Hydroxamic acid derivatives

Abstract

The invention encompasses novel compounds which are inhibitors of matrix metalloproteinase, ADAM or ADAM-TS enzymes, and which are useful for the treatment of diseases mediated by those enzymes, including degenerative diseases and certain cancers.

We claim:  
     
         1 . A compound of formula (I)  
       
         
           
           
               
               
           
         
       
       wherein R 2  is H, alkyl, alkenyl, alkynyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, cycloalkylalkyl, heterocyclo, heterocycloalkyl or cycloalkyl (any of which may be optionally substituted with one or more substituents selected from R 4 , W and WR 4 ); and 
 R 3  is H or alkyl;  
 or R 2 , R 3  and the carbon atom to which they are attached together represent a carbocyclic or heterocyclic ring (either of which may be substituted with one or more substitients chosen from R 4 , W and WR 4 );  
 A is a heterocyclic ring (attached to SO 2  through a nitrogen atom) optionally substituted with R 4 ;  
 B is an aryl or heteroaryl ring, optionally substituted with one or more R 5 ;  
 D is an aryl or heteroaryl ring, optionally substituted with one or more R 5 , or a heterocyclic ring (attached through a carbon atom) optionally substituted with R 4  at any available carbon atom or with R 14  at any available nitrogen atom;  
 provided that B and D are not both phenyl;  
 R 4  is OR 6 , COR 10 , CO 2 R 9 , CONR 7 R 8 , NR 10 R 11 , S(O) q R 10 , S(O) q NR 7 R 8 , CN, ═O or ═NOR 10 , provided that R 4  is not ═O or NOR 10  if a substituent on an aromatic ring;  
 R 5  is alkyl, cycloalkyl, CF 3 , OR 6 , COR 10 , S(O) q R 10 ,CO 2 R 9 , CONR 7 R 8 , S(O) q NR 7 R 8 , halogen, NR 10 R 11  or CN;  
 R 6  is H, alkyl, CF 3 , CHF 2 , CH 2 F, cycloalkyl, aryl, heteroaryl, heterocyclo, arylalkyl, heteroarylalkyl, heterocycloalkyl or cycloalkylalkyl;  
 R 7  and R 8 , which may be the same or different, are each H, alkyl, cycloalkyl, aryl, heteroaryl, heterocyclo, arylalkyl, heteroarylalkyl, heterocycloalkyl, cycloalkylalkyl, or R 7  and R 8  and the nitrogen to which they are attached together represent a heterocyclic ring;  
 R 9  is H, alkyl or cycloalkyl;  
 R 10  is H, alkyl, cycloalkyl, aryl, heteroaryl, heterocyclo, arylalkyl, heteroarylalkyl, heterocycloalkyl or cycloalkylalkyl; and  
 R 11  is H, alkyl, cycloalkyl, aryl, heteroaryl, heterocyclo, arylalkyl, heteroarylalkyl, heterocycloalkyl, cycloalkylalkyl, COR 12 , CONR 7 R 8 , S(O) q R 12  or S(O) q NR 7 R 8 ;  
 or R 10  and R 11  and the nitrogen atom to which they are attached together represent a heterocyclic ring optionally substituted by R 13 ;  
 R 12  or OR 6  or R 13 ;  
 R 13  is alkyl, cycloalkyl, aryl, heteroaryl, heterocyclo, arylalkyl, heteroarylalkyl, heterocycloalkyl or cycloalkylalkyl;  
 R 14  is H, alkyl or cycloalkyl  
 q is O, 1 or 2;  
 W is alkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclo or heterocycloalkyl; and  
 X is —O—, —CO—, S(O) q —, —N(R 10 )—, or is absent;  
 or a salt, solvate, hydrate, N-oxide, protected amino, protected carboxy or protected hydroxamic acid derivative thereof.  
 
     
     
         2 . The compound, according to  claim 1 , wherein R 14  is H.  
     
     
         3 . The compound, according to  claim 1 , wherein R 2  is not aryl.  
     
     
         4 . The compound, according to  claim 3 , wherein R 2  is an optionally substituted C 1-6  alkyl group.  
     
     
         5 . The compound, according to  claim 4 , wherein R 2  is isopropyl.  
     
     
         6 . The compound, according to  claim 1 , wherein R 3  is H.  
     
     
         7 . The compound, according to  claim 1 , wherein R 2 , R 3  and the carbon atom to which they are attached together are an optionally substituted C 3-7  cycloalkyl or C 3-7  heterocyclo group.  
     
     
         8 . The compound, according to  claim 7 , wherein R 2 , R 3  and the carbon to which they are attached together are a cyclobutyl, cyclopentyl, cyclohexyl or tetrahydropyranyl group.  
     
     
         9 . The compound, according to  claim 1 , wherein X is —O—, —CO—, or is absent.  
     
     
         10 . The compound, according to  claim 9 , wherein X is —O— or is absent.  
     
     
         11 . The compound, according to  claim 1 , wherein A is a piperidinyl or piperazinyl group.  
     
     
         12 . The compound, according to  claim 11 , wherein B is an optionally substituted pyridyl, pyrimidinyl, pyridazinyl or pyrazinyl group and D is an optionally substituted phenyl group.  
     
     
         13 . The compound, according to  claim 1 , wherein each of B and D is an optionally substituted pyridyl, pyrimidinyl, pyridazinyl or pyrazinyl group.  
     
     
         14 . The compound, according to  claim 1 , wherein B is an optionally substituted pyrimidinyl.  
     
     
         15 . The compound, according to  claim 1 , wherein B is an optionally substituted phenyl group and D is an optionally substituted furyl, thienyl or pyridyl group.  
     
     
         16 . The compound of  claim 1 , which is: 
 2-[4-(4-furan-2-ylphenyl)piperazine-1-sulfonylmethyl]-N-hydroxy-3-methylbutyramide;    4-[4-(4-thiophen-2-ylphenyl)piperazine-1-sulfonylmethyl]tetrahydropyran-4-carboxylic acid-N-hydroxyamide;    2-[4-(4-pyridin-3-ylphenyl)piperazine-1-sulfonylmethyl]-N-hydroxy-3-methyl-butyramide; or    4-[4-(4-pyridin-3-ylphenyl)piperazine-1-sulfonylmethyl]tetrahydropyran-4-carboxylic acid-N-hydroxyamide.    
     
     
         17 . The compound of  claim 1 , which is: 
 4-[4-(4-furan-2-ylphenyl)piperazine-1-sulfonylmethyl]tetrahydropyran-4-carboxylic acid-N-hydroxyamide;    4-{4-[5-(4-fluorophenyl)pyrimidin-2-yl]piperazine-1-sulfonylmethyl}tetrahydropyran-4-carboxylic acid-N-hydroxyamide;    2-(R)-{4-[5-(4-chlorophenyl)pyridin-2-yl]piperazine-1-sulfonylmethyl}-N-hydroxy-3-methylbutyramide;    2-(R)-{4-[5-(4-fluorophenyl)pyridin-2-yl]piperazine-1-sulfonylmethyl}-N-hydroxy-3-methylbutyramide; or    2-(R)-{4-[5-(4-fluorophenyl)pyridin-2-yloxy}piperazine-1-sulfonylmethyl}-N-hydroxy-3-methylbutyramide.    
     
     
         18 . The compound of  claim 1 , which is: 
 2-(R)-{4-[5-(4-fluorophenyl)pyrimidin-2-yl]piperazine-1-sulfonylmethyl}-N-hydroxy-3-methylbutyramide.    
     
     
         19 . The compound of  claim 1 , which is: 
 2-(R)-[4-(5-pyridin-3-yl-pyrimidin-2-yl)piperazine-1-sulfonylmethyl]-N-hydroxy-3-methylbutyramide;    2-(R)-[4-[5-(4-cyanophenyl)pryimidin-2-yl]piperazine-1-sulfonylmethyl}-N-hydroxy-3-methylbutyramide;    2-(R)-{4-[5-(3,4-dichlorophenyl)pyrimidin-2-yl]piperazine-1-sulfonylmethyl}-N-hydroxy-3-methylbutyramide;    2-(R)-{4-{5-(4-trifluoromethylphenyl)pyrimidin-2-yl}piperazine-1-sulfonylmethyl}-N-hydroxy-3-methylbutyramide;    1-{4-[5-(4-fluorophenyl)pyrimidin-2-yl]piperazine-1-sulfonylmethyl}cyclohexanecarboxylic acid-N-hydroxyamide; or    2-(R)-{4-[5-(4-chlorophenyl)pyrimidin-2-yl]piperidine-1-sulfonylmethyl}-N-hydroxy-3-methylbutyramide.    
     
     
         20 . A pharmaceutical composition for use in therapy, comprising a compound of formula (I)  
       
         
           
           
               
               
           
         
       
       wherein R 2  is H, alkyl, alkenyl, alkynyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, cycloalkylalkyl, heterocyclo, heterocycloalkyl or cycloalkyl (any of which may be optionally substituted with one or more substituents selected from R 4 , W and WR 4 ); and 
 R 3  is H or alkyl;  
 or R 2 , R 3  and the carbon atom to which they are attached together represent a carbocyclic or heterocyclic ring (either of which may be substituted with one or more substitients chosen from R 4 , W and WR 4 );  
 A is a heterocyclic ring (attached to SO 2  through a nitrogen atom) optionally substituted with R 4 ;  
 B is an aryl or heteroaryl ring, optionally substituted with one or more R 5 ;  
 D is an aryl or heteroaryl ring, optionally substituted with one or more R 5 , or a heterocyclic ring (attached through a carbon atom) optionally substituted with R 4  at any available carbon atom or with R 14  at any available nitrogen atom;  
 provided that B and D are not both phenyl;  
 R 4  is OR 6 , COR 10 , CO 2 R 9 , CONR 7 R 8 , NR 10 R 11 , S(O) q R 10 , S(O) q NR 7 R 8 , or ═NOR 10 , provided that R 4  is not ═O or NOR 10 if a substituent on an aromatic ring;  
 R 5  is alkyl, cycloalkyl, CF 3 , OR 6 , COR 10 , S(O) q R 10 , CO 2 R 9 , CONR 7 R 8 , S(O) q NR 7 R 8 , halogen, NR 10 R 11  or CN;  
 R 6  is H, alkyl, CF 3 , CHF 2 , CH 2 F, cycloalkyl, aryl, heteroaryl, heterocyclo, arylalkyl, heteroarylalkyl, heterocycloalkyl or cycloalkylalkyl;  
 R 7  and R 8 , which may be the same or different, are each H, alkyl, cycloalkyl, aryl, heteroaryl, heterocyclo, arylalkyl, heteroarylalkyl, heterocycloalkyl, cycloalkylalkyl, or R 7  and R 8  and the nitrogen to which they are attached together represent a heterocyclic ring;  
 R 9  is H, alkyl or cycloalkyl;  
 R 10  is H, alkyl, cycloalkyl, aryl, heteroaryl, heterocyclo, arylalkyl, heteroarylalkyl, heterocycloalkyl or cycloalkylalkyl; and  
 R 11  is H, alkyl, cycloalkyl, aryl, heteroaryl, heterocyclo, arylalkyl, heteroarylalkyl, heterocycloalkyl, cycloalkylalkyl, COR 12 , CONR 7 R 8 , S(O) q R 12  or S(O) q NR 7 R 8 ;  
 or R 10  and R 11  and the nitrogen atom to which they are attached together represent a heterocyclic ring optionally substituted by R 13 ;  
 R 12  or OR 6  or R 13 ;  
 R 13  is alkyl, cycloalkyl, aryl, heteroaryl, heterocyclo, arylalkyl, heteroarylalkyl, heterocycloalkyl or cycloalkylalkyl;  
 R 14  is H, alkyl or cycloalkyl  
 q is O, 1 or 2;  
 W is alkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclo or heterocycloalkyl; and  
 X is —O—, —CO—, S(O) q —, —N(R 10 )—, or is absent;  
 or a salt, solvate, hydrate, N-oxide, protected amino, protected carboxy or protected hydroxamic acid derivative thereof;  
 and a pharmaceutically-acceptable diluent or carrier.  
 
