IDO inhibitors

Patent metadata

Field	Value
Publication number	US-10167254-B2
Application number	US-201715584818-A
Country	US
Kind code	B2
Filing date	May 2, 2017
Priority date	Apr 3, 2015
Publication date	Jan 1, 2019
Grant date	Jan 1, 2019

Abstract

There are disclosed compounds 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.

First claim

What is claimed is:

1. A method for treating a cancer that is melanoma, lung cancer, head cancer, neck cancer, renal cell carcinoma, or bladder cancer in a human in need of such treatment comprising administering to said human a therapeutically effective amount of a compound according to 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 5 or 6 membered heterocyclyl having 1-4 ring vertices independently selected from O, N, S, 5 or 6 membered optionally substituted heteroaryl having 1-4 ring vertices independently selected from O, N, S, —NHCONHR 13 , —CONHSO 2 R 14 , —CONHCOR 13 , —SO 2 NHCOR 13 , —CONR 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, optionally substituted C 2 -C 10 alkynyl, optionally substituted 5-6 membered heterocyclyl having 1-4 ring vertices independently selected from O, N, S, optionally substituted phenyl, or optionally substituted 5-6 membered heteroaryl having 1-4 ring vertices independently selected from O, N, S;
R 14 is H, optionally substituted C 1 -C 10 alkyl, phenyl, or C 3-8 cycloalkyl;
R 2 and R 3 are independently -hydrogen, optionally substituted C 1 -C 10 alkyl, optionally substituted C 3-8 cycloalkyl, or optionally substituted phenyl; 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 heterocyclic ring;
R 4 and R 5 are independently 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 containing 0-3 heteroatoms selected form N, S and O, optionally substituted C 3 -C 8 cycloalkyl or optionally substituted heterocyclyl containing 0-3 heteroatoms selected form N, S and O; 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 optionally substituted 5 or 6 membered aryl, optionally substituted 5 or 6 membered heteroaryl having 1 to 4 ring vertices independently selected from O, N, S, optionally substituted C 3 -C 8 cycloalkyl optionally substituted 9 to 10 membered fused bicyclic heterocyclyl having 1 to 4 ring vertices independently selected from O, N, S, 9 to 10 membered fused bicyclic heteroaryl having 1 to 4 ring vertices independently selected from O, N, S or —COR 7 ;
R 7 is optionally substituted —CR 2 R 3 -5 or 6 membered aryl, optionally substituted —CR 2 R 3 -5 or 6 membered heteroaryl, —CR 2 R 3 -3 to 6 membered heterocyclyl, optionally substituted 5 or 6 membered aryl, optionally substituted 5 or 6 membered heteroaryl, optionally substituted C 3 -C 8 cycloalkyl, or optionally substituted 3 to 6 membered heterocyclyl; and
R x and R y are each independently 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 0-3 additional heteroatoms selected from —N—, —S— and —O—;
and/or a stereoisomer, a tautomer or a pharmaceutically acceptable salt thereof.

2. The method according to claim 1 wherein R x and R y are H, methyl, or methoxy.

3. The method according to claim 1 wherein R 2 and R 3 are each independently H, methyl, ethyl, methoxymethyl, haloalkyl, or alkoxy.

4. The method according to claim 1 , wherein R 1 is —COOH, —CONHSO 2 R 14 , —NHSO 2 R 14 , —CHCF 3 OH, or is selected from the group consisting of

5. The method according to claim 4 , wherein R 1 is —COOH, —CONHSO 2 R 14 , —NHSO 2 R 14 , —CHCF 3 OH,

6. The method according to claim 5 wherein R 1 is —COOH.

7. The method according to claim 1 wherein:
R 4 is optionally substituted C 1 to C 6 alkyl, optionally substituted C 3 to C 6 cycloalkyl; or selected from the group consisting of optionally substituted tetrahydropyranyl, optionally substituted azetidinyl, optionally substituted morpholinyl, optionally substituted piperidinyl, optionally substituted pyrrolidinyl, optionally substituted piperazinyl, or an optionally substituted heterocyclic ring selected from

8. The method according to claim 1 , wherein R 5 is —H, optionally substituted C 1 to C 6 alkyl, or optionally substituted C 3 to C 6 cycloalkyl.

9. The method according to claim 1 , wherein R 4 is C 1 to C 6 alkyl optionally substituted with hydroxyl; C 3 to C 6 cycloalkyl, optionally substituted with at least one of C 1 to C 6 alkyl, hydroxyl, and/or alkoxy; azetidinyl optionally substituted with hydroxyl, halo, or alkoxy; tetrahydropyranyl; morpholinyl optionally substituted with at least one of at least one of C 1 to C 6 alkyl and/or phenyl; piperidinyl optionally substituted with at least one of C 1 to C 6 alkyl, phenyl and/or benzyl; cyclohexyl; pyrrolidinyl optionally substituted with at least one of —OH, hydroxyalkyl, methoxyalkyl and/or haloalkyl; piperazinyl optionally substituted with at least one of C 1 to C 4 alkyl and/or —COOR 13 ;

optionally substituted with phenyl, —COOR 13 , alkyl, haloalkyl, or benzyl.

10. The method according to claim 1 , wherein R 4 is optionally substituted C 1 to C 6 alkyl.

11. The method according to claim 1 , wherein R 4 is optionally substituted tetrahydropyranyl.

12. The method according to claim 1 wherein R 4 is optionally substituted morpholinyl.

13. The method according to claim 1 wherein R 4 is optionally substituted piperidinyl.

14. The method according to claim 1 wherein R 4 is optionally substituted pyrrolidinyl.

15. The method according to claim 1 , wherein R 4 and R 5 are taken together with the nitrogen to which they are attached to form an optionally substituted heterocyclyl selected from the group consisting of morpholinyl, piperidinyl, azetidinyl, piperazinyl,

16. The method according to claim 1 , wherein R 6 is optionally substituted phenyl; optionally substituted pyrimidinyl; optionally substituted pyridyl; optionally substituted pyrazinyl, optionally substituted pyridazinyl, an optionally substituted heterocyclic ring selected from the group consisting of

or —COR 7 wherein R 7 is optionally sub

Assignees

• Bristol Myers Squibb Co

Inventors

• Balog James Aaron
• Cherney Emily Charlotte
• Guo Weiwei
• Huang Audris
• Markwalder Jay A
• Seitz Steven P
• Shan Weifang
• Williams David K
• Murugesan Natesan
• Nara Susheel Jethanand
• Roy Saumya
• Thangavel Soodamani
• Sistla Ramesh Kumar
• Cheruku Srinivas
• Thangathirupathy Srinivasan
• Kanyaboina Yadagiri
• Pulicharla Nagalakshmi

Classifications

• A61P37/02

  Immunomodulators · CPC title

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title

• A61P35/04

  specific for metastasis · CPC title

• A61P35/02

  specific for leukemia · CPC title

• A61P35/00

  Antineoplastic agents · CPC title