N-ureidoalkyl-piperidines as modulators of chemokine receptor activity

• US 6,525,069 B1
• Filed: 06/21/2000
• Issued: 02/25/2003
• Est. Priority Date: 12/18/1998
• Status: Expired due to Term

• Current Assignee: Bristol-Myers Squibb Pharma Company (Bristol-Myers Squibb Company)
• Original Assignee: Bristol-Myers Squibb Pharma Company (Bristol-Myers Squibb Company)
• Inventors: Zheng, Changsheng, Wacker, Dean A., Duncia, John V., Ko, Soo S., Delucca, George V., Kim, Ui Tae
• Primary Examiner(s): Chang, Ceila
• Application Number:
  US09/597,400
• Time in Patent Office: 979 Days
• Field of Search: 514/278, 514/307, 514/316, 514/318, 514/319, 514/323, 514/324, 514/327, 514/329, 514/330, 514/331, 546/139, 546/187, 546/193, 546/194, 546/201, 546/207, 546/208, 546/209, 546/214, 546/217, 546/221, 546/225, 546/228, 546/229, 546/231, 546/233, 546/331
• US Class Current: 514/316
• CPC Class Codes: C07D 207/06 with radicals, containing only hydrogen and carbon atoms, attached to ring carbon atoms
• CPC Class Codes: C07D 207/08 with hydrocarbon radicals, substituted by hetero atoms, attached to ring carbon atoms
• CPC Class Codes: C07D 211/14 with hydrocarbon or substituted hydrocarbon radicals attached to the ring nitrogen atom
• CPC Class Codes: C07D 211/18 with substituted hydrocarbon radicals attached to ring carbon atoms
• CPC Class Codes: C07D 211/28 to which a second hetero atom is attached
• CPC Class Codes: C07D 211/34 with hydrocarbon radicals, substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
• CPC Class Codes: C07D 211/36 with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
• CPC Class Codes: C07D 211/52 having an aryl radical as the second substituent in position 4
• CPC Class Codes: C07D 401/06 linked by a carbon chain containing only aliphatic carbon atoms
• CPC Class Codes: C07D 401/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 403/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 405/06 linked by a carbon chain containing only aliphatic carbon atoms
• CPC Class Codes: C07D 405/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 413/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 417/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 471/10 Spiro-condensed systems

Abstract

The present application describes modulators of CCR3 of formula (I):

or pharmaceutically acceptable salt forms thereof, useful for the prevention of asthma and other allergic diseases.

Claims

1. A compound of formula (I):

or stereoisomers or pharmaceutically acceptable salts thereof, wherein;

M is selected from CH₂, CHR⁵, CHR¹³, CR¹³R¹³, and CR⁵R¹³;

Q is selected from CH₂, CHR⁵, CHR¹³, CR¹³R¹³, and CR⁵R¹³;

J, K and L are independently selected from CH₂, CHR⁵, CHR⁶, CR⁶R⁶ and CR⁵R⁶;

with the proviso that at least one of J, K, or L contains R⁵;

Z is selected from O, S, NR^1a, CHCN, CHNO₂, and C(CN)₂;

R^1a is selected from H, C_1-6 alkyl, C_3-6 cycloalkyl, CONR^1bR^1b, OR^1b, CN, NO₂, and (CH₂)_wphenyl;

R^1b is independently selected from H, C_1-3 alkyl, C_3-6 cycloalkyl, and phenyl;

E is selected from;

ring A is a C_3-6 carbocyclic residue, provided that the C_3-6 carbocyclic residue in Ring A is not phenyl;

R¹ and R² are independently selected from H, C_1-6 alkyl, C_3-8 alkenyl, and C_3-8 alkynyl;

R³ is selected from a C_1-10 alkyl substituted with 0-5 R^3g, C_3-10 alkenyl substituted with 0-5 R^3g, and C_3-10 alkynyl substituted with 0-5 R^3g;

R^3g, at each occurrence, is independently selected from Cl, Br, I, F, NO₂, CN, NR^3aR^3a′

, OH, O(CHR′

)_rR^3d, SH, C(O)H, S(CHR′

)_rR^3d, C(O)OH, C(O)(CHR′

)_rR^3b, C(O)NR^3aR^3a′

, OC(O)NR^3aR^3a′

, NR^3aC(O)OR^3d, NR^3fC(O)(CHR′

)_rR^3b, C(O)O(CHR′

)_rR^3d, OC(O)(CHR′

)_rR^3b, C(═

NR^3f)NR^3aR^3a′

, NHC(═

NR^3f)NR^3fR^3f, S(O)_p(CHR′

)_rR^3b, S(O)₂NR^3aR^3a′

, NR^3fS(O)₂(CHR′

)_rR^3b, a C_3-10 carbocyclic residue substituted with 0-5 R¹⁵, and a 5-10 membered heterocyclic system containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-3 R¹⁵, provided that when R^3g is a carbocyclic residue or a heterocyclic system, R³ has at least one other R^3g, which is not a carbocyclic residue or a heterocyclic system;

R^3a and R^3a′

, at each occurrence, are selected from H, C_1-6 alkyl, C_3-8 alkenyl, C_3-8 alkynyl, a (CH₂)_r—

C_3-10 carbocyclic residue substituted with 0-5 R^3e, and a (CH₂)_r-5-10 membered heterocyclic system containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-2 R^3e;

R^3b, at each occurrence, is selected from C_1-6 alkyl, C_3-8 alkenyl, C_3-8 alkynyl, a (CH₂)_r—

C_3-6 carbocyclic residue substituted with 0-3 R^3e, and (CH₂)_r-5-6 membered heterocyclic system containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-2 R^3e;

R^3d, at each occurrence, is selected from C_3-8 alkenyl, C_3-8 alkynyl, methyl, CF₃, C_2-6 alkyl substituted with 0-3 R^3e, a (CH₂)_r—

C_3-10 carbocyclic residue substituted with 0-3 R^3e, and a (CH₂)_r5-6 membered heterocyclic system containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-3 R^3e;

R^3e, at each occurrence, is selected from C_1-6 alkyl, C_2-8 alkenyl, C_2-8 alkynyl, (CH₂)_rC_3-6 cycloalkyl, Cl, F, Br, I, CN, NO₂, (CF₂)_rCF₃, (CH₂)_rOC_1-5 alkyl, OH, SH, (CH₂)_rS(O)_pC_1-5 alkyl, (CH₂)_rNR^3fR^3f, and (CH₂)_rphenyl;

R^3f, at each occurrence, is selected from H, C_1-6 alkyl, C_3-6 cycloalkyl, and phenyl;

R⁴ is absent, taken with the nitrogen to which it is attached to form an N-oxide, or selected from C_1-6 alkyl, C_3-8 alkenyl, C_3-8 alkynyl, (CH₂)_rC_3-6 cycloalkyl, (CH₂)_qC(O)R^4b, (CH₂)_qC(O)NR^4aR^4a′

, (CH₂)_qC(O)OR^4b, and a (CH₂)_r—

C_3-10 carbocyclic residue substituted with 0-3 R^4c;

R^4a and R^4a′

, at each occurrence, are selected from H, C_1-6 alkyl, (CH₂)_rC_3-6 cycloalkyl, and phenyl;

R^4b, at each occurrence, is selected from C_1-6 alkyl, C_3-8 alkenyl, (CH₂)_rC_3-6 cycloalkyl, C_3-8 alkynyl, and phenyl;

R^4c, at each occurrence, is selected from C_1-6 alkyl, C_2-8 alkenyl, C_2-8 alkynyl, C_3-6 cycloalkyl, Cl, F, Br, I, CN, NO₂, (CF₂)_rCF₃, (CH₂)_rOC_1-5 alkyl, (CH₂)_rOH, (CH₂)_rSC_1-5 alkyl, (CH₂)_rNR^4aR^4a′

, and (CH₂)_rphenyl;

alternatively, R⁴ joins with R⁷, R⁹, R¹¹, or R¹⁴ to form a 5, 6 or 7 membered piperidinium spirocycle or pyrrolidinium spirocycle substituted with 0-3 R^a;

R⁵ is selected from a (CR⁵′

R⁵″

)_t—

C_3-10 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, C_1-6 alkyl, (CH₂)_rC_3-6 cycloalkyl, and phenyl;

R⁶, at each occurrence, is selected from C_1-6 alkyl, C_2-8 alkenyl, C_2-8 alkynyl, (CH₂)_rC_3-6 cycloalkyl, (CF₂)_rCF₃, CN, (CH₂)_rNR^6aR^6a′

, (CH₂)_rOH, (CH₂)_rOR^6b, (CH₂)_rSH, (CH₂)_rSR^6b, (CH₂)_rC(O)OH, (CH₂)_rC(O)R^6b, (CH₂)_rC(O)NR^6aR^6a′

, (CH₂)_rNR^6dC(O)R^6a, (CH₂)_rC(O) OR^6b, (CH₂)_rOC(O)R^6b, (CH₂)_rS(O)_pR^6b, (CH₂)_rS(O)₂NR^6aR^6a′

, (CH₂)_rNR^6dS(O)₂R^6b, and (CH₂)_tphenyl substituted with 0-3 R^6c;

