Hydroxamic and carboxylic acid derivatives

Abstract

Compounds having therapeutic utility are of formula (I) B—X—(CH 2 ) n —CR 2 R 3 —CR 4 R 5 —COY  (I) wherein n=0-1; X is S(O) 0-2 ; Y is OR 1 or NHOH; R 2 and R 4 are independently H or a group (optionally substituted with R 10 ) selected from C 1-6 alkyl, C 2-6 alkenyl, aryl, C 1-6 , alkyl-aryl, heteroaryl, C 1-6 alkyl-heteroaryl, heterocycloalkyl, C 1-6 alkyl-heterocycloalkyl, cycloalkyl and C 1-6 alkyl-cycloalkyl; and R 1 , R 3 and R 5 are independently H or C 1-6 alkyl; provided that not more than two of R 2 , R 3 , R 4 and R 5 are H; or any of CR 2 R 3 , CR 4 R 5 and CR 2 -CR 4 is a cycloalkyl or heterocycloalkyl ring optionally substituted with R 10 or a group (optionally substituted with R 10 ) selected from C 1-6 alkyl, aryl, C 1-6 alkyl-aryl, heteroaryl and C 1-6 alkyl-heteroaryl; B is heterocycloalkyl (optionally substituted by R 6 or R 7 ) bonded through carbon to X, or C 1-6 alkyl-heterocycloalkyl (optionally substituted with R 6 or R 7 ), or a group (substituted with R 6 ) selected from C 1-8 alkyl, C 2-6 alkenyl and C 2-6 alkynyl; R 6 is N(R 7 ) 2 , OR 7 , COR 7 , C(═NOR 19 )R 7 , NR 7 R 8 , S(O) 0-2 R 9 or SO 2 N(R 7 ) 2 ; R 7 is H or a group selected from C 1-6 alkyl, aryl, C 1-6 alkyl-aryl, heteroaryl, C 1-6 alkyl-heteroaryl, cycloalkyl, C 1-6 alkyl-cycloalkyl, heterocycloalkyl and C 1-6 alkyl-heterocycloalkyl, wherein said group is optionally substituted with R 9 , COR 9 , SO 0-2 R 9 , CO 2 R 9 , OR 9 , CONR 1 R 9 , NR 1 R 9 , halogen, CN, SO 2 NR 1 R 9 or NO 2 , and for each case of N(R 7 ) 2 the R 7 groups are the same or different or N(R 7 ) 2 is heterocycloalkyl optionally substituted with R 9 , COR 9 , SO 0-2 R 9 , CO 2 R 9 , OR 9 , CONR 1 R 9 , NR 1 R 9 , halogen, CN, SO 2 NR 1 R 9 or NO 2 ; R 8 is COR 7 , CON(R 7 ) 2 , CO 2 R 9 or SO 2 R 9 ; R 9 is C 1-6 alkyl, aryl, C 1-6 alkyl-aryl, heteroaryl or C 1-6 alkyl-heteroaryl; and R 10 is OR 7 , COR 8 , CO 2 R 1 , CON(R 7 ) 2 , NR 7 R 1 , S(O) 0-2 R 9 , SO 2 N(R 7 ) 2 , CN, halogen or cyclomidyl (optionally substituted with R 1 ); and the salts, solvates, hydrates, N-oxides, protected amino, protected carboxy and protected hydroxamic acid derivatives thereof.

We claim:  
     
         1 . A compound of formula (I) 
       B—S(O) 0-2 —(CH 2 ) 0-1 —CR 2 R 3 —CR 4 R 5 —COY   (I) wherein    Y is selected from the group consisting of OR 1  and NHOH;    R 2  and R 4  are independently selected from the group consisting of H and a moiety (optionally substituted with R 10 ) selected from C 1-6  alkyl, C 2-6  alkenyl, aryl, C 1-6  alkyl-aryl, heteroaryl, C 1-6  alkyl-heteroaryl, heterocycloalkyl, C 1-6  alkyl-heterocycloalkyl, cycloalkyl and C 1-6  alkyl-cycloalkyl;    R 1  and R 3  and R 5  are independently selected from the group consisting of H and C 1-6 alkyl;    provided that not more than two of R 2 , R 3 , R 4  and R 5  are H; or    any of CR 2 R 3 , CR 4 R 5  and CR 2 —CR 4  is a cycloalkyl or heterocycloalkyl ring optionally substituted with R 10  or a group (optionally substituted with R 10 ) selected from C 1-6  alkyl, aryl, C 1-6  alkyl-aryl, heteroaryl and C 1-6  alkyl-heteroaryl;    B is selected from the group consisting of C 1-8  alkyl, C 2-6  alkenyl and C 2-6  alkynyl, and is substituted with R 6 ;    R is selected from the group consisting of N(R 7 ) 2 , OR 7 , COR 7 , C(═NOR 9 )R 7 , NR 7 R 8 , S(O) 0-2 ,R 9 , and SO 2 N(R 7 ) 2 ;    R 7  is selected from the group consisting of H and a moiety selected from C 1-6  alkyl, aryl, C 1-6  alkyl-aryl, heteroaryl, C 1-6  alkyl-heteroaryl, cycloalkyl, C 1-6  alkyl-cycloalkyl, heterocycloalkyl and C 1-6  alkyl-heterocycloalkyl, wherein said moiety is optionally substituted with R 9 , COR 9 , SO 0-2 R 9 , CO 2 R 9 , OR 9 , CONR 1 R 9 , NR 1 R 9 , halogen, CN, SO 2 NR 1 R 9  or NO 2 , and for each case of N(R 7 ) 2  the R 7  groups are the same or different, or N(R 7 ) 2  is heterocycloalkyl optionally substituted with R 9 , COR 9 , SO 0-2 R 9 , CO 2 R 9 , OR 9 , CONR 1 R 9 , NR 1 R 9 , halogen, CN, SO 2 NR 1 R 9  or NO 2 ;    R 8  is selected from the group consisting of COR 7 , CON(R 7 ) 2 , CO 2 R 9  and SO 2 R 9 ;    R 9  is selected from the group consisting of C 1-6  alkyl, aryl, C 1-6  alkyl-aryl, heteroaryl and C 1-6  alkyl-heteroaryl; and    R 10  is selected from the group consisting of OR 7 , COR 7 , CO 2 R 1 , CON(R 7 ) 2 , NR 7 R 8 , S(O) 0-2 R 9 , SO 2 N(R 7 ) 2 , CN, halogen and cycloimidyl (optionally substituted with R 1 ); or    a salt, solvate, hydrate, N-oxide or protected amino, protected carboxy or protected hydroxamic acid derivative thereof.    
     
     
         2 . The compound of  claim 1 , wherein R 2  or R 4  is optionally substituted C 1-6  alkyl, C 1-6  alkyl-heteroaryl, or C 1-6  alkyl-heterocycloalkyl; or CR 2 R 3 , CR 4 R 5  or CR 2 —CR 4  forms the said optionally substituted ring.  
     
     
         3 . The compound of  claim 1 , wherein B is C 1-8  alkyl substituted with R 6 .  
     
     
         4 . The compound of  claim 3 , wherein B is C 1-8  alkyl substituted with OR 7 .  
     
     
         5 . The compound of  claim 4 , wherein R 7  is optionally substituted aryl or heteroaryl.  
     
     
         6 . The compound of  claim 1 , wherein S(O) 0-2  is SO 2 .  
     
     
         7 . The compound of  claim 1 , selected from the group consisting of methyl 4-((3-(3-pyridyloxy)propylsulfanyl)methyl)tetrahydropyran-4-carboxylate, methyl 4-((3-(3-pyridyloxy)propylsulfonyl)methyl)tetrahydropyran-4-carboxylate, and 4-((3-(4-pyridyloxy)propylsulfonyl)methyl)tetrahydropyran-4-carboxylate.  
     
