IP Library › Granted Patent US 9,643,972

Granted Patent B2

US 9,643,972 · App. 14/933,863 · Granted May 9, 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); Emily Charlotte Cherney (Newtown, PA); Weifang Shan (Princeton, NJ); Audris Huang (New Hope, PA)

Assignee: Flexus Biosciences, Inc.

C07D487/04 A61K31/416 A61K31/437 A61K31/4375 A61K31/47 A61K31/4709 A61K31/496 A61K31/506 A61K31/517 A61K31/519 A61K45/06 C07D215/06 C07D215/233 C07D217/04 C07D231/56 C07D239/74 C07D401/12 C07D401/14 C07D405/08 C07D417/08 C07D471/04

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Quick Facts

Patent No.: US 9,643,972
App. No.: 14/933,863
Granted: May 9, 2017
Kind: B2

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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 (376)

1. A compound having the formula (I):

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

the subscript n is 1; the subscript p is 1;

the ring designated as A is phenyl, 5- or 6-membered heteroaryl, or C 5-7 cycloalkyl;

Z is O;

B is N, C(OR 5a ), or C(R 3a );

each X is independently CHR 5 , C(O), or CH(OR 5a );

Q is N, C(CN), or CR 6 ;

D is a bond, O, C(R 5 ) 2 , or NR 5a ;

E is an optionally substituted 9- or 10-membered fused bicyclic heteroaryl;

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 , R 3a and R 4 are independently hydrogen, optionally substituted C 1 -C 6 alkyl, optionally substituted C 2 -C 6 alkenyl, optionally substituted C 2 -C 6 alkynyl, optionally substituted C 1 -C 6 haloalkyl, optionally substituted C 3 -C 6 cycloalkyl-C 1 -C 4 alkyl, optionally substituted aryl-C 1 -C 6 alkyl, fluorine, OH, CN, CO 2 H, C(O)NH 2 , N(R 5 ) 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 5 , —(CR 5 R 5 ) m N(R 5 ) 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, or optionally substituted 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 , or a pharmaceutically acceptable salt, hydrate or solvate thereof, wherein,

the subscript n is 1; the subscript p is 1;

the ring designated as A is phenyl, 5- or 6-membered heteroaryl, or C 5-7 cycloalkyl;

Z is O;

B is N, C(OR 5a ), or C(R 3a );

each X is independently CHR 5 , C(O), or CH(OR 5a );

Q is N, C(CN), or CR 6 ;

D is a bond, O, C(R 5 ) 2 , or NR 5a ;

E is an optionally substituted 9- or 10-membered fused bicyclic heteroaryl;

R 3 , R 3a 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 5 ) 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 5 , —(CR 5 R 5 ) m N(R 5 ) 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, or optionally substituted 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.

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

wherein Q is C(CN) or CR 6 .

4. The compound of claim 3 , having the formula:

5. The compound of claim 4 , having the formula:

6. The compound of claim 5 , having the formula:

wherein J 1 is CH, N or optionally C(R 2 ) when R 2 is attached to the ring vertex identified as J 1 .

7. The compound of claim 6 , having the formula:

8. The compound of claim 7 , having the formula:

9. The compound of claim 8 , having the formula:

10. The compound of claim 8 , having the formula:

11. The compound of claim 10 , having the formula:

12. The compound of claim 11 , having the formula:

13. The compound of claim 11 , having the formula:

14. The compound of claim 11 , having the formula:

15. The compound of claim 11 , having the formula:

16. The compound of claim 11 , having the formula:

17. The compound of claim 11 , having the formula:

18. The compound of claim 11 , having the formula:

19. The compound of claim 11 , having the formula:

20. The compound of claim 11 , having the formula:

21. The compound of claim 11 , having the formula:

22. The compound of claim 17 , having the formula:

which is substantially free of other isomers at the carbon atoms to which each of R 3a and R 6 are attached.

23. The compound of claim 17 , having the formula:

which is substantially free of other isomers at the carbon atoms to which each of R 3a and R 6 are attached.

24. The compound of claim 17 , having the formula:

wherein:

R 11 and R 12 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.

25. The compound of claim 24 , wherein R 6 is H, and R 11 and R 12 are each independently selected from the group consisting of halogen, CN and optionally substituted C 1 -C 4 alkyl.

26. The compound of claim 17 , having the formula:

wherein:

27. The compound of claim 17 , having the formula:

wherein:

28. The compound of claim 17 , having the formula:

29. The compound of claim 27 , having the formula:

which is substantially free of other isomers at the stereocenters of the cyclohexane ring.

