (h)C(=O)C 1-6 Haloalkyl; (i) C(=O)OH; (j)C(=O)OC 1-6 alkyl; (k)C(=O)OC 1-6 Haloalkyl; (l)C(=O)N(R f )2; (m)S(O) 0-2 (C 1-6 alkyl); (n)S(O) 0-2 (C 1-6 haloalkyl); (o)S(O) 1-2 N(R f )2; and (p)C 1-6 Alkyl, C 2-6 Alkenyl, or C 2-6 Alkynyl, each of which is optionally substituted by 1 to 6 R c replace; Each R b Independently selected from the group consisting of: -(L b ) b -R b1 and -R b1 ,in: Each b is independently 1, 2, or 3; Each -L b are 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 an alkylene group; and Each R b1 Independently selected from the group consisting of: C 3-10 Cycloalkyl, 4-10 membered heterocyclic group, C 6-10 aryl, and 5-10 membered heteroaryl, each of which is optionally substituted by 1-3 R g replace; Each R c are 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 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 optionally 1-3 R h Substituted C 1-6 alkyl; Each R f are independently selected from the group consisting of: H and optionally 1-3 R h Substituted C 1-6 alkyl; Each R g Independently selected from the group consisting of: R h , oxo, C 1-3 Alkyl, and C 1-3 haloalkyl; and Each R h are independently selected from the group consisting of: halo, cyano, -OH, -(C 0-3 Alkylene)-C 1-6 Alkoxy, -(C 0-3 Alkylene)-C 1-6 Haloalkoxy, -(C 0-3 Alkylene)-NH2, -(C 0-3 Alkylene)-N(H)(C 1-3 alkyl), and –(C 0-3 Alkylene)-N(C 1-3 Alkyl)2.

2. The compound as claimed in claim 1, wherein ring C is or Ring C is 3. The compound of any one of claims 1 or 2, wherein c1 is 0; or c1 is 1; and R Y is halogenated (eg, -F).

4. A compound as described in any one of claims 1 to 3, wherein R aN It is C 1-3 Alkyl (eg, methyl).

5. The compound of any one of claims 1-4, wherein X is CH.

6. The compound of any one of claims 1 to 5, wherein L C is the key.

7. The compound of claim 1, wherein The moiety is selected from the group consisting of: the moieties depicted in Table CM-1b: Table CM-1b 8. The compound of claim 7, wherein Part is or among them Part is 9. A compound as described in any one of claims 1 to 8, wherein -(A 1 ) m1 -Yes-C(R 4 R 4 )-CH2-* (e.g., -CF2-CH2-*), where * represents the same 2 ) m2 - attachment point.

10. The compound of any one of claims 1 to 9, wherein one R 3 It is C 3-6 cycloalkyl; and another R 3 is H; or One R 3 is cyclopropyl; and the other R 3 is H; or One R 3 is cyclopropyl; another R 3 is H; and -(A 1 ) m1 - is -CF2-CH2-*, where * represents 2 ) m2 - attachment point.

11. The compound of any one of claims 1 to 10, wherein each R 3 The attached carbon atom has an (S)-stereochemical configuration.

12. The compound of any one of claims 1 to 11, wherein X 1 It is CH.

13. A compound as described in any one of claims 1 to 12, wherein X a is N; and X b is CH; or X a is CH; and X b It is CH.

14. A compound as described in any one of claims 1 to 13, wherein R 6 is halo (e.g., -F, -Cl, -Br) or CN; or R 6 is -F; or R 6 It is -Cl.

15. The compound of any one of claims 1 to 14, wherein each R 2 It's H.

16. A compound as described in any one of claims 1 to 15, wherein m3 is 1; and X 3 It is C 1-3 Alkylene (e.g., methylene, ethylene, or isopropylene); or m3 is 0.

17. A compound as described in any one of claims 1 to 16, wherein R 1 It's H.

18. A compound as described in any one of claims 1 to 15, wherein m3 is 1; X 3 is optionally replaced by 1-3 R c Substituted C 1-3 Alkylene; and R 1 is H; or m3 is 1; X 3 It is C 1-3 Alkylene; and R 1 It's H.

19. A compound as described in any one of claims 1 to 15, wherein -(X 3 ) m3 -R 1 is methyl, ethyl, or isopropyl (eg, methyl).

20. A compound as described in any one of claims 1-8, wherein TBM is 21. The compound of claim 20, wherein m3 is 1; X 3 It is C 1-3 Alkylene; and R 1 It's H.

