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US 8,507,559 B2Granted
Cyclohexenyl modulators of chemokine receptor activity
AssigneeBristol-Myers Squibb Company
InventorsPercy H. Carter, Gregory D. Brown, George V. De Lucca, Douglas G. Batt, Rui-Qin Liu, Feng Qiu
Life of this patent
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Abstract
The present application describes modulators of MCP-1 or CCR-2 of formula, (I) or stereoisomers or prodrugs or pharmaceutically acceptable salts thereof, wherein T, W, X, Y, Z, R1, R2, R4 and R6, are defined herein. In addition, methods of treating and preventing inflammatory diseases such as asthma and allergic diseases, as well as autoimmune pathologies such as rheumatoid arthritis and transplant rejection using modulators of formula, (I) are disclosed.
Claims16
A compound of formula (I):
- or a stereoisomer or a pharmaceutically acceptable salt thereof, wherein:
- R1 is selected from —COOH or —C(═O)NHSO2R12;
- R2 is H or C1-6 alkyl;
- R4 is H, C1-4 alkyl, C1-4 alkoxy, or aryl wherein the C1-4 alkyl, C1-4 alkoxy and aryl may be optionally substituted with one or more R4a's;
- R4a is independently —OH, C1-4 alkoxy, —NHC(═O)C1-6 alkyl, aryl, or aryloxy;
- R6 is selected from H, —OH or C1-4 alkyl;
- R12 is C1-6 alkyl, haloC1-6 alkyl or aryl;
- T is H, C1-4 alkyl, haloC1-4 alkyl, C1-4 alkoxy, or halo;
- W is H, C1-4 alkyl, haloC1-4 alkyl, halo or aryl;
- X is H, C1-4 alkyl, C1-4 alkoxy, or halo;
- Y is H, C1-4 alkyl, haloC1-4 alkyl, C1-4 alkoxy, halo or aryl;
- Z is selected from H, Cl, C1-2 alkyl and C1-2 alkoxy;
- or alternatively any two adjacent T, W, X, Y and Z can be taken together to form a fused cycloalkyl, heteroaryl, heterocyclyl ring, which may be optionally substitute with one or more R4a's;
- provided that:
- (1) R2, R4, T, W, X, Y and Z are not all H;
- (2) X is not propyl or t-butyl when R2, T, W, X, Y and Z are H and R4 and R6 are methyl;
- (3) R4 is not methyl or phenyl, when R2, T, Y and Z are H, R6 is methyl, and X and W are both chloro;
- (4) W and Y are not both aryl;
- or
- (5) the compound is not
17 more elements
A compound or a stereoisomer or pharmaceutically acceptable salt thereof, wherein the compound is selected from:
- 6-(3,4-dichlorophenyl)-6-methylcyclohex-1-enecarboxylic acid,
- 6-(4-chlorophenyl)-6-methylcyclohex-1-enecarboxylic acid,
- (4RS,6RS)-6-(3-phenylphenyl)-4,6-dimethylcyclohex-1-enecarboxylic acid,
- (4RS,6RS)-6-(3-chloro-4-methylphenyl)-4,6-dimethylcyclohex-1-enecarboxylic acid,
- (4RS,6RS)-6-(3,4-difluorophenyl)-4,6-dimethylcyclohex-1-enecarboxylic acid,
- 6-(2-methoxyphenyl)-6-methyl methylcyclohex-1-enecarboxylic acid,
- 6-(3,4-dimethylphenyl)-6-methylcyclohex-1-enecarboxylic acid,
- 6-(3-chlorophenyl)-6-methylcyclohex-1-enecarboxylic acid,
- 6-methyl-6-(3-(trifluoromethyl)-phenyl)cyclohex-1-enecarboxylic acid,
- (4RS,6RS)-4,6-dimethyl-6-(3-(trifluoro-methyl)phenyl)cyclohex-1-enecarboxylic acid,
- (4RS,6RS)-6-(4-chloro-3-(trifluoromethyl)-phenyl)-4,6-dimethylcyclohex-1-enecarboxylic acid,
- (4RS,6RS)-6-(3,5-bis(trifluoromethyl)-phenyl)-4,6-dimethylcyclohex-1-enecarboxylic acid,
- (4RS,6RS)-6-(3,4-dimethylphenyl)-4,6-dimethylcyclohex-1-enecarboxylic acid,
- (4RS,6RS)-4,6-dimethyl-6-(napthalen-1-yl)cyclohex-1-enecarboxylic acid,
- (4RS,6RS)-4,6-dimethyl-6-p-tolylcyclohex-1-enecarboxylic acid,
- (4RS,6RS)-4,6-dimethyl-6-m-tolylcyclohex-1-enecarboxylic acid,
- (4RS,6RS)-6-(2,3-dimethylphenyl)-4,6-dimethylcyclohex-1-enecarboxylic acid,
- (4RS,6RS)-4,6-dimethyl-6-(naphthalen-2-yl)cyclohex-1-enecarboxylic acid,
- (4RS,6RS)-6-(4-chlorophenyl)-4,6-dimethylcyclohex-1-enecarboxylic acid,
- (4RS,6RS)-6-(4-fluorophenyl)-4,6-dimethylcyclohex-1-enecarboxylic acid,
- (4RS,6RS)-6-(3-fluorophenyl)-4,6-dimethylcyclohex-1-enecarboxylic acid,
- (4RS,6RS)-6-(4-fluoro-3-methylphenyl)-4,6-dimethylcyclohex-1-enecarboxylic acid,
- (4RS,6RS)-6-(2,5-dimethylphenyl)-4,6-dimethylcyclohex-1-enecarboxylic acid,
- (4RS,6RS)-6-(4-chloro-3,5-dimethylphenyl)-4,6-dimethylcyclohex-1-enecarboxylic acid,
- (4RS,6RS)-4,6-dimethyl-6-(4-methyl-naphthalen-l-yl)cyclohex-1-enecarboxylic acid,
- (4RS,6RS)-6-(3,5-dimethylphenyl)-4,6-dimethylcyclohex-1-enecarboxylic acid,
- (4RS,6RS)-6-(3,5-dichlorophenyl)-4,6-dimethylcyclohex-1-enecarboxylic acid,
- (4RS,6RS)-6-(3,4-dichlorophenyl)-4,6-dimethyl-N-(methylsulfonyl)cyclohex-1-enecarboxamide,
- (4RS,6RS)-6-(3,4-dichlorophenyl)-4,6-dimethyl-N-(trifluoromethylsulfonyl)-cyclohex-1-enecarboxamide,
- (4RS,6RS)-6-(3,4-dichlorophenyl)-4,6-dimethyl-N-(phenylsulfonyl)cyclohex-1-enecarboxamide,
- (4S,6S)-6-(4-chloro-3-(trifluoromethyl)-phenyl)-4,6-dimethylcyclohex-1-enecarboxylic acid,
- (4R,6R)-6-(4-chloro-3-(trifluoromethyl)phenyl)-4,6-dimethylcyclohex-1-enecarboxylic acid,
- (4RS,6SR)-6-(3,4-dichlorophenyl)-6-hydroxy-2,4,-dimethylcyclohex-1-enecarboxylic acid,
- (4RS,6RS)-6-(3,4-dichlorophenyl)-2,4,6-trimethylcyclohex-1-enecarboxylic acid,
- (4RS,6RS)-6-(4-chloro-3-(trifluoromethyl)-phenyl)-4-(hydroxymethyl)-6-methylcyclohex-1-enecarboxylic acid,
- (4RS,6RS)-6-(4-chloro-3-(trifluoromethyl)-phenyl)-4-(hydroxymethyl)-6-methylcyclohex-1-enecarboxylic acid,
- (4RS,6RS)-4-(tert-butoxymethyl)-6-(4-chloro-3-(trifluoromethyl)phenyl)-6-methylcyclohex-1-enecarboxylic acid,
- (4RS,6RS)-4-(acetamidomethyl)-6-(4-chloro-3-(trifluoromethyl)phenyl)-6-methylcyclohex-1-enecarboxylic acid, and
- (4RS,6RS)-4-(benzyloxy)-6-(4-chloro-3-(trifluoromethyl)phenyl)-6-methylcyclohex-1-enecarboxylic acid.
36 more elements
Dependencies are inferred from the claim text.