30. The compound of claim 27 , having the formula:

31. The compound of claim 27 , having the formula:

32. The compound of claim 28 , having the formula:

which is substantially free of other isomers at each of the three stereocenters shown.

33. The compound of claim 28 , having the formula:

which is substantially free of other isomers at each of the three stereocenters shown.

34. The compound of claim 31 , wherein R 1 is Cl, F, optionally substituted phenyl, or CN.

35. The compound of claim 31 , having the formula:

wherein R 1 is Cl, F, optionally substituted phenyl, or CN; and R 2 is H or F; and which is substantially free of other isomers at each of the three stereocenters shown.

36. The compound of claim 34 , wherein R 1 is Cl.

37. The compound of claim 34 , wherein R 1 is Cl; and R 3 is CH 3 .

38. The compound of claim 34 , having the formula:

which is substantially free of other isomers at each of the two stereocenters shown.

39. The compound of claim 34 , having the formula:

which is substantially free of other isomers at each of the two stereocenters shown.

40. The compound of claim 34 , having the formula:

which is substantially free of other isomers at each of the three stereocenters shown.

41. The compound of claim 1 that is

N-(4-chlorophenyl)-2-(trans-4-(quinolin-4-yl)cyclohexyl)acetamide;

N-(4-chlorophenyl)-2-(cis-4-(quinolin-4-yl)cyclohexyl)acetamide;

N-(4-cyanophenyl)-2-(trans-4-(quinolin-4-yl)cyclohexyl)acetamide;

N-(4-cyanophenyl)-2-(cis-4-(quinolin-4-yl)cyclohexyl)acetamide;

N-(4-fluorophenyl)-2-(trans-4-(quinolin-4-yl)cyclohexyl)acetamide;

N-(4-fluorophenyl)-2-(cis-4-(quinolin-4-yl)cyclohexyl)acetamide;

N-(4-fluorophenyl)-2-(cis-4-(quinolin-3-yl)cyclohexyl)acetamide;

N-(4-fluorophenyl)-2-(trans-4-(quinolin-3-yl)cyclohexyl)acetamide;

N-(4-chlorophenyl)-2-(cis-4-(quinolin-3-yl)cyclohexyl)acetamide;

N-(4-chlorophenyl)-2-(trans-4-(quinolin-3-yl)cyclohexyl)acetamide;

N-(4-cyanophenyl)-2-(cis-4-(quinolin-3-yl)cyclohexyl)acetamide;

N-(4-cyanophenyl)-2-(trans-4-(quinolin-3-yl)cyclohexyl)acetamide;

2-(4-(cis-1H-indazol-4-yl)cyclohexyl)-N-(4-cyanophenyl)acetamide;

2-(4-(trans-1H-indazol-4-yl)cyclohexyl)-N-(4-cyanophenyl)acetamide;

2-(4-(1H-indazol-4-yl)cyclohexyl)-N-(4-chlorophenyl)acetamide;

N-(4-fluorophenyl)-2-(cis-4-(quinolin-4-yl)cyclohexyl)propanamide;

N-(4-chlorophenyl)-2-(trans-4-(quinolin-4-yl)cyclohexyl)propanamide;

N-(4-chlorophenyl)-2-(cis-4-(quinolin-4-yl)cyclohexyl)propanamide;

(R)—N-(4-chlorophenyl)-2-(cis-4-(6-fluoroquinolin-4-yl)cyclohexyl)propanamide;

(S)—N-(4-chlorophenyl)-2-(trans-4-(quinolin-3-yl)cyclohexyl)propanamide;

(R)—N-(4-cyanophenyl)-2-(cis-4-(7-fluoroquinolin-4-yl)cyclohexyl)butanamide;

(R)—N-(4-chlorophenyl)-2-(cis-4-(7-fluoroquinolin-4-yl)cyclohexyl)butanamide;

(R)—N-(4-chlorophenyl)-2-(cis-4-(quinolin-4-yl)cyclohexyl)propamide;

(R)—N-(4-cyanophenyl)-2-(cis-4-(quinolin-4-yl)cyclohexyl)propamide;

(R)—N-(4-chlorophenyl)-2-(cis-4-(quinolin-4-yl)cyclohexyl)butanamide;

(S)—N-(4-chlorophenyl)-2-(trans-4-(quinolin-4-yl)cyclohexyl)butanamide;

N-(4-chlorophenyl)-2-(cis-4-(quinolin-4-yloxy)cyclohexyl)propanamide;

N-(4-chlorophenyl)-2-(cis-1-hydroxy-4-(quinolin-4-yl)cyclohexyl)acetamide;

N-(4-fluorophenyl)-2-(cis-4-(isoquinolin-4-yloxy)cyclohexyl)acetamide;

