Benzotriazole kinase modulators

1. A compound of the formula:

or a pharmaceutically acceptable salt thereof,

wherein

R is lower alkyl, hydroxy lower alkyl, or a radical selected from:

each R a is independently H, lower alkyl, OH, or hydroxy-lower alkyl;

each R b is independently H, lower alkyl, halo, nitro, or halo-lower alkyl;

p is 1, 2, 3, or 4;

X is O, CR 4 R 5 , C(═O), or S(O) x ;

R 1 is hydrogen, halo, alkyl, or NH 2 ;

each of R 3 is independently halo, —NO 2 , lower alkyl, —CN, —OR 7 , —NR 8 R 9 , —C(O)—R 7 , —O—C(O)R 7 , —CF 3 , —CHF 2 , —SO 2 —R 10 , or two of R 3 form alkylene dioxy;

R 4 is hydrogen, lower alkyl, cyano, —(CH 2 ) n OR 7 , —(CH 2 ) n NR 8 R 9 , —(CH 2 ) n —C(O)—NR 8 R 9 , —(CH 2 ) n —OC(O)NR 8 R 9 , —(CH 2 ) n —C(O)—OR 7 ; —NR 7 —SO 2 —R 10 , —(CH 2 ) n —NR 8 —C(O)—R 11 , or —(CH 2 ) n —NR 8 —C(O)—OR 6 ;

R 5 is hydrogen or alkyl;

or R 4 and R 5 together form alkylene dioxy;

R 6 is hydrogen, lower alkyl, heteroalkyl, cycloalkyl, heterocyclylalkyl, or —NR 8 R 9 ;

R 10 is alkyl, cycloalkyl, heterocyclylalkyl, or —NR 8 R 9 ;

R 11 is alkyl, cycloalkyl, heteroalkyl, or (heterocyclyl)alkyl;

R 2 and R 7 are each independently hydrogen, lower alkyl, hydroxyalkyl, or cycloalkyl;

R 8 is hydrogen, lower alkyl, or acyl;

R 9 is hydrogen, lower alkyl, heteroalkyl, aryl, heteroaryl, heterocyclyl, cycloalkyl;

or R 8 and R 9 together with the nitrogen atom to which they are connected to form a heterocyclyl comprising at least one nitrogen ring atom, optionally substituted with OH, oxo, lower alkyl, lower alkoxy, or acyl;

R 12 is H, lower alkyl, cycloalkyl, —C(O)—R 7 , —SO 2 —R 11 ;

each of m and x is independently an integer from 0 to 2;

Y is hydrogen, —(CH 2 ) n —OR 7 , —(CH 2 ) n —C(O)—R 7 or —(CH 2 ) n —C(O)OR 7 ;

each of y and z is independently 0 or 1; and

n is an integer from 0 to 4.

2. The compound of claim 1 , wherein R 2 is hydrogen or methyl.

3. The compound of claim 2 , wherein m is 0.

4. The compound of claim 3 , wherein R 1 is hydrogen, methyl, chloro, or fluoro.

5. The compound of claim 1 , wherein X is CR 4 R 5 .

6. The compound of claim 5 , wherein R 5 is hydrogen or methyl.

7. The compound of claim 5 , wherein z is 1, and R 4 is —NR 7 —SO 2 —R 10 .

8. The compound of claim 7 , wherein R 7 is hydrogen or methyl, and R 10 is methyl, ethyl, or —N(CH 3 ) 2 .

9. The compound of claim 5 , wherein z is 1, and R 4 is hydrogen, lower alkyl, cyano, —(CH 2 ) n OR 7 , or —(CH 2 ) n NR 8 R 9 , or R 4 and R 5 together form alkylene dioxy.

10. The compound of claim 9 , wherein R 4 is —(CH 2 ) n OR 7 ,n is 0 or 1, and R 7 is hydrogen or methyl.

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

12. The compound of claim 11 , wherein n is 0 and R 8 is hydrogen, and R 9 is hydrogen, pyrimidin-2-yl, or pyridin-2-yl.

13. The compound of claim 11 , wherein n is 0 and R 8 and R 9 together with the nitrogen atom to which they are connected to form 2,5-dioxo-pyrrolidin-1-yl.

14. The compound of claim 9 , wherein R 4 is hydrogen, methyl, ethyl, or cyano.

15. The compound of claim 9 , wherein R 4 and R 5 together form ethylene dioxy.

16. The compound of claim 5 , wherein z is 1, and R 4 is —(CH 2 ) n —NR 8 —C(O)R 11 , wherein n, R 8 , and R 11 are those defined in claim 1 .

17. The compound of claim 16 , wherein n is 0,R 8 is hydrogen or methyl, and R 11 is methyl, ethyl, methoxymethyl, hydroxymethyl, (morpholin-4-yl)methyl, or (4-methyl-piperazin-l-yl)methyl.

18. The compound of claim 5 , wherein z is 1, and R 4 is —(CH 2 ) n —C(O)—NR 8 R 9 .

19. The compound of claim 18 , wherein n is 0, and R 8 and R 9 together with the nitrogen atom to which they are connected to form morpholin-4-yl, pyrrolidin-1-yl, or 4-methyl-piperazin-1-yl.

20. The compound of claim 18 , wherein n is 0, and R 8 is hydrogen or methyl, and R 9 is (2-amino-2-methyl)propyl, (2-hydroxy)ethyl, tetrahydropyran-4-yl, cyclopropyl, or ethyl.

21. The compound of claim 5 , wherein z is 1, and R 4 is —(CH 2 ) n —C(O)—OR 7 .

22. The compound of claim 21 , wherein n is 0 and R 7 is hydrogen or methyl.

23. The compound of claim 5 , wherein R 4 and R 5 are hydrogen, z is 0,y is 1, and Y is hydroxy on the 3-position of the cyclopentyl ring moiety.

24. The compound of claim 5 , wherein R 4 and R 5 are hydrogen, z is 1, y is 1, and Y is hydroxy, hydroxymethyl, or —CO 2 CH 2 CH 3 group on the 2-position of the cyclohexyl ring moiety.

25. The compound of claim 1 , wherein z is 1, and X is O,C(═O,), or SO 2 .

26. The compound of claim 4 , wherein R is

z is 1, and X is O or CR 4 R 5 .

27. The compound of claim 26 , wherein X is O.

28. The compound of claim 26 , wherein X is CR 4 R 5 .

29. The compound of claim 28 , wherein R4 is —OH, —OR 7 , —C(O)NR 8 R 9 , —NR 8 R 9 , or —NR 7 SO 2 R 10 .

30. A composition comprising a compound of claim 1 and a pharmaceutically acceptable excipient.

31. A method for treating rheumatoid arthritis, comprising administering to a patient a therapeutically effective amount of a compound of claim 1 .

32. The compound of claim 1 , wherein R is a radical selected from:

and wherein m, p, y, z, X, Y, R a and R b are as recited in claim 1 .