BARBITURIC ACID DERIVATIVES AS INHIBITORS OF TNF-alpha CONVERTING ENZYME (TACE) AND/OR MATRIX METALLOPROTEINASES

A compound of formula I:

• or a stereoisomer or pharmaceutically acceptable salt form thereof, wherein;
• A is C(═O);
• B is O or S;
• L is O or S;
• W is selected from (CRaRa1)m, C2-3 alkenylene, and C2-3 alkynylene;
• U is absent or is selected from:
• O, NRa1, C(O), CRa(OH), 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;
• X is absent or is selected from C1-3 alkylene, C2-3 alkenylene, and C2-3 alkynylene;
• Y is absent or is selected from O, NRa1, S(O)pand C(O);
• Z is absent or is selected from:
• a C3-13 carbocycle substituted with 0-5 Rb;
• and a 5-14 membered heterocycle comprising carbon atoms and 1-4 heteroatoms selected from the group consisting of N, O, and S(O)p, and substituted with 0-5 Rb;
• Ua is absent or is selected from:
• O, NRa1, C(O), CRa(OH), 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 C1-10 alkylene, C2-10 alkenylene, and C2-10 alkynylene;
• Ya is absent or is selected from O, NRa1, S(O)p, and C(O);
• Za is selected from H, a C3-13 carbocycle substituted with 0-5 Rc, and a 5-14 membered heterocycle comprising 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 U, Y, Z, 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;
• provided that when Z is absent, Za is other than H;
• R1 and R2, together with the carbon atoms to which they are attached, combine to form a 5-7 membered carbocyclic or heterocyclic ring comprising carbon atoms, 0-2 ring heteroatoms selected from O, N, NR10, and S(O)p, and 0-2 double bonds, and substituted with 0-3 Rc;
• and the carbocyclic or heterocyclic ring is optionally fused to a 5-6 membered carbocycle substituted with 0-3 Rc or a 5-6 membered heterocycle consisting of carbon atoms and 1-3 heteroatoms selected from the group consisting of N, O, and S(O)p, and substituted with 0-3 Rc;
• R3 is selected from Q, C1-6 alkylene-Q, C2-6 alkenylene-Q, C2-6 alkynylene-Q, (CRaRa1)r1ORa1, (CRaRa1)r1NRa(CRaRa1)r-Q, (CRaRa1)r1C(O)(CRaRa1)r-Q, (CRaRa1)r1C(O)ORa1, (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)ORa1, (CRaRa1)r1OC(O)NRaRa1, (CRaRa1)r1NRaC(O)ORa1, (CRaRa1)r1NRaC(O)NRaRa1, (CRaRa1)r1S(O)p(CRaRa1)r-Q, (CRaRa1)r1SO2NRaRa1, (CRaRa1)r1NRaSO2(CRaRa1)r-Q, and (CRaRa1)r1NRaSO2NRaRa1;
• Q, at each occurrence, is independently selected from H, CHF2, CH2F, CF3, a C3-13 carbocycle substituted with 0-5 Rd, and a 5-14 membered heterocycle comprising carbon atoms and 1-4 heteroatoms selected from the group consisting of N, O, and S(O)p, and substituted with 0-5 Rd;
• R4 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;
• R5 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;
• n is 0 or 1;
• alternatively, when n is 1, R4 and R5, together with the carbon atom to which they are attached, combine to form a 3-8 membered carbocyclic or heterocyclic ring comprising carbon atoms, 0-2 ring heteroatoms selected from O, N, NRc, and S(O)p, and 0-2 double bonds, and substituted with 0-3 Rc;
• and the carbocyclic or heterocyclic ring is optionally fused to a 5-6 membered carbocycle substituted with 0-3 Rc or a 5-6 membered heterocycle consisting of carbon atoms and 1-3 heteroatoms selected from the group consisting of N, O, and S(O)p, and substituted with 0-3 Rc;
