IP Library › Granted Patent US 9,598,422

Granted Patent B2

US 9,598,422 · App. 14/933,879 · Granted Mar 21, 2017

Immunoregulatory agents

Inventors: Hilary Plake Beck (Emerald Hills, CA); Juan Carlos Jaen (Burlingame, CA); Maksim Osipov (Belmont, CA); Jay Patrick Powers (Pacifica, CA); Maureen Kay Reilly (Belmont, CA); Hunter Paul Shunatona (San Francisco, CA); James Ross Walker (Menlo Park, CA); Mikhail Zibinsky (Lodi, CA); James Aaron Balog (Lambertville, NJ); David K. Williams (Delran, NJ); Jay A. Markwalder (Lahaska, PA); Steven P. Seitz (Swarthmore, PA); Emily Charlotte Cherney (Newtown, PA); Liping Zhang (East Windsor, NJ); Weifang Shan (Princeton, NJ); Weiwei Guo (Lawrenceville, NJ); Audris Huang (New Hope, PA)

Assignee: Flexus Biosciences, Inc.

C07D487/04 A61K31/00 A61K31/136 A61K31/166 A61K31/277 A61K31/445 A61K31/4412 A61K31/47 A61K31/4709 A61K31/496 A61K31/519 A61K31/5377 A61K45/06 C07C211/45 C07C233/65 C07C255/50 C07D211/08 C07D213/68 C07D215/04 C07D215/233 C07C2101/14

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Quick Facts

Patent No.: US 9,598,422
App. No.: 14/933,879
Granted: Mar 21, 2017
Kind: B2

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USPTO Patent Center↗ Full Patent PDF↗

Abstract

Compounds that modulate the oxidoreductase enzyme indoleamine 2,3-dioxygenase, and compositions containing the compounds, are described herein. The use of such compounds and compositions for the treatment and/or prevention of a diverse array of diseases, disorders and conditions, including cancer- and immune-related disorders, that are mediated by indoleamine 2,3-dioxygenase is also provided.

Claims (167)

1. A compound of the formula (I):

or a pharmaceutically acceptable salt, hydrate or solvate thereof, wherein,

the subscript n is 1;

A is —C(O)—;

B is —NH—;

T is —CR 3 R 4 —;

D is C(R 5 );

E is C(R 6 );

V is a bond;

G is an optionally substituted quinolinyl;

J 1 is CH or C(R 2 ), when R 2 is attached to the ring vertex identified as J 1 ;

R 1 and R 2 are independently hydrogen, halogen, optionally substituted C 1 -C 4 haloalkyl, optionally substituted C 3 -C 6 cycloalkyl, optionally substituted 3- to 6-membered cycloheteroalkyl, optionally substituted phenyl, optionally substituted heteroaryl, optionally substituted C 1 -C 4 alkyl, optionally substituted C 1 -C 4 alkoxy, CN, SO 2 NH 2 , NHSO 2 CH 3 , NHSO 2 CF 3 , OCF 3 , SO 2 CH 3 , SO 2 CF 3 , or CONH 2 , and when R 1 and R 2 are on adjacent vertices of a phenyl ring they may be joined together to form a 5- or 6-membered cycloheteroalkyl ring having one or two ring vertices independently selected from O, N and S, wherein said cycloheteroalkyl ring is optionally substituted with from one to three members selected from fluoro and C 1 -C 3 alkyl;

R 3 and R 4 are independently hydrogen, optionally substituted C 1 -C 6 alkyl, optionally substituted C 1 -C 6 haloalkyl, fluorine, OH, CN, CO 2 H, C(O)NH 2 , N(R 5a ) 2 , optionally substituted —O—C 1 -C 6 alkyl, —(CR 5 R 5 ) m —OH, —(CR 5 R 5 ) m —CO 2 H, —(CR 5 R 5 ) m —C(O)NH 2 , —(CR 5 R 5 ) m —C(O)NHR 5a , —(CR 5 R 5 ) m N(R 5a ) 2 , —NH(CR 5 R 5 ) m CO 2 H or —NH(CR 5 R 5 ) m —C(O)NH 2 ;

each R 5 is independently H, F, OH, optionally substituted C 1 -C 6 alkyl or optionally substituted —O—C 1 -C 6 alkyl;

each R 5a is independently H, or optionally substituted C 1 -C 6 alkyl;

R 6 is H, OH, F, optionally substituted C 1 -C 6 alkyl, optionally substituted —O—C 1 -C 6 alkyl, or —N(R 5a ) 2 ;

and each m is independently 1, 2, or 3.