22. The compound of claim 20 or 21, wherein -(X 3 ) m3 -R 1 It is methyl, ethyl, or isopropyl.

23. A compound as described in any one of claims 20-22, wherein X a is CH; or X a It is N.

24. A compound as described in any one of claims 20-23, wherein R 6 It is -F or -Cl.

25. A compound as described in any one of claims 1-24, wherein L is -(L A ) n1 –, where L A and n1 are defined according to (AA).

26. A compound as described in any one of claims 1-25, wherein n1 is an integer from 1 to 5; or n1 is an integer from 2 to 4 (eg, 2 or 3).

27. The compound of any one of claims 1-26, wherein L is selected from the group consisting of: -L A4 -L A1 -L A4 - bb ; -L A4 -L A4 - bb ; -L A4 -L A1 -L A1 -L A4 - bb ; –L A4 -L A3 -L A4 - bb ;as well as -L A4 -L A1 -L A4 -L A3 - bb , where bb represents the point of attachment to ring C.

28. The compound of claim 27, wherein each L A4 Independently C 3-10 cycloalkylene or 4-12 membered heterocyclylene, each of which is optionally substituted by 1-6 R a replace; or Each L A4 are independently optionally substituted by 1-3 R a a substituted 4-12 (e.g., 4-10) membered heterocyclylene; or Each L A4 are independently optionally substituted by 1-3 R a a substituted monocyclic 4-6 membered nitrogen-containing heterocyclylene group; or One L A4 is optionally replaced by 1-3 R a a substituted monocyclic 4-6 membered nitrogen-containing heterocyclylene group; and Another L A4 is optionally replaced by 1-3 R a a substituted bicyclic 6-12 (eg, 6-10) membered nitrogen-containing heterocyclylene group; or One L A4 is optionally replaced by 1-3 R a a substituted monocyclic 4-6 membered nitrogen-containing heterocyclylene group; and Another L A4 is optionally replaced by 1-3 R a a substituted bicyclic spirocyclic 6-12 (eg, 6-10) membered nitrogen-containing heterocyclylene group; or Each L A4 Contains 1-2 ring nitrogen atoms and no additional ring heteroatoms.

29. The compound of claim 28, wherein L A4 Every R that exists on a Independently selected from the group consisting of: -F, CN, C 1-3 alkoxy, OH, and C optionally substituted with 1-3 F 1-3 alkyl.

30. The compound of claim 28, wherein L is -L A4 -L A1 -L A4 - bb .

31. The compound of claim 30, wherein L A1 It is -CH2-, -CHMe-, or -CMe2-.

32. The compound of claim 28, wherein L is -L A4 -L A3 -L A4 - bb .

33. The compound of claim 32, wherein L A3 It is -C(=O).

34. The compound of claim 28 or 29, wherein L is -L A4 -L A1 -L A4 -L A3 - bb , and L A3 It is C(=O).

35. The compound of claim 28, wherein L is -L A4 -L A1 -L A1 -L A4 - bb , and one or two L A1 It is CH2.

36. The compound of any one of claims 1-26, wherein L is selected from the group consisting of: -L A4 -L A3 - bb ; –L A4 -L A1 - bb ;as well as -L A4 -L A1 -L A3 - bb , where bb represents the point of attachment to ring C.

37. The compound of claim 36, wherein L is -L A4 -L A3 - bb .

38. The compound of claim 36 or 37, wherein L A3 is -NH- or -N(C 1-3 alkyl)-(e.g., -NH-).

39. A compound as described in any one of claims 36-38, wherein L A4 is optionally replaced by 1-6 R a a substituted 4-12 membered heterocyclylene; or L A4 is optionally replaced by 1-3 R a a substituted 4-12 (e.g., 6-10) membered nitrogen-containing heterocyclylene group; or L A4 is optionally replaced by 1-3 R a a substituted bicyclic spirocyclic 6-12 (eg, 6-10) membered nitrogen-containing heterocyclylene group; or L A4 Contains 1-2 ring nitrogen atoms and no additional ring heteroatoms.

40. The compound of claim 39, wherein L A4 Every R that exists on a Independently selected from the group consisting of: -F, CN, C 1-3 alkoxy, OH, and C optionally substituted with 1-3 F 1-3 alkyl.

