# US 2020/0399281 A1 · Pyrazolo[1,5-a]pyrazin-4-yl derivatives

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- Number: US 2020/0399281 A1
- Document ID: US20200399281A1
- Status: Published application
- Kind: A1
- Application number: 17/014,533
- Filed: 2020-09-08
- Published: 2020-12-24
- Earliest claimed: 2016-02-24
- Assignees: Pfizer Inc.
- Applicants: Pfizer Inc.
- Inventors: Matthew Frank BROWN; Alpay DERMENCI; Andrew FENSOME; Brian Stephen GERSTENBERGER; Matthew Merrill HAYWARD; Dafydd Rhys OWEN; Stephen Wayne WRIGHT; Li Huang XING; Xiaojing YANG
- Web page: https://patentgrep.com/patent/US20200399281A1

## CPC

- C07D 487/04: Ortho-condensed systems
- A61K 31/4985: Pyrazines or piperazines ortho- or peri-condensed with heterocyclic ring systems
- A61P 1/04: for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
- A61P 1/16: for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
- A61P 3/10: for hyperglycaemia, e.g. antidiabetics
- A61P 11/06: Antiasthmatics
- A61P 13/12: of the kidneys
- A61P 17/00: Drugs for dermatological disorders
- A61P 17/06: Antipsoriatics
- A61P 17/14: for baldness or alopecia
- A61P 19/02: for joint disorders, e.g. arthritis, arthrosis
- A61P 21/00: Drugs for disorders of the muscular or neuromuscular system
- A61P 25/00: Drugs for disorders of the nervous system
- A61P 25/28: for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
- A61P 29/00: Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
- A61P 37/00: Drugs for immunological or allergic disorders
- A61P 37/02: Immunomodulators
- A61P 37/06: Immunosuppressants, e.g. drugs for graft rejection
- A61P 37/08: Antiallergic agents (antiasthmatic agents A61P11/06; ophthalmic antiallergics A61P27/14)
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- 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

## Abstract

A compound having the structure: or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate of said compound or pharmaceutically acceptable salt, wherein A, A′ and A″ are independently O, C═O, C—R′ or N—R″, where R′ and R″ may independently be H, amino, —NR7COR6, COR6, —CONR7R8, C1-C6 alkyl, or hydroxy(C1-C6 alkyl), and R″ may be present or absent, and is present where the rules of valency permit, and where not more than one of A, A′ and A″ is O or C═O; R0 and R are independently H, Br, Cl, F, or C1-C6 alkyl; R1 is H, C1-C6 alkyl, or hydroxy(C1-C6 alkyl); R2 is selected from the group consisting of H, C1-C6 alkyl, C1-C6 alkoxy, hydroxy(C1-C6 alkyl), phenyl(C1-C6 alkyl), formyl, heteroaryl, heterocyclic, —COR6, —OCOR6, —COOR6, —NR7COR6, —CONR7R8, and —(CH2)n—W, where W is cyano, hydroxy, C3-C8 cycloalkyl, —SO2NR7R8, and —SO2—R9, where R9 is C1-C6 alkyl, C3-C8 cycloalkyl, heteroaryl, or heterocyclic; wherein each of said alkyl, cycloalkyl, heterocyclic, or heteroaryl may be unsubstituted or substituted by halo, cyano, hydroxy, or C1-C6 alkyl; X is C—R3 or N, where R3 may be H or C1-C6 alkyl; R4 and R5 are independently H, amino, C1-C6 alkyl, or hydroxy(C1-C6 alkyl); R6, R7 and R8 are each independently H, C1-C6 alkyl, C1-C4 alkoxy(C1-C6 alkyl), or C3-C8 cycloalkyl, said C1-C6 alkyl is optionally substituted by halo, CN or hydroxy; or, R7 and R8 together with the atom bonded thereto form a 5- or 6-membered ring, said ring being optionally substituted by halo, hydroxy, CN, or C1-C6alkyl; and, n is 0, 1, 2 or 3. Also provided are methods of treatment as Janus Kinase inhibitors and pharmaceutical compositions containing the compounds of the invention and combinations thereof with other therapeutic agents.

## Claims

### Claim at position 1

1-51. (canceled)

