N-hydroxy-2-(alkyl, aryl, or heteroaryl sulfanyl, sulfinyl or sulfonyl)-3-substituted alkyl, aryl or heteroarylamides as matrix metalloproteinase inhibitors

A method of inhibiting pathological condition or disorder mediated by matrix metalloproteinases in mammals which comprises administration to a mammal in need thereof a therapeutically effective amount of a matrix metalloproteinase inhibiting compound of the formula

• wherein:
• R1 is alkyl of 1 to 18 carbon atoms, optionally substituted with one or two groups selected independently from R5;
• alkenyl of 3 to 18 carbon atoms having 1 to 3 double bonds, optionally substituted with one or two groups selected independently from R5;
• alkynyl of 3 to 18 carbon atoms having 1 to 3 triple bonds, optionally substituted with one or two groups selected independently from R5;
• aryl of 6 to 10 carbon atoms, optionally substituted with one or two groups selected independently from R5;
• cycloalkyl of 3 to 8 carbon atoms, optionally substituted with one or two groups selected independently from R5;
• saturated or unsaturated 5 to 10 membered mono or bicyclic heterocycle containing one heteroatom selected from O, S or NR7, optionally substituted with one or two groups selected independently from R5;
• or heteroaryl-(CH2)0-6- wherein the heteroaryl group is 5 to 6membered with one or two heteroatoms selected independently from O, S, and N and may be optionally substituted with one or two groups selected independently from R5;
• A is —S—, —SO— or SO2—;
• R2 and R3, taken with the carbon atom to which they are attached, form a 5 to 7 membered heterocyclic ring containing O, S or N—R7 optionally having one or two double bonds;
• R4 is hydrogen,
• alkyl of 1 to 6 carbon atoms, optionally substituted with one or two groups selected independently from R5;
• alkenyl of 3 to 18 carbon atoms having 1 to 3 double bonds, optionally substituted with one or two groups selected independently from R5;
• alkynyl of 3 to 18 carbon atoms having 1 to 3 triple bonds, optionally substituted with one or two groups selected independently from R5;
• phenyl or naphthyl optionally substituted with one or two groups selected independently from R5;
• C3 to C8 cycloalkyl or bicycloalkyl optionally substituted with one or two groups selected independently from R5;
• saturated or unsaturated 5 to 10 membered mono or bicyclic heterocycle containing one heteroatom selected from O, S or NR7, optionally substituted with one or two groups selected independently from R5;
• R5 is H, C7-C11 aroyl, C2-C6 alkanoyl, CI to C12 alkyl, C2 to C12 alkenyl, C2-C12 alkynyl, F, Cl, Br, I, CN, CHO, C1-C6 alkoxy, aryloxy, heteroaryloxy, C3-C6 alkenyloxy, C3-C6 alkynyloxy, C1-C6 alkoxyaryl, C1-C6 alkoxyheteroaryl, C1-C6 alkylamino-C1-C6 alkoxy, C1-C2 alkylene dioxy, aryloxy-C-C6 alkyl amine, C1-C12 perfluoro alkyl, S(O)n-C1-C6 alkyl, S(O)n-aryl where n is 0, 1 or 2;
• OCOO C1-C6 alkyl, OCOOaryl, OCONR6, COOH, COO C1-C6 alkyl, COOaryl, CONR6R6, CONHOH, NR6R6, SO2NR6R6, NR6SO2aryl, -NR6CONR6R6, NHSO2CF3, SO2NHheteroaryl,SO2NHCOaryl, CONHSO2-C1-C6 alyl, CONHSO2aryl, SO2NHCOaryl, CONHSO2-C1-C6 alkyl, CONHSO2aryl, NH2, OH, aryl, heteroaryl, C3 to C8 cycloalkyl;
