Selective kinase inhibitors

1. A method of inhibiting an activity of JAK3 in a patient in need thereof, the method comprising contacting said JAK3 with a compound of Formula I:

or pharmaceutically acceptable salt thereof, wherein:

R 1 , R 2 , R 3 , and R 4 are each, independently, selected from H, halo, C 1-6 alkyl, C 1-6 haloalkyl, CN, NO 2 , OH, C 1-6 alkoxy, C 1-6 haloalkoxy, amino, C 1-6 alkylamino, and C 2-8 dialkylamino, wherein each of the C 1-6 alkyl, C 1-6 haloalkyl, is optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from halo, CN, NO 2 , C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, OR a , OC(O)R b , OC(O)NR c R d , C(O)R b , C(O)NR c R d , C(O)OR a , NR c R d , NR c C(O)R d , NR c C(O)OR a , NR c C(O)NR c R d , NR c S(O) 2 R b , NR c S(O) 2 NR c R d , SR a , S(O) 2 R b , and S(O) 2 NR c R d ;

R 5 is selected from H, halo, CN, NO 2 , OR a , OC(O)R b , OC(O)NR c R d , C(O)R b , C(O)NR c R d , C(O)OR a , NR c R d , NR c C(O)R d , NR c C(O)OR a , NR c C(O)NR c R d , NR c S(O) 2 R b , NR c S(O) 2 NR c R d , SR a , S(O) 2 R b , and S(O) 2 NR c R d , C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, and heterocycloalkylalkyl, wherein each of the C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, and heterocycloalkylalkyl is optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from halo, CN, NO 2 , C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, OR a , OC(O)R b , OC(O)NR c R d , C(O)R b , C(O)NR c R d , C(O)OR a , NR c R d , NR c C(O)R d , NR c C(O)OR a , NR c C(O)NR c R d , NR c S(O) 2 R b , NR c S(O) 2 NR c R d , SR a , S(O) 2 R b , and S(O) 2 NR c R d ;

—NR 8 —C(O)—C 2 -C 6 alkenyl;

each R 7 is independently selected from halo, CN, NO 2 , —NR 8 —W 1 —(CR 9 R 10 ) n R 11 , OR a , OC(O)R b , OC(O)NR c R d , C(O)R b , C(O)NR c R d , C(O)OR a , NR c R d , NR c C(O)R d , NR c C(O)OR a , NR c C(O)NR c R d , NR c S(O) 2 R b , NR c S(O) 2 NR c R d , SR a , S(O) 2 R b , and S(O) 2 NR c R d , C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, and heterocycloalkylalkyl, wherein each of the C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, and heterocycloalkylalkyl is optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from halo, CN, NO 2 , C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, OR a , OC(O)R b , OC(O)NR c R d , C(O)R b , C(O)NR c R d , C(O)OR a , NR c R d , NR c C(O)R d , N c C(O)OR a , NR c C(O)NR c R d , NR c S(O) 2 R b , NR c S(O) 2 NR c R d , SR a , S(O) 2 R b , and S(O) 2 NR c R d ;

each R 8 is independently selected from H, C 1-4 alkyl, and C 1-4 haloalkyl; C 2-6 alkenyl, C 2-6 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, heterocycloalkylalkyl, wherein each of the C 1-4 alkyl, C 1-4 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, and heterocycloalkylalkyl is optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from halo, CN, NO 2 , C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, OR a , OC(O)R b , OC(O)NR c R d , C(O)R b , C(O)NR c R d , C(O)OR a , NR c R d , NR c C(O)R d , NR c C(O)OR a , NR c C(O)NR c R d , NR c S(O) 2 R b , NR c S(O) 2 NR c R d , SR a , S(O) 2 R b , and S(O) 2 NR c R d ;

