Therapeutic pyrazolonaphthyridine derivatives

1. A compound of formula (I):

or tautomer thereof, or their pharmaceutically acceptable salts,

wherein:

R is hydrogen, or oxide;

Z 1 , Z 2 , Z 3 , and Z 4 are each independently N, or C(R 1 ), wherein at least one of Z 1 , Z 2 , Z 3 , or Z 4 are N and at least two of Z 1 , Z 2 , Z 3 , or Z 4 are C(R 1 );

each R 1 is independently selected from the group consisting of hydrogen, hydroxy, halo, cyano, B 1 , —CONR a R b , —NR a R b , hydroxy(C 1 -C 6 )alkyl, aryl, heteroaryl, heterocycle, 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, wherein at least one R 1 is B 1 ;

B 1 is

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 and R b are taken together with the nitrogen to which they are attached to 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 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, or (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, —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, aryl, heteroaryl, heterocycle, 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 , 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, or —NR a R b ;

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, arylC(O)—, —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 that has the formula Ia:

or a tautomer thereof, or their pharmaceutically acceptable salts,

wherein Y is CM or N.

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

or a tautomer thereof, or their pharmaceutically acceptable salts,

wherein Y is CM or N.

4. The compound of claim 2 , wherein at least one X is NL.

5. The compound of claim 3 , wherein at least one X is NL.

6. The compound of claim 1 , wherein

at least one B 1 is

7. The compound of claim 6 , wherein Z 1 is N.

8. The compound of claim 6 , wherein Z 2 is N.

9. The compound of claim 2 that has the formula Ih:

or a tautomer thereof, or their pharmaceutically acceptable salts,

wherein Y is CM or N.

10. The compound of claim 9 , wherein at least one X is NL.

11. The compound of claim 9 , wherein at least one X is oxygen.

12. The compound of claim 2 that has the formula Ik:

or a tautomer thereof, or their pharmaceutically acceptable salts,

wherein Y is CM or N.

13. The compound of claim 12 , wherein at least one X is NL.

14. The compound of claim 12 , wherein at least one X is oxygen.

15. The compound of claim 3 that has the formula In:

or a tautomer thereof, or their pharmaceutically acceptable salts,

wherein Y is CM or N.

16. The compound of claim 15 , wherein at least one X is NL.

17. The compound of claim 15 , wherein at least one X is oxygen.

18. The compound of claim 1 that has the formula Iq:

or a tautomer thereof, or their pharmaceutically acceptable salts,

wherein Y is CM or N.

19. The compound of claim 18 ,

wherein:

Z 1 is N; and

Z 2 is C(R 1 ).

20. The compound of claim 18 ,

wherein:

Z 2 is N; and

Z 1 is C(R 1 ).

21. The compound of claim 19 , wherein at least one X is NL.

22. The compound of claim 20 , wherein at least one X is NL.

23. The compound of claim 19 , wherein at least one X is oxygen.

24. The compound of claim 20 , wherein at least one X is oxygen.

25. A compound selected from the group consisting of:

or a tautomer thereof, or their pharmaceutically acceptable salts.

26. A pharmaceutical composition comprising:

a) a compound claim 1 ; and

b) a pharmaceutically acceptable carrier.