IP Library › Granted Patent US 9,833,449

Granted Patent B2

US 9,833,449 · App. 15/352,340 · Granted Dec 5, 2017

2-(azaindol-2-yl) benzimidazoles as PAD4 inhibitors

Inventors: Stephen John Atkinson (Stevenage, GB); Michael David Barker (Stevenage, GB); Matthew Campbell (Stevenage, GB); Hawa Diallo (Stevenage, GB); Clement Douault (Stevenage, GB); Neil Stuart Garton (Stevenage, GB); John Liddle (Stevenage, GB); Robert John Sheppard (Stevenage, GB); Ann Louise Walker (Stevenage, GB); Christopher Wellaway (Stevenage, GB); David Matthew Wilson (Stevenage, GB)

Assignee: GLAXO GROUP LIMITED

A61K31/4545

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Quick Facts

Patent No.: US 9,833,449
App. No.: 15/352,340
Granted: Dec 5, 2017
Kind: B2

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Abstract

Compounds of formula (I): wherein; R 1 is hydrogen or C 1-6 alkyl; R 2 is hydrogen, C 1-6 alkyl, perhalomethylC 0-5 alkyl-O—, or C 1-6 alkoxy; R 3 is hydrogen, C 1-6 alkyl, or C 1-6 alkoxyC 1-6 alkyl; R 4 is hydrogen, C 1-6 alkyl, perhalomethylC 1-6 alkyl; or unsubstituted C 3-6 cycloalkylC 1-6 alkyl; A is C—R 5 or N; B is C—R 6 or N; D is C—R 7 or N; with the proviso that at least one of A, B, and D, is N; R 5 is hydrogen or C 1-6 alkyl; R 6 is hydrogen or C 1-6 alkyl; R 7 is hydrogen, C 1-6 alkyl, C 1-6 alkoxy, or hydroxy; R 8 is hydrogen or C 1-6 alkyl, with the proviso that one of R 4 and R 8 is hydrogen; R 9 is hydrogen or hydroxy; R 10 is hydrogen or C 1-6 alkyl; and salts thereof are PAD4 inhibitors and may be useful in the treatment of various disorders, for example rheumatoid arthritis, vasculitis, systemic lupus erythematosus, ulcerative colitis, cancer, cystic fibrosis, asthma, cutaneous lupus erythematosis, and psoriasis.

Claims (114)

1. A method of treating ulcerative colitis, cancer, cystic fibrosis, asthma, cutaneous lupus erythematosus, or psoriasis, comprising administering to a patient in need thereof a PAD4 inhibitory affective amount of a compound of formula I:

or a pharmaceutically acceptable salt thereof, wherein:

R 1 is hydrogen or C 1-6 alkyl;

R 2 is hydrogen, C 1-6 alkyl, perhalomethylC 0-5 alkyl-O—, or C 1-6 alkoxy;

R 3 is hydrogen, C 1-6 alkyl, or C 1-6 alkoxyC 1-6 alkyl;

R 4 is hydrogen, C 1-6 alkyl, halomethylC 1-6 alkyl; or unsubstituted C 3-6 cycloalkylC 1-6 alkyl;

A is C—R 5 or N;

B is C—R 6 or N;

D is C—R 7 or N;

with the proviso that at least one of A, B, and D, is N;

R 5 is hydrogen or C 1-6 alkyl;

R 6 is hydrogen or C 1-6 alkyl;

R 7 is hydrogen, C 1-6 alkyl, C 1-6 alkoxy, or hydroxy;

R 8 is hydrogen or C 1-6 alkyl, with the proviso that one of R 4 and R 8 is hydrogen;

R 9 is hydrogen or hydroxy; and

R 10 is hydrogen or C 1-6 alkyl;

or a pharmaceutically acceptable composition comprising said compound of formula I.

2. The method according to claim 1 , wherein:

R 1 is hydrogen;

R 2 is hydrogen, C 1-6 alkyl or C 1-6 alkoxy;

R 3 is C 1-6 alkyl; and

R 4 is C 1-6 alkyl, unsubstituted C 3-6 cycloalkylC 1-6 alkyl, or perhalomethylC 1-6 alkyl.

3. The method according to claim 2 , wherein R 2 is C 1-6 alkoxy.

4. The method according to claim 2 , wherein:

R 5 is hydrogen;

R 6 is hydrogen;

R 7 is hydrogen, C 1-6 alkoxy, or hydroxyl; and

R 8 is hydrogen.

