Use of ep4 receptor antagonists in the treatment of cartilage disease

Abstract

This invention relates to a compound with EP4 antagonistic activity, or a pharmaceutically acceptable salt with EP4 receptor antagonistic activities, which is useful in the treatment of cartilage disease. This invention also relates to a compound of formula (I), (II), (III), (IV), (Va) or (Vb), or a pharmaceutically acceptable salt thereof with EP4 receptor antagonistic activities, which is useful in the treatment of cartilage disease. This invention also relates to a pharmaceutical composition for the treatment of cartilage disease which comprises a therapeutically effective amount of a compound of formula (I), (II), (III), (IV), (Va) or (Vb), or a pharmaceutically acceptable salt thereof. Further this invention relates to a method for the treatment of cartilage disease in an animal subject including a mammalian subject, which comprises administering to the animal subject including a mammalian subject a compound of the formula (I), (II), (IV), (Va) or (Vb), or a pharmaceutically acceptable salt thereof.

1 - 14 . (canceled) 
     
     
         15 . A method for the treatment of cartilage diseases, which comprises administering to an animal subject including a mammalian subject a therapeutically effective amount of a compound with EP4 antagonistic activity, or a pharmaceutically acceptable salt thereof. 
     
     
         16 . A method for the treatment of cartilage diseases, which comprises administering to an animal subject including a mammalian subject in need a therapeutically effective amount of a compound of the formula (I), (II), (III), (IV), (Va) or (Vb) or a pharmaceutically acceptable salt thereof: 
       
         
           
           
               
               
           
         
         wherein Y 1 , Y 2 , Y 3 , and Y 4  are independently selected from N, CH and C(L); 
         R 1  is H, C 1-8  alkyl, C 2-8  alkenyl, C 2-8  alkynyl, C 3-7  cycloalkyl, C 1-8  alkoxy, halo-substituted C 1-8  alkoxy, C 1-8  alkyl-S(O)m-, Q 1 -, pyrrolidinyl, piperidyl, oxopyrrolidinyl, oxopiperidyl, amino, mono- or di-(C 1-8  alkyl)amino, C 1-4  alkyl-C(═O)—N(R 3 )— or C 1-4 alkyl-S(O)m-N(R 3 )—, wherein said C 1-8  alkyl, C 2-8  alkenyl and C 2-8  alkynyl are optionally substituted with halo, C 1-3  alkyl, hydroxy, oxo, C 1-4  alkoxy-, C 1-4  alkyl-S(O)m-, C 3-7  cycloalkyl-, cyano, indanyl, 1,2,3,4-tetrahydronaphtyl, 1,2-dihydronaphtyl, pyrrolidinyl, piperidyl, oxopyrrolidinyl, oxopiperidyl, Q 1 -, Q 1 -C(═O)—, Q 1 -O—, Q 1 -S(O)m-, Q 1 -C 1-4  alkyl-O—, Q 1 -C 1-4  alkyl-S(O)m-, Q 1 -C 1-4  alkyl-C(O)—N(R 3 )—, Q 1 -C 1-4  alkyl-N(R 3 )— or C 1-4  alkyl-C(O)—N(R 3 )—; 
         Q 1  is a 5 to 12 membered monocyclic or bicyclic aromatic ring optionally containing up to 4 heteroatoms selected from O, N and S, and is optionally substituted with halo, C 1-4  alkyl, halo-substituted C 1-4  alkyl, hydroxy, C 1-4  alkoxy, halo-substituted C 1-4  alkoxy, C 1-4  alkylthio, nitro, amino, mono- or di-(C 1-4  alkyl)amino, cyano, HO—C 1-4  alkyl, C 1-4  alkoxy-C 1-4  alkyl, C 1-4  alkylsulfonyl, aminosulfonyl, C 1-4  alkylC(═O)—, HO(O═)C—, C 1-4  alkyl-O(O═)C—, R 3 N(R 4 )C(═O)—, C 1-4  alkylsulfonylamino, C 3-7  cycloalkyl, R 3 C(═O)N(R 4 )— or NH 2 (HN═)C—; 
         A is a 5 or 6 membered monocyclic aromatic ring optionally containing up to 3 heteroatoms selected from O, N and S, wherein said 5 or 6 membered monocyclic aromatic ring is optionally substituted with up to 3 substituents selected from halo, C 1-4  alkyl, halo-substituted C 1-4  alkyl, hydroxy, C 1-4  alkoxy, halo-substituted C 1-4  alkoxy, C 1-4  alkylthio, nitro, amino, mono- or di-(C 1-4  alkyl)amino, cyano, HO—C 1-4  alkyl, C 1-4  alkoxy-C 1-4  alkyl, C 1-4  alkylsulfonyl, aminosulfonyl, acetyl, R 3 N(R 4 )C(═O)—, HO(O═)C—, C 1-4  alkyl-O(O═)C—, C 1-4  alkylsulfonylamino, C 3-7  cycloalkyl, R 3 C(═O)N(R 4 )— and NH 2 (HN═)C—; 
         B is halo-substituted C 1-6  alkylene, C 3-7  cycloalkylene, C 2-6  alkenylene, C 2-6  alkynylene, —O—C 1-5  alkylene, C 1-2  alkylene-O—C 1-2  alkylene or C 1-6  alkylene optionally substituted with an oxo group or C 1-3  alkyl; 
         W is NH, N—C 1-4  alkyl, O, S, N—OR 5  or a covalent bond; 
         R 2  is H, C 1-4  alkyl, OH or C 1-4  alkoxy; 
         Z is a 5 to 12 membered monocyclic or bicyclic aromatic ring optionally containing up to 3 heteroatoms selected from O, N and S, wherein said 5 to 12 membered monocyclic or bicyclic aromatic ring is optionally substituted with halo, C 1-4  alkyl, halo-substituted C 1-4  alkyl, C 1-4  alkenyl, C 1-4  alkynyl, hydroxy, C 1-4  alkoxy, halo-substituted C 1-4  alkoxy, C 1-4  alkylthio, nitro, amino, mono- or di-(C 1-4  alkyl)amino, cyano, HO—C 1-4  alkyl, C 1-4  alkoxy-C 1-4  alkyl, C 1-4  alkylsulfonyl, aminosulfonyl, C 1-4  alkylC(═O)—, R 3 C(═O)N(R 4 )—, HO(O═)C—, C 1-4  alkyl-O(O═)C—, C 1-4  alkylsulfonylamino, C 3-7  cycloalkyl, NH 2 (HN═)C—, Q 2 -S(O)m-, Q 2 -O—, Q 2 -N(R 3 )— or Q 2 -; 
         L is halo, C 1-4  alkyl, halo-substituted C 1-4  alkyl, hydroxy, C 1-4  alkoxy, C 1-4  alkylthio, nitro, amino, mono- or di-(C 1-4  alkyl)amino, halo-substituted C 1-4  alkoxy, cyano, HO—C 1-4  alkyl, C 1-4  alkoxy-C 1-4  alkyl, C 1-4  alkylsulfonyl, aminosulfonyl, C 1-4  alkylC(═O)—, HO(O═)C—, C 1-4  alkyl-O(O═)C—, C 1-4  alkylsulfonylamino, C 3-7  cycloalkyl, R 3 C(═O)N(R 4 )—, NH 2 (HN═)C—, R 3 N(R 4 )C(═O)—, R 3 N(R 4 )S(O)m-, Q 2 -, Q 2 -C(═O)—, Q 2 -O—, Q 2 -C 1-4 alkyl-O—, or two adjacent L groups are optionally joined together to form an alkylene chain having 3 or 4 members in which one or two (non-adjacent) carbon atoms are optionally replaced by oxygen atoms; 
         m is 0, 1 or 2; 
         R 3  and R 4  are independently selected from H and C 1-4  alkyl; 
         R 5  is H, C 1-4  alkyl, C 1-4  alkyl-(O═)C— or C 1-4  alkyl-O—(O═)—C—; and 
         Q 2  is a 5 to 12 membered monocyclic or bicyclic aromatic ring, optionally containing up to 3 heteroatoms selected from O, N and S, wherein said 5 to 12 membered monocyclic or bicyclic aromatic ring is optionally substituted with halo, C 1-4  alkyl, halo-substituted C 1-4  alkyl, C 1-4  alkenyl, C 1-4  alkynyl, hydroxy, C 1-4  alkoxy, halo-substituted C 1-4  alkoxy, C 1-4  alkylthio, nitro, amino, mono- or di-(C 1-4  alkyl)amino, cyano, HO—C 1-4  alkyl, C 1-4  alkoxy-C 1-4  alkyl, C 1-4  alkylsulfonyl, aminosulfonyl, C 1-4  alkyl-(O═)C—, R 3 (R 4 )C(═O)N—, HO(O═)C—, C 1-4  alkyl-O(O═)C—, C 1-4  alkylsulfonylamino, C 3-7  cycloalkyl, C 1-4  alkyl-C(═O)NH— or NH 2 (HN═)C—; 
       
