Barbituric acid derivatives as inhibitors of TNF-alpha converting enzyme (TACE) and/or matrix metalloproteinases

A compound of formula I:

• 130
• or a stereoisomer or pharmaceutically acceptable salt form thereof, wherein;
• A is C(═O), C(═S) or CH2;
• B is O or S;
• L is O or S;
• W is selected from (CRaRa1)m, C2-3 alkenylene, and C2-3 alkynylene;
• Z is selected from:
• a C6-10 aryl substituted with 0-5 Rb and a 5-14 membered heteroaryl 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);
• provided that Ua—Xa—Ya forms a linker group of two or more backbone atoms;
• Za is selected from 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 Za is other than dihydro-2-oxo-thien-3-yl;
• provided that 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)p, or S(O)p—S(O)p group;
• R1 is selected from CHF2, CH2F, CF3, 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, (CRaRa1)r1NRaSO2NRaRa1, 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;
• 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;
• 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;
• provided that when A is C(═O), B is O, L is O,
• (i) R1 is C1-4 alkyl, allyl, isopropyl, or 2-propynyl, Ua—Xa—Ya is —OCH2—, and Z is phenylene, then Za is other than phenyl;
• (iii) R1 is C1-4 alkyl, allyl, isopropyl, or 2-propynyl, Z is phenylene, and Za is phenyl, then Ua—Xa—Ya forms other than —OCH2—;
• (iii) R1 is C1-4 alkyl, Ua—Xa—Ya is —OCH2—or —CH2OCO—, and Z is phenylene, then Za is other than phenyl;
• (iv) R1 is C1-4 alkyl, Z is phenylene, and Za is phenyl, then Ua—Xa Ya forms other than —OCH2—or —CH2OCO—;
• (v) R1 is OH, Ua—Xa—Ya is CONH, and Z is naphthalenyl, then Za is other than phenyl;
• (vi) R1 is OH, Z is naphthalenyl, and Za is phenyl, then Ua—Xa—Ya forms other than CONH;
• and
• provided that when A is C(═O), B is O, L is O, R1 is OH or OMe,
• (i) Ua—Xa—Ya is —NHCH2—, —N(Me)CH2—, —N(Et)CH2—or —N(COMe)CH2—, and Z is phenylene, then Za is other than phenyl;
• (ii) Z is phenylene and Za is phenyl, then Ua—Xa—Ya forms other than —NHCH2—, —N(Me)CH2—, —N(Et)CH2—or —N(COMe)CH2—.