     
     
         21 . A method for the treatment of cancer; inflammation; or an autoimmune, infectious or ocular disease; wherein said method comprises administering to a patient in need of such a treatment a compound of formula (I)  
       
         
           
           
               
               
           
         
       
       wherein R 2  is H, alkyl, alkenyl, alkynyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, cycloalkylalkyl, heterocyclo, heterocycloalkyl or cycloalkyl (any of which may be optionally substituted with one or more substituents selected from R 4 , W and WR 4 ); and 
 R 3  is H or alkyl;  
 or R 2 , R 3  and the carbon atom to which they are attached together represent a carbocyclic or heterocyclic ring (either of which may be substituted with one or more substitients chosen from R 4 , W and WR 4 );  
 A is a heterocyclic ring (attached to SO 2  through a nitrogen atom) optionally substituted with R 4 ;  
 B is an aryl or heteroaryl ring, optionally substituted with one or more R 5 ;  
 D is an aryl or heteroaryl ring, optionally substituted with one or more R 5 , or a heterocyclic ring (attached through a carbon atom) optionally substituted with R 4  at any available carbon atom or with R 14  at any available nitrogen atom;  
 provided that B and D are not both phenyl;  
 R 4  is OR 6 , COR 10 , CO 2 R 9 , CONR 7 R 8 , NR 10 R 11 , S(O) q R 10 , S(O) q NR 7 R 8 , CN, ═O or ═NOR 10 , provided that R 4  is not ═O or NOR 10 if a substituent on an aromatic ring;  
 R 5  is alkyl, cycloalkyl, CF 3 , OR 6 , COR 10 , S(O) q R 10 , CO 2 R 9 , CONR 7 R 8 , S(O) q NR 7 R 8 , halogen, NR 10 R 11  or CN;  
 R 6  is H, alkyl, CF 3 , CHF 2 , CH 2 F, cycloalkyl, aryl, heteroaryl, heterocyclo, arylalkyl, heteroarylalkyl, heterocycloalkyl or cycloalkylalkyl;  
 R 7  and R 8 , which may be the same or different, are each H, alkyl, cycloalkyl, aryl, heteroaryl, heterocyclo, arylalkyl, heteroarylalkyl, heterocycloalkyl, cycloalkylalkyl, or R 7  and R 8  and the nitrogen to which they are attached together represent a heterocyclic ring;  
 R 9  is H, alkyl or cycloalkyl;  
 R 10  is H, alkyl, cycloalkyl, aryl, heteroaryl, heterocyclo, arylalkyl, heteroarylalkyl, heterocycloalkyl or cycloalkylalkyl; and  
 R 11  is H, alkyl, cycloalkyl, aryl, heteroaryl, heterocyclo, arylalkyl, heteroarylalkyl, heterocycloalkyl, cycloalkylalkyl, COR  12 , CONR 7 R 8 , S(O) q R 12  or S(O) q NR 7 R 8 ;  
 or R 10  and R 11  and the nitrogen atom to which they are attached together represent a heterocyclic ring optionally substituted by R 13 ;  
 R 12  or OR 6  or R 13 ;  
 R 13  is alkyl, cycloalkyl, aryl, heteroaryl, heterocyclo, arylalkyl, heteroarylalkyl, heterocycloalkyl or cycloalkylalkyl;  
 R 14  is H, alkyl or cycloalkyl  
 q is O, 1 or 2;  
 W is alkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclo or heterocycloalkyl; and  
 X is —O—, —CO—, S(O) q —, —N(R 10 )—, or is absent;  
 or a salt, solvate, hydrate, N-oxide, protected amino, protected carboxy or protected hydroxamic acid derivative thereof.  
 