5. The method according to claim 4 , wherein R 9 is hydrogen.

6. The method according to claim 4 , wherein R 9 is hydroxy.

7. The method according to claim 4 , wherein R 10 is hydrogen.

8. The method according to claim 4 , wherein R 10 is C 1-6 alkyl.

9. The method according to claim 1 , wherein said compound, or pharmaceutically acceptable salt thereof, is selected from the group consisting of:

1-{[2-(1-ethyl-1H-pyrrolo[3,2-c]pyridin-2-yl)-1-methyl-1H-benzimidazol-5-yl]carbonyl}-3-piperidinamine;

(R)-(3-aminopiperidin-1-yl)(2-(1-ethyl-1H-pyrrolo[2,3-b]pyridin-2-yl)-1-methyl-1H-benzo[d]imidazol-5-yl)methanone;

(R)-(3-aminopiperidin-1-yl)(2-(l-ethyl-1H-pyrrolo[2,3-c]pyridin-2-yl)-1-methyl-1H-benzo[d]imidazol-5-yl)methanone;

(R)-(3-aminopiperidin-1-yl)(1-methyl-2-(1-(2,2,2-trifluoroethyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-benzo[d]imidazol-5-yl)methanone;

(R)-(3-aminopiperidin-1-yl)(2-(1-(cyclopropylmethyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1-methyl-1H-benzo[d]imidazol-5-yl)methanone;

(R)-(3-aminopiperidin-1-yl)(2-(1-ethyl-5-methoxy-1H-pyrrolo[2,3-b]pyridin-2-yl)-1-methyl-1H-benzo[d]imidazol-5-yl)methanone;

(R)-(3-aminopiperidin-1-yl)(2-(1-ethyl-5-methoxy-1H-pyrrolo[2,3-c]pyridin-2-yl)-1-methyl-1H-benzo[d]imidazol-5-yl)methanone;

2-(5-{[(3R)-3-amino-1-piperidinyl]carbonyl}-1-methyl-1H-benzimidazol-2-yl)-1-ethyl-1H-pyrrolo[2,3-b]pyridin-5-ol;

(R)-(3-aminopiperidin-1-yl)(2-(1-ethyl-1H-pyrrolo[2,3-b]pyridin-2-yl)-7-methoxy-1-methyl-1H-benzo[d]imidazol-5-yl)methanone;

(R)-(3-aminopiperidin-1-yl)(2-(1-(cyclopropylmethyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-7-methoxy-1-methyl-1H-benzo[d]imidazol-5-yl)methanone;

(R)-(3-aminopiperidin-1-yl)(7-methoxy-1-methyl-2-(1-(2,2,2-trifluoroethyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-benzo[d]imidazol-5-yl)methanone;

(3-aminopiperidin-1-yl)(2-(1-ethyl-1H-pyrrolo[2,3-b]pyridin-2-yl)-1-methyl-1H-benzo[d]imidazol-5-yl)methanone;

((3 S,4R)-3-amino-4-hydroxypiperidin-1-yl)(2-(1-(cyclopropylmethyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1-methyl-1H-benzo[d]imidazol-5-yl)methanone;

((3 S,4R)-3-amino-4-hydroxypiperidin-1-yl)(2-(1-(cyclopropylmethyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-7-methoxy-1-methyl-1H-benzo[d]imidazol-5-yl)methanone;

(R)-(3-aminopiperidin-1-yl)(2-(1-ethyl-1H-pyrrolo[2,3-b]pyridin-2-yl)-1-methyl-7-(trifluoromethoxy)-1H-benzo[d]imidazol-5-yl)methanone;

(R)-(3-aminopiperidin-1-yl)(7-methoxy-1-methyl-2-(1-neopentyl-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-benzo[d]imidazol-5-yl)methanone;

((R)-3-aminopiperidin-1-yl)(7-methoxy-1-methyl-2-(1-(2-methylbutyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-benzo[d]imidazol-5-yl)methanone;

(R)-(3-aminopiperidin-1-yl)(2-(1-ethyl-1H-pyrrolo[2,3-b]pyridin-2-yl)-7-methoxy-1-(2-methoxyethyl)-1H-benzo[d]imidazol-5-yl)methanone;

