N-UREIDOALKYL-PIPERIDINES AS MODULATORS OF CHEMOKINE RECEPTOR ACTIVITY

N-UREIDOALKYL-PIPERIDINES UTILISEES EN TANT QUE MODULATEURS DE L'ACTIVITE DES RECEPTEURS DES CHIMIOKINES

English 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.

French Abstract

La présente invention concerne des modulateurs de CCR3, de formule (I), ou leurs sels pharmaceutiquement acceptables, utiles dans la prévention de l'asthme et d'autres maladies allergiques.

Claims

What is Claimed is:
1. A compound of formula (I):
Image
or stereoisomers or pharmaceutically acceptable salts
thereof, wherein:
M is absent or 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 provisos:
1) at least one of M, J, K, L, or Q contains an R5;
and
2) when M is absent, J is selected from CH2, CHR5,
CHR13, and CR5R13;
Z is selected from O and S;
E is - (CHR7) - (CHR9)~ - (CHR11) - ;
R1 and R2 are independently selected from H, C1-8 alkyl, C2-8
alkenyl, C2-8 alkynyl, (CH2)r C3-6 cycloalkyl, and a
(CH2)r-C3-10 carbocyclic residue substituted with 0-5
R a;
R a, at each occurrence, is selected from C1-4 alkyl, C2-8
alkenyl, C2-8 alkynyl, (CH2)r C3-6 cycloalkyl, Cl, Br, I,
298




F, (CF2)r CF3, NO2, CN, (CH2)r NR b R b, (CH2)r OH, (CH2)r OR c,
(CH2)r SH, (CH2)r SR c, (CH2)r C(O)R b, (CH2)r C(O)NR b R b,
(CH2)r NR b C(O)R b, (CH2)r C(O)OR b, (CH2)r OC (O)R c,
(CH2)r CH(=NR b)NR b R b, (CH2)r NHC(=NR b)NR b R b, (CH2)r S(O)p R c,
(CH2)r S(O)2NR b R b, (CH2)r NR b S(O)2R c, and (CH2)r phenyl;
R b, at each occurrence, is selected from H, C1-6 alkyl, C3-6
cycloalkyl, and phenyl;
R c, at each occurrence, is selected from C1-6 alkyl, C3-6
cycloalkyl, and phenyl;
alternatively, R2 and R3 join to form a 5, 6, or 7-membered
ring substituted with 0-3 R a;
R3 is selected from a (CR3'R3")r-C3-10 carbocyclic residue
substituted with 0-5 R15 and a (CR3'R3")r-5-10 membered
heterocyclic system containing 1-4 heteroatoms
selected from N, O, and S, substituted with 0-3 R15;
R3' and R3", at each occurrence, are selected from H, C1-6
alkyl, (CH2)r C3-6 cycloalkyl, and phenyl;
R4 is absent, taken with the nitrogen to which it is
attached to form an N-oxide, or selected from C1-8
alkyl, C2-8 alkenyl, C2-8 alkynyl, (CH2)r C3-6
cycloalkyl, (CH2)q C(O)R4b, (CH2)q C(O)NR4a R4a',
(CH2)q C(O)OR4b, and a (CH2)r-C3-10 carbocyclic residue
substituted with 0-3 R4c;
R4a and R4a', at each occurrence, are selected from H, C1-6
alkyl, (CH2)r C3-6 cycloalkyl, and phenyl;
R4b, at each occurrence, is selected from C1-6 alkyl, C2-8
alkenyl, (CH2)r C3-6 cycloalkyl, C2-8 alkynyl, and
phenyl;
299




R4c, at each occurrence, is selected from C1-6 alkyl, C2-8
alkenyl, C2-8 alkynyl, C3-6 cycloalkyl, Cl, F, Br, I,
CN, NO2, (CF2)r CF3, (CH2)r OC1-5 alkyl, (CH2)r OH,
(CH2)r SC1-5 alkyl, (CH2)r NR4aR4a', and (CH2)r phenyl;
alternatively, R4 joins with R7, R9, or R11 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-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)r C3-6 cycloalkyl, and phenyl;
R6, at each occurrence, is selected from C1-6 alkyl, C2-8
alkenyl, C2-8 alkynyl, (CH2)r C3-6 cycloalkyl, (CF2)r CF3,
CN, (CH2)r NR6a R6a', (CH2)r OH, (CH2)r OR6b, (CH2)r SH,
(CH2)r SR6b, (CH2)r C(O)OH, (CH2)r C(O)R6b,
(CH2)r C(O)NR6a R6a', (CH2)r NR6d C(O)R6a (CH2)r C(O)OR6b,
(CH2)r OC(O)R6b, (CH2)r S(O)p R6b, (CH2)r S(O)2NR6a R6a',
(CH2)r NR6d S(O)2R6b, and (CH2)t phenyl 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)r CF3, (CH2)r OC1-
alkyl, (CH2)r OH, (CH2)r SC1-5 alkyl, and (CH2)r NR6d R6d;
300




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;
R7 at each occurrence, is selected from H or alternatively
R7 joins with R4 to form a 5, 6, or 7 membered
piperidinium spirocycle or pyrrolidinium spirocycle
substituted with 0-3R a;
R9 at each occurrence, is selected from H or alternatively
R9 joins with R4 to form a 5, 6, or 7 membered
piperidinium spirocycle or pyrrolidinium spirocycle
substituted with 0-3R a;
R11 at each occurrence, is selected from H, C1-6alkyl, C2-
8alkenyl, C2-8alkynyl, and a (CH2)r-C3-10 carbocyclic
residue substituted with 0-5 R11c, or alternatively R11
joins with R4 to form a 5, 6, or 7 membered
piperidinium spirocycle or pyrrolidinium spirocycle
substituted with 0-3R a;
R11a and R11a', at each occurrence, are selected from H, C1-6
alkyl, C2-8 alkenyl, C2-8 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;
R11b, at each occurrence, is selected from C1-6 alkyl, C2-8
alkenyl, C2-8 alkynyl, a (CH2)r-C3-6 carbocyclic residue
substituted with 0-2 R11e, and a (CH2)r-5-6 membered
301




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)r C3-6 cycloalkyl, Cl, Br, I,
F, (CF2)r CF3, NO2, CN, (CH2)r NR11f R11f, (CH2)r OH,
(CH2)r OC1-4 alkyl, (CH2)r SC1-4 alkyl, (CH2)r C(O)OH,
(CH2)r C(O)R11b, (CH2)r C(O)NR11f R11f, (CH2)r NR11f C(O)R11a,
(CH2)r C(O)OC1-4 alkyl, (CH2)r OC(O)R11b,
(CH2)r C(=NR11f)NR11f R11f, (CH2)r NHC(-NR11f)NR11f R11f,
(CH2)r S(O)p R11b, (CH2)r S(O)2NR11f R11f,
(CH2)r NR11f S(O)2R11b, and (CH2)r phenyl substituted with
0-3 R11e;
R11e, at each occurrence, is selected from C1-6 alkyl, C2-8
alkenyl, C2-8 alkynyl, C3-6 cycloalkyl, Cl, F, Br, I,
CN, NO2, (CF2)r CF3, (CH2)r OC1-5 alkyl, OH, SH, (CH2)r SC1-
alkyl, (CH2)r NR11f R11f, and (CH2)r phenyl;
R11f, at each occurrence, is selected from H, C1-6 alkyl,
and C3-6 cycloalkyl;
R13, at each occurrence, is selected from C1-6 alkyl, C2-8
alkenyl, C2-8 alkynyl, C3-6 cycloalkyl, (CF2)w CF3,
(CH2)q NR13a R13a', (CH2)q OH, (CH2)q OR13b, (CH2)q SH,
(CH2)q SR13b, (CH2)w C(O)OH, (CH2)w C(O)R13b,
(CH2)w C(O)NR13a R13a', (CH2)q NR13d C(O)R13a,
(CH2)w C(O)OR13b, (CH2)q OC(O)R13b, (CH2)w S(O)p R13b,
(CH2)w S(O)2NR13a R13a', (CH2)q NR13d S(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;
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R13c, at each occurrence, is selected from C1-6 alkyl, C3-6
cycloalkyl, Cl, F, Br, I, CN, NO2, (CF2)r CF3, (CH2)r OC1-
alkyl, (CH2)r OH, (CH2)r SC1-5 alkyl, and
(CH2)r NR13d R13d;
R13d, at each occurrence, is selected from H, C1-6 alkyl,
and C3-6 cycloalkyl;
R15, at each occurrence, is selected from C1-8 alkyl,
(CH2)r C3-6 cycloalkyl, Cl, Br, I, F, NO2, CN,
(CHR')r NR15a R15a', (CHR')r OH, (CHR')r O (CHR')r R15d,
(CHR')r SH, (CHR')r C(O)H, (CHR')r S(CHR')r R15d,
(CHR')r C(O)OH, (CHR')r C(O) (CHR')r R15b,
(CHR')r C(O)NR15a R15a', (CHR')r NR15f C(O) (CHR')r R15b,
(CHR')r NR15f C(O)NR15f R15f, (CHR')r C(O)O(CHR')r R15d,
(CHR')r OC(O)(CHR')r R15b, (CHR')r C (=NR15f)NR15a R15a',
(CHR')r NHC(=NR15f)NR15f R15f, (CHR')r S(O)p(CHR')r R15b,
(CHR')r S(O)2NR15a R15a', (CHR')r NR15f S(O)2(CHR')r R15b, C1-6
haloalkyl, C2-8 alkenyl substituted with 0-3 R', C2-8
alkynyl substituted with 0-3 R', (CHR')r phenyl
substituted with 0-3 R15e, and a (CH2)r-5-10 membered
heterocyclic system containing 1-4 heteroatoms
selected from N, O, and S, substituted with 0-2 R15e;
R', at each occurrence, is selected from H, C1-6 alkyl, C2-8
alkenyl, C2-8 alkynyl, (CH2)r C3-6 cycloalkyl, and
(CH2)r phenyl substituted with R15e;
R15a and R15a', at each occurrence, are selected from H, C1-6
alkyl, C2-8 alkenyl, C2-8 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;
303




R15b, at each occurrence, is selected from C1-6 alkyl, C2-8
alkenyl, C2-8 alkynyl, a (CH2)r-C3-6 carbocyclic residue
substituted with 0-3 R15e, and (CH2)r-5-6 membered
heterocyclic system containing 1-4 heteroatoms
selected from N, O, and S, substituted with 0-2 R15e;
R15d, at each occurrence, is selected from C2-8 alkenyl, C2-8
alkynyl, C1-6 alkyl substituted with 0-3 R15e a
(CH2)r-C3-10 carbocyclic residue substituted with 0-3
R15e, and a (CH2)r5-6 membered heterocyclic system
containing 1-4 heteroatoms selected from N, O, and S,
substituted with 0-3 R15e;
R15e, at each occurrence, is selected from C1-6 alkyl, C2-8
alkenyl, C2-8 alkynyl, (CH2)r C3-6 cycloalkyl, Cl, F, Br,
I, CN, NO2, (CF2)r CF3, (CH2)r OC1-5 alkyl, OH, SH,
(CH2)r SC1-5 alkyl, (CH2)r NR15f R15f, and (CH2)r phenyl;
R15f, at each occurrence, is selected from H, C1-6 alkyl,
C3-6 cycloalkyl, and phenyl;
R16, at each occurrence, is selected from C1-8 alkyl, C2-8
alkenyl, C2-8 alkynyl, (CH2)r C3-6 cycloalkyl, Cl, Br, I,
F, NO2, CN, (CHR')r NR16a R16a', (CHR')r OH,
(CHR')r O(CHR')r R16d, (CHR')r SH, (CHR')r C(O)H,
(CHR')r S(CHR')r R16d, (CHR')r C(O)OH,
(CHR')r C(O)(CHR')r R16b, (CHR')r C(O)NR16a R16a',
(CHR')r NR16f C(O)(CHR')r R16b, (CHR')r C(O)O(CHR')r R16d,
(CHR')r OC(O)(CHR')r R16b, (CHR')r C(=NR16f)NR16a R16a',
(CHR')r NHC(=NR16f)NR16f R16f, (CHR')r S(O)p(CHR')r R16b,
(CHR')r S(O)2NR16a R16a', (CHR')r NR16f S(O)2(CHR')r R16b, C1-6
haloalkyl, C2-8 alkenyl substituted with 0-3 R', C2-8
alkynyl substituted with 0-3 R', and (CHR')r phenyl
substituted with 0-3 R16e;
R16a and R16a', at each occurrence, are selected from H, C1-6
alkyl, C2-8 alkenyl, C2-8 alkynyl, a (CH2) r-C3-10
304




carbocyclic residue substituted with 0-5 R16e, and a
(CH2)r-5-10 membered heterocyclic system containing 1-4
heteroatoms selected from N, O, and S, substituted
with 0-2 R16e;
R16b, at each occurrence, is selected from C1-6 alkyl, C2-8
alkenyl, C2-8 alkynyl, a (CH2)r C3-6 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 C2-8 alkenyl, C2-8
alkynyl, C1-6 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)r C3-6 cycloalkyl, Cl, F, Br,
I, CN, NO2, (CF2)r CF3, (CH2)r OC1-5 alkyl, OH, SH,
(CH2)r SC1-5 alkyl, (CH2)r NR16f R16f, and (CH2)r phenyl;
R16f, at each occurrence, is selected from H, C1-5 alkyl,
and C3-6 cycloalkyl, and phenyl;
v is selected from 1 and 2;
t is selected from 1 and 2;
w is selected from 0 and 1;
r is selected from 0, 1, 2, 3, 4, and 5;
q is selected from 1, 2, 3, 4, and 5; and
p is selected from 0, 1, 2, and 3.
305


2. The compound of claim 1, wherein:
R4 is absent, taken with the nitrogen to which it is
attached to form an N-oxide, or selected from C1-8
alkyl, (CH2)r C3-5 cycloalkyl, and (CH2)r-phenyl
substituted with 0-3 R4c;
R4c, at each occurrence, is selected from C1-6 alkyl, C2-8
alkenyl, C2-8 alkynyl, C3-6 cycloalkyl, Cl, F, Br, I,
CN, NO2, (CF2)r CF3, (CH2)r OC1-5 alkyl, (CH2)r OH,
(CH2)r SC1-5 alkyl, (CH2)r NR4a R4a' and (CH2)r phenyl;
alternatively, R4 joins with R7, R9, or R11 to form a 5, 6
or 7 membered piperidinium spirocycle or pyrrolidinium
spirocycle substituted with 0-3 R a;
R1 and R2 are independently selected from H and C1-4 alkyl;
R6, at each occurrence, is selected from C1-4 alkyl, C2-8
alkenyl, C2-8 alkynyl, (CH2)r C3-6 cycloalkyl, (CF2)r CF3,
CN, (CH2)r OH, (CH2)r OR6b, (CH2)r C(O)R6b,
(CH2)r C(O)NR6a R6a', (CH2)r NR6d C(O)R6a and (CH2)t phenyl
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)r CF3, (CH2)r OC1-
alkyl, (CH2)r OH, (CH2)r SC1-5 alkyl, and (CH2)r NR6d R6d;
306



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, C3-5
cycloalkyl, (CH2)NR13a R13a', (CH2)OH, (CH2)OR13b,
(CH2)w C(O)R13b, (CH2)w C(O)NR13a R13a', (CH2)NR13d C(O)R13a,
(CH2)w S(O)2NR13a R13a', (CH2)NR13d S(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)r CF3, (CH2)r OC1-
alkyl, (CH2)r OH, and (CH2)r NR13d R13d;
R13d, at each occurrence, is selected from H, C1-6 alkyl,
and C3-6 cycloalkyl;
v is selected from 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:
R3 is selected from 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,
307



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:
Image
R16, at each occurrence, is selected from C1-8 alkyl,
(CH2)r C3-6 cycloalkyl, CF3, Cl, Br, I, F,
(CH2)r NR16a R16a', NO2, CN, OH, (CH2)r OR16d,
(CH2)r C(O)R16b, (CH2)r C(O)NR16aR16a', (CH2)r NR16f C(O)R16b,
(CH2)r S(O)p R16b, (CH2)r S(O)2NR16a R16a',
(CH2)r NR16f S(O)2R16b, and (CH2)r phenyl substituted with
0-3 R16e;
308



R16a and R16a', at each occurrence, are selected from H, C1-6
alkyl, C3-6 cycloalkyl, and (CH2)r phenyl substituted
with 0-3 R16e;
R16b, at each occurrence, is selected from H, C1-6 alkyl,
C3-6 cycloalkyl, and (CH2)r phenyl 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)r CF3, OH, and (CH2)r OC1-5 alkyl;
and
R16f, at each occurrence, is selected from H, and C1-5
alkyl.
5. The compound of claim 3, wherein the compound
formula (I) is:
Image
R16, at each occurrence, is selected from C1-8 alkyl,
(CH2)r C3-6 cycloalkyl, CF3, Cl, Br, I, F,
(CH2)r NR16a R16a', NO2, CN, OH, (CH2)r OR16d,
(CH2)r C(O)R16b, (CH2)r C(O)NR16a R16a', (CH2)r NR16f C(O)R16b,
(CH2)r S(O)p R16b, (CH2)r S(O)2NR16a R16a',
(CH2)r NR16f S(O)2R16b, and (CH2)r phenyl substituted with
0-3 R16e;
R16a and R16a', at each occurrence, are selected from H, C1-6
alkyl, C3-6 cycloalkyl, and (CH2)r phenyl substituted
with 0-3 R16e;
309



R16b, at each occurrence, is selected from H, C1-6 alkyl,
C3-6 cycloalkyl, and (CH2)r phenyl 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)r CF3, OH, and (CH2)r OC1-5 alkyl;
and
R16f, at each occurrence, is selected from H, and C1-5
alkyl.
6. The compound of claim 4, wherein:
R5 is CH2phenyl substituted with 0-3 R16;
E i s -CH2-(CH2)-(CH2);
r is selected from 0, 1, and 2.
7. The compound of claim 5, wherein:
E is -CH2-(CHR9)-CHR11;
R5 is CH2phenyl substituted with 0-3 R16; and
r is selected from 0, 1, and 2.
8. The compound of claim 6, wherein:
J is selected from CH2 and CHR5;
K is selected from CH2 and CHR5;
L is selected from CH2 and CHR5;
310



R3 is a C3-10 carbocyclic residue substituted with 0-3 R15,
wherein the carbocyclic residue is selected from
cyclopropyl, 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
R15, at each occurrence, is selected from C1-8 alkyl,
(CH2)r C3-6 cycloalkyl, CF3, Cl, Br, I, F,
(CH2)r NR15a R15a', NO2, CN, OH, (CH2)r OR15d,
(CH2)r C(O)R15b, (CH2)r C(O)NR15a R15a', (CH2)r NR15f C(O)R15b,
(CH2)r S(O)p R15b, (CH2)r S(O)2NR15a R15a',
(CH2)r NR15f S(O)2R15b, (CH2)r phenyl 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 0-2 R15e;
R15a and R15a', at each occurrence, are selected from H, C1-6
alkyl, C3-6 cycloalkyl, and (CH2)r phenyl substituted
with 0-3 R15e;
R15b, at each occurrence, is selected from H, C1-6 alkyl,
C3-6 cycloalkyl, and (CH2)r phenyl substituted with 0-3
R15e;
R15d, at each occurrence, is selected from C1-6 alkyl and
phenyl;
311



R15e, at each occurrence, is selected from C1-6 alkyl, Cl,
F, Br, I, CN, NO2, (CF2)r CF3, OH, and (CH2)r OC1-5 alkyl;
and
R15f, at each occurrence, is selected from H, and C1-5
alkyl.
9. The compound of claim 7, wherein:
K is selected from CH2 and CHR5;
L is selected from CH2 and CHR5;
R3 is a C3-10 carbocyclic residue substituted with 0-3 R15,
wherein the carbocyclic residue is selected from
cyclopropyl, 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
R15, at each occurrence, is selected from C1-8 alkyl,
(CH2)r C3-6 cycloalkyl, CF3, Cl, Br, I, F,
(CH2)r NR15a R15a', NO2, CN, OH, (CH2)r OR15d,
(CH2)r C(O)R15b, (CH2)r C(O)NR15a R15a', (CH2)r NR15f C(O)R15b,
(CH2)r S(O)p R15b, (CH2)r S(O)2NR15a R15a',
(CH2)r NR15f S(O)2R15b, (CH2)r phenyl 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 0-2 R15e;
312



R15a and R15a', at each occurrence, are selected from H, C1-6
alkyl, C3-6 cycloalkyl, and (CH2)r phenyl substituted
with 0-3 R15e;
R15b, at each occurrence, is selected from H, C1-6 alkyl,
C3-6 cycloalkyl, and (CH2)r phenyl substituted with 0-3
R15e;
R15d, at each occurrence, is selected from C1-6 alkyl and
phenyl;
R15e, at each occurrence, is selected from C1-6 alkyl, Cl,
F, Br, I, CN, NO2, (CF2)r CF3, OH, and (CH2)r OC1-5 alkyl;
and
R15f, at each occurrence, is selected from H, and C1-5 alkyl
10. 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;
R1 is H;
R2 is H;
R3 is a C3-10 carbocyclic residue substituted with 0-3 R15,
wherein the carbocyclic residue is selected from
cyclopropyl, cyclopentyl, cyclohexyl, phenyl, naphthyl
and adamantyl, and a (CR3'H)r-heterocyclic system
313



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-C3-10 carbocyclic residue
substituted with 1-5 R16 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
11. The compound of claim 1 and pharmaceutically
acceptable salt forms thereof, wherein the compound of
formula (I) is selected from:
N-(2-hydroxymethylphenyl)-N'-[3-[4-(phenylmethyl)-1-
piperidinyl]propyl]urea,
N-(3-carboethoxyphenyl)-N'-[3-[4-(phenylmethyl)-2-
piperidinyl]propyl]urea,
N-(3-cyanophenyl)-N'-[3-[4-(phenylmethyl)-1-piperidinyl]
propyl]urea,
N-[4-(benzyloxy)phenyl]-N'-[3-[4-(phenylmethyl)-1-
piperidinyl]propyl]urea,
314



N-(3-iodophenyl)-N'-[3-[4-(phenylmethyl)-1-piperidinyl]
propyl]urea,
N-(3-methoxyphenyl)-N'-[3-(4-(phenylmethyl)-1-piperidinyl]
propyl]urea,
N-phenyl-N'-[3-[4-(phenylmethyl)-1-piperidinyl]propyl]urea,
N-(4-carboethoxyphenyl)-N'-[3-[4-(phenylmethyl)-1-
piperidinyl]propyl]urea,
N-(4-fluorophenyl)-N'-[3-[4-(phenylmethyl)-1-piperidinyl]
propyl]urea,
N-(2-methoxyphenyl)-N'-[3-[4-(phenylmethyl)-1-
piperidinyl]propyl]urea,
N-(4-methoxyphenyl)-N'-[3-[4-(phenylmethyl)-1-
piperidinyl]propyl]urea,
N-(3-cyanophenyl)-N'-[3-[4-(4-fluorophenylmethyl)-1-
piperidinyl]propyl]urea,
N-(4-fluorophenyl)-N'-[3-[4-(4-fluorophenylmethyl)-1-
piperidinyl]propyl]urea,
N-(4-carboethoxyphenyl)-N'-[3-[4-(4-fluorophenylmethyl)-1-
piperidinyl]propyl]urea,
N-(3-cyanophenyl)-N'-[3-(4-((3,4-
methylenedioxy)phenylmethyl)-1-
piperidinyl]propyl]urea,
N-(3-methoxyphenyl)-N'-[3-[4-(4-fluorophenylmethyl)-1-
piperidinyl]propyl]urea,
315



N-(3-carboethoxyphenyl)-N'-[3-[4-((3,4-methylenedioxy)
phenylmethyl)-1-piperidinyl]propyl]urea,
N-(3-methoxyphenyl)-N'-[3-[4-((3,4-methylenedioxy)
phenylmethyl)-1-piperidinyl]propyl]urea,
N-(3-methoxyphenyl)-N'-[3-[4-((3-methoxy)phenylmethyl)-1-
piperidinyl]propyl]urea,
N-(3-cyanophenyl)-N'-[3-[4-(4-fluorophenylmethyl)-1-methyl-
1-piperidinium]propyl]urea iodide,
N-(4-cyanophenyl)-N'-[3-(4-(phenylmethyl)-1-piperidinyl]
propyl]urea,
N-(4-fluorophenyl)-N'-[3-[4-((3,4-methylenedioxy)
phenylmethyl)-1-piperidinyl]propyl]urea,
N-(4-fluorophenyl)-N'-[3-[4-(2,4-bisfluorophenylmethyl)-1-
piperidinyl]propyl]urea,
N-(3-methoxyphenyl)-N'-[3-[4-(2,4-bisfluorophenylmethyl)-1-
piperidinyl]propyl]urea,
N-(3-cyanophenyl)-N'-[3-[4-(2,4-bisfluorophenylmethyl)-1-
piperidinyl]propyl]urea,
N-(phenylmethyl)-N'-[3-[4-(4-fluorophenylmethyl)-1-
piperidinyl]propyl]urea,
N-[1-(2-phenylethyl)]-N'-(3-[4-(4-fluorophenylmethyl)-1-
piperidinyl]propyl]urea,
N-(2-fluorophenyl)-N'-[3-[4-(4-fluorophenylmethyl)-1-
piperidinyl]propyl]urea,
N-(3-fluorophenyl)-N'-[3-[4-(4-fluorophenylmethyl)-1-
piperidinyl]propyl]urea,
316



N-(cyclohexyl)-N'-[3-[4-(4-fluorophenylmethyl)-1-
piperidinyl]propyl]urea,
N-[1-[trans-2-phenylcyclopropyl]-N'-[3-[4-(4-fluorophenyl-
methyl)-1-piperidinyl]propyl]urea,
N-(3-methoxyphenyl)-N'-[3-[4-(4-methylphenylmethyl)-1-
piperidinyl]propyl)urea,
N-(3-cyanophenyl)-N'-[3-[4-(4-methylphenylmethyl)-1-
piperidinyl]propyl]urea,
N-(3-cyanophenyl)-N'-(3-[4-(4-chlorophenylmethyl)-1-
piperidinyl]propyl)urea,
N-(3-methoxyphenyl)-N'-[3-[4-(3-methoxyphenylmethyl)-1-
piperidinyl]propyl]urea,
N-(3-cyanophenyl)-N'-[3-[4-(3-methoxyphenylmethyl)-1-
piperidinyl]propyl]urea,
N-(4-fluorophenyl)-N'-[3-[4-(3-methoxyphenylmethyl)-1-
piperidinyl]propyl)urea,
N-(4-carboethoxyphenyl)-N'-[3-[4-(3-methoxyphenylmethyl)-1-
piperidinyl]propyl]urea,
N-(3-cyanophenyl)-N'-[3-[4-(2-fluorophenylmethyl)-1-
piperidinyl]propyl]urea
N-(3-fluorophenyl)-N'-(3-[4-(3-methoxyphenylmethyl)-1-
piperidinyl]propyl]urea,
N-(3-carboethoxyphenyl)-N'-[3-[4-(3-methoxyphenylmethyl)-1-
piperidinyl]propyl]urea,
317



N-[3-acetylphenyl]-N'-[3-[4-(4-fluorophenylmethyl)-1-
piperidinyl]propyl]urea,
N-[3-(alpha-hydroxyethyl)phenyl]-N'-[3-[4-(4-fluorophenyl-
methyl)-1-piperidinyl]propyl]urea,
N-[4-acetylphenyl]-N'-[3-[4-(4-fluorophenylmethyl)-1-
piperidinyl]propyl]urea,
N-(3-methoxyphenyl)-N'-[3-[4-(phenylmethyl)-1-piperidinyl]
propyl]urea,
cis-N-(3-methoxyphenyl)-N'-(3-[2,4-bis(phenylmethyl)-1-
piperidinyl]propyl]urea,
N-(3-acetylphenyl)-N'-[3-[4-(4-fluorophenylmethyl)-1-
piperidinyl]propyl]urea,
N-(3-methoxyphenyl)-N'-(3-[4-(4-fluorophenylmethylidenyl)-
1-piperidinyl]propyl]urea,
N-(4-acetylphenyl)-N'-[3-[4-(4-fluorophenylmethyl)-1-
piperidinyl]propyl]urea,
N-(3-(1-hydroxyethyl)phenyl)-N'-[3-[4-(4-
fluorophenylmethyl)-1-piperidinyl]propyl]urea
hydrochloride,
N-(3-acetylphenyl)-N'-[3-[4-(4-fluorophenylmethyl)-3-
(phenylmethyl)-1-piperidinyl]propyl]urea,
N-(4-fluorophenyl)-N'-[3-[4-(4-fluorophenylmethyl)-3-
(phenylmethyl)-1-piperidinyl]propyl]urea,
N-(3-methoxyphenyl)-N'-[3-[4-(4-fluorophenylmethyl)-3-
(phenylmethyl)-1-piperidinyl]propyl]urea,
318



N-(2-isopropylphenyl)-N'-[3-[4-(4-fluorophenylmethyl)-1-
piperidinyl]propyl]urea,
N-(2-trifluoromethylphenyl)-N'-[3-[4-(4-
fluorophenylmethyl)-Z-piperidinyl]propyl]urea,
N-(3-chlorophenyl)-N'-[3-[4-(4-fluorophenylmethyl)-1-
piperidinyl]propyl]urea,
N-(3-trifluoromethylphenyl)-N'-[3-[4-(4-
fluorophenylmethyl)-1-piperidinyl]propyl]urea,
N-(2-chlorophenyl)-N'-[3-[4-(4-fluorophenylmethyl)-2-
piperidinyl]propyl]urea,
N-(2,4-difluororophenyl)-N'-[3-[4-(4-fluorophenylmethyl)-1-
piperidinyl]propyl]urea,
N-(3-cyanophenyl)-N'-[3-[4-(4-fluorophenylmethyl)-1-
piperidinyl]propyl]urea, hydrochloride,
N-(3-cyanophenyl)-N'-[3-[4-(naphth-1-ylmethyl)-1-
piperidinyl]propyl]urea,
N-(4-fluorophenyl)-N'-[3-[4-(naphth-1-ylmethyl)-1-
piperidinyl)propyl]urea,
N-(3-methoxyphenyl)-N'-[3-[4-(naphth-1-ylmethyl)-1-
piperidinyl]propyl]urea,
N-(3-cyanophenyl)-N'-[3-[4-(3-methylphenylmethyl)-1-
piperidinyl]propyl)urea,
N-(3-methoxyphenyl)-N'-[3-[4-(3-methylphenylmethyl)-1-
piperidinyl]propyl]urea,
N-(4-cyanophenyl)-N'-[3-[4-(4-fluorophenylmethyl)-1-
piperidinyl]propyl]urea,
319



N-(4-fluorophenyl)-N'-[3-[4-(4-chlorophenyl)methyl-1-
piperidinyl]propyl]urea,
N-(3-methoxyphenyl)-N'-[3-[4-(4-chlorophenyl)methyl-1-
piperidinyl]propyl]urea,
N-(3-cyanophenyl)-N'-[3-[4-(3,4-bisfluorophenyl)methyl-1-
piperidinyl]propyl]urea,
N-(3-methoxyphenyl)-N'-[3-[4-(3,4-bisfluorophenyl)methyl-1-
piperidinyl]propyl]urea,
N-(4-fluorophenyl)-N'-[3-[4-(3,4-bisfluorophenyl)methyl-1-
piperidinyl]propyl]urea,
N-(3-methoxyphenyl)-N'-[3-[4-(3-fluorophenyl) methyl-1-
piperidinyl]propyl]urea,
N-(3-cyanophenyl)-N'-(3-[4-(3-chlorophenyl)methyl-1-
piperidinyl]propyl]urea,
N-(3-methoxyphenyl)-N'-[3-[4-(3-carbomethoxyphenyl)methyl-
1-piperidinyl]propyl]urea,
N-(3-cyanophenyl)-N'-[3-[4-(3-carbomethoxyphenyl)methyl-1-
piperidinyl]propyl]urea,
N-(3-acetylphenyl)-N'-[3-[4-(4-fluorophenyl)methyl-1-
piperidinyl]propyl]urea,
N-(3,5-diacetylphenyl)-N'-[3-[3-(4-fluorophenyl)methyl-1-
piperidinyl]propyl]urea,
N-(3-acetylphenyl)-N'-[3-[3-(4-fluorophenyl)methyl-1-
piperidinyl]propyl]urea,



320



N-(3,5-diacetylphenyl)-N'-[3-[4-(4-fluorophenyl)methyl-1-
piperidinyl]propyl]urea,
N-(3-cyanophenyl)-N'-[1-phenyl-3-[4-(4-fluorophenylmethyl)-
1-piperidinyl]propyl]urea,
N-(3-methoxyphenyl)-N'-[1-phenyl-3-[4-(phenylmethyl)-1-
piperidinyl]propyl]urea,
N-(3-cyanophenyl)-N'-[1-phenyl-3-[4-(phenylmethyl)-1-
piperidinyl]propyl]urea,
N-(1-adamantyl)-N'-[1-phenyl-3-[4-(phenylmethyl)-1-
piperidinyl]propyl]urea,
N-(4-fluorophenyl)-N'-[1-phenyl-3-[4-(phenylmethyl)-1-
piperidinyl]propyl]urea
N-(3-carboethoxyphenyl)-N'-[3-[3-(phenylmethyl)-1-
piperidinyl]propyl]urea,
N-(3-cyanophenyl)-N'-[3-[3-(phenylmethyl)-1-
piperidinyl]propyl]urea,
N-(4-fluorophenyl)-N'-[3-[3-(phenylmethyl)-1-
piperidinyl]propyl]urea,
N-phenyl-N'-[3-[3-(phenylmethyl)-1-piperidinyl]propyl)urea,
N-(1-adamantyl)-N'-[3-[3-(phenylmethyl)-1-
piperidinyl]propyl]urea,
N-(3-methoxyphenyl)-N'-[3-[3-(phenylmethyl)-1-
piperidinyl]propyl)urea,
N-(4-carboethoxyphenyl)-N'-[3-[3-(phenylmethyl)-1-
piperidinyl]propyl]urea,



321


N-phenyl-N'-[3-[3-(4-fluorophenyl)methyl-1-
piperidinyl]propyl]urea,
N-(3-cyanophenyl)-N'-[3-[3-(4-fluorophenyl)methyl-1-
piperidinyl]propyl]urea,
N-(1-adamantyl)-N'-[3-[3-(4-fluorophenyl)methyl-1-
piperidinyl)propyl]urea,
N-(3-methoxyphenyl)-N'-[3-[3-(4-fluorophenyl)methyl-1-
piperidinyl)propyl)urea,
N-(3-carboethoxyphenyl)-N'-[3-[3-(4-fluorophenyl)methyl-1-
piperidinyl]propyl)urea,
N-(4-fluorophenyl)-N'-[3-[3-(4-fluorophenyl)methyl-1-
piperidinyl]propyl]urea,
N-(3-cyanophenyl)-N'-[3-[3-[2-(phenyl)ethyl]-1-
piperidinyl)propyl)urea,
N-(3-carboethoxyphenyl)-N'-[3-[3-[2-(phenyl)ethyl]-1-
piperidinyl]propyl)urea,
N-(4-carboethoxyphenyl)-N'-[3-[3-[2-(phenyl)ethyl]-1-
piperidinyl]propyl]urea,
N-(4-fluorophenyl)-N'-[3-[3-[2-(phenyl)ethyl]-1-
piperidinyl)propyl)urea,
N-phenyl-N'-[3-[3-(2-(phenyl)ethyl]-1-
piperidinyl]propyl)urea,
N-(1-adamantyl)-N'-[3-[3-(2-(phenyl)ethyl)-1-
piperidinyl]propyl)urea,
N-(3-methoxyphenyl)-N'-[3-[3-[2-(phenyl)ethyl]-1-
piperidinyl]propyl]urea,



322



N-phenyl-N'-[3-[3-(4-fluorophenyl)methyl]-1-
pyrrolinyl]propyl]urea,
N-(3-cyanophenyl)-N'-[3-[3-(4-fluorophenyl)methyl-1-
pyrrolinyl]propyl]urea,
N-(3-methoxyphenyl)-N'-[3-[3-(4-fluorophenyl)methyl-1-
pyrrolinyl]propyl]urea,
N-(4-fluorophenyl)-N'-[3-[3-(4-fluorophenyl)methyl-1-
pyrrolinyl]propyl]urea,
N-(3-carboethoxyphenyl)-N'-[3-[3-(4-fluorophenyl)methyl-1-
pyrrolinyl]propyl]urea,
N-(4-carboethoxyphenyl)-N'-[3-[3-(4-fluorophenyl)methyl-1-
pyrrolinyl]propyl]urea,
N-(1-adamantyl)-N'-[3-[3-(4-fluorophenyl)methyl-1-
pyrrolinyl]propyl]urea,
N-phenyl-N'-[3-[3-(2-fluorophenyl)methyl-1-
piperidinyl]propyl]urea,
N-(3-cyanophenyl)-N'-[3-[3-(2-fluorophenyl)methyl-1-
piperidinyl]propyl]urea,
N-(3-methoxyphenyl)-N'-[3-[3-(2-fluorophenyl)methyl-1-
piperidinyl]propyl]urea,
N-(4-fluorophenyl)-N'-[3-[3-(2-fluorophenyl)methyl-1-
piperidinyl]propyl]urea,
N-(3-methoxyphenyl)-N'-[3-[3-(3-fluorophenyl)methyl-1-
piperidinyl]propyl]urea,



323



N-(3-cyanophenyl)-N'-[3-[3-(3-fluorophenyl)methyl-1-
piperidinyl]propyl]urea,
N-(4-fluorophenyl)-N'-[3-[3-(3-fluorophenyl)methyl-1-
piperidinyl]propyl]urea
N-[3-(1-methyltetrazol-5-yl)phenyl]-N'-[3-[4-(4-
fluorophenylmethyl)-1-piperidinyl]propyl]urea,
N-[3-(1-methyltetrazol-5-yl)phenyl] -N'-[3-[3-(4-
fluorophenylmethyl)-1-piperidinyl]propyl]urea,
N-[3,5-bis(1-methyltetrazol-5-yl)phenyl]-N'-[3-[4-(4-
fluorophenylmethyl)-1-piperidinyl]propyl)urea,
N-[3,5-bis(1-methyltetrazol-5-yl)phenyl]-N'-[3-[3-(4-
fluorophenylmethyl)-1-piperidinyl]propyl]urea,
N-[4-(1-methyltetrazol-5-yl)phenyl]-N'-[3-[4-(4-
fluorophenylmethyl)-1-piperidinyl]propyl]urea, and
N-[4-(1-methyltetrazol-5-yl)phenyl]-N'-[3-[3-(4-
fluorophenylmethyl)-1-piperidinyl)propyl]urea.
12. The compound of claim 1 and pharmaceutically
acceptable salt forms thereof, wherein the compound of
formula (I) is selected from:
N-(1-adamantyl)-N'-[3-[4-(phenylmethyl)-1-piperidinyl]
propyl)urea, and
N-[1-(trans-2-phenylcyclopropyl))-N'-[3-[4-(phenylmethyl)-
1-piperidinyl]propyl)urea.



324




13. The compound of claim 1 and pharmaceutically
acceptable salt forms thereof, wherein the compound of
formula (I) is selected from:
N-(3-methoxyphenyl)-N'-[3,-[1,4-bis(phenylmethyl)-1-
piperidinium]propyl]urea bromide,
N-(3-cyanophenyl)-N'-[3-[1,4-bis(phenylmethyl)-1-
piperidinium]propyl]urea bromide,
N-(3-methoxyphenyl)-N'-[3-[1-methyl-4-(phenylmethyl)-2-
piperidinium]propyl]urea bromide,
N-(3-cyanophenyl)-N'-[3-[1-methyl-4-(phenylmethyl)-1-
piperidinium]propyl]urea bromide,
N-(3-cyanophenyl)-N'-[3-[1-(carbomethoxymethyl)-4-
(phenylmethyl)-1-piperidinium]propyl]urea bromide,
N-(4-fluorophenyl)-N'-[3-[1-methyl-4-(phenylmethyl)-1-
piperidinium]propyl]urea bromide,
N-(4-fluorophenyl)-N'-[3-[1,4-bis(phenylmethyl)-1-
piperidinium]propyl]urea bromide,
N-(4-fluorophenyl)-N'-(3-[1-(carbomethoxymethyl)-4-
(phenylmethyl)-2-piperidinium]propyl]urea bromide,
N-(3-cyanophenyl)-N'-[3-[1-(cyanomethyl)-4-(phenylmethyl)-
1-piperidinium]propyl)urea bromide,
N-(3-cyanophenyl)-N'-[3-[1-(phenylcarbonylmethyl)-4-
(phenylmethyl)-1-piperidinium]propyl)urea bromide,
N-(2-methoxyphenyl)-N'-[3-[1-methyl-4-(phenylmethyl)-1-
piperidinium]propyl]urea bromide,



325



N-(4-methoxyphenyl)-N'-[3-[1-methyl-4-(phenylmethyl)-1-
piperidinium]propyl]urea bromide,
N-(3-methoxyphenyl)-N'-[3-[1-oxo-4-(phenylmethyl)-1-
piperidinium]propyl]urea, and
N-(3-methoxyphenyl)-N'-[3-[1-methyl-4-(phenylmethyl)-1-
piperidinium]propyl]urea iodide.
14. The compound of claim 1 and pharmaceutically
acceptable salt forms thereof, wherein the compound of
formula (I) is selected from:
N-(3-cyanophenyl)-N'-[4-[4-(phenylmethyl)-1-piperidinyl)
butyl]urea,
N-(3-acetylphenyl)-N'-[4-[4-(4-fluorophenylmethyl)-1-
piperidinyl]butyl]urea,
N-(3,5-diacetylphenyl)-N'-[4-[4-(4-fluorophenylmethyl)-1-
piperidinyl)butyl]urea,
N-(3-cyanophenyl)-N'-[4-[4-(4-fluorophenylmethyl)-1-
piperidinyl]butyl]urea,
N-(3-acetylphenyl)-N'-[4-[3-(4-fluorophenylmethyl)-1-
piperidinyl]butyl]urea,
N-(3,5-diacetylphenyl)-N'-[4-[3-(4-fluorophenylmethyl)-1-
piperidinyl]butyl]urea,
N-(3-cyanophenyl)-N'-[4-[3-(4-fluorophenylmethyl)-1-
piperidinyl)butyl]urea,
N-(3-methoxyphenyl)-N'-[4-[3-(4-fluorophenylmethyl)-1-
piperidinyl]butyl]urea,



326



N-(4-fluorophenyl)-N'-[4-[3-(4-fluorophenylmethyl)-1-
piperidinyl]butyl]urea,
N-phenyl-N'-[4-[3-(4-fluorophenylmethyl)-1-
piperidinyl]butyl]urea,N-[3-(2-methyltetrazol-5-yl)phenyl]-
N'-[4-[4-(4-fluorophenylmethyl)-1-piperidinyl)butyl]urea,
N-[3-(1-methyltetrazol-5-yl)phenyl]-N'-[4-[3-(4-
fluorophenylmethyl)-1-piperidinyl)butyl]urea,
N-[3,5-bis(1-methyltetrazol-5-yl)phenyl]-N'-[4-[4-(4-
fluorophenylmethyl)-1-piperidinyl)butyl]urea,
N-[3,5-bis(1-methyltetrazol-5-yl)phenyl]-N'-[4-[3-(4-
fluorophenylmethyl)-1-piperidinyl]butyl]urea,
N-(3-carbomethoxyphenyl)-N'-[4-[4-(phenylmethyl)-1-
piperidinyl]butyl]urea,
N-(3-iodophenyl)-N'-[4-[4-(phenylmethyl)-1-
piperidinyl]butyl] urea,
N-[1-(4-benzyloxyphenyl)]-N'-[4-[4-(phenylmethyl)-1-
piperidinyl]butyl]urea,
N-(1-adamantyl)-N'-[4-[4-(phenylmethyl)-1-
piperidinyl]butyl]urea,
N-(3-methoxyphenyl)-N'-[4-[4-(phenylmethyl)-2-
piperidinyl]butyl]urea,
N-phenyl-N'-[4-[4-(phenylmethyl)-1-piperidinyl)butyl]urea,
N-(3-methoxyphenyl)-N'-[4-[4-(phenylmethyl)-1-
piperidinyl]butyl)urea,
N-(4-carbomethoxyphenyl)-N'-[4-[4-(phenylmethyl)-1-
piperidinyl]butyl]urea,



327




N-(4-cyanophenyl)-N'-[4-[4-(phenylmethyl)-1-piperidinyl]
butyl]urea,
N-(3-acetylphenyl)-N'-{(2Z)-4-[3-(4-fluorobenzyl)-1-
piperidinyl]-2-butenyl}urea,
N-(3-acetylphenyl)-N'-{(2E)-4-[3-(4-fluorobenzyl)-1-
piperidinyl]-2-butenyl}urea,
N-(3-cyanophenyl}-N'-{(2Z)-4-[3-(4-fluorobenzyl)-1-
piperidinyl]-2-butenyl}urea,
N-(4-fluorophenyl)-N'-{(2Z)-4-[3-(4-fluorobenzyl)-1-
piperidinyl]-2-butenyl}urea, and
N-(3-acetylphenyl)-N'-{4-[3-(4-fluorobenzyl)-1-
piperidinyl]-2-butynyl}urea
15. A pharmaceutical composition, comprising a
pharmaceutically acceptable carrier and a therapeutically
effective amount of a compound of claim 1-14.
16. A method for modulation of chemokine receptor
activity comprising administering to a patient in need
thereof a therapeutically effective amount of a compound of
claim 1-14.
17. A method for treating or preventing inflammatory
diseases, comprising administering to a patient in need
thereof a therapeutically effective amount of a compound of
claim 1-14.



328



18. A method for treating or preventing asthma,
comprising administering to a patient in need thereof a
therapeutically effective amount of a compound of claim 1-
14.
19. A compound of formula (I):

Image

or stereoisomers or pharmaceutically acceptable salts
thereof, wherein:
M is absent or 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 provisos:
1) at least one of M, J, K, L, or Q contains an R5;
and
2) when M is absent, J is selected from CH2, CHR5,
CHR13, and CR5R13;
Z is selected from NR1a, CHCN, CHNO2, and C(CN)2;
R1a is selected from H, C1-6 alkyl, C3-6 cycloalkyl,
CONR1b R1b, OR1b, CN, NO2 , and (CH2)w phenyl ;
R1b is independently selected from H, C1-3 alkyl, C3-6
cycloalkyl, and phenyl;



329



E is -(CR7R8)-(CR9R10)v-(CR11R12)-,
R1 and R2 are independently selected from H, C1-8 alkyl, C2-8
alkenyl, C2-8 alkynyl, (CH2)r C3-6 cycloalkyl, and a
(CH2)r-C3-10 carbocyclic residue substituted with 0-5
R a;
R a, at each occurrence, is selected from C1-4 alkyl, C2-8
alkenyl, C2-8 alkynyl, (CH2)r C3-6 cycloalkyl, Cl, Br, I,
F, (CF2)r CF3, NO2, CN, (CH2)r NR b R b, (CH2)r OH, (CH2)r OR c,
(CH2)r SH, (CH2)r SR c, (CH2)r C(O)R b, (CH2)r C(O)NR b R b,
(CH2)r NR b C(O)R b, (CH2)r C(O)OR b, (CH2)r OC(O)R c,
(CH2)r CH(=NR b)NR b R b, (CH2)r NHC(=NR b)NR b R b, (CH2)r S(O)p R c,
(CH2)r S(O)2NR b R b, (CH2)r NR b S(O)2R c, and (CH2)r phenyl;
R b, at each occurrence, is selected from H, C1-5 alkyl, C3-6
cycloalkyl, and phenyl;
R c, at each occurrence, is selected from C1-6 alkyl, C3-6
cycloalkyl, and phenyl;
alternatively, R2 and R3 join to form a 5, 6, or 7-membered
ring substituted with 0-3 R a;
R3 is selected from a (CR3'R3")r-C3-10 carbocyclic residue
substituted with 0-5 R15 and a (CR3'R3")r-5-10 membered
heterocyclic system containing 1-4 heteroatoms
selected from N, O, and S, substituted with 0-3 R15;
R3' and R3", at each occurrence, are selected from H, C1-6
alkyl, (CH2)r C3-6 cycloalkyl, and phenyl;
R4 is absent, taken with the nitrogen to which it is
attached to form an N-oxide, or selected from C1-8
alkyl, C2-8 alkenyl, C2-8 alkynyl, (CH2)r-C3-6
cycloalkyl, (CH2)a C(O)R4b, (CH2)q C(O)NR4a R4a',



330




(CH2)q C(O)OR4b, and a (CH2)r-C3-10 carbocyclic residue
substituted with 0-3 R4c;
R4a and R4a', at each occurrence, are selected from H, C1-6
alkyl, (CH2)r C3-6 cycloalkyl, and phenyl;
R4b, at each occurrence, is selected from C1-6 alkyl, C2-8
alkenyl, (CH2)r C3-6 cycloalkyl, C2-8 alkynyl, and
phenyl;
R4c, at each occurrence, is selected from C1-6 alkyl, C2-8
alkenyl, C2-8 alkynyl, C3-6 cycloalkyl, Cl, F, Br, I,
CN, NO2, (CF2)r CF3, (CH2)r OC1-5 alkyl, (CH2)r OH,
(CH2)r SC1-5 alkyl, (CH2)r NR4a R4a', and (CH2)r phenyl;
alternatively, R4 joins with R7, R9, or R11 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-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)r C3-5 cycloalkyl, and phenyl;
R6, at each occurrence, is selected from C1-6 alkyl, C2-8
alkenyl, C2-8 alkynyl, (CH2)r C3-5 cycloalkyl, (CF2)r CF3,
CN, (CH2)r NR6a R6a', (CH2)r OH, (CH2)r OR6b, (CH2)r SH,
(CH2)r SR6b, (CH2)r C(O)OH, (CH2)r C(O)R6b,
(CH2)r C(O)NR6a R6a', (CH2)r NR6d C(O)R6a, (CH2)r C(O)OR6b,
(CH2)r OC(O)R6b, (CH2)r S(O)p R6b, (CH2)r S(O)2NR6a R6a'
(CH2)r NR6d S(O)2R6b, and (CH2)t phenyl substituted with 0-
3 R6 c;
R6a and R6a', at each occurrence, are selected from H, C1-6



331




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)r CF3, (CH2)r OC1-
alkyl, (CH2)r OH, (CH2)r SC1-5 alkyl, and (CH2)r NR6d R6d;
R6d, at each occurrence, is selected from H, C1-6 alkyl, and
C3-6 cycloalkyl;
R7, is selected from H, C1-6 alkyl, C2-8 alkenyl, C2-8
alkynyl, (CH2)q OH, (CH2)q SH, (CH2)a OR7d, (CH2)q SR7d,
(CH2)q NR7a R7a', (CH2)r C(O)OH, (CH2)r C(O)R7b,
(CH2)r C(O)NR7a R7a', (CH2)q NR7a C(O)R7a, (CH2)q NR7a C(O)H,
(CH2)r C(O)OR7b, (CH2)q OC(O)R7b, (CH2)q S(O)p R7b,
(CH2)q S(O)2NR7a R7a', (CH2)a NR7a S(O)2R7b, C1-6 haloalkyl,
a (CH2)r-C3-10 carbocyclic residue substituted with 0-3
R7c, and a (CH2)r-5-10 membered heterocyclic system
containing 1-4 heteroatoms selected from N, O, and S,
substituted with 0-2 R7c;
R7a and R7a', at each occurrence, are selected from H, C1-6
alkyl, C2-8 alkenyl, C2-8 alkynyl, a (CH2)r-C3-10
carbocyclic residue substituted with 0-5 R7e, and a
(CH2)r-5-10 membered heterocyclic system containing 1-4
heteroatoms selected from N, O, and S, substituted
with 0-3 R7e;
R7b, at each occurrence, is selected from C1-6 alkyl, C2-8
alkenyl, C2-8 alkynyl, a (CH2)r-C3-6 carbocyclic residue
substituted with 0-2 R7e, and a (CH2)r-5-6 membered
heterocyclic system containing 1-4 heteroatoms
selected from N, O, and S, substituted with 0-3 R7e;



332




R7c, at each occurrence, is selected from C1-6 alkyl, C2-8
alkenyl, C2-8 alkynyl, (CH2)r C3-6 cycloalkyl, Cl, Br, I,
F, (CF2)r CF3, NO2, CN, (CH2)r NR7f R7f, (CH2)r OH,
(CH2)r OC1-4 alkyl, (CH2)r SC1-4 alkyl, (CH2)r C(O)OH,
(CH2)r C(O)R7b, (CH2)r C(O)NR7f R7f, (CH2)r NR7f C(O)R7a,
(CH2)r C(O)OC1-4 alkyl, (CH2)r OC(O)R7b,
(CH2)r C(=NR7f)NR7f R7f, (CH2)r S(O)R7b,
(CH2)r NHC(=NR7f)NR7f R7f, (CH2)r S(O)2NR7f R7f,
(CH2)r NR7f S(O)2R7b, and (CH2)r phenyl substituted with 0-
3 R7e;
R7d, at each occurrence, is selected from C1-6 alkyl
substituted with 0-3 R7e, alkenyl, alkynyl, and a C3-10
carbocyclic residue substituted with 0-3 R7c;
R7e, at each occurrence, is selected from C1-6 alkyl, C2-8
alkenyl, C2-8 alkynyl, C3-6 cycloalkyl, Cl, F, Br, I,
CN, NO2, (CF2)r CF3, (CH2)r OC1-5 alkyl, OH, SH, (CH2)r SC1-
alkyl, (CH2)r NR7f R7f, and (CH2)r phenyl;
R7f, at each occurrence, is selected from H, C1-6 alkyl, and
C3-6 cycloalkyl;
R8 is selected from H, C1-6 alkyl, C3-6 cycloalkyl, and
(CH2)r phenyl substituted with 0-3 R8a;
R8a, 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)r CF3, (CH2)r OC1-5 alkyl, OH, SH, (CH2)r SC1-
alkyl, (CH2)r NR7f R7f, and (CH2)r phenyl;
alternatively, R7 and R8 join to form C3-7 cycloalkyl, or
=NR8b;
R8b is selected from H, C1-6 alkyl, C3-6 cycloalkyl, OH, CN,
and (CH2)r-phenyl;



333


R9, is selected from H, C1-6 alkyl, C2-8 alkenyl, C2-8
alkynyl, F, Cl, Br, I, NO2, CN, (CH2)r OH, (CH2)-SH,
(CH2)r OR9d, (CH2)r SR9d, (CH2)r NR9aR9a', (CH2)r C(O)OH,
(CH2)r C(O)R9b, (CH2)r C(O)NR9a R9a', (CH2)r NR9a C(O)R9a
(CH2)r NR9a C(O)H, (CH2)r NR9a C(O)NHR9a, (CH2)r C(O)OR9b,
(CH2)r OC(O)R9b, (CH2)r OC(O)NHR9a, ( (CH2)r S(O)p R9b
(CH2)r S(O)2NR9a R9a', (CH2)r NR9a S(O)2R9b, C1-6 haloalkyl,
a (CH2)r-C3-10 carbocyclic residue substituted with 0-5
R9c, and a (CH2)r-5-20 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, C2-8 alkenyl, C2-8 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;
R9b, at each occurrence, is selected from C1-6 alkyl, C2-8
alkenyl, C2-8 alkynyl, a (CH2)r-C3-6 carbocyclic residue
substituted with 0-2 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)r C3-6 cycloalkyl, Cl, Br, I,
F, (CF2)r CF3, NO2, CN, (CH2)r NR9f R9f, (CH2)r OH,
(CH2)r OC1-4 alkyl. (CH2)r SC1-4 alkyl, (CH2)r C(O)OH,
(CH2)r C(O)R9b, (CH2)r C(O)NR9f R9f, (CH2)r NR9f C(O)R9a,
(CH2)r C(O)OC1-4 alkyl, (CH2)r OC(O)R9b,
(CH2)r C(=NR9f)NR9f R9f, (CH2)r S(O)p R9b
(CH2)r NHC(=NR9f)NR9f R9f, (CH2)r S(O)2NR9f R9f,
(CH2)r NR9f S(O)2R9b, and (CH2)r phenyl substituted with 0-
3 R9e;



334



R9d, at each occurrence, is selected from C1-6 alkyl, C2-6
alkenyl, C2-6 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,
alkenyl, C2-8 alkynyl, (CH2)r C3-6 cycloalkyl, Cl, F, Br,
I, CN, NO2, (CF2)r CF3, (CH2)r OC1-5 alkyl , OH, SH,
(CH2)r SC1-5 alkyl, (CH2)r NR9f R9f, and (CH2)r phenyl;
R9f, at each occurrence, is selected from H, 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, (CH2)r OH, (CH2)r OR10d.
(CH2)r SR10d, (CH2)r NR10a R10a', (CH2)r C(O)OH,
(CH2)r C(O)R10b, (CH2)r C(O)NR10a R10a', (CH2)r NR10a C(O)R10a,
(CH2)r NR10a C(O)H, (CH2)r C(O)OR10b, (CH2)r OC(O)R10b.
(CH2)r S(O)p R10b, (CH2)r S(O)2NR10a R10a',
(CH2)r NR10a S(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, C2-8 alkenyl, C2-8 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;
R10b, at each occurrence, is selected from C1-6 alkyl, C2-8
alkenyl, C2-8 alkynyl, a (CH2)r-C3-6 carbocyclic residue
substituted with 0-2 R10e, and a (CH2)r-5-6 membered



335




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)r C3-5 cycloalkyl, Cl, Br, I,
F, (CF2)r CF3, NO2, CN, (CH2)r NR10f R10f (CH2)r OH,
(CH2)r OC1-4 alkyl, (CH2)r SC1-4 alkyl, (CH2)r C(O)OH,
(CH2)r C(O)R10b (CH2)r C(p)NR10f R10f, (CH2)r NR10f C(O)R10a
(CH2)r C(O)OC1-4 alkyl, (CH2)r OC(O)R10b
(CH2)r C(=NR10f)NR10f R10f, (CH2)r S(O)p R10b
(CH2)r NHC(=NR10f) NR10f R10f, (CH2)r S(O)2NR10f R10f,
(CH2)r NR10f S(O)2R10b, and (CH2)r phenyl substituted with
0-3 R10e;
R10d at each occurrence, is selected from C1-6 alkyl, C2-6
alkenyl, C2-6 alkynyl, a C3-10 carbocyclic residue
substituted with 0-3 R10c, 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 R10c.
R10e, at each occurrence, is selected from C1-6 alkyl, C2-8
alkenyl, C2-8 alkynyl, (CH2)r C3-5 cycloalkyl, Cl, F, Br,
I, CN, NO2, (CF2)r CF3, (CH2)r OC1-5 alkyl, OH, SH,
(CH2)r SC1-5 alkyl, (CH2)r NR10f R10f and (CH2)r phenyl;
R10f at each occurrence, is selected from H, C1-6 alkyl,
and C3-6 cycloalkyl;
alternatively, R9 and R10 join to form C3-7 cycloalkyl, 5-6-
membered cyclic ketal, or =O;
with the proviso that when R10 is -OH, R9 is not halogen,
cyano, or bonded to the carbon to which it is attached
through a heteroatom;



336



R11, is selected from H, C1-6 alkyl, C2-8 alkenyl, C2-8
alkynyl, (CH2)q OH, (CH2)q SH, (CH2)q OR11d, (CH2)q SR11d,
(CH2)q NR11a R11a', (CH2)r C(O)OH, (CH2)r C(O)R11b,
(CH2)r C(O)NR11a R11a', (CH2)q NR11a C(O)R11a,
(CH2)q NR11a C(O)NHR11a, (CH2)r C(O)OR11b. (CH2)q OC(O)R11b,
(CH2)q S(O)p R11b, (CH2)q S(O)2NR11a R11a',
(CH2)q NR11a S(O)2R11b, C1-6 haloalkyl, a (CH2)r-C3-10
carbocyclic residue substituted with 0-5 R11c, and a
(CH2)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, C2-8 alkenyl, C2-8 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;
R11b at each occurrence, is selected from C1-6 alkyl, C2-8
alkenyl, C2-8 alkynyl, a (CH2)r-C3-6 carbocyclic residue
substituted with 0-2 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)r C3-6 cycloalkyl, Cl, Br, I,
F, (CF2)r CF3, NO2, CN, (CH2)r NR11f R11f, (CH2)r OH,
(CH2)r OC1-4 alkyl, (CH2)r SC1-4 alkyl, (CH2)r C(O)OH,
(CH2)r C(O)R11b, (CH2)r C(O)NR11f R11f, (CH2)r NR11f C(O)R11a,
(CH2)r C(O)OC1-4 alkyl, (CH2)r OC(O)R11b,
(CH2)r C(=NR11f)NR11f R11f, (CH2)r NHC(=NR11f)NR11f R11f,
(CH2)r S(O)p R11b, (CH2)r S(O)2NR11f R11f,
(CH2)r NR11f S(O)2R11b and (CH2)r phenyl substituted with
0-3 R11e-



337




R11d, at each occurrence, is selected from C1-6 alkyl
substituted with 0-3 R11e, C2-5 alkenyl, C2-6 alkynyl,
and a C3-10 carbocyclic residue substitutes 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)r CF3, (CH2)r OC1-5 alkyl, OH, SH, (CH2)r SC1-
alkyl, (CH2)r NR11f R11f, and (CH2)r phenyl;
R11f, at each occurrence, is selected from H, C1-6 alkyl,
and C3-6 cycloalkyl;
R12 is selected from H, C1-6 alkyl, (CH2)q OH, (CH2)r C3-6
cycloalkyl, and (CH2)t phenyl substituted with 0-3 R12a;
R12a at each occurrence, is selected from C1-5 alkyl, C2-8
alkenyl, C2-8 alkynyl, C3-6 cycloalkyl, Cl, F, Br, I,
CN, NO2, (CF2)r CF3, (CH2)r OC1-5 alkyl, OH, SH, (CH2)r SC1-
5 alkyl, (CH2)r NR9f R9f, and (CH2)r phenyl;
alternatively, R11 and R12 join to form C3-7 cycloalkyl;
R13, at each occurrence, is selected from C1-6 alkyl, C2-8
alkenyl, C2-8 alkynyl, C3-6 cycloalkyl, (CF2)w CF3,
(CH2)NR13a R13a', (CH2)OH, (CH2)OR13b, (CH2)SH,
(CH2)SR13b, (CH2)w C(O)OH, (CH2)w C(O)R13b,
(CH2)w C(O)NR13aR13a', (CH2)NR13d C(O)R13a, (CH2)w C(O)OR13b,
(CH2)OC(O)R13b, (CH2)w S(O)p R13b, (CH2)w S(O)2NR13a R13a',
(CH2)NR13d S(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



338




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)r CF3, (CH2)r OC1-
alkyl, (CH2)r OH, (CH2)r SC1-5 alkyl, and
(CH2)r NR13d R13d;
R13d, at each occurrence, is selected from H, C1-6 alkyl,
and C3-6 cycloalkyl;
R15, at each occurrence, is selected from C1-8 alkyl,
(CH2)r C3-6 cycloalkyl, Cl, Br, I, F, NO2, CN,
(CHR')r NR15a R15a', (CHR')r OH, (CHR')r O(CHR')r R15d,
(CHR')r SH, (CHR')r C(O)H, (CHR')r S(CHR')r R15d,
(CHR')r C(O)OH, (CHR')r C(O)(CHR')r R15b,
(CHR')r C(O)NR15a R15a', (CHR')r NR15f C(O)(CHR')r R15b,
(CHR')r NR15f C(O)NR15f R15f(CHR')r C(O)O(CHR')r R15d,
(CHR')r OC(O)(CHR')r R15b, (CHR')r C(=NR15f)NR15a R15a',
(CHR')r NHC(=NR15f)NR15f R15f, (CHR')r S(O)p(CHR')r R15b,
(CHR')r S(O)2NR15a R15a', (CHR')r NR15f S(O)2(CHR')r R15b, C1-6
haloalkyl, C2-8 alkenyl substituted with 0-3 R', C2-8
alkynyl substituted with 0-3 R', (CHR')r phenyl
substituted with 0-3 R15e, and a (CH2)r-5-10 membered
heterocyclic system containing 1-4 heteroatoms
selected from N, O, and S, substituted with 0-2 R15e;
R', at each occurrence, is selected from H, C1-6 alkyl, C2-8
alkenyl, C2-8 alkynyl, (CH2)r C3-6 cycloalkyl, and
(CH2)r phenyl substituted with R15e;
R15a and R15a', at each occurrence, are selected from H, C1-5
alkyl, C2-8 alkenyl, C2-8 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;



339




R15b at each occurrence, is selected from C1-6 alkyl, C2-8
alkenyl, C2-8 alkynyl, a (CH2)r-C3-6 carbocyclic residue
substituted with 0-3 R15e, and (CH2)r-5-6 membered
heterocyclic system containing 1-4 heteroatoms
selected from N, O, and S, substituted with 0-2 R15e;
R15d, at each occurrence, is selected from C2-8 alkenyl, C2-8
alkynyl, C1-6 alkyl substituted with 0-3 R15e, a
(CH2)r-C3-10 carbocyclic residue substituted with 0-3
R15e, and a (CH2)r5-6 membered heterocyclic system
containing 1-4 heteroatoms selected from N, O, and S,
substituted with 0-3 R15e;
R15e, at each occurrence, is selected from C1-6 alkyl, C2-8
alkenyl, C2-8 alkynyl, (CH2)r C3-6 cycloalkyl, Cl, F, Br,
I, CN, NO2, (CF2)r CF3, (CH2)r OC1-5 alkyl, OH, SH,
(CH2)r SC1-5 alkyl, (CH2)r NR15f R15f, and (CH2)r phenyl ;
R15f, at each occurrence, is selected from H, C1-6 alkyl,
C3-5 cycloalkyl, and phenyl;
R16, at each occurrence, is selected from C1-8 alkyl, C2-8
alkenyl, C2-8 alkynyl, (CH2)r C3-6 cycloalkyl, Cl, Br, I,
F, NO2, CN, (CHR')r NR16a R16a', (CHR')r OH,
(CHR')r O(CHR')r R16d, (CHR')r SH, (CHR')r C(O)H,
(CHR')r S(CHR')r R16d, (CHR')r C(O)OH,
(CHR')r C(O)(CHR')r R16b, (CHR')r C(O)NR16a R16a',
(CHR')r NR16f C(O)(CHR')r R16b, (CHR')r C(O)O(CHR')r R16d,
(CHR)r OC(O)(CHR')r R16b, (CHR')r C(=NR16f)NR16a R16a',
(CHR')r NHC(=NR16f)NR16f R16f, (CHR')r S(O)p(CHR')r R16b,
(CHR')r S(O)2NR16a R16a', (CHR')r NR16f S(O)2 (CHR')r R16b, C1-6
haloalkyl, C2-8 alkenyl substituted with 0-3 R', C2-8
alkynyl substituted with 0-3 R', and (CHR')r phenyl
substituted with 0-3 R16e.
R16a and R16a', at each occurrence, are selected .from H, C1-6
alkyl, C2-8 alkenyl, C2-8 alkynyl, a (CH2)r-C3-10



340



carbocyclic residue substituted with 0-5 R16e, and a
(CH2)r-5-10 membered heterocyclic system containing 1-4
heteroatoms selected from N, O, and S, substituted
with 0-2 R16e;
R16b at each occurrence, is selected from C1-6 alkyl, C2-8
alkenyl, C2-8 alkynyl, a (CH2)r C3-6 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 C2-8 alkenyl, C2-8
alkynyl, C1-6 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)r C3-6 cycloalkyl, Cl, F, Br,
I, CN, NO2, (CF2)r CF3, (CH2)r OC1-5 alkyl, OH, SH,
(CH2)r SC1-5 alkyl, (CH2)r NR16f R16f, and (CH2)r phenyl;
R16f, at each occurrence, is selected from H, C1-5 alkyl,
and C3-6 cycloalkyl, and phenyl;
v is selected from 0, 1, and 2;
t is selected from 1 and 2;
w is selected from 0 and 1;
r is selected from 0, 1, 2, 3, 4, and 5;
q is selected from 1, 2, 3, 4, and 5; and
p is selected from 1, 2, and 3.



