Substituted tetrahydroquinolin compounds as indoleamine 2,3-dioxygenase (IDO) inhibitors
Disclosed herein is a compound of formula (I), or a pharmaceutically acceptable salt thereof: Also disclosed herein are uses of the compounds disclosed herein in the potential treatment or prevention of an IDO-associated disease or disorder. Also disclosed herein are compositions comprising a compound disclosed herein. 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:
A is selected from H, halogen, CN, and C 1-6 alkyl optionally substituted with 1-3 halogens;
Z 1 , Z 2 and Z 3 are each independently selected from CR 8 and N;
R 8 , if present, is H, halogen, C 1-6 alkyl, OC 0-6 alkyl, or NH 2 ;
R 1 and R 2 are independently selected from H, C 1-6 alkyl, and C 3-6 cycloalkyl, optionally substituted with C 3-6 cycloalkyl, or R 1 and R 2 , together with the carbon atom to which they are attached, optionally form C 3-6 cycloalkyl optionally substituted with C 3-6 cycloalkyl;
V is selected from C(O), CONH, and C 3-6 heterocycle containing 1-4 nitrogen, wherein the C 3-6 heterocycle is optionally substituted with CH 3 or CF 3 ;
R 3 is selected from H, C 1-6 alkyl, C 3-6 cycloalkyl, OC 1-6 -(alkyl, OC 3-6 cycloalkyl, C 3-10 heterocyclyl containing 1-4 nitrogen or oxygen, optionally substituted with halogen, C 1-6 alkyl or CF 3 , and phenyl optionally substituted with halogen;
R 4 and R 5 are each independently selected from H, OH, halogen, and C 1-6 alkyl;
R 6 is independently selected from H, OH, halogen, and C 1-6 alkyl;
and n is 0, 1, 2, 3, or 4.
2. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein A is selected from the group consisting of H, CF 3 , CH 3 , CN, or and Cl.
3. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein Z 1 is CH.
4. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein Z 1 is N.
5. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein Z 2 is CH.
6. The compound of any of claim 1 , or a pharmaceutically acceptable salt thereof, wherein Z 2 is N.
7. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein Vis C (O).
8. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein both R 1 and R 2 are independently selected from H and CH 3 , or together with the carbon atom to which they are attached, optionally form C 3-6 cycloalkyl optionally substituted with C 3-6 cycloalkyl.
9. The compound of claim 1 , or a pharmaceutically acceptable salt thereof wherein R 3 is selected from H, C 1-6 alkyl, C 3-6 cycloalkyl, OC 1-6 alkyl, OC 3-6 cycloalkyl, and C 3-10 heterocyclyl containing 1-4 nitrogen or oxygen, optionally substituted with halogen, C 1-6 alkyl or CF 3 .
10. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 3 is selected from H, CH 3 , cyclopropyl, tetrahydrofuran, OCH 3 , O-cyclopropyl, terahydropyran, OCH 2 CH 3 , of and phenyl optionally substituted with halogen.
11. A compound of formula Ia:
or a pharmaceutically acceptable salt thereof, wherein:
A is selected from H, halogen, CN, CH 3 , and CF 3 ;
Z 1 , Z 2 , and Z 3 are each independently selected from CH and N;
R 1 and R 2 together with the carbon atom to which they are attached form a C 3-6 cycloalkyl, wherein the cycloalkyl is optionally substituted with C 3-6 cycloalkyl; and
R 3 is selected from H, C 1-6 alkyl, C 3-6 cycloalkyl, OC 1-6 alkyl, OC 3-6 cycloalkyl, and C 3-10 heterocyclyl containing 1-4 nitrogen or oxygen, optionally substituted with halogen, C 1-6 alkyl or CF 3 .
12. The compound of claim 1 of formula Ib:
or a pharmaceutically acceptable salt thereof, wherein:
A is selected from H, halogen, CN, CH 3 , and CF 3 ;
Z 1 , Z 2 , and Z 3 are each independently selected from CH and N;
R 1 and R 2 are independently selected from H, CH 3 , and C 3-6 cycloalkyl, wherein the cycloalkyl is optionally substituted with C 3-6 cycloalkyl, or R 1 and R 2 ; together with the carbon atom to which they are attached, optionally form C 3-6 cycloalkyl, wherein the cycloalkyl is optionally substituted with C 3-6 cycloalkyl; and
R 3 is selected from H, C 1-6 alkyl, C 3-6 cycloalkyl, OC 1-6 alkyl, OC 3-6 cycloalkyl, and C 3-10 heterocyclyl containing 1-4 nitrogen or oxygen, optionally substituted with halogen, C 1-6 alkyl or CF 3 .
13. The compound of claim 1 of formula Ic:
or a pharmaceutically acceptable salt thereof, wherein:
A is selected from H, halogen, CN, CH 3 , and CF 3 ;
Z 1 , Z 2 , and Z 3 are each independently selected from CH and N;
V is C (O); and
R 3 is selected from H, C 1-6 alkyl, C 3-6 cycloalkyl, OC 1-6 alkyl, OC 3-6 cycloalkyl, and C 3-10 heterocyclyl containing 1-4 nitrogen or oxygen, optionally substituted with halogen, C 1-6 alkyl or CF 3 .
14. The compound of claim 1 of formula If:
or a pharmaceutically acceptable salt thereof, wherein:
A is selected from H, halogen, CN, CH 3 , and CF 3 ;
Z 1 , Z 2 , and Z 3 are each independently selected from CH and N; and
R 3 is selected from H, C 1-6 alkyl, C 3-6 cycloalkyl, OC 1-6 alkyl, OC 3-6 cycloalkyl, and C 3-10 heterocyclyl containing 1-4 nitrogen or oxygen, optionally substituted with halogen, C 1-6 alkyl or CF 3 .
15. The compound of claim 1 of formula Ig:
or a pharmaceutically acceptable salt thereof, wherein:
A is selected from H, halogen, CN, CH 3 , and CF 3 ;
Z 1 , Z 2 , and Z 3 are each independently selected from CH and N;
V is C (O); and
R 3 is selected from H, C 1-6 alkyl, C 3-6 cycloalkyl, OC 1-6 alkyl, OC 3-6 cycloalkyl, and C 3-10 heterocyclyl containing 1-4 nitrogen or oxygen, optionally substituted with halogen, C 1-6 alkyl or CF 3 .
16. A compound which is selected from:
or a pharmaceutically acceptable salt thereof.
17. A composition which comprises an inert carrier and a compound of claim 1 or a pharmaceutically acceptable salt thereof.
18. A method for treating an IDO-associated disease or disorder 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.
19. The method of claim 18 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.
20. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein n is 1.