R^6a and R^6a′

, at each occurrence, are selected from H, C_1-6 alkyl, C_3-6 cycloalkyl, and phenyl substituted with 0-3 R^6c;

R^6b, at each occurrence, is selected from C_1-6 alkyl, C_3-6 cycloalkyl, and phenyl substituted with 0-3 R^6c;

R^6c, at each occurrence, is selected from C_1-6 alkyl, C_3-6 cycloalkyl, Cl, F, Br, I, CN, NO₂, (CF₂)_rCF₃, (CH₂)_rOC_1-5 alkyl, (CH₂)_rOH, (CH₂)_rSC_1-5 alkyl, and (CH₂)_rNR^6dR^6d;

R^6d, at each occurrence, is selected from H, C_1-6 alkyl, and C_3-6 cycloalkyl;

with the proviso that when any of J, K or L is CR⁶R⁶ and R⁶ is bonded to the carbon to which it is attached through a heteroatom, the other R⁶ is not bonded to the carbon to which it is attached through a heteroatom;

R⁷, is selected from H, C_1-6 alkyl, C_2-8 alkenyl, C_2-8 alkynyl, (CH₂)_qOH, (CH₂)_qSH, (CH₂)_qOR^7d, (CH₂)_qSR^7d, (CH₂)_qNR^7aR^7a′

, (CH₂)_rC(O)OH, (CH₂)_rC(O)R^7b, (CH₂)_rC(O)NR^7aR^7a′

, (CH₂)_rOC(O)NR^7aR^7a′

, (CH₂)_qNR^7aC(O)OR^7b, (CH₂)_qNR^7aC(O)R^7a, (CH₂)_qNR^7aC(O)H, (CH₂)_rC(O)OR^7b, (CH₂)_qOC(O)R^7b, (CH₂)_qS(O)_pR^7b, (CH₂)_qS(O)₂NR^7aR^7a′

, (CH₂)_qNR^7aS(O)₂R^7b, C_1-6 haloalkyl, a (CH₂)_r—

C_3-10 carbocyclic residue substituted with 0-3 R^7c, and a (CH₂)_r-5-10 membered heterocyclic system containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-2 R^7c;

R^7a and R^7a′

, at each occurrence, are selected from H, C_1-6 alkyl, C_3-8 alkenyl, C_3-8 alkynyl, (CH₂)_rC_3-6 cycloalkyl, a (CH₂)_r—

C_3-10 carbocyclic residue substituted with 0-5 R^7e, and a (CH₂)_r-5-10 membered heterocyclic system containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-3 R^7e;

alternatively, R^7a and R^7a′

, along with the N to which they are attached, are joined to form a 5-6 membered heterocyclic system containing 1-2 heteroatoms selected from NR^7g, O, and S and optionally fused with a benzene ring or a 6-membered aromatic heterocycle;

R^7b, at each occurrence, is selected from C_1-6 alkyl, C_3-8 alkenyl, C_3-8 alkynyl, a (CH₂)_r—

C_3-6 carbocyclic residue substituted with 0-2 R^7e, and a (CH₂)_r-5-6 membered heterocyclic system containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-3 R^7e;

R^7c, at each occurrence, is selected from C_1-6 alkyl, C_2-8 alkenyl, C_2-8 alkynyl, (CH₂)_rC_3-6 cycloalkyl, Cl, Br, I, F, (CF₂)_rCF₃, NO₂, CN, (CH₂)_rNR^7fR^7f, (CH₂)_rOH, (CH₂)_rOC_1-4 alkyl, (CH₂)_rSC_1-4 alkyl, (CH₂)_rC(O)OH, (CH₂)_rC(O)R^7b, (CH₂)_rC(O)NR^7fR^7f, (CH₂)_rNR^7fC(O)R^7a, (CH₂)_rC(O)OC_1-4 alkyl, (CH₂)_rOC(O)R^7b, (CH₂)_rC(═

NR^7f)NR^7fR^7f, (CH₂)_rS(O)_pR^7b, (CH₂)_rNHC(═

NR^7f)NR^7fR^7f, (CH₂)_rS(O)₂NR^7fR^7f, (CH₂)_rNR^7fS(O)₂R^7b, and (CH₂)_rphenyl substituted with 0-3 R^7e;

R^7d, at each occurrence, is selected from methyl, CF₃, C_2-6 alkyl substituted with 0-3 R^7e, C_3-8 alkenyl, C_3-8 alkynyl, and a C_3-10 carbocyclic residue substituted with 0-3 R^7c;

R^7e, at each occurrence, is selected from C_1-6 alkyl, C_2-8 alkenyl, C_2-8 alkynyl, C_3-6 cycloalkyl, Cl, F, Br, I, CN, NO₂, (CF₂)_rCF₃, (CH₂)_rOC_1-5 alkyl, OH, SH, (CH₂)_rSC_1-5 alkyl, (CH₂)_rNR^7fR^7f, and (CH₂)_rphenyl;

R^7f, at each occurrence, is selected from H, C_1-6 alkyl, and C_3-6 cycloalkyl;

R⁷g is selected from H, C_1-6 alkyl, C_3-6 cycloalkyl, (CH₂)_rphenyl, C(O)R^7f, C(O)OR^7f, and SO₂R^7f;

R⁸ is selected from H, C_1-6 alkyl, C_3-6 cycloalkyl, and (CH₂)_tphenyl substituted with 0-3 R^8a;

R^8a, at each occurrence, is selected from C_1-6 alkyl, C_2-8 alkenyl, C_2-8 alkynyl, C_3-6 cycloalkyl, Cl, F, Br, I, CN, NO₂, (CF₂)_rCF₃, (CH₂)_rOC_1-5 alkyl, OH, SH, (CH₂)_rSC_1-5 alkyl, (CH₂)_rNR^7fR^7f, and (CH₂)_rphenyl;

R^8b is selected from H, C_1-6 alkyl, C_3-6 cycloalkyl, OH, CN, and (CH₂)_r-phenyl;

alternatively, R⁷ and R⁸ join to form C_3-7 cycloalkyl, ═

O or ═

NR^8b;

R⁹, is selected from H, C_1-6 alkyl, C_2-8 alkenyl, C_2-8 alkynyl, F, Cl, Br, I, NO₂, CN, (CH₂)_rOH, (CH₂)_rSH, (CH₂)_rOR^9d, (CH₂)_rSR^9d, (CH₂)_rNR^9aR^9a′

(CH₂)_rC(O)OH, (CH₂)_rC(O)R^9b, (CH₂)_rC(O)NR^9aR^9a′

, (CH₂)_rNR^9aC(O)R^9a, (CH₂)_rNR^9aC(O)H, (CH₂)_rOC(O)NR^9aR^9a′

, (CH₂)_rNR^9aC(O)OR^9b, (CH₂)_rNR^9aC(O)NHR^9a, (CH₂)_rC(O)OR^9b, (CH₂)_rOC(O)R^9b, (CH₂)_rS(O)_pR^9b, (CH₂)_rS(O)₂NR^9aR^9a′

, (CH₂)_rNR^9aS(O)₂R^9b, C_1-6 haloalkyl, a (CH₂)_r—

C_3-10 carbocyclic residue substituted with 0-5 R^9c, and a (CH₂)_r-5-10 membered heterocyclic system containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-3 R^9c;

R^9a and R^9a′

, at each occurrence, are selected from H, C_1-6 alkyl, C_3-8 alkenyl, C_3-8 alkynyl, a (CH₂)_r—

C_3-10 carbocyclic residue substituted with 0-5 R^9e, and a (CH₂)_r-5-10 membered heterocyclic system containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-3 R^9e;

alternatively, R^9a and R^9a′

, along with the N to which they are attached, are joined to form a 5-6 membered heterocyclic system containing 1-2 heteroatoms selected from NR^9g, O, and S and optionally fused with a benzene ring or a 6-membered aromatic heterocycle;

R^9b, at each occurrence, is selected from C_1-6 alkyl, C_3-8 alkenyl, C_3-8 alkynyl, a (CH₂)_r—

C_3-6 carbocyclic residue substituted with 0-2 R^9e, and a (CH₂)_r-5-6 membered heterocyclic system containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-3 R^9e;

R^9c, at each occurrence, is selected from C_1-6 alkyl, C_2-8 alkenyl, C_2-8 alkynyl, (CH₂)_rC_3-6 cycloalkyl, Cl, Br, I, F, (CF₂)_rCF₃, NO₂, CN, (CH₂)_rNR^9fR^9f, (CH₂)_rOH, (CH₂)_rOC_1-4 alkyl, (CH₂)_rSC_1-4 alkyl, (CH₂)_rC(O)OH, (CH₂)_rC(O)R^9b, (CH₂)_rC(O)NR^9fR^9f, (CH₂)_rNR^9fC(O)R^9a, (CH₂)_rC(O)OC_1-4 alkyl, (CH₂)_rOC(O)R^9b, (CH₂)_rC(═

NR^9f)NR^9fR^9f, (CH₂)_rS(O)_pR^9b, (CH₂)_rNHC(═

NR^9f)NR^9fR^9f, (CH₂)_rS(O)₂NR^9fR^9f, (CH₂)_rNR^9fS(O)₂R^9b, and (CH₂)_rphenyl substituted with 0-3 R^9e;

