Condensed N-Heterocyclic Compounds and their Use as CRF Receptor Antagonists

1 . A compound according to formula (IV)

wherein:

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)R2, nitro, hydroxy, —NR 3 R 4 , cyano and a group Z;

R 1 is hydrogen or C1-C6 alkyl;

R 2 is C1-C4 alkyl;

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 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;

R 8 is hydrogen;

R 9 is hydrogen;

R 10 is hydrogen;

R 11 is hydrogen;

R 12 is R 3 or —C(O)R 2 ;

D is CR 8 R 9 ;

G is CR 10 R 11 ;

Z is a 5-6 membered heterocycle, which may be substituted by 1 to 8 R 5 groups or a phenyl ring, which may be substituted by 1 to 4 R 5 groups;

m is an integer from 0 to 2; and

q is an integer from 0 to 2; or a pharmaceutically acceptable salt thereof.

2 . A compound according to claim 1 wherein:

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 or a group Z;

R 1 is hydrogen, C1-C6 alkyl;

R 2 is a C1-C4 alkyl;

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;

R 8 is hydrogen;

R 9 is hydrogen;

R 10 is hydrogen;

R 11 is hydrogen;

R 12 is hydrogen;

D is CR 8 R 9 ;

G is CR 10 R 11 ;

Z is a 5-6 membered heterocycle, which may be substituted by 1 to 8 R 5 groups or a phenyl ring, which may be substituted by 1 to 4 R 5 groups;

m is an integer from 0 to 2; and

q is 0; or a pharmaceutically acceptable salt thereof.

3 . A compound according to claim 2 wherein Z is selected from the group consisting of pyrimidinyl, pyridinyl, thiazolyl, pyrazolyl, triazolyl and phenyl; or a pharmaceutically acceptable salt thereof.

4 . A compound according to claim 2 wherein R is an aryl group selected from: 2,4-dichlorophenyl, 2-chloro-4-methylphenyl, 2-chloro-4-trifluoromethylphenyl, 2-chloro-4-methoxyphenyl, 2,4,5-trimethylphenyl, 2,4-dimethylphenyl, 2-methyl-4-methoxyphenyl, 2-methyl-4-ethoxyphenyl, 2-methyl-4-isopropoxyphenyl, 2-methyl-4-hydroxyphenyl, 2-methyl-4-chlorophenyl, 2-methyl-4-trifluoromethylphenyl, 2,4-dimethoxyphenyl, 2-methoxy-4-trifluoromethylphenyl, 2-methoxy-4-chlorophenyl, 3-methoxy-4-chlorophenyl, 2,5-dimethoxy-4-chlorophenyl, 2-methoxy-4-isopropylphenyl, 2-methoxy-4-trifluoromethylphenyl, 2-methoxy-4-isopropylphenyl, 2-methoxy-4-methylphenyl, 2-trifluoromethyl-4-chlorophenyl, 2,4-bis-trifluoromethylphenyl, 2-trifluoromethyl-4-methylphenyl, 2-trifluoromethyl-4-methoxyphenyl, 2-difluoromethyl-4-methoxyphenyl, 2-bromo-4-isopropylphenyl, 2-methyl-4-cyanophenyl, 2-chloro-4-cyanophenyl, 2-trifluoromethyl-4-cyanophenyl, 2-trifluoromethoxy-4-cyanophenyl, 2-ethyl-4-cyanophenyl, 2-methyl-4-trifluoromethoxyphenyl, 4-methyl-6-dimethylaminopyridin-3-yl, 2,6-bismethoxy-pyridin-3-yl, 2-methyl-6-methoxy-pyridin-3-yl, 2-trifluoromethyl-6-methoxy-pyridin-3-yl 3-chloro-5-trichloromethyl-pyridin-2-yl, 2-methyl-4-(pyrazol-1-yl)-phenyl, 2-methoxy-4-(pyrazol-1-yl)-phenyl, 2,4,6-trimethoxyphenyl, 2-methyl-4,5-benzodioxolyl, and 2-methyl-3,4-benzodioxolyl; or a pharmaceutically acceptable salt thereof.

