N-UREIDOALKYL-PIPERIDINES AS MODULATORS OF CHEMOKINE RECEPTOR ACTIVITY

N-UREIDOALKYL-PIPERIDINES UTILES COMME MODULATEURS DE L'ACTIVITE DU RECEPTEUR DE CHIMIOKINE

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 demande porte sur des modulateurs de CCR3 de la formule (I) ou sur des formes de sels de ceux-ci acceptables d'un point de vue pharmaceutique, ces modulateurs étant utiles dans la prévention de l'asthme et autres maladies allergiques.

Claims

What is Claimed is:
1. A compound of formula (I):
<IMG>
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 that:
1) at least one of J, K, or L contains R5;
2) when M is absent, J is selected from CH2, CHR5,
CHR13, and CR5R13;
Z is selected from O, S, 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;
282

R1b is independently selected from H, C1-3 alkyl, C3-6
cycloalkyl, and phenyl;
E is selected from:
<IMGS>
ring A is a C3-6 carbocyclic residue, provided that the
C3-6 carbocyclic residue in Ring A is not phenyl;
283

R1 and R2 are independently selected from H, C1-6 alkyl,
C3-8 alkenyl, and C3-8 alkynyl;
R3 is selected from a C1-10 alkyl substituted with 0-5
R3g, C3-10 alkenyl substituted with 0-5 R3g, and
C3-10 alkynyl substituted with 0-5 R3g;
R3g, at each occurrence, is independently selected from
Cl, Br, I, F, NO2, CN, NR3a R3a', OH, O(CHR')r R3d,
SH, C(O)H, S(CHR')r R3d, C(O)OH, C(O)(CHR')r R3b,
C(O)NR3a R3a', OC(O)NR3a R3a', NR3a C(O)OR3d,
NR3f C(O)(CHR')r R3b, C(O)O(CHR')r R3d,
OC(O)(CHR')r R3b, C(-NR3f)NR3a R3a',
NHC(=NR3f)NR3f R3f, S(O)p(CHR')r R3b, S(O)2NR3a R3a',
NR3f S(O)2(CHR')r R3b, a C3-10 carbocyclic residue
substituted with 0-5 R15, and a 5-10 membered
heterocyclic system containing 1-4 heteroatoms
selected from N, O, and S, substituted with 0-3
R15, provided that when R3g is a carbocyclic
residue or a heterocyclic system, R3 has at least
one other R3g, which is not a carbocyclic residue
or a heterocyclic system;
R3a and R3a', at each occurrence, are selected from H,
C1-6 alkyl, C3-8 alkenyl, C3-8 alkynyl, a (CH2)r-
C3-10 carbocyclic residue substituted with 0-5 R3e,
and a (CH2)r-5-10 membered heterocyclic system
containing 1-4 heteroatoms selected from N, O, and
S, substituted with 0-2 R3e;
284

R3b, at each occurrence, is selected from C1-6 alkyl,
C3-8 alkenyl, C3-8 alkynyl, a (CH2)r-C3-6
carbocyclic residue substituted with 0-3 R3e, and
(CH2)r-5-6 membered heterocyclic system containing
1-4 heteroatoms selected from N, O, anal S,
substituted with 0-2 R3e;
R3d, at each occurrence, is selected from C3-8 alkenyl,
C3-8 alkynyl, methyl, CF3, C2-6 alkyl substituted
with 0-3 R3e, a (CH2)r-C3-10 carbocyclic residue
substituted with 0-3 R3e, and a (CH2)r5-6 membered
heterocyclic system containing 1-4 heteroatoms
selected from N, O, and S, substituted with 0-3
R3e;
R3e, 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 S(O)p C1-5 alkyl,
(CH2)r NR3f R3f, and (CH2)r phenyl;
R3f, at each occurrence, is selected from H, C1-6 alkyl,
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 C1-6
alkyl, C3-8 alkenyl, C3-8 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;
285

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,
C3-8 alkenyl, (CH2)r C3-6 cycloalkyl, C3-8 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, R11, or R14 to form
a 5, 6 or 7 membered piperidinium spirocycle or
pyrrolidinium spirocycle substituted with 0-3 R a;
R5 is selected from a (CR5'R5")t-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,
286

(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 OC1-5 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;
with the proviso that when any of J, K or L is CR6R6 and
R6 is bonded to the carbon to which it is attached
through a heteroatom, the other R6 is not bonded to
the carbon to which it is attached through a
heteroatom;
R7, is selected from H, C1-6 alkyl, C2-8 alkenyl, C2-8
alkynyl, (CH2)q OH, (CH2)q SH, (CH2)q OR7d,
287

(CH2)q SR7d, (CH2)q NR7a R7a', (CH2)r C(O)OH,
(CH2)r C(O)R7b, (CH2)r C(O)NR7a R7a',
(CH2)r OC(O)NR7a R7a', (CH2)q NR7a C(O)OR7b,
(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, C3-8 alkenyl, C3-8 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;
alternatively, R7a and R7a', along with the N to which
they are attached, are joined to form a 5-6
membered heterocyclic system containing 1-2
heteroatoms selected from NR7g, O, and S and
optionally fused with a benzene ring or a 6-
membered aromatic heterocycle;
R7b, at each occurrence, is selected from C1-6 alkyl,
C3-8 alkenyl, C3-8 alkynyl, a (CH2)r-C3-6
carbocyclic residue substituted with 0-2 R7e, and a
(CH2)r-5-6 membered heterocyclic system containing
288

1-4 heteroatoms selected from N, O, and S,
substituted with 0-3 R7e;
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)pR7b, (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 methyl, CF3,
C2-6 alkyl substituted with 0-3 R7e, C3-8 alkenyl,
C3-8 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 SC1-5 alkyl, (CH2)r NR7f R7f, and
(CH2)r phenyl;
R7f, at each occurrence, is selected from H, C1-6 alkyl,
and C3-6 cycloalkyl;
R7g is selected from H, C1-6 alkyl, C3-6 cycloalkyl,
(CH2)r phenyl, C(O)R7f, C(O)OR7f, and SO2R7f;
289

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 SC1-5 alkyl, (CH2)r NR7f R7f, and
(CH2)r phenyl;
R8b is selected from H, C1-6 alkyl, C3-6 cycloalkyl, OH,
CN, and (CH2)r-phenyl;
alternatively, R7 and R8 join to form C3-7 cycloalkyl,
=O, or =NR8b;
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 NR9a R9a',
(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 OC(O)NR9a R9a', (CH2)r NR9a C(O)OR9b,
(CH2)r NR9a C(O)NHR9a, (CH2)r C(O)OR9b,
(CH2)r OC(O)R9b, (CH2)r S(O)p R9b,
(CH2)r S(O)2NR9a R9a', (CH2)r NR9a S(O)2R9b,
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;
290

R9a and R9a', at each occurrence, are selected from H,
C1-6 alkyl, C3-8 alkenyl, C3-8 alkynyl, a (CH2)r-
C3-10 carbocyclic residue substituted with 0-5 R9e,
and a (CH2)r-5-10 membered heterocyclic system
containing 1-4 heteroatoms selected from N, O, and
S, substituted with 0-3 R9e;
alternatively, R9a and R9a', along with the N to which
they are attached, are joined to form a 5-6
membered heterocyclic system containing 1-2
heteroatoms selected from NR9g, O, and S and
optionally fused with a benzene ring or a 6-
membered aromatic heterocycle;
R9b, at each occurrence, is selected from C1-6 alkyl,
C3-8 alkenyl, C3-8 alkynyl, a (CH2)r-C3-6
carbocyclic residue substituted with 0-2 R9e, and a
(CH2)r-5-6 membered heterocyclic system containing
1-4 heteroatoms selected from N, O, and S,
substituted with 0-3 R9e;
R9c, at each occurrence, is selected from C1-6 alkyl,
C2-8 alkenyl, C2-8 alkynyl, (CH2)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,
291

(CH2)r S(O)2NR9f R9f, (CH2)r NR9f S(O)2R9b, and
(CH2)r phenyl substituted with 0-3 R9e;
R9d, at each occurrence, is selected from C1-6 alkyl,
C3-6 alkenyl, C3-6 alkynyl, a C3-10 carbocyclic
residue substituted with 0-3 R9C, and a 5-6
membered heterocyclic system containing 1-4
heteroatoms selected from the group consisting of
N, O, and S substituted with 0-3 R9C;
R9e, at each occurrence, is selected from C1-6 alkyl,
C2-8 alkenyl, C2-8 alkynyl, (CH2)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;
R9g is selected from H, C1-6 alkyl, C3-6 cycloalkyl,
(CH2)r phenyl, C(O)R9f, C(O)OR9f, and SO2R9f;
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 OC(O)NR10a R10a', (CH2)r NR10a C(O)OR10b,
(CH2)r S(O)p R10b, (CH2)r S(O)2NR10a R10a',
292

(CH2)r NR10a S(O)2R10b, C1-6 haloalkyl, a (CH2)r-C3-
carbocyclic residue substituted with 0-5 R10c,
and a (CH2)r-5-10 membered heterocyclic system
containing 1-4 heteroatoms selected from N, O, and
S, substituted with 0-3 R10c;
R10a and R10a', at each occurrence, are selected from H,
C1-6 alkyl, C3-8 alkenyl, C3-8 alkynyl, a (CH2)r-
C3-10 carbocyclic residue substituted with 0-5
R10e, and a (CH2)r-5-10 membered heterocyclic
system containing 1-4 heteroatoms selected from N,
O, and S, substituted with 0-3 R10e;
alternatively, R10a and R10a', along with the N to which
they are attached, are joined to form a 5-6
membered heterocyclic system containing 1-2
heteroatoms selected from NR10g, O, and S and
optionally fused with a benzene ring or a 6-
membered aromatic heterocycle;
R10b, at each occurrence, is selected from C1-6 alkyl,
C3-8 alkenyl, C3-8 alkynyl, a (CH2)r-C3-6
carbocyclic residue substituted with 0-2 R10e, and
a (CH2)r-5-6 membered heterocyclic system
containing 1-4 heteroatoms selected from N, O, and
S, substituted with 0-3 R10e;
R10c, at each occurrence, is selected from C1-6 alkyl,
C2-8 alkenyl, C2-8 alkynyl, (CH2)r C3-6 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(O)NR10f R10f,
293

(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,
C3-6 alkenyl, C3-6 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 C3-6 cycloalkyl,
Cl, F, Br, I, CN, NO2, (CF2)r CF3, (CH2)r OC1-5
alkyl, OH, SH, (CH2)r SC1-5 alkyl, (CH2)r NR10f R10f,
and (CH2)r phenyl;
R10f, at each occurrence, is selected from H, C1-5
alkyl, and C3-6 cycloalkyl;
R10g is selected from H, C1-6 alkyl, C3-6 cycloalkyl,
(CH2)r phenyl, C(O)R10f, C(O)OR10h, and SO2R10h;
R10h, at each occurrence, is selected from C1-5 alkyl,
and C3-6 cycloalkyl;
alternatively, R9 and R10 join to form =O, a C3-10
cycloalkyl, a 5-6-membered lactone or lactam, or a
4-6-membered saturated heterocycle containing 1-2
294

heteroatoms selected from O, S, and NR10g and
optionally fused with a benzene ring or a 6-
membered aromatic heterocycle;
with the proviso that when either of R9 or R10 is
halogen, cyano, nitro, or bonded to the carbon to
which it is attached through a heteroatom, the
other of R9 or R10 is not bonded to the carbon to
which it is attached through a heteroatom;
R11, is selected from H, 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 OC(O)NR11a R11a',
(CH2)q NR11a C(O)OR11b, (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, C3-8 alkenyl, C3-8 alkynyl, a (CH2)r-
C3-10 carbocyclic residue substituted with 0-5
R11e, and a (CH2)r-5-10 membered heterocyclic
system containing 1-4 heteroatoms selected from N,
O, and S, substituted with 0-3 R11e;
295

alternatively, R11a and R11a', along with the N to which
they are attached, are joined to form a 5-6
membered heterocyclic system containing 1-2
heteroatoms selected from NR11g, 0, and S and
optionally fused with a benzene ring or a 6-
membered aromatic heterocycle;
R11b, at each occurrence, is selected from C1-6 alkyl,
C3-8 alkenyl, C3-8 alkynyl, a (CH2)r-C3-6
carbocyclic residue substituted with 0-2 R11e, and
a (CH2)r-5-6 membered heterocyclic system
containing 1-4 heteroatoms selected from N, O, and
S, substituted with 0-3 R11e;
R11c, at each occurrence, is selected from C1-6 alkyl,
C2-8 alkenyl, C2-8 alkynyl, (CH2)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)2R12b, and
(CH2)r phenyl substituted with 0-3 R11e;
R11d, at each occurrence, is selected from methyl, CF3,
C2-6 alkyl substituted with 0-3 R11e, C3-6 alkenyl,
C3-6 alkynyl, and a C3-10 carbocyclic residue
substituted with 0-3 R11c;
296

R11e, 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 SC1-5 alkyl, (CH2)r NR11f R11f, and
(CH2)r phenyl;
R11f, at each occurrence, is selected from H, C1-6
alkyl, and C3-6 cycloalkyl;
R11g is selected from H, C1-6 alkyl, C3-6 cycloalkyl,
(CH2)r phenyl, C(O)R11f, C(O)OR11h, and SO2R11h;
R11h, at each occurrence, is selected from C1-5 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 C1-6 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 SC1-5 alkyl, (CH2)r NR9f R9f, and
(CH2)r phenyl;
alternatively, R11 and R12 join to form a C3-10
cycloalkyl, a 5-6-membered lactone or lactam, or a
4-6-membered saturated heterocycle containing 2-2
heteroatoms selected from O, S, and NR11g and
optionally fused with a benzene ring or a 6-
membered aromatic heterocycle;
297

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)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 R23a',
(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
R13c, at each occurrence, is selected from C1-6 alkyl,
C3-6 cycloalkyl, Cl, F, Br, I, CN, NO2, (CF2)r CF3,
(CH2)r OC1-5 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;
R14, at each occurrence, is selected from C1-6 alkyl,
(CH2)r C3-6 cycloalkyl, C1, Br, I, F, NO2, CN,
(CHR')r NR14a R14a', (CHR')r OH, (CHR')r O(CHR')r R14d,
298

(CHR')r SH, (CHR')r C(O)H, (CHR')r S(CHR')r R14d,
(CHR')r C(O)OH, (CHR')r C(O)(CHR')r R14b,
(CHR')r C(O)NR14a R14a', (CHR')r NR14f C(O)(CHR')r R14b,
(CHR')r C(O)O(CHR')r R14d, (CHR')r OC(O)(CHR')r R14b,
(CHR')r C(=NR14f)NR14a R14a',
(CHR')r NHC(=NR14f)NR14f R14f,
(CHR')r S(O)p(CHR')r R14b, (CHR')r S(O)2NR14a R14a',
(CHR')r NR14f S(O)2(CHR')r R14b, 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 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, or two R14 substituents on adjacent atoms on
ring A form to join a 5-6 membered heterocyclic
system containing 1-3 heteroatoms selected from N,
0, and S substituted with 0-2 R14e;
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 R14e;
R14a and R14a', at each occurrence, are selected from H,
C1-6 alkyl, C3-8 alkenyl, C3-8 alkynyl, a (CH2)r-
C3-10 carbocyclic residue substituted with 0-5
R14e, and a (CH2)r-5-10 membered heterocyclic
system containing 1-4 heteroatoms selected from N,
O, and S, substituted with 0-2 R14e;
299

R14b, at each occurrence, is selected from C1-6 alkyl,
C3-8 alkenyl, C3-8 alkynyl, a (CH2)r-C3-6
carbocyclic residue substituted with 0-3 R14e, and
(CH2)r-5-6 membered heterocyclic system containing
1-4 heteroatoms selected from N, O, and S,
substituted with 0-2 R14e;
R14d, at each occurrence, is selected from C3-8 alkenyl,
C3-8 alkynyl, methyl, CF3, C2-6 alkyl substituted
with 0-3 R14e, a (CH2)r-C3-10 carbocyclic residue
substituted with 0-3 R14e, and a (CH2)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;
R a, at each occurrence, is selected from C1-6 alkyl,
C2-8 alkenyl, C2-8 alkynyl, (CH2)r C3-6 cycloalkyl,
300

C1, 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, C1-6 alkyl,
C3-6 cycloalkyl, and phenyl;
R c, at each occurrence, is selected from C1-6 alkyl, C3-
cycloalkyl, and phenyl;
R15, at each occurrence, is selected from C1-8 alkyl,
(CH2)r C3-6 cycloalkyl, C1, Br, I, F, NO2, CN,
(CHR2)r NR15a R15a', (CHR')r OH, (CHR')r O(CHR')r R15d,
(CHR2)r SH, (CHR')r C(O)H, (CHR')r S(CHR')r R15d,
(CHR2)r C(O)OH, (CHR')r C(O)(CHR')r R15b,
(CHR2)r C(O)NR15a R15a', (CHR')r NR15f C(O)(CHR')r R15b,
(CHR2)r NR15f C(O)NR15f R15f, (CHR')r C(O)O(CHR')r R15d,
(CHR2)r OC(O)(CHR')r R15b, (CH2)r OC(O)NR15a R15a',
(CH2)r NR15a C(O)OR15b, (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
301

with 0-3 R15e, and a (CH2)r-5-10 membered
heterocyclic system containing 1-4 heteroatoms
selected from N, 0, and S, substituted with 0-2
R15e
R15a and R15a', at each occurrence, are selected from H,
C1-6 alkyl, C3-8 alkenyl, C3-8 alkynyl, a (CH2)r-
C3-10 carbocyclic residue substituted with 0-5
R15e, and a (CH2)r-5-10 membered heterocyclic
system containing 1-4 heteroatoms selected from N,
O, and S, substituted with 0-2 R15e
alternatively, R15a and R15a', along with the N to which
they are attached, are joined to form a 5-6
membered heterocyclic system containing 1-2
heteroatoms selected from NR15g, O, and S and
optionally fused with a benzene ring or a 6-
membered aromatic heterocycle;
R15b, at each occurrence, is selected from C1-6 alkyl,
C3-8 alkenyl, C3-8 alkynyl, a (CH2)r-C3-6
carbocyclic residue substituted with 0-3 R15e, and
(CH2)r-5-6 membered heterocyclic system containing
1-4 heteroatoms selected from N, O, and S,
substituted with 0-2 R15e
R15d, at each occurrence, is selected from C3-8 alkenyl,
C3-8 alkynyl, methyl, CF3, C2-6 alkyl substituted
with 0-3 R15e, a (CH2)r-C3-10 carbocyclic residue
substituted with 0-3 R15e, and a (CH2)r5-6 membered
heterocyclic system containing 1-4 heteroatoms
302

