Benzylcycloalkyl amines as modulators of chemokine receptor activity

A compound of formula (I):

• or stereoisomers or pharmaceutically acceptable salts thereof, wherein:
• A is
• G is selected from —C(O)R3, —C(O)NR2R3, —C(O)OR3, —SO2NR2R3, —SO2R3, —C(═S)NR2R3, C(═NR1a)NR2R3, C(═CHCN)NR2R3, C(═CHNO2)NR2R3, and C(═C)(CN)2)NR2R3;
• W, at each occurrence, is independently selected from C or N, provided at least two of W are C;
• X is NR19;
• X1 and X2 are independently selected from C and N;
• Z1 is selected from C and N;
• Z2 is selected from NR1a, O, S and C;
• 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;
• R1a is independently selected from H, C1-6 alkyl, (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, (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 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, R2 and R3 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 hydrogen, C1-8 alkyl, C2-8 alkenyl, C2-8 alkynyl, (CH2)rC3-6 cycloalkyl, and a (CH2)r—C3-10 carbocyclic residue substituted with 0–5 Ra;
• alternatively, R4 joins with R8 or R11 to form a pyrrolidine or piperidine ring system substituted with 0–3 R4d;
• R4′ 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, 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;
• R4a and 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;
• R4d, is selected from H, C1-6 alkyl, (CHR′)qOH, (CHR′)qOR7a, (CHR′)qOC(O)R7b, (CHR′)qOC(O)NHR7a;
• R5 is selected from a (CR5′R5″)b —C3-10 carbocyclic residue substituted with 0–5 R16 and a (CR5′R5″) t-5–10 membered heterocyclic system containing 1–4 heteroatoms selected from N, O, and S, substituted with 0–3 R16 ;
• R5′ and R5″, at each occurrence, are selected from H, C1-6 alkyl, (CH2)rC3-6 cycloalkyl, and phenyl;
• 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;
• R15a and 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)O(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;
• R16a and 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, (CH2)qOH, (CH2)qSH, (CH2)qOR17d, (CH2)qSR17d, (CH2)qNR17aR17a′, (CH2)rC(O)OH, (CH2)rC(O)R17b, (CH2)rC(O)NR17aR17a′, (CH2)qNR17aC(O)R17b, (CH2)qNR17aC(O)H, (CH2)rC(O)OR17a, (CH2)qOC(O)R17b, (CH2)qS(O)pR17b, (CH2)qS(O)2NR17aR17a′, (CH2)qNR17aS(O)2R17b, C1-6 haloalkyl, a (CH2)r—C3-10 carbocyclic residue substituted with 0–3 R17c, and a (CH2)r-5–10 membered heterocyclic system containing 1–4 heteroatoms selected from N, O, and S, substituted with 0–2 R17c;
• R17a and 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)rC3-6 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, C2-6 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)R18a;
• (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;
• R18a and R18a′, at each occurrence, are selected from H, C1-6 alkyl, C3-8 alkenyl, C3-8 alkynyl, a (CH2)rC3-10 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)R18a, (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, C2-6 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;
• R19 is selected from C1-8 alkyl, C3-8 alkenyl, C3-8 alkynyl, —C(O)R19b, —C(O)NR19aR19a, —C(O)OR19a, and —SO2R19a, a (CHR′)r—C3-10 carbocyclic residue substituted with 0–3 R16, and a (CHR′)r-5–10 membered heterocyclic system containing 1–4 heteroatoms selected from N, O, and S, substituted with 0–2 R16;
• R19a is selected from C1-8 alkyl, C3-8 alkenyl, C3-8 alkynyl, C3-6 cycloalkyl, a (CR5′5R5″)t—C3-10 carbocyclic residue substituted with 0–5 R16 and a —(CR5′R5″)r-5–10 membered heterocyclic system containing 1–4 heteroatoms selected from N, O, and S, substituted with 0–3 R16;
• R19b is selected from H, C1-8 alkyl, C3-8 alkenyl, C3-8 alkynyl, C3-6 cycloalkyl, a (CR5′R5″)t—C3-10 carbocyclic residue substituted with 0–5 R16 and a (CR5′R5″)r-5–10 membered heterocyclic system containing 1–4 heteroatoms selected from N, O, and S, substituted with 0–3 R16;
• n, at each occurrence, is selected from 0, 1, 2, 3, 4, and 5;
• o, at each occurrence, is selected from 1 and 2;
• p, at each occurrence, is selected from 1 and 2;
• r, 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;
• s, at each occurrence, is selected from 0, 1, and 2;
• t, at each occurrence, is selected from 0, 1, 2, 3, 4, and 5;
• and
• u, at each occurrence, is independently selected from 0, 1, and 2.