Compounds and methods for IDO and TDO modulation, and indications therefor

Patent metadata

Field	Value
Publication number	US-10508085-B2
Application number	US-201715713502-A
Country	US
Kind code	B2
Filing date	Sep 22, 2017
Priority date	Sep 22, 2016
Publication date	Dec 17, 2019
Grant date	Dec 17, 2019

Abstract

Disclosed are compounds of Formula I(a):

or a pharmaceutically acceptable salt, a solvate, a tautomer, an isomer or a deuterated analog thereof, wherein R 4 , R 5 , R 6 , R 7 , G 1 , G 2 and Ring A are as described in any of the embodiments described in this disclosure; compositions thereof; and uses thereof.

First claim

We claim:

1. A compound of Formula I(c):

or a pharmaceutically acceptable salt, a solvate, a tautomer, a stereoisomer or a deuterated analog thereof, wherein:
R 4 , R 5 and R 6 are each independently H, halogen, alkyl, haloalkyl, —OCH 3 optionally substituted with 1-3 halogens, or C 3 -C 6 cycloalkyl optionally substituted with 1-3 halogens,
provided that at least one of R 4 , R 5 or R 6 is not H;
R 7 is one of the following groups (a)-(f):
(a) cycloalkenyl optionally substituted with 1-7 Z 1 and optionally substituted with 1 Z 4 ;
(b) heterocycloalkyl substituted with 1-9 Z 2 and optionally substituted with 1 Z 5 ;
(c) a bridged heterocyclic ring optionally substituted with 1-5 Z 2 and optionally substituted with 1 Z 5 ;
(d) a spiro ring system containing two heterocycloalkyl groups joined by one common spiro carbon atom, wherein the spiro ring system is optionally substituted on its carbon atoms with 1-8 Z 3 , and wherein the spiro ring system is optionally N-substituted with alkyl, haloalkyl, —CO 2 -alkyl, —C(O)NR 10 R 11 , —SO 2 NR 10 R 11 , —SO 2 -alkyl, SO 2 -haloalkyl, or —SO 2 -cycloalkyl substituted with 1-6 halogens;

