Cyclic sulfone derivatives as inhibitors of matrix metalloproteinases and/or TNF-Alpha converting enzyme (TACE)

A compound of formula I:

• 42
• or a stereoisomer or pharmaceutically acceptable salt form thereof, wherein;
• A is selected from:
• —COR5, —CO2H, —CO2R6, —C(O)NHOH, —C(O)NHOR5, —C(O)NHOR6, —NHRa, —N(OH)COR5, —N(OH)CHO, —SH, —CH2SH, —S(O)(═NH)Ra, —S(═NH)2Ra, —SC(O)Ra, —PO(OH)2, and —PO(OH)NHRa;
• ring B, including the shown carbon and sulfonyl groups, is a 4-8 membered heterocycle consisting of carbon atoms and, in addition to the sulfonyl group shown, 0-2 heteroatoms selected from O, N, NR10, and S(O)p, provided that ring B contains other than a S—S, O—O, or S—O bond;
• ring B consists of 0-1 double bonds and is substituted with 0-2 Rb;
• X is absent or is CR3R4;
• Ua is absent or is selected from:
• O, NRa1, C(O), C(O)O, OC(O), C(O)NRa1, NRa1C(O), OC(O)O, OC(O)NRa1, NRa1C(O)O, NRa1C(O)NRa1, S(O)p, S(O)pNRa1, NRa1S(O)p, and NRa1SO2NRa1;
• Xa is absent or is selected from:
• C1-4 alkylene, C2-4 alkenylene, and C2-4 alkynylene;
• Ya is absent or is selected from:
• O, NRa1, S(O)p, and C(O);
• provided that Ua—Xa—Ya form other than a bond or O;
• Za is a C3-13 carbocycle substituted with 0-5 Rc or a 5-14 membered heterocycle consisting of carbon atoms and 1-4 heteroatoms selected from the group consisting of N, O, and S(O)p, and substituted with 0-5 Rc;
• provided that Ua, Ya, and Za do not combine to form a N—N, N—O, O—N, O—O, S(O)p—O, O—S(O)por S(O)p—S(O)pgroup;
• R1 is selected from:
• H, C1-6 alkyl substituted with 0-1 Rb, C2-6 alkenyl substituted with 0-1 Rb, and C2-6 alkynyl substituted with 0-1 Rb;
• R2 is selected from:
• Q, —C1-6 alkylene-Q, —C2-6 alkenylene-Q, —C2-6 alkynylene-Q, (CRaRa1)r1O(CRaRa1)r-Q, —(CRaRa1)r1NRa(CRaRa1)r-Q, —(CRaRa1)r1C(O)(CRaRa1)r-Q, —(CRaRa1)r1C(O)O(CRaRa1)r-Q, —(CRaRa1)r1OC(O)(CRaRa1)r-Q, (CRaRa1)r1C(O)NRaRa1, —(CRaRa1)r1C(O)NRa(CRaRa1)r-Q, —(CRaRa1)r1NRaC(O)(CRaRa1)r-Q, —(CRaRa1)r1OC(O)O(CRaRa1)r-Q, —(CRaRa1)r1OC(O)NRa(CRaRa1)r-Q, —(CRaRa1)r1NRaC(O)O(CRaRa1)r-Q, —(CRaRa1)r1NRaC(O)NRa(CRaRa1)r-Q, —(CRaRa1)r1S(O)p(CRaRa1)r-Q, —(CRaRa1)r1SO2NRa(CRaRa1)r-Q, —(CRaRa1)r1NRaSO2(CRaRa1)r-Q, and —(CRaRa1)r1NRaSO2NRa(CRaRa1)r-Q;
• Q, at each occurrence, is independently selected from:
• H, a C3-13 carbocycle substituted with 0-5 Rd, and a 5-14 membered heterocycle consisting of carbon atoms and 1-4 heteroatoms selected from the group consisting of N, O, and S(O)p, and substituted with 0-5 Rd;
• alternatively, R1 and R2, together with the carbon atom to which they are attached, combine to form a 3-10 membered heterocyclic ring consisting of carbon atoms and 0-2 ring heteroatoms selected from O, N, NR10, and S(O)p, and substituted with 0-3 Rc;
• R3 is H or C1-4 alkyl;
• R4 is H or C1-4 alkyl;
• alternatively, R3 and R4 combine to form a 3-6 membered carbocyclic ring;
• R5, at each occurrence, is independently selected from:
• C1-10 alkyl substituted with 0-2 Rb, and C1-8 alkyl substituted with 0-2 Re;
• R6, at each occurrence, is independently selected from:
• phenyl, naphthyl, C1-10 alkyl-phenyl-C1-6 alkyl-, C3-11 cycloalkyl, C1-6 alkylcarbonyloxy-C1-3 alkyl-, C1-6 alkoxycarbonyloxy-C1-3 alkyl-, C2-10 alkoxycarbonyl, C3-6 cycloalkylcarbonyloxy-C1-3 alkyl-, C3-6 cycloalkoxycarbonyloxy-C1-3 alkyl-, C3-6 cycloalkoxycarbonyl, phenoxycarbonyl, phenyloxycarbonyloxy-C1-3 alkyl-, phenylcarbonyloxy-C1-3 alkyl-, C1-6 alkoxy-C1-6 alkylcarbonyloxy-C1-3 alkyl-, [5-(C1-5 alkyl)-1,3-dioxa-cyclopenten-2-one-yl]methyl, [5-(Ra)-1,3-dioxa-cyclopenten-2-one-yl]methyl, (5-aryl-1,3-dioxa-cyclopenten-2-one-yl)methyl, —C1-10 alkyl-NR7R7a, —CH(R8)OC(═O)R9, and —CH(R8)OC(═O)OR9;
• R7 is selected from:
• H, C1-10 alkyl, C2-6 alkenyl, C3-6 cycloalkyl-C1-3 alkyl-, and phenyl-C1-6 alkyl-;
• R7a is selected from:
• H, C1-10 alkyl, C2-6 alkenyl, C3-6 cycloalkyl-C1-3 alkyl-, and phenyl-C1-6 alkyl-;
• R8 is selected from:
• H and C1-4 alkyl;
• R9 is selected from:
• H, C1-8 alkyl substituted with 1-2 Rf, C3-8 cycloalkyl substituted with 1-2 Rf, and phenyl substituted with 0-2 Rb;
• R10, at each occurrence, is independently selected from:
• H, C1-6 alkyl substituted with 0-2 Rc1, C2-6 alkenyl substituted with 0-2 Rc1, C2-6 alkynyl substituted with 0-2 Rc1, (CRaRa1)sNRaRa1, —(CRaRa1)r1C(O)NRaOH, —(CRaRa1)r1C(O)Ra1, —(CRaRa1)r1C(O)ORa1, —(CRaRa1)r1C(S)ORa1, —(CRaRa1)r1C(O)NRaRa1, —(CRaRa1)sNRaC(O)Ra1, —(CRaRa1)r1C(S)NRaRa1, —(CRaRa1)sOC(O)NRaRa1, —(CRaRa1)SNRaC(O)ORa1, —(CRaRa1)sNRaC(O)NRaRa1, —(CRaRa1)r1S(O)pRa3, —(CRaRa1)r1SO2NRaRa1, —(CRaRa1)sNRaSO2Ra3, —(CRaRa1)sNRaSO2NRaRa1, —(CRaRa1)r1-C3-10 carbocycle substituted with 0-2 Rc1, and -(CRaRa1)r1-5-l4 membered heterocycle consisting of carbon atoms and 1-4 heteroatoms selected from the group consisting of N, O, and S(O)p, and substituted with 0-2 Rc1;
• Ra, at each occurrence, is independently selected from:
• H, C1-6 alkyl, phenyl, and benzyl;
• Ra1, at each occurrence, is independently selected from:
• H, C1-6 alkyl substituted with 0-1 Rg, C2-6 alkenyl substituted with 0-1 Rg, C2-6 alkynyl substituted with 0-1 Rg, and —(CH2)r-3-8 membered carbocyclic or heterocyclic ring consisting of carbon atoms and 0-2 ring heteroatoms selected from N, NR2a, O, and S(O)pand substituted with 0-3 Rg;
• alternatively, Ra and Ra1 when attached to a nitrogen are taken together with the nitrogen to which they are attached form a 5 or 6 membered heterocycle consisting of carbon atoms and 0-1 additional heteroatoms selected from N, NRa2, O, and S(O)p;
• Ra2, at each occurrence, is independently selected from:
• C1-4 alkyl, phenyl, and benzyl;
• Ra3, at each occurrence, is independently selected from:
• H, C1-6 alkyl substituted with 0-1 Rc1, C2-6 alkenyl substituted with 0-1 Rc1, C2-6 alkynyl substituted with 0-1 Rc1, and —(CH2)r-3-8 membered carbocyclic or heterocyclic ring consisting of carbon atoms and 0-2 ring heteroatoms selected from N, NR2a, O, and S(O)p, and substituted with 0-3 Rc1;
• Rb, at each occurrence, is independently selected from:
• C1-6 alkyl substituted with 0-1 Rc1, —ORa, Cl, F, Br, I, ═O, —CN, NO2, —NRaRa1, —C(O)Ra, —C(O)ORa, —C(O)NRaRa1, —C(S)NRaRa1, —NRaC(O)NRaRa1, —OC(O)NRaRa1, —NRaC(O)ORa, —S(O)2NRaRa1, —NRaS(O)2Ra3, —NRaS(O)2NRaRa1, —OS(O)2NRaRa1, —NRaS(O)2Ra3, —S(O)pRa3, CF3, —CF2CF3, —CHF2, —CH2F, and phenyl;
• Rc, at each occurrence, is independently selected from:
