Urea kinase inhibitors

1. A compound of formula (I)

or a therapeutically acceptable salt thereof, wherein

X is —N— or —CH—;

R 1 is selected from the group consisting of hydrogen, alkoxy, alkyl, amino, carboxy, cyano, halo, hydroxy, and hydroxyalkyl;

R 2 is selected from the group consisting of cyano and halo;

R 3 is selected from the group consisting of hydrogen, alkoxy, alkyl, amino, aminoalkyl, aminocarbonyl, arylalkyl, cyano, nitro, —CO 2 R 5 , —COR 5 , and —SR 5 ;

R 4 is selected from the group consisting of —(CHR 6 ) m OR 7 , and —(CH 2 ) n NR 8 R 9 ;

R 5 is selected from the group consisting of hydrogen, alkenyl, alkyl, aryl, arylalkyl, cycloalkyl, and (cycloalkyl)alkyl;

R 6 is selected from the group consisting of hydrogen, alkyl, aryl, and heteroaryl;

R 7 is selected from the group consisting of hydrogen, alkenyl, alkoxyalkoxyalkyl, alkoxyalkyl, alkoxycarbonylalkyl, alkylsulfanylalkyl, alkynyl, arylalkyl, arylcarbonylalkyl, aryloxyalkyl, arylsulfanylalkyl, cycloalkenyl, (cycloalkenyl)alkyl, cycloalkyl, (cycloalkyl)alkyl, heteroarylalkoxyalkyl, heteroarylalkyl, (heterocyclyl)alkoxyalkyl, and hydroxyalkyl;

R 8 and R 9 are independently selected from the group consisting of hydrogen, alkenyl, alkoxyalkyl, alkyl, alkylsulfanylalkyl, alkynyl, aminoalkyl, arylalkyl, cycloalkenyl, (cycloalkenyl)alkyl, cycloalkyl, (cycloalkyl)alkyl, heteroarylalkyl, (heterocyclyl)alkyl, and hydroxyalkyl;

m is 0–6; provided that when R 7 is hydrogen m is other than 0; and

n is 0–6; provided that when R 8 and R 9 are both hydrogen, n is other than 0.

2. The compound of claim 1 wherein X is —N—.

3. The compound of claim 1 wherein R 4 is —(CH 2 ) n NR 8 R 9 .

4. The compound of claim 3 wherein n is 0.

5. The compound of claim 4 wherein one of R 8 and R 9 is alkoxyalkyl and the other is selected from the group consisting of alkoxyalkyl and alkyl.

6. The compound of claim 5 selected from the group consisting of

N-{2-[bis(2-methoxyethyl)amino]-5-bromophenyl}-N′-(5-cyano-2-pyrazinyl)urea;

N-{5-bromo-2-[ethyl(2-methoxyethyl)amino]phenyl}-N′-(5-cyano-2-pyrazinyl)urea;

N-{2-[bis(2-methoxyethyl)amino]-5-chlorophenyl}-N′-(5-cyano-2-pyrazinyl)urea;

N-{5-chloro-2-[ethyl(2-methoxyethyl)amino]phenyl}-N′-(5-cyano-2-pyrazinyl)urea; and

N-{2-[bis(2-methoxyethyl)amino]-5-cyanophenyl}-N′-(5-cyano-2-pyrazinyl)urea.

7. The compound of claim 4 wherein one of R 8 and R 9 is arylalkyl and the other is selected from the group consisting of alkyl and hydroxyalkyl.

8. The compound of claim 7 selected from the group consisting of

N-{2-[benzyl(2-hydroxyethyl)amino]-5-bromophenyl)}-N′-(5-cyano-2-pyrazinyl)urea;

N-{5-bromo-2-[(2-hydroxy-2-phenylethyl)(methyl)amino]phenyl}-N′-(5-cyano-2-pyrazinyl)urea;

N-{2-[benzyl(2-hydroxyethyl)amino]-5-chlorophenyl}-N′-(5-cyano-2-pyrazinyl)urea;

N-{5-chloro-2-[(2-hydroxy-2-phenylethyl)(methyl)amino]phenyl}-N′-(5-cyano-2-pyrazinyl)urea; and

N-{5-cyano-2-[(2-hydroxy-2-phenylethyl)(methyl)amino]phenyl}-N′-(5-cyano-2-pyrazinyl)urea.

