Methyl- and trifluoromethyl-substituted pyrrolopyridine modulators of RORC2 and methods of use thereof
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.
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 of claim 13 .