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

Abstract

The present invention provides compounds of formula (I), processes for their preparation, pharmaceutical compositions containing them and their use in the treatment of conditions mediated by corticotropin-releasing factor (CRF).

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.