Arylalkyl pyrazole compounds as indoleamine 2,3-dioxygenase inhibitors
Disclosed herein are compounds of formula (I) which are inhibitors of an IDO enzyme: Also disclosed herein are uses of the compounds in the potential treatment or prevention of an IDO-associated disease or disorder. Also disclosed herein are compositions comprising these compounds. Further disclosed herein are uses of the compositions in the potential treatment or prevention of an IDO-associated disease or disorder.
1. A compound of formula (I), or a pharmaceutically acceptable salt thereof:
wherein:
m is 0 or 1; n is 0 or 1;
U is selected from (1) N and (2) CR a , wherein Ra is selected from: (a) H and (b) —OH;
V is selected from (1) N and (2) CR b , wherein R b is selected from: (1) H and (2) C 1-6 alkyl;
W is selected from (1) —O—, (2) —NR c —, and (3) —CR d R d —;
wherein R c is selected from:
(a) H,
(b) —OH, and
(c) —C(O)—C 1-6 alkyl, optionally substituted with —OH;
each occurrence of R d is independently selected from:
(a) H,
(b) halogen,
(c) —OH,
(d) —NH 2 ,
(e) —NH—C(O)—C 1-6 alkyl, optionally substituted with —OH,
(f) —NH—C(O)—O—C 1-6 alkyl,
(g) C 1-6 alkyl, optionally substituted 1-3 substituents independently selected from —OH and halogen, and
(h) —O—C 1-6 alkyl, optionally substituted with —OH;
Y is selected from (1) —O— and (2) —CH 2 —;
R is selected from:
(1) H,
(2) aryl,
(3) —O-aryl,
(4) —C(O)-aryl,
(5) heteroaryl, and
(6) —O-heteroaryl,
wherein each of the aryl of (2), (3), and (4) and each of the heteroaryl of (5) and (6) is optionally substituted with 1-3 substituents independently selected from:
(a) —OH,
(b) halogen,
(c) —CN, and
(d) C 1-6 alkyl, optionally substituted with 1-3 halogens;
each occurrence of R 1 is independently selected from: (1) H, (2) halogen, and (3) C 1-6 alkyl, optionally substituted with —OH;
R 2 is selected from: (1) H, (2) halogen, (3) —OH, (4) —O—C 1-6 alkyl, and (5) C 1-6 alkyl, optionally substituted with —OH;
each occurrence of R 3 is independently selected from: (1) H, (2) halogen, (3) —OH, (4) C 1-6 alkyl, optionally substituted with —OH, and (5) —O-heteroaryl, optionally substituted with 1-3 halogens; and
each occurrence of R 4 is independently selected from: (1) H, (2) halogen, (3) C 1-6 alkyl, optionally substituted with 1-3 halogens, and (4) C 3-6 cycloalkyl;
or alternatively, the two R 4 groups together with the two carbon atoms to which they are attached form a 5-7 membered monocyclic or bicyclic carbocyclyl, optionally substituted with 1-3 substituents independently selected from (a) halogen and (b) C 1-6 alkyl, wherein the C 1-6 alkyl is optionally substituted with halogen.
2. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein U is selected from (1) N, (2) CH, and (3) C(OH).
3. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein V is selected from (1) N and (2) CH.
4. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein W is selected from:
(1) —O—,
(2) —N(C(O)—C 1-4 alkyl)-, optionally substituted with —OH—, and
(3) —CR d R d —, wherein each occurrence of R d is independently selected from:
(a) H,
(b) halogen,
(c) —OH,
(d) —NH 2 ,
(e) —NH—C(O)—CH 3 , optionally substituted with —OH,
(f) —NH—C(O)—O—C 1-4 alkyl,
(g) C 1-4 alkyl, optionally substituted with 1-3 substituents independently selected from —OH and halogen, and
(h) —O—C 1-4 alkyl, optionally substituted with —OH.
5. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein W is selected from:
(1) —O—,
(2) —N(C(O)—CH 2 —OH)—,
(3) —CR d R d —, wherein each occurrence of R d is independently selected from:
(a) H,
(b) halogen,
(c) —OH,
(d) —NH 2 ,
(e) —NH—C(O)—CH 3 , optionally substituted with —OH,
(f) —NH—C(O)—O—CH 3 ,
(g) C 1-4 alkyl, optionally substituted with 1-3 substituents independently selected from —OH and halogen, and
(h) —O—C 1-4 alkyl, optionally substituted with —OH.
6. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein:
R is selected from:
(1) H,
(2) phenyl,
(3) —O-phenyl,
(4) —C(O)-phenyl,
(5) a 5-6 membered monocyclic heteroaryl,
(6) a 9-12 membered bicyclic fused heteroaryl, and
(7) —O-heteroaryl, wherein the heteroaryl is a 5-6 membered monocyclic heteroaryl,
wherein each of the phenyl of (2), (3), and (4) and each of the heteroaryl of (5), (6), and (7) is optionally substituted with 1-3 substituents independently selected from:
(a) —OH,
(b) halogen,
(c) —CN, and
(d) C 1-4 alkyl, optionally substituted with 1-3 halogens.
7. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein:
R is selected from:
(1) H,
(2) phenyl,
(3) —O-phenyl,
(4) —C(O)-phenyl,
(5) a heteroaryl selected from quinolinyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridinyl, and pyrimidinyl, and
(6) —O-heteroaryl, wherein the heteroaryl is selected from pyrazinyl, pyrazolyl, pyridazinyl, pyridinyl, and pyrimidinyl,
wherein each of the phenyl of (2), (3), and (4) and each of the heteroaryl of (5) and (6) is optionally substituted with 1-3 substituents independently selected from:
(a) —OH,
(b) halogen,
(c) —CN, and
(d) C 1-4 alkyl, optionally substituted with 1-3 halogens.
8. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein each occurrence of R 1 is independently selected from: (1) H, (2) halogen, and (3) methyl.
9. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 2 is selected from: (1) H, (2) halogen, (3) —OH, and (4) —O—C 1-4 alkyl.
10. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein each occurrence of R 3 is independently selected from: (1) H and (2) —O-pyridinyl, optionally substituted with halogen.
11. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein:
each occurrence of R 4 is independently selected from: (1) H, (2) halogen, (3) C 1-4 alkyl, optionally substituted with 1-3 halogens, and (4) cyclopropyl;
or alternatively, the two R 4 groups together with the two carbon atoms to which they are attached form a 5-6 membered carbocyclyl selected from:
(1) monocyclic saturated or partially unsaturated carbocyclyl,
(2) bicyclic fused saturated or partially unsaturated carbocyclyl, and
(3) monocyclic aromatic carbocyclyl;
wherein each of the carbocyclyl of (1), (2), and (3) is optionally substituted with 1-3 substituents independently selected from (a) halogen and (b) C 1-6 alkyl, optionally substituted with halogen.
12. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, of formula (Ia):
wherein:
m is 0 or 1; p is 0 or 1;
U is selected from (1) N, (2) CH, and (3) C(OH);
V is selected from (1) N and (2) CH;
W is selected from:
(1) —O—,
(2) —N(C(O)—CH 2 —OH)—,
(3) —CR d R d —, wherein each occurrence of R d is independently selected from:
(a) H,
(b) halogen,
(c) —OH,
(d) —NH 2 ,
(e) —NH—C(O)—CH 3 , optionally substituted with —OH,
(f) —NH—C(O)—O—CH 3 ,
(g) C 1-4 alkyl, optionally substituted with 1-3 substituents independently selected from —OH and halogen, and
(h) —O—C 1-4 alkyl, optionally substituted with —OH;
Y is selected from (1) —O— and (2) —CH 2 —;
R is selected from:
(1) H,
(2) aryl,
(3) —O-aryl,
(4) —C(O)-aryl,
(5) heteroaryl, and
(6) —O-heteroaryl,
wherein each of the aryl of (2), (3) and (4) and each of the heteroaryl of (5) and (6) is optionally substituted with 1-3 substituents independently selected from:
(a) —OH,
(b) halogen,
(c) —CN, and
(d) C 1-6 alkyl, optionally substituted with 1-3 halogens;
each occurrence of R 1 is independently selected from: (1) H, (2) halogen, and (3) C 1-6 alkyl, optionally substituted with —OH;
R 2 is selected from: (1) H, (2) halogen, (3) —OH, (4) —O—C 1-6 alkyl, and (5) C 1-6 alkyl, optionally substituted with —OH;
each occurrence of R 3 is independently selected from: (1) H, (2) halogen, (3) —OH, (4) C 1-6 alkyl, optionally substituted with —OH, and (5) —O-heteroaryl, optionally substituted with 1-3 halogens; and
each occurrence of R 5 is independently selected from: (1) H, (2) halogen, and (3) C 1-4 alkyl, optionally substituted with 1-3 halogens;
or alternatively, two R 5 groups on two adjacent ring carbons together with the two ring carbons form a 3-4 membered new carbocyclic ring.
13. The compound of claim 12 , or a pharmaceutically acceptable salt thereof:
wherein:
R is selected from:
(1) phenyl,
(2) —O-phenyl,
(3) —C(O)-phenyl,
(4) a heteroaryl selected from quinolinyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridinyl, and pyrimidinyl, and
(5) —O-heteroaryl, wherein the heteroaryl is selected from pyrazinyl, pyrazolyl, pyridazinyl, pyridinyl, and pyrimidinyl,
wherein each of the phenyl of (1), (2), and (3) and each of the heteroaryl of (4) and (5) is optionally substituted with 1-3 substituents independently selected from:
(a) —OH,
(b) halogen,
(c) —CN, and
(d) C 1-4 alkyl, optionally substituted with 1-3 halogens;
each occurrence of R 1 is independently selected from: (1) H, (2) halogen, and (3) methyl;
R 2 is selected from: (1) H, (2) halogen, (3) —OH, and (4) —O—C 1-4 alkyl;
each occurrence of R 3 is H; and
each occurrence of R 5 is independently selected from: (1) H, (2) halogen, and (3) C 1-4 alkyl, optionally substituted with 1-3 halogens.
14. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, of formula (Ib):
wherein:
m is 0 or 1;
U is selected from (1) N, (2) CH, and (3) C(OH);
V is selected from (1) N and (2) CH;
W is selected from:
(1) —O—,
(2) —N(C(O)—CH 2 —OH)—,
(3) —CR d R d —, wherein each occurrence of R d is independently selected from:
(a) H,
(b) halogen,
(c) —OH,
(d) —NH 2 ,
(e) —NH—C(O)—CH 3 , optionally substituted with —OH,
(f) —NH—C(O)—O—CH 3 ,
(g) C 1-4 alkyl, optionally substituted with 1-3 substituents independently selected from —OH and halogen, and
(h) —O—C 1-4 alkyl, optionally substituted with —OH;
Y is selected from (1) —O— and (2) —CH 2 —;
R is selected from:
(1) H,
(2) aryl,
(3) —O-aryl,
(4) —C(O)-aryl,
(5) heteroaryl, and
(6) —O-heteroaryl,
wherein each of the aryl of (2), (3) and (4) and each of the heteroaryl of (5) and (6) is optionally substituted with 1-3 substituents independently selected from:
(a) —OH,
(b) halogen,
(c) —CN, and
(d) C 1-6 alkyl, optionally substituted with 1-3 halogens;
each occurrence of R 1 is independently selected from: (1) H, (2) halogen, and (3) C 1-6 alkyl, optionally substituted with —OH;
R 2 is selected from: (1) H, (2) halogen, (3) —OH, (4) —O—C 1-6 alkyl, and (5) C 1-6 alkyl, optionally substituted with —OH; and
each occurrence of R 3 is independently selected from: (1) H, (2) halogen, (3) —OH, (4) C 1-6 alkyl, optionally substituted with —OH, and (5) —O-heteroaryl, optionally substituted with 1-3 halogens.
15. The compound of claim 14 , or a pharmaceutically acceptable salt thereof:
wherein:
R is selected from:
(1) phenyl,
(2) —O-phenyl,
(3) —C(O)-phenyl,
(4) a heteroaryl selected from quinolinyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridinyl, and pyrimidinyl, and
(5) —O-heteroaryl, wherein the heteroaryl is selected from pyrazinyl, pyrazolyl, pyridazinyl, pyridinyl, and pyrimidinyl,
wherein each of the phenyl of (1), (2), and (3) and each of the heteroaryl of (4) and (5) is optionally substituted with 1-3 substituents independently selected from:
(a) —OH,
(b) halogen,
(c) —CN, and
(d) C 1-4 alkyl, optionally substituted with 1-3 halogens;
each occurrence of R 1 is independently selected from: (1) H, (2) halogen, and (3) methyl;
R 2 is selected from: (1) H, (2) halogen, (3) —OH, and (4) —O—C 1-4 alkyl; and
each occurrence of R 3 is H.
16. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, of formula (Ic):
wherein:
m is 0 or 1;
U is selected from (1) N, (2) CH, and (3) C(OH);
V is selected from (1) N and (2) CH;
R is selected from:
(1) aryl,
(2) —O-aryl,
(3) —C(O)-aryl,
(4) heteroaryl, and
(5) —O-heteroaryl,
wherein each of the aryl of (1), (2) and (3) and each of the heteroaryl of (4) and (5) is optionally substituted with 1-3 substituents independently selected from:
(a) —OH,
(b) halogen,
(c) —CN, and
(d) C 1-6 alkyl, optionally substituted with 1-3 halogens;
R 2 is selected from: (1) H, (2) halogen, (3) —OH, (4) —O—C 1-6 alkyl, and (5) C 1-6 alkyl, optionally substituted with —OH; and
each occurrence of R 3 is independently selected from: (1) H, (2) halogen, (3) —OH, and (4) C 1-6 alkyl, optionally substituted with —OH.
17. The compound of claim 16 , or a pharmaceutically acceptable salt thereof:
wherein:
m is 1;
R is phenyl, optionally substituted with 1-3 substituents independently selected from:
(a) —OH,
(b) halogen, and
(c) C 1-4 alkyl, optionally substituted with 1-3 halogens;
R 2 is H; and
each occurrence of R 3 is H.
18. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, of formula (Id):
wherein:
m is 0 or 1; p is 0 or 1;
W is —CR d R d —, wherein each occurrence of R d is independently selected from:
(a) H,
(b) —OH,
(c) —NH—C(O)—CH 3 , optionally substituted with —OH, and
(d) —O—C 1-4 alkyl, optionally substituted with —OH;
R 3 is —O-heteroaryl, optionally substituted with 1-3 halogens; and
each occurrence of R 5 is independently selected from: (1) H, (2) halogen, and (3) C 1-4 alkyl, optionally substituted with 1-3 halogens;
or alternatively, two R 5 groups on two adjacent ring carbons together with the two ring carbons form a 3-4 membered new carbocyclic ring.