341



20. The compound of claim 19, wherein:
R4 is absent, taken with the nitrogen to which it is
attached to form an N-oxide, or selected from C1-8
alkyl, (CH2)r C3-6 cycloalkyl, and (CH2)r-phenyl
substituted with 0-3 R4c;
R4c, at each occurrence, is selected from C1-6 alkyl, C2-8
alkenyl, C2-8 alkynyl, C3-6 cycloalkyl, Cl, F, Br, I,
CN, NO2, (CF2)r CF3, (CH2)r OC1-5 alkyl, (CH2)r OH,
(CH2)r SC1-5 alkyl, (CH2)r NR4a R4a' and (CH2)r phenyl;
alternatively, R4 joins with R7, R9, or R11 to form a 5, 6
or 7 membered piperidinium spirocycle or pyrrolidinium
spirocycle substituted with 0-3 R a;
R1 and R2 are independently selected from H and C1-4 alkyl;
R6, at each occurrence, is selected from C1-4alkyl, C2-8
alkenyl, C2-8 alkynyl, (CH2)r C3-6 cycloalkyl, (CF2)r CF3,
CN, (CH2)r OH, (CH2)r OR6b, (CH2)r C(O)R6b,
(CH2)r C(O)NR6a R6a', (CH2)r NR6d C(O)R6a, and (CH2)t phenyl
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)r CF3, (CH2)r OC1-
alkyl, (CH2)r OH, (CH2)r SC1-5 alkyl, and (CH2)r NR6d R6d;



342




R6d, at each occurrence, is selected from H, C1-6 alkyl, and
C3-6 cycloalkyl;
R7, is selected from H, C1-3 alkyl, (CH2)r C3-5 cycloalkyl,
(CH2)q OH, (CH2)a OR7d, (CH2)q NR7aR7a', (CH2)r C(O)R7b,
(CH2)r C(O)NR7aR7a', (CH2)q NR7a C(O)R7a, C1-6 haloalkyl,
(CH2)r phenyl with 0-2 R7c;
R7a and R7a', at each occurrence, are selected from H, C1-6
alkyl, (CH2)r C3-5 cycloalkyl, a (CH2)r phenyl
substituted with 0-3 R7e;
R7b, at each occurrence, is selected from C1-6 alkyl, C2-8
alkenyl, C2-8 alkynyl, (CH2)r C3-6 cycloalkyl,
(CH2)r phenyl substituted with 0-3 R7e;
R7c, at each occurrence, is selected from C1-4 alkyl, C2-8
alkenyl, C2-8 alkynyl, (CH2)r C3-5 cycloalkyl, Cl, Br, I,
F, (CF2)r CF3, NO2, CN, (CH2)r NR7f R7f, (CH2)r OH,
(CH2)r OC1-4 alkyl, (CH2)r C(O)R7b, (CH2)r C(O)NR7f R7f,
(CH2)r NR7f C(O)R7 a, (CH2)r S(O)p R7b, (CH2)r S(O)2NR7f R7f,
(CH2)r NR7f S(O)2R7b, and (CH2)r phenyl substituted with 0-
2 R7e;
R7d, at each occurrence, is selected from C1-6 alkyl,
(CH2)r C3-6 cycloalkyl, (CH2)r phenyl substituted with 0-
3 R7e;
R7e, 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)r CF3, (CH2)r OC1-5 alkyl, OH, SH, (CH2)r SC1-
alkyl, (CH2)r NR7f R7f, and (CH2)r phenyl;
R7f, at each occurrence, is selected from H, C1-5 alkyl, and
C3-6 cycloalkyl;
R8 is H or joins with R7 to form C3-7 cycloalkyl or =NR8b;



343




R11, is selected from H, C1-6 alkyl, (CH2)r C3-5 cycloalkyl,
(CH2)q OH, (CH2)q OR11d, (CH2)q NR11aR11a', (CH2)r C(O)R11b,
(CH2)r C(O)NR11aR11a', (CH2)q NR11a C(O)R11a, C1-6 haloalkyl,
(CH2)r phenyl with 0-2, R11c, (CH2)r-5-10 membered
heterocyclic system containing 1-4 heteroatoms
selected from N, O, and S, substituted with 0-3 R15;
R11a and R11a', at each occurrence, are selected from H, C1-6
alkyl, (CH2)r C3-6 cycloalkyl, a (CH2)r phenyl
substituted with 0-3 R11e.
R11b, at each occurrence, is selected from C1-6 alkyl, C2-8
alkenyl, C2-8 alkynyl, (CH2)r C3-6 cycloalkyl,
(CH2)r phenyl substituted with 0-3 R11e.
R11c, at each occurrence, is selected from C1-4 alkyl, C2-8
alkenyl, C2-8 alkynyl, (CH2)r C3-5 cycloalkyl, Cl, Br, I,
F, (CF2)r CF3, NO2, CN, (CH2)r NR11f R11f, (CH2)r OH,
(CH2)r OC1-4 alkyl, (CH2)r C(O)R11b, (CH2)r C(O)NR11f R11f,
(CH2)r NR11f C(O)R11a, (CH2)r S(O)p R11b,
(CH2)r S(O)2NR11f R11f, (CH2)r NR11f S(O)2R11b, and
(CH2)r phenyl substituted with 0-2 R11e.
R11d, at each occurrence, is selected from C1-6 alkyl,
(CH2)r C3-5 cycloalkyl, (CH2)r phenyl substituted with 0-
3 R11e.
R11e, at each occurrence, is selected from C1-6 alkyl, C2-8
alkenyl, C2-8 alkynyl, C3-6 cycloalkyl, Cl, F, Br, I,
CN, NO2, (CF2)r CF3, (CH2)r OC1-5 alkyl, OH, SH, (CH2)r SC1-
alkyl, (CH2)r NR11f R11f, and (CH2)r phenyl;
R11f, at each occurrence, is selected from H, C1-5 alkyl and
C3-6 cycloalkyl;
R12 is H or joins with R11 to form C3-7 cycloalkyl;



344




R13, at each occurrence, is selected from C1-4 alkyl, C3-6
cycloalkyl, (CH2)NR13a R13a', (CH2)OH, (CH2)OR13b,
(CH2)w C(O)R13b (CH2)w C(O)NR13aR13a', (CH2)NR13d C(O)R13a,
(CH2)w S(O)2NR13a R13a', (CH2)NR13d S(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)r CF3, (CH2)r OC1-
alkyl, (CH2)r OH, and (CH2)r NR13d R13d;
R13d at each occurrence, is selected from H, C1-6 alkyl,
and C3-6 cycloalkyl;
v is selected from 1 and 2;
q is selected from 1, 2, and 3; and
r is selected from 0, 1, 2, and 3.
21. The compound of claim 20, wherein:
R3 is selected from 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,



345



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
R6 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, isoindolyl, piperidinyl, pyrrazolyl, 1,2,4-
triazolyl, 1,2,3-triazolyl, tetrazolyl, thiazolyl,
oxazolyl, pyrazinyl, and pyrimidinyl.
22. The compound of claim 21, wherein the compound of
formula (I) is:

Image

R16, at each occurrence, is selected from C1-8 alkyl,
(CH2)r C3-6 cycloalkyl, CF3, Cl, Br, I, F,
(CH2)r NR16a R16a', NO2, CN, OH, (CH2)r OR16d,
(CH2)r C(O)R16b, (CH2)r C(O)NR16a R16a', (CH2)r NR16f C(O)R16b,
(CH2)r S()p R16b (CH2)r S(O)2NR16a R16a',
(CH2)r NR16f S(O)2R16b and (CH2)r phenyl substituted with
0-3 R16e.
R16a and R16a', at each occurrence, are selected from H, C1-6
alkyl, C3-6 cycloalkyl, and (CH2)r phenyl substituted
with 0-3 R16e;



346



R16b, at each occurrence, is selected from H, C1-6 alkyl,
C3-6 cycloalkyl, and (CH2)r phenyl 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)r CF3, OH, and (CH2)r OC1-5 alkyl;
and
R16f at each occurrence, is selected from H, and C1-5
alkyl.
23. The compound of claim of claim 21, wherein the
compound of formula (I) is:

Image

R16, at each occurrence, is selected from C1-8 alkyl,
(CH2)r C3-6 cycloalkyl, CF3, Cl, Br, I, F,
(CH2)r NR16a R16a', NO2, CN, OH, (CH2)r OR16d,
(CH2)r C(O)R16b, (CH2)r C(O)NR16a R16a', (CH2)r NR16f C(O)R16b
(CH2)r S(O)p R16b, (CH2)r S(O)2NR16a R16a',
(CH2)r NR16f S(O)2R16b, and (CH2)r phenyl substituted with
0-3 R16e;
R16a and R16a', at each occurrence, are selected from H, C1-6
alkyl, C3-6 cycloalkyl, and (CH2)r phenyl substituted
with 0-3 R16e;
R16b, at each occurrence, is selected from H, C1-6 alkyl,
C3-6 cycloalkyl, and (CH2)r phenyl substituted with 0-3
R16e;



347



R16d, at each occurrence, is selected from C1-6 alkyl and
phenyl;
R16e, at each occurrence, is selected from C1-6 alkyl, C1,
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.
24. The compound of claim 22, wherein:
R5 is CH2phenyl substituted with 0-3 R16;
E is -CH2- (CR9R10) - (CR11R12);
R9, is selected from H, C1-6 alkyl, (CH2)rC3-6 cycloalkyl, F,
Cl, CN, (CH2)rOH, (CH2)rOR9d, (CH2)rNR9aR9a',
(CH2)rOC(O) NHR9a, (CH2)rphenyl substituted with 0-5 R9e,
and a heterocyclic system substituted with 0-2 R9e,
wherein the heterocyclic system is selected from
pyridyl, thiophenyl, furanyl, oxazolyl, and thiazolyl;
R9a and R9a', at each occurrence, are selected from H, C1-6
alkyl, C3-6 cycloalkyl, and (CH2)rphenyl substituted
with 0-3 R9e;
R9d, at each occurrence, is selected from C1-6 alkyl and
phenyl;
R9e, at each occurrence, is selected from C1-6 alkyl, C1, F,
Br, I, CN, NO2, (CF2)rCF3, OH, and (CH2)rOC1-5 alkyl;
R10 is selected from H, C1-5 alkyl, OH, and CH2OH;
alternatively, R9 and R10 join to form C3-7 cycloalkyl, 5-6-
membered cyclic ketal or =O;
348




with the proviso that when R10 is -OH, R9 is not halogen,
cyano, or bonded to the carbon to which it is attached
through a heteroatom;
R11 is selected from H, C1-8 alkyl, (CH2)rphenyl substituted
with 0-5 R11e, and a (CH2)r-heterocyclic system
substituted with 0-2 R11e, 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
R11e, at each occurrence, is selected from C1-6 alkyl, C1,
F, Br, I, CN, NO2, (CF2)rCF3, OH, and (CH2)rOC1-5 alkyl;
R12 is H;
alternatively, R11 and R12 join to form C3-7 cycloalkyl; and
r is selected from 0, l, and 2.
25. The compound of claim 23, wherein:
R5 is CH2phenyl substituted with 0-3 R16;
E is -CH2- (CR9R10) - (CR11R12);
R9, is selected from H, C1-6 alkyl, (CH2)rC3-6 cycloalkyl, F,
C1, CN, (CH2)rOH, (CH2)r-OR9d, (CH2)rNR9aR9a',
(CH2)rOC(O)NHR9a, (CH2)rphenyl substituted with 0-5 R9e,
and a heterocyclic system substituted with 0-2 R9e,
wherein the heterocyclic system is selected from
pyridyl, thiophenyl, furanyl, oxazolyl, and thiazolyl;
349




R9a and R9a', at each occurrence, are selected from H, C1-6
alkyl, C3_6 cycloalkyl, and (CH2)rphenyl substituted
with 0-3 R9e;
R9d, at each occurrence, is selected from Cl-6 alkyl and
phenyl;
R9e, at each occurrence, is selected from C1-6 alkyl, C1, F,
Br, I, CN, NO2, (CF2)rCF3, OH, and (CH2)rOC1-5 alkyl;
R10 is selected from H, C1-8 alkyl, OH, and CH2OH;
alternatively, R9 and R10 join to form C3-7 cycloalkyl, 5-,6-
membered cyclic ketal or =O;
with the proviso that when R10 is -OH, R9 is not halogen,
cyano, or bonded to the carbon to which it is attached
through a heteroatom;
R11 is selected from H, C1-8 alkyl, (CH2)rphenyl substituted
with 0-5 R11e, and a (CH2)r-heterocyclic system
substituted with 0-2 R11e, 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
R11e, at each occurrence, is selected from C1-6 alkyl, Cl,
F, Br, I, CN, NO2, (CF2)rCF3, OH, and (CH2)rOC1-5 alkyl;
R12 is H;
alternatively, R11 and R12 join to form C3-7 cycloalkyl; and
350




r is selected from 0, 1, and 2.
26. The compound of claim 24, 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 C3-10 carbocyclic residue substituted with 0-3 R15,
wherein the carbocyclic residue is selected from
cyclopropyl, 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
R15, at each occurrence, is selected from C1-8 alkyl,
(CH2)rC3-6 cycloalkyl, CF3, Cl, Br, I, F,
(CH2)rNR15aR15a', NO2, CN, OH, (CH2)rOR15d,
(CH2)rC(O)R15b, (CH2)rC(O)NR15aR15a',(CH2)rNR15fC(O)R15b,
(CH2)rS(O)pR15b, (CH2)rS(O)2NR15aR15a',
(CH2)rNR15fS(O)2R15b, (CH2)rphenyl 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 0-2 R15e;
351



R15a and R15a', at each occurrence, are selected from H, C1-6
alkyl, C3-6 cycloalkyl, and (CH2)rphenyl substituted
with 0-3 R15e;
R15b, at each occurrence, is selected from H, C1-6 alkyl,
C3-6 cycloalkyl, and (CH2)rphenyl substituted with 0-3
R15e;
R15d, at each occurrence, is selected from C1-6 alkyl and
phenyl;
R15e, at each occurrence, is selected from C1-6 alkyl, C1,
F, Br, I, CN, NO2, (CF2)rCF3, OH, and (CH2)rOC1-5 alkyl;
and
R15f, at each occurrence, is selected from H, and C1-5
alkyl.
27. The compound of claim 25, wherein:
K is selected from CH2 and CHR5;
L is selected from CH2 and CHR5;
R3 is a C3-10 carbocyclic residue substituted with 0-3 R15
wherein the carbocyclic residue is selected from
cyclopropyl, 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
352




R15, at each occurrence, is selected from C1-8 alkyl,
(CH2)rC3-5 cycloalkyl, CF3, C1, Br, I, F,
(CH2)rNR15aR15a' ,NO2, CN, OH, (CH2)rOR15d,
(CH2)rC(O) R15b, (CH2)rC(O)NR15aR15a',(CH2)rNR15fC(O)R15b,
(CH2)rS(O)pR15b, (CH2)rC(O)NR15aR15a',
(CH2)rNR15S(O)2R15b, (CH2)rphenyl 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 0-2 R15e;
R15a and R15a', at each occurrence, are selected from H, C1-6
alkyl, C3-6 cycloalkyl, and (CH2)rphenyl substituted
with 0-3 R15e;
R15b, at each occurrence, is selected from H, C1-6 alkyl,
C3-6 cycloalkyl, and (CH2)rphenyl substituted with 0-3
R15e;
R15d, at each occurrence, is selected from C1-6 alkyl and
phenyl;
R15e, at each occurrence, is selected from C1-6 alkyl, C1,
F, Br, I, CN, NO2, (CF2)rCF3, OH, and (CH2)rOC1-5 alkyl;
and
R15f, at each occurrence, is selected from H, and C1-5
alkyl.
28. The compound of claim 1 and pharmaceutically
acceptable salt forms thereof, wherein the compound of
formula (I) is selected from:
N"-cyano-N-(3-methoxyphenyl)-N'-[3-[4-(phenylmethyl)-1-
piperidinyl]propyl]guanidine,
N"-cyano-N-(3-methoxyphenyl)-N'-[3-[4-(4-
fluorophenylmethyl)-1-piperidinyl]propyl]guanidine.
353



N-(3-acetylphenyl)- N"-cyano-N'-[3-[4-(4-
fluorophenylmethyl)-1-piperidinyl]propyl]guanidine,
N-(3-acetylphenyl)-N"-cyano-N'-{3-[(3S)-3-(4-
fluorobenzyl)piperidinyl]propyl}guanidine,
N"-cyano-N-(3,5-diacetylphenyl)-N'-{3-[(3S)-3-(4-
fluorobenzyl)piperidinyl]propyl}guanidine,
N"-cyano-N-(3-[(3S)-3-(4-fluorobenzyl)piperidinyl]propyl}-
N'-[3-(1-methyl-1H-tetraazol-5-yl)phenyl]guanidine,
N"-cyano-N-(2,4-dimethoxyphenyl)-N'-{3-[(3S)-3-(4-
fluorobenzyl)piperidinyl]propyl}guanidine,
N-(5-acetyl-2-methoxyphenyl)-N"-cyano-N'-{3-[(3S)-3-(4-
fluorobenzyl)piperidinyl]propyl}guanidine,
N-(3-acetylphenyl)-N"-cyano-N'-{(3R, 4R)-5-[4-(4-
fluorobenzyl)piperidinyl]-4-hydroxy-1-methyl-3-
pentyl}guanidine,
N"-cyano-N-{3-[(3S)-3-(4-fluorobenzyl)piperidinyl]-2-(2E)-
propenyl}-N'-[3-(1-methyl-1H-tetraazol-5-
yl)phenyl]guanidine,
2-[(3-acetylanilino)({3-[(4-(4-
fluorobenzyl)piperidinyl]propyl}amino)methylene]malono
nitrite,
2-[ (3-acetylanilino) ({3- [(3S)-3-(4-
fluorobenzyl)piperidinyl]propyl}amino)methylene]malono
nitrite,
2-[[3-(1-methyl-1H-tetrazol-5-yl)anilino]({3-[(3S)-3-(4-
fluorobenzyl)piperidinyl]propyl}amino)methylene]malono
nitrite,
354



N-[(E)-(3-acetylanilino) ( {3-[ (3S)-3-(4-
fluorobenzyl)piperidinyl]propyl}amino)methylidene]urea
N- [ (E) - (3, 5-diacetylanilino) ( {3- [ (3S) -3- (4-
fluorobenzyl)piperidinyl]propyl}amino)methylidene]urea
,
N-[(E)-[3-(1-methyl-1H-tetrazol-5-yl)anilino]({3-[(3S)-3-
(4-
fluorobenzyl)piperidinyl]propyl}amino)methylidene]urea
'
Methyl (E) - (3 , 5-diacetylanilino) ( {3- [ (3S) -3- (4-
fluorobenzyl)piperidinyl]propyl}amino)methylidenecarba
mate,
1-(3-{ [ (E)-1-({3-[4-(4-
fluorobenzyl)piperidinyl]propyl}amino)-2-
nitroethenyl]amino}phenyl)ethanone, and
1-(3-{ [ (E)-1-({3-[ (3S)-3-(4-
fluorobenzyl)piperidinyl]propyl}amino)-2-
nitroethenyl]amino}phenyl)ethanone.
29. A compound of formula (I):
Image
or stereoisomers or pharmaceutically acceptable salts
thereof, wherein:
M is absent or selected from CH2, CHR5, CHR13, CR13R13, and
CR5R13;
Q is selected from CH2 , CHR5 , CHR13 , CR13R13 , and CR5R13 ;
355




J, K, and L are independently selected from CH2, CHR5, CHR6,
CR6R6 and CR5R6;
with the provisos:
1) at least one of M, J, K, L, or Q contains an R5;
and
2) when M is absent, J is selected from CH2, CHR5,
CHR13 , and CR5R13;
Z is selected from NR1a, CHCN, CHNO2, and C(CN)2;
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 selected from:
Image
356



Image
ring A is a C3-6 carbocyclic residue;
R1 and R2 are independently selected from H, C1-6 alkyl, C2-8
alkenyl, C2-8 alkynyl, (CH2)rC3-6 cycloalkyl, and a
(CH2)r-C3-10 carbocyclic residue substituted with 0-5
Ra;
Ra, at each occurrence, is selected from C1-6 alkyl, C2-8
alkenyl, C2-8 alkynyl, (CH2)rC3-6 cycloalkyl, C1, 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 ( 0 ) Rb , ( CH2 ) rC ( O ) ORb , ( CHI ) rOC ( O ) R~ ,
( CH2 ) rCH ( =NRb ) NRbRb , ( CH2 ) rNHC ( =NRb ) NRZ'Rb , ( CH2 ) r S ( 0 )
pR~ ,
(CH2)rS(O)2NRbRb, (CH2)rNR~'S(O)2R~, and (CH2)rphenyl;
Rb, at each occurrence, is selected from H, C1-6 alkyl, C3-6
cycloalkyl, and phenyl;
R~, at each occurrence, is selected from C1-6 alkyl, C3-5
cycloalkyl, and phenyl;
alternatively, R2 and R3 join to form a 5, 6, or 7-membered
ring substituted with 0-3 Ra;
R3 is selected from a (CR3'R3")r-C3-to carbocyclic residue
substituted with 0-5 R15 and a (CR3'R3")r-5-10 membered
heterocyclic system containing 1-4 heteroatoms
selected from N, O, and S, substituted with 0-3 Rls;
R3' and R3", at each occurrence, are selected from H, C1_s
alkyl, (CH2)rC3-6 cycloalkyl, and phenyl;
3 5 '7




R4 is absent, taken with the nitrogen to which it is
attached to form an N-oxide, or selected from C1-6
alkyl, C2-8 alkenyl, C2-8 alkynyl, (CH2)r C3-6
cycloalkyl, (CH2)q C(O)R4b, (CH2)q C(O)NR4a R4a',
(CH2)q C(O)OR4b, and a (CH2)r-C3-10 carbocyclic residue
substituted with 0-3 R4c;
R4a and R4a', at each occurrence, are selected from H, C1-6
alkyl, (CH2)r C3-6 cycloalkyl, and phenyl;
R4b, at each occurrence, is selected from C1-6 alkyl, C2-8
alkenyl, (CH2)r C3-5 cycloalkyl, C2-8 alkynyl, and
phenyl;
R4c, at each occurrence, is selected from C1-6 alkyl, C2-8
alkenyl, C2-8 alkynyl, C3-6 cycloalkyl, Cl, F, Br, I,
CN, NO2, (CF2)r CF3, (CH2)r OC1-5 alkyl, (CH2)r OH,
(CH2)r SC1-5 alkyl, (CH2)r NR4aR4a' and (CH1)r phenyl;
alternatively, R4 joins with R7, R9, or R11 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-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)r C3-6 cycloalkyl, and phenyl;
R6, at each occurrence, is selected from C1-6 alkyl, C2-8
alkenyl, C2-8 alkynyl, (CH2)r C3-5 cycloalkyl, (CF2)r CF3,
CN, (CH2)r NR6a R6a', (CH2)r OH, (CH2)r OR6b, (CH2)r SH,
(CH2)r SR6b, (CH2)r C(O)OH, (CH2)r C(O)R6b,
(CH2)r C(O)NR6a R6a', (CH2)r NR6d C(O)R6a, (CH2)r C(O)OR6b,
(CH2)r OC(O)R6b, (CH2)r S(O)p R6b, (CH2)r S(O)2NR6a R6a',



358




(CH2)r NR6d S(O)2R6b, and (CH2)t phenyl 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)r CF3, (CH2)r OC1-
alkyl, (CH2)r OH, (CH2)r SC1-5 alkyl, and (CH2)r NR6d R6d;
R6d, at each occurrence, is selected from H, C1-6 alkyl, and
C3-6 cycloalkyl;
R7, is selected from H, C1-6 alkyl, C2-8 alkenyl, C2-8
alkynyl, (CH2)q OH, (CH2)q SH, (CH2)q OR7d, (CH2)q SR7d,
(CH2)q NR7a R7a', (CH2)r C(O)OH, (CH2)r C(O)R7b,
(CH2)r-C(O)NR7a R7a', (CH2)q NR7a C(O)R7a, (CH2)q NR7a C(O)H,
(CH2)r C(O)OR7b, (CH2)q OC(O)R7b, (CH2)q S(O)p R7b,
(CH2)q S(O)2NR7a R7a', (CH2)q NR7a S(O)2R7b, C1-6 haloalkyl,
a (CH2)r-C3-10 carbocyclic residue substituted with 0-3
R7c, and a (CH2)r-5-10 membered heterocyclic system
containing 1-4 heteroatoms selected from N, O, and S,
substituted with 0-2 R7c;
R7a and R7a', at each occurrence, are selected from H, C1-6
alkyl, C2-8 alkenyl, C2-8 alkynyl, (CH2)r C3-6
cycloalkyl, a (CH2)r-C3-10 carbocyclic residue
substituted with 0-5 R7e, and a (CH2)r-5-10 membered
heterocyclic system containing 1-4 heteroatoms
selected from N, O, and S, substituted with 0-3 R7e;
R7b, at each occurrence, is selected from C1-6 alkyl, C2-8
alkenyl, C2-8 alkynyl, a (CH2)r-C3-6 carbocyclic residue



359



substituted with 0-2 R7e, and a (CH2)r-5-6 membered
heterocyclic system containing 1-4 heteroatoms
selected from N, O, and S, substituted with 0-3 R7e;
R7c, at each occurrence, is selected from C1-6 alkyl,
alkenyl, C2-8 alkynyl, (CH2)r C3-6 cycloalkyl, Cl, Br, I,
F, (CF2)r CF3, NO2, CN, (CH2)r NR7f R7f, (CH2)r OH,
(CH2)r OC1-4 alkyl, (CH2)r SC1-4 alkyl, (CH2)r C(O)OH,
(CH2)r C(O)R7b, (CH2)r C(O)NR7f R7f, (CH2)r NR7f C(O)R7a,
(CH2)r C(O)OC1-4 alkyl, (CH2)r OC(O)R7b,
(CH2)r C(=NR7f)NR7f R7f, (CH2)r S(O)p R7b.
(CH2)r NHC(=NR7f)NR7f R7f, (CH2)r S(O)2NR7f R7f,
(CH2)r NR7f S(O)2R7b, and (CH2)r phenyl substituted with 0-
3 R7e;
R7d, at each occurrence, is selected from C1-6 alkyl
substituted with 0-3 R7e, alkenyl, alkynyl, and a C3-10
carbocyclic residue substituted with 0-3 R7c;
R7e, at each occurrence, is selected from C1-6 alkyl, C2-8
alkenyl, C2-8 alkynyl, C3-6 cycloalkyl, Cl, F, Br, I,
CN, NO2, (CF2)r CF3, (CH2)r OC1-5 alkyl, OH, SH, (CH2)r SC1-
alkyl, (CH2)r NR7f R7f, and (CH2)r phenyl;
R7f, at each occurrence, is selected from H, C1-6 alkyl, and
C3-6 cycloalkyl;
R8 is selected from H, C1-6 alkyl, C3-6 cycloalkyl, and
(CH2)t phenyl substituted with 0-3 R8a;
R8a, 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)r CF3, (CH2)r OC1-5 alkyl, OH, SH, (CH2)r SC1-
alkyl, (CH2)r NR7f R7f, and (CH2)r phenyl;
alternatively, R7 and R8 join to form C3-7 cycloalkyl, or
=NR8b;



360




R8b is selected from H, C1-6 alkyl, C3-6 cycloalkyl, OH, CN,
and (CH2)r-phenyl;
R9, is selected from H, C1-6 alkyl, C2-8 alkenyl, C2-8
alkynyl, F, Cl, Br, I, NO2, CN, (CH2)r OH, (CH2)r SH,
(CH2)r OR9d, (CH2)r SR9d, (CH2)r N R9a R9a', (CH2)r C(O)OH,
(CH2)r C(O)R9b, (CH2)r C(p)NR9a R9a', (CH2)r NR9a C(O)R9a,
(CH2)r NR9a C(O)H, (CH2)r NR9a C(O)NHR9a, (CH2)r C(O)OR9b,
(CH2)r OC(O)R9b, (CH2)r OC(O)NHR9a, (CH2)r S(O)p R9b,
(CH2)r S(O)1NR9a R9a', (CH2)r NR9a S(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, C2-8 alkenyl, C2-8 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;
R9b, at each occurrence, is selected from C1-6 alkyl, C2-8
alkenyl, C2-8 alkynyl, a (CH2)r-C3-6 carbocyclic residue
substituted with 0-2 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)r C3-6 cycloalkyl, Cl, Br, I,
F, (CF2)r CF3, NO2, CN, (CH2)r NR9f R9f, (CH2)r OH,
(CH2)r OC1-4 alkyl, (CH2)r SC1-4 alkyl, (CH2)r C(O)OH,
(CH2)r C(O)R9b, (CH2)r C(O)NR9f R9f, (CH2)r NR9f C(O)R9a,
(CH2)r C(O)OC1-4 alkyl, (CH2)r OC(O)R9b,
(CH2)r C(=NR9f)NR9f R9f, (CH2)r S(O)p R9b,
(CH2)r NHC(=NR9f)NR9f R9f, (CH2)=S(O)2NR9f R9f,



361




(CHZ)rNR9fS(O)2R9b, and (CH2)rphenyl substituted with 0-
3 R9e;
R9d, at each occurrence, is selected from C1-6 alkyl, C2-6
alkenyl, C2-6 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, C2-6
alkenyl, C2-8 alkynyl, (CH2)rC3-6 cycloalkyl, C1, F, Br,
I, CN, N02, (CF2)rCF3, (CH2)rOCi-5 alkyl, OH, SH,
(CH2)rSCl-5 alkyl, (CH2)rNR9fR9f, and (CH2)rphenyl;
R9f, at each occurrence, is selected from H, C1-6 alkyl, and
C3-6 cycloalkyl;
R10, is selected from H, C1-6 alkyl, C2-8 alkenyl, C2-8
alkynyl, F, C1, Br, I, NO2, CN, (CH2)rOH, (CH2)rORl0d,
(CH2)rSRl0d (CH2)rNR10aR10a', (CH2)rC(0)OH,
( CH2 ) rC ( O ) RlOb ( CH2 ) rC ( O ) NR10aR10a' , ( CH2 ) rNRlOaC ( O ) RlOa
( CHZ ) rNRi 0aC ( O ) H , ( CH2 ) rC ( O ) ORlOb W CH2 ) rOC ( O ) R10b
( CH2 ) rS ( O ) F,RlOb ( CH2 ) rS ( O ) 2NR10aR10a' .
(CH2)rNR10aS(O)2R10b C1-6 haloalkyl, a (CH2)r-C3-10
carbocyclic residue substituted with 0-5 Rl0c, and a
(CH2)r-5-10 membered heterocyclic system containing 1-4
heteroatoms selected from N, 0, and S, substituted
with 0-3 Rl0c;
Rloa and Rl0a' at each occurrence, are selected from H, C1-5
alkyl, C2-8 alkenyl, C2-g alkynyl, a (CH2)r-C3-to
carbocyclic residue substituted with 0-5 Rl0e, and a
(CH2)r-5-10 membered heterocyclic system containing 1-4
heteroatoms selected from N, 0, and S, substituted
with 0-3 Rl0e;
362




Rl0b at each occurrence, is selected from C1-6 alkyl, C2-8
alkenyl, C2-8 alkynyl, a (CH2)r-C3-5 carbocyclic residue
substituted with 0-2 Rl0e, and a (CH2)r-5-6 membered
heterocyclic system containing 1-4 heteroatoms
selected from N, O, and S, substituted with 0-3 Rl0e-
Rl0c, at each occurrence, is selected from C1-6 alkyl, C2-8
alkenyl, C2-8 alkynyl, (CH2)rC3-6 cycloalkyl, C1, Br, I,
F, (CF2)rCF3, NO2, CN, (CH2)rNR10fR10f (CH2);OH,
(CH2)rOC1-4 alkyl, (CH2)rSCl-4 alkyl, (CH2)rC(0)OH,
(CH2)rC(O)Rl0b (CH2)rC(O)NRlofRl0f, (CH2)rNRl0fC(O)Rl0a
(CHZ)rC(O)OC1-4 alkyl, (CH2)rOC(O)Rl0b
(CH2)rC(=NRl0f)NR10fR10f (CH2)rS(O)pRl0b
(CH2)rNHC(=NRlOf)NR10fR10f (CH2)rS(0)2NR10fR10f
(CH2)rNRl0fS(0)2Rl0b, and (CH2)rphenyl substituted with
0-3 R10e.
Rl0d at each occurrence, is selected from C1-6 alkyl, C2-6
alkenyl, C2-6 alkynyl, a C3-10 carbocyclic residue
substituted with 0-3 Rl0c, 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 Rl0c
Rl0e, at each occurrence, is selected from C1-6 alkyl, C2-8
alkenyl, C2-8 alkynyl, (CH2)rC3-6 cYcloalkyl, C1, F, Br,
I, CN, NO2, (CF2)rCF3, (CH2)rOCl-5 alkyl, OH, SH,
(CH2)rSCl-5 alkyl, (CH2)rNRlofRl0f, and (CH2)rphenyl;
Rl0f, at each occurrence, is selected from H, C1-5 alkyl,
and C3-6 cycloalkyl;
alternatively, R9 and Rl0 join to form C3-7 cycloalkyl, 5-6-
membered cyclic ketal or =O;
363



with the proviso that when R10 is -OH, R9 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, (CH2)q OH, (CH2)q SH, (CH2)q OR11d, (CH2)q SR11d,
(CH2)q NR11a R11a', (CH2)r C(O)OH, (CH2)r C(O)R11b,
(CH2)r C(O)NR11a R11a', (CH2)q NR11a C(O)R11a,
(CH2)q NR11a C(O)NHR11a, (CH2)r C(O)OR11b, (CH2)q OC(O)R11b,
(CH2)q S(O)p R11b, (CH2)q S(O)2NR11a R11a',
(CH2)q NR11a S(O)2R11b, C1-6 haloalkyl, a (CH2)r-C3-10
carbocyclic residue substituted with 0-5 R11c, and a
(CH2)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, C2-8 alkenyl, C2-8 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;
R11b, at each occurrence, is selected from C1-6 alkyl, C2-8
alkenyl, C2-8 alkynyl, a (CH2)r-C3-6 carbocyclic residue
substituted with 0-2 R11e, and a (CH2)r-5-6 membered
heterocyclic system containing 1-4 heteroatoms
selected from N, O, and S, substituted with 0-3 R11a,
R11c, at each occurrence, is selected from C1-6 alkyl, C2-8
alkenyl, C2-8 alkynyl, (CH2)r C3-6 cycloalkyl, Cl, Br, I,
F, (CF2)r CF3, NO2, CN, (CH2)r NR11f R11f, (CH2)r OH,
(CH2)r OC1-4 alkyl, (CH2)r SC1-4 alkyl, (CH2)r C(O)OH,
(CH2)r C(O)R11b, (CH2)r C(O)NR11f R11f, (CH2)r NR11f C(O)R11a,
(CH2)r C(O)OC1-4 alkyl, (CH2)r OC(O)R11b,
(CH2)r C(=NR11f)NR11f R11f, (CH2)r NHC(=NR11f)NR11f R11f,
(CH2)r S(O)p R11b, (CH2)r S(O)2NR11f R11f,
364




(CH2)rNRllfS(O)2Rllb, and (CH2)rphenyl substituted with
0-3 Rlle;
Rlld, at each occurrence, is selected from C1-6 alkyl
substituted with 0-3 Rlle, C2-6 alkenyl, C2-6 alkynyl,
and a C3-l0 carbocyclic residue substituted with 0-3
Rllc;
Rlle, at each occurrence, is selected from C1-6 alkyl , C2-8
alkenyl, C2-8 alkynyl, C3-6 cycloalkyl, C1, F, Br, I,
CN, NO2, (CF2)rCF3, (CH2)rOCl-5 alkyl, OH, SH, (CH2)rSCl-
alkyl, (CH2)rNR11fR11f and (CH2)rphenyl;
Rllf, at each occurrence, is selected from H, C1-6 alkyl,
and C3-6 cycloalkyl;
R12 is selected from H, C1-6 alkyl, (CH2)qOH, (CH2)rC3-6
cycloalkyl, and (CH2)tphenyl substituted with 0-3 Rl2a.
Rl2a at each occurrence, is selected from C1-6 alkyl, C2-8
alkenyl, C2-8 alkynyl, C3-6 cycloalkyl, C1, F, Br, I,
CPJ, NO2, (CF2)rCF3, (CH2)rOCl-5 alkyl, OH, SH, (CH2)rSCl-
5 alkyl, (CH2)rNR9fR9f, and (CH2)rphenyl;
alternatively, R11 and R12 join to form C3-7 cycloalkyl;
R13, at each occurrence, is selected from C1-6 alkyl, C2-8
alkenyl, C2-8 alkynyl, C3-6 cycloalkyl, (CF2)wCF3,
(CH2) NR13aR13a', (CH2) OH, (CH2) ORl3b (CH2) SH,
(CH2)SRl3b (CH2)wC(O)OH, (CH2)wC(O)Rl3b
(CH2)wC(O)NR13aR13a', (CH2)NRl3dC(O)Rl3a (CH2)wC(O)ORl3b
(CH2)OC(O)Rl3b (CH2)wS(0)pRl3b (CH2)wS(O)2NR13aR13a',
(CH2)NRl3dS(O)2R13b, and (CH2)w-phenyl substituted with
0-3 Rl3c;
365




Rl3a and Rl3a', at each occurrence, are selected from H, C1-6
alkyl, C3-6 cycloalkyl, and phenyl substituted with 0-3
Rl3c;
Rl3b, at each occurrence, is selected from C1-6 alkyl, C3-6
cycloalkyl, and phenyl substituted with 0-3 Rl3c;
Rl3c, at each occurrence, is selected from C1-6 alkyl, C3-6
cycloalkyl, C1, F, Br, I, CN, NO2, (CF2)rCF3, (CH2)rOCl-
alkyl, (CHZ)rOH, (CH2)rSCl_5 alkyl, and
(CH2)rNR13dR13d;
Rl3d at each occurrence, is selected from H, C1-6 alkyl,
and C3-6 cycloalkyl;
R14, at each occurrence, is selected from C1-6 alkyl, C2-8
alkenyl, C2-8 alkynyl, (CH2)rC3-5 cycloalkyl, C1, Br, I,
F, NO2, CN, (CHR')rNR14aR14a' (CHR')rOH,
(CHR')rO(CHR')rRl4d, (CHR')rSH, (CHR')rC(O)H,
(CHR') rS (CHR') rRl4d, (CHR') rC(O) OH,
(CHR') rC (O) (CHR') rRl4b, (CHR') rC (O) NR14aR14a',
(CHR') rNRl4fC (O) (CHR') rRl4b (CHR') rC (O) O (CHR') rRl4d
(CHR') rOC (O) ( CHR') rRl4b (CHR') rC (=NR14f)NR14aR14a',
(CHR')rNHC(=NRl4f)NR14fR14f (CHR')rS(O)p(CHR')rRl4b
(CHR')rS(O)zNR14aR14a'~ (CHR')rNRl4fS(O)2(CHR')rRl4b 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 Rl4e, and a (CH2)r-5-10 membered
heterocyclic system containing 1-4 heteroatoms
selected from N, O, and S, substituted with 0-2 Rl5e.
R', at each occurrence, is selected from H, C1-6 alkyl, C2
alkenyl, C2-8 alkynyl, (CH2)rC3-6 cYcloalkyl, and
(CH?)rphenyl substituted with Rl4e;
Rl4a and Rl4a', at each occurrence, are selected from H, C1-6
alkyl, C2-8 alkenyl, C2-8 alkynyl, a (CH2)r-C3-10
366




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, C2-8
alkenyl, C2-8 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 C2-8 alkenyl, C2-8
alkynyl, C1-6 alkyl substituted with 0-3 R14e a
(CH2)r-C3-10 carbocyclic residue substituted with 0-3
R14e and a (CH2)r5-6 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)r C3-6 cycloalkyl, C1, F, Br,
I, CN, NO2, (CF2)r CF3, (CH2)r OC1-5 alkyl, OH, SH,
(CH2)r SC1-5 alkyl, (CH2)r NR14f R14f, and (CH2)r phenyl;
R14f, at each occurrence, is selected from H, C1-6 alkyl,
C3-6 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;
R15, at each occurrence, is selected from C1-6 alkyl, C2-8
alkenyl, C2-8 alkynyl, (CH2)r C3-6 cycloalkyl, C1, Br, I,
F, NO2, CN, (CHR')r NR15a R15a', (CHR')r OH,
(CHR')r O(CHR')r R15d, (CHR')r SH, (CHR')r C(O)H,
(CHR')r S(CHR')r R15d, (CHR')r C(O)OH,
(CHR')r C(O)(CHR')r R15b, (CHR')r C(O)NR15a R15a',



367



(CHR')r NR15f C(O)(CHR')r R15b, (CHR')r C(O)O(CHR')r R15d,
(CHR')r OC(O)(CHR')r R15b, (CHR')r C(O)NR15a R15a',
(CHR')r C(=NR15f)NR15a R15a', (CHR')r NHC(=NR15f)NR15f R15f,
(CHR')r S(O)p(CHR')r R15b, (CHR')r S(O)2NR15a R15a',
(CHR')r NR15f S(O)2(CHR')r R15b, C1-6 haloalkyl, C2-8
alkenyl substituted with 0-3 R', C2-8 alkynyl
substituted with 0-3 R', (CHR')r phenyl 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, C2-8 alkenyl, C2-8 alkynyl, a (CH2)r-C3-10
carbocyclic residue substituted with 0-5 R15e, and a
(CH2)r-5-10 membered heterocyclic system containing 1-4
heteroatoms selected from N, O, and S, substituted
with 0-2 R15e;
R15b, at each occurrence, is selected from C1-6 alkyl, C2-8
alkenyl, C2-8 alkynyl, a (CH2)r-C3-6 carbocyclic residue
substituted with 0-3 R15e, and (CH2)r-5-6 membered
heterocyclic system containing 1-4 heteroatoms
selected from N, O, and S, substituted with 0-2 R15e;
R15d at each occurrence, is selected from C2-8 alkenyl, C2-8
alkynyl, C1-6 alkyl substituted with 0-3 R15e, a
(CH2)r-C3-10 carbocyclic residue substituted with 0-3
R15e, and a (CH2)r5-6 membered heterocyclic system
containing 1-4 heteroatoms selected from N, O, and S,
substituted with 0-3 R15e;
R15e, at each occurrence, is selected from C1-6 alkyl, C2-8
alkenyl, C2-8 alkynyl, (CH2)r C3-6 cycloalkyl, C1, F, Br,
I, CN, NO2, (CF2)r CF3, (CH2)r OC1-5 alkyl, OH, SH,
(CH2)r SC1-5 alkyl, (CH2)r NR15f R15f, and (CH2)r phenyl;



368



R15f, at each occurrence, is selected from H, C1-6 alkyl,
C3-6 cycloalkyl, and phenyl;
R16, at each occurrence, is selected from C1-6 alkyl, C2-8
alkenyl, C2-8 alkynyl, (CH2)r C3-6 cycloalkyl, C1, Br, I,
F, NO2, CN, (CHR')r NR16a R16a' (CHR')r OH,
(CHR')r O(CHR')r R16d (CHR')r SH, (CHR')r C(O)H,
(CHR')r S(CHR')r R16d (CHR')r C(O)OH,
(CHR')r C(O)(CHR')r R16b (CHR')r C(O)NR16a R16a',
(CHR')r NR16f C(O)(CHR')r R16b, (CHR')r C(O)O(CHR')r R16d,
(CHR')r OC(O)(CHR')r R16b, (CHR')r C(=NR16f)NR16a R16a',
(CHR')r NHC(=NR16f)NR16f R16f, (CHR')r S(O)p(CHR')r R16b,
(CHR')r S(O)2NR16a R16a', (CHR')r NR16f S(O)2(CHR')r R16b, C1-6
haloalkyl, C2-8 alkenyl substituted with 0-3 R', C2-8
alkynyl substituted with 0-3 R', and (CHR')r phenyl
substituted with 0-3 R16e;
R16a and R16a', at each occurrence, are selected from H, C1-6
alkyl, C2-8 alkenyl, C2-8 alkynyl, a (CH2)r-C3-10
carbocyclic residue substituted with 0-5 R16e, and a
(CH2)r-5-10 membered heterocyclic system containing 1-4
heteroatoms selected from N, O, and S, substituted
with 0-2 R16e;
R16b, at each occurrence, is selected from C1-6 alkyl, C2-8
alkenyl, C2-8 alkynyl, a (CH2)r C3-6 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 C2-8 alkenyl, C2-8
alkynyl, C1-6 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;



369



R16e, at each occurrence, is selected from C1-6 alkyl, C2-8
alkenyl, C2-8 alkynyl, (CH2)r C3-6 cycloalkyl, C1, F, Br,
I, CN, NO2, (CF2)r CF3, (CH2)r OC1-5 alkyl, OH, SH,
(CH2)r SC1-5 alkyl, (CH2)r NR16f R16f, and (CH2)r phenyl;
R16f, at each occurrence, is selected from H, C1-6 alkyl,
and C3-6 cycloalkyl, and phenyl;
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
p is selected from 1, 2, and 3.
30. The compound of claim 29, wherein:
E is selected from:
Image



370



Image and Image;
R4 is absent, taken with the nitrogen to which it is
attached to form an N-oxide, or selected from C1-8
alkyl, (CH2)r C3-6 cycloalkyl, and (CH2)r -phenyl
substituted with 0-3 R4c;
R4c, at each occurrence, is selected from C1-6 alkyl, C2-8
alkenyl, C2-8 alkynyl, C3-6 cycloalkyl, C1, F, Br, I,
CN, NO2, (CF2)r CF3, (CH2)r OC1-5 alkyl, (CH2)r OH,
(CH2)r SC1-5 alkyl, (CH2)r NR4a R4a', and (CH2)r phenyl;
alternatively, R4 joins with R7 or R9 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 C1-4 alkyl;
R6, at each occurrence, is selected from C1-4 alkyl, C2-8
alkenyl, C2-8 alkynyl, (CH2)r C3-6 cycloalkyl, (CF2)r CF3,
CN, (CH2)r OH, (CH2)r OR6b, (CH2)r C(O)r 6b,
(CH2)r C(O)NR6a R6a', (CH2)r NR6d C(O)r 6a, and (CH2)t phenyl
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, C1, F, Br, I, CN, NO2, (CF2)r CF3, (CH2)r OC1-
alkyl, (CH2)r OH, (CH2)r SC1-5 alkyl, and (CH2)r NR6d R6d;



371



R6d, at each occurrence, is selected from H, C1-6 alkyl, and
C3-6 cycloalkyl;
R7, is selected from H, C1-3 alkyl, (CH2)r C3-6 cycloalkyl,
(CH2)q OH, (CH2)q OR7d, (CH2)q NR7a R7a', (CH2)r C(O)R7b,
(CH2)r C(O)NR7a R7a', (CH2)q NR7a C(O)R7a, C1-6 haloalkyl,
(CH2)r phenyl with O-2 R7c;
R7a and R7a', at each occurrence, are selected from H, C1-6
alkyl, (CH2)r C3-6 cycloalkyl, a (CH2)r phenyl
substituted with 0-3 R7e;
R7b, at each occurrence, is selected from C1-6 alkyl, C2-8
alkenyl, C2-8 alkynyl, (CH2)r C3-cycloalkyl,
(CH2)r phenyl substituted with 0-3 R7e;
R7c, at each occurrence, is selected from C1-4 alkyl, C2-8
alkenyl, C2-8 alkynyl, (CH2)r C3-6 cycloalkyl, Cl, Br, I,
F, (CF2)r CF3, NO2, CN, (CH2)r NR7f R7f, (CH2)r OH,
(CH2)r OC1-4 alkyl, (CH2)r C(O)R7b, (CH2)r C(O)NR7f R7f,
(CH2)r NR7f C(O)R7a, (CH2)r S(O)p R7b, (CH2)r S(O)2NR7f R7f,
(CH2)r NR7f S(O)2R7b, and (CH2)r phenyl substituted with 0-
2 R7e;
R7d, at each occurrence, is selected from C1-6 alkyl,
(CH2)r C3-6 cycloalkyl, (CH2)r phenyl substituted with 0-
3 R7e;
R7e, at each occurrence, is selected from C1-6 alkyl, C2-8
alkenyl, C2-8 alkynyl, C3-6 cycloalkyl, C1, F, Br, I,
CN, NO2, (CF2)r CF3, (CH2)r OC1-5 alkyl, OH, SH, (CH2)r SC1-
alkyl, (CH2)r NR7f R7f, and (CH2)r phenyl;
R7f, at each occurrence, is selected from H, C1-5 alkyl, and
C3-6 cycloalkyl;



372



R8 is H or joins with R7 to form C3-7 cycloalkyl or =NR8b;
R11, is selected from H, C1-6 alkyl, (CH2)r C3-6 cycloalkyl,
(CH2)q OH, (CH2)q OR11d (CH2)q NR11a R11a', (CH2)r C(O)r 11b
(CH2)r C(O)NR11a R11a', (CH2)q NR11a C(O)R11a, C1-6 haloalkyl,
(CH2)r phenyl with 0-2 R11c, (CH2)r-5-10 membered
heterocyclic system containing 1-4 heteroatoms
selected from N, O, and S, substituted with 0-3 R15;
R11a and R11a', at each occurrence, are selected from H, C1-6
alkyl, (CH2)r C3-6 cycloalkyl, a (CH2)r phenyl
substituted with 0-3 R11e;
R11b at each occurrence, is selected from C1-6 alkyl, C2-8
alkenyl, C2-8 alkynyl, (CH2)r C3-6 cycloalkyl,
(CH2)r phenyl substituted with 0-3 R11e;
R11c, at each occurrence, is selected from C1-4 alkyl, C2-8
alkenyl, C2-8 alkynyl, (CH2)r C3-6 cycloalkyl, Cl, Br, I,
F, (CF2)r CF3, NO2, CN, (CH2)r NR11f R11f, (CH2)r OH,
(CH2)r OC1-4 alkyl, (CH2)r C(O)R11b (CH2)r C(O)NR11f R11f,
(CH2)r NR12f C(O)R11a, (CH2)r S(O)p R11b,
(CH2)r S(O)2NR11f R11f, (CH2)r NR11f S(O)2R11b, and
(CH2)r phenyl substituted with 0-2 R11e;
R11d, at each occurrence, is selected from C1-6 alkyl,
(CH2)r C3-6 cycloalkyl, (CH2)r phenyl substituted with 0-
3 R11e;
R11e, at each occurrence, is selected from C1-6 alkyl, C2-8
alkenyl, C2-8 alkynyl, C3-6 cycloalkyl, Cl, F, Br, I,
CN, NO2, (CF2)r CF3, (CH2)r OC1-5 alkyl, OH, SH, (CH2)r SC1-
alkyl, (CH2)r NR11f R11f, and (CH2)r phenyl;
R11f, at each occurrence, is selected from H, C1-5 alkyl and
C3-6 cycloalkyl;
373



R12 is H or joins with R11 to form C3-7 cycloalkyl;
R13, at each occurrence, is selected from C1-4 alkyl, C3-6
cycloalkyl, (CH2)NR13a R13a', (CH2)OH, (CH2)OR13b,
(CH2)w C(O)R13b, (CH2)w C(O)NR13a R13a', (CH2)NR13d C(O)R13a,
(CH2)w S(O)2NR13a R13a', (CH2)NR13d S(O)2 R13b, 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)r CF3, (CH2)r OC1-
alkyl, (CH2)r OH, and (CH2)r NR13d R13d;
R13d at each occurrence, is selected from H, C1-6 alkyl,
and C3-6 cycloalkyl;
v is selected from 1 and 2;
q is selected from 1, 2, and 3; and
r is selected from 0, 1, 2, and 3.
31. The compound of claim 30, wherein:
ring A is selected from:
374



Image
R3 is selected from 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, isoindolyl, piperidinyl, pyrrazolyl, 1,2,4-
triazolyl, 1,2,3-triazolyl, tetrazolyl, thiazolyl,
oxazolyl, pyrazinyl, and pyrimidinyl.
375



32. The compound of claim 31, wherein the compound of
formula (I) is:

Image

R16, at each occurrence, is selected from C1-8 alkyl,
(CH2)r C3-6 cycloalkyl, CF3, Cl, Br, I, F,
(CH2)r NR16a R16a', NO2 CN, OH, (CH2)r OR16d,
(CH2)r C(O)R16b, (CH2)r C(O)NR16a R16a', (CH2)r NR16f C(O)R16b,
(CH2)r S(O)p R16b, (CH2)r S(O)2NR16a R16a',
(CH2)r NR16f S(O)2R16b, and (CH2)r phenyl substituted with
0-3 R16e;

R16a and R16a', at each occurrence, are selected from, H, C1-6
alkyl, C3-6 cycloalkyl, and (CH2)r phenyl substituted
with 0-3 R16e;

R16b, at each occurrence, is selected from H, C1-6 alkyl,
C3-6 cycloalkyl, and (CH2)r phenyl 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)r CF3, OH, and (CH2)r OC1-5 alkyl;
and

R16f at each occurrence, is selected from H, and C1-5
alkyl.

33. The compound of claim 32, wherein the compound of
formula (I) is:

Image

376



R16, at each occurrence, is selected from C1-8 alkyl,
(CH2)r C3-6 cYcloalkyl, CF3, Cl, Br, I, F,
(CH2)r NR16a R16a', NO2, CN, OH, (CH2)r OR16d,
(CH2)r C(O)R16b, (CH2)r C(O)NR16a R16a', (CH2)r NR16f C(O)R16b
(CH2)r S(O)p R16b, (CH2)r S(O)2NR16a R16a',
(CH2)r NR16f S(O)2R16b, and (CH2)r phenyl substituted with
0-3 R16e;

R16a and R16a', at each occurrence, are selected from H, C1-6
alkyl, C3-6 cycloalkyl, and (CH2)r phenyl substituted
with 0-3 R16e;

R16b at each occurrence, is selected from H, C1-6 alkyl,
C3-6 cycloalkyl, and (CH2)r phenyl 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)r CF3, OH, and (CH2)r OC1-5 alkyl;
and

R16f at each occurrence, is selected from H, and C1-5
alkyl.

34. The compound of claim 32, wherein:
R5 is CH2phenyl substituted with 0-3 R16;
R9, is selected from H, C1-6 alkyl, (CH2)r C3-6 cycloalkyl, F,
Cl, CN, (CH2)r OH, (CH2)r OR9d, (CH2)r NR9a R9a',
(CH2)r OC(O)NHR9a, (CH2)r phenyl substituted with 0-5 R9e,
and a heterocyclic system substituted with 0-2 R9e,
wherein the heterocyclic system is selected from
pyridyl, thiophenyl, furanyl, oxazolyl, and thiazolyl;

377



R9a and R9a', at each occurrence, are selected from H, C1-6
alkyl, C3-6 cycloalkyl, and (CH2)r phenyl substituted
with 0-3 R9e;

R9d, at each occurrence, is selected from C1-6 alkyl and
phenyl;

R9e, at each occurrence, is selected from C1-6 alkyl, Cl, F,
Br, I, CN, NO2, (CF2)r CF3, OH, and (CH2)r OC1-5 alkyl;

R10 is selected from H, C1-5 alkyl, OH, and CH2OH;

alternatively, R9 and R10 join to form C3-7 cycloalkyl, 5-6-
membered cyclic ketal or =O;

with the proviso that when R10 is -OH, R9 is not halogen,
cyano, or bonded to the carbon to which it is attached
through a heteroatom;

R11 is selected from H, C1-8 alkyl, (CH2)r phenyl substituted
with 0-5 R11e, and a (CH2)r -heterocyclic system
substituted with 0-2 R11e, 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

R11e, at each occurrence, is selected from C1-6 alkyl, Cl,
F, Br, I, CN, NO2, (CF2)r CF3, OH, and (CH2)r OC1-5 alkyl;

R12 is H;

alternatively, R11 and R12 join to form C3-7 cycloalkyl;

378



R14, at each occurrence, is selected from C1-8 alkyl,
(CH2)r C3-6 cycloalkyl, CF3, Cl, Br, I, F,
(CH2)r NR14aR14a', NO2, CN, OH, (CH2)r OR14d,
(CH2)r C(O)R14b, (CH2)r C(O)NR14a R14a', (CH2)r NR14f C(O)R14b,
(CH2)r S(O)p R14b, (CH2)r S(O)2NR14a R14a',
(CH2)r NR14f S(O)2R14b, (CH2)r phenyl substituted with 0-3
R14e.

R14a and R14a' at each occurrence, are selected from H, C1-6
alkyl, C3-6 cycloalkyl, and (CH2)r phenyl 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 0-2 R15e;

R14b, at each occurrence, is selected from H, C1-6 alkyl,
C3-6 cycloalkyl, and (CH2)r phenyl substituted with 0-3
R14e;

R14d, at each occurrence, is selected from C1-6 alkyl and
phenyl;

R14e, at each occurrence, is selected from C1-6 alkyl, Cl,
F, Br, I, CN, NO2, (CF2)r CF3, OH, and (CH2)r OC1-5 alkyl;
and

R14f, at each occurrence, is selected from H, and C1-5
alkyl; and

r is selected from 0, 1, and 2.

35. The compound of claim 33, wherein:
R5 is CH2 phenyl substituted with 0-3 R16;

R9, is selected from H, C1-6 alkyl, (CH2)r C3-6 cycloalkyl, F,
Cl, CN, (CH2)r OH, (CH2)r OR9d, (CH2)r NR9a R9a',

379



(CH2)r OC(O)NHR9a, (CH2)r phenyl substituted with 0-5 R9e,
and a heterocyclic system substituted with 0-2 R9e,
wherein the heterocyclic system is selected from
pyridyl, thiophenyl, furanyl, oxazolyl, and thiazolyl;

R9a and R9a', at each occurrence, are selected from H, C1-6
alkyl, C3-6 cycloalkyl, and (CH2)r phenyl substituted
with 0-3 R9e;

R9d, at each occurrence, is selected from C1-6 alkyl and
phenyl;

R9e, at each occurrence, is selected from C1-6 alkyl, Cl, F,
Br, I, CN, NO2, (CF2)r CF3, OH, and (CH2)r OC1-5 alkyl;

R10 is selected from H, C1-8 alkyl, OH, and CH2OH;

alternatively, R9 and R10 join to form C3-7 cycloalkyl, 5-6-
membered cyclic ketal or =O;

with the proviso that when R10 is -OH, R9 is not halogen,
cyano, or bonded to the carbon to which it is attached
through a heteroatom;

R11 is selected from H, C1-8 alkyl, (CH2)r phenyl substituted
with 0-5 R11e, and a (CH2)r -heterocyclic system
substituted with 0-2 R11e, 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

R11e, at each occurrence, is selected from C1-6 alkyl, Cl,
F, Br, I, ON, NO2, (CF2)r CF3, OH, and (CH2)r OC1-5 alkyl;

380



R12 is H;
alternatively, R11 and R12 join to form C3-7 cycloalkyl;

R14, at each occurrence, is selected from C1-8 alkyl,
(CH2)r C3-6 cycloalkyl, CF3, Cl, Br, I, F,
(CH2)r NR14aR14a', NO2, CN, OH, (CH2)r OR14d,
(CH2)r C(O)R14b, (CH2)r C(O)NR14a R14a', (CH2)r NR14f C(O)R14b,
(CH2)r S(O)p R14b, (CH2)r S(O)2NR14a R14a',
(CH2)r NR14f S(O)2R14b, (CH2)r phenyl 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 0-2 R15e.

R14a and R14a' at each occurrence, are selected from H, C1-6
alkyl, C3-6 cycloalkyl, and (CH2)r phenyl substituted
with 0-3 R14e.

R14b at each occurrence, is selected from H, C1-6 alkyl,
C3-6 cycloalkyl, and (CH2)r phenyl substituted with 0-3
R14e;

R14d, at each occurrence, is selected from C1-6 alkyl and
phenyl;

R14e at each occurrence, is selected from C1-6 alkyl, Cl,
F, Br, I, CN, NO2, (CF2)r CF3, OH, and (CH2)r OC1-5 alkyl;

R14f at each occurrence, is selected from H, and C1-5
alkyl; and

r is selected from 0, 1, and 2.

36. The compound of claim 34, wherein:
J is selected from CH2 and CHR5;

381



K is selected from CH2 and CHR5;
L is selected from CH2 and CHR5;

R3 is a C3-10 carbocyclic residue substituted with 0-3 R15,
wherein the carbocyclic residue is selected from
cyclopropyl, 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

R15, at each occurrence, is selected from C1-8 alkyl,
(CH2)r C3-5 cycloalkyl, CF3, Cl, Br, I, F,
(CH2)r NR15a R15a', NO2, CN, OH, (CH2)r OR15d,
(CH2)r C(O)R15b, (CH2)r C(O)NR15a R15a', (CH2)r NR15f C(O)R15b,
(CH2)r S(O)p R15b, (CH2)r S(O)2NR15a R15a',
(CH2)r NR15f S(O)2R15b, (CH2)r phenyl 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 0-2 R15e.

R15a and R15a', at each occurrence, are selected from H, C1-6
alkyl, C3-6 cycloalkyl, and (CH2)r phenyl substituted
with 0-3 R15e;

R15b, at each occurrence, is selected from H, C1-6 alkyl,
C3-6 cycloalkyl, and (CH2)r phenyl substituted with 0-3
R15e.

382




R15d, at each occurrence, is selected from C1-6 alkyl and
phenyl;

R15e, at each occurrence, is selected from C1-6 alkyl, Cl,
F, Br, I, CN, NO2, (CF2)r CF3, OH, and (CH2)r OC1-5 alkyl;
and
R15f, at each occurrence, is selected from H, and C1-5
alkyl.

37. The compound of claim 35, wherein:
K is selected from CH2 and CHR5;
L is selected from CH2 and CHR5;

R3 is a C3-10 carbocyclic residue substituted with 0-3 R15,
wherein the carbocyclic residue is selected from
cyclopropyl, 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

R15, at each occurrence, is selected from C1-8 alkyl,
(CH2)r C3-6 cycloalkyl, CF3, Cl, Br, I, F,
(CH2)r NR15a R15a', NO2, CN, OH, (CH2)r OR15d,
(CH2)r C(O)R15b, (CH2)r C(O)NR15a R15a', (CH2)r NR15f C(O)R15b,
(CH2)r S(O)p R15b, (CH2)r S(O)2NR15a R15a',
(CH2)r NR15f S(O)2R15b, and (CH2)r phenyl substituted with
0-3 R15e, and a (CH2)r -5-6 membered heterocyclic system

383



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, C3-6 cycloalkyl, and (CH2)r phenyl substituted
with 0-3 R15e.

R15b, at each occurrence, is selected from H, C1-6 alkyl,
C3-6 cycloalkyl, and (CH2)r phenyl substituted with 0-3
R15e.

R15d, at each occurrence, is selected from C1-6 alkyl and
phenyl;

R15e at each occurrence, is selected from C1-6 alkyl, Cl,
F, Br, I, CN, NO2, (CF2)r CF3, OH, and (CH2)r OC1-5 alkyl;
and

R15f at each occurrence, is selected from H and C1-5 alkyl.

38. The compound of claim 29 and pharmaceutically
acceptable salt forms thereof, wherein the compound of
formula (I) is selected from

N"-cyano-N-(3-acetylphenyl)-N'-[(1R,2S)-2-[[(3S)-3-(4
fluorobenzyl)piperidinyl]methyl]cyclohexyl]guanidine,

N"-cyano-N-(4-((1H)-1-methyl-tetrazol-5-yl)phenyl)-N'-
[(1R,2S)-2-[[(3S)-3-(4-
fluorobenzyl)piperidinyl]methyl]cyclohexyl]guanidine,

N"-cyano-N-(3-acetylphenyl)-N'-[(1R,2S)-2-[[4-(4-
fluorobenzyl)piperidinyl]methyl]cyclohexyl]guanidine,

N"-cyano-N-(phenyl)-N'-[(1R,2S)-2-[[4-(4-
fluorobenzyl)piperidinyl]methyl]cyclohexyl]guanidine,

384



N"-cyano-N-(phenyl)-N'-[(1R,2S)-2-[[(3S)-3-(4-
fluorobenzyl)piperidinyl]methyl]cyclohexyl]guanidine,

N"-cyano-N-(3-cyanophenyl)-N'-[(1R,2S)-2-[[(3S)-3-(4-
fluorobenzyl)piperidinyl]methyl]cyclohexyl]guanidine,

N"-cyano-N-(3-cyanophenyl)-N'-[(1R,2S)-2-[[4-(4-
fluorobenzyl)piperidinyl]methyl]cyclohexyl]guanidine,

N"-cyano-N-(2,4-dimethoxyphenyl)-N'-[(1R,2S)-2-[[(3S)-3-(4-
fluorobenzyl)piperidinyl)methyl]cyclohexyl]guanidine,

N"-cyano-N-(2,5-dimethoxyphenyl)-N'-[(1R,2S)-2-[[(3S)-3-(4-
fluorobenzyl)piperidinyl]methyl]cyclohexyl]guanidine,

N"-cyano-N-(4-((1H)-1-propyl-tetrazol-5-yl)phenyl)-N'-
[(1R,2S)-2-[[(3S)-3-(4-
fluorobenzyl)piperidinyl]methyl]cyclohexyl]guanidine,

N"-cyano-N-(1-adamantyl)-N'-[(1R,2S)-2-[[(3S)-3--(4-
fluorobenzyl)piperidinyl]methyl]cyclohexyl]guanidine,

N"-cyano-N-(2-adamantyl)-N'-[(1R,2S)-2-[[(3S)-3-(4-
fluorobenzyl)piperidinyl]methyl]cyclohexyl]guanidine,

N"-cyano-N-(ethoxycarbonylmethyl)-N'-[(1R,2S)-2-[[(3S)-3-
(4-fluorobenzyl)piperidinyl]methyl]cyclohexyl]guanidine,

N"-cyano-N-(5,6,7,8-tetrahydronaphth-1-yl)-N'-[(1R,2S)-2-
[[(3S)-3-(4-fluorobenzyl)piperidinyl]methyl]cyclohexyl]guanidine,

N"-cyano-N-(2,4-dimethylphenyl)-N'-[(1R,2S)-2-[[(3S)-3-(4-
fluorobenzyl)piperidinyl]methyl]cyclohexyl]guanidine,

385



N"-cyano-N-(2-methoxyphenyl)-N'-[(1R,2S)-2-[[(3S)-3-(4-
fluorobenzyl)piperidinyl]methyl]cyclohexyl]guanidine,

N"-cyano-N-(2-methyl-4-hydroxyphenyl)-N'-[(1R,2S)-2-[[(3S)-
3-(4-fluorobenzyl)piperidinyl]methyl]cyclohexyl]guanidine,

N"-cyano-N-(2,5-dimethylphenyl)-N'-[(1R,2S)-2-[[(3S)-3-(4-
fluorobenzyl)piperidinyl]methyl]cyclohexyl]guanidine,

N"-cyano-N-(2-phenylethyl)-N'-[(1R,2S)-2-[[(3S)-3-(4-
fluorobenzyl)piperidinyl]methyl)cyclohexyl]guanidine,

N"-cyano-N-(5-acetyl-2-methoxyphenyl)-N'-[(1R,2S)-2-[[(3S)-
3-(4-fluorobenzyl)piperidinyl]methyl]cyclohexyl]guanidine,

N"-cyano-N-(4-(4-morpholinyl)phenyl]-N'-[(1R,2S)-2-[[(3S)-
3-(4-fluorobenzyl)piperidinyl]methyl]cyclohexyl]guanidine,

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

2-{(5-acetyl-2-methoxyanilino)[((1R,2S)-2-([(3S)-3-(4-
fluorobenzyl)piperidinyl]methyl}cyclohexyl]amino}methy
lene)malonitrile,

1-[3-({1-[({(1R,2S)-2-[{3(S)-3-(4-
fluorobenzyl)piperidinyl)methyl}cyclohexyl)amino]-2-
nitroethenyl}amino)phenyl]ethanone,

1-{3-([1-{(2-[{4-(4-
fluorobenzyl)piperidinyl}methyl]phenyl)amino}-2-
nitroethenyl]amino)phenyl}ethanone,

386



N"-cyano-N-(3,5-diacetylphenyl)-1-N'-[2-[[4-(4-
fluorobenzyl)piperidinyl]methyl)3-(N-
methylcarbamoyl)phenyl]guanidine,

N"-cyano-N-(3-diacetylphenyl)-1-N'-[2-[[4-(4-
fluorobenzyl)piperidinyl]methyl]3-(N-
methylcarbamoyl)phenyl]guanidine, and

N"-cyano-N-[3-[(1H)-1-methyltetrazol-5-yl]phenyl]-1-N'-[2-
[[4-(4-fluorobenzyl)piperidinyl]methyl]3-(N-
methylcarbamoyl)phenyl]guanidine.

39. A pharmaceutical composition, comprising a
pharmaceutically acceptable carrier and a therapeutically
effective amount of a compound claim 19-38.

40. A pharmaceutical composition, comprising a
pharmaceutically acceptable carrier and a therapeutically
effective amount of a compound claim 29.

41. A method for modulation of chemokine receptor
activity comprising administering to a patient in need
thereof a therapeutically effective amount of a compound of
claim 19-38.

42. A method for modulation of chemokine receptor
activity comprising administering to a patient in need
thereof a therapeutically effective amount of a compound of
claim 29.

43. A method for treating or preventing inflammatory
diseases, comprising administering to a patient in need
thereof a therapeutically effective amount of a compound of
claim 19-38.

44. A method for treating or preventing inflammatory
diseases, comprising administering to a patient in need

387



thereof a therapeutically effective amount of a compound of
claim 29.

45. A method for treating or preventing asthma,
comprising administering to a patient in need thereof a
therapeutically effective amount of a compound of claim 19-
38.

46. A method for treating or preventing asthma,
comprising administering to a patient in need thereof a
therapeutically effective amount of a compound of claim 29.

47. A method for treating or preventing disorders,
comprising administering to a patient in need thereof a
therapeutically effective amount of a compound of claim 1-
18, said disorders being 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.

48. A method for treating or preventing disorders,
comprising administering to a patient in need thereof a
therapeutically effective amount of a compound of claim 19-
38, said disorders being 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,

388


Churg-Strauss syndrome, lymphoma, Hodgkin's disease, and
colonic carcinoma.

49. A method for treating or preventing disorders,
comprising administering to a patient in need thereof a
therapeutically effective amount of a compound of claim 29,
said disorders being 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.

389

Description

CA 02350730 2001-05-07
DEMANDES OU BREVETS VOLUMINEUX
LA PRESEN'fE PARTIE DE CETTE DEMANDS OU_ CE BREVET
COMPREND PLUS D'UN TOME.
CEC! EST LE TOME _ ~-DE c~
NOTE: Pour les tomes additionels, veuillez contacter le Bureau canadien des
brevets
JUMBO APPLlCATIONSIPATENTS
THIS SECTION ~F THE APPLICATION/PATENT CONTAINS MORE
THIS 1S VOLUME ~ _'OF -
NOTE..For additional volumes please contact'the Canadian Patent Offfice
~::. _ :.v . , ',' ~wv. .~ ~ : ~ ~ . v° - v- . :.':' .......: , -.:~'
,. . :<' ~. ~. __


CA 02350730 2001-05-07
WO 00/35451 PCT/US99/30332
TITLE
N-UREIDOALKYL-PIPERIDINES AS MODULATORS OF CHEMOKINE
RECF;PTOR ACTIVITY
FIELD OF THE INVENTION
This invention relates generally to modulators of
' chemokine receptor activity, pharmaceutical compositions
containing the same, and methods of using the same as
agents for treatment and prevention of inflammatory
diseases such as asthma and allergic diseases, as well as
autoimmune pathologies such as rheumatoid arthritis and
atherosclerosis.
BACKGROUND OF THE INVENTION
Chemokines are chemotactic cytokines, of molecular
weight 6-15 kDa, that are released by a wide variety of
cells to attract and activate, among other cell types,
macrophages, T and B lymphocytes, eosinophils, basophils
and neutrophils (reviewed in Luster, New Eng. J Med., 338,
436-445 (1998) and Rollins, Blood, 90, 909-928 (1997)).
There are two major classes of chemokines, CXC and CC,
depending on whether the first two cysteines in the amino
acid sequence are separated by a single amino acid (CXC) or
are adjacent (CC). The CXC chemokines, such as
interleukin-8 (IL-8), neutrophil-activating protein-2 (NAP-
2) and melanoma growth stimulatory activity protein (MGSA)
are chemotactic primarily for neutrophils and T
lymphocytes, whereas the CC chemokines, such as RANTES,
MIP-10L, MIP-1~, the monocyte chemotactic proteins (MCP-1,
MCP-2, MCP-3, MCP-4, and MCP-5) and the eotaxins (-1,-2,
and -3) are chemotactic for, among other cell types,
macrophages, T lymphocytes, eosinophils, dendritic cells,
and basophils. There also exist the chemokines
lymphotactin-l, lymphotactin-2 (both C chemokines), and
fractalkine (a CXXXC chemokine) that do not fall into
either of the major chemokine subfamilies.


