Selective inhibitors of protein arginine methyltransferase 5 (PRMT5)

Patent metadata

Field	Value
Publication number	US-12440506-B2
Application number	US-202017601485-A
Country	US
Kind code	B2
Filing date	Apr 3, 2020
Priority date	Apr 5, 2019
Publication date	Oct 14, 2025
Grant date	Oct 14, 2025

Abstract

The disclosure is directed to methods of treatment using compounds of Formula (I).

First claim

What is claimed:

1. A method of treating a disease or disorder selected from the group consisting of rejection of transplanted organs or tissue; graft-versus-host diseases multiple sclerosis, myasthenia gravis; pollen allergies; type I diabetes; psoriasis; Crohn's disease; ulcerative colitis, acute respiratory distress syndrome; influenza; COVID-19 (coronavirus disease); or rheumatic fever and post-infectious glomerulonephritis, in a patient in need thereof, comprising administering to said patient an effective amount of a compound of Formula I:

or a pharmaceutically acceptable salt or solvate thereof;
wherein
A is N or C—R 3 ;
R 1 is H, halo, —C 1 -C 6 alkyl, —C 1 -C 6 alkoxy, —C 1 -C 4 haloalkyl, —C 3 -C 6 cycloalkyl, —C 3 -C 6 halocycloalkyl, —C 1 -C 6 alkyl-O—C 1 -C 6 alkyl, —C 1 -C 6 alkyl-S(O)—C 1 -C 6 alkyl, —C 1 -C 6 alkyl-S(O) 2 —C 1 -C 6 alkyl, —CR 6 R 6′ CN, —NR 6 R 6′ , —NHCR 6 R 6′ CN, —NHCONR 6 R 6′ , —NHC(O)OR 7 , NHC(O)—C 1 -C 6 alkyl, NHC(O)—C 1 -C 6 haloalkyl, —NH—C 1 -C 6 alkyl-C(O)—C 1 -C 6 alkyl, —NHC(S)NR 6 R 6′ , —NH—O—R 6 , or —NH—NR 6 R 6′ ;
R 2 is H, halo, —C 1 -C 6 alkyl, or NH 2 ;
R 3 is H, halo, —C 1 -C 6 alkyl, —C 1 -C 6 alkoxy, —C 2 -C 6 alkenyl, or —C 2 -C 6 alkynyl;
R 4 is H, —C 1 -C 6 alkyl, —C 1 -C 6 haloalkyl, —C 2 -C 6 alkenyl, or —C 2 -C 6 alkynyl;
R 5 is H or —C 1 -C 6 alkyl;
R 6 and R 6′ are each independently H, C 1 -C 6 alkyl, or —C 1 -C 6 alk-OC 1 -C 6 alkyl;
or R 6 and R 6′ , together with the atom to which they are attached, form a C 2 -C 6 heterocycloalkyl ring or a C 3 -C 6 cycloalkyl ring;
R 7 is-C 1 -C 6 alkyl or —C 0 -C 6 alkyl-C 3 -C 6 cycloalkyl;
X is O, S, NH, or N(C 1 -C 6 alkyl), and Y is —(CR 9 R 9′ ) n —, —CR 9 ═CR 9′ —, C(═O), —C(═O)—(CR 9 R 9′ ) n —, —C(═O)—O—(CR 9 R 9′ ) n —, —CR 9 R 9′ —O—, —(CR 9 R 9′ ) n —O—(CR 9 R 9′ ) m —, —(CR 9 R 9′ ) n —NR 10 , C(═O)NR 10 , or CH—C 1 -C 4 alkyl-NH 2 ; or
X is —SO 2 — and Y is —(CR 9 R 9′ ) n —, —CR 9 ═CR 9′ —, —CR 9 R 9′ —O—, —(CR 9 R 9′ ) n —O—(CR 9 R 9′ ) m —, —(CR 9 R 9′ ) n —NR 10 , or CH—C 1 -C 4 alkyl-NH 2 ;
wherein n=1, 2, or 3; m=1 or 2;
each instance of R 9 or R 9′ is independently H, D, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, halo, —C 1 -C 6 alkoxy, or hydroxy;
R 10 is H or C 1 -C 6 alkyl;
Z is O, CH 2 , or CF 2 ; and
Ar is an optionally substituted 6-membered aryl ring, an optionally substituted 6-membered heteroaryl ring, or an optionally substituted 5-membered heteroaryl ring.

2. The method of claim 1 wherein R 1 is halo, —NR 6 R 6′ , —C 1 -C 6 alkyl, —C 1 -C 6 alkoxy, or —C 1 -C 6 alkyl-O—C 1 -C 6 alkyl.

