IP Library › Granted Patent US 10,399,967

Granted Patent B2

US 10,399,967 · App. 15/424,097 · Granted Sep 3, 2019

Compounds for inflammation and immune-related uses

Inventors: Shoujun Chen (Bedford, MA); Gary Bohnert (Wilmington, MA); Jun Jiang (Norwood, MA); Zhiqiang Xia (Acton, MA)

Assignee: PRCL RESEARCH INC.

C07D417/14 A61K31/165 A61K31/44 A61K31/497 C07D213/82 C07D401/12 C07D401/14 C07D405/14 C07D413/14

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Quick Facts

Patent No.: US 10,399,967
App. No.: 15/424,097
Granted: Sep 3, 2019
Kind: B2

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USPTO Patent Center↗ Full Patent PDF↗

Abstract

The invention relates to certain compounds or pharmaceutically acceptable salts, solvates, clathrates, or prodrugs thereof, that are useful as immunosuppressive agents and for treating and preventing inflammatory conditions, allergic disorders, and immune disorders.

Claims (511)

1. A method for relieving, altering, or affecting psoriasis or the symptom of psoriasis in a subject in need thereof, comprising administering to the subject an effective amount of a compound of formula:

or a pharmaceutically acceptable salt, or solvate thereof,

wherein,

B is optionally substituted benzimidazolyl, optionally substituted benzodioxolyl, optionally substituted phenyl, optionally substituted pyridinyl, optionally substituted pyrimidinyl, optionally substituted pyrrolyl, optionally substituted furanyl, optionally substituted thienyl, optionally substituted imidazolyl, optionally substituted pyrazolyl, optionally substituted oxazolyl, or optionally substituted thiazolyl, and wherein B is not haloalkyl substituted pyrazolyl or amido substituted thienyl;

c 1 and c 4 are both N and c 5 is CH;

X C2 is H;

D 1 is —NH—C(O)—, and

X E1 and X E2 are, independently, H, halo, cyano, nitro, optionally substituted C 1-6 alkyl, or optionally substituted amino.

2. The method of claim 1 or a pharmaceutically acceptable salt or solvate thereof, wherein,

and

X E1 is H, fluoro or chloro, and X E2 is H.

3. The method of claim 2 or a pharmaceutically acceptable salt or solvate thereof, wherein, B is substituted with one or more substituents selected from the group consisting of halo, OH, cyano, carboxyl, optionally substituted C 1-6 alkyl, optionally substituted C 1-6 haloalkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 3-8 cycloalkyl, optionally substituted C 1-6 alkoxy, optionally substituted C 1-6 haloalkoxy, optionally substituted C 3-8 cycloalkoxy, optionally substituted C 6-10 aryl, optionally substituted C 7-16 aralkyloxy, optionally substituted C 2-9 heterocyclyl, optionally substituted C 2-9 (heterocyclyl)oxy, optionally substituted C 3-12 heterocyclylalkyl, optionally substituted C 2-9 (heterocyclyl)alkynyl, optionally substituted C 1-6 alkylsulfonyl, optionally substituted C 1-6 alkylsulfonyloxy, optionally substituted C 1-6 alkylsulfamoyloxy, optionally substituted C 1-6 alkylcarbonyl, optionally substituted C 1-6 alkoxycarbonyl, and optionally substituted amino.

4. The method of claim 3 or a pharmaceutically acceptable salt or solvate thereof, wherein, B is phenyl optionally substituted by one or more halo, cyano, C 1-6 alkyl, C 1-6 alkoxy, C 3-8 cycloalkoxy, C 1-6 haloalkoxy, or C 2-9 heterocyclyl.

5. The method of claim 1 or a pharmaceutically acceptable salt or solvate thereof, wherein, B is

and each R B is, independently H, halo, cyano, C 1-6 alkyl, C 1-6 alkoxy, C 3-8 cycloalkoxy, C 1-6 haloalkoxy, or C 2-9 heterocyclyl.

6. The method of claim 1 or a pharmaceutically acceptable salt or solvate thereof, wherein B is

and each R B is, independently halo, cyano, C 1-6 alkyl, C 1-6 alkoxy, C 3-8 cycloalkoxy, C 1-6 haloalkoxy, C 2-9 heterocyclyl.

