Therapeutic 5,6,5-tricyclic analogs
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 negatively modulating the α5 subtype of GABA A , and use of the compound of formula I in the manufacture of a medicament for the treatment of GABA A receptor associated disorders. 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 tautomer thereof, or their pharmaceutically acceptable salts,
wherein:
Z 1 , Z 2 and Z 3 are each independently N (nitrogen), NR 7 or CR 8 , wherein at least one of Z 1 , Z 2 or Z 3 is NR 7 ;
R 7 is —C(═Y)NR 1 R 2 ;
R 8 is hydrogen, halo, (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;
Y is O (oxygen) or S (sulfur);
R 1 and R 2 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, hydroxy(C 1 -C 6 )alkyl, (C 1 -C 6 )alkylOR a , (C 1 -C 6 )alkyl optionally substituted with up to 5 fluoro, (C 1 -C 6 )alkyl optionally substituted with up to 5 chloro, (C 1 -C 6 )alkoxy optionally substituted with up to 5 fluoro, (C 1 -C 6 )alkylNR a R b , and aryl, or R 1 and R 2 are taken together with the nitrogen to which they are attached to form a heterocycle group optionally substituted with one or more R c ; wherein the heterocycle group optionally include one or more groups selected from O (oxygen), S(O) x , and NR d ;
x is 0, 1 or 2;
Ar is aryl, or heteroaryl, each optionally substituted with one or more M;
R 3 is hydrogen or oxide;
R 4 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, aryl, heteroaryl, heterocycle, (C 1 -C 6 )alkylaryl, —S(O) x (C 1 -C 6 )alkyl, —S(O)-aryl, or —C(O)(C 1 -C 6 )alkyl;
each R c is independently hydrogen, aryl, heteroaryl, heterocycle or (C 1 -C 6 )alkyl optionally substituted with up to 5 fluoro;
each R d is independently hydrogen, halo, oxo, hydroxy, —C(O)NR e R f , cyano, nitro, 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, (C 1 -C 6 )alkoxy optionally substituted with up to 5 fluoro, or (C 1 -C 6 )alkyl substituted with one or more R dd ;
R dd is hydroxyl, alkoxy, alkylamino or halo;
each M is independently hydrogen, halo, CF 3 , CF 2 H, hydroxy, methoxy, trifluoromethoxy, 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; and
each R e and R f is independently (C 1 -C 6 )alkyl.
2. The compound of claim 1 , wherein Ar is:
where W is CM or N (nitrogen).
3. The compound of claim 1 having the formula Ia:
or a tautomer thereof, or their pharmaceutically acceptable salts,
wherein W is CM or N (nitrogen); Y is O (oxygen) or S (sulfur); and each M is independently hydrogen, halo, CF 3 , CF 2 H, hydroxy, methoxy, (C 1 -C 6 )alkyl, hydroxy(C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, aryl, heteroaryl or heterocycle.
4. The compound of claim 1 having the formula Ib:
or a tautomer thereof, or their pharmaceutically acceptable salts,
wherein W is CM or N (nitrogen); Y is O (oxygen) or S (sulfur); and each M is independently hydrogen, halo, CF 3 , CF 2 H, hydroxy, methoxy, (C 1 -C 6 )alkyl, hydroxy(C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, aryl, heteroaryl or heterocycle.
5. The compound of claim 1 having the formula Ic:
or a tautomer thereof, or their pharmaceutically acceptable salts,
wherein W is CM or N (nitrogen); Y is O (oxygen) or S (sulfur); and each M is independently hydrogen, halo, CF 3 , CF 2 H, hydroxy, methoxy, (C 1 -C 6 )alkyl, hydroxy(C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, aryl, heteroaryl or heterocycle.
6. The compound of claim 1 having the formula Id:
or a tautomer thereof, or their pharmaceutically acceptable salts,
wherein W is CM or N (nitrogen); Y is O (oxygen) or S (sulfur); and each M is independently hydrogen, halo, CF 3 , CF 2 H, hydroxy, methoxy, (C 1 -C 6 )alkyl, hydroxy(C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, aryl, heteroaryl or heterocycle.
7. The compound of claim 1 having the formula Ie:
or a tautomer thereof, or their pharmaceutically acceptable salts,
wherein W is CM or N (nitrogen); Y is O (oxygen) or S (sulfur); and each M is independently hydrogen, halo, CF 3 , CF 2 H, hydroxy, methoxy, (C 1 -C 6 )alkyl, hydroxy(C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, aryl, heteroaryl or heterocycle.
8. The compound of claim 1 having the formula Ig:
or a tautomer thereof, or their pharmaceutically acceptable salts,
wherein W is CM or N (nitrogen); Y is O (oxygen) or S (sulfur); and each M is independently hydrogen, halo, CF 3 , CF 2 H, hydroxy, methoxy, (C 1 -C 6 )alkyl, hydroxy(C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, aryl, heteroaryl or heterocycle.
9. The compound of claim 1 having the formula IIa:
or a tautomer thereof, or their pharmaceutically acceptable salts,
wherein R 7 is —C(═O)NR 1 R 2 ; W is CM or N (nitrogen); and each M is independently hydrogen, halo, CF 3 , CF 2 H, hydroxy, methoxy, (C 1 -C 6 )alkyl, hydroxy(C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, aryl, heteroaryl or heterocycle.
10. The compound of claim 1 having the formula IIb:
or a tautomer thereof, or their pharmaceutically acceptable salts,
wherein R 7 is —C(═S)NR 1 R 2 ; wherein W is CM or N (nitrogen); and each M is independently hydrogen, halo, CF 3 , CF 2 H, hydroxy, methoxy, (C 1 -C 6 )alkyl, hydroxy(C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, aryl, heteroaryl or heterocycle.
11. A compound selected from the group consisting of:
or a tautomer thereof, or their pharmaceutically acceptable salts.
12. A pharmaceutical composition comprising:
a) a compound of claim 1 ; and
b) a pharmaceutically acceptable carrier.