AMINOTHIAZOLE COMPOUNDS AS C-KIT INHIBITORS

20240317731

18/259903

January 05, 2022

The invention relates to c-Kit inhibitors useful in the treatment of cancers, and other serine-threonine kinase mediated diseases, having a structure according to Formula (I): wherein X1, R1, R2, m, and n are described herein. [chemical expression included]

Theseus Pharmaceuticals, Inc. (Cambridge, MA, US)

1. A compound having a structure according to Formula (I), [chemical expression included] or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, or tautomer thereof, wherein n and m are independently 1, 2, or 3; X1 is O, NR3, CRxR3 or CHR3; each R1, R2, and R3 is independently H or X2; X2 is OH, O(C1-C6 alkyl), NH2, NHR4, or NR4R5; R4 and R5 are independently C1-C6 alkyl or R4 and R5, when both are present, combine to form a 4- to 6-membered heterocyclyl; Rx is C1-C6 alkyl; and wherein at least one of R1, R2, and R3 is X2.

2. The compound of claim 1, wherein X1 is O, NR3, or CHR3.

3. The compound of claim 1, wherein X1 is CRxR3 and Rx is Me.

4. The compound of claim 1, having a structure according to Formula (I′), [chemical expression included] or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, or tautomer thereof.

5. The compound of claim 4, having a structure according to Formula (I′-A), [chemical expression included] or a pharmaceutically acceptable salt, solvate, prodrug, or tautomer thereof.

6. The compound of claim 4, having a structure according to Formula (I′-B), [chemical expression included] or a pharmaceutically acceptable salt, solvate, prodrug, or tautomer thereof.

7. The compound of any one of claims 1-6, wherein X2 is OH, NH2, NHCH3, or N(CH3)2.

8. The compound of any one of claims 1-7, wherein X2 is NH2, NHCH3, or N(CH3)2.

9. A compound having a structure selected from the group consisting of: [chemical expression included] or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, or tautomer thereof.

10. The compound of claim 9, having the following structure, [chemical expression included] or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, or tautomer thereof.

11. The compound of claim 10, having the following structure, [chemical expression included] or a pharmaceutically acceptable salt, solvate, prodrug, or tautomer thereof.

12. The compound of claim 10, having the following structure, [chemical expression included] or a pharmaceutically acceptable salt, solvate, prodrug, or tautomer thereof.

13. The compound of claim 9, having the following structure, [chemical expression included] or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, or tautomer thereof.

14. The compound of claim 13, having the following structure, [chemical expression included] or a pharmaceutically acceptable salt, solvate, prodrug, or tautomer thereof.

15. The compound of claim 13, having the following structure, [chemical expression included] or a pharmaceutically acceptable salt, solvate, prodrug, or tautomer thereof.

16. The compound of claim 9, having the following structure, [chemical expression included] or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, or tautomer thereof.

17. The compound of claim 9, having the following structure, [chemical expression included] or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, or tautomer thereof.

18. The compound of claim 9, having the following structure, [chemical expression included] or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, or tautomer thereof.

19. The compound of claim 18, having the following structure, [chemical expression included] or a pharmaceutically acceptable salt, solvate, prodrug, or tautomer thereof.

20. The compound of claim 18, having the following structure, [chemical expression included] or a pharmaceutically acceptable salt, solvate, prodrug, or tautomer thereof.

21. A pharmaceutical composition comprising a compound of any one of claims 1 to 20, or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, or tautomer thereof, and a pharmaceutically acceptable diluent, excipient or carrier.

22. A method of treating a c-Kit-mediated disease or disorder, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of any one of claims 1 to 20, or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, or tautomer thereof.

23. The method of claim 22, wherein the cKit-mediated disease or disorder is selected from cell proliferative disorder, a fibrotic disorder, and a metabolic disorder.

24. The method of claim 23, wherein said cell proliferative disorder is cancer.

25. The method of claim 24, wherein said cancer is selected from the group consisting of leukemia, mast cell tumor, small cell lung cancer, testicular cancer, cancer of the gastrointestinal tract, cancer of the central nervous system, cancer of the female genital tract, sarcoma of neuroectodermal origin, and Schwann cell neoplasia associated with neurofibromatosis.

26. The method of claim 24, wherein said cancer is selected from the group consisting of small cell lung carcinoma, acute myeloid leukemia (AML), neuroblastoma, malignant melanomas, colorectal cancer, systemic mastocytosis (SM), and gastrointestinal stromal tumors (GISTs).

27. The method of claim 22, wherein said cKit-mediated disease or disorder is multiple sclerosis.

28. The method of claim 22, wherein said cKit-mediated disease or disorder is asthma.

29. The method of claim 22, wherein said cKit-mediated disease or disorder is an allergic reaction.

30. The method of claim 22, wherein said cKit-mediated disease or disorder is inflammatory arthritis.

31. The method of claim 22, wherein said cKit-mediated disease or disorder is mastocytosis.

32. A method of modulating c-Kit comprising administering to a subject a compound of any one of claims 1 to 20.

33. A method of inhibiting c-Kit comprising administering to a subject a compound of any one of claims 1 to 20.

34. A method of treating or preventing a disease in which c-Kit plays a role, comprising administering to a subject in need thereof an effective amount of a compound of any one of claims 1 to 20.

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edspap.20240317731