Tricyclic inhibitors of JAK
The present invention relates to the use of novel compounds of Formulae I-II, wherein the variables R, X 1 , X 2 , X 3 , Y 1 , Y 2 , Y 3 , Z 1 , and Z 2 are defined as described herein, which inhibit JAK and are useful for the treatment of auto-immune and inflammatory diseases.
1. A compound of Formula I
wherein:
Z 1 is CH;
Z 2 is CH or N;
X 1 is CH or N;
X 2 is CH 2 , NS(═O) 2 R 1 , or NC(═O)R 1′ ;
R 1 is lower alkyl;
R 1′ is H, amino, or R 1″ ;
R 1″ is lower alkyl, optionally substituted with one or more R 1′″ ;
R 1′″ is halogen, lower alkoxy, cyano, or amino;
X 3 is CHR 2 or S(═O) 2 ;
R 2 is H or lower alkyl;
Y 1 is H, lower alkyl, lower alkoxy, halogen, or lower haloalkyl;
Y 2 is H or lower alkyl; and
Y 3 is H, lower alkyl, lower alkoxy, halogen, or lower haloalkyl;
or a pharmaceutically acceptable salt thereof.
2. The compound of claim 1 , wherein Z 1 is CH and Z 2 is CH.
3. The compound of claim 2 , wherein X 1 is CH.
4. The compound of claim 2 , wherein X 1 is N.
5. The compound of claim 3 , wherein X 3 is S(═O) 2 .
6. The compound of claim 3 , wherein X 3 is CH 2 .
7. The compound of claim 6 , wherein X 2 is NS(═O) 2 CH 2 CH 3 .
8. The compound of claim 7 , wherein Y 2 is H and Y 3 is H.
9. The compound of claim 8 , wherein Y 1 is methyl.
10. The compound of claim 1 , wherein Z 1 is CH and Z 2 is N.
11. The compound of claim 10 , wherein Y 2 is H and X 3 is CH 2 .
12. The compound of claim 11 , wherein X 2 is NS(═O) 2 CH 2 CH 3 .
13. The compound of claim 12 , wherein Y 1 is methyl.
14. The compound of claim 11 , wherein Y 1 is H and X 2 is CH 2 .
15. The compound of claim 14 , wherein Y 3 is methyl.
16. The compound of claim 1 selected from the group consisting of:
8-(1,1-Dioxo-1λ 6 -thiomorpholin-4-yl)-3H-3,4,8a-triaza-as-indacene;
8-Cyclohexyl-3H-3,4,8a-triaza-as-indacene;
8-(2-Methyl-piperidin-1-yl)-3H-3,4,8a-triaza-as-indacene;
8-((3S,4S)-1-Ethanesulfonyl-4-methyl-piperidin-3-yl)-3H-3,4,8a-triaza-as-indacene;
8-((3S,4R)-1-Ethanesulfonyl-4-methyl-piperidin-3-yl)-3H-3,4,8a-triaza-as-indacene;
1-((1R,2S)-2-Methyl-cyclohexyl)-6H-2,3,5,6,8b-pentaaza-as-indacene;
1-((3R,4R)-1-Ethanesulfonyl-4-methyl-piperidin-3-yl)-6H-2,3,5,6,8b-pentaaza-as-indacene;
1-Cyclobexyl-6H-2,3,5,6,8b-pentaaza-as-indacene;
3-[(3S,4S)-4-Methyl-3-(6H-2,3,5,6,8b-pentaaza-as-indacen-1-yl)-piperidin-1-yl]-3-oxo-propionitrile; and
1-Cyclohexyl-6H-2,5,6,8b-tetraaza-as-indacene.
17. A compound of Formula II
wherein:
Z 1 is CH;
Z 2 is CH or N;
R is cycloalkyl or heterocycloalkyl, optionally substituted with one more R 1 ; and
R 1 is lower alkyl, halogen, lower haloalkyl, lower alkoxy, lower alkylsulfonyl, or C(═O)R 2 ;
R 2 is H, amino, or R 3 ;
R 3 is lower alkyl, optionally substituted with one or more R 4 ; and
R 4 is halogen, lower alkoxy, cyano, or amino;
or a pharmaceutically acceptable salt thereof.
18. A pharmaceutical composition comprising the compound of claim 17 , admixed with at least one pharmaceutically acceptable carrier, excipient or diluent.
19. The pharmaceutical composition of claim 18 , further comprising an additional therapeutic agent selected from a chemotherapeutic or anti-proliferative agent, an anti-inflammatory agent, an immunomodulatory or immunosuppressive agent, a neurotrophic factor, an agent for treating cardiovascular disease, an agent for treating diabetes, and an agent for treating immunodeficiency disorders.