• 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)rC(O)NRaOH, (CRaRa1)rC(O)Ra1, (CRaRa1)rC(O)ORa1, (CRaRa1)rC(S)ORa1, (CRaRa1)rC(O)NRaRa1, (CRaRa1)sNRaC(O)Ra1, (CRaRa1)rC(S)NRaRa1, (CRaRa1)sOC(O)NRaRa1, (CRaRa1)sNRaC(O)ORa1, (CRaRa1)sNRaC(O)NRaRa1, (CRaRa1)rS(O)pRa3, (CRaRa1)rSO2NRaRa1, (CRaRa1)sNRaSO2Ra3, (CRaRa1)sNRaSO2NRaRa1, (CRaRa1)r-C3-10 carbocycle substituted with 0-2 Rc1, and (CRaRa1)r-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 0-2 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 Re, C2-6 alkenyl substituted with 0-1 Re, C2-6 alkynyl substituted with 0-1 Re, and —(CH2)r-3-8 membered carbocyclic or heterocyclic ring comprising carbon atoms and 0-2 ring heteroatoms selected from N, NRa2, O, and S(O)p, and substituted with 0-3 Re;
• 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 comprising 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 comprising carbon atoms and 0-2 ring heteroatoms selected from N, NRa2, 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, SRa, 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, ORa, Cl, F, Br, I, ═O, —CN, NO2, CF3, CF2CF3, CH2F, CHF2, (CRaRa1)rNRaRa1, (CRaRa1)rC(═NCN)NRaRa1, (CRaRa1)rC(═NRa)NRaRa1, (CRaRa1)rC(═NORa)NRaRa1, (CRaRa1)r1C(O)NRaOH, (CRaRa1)r1C(O)Ra1, (CRaRa1)rC(O)ORa1, (CRaRa1)rC(S)ORa1, (CRaRa1)rC(O)NRaRa1, (CRaRa1)rNRaC(O)Ra1, (CRaRa1)rC(S)NRaRa1, (CRaRa1)rOC(O)NRaRa1, (CRaRa1)rNRaC(O)ORa1, (CRaRa1)rNRaC(O)NRaRa1, (CRaRa1)rS(O)pRa3, (CRaRa1)rSO2NRaRa1, (CRaRa1)rNRaSO2Ra3, (CRaRa1)rNRaSO2NRaRa1;
• 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)r-C3-10 carbocycle substituted with 0-2 Rc1;
• and (CRaRa1)r-5-14 membered heterocycle comprising 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 or heterocycle substituted with 0-2 Rc1 and comprising:
• carbon atoms, 0-4 ring heteroatoms selected from O, N, and S(O)p, and 0-2 double bonds, 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 D substituted with 0-2 Rc1 and consisting of carbon atoms, 0-2 heteroatoms selected from the group consisting of N, O, and S(O)p, and 0-3 double bonds;
• 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, RaNC(O)NRaRa1, OC(O)NRaRa1, RaNC(O)ORa1, S(O)2NRaRa1, NRaS(O)2Ra2, NRaS(O)2NRaRa1, OS(O)2NRaRa1, NRaS(O)2Ra2, S(O)pRa2, CF3, OCF3, CF2CF3, CH2F, and CHF2;
• Rd, at each occurrence, is independently selected from C1-6 alkyl substituted with 0-2 Re, C2-6 alkenyl, C2-6 alkynyl, ORa, Cl, F, Br, I, ═O, —CN, NO2, NRaRa1, C(O)Ra1, C(O)ORa, C(O)NRaRa1, C(S)NRaRa1, RaNC(O)NRaRa1, OC(O)NRaRa1, RaNC(O)ORa1, S(O)2NRaRa1, NRaS(O)2Ra3, NRaS(O)2NRaRa1, OS(O)2NRaRa1, NRaS(O)2Ra3, S(O)pRa3, CF3, CF2CF3, (CH2)r-C3-10 carbocycle substituted with 0-2 Re, and a (CH2)r-5-14 membered heterocycle comprising carbon atoms and 1-4 heteroatoms selected from the group consisting of N, O, and S(O)p, and substituted with 0-2 Re;
• Re, 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, RaNC(O)NRaRa, OC(O)NRaRa, RaNC(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;
• m, at each occurrence, is selected from 0, 1, 2 and 3;
• p, at each occurrence, 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 2, 3, and 4.