ARYL-PIPERIDINE DERIVATIVES

• US 20200131125A1
• Filed: 03/14/2018
• Published: 04/30/2020
• Est. Priority Date: 03/14/2017
• Status: Active Grant

• Current Assignee: Artax BioPharma Inc.
• Original Assignee: Artax BioPharma Inc.
• Inventors: MATEOS, Andres Gagete, CARULLA, Damia Tormo, CLAUZEL, Luc Marti, PALOMINO, Julio Castro
• Granted Patent: US 11,505,526 B2
• Time in Patent Office: Days
• CPC Class Codes: A61P 37/00 Drugs for immunological or allergic disorders
• CPC Class Codes: A61P 37/02 Immunomodulators
• CPC Class Codes: C07D 211/32 by oxygen atoms
• CPC Class Codes: C07D 211/56 Nitrogen atoms nitro radicals C07D211/38
• CPC Class Codes: C07D 401/06 linked by a carbon chain containing only aliphatic carbon atoms
• CPC Class Codes: C07D 417/06 linked by a carbon chain containing only aliphatic carbon atoms

Abstract

An aryl-piperidine derivative of formula I, wherein the meaning of R₃, X, Cz, and Cy is that specified in the description, for use as inhibitors of T cells.

Claims

1. A compound of formula I:

2. The compound of formula I, or the pharmaceutically acceptable salt thereof, or the pharmaceutical composition, for use according to claim 1, wherein the disease associated with an abnormal activation of T cells is selected from the group consisting of:

an autoimmune disease, a mast-cell mediated allergy, a rejection of an allotransplant or a xenotransplant of an organ or a tissue, a lymphoma and a T-cell leukaemia.

3. The compound of formula I, or the pharmaceutically acceptable salt thereof, or the pharmaceutical composition, for use according to claim 2, wherein the autoimmune disease is selected from the group consisting of:

rheumatoid arthritis, vitiligo, autoimmune hepatitis, myasthenia gravis, ankylosing spondylitis, inflammatory bowel disease, Crohn'"'"'s disease, ulcerative colitis, psoriatic arthritis, transplant rejection, psoriasis, type I diabetes, multiple sclerosis, systemic lupus erythematosus, asthma, uveitis and atopic dermatitis.

4. The compound of formula I, or the pharmaceutically acceptable salt thereof, or the pharmaceutical composition, for use according to any one of claims 1 to 3, wherein Cy represents a phenyl group, optionally substituted with one or more R₁ groups.

5. The compound of formula I, or the pharmaceutically acceptable salt thereof, or the pharmaceutical composition, for use according to any one of claims 1 to 3, wherein Cy represents a 5- or 6-membered aromatic heterocycle containing 1 or 2 heteroatoms selected from N, O and S at any available position on the ring, and wherein Cy is optionally substituted with one or more R₁ groups.

6. The compound of formula I, or the pharmaceutically acceptable salt thereof, or the pharmaceutical composition, for use according to any one of claims 1 to 5, wherein Cy is substituted with two R₁ groups.

7. The compound of formula I, or the pharmaceutically acceptable salt thereof, or the pharmaceutical composition, for use according to any one of claims 1 to 6, wherein Cz represents a phenyl group, optionally substituted with one or more R₁ groups.

8. The compound of formula I, or the pharmaceutically acceptable salt thereof, or the pharmaceutical composition, for use according to any one of claims 1 to 6, wherein the Cz represents a 5- or 6-membered aromatic heterocycle containing 1 or 2 heteroatoms selected from N, O and S at any available position on the ring, optionally substituted with one or more R₁ groups.

9. The compound of formula I, or the pharmaceutically acceptable salt thereof, or the pharmaceutical composition, for use according to any one of claims 1 to 8, wherein X represents —

CO—

or —

C(OH)—

.

10. The compound of formula I, or the pharmaceutically acceptable salt thereof, or the pharmaceutical composition, for use according to any one of claims 1 to 9, wherein R₃ represents ═

O.

11. The compound of formula I, or the pharmaceutically acceptable salt thereof, or the pharmaceutical composition, for use according to any one of claims 1 to 9, wherein R₃ represents —

H.

12. The compound of formula I, or the pharmaceutically acceptable salt thereof, or the pharmaceutical composition, for use according to claim 1, wherein the compound of formula I is selected from:

18. The compound, or the pharmaceutically acceptable salt thereof, or the pharmaceutical composition, for use according to any one of claims 1-12, wherein the compound is not a compound in Table A.

19. The compound, or the pharmaceutically acceptable salt thereof, or the pharmaceutical composition, for use according to claim 18, wherein the medicament is for treatment of a disease associated with an abnormal activation of T cells selected from the group consisting of:

an autoimmune disease, a mast-cell mediated allergy, a rejection of an allotransplant or a xenotransplant of an organ or a tissue, a lymphoma and a T-cell leukaemia.

20. The compound, or the pharmaceutically acceptable salt thereof, or the pharmaceutical composition, for use according to claim 19, wherein the autoimmune disease is selected from the group consisting of:

rheumatoid arthritis, vitiligo, autoimmune hepatitis, myasthenia gravis, ankylosing spondylitis, inflammatory bowel disease, Crohn'"'"'s disease, ulcerative colitis, psoriatic arthritis, transplant rejection, psoriasis, type I diabetes, multiple sclerosis, systemic lupus erythematosus, asthma, uveitis and atopic dermatitis.

13. A compound of formula I:

14. The compound of formula I, or the pharmaceutically acceptable salt thereof, according to claim 13, wherein X represents —

C(OH)—

, and wherein Cy and Cz independently represent a phenyl group, optionally substituted with one or two R₁ groups.