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 R 15f,
and (CH2)r phenyl;
R15f, at each occurrence, is selected from H, C1-6
alkyl, C3-6 cycloalkyl, and phenyl;
R15g is selected from H, C1-6 alkyl, C3-6 cycloalkyl,
(CH2)rphenyl, C(O)R15f, C(O)OR15h, and SO2R15h;
R15h, at each occurrence, is selected from C1-5 alkyl,
and C3-6 cycloalkyl;
R16, at each occurrence, is selected from C1-8 alkyl,
C2-8 alkenyl, C2-8 alkynyl, (CH2)r C3-6 cycloalkyl,
C1, Br, I, F, NO2, CN, (CHR')r NR16aR16a',
(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)NR16aR16a',
(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)NR16fR16f,
(CHR')r S(O)p(CHR')r R16b, (CHR')r S(O)2NR16aR16a',
303

(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')rphenyl
substituted with 0-3 R16e
R16a and R16a', at each occurrence, are selected from H,
C1-6 alkyl, C3-8 alkenyl, C3-8 alkynyl, a (CH2)r-
C3-10 carbocyclic residue substituted with 0-5
R16e, and a (CH2)r-5-10 membered heterocyclic
system containing 1-4 heteroatoms selected from N,
0, and S, substituted with 0-2 R16e
R16b, at each occurrence, is selected from C1-6 alkyl,
C3-8 alkenyl, C3-8 alkynyl, a (CH2)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 C3-8 alkenyl,
C3-8 alkynyl, methyl, CF3, C2-6 alkyl substituted
with 0-3 R16e, a (CH2)r-C3-10 carbocyclic residue
substituted with 0-3 R16e, and a (CH2)r-5-6
membered heterocyclic system containing 1-4
heteroatoms selected from N, O, and S, substituted
with 0-3 R16e
R16e, at each occurrence, is selected from C1-6 alkyl,
C2-8 alkenyl, C2-8 alkynyl, (CH2)rC3-6 cycloalkyl,
C1, F, Br, I, CN, NO2, (CF2)r CF3, (CH2)rOC1-5
304

alkyl, OH, SH, (CH2)rSC1-5 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;
g is selected from 0, 1, 2, 3, and 4;
t is selected from 1 and 2;
w is selected from 0 and 1;
r is selected from 0, 1, 2, 3, 4, and 5;
q is selected from 1, 2, 3, 4, and 5; and
p is selected from 0, 1, and 2.
2, The compound of claim 1, wherein:
Z is selected from O, S, NCN, NCONH2, CHNO2, and C(CN)2;
E is selected from:
305

<IMGS>
R4 is absent, taken with the nitrogen to which it is
attached to form an N-oxide, or selected from C1-8
alkyl, (CH2)rC3-6 cycloalkyl, and (CH2)r-phenyl
substituted with 0-3 R4c;
R4c, at each occurrence, is selected from C1-6 alkyl,
C3-8 alkenyl, C3-8 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 NR4aR4a', and
(CH2)r phenyl;
alternatively, R4 joins with R7 or R9 or R14 to form a
5, 6 or 7 membered piperidinium spirocycle
substituted with 0-3 R a;
R1 and R2 are independently selected from H and C1-4
alkyl;
306

R6, at each occurrence, is selected from C1-4 alkyl,
C2-8 alkenyl, C2-8 alkynyl, (CH2)rC3-6 cycloalkyl,
(CF2)r CF3, CN. (CH2)rOH, (CH2)r OR6b, (CH2)r C(O)R6b,
(CH2)r C(O)NR6aR6a', (CH2)r NR6dC(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, C1, F, Br, I, CN, NO2, (CF2)r CF3,
(CH2)r OC1-5 alkyl, (CH2)rOH, (CH2)r SC1-5 alkyl, and
(CH2)r NR6dR6d;
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 NR7aR7a',
(CH2)r C(O)R7b, (CH2)r C(O)NR7aR7a',
(CH2)q NR7aC(O)R7a, (CH2)qOC(O)NR7aR7a',
(CH2)q NR7aC(O)OR7b, C1-6 haloalkyl, (CH2)r phenyl
with 0-2 R7C;
307

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,
C3-8 alkenyl, C3-8 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 C3-6 cycloalkyl,
C1, 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 SC1-5 alkyl, (CH2)r NR7f R7f, and
(CH2)r phenyl;
R7f, at each occurrence, is selected from H, C1-5 alkyl,
and C3-6 cycloalkyl;
308

R8 is H or joins with R~ to form C3-~ cycloalkyl, =0, or
-NRBb:
R11, is selected from H, C1-6 alkyl, (CH2)rC3-6
cycloalkyl, (CH2)qOH, (CH2)qORlld~
(CH2)qNR11aR11a'~ (CH2)rC(0)Rllb~
(CH2)rC(O)NR12aR11a'~ (CH2)qNRllaC(O)Rlla~
(CH2)qOC(O)NR11aR11a'~ (CH2)qNRllaC(0)ORlla~ C1-6
haloalkyl, (CH2)rphenyl 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;
Rlla and Rlla'~ at each occurrence, are selected from H,
C1-6 alkyl, (CH2)rC3-6 cycloalkyl, a (CH2)rphenyl
substituted with 0-3 Rlle;
alternatively, Rlla and Rlla', along with the N to which
they are attached, are joined to form a 5-6
membered heterocyclic system containing 1-2
heteroatoms selected from NRllg, O, and S and
optionally fused with a benzene ring or a 6-
membered aromatic heterocycle;
Rllb, at each occurrence, is selected from C1-6 alkyl,
C2-g alkenyl, C2-g alkynyl, (CH~)rC3-6 cycloalkyl,
(CH2)rphenyl substituted with 0-3 Rlle
Rllc~ at each occurrence, is selected from C1_4 alkyl,
C2-g alkenyl, C2-g alkynyl, (CH~)rC3-6 cycloalkyl,
Cl, Br, I, F, (CF2)rCF3, N02, CN, (CH2)rNR11fR11f~
309

(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 C3-6 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 SC1-5 alkyl, (CH2)r NR11f R11f, and
(CH2)r phenyl;
R11f, at each occurrence, is selected from H, C1-5 alkyl
and C3-6 cycloalkyl;
R11g is selected from H, C1-6 alkyl, C3-6 cycloalkyl,
(CH2)r phenyl, C(O)R11f, C(O)OR11f, and SO2R11f;
R12 is H;
alternatively, R11 and R12 join to form a C3-10
cycloalkyl, a 5-6-membered lactone or lactam, or a
4-6-membered saturated heterocycle containing 1-2
heteroatoms selected from O, S, and NR11g and
optionally fused with a benzene ring or a 6-
membered aromatic heterocycle;
310

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)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 OC1-5 alkyl, (CH2)r OH, and (CH2)r NR13d R13d;
R13d, at each occurrence, is selected from H, C1-6
alkyl, and C3-6 cycloalkyl;
q is selected from 1, 2, and 3; and
r is selected from 0, 1, 2, and 3.
3. The compound of claims 1-2, wherein:
ring A is selected from:
311

<IMGS>
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 claims 1-3, wherein the
compound of formula (I-i) is:
<IMG>
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 OR6d,
(CH2)r C(O)R16b, (CH2)r C(O)NR16a R16a',
(CH2)r NR16f C(O)R16b, (CH2)r S(O)p R16b,
312

(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,
C1, 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 claims 1-3, wherein the
compound of formula (I-ii) is:
<IMG>
R16, at each occurrence, is selected from C1-8 alkyl,
(CH2)r C3-6 cycloalkyl, CF3, Cl, Br, I, F,
(CH3)r NR16a R16a', NO2, CN, OH, (CH3)r OR16d,
313

(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.
6. The compound of claims 1-4, 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 (CH2)r-heterocyclic
314

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, C1-5 alkyl, OH, and CH2OH;
R10g is selected from H, C1-6 alkyl, C3-6 cycloalkyl,
(CH2)r phenyl, C(O)R10f, C(O)OR10f, and SO2R10f;
alternatively, R9 and R10 join to form =O, a C3-10
cycloalkyl, a 5-6-membered lactone or lactam, or a
4-6-membered saturated heterocycle containing 1-2
heteroatoms selected from O, S, and NR10g and
optionally fused with a benzene ring or a 6-
membered aromatic heterocycle;
with the proviso that when either of R9 or R10 is
halogen, cyano, nitro, or bonded to the carbon to
which it is attached through a heteroatom, the
other of R9 or R10 is not bonded to the carbon to
which it is attached through a heteroatom;
315

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;
R11g is selected from H, C1-6 alkyl, C3-6 cycloalkyl,
(CH2)r phenyl, C(O)R11f, C(O)OR11f, and SO2R11f;
R12 is H;
alternatively, R11 and R12 join to form a C3-10
cycloalkyl, a 5-6-membered lactone or lactam, or a
4-6-membered saturated heterocycle containing 1-2
heteroatoms selected from O, S, and NR11g and
optionally fused with a benzene ring or a 6-
membered aromatic heterocycle;
R14, at each occurrence, is selected from C1-8 alkyl,
(CH2)r C3-6 cycloalkyl, CF3, Cl, Br, I, F,
(CH2)r NR14a R14a', NO2, CN, OH, (CH2)r OR14d,
(CH2)r C(O)R14b, (CH2)r C(O)NR14a R14a',
316

(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-5-10 membered heterocyclic system containing
1-4 heteroatoms selected from N, O, and S,
substituted with 0-2 R15e; or two R14 substituents
on adjacent atoms on ring A form to join a 5-6
membered heterocyclic system containing 1-3
heteroatoms selected from N, O, and S substituted
with 0-2 R15e;
R14a and R14a', at each occurrence, are selected from H,
C1-6 alkyl, C3-6 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
317

r is selected from 0, 1, and 2.
7. The compound of claims 1-3, and 5, 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 (CH2)r-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;
R10g is selected from H, C1-6 alkyl, C3-6 cycloalkyl,
(CH2)r phenyl, C(O)R10f, C(O)OR10f, and SO2R10f;
318

alternatively, R9 and R10 join to form =O, a C3-10
cycloalkyl, a 5-6-membered lactone or lactam, or a
4-6-membered saturated heterocycle containing 1-2
heteroatoms selected from O, S, and NR10g and
optionally fused with a benzene ring or a 6-
membered aromatic heterocycle;
with the proviso that when either of R9 or R10 is
halogen, cyano, nitro, or bonded to the carbon to
which it is attached through a heteroatom, the
other of R9 or R10 is not bonded to the carbon to
which it is attached through a heteroatom;
R11 is selected from H, 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-
alkyl;
R11g is selected from H, C1-6 alkyl, C3-6 cycloalkyl,
(CH2)r phenyl, C(O)R11f, C(O)OR11f, and SO2R11f;
R12 is H;
319

alternatively, R11 and R12 join to form a C3-10
cycloalkyl, a 5-6-membered lactone or lactam, or a
4-6-membered saturated heterocycle containing 1-2
heteroatoms selected from O, S, and NR11g and
optionally fused with a benzene ring or a 6-
membered aromatic heterocycle;
R14, at each occurrence, is selected from C1-8 alkyl,
(CH2)r C3-6 cycloalkyl, CF3, Cl, Br, I, F,
(CH2)r NR14a R14a', 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 R24a', (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; or two R14 substituents
on adjacent atoms on ring A form to join a 5-6
membered heterocyclic system containing 1-3
heteroatoms selected from N, O, and S substituted
with 0-2 R15e;
R14a and R14a', at each occurrence, are selected from H,
C1-6 alkyl, C3-6 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;
320

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.
8. The compound of claims 1-4 and 6, wherein:
J is selected from CH2 and CHR5;
K is selected from CH2 and CHR5;
L is selected from CH2 and CHR5;
R3 is selected from a C1-10 alkyl substituted with 0-3
R3g, C3-10 alkenyl substituted with 0-3 R3g, and
C3-10 alkynyl substituted with 0-3 R3g;
R3g, at each occurrence, is selected from Cl, Br, I, F,
NO2, CN, NR3a R3a', OH, O (CHR')r R3d, SH, C(O)H,
S(CHR')r R3d, C(O)OH, C(O)(CHR')r R3b, C(O)NR3a R3a',
NR3f C(O)(CHR')r R3b, C(O)O(CHR')r R3d,
OC(O)(CHR')r R3b, (CH2)r OC(O)NR3a R3a',
(CH2)q NR3a C(O)OR3a, S(O)p(CHR')r R3b, S(O)2NR3a R3a',
321

NR3f S(O)2(CHR')r R3b, phenyl substituted with 0-3
R15, and a heterocyclic system substituted with 0-3
R15, wherein the heterocyclic system is selected
from pyridinyl, thiophenyl, furanyl, indazolyl,
benzothiazolyl, benzimidazolyl, benzothiophenyl,
benzofuranyl, benzoxazolyl, benzisoxazolyl,
quinolinyl, isoquinolinyl, imidazolyl, indolyl,
indolinyl, isoindolyl, isothiadiazolyl, isoxazolyl,
piperidinyl, pyrrazolyl, 1,2,4-triazolyl, 1,2,3-
triazolyl, tetrazolyl, thiadiazolyl, thiazolyl,
oxazolyl, pyrazinyl, and pyrimidinyl, provided that
when R3g is a carbocyclic residue or a heterocyclic
system, R3 has at least one other R3g, which is not
a carbocyclic residue or a heterocyclic system;
R3a and R3a', at each occurrence, are selected from H,
C1-6 alkyl, C3-8 alkenyl, C3-8 alkynyl, and (CH2)r-
phenyl substituted with 0-3 R3e;
R3b, at each occurrence, is selected from C1-6 alkyl,
and (CH2)r-phenyl substituted with 0-3 R3e;
R3d, at each occurrence, is selected from C1-6 alkyl and
phenyl substituted with 0-3 R3e;
R3e, at each occurrence, is selected from C1-6 alkyl,
Cl, F, Br, I, CN, NO2, (CF2)r CF3, (CH2)r OC1-5
alkyl, OH;
R3f, at each occurrence, is selected from H, C1-5 alkyl;
322

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 OC(O)NR15a R15a',
(CH2)q NR15a C(O)OR15a, (CH2)r S(O)p R15b,
(CH2)r S(O)2NR15a R15a', (CH2)r NR15f S(p)2R15b,
(CH2)r phenyl substituted with 0-3 R15e, 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;
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;
alternatively, R15a and R15a', along with the N to which
they are attached, are joined to form a morpholine,
piperidine, or piperazine ring, and the piperazine
optionally substituted With R15g;
R15b, at each occurrence, is selected from H, C1-6
alkyl, C3-6 cycloalkyl, and (CH2)r phenyl
substituted with 0-3 R15e;
323

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.
9. The compound of claims 1-3, 5, and 7, wherein:
K is selected from CH2 and CHR5;
L is selected from CH2 and CHR5;
R3 is selected from a C1-10 alkyl substituted with 0-3
R3g, C3-10 alkenyl substituted with 0-3 R3g, and
C3-10 alkynyl substituted with 0-3 R3g;
R3g, at each occurrence, is selected from Cl, Br, I, F,
NO2, CN, NR3a R3a', OH, O(CHR')r R3d, SH, C(O)H,
S(CHR')r R3d, C(O)OH, C(O)(CHR')r R3b, C(O)NR3a R3a',
NR3f C(O)(CHR')r R3b, C(O)O(CHR')r R3d,
OC(O)(CHR')r R3b, (CH2)r OC(O)NR3a R3a',
(CH2)q NR3a C(O)OR3a, S(O)p(CHR')r R3b, S(O)2NR3a R3a',
NR3f S(O)2(CHR')r R3b, phenyl substituted with 0-3
R15, and a heterocyclic system substituted with 0-3
R15, wherein the heterocyclic system is selected
from pyridinyl, thiophenyl, furanyl, indazolyl,
benzothiazolyl, benzimidazolyl, benzothiophenyl,
324

benzofuranyl, benzoxazolyl, benzisoxazolyl,
quinolinyl, isoquinolinyl, imidazolyl, indolyl,
indolinyl, isoindolyl, isothiadiazolyl, isoxazolyl,
piperidinyl, pyrrazolyl, 1,2,4-triazolyl, 1,2,3-
triazolyl, tetrazolyl, thiadiazolyl, thiazolyl,
oxazolyl, pyrazinyl, and pyrimidinyl, provided that
when R3g is a carbocyclic residue or a heterocyclic
system, R3 has at least one other R3g, which is not
phenyl or a heterocyclic system;
R3a and R3a', at each occurrence, are selected from H,
C1-6 alkyl, C3-8 alkenyl, C3-8 alkynyl, and (CH2)r-
phenyl substituted with 0-3 R3e;
R3b, at each occurrence, is selected from C1-6 alkyl,
and (CH2)r-phenyl substituted with 0-3 R3e;
R3d, at each occurrence, is selected from C1-6 alkyl and
phenyl substituted with 0-3 R3e;
R3e, at each occurrence, is selected from C1-6 alkyl,
Cl, F, Br, I, CN, NO2, (CF2)r CF3, (CH2)r OC1-5
alkyl, OH;
R3f, at each occurrence, is selected from H, C1-5 alkyl;
R15, at each occurrence, is selected from C1-8 alkyl,
(CH2)r C3-6 cycloalkyl, CF3, Cl, Br, I, F,
(CH2)r NR15aR15a', 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 OC(O)NR15a R15a',
325

