Compositions and methods for inhibition of the JAK pathway

1. A compound of formula I:

or pharmaceutically acceptable salt thereof, wherein:

ring A is heteroaryl;

p is 0, 1, 2 or 3 when ring A is monocyclic or p is 0, 1, 2, 3, 4, or 5 when ring A is bi- or tricyclic;

q is 0, 1, 2 or 3;

X is selected from the group consisting of alkyl, substituted alkyl, hydroxy, alkoxy, substituted alkoxy, amino, substituted amino, carboxyl, carboxyl ester, cyano, halo, nitro, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkynyl, substituted cycloalkynyl;

Y is selected from the group consisting of hydrogen, alk 1 -SO 2 N(R 4 )R 5 and alk 1 -N(R 4 )SO 2 R 5 ;

W is selected from the group consisting of alk 2 -SO 2 N(R 6 )R 7 and alk 2 -N(R 6 )SO 2 R 7 ;

alk 1 and alk 2 are each independently a bond, straight or branched chain C 1-6 alkylene group, cycloalkylene or substituted cycloalkylene wherein:

if W is alk 2 -SO 2 N(R 6 )R 7 and alk 2 is a bond, then Y is alk 1 -N(R 4 )SO 2 R 5 and alk 1 is a bond;

R 1 is selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl and substituted cycloalkyl;

each R 2 independently is selected from the group consisting of alkyl, substituted alkyl, alkoxy, substituted alkoxy, alkynyl, 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 oxo;

wherein if R 2 is oxo, then the oxo substituent is attached to a nonaromatic portion of ring A; or

R 4 and one of R 2 together with the intervening atoms bound thereto form a heterocyclic or a substituted heterocyclic fused to ring A; or

R 5 and one of R 2 together with the intervening atoms bound thereto form a heterocyclic or a substituted heterocyclic fused to ring A;

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

each R 3 independently is selected from the group consisting of alkyl, substituted alkyl, alkoxy, substituted alkoxy, alkynyl, 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; or

R 6 and one of R 3 , together with the intervening atoms bound thereto, form a heterocyclic or a substituted heterocyclic fused to the ring containing Z 1 , Z 2 and Z 3 ; or

R 7 and one of R 3 , together with the intervening atoms bound thereto, form a heterocyclic or a substituted heterocyclic fused to the ring containing Z 1 , Z 2 and Z 3 ; or

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 − ; or

R 4 and R 5 together with the intervening atom or atoms bound thereto form a heterocyclic or substituted heterocyclic group; or

R 5 is selected from the group consisting of hydrogen, alkyl, substituted alkyl, amino, 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;

R 6 is selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, heterocyclic, substituted heterocyclic, carboxyl, carboxyl ester, aryl, substituted aryl, heteroaryl, substituted heteroaryl, acyl and M + , wherein M + is a counterion selected from the group consisting of K + , Na + , Li + or + N(R 8 ) 4 , wherein R 8 is hydrogen or alkyl, and the nitrogen of —SO 2 N(R 6 )R 7 or —N(R 6 )SO 2 R 7 is N − ; or

R 6 and R 7 together with the intervening atom or atoms bound thereto, form a heterocyclic or a substituted heterocyclic group; or

if W is alk 2 -SO 2 N(R 6 )R 7 , then R 6 and R 7 together with the nitrogen atom bound thereto optionally form —N═C(OR 9 ) 2 wherein each R 9 independently is an alkyl group; and

R 7 is selected from the group consisting of hydrogen, alkyl, substituted alkyl, amino, cycloalkyl, substituted cycloalkyl, heterocyclic, substituted heterocyclic, aryl, substituted aryl, heteroaryl, substituted heteroaryl, carboxyl, carboxyl ester, and acyl;

provided that when X is hydrogen, ring A is not benzimidazolyl or indazolyl.

2. The compound of claim 1 , wherein the compound is represented by formula II:

3. The compound of claim 2 wherein the compound is represented by formula III

4. The compound of claim 3 , wherein X is fluoro, alk 2 is —CH 2 — and each of R 6 and R 7 independently is hydrogen or alkyl.

5. The compound of claim 4 , wherein ring A is a bicyclic heteroaryl.

6. The compound of claim 5 , wherein:

wherein R is hydrogen or methyl.

7. The compound of claim 5 , wherein each R 2 independently is selected from the group consisting of alkyl, substituted alkyl, aminoacyl, alkynyl, and oxo; wherein if R 2 is oxo, then the oxo substituent is attached to a nonaromatic portion of ring A.