2. The compound of claim 1 , of the formula:

3. The compound of claim 1 , of the formula:

4. The compound of claim 1 , of the formula:

5. The compound of claim 1 , of the formula:

6. The compound of claim 1 that is:

4-Chloro-N—((R)-1-((1s,4S)-4-(6-fluoroquinolin-4-yl)cyclohexyl)ethyl)benzamide;

N—((R)-1-((1s,4S)-4-(6-fluoroquinolin-4-yl)cyclohexyl)ethyl)benzamide;

N—((R)-1-((1s,4S)-4-(6-fluoroquinolin-4-yl)cyclohexyl)ethyl)-2-methylbenzamide;

N—((R)-1-((1s,4S)-4-(6-fluoroquinolin-4-yl)cyclohexyl)ethyl)-3-methylbenzamide;

N—((R)-1-((1s,4S)-4-(6-fluoroquinolin-4-yl)cyclohexyl)ethyl)-4-methylbenzamide;

N—((R)-1-((1s,4S)-4-(6-fluoroquinolin-4-yl)cyclohexyl)ethyl)-2-methoxybenzamide;

N—((R)-1-((1s,4S)-4-(6-fluoroquinolin-4-yl)cyclohexyl)ethyl)-3-methoxybenzamide;

2-fluoro-N—((R)-1-((1s,4S)-4-(6-fluoroquinolin-4-yl)cyclohexyl)ethyl)benzamide;

3-fluoro-N—((R)-1-((1s,4S)-4-(6-fluoroquinolin-4-yl)cyclohexyl)ethyl)benzamide;

2-chloro-N—((R)-1-((1s,4S)-4-(6-fluoroquinolin-4-yl)cyclohexyl)ethyl)benzamide;

3-chloro-N—((R)-1-((1s,4S)-4-(6-fluoroquinolin-4-yl)cyclohexyl)ethyl)benzamide;

3,4-dichloro-N—((R)-1-((1s,4S)-4-(6-fluoroquinolin-4-yl)cyclohexyl)ethyl)benzamide;

4-fluoro-N—((R)-1-((1s,4S)-4-(6-fluoroquinolin-4-yl)cyclohexyl)ethyl)benzamide;

N—((R)-1-((1s,4S)-4-(6-fluoroquinolin-4-yl)cyclohexyl)ethyl)-[1,1′-biphenyl]-3-carboxamide;

3,5-dichloro-N—((R)-1-((1s,4S)-4-(6-fluoroquinolin-4-yl)cyclohexyl)ethyl)benzamide;

N—((R)-1-((1s,4S)-4-(6-fluoroquinolin-4-yl)cyclohexyl)ethyl)-4-methoxybenzamide;

N—((R)-1-((1s,4S)-4-(6-fluoroquinolin-4-yl)cyclohexyl)ethyl)-[1,1′-biphenyl]-2-carboxamide;

N—((R)-1-((1s,4S)-4-(6-fluoroquinolin-4-yl)cyclohexyl)ethyl)-[1,1′-biphenyl]-4-carboxamide;

4-Chloro-N—((R)-1-(cis-4-(6-fluoroquinolin-4-yl)cyclohexyl)propyl)benzamide;

4-Chloro-N—((S)-1-(cis-4-(6-fluoroquinolin-4-yl)cyclohexyl)propyl)benzamide;

4-Chloro-N—((R)-1-(trans-4-(6-fluoroquinolin-4-yl)cyclohexyl)propyl)benzamide;

4-Chloro-N—((S)-1-(trans-4-(6-fluoroquinolin-4-yl)cyclohexyl)propyl)benzamide;

4-Cyano-N—((R)-1-(cis-4-(6-fluoroquinolin-4-yl)cyclohexyl)propyl)benzamide;

4-Cyano-N—((S)-1-(cis-4-(6-fluoroquinolin-4-yl)cyclohexyl)propyl)benzamide;

4-Cyano-N—((R)-1-(trans-4-(6-fluoroquinolin-4-yl)cyclohexyl)propyl)benzamide;

4-Cyano-N—((S)-1-(trans-4-(6-fluoroquinolin-4-yl)cyclohexyl)propyl)benzamide;

4-cyano-N—((R)-1-(cis-4-(6-fluoroquinolin-4-yl)cyclohexyl)ethyl)benzamide;

