Tetrahydroquinoline sulfonamide and related compounds for use as agonists of RORγ and the treatment of disease

Patent metadata

Field	Value
Publication number	US-10442798-B2
Application number	US-201815890648-A
Country	US
Kind code	B2
Filing date	Feb 7, 2018
Priority date	May 5, 2014
Publication date	Oct 15, 2019
Grant date	Oct 15, 2019

Abstract

The invention provides tetrahydroquinoline sulfonamide compounds, tetrahydronaphthalene sulfonyl compounds, and related compounds, pharmaceutical compositions, methods of promoting RORy activity, methods of increasing the amount of IL-17 in a subject, and methods of treating cancer and other medical disorders using such compounds.

First claim

What is claimed is:

1. A compound represented by Formula I:

or a pharmaceutically acceptable salt thereof; wherein:
A is phenylene, 5-6 membered heteroarylene, or C 3-6 heterocycloalkylene;
R 1 represents independently for each occurrence halogen, C 1-6 alkyl, C 1-6 haloalkyl, or C 3-6 cycloalkyl;
R 2A is one of the following:
(i) C 1-6 alkyl, C 1-3 haloalkyl, C 3-6 cycloalkyl, —(C 1-6 alkylene)-(C 3-6 cycloalkyl), —O—(C 1-6 alkylene)-CO 2 R 4 , —O—(C 1-6 alkylene)-C(O)—(C 1-6 alkyl), —N(R 4 )—(C 1-6 alkylene)-CO 2 R 4 , or —N(R 4 )—(C 1-6 alkylene)-C(O)—(C 1-6 alkyl), wherein the C 1-6 alkyl, C 3-6 cycloalkyl, and C 1-6 alkylene are optionally substituted with 1 or 2 substituents independently selected from the group consisting of —CO 2 R 4 , —C(O)N(R 4 )(R 5 ), —C(O)—N(R 4 )—(C 1-4 alkylene)-CO 2 R 4 , —N(R 4 )C(O)R 8 , —CN, halogen, hydroxyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 haloalkyl, —N(R 4 )(R 5 ), —N(R 4 )C(O)N(R 4 )(R 5 ), —N(R 4 )CO 2 R 9 , —N(R 4 )S(O) 2 R 9 , and —N(R 4 ) S(O) 2 N(R 4 )(R 5 ); or
(ii) —CO 2 R 4 , —N(R 4 )C(O)R 9 , —N(R 4 )CO 2 R 9 , —N(R 4 )C(O)N(R 4 )(R 5 ), —N(R 4 )C(O)N(R 4 )(heteroaryl), —N(R 4 )S(O) 2 R 9 , —N(R 4 )(R 5 ), or —OH;
R 2B is C 1-6 alkyl, C 1-3 haloalkyl, or fluoro;
R 3 represents independently for each occurrence hydrogen, C 1-6 haloalkyl, halogen, hydroxyl, C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, —N(R 4 )(R 8 ), —O—(C 1-6 hydroxyalkyl), or —O—(C 1-6 alkylene)-CO 2 R 4 ; or two vicinal occurrences of R 3 are taken together with intervening atoms to form a 4-6 membered ring;
R 4 and R 5 each represent independently for each occurrence hydrogen, C 1-6 alkyl, or C 3-6 cycloalkyl; or an occurrence of R 4 and R 5 attached to the same nitrogen atom are taken together with the nitrogen atom to which they are attached to form a 3-8 membered heterocyclic ring;
R 6 and R 7 each represent independently for each occurrence hydrogen, fluoro, or C 1-6 alkyl, or R 6 and R 7 are taken together with the carbon atom to which they are attached to form a 3-6 membered carbocyclic ring; or R 6 and a vicinal occurrence of R 2B are taken together to form a bond;
R 8 represents independently for each occurrence C 1-6 alkyl, C 3-6 cycloalkyl, —(C 1-6 alkylene)-(C 3-6 cycloalkyl), or aryl, each of which is optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen, hydroxyl, and —CO 2 R 4 ; or R 8 is —CO 2 R 4 ;
R 9 represents independently for each occurrence C 1-6 alkyl, C 3-6 cycloalkyl, —(C 1-6 alkylene)-(C 3-6 cycloalkyl), C 1-6 haloalkyl, or C 1-6 hydroxyalkyl;
X is one of the following:
(i) —O-aralkyl, —O-heteroaralkyl, —O-phenyl, —O-heteroaryl, —O-(partially unsaturated bicyclic carbocyclyl), —O—(C 1-6 alkylene)-(C 3-6 cycloalkyl), —O—(C 3-6 cycloalkyl), —N(R 4 )-aralkyl, —N(R 4 )-phenyl, —N(R 4 )-(partially unsaturated bicyclic carbocyclyl), or —N(R 4 )—(C 1-6 alkylene)-(C 3-6 cycloalkyl), each of which is optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen, C 1-6 haloalkyl, C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, —S—(C 1-6 alkyl), hydroxyl, cyano, —C(O)R 9 , and —SO 2 R 9 ;
(ii) —S-aralkyl, —S-heteroaralkyl, —S-phenyl, —S-heteroaryl, —S-(partially unsaturated bicyclic carbocyclyl), —S—(C 1-6 alkylene)-(C 3-6 cycloalkyl), or —S—(C 3-6 cycloalkyl), each of which is optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen, C 1-6 haloalkyl, C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, —S—(C 1-6 alkyl), hydroxyl, cyano, —C(O)R 9 , and —SO 2 R 9 ;
(iii) —(C 2-6 alkenylene)-phenyl, —(C 2-6 alkenylene)-heteroaryl, —(C 2-6 alkenylene)-(partially unsaturated 8-10 membered bicyclic ring containing 0-3 heteroatoms), —(C 1-6 alkylene)-phenyl, —(C 1-6 alkylene)-heteroaryl, —(C 1-6 alkylene)-(partially unsaturated bicyclic heterocyclyl), —(C 1-6 alkylene)-(partially unsaturated bicyclic oxo-heterocyclyl), —(C 1-6 alkylene)-(C 3 -C 6 cycloalkyl), -(5-6 membered heterocycloalkylene)-phenyl, or —(C 3-6 cycloalkylene)-phenyl, each of which is optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen, C 1-6 haloalkyl, C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, —S—(C 1-6 alkyl), hydroxyl, cyano, —C(O)R 9 , and —SO 2 R 9 ;
(iv) —(C 2-6 alkenylene)-(C 1-6 alkyl), —(C 2-6 alkenylene)-(C 3-6 cycloalkyl), or

