Condensed n-heterocyclic compounds and their use as crf receptor antagonists

1 . A compound, including stereoisomers, of formula (I)

or a prodrug, or a pharmaceutically acceptable salt or solvate thereof, wherein the dashed line may represent a double bond;

R is aryl or heteroaryl, each of which may be substituted by 1 to 4 groups J selected from:

halogen, C1-C6 alkyl, C1-C6 alkoxy, halo C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halo C1-C6 alkoxy, —C(O)R 2 , nitro, hydroxy, —NR 3 R 4 , cyano, and or a group Z;

R 1 is hydrogen, C3-C7 cycloalkyl, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 thioalkyl, C2-C6 alkenyl, C2-C6 alkynyl, halo C1-C6 alkyl, halo C1-C6 alkoxy, halogen, NR 3 R 4 , or cyano;

R 2 is a C1-C4 alkyl, —OR 3 , or —NR 3 R 4 ;

R 3 is hydrogen or C1-C6 alkyl;

R 4 is hydrogen or C1-C6 alkyl;

R 5 is a C1-C6 alkyl, halo C1-C6 alkyl, C1-C6 alkoxy, halo C1-C6 alkoxy, C3-C7 cycloalkyl, hydroxy, halogen, nitro, cyano, —NR 3 R 4 , or —C(O)R 2 ;

R 6 is a C1-C6 alkyl, halo C1-C6 alkyl, C1-C6 alkoxy, halo C1-C6 alkoxy, C3-C7 cycloalkyl, hydroxy, halogen, nitro, cyano, —NR 3 R 4 , or —C(O)R 2 ;

R 7 is hydrogen, C1-C6 alkyl, halogen, halo, or C1-C6 alkyl;

R 8 is hydrogen, C3-C7 cycloalkyl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, NR 3 R 4 , or cyano;

R 9 is hydrogen, C3-C7 cycloalkyl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, NR 3 R 4 , or cyano;

R 10 is hydrogen, C3-C7 cycloalkyl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, NR 3 R 4 , or cyano;

R 11 is hydrogen, C3-C7 cycloalkyl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, NR 3 R 4 , or cyano;

R 12 is hydrogen, C3-C7 cycloalkyl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, NR 3 R 4 , or cyano;

R 13 is hydrogen, C3-C7 cycloalkyl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, NR 3 R 4 , or cyano;

R 14 is R 3 or —C(O)R 2 ;

D is CR 8 R 9 or is CR 8 when double bonded with G or A;

G is CR 10 R 11 or is CR 10 when double bonded with D or is CR 10 when double bonded with X when X is carbon;

A is CR 12 R 13 or is CR 12 when double bonded with D;

X is carbon or nitrogen;

Y is nitrogen or —CR 7 ;

W is a 4-8 carbocyclic membered ring, which may be saturated or may contain one to three double bonds, and

in which:

one carbon atom is replaced by a carbonyl or S(O) m ; and

one to four carbon atoms may optionally be replaced by oxygen, nitrogen or NR 14 , S(O) m , carbonyl, and such ring may be further substituted by 1 to 8 R 6 groups;

Z is a 5-6 membered heterocycle or a phenyl, which may be substituted by 1 to 8 R 5 groups;

m is an integer from 0 to 2.

2 . A compound according to claim 1 , in which W is selected from the following groups:

in which:

W1 represents a 1,3-dihydro-2H-imidazol-2-one derivative;

W2 represents a imidazolidin-2-one derivative;

W3 represents a tetrahydropyrimidin-2(1H)-one derivative;

W4 represents a 2,5-dihydro-1,2,5-thiadiazole 1-oxide derivative;

W5 represents a 1,2,5-thiadiazolidine 1-oxide derivative;

W6 represents a 2,5-dihydro-1,2,5-thiadiazole 1,1-dioxide derivative;

W7 represents a 1,2,6-thiadiazinane 1-oxide derivative;

W8 represents a 1,2,6-thiadiazinane 1,1-dioxide derivative;

W9 represents a pyrrolidin-2-one derivative;

W10 represents a 2,5-dihydro-1,2,5-thiadiazolidine 1,1-dioxide derivative;

W11 represents a 1,3-oxazolidin-2-one derivative;

W12 represents a isothiazolidine 1,1-dioxide derivative;

W13 represents a 2(1H)-pyridinone derivative;

W14 represents a 3(2H)-pyridazinone;

W15 represents a 2,3-piperazinedione derivative;

and q is an integer from 0 to 4; n is an integer from 0 to 6; p is an integer from 0 to 3; and m, R 6 and R 14 are defined as in claim 1; or a prodrug, or a pharmaceutically acceptable salt or solvate thereof.

3 . A compound according to claim 1 of formula (Ia), (Ib), (Ic), (Id), or (Ie),

in which R, R 1 , Z, Y, W, A, D, G are defined as in claim 1; or a prodrug, or a pharmaceutically acceptable salt or solvate thereof.

4 . A Compounds compound according to claim 1 , selected from the following group:

1-{1-[8-(2,4-dichlorophenyl)-2-methyl-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-4-yl]-1H-pyrazol-3-yl}-2-imidazolidinone;

1-{1-[8-(2,4-dichlorophenyl)-2-methyl-5,6,7,8-tetrahydro-4-quinazolinyl]-1H-pyrazol-3-yl}-2-imidazolidinone; and

1-{1-[8-(2,4-dichlorophenyl)-2-methyl-5,6,7,8-tetrahydro-1,8-naphthyridin-4-yl]-1H-pyrazol-3-yl}-2-imidazolidinone; or a prodrug, or a pharmaceutically acceptable salt or solvate thereof.

5 . A process for preparing a compound of formula (Ia) comprising the following steps:

in which

step a stands for the nucleophilic substitution with a suitable amine of compounds of formula (II), in basic conditions to give compounds (III);

step b stands for the protection of the amino group with a suitable protecting group;

step c stands for the oxidation of the double bond with a suitable oxidizing agent to give the aldehyde of compounds (V);

step d+e stands for formation of the aldehyde group of compounds (VII) through formation of the enol ether by Wittig reaction in the usual conditions, followed by acid hydrolysis (step e);

step f stands for the reduction of the aldehyde group of compounds (VII) to the alcohol of compounds (VIII) with a suitable reducing agent;

step g stands for the conversion of the alcohol of compounds (VIII) into a suitable leaving group;

step h stands for the deprotection of the amino group of compounds (IX);

step i stands for the intramolecular cyclization to give the cyclized compounds (X)

step j stands for conversion of the halogen derivative, preferably chloride, into compounds (Ia), by reaction with the suitable reactive -Z-W derivative, in basic conditions.

6 - 9 . (canceled)

10 . A pharmaceutical composition comprising a compound of claim 1 , or a prodrug, or a pharmaceutically acceptable salt or solvate thereof, in admixture with one or more physiologically acceptable carriers or excipients.

11 . A method for the treatment of a condition mediated by CRF (corticotropin-releasing factor), comprising administration of an effective amount of a compound according to claim 1 , or a prodrug, or a pharmaceutically acceptable salt or solvate thereof, to a mammal in need thereof.

12 . A method in the treatment of depression and anxiety, comprising administration of an effective amount of a compound according to claim 1 , or a prodrug, or a pharmaceutically acceptable salt or solvate thereof, to a mammal in need thereof.

13 . A method in the treatment of IBS (irritable bowel disease) and IBD (inflammatory bowel disease), comprising administration of an effective amount of a compound according to claim 1 , or a prodrug, or a pharmaceutically acceptable salt or solvate thereof, to a mammal in need thereof.