# US 2013/0158049 A1 · 7-azaindole inhibitors of crac

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- Number: US 2013/0158049 A1
- Document ID: US20130158049A1
- Status: Published application
- Kind: A1
- Application number: 13/716,535
- Filed: 2012-12-17
- Published: 2013-06-20
- Earliest claimed: 2011-12-20
- Assignees: Hoffmann-La Roche Inc.
- Inventors: Muzaffar Alam; Daisy Joe Du Bois; Ronald Charles Hawley; Niala Bhagirath; Joshua Kennedy-Smith; Robert Stephen Wilhelm
- Web page: https://patentgrep.com/patent/US20130158049A1

## CPC

- C07D 471/04: Ortho-condensed systems
- A61P 29/00: Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## Abstract

Disclosed are compounds of Formula (I): useful for treatment of autoimmune and inflammatory diseases associated with IL-2 inhibition via modulation of calcium release-activated calcium (CRAC) channels. Also disclosed are methods of making and using the compounds for treatment of diseases associated with CRAC channels.

## Claims

### Claim 1

A compound of Formula (I):
wherein:
Ar is
phenyl, unsubstituted or mono- or bi-substituted independently with halogen,
heteroaryl, unsubstituted or substituted with one or two substituents independently selected from lower alkyl and halogen, or
unsubstituted cycloalkyl; and
Ar′ is
phenyl, unsubstituted or substituted with one or two substituents independently selected from lower alkyl, —C(O)OCH3, —SO2N(CH3)2, —CN and alkoxy,
heteroaryl, unsubstituted or substituted with one or two substituents independently selected from lower alkyl, heteroaryl, —C(O)NHCH3, —C(O)NH(CH2)2OH, —SO2CH3 and haloalkyl,
or a pharmaceutically acceptable salt thereof.

### Claim 2 (depends on 1)

The compound according to claim 1, wherein Ar is phenyl, unsubstituted or mono- or bi-substituted independently with halogen, and Ar′ is heteroaryl, unsubstituted or substituted with one or two substituents independently selected from lower alkyl, heteroaryl, —C(O)NHCH3, —C(O)NH(CH2)2OH, —SO2CH3 and haloalkyl.

### Claim 3 (depends on 1)

The compound according to claim 1, wherein Ar is phenyl, unsubstituted or mono- or bi-substituted independently with halogen, and Ar′ is phenyl, unsubstituted or substituted with one or two substituents independently selected from lower alkyl, —C(O)OCH3, —SO2N(CH3)2, —CN and alkoxy.

### Claim 4 (depends on 1)

The compound according to claim 1, wherein Ar is heteroaryl, unsubstituted or substituted with one or two substituents independently selected from lower alkyl and halogen, and Ar′ is phenyl, unsubstituted or substituted with one or two substituents independently selected from lower alkyl, —C(O)OCH3, —SO2N(CH3)2, —CN and alkoxy.

### Claim 5 (depends on 1)

The compound according to claim 1, wherein Ar heteroaryl, unsubstituted or substituted with one or two substituents independently selected from lower alkyl and halogen, and Ar′ is heteroaryl, unsubstituted or substituted with one or two substituents independently selected from lower alkyl, heteroaryl, —C(O)NHCH3, —C(O)NH(CH2)2OH, —SO2CH3 and haloalkyl.

### Claim 6 (depends on 1)

The compound according to claim 1, wherein Ar is unsubstituted cycloalkyl and Ar′ is heteroaryl, unsubstituted or substituted with one or two substituents independently selected from lower alkyl, heteroaryl, —C(O)NHCH3, —C(O)NH(CH2)2OH, —SO2CH3 and haloalkyl.

### Claim 7 (depends on 1)

The compound according to claim 1, wherein Ar is phenyl bi-substituted independently with chlorine and fluorine.

### Claim 8 (depends on 1)

The compound according to claim 1, wherein Ar is methylpyridinyl, chloropyridinyl or dimethylisoxazolyl.

### Claim 9 (depends on 1)

The compound according to claim 1, wherein Ar is cyclohexyl.

### Claim 10 (depends on 1)

The compound according to claim 1, wherein Ar′ is pyrazolyl, thiazolyl, triazolyl or pyridinyl, substituted with one or two substituents independently selected from lower alkyl, heteroaryl, —C(O)NHCH3, —C(O)NH(CH2)2OH, —SO2CH3 and haloalkyl.

### Claim 11 (depends on 1)

The compound according to claim 1, wherein said compound is:
4-[2-(2,6-Difluoro-phenyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-3-methyl-benzoic acid methyl ester;
2-(2,6-Difluoro-phenyl)-5-(2,4-dimethoxy-phenyl)-1H-pyrrolo[2,3-b]pyridine;
4-[2-(2,6-Difluoro-phenyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-3,N,N-trimethyl-benzenesulfonamide;
2-(2,6-Difluoro-phenyl)-5-(2-ethyl-5-pyridin-3-yl-2H-pyrazol-3-yl)-1H-pyrrolo[2,3-b]pyridine;
2-(2,6-Difluoro-phenyl)-5-(5-methyl-2-pyridin-3-yl-thiazol-4-yl)-1H-pyrrolo[2,3-b]pyridine;
2-(2,6-Difluoro-phenyl)-5-(2-methyl-5-trifluoromethyl-2H-pyrazol-3-yl)-1H-pyrrolo[2,3-b]pyridine;
2-(2,6-Difluoro-phenyl)-5-(2-ethyl-5-trifluoromethyl-2H-pyrazol-3-yl)-1H-pyrrolo[2,3-b]pyridine;
2-(2,6-Difluoro-phenyl)-5-(5-methyl-2-oxazol-2-yl-thiazol-4-yl)-1H-pyrrolo[2,3-b]pyridine;
2-(2,6-Difluoro-phenyl)-5-(2-ethyl-5-pyridin-3-yl-2H-[1,2,4]triazol-3-yl)-1H-pyrrolo[2,3-b]pyridine;
2-(2,6-Difluoro-phenyl)-5-(2-methyl-5-pyridin-3-yl-2H-[1,2,4]triazol-3-yl)-1H-pyrrolo[2,3-b]pyridine; or
5-[2-(2,6-Difluoro-phenyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-4-methyl-pyridine-2-carboxylic acid methylamide;

