Therapeutic pyrazoloquinoline derivatives

1. A compound of formula (I):

or a tautomer thereof, or their pharmaceutically acceptable salts,

wherein

R is hydrogen, or oxide;

each R 1 is selected from the group consisting of hydrogen, hydroxy, halo, cyano, —CONR a R b , —NR a R b , hydroxy(C 1 -C 6 )alkyl, amino(C 1 -C 6 )alkyl, (C 1 -C 6 )alkyl optionally substituted with up to 5 fluoro, and (C 1 -C 6 )alkoxy optionally substituted with up to 5 fluoro;

R 2 is selected from the group consisting of hydrogen, hydroxy, halo, hydroxy(C 1 -C 6 )alkyl, (C 1 -C 6 )alkyl optionally substituted with up to 5 fluoro, and (C 1 -C 6 )alkoxy optionally substituted with up to 5 fluoro;

each R a and R b is independently hydrogen, (C 1 -C 6 )alkyl, —S(O) z (C 1 -C 6 )alkyl, —C(O)(C 1 -C 6 )alkyl, —C(O)NR g (C 1 -C 6 )alkyl, or —C(O)O(C 1 -C 6 )alkyl, or R a together with R b form a heterocycle group optionally substituted with one or more R d ; wherein the heterocycle group optionally include one or more groups selected from O (oxygen), S (sulfur), and NR c ;

each R c is independently hydrogen, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, —C(O)O(C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy(C 1 -C 6 )alkyl, hydroxy(C 1 -C 6 )alkyl, —C(O)NR g (C 1 -C 6 )alkyl, —S(O) z (C 1 -C 6 )alkyl, —C(O)(C 1 -C 6 )alkyl, (C 1 -C 6 )alkyl optionally substituted with up to 5 fluoro, or (C 1 -C 6 )alkoxy optionally substituted with up to 5 fluoro;

each R d is independently selected from the group consisting of hydrogen, halo, oxo, hydroxy, —C(O)NR e R f , —NR e R f , hydroxy(C 1 -C 6 )alkyl, (C 1 -C 6 )alkyl optionally substituted with up to 5 fluoro, and (C 1 -C 6 )alkoxy optionally substituted with up to 5 fluoro;

each R e and R f is independently selected from hydrogen, (C 1 -C 6 )alkyl, aryl, —C(O)(C 1 -C 6 )alkyl, —S(O) z (C 1 -C 6 )alkyl, —S(O) z NR g (C 1 -C 6 )alkyl, —C(O)NR g (C 1 -C 6 )alkyl, —C(O)(C 1 -C 6 )alkyl, or —C(O)O(C 1 -C 6 )alkyl;

R g is hydrogen, or (C 1 -C 6 )alkyl optionally substituted with up to 5 fluoro;

Ar is aryl optionally substituted with one or more M or heteroaryl optionally substituted with one or more M;

each Q is independently hydrogen, halo, oxo, hydroxy, —C(O)NR a R b , —NR a R b , (C 1 -C 6 )alkyl optionally substituted with up to 5 fluoro, (C 1 -C 6 )alkoxy optionally substituted with up to 5 fluoro, (C 1 -C 6 )alkyl optionally substituted with one or more R d , hydroxy(C 1 -C 6 )alkyl optionally substituted with one or more R d , aryl optionally substituted with one or more R d , or aryl(C 1 -C 6 )alkyl optionally substituted with one or more R d ;

each M is independently hydrogen, halo, CF 3 , CF 2 H, hydroxy, cyano, nitro, (C 1 -C 6 )alkyl, hydroxy(C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, —NR a R b , aryl, heteroaryl or heterocycle;

each X is independently NL, oxygen, C(Q) 2 , or S(O) z ;

each L is independently hydrogen, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, —C(O)O(C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy(C 1 -C 6 )alkyl, hydroxy(C 1 -C 6 )alkyl, aryl, heteroaryl, heterocycle, —CONR e R f , —S(O) z (C 1 -C 6 )alkyl, —C(O)(C 1 -C 6 )alkyl, —C(O)NR g (C 1 -C 6 )alkyl, (C 1 -C 6 )alkyl optionally substituted with up to 5 fluoro, or (C 1 -C 6 )alkoxy optionally substituted with up to 5 fluoro;

p is an integer selected from 0, 1, 2 and 3,

z is an integer selected from 0, 1, and 2; and

n is an integer selected from 0, 1, and 2.

2. The compound of claim 1 , wherein Ar is a heteroaryl selected from the group consisting of thienyl and pyridyl, each optionally substituted with one or more M.

3. The compound of claim 1 that has the formula Ia:

or a tautomer thereof, or their pharmaceutically acceptable salts,

wherein Y is CM or N.

4. The compound of claim 3 that has the formula Ib:

or a tautomer thereof, or their pharmaceutically acceptable salts,

wherein Y is CM or N.

5. The compound of claim 4 that has the formula Ic:

or a tautomer thereof, or their pharmaceutically acceptable salts,

wherein Y is CM or N.

6. The compound of claim 4 that has the formula Id:

or a tautomer thereof, or their pharmaceutically acceptable salts, wherein Y is CM or N.

