Pyrazolo[1,5-A]pyrazin-4-yl and related derivatives

Patent metadata

Field	Value
Publication number	US-11254668-B2
Application number	US-201816638271-A
Country	US
Kind code	B2
Filing date	Aug 9, 2018
Priority date	Aug 14, 2017
Publication date	Feb 22, 2022
Grant date	Feb 22, 2022

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 variables are defined in the specification. 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:

or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate of said compound or pharmaceutically acceptable salt, wherein:
W is H, halo, or is selected from the group consisting of:

A, A′ and A″ are independently O, S, C═O, C—R′, N or N—R″, where R′ and R″ may independently be H, amino, —NR 7 COR 6 , COR 6 , —CONR 7 R 8 , —NHSO 2 (C 1 -C 6 alkyl), C 1 -C 6 alkyl, halo, amino(C 1 -C 6 alkyl)-, C 3 -C 8 cycloalkyl, heteroaryl, heterocyclic, heterocyclic(C 1 -C 6 alk-yl)-, hydroxy(C 1 -C 6 alkyl)-, or hydroxy(halo-C 1 -C 6 alkyl)-, where each said moiety may be present or absent, and is present where the rules of valency permit, subject to the proviso that not more than one of A, A′ and A″ is O, S or C═O; where C 1 -C 6 alkyl is optionally substituted by OH, halo, N(C 1 -C 6 alkyl) and heterocyclic;
R 0 is H, D or C 1 -C 6 alkyl-;
Y, Z, and Z′ are independently C—R 1 , or N, where R 1 is H, halo, amino, —NR 7 COR 6 , COR 6 , —CONR 7 R 8 , —NHSO 2 (C 1 -C 6 alkyl), C 1 -C 6 alkyl, halo, amino(C 1 -C 6 alkyl)- or hydroxy(C 1 -C 6 alkyl)-;
Y′ is O, C—R 1 or N, where R 1 is H, halo, amino, —NR 7 COR 6 , COR 6 , —CONR 7 R 8 , —NHSO 2 (C 1 -C 6 alkyl), C 1 -C 6 alkyl, halo, amino(C 1 -C 6 alkyl)- or hydroxy(C 1 -C 6 alkyl)-;
Q is CN or CONH 2 ;
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)-, C 3 -C 8 cycloalkyl, halo(C 3 -C 8 cycloalkyl), spirocyclic, formyl, heteroaryl, heterocyclic, —COR, —OCOR, —COOR, —NR 7 COR, 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; or, R 2 and R 3 when taken together forms a C 3 -C 8 cycloalkyl group or C 4 -C 8 heterocyclic group; wherein heterocyclic or heteroaryl group may be substituted by C 1 -C 6 alkyl, halo or hydroxy;
X is C—R 3 or N, where R 3 may be H or C 1 -C 6 alkyl;
R 4 , R 5 and R 6 are independently H, halo, amino, —OH, —CO 2 H, —CONH 2 , C 1 -C 6 alkyl, C 1 -C 6 alkoxy-, —hydroxy(C 1 -C 6 alkoxy)-, hydroxy(C 1 -C 6 alkoxy)-, heteroaryl-, heterocyclic-, —SO 2 NH 2 , —NHSO 2 (C 1 -C 6 alkyl), —NHCO(C 1 -C 6 alkyl), —NHCO 2 (C 1 -C 6 alkyl), —SO 2 (C 1 -C 6 alkyl), amino(C 1 -C 6 alkoxy), amino(C 1 -C 6 alkyl)- or hydroxy(C 1 -C 6 alkyl)-;
R, 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.

