Hydroxamate sulfonamides as cd23 shedding inhibitors
A class of piperidine and related heterocyclic derivatives, C-substituted by a substituted aryl or heteroaryl moiety, and N-substituted by an ethylsulfonyl group which in turn is substituted at the 2-position by a hydroxamic acid moiety and also by a range of alternative substituents, being potent inhibitors of CD23 shedding, are useful in the treatment and/or prevention of allergic, inflammatory and neoplastic diseases.
1 . A compound of formula (1):
wherein:
Cy is an aryl or heteroaryl group;
m is zero or the integer 1, 2 or 3;
n is zero or the integer 1, 2 or 3; in which the sum of m and n is zero or the integer 1, 2 or 3;
R 1 is a group selected from C 1-6 alkyl, aryl, heteroaryl, heterocycloalkyl, C 3-6 cycloalkyl, -C 1-6 alkylaryl, -C 1-6 alkylheteroaryl, -C 1-6 alkylheterocycloalkyl and -C 1-6 alkylC 3-6 cycloalkyl, in which each aryl of and heteroaryl group, present as or as part of the group R 1 , is optionally substituted with 1, 2 or 3 R 7 substituents; and in which each alkyl, heterocycloalkyl and cycloalkyl group, present as or as part of the group R 1 , is optionally substituted with 1, 2 or 3 R 8 substituents;
each R 7 is, independently, F. Cl, Br, C 1-6 l C 1-6 haloalkyl. 1-6 alkox C 1-6 haloalkoxy, —CN, —CO 2 R 7a , CON(R 7a ) 2 or COR 7a ;
each R 7a is, independently, a hydrogen atom, or a C 1-6 alkyl or C 1-6 haloalkyl group;
each R 8 is, independently, F, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, ═O, ═NOR 10 , —CO 2 R 8a , CON(R 8a ) 2 or COR 8a ;
each R 8a is, independently, a hydrogen atom, or a C 1-6 alkyl or C 1-6 haloalkyl group;
R 10 is a hydrogen atom or a C 1-3 alkyl group;
R 2 is a hydrogen atom or a C 1-3 alkyl group;
or R 1 and R 2 together with the carbon atom to which they are attached form a C 3-6 cycloalkyl or heterocycloalkyl group optionally substituted with 1, 2 or 3 R 9 substituents;
each R 9 is, independently, F, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, ═O, ═NOR 10 , —CO 2 R 8a , —CON(R 8a ) 2 or —COR 8a ;
R 3 is F, Cl, Br, C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy or —CN;
R 4 is hydrogen, F, Cl, of Br, C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy, —CN, —SO 2 R 5 , —SO 2 N(R 6 ) 2 , —CON(R 6 ) 2 , —N(R 6 ) 2 , —NHSO 2 R 5 or —NHCOR 5 ;
R 5 is a C 1-3 alkyl group;
each R 6 is, independently, a hydrogen atom or a C 1-3 alkyl group; and
R a and R b , which may be the same or different, are each hydrogen or C 1-3 alkyl, or R a and R b together with the carbon atom to which they are attached form a C 3-6 cycloalkyl or heterocycloalkyl group optionally substituted with 1, 2, or 3 R 9 substituents; or a salt, solvate, hydrate, tautomer, isomer or N-oxide thereof.
2 . A compound according to claim 1 of formula (2):
or a salt, solvate, hydrate, tautomer, isomer or N-oxide thereof.
3 . A compound according to claim 1 of formula (3):
or a salt, solvate, hydrate, tautomer, isomer or N-oxide thereof.
4 . A compound according to claim 3 of formula (4):
or a salt, solvate, hydrate, tautomer, isomer or N-oxide thereof.
5 . A compound according to claim 1 wherein Cy is a phenyl group.
6 . A compound according to claim 1 wherein R a and R b i are each a hydrogen atom.
7 . A compound according to claim 1 wherein m is the integer 1 and n is zero or the integer 1.
8 . A compound according to claim 1 wherein n is the integer 1.
9 . A compound according to claim 1 wherein R 1 is a group selected from C 1-6 alkyl, phenyl, heteroaryl, heterocycloalkyl, C 3-6 cycloalkyl, —(CH 2 ) 1-2 phenyl, —(CH 2 ) 1-2 heteroaryl, —(CH 2 ) 1-2 heterocycloalkyl and —(CH 2 ) 1-2 C 3-6 cycloalkyl, each of which is optionally substituted.
10 . A compound according to claim 9 wherein R 1 is a group selected from optionally substituted C 1-6 alkyl, phenyl, heterocycloalkyl, C 3-6 cycloalkyl and —(CH 2 ) 1-2 phenyl.
11 . A compound according to claim 1 wherein R 1 and R 2 together with the carbon atom to which they are attached form an optionally substituted C 3-6 cycloalkyl group.
12 . A compound according to claim 11 in which R 1 and R 2 together with the carbon atom to which they are attached form a cyclobutyl group.
13 . A compound according to claim 1 wherein R 3 is F, Cl, methyl, ethyl, isopropyl, —CF 3 , —CF 2 H, methoxy, ethoxy, —OCF 3 , —OCF 2 H or —CN.
14 . A compound according to claim 1 wherein R 4 is hydrogen, F, Cl, methyl, —CF 3 , methoxy or —OCF 2 H.
15 . A compound according to claim 1 wherein R 3 is F, Cl, C 1-3 alkyl or C 1-3 alkoxy.
16 . A compound according to claim 15 wherein R 3 is a C 1-3 alkyl or C 1-3 alkoxy group.
17 . A compound according to claim 15 wherein R 3 is a methyl or methoxy group.
18 . A compound which is:
2-[4-(2-methoxyphenyl)piperidine-1-sulfonylmethyl]—N-hydroxy-3-methylbutyramide;
2-[4-(2-methyl-4-fluorophenyl)piperidine-1-sulfonylmethyl]—N-hydroxy-3-methylbutyramide;
2-benzyl-N-hydroxy-3-[4-(2-methoxyphenyl)piperidine-1-sulfonyl]propionamide;
2-benzyl-N-hydroxy-3-[4-(2-methylphenyl)piperidine-1-sulfonyl]propionamide;
N-hydroxy-3-[4-(2-methoxyphenyl)piperidine-1-sulfonyl] −2-phenylpropionamide;
2(R)-[4-(2-methoxyphenyl)piperidine-1-sulfonylmethyl]—N-hydroxy-3-methylbutyramide;
2(R)- [4-(2-methylphenyl)piperidine-1-sulfonylmethyl]—N-hydroxy-3-methylbutyramide;
1-[4-(2-methoxyphenyl)piperidine-1-sulfonylmethyl]cyclobutane carboxylic acid hydroxyamide;
1-[4-(2-methylphenyl)piperidine-1-sulfonylmethyl]cyclobutane carboxylic acid hydroxyamide; and the salts, olates, hydrates, tautomers, isomers or N oxide thereof or a salt, solvate, hydrate, tautomer, isomer or N-oxide thereof.
19 . A pharmaceutical composition comprising a compound according to claim 1 together with one or more pharmaceutically acceptable carriers, excipients or diluents.