19. The compound of claim 18 , or a pharmaceutically acceptable salt thereof:
wherein:
m is 0 or 1; p is 0 or 1;
W is —CR d R d —, wherein each occurrence of R d is independently selected from:
(a) H,
(b) —OH,
(c) —NH—C(O)—CH 3 , and
(d) —O—C 1-4 alkyl, optionally substituted with —OH;
R 3 is —O-pyridinyl, optionally substituted with halogen; and
each occurrence of R 5 is independently selected from: (1) H and (2) halogen;
or alternatively, two R 5 groups on two adjacent ring carbons together with the two ring carbons form a new cyclopropyl ring.
20. The compound of claim 1 selected from the group consisting of:
(1-(2-(1-(2,3-dimethylphenyl)piperidin-4-yl)ethyl)-1,4,5,6-tetrahydrocyclopenta[c]pyrazol-3-yl)(4-hydroxypiperidin-1-yl)methanone,
[1-[2-[1-(3-fluorophenyl)piperidin-1-ium-4-yl]ethyl]-5,6-dihydro-4H-cyclopenta[c]pyrazol-3-yl]-(4-hydroxy-1-piperidyl)methanone,
[1-[2-[1-(3-chloro-2-methyl-phenyl)piperidin-1-ium-4-yl]ethyl]-5,6-dihydro-4H-cyclopenta[c]pyrazol-3-yl]-(4-hydroxy-1-piperidyl)methanone,
(4-hydroxy-1-piperidyl)-[1-[2-[1-[3-(trifluoromethyl)phenyl]-4-piperidyl]ethyl]-5,6-dihydro-4H-cyclopenta[c]pyrazol-3-yl]methanone,
[1-[2-[1-(2,3-difluorophenyl)piperidin-1-ium-4-yl]ethyl]-5,6-dihydro-4H-cyclopenta[c]pyrazol-3-yl]-(4-hydroxy-1-piperidyl)methanone,
[1-[2-[1-(6-fluoroquinolin-1-ium-4-yl)-4-piperidyl]ethyl]-5,6-dihydro-4H-cyclopenta[c]pyrazol-3-yl]-(4-hydroxy-1-piperidyl)methanone,
(4-hydroxy-1-piperidyl)-[1-[2-[1-[3-(trifluoromethyl)pyridin-1-ium-4-yl]-4-piperidyl]ethyl]-5,6-dihydro-4H-cyclopenta[c]pyrazol-3-yl]methanone,
(1-(2-(1-(4-fluoro-2,3-dimethylphenyl)piperidin-4-yl)ethyl)-1,4,5,6-tetrahydrocyclopenta[c]pyrazol-3-yl)(4-fluoro-4-(hydroxymethyl)piperidin-1-yl)methanone,
[1-[2-[1-(4-fluoro-2,3-dimethyl-phenyl)piperidin-1-ium-4-yl]ethyl]-5,6-dihydro-4H-cyclopenta[c]pyrazol-3-yl]-[4-(fluoromethyl)-4-hydroxy-1-piperidyl]methanone,
[1-[2-[1-(3-chloro-2-methyl-phenyl)piperidin-1-ium-4-yl]ethyl]-5,6-dihydro-4H-cyclopenta[c]pyrazol-3-yl]-[4-fluoro-4-(hydroxymethyl)-1-piperidyl]methanone,
1-[4-[1-[2-[1-(4-fluoro-2,3-dimethyl-phenyl)piperidin-1-ium-4-yl]ethyl]-5,6-dihydro-4H-cyclopenta[c]pyrazole-3-carbonyl]piperazin-1-yl]-2-hydroxy-ethanone,
1-[4-[1-[2-[1-(3-chloro-2-methyl-phenyl)piperidin-1-ium-4-yl]ethyl]-5,6-dihydro-4H-cyclopenta[c]pyrazole-3-carbonyl]piperazin-1-yl]-2-hydroxy-ethanone,
[1-[2-[1-(4-fluoro-2,3-dimethyl-phenyl)piperidin-1-ium-4-yl]ethyl]-5,6-dihydro-4H-cyclopenta[c]pyrazol-3-yl]-(3-fluoro-4-hydroxy-1-piperidyl)methanone,
[1-[2-[1-(3-chloro-2-methyl-phenyl)piperidin-1-ium-4-yl]ethyl]-5,6-dihydro-4H-cyclopenta[c]pyrazol-3-yl]-(3-fluoro-4-hydroxy-1-piperidyl)methanone,
[1-[2-[1-(3-chloro-2-methyl-phenyl)piperidin-1-ium-4-yl]ethyl]-5,6-dihydro-4H-cyclopenta[c]pyrazol-3-yl]-(3-fluoro-4-hydroxy-1-piperidyl)methanone,
N-(1-(1-(2-(1-(2-(trifluoromethyl)phenyl)piperidin-4-yl)ethyl)-4,5,6,7-tetrahydro-1H-indazole-3-carbonyl)piperidin-4-yl)acetamide,