R^9d, at each occurrence, is selected from C_1-6 alkyl, C_3-6 alkenyl, C_3-6 alkynyl, a C_3-10 carbocyclic residue substituted with 0-3 R^9c, 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 R^9c;

R^9e, at each occurrence, is selected from C_1-6 alkyl, C_2-8 alkenyl, C_2-8 alkynyl, (CH₂)_rC_3-6 cycloalkyl, Cl, F, Br, I, CN, NO₂, (CF₂)_rCF₃, (CH₂)_rOC_1-5 alkyl, OH, SH, (CH₂)_rSC_1-5 alkyl, (CH₂)_rNR^9fR^9f, and (CH₂)_rphenyl;

R^9f, at each occurrence, is selected from H, C_1-6 alkyl, and C_3-6 cycloalkyl;

R^9g is selected from H, C_1-6 alkyl, C_3-6 cycloalkyl, (CH₂)_rphenyl, C(O)R^9f, C(O)OR^9f, and SO₂R^9f;

R¹⁰, is selected from H, C_1-6 alkyl, C_2-8 alkenyl, C_2-8 alkynyl, F, Cl, Br, I, NO₂, CN, (CH₂)_rOH, (CH₂)_rOR^10d, (CH₂)_rSR^10d, (CH₂)_rNR^10aR^10a′

, (CH₂)_rC(O)OH, (CH₂)_rC(O)R^10b, (CH₂)_rC(O)NR^10aR^10a′

, (CH₂)_rNR^10aC(O)R^10a, (CH₂)_rNR^10aC(O)H, (CH₂)_rC(O)OR^10b, (CH₂)_rOC(O)R^10b, (CH₂)_rOC(O)NR^10aR^10a′

, (CH₂)_rNR^10aC(O)OR^10b, (CH₂)_rS(O)_pR^10b, (CH₂)_rS(O)₂NR^10aR^10a′

, (CH₂)_rNR^10aS(O)₂R^10b, C_1-6 haloalkyl, a (CH₂)_r—

C_3-10 carbocyclic residue substituted with 0-5 R^10c, and a (CH₂)_r-5-10 membered heterocyclic system containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-3 R^10c;

R^10a and R^10a′

, at each occurrence, are selected from H, C_1-6 alkyl, C_3-8 alkenyl, C_3-8 alkynyl, a (CH₂)_r—

C_3-10 carbocyclic residue substituted with 0-5 R^10e, and a (CH₂)_r-5-10 membered heterocyclic system containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-3 R^10e;

alternatively, R^10a and R^10a′

, along with the N to which they are attached, are joined to form a 5-6 membered heterocyclic system containing 1-2 heteroatoms selected from NR^10g, O, and S and optionally fused with a benzene ring or a 6-membered aromatic heterocycle;

R^10b, at each occurrence, is selected from C_1-6 alkyl, C_3-8 alkenyl, C_3-8 alkynyl, a (CH₂)_r—

C_3-6 carbocyclic residue substituted with 0-2 R^10e, and a (CH₂)_r-5-6 membered heterocyclic system containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-3 R^10e;

R^10c, at each occurrence, is selected from C_1-6 alkyl, C_2-8 alkenyl, C_2-8 alkynyl, (CH₂)_rC_3-6 cycloalkyl, Cl, Br, I, F, (CF₂)_rCF₃, NO₂, CN, (CH₂)_rNR^10fR^10f, (CH₂)_rOH, (CH₂)_rOC_1-4 alkyl, (CH₂)_rSC_1-4 alkyl, (CH₂)_rC(O)OH, (CH₂)_rC(O)R^10b, (CH₂)_rC(O)NR^10fR^10f, (CH₂)_rNR^10fC(O)R^10a, (CH₂)_rC(O)OC_1-4 alkyl, (CH₂)_rOC(O)R^10b, (CH₂)_rC(═

NR^10f)NR^10fR^10f, (CH₂)_rS(O)_pR^10b, (CH₂)_rNHC(═

NR^10f)NR^10fR^10f, (CH₂)_rS(O)₂NR^10fR^10f, (CH₂)_rNR^10fS(O)₂R^10b, and (CH₂)_rphenyl substituted with 0-3 R^10e;

R^10d, at each occurrence, is selected from C_1-6 alkyl, C_3-6 alkenyl, C_3-6 alkynyl, a C_3-10 carbocyclic residue substituted with 0-3 R^10c, 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 R^10c;

R^10e, at each occurrence, is selected from C_1-6 alkyl, C_2-8 alkenyl, C_2-8 alkynyl, (CH₂)_rC_3-6 cycloalkyl, Cl, F, Br, I, CN, NO₂, (CF₂)_rCF₃, (CH₂)_rOC_1-5 alkyl, OH, SH, (CH₂)_rSC_1-5 alkyl, (CH₂)_rNR^10fR^10f, and (CH₂)_rphenyl;

R^10f, at each occurrence, is selected from H, C_1-5 alkyl, and C_3-6 cycloalkyl;

R^10g is selected from H, C_1-6 alkyl, C_3-6 cycloalkyl, (CH₂)_rphenyl, C(O)R^10f, C(O)OR^10h, and SO₂R^10h;

R^10h, at each occurrence, is selected from C_1-5 alkyl, and C_3-6 cycloalkyl;

alternatively, R⁹ and R¹⁰ join to form ═

O, a C_3-10 cycloalkyl, a 5-6-membered lactone or lactam, or a 4-6-membered saturated heterocycle containing 1-2 heteroatoms selected from O, S, and NR^10g and optionally fused with a benzene ring or a 6-membered aromatic heterocycle;

with the proviso that when either of R⁹ or R¹⁰ is halogen, cyano, nitro, or bonded to the carbon to which it is attached through a heteroatom, the other of R⁹ or R¹⁰ is not bonded to the carbon to which it is attached through a heteroatom;

R¹¹, is selected from H, C_1-6 alkyl, C_2-8 alkenyl, C_2-8 alkynyl, (CH₂)_qOH, (CH₂)_qSH, (CH₂)_qOR^11d, (CH₂)_qSR^11d, (CH₂)_qNR^11aR^11a′

, (CH₂)_rC(O)OH, (CH₂)_rC(O)R^11b, (CH₂)_rC(O)NR^11aR^11a′

, (CH₂)_qNR^11aC(O)R^11a, (CH₂)_qOC(O)NR^11aR^11a′

, (CH₂)_qNR^11aC(O)OR^11b, (CH₂)(NR^11aC(O)NHR^11a, (CH₂)_rC(O)OR^11b, (CH₂)_qOC(O)R^11b, (CH₂)_qS(O)_pR^11b, (CH₂)_qS(O)₂NR^11aR^11a′

, (CH₂)_qNR^11aS(O)₂R^11b, C_1-6 haloalkyl, a (CH₂)_r—

C_3-10 carbocyclic residue substituted with 0-5 R^11c, and a (CH₂)_r-5-10 membered heterocyclic system containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-3 R^11c;

R^11a and R^11a′

, at each occurrence, are selected from H, C_1-6 alkyl, C_3-8 alkenyl, C_3-8 alkynyl, a (CH₂)_r—

C_3-10 carbocyclic residue substituted with 0-5 R^11e, and a (CH₂)_r-5-10 membered heterocyclic system containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-3 R^11e;

alternatively, R^11a and R^11a′

, along with the N to which they are attached, are joined to form a 5-6 membered heterocyclic system containing 1-2 heteroatoms selected from NR^11g, O, and S and optionally fused with a benzene ring or a 6-membered aromatic heterocycle;

R^11b, at each occurrence, is selected from C_1-6 alkyl, C_3-8 alkenyl, C_3-8 alkynyl, a (CH₂)_r—

C_3-6 carbocyclic residue substituted with 0-2R^11e, and a (CH₂)_r-5-6 membered heterocyclic system containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-3 R^11e;

R^11c, at each occurrence, is selected from C_1-6 alkyl, C_2-8 alkenyl, C_2-8 alkynyl, (CH₂)_rC_3-6 cycloalkyl, Cl, Br, I, F, (CF₂)_rCF₃, NO₂, CN, (CH₂)_rNR^11fR^11f, (CH₂)_rOH, (CH₂)_rOC1-4 alkyl, (CH₂)_rSC_1-4 alkyl, (CH₂)_rC(O)OH, (CH₂)_rC(O)R^11b, (CH₂)_rC(O)NR^11fR^11f, (CH₂)_rNR^11fC(O)R^11a, (CH₂)_rC(O)OC_1-4 alkyl, (CH₂)_rOC(O)R^11b, (CH₂)_rC(═

NR^11f)NR^11fR^11f, (CH₂)_rNHC(═

NR^11f)NR^11fR^11f, (CH₂)_rS(O)_pR^11b, (CH₂)_rS(O)₂NR^11fR^11f, (CH₂)_rNR^11fS(O)₂R^11b, and (CH₂)_rphenyl substituted with 0-3 R^11e;

R_11d, at each occurrence, is selected from methyl, CF₃, C_2-6 alkyl substituted with 0-3 thulle, C_3-6 alkenyl, C_3-6 alkynyl, and a C_3-10 carbocyclic residue substituted with 0-3 R^11c;

