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

Patent metadata

Field	Value
Publication number	US-10364237-B2
Application number	US-201715848241-A
Country	US
Kind code	B2
Filing date	Dec 20, 2017
Priority date	May 5, 2014
Publication date	Jul 30, 2019
Grant date	Jul 30, 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 method of promoting the activity of RORγ, comprising exposing a RORγ to an effective amount of a compound of Formula I or IV, or a pharmaceutically acceptable salt thereof, to promote the activity of said RORγ; wherein Formula I is represented by:

wherein:
A is phenylene or 5-6 membered heteroarylene;
R 1 represents independently for each occurrence halogen, C 1-6 alkyl, C 1-6 haloalkyl, or C 3-6 cycloalkyl;
R 2A is C 1-6 alkyl 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, and —N(R 4 )(R 5 );
R 2B is C 1-6 alkyl, C 1-3 haloalkyl, or fluoro;
R 3 represents independently for each occurrence C 1-6 haloalkyl, halogen, C 1-6 alkyl, C 1-6 alkoxy, or —O—(C 1-6 alkylene)-OH;
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 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:
—(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), 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 ; or
—(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;

Y is —O—;
m and p each represent independently for each occurrence 0, 1, or 2; and
n is 1, 2, or 3; and
Formula IV is represented by:

wherein:
A is phenylene or 5-6 membered heteroarylene;
R 1 represents independently for each occurrence halogen, C 1-6 alkyl, C 1-6 haloalkyl, or C 3-6 cycloalkyl;
R 2A is C 1-6 alkyl substituted with 1 or 2 substituents independently selected from the group consisting of —CO 2 R 4 , —C(O)N(R 4 )(R 5 ), —N(R 4 )C(O)R 8 , —CN, halogen, hydroxyl, C 1-6 alkoxy, C 1-6 haloalkoxy, and —N(R 4 )(R 5 ); or
R 2B is C 1-6 alkyl, C 1-3 haloalkyl, or fluoro;
R 3 represents independently for each occurrence C 1-6 haloalkyl, halogen, hydroxyl, C 1-6 alkyl, C 1-6 alkoxy, or —O—(C 1-6 hydroxyalkyl);
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 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, or —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 C 4-7 cycloalkenyl 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 —O—;
m and p each represent independently for each occurrence 0, 1, or 2; and
n is 1, 2, or 3.

2. The method of claim 1 , wherein the compound is a compound of Formula I or a pharmaceutically acceptable salt thereof.

3. The method of claim 1 , wherein the compound is a compound of Formula IV or a pharmaceutically acceptable salt thereof.

4. A method of promoting the activity of RORγ, comprising exposing a RORγ to an effective amount of a compound of Formula I-C to promote the activity of said RORγ; wherein Formula I-C is represented by:

or a pharmaceutically acceptable salt thereof; wherein:
A is phenylene or pyridinylene;
R 1 represents independently for each occurrence halogen, methyl, ethyl, or cyclopropyl;
R 2A is C 1-6 alkyl substituted with 1 or 2 substituents independently selected from the group consisting of —CO 2 R 4 , —C(O)N(R 4 )(R 5 ), —N(R 4 )C(O)R 8 , halogen, hydroxyl, C 1-6 alkoxy, C 1-6 haloalkoxy, and —N(R 4 )(R 5 );
R 2B is methyl or ethyl;
R 3 represents independently for each occurrence C 1-3 haloalkyl, halogen, C 1-3 alkyl, or —O—(C 1-6 hydroxyalkyl);
R 4 and R 5 each represent independently for each occurrence hydrogen or methyl; 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 8 represents independently for each occurrence C 1-6 alkyl, C 3-6 cycloalkyl, or —(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, hydroxyl, and —CO 2 R 4 ;
X is —(C 2-6 alkenylene)-phenyl 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, and C 1-6 haloalkoxy;
m and p are independently 0 or 1; and
n is 1 or 2.

5. The method of claim 4 , wherein A is phenylene.

6. The method of claim 5 , wherein R 2A is C 1-6 alkyl substituted with —CO 2 R 4 .

7. The method of claim 6 , wherein R 3 represents independently for each occurrence trifluoromethyl, m and p are 0, and n is 1.

8. The method of claim 4 , wherein X is —(C 2-4 alkenylene)-phenyl substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen and C 1-6 haloalkyl.

9. The method of claim 5 , wherein X is —(C 2-4 alkenylene)-phenyl substituted with 1 or 2 substituents independently selected from the group consisting of chloro, fluoro, and trifluoromethyl, and said substituents are located at the ortho positions of the phenyl group.

10. A method of promoting the activity of RORγ, comprising exposing a RORγ to an effective amount of a compound selected from the following or a pharmaceutically acceptable salt thereof, to promote the activity of said RORγ:

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