### Claim 12 (depends on 1)

The compound according to claim 1, wherein said compound is:
5-[2-(2,6-Difluoro-phenyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-4-methyl-pyridine-2-carboxylic acid (2-hydroxy-ethyl)-amide;
2-(2,6-Difluoro-phenyl)-5-(5-ethyl-2-pyridin-3-yl-thiazol-4-yl)-1H-pyrrolo[2,3-b]pyridine;
2-(2,6-Difluoro-phenyl)-5-(5-methyl-2-pyrazin-2-yl-thiazol-4-yl)-1H-pyrrolo[2,3-b]pyridine;
2-(2-Chloro-6-fluoro-phenyl)-5-(2-methyl-5-trifluoromethyl-2H-pyrazol-3-yl)-1H-pyrrolo[2,3-b]pyridine;
4-[2-(2-Chloro-6-fluoro-phenyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-3,N,N-trimethyl-benzenesulfonamide;
2-(2-Chloro-6-fluoro-phenyl)-5-(2-ethyl-5-pyrazin-2-yl-2H-pyrazol-3-yl)-1H-pyrrolo[2,3-b]pyridine;
2-(2-Chloro-6-fluoro-phenyl)-5-(5-methyl-2-pyrazin-2-yl-thiazol-4-yl)-1H-pyrrolo[2,3-b]pyridine;
4-[2-(2-Chloro-6-fluoro-phenyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-3-methoxy-benzonitrile;
2-(2-Chloro-6-fluoro-phenyl)-5-(6-methanesulfonyl-4-methyl-pyridin-3-yl)-1H-pyrrolo[2,3-b]pyridine;
5-(2-Ethyl-5-pyrazin-2-yl-2H-pyrazol-3-yl)-2-(3-methyl-pyridin-4-yl)-1H-pyrrolo[2,3-b]pyridine; or
5-(1-Ethyl-3-(pyridin-3-yl)-1H-pyrazol-5-yl)-2-(3-methylpyridin-4-yl)-1H-pyrrolo[2,3-b]pyridine;

### Claim 13 (depends on 1)

The compound according to claim 1, wherein said compound is:
5-(1-ethyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)-2-(3-methylpyridin-4-yl)-1H-pyrrolo[2,3-b]pyridine;
5-(4-Methyl-6-(methylsulfonyl)pyridin-3-yl)-2-(3-methylpyridin-4-yl)-1H-pyrrolo[2,3-b]pyridine;
5-(1-Ethyl-3-(pyrazin-2-yl)-1H-pyrazol-5-yl)-2-(4-methylpyridin-3-yl)-1H-pyrrolo[2,3-b]pyridine;
5-(2-Ethyl-5-pyrazin-2-yl-2H-pyrazol-3-yl)-2-(4-methyl-pyridin-3-yl)-1H-pyrrolo[2,3-b]pyridine;
5-(4-Methyl-6-(methylsulfonyl)pyridin-3-yl)-2-(4-methylpyridin-3-yl)-1H-pyrrolo[2,3-b]pyridine;
2-(4-chloropyridin-3-yl)-5-(1-ethyl-3-(pyridin-3-yl)-1H-pyrazol-5-yl)-1H-pyrrolo[2,3-b]pyridine;
2-(4-Chloropyridin-3-yl)-5-(4-methyl-6-(methylsulfonyl)pyridin-3-yl)-1H-pyrrolo[2,3-b]pyridine;
2-(3,5-Dimethyl-isoxazol-4-yl)-5-(2-ethyl-5-pyridin-3-yl-2H-pyrazol-3-yl)-1H-pyrrolo[2,3-b]pyridine;
2-cyclohexyl-5-(4-methyl-6-(methylsulfonyl)pyridin-3-yl)-1H-pyrrolo[2,3-b]pyridine;
2-Cyclohexyl-5-(1-ethyl-3-(pyridin-3-yl)-1H-pyrazol-5-yl)-1H-pyrrolo[2,3-b]pyridine; or
2-Cyclohexyl-5-(1-ethyl-3-(pyrazin-2-yl)-1H-pyrazol-5-yl)-1H-pyrrolo[2,3-b]pyridine.

### Claim 14 (depends on 1)

A pharmaceutical composition, comprising a therapeutically effective amount of a compound according to claim 1 and a pharmaceutically acceptable carrier.

### Claim 15 (depends on 1)

A method for treating arthritis, comprising the step of administering a therapeutically effective amount of a compound according to claim 1 to a subject in need thereof.

### Claim 16 (depends on 1)

A method for treating a respiratory disorder selected from chronic obstructive pulmonary disorder (COPD), asthma, and bronchospasm, comprising the step of administering a therapeutically effective amount of a compound according to claim 1 to a subject in need thereof.