7. The method of claim 6 or a pharmaceutically acceptable salt or solvate thereof, wherein one of R B is chloro, cyano, methyl, ethyl, cyclopropyloxy, methoxy or ethoxy, and the other R B is 1-methyl-1H-pyrazol-4yl, 1H-pyrazol-4yl, 2-methyloxazol-4yl, isoxazol-3yl, 5methyl-isoxazol-3yl, 2-methylthiazol-4yl, 5-methylthiazol-4yl, 2-methyl-2H-tetrazol-5yl, cyclopropyloxy or methoxy.

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

Structure

Compound Name

N-(5-(2-chloro-5-( 1 H-pyrazol-4- yl)phenyl)pyrazin-2-yl)-4- methylnicotinamide

N-(5-(2-ethoxy-5-(1-methyl- 1 H- pyrazol-4-yl)phenyl)pyrazin-2-yl)- 4-methylnicotinamide

N-(5-(2-chloro-5-(2- methylthiazol-4- yl)phenyl)pyrazin-2-yl)-4- methylnicotinamide

5-fluoro-N-(5-(2-methoxy-5-(1- methyl- 1 H-pyrazol-4- yl)phenyl)pyrazin-2-yl)-4- methylnicotinamide

N-(5-(2-ethyl-5-(1-methyl- 1 H- pyrazol-4-yl)phenyl)pyrazin-2-yl)- 4-methylnicotinamide

N-(5-(2-chloro-5-(5- methylthiazol-2- yl)phenyl)pyrazin-2-yl)-4- methylnicotinamide

N-(5-(2-chloro-5-(pyrimidin-2- yloxy)phenyl)pyrazin-2-yl)-4- methylnicotinamide

N-(5-(2-isopropoxy-5-(1-methyl- 1 H-pyrazol-4-yl)phenyl)pyrazin-2- yl)-4-methylnicotinamide

5-fluoro-4-methyl-N-(5-(5-(1- methyl- 1 H-pyrazol-4-yl)-2- (trifluoromethoxy)phenyl)pyrazin- 2-yl)nicotinamide

N-(5-(2-chloro-5-(3-fluoropyridin- 4-yl)phenyl)pyrazin-2-yl)-4- methylnicotinamide

N-(5-(2-chloro-5-(2-methyl-2H- tetrazol-5-yl)phenyl)pyrazin-2-yl)- 5-fluoro-4-methylnicotinamide

N-(5-(2-ethyl-5-(2-methyl-2H- tetrazol-5-yl)phenyl)pyrazin-2- 5-fluoro-4-methylnicotinamide

N-(5-(2-chloro-5-((6- (trifluoromethyl)pyridin-2- yl)oxy)phenyl)pyrazin-2-yl)-4- methylnicotinamide

N-(5-(5-((3-fluoropyridin-2- yl)oxy)-2-methylphenyl)pyrazin- 2-yl)-4-methylnicotinamide

N-(5-(5-((3-fluoropyridin-2- yl)oxy)-2- (trifluoromethoxy)phenyl)pyrazin- 2-yl)-4-methylnicotinamide

N-(5-(2-cyano-5-(oxetan-3- yloxy)phenyl)pyrazin-2-yl)-4- methylnicotinamide

4-methyl-N-(5-(2-methyl-5- (pyridin-3- ylethynyl)phenyl)pyrazin-2- yl)nicotinamide

4-methyl-N-(5-(2-methyl-5-(2- methyl-2H-tetrazol-5- yl)phenyl)pyrazin-2- yl)nicotinamide

N-(5-(2-chloro-5-(pyridin-2- yloxy)phenyl)pyrazin-2-yl)-4- methylnicotinamide

4-methyl-N-(5-(6- methylbenzo[d][1,3]dioxol-5- yl)pyrazin-2-yl)nicotinamide

4-methyl-N-(5-(5-(pyridin-2- yloxy)-2- (trifluoromethoxy)phenyl)pyrazin- 2-yl)nicotinamide

4-methyl-N-(5-(2-methyl-5-(1- methyl- 1 H-pyrazol-4- yl)phenyl)pyrazin-2- yl)nicotinamide

N-(5-(2-chloro-5-(1-methyl- 1 H- pyrazol-4-yl)phenyl)pyrazin-2-yl)- 4-methylnicotinamide

N-(5-(2-chloro-5-(pyridin-2- yloxy)phenyl)pyrazin-2-yl)-5- fluoro-4-methylnicotinamide

N-(5-(2-ethyl-5-(2-methyl-2H- tetrazol-5-yl)phenyl)pyrazin-2-yl)- 4-methylnicotinamide

N-(5-(2-chloro-5-(2-methyl-2H- tetrazol-5-yl)phenyl)pyrazin-2-yl)- 4-methylnicotinamide