• or saturated or unsaturated 5 to 10 membered mono or bicyclic heterocycle containing one heteroatom selected from O, S or NR7, wherein C1-C6 alkyl is straight or branched, heteroaryl is a 5-10 membered mono or bicyclic heteroaryl group having 1 to 3 heteroatoms selected independently from O, S or NR7 and aryl is phenyl or naphthyl, optionally substituted by 1 or 2 groups selected from halogen, cyano, amino, nitro, C1-C6 alkyl, C1-C6 alkoxy, or hydroxy;
• R6 is H, C1 to C18 alkyl optionally substituted with OH;
• C3 to C6 alkenyl, C3 to C6 alkynyl, C1 to C6 perfluoro alkyl, S(O)n-C1-C6 alkyl S(O), aryl where n is 0, 1 or 2;, or COheteroaryl, wherein heteroaryl is a 5-10 membered mono or bicyclic heteroaryl group having 1 to 3 heteroatoms selected independently from O, S or NR7 and aryl is phenyl or naphthyl, optionally substituted by 1 or 2 groups selected from halogen, cyano, amino, nitro, C1-C6 alkyl, C1-C6 alkoxy, or hydroxy;
• and R7 is C7-C11 aroyl, C2-C6 alkanoyl, C1-C12 perfluoro alkyl, S(O)n-C1-C6-alkyl, S(O)n-aryl where n is 0, 1 or 2;
• COO-C1-C6-alkyl, COOaryl, CONHR6, CONR6R6, CONHOH, SO2NR6R6, SO2CF3, SO2NHheteroaryl, SO2NHCOaryl, CONHSO-C1-C6-alkyl, CONHSO2aryl, aryl, or heteroaryl, where aryl is phenyl or naphthyl, optionally substituted by 1 or 2 groups selected independently from halogen, cyano, amino, nitro, C1-C6 alkyl, C1-C6 alkoxy, or hydroxy;
• and heteroaryl is a 5-10 membered mono or bicyclic heteroaryl group having 1 to 3 heteroatoms selected independently from O, S or N—C1-C6 alkyl;
• alkyl of 1 to 18 carbon atoms, optionally substituted with one or two groups selected independently from R5;
• alkenyl of 3 to 18 carbon atoms having from 1 to 3 double bonds, optionally substituted with one or two groups selected independently from R5;
• alkynyl of 3 to 18 carbon atoms having from 1 to 3 triple bonds, optionally substituted with one or two groups selected independently from R5;
• arylalkyl of 7 to 16 carbon atoms, wherein aryl is optionally substituted with one or two groups selected independently from R5;
• heteroarylalkyl wherein alkyl is from 1 to 6 carbon atoms and heteroaryl contains 1 or 2 heteroatoms selected from O, S or N and is optionally substituted with one or two groups selected independently from R5;
• biphenylalkyl of 13 to 18 carbon atoms, wherein biphenyl is optionally substituted with one or two groups selected independently from R5;
• arylalkenyl of 8 to 16 carbon atoms, wherein aryl is optionally substituted with one or two groups selected independently from R5;
• cycloalkylalkyl or bicycloalkylalkyl of 4 to 12 carbon atoms, wherein the cycloalkyl or bicycloalkyl group is optionally substituted with one or two groups selected independently from R5;
• saturated or unsaturated mono or bicyclic heterocycle containing one heteroatom selected from O, S or N—C1-C6 alkyl, optionally substituted with one or two groups selected independently from R5;
• or
• R8R9N—C1-C6-alkoxyaryl-C1-C6-alkyl where R8 and R9 are independently selected from C1-C6 alkyl or R8 and R9 together with the interposed nitrogen forms a 5-7 membered saturated heterocyclic ring optionally containing an oxygen atom, wherein the aryl group is phenyl or naphthyl;
• or a pharmaceutically acceptable salt thereof.