41. The compound of any one of claims 1-27, wherein L is selected from the group consisting of a moiety depicted in Table L or Table L1-a, wherein bb represents the point of attachment to Ring C.

42. The compound of claim 1, wherein the compound is a compound having formula (I-aa): or a pharmaceutically acceptable salt thereof, wherein: X a is N or CH; R 6 is -F or -Cl; m3 is 1, X 3 It is C 1-3 Alkylene, and R 1 It is H; Ring C is selected from the group consisting of: Where: c1 is 0 or 1, R Y is selected from halo (e.g., -F) and C optionally substituted with 1-3 F 1-3 The group consisting of alkyl groups, and R aN It is C 1-3 alkyl; L is selected from the group consisting of: -L A4 -L A1 -L A4 - bb ; -L A4 -L A1 -L A1 -L A4 - bb ; -L A4 -L A4 - bb ; –L A4 -C(=O)-L A4 - bb ;as well as –L A4 -L A1 -L A4 -C(=O)- bb , wherein bb represents the point of attachment to ring C; and L A1 is CH2, CHMe, or CMe2; Each L A4 are independently optionally substituted by 1-3 R a A substituted 4-12 membered nitrogen-containing heterocyclylene group, wherein: L A4 Every R that exists on a Independently selected from the group consisting of: -F, CN, C 1-3 alkoxy, OH, and C optionally substituted with 1-3 F 1-3 Alkyl; or The compound is a compound having formula (Ia): or a pharmaceutically acceptable salt thereof, wherein: X a is N or CH; R 6 is -F or -Cl; m3 is 1, X 3 It is C 1-3 Alkylene, and R 1 It is H; Ring C is selected from the group consisting of: L is selected from the group consisting of: -L A4 -L A1 -L A4 - bb ; -L A4 -L A1 -L A1 -L A4 - bb ; -L A4 -L A4 - bb ; –L A4 -C(=O)-L A4 - bb ;as well as –L A4 -L A1 -L A4 -C(=O)- bb , wherein bb represents the point of attachment to ring C; and L A1 is CH2, CHMe, or CMe2; Each L A4 are independently optionally substituted by 1-3 R a A substituted 4-12 membered nitrogen-containing heterocyclylene group, wherein: L A4 Every R that exists on a Independently selected from the group consisting of: -F, CN, C 1-3 alkoxy, OH, and C optionally substituted with 1-3 F 1-3 Alkyl; or The compound is a compound having formula (I-aa-1): or a pharmaceutically acceptable salt thereof, wherein: X a is N or CH; R 6 is -F or -Cl; m3 is 1, X 3 It is C 1-3 Alkylene, and R 1 It is H; Ring C is selected from the group consisting of: Where: c1 is 0 or 1, R Y is selected from halo (e.g., -F) and C optionally substituted with 1-3 F 1-3 The group consisting of alkyl groups, and R aN It is C 1-3 alkyl; L A1 is CH2, CHMe, or CMe2; and Each L A4 are independently optionally substituted by 1-3 R a A substituted monocyclic 4-6 membered nitrogen-containing heterocyclylene group, wherein: Each L A4 contains 1-2 ring nitrogen atoms and no additional ring heteroatoms, and L A4 Every R that exists on a Independently selected from the group consisting of: -F, CN, C 1-3 alkoxy, OH, and C optionally substituted with 1-3 F 1-3 Alkyl; or The compound is a compound having formula (Ia-1): or a pharmaceutically acceptable salt thereof, wherein: X a is N or CH; R 6 is -F or -Cl; m3 is 1, X 3 It is C 1-3 Alkylene, and R 1 It is H; Ring C is selected from the group consisting of: L A1 is CH2, CHMe, or CMe2; and Each L A4 are independently optionally substituted by 1-3 R a A substituted monocyclic 4-6 membered nitrogen-containing heterocyclylene group, wherein: Each L A4 contains 1-2 ring nitrogen atoms and no additional ring heteroatoms, and L A4 Every R that exists on a Independently selected from the group consisting of: -F, CN, C 1-3 alkoxy, OH, and C optionally substituted with 1-3 F 1-3 Alkyl; or The compound is a compound having formula (I-aa-2): or a pharmaceutically acceptable salt thereof, wherein: X a is N or CH; R 6 is -F or -Cl; m3 is 1, X 3 It is C 1-3 Alkylene, and R 1 It is H; Ring C is selected from the group consisting of: Where: c1 is 0 or 1, R Y is selected from halo (e.g., -F) and C optionally substituted with 1-3 F 1-3 The group consisting of alkyl groups, and R aN It is C 1-3 alkyl; L A1 is CH2, CHMe, or CMe2; Z 1 and Z 2 Independently selected from the group consisting of: CH, CR a4 , and N; Z 3 and Z 4 Independently selected from the group consisting of: CH, CR a5 , and N, The condition is Z 1 and Z 2 At least one of them is N; Z 3 and Z 4 At least one of them is N; and when Z 2 When N is 3 Is CH or CR a5 ; m4 and m5 are independently selected from the group consisting of: 0, 1, and 2; and Each R a4 and R a5 Independently selected from the group consisting of: -F, CN, C 1-3 alkoxy, OH, and C optionally substituted with 1-3 F 1-3 Alkyl; or The compound is a compound having formula (Ia-2): or a pharmaceutically acceptable salt thereof, wherein: X a is N or CH; R 6 is -F or -Cl; m3 is 1, X 3 It is C 1-3 Alkylene, and R 1 It is H; Ring C is selected from the group consisting of: L A1 is CH2, CHMe, or CMe2; Z 1 and Z 2 Independently selected from the group consisting of: CH, CR a4 , and N; Z 3 and Z 4 Independently selected from the group consisting of: CH, CR a5 , and N, The condition is Z 1 and Z 2 At least one of them is N; Z 3 and Z 4 At least one