7. The compound of claim 4 that has the formula Ie:

or a tautomer thereof, or their pharmaceutically acceptable salts,

wherein Y is CM or N.

8. The compound of claim 4 that has the formula If:

or a tautomer thereof, or their pharmaceutically acceptable salts,

wherein Y is CM or N.

9. The compound of claim 3 that has the formula Ig:

or a tautomer thereof, or their pharmaceutically acceptable salts,

wherein Y is CM or N.

10. The compound of claim 9 that has the formula Ih:

or a tautomer thereof, or their pharmaceutically acceptable salts,

wherein Y is CM or N.

11. The compound of claim 9 that has the formula Ii:

or a tautomer thereof, or their pharmaceutically acceptable salts,

wherein Y is CM or N.

12. The compound of claim 9 that has the formula Ij:

or a tautomer thereof, or their pharmaceutically acceptable salts,

wherein Y is CM or N.

13. The compound of claim 9 that has the formula Ik:

or a tautomer thereof, or their pharmaceutically acceptable salts,

wherein Y is CM or N.

14. The compound of claim 3 that has the formula Il:

or a tautomer thereof, or their pharmaceutically acceptable salts,

wherein Y is CM or N.

15. The compound of claim 14 that has the formula Im:

or a tautomer thereof, or their pharmaceutically acceptable salts,

wherein Y is CM or N.

16. The compound of claim 14 that has the formula In:

or a tautomer thereof, or their pharmaceutically acceptable salts,

wherein Y is CM or N.

17. The compound of claim 14 that has the formula Io:

or a tautomer thereof, or their pharmaceutically acceptable salts,

wherein Y is CM or N.

18. The compound of claim 14 that has the formula Ip:

or a tautomer thereof, or their pharmaceutically acceptable salts,

wherein Y is CM or N.

19. The compound of claim 18 that has the formula Iq:

or a tautomer thereof, or their pharmaceutically acceptable salts,

wherein Y is CM or N.

20. The compound of claim 18 that has the formula Ir:

or a tautomer thereof, or their pharmaceutically acceptable salts,

wherein Y is CM or N.

21. The compound of claim 3 that has the formula Is:

or a tautomer thereof, or their pharmaceutically acceptable salts,

wherein Y is CM or N.

22. The compound of claim 21 that has the formula It:

or a tautomer thereof, or their pharmaceutically acceptable salts,

wherein Y is CM or N.

23. The compound of claim 21 that has the formula Iu:

or a tautomer thereof, or their pharmaceutically acceptable salts,

wherein Y is CM or N.

24. The compound of claim 21 that has the formula Iv:

or a tautomer thereof, or their pharmaceutically acceptable salts,

wherein Y is CM or N.

25. The compound of claim 21 that has the formula Iw:

or a tautomer thereof, or their pharmaceutically acceptable salts,

wherein Y is CM or N.

26. The compound of claim 25 that has the formula Ix:

or a tautomer thereof, or their pharmaceutically acceptable salts,

wherein Y is CM or N.

27. The compound of claim 25 that has the formula Iy:

or a tautomer thereof, or their pharmaceutically acceptable salts,

wherein Y is CM or N.

28. The compound of claim 3 that has the formula Iz:

or a tautomer thereof, or their pharmaceutically acceptable salts,

wherein Y is CM or N.

29. The compound of claim 28 that has the formula Iaa:

or a tautomer thereof, or their pharmaceutically acceptable salts,

wherein Y is CM or N.

30. The compound of claim 29 that has the formula Iab:

or a tautomer thereof, or their pharmaceutically acceptable salts,

wherein Y is CM or N.

31. The compound of claim 29 that has the formula Iac:

or a tautomer thereof, or their pharmaceutically acceptable salts,

wherein Y is CM or N.

32. The compound of claim 29 that has the formula Iad:

or a tautomer thereof, or their pharmaceutically acceptable salts,

wherein Y is CM or N.

33. The compound of claim 29 that has the formula Iae:

or a tautomer thereof, or their pharmaceutically acceptable salts,

wherein Y is CM or N.

34. The compound of claim 28 that has the formula Iaf:

or a tautomer thereof, or their pharmaceutically acceptable salts,

wherein Y is CM or N.

35. The compound of claim 34 that has the formula Iag:

or a tautomer thereof, or their pharmaceutically acceptable salts,

wherein Y is CM or N.

36. The compound of claim 34 that has the formula Iah:

or a tautomer thereof, or their pharmaceutically acceptable salts,

wherein Y is CM or N.

37. The compound of claim 34 that has the formula Iaj:

or a tautomer thereof, or their pharmaceutically acceptable salts,

wherein Y is CM or N.

38. The compound of claim 34 that has the formula Iak:

or a tautomer thereof, or their pharmaceutically acceptable salts,

wherein Y is CM or N.

39. The compound of claim 1 , having the structure

or a tautomer thereof, or their pharmaceutically acceptable salts.

40. A pharmaceutical composition comprising:

a) compound of claim 1 ; and

b) a pharmaceutically acceptable carrier.