N-(4-fluorophenyl)-2-(trans-4-(isoquinolin-4-yloxy)cyclohexyl)acetamide;

N-(4-cyanophenyl)-2-(cis-4-(quinolin-4-yloxy)cyclohexyl)acetamide;

N-(4-chlorophenyl)-2-(trans-1-hydroxy-4-(quinolin-4-yl)cyclohexyl)acetamide;

N-(4-fluorophenyl)-2-(trans-1-hydroxy-4-(quinolin-4-yl)cyclohexyl)acetamide;

(R)—N-(4-cyanophenyl)-2-(cis-4-(quinolin-4-yloxy)cyclohexyl)propanamide;

(S)—N-(4-fluorophenyl)-2-(cis-4-(quinolin-4-yloxy)cyclohexyl)propanamide;

N-(4-chlorophenyl)-2-(trans-4-(quinolin-4-yl)cyclohexyl)pent-4-enamide;

2-(4-(1H-pyrazolo[3,4-b]pyridin-4-yl)cyclohexyl)-N-(4-chlorophenyl) acetamide;

N-(4-fluorophenyl)-2-(cis-4-(quinazolin-4-yl)cyclohexyl)acetamide;

N-(4-fluorophenyl)-2-(4-(quinazolin-4-yl)cyclohexyl)acetamide;

N-(4-chlorophenyl)-2-(cis-4-(quinazolin-4-yl)cyclohexyl)acetamide;

N-(4-chlorophenyl)-2-(trans-4-(quinazolin-4-yl)cyclohexyl)acetamide;

N-(4-chlorophenyl)-2-(4-(1,5-naphthyridin-4-yl)cyclohexyl)acetamide;

N-(4-chlorophenyl)-2-(cis-4-(quinolin-3-yl)cyclohexyl)propanamide;

N-(4-fluorophenyl)-2-(trans-4-(quinolin-3-yl)cyclohexyl)propanamide;

N-(4-chlorophenyl)-2-((trans)-4-(isoquinolin-1-yl)cyclohexyl)acetamide;

N-(4-chlorophenyl)-2-((cis)-4-(isoquinolin-1-yl)cyclohexyl)acetamide;

N-(4-chlorophenyl)-2-((cis)-4-(isoquinolin-8-yl)cyclohexyl)acetamide;

N-(4-chlorophenyl)-2-((trans)-4-isoquinolin-8-yl)cyclohexyl)acetamide;

N-(4-chlorophenyl)-2-((trans)-4-(isoquinolin-5-yl)cyclohexyl)acetamide;

N-(4-fluorophenyl)-2-(cis-4-(quinolin-3-yl)cyclohexyl)propanamide;

N-(4-cyanophenyl)-2-((cis)-4-(quinolin-4-yl)cyclohexyl)pent-4-enamide;

(R)-2-((cis)-4-(6-fluoroquinolin-4-yl)cyclohexyl)-N-phenylpropanamide;

(R)—N-(4-fluoro-2-methylphenyl)-2-((cis)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propanamide;

(R)-2-((cis)-4-(6-fluoroquinolin-4-yl)cyclohexyl)-N-(4-(trifluoromethyl)phenyl)propanamide;

(R)—N-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-2-((cis)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propanmide;

(R)—N-(2-ethoxyphenyl)-2-((cis)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propanamide;

(R)—N-(3-(difluoromethyl)phenyl)-2-((cis)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propanamide;

(R)—N-(4-chloro-2-methylphenyl)-2-((cis)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propanamide;

(R)—N-(3-chlorophenyl)-2-((cis)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propanamide;

(R)—N-(3,4-dichlorophenyl)-2-((cis)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propanamide;

methyl 3-((R)-2-((cis)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propanamido)benzoate;

methyl 4-((R)-2-((cis)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propanamido)benzoate;

(R)-2-((cis)-4-(6-fluoroquinolin-4-yl)cyclohexyl)-N-methyl-N-phenylpropanamide;

(R)-2-((cis)-4-(6-fluoroquinolin-4-yl)cyclohexyl)-N-(3-(trifluoromethyl)phenyl)propanamide;

(R)-2-((cis)-4-(6-fluoroquinolin-4-yl)cyclohexyl)-N-(4-phenoxyphenyl)propanamide;

(R)-2-((cis)-4-(6-fluoroquinolin-4-yl)cyclohexyl)-N-(m-tolyl)propanamide;

(R)-2-((cis)-4-(6-fluoroquinolin-4-yl)cyclohexyl)-N-(3-phenoxyphenyl)propanamide;