9. The compound of claim 1 wherein R 4 is —(CHR 6 ) m OR 7 .

10. The compound of claim 9 wherein m is 0.

11. The compound of claim 10 wherein R 7 is selected from the group consisting of alkoxyalkyl and alkylsulfanylalkyl.

12. The compound of claim 11 selected from the group consisting of

N-[5-chloro-2-(2-methoxy-1-methylethoxy)phenyl]-N′-(5-cyano-2-pyrazinyl)urea;

N-[5-chloro-2-(2-ethoxy-1-methylethoxy)phenyl]-N′-(5-cyano-2-pyrazinyl)urea;

N-[5-chloro-2-(2-methoxyethoxy)phenyl]-N′-(5-cyano-2-pyrazinyl)urea;

N-[5-chloro-2-(2-isopropoxyethoxy)phenyl]-N′-(5-cyano-2-pyrazinyl)urea;

N-[5-chloro-2-(2-ethoxyethoxy)phenyl]-N′-(5-cyano-2-pyrazinyl)urea;

N-{5-chloro-2-[2-(methylsulfanyl)ethoxy]phenyl}-N′-(5-cyano-2-pyrazinyl)urea; and

N-[5-chloro-2-(3-methoxy-3-methylbutoxy)phenyl]-N′-(5-cyano-2-pyrazinyl)urea.

13. The compound of claim 10 wherein R 7 is (cycloalkyl)alkyl.

14. The compound of claim 13 selected from the group consisting of

N-{5-chloro-2-[(2-methylcyclopropyl)methoxy]phenyl}-N′-(5-cyano-2-pyrazinyl)urea;

N-[5-chloro-2-(cyclopropylmethoxy)phenyl]-N′-(5-cyano-2-pyrazinyl)urea;

N-{5-chloro-2-[(1-methylcyclopropyl)methoxy]phenyl}-N′-(5-cyano-2-pyrazinyl)urea;

N-[5-chloro-2-(2-cyclohexylethoxy)phenyl]-N′-(5-cyano-2-pyrazinyl)urea;

N-{2-[(1S,4S)-bicyclo[2.2.1]hept-2-ylmethoxy]-5-chlorophenyl}-N′-(5-cyano-2-pyrazinyl)urea; and

ethyl 2-{[4-chloro-2-({[(5-cyano-2-pyrazinyl)amino]carbonyl}amino)phenoxy]methyl}cyclopropanecarboxylate.

15. The compound of claim 10 wherein R 7 is selected from the group consisting of alkenyl, alkoxyalkoxyalkyl, alkynyl, haloalkyl, and hydroxyalkyl.

16. The compound of claim 15 selected from the group consisting of

N-(5-chloro-2-{[(2S)-2,3-dihydroxypropyl]oxy}phenyl)-N′-(5-cyano-2-pyrazinyl)urea;

N-(5-chloro-2-{[(2R)-2,3-dihydroxypropyl]oxy}phenyl)-N′-(5-cyano-2-pyrazinyl)urea;

N-{5-chloro-2-[2-(2-methoxyethoxy)ethoxy]phenyl}-N′-(5-cyano-2-pyrazinyl)urea;

N-[2-(allyloxy)-5-chlorophenyl]-N′-(5-cyano-2-pyrazinyl)urea;

N-{5-chloro-2-[(3-methyl-2-butenyl)oxy]phenyl}-N′-(5-cyano-2-pyrazinyl)urea;

N-[5-chloro-2-(3-pentynyloxy)phenyl]-N′-(5-cyano-2-pyrazinyl)urea; and

N-[5-chloro-2-(2-chloro-1-methoxyethoxy)phenyl]-N′-(5-cyano-2-pyrazinyl)urea.

17. The compound of claim 10 wherein R 7 is selected from the group consisting of alkoxycarbonylalkyl, arylcarbonylalkyl, aryloxyalkyl, cycloalkenyl, cycloalkyl, and heteroarylalkoxyalkyl.

18. The compound of claim 17 selected from the group consisting of

N-[5-chloro-2-(2-cyclohexen-1-yloxy)phenyl]-N′-(5-cyano-2-pyrazinyl)urea;

N-{2-[2-(4-bromophenoxy)ethoxy]-5-chlorophenyl}-N′-(5-cyano-2-pyrazinyl)urea;

N-(5-chloro-2-{2-[3-(6-methyl-2-pyridinyl)propoxy]ethoxy}phenyl)-N′-(5-cyano-2-pyrazinyl)urea;

N-[5-chloro-2-(2-oxo-2-phenylethoxy)phenyl]-N′-(5-cyano-2-pyrazinyl)urea;

N-[5-chloro-2-(3-cyclopenten-1-yloxy)phenyl]-N′-(5-cyano-2-pyrazinyl)urea;

N-(5-chloro-2-{[(3R,4S)-3,4-dihydroxycyclopentyl]oxy}phenyl)-N′-(5-cyano-2-pyrazinyl)urea;

N-(5-chloro-2-{[(1S,3R)-3-hydroxycyclopentyl]oxy}phenyl)-N′-(5-cyano-2-pyrazinyl)urea; and

ethyl 6-[4-chloro-2-({[(5-cyano-2-pyrazinyl)amino]carbonyl}amino)phenoxy]hexanoate.

19. The compound of claim 1 wherein

X is —N—;

R 1 is cyano;

R 2 is selected from the group consisting of cyano and halo; and

R 3 is hydrogen.

20. A pharmaceutical composition comprising a compound of claim 1 or a therapeutically acceptable salt thereof, in combination with a therapeutically acceptable carrier.