15. The compound of formula I, or a pharmaceutically acceptable salt thereof, according to claim 13, of formula:

16. A pharmaceutical composition that comprises a compound of formula I, or a pharmaceutically acceptable salt thereof, according to any one of claims 13 to 15, and one or more pharmaceutically acceptable excipients.

17. A compound of formula I, or a pharmaceutically acceptable salt thereof according to any one of claims 13 to 15, or a pharmaceutical composition according to claim 16, for use as a medicament.

21. A compound of formula (III):

22. The compound of claim 21, of Formula IV:

23. The compound of claim 21, of Formula V:

24. The compound of claim 21, of Formula VI:

25. The compound of claim 21, of Formula VII:

26. The compound of any one of claims 21-25, wherein Cy is phenyl, optionally substituted with one or more R₁ groups.

27. The compound of any one of claims 21-25, wherein Cy is a 5-membered aromatic heterocycle containing 1 or 2 heteroatoms selected from O, N and S at any available position on the ring, optionally substituted with one or more R₁ groups.

28. The compound of any one of claims 21-25, wherein Cy is a 6-membered aromatic heterocycle containing 1 or 2 heteroatoms selected from O, N and S at any available position on the ring, optionally substituted with one or more R₁ groups.

29. The compound of any one of claims 21-28, wherein Cy is selected from:

30. The compound of any one of claims 21-29, wherein Cz is phenyl, optionally substituted with one or more R₁ groups.

31. The compound of any one of claims 21-29, wherein Cz is a 5-membered aromatic heterocycle containing 1 or 2 heteroatoms selected from O, N and S at any available position on the ring, optionally substituted with one or more R₁ groups.

32. The compound of any one of claims 21-29, wherein Cz is a 6-membered aromatic heterocycle containing 1 or 2 heteroatoms selected from O, N and S at any available position on the ring, optionally substituted with one or more R₁ groups.

33. The compound of any one of claims 21-29, wherein Cz is phenyl, optionally substituted with one R₁ group, wherein R₁ is halogen or —

C_1-4alkyl.

34. The compound of any one of claims 21-29, wherein Cz is selected from:

35. The compound of any one of claims 21-29, wherein Cz is selected from:

36. The compound of any one of claims 21-35, wherein each R₁ independently represents halogen or —

C_1-4alkyl.

37. The compound of any one of claims 21-36, wherein Cz is optionally substituted with one R₁ group, which is —

Cl.

38. The compound of any one of claims 21-36, wherein Cz is optionally substituted with one R₁ group, which is —

CH₃.

39. A pharmaceutical composition comprising the compound of any one of claims 21-38, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, adjuvant, or vehicle.

40. A compound of formula (III):

42. The compound for use according to claim 40 or 41, of Formula IV:

43. The compound for use according to claim 40 or 41, of Formula V:

44. The compound for use according to claim 40 or 41, of Formula VI:

45. The compound for use according to claim 40 or 41, of Formula VII:

59. The compound, or the pharmaceutically acceptable salt thereof, for use according to claim 40, wherein the disease associated with an abnormal activation of T cells is selected from the group consisting of:

an autoimmune disease, a mast-cell mediated allergy, a rejection of an allotransplant or a xenotransplant of an organ or a tissue, a lymphoma and a T-cell leukaemia.

60. The compound, or the pharmaceutically acceptable salt thereof, for use according to claim 59, wherein the autoimmune disease is selected from the group consisting of:

rheumatoid arthritis, vitiligo, autoimmune hepatitis, myasthenia gravis, ankylosing spondylitis, inflammatory bowel disease, Crohn'"'"'s disease, ulcerative colitis, psoriatic arthritis, transplant rejection, psoriasis, type I diabetes, multiple sclerosis, systemic lupus erythematosus, asthma, uveitis and atopic dermatitis.

41. A compound of formula (III):

46. The compound of any one of claims 41-45, wherein Cy is phenyl, optionally substituted with one or more R₁ groups.

47. The compound of any one of claims 41-45, wherein Cy is a 5-membered aromatic heterocycle containing 1 or 2 heteroatoms selected from O, N and S at any available position on the ring, optionally substituted with one or more R₁ groups.

48. The compound of any one of claims 41-45, wherein Cy is a 6-membered aromatic heterocycle containing 1 or 2 heteroatoms selected from O, N and S at any available position on the ring, optionally substituted with one or more R₁ groups.

49. The compound of any one of claims 41-48, wherein Cy is selected from:

50. The compound of any one of claims 41-49, wherein Cz is phenyl, optionally substituted with one or more R₁ groups.

51. The compound of any one of claims 41-49, wherein Cz is a 5-membered aromatic heterocycle containing 1 or 2 heteroatoms selected from O, N and S at any available position on the ring, optionally substituted with one or more R₁ groups.

52. The compound of any one of claims 41-49, wherein Cz is a 6-membered aromatic heterocycle containing 1 or 2 heteroatoms selected from O, N and S at any available position on the ring, optionally substituted with one or more R₁ groups.

53. The compound of any one of claims 41-49, wherein Cz is phenyl, optionally substituted with one R₁ group, wherein R₁ is halogen or —

C_1-4alkyl.

54. The compound of any one of claims 41-49, wherein Cz is selected from:

55. The compound of any one of claims 41-49, wherein Cz is selected from:

56. The compound of any one of claims 41-55, wherein each R₁ independently represents halogen or —

C_1-4alkyl.

57. The compound of any one of claims 41-56, wherein Cz is optionally substituted with one R₁ group, which is —

Cl.

58. The compound of any one of claims 41-56, wherein Cz is optionally substituted with one R₁ group, which is —

CH₃.