Piperidine amides as modulators of chemokine receptor activity
First Claim
Patent Images
1. A compound of formula (I):
-
or stereoisomers or pharmaceutically acceptable salts thereof, wherein;
M selected from CH2, CHR5, CHR13, CR13R13, and CR5R13;
Q is selected from CH2, CHR5, CHR13, CR13R13, and CR5R13;
K is selected from CH2, CHR5 and CHR6;
J and L are independently selected from CH2, CHR5, CHR6, CR6R6 and CR5R6;
with the proviso that at least one of M, J, K, L, or Q contains an R5;
Z is selected from O, 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 —
(C═
O)—
(CR9R10)v—
(CR11R12)—
, —
(SO2)—
(CR9R10)v—
(CR11R12)—
, Ring A is a C3-8 carbocyclic residue;
R2 is 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 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;
R3 is selected from a (CR3′
R3″
)r—
C3-8 carbocyclic residue substituted with 0-5 R15;
a (CR3′
R3″
)r—
C9-10 carbocyclic residue substituted with 0-4 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;
R5 is selected from a (CR5′
R5″
)t—
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;
R6, at each occurrence, is selected from C1-6 alkyl, C2-8 alkenyl, C2-8 alkynyl, (CH2)rC3-6 cycloalkyl, (CF2)rCF3, CN, (CH2)rNR6aR6a′
, (CH2)rOH, (CH2)rOR6b, (CH2)rSH, (CH2)rSR6b, (CH2)rC(O)OH, (CH2)rC(O)R6b, (CH2)rC(O)NR6aR6a′
, (CH2)rNR6dC(O)R6a, (CH2)rC(O)OR6b, (CH2)rOC(O)R6b, (CH2)rS(O)pR6b, (CH2)rS(O)2NR6aR6a′
, (CH2)rNR6dS(O)2R6b, and (CH2)tphenyl substituted with 0-3 R6c;
R6a and R6a′
, at each occurrence, are selected from H, C1-6 alkyl, C3-6 cycloalkyl, and phenyl substituted with 0-3 R6c;
R6b, at each occurrence, is selected from C1-6 alkyl, C3-6 cycloalkyl, and phenyl substituted with 0-3 R6c;
R6c, at each occurrence, is 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)rNR6dR6d;
R6d, at each occurrence, is selected from H, C1-6 alkyl, and C3-6 cycloalkyl;
with the proviso that when any of J, K, or L is CR6R6 and R6 is halogen, cyano, nitro, or bonded to the carbon to which it is attached through a heteroatom, the other R6 is not halogen, cyano, or bonded to the carbon to which it is attached through a heteroatom;
R9, is selected from H, C1-6 alkyl, C2-8 alkenyl, C2-8 alkynyl, F, Cl, Br, I, NO2, CN, (CHR′
)rOH, (CH2)rOR9d, (CH2)rSR9d, (CH2)rNR9aR9a′
, (CH2)rC(O)OH, (CH2)rC(O)R9b, (CH2)rC(O)NR9aR9a′
, (CH2)rNR9aC(O)R9a, (CH2)rNR9aC(O)H, (CH2)rC(O)OR9b, (CH2)rOC(O)R9b, (CH2)rOC(O)NR9aR9a′
, (CH2)rNR9aC(O)OR9b, (CH2)rS(O)pR9b, (CH2)rS(O)2NR9aR9a′
, (CH2)rNR9aS(O)2R9b, C1-6 haloalkyl, a (CH2)r—
C3-10 carbocyclic residue substituted with 0-5 R9c, and a (CH2)r-5-10 membered heterocyclic system containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-3 R9c;
R9a and R9a′
, at each occurrence, are selected from H, C1-6 alkyl, C3-8 alkenyl, C3-8 alkynyl, a (CH2)r—
C3-10 carbocyclic residue substituted with 0-5 R9e, and a (CH2)r-5-10 membered heterocyclic system containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-3 R9e;
alternatively, R9a and R9a′
, along with the N to which they are attached, join to form a 5-6 membered heterocyclic system containing 1-2 heteroatoms selected from NR9g, O, and S and optionally fused with a benzene ring or a 6-membered aromatic heterocycle;
R9b, at each occurrence, is 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-5-6 membered heterocyclic system containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-3 R9e;
R9c, at each occurrence, is selected from C1-6 alkyl, C2-8 alkenyl, C2-8 alkynyl, (CH2)rC3-6 cycloalkyl, Cl, Br, I, F, (CF2)rCF3, NO2, CN, (CH2)rNR9fR9f, (CH2)rOH, (CH2)rOR9b, (CH2)rSR9b, (CH2)rC(O)OH, (CH2)rC(O)R9b, (CH2)rC(O)NR9fR9f, (CH2)rNR9fC(O)R9a, (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 selected from C1-6 alkyl, C3-6 alkenyl, C3-6 alkynyl, a C3-10 carbocyclic residue substituted with 0-3 R9c, and a 5-6 membered heterocyclic system containing 1-4 heteroatoms selected from the group consisting of N, O, and S substituted with 0-3 R9c;
R9e, at each occurrence, is selected from C1-6 alkyl, C2-8 alkenyl, C2-8 alkynyl, (CH2)rC3-6 cycloalkyl, Cl, F, Br, I, CN, NO2, (CF2)rCF3, (CH2)rOC1-5 alkyl, OH, SH, (CH2)rSC1-5 alkyl, (CH2)rNR9fR9f, and (CH2)rphenyl, wherein the phenyl on the (CH2)rphenyl is substituted with 0-5 substituents selected from F, Cl, Br, I, NO2, C1-6 alkyl, OH, and NR9fR9f;
R9f, at each occurrence, is 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 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 and R10a′
, at each occurrence, are selected from H, C1-6 alkyl, C3-8 alkenyl, C3-8 alkynyl, a (CH2)r—
C3-10 carbocyclic residue substituted with 0-5 R10e, and a (CH2)r-5-10 membered heterocyclic system containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-3 R10e;
alternatively, R10a and R1a′
, 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 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-5-6 membered heterocyclic system containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-3 R10e;
R10c, at each occurrence, is selected from C1-6 alkyl, C2-8 alkenyl, C2-8 alkynyl, (CH2)rC3-6 cycloalkyl, Cl, Br, I, F, (CF2)rCF3, NO2, CN, (CH2)rNR10fR10f, (CH2)rOH, (CH2)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 selected from C1-6 alkyl, C3-6 alkenyl, C3-6 alkynyl, and a C3-10 carbocyclic residue substituted with 0-3 R10c;
R10e, at each occurrence, is selected from C1-6 alkyl, C2-8 alkenyl, C2-8 alkynyl, (CH2)rC3-6 cycloalkyl, Cl, F, Br, I, CN, NO2, (CF2)rCF3, (CH2)rOC1-5 alkyl, OH, SH, (CH2)rSC1-5 alkyl, (CH2)rNR10fR10f, and (CH2)rphenyl;
R10f, at each occurrence, is selected from H, C1-6 alkyl, and C3-6 cycloalkyl;
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 selected from H, C1-6 alkyl, C3-6 cycloalkyl;
alternatively, R9 and R10 join to form ═
O, a C3-10 cycloalkyl, a 5-6-mernbered 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;
with the proviso that when either of R9 or R10 is bonded to the carbon to which it is attached through a heteroatom, then the other of R9 or R10 is not halogen, cyano, or bonded to the carbon to which it is attached through a heteroatom;
R11, is selected from H, C1-6 alkyl, C2-8 alkenyl, C2-8 alkynyl, (CR′
R17)qOH, (CH2)qSH, (CR′
R17)qOR11d, (CH2)qSR11d, (CR′
R17)qNR11aR11a′
,(CH2)rC(O)OH, (CH2)rC(O)R11b, (CH2)rC(O)NR11aR11a′
, (CH2)qNR11aC(O)R11a, (C2)qOC(O)NR11aR11a′