N-(5-(2,5-dimethoxy- 1 H- benzo[d]imidazol-1-yl)pyrazin-2- yl)-4-methylnicotinamide

N-(5-(2-chloro-5- cyclopropoxyphenyl)pyrazin-2- yl)-4-methylnicotinamide

N-(5-(5-methoxy-2- (trifluoromethyl)- 1 H- benzo[d]imidazol-1-yl)pyrazin-2- yl)-4-methylnicotinamide

N-(5-(5-cyclopropoxy-2- methylphenyl)pyrazin-2-yl)-4- methylnicotinamide

4-methyl-3-(5-(4- methylnicotinamido)pyrazin-2- yl)phenyl dimethylsulfamate

4-methyl-3-(5-(4- methylnicotinamido)pyrazin-2- yl)phenyl methanesulfonate

N-(5-(5-cyclopropoxy-2- methylphenyl)pyrazin-2-yl)-5- fluoro-4-methylnicotinamide

N-(5-(2-chloro-5-(1,5-dimethyl- 1 H-pyrazol-4-yl)phenyl)pyrazin-2- yl)-4-methylnicotinamide

5-bromo-N-(5-(2-chloro-5- cyclopropoxyphenyl)pyrazin-2- yl)-4-methylnicotinamide

N-(5-(2-chloro-5-((3- fluoropyridin-2- yl)oxy)phenyl)pyrazin-2-yl)-4- methylnicotinamide

N-(5-(2-cyclopropoxy-5-(1- methyl- 1 H-pyrazol-4- yl)phenyl)pyrazin-2-yl)-4- methylnicotinamide

N-(5-(2-chloro-5- cyclopropoxyphenyl)pyrazin-2- yl)-4-methylnicotinamide hydrochloride

4-chloro-3-(5-(4- methylnicotinamido)pyrazin-2- yl)phenyl methanesulfonate

4-methyl-N-(5-(2-methyl-5-(1- methyl- 1 H-pyrazol-3- yl)phenyl)pyrazin-2- yl)nicotinamide

N-(5-(2-methoxy-5-(1-methyl- 1 H- pyrazol-4-yl)phenyl)pyrazin-2-yl)- 4-methylnicotinamide

5-chloro-N-(5-(2-chloro-5-(1- methyl- 1 H-pyrazol-4- yl)phenyl)pyrazin-2-yl)-4- methylnicotinamide

5-bromo-N-(5-(2-chloro-5-(1- methyl- 1 H-pyrazol-4- yl)phenyl)pyrazin-2-yl)-4- methylnicotinamide

N-(5-(2-chloro-5-(1-methyl- 1 H- pyrazol-4-yl)phenyl)pyrazin-2-yl)- 5-fluoro-4-methylnicotinamide

4-methyl-N-(5-(2-methyl-5-(2- methylthiazol-4- yl)phenyl)pyrazin-2- yl)nicotinamide

N-(5-(2-chloro-5-(1-methyl- 1 H- pyrazol-4-yl)phenyl)pyrazin-2-yl)- 4,5-dimethylnicotinamide

N-(5-(2-chloro-5-(1-methyl- 1 H- pyrazol-4-yl)phenyl)pyrazin-2-yl)- 5-ethyl-4-methylnicotinamide

N-(5-(2-chloro-5-(1-methyl- 1 H- pyrazol-4-yl)phenyl)pyrazin-2-yl)- 5-cyano-4-methylnicotinamide

N-(5-(2-ethyl-5-((5- methylisoxazol-3- yl)oxy)phenyl)pyrazin-2-yl)-4- methylnicotinamide

N-(5-(2-chloro-5-(1-methyl- 1 H- pyrazol-4-yl)phenyl)pyrazin-2-yl)- 4-methylnicotinamide hydrochloride

5-fluoro-N-(5-(5-((3- fluoropyridin-2-yl)oxy)-2- methylphenyl)pyrazin-2-yl)-4- methylnicotinamide

N-(5-(2-chloro-5- isopropoxyphenyl)pyrazin-2-yl)-4- methylnicotinamide

N-(5-(2-chloro-5- cyclopropoxyphenyl)pyrazin-2- yl)-4-methylnicotinamide hydrochloride

N-(5-(2-chloro-5-(oxetan-3- yloxy)phenyl)pyrazin-2-yl)-5- fluoro-4-methylnicotinamide

