Inhibitors of indoleamine-2,3-dioxygenase for the treatment of cancer
There are disclosed compounds of formula (I) that modulate or inhibit the enzymatic activity of indoleamine-2,3-dioxygenase (IDO), pharmaceutical compositions containing said compounds and methods of treating proliferative disorders, such as cancer, viral infections and/or inflammatory disorders utilizing the compounds of the invention.
1. A compound of Formula I:
wherein:
Y is N, CH, or CF;
V is N, CH, or CF;
R 1 is —COOH, —COOC 1 -C 6 alkyl, —CONH 2 , —CN, optionally substituted heterocyclyl, optionally substituted heteroaryl, —NHCONHR 13 , —CONHSO 2 R 14 , —CONHCOR 13 , —SO 2 NHCOR 13 , —CONHSO 2 NR 13 R 14 , —SO 2 NHR 13 , —NHCONHSO 2 R 13 , —CHCF 3 OH, —COCF 3 , —CR 2 R 3 OH, or —NHSO 2 R 13 ;
R 13 is H, optionally substituted C 1 -C 10 alkyl, optionally substituted C 3 -C 8 cycloalkyl, optionally substituted C 2 -C 10 alkenyl or optionally substituted C 2 -C 10 alkynyl;
R 14 is H or optionally substituted C 1 -C 10 alkyl;
R 2 is H, optionally substituted C 1 -C 10 alkyl, optionally substituted C 3-6 cycloalkyl, optionally substituted heterocyclyl, or optionally substituted aryl;
R 3 is H, optionally substituted C 1 -C 10 alkyl, optionally substituted C 3-6 cycloalkyl, optionally substituted heterocyclyl, or optionally substituted aryl; or
R 2 and R 3 are taken together with the carbon to which they are attached to form an optionally substituted 3- to 6-membered carbocyclic or a 3- to 6-membered heterocyclic ring;
R x is H, optionally substituted C 1 -C 10 alkyl, optionally substituted C 1 -C 10 alkoxy, or optionally substituted C 3 -C 8 cycloalkyl;
R y is H, optionally substituted C 1 -C 10 alkyl, optionally substituted C 1 -C 10 alkoxy, or optionally substituted C 3 -C 8 cycloalkyl; or
R x and R y are taken together with the carbon to which they are attached to form a 3- to 7-membered heterocyclic ring containing 1-3 heteroatoms selected from —N—, —S—, and —O—;
R 4 is optionally substituted heterocyclyl;
R 5 is H, optionally substituted C 1 -C 10 alkyl, optionally substituted C 1 -C 10 -alkoxy-C 1 -C 10 -alkyl, optionally substituted C 1 -C 10 alkoxy, optionally substituted aryl, optionally substituted aryl-C 1 -C 10 -alkyl, optionally substituted 5- to 8-membered heteroaryl, optionally substituted C 3 -C 8 cycloalkyl or optionally substituted heterocyclyl; or
R 4 and R 5 are taken together with the nitrogen to which they are attached to form a 4- to 8-membered optionally substituted heterocyclic ring containing 0-3 additional heteroatoms selected from —N—, —S— and —O—; or
R 4 and R 5 are taken together with the nitrogen to which they are attached to form a 6- to 10-membered optionally substituted heterobicyclic ring containing 0-3 additional heteroatoms selected from —N—, —S—, and —O—;
R 6 is —C(O)NHR 8 ; and
R 8 is optionally substituted aryl, optionally substituted heteroaryl, optionally substituted C 3 -C 8 cycloalkyl, or optionally substituted heterocyclyl;
or a stereoisomer thereof or a tautomer thereof;
or a pharmaceutically acceptable salt thereof.
2. The compound of claim 1 , wherein Y and V are each CH.
3. The compound of claim 1 or claim 2 , wherein R 1 is —COOH.
4. The compound of claim 1 , wherein one of R 2 and R 3 is H and the other is optionally substituted C 1 -C 10 alkyl, optionally substituted C 3-6 cycloalkyl, optionally substituted heterocyclyl, or optionally substituted aryl.
5. The compound of claim 1 , wherein R 2 and R 3 are each independently optionally substituted C 1 -C 10 alkyl.
6. The compound of claim 1 , wherein R x and R y are each H.
7. The compound of claim 1 , wherein R 4 is optionally substituted heterocyclyl and R 5 is optionally substituted C 1 -C 10 alkyl.
8. The compound of claim 1 , wherein R 4 and R 5 are taken together with the nitrogen to which they are attached to form a 4- to 8-membered optionally substituted heterocyclic ring containing 0-3 additional heteroatoms selected from —N—, —S— and —O—.
9. The compound of claim 1 , wherein R 8 is optionally substituted aryl.
10. The compound of claim 1 , wherein R 8 is optionally substituted heteroaryl.
11. The compound of claim 1 , wherein R 8 is optionally substituted heterocyclyl.
12. A pharmaceutical composition comprising a compound of claim 1 and a pharmaceutically acceptable excipient.
13. A method of treating a cancer that is melanoma, lung cancer, head cancer, neck cancer, renal cell carcinoma, or bladder cancer, in a patient in need of such treatment, comprising administering to the patient a therapeutically effective amount of a compound according to claim 1 .