(R)-2-((cis)-4-(6-fluoroquinolin-4-yl)cyclohexyl)-N-(2-phenoxyphenyl)propanamide;

(R)-2-((cis)-4-(6-fluoroquinolin-4-yl)cyclohexyl)-N-(pyridin-4-yl)propanamide;

(R)-2-((cis)-4-(6-fluoroquinolin-4-yl)cyclohexyl)-N-(thiazol-2-yl)propanamide;

(R)-2-((cis)-4-(6-fluoroquinolin-4-yl)cyclohexyl)-N-(pyridin-3-yl)propanamide;

(R)—N-(2-fluorophenyl)-2-((cis)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propanamide;

(R)—N-(4-ethoxyphenyl)-2-((cis)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propanamide;

(R)—N-(3-cyanophenyl)-2-((cis)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propanamide;

(R)—N-(3-chloro-4-methylphenyl)-2-((cis)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propanamide;

(R)—N-(3-fluorophenyl)-2-((cis)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propanamide;

(R)—N-(3-cyano-4-(trifluoromethyl)phenyl)-2-((cis)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propanamide;

N-(4-chlorophenyl)-2-((trans)-4-((7-(trifluoromethyl)quinolin-4-yl)oxy)cyclohexyl)butanamide;

N-(4-chlorophenyl)-2-((trans)-4-((2-(trifluoromethyl)quinolin-4-yl)oxy)cyclohexyl)butanamide;

N-(4-chlorophenyl)-2-((trans)-4-(quinolin-4-yloxy)cyclohexyl)butanamide;

N-(4-chlorophenyl)-2-((trans)-4-((8-(trifluoromethyl)quinolin-4-yl)oxy)cyclohexyl)butanamide;

2-(4-((R)-3-((4-Chlorophenyl)amino)-2-((cis)-4-(6-fluoroquinolin-4-yl)cyclohexyl)-3-oxopropyl)phenyl)-2-propanoic acid;

N-(4-chlorophenyl)-2-((cis)-4-((2-(trifluoromethyl)quinolin-4-yl)oxy)cyclohexyl)butanamide;

N-(4-chlorophenyl)-2-((cis)-4-((6-(trifluoromethyl)quinolin-4-yl)oxy)cyclohexyl)butanamide;

N-(4-chlorophenyl)-2-(4-((4-chloroquinolin-6-yl)oxy)piperidin-1-yl)acetamide;

N-(4-chlorophenyl)-2-(4-((4-chloroquinolin-6-yl)oxy)piperidin-1-yl)propanamide;

2-(4-((4-chloroquinolin-6-yl)oxy)piperidin-1-yl)-N-(p-tolyl)propanamide;

N-(4-chlorophenyl)-2-(4-((6-fluoroquinolin-4-yl)oxy)piperidin-1-yl)acetamide;

N-(4-chlorophenyl)-2-(4-((6-fluoroquinolin-4-yl)oxy)piperidin-1-yl)propanamide;

2-(4-((6-fluoroquinolin-4-yl)oxy)piperidin-1-yl)-N-(p-tolyl)butanamide;

N-(4-chlorophenyl)-2-(4-((6-fluoroquinolin-4-yl)oxy)piperidin-1-yl)butanamide;

N-(4-fluorophenyl)-2-(4-((6-fluoroquinolin-4-yl)oxy)piperidin-1-yl)propanamide;

N-(4-ethoxyphenyl)-2-(4-((6-fluoroquinolin-4-yl)oxy)piperidin-1-yl)propanamide;

2-(4-((6-fluoroquinolin-4-yl)oxy)piperidin-1-yl)-N-(p-tolyl)propanamide;

N-(4-chlorophenyl)-2-(4-((6-fluoroquinolin-4-yl)oxy)piperidin-1-yl)-3-methylbutanamide;

N-(4-chlorophenyl)-2-(1-(quinolin-4-ylmethyl)piperidin-4-yl)acetamide;

N-(4-fluorophenyl)-(1-(quinolin-4-ylmethyl)piperidin-4-yl)acetamide;

N-(4-fluorophenyl)-2-(1-(6-fluoroquinolin-4-yl)piperidin-4-yl)acetamide;

N-(4-chlorophenyl)-2-(1-(6-fluoroquinolin-4-yl)piperidin-4-yl)acetamide;

N-(4-bromophenyl)-2-(1(6-fluoroquinolin-4-yl)piperidin-4-yl)acetamide;

N-(2-fluoro-4-methylphenyl)-2-(1-(6-fluoroquinolin-4-yl)piperidin-4-yl)acetamide;

N-(4-chloro-2-methylphenyl)-2-(1-(6-fluoroquinolin-4-yl)piperidin-4-yl)acetamide;

