Multiple kinase pathway inhibitors

1. A compound having the structural formula of Structural Formula (I):

or a pharmaceutically acceptable salt thereof, wherein:

R1 is a nitrogen-containing five- or six-membered heteroaryl in which at least one ring nitrogen atom is adjacent to the carbon linking R1 to the amino group, optionally substituted with 1, 2, or 3 groups independently selected from the group consisting of:

hydroxyl;

halogen;

C1-C3 alkyl;

hydroxyl (C1-C3)alkylamino, optionally linked to R1 through a carbonyl group;

hydroxyl (C1-C3) dialkylamino, optionally linked to R1 through a carbonyl group;

C1-C3 alkylamino, optionally linked to R1 through a carbonyl group;

C1-C3 dialkylamino, optionally linked to R1 through a carbonyl group;

(C1-C3)alkylamino(C1-C3)alkyl, optionally linked to R1 through a carbonyl group;

(C1-C3)dialkylamino(C1-C3)alkyl, optionally linked to R1 through a carbonyl group;

(C1-C3)alkylamino(C2-C3)alkoxyl, optionally linked to R1 through a carbonyl group;

(C1-C3) dialkylamino(C2-C3)alkoxyl, optionally linked to R1 through a carbonyl group;

(C1-C3)alkylamino(C2-C3)alkylamino, optionally linked to R1 through a carbonyl group;

(C1-C3)dialkylamino(C2-C3)alkylamino, optionally linked to R1 through a carbonyl group;

(C1-C3)alkylamino(C2-C3)dialkylamino, optionally linked to R1 through a carbonyl group;

(C1-C3)dialkylamino(C2-C3)dialkylamino, optionally linked to R1 through a carbonyl group;

(C1-C3)alkoxyl(C2-C3)alkylamino, optionally linked to R1 through a carbonyl group;

(C1-C3)alkoxyl(C2-C3)dialkylamino, optionally linked to R1 through a carbonyl group; and

a three- to six-member heterocyclic ring containing 1 or 2 heteroatoms selected from O, N, and S; and, independently,

(1) optionally is substituted with (C1-C3) alkyl, (C1-C3) hydroxylalkyl, (C1-C3) alkoxyl (C1-C3)alkyl, or (C1-C3)alkylamino(C1-C3)alkyl, and

(2) optionally is linked to the five- or six-member heteroaryl through a carbonyl group;

when R1 is substituted then R2 is:

hydrogen;

C1-C6 alkyl, optionally substituted with 1, 2, or 3 groups selected from hydroxyl, methoxyl, ethoxyl, methylamino, N,N-dimethyl amino, ethylamino, N,N-diethylamino, and methylsulfanyl;

a three- to six-member cycloalkyl, optionally substituted with 1, 2, or 3 groups selected from hydroxyl, methoxyl, ethoxyl, methylamino, N,N-dimethyl amino, ethylamino, N,N-diethylamino, and methylsulfanyl;

a three- to six-member heterocyclic ring, optionally substituted with 1, 2, or 3 groups selected from hydroxyl, C1-C3 alkyl, methoxyl, ethoxyl, methylamino, N,N-dimethyl amino, ethylamino, N,N-diethylamino, and methylsulfanyl;

phenyl, optionally substituted with 1, 2, or 3 groups selected from hydroxyl, methoxyl, ethoxyl, methylamino, N,N-dimethyl amino, ethylamino, N,N-diethylamino, and methylsulfanyl; or

heteroaryl, optionally substituted with 1, 2, or 3 groups selected from hydroxyl, methoxyl, ethoxyl, methylamino, N,N-dimethyl amino, ethylamino, N,N-diethylamino, and methylsulfanyl;

when R1 is unsubstituted then R2 is:

hydrogen;

C2-C6 alkyl, optionally substituted with 1, 2, or 3 groups selected from hydroxyl, methoxyl, ethoxyl, methylamino, N,N-dimethyl amino, ethylamino, N,N-diethylamino, and methylsulfanyl;

a three- to six-member cycloalkyl, optionally substituted with 1, 2, or 3 groups selected from hydroxyl, methoxyl, ethoxyl, methylamino, N,N-dimethyl amino, ethylamino, N,N-diethylamino, and methylsulfanyl;

a three- to six-member heterocyclic ring, optionally substituted with 1, 2, or 3 groups selected from hydroxyl, C1-C3 alkyl, methoxyl, ethoxyl, methylamino, N,N-dimethyl amino, ethylamino, N,N-diethylamino, and methylsulfanyl;

phenyl, optionally substituted with 1, 2, or 3 groups selected from hydroxyl, methoxyl, ethoxyl, methylamino, N,N-dimethyl amino, ethylamino, N,N-diethylamino, and methylsulfanyl; or

heteroaryl, optionally substituted with 1, 2, or 3 groups selected from hydroxyl, methoxyl, ethoxyl, methylamino, N,N-dimethyl amino, ethylamino, N,N-diethylamino, and methylsulfonyl; and