• H, C1-6 alkyl substituted with 0-2 Rc1, C2-6 alkenyl substituted with 0-2 Rc1, C2-6 alkynyl substituted with 0-2 Rc1, —ORa, Cl, F, Br, I, ═O, —CN, NO2, CF3, —OCF3, —CF2CF3, —CH2F, —CHF2, —(CRaRa1)r1NRaRa1, —(CRaRa1)r1C(═NCN)NRaRa1, —(CRaRa1)r1C(═NRa)NRaRa1, —(CRaRa1)r1C(═NORa)NRaRa1, —(CRaRa1)r1C(O)NRaOH, —(CRaRa1)r1C(O)Ra1, —(CRaRa1)r1C(O)ORa1, —(CRaRa1)r1C(S)ORa1, —(CRaRa1)r1C(O)NRaRa1, —(CRaRa1)r1NRaC(O)Ra1, —(CRaRa1)r1C(S)NRaRa1, —(CRaRa1)r1OC(O)NRaRa1, —(CRaRa1)r1NRaC(O)ORa1, —(CRaRa1)r1NRaC(O)NRaRa1, —(CRaRa1)r1S(O)pRa3, —(CRaRa1)r1SO2NRaRa1, —(CRaRa1)r1NRaSO2Ra3, —(CRaRa1)r1NRaSO2NRaRa1, —(CRaRa1)r1—C3-10 carbocycle substituted with 0-2 Rc1, and —(CRaRa1)r1-5-l4 membered heterocycle consisting of carbon atoms and 1-4 heteroatoms selected from the group consisting of N, O, and S(O)p, and substituted with 0-2 Rc1;
• alternatively, when two Rc groups are attached to the same carbon atom they form a spiro ring C that is a 3-11 membered carbocycle substituted with 0-2 Rc1or a 3-13 membered heterocycle consisting of:
• carbon atoms, 0-3 carbonyl groups, 0-4 double bonds, and from 1-5 ring heteroatoms selected from O, N, and S(O)p, and substituted with 0-2 Rc1, provided that ring C contains other than a S—S, O—O, or S—O bond;
• alternatively, when two Rc groups are attached to adjacent carbon atoms, together with the carbon atoms to which they are attached they form a 5-7 membered carbocyclic or heterocyclic ring consisting of:
• carbon atoms, 0-2 heteroatoms selected from the group consisting of N, O, and S(O)p, and 0-3 double bonds, and substituted with 0-2 Rc1;
• Rc1, at each occurrence, is independently selected from:
• H, C1-6 alkyl, —ORa, Cl, F, Br, I, ═O, —CN, NO2, —NRaRa1, —C(O)Ra, —C(O)ORa, —C(O)NRaRa1, —NRaC(O)NRaRa1, —OC(O)NRaRa1, —NRaC(O)ORa1, —S(O)2NRaRa1, —NRaS(O)2Ra2, —NRaS(O)2NRaRa1, —OS(O)2NRaRa1, —NRaS(O)2Ra2, —S(O)2Ra2, CF3, —OCF3, —CF2CF3, —CH2F, and —CHF2;
• Rd, at each occurrence, is independently selected from:
• C1-6 alkyl, —ORa, Cl, F, Br, I, ═O, —CN, NO2, —NRaRa1, —C(O)Ra, —C(O)ORa, —C(O)NRaRa1, —C(S)NRaRa1, —NRaC(O)NRaRa1, —OC(O)NRaRa1, —NRaC(O)ORa1, —S(O)2NRaRa1, —NRaS(O)2Ra3, —NRaS(O)2NRaRa1, —OS(O)2NRaRa1, —NRaS(O)2Ra3, —S(O)pRa3, CF3, —CF2CF3, C3-10 carbocycle, and a 5-14 membered heterocycle consisting of carbon atoms and 1-4 heteroatoms selected from the group consisting of N, O, and S(O)p;
• Re, at each occurrence, is independently selected from:
• phenyl substituted with 0-2 Rb, and biphenyl substituted with 0-2 Rb;
• Rf, at each occurrence, is independently selected from:
• C1-4 alkyl, C3-8 cycloalkyl, C1-5 alkoxy, and phenyl substituted with 0-2 Rb;
• Rg, at each occurrence, is independently selected from:
• H, C1-6 alkyl, —ORa, Cl, F, Br, I, ═O, —CN, NO2, —NRaRa, —C(O)Ra, —C(O)ORa, —C(O)NRaRa, —NRaC(O)NRaRa, —OC(O)NRaRa, —NRaC(O)ORa, —S(O)2NRaRa, —NRaS(O)2Ra2, —NRaS(O)2NRaRa, —OS(O)2NRaRa, —NRaS(O)2Ra2, —S(O)pRa2, CF3, —OCF3, —CF2CF3, —CH2F, and —CHF2;
• p, at each occurrence, is selected from 0, 1, and 2;
• q is selected from 0, 1, and 2;
• r, at each occurrence, is selected from 0, 1, 2, 3, and 4;
• r1, at each occurrence, is selected from 0, 1, 2, 3, and 4;
• and,
• s, at each occurrence, is selected from 1, 2, 3, and 4.