A method of treating a pathological condition or disorder mediated by TNF-α converting enzyme (TACE) in mammals which comprises administration to a mammal in need thereof a therapeutically effective amount of a TACE inhibiting compound of the formula

• wherein:
• R1 is alkyl of 1 to 18 carbon atoms, optionally substituted with one or two groups selected independently from R5;
• alkenyl of 3 to 18 carbon atoms having 1 to 3 double bonds, optionally substituted with one or two groups selected independently from R5;
• alkynyl of 3 to 18 carbon atoms having 1 to 3 triple bonds, optionally substituted with one or two groups selected independently from R5;
• aryl of 6 to 10 carbon atoms, optionally substituted with one or two groups selected independently from R5;
• cycloakyl of 3 to 8 carbon atoms, optionally substituted with one or two groups selected independently from R5;
• saturated or unsaturated 5 to 10 membered mono or bicyclic heterocycle containing one heteroatom selected from O, S or NR7, optionally substituted with one or two groups selected independently from R5;
• or heteroaryl-(CH2)0-6- wherein the heteroaryl group is 5 to 6 membered with one or two heteroatoms selected independently from O, S, and N and may be optionally substituted with one or two groups selected independently from R5;
• A is —S—, —SO— or SO2—;
• R2 and R3, taken with the carbon atom to which they are attached, form a 5 to 7 membered heterocyclic ring containing O, S or N—R7 optionally having one or two double bonds;
• R4 is hydrogen,
• alkyl of 1 to 6 carbon atoms, optionally substituted with one or two groups selected independently from R5;
• alkenyl of 3 to 18 carbon atoms having 1 to 3 double bonds, optionally substituted with one or two groups selected independently from R5;
• alkynyl of 3 to 18 carbon atoms having 1 to 3 triple bonds, optionally substituted with one or two groups selected independently from R5;
• phenyl or naphthyl optionally substituted with one or two soups selected independently from R5;
• C3 to C8 cycloalkyl or bicycloalkyl optionally substituted with one or two groups selected independently from R5;
• saturated or unsaturated 5 to 10 membered mono or bicyclic heterocycle containing one heteroatom selected from O, S or NR7, optionally substituted with one or two groups selected independently from R5;
• R5 is H, C7-C11 aroyl, C2-C6 alkanoyl, C1 to C12 alkyl, C2 to C12 alkenyl, C2-C12 alkynyl, F, Cl, Br, I, CN, CHO, C1-C6 alkoxy, aryloxy, heteroaryloxy, C3-C6 alkenyloxy, C3-C6 alkynyloxy, C1-C6 alkoxyaryl, C1-C6 alkoxyheteroaryl, C1-C6 alkylamino-C1-C6 alkoxy, C1-C2 alkylene dioxy, aryloxy-C1-C6 alkyl amine, C1-C12 perfluoro alkyl, S(O)n-C1-C6 alkyl, S(O)n-aryl where n is 0, 1 or 2;
• OCOO C1-C6 alkyl, OCOOaryl, OCONR6, COOH, COO C1-C6 aLkyl, COOaryl, CONR6R6, CONHOH, NR6R6, SO2NR6R6, NR6SO2aryl, —NR6CONR6R6, NHSO2CF3, SO2Nheteroaryl, SO2NHCOaryl, CONHSO2-C1-C6 alkyl, CONHSO2aryl, SO2NHCOaryl, CONHSO2-C1-C6 alkyl, CONHSO2aryl, NH2, OH, aryl, heteroaryl, C3 to C8 cycloalkyl;
• or saturated or unsaturated 5 to 10 membered mono or bicyclic heterocycle containing one heteroatom selected from O, S or NR7, wherein C1-C6 alkyl is straight or branched, heteroaryl is a 5-10 membered mono or bicyclic heteroaryl group having 1 to 3 heteroatoms selected independently from O, S or NR7 and aryl is phenyl or naphthyl, optionally substituted by 1 or 2 groups selected from halogen, cyano, amino, nitro, C1-C6 alkyl, C1-C6 alkoxy, or hydroxy;
• R6 is H, C1 to C18 alkyl optionally substituted with OH;
• C3 to C6 alkenyl, C3 to C6 alkynyl, C1 to C6 perfluoro alkyl, S(O)n-C1-C6 alkyl S(O)n aryl where n is 0, 1 or 2, or COheteroaryl, wherein heteroaryl is a 5-10 membered mono or bicyclic heteroaryl group having 1 to 3 heteroatoms selected independently from O, S or NR7 and aryl is phenyl or naphthyl, optionally substituted by 1 or 2 groups selected from halogen, cyano, amino, nitro, C1-C6 alkyl, C1-C6 alkoxy, or hydroxy;
• and R7 is C7-C11 aroyl, C2-C6 alkanoyl, C1-C12 perfluoro alkyl, S(O)n-C1-C6-alkyl, S(O)n-aryl where n is 0, 1 or 2;
