Compounds useful as inhibitors of indoleamine 2,3-dioxygenase and/or tryptophan dioxygenase

Patent metadata

Field	Value
Publication number	US-11173145-B2
Application number	US-201816478076-A
Country	US
Kind code	B2
Filing date	Jan 16, 2018
Priority date	Jan 17, 2017
Publication date	Nov 16, 2021
Grant date	Nov 16, 2021

Abstract

Compounds of formula (VII), which are useful as inhibitors of indoleamine 2,3-dioxygenase and/or tryptophan dioxygenase, are provided. Also provided are pharmaceutical compositions, kits comprising said compounds, and methods and uses pertaining to said compounds.

First claim

The invention claimed is:

1. A compound of formula (VII),

or a pharmaceutically acceptable salt thereof, wherein one but not both of the dashed bonds may optionally be a carbon-carbon double bond, and wherein:
W is selected from C and CH;
a is selected from 0 and 1;
b is selected from 0, 1, and 2;
c is selected from 0 and 1;
d is selected from 0 and 1;
e is selected from 0 and 1;
f is selected from 0, 1, and 2;
A is selected from O, C(O), and S(O) 2 ;
J is in each case independently selected from oxo, OH, CN, halogen, and C 1-3 -alkyl;
X 1 is selected from C(R 8 )(R 9 ), N(R 10 ), O, and S;
X 2 is selected from C(R 11 )(R 12 ), N(R 13 ) and O;
Y is selected from
C 6-10 -aryl, and
5- to 10-membered heteroaryl comprising 1, 2, 3, or 4 ring heteroatoms selected from N, S, and O,
wherein said aryl and heteroaryl are optionally substituted by one or more groups independently selected from R 14 ;

R 1 is selected from
H,
(G) n -(C 1-6 -alkyl),
(G) n -(C 3-8 -cycloalkyl),
N 3 ,
(G) n -heterocycloalkyl, wherein said heterocycloalkyl is a 3- to 6-membered heterocycloalkyl comprising 1, 2, or 3 ring heteroatoms selected from N, S, and O,
(G) n -(C 5-8 -cycloalkenyl),
(G) n -heterocycloalkenyl, wherein said heterocycloalkenyl is a 5- to 6-membered heterocycloalkenyl comprising 1, 2, or 3 ring heteroatoms selected from N, S, and O,
(G) n -(C 6-10 -aryl), and
(G) n -heteroaryl, wherein said heteroaryl is a 5- to 10-membered heteroaryl comprising 1, 2, 3, or 4 ring heteroatoms selected from N, S, and O,
wherein G in each case is independently selected from C(R 8 )(R 9 ), C(O), S(O) 2 , C(O)NR 10 , and S(O) 2 NR 10 ; and wherein n in each case is selected from 0 and 1, and
wherein said alkyl, cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, aryl, and heteroaryl are optionally substituted by one or more groups independently selected from R 15 ;

R 2 , R 3 , R 4 , R 6 , R 7 , R 8 , R 9 , R 11 , and R 12 are in each case independently selected from
H,
halogen,
CN,
OH,
(C 0-4 -alkyl)-SO 2 R 17 ,
(C 0-4 -alkyl)-N(R 18 ) 2 ,
(C 0-4 -alkyl)-NHCOR 19 ,
(C 0-4 -alkyl)-NHSO 2 R 20 ,
(C 0-4 -alkyl)-CON(R 21 ) 2 ,
(C 0-4 -alkyl)-CO 2 R 22 ,
(C 0-4 -alkyl)-SO 2 N(R 23 ) 2 ,
C 1-6 -alkyl,
O—(C 1-6 -alkyl),
C 3-8 -cycloalkyl,
3- to 6-membered heterocycloalkyl comprising 1, 2, or 3 ring heteroatoms selected from N, S, and O,
C 5-8 -cycloalkenyl,
5- to 6-membered heterocycloalkenyl comprising 1, 2, or 3 ring heteroatoms selected from N, S, and O,
C 6-10 -aryl, and
5- to 10-membered heteroaryl comprising 1, 2, 3, or 4 ring heteroatoms selected from N, S, and O, or
one or both geminal R 3 and R 4 pairs, taken together with the carbon atom to which they are attached, independently forms a 3- to 6-membered cycloalkyl group or a 3- to 6-membered heterocycloalkyl group which comprises 1, 2, or 3 ring heteroatoms selected from N, S, and O,
wherein said alkyl, cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, aryl, and heteroaryl are optionally substituted by one or more groups independently selected from R 16 ;

