Compositions and methods for inhibition of the JAK pathway
The invention encompasses compounds having formula I 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, are therapeutically useful.
1. A compound having a formula
or a pharmaceutically acceptable salt thereof, wherein:
p is 0, 1, 2 or 3;
q is 0, 1, 2 or 3;
X is selected from the group consisting of hydrogen, alkyl, substituted alkyl, hydroxy, alkoxy, substituted alkoxy, amino, substituted amino, carboxyl, carboxyl ester, cyano, halo, nitro, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkynyl, and substituted cycloalkynyl;
Y is alk-SO 2 N(R 4 )R 5 or alk-N(R 4 )SO 2 R 5 ;
alk is selected from the group consisting of straight or branched chain C 1-6 alkylene group, cycloalkylene and substituted cycloalkylene;
each R 2 independently is selected from the group consisting of alkyl, substituted alkyl, alkoxy, substituted alkoxy, alkynyl, substituted alkynyl, cycloalkynyl, substituted cycloalkynyl, alkynyloxy, 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 R 4 and one of R 2 together with the intervening atoms bound thereto form a heterocyclic or a substituted heterocyclic fused to the phenyl ring;
or R 5 and one of R 2 together with the intervening atoms bound thereto form a heterocyclic or a substituted heterocyclic fused to the phenyl ring;
each R 3 independently is selected from the group consisting of alkyl, substituted alkyl, alkoxy, substituted alkoxy, alkynyl, substituted alkynyl, cycloalkynyl, substituted cycloalkynyl, alkynyloxy, 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, halo, and aminosulfonyl;
R 4 is selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, heterocyclic, substituted heterocyclic, aryl, substituted aryl, heteroaryl, substituted heteroaryl, acyl and M + , wherein M + is a counterion selected from the group consisting of K + , Na + , Li + and + N(R 8 ) 4 , wherein R 8 is hydrogen or alkyl, and the nitrogen of —SO 2 N(R 4 )R 5 or —N(R 4 )SO 2 R 5 is N − ; and
R 5 is selected from the group consisting of hydrogen, alkyl, substituted alkyl, amine, cycloalkyl, substituted cycloalkyl, heterocyclic, substituted heterocyclic, aryl, substituted aryl, heteroaryl, substituted heteroaryl, and acyl; or
R 4 and R 5 together with the intervening atom or atoms bound thereto form a heterocyclic or a substituted heterocyclic group.
2. The compound of claim 1 wherein the compound has a formula
3. The compound of claim 2 , wherein alk is C 1-2 alkyl.
4. The compound of claim 3 , wherein X is halo, alkyl or haloalkyl.
5. The compound of claim 4 , wherein p is 0, 1, or 2 and R 2 is halo.
6. The compound of claim 5 , wherein q is 0, 1, or 2 and R 3 is alkyl.
7. The compound of claim 6 , wherein each of R 4 and R 5 independently is selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkynyl, substituted alkynyl, acyl, and carboxyl ester; or R 4 and R 5 together with the nitrogen atom bound thereto optionally form —N═C(OR 9 ) 2 wherein each R 9 is independently an alkyl group.
8. The compound of claim 7 , wherein each of R 4 and R 5 is independently selected from the group consisting of hydrogen and acyl.
9. The compound of claim 2 , wherein the compound has a formula
10. The compound of claim 1 wherein the compound has a formula
11. The compound of claim 10 , wherein X is halo.
12. The compound of claim 11 , wherein X is fluoro.
13. The compound of claim 12 , wherein p is 0 and q is 0 or 1.
14. The compound of claim 12 , wherein q is 1 or 2 and R 3 is alkyl.
15. The compound of claim 12 , wherein alk is —CH 2 — and each of R 4 and R 5 independently is selected from the group consisting of hydrogen, alkyl, alkynyl, cycloalkyl and heterocyclic.
16. A method of inhibiting an activity of a JAK kinase, comprising contacting the JAK kinase with an amount of a compound according to claim 1 effective to inhibit an activity of the JAK kinase.
17. The method according to claim 16 comprising contacting in vitro a JAK3 kinase with an amount of a compound according to claim 1 effective to inhibit an activity of the JAK3 kinase.
18. A method of treating or preventing rheumatoid arthritis, comprising administering to a subject an effective amount of a compound according to claim 1 .
19. The method of claim 18 in which the compound is administered in combination with, or adjunctively to, a compound that inhibits Syk kinase with an IC 50 in the range of at least 10 μM.