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US 2003/0158231 A1Published application
Sulfonamide compounds as protease inhibitors
AssigneeAxys Pharmaceuticals, Inc.
InventorJames Palmer
Life of this patent
Estimating the term…
Abstract
The present invention relates to novel cysteine protease inhibitors; the pharmaceutically acceptable salts and N-oxides thereof; their uses as therapeutic agents and the methods of their making.
Claims20
A compound of Formula I:
- 136
- in which:
- R1and R2 independently are —R8, —X2OR8, —X2SR8, —X2S(O)R8, —X2S(O)2R8, —X2C(O)R8, —X2C(OR7)R7R8, —X2C(O)OR8, —X2NR7R8, —X2NR7C(O)OR8, —X2C(O)NR7R8, —X2S(O)2NR7R8, —X2NR7C(O)NR7R8 or —X2NR7C(NR7)NR7R8, wherein X2 is (C1-6)alkylene, R7 is hydrogen or (C1-6)alkyl;
- R8 is hydrogen, (C1-6)alkyl, (C3-12)cycloalkyl(C0-3)alkyl, hetero(C5-12)cycloalkyl(C0-3)alkyl, (C6-12)aryl(C0-3)alkyl, hetero(C5-12)aryl(C0-3)alkyl, (C9-12)bicycloaryl(C0-3)alkyl or hetero(C8-12)bicyclo-aryl(C0-3)alkyl;
- wherein within R8 said cycloalkyl, heterocycloalkyl, aryl, heteroaryl, bicycloaryl or heterobicycloaryl ring may be substituted with halo, —R9, —X3OR9, —X3SR9, —X3S(O)R9, —X3S(O)2R9, —X3C(O)R9, —X3C(OR9)R9, —X3C(O)OR9, —X3NR9R10, —X3NR9C(O)OR9, —X3C(O)NR9R10, —X3S(O)2NR9R10, —X3NR9C(O)NR9R10 or —X3NR9C(NR9)NR9R10;
- wherein X3 is a bond or (C1-6)alkylene, R9 is hydrogen or (C1-6)alkyl and R10 is cycloalkyl;
- R3 is —R11, —X3OR11, —X3SR11, —X3S(O)R11, —X3S(O)2R11, —X3C(O)R11, —X3C(O)OR11, —X3NR11R12, —X3NR12C(O)OR11, —X3C(O)NR11R12, —X3S(O)2NR11R12, —X3NR12C(O)NR11R12 or —X3NR12C(NR12)NR11R12, wherein X3 is as described above, R11 is hydrogen, (C1-6)alkyl, halo(C1-6)alkyl, (C3-12)cycloalkyl(C0-3)alkyl, hetero(C5-12)cycloalkyl-(C0-3)alkyl, (C6-12)aryl(C0-3)alkyl, hetero(C5-12)aryl(C0-3)alkyl, (C9-12)bicycloaryl(C0-3)alkyl or hetero(C8-12)bicycloaryl(C0-3)alkyl and R12 is hydrogen or (C1-6)alkyl, wherein any 1 to 3 annular atoms of any aromatic ring with available valences comprising R3 are optionally independently substituted with halo, nitro, cyano, (C1-6)alkyl, halo-substituted(C1-6)alkyl, —OR7, —C(O)R7, —C(O)OR7, —C(O)NR7R7, —S(O)2NR7R7, —X2NR7R7, —X2NR7C(O)OR7, —X2NR7C(O)NR7R7 or —X2NR7C(NR7NR7R7, wherein X2 and R7 are as defined above;
- R4 is hydrogen or (C1-6)alkyl;
- R5 is (C1-6)alkyl, halo(C1-6)alkyl, (C3-12)cycloalkyl(C0-3)alkyl, or —X2S(O)R14 where X2 is as defined above and R14 is (C3-12)cycloalkyl(C0-3)alkyl, hetero(C5-12)cycloalkyl(C0-3)alkyl;
- (C6-12)aryl(C0-3)alkyl, hetero(C5-12)aryl(C0-3)alkyl, (C9-12)bicycloaryl(C0-3)alkyl or hetero(C8-12)bicycloaryl(C0-3)alkyl;
- or R4 and R5 together with the carbon atom to which R4 and R5 are attached form (C3-7)cycloalkylene;
- R6 is hydrogen or —X4X5R13, wherein X is —C(O)—, X5 is a bond, —O— or —NR12—, wherein R12 is as defined above, and R13 is (C1-6)alkyl, —R14, —X3OR14, —X3SR14, —X3S(O)R14, —X3S(O)2R14, —X3C(O)R14, —X3C(O)OR14, —X3NR14R15, X3NR15C(O)OR14, —X3C(O)NR14R15, —X3S(O)2NR14R15, —X3NR15C(O)NR14R15 or —X3NR15C(NR15)NR14R15, wherein X3 is as defined above;
- R14 is (C3-12)cycloalkyl(C0-3)alkyl, hetero(C5-12)cycloalkyl(C0-3)alkyl, (C6-12)aryl(C0-3)alkyl, hetero(C5-12)aryl(C0-3)alkyl, (C9-12)bicycloaryl(C0-3)alkyl or hetero(C8-12)bicycloaryl(C0-3)alkyl;
- R15 is hydrogen or (C1-6)alkyl;
- and within R14 said cycloalkyl, heterocycloalkyl, aryl, heteroaryl, bicycloaryl or heterobicycloaryl ring may be substituted with —OCF3, —CF3, —OH, halo, —R16, —X3OR16, —X3OR15, —X3C(O)R15, —X3SR16, —X3S(O)R16, —R15, —X 3S(O)2R16, —X3C(O)OR15, —X3NR15R15, —X3NR15C(O)OR15, —X3C(O)NR15R16, —X3S(O)2NR15R16, —X3NR15C(O)NR15R15 or —X3NR15C(NR15)NR15R16, wherein X3 and R15 are as defined above and R16 is (C3-12)cycloalkyl(C0-3)alkyl, hetero(C5-12)cycloalkyl(C0-3)alkyl, (C6-12)aryl(C0-3)alkyl, hetero(C5-12)aryl(C0-3)alkyl, (C9-12)bicycloaryl(C0-3)alkyl or hetero(C8-12)bicycloaryl-C0-3)alkyl and within R16 said cycloalkyl, heterocycloalkyl, aryl, heteroaryl, bicycloaryl or heterobicycloaryl ring may be substituted with —R15, —R17, —X3OR17, —X3SR17, —X3S(O)R17, —X3S(O)2R17, —X3C(O)R17, —X3C(O)OR17, —X3NR15R17, —X3NR15R15, —X3NR15C(O)OR17, —X3C(O)NR15R17, —X3S(O)2NR15R17, —X3NR15C(O)NR15R17 or —X3NR15C(NR15)NR15R17, wherein X3 and R15 are as defined above and R17 is (C3-12)cycloalkyl(C0-3)alkyl, hetero(C5-12)cycloalkyl(C0-3)alkyl, (C6-12)aryl(C0-3)alkyl, hetero(C5-12)aryl(C0-3)alkyl, (C9-12)bicycloaryl(C0-3)alkyl or hetero(C8-12)bicycloaryl(C0-3)alkyl and within R17 said cycloalkyl, heterocycloalkyl, aryl, heteroaryl, bicycloaryl or heterobicycloaryl ring may be substituted with —R18, —X3OR18, —X3SR18, -X3S(O)R18, —X3S(O)2R18, —X3C(O)R18, —X3C(O)OR18, —X3NR15R18, —X3NR15C(O)OR18, —X3C(O)NR15R18, —X3S(O)2NR15R18, —X3NR15C(O)NR15R18 or —X3NR15C(NR15)NR15R18, wherein X3 and R15 are as defined above and R18 is (C3-12)cycloalkyl(C0-3)alkyl, hetero(C5-12)cycloalkyl(C0-3)alkyl, (C6-12)aryl(C0-3)alkyl, hetero(C5-12)aryl(C0-3)alkyl, (C9-12)bicycloaryl(C0-3)alkyl or hetero(C8-12)bicycloaryl(C0-3)alkyl;
- with the proviso that only one (C9-12)bicycloaryl(C0-3)alkyl or hetero(C8-12)bicycloaryl(C0-3)alkyl is present within R6, or a pharmaceutically acceptable salt thereof.