• COO-C1-C6-alkyl, COOaryl, CONHR6, CONR6R6, CONHOH, SO2NR6R6, SO2CF3, SO2NHheteroaryl, SO2NHCOaryl, CONHSO-C1-C6-alkyl, CONHSO2aryl, aryl, or heteroaryl, where aryl is phenyl or naphthyl, optionally substituted by 1 or 2 groups selected independently from halogen, cyano, amino, nitro, C1-C6 alkyl, C1-C6 alkoxy, or hydroxy;
• and heteroaryl is a 5-10 membered mono or bicyclic heteroaryl group having 1 to 3 heteroatoms selected independently from O, S or N-C1-C6 alkyl;
• alkyl of 1 to 18 carbon atoms, optionally substituted with one or two groups selected independently from R5;
• alkenyl of 3 to 18 carbon atoms having from 1 to 3 double bonds, optionally substituted with one or two groups selected independently from R5;
• alkynyl of 3 to 18 carbon atoms having from 1 to 3 triple bonds, optionally substituted with one or two groups selected independently from R5;
• arylalkyl of 7 to 16 carbon atoms, wherein aryl is optionally substituted with one or two groups selected independently from R5;
• heteroarylalkyl wherein alkyl is from 1 to 6 carbon atoms and heteroaryl contains 1 or 2 heteroatoms selected from O, S or N and is optionally substituted with one or two groups selected independently from R5;
• biphenylalkyl of 13 to 18 carbon atoms, wherein biphenyl is optionally substituted with one or two groups selected independently from R5;
• arylalkenyl of 8 to 16 carbon atoms, wherein aryl is optionally substituted with one or two groups selected independently from R5;
• cycloalkylalkyl or bicycloalkylalkyl of 4 to 12 carbon atoms, wherein the cycloalkyl or bicycloalkyl group is optionally substituted with one or two groups selected independently from R5;
• saturated or unsaturated mono or bicyclic heterocycle containing one heteroatom selected from O, S or N-C1-C6 alkyl, optionally substituted with one or two groups selected independently from R5;
• or
• R8R9N-C1-C6-alkoxyaryl-C1-C6-alkyl where R8 and R9 are independently selected from C1-C6 alkyl or R8 and R9 together with the interposed nitrogen forms a 5-7 membered saturated heterocyclic ring optionally containing an oxygen atom, wherein the aryl group is phenyl or naphthyl;
• or a pharmaceutically acceptable salt thereof.

A pharmaceutical composition comprising a pharmaceutical carrier and a therapeutically effective amount of a matrix metalloproteinase or TACE inhibiting compound according to the formula

• wherein:
• R1 is alkyl of 1 to 18 carbon atoms, optionally substituted with one or two groups selected independently from R5;
• alkenyl of 3 to 18 carbon atoms having 1 to 3 double bonds, optionally substituted with one or two groups selected independently from R5;
• alkynyl of 3 to 18 carbon atoms having 1 to 3 triple bonds, optionally substituted with one or two groups selected independently from R5;
• aryl of 6 to 10 carbon atoms, optionally substituted with one or two groups selected independently from R5;
• cycloalkyl of 3 to 8 carbon atoms, optionally substituted with one or two groups selected independently from R5;
• saturated or unsaturated 5 to 10 membered mono or bicyclic heterocycle containing one heteroatom selected from O, S or NR7, optionally substituted with one or two groups selected independently from R5;
• or heteroaryl-(CH2)0-6- wherein the heteroaryl group is S to 6 membered with one or two heteroatoms selected independently from O, S, and N and may be optionally substituted with one or two groups selected independently from R5;
• A is —S—, —SO— or SO2—;
• R2 and R3, taken with the carbon atom to which they are attached, form a 5 to 7 membered heterocyclic ring containing O, S or N—R7 optionally having one or two double bonds;
• R4 is hydrogen,
• alkyl of 1 to 6 carbon atoms, optionally substituted with one or two groups selected independently from R5;
• alkenyl of 3 to 18 carbon atoms having 1 to 3 double bonds, optionally substituted with one or two groups selected independently from R5;
• alkynyl of 3 to 18 carbon atoms having 1 to 3 triple bonds, optionally substituted with one or two groups selected independently from R5;
• phenyl or naphthyl optionally substituted with one or two groups selected independently from R5;
• C3 to C8 cycloalkyl or bicycloalkyl optionally substituted with one or two groups selected independently from R5;