(CH2)q NR15a C(O)OR15a, (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
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;
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;
alternatively, R15a and R15a', along with the N to which
they are attached, are joined to form a morpholine,
piperidine, or piperazine ring, and the piperazine
optionally substituted with R15g;
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;
326

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 claims 1-4, 6, and 8, wherein:
E is <IMG>
Z is selected from O and N(CN);
R3 is selected from C3-8 alkyl wherein the C3-8 alkyl is
selected from methyl, ethyl, propyl, i-propyl,
butyl, i-butyl, t-butyl, pentyl, methylpentyl,
dimethylpentyl, and trimethylpentyl, and wherein
the C3-8 alkyl is substituted with 0-2 R3g;
R3g, at each occurrence is selected from C(O)OR3b, OR3b
OH, OC (O) H, NHC (O) R3b, CN, NR3a R3a', and phenyl;
R3a and R3a', at each occurrence, are selected from H and
methyl;
R3b, at each occurrence, is selected from H, methyl,
ethyl, propyl, and phenyl; and
R16 is selected from F, Cl, Br, and I.
327

11. The compound of claims 1-3, 5, 7, and 9,
wherein:
E is <IMG>
Z is selected from O and N(CN);
R3 is selected from C3-8 alkyl wherein the C3-8 alkyl is
selected from methyl, ethyl, propyl, i-propyl,
butyl, i-butyl, t-butyl, pentyl, methylpentyl,
dimethylpentyl, and trimethylpentyl, and wherein.
the C3-8 alkyl is substituted with 0-2 R3g;
R3g, at each occurrence is selected from C(O)OR3b, OR3b,
OH, OC (O) H, NHC (O) R3b, CN, NR3a R3a', and phenyl;
R3a and R3a', at each occurrence, are selected from H and
methyl;
R3b, at each occurrence, is selected from H, methyl,
ethyl, propyl, and phenyl; and
R16 is selected from F, Cl, Br, and I.
12. The compound of claim 1 and pharmaceutically
acceptable salt forms thereof, wherein the compound of
formula (I) is selected from:
N-(t-butyl)-N'-[(1R,2S)-2-[[(3S)-3-(4-
fluorophenyl)methyl)piperidinyl]methyl]cyclohexy
1]-urea,
328

N-(i-propyl)-N'-[(1R,2S)-2-[[(3S)-3-(4-
fluorophenyl)methyl)piperidinyl]methyl]cyclohexy
1]-urea,
N-(ethoxycarbonylmethyl)-N'-[(1R,2S)-2-[[(3S)-3-(4-
fluorophenyl)methyl)piperidinyl]methyl]cyclohexy
1]-urea,
N-[(1R,S)-1-(methoxycarbonyl)-2-methyl-propyl]-N'-
[(1R,2S)-2-[[(3S)-3-(4-
fluorophenyl)methyl)piperidinyl]methyl]cyclohexy
1]-urea,
N-[(1S)-1-(methoxycarbonyl)-2-phenylethyl]-N'-
[(1R,2S)-2-[[(3S)-3-(4-
fluorophenyl)methyl)piperidinyl]methyl]cyclohexy
1]-urea,
N-[2,4,4-trimethyl-2-pentyl]-N'-[(1R,2S)-2-[[(3S)-3-
(4-
fluorophenyl)methyl)piperidinyl]methyl]cyclohexy
1]-urea,
N-[(1S)-2-hydroxy-1-phenylethyl]-N'-[(1R,2S)-2-[[(3S)-3-
(4-
fluorophenyl)methyl)piperidinyl]methyl]cyclohexyl]-
urea,
2-({[(1R,2S)-2-{[(3S)-3-(4-
fluorobenyl)piperidinyl]methyl}cyclohexyl)amino}car
bonyl}amino)acetamide,
N-(2-methoxyethyl)-N'-(1R,2S)-2-[[(3S)-3-(4-
fluorophenyl)methyl)piperidinyl]methyl]cyclohexyl]-
urea,~
329

N-(2-ethoxyethyl)-N'-(1R,2S)-2-[[(3S)-3-(4-
fluorophenyl)methyl)piperidinyl]methyl]cyclohexyl]-
urea,
N"-cyano-N-(ethoxycarbonylmethyl)-N'-(1R,2S)-2-[[(3S)-3-
(4-
fluorophenyl)methyl)piperidinyl]methyl]cyclohexyl]-
guanidine,
2-{[((1R,2S)-2-{[(3S)-3-(4-
fluorobenzyl)piperidinyl]methyl}cyclohexyl)amino][(
2-methoxyethyl)amino]methylene}malonitrile,
N"-cyano-N-(2-phenoxyethyl)-N'-(1R,2S)-2-[[(3S)-3-(4-
fluorophenyl)methyl)piperidinyl]methyl]cyclohexyl]-
guanidine,
N"-cyano-N-(2-methoxyethyl)-N'-(1R,2S)-2-[[(3S)-3-(4-
fluorophenyl)methyl)piperidinyl]methyl]cyclohexyl]-
guanidine,
N-(2-dimethylaminoethyl)-N'-{(1R,2R)-2-[(3S)-3-(4-
fluorobenzyl)piperidine-1-carbonyl]cyclohexyl}-
urea, and
N"-cyano-N-(2-ethoxyethyl)-N'-(1R,2S)-2-[[(3S)-3-(4-
fluorophenyl)methyl)piperidinyl]methyl]cyclohexyl]-
guanidine.
13. A pharmaceutical composition, comprising a
pharmaceutically acceptable carrier and a
therapeutically effective amount of a compound of claims
1-12.
330

14. A method for modulation of chemokine receptor
activity comprising administering to a patient in need
thereof a therapeutically effective amount of a compound
of claims 1-12.
15. A method for modulation of chemokine receptor
activity comprising contacting a CCR3 receptor with an
effective inhibitory amount of a compound of Claims 1-
12.
16. A method for treating or preventing
inflammatory diseases, comprising administering to a
patient in need thereof a therapeutically effective
amount of a compound of claims 1-12.
17. A method for treating or preventing asthma,
comprising administering to a patient in need thereof a
therapeutically effective amount of a compound of claims
1-12.
18. A method for treating or preventing
inflammatory disorder comprising administering to a
patient in need thereof a therapeutically effective
amount of a compound of Claims 1-12, wherein the
inflammatory disorder is selected from asthma, allergic
rhinitis, atopic dermatitis, inflammatory bowel
diseases, idiopathic pulmonary fibrosis, bullous
pemphigoid, helminthic parasitic infections, allergic
colitis, eczema, conjunctivitis, transplantation,
familial eosinophilia, eosinophilic cellulitis,
eosinophilic pneumonias, eosinophilic fasciitis,
eosinophilic gastroenteritis, drug induced eosinophilia,
HIV infection, cystic fibrosis, Churg-Strauss syndrome,
lymphoma, Hodgkin's disease, and colonic carcinoma.
331

19. The method of Claim 18 for treating or
preventing disorders selected from asthma, allergic
rhinitis, atopic dermatitis, and inflammatory bowel
diseases.
332

Description

CA 02413421 2002-12-19
WO 01/98270 PCT/USO1/19752
TITLE
N-UREIDOALKYL-PIPERIDINES AS MODULATORS OF CHEMOKINE
RECEPTOR 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-loG, MIP-1(3, 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-1, lymphotactin-2
(both C chemokines), and fractalkine (a CXXXC chemokine)

CA 02413421 2002-12-19
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that do not fall into either of the major chemokine
subfamilies.
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." On 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-loG, 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-loG, RANTES, MIP-
1(3] (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-CKR-7") [ELC] (Yoshie et al., J.
Leukoc. Biol. 62, 634-644 (1997)); CCR-8 (or "CKR-8" or
2

CA 02413421 2002-12-19
WO 01/98270 PCT/USO1/19752
"CC-CKR-8" ) [I-309, TARC, MIP-1(3] (Napolitano et al. , J.
Immunol., 157, 2759-2763 (1996), Bernardini et al., Eur.
J. Immunol., 28, 582-588 (1998)); and CCR-10 (or "CKR-
10" or "CC-CKR-10") [MCP-1, MCP-3] (Bonini et al, DNA
and Cell Biol., 16, 1249-1256 (1997)).
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, CCR5 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
3

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modulate chemokine receptors would also be useful in
infectious diseases such as by blocking infection of
CCR3 expressing cells by HTV 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.
WO 98/25604 describes spiro-substituted azacycles
which are useful as modulators of chemokine receptors:
H2~m
'(CI
H~~
wherein R1 is C1_6 alkyl, optionally substituted with
functional groups such as -NR6CONHR7, wherein R6 and R7
may be phenyl further substituted with hydroxy, alkyl,
cyano, halo and haloalkyl. Such spiro compounds are not
considered part of the present invention.
WO 95113069 is directed to certain piperidine,
pyrrolidine, and hexahydro-1H-azepine compounds of
general formula:
H ,R4
Ri-~--NHCO-A-f~
C~=O Rs
~N W
X
(CH2~~
R3 Y
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.
4

CA 02413421 2002-12-19
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WO 93/06108 discloses pyrrolobenzoxazine
derivatives as 5-hydroxytryptamine (5-HT) agonists and
antagonists:
1
R5
N /
R2
Rs
CONH-(A)ri R4
wherein A is lower alkylene and R4 may be phenyl
optionally substituted with halogen.
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:
3
HN ~ R4 R7
R2 ~ / NHCO-B-(CH2)~ N\
R102C \ I R
R5
wherein B may be NH, NR1, 0, 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.
5

CA 02413421 2002-12-19
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SUMMARY 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
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 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):
6

CA 02413421 2002-12-19
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4 Z
I~ ~E-N~-R3
L-Q 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
[1] In one embodiment, the present invention
provides novel compounds of formula (I):
Z
M R4
I~ ~ E-N~-R3
~-Q R1 R2
(I)
or stereoisomers or pharmaceutically acceptable salts
thereof, wherein:
M is absent or selected from CH2, CHRS, CHR13, CR13R13~
and CR5R13~
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 that:
1) at least one of J, K, or L contains R5;
7

CA 02413421 2002-12-19
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2) when M is absent, J is selected from CH2, CHRS,
CHR13, and CR5R13;
Z is selected from 0, S, NRla, CHCN, CHN02, and C(CN)2;
R1a is selected from H, C1_6 alkyl, C3_6 cycloalkyl,
CONRIbRIb~ ORlb~ CN, N02, and (CH2)wphenyl;
R1b is independently selected from H, C1_3 alkyl, C3-6
cycloalkyl, and phenyl;
E is selected from:
R8
R~
A A
~R 14)9 ~R 14)9 R9 'R10 ~R 149
11 12
7 8
A
R9 R10 ~R14)9
11 12 R9 10 7 Rg 9 10
A W A - R11 R12 A - R~11 R12
~R 14)g / ~R 14)g ' ~R 14)9
9 10
7 8 11 R12 7 8 R R Rs R9 R1o
A w A X11 R12 ~ A
R R~RIO '~~
~R 149 R R10 {R 149 ~R 14)9
and
8

CA 02413421 2002-12-19
WO 01/98270 PCT/USO1/19752
R~ R8 9 Rio 11 R12
Rs~R1o A
~R 14).
9
ring A is a C3-6 carbocyclic residue, provided that the
C3-6 carbocyclic residue in Ring A is not phenyl;
R1 and R2 are independently selected from H, C1-6 alkyl,
C3-g alkenyl, and C3_g alkynyl;
R3 is selected from a C1-10 alkyl substituted with 0-5
R3g. C3-10 alkenyl substituted with 0-5 R3g, and
C3-10 alkynyl substituted with 0-5 R3g;
R3g, at each occurrence, is independently selected from
C1, Br, I, F, N02, CN, NR3aR3a', OH, O(CHR')rR3d,
SH, C (0) H, S (CHR ~ ) rR3d, C (O) OH, C (O) (CHR' ) rR3b,
C (O) NR3aR3a' , OC (O) NR3aR3a' ~ NR3aC (0) oR3d,
NR3fC(O)(CHR')rR3b, C(O)O(CHR')rR3d,
OC(O)(CHR')rR3b~ C(=NR3f)NR3aR3a'.
2 0 NHC ( =NR3 f ) NR3 f R3 f , S ( 0 ) p ( CHR' ) rR3 b , S ( O ) 2NR3 aR3 a'
,
NR3fS(0)2(CHR')rR3b, a C3_1o carbocyclic residue
substituted with 0-5 R15, and a 5-10 membered
heterocyclic system containing 1-4 heteroatoms
selected from N, 0, and S, substituted with 0-3
R15, provided that when R3g is a carbocyclic
residue or a heterocyclic system, R3 has at least
one other R3g, which is not a carbocyclic residue
or a heterocyclic system;
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CA 02413421 2002-12-19
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R3a and R3a~, at each occurrence, are selected from H,
C1_6 alkyl, C3-g alkenyl, C3_g alkynyl, a (CH2)r-
C3-10 carbocyclic residue substituted with 0-5 R3e,
and a (CH2)r-5-10 membered heterocyclic system
containing 1-4 heteroatoms selected from N, O, and
S, substituted with 0-2 R3e;
R3b, at each occurrence, is selected from C1_6 alkyl,
C3-g alkenyl, C3_g alkynyl, a (CH2)r-C3-6
carbocyclic residue substituted with 0-3 R3e, and
(CH2)r-5-6 membered heterocyclic system containing
1-4 heteroatoms selected from N, O, and S,
substituted with 0-2 R3e;
R3d, at each occurrence, is selected from C3-g alkenyl,
C3-g alkynyl, methyl, CF3, C~-6 alkyl substituted
with 0-3 R3e, a (CH2)r-C3-10 carbocyclic residue
substituted with 0-3 R3e, and a (CH2)r5-6 membered
heterocyclic system containing 1-4 heteroatoms
selected from N, O, and S, substituted with 0-3
R3e:
R3e, at each occurrence, is selected from C1-6 alkyl,
C2_g alkenyl, C2-g alkynyl, (CH2)rC3-6 CYCloalkyl,
C1, F, Br, I, CN, N02, (CF2)rCF3, (CH2)rOC1-5
alkyl, OH, SH, (CH2)rS(O)pC1-5 alkyl,
(CH2)rNR3fR3f~ and (CH2)rphenyl;
R3f, at each occurrence, is selected from H, C1_6 alkyl,
C3_6 cycloalkyl, and phenyl;

CA 02413421 2002-12-19
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R4 is absent, taken with the nitrogen to which it is
attached to form an N-oxide, or selected from C1-6
alkyl, C3-g alkenyl, C3-g alkynyl, (CH2)rC3-6
cycloalkyl, (CH2)qC(O)R4b, (CH2)qC(O)NR4aR4a'~
(CH2)qC(O)OR4b, and a (CH2)r-C3-10 carbocyclic
residue substituted with 0-3 R4c;
R4a and Rya', at each occurrence, are selected from H,
C1-6 alkyl, (CH2)rC3-6 cYcloalkyl, and phenyl;
R4b, at each occurrence, is selected from C1-6 alkyl,
C3-g alkenyl, (CH2)rC3-6 cYcloalkyl, C3-g 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)rOC1-5 alkyl,
(CH2)rOH, (CH2)rSC1-5 alkyl, (CH2)rNR4aR4a', and
(CH2)rphenyl;
alternatively, R4 joins with R~, R9, R11, or R14 to form
a 5, 6 or 7 membered piperidinium spirocycle or
pyrrolidinium spirocycle substituted with 0-3 Ra;
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;
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CA 02413421 2002-12-19
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R5~ and R5~~, at each occurrence, are selected from H,
C1-6
alkyl, (CH2)rC3-6 cYcloalkyl, and phenyl;
R6, at each occurrence, is selected from C1-6 alkyl,
C2-g alkenyl, C2-g alkynyl, (CH2)rC3-6 CYCloalkyl,
(CF2)rCF3. CN. (CH2)rNR6aR6a'. (CH2)r~H.
(CH2)rOR6b. (CH2)rSH. (CH2)rSR6b. (CH2)rC(O)OH.
(CH2)rC(O)R6b~ (CH2)rC(O)NR6aR6a'.
(CH2)rNR6dC(O)R6a~ (CH2)rC(O)OR6b. (CH2)rOC(0)R6b.
(CH2)rS(O)pR6b. (CH2)rS(O)2NR6aR6a'.
(CH2)rNR6dS(O)2R6b, and (CH2)tphenyl substituted
with 0-3 R6C;
R6a and R6a~, at each occurrence, are selected from H,
C1-6
alkyl, C3-6 cycloalkyl, and phenyl substituted with
0-3 R6c;
R6b, at each occurrence, is selected from C1-6 alkyl,
C3-6
cycloalkyl, and phenyl substituted with 0-3 R6c;
R6c, at each occurrence, is selected from C1-g alkyl,
C3-6 cycloalkyl, Cl, F, Br, I, CN, N02, (CF2)rCF3,
(CH2)rOC1-5 alkyl, (CH2)rOH, (CH2)rSC1-5 alkyl, and
(CH2)rNR6dR6d;
R6d, at each occurrence, is selected from H, C1-6 alkyl,
and C3-6 cycloalkyl;
12

