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

Patent metadata

Field	Value
Publication number	US-10189777-B2
Application number	US-201515308734-A
Country	US
Kind code	B2
Filing date	May 5, 2015
Priority date	May 5, 2014
Publication date	Jan 29, 2019
Grant date	Jan 29, 2019

Abstract

The invention provides benzenesulfonamido and related compounds, pharmaceutical compositions, methods of promoting RORγ activity, increasing the amount of IL-17 in a subject, and treating cancer using such benzenesulfonamido and related 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 2 is C 1-6 alkyl optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen, hydroxyl, and C 1-6 alkoxy;
R 3 is C 1-6 haloalkyl;
R 4 represents independently for each occurrence hydrogen, C 1-6 alkyl, or C 3-6 cycloalkyl;
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, hydroxyl, and cyano;
(ii) —(C 2-6 alkenylene)-phenyl, —(C 2-6 alkenylene)-heteroaryl, —(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), -(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, hydroxyl, and cyano; or
(iii) —(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, hydroxyl, and cyano;
m is 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 2 is C 1-6 alkyl optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen, hydroxyl, and C 1-6 alkoxy;
R 3 is C 1-6 haloalkyl;
R 4 represents independently for each occurrence hydrogen, C 1-6 alkyl, or C 3-6 cycloalkyl;
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), —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, and C 1-6 haloalkoxy;
(ii) —(C 2-6 alkenylene)-phenyl, —(C 2-6 alkenylene)-heteroaryl, —(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), or -(5-6 membered heterocycloalkylene)-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, and C 1-6 haloalkoxy; or
(iii) —(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), or —N(R 4 )—(C 1-6 alkylene)—(C3- 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, and C 1-6 haloalkoxy;
m is 0, 1, or 2; and
n is 1, 2, or 3.

3. The compound of claim 2 , wherein A is phenylene.

4. The compound of claim 2 , wherein A is a 5-6 membered heteroarylene.

5. The compound of claim 3 , wherein n is 1.

6. The compound of claim 5 , wherein R 3 is trifluoromethyl.

7. The compound of claim 5 , wherein R 2 is C 1-6 alkyl.

8. The compound of claim 5 , wherein R 2 is ethyl or propyl.

9. The compound of claim 2 , wherein Xis —O-aralkyl, —O-heteroaralkyl, —O-phenyl, —O-heteroaryl, —O-(partially unsaturated bicyclic carbocyclyl), —O—(C 1-6 alkylene)—(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, and C 1-6 haloalkoxy.

10. The compound of claim 3 , wherein X is —O-aralkyl or —O-(partially unsaturated bicyclic carbocyclyl), each of which is optionally substituted with 1 or 2 substituents independently selected from the group consisting of halogen and C 1-6 haloalkyl.

11. The compound of claim 8 , wherein X is —O-benzyl substituted with 1 or 2 substituents independently selected from the group consisting of chloro, bromo, and fluoro.

12. The compound of claim 8 , wherein X is —O—(C 1-6 alkylene)-phenyl or —N(R 4 )—(C 1-6 alkylene)-phenyl, each of which is 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, where at least one substituent is present at the ortho position on the phenyl group in variable X.

13. The compound of claim 2 , wherein X is —(C 1-6 alkylene)-heteroaryl, —(C 1-6 alkylene)-(partially unsaturated bicyclic heterocyclyl), —(C 1-6 alkylene)-(partially unsaturated bicyclic oxo-heterocyclyl), or -(5-6 membered heterocycloalkylene)-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, and C 1-6 haloalkoxy.

14. The compound of claim 3 , wherein X is —(C 1-6 alkylene)-Z 1 , wherein Z 1 is —O-aralkyl, —N(R 4 )-aralkyl, or —N(R 4 )-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, and C 1-6 alkyl.

15. The compo

Assignees

• Lycera Corp

Inventors

• Aicher Thomas D
• Skalitzky Donald J
• Taylor Clarke B
• Van Huis Chad A

Classifications

• A61P43/00

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

• A61P37/04

  Immunostimulants · CPC title

• A61P31/04

  Antibacterial agents · CPC title

• A61P5/00

  Drugs for disorders of the endocrine system · CPC title

• A61P35/00

  Antineoplastic agents · CPC title