# US 10,766,883 B2 · Aminopyrazoles as janus kinase inhibitors

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- Number: US 10,766,883 B2
- Document ID: US10766883B2
- Status: Granted
- Kind: B2
- Application number: 16/468,465
- Filed: 2017-12-07
- Published: 2019-10-31
- Granted: 2020-09-08
- Earliest claimed: 2016-12-14
- Assignees: Merck Sharp & Dohme Corp.
- Applicants: Merck Sharp & Dohme Corp.
- Inventors: Peter Fuller; Jason Brubaker; Hongbo Zeng; Joshua Close; Jonathan Young
- Web page: https://patentgrep.com/patent/US10766883B2

## CPC

- C07D 405/04: directly linked by a ring-member-to-ring-member bond
- A61P 35/00: Antineoplastic agents
- A61P 37/00: Drugs for immunological or allergic disorders
- C07D 405/14: containing three or more hetero rings
- C07D 413/14: containing three or more hetero rings
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## Abstract

The instant invention provides compounds which are JAK inhibitors, and as such are useful for the treatment of JAK-mediated diseases such as rheumatoid arthritis, asthma, COPD and cancer.

## Claims

### Claim 1

A compound selected from:
3-((4-Chloro-3-methoxyphenyl)amino)-1-(4-cyanotetrahydro-2H-pyran-3-yl)-1H-pyrazole-4-carboxamide;
3-((4-chloro-3-(methylthio)phenyl)amino)-1-(4-cyanotetrahydro-2H-pyran-3-yl)-1H-pyrazole-4-carboxamide;
3-((4-cyano-3-methoxyphenyl)amino)-1-(4-cyanotetrahydro-2H-pyran-3-yl)-1H-pyrazole-4-carboxamide;
3-((4-cyano-3-(2-fluoropropan-2-yl)phenyl)amino)-1-(4-cyanotetrahydro-2H-pyran-3-yl)-1H-pyrazole-4-carboxamide; and
1-(4-cyanotetrahydro-2H-pyran-3-yl)-3-((3-methylbenzo[d]isoxazol-5-yl)amino)-1H-pyrazole-4-carboxamide;
or a pharmaceutically acceptable salt thereof.

### Claim 2 (depends on 1)

A compound according to claim 1, selected from:
3-((4-Chloro-3-methoxyphenyl)amino)-1-((3R,4S)-4-cyanotetrahydro-2H-pyran-3-yl)-1H-pyrazole-4-carboxamide;
3-((4-chloro-3-(methylthio)phenyl)amino)-1-((3R,4S)-4-cyanotetrahydro-2H-pyran-3-yl)-1H-pyrazole-4-carboxamide;
3-((4-cyano-3-methoxyphenyl)amino)-1-((3R,4S)-4-cyanotetrahydro-2H-pyran-3-yl)-1H-pyrazole-4-carboxamide;
3-((4-cyano-3-(2-fluoropropan-2-yl)phenyl)amino)-1-((3R,4S)-4-cyanotetrahydro-2H-pyran-3-yl)-1H-pyrazole-4-carboxamide; and
1-((3R,4S)-4-cyanotetrahydro-2H-pyran-3-yl)-3-((3-methylbenzo[d]isoxazol-5-yl)amino)-1H-pyrazole-4-carboxamide;
or a pharmaceutically acceptable salt thereof.

### Claim 3 (depends on 1)

A compound according to claim 1 which is 3-((4-Chloro-3-methoxyphenyl)amino)-1-(4-cyanotetrahydro-2H-pyran-3-yl)-1H-pyrazole-4-carboxamide, or a pharmaceutically acceptable salt thereof.

### Claim 4 (depends on 2)

A compound according to claim 2, which is 3-((4-Chloro-3-methoxyphenyl)amino)-1-((3R,4S)-4-cyanotetrahydro-2H-pyran-3-yl)-1H-pyrazole-4-carboxamide, or a pharmaceutically acceptable salt thereof.