• saturated or unsaturated 5 to 10 membered mono or bicyclic heterocycle containing one heteroatom selected from O, S or NR7, optionally substituted with one or two groups selected independently from R5;
• R5 is H, C7-C11 aroyl, C2-C6 alkanoyl, C1 to C12 alkyl, C2 to C12 alkenyl, C2-C12 alkynyl, F, Cl, Br, I, CN, CHO, C1-C6 alkoxy, aryloxy, heteroaryloxy, C3-C6 alkenyloxy, C3-C6 alkynyloxy, C1-C6 alkoxyaryl, C1-C6 alkoxyheteroaryl, C1-C6 alkyamino-C1-C6 alkoxy, C1-C2 alkylene dioxy, aryloxy-C1-C6 alky amine, C1-C12 perfluoro alkyl, S(O)n-C1-C6 alkyl, S(O)n-aryl where n is 0, 1 or 2;
• OCOO C1-C6 alkyl, OCOaryl, OCONR6, COOH, COO C1-C6 alkyl, COOaryl, CONR6R6, CONHOH, NR6R6, SO2NR6R6, NR6SO2aryl, -NR6CONR6R6, NHSO2CF3, SO2NHheteroaryl,SO2NHCOaryl, CONHSO2-C1-C6 alkyl, CONHSO2aryl, SO2NHCOaryl, CONHSO2-C1-C6 alkyl, CONHSO2aryl, NH2, OH, aryl, heteroaryl, C3 to C8 cycloalkyl;
• or saturated or unsaturated 5 to 10 membered mono or bicyclic heterocycle containing one heteroatom selected from O, S or NR7, wherein C1-C6 alkyl is straight or branched, heteroaryl is a 5-10 membered mono or bicyclic heteroaryl group having 1 to 3 heteroatoms selected independently from O, S or NR7 and aryl is phenyl or naphthyl, optionally substituted by 1 or 2 groups selected from halogen, cyano, amino, nitro, C1-C6 alkyl, C1-C6 alkoxy, or hydroxy;
• R6 is H, C1 to C18 alkyl optionally substituted with OH;
• CJ to C6 alkenyl, C3 to C6 alkynyl, C1 to C6 perfluoro alkyl, S(O)n-C1-C6 alkyl S(O)n aryl where n is 0, 1 or 2;, or COheteroaryl, wherein heteroaryl is a 5-10 membered mono or bicyclic heteroaryl group having 1 to 3 heteroatoms selected independently from O, S or NR7 and aryl is phenyl or naphthyl, optionally substituted by 1 or 2 groups selected from halogen, cyano, amino, nitro, C1-C6 alkyl, C1-C6 alkoxy, or hydroxy;
• and R7 is C7-C11 aroyl, C2-C6 alkanoyl, C1-C12 perfluoro alkyl, S(O)n-C1-C6-alkyl, S(O)n-aryl where n is 0, 1 or 2;
• COO-C1-C6-alkyl, COOaryl, CONHR6, CONR6R6, CONHOH, SO2NR6R6, SO2CF3, SO2Nheteroaryl, SO2NHCOaryl, CONHSO-C1-C6-alkyl, CONHSO2aryl, aryl, or heteroaryl, where aryl is phenyl or naphthyl, optionally substituted by 1 or 2 groups selected independently from halogen, cyano, amino, nitro, C1-C6 alkyl, C1-C6 alkoxy, or hydroxy;
• and heteroaryl is a 5-10 membered mono or bicyclic heteroaryl group having 1 to 3 heteroatoms selected independently from O, S or N—-C1-C6 alkyl;
• alkyl of 1 to 18 carbon atoms, optionally substituted with one or two groups selected independently from R5;
• alkenyl of 3 to 18 carbon atoms having from 1 to 3 double bonds, optionally substituted with one or two groups selected independently from R5;
• alkynyl of 3 to 18 carbon atoms having from 1 to 3 triple bonds, optionally substituted with one or two groups selected independently from R5;
• arylalkyl of 7 to 16 carbon atoms, wherein aryl is optionally substituted with one or two groups selected independently from R5;
• heteroarylalkyl wherein alkyl is from 1 to 6 carbon atoms and heteroaryl contains 1 or 2 heteroatoms selected from O, S or N and is optionally substituted with one or two groups selected independently from R5;
• biphenylalkyl of 13 to 18 carbon atoms, wherein biphenyl is optionally substituted with one or two groups selected independently from R5;
• arylalkenyl of 8 to 16 carbon atoms, wherein aryl is optionally substituted with one or two groups selected independently from R5;
• cycloalkylalkyl or bicycloalkylalkyl of 4 to 12 carbon atoms, wherein the cycloalkyl or bicycloalkyl group is optionally substituted with one or two groups selected independently from R5;
• saturated or unsaturated mono or bicyclic heterocycle containing one heteroatom selected from O, S or N—C1-C6 alkyl, optionally substituted with one or two groups selected independently from R5;
• or
• R8R9N—C1-C6-alkoxyaryl-C1-C6-alkyl where R8 and R9 are independently selected from C1-C6 alkyl or R8 and R9 together with the interposed nitrogen forms a 5-7 membered saturated heterocyclic ring optionally containing an oxygen atom, wherein the aryl group is phenyl or naphthyl;
• or a pharmaceutically acceptable salt thereof.