Bicyclic and tricyclic amines as modulators of chemokine receptor activity

A compound of formula (I):

• A-E-NR1-G (I)
• or stereoisomers or pharmaceutically acceptable salts thereof, wherein:
• A is selected from
• 61
• E is selected from —(CR7R8)—(CR9R10)v—(CR11R12),
• 62
• ring D is selected from a C3-6 carbocyclic residue and a 5 or 6 membered heterocycle;
• G is selected from —C(O)R3, —C(O)NR2R3, —C(O)OR3, —SO2NR2R3, —SO2R3, —C(═S)NR2R3, C(═NR1a)NR2R3, C(═CHCN)NR2R3,
• 63
• W, at each occurrence, is independently selected from C or N, provided at least two of W are C;
• X1 and X2 are independently selected from C and N;
• Z1 is selected from C and N;
• Z2 is selected from NR1′, O, S and C;
• R1, R1′and R2 are independently selected from H, C1-8 alkyl, C3-8 alkenyl, C3-8 alkynyl, (CH2)rC3-6 cycloalkyl, and a (CH2)r-C3-10 carbocyclic residue substituted with 0-5 Ra;
• R1a is independently selected from H, C1-6 alkyl, —OH, —CN, —NO2, (CH2)rC3-6 cycloalkyl, and a (CH2)r-C3-10 carbocyclic residue substituted with 0-5 Ra;
• Ra, at each occurrence, is selected from C1-4 alkyl, C2-8 alkenyl, C2-8 alkynyl, (CHR′)rC3-6 cycloalkyl, Cl, Br, I, F, (CF2)rCF3, NO2, CN, (CHR′)rNRbRb, (CHR′)rOH, (CHR′)rORc, (CHR′)rSH, (CHR′)rSRc, (CHR′)rC(O)Rb, (CHR′)rC(O)NRbRb, (CHR′)rNRbC(O)Rb, (CHR′)rC(O)ORb, (CHR′)rOC(O)Rc, (CHR′)rCH(═NRb)NRbRb, (CHR′)rNHC(═NRb)NRbRb, (CHR′)rS(O)pRc, (CHR′)rS(O)2NRbRb, (CHR′)rNRbS(O)2Rc, and (CHR′)rphenyl;
• Rb, at each occurrence, is selected from H, C1-6 alkyl, C3-6 cycloalkyl, and phenyl;
• Rc, at each occurrence, is selected from C1-6 alkyl, C3-6 cycloalkyl, and phenyl;
• alternatively, R1 and R2 join to form a 5, 6, or 7-membered ring substituted with 0-3 Ra;
• R3 is selected from a (CR3′R3″)r-C3-10 carbocyclic residue substituted with 0-5 R15 and a (CR3′R3″)r-5-10 membered heterocyclic system containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-3 R15;
• R3′and R3″, at each occurrence, are selected from H, C1-6 alkyl, (CH2)rC3-6 cycloalkyl, and phenyl;
• R4 is absent, taken with the nitrogen to which it is attached to form an N-oxide, or selected from C1-8 alkyl, C3-8 alkenyl, C3-8 alkynyl, (CH2)rC3-6 cycloalkyl, (CH2)qC(O)R4b, (CH2)qC(O)NR4aR4a′, (CH2)qC(O)OR4a, and a (CH2)r-C3-10 carbocyclic residue substituted with 0-3 R4c;
• R4aand R4a′, at each occurrence, are selected from H, C1-6 alkyl, (CH2)rC3-6 cycloalkyl, and phenyl;
• R4b, at each occurrence, is selected from C1-6 alkyl, C2-8 alkenyl, (CH2)rC3-6 cycloalkyl, C2-8 alkynyl, and phenyl;
• R4c, at each occurrence, is selected from C1-6 alkyl, C2-8 alkenyl, C2-8 alkynyl, C3-6 cycloalkyl, Cl, F, Br, I, CN, NO2, (CF2)rCF3, (CH2)rOC1-5 alkyl, (CH2)rOH, (CH2)rSC1-5 alkyl, (CH2)rNR4aR4a′, and (CH2)rphenyl;