(S)-(3-aminopiperidin-1-yl)(2-(1-ethyl-1H-pyrrolo[2,3-b]pyridin-2-yl)-7-methoxy-1-methyl-1H-benzo[d]imidazol-5-yl)methanone;

(R)-(3-aminopiperidin-1-yl)(2-(1-ethyl-1H-pyrrolo[2,3-b]pyridin-2-yl)-1-isobutyl-7-methoxy-1H-benzo[d]imidazol-5-yl)methanone;

(R)-(3-aminopiperidin-1-yl)(7-methoxy-2-(1-(2-methoxy-2-methylpropyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1-methyl-1H-benzo[d]imidazol-5-yl)methanone;

(R)-(3-aminopiperidin-1-yl)(2-(1-isobutyl-1H-pyrrolo[2,3-b]pyridin-2-yl)-7-methoxy-1-methyl-1H-benzo[d]imidazol-5-yl)methanone; and

((cis)-5-amino-2-methylpiperidin-1-yl)(2-(1-(cyclopropylmethyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-7-methoxy-1-methyl-1H-benzo[d]imidazol-5-yl)methanone.

10. The method according to claim 1 , wherein said method comprises administering to said patient a pharmaceutically acceptable composition comprising said compound of formula I.

11. A method of inhibiting PAD4, comprising contacting the PAD4 with a compound of formula I:

or a pharmaceutically acceptable salt thereof, wherein:

R 1 is hydrogen or C 1-6 alkyl;

R 2 is hydrogen, C 1-6 alkyl, perhalomethylC 0-5 alkyl-O—, or C 1-6 alkoxy;

R 3 is hydrogen, C 1-6 alkyl, or C 1-6 alkoxyC 1-6 alkyl;

R 4 is hydrogen, C 1-6 alkyl, halomethylC 1-6 alkyl; or unsubstituted C 3-6 cycloalkylC 1-6 alkyl;

A is C—R 5 or N;

B is C—R 6 or N;

D is C—R 7 or N;

with the proviso that at least one of A, B, and D, is N;

R 5 is hydrogen or C 1-6 alkyl;

R 6 is hydrogen or C 1-6 alkyl;

R 7 is hydrogen, C 1-6 alkyl, C 1-6 alkoxy, or hydroxy;

R 8 is hydrogen or C 1-6 alkyl, with the proviso that one of R 4 and R 8 is hydrogen;

R 9 is hydrogen or hydroxy; and

R 10 is hydrogen or C 1-6 alkyl;

or a pharmaceutically acceptable composition comprising said compound of formula I.

12. The method according to claim 11 , wherein:

R 1 is hydrogen;

R 2 is hydrogen, C 1-6 alkyl or C 1-6 alkoxy;

R 3 is C 1-6 alkyl; and

R 4 is C 1-6 alkyl, unsubstituted C 3-6 cycloalkylC 1-6 alkyl, or perhalomethylC 1-6 alkyl.

13. The method according to claim 12 , wherein R 2 is C 1-6 alkoxy.

14. The method according to claim 12 , wherein:

R 5 is hydrogen;

R 6 is hydrogen;

R 7 is hydrogen, C 1-6 alkoxy, or hydroxyl; and

R 8 is hydrogen.

15. The method according to claim 14 , wherein R 9 is hydrogen.

16. The method according to claim 14 , wherein R 9 is hydroxy.

17. The method according to claim 14 , wherein R 10 is hydrogen.

18. The method according to claim 14 , wherein R 10 is C 1-6 alkyl.

19. The method according to claim 11 , wherein said compound, or pharmaceutically acceptable salt thereof, is selected from the group consisting of:

1-{[2-(1-ethyl-1H-pyrrolo[3,2-c]pyridin-2-yl)-1-methyl-1H-benzimidazol-5-yl]carbonyl}-3-piperidinamine;

(R)-(3-aminopiperidin-1-yl)(2-(1-ethyl-1H-pyrrolo[2,3-b]pyridin-2-yl)-1-methyl-1H-benzo[d]imidazol-5-yl)methanone;

(R)-(3-aminopiperidin-1-yl)(2-(1-ethyl-1H-pyrrolo[2,3-c]pyridin-2-yl)-1-methyl-1H-benzo[d]imidazol-5-yl)methanone;