### Claim 5 (depends on 1)

A compound according to claim 1, which is 3-((4-chloro-3-(methylthio)phenyl)amino)-1-(4-cyanotetrahydro-2H-pyran-3-yl)-1H-pyrazole-4-carboxamide, or a pharmaceutically acceptable salt thereof.

### Claim 6 (depends on 2)

A compound according to claim 2, which is 3-((4-chloro-3-(methylthio)phenyl)amino)-1-((3R,4S)-4-cyanotetrahydro-2H-pyran-3-yl)-1H-pyrazole-4-carboxamide, or a pharmaceutically acceptable salt thereof.

### Claim 7 (depends on 1)

A compound according to claim 1, which is 3-((4-cyano-3-(2-fluoropropan-2-yl)phenyl)amino)-1-(4-cyanotetrahydro-2H-pyran-3-yl)-1H-pyrazole-4-carboxamide, or a pharmaceutically acceptable salt thereof.

### Claim 8 (depends on 2)

A compound according to claim 2, which is 3-((4-cyano-3-methoxyphenyl)amino)-1-((3R,4S)-4-cyanotetrahydro-2H-pyran-3-yl)-1H-pyrazole-4-carboxamide, or a pharmaceutically acceptable salt thereof.

### Claim 9 (depends on 2)

A compound according to claim 2, which is 3-((4-cyano-3-(2-fluoropropan-2-yl)phenyl)amino)-1-((3R,4S)-4-cyanotetrahydro-2H-pyran-3-yl)-1H-pyrazole-4-carboxamide, or a pharmaceutically acceptable salt thereof.

### Claim 10 (depends on 2)

A compound according to claim 2, which is 1-((3R,4S)-4-cyanotetrahydro-2H-pyran-3-yl)-3-((3-methylbenzo[d]isoxazol-5-yl)amino)-1H-pyrazole-4-carboxamide or a pharmaceutically acceptable salt thereof.

### Claim 11 (depends on 1)

A pharmaceutical composition comprising a compound of claim 1 or a pharmaceutically acceptable salt, or a stereoisomer thereof and a pharmaceutically acceptable carrier.

### Claim 12 (depends on 1)

A method for the treatment of a JAK-mediated disease comprising administering to a patient in need thereof a therapeutically effective amount of a compound of claim 1 or a stereoisomer, or a pharmaceutically acceptable thereof.

### Claim 13 (depends on 1)

A method of treating a condition in a mammal that can be ameliorated by the selective inhibition of a Janus kinase JAK1 relative to JAK 2 and JAK 3 which condition is selected from, arthritis, asthma and obstructive airways diseases, autoimmune diseases or disorders, and cancer comprising administering to the mammal in need of such treatment, a therapeutically effective amount of a compound according to claim 1 or a pharmaceutically acceptable salt or a stereoisomer thereof.

### Claim 14 (depends on 13)

A method according to claim 13, wherein said condition is arthritis.

### Claim 15 (depends on 14)

A method according to claim 14, wherein said condition is selected from rheumatoid arthritis, juvenile arthritis, and psoriatic arthritis.

### Claim 16 (depends on 13)

A method according to claim 13, wherein said condition is asthma or obstructive airways diseases.

### Claim 17 (depends on 13)

A method according to claim 13, wherein said condition is selected from: chronic asthma, late asthma, airway hyper-responsiveness, bronchitis, bronchial asthma, allergic asthma, intrinsic asthma, extrinsic asthma, dust asthma, recurrent airway obstruction, and chronic obstruction pulmonary disease (COPD), and emphysema.

### Claim 18 (depends on 13)

A method according to claim 13, wherein said condition is autoimmune diseases or disorders.

### Claim 19 (depends on 1)

A method of treating asthma in a mammal in need thereof, comprising administering a therapeutically effective amount of a compound according to claim 1 or a pharmaceutically acceptable salt or a stereoisomer, thereof.

### Claim 20 (depends on 1)

A method of treating arthritis in a mammal in need thereof, comprising administering a therapeutically effective amount of a compound according to claim 1 or a pharmaceutically acceptable salt or stereoisomer, thereof.