IP Library › Granted Patent US 10,822,341
Granted Patent B2
US 10,822,341 · App. 16/181,596 · Granted Nov 3, 2020

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

Inventors: Matthew Frank Brown (Stonington, CT); Alpay Dermenci (East Lyme, CT); Andrew Fensome (Harvard, MA); Brian Stephen Gerstenberger (Brookline, MA); Matthew Merrill Hayward (Old Lyme, CT); Dafydd Rhys Owen (Concord, MA); Stephen Wayne Wright (Old Lyme, CT); Li Huang Xing (Lexington, MA); Xiaojing Yang (Waterford, CT)
Assignee: Pfizer Inc.
C07D487/04
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Quick Facts
Patent No.
US 10,822,341
App. No.
16/181,596
Granted
Nov 3, 2020
Kind
B2
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.

Claims (83)

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 -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 method of claim 5 , wherein [R′ in the compound having structure (Ic) is C 1 -C 6 alkyl and] R 5 is H.

7. The method of claim 1 , wherein the compound has 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 , —OCOR 6 , —COOR 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 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.

8. The method of claim 7 , wherein R″ in the compound having structure (Id) is C 1 -C 6 alkyl and R 5 is H.

9. The method of claim 1 , wherein the compound has the structure (Ie):

or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate of said compound or pharmaceutically acceptable salt, wherein:

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 formyl, heteroaryl, heterocyclic —COR 6 , —OCOR 6 , ——COOR 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 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.

10. The method of claim 9 , wherein R 2 in the compound having structure (Ie) is —(CH 2 ) n —W, where W is cyano and n is 1, 2 or 3.

11. The method of claim 1 , wherein the compound has the structure (If):

or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate of said compound or pharmaceutically acceptable salt, wherein:

R″ is H, C 1 -C 6 alkyl, or hydroxy(C 1 -C 6 alkyl)-; and,

R 5 is H, amino, C 1 -C 6 alkyl, or hydroxy(C 1 -C 6 alkyl)-.

12. The method of claim 11 , wherein R″ in the compound having structure (If) is C 1 -C 6 alkyl and R 5 is H.

13. The method of claim 1 , wherein the compound is selected from the group consisting of:

(1r,3r)-3-(4-(6-(3-amino-1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)-1H-pyrazol-1-yl)-3-(cyanomethyl)cyclobutane-1-carbonitrile;

2,2′-(3-(4-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)-1H-pyrazol-1-yl)azetidine-1,3-diyl)diacetonitrile;

2-((1s,3r)-1-(4-(6-(5-(hydroxymethyl)-1H-pyrazol-3-yl)pyrazolo[1,5-a]pyrazin-4-yl)-1H-pyrazol-1-yl)-3-methoxycyclobutyl)acetonitrile;

5-(4-(1-((1s,3r)-1-(cyanomethyl)-3-methoxycyclobutyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-6-yl)-1H-pyrazole-3-carboxamide;

(1s, 35)-3-(cyanomethyl)-3-(4-(6-(5-(hydroxymethyl)isoxazol-3-yl)pyrazolo[1,5-a]pyrazin-4-yl)-1H-pyrazol-1-yl)cyclobutane-1-carbonitrile;

(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;

(1s, 35)-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;

(1r, 3r)-3-(cyanomethyl)-3-(4-(3-methyl-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)-1H-pyrazol-1-yl)cyclobutane-1-carbonitrile;

2-((1r,3s)-1-(4-(6-(3-amino-1H-pyrazol-5-yl)pyrazolo[1,5-a]pyrazin-4-yl)-1H-pyrazol-1-yl)-3-methoxycyclobutyl)acetonitrile;

2-(1-ethyl-3-(4-(6-(5-(hydroxymethyl)-1H-pyrazol-3-yl)pyrazolo[1,5-a]pyrazin-4-yl)-1H-pyrazol-1-yl)azetidin-3-yl)acetonitrile;

(1r, 3r)-3-(Cyanomethyl)-3-(4-(6-(1-methyl-3-oxo-2,3-dihydro-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)-1H-pyrazol-1-yl)cyclobutane-1-carbonitrile (trans isomer); and

(1r, 3r)-3-(cyanomethyl)-3-(4-(6-(1-(hydroxymethyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)-1H-pyrazol-1-yl)cyclobutane-1-carbonitrile;

or, a pharmaceutically acceptable salt thereof.

14. The method of claim 11 , wherein the compound is (1r,3r)-3-(4-(6-(3-amino-1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)-1H-pyrazol-1-yl)-3-(cyanomethyl)cyclobutane-1-carbonitrile, or a pharmaceutically acceptable salt thereof.

15. The method of claim 1 , wherein the compound is 2,2′-(3-(4-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)-1H-pyrazol-1-yl)azetidine-1,3-diyl)diacetonitrile, or a pharmaceutically acceptable salt thereof.

16. The method of claim 1 , wherein the compound is 2-((1s,3r)-1-(4-(6-(5-(hydroxymethyl)-1H-pyrazol-3-yl)pyrazolo[1,5-a]pyrazin-4-yl)-1H-pyrazol-1-yl)-3-methoxycyclobutyl)acetonitrile, or a pharmaceutically acceptable salt thereof.

17. The method of claim 1 , wherein the compound is 5-(4-(1-((1s,3r)-1-(cyanomethyl)-3-methoxycyclobutyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-6-yl)-1H-pyrazole-3-carboxamide, or a pharmaceutically acceptable salt thereof.

18. The method of claim 1 , wherein the compound is (1s,35)-3-(cyanomethyl)-3-(4-(6-(5-(hydroxymethyl)isoxazol-3-yl)pyrazolo[1,5-a]pyrazin-4-yl)-1H-pyrazol-1-yl)cyclobutane-1-carbonitrile, or a pharmaceutically acceptable salt thereof.

19. The method of claim 11 , 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.

20. The method of claim 11 , wherein the compound is (1s,35)-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.

21. The method of claim 1 , wherein the compound is (1r, 3r)-3-(cyanomethyl)-3-(4-(3-methyl-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.

22. The method of claim 1 , wherein the compound is 2-((1r,3s)-1-(4-(6-(3-amino-1H-pyrazol-5-yl)pyrazolo[1,5-a]pyrazin-4-yl)-1H-pyrazol-1-yl)-3-methoxycyclobutyl)acetonitrile, or a pharmaceutically acceptable salt thereof.

23. The method of claim 1 , wherein the compound is 2-(1-ethyl-3-(4-(6-(5-(hydroxymethyl)-1H-pyrazol-3-yl)pyrazolo[1,5-a]pyrazin-4-yl)-1H-pyrazol-1-yl)azetidin-3-yl)acetonitrile, or, a pharmaceutically acceptable salt thereof.

Continuity (3)
Division 15437618 · Feb 21, 2017
Provisional Application 62299130 · Feb 24, 2016
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