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 method of treating an animal in need of enhancement of memory or cognition comprising administering to the animal an effective amount of 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, 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;
each R a and R b are independently hydrogen, (C 1 -C 6 )alkyl, aryl, (C 1 -C 6 )alkylOC(O)—, or arylOC(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 comprise one or more groups selected from the group consisting of 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(O)Oaryl, (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, heteroaryl, heterocycle, arylO(C 1 -C 6 )alkyl, —C(O)NR g (C 1 -C 6 )alkyl, —C(O)NR g aryl, —S(O) z (C 1 -C 6 )alkyl, —S(O) z aryl, —C(O)(C 1-6 )alkyl, arylC(O)—, (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, aryl, aryl(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, aryl, —S(O) z (C 1 -C 6 )alkyl, —S(O) z aryl, —CONR g (C 1 -C 6 alkyl), (C 1 -C 6 )alkylC(O)—, arylC(O)—, (C 1 -C 6 )alkylOC(O)—, and arylOC(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 comprise one or more groups selected from the group consisting of 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, —NR a R b , aryl, heteroaryl or heterocycle.
2. The method of claim 1 , 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 comprise one or more groups selected from the group consisting of O (oxygen), S(O) z , 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(O)Oaryl, (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 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)—; 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 .
3. The method of claim 1 , wherein said animal has age-associated memory impairment.
4. The method of claim 1 , wherein said animal has mild cognitive impairment.
5. The method of claim 1 , wherein said animal has Alzheimer's disease.
6. The method of claim 1 , wherein the animal is a mammal.
7. The method of claim 1 , wherein the animal is an aged animal.
8. A method of treating an animal in need of enhancement of memory or cognition comprising administering to the animal an effective amount of 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 comprise one or more groups selected from the group consisting of 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 comprise one or more groups selected from the group consisting of 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 .
9. The method of claim 8 , wherein Ar is a heteroaryl selected from the group consisting of thienyl and pyridyl, each optionally substituted with one or more R 8 .
10. The method of claim 8 ,
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 comprise one or more groups selected from the group consisting of O (oxygen), and NR c ; and
R 7 is hydrogen or (C 1 -C 6 )alkyl optionally substituted with up to 5 fluoro.
11. The method of claim 8 , wherein said animal has Alzheimer's disease.
12. The method of claim 8 , wherein said animal has an anxiety disorder, sleep disorder, depression, or schizophrenia.
13. The method of claim 8 , wherein said animal has Parkinson's disease, or Huntington's disease.
14. The method of claim 8 , wherein said animal has head trauma.