CA 02413421 2002-12-19
WO 01/98270 PCT/USO1/19752
with the proviso that when any of J, K or L is CR6R6 and
R6 is bonded to the carbon to which it is attached
through a heteroatom, the other R6 is not bonded to
the carbon to which it is attached through a
heteroatom;
R~, is selected from H, C1_6 alkyl, C2-g alkenyl, C2_g
alkynyl, (CH2)qOH, (CH2)qSH, (CH2}qOR~d,
(CH2)qSR7d, (CH2)qNR~aR7a', (CH2)rC(0)OH,
(CH2)rC(O)R~b, (CH2)rC(O)NR~aR~a',
(CH2)rOC(O)NR~aR~a', (CH2)qNR~aC(0)OR~b,
( CH2 ) qNR~ aC ( O ) R7 a, ( CH2 ) qNR~ aC ( O ) H. ( CH2 ) rC ( O ) OR~b,
(CH2)qOC(O)R~b, (CH2)qS(O)pR7b,
(CH2)qS(0)2NR7aR7a', (CH2)qNR~aS(O)2R7b, C1_6
haloalkyl, a (CH2)r-C3-10 carbocyclic residue
substituted with 0-3 RFC, and a (CH2)r-5-10
membered heterocyclic system containing 1-4
heteroatoms selected from N, O, and S, substituted
with 0-2 Roc;
25
Rya and R~a~, at each occurrence, are selected from H,
C1-6 alkyl, C3_g alkenyl, C3_g alkynyl, (CH2)rC3-6
cycloalkyl, a (CH2)r-C3-10 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;
alternatively, Rya and R7a~, along with the N to which
they are attached, are joined to form a 5-6
membered heterocyclic system containing 1-2
13

CA 02413421 2002-12-19
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heteroatoms selected from NR7g, O, and S and
optionally fused with a benzene ring or a 6-
membered aromatic heterocycle;
Rib, at each occurrence, is selected from C1-6 alkyl,
C3_g alkenyl, C3_g 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;
RFC, at each occurrence, is selected from C1-6 alkyl,
C2_g alkenyl, C2_g alkynyl, (CH2)rC3-6 cYcloalkyl,
Cl, Br, I, F, (CF2)rCF3, N02, CN, (CH2)rNR~fR7f~
(CH2)rOH, (CH2)rOC1-4 alkyl, (CH2)rSC1-4 alkyl,
(CH2)rC(O)OH, (CH2)rC(O)R7b, (CH2)rC(O)NR~fR7f,
(CH2)rNR~fC(O)R7a~ (CH2)rC(O)OC1-4 alkyl,
(CH2)rOC(O)R~b, (CH2)rC(=NR~f)NR~fR7f~
(CH2)rS(O)pR~b, (CH2)rNHC(=NR~f)NR~fR7f~
(CH2)rS(O)2NR~fR7f~ (CH2)rNR~fS(O)2R7b~ and
(CH2)rphenyl substituted with 0-3 Rye;
Rid, at each occurrence, is selected from methyl, CF3,
C2-6 alkyl substituted with 0-3 Rye, C3-g alkenyl,
C3-g alkynyl, and a C3-10 carbocyclic residue
substituted with 0-3 Roc;
Rye, at each occurrence, is selected from C1-6 alkyl,
C2-g alkenyl, C2_g alkynyl, C3-6 cycloalkyl, Cl, F,
Br, I, CN, N02, (CF2)rCF3, (CH2)rOC1-5 alkyl, OH,
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CA 02413421 2002-12-19
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SH, (CH2)rSC1-5 alkyl, (CH2)rNR~fR~f, and
(CH2)rphenyl;
Ref, at each occurrence, is selected from H, C1_6 alkyl,
and C3-6 cycloalkyl;
Rig is selected from H, C1-6 alkyl, C3-6 cycloalkyl,
(CH~)rphenyl, C(0)R~f, C(O)OR~f, and S02R~f;
R8 is selected from H, C1-6 alkyl, C3-6 cycloalkyl, and
(CH2)tphenyl substituted with 0-3 R8a;
R8a, at each occurrence, is selected from C1_6 alkyl,
C~-g alkenyl, C2-g alkynyl, C3-6 cycloalkyl, Cl, F,
Br, I, CN, N02, (CF2)rCF3, (CH2)rOC1-5 alkyl, OH,
SH, (CH~)rSC1-5 alkyl, (CH2)rNR~fR~f, and
(CH2)rphenyl;
Rgb is selected from H, C1-6 alkyl, C3_6 cycloalkyl, ~OH,
CN, and (CH2)r-phenyl;
alternatively, R~ and R8 join to form C3-~ cycloalkyl,
=O, or =NR8b;
R9, is selected from H, C1-6 alkyl, C~-g alkenyl, C2-g
alkynyl, F, Cl, Br, I, N02, CN, (CH~)rOH, (CH2)rSH,
(CH2)rOR9d, (CH2)rSR9d, (CH2)rNR9aR9a',
(CH2)rC(0)OH, (CH2)rC(O)R9b~ (CH2)rC(O)NR9aR9a',
(CH2)rNR9aC(O)R9a, (CH2)rNR9aC(O)H,
(CH2)rOC(O)NR9aR9a', (CH2)rNR9aC(O)OR9b,

CA 02413421 2002-12-19
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(CH2)rNR9aC(0)NHR9a, (CH2)rC(O)OR9b.
( CH2 ) rOC ( O ) R9b. ( CH2 ) rS ( 0 ) pR9b.
(CH2)rS(O)2NR9aR9a'. (CH2)rNR9aS(O)2R9b~ C1-6
haloalkyl, a (CH2)r-C3-10 carbocyclic residue
substituted with 0-5 R9C, and a (CH2)r-5-10
membered heterocyclic system containing 1-4
heteroatoms selected from N, O, and S, substituted
with 0-3 R9C;
R9a and R9a~, at each occurrence, are selected from H,
C1-6 alkyl, C3-g alkenyl, C3-g alkynyl, a (CH2)r-
C3-10 carbocyclic residue substituted with 0-5 R9e,
and a (CH2)r-5-10 membered heterocyclic system
containing 1-4 heteroatoms selected from N, O, and
S, substituted with 0-3 R9e;
alternatively, R9a and R9a~, along with the N to which
they are attached, are joined to form a 5-6
membered heterocyclic system containing 1-2
heteroatoms selected from NR9g, 0, and S and
optionally fused with a benzene ring or a 6-
membered aromatic heterocycle;
R9b, at each occurrence, is selected from C1-6 alkyl,
C3-g alkenyl, C3_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, 0, and S,
substituted with 0-3 R9e;
R9c, at each occurrence, is selected from C1-6 alkyl,
C2_g alkenyl, C2_g alkynyl, (CH2)rC3-6 cYcloalkyl,
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Cl, Br, I, F, (CF2)rCF3, N02, CN, (CH2)rNR9fR9f~
(CH2)rOH, (CH2)rOC1-4 alkyl, (CH2)rSC1-g alkyl,
(CH2)rC(0)OH, (CH2)rC(O)R9b~ (CH2)rC(0)NR9fR9f~
(CH2)rNR9fC(O)R9a~ (CH2)rC(0)OC1-4 alkyl,
(CH~)rOC(0)R9b, (CH2)rC(=NR9f)NR9fR9f~
(CH2)rS(0)pR9b, (CH2)rNHC(=NR9f)NR9fR9f~
(CH2)rS(0)2NR.9fR9f~ (CH2)rNR9fS(0)2R9b~ and
(CH2)rphenyl substituted with 0-3 R9e;
R9d, at each occurrence, is selected from C1-6 alkyl,
C3-6 alkenyl, C3-6 alkynyl, a C3-10 carbocyclic
residue substituted with 0-3 R9C, and a 5-6
membered heterocyclic system containing 1-4
heteroatoms selected from the group consisting of
N, O, and S substituted with 0-3 R9C;
R9e, at each occurrence, is selected from C1-6 alkyl,
C2-g alkenyl, C~-g alkynyl, (CH~)rC3-6 cycloalkyl,
Cl, F, Br, I, CN, N02, (CF2)rCF3, (CH2)rOC1-5
alkyl, OH, SH, (CH2)rSC1-5 alkyl, (CH~)rNR9fR9f~
and (CH2)rphenyl;
R9f, at each occurrence, is selected from H, C1-6 alkyl,
and C3-6 cycloalkyl;
R9g is selected from H, C1-6 alkyl, C3-6 cycloalkyl,
(CH~)rphenyl, C(O)R9f, C(O)OR9f, and S02R9f;
R10, is selected from H, C1-g alkyl, C~-g alkenyl, C2-g
alkynyl, F, C1, Br, I, N02, CN, (CH2)rOH,
17

CA 02413421 2002-12-19
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(CH2)rOR.lOd~ (Cg2)rSRlOd~ (CH2)rNR10aR10a',
(CH2)rC(0)OH, (CH2)rC(O)RlOb~ (CH2)rC(O)NR10aR10a'.
(CH2)rNRlOaC(0)RlOa~ (CH2)rNRlOaC(0)H.
(CH2)rC(O)ORlOb~ (CH2)rpC(O)RlOb~
(CH2)rOC(O)NR10aR10a'~ (CH2)rNRlOaC(O)ORlOb~
(CH2)rS(O)pRlOb~ (CH2)rS(0)2NR10aR10a',
(CH2)rNRlOaS(O)2R10b~ C1-6 haloalkyl, a (CH2)r-C3-
carbocyclic residue substituted with 0-5 RlOc
and a (CH2)r-5-10 membered heterocyclic system
10 containing 1-4 heteroatoms selected from N, 0, and
S, substituted with 0-3 RlOc
RlOa and RlOa', at each occurrence, are selected from H,
C1-~ alkyl, C3-g alkenyl, C3-g alkynyl, a (CH2)r-
C3-10 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
alternatively, RlOa and RIOa~, along with the N to which
they are attached, are joined to form a 5-6
membered heterocyclic system containing 1-2
heteroatoms selected from NRl~g, O, and S and
optionally fused with a benzene ring or a 6-
membered aromatic heterocycle;
RlOb~ at each occurrence, is selected from C1-6 alkyl,
C3-g alkenyl, C3-g alkynyl, a (CH2)r-C3-6
carbocyclic residue substituted with 0-2 RlOe, and
a (CH2)r-5-6 membered heterocyclic system
18

CA 02413421 2002-12-19
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containing 1-4 heteroatoms selected from N, 0, and
S, substituted with 0-3 RlOe;
RlOc~ at each occurrence, is selected from C1_6 alkyl,
C2-g alkenyl, C2_g alkynyl, (CH2)rC3-6 cYcloalkyl,
Cl, Br, I, F, (CF2)rCF3, N02, CN, (CH2)rNR10fR10f~
(CH2)rOH, (CH2)rOC1-4 alkyl, (CH2)rSC1-4 alkyl,
( CH2 ) rC ( 0 ) OH , ( CH2 ) rC ( O ) R1 Ob ~ ( CH2 ) rC ( O ) NR10 f R10 f
(CH2)rNRlOfC(O)RlOa~ (CH2)rC(0)OC1_4 alkyl,
(CH2)rOC(O)RlOb~ (CH2)rC(=NRlOf)NR10fR10f~
(CH2)rS(O)pRlOb, (CH2)rNHC(=NRlOf)NR10fR10f~
(CH2)rs(O)2NR.10fR10f~ (CH2)rNRlOfs(0)2R10b~ and
(CH2)rphenyl substituted with 0-3 R.lOe;
RlOd, at each occurrence, is selected from C1_6 alkyl,
C3-6 alkenyl, C3_6 alkynyl, a C3-10 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_g alkenyl, C2-g alkynyl, (CH2)rC3-6 cycloalkyl,
C1, F, Br, I, CN, N02, (CF2)rCF3, (CH2)rOC1-5
alkyl, OH, SH, (CH2)rSC1_5 alkyl, (CH2)rNR10fR10f~
and (CH2)rphenyl;
RlOf, at each occurrence, is selected from H, C1-5
alkyl, and C3_6 cycloalkyl;
19

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RlOg is selected from H, C1-6 alkyl, C3-6 cycloalkyl,
(CH2)rphenyl, C(O)RlOf, C(O)ORlOh, and S02R10h~
RlOh~ at each occurrence, is selected from C1-5 alkyl,
and C3-6 cycloalkyl;
alternatively, R9 and R10 join to form =O, a C3-10
cycloalkyl, a 5-6-membered lactone or lactam, or a
4-6-membered saturated heterocycle containing 1-2
heteroatoms selected from O, S, and NRlOg and
optionally fused with a benzene ring or a 6-
membered aromatic heterocycle;
with the proviso that when either of R9 or R1~ is
halogen, cyano, nitro, or bonded to the carbon to
which it is attached through a heteroatom, the
other of R9 or R1~ is not bonded to the carbon to
which it is attached through a heteroatom;
R11, is selected from H, C1-6 alkyl, C2-g alkenyl, C2_g
alkynyl, (CH2)qOH, (CH2)qSH, (CH2)qORlld,
(CH2 ) qSRlld~ (CH2 ) qNR11aR11a' . (CH2 ) rC (O) OH.
(CH2)rC(O)Rllb, (CH2)rC(O)NR11aR11a'~
(CH2)qNRllaC(O)Rlla~ (CH2)qOC(O)NR11aR11a'~
(CH2)qNRllaC(0)ORllb~ (CH2)qNRllaC(O)NHRlla~
(CH2)rC(O)ORllb, (CH2)qOC(O)Rllb, (CH2)qS(O)pRllb~
(CH2)qS(0)2NR11aR11a'. (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

CA 02413421 2002-12-19
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heteroatoms selected from N, O, and S, substituted
with 0-3 Rllc;
Rlla and Rlla', at each occurrence, are selected from H,
C1-6 alkyl, C3-g alkenyl, C3-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;
alternatively, Rlla and Rlla', along with the N to which
they are attached, are joined to form a 5-6
membered heterocyclic system containing 1-2
heteroatoms selected from NRllg, O, and S and
optionally fused with a benzene ring or a 6-
membered aromatic heterocycle;
Rllb~ at each occurrence, is selected from C1-6 alkyl,
C3_g alkenyl, C3_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, 0, and
S, substituted with 0-3 Rlle;
Rllc, at each occurrence, is selected from C1-6 alkyl,
C2-g alkenyl, C2_g alkynyl, (CH2)rC3-6 cYcloalkyl,
Cl, Br, I, F, (CF2)rCF3, N02, CN, (CH2)rNR11fR11f~
(CH2)rOH, (CH2)rOC1_4 alkyl, (CH2)rSC1-g alkyl,
(CH2)rC(O)OH, (CH2)rC(O)Rllb, (CH2)rC(O)NR11fR11f~
(CH2 ) rNRllfC (O) Rlla~ (CH2 ) rC (O) OC1-4 alkyl,
(CH2)rOC(O)Rllb~ (CH2)rC(=NRllf)NR11fR11f~
21

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(CH2)r~C(=NRllf)NR11fR11f~ (CH2)rS(0)pRllb~
(CH2)rS(0)2NR11fR11f~ (CH2)rNRllfS(0)2R11b~ and
(CH2)rphenyl substituted with 0-3 Rlle;
Rlld, at each occurrence, is selected from methyl, CF3,
C2-6 alkyl substituted with 0-3 Rlle, C3-6 alkenyl,
C3-6 alkynyl, and a C3-10 carbocyclic residue
substituted with 0-3 Rllc;
Rlle, 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)rOC1-5 alkyl, OH,
SH, (CH2)rSC1-5 alkyl, (CH2)rNR11fR11f~ and
(CH2)rphenyl;
Rllf~ at each occurrence, is selected from H, C1-6
alkyl, and C3-6 cycloalkyl;
Rllg is selected from H, C1_6 alkyl, C3-6 cycloalkyl,
(CH2)rphenyl, C(O)Rllf, C(O)ORllh, and S02R11h;
Rllh~ at each occurrence, is selected from C1-5 alkyl,
and C3-( 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-g alkenyl, C2-g alkynyl, C3-6 cycloalkyl, C1, F,
22

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Br, I, CN, N02, (CF2)rCF3. (CH2)rOC1-5 alkyl, OH,
SH, (CH2)rSC1-5 alkyl, (CH2)rNRgfR9f, and
(CH2)rphenyl;
alternatively, R11 and R12 join to form a C3-10
cycloalkyl, a 5-6-membered lactone or lactam, or a
4-6-membered saturated heterocycle containing 1-2
heteroatoms selected from O, S, and NRllg and
optionally fused with a benzene ring or a 6-
membered aromatic heterocycle;
R13, at each occurrence, is selected from C1-6 alkyl,
C2-g alkenyl, C2-g alkynyl, C3-6 cycloalkyl,
(CF2)wCF3. (CH2)NR13aR13a'. (CH2)qOH, (CH2)qORl3b~
(CH2)qSH, (CH2)qSRl3b, (CH2)wC(O)OH,
(CH2)'"~C(O)Rl3b, (CH2)wC(O)NR13aR13a'
(CH2)qNRl3dC(O)Rl3a~ (CH2)wC(O)ORl3b~
(CH2)qOC(O)Rl3b, (CH2)wS(O)pRl3b~
(CH2)wS(O)2NR13aR13a', (CH2)qNRl3ds(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;
23