each Y is independently H, D, halogen, alkyl, or haloalkyl, or 2 Y groups join together with the carbon atom to which they are attached to form a cycloalkyl optionally substituted with 1-3 halogens;
R 8 is H, —CH 3 , —CFH 2 , —CF 2 H or —CF 3 ;
R 8b is H, F, Cl, —CH 3 , —CFH 2 , —CF 2 H or —CF 3 ;
R 9 is —(CY 2 ) 0-3 —R 12 ;
or R 8 and R 9 join together with the carbon atom to which they are attached to form one of the following groups (a)-(e):
(a) a cycloalkyl optionally substituted with 1-9 Z 2 and optionally substituted with 1 Z 5 or 1-2 Z 6 ;
(b) a heterocycloalkyl optionally substituted with 1-9 Z 2 and optionally substituted with 1 Z 5 ;
(c) a spiro ring system containing two cycloalkyl groups joined by one common spiro carbon atom, wherein the spiro ring system is optionally substituted with 1-9 Z 2 and optionally substituted with 1 Z 5 or 1-2 Z 6 ;
(d) a spiro ring system containing one cycloalkyl and one heterocycloalkyl joined by one common spiro carbon atom, wherein the spiro ring system is optionally substituted on its carbon atoms with 1-9 Z 3 , and wherein the spiro ring system is optionally N-substituted with alkyl, haloalkyl, —CO 2 -alkyl, —C(O)NR 10 R 11 , —SO 2 NR 10 R 11 , —SO 2 -alkyl, SO 2 -haloalkyl, or —SO 2 -cycloalkyl substituted with 1-6 halogens; or
(e) a spiro ring system containing one cycloalkyl and one a bridged ring joined by one common spiro carbon atom, wherein the spiro ring system is optionally substituted with 1-5 Z 2 and optionally substituted with 1 Z 5 ;
R 10 is H, alkyl, or haloalkyl;
R 11 is H, alkyl, haloalkyl, cyanoalkyl, CN, alkynyl, phenyl optionally substituted with 1-4 J 3 , heteroaryl optionally substituted with 1-4 J 3 , heterocycloalkyl optionally substituted with 1-4 J 3 , -alkylene-C(O)—OH, -alkylene-C(O)—NH 2 , -alkylene-C(O)—N(H)-alkyl, -alkylene-C(O)—N(alkyl) 2 , alkoxy, -alkylene-C(O)-phenyl optionally substituted with 1-4 J 3 , —C(O)—O-alkyl, alkylene-C(O)—O-alkyl, hydroxyalkyl, cycloalkyl optionally substituted with 1-4 J 3 , cycloalkylalkyl optionally substituted with 1-4 J 3 , -alkylene-phenyl optionally substituted with 1-4 J 3 , -alkylene-SO 2 -phenyl optionally substituted with 1-4 J 3 , -alkylene-SO 2 -alkyl, -alkylene-NH—SO 2 —C 1 -C 6 alkyl, alkoxyalkyl, alkoxycarbonyl, alkylcycloalkyl optionally substituted with 1-4 J 3 , -alkylene-heterocycloalkyl optionally substituted with 1-4 J 3 , -alkylene-heteroaryl optionally substituted with 1-4 J 3 , or —C(O)— phenyl optionally substituted with 1-4 J 3 ;
R 12 is one of the following groups (a)-(g):
(a) a saturated cycloalkyl optionally substituted with 1-9 Z 2 and optionally substituted with 1 Z 5 or 1-2 Z 6 ;
(b) an unsaturated cycloalkyl optionally substituted with 1-7 Z 2 and optionally substituted with 1 Z 5 ;
(c) a heterocycloalkyl optionally substituted 1-9 Z 2 and optionally substituted with 1 Z 5 ;
(d) phenyl optionally substituted with 1-2 Z 2 ;
(e) a bridged ring optionally substituted with 1-5 Z 2 and the bridged ring is optionally substituted on a carbon atom with —N(H)(SO) 2 -alkyl and the bridged ring is optionally N-substituted with alkyl, haloalkyl, —SO 2 -alkyl, —SO 2 -haloalkyl; —CO 2 -alkyl, —C(O)NR 10 R 11 , —SO 2 NR 10 R 11 , or —SO 2 -cycloalkyl substituted with 1-5 halogens;
(f) heteroaryl optionally substituted with 1-2 Z 2 ; or
(g) alkyl optionally substituted with 1-2 G groups;
each G is independently —CF 3 , C 3-6 cycloalkyl, CN, NH 2 , N(H)alkyl, —N(H)C(O)-alkyl, or —N(C 1 -C 6 alkyl) 2 ;
J 1 is C 1 -C 6 alkyl optionally substituted with 1-4 J 3 , —C 1 -C 6 alkylene-C 1 -C 6 alkoxy, C 1 -C 6 cyanoalkyl, C 1 -C 6 hydroxyalkyl, C 0 -C 3 alkylene-C 3 -C 6 cycloalkyl optionally substituted with 1-4 J 3 , C 0 -C 3 alkylene-phenyl optionally substituted with 1-4 J 3 , —C 0 -C 3 alkylene-5-6 membered heteroaryl optionally substituted with 1-4 J 3 , —C 0 -C 3 alkylene-4-6 membered heterocycloalkyl optionally substituted with 1-4 J 3 ;
J 2 is H, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl;
each J 3 is independently halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, OH, C 1 -C 6 alkoxy optionally substituted with 1-3 halogens, CN, —C 0 -C 3 alkylene-4-6 membered heterocycloalkyl optionally substituted with C 1 -C 3 alkyl, —S(O) 2 —C 1 -C 6 alkyl, —NH 2 , —N(H)—C 1 -C 6 alkyl, or —N(C 1 -C 6 alkyl) 2 , provided that when J 3 is attached to nitrogen, J 3 cannot be halogen, OH, CN, NH 2 , —N(H)—C 1 -C 6 alkyl, or —N(C 1 -C 6 alkyl) 2 ;
each Z 1 is independently CN, halogen, alkyl, or haloalkyl;
each Z 2 is independently —OH, CN, halogen, alkyl, cycloalkyl optionally substituted with 1-3 halogens, hydroxyalkyl, haloalkyl, —NH 2 , —N(H)alkyl, —N(alkyl) 2 , alkoxyl optionally substituted with halo or phenyl, 5-6 membered heterocycloalkyl, or 5-6 membered heteroaryl, provided that when Z 2 is attached to nitrogen, Z 2 cannot be —OH, CN, halogen, alkoxyl, —NH 2 , —N(H)alkyl, or —N(alkyl) 2 ;
each Z 3 is independently CN, halogen, alkyl or haloalkyl;
Z 4 is alkoxyalkyl, phenyl optionally substituted with 1-3 halogens, —SO 2 -alkyl, —SO 2 -haloalkyl, —SO 2 -cycloalkyl optionally substituted with 1-6 halogens, —C(O)NR 10 R 11 , —SO 2 NR 10 R 11 , —N(H)SO 2 -alkyl, —N(H)SO 2 -cycloalkyl optionally substituted with 1-6 halogens, or —N(H)SO 2 -haloalkyl;
Z 5 is alkoxyalkyl, —SO 2 -alkyl, —CO 2 -alkyl, —C(O)J 1 , CO 2 J 2 , —C 0 -C 4 alkylene-phenyl optionally substituted with 1-4 J 3 , —C 0 -C 4 alkylene-CH(phenyl) 2 optionally substituted with 1-4 J 3 , —C 0 -C 4 alkylene-CH(C 3 -C 6 cycloalkyl) 2 optionally substituted with 1-4 J 3 , —SO 2 -haloalkyl, —SO 2 -cycloalkyl optionally substituted with 1-6 J 3 , —SO 2 -heterocycloalkyl optionally substituted with 1-6 J 3 , —SO 2 -heteroaryl optionally substituted with 1-6 J 3 , —SO 2 -aryl optionally substituted with 1-6 J 3 , —C(O)NR 10 R 11 , —SO 2 NR 10 R 11 , —N(H)SO 2 -alkyl optionally substituted with 1-6 J 3 , —N(H)SO 2 -aryl optionally substituted with 1-6 J 3 , —N(H)SO 2 -cycloalkyl optionally substituted with 1-6 J 3 , —N(H)SO 2 -heterocyloalkyl optionally substituted with 1-6 J 3 , —N(H)SO 2 -heteroaryl optionally substituted with 1-6 J 3 , —N(H)SO 2 -haloalkyl, optionally substituted with 1-6 J 3 , —C(O)—N(H)SO 2 -alkyl optionally substituted with 1-6 J 3 , —C(O)—N(H)SO 2 -ary

Assignees

• Plexxikon Inc

Inventors

• Zhang Jiazhong
• Powers Hannah
• Albers Aaron
• Pham Phuongly
• Wu Guoxian
• Buell John
• Spevak Wayne
• Guo Zuojun
• Walleshauser Jack
• Zhang Ying

Classifications

• A61P3/10

  for hyperglycaemia, e.g. antidiabetics · CPC title

• A61P43/00

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

• A61P37/06

  Immunosuppressants, e.g. drugs for graft rejection · CPC title

• A61P37/00

  Drugs for immunological or allergic disorders · CPC title

• A61P35/04

  specific for metastasis · CPC title