Compositions and methods for inhibition of the JAK pathway
The invention encompasses compounds having formula I-V and the compositions and methods using these compounds in the treatment of conditions in which modulation of the JAK pathway or inhibition of JAK kinases, particularly JAK3, may be therapeutically useful.
1. A compound of formula IV
or a pharmaceutically acceptable salt thereof, wherein:
ring A is aryl;
p is 0, 1, 2 or 3;
q is 0, 1, 2 or 3;
R and R 4 independently are hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, acyl, cycloalkyl or substituted cycloalkyl;
each R 2 independently is alkyl, substituted alkyl, alkoxy, substituted alkoxy, amino, substituted amino, aryl, substituted aryl, aryloxy, substituted aryloxy, cyano, cycloalkyl, substituted cycloalkyl, cycloalkoxy, substituted cycloalkoxy, heteroaryl, substituted heteroaryl, heteroaryloxy, substituted heteroaryloxy, heterocyclic, substituted heterocyclic, heterocyclyloxy, substituted heterocyclyloxy, aminoacyl, aminoacyloxy, carboxyl, carboxyl ester, carbonate ester nitro, and halo, or two of R 2 on the same carbon form an oxy (═O);
each R 3 independently is hydrogen, alkyl, substituted alkyl, alkoxy, substituted alkoxy, cycloalkyl or substituted cycloalkyl, halo, heterocyclic, substituted heterocyclic or sulfonylamine;
X is alkyl, substituted alkyl, alkoxy, substituted alkoxy, amino, substituted amino, carboxyl, carboxyl ester, cyano, halo, nitro, alkenyl, substituted alkenyl, alkynyl or substituted alkynyl;
W is C 1 -C 3 alkylene, substituted C 1 -C 3 alkylene, C 2 -C 3 alkenylene and substituted C 2 -C 3 alkenylene wherein one or more of the carbon atoms have been replaced with a moiety selected from oxygen, sulfur, S(O), S(O)2, C(O), or NR 8 where R 8 is selected from the group consisting of hydrogen and alkyl or is a bond participating in a —N═C<site of unsaturation; and
each Z 1 , Z 2 and Z 3 independently is carbon or nitrogen.
2. The compound according to claim 1 wherein ring A is phenyl.
3. The compound according to claim 1 wherein R 2 is alkyl, substituted alkyl, alkoxy, halo or heteroaryl.
4. The compound according to claim 1 wherein R 2 is —C 1 , —F, —CH 3 , pyrazolyl, —OCH 3 , —CH 2 OH, or —CF 3 .
5. The compound according to claim 2 wherein R 2 is in the 3 and/or the 4 position.
6. The compound according to claim 1 wherein R 3 is alkyl, alkoxy, halo, heterocycle, or sulfonylamine.
7. The compound according to claim 6 wherein R 3 is —CH 3 , —C 1 , —F, —OCH 3 piperizinyl.
8. The compound according to claim 1 wherein X is halo or alkyl.
9. The compound according to claim 8 wherein X is chloro, fluoro or methyl.
10. The compound according to claim 1 wherein Z 1 , Z 2 , and Z 3 are carbon.
11. The compound according to claim 1 wherein R 4 is hydrogen, alkyl, substituted alkyl or acyl.
12. The compound according to claim 1 wherein R and R 4 are hydrogen or alkyl.
13. The compound according to claim 1 wherein R and R 4 are hydrogen or methyl.
14. A pharmaceutical formulation, comprising:
a compound according to claim 1 ; and
at least one pharmaceutically acceptable excipient, diluent, preservative, stabilizer, or mixtures thereof.
15. A method, comprising contacting a JAK kinase with a compound according to claim 1 in an amount effective to inhibit an activity of the JAK kinase.
16. The method according to claim 15 comprising contacting the JAK kinase in vitro or in vivo.
17. The method according to claim 15 for inhibiting a signal wherein contacting the JAK kinase inhibits a transduction cascade.
18. The method of claim 15 in which the JAK kinase is contacted with the compound according to claim 1 in combination with, or adjunctively to, a second compound that inhibits a JAK kinase.
19. The method according to claim 15 for treating allograft transplant rejection in a transplant recipient, comprising contacting the JAK kinase in the transplant recipient with an amount of a compound according to claim 1 effective to treat the rejection.