CA 02413421 2002-12-19
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Rl3c~ at each occurrence, is selected from C1-6 alkyl,
C3-6 cycloalkyl, C1, F, Br, I, CN, N02, (CF2)rCF3,
(CH2)rOC1-5 alkyl, (CH2)rOH, (CH2)rSC1-5 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,
(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(O)(CHR~)rRl4b~
(CHR~)rC(O)O(CHR~)rRl4d, (CHR~)rOC(O)(CHR~)rRl4b~
(CHR~)rC(=NRl4f)NR14aR14a'~
(CHR~)rNHC(=NRl4f)NR14fR14f~
(CHR ~ ) rS (O) p (CHR ~ ) ~.Rl4b, (CHR ~ ) rS (0) 2NR14aR14a'
(CHR~)rNRl4fS(O)2(CHR~)rRl4b, C1-6 haloalkyl, C2-g
alkenyl substituted with 0-3 R~, C2-g 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
Rl4e~ or two R14 substituents on adjacent atoms on
ring A form to join a 5-6 membered heterocyclic
system containing 1-3 heteroatoms selected from N,
0, and S substituted with 0-2 Rl4e;
24

CA 02413421 2002-12-19
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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 Rl4e;
Rl4a and Rl4a~, at each occurrence, are selected from H,
C1-6 alkyl, C3-g alkenyl, C3-g alkynyl, a (CH2)r-
C3-10 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,
C3-g alkenyl, C3_g alkynyl, a (CH2)r-C3-6
carbocyclic residue substituted with 0-3 Rl4e, and
(CH2)r-5-6 membered heterocyclic system containing
1-4 heteroatoms selected from N, O, and S,
substituted with 0-2 Rl4e;
Rl4d~ at each occurrence, is selected from C3-g alkenyl,
C3-g alkynyl, methyl, CF3, C2-6 alkyl substituted
with 0-3 Rl4e, a (CH2)r-C3-10 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_6 alkyl,
C2-g alkenyl, C2_g alkynyl, (CH2)rC3-6 cYcloalkyl,
Cl, F, Br, T, CN, N02, (CF2)rCF3, (CH2)r0C1-5
alkyl, OH, SH, (CH2)rSC1-5 alkyl, (CH2)rNR14fR14f~
and (CH2)rphenyl;

CA 02413421 2002-12-19
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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;
Ra, at each occurrence, is selected from C1_6 alkyl,
CZ-g alkenyl, C2_g alkynyl, (CH2)rC3-6 cycloalkyl,
C1, Br, I, F, (CF2)rCF3, N02, 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, (CH2)rOC(0)Rc, (CH2)rCH(=NRb)NRbRb,
(CH2)rNHC(=NRb)NRbRb, (CH2)rS(O)pRc,
(CH2)rS(O)2NRbRb, (CH2)rNRbS(O)2Rc, and
(CH2)rphenyl;
Rb, at each occurrence, is selected from H, C1-6 alkyl,
C3_6 cycloalkyl, and phenyl;
Rc, at each occurrence, is selected from C1_6 alkyl, C3-
cycloalkyl, and phenyl;
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~)rRl5d~
(CHR~)rSH, (CHR~)rC(O)H, (CHR~)rS(CHR~)rRlSd~
(CHR~)rC(O)OH, (CHR~)rC(O)(CHR~)rRl5b~
26

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(CHR~)rC(0)NR15aR15a'~ (CHR~)rNRl5fC(O)(CHR~)rRl5b~
(CHR~)rNRl5fC(O)NR15fR15f~ (CHR')rC(O)O(CHR')z.Rl5d~
(CHR')rOC(O)(CHR~)rRl5b, (CH2)rOC(O)NR15aR15a'~
(CH2)rNRl5aC(O)ORl5b~ (CHR~)rC(=NRl5f)NR15aR15a',
(CHR~)rNHC(=NRl5f)NR15fR15f~
(CHR~)rS(0)p(CHR~)rRl5b, (CHR~)rS(O)2NR15aR15a'~
(CHR~)rNRlSfS(O)2(CHR~)rRlSb, C1-6 haloalkyl, C2-g
alkenyl substituted with 0-3 R~, C2-g alkynyl
substituted with 0-3 R~, (CHR~)rphenyl substituted
with 0-3 Rl5e, and a (CH2)r-5-10 membered
heterocyclic system containing 1-4 heteroatoms
selected from N, O, and S, substituted with 0-2
Rl5e
Rl5a and Rl5a', at each occurrence, are selected from H,
C1-6 alkyl, C3-g alkenyl, C3-g alkynyl, a (CH2)r-
C3-10 carbocyclic residue substituted with 0-5
Rl5e~ and a (CH2)r-5-10 membered heterocyclic
system containing 1-4 heteroatoms selected from N,
0, and S, substituted with 0-2 Rl5e;
alternatively, Rl5a and Rl5a'~ along with the N to which
they are attached, are joined to form a 5-6
membered heterocyclic system containing 1-2
heteroatoms selected from NRlSg, O, and S and
optionally fused with a benzene ring or a 6-
membered aromatic heterocycle;
Rl5b~ at each occurrence, is selected from C1-6 alkyl,
C3-g alkenyl, C3-g alkynyl, a (CH2)r-C3-6
27

CA 02413421 2002-12-19
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carbocyclic residue substituted with 0-3 Rl5e, and
(CH2)r-5-6 membered heterocyclic system containing
1-4 heteroatoms selected from N, 0, and S,
substituted with 0-2 RlSe;
RlSd, at each occurrence, is selected from C3-g alkenyl,
C3-g alkynyl, methyl, CF3, C2-6 alkyl substituted
with 0-3 RlSe, a (CH2)r-C3-10 carbocyclic residue
substituted with 0-3 RlSe, and a (CH2)r5-6 membered
heterocyclic system containing 1-4 heteroatoms
selected from N, 0, and S, substituted with 0-3
Rl5e;
Rl5e~ at each occurrence, is selected from C1_6 alkyl,
C2-g alkenyl, C2_g alkynyl, (CH2)rC3-6 cYcloalkyl,
C1, F, Br, I, CN, N02, (CF2)rCF3, (CH2)rOC1-5
alkyl, OH, SH, (CH2)rSC1-5 alkyl, (CH2)rNR15fR15f~
and (CH2)rphenyl;
RlSf, at each occurrence, is selected from H, C1-6
alkyl, C3-6 cycloalkyl, and phenyl;
RlSg is selected from H, C1-6 alkyl, C3-6 cycloalkyl,
(CH2)rphenyl, C(O)RlSf~ C(O)ORl5h, and S02R15h~
Rl5h~ at each occurrence, is selected from C1-5 alkyl,
and C3-6 cycloalkyl;
R16, at each occurrence, is selected from C1-g alkyl,
C2-g alkenyl, C2-g alkynyl, (CH2)rC3-6 cYcloalkyl,
C1, Br, I, F, N02, CN, (CHR~)rNR16aR16a'~
28

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(CHR~)rOH, (CHR~)r0(CHR~)rRl6d, (CHR~)rSH,
(CHR~)rC(0)H, (CHR~)rS(CHR~)rRl6d, (CHR~)rC(0)OH,
(CHR~)rC(O)(CHR~)rRl6b, (CHR~)rC(O)NR16aR16a'~
(CHR~ ) rNRl6fC (O) (CHR~ ) z.Rl6b~
(CHR~)rC(0)0(CHR~)rRl6d, (CHR~)rOC(0)(CHR~)rRl6b~
(CHR')rC(=NRl6f)NR16aR16a'~
(CHR')rNHC(=NRl6f)NR16fR16f~
(CHR~)rS(O)p(CHR~)rRl6b, (CHR~)rS(O)2NR16aR16a'~
(CHR~)rNRl6fS(0)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, C3-g alkenyl, C3-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 R.l6e
Rl6b, at each occurrence, is selected from C1-6 alkyl,
C3-g alkenyl, C3-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, 0, and
S, substituted with 0-2 Rl6e
Rl6d~ at each occurrence, is selected from C3-g alkenyl,
C3_g alkynyl, methyl, CF3, C2-6 alkyl substituted
29

CA 02413421 2002-12-19
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with 0-3 Rl6e, a (CH2)r-C3-10 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-~ alkyl,
C2-g alkenyl, C2-g alkynyl, (CH2)rC3-6 CYcloalkyl,
C1, F, Br, I, CN, N02, (CF2)rCF3. (CH2)rOC1-5
alkyl, OH, SH, (CH2)rSC1-5 alkyl, (CH2)rNR16fR16f~
and (CH2)rphenyl;
Rl6f~ at each occurrence, is selected from H, C1-5
alkyl, and C3-6 cycloalkyl, and phenyl;
g is selected from 0, 1, 2, 3, and 4;
t is selected from 1 and 2;
w is selected from 0 and 1;
r is selected from 0, 1, 2, 3, 4, and 5;
q is selected from 1, 2, 3, 4, and 5;
p is selected from 0, 1, and 2;
the compounds of Formula (I) do not include the
compounds disclosed in U.S. Patent Application No.
09/466,442 filed December 17, 1999.
[2] In another embodiment, the present invention
provides novel compounds of formula (I):

CA 02413421 2002-12-19
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Z is selected from 0, S, NCN, NCONH2, CHN02, and C(CN)2;
E is selected from:
7 R8 11 12
7 8 7 8
A A
(R 14)9 Rg R10 (R 14)9 Rg R10 (R 14)9
11 12 Rg 10 7 R8 9 10
A \ A - R11 R12 A ~ R~11 R12
(R 14)9 ' (R 14)9 ' (R 14)9 ~ and
8 11 R12
A
(R 14)9
R4 is absent, taken with the nitrogen to which it is
attached to form an N-oxide, or selected from C1-g
alkyl, (CH2)rC3-6 cYcloalkyl, and (CH~)r-phenyl
substituted with 0-3 R4c;
R4c, at each occurrence, is selected from C1-6 alkyl,
C3-g alkenyl, C3-g alkynyl, C3-6 cycloalkyl, Cl, F,
Br, I, CN, N02, (CF2)rCF3. (CH2)rOC1_5 alkyl,
(CH~)rOH, (CH2)rSC1-5 alkyl, (CH2)rNR4aR4a', and
(CH2)rphenyl;
alternatively, R4 joins with R~ or R9 or R14 to form a
5, 6 or 7 membered piperidinium spirocycle
substituted with 0-3 Ra;
31

CA 02413421 2002-12-19
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R1 and R2 are independently selected from H and C1-4
alkyl;
R6, at each occurrence, is selected from C1-g alkyl,
C2-g alkenyl, C2-g alkynyl, (CH2)rC3-6 cycloalkyl,
(CF2)rCF3, CN, (CH2)rOH, (CH2)rOR6b, (CH2)rC(O)R6b~
(CH2 ) 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,
C3-6 cycloalkyl, C1, F, Br, I, CN, N02, (CF~)rCF3,
(CH2)rOC1-5 alkyl, (CH2)rOH, (CH2)rSC1-5 alkyl, and
(CH2)rNR6dR6d~
R6d, at each occurrence, is selected from H, C1-6 alkyl,
and C3-6 cycloalkyl;
R~, is selected from H, C1-3 alkyl, (CH2)rC3-6
cycloalkyl, (CH2)qOH, (CH2)qOR~d, (CH2)qNR~aR~a~,
(CH2)rC(O)R7b~ (CH2)rC(O)NR~aR7a',
(CH2)qNR~aC(O)R~a, (CH2)qOC(O)NR~aR7a',
32

CA 02413421 2002-12-19
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(CH2)qNR~aC(O)OR~b, C1-6 haloalkyl, (CH3)rphenyl
with 0-2 Roc;
Rya and R~a~, at each occurrence, are selected from H,
C1-6 alkyl, (CH~)rC3-6 cycloalkyl, a (CH2)rphenyl
substituted with 0-3 Rye;
Rib, at each occurrence, is selected from C1_6 alkyl,
C3-g alkenyl, C3-g alkynyl, (CH2)rC3-6 CYcloalkyl,
(CH3)rphenyl substituted with 0-3 Rye;
Roc, at each occurrence, is selected from C1_4 alkyl,
C2-g alkenyl, C~-g alkynyl, (CH2)rC3-6 cYcloalkyl,
Cl, Br, I, F, (CF2)rCF3, N03, CN, (CH2)rNR~fR7f~
(CH2)xOH, (CH2)rOC1-g alkyl, (CH2)rC(O)R7b~
(CH2)rC(0)NR~fR7f~ (CH2)rNR7fC(O)R7a~
(CH2)rs(O)pR~b. (CH2)rS(O)2NR~fR7f~
(CH3)rNR~fS(O)2R~b, and (CH2)rphenyl substituted
with 0-2 Rye;
Rid, at each occurrence, is selected from C1-6 alkyl,
(CH~)rC3-6 cycloalkyl, (CH2)rphenyl substituted
with 0-3 Rye;
Rye, at each occurrence, is selected from C1-6 alkyl,
C2-g alkenyl, C2-g alkynyl, C3-6 cycloalkyl, Cl, F,
Br, I, CN, N02, (CF3)rCF3, (CH3)rOC1-5 alkyl, OH,
SH, (CH2)rSC1-5 alkyl, (CH2)rNR~fR7f~ and
(CH2)rphenyl;
33

CA 02413421 2002-12-19
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Ref, at each occurrence, is selected from H, C1-5 alkyl,
and C3-6 cycloalkyl;
R8 is H or joins with R~ to form C3_~ cycloalkyl, =O, or
=NRgb;
R11, is selected from H, C1_6 alkyl, (CH2)rC3-6
cycloalkyl, (CH2)qOH, (CH2)qORlld~
(CH2)qNR11aR11a'~ (CH2)rC(O)Rllb~
(CH2)rC(O)NR11aR11a'~ (CH2)qNRllaC(O)Rlla~
(CH2)qOC(O)NR11aR11a'~ (CH2)qNRllaC(O)ORlla, C1-6
haloalkyl, (CH2)rphenyl 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;
Rlla and Rlla', at each occurrence, are selected from H,
C1-6 alkyl, (CH2)rC3-6 cYcloalkyl, a (CH2)rphenyl
substituted with 0-3 Rlle;
alternatively, Rlla and Rlla', along with the N to which
they are attached, are joined to form a 5-6
membered heterocyclic system containing 1-2
heteroatoms selected from NRllg, O, and S and
optionally fused with a benzene ring or a 6-
membered aromatic heterocycle;
Rllb~ at each occurrence, is selected from C1-6 alkyl,
C2-g alkenyl, C2-g alkynyl, (CH2)rC3-6 CYcloalkyl,
(CH2)rphenyl substituted with 0-3 Rlle;
34

CA 02413421 2002-12-19
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R11C, at each occurrence, is selected from C1-4 alkyl,
C2_g alkenyl, C2_g alkynyl, (CH2)rC3-6 CYCloalkyl,
C1, Br, I, F, (CF2)rCF3, N02, CN, (CH2)rNR11fR11f~
(CH2)rOH, (CH2)rOC1-4 alkyl, (CH2)rC(O)Rllb~
(CH2)rC(O)NR11fR11f~ (CH2)rNRllfC(O)Rlla~
(CH2)rS(O)pRllb~ (CH2)rS(O)2NR11fR11f~
(CH2)rNRllfS(O)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-g alkenyl, C2-g alkynyl, C3-6 cycloalkyl, Cl, F,
Br, I, CN, N02, (CF2)rCF3, (CH2)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;
Rllg is selected from H, C1_6 alkyl, C3_6 cycloalkyl,
(CH2)rphenyl, C(O)Rllf, C(O)ORllf, and S02R11f;
R12 is H;
alternatively, R11 and R12 join to form a C3-10
cycloalkyl, a 5-6-membered lactone or lactam, or a
4-6-membered saturated heterocycle containing 1-2

CA 02413421 2002-12-19
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heteroatoms selected from O, S, and NRllg and
optionally fused with a benzene ring or a 6-
membered aromatic heterocycle;
R13, at each occurrence, is selected from C1-g alkyl,
C3-6 cycloalkyl, (CH2)NR13aR13a'~ (CH2)pH,
(CH2)ORl3b~ (CH2)wC(O)Rl3b~ (CH2)wC(O)NR13aR13a'~
(CH2)NRl3dC(O)Rl3a~ (CH2)wS(O)2NR13aR13a'~
(CH2)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_6 cycloalkyl, C1, F, Br, I, CN, N02, (CF2)rCF3.
(CH2)rOC1-5 alkyl, (CH2)rOH, and (CH2)rNR13dR13d;
Rl3d~ at each occurrence, is selected from H, C1-6
alkyl, and C3-6 cycloalkyl;
q is selected from 1, 2, and 3; and
r is selected from 0, 1, 2, and 3.
[3] In another embodiment, the present invention
provides novel compounds of formula (I):
36

CA 02413421 2002-12-19
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ring A is selected from:
~''i ~ ~ .~r''J ~i
14
~R14)9 (R14)9 ~ (R ~9 (R14)9
'R14 \~ ~ R14
and
R5 is selected from (CRS~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, indolinyl, isoindolyl,
isothiadiazolyl, isoxazolyl, piperidinyl,
pyrrazolyl, 1,2,4-triazolyl, 1,2,3-triazolyl,
tetrazolyl, thiadiazolyl, thiazolyl, oxazolyl,
pyrazinyl, and pyrimidinyl.
[4] In another embodiment, the present invention
provides novel compounds of formula (I-i):
O
I~~ -E-N~-R3
L~ H H
(I-i)
R16, at each occurrence, is selected from C1-g alkyl,
(CH2)rC3-6 cycloalkyl, CF3, Cl, Br, I, F,
(CH2)rNR16aR16a'~ Np2, CN, OH, (CH2)rORl6d~
(CH2)rC(O)Rl6b, (CH2)rC(O)NR16aR16a'~
37

CA 02413421 2002-12-19
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(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 (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 R.l6e;
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)rOC1-5 alkyl; and
R.l6f, at each occurrence, is selected from H, and C1-5
alkyl.
[5] In another embodiment, the present invention
provides novel compounds of formula (I-ii):
O
-E-N~-R3
H H
(I-ii)
R16, at each occurrence, is selected from C1-g alkyl,
(CH2)rC3-6 CYcloalkyl, CF3, Cl, Br, I, F,
38