N-[1-[1-[2-[1-(3-fluoro-2-methyl-phenyl)-4-piperidyl]ethyl]-4,5,6,7-tetrahydroindazole-3-carbonyl]-4-piperidyl]acetamide,
N-[1-[1-[2-[1-(3,4-difluoro-2-methyl-phenyl)-4-piperidyl]ethyl]-4,5,6,7-tetrahydroindazole-3-carbonyl]-4-piperidyl]acetamide,
N-[1-[1-[2-[1-(2,3-dichlorophenyl)-4-piperidyl]ethyl]-4,5,6,7-tetrahydroindazole-3-carbonyl]-4-piperidyl]acetamide,
N-[1-[1-[2-[1-(3-chloro-2-methyl-phenyl)-4-piperidyl]ethyl]-4,5,6,7-tetrahydroindazole-3-carbonyl]-4-piperidyl]acetamide,
N-[1-[1-[2-[1-(2-chlorophenyl)-4-piperidyl]ethyl]-4,5,6,7-tetrahydroindazole-3-carbonyl]-4-piperidyl]acetamide,
N-[1-[1-[2-[1-[2-methyl-3-(trifluoromethyl)phenyl]-4-piperidyl]ethyl]-4,5,6,7-tetrahydroindazole-3-carbonyl]-4-piperidyl]acetamide,
N-[1-[1-[2-[1-(4-fluoro-2-methyl-phenyl)-4-piperidyl]ethyl]-4,5,6,7-tetrahydroindazole-3-carbonyl]-4-piperidyl]acetamide,
N-[1-[1-[2-[1-(3,5-difluoro-2-pyridyl)-4-piperidyl]ethyl]-4,5,6,7-tetrahydroindazole-3-carbonyl]-4-piperidyl]acetamide,
N-[1-[1-[2-[1-(3-methylpyrazin-2-yl)-4-piperidyl]ethyl]-4,5,6,7-tetrahydroindazole-3-carbonyl]-4-piperidyl]acetamide,
N-[1-[1-[2-[1-(3,5-dimethyl-2-pyridyl)-4-piperidyl]ethyl]-4,5,6,7-tetrahydroindazole-3-carbonyl]-4-piperidyl]acetamide,
N-[1-[1-[2-[1-(5-methylpyrazin-2-yl)-4-piperidyl]ethyl]-4,5,6,7-tetrahydroindazole-3-carbonyl]-4-piperidyl]acetamide,
N-[1-[1-[2-[1-(2-methyl-3-pyridyl)-4-piperidyl]ethyl]-4,5,6,7-tetrahydroindazole-3-carbonyl]-4-piperidyl]acetamide,
N-[1-[1-[2-[1-(6-methyl-3-pyridyl)-4-piperidyl]ethyl]-4,5,6,7-tetrahydroindazole-3-carbonyl]-4-piperidyl]acetamide,
N-[1-[1-[2-[1-(5,6-dimethyl-3-pyridyl)-4-piperidyl]ethyl]-4,5,6,7-tetrahydroindazole-3-carbonyl]-4-piperidyl]acetamide,
N-[1-[1-[2-[1-(6-methylpyrazin-2-yl)-4-piperidyl]ethyl]-4,5,6,7-tetrahydroindazole-3-carbonyl]-4-piperidyl]acetamide,
N-[1-[1-[2-[1-(3-methyl-4-pyridyl)-4-piperidyl]ethyl]-4,5,6,7-tetrahydroindazole-3-carbonyl]-4-piperidyl]acetamide,
N-[1-[1-[2-[1-(6-chloropyridazin-3-yl)-4-piperidyl]ethyl]-4,5,6,7-tetrahydroindazole-3-carbonyl]-4-piperidyl]acetamide,
N-[1-[1-[2-[1-[3-fluoro-4-(trifluoromethyl)-2-pyridyl]-4-piperidyl]ethyl]-4,5,6,7-tetrahydroindazole-3-carbonyl]-4-piperidyl]acetamide,
N-[1-[1-[2-[1-[3-fluoro-4-(trifluoromethyl)-2-pyridyl]-4-piperidyl]ethyl]-4,5,6,7-tetrahydroindazole-3-carbonyl]-4-piperidyl]acetamide,
N-[1-[1-[2-[1-[3-chloro-5-(trifluoromethyl)-2-pyridyl]-4-piperidyl]ethyl]-4,5,6,7-tetrahydroindazole-3-carbonyl]-4-piperidyl]acetamide,
N-[1-[1-[2-[1-[4-(trifluoromethyl)-2-pyridyl]-4-piperidyl]ethyl]-4,5,6,7-tetrahydroindazole-3-carbonyl]-4-piperidyl]acetamide,
N-[1-[1-[2-[1-(6-chloro-2-pyridyl)-4-piperidyl]ethyl]-4,5,6,7-tetrahydroindazole-3-carbonyl]-4-piperidyl]acetamide,
N-[1-[1-[2-[1-(3-cyano-2-pyridyl)-4-piperidyl]ethyl]-4,5,6,7-tetrahydroindazole-3-carbonyl]-4-piperidyl]acetamide,
N-[1-[1-[2-[1-(4-cyano-2-pyridyl)-4-piperidyl]ethyl]-4,5,6,7-tetrahydroindazole-3-carbonyl]-4-piperidyl]acetamide,
(1-(2-(1-(3-chlorobenzoyl)piperidin-4-yl)ethyl)-1,4,5,6-tetrahydrocyclopenta[c]pyrazol-3-yl)(4-hydroxypiperidin-1-yl)methanone,
