Piperizinones as modulators of chemokine receptor activity

A compound of formula (I):

• 118
• or stereoisomers or pharmaceutically acceptable salts thereof, wherein:
• Ring D is a 6-membered ring heterocycle wherein B is O, S, or NR17 with the heterocycle further containing at least one carbonyl or sulfonyl therein;
• R4 is selected from H, R5 and R13;
• R17 is selected from H, R5 and R18;
• with the proviso that Ring D contains at least one R5;
• Z is selected from 0 S, NR1a, C(CN)2, CH(NO2), and CHCN;
• R1a is selected from H, C1-6 alkyl, C3-6 cycloalkyl, CONR1bR1b, OR1b, CN, NO2, and (CH2)wphenyl;
• R1b is independently selected from H, C1-3 alkyl, C3-6 cycloalkyl, and phenyl;
• E is —(CR7CR8)—(CR9R10)v—(CR11R12), —(C═O)—(CR9R10)v—(CR11R12)—, —(SO2)—(CR9R10)v—(CR11R12)—,
• 119 120
• Ring A is a C3-8 carbocyclic residue;
• R1 and R2 are independently selected from H, C1-8 alkyl, C3-8 alkenyl, C3-8 alkynyl, and a (CH2)r—C3-10 carbocyclic residue substituted with 0-5 Ra;
• Ra, at each occurrence, is independently selected from C1-4 alkyl, C2-8 alkenyl, C2-8 alkynyl, (CH2)rC3-6 cycloalkyl, Cl, Br, I, F, (CF2)rCF3, NO2, CN, (CH2)rNRbRb, (CH2)rOH, (CH2)rORC, (CH2)rSH, (CH2)rSRC, (CH2)rC(O)Rb, (CH2)rC(O)NRbRb, (CH2)rNRbC(O)Rb, (CH2)rC(O)ORb, (CH2)rOC(O)RC, (CH2)rCH(═NRb)NRbRb, (CH2)rNHC(═NRb)NRbRb, (CH2)rS(O)pRC, (CH2)rS(O)2NRbRb, (CH2)rNRbS(O)2RC, and (CH2)rphenyl;
• Rb, at each occurrence, is independently selected from H, C1-6 alkyl, C3-6 cycloalkyl, and phenyl;
• Rc, at each occurrence, is independently selected from C1-6 alkyl, C3-6 cycloalkyl, and phenyl;
• R3 is selected from a (CR3aR3b)r—C3-8 carbocyclic residue substituted with 0-5 R15;
• and a (CR3aR3b)r-5-10 membered heterocyclic system containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-3 R15;
• R3a and R3b, at each occurrence, are independently selected from H, C1-6alkyl, (CH2)rC3-6 cycloalkyl, and phenyl;
• R5 is selected from a (CR5aR5b)t—C3-10 carbocyclic residue substituted with 0-5 R16 and a (CR5aR5b)t-5-10 membered heterocyclic system containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-3 R16;
• R5a and R5b, at each occurrence, are selected from H, C1-6 alkyl, (CH2)rC3-6 cycloalkyl, and phenyl;
• R7, is selected from H, C1-6 alkyl, C2-8 alkenyl, C2-8 alkynyl, (CH2)qOH, (CH2)qSH, (CH2)qOR7d, (CH2)qSR7d, (CH2)qNR7aR7a, (CH2)rC(O)OH, (CH2)rC(O)R7b, (CH2)rC(O)NR7aR7a, (CH2)qNR7aC(O)R7a, (CH2)qNR7aC(O)H, (CH2)rC(O)OR7b, (CH2)qOC(O)R7b, (CH2)qS(O)pR7b, (CH2)qS(O)2NR7aR7a, (CH2)qNR7aS(O)2R7b, C1-6 haloalkyl, a (CH2)r—C3-10 carbocyclic residue substituted with 0-3 R7c, and a (CH2)r-5-10 membered heterocyclic system containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-2 R7c;
• R7a, at each occurrence, is independently selected from H, C1-6 alkyl, C2-8 alkenyl, C2-8 alkynyl, (CH2)rC3-6 cycloalkyl, a (CH2)r—C3-10 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 independently 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 independently 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)R7a, (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 independently selected from methyl, CF3 C2-6 alkyl substituted with 0-3 R7e, alkenyl, alkynyl, and a C3-10 carbocyclic residue substituted with 0-3 R7c;
• R7e, at each occurrence, is independently 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 independently 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 independently 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)rNR8fR8f, and (CH2)rphenyl;
• alternatively, R7 and R8 join to form C3-7 cycloalkyl, or ═NR8b;
• R8b is selected from H, C1-6 alkyl, C3-6 cycloalkyl, OH, CN, and (CH2)r-phenyl;
• R8f, at each occurrence, is independently selected from H, C1-6 alkyl, and C3-6 cycloalkyl;
• R9, is selected from H, C1-6 alkyl, C2-8 alkenyl, C2-8 alkynyl, F, Cl, Br, I, NO2, CN, (CHR′)rOH, (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′)rC(O)OR9b, (CHR′)rOC(O)R9b, (CHR′)rOC(O)NR9aR9a, (CHR′)rNR9aC(O)OR9b, (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;
• R9a at each occurrence, is independently 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-4-10 membered heterocyclic system containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-3 R9e;
• alternatively, two R9 as, along with the N to which they are attached, join to form a 5-6 membered heterocyclic system containing 1-2 heteroatoms selected from NR99, O, and S and optionally fused with a benzene ring or a 6-membered aromatic heterocycle;
• R9b, at each occurrence, is independently selected from C1-6 alkyl, C3-8 alkenyl, C3-8 alkynyl, a (CH2)r—C3-6 carbocyclic residue substituted with 0-2 R9e, and a (CH2)r-4-6 membered heterocyclic system containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-3 R9e;
• R9c, at each occurrence, is independently 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)rOR9b, (CH2)rSR9b, (CH2)rC(O)OH, (CH2)rC(O)R9b, (CH2)rC(O)NR9fR9f, (CH2)rNR9fC(O)R9b, (CH2)rC(O)OR9b, (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 independently selected from methyl, CF3, C2-6 alkyl residue 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 independently 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, wherein the phenyl on the (CH2)rphenyl is substituted with 0-5 substituents selected from F, Cl, Br, I, NO2, C1-6alkyl, OH, and NR9fR9f;
• R9f, at each occurrence, is independently selected from H, C1-6 alkyl, and C3-6 cycloalkyl;
• R9g is selected from H, C1-6 alkyl, C3-6 cycloalkyl, (CH2)rphenyl, C(O)R9f, C(O)OR9h, and SO2R9h;
• R9h, at each occurrence, is independently selected from 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, (CHR′)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)OR10b, (CH2)rOC(O)R10b, (CH2)rOC(O)NR10aR10a, (CH2)rNR10aC(O)OR10b, (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, at each occurrence, is independently 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-4-10 membered heterocyclic system containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-3 R10e;
• alternatively, two R10as, along with the N to which they are attached, join to form a 5-6 membered heterocyclic system containing 1-2 heteroatoms selected from NR10g, O, and S and optionally fused with a benzene ring or a 6-membered aromatic heterocycle;
• R10b, at each occurrence, is independently selected from C1-6 alkyl, C3-8 alkenyl, C3-8 alkynyl, a (CH2)r—C3-6 carbocyclic residue substituted with 0-2 R10e, and a (CH2)r-4-6 membered heterocyclic system containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-3 R10e;
• R10c, at each occurrence, is independently 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)rOR10b, (CH2)rSR10b, (CH2)rC(O)OH, (CH2)rC(O)R10b, (CH2)rC(O)NR10fR10f, (CH2)rNR10fC(O)R10a, (CH2)rC(O)OR10b, (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 independently selected from methyl, CF3, C2-6 alkyl substituted with 0-3 R10e, C3-6 alkenyl, C3-6 alkynyl, and a C3-10 carbocyclic residue substituted with 0-3 R10c;
• R10e, at each occurrence, is independently 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)rSC1-15 alkyl, (CH2)rNR10fR10f, and (CH2)rphenyl;
• R10f, at each occurrence, is independently selected from H, C1-6 alkyl, and C3-6 cycloalkyl;
• R10g is selected from H, C1-6 alkyl, C3-6 cycloalkyl, (CH2)rphenyl, C(O)R10f, SO2R10h, and C(O)O R10h;
• R10h, at each occurrence, is independently selected from H, C1-6 alkyl, C3-6 cycloalkyl;
• alternatively, R9 and R10 join to form ═O, a C3-10 cycloalkyl, a 5-6-membered lactone or lactam, or a 4-6-membered saturated heterocycle containing 1-2 heteroatoms selected from O, S, and NR10g and optionally fused with a benzene ring or a 6-membered aromatic heterocycle;
• R11, is selected from H, C1-6 alkyl, C2-8 alkenyl, C2-8 alkynyl, (CR′R′)qOH, (CH2)qSH, (CR′R′)qOR11d, (CHR′)qSR11d, (CR′R′)qNR11aR11a, (CHR′)rC(O)OH, (CHR′)rC(O)R11b, (CHR′)rC(O)NR11aR11a, (CHR′)qNR11aC(O)R11a, (CHR′)qOC(O)NR11aR11a, (CHR′)qNR11aC(O)OR11b, (CHR′)qNR11aC(O)NHR11a, (CHR′)rC(O)OR11b, (CHR′)qOC(O)R11b, (CHR′)qS(O)pR11b, (CHR′)qS(O)2NR11aR11a, (CHR′)qNR11aS(O)2R11b, C1-6 haloalkyl, a (CHR′)r—C3-10 carbocyclic residue substituted with 0-5 R11c, and a (R′R17)r-5-10 membered heterocyclic system containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-3 R11c;
• R11a, at each occurrence, is independently 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;
• alternatively, two R11as, along with the N to which they are attached, join to form a 5-6 membered heterocyclic system containing 1-2 heteroatoms selected from NR11g, O, and S and optionally fused with a benzene ring or a 6-membered aromatic heterocycle;
• R11b, at each occurrence, is independently selected from C1-6 alkyl, C3-8 alkenyl, C3-8 alkynyl, a (CH2)r—C3-6 carbocyclic residue substituted with 0-2 R11e, and a (CH2)r-4-6 membered heterocyclic system containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-3 R11e;
• R11c, at each occurrence, is independently 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 independently 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 independently 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, wherein the phenyl on the (CH2)rphenyl is substituted with 0-5 substituents selected from F, Cl, Br, I, NO2, C1-6alkyl, OH, and NR11fR11f;
• R11f, at each occurrence, is independently selected from H, C1-6 alkyl, and C3-6 cycloalkyl;
• R11g is selected from H, C1-6 alkyl, C3-6 cycloalkyl, (CH2)rphenyl, C(O)R11f, C(O)OR11h, and SO2R11h;
• R11h, at each occurrence, is independently selected from C1-6 alkyl, and C3-6 cycloalkyl;
• R12, is selected from H, C1-6 alkyl, C2-8 alkenyl, C2-8 alkynyl, (CHR′)qOH, (CH2)qSH, (CHR′)qOR12d, (CH2)qSR12d, (CHR′)qNR12aR12a, (CH2)rC(O)OH, (CH2)rC(O)R12b, (CH2)rC(O)NR12aR12a, (CH2)qNR12aC (O)R12a, (CH2)rOC(O)NR12aR12a, (CH2)rNR12aC (O)OR12b, (CH2)qNR12aC (O)NHR12a, (CH2)rC(O)OR12b, (CH2)qOC(O)R12b, (CH2)qS(O)pR12b, (CH2)qS(O)2NR12aR12a, (CH2)qNR12aS(O)2R12b, C1-6 haloalkyl, a (CH2)r—C3-10 carbocyclic residue substituted with 0-5 R12c, and a (CR′R17)r-5-10 membered heterocyclic system containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-3 R12c;
• R12a, at each occurrence, is independently selected from H, C1-6 alkyl, C3-8 alkenyl, C3-8 alkynyl, a (CH2)r—C3-10 carbocyclic residue substituted with 0-5 R12e, and a (CH2)r-4-10 membered heterocyclic system containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-3 R12e;
• alternatively, two R12aS, along with the N to which they are attached, join to form a 5-6 membered heterocyclic system containing 1-2 heteroatoms selected from NR12g, O, and S and optionally fused with a benzene ring or a 6-membered aromatic heterocycle;
• R12b at each occurrence, is independently selected from C1-6 alkyl, C3-8 alkenyl, C3-8 alkynyl, a (CH2)r—C3-6 carbocyclic residue substituted with 0-2 R12e, and a (CH2)r-4-6 membered heterocyclic system containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-3 R12e;
• R12c, at each occurrence, is independently selected from C1-6 alkyl, C2-8 alkenyl, C2-8 alkynyl, (CH2)rC3-6 cycloalkyl, Cl, Br, I, F, (CF2)rCF3, NO2, CN, (CH2)rNR12fR12f, (CH2)rOH, (CH2)rOC1-4 alkyl, (CH2)rSC1-4 alkyl, (CH2)rC(O)OH, (CH2)rC(O)R12b, (CH2)rC(O)NR12fR12f, (CH2)rNR12fC(O)R12a, (CH2)rC(O)OC1-4 alkyl, (CH2)rOC(O)R12b, (CH2)rC(═NR12f)NR12fR12f, (CH2)rNHC(═NR12f)NR12R12f, (CH2)rS(O)pR12b, (CH2)rS(O)2NR12fR12f, (CH2)rNR12fS(O)2R12b, and (CH2)rphenyl substituted with 0-3 R12e;
• R12d, at each occurrence, is independently selected from methyl, CF3, C2-6 alkyl substituted with 0-3 R12e, C3-6 alkenyl, C3-6 alkynyl, and a C3-10 carbocyclic residue substituted with 0-3 R12c;
• R12e, at each occurrence, is independently 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)rNR12fR12f, and (CH2)rphenyl;
• R12f, at each occurrence, is independently selected from H, C1-6 alkyl, and C3-6 cycloalkyl;
• R12g is selected from H, C1-6 alkyl, C3-6 cycloalkyl, (CH2)rphenyl, C(O)R12f, C(O)OR12h, and SO2R12h;
• R12h, at each occurrence, is independently selected from C1-6 alkyl, and C3-6 cycloalkyl;
• alternatively, R11 and R12 join to form a C3-10 cycloalkyl, a 5-6-membered lactone or lactam, or a 4-6-membered saturated heterocycle containing 1-2 heteroatoms selected from O, S, and NR11 g and optionally fused with a benzene ring or a 6-membered aromatic heterocycle;
• R13, at each occurrence, is independently selected from C1-6 alkyl, C2-8 alkenyl, C2-8 alkynyl, C3-6 cycloalkyl, (CF2)wCF3, (CH2)qNR13aR13a, (CHR′)qOH, (CH2)qOR13b, (CH2)qSH, (CH2)qSR13b, (CH2)wC(O)OH, (CH2)wC(O)R13b, (CH2)wC(O)NR13aR13a, (CH2)qNR13dC(O)R13a, (CH2)wC(O)OR13b, (CH2)qOC(O)R13b, (CH2)wS(O)pR13b, (CH2)wS(O)2NR13aR13a, (CH2)qNR13dS(O)2R13b, and (CH2)w-phenyl substituted with 0-3 R13c;
• R13a, at each occurrence, is independently selected from H, C1-6 alkyl, C3-6 cycloalkyl, and phenyl substituted with 0-3 R13c;
• R13b, at each occurrence, is independently selected from C1-6 alkyl, C3-6 cycloalkyl, and phenyl substituted with 0-3 R13c;
• R13c, at each occurrence, is independently selected from C1-6 alkyl, C3-6 cycloalkyl, Cl, F, Br, I, CN, NO2, (CF2)rCF3, (CH2)rOC1-5 alkyl, (CH2)rOH, (CH2)rSC1-5 alkyl, and (CH2)rNR13dR13d;
• R13d, at each occurrence, is independently selected from H, C1-6 alkyl, and C3-6 cycloalkyl;
• R14, at each occurrence, is independently selected from H, C1-6 alkyl, C2-8 alkenyl, C2-8 alkynyl, (CH2)rC3-6 cycloalkyl, Cl, Br, I, F, NO2, CN, (CHR′)rNR14aR14a, (CHR′)rOH, (CHR′)rO(CHR′)rR14d, (CHR′)rSH, (CHR′)rC(O)H, (CHR′)rS(CHR′)rR14d, (CHR′)rC(O)OH, (CHR′)rC(O)(CHR′)rR14b, (CHR′)rC(O)NR14aR14a, (CHR′)rNR14fC(O) (CHR′)rR14b, (CHR′)rOC(O)NR14aR14a, (CHR′)rNR14fC(O)O(CHR′)rR14b, (CHR′)rC(O)O(CHR′)rR14d, (CHR′)rOC(O) (CHR′)rR14b, (CHR′)rC(═NR14f)NR14aR14a, (CHR′)rNHC(═NR14f)NR14fR14f, (CHR′)rS(O)p(CHR′)rR14b, (CHR′)rS(O)2NR14aR14a, (CHR′)rNR14fS(O)2(CHR′)rR14b, 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 R14e, and a (CH2)r-4-10 membered heterocyclic system containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-2 R15e, or two R14 substituents on adjacent atoms on ring A form to join a 5-6 membered heterocyclic system containing 1-3 heteroatoms selected from N, O, and S substituted with 0-2 R15e;
• R14a, at each occurrence, is independently selected from H, C1-6 alkyl, C3-8 alkenyl, C3-8 alkynyl, a (CH2)r—C3-10 carbocyclic residue substituted with 0-5 R14e, and a (CH2)r-4-10 membered heterocyclic system containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-2 R14e;
• R14b, at each occurrence, is independently selected from C1-6 alkyl, C3-8 alkenyl, C3-8 alkynyl, a (CH2)r—C3-6 carbocyclic residue substituted with 0-3 R14e, and (CH2)r-4-6 membered heterocyclic system containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-2 R14e;
• R14d, at each occurrence, is independently selected from C3-8 alkenyl, C3-8 alkynyl, methyl, CF3, C2-6 alkyl substituted with 0-3 R14e, a (CH2)r—C3-10 carbocyclic residue substituted with 0-3 R14e, and a (CH2)r4-6 membered heterocyclic system containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-3 R14e;
• R14e, at each occurrence, is independently 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)rSC1-15 alkyl, (CH2)rNR14fR14f, and (CH2)rphenyl;
• R14f, at each occurrence, is independently selected from H, C1-6 alkyl, C3-6 cycloalkyl, and phenyl;
• R15, at each occurrence, is independently selected from C1-8 alkyl, (CH2)rC3-6 cycloalkyl, Cl, Br, I, F, NO2, CN, (CR′R′)rNR15aR15a, (CR′R′)rOH, (CR′R′)rO(CHR′)rR15d, (CR′R′)rSH, (CR′R′)rC(O)H, (CR′R′)rS(CHR′)rR15d, (CR′R′)rC(O)OH, (CR′R′)rC(O) (CHR′)rR15b, (CR′R′)rC(O)NR15aR15a, (CR′R′)rNR15fC(O) (CHR′)rR15b (CR′R′)rOC(O)NR15aR15a, (CR′R′)rNR15fC(O)O(CHR′)rR15b, (CR′R′)rNR15fC(O)NR15fR15f, (CR′R′)rC(O)O(CHR′)rR15d, (CR′R′)rOC(O) (CHR′)rR15b, (CR′R′)rC(═NR15f)NR15aR15a, (CR′R′)rNHC(═NR15f)NR15fR15f, (CR′R′)rS(O)p(CHR′)rR15b, (CR′R′)rS(O)2NR15aR15a, (CR′R′)rNR15fS(O)2(CHR′)rR15b, C1-6 haloalkyl, C2-8 alkenyl substituted with 0-3 R′, C2-8 alkynyl substituted with 0-3 R′, (CR′R′)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;
• R15a, at each occurrence, is independently 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;
• alternatively, two R15 as, along with the N to which they are attached, join to form a 5-6 membered heterocyclic system containing 1-2 heteroatoms selected from NR15h, O, and S and optionally fused with a benzene ring or a 6-membered aromatic heterocycle;
• R15b, at each occurrence, is independently selected from C1-6 alkyl, C3-8 alkenyl, C3-8 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 independently 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 independently 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, (CH2)rphenyl, and a heterocycle substituted with 0-1 R15g, wherein the heterocycle is selected from imidazole, thiazole, oxazole, pyrazole, 1,2,4-triazole, 1,2,3-triazole, isoxazole, and tetrazole,;
• R15f, at each occurrence, is independently selected from H, C1-6 alkyl, C3-6 cycloalkyl, and phenyl;
• R15g is selected from methyl, ethyl, acetyl, and CF3;
• R15h is selected from H, C1-6 alkyl, C3-6 cycloalkyl, (CH2)rphenyl, C(O)R15f, C(O)OR15i, and SO2R15i;
• R15i, at each occurrence, is independently selected from C1-6 alkyl, C3-6 cycloalkyl;
• R16, at each occurrence, is independently 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)O(CHR′)rR16d, (CHR′)rOC(O) (CHR′)rR16b, (CHR′)rC(═NR16f)NR16aR16a, (CHR′)rNHC(═NR16f)NR16fR16f, (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;
• R16a, at each occurrence, is independently 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 independently selected from C1-6 alkyl, C3-8 alkenyl, C3-8 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 independently 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 independently 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 independently selected from H, C1-5 alkyl, and C3-6 cycloalkyl, and phenyl;
• R′, at each occurrence, is independently selected from H, C1-6 alkyl, C2-8 alkenyl, C2-8 alkynyl, (CH2)rC3-6 cycloalkyl, and (CH2)rphenyl substituted with Re;
• Re 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)rNRfRf, and (CH2)rphenyl;
• Rf is selected from H, C1-5 alkyl, and C3-6 cycloalkyl, and phenyl;
• R18, at each occurrence, is independently selected from H, C1-6 alkyl, C3-6 alkenyl, C3-6 alkynyl, C(O)—C3-6 alkyl, C(O)—C3-6 alkenyl, C(O)—C3-6 alkynyl, (CH2)rC3-6 cycloalkyl, and (CH2)rphenyl substituted with Re;
• R19 is absent, taken with the nitrogen to which it is attached to form an N-oxide, or selected from C1-8 alkyl, C2-8 alkenyl, C2-8 alkynyl, (CH2)rC3-6 cycloalkyl, (CH2)qC(O)R19b, (CH2)qC(O)NR19aR19a, (CH2)qC(O)OR19b, and a (CH2)r—C3-10 carbocyclic residue substituted with 0-3 R19c;
• R19a, at each occurrence, is selected from H, C1-6 alkyl, (CH2)rC3-6 cycloalkyl, and phenyl;
• R19b, at each occurrence, is selected from C1-6 alkyl, C2-8 alkenyl, (CH2)rC3-6 cycloalkyl, C2-8 alkynyl, and phenyl;
• R19c, 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)rNR19aR19a, and (CH2)rphenyl;
• alternatively, R19 joins with R7, R9, or R11 to form a 5, 6 or 7 membered piperidinium spirocycle or pyrrolidinium spirocycle substituted with 0-3 Ra;
• g is selected from 0, 1, 2, and 3;
• v is selected from 0, 1, and 2;
• t is selected from 1 and 2;
• w is selected from 0 and 1;
• r is selected from 0, 1, 2, 3, 4, and 5;
• q is selected from 1, 2, 3, 4, and 5;
• and
• p is selected from 0, 1, and 2.