• R7, is selected from H, C1-6 alkyl, C2-8 alkenyl, C2-8 alkynyl, (CHR′)qOH, (CHR′)qSH, (CHR′)qOR7d, (CHR′)qSR7d, (CH2 CHR′)qNR7aR7a′, (CHR′)rC(O)OH, (CHR′)rC(O)R7b, (CHR′)rC(O)NR7aR7a′, (CHR′)qNR7aC(O)R7b, (CHR′)qNR7aC(O)H, (CHR′)rC(O)OR7a, (CHR′)qOC(O)R7b, (CHR′)qS(O)pR7b, (CHR′)qS(O)2NR7aR7a′, (CHR′)qNR7aS (O)2R7b, (CHR′)qNHC(O)NR7aR7a′, (CHR′)qNHC(O)OR7a, (CHR′)qOC(O)NR7aR7a′, C1-6 haloalkyl, a (CHR′)r-C3-10 carbocyclic residue substituted with 0-3 R7c, and a (CHR′)r-5-10 membered heterocyclic system containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-2 R7c;
• R7aand R7a′, at each occurrence, are selected from H, C1-6 alkyl, C3-8 alkenyl, C3-8 alkynyl, a (CH2)r-C3-11 carbocyclic residue substituted with 0-5 R7e, and a (CH2)r-5-10 membered heterocyclic system containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-3 R7e;
• R7b, at each occurrence, is selected from C1-6 alkyl, C2-8 alkenyl, C2-8 alkynyl, a (CH2)r-C3-6 carbocyclic residue substituted with 0-2 R7e, and a (CH2)r-5-6 membered heterocyclic system containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-3 R7e;
• R7c, at each occurrence, is selected from C1-6 alkyl, C2-8 alkenyl, C2-8 alkynyl, (CH2)rC3-6 cycloalkyl, Cl, Br, I, F, (CF2)rCF3, NO2, CN, (CH2)rNR7fR7f, (CH2)rOH, (CH2)rOC1-4 alkyl, (CH2)rSC1-4 alkyl, (CH2)rC(O)OH, (CH2)rC(O)R7b, (CH2)rC(O)NR7fR7f, (CH2)rNR7fC(O)R7b, (CH2)rC(O)OC1-4 alkyl, (CH2)rOC(O)R7b, (CH2)rC(═NR7f)NR7fR7f, (CH2)rS(O)pR7b, (CH2)rNHC(═NR7f)NR7fR7f, (CH2)rS(O)2NR7fR7f, (CH2)rNR7fS(O)2R7b, and (CH2)rphenyl substituted with 0-3 R7e;
• R7d, at each occurrence, is selected from methyl, CF3, C2-6 alkyl substituted with 0-3 R7e, C3-6 alkenyl, C3-6 alkynyl, and a C3-10 carbocyclic residue substituted with 0-3 R7c;
• R7e, at each occurrence, is selected from C1-6 alkyl, C2-8 alkenyl, C2-8 alkynyl, C3-6 cycloalkyl, Cl, F, Br, I, CN, NO2, (CF2)rCF3, (CH2)rOC1-5 alkyl, OH, SH, (CH2)rSC1-5 alkyl, (CH2)rNR7fR7f, and (CH2)rphenyl;
• R7f, at each occurrence, is selected from H, C1-6 alkyl, and C3-6 cycloalkyl;
• R8 is selected from H, C1-6 alkyl, C3-6 cycloalkyl, and (CH2)rphenyl substituted with 0-3 R8a;
• R8a, at each occurrence, is selected from C1-6 alkyl, C2-8 alkenyl, C2-8 alkynyl, C3-6 cycloalkyl, Cl, F, Br, I, CN, NO2, (CF2)rCF3, (CH2)rOC1-5 alkyl, OH, SH, (CH2)rSC1-5 alkyl, (CH2)rNR7fR7f, and (CH2)rphenyl;
• alternatively, R7 and R8 join to form C3-7 cycloalkyl, ═NR8b, or ═O;
• R8bis selected from H, C1-6 alkyl, C3-6 cycloalkyl, OH, CN, and (CH2)r-phenyl;