N-(4-fluorophenyl)-2-(1-(6-fluoroquinolin-4-yl)-4-methylpiperidin-4-yl)acetamide;

N-(4-chlorophenyl)-2-(1-(6-fluoroquinolin-4-yl)-4-methylpiperidin-4-yl)acetamide;

2-(1-(6-fluoroquinolin-4-yl)-4-methylpiperidin-4-yl)-N-(2-methoxypyrimidin-5-yl)acetamide;

N-(4-ethoxyphenyl)-2-(1-(6-fluoroquinolin-4-yl)-4-methylpiperidin-4-yl)acetamide;

N-(4-chlorophenyl)-2-(4-(6-fluoroquinolin-4-yl)piperazin-1-yl)propanamide;

N-(4-fromophenyl)-2-(4-(6-fluoroquinolin-4-yl)piperazin-1-yl)propanamide;

2-(4-(6-fluoroquinolin-4-yl)piperazin-1-yl)-N-phenylpropanamide;

N-(4-chlorophenyl)-2-(4-(6-fluoroquinolin-4-yl)piperazin-1-yl)butanamide;

2-(4-(6-fluoroquinolin-4-yl)piperazin-1-yl)-N-phenylbutanamide;

N-(4-chlorophenyl)-2-(4-(6-fluoroquinolin-4-yl)piperazin-1-yl)-3-methoxypropanamide;

N-(4-fluorophenyl)-2-(4-(6-fluoroquinolin-4-yl)piperazin-1-yl)-3-methoxypropanamide;

2-(4-((R)-3-((4-cyanophenyl)amino)-2-((cis)-4-(6-fluoroquinolin-4-yl)cyclohexyl)-3-oxopropyl)phenyl)propanoic acid;

(R)—N-cyclohexyl-2-((cis)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propanamide;

N-cyclohexyl-2-((cis)-4-(6-fluoroquinolin-4-yl)cyclohexyl)acetamide;

N-(4-chlorophenyl)-2-(cis-trans-4-(pyrazolo[1,5-a]pyrimidin-7-yl)cyclohexyl)propanamide;

N-(4-chlorophenyl)-2-(trans-4-(pyrazolo[1,5-a]pyrimidin-7-yl)cyclohexyl)propanamide;

(S)—N-(4-chlorophenyl)-2-((cis)-4-(pyrazolo[1,5-a]pyrimidin-7-yl)cyclohexyl)propanamide;

(R)—N-(4-chlorophenyl)-2-((cis)-4-(pyrazolo[1,5-a]pyrimidin-7-yl)cyclohexyl)propanamide;

(R)—N-(4-chlorophenyl)-2-((trans)-4-(pyrazolo[1,5-a]pyrimidin-7-yl)cyclohexyl)propanamide;

2-(cis-4-(1,8-naphthyridin-4-yl)cyclohexyl)-N-(4-chlorophenyl)propanamide;

2-trans-4-(1,8-naphthyridin-4-yl)cyclohexyl)-N-(4-chlorophenyl)propanamide;

(S)-2-((cis)-4-(1,8-naphthyridin-4-yl)cyclohexyl)-N-(4-chlorophenyl)propanamide;

(R)-2-((cis)-4-(1,8-naphthyridin-4-yl)cyclohexyl)-N-(4-chlorophenyl)propanamide;

2-(trans-4-(1H-pyrazolo[4,3-b]pyridin-7-yl)cyclohexyl)-N-(4-chlorophenyl)propanamide;

(S)-2-((cis)-4-(1H-pyrazolo[4,3-b]pyridin-7-yl)cyclohexyl)-N-(4-chlorophenyl)propanamide;

(R)-2-((cis)-4-(1H-pyrazolo[4,3-b]pyridin-7-yl)cyclohexyl)-N-(4-chlorophenyl)propanamide;

(S)-2-((trans)-4-(1H-pyrazolo[4,3-b]pyridin-7-yl)cyclohexyl)-N-(4-chlorophenyl)propanamide;

(R)-2-((trans)-4-(1H-pyrazolo[4,3-b]pyridin-7-yl)cyclohexyl)-N-(4-chlorophenyl)propanamide;

N-(cis-4-chlorophenyl)-2-(4-(6-iodoquinolin-4-yl)cyclohexyl)propanamide;

N-(trans-4-chlorophenyl)-2-(4-(6-iodoquinolin-4-yl)cyclohexyl)propanamide;

(S)—N-(4-chlorophenyl)-2-((cis)-4-(6-iodoquinolin-4-yl)cyclohexyl)propanamide;

(R)—N-(4-chlorophenyl)-2-((cis)-4-(6-iodoquinolin-4-yl)cyclohexyl)propanamide;

(S)—N-(4-chlorophenyl)-2-((trans)-4-(6-iodoquinolin-4-yl)cyclohexyl)propanamide;

(R)—N-(4-chlorophenyl)-2-((trans)-4-(6-iodoquinolin-4-yl)cyclohexyl)propanamide;

2-((trans)-4-((1,8-naphthyridin-4-yl)oxy)cyclohexyl)-N-(4-chlorophenyl)propanamide;

N-(4-chlorophenyl)-2-(4-(6-fluoroquinolin-4-yl)cyclohexyl)butanamide;

(R)—N-(4-chlorophenyl)-4-hydroxy-2-((cis)-4-(quinolin-4-yl)cyclohexyl)butanamide;

N-(4-chlorophenyl)-2-((cis)-4-cyano-4-(quinolin-4-yl)cyclohexyl)acetamide;

N-(4-chlorophenyl)-2-((trans)-4-cyano-4-(quinolin-4-yl)cyclohexyl)acetamide;

(R)—N-(4-chlorophenyl)-5-hydroxy-2-((cis)-4-(quinolin-4-yl)cyclohexyl)pentanamide;

N-(4-chlorophenyl)-2-(1-methoxy-4-(quinolin-4-yl)cyclohexyl)acetamide;

N-(4-fluorophenyl)-2-(4-hydroxy-4-(quinolin-4-yl)cyclohexyl)acetamide;

N-(4-chlorophenyl)-2-(4-hydroxy-4-(quinolin-4-yl)cyclohexyl)acetamide;

(R)—N-(4-chlorophenyl)-2-((1S,4S)-4-(7-fluoroquinolin-4-yl)cyclohexyl)propanamide;

(R)—N-(4-fluorophenyl)-2-((1S,4S)-4-(7-fluoroquinolin-4-yl)cyclohexyl)propanamide;

(R)—N-(4-cyanophenyl)-2-((1S,4S)-4-(7-fluoroquinolin-4-yl)cyclohexyl)propanamide;

(R)—N-(4-fluorophenyl)-2-((1S,4S)-4-(7-fluoroquinolin-4-yl)cyclohexyl)butanamide;

(R)—N-(4-chlorophenyl)-2-((1R,4R)-4-(quinolin-4-yl)cyclohexyl)butanamide;

(R)—N-(4-fluorophenyl)-2-((1R,4R)-4-(quinolin-4-yl)cyclohexyl)butanamide;

(S)—N-(4-cyanophenyl)-2-((1R,4S)-4-(quinolin-4-yl)cyclohexyl)butanamide;

(R)—N-(4-chlorophenyl)-2-((1S,4R)-4-(quinolin-4-yl)cyclohexyl)pent-4-ynamide;

N-(4-chlorophenyl)-2-((1S,4S)-4-(quinolin-4-yl)cyclohexyl)pentanamide;

5-((4-chlorophenyl)amino)-5-oxo-4-((1S,4S)-4-(quinolin-4-yl)cyclohexyl)pentanoic acid;

N-(4-chlorophenyl)-2-((1S,4S)-4-(8-fluoroquinolin-4-yl)cyclohexyl)acetamide;

N-(4-fluorophenyl)-2-((1R,4R)-4-(8-fluoroquinolin-4-yl)cyclohexyl)acetamide;

(R)—N-(2-fluorophenyl)-2-((1S,4S)-4-(quinolin-4-yl)cyclohexyl)propanamide;

(R)-2-((1S,4S)-4-(quinolin-4-yl)cyclohexyl)-N-(4-(trifluoromethoxy)phenyl)propanamide;

(R)—N-(3-fluoro-4-(trifluoromethyl)phenyl)-2-((1S,4S)-4-(quinolin-4-yl)cyclohexyl)propanamide;

(R)—N-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-2-((1S,4S)-4-(quinolin-4-yl)cyclohexyl)propanamide;

(R)—N-(3-chloro-4-fluorophenyl)-2-((1S,4S)-4-(quinolin-4-yl)cyclohexyl)propanamide;

(R)—N-(4-chlorophenyl)-5-methyl-2-((1S,4S)-4-(quinolin-4-yl)cyclohexyl)hex-4-enamide;

(S)—N-(4-chlorophenyl)-2-((1S,4R)-4-(quinolin-4-yl)cyclohexyl)propanamide;

(R)—N-(4-chloro-2-fluorophenyl)-2-((1S,4S)-4-(quinolin-4-yl)cyclohexyl)propanamide;