[4-[2-[3-(4-hydroxypiperidine-1-carbonyl)-5,6-dihydro-4H-cyclopenta[c]pyrazol-1-yl]ethyl]-1-piperidyl]-phenyl-methanone,
((2R,6S)-2,6-dimethylmorpholino)(1-(2-(1-(2,3-dimethylphenyl)piperidin-4-yl)-2-hydroxyethyl)-1,4,5,6-tetrahydrocyclopenta[c]pyrazol-3-yl)methanone,
((2R,6S)-2,6-dimethylmorpholino)(1-(2-(1-(2,3-dimethylphenyl)piperidin-4-yl)-2-methoxyethyl)-1,4,5,6-tetrahydrocyclopenta[c]pyrazol-3-yl)methanone,
((2R,6S)-2,6-dimethylmorpholino)(1-(2-(1-(2,3-dimethylphenyl)piperidin-4-yl)-2-fluoroethyl)-1,4,5,6-tetrahydrocyclopenta[c]pyrazol-3-yl)methanone,
1-(4-(1-(2-(4-(4-fluoro-2,3-dimethylphenyl)cyclohexyl)ethyl)-1,4,5,6-tetrahydrocyclopenta[c]pyrazole-3-carbonyl)piperazin-1-yl)-2-hydroxyethan-1-one,
(1-(2-(4-(4-fluoro-2,3-dimethylphenyl)cyclohexyl)ethyl)-1,4,5,6-tetrahydrocyclopenta[c]pyrazol-3-yl)(4-fluoro-4-(hydroxymethyl)piperidin-1-yl)methanone,
(1-(2-(4-(4-fluoro-2,3-dimethylphenyl)cyclohexyl)ethyl)-1,4,5,6-tetrahydrocyclopenta[c]pyrazol-3-yl)(4-fluoro-4-(hydroxymethyl)piperidin-1-yl)methanone,
(1-(2-((1s,4S)-4-(3-chloro-2-methylphenoxy)cyclohexyl)ethyl)-1,4,5,6-tetrahydrocyclopenta[c]pyrazol-3-yl)((2R,6S)-2,6-dimethylmorpholino)methanone,
(1-((4-(3-chloro-2-methylphenoxy)cyclohexyl)methyl)-1,4,5,6-tetrahydrocyclopenta[c]pyrazol-3-yl)((2R,6S)-2,6-dimethylmorpholino)methanone,
(1-((4-(3-chloro-2-methylphenoxy)cyclohexyl)methyl)-1,4,5,6-tetrahydrocyclopenta[c]pyrazol-3-yl)((2R,6S)-2,6-dimethylmorpholino)methanone,
1-(4-(1-(2-((1s,4s)-4-(2-chloro-5-methylphenoxy)cyclohexyl)ethyl)-1,4,5,6-tetrahydrocyclopenta[c]pyrazole-3-carbonyl)piperazin-1-yl)-2-hydroxyethan-1-one,
(1-(2-((1s,4s)-4-(2-chloro-5-methylphenoxy)cyclohexyl)ethyl)-1,4,5,6-tetrahydrocyclopenta[c]pyrazol-3-yl)(4-fluoro-4-(hydroxymethyl)piperidin-1-yl)methanone,
1-(4-(1-(2-((1r,4r)-4-(2-chloro-5-methylphenoxy)cyclohexyl)ethyl)-1,4,5,6-tetrahydrocyclopenta[c]pyrazole-3-carbonyl)piperazin-1-yl)-2-hydroxyethan-1-one,
(1-(2-((1r,4r)-4-(2-chloro-5-methylphenoxy)cyclohexyl)ethyl)-1,4,5,6-tetrahydrocyclopenta[c]pyrazol-3-yl)(4-fluoro-4-(hydroxymethyl)piperidin-1-yl)methanone,
N-(1-(1-(2-((1s,4s)-4-(2-methylphenoxy)cyclohexyl)ethyl)-1,4,5,6-tetrahydrocyclopenta[c]pyrazole-3-carbonyl)piperidin-4-yl)acetamide,
N-(1-(1-(2-((1s,4s)-4-((3-methylpyridin-2-yl)oxy)cyclohexyl)ethyl)-1,4,5,6-tetrahydrocyclopenta[c]pyrazole-3-carbonyl)piperidin-4-yl)acetamide,
N-(1-(1-(2-((1s,4s)-4-((3-(trifluoromethyl)pyridin-2-yl)oxy)cyclohexyl)ethyl)-1,4,5,6-tetrahydrocyclopenta[c]pyrazole-3-carbonyl)piperidin-4-yl)acetamide,
N-(1-(1-(2-((1s,4s)-4-((4-methylpyridin-3-yl)oxy)cyclohexyl)ethyl)-1,4,5,6-tetrahydrocyclopenta[c]pyrazole-3-carbonyl)piperidin-4-yl)acetamide,
N-(1-(1-(2-((1s,4s)-4-(2-(trifluoromethyl)phenoxy)cyclohexyl)ethyl)-1,4,5,6-tetrahydrocyclopenta[c]pyrazole-3-carbonyl)piperidin-4-yl)acetamide,
N-(1-(1-(2-((1s,4s)-4-((3-cyano-4-methylpyridin-2-yl)oxy)cyclohexyl)ethyl)-1,4,5,6-tetrahydrocyclopenta[c]pyrazole-3-carbonyl)piperidin-4-yl)acetamide,