N-(5-(2-chloro-5- cyclobutoxyphenyl)pyrazin-2- yl)-5-fluoro-4- methylnicotinamide

5-chloro-N-(5-(5-cyclopropoxy- 2-methylphenyl)pyrazin-2-yl)- 4-methylnicotinamide

N-(5-(2-chloro-5- (cyclohexyloxy)phenyl)pyrazin- 2-yl)-5-fluoro-4- methylnicotinamide

N-(5-(2-cyano-5- cyclopropoxyphenyl)pyrazin-2- yl)-5-fluoro-4- methylnicotinamide

N-(5-(2-chloro-5- (cyclopropylmethoxy)phenyl) pyrazin-2-yl)-4- methylnicotinamide

N-(5-(2-cyano-5- cyclopropoxyphenyl)pyrazin-2- yl)-4-methylnicotinamide

N-(5-(2-chloro-5- (cyclopentyloxy)phenyl)pyrazin- 2-yl)-4-methylnicotinamide

N-(5-(2-chloro-5- cyclopropoxyphenyl)pyrazin-2- yl)-5-fluoro-4- methylnicotinamide

N-(5-(5-cyclopropoxy-2- ethylphenyl)pyrazin-2-yl)-5- fluoro-4-methylnicotinamide

N-(5-(5-cyclopropoxy-2- ethylphenyl)pyrazin-2-yl)-4- methylnicotinatnide

N-(5-(2-chloro-5- isopropoxyphenyl)pyrazin-2- yl)-4-methylnicotinamide

5-fluoro-4-methyl-N-(5-(2- methyl-5-((5-methylthiazol-2- yl)oxy)phenyl)pyrazin-2- yl)nicotinamide

4-methyl-N-(5-(2-methyl-5-((3- methyl-1,2,4-thiadiazol-5- yl)oxy)phenyl)pyrazin-2- yl)nicotinamide

5-fluoro-4-methyl-N-(5-(2- methyl-5-((3-methyl-1,2,4- thiadiazol-5- yl)oxy)phenyl)pyrazin-2- yl)nicotinamide

N-(5-(2-chloro-5- (trifluoromethoxy)phenyl)pyrazin- 2-yl)-4-methylnicotinamide

N-(5-(2-ethyl-5- (trifluoromethoxy)phenyl)pyrazin- 2-yl)-4-methylnicotinamide

5-fluoro-4-methyl-N-(5-(2- methyl-5-(pyrimidin-2- yloxy)phenyl)pyrazin-2- yl)nicotinamide

N-(5-(2-chloro-5-(pyrimidin-2- yloxy)phenyl)pyrazin-2-yl)-5- fluoro-4-methylnicotinamide

or a pharmaceutically acceptable salt, or solvate thereof.

9. The method of claim 1 wherein the compound is

or a pharmaceutically acceptable salt, or solvate thereof.

10. The method of claim 1 wherein the compound is

or a pharmaceutically acceptable salt, or solvate thereof.

11. A method for relieving, altering, or affecting rheumatoid arthritis or the symptom of rheumatoid arthritis in a subject in need thereof, comprising administering to the subject an effective amount of a compound of formula:

or a pharmaceutically acceptable salt, or solvate thereof,

wherein,

c 1 and c 4 are both N and c 5 is CH;

X C2 is H:

D 1 is —NH—C(O)—, and

X E1 and X E2 are, independently, H, halo, cyano, nitro, optionally substituted C 1-6 alkyl, or optionally substituted amino.

12. A method for relieving, altering, or affecting ulcerative colitis or the symptom of ulcerative colitis in a subject in need thereof, comprising administering to the subject an effective amount of a compound of formula:

or a pharmaceutically acceptable salt, or solvate thereof,

wherein,

c 1 and c 4 are both N and c 5 is CH;

X C2 is H:

D 1 is —NH—C(O)—, and

X E1 and X E2 are, independently, H, halo, cyano, nitro, optionally substituted C 1-6 alkyl, or optionally substituted amino.

13. A method for relieving, altering, or affecting Crohn's disease or the symptoms of Crohn's disease disease in a subject in need thereof, comprising administering to the subject an effective amount of a compound of formula:

or a pharmaceutically acceptable salt, or solvate thereof,

wherein,

c1 and c4 are both N and c5 is CH;

X C2 is H;

D 1 is —NH—C(O)—, and

X E1 and X E2 are, independently, H, halo, cyano, nitro, optionally substituted C 1-6 alkyl, or optionally substituted amino.