CA 02350730 2001-05-07
WO 00/35451 PCT/US99/30332
The chemokines bind to specific cell-surface receptors
belonging to the family of G-protein-coupled seven-
transmembrane-domain proteins (reviewed in Horuk, Trends
Pharm. Sci., 15, 159-165 (1994)) which are termed
"chemokine receptors." pn binding their cognate ligands,
chemokine receptors transduce an intracellular signal
through the associated trimeric G proteins, resulting in,
among other responses, a rapid increase in intracellular
calcium concentration, changes in cell shape, increased
expression of cellular adhesion molecules, degranulation,
and promotion of cell migration. There are at least ten
human chemokine receptors that bind or respond to CC
chemokines with the following characteristic patterns: CCR-
1 (or "CKR-1" or "CC-CKR-1") [MIP-loc, MCP-3, MCP-4, RANTES]
(Ben-Barruch, et al., Cell, 72, 415-425 (1993), Luster, New
Eng. J. Med., 338, 436-445 (1998)); CCR-2A and CCR-2B (or
"CKR-2A"/"CKR-2B" or "CC-CKR-2A"/"CC-CKR-2B") (MCP-1, MCP-
2, MCP-3, MCP-4, MCP-5] (Charo et al., Proc. Natl. Acad.
Sci. USA, 91, 2752-2756 (1994), Luster, New Eng. J. Med.,
338, 436-445 (1998)); CCR-3 (or "CKR-3" or "CC-CKR-3")
(eotaxin-1, eotaxin-2, RANTES, MCP-3, MCP-4] (Combadiere,
et al., J. Biol. Chem., 270, 16491-16494 (1995), Luster,
New Eng. J. Med., 338, 436-445 (1998)); CCR-4 (or "CKR-4~
or "CC-CKR-4") [TARC, MIP-la, RANTES, MCP-1] (Power et al.,
J. Biol. Chem., 270, 19495-19500 (1995), Luster, New Eng.
J. Med., 338, 436-445 (1998)); CCR-5 (or "CKR-5" OR "CC-
CKR-5") [MIP-lOf" RANTES, MIP-1~] (Sanson, et al.,
Biochemistry, 35, 3362-3367 (1996)); CCR-6 (or "CKR-6~ or
"CC-CKR-6") [LARC] (Baba et al., J. Biol. Chem., 272,
14893-14898 (1997)); CCR-7 (or "CKR-7" or "CC-CRR-7") [ELC]
(Yoshie et al., J. Leukoc. Biol. 62, 634-644 (1997)); CCR-8
(or "CKR-8" or "CC-CKR-8") [I-309, TARO, MIP-1~]
(Napolitano et al., J. Immunol., 157, 2759-2763 (1996),
Bernardini et al., Eur. J. Immunol., 28, 582-588 (1998));
and CCR-10 (or "CKR-20" or "CC-CKR-10") [MCP-1, MCP-3]
(Bonini et al, DNA and Cell Biol., 16, 1249-1256 (1997)).
2


CA 02350730 2001-05-07
WO 00/35451 PCT/US99/30332
In addition to the mammalian chemokine receptors,
mammalian cytomegaloviruses, herpesviruses and poxviruses
have been shown to express, in infected cells, proteins
with the binding properties of chemokine receptors
(reviewed by Wells and Schwartz, Curr. Opin. Biotech., 8,
741-748 (1997)). Human CC chemokines, such as RANTES and
MCP-3, can cause rapid mobilization of calcium via these
virally encoded receptors. Receptor expression may be
permissive for infection by allowing for the subversion of
normal immune system surveillance and response to
infection. Additionally, human chemokine receptors, such
as CXCR4, CCR2, CCR3, CCRS and CCR8, can act as co-
receptors for the infection of mammalian cells by microbes
as with, for example, the human immunodeficiency viruses
(HIV).
Chemokine receptors have been implicated as being
important mediators of inflammatory, infectious, and
immunoregulatory disorders and diseases, including asthma
and allergic diseases, as well as autoimmune pathologies
such as rheumatoid arthritis and atherosclerosis. For
example, the chemokine receptor CCR-3 plays a pivotal role
in attracting eosinophils to sites of allergic inflammation
and in subsequently activating these cells. The chemokine
ligands for CCR-3 induce a rapid increase in intracellular
calcium concentration, increased expression of cellular
adhesion molecules, cellular degranulation, and the
promotion of eosinophil migration. Accordingly, agents
which modulate chemokine receptors would be useful in such
disorders and diseases. In addition, agents which modulate
chemokine receptors would also be useful in infectious
diseases such as by blocking infection of CCR3 expressing
cells by HIV or in preventing the manipulation of immune
cellular responses by viruses such as cytomegaloviruses.
A substantial body of art has accumulated over the
past several decades with respect to substituted
piperidines and pyrrolidines. These compounds have
implicated in the treatment of a variety of disorders.
3


CA 02350730 2001-05-07
WO 00/35451 PCT/US99/30332
WO 98/25604 describes spiro-substituted azacycles
which are useful as modulators of chemokine receptors:
~m
wherein R1 is C1_6 alkyl, optionally substituted with
functional groups such as -NR6CONHR~, wherein R6 and R~ may
be phenyl further substituted with hydroxy, alkyl, cyano,
halo and haloalkyl. Such spiro compounds are not
20 considered part of the present invention.
WO 95/13069 is directed to certain piperidine,
pyrrolidine, and hexahydro-1H-azepine compounds of general
formula:
wherein A may be substituted alkyl or Z-substituted alkyl,
with Z=NR6a or O. Compounds of this type are claimed to
promote the release of growth hormone in humans and
animals.
WO 93/06108 discloses pyrrolobenzoxazine derivatives
as 5-hydroxytryptamine (5-HT) agonists and antagonists:
wherein A is lower alkylene and R4 may be phenyl optionally
substituted with halogen.
4


CA 02350730 2001-05-07
WO 00/35451 PCT/US99/30332
U.S. Pat. No. 5,668,151 discloses Neuropeptide Y (NPY)
antagonists comprising 1,4-dihydropyridines with a
piperidinyl or tetrahydropyridinyl-containing moiety
attached to the 3-position of the 4-phenyl ring:
~C O-B-(C H~,f- ~.
wherein B may be NH, NR1, O, or a bond, and R~ may be
substituted phenyl, benzyl, phenethyl and the like.
These reference compounds are readily distinguished
structurally by either the nature of the urea
functionality, the attachment chain, or the possible
substitution of the present invention. The prior art does
not disclose nor suggest the unique combination of
structural fragments which embody these novel piperidines
and pyrrolidines as having activity toward the chemokine
receptors.
SUN~IARY OF THE INVENTION
Accordingly, one object of the present invention is to
provide novel agonists or antagonists of CCR-3, or
pharmaceutically acceptable salts or prodrugs thereof.
It is another object of the present invention to
provide pharmaceutical compositions comprising a
pharmaceutically acceptable carrier and a therapeutically
effective amount of at least one of the compounds of the
present invention or a pharmaceutically acceptable salt or
prodrug form thereof.
It is another object of the present invention to
. 30 provide a method for treating inflammatory diseases and
allergic disorders comprising administering to a host in
need of such treatment a therapeutically effective amount
of at least one of the compounds of the present invention
5


CA 02350730 2001-05-07
WO 00/35451 PCT/fJS99/30332
or a pharmaceutically acceptable salt or prodrug form
thereof .
It is another object of the present invention to
provide novel N-ureidoalkyl-piperidines for use in therapy.
It is another object~.of the present invention to
provide the use of novel N-ureidoalkyl-piperidines for the
manufacture of a medicament for the treatment of allergic
disorders.
In another embodiment, the present invention provides
novel N-ureidoalkyl-piperidines for use in therapy.
In another embodiment, the present invention provides
the use of novel N-ureidoalkyl-piperidines for the
manufacture of a medicament for the treatment of allergic
disorders.
These and other objects, which will become apparent
during the following detailed description, have been
achieved by the inventors~ discovery that compounds of
formula (I):
_R3
2 0 L-0 Ri R2
(I)
or stereoisomers or pharmaceutically acceptable salts
thereof, wherein E, Z, M, J, K, L, Q, R1, R2, R3, and R4 are
defined below, are effective modulators of chemokine
activity.
DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS
[ll Thus, in a first embodiment, the present invention
provides novel compounds of formula (I):
3
1 R
L-Gl Rt R2
(I)
6


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WO 00/35451 PCT/US99/30332
or stereoisomers or pharmaceutically acceptable salts
thereof, wherein:
M is absent or selected from CH2, CHR5, CHR13, CR13R13, and
CRSR13 ;
Q is selected from CH2, CHRS, CHR13, CR13R13, and CR5R13;
J, K, and L are independently selected from CH2, CHRS, CHR6,
CR6R6 and CR5R6;
with the provisos:
1) at least one of M, J, K, L, or Q contains an R5;
and
2) when M is absent, J is selected from CH2, CHRS,
CHR13 , arid CR5R13 ;
Z is selected from O and S;
E is - ( CHR' ) - ( CHR' ) ~- ( CHRll ) - ;
R1 and Rz are independently selected from H, C1_g alkyl, CZ_g
alkenyl, C2_8 alkynyl, (CH2)rC3-s cycloalkyl, and a
(CH2)r-C3-to carbocyclic residue substituted with 0-5
Ra:
Ra, at each occurrence, is selected from Ci_q alkyl, C2_8
alkenyl, C2_g alkynyl, (CH2)rC3-6 cYcloalkyl, C1, Br, I,
F. (CF2)rCF3. N02, CN, (CHZ)rNRbRb, (CH2)rOH, (CH2)rOR~,
(CH2)rSH, (CH2)rSR~, (CH2)rC(O)Rb, (CH2)rC(0)NRbRb.
( CH2 ) rNRbC ( O ) Rb, ( CH2 ) rC ( O ) ORb. ( CH2 ) rOC ( 0 ) R~ ,
( CH2 ) rCH ( =NRb ) NRbR~' . ( CH 2 ) rNHC ( =NRb ) NRbRb . ( CH2 ) rS ( 0 )
pR~ ,
(CH2)rS(O)2NRbRb, (CHz)rNRbS(O)2R~, and (CH2)rphenyl;
7


CA 02350730 2001-05-07
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Rb, at each occurrence, is selected from H, Cl_6 alkyl, C3-s
cycloalkyl, and phenyl;
Rte, at each occurrence, is selected from CI_6 alkyl, C3-s
cycloalkyl, and phenyl;
alternatively, RZ and R3 join to form a 5, 6, or 7-membered
ring substituted with 0-3 Ra;
R3 is selected from a (CR3'R3")r-C3-to carbocyclic residue
substituted with 0-5 R15 and a (CR3'R3")r-5-10 membered
heterocyclic system containing 1-4 heteroatoms
selected from N, 0, and S, substituted with 0-3 R15;
R3' and R3", at each occurrence, are selected from H, C1_s
alkyl, (CH2)rC3-6 cYcloalkyl, and phenyl;
R4 is absent, taken with the nitrogen to which it is
attached to form an N-oxide, or selected from C1_8
alkyl, C2_8 alkenyl, C2_8 alkynyl, (CHZ)rC3-6
cycloalkyl, (CH2)qC(O)R4b, (CH2)qC(O)NR4aR4a~
(CH2)qC(O)OR4b, and a (CH2)r-C
3-to carbocyclic residue
substituted with 0-3 R4c
R4a and R4a', at each occurrence, are selected from H, C1_5
alkyl, (CH2)rC3-s cYcloalkyl, and phenyl;
R4b. at each occurrence, is selected from C~_6 alkyl,
alkenyl, (CH2)rC3-6 cYcloalkyl, C2_8 alkynyl, and
phenyl;
R4~, at each occurrence, is selected from C1_6 alkyl, C
alkenyl, C2_8 alkynyl, C3-6 cycloalkyl, C1, F, Br, I,
CN, N02, (CF2)YCF3. (CH2)rOCl_5 alkyl, (CH2)rOH,
(CH2)rSCl_5 alkyl, (CH2)rNR4aR4a' and (CH2)rphenyl;
8


CA 02350730 2001-05-07
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alternatively, R4 joins with R~, R9, or R~l to form a 5, 6
or 7 membered piperidinium spirocycle or p~rrrolidinium
spirocycle substituted with 0-3 Ra;
R5 is selected from a (CRS~'R5" ) t-C3-to carbocyclic residue
substituted with 0-5 R16 and a (CRS'RS")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_s
alkyl, (CHZ)rC3-s cYcloalkyl, and phenyl;
R6, at each occurrence, is selected from C1_6 alkyl, C2_g
alkenyl, C2_8 alkynyl, (CH2)rC3-6 cYcloalkyl, (CFZ)rCF3,
CN, (CH2)rNR6aR6a'. (CH2)rOH, (CH2)rOR6b, (CH2)rSH,
(CH2)rSR6b, (CH2)rC(p)OH, (CH2)rC(O)R6b,
(CH2)rC(O)NR6aR6a'. (CH2)rNR6dC(O)R6a, (CH2)rC(p)OR6b,
(CH2)rOC(O)R6b, (CH2)rS(O)pR6b~ (CH2)rS(O)2NR6aR6a'.
(CH2)rNR6dS(O)2R6b~ and (CH2)tphenyl substituted with 0-
3 RSc;
R6a ~d Rsa' , at each occurrence, are selected from H, C1_s
alkyl, C3_6 cycloalkyl, and phenyl substituted with 0-3
R6c
R6b. at each occurrence, is selected from C1_6 alkyl, C3_s
cycloalkyl, and phenyl substituted with 0-3 R6c
R6c, at each occurrence, is selected from C1_6 alkyl, C3-6
cycloalkyl, C1, F, Br, I, CN, N02, (CF2)rCF3, (CH2)rOCi-
5 alkyl, (CH2)rOH, (CH2)rSCl-5 alkyl, and (CHZ)rNR6dR6d;
R6d, at each occurrence, is selected from H, C1_6 alkyl, and
C3-s 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
9


CA 02350730 2001-05-07
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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;
R' at each occurrence, is selected from H or alternatively
R' joins with R° to form a 5, 6, or 7 membered
piperidinium spirocycle or pyrrolidinium spirocycle
substituted with 0-3R°;
R' at each occurrence,, is selected from H or alternatively
R' joins with R° to form a 5, 6, or 7 membered
piperidinium spirocycle or pyrrolidinium spirocycle
substituted with 0-3R°;
R11 at each occurrence, is selected from H, C1_6alkyl, C2_
Balkenyl , C2_8alkynyl , and a (CH2 ) r-C3_lo carbocyclic
residue substituted with 0-5 Rl~c, or alternatively R11
joins with R° to form a 5, 6, or 7 membered
piperidinium spirocycle or pyrrolidinium spirocycle
substituted with 0-3R°;
Rlia ~d Rlla~~ at each occurrence, are selected from H,
alkyl, C2_8 alkenyl, C2_8 alkynyl, a (CH2) r-C3-1o
carbocyclic residue substituted with 0-5 Rlle, and a
(CH2)r-5-10 membered heterocyclic system containing 1-4
heteroatoms selected from N, O, and S, substituted
with 0-3 Rlle;
Rllb, at each occurrence, is selected from C1_6 alkyl, C2_e
alkenyl, C2_a alkynyl, a (CH2)r-C3-s carbocyclic residue
substituted with 0-2 Rlle, and a (CH2)r-5-6 membered
heterocyclic system containing 1-4 heteroatoms
selected from N, O, and S, substituted with 0-3 Rlle.
'
Rllc, at each occurrence, is selected from Ci_6 alkyl, C2_8
alkenyl, C2_g alkynyl, (CH2)rC3-6 cycloalkyl, Cl, Br, I,


CA 02350730 2001-05-07
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F, (CF2 ) rCF3. N02. CN, (CH2 ) rNRllfRllf ~ (CH2 ) rOH,
(CH2)rOCl_4 alkyl, (CH2)rSCl_4 alkyl, (CHz)rC(O)OH,
(CH2)rC(O)Rllb~ (CH2)rC(O)NRllfRllf~ (CH2)rNRllfC(O)Rlla~
(CH2)rC(O)OC1_4 alkyl, (CH2)rOC(0)Rllb~
(CH2 ) rC (=NRllf ) ~llfRllf ~ (CH2 ) rNHC (-NRllf ) ~llfRllf
(CHZ)rS(0)pRllb, (CH2)rS(O)2NR11fRllf~
(CH2)rNRllfS(O)2Rilb~ and (CH2)rphenyl substituted with
0-3 Rlle;
RIIe~ at each occurrence, is selected from Cl_6 alkyl, C
alkenyl, C2_8 alkynyl, C3_6 cycloalkyl, C1, F, Br, I,
CN, N02, (CF2)rCF3, (CH2)rOCl_5 alkyl, OH, SH, (CH2)rSCl_
5 alkyl, (CH2)rNRllfRllf~ ~d (CH2)rphenyl;
Rllf~ at each occurrence, is selected from H, C1_6 alkyl,
and C3_6 cycloalkyl;
R13, at each occurrence, is selected from C1_6 alkyl, C2_8
alkenyl, C2_8 alkynyl, C3_6 cycloalkyl, (CF2)wCF3,
(CH2)NR13aR13a'. (CH2)qOH, (CH2)QORl3b~ (CHZ)qSH,
(CH2)qSRl3b, (CH2)wC(O)OH, (CH2)~",C(O)Rl3b~
(CH2)wC(O)NR13aR13a', (CH2)qI~TRI3dC(0)Rl3a~
(CH2)wC(0)ORl3b, (CH2)QOC(O)Rl3b, (CH2)wS(O)pRl3b~
(CH2 ) wS (p) 2NR13aR13a' . (CH2 ) qNRl3dS (O) 2R13b, and (CH2 ) w_
phenyl substituted with 0-3 Rl3c;
RI3a and Rl3a' , at each occurrence, are selected from H, C1_6
alkyl, C3_6 cycloalkyl, and phenyl substituted with 0-3
Rl3c;
Rl3b~ at each occurrence, is selected from Cl_6 alkyl, C3_s
cycloalkyl, and phenyl substituted with 0-3 Rl3c
Rl3c~ at each occurrence, is selected from C1_6 alkyl, C3_6
cycloalkyl, C1, F, Br, I, CN, N02, (CF2)rCF3, (CHZ)rOCl-
5 alkyl, (CH2) rOH, (CH2 ) rSCl_5 alkyl, and
(CHz)rNR13dR13d.
11


CA 02350730 2001-05-07
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Rl3d, at each occurrence, is selected from H, C1_6 alkyl,
and C3-6 cycloalkyl;
R15, at each occurrence, is selected from C1_g alkyl,
(CH2)rC3-6 cycloalkyl, C1, Br, I, F, N02, CN,
(CHR')rNR15aR15a', (CHR')rOH, (CHR')r0(CHR')rRlSd,
(CHR' ) rSH, (CHR' ) rC (O) H, (CHR' ) rS (CHR~ ) rRl5d,
( CHR' ) rC ( 0 ) OH , ( CHR' ) rC ( O ) ( CHR' ) rRlSb,
(CHR' ) rC (0) NR15aR15a' . (CHR' ) rNRlSfC (O) (CHR' ) rRlSb,
(CHR' ) rNRlSfC (O) NR15fR15f, (CHR' ) rC (O) 0 (CHR' ) rRlSd,
(CHR' ) rOC (O) (CHR' ) rRlSb, (CHR' ) rC (=NRl5f ) ~15aR15a' .
(CHR')rNHC(=NRl5f)~15fR15f, (CHR')rS(O)p(CHR')rRlSb,
(CHR' ) rS (0) 2NR15aR15a' , (CHR' ) rNRlSfS (0) 2 (CHR' ) rRlSb~ C1-5
haloalkyl, C2_8 alkenyl substituted with 0-3 R', C2_8
alkynyl substituted with 0-3 R', (CHR')rphenyl
substituted with 0-3 RlSe, and a (CHZ)r-5-IO membered
heterocyclic system containing 1-4 heteroatoms
selected from N, O, and S, substituted with 0-2 RlSe
R', at each occurrence, is selected from H, C1_6 alkyl, C2_8
alkenyl, C2_g alkynyl, (CH2)rC3-6 cycloalkyl, and
(CH2)rphenyl substituted with RlSe;
RlSa and RlSa~, at each occurrence, are selected from H, C1_s
alkyl, C2_8 alkenyl, C2_g alkynyl, a (CHZ)r-C3-to
carbocyclic residue substituted with 0-5 RlSe, and a
(CHZ)r-5-10 membered heterocyclic system containing 1-4
heteroatoms selected from N, 0, and S, substituted
with 0-2 RlSe
RlSb, at each occurrence, is selected from C1_6 alkyl, CZ_8
alkenyl, C2_a alkynyl, a (CH2)r-C3-6 carbocyclic residue
substituted with 0-3 RlSe~ and (CH2)r-5-6 membered
heterocyclic system containing 1-4 heteroatoms
selected from N, O, and S, substituted with 0-2 RlSe
12


CA 02350730 2001-05-07
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RlSd~ at each occurrence, is selected from C2_8 alkenyl, C2_a
alkynyl, C1_6 alkyl substituted with 0-3 RlSe, a
(CH2)r-C3-to carbocyclic residue substituted with 0-3
RISe, and a (CH2)r5-6 membered heterocyclic system
containing 1-4 heteroatoms selected from N, O, and S,
substituted with 0-3 RlSe;
RlSe~ at each occurrence, is selected from C1_6 alkyl, C2_8
alkenyl, C2_8 alkynyl, (CHZ)rC3-6 cYcloalkyl, C1, F, Br,
I, CN, N02, (CF2)rCF3, (CH2)rOCl_5 alkyl, OH, SH,
(CH2)rSCl_5 alkyl, (CH2)rNR15fR15f~ and (CH2)rphenyl;
RlSf~ at each occurrence, is selected from H, C1_6 alkyl,
C3-6 cycloalkyl, and phenyl;
R16, at each occurrence, is selected from C1_g alkyl, C2_8
alkenyl, CZ_g alkynyl, (CH2)rC3_6 cycloalkyl, C1, Br, I,
F, N02, CN, (CHR')rNR16aR16a'~ (CHR')rOH,
(CHR')r0(CHR')rRl6d, (CHR')rSH, (CHR')rC(O)H,
(CHR')rS(CHR')rRl6d, (CHR')rC(O)OH,
( CHR' ) rC ( O ) ( CHR' ) rRl6b, ( CHR' ) rC ( O ) NR16aR16a'
(CHR' ) rNRl6fC (O) (CHR' ) rRl6b~ (CHR' ) rC (O) O (CHR' ) rRl6d~
( CHR' ) rOC ( O ) ( CHR' ) rRl6b , ( CHR' ) rC ( =X16 f ) ~16aR16a'
(CHR')rNHC(=NRl6f)NR16fR16f~ (CHR')rS(O)p(CHR')rRl6b~
(CHR')rS(0)2NR16aR16a', (CHR')rNRl6fS(O)2(CHR')rRl6b, C1_6
haloalkyl, C2_g alkenyl substituted with 0-3 R', C2_8
alkynyl substituted with 0-3 R', and (CHR')rphenyl
substituted with 0-3 Rlse
Rl6a and Rl6a' , at each occurrence, are selected from H, C1_6
alkyl, C2_g alkenyl, C2_g alkynyl, a (CH2)r-C3-10
carbocyclic residue substituted with 0-5 Rlse, and a
(CH2)r-5-10 membered heterocyclic system containing 1-4
heteroatoms selected from N, O, and S, substituted
with 0-2 Rl6e
13


CA 02350730 2001-05-07
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Rl6b~ at each occurrence, is selected from C1_6 alkyl, C2_g
alkenyl, CZ_e alkynyl, a (CH2)rC3-6 carbocyclic residue
substituted with 0-3 Rl6e, and a (CH2)r-5-6 membered
heterocyclic system containing 1-4 heteroatoms
selected from N, 0, and S, substituted with 0-2 Rise;
Rl6d~ at each occurrence, is selected from C2_8 alkenyl, C2_8
alkynyl, CI_s alkyl substituted with 0-3 Rlse, a
(CH2)r-C3-to carbocyclic residue substituted with 0-3
Rl6e, and a (CH2)r-5-6 membered heterocyclic system
containing 1-4 heteroatoms selected from N, O, and S,
substituted with 0-3 Rl6e
Rl6e~ at each occurrence, is selected from C1_6 alkyl, C2_8
alkenyl, C2_8 alkynyl, (CH2)rC3_s cycloalkyl, C1, F, Br,
I, CN, N02, (CF2)rCF3, (CH2)rOC1_5 alkyl, OH, SH,
(CH2)rSC1_5 alkyl, (CH2)rNR16fR16f~ ~d (CH2)rphenyl;
Rl6f~ at each occurrence, is selected from H, C1-5 alkyl,
and C3-6 cycloalkyl, and phenyl;
v is selected from 2 and 2;
t is selected from 1 and 2;
w is selected from 0 and 1;
r is selected from 0, 1, 2, 3, 4, and 5;
q is selected from 1, 2, 3, 4, and 5; and
p is selected from 0, 1, 2, and 3.
[2] In a preferred embodiment, the present invention
provides novel compounds of formula (I), wherein:
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CA 02350730 2001-05-07
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R4 is absent, taken with the nitrogen to which it is
attached to form an N-oxide, or selected from C1_B
alkyl, (CH2)rC3-s cycloalkyl: and (CH2)r-phenyl
substituted with 0-3 RQc;
R4c, at each occurrence, is selected from C1_6 alkyl, C2_g
alkenyl, C2_g alkynyl, C3_6 cycloalkyl, C1, F, Br, I,
CN, N02, (CFZ)rCF3. (CHZ)rOCl_5 alkyl, (CH2)rOH,
(CHZ)rSCl_5 alkyl, (CH2)rNR4aR9a~, and (CH2)rphenyl;
alternatively, R4 joins with R~, R9, or R11 to form a 5, 6
or 7 membered piperidinium spirocycle or pyrrolidinium
spirocycle substituted with 0-3 Ra;
R1 and RZ are independently 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,
(CHZ)rC(0)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-s
cycloalkyl, C1, F, Br, I, CN, N02, (CF2)rCF3, (CH2)rOCi-
5 alkyl , ( CH2 ) rOH, ( CHZ ) rSCl_5 alkyl , and ( CH2 ) rNR6dR6d;
R6d, at each occurrence, is selected from H, CZ_6 alkyl, and
C3_6 cycloalkyl;
~. 5


CA 02350730 2001-05-07
WO 00!35451 PCT/US99l30332
R13, at each occurrence, is selected from C1_q alkyl, C3-s
cycloalkyl, (CH2 ) NR13aR13a~ ~ (CH2 ) OH, (CH2 ) ORl3b
(CH2),",C(0)Rl3b~ (CH2)wC(O)NR13aR13a'. (CHz)NRl3dC(0)Rl3a~
(CHZ)~",S (O) 2NR13aR13a'. (CHZ)NRl3dS (O) 2R13b, and
(CH2)w-phenyl substituted with 0-3 Rl3c;
Rl3a and Rl3a'~ at each occurrence, are selected from H, C1_6
alkyl, C3_6 cycloalkyl, and phenyl substituted with 0-3
Rl3c.
Rl3b, at each occurrence, is selected from C1_6 alkyl, C3_6
cycloalkyl, and phenyl substituted with 0-3 Rl3c;
Rl3c~ at each occurrence, is selected from C1_6 alkyl, C3-s
cycloalkyl, C1, F, Br, I, CN, N02, (CFZ)rCF3, (CH2)rOCl_
5 alkyl, (CH2)=OH, and (CHz)rNR13dR13d~
Rl3d~ at each occurrence, is selected from H, C1_6 alkyl,
and C3_6 cycloalkyl;
v is selected from 1 and 2;
q is selected from 1, 2, and 3; and
r is selected from 0, 1, 2, and 3.
[3] In a more preferred embodiment, the present invention
provides novel compounds of formula (I), wherein:
R3 is selected from 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,
16


CA 02350730 2001-05-07
WO 00!35451 PCT/US99/30332
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] In an even more preferred embodiment, the present
invention provides novel compounds of formula (I-i),
wherein the compound of formula (I-i) is:
--E..~ -Rs
H H
(I-i)
R16, at each occurrence, is selected from C1_$ alkyl,
(CH2)rC3-6 cycloalkyl, CF3, C1, Br, I, F,
(CH2)rNR16aR16a~~ N02. CN, OH, (CH2)rORl6d~
(CH2)rC(O)Rl6b, (C:~2)rC(O)NR16aR16a~. (CH2)rNRl6fC(O)Rl6b~
(CH2)rS(O)pRl6b~ (CH2)rS(O)2NR16aR16a~
(CHZ)rNR~6fS(p)2R16b~ and (CH2)=phenyl substituted with
0-3 Rl6e
17


CA 02350730 2001-05-07
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Rl6a and Rl6a', at each occurrence, are selected from H, C1_6
alkyl, C3_6 cycloalkyl, and (CH2)rphenyl substituted
with 0-3 Rl6e
Rl6b~ at each occurrence, is selected from H, C1_6 alkyl,
C3-6 cycloalkyl, and (CH2)rphenyl substituted with 0-3
Rl6e
Rl6d~ at each occurrence, is selected from Cz_6 alkyl and
phenyl;
Rl6e~ at each occurrence, is selected from C1_6 alkyl, C1,
F, Br, I, CN, N02, (CF2)rCF3, OH, and (CH2)rOCl_5 alkyl;
and
Rl6f~ at each occurrence, is selected from H, and C1-5
alkyl.
[5] In another even more preferred embodiment, the present
invention provides novel compounds of formula (I-ii),
wherein the compound formula (I-ii) is:
~_
L../
H H
(I-ii)
R16, at each occurrence, is selected from C1_8 alkyl,
(CH2)rC3-6 cYcloalkyl, CF3, C1, Br, I, F,
(CH2)rNR16aR16a'~ N02. ~. OH, (CHZ)rORl6d~
( CH2 ) rC ( O ) Rl6b ~ ( CH2 ) rC ( O ) NR16aR16a' . ( CH2 ) rNRl 6 fC ( O )
Rl6b
(CH2)rS(O)pRl6b~ (CH2)rS(O)z~16aR16a'~
(CH2)rNRl6fg(O)2R16b, ~d (CH2)rphenyl substituted with
0-3 nl6e~
Rl6a and Rl6a'~ at each occurrence, are selected from H, C1_6
alkyl, C3_6 cycloalkyl, and (CH2)rphenyl substituted
with 0-3 Rl6e;
18


CA 02350730 2001-05-07
WO 00/35451 PCT/US99/30332
Rl6b~ at each occurrence, is selected from H, C1_6 alkyl,
C3_6 cycloalkyl, and (CH2)rphenyl substituted with 0-3
Rl6e
R~6d, at each occurrence, is selected from C1_6 alkyl and
phenyl;
Rl6e~ at each occurrence, is selected from C1_6 alkyl, C1,
F, Br, I, CN, N02, (CFz)rCF3, OH, and (CHZ)rOCl_5 alkyl;
and
Rl6f~ at each occurrence, is selected from H, and C1-5
alkyl.
[6] In a preferred embodiment, the present invention
provides novel compounds of formula (I-i) wherein:
R5 is CH2phenyl substituted with 0-3 R16
E is -CH2- (CH2 ) - (CH2 ) ;
r is selected from 0, 1, and 2.
[7]. In another preferred embodiment, the present
invention provides novel compounds of formula (I-ii),
wherein:
E is -CH2 - ( CHR9 ) -CHR11;
R5 is CH2phenyl substituted with 0-3 R16; and
r is selected from 0, 1, and 2.
[8] In a more preferred embodiment, the present invention
provides novel compounds of formula (I-i), wherein:
19


CA 02350730 2001-05-07
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J is selected from CH2 and CHRS;
K is selected from CH2 and CHRS;
S L is selected from CH2 and CHRS;
R3 is a C3_lo carbocyclic residue substituted with 0-3 R15,
wherein the carbocyclic residue is selected from
cyclopropyl, 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
R15, at each occurrence, is selected from C1_8 alkyl,
(CH2)rC3-6 cycloalkyl, CF3, C1, Br, I, F,
(CH2)rNR15aR15a'~ N02~ CN, OH, (CH2)rORl5d.
(CH2)rC(p)Rl5b. (CHZ)=C(p)NR15aR15a', (CH2)rNRlSfC(0)RlSb.
(CHz)rS(O)pRlSb. (CH2)rS(O)2NR15aR15a'.
(CH2)rNRlSfg(O)2R15b. (CH2)rphenyl Substituted with 0-3
Rl5e. and a (CH2)r-5-6 membered heterocyclic system
containing 1-4 heteroatoms selected from N, O, and S,
substituted with 0-2 RlSe.
RlSa ~d RlSa~, at each occurrence, are selected from H, C
alkyl, C3_6 cycloalkyl, and (CH2)rphenyl substituted
with 0-3 RlSe;
Rl.Sb. at each occurrence, is selected from H, Cl_6 alkyl,
C3_6 cycloalkyl, and (CH2)rphenyl substituted with 0-3
Rl5e.


CA 02350730 2001-05-07
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RlSd, at each occurrence, is selected from C1_6 alkyl and
phenyl;
Rlse~ at each occurrence, .is selected from C1_6 alkyl, C1,
F, Br, I, CN, NOZ, (CF2)rCF3, OH, and (CH2)rOCl_5 alkyl;
and
RlSf~ at each occurrence, is selected from H, and C1-5
alkyl.
[9~ In another more preferred embodiment, the present
invention provides novel compounds of formula (I-ii),
wherein:
K is selected from CH2 and CHRS;
L is selected from CH2 and CHRS;
R3 is a C3_lo carbocyclic residue substituted with 0-3 R15,
wherein the carbocyclic residue is selected from
cyclopropyl, 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
R15, at each occurrence, is selected from C1_8 alkyl,
(CH2)rC3_6 cycloalkyl, CF3, C1, Br, I, F,
(CH2)rNR15aR15a', N02, CN, OH, (CH2)rORlSd~
(CHZ)rC(O)RlSb, (CH2)rC(O)NR15aR15a'~ (CH2)rNRl5fC(O)Rl5b~
21


CA 02350730 2001-05-07
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(CH2)rS(O)pRlSb~ (CH2)rS(0)2NR15aR15a'.
(CH2)rNRlSfS(O)2R15b~ (CH2)rphenyl substituted with 0-3
RlSe, and a (CH2)r-5-6 membered heterocyclic system
containing 1-4 heteroatoms selected from N, O, and S,
substituted with 0-2. RlSe
RlSa and RlSa', at each occurrence, are selected from H, C1_6
alkyl, C3_6 cycloalkyl, and (CH2)rphenyl substituted
with 0-3 RlSe;
R25b, at each occurrence, is selected from H, C1_6 alkyl,
C3_6 cycloalkyl, and (CH2)rphenyl substituted with 0-3
RlSe
RlSd, at each occurrence, is selected from C1_6 alkyl and
phenyl;
RlSe, at each occurrence, is selected from C1_6 alkyl, C1,
F, Br, I, CN, N02, (CF2)rCF3, OH, and (CH2)rOCl_5 alkyl;
and
RlSf, at each occurrence, is selected from H, and C1_5 alkyl
[10~ In a preferred embodiment, the present invention
provides novel compounds of formula (I), wherein:
M is absent or selected from CHz;
Q is CHz;
J is CHI;
K and L are independently selected from CHI and CHRS;
Z is O;
Rl is H;
22


CA 02350730 2001-05-07
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RZ is H;
R3 is a C3_1o carbocyclic residue substituted with 0-3 R15,
wherein the carbocyclic residue is selected from
cyclopropyl, 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,
2,2,3-triazolyl, tetrazolyl, thiadiazolyl, thiazolyl,
oxazolyl, pyrazinyl, and pyrimidinyl; and
RS is selected from a CHZ-C3_,a carbocyclic residue
substituted with 1-5 R'6 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
35
[1-11] In a further even more preferred embodiment, the
present invention provides novel compounds of formula (I)
and pharmaceutically acceptable salt forms thereof, wherein
the compound of formula I is selected from:
N-(2-hydroxymethylphenyl)-N'-[3-[4-(phenylmethyl)-1-
piperidinyl]propyl]urea,
23


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N-(3-carboethoxyphenyl)-N'-[3-[4-(phenylmethyl)-1-
piperidinyl]propyl]urea,
N-(3-cyanophenyl)-N'-[3-[4-(phenylmethyl)-1-piperidinyl]
propyl]urea,
N-[4-(benzyloxy)phenyl]-N'-[3-[4-(phenylmethyl)-1-
piperidinyl]propyl]urea,
N-(3-iodophenyl)-N'-[3-[4-(phenylmethyl)-1-piperidinyl)
propyl]urea,
N-(3-methoxyphenyl)-N'-[3-[4-(phenylmethyl)-1-piperidinyl]
propyl]urea,
N-phenyl-N'-[3-[4-(phenylmethyl)-1-piperidinyl]propyl]urea,
N-(4-carboethoxyphenyl)-N'-[3-[4-(phenylmethyl)-1-
piperidinyl]propyl]urea,
N-(4-fluorophenyl)-N'-[3-[4-(phenylmethyl)-1-piperidinyl]
propyl]urea,
N-(2-methoxyphenyl)-N'-[3-[4-(phenylmethyl)-1-
piperidinyl]propyl]urea,
N-(4-methoxyphenyl)-N'-[3-[4-(phenylmethyl)-1-
piperidinyl]propyl]urea,
N-(3-cyanophenyl)-N'-j3-[4-(4-fluorophenylmethyl)-1-
piperidinyl]propyl]urea,
N-(4-fluorophenyl)-N'-[3-[4-(4-fluorophenylmethyl)-1-
piperidinyl]propyl]urea,
N-(4-carboethoxyphenyl)-N'-[3-[4-(4-fluorophenylmethyl)-1~
piperidinyl]propyl]urea,
24


CA 02350730 2001-05-07
WO 00/35451 PCT/US99/30332
N-(3-cyanophenyl)-N'-[3-[4-((3,4-
methylenedioxy)phenylmethyl)-1-
piperidinyl]propyl]urea,
N-(3-methoxyphenyl)-N'-[3-[4-(4-fluorophenylrnethyl)-1-
piperidinyl]propyl]urea,
N-(3-carboethoxyphenyl)-N'-[3-[4-((3,4-methylenedioxy)
phenylmethyl)-1-piperidinyl]propyl]urea,
N-(3-methoxyphenyl)-N'-[3-[4-((3,4-methylenedioxy)
phenylmethyl)-1-piperidinyl]propyl]urea,
N-(3-methoxyphenyl)-N'-[3-[4-((3-methoxy)phenylmethyl)-1-
piperidinyljpropyl]urea,
N-(3-cyanophenyl)-N'-[3-[4-(4-fluorophenylmethyl)-1-methyl-
1-piperidinium]propyl]urea iodide,
N-(4-cyanophenyl)-N'-[3-[4-(phenylmethyl)-1-piperidinyl]
propyl]urea,
N-(4-fluorophenyl)-N'-[3-[4-((3,4-methylenedioxy)
phenylmethyl)-1-piperidinyljpropyl]urea,
N-(4-fluorophenyl)-N'-[3-[4-(2,4-bisfluorophenylmethyl)-1-
piperidinyl]propyl)urea,
N-(3-methoxyphenyl)-N'-[3-[4-(2,4-bisfluorophenylmethyl)-1-
piperidinyl]propyl]urea,
N-(3-cyanophenyl)-N'-[3-[4-(2,4-bisfluorophenylmethyl)-1-
piperidinyl]propyl]urea,
N-(phenylmethyl)-N'-[3-[4-(4-fluorophenylmethyl)-1-
piperidinyl]propyljurea,


CA 02350730 2001-05-07
WO 00/35451 PCT/US99/30332
N-[1-(2-phenylethyl)]-N'-[3-[4-(4-fluorophenylmethyl)-1-
piperidinyl]propyl]urea,
N-(2-fluorophenyl)-N'-[3-[4-(4-fluorophenylmethyl)-1-
piperidinyl]propyl]urea,
N-(3-fluorophenyl}-N'-[3-[4-(4-fluorophenylmethyl)-1-
piperidinyl]propyl]urea,
N-(cyclohexyl)-N'-[3-[4-(4-fluorophenylmethyl)-1-
piperidinyl]propyl]urea,
N-[1-[trans-2-phenylcyclopropyl)-N'-[3-[4-(4-fluorophenyl-
methyl)-1-piperidinyl]propyl]urea,
N-(3-methoxyphenyl)-N'-[3-[4-(4-methylphenylmethyl)-1-
piperidinyl]propyl]urea,
N-(3-cyanophenyl)-N'-[3-[4-(4-methylphenylmethyl)-1-
piperidinyl]propyl]urea,
N-(3-cyanophenyl)-N'-[3-[4-(4-chlorophenylmethyl)-1-
piperidinyl]propyl]urea,
N-(3-methoxyphenyl)-N'-[3-[4-(3-methoxyphenylmethyl)-1-
piperidinyl]propyl]urea,
N-(3-cyanophenyl)-N'-[3-[9-(3-methoxyphenylmethyl)-1-
piperidinyl]propyl]urea,
N-(4-fluorophenyl)-N'-[3-[4-(3-methoxyphenylmethyl)-1-
piperidinyl]propyl]urea,
N-(4-carboethoxyphenyl)-N'-[3-[4-(3-methoxyphenylmethyl}-1-
piperidinyl]propyl]urea,
26


CA 02350730 2001-05-07
WO 00/35451 PCT/US99/30332
N-(3-cyanophenyl)-N'-[3-[4-(2-fluorophenylmethyl)-1-
piperidinyl]propyl]urea,
N-(3-fluorophenyl)-N'-[3-[4-(3-methoxyphenylmethyl)-1-
piperidinyl]propyl]urea,
N-(3-carboethoxyphenyl)-N'-[3-[4-(3-methoxyphenylmethyl)-1-
piperidinyl]propyl]urea,
N-[3-acetylphenyl]-N'-[3-[4-(4-fluorophenylmethyl)-1-
piperidinyl]propyl]urea,
N-[3-(alpha-hydroxyethyl)phenyl]-N'-[3-[4-(4-fluorophenyl-
methyl)-1-piperidinyl]propyl]urea,
N-[4-acetylphenyl]-N'-[3-[4-(4-fluorophenylmethyl)-1-
piperidinyl]propyl]urea,
N-(3-methoxyphenyl)-N'-[3-[4-(phenylmethyl)-1-piperidinyl]
propyl]urea,
cis-N-(3-methoxyphenyl)-N'-[3-[2,4-bis(phenylmethyl)-1-
piperidinyl]propyl]urea,
N-(3-acetylphenyl)-N'-[3-[4-(4-fluorophenylmethyl)-1-
piperidinyl]propyl]urea,
N-(3-methoxyphenyl)-N'-[3-[4-(4-fluorophenylmethylidenyl)-
1-piperidinyl]propyl]urea,
N-(4-acetylphenyl)-N'-[3-[4-(4-fluorophenylrnethyl)-1-
piperidinyl]propyl]urea,
N-(3-(1-hydroxyethyl)phenyl)-N'-[3-[4-(4-
fluorophenylmethyl)-1-piperidinyl]propyl]urea
hydrochloride,
27


CA 02350730 2001-05-07
WO 00135451 PCT/US99/30332
N-(3-acetylphenyl)-N'-[3-[4-(4-fluorophenylmethyl)-3-
(phenylmethyl)-1-piperidinyl]propyl]urea,
N-(4-fluorophenyl)-N'-[3-[4-(4-fluorophenylmethyl)-3-
(phenylmethyl)-1-piperidinyl]propyl]urea,
N-(3-methoxyphenyl)-N'-[3-[4-(4-fluorophenylmethyl)-3-
(phenylmethyl)-1-piperidinyl]propyl]urea,
N-(2-isopropylphenyl)-N'-[3-[4-(4-fluorophenylmethyl)-1-
piperidinyl]propyl]urea,
N-(2-trifluoromethylphenyl)-N'-[3-[4-(4-
fluorophenylmethyl)-1-piperidinyl]propyl]urea,
N-(3-chlorophenyl)-N'-[3-[4-(4-fluorophenylmethyl}-1-
piperidinyl]propyl]urea,
N-(3-trifluoromethylphenyl)-N'-[3-[4-(4-
fluorophenylmethyl)-1-piperidinyl]propyl]urea,
N-(2-chlorophenyl)-N'-[3-[4-(4-fluorophenylmethyl)-1-
piperidinyl]propyl]urea,
N-(2,4-difluororophenyl)-N'-(3-[4-(4-fluorophenylmethyl}-1-
piperidinyl]propyl]urea,
N- ( 3-cyanophenyl } -~N' - [ 3 - [ 4- ( 4-f luorophenylmethyl ) -1-
piperidinyl]propyl]urea, hydrochloride,
N-(3-cyanophenyl}-N'-[3-[4-(naphth-1-ylmethyl)-1-
piperidinyl]propyl]urea,
N-(4-fluorophenyl)-N'-[3-[4-(naphth-1-ylmethyl)-1-
piperidinyl]propyl]urea,
N- ( 3 -methoxyphenyl ) -N' - [ 3- [ 4-- (naphth-1-ylmethyl ) -1-
piperidinyl]propyl]urea,
28


CA 02350730 2001-05-07
WO 00/35451 PCT/US99130332
N-(3-cyanophenyl)-N'-[3-[4-(3-methylphenylmethyl)-1-
piperidinyl]propyl]urea,
N-(3-methoxyphenyl)-N'-(3-[4-(3-methylphenylmethyl)-1-
piperidinyl]propyl]urea,
N-(4-cyanophenyl)-N'-[3-(4-(4-fluorophenylmethyl)-1-
piperidinyl)propyl]urea,
N-(4-fluorophenyl)-N'-[3-[4-(4-chlorophenyl)methyl-1-
piperidinyl]propyl]urea,
N-(3-methoxyphenyl)-N'-[3-[4-(4-chlorophenyl)methyl-1-
piperidinyl]propyl]urea,
N-(3-cyanophenyl)-N'-[3-[4-(3,4-bisfluorophenyl)methyl-1-
piperidinyl]propyl]urea,
N-(3-methoxyphenyl)-N'-[3-[4-(3,4-bisfluorophenyl)methyl-1-
piperidinyl]propyl]urea,
N-(4-fluorophenyl)-N'-[3-[4-(3,4-bisfluorophenyl)methyl-1-
piperidinyl]propyl]urea,
N-(3-methoxyphenyl)-N'-[3-[4-(3-fluorophenyl) methyl-1-
piperidinyl]propyl]urea,
N-(3-cyanophenyl)-N'-[3-[4-(3-chlorophenyl)methyl-1-
piperidinyl]propyl]urea,
N-(3-methoxyphenyl)-N'-(3-[4-(3-carbomethoxyphenyl)a~ethyl-
1-piperidinyl]propyl]urea,
N-(3-cyanophenyl)-N'-[3-[4-(3-carbomethoxyphenyl)methyl-1-
piperidinyl]propyl]urea,
29


CA 02350730 2001-05-07
WO 00/35451 PCT/US99/30332
N-(3-acetylphenyl)-N'-[3-[4-(4-fluorophenyl)methyl-1-
piperidinyl]propyl]urea,
N-(3,5-diacetylphenyl)-N'-[3-[3-(4-fluorophenyl)methyl-1-
piperidinyl]propyl]urea,
N-(3-acetylphenyl)-N'-[3-[3-(4-fluorophenyl)methyl-1-
piperidinyl]propyl]urea;
N-(3,5-diacetylphenyl)-N'-[3-[4-(4-fluorophenyl)methyl-1-
piperidinyl]propyl]urea,
N-(3-cyanophenyl)-N'-[1-phenyl-3-[4-(4-fluorophenylrnethyl)-
1-piperidinyl]propyl]urea,
N-(3-methoxyphenyl)-N'-[1-phenyl-3-[4-(phenylmethyl)-1-
piperidinyl]propyl]urea,
N-(3-cyanophenyl)-N'-[1-phenyl-3-[4-(phenylmethyl)-1-
piperidinyl]propyl]urea,
N-(1-adamantyl)-N'-[1-phenyl-3-[4-(phenylmethyl)-1-
piperidinyl]propyl]urea,
N-(4-fluorophenyl)-N'-[1-phenyl-3-[4-(phenylmethyl)-1-
piperidinyl]propyl]urea
N-(3-carboethoxyphenyl)-N'-[3-[3-(phenylmethyl)-1-
piperidinyl]propyl]urea,
N-(3-cyanophenyl)-N'-(3-[3-(phenylmethyl)-1-
piperidinyl]propyl]urea,
N-(4-fluorophenyi)-N'-[3-(3-(phenylmethyl)-1-
piperidinyl]propyl]urea,
N-phenyl-N'-[3-[3-(phenylmethyl)-1-piperidinyl]propyl)urea,


CA 02350730 2001-05-07
WO 00/35451 PCT/US99/30332
N-(1-adamantyl)-N'-[3-[3-(phenylmethyl)-1-
piperidinyl]propyl]urea,
N-(3-methoxyphenyl)-N'-[3-[3-(phenylmethyl)-1-
piperidinyl)propyl]urea,
N-(4-carboethoxyphenyl)-N'-[3-[3-(phenylmethyl)-1-
piperidinyl]propyl]urea,
N-phenyl-N'-[3-[3-(4-fluorophenyl)methyl-1-
piperidinyl]propyl]urea,
N-(3-cyanophenyl)-N'-[3-[3-(4-fluorophenyl)methyl-1-
piperidinyl]propyl]urea,
N-(1-adamantyl)-N'-[3-[3-(4-fluorophenyl)methyl-1-
piperidinyl]propyl]urea,
N-(3-methoxyphenyl)-N'-[3-[3-(4-fluorophenyl)methyl-1-
piperidinyl]propyl]urea,
N-(3-carboethoxyphenyl)-N'-[3-[3-(4-fluorophenyl)methyl-1-
piperidinyl]propyl]urea,
N-(4-fluorophenyl)-N'-[3-[3-(4-fluorophenyl)methyl-1-
piperidinyl]propyl]urea,
N-(3-cyanophenyl)-N'-[3-[3-[2-(phenyl)ethyl]-1-
piperidinyl]propyl]urea,
N-(3-carboethoxyphenyl)-N'-[3-[3-[2-(phenyl)ethyl]-1-
piperidinyl]propyl]urea,
N-(4-carboethoxyphenyl)-N'-[3-[3-[2-(phenyl)ethyl]-1-
piperidinyl)propyl]urea,
N-(4-fluorophenyl)-N'-[3-[3-[2-(phenyl)ethyl]-1-
piperidinyl]propyl]urea,
31


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N-phenyl-N'-[3-[3-[2-(phenyl)ethyl]-1-
piperidinyl]propyl]urea,
N-(1-adamantyl)-N'-[3-[3-[2-(phenyl)ethyl]-1-
piperidinyl]propyl]urea,
N- ( 3 -me thoxyphenyl ) -N' - [ 3 - [ 3 - [ 2 - ( phenyl ) ethyl ] -1-
piperidinyl]propyl]urea,
N-phenyl-N'-[3-[3-(4-fluorophenyl)methyl]-1-
pyrrolinyl]propyl]urea,
N-(3-cyanophenyl)-N'-[3-[3-(4-fluorophenyl)methyl-1-
pyrrolinyl]propyl]urea,
N-(3-methoxyphenyl)-N'-[3-[3-(4-fluorophenyl)methyl-1-
pyrrolinyl]propyl]urea,
N- (4-fluorophenyl) -N' - [3- [3- (4-fluorophenyl)methyl-1-
pyrrolinyl]propyl]urea,
N-(3-carboethoxyphenyl)-N'-[3-[3-(4-fluorophenyl)methyl-1-
pyrrolinyl]propyl]urea,
N-(4-carboethoxyphenyl)-N'-(3-[3-(4-fluorophenyl)methyl-1-
pyrrolinyl]propyl]urea,
N-(1-adamantyl)-N'-[3-[3-(4-fluorophenyl)methyl-1-
pyrrolinyl]propyl]urea,
N-phenyl-N'-[3-[3-(2-fluorophenyl)methyl-1-
piperidinyl]propyl]urea,
N-(3-cyanophenyl)-N'-[3-[3-(2-fluorophenyl)methyl-1-
piperidinyl]propyl]urea,
32


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N-(3-methoxyphenyl)-N'-[3-[3-(2-fluorophenyl)methyl-1-
piperidinyl]propyl]urea,
N-(4-fluorophenyl)-N'-[3-[3-(2-fluorophenyl)methyl-1-
piperidinyl]propyl]urea,
N-(3-methoxyphenyl)-N'-(3-[3-(3-fluorophenyl)methyl-1-
piperidinyl]propyl]urea,
N-(3-cyanophenyl)-N'-[3-[3-(3-fluorophenyl)methyl-1-
piperidinyl]propyl]urea,
N-(4-fluorophenyl)-N'-[3-[3-(3-fluorophenyl)methyl-1-
piperidinyl]propyl]urea
N-[3-(1-methyltetrazol-5-yl)phenyl]-N'-[3-[4-(4-
fluorophenylmethyl)-1-piperidinyl]propyl]urea,
N-(3-(1-methyltetrazol-5-yl)phenyl]-N'-[3-[3-(4-
fluorophenylmethyl)-1-piperidinyl]propyl]urea,
N-[3,5-bis(1-methyltetrazol-5-yl)phenyl]-N'-[3-[4-(4-
fluorophenylmethyl)-1-piperidinyl]propyl]urea,
N-[3,5-bis(1-methyltetrazol-5-yl)phenyl]-N'-[3-[3-(4-
fluorophenylmethyl)-1-piperidinyl]propyl]urea,
N-(4-(1-methyltetrazol-5-yl)phenyl]-N'-[3-[4-(4-
fluorophenylmethyl)-1-piperidinyl]propyl]urea, and
N-[4-(1-methyltetrazol-5-yl)phenyl]-N'-[3-[3-(4-
fluorophenylmethyl)-1-piperidinyl]propyl]urea.
[1-12] In a further even more preferred embodiment, the
present invention provides novel compounds of formula (I)
33


CA 02350730 2001-05-07
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and pharmaceutically acceptable salts form thereof, wherein
the compound of formula I is selected from:
N-(1-adamantyl)-N'-[3-[4-(phenylmethyl)-1-piperidinyl]
propyl]urea, and
N-[1-(trans-2-phenylcyclopropyl)]-N'-[3-[4-(phenylmethyl)-
1-piperidinyl]propyl]urea.
[1-13] In a further even more preferred embodiment, the
present invention provides novel compounds of formula (I)
and pharmaceutically acceptable salts form thereof, wherein
the compound of formula I is selected from:
N-(3-methoxyphenyl)-N'-[3-[1,4-bis(phenylmethyl)-1-
piperidinium]propyl]urea bromide,
N-(3-cyanophenyl}-N'-(3-(1,4-bis(phenylmethyl)-1-
piperidinium]propyl]urea bromide,
N-(3-methoxyphenyl)-N'-[3-[1-methyl-4-(phenylmethyl)-1-
piperidinium]propyl]urea bromide,
N-(3-cyanophenyl)-N'-[3-[1-methyl-4-(phenylmethyl)-1-
piperidinium]propyl]urea bromide,
N-(3-cyanophenyl)-N'-[3-[1-(carbomethoxymethyl)-4-
(phenylmethyl)-1-piperidinium]propyl]urea bromide,
N-(4-fluorophenyl)-N'-[3-[1-methyl-4-(phenylmethyl)-1-
piperidinium]propyl]urea bromide,
N-(4-fluorophenyl)-N'-[3-[1,4-bis(phenylmethyl)-1-
piperidinium]propyl]urea bromide,
N-(4-fluorophenyl)-N'-(3-[1-(carbomethoxyrnethyl)-4-
(phenylmethyl)-1-piperidinium]propyl3urea bromide,
34


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N-(3-cyanophenyl)-N'-[3-[1-(cyanomethyl)-4-(phenylmethyl)-
1-piperidinium]propyl]urea bromide,
N-(3-cyanophenyl)-N'-[3-[1-(phenylcarbonylmethyl)-4
(phenylmethyl)-1-piperidinium]propyl]urea bromide,
N-(2-methoxyphenyl)-N'-[3-[1-methyl-4-(phenylmethyl)-1-
piperidinium]propyl]urea bromide,
N-(4-methoxyphenyl)-N'-[3-[1-methyl-4-(phenylmethyl)-1-
piperidinium]propyl]urea bromide,
N-(3-methoxyphenyl)-N'-[3-[1-oxo-4-(phenylmethyl)-1-
piperidinium]propyl]urea, and
N-(3-methoxyphenyl)-N'-[3-[1-methyl-4-(phenylmethyl)-1-
piperidinium]propyl]urea iodide.
[1-14) In a further even more preferred embodiment, the
present invention provides novel compounds of formula (I)
and pharmaceutically acceptable salts form thereof, wherein
the compound of formula I is selected from:
N-(3-cyanophenyl)-N'-[4-[4-(phenylmethyl)-1-piperidinyl]
butyl]urea,
N-(3-acetylphenyl)-N'-[4-[4-(4-fluorophenylmethyl)-1-
piperidinyl]butyl]urea,
N-(3,5-diacetylphenyl)-N'-[4-[4-(4-fluorophenylmethyl)-1-
piperidinyl]butyl]urea,
N-(3-cyanophenyl)-N'-[4-[4-(4-fluorophenylmethyl)-1-
piperidinyl]butyl]urea,
N-(3-acetylphenyl)-N'-[4-[3-(4-fluorophenylmethyl)-1-
piperidinyl]butyl]urea,


CA 02350730 2001-05-07
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N-(3,5-diacetylphenyl)-N'-[4-[3-(4-fluorophenylmethyl)-1-
piperidinyl]butyl]urea,
N-(3-cyanophenyl)-N'-[4-[3-(4-fluorophenylmethyl)-1-
piperidinyl]butyl]urea,
N-(3-methoxyphenyl)-N'-[4-[3-(4-fluorophenylmethyl)-1-
piperidinyl]butyl]urea,
N-(4-fluorophenyl)-N'-[4-[3-(4-fluorophenylmethyl)-1-
piperidinyl]butyl]urea,
N-phenyl-N'-[4-[3-(4-fluorophenylmethyl)-1-
piperidinyl]butyl]urea,N-[3-(1-methyltetrazol-5-yl)phenyl]-
N'-[4-[4-(4-fluorophenylmethyl)-1-piperidinyl]butyl]urea,
N-[3-(1-methyltetrazol-5-yl)phenyl]-N'-[4-[3-(4-
fluorophenylmethyl)-1-piperidinyl]butyl]urea,
N-[3,5-bis(1-methyltetrazol-5-yl)phenyl]-N'-[4-[4-(4-
fluorophenylmethyl)-1-piperidinyl]butyl]urea,
N-[3,5-bis(1-methyltetrazol-5-yl)phenyl]-N'-[4-[3-(4-
fluorophenylmethyl)-Z-piperidinyl]butyl]urea,
N-(3-carbomethoxyphenyl)-N'-[4-[4-(phenylmethyl)-1-
piperidinyl]butyl]urea,
N-(3-iodophenyl)-N'-[4-[4-(phenylmethyl)-1-
piperidinyl]butyl] urea,
N-[1-(4-benzyloxyphenyl)]-N'-[4-[4-(phenylmethyl)-1-
piperidinyl]butyl]urea,
N-(1-adamantyl)-N'-[4-[4-(phenylmethyl)-1-
piperidinyl]butyl]urea,
36


CA 02350730 2001-05-07
WO 00/35451 PCT/US99/30332
N-(3-methoxyphenyi)-N'-[4-[4-(phenylmethyl)-1-
piperidinyl]butyl]urea,
N-phenyl-N'-[4-[4-(phenylmethyl)-1-piperidinyl]butyl]urea,
N-(3-methoxyphenyl)-N'-[4-[4-(phenylmethyl)-1-
piperidinyl]butyl]urea,
N-(4-carbomethoxyphenyl)-N'-[4-[4-(phenylmethyl)-1-
piperidinyl]butyl]urea,
N-(4-cyanophenyl)-N'-[4-[4-(phenylmethyl)-1-piperidinyl]
butyl]urea,
N-(3-acetylphenyl)-N'-{(2Z)-4-[3-(4-fluorobenzyl)-1-
piperidinyl]-2-butenyl}urea,
N-(3-acetylphenyl)-N'-{(2E)-4-[3-(4-fluorobenzyl)-1-
piperidinyl]-2-butenyl}urea,
N-(3-cyanophenyl)-N'-{(2Z)-4-[3-(4-fluorobenzyl)-1-
piperidinyl]-2-butenyl}urea,
N-(4-fluorophenyl)-N'-{(2Z)-4-[3-(4-fluorobenzyl)-1-
piperidinyl]-2-butenyl}urea, and
N-(3-acetylphenyl)-N'-{4-[3-(4-fluorobenzyl)-1-
piperidinyl]-2-butynyl}urea
[15] In another embodiment, the present invention
provides a pharmaceutical composition, comprising a
pharmaceutically acceptable carrier and a therapeutically
effective amount of a compound of the present invention.
[16] In another embodiment, the present invention provides
a method for modulation of chemokine receptor activity
comprising administering to a patient in need thereof a
37


CA 02350730 2001-05-07
WO OOI35451 PCT/US99/30332
therapeutically effective amount of the compounds of the
present invention.
[17] In another embodiment, the present invention provides
a method for treating or preventing inflammatory diseases,
comprising administering to a patient in need thereof a
therapeutically effective amount of a compound of the
present invention.
[18] In another embodiment, the present invention provides
a method for treating or preventing asthma, comprising
administering to a patient in need thereof a
therapeutically effective amount of a compound of the
present invention.
[19) Thus, in another embodiment, the present invention
provides novel compounds of formula (I):
3
-R
L-D ~~ R2
(I)
or stereoisomers or pharmaceutically acceptable salts
thereof, wherein:
M is absent or selected from CH2 , CHRS , CHR13 , CR13R13 , and
CR5RI3 ;
Q is selected from CH2, CHRS, CHR13, CR13R13, and CR5R13;
J, K, and L are independently selected from CH2, CHRS, CHR6,
CR6R6 and CRSR6;
with the provisos:
1) at least one of M, J, K, L, or Q contains an R5;
and
38


CA 02350730 2001-05-07
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2) when M is absent, J is selected from CH2, CHRS,
CHR13, and CR5R13;
Z is selected from NRla, CHCN, CHN02, and C(CN)2;
_
Rla is selected from H, C1_6 alkyl, C3_6 cycloalkyl,
CONRIbRib ~ ORib ~ CN, N02 , and ( CH2 ) Wphenyl ;
~1b is independently selected from H, C1_3 alkyl, C3_6
cycloalkyl, and phenyl;
E i s - ( CR~Rg ) - ( CR9R10 ) ~- ( CR11R12 ) _
R1 and R2 are independently selected from H, C1_g alkyl, C2_g
alkenyl, C2_8 alkynyl, (CH2)rC3_s cycloalkyl, and a
(CH2)r-C3_lp carbocyclic residue substituted with 0-5
Rah
Ra, at each occurrence, is selected from C1_4 alkyl, C2_g
alkenyl, C2_8 alkynyl, (CH2)rC3_6 cycloalkyl, C1, Br, I,
F. (CF2)rCF3, N02. CN, (CH2)rNRbRb. (CH2)rOH, {CH2)rOR~,
(CH2)rSH, {CH2)rSR~, (CH2)rC(O)Rb. (CH2)rC{O)NRbRZ',
( CH2 ) rNRZ'C ( O ) Rb, ( CH2 ) rC { O ) ORb, ( CH2 ) rOC ( O ) R~ ,
(CH2)rCH(=NRb)NRbRb. (CH2)rNHC(=NRb)NRbRb. (CH2)rS{O)pR~,
(CH2)rS(O)2NRbRb. (CH2)rNRbS(O)2R~, and (CH2)rphenyl;
Rb, at each occurrence, is selected from H, C1_6 alkyl, C3-6
cycloalkyl, and phenyl;
R~, at each occurrence, is selected from C1-6 alkyl, C3-6
cycloalkyl, and phenyl;
alternatively, R2 and R3 join to form a 5, 6, or 7-membered
ring substituted with 0-3 Ra;
R3 is selected from a (CR3'R3")r-C3_io carbocyclic residue
substituted with 0-5 R15 and a (CR3'R3')r-5-10 membered
39


CA 02350730 2001-05-07
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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_s
alkyl, (CH2)rC3_s cycloalkyl, and phenyl;
R4 is absent, taken with the nitrogen to which it is
attached to form an N-oxide, or selected from C1_8
alkyl, C2_g alkenyl, C2_g alkynyl, (CH2)rC3-6
cycloalkyl, (CH2)qC(O)R4b, (CH2)qC(O)NR4aR4a'~
(CH2 ) qC (O) OR4b, and a (CHZ ) r-C3-1o carbocyclic residue
substituted with 0-3 R4c;
R4a and R4a', at each occurrence, are selected from H, C1_s
alkyl, (CHZ)rC3-6 cycloalkyl, and phenyl;
R4b, at each occurrence, is selected from C1_6 alkyl, C2_g
alkenyl, (CH2)rC3_6 cycloalkyl, C2_8 alkynyl, and
phenyl;
R4c, at each occurrence, is selected from C1_6 alkyl, C2_g
alkenyl, C2_g alkynyl, C3_6 cycloalkyl, C1, F, Br, I,
CN, N02, (CF2)rCF3, (CH2)rOCl_5 alkyl, (CH2)rOH,
(CH2)rSCl_5 alkyl, (CH2)rNR4aR4a~, and (CHz)rphenyl;
alternatively, R4 joins with R~, R9, or R11 to form a 5, 6
or 7 membered piperidinium spirocycle or pyrrolidinium
spirocycle substituted with 0-3 Ra;
3 0 R5 is selected from a (CRS'RS" ) t-C3_lo carbocyclic residue
substituted with 0-5 R16 and a (CR5'R5")t-5-10 mernbered
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_s
alkyl, (CH2)rC3-6 cycloalkyl, and phenyl;


CA 02350730 2001-05-07
WO 00/35451 PCT/US99/30332
Rs, at each occurrence, is selected from C1_6 alkyl, C2_g
alkenyl, Cz_g 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,
(CHZ)rC(O)NR6aR6a', (CH2)rNR6dC(O)R6a. (CH2)rC(O)OR6b,
(CH2 ) rOC (0) R6b, (CH2 ) rS (O) pR6b. (CHz ) rS (O) 2NR6aR6a'
(CH2)rNR6dS(0)ZR6b, and (CH2)tphenyl substituted with 0-
3 Rsc;
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, C1, F, Br, I, CN, N02, (CF2)rCF3, (CH2)rOCl_
5 alkyl, (CH2)rOH, (CH2)rSCl_5 alkyl, and (CH2)rNR6dR6d~
R6d, at each occurrence, is selected from H, C1_6 alkyl, and
C3-6 cycloalkyl;
R~, is selected from H, C1_6 alkyl, C2_g alkenyl, C2_g
alkynyl, (CH2)qOH, (CH2)qSH, (CH2)qOR~d, (CH2)qSR~d,
(CH2)qNR~aR7a'. (CHZ)rC(O)OH, (CH2)rC(O)R~b,
(CH2)rC(O)NR~aR7a', (CH2)qNR~aC(O)R7a, (CH2)qNR~aC(O)H,
(CH2)rC(O)OR~b, (CH2)qOC(O)R~b, (CH2)qS(O)pR7b.
(CH2)qS(O)2NR7aR7a'. (CH2)qNR~aS(O)2R7b, Ci-6 haloalkyl,
a (CH2)r-C3-1o carbocyclic residue substituted with 0-3
Roc, and a (CH2)r-5-10 membered heterocyclic system
containing 1-4 heteroatoms selected from N, O, and S,
substituted with 0-2 R~~;
Rya and Rya', at each occurrence, are selected from H, Ci
alkyl, C2_g alkenyl, C2_g alkynyl, a (CH2)r-C3_lo
carbocyclic residue substituted with 0-5 R7e, and a
41


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(CH2)r-5-10 membered heterocyclic system containing 1-4
heteroatoms selected from N, O, and S, substituted
with 0-3 Rye;
Rib, at each occurrence, is selected from C1_6 alkyl, C2_
alkenyl, C2_8 alkynyl, a (CH2)r-C3-6 carbocyclic residue
substituted with 0-2 Rye, and a (CH2)r-5-6 membered
heterocyclic system containing 1-4 heteroatoms
selected from N, O, and S, substituted with 0-3 Rye;
R~~, at each occurrence, is selected from C1_6 alkyl, Cz_a
alkenyl, C2_g alkynyl, (CH2)rC3-6 cycloalkyl, Cl, Br, I,
F, (CF2}rCF3, N02, CN, (CH2)rNR~fR7f, (CH2)rOH,
(CH2)rOCl_q alkyl, (CH2)rSCl_4 alkyl, (CH2)rC(0)OH,
(CH2)rC(O)R~b, (CH2)rC(O)NR~fR7f, (CHZ)rNR7fC(0)R7a.
(CHz ) rC (O) OC1_4 alkyl, (CH2 ) rOC (0) R~~',
( CH2 ) rC ( =NR~ f ) NR~ f R7 f ~ ( CH2 ) rS ( O ) pR7b,
CH2 ) rNHC ( =NR~ f ) NR~ f R7 f , ( CH2 ) rS ( O ) 2NR7 fR7 f
(CH2)rNR~fS(O)2R~b, and (CH2)rphenyl substituted with 0-
3 Rye;
Rid, at each occurrence, is selected from C1_6 alkyl
substituted with 0-3 Rye, alkenyl, alkynyl, and a C3_lo
carbocyclic residue substituted with 0-3 R7~;
30
Rye, at each occurrence, is selected from C1_6 alkyl, C2_8
alkenyl, C2_a alkynyl, C3_6 cycloalkyl, C1, F, Br, I,
CN, N02, (CF2)rCF3, (CH2}rOCl_5 alkyl, OH, SH, (CH2)rSCl_
s alkyl . ( CH2 ) rNR~ fR7 f , and ( CH2 ) rPhenyl ;
Ref, at each occurrence, is selected from H, CZ-6 alkyl, and
C3-6 cycloalkyl;
R8 is selected from H, C1_6 alkyl, C3~6 cycloalkyl, and
(CH2)rphenyl substituted with 0-3 Rya;
42


CA 02350730 2001-05-07
WO 00/35451 PCT/US99/30332
R8a, at each occurrence, is selected from C1_6 alkyl, C2_8
alkenyl, C2_8 alkynyl, C3-6 cycloalkyl, Cl, F, Br, I,
CN, N02, (CF2)rCF3, (CH2)rOCl_5 alkyl, OH, SH, {CH2)rSCl_
alkyl, (CH2)rNR~fR~f, and (CH2)rphenyl;
5
alternatively, R~ and R8 join to form C3_~ cycloalkyl, or
=~8b;
R8b is selected from H, C1-6 alkyl, C3_6 cycloalkyl, OH, CN,
and (CH2)r-phenyl;
R9, is selected from H, C1_6 alkyl, C2_g alkenyl, C2_$
alkynyl, F, C1, Br, I, N02, CN, {CH2)rOH, (CH2)rSH,
(CH2)rOR9d, (CH2)rSR9d, (CH2)rNR9aR9a'. (CH2)zC(O)OH,
( CH2 ) rC ( O ) R9t', ( CH2 ) rC ( O ) NR9aR9a' . ( CH2 ) rNR9aC ( 0 ) R9a,
(CH2)rNR9aC(O)H. (CH2)rNR9aC(0)NHR9a, (CH2)rC{O)OR9b,
( CH2 ) rOC ( 0 ) R9b, ( CHZ ) rOC ( 0 ) NHR9°, ( CH2 ) rS ( 0 ) pR9b.
{CH2)=S(O)2NR9aR9a'. (CH2)rNR9aS(O)2R9b, C1-6 haloalkyl,
a (CH2)r-C3-1o carbocyclic residue substituted with 0-5
Rg~, 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, C2_g alkenyl, C2_g alkynyl, a (CH2)r-C3-1o
carbocyclic residue substituted with 0-5 R9e, and a
(CH2)r-5-10 membered heterocyclic system containing 1-4
heteroatoms selected from N, 0, and S, substituted
with 0-3 R9e;
R9b, at each occurrence, is selected from C1_6 alkyl, CZ_8
alkenyl, C2_g alkynyl, a (CHZ)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;
43


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WO 00/35451 PCT/US99/30332,
R9c, at each occurrence, is selected from C1_6 alkyl, C2_$
alkenyl, C2_8 alkynyl, (CH2)rC3-6 cycloalkyl, C1, Br, I,
F. (CF2)rCF3. NO2. CN, (CH2)rNR9fR9f, (CHZ)rOH,
(CH2)rOCl_4 alkyl, (CHZ)rSCl_q alkyl, (CH2)rC(O)OH,
(CH2)rC(0)R9b, (CH2)rC(O)NR9fR9f~ (CH2)rNR9fC(0)R9a.
(CH2)rC(0)OC1_4 alkyl, (CH2)rOC(O)R9b,
(CH2)rC(=NR9f)NR9fR9f~ (CH2)rS(OjpR9b~
(CH2)rNHC(=NR9f)NR9fR9f~ (CH2)rg(0)2NR9fR9f~
(CH2)rNR9fS(O)2R9b, and (CH2)rphenyl substituted with 0-
3 R9e
R9d, at each occurrence, is selected from C1_6 alkyl, C2-6
alkenyl, C2_6 alkynyl, a C3_lo 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, CZ_g
alkenyl, Cz_g alkynyl, (CH2)rC3_6 cycloalkyl, C1, F, Br,
I, CN, N02, (CF2)rCF3, (CH2)rOCl_5 alkyl, OH, SH,
(CH2)rSCl_5 alkyl, (CH2)rNR9fR9f~ and (CH2)=phenyl;
R9f, at each occurrence, is selected from H, C1-6 alkyl, and
C3-6 cycloalkyl;
R10, is selected from H, Cl_6 alkyl, C2_8 alkenyl, C2_8
alkynyl, F, C1, Br, I, N02, CN, (CH2)rOH, (CH2)rORlOd~
(CH2 ) rSRZOd, (CH2 ) r~l0aR10a' . (CH2 ) rC (O) OH,
3 0 ( CH2 ) rC ( 0 ) Rl Ob, ( CH2 ) rC ( O ) NR10aR10a' , ( CH2 ) rNRlOaC ( O
) RlOa
( CH2 ) rNRlOaC ( O ) H , ( CH2 ) rC ( O ) OR 1 Ob ~ ( CH2 ) rOC ( O ) RlOb
(CH2) rS (0) pRlOb, (CH2 ) rS (O) zNR10aR10a' ,
(CH2)rNRlOaS(O)2R10b~ C1-6 haloalkyl, a (CH2)r.-C3_10
carbocyclic residue substituted with 0-5 RlOc, and a
(CH2)r-5-10 membered heterocyclic system containing 1-4
heteroatoms selected from N, 0, and S, substituted
with 0--3 Rloc
44


CA 02350730 2001-05-07
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Rloa and Rloa~, at each occurrence, are selected from H,
alkyl, C2_e alkenyl, C2_8 alkynyl, a (CHz)r-C3-1o
carbocyclic residue substituted with 0-5 Rloe, and a
(CH2)r-5-10 membered,.heterocyclic system containing 1-4
heteroatoms selected from N, 0, and S, substituted
with 0-3 Rloe;
Rlob~ at each occurrence, is selected from Cl_6 alkyl, C
alkenyl, C2_8 alkynyl, a (CH2)r-C3-5 carbocyclic residue
substituted with 0-2 Rloe, and a (CH2)r-5-6 membered
heterocyclic system containing 1-4 heteroatoms
selected from N, O, and S, substituted with 0-3 Rloe
Rloc, at each occurrence, is selected from C1_6 alkyl, C2_8
alkenyl, C2_a alkynyl, (CH2)rC3-6 cycloalkyl, C1, Br, I,
F. (CF2)rCF3, N02. CN, (CH2)rNR10fR10f~ (CH2)rOH,
(CH2)rOCl_q alkyl, (CH2)rSCl_4 alkyl, (CH2)rC(O)OH,
(CH2)rC(O)RlOb, (CH2)rC(O)NR10fR10f~ (CH2)rNRlOfC(O)RlOa~
(CH2) rC (O) OC1_q alkyl, (CHZ ) rOC (O) RlOb,
(CH2)rC(=NRlOf)~lOfRlOf~ {CH2)=S(O)pRlob,
(CH2)rNHC(=NRlOf)~lOfRlOf~ (CH2)rS(O)2NRlOfRlOf~
(CH2)rNRlofS(0)2Rlob, and (CH2)rphenyl substituted with
0-3 RlOe;
Rlod~ at each occurrence, is selected from Cl_6 alkyl, CZ-s
alkenyl, CZ_6 alkynyl, a C3_1o carbocyclic residue
substituted with 0-3 Rloc, and a 5-6 membered
heterocyclic system containing 1-4 heteroatoms
selected from the group consisting of N, 0, and S
substituted with 0-3 Rloc;
Rloe~ at each occurrence, is selected from Cl_6 alkyl, C2
alkenyl, C2_8 alkynyl, (CH2)rC3-6 cYcloalkyl, C1, F, Br,
I, CN, N02, (CF2)rCF3, (CH2)rOCl_5 alkyl, OH, SH,
(CHZ)rSCl_5 alkyl, (CH2)r.NRlofRlOf~ and (CH2)rphenyl;