N-(4-cyanophenyl)-2-((1R,4R)-4-(quinolin-4-yl)cyclohexyl)pent-4-enamide;

(R)—N-(4-fluorophenyl)-2-((1S,4S)-4-(quinolin-4-yl)cyclohexyl)propanamide;

(R)—N-(5-chloropyridin-2-yl)-2-((1S,4S)-4-(quinolin-4-yl)cyclohexyl)propanamide;

(R)-2-((1S,4S)-4-(quinolin-4-yl)cyclohexyl)-N-(4-(trifluoromethyl)phenyl)propanamide;

(R)—N-(4-chloro-3-fluorophenyl)-2-((1S,4S)-4-(quinolin-4-yl)cyclohexyl)propanamide;

(R)—N-(4-cyano-3-fluorophenyl)-2-((1S,4S)-4-(quinolin-4-yl)cyclohexyl)propanamide;

(R)—N-(4-fluorophenyl)-2-((1S,4S)-4-(quinolin-4-yl)cyclohexyl)pent-4-enamide;

(R)—N-(3,4-difluorophenyl)-2-((1S,4S)-4-(quinolin-4-yl)cyclohexyl)propanamide;

N-(4-chlorophenyl)-2-((1S,4S)-4-(6,8-difluoroquinolin-4-yl)cyclohexyl)acetamide;

2-((1S,4S)-4-(6,8-difluoroquinolin-4-yl)cyclohexyl)-N-(4-fluorophenyl)acetamide;

2-((1R,4R)-4-(6,8-difluoroquinolin-4-yl)cyclohexyl)-N-(4-fluorophenyl)acetamide;

N-(4-chlorophenyl)-2-((1R,4R)-4-(quinolin-4-yloxy)cyclohexyl)acetamide;

N-(4-chlorophenyl)-2-((1S,4S)-4-(quinolin-4-yloxy)cyclohexyl)acetamide;

N-(4-chlorophenyl)-2-(1-hydroxy-4-(quinolin-4-yl)cyclohexyl)acetamide;

N-(4-cyanophenyl)-2-((1R,4R)-4-(quinolin-4-yloxy)cyclohexyl)acetamide;

N-(4-chlorophenyl)-2-((1R,4R)-1-hydroxy-4-(quinolin-4-yl)cyclohexyl)acetamide;

N-(4-fluorophenyl)-2-((1R,4R)-1-hydroxy-4-(quinolin-4-yl)cyclohexyl)acetamide;

N-(4-chlorophenyl)-2-((1S,4S)-1-hydroxy-4-(quinolin-4-yl)cyclohexyl)acetamide;

(S)—N-(4-fluorophenyl)-2-((1R,4S)-1-hydroxy-4-(quinolin-4-yl)cyclohexyl)propanamide;

(S)—N-(4-cyanophenyl)-2-((1R,4S)-1-hydroxy-4-(quinolin-4-yl)cyclohexyl)propanamide;

N-(4-chlorophenyl)-2-((1S,4S)-4-(2-(trifluoromethyl)quinolin-4-yl)cyclohexyl)acetamide;

N-(4-chlorophenyl)-2-((1R,4R)-4-(2-(trifluoromethyl)quinolin-4-yl)cyclohexyl)acetamide;

N-(4-fluorophenyl)-2-((1R,4R)-4-(2-(trifluoromethyl)quinolin-4-yl)cyclohexyl)acetamide;

N-(4-fluorophenyl)-2-((1S,4S)-4-(2-(trifluoromethyl)quinolin-4-yl)cyclohexyl)acetamide;

N-(4-fluorophenyl)-2-((1S,4S)-4-(8-(trifluoromethyl)quinolin-4-yl)cyclohexyl)acetamide;

N-(4-chlorophenyl)-2-((1R,4R)-4-(8-(trifluoromethyl)quinolin-4-yl)cyclohexyl)acetamide;

N-(4-chlorophenyl)-2-((1S,4S)-4-(8-trifluoromethyl)quinolin-4-yl)cyclohexyl)acetamide;

(R)—N-(4-fluorophenyl)-2-((1S,4S)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propanamide;

(R)—N-(4-cyanophenyl)-2-((1S,4S)-4-(8-fluoroquinolin-4-yl)cyclohexyl)propanamide;

2-(4-((R)-3-((4-chlorophenyl)amino)-3-oxo-2-((1S,4S)-4-(quinolin-4-yl)cyclohexyl)propyl)phenyl)acetic acid;

(R)—N-(4-chlorophenyl)-2-((1S,4S)-4-(8-fluoroquinolin-4-yl)cyclohexyl)propanamide;