CA 02413421 2002-12-19
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(CH2)rNR16aR16a', Np2, CN, OH, (CH2)rORl6d,
(CH2)rC(O)Rl6b, (CH2)rC(O)NR16aR16a',
(CH2)rNRl6fC(0)Rl6b~ (CH2)rS(0)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 (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 C1-0 alkyl,
Cl, F, Br, I, CN, N02, (CF2)rCF3, OH, and
(CH2)rOC1-5 alkyl; and
Rl6f, at each occurrence, is selected from H, and C1-5
alkyl.
[6] In another embodiment, the present invention
provides novel compounds of formula (I-i):
R5 is CH2phenyl substituted with 0-3 R16;
Rg, is selected from H, C1-6 alkyl, (CH2)rC3-6
cycloalkyl, F, C1, CN, (CH2)rOH, (CH2)rOR9d,
39

CA 02413421 2002-12-19
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(CH2)rNR9aR9a', (CH2)rOC(O)NHR9a, (CH2)rphenyl
substituted with 0-5 R9e, and (CH2)r-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, (CF2)rCF3, OH, and
(CH2)rOC1-5 alkyl;
R10 is selected from H, C1-5 alkyl, OH, and CH20H;
RlOg is selected from H, C1-6 alkyl, C3-6 cycloalkyl,
(CH2)rphenyl, C(O)RlOf, C(O)ORlOf, and S02R10f;
alternatively, R9 and R10 join to form =O, a C3-10
cycloalkyl, a 5-6-membered lactone or lactam, or a
4-6-membered saturated heterocycle containing 1-2
heteroatoms selected from O, S, and NRlOg and
optionally fused with a benzene ring or a 6-
membered aromatic heterocycle;
with the proviso that when either of R9 or R1~ is
halogen, cyano, vitro, or bonded to the carbon to
which it is attached through a heteroatom, the

CA 02413421 2002-12-19
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other of R9 or R1~ is not 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,
Cl, F, Br, I, CN, N02, (CF2)rCF3, OH, and
(CH2)rOC1-5 alkyl;
Rllg is selected from H, C1-6 alkyl, C3-6 cycloalkyl,
(CH2)rphenyl, C(O)Rllf, C(O)ORllf, and S02R11f;
R12 is H;
alternatively, R11 and R12 join to form a C3-10
cycloalkyl, a 5-6-membered lactone or lactam, or a
4-6-membered saturated heterocycle containing 1-2
heteroatoms selected from O, S, and NRllg and
optionally fused with a benzene ring or a 6-
membered aromatic heterocycle;
R14, at each occurrence, is selected from C1-g alkyl,
(CH2)rC3-6 cycloalkyl, CF3, C1, Br, I, F,
41

CA 02413421 2002-12-19
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(CH2)rNR14aR14a'~ N02, CN, OH, (CH2)rORl4d~
(CH2)rC(O)Rl4b, (CH2)rC(O)NR14aR14a'~
(CH2)rNR.l4fC(p)Rl4b~ (CH2)rS(O)pRl4b~
(CH2)rS(O)2NR14aR14a', (CH2)rNRl4fS(p)2R14b~
(CH2)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; or two R14 substituents
on adjacent atoms on ring A form to join a 5-6
membered heterocyclic system containing 1-3
heteroatoms selected from N, 0, and S substituted
with 0-2 RlSe;
Rl4a and Rl4a', at each occurrence, are selected from H,
C1-~ alkyl, C3-6 cycloalkyl, and (CH2)rphenyl
substituted with 0-3 Rl4e, and a (CH2)r-5-6
membered heterocyclic system containing 1-4
heteroatoms selected from N, 0, and S, substituted
with 0-2 Rl5e;
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-( alkyl
and phenyl;
Rl4e, at each occurrence, is selected from C1-6 alkyl,
Cl, F, Br, I, CN, N02, (CF2)rCF3, OH, and
(CH2)rOC1-5 alkyl; and
42

CA 02413421 2002-12-19
WO 01/98270 PCT/USO1/19752
Rl4f~ at each occurrence, is selected from H, and C1-5
alkyl;
and
r is selected from 0, 1, and 2.
[7] In another embodiment, the present invention
provides novel compounds of formula (I-ii):
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', (CH2)rOC(0)NHR9a, (CH2)rphenyl
substituted with 0-5 R9e, and (CH2)r-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,
Cl, F, Br, I, CN, N02, (CF2)rCF3, OH, and
(CH2)rOC1-5 alkyl;
R10 is selected from H, C1-g alkyl, OH, and CH20H;
43

CA 02413421 2002-12-19
WO 01/98270 PCT/USO1/19752
RlOg is selected from H, C1-6 alkyl, C3-6 cycloalkyl,
(CH2)rphenyl, C(O)RlOf~ C(0)ORlOf~ and S02R10f;
alternatively, R9 and R10 join to form =O, a C3-10
cycloalkyl, a 5-6-membered lactone or lactam, or a
4-6-membered saturated heterocycle containing 1-2
heteroatoms selected from 0, S, and NRlOg and
optionally fused with a benzene ring or a 6-
membered aromatic heterocycle;
with the proviso that when either of R9 or R1~ is
halogen, cyano, nitro, or bonded to the carbon to
which it is attached through a heteroatom, the
other of R9 or R1~ is not 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)rOC1-
5 alkyl;
44

CA 02413421 2002-12-19
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Rllg is selected from H, C1-6 alkyl, C3_6 cycloalkyl,
(CH2)rphenyl, C(O)Rllf, C(O)ORllf, and S02R11f;
R12 is H;
alternatively, R11 and R12 join to form a C3-10
cycloalkyl, a 5-6-membered lactone or lactam, or a
4-6-membered saturated heterocycle containing 1-2
heteroatoms selected from O, S, and NRllg and
optionally fused with a benzene ring or a 6-
membered aromatic heterocycle;
R14, at each occurrence, is selected from C1-g alkyl,
(CH2)rC3-6 CYcloalkyl, CF3, Cl, Br, I, F,
(CH2)rNR14aR14a'~ N02, CN, OH, (CH2)rORl4d,
(CH2)rC(O)Rl4b~ (CH2)rC(O)NR14aR24a'~
(CH2)rNRl4fC(0)Rl4b~ (CH2)rS(O)pRl4b~
(CH2)rS(O)2NR14aR14a', (CH2)rNRl4fs(0)2R14b~
(CH2)rphenyl substituted 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 Rl5e; or two R14 substituents
on adjacent atoms on ring A form to join a 5-6
membered heterocyclic system containing 1-3
heteroatoms selected from N, O, and S substituted
with 0-2 Rl5e
Rl4a and R1'~a~, at each occurrence, are selected from H,
C1_6 alkyl, C3-6 cycloalkyl, and (CH2)rphenyl
substituted with 0-3 Rl4e;

CA 02413421 2002-12-19
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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;
Rl4e, at each occurrence, is selected from C1_6 alkyl,
C1, F, Br, I, CN, N02 , (CF2 ) rCF3 , OH, and
(CH2)rOCl~5 alkyl;
Rl4f~ at each occurrence, is selected from H, and C1-5
alkyl;
and
r is selected from 0, 1, and 2.
[8] In another embodiment, the present invention
provides novel compounds of formula (I-i):
J is selected from CH2 and CHRS;
K is selected from CH2 and CHRS;
L is selected from CH2 and CHRS;
R3 is selected from a C1-10 alkyl substituted with 0-3
R3g. C3-10 alkenyl substituted with 0-3 R3g, and
C3_10 alkynyl substituted with 0-3 R3g;
R3g, at each occurrence, is selected from Cl, Br, T, F,
N02, CN, NR3aR3a', OH, O(CHR')rR3d, SH, C(O)H,
46

CA 02413421 2002-12-19
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S (CHR~ ) rR3d, C (O) OH, C (O) (CHR~ ) rR3b, C (O)NR3aR3a'
NR3fC (O) (CHR~ ) rR3b, C (0) O (CHR~ ) rR3d,
OC(O)(CHR~)rR3b, (CH2)rOC(O)NR3aR3a'~
(CH2 ) qNR3aC (0) OR3a, S (0) p (CHR~ ) rR3b, S (0) 2NR3aR3a' .
NR3fS(O)2(CHR~)rR3b, phenyl substituted with 0-3
R15, and a heterocyclic system substituted with 0-3
R15, wherein the heterocyclic system is selected
from pyridinyl, thiophenyl, furanyl, indazolyl,
benzothiazolyl, benzimidazolyl, benzothiophenyl,
benzofuranyl, benzoxazolyl, benzisoxazolyl,
quinolinyl, isoquinolinyl, imidazolyl, indolyl,
indolinyl, isoindolyl, isothiadiazolyl, isoxazolyl,
piperidinyl, pyrrazolyl, 1,2,4-triazolyl, 1,2,3-
triazolyl, tetrazolyl, thiadiazolyl, thiazolyl,
oxazolyl, pyrazinyl, and pyrimidinyl, provided that
when R3g is a carbocyclic residue or a heterocyclic
system, R3 has at least one other R3g, which is not
a carbocyclic residue or a heterocyclic system;
R3a and R3a~, at each occurrence, are selected from H,
C1-6 alkyl, C3_g alkenyl, C3-g alkynyl, and (CH2)r-
phenyl substituted with 0-3 R3e;
R3b, at each occurrence, is selected from C1-6 alkyl,
and (CH2)r-phenyl substituted with 0-3 R3e;
R3d, at each occurrence, is selected from C1-6 alkyl and
phenyl substituted with 0-3 R3e;
R3e, at each occurrence, is selected from C1-6 alkyl,
Cl, F, Br, I, CN, N02, (CF2)rCF3, (CH2)rOC1-5
alkyl, OH;
47

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R3f, at each occurrence, is selected from H, C1-5 alkyl;
R15, at each occurrence, is selected from C1-g alkyl,
(CH2)rC3-6 cycloalkyl, CF3, C1, Br, I, F,
(CH2)rNR15aR15a'~ N02, CN, OH, (CH2)rORl5d~
(CH2)rC(O)Rl5b, (CH2)rC(O)NR15aR15a'.
(CH2)rNRl5fC(O)Rl5b~ (CH2)rOC(O)NR15aR25a',
(CH2)qNRl5aC(O)ORl5a~ (CH2)rS(O)pRl5b~
(CH2)rS(O)2NR15aR15a', (CH2)rNRl5fS(p)2R15b~
(CH2)rphenyl substituted with 0-3 R.l5e, 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;
Rl5a and Rl5a', at each occurrence, are selected from H,
C1-6 alkyl, C3_6 cycloalkyl, and (CH2)rphenyl
substituted with 0-3 Rl5e;
alternatively, Rl5a and Rl5a', along with the N to which
they are attached, are joined to form a morpholine,
piperidine, or piperazine ring, and the piperazine
optionally substituted with RlSg;
48

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g,l5b~ at each occurrence, is selected from H, C1-6
alkyl, C3-6 cycloalkyl, and (CH2)rphenyl
substituted with 0-3 Rl5e;
RlSd, at each occurrence, is selected from C1-6 alkyl
and phenyl;
Rl5e~ at each occurrence, is selected from C1-6 alkyl,
Cl, F, Br, I, CN, N02, (CF2)rCF3, OH, and
(CH2)rOC1-5 alkyl; and
Rl5f~ at each occurrence, is selected from H, and C1_5
alkyl.
[9] In another embodiment, the present invention
provides novel compounds of formula (I-ii):
K is selected from CH2 and CHRS;
L is selected from CH2 and CHRS;
R3 is selected from a C1-10 alkyl substituted with 0-3
R3g. C3-10 alkenyl substituted with 0-3 R3g, and
C3-10 alkynyl substituted with 0-3 R3g;
R3g, at each occurrence, is selected from Cl, Br, I, F,
N02, CN, NR3aR3a'~ OH, O(CHR')rR3d, SH, C(0)H,
S (CHR ~ ) rR3d, C (O) OH, C (O) (CHR' ) rR3b, C (O) NR3aR3a'
NR3fC(O)(CHR')rR3b, C(O)O(CHR')rR3d,
OC(O)(CHR')rR3b, (CH2)rOC(0)NR3aR3a'~
(CH2)qNR3aC(O)OR3a, S(O)p(CHR')rR3b, S(0)2NR3aR3a',
49

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NR3fS(O)2(CHR~)rR3b, phenyl substituted with 0-3
R15, and a heterocyclic system substituted with 0-3
R15, wherein the heterocyclic system is selected
from pyridinyl, thiophenyl, furanyl, indazolyl,
benzothiazolyl, benzimidazolyl, benzothiophenyl,
benzofuranyl, benzoxazolyl, benzisoxazolyl,
quinolinyl, isoquinolinyl, imidazolyl, indolyl,
indolinyl, isoindolyl, isothiadiazolyl, isoxazolyl,
piperidinyl, pyrrazolyl, 1,2,4-triazolyl, 1,2,3-
triazolyl, tetrazolyl, thiadiazolyl, thiazolyl,
oxazolyl, pyrazinyl, and pyrimidinyl, provided that
when R3g is a carbocyclic residue or a heterocyclic
system, R3 has at least one other R3g, which is not
phenyl or a heterocyclic system;
R3a and R3a~, at each occurrence, are selected from H,
C1-6 alkyl, C3-g alkenyl, C3-g alkynyl, and (CH2)r-
phenyl substituted with 0-3 R3e;
R3b, at each occurrence, is selected from C1-6 alkyl,
and (CH2)r-phenyl substituted with 0-3 R3e;
R3d, at each occurrence, is selected from C1-6 alkyl and
phenyl substituted with 0-3 R3e;
R3e, at each occurrence, is selected from C1-6 alkyl,
Cl, F, Br, I, CN, N02, (CF2)rCF3, (CH2)rOC1-5
alkyl, OH;
R3f, at each occurrence, is selected from H, C1-5 alkyl;

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R15, at each occurrence, is selected from C1-g alkyl,
(CH2)rC3-6 cycloalkyl, CF3, C1, Br, I, F,
(CH2)rNR15aR15a'~ N02~ CN, OH, (CH2)rORlSd~
(CH2)rC(O)Rl5b, (CH2)rC(O)NR15aR15a'~
(CH2)rNRl5fC(0)Rl5b~ (CH2)rOC(O)NR15aR15a'~
(CH2)qNRl5aC(O)ORl5a~ (CH2)rS(O)pRl5b~
(CH2)rs(O)2NR15aR15a', (CH2)rNRl5fs(O)2R15b~
(CH2)rphenyl substituted with 0-3 Rl5e, 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;
Rl5a and Rl5a', at each occurrence, are selected from H,
C1-6 alkyl, C3-6 cycloalkyl, and (CH2)rphenyl
substituted with 0-3 Rl5e;
alternatively, RlSa and Rl5a', along with the N to which
they are attached, are joined to form a morpholine,
piperidine, or piperazine ring, and the piperazine
optionally substituted with R~-5g;
Rl5b~ at each occurrence, is selected from H, C1-6
alkyl, C3-6 cycloalkyl, and (CH2)rphenyl
substituted with 0-3 Rl5e;
51

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R25d~ at each occurrence, is selected from C1_6 alkyl
and phenyl;
Rl5e~ at each occurrence, is selected from C1-6 alkyl,
C1, F, Br, I, CN, N02, (CF2)rCF3, OH, and
(CH2)rOC1-5 alkyl; and
Rl5f~ at each occurrence, is selected from H, and C1-5
alkyl.
[10] In another embodiment, the present invention
provides novel compounds of formula (I-i):
E is ;
Z is selected from O and N(CN);
R3 is selected from C3_8 alkyl wherein the C3_8 alkyl is
selected from methyl, ethyl, propyl, i-propyl,
butyl, i-butyl, t-butyl, pentyl, methylpentyl,
dimethylpentyl, and trimethylpentyl, and wherein
the C3_g alkyl is substituted with 0-2 R3g;
R3g, at each occurrence is selected from C (O) OR3b, OR.3b
OH, OC (O) H, NHC (O) R3b, CN, NR3aR3a~ , and phenyl;
R3a and R3a', at each occurrence, are selected from H and
methyl;
R3b, at each occurrence, is selected from H, methyl,
ethyl, propyl, and phenyl; and
52

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R~-6 is selected from F, Cl, Br, and I.
[11] In another embodiment, the present
invention provides novel compounds of formula (I-ii):
E is ;
Z is selected from O and N(CN);
R3 is selected from C3_8 alkyl wherein the C3_8 alkyl is
selected from methyl, ethyl, propyl, i-propyl,
butyl, i-butyl, t-butyl, pentyl, methylpentyl,
dimethylpentyl, and trimethylpentyl, and wherein
the C3_~ alkyl is substituted with 0-2 R3g;
R3g, at each occurrence is selected from C(O)OR3b, OR3b,
OH, OC (O) H, NHC (O) R3b, CN, NR3aR3a~ , and phenyl;
R3a and R3a~, at each occurrence, are selected from H and
methyl;
R3b, at each occurrence, is selected from H, methyl,
ethyl, propyl, and phenyl; and
R16 is selected from F, C1, Br, and I.
[12] Tn another embodiment, the present invention
provides novel compounds of formula (I), wherein the
compound of formula (I) is selected from:
53