5 . A compound according to claim 1 selected from:

1-{1-[1-(4-Methoxy-2-methylphenyl)-6-methyl-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl]-1H-pyrazol-3-yl}-3-methylimidazolidin-2-one;

1-{1-[1-(2,4-Dichlorophenyl)-6-methyl-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl]-1H-pyrazol-3-yl}imidazolidin-2-one;

1-(1-{1-[2,4-Bis(trifluoromethyl)phenyl]-6-methyl-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl}-1H-pyrazol-3-yl)-2-imidazolidinone;

1-{1-[1-(4-Hydroxy-2-methylphenyl)-6-methyl-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl]-1H-pyrazol-3-yl}-2-imidazolidinone;

1-(1-{1-[4-(Ethyloxy)-2-methylphenyl]-6-methyl-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl}-1H-pyrazol-3-yl)-2-imidazolidinone;

1-[1-(6-Methyl-1-{2-methyl-4-[(1-methylethyl)oxy]phenyl}-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrazol-3-yl]-2-imidazolidinone;

1-[1-(6-Methyl-1-{2-methyl-4-[(trifluoromethyl)oxy]phenyl}-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrazol-3-yl]-2-imidazolidinone;

3-Methyl-4-{6-methyl-4-[3-(2-oxo-1-imidazolidinyl)-1H-pyrazol-1-yl]-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-1-yl}benzonitrile;

1-(1-{6-Methyl-1-[2-methyl-4-(1H-pyrazol-1-yl)phenyl]-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl}-1H-pyrazol-3-yl)-2-imidazolidinone;

4-{6-Methyl-4-[3-(2-oxo-1-imidazolidinyl)-1H-pyrazol-1-yl]-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-1-yl}-3-(trifluoromethyl)benzonitrile;

1-(1-{1-[2-(Difluoromethyl)-4-(methyloxy)phenyl]-6-methyl-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl}-1H-pyrazol-3-yl)-2-imidazolidinone;

4-{6-Methyl-4-[3-(2-oxo-1-imidazolidinyl)-1H-pyrazol-1-yl]-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-1-yl}-3-[(trifluoromethyl)oxy]benzonitrile;

3-Ethyl-4-{6-methyl-4-[3-(2-oxo-1-imidazolidinyl)-1H-pyrazol-1-yl]-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-1-yl}benzonitrile;

1-(1-{6-Methyl-1-[2-(methyloxy)-4-(1H-pyrazol-1-yl)phenyl]-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl}-1H-pyrazol-3-yl)-2-imidazolidinone;

1-{1-[6-Methyl-1-(6-methyl-1,3-benzodioxol-5-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl]-1H-pyrazol-3-yl}-2-imidazolidinone;

1-(1-{6-Methyl-1-[2,4,6-tris(methyloxy)phenyl]-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl}-1H-pyrazol-3-yl)-2-imidazolidinone;

1-{1-[6-Methyl-1-(6-methyl-1,3-benzodioxol-5-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl]-1H-pyrazol-3-yl}-2-imidazolidinone;

1-(1-{2,6-Dimethyl-1-[2-methyl-4-(methyloxy)phenyl]-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl}-1H-pyrazol-3-yl)-2-imidazolidinone;

1-(5-Methyl-1-{6-methyl-1-[2-methyl-4-(methyloxy)phenyl]-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl}-1H-pyrazol-3-yl)-2-imidazolidinone; and

1-[1-(1-{4-[(difluoromethyl)oxy]-2-methylphenyl}-6-methyl-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrazol-3-yl]-2-imidazolidinone; or a pharmaceutically acceptable salt thereof.

6 . A pharmaceutical composition comprising a compound according to claim 1 , or a pharmaceutically acceptable salt thereof, in admixture with one or more physiologically acceptable carriers or excipients.

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

8 . A method, according to claim 7 , for the treatment of depression or anxiety, comprising administration of an effective amount of a compound according to claim 1 , or a pharmaceutically acceptable salt thereof.

9 . A method, according to claim 7 , for the treatment of IBS (irritable bowel disease) or IBD (inflammatory bowel disease), comprising administration of an effective amount of a compound according to claim 1 , or a pharmaceutically acceptable salt thereof.