, (CH2)qNR11aC(O)OR11b, (CH2)qNR11aC(O)NHR11a, (CH2)rC(O)OR11b, (CH2)qOC(O)R11b, (CH2)qS(O)pR11b, (CH2)qS(O)2NR11aR11a′
, (CH2)qNR11aS(O)2R11b, C1-6 haloalkyl, a (CH2)r—
C3-10 carbocyclic residue substituted with 0-5 R11c, and a (R′
R17)r-5-10 membered heterocyclic system containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-3 R11c;
R11a and R11a′
, at each occurrence, are selected from H, C1-6 alkyl, C3-8 alkenyl, C3-8 alkynyl, a (CH2)r—
C3-10 carbocyclic residue substituted with 0-5 R11e, and a (CH2)r-5-10 membered heterocyclic system containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-3 R11e;
alternatively, R11a and R11a′
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 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-5-6 membered heterocyclic system containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-3 R11e;
R11c, at each occurrence, is selected from C1-6 alkyl, C2-8 alkenyl, C2-8 alkynyl, (CH2)rC3-6 cycloalkyl, Cl, Br, I, F, (CF2)rCF3, NO2, CN, (CH2)rNR11fR11f, (CH2)rOH, (CH2)rOC1-4 alkyl, (CH2)rSC1-4 alkyl, (CH2)rC(O)OH, (CH2)rC(O)R11b, (CH2)rC(O)NR11fR11f, (CH2)rNR11fC(O)R11a, (CH2)rC(O)OC1-4 alkyl, (CH2)rOC(O)R11b, (CH2)rC(═
NR11f)NR11fR11f, (CH2)rNHC(═
NR11f)NR11fR11f, (CH2)rS(O)pR11b, (CH2)rS(O)2NR11fR11f, (CH2)rNR11fS(O)2R11b, and (CH2)rphenyl substituted with 0-3 R11e;
R11d, at each occurrence, is selected from C1-6 alkyl, C3-6 alkenyl, C3-6 alkynyl, and a C3-10 carbocyclic residue substituted with 0-3 R11c;
R11e, at each occurrence, is selected from C1-6 alkyl, C2-8 alkenyl, C2-8 alkynyl, C3-6 cycloalkyl, Cl, F, Br, I, CN, NO2, (CF2)rCF3, (CH2)rOC1-5 alkyl, OH, SH, (CH2)rSC1-5 alkyl, (CH2)rNR11fR11f, and (CH2)rphenyl, wherein the phenyl on the (CH2)rphenyl is substituted with 0-5 substituents selected from F, Cl, Br, I, NO2, C1-6 alkyl, OH, and NR9fR9f;
R11f, at each occurrence, is 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 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 (R′
R17)r-5-10 membered heterocyclic system containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-3 R12c;
R12a and R12a′
, 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 R12e, and a (CH2)r-5-10 membered heterocyclic system containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-3 R12e;
alternatively, R12a and R12a′
, 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 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-5-6 membered heterocyclic system containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-3 R12e;
R12c, 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)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)NR12fR12f, (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 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 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 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 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 NR11g and optionally fused with a benzene ring or a 6-membered aromatic heterocycle;
R13, at each occurrence, is 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 and R13a′
, at each occurrence, are selected from H, C1-6 alkyl, C3-6 cycloalkyl, and phenyl substituted with 0-3 R13c;
R13b, at each occurrence, is selected from C1-6 alkyl, C3-6 cycloalkyl, and phenyl substituted with 0-3 R13c;
R13c, at each occurrence, is 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 selected from H, C1-6 alkyl, and C3-6 cycloalkyl;
R14, at each occurrence, is 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-5-10 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 and R14a′
, 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 R14e, and a (CH2)r-5-10 membered heterocyclic system containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-2 R14e;
R14b, at each occurrence, is 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-5-6 membered heterocyclic system containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-2 R14e;
R14d, at each occurrence, is 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)r-5-6 membered heterocyclic system containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-3 R14e;
R14e, 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)rNR14fR14f, and (CH2)rphenyl;
R14f, at each occurrence, is selected from H, C1-6 alkyl, C3-6 cycloalkyl, and phenyl;
R15, at each occurrence, is selected from C1-8 alkyl, (CH2)rC3-6 cycloalkyl, Cl, Br, I, F, NO2, CN, (CR′
R17)rNR15aR15a′
, (CR′
R17)rOH, (CR′
R17)rO(CHR′
)rR15d, (CR′
R17)rSH, (CR′
R17)rC(O)H, (CR′
R17)rS(CHR′
)rR15d, (CR′
R17)rC(O)OH, (CR′
R17)rC(O) (CHR′
)rR15b, (CR′
R17)rC(O)NR15aR15a′
, (CR′
R17)rNR15fC(O) (CHR′
)rR15b, (CR′
R17)rOC (O)NR15aR15a′
, (CR′
R17)rNR15fC(O)O(CHR′
)rR15b, (CR′
R17)rNR15fC(O)NR15fR15f, (CR′
R17)rC(O)O(CHR′
)rR15d, (CR′
R17)rOC(O)(CHR′
)rR15b, (CR′
R17)rC(═
NR15f)NR15aR15a′
, (CR′
R17)rNHC(═
NR15f)NR15fR15f, (CR′
R17)rS(O)p(CHR′
)rR15b, (CR′
R17)rS(O)2NR15aR15a′
, (CR′
R17)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′
R17)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 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;
alternatively, R15a and R15a′
, along with the N to which they are attached, jointo 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 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-5-6membered 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)r-5-6 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, 2-cyanoethyl, 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 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 selected from C1-6 alkyl, C3-6 cycloalkyl;
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)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 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, 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 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, at each occurrence, is independently selected from H and methyl;
R′
, at each occurrence, is selected from H, C1-6 alkyl, C3-8 alkenyl, C3-8 alkynyl, (CH2)rC3-6 cycloalkyl, and (CH2)rphenyl substituted with R15e;
g is selected from 0, 1, 2, 3, and 4;
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
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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.