CA 02350730 2001-05-07
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Rlof~ at each occurrence, is selected from H, C1-6 alkyl,
and C3-6 cycloalkyl;
alternatively, R9 and Rl~ join to form C3_~ cycloalkyl, 5-6-
membered cyclic ketal, or =0;
with the proviso that when R1~ is -OH, R9 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_g alkenyl, C2_8
alkynyl, (CH2 ) qOH, (CH2 ) qSH, (CH2 ) qORlld~ (CH2 ) qSRlld~
(CH2)qNRIIaRIla~~ (CH2)rC(O)OH, (CHZ)rC(O)Rllb~
( CH2 ) rC ( O ) NRllaRlla' , ( CH2 ) qNRllaC ( O ) Rlla
(CHZ)qNRllaC(O)NHRlla~ (CHZ)rC(O)ORllb (CH2)qOC(0)Rllb~
(CH2)qS(O)pRllb~ (CH2)qS(O)2NR11aRlla'~
(CH2) qNRllaS (O) 2R11b~ C1-6 haloalkyl, a (CH2) r-C3-10
carbocyclic residue substituted with 0-5 Rllc, and a
(CH2)r-5-10 membered heterocyclic system containing 1-4
heteroatoms selected from N, O, and S, substituted
with 0-3 Rllc
Rlla ~d Rlla' , at each occurrence, are selected from H, C1_s
alkyl, C2_g alkenyl, C2_g alkynyl, a (CH2)r-C3-10
carbocyclic residue substituted with 0-5 Rlle, and a
(CH2)r-5-10 membered heterocyclic system containing 1-4
heteroatoms selected from N, 0, and S, substituted
with 0-3 Rlle
Rllb, at each occurrence, is selected from C1_6 alkyl, C2_g
alkenyl, C2_g alkynyl, a (CH2)r-C3_6 carbocyclic residue
substituted with 0-2 Rlle~ and a (CH2)r-5-6 membered
heterocyclic system containing 1-4 heteroatoms
selected from N, O, and S, substituted with 0-3 Rlle
Rllc ~ at each occurrence, is selected from Cl_6 alkyl, C2_g
alkenyl, CZ_g alkynyl, (CH2)rC3-s cycloalkyl, C1, Br, I,
46


CA 02350730 2001-05-07
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F, (CF2 ) rCF3 , N02 , CN, ( CH2 ) rNRllfRllf ~ (CH2 ) =OH,
(CH2)rOCl_q alkyl, (CH2}rSCl_4 alkyl, (CH?)rC(0)OH,
(CH2)rC(O)Rilb~ (CH2)rC(O)NRilfRllf~ (CHZ)rNRilfC(O)Rila~
(CH2)rC(0}OCl_4 alkyl, (CH2)rOC(O}Rllb~
(CHZ)rC(=NRilf)~llfRllf~ (CH2)r~C(-NRllf)~11fR11f~
(CH2)rS(p}pRllb~ (CH2)rS(O)2NRilfRllf~
(CH2}rNRllfS(O)2Rllb~ and (CH2)rphenyl substituted with
0-3 Rlle
Rild, at each occurrence, is selected from C1_6 alkyl
substituted with 0-3 Riie, C2-6 alkenyl, C2_6 alkynyl,
and a C3_lo carbocyclic residue substituted with 0-3
Rllc
Riie, at each occurrence, is selected from C1_6 alkyl, C2_8
alkenyl, C2_8 alkynyl, C3_6 cycloalkyl, C1, F, Br, I,
CN, N02, (CF2)rCF3, (CH2)rOCl_5 alkyl, OH, SH, (CH2)rSCl_
5 alkyl, (CH2)rNR11fR11f~ and (CH2)rphenyl;
Riif, at each occurrence, is selected from H, C1_6 alkyl,
and C3_6 cycloalkyl;
R12 is selected from H, C1_6 alkyl, (CH2)qOH, (CH2)rC3_6
cycloalkyl, and (CH2)tphenyl substituted with 0-3 Rl2a;
Ri2a~ at each occurrence, is selected from C1_6 alkyl, C2_g
alkenyl, C2_8 alkynyl, C3_6 cycloalkyl, C1, F, Br, I,
CN, N02, (CF2)rCF3, (CH2)rOCl_5 alkyl, OH, SH, (CH2)rSCl_
5 alkyl, (CH2)rNR9fR9f, and (CH2)rphenyl;
alternatively, Rii and R12 join to form C3_~ cycloalkyl;
Ri3, at each occurrence, is selected from C1_6 alkyl, C2_8
alkenyl, C2_8 alkynyl, C3_6 cycloalkyl, (CF2),",CF3,
(CH2 ) ~13aR13a' ~ (CH,2 ) OH, (CH2 ) ORi3b, (CH2 ) SH,
(CH2)SRl3b, (CHZ)wC(O)OH, (CH2),,,,C(O)Rl3b~
(CH2),",C(O)NR13aR13a'. (CH2)NRl3dC(O)Ri3a~ (CH2)wC(O)ORl3b~
47


CA 02350730 2001-05-07
WO 00/35451 PCT/US9913033~'
(CH2)OC(0)Rl3b, (CH2)wS(O)pRl3b, (CHZ)wS(O)2NR13aR13a'.
(CH2)NRl3dS(O)2RI3b~ and (CH2)w-phenyl Substituted With
0-3 Rl3c;
Rl3a and Rl3a' , at each occurrence, are selected from H, C1_6
alkyl, C3_6 cycloalkyl, and phenyl substituted with 0-3
Rl3c;
Rl3b~ at each occurrence, is selected from C1_6 alkyl, C3_s
cycloalkyl, and phenyl substituted with 0-3 Rl3c;
Rl3c, at each occurrence, is selected from C1_6 alkyl, C3-5
cycloalkyl, C1, F, Br, I, CN, N02, (CF2)rCF3, (CH2)rOCl_
alkyl, (CH2)rOH, (CH2)rSCl_5 alkyl, and
(CH2 ) rj~jR13dR13d~
Rl3d, at each occurrence, is selected from H, C1_6 alkyl,
and C3_6 cycloalkyl;
R15, at each occurrence, is selected from C1_a alkyl,
(CH2)rC3-6 cycloalkyl, C1, Br, I, F, N02, CN,
Cue' ) rNg15aR15a' ~ ( CHR' ) rOH , ( CHR' ) r0 ( CHR' ) rRl 5d
(CHR' ) rSH, (CHR' ) rC (O) H, (CHR' ) rS (CHR~ ) rRlSd,
( CHR' ) rC ( O ) OH, ( CHR' ) rC ( O ) ( CHR' ) rRlSb
(CHR' ) rC (O)NR15aR15a' . (CHR' ) rNRlSfC (O) (CHR' ) =RlSb,
(C~')r~lSfC(O)~15fR15f~ (CHR')rC(O)O(CHR')=RlSd~
( CHR' ) rOC ( 0 ) ( CHR' ) rRlSb ~ ( CHR' ) rC ( =NR15 f ) ~15aR15a'
(CHR')z.NHC(=NRlSf)~l5fRl5f~ (C~')rS(O)p(CHR')rRlSb~
(CHR' ) rS (O) ZNRI5aRl5a'. (CHR' ) rNRl5fS (O) 2 (CHR' ) rRlSb~ C1-5
haloalkyl, C2_8 alkenyl substituted with 0-3 R' , C2_e
alkynyl substituted with 0-3 R', (CHR')rphenyl
substituted with 0-3 Rlse~ and a (CH2)r-5-10 membered
heterocyclic system containing 1-4 heteroatoms
selected from N, O, and S, substituted with 0-2 RlSe;
48


CA 02350730 2001-05-07
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R', at each occurrence, is selected from H, C1_6 alkyl, C2_g
alkenyl, C2_g alkynyl, (CH2)rC3-6 cycloalkyl, and
(CH2)rphenyl substituted with RlSe;
RlSa ~d RlSa' ~ at each occurrence, are selected from H, C1_6
alkyl, C2_B alkenyl, C2_e alkynyl, a (CH2)r-C3-10
carbocyclic residue substituted with 0-5 RlSe, and a
(CH2)r-5-10 membered heterocyclic system containing 1-4
heteroatoms selected from N, 0, and S, substituted
with 0-2 RlSe
RlSb~ at each occurrence, is selected from C1_6 alkyl, C2_8
alkenyl, C2_8 alkynyl, a (CH2)r-C3-6 carbocyclic residue
substituted with 0-3 RlSe, and (CH2)r-5-s membered
heterocyclic system containing Z-4 heteroatoms
selected from N, O, and S, substituted with 0-2 RZ5e
RlSd~ at each occurrence, is selected from C2_8 alkenyl,
alkynyl, C1_6 alkyl substituted with 0-3 Rise, a
(CH2)r-C3-1o carbocyclic residue substituted with 0-3
RlSe, and a (CH2)r5-6 membered heterocyclic system
containing 1-4 heteroatoms selected from N, O, and S,
substituted with 0-3 Rl5e
RlSe~ at each occurrence, is selected from C1_6 alkyl, CZ_s
alkenyl, C2_8 alkynyl, (CH2)rC3-s cYcloalkyl, C1, F, Br,
I. CN, NO2, (CF2)rCF3, (CH2)rOCl-5 alkyl, OH, SH,
(CH2)rSCl_5 alkyl, (CH2)rNR15fR15f~ and (CH2)rphenyl;
RlSf, at each occurrence, is selected from H, C1_6 alkyl,
Cs-6 cycloalkyl, and phenyl;
R16, at each occurrence, is selected from C1_8 alkyl, C2_g
alkenyl, C2_8 alkynyl, (CHZ)rC3-s cYcloalkyl, C1, Br, I,
F, N02, CN, (CHR')rNR16aR16a', (C~')rOH,
(CHR')=O(CHR')rRi6d, (CHR')rSH, (CHR')rC(O)H,
(CHR' ) rS (CHR' ) rRl6d~ (C~' ) rC (0) OH,
49


CA 02350730 2001-05-07
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(CHR')rC(O)(CHR')rRl6b, (CHR')rC(O)NR16aR16a'~
(CHR' ) rNRl6fC (O) (CHR' ) rRl6b, (CHR' ) rC (O) O (CHR' ) rRl6d~
( CHR' ) rOC ( 0 ) ( CHR' ) rRl6b ~ ( CHR' ) rC ( =NR16 f ) NR16aR16a'
( CHR' ) rNHC ( =NR16 f ) NR16 fRl6 f ~ ( CHR' ) rS ( O ) p ( CHR' ) rRl6b
(CHR')rS(O)2NR16aR16a'. (CHR')rNRl6fS(O)2(CHR')rRl6b~ 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 Rl6e;
Rl6a and Rl6a', at each occurrence, are selected from H, C1-6
alkyl, C2_g alkenyl, C2_g alkynyl, a (CH2)r-C3-l0
carbocyclic residue substituted with 0-5 Rlse~ and a
(CH2)r-5-.IO membered heterocyclic system containing 1--4
heteroatoms selected from N, O, and S, substituted
with 0-2 Rl6e;
Rl6b~ at each occurrence, is selected from C1_6 alkyl, C2_e
alkenyl, C2_g alkynyl, a (CH2)rC3-6 carbocyclic residue
substituted with 0-3 Rl6e, and a (CH2)r-5-6 membered
heterocyclic system containing 1-4 heteroatoms
selected from N, O, and S, substituted with 0-2 Rl6e;
Rl6d~ at each occurrence, is selected from C2_B alkenyl, CZ_8
alkynyl, C1_6 alkyl substituted with 0-3 Rlse~ a
(CH2)r-C3-to carbocyclic residue substituted with 0-3
Rl6e~ ~d a (CH2)r-5-6 membered heterocyclic system
containing 1-4 heteroatoms selected from N, O, and S,
substituted with 0-3 Rl6e.
Rl6e, at each occurrence, is selected from Cl_6 alkyl, C2_8
alkenyl, C2_8 alkynyl, (CH2)rC3-6 cYcloalkyl, C1, F, Br,
I, CN, N02, (CFZ)rCF3, (CH2)rOCl_5 alkyl, OH, SH,
(CHZ)rSCl-5 alkyl, (CH2)rNR16fR16f~ and (CH2)rphenyl;
Rl6f, at each occurrence, is selected from H, C1-5 alkyl,
and C3_6 cycloalkyl, and phenyl;


CA 02350730 2001-05-07
WO 00/35451 PCT/US99/30332
v is selected from 0, 1, and 2;
t is selected from 1 and 2;
w is selected from 0 and~.l;
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 1, 2, and 3.
[20l In a preferred embodiment, the present invention
provides novel compounds of formula (I), wherein:
R4 is absent, taken with the nitrogen to which it is
attached to form an N-oxide, or selected from C1_e
alkyl, (CHZ)rC3-5 cycloalkyl, and (CH2)r-phenyl
substituted with 0-3 R4c;
R4c, at each occurrence, is selected from C1_6 alkyl, C2_8
alkenyl, C2_8 alkynyl, C3-6 cycloalkyl, Cl, F, Br, I,
CN, N02, (CF2)rCF3, (CH2)rOCl_5 alkyl, (CH2)rOH,
(CH2)rSCl_5 alkyl, (CH2)=NR4aR4a'~ and (CH2)=phenyl;
alternatively, R4 joins with R~, R9, or R11 to form a 5, 6
or 7 membered piperidinium spirocycle or pyrrolidinium
spirocycle substituted with 0-3 Ra;
R1 and R2 are independently selected from H and C1_q alkyl;
R6, at each occurrence, is selected from Cl_4 alkyl, C2_8
alkenyl, C2_g 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 Rsc;
51


CA 02350730 2001-05-07
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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, C1, F, Br, I, CN, N02, (CF2)rCF3, (CH2)rOCl-
5 alkyl, (CH2)rOH, (CH2)rSCl_5 alkyl, and (CH2)rNR6dR6d~
R6a, at each occurrence, is selected from H, C1_6 alkyl, and
C3-6 cycloalkyl;
R~, is selected from H, C1_3 alkyl, (CH2)rC3-s cycloalkyl,
(CH2)qOH, (CH2)qOR~d, (CH2)qNR?aR7a', (CH2)rC(0)R~b,
(CH2)rC(O)NR~aR7a', (CH2)qNR~aC(O)R~a, C1_6 haloalkyl,
(CHZ)rphenyl with 0-2 Roc;
Rya and Rya', at each occurrence, are selected from H, C1
alkyl, (CH2)rC3-6 cYcloalkyl, a (CH2)rphenyl
substituted with 0-3 Rye;
Rib, at each occurrence, is selected from C1_6 alkyl, CZ_g
alkenyl, C2_g alkynyl, (CH2)rC3-5 cycloalkyl,
(CH2)rPhenyl substituted with 0-3 Rye;
Roc, at each occurrence, is selected from C1_4 alkyl, C2_g
alkenyl, C2_8 alkynyl, (CH2)rC3-6 cycloalkyl, C1, Br, I,
F, (CF2)rCF3, N02, CN, (CHz)rNR~fR7f, (CH2)rOH,
(CHZ)rOCl_4 alkyl, (CH2)rC(O)R~b, (CH2)rC{O)NR~fR7f~
(CH2)rNR~fC(O)R~a, (CH2)rS(O)pR7b~ (CH2)rS(O)2NR7fR7f~
(CH2)rNR~fS(0)2R~b, and (CHZ)rphenyl substituted with 0-
2 Rye;
52


CA 02350730 2001-05-07
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Rid, at each occurrence, is selected from C1_6 alkyl,
(CH2)rC3-6 cYcloalkyl, (CH2)rphenyl substituted with 0-
3 Rye;
Rye, at each occurrence, is selected from C1_6 alkyl, C
alkenyl, C2_8 alkynyl, C3_6 cycloalkyl, Cl, F, Br, I,
CN, N02. (CF2)rCF3. (CH2)rOCl_5 alkyl, OH, SH, (CH2)rSCl_
5 alkyl , ( CH2 ) rNR~ fR~ f , and ( CH2 ) =phenyl ;
Ref, at each occurrence, is selected from H, C1_5 alkyl, and
C3-6 cycloalkyl;
RB is H or joins with R~ to form C3_~ cycloalkyl or =NReb;
R11, is selected from H, C1_6 alkyl, (CH2)rC3-6 cYcloalkyl,
(CH2)qOH, (CH2)qORlld, (CH2)qNRllaRlla'~ (CH2)rC(0)Rllb~
(CH2 ) rC (O) NRllaRlla~ ~ (CH2 ) qNRllaC (O) Rlla~ C1-6 haloalkyl,
(CH2)rphenyl with 0-2 Rllc~ (CH2)r-5-10 membered
heterocyclic system containing 1-4 heteroatoms
selected from N, O, and S, substituted with 0-3 R15;
Rlla and Rlla~, at each occurrence, are selected from H, C1_s
alkyl, (CH2)rC3-6 cYcloalkyl, a (CH2)rphenyl
substituted with 0-3 Rlle.
Rllb~ at each occurrence, is selected from C1_6 alkyl, C
alkenyl, C2_g alkynyl, (CH2)rC3-s cYcloalkyl,
(CH2)rphenyl substituted with 0-3 Rlle
Rllc, at each occurrence, is selected from C1_4 alkyl, C2_8
alkenyl, C2_8 alkynyl, (CH2)rC3-6 cycloalkyl, C1, Br, I,
F. (CFZ)rCF3, N02, CN, (CH2)rNRllfRllf~ (CH2)=OH,
(CHZ)rOCl_q alkyl, (CH2)=C(O)Rllb, (CH2)rC(O)NRllfRllf~
(CH2)rNRllfC(O)Rlla~ (CH2)rS(0)pRllb~
(CHZ ) rS (0) 2NR11fRllf ~ (CH2 ) rNRllfS (O) 2Rllb~ arid
(CH2)rphenyl substituted with 0-2 Rlle;
53


CA 02350730 2001-05-07
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Rlld, at each occurrence, is selected from C1_6 alkyl,
(CH2)rC3-5 cYcloalkyl, (CH2)rphenyl substituted with 0-
3 Rlle
Rlle, at each occurrence,~is selected from C1_6 alkyl, C
alkenyl, C2_8 alkynyl, C3_6 cycloalkyl, C1, F, Br, I,
CN, N02, (CF2)rCF3, (CHZ)rOC1_5 alkyl, OH, SH, (CH2)rSC1_
5 alkyl, (CH2)rNR11fR11f~ and (CH2)rphenyl;
Rllf, at each occurrence, is selected from H, C1_5 alkyl and
C3_6 cycloalkyl;
R12 is H or joins with R11 to form C3_~ cycloalkyl;
R13, at each occurrence, is selected from C1_4 alkyl, C3-s
cycloalkyl, (CH2 ) NR13aR13a' , (CH2 ) pH, (CH2 ) ORl3b~
(CH2)~,,C(0)Rl3b~ (CH2)'",C(O)NR13aR13a'. (CH2)NRl3dC(O)Rl3a~
(CH2 ) wS (0) 2NR13aR13a' ~ (CH2 ) NRl3dS (O) ZRl3b~ and
(CH2)W-phenyl substituted with 0-3 Rl3c;
Rl3a and Rl3a' , at each occurrence, are selected from H, C1-6
alkyl, C3_6 cycloalkyl, and phenyl substituted with 0-3
Rl3c
Rl3b~ at each occurrence, is selected from C1_6 alkyl, C3-6
cycloalkyl, and phenyl substituted with 0-3 Rl3c;
Rl3c~ at each occurrence, is selected from C1_6 alkyl, C3-s
cycloalkyl, C1, F, Br, I, CN, N02, (CF2)rCF3, (CH2)rOC1_
5 alkyl, (CH2)rOH, arid (CH2)rNR13dR13d~
Rl3d~ at each occurrence, is selected from H, C1_6 alkyl,
and C3_6 cycloalkyl;
v is selected from 1 and 2;
q is selected from 1, 2, and 3; and
54
..


CA 02350730 2001-05-07
WO OOI35451 PCTNS99/30332
r is selected from 0, l, 2, and 3.
[21] In a more preferred embodiment, the present invention
provides novel compounds of formula (I), wherein:
R3 is selected from 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,
25 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 (CRS'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, isoindolyl, piperidinyl, pyrrazolyl, 1,2,4-
triazolyl, 1,2,3-triazolyl, tetrazolyl, thiazolyl,
oxazolyl, pyrazinyl, and pyrirnidinyl.
[22] In an even more preferred embodiment, the present
invention provides novel compounds of formula (I-i),
wherein the compound of formula (I-i) is:


CA 02350730 2001-05-07
WO 00/35451 PCT/US99/30332
Z
J II
K ~N-E-N~N-R3
H H
(I-i)
R16, at each occurrence, is selected from C1_g alkyl,
(CH2)rC3-6 cycloalkyl, CF3, C1, Br, I, F,
(CHZ)rNR16aR16a' N02~ CN, OH, (CH2)rORl6d~
(CH2)rC(O)Rl6br (CH2)rC(O)NR16aR16a'. (CH2)rNRl6fC(O)Rl6b~
(CH2)rS(O)pRl6b~ (CH2)rS(O)2NR16aR16a'.
(CH2)rNRl6fs(O)2R16b~ and (CH2)rphenyl substituted with
0-3 Rl6e
Rl6a and Rl6a', at each occurrence, are selected from H, C1-6
alkyl, C3_6 cycloalkyl, and (CHZ)rphenyl substituted
with 0-3 Rl6e
Rl6b, at each occurrence, is selected from H, C1_6 alkyl,
C3_6 cycloalkyl, and (CH2)rphenyl substituted with 0-3
Rl6e.
Rl6d, at each occurrence, is selected from C1_6 alkyl and
phenyl;
Rl6e~ at each occurrence, is selected from C1_6 alkyl, C1,
F, Br, I, CN, N02, (CF2)rCF3, OH, and (CH2)rOCl_5 alkyl;
and
Rl6f~ at each occurrence, is selected from H, and C1_~
alkyl.
[23] In another even more preferred embodiment, the
present invention provides novel compounds of formula (I-
ii), wherein the compound formula (I-ii) is:
Z
K~ -E-N~NvRs
H H
56


CA 02350730 2001-05-07
WO 00/35451 PCT/US99/30332
(I-ii)
R16, at each occurrence, is selected from C1_$ alkyl,
(CH2)rC3-6 cYcloalkyl, CF3, C1, Br, I, F,
(CH2 ) rNR16aR16a' ~ N02 ~ CN, OH, (CH2 ) rORl6d~
( CH2 ) rC ( O ) Rl6b, ( CH2 ) rC ( O ) NR16aR16a' . ( CH2 ) rNRl6 f C ( 0 )
Rl6b
(CH2 ) rS (O)pRl6b~ (CH2 ) rS (O) 2NR16aR16a'.
(CHZ)rNRl6fS(O)2R16b~ and (CH2)rphenyl substituted with
0-3 Rl6e;
Rl6a and Rlsa~, at each occurrence, are selected from H, C1_6
alkyl, C3_6 cycloalkyl, and (CH2)rphenyl substituted
with 0-3 Rl6e;
Rlsb~ at each occurrence, is selected from H, C1_6 alkyl,
C3_6 cycloalkyl, and (CH2)rphenyl substituted with 0-3
Rl6e
Rl6d~ at each occurrence, is selected from C1_6 alkyl and
phenyl;
Rl6e~ at each occurrence, is selected from C1_6 alkyl, C1,
F, Br, I, CN, N02, (CF2)rCF3, OH, and (CH2)rOCl_5 alkyl;
and
Rl6f, at each occurrence, is selected from H, and C1-5
alkyl.
[24] In a preferred embodiment, the present invention
provides novel compounds of formula (I-i) wherein:
R5 is CH2phenyl substituted with 0-3 R16;
E is -CH2- (CR9R1~) - (CR11R12 )
R9, is selected from H, C1_6 alkyl, (CH2)rC3-6 cYcloalkyl, F,
C1, CN, (CH2)rOH, (CH2)rO.R9d, (CH2)rNR9aR9a'~
S7


CA 02350730 2001-05-07
WO OOI35451
PCT/US99/3033?
(CH~)rOC(O)NHR9°, (CH2)rphenyl substituted with 0-5 R9e,
and a heterocyclic system substituted with 0-2 R9e,
wherein the heterocyclic system is selected from
pyridyl, thiophenyl, furanyl, oxazolyl, and thiazolyl;
R9a and R9a', at each occurrence, are selected from H, C1-6
alkyl, C3_6 cycloalkyl, and (CH2)rphenyl substituted
with 0-3 R9e;
R9d, at each occurrence, is selected from C1_6 alkyl and
phenyl;
R9e, at each occurrence, is selected from C1_6 alkyl, C1, F,
Br, I, CN, N02, (CFZ)rCF3, OH, and (CH2)rOCl_5 alkyl;
R1~ is selected from H, C1_5 alkyl, OH, and CH20H;
alternatively, R9 and R1~ join to form C3_~ cycloalkyl, 5-6-
membered cyclic ketal or =O;
with the proviso that when Rlo is -OH, R9 is not halogen,
cyano, or bonded to the carbon to which it is attached
through a heteroatom;
R11 is selected from H, C1_8 alkyl, (CH2)rphenyl substituted
with 0-5 Rlle, and a (CH2)r-heterocyclic system
substituted with 0-2 Rlie~ 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
Rlle~ at each occurrence, is selected from CI_6 alkyl, Cl,
F, Br, I, CN, N02, (CF2)rCF3, OH, and (CH2)~OC~_5 alkyl;
58


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R12 is H;
alternatively, R11 and R12 join to form C3_~ cycloalkyl; and
r is selected from 0, 1, and 2.
[25]. In another preferred embodiment, the present
invention provides novel compounds of formula (I-ii),
wherein:
R5 is CH2phenyl substituted with 0-3 R16;
E is -CH2- (CR9R1~) - (CR11R12 )
R9, is selected from H, C1_6 alkyl, (CH2)rC3-6 cycloalkyl, F,
C1, CN, (CH2)rOH, (CH2)rOR9d, (CH2)=NR9aR9a',
(CHz) rOC (0)NHR'°, (CH2) rphenyl substituted with 0-5 R9e,
and a heterocyclic system substituted with 0-2 R9e,
wherein the heterocyclic system is selected from
pyridyl, thiophenyl, furanyl, oxazolyl, and thiazolyl;
R9a and R9a', at each occurrence, are selected from H, C1_6
alkyl, C3_6 cycloalkyl, and :.'.HZ)rphenyl substituted
with 0-3 R9e;
R9d, at each occurrence, is selected from C1_6 alkyl and
phenyl;
R9e, at each occurrence, is selected from C1_6 alkyl, C1, F,
Br, I, CN, N02, (CF2)rCF" OH, and (CH2)rOCl_5 alkyl;
R1~ is selected from H, C1_g alkyl, OH, and CH20H;
alternatively, R9 and R1~ join to form C3_~ cycloalkyl, 5-6-
membered cyclic ketal or =O;
59


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with the proviso that when Rlo is -OH, R9 is not halogen,
cyano, or bonded to the carbon to which it is attached
through a heteroatom;
R11 is selected from H, Ci_g alkyl, (CH2)rphenyl substituted
with 0-5 Rlle~ and a (CH2)r-heterocyclic system
substituted with 0-2 Rlle, 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
Rlle~ at each occurrence, is selected from C1_6 alkyl, C1,
F, Br, I, CN, N02, (CF2)rCF3, OH, and (CH2)rOCl_5 alkyl;
R12 is H;
alternatively, R11 and R12 join to form C3_~ cycloalkyl; and
r is selected from 0, 1, and 2.
[26] In a more preferred embodiment, the present invention
provides novel compounds of formula (I-i), wherein:
J is selected from CH2 and CHRS;
K is selected from CHZ and CHRS;
L is selected from CH2 and CHRS;
R3 is a C3_lo carbocyclic residue substituted with 0-3 R15,
wherein the carbocyclic residue is selected from
cyclopropyl, cyclopentyl, cyclohexyl, phenyl, naphthyl
and adamantyl, and a (CR3'H)r-heterocyclic system


CA 02350730 2001-05-07
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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-triazolyi,
1,2,3-triazolyl, tetrazolyl, thiadiazolyl, thiazolyl,
oxazolyl, pyrazinyi, and pyrimidinyl; and
R15, at each occurrence, is selected from C1_8 alkyl,
(CH2)rC3_6 cycloalkyl, CF3, C1, Br, I, F,
(CH2)rNR15aR15a'~ Np2~ CN, OH, (CHZ)rORl5d~
(CH2)rC(O)RlSb~ (CH2)rC(O)NR15aR15a', (CH2)rNRlSfC(O)RlSb~
(CH2)rS(O)pRlSb~ (CH2)rS(O)2NR15aR15a'.
(CH2)rNRl5fS(O)2R15b~ (CH2)rphenyl substituted with 0-3
RlSe~ and a (CH2)r-5-6 membered heterocyclic system
containing 1-4 heteroatoms selected from N, O, and S,
substituted with 0-2 RlSe.
RlSa ~d RlSa' ~ at each occurrence, are selected from H, C1_6
alkyl, C3_6 cycloalkyl, and (CH2)rphenyl substituted
with 0-3 RlSe
RISb~ at each occurrence, is selected from H, C1_6 alkyl,
C3_6 cycloalkyl, and (CH2)rphenyl substituted with 0-3
RlSe
RlSd, at each occurrence, is selected from C1_6 alkyl and
phenyl;
RlSe~ at each occurrence, is selected from C1_6 alkyl, C1~
F, Br, I, CN, N02, (CF2)rCF3, OH, and (CH2)rOCl_5 alkyl;
and
RlSf~ at each oecurrence, is selected from H, and C1-5
alkyl.
61


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[27] In another more preferred embodiment, the present
invention provides novel compounds of formula (I-ii),
wherein:
K is selected from CHz and CHRS;
L is selected from CH2 and CHRS;
R3 is a C3_lo carbocyclic residue substituted with 0-3 R15,
wherein the carbocyclic residue is selected from
cyclopropyl, 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, benzoxazolyi,
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
R15, at each occurrence, is selected from C1_8 alkyl,
(CH2)rC3-6 cYcloalkyl, CF3, C1, Br, I, F,
( CH2 ) rNR15aR15a' ~ N02 , CN, OH, ( CH2 ) rORlSd
( CHz ) rC ( 0 ) RlSb ~ ( CH2 ) rC ( O ) NR15aR15a' ~ ( CH2 ) rNRlS fC ( O )
RlSb
(CHZ)rS(O)pRlSb~ (CH2)rS(0)2NR15aR15a'.
(CH2)r~lSfS(O)2R15b~ (CH2)rphenyl substituted with 0-3
RlSe~ ~d a (CH2)r-5-6 membered heterocyclic system
containing 1-4 heteroatoms selected from N, O, and S,
substituted with 0-2 RlSe
RlSa and RlSa'~ at each occurrence, are selected from H, C1-6
alkyl, C3_6 cycloalkyl, and (CH2)rphenyl substituted
with 0-3 RlSe;
62


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RlSb~ at each occurrence, is selected from H, C1_6 alkyl,
C3_6 cycloalkyl, and (CH2)rphenyl substituted with 0-3
RlSe
RlSd, at each occurrence, is selected from C1_6 alkyl and
phenyl;
RlSe~ at each occurrence, is selected from C1_6 alkyl, C1,
F, Br, I, CN, N02, (CF2)rCF3, OH, and (CH2)rOCl-5 alkyl;
and
RlSf~ at each occurrence, is selected from H, and C1-5
alkyl.
(28] In a further even more preferred embodiment, the
present invention provides,novel compounds of formula (I)
and pharmaceutically acceptable salt forms thereof, wherein
the compound of formula I is selected from:
N"-cyano-N-(3-methoxyphenyl)-N'-[3-[4-(phenylmethyl)-1-
piperidinyl]propyl]guanidine,
N"-cyano-N-(3-methoxyphenyl)-N~-[3-[4-(4-
fluorophenylmethyl)-1-piperidinyl]propyl]guanidine.
N-(3-acetylphenyl)- N"-cyano-N'-[3-[4-(4-
fluorophenylmethyl)-1-piperidinyl]propyl]guanidine,
N-(3-acetylphenyl)-N"-cyano-N'-(3-[(3S)-3-(4-
fluorobenzyl)piperidinyl]propyl}guanidine,
N" -cyano-N- ( 3 , 5-diacetylphenyl ) -N' - { 3 - [ ( 3 S) -3 - ( 4-
fluorobenzyl)piperidinyl]propyl}guanidine,
N"-cyano-N-{3-((3S)-3-(4-fluorobenzyl)piperidinyl]propyl}-
N'-[3-(1-methyl-1H-tetraazol-5-yl)phenyl]guanidine,
N"-cyano-N- (2, 4-dimethoxyphenyl) -N'-(3- [ (3S) -3- (4-
fluorobenzyl)piperidinyl]propyl}guanidine,
63


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N-(5-acetyl-2-methoxyphenyl)-N"-cyano-N'-{3-[(3S)-3-(4-
fluorobenzyl)piperidinyl]propyl}guanidine,
N-(3-acetylphenyl)-N"-cya~o-N'-{(3R, 4R)-5-[4-(4-
fluorobenzyl)piperidinyl]-4-hydroxy-1-methyl-3-
pentyl}guanidine,
N"-cyano-N-{3- [ (3S) -3- (4-fluorobenzyl)piperidinyl] -2- (2E) -
propenyl}-N'-[3-(1-methyl-1H-tetraazol-5-
yl)phenyl]guanidine,
2-[(3-acetylanilino)((3-[(4-(4-
fluorobenzyl)piperidinyl]propyl}amino)methylene]malono
nitrile,
2-[ (3-acetylanilino) ({3-[ (3S)-3-(4-
fluorobenzyl)piperidinyl]propyl}amino)methylene]malono
nitrile,
2- [ [3- (1-methyl-1H-tetrazol-5-yl) anilino] ( {3- [ (3S) -3- (4-
fluorobenzyl)piperidinyl]propyl}amino)methylene]malono
nitrile,
N- [ (E) - (3-acetylanilino) ( {3- [ (3S) -3- (4-
fluorobenzyl)piperidinyl]propyl}amino)methylidene]urea
N- [ (E) - (3, 5-diacetylanilino) ( (3- j (3S) -3- (4-
fluorobenzyl)piperidinyl]propyl}amino)methylidene]urea
N-[(E)-[3-(1-methyl-1H-tetrazol-5-yl)anilino]{{3-[(3S)-3-
(4-
fluorobenzyl)piperidinyl]propyl}amino)methylidene]urea
64


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Methyl (E) - (3, 5-diacetylanilino) ( (3- [ (3S) -3- (4-
fluorobenzyl)piperidinyl]propyl}amino)methylidenecarba
mate,
1-(3-([(E)-1-({3-[4-(4-
fluorobenzyl)piperidinyl]propyl}amino)-2-
nitroethenyl)amino}phenyl)ethanone, and
1-(3-{ [ (E)-1-({3-[ (3S)-3-(4-
fluorobenzyl)piperidinyl]propyl}amino)-2-
nitroethenyl]amino}phenyl)ethanone.
(29] In another embodiment, the present invention provides
novel compounds of formula (I):
_R3
2 0 L-O
(I)
or stereoisomers or pharmaceutically acceptable salts
thereof, wherein:
M is absent or selected from CH2, CHRS, CHR13, CR13R13, and
CRSR13~
Q is selected from CH2, CHR5, CHR13, CR13R13, and CR5R13;
J, K, and L are independently selected from CH2, CHRS, CHR6,
CR6R6 and CR5R6;
with the provisos:
1) at least one of M, J, K, L, or Q contains an R5;
and


CA 02350730 2001-05-07
WO 00/35451 PCT/US99/30332
2) when M is absent, J is selected from CH2, CHRS,
CHR13 , and CRSRI3
Z is selected from NRla, CHCN, CHNOz, and C(CN)2;
Rla is selected from H, C1_6 alkyl, C3_6 cycloalkyl,
CONRIbRI,b ~ pRib , CN, NOZ , and ( CH2 ) Wphenyl ;
Rlb is independently selected from H, C1_3 alkyl, C3_s
cycloalkyl, and phenyl;
E is selected from:
7 R8 11 12
R~ a ~ s
A A A
(R14)s (R14)g R9 ~R1° (R14)g Rs ~io (R14)g
11 12 s 10 ~ Rg 9 10
A ~ A Rii R12 A 11 R12
(R 14)g (R 14)9 (R 14)9
9 10
a 11 R12 ~ s R s Rs Rio
X11 R12
R R9~Rio '~
~R 14)g ' R R 1 ° ~R 14~g , (R 14)g r and
R~ g s 10 11812
R ~1° A _
~-'~ 14)
9
ring A is a C3_6 carbocyclic residue;
R1 and RZ are independently selected from H, C~~6 alkyl,
alkenyl, C2_g alkynyl, (CH2)rC3_6 cycloalkyl, and a
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(CH2)r-C3-1o carbocyclic residue substituted with 0-5
Ra;
Ra, at each occurrence, is selected from C1_6 alkyl, C2_g
alkenyl, C2_g alkynyl, (CH2)rC3-6 cYcloalkyl, C1, Br, I,
F, (CF2)rCF3. NO2, CN, (CH2)rNRbRb. (CH2)rOH, (CH2)rOR~,
(CH2)rSH, (CH2)rSR~, (CH2)rC(O)Rb, (CH2)rC(O)NRbRb,
( CH2 ) rNRbC ( O ) R~', ( CH2 ) rC ( O ) ORb, ( CH2 ) rOC ( O ) R~ ,
( CH2 ) rCH ( =NR~' ) NRr'Rb , ( CH2 ) rNHC ( =NRb ) NRbRb , ( CH2 ) r S ( 0 )
pR~ ,
(CH2)rS(O)2NRbRb, (CH2)rNRbS(O)2R~, and (CH2)rphenyl;
Rb, at each occurrence, is selected from H, C1-6 alkyl, C3-6
cycloalkyl, and phenyl;
Rte, at each occurrence, is selected from C1_6 alkyl, C3-6
cycloalkyl, and phenyl;
alternatively, R2 and R3 join to form a 5, 6, or 7-membered
ring substituted with 0-3 Ra;
R3 is selected from a (CR3'R3")r-C3-so carbocyclic residue
substituted with 0-5 R15 and a (CR3'R3")r-5-10 mernbered
heterocyclic system containing 1-4 heteroatoms
selected from N, O, and S, substituted with 0-3 R15;
R3' and R3", at each occurrence, are selected from H, C1_6
alkyl, (CH2)rC3-6 cycloalkyl, and phenyl;
R4 is absent, taken with the nitrogen to which it is
attached to form an N-oxide, or selected from C1_6
alkyl, C2_8 alkenyl, C2_8 alkynyl, (CH2)rC3-s
cycloalkyl, (CH2)qC(O)R4b, (CH2)qC(0)NR4aR4a'~
(CH2 ) qC (O) OR4b, and a (CH2 ) r-C3-io carbocyclic residue
substituted with 0-3 Rq~;
R4a and R4a', at each occurrence, are selected from H, C1_6
alkyl, (CH2)rC3-6 cYcloalkyl, and phenyl;
6~


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R4b, at each occurrence, is selected from C1_6 alkyl, CZ_8
,alkenyl, (CH2)rC3-6 cYcloalkyl, C2_g alkynyl, and
phenyl;
R4c, at each occurrence, is selected from C1_6 alkyl, C2_g
alkenyl, C2_e alkynyl, C3_6 cycloalkyl, C1, F, Br, I,
CN, N02, (CFZ)rCF3, (CH2)rOCl_5 alkyl, (CHZ)=OH,
(CH2)rSCl_5 alkyl, (CH2)rNR4aR4a', and (CH2)rphenyl;
alternatively, R4 joins with R~, R9, or R11 to form a 5, 6
or 7 membered piperidinium spirocycle or pyrrolidinium
spirocycle substituted with 0-3 Ra;
15 R5 is selected from a (CRS'R5")t-C3_1o carbocyclic residue
substituted with 0-5 R16 and a (CRS'R5")t-5-10 membered
heterocyclic system containing 1-4 heteroatoms
selected from N, O, and S, substituted with 0-3 Rls;
20 R5' and RS", at each occurrence, are selected from H, C1_s
alkyl, (CH2)rC3-5 cycloalkyl, and phenyl;
R6, at each occurrence, is selected from C1_6 alkyl, C2_g
alkenul, CZ_8 alkynyl, (CH2)rC3-6 cYcloalkyl, (CF2)rCF3,
CN, (CHz)rNR6aR6a', (CH2)rOH, (CH2)rOR6b, (CH2)rSH,
(CH2)rSR6b, (CH2)rC(O)OH, (CH2)=C{O)R6b,
(CH2)rC(O)NR6aR6a'. (CH2)rNR6dC(O)R6a, {CH2)rC(O)OR6b,
{CH2)zOC{O)R6b, (CHZ)rS(O)pR6b, {CH2)rS(O)2NR6aR6a'.
(CH2)rNR6aS(O)2R6b, and (CH2)tphenyl substituted with 0-
3 R6c;
R6a and R6a', at each occurrence, are selected from H, C1
alkyl, C3_6 cycloalkyl, and phenyl substituted with 0-3
R6c;
R6b, at each occurrence, is selected from C1_6 alkyl, C3_s
cycloalkyl, a.nd phenyl substituted with 0-3 R6c;
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R6~, at each occurrence, is selected from C1_6 alkyl, C3-6
cycloalkyl, C1, F, Br, I, CN, N02, (CF2)rCF3, (CH2)rOCl_
alkyl, (CH2)rOH, (CH2)rSCl_5 alkyl, and (CH2)rNR6dR6d;
5
R6d, at each occurrence, is selected from H, C1_6 alkyl, and
C3-6 cycloalkyl;
R~, is selected from H, C1-6 alkyl, Cz_8 alkenyl, C2_g
alkynyl, (CH2)qOH, (CH2)qSH, (CH2)qOR~d, (CHZ)qSR~d,
( CH2 ) qNR~aR7a' , ( CH2 ) rC ( O ) OH, ( CH2 ) rC ( O ) R~1',
(CH2)rC(O)NR~aR7a', (CH2)qNR~aC(O)R~a, (CH2)qNR~aC(O)H.
(CH2)rC(O)OR~b, (CH2)qOC{O)R~b, (CH2)qS(O)pR~b,
(CH2)qS(O)2NR~aR7a'. (CH2)qNR~aS(O)ZR7b, C1_6 haloalkyl,
a (CH2)r-C3-1o carbocyclic residue substituted with 0-3
R~~, and a (CH2)r-5-10 membered heterocyclic system
containing 1-4 heteroatoms selected from N, O, and S,
substituted with 0-2 R~~;
Rya and Rya' , at each occurrence, are selected from H, C~_6
alkyl, C2_g alkenyl, C2_8 alkynyl, (CH2)rC3-6
cycloalkyl, a (CH2)r-C3-1o carbocyclic residue
substituted with 0-5 Rye, and a (CH2)r-5-10 membered
heterocyclic system containing 1-4 heteroatoms
selected from N, O, and S, substituted with 0-3 Rye;
Rib, at each occurrence, is selected from C1_6 alkyl, C2_8
alkenyl, C2_a alkynyl, a (CH2)r-C3-6 carbocyclic residue
substituted with 0-2 Rye, and a (CH2)r-5-6 membered
heterocyclic system containing 1-4 heteroatoms
selected from N, O, and S, substituted with 0-3 Rye;
R~~, at each occurrence, is selected from C1-6 alkyl, C2_e
alkenyl, C2_8 alkynyl, (CfI~) rC3_6 cycloalkyl, C1, Br, I,
F, (CF2)rCF3. N02, CN, (CH2)rNR~fR7f, (CH2)rOH,
(CH2)~OC1_4 alkyl, (CHz)rSC1-4 alkyl, (CH2)rC{O)OH,
(CH2)rC(O)R~b, (CH2)=C(O)NR~fR7f, (CH2)rNR~fC(O)R7a~
69


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(CH2)rC(O)OC1_4 alkyl, (CH2)rOC(O)R~b,
(CH2)rC(=NR7f)NR~fR7f~ (CH2}rS(O)pR7b~
(CH2)rNHC(-NR7f)NR7fR7f~ (CH2)rS(O)2NR7fR7f~
(CH2)rNR~fS(0}2R~b, and (CH2)rphenyl substituted with 0-
3 Rye;
Rid, at each occurrence, is selected from C1_6 alkyl
substituted with 0-3 Rye, alkenyl, alkynyl, and a C3_1Q
carbocyclic residue substituted with 0-3 R~~;
Rye, at each occurrence, is selected from C1_6 alkyl, C2_8
alkenyl, C2_g alkynyl, C3_6 cycloalkyl, C1, F, Br, I,
CN, N02, (CF2)rCF3, (CH2)rOCl_5 alkyl, OH, SH, (CHZ)rSC2_ .
alkyl, (CHz)rNR~fR~f, and (CH2)rphenyl;
Ref, at each occurrence, is selected from H, Cz_6 alkyl, and
C3-6 cycloalkyl;
R8 is selected from H, C~_6 alkyl, C3_6 cycloalkyl, and
(CH2)tphenyl substituted with 0-3 Rea
Rsa, at each occurrence, is selected from C1_6 alkyl, C2_8
alkenyl, C2_g alkynyl, C3_6 cycloalkyl, C1, F, Br, I,
CN, N02, (CF2)rCF3, (CH2)rOCl_S alkyl, OH, SH, (CH2)rSCl_
5 alkyl, (CHZ)rNR~fR~f, and (CH2)rphenyl;
alternatively, R~ and R8 join to form C3_~ cycloalkyl, or
=j~8b;
Rab is selected from H, C1_6 alkyl, C3_6 cycloalkyl, OH, CN,
and (CH2)r-phenyl;
R9 , is selected from H, C1_6 alkyl, C2_8 alkenyl , C2_g
alkynyl, F, C1, Br, I, NOz, CN, (CH2)rOH, (CH2)rSH,
(CH2)rOR9d, (CH2)rSR9d, (CHz)rNR9aR9a', (CH2)rC(O}OH,
(CH2)rC(O)R9b, (CH2)rC(p)NR9aR9a', (CHZ}rNR9aC(0)R9a,
(CH2)rNR9aC(O}H, (CH2)rNR9aC(O)NHR9a, (CH2)z.C(0)OR9b,


CA 02350730 2001-05-07
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(CHZ)rOC(0)R9b, (CHz)rOC(0)NHR'°, (CH2)rS(O)pR9b~
(CH2)rS(O)2NR9aR9a'~ (CH2)rNR9aS(0)ZR9b, C1_6 haloalkyl,
a (CH2)r-C3_lo carbocyclic residue substituted with 0-5
R9~, and a (CH2)r-5-10 membered heterocyclic system
containing 1-4 heteroatoms selected from N, 0, and S,
substituted with 0-3 R9~;
R9a and R9a', at each occurrence, are selected from H. C1_6
alkyl, C2_e alkenyl, C2_g alkynyl, a (CH2)r-C3-10
carbocyclic residue substituted with 0-5 R9e, and a
(CHZ)r-5-10 membered heterocyclic system containing 1-4
heteroatoms selected from N, O, and S, substituted
with 0-3 R9e;
R9b, at each occurrence, is selected from C1_6 alkyl, C2_g
alkenyl, C2_g 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;
R9~, at each occurrence, is selected from C1_6 alkyl, C2_8
alkenyl, C2_g alkynyl, (CH2)rC3-6 cYcloalkyl, C1, Br, I,
F, (CF2)rCF3, N02, CN, (CH2)rNR9fR9f, (CH2)rOH,
(CH2)rOCl_q alkyl, (CH2)rSCl_q alkyl, (CH2)rC(O)OH,
(CH2)rC(O)R9b, (CH2)rC(O)NR9fR9f, (CH2)rNR9fC(O)R9a~
(CH2 ) rC (O) OCl_q alkyl, (CH2 ) rOC (0) R9b.
(CH2)rC(=NR9f)NR9fR9f~ (CH2)rS(O)pR9b~
(CH2)rNHC(=NR9f)NR9fR9f~ (CH2)rS(O)2NR9fR9f~
(CH2)rNR9fS(0)2R9b~ and (CH2)rphenyl substituted with 0-
3 R9e;
R9d, at each occurrence, is selected from C1_s alkyl. C2-s
alkenyl, C2-6 alkynyl, a C3_io carbocyclic residue
substituted with 0-3 R9~, 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 R9~;
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R9e, at each occurrence, is selected from C1_6 alkyl, C2_8
alkenyl, C2_g alkynyl, (CH2)rC3-6 cYcloalkyl, Cl, F, Br,
I, CN, N02, (CF2)rCF3, (CH2)rOC1_5 alkyl, OH, SH,
(CH2)rSC1_5 alkyl, (CH2)rNR9fR9f, and (CH2)rphenyl;
R9f, at each occurrence, is selected from H, C1_6 alkyl, and
C3_6 cycloalkyl;
Rlo, is selected from H, C1_6 alkyl, CZ_g alkenyl, C2_8
alkynyl, F, C1, Br, I, N02, CN, (CH2)rOH, (CH2)rORlOd~
(CH2)rSRlOd~ (CH2)rNR10aR10a'. (CH2)rC(O)OH,
( CH2 ) rC ( O ) RlOb ~ ( CH2 ) rC ( O ) NR10aR10a' . ( CH2 ) rNRlOaC ( O )
RlOa
( CH2 ) rNRlOaC ( O ) H , ( CH2 ) rC ( O ) ORlOb ~ ( CH2 ) rOC ( O ) Rl Ob
( CH2 ) rS ( O ) pRl Ob, ( CH2 ) rS ( O ) 2NR10aR10a' .
(CH2)rNRlOaS(O)2R10b~ C1-6 halOalkyl, a (CH2)r-C3-1C
carbocyclic residue substituted with 0-5 Rloc, and a
(CH2)r-5-10 membered heterocyclic system containing 1-4
heteroatoms selected from N, O, and S, substituted
with 0-3 Rloc
Rloa and Rloa' , at each occurrence, are selected from H, C1_6
alkyl, C2_8 alkenyl, C2_8 alkynyl, a (CH2)r-C3-to
carbocyclic residue substituted with 0-5 Rloe, and a
(CH2)r-5-10 membered heterocyclic system containing 1-4
heteroatoms selected from N, O, and S, substituted
with 0-3 Rloe;
Rlob~ at each occurrence, is selected from Cl_6 alkyl, C2_8
alkenyl, C2_8 alkynyl, a (CH2)r-C3-6 carbocyclic residue
substituted with 0-2 Rloe, and a (CH2)r-5-6 membered
heterocyclic system containing 1-4 heteroatoms
selected from N, O, and S, substituted with 0-3 Rloe
Rloc, at each occurrence, is selected from C1_6 alkyl, C2_8
alkenyl, CZ_8 alkynyl, (CHZ)rC3-s cYcloalkyl, C1, Br, I,
F, (CF2)rCF3. NO2, CN, (CH2)rNR10fR10f (CHZ)rOH,
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(CH2)rOCl_q alkyl, (CH2)rSCl_q alkyl, (CH2)rC(O)OH,
(CH2)rC(O)RlOb, (CH2)rC(0)NR10fR10f~ (CH2)rNRlOfC(0)RlOa~
(CH2 ) rC (0) OC1_4 alkyl, (CHZ ) rOC (O) RlOb
(CH2)rC(=NRlOf)~lOfRlOf~ (CH2)rS(O)pRlOb~
(CH2)rNHC(=NRlOf)NR10fR10f~ (CH2)rS(O)2NRlOfRlOf~
(CH2)rNRlofS(O)2R10b~ and (CHZ)rphenyl substituted with
0-3 Rloe
Rlod, at each occurrence, is selected from Cl_6 alkyl, C2_6
alkenyl, C2-6 alkynyl, a C3_io carbocyclic residue
substituted with 0-3 Rloc~ 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 Rloc.
Rloe~ at each occurrence, is selected from C1_6 alkyl, C2_8
alkenyl, C2_a alkynyl, (CH2)rC3_6 cycloalkyl, C1, F, Br,
I, CN, NO2, (CF2)rCF3, (CH2)rOCl_5 alkyl, OH, SH,
(CH2)rSCl_5 alkyl, (CH2)rNRlofRlOf~ and (CH2)=phenyl;
Rlof~ at each occurrence, is selected from H, C1_5 alkyl,
and C3_6 cycloalkyl;
alternatively, R9 and R10 join to form C3_~ cycloalkyl, 5-6-
membered cyclic ketal or =O;
with the proviso that when R10 is -OH, R9 is not halogen,
cyano, or bonded to the carbon to which it is attached
through a heteroatom;
R11, is selected from H, Cl_6 alkyl, C2_8 alkenyl, C2_8
alkynyl, (CH2)qOH, (CH2)qSH, (CH2)qORlid, (CH2)qSRlld~
(CH2)qNRllaRlla'~ (CH2)rC(O)OH, (CH2)rC(O)Rllb~
(CH2)rC(O)NRllaRlla', (CH2)qNRllaC(O)Rlla~
(CH2)qNRllaC(O)NHRlla~ (CH2)rC(O)ORllb~ (CH2)qOC(O)Rllb~
(CH2)qS(O)pRllb, (CH2)qS(O)ZNRIIaRlla~~
(CH2)qNRllaS(o)2R11b~ C1-6 haloalkyl, a (CH2)r-C3-10
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carbocyclic residue substituted with 0-5 Rllc, and a
(CH2)r-5-10 membered heterocyclic system containing 1-4
heteroatoms selected from N, 0, and S, substituted
with 0-3 Rllc
Rlla and Rlla' , at each occurrence, are selected from H, C1_6
alkyl, CZ_8 alkenyl, C2_g alkynyl, a (CH2)r-C3-to
carbocyclic residue substituted with 0-5 Rlle~ and a
(CH2)r-5-10 membered heterocyclic system containing 1-4
heteroatoms selected from N, O, and S, substituted
with 0-3 Rlle
Rllb~ at each occurrence, is selected from C1_6 alkyl, C2_g
alkenyl, C2_8 alkynyl, a (CH2)r-C3-6 carbocyclic residue
substituted with 0-2 Rlle, and a (CH2)r-5-6 membered
heterocyclic system containing 1-4 heteroatoms
selected from N, O, and S, substituted with 0-3 Rlle
Rllc~ at each occurrence, is selected from C1_6 alkyl, C2_8
alkenyl, C2-8 alkynyl, (CHz)rC3_6 cycloalkyl, Cl, Br, I,
F, (CF2)rCF3, N02, CN, (CH2)rNRllfRllf~ (CH2)rOH,
(CH2)rOCl_4 alkyl, (CH2)rSCl_4 alkyl, (CH2)rC(O)OH,
(CH2)rC(O)Rllb~ (CH2)rC(O)NRllfRllf~ (CH2)rNRllfC(O)Rlla~
(CH2)rC(O)OC1_4 alkyl, (CH2)rOC(O)Rllb~
(CH2)r['(=~llf)~llfRllf~ (CH2)r~f~(-NRllf)~llfRllf~
(CH2)rS(O)pRllb, (CH2)rS(O)2NR11fR11f~
(CH2)rNRllfs(O)2Rllb~ and (CH2)rphenyl substituted with
0-3 Rlle
Rlld, at each occurrence, is selected from C1_6 alkyl
substituted with 0-3 Rlle, C2-5 alkenyl, C2_6 alkynyl,
and a C3-1o carbocyclic residue substituted with 0-3
Rllc
Rlle, at each occurrence, is selected from Cl_6 alkyl, C2_8 ,
alkenyl, CZ_8 alkynyl, C3-6 cyeloalkyl, C1, F, Br, I,
74
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CN, N02, (CF2)rCF3, (CH2)rOC1_5 alkyl, OH, SH, (CH2)rSC1_
alkyl, (CH2)rNR11fR11f~ and (CH2)rphenyl;
Rllf~ at each occurrence, is selected from H, C1_6 alkyl,
5 and C3_6 cycloalkyl;
R12 is selected from H, C1_6 alkyl, (CH2)qOH, (CH2)rC3-6
cycloalkyl, and (CH2)tphenyl substituted with 0-3 Rl2a
Rl2a~ at each occurrence, is selected from C1_6 alkyl, C2_8
alkenyl, C2_8 alkynyl, C3_6 cycloalkyl, C1, F, Br, I,
CN, N02, (CF2)rCF3, (CH2)rOC1_5 alkyl, OH, SH, (CH2)rSC1_
S alkyl , ( CH2 ) rNR9 fR9 f , and ( CH2 ) =phenyl ;
alternatively, R11 and R12 join to form C3_~ cycloalkyl;
R13, at each occurrence, is selected from C1_6 alkyl, C2_g
alkenyl, C2_g alkynyl, C3_6 cycloalkyl, (CF2)WCF3,
(CH2)NR13aR13a'~ (CH2)OH, (CH2)ORl3b~ (CH2)SH,
(CH2)SRl3b, (CH2),"~C(O)OH, {CH2)~",C(O)Rl3b~
(CH2)~,~C(O)NR13aR13a'~ (CH2)NRl3dC(O)Rl3a~ (CH2)""C(O)ORl3b~
(CH2)OC(O)Rl3b~ (CH2)~"iS(O)pRl3b, (CH2)v,,S(O)2NR13aR13a'~
(CH2)NRl3dS(0)2R13b~ and (CH2)W-phenyl substituted with
0-3 Rl3c
Rl3a and Rl3a', at each occurrence, are selected from H, C1_s
alkyl, C3_6 cycloalkyl, and phenyl substituted with 0-3
Rl3c
Rl3b, at each occurrence, is selected from C1_6 alkyl, C3_6
cycloalkyl, and phenyl substituted with 0-3 Rl3c;
Rl3c~ at each occurrence, is selected from C1_6 alkyl, C3-6
cycloalkyl, C1, F, Br, I, CN, N02, (CF2)rCF3, (CH2)rOC1_
3 5 5 alkyl , ( CH2 ) rOH , ( CH2 ) ZSC1_.5 alkyl , and
(CH2)rNR13dR13d~


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Rl3d~ at each occurrence, is selected from H, C1_6 alkyl,
and C3-6 cycloalkyl;
R14, at each occurrence, is selected from C1_6 alkyl, C2_g
alkenyl, C2_g alkynyl, (CH2)rC3-6 cYcloalkyl, C1, Br, I,
F, N02, CN, (CHR')rNR14aR14a'~ (CHR')rOH,
(CHR')r0(CHR')rRl4d, (CHR')rSH, (CHR')rC(O)H,
(CHR')rS(CHR~)rRl4d~ (CHR')rC(0)OH,
(CHR')rC(O)(CHR')rRl4b, (CHR')rC(O)NR14aR14a'~
(CHR' ) rNRl4fC (0) (CHR' ) rRl4b, (CHR' ) rC (0) 0 (CHR' ) rRl4d~
( CHR' ) rOC ( O ) ( CHR' ) rRl4b , ( CHR' ) rC ( =NR14 f ) ~14aR14a'
(CHR' ) rNHC (=NRl4f) NR14fR14f ~ (CHR' ) rS (O) p (CHR' ) rRl4b~
(CHR')rS(O)2NR14aR14a'~ (CHR')=NRl4fS(O)2(CHR')rRl4b, C1-6
haloalkyl, C2_8 alkenyl substituted with 0-3 R', Cz_8
alkynyl substituted with 0-3 R', (CHR')rphenyl
substituted with 0-3 Rl4e, and a (CH2)r-5-10 membered
heterocyclic system containing 1-4 heteroatoms
selected from N, O, and S, substituted with 0-2 RlSe;
R', at each occurrence, is selected from H, C1_6 alkyl, C2-g
alkenyl, CZ_g alkynyl, (CH2)rC3-6 cycloalkyl, and
(CH2)rphenyl substituted with Rl4e;
Rl4a and Rl4a', at each occurrence, are selected from H, C1_6
alkyl, C2_8 alkenyl, C2_8 alkynyl, a (CHZ)r-C3-io
carbocyclic residue substituted with 0-5 Rl4e, and a
(CH2)r-5-10 membered heterocyclic system containing 1-4
heteroatoms selected from N, O, and S, substituted
with 0-2 Rl4e;
Rl4b~ at each occurrence, is selected from C1_6 alkyl, C2_8
alkenyl, C2_g alkynyl, a (CH2)r-C3_6 carbocyclic residue
substituted with 0-3 Rl4e, and (CH2)=-5-6 membered
heterocyclic system containing 1-4 heteroatoms
selected from N, O, and S, substituted with 0-2 Rl4e
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Rl4d~ at each occurrence, is selected from C2_8 alkenyl,
alkynyl, C1_6 alkyl substituted with 0-3 Rl4e, a
(CH2)r-C3-1o carbocyclic residue substituted with 0-3
Rl4e~ and a (CH2)r5-6 membered heterocyclic system
containing 1-4 heteroatoms selected from N, O, and S,
substituted with 0-3 Rl4e;
Rl4e~ at each occurrence, is selected from C1_s alkyl, C
alkenyl, Cz_8 alkynyl, (CH2)rC3_6 cycloalkyl, C1, F, Br,
I, CN, N02, (CFZ)rCF3, (CH2)rOC1_5 alkyl, OH, SH,
(CH2)rSC1_5 alkyl, (CH2)rNR14fR14f~ and (CH2)rphenyl;
Rl4f~ at each occurrence, is selected from H, C1_6 alkyl,
C3-6 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 Ra;
R15, at each occurrence, is selected from C1_6 alkyl, C2_8
alkenyl, CZ_8 alkynyl, (CH2)=C3-6 cycloalkyl, C1, Br, I,
F, N02, CN, (CHR')rNR15aR15a'~ (CHR')rOH,
(CHR')r0(CHR')rRlSd, (CHR')rSH, (CHR')rC(O)H,
(CHR')rS(CHR~)rRlSd, (CHR')rC(O)OH,
(CHR')rC(O)(CHR')rRl5b~ (CHR')=C(0)NRl5aRl5a~~
( CHR' ) rNRlS f C ( O ) ( CHR' ) rRlSb ~ ( CHR' ) rC ( O ) 0 ( CHR' ) rRlS d
( CHR' ) rOC ( O ) ( CHR' ) rRlSb, ( CHR' ) rC ( 0 ) NR15aR15a'
(CHR' ) rC (-NRlSf ) ~l5aRl5a' ~ (CHR' ) rNHC (=NRlSf ) NR15fR15f
(CHR')rS(O)p(CHR')rRlSb~ (CHR')rS(0)2NR15aR15a~~
{CHR')rNRlSfS(O)2(CHR')rRlSb, C1-6 haloalkyl, C2_g
alkenyl substituted with 0-3 R', C2_e alkynyl
substituted with 0-3 R', (CHR')rphenyl substituted with
0-3 RlSe, and a (CH2)=-5-10 membered heterocyclic
system containing 1-4 heteroatoms selected from N, O,
and S, substituted with 0-2 RlSe;
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RlSa and RlSa' , at each occurrence, are selected from H, C1-6
alkyl, C2_8 alkenyl, C2_e alkynyl, a (CH2) r-C3-to
carbocyclic residue substituted with 0-5 RlSe, and a
(CH2)r-5-10 membered heterocyclic system containing 1-4
heteroatoms selected from N, O, and S, substituted
with 0-2 RlSe;
RlSb, at each occurrence, is selected from C1_6 alkyl, CZ_8
alkenyl, C2_8 alkynyl, a (CH2)r-C3-6 carbocyclic residue
substituted with 0-3 RlSe, and (CH2)r-5-6 membered
heterocyclic system containing 1-4 heteroatoms
selected from N, O, and S, substituted with 0-2 RlSe;
RlSd, at each occurrence, is selected from C2_8 alkenyl, C2-a
alkynyl, C1_6 alkyl substituted with 0-3 RlSe~ a
(CH2)r-C3_1o carbocyclic residue substituted with 0-3
RlSe, and a (CH2)r5-6 membered heterocyclic system
containing 1-4 heteroatoms selected from N, O, and S,
substituted with 0-3 Rlse;
RlSe~ at each occurrence, is selected from C1_6 alkyl, C2_8
alkenyl, C2_g alkynyl, (CH2)rC3-6 cYcloalkyl, C1, F, Br,
I, CN, N02, (CF2)rCF3, (CH2)rOCl_5 alkyl, OH, SH,
(CH2)rSCl_5 alkyl, (CH2)rNR15fR15f, and (CH2)rphenyl;
RlSf~ at each occurrence, is selected from H, C1_6 alkyl,
C3-6 cycloalkyl, and phenyl;
R16, at each occurrence, is selected from C1_6 alkyl, C2_g
alkenyl, C2_8 alkynyl, (CHZ)rC3-6 cYcloalkyl, C1, Br, I,
F, N02, CN, (CHR')rNR16aR16a'~ (CHR')rOH,
(CHR')r0(CHR')rRl6d, (CHR')rSH, (CHR')rC(O)H,
(CHR')rS(CHR')rRl6d, (CHR')rC(O)OH,
(CHR' ) rC (O) (CHR' ) rRl6b, (CHR' ) rC (O) NR16aR16a'
(CHR' ) rNRl6fC (O) (CHR' ) rRl6b~ (CHR' ) rC (O) O (CHR' ) ~.Rl6d,
( CHR' ) rOC ( O ) ( CHR' ) rRl6b, ( CHR' ) rC ( =NR16 f ) ~l6aRl6a'
(CHR' ) rNHC (=NRl6f ) NR16fR16f ~ (CHR' ) rS (O) p (CHR' ) rRl6b~
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(CHR' ) rS (0) 2NR16aR16a' , (CHR' ) rNRl6fS (p) 2 (CHR' ) rRl6b, C1-6
haloalkyl, C2_g alkenyl substituted with 0-3 R', C2_g
alkynyl substituted with 0-3 R', and (CHR')rphenyl
substituted with 0-3 Rl6e;
Rl6a and Rl6a~ , at each occurrence, are selected from H, C1-6
alkyl, CZ_g alkenyl, C2_g alkynyl, a (CH2)r-C3-10
carbocyclic residue substituted with 0-5 Rl6e, and a
(CH2)r-5-10 membered heterocyclic system containing 1-4
heteroatoms selected from N, O, and S, substituted
with 0-2 Rl6e
Rl6b~ at each occurrence, is selected from C1_6 alkyl, Cz_e
alkenyl, C2_g alkynyl, a (CH2)rC3-6 carbocyclic residue
substituted with 0-3 Rl6e, and a (CH2)r-5-6 membered
heterocyclic system containing 1-4 heteroatoms
selected from N, O, and S, substituted with 0-2 Rl6e;
Rlsd~ at each occurrence, is selected from C2_g alkenyl, C2_g
alkynyl, C1_6 alkyl substituted with 0-3 Rlse~ a
(CH2)r-C3-1o carbocyclic residue substituted with 0-3
Rl6e, and a (CH2)r-5-6 membered heterocyclic system
containing 1-4 heteroatoms selected from N, O, and S,
substituted with 0-3 Rl6e.
Rl6e~ at each occurrence, is selected from C1_6 alkyl, CZ_g
alkenyl, C2_g alkynyl, (CH2)rC3-6 cycloalkyl, C1, F, Br,
I, CN, N02, (CF2)rCF3, (CH2)rOCl_5 alkyl, OH, SH,
(CH2 ) rSCl_5 alkyl, (CH2 ) rNR16fR16f ~ and (CH2 ) rphenyl;
Rl6f~ at each occurrence, is selected from H, C1_6 alkyl,
and C3_6 cycloalkyl, and phenyl;
g is selected from 0, 1, 2, 3, and 4;
v is selected from 0, 1, and 2;
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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 2, 2, 3, 4, and 5; and
p is selected from 1, 2, and 3.
[30] In a preferred embodiment, the present invention
provides novel compounds of formula (I), wherein:
E is selected from:
7 Rg 11 12
7 8 7 g
A A A '
(R1a)9 Rs Rio (R14)9 Rs R1o (R14)s
11 12 ' ,
A
(R 14)9
Rs 10 ~ g s 10
g 11 R12
A R11 R12 A - 11 R12 A
(R 14) (R 14) 14
R 9
9 , and ~ ) ;
R4 is absent, taken with the nitrogen to which it is
attached to form an N-oxide, or selected from C1_g
alkyl, (CH2)rC3-s cYcloalkyl, and (CHZ)r-phenyl
substituted with 0-3 R4c;
R4c, at each occurrence, is selected from CI._fi alkyl, C2_g
alkenyl, C2_8 alkynyl, C3_6 cycloalkyl, C1, F, Br, I,
CN, N02, (CF2)rCF~, (CH2)rOCl_5 alkyl, (CH2)rOH,
(CH2)rSCl_5 alkyl, (CH2)rNR4aR4a~, and (CH2)rphenyl;


CA 02350730 2001-05-07
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alternatively, R4 joins with R~ or R9 to form a 5, 6 or 7
membered piperidinium spirocycle substituted with 0-3
Ra;
R1 and R2 are independently selected from H and C1_4 alkyl;
R6, at each occurrence, is selected from C1_4 alkyl, CZ_8
alkenyl, C2_g alkynyl, (CH2)rC3_6 cycloalkyl, (CF2)rCF3,
CN, ( CH2 ) rOH, ( CH2 ) rOR6b, ( CHz ) rC ( 0 ) 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-s
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, C1, F, Br, I, CN, N02, (CFZ)rCF3, (CH2)rOCl_
5 alkyl, (CH2)rOH, (CHZ)rSCl_5 alkyl, and (CHZ)rNR6dR6d~
R6d, at each occurrence, is selected from H, C1_6 alkyl, and
C3-6 cycloalkyl;
R~, is selected from H, C1_3 alkyl, (CH2)rC3-6 cycloalkyl,
(CH2)qOH, (CH2)qOR?d, (CH2)qNR7aR~a'~ (CH2)rC(O)R7b,
(CHZ) rC (O)NR~aR~a' , (CH2) qNR~aC (O)R~a, C1_6 haloalkyl,
(CH2)rphenyl with 0-2 RFC;
Rya and Rya' , at each occurrence, are selected from H, C1-s
alkyl, (CH2)rC3-6 cycloalkyl, a (CH2)rphenyl
substituted with 0-3 Rye;
81