3. The method of claim 2 , wherein R 1 is halo, —F, or —Cl.

4. The method of claim 2 , wherein R 1 is —NH 2 .

5. The method of claim 2 , wherein R 1 is —CH 3 .

6. The method of claim 2 , wherein R 1 is —CH 2 —O—CH 2 CH 3 .

7. The method of claim 1 , wherein R 2 is H.

8. The method of claim 1 , wherein R 4 is H or —C 1 -C 6 alkyl.

9. The method of claim 8 , wherein R 4 is H.

10. The method of claim 8 , wherein R 4 is methyl.

11. The method of claim 1 , wherein R 5 is H.

12. The method of claim 1 , wherein R 5 is —CH 3 .

13. The method of claim 1 , wherein Ar is an optionally substituted 6-membered aryl ring.

14. The method of claim 13 , wherein the 6-membered aryl ring is substituted with —F, or —Cl.

15. The method of claim 13 , wherein the 6-membered aryl ring is substituted with one or more —CH 3 , CF 3 , or —OCF 3 groups.

16. The method of claim 1 , wherein Ar is an optionally substituted 6-membered heteroaryl ring.

17. The method of claim 16 , wherein the 6-membered heteroaryl ring is substituted with —F, or —Cl.

18. The method of claim 16 , wherein the 6-membered heteroaryl ring is substituted with one or more —CH 3 , CF 3 , or —OCF 3 groups.

19. The method of claim 1 , wherein Ar is an optionally substituted 5-membered heteroaryl ring.

20. The method of claim 19 , wherein the 5-membered heteroaryl ring is substituted with —F, or —Cl.

21. The method of claim 19 , wherein the 5-membered heteroaryl ring is substituted with one or more —CH 3 , CF 3 , or —OCF 3 groups.

22. The method of claim 1 , wherein X is O.

23. The method of claim 1 , wherein X is S.

24. The method of claim 1 , wherein X is SO 2 .

25. The method of claim 1 , wherein X is NH.

26. The method of claim 1 , wherein X is N(CH 3 ).

27. The method of claim 1 , wherein Y is —(CR 9 R 9′ ) n .

28. The method of claim 27 , wherein —(CR 9 R 9′ ), is —CH 2 —, —CH 2 CH 2 —, —CH 2 CH 2 CH 2 —, —C(CH 3 ) 2 —, or —CF 2 —.

29. The method of claim 1 , wherein Y is —CR 9 ═CR 9′ —.

30. The method of claim 1 , wherein Y is —C(═O)—(CR 9 R 9′ ) n —.

31. The method of claim 1 , wherein Y is —C(═O)—O—(CR 9 R 9′ ) n —.

32. The method of claim 1 , wherein Y is —CR 9 R 9′ —O.

33. The method of claim 1 , wherein Y is —(CR 9 R 9′ ) n —O—(CR 9 R 9′ ) m —.

34. The method of claim 1 , wherein Y is C(═O).

35. The method of claim 1 , wherein Y is CH—C 1 -C 4 alkyl-NH 2 .

36. The method of claim 1 wherein Y is —(CR 9 R 9′ ) n —NR 10 .

37. The method of claim 1 , wherein Y is —C(═O)NR 10 .

38. The method of claim 27 , wherein each R 9 and each R 9′ is independently H, D, —CH 3 , OH, —OCH 3 , F, or CF 3 .

39. The method of claim 27 , wherein n=1.

40. The method of claim 27 , wherein n=2.

41. The method of claim 27 , wherein n=3.

42. The method of claim 33 wherein m=1.

43. The method of claim 33 wherein m=2.

44. The method of claim 1 , wherein Z is O.

45. The method of claim 1 , wherein Z is CH 2 .

46. The method of claim 1 , wherein Z is CF 2 .

47. The method of claim 1 , wherein A is N.

48. The method of claim 1 , wherein A is C—R 3 .

49. The method of claim 48 , wherein R 3 is H.

50. The method of claim 48 , wherein R 3 is —F.

Assignees

• Prelude Therapeutics Inc

Inventors

• Lin Hong
• Luengo Juan
• Shetty Rupa
• Hawkins Michael
• Pitis Philip
• Villarroya Gisela Saborit

Classifications

• A61P11/00

  Drugs for disorders of the respiratory system · CPC title

• A61P31/16

  for influenza or rhinoviruses · CPC title

• A61P31/14

  for RNA viruses · CPC title

• A61P37/08

  Antiallergic agents (antiasthmatic agents A61P11/06; ophthalmic antiallergics A61P27/14) · CPC title

• A61P37/00

  Drugs for immunological or allergic disorders · CPC title