     
         8 . The compound of  claim 1 , selected from the group consisting of 2-(3-phenoxypropylsulfanyl)cyclopentanecarboxylic acid methyl ester, 2-(3-phenoxypropane-1-sulfonyl)cyclopentanecarboxylic acid methyl ester, 2-(3-phenoxypropane-1-sulfonyl)cyclopentanecarboxylic acid and 2-(3-phenoxypropane-1-sulfonyl)cyclopentanecarboxylic acid hydroxyamide.  
     
     
         9 . A pharmaceutical composition for the use in therapy, comprising a compound of  claim 1 , and a pharmaceutically-acceptable diluent or carrier.  
     
     
         10 . A method for the treatment of a condition selected from the group consisting of asthma, inflammation, inflammatory diseases, autoimmune, infectious or ocular diseases, age-related macular degeneration, and cancer, which comprises administering to a subject in need thereof an effective amount of a compound of  claim 1 .  
     
     
         11 . A compound of formula (I) 
       B—S(O) 0-2 —(CH 2 ) 0-1 —CR 2 R 3 —CR 4 R 5 —COY   (I)  
       wherein 
 Y is selected from the group consisting of OR 1  and NHOH;  
 R 2  and R 4  are independently selected from the group consisting of H and a moiety (optionally substituted with R 10 ) selected from C 1-6  alkyl, C 1-6  alkenyl, aryl, C 1-6  alkyl-aryl, heteroaryl, C 1-6  alkyl-heteroaryl, heterocycloalkyl, C 1-6  alkyl-heterocycloalkyl, cycloalkyl and C 1-6  alkyl-cycloalkyl;  
 R 1 , R 3  and R 5  are independently selected from the group consisting of H and C 1-6  alkyl;  
 provided that not more than two of R 2 , R 3 , R 4  and R 5  are H; or  
 any of CR 2 R 3 , CR 4 R 5  and CR 2 -CR 4  is a cycloalkyl or heterocycloalkyl ring optionally substituted with R 10  or a group (optionally substituted with R 10 ) selected from C 1-6  alkyl, aryl, C 1-6  alkyl-aryl, heteroaryl and C 1-6  alkyl-heteroaryl;  
 B is C 1-6  alky-heterocycloalkyl group optionally substituted with R 6  or R 7 ;  
 R 6  is selected from the group consisting of N(R 7 ) 2 , OR 7 , COR 7 , C(═NOR 9 )R 7 , NR 7 R 8 , S(O) 0-2 R 9  and SO 2 N(R 7 ) 2 ;  
 R 7  is selected from the group consisting of H and a moiety selected from C 1-6  alkyl, aryl, C 1-6  alky-aryl, heteroaryl, C 1-6  alky-heteroaryl, cycloalkyl, C 1-6  alkyl-cycloalkyl, heterocycloalkyl and C 1-6  alkyl-heterocycloalkyl, wherein said moiety is optionally substituted with R 9 , COR 9 , SO 0-2 R 9 , CO 2 R 9 , OR 9 , CONR 1 R 9 , NR 1 R 9 , halogen, CN, SO 2 NR 1 R 9  or NO 2 , and for each case of N(R 7 ) 2  the R 7  groups are the same or different, or N(R 7 ) 2  is heterocycloalkyl optionally substituted with R 9 , COR 9 , SO 0-2 R 9 , CO 2 R 9 , OR 9 , CONR 1 R 9 , NR 1 R 9 , halogen, CN, SO 2 NR 1 R 9  or NO 2 ;  
 R 8  is selected from the group consisting of COR 7 , CON(R 7 ) 2 , CO 2 R 9  and SO 2 R 9 ;  
 R 9  is selected from the group consisting of C 1-6  alkyl, aryl, C 1-6  alkyl-aryl, heteroaryl and C 1-6  alkyl-heteroaryl; and  
 R 10  is selected from the group consisting of OR 7 , COR 7 , CO 2 R 1 , CON(R 7 ) 2 , NR 7 R 8 , S(O) 0-2 R 9 , SO 2 N(R 7 ) 2 , CN, halogen and cycloimidyl (optionally substituted with R 1 ); or  
 a salt, solvate, hydrate, N-oxide or protected amino, protected carboxy or protected hydroxamic acid derivative thereof.  
 
