Acetylenic α-amino acid-based sulfonamide hydroxamic acid tace inhibitors

A method of inhibiting pathological changes mediated by TNF-α converting enzyme (TACE) in a mammal in need thereof which comprises administering to said mammal a therapeutically effective amount of a compound having the formula:

• wherein:
• X is SO2 or —P(O)—R10;
• Y is aryl or heteroaryl, with the proviso that X and Z may not be bonded to adjacent atoms of Y;
• Z is O, NH, CH2 or S;
• R2 is hydrogen, aryl, aralkyl, heteroaryl, heteroaralkyl, cycloalkyl of 3-6 carbon atoms, piperidinyl, piperazinyl, morpholinyl, tetrahydropyranyl, tetrahydrofuranyl, pyrrolidinyl, alkyl of 1-6 carbon atoms, alkenyl of 2-6 carbon atoms, alkynyl of 2-6 carbon atoms;
• R1 and R3, together with the atoms to which they are attached, may form a 6 membered ring wherein R1 and R3 represent divalent moieties of the formula:
• wherein Q is a carbon-carbon single or double bond, O, S, SO, SO2, —N—R11, or —CONR14;
• m=2-3
• s is 0-2;
• provided that Q, s, and m, taken together represent 4 atoms;
• R4 and R5 are each, independently, hydrogen or alkyl of 1-6 carbon atoms, —CN, or —CCH;
• R6 is hydrogen, aryl, heteroaryl, alkyl of 1-6 carbon atoms, alkenyl of 2-6 carbon atoms, alkynyl of 2-6 carbon atoms, cycloalkyl of 3-6 carbon atoms, piperidinyl, piperazinyl, morpholinyl, tetrahydropyranyl, tetrahydrofuranyl, pyrrolidinyl;
• R8 and R9 are each, independently, hydrogen, alkyl of 1-6 carbon atoms, alkenyl of 2-6 carbon atoms, alkynyl of 2-6 carbon atoms, cycloalkyl of 3-6 carbon atoms, aryl, aralkyl, heteroaryl, heteroaralkyl, piperidinyl, piperazinyl, morpholinyl, tetrahydropyranyl, tetrahydrofuranyl, pyrrolidinyl;
• R10 is alkyl of 1-6 carbon atoms, cycloalkyl of 3-6 carbon atoms, aryl or heteroaryl;
• R11 is hydrogen, alkyl of 1-6 carbon atoms, cycloalkyl of 3-6 carbon atoms, aryl, heteroaryl, —S(O)nR, —COOR8, —CONR8R9, —SO2NRR9 or —COR8;
• R12 and R13 are independently selected from H, —OR, —NR8R9, alkyl of 1-6 carbon atoms, alkenyl of 2-6 carbon atoms, alkynyl of 2-6 carbon atoms, cycloalkyl of 3-6 carbon atoms, aryl, heteroaryl, —COOR8;
• —CONR8R9;
• or R12 and R13 together form a —C3-C6-cycloalkyl of 3-6 carbon atoms or a —C5-C8-cycloheteroalkyl ring;
• or R12 and R13, together with the carbon to which they are attached, form a carbonyl group;
• R14 is hydrogen, aryl, heteroaryl, alkyl of 1-6 carbon atoms or cycloalkyl of 3-6 carbon atoms;
• and n is 0-2;
• or a pharmaceutically acceptable salt thereof.

A pharmaceutical composition comprising a compound having the formula:

• wherein:
• X is SO2 or —P(O)—R10;
• Y is aryl or heteroaryl, with the proviso that X and Z may not be bonded to adjacent atoms of Y;
• Z is O, NH, CH2 or S;
• R2 is hydrogen, aryl, aralkyl, heteroaryl, heteroaralkyl, cycloalkyl of 3-6 carbon atoms, piperidinyl, piperazinyl, morpholinyl, tetrahydropyranyl, tetrahydrofuranyl, pyrrolidinyl, alkyl of 1-6 carbon atoms, alkenyl of 2-6 carbon atoms, alkynyl of 2-6 carbon atoms;
• R1 and R3, together with the atoms to which they are attached, may form a 6 membered ring wherein R1 and R3 represent divalent moieties of the formula:
• wherein Q is a carbon-carbon single or double bond, O, S, SO, SO2, —N—R11, or —CONR14;
• m=2-3
• s is 0-2;
• provided that Q, s, and m, taken together represent 4 atoms;
• R4 and R5 are each, independently, hydrogen or alkyl of 1-6 carbon atoms, —CN, or —CCH;
• R6 is hydrogen, aryl, heteroaryl, alkyl of 1-6 carbon atoms, alkenyl of 2-6 carbon atoms, alkynyl of 2-6 carbon atoms, cycloalkyl of 3-6 carbon atoms, piperidinyl, piperazinyl, morpholinyl, tetrahydropyranyl, tetrahydrofuranyl, pyrrolidinyl;
• R8 and R9 are each, independently, hydrogen, alkyl of 1-6 carbon atoms, alkenyl of 2-6 carbon atoms, alkynyl of 2-6 carbon atoms, cycloalkyl of 3-6 carbon atoms, aryl, aralkyl, heteroaryl, heteroaralkyl, piperidinyl, piperazinyl, morpholinyl, tetrahydropyranyl, tetrahydrofuranyl, pyrrolidinyl;
• R10 is alkyl of 1-6 carbon atoms, cycloalkyl of 3-6 carbon atoms, aryl or heteroaryl;
• R11 is hydrogen, alkyl of 1-6 carbon atoms, cycloalkyl of 3-6 carbon atoms, aryl, heteroaryl, —S(O)nR8, —COOR8, —CONR8R8, —SO2NR8R9 or —COR8;
• R12 and R13 are independently selected from H, —OR8, —NR8R9, alkyl of 1-6 carbon atoms, alkenyl of 2-6 carbon atoms, alkynyl of 2-6 carbon atoms, cycloalkyl of 3-6 carbon atoms, aryl, heteroaryl, —COOR8;
• —CONR8R9;
• or R12 and R13 together form a —C3-C6-cycloalkyl of 3-6 carbon atoms or a —C5-C8-cycloheteroalkyl ring;
• or R12 and R13, together with the carbon to which they are attached, form a carbonyl group;
• R14 is hydrogen, aryl, heteroaryl, alkyl of 1-6 carbon atoms or cycloalkyl of 3-6 carbon atoms;
• and n is 0-2;
• or a pharmaceutically acceptable salt thereof.