13 more elements
A compound selected from the group consisting of:
- benzyl (1S-{1S-[(4-methoxyphenylsulfamoyl)-methyl]-3-phenyl-propylcarbamoyl}-3-methyl-butyl)-carbamate;
- benzyl (1S-{1S-[(4-methoxyphenylsulfamoyl)-methyl]-3-phenyl-propylcarbamoyl}-2-methyl-butyl)-carbamate;
- tert-butyl (1S-{1S-[(4-methoxyphenylsulfamoyl)-methyl]-3-phenyl-propylcarbamoyl}-3-methyl-butyl)-carbamate;
- benzyl (1S-{1S-[(3-acetyl-phenylsulfamoyl)-methyl]-3-phenyl-propylcarbamoyl}-3-methyl-butyl)-carbamate;
- N-{1S-[1S-(4-methoxyphenylsulfamoylmethyl)-3-phenylpropylcarbamoyl]-2-methylbutyl}-4-methylpiperazine-1-carboxamide;
- benzyl {1S-[2-(4-methoxyphenylsulfamoyl)-ethylcarbamoyl]-2-methyl-butyl}-carbamate;
- (2-cyclohexyl-1S-{3-phenyl-1S-[(2-phenylaminoethylsulfamoyl)-methyl]-propylcarbamoyl}ethyl)-carbamic acid tert-butyl ester;
- 4-dimethylamino-N-(1S-{1S-[(4-methoxyphenylsulfamoyl)methyl]-3-phenyl-propylcarbamoyl}-3-methylbutyl)-benzamide;
- quinoline-6-carboxylic acid (1S-{1S-[(4-methoxyphenylsulfamoyl)methyl]-3-phenyl-propylcarbamoyl}-3-methyl-butyl)-amide;
- morpholine-4-carboxylic acid (2-cyclohexyl-1S-{3-phenyl-1S-[(2-phenylamino-ethylsulfamoyl)methyl]-propylcarbamoyl}ethyl)amide;
- 4-(2-dimethylaminothiazol-4-yl)-N-{1SS-[2-(4-methoxyphenylsulfamoyl)-ethylcarbamoyl]-3-methyl-butyl}benzamide;
- 2S-acetylamino-3-cyclohexyl-N-{1-[(4-methoxyphenylsulfamoyl)-methyl]-3-phenyl-propyl}propionamide;
- 2R-acetylamino-3-cyclohexyl-N-{1-[(4-methoxyphenylsulfamoyl)methyl]-3-phenyl-propyl}propionamide;
- 2RS-acetylamino-3-cyclohexyl-N-{1-[(4-hydroxyphenylsulfamoyl)methyl]-3-phenyl-propyl}-propionamide;
- benzyl [6-(4-methoxyphenylsulfamoyl)-5S-(4-methyl-2S-{4-[2-(pyridin-3-ylamino)thiazol-4-yl]-benzoylamino}pentanoylamino)hexyl]carbamate;
- N-(1S-{1S-[(4-methoxyphenylsulfamoyl)methyl]-3-phenylpropylcarbamoyl}-3-methyl-butyl)-4-[2-(pyridin-3-ylamino)thiazol-4-yl]-benzamide;
- N-(1S-{1S-[(4-methoxyphenylsulfamoyl)methyl]-3-phenyl-propylcarbamoyl}-3-methyl-butyl)-nicotinamide;
- N-(1S-{1S-[(4-methoxyphenylsulfamoyl)-methyl]-3-phenylpropylcarbamoyl}-3-methyl-butyl)-isonicotinamide;
- N-{1-[1-(4-methoxyphenylsulfamoylmethyl)-3-phenylpropylcarbamoyl]-3-methylbutyl}-1H-indole-5-carboxamide;
- tert-butyl [3-(1S-{1S-[(4-methoxyphenylsulfamoyl)-methyl]-3-phenylpropylcarbamoyl}-3-methyl-butylcarbamoyl)phenyl]-carbamate;
- 3-amino-N-(1S-{1S-[(4-methoxyphenylsulfamoyl)-methyl]-3-phenylpropylcarbamoyl}-1-3-methyl-butyl)-benzamide;
- N-(1S-{5-amino-1S-[(4-methoxyphenylsulfamoyl)methyl]pentylcarbamoyl}-3-methyl-butyl)-4-[2-(pyridin-3-ylamino)-thiazol-4-yl]-benzamide;
- benzyl [1S-(1S-{[3-(1-hydroxyethyl)phenylsulfamoyl]methyl}-3-phenylpropyl-carbamoyl)-3-methylbutyl]-carbamate;
- morpholine 4-carboxylic acid (1S-{5-amino-1S-[(4-methoxyphenylsulfamoyl)methyl]-pentylcarbamoyl}-2-phenylmethanesulfonylethyl)amide;
- (5S-[2S-(morpholin-4-ylcarbonyl)amino]-3-phenylmethanesulfonylpropionylamino}-6-phenylsulfamoylhexyl)carbamic acid benzyl ester;
- morpholine 4-carboxylic acid (1S-{1S-[(4-methoxyphenylsulfamoyl)methyl]-3-phenylpropylcarbamoyl}2-phenylmethanesulfonylethyl)amide;
- N-(1S-{1S-[(4-methoxy-phenylsulfamoyl)-methyl]-3-phenyl-propylcarbamoyl}-cyclohexyl)-4-[2-(4-methylpiperazin-1-yl)thiazol-4-yl]benzamide;
- and
- N-(1S-{1S-[(4-methoxy-phenylsulfamoyl)-methyl]-3-phenyl-propylcarbamoyl}-cyclohexyl)-4-(4-propylpiperazin-1-yl)-benzamide;
- or
- a pharmaceutically acceptable salt thereof.
28 more elements
Dependencies are inferred from the claim text.