R 9 and R 10 are each, independently, selected from H, C 1-4 alkyl, and C 1-4 haloalkyl;

each R 11 is independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, heterocycloalkylalkyl, halo, CN, NO 2 , OR a11 , NR c11 R d11 , NR c11 C (O)R d11 , NR c11 C(O)OR a11 , NR c11 C(O)NR c11 R d11 , NR c11 S(O)R b11 , NR c11 S(O) 2 R b11 , NR c11 S(O)NR c11 R d11 , and NR c11 S(O) 2 NR c11 R d11 , wherein each of the C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, and heterocycloalkylalkyl is optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from halo, CN, NO 2 , C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, OR a , OC(O)R b , OC(O)NR c R d , C(O)R b , C(O)NR c R d , C(O)OR a , NR c R d , NR c C(O)R d , NR c C(O)OR a , NR c C(O)NR c R d , NR c S(O) 2 R b , NR c S(O) 2 NR c R d , SR a , S(O) 2 R b , S(O) 2 NR c R d , SC(O)R b , —S(O)—C 1-6 alkyl, —S—C 1-6 alkyl, and —O—S(O) 2 —C 1-6 alkyl;

R 12 and R 13 are each, independently, selected from H, C 1-4 alkyl, and C 1-4 haloalkyl;

R 14 and R 15 are each, independently, selected from H, C 1-4 alkyl, and C 1-4 haloalkyl;

each W 1 is independently selected from —C(R 12 )(R 13 )—, —C(R 12 )═C(R 16 )—, —C(O)—, —S(O)—, —S(O) 2 —, and —C(S)—;

R 16 is selected from H, C 1-4 alkyl, and C 1-4 haloalkyl;

or R 16 and —(CR 9 R 10 ) n R 11 together with the C atom to which they are attached form a 4-, 5-, 6- or 7-membered cycloalkyl or heterocycloalkyl group, each optionally substituted with 1, 2, 3, 4, or 5 substituents each independently selected from OH, C 1-6 alkoxy, oxo, C 1-6 haloalkoxy, amino, C 1-6 alkylamino, C 2-8 dialkylamino, halo, C 1-6 alkyl, C 1-6 haloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl or heterocycloalkyl;

each R a11 is independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, heterocycloalkylalkyl, C 2-6 alkenyl, C 2-6 alkynyl, aryl, cycloalkyl, heteroaryl and heterocycloalkyl, wherein each of the C 1-6 alkyl, C 1-6 haloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, heterocycloalkylalkyl, C 2-6 alkenyl, C 2-6 alkynyl, aryl, cycloalkyl, heteroaryl, and heterocycloalkyl is optionally substituted with 1, 2, 3, 4, or 5 substituents each independently selected from OH, CN, amino, halo, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl and heterocycloalkyl;

each R b11 is independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, heterocycloalkylalkyl, C 2-6 alkenyl, C 2-6 alkynyl, aryl, cycloalkyl, heteroaryl, and heterocycloalkyl, wherein each of the C 1-6 alkyl, C 1-6 haloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, heterocycloalkylalkyl, C 2-6 alkenyl, C 2-6 alkynyl, aryl, cycloalkyl, heteroaryl and heterocycloalkyl is optionally substituted with 1, 2, 3, 4, or 5 substituents each independently selected from OH, CN, amino, halo, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl and heterocycloalkyl;

R c11 and R d11 are independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, heterocycloalkylalkyl, C 2-6 alkenyl, C 2-6 alkynyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl, wherein each of the C 1-6 alkyl, C 1-6 haloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, heterocycloalkylalkyl, C 2-6 alkenyl, C 2-6 alkynyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from halo, CN, NO 2 , C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, —Y 1 —Z 1 , OR a , OC(O)R b , OC(O)NR c R d , C(O)R b , C(O)NR c R d , C(O)OR a , NR c R d , NR c C(O)R d , NR c C(O)OR a , NR c C(O)NR c R d , NR c S(O) 2 R b , NR c S(O) 2 NR c R d , SR a , S(O) 2 R b , and S(O) 2 NR c R d ;

