Compounds useful as inhibitors of indoleamine 2,3-dioxygenase

Patent metadata

Field	Value
Publication number	US-9499497-B2
Application number	US-201514722413-A
Country	US
Kind code	B2
Filing date	May 27, 2015
Priority date	Nov 20, 2012
Publication date	Nov 22, 2016
Grant date	Nov 22, 2016

Abstract

The present invention relates to compounds useful as inhibitors of indoleamine 2,3-dioxygenase (IDO). The invention also relates to pharmaceutically acceptable compositions comprising the compounds of this invention; methods of treating of various diseases, disorders, and conditions using the compounds of this invention; processes for preparing the compounds of this invention; intermediates for the preparation of the compounds of this invention; and methods of using the compounds in in vitro applications.
The compounds of this invention have formula I-A:

wherein the variables are as defined herein.

First claim

We claim:

1. A compound of formula I-A:

or a pharmaceutically acceptable salt thereof, wherein:
n is 0-4;
X is halo;
Z 1 , Z 2 , and Z 3 are CH or N, wherein CH is optionally substituted with R 1 or X;
R 1 is independently selected from halo; —CN; Q X ; or a C 1-10 aliphatic chain wherein up to four methylene units of the aliphatic chain are optionally replaced with —O—, —NR—, —S—, —C(O)—, S(O)—, or —S(O) 2 —; R 1 is optionally substituted with 0-5 J 1 groups;
Q X is a 3-7 membered monocyclic fully saturated, partially unsaturated, or aromatic ring containing 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur;
J 1 is independently selected from halo; —CN; Q Y ; or a C 1-6 aliphatic chain wherein up to three methylene units of the aliphatic chain are optionally replaced with —O—, —NR—, —S—, —C(O)—, S(O)—, or —S(O) 2 —; J 1 is optionally substituted with 0-5 J 2 groups; or
two occurrences of J 1 on the same atom, together with the atom to which they are attached, form a 3-6 membered non-aromatic monocyclic ring; the ring formed by two occurrences of J 1 on the same atom is optionally substituted with 0-3 J 2A groups; or
two occurrences of J 1 , together with Q X , form a bridged ring system;
Q Y is independently selected from a 3-7 membered monocyclic fully saturated, partially unsaturated, or aromatic ring containing 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur; or an 8-12 membered bicyclic fully saturated, partially unsaturated, or aromatic ring containing 0-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur;
J 2 is independently selected from halo; ═O; —CN; a 3-6 membered aromatic or non-aromatic ring containing 0-3 heteroatoms selected from oxygen, nitrogen, or sulfur; or C 1-4 aliphatic chain wherein up to two methylene units of the aliphatic chain are optionally replaced with —O—, —NR—, —S—, —C(O)—, S(O)—, or —S(O) 2 —; J 2 is optionally substituted with 0-5 J 3 groups; or
two occurrences of J 2 , together with the atom or atoms to which they are attached, form a 3-6 membered aromatic or non-aromatic monocyclic ring; the ring formed by two occurrences of J 2 is optionally substituted with 0-3 J 3A groups; or
two occurrences of J 2 , together with Q Y , form a bridged ring system;
J 2A is independently selected from halo or a C 1-4 aliphatic chain wherein up to two methylene units of the aliphatic chain are optionally replaced with —O—, —NR—, —S—, —S(O)—, —S(O) 2 , or —C(O);
J 3 and J 3A are independently selected from halo or C 1-4 alkyl; and
R is independently selected from H or C 1-6 aliphatic.

2. The compound of claim 1 , wherein each R 1 is independently a C 1-10 aliphatic chain wherein up to four methylene units of the aliphatic chain are optionally replaced with —O—.

3. The compound of claim 1 , wherein Z 3 is CH, wherein CH is optionally substituted with X.

4. The compound of claim 3 , wherein each R 1 is independently a C 1-10 aliphatic chain wherein up to four methylene units of the aliphatic chain are optionally replaced with —O—.

5. The compound of claim 4 , wherein R 1 is independently selected from the group consisting of C 1-6 alkyl, —(C 1-4 alkyl)O(C 1-4 alkyl), and alkenyl.

6. The compound of claim 1 , wherein Z 1 , Z 2 , and Z 3 are independently CH, wherein CH is optionally substituted with X.

