IP Library › Granted Patent US 11,661,419
Granted Patent B2
US 11,661,419 · App. 17/126,358 · Granted May 30, 2023

Benzimidazole derivative compounds and uses thereof

Inventors: Scott William Bagley (Mystic, CT); Agustin Casimiro-Garcia (Concord, MA); Xiayun Cheng (Old Saybrook, CT); Jennifer Elizabeth Davoren (Cambridge, MA); Rajiah Aldrin Denny (Sharon, MA); Brian Stephen Gerstenberger (Cambridge, MA); Frank Eldridge Lovering (Acton, MA); Mihir Dineshkumar Parikh (East Greenwich, RI); Joseph Walter Strohbach (Wentzville, MO); John Isidro Trujillo (Ledyard, CT)
Assignee: Pfizer Inc.
C07D413/14A61K45/06A61P17/00
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Quick Facts
Patent No.
US 11,661,419
App. No.
17/126,358
Granted
May 30, 2023
Kind
B2
Abstract

The invention relates to benzimidazoles of Formula (I) and pharmaceutically acceptable salts thereof, wherein R 1 to R 6 are as defined in the description; to their use in medicine; to compositions containing them; to processes for their preparation; and to intermediates used in such processes. The benzimidazoles of Formula (I) are ITK inhibitors and are therefore potentially useful in the treatment of a wide range of disorders including, atopic dermatitis.

Claims (41)

1. A compound of Formula (I)

or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate of said compound or said salt, wherein:

each R 1 is independently H or F;

R 2 is H, (C 1 -C 4 )alkyl, hydroxy(C 1 -C 4 )alkyl, (C 1 -C 4 )alkoxy(C 1 -C 4 )alkyl or (C 1 -C 4 )alkyl substituted by one, two or three F;

each R 3 is independently H, F, (C 3 -C 5 )cycloalkyl, (C 1 -C 4 )alkyl or (C 1 -C 4 )alkyl substituted by one, two or three F; or both R 3 taken together with the carbon atom to which they are attached form (C 3 -C 5 )cycloalkyl;

R 4 is selected from

wherein each heterocycle is optionally substituted by one or two substituents independently selected from oxo, (C1-C4)alkyl, hydroxy(C1-C4)alkyl and (C1-C4)alkyl substituted by one, two or three F; and

R 5 and R 6 are independently H; halogen; OH; CN; (C 1 -C 6 )alkyl; hydroxy(C 1 -C 6 )alkyl; (C 1 -C 4 )alkoxy(C 1 -C 6 )alkyl; (C 1 -C 6 )alkyl substituted by one, two or three F; (C 1 -C 6 )alkoxy; or (C 1 -C 6 )alkoxy substituted by (C 1 -C 4 )alkoxy.

2. A compound according to claim 1 , or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate of said compound or said salt, wherein each R 1 is H.

3. A compound according to claim 1 , or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate of said compound or said salt, wherein R 2 is H or (C1-C4)alkyl.

4. A compound according to claim 3 , or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate of said compound or said salt, wherein R 2 is methyl.

5. A compound according to claim 1 , or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate of said compound or said salt, wherein each R 3 is independently H, F or (C 1 -C 4 )alkyl.

6. A compound according to claim 5 , or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate of said compound or said salt, wherein each R 3 is independently H, F or methyl.

7. A compound according to claim 6 , or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate of said compound or said salt, wherein one R 3 is H and the other R 3 is methyl.

8. A compound according to claim 7 of Formula (Ia)

or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate of said compound or said salt.

9. A compound according to claim 1 , or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate of said compound or said salt, wherein R 4 is

optionally substituted by one or two substituents independently selected from oxo, (C 1 -C 4 )alkyl and hydroxy(C1-C4)alkyl.

10. A compound according to claim 9 , or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate of said compound or said salt, wherein R 4 is

11. A compound according to claim 10 , or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate of said compound or said salt, wherein R 4 is

12. A compound according to claim 1 , or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate of said compound or said salt, wherein R 5 and R 6 are independently H; halogen; OH; CN; (C 1 -C 3 )alkyl; hydroxy(C 1 -C 3 )alkyl; (C1-C3)alkoxy(C1-C3)alkyl; (C1-C3)alkyl substituted by one, two or three F; (C1-C3)alkoxy; or (C1-C3)alkoxy substituted by (C1-C3)alkoxy.

13. A compound according to claim 12 , or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate of said compound or said salt, wherein R 5 is H, halogen, CN, (C 1 -C 3 )alkyl, (C 1 -C 3 )alkoxy or (C 1 -C 3 )alkoxy substituted by (C 1 -C 3 )alkoxy.