5-(3-fluoro-4-methoxyphenyl)-N—((R)-1-(cis-4-(6-fluoroquinolin-4-yl)cyclohexyl)ethyl)picolinamide;

(R)-1-(cis-4-(6-fluoroquinolin-4-yl)cyclohexyl)-N-methylethanamine;

N—((R)-1-(cis-4-(6-fluoroquinolin-4-yl)cyclohexyl)ethyl)-4-(1H-pyrrol-1-yl)benzamide;

N—((R)-1-(cis-4-(6-fluoroquinolin-4-yl)cyclohexyl)ethyl)-4-(1H-imidazol-1-yl)benzamide;

4-chloro-N—((R)-1-((1s,4S)-4-(6-fluoroquinolin-4-yl)cyclohexyl)but-3-en-1-yl)benzamide;

N—((R)-1-((1s,4S)-4-(6-fluoroquinolin-4-yl)cyclohexyl)but-3-en-1-yl)-[1,1′-biphenyl]-4-carboxamide

N-1-((1 S,4S)-4-(quinolin-3-yl)cyclohexyl)propyl)-[1,1′-biphenyl]-4-carboxamide;

N-(1-((1R,4R)-4-(quinolin-3-yl)cyclohexyl)propyl)-[1,1′-biphenyl]-4-carboxamide;

N—((R)-1-((1s,4S)-4-(quinolin-3-yl)cyclohexyl)propyl)-[1,1′-biphenyl]-4-carboxamide;

N—((S)-1-((1s,4R)-4-(quinolin-3-yl)cyclohexyl)propyl)-[1,1′-biphenyl]-4-carboxamide;

N—((R)-1-((1r,4R)-4-(quinolin-3-yl)cyclohexyl)propyl)-[1,1′-biphenyl]-4-carboxamide;

N—((S)-1-((1r,4S)-4-(quinolin-3-yl)cyclohexyl)propyl)-[1,1′-biphenyl]-4-carboxamide;

4-chloro-N—((R)-1-(cis-4-(quinolin-3-yl)cyclohexyl)propyl)benzamide;

4-chloro-N—((S)-1-(cis-4-(quinolin-3-yl)cyclohexyl)propyl)benzamide;

4-chloro-N—((R)-1-(trans-4-(quinolin-3-yl)cyclohexyl)propyl)benzamide;

4-chloro-N—((S)-1-(trans-4-(quinolin-3-yl)cyclohexyl)propyl)benzamide;

N-(1-((1s,4s)-4-(6-(trifluoromethyl)quinolin-4-yl)cyclohexyl)propyl)biphenyl-4-carboxamide;

N—((R)-1-((1s,4S)-4-(6-fluoroquinolin-4-yl)cyclohexyl)ethyl)-4-(5-methyl-1,3,4-oxadiazol-2-yl)benzamide;

N—((R)-1-((1s,4S)-4-(6-fluoroquinolin-4-yl)cyclohexyl)ethyl)-4-(pyrazin-2-yl)benzamide;

N—((R)-1-((1s,4S)-4-(6-fluoroquinolin-4-yl)cyclohexyl)ethyl)-4-(pyrimidin-5-yl)benzamide;

N—((R)-1-((1s,4S)-4-(6-fluoroquinolin-4-yl)cyclohexyl)ethyl)-4-(1-methyl-1H-imidazol-4-yl)benzamide;

N—((R)-1-((1s,4S)-4-(6-fluoroquinolin-4-yl)cyclohexyl)ethyl)-4-(2-methoxypyrimidin-4-yl)benzamide;

N—((R)-1-((1s,4S)-4-(6-fluoroquinolin-4-yl)cyclohexyl)ethyl)-4-(6-methylsulfonyl)pyridin-3-yl)benzamide;

N—((R)-1-((1s,4S)-4-(6-fluoroquinolin-4-yl)cyclohexyl)ethyl)-4-(2-methylthiazol-5-yl)benzamide;

N—((R)-1-((1s,4S)-4-(6-fluoroquinolin-4-yl)cyclohexyl)ethyl)-4-(5-methoxypyridin-2-yl)benzamide;

4-(2-cyanopyrimidin-5-yl)-N—((R)-1-((1s,4S)-4-(6-fluoroquinolin-4-yl)cyclohexyl)ethyl)benzamide;

N—((R)-1-((1s,4S)-4-(6-fluoroquinolin-4-yl)cyclohexyl)ethyl)-4-(2-methoxythiazol-4-yl)benzamide;