       
         
           
           
               
               
           
         
         wherein A represents a phenyl group or a pyridyl group; 
         B represents an aryl group or a heteroaryl group; 
         E represents a 1,4-phenylene group; 
         R 1  and R 2  independently represent a hydrogen atom, a halogen atom, an alkyl group having from 1 to 4 carbon atoms, an alkoxy group having from 1 to 4 carbon atoms, a haloalkyl group having from 1 to 4 carbon atoms, a haloalkoxy group having from 1 to 4 carbon atoms, a cyano group or an aminocarbonyl group; 
         R 3  and R 4  independently represent a hydrogen atom or an alkyl group having from 1 to 4 carbon atoms; or R 3  and R 4  may be joined together to form an alkylene chain having 2 to 6 carbon atoms; 
         R 5  represents —CO 2 H, CO 2 W, 
       
       
         
           
           
               
               
           
         
         R 6  represents an alkyl group having from 1 to 6 carbon atoms, a cycloalkyl group having from 3 to 7 ring atoms, an aryl group or a heteroaryl group; 
         X represents a methylene group, an oxygen atom or a sulfur atom; 
         said aryl groups have from 6 to 10 carbon atoms; 
         said heteroaryl groups are 5 to 10-membered aromatic heterocyclic groups containing from 1 to 3 heteroatoms selected from the group consisting of sulfur atom, oxygen atom and nitrogen atom; 
         said aryl groups and said heteroaryl groups referred to in the definitions of B are unsubstituted or are substituted by at least one substituent selected from the group consisting of substituents alpha; 
         said 1,4-phenylene group referred to in the definition of E is unsubstituted or is substituted by at least one substituent selected from the group consisting of substituents beta; 
         said aryl groups and said heteroaryl groups referred to in the definitions of R 6  and alpha are unsubstituted or are substituted by at least one substituent selected from the group consisting of substituents beta; 
         said substituents alpha are selected from the group consisting of halogen atoms, alkyl groups having from 1 to 4 carbon atoms, alkoxy groups having from 1 to 4 carbon atoms, haloalkyl groups having from 1 to 4 carbon atoms, haloalkoxy groups having from 1 to 4 carbon atoms, cyano groups, alkynyl groups having from 2 to 6 carbon atoms, alkanoyl groups having from 1 to 5 carbon atoms, cycloalkyl groups having from 3 to 7 ring atoms, heteroaryl groups, aryl groups, aralkoxy groups having from 7 to 10 carbon atoms, arylcarbonyl groups, two adjacent alpha groups are optionally joined together to form an alkylene or an alkenylene chain having 3 or 4 carbon atoms, aminocarbonyl groups, alkenyl groups having from 2 to 5 carbon atoms, alkylthio groups having from 1 to 4 carbon atoms, aminosulfinyl groups, aminosulfonyl groups, hydroxy groups, hydroxyalkyl groups having from 1 to 4 carbon atoms, nitro groups, amino groups, carboxy groups, alkoxycarbonyl groups having from 2 to 5 carbon atoms, alkoxyalkyl groups having from 1 to 4 carbon atoms, alkylsulfonyl groups having from 1 to 4 carbon atoms, alkanoylamino groups having from 1 to 4 carbon atoms, alkanoyl (alkyl) amino groups having from 1 to 6 carbon atoms, alkanoylaminoalkyl groups having from 1 to 6 carbon atoms in both the alkanoyl and alkyl part, alkanoyl (alkyl) aminoalkyl groups having from 1 to 6 carbon atoms in both the alkanoyl and each alkyl part, alkylsulfonylamino groups having from 1 to 4 carbon atoms, mono- or di-alkylaminocarbonyl groups having from 1 to 6 carbon atoms, mono- or di-alkylaminosulfinyl groups having from 1 to 6 carbon atoms, mono- or di-alkylaminosulfonyl groups having from 1 to 6 carbon atoms, aminoalkyl groups having from 1 to 4 carbon atoms, mono- or di-alkylamino groups having from 1 to 6 carbon atoms, mono- or di-alkylaminoalkyl groups having from 1 to 6 carbon atoms in each alkyl part, aralkyl groups having from 7 to 10 carbon atoms, heteroarylalkyl groups having from 1 to 4 carbon atoms in the alkyl part, heteroarylalkoxy groups having from 1 to 4 carbon atoms in the alkoxy part and alkylsulfonylamino groups having from 1 to 4 carbon atoms; 
         said substituents beta are selected from the group consisting of halogen atoms, alkyl groups having from 1 to 4 carbon atoms, alkoxy groups having from 1 to 4 carbon atoms, haloalkyl groups having from 1 to 4 carbon atoms, haloalkoxy groups having from 1 to 4 carbon atoms and cyano groups; 
         W is a pharmaceutically acceptable ester prodrug group; with the proviso R 1  and R 2  do not represent a hydrogen atom simultaneously; 
       