R^11e, at each occurrence, is selected from C_1-6 alkyl, C_2-8 alkenyl, C_2-8 alkynyl, C_3-6 cycloalkyl, Cl, F, Br, I, CN, NO₂, (CF₂)_rCF₃, (CH₂)_rOC_1-5 alkyl, OH, SH, (CH₂)_rSC_1-5 alkyl, (CH₂)_rNR^11fR^11f, and (CH₂)_rphenyl;

R^11f, at each occurrence, is selected from H, C_1-6 alkyl, and C_3-6 cycloalkyl;

R^11g is selected from H, C_1-6 alkyl, C_3-6 cycloalkyl, (CH₂)_rphenyl, C(O)R^11f, C(O)OR^11h, and SO₂R^11h;

R^11h, at each occurrence, is selected from C_1-5 alkyl, and C_3-6 cycloalkyl;

R¹² is selected from H, C_1-6 alkyl, (CH₂)_qOH, (CH₂)_rC_3-6 cycloalkyl, and (CH₂)_tphenyl substituted with 0-3 R^12a;

R^12a, at each occurrence, is selected from C_1-6 alkyl, C_2-8 alkenyl, C_2-8 alkynyl, C_3-6 cycloalkyl, Cl, F, Br, I, CN, NO₂, (CF₂)_rCF₃, (CH₂)_rOC_1-5 alkyl, OH, SH, (CH₂)_rSC_1-5 alkyl, (CH₂)_rNR^9fR^9f, and (CH₂)_rphenyl;

alternatively, R¹¹ and R¹² join to form a C_3-10 cycloalkyl, a 5-6-membered lactone or lactam, or a 4-6-membered saturated heterocycle containing 1-2 heteroatoms selected from O, S, and NR^11g and optionally fused with a benzene ring or a 6-membered aromatic heterocycle;

R¹³, at each occurrence, is selected from C_1-6 alkyl, C_2-8 alkenyl, C_2-8 alkynyl, C_3-6 cycloalkyl, (CF₂)_wCF₃, (CH₂)NR^13aR^13a′

, (CH₂)_qOH, (CH₂)_qOR^13b, (CH₂)_qSH, (CH₂)_qSR^13b, (CH₂)_wC(O)OH, (CH₂)_wC(O)R^13b, (CH₂)_wC(O)NR^13aR^13a′

, (CH₂)_qNR^13dC(O)R^13a, (CH₂)_wC(O)OR^13b, (CH₂)_qOC(O)R^13b, (CH₂)_wS(O)_pR^13b, (CH₂)_wS(O)₂NR^13aR^13a′

, (CH₂)_qNR^13dS(O)₂R^13b, and (CH₂)_w-phenyl substituted with 0-3 R^13c;

R^13a and R^13a′

, at each occurrence, are selected from H, C_1-6 alkyl, C_3-6 cycloalkyl, and phenyl substituted with 0-3 R^13c;

R^13b, at each occurrence, is selected from C_1-6 alkyl, C_3-6 cycloalkyl, and phenyl substituted with 0-3 R^13c;

R^13c, at each occurrence, is selected from C_1-6 alkyl, C_3-6 cycloalkyl, Cl, F, Br, I, CN, NO₂, (CF₂)_rCF₃, (CH₂)_rOC_1-5 alkyl, (CH₂)_rOH, (CH₂)_rSC_1-5 alkyl, and (CH₂)_rNR^13dR^13d;

R^13d, at each occurrence, is selected from H, C_1-6 alkyl, and C_3-6 cycloalkyl;

R¹⁴, at each occurrence, is selected from C_1-6 alkyl, (CH₂)_rC_3-6 cycloalkyl, Cl, Br, I, F, NO₂, CN, (CHR′

)_rNR^14aR^14a′

, (CHR′

)_rOH, (CHR′

)_rO(CHR′

)_rR^14d, (CHR′

)_rSH, (CHR′

)_rC(O)H, (CHR′

)_rS(CHR′

)_rR^14d, (CHR′

)_rC(O)OH, (CHR′

)_rC(O)(CHR′

)_rR^14b, (CHR′

)_rC(O)NR^14aR^14a′

, (CHR′

)_rNR^14fC(O)(CHR′

)_rR^14b, (CHR′

)_rC(O)O(CHR′

)_rR^14d, (CHR′

)_rOC(O)(CHR′

)_rR^14b, (CHR′

)_rC(═

NR^14f)NR^14aR^14a′

, (CHR′

)_rNHC(═

NR^14f)NR^14fR^14f, (CHR′

)_rS(O)_p(CHR′

)_rR^14b, (CHR′

)_rS(O)₂NR^14aR^14a′

, (CHR′

)_rNR^14fS(O)₂(CHR′

)_rR^14b, C_1-6 haloalkyl, C_2-8 alkenyl substituted with 0-3 R′

, C_2-8 alkynyl substituted with 0-3 R′

, (CHR′

)_rphenyl substituted with 0-3 R^14e, and a (CH₂)_r-5-10 membered heterocyclic system containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-2 R^14e, 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 R^14e;

R′

, at each occurrence, is selected from H, C_1-6 alkyl, C_2-8 alkenyl, C_2-8 alkynyl, (CH₂)_rC_3-6 cycloalkyl, and (CH₂)_rphenyl substituted with R^14e, ;

R^14a and R^14a′

, at each occurrence, are selected from H, C_1-6 alkyl, C_3-8 alkenyl, C_3-8 alkynyl, a (CH₂)_r—

C_3-10 carbocyclic residue substituted with 0-5 R^14e, and a (CH₂)_r-5-10 membered heterocyclic system containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-2 R^14e;

R^14b, at each occurrence, is selected from C_1-6 alkyl, C_3-8 alkenyl, C_3-8 alkynyl, a (CH₂)_r—

C_3-6 carbocyclic residue substituted with 0-3 R^14e, and (CH₂)_r-5-6 membered heterocyclic system containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-2 R^14e;

R^14d, at each occurrence, is selected from C_3-8 alkenyl, C_3-8 alkynyl, methyl, CF₃, C_2-6 alkyl substituted with 0-3 R^14e, a (CH₂)_r—

C_3-10 carbocyclic residue substituted with 0-3 R^14e, and a (CH₂)_r-5-6 membered heterocyclic system containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-3 R^14e;

R^14e, at each occurrence, is selected from C_1-6 alkyl, C_2-8 alkenyl, C_2-8 alkynyl, (CH₂)_rC_3-6 cycloalkyl, Cl, F, Br, I, CN, NO₂, (CF₂)_rCF₃, (CH₂)_rOC_1-5 alkyl, OH, SH, (CH₂)_rSC_1-5 alkyl, (CH₂)_rNR^14fR^14f, and (CH₂)_rphenyl;

R^14f, at each occurrence, is selected from H, C_1-6 alkyl, C_3-6 cycloalkyl, and phenyl;

alternatively, R¹⁴ joins with R⁴ to form a 5, 6 or 7 membered piperidinium spirocycle or pyrrolidinium spirocycle fused to ring A, the spirocycle substituted with 0-3 R^a;

R^a, at each occurrence, is selected from C_1-6 alkyl, C_2-8 alkenyl, C_2-8 alkynyl, (CH₂)_rC_3-6 cycloalkyl, Cl, Br, I, F, (CF₂)_rCF₃, NO₂, CN, (CH₂)_rNR^bR^b, (CH₂)_rOH, (CH₂)_rOR^c, (CH₂)_rSH, (CH₂)_rSR^c, (CH₂)_rC(O)R^b, (CH₂)_rC(O)NR^bR^b, (CH₂)_rNR^bC(O)R^b, (CH₂)_rC(O)OR^b, (CH₂)_rOC(O)R^c, (CH₂)_rCH(═

NR^b)NR^bR^b, (CH₂)_rNHC(═

NR^b)NR^bR^b, (CH₂)_rS(O)_pR^c, (CH₂)_rS(O)₂NR^bR^b, (CH₂)_rNR^bS(O)₂R^c, and (CH₂)_rphenyl;

R^b, at each occurrence, is selected from H, C_1-6 alkyl, C_3-6 cycloalkyl, and phenyl;

R^c, at each occurrence, is selected from C_1-6 alkyl, C_3-6 cycloalkyl, and phenyl;

R¹⁵, at each occurrence, is selected from C_1-8 alkyl, (CH₂)_rC_3-6 cycloalkyl, Cl, Br, I, F, NO₂;

CN, (CHR′

)_rNR^15aR^15a′

, (CHR′

)_rOH, (CHR′

)_rO(CHR′

)_rR^15d, (CHR′

)_rSH, (CHR′

)_rC(O)H, (CHR′

)_rS(CHR′

)_rR^15d, (CHR′

)_rC(O)OH, (CHR′

)_rC(O)(CHR′

)_rR^15b, (CHR′

)_rC(O)NR^15aR^15a′

, (CHR′

)_rNR^15fC(O)(CHR′

)_rR^15b, (CHR′

)_rNR^15fC(O)NR^15fR^15f, (CHR′

)_rC(O)O(CHR′

)_rR^15d, (CHR′

)_rOC(O)(CHR′

)_rR^15b, (CH₂)_rOC(O)NR^15aR^15a′

, (CH₂)_rNR^15aC(O)OR^15b, (CHR′

)_rC(═

NR^15f)NR^15aR^15a′

(CHR′

)_rNHC(═

NR^15f)NR^15fR^15f, (CHR′

)_rS(O)_p(CHR′

)_rR^15b, (CHR′

)_rS(O)₂NR^15aR^15a′

, (CHR′

)_rNR^15fS(O)₂(CHR′

)_rR^15b, C_1-6 haloalkyl, C_2-8 alkenyl substituted with 0-3 R′

, C_2-8 alkynyl substituted with 0-3 R′

, (CHR′

)_rphenyl substituted with 0-3 R^15e, and a (CH₂)_r-5-10 membered heterocyclic system containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-2 R^15e;

R^15a and R^15a′

, at each occurrence, are selected from H, C_1-6 alkyl, C_3-8 alkenyl, C_3-8 alkynyl, a (CH₂)_r—

C_3-10 carbocyclic residue substituted with 0-5 R^15e, and a (CH₂)_r-5-10 membered heterocyclic system containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-2 R^15e;

alternatively, R^15a and R^15a′

, along with the N to which they are attached, are joined to form a 5-6 membered heterocyclic system containing 1-2 heteroatoms selected from NR^15g, O, and S and optionally fused with a benzene ring or a 6-membered aromatic heterocycle;

R^15b, at each occurrence, is selected from C_1-6 alkyl, C_3-8 alkenyl, C_3-8 alkynyl, a (CH₂)_r—

C_3-6 carbocyclic residue substituted with 0-3 R^15e, and (CH₂)_r-5-6 membered heterocyclic system containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-2 R^15e;

R^15d, at each occurrence, is selected from C_3-8 alkenyl, C_3-8 alkynyl, methyl, CF₃, C_2-6 alkyl substituted with 0-3 R^15e, a (CH₂)_r—

C_3-10 carbocyclic residue substituted with 0-3 R^15e, and a (CH₂)_r-5-6 membered heterocyclic system containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-3 R^15e;

R^15e, at each occurrence, is selected from C_1-6 alkyl, C_2-8 alkenyl, C_2-8 alkynyl, (CH₂)_rC_3-6 cycloalkyl, Cl, F, Br, I, CN, NO₂, (CF₂)_rCF₃, (CH₂)_rOC_1-5 alkyl, OH, SH, (CH₂)_rSC_1-5 alkyl, (CH₂)_rNR^15fR^15f, and (CH₂)_rphenyl;

R^15f, at each occurrence, is selected from H, C_1-6 alkyl, C_3-6 cycloalkyl, and phenyl;

R^15g is selected from H, C_1-6 alkyl, C_3-6 cycloalkyl, (CH₂)_rphenyl, C(O)R^15f, C(O)OR^15h, and SO₂R^15h;

R^15h, at each occurrence, is selected from C_1-5 alkyl, and C_3-6 cycloalkyl;

R¹⁶, at each occurrence, is selected from C_1-8 alkyl, C_2-8 alkenyl, C_2-8 alkynyl, (CH₂)_rC_3-6 cycloalkyl, Cl, Br, I, F, NO₂, CN, (CHR′

)_rNR^16aR^16a′

, (CHR′

)_rOH, (CHR′

)_rO(CHR′

)_rR^16d, (CHR′

)_rSH, (CHR′

)_rC(O)H, (CHR′

)_rS(CHR′

)_rR^16d, (CHR′

)_rC(O)OH, (CHR′

)_rC(O)(CHR′

)_rR^16b, (CHR′

)_rC(O)NR^16aR^16a′

, (CHR′

)_rNR^16fC(O)(CHR′

)_rR^16b, (CHR′

)_rC(O)O(CHR′

)_rR^16d, (CHR′

)_rOC(O)(CHR′

)_rR^16b, (CHR′

)_rC(═

NR^16f)NR^16aR^16a′

, (CHR′

)_rNHC(═

NR^16f)NR^16fR^16f, (CHR′

)_rS(O)_p(CHR′

)_rR^16b, (CHR′

)_rS(O)₂NR^16aR^16a′

, (CHR′

)_rNR^16fS(O)₂(CHR′

)_rR^16b, C_1-6 haloalkyl, C_2-8 alkenyl substituted with 0-3 R′

, C_2-8 alkynyl substituted with 0-3 R′

, and (CHR′

)_rphenyl substituted with 0-3 R^16e;

R^16a and R^16a′

, at each occurrence, are selected from H, C_1-6 alkyl, C_3-8 alkenyl, C_3-8 alkynyl, a (CH₂)_r—

C_3-10 carbocyclic residue substituted with 0-5 R^16e, and a (CH₂)_r-5-10 membered heterocyclic system containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-2 R^16e;

R^16b, at each occurrence, is selected from C_1-6 alkyl, C_3-8 alkenyl, C_3-8 alkynyl, a (CH₂)_rC_3-6 carbocyclic residue substituted with 0-3 R^16e, and a (CH₂)_r-5-6 membered heterocyclic system containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-2 R^16e;

R^16d, at each occurrence, is selected from C_3-8 alkenyl, C_3-8 alkynyl, methyl, CF₃, C_2-6 alkyl substituted with 0-3 R^16e, a (CH₂)_r—

C_3-10 carbocyclic residue substituted with 0-3 R^16e, and a (CH₂)_r-5-6 membered heterocyclic system containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-3 R^16e;

R^16e, at each occurrence, is selected from C_1-6 alkyl, C_2-8 alkenyl, C_2-8 alkynyl, (CH₂)_rC_3-6 cycloalkyl, Cl, F, Br, I, CN, NO₂, (CF₂)_rCF₃, (CH₂)_rOC_1-5 alkyl, OH, SH, (CH₂)_rSC_1-5 alkyl, (CH₂)_rNR^16fR^16f, and (CH₂)_rphenyl;

R^16f, at each occurrence, is selected from H, C_1-5 alkyl, and C_3-6 cycloalkyl, and phenyl;

g is selected from 0, 1, 2, 3, and 4;

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.

2. The compound of claim 1, wherein:

Z is selected from O, S, NCN, NCONH₂, CHNO₂, and C(CN)₂;

E is selected from;

R⁴ is absent, taken with the nitrogen to which it is attached to form an N-oxide, or selected from C_1-8 alkyl, (CH₂)_rC_3-6 cycloalkyl, and (CH₂)_r-phenyl substituted with 0-3 R^4c;

R^4c, at each occurrence, is selected from C_1-6 alkyl, C_3-8 alkenyl, C_3-8 alkynyl, C_3-6 cycloalkyl, Cl, F, Br, I, CN, NO₂, (CF₂)_rCF₃, (CH₂)_rOC_1-5 alkyl, (CH₂)_rOH, (CH₂)_rSC_1-5 alkyl, (CH₂)_rNR^4aR^4a′

, and (CH₂)_rphenyl;

alternatively, R⁴ joins with R⁷ or R⁹ or R¹⁴ to form a 5, 6 or 7 membered piperidinium spirocycle substituted with 0-3 R^a;

R¹ and R² are independently selected from H and C_1-4 alkyl;

R⁶, at each occurrence, is selected from C_1-4 alkyl, C_2-8 alkenyl, C_2-8 alkynyl, (CH₂)_rC_3-6 cycloalkyl, (CF₂)_rCF₃, CN, (CH₂)_rOH, (CH₂)_rOR^6b, (CH₂)_rC(O)R^6b, (CH₂)_rC(O)NR^6aR^6a′

, (CH₂)_rNR^6dC(O)R^6a, and (CH₂)_tphenyl substituted with 0-3 R^6c;

R^6a and R^6a′

, at each occurrence, are selected from H, C_1-6 alkyl, C_3-6 cycloalkyl, and phenyl substituted with 0-3 R^6c;

R^6b, at each occurrence, is selected from C_1-6 alkyl, C_3-6 cycloalkyl, and phenyl substituted with 0-3 R^6c;

R^6c, at each occurrence, is selected from C_1-6 alkyl, C_3-6 cycloalkyl, Cl, F, Br, I, CN, NO₂, (CF₂)_rCF₃, (CH₂)_rOC_1-5 alkyl, (CH₂)_rOH, (CH₂)_rSC_1-5 alkyl, and (CH₂)_rNR^6dR^6d;

R^6d, at each occurrence, is selected from H, C_1-6 alkyl, and C_3-6 cycloalkyl;

R⁷, is selected from H, C_1-3 alkyl, (CH₂)_rC_3-6 cycloalkyl, (CH₂)_qOH, (CH₂)_qOR^7d, (CH₂)_qNR^7aR^7a′

, (CH₂)_rC(O)R^7b, (CH₂)_rC(O)NR^7aR^7a′

, (CH₂)_qNR^7aC(O)R^7a, (CH₂)_qOC(O)NR^7aR^7a′

, (CH₂)_qNR^7aC(O)OR^7b, C_1-6 haloalkyl, (CH₂)_rphenyl with 0-2 R^7c;

R^7a and R^7a′

, at each occurrence, are selected from H, C_1-6 alkyl, (CH₂)_rC_3-6 cycloalkyl, a (CH₂)_rphenyl substituted with 0-3 R^7e;

R^7b, at each occurrence, is selected from C_1-6 alkyl, C_3-8 alkenyl, C_3-8 alkynyl, (CH₂)_rC_3-6 cycloalkyl, (CH₂)_rphenyl substituted with 0-3 R^7e;

R^7c, at each occurrence, is selected from C_1-4 alkyl, C_2-8 alkenyl, C_2-8 alkynyl, (CH₂)_rC_3-6 cycloalkyl, Cl, Br, I, F, (CF₂)_rCF₃, NO₂, CN, (CH₂)_rNR^7fR^7f, (CH₂)_rOH, (CH₂)_rOC_1-4 alkyl, (CH₂)_rC(O)R^7b, (CH₂)_rC(O)NR^7fR^7f, (CH₂)_rNR^7fC(O)R^7a, (CH₂)_rS(O)_pR^7b, (CH₂)_rS(O)₂NR^7fR^7f, (CH₂)_rNR^7fS(O)₂R^7b, and (CH₂)_rphenyl substituted with 0-2 R^7e;

R^7d, at each occurrence, is selected from C_1-6 alkyl, (CH₂)_rC_3-6 cycloalkyl, (CH₂)_rphenyl substituted with 0-3 R^7e;

R^7e, at each occurrence, is selected from C_1-6 alkyl, C_2-8 alkenyl, C_2-8 alkynyl, C_3-6 cycloalkyl, Cl , F, Br, I, CN, NO₂, (CF₂)_rCF₃, (CH₂)_rOC_1-5 alkyl, OH, SH, (CH₂)_rSC_1-5 alkyl, (CH₂)_rNR^7fR^7f, and (CH₂)_rphenyl;

R^7f, at each occurrence, is selected from H, C_1-5 alkyl, and C_3-6 cycloalkyl;

R⁸ is H or joins with R⁷ to form C_3-7 cycloalkyl, ═

O, or ═

NR^8b;

R¹¹, is selected from H, C_1-6 alkyl, (CH₂)_rC_3-6 cycloalkyl, (CH₂)_qOH, (CH₂)_qOR^11d, (CH₂)_qNR^11aR^11a′

, (CH₂)_rC(O)R^11b, (CH₂)_rC(O)NR^11aR^11a′

, (CH₂)_qNR^11aC(O)R^11a, (CH₂)_qOC(O)NR^11aR^11a′

, (CH₂)_qNR^11aC(O)OR^11a, C_1-6 haloalkyl, (CH₂)_rphenyl with 0-2 R^11c, (CH₂)_r-5-10 membered heterocyclic system containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-3 R¹⁵;

R^11a and R^11a′

, at each occurrence, are selected from H, C_1-6 alkyl, (CH₂)_rC_3-6 cycloalkyl, a (CH₂)_rphenyl substituted with 0-3 R^11e;

alternatively, R^11a and R^11a′

, along with the N to which they are attached, are joined to form a 5-6 membered heterocyclic system containing 1-2 heteroatoms selected from NR^11g, O, and S and optionally fused with a benzene ring or a 6-membered aromatic heterocycle;

R^11b, at each occurrence, is selected from C_1-6 alkyl, C_2-8 alkenyl, C_2-8 alkynyl, (CH₂)_rC_3-6 cycloalkyl, (CH₂)_rphenyl substituted with 0-3 R^11e;

R^11c, at each occurrence, is selected from C_1-4 alkyl, C_2-8 alkenyl, C_2-8 alkynyl, (CH₂)_rC_3-6 cycloalkyl, Cl, Br, I, F, (CF₂)_rCF₃, NO₂, CN, (CH₂)_rNR^11fR^11f, (CH₂)_rOH, (CH₂)_rOC_1-4 alkyl, (CH₂)_rC(O)R^11b, (CH₂)_rC(O)NR^11fR^11f, (CH₂)_rNR^11fC(O)R^11a, (CH₂)_rS(O)_pR^11b, (CH₂)_rS(O)₂NR^11fR^11f, (CH₂)_rNR^11fS(O)₂R^11b, and (CH₂)_rphenyl substituted with 0-2 R^11e;

R^11d, at each occurrence, is selected from C_1-6 alkyl, (CH₂)_rC_3-6 cycloalkyl, (CH₂)_rphenyl substituted with 0-3 R^11e;

R^11e, at each occurrence, is selected from C_1-6 alkyl, C_2-8 alkenyl, C_2-8 alkynyl, C_3-6 cycloalkyl, Cl, F, Br, I, CN, NO₂, (CF₂)_rCF₃, (CH₂)_rOC_1-5 alkyl, OH, SH, (CH₂)_rSC_1-5 alkyl, (CH₂)_rNR^11fR^11f, and (CH₂)_rphenyl;

R^11f, at each occurrence, is selected from H, C_1-5 alkyl and C_3-6 cycloalkyl;

R^11g is selected from H, C_1-6 alkyl, C_3-6 cycloalkyl, (CH₂)_rphenyl, C(O)R^11f, C(O)OR^11f, and SO₂R^11f;

R¹² is H;

alternatively, R¹¹ and R¹² join to form a C_3-10 cycloalkyl, a 5-6-membered lactone or lactam, or a 4-6-membered saturated heterocycle containing 1-2 heteroatoms selected from O, S, and NR^11g and optionally fused with a benzene ring or a 6-membered aromatic heterocycle;

R¹³, at each occurrence, is selected from C_1-4 alkyl, C_3-6 cycloalkyl, (CH₂)NR^13aR^13a′

, (CH₂)OH, (CH₂)OR^13b, (CH₂)_wC(O)R^13b, (CH₂)_wC(O)NR^13aR^13a′

, (CH₂)NR^13dC(O)R^13a, (CH₂)_wS(O)₂NR^13aR^13a′

, (CH₂)NR^13dS(O)₂R^13b, and (CH₂)_w-phenyl substituted with 0-3 R^13c;

R^13a and R^13a′

, at each occurrence, are selected from H, C_1-6 alkyl, C_3-6 cycloalkyl, and phenyl substituted with 0-3 R^13c;

R^13b, at each occurrence, is selected from C_1-6 alkyl, C_3-6 cycloalkyl, and phenyl substituted with 0-3 R^13c;

R^13c, at each occurrence, is selected from C_1-6 alkyl, C_3-6 cycloalkyl, Cl, F, Br, I, CN, NO₂, (CF₂)_rCF₃, (CH₂)_rOC_1-5 alkyl, (CH₂)_rOH, and (CH₂)_rNR^13dR^13d;

R^13d, at each occurrence, is selected from H, C_1-6-alkyl, and C_3-6 cycloalkyl;

q is selected from 1, 2, and 3; and

r is selected from 0, 1, 2, and 3.

3. The compound of claim 2, wherein:

ring A is selected from;

R⁵ is selected from (CR⁵′

H)_t-phenyl substituted with 0-5 R¹⁶; and

a (CR⁵′

H)_t-heterocyclic system substituted with 0-3 R¹⁶, wherein the heterocyclic system is selected from pyridinyl, thiophenyl, furanyl, indazolyl, benzothiazolyl, benzimidazolyl, benzothiophenyl, benzofuranyl, benzoxazolyl, benzisoxazolyl, quinolinyl, isoquinolinyl, imidazolyl, indolyl, indolinyl, isoindolyl, isothiadiazolyl, isoxazolyl, piperidinyl, pyrrazolyl, 1,2,4-triazolyl, 1,2,3-triazolyl, tetrazolyl, thiadiazolyl, thiazolyl, oxazolyl, pyrazinyl, and pyrimidinyl.

4. The compound of claim 3, wherein the compound of formula (I-i) is:

R¹⁶, at each occurrence, is selected from C_1-8 alkyl, (CH₂)_rC_3-6 cycloalkyl, CF₃, Cl, Br, I, F, (CH₂)_rNR^16aR^16a′

, NO₂, CN, OH, (CH₂)_rOR^16d, (CH₂)_rC(O)R^16b, (CH₂)_rC(O)NR^16aR^16a′

, (CH₂)_rNR^16fC(O)R^16b, (CH₂)_rS(O)_pR^16b, (CH₂)_rS(O)₂NR^16aR^16a′

, (CH₂)_rNR^16fS(O)₂R^16b, and (CH₂)_rphenyl substituted with 0-3 R^16e;

R^16a and R^16a′

, at each occurrence, are selected from H, C_1-6 alkyl, C_3-6 cycloalkyl, and (CH₂)_rphenyl substituted with 0-3 R^16e;

R^16b, at each occurrence, is selected from H, C_1-6 alkyl, C_3-6 cycloalkyl, and (CH₂)_rphenyl substituted with 0-3 R^16e;

R^16d, at each occurrence, is selected from C_1-6 alkyl and phenyl;

R^16e, at each occurrence, is selected from C_1-6 alkyl, Cl, F, Br, I, CN, NO₂, (CF₂)_rCF₃, OH, and (CH₂)_rOC_1-5 alkyl; and

R^16f, at each occurrence, is selected from H, and C_1-5 alkyl.

5. The compound of claim 4, wherein:

R⁵ is CH₂phenyl substituted with 0-3 R¹⁶;

R⁹, is selected from H, C_1-6 alkyl, (CH₂)_rC_3-6 cycloalkyl, F, Cl, CN, (CH₂)_rOH, (CH₂)_rOR^9d, (CH₂)_rNR^9aR^9a′

, (CH₂)_rOC(O)NHR^9a, (CH₂)_rphenyl substituted with 0-5 R^9e, and (CH₂)_r-heterocyclic system substituted with 0-2 R^9e, wherein the heterocyclic system is selected from pyridyl, thiophenyl, furanyl, oxazolyl, and thiazolyl;

R^9a and R^9a′

, at each occurrence, are selected from H, C_1-6 alkyl, C_3-6 cycloalkyl, and (CH₂)_rphenyl substituted with 0-3 R^9e;

R^9d, at each occurrence, is selected from C_1-6 alkyl and phenyl;

R^9e, at each occurrence, is selected from C_1-6 alkyl, Cl, F, Br, I, CN, NO₂, (CF2)_rCF₃, OH, and (CH₂)_rOC_1-5 alkyl;

R¹⁰ is selected from H, C_1-5 alkyl, OH, and CH₂OH;

R^10g is selected from H, C_1-6 alkyl, C_3-6 cycloalkyl, (CH₂)_rphenyl, C(O)R^10f, C(O)OR^10f, and SO₂R^10f;

alternatively, R⁹ and R¹⁰ join to form ═

O, a C_3-10 cycloalkyl, a 5-6-membered lactone or lactam, or a 4-6-membered saturated heterocycle containing 1-2 heteroatoms selected from O, S, and NR^10g and optionally fused with a benzene ring or a 6-membered aromatic heterocycle;

with the proviso that when either of R⁹ or R¹⁰ is halogen, cyano, nitro, or bonded to the carbon to which it is attached through a heteroatom, the other of R⁹ or R¹⁰ is not bonded to the carbon to which it is attached through a heteroatom;

R¹¹ is selected from H, C_1-8 alkyl, (CH₂)_rphenyl substituted with 0-5 R^11e, and a (CH₂)_r-heterocyclic system substituted with 0-2 R^11e, wherein the heterocyclic system is selected from pyridinyl, thiophenyl, furanyl, indazolyl, benzothiazolyl, benzimidazolyl, benzothiophenyl, benzofuranyl, benzoxazolyl, benzisoxazolyl, quinolinyl, isoquinolinyl, imidazolyl, indolyl, isoindolyl, piperidinyl, pyrrazolyl, 1,2,4-triazolyl, 1,2,3-triazolyl, tetrazolyl, thiazolyl, oxazolyl, pyrazinyl, and pyrimidinyl; and

R^11e, at each occurrence, is selected from C_1-6 alkyl, Cl, F, Br, I, CN, NO₂, (CF₂)_rCF₃, OH, and (CH₂)_rOC_1-5 alkyl;

R^11g is selected from H, C_1-6 alkyl, C_3-6 cycloalkyl, (CH₂)_rphenyl, C(O)R^11f, C(O)OR^11f, and SO₂R^11f;

R¹² is H;

alternatively, R¹¹ and R¹² join to form a C_3-10 cycloalkyl, a 5-6-membered lactone or lactam, or a 4-6-membered saturated heterocycle containing 1-2 heteroatoms selected from O, S, and NR^11g and optionally fused with a benzene ring or a 6-membered aromatic heterocycle;

R¹⁴, at each occurrence, is selected from C_1-8 alkyl, (CH₂)_rC_3-6 cycloalkyl, CF₃, Cl, Br, I, F, (CH₂)_rNR^14aR¹⁴′

, NO₂, CN, OH, (CH₂)_rOR^14d, (CH₂)_rC(O)R^14b, (CH₂)_rC(O)NR^14aR^14a′

, (CH₂)_rNR^14fC(O)R^14b, (CH₂)_rS(O)_pR^14b, (CH₂)_rS(O)₂NR^14aR^14a′

, (CH₂)_rNR^14fS(O)₂R^14b, (CH₂)_rphenyl substituted with 0-3 R^14e, and a (CH₂)_r-5-10 membered heterocyclic system containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-2 R^15e;

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 R^15e;

R^14a and R^14a′

, at each occurrence, are selected from H, C_1-6 alkyl, C_3-6 cycloalkyl, and (CH₂)_rphenyl substituted with 0-3 R^14e, and a (CH₂)_r-5-6 membered heterocyclic system containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-2 R^15e;

R^14b, at each occurrence, is selected from H, C_1-6 alkyl, C_3-6 cycloalkyl, and (CH₂)_rphenyl substituted with 0-3 R^14e,

R^14d, at each occurrence, is selected from C_1-6 alkyl and phenyl;

R^14e, at each occurrence, is selected from C_1-6 alkyl, Cl, F, Br, I, CN, NO₂, (CF₂)_rCF₃, OH, and (CH₂)_rOC_1-5 alkyl; and

R^14f, at each occurrence, is selected from H, and C_1-5 alkyl;

and

r is selected from 0, 1, and 2.

6. The compound of claim 5, wherein:

J is selected from CH₂ and CHR⁵;

K is selected from CH₂ and CHR⁵;

L is selected from CH₂ and CHR⁵;

R³ is selected from a C_1-10 alkyl substituted with 0-3 R^3g, C_3-10 alkenyl substituted with 0-3 R^3g, and C_3-10 alkynyl substituted with 0-3 R^3g;

R^3g, at each occurrence, is selected from Cl, Br, I, F, NO₂, CN, NR^3aR^3a′

, OH, O(CHR′

)_rR^3d, SH, C(O)H, S(CHR′

)_rR^3d, C(O)OH, C(O)(CHR′

)_rR^3b, C(O)NR^3aR^3a′

, NR^3fC(O)(CHR′

)_rR^3b, C(O)O(CHR′

)_rR^3d, OC(O)(CHR′

)_rR^3b, (CH₂)_rOC(O)NR^3aR^3a′

, (CH₂)_qNR^3aC(O)OR^3a, S(O)_p(CHR′

)_rR^3b, S(O)₂NR^3aR^3a′

, NR^3fS(O)₂(CHR′

)_rR^3b, phenyl substituted with 0-3 R¹⁵, and a heterocyclic system substituted with 0-3 R¹⁵, wherein the heterocyclic system is selected from pyridinyl, thiophenyl, furanyl, indazolyl, benzothiazolyl, benzimidazolyl, benzothiophenyl, benzofuranyl, benzoxazolyl, benzisoxazolyl, quinolinyl, isoquinolinyl, imidazolyl, indolyl, indolinyl, isoindolyl, isothiadiazolyl, isoxazolyl, piperidinyl, pyrrazolyl, 1,2,4-triazolyl, 1,2,3-triazolyl, tetrazolyl, thiadiazolyl, thiazolyl, oxazolyl, pyrazinyl, and pyrimidinyl, provided that when R^3g is a carbocyclic residue or a heterocyclic system, R³ has at least one other R^3g, which is not phenyl or a heterocyclic system;

R^3a and R^3a′

, at each occurrence, are selected from H, C_1-6 alkyl, C_3-8 alkenyl, C_3-8 alkynyl, and (CH₂)_r-phenyl substituted with 0-3 R^3e;

R^3b, at each occurrence, is selected from C_1-6 alkyl, and (CH₂)_r-phenyl substituted with 0-3 R^3e;

R^3d, at each occurrence, is selected from C_1-6 alkyl and phenyl substituted with 0-3 R^3e;

R^3e, at each occurrence, is selected from C_1-6 alkyl, Cl, F, Br, I, CN, NO₂, (CF₂)_rCF₃, (CH₂)_rOC_1-5 alkyl, OH;

R^3f, at each occurrence, is selected from H, C_1-5 alkyl;

R¹⁵, at each occurrence, is selected from C_1-8 alkyl, (CH₂)_rC_3-6 cycloalkyl, CF₃, Cl, Br, I, F, (CH₂)_rNR^15aR^15a′

, NO₂, CN, OH, (CH₂)_rOR^15d, (CH₂)_rC(O)R^15b, (CH₂)_rC(O)NR^15aR^15a′

, (CH₂)_rNR^15fC(O)R^15b, (CH₂)_rOC(O)NR^15aR^15a′

, (CH₂)_qNR^15aC(O)OR^15a, (CH₂)_rS(O)_pR^15b, (CH₂)_rS(O)₂NR^15aR^15a, (CH₂)_rNR^15fS(O)₂R^15b, (CH₂)_rphenyl substituted with 0-3 R^15e, and a heterocyclic system substituted with 0-3 R¹⁵, wherein the heterocyclic system is selected from pyridinyl, thiophenyl, furanyl, indazolyl, benzothiazolyl, benzimidazolyl, benzothiophenyl, benzofuranyl, benzoxazolyl, benzisoxazolyl, quinolinyl, isoquinolinyl, imidazolyl, indolyl, indolinyl, isoindolyl, isothiadiazolyl, isoxazolyl, piperidinyl, pyrrazolyl, 1,2,4-triazolyl, 1,2,3-triazolyl, tetrazolyl, thiadiazolyl, thiazolyl, oxazolyl, pyrazinyl, and pyrimidinyl;

R^15a and R^15a′

, at each occurrence, are selected from H, C_1-6 alkyl, C_3-6 cycloalkyl, and (CH₂)_rphenyl substituted with 0-3 R^15e;

alternatively, R^15a and R^15a′

, along with the N to which they are attached, are joined to form a morpholine, piperidine, or piperazine ring, and the piperazine optionally substituted with R^15g;

R^15b, at each occurrence, is selected from H, C_1-6 alkyl, C_3-6 cycloalkyl, and (CH₂)_rphenyl substituted with 0-3 R^15e;

R^15d, at each occurrence, is selected from C_1-6 alkyl and phenyl;

R^15e, at each occurrence, is selected from C_1-6 alkyl, Cl, F, Br, I, CN, NO₂, (CF₂)_rCF₃, OH, and (CH₂)_rOC_1-5 alkyl; and

R^15f, at each occurrence, is selected from H, and C_1-5 alkyl.

7. The compound of claim 6, wherein:

E is

Z is selected from O and N(CN);

R³ is selected from C_3-8 alkyl selected from methyl, ethyl, propyl, i-propyl, butyl, i-butyl, t-butyl, pentyl, methylpentyl, dimethylpentyl, and trimethylpentyl, wherein the C_3-8 alkyl is substituted with 0-2 R^3g;

R^3g, at each occurrence is selected from C(O)OR^3b, OR^3b, OH, OC(O)H, NHC(O)R^3b, CN, and NR^3aR^3a′

;

R^3a and R^3a′

, at each occurrence, are selected from H and methyl;

R^3b, at each occurrence, is selected from H, methyl, ethyl, propyl, and phenyl; and

R¹⁶ is selected from F, Cl, Br, and I.

8. The compound of claim 1 and pharmaceutically acceptable salt forms thereof, wherein the compound of formula (I) is selected from:

N-(t-butyl)-N′

-[(1R,2S)-2-[[(3S)-3-(4-fluorophenyl)methyl)piperidinyl]methyl]cyclohexyl]-urea,

N-(i-propyl)-N′

-[(1R,2S)-2-[[(3S)-3-(4-fluorophenyl)methyl)piperidinyl]methyl]cyclohexyl]-urea,

N-(ethoxycarbonylmethyl)-N′

-[(1R,2S)-2-[[(3S)-3-(4-fluorophenyl)methyl)piperidinyl]methyl]cyclohexyl]-urea,

N-[(1R,S)-1-(methoxycarbonyl)-2-methyl-propyl]-N′

-[(1R,2S)-2-[[(3S)-3-(4-fluorophenyl)methyl)piperidinyl]methyl]cyclohexyl]-urea,

N-[(1S)-1-(methoxycarbonyl)-2-phenylethyl]-N′

-[(1R,2S)-2-[[(3S)-3-(4-fluorophenyl)methyl)piperidinyl]methyl]cyclohexyl]-urea,

N-[2,4,4-trimethyl-2-pentyl]-N′

-[(1R,2S)-2-[[(3S)-3-(4-fluorophenyl)methyl)piperidinyl]methyl]cyclohexyl]-urea,

N-[(1S)-2-hydroxy-1-phenylethyl]-N′

-[(1R,2S)-2-[[(3S)-3-(4-fluorophenyl)methyl)piperidinyl]methyl]cyclohexyl]-urea,

2-({[(1R,2S)-2-{[(3S)-3-(4-fluorobenyl)piperidinyl]methyl}cyclohexyl}amino}carbon yl}amino)acetamide,

N-(2-methoxyethyl)-N′

-(1R,2S)-2-[[(3S)-3-(4-fluorophenyl)methyl)piperidinyl]methyl]cyclohexyl]-urea,

N-(2-ethoxyethyl)-N′

-(1R,2S)-2-[[(3S)-3-(4-fluorophenyl)methyl)piperidinyl]methyl]cyclohexyl]-urea,

N″

-cyano-N-(ethoxycarbonylmethyl)-N′

-(1R,2S)-2-[[(3S)-3-(4-fluorophenyl)methyl)piperidinyl]methyl]cyclohexyl]-guanidine,

2-{[((1R,2S)-2-{[(3S)-3-(4-fluorobenzyl)piperidinyl]methyl}cyclohexyl)amino][(2-methoxyethyl)amino]methylene}malonitrile,

N″

-cyano-N-(2-phenoxyethyl)-N′

-(1R,2S)-2-[[(3S)-3-(4-fluorophenyl)methyl)piperidinyl]methyl]cyclohexyl]-guanidine,

N″

-cyano-N-(2-methoxyethyl)-N′

-(1R,2S)-2-[[(3S)-3-(4-fluorophenyl)methyl)piperidinyl]methyl]cyclohexyl]-guanidine,

N-(2-dimethylaminoethyl)-N′

-{(1R,2R)-2-[(3S)-3-(4-fluorobenzyl)piperidine-1-carbonyl]cyclohexyl}-urea, and

N″

-cyano-N-(2-ethoxyethyl)-N′

-(1R,2S)-2-[[(3S)-3-(4-fluorophenyl)methyl)piperidinyl]methyl]cyclohexyl]-guanidine.

9. A pharmaceutical composition, comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of claim 1.

10. A method for treating inflammatory diseases, comprising administering to a patient in need thereof a therapeutically effective amount of a compound of claim 1.

11. A method for treating asthma, comprising administering to a patient in need thereof a therapeutically effective amount of a compound of claim 1.

12. A method for treating inflammatory disorder comprising administering to a patient in need thereof a therapeutically effective amount of a compound of claim 1, wherein the inflammatory disorder is selected from asthma, allergic rhinitis, atopic dermatitis, inflammatory bowel diseases, idiopathic pulmonary fibrosis, bullous pemphigoid, helminthic parasitic infections, allergic colitis, eczema, conjunctivitis, transplantation, familial eosinophilia, eosinophilic cellulitis, eosinophilic pneumonias, eosinophilic fasciitis, eosinophilic gastroenteritis, drug induced eosinophilia, HIV infection, cystic fibrosis, Churg-Strauss syndrome, lymphoma, Hodgkin'"'"'s disease, and colonic carcinoma.

13. The method of claim 12 for treating disorders selected from asthma, allergic rhinitis, atopic dermatitis, and inflammatory bowel diseases.

14. A method for treating inflammatory diseases which are at least partially mediated by CCR3, comprising administering to a patient in need thereof a therapeutically effective amount of a compound of claim 1.

15. A pharmaceutical composition, comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of claim 4.

16. A method for treating inflammatory diseases which are at least partially modulated by CCR3, comprising administering to a patient in need thereof a therapeutically effective amount of a compound of claim 4.

17. A method for treating asthma, comprising administering to a patient in need thereof a therapeutically effective amount of a compound of claim 4.

18. A pharmaceutical composition, comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of claim 7.

19. A method for treating inflammatory diseases which are at least partially mediated by CCR3, comprising administering to a patient in need thereof a therapeutically effective amount of a compound of claim 7.

20. A method for treating asthma, comprising administering to a patient in need thereof a therapeutically effective amount of a compound of claim 7.

21. A method for treating inflammatory disorder comprising administering to a patient in need thereof a therapeutically effective amount of a compound of claim 7, wherein the inflammatory disorder is selected from asthma, allergic rhinitis, atopic dermatitis, inflammatory bowel diseases, idiopathic pulmonary fibrosis, bullous pemphigoid, helminthic parasitic infections, allergic colitis, eczema, conjunctivitis, transplantation, familial eosinophilia, eosinophilic cellulitis, eosinophilic pneumonias, eosinophilic fasciitis, eosinophilic gastroenteritis, drug induced eosinophilia, HIV infection, cystic fibrosis, Churg-Strauss syndrome, lymphoma, Hodgkin'"'"'s disease, and colonic carcinoma.

22. The method of claim 21 for treating disorders selected from asthma, allergic rhinitis, atopic dermatitis, and inflammatory bowel diseases.

23. A method for treating inflammatory diseases which are at least partially mediated by CCR3, comprising administering to a patient in need thereof a therapeutically effective amount of a compound of claim 7.

24. A method for treating inflammatory disorder comprising administering to a patient in need thereof a therapeutically effective amount of a compound of claim 4, wherein the inflammatory disorder is selected from asthma, allergic rhinitis, atopic dermatitis, inflammatory bowel diseases, idiopathic pulmonary fibrosis, bullous pemphigoid, helminthic parasitic infections, allergic colitis, eczema, conjunctivitis, transplantation, familial eosinophilia, eosinophilic cellulitis, eosinophilic pneumonias, eosinophilic fasciitis, eosinophilic gastroenteritis, drug induced eosinophilia, HIV infection, cystic fibrosis, Churg-Strauss syndrome, lymphoma, Hodgkin'"'"'s disease, and colonic carcinoma.

25. The method of claim 24 for treating disorders selected from asthma, allergic rhinitis, atopic dermatitis, and inflammatory bowel diseases.

26. The method of claim 22 for treating disorders selected from allergic rhinits.

27. The method of claim 22 for treating disorders selected from atopic dermatitis.

28. The method of claim 22 for treating disorders selected from inflammatory bowel diseases.