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Rib, at each occurrence, is selected from C1_6 alkyl, C2_8
alkenyl, C2_8 alkynyl, (CH2)rC3-6 cYcloalkyl,
(CHZ)rphenyl substituted with 0-3 Rye;
R~~, at each occurrence, is selected from C1_g alkyl, C2_g
alkenyl, C2_g alkynyl, (CH2)rC3-6 cycloalkyl, C1, Br, I,
F, (CF2)rCF3, N02, CN, (CH2)rNR~fR7f~ (CH2)rOH,
(CH2)rOCl_g alkyl. (CH2)rC(0)R7b, (CH2)rC(O)NR~fR7f~
(CHz)rNR~fC(O)R7a~ (CH2)rS(O)pR~b, (CH2)rS(O)ZNR~fR7f~
(CHz)rNR~fS(O)2R~b, and (CH2)rphenyl substituted with 0-
2 Rye;
Rid, at each occurrence, is selected from C1_6 alkyl,
(CH2)rC3-6 cYcloalkyl, (CH2)rphenyl substituted with 0-
3 Rye;
Rye, at each occurrence, is selected from C1_6 alkyl, C2_8
alkenyl, C2_g alkynyl, C3-6 cycloalkyl, C1, F, Br, I,
CN, N02, (CF2 ) rCF3 , (CH2 ) rOCl_5 alkyl, OH, SH, (CH2 ) rSCl_
5 alkyl, (CH2)rNR~fR~f, and (CH2)rphenyl;
Ref, at each occurrence, is selected from H, C1_5 alkyl, and
C3-6 cycloalkyl;
Rg is H or joins with R~ to form C3_~ cycloalkyl or =NRBb;
R11, is selected from H, C1_6 alkyl, (CH2)rC3-6 cYcloalkyl,
(CH2)qOH, (CH2)qORlld, (CH2)qNRllaRlla'. (CHZ)rC(O)Rllb~
(CH2) rC (O)NRllaRlla' ~ (CH2) qNRllaC (O) Rlla~ C1-6 haloalkyl,
(CH2)rphenyl with 0-2 Rllc, (CH2)r_5-10 membered
heterocyclic system containing 1-4 heteroatoms
selected from N, O, and S, substituted with 0-3 R15;
Rlla ~d Rlla' ~ at each occurrence, are selected from H, C1-6
alkyl, (CH2)rC3-s cYcloalkyl, a (CH2)rphenyl
substituted with 0-3 Rlle;
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Rllb~ at each occurrence, is selected from C1_6 alkyl, C
alkenyl, C2_g alkynyl, (CH2)rC3-6 cycloalkyl,
(CH2)rphenyl substituted with 0-3 Rlle;
Rllc, at each occurrence, -is selected from C1_4 alkyl, C2_g
alkenyl, C2_8 alkynyl, (CH2)rC3-6 cycloalkyl, C1, Br, I,
F, (CF2 ) rCF3 , N02 , CN, (CH2 ) rNRllfRllf ~ (CH2 ) rOH,
(CH2) rOCl_4 alkyl, (CH2 ) rC (O) Rllb, (CH2 ) rC (O)NRllfRllf
(CH2)r~llfC(O)Rlla~ (CH2)rS(0)pRllb~
(CH2) rS (O) 2NR11fRllf ~ (CH2 ) rNRllfS (0) 2R11b~ and
(CH2)rphenyl substituted with 0-2 Rlle;
Rlld, at each occurrence, is selected from C1_6 alkyl,
(CH2)rC3-6 cYcloalkyl, (CH2)rphenyl substituted with 0-
3 Rlle
Rlle~ at each occurrence, is selected from C1_6 alkyl, C2
alkenyl, Cz_8 alkynyl, C3_6 cycloalkyl, C1, F, Br, I,
CN, N02, (CF2)rCF3, (CH2)rOCl_5 alkyl, OH, SH, (CH2)rSCl_
5 alkyl, (CHZ)rNRllfRllf~ and (CH2)rphenyl;
Rllf~ at each occurrence, is selected from H, C1-5 alkyl and
C3-6 cycloalkyl;
R12 is H or joins with R11 to form C3_~ cycloalkyl;
R13, at each occurrence, is selected from C1_4 alkyl, C3-6
cycloalkyl, (CH2)NRl3aRl3a'~ (CH2)OH, (CH2)ORl3b~
(CH2)WC(O)Rl3b, (CH2)~",C(O)NRl3aRl3a', (CH2)NRl3dC(0)Rl3a~
(CH2)WS(O)2NR13aR13a'~ (CH2)NRl3dS(O)2R13b~ and
(CHZ)W-phenyl substituted with 0-3 Rl3c;
Rl3a and Rl3a' ~ at each occurrence, are selected from H, C1_s
alkyl, C3_6 cycloalkyl, and phenyl substituted with 0-3
Rl3c
Rl3b~ at each occurrence, is selected from C1_6 alkyl, C3_s
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cycloalkyl, and phenyl substituted with 0-3 Rl3c
R23c~ at each occurrence, is selected from C1_6 alkyl, C3-s
cycloalkyl, C1, F, Br, I, CN, NO2, (CF2)rCF3, (CH2)rOC1_
5 alkyl, (CH2)rOH, arid (CH2)rNR13dR13d;
Rl3d, at each occurrence, is selected from H, C1_6 alkyl,
and C3_6 cycloalkyl;
v is selected from 1 and 2;
q is selected from 1, 2, and 3; and
r is selected from 0, 1, 2, and 3.
[31] In a more preferred embodiment, the present invention
provides novel compounds of formula (I), wherein:
ring A is selected from:
14
(R )9 ([~ X4)9 ' (R 14)9 ~"' (R~4)9
(R~4)
9
R'
( ~s , and (R X4)9 ;
R3 is selected from 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)=-heterocyclic
system substituted with 0-3 R25, wherein the
heterocyclic system is selected from pyridiriyl,
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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, isoindolyl, piperidinyl, pyrrazolyl, 1,2,4-
triazolyl, 1,2,3-triazolyl, tetrazolyl, thiazolyl,
oxazolyl, pyrazinyl, and pyrimidinyl.
[32]. In an even more preferred embodiment, the present
invention provides novel compounds of formula (I-i),
wherein the compound of formula (I-i) is:
Z
J
K ~N-E-N~N-R3
~ H H
(I-i)
R16, at each occurrence, is selected from C1_8 alkyl,
(CH2)=C3_6 cycloalkyl, CF3, C1, Br, I, F,
{CH2)rNR16aR16a'~ Np2, CN, OH, (CH2)rORl6d
16b 16a 16a' , 16f 16b
(CH2)rC(O)R , (CH2)rC(0)NR R , (CH2)rNR C(O)R ,
(CH2)rS(O)pRl6b~ (CH2)rS(O)2NR16aR16a'.
(CH2)rNRl6fS(O)2R16b~ and (CH2)=phenyl. substituted with
0-3 Rl6e
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Rl6a and Rl6a' ~ at each occurrence, are selected from H, C1_6
alkyl, C3_6 cycloalkyl, and (CH2)rphenyl substituted
with 0-3 Rl6e;
Rl6b, at each occurrence, is selected from H, C1_6 alkyl,
C3_6 cycloalkyl, and (CH2)rphenyl substituted with 0-3
Rl6e
Rl6d~ at each occurrence, is selected from C1_6 alkyl and
phenyl;
Rl6e, at each occurrence, is selected from C1_6 alkyl, C1,
F, Br, I, CN, N02, (CF2)rCF3, OH, and (CH2)rOCl_5 alkyl;
and
Rl6f, at each occurrence, is selected from H, and C1-5
alkyl.
j33) In an another even more preferred embodiment, the
present invention provides novel compounds of formula (I-
ii), wherein (I-ii) is:
Z
N-E_N~N-Ra
L-~/ ' '
H H
(I-ii)
R16, at each occurrence, is selected from C1_e alkyl,
(CH2)=C3_6 cycloalkyl, CF3, C1, Br, I, F,
(CH2) rNR16aR16a' ~ NOZ. CN, OH, (CH2) rORl6d~
(CH2)rC(01R16b (CH2)rC(p)NR16aR16a'. (CH2)rNRl6fC(O)Rl6b~
(CH2)rS(0)pRl6b, (CH2)rS(O)2NR16aR16a'~
(CH2) rNRl6fS (O) 2R16b~ ~d (CH2) rphenyl substituted with
0-3 Rl6e;
Rl6a and Rlsa~, at each occurrence, are selected from H, C1_6
alkyl, C3_6 cycloalkyl, and (CH2)rphenyl substituted
with 0-3 Rl6e;
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Rl6b~ at each occurrence, is selected from H, C1_6 alkyl,
C3_6 cycloalkyl, and (CHZ)rphenyl substituted with 0-3
RlSe.
Rl6d~ at each occurrence, is selected from C1_6 alkyl and
phenyl;
Rl6e~ at each occurrence, is selected from C1_6 alkyl, C1,
F, Br, I, CN, N02, (CFZ)rCF3, OH, and (CH2)rOCl_5 alkyl;
and
Rl6f~ at each occurrence, is selected from H, and C1-5
alkyl.
[34] In a preferred embodiment, the present invention
provides novel compounds of formula (I-i), wherein:
RS is CH2phenyl substituted with 0-3 R16;
R9, is selected from H, C1_6 alkyl, (CH2)rC3-6 cYcloalkyl, F,
C1, CN, (CHZ)rOH, (CH2)rOR9d, (CH2)rNR9$R9a'~
(CHZ)rOC(O)NHR9°, (CH2)rphenyl substituted with 0-5 R9e,
and a heterocyclic system substituted with 0-2 R9e,
wherein the heterocyclic system is selected from
pyridyl, thiophenyl, furanyl, oxazolyl, and thiazolyl;
R9a and R9a', at each occurrence, are selected from H, C1_6
alkyl, C3_6 cycloalkyl, and (CH2)rphenyl substituted
with 0-3 R9e;
Rya, at each occurrence, is selected from C1_6 alkyl and
phenyl;
R9e, at each occurrence, is selected from C1_6 alkyl, C1, F,
Br, I, CN, N02, (CF2)rCF3, OH, and (CH2)rOCl_5 alkyl;
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R1~ is selected from H, C1_5 alkyl, OH, and CH20H;
alternatively, R9 and R10 join to form C3_~ cycloalkyl, 5-6-
membered cyclic ketal or =0;
with the proviso that when R1~ is -OH, R9 is not halogen,
cyano, or bonded to the carbon to which it is attached
through a heteroatom;
R11 is selected from H, C1_g alkyl, (CH2)rphenyl substituted
with 0-5 Rlle, and a (CH2)r-heterocyclic system
substituted with 0-2 Rlle, 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
Rlle. at each occurrence, is selected from C1-6 alkyl, C1,
F, Br, I, CN, N02, (CF2)rCF3, OH, and (CH2)rOCl_5 alkyl;
R12 is H;
alternatively, R11 and R12 join to form C3_~ cycloalkyl;
R14, at each occurrence, is selected from C1_8 alkyl,
(CHZ)rC3-6 cYcloalkyl, CF3, C1, Br, I, F,
(CH2)rNR14aR14a'. N02~ CN, OH, (CH2)rORl4d.
(CH2)rC(O)Rl4b. (CH2)rC(O)NR14aR14a'~ (CH2)rNRl4fC(0)Rl4b~
(CH2)rS(O)pRl4b. (CH2)rS(O)2NR14aR14a'.
(CHZ)rNRl4fS(O)2R14b. (CH2)rPhenyl substituted with 0-3
Rl4e;
Rl4a and Rl4a', at each occurrence, are selected from H,
alkyl, C3_6 cycloalkyl, and (CHZ)rphenyl substituted
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with 0-3 Rl4e~ and a (CH2)r-5-6 membered heterocyclic
system containing 1-4 heteroatoms selected from N, O,
and S, substituted with 0-2 RlSe;
Rl4b, at each occurrence, is selected from H, C1_6 alkyl,
C3_6 cycloalkyl, and (CH2)rphenyl substituted with 0-3
Rl4e;
Rl4d, at each occurrence, is selected from C1_6 alkyl and
phenyl;
20
Rl4e, at each occurrence, is selected from C1_6 alkyl, Cl,
F, Br, I, CN, N02, (CF2)rCF3, OH, and (CH2)rOCl_5 alkyl;
and
Rl4f~ at each occurrence, is selected from H, and C1-5
alkyl; and
r is selected from 0, 1, and 2.
[35] In a preferred embodiment, the present invention
provides novel compounds of formula (I-ii), wherein:
R5 is CH2phenyl substituted with 0-3 R16;
R9, is selected from H, C1_6 alkyl, (CH2)rC3-6 cycloalkyl, F,
C1, CN, (CH2)rOH~ (CH2)rOR9d, (CH2)rNR9aR9a'~
(CHz) rOC (0) NHR'°, (CH2 ) rphenyl substituted with 0-5 R9e,
and a heterocyclic system substituted with 0-2 R9e,
wherein the heterocyclic system is selected from
pyridyl, thiophenyl, furanyl, oxazolyl, and thiazolyl;
R9a and R9a', at each occurrence, are selected from H, C1_6
alkyl, C3_6 cycloalkyl, and (CH2)rphenyl substituted
with 0-3 R9e;
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R9d, at each occurrence, is selected from C1_6 alkyl and
phenyl;
R9e, at each occurrence, is selected from C1_6 alkyl, C1, F,
Br, I, CN, N02, (CFZ)rCF3, OH, and (CH2)rOCl_5 alkyl;
R1~ is selected from H, C1_e alkyl, OH, and CH20H;
alternatively, R9 and R1~ join to form C3_~ cycloalkyl, 5-6-
membered cyclic ketal or =O;
with the proviso that when R1~ is -OH, R9 is not halogen,
cyano, or bonded to the carbon to which it is attached
through a heteroatom;
R11 is selected from H, C1_g alkyl, (CH2)rphenyl substituted
with 0-5 Rlle, and a (CH2)r-heterocyclic system
substituted with 0-2 Rlle, 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
Rlle~ at each occurrence, is selected from C1_6 alkyl, C1,
F, Br, I, CN, N02, (CF2)=CF3, OH, and (CH2)rOCl_5 alkyl;
R12 is H;
alternatively, R11 and R12 join to form C3__~ cycloalkyl;
R14, at each occurrence, is selected from C1_a alkyl,
(CH2)rC3-6 cYcloalkyl, CF3, C1, Br, I, F,
(CH2)rNR14aR14a'~ N02, CN, OH, (CHZ)rORl4d~
(CH2)rC(0)Rl4b, (CH2)rC(O)NR14aR14a°, (CH2)rNRl4fC(O)Rl4b


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( CH2 ) rS ( 0 ) pRl4b, ( CH2 ) rS ( O ) 2NR14aRl4a'
(CH2)rNRl4fS{0)2R14b~ (CH2)rphenyl substituted with 0-:l
Rl4e~ and a (CH2)r-5-6 membered heterocyclic system
containing 1-4 heteroatorns selected from N, O, and S,
substituted with 0-2 Ri~e;
Rl4a and Rl4a', at each occurrence, are selected from H, Ci_s
alkyl, C3_6 cycloalkyl, and (CH2)rphenyl substituted
with 0-3 Rl4e
Rl4b~ at each occurrence, is selected from H, Ci_6 alkyl,
C3_6 cycloalkyl, and (CHz)rphenyl substituted with 0-3
Rl4e
Rl4d, at each occurrence, is selected from Ci_6 alkyl and
phenyl;
Rl4e~ at each occurrence, is selected from Ci_6 alkyl, C1,
F, Br, I, CN, N02, (CF2 ) rCF3, OH, and (CH2 ) rOCi_5 alkyl;
Rl4f~ at each occurrence, is selected from H, and C1-5
alkyl; and
30
r is selected from 0, 1,, and 2.
[36] In a more preferred embodiment, the present invention
provides novel compounds of formula (I-i), wherein:
J is selected from CH2 and CHRS;
K is selected from CHZ and CHRS;
L is selected from CH2 and CHRS;
R3 is a C3_io carbocyclic residue substituted with 0-3 R15,
wherein the carbocyclic residue is selected from
cyclopropyl, cyclopentyl, cyclohexyl, phenyl, naphthyl
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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
R15, at each occurrence, is selected from C1_8 alkyl,
(CH2)rC3_6 cycloalkyl, CF3, C1, Br, I, F,
(CH2)rNR15aR15a'. N02. CN, OH, (CHZ)rORlSd.
(CH2) rC (0) RlSb. (CH2) rC (O)NR15aR15a' . (CHZ ) rNRlSfC (O) Rl5b.
(CH2)rS(O)pRlSb. (CH2)rS(O)2NR15aRi5a'.
(CH2) rNRlSfS (p) 2R15b. (CH2 ) rphenyl substituted with 0-3
RlSe. and a (CH2)r-5-6 membered heterocyclic system
containing 1-4 heteroatoms selected from N, O, and S,
substituted with 0-2 RlSe;
RlSa and RlSa'. at each occurrence, are selected from H, C1_6
alkyl, C3_6 cycloalkyl, and (CH2)rphenyl substituted
with 0-3 RlSe;
RlSb. at each occurrence, is selected from H, C1_6 alkyl,
C3_6 cycloalkyl, and (CH2)rphenyl substituted with 0-3
RlSe;
RlSd. at each occurrence, is selected from C1_6 alkyl and
phenyl;
RlSe. at each occurrence, is selected from C1_6 alkyl, C1,
F, Br, I, CN, NO2, (CF2)rCF3, OH, and (CH2)rOCl_5 alkyl;
and
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RlSf, at each occurrence, is selected from H, and C1-5
alkyl.
[37] In a more preferred embodiment, the present invention
provides novel compounds of formula (I-ii), wherein:
K is selected from CHZ and CHRS;
L is selected from CH2 and CHRS;
R3 is a C3_lo carbocyclic residue substituted with 0-3 R15,
wherein the carbocyclic residue is selected from
cyclopropyl, 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
R15, at each occurrence, is selected from C1_8 alkyl,
(CH2)rC3_~ cycloalkyl, CF3, C1, Br, I, F,
(CH2)=NR15dR15a', Np2. CN, OH, (CH2)rORlSd~
(CH2)rC(O)RlSb, (CH2)rC(O)NRl5aRl5a'. (CH2)rNRl5fC(O)RlSb~
(CH2)rS(O)pRlSb~ (CH2)rS(O)2NR15aRlSa'.
(CH2)rNRlSfs(O)2R15b~ and (CH2)rphenyl substituted with
0-3 RlSe, and a (CH2)r-5-6 membered heterocyclic system
containing 1-4 heteroatoms selected from N, O, and S,
substituted with 0-2 RlSe.
Rl5a and RlSa' ~ at each occurrence, are selected from H, C1_s
alkyl, C3_6 cycloalkyl, and (CH2)rphenyl substituted
with 0-3 RlSe
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Rlsb~ at each occurrence, is selected from H, CI_6 alkyl,
C3_6 cycloalkyl, and (CHz)rphenyl substituted with 0-3
RlSe;
Rl5d~ at each occurrence, is selected from C1_6 alkyl and
phenyl;
Rlse~ at each occurrence, is selected from C1-6 alkyl, C1,
F, Br, I, CN, NO2, (CF2)=CF3, OH, and (CH2)rOCl_s alkyl;
and
Rlsf~ at each occurrence, is selected from H and C1-s alkyl.
[38] In a further even more preferred embodiment, the
present invention provides novel compounds of formula (I)
and pharmaceutically acceptable salt forms thereof, wherein
the compound of formula (I) is selected from
N"-cyano-N-(3-acetylphenyl)-N'-[(1R,2S)-2-[[(3S)-3-(4-
fluorobenzyl)piperidinyl]methyl]cyclohexyl]guanidine,
N"-cyano-N-(4-((1H)-1-methyl-tetrazol-5-yl)phenyl)-N'-
[ (1R,2S)-2-[ [ (3S)-3-(4-
fluorobenzyl)piperidinyl]methyl]cyclohexyl]guanidine,
N"-cyano-N-(3-acetylphenyl)-N'-[(1R,2S)-2-[[4-(4-
fluorobenzyl)piperidinyl]methyl]cyclohexyl]guanidine,
N"-cyano-N-(phenyl)-N'-[(1R,2S)-2-[[4-(4-
fluorobenzyl)piperidinyl]methyl]cyclohexyl]guanidine,
N"-cyano-N-(phenyl)-N'-[(1R,2S)-2-[[(3S)~-3-(4-
fluorobenzyl)piperidinyl]methyl]cyclohexyl]guanidine,
N"-cyano-N-(3-cyanophenyl)-N'-[(1R,2S)-2--[[(3S)-3-(4-
fluorobenzyl)piperidinyl]methyl]cyclohexyl]guanidine,
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N"-cyano-N-(3-cyanophenyl)-N'-[(1R,2S)-2-[[4-(4-
fluorobenzyl)piperidinyl]methyl]cyclohexyl]guanidine,
N"-cyano-N-(2,4-dimethoxyphenyl)-N'-[(1R,2S)-2-[[(3S)-3-(4-
fluorobenzyl)piperidinyl]methyl]cyclohexyl]guanidine,
N"-cyano-N-(2,5-dimethoxyphenyl)-N'-[(1R,2S)-2-[[(3S)-3-(4-
fluorobenzyl)piperidinyl]methyl]cyclohexyl]guanidine,
N"-cyano-N-(4-((1H)-1-propyl-tetrazol-5-yl)phenyl)-N'-
[(1R,2S)-2-[[(3S)-3-(4-
fluorobenzyl)piperidinyl]methyl]cyclohexyl]guanidine,
N"-cyano-N-(1-adamantyl)-N'-[(1R,2S)-2-[[(3S)-3--(4-
fluorobenzyl)piperidinyl]methyl]cyclohexyl]guanidine,
N"-cyano-N-(2-adamantyl)-N'-[(1R,2S)-2-[[(3S)-3-(4-
fluorobenzyl)piperidinyl]methyl]cyclohexyl]guanidine,
N"-cyano-N-(ethoxycarbonylmethyl)-N'-[(1R,2S)-2-[[(3S)-3-
(4-
fluorobenzyl)piperidinyl]methyl]cyclohexyl]guanidine,
N"-cyano-N-(5,6,7,8-tetrahydronaphth-1-yl)-N'-[(1R,2S)-2-
[ [ (3S) -3- (4-
fluorobenzyl)piperidinyl]methyl]cyclohexyl]guanidine,
N"-cyano-N-(2,4-dimethylphenyl)-N'-[(1R,2S)-2-[[(3S)-3-(4-
fluorobenzyl)piperidinyl]methyl]cyclohexyl]guanidine,
N"-cyano-N-(2-methoxyphenyl)-N'-[(1R,2S)-2-[[(3S)-3-(4-
fluorobenzyl)piperidinyl]methyl]cyclohexyl]guanidine,
N"-cyano-N-(2-methyl-4-hydroxyphenyl)-N'-[(1R,2S)-2-[[(3S)-
3- (4-
fluorobenzyl)piperidinyl]methyl]cyclohexyl]guanidine,


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N"-cyano-N-(2,5-dimethylphenyl)-N'-[(1R,2S)-2-[[(3S)-3-(4-
fluorobenzyl)piperidinyl]methyl]cyclohexyl]guanidine,
N"-cyano-N-(2-phenylethyl~)-N'-[(1R,2S)-2-[[(3S)-3-(4-
fluorobenzyl)piperidinyl]methyl]cyclohexyl]guanidine,
N"-cyano-N-(5-acetyl-2-methoxyphenyl)-N'-[(1R,2S)-2-[[(3S)-
3-(4-
fluorobenzyl)piperidinyl]methyl]cyclohexyl]guanidine,
N"-cyano-N-[4-(4-morpholinyl)phenyl]-N'-[(2R,2S)-2-[[(3S)-
3-(4-
fluorobenzyl)piperidinyl]methyl]cyclohexyl]guanidine,
2-{(3-acetylanilino)[((1R,2S)-2-{[(3S)-3-(4-
fluorobenzyl)piperidinyl]methyl}cyclohexyl]amino}methy
lene}malonitrile,
2-{(5-acetyl-2-methoxyanilino)[((1R,2S)-2-{[(3S)-3-(4-
fluorobenzyl)piperidinyl]methyl}cyclohexyl]amino}methy
lene}malonitrile,
1-[3-({1-[({(1R,2S)-2-[{3(S)-3-(4-
fluorobenzyl)piperidinyl]methyl}cyclohexyl)amino]-2-
nitroethenyl}amino)phenyl]ethanone,
1-{3-([1-{ (2-[{4-(4-
fluorobenzyl)piperidinyl}methyl]phenyl)amino}-2-
nitroethenyl]amino)phenyl}ethanone,
N"-cyano-N-(3,5-diacetylphenyl)-1-N'-[2-[[4-(4-
fluoYobenzyl)piperidinyl]methyl]3-(N-
methylcarbamoyl)phenyl]guanidine,
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N"-cyano-N-(3-diacetylphenyl)-1-N'-[2-[[4-(4-
fluorobenzyl)piperidinyl]methyl]3-(N-
methylcarbamoyl)phenyl]guanidine, and
N"-cyano-N-[3-[(1H)-1-methyltetrazol-5-yl]phenyl]-1-N'-[2-
[[4-(4-fluorobenzyl)piperidinyl]methyl]3-(N-
methylcarbamoyl)phenyl]guanidine.
In another embodiment, the present invention provides
a pharmaceutical composition, comprising a pharmaceutically
acceptable carrier and a therapeutically effective amount
of a compound of the present invention.
In another embodiment, the present invention provides
a method for modulation of chemokine receptor activity
comprising administering to a patient in need thereof a
therapeutically effective amount of a compound of the
present invention.
In another embodiment, the present invention provides
a method for treating inflammatory disorders comprising
administering to a patient in need thereof a
therapeutically effective amount of a compound of the
present invention
In another embodiment, the present invention provides
a method for treating or preventing disorders 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.
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DEFINITIONS
The compounds herein described may have asymmetric
centers. Compounds of the present invention containing an
asymmetrically substituted atom may be isolated in
optically active or racem~ic forms. It is well known in the
art how to prepare optically active forms, such as by
resolution of racemic forms or by synthesis from optically
active starting materials. Many geometric isomers of
olefins, C=N double bonds, and the like can also be present
in the compounds described herein, and all such stable
isomers are contemplated in the present invention. Cis and
traps geometric isomers of the compounds of the present
invention are described and may be isolated as a mixture of
isomers or as separated isomeric forms. All chiral,
diastereomeric, racemic forms and all geometric isomeric
forms of a structure are intended, unless the specific
stereochemistry or isomeric form is specifically indicated.
The term "substituted,~ as used herein, means that any
one or more hydrogens on the designated atom is replaced
with a selection from the indicated group, provided that
the designated atom's normal valency is not exceeded, and
that the substitution results in a stable compound. When a
substitent is keto (i.e., =O), then 2 hydrogens on the atom
are replaced.
When any variable (e. g., Ra) occurs more than one time
in any constituent or formula for a compound, its
definition at each occurrence is independent of its
definition at every other occurrence. Thus, for example,
if a group is shown to be substituted with 0-2 Ra, then
said group may optionally be substituted with up to two Ra
groups and Ra at each occurrence is selected independently
from the definition of Ra. Also, combinations of
substituents and/or variables are permissible only if such
combinations result in stable compounds.
when a bond to a substituent is shown to cross a bond
connecting two atoms in a ring, then such substituent may
be bonded to any atom on the ring. When a substituent is
98


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WO 00/35451 PCT/US99/30332
listed without indicating the atom via which such
substituent is bonded to the rest of the compound of a
given formula, then such substituent may be bonded via any
atom in such substituent. Combinations of substituents
and/or variables are permissible only if such combinations
result in stable compounds.
As used herein, "C1_8 alkyl" is intended to include
both branched and straight-chain saturated aliphatic
hydrocarbon groups having the specified number of carbon
atoms, examples of which include, but are not limited to,
methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, sec-
butyl, t-butyl, pentyl, and hexyl. C1_g alkyl, is intended
to include Cl, C2, C3, Cq, C5, C6, C~, and Cg alkyl groups.
~Alkenyl" is intended to include hydrocarbon chains of
either a straight or branched configuration and one or more
unsaturated carbon-carbon bonds which may occur in any
stable point along the chain, such as ethenyl, propenyl,
and the like. "Alkynyl" is intended to include hydrocarbon
chains of either a straight or branched configuration and
one or more unsaturated triple carbon-carbon bonds which
may occur in any stable point along the chain, such as
ethynyl, propynyl, and the like. "C3_6 cycloalkyl" is
intended to include saturated ring groups having the
specified number of carbon atoms in the ring, including
mono-, bi-, or poly-cyclic ring systems, such as
cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and
cycloheptyl in the case of C~ cycloalkyl. C3_6 cycloalkyl,
is intended to include C3, C4, C5, and C6 cycloalkyl groups
"Halo" or "halogen" as used herein refers to fluoro,
chloro, bromo, and iodo; and "haloalkyl" is intended to
include both branched and straight-chain saturated
aliphatic hydrocarbon groups, for example CF3, having the
specified number of carbon atoms, substituted with 1 or
more halogen (for example -C"FW where v = 1 to 3 and w = 1
to (2v+1)).
The compounds of Formula I can also be quaternized by
standard techniques such as alkylation of the piperidine or
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pyrrolidine with an alkyl halide to yield quaternary
piperidinium salt products of Formula I. Such quaternary
piperidinium salts would include a counterion. As used
herein, "counterion" is used to represent a small,
negatively charged species such as chloride, bromide,
hydroxide, acetate, sulfate, and the like.
As used herein, the term "piperidinium spirocycle or
pyrrolidinium spirocycle" is intented to mean a stable
spirocycle ring system, in which the two rings form a
quarternary nitrogene at the ring junction.
As used herein, the term "5-6-membered cyclic ketal"
is intended to mean 2,2-disubstituted 1,3-dioxolane or 2,2-
disubstituted 1,3-dioxane and their derivatives.
As used herein, "carbocycle" or "carbocyclic residue"
is intended to mean any stable 3, 4, 5, 6, or 7-membered
monocyclic or bicyclic or 7, 8, 9, 10, 11, 12, or
13-membered bicyclic or tricyclic, any of which may be
saturated, partially unsaturated, or aromatic. Examples of
such carbocycles include, but are not limited to,
cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,
cycloheptyl, adamantyl, cyclooctyl,; [3.3.0]bicyclooctane,
[4.3.0]bicyclononane, [4.4.0]bicyclodecane (decalin),
[2.2.2]bicyclooctane, fluorenyl, phenyl, naphthyl, indanyl,
adamantyl, or tetrahydronaphthyl (tetralin).
As used herein, the term "heterocycle" or
"heterocyclic system~ is intended to mean a stable 5, 6, or
7-membered monocyclic or bicyclic or 7, 8, 9, or 10-
membered bicyclic heterocyclic ring which is saturated,
partially unsaturated or unsaturated (aromatic), and which
consists of carbon atoms and 1, 2, 3, or 4 heteroatoms
independently selected from the group consisting of N, NH,
O and S and including any bicyclic group in which any of
the above-defined heterocyclic rings is fused to a benzene
ring. The nitrogen and sulfur heteroatoms may optionally
be oxidized. The heterocyclic ring may be attached to its
pendant group at any heteroatom or carbon atom which
results in a stable structure. The heterocyclic rings
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WO 00/35451 PCT/US99/30332
described herein may be substituted on carbon or on a
nitrogen atom if the resulting compound is stable. If
specifically noted, a nitrogen in the heterocycle may
optionally be quaternized. It is preferred that when the
total number of S and O atoms in the heterocycle exceeds 1,
then these heteroatoms are not adjacent to one another. As
used herein, the term "aromatic heterocyclic system" is
intended to mean a stable 5- to 7- membered monocyclic or
bicyclic or 7- to 10-membered bicyclic heterocyclic
aromatic ring which consists of carbon atoms and from 1 to
4 heterotams independently selected from the group
consisting of N, O and S.
Examples of heterocycles include, but are not limited
to, 1H-indazole, 2-pyrrolidonyl, 2H,6H-1,5,2-dithiazinyl,
2H-pyrrolyl, 3H-indolyl, 4-piperidonyl, 4aH-carbazole, 4H-
quinolizinyl, 6H-1,2,5-thiadiazinyl, acridinyl, azocinyl,
benzimidazolyl, benzofuranyl, benzothiofuranyl,
benzothiophenyl, benzoxazolyl, benzthiazolyl,
benztriazolyl, benztetrazolyl, benzisoxazolyl,
benzisothiazolyl, benzimidazalonyl, carbazolyl,
4aH-carbazolyl, ~-carbolinyl, chromanyl, chromenyl,
cinnolinyl, decahydroquinolinyl, 2H,6H-1,5,2-dithiazinyl,
dihydrofuro[2,3-b]tetrahydrofuran, furanyl, furazanyl,
imidazolidinyl, imidazolinyl, imidazolyl, 1H-indazolyl,
indolenyl, indolinyl, indolizinyl, indolyl,
isobenzofuranyl, isochromanyl, isoindazolyl, isoindolinyl,
isoindolyl, isoquinolinyl (benzimidazolyl), isothiazolyl,
isoxazolyl, morpholinyl, naphthyridinyl,
octahydroisoquinolinyl, oxadiazolyl, 1,2,3-oxadiazolyl,
1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl,
oxazolidinyl., oxazolyl, oxazolidinylperimidinyl,
phenanthridinyl, phenanthrolinyl, phenarsazinyl,
phenazinyl, phenothiazinyl, phenoxathiinyl, phenoxazinyl,
phthalazinyl, piperazinyl, piperidinyl, pteridinyl,
piperidonyl, 4-piperidonyl, pteridinyl, purinyl, pyranyl,
pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolyl,
pyridazinyl, pyridooxazole, pyridoimidazole,
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pyridothiazole, pyridinyl, pyridyl, pyrimidinyl,
pyrrolidinyl, pyrrolinyl, pyrrolyl, quinazolinyl,
quinolinyl, 4H-quinolizinyl, quinoxalinyl, quinuclidinyl,
carbolinyl, tetrahydrofuranyl, tetrahydroisoquinolinyl,
tetrahydroquinolinyl, 6H-1,2,5-thiadiazinyl, 1,2,3-
thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl,
1,3,4-thiadiazolyl, thianthrenyl, thiazolyl, thienyl,
thienothiazolyl, thienooxazolyl, thienoimidazolyl,
thiophenyl, triazinyl, 1,2,3-triazolyl, 1,2,4-triazolyl,
1,2,5-triazolyl, 1,3,4-triazolyl, tetrazolyl, and
xanthenyl. Preferred heterocycles include, but are not
limited to, pyridinyl, thiophenyl, furanyl, indazolyl,
benzothiazalyl, benzimidazolyl, benzothiaphenyl,
benzofuranyl, benzoxazolyl, benzisoxazolyl, quinolinyl,
isoquinolinyl, imidazolyl, indolyl, isoidolyl, piperidinyl,
piperidonyl, 4-piperidonyl, piperonyl, pyrrazolyl, 1,2,4-
triazolyl, 1,2,3-triazolyl, tetrazolyl, thiazolyl,
oxazolyl, pyrazinyl, and pyrimidinyl. Also included are
fused ring and spiro compounds containing, for example, the
above heterocycles.
The phrase "pharmaceutically acceptable" is employed
herein to refer to those compounds, materials,
compositions, and/or dosage forms which are, within the
scope of sound medical judgment, suitable for use in
contact with the tissues of human beings and animals
without excessive toxicity, irritation, allergic response,
or other problem or complication, commensurate with a
reasonable benefit/risk ratio.
As used herein, "pharmaceutically acceptable salts"
refer to derivatives of the disclosed compounds wherein the
parent compound is modified by making acid or base salts
thereof. Examples of pharmaceutically acceptable salts
include, but are not limited to, mineral or organic acid
salts of basic residues such as amines; alkali or organic
salts of acidic residues such as carboxylic acids; and the
like. The pharmaceutically acceptable salts include the
conventional non-toxic salts or the quaternary ammonium
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' WO 00/35451 PCT/US99/30332
salts of the parent compound formed, for example, from non-
toxic inorganic or organic acids. For example, such
conventional non-toxic salts include those derived from
inorganic acids such as hydrochloric, hydrobrornic,
sulfuric, sulfamic, phosphoric, nitric and the like; and
the salts prepared from organic acids such as acetic,
propionic, succinic, glycolic, stearic, lactic, malic,
tartaric, citric, ascorbic, pamoic, malefic, hydroxymaleic,
phenylacetic, glutamic, benzoic, salicylic, sulfanilic, 2-
acetoxybenzoic, fumaric, toluenesulfonic, methanesulfonic,
ethane disulfonic, oxalic, isethionic, and the like.
The pharmaceutically acceptable salts of the present
invention can be synthesized from the parent compound which
contains a basic or acidic moiety by conventional chemical
methods. Generally, such salts can be prepared by reacting
the free acid or base forms of these compounds with a
stoichiometric amount of the appropriate base or acid in
water or in an organic solvent, or in a mixture of the two;
generally, nonaqueous media like ether, ethyl acetate,
ethanol, isopropanol, or acetonitrile are preferred. Lists
of suitable salts are found in Remington's Pharmaceutical
Sciences, 17th ed., Mack Publishing Company, Easton, PA,
1985, p. 1418, the disclosure of which is hereby
incorporated by reference.
Since prodrugs are known to enhance numerous desirable
qualities of pharmaceuticals (e. g., solubility,
bioavailability, manufacturing, etc...) the compounds of
the present invention may be delivered in prodrug form.
Thus, the present invention is intended to cover prodrugs
of the presently claimed compounds, methods of delivering
the same and compositions containing the same. "Prodrugs"
are intended to include any covalently bonded carriers
which release an active parent drug of the present
invention in vivo when such prodrug is administered to a
mammalian subject. Prodrugs the present invention are
prepared by modifying functional groups present in the
compound in such a way that the modifications are cleaved,
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WO 00/35451 PCT/US99/30332
either in routine manipulation or in vivo, to the parent
compound. Prodrugs include compounds of the present
invention wherein a hydroxy, amino, or sulfhydryl group is
bonded to any group that, when the prodrug of the present
invention is administered to a mammalian subject, it
cleaves to form a free hydroxyl, free amino, or free
sulfhydryl group, respectively. Examples of prodrugs
include, but are not limited to, acetate, formate and
benzoate derivatives of alcohol and amine functional groups
in the compounds of the present invention.
"Stable compound" and "stable structure" are meant to
indicate a compound that is sufficiently robust to survive
isolation to a useful degree of purity from a reaction
mixture, and formulation into an efficacious therapeutic
agent.
SYNTHESIS
The compounds of Formula I can be prepared using the
reactions and techniques described below. The reactions
are performed in a solvent appropriate to the reagents and
materials employed and suitable for the transformations
being effected. It will be understood by those skilled in
the art of organic synthesis that the functionality present
on the molecule should be consistent with the
transformations proposed. This will sometimes require a
judgment to modify the order of the synthetic steps or to
select one particular process scheme over another in order
to obtain a desired compound of the invention. It will
also be recognized that another major consideration in the
planning of any synthetic route in this field is the
judicious choice of the protecting group used for
protection of the reactive functional groups present in the
compounds described in this invention. An authoritative
account describing the many alternatives to the trained
practitioner is Greene and Wuts (Protective Groups In .
Organic Synthesis, Wiley and Sons, 1991).
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Generally, compounds described in the scope of this
patent application can be synthesized by the route
described in Scheme 1. The appropriately substituted
pyrrolidine (n=0) or piperidine (n=1) 1_ is alkylated by a
N-protected alkylhalide (halide = C1, Br, I), mesylate,
tosylate or triflate, 2_, (where E represents a linkage
described within the scope of this application in its fully
elaborated form with the appropriate protecting groups as
understood by one skilled in the art or in a precursor form
which can be later elaborated into its final form by
methods familiar to one skilled in the art) with or without
base or an acid scavenger to yield the piperidinyl- or
pyrrolidinylalkyl protected amine 3. If the halide is not
I, then KI can also be added to facilitate the
displacement, provided the solvent is suitable, such as an
alcohol, 2-butanone, DMF or DMSO, amongst others. The
displacement can be performed at room temperature to the
reflux temperature of the solvent. The protecting group is
subsequently removed to yield amine ~. Protecting groups
include phthalimide which can be removed by hydrazine, a
reaction familiar to one skilled in the art; bis-BOC which
can be removed by either TFA or HC1 dissolved in a suitable
solvent, both procedures being familiar to one skilled in
the art; a nitro group instead of an amine which can be
reduced to yield an amine by conditions familiar to one
skilled in the art; 2,4-dimethyl pyrrole (S. P. Breukelman,
et al. J. Chem. Soc. Perkin Trans. I, 1984, 2801); N-
1,1,4,4-Tetramethyl-disilylazacyclopentane (STABASE) (S.
Djuric, J. Venit, and P. Magnus Tet. Lett 1981, 22, 1787)
and other protecting groups. Reaction with an isocyanate or
isothiocyanate _5 (Z = O,S) yields urea or thiourea 6.
Reaction with a chloroformate or chlorothioformate 7
(Z=O,S) such as o-, p-nitrophenyl-chloroformate or
phenylchloroformate (or their thiocarbonyl equivalents),
followed by diplacement with an amine 9_, also yields the
corresponding urea or thiourea 6. Likewise, reaction of
carbamate _8 (X = H, or 2- or 4-N02) with disubstituted
105


CA 02350730 2001-05-07
WO 00/35451 PCT/US99/303~2
amine 10 yields trisubstituted urea or thiourea _12.
Reaction of the amine 4 with an N,N-disubstituted carbamoyl
chloride 11 (or its thiocarbonyl equivalent) yields the
corresponding N,N-disubstituted urea or thiourea _12.
Amine 4 can also be reductively- aminated to yield 13 by
conditions familiar to one skilled in the art and by the
following conditions: Abdel-Magid, A. F., et al. Tet. Lett.
1990, 31, (39) 5595-5598. This secondary amine can
subsequently be reacted with isocyanates or isothiocyanates
to yield trisubstituted ureas 14 or with carbamoyl
chlorides to yield tetrasubstituted ureas 15.
1.06


CA 02350730 2001-05-07
' WO 00135451 PCT/US99/30332
SCHEME 1
H
~- P
+ ~~_P -
RS 1 n P=protecting,group 5 'n
R 3
X=leaving group: Cl,Br,I,
ri=0 , 1 OTs , OMs , OTf , etc
E=linker
F-NH- ( C=Z ) -NR2R 3 ~2
~ C1- (C=Z ) -NR2R3
11 5 'n
R5 n 12 R 4
C1-(C=Z)-OPh R3N=C=Z
R2R3~ 7 5
F~-NH- ( C=Z ) -OPh- Y ~~- ( C=Z ) -NH-R 3
R3NH2
Jn 6
RS n g 9 RS
R2CH0
Y = H, o- or p-N02 Na(Ac0)3BH /
F~-NRz - ( C=Z ) -NHR 3
R3N=C=Z ~Rz
5
i
RS n 14 ~ n 13
R5
~--~Rz- (C=Z ) -NR2R3 Cl- (C=Z) -NR2R3
Z=O or S 11
RS n 15
One can also convert amine ~, into an isocyanate,
isothiocyanate, carbamoyl chloride or its thiocarbonyl
5 equivalent (isocyanate: Nowakowski, J. J Prakt. Chem/Chem-
Ztg 1996, 338 (7), 667-671; Knoelker, H.-J. et al., Angew.
Chem. 1995, 107 (22), 2746-2749; Nowick, J. S.et al., J.
Org. Chem. 1996, 61 (11), 3929-3934; Staab, H. A.; Benz,
107


CA 02350730 2001-05-07
WO 00135451 PCT/US99/30332
W.; Angew Chem 1961, 73; isothiocyanate: Strekowski L.et
al., J. Heterocycl. Chem. 1996, 33 (6), 1685-1688;
Kutschy, Pet al., Synlett. 1997, (3), 289-290) carbamoyl
chloride: Hintze, F.; Hoppe, D.; Synthesis (1992) 12, 1216-
~5 1218; thiocarbamoyl chloride: Ried, W.; Hillenbrand, H.;
Oertel, G.; Justus Liebigs Ann Chem 1954, 590) (these
reactions are not shown in Scheme 1). These isocyanates,
isothiocyantes, carbamoyl chlorides or thiocarbamoyl
chlorides can then be reacted with R2R3NH to yield di- or
trisubstituted ureas or thioureas 12. An additional urea
forming reaction involves the reaction of
carbonyldiimidazole (CDI) (Romine, J. L.; Martin, S. W.;
Meanwell, N. A.; Epperson, J. R.; Synthesis 1994 (8), 846-
850) with 4 followed by reaction of the intermediate
imidazolide with 9 or in the reversed sequence (9 + CDI,
followed by 4). Activation of imidazolide intermediates
also facilitates urea formation (Bailey, R. A., et al.,
Tet. Lett. 1998, 39, 6267-6270). One can also use 13 and
10 with CDI. The urea forming reactions are done in a non-
hydroxylic inert solvent such as THF, toluene, DMF, etc.,
at room temperature to the reflux temperature of the
solvent and can employ the use of an acid scavenger or base
when necessary such as carbonate and bicarbonate salts,
triethylamine, DBU, Hunigs base, DMAP, etc.
Substituted pyrrolidines and piperidines _2 can either
be obtained commercially or be prepared as shown in Scheme
2. Commercially available N-benzylpiperid-3-one ~ can be
debenzylated and protected with a BOC group employing
reactions familiar to one skilled in the art. Subsequent
Wittig reaction followed by reduction and deprotection
yields piperidine 20 employing reactions familiar to one
skilled in the art. Substituted pyrrolidines may be made
by a similar reaction sequence. Other isomers and analogs
around the piperidine ring can also be made by a similar
reaction sequence. Chiral pyrrolidines/piperidines can be
synthesized via asymmetric hydrogenation of 18 using chiral
catalysts (see Parshall, G.W. Homogeneous Catalysis, John
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CA 02350730 2001-05-07
WO 00/35451 PCT/US99/30332
Wiley and Sons, New York: 1980, pp. 43-45; Collman, J.P.,
Hegedus, L.S. Principles and Applications of
Organotransition Metal Chemistry, University Science Books,
Mill Valley, CA, 1980, pp. 341-348).
SCHEME 2
H2/Pd Wittig H2/Pd
--s
BOCZ O g
B~ BOC
17 18
16
R5
H+
19
BOC 20
H
The cyanoguanidines (Z = N-CN) can be synthesized by
the method of K. S. Atwal, et al. and references contained
therein (J. Med. Chem. (1998) 41, 217-275). The
nitroethylene analog (Z = C-N02) can be synthesized by the
method of F. Moimas, et al. (Synthesis 1985, 509-510) and
references contained therein. The malononitrile analog (Z
- C(CN)2) may be synthesized by the method of S. Sasho, et
al. (J. Med. Chem. 1993, 36, 572-579).
Guanidines (Z=NRla) can be synthesized by the methods
outlined in Scheme 3. Compound 21 where Z=S can be
methylated to yield the methylisothiourea ~. Displacement
of the SMe group with amines yields substituted guanidines
23 (see H. King and I. M. Tonkin J. Chem. Soc. 1946, 1063
and references therein). Alternatively, reaction of
thiourea ~ with amines in the presence of triethanolamine
and "lac sulfur" which facilitates the removal of H2S
yields substituted guanidines 23 (K. Ramadas, Tet. Lett.
1996, 37, 5161 and referenees therein). Finally, the use
of carbonimidoyldichloride 2~, or 25 followed by sequential
109


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WO 00/35451 PCT/US99/30332
displacements by amines yields the corresponding
substituted guanidine 23 (S. Nagarajan, et al., Syn. Comm.
1992, 22, 1191-8 and references therein). In a similar
manner, carbonimidoyldichlorides, R2-N=C(C1)2 (not shown in
Scheme 3) and R3-N=C(C1)2 (not shown) can also be reacted
sequentially with amines to yield di- and trisubstituted
guanidine 23.
SCHEME 3
~1 _ ( C=S ) _~ la ~1 _ ( C=NHRla ) -SMe
CH3 I
R5 n 21 R5 n 22
n= 0 , 1
~zR3
N(CH20H)3,
"lac sulfur~, ~~-(C=NHRla)-lVRzR3
R2R 3NH w
l/
l.HzNR", Et3N RS n 23
2 . HNR2R3 or
1 . HNR2R3 , Et3N 1 . HNR2R3 , Et3N
2 . HzNR" 2 . 13 or
1 . 13 , Et3N
N=C ( C 1 ) z 2 . HNRZR3
l Rla-N=C ( C1 ) 2
/n 2 4
R 25
A method for introducing substituents in linkage E is
that of A. Chesney et al. (Syn. Comm. 1990, 20 (20), 3167-
3180) as shown in Scheme 4. Michael reaction of
pyrrolidine or piperidine _1 with Michael acceptor 26 yields
intermediate 27 which can undergo subsequent reactions in
the same pot. For example, reduction yields alcohol _2_8
which can be elaborated to the amine ~9 by standard
procedures familiar to one skilled in the art. Some of
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CA 02350730 2001-05-07
WO 00/35451 PCT/US99/30332
these include mesylation or tosylation followed by
displacement with NaN3 followed by reduction to yield amine
29. Another route as depicted in Scheme 4 involves
reaction with diphenylphosphoryl azide followed by
reduction of the azide to~ yield amine 29.
SCHEME 4
g 9
9
7 / O Michael
R5 n -----
1 g _m ~ Rs n Rl i
26 27
n=0, 1 Ri2Li or Rl2MgBr
g 9 NaBH4 31
9
OH
R5 n R11 ~--OH
2 8 R5 - v ~n Rl l R12
(Ph0)2(p=O)N3 32
(Ph0)2(p=O)N3
H2. pd/C
H2, Pd/C
7 g 9
7 g 9
~2
2
R5 n Rli
2 9 R5 n R11 Rlz 3 3
as described as described
previously
_ previously
1- ( C=Z ) -NR2 R3 - ( C=Z ) -~2 R3
30 1- 34
111


CA 02350730 2001-05-07
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The mesylate or tosylate can also be displaced by
other nucleophiles such as NH3, BOC2N-, potassium
phthalimide, etc., with subsequent deprotection where
necessary to yield amines 29. Finally, 29 can be converted
to urea or thiourea 30 by procedures discussed for Scheme 1
or to the compounds of this invention by procedures
previously discussed. Similarly, aldehyde 27 may be
reacted with a lithium or a Grignard reagent 31 to yield
alcohol adduct 32. This in turn can be converted to urea
or thiourea 34 in the same way as discussed for the
conversion of 28 to 30.
Scheme 5 shows that intermediate 36 can be extended
via a Wittig reaction (A. Chesney, et al. Syn. Comm. 1990,
(20), 3167-3180) to yield 37. This adduct can be
15 reduced catalytically to yield 38 or by other procedures
familiar to one skilled in the art. Alkylation yields 39,
followed by saponification and Curtius rearrangement (T. L.
Capson and C. D. Poulter, Tet. Lett., (1984) 25, 3515-3518)
followed by reduction of vhe benzyl protecting group yields
20 amine 40 which can be elaborated further as was described
earlier in Scheme 1 and elsewhere in this application to
make the compounds of this invention. Dialkyllithium
cuprate, organocopper, or copper-catalyzed Grignard
addition (for a review, see G. H. Posner, "An Introduction
to Synthesis Using Organocopper Reagents", J. Wiley, New
York, 1980; Organic Reactions, 19, 1 (1972)) to alpha, beta-
unsaturated ester 37 yields 41 which can undergo subsequent
transformations just discussed to yield amine 43 which can
be elaborated further to the compounds of this invention as
was described earlier. The intermediate enolate ion
obtained upon cuprate addition to 37 can also be trapped by
an electrophile to yield 42 (for a review, see R. J. K.
Taylor, Synthesis 1985, 364). Likewise, another 2-carbon
homologation is reported by A. Chesney et al. (ibid.) on
intermediate 36 which involves reacting 36 with an enolate
anion to yield aldol condensation product 42 where R12-OH.
The OH group can undergo synthetic transformations which
112
,.


CA 02350730 2001-05-07
WO 00/35451 PCTNS99/30332
are familiar to one skilled in the art and which will be
discussed in much detail later on in the application.
Chiral auxilliaries can also be used to introduce stereo-
and enantioselectivity in these aldol condensations,
procedures which are familiar to one skilled in the art.
113


CA 02350730 2001-05-07
WO 00/35451 PCT/US99/3(3332
SCHEME 5
g 9
H
RS 1n R ~ 0 Michael Rxn
~0
1 Ra R9 ' R5 n R9
36
n=0, 1 35 11
Wittig ~ pph
- ~ ~OMe
H2 Pd / C
OMe
OMe
38
1 . LllA
2 . R 12X .i /
R9
1 . -OH 11 12
2 . ( Ph0 ) 2 ( P O ) N3 R9i
R5 n ,~~ ~2
3.BnOH
39 4.H2 Pd/C 40
to compounds
by methods
g previously
discussed
11 as above 11
n R 9~2 OMe
R R R5 ~n R9 Rio
44 41 p (Rlo)2CuLi
1.LDA
to compounds
by methods 2 . Rl2x
previously ~ ~ a ' a 9 2 . R12X
discussed ~ 11 R
12 as
' li
above 12
_.
R5 'n R9 Rio NH2 R5 n R9 R1° OMe
43 42
Examples of such methods are taught in D. A. Evans, et al.,
J. Am. Chem. Soc. 1981, 103, 2127; D. A. Evans, J. Am.
5 Chem.Soc. 1982, 104, 1737; D. A. Evans, J. Am. Chem. Soc.
114


CA 02350730 2001-05-07
' WO 00/35451 PC'f/US99/30332
1986, 108, 2476; D. A. Evans. et al., J. Am. Chem. Soc.
1986, 108, 6757; D. A. Evans, J. Am. Chem. Soc. 1986, 108,
6395; D. A. Evans, J. Am. Chem. Soc. 1985, 107, 4346; A.
G. Myers, et al., J. Am. Chem. Soc. 1997, 119, 6496. One
can also perform an enantioselective alkylation on esters
38 or 41 with R12X where X is a leaving group as described
in Scheme 1, provided the ester is first attached to a
chiral auxiliary (see above references of Evans, Myers and
Mauricio de L. Vanderlei, J. et al., Synth. Commum. 1998,
28, 3047).
One can also react alpha,beta-unsaturated ester
(Scheme 6) with Corey's dimethyloxosulfonium methylide
(E.J. Corey and M. Chaykovsky, J. Am. Chem. Soc. 1965, 87,
1345) to form a cyclopropane which can undergo eventual
Curtius rearrangement and subsequent elaboration to the
compounds of this invention wherein the carbon containing
R9R1~ is tied up in a cyclopropane ring with the carbon
containing R11R12_ In addition, compound 48 can also
undergo the analogous reactions just described to form
cyclopropylamine 50 which can be further elaborated into
the compounds of this invention as described previously.
Compound 48 may be synthesized by an alkylation reaction of
pyrrolidine/piperidine ~ with bromide 47 in an inert
solvent employing the conditions as described for the
alkylation of 2 onto _1 in Scheme 1.
Another way to synthesize the compounds in the scope
of this application is shown in Scheme 7. Michael reaction
of amine ~ with an acrylonitrile 51 (as described by I.
Roufos in J. Med. Chem. 1996, 39, 1514-1520) followed by
Raney-Nickel hydrogenation yields amine ~3 which can be
elaborated to the compounds of this invention as previously
described.
115


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WO 00/35451 PCT/US99/3U332
SCHEME 6
I-
NaH,
THF
37
1 . -OH
2 . ( Ph0 ) 2 ( P=O ) N3
3.BnOH
4.H2 Pd/C
g 9
to compounds 11
by methods -.
previously ,
discussed R5 'n R9 NH2
46
7 8
I_
COZ Me -----
Me
R5 n R11 NaH,
48 THF
49
s 1.'OH
1 + 2 . ( Ph0 ) 2 ( P=O ) N3
Br ~ 3.BnOH
47 C02Me 4. H2 Pd/C
R11
7 8 9
to compounds
by methods
previously
discussed RS n R11
In Schemes 4,5, and 6, we see that there is no gem-
substitution on the alpha-carbon to the electron-
s withdrawing group of what used to be the Michael acceptor.
In other words, in Scheme 4, there is no R10 gem to R9; in
Scheme 5, there is no R10 gem to one of the Rss and in
116


CA 02350730 2001-05-07
WO 00/35451 PCT/US99/30332
Scheme 7 there is no R10 gem to R9. Gem-substitution can
be introduced by reacting pyrrolidine or p:~.peridine 1 with
the epoxide of Michael acceptors 26, 35, and 51 to yield
the corresponding alcohols (for amines reacting with
epoxides of Michael acceptors, see Charvillon, F. B.;
Amouroux, R.; Tet. Lett. 1996, 37, 5103-5106; Chong, J.
M.; Sharpless, K. B.; J Org Chem 1985, 50, 1560). These
alcohols eventually can be further elaborated into R10 by
one skilled in the art, as, for example, by tosylation of
the alcohol and cuprate displacement (Hanessian, S.;
Thavonekham, B.; DeHoff, B.; J Org. Chem. 1989, 54, 5831),
etc., and by other displacement reactions which will be
discussed in great detail later on in this application.
SCH~ 7
R~
H CN
Ra-Ni /Hz
+ R _
R ~ CN -r 9
R5 n
1 Re R5 n
52
n=0,1 51
R~
CHz -NHz
to compounds
R9 by methods previously
discussed
RS n
53
Further use of epoxides to synthesize compounds of
this invention are shown in Scheme 8. Reaction of pyrrole
or piperidine ,~ with epoxide 54 yields protected amino-
alcohol 55. This reaction works exceptionaly well when R~
and Re are H hut is not limited thereto. The reaction is
performed in an inert solvent at room temperature to the
reflex temperature of the solvent. Protecting groups on
the nitrogen atom of 54 include BOC and CBZ but are not
limited thereto. The hydroxyl group can be optionally
117

i
CA 02350730 2001-05-07
WO 00/35451
PCT/US99/30332
protected by a variety of protecting groups familiar to one
skilled in the art.
SCHEME 8
H R~ 9or10 ~ 8 9or10
+ Rs NH- p OH
R5 n R1 -~-~
R12
1 ~ p
54
R5 n R11 R12
n=0,1 55
[0]
~ -P
( R9or1 o-H )
D7 ,R8 p9orlQ
_P
57 ~
R9or10-M R~~n R1- 1 Rlz
where M=Li,MgBr, 56
MgCl, ZnCl, etc.
_P
7 8 9or10
to compounds
OH
by methods
~- P previously
discussed
Rs ~ ~n R11 R12
58
Deprotection of the nitrogen by methods familiar to one
skilled in the art yields 56 which can be elaborated to the
compounds of this invention by the procedures previously
discussed. If R9=H, then oxidation, for example, by using
PCC (Corey E.J. and Suggs, J.W., Tet, Lett. 1975, 31, 2647-
2650) or with the Dess-Martin periodinane (Dess, D.B. and
Martin, J.C., J. Org. Chem. 1983, 48, 4155-4156) yields
ketone 57 which may undergo nucleophilic 1,2-addition with
organometallic reagents such as alkyl- or aryllithiums,
118


CA 02350730 2001-05-07
WO OOI35451 PCT/US99/30332
Grignards, or zinc reagents, with or without CeCl3 (T.
Imamoto, et al., Tet. Lett. 1985, 26, 4763-4766; T.
Imamoto, et al., Tet. Lett. 1984, 25, 4233-4236) in aprotic
solvents such as ether, dioxane, or THF to yield alcohol
58. The hydroxyl group can be optionally protected by a
variety of protecting groups familiar to one skilled in the
art. Deprotection of the nitrogen yields 56 which can be
finally elaborated to the compounds of this invention as
previously discussed. Epoxides disclosed by structure 54
may be synthesized enantio-selectively from amino acid
starting materials by the methods of Dellaria, et al. J Med
Chem 1987, 30 (11), 2137, and Luly, et aI. J Org Chem
1987, 52 (8), 1487.
The carbonyl group of ketone 57 in Scheme 8 may
undergo Wittig reactions followed by reduction of the
double bond to yield alkyl, arylalkyl, heterocyclic-alkyl,
cycloalkyl, cycloalkylalkyl, etc. substitution at that
position, reactions that are familiar to one skilled in the
art. Wittig reagents can also contain functional groups
which after reduction of the double bond yield the
following functionality: esters (Buddrus, J. Angew Chem.,
1968, 80), nitriles (Cativiela, C.et al., Tetrahedron
1996, 52 (16), 5881-5888.), ketone (Stork, G.et al., J Arn
Chem Soc 1996, 118 (43), 10660-10661), aldehyde and
methoxymethyl (Bertram, G.et al., Tetrahedron Lett 1996, 37
(44), 7955-7958.), gamma-butyrolactone Vidari, G.et
al.,Tetrahedron: Asymmetry 1996, 7 (10), 3009-3020.),
carboxylic acids (Svoboda, J.et al., Collect Czech Chem
Cornmun 1996, 61 (10), 1509-1519), ethers (Hamada, Y.et
al., Tetrahedron Lett 1984, 25 (47), 5413), alcohols (after
hydrogenation and deprotection--Schonauer, K.; Zbiral, E.;
Tetrahedron Lett 1983, 24 (6), 573), amines (Marxer, A.;
Leutert, T. Helv Chim Acta, 1978, 61) etc., all of which
may further undergo transformations familiar to one skilled
in the art to form a wide variety of functionality at this
position.
119


CA 02350730 2001-05-07
WO 00/35451 PCT/US99/30332
Scheme 9 summarizes the displacement chemistry and
subsequent elaborations that can be used to synthesize the
R9 groups. In Scheme 9 we see that alcohol 55 or 58 may be
tosylated, mesylated, triflated, or converted to a halogen
by methods familiar to one skilled in the art to produce
compound 59. (Note that all of the following reactions in
this paragraph can be also performed on the compounds,
henceforth called carbon homologs of 55 or 58 where OH can
be (CH2)rOH - -and it is also understood that these carbon
homologs may have substituents on the methylene groups as
well). For example, a hydroxyl group may be converted to a
bromide by CBr4 and Ph3P (Takano, S. Heterocycles 1991, 32,
1587). For other methods of converting an alcohol to a
bromide or to a chloride or to an iodide see R.C. Larock,
Comprehensive Organic Transformations, VCH Publishers, New
York, 1989, pp. 354-360. Compound 59 in turn may be
displaced by a wide variety of nucleophiles as shown in
Scheme 9 including but not limited to azide, cyano,
malonate, cuprates, potassium thioacetate, thiols, amines,
etc., all nucleophilic displacement reactions being
familiar to one skilled in the art. Displacement by
nitrite yields a one-carbon homologation product. Nitrite
60 can be reduced with DIBAL to yield aldehyde 61. This
aldehyde can undergo reduction to alcohol 62 with, for
example, NaBH4 which in turn can undergo all of the SN2
displacement reactions mentioned for alcohol 55 or 58.
Alcohol 62 is a one carbon homolog of alcohol 55 or 58.
Thus one can envision taking alcohol 62, converting it to a
leaving group X as discussed above for compound 55 or 58,
and reacting it with NaCN or KCN to form a nitrite,
subsequent DIBAL reduction to the aldehyde and subsequent
NaBH4 reduction to the alcohol resulting in a two carbon
homologation product. This alcohol can undergo activation
followed by the same SN2 displacement reactions discussed
previously, ad infinitum, to result in 3,4,5...etc. carbon
homologation products. Aldehyde 61 can also be reacted
with a lithium or Grignard reagent to form an alcohol 61a
120


CA 02350730 2001-05-07
WO 00/35451 PCT/US99/30332
which can also undergo the above displacement reactions.
Oxidation by methods familiar to one skilled in the art
yields ketone 6~b. Displacement by malonate yields malonic
ester 63 which can be saponified and decarboxylated to
yield carboxylic acid 64, a two carbon homologation
product. Conversion to ester f5 (A. Hassner and V.
Alexanian, Tet. Lett, 1978, 46, 4475-8) and reduction with
LAH yields alcohol ~8 which can undergo all of the
displacement reactions discussed for alcohol 55 or ~.
Alcohols may be converted to the corresponding fluoride _70
by DAST (diethylaminosulfur trifluoride) (Middleton, W. J.;
Bingham, E. M.; Org. Synth. 1988, VI, pg. 835). Sulfides
7~ can be converted to the corresponding sulfoxides _72
(p=1) by sodium metaperiodate oxidation (N. J. Leonard, C.
R. Johnson J. Org. Chem. 1962, 27, 282-4) and to sulfones
72 (p=2) by Oxone~ (A. Castro, T.A. Spencer J. Org. Chem.
1992, 57, 3496-9). Sulfones 72 can be converted to the
corresponding sulfonamides 73 by the method of H.-C. Huang,
E. et al., Tet. Lett. (1994) 35, 7201-7204 which involves
first, treatment with base followed by reaction with a
trialkylborane yielding a sulfinic acid salt which can be
reacted with hydroxylamine-O-sulfonic acid to yield a
sulfonamide. Another route to sulfonamides involves
reaction of amines with a sulfonyl chloride (G. Hilgetag
and A. Martini, Preparative Organic Chemistry, New York:
John Wiley and Sons, 1972, p.679). This sulfonyl chloride
(not shown in Scheme 9) can be obtained from the
corresponding sulfide (71 where R9d=H in Scheme 9, the
hydrolysis product after thioacetate displacement),
disulfide, or isothiouronium salt by simply reacting with
chlorine in water. The isothiouronium salt may be
synthesized from the corresponding halide, mesylate or
tosylate 59 via reaction with thiourea (for a discussion on
the synthesis of sulfonyl chlorides see G. Hilgetag and A.
Martini, ibid., p. 670). Carboxylic acid 64 can be
converted to amides 6~f by standard coupling procedures or
via an acid chloride by Schotten-Baumann chemistry or to a
121


CA 02350730 2001-05-07
WO 00/35451 PCT/US99/30332
Weinreb amide (66: R9a=OMe, R9a'= Me in Scheme 9) (S. Nahm
and S. M. Weinreb, Tet. Lett., 1981, 22, 3815-3818) which
can undergo reduction to an aldehyde 67 (R9b=H in Scheme 9)
with LAH (S. Nahm and S. M. Weinreb, ibid.) or reactions
with Grignard reagents to~form ketones 67 (S. Nahm and S.
M. Weinreb, ibid.). The aldehyde 67 obtained from the
Weinreb amide reduction can be reduced to the alcohol with
NaBH4. The aldehyde or ketone 67 (or 61 or 61b for that
matter) can undergo Wittig reactions as discussed
previously followed by optional catalytic hydrogenation of
the olefin. This Wittig sequence is one method for
synthesizing the carbocyclic and heterocyclic substituted
systems at R9 employing the appropriate carbocyclic or
heterocyclic Wittig (or Horner-Emmons) reagents. Of
course, the Wittig reaction may also be used to synthesize
alkenes at R9 and other functionality as well. Ester 65 can
also form amides 66 by the method of Weinreb (A. Basha, M.
Lipton, and S.M. Weinreb, Tet. Lett. 1977, 48, 4171-74) (J.
I. Levin, E. Turos, S. M. Weinreb, Syn. Comm. 1982, 12,
989-993). Alcohol 68 can be converted to ether 69 by
procedures familiar to one skilled in the art, for example,
NaH, followed by an alkyliodide or by Mitsunobu chemistry
(Mitsunobu, O. Synthesis, 1981, I-28). Alcohol 55 or 58,
62, or 68, can be acylated by procedures familiar to one
skilled in the art, for example, by Schotten-Baumann
conditions with an acid chloride or by an anhydride with a
base such as pyridine to yield 78. Halide, mesylate,
tosylate or triflate 59 can undergo displacement with azide
followed by reduction to yield amine 74 a procedure
familiar to one skilled in the art. This amine can undergo
optional reductive amination and acylation to yield 75 or
reaction with ethyl formate (usually refluxing ethyl
formate) to yield formamide 75. Amine 74 can again undergo
optional reductive amination followed by reaction with a
sulfonyl chloride to yield 76, for example under Schotten-
Baumann conditions as discussed previously. This same
sequence may be employed for amine 60a, the reduction
122


CA 02350730 2001-05-07
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product of nitrile 60. Tosylate 59 can undergo
displacement with cuprates to yield 77 (Hanessian, S.;
Thavonekham, B.; DeHoff, B.; J Org. Chem. 1989, 54, 5831).
Aldehyde 61 or its homologous extensions can be reacted
with a carbon anion of an aryl (phenyl, naphthalene, etc.)
or heterocyclic group to yield an aryl alcohol or a
heterocyclic alcohol. If necessary, CeCl3 may be added (T.
Imamoto, et al., Tet. Lett. 1985, 26, 4763-4766; T.
Imamoto, et al., Tet. Lett. 1984, 25, 4233-4236). This
alcohol may be reduced with Et3SiH and TFA (J. Org. Chem.
1969, 34, 4; J. Org. Chem. 1987, 52, 2226) (see discussion
of aryl and heterocyclic anions for Schemes 20-22). These
aryl and heterocyclic anions may also be alkylated by 59.
(or its carbon homology to yield compounds where R9
contains an aryl or heterocyclic group. Compound 59 or its
carbon homologs may be alkylated by an alkyne anion to
produce alkynes at R9 (see R.C. Larock, Comprehensive
Organic Transformations, New York, 1989, VCH Publishers, p
297). In addition, carboxaldehyde 61 or its carbon
homologs can undergo 1,2-addition by an alkyne anion
(Johnson, A.W. The Chemistry of Acetylenic Compounds. V.
1. "Acetylenic Alcohols," Edward Arnold and Co., London
(1946)). Nitro groups can be introduced by displacing
bromide 59 (or its carbon homologs) with sodium nitrite in
DMF (J.K. Stille and E.D. Vessel J. Org. Chem. 1960, 25,
478-490) or by the action of silver nitrite on iodide 59 or
its carbon homologs (Org. Syntheses ~, 37-39).
123


CA 02350730 2001-05-07
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SCHEME 9
to
8 10 ~ 8 10 10
7 ~ ~ R9d ( O ) 9d
'O ( CO) R9b (0~
\ ~. --
78 ' 70 ~' ' 71 72
1.
KSAc 10
2 . -OH ~ ' ( O ) 2~9a
DAST
3 . R9'jX R9a'
or KSR9d /~ ~ 73
to
OH ~ 8 10
-p w
R5 n R11 Rla 5 9 - p
55 or 58 R5 n Rll R12
If an anion is made of the pyrrolidine/piperidine _1
with LDA or n-BuLi, etc., then that anion in a suitable
nonhydroxylic solvent such as THF, ether, dioxane, etc.,
can react in a Michael-type fashion (2,4-addition) with an
alpha, beta-unsaturated ester to yield an intermediate
enolate which can be quenched with an electrophile (R9X)
(where X is as described in Scheme 1) (Uyehara, T.; Asao,
N.; Yamamoto, Y.; J Chem Soc, Chem Commun 1987, 1410) as
shown in Scheme 10.
124


CA 02350730 2001-05-07
' WO 00/35451 PCT/US99/30332
SCHEME 9 (con't)
_ P _--s _ P
1, 1,
55 or 58 , 59
X=OTs ; ( R9 ) 2CuLi KCN' Et OEt
- Na
to
R1o ~ OE
1 . N 7 B i0
\ 2. [H 60 ~ 0
77
r'~C OEt
R1o
l0 63
y ~z ~ - CHZ OH io
CHO
74
62
1 . R98'CHO
Na (Ac0) 3HH 1 .R9aCH0, 61 1 - OH
2 . R9bS02C1 Na (Ac0) 3BH 2 -H+.
2 . R9aCOC1 or -C02
~OH to
Et0 ( C=O ) H , D
R CH2NH2
' NRa SO2Rb
61 a 'N;"
76 l0 60a
NHR 9a'C ( O ) R9a H
(or -NHCHO) 7 a to
to
7 B 10 reductive
b _
OR9d ~ ~ 0 amination +
acylation 64
if desired
61b
OH Rg R9aR9a' R9b
7 10
10 7 8 10 7 8 10
LAH
1
68 ~ \ ~ 65
67 GG
L H
125


CA 02350730 2001-05-07
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It is to be understood that R9 is either in its final form
or in a suitable protected precursor form. This
electrophile can be a carbon-based electrophile, some
examples being formaldehyde to introduce a CH20H group, an
aldehyde or a ketone which also introduces a one-carbon
homologated alcohol, ethylene oxide (or other epoxides)
which introduces a -CH2CH20H group (a two-carbon homologated
alcohol), an alkyl halide, etc., all of which can be later
elaborated into R9. It can also be an oxygen-based
electrophile such as MCPBA, Davis~ reagent (Davis, F. A.;
Haque, M. S.; J Org Chem 1986, 51 (21),4083; Davis, F. A.;
Vishwaskarma, L. C.; Billmers, J. M.; Finn, J.; J Org Chem
1984, 49, 3241) or Mo05 (Martin, T. et al., J Org Chem
1996, 61 (18), 6450-6453) which introduces an OH group.
These OH groups can undergo the displacement reactions
discussed previously in Scheme 9 or protected by suitable
protecting groups and deprotected at a later stage when the
displacement reactions decribed in Scheme 9 can be
performed. In addition, these OH groups can also undergo
displacement reactions with heterocycles as described for
Schemes 19-22 to introduce N- or C-substituted heterocycles
at this position. Ester 80 can be converted into its
Weinreb amide 82 (S. Nahm and S. M. Weinreb, Tet. Lett.,
1981, 22, 3815-3818) or Weinreb amide 82 can be synthesized
via Michael-type addition of _1 to alpha, beta-unsaturated
Weinreb amide 83. Subsequent reaction with a Grignard
reagent forms ketone 85. This ketone can also be
synthesized in one step directly from _1 and alpha,beta-
unsaturated ketone 84 using the same procedure. This
ketone may be reduced with LAH, NaBH4 or other reducing
agents to form alcohol 86. Or else, ketone 85 can be
reacted with an organolithium or Grignard reagents to form
tertiary alcohol 87 . Or else, ester 80 can be directly
reduced with LiBH4 or LAH to yield primary alcohol 88.
126
,.. q _.....

