Pyrazolo[1,5-A]PYRAZIN-4-YL derivatives

Patent metadata

Field	Value
Publication number	US-10144738-B2
Application number	US-201715437618-A
Country	US
Kind code	B2
Filing date	Feb 21, 2017
Priority date	Feb 24, 2016
Publication date	Dec 4, 2018
Grant date	Dec 4, 2018

Abstract

A compound having the structure:

or a pharmaceutically acceptable salt thereof, wherein A, A′ and A″ are independently O, C═O, etc.; R 0 and R are independently H, Br, Cl, F, or C 1 -C 6 alkyl; R 1 is H, C 1 -C 6 alkyl, or hydroxy(C 1 -C 6 alkyl); R 2 is selected from the group consisting of H, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, etc.; R 6 , R 7 and R 8 are each independently H, C 1 -C 6 alkyl, C 1 -C 4 alkoxy(C 1 -C 6 alkyl), etc.; 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.

First claim

What is claimed is:

1. A compound having the structure (I):

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, —NR 7 COR 6 , COR 6 , —CONR 7 R 8 , C 1 -C 6 alkyl, or hydroxy(C 1 -C 6 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;
R 0 and R are independently H, Br, Cl, F, or C 1 -C 6 alkyl;
R 1 is H, C 1 -C 6 alkyl, or hydroxy(C 1 -C 6 alkyl)-;
R 2 is selected from the group consisting of H, C 1 -C 6 alkyl-, C 1 -C 6 alkoxy-, hydroxy(C 1 -C 6 phenyl(C 1 -C 6 formyl, heteroaryl, heterocyclic, —COR 6 , —OCOR 6 , —COOR 6 , —NR 7 COR 6 , CONR 7 R 8 , and —(CH 2 ) n —W, where W is cyano, hydroxy, C 3 -C 8 cycloalkyl, —SO 2 NR 7 R 8 , and —SO 2 —R 9 , where R 9 is C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, heteroaryl, or heterocyclic; wherein each of said alkyl, cycloalkyl, heterocyclic, or heteroaryl may be unsubstituted or substituted by halo, cyano, hydroxy, or C 1 -C 6 alkyl;
X is C—R 3 or N, where R 3 may be H, C 1 -C 6 alkyl, amino, cyano, or C 1 -C 6 alkoxy;
R 4 and R 5 are independently H, amino, C 1 -C 6 alkyl, or hydroxy(C 1 -C 6 alkyl)-;
R 6 , R 7 and R 5 are each independently H, C 1 -C 6 alkyl, C 1 -C 4 alkoxy(C 1 -C 6 alkyl) or C 3 -C 8 cycloalkyl, said C 1 -C 6 alkyl is optionally substituted by halo, CN or hydroxy; or, R 7 and R 5 together with the atom bonded thereto form a 5- or 6-membered ring, said ring being optionally substituted by halo, hydroxy, CN, or C 1 -C 6 alkyl;
and, n is 0, 1, 2 or 3.

2. The compound of claim 1 having the structure (Ia):

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, —NR 7 COR 6 , COR 6 , —CONR 7 R 8 , C 1 -C 6 alkyl, or hydroxy(C 1 -C 6 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;
R 0 and R are independently H, Br, Cl, F, or C 1 -C 6 alkyl;
R 1 is H, C 1 -C 6 alkyl, or hydroxy(C 1 -C 6 alkyl);
R 2 is selected from the group consisting of H, C 1 -C 6 alkyl-, C 1 -C 6 alkoxy-, hydroxy(C 1 -C 6 phenyl(C 1 -C 6 formyl, heteroaryl, heterocyclic, —COR 6 , —OCOR 6 , —COOR 6 , —NR 7 COR 6 , —CONR 7 R 8 , and —(CH 2 ) n —W, where W is cyano, hydroxy, C 3 -C 8 cycloalkyl, —SO 2 NR 7 R 8 , and —SO 2 —R 9 , where R 9 is C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, heteroaryl, or heterocyclic; wherein each of said alkyl, cycloalkyl, heterocyclic, or heteroaryl may be unsubstituted or substituted by halo, cyano, hydroxy, or C 1 -C 6 alkyl;
R 3 may be H, C 1 -C 6 alkyl, amino, cyano, or C 1 -C 6 alkoxy;
R 4 and R 5 are independently H, amino, C 1 -C 6 alkyl, or hydroxy(C 1 -C 6 alkyl)-;
R 6 , R 7 and R 5 are each independently H, C 1 -C 6 alkyl, C 1 -C 4 alkoxy(C 1 -C 6 alkyl)-, or C 3 -C 8 cycloalkyl, said C 1 -C 6 alkyl is optionally substituted by halo, CN or hydroxy; or, R 7 and R 5 together with the atom bonded thereto form a 5- or 6-membered ring, said ring being optionally substituted by halo, hydroxy, CN, or C 1 -C 6 alkyl;
and, n is 0, 1, 2 or 3.