N-(1-(1-(2-((1s,4s)-4-((2,6-dimethylpyridin-3-yl)oxy)cyclohexyl)ethyl)-1,4,5,6-tetrahydrocyclopenta[c]pyrazole-3-carbonyl)piperidin-4-yl)acetamide,
N-(1-(1-(2-((1s,4s)-4-((2,4-dimethylpyrimidin-5-yl)oxy)cyclohexyl)ethyl)-1,4,5,6-tetrahydrocyclopenta[c]pyrazole-3-carbonyl)piperidin-4-yl)acetamide,
N-(1-(1-(2-((1s,4s)-4-((4-methylpyridazin-3-yl)oxy)cyclohexyl)ethyl)-1,4,5,6-tetrahydrocyclopenta[c]pyrazole-3-carbonyl)piperidin-4-yl)acetamide,
N-[1-[1-[2-[4-(2-chlorophenoxy)cyclohexyl]ethyl]-5,6-dihydro-4H-cyclopenta[c]pyrazole-3-carbonyl]-4-piperidyl]acetamide,
N-(1-(4-bromo-1-(2-((1s,4s)-4-((3-methylpyridin-2-yl)oxy)cyclohexyl)ethyl)-1H-pyrazole-3-carbonyl)-piperidin-4-yl)acetamide,
N-(1-(1-(2-((1s,4s)-4-((3-methylpyridin-2-yl)oxy)cyclohexyl)ethyl)-1H-pyrazole-3-carbonyl)piperidin-4-yl)acetamide,
N-(1-(1-(2-((1s,4s)-4-((3-methylpyridin-2-yl)oxy)cyclohexyl)ethyl)-4-(3,3,3-trifluoropropyl)-1H-pyrazole-3-carbonyl)piperidin-4-yl)acetamide,
N-(1-(4-cyclopropyl-1-(2-((1s,4s)-4-((3-methylpyridin-2-yl)oxy)cyclohexyl)ethyl)-1H-pyrazole-3-carbonyl)piperidin-4-yl)acetamide,
(1-(2-(4-(2,3-dimethylphenyl)piperazin-1-yl)ethyl)-1H-indazol-3-yl)(pyrrolidin-1-yl)methanone,
N-(1-(1-(((2S,4S)-4-((5-chloropyridin-2-yl)oxy)tetrahydro-2H-pyran-2-yl)methyl)-5,5-difluoro-4,5,6,7-tetrahydro-1H-indazole-3-carbonyl)piperidin-4-yl)acetamide,
6-{3-[4-(acetylamino)piperidine-1-carbonyl]-5,5-difluoro-4,5,6,7-tetrahydro-1H-indazol-1-yl}-1,5-anhydro-3-O-(5-chloropyridin-2-yl)-2,4,6-trideoxy-D-erythro-hexitol,
1-{3-[4-(acetylamino)piperidine-1-carbonyl]-5,5-difluoro-4,5,6,7-tetrahydro-1H-indazol-1-yl}-2,6-anhydro-4-O-(5-chloropyridin-2-yl)-1,3,5-trideoxy-D-erythro-hexitol,
2,6-anhydro-1,3,5-trideoxy-4-O-(3-fluoropyridin-2-yl)-1-[(3bR,4aR)-3-(4-hydroxypiperidine-1-carbonyl)-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl]-D-erythro-hexitol,
2,6-anhydro-1,3,5-trideoxy-4-O-(3-fluoropyridin-2-yl)-1-{(3bR,4aR)-3-[4-(2-hydroxyethoxy)piperidine-1-carbonyl]-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl}-D-erythro-hexitol,
(4-hydroxypiperidin-1-yl)((3bR,4aR)-1-(2-((1s,4S)-4-((3-methylpyridin-2-yl)oxy)cyclohexyl)ethyl)-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-3-yl)methanone,
[(3R,4S)-3-fluoro-4-hydroxypiperidin-1-yl][(3bR,4aR)-1-(2-{trans-4-[(3-methylpyridin-2-yl)oxy]cyclohexyl}ethyl)-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-3-yl]methanone,
[(3R,4S)-3-fluoro-4-hydroxypiperidin-1-yl][(3bR,4aR)-1-(2-{cis-4-[(3-methylpyridin-2-yl)oxy]cyclohexyl}ethyl)-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-3-yl]methanone,
[(6S)-6-(difluoromethyl)-1-(2-{cis-4-[(3-methylpyridin-2-yl)oxy]cyclohexyl}ethyl)-4,5,6,7-tetrahydro-1H-indazol-3-yl](4-hydroxypiperidin-1-yl)methanone,
(4-aminopiperidin-1-yl)[5,5-difluoro-1-(2-{cis-4-[(3-methylpyridin-2-yl)oxy]cyclohexyl}ethyl)-4,5,6,7-tetrahydro-1H-indazol-3-yl]methanone,