CA 02350730 2001-05-07
, WO 00/35451 PCT/US99/30332
SCHEME 10
R~
H ~ 10
R ~ l.BuLi
~OMe
Re 0 --
9 ~Rlo
Rs n 2 . R X
7 9 OMe Rs Jn
1 80
n 0,1 1.
R ~ R1o R~ 8
R~ io 84
O 1/~\ ~OH
R8 O R'9 'Rio
Rllorl2
l.BuLi N(CH3)OMe 2.R9X Rs n
81
2 . R9X ~ 83
R'7 s
R~
~ ~N(CH3)OMe ~ Rllorl2
R9 'R1D Rll 9 io
MgBr or ~ R ~R
Rs Jn 82 Ri2MgBr Rs n
R~ a _p
Rllorl2 R11or12MgBr
Rs 'Rio R7 s H
R5 ~n 8 9 ~ a H
Rllorl2 R12
Rllor l2MgBr ~9'R1D ~ ~ 'Rll
Rs n 9 Rio
Rs 'n
-p 86 ~ 87
R 1
R~2 ~ r
9 .Rio ~ 7 B
OH ~ NH 2
to co OOH
9 0 mpounds ~ ~ to
by methods ~ R R
previoiusly R5 n
described
88
Alcohols 86, 87 , and 88 can all be tosylated, mesylated,
triflated, or converted to a halogen by methods discussed
5 previously and displaced with an amine nucleophile such as
azide, diphenylphosphoryl azide (with or without DEAD and
127


CA 02350730 2001-05-07
WO 00/35451 PCTNS99/3~332
Ph3P), phthalimide, etc. as discussed previously (and which
are familiar to one skilled in the art) and after reduction
(azide) or deprotection with hydrazine (phthalimide), for
example, yield the corresponding amines. These can then be
elaborated into the compounds of this invention as
discussed previously. Ketone 85 can also be converted into
imine 89 which can be reacted with a Grignard reagent or
lithium reagent, etc., to form a protected amine 90 which
can be deprotected and elaborated into the compounds of
this invention as discussed previously. Some protecting
groups include benzyl and substituted benzyl which can be
removed by hydrogenation, and cyanoethyl, which can be
removed with aqueous base, etc. It is to be understood
that R~-12 in Scheme 10 can be in their final form or in
precursor form which can be elaborated into final form by
procedures familiar to one skilled in the art.
Magnesium amides of amines have been used to add in a
Michael-type manner to alpha, beta-unsaturated esters where
the substituents at the beta position of the unsaturated
ester are tied together to form a cyclopentane ring (for
example, compound 79 where R~ and R8 are taken together to
be -(CH2)4-) (Kobayashi, K. et al., Bull Chem Soc Jpn, 1997,
70 (7), 1697-1699). Thus reaction of pyrrolidine or
piperidine _1 with cycloalkylidine esters 79 as in Scheme 10
yields esters 80 where R~ and R8 are taken together to form
a cycloalkyl ring. Subsequent elaboration yields compounds
of this invention where R~ and R8 are taken together to form
a cycloalkyl ring.
Compounds of structure 95a may also be synthesized
from epoxyalcohols which are shown in Scheme 11. Allylic
alcohol 91 can be epoxidized either stereoselectively
using VO(acac)2 catalyst (for a review, see Evans: Chem.
Rev. 1993, 93, 1307) or enantioselectively (Sharpless: J.
Am. Chem. Soc. 1987, 109, 5765) to epoxyalcohol 92. SN2
displacement of the alcohol using zinc azide and
triphenylphosphine (Yoshida, A. J. Org. Chem. 57, 1992,
1321-1322) or diphenylphosphoryl azide, L7EAD, and
128
,.


CA 02350730 2001-05-07
WO 00135451 PCT/US99/30332
triphenylphosphine (Saito, A. et al., Tet. Lett. 1997, 38
(22), 3955-3958) yields azidoalcohol 93. Hydrogenation over
a Pd catalyst yields aminoalcohol ~4_. This can be
protected in situ or in a subsequent step with BOC20 to put
on a BOC protecting group, or with CBZ-Cl and base to put
on a CBZ-group or other protecting groups. Alternatively,
the amino group can be reacted with an isocyanate, an
isothiocyanate, a carbamoyl chloride, or any reagent
depicted in Scheme 1 to form 95 which can be alkylated with
_1 to form the compounds of this invention.
129


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SCHEME 11
9 9
R ' R
Re OH RB OH
-s
R1 R1
R12 R12
91 92
9
R ~ R~ 9
B 2 s
R R8
R1
R12 R1
12
93
94
R~ 9 R
R8 P Re - ( C=Z ) NR2R3
1
R R12 Rl 12
R
54 95
H
as in Scheme 8 R5 'n
1
n=0,1
_ ( C=Z ) NR2R3
n
95a
Sometimes amine 1 might have to be activated with
Lewis acids in order to open the epoxide ring (Fujiwara,
M.; Imada, M.; Baba, A.; Matsuda, H.;Tetrahedron Lett 1989,
30, 739; Caron, M.; Sharpless, K. B.; J Org Chem 1985, 50,
1557) or 1 has to be deprotonated and used as a metal
amide, for example the lithium amide (Gorzynsk.i-Smith, J.;
Synthesis 1984 (8), 629) or MgBr amide (Carre, M. C.;
130


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WO 00/35451 PC'~'/US99/30332
Houmounou, J. P.; Caubere, P.; Tetrahedron Lett 1985, 26,
3107) or aluminum amide (Overman, L. E.; Flippin, L. A.;
Tetrahedron Lett 1981, 22, 195).
The quaternary salts (where R4 is present as a
substituent) of pyrrolidines and piperidines can be
synthesized by simply reacting the amine with an alkylating
agent, such as methyl iodide, methyl bromide, ethyl iodide,
ethyl bromide, ethyl or methyl bromoacetate,
bromoacetonitrile, allyl iodide, allylbromide, benzyl
bromide, etc. in a suitable solvent such as THF, DMF, DMSO,
etc. at room temperature to the reflux temperature of the
solvent. Spiroquaternary salts can be synthesized in a
similar manner, the only difference being that the
alkylating agent is located intramolecularly as shown iri
Scheme 12. It is understood by one skilled in the art that
functional groups might not be in their final form to
permit cyclization to the quaternary ammonium salt and
might have to be in precursor form or in protected form to
be elaborated to their final form at a later stage. For
example, the NR1(C=Z)NR2R3 group on the rightmost phenyl
ring of compound 1Q4 might exist as a nitro group precursor
for ease of manipulation during quaternary salt formation.
Subsequent reduction and NR1(C=Z)NR2R3 group formation
yields product ~. The leaving groups represented by X in
Scheme 12 may equal those represented in Scheme 1, but are
not limited thereto. N-oxides of pyrrolidines and
piperidines can be made by the procedure of L_ W. Deady
(Syn. Comm. 1977, 7, 509-514). This simply entails
reacting the pyrrolidine or piperidine with MCPBA, for
example, in an inert solvent such as methylene chloride.
131

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SCHEME 12
X4 8
11812 7 g 11812
1 (C=Z ) NR2R3 X ~ NRl ( C=Z ) NR2R3
R Rlo X=leaving
Rs~lo
Rs n group R5 ~n
n=0,1 96
97
8 21
R 812 R8 11 812
X- R
1 (C Z) NR2R3 1 (C=Z) NR2R3
/9 ~Rlo ~ + ~Rlo
Rs n ~ Q_X ~~R9
Rs n
n=0,1
99
X 12
R a ~11 12 811 NR1 ( C-Z ) NR2R3
X_ R
NR1 (C=Z) NR2R3 ~ Rlo
R9 Rlo --a
R9
s n
R 100 RS~nR R 101
12
9 10 ~ 11 1 (C=Z) NR2R3
R
RI to
1 ( C=Z ) NR2R3 X R
w + ~R9
R9 Rlo
p l l 812 ~ 810
RS ~n ~' 5 n R9
R4_X R R R8
102 103
~1 ( C=Z ) NR2R 3
X_84_814\ , (C=Z) NR2R3
s .
y~ Ry Rlo
Rs - , Jn 104 105
h '
Multisubstituted pyrrolidines and piperidines may be
synthesized by the methods outlined in Scheme 13.
Monoalkylation of 106 via an enolate using LDA or potassium
132


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WO 00135451 PCT/US99/30332
hexamethyldisilazane, or converting 106 first to an
enamine, or by using other bases, all of which can be done
in THF, ether, dioxane, benzene, or an appropriate non-
hydroxylic solvent at -78 oC to room temperature with an
alkylating agent such asvmethyl iodide, benzyl bromide,
etc. where X is as defined in Scheme 1, yields product 107.
This product can subsequently undergo alkylation again
under thermodynamic or kinetic conditions and afterwards,
if need be, can undergo two more alkylations to produce
tri- and tetrasubstituted analogs of X07. The
thermodynamic or kinetic conditions yield regioselectively
alkylated products (for a discussion on thermodynamic vs.
kinetic alkylations see H. House Modern Synthetic
Reactions, W. A. Benjamin, Inc. (Menlo Park, CA: 1972)
chapter 9).
SCHEME 13
R R
~Ph 1. Base Ph Ph
n 2. R5-X
106 107n Sp n
108
n=0,1 X = leaving group R5p=precursor to RS
H2 / Pd or
Pd(OH)2
R H
to compounds.by
methods previously
described
RS n
109
cis and trans
133


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WO 00/35451 PCT/US99/30332
SCHEME 14
C02 Et C02 Et C02 Et
BoC2o l.Base Rs
---~
2 . R 6X
H B~ X=leaving OC
110 111 112
group as
defined in 1. [H]
Scheme 1 2.Swern
5*
CH2R CH ( OH) RS* RS*MgBr or CHO
~Rs
.~ ~Rs s Rs
R5*Li
B~ BOC BOC 113
lI9 118
Wittig
CHZ R5 * CH2 CHZR 5 * CH= CHR5
R6 R6 H2 Pd/C
.~ ~Rs
H BOC 116
120 ~ 114
H+1
CH2 CHzR 5* CH= CHRS *
~Rs ~R6
1
H 117 ~ H 115
RS*=R5 or a
precursor
thereof to products by methods
previously described
Subsequent Wittig olef ination yields compound X08.
Hydrogenation (asymmetric hydrogenation is an option here:
Parshall, G.W. Homogeneous Catalysis, John Wiley and Sons, '
New York: 1980, pp. 43-45; Collman, J.P., Hegedus, L.S.
Principles and Applications of Organotransition Metal
Chemistry, University Science Books, Mill Valley, CA, 1980,
pp. 341-348) yields pyrrolidine or piperidine 109 which can
134


CA 02350730 2001-05-07
W O 00/3545 i
PCTNS99/30332
be resolved into its relative and/or absolute isomers at
this stage or later on in the synthesis either by
crystallization, chromatographic techniques, or other
methods familiar to one skilled in the art. The amine 109
an then be elaborated into the compounds of this invention
by methods discussed previously (Scheme 1). The carbonyl-
containing intermediate 107 in Scheme 13 can also be
reduced to the methylene analog via a Wolff-Kishner
reduction and modifications thereof, or by other methods
familiar to one skilled in the art. The carbonyl group can
also be reduced to an OH group, which can undergo all of
the reactions described in Scheme 9 to synthesize the R6
groups. This piperidine or pyrrolidine can be deprotected
and elaborated to the compounds of this invention by
methods discussed earlier. Thus, mono-, di-, tri-, or
tetraalkylated carbonyl-containing pyrrolidines or
piperidines can be synthesized, which in turn can be
reduced to the corresponding -CH2- analogs employing the
Wolff-Kishner reduction or other methods.
Another method for synthesizing gem-substituted
pyrrolidines and piperidines is shown in Scheme 14. It is
understood by one skilled in the art that some of the steps
in this scheme can be rearranged. It is also understood
that gem-disubstitution is only shown at only one position
on the piperidine ring and that similar transformations may
be performed on other carbon atoms as well, both for
piperidine and pyrrolidine. Thus, 3-carboethoxypiPeridine
~0 may be BOC-protected and alkylated employing a base
such as LDA, KHMDS, LHDMS, etc., in THF, ether, dioxane,
etc. at -78 °C to room temperature, and an alkylating agent
R6X where X is a halide (halide = C1, Br, I1, mesylate,
tosylate or triflate, to yield . Reduction using DIBAL,
for example, and if necessary followed by oxidation such as
a Swern oxidation (S. L. Huang, K. Omura, D. Swern J. Org.
Chem. 1976, 41, 3329-32) yields aldehyde ~3_. Wittig
olefination (~.~4_) followed by deprotection yields ~ which
may be elaborated as described previously into the
135


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WO 00/35451
PCT/US99/30332
compounds of this invention. Reduction of the Wittig
adduct 114 yields 116 which may be deprotected to yield 1
17
which may be in turn elaborated as described previousl
Y
into the compounds of this invention. Reaction of
aldehyde 113 with an alkyllithium or Grignard rea
gent
yields alcohol 118 which may be reduced catalyticall o
Y r
with Et3SiH/TFA (J. Org. Chem. 1969, 34~ 4; J. Or C
9. hem.
1987, 52, 2226) if RS* (R5* _ R5 or a precursor thereof
is
aromatic to yield 119. If R5* is not aromatic, then the OH
may be reduced by the method of Barton (Barton, D.
H. R.,
Jaszberenyi, J. C. Tet. Lett. 1989, 30, 2619 and other
references therein). Once tosylated, the alcohol can a
lso
be displaced with dialkyllithium cuprates (not shown
(Hanessian, S.; Thavonekham, B.; DeHoff, B . J Or C
'' 3. hem.
1989, 54, 5831). Deprotection if necessary field
Y s 120
which may be elaborated as described previously into
the
compounds of this invention.
136
r


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WO 00/35451 PCTNS99/30332
SCHEME 15
R R
n 1. s-BuLi )n
R 5orR13
TMEDA
BOC
OC 2 , R5- or R13-X 122
121
X=as defined
n=0,1 in Scheme 1 1, s-BuLi
TN~DA
2. R5- or R13-X
R~ . / n R
1. s-BuLi
13~ RSO rRl3 s ~ n
R orR R5orR13 TMEDA
OC 5 _ 5~ 5 13
B 2 . R R ~R orR
124 or R13-X or Rl3 BOC
123
1. s-BuLi
TMEDA
2. R5- or R13-X
R
R13r5o~ R50r'R13
R5orR13~ ~R5orR13
BOC
125
A method for the alkylation of alkyl groups, arylalkyl
groups, allylic groups, propargylic groups, etc., and a
5 variety of other electrophiles onto the pyrrolidinyl and/or
piperidinyl alpha-carbons (alpha to the ring nitrogen atom)
is represented by the work of Peter Beak, et al. as shown
in Scheme 15. It is understood by one skilled in the art
that the R5 and R13 groups are either in their precursor,
protected, or final form. Only one R5 group is shown to
be substituted on piperidine/pyrrolidine ~. However it
is understood by one skilled in the art that additional
functionality may be present on the ring in either
137


CA 02350730 2001-05-07
WO 00/35451 PCT/US99/30332
precursor, protected, or final form. Thus lithiation with
an alkyllithium reagent such as n-BuLi or s-BuLi as shown,
followed by quenching with an electrophilic species such as
R5X or R13X where X is as defined in Scheme 1 and R5 and R13
are in their precursor, protected, or final form, yields
monoalkylated piperidine/pyrrolidine 122. This alkylation
may occur either stereoselectively (P. Beak and W.K. Lee
J. Org. Chem. 1990, 55, 2578-2580) or enantioselectively if
sparteine is included as a source of chirality (P. Beak, et
al., J. Am. Chem. Soc. 1994, 116, 3231-3239). The
alkylation process may be repeated up to three more times
as shown in Scheme 15 to result in di-, tri-, and
tetrasubstitution at the alpha-positions.
Compounds where R9 and R1~ form a cyclic 3,4,5,6, or 7-
membered ring can be synthesized by the methods disclosed
in Scheme 16. These same methods may also be used to
synthesize gem-disubstituted compounds in which R9 can be
different from R1~ by step-wise alkylation of the malonate
derivative. Of course, this scheme may be used to
synthesize compounds where R1~=H also. For example, a
cyclohexyl-fused malonate may be synthesized by Michael
addition and alkylation of I(CH2)qCH=CCOZMe with dimethyl
malonate employing NaH/DMF (Desmaele, D.; Louvet, J.-M.;
Tet Lett 1994, 35 (16), 2549-2552) or by a double Michael
addition (Reddy, D. B., et al., Org. Prep. Proced. Int. 24
(1992) 1, 21 -26) (Downes, A. M.; Gill, N. S.; Lions, F.; J
Am Chem or by an alkylation followed by a second
intromolecular alkylation employing an iodoaldehyde (Suami,
T.; Tadano, K.; Kameda, Y.; Iimura, Y.; Chem Lett 1984,
1919), or by an alkylation followed by a second
intramolecular alkylation employing an alkyl dihalide
(Kohnz, H.; Dull, B.; Mullen, K.; Angew Chem 1989, 101
(10), 1375), etc.
138
~ ,..


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WO 00/35451 PCT/LJS99/30332
SCHEME 16
R9 Rlo R9 Rio
diethyl ~ pEt OEt s H
malonate -' ~OEt
126 127
H
R5 n
r
1
n=0,1
t (H)
1.
129
128
1 j U 1~
to compounds by methods
previously described
Subsequent monosaponification (Pallai, P.V., Richman,
S., Struthers, R.S., Goodman, M. Int. J. Peptide Protein
Res. 1983, 21, 84-92; M. Goodman Int. J. Peptide Protein
Res. 19831, 17, 72-88), standard coupling with pyrrolidine/
piperidine 1 yields 128. Reduction with borane yielus 129
followed by reduction with LAH yields X30 which can be then
converted to amine 131 and then to the compounds of this
invention by procedures as discussed previously. Ester 12~
can also be converted to a Weinreb amide and elaborated to
the compounds of this invention as described in Scheme 10
for ester 80 which would introduce substituents R11 and R12.
139


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WO 00/35451 PCT/US99/30332
Scheme 17 describes another method for the synthesis
of compounds where R9 and R1~ are taken together to form
cycloalkyl groups. Aminoalcohols 132 are found in the
literature (CAS Registry Nos. for n = 0,2,2,3,
respectively: 45434-02-4; 2041-56-7, 2239-31-8, 2041-57-8).
They can easily be protected, as with a BOC group (or CBZ,
or any other compatible protecting group) by known
procedures familiar to one skilled in the art to yield
alcohols 133. The alcohols can then be activated either by
conversion to a halide or to a mesylate, tosylate or
triflate by methods familiar to one skilled in the art and
as discussed previously, and then alkylated with
pyrrolidine/piperidine 1 by the conditions described in
Scheme 1 to yield I35. Subsequent deprotection yields
amine 136 which can be elaborated to the compounds of this
invention as described previously. Of course, alcohol 133
can be oxidized to the aldehyde and then reacted with
R~°rBMgBr or R~~raLi with or without CeCl3 to yield the
corresponding alcohol 133 where instead of -CH20H, we would
have -CHR~~r80H. This oxidation-I,2-addition sequence may
be repeated to yield a tertiary alcohol. The alcohol may
then be tosylated, mesylated, triflated, or converted to
C1, Br, or I by procedures familiar to one skilled in the
art to yield 134 and then displaced with
pyrrolidine/piperidine 1 to yield I35. Subsequent
deprotection yields 136 which may undergo elaboration to
the compounds of this invention as discussed previously.
140
~ .,.,~


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WO 00/35451 PCT/US99/30332
SCHEME 17
(CH2)n (CH2)n (CHZ)n
H2N-CH2 '~ BOC-NH-CH2 --~gOC-NH-CH2
BOCZO
OH OH g
n=0,1,2,3 133
134
132 "
R5 'n
1
n=0,1
.... ,
n_
(H+)
,.,., ,
13 6 R7
135
to compounds by
previously described
- BOC
A method to introduce cycloalkyl groups at RllRlz is
shown in Scheme 18. Protection of the nitrogen of
compounds 137 which are commercially available yields 138
(the protecting group may be BOC, CBZ, or any other
compatible protecting group) by procedures familiar to one
skilled in the art. Esterification by any one of a number
procedures familiar to one skilled in the art (for example
A. Hassner and V. Alexanian, Tet. Lett, 1978, 46, 4475-8)
followed by reduction with DIBAL (or alternatively
reduction to the alcohol with, for example, LiBH4, followed
by Swern oxidation (op. cit.)) yields aldehyde ~. One
carbon homologation via the Wittig reaction followed by
hydrolysis of the, vinyl ether yields aldehyde 141.
Reductive amination (Abdel-Magid, A. F., et al. Tet. Lett.
1990, 31, (39) 5595-5598) yields 142 followed by
141


CA 02350730 2001-05-07
WO 00/35451 PCT/US99/30332
deprotection yields amine 143 which can be elaborated to
the compounds of this invention by the methods previously
discussed. Of course, aldehyde 139 can be reacted with
R9orloMgBr or R9orloLi with or without CeCl3 to yield an
alcohol which can be oxidized to a ketone. Wittig one-
carbon homologation on this ketone as described above
followed by hydrolysis yields 141 where the -CH2CH0 is
substituted with one R9orio group (-CHR9orlo CHO) .
SCHEME 18
(CH2)n BOCzO (CH2)n (CH2)r,
H2 ~ BOC ---~ BOC
2.ROH
COO H DCC C02 R CHO
n=0, l, 2, 3 DAP 138 139
137
(CH2)n H+ (CH2)n
~-- BOC
B OC CH2 CHO CH= CHOMe
1,
Na(Ac0)3BH 141 140
t r-~u_ v
- BOC
~H+~ to compounds
-~ by methods
described
previously
R7 11
R, ..
142 143
Aldehyde 141 (-CH2CH0) or its monosubstituted analog
synthesized above (-CHR9or1oCH0) can undergo alkylation with
R9orloX where X is as defined in Scheme 1 to yield compound
X41 containing one or both of the R9 and Rlo substituents
alpha to the aldehyde group. Alkylati.on can be performed
using LDA or lithium bistrimethylsilyl amide amongst other
bases in an inert solvent such as ether, THF, etc., at -78
142


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WO 00/35451 PCT/US99/30332
°C to room temperature. Aldehyde ~ (-CH2CH0)or its
substit~.~ted analogs synthesized above (i.e., -CHR9R1~CH0)
can undergo reductive amination with _1 and subsequent
elaboration to the compounds of this invention. Aldehyde
141 (-CH2CH0)or its substituted analogs synthesized above
(i.e., -CHR9R1~CH0) can also undergo 1,2-addition with
R~°rBMgBr or R~°rBLi to yield the corresponding alcohol -
CH2CHR~°reOH or -CHR9R1~CHR~°r80H. The alcohol may then be
tosylated, mesylated, triflated, or converted to C1, Br, or
I by procedures familiar to one skilled in the art and
displaced with pyrrolidine/piperidine _1 to yield, after
subsequent deprotection and elaboration, the compounds of
this invention. Or else alcohol -CH2CHR~°r80H or -
CR9R1~CHR~°r80H can be oxidized (i.e., Swern, op. cit.) to
the ketone and reductively arninated with 1 and subsequently
elaborated to the compounds of this invention. Or else
alcohol -CH2CHR~°r80H or -CR9R1~CHR~°=gOH can be oxidized
(i.e., Swern, op. cit.) to the ketone and reacted once more
with R~°r8MgBr or R~°rBLi to yield the corresponding alcohol
-CH2CR~R80H or -CR9R1~CR~ReOH. If the ketone enolizes easily,
CeCl3 may be used together with the Grignard or lithium
reagent. The alcohol can again be tosylated, mesylated,
triflated, or converted to Cl, Br, or I by procedures
familiar to one skilled in the art and displaced with
pyrrolidine/ piperidine _1 to yield, after subsequent
deprotection and elaboration, the compounds of this
invention. Thus each one of the R~, R8, R9, and R1~ groups
may be introduced into compounds ~, and 143 and and,
of course, in the compounds of this invention, by the
methods discussed above.
A method for the synthesis of N-substituted
heterocycles at RS is shown in Scheme 19. The heterocycle
can be deprotonated with NaH or by other bases familiar to
one skilled in the art, in a solvent such as DMF, THF, or
another appropriate non-hydroxylic solvent and reacted with
piperidine or pyrrolidine 143 at room temperature to the
reflux temperature of the solvent. Deprotection and
143


CA 02350730 2001-05-07
WO 00/35451 PCT/US99/30332
elaboration as described before yields compounds where R5
contains an N-substituted heterocycle. If the nitrogen
atom of the heterocycle is sufficiently nucleophilic, then
an acid scavenger, such as K2C03, KHC03, Na2C03, NaHC03,
amongst others, can be used in place of NaH, employing THF,
DMF, or methyl ethyl ketone as solvents. In this case
hydroxylic solvents may be used as well, such as methanol,
ethanol, etc. from room temperature to the reflux
temperature of the solvent. Compound 143 as well as its
other positional isomers are available, for example, from
commercially available 4-hydroxymethylpiperidine, 2-, 3-,
and 4-carboethoxypiperidine, L- or D-proline ethyl ester,
or from methyl 1-benzyl-5-oxo-3-pyrrolidinecarboxylate by
methods familiar to one skilled in the art and as discussed
previously in this application.
SCHEME 19
he' rocycle heterocycle
BOC
H
NaH or KZC03
X
143
n=0,1
deprotect
X = leaving group to compounds by
methods
described
previously
A method for the synthesis of C-substituted
heterocycles at R5 is shown in Scheme 20. Many
heterocycles such as the ones shown in Scheme 20, but not
limited thereto, can be metallated with strong bases such
as LDA, n-BuLi, sec-BuLi, t-BuLi, etc. t.o yield the
corresponding anionic species. These anions may also be
generated via halogen-metal. exchange employing n-BuLi, or
other alkyllithium reagents. These reactions may be
144


CA 02350730 2001-05-07
WO 00/35451 PCT/US99/30332
performed in THF, ether, dioxane, DME, benzene, etc. at -78
°C to room temperature.
SCHEME 20
..~ ~ (_)
(_)
x
(_) (-) ~ (_) heterocycle
HOC ~ t
'' ( CH ) m
X
'n ~ (_)
(-) (-) Boc
143 ~ 145
n=0,1
X = leaving m=1,2
w
group ~ (_)
described
in Scheme 1 C02Li
to compounds
by methods
described
i (_) ~ (-)
previously
R=suitable protecting
(_) I (-) group or functional
group
etc.
For reviews of these metallations and halogen-metal
exchange reactions see Organometallics in Organic
Synthesis, FMC Corp., Lithium Division, 1993, pp. 17-39;
Lithium Link, FMC Corp., Spring 1993, pp. 2-17; n-
Butyllithium in Organic Synthesis, Lithium Corp. of
America, 1982, pp. 8-16; G. Heinisch, T. Langer, P.
Lukavsky, J. Het. Chem. 1997, 34, 17-19. The anions can
then be quenched with electrophile 143 or its positional
isomers to yield the corresponding C-alkylated heterocyclic
pyrrolidine or piperidine ~4~5.
145


CA 02350730 2001-05-07
WO 00/35451 PCT/US99/30332
SCHEME 21
1 (-) ~ (-)
i
R
he'.
BOC ~ ~(-) (-) (-)
>.
H n ~ (-)
146 ~ ~ ( )
n=G , 1
(H]
~ (-)
02Li (')
C02 Li
etc . hetE -
R=suitable protecting
group or functional
group
to compounds
by methods described
previously "
Another method for the synthesis of C-substituted
heterocyclic-methylpyrrolidines or piperidines is shown in
Scheme 21. The protected aldehyde 146 is reacted with the
anion of the heterocycle (its generation as described
previously) at -78 °C to room temperature with or without
CeCl3 in an inert solvent such as THF, ether, dioxane, DME,
benzene, etc. to yield carbinol 147. Catalytic
hydrogenation of the alcohol yields the corresponding
methylene compound 145. Other reduction methods include
Et3SiH/TFA (J. Org. Chem. 1969, 34, 4; J. Org. Chem. 1987,
52, 2226) amongst others familiar to one skilled in the
art. It is understood by one skilled in the art that the
aldehyde group can be located in other positions instead
of, for example, the 4-position of piperidine in compound
146
~.


CA 02350730 2001-05-07
WO 00/35451 PCT/US99/30332
as depicted in Scheme 21. It is to be understood that
other heterocycles may also be used besides the ones shown
in Scheme 20 and 21.
The anions of the methyl-substituted heterocycles may
also be reacted with a BOC-protected piperidone or
pyrrolidone (148) to yield alcohols 149 as shown in Scheme
22 (see above reviews on metallations for references).
These alcohols may be reduced using Pt02 and TFA (P. E.
Peterson and C. Casey, J. Org. Chem. 1964, 29, 2325-9) to
yield piperidines and pyrrolidines 150. These can
subsequently be taken on to the compounds of this invention
as described previously. It is understood by one skilled
in the art that the carbonyl group can be located in other
positions instead of, for example, the 4-position of
piperidine in compound 148 as depicted in Scheme 22. It is
to be understood that other heterocycles may also be used
besides the ones shown in Scheme 22.
SCHEME 2 2
heterocycle
BOC ~ (_) (-) ~ /
/n H
~'BOC
(-) 149 n
148 (_)
n=0, 1
etc. TFA, Et3SiH
R=suitable protecting
group or functional heterocycle
group
to compounds of by
methods described
previously
as
One may also react aryl (phenyl, naphthyl, etc.)
anions, generated either by halogen-metal exchange or by
ortho-directed metallation (Snieckus, V. Chem. Rev. 1990,
147


CA 02350730 2001-05-07
WO OOI3545I PCT/US99/30332
90, 879-933) using n- or s- or t-BuLi in a non-hydroxylic
solvent such as THF, ether, etc., with or without TMEDA and
allow them to react with compounds 143, 146, and 148 with
subsequent elaboration to yield the compounds of this
invention by the methods~depicted in Schemes 19-22.
Another method for the preparation of C-substituted
heterocycles is shown in Scheme 23. Protected piperidone
148 undergoes a Wittig reaction with heterocyclic
phosphorous ylides to yield 151. Hydrogenation over a
noble metal catalyst such as Pd in an alcoholic solvent or
with an optically active transition metal catalyst (see
asymmetric hydrogenation references of Parshall and
Coleman, op. cit.) yields 152 which can be further
elaborated into the compounds of this invention by the
procedures described previously. It will be appreciated by
one skilled in the art that the carbonyl group can be
located in other positions instead of, for example, the 4-
position of piperidine in compound 148 as depicted in
Scheme 23. It is to be understood that other heterocycles
may also be used besides the ones shown in Scheme 23.
148
r .. ._


CA 02350730 2001-05-07
WO 00/35451 PCT/US99/30332
Scheme 23
Ph3
heteroc cle
BOC ~ / Ph3 Y
n
148 PPh3
n=0,1 PPh3
etc.
R=suitable protecting
group or functional
group
hetE '
to compounds
by methods
described ''
previously
..
Syntheses of amines ~, 10, and the amines which are
precursors to isocyanates or isothiocyanates 5 will now be
discussed. For example, 3-nitrobenzeneboronic acid (1~:
Scheme 24) is commerically available and can undergo Suzuki
couplings (Suzuki, A. Pure Appl. Chem. 1991, 63, 419) with
a wide variety of substituted iodo- or bromo aryls (aryls
such as phenyl, naphthalene, etc.), heterocycles, alkyls,
akenyls (Moreno-manas, M., et al., J. Org. Chem., 1995, 60,
2396), or alkynes. It can also undergo coupling with
triflates of aryls, heterocycles, etc. (Fu, J.-m, Snieckus,
V. Tet. Lett. 1990, 31, 1665-1668). Both of the above
reactions can also undergo carbonyl insertion in the
presence of an atmosphere of carbon monoxide (Ishiyama, et
al., Tet. Lett. 1993, 34, 7595). These nitro-containing
compounds (155 and X57) can then be reduced to the
corresponding amines either via catalytic hydrogenation, or
via a number of chemical methods such as Zn/CaCl2 (Sawicki,
E. J Org Chem 1956, 21). The carbonyl insertion compounds
149


CA 02350730 2001-05-07
WO 00/35451 PCT/US99/3033.2
(158) can also undergo reduction of the carbonyl group to
either the CHOH or CH2 linkages by methods already
discussed (NaBH4 or Et3SiH, TFA, etc.). These amines can
then be converted to isocyanate 5 via the following methods
(Nowakowski, J. J Prakt Chem/Chem-Ztg 1996, 338 (7), 667-
671; Knoelker, H.-J. et al., Angew Chem 1995, 107 (22),
2746-2749; Nowick, J. S.et al., J Org Chem 1996, 61
(11), 3929-3934; Staab, H. A.; Benz, W.; Angew Chem 1961,
73); to isothiocyanate 5 via the following methods
(Strekowski L.et al., J Heterocycl Chem 1996, 33 (6), 1685-
1688; Kutschy, Pet al., Synlett 1997, (3), 289-290); to
carbamoyl chloride 11 (after 156 or 158 is reductively
aminated with an R2 group) (Hintze, F.; Hoppe, D.;
Synthesis (1992) 12, 1216-1218); to thiocarbamoyl chloride
11 (after 156 or 158 is reductively- aminated with an R2
group) (Ried, W.; Hillenbrand, H.; Oertel, G.; Justus
Liebigs Ann Chem 1954, 590); or just used as 9, or 10
(after 156 or 158 is reductively aminated with an R2
group), in synthesizing the compounds of this invention by
the methods depicted in Scheme 1.
150


CA 02350730 2001-05-07
WO 00/35451 PCT/US99/30332
SCHEME 24
02
Suzuki-type 02
X-~ coupling
B (OH) 2 X=Br, I, OTf
153 154 155
Suzuki-type
coupling, CO (g) ~H~
2
n2
0
158 O 157 156
make isocyanate or
isothiocyanate ~,
or carbamoyl chlorides
or used as ~ or ~ to make
the compounds of this
invention as described for
the compounds of Scheme 1
Likewise, protected aminobromobenzenes or triflates or
protected aminobromoheterocycles or triflates 159 (Scheme
25) may undergo Suzuki-type couplings with arylboronic
acids or heterocyclic boronic acids (160) These same
bromides or triflates _15~ may also undergo Stille-type
coupling (Echavarren, A. M., Stille, J.K. J. Am. Chem.
Soc., 1987, 109, 5478-5486) with aryl, vinyl, or
heterocyclic stannanes X63. Bromides or triflates 159 may
also undergo Negishi-type coupling with other aryl or
heterocyclic bromides 1~4 (Negishi E. Accts. Chem. Res.
1982, 15, 340; M. Sletzinger, et al., Tet. Lett. 1985, 26,
2951). Deprotection of the amino group yields an amine
with can be coupled to make a urea and other linkers
151


CA 02350730 2001-05-07
WO OOI35451 PCT/US99/30332
containing Z as described above and for Scheme 1. Amino
protecting groups include phthalimide, 2,4-dimethyl pyrrole
(S. P. Breukelman, et al. J. Chem. Soc. Perkin Trans. I,
1984, 2801); N-1,1,4,4-Tetramethyldisilyl-azacyclopentane
(STABASE) (S. Djuric, J.~Venit, and P. Magnus Tet. Lett
1981, 22, 1787) and others familiar to one skilled in the
art.
SCHEME 2 5
P Suzuki-type -P
coupling
+ (HO) 2
Br,I,OTf 160
159
Stille-type 161
coupliing
9 + Bu3 Srr-
163 -P
Negishi-type
coupling
159 + Br or
vn2
164
make isocyanate or
isothiocyanate _5, s
or carbamoyl chlorides 11,
or used as 9 or 10 to make 1 62
the compounds of this
invention as described for
the compounds of Scheme 1
Compounds where R7 and R8 are taken together to form
=NRBb can be synthesized by the methods in Scheme 25a.
Reacting 1 with nitrile a with CuCl catalysis forms amidine
b where R8b is H (Rousselet, G.; Capdevielle, P.; Maumy,
M.; Tetrahedron Lett. 1993, 34 (40), 6395-6398). Note that
the urea portion may be in final form or in precursor form
(for example, a protected nitrogen atom; P = protecting
group such as STABASE, bis-BOC, etc., as was discussed
previously) which may be subsequently elaborated into the
compounds of this invention. Compounds b may be also
synthesized by reacting iminoyl chloride c with
152


CA 02350730 2001-05-07
WO 00/35451 PCT/US99/30332
pyrrolidine/piperidine 1 to yield b where R8b is not H
(Povazanec, F., et al., J. J. Heterocycl. Chem., 1992,
29, 6, 1507-1512). Iminoyl chlorides are readily
available from the corresponding amide via PC15 or
CC14/PPh3 (Duncia, J.V. ~t al., J. Org. Chem., 1991, 56,
2395-2400). Again, the urea portion may be in final form
or in precursor form.
Scheme 25a
H R9 Rio
R' NRl(C=Z)NR2R3 or N-P
R~ n ~Ri2 --1
1 N R8 R11
n=0,1 a
R 1 (C=Z) NR2R3
.2
R9 Rio
+ R~ NR1(C=Z)NR2R3 or N-P
R5 n C B Rl~'R12 -~ b
1
NR8 b
n=0,1 c
Many amines are commercially available and can be used
as _9, 10, or used as precursors to isocyanates or
isothiocyanates _5. There are numerous methods for the
synthesis of non-commercially available amines familiar to
one skilled in the art. For example, aldehydes and ketones
may be converted to their O-benzyl oximes and then reduced
with LAH to form an amine (Yamazaki, S.; Ukaji, Y.;
153


CA 02350730 2001-05-07
WO 00/35451 PCT/US99/30332
Navasaka, K.; Bull Chem Soc Jpn 1986, 59, 525). Ketones
and trifluoromethylketones undergo reductive amination in
the presence of TiCl4 followed by NaCNBH4 to yield amines
(Barney, C.L., Huber, E.W., McCarthy, J.R. Tet. Lett. 1990,
31, 5547-5550). Aldehydes and ketones undergo reductive
amination with Na(Ac0)3BH as mentioned previously to yield
amines (Abdel-Magid, A. F., et al. Tet. Lett. 1990, 31,
(39) 5595-5598). Amines may also be synthesized from
aromatic and heterocyclic OH groups (for example, phenols)
via the Smiles rearrangement (Weidner, J.J., Peet, N.P. J.
Het. Chem., 1997, 34, 1857-1860). Azide and nitrile
displacements of halides, tosylates, mesylates, triflates,
etc. followed by LAH or other types or reduction methods
yield amines. Sodium diformyl amide (Yinglin, H., Hongwen,
H. Synthesis 1989 122), potassium phthalimide, and bis-BOC-
amine anion can all displace halides, tosylates, mesylates,
etc., followed by standard deprotection methods to yield
amines, procedures which are familiar to one skilled in the
art. Other methods to synthesize more elaborate amines
involve the Pictet-Spengler reaction, imine/immonium ion
Diels-Alder reaction (Larsen, S.D.; Grieco, P.A. J: Am.
Chem. Soc. 1985, 107, 1768-69; Grieco, P.A., et al., J.
Org. Chem. 1988, 53, 3658-3662; Cabral, J. Laszlo, P. Tet.
Lett. 1989, 30, 7237-7238; amide reduction (with LAH or
diborane, for example), organometallic addition to imines
(Bocoum, A. et al., J. Chem. Soc. Chem. Comm. 2993, 1542-4)
and others all of which are familiar to one skilled in the
art.
Compounds containing an alcohol side-chain alpha to
the nitrogen of the piperidine/pyrrolidine ring can be
synthesized as shown in Scheme 25b. Only the piperidine
case is exemplified, and it is to be understood by one
skilled in the art that the alpha-substituted pyrrolidines
may be synthesized by a similar route. It is also
understood that appropriate substituents may be present on
the piperidine/pyrrolidine ring. A 4-benzylpiperidine 196
is protected with a BOC group. The BOC-piperidine 197 is
154


CA 02350730 2001-05-07
WO 00/35451 PCT/US99/30332
then metallated under conditions similar to those Beak, et
al. (P. Beak and W.-K. Lee, J. Org. Chem. 1990, 55, 2578-
2580, and references therein) and quenched with an aldehyde
to yield alcohol 298. The metallation may also be done
enantioselectively using sparteine (P. Beak, S.T. Kerrick,
S. Wu, J. Chu J. Am. Chem. Soc. 1994, 116, 3231-3239).
This alcohol can be deprotonated with NaH and cyclized to
carbamate 198a which permits structural assignments of the
erythro and threo isomers. Deprotection with base yields
aminoalcohol 199. Subsequent N-alkylation yields
phthalimidoalkylpiperidine 201. It is to be understood
that the alkyl chain does not necessarily have to be n-
propyl, but that n-propyl was chosen for demonstration
purposes only. Deprotection of the phthalimido group with
hydrazine yields amine 202. Finally, reaction with an
isocyanate or via any of the previously described
conditions described in Scheme 1 yields urea 203. If an
isocyanate is used, the isocyanate can add twice to yield
urea-carbamate 204.
155

CA 02350730 2001-05-07
WO 00/35451 PCT1US99/30332
Schane 25b
O
N.H N~p
v -
Di-t-butyl Bicarbonate
'IxF' , 0 C to 2 5 C
197
196 p 1) EtZo, ~, -70 °c
~ 2) sec-BuLi,
N p'_ ° °
-70 C to -30 C &
OH
O again to -70 °C
R ~ N ~ 3) RCHO,
1 g g O -70 °C to -30 °C then
v=
R quench with water
NaOH, EtOH,
reflex, 3h ~ 195a + threo
erythro
0
OH K2~. KI, 2-butanone NON
OH
i R
t o
I o il R
199 Br~N ~ ~ ~ 20I
0
2 0 0 N2H4 , EtOH
O
N ~N ~NHR3
OH H R3NC0
i R 203
+ O THF, 25 °c _ N OH ~z
N ~N~NHR3
O H
R O ~R3 202
204
Compounds where Z = N-CN, CHN02, and C(CN)2 can be
synthesized by the methods shown in Scheme 25c. Thus amine
208 reacts with malononitrile 207 neat or in an inert
solvent at room temperature to the reflex temperature of
the solvent, or at the melting point of the solid/solid
mixture, to yield malononitrile 206. This in turn can
undergo reaction with amine 205 under similar conditions
stated just above to yield molononitrile 209. Likewise, a
similar reaction sequence may be used to make 212 and 215
156


CA 02350730 2001-05-07
10
WO 00/35451 PCT/US99/30332
[for Z = C(CN) 2J, see for example P. Traxler, et al., J.
Med. Chem. (1997), 40, 3601-3616; for Z = N-CN, see K. S.
Atwal, J. Med. Chem. (1998) 41, 271; for Z = CHN02, see J.
M. Hoffman, et al., J. Med. Chem. (1983) 26, 140-144).
Scheme 25c.
+ R2R3NH
S
207 208
NC CN
\S /
NC CN
NC CN
5 ~N/E\~ I 2 5 ~N/E\N N/R
R ~ R1 + \S N/R ~ R ~ Rl R2
13
205 206 R 209
O2N
NOz
/E~ /E~ I iR3
~N ~ ~N N N
R5 ~ R1 + \S I N'/R3 .-~ R5 Rl R2
i2
205 210 R 212
N02
+ R2R3NH
\ /
S S
211 208
157


CA 02350730 2001-05-07
WO 00/35451 YCT/US99/30332
,,.rCN
N
~N/E\~ ~ NfCN E
R ~ + N/ ~ ~ /R3
Ri ~ ~ R3 ~ R5 ~ N N
/ I1 12
0 N ~ R R
205 214 Rz
215
N/CN /
+ RZR3NH
O
0
213 208
E
The compounds of this invention and their preparation
can be understood further by the following working
examples. These examples are meant to be illustrative of
the present invention, and are not to be taken as limiting
thereof.
EXAMPLE 1
Part A: Preparation of 4-benzyl-1-(3-N-phthalimido-n-prop-
1-yl)piperidine
V
I5
4-benzylpiperidine (8.0 g , 45.6 mmol, 1eq), N-(3-
bromopropyl)-phthalimide (I3.5 g, 50.2 mmol, 1.1 eq),
potassium iodide (7.6 g, 45.6 mmol, 1 eq) and potassium
carbonate (2.6 g, 91.3 mmol, 2 eq) were refluxed in 125 mL
of 2-butanone. The reaction was worked up after 5 hours by
filtering off the inorganic solids then adding EtOAc and
rinsing the organic layer 2X with water. The organic layer
was dried over magnesium sulfate then the solvent removed
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CA 02350730 2001-05-07
WO 00/35451 PCT/US99/30332
in vacuo to obtain an amber oil. The oil was purified by
flash chromatography in 100 EtOAc to remove impurities
then 8:2 chloroform/methanol to isolate 3.67 g of the
product as a light amber oil. NMR(300 MHz, CDC13) 8 8.00-
7 . 80 (m, 2H) ; 7 . 80-7 . 60 (3n, 2H) ; 7 .35-7 . 10 (m, 3H) ; 7 . 08 (d,
2H, J=7 Hz); 3.76 (t, 2H, J = 7 Hz); 2.83 (d, 2H, J=10 Hz);
2.45-2.30 (m, 4H); 1.95-1.30 (m, 7H); 1.20-0.90 (m, 2H).
Part B: Preparaton of 4-benzyl-1-(3-amino-n-prop-1-
yl)piperidine
~~z
4-benzyl-1-(3-N-phthalimido-n-prop-1-yl)piperidine
(13.72 g, 37.9 mmol, 1 eq.) was dissoved in 200 mL of EtOH
at 25 oC under N2, the anhydrous hydrazine (2.38 mL, 75.7
mmol, 2 eq.) was added. The solution was then refluxed
during which time a white precipitate formed. The reaction
was worked up after refluxing 4 hours by filtering off the
solids. The solvent was removed in vacuo to obtain an oil
which was re-rotovapped from toluene to remove excess
hydrazine. Obtained an oil which was stirred in Et20.
Insoluble material was filtered then the solvent removed in
vacuo to obtain 5.558 of an amber oil as product. NMR
(300 MHz, CDC13) b 7.40-7.21 (m, 2H); 7.21-7.05 (m, 3H);
2.92 (d, 2H, J=10 Hz) ; 2.73 (t, 2H, J=7 Hz) ; 2 .53 (d, 2H,
J=7 Hz); 2.40-2.20 (m, 2H); 1.84 (t of t, 2H, J=7,7 Hz);
1.75-1.10 (m, 9H).
Part C: N-(3-cyanophenyl)-N'-[3-[4-(phenylmethyl)-1-
piperidinyl]propyl]urea
r
H H ~N
159


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4-benzyl-1-(3-amino-n-prop-1-yl)piperidine (300 mg,
1.29 mmol, 1 eq} was dissoved in THF at 25 oC under N2 then
3-cyanophenyl isocyanate (186 mg, 1.29 mmol, 1 eq) was
added. TLC after 30 minutes shows the reaction complete.
The solvent was removed in vacuo then the residue was
purified over silica gel in 100 EtOAc to 8:2
chloroform/MeOHto yield 437 mg of an amber oil as product.
NMR (300 MHz, DMSO-d6) 8 9.90-9.50 (m, 1H); 9.32 (s, 1H);
7.93 (s, 1H); 7.59 (d, 1H, J= 7Hz); 7.43 (t, 1H, J= 7Hz);
7.40-7.24 (m, 3H); 7.24-7.10 (m, 3H); 6.68 (t, 1H, J=7 Hz);
3.50-3.25 (m, 2H); 3.25-3.07 (m, 2H); 3.07-2_90 (m, 2H);
2.90-2.60 (m, 2H); 2.60-2.40 (m, 2H); 2.00-1.60 (m, 5H);
1.60-1.30 (m, 2H).
EXAMPLE 2
Part A: Preparation of 4-benzyl-1-carbomethoxymethyl-1-
[3-(3-cyanophenylaminocarbonylamino)prop-1-yl]piperidinium
bromide
Br-
H H
4-benzyl-1-[3-(3-cyanophenylaminocarbonylamino)prop-1-
yljpiperidine (50mg, 0_133 mmol, ~ eq}, was dissoved in
acetone at 25 oC under N2 then methyl bromoacetate (l3uL,
0.133 mmol, 1 eq),was added. After 16 hours, the solvent
was removed in vacuo and the residue was purified over
silica gel in 100 EtOAc to 8:2 chloroform/MeOH to yield 50
mg of white solids as product. NMR (30GMHz, CD30D) 8 8.00-
7.80 (m, 1H) ; 7.65-7_45 (m, 1H); 7.45-7.33 (m, IH); 7.33-
7.05 (m, 6H); 4.50-4.25 (m, 2H); 4.00-3.60 (m, 5H); 3.50-
3.20 (m, 6H); 2.70-2.50 (m, 2H); 2.10-1.60 (m, 7H).
EXAMPLE 3
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CA 02350730 2001-05-07
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Part A: Preparation of 1-(t-Butoxycarbonyl)-3-piperidone
i . H2, Pd/C, CH30H,
23 °C
C1
ii. (Boc)20, NaHC03,
THF, 23 °C
86~
To a deep yellow solution of 1-benzyl-3-piperidone
hydrochloride (3.00 g, 1.33 mmol, 1 equiv) in methanol (100
mL) was added 10 wt. ~ (dry basis) palladium on activated
carbon (600 mg) under a stream of nitrogen. The resulting
black suspension was deoxygenated by alternate evacuation
and flushing with nitrogen (3x) followed by alternate
evacuation and flushing with hydrogen (3x). The reaction
suspension was then shaken vigorously under a hydrogen
atmosphere of 55 psi. After 12 hours, gravity filtration
of the supsension and concentration of the resulting
filtrate in vacuo yielded crude 3-piperidone as a viscous
light green oil. The oil was immediately treated with
tetrahydrofuran (150 m.L) and di-t-butyldicarbonate (4.73 g,
21.7 mmol, 0.98 equiv). Upon addition of saturated aqueous
sodium bicarbonate (25 mL), the oil completely dissolved to
give a light yellow suspension. After stirring the
suspension vigorously for 2 hours, the now white suspension
was poured into aqueous hydrogen chloride (1N, 100 mL), and
the layers were separated. The aqueous layer was extracted
with ethyl acetate (3 x 70 mL), and the combined organic
layers were washed with saturated aqueous sodium chloride
(50 mL), dried over sodium sulfate, and filtered.
Concentration of the resulting filtrate in vacuo yielded 1-
(t-butoxyarbonyl)-3-piperidone (3.79 g, 86~) as a white
oily solid. 1~H Nl~t (300 l~iz, CDC13), 8:3.94 (s, 2H), 3.53
(t, 2H, J = 6 Hz), 2.41 (t, 2H, J = 7 Hz), 1.92 (m, 2H),
1.41 (s, 9H)
Part B: Preparation of 1',3-(2H)-Dehydro-3-benzyl-1-(t-
butoxycarbonyl)piperidine
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NaH, Bn(0)P(OEt)2
DME, 23-80 °C
0 O
23~
To a flame-dried 100-mL flask charged with sodium
hydride (60~ wt. dispersion in mineral oil; 601 mg, 15.0
mmol, 2.3 equiv)) and 1,2-dimethoxyethane (20 mL) was added
benzyl diethylphosphite (3.42 g, 3.13 mL, 15.0 mmol, 2.3
equiv) dropwise over a period of 5 min. After 20 min, 1-
(t-butoxycarbonyl)-3-piperidone was added in one portion to
the pale yellow suspension. The flask was fitted with a
relfux condensor, and the resulting yellow-gray suspension
at heated under reflux conditions for 2 hrs. Upon cooling
to 23 °C, the reaction was poured into aqueous hydrogen
chloride (0.20 N, 100 mL) and diethyl ether (75 mL). The
I5 layers were separated and the aqueous layer was basified
with saturated aqueous sodium bicarbonate to pH 9. The
aqueous layer was extracted with diethyl ether (4 x 75 mL),
and the combined organic layers were dried over sodium
sulfate. Filtration, concentration in vacuo, and
purification of the resulting residue by flash column
chromatography (5~ ethyl acetate in hexanes) afforded a
mixture of the desired olefin (410 mg, 23~) and the
corresponding ethoxycarbamate (550 mg, 34~) as a clear oil.
The ethoxycarbamate was removed in the subsequent step by
flash column chromatography. 1H NMR (300 MHz, CDC13), $:
7.30 (m, 2H), 7.18 (m, 3H), 6.42 (s, 1H), 4.02 (s, 2H),
3.50 (t, 2H, J = 6 Hz), 2.51 (t, 2H, J = 5 Hz), 1.61 (m,
2H), 1.49 (s, 9H)_ MS (CI), m+/z: (M+H)+ = 274, [(M+H)+ -
(-C(O)OC(CH3)3)) 174.
Part C: Preparation of 1-(t-Butoxycarbonyl)s3-
benzylpiperidine
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CA 02350730 2001-05-07
WO 00/35451 PCT/US99/30332
Hz. Pd/C
CH30H, 23 °C
99~
To a solution of impure product (410 mg, 1.50 mmol)
obtained in the previous step in methanol (100 mL) was
added 10 wt. ~ (dry basis) palladium on activated carbon
(200 mg) under a stream of nitrogen. The resulting black
suspension was deoxygenated by alternate evacuation and
flushing with nitrogen (3x) followed by alternate
evacuation and flushing with hydrogen (3x). The reaction
suspension was then shaken vigorously under a hydrogen
atmosphere of 55 psi. After 12 hours, gravity filtration
of the supsension and concentration of the resulting
filtrate in vacuo resulted in a pale yellow residue.
Purification of this residue by flash column chromatography
afforded 1-(t-butoxycarbonyl)-3-benzyl-piperidine~(407 mg,
99~) as a clear oil. 1H NMR (300 MHz, CDC13), $: 7.23 (m,
2H), 7.14 (m, 3H), 3.86 (m, ZH), 2.75 (br m, 1H), 2.51 (m,
3H), 1.70 (br. m, 2H), 1.64 (br, m, 1H), 1.41 (s, 9H), 1.34
(br. m, 1H), 1.09 (br. m, 1H). MS (CI), m+/z: (M+ + 1)
276, [(M+H)+ - (-C(O)OC(CH3)3)l - 176.
Part D: 3-Benzylpiperidine hydrochloride
HC1
~ HC1
To a solution of 1-(t-butoxycarbonyl)-3-
benzylpiperidine (400 mg, 1.45 mmol) in methanol (5 mL) was
added hydrogen chloride in dioxane (4M, 15 mL). The
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resulting yellow solution was stirred for 1 hr, at which
time the reaction was concentrated in vacuo to provide 3-
benzylpiperidine hydrochloride (308 mg, 1000) as an
amorphous solid. 1H NMR (300 MHz, CD30D), 8: 7.27 (m,
2H, ) , 7.19 (m, 3H) , 3 .29 (br. d, 1H, J = l2Hz) , 3 .20 (br.
d, 1H, J = 12 Hz), 2.87 (br. t, 1H, J = 12 Hz), 2.67 (m,
~.H), 2.60 (d, 2H, J = 7Hz), 2.08 (m, 1H) 1.70-1.87 (m, 3H),
1.26 (m, 1H). MS (CI), m+/z: (M+H)+ = 176.
Part E: Preparation of N-(3-methoxyphenyl)-N'-[3-[3-
[(phenyl)methyl]-1-piperidinyl]propyl]urea
3
The above compound was prepared by the methods similar
to the ones employed in Example 1, part C.
1H NMR (300 MHz, CD30D), 8:7.29-7.23 (m, 4H); 7/07 (d, 1H,
J=9 Hz); 7.02 (m, 1H); 6.78 (d, 1H, J = 9 Hz); 6.60 (d,
1H, J = 9 Hz); 3.77 (s, 3H); 3.30 (m, 2H); 2.80 (m, 2H);
2.53-2.32 (m, 4H); 1.85-1.55 (m, 7H); 1.44-0.78 (m, 2H).
MS (ESI), m+/z: (M+H)+ = 382.
EXAMPLE 4
Part A: Preparation of a,a'-Dibromo-3-nitro-o-xylene
B _
~+
~O
3-Nitro-o-xylene (lO.Og, 66.14 mmol, 1.00 eq), N-
bromosuccinimide (24.14 g, 135.6 mmol, 2.05 eq), and
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benzoyl peroxide (0.8 g, 3.30 mmol, 0.5 eq) were refluxed
under N2 in 200 ml of carbon tetrachloride. The reaction
was worked up after two days by washing with 3 x 100 ml of
water. The organic phase was dried over sodium sulfate,
then the solvent was removed in vacuo to obtain an amber
oil. The oil was purified by flash chromatography on a 8
cm x 20 cm quartz column, eluting with 7.5$ EtOAc/Hexanes
to yield 4.46 g of product as a sticky solid. NMR (300
MHz, CDC13) $ 7.88 (d, 2H, J=7 Hz), 7.64 (d, 1H, J=7 Hz),
7 .48 dd, 1H, J=8 Hz) , 4.86 (s, 2H) , 4.69 (s, 2H) .
Part B: Preparation of 1,3-Dihydro-4'-[4-
fluorophenylmethyl)-4-vitro-spiro[2H-isoindole-2,1'-
piperidinium) bromide
~+ 0
F
Br-'
4-Fluorobenzylpiperidine (0.94 g, 4.86 mmol, 1.0 eq),
a,a'-dibromo-3-vitro-o-xylene (1.50 g, 4.86 mmol, 1.0 eq),
and sodium carbonate (2.57 g, 24.3 mmol, 5.0 eq) were
combined in 20 ml THF and stirred at 25~ C under N2, during
which time a white solid precipitated from the reaction
mixture. The reaction was worked up after 22 hours by
filtering the solids and rinsing with THF. The solids were
dissolved in methanol and applied to a 3.5 cm x 5 cm quartz
column via silica plug. The product was eluted with 20~
MeOH/CHC13 to yield 1.04 g of a white foam. NMR (300 MHz,
CD30D) 8 8.27 (d, 1~~, J=8 Hz), 7.84 -7.80 (m, 1H), ?.75-
7.69 (m, 1H), 7.23 (m, 2H), 7.01 (dd, 2H, J=8 Hz, 8 Hz),
5.38-5.37 (m, 2H), 5.09 (s, 1H), 5.04 (s, 1H), 3.80-3.72
(m, 2H), 3.65-3.54 (m, 2H), 2.71-2.68 (m, 2H), 2.05-1.75
(m, 5H).
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' Part C: Preparation of 4-Amino-1, 3-dihydro-4'-[4-
fluorophenylmethyl)-spiro[2H-isoindole-2,1'-piperidinium]
bromide
I+ 2
1,3-Dihydro-4'-[4-fluorophenylmethyl]-4-nitro-
spiro[2H-isoindole-2,1'-piperidinium] bromide (1.03 g, 2.46
mmol, 1.0 eq), zinc (5.32 g, 81.5 mmol, 33.0 eq), and
calcium chloride (0.18 g, 1.60 mmol, 0.65 eq) were refluxed
under N2 in 25 ml of a 78~ ethanol/water solution. The
reaction was worked up after 5 hours by filtering through
Celite~ and rinsing the cake with methanol. The filtrate
was concentrated in vacuo to a mixture of water and an
amber oil. The mixture was dissolved in 50 ml of 2-
propanol, and concentrated in vacuo to remove excess water.
The resulting yellow foam was dissolved in methanol and
applied to a 3.5 cm x 5 cm quartz column via silica plug.
The product was eluted with 20$ MeOH/CHC13 to yield 0.81g
of a yellow foam. NMR (300 ~z, DMSO) $ 7.27-7.05 (m, 5H),
6.61-6.53 (m, 2H), 5.43-5.41 (m, 2H), 4.80 (bs, 1H), 4.74
(bs, 2H), 4.63 (bs, 1H), 3.62-3.43 (m, 4H), 2.60 (bd, 2H,
J=7 Hz), 1.98-1.59 (m, 5H).
Part D: Preparation of N-[1,3-Dihydro-4'-[4-fluorophen 1-
Y
methyl]spiro[2H isoindole-2,1'-piperdinium-4-yl)-N'-4-
fluorophenylurea bromide
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4-Amino-1, 3-dihydro-4'-[4-fluorophenylmethyl]-
spiro[2H-isoindole-2, 1'-piperidinium] bromide (0.33 g,
0.84 mmol, 1.0 eq), and 4-fluorophenyl isocyanate (0.23 g,
1.69 mmol, 2.0 eq) were combined in 3 ml DMF and stirred at
25~ C under N2 . The reaction was worked up after 22
hours by removing the solvent in vacuo, dissolving the
residue in methanol, and applying the mixture to a 3.5 cm x
cm quartz column via silica plug. The product was
eluted with 10~ MeOH/CHC13 to yield 65 mg of a yellow foam.
10 NMR (300 MHz, DMSO) 8 9.18 (s, 1H), 9.00 (s, 1H), 7.49-7.43
(m, 2H), 7.41-7.34 (m, 2H), 7.26-7.21 (m, 2H), 7.17-7.10
(m, 5H), 4.94 (s, 2H), 4.80 (s, 2H), 3.63-3.45 (m, 4H),
2.61 (bd, j=7 Hz), 1.91-I.62 (m, 5H)
15 EXAMPLE 5
Part A. Preparation of 4-benzyl-1-(3-hydroxy-3-phenylprop-
1-yl)piperidine
To a flame-dried 3-neck flask under a N2 atmosphere
with a magnetic stirring bar, 4-benzylpiperidine (5.00 mL,
28 mmol, 1 eq), DBU (42 uL, 0.28 mmol, 0.01 eq), and THF
(100 mL) were added, mixed, and cooled to -15 °C using a
CC14/C02(s) bath_ Acrolein (1.87 mL, 28 mmol, 1 eq) was
then syringed in slowly during 10 minutes maintaining the
temp. at -15 °C. After 0.5 hours at -15 °C, phenylmagnesium
chloride (2.0 M, 14.0 mL, 28 mmol, 1 eq) was syringed in
slowly and the contents allowed to slowly warm to room
temperature and then stirred for 48 h. The reaction was
worked up by adding 0.1 N NaOH and EtOAc (200 mL each).
The viscous magnesium salts were suction filtered through
fiberglass filter paper'. The layers were separated and the
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CA 02350730 2001-05-07
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aqueous layer was extracted again with ethyl acetate (2 x
200 mL). The organic layers were combined, washed with
brine (1 x 200 mL), dried (MgS04) and the solvent removed
in vacuo to yield 7.39 g of an amber oil. Flash
chromatography in 100 ethyl actetate yielded 2.48 g of an
orange oil. NMR (CDC13) $ 7.40-7.10 (m, lOH); 4.93 (d of
d, 1H, J=3,7 Hz); 3.12-2.96 (m, 2H); 2.68-2.46 (m, 4H);
2. 01 (t of d, 1H, J=2, 10 Hz) ; 1.86-1.26 (m, 8H) . ESI MS
detects (M+H)+ = 310.
Part B: Preparation of 4-benzyl-1-(3-azido-3-phenylprop-1-
yl)piperidine
3
The product from part A (209 mg, 0.675 mmol, 1 eq),
DBU (123 mg, 0.810 mmol, 1.2 eq), diphenylphosphoryl azide
(0.175 mL, 0.810 mmol, 2.2 eq), and toluene (1.0 mL) were
mixed and stirred overnight at room temperature under a NZ
atmosphere. The reaction was then worked up by adding
ethyl acetate (50 mL), washing with water (3 x 25 mL),
followed by washing with brine (1 x 25 mL), drying (MgS04)
and removing the solvent in vacuo to yield 277 mg of an
amber oil. Flash chromatography in 1:I hexane/ethyl
acetate yielded 84 mg of product as an oil. NMR (CDC13) $
7.41-7.09 (m, 10 H); 4.56 (t, 1H, J=7 Hz); 3.83 (m, 2H);
2.52 (d, 2H, J=7 Hz); 2.32 (t, 2H, J=7 Hz); 2.30-1.77 (m,
5H); 2.59 (m, 2H); 1.98 (m, 1H); 1.39-1.26 (m, 4H). IR
(neat) 2095 cm-1.
Part C: Preparation of 4-benzyl-1-(3-amino-3-phenylprop-1-
yl)piperidine
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CA 02350730 2001-05-07
' WO 00/35451 PCT/US99/30332
The compound from part B (100 mg), 10~ Pd on carbon
(120 mg), and methanol (100 mL) were carefully combined in
a flask under a N2 atmosphere. The contents were then
submitted to 1 atm of H2 being delivered via a sparge tube
for 0.5 h at room temperature. Filtration of the contents
through Celite~ and removal of the solvent in vacuo yielded_
70 mg of product. NMR (CDC13) (key peak only) 83.94 (t, 1,
J = 7 Hz). NH4-CI MS detects (M+H)+ = 309.
Part D: N-(3-cyanophenyl)-N'-[3-[4-(phenylmethyl)-1-
piperidinyl]-1-phenylpropyl]urea
n ~N
The compound from Part C (57 mg, 0.185 mmol, 1 eq) was
mixed and stirred with 3-cyanophenylisocyanate 26.6 mg,
0.185 mmol, 1 eq) in THF (1 mL) overnight at room
temperature under a N2 atmosphere. The solvent was removed
in vacuo and the residue flash chromatographed on silica
gel in 3:1 to 1:1 hexane/ethyl acetate to 100 ethyl
acetate to yield 44.3 mg of a yellow oil. NMR (CDC13)
8 7.58 (s, 1H); 7.52 (d, 1H, J = 9 Hz); 7.42 (s, 1H);
7.30-7.17 9m, 8H); 7.12 (m, 3H); 4.82 (m, 1H); 2.97-2.80
(m, 3H); 2.52 (d, 2H, J=7 Hz); 2.35 (m, 2H); 2.05-1.85
(m, 4H); 1.81-1.60 (m, 2H); 1.54 (m, 1H); 1.25 (m, 1H).
ESI MS detects (M+H)+ = 453.
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CA 02350730 2001-05-07
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EXAMPLE 6
Part A: Preparation of 2-benzyloxycarbonylamino-1-phenyl-
3-butene.
To a stirred suspension of methyltriphenylphosphonium
bromide (10.72 g, 0.03 moles) in 200 mL of dry
tetrahydofuran at -78°C was added dropwise 1.6M n-butyl
lithium (17.5 mL, 0.028 moles), and the mixture was stirred
for 0.5 hrs at -78 - -20°C. Then was added a solution of N-
Cbz-phenylalaninal (5.67 g, 0.02 moles) in 50 mL of dry
tetrahydrofuran, and the mixture was stirred for 16 hrs at
room temperature. After addition of saturated NH4C1 (50 mL)
the mixture was extracted with EtOAc, and the extract was
washed with water and brine. It was dried over Na2S04 and
evaporated to give an oily residue. The crude product was
purified by column chromatograpy on silica gel with elution
by 5:95 EtOAc-hexane to give pure 2-benzyloxycarbonylamino-
1-phenyl-3-butene.
Part B: Preparation of 2-benzyloxycarbonylamino-1-phenyl-
3,4-epoxy-butane.
To a stirred solution of 2-benzyloxycarbonylamino-1-
phenyl-3-butene (1.43 g, 5.08 mmoles) in 20 mL of CH2C12
was added 3-chloroperoxybenzoic acid (2.19 g, 60~, 7.62
mmoles) in several portions, and the mixture was stirred at
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CA 02350730 2001-05-07
~ WO 00/35451 PCT/U~99/30332
room temperature for 30 hrs. After addition of EtOAc (60
mL), the mixture was washed with saturated NaHC03 and
brine, and the organic layer was dried over Na2S04.
Evaporation of the solvent afforded an oily residue. The
crude product was purified by column chromatography on
silica gel with elution by 2:8 EtOAc-hexane to give pure 2-
benzyloxycarbonylamino-1-phenyl-3,4-epoxy-butane.
Part C: Preparation of 2-benzyloxycarbonylamino-4-[4-(4-
fluorophenyl)methyl-1-piperidinyl]-1-phenyl-butan-3-ol.
A solution of 4-(4-fluorophenyl)methyl-piperidine
(0.515 g, 2.314 mmoles) and 2-benzyloxycarbonylamino-1-
phenyl-3,4-epoxy-butane (0.688 g, 2.314 mmoles) in 5 mL of
DMF was stirred for 4 hours at 100°C and cooled to room
temperature. After addition of EtOAc (30 mL), the mixture
was washed with water (2x) and brine. The oranic solution
was dried over Na2S04, and evaporated to give an oily
residue. It was then purified by passing through a plug of
silica gel with elution by EtOAc to give pure product.
Part D: Preparation of 2-amino-4-[4-(4-fluorophenyl)methyl-
1-piperidinyl]-1-phenyl-butan-3-ol.
2
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CA 02350730 2001-05-07
WO 00/35451 PCT/US99/30332
The above product was dissolved in 10 mL of ethanol,
and was added 0.1 g of 10~ Pd on carbon. The mixture was
stirred under hydrogen (1 atm) for 8 hours, and filtered
through Celite. Evaporation of the solvent gave the titled
product as solid (0.662 g}.
Part E: Preparation of N-(3-cyanophenyl)-N'-[1-benzyl-2-
hydroxy-3-[4-(4-fluorophenylmethyl}-1-
piperidinyl]propyl]urea
H H ~N
H
To a solution of 2-amino-4-[4-(4-fluorophenyl)methyl-
1-piperidinyl]-1-phenyl-butan-3-of (50 mg, 0.14 mmoles) in
2.5 mL of dry THF was added 3-cyanophenyl isocyanate (20.2
mg, 0.14 mmoles) and the mixture was stirred for 15 minutes
at room temperature. Then the solvent was evaporated off to
give an oily residue. It was purified by column
chromatography on silica gel with elution by EtOAc to give
pure titled compound as an amorphous solid.
MS (ES+) for C3pH33FN402 - 501.
The following examples were prepared by the procedures
previously described in Schemes 1-25 , Examples 1-6 and/or
by procedures familiar to one skilled in the art.
TAB
172

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' WO 00/35451 PCT/US99/30332
N~~ ~ R3 Cr~l~H ~ ~ H H
H H ~ R3
0 ~ R3
a b 0
c
N~ ~ R3 /~ H ~ G H H H
N N' G ~/~r R3 /~N~ 1R
H H ~' R3
0
f
G~N~H~ G HHH HHH
R3 ~ TI G'~ IS
R3 R
3
0 Ph 0 p
h i
G~N H N N.R ~N H N N. G H H
3 Y R3 '~N N N.
~ T R
P 0 Prf O
~ k 1
Ex # Core G R3 M+1


7 _a Ph ~ 3-C02Et 410
-
Ph


8 a Ph _ 464
_
3-I-Ph


a Ph 1-adamant 1 396


a Ph 3-OCH3-Ph 368


11 a Ph Ph 338


12 a Ph 4-F-Ph 356


13 a Ph 4-C02Et-Ph 420


24 a Ph 4-CN-Ph 363


b Ph 1-adamant 1 410


16 b Ph 2-F-5-CF3-Ph 438


17 b Ph 2-na hth 1 402


18 b Ph 2-F-5-N02-Ph 415


19 b Ph 4-N(CH3)2-Ph 395


b Ph 2-N02-Ph 397


21 b Ph 2-C2H5-Ph 380


22 b Ph 4-CF4-Ph 420


23 b Ph 3,5-diCF3-Ph 488


24 b Ph 3-C02Et-Ph 424


b Ph 3-CN-Ph 377


26 b Ph 4-OBn-Ph 458


27 b Ph 2-Ph-Ph 428
28 b Ph 2-BrPh 431
29 b Ph 4-I-Ph 478
b Ph 3-I-Ph 478


31 b Ph 4-OEt-Ph 396


32 b Ph 4-nBu-Ph 408


33 b Ph 4-nBuO-Ph 424
34 b Ph CH(Bn)C02Et 452


173


CA 02350730 2001-05-07
WO 00/35451 PCT/US99/30332
35 b Ph CH(iPr)C02Et ~ 404


36 b Ph nC8H17 3gg


37 b Ph 3-OCH3-Ph 382


38 b Ph Ph 352


39 b Ph 4-C02Et-Ph 424


40 b Ph 4-F-Ph 370


41 b Ph 2-Phenyl- 392


cyclopro 1


42 b Ph 2-OCH3-Ph 382


43 b Ph 4-OCH3-Ph 382


44 b 4-F-Ph 3-CN-Ph 395


45 b 4-F-Ph 4-F-Ph 388


46 b 4-F-Ph 4-C02Et-Ph 442


47 b 3,4-OCH20-Ph 3-CN-Ph 421


48 b 4-F-Ph 3-OCH3-Ph 400


49 b 3,4-OCH20-Ph 3-C02Et-Ph 468


50 b 3,4-OCH20-Ph 3-OCH3-Ph 426


51 b 4-OCH3-Ph 3-OCH3-Ph 412


52 b 4-OCH3-Ph 4-F-ph 400


53 b Ph 4-CN-Ph 377


54 b 3,4-OCH20-Ph 4-F-Ph 414


55 b 4-OCH3-Ph 4-CN-Ph 407


56 b 2,4-diF-Ph 4-F-Ph 406


57 b 2,4-diF-Ph 3-OCH3-Ph 418


58 b 2,4-diF-Ph 3-CN-Ph 413


59 b 3-CF3-Ph 4-F-Ph 438


60 b 3-CF3-Ph 3-OCH3-Ph 450


61 b 4-F-Ph CH2Ph 384


62 b 4-F-Ph CH2CH2Ph 39g


63 b 4-F-Ph 2-F-Ph 388


64 b 4-F-Ph 3-F-Ph 388


65 b 4-F-Ph
cYclohexyl 376


66 b 4-F-Ph iPr 336


67 b 4-F-Ph 2-phenyl- 410


c clo ropyl
68


b 4-CF3-Ph 3-CN-Ph 445


69 b 3-CF3-Ph 3-CN-Ph 445


70 b 4-CH3-Ph 3-OCH3-Ph 396


71 b 4-CH3-Ph 3-CN-Ph 391


72 b 4-C1-Ph 3-CN-Ph 411


73 b 4-CF3-Ph 4-C02Et-Ph 492


74 b 3-OCH3-Ph 3-OCH3-Ph 412


75 b 3-OCH3-Ph 3-CN-Ph 407


76 b 4-C02CH3-Ph 3-OCH3-Ph 440


77 b 4-C02CH3-Ph 3-CN-Ph 435


78 b 4-C02CH3-Ph 4-F-Ph 428


79 b 4-C02CH3-Ph 4-C02CH3-Ph 482


80 b 4-CF3-Ph 4-F-Ph 438


81 b 4-CF3-Ph 3-OCH3-Ph 450


82 b 3-OCH3-Ph 4-F-Ph 400


83 b 3-OCH3-Ph 4-C02Et-Ph 454


84 b 2-F-Ph 3-CN-Ph 395


85 b 3-OCH3-Ph 3-F-Ph - 400


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CA 02350730 2001-05-07
WO 00/35451 PCT/US99/30332
86 b 2-F-Ph 3-OCH3-Ph 400
~ '--
~


8 b 7 3-C0~2E Ph 454
-
3-OCH3


88 b 2-F-Ph 3-F-Ph 388


89 b 2-F-Ph 4-F-Ph 388


90 b 2-F-Ph 3-C02Et-Ph 442


91 b 3-F-Ph 3-CN-Ph 395


92 b 3,4-diF-ph 3-CN-Ph


413
93 b 3,4-diF-Ph 3-OCH3-Ph


418
94 b 4-C1-Ph 4-F-Ph


404
95 b 4-C1-Ph 3-OCH3-Ph


416
96 b 2-F-Ph 4-C02Et-Ph


442
b 3-F-Ph 3-OCH3-Ph .


400
_98 b 3-F-Ph 4-F-Ph 3


88
99 b 3-F-Ph 4-C02Et-Ph 442


100 b 3;4-diF-Ph 4-F-ph


406
101 b 3-C1-Ph 3-CN-Ph


411
102 b 4-F-Ph 3-COCH3-Ph


412
103 b 3,5-diF-Ph 3-CN-Ph


413
104 b 3,5-diF-Ph 3-OCH3-Ph


418
105 b 4-F-Ph 4-COCH3-Ph


412
106 b 1-na hth 1 3-CN-Ph


427
107 b 1-na hth 1 4-F-Ph


420
108 b 1-na hth 1 3-OCH3-Ph


432
109 b 3-CH3-Ph 3-CN-Ph


391
110 b 3-CH3-Ph 4-F-Ph


384
111 b 3-CH3-ph 3-OCH3-ph


396
112 b 4-F-Ph 2-iPr-Ph


412
113 b 4-F-Ph 2-CF3-Ph


438
114 b 4-F-Ph 3-C1-ph


404
115 b 4-F-Ph 3-CF3-ph


438
116 b 4-F-Ph 4-Ph-Ph


446
117 b 4-F-Ph 2-C1-Ph


404
118 b 4-F-Ph 2,4-diF-Ph 406


119 c Ph 3-C02Et-Ph 424


120 c Ph 3-CN-Ph 377


121 c Ph 4-F-Ph 370


122 c Ph Ph 352


123 c Ph 1-adamant 1 410


124 c Ph 4-C02Et-Ph 424


125 c 4-F-Ph Ph


370
126 c 4-F-Ph 3-CN-Ph


395
127 c 4-F-Ph 1-adamant 1


428
128 c 4-F-Ph 3-OCH3-Ph


400
129 c 4-F-Ph 3-C02Et-Ph 442


130 c 4-F-Ph 4-F-Ph 3gg


130a c 4-F-Ph 3-COCH3-Ph 412


131 c 2-F-Ph Ph


370
132 c 2-F-Ph ~ 3-CN-Ph


395
133 c 2-F-Ph 3-OCH3-Ph


400
134 c 2-F-ph 4-F-Ph


388
135 c 3-F-Ph 3-OCH3-Ph


400
136 c 3-F-Ph 3-CN-Ph


395
137 c 2,4-diF-Ph 3-CN-Ph


413


175


CA 02350730 2001-05-07
WO 00/35451 PCTlUS99/30332
138 c 2,4-diF-Ph 3-OCH3-Ph 418


139 c 2,4-diF-Ph Ph 388


140 c 2,4-diF-Ph 4-F-Ph 406


141 c 2,4-diF-Ph 3-COCH3-Ph 430


142 d Ph 3-CN-Ph 392


143 d Ph 3-C02Et-Ph 438


144 d Ph 3-I-Ph 492


145 d Ph 4-OCH2Ph-Ph 472


146 d Ph 1-adamantyl 424


147 d Ph 3-OCH3-Ph 396


148 d Ph Ph 366


149 d Ph 4-F-Ph 384


150 d Ph 4-C02Et-Ph 438


151 d Ph 4-CN-Ph 391


152 a 4-F-Ph Ph 356


153 a 4-F-Ph 3-CN-Ph 381


154 a 4-F-Ph 3-OCH3-Ph 386


155 a 4-F-Ph 4-F-Ph 374


156 a 4-F-Ph 3-C02Et-Ph 428


157 a 4-F-Ph 4-C02Et-Ph 428


158 a 4-F-Ph 1-adamant 1 414


159 f 4-F-Ph 3-CN-Ph 411


160 f 4-F-Ph 3-OCH3-Ph 416


161 j Ph Ph 458


162 Ph 3-CN-Ph 483


163 j Ph 3-OCH3-Ph 488


164 j 4-F-Ph 3-OCH3-Ph 506


165 4-F-Ph 4-F-Ph 494


166 j 4-F-Ph 1-adamantyl 534


167 I Ph 3-OCH3-Ph 458


168 1 Ph 1-adamantyl 486


169 c imidazol-1- 1 3-OCH3-Ph 372


All stereocenters are (+/-) unless otherwise indicated
TABLE 2**
R5 a R5b
R5C il ~2
YI +
I ~N~ n~~ Z
R4 00
X -
m
Ex Y Z R4 X R5a R5b R5c R1 R2
#


170 H H - - H H H H ph


171 H H - - H H H H CH3


172 H 3-OCH3 CH2Ph Br H H H H H


173 H 3-CN - - C02E H H H H
t


174 H 3-OCH3 CH3 I H H H H H


275 H 3-CN CH3 I H H H H H


176


CA 02350730 2001-05-07
WO 00/35451 PCT/US99/30332
176 H 3-CN CH2Ph Br H H H


H H
177 H 3-CN - - H


H H CH2P H


h
178 H 3-CN - - H


H H Et H
179 H 4-F CH3 I H


H H H H
180 H 4-F CH2Ph Br H H


H H H
181 H 4-F CH2C02CH Br H H


H H H


3


182 H 3-CN CH2CN Br H H H H


H
183 H 3-CN CH2COPh Br H H H


H H
184 H 2-OCH3 CH3 I H H


H H H
185 H 4-OCH3 CH3 I H


H H H H
186 F 3-CN CH3 I H


H H H H
187 H 3-CN -


- H H H
188 H 3-OCH3 O - H


H H H H
189 H 3-OCH3 -


- CH2P


h
190 F 3-CN CH3 I H H


H H H
191 F 3- -


- H CH2P H H H


COCH3 h


192 F 4-F-Ph - - H CH2P H


H H


h
193 F 3-OCH3 - - H CH2P


H H H


h
194 H 3-OCH3 - - H


H H CH2P H


h
195 H 3-CN - - H


H H CH2P H


h


**All compounds are amorphous unless otherwise indicted.
TABLE 3**
X_ ~~:~~-~~Z Y X_ F~~~ Z
Y~ + N O ~,~~N
0
Ex # Core Z X


19 6 n H 3 -CN Br


197 n H 3-CN Br


198 n H 4-F Br


199 n H 4-F Br


200 n F 3- CN Br


201 n F 3-CN Br


202 n F 3-OCH3 Br


203 n F 3-OCH3 Br


204 o F 4-F Br


205 o F 4-F Br


206 o F 3-OCH3 gr


207 o F 3-OCH3 Br


177


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208 0
209 o F 3=cN Br
Br
**All compounds are amorphous unless otherwise indicted.
The compounds of the present invention in which E
contains ring A can be prepared in a number of ways well
known to one skilled in the art of organic synthesis. As
shown in Scheme 26, 4-benzyl piperidine is N-alkylated with
an alkylating agent, such as 165 (2-vitro-benzyl bromide (X
= Br, R14 = H), Scheme 26) to give the N-benzyl compound
166. The vitro group of 166 is then reduced using
catalytic hydrogenation to give the corresponding aniline
167. The aniline can be converted to the carbamate 168
using chloro-phenyl formate. The carbamate 168 can then be
reacted with various amines to give the urea 169.
Alternatively, the aniline 167 can be reacted with the
appropriate isocyanates to give the urea 169 directly. The
saturated ring analogs can also be used. For ex~ple, 4-
benzyl piperidine can be alkylated with the urea mesylate
185 (Scheme 30) to give corresponding cyclohexyl derivative
186.
As shown in Scheme 27, 4-benzyl piperidine can also be
N-alkylated with the phenacyl bromide 170 to give the vitro
ketone 171. The vitro group of 171 is then reduced using
catalytic hydrogenation to give the corresponding aniline
172. The aniline 172 can be reacted with the appropriate
isocyanates to give the ketone urea _173. The ketone of 173
can be reduced with NaBH4 to give the alcohol 174.
Alternatively, the epoxide I75 (R14 - H) can be opened
with the 4-benzyl piperidine to give the corres o
p nding
vitro benzyl alcohol which is hydrogenated to give the
aniline alcohol 176. The aniline 276 may be treated with
various isocyanates to give the urea alcohols 174.
The 4-benzyl piperidine can also be N-al.kylated with
3-cyanobenzyl bromide (177, Scheme 28
) to give true cyano
analog 178. The cyano group is reduced using Raney nickel
278


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WO 00/35451 PCT/US99/30332
to give the corresponding benzyl amine 179. Treatment of
179 with isocyanates gives the urea 180.
As shown in Scheme 29, treatment of 3-cyano aniline
with phenylisocyanate gives the urea 82. The cyano group
of 182 is converted to the imidate 183 by HC1/ethanol.
Reaction with 4-benzyl piperidine in ethanol then gives the
amidine 184.
The saturated ring analogs can also be synthesized
using analogous procedures as outlined in Schemes 30 and
31. For example, 4-benzyl piperidine can be alkylated with
the urea mesylate 185 (Scheme 29) to give corresponding
cyclohexyl derivative 186. Alternatively, starting with the
enantiomerically pure amino alcohol 187 [J. Am. Chem. Soc.
1996, 118, 5502-5503 and references therein] one can
protect the nitrogen to give the N-Cbz alcohol 188. Swern
oxidation of the alcohol gives the aldehyde 89. Reductive
amination with piperidine analogs gives the cyclohexyl
methyl-1-piperidinyl analogue ~. The Cbz group is removed
by catalytic hydrogenation to give the free amine 191,
which is treated with a phenylisocyanate to give the
desired urea analogue ~ Several examples using these
synthetic methods are listed in Table 3a and Table 3.1.
179


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SCHEME 26
x
\ 1
R14 ~ ~ +
A
NOz ~ RW-~ -\
165 ENO
z
X = C1, Br, MsO, etc.
166
' ' 1B
R14~! \
/ C
1a i
R /
NH2
168 \ D E
167
R1
169
A: DMF/KZC03/RT or THF/RT. B:lO~Pd/C, H 2 50 psi.
C: THF/Et 3N/chlorophenylformate. D:NHR/DMF/50°C.
E: R-N=C=O/THF
180


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SCHEME 27
r \
\
Rla i + - ~ \ v
R14
A
NOz 171
170
B
r
v
\ ~ ( / \
R1~ / C \ /
~R ~ R1~/
p ~z 172
173
D D
H \ H \
\ ~/
R1~ R1~ \
/ C
~~R ~'-- / ~z 17 6
0
A, B
174
\ v
R14 ( +
NO
z
r
175
A: DMF/K2C03/RT or DMF/50°C. B:10%Pd/C, ji50
psi. C: R-N=C=O/THF. D:NaBI~/MeOH/RT
181


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SCHF2~ 2 8
Br \ / A N w
N
178
CN CN
177 ~ g
,_,
N
C N
O
N--~ ~ 17 9
N-R
180 N~
A: DMF/KZC03/RT B:Raney nickel,
HZ 50 psi. C: R-N=C=O/THF.
SCHEME 29
NH
CN
A' ~ ~ CN B' ~ ~ pEt C ~ ~
/ / / ~ / V w
NH2 T T
O / O ~ / O
/
182 183 184
A: R-N=C=O/THF. B:EtOH/HCl/RT
C: 4-benzylpiperidine/EtOH/RT
SCHEME 3 0
OH OMs
A,B
C
~~ N~ ~ OMe '
N~ ( ~ OMe
~0
185 O /
186
A: R-N=C=O/DMF. B:Ms-Cl/THF
C:4-benzylpiperidine/DMF/RT
182