of them is N; and when Z 2 When N is 3 Is CH or CR a5 ; m4 and m5 are independently selected from the group consisting of: 0, 1, and 2; and Each R a4 and R a5 Independently selected from the group consisting of: -F, CN, C 1-3 alkoxy, OH, and C optionally substituted with 1-3 F 1-3 Alkyl; or The compound is a compound having formula (I-aa-3): or a pharmaceutically acceptable salt thereof, wherein: X a is N or CH; R 6 is -F or -Cl; m3 is 1, X 3 It is C 1-3 Alkylene, and R 1 It is H; Ring C is selected from the group consisting of: Where: c1 is 0 or 1, R Y is selected from halo (e.g., -F) and C optionally substituted with 1-3 F 1-3 The group consisting of alkyl groups, and R aN It is C 1-3 alkyl; L A1 is CH2, CHMe, or CMe2; and One L A4 is optionally replaced by 1-3 R a a substituted monocyclic 4-6 membered nitrogen-containing heterocyclylene group; and Another L A4 is optionally replaced by 1-3 R a A substituted bicyclic 6-12 membered nitrogen-containing heterocyclylene group, wherein: L A4 Every R that exists on a Independently selected from the group consisting of: -F, CN, C 1-3 alkoxy, OH, and C optionally substituted with 1-3 F 1-3 Alkyl; or The compound is a compound having formula (Ia-3): or a pharmaceutically acceptable salt thereof, wherein: X a is N or CH; R 6 is -F or -Cl; m3 is 1, X 3 It is C 1-3 Alkylene, and R 1 It is H; Ring C is selected from the group consisting of: L A1 is CH2, CHMe, or CMe2; One L A4 is optionally replaced by 1-3 R a a substituted monocyclic 4-6 membered nitrogen-containing heterocyclylene group; and Another L A4 is optionally replaced by 1-3 R a A substituted bicyclic 6-12 membered nitrogen-containing heterocyclylene group, wherein: L A4 Every R that exists on a Independently selected from the group consisting of: -F, CN, C 1-3 alkoxy, OH, and C optionally substituted with 1-3 F 1-3 Alkyl; or The compound is a compound having formula (I-aa-4): or a pharmaceutically acceptable salt thereof, wherein: X a is N or CH; R 6 is -F or -Cl; m3 is 1, X 3 It is C 1-3 Alkylene, and R 1 It is H; Ring C is selected from the group consisting of: Where: c1 is 0 or 1, R Y is selected from halo (e.g., -F) and C optionally substituted with 1-3 F 1-3 The group consisting of alkyl groups, and R aN It is C 1-3 alkyl; L A1 is CH2, CHMe, or CMe2; Z 1 and Z 2 Independently selected from the group consisting of: CH, CR a4 , and N; Z 3 and Z 4 Independently selected from the group consisting of: CH, CR a5 , and N, The condition is Z 1 and Z 2 At least one of them is N; Z 3 and Z 4 At least one of them is N; and when Z 2 When N is 3 Is CH or CR a5 ; m4 and m6 are independently 0 or 1; m5 is 0, 1, or 2; and Each R a4 , R a5 , and R a6 Independently selected from the group consisting of: -F, CN, C 1-3 alkoxy, OH, and C optionally substituted with 1-3 F 1-3 Alkyl; or The compound is a compound having formula (Ia-4): or a pharmaceutically acceptable salt thereof, wherein: X a is N or CH; R 6 is -F or -Cl; m3 is 1, X 3 It is C 1-3 Alkylene, and R 1 It is H; Ring C is selected from the group consisting of: L A1 is CH2, CHMe, or CMe2; Z 1 and Z 2 Independently selected from the group consisting of: CH, CR a4 , and N; Z 3 and Z 4 Independently selected from the group consisting of: CH, CR a5 , and N, The condition is Z 1 and Z 2 At least one of them is N; Z 3 and Z 4 At least one of them is N; and when Z 2 When N is 3 Is CH or CR a5 ; m4 and m6 are independently 0 or 1; m5 is 0, 1, or 2; and Each R a4 , R a5 , and R a6 Independently selected from the group consisting of: -F, CN, C 1-3 alkoxy, OH, and C optionally substituted with 1-3 F 1-3 Alkyl; or The compound is a compound having formula (I-bb): or a pharmaceutically acceptable salt thereof, wherein: X a is N or CH; R 6 is -F or -Cl; m3 is 1, X 3 It is C 1-3 Alkylene, and R 1 It is H; Ring C is selected from the group consisting of: Where: c1 is 0 or 1, R Y is selected from halo (e.g., -F) and C optionally substituted with 1-3 F 1-3 The group consisting of alkyl groups, and R aN It is C 1-3 alkyl; L is for –L A4 -L A3 - bb or –L A4 -L A1 -L A3 - bb , where bb represents the point of attachment to ring C; and L A4 is optionally replaced by 1-3 R a A substituted 4-12 membered nitrogen-containing heterocyclylene group, wherein: L A4 Every R that exists on a Independently selected from the group consisting of: -F, CN, C 1-3 alkoxy, OH, and C optionally substituted with 1-3 F 1-3 Alkyl; or The compound is a compound having formula (Ib): or a pharmaceutically acceptable salt thereof, wherein: X a is N or CH; R 6 is -F or -Cl; m3 is 1, X 3 It is C 1-3 Alkylene, and R 1 It is H; Ring C is selected from the group consisting of: L is for –L A4 -L A3 - bb or –L A4 -L A1 -L A3 - bb , where bb represents the point of attachment to ring C; and L A4 is optionally replaced by 1-3 R a A substituted 4-12 membered nitrogen-containing heterocyclylene group, wherein: L A4 Every R that exists on a Independently selected from the group consisting of: -F, CN, C 1-3 alkoxy, OH, and C optionally substituted with 1-3 F 1-3 alkyl.