tert-butyl {1-[5,5-difluoro-1-(2-{cis-4-[(3-methylpyridin-2-yl)oxy]cyclohexyl}ethyl)-4,5,6,7-tetrahydro-1H-indazole-3-carbonyl]piperidin-4-yl}carbamate,
[(6R)-6-(difluoromethyl)-1-(2-{cis-4-[(3-methylpyridin-2-yl)oxy]cyclohexyl}ethyl)-4,5,6,7-tetrahydro-1H-indazol-3-yl](4-hydroxypiperidin-1-yl)methanone,
(4-aminopiperidin-1-yl)[(3bR,4aR)-1-(2-{cis-4-[(3-methylpyridin-2-yl)oxy]cyclohexyl}ethyl)-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-3-yl]methanone,
tert-butyl {1-[(3bR,4aR)-1-(2-{cis-4-[(3-methylpyridin-2-yl)oxy]cyclohexyl}ethyl)-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazole-3-carbonyl]piperidin-4-yl}carbamate,
[5,5-difluoro-1-(2-{cis-4-[(3-methylpyridin-2-yl)oxy]cyclohexyl}ethyl)-4,5,6,7-tetrahydro-1H-indazol-3-yl][4-(2-hydroxyethoxy)piperidin-1-yl]methanone,
[4-(2-hydroxyethoxy)piperidin-1-yl][(3bR,4aR)-1-(2-{cis-4-[(3-methylpyridin-2-yl)oxy]cyclohexyl}ethyl)-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-3-yl]methanone,
(4-hydroxy-4-methylpiperidin-1-yl)[(3bR,4aR)-1-(2-{cis-4-[(3-methylpyridin-2-yl)oxy]cyclohexyl}ethyl)-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-3-yl]methanone,
N-{1-[(3bR,4aR)-1-(2-{cis-4-[(3-methylpyridin-2-yl)oxy]cyclohexyl}ethyl)-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazole-3-carbonyl]piperidin-4-yl}acetamide,
2-hydroxy-1-(4-((3bR,4aR)-1-(2-((1s,4S)-4-((3-methylpyridin-2-yl)oxy)cyclohexyl)ethyl)-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazole-3-carbonyl)piperazin-1-yl)ethan-1-one,
(1-(2-(4-(2,3-dimethylphenyl)cyclohexyl)ethyl)-1,4,5,6-tetrahydrocyclopenta[c]pyrazol-3-yl)(4-hydroxypiperiin-1-yl)methanone,
(1-(2-(4-(2,3-dimethylphenyl)cyclohexyl)ethyl)-1,4,5,6-tetrahydrocyclopenta[c]pyrazol-3-yl)(4-hydroxypiperiin-1-yl)methanone,
((3bR,4aR)-1-(2-(1-(3-chloro-2-methylphenyl)-4-hydroxypiperidin-4-yl)ethyl)-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-3-yl)((3R,4S)-3-fluoro-4-hydroxypiperidin-1-yl)methanone,
((3bR,4aR)-1-(2-(1-(3-chloro-2-methylphenyl)-4-hydroxypiperidin-4-yl)ethyl)-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-3-yl)((3S,4R)-3-fluoro-4-hydroxypiperidin-1-yl)methanone,
((3bR,4aR)-1-(2-(4-(2,3-dimethylphenyl)piperazin-1-yl)ethyl)-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-3-yl)(4-hydroxypiperidin-1-yl)methanone,
N-(1-((3bR,4aR)-1-(2-(4-(2,3-dimethylphenyl)piperazin-1-yl)ethyl)-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazole-3-carbonyl)piperidin-4-yl)acetamide,
((3bR,4aR)-1-(2-(4-(3-chloro-2-methylphenyl)piperazin-1-yl)ethyl)-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-3-yl)(4-hydroxypiperidin-1-yl)methanone,
N-(1-((3bR,4aR)-1-(2-(4-(3-chloro-2-methylphenyl)piperazin-1-yl)ethyl)-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazole-3-carbonyl)piperidin-4-yl)acetamide,
1-(2-(1-(2,3-dimethylphenyl)piperidin-4-yl)ethyl)-1H-indazol-3-yl)(pyrrolidin-1-yl)methanone, and
(1-(2-(4-(2,3-dimethylphenyl)piperidin-1-yl)ethyl)-1H-indazol-3-yl)(pyrrolidin-1-yl)methanone;
or a pharmaceutically acceptable salt thereof.