14. A compound according to claim 13 , or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate of said compound or said salt, wherein R 6 is H; halogen; OH; CN; (C 1 -C 3 )alkyl; hydroxy(C 1 -C 3 )alkyl; (C 1 -C 3 )alkoxy(C 1 -C 3 )alkyl; (C 1 -C 3 )alkyl substituted by one, two or three F; or (C 1 -C 3 )alkoxy.

15. A compound according to claim 1 , or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate of said compound or said salt, selected from:

(S)—N-methyl-N-(6-methyl-2-((4aS,5aR)-5a-methyl-1,4,4a,5,5a,6-hexahydrocyclopropa[f]indazol-3-yl)-1H-benzo[d]imidazol-5-yl)-2-morpholinopropanamide;

(R)—N-methyl-N-(2-((4aS,5aR)-5a-methyl-1,4,4a,5,5a,6-hexahydrocyclopropa[f]indazol-3-yl)-1H-benzo[d]imidazol-5-yl)-2-(tetrahydro-2H-pyran-4-yl-)propanamide;

(R)—N-(7-fluoro-2-(4aS,5aR)-5a-methyl-1,4,4a,5,5a,6-hexahydrocyclopropa[f]indazol-3-yl)-1H-benzo[d]imidazol-5-yl)-N-methyl-2-(tetrahydro-2H-pyran-4-yl)propanamide;

(S)—N-(7-fluoro-2-((4aS,5aR)-5a-methyl-1,4,4a,5,5a,6-hexahydrocyclopropa[f]indazol-3-yl)-1H-benzo[d]imidazol-5-yl)-N-methyl-2-morpholinopropanamide;

(S)—N-ethyl-N-(7-fluoro-2-((4aS,5aR)-5a-methyl-1,4,4a,5,5a,6-hexahydrocyclopropa[f]indazol-3-yl)-1H-benzo[d]imidazol-5-yl)-2-morpholinopropanamide;

(S)—N-(6,7-difluoro-2-(4aS,5aR)-5a-methyl-1,4,4a,5,5a,6-hexahydrocyclopropa[f]indazol-3-yl)-1H-benzo[d]imidazol-5-yl)-N-methyl-2-morpholinopropanamide;

(S)—N-(6,7-difluoro-2-(4aS,5aR)-5a-methyl-1,4,4a,5,5a,6-hexahydrocyclopropa[f]indazol-3-yl)-1H-benzo[d]imidazol-5-yl)-N-ethyl-2-morpholinopropanamide;

(S)—N-(7-fluoro-6-methyl-2-((4aS,5aR)-5a-methyl-1,4,4a,5,5a,6-hexahydrocyclopropa[f]indazol-3-yl)-1H-benzo[d]imidazol-5-yl)-N-methyl-2-morpholinopropanamide; and

(S)—N-methyl-N-(7-methyl-2-((4aS,5aR)-5a-methyl-1,4,4a,5,5a,6-hexahydrocyclopropa[f]indazol-3-yl)-1H-benzo[d]imidazol-5-yl)-2-morpholinopropanamide.

16. The compound according to claim 15 which is (S)—N-methyl-N-(6-methyl-2-((4aS,5aR)-5a-methyl-1,4,4a,5,5a,6-hexahydrocyclopropa[f]indazol-3-yl)-1H-benzo[d]imidazol-5-yl)-2-morpholinopropanamide, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate of said compound or said salt.

17. The compound according to claim 15 which is (R)—N-methyl-N-(2-((4aS,5aR)-5a-methyl-1,4,4a,5,5a,6-hexahydrocyclopropa[f]indazol-3-yl)-1H-benzo[d]imidazol-5-yl)-2-(tetrahydro-2H-pyran-4-yl)propanamide, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate of said compound or said salt.

18. The compound according to claim 16 which is (S)—N-methyl-N-(6-methyl-2-((4aS,5aR)-5a-methyl-1,4,4a,5,5a,6-hexahydrocyclopropa[f]indazol-3-yl)-1H-benzo[d]imidazol-5-yl)-2-morpholinopropanamide, or a hydrate thereof.

19. A compound which is (S)—N-methyl-N-(6-methyl-2-(4aS,5aR)-5a-methyl-1,4,4a,5,5a,6-hexahydrocyclopropa[f]indazol-3-yl)-1H-benzo[d]imidazol-5-yl)-2-morpholinopropanamide, dihydrate.

20. A compound which is

21. A pharmaceutical composition comprising a compound according to claim 1 and a pharmaceutically acceptable excipient.

22. The pharmaceutical composition according to claim 21 adapted for topical administration.

23. The pharmaceutical composition according to claim 22 including one or more additional therapeutic agents.

Assignments (1)
ASSIGNEE ADDRESS CORRECTION Recorded Mar 20, 2023
From: PFIZER INC.
To: PFIZER INC.
Reel/Frame 063119/0087 →