N—((R)-1-((1s,4S)-4-(6-fluoroquinolin-4-yl)cyclohexyl)ethyl)-4′-(2-hydroxypropan-2-yl)biphenyl-4-carboxamide;

N—((R)-1-((1s,4S)-4-(6-fluoroquinolin-4-yl)cyclohexyl)ethyl)-4-(thiazol-4-yl)benzamide;

N—((R)-1-((1s,4S)-4-(6-fluoroquinolin-4-yl)cyclohexyl)ethyl)-4-(1,3,4-oxadiazol-2-yl)benzamide;

N—((R)-1-((1s,4S)-4-(6-fluoroquinolin-4-yl)cyclohexyl)ethyl)-4-(6-methoxypyridin-3-yl)benzamide;

N—((R)-1-((1s,4S)-4-(6-fluoroquinolin-4-yl)cyclohexyl)ethyl)-4-morpholinobenzamide;

4-cyclopropyl-N—((R)-1((1s,4S)-4-(6-fluoroquinolin-4-yl)cyclohexyl)ethyl)benzamide;

N—((R)-1-((1s,4S)-4-(6-fluoroquinolin-4-yl)cyclohexyl)ethyl)-4-(1-methylcyclopropyl)benzamide;

N—((R)-1-((1s,4S)-4-(6-fluoroquinolin-4-yl)cyclohexyl)ethyl)-4-(trifluoromethyl)benzamide;

N—((R)-1-((1s,4S)-4-(6-fluoroquinolin-4-yl)cyclohexyl)ethyl)-4-(oxazol-5-yl)benzamide;

N—((R)-1-((1s,4S)-4-(6-fluoroquinolin-4-yl)cyclohexyl)ethyl)-4-(1-methyl-1H-1,2,4-triazol-5-yl)benzamide;

N—((R)-1-((1s,4S)-4-(6-fluoroquinolin-4-yl)cyclohexyl)ethyl)-4-(5-methylthiazol-2-yl)benzamide;

4-(5-cyanothiazol-2-yl)-N—((R)-1-((1s,4S)-4-(6-fluoroquinolin-4-yl)cyclohexyl)ethyl)benzamide;

4-chloro-N-(1-((1s,4s)-4-(6-(trifluoromethyl)quinolin-4-yl)cyclohexyl)propyl)benzamide;

4-(1H-pyrrol-1-yl)-N-(1-((1s,4S)-4-(6-(trifluoromethyl)quinolin-4-yl)cyclohexyl)propyl)benzamide;

N-(1-(4-(6-fluoroquinolin-4-yl)cyclohexyl)propyl)-4-(thiazol-2-yl)benzamide; or

N-(1-(4-(6-fluoroquinolin-4-yl)cyclohexyl)propyl)bi-phenyl-4-carboxamide;

or a pharmaceutically acceptable salt thereof.

7. A pharmaceutical composition comprising a compound of claim 1 , and a pharmaceutically acceptable excipient.

8. A combination comprising a compound of claim 1 and at least one additional therapeutic agent.

9. The combination of claim 8 , wherein the at least one additional therapeutic agent is a chemotherapeutic agent, an immune- and/or inflammation-modulating agent, an anti-hypercholesterolemia agent, or an anti-infective agent.

10. The combination of claim 8 , wherein the at least one additional therapeutic agent is an immune checkpoint inhibitor.

11. The combination of claim 10 , wherein said immune checkpoint inhibitor is selected from the group consisting of ipilimumab, nivolumab and pembrolizumab.

12. The compound of claim 1 , wherein G is unsubstituted.

13. The compound of claim 1 , wherein G is substituted.

14. The compound of claim 13 , wherein the G is substituted with halogen.

15. The compound of claim 1 , wherein R 5 is H or C 1 -C 6 alkyl.

16. The compound of claim 1 , wherein R 5 is H.

17. The compound of claim 1 , wherein R 6 is H, OH, F, C 1 -C 6 alkyl, —O—C 1 -C 6 alkyl, or —N(R 5a ) 2 .

18. The compound of claim 1 , wherein R 6 is H or C 1 -C 6 alkyl.

19. The compound of claim 1 , wherein R 6 is H.

20. The compound of claim 1 , wherein R 3 and R 4 are independently hydrogen or optionally substituted C 1 -C 6 alkyl.

21. The compound of claim 1 , wherein R 3 and R 4 are independently hydrogen or C 1 -C 6 alkyl.

22. The compound of claim 1 that is: