Azinone and diazinone V3 inhibitors for depression and stress disorders

1. A compound of formula:

or a pharmaceutically acceptable salt thereof, wherein

X 4 -X 5 is chosen from CR 4 —CR 5 ;

one of X 6 , X 7 and X 8 is N and the other two are CR 4 and CR 5 ;

R 1 is chosen from (C 1-10 )alkyl, (C 3-10 )cycloalkyl, and [(C 3-10 )cycloalkyl(C 1-2 )alkyl], said (C 1-10 )alkyl, (C 3-10 )cycloalkyl, and [(C 3-10 )cycloalkyl(C 1-2 )alkyl] being optionally substituted with one or more halogens, (C 1-6 )alkoxy, (C 2-6 )alkenyl, (C 2-6 )alkynyl, phenyl or benzyl;

Ar is chosen from

(i) (C 6-10 )aryl, optionally substituted within 1-3 substituents selected from halogen, hydroxy, cyano, COOR 5 , phenyl, (C 5-6 )heteroaryl, (C 1-6 )alkyl, (C 3-6 )cycloalkyl, (C 1-6 )alkyloxy and (C 3-6 )cycloalkyloxy, said (C 1-6 )alkyl, (C 3-6 )cycloalkyl, (C 1-6 )alkyloxy and (C 3-6 )cycloalkyloxy being optionally substituted with one or more halogens;

(ii) (C 5-10 )heteroaryl optionally substituted with a substituent selected from methyl, (C 1-6 )alkyloxy or halogen; and

(iii) (C 4-7 )cycloalkyl;

R 4 and R 5 are independently chosen from H, (C 1-6 )alkyl, (C 1-6 )alkyloxy or halogen, said (C 1-6 )alkyl, (C 1-6 )alkyloxy being optionally substituted with one or more halogens;

G is a linking moiety spanning 4 to 7 atoms between termini; and

R 8 and R 9 are hydrogen or alkyl, or NR 8 R 9 is a saturated nitrogenous heterocycle of 3-10 carbons in one or two rings.

2. A compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein G is a linking moiety spanning 4 to 7 atoms between termini, said linking moiety incorporating at least one of

(a) an sp2 hybridized carbon,

(b) a cyclic structure, and

(c) when the nitrogen bearing R 8 and R 9 is part of a 4- to 7-membered nitrogenous heterocycle, G may additionally be —(C 4-7 )alkylene or —N(R 10 )—(C 3-6 )alkylene; and R 10 is H or (C 1-6 )alkyl.

3. A compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein at least one of R 8 and R 9 is other than hydrogen.

4. A compound of formula

or a pharmaceutically acceptable salt thereof, wherein

R 1 is C 3 -C 6 alkyl;

X 4 -X 5 is CR 4 —CR 5 ;

R 4 and R 5 are independently chosen from H, (C 1-6 )alkyl, (C 1-6 )alkyloxy or halogen, said (C 1-6 )alkyl, (C 1-6 )alkyloxy being optionally substituted with one or more halogens;

Ar is chosen from

(i) (C 6-10 )aryl, optionally substituted with 1-3 substituents selected from halogen, hydroxy, cyano, COOR 5 , phenyl, (C 5-6 )heteroaryl, (C 1-6 )alkyl, (C 3-6 )cycloalkyl, (C 1-6 )alkyloxy and (C 3-6 )cycloalkyloxy, said (C 1-6 )alkyl, (C 3-6 )cycloalkyl, (C 1-6 )alkyloxy and (C 3-6 )cycloalkyloxy being optionally substituted with one or more halogens;

(ii) (C 5-10 )heteroaryl optionally substituted with a substituent selected from methyl, (C 1-6 )alkyloxy or halogen; and

(iii) (C 4-7 )cycloalkyl; and

R 10 is H or (C 1-6 )alkyl;

and

is a saturated nitrogenous heterocycle of 3 to 10 carbons in one or two rings.

5. A compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein both of R 8 and R 9 are other than hydrogen.

6. A compound of formula:

or a pharmaceutically acceptable salt thereof, wherein

X 4 -X 5 is chosen from CR 4 —CR 5 ;

R 1 is chosen from (C 1-10 )alkyl, (C 3-10 )cycloalkyl, [(C 3-10 )cycloalkyl(C 1-2 )alkyl], said (C 1-10 )alkyl, (C 3-10 )cycloalkyl, and [(C 3-10 )cycloalkyl(C 1-2 )alkyl] being optionally substituted with one or more halogens, (C 1-6 )alkoxy, (C 2-6 )alkenyl, (C 2-6 )alkynyl, phenyl or benzyl;

Ar is (C 6-10 )aryl, optionally substituted with 1-3 substituents selected from halogen, hydroxy, cyano, COOR 5 , phenyl, (C 5-6 )heteroaryl, (C 1-6 )alkyl, (C 3-6 )cycloalkyl, (C 1-6 )alkyloxy and (C 3-6 )cycloalkyloxy, said (C 1-6 )alkyl, (C 3-6 )cycloalkyl, (C 1-6 )alkyloxy and (C 3-6 )cycloalkyloxy being optionally substituted with one or more halogens, or Ar is a (C 5-10 )heteroaryl optionally substituted with a substituent selected from methyl, (C 1-6 )alkyloxy or halogen or R 2 is (C 4-7 )cycloalkyl;

R 4 and R 5 are independently chosen from H, (C 1-6 )alkyl, (C 1-6 )alkyloxy or halogen, said (C 1-6 )alkyl, (C 1-6 )alkyloxy being optionally substituted with one or more halogens;

R 8 and R 9 are hydrogen or alkyl, or NR 8 R 9 is a 4- to 7-membered nitrogenous heterocycle;

G is a linking moiety spanning 4 to 7 atoms between termini, said linking moiety incorporating at least one of

(a) an sp2 hybridized carbon,

(b) a cyclic structure, and

(c) when the nitrogen bearing R 8 and R 9 is part of a 4- to 7-membered nitrogenous heterocycle, G may additionally be —(C 4-7 )alkylene or —N(R 10 )—(C 3-6 )alkylene; and

R 10 is H or (C 1-6 )alkyl.

7. A compound chosen from formulae:

or a pharmaceutically acceptable salt thereof, wherein

X 4 -X 5 is chosen from CR 4 —CR 5 ;

R 1 is chosen from (C 1-10 )alkyl, (C 3-10 )cycloalkyl, [(C 3-10 )cycloalkyl(C 1-2 )alkyl], said (C 1-10 )alkyl, (C 3-10 )cycloalkyl, and [(C 3-10 )cycloalkyl(C 1-2 )alkyl] being optionally substituted with one or more halogens, (C 1-6 )alkoxy, (C 2-6 )alkenyl, (C 2-6 )alkynyl, phenyl or benzyl;

Ar is (C 6-10 )aryl, optionally substituted with 1-3 substituents selected from halogen, hydroxy, cyano, COOR 5 , phenyl, (C 5-6 )heteroaryl, (C 1-6 )alkyl, (C 3-6 )cycloalkyl, (C 1-6 )alkyloxy and (C 3-6 )cycloalkyloxy, said (C 1-6 )alkyl, (C 3-6 )cycloalkyl, (C 1-6 )alkyloxy and (C 3-6 )cycloalkyloxy being optionally substituted with one or more halogens, or Ar is a (C 5-10 )heteroaryl optionally substituted with a substituent selected from methyl, (C 1-6 )alkyloxy or halogen or R 2 is (C 4-7 )cycloalkyl;

R 4 and R 5 are independently chosen from H, (C 1-6 )alkyl, (C 1-6 )alkyloxy or halogen, said (C 1-6 )alkyl, (C 1-6 )alkyloxy being optionally substituted with one or more halogens;

R 10 is H or (C 1-6 )alkyl;

E is (C 2-10 )hydrocarbon; and

is a saturated nitrogenous heterocycle of 3 to 10 carbons in one or two rings.

8. A compound according to claim 7 or a pharmaceutically acceptable salt thereof, wherein

is a piperidine or morpholine ring.

9. A compound of formula:

or a pharmaceutically acceptable salt thereof, wherein

X 4 -X 5 is chosen from CR 4 —CR 5 ;

R 1 is chosen from (C 1-10 )alkyl, (C 3-10 )cycloalkyl, [(C 3-10 )cycloalkyl(C 1-2 )alkyl], said (C 1-10 )alkyl, (C 3-10 )cycloalkyl, and [(C 3-10 )cycloalkyl(C 1-2 )alkyl] being optionally substituted with one or more halogens, (C 1-6 )alkoxy, (C 2-6 )alkenyl, (C 2-6 )alkynyl, phenyl or benzyl;

Ar is (C 6-10 )aryl, substituted with 1-3 substituents selected from halogen, hydroxy, cyano, COOR 5 , phenyl, (C 5-6 )heteroaryl, (C 1-6 )alkyl, (C 3-6 )cycloalkyl, (C 1-6 )alkyloxy and (C 3-6 )cycloalkyloxy, said (C 1-6 )alkyl, (C 3-6 )cycloalkyl, (C 1-6 )alkyloxy and (C 3-6 )cycloalkyloxy being optionally substituted with one or more halogens, or Ar is a (C 5-10 )heteroaryl optionally substituted with a substituent selected from methyl, (C 1-6 )alkyloxy or halogen or R 2 is (C 4-7 )cycloalkyl;

R 4 and R 5 are independently chosen from H, (C 1-6 )alkyl, (C 1-6 )alkyloxy or halogen, said (C 1-6 )alkyl, (C 1-6 )alkyloxy being optionally one or more halogens;

R 8 and R 9 are hydrogen or alkyl, or NR 8 R 9 is a saturated nitrogenous heterocycle of 3-10 carbons in one or two rings;

J is a direct bond or (C 1-6 )hydrocarbon; and

is a single ring carbocycle or heterocycle of 4 to 7 atoms or a two ring carbocycle or heterocycle of 9 to 13 atoms.

10. A compound according to claim 9 or a pharmaceutically acceptable salt thereof, wherein

is a five or six-membered nitrogenous heterocycle and J is methylene, ethylene or propylene.

11. A compound according to claim 10 or a pharmaceutically acceptable salt thereof, wherein —NR 8 R 9 is chosen from

12. A compound according to claim 6 of formula:

or a pharmaceutically acceptable salt thereof, wherein

is a nitrogenous single ring heterocycle of 6 to 8 atoms or a two ring heterocycle of 9 to 13 atoms in which the nitrogen labeled b is the nitrogen of claim 1 and the nitrogen labeled a is subsumed in the definition of G in claim 1 .

13. A compound according to claim 12 or a pharmaceutically acceptable salt thereof, wherein

is a hexahydro-1,4-diazepine ring.

14. A compound according to claim 6 chosen from

formulae:

or a pharmaceutically acceptable salt thereof, wherein

is a saturated nitrogenous heterocycle of 3 to 10 carbons in one or two rings; and R 8 is chosen from hydrogen and C 1-10 hydrocarbon.

15. A compound according to claim 14 or a pharmaceutically acceptable salt thereof, wherein

is a piperidine ring and R 8 is methyl.

16. A compound chosen from formulae:

or a pharmaceutically acceptable salt thereof, wherein X 4 -X 5 is CR 4 —CR 5 ;

R 1 is chosen from (C 1-10 )alkyl, (C 3-6 )cycloalkyl, (C 3-6 )cycloalkyl (C 1-2 )alkyl, said (C 1-10 )alkyl, (C 3-6 )cycloalkyl, and (C 3-6 )cycloalkyl (C 1-2 )alkyl being optionally substituted with one or more halogens, (C 2-6 )alkenyl, (C 2-6 )alkynyl, phenyl or benzyl;

Ar is (C 6-10 )aryl, optionally substituted with 1-3 substituents selected from halogen, hydroxy, cyano, COOR 5 , phenyl, (C 5-6 )heteroaryl, (C 1-6 )alkyl, (C 3-6 )cycloalkyl, (C 1-6 )alkyloxy and (C 3-6 )cycloalkyloxy, said (C 1-6 )alkyl, (C 3-6 )cycloalkyl, (C 1-6 )alkyloxy and (C 3-6 )cycloalkyloxy being optionally substituted with one or more halogens, or Ar is a (C 5-10 )heteroaryl optionally substituted with a substituent selected from methyl, (C 1-6 )alkyloxy or halogen or R 2 is (C 4-7 )cycloalkyl;

R 4 and R 5 are independently chosen from H, (C 1-6 )alkyl, (C 1-6 )alkyloxy or halogen, said (C 1-6 )alkyl, (C 1-6 )alkyloxy being optionally substituted with one or more halogens;

R 10 is H or (C 1-6 )alkyl; and

Pyr is chosen from imidazole and optionally substituted pyridine attached through a carbon.

17. A compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R 1 is chosen from C 3-6 alkyl, cycloalkyl and C 1-3 alkyl substituted with phenyl, methoxy or alkynyl.

18. A compound according to claim 17 or a pharmaceutically acceptable salt thereof, wherein R 1 is chosen from t-butyl, isopropyl, cyclopentyl, α-methylbenzyl, methoxypropyl and propargyl.

19. A compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein Ar is chosen from phenyl and phenyl substituted with halogen, methyl or methoxy.

20. A pharmaceutical formulation comprising a pharmaceutically acceptable carrier and a compound according to claim 1 or a phamaceutically acceptable salt thereof.

21. A method for treating a disorder chosen from depression, and stress disorders, comprising administering to a patient in need thereof a therapeutically effective amount of a compound according to claim 1 or a pharmaceutically acceptable salt thereof.