       
         
           
           
               
               
           
         
         wherein X represents —CH or a nitrogen atom; 
         Y represents —NR 4 , an oxygen atom or a sulfur atom; 
         R 4  represents a hydrogen atom or an alkyl group having from 1 to 3 carbon atoms; 
         Z represents a hydrogen atom or a halogen atom; 
         R 1  represents an alkyl group having from 1 to 6 carbon atoms optionally substituted with an alkoxy group having from 1 to 6 carbon atoms or a cycloalkyl group having from 3 to 7 carbon atoms; a cycloalkyl group having from 3 to 7 carbon atoms optionally substituted with an alkyl group having from 1 to 3 carbon atoms; a phenyl group optionally substituted with one or more substituents alpha; or a group Het 1  optionally substituted with one or more substituents alpha; 
         Het 1  represents a heterocyclic group having from 4 to 7 ring atoms which contains either from 1 to 4 nitrogen ring heteroatoms or from 0 to 2 nitrogen ring heteroatoms and 1 oxygen or 1 sulfur ring heteroatom; 
         R 2  and R 3  independently represent a hydrogen atom or an alkyl group having from 1 to 3 carbon atoms; or R 2  and R 3  together form an alkylene chain having from 3 to 6 carbon atoms; and 
         said substituent alpha is selected from the group consisting of halogen atoms, alkyl groups having from 1 to 4 carbon atoms, haloalkyl groups having from 1 to 4 carbon atoms, hydroxy groups, alkoxy groups having from 1 to 4 carbon atoms, haloalkoxy groups having from 1 to 4 carbon atoms, cyano groups, hydroxy alkyl groups having from 1 to 4 carbon atoms, alkoxyalkyl groups having from 1 to 4 carbon atoms in alkoxy and alky groups, alkylsulfonyl groups having from 1 to 4 carbon atoms, alkanoyl groups having from 2 to 5 carbon atoms, alkenyl groups having from 2 to 4 carbon atoms, alkynyl groups having from 2 to 4 carbon atoms, alkylthio groups having from 1 to 4 carbon atoms, nitro groups, amino groups, mono- or di-alkylamino groups having from 1 to 4 carbon atoms, aminosulfonyl groups, alkoxycarbonyl groups having from 1 to 4 carbon atoms, alkylsulfonylamino groups having from 1 to 4 carbon atoms, cycloalkyl groups having from 3 to 7 carbon atoms and a mono- or di-alkylaminocarbonyl groups having from 1 to 6 carbon atoms; 
         or a pharmaceutically acceptable ester of such compound; 
       
       
         
           
           
               
               
           
         
         wherein X and Y are independently selected from the group consisting of: N and C(R 11 ), wherein each R 11  is independently selected from the group consisting of: hydrogen, halo and C 1-4  alkyl; 
         B is selected from the group consisting of: —C(R 5 )(R 6 )—, —O—, —S—, —S(O)—, —SO 2 —, —C(R 5 )(R 6 )—C(R 7 )(R 8 )—, —O—C(R 5 )(R 6 )—, —S—C(R 5 )(R 6 )—, —S(O)—C(R 5 )(R 6 )— and —SO 2 —C(R 5 )(R 6 )—; 
         C is selected from the group consisting of aryl and heteroaryl, or a fused analog of aryl or heteroaryl, each optionally substituted with one to three substituents independently selected from R 10 ; 
         E is selected from the group consisting of: —C(O)OH, —C(O)OC 1-4 alkyl, tetrazolyl and 
       
       
         
           
           
               
               
           
         
         wherein R is selected from the group consisting of: C 1-4  alkyl, aryl and heteroaryl, or a fused analog of aryl or heteroaryl, wherein aryl and heteroaryl or the fused analogs thereof are optionally substituted with one to three substituents independently selected from R 10 ; 
         R 1  to R 8  are independently selected from the group consisting of: H, halo, —O—R 12 , C 1-6 alkyl and C 3-6  cycloalkyl, and one or more pairs of R 1  and R 2 , R 5  and R 6 , and R 7  and R 8  may be joined together with the carbon atom to which they are attached to form a 3- to 5-membered monocyclic cycloalkyl ring, and R 5  and R 6  or R 7  and R 8  may be joined together to form carbonyl; 
         R 9  is independently selected from the group consisting of: halo, hydroxyl and C 1-4  alkyl; 
         R 10  is selected from the group consisting of: halo, cyano, C 1-4  alkyl, C 1-4  fluoroalkyl, C 1-4  alkoxy, C 1-4  thioalkoxy and C 1-4  fluoroalkoxy; and 
         each R 12  is selected from the group consisting of: H, C 1-4  alkyl, C 3-6  cycloalkyl and heterocyclyl. 
       
     
     
         17 . The method of  claim 16 , wherein the compound of (I), (II), (III), (IV), (Va) or (Vb) is selected from:
 3-[2-(4-{2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl}phenyl)ethyl]-1-[(4-methylbenzene)sulfonyl]urea;   3-[2-(4-{2-ethyl-4,6-dimethyl-1H-imidazo[4,5-c]pyridin-1-yl}phenyl)ethyl]-1-[(4-methylbenzene)sulfonyl]urea;   1-{2-[4-(5-acetyl-2-ethyl-1H-1,3-benzodiazol-1-yl)phenyl]ethyl}-3-[(4-methylbenzene)sulfonyl]urea;   3-{2-[4-(2-ethyl-5-methoxy-1H-1,3-benzodiazol-1-yl)phenyl]ethyl}-1-[(4-methylbenzene)sulfonyl]urea;   2-{4-[6-chloro-2-ethyl-5-(trifluoromethyl)-1H-1,3-benzodiazol-1-yl]phenyl}ethyl N-[(4-methylbenzene)sulfonyl]carbamate;   3-{2-[4-(6-chloro-5-cyano-2-ethyl-1H-1,3-benzodiazol-1-yl)phenyl]ethyl}-1-[(4-methylbenzene)sulfonyl]urea;   2-(4-{2-ethyl-4,6-dimethyl-1H-imidazo[4,5-c]pyridin-1-yl}phenyl)ethyl N-[(4-methylbenzene)sulfonyl]carbamate;   2-(4-{2-tert-butyl-4,6-dimethyl-1H-imidazo[4,5-c]pyridin-1-yl}phenyl)ethyl N-[(4-methylbenzene)sulfonyl]carbamate;   2-[4-(5-carbamoyl-6-chloro-2-ethyl-1H-1,3-benzodiazol-1-yl)phenyl]ethyl N-[(4-methylbenzene)sulfonyl]carbamate;   1-(2-{4-[2-ethyl-5-(1-hydroxyethyl)-1H-1,3-benzodiazol-1-yl]phenyl}ethyl)-3-[(4-methylbenzene)sulfonyl]urea;   1-(2-{4-[6-chloro-2-(2-hydroxypropan-2-yl)-5-(trifluoromethyl)-1H-1,3-benzodiazol-1-yl]phenyl}ethyl)-3-[(4-methylbenzene)sulfonyl]urea;   2-{4-[6-chloro-2-(pyridin-2-yl)-5-(trifluoromethyl)-1H-1,3-benzodiazol-1-yl]phenyl}ethyl N-[(4-methylbenzene)sulfonyl]carbamate;   3-(2-{5-[6-chloro-2-ethyl-5-(trifluoromethyl)-1H-1,3-benzodiazol-1-yl]pyridin-2-yl}ethyl)-1-[(4-methylbenzene)sulfonyl]urea;   2-{4-[6-chloro-2-ethyl-5-(trifluoromethyl)-1H-1,3-benzodiazol-1-yl]phenyl}ethyl N-[(2-chlorobenzene)sulfonyl]carbamate;   3-(2-{4-[5,7-dimethyl-2-(methylamino)-3H-imidazo[4,5-b]pyridin-3-yl]phenyl}ethyl)-1-[(4-methylbenzene)sulfonyl]urea;   4-((1S)-1-{[5-chloro-2-(4-fluorophenoxy)benzoyl]amino}ethyl)benzoic acid;   4-[(1S)-1-({[5-chloro-2-(4-fluorophenoxy)pyridin-3-yl]carbonyl}amino)ethyl]benzoic acid;   4-[(1S)-1({[5-chloro-2-(3-cyanophenoxy)pyridin-3-yl]carbonyl}amino)ethyl]benzoic acid;   4-[(1S)-1-({[5-chloro-2-(3-fluorophenoxy)pyridin-3-yl]carbonyl}amino)ethyl]benzoic acid;   4-[(1S)-1-({[5-chloro-2-(3-chlorophenoxy)pyridin-3-yl]carbonyl}amino)ethyl]benzoic acid;   4-((1S)-1-{[5-chloro-2-(3-fluorophenoxy)benzoyl]amino}ethyl)benzoic acid;   4-((1S)-1-{[5-chloro-2-(3-chlorophenoxy)benzoyl]amino}ethyl)benzoic acid;   4-[(1S)-1-({[5-chloro-2-(2-chloro-4-fluorophenoxy)pyridin-3-yl]carbonyl}amino)ethyl]benzoic acid;   4-[(1S)-1-({[5-chloro-2-(3,4-difluorophenoxy)pyridin-3-yl]carbonyl}amino)ethyl]benzoic acid;   4-[(1S)-1-({[5-chloro-2-(2,3-difluorophenoxy)pyridin-3-yl]carbonyl}amino)ethyl]benzoic acid;   4-((1S)-1-{[5-chloro-2-(2,3-difluorophenoxy)benzoyl]amino}ethyl)benzoic acid;   4-((1S)-1-{[5-chloro-2-(3,4-difluorophenoxy)benzoyl]amino}ethyl)benzoic acid;   4-[(1S)-1-({[5-chloro-2-(3-chloro-5-fluorophenoxy)pyridin-3-yl]carbonyl}amino)ethyl]benzoic acid;   4-[(1S)-1-({5-chloro-2-[(4-chlorophenoxy)methyl]benzoyl}amino)ethyl]benzoic acid;   4-[(1S)-1-({5-chloro-2-[(3-chlorophenoxy)methyl]benzoyl}amino)ethyl]benzoic acid;   4-[(1S)-1-({5-chloro-2-[(4-fluorophenoxy)methyl]benzoyl}amino)ethyl]benzoic acid;   4-[(1S)-1-({5-chloro-2-[(3,4-difluorophenoxy)methyl]benzoyl}amino)ethyl]benzoic acid;   4-[(1S)-1-({5-chloro-2-[(2,4-difluorophenoxy)methyl]benzoyl}amino)ethyl]benzoic acid;   4-{(1S)-1-[({5-chloro-2-[(3-chlorophenoxy)methyl]pyridin-3-yl}carbonyl)amino]ethyl}benzoic acid;   4-[(1S)-1-({5-chloro-2-[(3,5-difluorophenoxy)methyl]benzoyl}amino)ethyl]benzoic acid;   4-[(1S)-1-({5-chloro-2-[(3-fluorophenoxy)methyl]benzoyl}amino)ethyl]benzoic acid;   4-{(1S)-1-[({2-[(4-chlorophenoxy)methyl]-5-fluoropyridin-3-yl}carbonyl)amino]ethyl}benzoic acid;   4-{(1S)-1-({5-chloro-2-[(cyclohexylmethoxy)methyl]benzoyl}amino)ethyl}benzoic acid;   4-((4-(5-methoxypyridin-2-yl)phenoxy)methyl)-5-methyl-N-(o-tolylsulfonyl)furan-2-carboxamide,   5-chloro-3-[(3-chlorophenyl)methyl]-N-[1-[4-(2H-tetrazol-5-yl)phenyl]ethyl]-2-thiophenecarboxamide,   2,5-dimethyl-N-[(1S)-1-[4-[[(methylsulfonyl)amino]carbonyl]phenyl]ethyl]-4-[[4-(trifluoromethyl)phenyl]methyl]-3-thiophenecarboxamide,   2,5-dimethyl-N-[(1S)-1-[4-[[(phenylsulfonyl)amino]carbonyl]phenyl]ethyl]-4-[[4-(trifluoromethyl)phenyl]methyl]-3-thiophenecarboxamide,   2,5-dimethyl-N-[1-[4-(2H-tetrazol-5-yl)phenyl]cyclopropyl]-4-[[3-(trifluoromethyl)phenyl]methyl]-3-thiophenecarboxamide,   2,5-dimethyl-N-[1-[4-(2H-tetrazol-5-yl)phenyl]cyclopropyl]-4-[[4-(trifluoromethyl)phenyl]methyl]-3-thiophenecarboxamide,   2-chloro-4-[[[[4-[(3-chlorophenyl)methyl]-2,5-dimethyl-3-thienyl]carbonyl]amino]methyl]-benzoic acid,   4-[(1R)-1-[[[2,5-dichloro-4-[(3-chlorophenyl)methyl]-3-thienyl]carbonyl]amino]ethyl]-benzoic acid,   4-[(1S)-1-[[[2,5-dibromo-4-[(3-chlorophenyl)methyl]-3-thienyl]carbonyl]amino]ethyl]-benzoic acid,   4-[(1S)-1-[[[2,5-dichloro-4-(3-chlorobenzoyl)-3-thienyl]carbonyl]amino]ethyl]-benzoic acid,   4-[(1S)-1-[[[2,5-dichloro-4-[(3-chlorophenyl)[(tetrahydro-2H-pyran-2-yl)oxy]methyl]-3-thienyl]carbonyl]amino]ethyl]-benzoic acid,   4-[(1S)-1-[[[2,5-dichloro-4-[(3-chlorophenyl)hydroxymethyl]-3-thienyl]carbonyl]amino]ethyl]-benzoic acid,   4-[(1S)-1-[[[2,5-dichloro-4-[(3-chlorophenyl)methyl]-3-thienyl]carbonyl]amino]ethyl]-benzoic acid,   4-[(1S)-1-[[[2,5-dichloro-4-[[3-(trifluoromethyl)phenyl]methyl]-3-thienyl]carbonyl]amino]ethyl]-benzoic acid,   4-[(1S)-1-[[[2,5-dimethyl-4-[[3-(trifluoromethyl)phenyl]methyl]-3-thienyl]carbonyl]amino]ethyl]-benzoic acid,   4-[(1S)-1-[[[2,5-dimethyl-4-[[4-(trifluoromethyl)phenyl]methyl]-3-thienyl]carbonyl]amino]ethyl]-benzoic acid,   4-[(1S)-1-[[[2,5-dimethyl-4-[[4-(trifluoromethyl)phenyl]methyl]-3-thienyl]carbonyl]amino]ethyl]-benzoic acid,   4-[(1S)-1-[[[4-[(3-chlorophenyl)methyl]-2,5-dimethyl-3-thienyl]carbonyl]amino]ethyl]-benzoic acid,   4-[(1S)-1-[[[4-[(3-chlorophenyl)methyl]-3-thienyl]carbonyl]amino]ethyl]-benzoic acid,   4-[(1S)-1-[[[4-[(4-chlorophenyl)methyl]-2,5-dimethyl-3-thienyl]carbonyl]amino]ethyl]-benzoic acid,   4-[(1S)-1-[[[5-bromo-4-[(3-chlorophenyl)methyl]-3-thienyl]carbonyl]amino]ethyl]-benzoic acid,   4-[[[[2,5-dichloro-4-[(3-chlorophenyl)methyl]-3-thienyl]carbonyl]amino]methyl]-benzoic acid,   4-[1-[[[2,5-dimethyl-4-[[3-(trifluoromethyl)phenyl]methyl]-3-thienyl]carbonyl]amino]cyclopropyl]-benzoic acid,   4-[1-[[[5-chloro-3-[(3-chlorophenyl)methyl]-2-thienyl]carbonyl]amino]ethyl]-benzoic acid, and   4-{1-[({2,5-dimethyl-4-[4-(trifluoromethyl)benzyl]-3-thienyl}carbonyl)amino]cyclopropyl}benzoic acid,   or a pharmaceutically acceptable salt thereof.   
     
     
         18 . The method of  claim 16 , wherein the compound of (I), (II), (III), (IV), (Va) or (Vb) is selected from:
 3-[2-(4-{2-ethyl-4,6-dimethyl-1H-imidazo[4,5-c]pyridin-1-yl}phenyl)ethyl]-1-[(4-methylbenzene)sulfonyl]urea;   4-[(1S)-1-({[5-chloro -2-(3-fluorophenoxy)pyridin-3-yl]carbonyl}amino)ethyl]benzoic acid;   4-{(1S)-1-[({5-chloro-2-[(3-chlorophenoxy)methyl]pyridin-3-yl}carbonyl)amino]ethyl}benzoic acid;   4-((4-(5-methoxypyridin-2-yl)phenoxy)methyl)-5-methyl-N-(o-tolylsulfonyl)furan-2-carboxamide;   4-{1-[({2,5-dimethyl-4-[4-(trifluoromethyl)benzyl]-3-thienyl}carbonyl)amino]cyclopropyl}benzoic acid,   or a pharmaceutically acceptable salt thereof.   
     
     
         19 . The method of  claim 18 , wherein the compound of (I), (II), (III) or (IV) is selected from:
 3-[2-(4-{2-ethyl-4,6-dimethyl-1H-imidazo[4,5-c]pyridin-1-yl}phenyl)ethyl]-1-[(4-methylbenzene)sulfonyl]urea;   4-[(1S)-1-({[5-chloro -2-(3-fluorophenoxy)pyridin-3-yl]carbonyl}amino)ethyl]benzoic acid;   4-{(1S)-1-[({5-chloro-2-[(3-chlorophenoxy)methyl]pyridin-3-yl}carbonyl)amino]ethyl}benzoic acid; and   4-((4-(5-methoxypyridin-2-yl)phenoxy)methyl)-5-methyl-N-(o-tolylsulfonyl)furan-2-carboxamide,   or a pharmaceutically acceptable salt thereof.   
     
     
         20 . A pharmaceutical composition for the treatment of cartilage disease which comprises a therapeutically effective amount of a compound of the formula (I), (II), (III), (IV), (Va) or (Vb) defined in  claim 16  or a pharmaceutically acceptable salt thereof. 
     
     
         21 . The pharmaceutical composition of  claim 20 , which further comprises a therapeutically effective amount of one or more additional compounds known to be useful in the treatment or prevention of cartilage disease or the symptoms thereof. 
     
     
         22 . The method of  claim 16 , which further comprises administering a therapeutically effective amount of one or more additional compounds known to be useful in the treatment or prevention of cartilage disease thereof. 
     
     
         23 . The method of  claim 22 , wherein the one or more additional compounds known to be useful in the treatment or prevention of cartilage disease or the symptoms thereof are selected from NSAIDs, COX-2 inhibitors, steroids, matrix metalloproteinase inhibitors and hyaluronic acid. 
     
     
         24 . A method for the treatment of cartilage diseases in an animal subject including a mammalian subject, which comprises administering to the animal subject including a mammalian subject a compound of the formula (I), (II), (III), (IV), (Va) or (Vb) or a pharmaceutically acceptable salt thereof: 
       
         
           
           
               
               
           
         
         wherein Y 1 , Y 2 , Y 3 , and Y 4  are independently selected from N, CH and C(L); 
         R 1  is H, C 1-8  alkyl, C 2-8  alkenyl, C 2-8  alkynyl, C 3-7  cycloalkyl, C 1-8  alkoxy, halo-substituted C 1-8  alkoxy, C 1-8  alkyl-S(O)m-, Q 1 -, pyrrolidinyl, piperidyl, oxopyrrolidinyl, oxopiperidyl, amino, mono- or di-(C 1-8  alkyl)amino, C 1-4  alkyl-C(═O)—N(R 3 )— or C 1-4 alkyl-S(O)m-N(R 3 )—, wherein said C 1-8  alkyl, C 2-8  alkenyl and C 2-8  alkynyl are optionally substituted with halo, C 1-3  alkyl, hydroxy, oxo, C 1-4  alkoxy-, C 1-4  alkyl-S(O)m-, C 3-7  cycloalkyl-, cyano, indanyl, 1,2,3,4-tetrahydronaphtyl, 1,2-dihydronaphtyl, pyrrolidinyl, piperidyl, oxopyrrolidinyl, oxopiperidyl, Q 1 -, Q 1 -C(═O)—, Q 1 -O—, Q 1 -S(O)m-, Q 1 -C 1-4  alkyl-O—, Q 1 -C 1-4  alkyl-S(O)m-, Q 1 -C 1-4  alkyl-C(O)—N(R 3 )—, Q 1 -C 1-4  alkyl-N(R 3 )— or C 1-4  alkyl-C(O)—N(R 3 )—; 
         Q 1  is a 5 to 12 membered monocyclic or bicyclic aromatic ring optionally containing up to 4 heteroatoms selected from O, N and S, and is optionally substituted with halo, C 1-4  alkyl, halo-substituted C 1-4  alkyl, hydroxy, C 1-4  alkoxy, halo-substituted C 1-4  alkoxy, C 1-4  alkylthio, nitro, amino, mono- or di-(C 1-4  alkyl)amino, cyano, HO—C 1-4  alkyl, C 1-4  alkoxy-C 1-4  alkyl, C 1-4  alkylsulfonyl, aminosulfonyl, C 1-4  alkylC(═O)—, HO(O═)C—, C 1-4  alkyl-O(O═)C—, R 3 N(R 4 )C(═O)—, C 1-4  alkylsulfonylamino, C 3-7  cycloalkyl, R 3 C(═O)N(R 4 )— or NH 2 (HN═)C—; 
         A is a 5 or 6 membered monocyclic aromatic ring optionally containing up to 3 heteroatoms selected from O, N and S, wherein said 5 or 6 membered monocyclic aromatic ring is optionally substituted with up to 3 substituents selected from halo, C 1-4  alkyl, halo-substituted C 1-4  alkyl, hydroxy, C 1-4  alkoxy, halo-substituted C 1-4  alkoxy, C 1-4  alkylthio, nitro, amino, mono- or di-(C 1-4  alkyl)amino, cyano, HO—C 1-4  alkyl, C 1-4  alkoxy-C 1-4  alkyl, C 1-4  alkylsulfonyl, aminosulfonyl, acetyl, R 3 N(R 4 )C(═O)—, HO(O═)C—, C 1-4  alkyl-O(O═)C—, C 1-4  alkylsulfonylamino, C 3-7  cycloalkyl, R 3 C(═O)N(R 4 )— and NH 2 (HN═)C—; 
         B is halo-substituted C 1-6  alkylene, C 3-7  cycloalkylene, C 2-6  alkenylene, C 2-6  alkynylene, —O—C 1-5  alkylene, C 1-2  alkylene-O—C 1-2  alkylene or C 1-6  alkylene optionally substituted with an oxo group or C 1-3  alkyl; 
         W is NH, N—C 1-4  alkyl, O, S, N—OR 5  or a covalent bond; 
         R 2  is H, C 1-4  alkyl, OH or C 1-4  alkoxy; 
         Z is a 5 to 12 membered monocyclic or bicyclic aromatic ring optionally containing up to 3 heteroatoms selected from O, N and S, wherein said 5 to 12 membered monocyclic or bicyclic aromatic ring is optionally substituted with halo, C 1-4  alkyl, halo-substituted C 1-4  alkyl, C 1-4  alkenyl, C 1-4  alkynyl, hydroxy, C 1-4  alkoxy, halo-substituted C 1-4  alkoxy, C 1-4  alkylthio, nitro, amino, mono- or di-(C 1-4  alkyl)amino, cyano, HO—C 1-4  alkyl, C 1-4  alkoxy-C 1-4  alkyl, C 1-4  alkylsulfonyl, aminosulfonyl, C 1-4  alkylC(═O)—, R 3 C(═O)N(R 4 )—, HO(O═)C—, C 1-4  alkyl-O(O═)C—, C 1-4  alkylsulfonylamino, C 3-7  cycloalkyl, NH 2 (HN═)C—, Q 2 -S(O)m-, Q 2 -O—, Q 2 -N(R 3 )— or Q 2 -; 
         L is halo, C 1-4  alkyl, halo-substituted C 1-4  alkyl, hydroxy, C 1-4  alkoxy, C 1-4  alkylthio, nitro, amino, mono- or di-(C 1-4  alkyl)amino, halo-substituted C 1-4  alkoxy, cyano, HO—C 1-4  alkyl, C 1-4  alkoxy-C 1-4  alkyl, C 1-4  alkylsulfonyl, aminosulfonyl, C 1-4  alkylC(═O)—, HO(O═)C—, C 1-4  alkyl-O(O═)C—, C 1-4  alkylsulfonylamino, C 3-7  cycloalkyl, R 3 C(═O)N(R 4 )—, NH 2 (HN═)C—, R 3 N(R 4 )C(═O)—, R 3 N(R 4 )S(O)m-, Q 2 -, Q 2 -C(═O)—, Q 2 -O—, Q 2 -Ci_4alkyl-O—, or two adjacent L groups are optionally joined together to form an alkylene chain having 3 or 4 members in which one or two (non-adjacent) carbon atoms are optionally replaced by oxygen atoms; 
         m is 0, 1 or 2; 
         R 3  and R 4  are independently selected from H and C 1-4  alkyl; 
         R 5  is H, C 1-4  alkyl, C 1-4  alkyl-(O═)C— or C 1-4  alkyl-O—(O═)—C—; and 
         Q 2  is a 5 to 12 membered monocyclic or bicyclic aromatic ring, optionally containing up to 3 heteroatoms selected from O, N and S, wherein said 5 to 12 membered monocyclic or bicyclic aromatic ring is optionally substituted with halo, C 1-4  alkyl, halo-substituted C 1-4  alkyl, C 1-4  alkenyl, C 1-4  alkynyl, hydroxy, C 1-4  alkoxy, halo-substituted C 1-4  alkoxy, C 1-4  alkylthio, nitro, amino, mono- or di-(C 1-4  alkyl)amino, cyano, HO—C 1-4  alkyl, C 1-4  alkoxy-C 1-4  alkyl, C 1-4  alkylsulfonyl, aminosulfonyl, C 1-4  alkyl-(O═)C—, R 3 (R 4 )C(═O)N—, HO(O═)C—, C 1-4  alkyl-O(O═)C—, C 1-4  alkylsulfonylamino, C 3-7  cycloalkyl, C 1-4  alkyl-C(═O)NH— or NH 2 (HN═)C—; 
       