39 Citations
31 Claims
-
1. A compound of formula (I):
-
or stereoisomers or pharmaceutically acceptable salts thereof, wherein; M selected from CH2, CHR5, CHR13, CR13R13, and CR5R13;
Q is selected from CH2, CHR5, CHR13, CR13R13, and CR5R13;
K is selected from CH2, CHR5 and CHR6;
J and L are independently selected from CH2, CHR5, CHR6, CR6R6 and CR5R6;
with the proviso that at least one of M, J, K, L, or Q contains an R5;
Z is selected from O, 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 —
(C═
O)—
(CR9R10)v—
(CR11R12)—
, —
(SO2)—
(CR9R10)v—
(CR11R12)—
,Ring A is a C3-8 carbocyclic residue;
R2 is 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 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;
R3 is selected from a (CR3′
R3″
)r—
C3-8 carbocyclic residue substituted with 0-5 R15;
a (CR3′
R3″
)r—
C9-10 carbocyclic residue substituted with 0-4 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;
R5 is selected from a (CR5′
R5″
)t—
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;
R6, at each occurrence, is selected from C1-6 alkyl, C2-8 alkenyl, C2-8 alkynyl, (CH2)rC3-6 cycloalkyl, (CF2)rCF3, CN, (CH2)rNR6aR6a′
, (CH2)rOH, (CH2)rOR6b, (CH2)rSH, (CH2)rSR6b, (CH2)rC(O)OH, (CH2)rC(O)R6b, (CH2)rC(O)NR6aR6a′
, (CH2)rNR6dC(O)R6a, (CH2)rC(O)OR6b, (CH2)rOC(O)R6b, (CH2)rS(O)pR6b, (CH2)rS(O)2NR6aR6a′
, (CH2)rNR6dS(O)2R6b, and (CH2)tphenyl substituted with 0-3 R6c;
R6a and R6a′
, at each occurrence, are selected from H, C1-6 alkyl, C3-6 cycloalkyl, and phenyl substituted with 0-3 R6c;
R6b, at each occurrence, is selected from C1-6 alkyl, C3-6 cycloalkyl, and phenyl substituted with 0-3 R6c;
R6c, at each occurrence, is 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)rNR6dR6d;
R6d, at each occurrence, is selected from H, C1-6 alkyl, and C3-6 cycloalkyl;
with the proviso that when any of J, K, or L is CR6R6 and R6 is halogen, cyano, nitro, or bonded to the carbon to which it is attached through a heteroatom, the other R6 is not halogen, cyano, or bonded to the carbon to which it is attached through a heteroatom;
R9, is selected from H, C1-6 alkyl, C2-8 alkenyl, C2-8 alkynyl, F, Cl, Br, I, NO2, CN, (CHR′
)rOH, (CH2)rOR9d, (CH2)rSR9d, (CH2)rNR9aR9a′
, (CH2)rC(O)OH, (CH2)rC(O)R9b, (CH2)rC(O)NR9aR9a′
, (CH2)rNR9aC(O)R9a, (CH2)rNR9aC(O)H, (CH2)rC(O)OR9b, (CH2)rOC(O)R9b, (CH2)rOC(O)NR9aR9a′
, (CH2)rNR9aC(O)OR9b, (CH2)rS(O)pR9b, (CH2)rS(O)2NR9aR9a′
, (CH2)rNR9aS(O)2R9b, C1-6 haloalkyl, a (CH2)r—
C3-10 carbocyclic residue substituted with 0-5 R9c, and a (CH2)r-5-10 membered heterocyclic system containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-3 R9c;
R9a and R9a′
, at each occurrence, are selected from H, C1-6 alkyl, C3-8 alkenyl, C3-8 alkynyl, a (CH2)r—
C3-10 carbocyclic residue substituted with 0-5 R9e, and a (CH2)r-5-10 membered heterocyclic system containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-3 R9e;
alternatively, R9a and R9a′
, along with the N to which they are attached, join to form a 5-6 membered heterocyclic system containing 1-2 heteroatoms selected from NR9g, O, and S and optionally fused with a benzene ring or a 6-membered aromatic heterocycle;
R9b, at each occurrence, is 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-5-6 membered heterocyclic system containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-3 R9e;
R9c, at each occurrence, is selected from C1-6 alkyl, C2-8 alkenyl, C2-8 alkynyl, (CH2)rC3-6 cycloalkyl, Cl, Br, I, F, (CF2)rCF3, NO2, CN, (CH2)rNR9fR9f, (CH2)rOH, (CH2)rOR9b, (CH2)rSR9b, (CH2)rC(O)OH, (CH2)rC(O)R9b, (CH2)rC(O)NR9fR9f, (CH2)rNR9fC(O)R9a, (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 selected from C1-6 alkyl, C3-6 alkenyl, C3-6 alkynyl, a C3-10 carbocyclic residue substituted with 0-3 R9c, and a 5-6 membered heterocyclic system containing 1-4 heteroatoms selected from the group consisting of N, O, and S substituted with 0-3 R9c;
R9e, at each occurrence, is selected from C1-6 alkyl, C2-8 alkenyl, C2-8 alkynyl, (CH2)rC3-6 cycloalkyl, Cl, F, Br, I, CN, NO2, (CF2)rCF3, (CH2)rOC1-5 alkyl, OH, SH, (CH2)rSC1-5 alkyl, (CH2)rNR9fR9f, and (CH2)rphenyl, wherein the phenyl on the (CH2)rphenyl is substituted with 0-5 substituents selected from F, Cl, Br, I, NO2, C1-6 alkyl, OH, and NR9fR9f;
R9f, at each occurrence, is 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 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 and R10a′
, at each occurrence, are selected from H, C1-6 alkyl, C3-8 alkenyl, C3-8 alkynyl, a (CH2)r—
C3-10 carbocyclic residue substituted with 0-5 R10e, and a (CH2)r-5-10 membered heterocyclic system containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-3 R10e;
alternatively, R10a and R1a′
, 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 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-5-6 membered heterocyclic system containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-3 R10e;
R10c, at each occurrence, is selected from C1-6 alkyl, C2-8 alkenyl, C2-8 alkynyl, (CH2)rC3-6 cycloalkyl, Cl, Br, I, F, (CF2)rCF3, NO2, CN, (CH2)rNR10fR10f, (CH2)rOH, (CH2)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 selected from C1-6 alkyl, C3-6 alkenyl, C3-6 alkynyl, and a C3-10 carbocyclic residue substituted with 0-3 R10c;
R10e, at each occurrence, is selected from C1-6 alkyl, C2-8 alkenyl, C2-8 alkynyl, (CH2)rC3-6 cycloalkyl, Cl, F, Br, I, CN, NO2, (CF2)rCF3, (CH2)rOC1-5 alkyl, OH, SH, (CH2)rSC1-5 alkyl, (CH2)rNR10fR10f, and (CH2)rphenyl;
R10f, at each occurrence, is selected from H, C1-6 alkyl, and C3-6 cycloalkyl;
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 selected from H, C1-6 alkyl, C3-6 cycloalkyl;
alternatively, R9 and R10 join to form ═
O, a C3-10 cycloalkyl, a 5-6-mernbered 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;
with the proviso that when either of R9 or R10 is bonded to the carbon to which it is attached through a heteroatom, then the other of R9 or R10 is not halogen, cyano, or bonded to the carbon to which it is attached through a heteroatom;
R11, is selected from H, C1-6 alkyl, C2-8 alkenyl, C2-8 alkynyl, (CR′
R17)qOH, (CH2)qSH, (CR′
R17)qOR11d, (CH2)qSR11d, (CR′
R17)qNR11aR11a′
,(CH2)rC(O)OH, (CH2)rC(O)R11b, (CH2)rC(O)NR11aR11a′
, (CH2)qNR11aC(O)R11a, (C2)qOC(O)NR11aR11a′
, (CH2)qNR11aC(O)OR11b, (CH2)qNR11aC(O)NHR11a, (CH2)rC(O)OR11b, (CH2)qOC(O)R11b, (CH2)qS(O)pR11b, (CH2)qS(O)2NR11aR11a′