3. The compound of claim 1 having the structure (Ib):

or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate of said compound or pharmaceutically acceptable salt, wherein:
R″ is H, —COR 6 , —CONR 7 R 8 , C 1 -C 6 alkyl, or hydroxy(C 1 -C 6 alkyl)-;
R 0 and R are independently H, Br, Cl, F, or C 1 -C 6 alkyl;
R 1 is H, C 1 -C 6 alkyl, or hydroxy(C 1 -C 6 alkyl);
R 2 is selected from the group consisting of H, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, hydroxy(C 1 -C 6 alkyl), phenyl(C 1 -C 6 alkyl), formyl, heteroaryl, heterocyclic, —COR 6 , —OCOR 6 , —COOR 6 , —NR 7 COR 6 , —CONR 7 R 8 , and —(CH 2 ) n —W, where W is cyano, hydroxy, C 3 -C 8 cycloalkyl, —SO 2 NR 7 R 8 , and —SO 2 —R 9 , where R 9 is C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, heteroaryl, or heterocyclic; wherein each of said alkyl, cycloalkyl, heterocyclic, or heteroaryl may be unsubstituted or substituted by halo, cyano, hydroxy, or C 1 -C 6 alkyl;
R 3 may be H, C 1 -C 6 alkyl, amino, cyano, or C 1 -C 6 alkoxy;
R 5 is independently H, amino, C 1 -C 6 alkyl, or hydroxy(C 1 -C 6 alkyl);
R 6 , R 7 and R 8 are each independently H, C 1 -C 6 alkyl, C 1 -C 4 alkoxy(C 1 -C 6 alkyl), or C 3 -C 8 cycloalkyl, said C 1 -C 6 alkyl is optionally substituted by halo, CN or hydroxy; or, R 7 and R 8 together with the atom bonded thereto form a 5- or 6-membered ring, said ring being optionally substituted by halo, hydroxy, CN, or C 1 -C 6 alkyl;
and, n is 0, 1, 2 or 3.

4. The compound of claim 3 wherein R″ is C 1 -C 6 alkyl and R 5 is H.

5. The compound of claim 1 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, —COR 6 , —CONR 7 R 8 , C 1 -C 6 alkyl-, or hydroxy(C 1 -C 6 alkyl)-;
R 2 is selected from the group consisting of H, C 1 -C 6 alkyl, C 1 -C 6 alkoxy-, hydroxy(C 1 -C 6 alkyl)-, phenyl(C 1 -C 6 alkyl-), formyl, heteroaryl, heterocyclic, —COR 6 , —OCOR 6 , —COOR 6 , —NR 7 COR 6 , —CONR 7 R 8 , and —(CH 2 ) n —W, where W is cyano, hydroxy, C 3 -C 8 cycloalkyl, —SO 2 NR 7 R 8 , and —SO 2 —R 9 , where R 9 is C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, heteroaryl, or heterocyclic; wherein each of said alkyl, cycloalkyl, heterocyclic, or heteroaryl may be unsubstituted or substituted by halo, cyano, hydroxy, or C 1 -C 6 alkyl;
R 3 is H, C 1 -C 6 alkyl, amino, cyano, or C 1 -C 6 alkoxy-;
R 5 is H, amino, C 1 -C 6 alkyl, or hydroxy(C 1 -C 6 alkyl)-;
R 6 , R 7 and R 8 are each are each independently H, C 1 -C 6 alkyl, C 1 -C 4 alkoxy(C 1 -C 6 alkyl)-, or C 3 -C 8 cycloalkyl, said C 1 -C 6 alkyl is optionally substituted by halo, CN or hydroxy; or, R 7 and R 8 together with the atom bonded thereto form a 5- or 6-membered ring, said ring being optionally substituted by halo, hydroxy, CN, or C 1 -C 6 alkyl;
and, n is 0, 1, 2 or 3.

6. The compound of claim 5 wherein R″ is C 1 -C 6 alkyl and R 5 is H.

7. The compound of claim 1 having the structure (Id):

or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate of said compound or pharmaceutically acceptable salt, wherein:
R″ is H, —COR 6 , —CONR 7 R 8 , C 1 -C 6 alkyl, or hydroxy(C 1 -C 6 alkyl)-;
R 2 is selected from the group consisting of H, C 1 -C 6 alkyl, C 1 -C 6 alkoxy-, hydroxy(C 1 -C 6 alkyl)-, phenyl(C 1 -C 6 alkyl)-, formyl, heteroaryl, heterocyclic, —COR 6 , —O

Assignees

• Pfizer

Inventors

• Brown Matthew Frank
• DERMENCI Alpay
• Fensome Andrew
• Gerstenberger Brian Stephen
• Hayward Matthew Merrill
• Owen Dafydd Rhys
• Wright Stephen Wayne
• Xing Li Huang
• Yang Xiaojing

Classifications

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title

• A61P37/08

  Antiallergic agents (antiasthmatic agents A61P11/06; ophthalmic antiallergics A61P27/14) · CPC title

• A61P37/06

  Immunosuppressants, e.g. drugs for graft rejection · CPC title

• A61P37/02

  Immunomodulators · CPC title

• A61P37/00

  Drugs for immunological or allergic disorders · CPC title