7. The compound of claim 6 , wherein each R 1 is independently a C 1-10 aliphatic chain wherein up to four methylene units of the aliphatic chain are optionally replaced with —O—.

8. The compound of claim 7 , wherein each R 1 is independently selected from the group consisting of C 1-6 alkyl, —(C 1-4 alkyl)O(C 1-4 alkyl), and alkenyl.

9. The compound of claim 1 , wherein X is fluoro.

10. The compound of claim 1 , wherein X is chloro.

11. A compound of formula I-B:

or a pharmaceutically acceptable salt thereof, wherein:
n is 0-4;
X is bromo or chloro; and
Z 1 and Z 2 are CH, wherein CH is optionally substituted with R 1 ;
R 1 is independently selected from halo; —CN; Q X ; or a C 1-10 aliphatic chain wherein up to four methylene units of the aliphatic chain are optionally replaced with —O—, —NR—, —S—, —C(O)—, S(O)—, or —S(O) 2 —; R 1 is optionally substituted with 0-5 J 1 groups;
Q X is a 3-7 membered monocyclic fully saturated, partially unsaturated, or aromatic ring containing 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur;
J 1 is independently selected from halo; —CN; Q Y ; or a C 1-6 aliphatic chain wherein up to three methylene units of the aliphatic chain are optionally replaced with —O—, —NR—, —S—, —C(O)—, S(O)—, or —S(O) 2 —; J 1 is optionally substituted with 0-5 J 2 groups; or
two occurrences of J 1 on the same atom, together with the atom to which they are attached, form a 3-6 membered non-aromatic monocyclic ring; the ring formed by two occurrences of J 1 on the same atom is optionally substituted with 0-3 J 2A groups; or
two occurrences of J 1 , together with Q X , form a bridged ring system;
Q Y is independently selected from a 3-7 membered monocyclic fully saturated, partially unsaturated, or aromatic ring containing 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur; or an 8-12 membered bicyclic fully saturated, partially unsaturated, or aromatic ring containing 0-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur;
J 2 is independently selected from halo; ═O; —CN; a 3-6 membered aromatic or non-aromatic ring containing 0-3 heteroatoms selected from oxygen, nitrogen, or sulfur; or C 1-4 aliphatic chain wherein up to two methylene units of the aliphatic chain are optionally replaced with —O—, —NR—, —S—, —C(O)—, S(O)—, or —S(O) 2 —; J 2 is optionally substituted with 0-5 J 3 groups; or
two occurrences of J 2 , together with the atom or atoms to which they are attached, form a 3-6 membered aromatic or non-aromatic monocyclic ring; the ring formed by two occurrences of J 2 is optionally substituted with 0-3 J 3A groups; or
two occurrences of J 2 , together with Q Y , form a bridged ring system;
J 2A is independently selected from halo or a C 1-4 aliphatic chain wherein up to two methylene units of the aliphatic chain are optionally replaced with —O—, —NR—, —S—, —S(O)—, —S(O) 2 , or —C(O);
J 3 and J 3A are independently selected from halo or C 1-4 alkyl; and
R is independently selected from H or C 1-6 aliphatic.

12. The compound of claim 11 , wherein each R 1 is independently a C 1-8 aliphatic chain wherein up to four methylene units of the aliphatic chain are optionally replaced with —O.

13. The compound of claim 12 , wherein R 1 is independently selected from the group consisting of C 1-6 alkyl, —(C 1-4 alkyl)O(C 1-4 alkyl), and alkenyl.

14. The compound of claim 12 , wherein n is 1.

15. The compound of claim 11 , wherein X is chloro.

16. The compound of claim 11 , wherein n is 0.

17. The compound of claim 11 , wherein X is bromo.

18. A compound of claim 11 having the structure:

or a pharmaceutically acceptable salt thereof.

19. A pharmaceutically acceptable salt of the compound of claim 18 .

20. A composition comprising a compound of claim 18 ,

Assignees

• Vertex Pharma

Inventors

• Boyall Dean
• Davis Christopher
• Dodd James
• Everitt Simon
• Miller Andrew
• Weber Peter
• Westcott James
• Young Stephen
• Settimo Luca

Classifications

• A61P43/00

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

• A61P25/04

  Centrally acting analgesics, e.g. opioids · CPC title

• A61P31/12

  Antivirals · CPC title

• A61P25/18

  Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia · CPC title

• A61P29/00

  Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID] · CPC title