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N-(t-butyl)-N'-[(1R,2S)-2-[[(3S)-3-(4-
fluorophenyl)methyl)piperidinyl]methyl]cyclohexy
1]-urea,
N-(i-propyl)-N'-[(1R,2S)-2-[[(3S)-3-(4-
fluorophenyl)methyl)piperidinyl]methyl]cyclohexy
1 ] -urea,
N-(ethoxycarbonylmethyl)-N'-[(2R,2S)-2-[[(3S)-3-(4-
fluorophenyl)methyl)piperidinyl]methyl]cyclohexy
1]-urea,
N-[(1R,S)-1-(methoxycarbonyl)-2-methyl-propyl]-N'-
[ (~.R, 2S) -2- [ [ (3S) -3- (4-
fluorophenyl)methyl)piperidinyl]methyl]cyclohexy
l ] -urea,
N-[(1S)-1-(methoxycarbonyl)-2-phenylethyl]-N'-
[(1R,2S)-2-[[(3S)-3-(4-
fluorophenyl)methyl)piperidinyl]methyl]cyclohexy
1]-urea,
N-[2,4,4-trimethyl-2-pentyl]-N'-[(1R,2S)-2-[[(3S)-3-
(4-
fluorophenyl)methyl)piperidinyl]methyl]cyclohexy
1]-urea,
N-[(1S)-2-hydroxy-1-phenylethyl]-N'-[(1R,2S)-2-[[(3S)-3-
(4-
fluorophenyl)methyl)piperidinyl]methyl]cyclohexyl]-
urea,
2- ( { [ (1R, 2S) -2-{ [ (3S) -3- (4-
fluorobenyl)piperidinyl]methyl}cyclohexyl)amino}car
bonyl}amino)acetamide,
54

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N-(2-methoxyethyl)-N'-(1R,2S)-2-[[(3S)-3-(4-
fluorophenyl)methyl)piperidinyl]methyl]cyclohexyl]-
urea,
N-(2-ethoxyethyl)-N'-(1R,2S)-2-[[(3S)-3-(4-
fluorophenyl)methyl)piperidinyl]methyl]cyclohexyl]-
urea,
N"-cyano-N-(ethoxycarbonylmethyl)-N'-(1R,2S)-2-[[(3S)-3-
(4-
fluorophenyl)methyl)piperidinyl]methyl]cyclohexyl]-
guanidine,
2-{[((1R,2S)-2-{[(3S)-3-(4-
fluorobenzyl)piperidinyl]methyl}cyclohexyl)amino][(
2-methoxyethyl)amino]methylene}malonitrile,
N"-cyano-N-(2-phenoxyethyl)-N'-(1R,2S)-2-[[(3S)-3-(4-
fluorophenyl)methyl)piperidinyl]methyl]cyclohexyl]-
guanidine,
N"-cyano-N-(2-methoxyethyl)-N'-(1R,2S)-2-[[(3S)-3-(4-
fluorophenyl)methyl)piperidinyl]methyl]cyclohexyl]-
guanidine,
N-(2-dimethylaminoethyl)-N'-{(1R,2R)-2-[(3S)-3-(4-
fluorobenzyl)piperidine-1-carbonyl]cyclohexyl}-
urea, and
N"-cyano-N-(2-ethoxyethyl)-N'-(1R,2S)-2-[[(3S)-3-(4-
fluorophenyl)methyl)piperidinyl]methyl]cyclohexyl]-
guanidine.

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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 the
compounds of the present invention.
In a fifth 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.
In a fifth 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.
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.
56

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In a preferred embodiment, the present invention
provides a method for modulation of chemokine receptor
activity comprising contacting a CCR3 receptor with an
effective inhibitory 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.
In a preferred embodiment, the present invention
provides a method for treating or preventing disorders
selected from asthma, allergic rhinitis, atopic
dermatitis, and inflammatory bowel diseases.
In a more preferred embodiment, the present
invention provides a method for treating or preventing
disorders wherein the disorder is asthma.
57

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In a more preferred embodiment, the present
invention provides a method for treating or preventing
disorders wherein the disorder is allergic rhinitis.
In a more preferred embodiment, the present
invention provides a method for treating or preventing
disorders wherein the disorder is atopic dermatitis.
In a more preferred embodiment, the present
invention provides a method for treating or preventing
disorders wherein the disorder is inflammatory bowel
diseases.
In another embodiment, K is selected from CHR5 or
CR6R5.
In another embodiment, L is selected from CHRS or
2 0 CR6R5
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 racemic 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 trans geometric isomers of the
compounds of the present invention are described and may
58

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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 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
59

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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 C1, C2, C3, Cg, C5, C6, C7, 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_g 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 C7 cycloalkyl. C3-6
cycloalkyl, is intended to include C3, Cg, 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 -CVFW 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 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

CA 02413421 2002-12-19
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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, 0 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
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at any heteroatom or carbon atom which results in a
stable structure. The heterocyclic rings 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, ~i-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,
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phenothiazinyl, phenoxathiinyl, phenoxazinyl,
phthalazinyl, piperazinyl, piperidinyl, pteridinyl,
piperidonyl, 4-piperidonyl, pteridinyl, purinyl,
pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl,
pyrazolyl, pyridazinyl, pyridooxazole, pyridoimidazole,
pyridothiazole, pyridinyl, pyridyl, pyrimidinyl,
pyrrolsdinyl, 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, benzothiazolyl,
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.
63

CA 02413421 2002-12-19
WO 01/98270 PCT/USO1/19752
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 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, hydrobromic, 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,
64

CA 02413421 2002-12-19
WO 01/98270 PCT/USO1/19752
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, 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

CA 02413421 2002-12-19
WO 01/98270 PCT/USO1/19752
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 Grou~as In Organic Synthesis, Wiley
and Sons, 1991).
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 = Cl, 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
66

CA 02413421 2002-12-19
WO 01/98270 PCT/USO1/19752
performed at room temperature to the reflux temperature
of the solvent. The protecting group is subsequently
removed to yield amine 4. 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 HCl 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 1982, 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
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.
67

CA 02413421 2002-12-19
WO 01/98270 PCT/USO1/19752
SCHEME 1
NCH E~~- P
/E-N-P
X 2
R5 n )
1 P=protecting group 5 'n
R 3
X=leaving group: Cl,Br,I,
n=0, 1 OTs, OMs, OTf, etc
E=linker
E---NH
E-NH- ( C=Z ) _NR2R3 2
~ Cl- (C=Z) -NR~R3 ~ ~n
11
R5 n 12 R5 4
Cl-(C=Z)-OPh R3N=C=Z
R~R3N 7 5
E-NH- (C=Z) -OPh-Y E'~ (C z) NH R3
R3NH2 _
) n
R5 /n 8 9 R5
R~CHO
Y = H, o- or p-N02 Na(Ac0)3BH /
E-NR2-(C=Z)-NHR3
R3N=C=Z
E-NHR~
5
R5 n 14 / )
R5 'n 13
F~-NR2- (C=Z ) -NR2R3 C1- (C=Z ) -NR2R3
Z=O or S 11
R5 n 15
One can also convert amine 4 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
68

CA 02413421 2002-12-19
WO 01/98270 PCT/USO1/19752
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; 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, 1216-1218; 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 1 can
either be obtained commercially or be prepared as shown
in Scheme 2. Commercially available N-benzylpiperid-3-
one 16 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.
69

CA 02413421 2002-12-19
WO 01/98270 PCT/USO1/19752
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 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 H~/Pd
BOC2 O Rxn
BOC BOC
17 18
16
R5
H'E'
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).

CA 02413421 2002-12-19
WO 01/98270 PCT/USO1/19752
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 22.
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 21 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
references therein). Finally, the use of
carbonimidoyldichloride 24, or 25 followed by sequential
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(Cl)2 (not shown) can
also be reacted sequentially with amines to yield di-
and trisubstituted guanidine 23.
71

CA 02413421 2002-12-19
WO 01/98270 PCT/USO1/19752
SCHEME 3
Fr-NR1- (C=S ) -NHRla ~Ngl- (C=NHRla) -SMe
CH3I a
'n
R5 21 R5 n 2 2
n=0,1
HNR~R3
N(CHZOH)3,
"lac sulfur" , E-NR1- (C=NHRia) -NR2R3
R2R3NH
'n
1. H2NR", Et3N R 23
2 . HNR~R3 or
1 . HNR~R3 , Et3N 1 . HNR2R3 , Et3N
2 . H~NR" 2 . 13 or
1. 13, Et3N
2 . HNR2R3
~N=C (C1) ~
I~ R1a_N-C (C1)2
R5 n 24 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 2&
yields intermediate 27 which can undergo subsequent
reactions in the same pot. For example, reduction
yields alcohol 28 which can be elaborated to the amine
29 by standard procedures familiar to one skilled in the
art. Some of 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.
72

CA 02413421 2002-12-19
WO 01/98270 PCT/USO1/19752
SCHEME 4
~H
+ ~ ~ p Michael
R5 n ~ Rx
1 R$ R11
26 27
n=0 , 1 Rl2Li or Rl2MgBr
31
NaBH4
OH
R5 n R11
2 8 1~
( Ph0 ) 2 ( P=0 ) N3 3 2
( Ph0 ) 2 ( P=0 ) N3
H2, Pd/C
H2, Pd/C
a7 ~$ R9
R:J 11 w R5 - wn R11 R12 3 3
29 as described
as described
,~ previously previously
_ (C=Z ) _NR2R3 _ (C=Z ) _NR2R3
h
1,. ~ 3 4
The mesylate or tosylate can also be displaced by
5 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
73

CA 02413421 2002-12-19
WO 01/98270 PCT/USO1/19752
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 (20), 3167-3180) to yield 37. This adduct can
be 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 the benzyl protecting group yields 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 R1~=OH. The OH
group can undergo synthetic transformations which are
familiar to one skilled in the art and which will be
74

CA 02413421 2002-12-19
WO 01/98270 PCT/USO1/19752
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.

CA 02413421 2002-12-19
WO 01/98270 PCT/USO1/19752
SCHEME 5
7 $ R9
~H
+ R~ O Michael Rxn ~ ~O
"n / ' S n R9
s
R 1 R R9 R 36
11
n=0,1 ~ 35 Wittig ~ PPh3
OMe
H2 Pd/C
1.LDA '°
37
2 . R1~X
R7 $ R9
1 . OH R11 12
2 . ( Ph0 ) 2 ( P=O ) N3 R5 n R9~
I
3.BnOH
39 4.H2 Pd/C 40
to compounds
by methods
R9 8 9 previously
discussed
Rll as above 11
R5 'n R9 Rlo NH2 R5 n R9 Rlo OMe
44 41 ~ (Rl°)2CuLi
1.LDA
to compounds
by methods 8 R9 ~ ' R12X 8 ~
previously ~ ~ ~ R R9 2 R12X,(
discussed ~ 11 12 aS 11
above ~ R12
OMe
R5 ri R9 R10 NH2 R5 n R9 R10
43 42 O
Examples of such methods are taught in D. A. Evans, et
al., J. Am. Chem. Soc. 1981, 103, 2127; D. A. Evans, J.
76

CA 02413421 2002-12-19
WO 01/98270 PCT/USO1/19752
Am. Chem.Soc. 1982, 104, 1737; D. A. Evans, J. Am.
Chem. Soc. 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 37
(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 1
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 1 with an acrylonitrile 51 (as
described by I. Roufos in J. Med. Chem. 1996, 39, 1514-
1520) followed by Raney-Nickel hydrogenation yields
amine 53 which can be elaborated to the compounds of
this invention as previously described.
77

CA 02413421 2002-12-19
WO 01/98270 PCT/USO1/19752
SCHEME 6
_ ~ _
NaH,
THF
4~
37
1. -OH
2 . ( Ph0 ) ~ ( P=O ) N3
3.BnOH
4.H2 Pd/C
g 9
to compounds R11
by methods ~
previously \ /
discussed R5 Jn Rg v ~2
46
7 8 Rg
Me ~ + C02Me
NaH,
R5 n R11
THF
49
Rg 1 . -OH
2 . ( Ph0 ) ~ ( P=O ) N3
1 +
Br ~ 3.BnOH
47 CO2Me 4 . H2 Pd/C
R11
7 8 Rg
to compounds
by methods ~ ~ +
previously ~
discussed 5 " n R11
R
In Schemes 4,5, and 6, we see that there is no gem-
s substitution on the alpha-carbon to the electron-
78

CA 02413421 2002-12-19
WO 01/98270 PCT/USO1/19752
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 R9s and in Scheme 7 there is no R10 gem to R9.
Gem-substitution can be introduced by reacting
pyrrolidine or piperidine 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.
SCHEME 7
R
H
' CN Ra-Ni/H~
) R ~ CN --~
5 'n
R )
1 R$ R~ 'n
n=0,1 51
52
CHI -NHS
,~ to compounds
by methods previously
discussed
R5 n
R
w
R9
53
Further use of epoxides to synthesize compounds of
this invention are shown in Scheme 8. Reaction of
79

CA 02413421 2002-12-19
WO 01/98270 PCT/USO1/19752
pyrrole or piperidine 1 with epoxide 54 yields protected
amino-alcohol 55. This reaction works exceptionaly well
when R~ and R8 are H but is not limited thereto. The
reaction is performed in an inert solvent at room
temperature to the reflux 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 protected by a variety of protecting
groups familiar to one skilled in the art.
SCHEME 8
"/H R~ 9or10
1V + NH- P
R8 _
1
R5 n R ~12 - P
R
1 54
n=0, 1 55
-P
0
R9or10=H
_P
57
R9or10 _M 1,.
56
where M=Li,MgBr,
MgCl, ZnCl, etc.
_P
a
7 R9or10 to compounds
OH by methods
previously
discussed
_P
R5 v ~ ~n R11 R12
58

CA 02413421 2002-12-19
WO 01/98270 PCT/USO1/19752
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 (Dens, 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, 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 al. 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 Am Chem Soc 1996, 118 (43), 10660-
10661), aldehyde and methoxymethyl (Bertram, G.et al.,
81

CA 02413421 2002-12-19
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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 Commun 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.
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 nitrile
yields a one-carbon homologation product. Nitrile 60
82

CA 02413421 2002-12-19
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can be reduced with DIBAL to yield aldehyde 61. This
aldehyde can undergo reduction to alcohol 62 with, for
example, NaBHg 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
nitrile, 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 which can also undergo
the above displacement reactions. Oxidation by methods
familiar to one skilled in the art yields ketone 61b.
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 65 (A. Hassner and V. Alexanian, Tet. Lett,
1978, 46, 4475-8) and reduction with LAH yields alcohol
68 which can undergo all of the displacement reactions
discussed for alcohol 55 or 58. 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 71 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.
83

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(1994) 35, 7201-7204 which involves first, treatment
with base followed by reaction with a trialkylborane
yielding a sulfiniv 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 Svheme 9, the
hydrolysis product after thioacetate displavement),
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). Carboxyliv avid 64 can
be converted to amides 66 by standard coupling
provedures or via an acid chloride by Schotten-Baumann
chemistry or to a 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 NaBHg. 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 varbocyclic and heterocyclic
substituted systems at R9 employing the appropriate
carbovyclic or heterocyclic Wittig (or Horner-Emmons)
reagents. Of course, the Wittig reavtion may also be
84

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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, 1-28). 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 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

CA 02413421 2002-12-19
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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 34, 37-39).
SCHEME 9
10 10
1 ~ 10 9d ' 9d
'7 ~ R LOl ~ (O)pR
O(CO)R9b
7 8 ,,,.~~ 7 0 ~ 71 7 2
1.KSAc
2.-OH ~ (O)2N,R9a
DAST 3 . R9dX ~R9a
or KSR9d ~/~ ~ 73
n7 ,R8 R10
-P
5 9 ~NH- P
1~
5 5 o r 5 8 R5~ ~n R11 R12
86

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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 (1,4-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.
87

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SCHEME 9 (con't)
-P ~ -P
k ;n
55 or 58 , 59
X=OTs; (R9)aCuLi KCN I Et OEt
- Na
R9 10
-~ Rlo ~ CN OE
s
1 . N ~ Rio
2. [H 60 ~ O
77
OEt
Rlo
63
~2 ~ ' CHZ OH 10
CHO
74 ~
62 ~ LAH
l . R9aCH0
Na (Ac0) gBH 1 . R9aCH0, 61 1 . -OH
2 . R9bS0 C1 2 . H+,
2 Na(Ac0)gBH R10
2 . R9aCOC1 or -C02
C_OH to
R10 Et0 (c=o) H, D ~~ H R CH2NH2
NRa S02Rb
61a
,~,.~ 76 to ~ 60a
~R9aC ( O) R9a H
(or -NHCHO) ~ $ Rio
v 75
R1o
8 b R10 ~-0 reductive
OR9d amination +
i R acylation 64
\ 69 ~ if desired
61b
OH R9 b R9a R9a ' R9 b
R LAH ~ $ Rlo ~ ~ $ Rlo ~ $ R1o
68 ' ~ ~ ~ 66 ~ '~ 65
67 ,- r a /
88

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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
89

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form tertiary alcohol 87 . Or else, ester 80 can be
directly reduced with LiBH4 or LAH to yield primary
alcohol 88.