, (CH2)qNR11aS(O)2R11b, C1-6 haloalkyl, a (CH2)r—
C3-10 carbocyclic residue substituted with 0-5 R11c, and a (R′
R17)r-5-10 membered heterocyclic system containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-3 R11c;
R11a and R11a′
, at each occurrence, are selected from H, C1-6 alkyl, C3-8 alkenyl, C3-8 alkynyl, a (CH2)r—
C3-10 carbocyclic residue substituted with 0-5 R11e, and a (CH2)r-5-10 membered heterocyclic system containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-3 R11e;
alternatively, R11a and R11a′
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 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-5-6 membered heterocyclic system containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-3 R11e;
R11c, at each occurrence, is selected from C1-6 alkyl, C2-8 alkenyl, C2-8 alkynyl, (CH2)rC3-6 cycloalkyl, Cl, Br, I, F, (CF2)rCF3, NO2, CN, (CH2)rNR11fR11f, (CH2)rOH, (CH2)rOC1-4 alkyl, (CH2)rSC1-4 alkyl, (CH2)rC(O)OH, (CH2)rC(O)R11b, (CH2)rC(O)NR11fR11f, (CH2)rNR11fC(O)R11a, (CH2)rC(O)OC1-4 alkyl, (CH2)rOC(O)R11b, (CH2)rC(═
NR11f)NR11fR11f, (CH2)rNHC(═
NR11f)NR11fR11f, (CH2)rS(O)pR11b, (CH2)rS(O)2NR11fR11f, (CH2)rNR11fS(O)2R11b, and (CH2)rphenyl substituted with 0-3 R11e;
R11d, at each occurrence, is selected from C1-6 alkyl, C3-6 alkenyl, C3-6 alkynyl, and a C3-10 carbocyclic residue substituted with 0-3 R11c;
R11e, at each occurrence, is selected from C1-6 alkyl, C2-8 alkenyl, C2-8 alkynyl, C3-6 cycloalkyl, Cl, F, Br, I, CN, NO2, (CF2)rCF3, (CH2)rOC1-5 alkyl, OH, SH, (CH2)rSC1-5 alkyl, (CH2)rNR11fR11f, and (CH2)rphenyl, wherein the phenyl on the (CH2)rphenyl is substituted with 0-5 substituents selected from F, Cl, Br, I, NO2, C1-6 alkyl, OH, and NR9fR9f;
R11f, at each occurrence, is 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 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 (R′
R17)r-5-10 membered heterocyclic system containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-3 R12c;
R12a and R12a′
, 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 R12e, and a (CH2)r-5-10 membered heterocyclic system containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-3 R12e;
alternatively, R12a and R12a′
, 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 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-5-6 membered heterocyclic system containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-3 R12e;
R12c, 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)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)NR12fR12f, (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 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 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 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 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 NR11g and optionally fused with a benzene ring or a 6-membered aromatic heterocycle;
R13, at each occurrence, is 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 and R13a′
, at each occurrence, are selected from H, C1-6 alkyl, C3-6 cycloalkyl, and phenyl substituted with 0-3 R13c;
R13b, at each occurrence, is selected from C1-6 alkyl, C3-6 cycloalkyl, and phenyl substituted with 0-3 R13c;
R13c, at each occurrence, is 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 selected from H, C1-6 alkyl, and C3-6 cycloalkyl;
R14, at each occurrence, is 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-5-10 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 and R14a′
, 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 R14e, and a (CH2)r-5-10 membered heterocyclic system containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-2 R14e;
R14b, at each occurrence, is 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-5-6 membered heterocyclic system containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-2 R14e;
R14d, at each occurrence, is 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)r-5-6 membered heterocyclic system containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-3 R14e;
R14e, 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)rNR14fR14f, and (CH2)rphenyl;
R14f, at each occurrence, is selected from H, C1-6 alkyl, C3-6 cycloalkyl, and phenyl;
R15, at each occurrence, is selected from C1-8 alkyl, (CH2)rC3-6 cycloalkyl, Cl, Br, I, F, NO2, CN, (CR′
R17)rNR15aR15a′
, (CR′
R17)rOH, (CR′
R17)rO(CHR′
)rR15d, (CR′
R17)rSH, (CR′
R17)rC(O)H, (CR′
R17)rS(CHR′
)rR15d, (CR′
R17)rC(O)OH, (CR′
R17)rC(O) (CHR′
)rR15b, (CR′
R17)rC(O)NR15aR15a′
, (CR′
R17)rNR15fC(O) (CHR′
)rR15b, (CR′
R17)rOC (O)NR15aR15a′
, (CR′
R17)rNR15fC(O)O(CHR′
)rR15b, (CR′
R17)rNR15fC(O)NR15fR15f, (CR′
R17)rC(O)O(CHR′
)rR15d, (CR′
R17)rOC(O)(CHR′
)rR15b, (CR′
R17)rC(═
NR15f)NR15aR15a′
, (CR′
R17)rNHC(═
NR15f)NR15fR15f, (CR′
R17)rS(O)p(CHR′
)rR15b, (CR′
R17)rS(O)2NR15aR15a′
, (CR′
R17)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′
R17)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 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;
alternatively, R15a and R15a′
, along with the N to which they are attached, jointo 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 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-5-6membered 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)r-5-6 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, 2-cyanoethyl, 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 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 selected from C1-6 alkyl, C3-6 cycloalkyl;
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)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 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, 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 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, at each occurrence, is independently selected from H and methyl;
R′
, at each occurrence, is selected from H, C1-6 alkyl, C3-8 alkenyl, C3-8 alkynyl, (CH2)rC3-6 cycloalkyl, and (CH2)rphenyl substituted with R15e;
g is selected from 0, 1, 2, 3, and 4;
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 - View Dependent Claims (2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31)
Z is selected from O, S, N(CN), and N(CONH2);
R2 is selected from H and C1-4 alkyl;
R6, at each occurrence, is selected from C1-4 alkyl, C2-8 alkenyl, C2-8 alkynyl, (CH2)rC3-6 cycloalkyl, (CF2)rCF3, CN, (CH2)rOH, (CH2)rOR6b, (CH2)rC(O)R6b, (CH2)rC(O)NR6aR6a′
, (CH2)rNR6dC(O)R6a, and (CH2)tphenyl substituted with 0-3 R6c;
R6a and R6a′
, at each occurrence, are selected from H, C1-6 alkyl, C3-6 cycloalkyl, and phenyl substituted with 0-3 R6c;
R6b, at each occurrence, is selected from C1-6 alkyl, C3-6 cycloalkyl, and phenyl substituted with 0-3 R6c;
R6c, at each occurrence, is 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)rNR6dR6d;
R6d, at each occurrence, is selected from H, C1-6 alkyl, and C3-6 cycloalkyl;
R13, at each occurrence, is selected from C1-4 alkyl, C3-6 cycloalkyl, (CH2)NR13aR13a′
, (CHR′
)OH, (CH2)OR13b, (CH2)wC(O)R13b, (CH2)wC(O)NR13aR13a′
, (CH2)NR13dC(O)R13a, (CH2)wS(O)2NR13aR13a′
, (CH2)NR13dS(O)2R13b, and (CH2)w-phenyl substituted with 0-3 R13c;
R13a and R13a′
, at each occurrence, are selected from H, C1-6 alkyl, C3-6 cycloalkyl, and phenyl substituted with 0-3 R13c;
R13b, at each occurrence, is selected from C1-6 alkyl, C3-6 cycloalkyl, and phenyl substituted with 0-3 R13c;
R13c, at each occurrence, is selected from C1-6 alkyl, C3-6 cycloalkyl, Cl, F, Br, I, CN, NO2, (CF2)rCF3, (CH2)rOC1-5 alkyl, (CH2)rOH, and (CH2)rNR13dR13d;
R13d, at each occurrence, is selected from H, C1-6 alkyl, and C3-6 cycloalkyl;
v is selected from 0, 1 and 2;
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:
-
E is —
(C═
O)—
(CR9R10)v—
(CR11R12)—
, —
(SO2)—
(CR9R10)v—
(CR11R12)—
,R3 is selected from (CH2)2N(CH3)2, a (CR3′
H)r-carbocyclic residue substituted with 0-5 R15, wherein the carbocyclic residue is selected from phenyl, C3-6 cycloalkyl, naphthyl, and adamantyl; and
a (CR3′
H)r-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; and
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) is:
-
R16, at each occurrence, is selected from C1-8 alkyl, (CH2)rC3-6 cycloalkyl, CF3, Cl, Br, I, F, (CH2)rNR16aR16a′
, NO2, CN, OH, (CH2)rOR16d, (CH2)rC(O)R16b, (CH2)rC(O)NR16aR16a′
, (CH2)rNR16fC(O)R16b, (CH2)rS(O)pR16b, (CH2)rS(O)2NR16aR16a′
, (CH2)rNR16fS(O)2R16b, and (CH2)rphenyl substituted with 0-3 R16e;
R16a and R16a′
, at each occurrence, are selected from H, C1-6 alkyl, C3-6 cycloalkyl, and (CH2)rphenyl substituted with 0-3 R16e;
R16b, at each occurrence, is selected from C1-6 alkyl, C3-6 cycloalkyl, and (CH2)rphenyl substituted with 0-3 R16e;
R16d, at each occurrence, is selected from C1-6 alkyl and phenyl;
R16e, at each occurrence, is selected from C1-6 alkyl, Cl, F, Br, I, CN, NO2, (CF2)rCF3, OH, and (CH2)rOC1-5 alkyl; and
R16f, at each occurrence, is selected from H, and C1-5 alkyl.
-
-
5. The compound of claim 4, wherein:
-
R5 is CH2phenyl substituted with 0-3 R16;
E is —
(C═
O)—
(CR9R10)v—
(CR11R12)—
, orr 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 a (CH2)r—
C3-10 carbocyclic residue substituted with 0-3 R15, wherein the carbocyclic residue is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, naphthyl and adamantyl, and a (CR3′
H)r-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.
-
-
7. The compound of claim 3, wherein:
-
M is absent or selected from CH2;
Q is CH2;
J is CH2;
K and L are independently selected from CH2 and CHR5;
Z is O, S, NCN, or NCONH2;
R1 is H;
R2 is H;
R3 is selected from a (CH2)rN(CH3)2, a (CH2)r—
C3-10carbocyclic residue substituted with 0-3 R15, wherein the carbocyclic residue is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, naphthyl and adamantyl, and a (CR3′
H)r-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; and
R5 is selected from a CH2-phenyl substituted with 0-5 R16 and a CH2-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.
-
-
8. The compound of formula (II) of claim 6:
-
or stereoisomers or pharmaceutically acceptable salts thereof, wherein; J, K, and L are independently selected from CH2 and CHR5;
Z is selected from O, and N(CN);
E is —
(C═
O)—
(CR9R10)v—
CR11R12—
, orRing A is cyclohexyl;
R3 is selected from (CH2)rN(CH3)2, cyclopropyl, —
CH2-cyclopropyl, phenyl substituted with 0-2 R15; and
a (CH2)r-5-10 membered heterocyclic system containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-2 R15, wherein the heterocyclic system is selected from morpholinyl, pyridinyl, and thiazolyl;
R5 is selected from a —
CH2-phenyl substituted with 0-2 R16;
R9 is selected from H, OH, N(CO)CH3, and NR9aR9a′
;
R9a and R9a′
, at each occurrence, are selected from H, methyl, ethyl, propyl, butyl, i-butyl;
alternatively, R9 and R10 join to form cyclohexyl;
R11 is selected from H, methyl, (CH2)rCONR11aR11a′
, C(O)OR11b, and a (CH2)-heterocyclic system, wherein the heterocyclic system is selected from morpholinyl and piperidinyl;
R11a and R11a′
are independently selected from H, methyl, ethyl, propyl, i-propyl, butyl, i-butyl and t-butyl;
alternatively, R11a and R11a′
along with the N to which they are attached, join to form a 5-6 membered heterocyclic system, wherein the heterocyclic system is selected from morpholinyl, piperidinyl, pyrrolidinyl, azapanyl, and N-methylpiperazinyl;
R11b is CH2-phenyl;
R11g is selected from H, methyl, ethyl, propyl, i-propyl, C(O)OR11h, and SO2R11h;
R11h is selected from methyl, ethyl, propyl, i-propyl, butyl, i-butyl and t-butyl;
R12 is H;
or alternatively, R11 and R12 join to form cyclopropyl, cyclopentyl, cyclohexyl, benzocyclopentyl, benzocyclohexyl, tetrahydropyan, tetrahydrofuran, or a 5-6-membered saturated heterocycle containing NR11g selected from pyrrolidine, and piperidine ring;
R15, at each occurrence, is selected from methyl, ethyl, propyl, i-propyl, butyl, i-butyl, pentyl, CF3, Cl, Br, I, F, NO2, CN, OH, OCH3, C(O)OR15b, C(O)OH, C(O)CH3, C(O)NR15aR15a′ and
a 5-6 membered heterocyclic system containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-2 R15e, wherein the heterocyclic system is selected from triazolyl, imidazolyl, tetrazolyl, pyrazolyl, oxazolyl, and isoxazolyl;
R15a and R15a′
are selected from hydrogen, methyl, ethyl, propyl, i-propyl, butyl, t-butyl, and a heterocyclic system containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-2 R15e, wherein the heterocyclic system is selected from morpholinyl;
R15b is selected from methyl and benzyl;
R15e is selected from methyl, ethyl and 2-cyanoethyl;
R16, at each occurrence, is selected from Cl, Br, I, and F, v is 0 or 1; and
r is 0, 1, or 2.
-
-
9. The compound of claim 1 wherein the compound is selected from:
-
N-(3,5-diacetylphenyl)-N′
-[3-[(3S)-3-[(4-fluorophenyl)methyl]piperidinyl]-3-oxopropyl]-urea;
N″
-cyano-N-(3,5-diacetylphenyl)-N′
-[3-[(3S)-3-[(4-fluorophenyl)methyl]piperidinyl]-3-oxopropyl]-guanidine;
N-(3-acetylphenyl)-N′
-[(1S,2S)-2-[[(3S)-3-[(4-fluorophenyl)methyl]piperidinyl]carbonyl]cyclohexyl]-urea;
N-(3-acetylphenyl)-N′
-[(1R,2R)-2-[[(3S)-3-[(4-fluorophenyl)methyl]piperidinyl]carbonyl]cyclohexyl]-urea;
N′
-[(1R,2R)-2-[[(3S)-3-[(4-fluorophenyl)methyl]piperidinyl]carbonyl]cyclohexyl]-N′
-[3-(1-methyl-1H-tetrazol-5-yl)phenyl]-urea;
N-[(1R,2R)-2-[[(3S)-3-[(4-fluorophenyl)methyl]piperidinyl]carbonyl]cyclohexyl]-N′
-[4-(1-methyl-1H-tetrazol-5-yl)phenyl]-urea;
N″
-cyano-N-[(1R,2R)-2-[[(3S)-3-[(4-fluorophenyl)methyl]piperidinyl]carbonyl]cyclohexyl]-N′
-[4-(1-methyl-1H-tetrazol-5-yl)phenyl]-guanidine;
N-[(1R,2R)-2-[[(3S)-3-[(4-fluorophenyl)methyl]piperidinyl]carbonyl]cyclohexyl]-N′
-(4-pyridinyl)-urea;
N-[(1R,2R)-2-[[(3S)-3-[(4-fluorophenyl)methyl]piperidinyl]carbonyl]cyclohexyl]-N′
-[2-(4-morpholinyl)ethyl]-urea;
N″
-cyano-N-[(1R,2R)-2-[[(3S)-3-[(4-fluorophenyl)methyl]piperidinyl]carbonyl]cyclohexyl]-N′
-[3-(1-methyl-1H-tetrazol-5-yl)phenyl]-guanidine;
N-(5-acetyl-4-methyl-2-thiazolyl)-N′
-[(1R,2R)-2-[[(3S)-3-[(4-fluorophenyl)methyl]piperidinyl]carbonyl]cyclohexyl]-urea;
N-(3-acetylphenyl)-N′
-[1-[[(3S)-3-[(4-fluorophenyl)methyl]piperidinyl]carbonyl]cyclohexyl]-urea;
N-[3,5-bis(1-methyl-1H-tetrazol-5-yl)phenyl]-N′
-[(1R,2R)-2-[[(3S)-3-[(4-fluorophenyl)methyl]piperidinyl]carbonyl]cyclohexyl]-urea;
N-[3,5-di(1H-imidazol-1-yl)phenyl]-N′
-[(1R,2R)-2-[[(3S)-3-[(4-fluorophenyl)methyl]piperidinyl]carbonyl]cyclohexyl]-urea;
N-[3,5-di(1H-1,2,4-triazol-1-yl)phenyl]-N′
-[(1R,2R)-2-[[(3S)-3-[(4-fluorophenyl)methyl]piperidinyl]carbonyl]cyclohexyl]-urea;
N-(3-acetylphenyl)-N′
-[1-[[(3S)-3-[(4-fluorophenyl)methyl]piperidinyl]carbonyl]cyclopentyl]-urea;
N-(3-acetylphenyl)-N′
-[1-[[(3S)-3-[(4-fluorophenyl)methyl]piperidinyl]carbonyl]cyclopropyl]-urea;
N-(3-acetylphenyl-N′
-[2-[[(3S)-3-[(4-fluorophenyl)methyl]piperidinyl]carbonyl]-2,3-dihydro-1H-inden-2-yl]-urea;
N-(3-acetylphenyl)-N′
-[2-[[(3S)-3-[(4-fluorophenyl)methyl]piperidinyl]carbonyl]-1,2,3,4-tetrahydro-2-naphthalenyl]-urea;
N-(5-acetyl-4-methyl-2-thiazolyl)-N′
-[1-[[(3S)-3-[(4-fluorophenyl)methyl]piperidinyl]carbonyl]cyclopropyl]-urea;
N-(3-acetylphenyl)-N′
-[2-[(3S)-3-[(4-fluorophenyl)methyl]piperidinyl]-2-oxoethyl]-urea;
N-[3,5-bis (1-ethyl-1H-tetrazol-5-yl)phenyl]-N′
-[(1R,2R)-2-[[(3S)-3-[(4-fluorophenyl)methyl]piperidinyl]carbonyl]cyclohexyl]-urea;
N-[1-[[(3S)-3-[(4-fluorophenyl)methyl]piperidinyl]carbonyl]cyclopropyl]-N′
-[3-(1-methyl-1H-tetrazol-5-yl)phenyl]-urea;
(alpha-1S,3S)-3-[(4-fluorophenyl)methyl]-alpha-[[[[3-(1-methyl-1H-tetrazol-5-yl)phenyl]amino]carbonyl]amino]-gamma-oxo-1-piperidinebutanoic acid, phenylmethyl ester;
(alpha-1S,3S)-3-[(4-fluorophenyl)methyl]-N-methyl-alpha-[[[[3-(1-methyl-1H-tetrazol-5-yl)phenyl]amino]carbonyl]amino]-gamma-oxo-1-piperidinebutanamide;
N-[(1S)-3-[(3S)-3-[(4-fluorophenyl)methyl]piperidinyl]-1-(4-morpholinylcarbonyl)-3-oxopropyl]-N′
-[3-(1-methyl-1H-tetrazol-5-yl)phenyl]-urea;
3-[[[[(1R,2R)-2-[[(3S)-3-[(4-fluorophenyl)methyl]piperidinyl]carbonyl]cyclohexyl]amino]carbonyl]amino]-benzoic acid, ethyl ester;
3-[[[[(1R,2R)-2-[[(3S)-3-[(4-fluorophenyl)methyl]piperidinyl]carbonyl]cyclohexyl]amino]carbonyl]amino]benzoic acid;
N-[1-[[(3S)-3-[(4-fluorophenyl)methyl]piperidinyl]carbonyl]cyclopropyl]-N′
-[3-(4-morpholinylcarbonyl)phenyl]-urea;
N-[(1R,2R)-2-[[(3S)-3-[(4-fluorophenyl)methyl]piperidinyl]carbonyl]cyclohexyl]-N′
-[2-methoxy-5-(1-methyl-1H-tetrazol-5-yl)phenyl]-urea;
N-[3-[1-(2-cyanoethyl)-1H-tetrazol-5-yl]phenyl]-N′
-[(1R,2R)-2-[[(3S)-3-[(4-fluorophenyl)methyl]piperidinyl]carbonyl]cyclohexyl]-urea;
N-[(1R,2R)-2-[[(3S)-3-[(4-fluorophenyl)methyl]piperidinyl]carbonyl]cyclohexyl]-N′
-[3-(1H-tetrazol-5-yl)phenyl]-urea;
3-[[[[1-[[(3S)-3-[(4-fluorophenyl)methyl]piperidinyl]carbonyl]cyclopropyl]amino]carbonyl]amino]-4-methoxy-N-methyl-benzamide;
N-[1-[[(3S)-3-[(4-fluorophenyl)methyl]piperidinyl]carbonyl]cyclopropyl]-N′
-[2-methoxy-5-(4-morpholinylcarbonyl)phenyl]-urea;
N-[(1S)-3-[(3S)-3-[(4-fluorophenyl)methyl]piperidinyl]-3-oxo-1-(1-pyrrolidinylcarbonyl)propyl]-N′
-[3-(1-methyl-1H-tetrazol-5-yl)phenyl]-urea;
-(alpha-1S,3S)-N-(1,1-dimethylethyl)-3-[(4-fluorophenyl)methyl]-alpha-[[[[3-(1-methyl-1H-tetrazol-5-yl)phenyl]amino]carbonyl]amino]-gamma-oxo-1-piperidinebutanamide, N-[(1S)-3-[(3S)-3-[(4-fluorophenyl)methyl]piperidinyl]-3-oxo-1-(1-piperidinylcarbonyl)propyl]-N′
-1-[3-(1-methyl-1H-tetrazol-5-yl)phenyl]-urea;
N-(3-acetylphenyl)-N′
-[(2S)-2-amino-3-[(3S)-3-[(4-fluorophenyl)methyl]piperidinyl]-3-oxopropyl]-urea;
N-(3-acetylphenyl)-N′
-[(2R)-2-amino-3-[(3S)-3-[(4-fluorophenyl)methyl]piperidinyl]-3-oxopropyl]-urea;
3-[[[[1-[[(3S)-3-[(4-fluorophenyl)methyl]piperidinyl]carbonyl]cyclopropyl]amino]carbonyl]amino]-4-methoxybenzamide;
N-[(1S)-3-[(3S)-3-[(4-fluorophenyl)methyl]piperidinyl]-1-[(4-methyl-1-piperazinyl)carbonyl]-3-oxopropyl]-N′
-[3-(1-methyl-1H-tetrazol-5-yl)phenyl]-urea;
N-[(1S)-3-[(3S)-3-[(4-fluorophenyl)methyl]piperidinyl]-1-(4-morpholinylmethyl)-3-oxopropyl]-N′
-[3-(1-methyl-1H-tetrazol-5-yl)phenyl]-urea;
N″
-cyano-N-[(1S)-3-[(3S)-3-[(4-fluorophenyl)methyl]piperidinyl]-1-(4-morpholinylmethyl)-3-oxopropyl]-N′
-[3-(1-methyl-1H-tetrazol-5-yl)phenyl]-guanidine3-[(4-fluorophenyl)methyl]-N,N-dimethyl-alpha-[[[[3-(1-methyl-1H-tetrazol-5-yl)phenyl]amino]carbonyl]amino]-gamma-oxo-(alpha-1S,3S)-1-piperidinebutanamide N-{(1S)-1-({[(3-acetylanilino)carbonyl]amino}methyl)-2-[(3S)-3-(4-fluorobenzyl)piperidinyl]-2-oxoethyl}acetamide;
N-{(1R)-1-({[(3-acetylanilino)carbonyl]amino}methyl)-2-[(3S)-3-(4-fluorobenzyl)piperidinyl]-2-oxoethyl}acetamide;
3-[({[(1S)-3-[(3S)-3-(4-fluorobenzyl)-1-piperidinyl]-1-(4-morpholinylmethyl)-3-oxopropyl]amino}carbonyl)amino]-N-methylbenzamide;
N-(3-chlorophenyl)-N′
-[(1S)-3-[(3S)-3-(4-fluorobenzyl)-1-piperidinyl]-1-(4-morpholinylmethyl)-3-oxopropyl]urea;
N-(3-cyanophenyl)-N′
-[(1S)-3-[(3S)-3-(4-fluorobenzyl)-1-piperidinyl]-1-(4-morpholinylmethyl)-3-oxopropyl]urea;
N-[(1S)-3-[(3S)-3-(4-fluorobenzyl)-1-piperidinyl]-1-(4-morpholinylmethyl)-3-oxopropyl]-N′
-(3-methoxyphenyl) urea;
N-cyclopropyl-N′
-[(1S)-3-[(3S)-3-(4-fluorobenzyl)-1-piperidinyl]-1-(4-morpholinylmethyl)-3-oxopropyl]ureaN-(cyclopropylmethyl)-N′
-[(1S)-3-[(3S)-3-(4-fluorobenzyl)-1-piperidinyl]-1-(4-morpholinylmethyl)-3-oxopropyl]urea;
benzyl 3-[({[(1S)-3-[(3S)-3-(4-fluorobenzyl)-1-piperidinyl]-1-(4-morpholinylmethyl)-3-oxopropyl]amino}carbonyl) amino]-4-methoxybenzoate;
N-(5-acetyl-4-methyl-1,3-thiazol-2-yl)-N′
-[(1S)-3-[(3S)-3-(4-fluorobenzyl)-1-piperidinyl]-3-oxo-1-(1-piperidinylmethyl)propyl]urea;
N-[(1S,2R)-3-[(3S)-3-(4-fluorobenzyl)-1-piperidinyl]-2-methyl-1-(4-morpholinylcarbonyl)-3-oxopropyl]-N′
-[3-(1-methyl-1H-tetraazol-5-yl)phenyl]urea;
3-[(}[(1S,2R)-3-[(3S)-3-(4-fluorobenzyl)-1-piperidinyl]-2-methyl-1-(4-morpholinylcarbonyl)-3-oxopropyl]amino}carbonyl)amino]-N-methylbenzamide;
N-(3,5-diacetylphenyl)-N′
-{(1R)-3-[(3S)-3-(4-fluorobenzyl)-1-piperidinyl]-1-methyl-3-oxopropyl}urea;
N-{(1R)-3-[(3S)-3-(4-fluorobenzyl)-1-piperidinyl]-1-methyl-3-oxopropyl}-N′
-[3-(1-methyl-1H-tetraazol-5-yl) phenyl]urea;
N-{(2S)-3-[(3S)-3-(4-fluorobenzyl)-1-piperidinyl]-2-methyl-3-oxopropyl}-N′
-[3-(1-methyl-1H-tetraazol-5-yl)phenyl]urea;
N-(3-acetylphenyl)-N′
-[(1S)-1-{[tert-butyl(methyl)amino]methyl}-3-[(3S)-3-(4-fluorobenzyl)-1-piperidinyl]-3-oxopropyl]urea;
N-{(2R)-3-[(3S)-3-(4-fluorobenzyl)-1-piperidinyl]-2-methyl-3-oxopropyl}-N′
-[3-(1-methyl-1H-tetraazol-5-yl)phenyl]urea;
(2S)-N-cyclopropyl-4-[(3S)-3-(4-fluorobenzyl)-1-piperidiriyl]-2-[({[3-(1-methyl-1H-tetraazol-5-yl)phenyl]amino}carbonyl)amino]-4-oxobutanamide;
N-((1R)-2-[(3S)-3-(4-fluorobenzyl)-1-piperidinyl]-1-{[({[3-(1-methyl-1H-tetraazol-5-yl)phenyl]amino}carbonyl)amino]methyl}-2-oxoethyl)acetamide;
N-[(1S)-3-[(3S)-3-(4-fluorobenzyl)-1-piperidinyl]-1-(hexahydro-1H-azepin-1-ylcarbonyl)-3-oxopropyl]-N′
-[3-(1-methyl-1H-tetraazol-5-yl)phenyl]urea;
N-(1-{2-[(3S)-3-(4-fluorobenzyl)-1-piperidinyl]-2-oxoethyl}cyclopropyl)-N′
-[3-(1-methyl-1H-tetraazol-5-yl) phenyl]urea;
N-((1R)-2-[(3S)-3-(4-fluorobenzyl)-1-piperidinyl]-1-{[({[3-(1-methyl-1H-tetraazol-5-yl)phenyl]amino}carbonyl)amino]methyl}-2-oxoethyl)-2,2-dimethylpropanamide;
N-{(1R)-1-[({[(5-acetyl-4-methyl-1,3-thiazol-2-yl)amino]carbonyl}amino)methyl]-2-[(3S)-3-(4-fluorobenzyl)-1-piperidinyl]-2-oxoethyl]-2,2-dimethylpropanamide;
N-{(1S)-1-{[tert-butyl(methyl)amino]methyl}-3-[(3S)-3-(4-fluorobenzyl)-1-piperidinyl]-3-oxopropyl}-N′
-[3-(1-methyl-1H-tetraazol-5-yl)phenyl]urea;
N-(5-acetyl-4-methyl-1,3-thiazol-2-yl)-N′
-{(2R)-2-(diisobutylamino)-3-[(3S)-3-(4-fluorobenzyl)-1-piperidinyl]-3-oxopropyl}urea;
N-{(2R)-2-(diisobutylamino)-3-[(3S)-3-(4-fluorobenzyl)-1-piperidinyl]-3-oxopropyl}-N′
-[3-(1-methyl-1H-tetraazol-5-yl)phenyl]urea;