     
     
         22 . A method for the treatment of graft versus host reactions, psoriasis, atopic dermatitis, rhinitis, eczema, systemic lupus erythematosus, solid organ transplant or cystic fibrosis, wherein said method comprises administering to a patient in need of such treatment a compound of formula (I)  
       
         
           
           
               
               
           
         
       
       wherein R 2  is H, alkyl, alkenyl, alkynyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, cycloalkylalkyl, heterocyclo, heterocycloalkyl or cycloalkyl (any of which may be optionally substituted with one or more substituents selected from R 4 , W and WR 4 ); and 
 R 3  is H or alkyl;  
 or R 2 , R 3  and the carbon atom to which they are attached together represent a carbocyclic or heterocyclic ring (either of which may be substituted with one or more substitients chosen from R 4 , W and WR 4 );  
 A is a heterocyclic ring (attached to SO 2  through a nitrogen atom) optionally substituted with R 4 ;  
 B is an aryl or heteroaryl ring, optionally substituted with one or more R 5 ;  
 D is an aryl or heteroaryl ring, optionally substituted with one or more R 5 , or a heterocyclic ring (attached through a carbon atom) optionally substituted with R 4  at any available carbon atom or with R 14  at any available nitrogen atom;  
 provided that B and D are not both phenyl;  
 R 4  is OR 6 , COR 10 , CO 2 R 9 , CONR 7 R 8 , NR 10 R 11 , S(O) q R 10 , S(O) q NR 7 R 8 , CN, ═O or ═NOR 10 , provided that R 4  is not ═O or NOR 10 if a substituent on an aromatic ring;  
 R 5  is alkyl, cycloalkyl, CF 3 , OR 6 , COR 10 , S(O)R q   10 , CO R 9 ,  2 CONR 7 R 8 , S(O) q NR 7 R 8 , halogen, NR 10 R 11  or CN;  
 R 6  is H, alkyl, CF 3 , CHF 2 , CH 2 F, cycloalkyl, aryl, heteroaryl, heterocyclo, arylalkyl, heteroarylalkyl, heterocycloalkyl or cycloalkylalkyl;  
 R 7  and R 8 , which may be the same or different, are each H, alkyl, cycloalkyl, aryl, heteroaryl, heterocyclo, arylalkyl, heteroarylalkyl, heterocycloalkyl, cycloalkylalkyl, or R 7  and R 8  and the nitrogen to which they are attached together represent a heterocyclic ring;  
 R 9  is H, alkyl or cycloalkyl;  
 R 10  is H, alkyl, cycloalkyl, aryl, heteroaryl, heterocyclo, arylalkyl, heteroarylalkyl, heterocycloalkyl or cycloalkylalkyl; and  
 R 11  is H, alkyl, cycloalkyl, aryl, heteroaryl, heterocyclo, arylalkyl, heteroarylalkyl, heterocycloalkyl, cycloalkylalkyl, COR 12 , CONR 7 R 8 , S(O) q R 12  or S(O) q NR 7 R 8 ;  
 or R 10  and R 11  and the nitrogen atom to which they are attached together represent a heterocyclic ring optionally substituted by R 13 ;  
 R 12  or OR 6  or R 13 ;  
 R 13  is alkyl, cycloalkyl, aryl, heteroaryl, heterocyclo, arylalkyl, heteroarylalkyl, heterocycloalkyl or cycloalkylalkyl;  
 R 14  is H, alkyl or cycloalkyl  
 q is O, 1 or 2;  
 W is alkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclo or heterocycloalkyl; and  
 X is —O—, —CO—, S(O) q —, —N(R 10 )—, or is absent;  
 or a salt, solvate, hydrate, N-oxide, protected amino, protected carboxy or protected hydroxamic acid derivative thereof.  
 