14. A method of modulating a CRAC ion channel activity in a subject, wherein said method comprises administering to a subject in need thereof an effective amount of a compound of formula:

or a pharmaceutically acceptable salt, or solvate thereof,

wherein,

c 1 and c 4 are both N and c 5 is CH;

X C2 is H;

D 1 is —NH—C(O)—, and

X E1 and X E2 are, independently, H, halo, cyano, nitro, optionally substituted C 1-6 alkyl, or optionally substituted amino.

15. A method of inhibiting cytokine production in a subject in need thereof, wherein said method comprises administering an effective amount of a compound of formula:

or a pharmaceutically acceptable salt, or solvate thereof,

wherein,

X C2 is H; c 1 and c 4 are both N and c 5 is CH;

D 1 is —NH—C(O)—, and

X E1 and X E2 are, independently, H, halo, cyano, nitro, optionally substituted C 1-6 alkyl, or optionally substituted amino.

16. A method for treating atopic dermatitis, wherein said method comprises administering an effective amount of a compound of formula:

or a pharmaceutically acceptable salt, or solvate thereof,

wherein,

X C2 is H; c 1 and c 4 are both N and c 5 is CH;

D 1 is —NH—C(O)—, and

X E1 and X E2 are, independently, H, halo, cyano, nitro, optionally substituted C 1-6 alkyl, or optionally substituted amino.

17. The method of claim 11 or a pharmaceutically acceptable salt or solvate thereof, wherein,

and

X E1 is H, fluoro or chloro, and X E2 is H.

18. The method of claim 17 or a pharmaceutically acceptable salt or solvate thereof, wherein, B is substituted with one or more substituents selected from the group consisting of halo, OH, cyano, carboxyl, optionally substituted C 1-6 alkyl, optionally substituted C 1-6 haloalkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 3-8 cycloalkyl, optionally substituted C 1-6 alkoxy, optionally substituted C 1-6 haloalkoxy, optionally substituted C 3-8 cycloalkoxy, optionally substituted C 6-10 aryl, optionally substituted C 7-16 aralkyloxy, optionally substituted C 2-9 heterocyclyl, optionally substituted C 2-9 (heterocyclyl)oxy, optionally substituted C 3-12 heterocyclylalkyl, optionally substituted C 2-9 (heterocyclyl)alkynyl, optionally substituted C 1-6 alkylsulfonyl, optionally substituted C 1-6 alkylsulfonyloxy, optionally substituted C 1-6 alkylsulfamoyloxy, optionally substituted C 1-6 alkylcarbonyl, optionally substituted C 1-6 alkoxycarbonyl, and optionally substituted amino.

19. The method of claim 18 or a pharmaceutically acceptable salt or solvate thereof, wherein, B is phenyl optionally substituted by one or more halo, cyano, C 1-6 alkyl, C 1-6 alkoxy, C 3-8 cycloalkoxy, C 1-6 haloalkoxy, or C 2-9 heterocyclyl.

20. The method of claim 11 or a pharmaceutically acceptable salt or solvate thereof, wherein, B is

and each R B is, independently H, halo, cyano, C 1-6 alkyl, C 1-6 alkoxy, C 3-8 cycloalkoxy, C 1-6 haloalkoxy, or C 2-9 heterocyclyl.

21. The method of claim 11 or a pharmaceutically acceptable salt or solvate thereof, wherein B is

and each R B is, independently halo, cyano, C 1-6 alkyl, C 1-6 alkoxy, C 3-8 cycloalkoxy, C 1-6 haloalkoxy, C 2-9 heterocyclyl.

22. The method of claim 21 or a pharmaceutically acceptable salt or solvate thereof, wherein one of R B is chloro, cyano, methyl, ethyl, cyclopropyloxy, methoxy or ethoxy, and the other R B is 1-methyl-1H-pyrazol-4yl, 1H-pyrazol-4yl, 2-methyloxazol-4yl, isoxazol-3yl, 5methyl-isoxazol-3yl, 2-methylthiazol-4yl, 5-methylthiazol-4yl, 2-methyl-2H-tetrazol-5yl, cyclopropyloxy or methoxy.

23. The method of claim 11 , wherein the compound is selected from the group consisting of:

Structure

Compound Name

N-(5-(2-chloro-5-( 1 H-pyrazol-4- yl)phenyl)pyrazin-2-yl)-4- methylnicotinamide

N-(5-(2-ethoxy-5-(1-methyl- 1 H- pyrazol-4-yl)phenyl)pyrazine-2-yl)- 4-methylnicotinamide