N-(5-acetyl-4-methyl-1,3-thiazol-2-yl)-N′
-{(1S)-1-{[tert-butyl(methyl)amino]methyl}-3-[(3S)-3-(4-fluorobenzyl)-1-piperidinyl]-3-oxopropyl}ureaN-{(1R)-3-[(3S)-3-(4-fluorobenzyl)-1-piperidinyl]-1-methyl-3-oxopropyl}-N′
-(4-pyridinyl)urea;
N-(5-acetyl-4-methyl-1,3-thiazol-2-yl)-N′
-{(1R,2R)-3-[(3S)-3-(4-fluorobenzyl)-1-piperidinyl]-2-hydroxy-1-methyl-3-oxopropyl}urea;
N-(3,5-diacetylphenyl)-N′
-{(1R,2R)-3-[(3S)-3-(4-fluorobenzyl)-1-piperidinyl]-2-hydroxy-1-methyl-3-oxopropyl}urea;
N-{3-[(dimethylamino)methyl]phenyl}-N′
-((1R,2R)-2-{[(3R)-3-(4-fluorobenzyl)-1-piperidinyl]carbonyl}cyclohexyl)urea;
3-({[(1-{[(3S)-3-(4-fluorobenzyl)-1-piperidinyl]carbonyl}cyclopropyl)amino]carbonyl}amino)benzamide;
N-(1-{[(3S)-3-(4-fluorobenzyl)-1-piperidinyl]carbonyl}cyclopropyl)-N′
-[2-methoxy-5-(1-methyl-1H-tetraazol-5-yl)phenyl]urea;
N-(1-{[(3S)-3-(4-fluorobenzyl)-1-piperidinyl]carbonyl}cyclopropyl)-N′
-[3-(5-methyl-1H-tetraazol-1-yl)phenyl]urea;
N-{(1R)-2-[(3S)-3-(4-fluorobenzyl)-1-piperidinyl]-1-methyl-2-oxoethyl}-N′
-[3-(1-methyl-1H-tetraazol-5-yl)phenyl]urea; and
N-(3,5-diacetylphenyl)-N′
-{(1S)-2-[(3S)-3-(4-fluorobenzyl)-1-piperidinyl]-1-methyl-2-oxoethyl}urea.
-
-
10. A pharmaceutical composition, comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound according to claim 1.
-
11. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound according to claim 1, or a pharmaceutically acceptable salt thereof.
-
12. A method for inhibition of chemokine receptor activity for the treatment of an inflammatory disease comprising administering to a patient in need thereof a therapeutically effective amount of a compound according to claim 1.
-
13. A method for treating asthma, comprising administering to a patient in need thereof a therapeutically effective amount of a compound according to claim 1.
-
14. The method of claim 12 wherein inhibition of chemokine receptor activity comprises contacting a CCR3 receptor with an effective inhibitory amount of the compound.
-
15. A method for treating inflammatory disorders comprising administering to a patient in need thereof a therapeutically effective amount of a compound according to claim 1, or a pharmaceutically acceptable salt thereof.
-
16. A method according to claim 15, wherein the 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.
-
17. The method according to claim 16, wherein the disorder is selected from asthma, allergic rhinitis, atopic dermatitis, and inflammatory bowel diseases.
-
18. The method according to claim 17, wherein the disorder is asthma.
-
19. A pharmaceutical composition, comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound according to claim 4.
-
20. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound according to claim 4, or a pharmaceutically acceptable salt thereof.
-
21. A method for inhibition of chemokine receptor activity for the treatment of an inflammatory disease comprising administering to a patient in need thereof a therapeutically effective amount of a compound according to claim 4.
-
22. The method of claim 21 wherein inhibition of chemokine receptor activity comprises contacting a CCR3 receptor with an effective inhibitory amount of the compound.
-
23. A method for treating asthma, comprising administering to a patient in need thereof a therapeutically effective amount of a compound according to claim 4.
-
24. A method for treating inflammatory disorders comprising administering to a patient in need thereof a therapeutically effective amount of a compound according to claim 8, or a pharmaceutically acceptable salt thereof.
-
25. A method according to claim 24, wherein the 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.
-
26. The method according to claim 25, wherein the disorder is selected from asthma, allergic rhinitis, atopic dermatitis, and inflammatory bowel diseases.
-
27. The method according to claim 26, wherein the disorder is asthma.
-
28. A method for treating inflammatory disorders comprising administering to a patient in need thereof a therapeutically effective amount of a compound according to claim 9, or a pharmaceutically acceptable salt thereof.
-
29. A method according to claim 28, wherein the 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.
-
30. The method according to claim 29, wherein the disorder is selected from asthma, allergic rhinitis, atopic dermatitis, and inflammatory bowel diseases.
-
31. The method according to claim 30, wherein the disorder is asthma.
Specification