R 5 , R 10 and R 13 are in each case independently selected from
H,
C 1-6 -alkyl,
C 3-8 -cycloalkyl,
3- to 6-membered heterocycloalkyl comprising 1, 2, or 3 ring heteroatoms selected from N, S, and O,
C 5-8 -cycloalkenyl,
5- to 6-membered heterocycloalkenyl comprising 1, 2, or 3 ring heteroatoms selected from N, S, and O,
C 6-10 -aryl, and
5- to 10-membered heteroaryl comprising 1, 2, 3, or 4 ring heteroatoms selected from N, S, and O,
optionally wherein one of R 3 and R 5 , together with one of R 11 and R 13 and the atoms intervening between them, may form a 5- or 6-membered cycloalkyl, cycloalkenyl or aryl group, or a 5- or 6-membered heterocycloalkyl, heterocycloalkenyl or heteroaryl group which comprises 1, 2, 3, or 4 ring heteroatoms selected from N, S, and O;
wherein said alkyl, cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, aryl, and heteroaryl are optionally substituted by one or more groups independently selected from R 24 ;

any two R 14 substituents on adjacent ring atoms may, together with the ring atoms to which they are attached, independently form a 5- or 6-membered cyclic group optionally comprising 1, 2, or 3 ring heteroatoms selected from N, S, and O, which cyclic group is optionally substituted by one or more groups independently selected from halogen, C 1-4 -alkyl, and C 1-4 -haloalkyl, and
any remaining R 14 is in each case independently selected from
halogen,
CN,
OH,
C 1-6 -alkyl,
O—(C 1-6 -alkyl),
O—(C 1-6 -haloalkyl),
O—(C 1-6 -alkyl-C 3-6 -cycloalkyl),
(C 0-4 -alkyl)-SO 2 R 17 ,
(C 0-4 -alkyl)-N(R 18 ) 2 ,
(C 0-4 -alkyl)-NHCOR 19 ,
(C 0-4 -alkyl)-NHSO 2 R 20 ,
(C 0-4 -alkyl)-CON(R 21 ) 2 ,
(C 0-4 -alkyl)-CO 2 R 22 ,
(C 0-4 -alkyl)-SO 2 N(R 23 ) 2 , and
(C 0-4 -alkyl)-heteroaryl,
wherein said heteroaryl is a 5- to 10-membered heteroaryl comprising 1, 2, 3, or 4 ring heteroatoms selected from N, S, and O;