(R)—N-(4-chlorophenyl)-2-((1S,4S)-4-(quinolin-3-yl)cyclohexyl)propanamide;

(R)—N-(4-chlorophenyl)-2-((1R,4R)-4-(quinolin-3-yl)cyclohexyl)propanamide;

(S)—N-(4-chlorophenyl)-2-((1S,4R)-4-(quinolin-3-yl)cyclohexyl)propanamide;

(R)—N-(4-fluorophenyl)-2-((1S,4S)-4-(quinolin-4-yl)cyclohexyl)butanamide;

(S)—N-(4-fluorophenyl)-2-((1R,4S)-4-(quinolin-4-yl)cyclohexyl)butanamide;

N-(4-chlorophenyl)-2-((1R,4R)-4-(8-fluoroquinolin-4-yl)cyclohexyl)acetamide;

N-(4-fluorophenyl)-2-((1S,4S)-4-(8-fluoroquinolin-4-yl)cyclohexyl)acetamide;

(R)—N-(4-chlorophenyl)-2-((1S,4S)-4-(quinolin-4-yl)cyclohexyl)pent-4-enamide;

(R)—N-(4-chlorophenyl)-2-((1S,4S)-4-(8-(trifluoromethyl)quinolin-4-yl)cyclohexyl)propanamide;

(R)—N-(4-chlorophenyl)-2-((1S,4S)-4-(2-(trifluoromethyl)quinolin-4-yl)cyclohexyl)propanamide;

(R)—N-(4-chlorophenyl)-2-((1S,4S)-4-(quinolin-4-yloxy)cyclohexyl)propanamide;

(S)—N-(4-chlorophenyl)-2-((1S,4R)-4-(quinolin-4-yloxy)cyclohexyl)propanamide;

N-(4-chlorophenyl)-2-(trans-4-(6-fluoroquinolin-4-yl)-1-hydroxycyclohexyl)propanamide;

N-(4-chlorophenyl)-2-(cis-4-(6-fluoroquinolin-4-yl)-1-hydroxycyclohexyl)propanamide;

N-(4-chlorophenyl)-2-(trans-1-fluoro-4-(6-fluoroquinolin-4-yl)cyclohexyl)propanamide;

N-(4-chlorophenyl)-2-(trans-4-(6-fluoroquinolin-4-yl)-4-hydroxycyclohexyl)propanamide;

N-(4-chlorophenyl)-2-(cis-4-(6-fluoroquinolin-4-yl)-4-hydroxycyclohexyl)propanamide;

(R)—N-(4-chloro-2-hydroxyphenyl)-2-(cis-4-(6-fluoroquinolin-4-yl)cyclohexyl)propanamide;

(R)—N-(4-chloro-3-hydroxyphenyl)-2-(cis-4-(6-fluoroquinolin-4-yl)cyclohexyl)propanamide;

(R)—N-((2S)-bicyclo[2.2.1]heptan-2-yl)-2-(cis-4-(6-fluoroquinolin-4-yl)cyclohexyl)propanamide;

(R)—N-(2-amino-4-chlorophenyl)-2-(cis-4-(6-fluoroquinolin-4-yl)cyclohexyl)pent-4-enamide;

2-(1-(6-fluoroquinolin-4-yl)-4-methylpiperidin-4-yl)-N-(1-methylcyclohexyl)acetamide;

N-(4-chlorophenyl)-2-(1-(6-fluoroquinolin-4-yl)piperidin-4-yl)butanamide;

N-(4-chlorophenyl)-2-(4-(6-fluoroquinolin-4-yl)piperazin-1-yl)pentanamide;

2-(4-(6-fluoroquinolin-4-yl)piperazin-1-yl)-N-(1-methylcyclohexyl)pentanamide;

cis-N-(4-chlorophenyl)-2-(4-(3-methyl-3H-imidazo[4, 5-b]pyridin-7-yl)cyclohexyl)propanamide;

trans-N-(4-chlorophenyl)-2-(4-(3-methyl-3H-imidazo[4,5-b]pyridin-7-yl)cyclohexyl)propanamide; or

N-(4-chlorophenyl)-2-(4-(3-methyl-3H-imidazo[4,5-b]pyridin-7-yl)cyclohexyl)propanamide;

or a stereoisomer thereof or a pharmaceutically acceptable salt thereof.

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

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

44. The combination of claim 43 , 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.

45. The combination of claim 43 , wherein the at least one additional therapeutic agent is an immune checkpoint inhibitor.

46. The combination of claim 45 , wherein said immune checkpoint inhibitor is selected from the group consisting of ipilimumab, nivolumab and pembroluzimab.

47. The compound of claim 1 that is