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SCHBME 31
OH
g OH
b
---~- --1~
,~~z
.~NH-CBZ
187 188
F F
O
H N
N
d
.~NH-CBZ
.~~~'N-CBZ
189 H
190
F F
N N
a
.,~~~NH2 --
~~~~'N~ N ~ OMe
~0 ~ /
191
192
a:Benzyl chloroformate/NazC03/CHZClZ. b.Swern Ox.
c:NaBH(OAc)3 d:H2/10~ Pd/C e:R-N=C=O/THF.
183


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SCHEME 31a
OH
a OH
b
.~NH2
I~NH-CBZ
187
188
O
H
N
// N
-.~ ~/ d
NH-CBZ -----
c '~~~~N-CBZ
189 H
193
N
// N
Va
'~~.~2 ~ O
N N \
194 O
195
a:Benzyl chloroformate/NazC03/CH2Clz. b.Swern Ox.
c:NaBHtOAc;3 d:H~/10~ Pd/C e:R-N=C=O/THF.
The following examples were synthesized using the
methods outlined in Schemes 26-31a. These examples are
meant to be illustrative of the present invention, and are
not to be limiting thereof.
EXAMPLE 218
N-[1-(phenylmethyl)4-piperidinyl)-N~-[2-[[4-
(phenylmethyl)-1-piperidinyl]-methyl)phenyl)urea.
A solution of 4-benzylpiperidine (1.75 g, 10 mmol) in
25 mL of DMF was treated with 2-nitrobenzyl bromide (2.16
g, 10 mmol) and K~C03 (1.38 g, 10 mmol) and the reaction
184


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' WO 00/35451 PCT/US99/30332
mixture stirred at room temperature for 2 h. The mixture
was diluted with water and. extracted into ethyl acetate.
The organic extracts were washed successively with water
and brine, and the organic solvent removed under vacuum on
a rotary evaporator to give 166 (Scheme 26, R~4 - H) as a
yellow oil.
The oil was re-dissolved in ethyl acetate (50 ml) and
treated with 10~ Pd/C and hydrogenated at 50 psi hydrogen
at room temperature for 40 min. The solution was then
filtered and the solvent removed under vacuum to give the
aniline 167 as a white solid. The aniline was purified by
chromatography (MPLC, 40o ethyl acetate/ hexane; silica
gel) to give 2:0 g of aniline 167 as a white solid.
A solution of aniline 167 (1.2 g, 4.3 mmol) in THF was
treated with Et3N (1.0 g, 10 mmol) and cooled in an ice
bath to °0 C. Chlorophenyl formate (0.71 g, 4.5 mmol) was
added to the mixture and stirred for 1 h. The mixture was
diluted with water and extracted into ethyl acetate. The
extracts were washed with water and brine, and the solvent
removed under vacuum to give the phenyl carbamate 168 as an
off-white solid. The crude product was used without
further purification.
A solution of phenylcarbamate 168 (0.2 g, 0.5 mmol) in
DMF is treated with 4-amino-1-benzylpiperidine (95 mg, 0.5
mmol) and K2C03 (138 mg, 1 mmol) and the mixture was heated
at 50 °C for 2 h. The mixture was diluted with water and
extracted into ethyl acetate. The extracts were washed
with water and brine; and the solvent removed under vacuum.
The residue was purified by chromatography (MPLC, 0-25
MeOH/ethyl acetate; silica gel) to give 200 mg of the
target compound as a white solid. esi ms: (M+H)' - 497.
EXAMPLE 219
N-(2,5-difluorophenyl)-N'-[2-[[4-(phenylmethyl)-1
piperidinyl]-methyl]phenyl]urea.
185


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14
A solution of aniline 167 (Scheme 26; (R - H)) (140
mg, 0.5 mmol) in THF is treated with 2,5-difluoro-
isocyanate (80 mg, 0.5 mmol) at room temperature for 1 h.
The solvent is removed under vacuum and the residue was
purified, by chromatography (MPLC, 20~ EtOAc/Hexane, silica
gel) to give the desired urea as a white solid. esi ms:
(M+H)+ - 436.
EXAMPLE 220
N-(2,5-difluorophenyl)-N'-[[3-[[4-(phenylmethyl)-1-
piperidinyl)methyl]phenyl]methyl)urea.
A solution of 4-benzylpiperidine (1.75 g, 10 mmol) in
25 mL of DMF was treated with 3-cyanobenzyl bromide 177
(1.96 g, 10 mmol) and KzC03 (2.76 g, 20 mmol) and the
reaction mixture stirred at room temperature for 2 h. The
mixture was diluted with water and extracted into ethyl
acetate. The organic extracts were washed successively with
water and brine, and the organic solvent removed under
vacuum on a rotary evaporator to give 178 (Scheme 28) as a
yellow oil.
To a suspension of Raney nickel (2.0 g) in EtOH
(saturated with NH3~gas>) was added crude 178 (Scheme 28)
(1.45 g, 5 mmol) and hydrogenated at 50 psi for 3 days.
The solution was then filtered and the solvent removed
under vacuum to give the amine 179 as a yellow oil. A
solution of amine 179 (200 mg, 0.68 mmol) in THF is treated
with 2,5-difluoroisocyanate (115 mg, 0.74 mmol) at room
temperature for 1 hour. The solvent is removed under vacuum
and the residue is washed with 1 NaOH and water to give the
desired urea as a white solid. esi ms: (M+H)' _ 450.
EXAMPLE 221
N-(2,5-difluorophenyl)-N'-[2-[[4-(phenylmethyl)-1
piperidinyl]acetyl]phenyl]urea
186


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To an ice cold solution of 2-bromo-2'-nitro-
acetophenone 170 (2.4 g, 10 mmol) in DMF is added 4-
benzylpiperidine (1.75 g, 10 mmol) and stirred for 30 min.
The solution was poured into a mixture of K2C03 (1.38 g, 10
mmol) in water/ice and extracted into ethyl acetate. The
ethyl acetate extract was washed several times with water.
The resultant ethyl acetate solution of crude nitroketone
171 is treated with 10~ Pd/C and hydrogenated at 50 psi
hydrogen at room temperature for 40 min. The solution was
then filter, the solvent removed under vacuum, and the
residue purified by chromatography (MPLC, 30~ ethyl
acetate/hexane; silica gel) t.o give 1.8 g of aniline 172 as
a tan/brown solid.
A solution of aniline 172 (Scheme 27) (310 mg, 1.0
mmol) in THF is treated with 2,5-difluoroisocyanate (160
mg, 1.0 mmol) at room temperature for 1 h. The solvent is
removed under vacuum and the residue is purified by
chromatography (MPLC, 20o EtOAc/Hexane, silica gel) to give
420 mg of the desired urea-ketone 173 as a white solid. esi
ms: (M+H)+ - 464.
EXAMPLE 222
N-(2,5-difluorophenyl)-N'-[2-[2-[4-(phenylmethyl)-1-
piperidinyl]-1-hydroxyethyl]phenyl]urea
A solution of the urea-ketone 173 (260 mg, 0.56 mmol)
in MeOH is treated with NaBH9 (400 mg, 11 mmol) at room temp
for 1 hour. The solvent is removed under vacuum and the
residue is treated with 1 N NaOH and extracted into EtOAc.
The extracts are washed with water, brine and the solvent
removed under vacuum to give the desired alcohol 174 as a
white solid. esi ms: (M+H)f - 466.
EXAMPLE 223
N-[3-[imino-[4-(phenylmethyl)-1-piperidinyl]methyl]
phenyl]-N'-phenylurea
187


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A solution of 3-cyanoaniline (3.54 g, 30 mmol) in THF
is treated with phenylisocyanate (3.58 g, 30 mmol) at room
temperature for 1 h. The solvent is removed under vacuum
and the residue is titurated with hexane to give 7 grams of
urea 182 (Scheme 29) as a white solid. Urea 182 (1.0 g,
4.2 mmol) is dissolved in EtOH, cooled in an ice bath while
HC1 is bubbled-in for 20 min. The solution is left
standing at room temperature for 24 h. The solvent is
removed under vacuum to give 1.1 g of the imidate 183 as a
white solid. The crude imidate (0.5 g, 1.8 mmol) was
dissolved in EtOH and treated with 4-benzyl-piperidine (1.8
g, 10 mmol) at room temperature for 2 days. The solvent was
removed under vacuum and the residue was purified by
chromatography (MPLC, 0 to 30~ MeOH/EtOAc, silica gel) to
give 200 mg of the desired amidine 184 (Scheme 29) as a
white solid. esi ms: (M+H); - 413.
EXAMPLE 416
N-(3-methoxyphenyl)-N'-[(1R,2S)-2-[[(4-phenylmethyl)
piperidinyl]methyl]cyclohexyl]urea.
Step a: To a solution of (R,R) amino alcohol 187 [J. Am.
Chem. Soc. 1996, 118, 5502-5503 and references therein]
(1.9 g, 14.7 mmol) in CHZCl~ (50 mL) is added SO ml of an
aqueous solution of Na~C03 (2.4 g, 28.9 mmol). While
stirring, benzyl chloroformate (2.51 g, 14.7 mmol) is added
and the mixture is stirred at room temperature for 1 h. The
organic layer is separated and washed with water and brine.
The solution is concentrated on a rotary evaporator and the
residue is chromatographed on silica gel (30~ ethyl
acetate/hexane) to give 3.1 g (12 mmol) of 188 as a white
solid. 1H NMR (300 MHz, CDC1~) 8 7.40-7 .29 (m, S H) , 5.11
(s, 2 H) , 4 . 71 (bd, 1 H) , 3 .76-3 .71 (m, 1 H) , 3 .53--3 .28 (m,
3 H), 2.00-1.9S (m, 1 H}, 1.90-1.09 (m, 8 H}. MS AP' (M+H)'
- 264.3 (100
188


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WO 00/35451 PCT/US99/30332
Step b: A solution of DMSO (2.52 g, 30 mmol) in CH~C12
(50 mL) is cooled to -78°C. To this solution is added drop-
wise oxalyl chloride (1.81 g, 14 mmol) and the resulting
solution is stirred for an additional 10 min. Then a
solution of alcohol 188 (2.5 g, 9.5 mmol) in CH2C12 (70 ml)
is added via an addition funnel and stirred for 10 min.
Then Et3N (5.0 g, 50 mmol) is added and the solution is
allowed to warm to room temperature. The solution is
diluted with water and the organic layer washed with water,
1 N HC1, and brine. The organic layer is dried over Na2S0q,
filtered, and concentrated to give 2.5 g (9.5 mmol) of the
aldehyde 189 as a white solid. 1H NMR (300 MHz, CDC13) $
9.59 (d, 3.6 Hz, 1 H), 7.38-7.28 (m, 5 H), 5.07 (m, 2 H),
4.69 (m, 1 H), 3.84 (m, 21 H), 2.19-2.11 (m,l H), 2.09-2.01
( m, 1 H), 1.86-1.75 (m, 3 H), 1.54-1.17 (m, 4 H).
Step c: A solution of aldehyde ,~89 (2.0 g, 7.7 mmol) ,
4-(4-fluorophenylmethyl)piperidine hydrochloride (1.8 g,
7.8 mmoI) in dichloroethane (80 ml) was treated with
Na(OAc)3BH (3.23 g, 15 mmol) and 1 ml AcOH and stirred
overnight at room temperature. The resulting solution was
diluted with methylene chloride and washed with 1 n NaOH,
water, and brine. The organic solvents were removed under
vacuum and the residue chromatographed on silica gel (50%
EtOAc/hex - 100% EtOAc) to give 3.0 g (6_8 mmol) of 190 as
an oil.
Step d: A solution of 190 (3.0 g, 6.8 mmol) in MeOH
was treated with 1.5 g of 10% Pd/C and hydrogenated at 50
psi overnight in a Parr apparatus. The mixture was filtered
and the filtrate concentrated on a rotary evaporator to
give 1.8 g (5.9 mmol) of the amine 191 as an oil.
Step e: A solution of amine 191 (200 mg, 0.67 mmol) in
THF is treated with 3-methoxyphenyl isocyanate (110 mg,
0.75 mmol) and the mixture is stirred for 30 min. The
solvent is removed on a rotary evaporator and the residue
is chromatographed on silica gel (50% EtOAc/hex - 100%
189


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PCT/US99/30332
EtOAc) to give 250 mg of urea 192 as a solid. MS esi:
(M+H)' - 454 . 4 (1000 , HRMS (M+H)' - 454 .2875.
EXAMPLE 415
N-(3-acetvlphenyl)~-N'-((1R 2S)-2-(f(3S) 3 (4
fluorophenyl)methyllpiperidinyllmeth~rllcyclohexyllurea
Step a: To a solution of (R, R) amino alcohol 187 [J.Org.
Ch em. 1996, 61, 5557-5563; J. Am. Cherri. Soc. 1996, 118,
5502-5503] (9.5 g, 73.8 mmol) in CHzCl2 (200 mL) is added
200 ml of an aqueous solution of Na2C03 (15 g, 141 mmol).
While stirring, benzyl chloroformate (12.6 g, 73.8 mmol) is
added slowly and the mixture is stirred at room temperature
for 1 h. The organic layer is separated and washed with
water and brine. The organic solvent is removed on a rotary
evaporator to give a white solid. The solid is
recrystallized from hexane to give 16.3 g (62 mmol) of the
alcohol 188 (Scheme 31a)as a white solid. 1H NMR (300 MHz,
CDC13) $ 7.40-7.29 (m, S H), 5.11 (s, 2 H), 4.71 (bd, 1 H),
3.76-3.71 (m, 1 H), 3.53-3.28 (m, 3 H), 2.00-1.95 (m, 1 H),
1 . 90-1. 09 (m, 8 H) . MS AP' (M+H) ~ - 264 . 3 ( 100 0)
Step b: A solution of DMSO (36 g, 430 mmol) in CH~C12 (200
mL) is cooled to -78°C. To this solution is added drop-wise
oxalyl chloride (27.41 g, 216 mmol) and the resulting
solution is stirred for an additional 10 min. A solution of
alcohol 188 (38 g, 144 mmol) in CHzCl2 (150 ml) is added via
an addition funnel and stirred for 10 min. Then, Et3N (58
g, 570 mmol) is added and the solution is stirred for 20
min and the ice bath removed and stirred for an additional
30 min. The solution is diluted with water and the organic
layer separated and washed with water, 1 N HCl, and brine.
The organic layer is dried over Na2SOQ, filtered, and
concentrated to give 38 g of aldehyde 189 as a white solid.
The solid is recrystallized from hexane to give 19.7 grams
of a first crop of aldehyde 189 as white needles. A second
crop gave an additional 11 grams. lei NMR (300 MHz, CDC13) $
190
.. .


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' WO 00/35451 PCT/US99/30332
9.59 (d, 3.6 Hz, 1 H), 7.38-7.28 (m, 5 H), 5.07 (m, 2 H),
4.69 (m, 1 H), 3.84 (m, 21 H), 2.19-2.11 (m,l H), 2.09-2.01
( m, 1 H), 1.86-1.75 (m, 3 H), 1.54-1.17 (m, 4 H).
Step c: A solution of aldehyde 189 (19.6 g, 75 mmol) and
(3S)-3-(4-fluorophenylmethyl)piperidine (14.5 g, 75 mmol)
in dichloroethane (400 ml) was treated with Na(OAc)~BH (32
g, 152 mmol) and stirred overnight at room temperature. The
resulting solution was poured slowly into a stirred mixture
of ice/water/1 N NaOH and stirred for 20 min. The organic
layer was separated and washed water, and brine. The
solution was dried over MgSOa and the organic solvent was
removed under vacuum and the residue chromatographed on
basic alumina (50$ EtOAc/hexane) to give 32.1 g (73 mmol)
of amine 193 as mixture of (15~)cis and trans isomers. 1H
NMR (300 MHz, CDC13) b 7.79 (bs, 1 H), 7.38-7.29 (m, 5 H),
6.95-6.84 (m, 4 H), 5.08 (m, 2 H), 3.71 (m, 1 H, cis isomer
), 3.06 (m, 1 H, trans isomer), 2.80 (m, 1 H), 2.55-2.36
(m, 2 H), 2.30 (dd, J = 9 Hz, J = 13 Hz, 1 H, trans
isomer), 2.05 (dd, J = 2 Hz, J = 13 Hz , 1 H, trans
isomer), 1.81-0.90 (m, 16 H).
Step d: A solution of 193 (32 g, 73 mmol) in MeOH was
treated with 8 g of loo Pd/C and hydrogenated at 50 psi
overnight in a Parr apparatus. The mixture was filtered and
the filtrate concentrated on a rotary evaporator to give 20
g (65 mmol) of the amine 194, which was used without
further purification.
Step e: A solution of amine 194 (10 g, 32.8 mmol) in THF is
treated with 3-acetylyphenyl isocyanate (5.3 g, 32.8 mmol)
and the mixture is stirred for 30 min. The solvent is
removed on a rotary evaporator and the residue is
chromatographed on silica gel (0.5:4.5:95 NHaOH/MeOH/CHzCl~)
to give 11 g of urea 195 (Example 415) as a solid. Also
obtained 2 g of cis isomer (Example 416a). The urea Example
415 was further purified by a second chromatography on
silica gel (40:60:1 EtAc/Hex/TEA) and final
191


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recrystallization from ether to give crystalline solid. mp
115-117 °C, [a] °~5 - +16 . 8° (CH30H, c = 0 . 23 g/dL) .
'H NMR
(300 MHz, CDC13) 87.86 (m, 1 H), 7.78 (bs, 1 H), 7.68-7.64
(m, 1 H), 7.62-7.59(m, 1 H), 7.38 (t, J = 8 Hz, 1 H), 6.95-
6.90 (m, 2 H), 6.79-6.72 (m, 2 H), 6.25 (s, 1 H), 3.21 (dt,
J = 3 Hz, 11 Hz, 1 H), 3.00-2.97 (m, 1 H), 2.66-2.56 (m, 1
H), 2.61 (s, 3 H), 2.44-2.32 (m, 4 H), 2.06 (dd, J = 2 Hz,
J = 13 Hz, 1 H) , 1 . 80-0 . 86 (m, 15 H) . MS esi : (M+H)' - 466. 3
(1000 . Anal. Calcd for CzBH36N30zF: C, 72.23; H 7.70; N,
9.02. Found: C, 72.33; H, 7.91; N, 9.00.
EXAMPLE 415a
N-(3-acetyl~henvl)-N'-f(1R 2S)-2-ff(3S)-3-(4
fluorophenvl)methvllpiperidinyllmethyllc~rclohexyllurea
Hvdrochloride
A solution of example 415 (15 g, 32 mmol) in 300 ml of THF
was cooled in an ice bath and treated drop-wise with 36 ml
of a 1 M HC1/ether solution. The resulting solution was
stirred for 30 min and concentrated in vacuo. The resulting
solid was titurated with ether and the resulting white
solid dried under high vacuum overnight to give 16 g of the
hydrochloride salt. mp 58-60 °C. [a]pz5 - +20.0 ° (CH30H, c =
0.23 g/dL). 'H NMR (400 MHz, DMSO-D6) 8 9.61 (s, 1 H), 9.15
(s, 1 H), 8_00 (m, 1 H), 7.63-7.61 (m, 1 H), 7.51-7.49(m, 1
H), 7.39-7.34 (m, 1 H), 7.22-7.17 (m, 2 H), 7.09-7.04 (m, 2
H), 6.86 (d, J = 8 Hz, 1 H), 3.47-3.3i (m, 4 H), 3.11 (m, 1
H), 2.98-2.82 (m, 2 H), 2.67-2.62 (dd, J = 5 Hz, J = 13 Hz,
1 H), 2.58-2.50 (m, 2 H), 2.52 (s, 3 H), 2.39 (dd, J = 8
Hz, J = 13 Hz, 1 H), 2.16-2.06 (m, 2 H), 1.84-1.556 (m, 7
H), 1.30-1.00 (m, 4 H). Anal. Calcd for
C2BH3,N30~FC1 ~Hz0 ~THFo_zs : C, 64 . 73 ; H 7 . 68 ; N, 7 . 81 . Found : C,
64.89; H, 7.41; N, 7.81.
EXAMPLE 415b
192
,.


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N-(3-acetylphenyl)-N'-f(1R.2S)-2-f~(3S)-3-(4
fluorophenyl)methyllpiaeridinyl3methyllcyclohexyllurea
Benzenesulfonate.
Bezenesulfonic acid monohydrate (1.06 g, 6 mmol) was dried
by azeotroping off the water of a benzene solution (twice)
and adding the dried acid solution to a solution of example
415 (2.81 g, 6 mmol) in toluene (40 ml). The solvents were
removed in vacuo (twice) and the resulting residue
recrystallized twice from toluene and dried under high
vacuum overnight give 2.77 g of benzenesulfonic acid salt
as a white solid. mp 157-159 °C. [oc]DZ5 - +16.9 ° (CH30H, c -
0.23 g/dL) . Anal. Calcd for C3aH4zN~O5FS: C, 65.47; H 6.80;
N, 6.75; S, 5.14. Found: C, 65.48; H, 6.80; N, 6.70; S,
5.35.
The compounds of Table 3a and Table 3.1 were prepared
by procedures described in Schemes 26-31A, other examples
and methods taught herein, and procedures familiar to one
skilled in the art.
TABLE 3a
193


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R16
' / N,E R
N,E
14 ~ 3
R ,~ ~~ N-R Rla / ,R3
4~ 2 H 4~ 2 H
P q
R16
N, R ~ / + NiCH3
E E
5!' '1J
Rla \ ~ 2 N_R3 Rla ~~Z N_R3
H q ' H
3
3
r
s
Ex Core R1 E Z R14 R3 MS
#


M+Hi


218 1-
p H CHZ (1) (phenylmethyl) 497


NH H _4_


pi eridinyl]


2,5-
219 p H CHZ (1) difluorophenyl 436


NH H


2,5-
220 p H CH2 (2) difluorophenyl 450


CHZNH H


2,5-
221 p H _~ (1) difluorophenyl 464
~,


~ NH H


O


2,5-
222 p H ;~ (1) difluorophenyl 466
~


~ NH H


OH


223 phenyl


p H C=~ (2) 413


NH H


224
p H CHz (2) (phenylmethyl) 497


NH H -4-


piperidinyl ]


2-(4-
225 p H CHZ (1) fluorophenyl)-- 446


H ethyl


194


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WO 00/35451 PCT/US99/30332
3-


226 p H CHZ (1) H hydroxypropyl 382


NH


2-(1-


227 p H CHz (1) H piperidinyl)- 435


NH ethyl


2-
~,


228 p H CHZ (1) H (dimethylamino 395


NH )ethyl


4_


229 p H CHZ (1) H (phenylrnethyl) 483


NH -1-piperazine


4-


230 p H CHz (1) H (phenylmethyl) 482


NH -1-piperidine


(1~ 3-


231 p H CHZ (1) H benzodioxol-5- 458


NH ylmethyl)


2, 2-


232 p H CHz (1) H (diphenyl)ethy 504


NH


4- ( 4-


233 p H CHz (1) H chlorophenyl)- 518


NH 4-hydroxy-1-


piperidine


4-phenyl-4-


234 p H CHZ (1) H hydroxy-1- 484


NH piperidine


4-phenyl-1-


235 p H CH2 (1) H piperidine 468


NH


(1H)-indazol-


236 p H CHz (1) H 5-yl 440


NH


(1H)-indazol-


237 p H CHz (1) H 6-yl 440


NH


phenylmethyl


238 p H CH2 (1) H 414



1,3-


239 p H CHZ (1) H benzodioxol-5- 444


yl


195


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(3-4)
240 p H CH2 (1) 1_


(phenylmethyl) 541


NH ~ _4_


piperidinyl]


O


(3-4) 2-(4_
241 p H CHz (1)


fluorophenyl)- 490


NH ~ ethyl


'O


(3-4) 4-((2-
242 p H CHI (1)


phenyl)ethyl) 541
O


-1-piperazine


'O


243 (3-4) (1H)-indazol-
P H CH ( 1


Z ) 5
O -Y1 484


NH


'O


244 (3-4) (1H)-indazol-
P H CH (1


2 ) 6-yl 484


NH


'O


(3-4) benzothiazol-
245 p H CH 1


2 (
) 6-Y1 501


O
'O


[2- (4-
246 p H CHI (1) (4) fluorophenyl)- 462


OH eth 1



1-
247 P H CHz (1) (4) (phenylmethyl) 513


NH OH _4_


i eridin 1]


(3-4) 3-phenylpropyl
248 p H


CHz (1)
486


O
'O


249 (1H)-indazol-
P H CH (2 )


2 H 5-yl 440


NH


250 p H CHz (2) H


fluorophenyl)- 446


ethyl


196


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2~5-


251 p H bond (1) H difiuorophenyl 422


NH


Phenyl


252 p H CH2 (1) H 400


NH


4-


253 p H CHz (1) H methoxyphenyl 430


NH


3_


254 p H CHz (1) H methoxyphenyl 430


NH


3 _


255 q 4-F CHZ (2) H methoxyphenyl 454


NH


3-acetylphenyl


256 q 4-F CHZ (2) H 466


NH



257 r H CH2 (1) H methoxyphenyl 430


NH


3-cyanophenyl


258 p H CH2 (2) H 425


NH


3-cyanophenyl


259 p H CH2 (3) H 425


NH


- 4-


260 p H CHZ (3) H methoxyphenyl 430


NH


2-phenylethyl


261 p H CHZ (3) H 428


NH


3-carboethoxy-


262 p H CHZ (1) H phenyl 472


NH


3-cyanophenyl


263 p H CHz (1) H 425


NH


phenyl '


264 p 4-F CH2 (1) H 418


NH


phenyl


265 p H CHz (1) H 490


N-


Benzyl


3-cyanophenyl


266 p H CH2 (1) H 515


N-


Benzyl


197


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2-Phenylethyl


267 p H CHZ (1) H 428


NH


(3-4) 3-cyanophenyl


268 p H CHz (1) 469



'O


(3-4) 3-carboethoxy-


269 p H CHZ (1) phenyl 516


NH O


'O


(3-4) 4-carboethoxy-


270 p H CHz (1) phenyl 516


NH o


'O


phenyl


271 p H CH2 (1) (4) 416


NH OH


3-cyanophenyl


272 p H CHZ (1) (4) 441


NH OH


(4) 3-


273 p H CHz (1) methoxyphenyl 524


NH O~~
fJ


S


CH3


(4) Trans-2-


274 p H CH2 (1) phenyl- 534


cyclopropyl



w0 CH3


(3) 3-cyanophenyl


275 P H CHz (1) 483


NH CO~Me


(3 ) 3-


276 p H CHz (1) methoxyphenyl 488


NH CO_Me


198
r.. ..


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WO 00/35451 PCT/US99130332
(4) 3-cyanophenyl


277 p H CHZ (1) 519


NH O'


-O CH3


(3) 3-


278 p H CH2 (1) methoxyphenyl 460


NH OOH


(3) 3-cyanophenyl


279 p H CHZ (1) 455


NH ~JH


(4) 3-cyanophenyl


280 p 4-F CHz (1) 501


NH COZMe


(5) 3-cyanophenyl


280a p 4-F CHZ (1) 501


NH CO~Me


(5) 3-cyanophenyl


280b p 4-F CH2 (1) 500


NH CONMe


(5) 3-cyanophenyl


280c p 4-F CHz (1) 486


NH CONHz


(5) 3-(1-


280d P 4-F CHZ (1) hydroxyethyl)- 520


NH COzMe phenyl


(5) phenyl


280e r H CHZ (1) 458


NH C02Me


(5) phenyl


280f P 4-F CHz (1) 462


NH COzH


(5) 3-cyanophenyl


2808 r H CH2 (1) 483


NH CO~Me


(5) 3-


280h r H CH2 (1) methoxyphenyl 488


NH COzMe


199


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3-acetylphenyl
2801 r H CH 1


z ( 500
)


NH COZMe


(5) 3-acetylphenyl
280j p 4-F CH 1


z (
)


518
HC1 ( sa NH CO,Me


lt) '


(5) 3-cyanophenyl
280k p 4-F CH 1


Z (
)


501
HC1 ( sa NH COzMe


lt)


28I p 4-F CHz (1) (4) Phenyl


NH CO.Me
476


281a p 4-F CH2 (1) (5) I phenyl


CO,Me
476


281b p 4-F CH~ (1) (5) phenyl


~TH CONMe
475


281c p 4-F CH2 (1) (5) phenyl


NH CONH 461


2


3-
282 p 4-F CH2 (1) (4)


methoxyphenyl 506


NH


CO.Me


3-
282a p 4-F CH, (1) 5)
(


methoxyphenyl 506


NH


CO,Me


?82b p 4-F CHI (1) (5)


methoxyphenyl 505


NH CONMe


(5) 3-acetylphenyl
!82c p 4-F CH 1


z )
(


518
COzMe


(5) 3-acetylphenyl
82d p 4-F CH 1


Z (
)


517
NH CONMe


(5) 3-acetylphenyl
82e p 4-F


CHI (1)


503
NH COl~H


z


200


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WO 00/35451 PCT/US99/30332
(4) 3-cyanophenyl


283 p 4-F CHz (1) 473


NH OOH


3-cyanophenyl


284 p 4-F CH2 (1) (3-4) 493


fused


Phenyl


3-


285 p 4-F CHZ (1) (3-4) methoxyphenyl 498


fused


Phenyl


3-cyanophenyl


286 p 4-F CH2 (1) (4) 562


NH


-CONPh


3-cyanophenyl


286a p 4-F CHZ (1) (5)
562


NH


-CONPh


3-acetylphenyl


286b p 4-F CHZ (1) (5) 579


NH


-CONPh


(4) 3-


287 p 4-F CH2 (1) methoxyphenyl 478


NH OOH


(4) 3-cyanophenyl


288 p 4-F CHZ (1) 500


NH CONMe


(4) 3-cyanophenyl


288a p 4-F CH2 (1) 500


HC1(sa NH CONMe


lt)


(5) 3-acetylphenyl


288b p 4 CH2 ( 1 517
-F )


HC1(sa NH CONMe


lt)


(5) 3-acetylphenyl


288c p 4-F CHz (1) 574


NH CON


( CHa
) 2


NMe 2


(5) 3-acetylphenyl


288d p 4-F CHZ (1) 557


NH CON


( CHZ
) z


NMe2


201


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WO 00/35451 PCT/1JS99/30332
(5) 3-acetylphenyl
288e p 4-F CH2 (1)


453
NH CON


C3Hs


(5) 3-acetylphenyl
288f p 4-F CH (1


z ) 531


CON


C3H5


(5) 3_
2889 p 4-F CHZ (1}


methoxyphenyl 519


NH CONMez


(5) 3-acetylphenyl
288h p 4-F CH 1


z ( 531
)


NH CONMe2


(5) 3-acetylphenyl
288i p 4-F CHz (1)


580
NH CON(2-


pyridi


nyl)


_ (5) 3_
288 p 4 CHz (1)
F


methoxyphenyl 568


NH CONMez


2,5-
289 P H CH2 (1) H difluorophen 45
l


y 0
CH~NH


290 3-cyanophenyl
P H CH2 ( 1
)


H 4 3
CH2NH 9


3-carboethoxy-
2 91 p H CH ( 1


z ) H
Phenyl 4 8
6


CHzNH


292 3_
p H CHI (1) H


methoxyphenyl 444


CHzNH


4-
293 p H CH2 (1) methoxyphenyl 444


CHZNH H


3-
294 p H ,~ ~ (1) H methoxyphenyl 460


NH


OH


3-
295 r H .~ ~ (1) H methoxyphenyl 460


NH


OH


202


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WO 00/35451 PCT/US99/30332
3-cyanophenyl


296 p H ,~ (1) H 455
~


~ NH


OH


3-carboethoxy-


297 p H ,~ (1) H phenyl 502



OH


phenyl


298 p H ,~ (1) H 430
~


~ NH


OH


(5) phenyl


299 p 4-F CHz ( 1
) 448


~ ~H


phenyl
H _~
~


300 p ~ ( 1 443
)


NOH NH H


phenyl


3 O p H .~ ( 2 H 42
1 ~, ) 8


~ NH


O


phenyl


302 p H ,~ (2) H 430
~


~ NH


OH


phenyl


303 p 4-F ,~ (1) H 448
~


~ NH


OH


-_3_


304 p 4-F ,~ (1) H methoxyphenyl 478
~


~ NH


OH


3-cyanophenyl


305 p 4-F ,~ (1) H 473
~


~ NH


OH


( 3-4 3 -cyanophenyl
)


306 p H _~ (1) 499
~


~ NH


O


203


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WO 00/35451 PCT/US99/30332
3-cyanophenyl


307 p H CH2- (1) H 439


CH2 NH


3-cyanaphenyl


308 p 4-F CH2- ,( 1 H 457
)


CH2 NH


3-


309 p H CHz- (1) H methoxyphenyl 444


CH2 NH


3-


310 p 4-F CHZCH2 (1) H metho
xyphenyl 462


NH


3-


311 r H CH2- (1) H methoxyphenyl 444


CHz NH


3-acetylphenyl


312 p 4-F CH2- (1) H
474


CHI NH


4-fluorophenyl


313 p 4-F CHZ- (1) H 450


CHZ NH


1-adamantyl


314 p 4-F CHZ- (1) H 490


CH2 NH


( 3-4 3 -cyanophenyl
~


315 s H CH2 (1) 483


NH O
(M+)


'O


3-cyanophenyl


316 s H CHZ (1) (4) 455


NH OH ( M+
)


3-cyanophenyl


317 s H CH2 (1) (4) 539


NH o- (M+
)


f2-THP)


204


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TABLE 3.1
~Ris R~s
2 N
Z NV
1
HN NHR3
HN~NHR3
!'O
a b
R~s
2 N
HN~NHR3
O
C
Ex Core R16 Stereo- Salt MS
#


3 M+H+
chemistry Form R


400 a H 1,2 traps - 3-methoxylphenyl 436


racemic


401 a 4-F 1,2 traps - 3-methoxylphenyl 454


racemic


402 a H 1,2 cis - 3-methoxylphenyl 436


racemic


403 a 4-F 1,2 traps - 3-cyanophenyl 449


racemic


403a a 4-F 1,2 traps - 3-acetylphenyl 466


racemic


403b a 4-F 1,2 traps - 3-nitrophenyl 469


racemic


403c a 4-F 1,2 traps - 4-nitrophenyl 469


racemic


403d a 4-F 1,2 traps - 4-pyridinyl 425


racemic


403e a 4-F 1,2 traps HC1 3-acetylphenyl 466


racemic


403f a 4-F 1,2 traps - (1H)-indazol-5-yl 464


racemic


404 a 4-F 1S,2R - 3-acetylphenyl 466


405 a 4-F 1S,2R - 3-cyanophenyl 449


406 a 4-F 1S,2R - 3-methoxylphenyl 454
L I I I I


205


CA 02350730 2001-05-07
WO 00!35451 PCT/US99/30332
407 a 4-F 1S,2R - phenyl 424


408 a 4-F 1R,2S - 3-acetylphenyl 466


409 a 4-F 1R,2S - 3-cyanophenyl 449


410 a 4-F 1R,2S - 3-methoxyphenyl 454


411 a 4-F 1R,2S - phenyl 424


412 a 4-F 1R,2S - phenylmethyl 438


413 a 4-F 1R,2S - (1H)-indazol-5-yl 464


414 a 4-F 1R,2S - (1H)-indol-5-yl 463


414a b H 1,2 traps - 3-methoxyphenyl 464
(3RS)
racemic


414b b H 1,2 traps - 3-cyanophenyl 431
(3RS)
racemic


414c b H 1,2 traps - 3-acetylphenyl 448
(3RS)
racemic


414d b 4-F 1,2 traps - 3-acetylphenyl 466
(3RS)
racemic


414e b 4-F 1,2 traps - 3-cyanophenyl 449
(3RS)
racemic


414f b 4-F 1,2 traps - 3-methoxyphenyl 454
(3RS)
racemic


4148 b 4-F 1,2 traps - 3-nitrophenyl 469
(3RS)
racemic


415 b 4-F 1R,2S,3S - 3-acetylphenyl 466


415a b 4-F 1R,2S,3S HCl 3-acetylphenyl 466


415b b 4-F 1R,2S,3S Besyl 3-acetylphenyl 466


416 b 4-F 1R,2S,3R - 3-acetylphenyl 466


416a b 4-F 1R,2R,3S - 3-acetylphenyl 466


416b b 4-F 1R,2S,3R HCl 3-acetylphenyl 466


417 b 4-F 1R,2S,3S - 3-cyanophenyl 449


418 b ~ 4-F 1R, 2S, ~ - 3-cyanophenyl i 449
~ ~ 3R


206


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WO 00/35451 PCT/US99/30332
419 b 4-F 1R,2S,3S - 3-methoxylphenyl 454


420 b 4-F 1R,2S,3R - 3-methoxylphenyl 454


421 b 4-F 1R,2S,3S - 4-fluorohenyl 442


422 b 4-F 1R,2S,3R, - 4-fluorohenyl 442


423 b 4-F 1R,2S,3S - phenyl 424


424 b 4-F 1R,2S,3S - (1H)-indazol-5-yl 464


425 b 4-F 1R,2S,3S - (1H)-indazol-6-yl 464


426 b 4-F 1R,2S,3S - benzthiazol-6-yl 481


427 b 4-F 1R,2S,3S - (1H)-indol-5-yl 463


428 b 4-F 1R,2S,3S - (1H)-indoi-6-yl 463


429 b 4-F 1R,2S,3S - (IH)-2,3- 491
dimethylindol-5-
1


430 b 4-F 1R,2S,3S - benzimidazol-5-yl 464


431 b 4-F 1R,2S,3S - indolin-5-yl 465


432 b 4-F 1R,2S,3S - 3-cyano-4- 467
fluoro henyl


433 b 4-F 1R,2S,3S - 3-acetyl-4- 484
fluoro henyl


434 b 4-F 1R,2S,3S - 3,5-diacetylphenyl 508


435 b 4-F 1R,2S,3S - 3-(1- 468
hydroxyethyl)-
henyl


436 b 4-F 1R,2S,3S - 4-methyl-thiazol- 445
2- 1


437 b 4-F 1R,2S,3S - 4-methyl-5-acetyl- 487
thiazol-2-yl


438 b 4-F 1R,2S,3S - 1,3,4-thiadiazol- 432
2- 1


439 b 4-F 1R,2S,3S - 4-chlorol- 515
benzthiazol-2-yl


440 b 4-F 1R,2S,3S - thiazol-2-yl 431


441 b 4-F 1R,2S,3S - 5-methyl-isoxazol- 429
_ 3-yl


442 b 4-F 1R,2S,3S - 1-methyl-pyrazol- 428
3- 1


443 b 4-F 1R,2S,3S - 4-(1,2,4-triazol- 491
1- 1 ) hen 1


443a b 4-F 1R,2R,3S - 4-(1,2,4-triazol- 491
1- 1 ) henyl


444 b 4-F 1R,2S,3S - (1H)-3-chloro- 499
indazol-5- 1


207


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WO 00/35451 PCT/US99/30332
445 b 4-F 1R,2S,3S - 4-fluorophenyl 492


446 b 4-F 1R,2S,3S - 4-chlorophenyl 458


447 b 4-F 1R,2S,3S - 4-bromophenyl 502


448 b 4-F 1R,2S,3S. - 3-bromophenyl 502


449 b 4-F 1R,2S,3S - 3-fluorophenyl 442


450 b 4-F 1R,2S,3S - 3,4-difluorophenyl 460


451 b 4-F 1R,2S,3S - 3-chloro-4- 476
fluorophenyl


452 b 4-F 1R,2S,3S - 3,5-dichlorophenyl 492


453 c 4-F 1R,2S,3S - 3-acetylphenyl 452


454 c 4-F 1R,2S,3R - 3-acetylphenyl 452


455 c 4-F 1R,2R,3S - 3-acetylphenyl 452


456 c 4-F 1R,2S,3S - 3-cyanophenyl 435


457 c 4-F 1R,2S,3R - 3-cyanophenyl 435


458 c 4-F 1R,2R,3S - 3-cyanophenyl 435


458a c 4-F 1R,2R,3R - 3-cyanophenyl 435


459 c 4-F 1R,2S,3S - phenyl 410


460 c 4-F 1R,2S,3R - phenyl 410


461 c 4-F 1R,2R,3S - phenyl 410


462 b 4-F 1R,2S,3S - (1H)-5-amino- 464
indazol-1-yl


463 b 4-F 1R,2S,3S - 3-chlorophenyl 458


464 b 4-F 1R,2S,3S - 3-fluoro-4- 456
methyl henyl


465 b 4-F 1R,2S,3S - 3-cyano-4-(1- 515
yrazolyl) hen 1


466 b 4-F 1R,2S,3S - 2-methylphenyl 454


467 b 4-F 1R,2S,3S - 2-methylphenyl 438


468 b 4-F 1R,2S,3S - 2,4-dimethylphenyl 452


469 b 4-F 1R,2S,3S - 2,4- 484
dimetho hen 1


470 b 4-F IR,2S,3S - 2,5- 484
dimethoxyphenyl


208


CA 02350730 2001-05-07
WO 00/35451 PCT/IJS99/30332
i 471 b 4-F 1R,2S,3S - 2-methoxy-5- 468


meth 1 henyl


472 b 4-F 1R,2S,3S - 2-methyl-5- 456
i


~ f luoro her. 1


473 b 4-F 1R,2S,3S - 3,5-bis((1H)-1- 588


methyltetrazol-5-


1) hen 1
'


474 b 4-F 1R,2S,3S - (3-((1H)-1- 506


methyltetrazol-5-


yl)phen 1


475 b 4-F 1R,2S,3S - (4- 517


(carboethoxymethyl


)thiazol-2- 1


476 b 4-F 1R,2S,3S - 5-bromothiazol-2- 509


1


477 b 4-F 1R,2S,3S - 4,5-di(4- 619


fluorophenyl)thiaz


ol-2-yl


478 b 4-F 1R,2S,3S - 2-fluorophenyl 442


479 b 4-F 1R,2S,3S - 2-chlorophenyl 458


480 b 4-F 1R,2S,3S CF,CO,H indanon-6-yl 478


481 b 4-F~1R, 2S, 3S CF,CO,H indanon-4-yl 478


482 b 4-F 1R, 2S, 3S CF,CO,H 4- 466


(iso ro 1) hen 1


483 b 4-F 1R, 2S, 3S CF,CO,H 3-nitro-4- 483


meth 1 hen 1


484 b 4-F 1R,2S,3S CF,CO,H trans-2- 464


phenylcycloprop-1-


1


485 b 4-F 1R,2S,3S CF,CO,H 2,4-difluorophenyl 460


486 b 4-F 1R,2S,3S CF,CO,H 2,5-difluorophenyl 460


487 b 4-F 1R,2S,3S CF,CO,H 2,4-dichlorophenyl 492


488 b 4-F 1R,2S,3S CF,CO,H 2,5-dichlorophenyl 492


489 b 4-F 1R,2S,3S CF,CO,H 2-methoxyphenyl 454


490 b 4-F 1R,2S,3S CF,CO,H 2,4-dimethoxy- 484


hen 1


491 b 4-F 1R, 2S, 3S CF,CO,H 2, 5- 484


dimetho hen 1


492 b 4-F 1R, 2S, 3S CF,CO,H 2- 492


trifluoromethylyph


en 1


493 b 4-F 1R,2S,3S CF,CO,H 2-methylphenyl 438


494 b 4-F 1R, 2S, 3S CF,CO,H 3- 492


trifluoromethyly-


henyl


209


CA 02350730 2001-05-07
WO 00/35451 PCT/US99/30332
495 b 4-F 1R, 2S, CF,CO,H 3-methylphenyl 438
3S 1


496 b 4-F 1R,2S,3S CF~CO,H 4-methoxyphenyl 454


497 b 4-F 1R,2S,3S CF,CO,H 4-carboethoxy- 496
phenyl


498 b 4-F 1R, 2S, CF,CO,H 4- 492
3S trifluoromethyly-
henyl


499 b 4-F 1R, 2S, CF,CO,H 4-methylphenyl 438
3S


500 b 4-F 1R,2S,3S CF,CO,H 2-fluorophenyl 442


501 b 4-F 1R,2S,3S CF,CO,H 2-chloropheny 458


502 b 4-F 1R,2S,3S CF,CO,H 2-nitrophenyl 469


503 b 4-F 1R,2S,3S CF,CO,H 2,4-dichlorophenyl 563


504 b 4-F 1R,2S,3S CF,CO,H 3-nitrophenyl 469


505 b 4-F 1R, 2S, CF,CO,H 3, 5-di 560
3S (trif luoromethyly)
-phenyl


506 b 4-F 1R, 2S, CF,CO,H 2, 4- 452
3S dimeth 1 henyl


507 b 4-F 1R,2S,3S CF,CO,H 2,4-dimethoxy-5- 518
chloro henyl


508 b 4-F 1R, 2S, CF~CO,H 3 , 4, 5- 514
3S trimetho hen 1


509 b 4-F 1R,2S,3S CF,CO,H 3,5-dimethylphenyl 452


510 b 4-F 1R,2S,3S CF,CO,H 3-trifluorornethyl- 526
4-chloro henyl


511 b 4-F 1R,2S,3S CF~CO,H 4-phenoxyphenyl 516


512 b 4-F 1R,2S,3S CF,CO,H 4-ethoxyphenyl 468


513 b 4-F 1R,2S,3S CF,CO,H 4-thiomethylphenyl 470


514 b 4-F 1R, 2S, CF,CO,H 2-naphthyl 474
3S


515 b 4-F 1R,2S,3S CF,CO,H 4-acetylphenyl 466


516 b 4-F 1R,2S,3S CF,CO,H 2,6-dichloro- 493
pyridin-4- 1


517 b 4-F 1R, 2S, CF,CO,H 5-indan-~4-yl 464
3S


518 b 4-F 1R,2S,3S CF,CO,H 4-chloronaphth-1- 508
yl


519 b 4-F 1R, 2S, CF,CO,H 3-fluoro-4- 472
3S metho henyl


520 b 4-F 1R, 2S, CF~CO,H 4- 502
3S (methylsulfonyl)-
phenyl)


210
q


CA 02350730 2001-05-07
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PCT/US99/30332
521 b 4-F 1R, 2S, CF,CO,H 3- 502
3S


(methylsulfonyl)-


hen 1


522 b 4-F 1R, 2S, CFzCO,H 2- ( (1H) -pyrrol-1-489
3S


)


523 b 4-F 1R, 2S, CF,CO,H 1, 3-ben 468
3S zodioxol-5-


yI
~


524 b 4-F 1R,2S,3S CF,CO,H 1-acetylindolin-6- 507


1


525 b 4-F 1R, 2S, CF~CO,H 4- ( 6- 571
3S


methylbenzothiazol


-2- 1) hen 1


526 b 4-F 1R, 2S, CF,CO,H 4- ( (2 , 2- 523
3S


dimethylpropanoyl)


amino) hen 1


527 b 4-F 1R, 2S, CF,CO,H 4- (1- 506
3S


methyltetrazol-5-


1 ) phen 1


528 b 4-F 1R, 2S, CF,CO,H 4- ( 1- 509
3S


mo holino) hen 1


529 b 4-F 1R,2S,3S CF,CO,H quinolin-8-yl 475


530 b 4-F 1R,2S,3S CF;CO,H 3-hydroxyphenyl 440


531 b 4-F 1R,2S,3S CF,CO,H 4-(acetylamino)- 481


hen 1


532 b 4-F 1R,2S,3S CF,CO,H 4-hydroxyphenyl 440


533 b 4-F 1R,2S,3S CF,CO,H 3-hydroxy-4- 470


metho henyl


534 b 4-F 1R,2S,3S CFzCO,H 3-(acetylamino)- 481


hen 1


535 b 4-F 1R,2S,3S CF,CO,H 4-fluoro-3- 456


meth lphenyl


536 b 4-F 1R,2S,3S CF~CO,H 3-methoxy-4- 468


meth lphen 1


537 b 4-F 1R,2S,3S CF,CO,H 4-chloro-3- 472


meth 1 hen 1


538 b 4-F 1R, 2S, CF~CO,H 4- (N- 481
3S


methylcarboxamide)


hen 1


539 b 4-F 1R,2S,3S CF,CO,H 1-adamantyl 482


540 b 4-F 1R,2S,3S CF,CO,H quinolin-5-yl 475


541 b 4-F 1R,2S,3S CF,CO,H quinolin-6-yl 475


542 b 4-F 1R,2S,3S CF,CO,H 1,4-benzodioxan-6- 482


1


543 b 4-F 1R,2S,3S CF,CO,H isoquinolin-5-yl 475


544 b 4-F 1R, 2S, CF,CO~H 4- (sulfonamide) 503
3S -


hen 1


545 b 4-F 1R,2S,3S CF,CO,H benzotriazol-5-yl 465


211


CA 02350730 2001-05-07
WO 00/35451 PCT/US99/30332
546 b 4-F 1R,2S,3S CF~CO~H 2-hydroxy-4- 454


meth 1 henyl


547 b 4-F 1R, 2S, CF.~CO~H3-hydroxy-4- 454
3S


methylphenyl


548 b 4-F 1R, 2S, CF.~CO~H2-methyl- 495
3S


benzothiazol-5-yl


549 b 4-F 1R, 2S, CF.~CO~H(4- 468
3S .


methoxylphenyl)-


methyl


550 b 4-F 1R,2S,3S CF~CO~H (4-fluorophenyl)- 456


meth 1


551 b 4-F 1R,2S,3S CF.~CO~H(4-methylphenyl)- 452


methyl


552 b 4-F 1R, 2S, CF.~CO~H(1R) -1- 452
3S


(phenyl)ethyl


553 b 4-F 1R,2S,3S CF~CO~H 1-acetylindolin-5- 507


yl


554 b 4-F 1R,2S,3S CF~CO~H 5,6,7,8- 478


tetrahydronaphth-


1-yl


555 b 4-F 1R,2S,3S CF~CO~H 3-acetyl-4- 482


h dro hen 1


556 b 4-F 1R,2S,3S CF~CO~H 4-(Piperidin-1- 507


yl) henyl


557 b 4-F 1R, 2S, CF.~CO~HcYclohexyl 430
3S


558 b 4-F 1R,2S,3S CF~CO~H 2-methoxyphenyl 468


559 b 4-F 1R,2S,3S 2,6-dimethylphenyl 452
CF~CO~H


560 b 4-F 1R, 2S, CF.~CO~H2-ethylphenyl 452
3S


561 b 4-F 1R,2S,3S CF~CO~H 2,4,6- 466


trimeth lphen 1


562 b 4-F 1R, 2S, CF.~CO~H2, 5- 484
3S


dimethox henyl


563 b 4-F 1R,2S,3S CF~CO~H t-butyl 404


564 b 4-F 1R, 2S, CF.~CO~Hi-Propyl 390
3S


565 b 4-F 1R,2S,3S Ethoxycarbonyl- 434
CF~CO~H


meth 1)


566 b 4-F 1R, 2S, CF.~CO~H2- 508
3S


trifluoromethoxy-


hen 1


567 b 4-F 1R,2S,3S CF~CO~H (1R,S)-1-- 462


(methoxycarbonyl)-


2-meth 1-pro 1


568 b 4-F 1R,2S,3S CF~CO~H ~(1S)-1- 510


(methoxycarbonyl)-


2-phenylethyl


569 b 4-F 1R,2S,3S CF~CO'H 24,4-trimethyl-2- 460


ent 1


570 ~ ~ ~ 1R, 2S, ~ CF.~CO~H~ 2-Phenylethyl 452
b 4-F 3S


212


CA 02350730 2001-05-07
WO 00/35451 PCT/US99/30332
571 b 4-F 1R,2S,3S CF CO 3-acetylphenyl 466
H


572 b 4-F 1R,2S,3S CF~CO~H 2-carbomethoxy- 482


hen 1


573 b 4-F 1R,2S,3S (1S)-1- 452
CF~CO~H


(phenyl)ethyl


574 b 4-F 1R, 2S, 3S CF.~CO~H4- (Phenyl ) phenyl 500
.


575 b 4-F 1R,2S,3S CF.~CO~H1-naphthyl 474


576 b 4-F 1R,2S,3S CF~CO~H 2-(Phenyl)phenyl 500


577 b 4-F 1R,2S,3S CF~CO~H phenylmethoxy 454


578 b 4-F 1R,2S,3S CF~CO~H 3,4- 484


dimetho hen 1


579 b 4-F 1R, 2S, 3S CF.~CO~H_ 520
(3H) -2-


ethylquinazolin-4-


on-3- 1


580 b 4-F 1R,2S,3S _ 425
CF~CO~H 3-pyridinyl


581 b 4-F 1R,2S,3S &-methoxy-3- 455
CF.~CO~H


p ridinyl


582 b 4-F 1R,2S,3S -2-methylquinolin- 489
CF.~CO~H


8- 1


583 b 4-F 1R,2S,3S CF.~CO~H2-methylnaphth-1- 488


1


584 b 4-F 1R,2S,3S CF~CO~H 4-((1H)-1-propyl- 534


tetrazol-5-


1) hen 1


585 b 4-F 1R,2S,3S CF~CO~H 3-aminophenyl 439


586 b 4-F 1R,2S,3S - 3-(acetylamino)- 481


hen 1


587 b 4-F 1R, 2S, 3S CF.~CO~H3- (N- 481


methylcarbamoyl)-


hen 1


588 b 4-F 1R, 2S, 3S CF.~CO~H2-nitro-4- 499


metho henyl


589 b 4-F 1R,2S,3S CF~CO~H 8-hydroxyquinolin- 491


5-yl


590 b 4-F 1R,2S,3S 3-methylpyridin-2- 439
CF~CO~H


1


591 b 4-F 1R,2S,3S CF.~CO~Hisoquinolin-1-yl 475


Example 318
213


CA 02350730 2001-05-07
WO 00/3545t PCT/US99/30332
O
N ~0~
Part A: Preparation of 1-t-butyloxvcarbonyl 4
benzylpiperidine
4-benzylpiperidine (10.0 g, 57.1 mmol, 1.0 eq.) was
dissolved in 100 mL of THF under N2 and subsequently cooled
to 0 °C. Di-tert-butyl dicarbonate (11.21 g, 51.3 mmol, 0.9
eq.) dissolved in 50 mL of THF, was added dropwise. Gas,
evolution was observed. Once gas evolution ceased, the ice
bath was removed. After 20 hours, the THF was removed in
vacuo then the residue was dissolved in EtOAc and rinsed 3X
with 1N citric acid, 1X with brine. The organic was dried
over magnesium sulfate and stripped to yield 15.4 g of
colorless oil as
product. Yield = 97.90. IJMR (300 MHz, CDC13)S 7.35-7.17
(m,3H); 7.14 (d, 2H, J = 7 Hz); 4.20-3.90 (m, 2H); 2.75-
2.55 (m, 2H); 2.54 (d, 2H, J = 7 Hz); 1.70-1.50 (m, 3H);
1.46 (s, 9H); 1.20-1.00 (m, 2H).
214


CA 02350730 2001-05-07
WO 00/35451 PCT/US99/30332
0 0
a I'
N~O
)H + ~~ , OH
erythro threo
Part B: Preparation of erythro-and threo-cis-4-benzyl-
1-t-butoxycarbonyl-~-ethylpiperidinemethanol
1-t-butyloxycarbonyl-4-benzylpiperidine (5.0 g, 18.2
mmol, 1.0 eq. ) was dissolved in EtzO at 25 °C under Nz and
cooled to -78 °C. N,N,N',N'-Tetramethylethylenediamine
(TMEDA) (3.29 mL, 21.8 mmol, 1.2 eq.) was added followed by
the dropwise addition of sec-butyllithium (16.76 mL, 21.8
mmol, 1.2 eq.). The reaction was allowed to warm and stir
at -30 °C for 30 minutes then again cooled to -78 °C. Once
cool, propionaldehyde (1.31 mL, 20.0 mmol, 1.1 eq.) was
added neat. The reaction was allowed warmed to warm to -30
°C then immediately quenched with 10 mL of water and the
organic layer was separated. The aqueous layer was
extracted 2X more with EtzO. The organic layers were
combined, dried over magnesium sulfate and the solvent
removed in vacuo to yield a colorless oil which was
purified by flash chromatography in 4 . 1 to 1 _ 1 hexane/
EtOAc. Obtained 0.68 g of a colorless oil as isomer A,
yield = 11.2 and 0.91 g of a colorless oil as isomer B,
yield = 15Ø
Isomer A NMR (300 MHz, CDC1~)87.40-7.25 (m, 2H); 7.21 (d,
1H, J = 7 Hz); 7.16 (d, 2H, J = 7 Hz); 3.60-3.30 (m, 2H);
2.56 (d, 2H J = 7 Hz); 1.90-1.00 (m, 7H); 1.46 (s, 9H);
1.00-0.70 (m, 5H).
Isomer B NMR (300 MHz, CDC13)S 7.30-7.23 (m, 2H); 7.20 (d,
1H, J = 7 Hz); 7.14 (d, 2H, J = 7 Hz.); 3.60-3.20 (m, 2H);
215


CA 02350730 2001-05-07
WO 00/35451 PCT/US99/30332
2.60-2.40 (m, 2H); 1.90-1.00 (m, 9H); 1.44 (s, 9H); 0.96
( t, 3H, J = 7 Hz ) .
O
S
erythro
Part C: Structure determination of Isomer B via cyclization
to 4a,6a,7a-4-benzyl-7-ethyl-8-oxa-1-
azabicyclo[4.3.0]nonane-9-one
Isomer B (60 mg, 0.18 mmol, 1 eq.) was dissolved in DMF at
°C under N2 then NaH (7.9 mg, 0.198 mmol, 1 eq.) was
added. After 20 hours, 2 mL of water was added followed by
EtOAc. The layers were separated. The aqueous layer was
20 extracted 2X more with EtOAc. The organic layers were
combined, dried over magnesium sulfate, and the solvent
removed in vacuo to yield an oil which was purified over
silica gel in 9:1 to 1:1 hexane/EtOAc_ Obtained 30 mg.
Yield = 64~. Product structure confirmed by N.O.E. NMR
25 (300 MHz, CDC13) 8 7.40-7.20 (m, 3H) ; 7.16 (d, 2H, J = 7
Hz); 4.45-4.25 (m, 1H); 4.00-3.80 (m, 1H); 3.65-3.45 (m,
1H); 2.95-2.70 (m, 1H); 2.65-2.45 (m, 2H); 1.85-1.40 (m,
4H); 1.40-1.00 (m, 6H).
216
,..,


CA 02350730 2001-05-07
WO 00/35451 PCT/US99/30332
)H
Part D: Preparation of erythro-cis-4-benzyl-oc-
ethylpiperidinemethanol
Erythro-cis-4-benzyl-1-t-butoxycarbonyl-~-
ethylpiperidinemethanol(isomer B from part B)(815 mg, 2.44
mmol, 1 eq.) was dissolved in 8 mL of ethanol at 25 °C under
Nz . NaOH ( 3 91 mg , 9 . 7 8 mmo 1, 4 eq . ) was added and the
mixture refluxed for 4 hours. The solvent was removed in
vacuo to yield an oil. Water was added followed by EtOAc.
The layers were separated. The aqueous layer was extracted
2X more with EtOAc. The organic layers were combined dried
over magnesium sulfate, and the solvent removed in vacuo to
yield 390 mg of an oil. Yield = 68~. NMR (300 MHz, CDC13)
~ 7.35-7.20 (m, 2H); 7.23-7.00 (m, 3H); 3.75-3.65 (m, 1H);
3.20-3.00 (m, 1H); 2.90-2.40 (m, 4H); 1.70-1.50 (m, 2H);
1.50-1.30 (m, 1H); 1.20-0.80 (m, 5H).
O
a
)H 0
Part E: Preparation of erythro-cis-4-benzyl-a-ethyl-1-
(3-N-phthalimido-n-prop-1-yl)piperidinemethanol
Erythro-cis-4-benzyl-a-ethylpiperidinemethanol
217


CA 02350730 2001-05-07
WO 00/35451 PCT/US99/30332
(195 mg, 0.84 mmol, 1 eq.), N-(3-bromopropyl)phthalimide
(224 mg, 0.84 mmol, 1 eq.), potassium iodide (139 mg, 0.84
mmol, 1 eq.), and potassium carbonate (231 mg, 0.84 mmol, 1
eq.) were refluxed in 10 mL of 2-butanone for 3 hours. The
reaction was worked up by__filtering off the inorganic
solids. The filtrate solvent was removed in vacuo to yield
an oil. Purified by flash chromatography in 100$ EtOAc
then 4:1 chloroform/MeOH. Obtained 200 mg. Yield = 57~.
NMR (300 MHz, CDC1,) 8 7.95-7.80 (m, 2H); 7.80-7.65 (m,
2H); 7.35-7.00 (m, 5H); 3.90-3.60 (m, 3H); 3.20-2.90 (m,
2H); 2.65-2.30 (m, 3H); 2.20-2.00 (m, 2H); 2.00-1.75 (m,
2H); 1.70-1.40 (m, 4H); 1.35-0.90 (m, 3H); 0.96 (t, 3H, J =
7 Hz ) .
._ /''NHZ
)H
Part F: Preparation of erythro-cis-1-(3-amino-n-prop-
1-yl)-4-benzyl-a-ethylpiperidinemethanol
Erythro-cis-4-benzyl-a-ethyl-1-(3-N-phthalimido-n-
prop-1-yl)piperidinemethanol(200 mg, 0.48 mmol, 1 eq.) was
dissolved in 5 mL of ethanol at 25 °C under Nz. Anhydrous
hydrazine (0.03mL, 0.95 mmol, 2 eq.) was added and the
reaction refluxed for 3 hours during which time a white
precipitate (phthalhydrazide) formed. Once cool, The
solids were filtered. The filtrate solvent was removed in
vacuo to yield an oil which was stirred in EtzO. The
triturated solids were filtered and the filtrate solvent
was removed in vacuo to yield 120 mg of an oi.l. Yield =
87~. NMR (300 MHz, CDC13) b 7.27(t, 2H, J = 7 Hz); 7.17
(d,


1H, J Hz); 7.13 (d, 2H, J 7 Hz); 3.70-3.30 (m, 2H);
= 7 =


3.20-3.00(m, 2H); 3.00-2.70 2H); 2.70-2.40 (m, 2H);
(m,


218
p


CA 02350730 2001-05-07
' WO 00/35451 PCT/US99/30332
2.30-2.10 (m, 1H); 2.10-1.90 (m, 2H); 1.90-1.40 (m, 5H);
1.40-1.00 (m, 3H); 0.96 (t, 3H, J = 7 Hz).
O / ' O v
'' w ~~
~N O + .., ~N~N 0
H H H H
H
)H
t0 /
O
Part G: preparation of erythro-cis-1-[3-(3-
acetylphenylaminocarbonylamino)-n-prop-1-yl]-4-benzyl-a-
ethylpiperidinemethanol and erythro-cis-1-[3-(3-
acetylphenylaminocarbonylamino)-n-prop-1-yl]-2-[1-(3-
acetylphenylaminocarbonyloxy)-n-prop-1-yl)-4-
benzylpiperidine
Erythro-cis-1-(3-amino-n-prop-1-yl)-4-benzyl-a-
ethylpiperidinemethanol (120 mg, 0.41 mmol, 1 eq.) was
dissolved in 5 mL of THF at 25 °C under Nz then 3-
acetylphenyl isocyanate added neat. After 1 hour the
solvent was removed in vacuo to yield an oil. Purified by
flash chromatography in 100 EtOAc to 4:1 chloroform/MeOH.
Isolated mono-addition product (product A) along with an
additional bis-addition product (product B). Prouct A
yielded 81 mg of an oil. Yield = 43~. Product B yielded
43 mg of an oil.
Product A NMR (300 MHz, CDC1~) 8 7.86 (bs, 1H); 7.73 (d, 1H,
J = 7 Hz); 7.60 (s, 1H); 7.56 (d, 1H, J = 7 Hz); 7.40-7.15
(m, 4H); 7.12 (d, 2H, J = 7 Hz); 6.30-6.05 (m, 1H); 4.00-
3.80 (m, 1H); 3.50-3.30 (m, 1H); 3.30-2.90 (m, 5H); 2.60-
2.40 (m, 2H); 2.57 (s, 3H); 2.30-2.10 (m, 1H); 2.10-1.90
219


CA 02350730 2001-05-07
WO 00/35451 PCT/US99/30332
(m, 2H); 1.80-1.40 (m, 5H); 1.30-1.05 (m, 2H); 0.94 (t, 3H,
J = 7 Hz).
Product B NMR (300 MHz, CDC13) ~ 10.80-10.60 (m, 1H); 8.20-
8.00 (m, 1H) ; 7.91 (bs, lei) ; 7.80-7.18 (m, 9H) ; 7.11 (d,
2H, J = 7 Hz); 6.20-6.00 (m, 1H); 5.20-5.00 (m, 1H); 3.50-
3.00 (m, 4H); 2.57 (s, 3H); 2.56 (s, 3H); 2.55-2.00 (m,
5H); 2.00-1.00 (m, lOH); 1.00-0.80 (m, 3H)
Product A was separated into its enantiomers employing a
Daicel Chiral Pack AD column, eluting with 0.1%
diethylamine in methanol. (-)-isomer [a]DZ5 (c - 0.300 g/dL,
MeOH) - -14.9°. (+)-isomer [Ct]DZ5 (c = 0.290 g/dL, MeOH) -
+20.2°.
The following compounds can be synthesized by the methods
discussed previously:
220


CA 02350730 2001-05-07
WO OOI35451 PCT/US99/30332
TABLE 3b.
4
R3 5 4
O'1 61 -,~~3 6 / .~ R3
O 1 ,' 3
~N~r' 2 l''N 2
N H H ~~'' N ,
OH H H
OH
c d
5 4
6 / / R3
O 1 ' ~ 3
~N~N 2
H
0~~
'1 \
O ~ ~ R3
Ri /
a
5
Cores R1 R2 R2a, R2b R3
M+1


319 a,b H CH3 ~ --- 3-COCH3 438


320 a,b H CH3 -- 4-N02 441


321 a,b H CH3CH2 ---~ 3-COCH3 452


322 c H --- CH3, CH3 3-COCH3 452


323 a,b H CH3CH2CH2 --- 3-COCH3 466


Rz
R1
Ri
a b
5
6 / ~ R3 O 6 / ~3R3
O i ~. t 3 1 w. ~
N~N 2 ~N~N 2
' H H H
H
OH
/ R~R2b 0 ~ ~ R3
R1 /
R1 m
221


CA 02350730 2001-05-07
WO 00/35451 PCT/US99/30332
324 a,b H (CH3)2CH --- 3-COCH3 466


325 a,b H CH3CH2CH2CH2 --- 3-COCH3 480


326 a,b H (CH3)2CHCH2 --- 3-COCH3 480


327 d,e H CH3CH2 --- 3-COCH3 613


328 d,e H CH3CH2~CH2 --- 3-COCH3 627


329 d,e H (CH3)2CH --- 3-COCH3 627
I


330 d,e H CH3CH2CH2CH2 --- 3-COCH3 641
I


331 d,e H (CH3)2CHCH2 --- ~COCH3 641
~ ~ ~


Example 332
Part A Pret~aration of N-cyano-N'-3-
methoxvohenvlcarbamimidic acid phenyl ester
~N
O_ 'N \ O~
m-Anisidine (4.56 mL, 4.06 mmol, 1 eq.), and
diphenylcyanocarbonimidate (967 mg, 4.06 mmol, 1 eq.) were
mixed and refluxed in acetonitrile under N2 for 1 hour.
Solids precipitated. The reaction was worked up by
filtering off the solids. Obtained 580 mg as product.
M.P. - 170.0 - 171.0 °C. NMR (300 MHz, DMSO-ds) 8 8.70 -
8.50 (m, 1H); 7.43 (t, 2H, J = 7 Hz); 7.40 - 7.20 (m, 2H);
7.14 (d, 2H, J = 7 Hz); 7.00 - 6.80 (m, 2H); 6.80 - 6.70
(m, 1H); 3.80 (s, 3H).
Part B Preparation of N " -cvano-N'-(3-f4-(4-
f luorobenzyl ) t~iperidinel propel-N- ( 3-methoxvphenyl )__quanidine
222
r ...,..,.v u. .


CA 02350730 2001-05-07
WO 00/35451 PCT/US99/30332
N~ i
NON N ~ O~
3-(4-(4-fluorophenylmethyl)piperidin-1-yl)propylamine,
(synthesized in a similar fashion to the previously
described des-fluoro compound) (53 mg, 0.20 mmol, 1 eq.)
and the product from Part A (50 mg, 0.20 mmol, 1 eq.) were
mixed and refluxed in 2-propanol under Nz for 1 hour. The
reaction was stripped and the residue then purified over
silica gel in 100 ~ ethyl acetate followed by 8:2
chloroform/methanol. Obtained 55 mg of off-white solids as
product. NMR (300 MHz, CDC1,) b 7.33 (t, 1H, J = 7 Hz);
7.10 - 6.90 (m, 4H); 6.90 - 6.80 (m, 3H); 3.83 (s, 3H);
3.50 - 3.35 (m, 2H); 2.90 - 2.70 (m, 2H); 1.50 - 1.20 (m,
3H). Mass Spec detects 424 (M+H).
Example 334
Part A: Preparation of f(Methvlthio)(3-acetylphenvl
amino)lmethylenepropanedinitrile
N
~S N
O
(Bis(methylthio)methylene]propanedinitrile 3.00 g,
17.6 mmol, 1 eq.), and 3~amino-acetophenone (2.38 g, 17.6
mmol, 1 eq.), were mixed and refluxed under N2 in ethanol
for 16 hours. Solids precipitated while cooling to 25 °C.
The solids were filtered. Obtained 1.86 g of tan solids.
M.P. - 165.0 - 166.5 °C. NMR (300 MHz, DMSO-ds) 8 10.66
(m, 1H); 7.90 - 7.80 (m, 2H); 7.60 - 7.50 (m, 2H); 2.60 (s,
3H); 2.54 (s, 3H).
223


CA 02350730 2001-05-07
WO 00/35451 PCT/US99/30332
Part B: Preparation of 2-((3-acetylanilino)({3-(4-(4-
fluorobenzyl)-1-piperidinyl]propyl)
amino)methylene]malononitrile
N\ , N
~I
N N N
O
3-(4-(4-fluorophenylmethyl)piperidin-1-yl)propylamine,
49 mg, 0.194 mmol, 1 eq.) and the product from Part A (50
mg, 0.194 mmol, 1 eq.) were mixed then stirred under N2
overnight. The reaction was stripped and the residue
purified over chloroform/methanol. Obtained 17 mg of a
white amphorphous solid. NMR (300 MHz, CDC13) ~ 7.82 (d,
1H, J = 7 Hz); 7.73(s, 1H); 7.51 (t, 1H, J= 7 Hz); 7.34 (d,
1H, J = 7Hz); 7.10-6.80 (m, 4H); 3.28 (m, 2H); 2.62 (s,
3H); 2.64-2.40 (m,2H); 2.40-2.25 (m, 2H); 2.05-1.70 (m,
2H); 1.70-1.35 (m, 3H); 1.20-0.80 (m, 2H).
Mass Spec detects 460 (M+H).
Example 335
Part A: Preparation of N-(1-(methylthio)-2-
nitroethenyl]-3-acetylbenzenamine
0
H
/S N
2 5 02N
A neat mixture of 1,1-bismethylthio-2-nitroethylene
(6.5 g, 38.5 mmol, 10 eq) and 3-aminoacetophenone (0.5 g,
3.85 mmol, 1eq) was melted together and heated at 140° C for
four hours. The mixture was cooled to room temperature,
then subjected to flash chromatography, eluting with 50~
224
.,.._.~ ,.,


CA 02350730 2001-05-07
' WO 00/35451 PCT/US99/30332
ethyl acetate/hexanes, to yield 0.63 g of a yellow powder
as product. Yield = 65~. NMR (300 MHz, CDC1,) b 11.82 (bs,
1H), 7.95-7.91 (m, 2H), 7.59-7.48 (m, 2H), 6.73 (s, 1H),
2.65 (s, 3H), 2.41 (s, 3H).
Part B: Preparation of 1-(3-{[(E)-1-((-[4-(4-
fluorobenzyl)-1-piperidinyl]propyl)amino)-2-
nitroethylenyl]amino)phenyl)ethanone
1 O
H H
F, / N N N
OZN
To a suspension of N-[1-(methylthio)-2-nitroethenyl]-
3-acetylbenzenamine (0.30 g, 1.19 mmol, 1.00 eq) in 20 ml
of methanol was added 3-(4-fluorobenzyl)piperidin-1-
yl)propylamine (0.31 g, 1.25 mmol, 1.05 eq), and the
mixture was stirred at room temperature. After three days,
a colorless solution was observed. The solvent was removed
in-vacuo, and the residue was subjected to flash
chromatography, eluting with 10~ methanol/chloroform, to
yield 0.38 g of an orange glass as product. Yield = 70~.
NMR (300 MHz, CDClj) b 10.51 (bs, 1H) , 7.92 (d, 1H, j - 8
Hz), 7.72 (bs, 1H), 7.54 (dd, 1H, j - 8 Hz, 8 Hz), 7.35
(bd, 1H), 6.90-6.88 (m, 5H), 6.17 (s, 1H), 3.54 (bs, 2H),
2.92-2.84 (m, 2H), 2.63 (s, 3H), 2.51 (m, 2H), 1.99-1.91
(m, 4H), 1.55-1.50 (m, 3H), 0.88-0.85 (m, 2H). MS (ESI)
detects (M+H)' - 455.
The following compounds can be prepared by procedures
described previously:
Table 3c
225


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Table 3c
\ H H \
N~N~N~R F ~ ~ ""..~N~N
Z 3 z R3
F \ \ Z
~ ~w ~ N ~".~ vN
H H F I ~N~'N'R3
,,N~N~ H H
Z R3 d
F ~ i ",.-~N
H H
\ ',,,N Z N~R3
Core Z R3 Mass
Spec
M+1


332 a N-CN 3-methoxyphenyl 424


333 i a N-CN 3-acetylphenyl 460


334 I a C(CN)2 3-acetylphenyl 460


335 a CHN02 3-acetylphenyl 455


336 b N-CN 3-acetylphenyl 436


337 b ~ C(CN)23-acetylphenyl 460


338 b I NCONH23-acetylphenyl 454


339 I b CHN02 3-acetylphenyl 455


340 b N-CN 3,5-diacetylphenyl 478


341 b NCONH2 3,5-diacetylphenyl 496


342 b NC02CH3 3,5-diacetylphenyl 511


343 b C(CN)2 3,5-diacetylphenyl


344 b N-CN 3-(1-methyl-1H- 476
tetrazol-5-yl)phenyl


345 b ' C(CN)2 3-(1-methyl-1H- 500
tetrazol-5-yl)phenyl


346 b NCONH2 3-(1-methyl-1H- 494
tetrazol-5-yl)pheny7.


347 b ( N-CN 2,4-dimethoxy-phenyl 454


226


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348 b N-CN 5-acetyl-2-methoxy- 466
phenyl


349 d I N-CN 3-(1-methyl-1H- 4gg
tetrazol-5-yl)phenyl


350 c N-CN ~ phenyl 44~


351 c N-CN 3-acetylphenyl 490


352 c I N-CN 3-cyanopneyl 473


353 c N-CN 2,4-dimethoxyphenyl 508


354 c N-CN 2,5-dimethoxyphenyl 508


355 ' N-CN 5-acetyl-2-methoxy- 520
c phenyl


356 c N-CN 2,4-dimethylphenyl 476


357 ~ N-CN 4-(1-methyl-1H- 530
c tetrazol-5-yl)phenyl


358 c N-CN 4-(1-propyl-1H- 558
tetrazol-5-yl)phenyl


359 c N-CN 5,6,7,8-tetrahydro- 502
naphthy-2-yl-phenyl I


360 ~ c N-CN 4-(4-morpholinyl)- 533
phenyl


361 C N-CN 2,5-dimethylphenyl


362 c N-CN 4-hydroxy-2-
methylphenyl


363 c N-CN 2-methylphenyl


364 ~ c N-CN 2-phenylethyl


365 c N-CN 1-adamantyl


366 c N-CN 2-adamantyl


367 c C(CN)2 3-acetylphenyl 514


368 c C(CN)2 5-acetyl-2-methoxy- 544
phenyl


369 c CHN02 3-acetylphenyl 509


370 a CHN02 3-acetylphenyl 560
I


371 a N-CN 3,5-diacetylphenyl 583


372 a N-CN 3-acetylphenyl 541


373 a N-CN 4-(1-propyl-1H- 581
tetrazol-5-yl)phenyl


227


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WO 00/35451 PCT/US99/3U332
The following tables contain representative examples
of the present invention, and may be prepared by procedures
described above, or methods familiar to one skilled in the
art. Each entry in each table is intended to be paired
with each formulae at the start of the table. For example,
Entry 1 in Table 4 is intended to be paired with each of
formulae la-44.
TABLE 4*
G H H
G~N~. ~ R3 /~Nw/~. N N_ R G'~N~ ~ R3
N N ~ 3 N' _ N'
H H p H H
la 2a 3a
H H
N ~ R ~~~N~ N N. N
C~,~ ~/''N N z R3 ~ ~~N.R3
H H p H H
lb 2b 3b
H H
G~Nw/''N~NR3 G~N~N~N_R3 G~N~N~N'R3
H H p H H
7
G/~N~ G~N ~N~
a H ~ H G a H
H~' Ia R3 ~ nI R3 HNY IS R3
8a 0O 9a ~ 10 O
G~,~N~ ~~,~N ~N
a H T H G ~ H
HNYN. R3 ~'N. R3 HNYIvL R3
8b O 9b O 11 O
1 H ~ H
HN O N; R3 HN~N,R3
12a 13a O '
228


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PCT/US99/30332
H ~ H
~~~ R3 ~~~R
3
12b O 13b O
G~N~ ~N
H G ~ H
f Is
R3 HNY N. R3
14 0 15 O
G
HN ~
R3 ~ R3
16a O 17a O
HN N- ~ IH~L
R3 ~ R3
16b O 17b
N
G~ ~ H R~N
1
R3 ~ R3
18 O 19 O
G'~N~N~MR3 G/~N~~N~~R3
H H H H
20a 21a
O
~~~ N~ N.R3 O~~n~, ~ R3
H H H H
20b 21b
R~~~N~N_R2 R~~N~N.R2
H H 1 H H
22 23
G/~N~ N N. R 6;~~N.~ N N_ ~N H N N.
R3 G ~ Y R3
0 0 O
24 25 26
H OH
G/~N H N N_ C~N N N. ~N N N_
R3 ~ R3 G ~ Y R3
Me O Me 0 Me O
27 28 29
229


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WO 00/35451 PCT/US99/30332
H ~ H
G~N H N N. N~N N_R3 G N~N~N.R3
~- Y R3 Y
iPrO iPrO iPrO
30 31 32
G~~ H H H C~~ H H H ~ H H H
N~N~N.R3 N~N~N.R3 G N~N N_R3
iBuO iBuO iB 0
33 34 35
G~ H H H C n H H H Q
N~N~N_R3 ;~ ,N~N~N_R3 H H H R
G N~N~N.
Ph O Ph 0
36 37 Ph O
38
OH H N. G~~ H H N, ~N H H N.
R3 ~ R3 G ~ R3
Ph 0 Ph 0 Ph 0
39 40 41
H ~ ~~,~ H H N. ~N H H N.
R3 ~ R3 G ~ R3
Ph O ph O p O
42 43 44
Entry G ~ R3


1 4-F-Ph Ph


2 4-F-Ph 3-CN-Ph


3 4-F-Ph 3-COCH3-Ph


4 4-F-Ph 3-C02Me-Ph


4-F-Ph 3-C02Et-Ph


6 4-F-Ph 3-C02H-Ph


7 4-F-Ph 3-CONH2-Ph


8 4-F-Ph 3-CONHMe-Ph


9 4-F-Ph 3-F-Ph


4-F-Ph 3-C1-Ph


11 4-F-Ph 3-Br-Ph


12 4-F-Ph 3-N02-Ph


13 4-F-Ph 3-NH2-Ph


14 4-F-Ph 3-NI3Me-Ph


4-F-Ph 3-NMe2-Ph


16 4-F-Ph 3-NHCOCH3-Ph


17 4-F-Ph 3-S02NH2-Ph


18 4-F-Ph 3-S02NHMe-Ph


19 4-F-Ph 3-CF3-Ph


4-F-Ph 3-OCH3-Ph


21 4-F-Ph 3-OPh-Ph


22 4-F-Ph 3-OCF3-Ph


23 4-F-Ph 3-SCH3-Ph


24 4-F-Ph 3-SOCH3-Ph


4-F-Ph 3-S02CH3-Ph i


230
,. .. w.w~...,...... ..


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26 4-F-Ph 3-OH-Ph


2~ 4-F-Ph 3-CH20H-Ph


2 8 4 -F- Ph 3 -CHOHCH3 -Ph


29 4-F-Ph 3-COH(CH3)2-Ph


30 4-F-Ph 3-CHOHPh-Ph


31 4-F-Ph 3-CH3-Ph


32 4-F- Ph 3-C2H5-Ph


33 4-F-Ph 3-iPr-Ph


34 4-F-Ph 3-tBu-Ph


35 4-F-Ph 3-Ph-Ph


36 4-F-Ph 3-CH2Ph-Ph


3~ 4-F-Ph 3-CH2C02Me-Ph


38 4-F-Ph 3-(1- i eridin 1)-ph


39 4-F-Ph 3-(1- rrolidin 1)-Ph


40 4-F-Ph 3-(2-imidazolyl)-Ph


41 4-F-Ph 3-(1-imidazol 1)-Ph


42 4-F-Ph 3-(2-thiazol 1)-Ph


43 4-F-Ph 3-(3- razol 1)-Ph


44 4-F-Ph 3-(1- razolyl)-Ph


45 4-F-Ph 3-(1-tetrazol 1)-Ph


46 4-F-Ph 3-(5-tetrazol 1)-Ph


4~ 4-F-Ph
3-(2- yrid 1)-Ph


4g 4-F-Ph 3-(2-thienyl)-Ph


49 4-F-Ph 3-(2-furan 1)-Ph


50 4-F-Ph 4-CN-Ph


51 4-F-Ph 4-COCH3-Ph


52 4-F-Ph 4-C02Me-Ph


53 4-F-Ph 4-C02Et-Ph


54 4-F-Ph 4-C02H-Ph


55 4-F-Ph 4-CONH2-Ph


56 4-F-Ph 4-CONHMe-Ph


5~ 4-F-Ph 4-CONHPh-Ph


58 4-F-Ph 4-NHCONH2-Ph


59 4-F-Ph 4-F-Ph


60 4-F-Ph 4-C1-Ph


61 4-F-Ph 4-Br-Ph


62 4-F-Ph 4-N02-Ph


63 4-F-Ph 4-NH2-Ph


64 4-F-Ph 4-NHMe-Ph


65 4-F-Ph 4-NMe2-Ph


66 4-F-Ph 4-NHCOCH3-Ph


4-F-Ph 4-S02NH2-Ph


68 4-F-Ph 4-S02NHMe-Ph


69 4-F-Ph 4-CF3-Ph


~0 4-F-Ph 4-OCH3-Ph


4-F-Ph 4-OPh-Ph


~2 4-F-Ph 4-OCF3-Ph


~3 4-F-Ph 4-SCH3-Ph


~4 4-F-Ph 4-SOCH3-Ph


~5 4-F-Ph 4-S02CH3-Ph


4-F-Ph 4-OH-Ph


4-F-ph 4-CH20H-Ph


~8 4-F-Ph 4-CHOHCH3-Ph


231


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79 4-F-Ph 4-COH(CH3)2-Ph


80 4-F-Ph 4-CH3-Ph


81 4-F-Ph 4-C2H5-Ph


82 4-F-Ph 4-iPr-Ph


83 4-F-Ph 4-tBu-Ph


84 4-F-Ph 4-Ph-Ph


85 4-F-Ph 4-CH2Ph-Ph


86 4-F-Ph 4-CH2C02Me-Ph


87 4-F-Ph 4-(1- i eridinyl)-Ph


88 4-F-Ph 4-(1-pyrrolidin 1)-Ph


89 4-F-Ph 4-(2-imidazolyl)-Ph


90 4-F-Ph 4-(1-imidazol 1)-Ph


91 4-F-Ph 4-(2-thiazol 1)-Ph


92 4-F-Ph 4-(3- razolyl)-Ph


93 4-F-Ph 4-(1-pyrazolyl)-Ph


94 4-F-Ph 4-(1-tetrazol 1)-Ph


95 4-F-Ph 4-(5-tetrazolyl)-Ph


96 4-F-Ph 4-(2-p rid 1)-Ph


97 4-F-Ph 4-(2-thienyl)-Ph


98 4-F-Ph 4-(2-furanyl)-Ph


99 4-F-Ph 2-CN-Ph


100 4-F-Ph 2-COCH3-Ph


101 4-F-Ph 2-C02Me-Ph


102 4-F-Ph 2-C02Et-Ph


103 4-F-Ph 2-C02H-Ph


104 4-F-Ph 2-CONH2-Ph


105 4-F-Ph 2-CONHMe-Ph


106 4-F-Ph 2-F-Ph


107 4-F-Ph 2-Cl-Ph


108 4-F-Ph 2-Br-Ph


109 4-F-Ph 2-N02-Ph


110 4-F-Ph 2-NH2-Ph


111 4-F-Ph 2-NHMe-Ph


112 4-F-Ph 2-NMe2-Ph


I13 4-F-Ph 2-NHCOCH3-Ph


114 4-F-Ph 2-S02NH2-Ph


115 4-F-Ph 2-S02NHMe-Ph


116 4-F-Ph 2-CF3-Ph


117 4-F-Ph 2-OCH3-Ph


118 4-F-Ph 2-OPh-Ph


119 4-F-Ph 2-OCF3-Ph


120 4-F-Ph 2-SCH3-Ph


121 4-F-Ph 2-SOCH3-Ph


122 4-F-Ph 2-S02CH3-Ph


123 4-F-Ph 2-OH-Ph


124 4-F-Ph 2-CH20H-Ph


125 4-F-Ph 2-CHOHCH3-Ph


126 4-F-Ph 2-COH(CH3)2-Ph


127 4-F-Ph 2-CHOHPh-Ph


128 4-F-Ph 2-CH3-Ph


129 4-F-Ph 2-C2H5-Ph


130 4-F-Ph 2-iPr-Ph


. 131 4-F-Ph 2-tBu-Ph


232
._


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132 4-F-Ph 2-Ph-Ph


133 4-F-P_h 2-CH2Ph-Ph


134 4-F-Ph __
2-CH2C02Me-Ph


135 4-F-Ph 2- (1- it~eridin 1 ) -Ph
136 4-F-Ph 2-(1- rrolidin 1)-Ph
137 4-F-Ph 2-(2-imidazolyl)-Ph
138 4-F~Ph 2-(1-imidazolyl)-Ph
139 4-F-Ph 2-(2-thiazol 1)-Ph
140 4-F-Ph 2-(3- razol 1)-Ph
141 4-F-Ph 2-(1- razol 1)-Ph
142 4-F-Ph 2-(1-tetrazolyl)-Ph
143 4-F-Ph 2-(5-tetrazol 1)-Ph
144 4-F-Ph 2-(2- rid 1)-Ph
145 4-F-Ph 2-(2-thien 1)-Ph
146 4-F-Ph 2- (2-furan 1) -Ph
147 4-F-Ph 2,4-diF-Ph
148 4-F-Ph 2,5-diF-Ph
149 4-F-Ph 2,6-diF-Ph


150 4-F-Ph 3,4-diF-Ph


151 4-F-Ph 3,5-diF-Ph


152 4-F-Ph 2,4-diCl-Ph


153 4-F-Ph 2,5-diCl-Ph
154 4-F-Ph 2,6-diCl-Ph


155 4-F-Ph 3,4-diCl-Ph
156 4-F-Ph 3,5-diCl-Ph


157 4-F-Ph 3,4-diCF3-Ph


158 4-F-Ph 3,5-diCF3-Ph


159 4-F-Ph 5-C1-2-Me0-Ph


160 4-F-Ph 5-C1-2-Me-Ph


161 4-F-Ph 2-F-5-Me-Ph


162 4-F-Ph 2-F-5-N02-Ph


163 4-F-Ph 3,4-OCH20-Ph


164 4-F-Ph 3,4-OCH2CH20-Ph


165 4-F-Ph 2-Me0-4-Me-Ph
166 4-F-Ph 2-Me0-5-Me-Ph


167 4-F-Ph 1-na hth 1


168 4-F-Ph 2-na hth 1


169 4-F-Ph 2-thienyl
170 4-F-Ph 3-thien 1


171 4-F-Ph 2-furan 1


172 4-F-Ph 3-furan 1


173 4-F-Ph 2- rid 1


174 4-F-Ph 3- rid 1


175 4-F-Ph 4- yrid 1
176 4-F-Ph 2-indol 1


177 4-F-Ph 3-indol 1


178 4-F-Ph 5-indolyl
179 4-F-Ph 6-indol 1


180 4-F-Ph 3-indazol 1


181 4-F-Ph 5-indazol 1


182 4-F-Ph 6-indazol 1


183 4-F-Ph 2-imidazol 1


184 ~ 4-F-Ph
3 pyrazolyl


233


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185 4-F-Ph 2-thiazol 1


186 4-F-Ph 5-tetrazolyl


187 4-F-Ph 2-benzimidazolyl


188 4-F-Ph 5-benzimidazolyl


189 4-F-Ph 2-benzothiazol 1


190 4-F-Ph 5-benzothiazolyl


191 4-F-Ph 2-benzoxazol 1


192 4-F-Ph 5-benzoxazol 1


193 4-F-Ph 1-adamantyl


194 4-F-Ph 2-adamantyl


195 4-F-Ph t-Bu


196 2-F-Ph 3-CN-Ph


197 2-F-Ph 3-COCH3-Ph


198 2-F-Ph 3-C02Me-Ph


199 2-F-Ph 3-C02Et-Ph


200 2-F-Ph 3-C02H-Ph


201 2-F-Ph 3-CONH2-Ph


202 2-F-Ph 3-F-Ph


203 2-F-Ph 3-C1-Ph


204 2-F-Ph 3-NH2-Ph


205 2-F-Ph 3-S02NH2-Ph


206 2-F-Ph 3-CF3-Ph


207 2-F-Ph 3-OCH3-Ph


208 2-F-Ph 3-OEt-Ph


209 2-F-Ph 3-OCF3-Ph


210 2-F-Ph 3-S02CH3-Ph


211 2-F-Ph 3-OH-Ph


212 2-F-Ph 3-CH3-Ph


213 2-F-Ph 3-C2H5-Ph


214 2-F-Ph 4-CN-Ph


215 2-F-Ph 4-COCH3-Ph


216 2-F-Ph 4-C02Me-Ph


217 2-F-Ph 4-C02Et-Ph


218 2-F-Ph 4-C02H-Ph


219 2-F-Ph 4-CONH2-Ph


220 2-F-Ph 4-F-Ph


221 2-F-Ph 4-C1-Ph


222 2-F-Ph 4-NH2-Ph


223 2-F-Ph 4-S02NH2-Ph


224 2-F-Ph 4-CF3-Ph


225 2-F-Ph 4-OCH3-Ph


226 2-F-Ph 4-OEt-Ph


227 2-F-Ph 4-OCF3-Ph


228 - 2-F-Ph 4-S02CH3-Ph


229 2-F-Ph 4-OH-Ph


230 2-F-Ph 4-CH3-Ph


231 2-F-Ph 4-C2H5-Ph


232 2-F-Ph 2,4-diF-Ph


233 2-F-Ph 2,5-diF-Ph


234 2-F-Ph 3,4-diF-Ph


235 2-F-Ph 3,5-diF-Ph


236 2-F-Ph 2,4-diCl-Ph


237 2-F-Ph 2,5-diCl-Ph


234
. .. , ."..


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238 2-F-Ph 3,4-diCl-Ph


239 2-F-P_h 3,5-diCl-Ph


240 2-F-Ph 3,4-OCH20-Ph


241 2-F-Ph 3,4-OCH2CH20-Ph


242 2-F-Ph 2-thien 1


_243 2-F-Ph 2-furan 1


244 2-F--Ph 2-p rid 1


245 2-F-Ph 4- id 1


246 2-F-Ph 2-imidazolyl


247 2-F-Ph 3- razol 1


248 2-F-Ph 2-thiazolyl


249 2-F-Ph 5-tetrazol 1


250 2-F-Ph 1-adamant 1


251 2,4-diF-Ph 3-CN-Ph


252 2,4-diF-Ph 3-COCH3-Ph


253 2,4-diF-Ph 3-C02Me-Ph


254 2,4-diF-Ph 3-C02Et-Ph


255 2,4-diF-Ph 3-C02H-Ph


256 2,4-diF-Ph 3-CONH2-Ph


257 2,4-diF-Ph 3-F-Ph


258 2,4-diF-Ph 3-C1-Ph


259 2,4-diF-Ph 3-NH2-Ph


260 2,4-diF-Ph 3-S02NH2-Ph


261 2,4-diF-Ph 3-CF3-Ph


262 2,4-diF-Ph 3-OCH3-Ph


263 2,4-diF-Ph 3-OEt-Ph


264 2,4-diF-Ph 3-OCF3-Ph


265 2,4-diF-Ph 3-S02CH3-Ph


266 2,4-diF-Ph 3-OH-Ph


267 2,4-diF-Ph 3-CH3-Ph


268 2,4-diF-Ph 3-C2H5-Ph


269 2,4-diF-Ph 4-CN-Ph


270 2,4-diF-Ph 4-COCH3-Ph


271 2,4-diF-Ph 4-C02Me-Ph


272 2,4-diF-Ph 4-C02Et-Ph


273 2,4-diF-Ph 4-C02H-Ph


274 2,4-diF-Ph 4-CONH2-Ph


275 2,4-diF-Ph 4-F-Ph


276 2,4-diF-Ph 4-C1-Ph


277 2,4-diF-Ph 4-NH2-Ph


278 2,4-diF-Ph 4-S02NH2-Ph


279 2,4-diF-Ph 4-CF3-Ph


280 2,4-diF-Ph 4-OCH3-Ph


281 2,4-diF-Ph 4-OEt-Ph


282 2,4-diF-Ph 4-OCF3-Ph


283 2,4-diF-Ph 4-S02CH3-Ph


284 2,4-diF-Ph 4-OH-Ph


285 2,4-diF-Ph 4-CH3-Ph


286 2,4-diF-Ph 4-C2H5-Ph


287 2,4-diF-Ph 2,4-diF-Ph


288 2,4-diF-Ph 2,5-diF-Ph


289 2,4-diF-Ph 3,4-diF-Ph


290 2,4-diF-Ph 3,5-diF-Ph


235


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291 2,4-diF-Ph 2,4-diCl-Ph


292 2,4-diF-Ph 2,5-diCl-Ph


293 2,4-diF-Ph 3,4-diCl-Ph


294 2,4-diF-Ph 3,5-diCl-Ph


295 2,4-diF-Ph 3,4-OCH20-Ph


296 2,4-diF-Ph 3,4-OCH2CH20-Ph


297 2,4-d,iF-Ph 2-thienyl


298 2,4-diF-Ph 2-furan 1


299 2,4-diF-Ph 2-p rid 1


300 2,4-diF-Ph 4- rid 1


301 2,4-diF-Ph 2-imidazolyl


302 2,4-diF-Ph 3- razol 1


303 2,4-diF-Ph 2-thiazolyl


304 2,4-diF-Ph 5-tetrazol 1


305 2,4-diF-Ph 1-adamantyl


306 4-C1-Ph Ph


307 4-C1-Ph 3-CN-Ph


308 4-C1-Ph 3-COCH3-Ph


309 4-C1-Ph 3-C02Me-Ph


310 4-Cl-Ph 3-C02Et-Ph


311 4-C1-Ph 3-C02H-Ph


312 4-Cl-Ph 3-CONH2-Ph


313 4-C1-Ph 3-CONHMe-Ph


314 4-C1-Ph 3-F-Ph


315 4-C1-Ph 3-C1-Ph


316 4-C1-Ph 3-Br-Ph


317 4-C1-Ph 3-N02-Ph


318 4-Cl-Ph 3-NH2-Ph


319 4-C1-Ph 3-NHMe-Ph


320 4-C1-Ph 3-NMe2-Ph


321 4-C1-Ph 3-NHCOCH3-Ph


322 4-Cl-Ph 3-S02NH2-Ph


323 4-C1-Ph 3-S02NHMe-Ph


324 4-C1-Ph 3-CF3-Ph


325 4-Cl-Ph 3-OCH3-Ph


326 4-Cl-Ph 3-OPh-Ph


327 4-Cl-Ph 3-OCF3-Ph


328 4-C1-Ph 3-SCH3-Ph


329 4-Cl-Ph 3-SOCH3-Ph


330 4-C1-Ph 3-S02CH3-Ph


331 4-Cl-Ph 3-OH-Ph


332 4-C1-Ph 3-CH20H-Ph


333 4-C1-Ph 3-CHOHCH3-Ph


334 4-C1-Ph 3-COH(CH3)2-Ph


335 4-C1-Ph 3-CHOHPh-Ph


336 4-C1-Ph 3-CH3-Ph


337 4-C1-Ph 3-C2H5-Ph


338 4-C1-Ph 3-iPr-Ph


339 4-C1-Ph 3-tBu-Ph


340 4-Cl-Ph 3-Ph-Ph


342 4-Cl-Ph 3-CH2Ph-Ph


342 4-C1-Ph 3-CH2C02Me-Ph


343 4-Cl-Ph 3-(1-piperidinyl)-Ph


236


CA 02350730 2001-05-07
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344 ~ 4-C1-Ph 3-(1-pyrrolidinyl)-Ph


345 4-C1-Ph 3-(2-imidazolyl)-Ph


346 _ 3-(1-imidazol 1)-Ph
4-C1-Ph


347 4-C1-Ph 3-(2-thiazol 1)-Ph


348 4-C1-Ph 3-(3- razolyl)-Ph


349 4-C1-Ph 3-(1-pyrazol 1)-Ph


350 4-Cl--Ph _
3-(1-tetrazol 1)-Ph


351 4-C1-Ph 3-(5-tetrazolyl)-Ph


352 4-C1-Ph 3-(2- rid 1)-Ph


353 4-C1-Ph 3-(2-thienyl)-Ph


354 4-C1-Ph 3-(2-furan 1)-Ph


355 4-C1-Ph 4-CN-Ph


356 4-C1-Ph 4-COCH3-Ph


357 4-C1-Ph 4-C02Me-Ph


358 4-C1-Ph 4-C02Et-Ph


359 4-C1-Ph 4-C02H-Ph


360 4-C1-Ph 4-CONH2-Ph


361 4-C1-Ph 4-CONHMe-Ph


362 4-C1-Ph 4-CONHPh-Ph


363 4-C1-Ph 4-NHCONH2-Ph


364 4-C1-Ph 4-F-Ph


365 4-C1-Ph 4-C1-Ph


366 4-C1-Ph 4-Br-Ph


367 4-C1-Ph 4-N02-Ph


368 4-C1-Ph 4-NH2-Ph


369 4-C1-Ph 4-NHMe-Ph


370 4-C1-Ph 4-NMe2-Ph


371 4-C1-Ph 4-NHCOCH3-Ph


372 4-Cl-Ph 4-S02NH2-Ph


373 4-C1-Ph 4-S02NHMe-Ph


374 4-C1-Ph 4-CF3-Ph


375 4-C1-Ph 4-OCH3-Ph


376 4-Cl-Ph 4-OPh-Ph


377 4-C1-Ph 4-OCF3-Ph


378 4-C1-Ph 4-SCH3-Ph


379 4-C1-Ph 4-SOCH3-Ph


380 4-C1-Ph 4-S02CH3-Ph


381 4-C1-Ph 4-OH-Ph


382 4-C1-Ph 4-CH20H-Ph


383 4-C1-Ph 4-CHOHCH3-Ph


384 4-C1-Ph 4-COH(CH3)2-Ph


385 4-C1-Ph H3-Ph
4-C


386 4-C1-Ph _
4-C2H5-Ph


387 4-C1-Ph 4-iPr-Ph


388 4-C1-Ph 4-tBu-Ph


389 4-C1-Ph 4-Ph-Ph


390 4-C1-Ph _
4-CH2Ph-Ph


391 4-C1-Ph 4-CH2C02Me-Ph


392 4-C1-Ph 4-(1- i eridin 1)-Ph


393 4-C1-Ph 4-(1- rrolidin 1)-Ph


394 4-C1-Ph 4-(2-imidazol 1)-Ph


395 4-C1-Ph 4-(1-imidazol 1)-Ph


396 4-C1-Ph 4-(2-thiazolyl)-Ph


237


CA 02350730 2001-05-07
WO 00135451 PCT/US99/30332
397 4-Cl-Ph 4-(3- razol 1)-Ph


398 4-Cl-Ph 4-(1-pyrazol 1)-Ph


399 4-Cl-Ph 4-(1-tetrazolyl)-Ph


400 4-C1-Ph 4-(5-tetrazol 1)-Ph


401 4-C1-Ph 4-(2- rid 1)-Ph


402 4-C1-Ph 4-(2-thien 1)-Ph


403 4-Cl-Ph 4-(2-furanyl)-Ph


404 4-Cl-Ph 2-CN-Ph


405 4-C1-Ph 2-COCH3-Ph


406 4-C1-Ph 2-C02Me-Ph


407 4-Cl-Ph 2-C02Et-Ph


408 4-Cl-Ph 2-C02H-Ph


409 4-C1-Ph 2-CONH2-Ph


410 4-Cl-Ph 2-CONHMe-Ph


411 4-Cl-Ph 2-F-Ph


412 4-C1-Ph 2-C1-Ph


413 4-C1-Ph 2-Br-Ph


414 4-Cl-Ph 2-N02-Ph


415 4-C1-Ph 2-NH2-Ph


416 4-Cl-Ph 2-NHMe-Ph


417 4-Cl-Ph 2-NMe2-Ph


418 4-C1-Ph 2-NHCOCH3-Ph


419 4-C1-Ph 2-S02NH2-Ph


420 4-C1-Ph 2-S02NHMe-Ph


421 4-C1-Ph 2-CF3-Ph


422 4-Cl-Ph 2-OCH3-Ph


423 4-Cl-Ph 2-OPh-Ph


424 4-C1-Ph 2-OCF3-Ph


425 4-C1-Ph 2-SCH3-Ph


426 4-Cl-Ph 2-SOCH3-Ph


427 4-C1-Ph 2-S02CH3-Ph


428 4-C1-Ph 2-OH-Ph


429 4-C1-Ph 2-CH20H-Ph


430 4-C1-Ph 2-CHOHCH3-Ph


431 4-C1-Ph 2-COH(CH3)2-Ph


432 4-C1-Ph 2-CHOHPh-Ph


433 4-C1-Ph 2-CH3-Ph


434 4-Cl-Ph 2-C2H5-Ph


435 4-C1-Ph 2-iPr-Ph


436 4-C1-Ph 2-tBu-Ph


437 4-C1-Ph 2-Ph-Ph


438 4-C1-Ph 2-CH2Ph-Ph


439 4-Cl-Ph 2-CH2C02Me-Ph


440 4-C1-Ph 2-(1- i eridin 1)-Ph


441 4-C1-Ph 2-(1- rrolidin 1)-Ph


442 4-C1-Ph 2-(2-imidazol 1)-Ph


443 4-C1-Ph 2-(1-imidazol 1)-Ph


444 4-C1-Ph 2-(2-thiazolyl)-Ph


445 4-C1-Ph 2-(3- yrazol 1)-Ph


446 4-C1-Ph 2-(1- razol 1)-Ph


447 4-C1-Ph 2-(1-tetrazolyl)-Ph


448 4-C1-Ph 2-(5-tetrazol 1)-Ph


449 4-C1-Ph 2-(2-pyridyl)-Ph


238
. ~~..,


CA 02350730 2001-05-07
WO 00/35451 PCT/US99/30332
450 _ 4-C1-Ph_ 2-(2-thienyl)-Ph


451 4-C1-Ph 2-(2-furan 1)-Ph


452 4-Cl-Ph 2,4-diF-Ph


453 4-C1-Ph 2,5-diF-Ph


454 4-C1-Ph 2,6-diF-Ph


455 4-Cl-Ph 3,4-diF-Ph


456 4-Ci-Ph 3,5-diF-Ph


45? 4-C1-Ph 2,4-diCl-Ph


458 4-C1-Ph 2,5-diCl-Ph


459 4-C1-Ph 2,6-diCl-Ph


460 4-C1-Ph 3,4-diCl-Ph


461 4-C1-Ph 3,5-diCl-Ph


462 4-C1-Ph 3,4-diCF3-Ph


463 4-C1-Ph 3,5-diCF3-Ph


464 4-C1-Ph 5-C1-2-Me0-Ph


465 4-C1-Ph 5-C1-2-Me-Ph


466 4-C1-Ph 2-F-5-Me-Ph


467 4-C1-Ph 2-F-5-N02-Ph


468 4-C1-Ph 3,4-OCH20-Ph


469 4-C1-Ph 3,4-OCH2CH20-Ph


470 4-C1-Ph 2-Me0-4-Me-Ph


471 4-C1-Ph 2-Me0-5-Me-Ph


472 4-C1-Ph 1-naphth 1


473 4-C1-Ph 2-na hth 1


474 4-C1-Ph 2-thien 1


475 4-Cl-Ph 3-thien 1


476 4-Cl-Ph 2-furan 1


477 4-Cl-Ph 3-furanyl


478 4-C1-Ph 2- rid I


479 4-C1-Ph 3- rid 1


480 4-C1-Ph 4- rid 1


481 4-C1-Ph 2-indol 1


482 4-CI-Ph 3-indol 1


483 4-C1-Ph 5-indolyl


484 4-C1-Ph 6-indol 1


485 4-C1-Ph 3-indazol 1


486 4-C1-Ph 5-indazol 1


487 4-C1-Ph 6-indazol 1


488 4-C1-Ph 2-imidazol 1


489 4-C1-Ph 3- razol 1


490 4-C1-Ph 2-thiazol 1


491 4-C1-Ph 5-tetrazol 1


492 4-C1-Ph 2-benzimidazol 1


493 4-C1-Ph 5-benzimidazol 1


494 4-C1-Ph 2-benzothiazol 1


495 4-C1-Ph 5-benzothiazol 1


496 4-C1-Ph 2-benzoxazol 1


497 4-C1-Ph 5-benzoxazol 1


498 4-C1-Ph 1-adamant 1


499 4-C1-Ph 2-adamantyl


500 4-C1-Ph t-Bu


501 2-C1-Ph 3-CN-Ph


502 I 2-C1-Ph 3 COCH3 Ph


239


CA 02350730 2001-05-07
WO 00/35451 PCT/US99/30332
503 2-C1-Ph 3-C02Me-Ph


504 2-C1-Ph 3-C02Et-Ph


505 2-C1-Ph 3-C02H-Ph


506 2-C1-Ph 3-CONH2-Ph


507 2-Cl-Ph 3-F-Ph


508 2-C1-Ph 3-C1-Ph


509 2-C1--Ph 3-NH2-Ph


510 2-C1-Ph 3-S02NH2-Ph


511 2-C1-Ph 3-CF3-Ph


512 2-Cl-Ph 3-OCH3-Ph


513 2-C1-Ph 3-OEt-Ph


514 2-C1-Ph 3-OCF3-Ph


515 2-C1-Ph 3-S02CH3-Ph


516 2-C1-Ph 3-OH-Ph


517 2-C1-Ph 3-CH3-Ph


518 2-C1-Ph 3-C2H5-Ph


519 2-Cl-Ph 4-CN-Ph


520 2-C1-Ph 4-COCH3-Ph


521 2-Cl-Ph 4-C02Me-Ph


522 2-C1-Ph 4-C02Et-Ph


523 2-C1-Ph 4-C02H-Ph


524 2-C1-Ph 4-CONH2-Ph


525 2-C1-Ph 4-F-Ph


526 2-C1-Ph 4-C1-Ph


527 2-C1-Ph 4-NH2-Ph


528 2-C1-Ph 4-S02NH2-Ph


529 2-C1-Ph 4-CF3-Ph


530 2-Cl-Ph 4-OCH3-Ph


531 2-Cl-Ph 4-OEt-Ph


532 2-C1-Ph 4-OCF3-Ph


533 2-C1-Ph 4-S02CH3-Ph


534 2-C1-Ph 4-OH-Ph


535 2-C1-Ph 4-CH3-Ph


536 2-C1-Ph 4-C2H5-Ph


537 2-Cl-Ph 2,4-diF-Ph


538 2-C1-Ph 2,5-diF-Ph


539 2-C1-Ph 3,4-diF-Ph


540 2-C1-Ph 3,5-diF-Ph


541 2-Cl-Ph 2,4-diCl-Ph


542 2-C1-Ph 2,5-diCl-Ph


543 2-Cl-Ph 3,4-diCl-Ph


544 2-C1-Ph 3 , 5-diCl-Ph


545 2-C1-Ph 3,4-OCH20-Ph


546 2-C1-Ph 3,4-OCH2CH20-Ph


547 2-C1-Ph 2-thien 1


548 2-C1-Ph 2-furan 1


549 2-Cl-Ph 2- yridyl


550 2-C1-Ph 4- yridyl


551 2-C1-Ph 2-imidazol 1


552 2-C1-Ph 3- razol 1


553 2-C1-Ph 2-thiazolyl


554 2-C1-Ph 5-tetrazolyl


555 2-C1-Ph 1-adamantyl


240


CA 02350730 2001-05-07
WO 00/35451 PCT/US99/30332
556 2,4-diCl-Ph 3-CN-Ph


557 2,4-diCl-Ph 3-COCH3-Ph


558 2,4-diCl-Ph 3-C02Me-Ph


559 2,4-diCl-Ph 3-C02Et-Ph


560 2,4-diCl-Ph 3-C02H-Ph


561 2,4-diCl-Ph 3-CONH2-Ph


562 2,4-diCl-Ph 3-F-Ph


563 2,4-diCl-Ph 3-C1-Ph


564 2,4-diCl-Ph 3-NH2-Ph


565 2,4-diCl-Ph 3-S02NH2-Ph


566 2,4-diCl-Ph 3-CF3-Ph


567 2,4-diCl-Ph 3-OCH3-Ph


568 2,4-diCl-Ph 3-OEt-Ph


569 2,4-diCl-Ph 3-OCF3-Ph


570 2,4-diCl-Ph 3-S02CH3-Ph


571 2,4-diCl-Ph 3-OH-Ph


572 2,4-diCl-Ph 3-CH3-Ph


573 2,4-diCl-Ph 3-C2H5-Ph


574 2,4-diCl-Ph 4-CN-Ph


575 2,4-diCl-Ph 4-COCH3-Ph


576 2,4-diCl-Ph 4-C02Me-Ph


577 2,4-diCl-Ph 4-C02Et-Ph


578 2,4-diCl-Ph 4-C02H-Ph


579 2,4-diCl-Ph 4-CONH2-Ph


580 2,4-diCl-Ph 4-F-Ph


581 2,4-diCl-Ph 4-C1-Ph


582 2,4-diCl-Ph 4-NH2-Ph


583 2,4-diCl-Ph 4-S02NH2-Ph


584 2,4-diCl-Ph 4-CF3-Ph


585 2,4-diCl-Ph 4-OCH3-Ph


586 2,4-diCl-Ph 4-OEt-Ph


587 2,4-diCl-Ph 4-OCF3-Ph


588 2,4-diCl-Ph 4-S02CH3-Ph


589 2,4-diCl-Ph 4-OH-Ph


590 2,4-diCl-Ph 4-CH3-Ph


591 2,4-diCl-Ph 4-C2H5-Ph


592 2,4-diCl-Ph 2,4-diF-Ph


593 2,4-diCl-Ph 2,5-diF-Ph


594 2,4-diCl-Ph 3,4-diF-Ph


595 2,4-diCl-Ph 3,5-diF-Ph


596 2,4-diCl-Ph 2,4-diCl-Ph


597 2,4-diCl-Ph 2,5-diCl-Ph


598 2,4-diCl-Ph 3,4-diCl-Ph


599 2,4-diCl-Ph 3,5-diCl-Ph


600 2,4-diCl-Ph 3,4-OCH20-Ph


601 2,4-diCl-Ph 3,4-OCH2CH20-Ph


602 2,4-diCl-Ph 2-thien 1


603 2,4-diCl-Ph 2-furan 1


604 2,4-diCl-Ph 2- rid 1


605 2,4-diCl-Ph 4- rid 1


606 2,4-diCl-Ph 2-imidazolyl
607 2,4-diCl-Ph 3- razol 1


608 2,4-diCl-Ph 2-thiazol 1


241.


CA 02350730 2001-05-07
WO 00/35451 PCT/US99/30332
609 2,4-diCl-Ph 5-tetrazolyl


610 2,4-diCl-Ph 1-adamantyl


611 3-OCH3-Ph 3-CN-Ph


612 3-OCH3-Ph 3-COCH3-Ph


613 3-OCH3-Ph 3-C02Me-Ph


614 3-OCH3-Ph 3-C02Et-Ph


615 3-OCH3-Ph 3-C02H-Ph


616 3-OCH3-Ph 3-CONH2-Ph


617 3-OCH3-Ph 3-F-Ph


618 3-OCH3-Ph 3-C1-Ph


619 3-OCH3-Ph 3-NH2-Ph


620 3-OCH3-Ph 3-S02NH2-Ph


621 3-OCH3-Ph 3-CF3-Ph


622 3-OCH3-Ph 3-OCH3-Ph


623 3-OCH3-Ph 3-OEt-Ph


624 3-OCH3-Ph 3-OCF3-Ph


625 3-OCH3-Ph 3-S02CH3-Ph


626 3-OCH3-Ph 3-OH-Ph


627 3-OCH3-Ph 3-CH3-Ph


628 3-OCH3-Ph 3-C2H5-Ph


629 3-OCH3-Ph 4-CN-Ph


630 3-OCH3-Ph 4-COCH3-Ph


631 3-OCH3-Ph 4-C02Me-Ph


632 3-OCH3-Ph 4-C02Et-Ph


633 3-OCH3-Ph 4-C02H-Ph


634 3-OCH3-Ph 4-CONH2-Ph


635 3-OCH3-Ph 4-F-Ph


636 3-OCH3-Ph 4-C1-Ph


637 3-OCH3-Ph 4-NH2-Ph


638 3-OCH3-Ph 4-S02NH2-Ph


639 3-OCH3-Ph 4-CF3-Ph


640 3-OCH3-Ph 4-OCH3-Ph


641 3-OCH3-Ph 4-OEt-Ph


642 3-OCH3-Ph 4-OCF3-Ph


643 3-OCH3-Ph 4-S02CH3-Ph


644 3-OCH3-Ph 4-OH-Ph


645 3-OCH3-Ph 4-CH3-Ph


646 3-OCH3-Ph 4-C2H5-Ph


647 3-OCH3-Ph 2,4-diF-Ph


648 3-OCH3-Ph 2,5-diF-Ph


649 3-OCH3-Ph 3,4-diF-Ph


650 3-OCH3-Ph 3,5-diF-Ph


651 3-OCH3-Ph 2,4-diCl-Ph


652 3-OCH3-Ph 2,5-diCl-Ph


653 3-OCH3-Ph 3,4-diCl-Ph


654 3-OCH3-Ph 3,5-diCl-Ph


655 3-OCH3-Ph 3,4-OCH20-Ph


656 3-OCH3-Ph 3,4-OCH2CH20-Ph


657 3-OCH3-Ph 2-thien 1


658 3-OCH3-Ph 2-furanyl


659 3-OCH3-Ph 2-pyridyl


660 3-OCH3-ph 4- rid 1


661 3-OCH3-ph 2-imidazolyl


242


CA 02350730 2001-05-07
WO 00/35451 PCT/US99/30332
662 3_-OCH3-Ph 3- razol 1


663 3-OCH3-Ph 2-thiazol 1


664 3-OCH3-Ph 5-t.etrazolyl


665 3-OCH3-Ph 1-adamant 1


666 2-thien 1 3-CN-Ph


667 2-thien 1 3-COCH3-Ph


668 2-thien 1 3-F-Ph


669 2-thien 1 _
- 3-C1-Ph


670 2-thien 1 3-NH2-Ph


671 2-thien 1 - 3-OCH3-Ph


672 2-thien 1 3-OH-Ph


673 2-thien 1 4-CN-Ph


674 2-thien 1 4-COCH3-Ph


675 2-thien 1 4-F-Ph


676 2-thienyl 4-C1-Ph


677 2-thien 1 4-NH2-Ph


678 2-thien 1 4-OCH3-Ph


679 2-thien 1 4-OH-Ph


680 2-thien 1 3 , 4-diF-Ph


681 2-thien 1 3,5-diF-Ph


682 2-thien 1 3,4-diCl-Ph


683 2-thien 1 3,5-diCl-Ph


684 2-thien 1 3,4-OCH20-Ph


685 2-thien 1 3,4-OCH2CH20-Ph


686 3-thien 1 3-CN-Ph


687 3-thien 1 3-COCH3-Ph


688 3-thien 1 3-F-Ph


689 3-thien 1 3-C1-Ph


690 3-thien 1 3-NH2-Ph


691 3-thien 1 3-OCH3-Ph


692 3-thien 1 3-OH-Ph


693 3-thien 1 4-CN-Ph


694 3-thien 1 _
4-COCH3-Ph


695 3-thien 1 4-F-Ph


696 3-thien 1 4-C1-Ph


697 3-thien 1 4-NH2-Ph


698 3-thien 1 4-OCH3-Ph


699 3-thien 1 4-OH-Ph


700 3-thien 1 3,4-diF-Ph
-


701 3-thien 1 3,5-diF-Ph


702 3-thien 1 3,4-diCl-Ph


703 3-thien 1 3,5-diCl-Ph


704 3-thienyl 3,4-OCH20-Ph


705 3-thien 1 3,4-OCH2CH20-Ph


706 2-furan 1 3-CN-Ph


707 2-furan 1 3-COCH3-Ph


708 2-furan 1 3-F-Ph


709 2-furan 1 3-C1-Ph


710 2-furan 1 3-NH2-Ph


711 2-furan 1 3-OCH3-Ph


712 2-furan 1 3-OH-Ph


713 2-furan 1 4-CN-Ph


714 ~ 2-furanyl j 4-COCH3-Ph


243


CA 02350730 2001-05-07
WO 00/35451 PCT/US99/30332
715 2-furan 1 4-F-Ph


716 2-furan 1 4-C1-Ph


717 2-furan 1 4-NH2-Ph


718 2-furan 1 4-OCH3-Ph


719 2-furanyl 4-OH-Ph


720 2-furan 1 3,4-diF-Ph


721 2-furanyl 3,5-diF-Ph


722 2-furanyl 3,4-diCl-Ph


723 2-furanyl 3,5-diCl-Ph


724 2-furanyl 3,4-OCH20-Ph


725 2-furan 1 3,4-OCH2CH20-Ph


726 3-furanyl 3-CN-Ph


727 3-furanyl 3-COCH3-Ph


7_28_ 3-furanyl 3 -F-Ph


729 3-furanyl 3-Cl-Ph


730 3-furan 1 3-NH2-Ph


732 3-furan 1 3-OCH3-Ph


732 3-furan 1 3-OH-Ph


733 3-furanyl 4-CN-Ph


734 3-furan 1 4-COCH3-Ph


735 3-furan 1 4-F-Ph


736 3-furan 1 4-C1-Ph


737 3-furan 1 4-NH2-Ph


738 3-furan 1 4-OCH3-Ph


739 3-furan 1 4-OH-Ph


740 3-furanyl 3,4-diF-Ph


741 3-furan 1 3,5-diF-Ph


742 3-furanyl 3,4-diCl-Ph


743 3-furan 1 3,5-diCl-Ph


744 3-furan 1 3,4-OCH20-Ph


745 3-furanyl 3,4-OCH2CH20-Ph


746 2- ridyl 3-CN-Ph


747 2- yrid 1 3-COCH3-Ph


748 2- rid 1 3-F-Ph


749 2-pyridyl 3-C1-Ph


750 2-pyrid 1 3-NH2-Ph


751 2- rid 1 3-OCH3-Ph


752 2- rid 1 3-OH-Ph


753 2- ridyl 4-CN-Ph


754 2- yrid 1 4-COCH3-Ph


755 2- rid 1 4-F-Ph


756 2- rid 1 4-Cl-Ph


757 2- yrid 1 4-NH2-Ph


758 2- rid 1 4-OCH3-Ph


759 2- rid 1 4-OH-Ph


760 2- yrid 1 3,4-diF-Ph


761 2-pyrid 1 3,5-diF-Ph


762 2- ridyl 3,4-diCl-Ph


763 2- rid 1 3,5-diCl-Ph


764 2-p rid 1 3,4-OCH20-Ph


765 2-pyridyl
3,4-OCH2CH20-Ph


766 3- rid 1 3-CN-Ph


767 3-pyridyl
3-COCH3-Ph


244


CA 02350730 2001-05-07
WO 00/35451 PCT/US99/30332
768 3- rid rl 3-F-Ph


769 3-pyridyl 3-C1-Ph


770 3- rid 1 3-NH2-Ph


771 3- rid 1 3-OCH3-Ph


772 3- rid 1 3-OH-Ph


773 3- rid 1 4-CN-Ph


774 3- ridyl 4-COCH3-Ph


775 3- rid 1 4-F-Ph


776 3- rid 1 4-C1-Ph


777 3- ridyl 4-NH2-Ph


778 3- rid 1 4-OCH3-Ph


779 3- rid 1 4-OH-Ph


780 3- rid 1 3,4-diF-Ph


781 3- rid 1 3,5-diF-Ph


782 3- ridyl 3,4-diCl-Ph


783 3- rid 1 3,5-diCl-Ph


784 3-p rid 1 3,4-OCH20-Ph


785 3- rid 1 3,4-OCH2CH20-Ph


786 4- rid 1 3-CN-Ph


787 4- yridyl 3-COCH3-Ph


788 4- rid 1 3-F-Ph


789 4- rid 1 3-Cl-Ph


790 4- ridyl 3-NH2-Ph


791 4- rid 1 3-OCH3-Ph


792 4-p ridyl 3-OH-Ph


793 4- rid 1 4-CN-Ph


794 4-pyrid 1 4-COCH3-Ph


795 4- rid 1 4-F-Ph


796 4- rid 1 4-C1-Ph


797 4- rid 1 4-NH2-Ph


798 4-p rid 1 4-OCH3-Ph


799 4- rid 1 4-OH-Ph


800 4- rid 1 3,4-diF-Ph


801 4- rid 1 3,5-diF-Ph


802 4- ridyl 3,4-diCl-Ph


803 4- rid 1 3,5-diCl-Ph


804 4- rid 1 3,4-OCH20-Ph


805 4- rid 1 3,4-OCH2CH20-Ph


806 3-indol 1 3-CN-Ph


807 3-indol 1 3-COCH3-Ph


808 3-indol 1 3-F-Ph


809 3-indol 1 3-C1-Ph


810 3-indol 1 3-NH2-Ph


811 3-indol 1 3-OCH3-Ph


812 3-indol 1 3-OH-Ph


813 3-indol 1 4-CN-Ph


814 3-indol 1 4-COCH3-Ph


815 3-indol 1 4-F-Ph


816 3-indol 1 4-C1-Ph


817 3-indol 1 4-NH2-Ph


818 3-indol 1 4-OCH3-Ph


819 3-indol 1 4-OH-Ph


820 3-indolyl 3,4-diF-Ph


245


CA 02350730 2001-05-07
WO 00/35451 PCT/US99/30332
821 3-indol 1 3,5-diF-Ph


_
822 3-indolyl 3,4-diCl-Ph


823 3-indolyl 3,5-diCl-Ph


824 3-indolyl 3,4-OCH20-Ph


825 3-indol 1 3,4-OCH2CH20-Ph


826 5-indol 1 3-CN-Ph


827 5-indolyl 3-COCH3-Ph


828 5-indol 1 3-F-Ph


829 5-indol 1 3-Cl-Ph


830 5-indol 1 3-NH2-Ph


831 5-indolyl 3-OCH3-Ph


832 5-indolyl 3-OH-Ph


833 5-indol 1 4-CN-Ph


834 5-indol 1 4-COCH3-Ph


835 5-indolyl 4-F-Ph


836 5-indol 1 4-C1-Ph


837 5-indol 1 4-NH2-Ph


838 5-indolyl 4-OCH3-Ph


839 5-indolyl 4-OH-Ph


840 5-indol 1 3,4-diF-Ph


841 5-indolyl 3,5-diF-Ph


842 5-indol 1 3,4-diCl-Ph


843 5-indolyl 3,5-diCl-Ph


844 5-indol 1 3,4-OCH20-Ph


845 5-indolyl 3,4-OCH2CH20-Ph


846 5-indazolyl 3-CN-Ph


847 5-indazolyl 3-COCH3-Ph


848 5-indazol 1 3-F-Ph


849 S-indazol 1 3-C1-Ph


850 5-indazol 1 3-NH2-Ph


851 5-indazolyl 3-OCH3-Ph


852 5-indazol 1 3-OH-Ph


853 5-indazol 1 4-CN-Ph


854 5-indazol 1 4-COCH3-Ph


855 5-indazolyl 4-F-Ph


856 5-indazol 1 4-Cl-Ph


857 5-indazol 1 4-NH2-Ph


858 5-indazol 1 4-OCH3-Ph


859 5-indazolyl 4-OH-Ph


860 5-indazolyl 3,4-diF-Ph


861 5-indazol 1 3,5-diF-Ph


862 5-indazolyl 3,4-diCl-Ph


863 5-indazolyl 3,5-diCl-Ph


864 5-indazol 1 3,4-OCH20-Ph


865 5-indazol 1 3,4-OCH2CH20-Ph


866 5-benzimidazol 1 3-CN-Ph


867 5-benzimidazol 1 3-COCH3-Ph


868 5-benzimidazolyl 3-F-Ph


869 5-benzimidazol 1 3-Cl-Ph


870 5-benzimidazol 1 3-NH2-Ph


_871 5-benzimidazolyl 3-OCH3-Ph


872 5-benzimidazolyl 3-OH-Ph


873 5-benzimidazolyl 4-CN-Ph


246
,... ~a....


CA 02350730 2001-05-07
WO 00/35451 PCT/US99/30332
8?4 5-benzimidazol 1 4-COCH3-Ph


8?5 5-benzimidazol 1 4-F-Ph


8?6 5-benzimidazolyl 4-C1-Ph


8?7 5-benzimidazol 1 4-NH2-Ph


8?8 5-benzimidazol 1 4-OCH3-Ph


879 5-benzimidazol 1 4-OH-Ph


880 5-benzimidazol 1 3,4-diF-Ph


881 5-benzimidazolyl 3,5-diF-Ph


882 5-benzimidazol 1 3,4-diCl-Ph


883 5-benzimidazol 1 3,5-diCl-Ph


884 5-benzimidazol 1 3,4-OCH20-Ph


885 5-benzimidazol 1 3,4-OCH2CH20-Ph


886 5-benzothiazol 1 3-CN-Ph


88? 5-benzothiazol 1 3-COCH3-Ph


888 5-benzothiazolyl 3-F-Ph


889 5-benzothiazol 1 3-C1-Ph


890 5-benzothiazol 1 3-NH2-Ph


891 5-benzothiazol 1 3-OCH3-Ph


892 5-benzothiazol 1 3-OH-Ph


893 5-benzothiazolyl 4-CN-Ph


894 5-benzothiazol 1 4-COCH3-Ph


895 5-benzothiazol 1 4-F-Ph


896 5-benzothiazol 1 4-Cl-Ph


897 5-benzothiazolyl 4-NH2-Ph


898 5-benzothiazol 1 4-OCH3-Ph


899 5-benzothiazol I 4-OH-Ph


900 5-benzothiazol 1 3,4-diF-Ph


901 5-benzothiazol 1 3,5-diF-Ph


902 5-benzothiazol 1 3,4-diCl-Ph


903 5-benzothiazol 1 3,5-diCl-Ph


904 5-benzothiazol 1 3,4-OCH20-Ph


905 5-benzothiazol 1 3,4-OCH2CH20-Ph


906 5-benzoxazol 1 3-CN-Ph


907 5-benzoxazol 1 3-COCH3-Ph


908 5-benzoxazol 1 3-F-Ph


909 5-benzoxazol 1 3-C1-Ph


910 5-benzoxazol 1 3-NH2-Ph


911 5-benzoxazolyl 3-OCH3-Ph


912 5-benzoxazol 1 3-OH-Ph


913 5-benzoxazol 1 4-CN-Ph


914 5-benzoxazol 1 4-COCH3-Ph


915 5-benzoxazol 1 4-F-Ph


916 5-benzoxazol 1 4-C1-Ph


917 5-benzoxazol 1 4-NH2-Ph


918 5-benzoxazol 1 4-OCH3-Ph


919 5-benzoxazol 1 4-OH-Ph


920 5-benzoxazol 1 3,4-diF-Ph


921 5-benzoxazolyl __
3,5-diF-Ph


922 5-benzoxazolyl ~ 3,4-diCl-Ph


923 5-benzoxazol 1 3,5-diCl-Ph


924 5-benzoxazol 1 3,4-OCH20-Ph


925 5-benzoxazolyl 3 4-OCH~~u~n-p~,


247


CA 02350730 2001-05-07
WO 00/35451 PCT/US99/30332
TABLE 6*
O O 3 0
HN'l N-R3 HN ~ N.R HN~ N.R3
H F H ~. H
R a R a R a
0
HN~ H R3 HN~ N-R3 HN'l N Ra
CY ' " ~ H v H
C1 F
is a
R R a
Ot
C1 ~ HN~N-R3
r H
1
O O
F ~ .R' a ~ R3
HN H ~ HN
8
CI
1
is p is
~' 3
7 ~'rG~~~ H N ~ N ~R
H
0 O
HNJ~N-R3 ° HN~N.R3
H H
F 11
4 a
~~N_R
H
~ p F F
!, 11 ~' ,N, R3 ~ R3
~H R1a ~ H
14 F
F
R a Rla
13 C1 HN H_R 15
C1 ~ C
s 17 ~ R3
N H R R1 a ~ H
C 1~~~~~ C
C1
is R a
16 18
248
~...

CA 02350730 2001-05-07
DEMANDES OU BREVETS VOLUMINEUX
LA PRESENTS PARTIE DE CETTE DEMANDS OU CE BREVET
COMPREND PLUS D'UN TOME_ ~
CECI EST LE TOME _ ~'DE c1
NOTE: Pour les tomes additionels, veuillez contacier le Bureau canadien des
brevets '
JUMBO APPL:ICATIONS/PATE~1TS
THIS SECTION OF THE APPUCATIONIPATENT CONTAINS MORE
THAN ONE VOLUME
THIS IS VOLUME ~ -- DF _ ,
WOTE: For additional volumes ~piease contact'the Canadian Patent Ufif~ca
~ _ ~ < ~'-

Representative Drawing