Therapeutic pyrazoloquinoline urea derivatives
The invention provides a novel chemical series of formula I, as well as methods of use thereof for binding to the benzodiazepine site of the GABA A receptor and modulating GABA A , and use of the compound of formula I for the treatment of GABA A receptor associated disorders. The general structure of formula I is shown below: The invention further provides a method of modulation of one or more GABA A subtypes in an animal comprising administering to the animal an effective amount of a compound of formula (I).
1. A compound of formula I:
or a pharmaceutically acceptable salt thereof,
wherein:
R 1 , R 2 , R 3 , and R 4 are each independently 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;
each R a and R b are independently hydrogen, (C 1 -C 6 )alkyl, or (C 1 -C 6 )alkylOC(O)—, 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(O) z , and NR c ;
each z is an integer selected from 0, 1, and 2;
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, (C 1 -C 6 )alkylO(CH 2 ) m —, hydroxy(C 1 -C 6 )alkyl, aryl, —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 m is an integer selected from 2, 3, 4, 5, and 6;
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;
R e and R f are each independently selected from the group consisting of hydrogen, (C 1 -C 6 )alkyl, —S(O) z (C 1 -C 6 )alkyl, —CONR g (C 1 -C 6 alkyl), (C 1 -C 6 )alkylC(O)—, and (C 1 -C 6 )alkylOC(O)—;
R g is hydrogen or (C 1 -C 6 )alkyl;
R 5 and R 6 are each independently selected from the group consisting of hydrogen, (C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, and aryl, or R 5 and R 6 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(O) z , and NR c ;
R 7 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;
Ar is aryl, or heteroaryl, each optionally substituted with one or more R 8 ; and
each R 8 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 .
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 R 8 .
3. The compound of claim 1 ,
wherein:
R 1 , R 2 , R 3 , and R 4 are each independently hydrogen, halo, cyano, (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;
R 5 and R 6 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), and NR c ; and
R 7 is hydrogen or (C 1 -C 6 )alkyl optionally substituted with up to 5 fluoro.
4. The compound of claim 1 that has the formula Ia:
or a pharmaceutically acceptable salt thereof.
5. The compound of claim 1 wherein R 5 and R 6 , together with the nitrogen to which they are attached, form a piperidinyl, pyrrolidinyl, morpholinyl, or thiomorpholinyl ring.
6. The compound of claim 1 that has the formula Ib
or a pharmaceutically acceptable salt thereof,
wherein:
X is N(R c ), O (oxygen), C(R d ) 2 , or S(O) z ;
z is an integer selected from 0, 1, and 2;
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; and
n is an integer selected from 0, 1, and 2; with the proviso that when n=0 then X is C(R d ) 2 .
7. The compound of claim 6 that has the formula Ic:
or a pharmaceutically acceptable salt thereof.
8. The compound of claim 4 that has the formula Id:
or a pharmaceutically acceptable salt thereof,
wherein
n is an integer selected from 0, 1, and 2.
9. The compound of claim 8 wherein n is 0.
10. The compound of claim 8 wherein n is 1.
11. The compound of claim 8 wherein n is 2.
12. The compound of claim 8 wherein R 2 is Methyl.
13. The compound of claim 8 wherein R 2 is trifluoromethyl.
14. The compound of claim 8 wherein R 2 is fluoro.
15. The compound of claim 8 wherein R 2 is OMe.
16. The compound of claim 8 wherein R 3 is Methyl.
17. The compound of claim 8 wherein R 3 is fluoro.
18. The compound of claim 8 wherein R 3 is OMe.
19. The compound of claim 8 wherein R 7 is Methyl.
20. The compound of claim 8 wherein R 2 and R 3 are fluoro.
21. The compound of claim 8 wherein R 2 and R 3 are Methyl.
22. The compound of claim 8 wherein R 2 is fluoro and R 3 is methyl.
23. The compound of claim 8 that has the formula Ie:
or a pharmaceutically acceptable salt thereof.
24. The compound of claim 1 that has the formula II:
or a pharmaceutically acceptable salt thereof,
wherein:
each Y is independently N or C(R 8 ).
25. The compound of claim 24 wherein R 5 and R 6 , together with the nitrogen to which they are attached, form a piperidinyl, pyrrolidinyl, morpholinyl, or thiomorpholinyl ring, each optionally substituted with one or more R d .
26. The compound of claim 24 that has the formula IIb:
or a pharmaceutically acceptable salt thereof,
wherein:
n is an integer selected from 0, 1, and 2.
27. The compound of claim 26 wherein n is 0.
28. The compound of claim 26 wherein n is 1.
29. The compound of claim 26 wherein n is 2.
30. The compound of claim 26 wherein R 2 is Methyl.
31. The compound of claim 26 wherein R 2 is trifluoromethyl.
32. The compound of claim 26 wherein R 2 is fluoro.
33. The compound of claim 26 wherein R 2 is OMe.
34. The compound of claim 26 wherein R 3 is Methyl.
35. The compound of claim 26 wherein R 3 is fluoro.
36. The compound of claim 26 wherein R 3 is OMe.
37. The compound of claim 26 wherein R 7 is Methyl.
38. The compound of claim 26 wherein R 2 and R 3 are fluoro.
39. The compound of claim 26 wherein R 2 and R 3 are Methyl.
40. The compound of claim 26 wherein R 2 is fluoro and R 3 is methyl.
41. The compound of claim 26 that has the formula IIc:
or a pharmaceutically acceptable salt thereof.
42. The compound of claim 24 that has the formula IId:
or a pharmaceutically acceptable salt thereof.
43. The compound of claim 24 that has the formula IIe:
or a pharmaceutically acceptable salt thereof.
44. The compound of claim 24 that has the formula IIf:
or a pharmaceutically acceptable salt thereof.
45. The compound of claim 1 that is selected from the group consisting of
or a pharmaceutically acceptable salt thereof.
46. A pharmaceutical composition comprising:
a) a compound of claim 1 ; and
b) a pharmaceutically acceptable carrier.