each of which is optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen, C 1-6 haloalkyl, C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, —S—(C 1-6 alkyl), hydroxyl, cyano, —C(O)R 9 , and —SO 2 R 9 , wherein A* is a 5-8 membered, partially saturated carbocyclic or heterocyclic ring; or
(v) —(C 1-6 alkylene)-Z 1 or —(C 2-6 alkenylene)-Z 1 , wherein Z 1 is —O-aralkyl, —O— heteroaralkyl, —O-phenyl, —O-heteroaryl, —O-(partially unsaturated bicyclic carbocyclyl), —O—(C 1-6 alkylene)-(C 3-6 cycloalkyl), —O—(C 3-6 cycloalkyl), —N(R 4 )-aralkyl, —N(R 4 )-phenyl, —N(R 4 )-(partially unsaturated bicyclic carbocyclyl), —N(R 4 )—(C 1-6 alkylene)-(C 3-6 cycloalkyl), or —N(R 4 )—(C 3-6 cycloalkyl), each of which is optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen, C 1-6 haloalkyl, C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, —S—(C 1-6 alkyl), hydroxyl, cyano, —C(O)R 9 , and —SO 2 R 9 ;
Y is —C(R 6 )(R 7 )—, —C(O)—, or —S(O) p —;
m and p each represent independently for each occurrence 0, 1, or 2; and
n is 1, 2, or 3.

2. The compound of claim 1 , wherein the compound is represented by Formula I-A:

or a pharmaceutically acceptable salt thereof; wherein:
A is phenylene or a 5-6 membered heteroarylene;
R 1 represents independently for each occurrence halogen, C 1-6 alkyl, or C 3-6 cycloalkyl;
R 2A is C 1-6 alkyl or C 3-6 cycloalkyl, wherein the C 1-6 alkyl or C 3-6 cycloalkyl are optionally substituted with 1 or 2 substituents independently selected from the group consisting of —CO 2 R 4 , —N(R 4 )C(O)(C 1-6 alkyl), —CN, halogen, hydroxyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 haloalkyl, and —N(R 4 )(R 5 ); or R 2A is —CO 2 R 4 or —N(R 4 )C(O)(C 1-6 alkyl);
R 2B is C 1-6 alkyl or C 1-3 haloalkyl;
R 3 represents independently for each occurrence hydrogen, C 1-6 haloalkyl, halogen, hydroxyl, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, or —O—(C 1-6 alkylene)-OH; or two vicinal occurrences of R 3 are taken together with intervening atoms to form a 4-6 membered ring;
R 4 and R 5 each represent independently for each occurrence hydrogen, C 1-6 alkyl, or C 3-6 cycloalkyl; or an occurrence of R 4 and R 5 attached to the same nitrogen atom are taken together with the nitrogen atom to which they are attached to form a 3-7 membered heterocyclic ring;
R 6 and R 7 each represent independently for each occurrence hydrogen or C 1-6 alkyl, or R 6 and R 7 are taken together with the carbon atom to which they are attached to form a 3-6 membered carbocyclic ring;
X is one of the following:
(i) —O-aralkyl, —O-heteroaralkyl, —O-phenyl, —O-heteroaryl,

Assignees

• Lycera Corp

Inventors

• Aicher Thomas D
• Taylor Clarke B
• Vanhuis Chad A

Classifications

• A61P43/00

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

• A61P37/02

  Immunomodulators · CPC title

• A61P37/00

  Drugs for immunological or allergic disorders · CPC title

• A61P35/02

  specific for leukemia · CPC title

• A61P35/00

  Antineoplastic agents · CPC title