• R9, is selected from H, C1-6 alkyl, C2-8 alkenyl, C2-8 alkynyl, F, Cl, Br, I, NO2, CN, (CHR′)rOH, (CHR′)rSH, (CHR′)rOR9d, (CHR′)rSR9d, (CHR′)rNR9aR9a′, (CHR′)rC(O)OH, (CHR′)rC(O)R9b, (CHR′)rC(O)NR9aR9a′, (CHR′)rNR9aC(O)R9b, (CHR′)rNR9aC(O)H, (CHR′)rNR9aC(O)NR9aR9a, (CHR′)rC(O)OR9a, (CHR′)rOC(O)R9b, (CHR′)rS(O)pR9b, (CHR′)rS(O)2NR9aR9a′, (CHR′)rNR9aS(O)2R9b, C1-6 haloalkyl, a (CHR′)r-C3-10 carbocyclic residue substituted with 0-5 R9c, and a (CHR′)r-5-10 membered heterocyclic system containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-3 R9c;
• R9aand R9a′, at each occurrence, are selected from H, C1-6 alkyl, C3-8 alkenyl, C3-8 alkynyl, a (CH2)r-C3-10 carbocyclic residue substituted with 0-5 R9e, and a (CH2)r-5-10 membered heterocyclic system containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-3 R9e;
• R9b, at each occurrence, is selected from C1-6 alkyl, C2-8 alkenyl, C2-8 alkynyl, a (CH2)r-C3-6 carbocyclic residue substituted with 0-2 R9e, and a (CH2)r-5-6 membered heterocyclic system containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-3 R9e;
• R9c, at each occurrence, is selected from C1-6 alkyl, C2-8 alkenyl, C2-8 alkynyl, (CH2)rC3-6 cycloalkyl, Cl, Br, I, F, (CF2)rCF3, NO2, CN, (CH2)rNR9fR9f, (CH2)rOH, (CH2)rOC1-4 alkyl, (CH2)rSC1-4 alkyl, (CH2)rC(O)OH, (CH2)rC(O)R9b, (CH2)rC(O)NR9fR9f, (CH2)rNR9fC(O)R9b, (CH2)rC(O)OC1-4 alkyl, (CH2)rOC(O)R9b, (CH2)rC(═NR9f)NR9fR9f, (CH2)rS(O)pR9b, (CH2)rNHC(═NR9f)NR9fR9f, (CH2)rS(O)2NR9fR9f, (CH2)rNR9fS(O)2R9b, and (CH2)rphenyl substituted with 0-3 R9e;
• R9d, at each occurrence, is selected from methyl, CF3, C2-6 alkyl substituted with 0-3 R9e, C3-6 alkenyl, C3-6 alkynyl, a C3-10 carbocyclic residue substituted with 0-3 R9c, and a 5-6 membered heterocyclic system containing 1-4 heteroatoms selected from the group consisting of N, O, and S substituted with 0-3 R9c;
• R9e, at each occurrence, is selected from C1-6 alkyl, C2-8 alkenyl, C2-8 alkynyl, (CH2)rC3-6 cycloalkyl, Cl, F, Br, I, CN, NO2, (CF2)rCF3, (CH2)rOC1-5 alkyl, OH, SH, (CH2)rSC1-5 alkyl, (CH2)rNR9fR9f, and (CH2)rphenyl;
• R9f, at each occurrence, is selected from H, C1-6 alkyl, and C3-6 cycloalkyl;
• R10, is selected from H, C1-6 alkyl, C2-8 alkenyl, C2-8 alkynyl, F, Cl, Br, I, NO2, CN, (CH2)rOH, (CH2)rOR10d, (CH2)rSR10d, (CH2)rNR10aR10a′, (CH2)rC(O)OH, (CH2)rC(O)R10b, (CH2)rC(O)NR10aR10a′, (CH2)rNR10aC(O)R10a, (CH2)rNR10aC(O)H, (CH2)rC(O)OR10a, (CH2)rOC(O)R10b, (CH2)rS (O) pR10b, (CH2)rS (O)2NR10aR10a′, (CH2)rNR10aS(O)2R10b, C1-6 haloalkyl, a (CH2)r-C3-10 carbocyclic residue substituted with 0-5 R10c, and a (CH2)r-5-10 membered heterocyclic system containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-3 R10c;
• R10a and R10a′, at each occurrence, are selected from H, C1-6 alkyl, C3-8 alkenyl, C3-8 alkynyl, a (CH2)r-C3-10 carbocyclic residue substituted with 0-5 R10e, and a (CH2)r-5-10 membered heterocyclic system containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-3 R10e;
• R10b, at each occurrence, is selected from C1-6 alkyl, C2-8 alkenyl, C2-8 alkynyl, a (CH2)r-C3-6 carbocyclic residue substituted with 0-2 R10e, and a (CH2)r-5-6 membered heterocyclic system containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-3 R10e;
• R10c, at each occurrence, is selected from C1-6 alkyl, C2-8 alkenyl, C2-8 alkynyl, (CH2)rC3-6 cycloalkyl, Cl, Br, I, F, (CF2)rCF3, NO2, CN, (CH2)rNR10fR10f, (CH2)rOH, (CH2)rOC1-4 alkyl, (CH2)rSC1-4 alkyl, (CH2)rC(O)OH, (CH2)rC(O)R10b, (CH2)rC(O)NR10fR10f, (CH2)rNR10fC(O)R10a, (CH2)rC(O)OC1-4 alkyl, (CH2)rOC(O)R10b, (CH2)rC(═NR10f)NR10fR10f, (CH2)rS(O)pR10b, (CH2)rNHC(═NR10f)NR10fR10f, (CH2)rS(O)2NR10fR10f, (CH2)rNR10fS(O)2R10b, and (CH2)rphenyl substituted with 0-3 R10e;
• R10d, at each occurrence, is selected from methyl, CF3, C2-6 alkyl substituted with 0-3 R10e, C3-6 alkenyl, C3-6 alkynyl, a C3-10 carbocyclic residue substituted with 0-3 R10c, and a 5-6 membered heterocyclic system containing 1-4 heteroatoms selected from the group consisting of N, O, and S substituted with 0-3 R10c;
• R10e, at each occurrence, is selected from C1-6 alkyl, C2-8 alkenyl, C2-8 alkynyl, (CH2)rC3-6 cycloalkyl, Cl, F, Br, I, CN, NO2, (CF2)rCF3, (CH2)rOC1-5 alkyl, OH, SH, (CH2)rSC1-5 alkyl, (CH2)rNR10fR10f, and (CH2)rphenyl;
• R10f, at each occurrence, is selected from H, C1-6 alkyl, and C3-6 cycloalkyl;
• alternatively, R9 and R10 join to form C3-7 cycloalkyl, 5-6-membered cyclic ketal, or ═O;
• with the proviso that when R10 is —OH, R9 is not halogen, cyano, or bonded to the carbon to which it is attached through a heteroatom;
• R11, is selected from H, C1-6 alkyl, C2-8 alkenyl, C2-8 alkynyl, (CH2)qOH, (CH2)qSH, (CH2)qOR11d, (CH2)qSR11d, (CH2)qNR11aR11a′, (CH2)rC(O)OH, (CH2)rC(O)R11b, (CH2)rC(O)NR11aR11a′, (CH2)qNR11aC(O)R11b, (CH2)qNR11aC(O)NR11aR11a, (CH2)rC(O)OR11a, (CH2)qOC(O)R11b, (CH2)qS(O)pR11b, (CH2)qS(O)2NR11aR11a′, (CH2)qNR11aS(O)2R11b, C1-6 haloalkyl, a (CH2)r-C3-10 carbocyclic residue substituted with 0-5 R11c, and a (CH2)r-5-10 membered heterocyclic system containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-3 R11c;
• R11a and R11a′, at each occurrence, are selected from H, C1-6 alkyl, C3-8 alkenyl, C3-8 alkynyl, a (CH2)r-C3-10 carbocyclic residue substituted with 0-5 R11e, and a (CH2)r-5-10 membered heterocyclic system containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-3 R11e;
• R11b, at each occurrence, is selected from C1-6 alkyl, C2-8 alkenyl, C2-8 alkynyl, a (CH2)r-C3-6 carbocyclic residue substituted with 0-2 R11e, and a (CH2)r-5-6 membered heterocyclic system containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-3 R11e;
• R11c, at each occurrence, is selected from C1-6 alkyl, C2-8 alkenyl, C2-8 alkynyl, (CH2)rC3-6 cycloalkyl, Cl, Br, I, F, (CF2)rCF3, NO2, CN, (CH2)rNR11fR11f, (CH2)rOH, (CH2)rOC1-4 alkyl, (CH2)rSC1-4 alkyl, (CH2)rC(O)OH, (CH2)rC(O)R11b, (CH2)rC(O)NR11fR11f, (CH2)rNR11fC(O)R11a, (CH2)rC(O)OC1-4 alkyl, (CH2)rOC(O)R11b, (CH2)rC(═NR11f)NR11fR11f, (CH2)rNHC(═NR11f)NR11fR11f, (CH2)rS(O)pR11b, (CH2)rS(O)2NR11fR11f, (CH2)rNR11fS(O)2R11b, and (CH2)rphenyl substituted with 0-3 R11e;
• R11d, at each occurrence, is selected from methyl, CF3, C2-6 alkyl substituted with 0-3 R11e, C3-6 alkenyl, C3-6 alkynyl, and a C3-10 carbocyclic residue substituted with 0-3 R11c;
• R11e, at each occurrence, is selected from C1-6 alkyl, C2-8 alkenyl, C2-8 alkynyl, C3-6 cycloalkyl, Cl, F, Br, I, CN, NO2, (CF2)rCF3, (CH2)rOC1-5 alkyl, OH, SH, (CH2)rSC1-5 alkyl, (CH2)rNR11fR11f, and (CH2)rphenyl;
• R11f, at each occurrence, is selected from H, C1-6 alkyl, and C3-6 cycloalkyl;
• R12 is selected from H, C1-6 alkyl, (CH2)qOH, (CH2)rC3-6 cycloalkyl, and (CH2)tphenyl substituted with 0-3 R12a;
• R12a, at each occurrence, is selected from C1-6 alkyl, C2-8 alkenyl, C2-8 alkynyl, C3-6 cycloalkyl, Cl, F, Br, I, CN, NO2, (CF2)rCF3, (CH2)rOC1-5 alkyl, OH, SH, (CH2)rSC1-5 alkyl, (CH2)rNR9fR9f, and (CH2)rphenyl;
• alternatively, R11 and R12 join to form C3-7 cycloalkyl;
• R14 is selected from C1-4 alkyl, C2-8 alkenyl, C2-8 alkynyl, (CH2)rC3-6 cycloalkyl, C(O)NR14aR14a′, C(O)R14b, C(O)OC1-4 alkyl, (CH2)rS(O)pR14b, (CH2)rphenyl substituted with 0-3 R14c, OR14a, NR14aR14a′, ═O, and NR14aC(O)R14a′;
• R14aand R14a′, at each occurrence, are selected from H, C1-6 alkyl, (CH2)rC3-6 cycloalkyl, and (CH2)rphenyl substituted with 0-3 R14c, and a (CH2)r-5-10 membered heterocyclic system containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-2 R14c;
• R14b, at each occurrence, is selected from C1-6 alkyl, (CH2)rC3-6 cycloalkyl, and (CH2)rphenyl substituted with 0-3 R14c, and a (CH2)r-5-10 membered heterocyclic system containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-2 R14c;
• and
• R14c, at each occurrence, is selected from C1-6 alkyl, (CH2)rC3-6 cycloalkyl, Cl, F, Br, I, CN, NO2, (CF2)rCF3, (CH2)rOC1-5 alkyl, OH, (CH2)wphenyl;
• R15, at each occurrence, is selected from C1-8 alkyl, (CH2)rC3-6 cycloalkyl, Cl, Br, I, F, NO2, CN, (CHR′)rNR15aR15a′, (CHR′)rOH, (CHR′)rO(CHR′)rR15d, (CHR′)rSH, (CHR′)rC(O)H, (CHR′)rS(CHR′)rR15d, (CHR′)rC(O)OH, (CHR′)rC(O) (CHR′)rR15b, (CHR′)rC(O)NR15aR15a′, (CHR′)rNR15fC(O) (CHR′)rR15b, (CHR′)rNR15fC(O)NR15aR15a′, (CHR′)rC(O)O(CHR′)rR15d, (CHR′)rOC(O) (CHR′)rR15b, (CHR′)rC(═NR15f)NR15aR15a′, (CHR′)rNHC(═NR15f)NR15aR15a′, (CHR′)rS(O)p(CHR′)rR15b, (CHR′)rS(O)2NR15aR15a′, (CHR′)rNR15fS(O)2(CHR′)rR15b, C1-6 haloalkyl, C2-8 alkenyl substituted with 0-3 R′, C2-8 alkynyl substituted with 0-3 R′, (CHR′)rphenyl substituted with 0-3 R15e, and a (CH2)r-5-10 membered heterocyclic system containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-2 R15e;
• R′, at each occurrence, is selected from H, C1-6 alkyl, C2-8 alkenyl, C2-8 alkynyl, (CH2)rC3-6 cycloalkyl, and (CH2)rphenyl substituted with R15e;
• R15aand R15a′, at each occurrence, are selected from H, C1-6 alkyl, C3-8 alkenyl, C3-8 alkynyl, a (CH2)r-C3-10 carbocyclic residue substituted with 0-5 R15e, and a (CH2)r-5-10 membered heterocyclic system containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-2 R15e;
• R15b, at each occurrence, is selected from C1-6 alkyl, C2-8 alkenyl, C2-8 alkynyl, a (CH2)r-C3-6 carbocyclic residue substituted with 0-3 R15e, and (CH2)r-5-6 membered heterocyclic system containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-2 R15e;
• R15d, at each occurrence, is selected from C3-8 alkenyl, C3-8 alkynyl, methyl, CF3, C2-6 alkyl substituted with 0-3 R15e, a (CH2)r-C3-10 carbocyclic residue substituted with 0-3 R15e, and a (CH2)r5-6 membered heterocyclic system containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-3 R15e;
• R15e, at each occurrence, is selected from C1-6 alkyl, C2-8 alkenyl, C2-8 alkynyl, (CH2)rC3-6 cycloalkyl, Cl, F, Br, I, CN, NO2, (CF2)rCF3, (CH2)rOC1-5 alkyl, OH, SH, (CH2)rSC1-5 alkyl, (CH2)rNR15fR15f, and (CH2)rphenyl;
• R15f, at each occurrence, is selected from H, C1-6 alkyl, C3-6 cycloalkyl, and phenyl;
• R16, at each occurrence, is selected from C1-8 alkyl, C2-8 alkenyl, C2-8 alkynyl, (CH2)rC3-6 cycloalkyl, Cl, Br, I, F, NO2, CN, (CHR′)rNR16aR16a′, (CHR′)rOH, (CHR′)rO(CHR′)rR16d, (CHR′)rSH, (CHR′)rC(O)H, (CHR′)rS(CHR′)rR16d, (CHR′)rC(O)OH, (CHR′)rC(O) (CHR′)rR16b, (CHR′)rC(O)NR16aR16a′, (CHR′)rNR16fC(O) (CHR′)rR16b, (CHR′)rC(O)0(CHR′)rR16d, (CHR′)rOC(O) (CHR′)rR16b, (CHR′)rC(═NR16f)NR16aR16a, (CHR′)rNHC(═NR16f)NR16aR16a′, (CHR′)rS(O)p(CHR′)rR16b, (CHR′)rS(O)2NR16aR16a′, (CHR′)rNR16fS(O)2(CHR′)rR16b, C1-6 haloalkyl, C2-8 alkenyl substituted with 0-3 R′, C2-8 alkynyl substituted with 0-3 R′, and (CHR′)rphenyl substituted with 0-3 R16e;
• R16aand R16a′, at each occurrence, are selected from H, C1-6 alkyl, C3-8 alkenyl, C3-8 alkynyl, a (CH2)r-C3-10 carbocyclic residue substituted with 0-5 R16e, and a (CH2)r-5-10 membered heterocyclic system containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-2 R16e;
• R16b, at each occurrence, is selected from C1-6 alkyl, C2-8 alkenyl, C2-8 alkynyl, a (CH2)rC3-6 carbocyclic residue substituted with 0-3 R16e, and a (CH2)r-5-6 membered heterocyclic system containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-2 R16e;
• R16d, at each occurrence, is selected from C3-8 alkenyl, C3-8 alkynyl, methyl, CF3, C2-6 alkyl substituted with 0-3 R16e, a (CH2)r-C3-10 carbocyclic residue substituted with 0-3 R16e, and a (CH2)r-5-6 membered heterocyclic system containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-3 R16e;
• R16e, at each occurrence, is selected from C1-6 alkyl, C2-8 alkenyl, C2-8 alkynyl, (CH2)rC3-6 cycloalkyl, Cl, F, Br, I, CN, NO2, (CF2)rCF3, (CH2)rOC1-5 alkyl, OH, SH, (CH2)rSC1-5 alkyl, (CH2)rNR16fR16f, and (CH2)rphenyl;
• R16f, at each occurrence, is selected from H, C1-5 alkyl, and C3-6 cycloalkyl, and phenyl;
• R17, is selected from H, C1-6 alkyl, C2-8 alkenyl, C2-8 alkynyl, (CHR′)rOH, (CHR′)rSH, (CHR′)rOR17d, (CHR′)rSR17d, (CHR′)rNR17aR17a′, (CHR′)rC(O)OH, (CHR′)rC(O)R17b, (CHR′)rC(O)NR17aR17a′, (CHR′)rNR17aC(O)R17b, (CHR′)rNR17aC(O)H, (CHR′)rC(O)OR17a, (CHR′)rOC(O)R17b, (CHR′)rS(O)pR17b, (CHR′)rS(O)2NR17aR17a′, (CHR′)rNR17aS(O)2R17b, C1-6 haloalkyl, a (CHR′)r-C3-10 carbocyclic residue substituted with 0-3 R17c, and a (CHR′)r-5-10 membered heterocyclic system containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-2 R17c;
• R17aand R17a′, at each occurrence, are selected from H, C1-6 alkyl, C3-8 alkenyl, C3-8 alkynyl, a (CH2)r-C3-10 carbocyclic residue substituted with 0-5 R17e, and a (CH2)r-5-10 membered heterocyclic system containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-3 R17e;
• R17b, at each occurrence, is selected from C1-6 alkyl, C2-8 alkenyl, C2-8 alkynyl, a (CH2)r-C3-6 carbocyclic residue substituted with 0-2 R17e, and a (CH2)r-5-6 membered heterocyclic system containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-3 R17e;
• R17c, at each occurrence, is selected from C1-6 alkyl, C2-8 alkenyl, C2-8 alkynyl, (CH2)rC3-6 cycloalkyl, Cl, Br, I, F, (CF2)rCF3, NO2, CN, (CH2)rNR17fR17f, (CH2)rOH, (CH2)rOC1-4 alkyl, (CH2)rSC1-4 alkyl, (CH2)rC(O)OH, (CH2)rC(O)R17b, (CH2)rC(O)NR17fR17f, (CH2)rNR17fC(O)R17a, (CH2)rC(O)OC1-4 alkyl, (CH2)rOC(O)R17b, (CH2)rC(═NR17f)NR17fR17f, (CH2)rS(O)pR17b, (CH2)rNHC(═NR17f)NR17fR17f, (CH2)rS(O)2NR17fR17f, (CH2)rNR17fS(O)2R17b, and (CH2)rphenyl substituted with 0-3 R17e;
• R17d, at each occurrence, is selected from methyl, CF3, C1-6 alkyl substituted with 0-3 R17e, C3-6 alkenyl, C3-6 alkynyl, and a C3-10 carbocyclic residue substituted with 0-3 R17c;
• R17e, at each occurrence, is selected from C1-6 alkyl, C2-8 alkenyl, C2-8 alkynyl, C3-6 cycloalkyl, Cl, F, Br, I, CN, NO2, (CF2)rCF3, (CH2)rOC1-5 alkyl, OH, SH, (CH2)rSC1-5 alkyl, (CH2)rNR17fR17f, and (CH2)rphenyl;
• R17f, at each occurrence, is selected from H, C1-6 alkyl, and C3-6 cycloalkyl;
• R18, is selected from H, C1-6 alkyl, C2-8 alkenyl, C2-8 alkynyl, (CHR′)qOH, (CHR′)qSH, (CHR′)qOR18d, (CHR′)qSR18d, (CHR′)qNR18aR18a′, (CHR′)rC(O)OH, (CHR′)rC(O)R18b, (CHR′)rC(O)NR18aR18a′, (CHR′)qNR18aC(O)R18b, (CHR′)qNR18aC(O)H, (CHR′)rC(O)OR18a, (CHR′)qOC(O)R18b, (CHR′)qS(O)pR18b, (CHR′)qS(O)2NR18aR18a′, (CHR′)qNR18aS(O)2R18b, C1-6 haloalkyl, a (CHR′)r-C3-10 carbocyclic residue substituted with 0-3 R18c, and a (CHR′)r-5-10 membered heterocyclic system containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-2 R18c;
• R18aand R18a′, at each occurrence, are selected from H, C1-6 alkyl, C3-8 alkenyl, C3-8 alkynyl, a (CH2)r-C3-10 carbocyclic residue substituted with 0-5 R18e, and a (CH2)r-5-10 membered heterocyclic system containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-3 R18e;
• R18b, at each occurrence, is selected from C1-6 alkyl, C2-8 alkenyl, C2-8 alkynyl, a (CH2)r-C3-6 carbocyclic residue substituted with 0-2 R18e, and a (CH2)r-5-6 membered heterocyclic system containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-3 R18e;
• R18c, at each occurrence, is selected from C1-6 alkyl, C2-8 alkenyl, C2-8 alkynyl, (CH2)rC3-6 cycloalkyl, Cl, Br, I, F, (CF2)rCF3, NO2, CN, (CH2)rNR18fR18f, (CH2)rOH, (CH2)rOC1-4 alkyl, (CH2)rSC1-4 alkyl, (CH2)rC(O)OH, (CH2)rC(O)R18b, (CH2)rC(O)NR18fR18f, (CH2)rNR18fC(O)R18b, (CH2)rC(O)OC1-4 alkyl, (CH2)rOC(O)R18b, (CH2)rC(═NR18f)NR18fR18f, (CH2)rS(O)pR18b, (CH2)rNHC(═NR18f)NR18fR18f, (CH2)rS(O)2NR18fR18f, (CH2)rNR18fS(O)2R18b, and (CH2)rphenyl substituted with 0-3 R18e;
• R18d, at each occurrence, is selected from methyl, CF3, C1-6 alkyl substituted with 0-3 R18e, C3-6 alkenyl, C3-6 alkynyl, and a C3-10 carbocyclic residue substituted with 0-3 R18c;
• R18e, at each occurrence, is selected from C1-6 alkyl, C2-8 alkenyl, C2-8 alkynyl, C3-6 cycloalkyl, Cl, F, Br, I, CN, NO2, (CF2)rCF3, (CH2)rOC1-5 alkyl, OH, SH, (CH2)rSC1-5 alkyl, (CH2)rNR18fR18f, and (CH2)rphenyl;
• R18f, at each occurrence, is selected from H, C1-6 alkyl, and C3-6 cycloalkyl;
• a is selected from 0 and 1;
• b is selected from 0 and 1, wherein if a=0, then b=1;
• c is selected from 0, 1, and 2;
• d is selected from 0, 1, and 2, wherein c+d equals 1 or 2;
• provided that if b=1, c=1, and d=1 then E cannot be —(CR7R8)—(CR9CR10)v—(CR11CR12)—;
• e is selected from 0 and 1;
• f is selected from 0 and 1, wherein e+f equals 1 or 2;
• g is selected from 0, 1, 2 and 3;
• h is selected from 0 and 1;
• i is selected from 1, 2, 3, 4, and 5;
• j is selected from 0, 1, 2, 3, 4, and 5;
• k is selected from 0, 1, and 2;
• l is selected from 0, 1, 2 and 3, wherein 1+h equals 2 or 3;
• v, at each occurrence, is independently selected from 0, 1, and 2;
• t, at each occurrence, is selected from 1 and 2;
• w, at each occurrence, is selected from 0 and 1;
• r, at each occurrence, is selected from 0, 1, 2, 3, 4, and 5;
• s, at each occurrence, is selected from 0, 1, 2, 3, 4, and 5;
• q, at each occurrence, is selected from 1, 2, 3, 4, and 5;
• and
• p, at each occurrence, is selected from 1 and 2.