### Claim 52

A method of treating a psoriasis comprising administering to a subject suffering therefrom a therapeutically effective amount of a compound having the structure the compound has the structure (Ic):
or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate of said compound or pharmaceutically acceptable salt, wherein:
R″ is H, —COR6, —CONR7R8, C1-C6 alkyl-, or hydroxy(C1-C6 alkyl)-;
R2 is selected from the group consisting of H, C1-C6 alkyl, C1-C6 alkoxy-, hydroxy(C1-C6 alkyl)-, phenyl(C1-C6 alkyl-), formyl, heteroaryl, heterocyclic, —COR6, —OCOR6, —COOR6, —NR7COR6, —CONR7R8, and —(CH2)n—W, where W is cyano, hydroxy, C3-C8 cycloalkyl, —SO2NR7R8, and —SO2—R9, where R9 is C1-C6 alkyl, C3-C8 cycloalkyl, heteroaryl, or heterocyclic; wherein each of said alkyl, cycloalkyl, heterocyclic, or heteroaryl may be unsubstituted or substituted by halo, cyano, hydroxy, or C1-C6 alkyl;
R3 is H, C1-C6 alkyl, amino, cyano, or C1-C6 alkoxy-;
R5 is H, amino, C1-C6 alkyl, or hydroxy(C1-C6 alkyl)-;
R6, R7 and R8 are each independently H, C1-C6 alkyl, C1-C4 alkoxy(C1-C6 alkyl)-, or C3-C8 cycloalkyl, said C1-C6 alkyl is optionally substituted by halo, CN or hydroxy; or, R7 and R8 together with the atom bonded thereto form a 5- or 6-membered ring, said ring being optionally substituted by halo, hydroxy, CN, or C1-C6 alkyl;
and, n is 0, 1, 2 or 3.

### Claim 53 (depends on 52)

The method of claim 52, wherein R″ is C1-C6 alkyl.

### Claim 54 (depends on 52)

The method of claim 52, wherein R″ is C1-C6 alkyl and R5 is H.

### Claim 55 (depends on 52)

The method of claim 52, wherein the compound is (1r,3r)-3-(cyanomethyl)-3-(4-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)-1H-pyrazol-1-yl)cyclobutane-1-carbonitrile, or a pharmaceutically acceptable salt thereof.

### Claim 56

A method of treating a psoriasis comprising administering to a subject suffering therefrom a therapeutically effective amount of the compound (1r,3r)-3-(cyanomethyl)-3-(4-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)-1H-pyrazol-1-yl)cyclobutane-1-carbonitrile, or a pharmaceutically acceptable salt thereof.

### Claim 57

A method of treating inflammatory bowel disease comprising administering to a subject suffering therefrom a therapeutically effective amount of a compound having the structure (Ic):
or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate of said compound or pharmaceutically acceptable salt, wherein:
R″ is H, —COR6, —CONR7R8, C1-C6 alkyl-, or hydroxy(C1-C6 alkyl)-;
R2 is selected from the group consisting of H, C1-C6 alkyl, C1-C6 alkoxy-, hydroxy(C1-C6 alkyl)-, phenyl(C1-C6 alkyl-), formyl, heteroaryl, heterocyclic, —COR6, —OCOR6, —COOR6, —NR7COR6, —CONR7R8, and —(CH2)n—W, where W is cyano, hydroxy, C3-C8 cycloalkyl, —SO2NR7R8, and —SO2—R9, where R9 is C1-C6 alkyl, C3-C8 cycloalkyl, heteroaryl, or heterocyclic; wherein each of said alkyl, cycloalkyl, heterocyclic, or heteroaryl may be unsubstituted or substituted by halo, cyano, hydroxy, or C1-C6 alkyl;
R3 is H, C1-C6 alkyl, amino, cyano, or C1-C6 alkoxy-;
R5 is H, amino, C1-C6 alkyl, or hydroxy(C1-C6 alkyl)-;
R6, R7 and R8 are each independently H, C1-C6 alkyl, C1-C4 alkoxy(C1-C6 alkyl)-, or C3-C8 cycloalkyl, said C1-C6 alkyl is optionally substituted by halo, CN or hydroxy; or, R7 and R8 together with the atom bonded thereto form a 5- or 6-membered ring, said ring being optionally substituted by halo, hydroxy, CN, or C1-C6 alkyl;
and, n is 0, 1, 2 or 3.

### Claim 58 (depends on 57)

The method of claim 57, wherein R″ is C1-C6 alkyl.

### Claim 59 (depends on 57)

The method of claim 57, wherein R″ is C1-C6 alkyl and R5 is H.

### Claim 60 (depends on 57)

The method of claim 57, wherein the compound is (1r,3r)-3-(cyanomethyl)-3-(4-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)-1H-pyrazol-1-yl)cyclobutane-1-carbonitrile, or a pharmaceutically acceptable salt thereof.

### Claim 61

A method of treating inflammatory bowel disease comprising administering to a subject suffering therefrom a therapeutically effective amount of the compound (1r,3r)-3-(cyanomethyl)-3-(4-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)-1H-pyrazol-1-yl)cyclobutane-1-carbonitrile, or a pharmaceutically acceptable salt thereof.