or R c11 and R d11 together with the N atom to which they are attached form a 4-, 5-, 6- or 7-membered heterocycloalkyl group or heteroaryl group, each optionally substituted with 1, 2, 3, 4, or 5 substituents each independently selected from halo, CN, NO 2 , C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, —Y 1 —Z 1 , OR a , OC(O)R b , OC(O)NR C R d , C(O)R b , C(O)NR c R d , C(O)OR a , NR c R d , NR c C(O)R d , NR c C(O)OR a , NR c C(O)NR c R d , NR c S(O) 2 R b , NR c S(O) 2 NR c R d , SR a , S(O) 2 R b , and S(O) 2 NR c R d ;

each Y 1 is independently selected from absent, C 1-6 alkylenyl, C 2-6 alkenylenyl, C 2-6 alkynylenyl, —(CR 14 R 15 ) p1 —O—(CR 14 R 15 ) p2 —, —(CR 14 R 15 ) p1 —S—(CR 14 R 15 ) p2 —, —(CR 14 R 15 ) p1 —NR e —(CR 14 R 15 ) p2 —, —(CR 14 R 15 ) p1 —C(O)—(CR 14 R 15 ) p2 —, —(CR 14 R 15 ) p1 —C(O)O—(CR 14 R 15 ) p2 —, —(CR 14 R 15 ) p1 —C(O)NR e —(CR 14 R 15 ) p2 —, —(CR 14 R 15 ) p1 , —S(O) 2 —(CR 14 R 15 ) p2 —, —(CR 14 R 15 ) p1 —S(O)NR e —(CR 14 R 15 ) p2 —, —(CR 14 R 15 ) p1 —S(O) 2 NR e —(CR 14 R 15 ) p2 —, and —(CR 14 R 15 ) p1 —NR e C(O)NR f —(CR 14 R 15 ) p2 —, wherein each of the C 1-6 alkylenyl, C 2-6 alkenylenyl and C 2-6 alkynylenyl is optionally substituted by 1, 2, or 3 substituents independently selected from halo, OH, CN, amino, C 1-6 alkylamino, C 2-8 dialkylamino, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl and heterocycloalkyl;

each Z 1 is independently selected from C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, arylalkyl, cycloalkylalkyl, heteroarylalkyl, heterocycloalkylalkyl, aryl, cycloalkyl, heteroaryl, and heterocycloalkyl, each optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, halo, CN, NO 2 , OR a , OC(O)R b , OC(O)NR c R d , C(O)R b , C(O)NR c R d , C(O)OR a , NR c R d , NR c C(O)R d , NR c C(O)OR a , NR c C(O)NR c R d , NR c S(O) 2 R b , NR c S(O) 2 NR c R d , SR a , S(O) 2 R b , and S(O) 2 NR c R d ;

each R a is independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, heterocycloalkylalkyl, C 2-6 alkenyl, C 2-6 alkynyl, aryl, cycloalkyl, heteroaryl, and heterocycloalkyl, wherein each of the C 1-6 alkyl, C 1-6 haloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, heterocycloalkylalkyl, C 2-6 alkenyl, C 2-6 alkynyl, aryl, cycloalkyl, heteroaryl and heterocycloalkyl is optionally substituted with 1, 2, 3, 4, or 5 substituents each independently selected from OH, CN, amino, C 1-6 alkylamino, C 2-8 dialkylamino, halo, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, and heterocycloalkyl;

each R b is independently selected from H, NH 2 , C 1-6 alkyl, C 1-6 haloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, heterocycloalkylalkyl, C 2-6 alkenyl, C 2-6 alkynyl, aryl, cycloalkyl, heteroaryl, and heterocycloalkyl, wherein each of the C 1-6 alkyl, C 1-6 haloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, heterocycloalkylalkyl, C 2-6 alkenyl, C 2-6 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, and heterocycloalkylalkyl is optionally substituted with 1, 2, 3, 4, or 5 substituents each independently selected from OH, C 1-6 alkoxy, C 1-6 haloalkoxy, amino, C 1-6 alkylamino, C 2-8 dialkylamino, halo, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 haloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl and heterocycloalkyl;

