Compositions and methods for inhibition of the JAK pathway

1. A method of inhibiting a signal transduction cascade in which JAK3 kinase plays a role, comprising contacting a cell expressing a receptor involved in such a signaling cascade with a compound having formula II, or a pharmaceutically acceptable salt thereof, in an amount effective to inhibit the signal transduction cascade

wherein:

X is fluoro or methyl;

R is selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl and substituted cycloalkyl;

ring A is phenyl;

Y is selected from the group consisting of a bond, —NR 7 —, —C(O)NR 7 —, —NR 7 C(O), —NR 7 C(O)O—, —OC(O)NR 7 —, —NR 7 C(O)NR 7 —, oxygen and sulfur, where R 7 is independently hydrogen, alkyl or substituted alkyl;

alk is methylene, ethylene, or n-propylene;

R 1 is selected from the group consisting of cyano, acylamino, aminoacyl, aryl, substituted aryl, carboxyl, carboxyl ester, carboxyl ester oxy, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic, acyl, aminoacyloxy, and aminocarbonylamino; or

R 1 -alk-Y— is R 10 —C(O)—S-alk-C(O)—, wherein alk is as defined herein and R 10 is alkyl or substituted alkyl; or

R 1 -alk-Y— is R 11 R 12 NS(O) 2 —, wherein R 11 and R 12 independently are alkyl or substituted alkyl;

p is 0, 1, 2 or 3;

each R 2 independently is selected from the group consisting of alkyl, substituted alkyl, alkoxy, substituted alkoxy, amino, substituted amino, aryloxy, substituted aryloxy, cycloalkyl, substituted cycloalkyl, cycloalkoxy, substituted cycloalkoxy, heteroaryloxy, substituted heteroaryloxy, heterocyclyloxy, substituted heterocyclyloxy, nitro, and halo;

Z 1 , Z 2 , and Z 3 are carbon;

q is 1, 2 or 3;

each R 3 independently is selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkoxy, substituted alkoxy, cycloalkyl or substituted cycloalkyl, halo, heterocyclic and substituted heterocyclic;

R 4 is selected from the group consisting of hydrogen, alkyl, substituted alkyl, acyl and M + , wherein M + is a metal counterion selected from the group consisting of K + , Na + , Li + , or + N(R 6 ) 4 , wherein R 6 is hydrogen or alkyl, and the nitrogen of SO 2 NR 4 W is N − , a divalent counterion selected from the group consisting of Ca 2+ , Mg 2 +, and Ba 2+ , and the nitrogen of SO 2 NR 4 W is N − ; and

W is selected from the group consisting of 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.

2. A pharmaceutical formulation, comprising:

a compound having formula II, or a pharmaceutically acceptable salt thereof,

wherein:

X is fluoro or methyl;

R is selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl and substituted cycloalkyl;

ring A is phenyl;

Y is selected from the group consisting of a bond, —NR 7 —, —C(O)NR 7 —, —NR 7 C(O), —NR 7 C(O)O—, —OC(O)NR 7 —, —NR 7 C(O)NR 7 —, oxygen and sulfur, where R 7 is independently hydrogen, alkyl or substituted alkyl;

alk is methylene, ethylene or n-propylene;

R 1 is selected from the group consisting of cyano, acylamino, aminoacyl, aryl, substituted aryl, carboxyl, carboxyl ester, carboxyl ester oxy, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic, acyl, aminoacyloxy, and aminocarbonylamino; or

R 1 -alk-Y— is R 10 —C(O)—S-alk-C(O)—, wherein alk is as defined herein and R 10 is alkyl or substituted alkyl; or

R 1 -alk-Y— is R 11 R 12 NS(O) 2 —, wherein R 11 and R 12 independently are alkyl or substituted alkyl;

p is 0, 1, 2 or 3;

each R 2 independently is selected from the group consisting of alkyl, substituted alkyl, alkoxy, substituted alkoxy, amino, substituted amino, aryloxy, substituted aryloxy, cycloalkyl, substituted cycloalkyl, cycloalkoxy, substituted cycloalkoxy, heteroaryloxy, substituted heteroaryloxy, heterocyclyloxy, substituted heterocyclyloxy, nitro, and halo;

Z 1 , Z 2 , and Z 3 are carbon;

q is 1, 2 or 3;

each R 3 independently is selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkoxy, substituted alkoxy, cycloalkyl or substituted cycloalkyl, halo, heterocyclic and substituted heterocyclic;

R 4 is selected from the group consisting of hydrogen, alkyl, substituted alkyl, acyl and M + , wherein M + is a metal counterion selected from the group consisting of K + , Na + , Li + , or + N(R 6 ) 4 , wherein R 6 is hydrogen or alkyl, and the nitrogen of SO 2 NR 4 W is N − , a divalent counterion selected from the group consisting of Ca 2+ , Mg 2 +, and Ba 2+ , and the nitrogen of SO 2 NR 4 W is N 31 ; and

W is selected from the group consisting of 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

at least one pharmaceutically acceptable excipient, diluent, preservative, or stabilizer, or mixtures thereof.

3. The method of claim 1 in which the compound is administered in combination with, or adjunctively to, a second compound that inhibits JAK3 kinase.

4. The method of claim 1 wherein the compound has a formula IIA:

5. The method of claim 4 , wherein R 4 is selected from the group consisting of hydrogen, alkyl, substituted alkyl and acyl.

6. The pharmaceutical formulation of claim 2 wherein the compound has a formula IIA

7. The pharmaceutical formulation of claim 6 , wherein R 4 is selected from the group consisting of hydrogen, alkyl, substituted alkyl and acyl.