### Claim 62

A method of treating ulcerative colitis comprising administering to a subject suffering therefrom a therapeutically effective amount of a compound having the structure (Ic):
or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate of said compound or pharmaceutically acceptable salt, wherein:
R″ is H, —COR6, —CONR7R8, C1-C6 alkyl-, or hydroxy(C1-C6 alkyl)-;
R2 is selected from the group consisting of H, C1-C6 alkyl, C1-C6 alkoxy-, hydroxy(C1-C6 phenyl(C1-C6 alkyl-), formyl, heteroaryl, heterocyclic, —COR6, —OCOR6, —COOR6, —NR7COR6, —CONR7R8, and —(CH2)n—W, where W is cyano, hydroxy, C3-C8 cycloalkyl, —SO2NR7R8, and —SO2—R9, where R9 is C1-C6 alkyl, C3-C8 cycloalkyl, heteroaryl, or heterocyclic; wherein each of said alkyl, cycloalkyl, heterocyclic, or heteroaryl may be unsubstituted or substituted by halo, cyano, hydroxy, or C1-C6 alkyl;
R3 is H, C1-C6 alkyl, amino, cyano, or C1-C6 alkoxy-;
R5 is H, amino, C1-C6 alkyl, or hydroxy(C1-C6 alkyl)-;
R6, R7 and R8 are each independently H, C1-C6 alkyl, C1-C4 alkoxy(C1-C6 alkyl)-, or C3-C8 cycloalkyl, said C1-C6 alkyl is optionally substituted by halo, CN or hydroxy; or, R7 and R8 together with the atom bonded thereto form a 5- or 6-membered ring, said ring being optionally substituted by halo, hydroxy, CN, or C1-C6 alkyl;
and, n is 0, 1, 2 or 3.

### Claim 63 (depends on 62)

The method of claim 62, wherein R″ is C1-C6 alkyl.

### Claim 64 (depends on 62)

The method of claim 62, wherein R″ is C1-C6 alkyl and R5 is H.

### Claim 65 (depends on 62)

The method of claim 62, wherein the compound is (1r,3r)-3-(cyanomethyl)-3-(4-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)-1H-pyrazol-1-yl)cyclobutane-1-carbonitrile, or a pharmaceutically acceptable salt thereof.

### Claim 66

A method of treating ulcerative colitis comprising administering to a subject suffering therefrom a therapeutically effective amount of the compound (1r,3r)-3-(cyanomethyl)-3-(4-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)-1H-pyrazol-1-yl)cyclobutane-1-carbonitrile, or a pharmaceutically acceptable salt thereof.

### Claim 67

A method of treating Type I Diabetes Mellitus comprising administering to a subject suffering therefrom a therapeutically effective amount of a compound having the structure (Ic):
or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate of said compound or pharmaceutically acceptable salt, wherein:
R″ is H, —COR6, —CONR7R8, C1-C6 alkyl-, or hydroxy(C1-C6 alkyl)-;
R2 is selected from the group consisting of H, C1-C6 alkyl, C1-C6 alkoxy-, hydroxy(C1-C6 phenyl(C1-C6 alkyl-), formyl, heteroaryl, heterocyclic, —COR6, —OCOR6, —COOR6, —NR7COR6, —CONR7R8, and —(CH2)n—W, where W is cyano, hydroxy, C3-C8 cycloalkyl, —SO2NR7R8, and —SO2—R9, where R9 is C1-C6 alkyl, C3-C8 cycloalkyl, heteroaryl, or heterocyclic; wherein each of said alkyl, cycloalkyl, heterocyclic, or heteroaryl may be unsubstituted or substituted by halo, cyano, hydroxy, or C1-C6 alkyl;
R3 is H, C1-C6 alkyl, amino, cyano, or C1-C6 alkoxy-;
R5 is H, amino, C1-C6 alkyl, or hydroxy(C1-C6 alkyl)-;
R6, R7 and R8 are each independently H, C1-C6 alkyl, C1-C4 alkoxy(C1-C6 alkyl)-, or C3-C8 cycloalkyl, said C1-C6 alkyl is optionally substituted by halo, CN or hydroxy; or, R7 and R8 together with the atom bonded thereto form a 5- or 6-membered ring, said ring being optionally substituted by halo, hydroxy, CN, or C1-C6 alkyl;
and, n is 0, 1, 2 or 3.

### Claim 68 (depends on 67)

The method of claim 67, wherein R″ is C1-C6 alkyl.

### Claim 69 (depends on 67)

The method of claim 67, wherein R″ is C1-C6 alkyl and R5 is H.

### Claim 70 (depends on 67)

The method of claim 67, wherein the compound is (1r,3r)-3-(cyanomethyl)-3-(4-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)-1H-pyrazol-1-yl)cyclobutane-1-carbonitrile, or a pharmaceutically acceptable salt thereof.

### Claim 71

A method of treating Type I Diabetes Mellitus comprising administering to a subject suffering therefrom a therapeutically effective amount of the compound (1r,3r)-3-(cyanomethyl)-3-(4-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)-1H-pyrazol-1-yl)cyclobutane-1-carbonitrile, or a pharmaceutically acceptable salt thereof.