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

Patent metadata

Field	Value
Publication number	US-11046649-B2
Application number	US-201916514382-A
Country	US
Kind code	B2
Filing date	Jul 17, 2019
Priority date	Jul 17, 2018
Publication date	Jun 29, 2021
Grant date	Jun 29, 2021

Abstract

The present invention relates to bicyclic compounds and compositions and methods which may be useful as inhibitors of IDO1, IDO2, and TDO for the treatment or prevention of diseases such as cancer.

First claim

What is claimed is:

1. A compound of structural Formula I

or a salt or tautomer thereof, wherein:
L 1a is L 1 -R 1 and L 1b is H;
either R 2a is R 2 and R 2b is H, or R 2a is H and R 2b is R 2 ;
L 1 is chosen from a bond, —O—, —N(R 5 )—, C(R 5a )(R 5b )—, and —S—;
L 2 is chosen from —C(O)NH—, —C(NR 4 )NH—, —NHC(O)—, —NHC(NR 4 )—, —N(R 4 )CH(R 6 )—, and —CH(R 6 )N(R 4 )—,
or L 2 is

or L 2 is chosen from

forming a bicyclic ring system with R 3 when R 3 is cyclic;
Y 1 , Y 2 , Y 3 , Z 1 , Z 2 , and Z 5 are independently chosen from CH, C(R 9 ), N, NH, N(R 9 ), O, and S;
Z 4 is chosen from C and N;
R 1 is H or is chosen from alkyl, aryl, cycloalkyl, heteroaryl, and heterocycloalkyl, any of which is optionally substituted with one or more R 7 groups;
R 2 is H or is chosen from alkyl, aryl, cycloalkyl, heteroaryl, and heterocycloalkyl, any of which is optionally substituted with one or more R 8 groups;
R 3 is H or is chosen from alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, (aryl)aryl, (aryl)heteroaryl, (heteroaryl)aryl, (heteroaryl)heteroaryl, (aryl)cycloalkyl, (heteroaryl)cycloalkyl, (cycloalkyl)aryl, and (heterocycloalkyl)aryl, any of which is optionally substituted with one or more R 9 groups;
R 4 is H or is chosen from alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, any one of which is optionally substituted with one or more R 10 groups;
or R 3 and R 4 , together with the intervening atoms, form a first heteroaryl ring, which is optionally fused with a second aryl or heteroaryl ring to form a bicyclic heteroaryl system, said first heteroaryl ring or bicyclic heteroaryl system is optionally substituted with one or more R 10 groups;
each R 5 , R 5a , and R 5b is independently H or is chosen from alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl;
R 6 is chosen from CF 3 , CF 2 CF 3 , and CF 2 CH 3 ;
each R 7 , R 8 , R 9 , and R 10 is independently chosen from halo, haloalkyl, hydroxy, alkyl, amino, hydroxyalkyl, alkoxy, alkoxyalkyl, cyano, cyanoalkyl, NHC(O)R 11 , NHS(O) 2 R 12 , NHC(O)NHR 12 , C(O)OR 12 , S(O) 2 NHR 12 , C 3-6 cycloalkyl optionally substituted with one or two R 11 , C 3-6 heterocycloalkyl optionally substituted with one or two R 11 , phenyl optionally substituted with one or two R 11 , and 5-6 membered heteroaryl optionally substituted with one or two R 11 ;
each R 11 is independently chosen from halo, haloalkyl, hydroxy, alkyl, amino, C 3-6 cycloalkyl, hydroxyalkyl, alkyl, alkoxy, and cyano; and
R 12 is chosen from H and alkyl.

2. The compound as recited in claim 1 , or a salt or tautomer thereof, wherein R 2a is R 2 and R 2b is H.

3. The compound as recited in claim 1 , or a salt or tautomer thereof, wherein R 2a is H and R 2b is R 2 .

4. The compound as recited in claim 1 , or a salt or tautomer thereof, wherein
L 1 is chosen from a bond, —O— and —N(R 5 )—;
L 2 is chosen from —C(O)NH— and NHC(O)—;
R 1 is aryl or heteroaryl, and is optionally substituted with one or more R 7 groups;
R 2 is H or is chosen from alkyl, cycloalkyl, and heterocycloalkyl, any of which is optionally substituted with one or more R 8 groups;
R 3 is H or is chosen from alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, (aryl)aryl, (aryl)heteroaryl, (heteroaryl)aryl, (heteroaryl)heteroaryl, (aryl)cycloalkyl, and (heteroaryl)cycloalkyl, any of which is optionally substituted with one or more R 9 groups;
R 4 is H or is chosen from alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, any one of which is optionally substituted with one or more R 10 groups;
or R 3 and R 4 , together with the intervening atoms, form a first heteroaryl ring, which is optionally fused with a second aryl or heteroaryl ring to form a bicyclic heteroaryl system, said first heteroaryl ring or bicyclic heteroaryl system is optionally substituted with one or more R 10 groups;
R 5 is H or is chosen from alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl; and
each R 7 , R 8 , R 9 , and R 10 is independently chosen from alkyl, C 3-6 cycloalkyl, halo, hydroxy, alkoxy, and cyano.