       
         
           
           
               
               
           
         
         wherein A represents a phenyl group or a pyridyl group; 
         B represents an aryl group or a heteroaryl group; 
         E represents a 1,4-phenylene group; 
         R 1  and R 2  independently represent a hydrogen atom, a halogen atom, an alkyl group having from 1 to 4 carbon atoms, an alkoxy group having from 1 to 4 carbon atoms, a haloalkyl group having from 1 to 4 carbon atoms, a haloalkoxy group having from 1 to 4 carbon atoms, a cyano group or an aminocarbonyl group; 
         R 3  and R 4  independently represent a hydrogen atom or an alkyl group having from 1 to 4 carbon atoms; or R 3  and R 4  may be joined together to form an alkylene chain having 2 to 6 carbon atoms; 
         R 5  represents —CO 2 H, CO 2 W, 
       
       
         
           
           
               
               
           
         
         R 6  represents an alkyl group having from 1 to 6 carbon atoms, a cycloalkyl group having from 3 to 7 ring atoms, an aryl group or a heteroaryl group; 
         X represents a methylene group, an oxygen atom or a sulfur atom; 
         said aryl groups have from 6 to 10 carbon atoms; 
         said heteroaryl groups are 5 to 10-membered aromatic heterocyclic groups containing from 1 to 3 heteroatoms selected from the group consisting of sulfur atom, oxygen atom and nitrogen atom; 
         said aryl groups and said heteroaryl groups referred to in the definitions of B are unsubstituted or are substituted by at least one substituent selected from the group consisting of substituents alpha; 
         said 1,4-phenylene group referred to in the definition of E is unsubstituted or is substituted by at least one substituent selected from the group consisting of substituents beta; 
         said aryl groups and said heteroaryl groups referred to in the definitions of R 6  and alpha are unsubstituted or are substituted by at least one substituent selected from the group consisting of substituents beta; 
         said substituents alpha are selected from the group consisting of halogen atoms, alkyl groups having from 1 to 4 carbon atoms, alkoxy groups having from 1 to 4 carbon atoms, haloalkyl groups having from 1 to 4 carbon atoms, haloalkoxy groups having from 1 to 4 carbon atoms, cyano groups, alkynyl groups having from 2 to 6 carbon atoms, alkanoyl groups having from 1 to 5 carbon atoms, cycloalkyl groups having from 3 to 7 ring atoms, heteroaryl groups, aryl groups, aralkoxy groups having from 7 to 10 carbon atoms, arylcarbonyl groups, two adjacent alpha groups are optionally joined together to form an alkylene or an alkenylene chain having 3 or 4 carbon atoms, aminocarbonyl groups, alkenyl groups having from 2 to 5 carbon atoms, alkylthio groups having from 1 to 4 carbon atoms, aminosulfinyl groups, aminosulfonyl groups, hydroxy groups, hydroxyalkyl groups having from 1 to 4 carbon atoms, nitro groups, amino groups, carboxy groups, alkoxycarbonyl groups having from 2 to 5 carbon atoms, alkoxyalkyl groups having from 1 to 4 carbon atoms, alkylsulfonyl groups having from 1 to 4 carbon atoms, alkanoylamino groups having from 1 to 4 carbon atoms, alkanoyl (alkyl) amino groups having from 1 to 6 carbon atoms, alkanoylaminoalkyl groups having from 1 to 6 carbon atoms in both the alkanoyl and alkyl part, alkanoyl (alkyl) aminoalkyl groups having from 1 to 6 carbon atoms in both the alkanoyl and each alkyl part, alkylsulfonylamino groups having from 1 to 4 carbon atoms, mono- or di-alkylaminocarbonyl groups having from 1 to 6 carbon atoms, mono- or di-alkylaminosulfinyl groups having from 1 to 6 carbon atoms, mono- or di-alkylaminosulfonyl groups having from 1 to 6 carbon atoms, aminoalkyl groups having from 1 to 4 carbon atoms, mono- or di-alkylamino groups having from 1 to 6 carbon atoms, mono- or di-alkylaminoalkyl groups having from 1 to 6 carbon atoms in each alkyl part, aralkyl groups having from 7 to 10 carbon atoms, heteroarylalkyl groups having from 1 to 4 carbon atoms in the alkyl part, heteroarylalkoxy groups having from 1 to 4 carbon atoms in the alkoxy part and alkylsulfonylamino groups having from 1 to 4 carbon atoms; 
         said substituents beta are selected from the group consisting of halogen atoms, alkyl groups having from 1 to 4 carbon atoms, alkoxy groups having from 1 to 4 carbon atoms, haloalkyl groups having from 1 to 4 carbon atoms, haloalkoxy groups having from 1 to 4 carbon atoms and cyano groups; 
         W is a pharmaceutically acceptable ester prodrug group; with the proviso R 1  and R 2  do not represent a hydrogen atom simultaneously; 
       
