Isoxazoline derivatives as inhibitors of matrix metalloproteinases and/or TNF-α converting enzyme

A compound of formula I or II:

• or a stereoisomer or pharmaceutically acceptable salt form thereof, wherein;
• A is —C(O)NHOH, —C(O)NHOR5, —C(O)NHOR6, —N(OH)COR5, or —N(OH)CHO;
• U is absent or is 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, or NRa1SO2NRa1;
• X is absent or is C1-10 alkylene, C2-10 alkenylene, or C2-10 alkynylene;
• Y is absent or is O, NRa1, S(O)p, or C(O);
• Z is a C3-13 carbocycle substituted with 1–5 Rb, or a 5–14 membered heterocycle consisting of carbon atoms and 1–4 heteroatoms selected from N, O, and S(O)p, and substituted with 1–5 Rb;
• Za is H, C3-13 carbocycle substituted with 1–5 Rc, or a 5–14 membered heterocycle consisting of carbon atoms and 1–4 heteroatoms selected from N, O, and S(O)p, and substituted with 1–5 Rc;
• provided that U, Y, Z, 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 Q, C1-6 alkylene-Q, C2-6 alkenylene-Q, C2-6 alkynylene-Q, —(CRaRa1)rO(CRaRa1)s-Q, —(CRaRa1)rNRa(CRaRa1)s-Q, —(CRaRa1)rC(O)(CRaRa1)s-Q, —(CRaRa1)rC(O)O(CRaRa1)s-Q, —(CRaRa1)rOC(O)(CRaRa1)s-Q, —(CRaRa1)rC(O)NRaRa1, —(CRaRa1)rC(O)NRa(CRaRa1)s-Q, —(CRaRa1)rNRaC(O)(CRaRa1)s-Q, —(CRaRa1)rOC(O)O(CRaRa1)s-Q, —(CRaRa1)rOC(O)NRa(CRaRa1)s-Q, —(CRaRa1)rNRaC(O)O(CRaRa1)s-Q, —(CRaRa1)rNRaC(O)NRa(CRaRa1)s-Q, —(CRaRa1)rS(O)p(CRaRa1)s-Q, —(CRaRa1)rSO2NRa(CRaRa1)s-Q, —(CRaRa1)rNRaSO2(CRaRa1)s-Q, or —(CRaRa1)rNRaSO2NRa(CRaRa1)s-Q;
• Q is, independently at each occurrence, H, CHF2, CH2F, CF3, a C3-13 carbocycle substituted with 0–5 Rd, or a 5–14 membered heterocycle consisting of carbon atoms and 1–4 heteroatoms selected from N, O, and S(O)p, and substituted with 0–5 Rd;
• R2 is Q1, C1-6 alkylene-Q1, C2-6 alkenylene-Q1, C2-6 alkynylene-Q1, —(CRaRa1)rO(CRaRa1)s-Q, —(CRaRa1)rNRa(CRaRa1)s-Q1, —(CRaRa1)rC(O)(CRaRa1)s-Q1, —(CRaRa1)rC(O)O(CRaRa1)s-Q1, —(CRaRa1)rC(O)NRaRa1, or —(CRaRa1)rC(O)NRa(CRaRa1)s-Q1,
• Q1 is, independently at each occurrence, H, a C3-13 carbocycle substituted with 0–5 Rd, or a 5–14 membered heterocycle consisting of carbon atoms and 1–4 heteroatoms selected from N, O, and S(O)p, and substituted with 0–5 Rd;
• alternatively, R1 and R2 combine, along with the carbon atom to which they are attached, to form a 3–7 membered carbocyclic or heterocyclic ring consisting of:
• carbon atoms and 0–3 heteroatoms selected from the group consisting of N, O, and S(O)p and substituted with 0–2 Rd;
• R3 is Q, C1-6 alkylene-Q, C2-6 alkenylene-Q, C2-6 alkynylene-Q, —(CRaRa1)rO(CRaRa1)s-Q, —(CRaRa1)rNRa(CRaRa1)s-Q, —(CRaRa1)rC(O)(CRaRa1)s-Q, —(CRaRa1)rC(O)O(CRaRa1)s-Q, —(CRaRa1)rOC(O)(CRaRa1)s-Q, —(CRaRa1)rC(O)NRaRa1, —(CRaRa1)rC(O)NRa(CRaRa1)s-Q, —(CRaRa1)rNRaC(O)(CRaRa1)s-Q, —(CRaRa1)rOC(O)O(CRaRa1)s-Q, —(CRaRa1)rOC(O)NRa(CRaRa1)s-Q, —(CRaRa1)rNRaC(O)O(CRaRa1)s-Q, —(CRaRa1)rNRaC(O)NRa(CRaRa1)s-Q, —(CRaRa1)rS(O)p(CRaRa1)s-Q, —(CRaRa1)rSO2NRa(CRaRa1)s-Q, —(CRaRa1)rNRaSO2(CRaRa1)s-Q, or —(CRaRa1)rNRaSO2NRa(CRaRa1)s-Q;
• alternatively, R1 and R3 combine, along with the carbon atom to which they are attached, to form a 3–7 membered carbocyclic or heterocyclic ring consisting of:
• carbon atoms and 0–3 heteroatoms selected from the group consisting of N, O, and S(O)p and substituted with 0–2 Rd;
• alternatively, when R1 and R3 combine to form a carbocyclic or heterocyclic ring, the R2 and R4 combine to form a double bond;
• R4 is Q1, C1-6 alkylene-Q1, C2-6 alkenylene-Q1, C2-6 alkynylene-Q1, —(CRaRa1)rO(CRaRa1)s-Q1, —(CRaRa1)rNRa(CRaRa1)s-Q1, —(CRaRa1)rC(O)(CRaRa1)s-Q1, —(CRaRa1)rC(O)O(CRaRa1)s-Q1, —(CRaRa1)rC(O)NRaRa1, or —(CRaRa1)rC(O)NRa(CRaRa1)s-Q1,
• alternatively, R3 and R4 combine, along with the carbon atom to which they are attached, to form a 3–7 membered carbocyclic or heterocyclic ring consisting of:
• carbon atoms and 0–3 heteroatoms selected from the group consisting of N, O, and S(O)p and substituted with 0–2 Rd;
• R4a is Q, C1-6 alkylene-Q, C2-6 alkenylene-Q, C2-6 alkynylene-Q, —(CRaRa1)rO(CRaRa1)s-Q, —(CRaRa1)rNRa(CRaRa1)s-Q, —(CRaRa1)rC(O)(CRaRa1)s-Q, —(CRaRa1)rC(O)O(CRaRa)s-Q, —(CRaRa1)rC(O)NRaRa1, —(CRaRa1)rC(O)NRaORa, —(CRaRa1)rC(O)NRa(CRaRa1)s-Q, —(CRaRa1)rNRaC(O)(CRaRa1)s-Q, —(CRaRa1)rNRaC(O)O(CRaRa1)s-Q, —(CRaRa1)rS(O)p(CRaRa1)s-Q, or —(CRaRa1)rSO2NRa(CRaRa1)s-Q;
• alternatively, R1 and R4a in Formula I combine, along with the carbon atoms to which they are attached, to form a 3–7 membered carbocyclic or heterocyclic ring consisting of:
• carbon atoms and 0–3 heteroatoms selected from the group consisting of N, O, and S(O)p and substituted with 0–3 Rd, provided that n is 0;
• alternatively, R3 and R4a in Formula I combine, along with the carbon atoms to which they are attached, to form a 3–7 membered carbocyclic or heterocyclic ring consisting of:
• carbon atoms and 0–3 heteroatoms selected from the group consisting of N, O, and S(O)p and substituted with 0–2 Rd;
• Ra is, independently at each occurrence, H, C1-6 alkyl, phenyl, or benzyl;
• Ra1 is, independently at each occurrence, 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, or —(CH2)r-3–8 membered carbocyclic or heterocyclic ring consisting of carbon atoms and 0–2 ring heteroatoms selected from N, NRa2, O, and S(O)p, and substituted with 0–3 Rc1;
• alternatively, Ra and Ra1 when attached to a nitrogen, together with the nitrogen to which they are attached, combine to form a 5 or 6 membered heterocycle consisting of carbon atoms and from 0–1 additional heteroatoms selected from N, NRa2, O, and S(O)p;
• Ra2 is, independently at each occurrence, C1-4 alkyl, phenyl, or benzyl;
• Ra3 is, independently at each occurrence, 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, or —(CH2)r-3–8 membered carbocyclic or heterocyclic ring consisting of carbon atoms and 0–2 ring heteroatoms selected from N, NRa2, O, and S(O)p, and substituted with 0–3 Rc1;
• Rb is, independently at each occurrence, H, 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, —S(O)pRa3, CF3, CF2CF3, CHF2, CH2F, or phenyl;
• Rc is, independently at each occurrence, 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)rC(O)NRaOH, —(CRaRa1)rC(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, or —(CRaRa1)r-5–14 membered heterocycle consisting of carbon atoms and 1–4 heteroatoms selected from N, O, and S(O)p, and substituted with 0–2 Rc1;
• alternatively, when two Rc groups are attached to the sarne carbon atom, they form a 3–8 membered carbocyclic or heterocyclic spiro ring C substituted with 0–2 Rc1 and consisting of 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 and 0–2 heteroatoms selected from N, O, and S(O)p;
• Rc1 is, independently at each occurrence, H, C1-4 alkyl, ORa, Cl, F, Br, I, ═O, CF3, CN, NO2, —C(O)Ra, —C(O)ORa, —C(O)NRaRa, or —S(O)pRa;
• Rd is, independently at each occurrence, C1-6 alkyl, ORa, Cl, F, Br, I, ═O, CN, NO2, —NRaRa1, —C(O)Ra, —C(O)ORa, —C(O)NRaRa1, —C(O)NRaORa, —C(S)NRaRa1, —NRaC(O)NRaRa1, —OC(O)NRaRa1, —NRaC(O)ORa, —S(O)2NRaRa1, —NRaS(O)2Ra3, —NRaS(O)2NRaRa1, —OS(O)2NRaRa1, —S(O)pRa3, CF3, CF2CF3, C3-10 carbocycle, or a 5–14 membered heterocycle consisting of carbon atoms and 1–4 heteroatoms selected from N, O, and S(O)p;
• R5 is, independently at each occurrence, C1-10 alkyl substituted with 0–2 Rb, or C1-8 alkyl substituted with 0–2 Re;
• Re is phenyl substituted with 0–2 Rb, or biphenyl substituted with 0–2 Rb;
• R6 is, 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–C5 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, or —CH(R8)OC(═O)OR9;
• R7 is H, C1-10 alkyl, C2-6 alkenyl, C3-6 cycloalkyl-C1-3 alkyl-, or phenyl-C1-6 alkyl-;
• R7a is H, C1-10 alkyl, C2-6 alkenyl, C3-6 cycloalkyl-C1-3 alkyl-, or phenyl-C1-6 alkyl-;
• R8 is H or C1-4 linear alkyl;
• R9 is H, C1-8 alkyl substituted with 1–2 Rf, C3-8 cycloalkyl substituted with 1–2 Rf, or phenyl substituted with 0–2 Rb;
• Rf is, independently at each occurrence, C1-4 alkyl, C3-8 cycloalkyl, C1-5 alkoxy, or phenyl substituted with 0–2 Rb;
• n is 0 or 1;
• p, at each occurrence, is selected from 0, 1, and 2;
• r, at each occurrence, is selected from 0, 1, 2, 3, and 4;
• and
• s, at each occurrence, is selected from 0, 1, 2, 3, and 4.