43. The compound of claim 1, wherein the compound is selected from the group consisting of a compound in Table C1 or a pharmaceutically acceptable salt thereof.

44. A pharmaceutical composition comprising a compound according to any one of claims 1 to 43 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

45. A method for treating cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound according to any one of claims 1-43 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 44.

46. ​​The method of claim 45, wherein the cancer is a hematological cancer, breast cancer, gastrointestinal cancer, brain cancer, lung cancer, or a combination thereof.

47. The method of claim 46, wherein the hematological cancer is diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL), diffuse histiocytic lymphoma (DHL), intravascular large B-cell lymphoma (IVLBCL), small lymphocytic lymphoma (SLL), Burkitt's lymphoma (BL), mantle cell lymphoma (MCL), peripheral T-cell lymphoma (PTCL), chronic lymphocytic leukemia (CLL), acute lymphocytic leukemia (ALL), or chronic myeloid leukemia (CML).

48. The method of claim 47, wherein the hematological cancer is selected from the group consisting of DLBCL, FL, MCL, BL, PTCL, and ALL (e.g., B-ALL); or The hematological cancer is FL or DLBCL; or The blood cancer is DLBCL; or The hematological cancer is FL; or the haematological cancer is BL; or The blood cancer is PTCL; or The hematological cancer is ALL (eg, B-ALL).

49. The method of any one of claims 46-48, wherein the therapeutically effective amount of the compound of any one of claims 1-43 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 44 is administered to the subject as a monotherapy.