R3 is:

halogen;

C1-C6 alkyl;

C1-C6 hydroxylalkyl;

C1-C6 alkylcarbonyl;

C1-C6 perfluoroalkyl;

C3-C6 cycloalkyl;

C2-C6 alkenyl, optionally substituted with 1, 2, or 3 substituents selected from the group consisting of C1-C3 alkoxyl, C1-C3 alkoxylcarbonyl, and trifluoromethyl;

C2-C6 alkynyl, optionally substituted with 1, 2, or 3 substituents selected from the group consisting of C1-C3 alkoxyl, hydroxyl, C1-C6 alkyl, trifluoromethyl;

phenyl, optionally substituted with 1, 2, or 3 substituents selected from the group consisting of halogen, C1-C3 alkoxyl, and trifluoromethyl; and

a five- to six-member heteroaryl, optionally substituted with 1, 2, or 3 substituents selected from the group consisting of halogen, C1-C3 alkoxyl, and trifluoromethyl.

2. The compound of claim 1 having an IC 50 ≦1 μM for at least one tyrosine kinase selected from BTK, SRC, and LYN.

3. The compound of claim 2 having an IC 50 ≦1 μM for at least two tyrosine kinases selected from BTK, SRC, and LYN.

4. The compound of claim 3 having an IC 50 ≦1 μM for BTK, SRC, and LYN.

5. The compound of claim 2 having an IC 50 ≦0.1 μM for at least one tyrosine kinase selected from BTK, SRC, and LYN.

6. The compound of claim 5 having an IC 50 ≦0.1 μM for at least two tyrosine kinases selected from BTK, SRC, and LYN.

7. The compound of claim 6 having an IC 50 ≦0.1 μM for BTK, SRC, and LYN.

8. The compound of claim 2 , wherein IC 50 is determined by measuring consumption of ATP or using an isotopic detection of phosphorylation.

9. The compound of claim 8 , wherein IC 50 is determined by measuring consumption of ATP and the consumption of ATP determined through luminescence.

10. The compound of claim 8 , wherein IC 50 is determined using an isotopic detection of phosphorylation and wherein said isotopic detection comprises radiologic detection of 32 P.

11. The compound of claim 1 having a tissue culture EC 50 ≦10 μM or having a tissue culture EC 50 ≦1 μM.

12. The compound of claim 11 , wherein the EC 50 is determined:

(a) using a dasatinib-resistant cell line; or

(b) using a dasatinib-resistant cell line, wherein the dasatinib-resistant cell line is Ramos;

(c) using a dasatinib-sensitive cell line; or

(d) using a dasatinib-sensitive cell line, wherein the dasatinib-sensitive cell line is DoHH2.

13. The compound of claim 2 having IC 50 ≦1 μM for non-tyrosine kinases.

14. The compound of claim 2 having IC 50 ≦1 μM for Aurora kinases, MAPP kinases, and CDK kinases.

15. The compound of claim 1 capable of inducing G1 arrest.

16. A pharmaceutical composition comprising:

(a) a pharmaceutically acceptable vehicle; and

(b) a compound of claim 1 or a pharmaceutically acceptable salt thereof.

17. A method of inhibiting kinase activity, comprising contacting a Bruton's tyrosine kinase with a compound of claim 1 or a pharmaceutically acceptable salt thereof, whereby kinase activity of the Bruton's tyrosine kinase is inhibited.

18. The method of claim 17 , wherein the contacting occurs:

(a) in a cell-free system;

(b) in a cell;

(c) in a cell in vitro; or

(d) in a cell in a patient.

19. The compound of claim 1 , wherein R1 is optionally substituted pyridinyl, optionally substituted pyrimidinyl, optionally substituted pyridazinyl, optionally substituted thiazolyl or optionally substituted imidazolyl.

20. The compound of claim 19 , wherein R1 is substituted with 1, 2 or 3 groups selected from halogen, C1-C3 alkyl or (C1-C3)dialkylamino(C2-C3)alkoxyl.

21. The compound of claim 1 , wherein R2 is H, optionally substituted C1-C3 alkyl, an optionally substituted 3-6 membered cycloalkyl ring, an optionally substituted 3-6 membered heterocyclic ring, optionally substituted phenyl or optionally substituted pyridinyl.

22. The compound of claim 21 , wherein the C1-C3 alkyl is substituted with methoxyl or N,N-dimethylamino.

23. The compound of claim 1 , wherein R3 is phenyl, optionally substituted with 1, 2 or 3 substituents selected from the group consisting of halogen, C1-C3 alkoxyl and trifluoromethyl.

24. The compound of claim 1 , wherein the compound has one of the following structures: