Cyclic derivatives as modulators of chemokine receptor activity

A compound of formula (I):

• or a stereoisomer or a pharmaceutically acceptable salt thereof, wherein:
• ring B is a cyclohexyl group, ring B being substituted with 0–2 R5;
• X is selected from O or S;
• Z is —NR9—;
• wherein neither Z nor R13 are connected to a carbon atom labeled (b);
• bond (a) is a single bond;
• E is selected from —S(O)pCHRe—, —CHReNRe—, —C(O)—NRe—, —NReC(O)NRe—, —SO2—NRe—, and —NReSO2NRe—;
• Re is independently selected from H and C1-3 alkyl;
• R1 is selected from a C6-10 aryl group substituted with 0–5 R6;
• R2 is selected from a 5–10 membered heteroaryl system containing 1–4 heteroatoms selected from N, O, and S, substituted with 0–3 R7;
• R5, at each occurrence, is independently selected from H, ═O, C1-6 alkyl, C2-8 alkenyl, C2-8 alkynyl, (CRR)rOH, (CRR)rSH, (CRR)rOR5d, ′(CRR)rSR5d, (CRR)rNR5aR5a, (CRR)rN(→O)R5aR5a, N3, (CRR)rC(O)OH, (CRR)rC(O)R5b, (CRR)rC(O)NR5aR5a, (CRR)rNR5aC(O)R5b, (CRR)rOC(O)NR5aR5a, (CRR)rNR5aC(O)OR5d, (CRR)rNR5aC(O)NR5aR5a, (CRR)rNR5aC(O)H, (CRR)rC(O)OR5d, (CRR)rOC(O)R5b, (CRR)rS(O)pR5b, (CRR)rS(O)2NR5aR5a, (CRR)rNR5aS(O)2R5b, (CRR)rNR5aS(O)2NR5aR5a, C1-6 haloalkyl, a (CRR)r—C3-10 carbocyclic residue substituted with 0–3 R5c, and a (CRR)r-5–10 membered heterocyclic system containing 1–4 heteroatoms selected from N, O, and S, substituted with 0–2 R5c;
• R5a, at each occurrence, is independently selected from H, methyl substituted with 0–1 R5g, C2-6 alkyl substituted with 0–2 R5e, C3-8 alkenyl substituted with 0–2 R5e, C3-8 alkynyl substituted with 0–2 R5e, a (CH2)r—C3-10 carbocyclic residue substituted with 0–5 R5e, and a (CH2)r-5–10 membered heterocyclic system containing 1–4 heteroatoms selected from N, O, and S, substituted with 0–3 R5e;
• R5b, at each occurrence, is selected from C1-6 alkyl substituted with 0–3 R5e, C3-8 alkenyl substituted with 0–2 R5e, C3-8 alkynyl substituted with 0–2 R5e, a (CH2)rC3-6 carbocyclic residue substituted with 0–2 R5e, and a (CH2)r-5–6 membered heterocyclic system containing 1–4 heteroatoms selected from N, O, and S, substituted with 0–3 R5e;
• R5c, 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)rNR5fR5f, (CH2)rOH, (CH2)rOC1-4 alkyl, (CH2)rSC1-4 alkyl, (CH2)rC(O)OH, (CH2)rC(O)R5b, (CH2)rC(O)NR5fR5f, (CH2)rOC(O)NR5fR5f, (CH2)rNR5fC(O)R5b, (CH2)rC(O)OC1-4 alkyl, (CH2)rNR5fC(O)OC1-4 alkyl, (CH2)rOC(O)R5b, (CH2)rC(═NR5f)NR5fR5f, (CH2)rS(O)pR5b, (CH2)rNHC(═NR5f)NR5fR5f, (CH2)rS(O)2NR5fR5f, (CH2)rNR5fS(O)2R5b, and (CH2)rphenyl substituted with 0–3 R5e;
• R5d, at each occurrence, is selected from methyl, CF3, C2-6 alkyl substituted with 0–2 R5e, C3-8 alkenyl substituted with 0–2 R5e, C3-8 alkynyl substituted with 0–2 R5e, and a C3-10 carbocyclic residue substituted with 0–3 R5e;
• R5e, 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)rNR5fR5f, and (CH2)rphenyl;
• R5f, at each occurrence, is selected from H, C1-6 alkyl, and C3-6 cycloalkyl;
• R5g is independently selected from —C(O)R5b, —C(O)OR5d, —C(O)NR5fR5f, —CN, and (CH2)rphenyl;
• R, at each occurrence, is selected from H, C1-6 alkyl substituted with R5e, C2-8 alkenyl, C2-8 alkynyl, (CH2)rC3-6 cycloalkyl, and (CH2)rphenyl substituted with R5e;
• R6, 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, (CR′R′)rNR6aR6a, (CR′R′)rOH, (CR′R′)rO(CR′R′)rR6d, (CR′R′)rSH, (CR′R′)rC(O)H, (CR′R′)rS(CR′R′)rR6d, (CR′R′)rSC(O)(CR′R′)rR6b, (CR′R′)rC(O)OH, (CR′R′)rC(O)(CR′R′)rR6b, (CR′R′)rNR6aR6a, (CR′R′)rC(O)NR6aR6a, (CR′R′)rNR6fC(O)(CR′R′)rR6b, (CR′R′)rC(O)O(CR′R′)rR6d, (CR′R′)rOC(O)(CR′R′)rR6b, (CR′R′)rOC(O)NR6a(CR′R′)rR6d, (CR′R′)rNR6aC(O)NR6a(CR′R′)rR6d, (CR′R′)rNR6aC(S)NR6a(CR′R′)rR6d, (CR′R′)rNR6fC(O)O(CR′R′)rR6b, (CR′R′)rC(═NR6f)NR6aR6a, (CR′R′)rNHC(═NR6f)NR6fR6f, (CR′R′)rS(O)p(CR′R′)rR6b, (CR′R′)rS(O)2NR6aR6a, (CR′R′)rNR6fS(O)2NR6aR6a, (CR′R′)rNR6fS(O)2(CR′R′)rR6b, 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 R6e, and a (CH2)r-5–6 membered heterocyclic system containing 1–2 heteroatoms selected from N, O, and S, substituted with 0–2 R6e;
• alternatively, two R6 on adjacent atoms on R1 may join to form a cyclic acetal;
• R6a, at each occurrence, is selected from H, methyl substituted with 0–1 R6g, C2-6 alkyl substituted with 0–2 R6e, C3-8 alkenyl substituted with 0–2 R6e, C3-8 alkynyl substituted with 0–2 R6e, a (CH2)r—C3-10 carbocyclic residue substituted with 0–5 R6e, and a (CH2)r-5–10 membered heterocyclic system containing 1–4 heteroatoms selected from N, O, and S, substituted with 0–2 R6e;
• R6b, at each occurrence, is selected from H, C1-6 alkyl substituted with 0–2 R6e, C3-8 alkenyl substituted with 0–2 R6e, C3-8 alkynyl substituted with 0–2 R6e, a (CH2)rC3-6 carbocyclic residue substituted with 0–3 R6e, and a (CH2)r-5–6 membered heterocyclic system containing 1–4 heteroatoms selected from N, O, and S, substituted with 0–2 R6e;
• R6d, at each occurrence, is selected from C3-8 alkenyl substituted with 0–2 R6e, C3-8 alkynyl substituted with 0–2 R6e, methyl, CF3, C2-6 alkyl substituted with 0–3 R6e, C2-4 haloalkyl, a (CH2)r—C3-10 carbocyclic residue substituted with 0–3 R6e, and a (CH2)r-5–6 membered heterocyclic system containing 1–4 heteroatoms selected from N, O, and S, substituted with 0–3 R6e;
• R6e, 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)rNR6fR6f, and (CH2)rphenyl;
• R6f, at each occurrence, is selected from H, C1–5 alkyl, and C3–6 cycloalkyl, and phenyl;
• R6g is independently selected from —C(O)R6b, —C(O)OR6d, —C(O)NR6fR6f, and (CH2)rphenyl;
• R7, 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, (CR′R′)rNR7aR7a, (CR′R′)rOH, (CR′R′)rO(CR′R′)rR7d, (CR′R′)rSH, (CR′R′)rC(O)H, (CR′R′)rS(CR′R′)rR7d, (CR′R′)rC(O)OH, (CR′R′)rC(O)(CR′R′)rR7b, (CR′R′)rC(O)NR7aR7a, (CR′R′)rNR7fC(O)(CR′R′)rR7b, (CR′R′)rC(O)O(CR′R′)rR7d, (CR′R′)rOC(O)(CR′R′)rR7b, (CR′R′)rOC(O)NR7a(CR′R′)rR7a, (CR′R′)rNR7aC(O)NR7a(CR′R′)rR7a, (CR′R′)rNR7fC(O)O(CR′R′)rR7d, (CR′R′)rC(═NR7f)NR7aR7a, (CR′R′)rNHC(═NR7f)NR7fR7f, (CR′R′)rS(O)p(CR′R′)rR7b, (CR′R′)rS(O)2NR7aR7a, (CR′R′)rNR7aS(O)2NR7aR7a, (CR′R′)rNR7fS(O)2(CR′R′)rR7b, C1–6 haloalkyl, C2-8 alkenyl substituted with 0–3 R′, C2-8 alkynyl substituted with 0–3 R′, (CR′R′)r C3-10 carbocyclic residue and (CR′R′)rphenyl substituted with 0–3 R7e;
• alternatively, two R7 on adjacent atoms on R2 may join to form a cyclic acetal;
• R7a, at each occurrence, is independently selected from H, methyl substituted with 0–1 R7g, C2-6 alkyl substituted with 0–2 R7e, C3-8 alkenyl substituted with 0–2 R7e, C3-8 alkynyl substituted with 0–2 R7e, 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 0–2 R7e;
• R7b, at each occurrence, is selected from C1-6 alkyl substituted with 0–2 R7e, C3-8 alkenyl substituted with 0–2 R7e, C3-8 alkynyl substituted with 0–2 R7e, a (CH2)rC3-6 carbocyclic residue substituted with 0–3 R7e, and a (CH2)r-5–6 membered heterocyclic system containing 1–4 heteroatoms selected from N, O, and S, substituted with 0–2 R7e;
• R7d, at each occurrence, is selected from C3-8 alkenyl substituted with 0–2 R7e, C3-8 alkynyl substituted with 0–2 R7e, methyl, CF3, C2-4 haloalkyl, C2-6 alkyl substituted with 0–3 R7e, a (CH2)rC3-10 carbocyclic residue substituted with 0–3 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;
• R7e, 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, C(O)OC1-5 alkyl, (CH2)rSC1-5 alkyl, (CH2)rNR7fR7f, and (CH2)rphenyl;
• R7f, at each occurrence, is selected from H, C1-5 alkyl, and C3-6 cycloalkyl, and phenyl;
• R7g is independently selected from —C(O)R7b, —C(O)OR7d, —C(O)NR7fR7f, and (CH2)rphenyl;
• R′, at each occurrence, is selected from H, C1-6 alkyl substituted with R6e, C2-8 alkenyl, C2-8 alkynyl, (CH2)rC3-6 cycloalkyl, and (CH2)rphenyl substituted with R6e;
• R9 is selected from H, C1-4 alkyl, C3-4 cycloalkyl, —C(O)H, and —C(O)—C1-4alkyl;
• R10 is independently selected from H, and C1-4alkyl substituted with 0–1 R10b, alternatively, two R10 form ═O;
• R10b, at each occurrence, is independently selected from —OH, —SH, —NR10cR10c, —C(O)NR10cR10C, and —NHC(O)R10c;
• R10c is selected from H, C1-4 alkyl and C3-6 cycloalkyl;
• R11 is selected from H, C1-4 alkyl, (CHR)qOH, (CHR)qSH, (CHR)qOR11d, (CHR)qS(O)pR11d, (CHR)rC(O)R11b, (CHR)rNR11aR11a, (CHR)rC(O)NR11aR11a, (CHR)rC(O)R11aOR11d, (CHR)qNR11aC(O)R11b, (CHR)qNR11aC(O)OR11d, (CHR)qOC(O)NR11aR11a, (CHR)rC(O)OR11d, a (CHR)r—C3-6 carbocyclic residue substituted with 0–5 R11e, and a (CHR)r-5–10 membered heterocyclic system containing 1–4 heteroatoms selected from N, O, and S, substituted with 0–3 R11e;
• R11a, at each occurrence, is independently selected from H, C1-4 alkyl, C3-4 alkenyl, C3-4 alkynyl, (CH2)rC3-6 cycloalkyl, a (CH2)rC3-6 carbocyclic residue substituted with 0–5 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;
• R11b, at each occurrence, is independently selected from C1-4 alkyl, C2-4 alkenyl, C2-4 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;
• R11d, at each occurrence, is independently selected from H, methyl, —CF3, C2-4 alkyl, C3-6 alkenyl, C3-6 alkynyl, a C3-6 carbocyclic residue substituted with 0–3 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;
• 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, —O—C1-6 alkyl, 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, C1-4 alkyl, (CHR)qOH, (CHR)qSH, (CHR)qOR12d, (CHR)qS(O)pR12d, (CHR)rC(O)R12b, (CHR)rNR12aR12a, (CHR)rC(O)NR12aR12a, (CHR)rC(O)NR12aOR12d, (CHR)qNR12aC(O)R12b, (CHR)qNR12aC(O)OR12d, (CHR)qOC(O)NR12aR12a, (CHR)rC(O)OR12d, a (CHR)r—C3-6 carbocyclic residue substituted with 0–5 R12e, and a (CHR)r-5–10 membered heterocyclic system containing 1–4 heteroatoms selected from N, O, and S, substituted with 0–3 R12e;
• R12a, at each occurrence, is independently selected from H, C1-4 alkyl, C3-4 alkenyl, C3-4 alkynyl, (CH2)rC3-6 cycloalkyl, a (CH2)r—C3-6 carbocyclic residue substituted with 0–5 R12e, and a (CH2)r-5–6 membered heterocyclic system containing 1–4 heteroatoms selected from N, O, and S, substituted with 0–3 R12e;
• R12b, at each occurrence, is independently selected from C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, a (CH2)rC3-6 carbocyclic residue substituted with 0–2 R12e, and a (CH2)r-5–6 membered heterocyclic system containing 1–4 heteroatoms selected from N, O, and S, substituted with 0–3 R12e;
• R12d, at each occurrence, is independently selected from H, methyl, —CF3, C2-4 alkyl, C3-6 alkenyl, C3-6 alkynyl, a C3-6 carbocyclic residue substituted with 0–3 R12e, and a (CH2)r-5–6 membered heterocyclic system containing 1–4 heteroatoms selected from N, O, and S, substituted with 0–3 R12e;
• R12e, 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, —O—C1-6 alkyl, SH, (CH2)rSC1-5 alkyl, (CH2)rNR12fR12f, and (CH2)rphenyl;
• R12f, at each occurrence, is selected from H, C1-6 alkyl, and C3-6 cycloalkyl;
• R13, at each occurrence, is independently selected from H, and C1-4alkyl substituted with 0–1 R13b, —OH, —NH2, F, Cl, Br, I, —OR13a, —N(R13a)2, and C1-4 alkyl substituted with 0–3 R13b;
• R13a is selected from H, C1-4 alkyl and C3-6 cycloalkyl;
• R13b, at each occurrence, is independently selected from —OH, —SH, —NR13cR13c, —C(O)NR13cR13c, and —NHC(O)R13c;
• R13c is selected from H, C1-4 alkyl and C3-6 cycloalkyl;
• l is selected from 1, 2 and 3;
• n is 1;
• m is selected from 0 and 1;
• p, at each occurrence, is independently selected from 0, 1, and 2;
• q, at each occurrence, is independently selected from 1, 2, 3, and 4;
• r, at each occurrence, is independently selected from 0, 1, 2, 3, and 4;
• t, at each occurrence, is independently selected from 2, 3, and 4;
• s is selected from 0 and 1.