8. The compound of claim 4 , wherein Y is -alk 1 -N(R 4 )SO 2 R 5 .

9. The compound of claim 8 , wherein alk 1 is —CH 2 — and each of R 4 and R 5 independently is hydrogen or alkyl.

10. The compound of claim 4 , wherein Y is -alk 1 -SO 2 N(R 4 )R 5 .

11. The compound of claim 10 , wherein alk 1 is a bond and each of R 4 and R 5 independently is hydrogen or alkyl.

12. The compound of claim 10 , wherein alk 1 is —CH 2 — and each of R 4 and R 5 independently is selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, heterocyclic and substituted heterocyclic.

13. The compound of claim 2 wherein the compound is represented by formula IV:

14. The compound of claim 13 , wherein Y is hydrogen or alk 1 -N(R 4 )SO 2 R 5 and X is halo, methyl or trifluoromethyl.

15. The compound of claim 14 , wherein X is fluoro.

16. The compound of claim 14 , wherein each of alk 1 and alk 2 is —CH 2 — or —CH 2 CH 2 — and each of R 4 , R 5 , R 6 and R 7 independently is selected from the group consisting of hydrogen, cycloalkyl, and heteroaryl.

17. The compound of claim 14 , wherein alk 2 is —CH 2 — and R 6 and one of R 3 together with the intervening atoms bound thereto, form a heterocyclic or substituted heterocyclic.

18. The compound of claim 17 , wherein the compound is represented by formula V:

19. The compound of claim 14 , wherein ring A is

and Y is hydrogen.

20. The compound of claim 1 selected from the group consisting of:

IV-5 N2-(3-Aminosulfonylmethylenephenyl)-5-fluoro-N-4-[2-(2-N-morpholinoethylaminoacarbonyl)benzofuran-5-yl]-2,4-pyrimidinediamine;

IV-2 N2-[3-(Aminosulfonylmethylene)phenyl]-N-4-[2,2-dimethyl-3-oxo-4-methyl-pyrid[1,4]oxazin-7-yl]-5-fluoro-2,4-pyrimidinediamine;

IV-3 N2-(3-Aminosulfonylmethylphenyl)-5-fluoro-N-4-[1-(propyn-3-yl)indol-5-yl]-2,4-pyrimidinediamine;

IV-4 N2-[3-(Aminosulfonylmethylene)phenyl]-N4-(3-cyanomethylene-1H-indol-5-yl)-5-fluoro-2,4-pyrimidinediamine;

IV-1 N2-[3-(Aminosulfonylmethylene)phenyl]-N-4-[2,2-dimethyl-3-oxo-4H-pyrid[1,4]oxazin-7-yl]-5-fluoro-2,4-pyrimidinediamine;

III-3 N2-(2-Aminosulfonyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-N4-(2,2-dimethyl-3-oxo-4H-5-pyrid[1,4]oxazin-6-yl)-5-fluoro-2,4-pyrimidinediamine;

V-1 N2-(4-Aminosulfonyl)phenyl-5-fluoro-N4-(2,2-dioxo-5-fluoro-1,3-dihydrobenzo[c]isothiazol-6-yl)-2,4-pyrimidinediamine;

V-2 N2-(3-Aminosulfonyl)phenyl-5-fluoro-N4-(2,2-dioxo-5-fluoro-1,3-dihydrobenzo[c]isothiazol-6-yl)-2,4-pyrimidinediamine;

V-3 N2-(3-Aminosulfonyl-4-methyl)phenyl-5-fluoro-N4-(2,2-dioxo-5-fluoro-1,3-dihydrobenzo[c]isothiazol-6-yl)-2,4-pyrimidinediamine;

V-4 N4-[2,2-Dimethyl-3-oxo-4H-pyrid[1,4]oxazin-7-yl]-N2-[3,3-dioxo-1H-benzo[e][1,3,4]oxathiazin-7-yl]-5-fluoro-2,4-pyrimidinediamine;

V-5 N2-(3-Benzyl-cyclopropanesulfonamide)-N4-(3,4-tetrahydropyrid[1]pyranon-6-yl)-5-methyl-2,4-pyrimidinediamine;

III-4 N2-(2-Aminosulfonyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-N4-(4-(prop-2-ynyloxy)phenyl)-5-fluoro-2,4-pyrimidinediamine; and

N2-(3-Benzyl-cyclopropanesulfonamide)-N4-(3,4-dihydroquinolin-1H-6-yl)-5-methyl-2,4-pyrimidinediamine.

21. A pharmaceutical formulation comprising a compound according to claim 1 .

22. The compound of claim 1 , wherein ring A is