R c and R d are independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, heterocycloalkylalkyl, C 2-6 alkenyl, C 2-6 alkynyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl, wherein each of the C 1-6 alkyl, C 1-6 haloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, heterocycloalkylalkyl, C 2-6 alkenyl, C 2-6 alkynyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl and heterocycloalkylalkyl is optionally substituted with 1, 2, 3, 4, or 5 substituents each independently selected from OH, C 1-6 alkoxy, C 1-6 haloalkoxy, amino, C 1-6 alkylamino, C 2-8 dialkylamino, halo, C 1-6 alkyl, C 1-6 haloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl and heterocycloalkyl;

or R c and R d together with the N atom to which they are attached form a 4-, 5-, 6- or 7-membered heterocycloalkyl group that is optionally substituted with 1, 2, 3, 4, or 5 substituents each independently selected from OH, C 1-6 alkoxy, C 1-6 haloalkoxy, amino, C 1-6 alkylamino, C 2-8 dialkylamino, halo, C 1-6 alkyl, C 1-6 haloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl or heterocycloalkyl;

R e and R f are each, independently, selected from H, C 1-6 alkyl, C 1-6 haloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, heterocycloalkylalkyl, C 2-6 alkenyl, C 2-6 alkynyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, wherein each of the C 1-6 alkyl, C 1-6 haloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, heterocycloalkylalkyl, C 2-6 alkenyl, C 2-6 alkynyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl is optionally substituted with 1, 2, 3, 4, or 5 substituents each independently selected from OH, C 1-6 alkoxy, C 1-6 haloalkoxy, amino, C 1-6 alkylamino, C 2-8 dialkylamino, halo, C 1-6 alkyl, C 1-6 haloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, and heterocycloalkyl;

m is 0, 1, 2, 3, or 4;

each n is independently 0, 1, 2, 3, or 4;

each p1 is independently 0, 1, 2, or 3; and

each p2 is independently 0, 1, 2, or 3.

2. The method of claim 1 wherein R 1 , R 2 , R 3 , and R 4 are each, independently, selected from H, halo, C 1-6 alkyl, and C 1-6 haloalkyl.

3. The method of claim 1 wherein R 5 is selected from H, halo, C 1-6 alkyl, C 1-6 haloalkyl, CN, NO 2 , C 1-6 alkoxy, and C 1-6 haloalkoxy.

4. The method of claim 1 wherein R 5 is selected from H, halo, C 1-6 alkyl, and C 1-6 haloalkyl.

5. The method of claim 1 wherein each W 1 is —C(O)—.

6. The method of claim 1 wherein each R 7 is independently selected from halo, C 1-6 alkyl, C 1-6 haloalkyl, CN, NO 2 , —NR 8 —C(O)—(CR 9 R 10 ) n R 11 , OH, C 1-6 alkoxy, C 1-6 haloalkoxy, amino, C 1-6 alkylamino, and C 2-8 dialkylamino.

7. The method of claim 1 wherein each R 8 is H or methyl.

8. The method of claim 1 wherein each R 8 is H.

9. The method of claim 1 wherein the compound of Formula I is a compound of Formula II:

10. The method of claim 1 wherein the compound of Formula I is:

11. The method of claim 1 wherein n is 0.

12. The method of claim 1 wherein n is 1.

13. The method of claim 1 wherein each R 11 is independently selected from C 1-6 alkyl, C 1-6 haloalkyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, halo, CN, OR a11 , and NR c11 R d11 , wherein each of the C 1-6 alkyl, C 1-6 haloalkyl, aryl, cycloalkyl, heteroaryl, and heterocycloalkyl is optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from halo, CN, NO 2 , C 1-6 alkyl, C 1-6 haloalkyl, OH, C 1-6 alkoxy, and C 1-6 haloalkoxy.

14. The method of claim 1 , wherein the compound of Formula I or pharmaceutically acceptable salt thereof is N-(3-(quinoxalin-2-yl)phenyl)acrylamide.

15. A method of inhibiting an activity of JAK3 comprising contacting said JAK3 with

N-(3-acetamido-5-(quinoxalin-2-yl)phenyl)acrylamide,

or a pharmaceutically acceptable salt thereof.