     
     
         23 . A method for the treatment of rheumatoid arthritis, osteoarthritis, osteoporosis, Crohn's Disease, ulcerative colitis, multiple sclerosis, periodonitis, bone resorption, bacterial infections, epidermolysis bullosa, tumour growth, angiogenesis, ophthalmological disease, retinopathy, asthma, emphysema, bronchitis or chronic obstructive pulmonary disease (COPD); wherein said method comprises administering to a patient in need of such treatment a compound of formula (I)  
       
         
           
           
               
               
           
         
       
       wherein R 2  is H, alkyl, alkenyl, alkynyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, cycloalkylalkyl, heterocyclo, heterocycloalkyl or cycloalkyl (any of which may be optionally substituted with one or more substituents selected from R 4 , W and WR 4 ); and 
 R 3  is H or alkyl;  
 or R 2 , R 3  and the carbon atom to which they are attached together represent a carbocyclic or heterocyclic ring (either of which may be substituted with one or more substitients chosen from R 4 , W and WR 4 );  
 A is a heterocyclic ring (attached to SO 2  through a nitrogen atom) optionally substituted with R 4 ;  
 B is an aryl or heteroaryl ring, optionally substituted with one or more R 5 ;  
 D is an aryl or heteroaryl ring, optionally substituted with one or more R 5 , or a heterocyclic ring (attached through a carbon atom) optionally substituted with R 4  at any available carbon atom or with R 14  at any available nitrogen atom;  
 provided that B and D are not both phenyl;  
 R 4  is OR 6 , COR 10 , CO 2 R 9 , CONR 7 R 8 , NR 10 R 11 , S(O) q R 10 ,S(O) q NR 7 R 8 , CN, ═O or ═NOR 10 , provided that R 4  is not ═O or NOR 10  if a substituent on an aromatic ring;  
 R 5  is alkyl, cycloalkyl, CF 3 , OR 6 , COR 10 , S(O)R q   10 COR 9 ,  2 CONR 7 R 8 , S(O) q NR 7 R 8 , halogen, NR 10 R 11  or CN;  
 R 6  is H, alkyl, CF 3 , CHF 2 CH F   2 , cycloalkyl, aryl, heteroaryl, heterocyclo, arylalkyl, heteroarylalkyl, heterocycloalkyl or cycloalkylalkyl;  
 R 7  and R 8 , which may be the same or different, are each H, alkyl, cycloalkyl, aryl, heteroaryl, heterocyclo, arylalkyl, heteroarylalkyl, heterocycloalkyl, cycloalkylalkyl, or R 7  and R 8  and the nitrogen to which they are attached together represent a heterocyclic ring;  
 R 9  is H, alkyl or cycloalkyl;  
 R 10  is H, alkyl, cycloalkyl, aryl, heteroaryl, heterocyclo, arylalkyl, heteroarylalkyl, heterocycloalkyl or cycloalkylalkyl; and  
 R 11  is H, alkyl, cycloalkyl, aryl, heteroaryl, heterocyclo, arylalkyl, heteroarylalkyl, heterocycloalkyl, cycloalkylalkyl, COR 12 , CONR 7 R 8 , S(O) q R 12  or S(O) q NR 7 R 8 ;  
 or R 10  and R 11  and the nitrogen atom to which they are attached together represent a heterocyclic ring optionally substituted by R 13 ;  
 R 12  or OR 6  or R 13 ;  
 R 13  is alkyl, cycloalkyl, aryl, heteroaryl, heterocyclo, arylalkyl, heteroarylalkyl, heterocycloalkyl or cycloalkylalkyl;  
 R 14  is H, alkyl or cycloalkyl  
 q is O, 1 or 2;  
 W is alkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclo or heterocycloalkyl; and  
 X is —O—, —CO—, S(O) q —, —N(R 10 )—, or is absent;  
 or a salt, solvate, hydrate, N-oxide, protected amino, protected carboxy or protected hydroxamic acid derivative thereof.  
 
     
     
         24 . The method, according to  claim 23 , which is used to treat an ocular condition involving neovascularisation.  
     
     
         25 . The method, according to  claim 24 , wherein the condition is diabetic retinopathy, retinopathy of prematurity or age-related macular degeneration.  
     
     
         26 . The method, according to  claim 24 , wherein the condition is age-related macular degeneration.