[3.3.1] bicyclo compounds as indoleamine 2,3-dioxygenase inhibitors
Disclosed herein are compounds of formula (I) which are inhibitors of an IDO enzyme: (I). 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:
V is selected from
and
each of R 1 and R 2 is independently selected from:
(i) aryl, and
(ii) heterocyclyl;
wherein each of the aryl of (i) and heterocyclyl of (ii) is optionally substituted with one to four substituents independently selected from:
(a) halogen, and
(b) C 1-6 alkyl, optionally substituted with one to four halogens.
2. The compound of claim 1 , or a pharmaceutically acceptable salt thereof,
wherein R 1 is selected from:
(i) phenyl, optionally substituted with one to three halogens; and
(ii) heterocyclyl, optionally substituted with one to three substituents independently selected from: (a) halogen and (b) C 1-6 alkyl, optionally substituted with one to three halogens.
3. The compound of claim 2 , or a pharmaceutically acceptable salt thereof,
wherein R 1 is a heterocyclyl selected from phthalazinyl, pyridinyl, pyrimidinyl, quinazolinyl and quinolinyl; wherein the heterocyclyl is optionally substituted with one to three substituents independently selected from: (a) halogen and (b) C 1-6 alkyl.
4. The compound of claim 2 , or a pharmaceutically acceptable salt thereof,
wherein R 1 is quinolinyl, optionally substituted with one to three substituents independently selected from: (a) halogen and (b) C 1-4 alkyl.
5. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 2 is selected from:
(i) phenyl, optionally substituted with one to three substituents independently selected from: (a) halogen and (b) C 1-6 alkyl, optionally substituted with one to three halogens; and
(ii) heterocyclyl, optionally substituted with one to three substituents independently selected from: (a) halogen and (b) C 1-6 alkyl, optionally substituted with one to four halogens.
6. The compound of claim 5 , or a pharmaceutically acceptable salt thereof,
wherein R 2 is phenyl, optionally substituted with one to three substituents independently selected from: (a) halogen and (b) C 1-4 alkyl.
7. The compound of claim 1 , or a pharmaceutically acceptable salt thereof,
wherein:
R 1 is a heterocyclyl, optionally substituted with one to three substituents independently selected from: (a) halogen and (b) C 1-6 alkyl, optionally substituted with one to three halogens; and
R 2 is aryl, optionally substituted with one to three substituents independently selected from: (a) halogen and (b) C 1-6 alkyl, optionally substituted with one to three halogens.
8. The compound of claim 7 , or a pharmaceutically acceptable salt thereof,
wherein R 1 is a heterocyclyl selected from pyridinyl, pyrimidinyl, quinazolinyl and quinolinyl; optionally substituted with one to three substituents independently selected from: (a) halogen and (b) C 1-4 alkyl, optionally substituted with one to three halogens; and
R 2 is phenyl, optionally substituted with one to three halogens.
9. The compound of claim 1 of formula (Ia), or a pharmaceutically acceptable salt thereof:
wherein:
R 1 is a heterocyclyl selected from pyridinyl, pyrimidinyl, quinazolinyl and quinolinyl; optionally substituted with one to three substituents independently selected from: (a) halogen and (b) C 1-4 alkyl, optionally substituted with one to three halogens; and
R 2 is phenyl, optionally substituted with one to three halogens.
10. The compound of claim 9 , or a pharmaceutically acceptable salt thereof,
wherein R 1 is a quinolinyl, optionally substituted with one to three halogens.
11. The compound of claim 1 of formula (Ib), or a pharmaceutically acceptable salt thereof:
wherein:
R 1 is a heterocyclyl selected from pyridinyl, pyrimidinyl, quinazolinyl and quinolinyl; optionally substituted with one to three substituents independently selected from: (a) halogen and (b) C 1-4 alkyl, optionally substituted with one to three halogens; and
R 2 is phenyl, optionally substituted with one to three halogens.
12. The compound of claim 11 , or a pharmaceutically acceptable salt thereof,
wherein R 1 is a quinolinyl, optionally substituted with one to three halogens.
13. The compound of claim 1 selected from:
N-(4-chlorophenyl)-6-(6-fluoroquinolin-4-yl)bicyclo[3.3.1]nonane-2-carboxamide, and 4-chloro-N-(6-(6-fluoroquinolin-4-yl)bicyclo[3.3.1]nonan-2-yl)benzamide;
or a pharmaceutically acceptable salt thereof.
14. A composition which comprises an inert carrier and a compound of claim 1 or a pharmaceutically acceptable salt thereof.
15. A method for treating an IDO-associated disease or disorder, wherein the IDO-associated disease or disorder is selected from cancer, viral infection, HCV infection, depression, neurodegenerative disorders, trauma, age-related cataracts, organ transplantation, and autoimmune diseases, in a mammalian subject which comprises administering to the subject an effective amount of a compound of claim 1 or a pharmaceutically acceptable salt thereof.
16. A method for treating an IDO-associated disease or disorder, wherein the IDO-associated disease or disorder is selected from cancer, viral infection, HCV infection, depression, neurodegenerative disorders, trauma, age-related cataracts, organ transplantation, and autoimmune diseases, in a mammalian subject which comprises administering to the subject an effective amount of a compound of claim 1 or a pharmaceutically acceptable salt thereof in combination with another anti-cancer agent.
17. A method for treating an IDO-associated disease or disorder, wherein the IDO-associated disease or disorder is selected from cancer, viral infection, HCV infection, depression, neurodegenerative disorders, trauma, age-related cataracts, organ transplantation, and autoimmune diseases, in a mammalian subject which comprises administering to the subject an effective amount of a compound of claim 1 or a pharmaceutically acceptable salt thereof in combination with two additional anti-cancer agents.
18. The method of claim 15 wherein the cancer is selected from colon cancer, pancreas cancer, breast cancer, prostate cancer, lung cancer, brain cancer, ovarian cancer, cervical cancer, testes cancer, renal cancer, head and neck cancer, lymphoma, leukemia and melanoma.