     
     
         12 . The compound of  claim 11 , wherein R 2  or R 4  is optionally substituted C 1-6  alkyl, C 1-6  alkyl-heteroaryl, or C 1-6  alkyl-heterocycloalkyl; or CR 2 R 3 , CR 4 R 5  or CR 2 —CR 4  forms the said optionally substituted ring.  
     
     
         13 . The compound of  claim 11 , wherein the alkyl group in B is selected from the group consisting of ethyl and propyl.  
     
     
         14 . The compound of  claim 11 , wherein the heterocycloalkyl group in B is selected from the group consisting of azetidinyl, pyrrolidinyl and piperdinyl, aryl which is substituted with R 7 .  
     
     
         15 . The compound of  claim 14 , wherein R 7  is optionally substituted aryl or heteroaryl.  
     
     
         16 . The compound of  claim 11 , wherein S(O) 0-2  is SO 2 .  
     
     
         17 . The compound of  claim 11 , selected from the group consisting of 
 1-{2-[1-(4-nitrophenyl)pyrrolidin-3-yl]ethylsulfanylmethyl}cyclobutanecarboxylic acid ethyl ester,    1-{2-[1-(4-nitrophenyl)pyrrolidin-3-yl]ethanesulfonylmethyl}cyclobutanecarboxylic acid ethyl ester,    1-{2-[1-(4-nitrophenyl)pyrrolidin-3-yl]ethanesulfonylmethyl}cyclobutanecarboxylic acid and    2-(piperidin-4-ylsulfanyl)cyclopentanecarboxylic acid methyl ester.    
     
     
         18 . A pharmaceutical composition for use in therapy, comprising a compound of  claim 11 , and a pharmaceutically-acceptable diluent or carrier.  
     
     
         19 . A method for the treatment of a condition selected from the group consisting of asthma, inflammation, inflammatory diseases, autoimmune, infectious or ocular diseases, age-related macular degeneration, and cancer, which comprises administering to a subject in need thereof an effective amount of a compound of  claim 11 .  
     