2. The compound of claim 1 wherein X is C.

3. The compound of claim 1 wherein R 2 is CN and R 4 is H.

4. The compound of claim 1 wherein Y is CH or N.

5. The compound of claim 1 wherein Z is N and Z′ is CH.

6. 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, S, C═O, C—R′, N or N—R″, where R′ and R″ may independently be H, amino, —NR 7 COR 6 , COR 6 , —CONR 7 R 8 , —NHSO 2 (C 1 -C 6 alkyl), C 1 -C 6 alkyl, halo, amino(C 1 -C 6 alkyl)-, C 3 -C 8 cycloalkyl, heteroaryl, heterocyclic, heterocyclic(C 1 -C 6 alk-yl)-, hydroxy(C 1 -C 6 alkyl)-, or hydroxy(halo-C 1 -C 6 alkyl)-, where each said moiety may be present or absent, and is present where the rules of valency permit, subject to the proviso that not more than one of A, A′ and A″ is O, S or C═O; where C 1 -C 6 alkyl is optionally substituted by OH, halo, N(C 1 -C 6 alkyl) and heterocyclic;
R 0 is H, D or C 1 -C 6 alkyl-;
Z is C—R 1 or N, where R 1 is H, halo, amino, —NR 7 COR 6 , COR 6 , —CONR 7 R 8 , —NHSO 2 (C 1 -C 6 alkyl), C 1 -C 6 alkyl, halo, amino(C 1 -C 6 alkyl)- or hydroxy(C 1 -C 6 alkyl)-; Z″ and Z″′ are independently C—R′ or N—R″;
R 5 and R 6 are independently H, halo, amino, —OH, —CO 2 H, —CONH 2 , C 1 -C 6 alkyl, C 1 -C 6 alkoxy-, —hydroxy(C 1 -C 6 alkoxy)-, hydroxy(C 1 -C 6 alkoxy)-, heteroaryl-, heterocyclic-, —SO 2 NH 2 , —NHSO 2 (C 1 -C 6 alkyl), —NHCO(C 1 -C 6 alkyl), —NHCO 2 (C 1 -C 6 alkyl), —SO 2 (C 1 -C 6 alkyl), amino(C 1 -C 6 alkoxy), amino(C 1 -C 6 alkyl)- or hydroxy(C 1 -C 6 alkyl)-; and,
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.

7. 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:
W is H, halo, or is selected from the group consisting of:

A, A′ and A″ are independently O, S, C═O, C—R′, N or N—R″, where R′ and R″ may independently be H, amino, —NR 7 COR 6 , COR 6 , —CONR 7 R 8 , —NHSO 2 (C 1 -C 6 alkyl), C 1 -C 6 alkyl, halo, amino(C 1 -C 6 alkyl)-, C 3 -C 8 cycloalkyl, heteroaryl, heterocyclic, heterocyclic(C 1 -C 6 alk-yl)-, hydroxy(C 1 -C 6 alkyl)-, or hydroxy(halo-C 1 -C 6 alkyl)-, where each said moiety may be present or absent, and is present where the rules of valency permit, subject to the proviso that not more than one of A, A′ and A″ is O, S or C═O; where C 1 -C 6 alkyl is optionally substituted by OH, halo, N(C 1 -C 6 alkyl) and heterocyclic;
R 0 is H, D or C 1 -C 6 alkyl-;
R 5 and R 6 are independently H, halo, amino, —OH, —CO 2 H, —CONH 2 , C 1 -C 6 alkyl, C 1 -C 6 alkoxy-, —hydroxy(C 1 -C 6 alkoxy)-, hydroxy(C 1 -C 6 alkoxy)-, heteroaryl-, heterocyclic-, —SO 2 NH 2 , —NHSO 2 (C 1 -C 6 alkyl), —NHCO(C 1 -C 6 alkyl), —NHCO 2 (C 1 -C 6 alkyl), —SO 2 (C 1 -C 6 alkyl), amino(C 1 -C 6 alkoxy), amino(C 1 -C 6 alkyl)- or hydroxy(C 1 -C 6 alkyl)-; and,
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.

8. The compound

Assignees

• Pfizer

Inventors

• Gerstenberger Brian Stephen
• Fensome Andrew
• Owen Dafydd Rhys
• Brown Matthew Frank
• Hayward Matthew Merrill
• Vajdos Felix
• Xing Li Huang
• Wright Stephen Wayne

Classifications

• C07D401/04

  directly linked by a ring-member-to-ring-member bond · CPC title

• C07D487/04

  Ortho-condensed systems · CPC title

• C07D471/04 Primary

  Ortho-condensed systems · CPC title

• C07D401/14

  containing three or more hetero rings · CPC title

• C07D405/14

  containing three or more hetero rings · CPC title