Pyrazolo[1,5-a]pyrazin-4-yl derivatives

Patent metadata

Field	Value
Publication number	US-10822341-B2
Application number	US-201816181596-A
Country	US
Kind code	B2
Filing date	Nov 6, 2018
Priority date	Feb 24, 2016
Publication date	Nov 3, 2020
Grant date	Nov 3, 2020

Abstract

A compound 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, —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 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; X is C—R 3 or N, where R 3 may be H or C 1 -C 6 alkyl; 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 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. 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 method of treating a disease or condition selected from [inflammation, autoimmune disease, systemic lupus erythematous, lupus nephritis, discoid lupus, cutaneous lupus, central nervous system lupus,] rheumatoid arthritis, psoriatic arthritis, inflammatory bowel disease, Crohn's disease, ulcerative colitis, [asthma, allergic asthma, Type I diabetes, polymyositis, dermatomyositis, type I interferonopathies including Aicardi-Goutières syndrome and other mendelian diseases of overexpression of type I interferon, multiple sclerosis, primary progressive multiple sclerosis, relapsing remitting multiple sclerosis, primary biliary cirrhosis also known as primary biliary cholangitis, primary sclerosing cholangitis, autoimmune hepatitis, non-alcoholic fatty liver disease, non-alcoholic steatohepatitis,] psoriasis, [dermatomyositis, scleroderma,] atopic dermatitis, vitiligo, and alopecia areata, [spondylopathy, ankylosing spondylitis, Alzheimer's disease, neuro-inflammation] comprising administering to a subject suffering from said disease or condition a therapeutically effective amount of 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 alkyl)-, phenyl(C 1 -C 6 alkyl)-, formyl, heteroaryl, heterocyclic, —COR 6 , —OCOR 8 , —COOR 6 , —NR 7 COR 8 , 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 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 method of claim 1 , wherein the compound has 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 8 , 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 alkyl)-, phenyl(C 1 -C 6 alkyl)-, formyl, heteroaryl, heterocyclic, —COR 6 , —OCOR 6 , —COOR 6 , —NR 7 COR 8 , —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 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.

3. The method of claim 1 , wherein the compound has 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 method of claim 3 , wherein R″ in the compound having structure (Ib) is C 1 -C 6 alkyl and R 5 is H.

5. The method of claim 1 , wherein 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, —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 -

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

• A61K31/4985 Primary

  Pyrazines or piperazines ortho- or peri-condensed with heterocyclic ring systems · CPC title

• A61P37/06

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

• A61P37/00

  Drugs for immunological or allergic disorders · CPC title

• A61P21/00

  Drugs for disorders of the muscular or neuromuscular system · CPC title

• A61P19/02

  for joint disorders, e.g. arthritis, arthrosis · CPC title