R 15 is in each case independently selected from halogen,
CN,
OH,
oxo,
NO 2 ,
C 1-6 -alkyl,
C 2-6 -alkenyl,
C 2-6 -alkynyl,
(C 0-4 -alkyl)-O—(C 1-6 -alkyl),
(C 0-4 -alkyl)-SO 2 R 17 ,
(C 0-4 -alkyl)-N(R 18 ) 2 ,
(C 0-4 -alkyl)-NHCOR 19 ,
(C 0-4 -alkyl)-NHSO 2 R 20 ,
(C 0-4 -alkyl)-CON(R 21 ) 2 ,
(C 0-4 -alkyl)-CO 2 R 22 ,
(C 0-4 -alkyl)-SO 2 N(R 23 ) 2 ,
(C 0-4 -alkyl)-heteroaryl, wherein said heteroaryl is a 5- to 10-membered heteroaryl comprising 1, 2, 3, or 4 ring heteroatoms selected from N, S, and O,
(C 0-4 -alkyl)-heterocycloalkenyl, wherein said heterocycloalkenyl is a 5- to 10-membered heterocycloalkenyl comprising 1 or 2 ring heteroatoms selected from N and O,
(C 0-4 -alkyl)-heterocycloalkyl, wherein said heterocycloalkyl is a 4- to 6-membered heterocycloalkyl comprising 1 or 2 ring heteroatoms selected from N and O,
(C 0-4 -alkyl)-aryl, wherein said aryl is a 6- to 10-membered aryl,
(C 0-4 -alkyl)-cycloalkenyl, wherein said cycloalkenyl is a 5- to 8-membered cycloalkenyl, and
(C 0-4 -alkyl)-cycloalkyl, wherein said cycloalkyl is a 3- to 8-membered cycloalkyl,
wherein said alkyl, alkenyl, alkynyl, heteroaryl, heterocycloalkenyl, heterocycloalkyl, aryl, cycloalkenyl, and cycloalkyl are optionally substituted by one or more groups independently selected from halogen, OH, O—(C 1-4 -alkyl), oxo, C(O)—(C 1-4 -alkyl), C(O)O—(C 1-4 -alkyl), and NH 2 ;

R 16 and R 24 are in each case independently selected from
halogen,
CN,
OH,
C 1-6 -alkyl,
O—(C 1-6 -alkyl),
(C 0-4 -alkyl)-SO 2 R 17 ,
(C 0-4 -alkyl)-N(R 18 ) 2 ,
(C 0-4 -alkyl)-NHCOR 19 ,
(C 0-4 -alkyl)-NHSO 2 R 20 ,
(C 0-4 -alkyl)-CON(R 21 ) 2 ,
(C 0-4 -alkyl)-CO 2 R 22 ,
(C 0-4 -alkyl)-SO 2 N(R 23 ) 2 ,
(C 0-4 -alkyl)-heteroaryl, wherein said heteroaryl is a 5- to 10-membered heteroaryl comprising 1, 2, 3, or 4 ring heteroatoms selected from N, S, and O,
(C 0-4 -alkyl)-heterocycloalkenyl, wherein said heterocycloalkenyl is a 5- to 6-membered heterocycloalkenyl comprising 1 or 2 ring heteroatoms selected from N and O,
(C 0-4 -alkyl)-heterocycloalkyl, wherein said heterocycloalkyl is a 4- to 6-membered heterocycloalkyl comprising 1 or 2 ring heteroatoms selected from N and O,
(C 0-4 -alkyl)-aryl, wherein said aryl is a 6- to 10-membered aryl,
(C 0-4 -alkyl)-cycloalkenyl, wherein said cycloalkenyl is a 5- to 8-membered cycloalkenyl, and
(C 0-4 -alkyl)-cycloalkyl, wherein said cycloalkyl is a 3- to 8-membered cycloalkyl,
wherein said alkyl, heteroaryl, heterocycloalkenyl, heterocycloalkyl, aryl, cycloalkenyl, and cycloalkyl are optionally substituted by one or more groups independently selected from halogen; and

R 17 to R 23 are in each case independently selected from
H,
C 1-6 -alk

Assignees

• Univ Texas

Inventors

• Lewis Richard T
• Hamilton Matthew
• Jones Philip
• Petrocchi Alessia
• Reyna Naphtali
• Cross Jason
• Han Michelle
• Soth Michael
• Mcafoos Timothy
• Tremblay Martin

Classifications

• A61P1/04

  for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants · CPC title

• A61K31/502

  ortho- or peri-condensed with carbocyclic ring systems, e.g. cinnoline, phthalazine · CPC title

• A61P25/18

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

• C07D241/24

  Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals · CPC title

• A61P25/00

  Drugs for disorders of the nervous system · CPC title