Methyl- and trifluoromethyl-substituted pyrrolopyridine modulators of RORC2 and methods of use thereof

Patent metadata

Field	Value
Publication number	US-9670201-B2
Application number	US-201514864840-A
Country	US
Kind code	B2
Filing date	Sep 24, 2015
Priority date	Sep 26, 2014
Publication date	Jun 6, 2017
Grant date	Jun 6, 2017

Abstract

The present invention provides methyl- and trifluoromethyl-substituted pyrrolopyridines, pharmaceutical compositions thereof, methods of modulating RORγ activity and/or reducing the amount of IL-17 in a subject, and methods of treating various medical disorders using such pyrrolopyridines and pharmaceutical compositions thereof.

First claim

We claim:

1. A compound of Formula I:

or a pharmaceutically acceptable salt, pharmaceutically active metabolite, pharmaceutically acceptable prodrug, or pharmaceutically acceptable solvate thereof, wherein,
Y is —CF 3 ;
X is phenyl optionally substituted with one, two, three, four or five substituents independently selected from the group consisting of —CH 3 , —CH 2 CH 3 , —CH 2 OH, —OH,
—OCH 3 , —SCH 3 , —OCH 2 CH 3 , —OCH 2 CH 3 , —OCH 2 CH 2 OH, —OCH 2 CH 2 OCH 3 , —F, —Cl, —Br and —CN;
R 1 is —CH 3 or —CH 2 CH 3 ;
W is

each optionally substituted with one, two, three, four or five —CH 3 ; and
R 2 is (C 1 -C 6 )alkyl, (C 3 -C 10 )cycloalkyl, phenyl, tetrahydrothiophenyl, thietanyl or indanyl, optionally substituted with one, two, three, four or five substituents independently selected for each occurrence from the group consisting of —F, —Cl, —Br, —OH, (C 1 -C 3 )alkyl, (C 1 -C 3 )haloalkyl and (C 3 -C 10 )cycloalkyl.

2. A compound of Formula I:

or a pharmaceutically acceptable salt, pharmaceutically active metabolite, pharmaceutically acceptable prodrug, or pharmaceutically acceptable solvate thereof, wherein,
Y is —CH 3 or —CF 3 ;
X is phenyl optionally substituted with one, two, three, four or five substituents independently selected from the group consisting of —CH 3 , —CH 2 CH 3 , —CH 2 OH, —OH,
—OCH 3 , —SCH 3 , —OCH 2 CH 3 , —OCH 2 CH 2 OH, —OCH 2 CH 2 OCH 3 , —F, —Cl, —Br and —CN;
R 1 is —CH 3 or —CH 2 CH 3 ;
W is

and
R 2 is (C 1 -C 5 )alkyl, (C 3 -C 10 )cycloalkyl, phenyl, tetrahydrothiophenyl, thietanyl or indanyl, optionally substituted with one, two, three, four or five substituents independently selected for each occurrence from the group consisting of —F, —Cl, —Br, —OH, (C 1 -C 3 )alkyl, (C 1 -C 3 )haloalkyl and (C 3 -C 10 )cycloalkyl.

3. A compound of Formula I:

or a pharmaceutically acceptable salt, pharmaceutically active metabolite, pharmaceutically acceptable prodrug, or pharmaceutically acceptable solvate thereof, wherein,
Y is —CH 3 or —CF 3 ;
X is phenyl optionally substituted with one, two, three, four or five substituents independently selected from the group consisting of —CH 3 , —CH 2 CH 3 , —CH 2 OH, —OH,
—OCH 3 , —SCH 3 , —OCH 2 CH 3 , —OCH 2 CH 2 OH, —OCH 2 CH 2 OCH 3 , —F, —Cl, —Br and —CN;
R 1 is —CH 3 or —CH 2 CH 3 ;
W is

and
R 2 is (C 1 -C 6 )alkyl, (C 3 -C 10 )cycloalkyl, phenyl, tetrahydrothiophenyl, thietanyl or indanyl, optionally substituted with one, two, three, four or five substituents independently selected for each occurrence from the group consisting of —F, —Cl, —Br, —OH, (C 1 -C 3 )alkyl, (C 1 -C 3 )haloalkyl and (C 3 -C 10 )cycloalkyl.

4. The compound of claim 1 , 2 , or 3 , wherein R 2 (C 1 -C 6 )alkyl optionally substituted with one, two, three, four or five substituents independently selected for each occurrence from the group consisting of —F, —Cl, —Br, —OH, (C 1 -C 3 )alkyl, (C 1 -C 3 )haloalkyl and (C 3 -C 10 )cycloalkyl.

5. The compound of claim 1 , 2 , or 3 , wherein R 2 is (C 1 -C 6 )alkyl.

6. The compound of claim 1 , 2 , or 3 , wherein R 2 is methyl substituted with (C 3 -C 5 )cycloalkyl.

7. The compound of claim 1 , 2 , or 3 , wherein R 2 is ethyl substituted with —CF 3 .

8. The compound of claim 1 , 2 , or 3 , wherein R 2 is ethyl substituted with —OH and —CF 3 .

9. A compound selected from the group consisting of

and pharmaceutically acceptable salts thereof.

10. The compound of claim 1 wherein the compound is

or a pharmaceutically acceptable salts thereof.

11. A compound having the structure:

or a pharmaceutically acceptable salt thereof.

12. The compound of claim 1 , wherein the compound is

or a pharmaceutically acceptable salt thereof.

13. A pharmaceutical composition comprising a compound according to claim 1 , 2 or 3 , or a pharmaceutically acceptable salt, pharmaceutically active metabolite, pharmaceutically acceptable prodrug, or pharmaceutically acceptable solvate thereof, admixed with a pharmaceutically acceptable carrier, excipient or dilutant.

14. A method of inhibiting RORC2 comprising of administering to a patient an effective amount of a pharmaceutical composition

Assignees

• Pfizer

Inventors

• Schnute Mark Edward
• Flick Andrew Christopher
• Jones Peter
• Kaila Neelu
• Mente Scot Richard
• Trzupek John David
• Vazquez Michael L
• Wennerstål Göran Mattias
• Xing Li
• Zamaratski Edouard
• Zhang Liying

Classifications

• A61P43/00

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

• A61P7/02

  Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors · CPC title

• A61P37/02

  Immunomodulators · CPC title

• A61P37/08

  Antiallergic agents (antiasthmatic agents A61P11/06; ophthalmic antiallergics A61P27/14) · CPC title

• A61P37/06

  Immunosuppressants, e.g. drugs for graft rejection · CPC title