# US 9,518,054 B2 · 2-(azaindol-2-yl) benz imidazoles as PAD4 inhibitors

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- Number: US 9,518,054 B2
- Document ID: US9518054B2
- Status: Granted
- Kind: B2
- Application number: 14/816,246
- Filed: 2015-08-03
- Published: 2016-01-14
- Granted: 2016-12-13
- Earliest claimed: 2015-08-03
- Assignees: Glaxo Group Limited
- Applicants: Glaxo Group Limited
- Inventors: Stephen John Atkinson; Michael David Barker; Matthew Campbell; Hawa Diallo; Clement Douault; Neil Stuart Garton; John Liddle; Robert John Sheppard; Ann Louise Walker; Christopher Wellaway; David Matthew Wilson
- Web page: https://patentgrep.com/patent/US9518054B2

## CPC

- A61K 31/4545: containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
- A61K 31/407: condensed with other heterocyclic ring systems, e.g. ketorolac, physostigmine
- A61K 31/4184: condensed with carbocyclic rings, e.g. benzimidazoles
- A61P 1/04: for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
- A61P 11/06: Antiasthmatics
- A61P 17/06: Antipsoriatics
- A61P 19/02: for joint disorders, e.g. arthritis, arthrosis
- A61P 29/00: Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
- A61P 35/00: Antineoplastic agents
- A61P 37/00: Drugs for immunological or allergic disorders
- A61P 37/02: Immunomodulators
- C07D 471/04: Ortho-condensed systems
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)

## Abstract

Compounds of formula (I) wherein; R1 is hydrogen or C1-6alkyl; R2 is hydrogen, C1-6alkyl, perhalomethylC0-5alkyl-O—, or C1-6alkoxy; R3 is hydrogen, C1-6alkyl, or C1-6alkoxyC1-6alkyl; R4 is hydrogen, C1-6alkyl, perhalomethylC1-6alkyl; or unsubstituted C3-6cycloalkylC1-6alkyl; A is C—R5 or N; B is C—R6 or N; D is C—R7 or N; with the proviso that at least one of A, B, and D, is N; R5 is hydrogen or C1-6alkyl; R6 is hydrogen or C1-6alkyl; R7 is hydrogen, C1-6alkyl, C1-6alkoxy, or hydroxy; R8 is hydrogen or C1-6alkyl, with the proviso that one of R4 and R8 is hydrogen; R9 is hydrogen or hydroxy; R10 is hydrogen or C1-6alkyl; 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

### Claim 1

A method of treating rheumatoid arthritis comprises administering to a patient in need thereof a PAD4 inhibitory effective amount of a compound of formula I:
or a pharmaceutically acceptable salt thereof, wherein:
R1 is hydrogen or C1-6alkyl;
R2 is hydrogen, C1-6alkyl, perhalomethylC0-5alkyl-O—, or C1-6alkoxy;
R3 is hydrogen, C1-6alkyl, or C1-6alkoxyC1-6alkyl;
R4 is hydrogen, C1-6alkyl, halomethylC1-6alkyl; or unsubstituted C3-6cycloalkylC1-6alkyl;
A is C—R5 or N;
B is C—R6 or N;
D is C—R7 or N;
with the proviso that at least one of A, B, and D, is N;
R5 is hydrogen or C1-6alkyl;
R6 is hydrogen or C1-6alkyl;
R7 is hydrogen, C1-6alkyl, C1-6alkoxy, or hydroxy;
R8 is hydrogen or C1-6alkyl, with the proviso that one of R4 and R8 is hydrogen;
R9 is hydrogen or hydroxy; and
R10 is hydrogen or C1-6alkyl;
or a pharmaceutically acceptable composition comprising said compound of formula I.

### Claim 2 (depends on 1)

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

### Claim 3 (depends on 2)

The method according to claim 2, wherein:
R1 is hydrogen;
R2 is hydrogen, C1-6alkyl or C1-6alkoxy;
R3 is C1-6alkyl; and
R4 is C1-6alkyl, unsubstituted C3-6cycloalkylC1-6alkyl, or perhalomethylC1-6alkyl.

### Claim 4 (depends on 3)

The method according to claim 3, wherein:
R5 is hydrogen;
R6 is hydrogen;
R7 is hydrogen, C1-6alkoxy, or hydroxyl; and
R8 is hydrogen.

### Claim 5 (depends on 4)

The method according to claim 4, wherein R9 is hydrogen.

### Claim 6 (depends on 4)

The method according to claim 4, wherein R9 is hydroxy.

### Claim 7 (depends on 4)

The method according to claim 4, wherein R10 is hydrogen.

### Claim 8 (depends on 4)

The method according to claim 4, wherein R10 is C1-6alkyl.

### Claim 9 (depends on 2)

The method according to claim 2, 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;
(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;
((3S,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;
((3S,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-(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.