       
         
           
           
               
               
           
         
         wherein X represents —CH or a nitrogen atom; 
         Y represents —NR 4 , an oxygen atom or a sulfur atom; 
         R 4  represents a hydrogen atom or an alkyl group having from 1 to 3 carbon atoms; 
         Z represents a hydrogen atom or a halogen atom; 
         R 1  represents an alkyl group having from 1 to 6 carbon atoms optionally substituted with an alkoxy group having from 1 to 6 carbon atoms or a cycloalkyl group having from 3 to 7 carbon atoms; a cycloalkyl group having from 3 to 7 carbon atoms optionally substituted with an alkyl group having from 1 to 3 carbon atoms; a phenyl group optionally substituted with one or more substituents alpha; or a group Het 1  optionally substituted with one or more substituents alpha; 
         Het 1  represents a heterocyclic group having from 4 to 7 ring atoms which contains either from 1 to 4 nitrogen ring heteroatoms or from 0 to 2 nitrogen ring heteroatoms and 1 oxygen or 1 sulfur ring heteroatom; 
         R 2  and R 3  independently represent a hydrogen atom or an alkyl group having from 1 to 3 carbon atoms; or R 2  and R 3  together form an alkylene chain having from 3 to 6 carbon atoms; and 
         said substituent alpha is selected from the group consisting of halogen atoms, alkyl groups having from 1 to 4 carbon atoms, haloalkyl groups having from 1 to 4 carbon atoms, hydroxy groups, alkoxy groups having from 1 to 4 carbon atoms, haloalkoxy groups having from 1 to 4 carbon atoms, cyano groups, hydroxy alkyl groups having from 1 to 4 carbon atoms, alkoxyalkyl groups having from 1 to 4 carbon atoms in alkoxy and alky groups, alkylsulfonyl groups having from 1 to 4 carbon atoms, alkanoyl groups having from 2 to 5 carbon atoms, alkenyl groups having from 2 to 4 carbon atoms, alkynyl groups having from 2 to 4 carbon atoms, alkylthio groups having from 1 to 4 carbon atoms, nitro groups, amino groups, mono- or di-alkylamino groups having from 1 to 4 carbon atoms, aminosulfonyl groups, alkoxycarbonyl groups having from 1 to 4 carbon atoms, alkylsulfonylamino groups having from 1 to 4 carbon atoms, cycloalkyl groups having from 3 to 7 carbon atoms and a mono- or di-alkylaminocarbonyl groups having from 1 to 6 carbon atoms; 
         or a pharmaceutically acceptable ester of such compound; 
       
       
         
           
           
               
               
           
         
         wherein X and Y are independently selected from the group consisting of: N and C(R 11 ), wherein each R 11  is independently selected from the group consisting of: hydrogen, halo and C 1-4  alkyl; 
         B is selected from the group consisting of: —C(R 5 )(R 6 )—, —O—, —S—, —S(O)—, —SO 2 —, —C(R 5 )(R 6 )—C(R 7 )(R 8 )—, —O—C(R 5 )(R 6 )—, —S—C(R 5 )(R 6 )—, —S(O)—C(R 5 )(R 6 )— and —SO 2 —C(R 5 )(R 6 )—; 
         C is selected from the group consisting of aryl and heteroaryl, or a fused analog of aryl or heteroaryl, each optionally substituted with one to three substituents independently selected from R 10 ; 
         E is selected from the group consisting of: —C(O)OH, —C(O)OC 1-4 alkyl, tetrazolyl and 
       
       
         
           
           
               
               
           
         
         wherein R is selected from the group consisting of: C 1-4  alkyl, aryl and heteroaryl, or a fused analog of aryl or heteroaryl, wherein aryl and heteroaryl or the fused analogs thereof are optionally substituted with one to three substituents independently selected from R 10 ; 
         R 1  to R 8  are independently selected from the group consisting of: H, halo, —O—R 12 , C 1-6 alkyl and C 3-6  cycloalkyl, and one or more pairs of R 1  and R 2 , R 5  and R 6 , and R 7  and R 8  may be joined together with the carbon atom to which they are attached to form a 3- to 5-membered monocyclic cycloalkyl ring, and R 5  and R 6  or R 7  and R 8  may be joined together to form carbonyl; 
         R 9  is independently selected from the group consisting of: halo, hydroxyl and C 1-4  alkyl; 
         R 10  is selected from the group consisting of: halo, cyano, C 1-4  alkyl, C 1-4  fluoroalkyl, C 1-4  alkoxy, C 1-4  thioalkoxy and C 1-4  fluoroalkoxy; and 
         each R 12  is selected from the group consisting of: H, C 1-4  alkyl, C 3-6  cycloalkyl and heterocyclyl. 
       
     
     
         25 . The method of  claim 24 , which further comprises administering a therapeutically effective amount of one or more additional compounds known to be useful in the treatment or prevention of cartilage disease thereof.