10 . A process for the preparation of the compound according to claim 1 , corresponding to a compound of formula (IIr) in which:

R is 4-methoxy-2-methyl-phenyl;

X 1 is oxygen;

Y is CH—;

Lg is triflate and

Z—W is:

starting from the corresponding compound of formula (XXIII), comprising the following steps as in Scheme 2:

in which:

step a′ stands for the formation of the pyrrolidinone moiety of compounds (XXIV), which will form the cycle B present in the final compounds (IIr), by reacting the compounds (XXIII) with a reactive derivative of the butyric acid, such as 4-chlorobutyryl chloride; followed by a cyclisation reaction in basic conditions;

step b′ stands for amidine formation by reacting the compounds (XXIV) with a 3-aminocrotonate derivative and POCl 3 when X 1 is oxygen; or

stands for alkylation of the amidine formation by reacting the compound (XXIV) with a butynoate derivative, when X 1 is NH;

step c′ stands for the cyclisation of the compounds (XXV) or (XXVa) in basic conditions to give the hydroxy pyridine precursor of cycle A in the final compounds (IIr);

step d′ stands for the formation of a reactive derivative of the hydroxy pyridine of compounds (XXVI) by reaction with, triflic anhydride;

step e′ stands for nucleophilic displacement of the leaving group of compounds (XXVII) to give the halogenated compounds (XXVIII);

step f′ stands for the arylation reaction with the suitable —Z—W derivative by a metal catalysed coupling reaction procedure to give the final compounds (IIr); such —Z—W derivative may be suitably protected with a P group, as defined in Scheme 1,

step g′ stands for activation of carbon 3 by the addition of an electron-withdrawing group;

step h′ corresponds to step b)′ when X1 is oxygen.

step i′ stands for a metal-halogen exchange reaction followed by a trans-metalation reaction with a suitable metalating agent;

step j′ stands for the cyclisation of the p-amidoester of formula (XXIVb) with a salt of a substituted amidine in order to form the pyrimidine cycle A, when Y is N;

step m′ stands for conversion of the hydroxy group into an halogen by the halogenation reaction carried out using treatment with PO(Hal) 3 .

11 . An intermediate compound which is 1-(4-Methoxy-2-methylphenyl)pyrrolidin-2-one.

12 . An intermediate compound which is ethyl 3-{[1-(4-methoxy-2-methylphenyl)pyrrolidin-2-ylidene]amino}but-2-enoate.

13 . An intermediate compound which is 1-(4-Methoxy-2-methylphenyl)-6-methyl-1,2,3,7-tetrahydro-4H-pyrrolo[2,3-b]pyridin-4-one.

14 . An intermediate compound which is 1-(4-Methoxy-2-methylphenyl)-6-methyl-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl trifluoromethanesulfonate.

15 . An intermediate compound which is 4-Iodo-6-methyl-1-[2-methyl-4-(methyloxy)phenyl]-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine.

16 . An intermediate compound which is 1-[2-Methyl-4-(methyloxy)phenyl]-2-pyrrolidinimine.

17 . An intermediate compound which is 4-{[2-Methyl-4-(methyloxy)phenyl]amino}butanenitrile.

18 . An intermediate compound which is N-(2-Chloroethyl)-3-({[(2-chloroethyl)amino]carbonyl}amino)-1H-pyrazole-1-carboxamide.

19 . An intermediate compound which is N-(2-Chloroethyl)-3-(2-oxoimidazolidin-1-yl)-1H-pyrazole-1-carboxamide.

20 . An intermediate compound which is 1-(1H-Pyrazol-3-yl)imidazolidin-2-one.

21 . An intermediate compound which is 4-{[2-Methyl-4-(methyloxy)phenyl]amino}butanenitrile.

22 . An intermediate compound which is 1-[2-Methyl-4-(methyloxy)phenyl]-2-pyrrolidinimine.

23 . A method for the treatment of a condition mediated by CRF (corticotropin-releasing factor), comprising administration of an effective amount of the compound 1-{1-[1-(4-Methoxy-2-methylphenyl)-6-methyl-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl]-1H-pyrazol-3-yl}imidazolidin-2-one, or a pharmaceutically acceptable salt thereof, to a mammal in need of treatment thereof.

24 . A method, according to claim 23 , for the treatment of depression or anxiety, comprising administration of an effective amount of a compound according to claim 1 , or a pharmaceutically acceptable salt thereof.

25 . A method, according to claim 23 , for the treatment of IBS (irritable bowel disease) or IBD (inflammatory bowel disease), comprising administration of an effective amount of a compound according to claim 1 , or a pharmaceutically acceptable salt thereof.