     
         20 . A compound of formula (I) 
       B—S(O) 0-2 —(CH 2 ) 0-1 —CR 2 R 3 —CR 4 R 5 —COY   (I) 
       wherein 
 Y is selected from the group consisting of OR 1  and NHOH;  
 R 2  and R 4  are independently selected from the group consisting of H and a moiety (optionally substituted with R 10 ) selected from C 1-6  alkyl, C 2-6  alkenyl, aryl, C 1-6  alkyl-aryl, heteroaryl, C 1-6  alkyl-heteroaryl, heterocycloalkyl, C 1-6  alkyl-heterocycloalkyl, cycloalkyl and C 1-6  alkyl-cycloalkyl;  
 R 1 , R 3  and R 5  are independently selected from the group consisting of H and C 1-6  alkyl;  
 provided that not more than two of R 2 , R 3 , R 4  and R 5  are H; or  
 any of CR 2 R 3 , CR 4 R 5  and CR 2 -CR 4  is a cycloalkyl or heterocycloalkyl ring optionally substituted with R 10  or a group (optionally substituted with R 10 ) selected from C 1-6  alkyl, aryl, C 1-6  alkyl-aryl, heteroaryl and C 1-6  alkyl-heteroaryl;  
 B is heterocycloalkyl, optionally substituted with R 6  or R 7 , bonded through a C atom to S(O) 0-2 .  
 R 6  is selected from the group consisting of N(R 7 ) 2 , OR 7 , COR 7 , C(═NOR 9 )R 7 , NR 7 R 8 , S(O) 0-2 R 9  and SO 2 N(R 7 ) 2 ;  
 R 7  is selected from the group consisting of H and a moiety selected from C 1-6  alkyl, aryl, C 1-6  alkyl-aryl, heteroaryl, C 1-6  alky-heteroaryl, cycloalkyl, C 1-6  alky-cycloalkyl, heterocycloalkyl and C 1-6  alkyl-heterocycloalkyl, wherein said moiety is optionally substituted with R 9 , COR 9 , SO 0-2 R 9 , CO 2 R 9 , OR 9 , CONR 1 R 9 , NR 1 R 9 , halogen, CN, SO 2 NR 1 R 9  or NO 2 , and for each case of N(R 7) 2  the R 7  groups are the same or different, or N(R 7 ) 2  is heterocycloalkyl optionally substituted with R 9 , COR 9 , SO 0-2 R 9 , CO 2 R 9 , OR 9 , CONR 1 R 9 , NR 1 R 9 , halogen, CN, SO 2 NR 1 R 9  or NO 2 ;  
 R 8  is selected from the group consisting of COR 7 , CON(R 7 ) 2 , CO 2 R 9  and SO 2 R 9 ;  
 R 9  is selected from the group consisting of C 1-6  alkyl, aryl, C 1-6  alkyl-aryl, heteroaryl and C 1-6  alky-heteroaryl; and  
 R 10  is selected from the group consisting of OR 7 , COR 7 , CO 2 R 1 , CON(R 7 ) 2 , NR 7 R 8 , S(O) 0-2 R 9 , SO 2 N(R 7 ) 2 , CN, halogen and cycloimidyl (optionally substituted with R 1 ); or  
 a salt, solvate, hydrate, N-oxide or protected amino, protected carboxy or protected hydroxamic acid derivative thereof.  
 
     
     
         21 . The compound of  claim 20 , wherein R 2  or R 4  is optionally substituted C 1-6  alkyl, C 1-6  alkyl-heteroaryl, or C 1-6  alkyl-heterocycloalkyl; or CR 2 R 3 , CR 4 R 5  or CR 2 —CR 4  forms the said optionally substituted ring.  
     
     
         22 . The compound of  claim 20 , wherein B is selected from the group consisting of azetidinyl, pyrrolidinyl and piperidinyl, any of which is substituted with R 7 .  
     
     
         23 . The compound of  claim 22 , wherein R 7  is optionally substituted aryl or heteroaryl.  
     
     
         24 . The compound of  claim 20 , wherein S(O) 0-2  is SO 2 .  
     
     
         25 . The compound of  claim 20 , selected from the group consisting of 
 4-(1-methoxycarbonylcyclohexylmethylsulfanyl)piperidine- 1-carboxylic acid tert-butyl ester,    2-(piperidin-4-ylsulfanyl)cyclopentanecarboxylic acid methyl ester,    1-(piperidin-4-ylsulfanylmethyl)cyclohexanecarboxylic acid methyl ester,    2-[1-(4-cyanophenyl)piperidin-4-ylsulfanyl]cyclopentane-carboxylic acid methyl ester,    1-[1-(4-nitrophenyl)piperidin-4-ylsulfanylmethyl]cyclohexanecarboxylic acid methyl ester,    2-[1-(4-cyanophenyl)piperidin-4-ylsulfanyl]cyclopentanecarboxylic acid,    1-[1-(4-nitrophenyl)piperidin-4-ylsulfanylmethyl]cyclohexanecarboxylic acid and    1-[1-(4-nitrophenyl)piperidin-4-ylsulfinylmethyl]cyclohexanecarboxylic acid.    
     
     
         26 . A pharmaceutical composition for use in therapy, comprising a compound of  claim 20 , and a pharmaceutically-acceptable diluent or carrier.  
     
     
         27 . A method for the treatment of a condition selected from the group consisting of asthma, inflammation, inflammatory diseases, autoimmune, infectious or ocular diseases, age-related macular degeneration, and cancer, which comprises administering to a subject in need thereof an effective amount of a compound of  claim 20.