5. The compound as recited in claim 1 , having structural Formula II:

or a salt or tautomer thereof, wherein:
L 1 is chosen from a bond, —O—, —N(R 5 )—, C(R 5a )(R 5b )—, and —S—;
R 1 is H or is chosen from alkyl, aryl, cycloalkyl, heteroaryl, and heterocycloalkyl, any of which is optionally substituted with one or more R 7 groups;
R 2 is H or is chosen from alkyl, aryl, cycloalkyl, heteroaryl, and heterocycloalkyl, any of which is optionally substituted with one or more R 8 groups;
R 3 is H or is chosen from alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, (aryl)aryl, (aryl)heteroaryl, (heteroaryl)aryl, (heteroaryl)heteroaryl, (aryl)cycloalkyl, and (heteroaryl)cycloalkyl, any of which is optionally substituted with one or more R 9 groups;
each R 5 , R 5a , and R 5b is independently H or is chosen from alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl;
each R 7 , R 8 , and R 9 is independently chosen from halo, haloalkyl, hydroxy, alkyl, amino, C 3-6 cycloalkyl, hydroxyalkyl, alkoxy, alkoxyalkyl, cyano, cyanoalkyl, NHC(O)R 11 , NHS(O) 2 R 12 , NHC(O)NHR 12 , C(O)OR 12 , S(O) 2 NHR 12 , C 3-6 cycloalkyl optionally substituted with one or two R 11 , C 3-6 heterocycloalkyl optionally substituted with one or two R 11 , phenyl optionally substituted with one or two R 11 , and 5-6 membered heteroaryl optionally substituted with one or two R 11 ;
each R 11 is independently chosen from halo, haloalkyl, hydroxy, alkyl, amino, C 3-6 cycloalkyl, hydroxyalkyl, alkyl, alkoxy, and cyano; and
R 12 is chosen from H and alkyl.

6. The compound as recited in claim 5 , or a salt or tautomer thereof, wherein
L 1 is chosen from a bond, —O—, and —N(R 5 )—;
R 1 is aryl or heteroaryl, and is optionally substituted with one or more R 7 groups;
R 2 is H or is chosen from alkyl, cycloalkyl, and heterocycloalkyl, any one of which is optionally substituted with one or more R 8 groups;
R 3 is H or is chosen from alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, any one of which is optionally substituted with one or more R 9 groups;
R 5 is H or is chosen from alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl; and
each R 7 , R 7 , and R 9 is independently chosen from alkyl, C 3-6 cycloalkyl, halo, hydroxy, alkoxy, and cyano.

7. The compound as recited in claim 5 , or a salt or tautomer thereof, wherein
R 3 is chosen from cycloalkyl, (aryl)cycloalkyl, and (heteroaryl)cycloalkyl, any of which is optionally substituted with one or more R 9 groups;
each R 9 is independently chosen from halo, haloalkyl, hydroxy, alkyl, amino, C 3-6 cycloalkyl, hydroxyalkyl, alkoxy, alkoxyalkyl, cyano, cyanoalkyl, C(O)OR 12 ; and
R 12 is chosen from H and alkyl.

8. The compound as recited in claim 1 , having structural Formula III:

or a salt or tautomer thereof, wherein:
L 1 is chosen from a bond, —O—, —N(R 5 )—, C(R 5a )(R 5b )—, and —S—;
L 2 is chosen from —C(O)NH—, —C(NR 4 )NH—, —NHC(O)—, —NHC(NR 4 )—, —N(R 4 )CH(R 6 )—, and —CH(R 6 )N(R 4 )—;
R 1 is H or is chosen from alkyl, aryl, cycloalkyl, heteroaryl, and heterocy

Assignees

• Univ Texas

Inventors

• Lewis Richard T
• Hamilton Matthew
• Jones Philip
• Petrocchi Alessia
• Reyna Naphtali
• Mcafoos Timothy
• Cross Jason Bryant
• Soth Michael J

Classifications

• C07D215/233 Primary

  only one oxygen atom which is attached in position 4 · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• C07D401/12

  linked by a chain containing hetero atoms as chain links · CPC title

• A61K31/437

  the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline · CPC title

• C07D487/04

  Ortho-condensed systems · CPC title