50. The method of any one of claims 46-48, comprising administering to the subject an additional therapy or therapeutic agent.

51. The method of claim 50, wherein the additional therapy or therapeutic agent is a PI3K inhibitor, an Abl inhibitor (e.g., a BCR-Abl inhibitor), a BTK inhibitor, a JAK inhibitor, a BRaf inhibitor, a MEK inhibitor, a BCL-2 inhibitor, a Bcl-X inhibitor, a L inhibitors, XPO1 inhibitors, inhibitors of polycomb repressive complex 2 (PRC2), immunomodulatory imide drugs, anti-CD19 therapy, anti-CD20 therapy, anti-CD3 therapy, chemotherapy, or a combination thereof.

52. A method for treating an autoimmune disorder in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound of any one of claims 1-43 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 44.

53. A method for treating a lymphoproliferative disease in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound of any one of claims 1-43 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 44.

54. A compound having formula (SI): or a salt thereof, wherein: Ring C is selected from the group consisting of: Where: c1 is 0 or 1, R Y is selected from halo (e.g., -F) and C optionally substituted with 1-3 F 1-3 The group consisting of alkyl groups, and R aN It is C 1-3 alkyl, and yy represents the point of attachment to L; L is selected from the group consisting of: -L A4 -L A1 -L A4 - bb ; -L A4 -L A1 -L A1 -L A4 - bb ; -L A4 -L A4 - bb ; –L A4 -C(=O)-L A4 - bb ;as well as –L A4 -L A1 -L A4 -C(=O)- bb , wherein bb represents the point of attachment to ring C; and L A1 is CH2, CHMe, or CMe2; Each L A4 are independently optionally substituted by 1-3 R a A substituted 4-12 membered nitrogen-containing heterocyclylene group, wherein: L A4 Every R that exists on a Independently selected from the group consisting of: -F, CN, C 1-3 alkoxy, OH, and C optionally substituted with 1-3 F 1-3 Alkyl; or A compound of formula (SI-A) or formula (SI-B): or a salt thereof, wherein: c1 is 0 or 1; R Y Selected from the group consisting of: halo (e.g., -F) and C optionally substituted with 1-3 F 1-3 alkyl; R aN It is C 1-3 alkyl; L A1 is CH2, CHMe, or CMe2; Each L A4 are independently optionally substituted by 1-3 R a A substituted 4-12 membered nitrogen-containing heterocyclylene group, wherein: L A4 Every R that exists on a Independently selected from the group consisting of: -F, CN, C 1-3 alkoxy, OH, and C optionally substituted with 1-3 F 1-3 Alkyl; or A compound having formula (SI-A-1) and formula (SI-B-1): or a salt thereof, wherein: c1 is 0 or 1; R Y Selected from the group consisting of: halo (e.g., -F) and C optionally substituted with 1-3 F 1-3 alkyl; R aN It is C 1-3 alkyl; L A1 is CH2, CHMe, or CMe2; Z 2 , Z 3 , and Z 4 Independently selected from the group consisting of: CH, CR a4 , and N, provided that Z 3 and Z 4 At least one of them is N; when Z 2 When N is 3 Is CH or CR a4 ; and when Z 3 When N is 2 Is CH or CR a4 ; m4 and m5 are independently 0, 1, or 2; and Each R a4 and R a5 Independently selected from the group consisting of: -F, CN, C 1-3 alkoxy, OH, and C optionally substituted with 1-3 F 1-3 Alkyl; or A compound having formula (SI-A-2) or formula (SI-B-2): or a salt thereof, wherein: c1 is 0 or 1; R Y Selected from the group consisting of: halo (e.g., -F) and C optionally substituted with 1-3 F 1-3 alkyl; R aN It is C 1-3 alkyl; L A1 is CH2, CHMe, or CMe2; Z 2 , Z 3 , and Z 4 Independently selected from the group consisting of: CH, CR a4 , and N, provided that Z 3 and Z 4 At least one of them is N; when Z 2 When N is 3 Is CH or CR a4 ; and when Z 3 When N is 2 Is CH or CR a4 ; m4, m5, and m6 are independently 0, 1, or 2; and Each R a4 , R a5 , and R a6 Independently selected from the group consisting of: -F, CN, C 1-3 alkoxy, OH, and C optionally substituted with 1-3 F 1-3 alkyl.

55. Any of the compounds, compositions, combinations, pharmaceutical compositions, methods, uses and processes substantially as provided herein.

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