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SCHEME 10
R7 Rs
H ~ 10
R l.BuLi
+ 8 _ O ~ 'OMe
R ~ ~ Rg R1o
R5 n ~ 2 . R X
7 9 OMe R5 n 8 0
1
n-0,1 1.
R ~ R1o R7
R~ 10 8 4 OH
V
R8 O R11 or12 ) R' 9 'R10
g 5 'n
N(CH3)OMe 2.R X R
l.BuLi g1
2.RgX 83
R~
R~ 8
_ ' ' 11or12
~/~N(CH3)OMe R
g 10 ~
) R R RllMgBr or R' 9 'R10
R5 'n 82 R12M Br 5 n
R 85
R~ 8 -P
R11or12Mg.Br
' 'R11 or12
Rg 'R10 ~ 8 H
, R
s 'n R~ R8 H
R 8 9 R12
' ~ 'R11 or12
' ~R11
Rllor l2MgBr ~ Rg R10 g 10
l ~R
R5 n 5 /n
R
1 N-P 86 ~ 87
R
' 12
R
Rg R10 ~ OH -~ NH2 R~ 8
9 0 ~ ~ ~ 'OH
to compounds ~ ~ ~ Rg R10
by methods
previoiusly R5 n
described 88
91

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Alcohols 86, 87 , and 88 can all be tosylated,
mesylated, triflated, or converted to a halogen by
methods discussed previously and displaced with an amine
nucleophile such as azide, diphenylphosphoryl azide
(with or without DEAD and 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 R7 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 R7 and R8 are taken together to form a
cycloalkyl ring. Subsequent elaboration yields compounds
of this invention where R7 and R8 are taken together to
form a cycloalkyl ring.
92

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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, DEAD, and
triphenylphosphine (Saito, A. et al., Tet. Lett. 1997,
38 (22), 3955-3958) yields azidoalcohol 93.
Hydrogenation over a Pd catalyst yields aminoalcohol 94.
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.
93

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SCHEME 11
R7 9 R7 9
R~ OH Rg OH
1
R1 R12 R R12
91 92
R7 9 R'7 9
R$ 2 Rg N3
1
R R12 R1 12
R
93
94
9 9
R.~ R
R8 NH_ P R8 NH- ( C=z ) NR2R3
R1 R1
R12 R12
54
H
as in Scheme 8 R5 /n
1
n=0,1
0
- ( C=Z ) NR2R3
n_
95a
Sometimes amine 1 might have to be activated with
Lewis acids in order to open the epoxide ring (Fujiwara,
5 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
94

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a metal amide, for example the lithium amide (Gorzynski-
Smith, J.; Synthesis 1984 (8), 629) or MgBr amide
(Carte, M. C.; 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 in 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 104 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 105. 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.

CA 02413421 2002-12-19
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SCHEME 12
X4_~ 8
11 R12
7
NRl ( C=Z ) NR2R3 x 1 ( C-Z ) NR.2R3
R Rlo X=leaving
R5 n group
RJ 11
n=0,1 96 97
s
R~ 11 R12 X- R~ R8 11 R12
NR.1 ( C=Z ) NR.2R3 NR1 ( C=Z ) NR.2R3
~R10 ~ ~R10
R5 n R4 _ X R~ Jn R~R9
n=0,1 99
98
12
11
X_ R4/R ~1 ~C=z) ~2R3
1 ~ C=Z ) ~2R3 I + R10
R9
k ~ ~ J R5 n R~ R$ 101
R~ 8 g 10 1 (C=Z) ~2R3
~1 ~ C-Z ) ~2R3 ~ .0
'a9 a10 =
R5 wn,
R4 _ X 7
102 lu.~
~ C=z ) ~2R3
~1 ~ C=z ) ~2R3
R~~R1
X-
' 10
h X04 R~~)n R9 R 105
96

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Multisubstituted pyrrolidines and piperidines may
be synthesized by the methods outlined in Scheme 13.
Monoalkylation of 106 via an enolate using LDA or
potassium 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 as methyl
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 107. 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. (Memo
Park, CA: 1972) chapter 9).
97

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SCHEME 13
w ~ R R
Ph 1. Base ph ~Ph
n 2. R5-X ~~n
n Rsp
106 107 108
n=0,1 X = leaving group R5p=precursor to R5
H2 / Pd or
Pd(OH)2
R H
to compounds by ~I~
methods previously
described
R5s n
109
cis and traps
98

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SCHEME 14
CO~Et CO~Et CO~Et
BOC20 1 . Base 'R6
2 . R 6X
H BOC BOC
110 111 X=leaving
group as 112
defined in 1, [H]
Scheme 1 2.Swern
CH~R5* CH ( OH) R5 * R5*MgBr or CHO
'R6 ~ R6 ~ R6
R5*Li
BOC BOC BOC 113
119 118
Wittig
CHI R5* CHI CHAR 5* CH= CHR5
R6 Rg H~ Pd/C R6
H BOC 116 BOC 114
120
H+~ H+
5* 5*
CHI CHAR CH= CHR
R6 'R6
1
H 115
H 117
R5*=R5 or a
precursor
thereof to products by methods
previously described
Subsequent Wittig olefination yields compound 108.
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
99

CA 02413421 2002-12-19
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Organotransition Metal Chemistry, University Science
Books, Mill Valley, CA, 1980, pp. 341-348) yields
pyrrolidine or piperidine 109 which can 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 110 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
100

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R6X where X is a halide (halide = C1, Br, I), mesylate,
tosylate or triflate, to yield 112. 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 113. Wittig olefination (114) followed by
deprotection yields 115 which may be elaborated as
described previously into the compounds of this
invention. Reduction of the Wittig adduct 114 yields
116 which may be deprotected to yield 117 which may be
in turn elaborated as described previously into the
compounds of this invention. Reaction of aldehyde 113
with an alkyllithium or Grignard reagent yields alcohol
118 which may be reduced catalytically or with
Et3SiH/TFA (J. Org. Chem. 1969, 34, 4; J. Org. Chem.
1987, 52, 2226) if R5* (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 also be displaced with dialkyllithium
cuprates (not shown) (Hanessian, S.; Thavonekham, B.;
DeHoff, B.; J Org. Chem. 1989, 54, 5831). Deprotection
if necessary yields 120 which may be elaborated as
described previously into the compounds of this
invention.
101

CA 02413421 2002-12-19
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SCHEME 15
R R
n 1. s-BuLi ,n
R5orR13
TMEDA
BOC
BOC 2 . R5- or R13 -X 12 2
121
X=as defined
n=0,1 in Scheme 1 1, s-BuLi
TMEDA
2. R5- or R13-X
R~ ~ n R
1. s-BuLi
R5o rRl3
R5orR13 R5orR13 TMEDA
5~ 5 13
BOC 2 . R - R ~ R o rR
124 or R13-X or R13 BOC
123
1. s-BuLi
TMEDA
2. R5- or R13-X
R
R13r5oR~ R50z'R13
R50rR13/\ ~g,5orR13
BOC
125
A method for the alkylation of alkyl groups,
arylalkyl groups, allylic groups, propargylic groups,
5 etc., and a 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
102

CA 02413421 2002-12-19
WO 01/98270 PCT/USO1/19752
substituted on piperidine/pyrrolidine 121. However it
is understood by one skilled in the art that additional
functionality may be present on the ring in either
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 R~-3 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)4CH=CC02Me
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. Proved. 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
103

CA 02413421 2002-12-19
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an alkyl dihalide (Kohnz, H.; Dull, B.; Mullen, K.;
Angew Chem 1989, 101 (10), 1375), etc.
SCHEME 16
R9 R10 R9 R10
diethyl ~ OEt pEt > H OEt
malonate
126 127
H
R5 n
1
n=0,1
t LH~
h h
129 128
h 1s a h
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 yields 129 followed by reduction
104

CA 02413421 2002-12-19
WO 01/98270 PCT/USO1/19752
with LAH yields 130 which can be then converted to amine
131 and then to the compounds of this invention by
procedures as discussed previously. Ester 129 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.
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 =
0,1,2,3, 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 135.
Subsequent deprotection yields amine 136 which can be
elaborated to the compounds of this invention as
described previously. Of course, alcohol 233 can be
oxidized to the aldehyde and then reacted with R7°r8MgBr
or R7°r8Li with or without CeCl3 to yield the
corresponding alcohol 133 where instead of -CH20H, we
would have -CHR7°r80H. This oxidation-1,2-addition
sequence may be repeated to yield a tertiary alcohol.
The alcohol may then be tosylated, mesylated, triflated,
or converted to Cl, Br, or T by procedures familiar to
one skilled in the art to yield 134 and then displaced
with pyrrolidine/piperidine 1 to yield 135. Subsequent
deprotection yields 136 which may undergo elaboration to
the compounds of this invention as discussed previously.
105

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SCHEME 17
(CH2)n (CH2)n (CH2)n
H N-C H ~ BOC -NH-C H2 ~ BOC -NH-C H2
2 2
BOC~O
OH OH X
n=0,1,2,3 133 H 134
132
R5 n
1
n=0, 1
~rr ,
- BOC
n_
CH+l
a
136
135
to compounds by
previously described
A method to introduce cycloalkyl groups at R11R12
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.))
106

CA 02413421 2002-12-19
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yields aldehyde 139. 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 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 R9orloMggr or
R9or10L1 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 -CH~CHO is
substituted with one R9orlo group (-CHR9orlo CHO) .
SCHEME 18
(CH~)n BOCZO (CH2)n (CH2)n
H2 ~ BOC ~ BOC
2.ROH C02R CHO
COOH DCC
n=0,1,2,3 Dip 138 139
137
(CH2)n H+ (CH2)n
~-- BOC
B OC CHI CHO CH= CHOMe
1,
Na(Ac0)3BH 141 140
Inv_ v
-BOC + to compounds
~H ~ -~ by methods
described
previously
R~ R~ 11
142 143
107

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Aldehyde 141 (-CH2CH0) or its monosubstituted analog
synthesized above (-CHR9°rloCHO) can undergo alkylation
with R9or10X where X is as defined in Scheme 1 to yield
compound 141 containing one or both of the Rg and RZ~
substituents alpha to the aldehyde group. Alkylation
can be performed using LDA or lithium bistrimethylsilyl
amide amongst other bases in an inert solvent such as
ether, THF, etc., at -78 °C to room temperature.
Aldehyde 141 (-CH~CHO)or its substituted 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., -CHR9R2~CH0) can also undergo 1,2-addition with
R7°rgMgBr or R7°r8Li to yield the corresponding alcohol -
CH2CHR~°r80H or -CHR9R1~CHR7°r80H. The alcohol may then
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. Or else alcohol -
CH2CHR7°r80H or -CR9R1~CHR7°r80H can be oxidized (i.e.,
Swern, op. cit.) to the ketone and reductively aminated
with 1 and subsequently elaborated to the compounds of
this invention. Or else alcohol -CH2CHR~°r80H or -
CR9R1~CHR7°r80H can be oxidized (i.e., Swern, op. cit.)
to the ketone and reacted once more with R~°r8MgBr or
R7°r8Li to yield the corresponding alcohol -CH2CR7R80H or
-CR9R1~CR7RgOH. 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 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
108

CA 02413421 2002-12-19
WO 01/98270 PCT/USO1/19752
invention. Thus each one of the R7, R8, R9, and R10
groups may be introduced into compounds 141, 142 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 R5 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 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.
109

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SCHEME 19
heterocycle het~
~BOC
H
n NaH or KaC03
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. to 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
performed in THF, ether, dioxane, DME, benzene, etc. at
-78 °C to room temperature.
110

CA 02413421 2002-12-19
WO 01/98270 PCT/USO1/19752
SCHEME 20
w (-)
/ \ (_)
i
R
(-) (_) ~ (-) heterocycle
BOC C
." N N N
> (
_ wn ~ (_)
X
143 ~ ~ ( ) ~ / ' (')
~N
n=0,1
X = leaving m=1,2
group ' _
described ~ / ( )
in Scheme 1
C02 Li
to compounds
by methods
described
(_) ~ (-) previously
N
R=suitable protecting
(_) (_) group or functional
group
1v N
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 145.
111

CA 02413421 2002-12-19
WO 01/98270 PCT/USO1/19752
SCHEME 21
(_)
i
R ~ heterocycle
Boc ~ ~(-) ~ (-) ~ (-)
C C
N N N
\ () \
H _
146 ~ ~( ) / ' ( )
NON
n=0 , 1
\ ~ \ \ fH~
(-) ~ / /
CO2Li COZLi )
etc. heterocycle
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 Et3SiHlTFA (J. Org. chem. 1969, 34, 4;
J. Org. Chem. 1987, 52, 2226) amongst others familiar to
112

CA 02413421 2002-12-19
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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 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.
113

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WO 01/98270 PCT/USO1/19752
SCHEME 22
het
~BOC ~ , (-) ~ ~-- (-)
C
a N
'n
(-)
C
148 N (-)
n=0 , 1 N
etc. TFA, Et3SiH
R=suitable protecting
group or functional heterocycle
group ~r
to compounds of by
methods described
previously 150
n
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, 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
114

CA 02413421 2002-12-19
WO 01/98270 PCT/USO1/19752
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.
Scheme 23
Ph3 het ~ocycle
C , Ph3C
N
n
C
148 N PPh3 ~ ~ 151 n
n=0, 1 N PPh3
etc.
R=suitable protecting
group or functional
group
net
to compounds
by methods
described
previously
Syntheses of amines 9, 10, and the amines which are
precursors to isocyanates or isothiocyanates 5 will now
be discussed. For example, 3-nitrobenzeneboronic acid
(153: Scheme 24) is commerically available and can
undergo Suzuki couplings (Suzuki, A. Pure Appl. Chem.
1991, 63, 419) with a wide variety of substituted indo-
or bromo aryls (aryls such as phenyl, naphthalene,
etc.), heterocycles, alkyls, akenyls (Moreno-manas, M.,
115

CA 02413421 2002-12-19
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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 157) can then be reduced to the corresponding
amines either via catalytic hydrogenation, or via a
number of chemical methods such as Zn/CaCl~ (Sawicki, E.
J Org Chem 1956, 21). The carbonyl insertion compounds
(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 2996, 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.
116

CA 02413421 2002-12-19
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SCHEME 24
NO2 O
Suzuki-type
X-O coupling
B (OH) 2 X=Br, I, OTf /
153 . 154 155
Suzuki-type
coupling, CO (g) ~H~
~ h.2 NO~
un2
\ \
/ fHl / ~ \
o ~o /
158 O 157 O 156
make isocyanate or
isothiocyanate 5,
or carbamoyl chlorides 11,
or used as _9 or _10 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 159 may also undergo
Stifle-type coupling (Echavarren, A. M., Stifle, J.K. J.
Am. Chem. Soc., 1987, 109, 5478-5486) with aryl, vinyl,
or heterocyclic stannanes 163. Bromides or triflates
159 may also undergo Negishi-type coupling with other
aryl or heterocyclic bromides 164 (Negishi E. Accts.
Chem. Res. 1982, 15, 340; M. Sletzinger, et al., Tet.
117

CA 02413421 2002-12-19
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Lett. 1985, 26, 2951). Deprotection of the amino group
yields an amine with can be coupled to make a urea and
other linkers 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 25
-P Suzuki-type -p
coupling
+ (HO) 2H~
Br,I,OTf 160
159
Stille-type 161
coupliing
9 + Bu3 Srr
163 p
Negishi-type
coupling
159 + Br or
164
make isocyanate or
isothiocyanate 5,
or carbamoyl chlorides 11,
or used as 9 or 10 to make 162
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
15 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
118

CA 02413421 2002-12-19
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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
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. et 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 R1o
R~ NRl (C=Z) NR2R3 or N-P
R5 Jn ~R12
1 N Rs Rll
n=0, 1 a
(C=Z) ~2R3
R
H R9 R1o
+ R~ NR1(C=Z)NR2R3 or N-P
R5 Jn C 8 ~Rs2 ~ b
1 R Rll
NR8 b
n=0,1 c
119

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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.; 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.
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CA 02413421 2002-12-19
WO 01/98270 PCT/USO1/19752
Chem. Soc. Chem. Comm. 1993, 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 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 198. 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.
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Scheme 25b O
N'H N~O
v
Di-t-butyl dicarbonate
THF, o c to 25 c ~ ~ 197
196 p 1) Et2o, TMEDA, -70 °c
2) sec-BuLi,
N O ~ -70 °C to -30 °C &
OH Q again to -70 °C
1
R ~ 'N 3 ) RCHO,
1 9 8 O -70 °C to -30 °c then
v-
H R quench with water
NaOH, EtOH,
reflux,3h \ I 195a '~' threo
erythro
0
NH
OH H~C03 , HI, 2-butanone N ~N
_ OH
R 1" o
o , R
19 9 Br~N ~ ~ \ ~ 2 01
0
2 0 0 N2H4, EtOH
O
N ~N~NHR3
OH H R3NC0
R 203 N~NH
THF', 25 °C OH 2
O
N ~N~NHR3 / I R
O H
v R ~ NHR3 2 0 2
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 reflux
temperature of the solvent, or at the melting point of
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WO 01/98270 PCT/USO1/19752
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 [for Z = C(CN)
2], 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).
15
Scheme 25c.
+ R2R3NH
207 208
NC CN
\S S/
NC CN
NC CN
s_~N/E\~ ( 2 5_~N/E\N NiR
R ~ Rl + \S N R ~ R ~ R1 R2
1 3
205 206 R 209
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WO 01/98270 PCT/USO1/19752
02N
N02 ~ 3
~N E\~ ~N/E\N NiR
R5 ~ Rl + ~s I N/R3 -~ R5 ~ R1 Rz
12
205 210 R 212
N0~
RzR3NH
S S
211 208
~.rCN
N
/~ E CN ~ 3
s I N \~ / N~ /Ew ~ /R
R- I + ( 5 ~N N N
Rl ~ ~ /R3 --~ R ~ Rl R2
O N
205 214 R~ 215
/CN ~,
+ RZR3NH
O 0
213 208
Compounds where R11 and R12 join to form a
cycloalkyl compounds can be synthesized by the methods
shown in Scheme 25d. It is to be understood that the
cyclopropyl case shown in Scheme 25d has been chosen
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WO 01/98270 PCT/USO1/19752
only to serve as an example and that other protected
aminoacids in place of 216 may also be employed. Thus,
BOC-1-aminocyclopropane-1-carboxylic acid 216 is coupled
to (S)-3-(4-fluorobenzyl)piperidine using a common amide
forming reagent such as BOP, HBTU or HATU to furnish the
amide tert-1-{[(3S)-3-(4-fluorobenzyl)
piperidinyl]carbonyl}cyclopropylcarbamate (217). Then
the amide is reduced to the corresponding amine by a
reducing agent such as but not limited to BH3 in THF at
room temperature, followed by the removal of BOC
protecting group with TFA and neutralization to afford
the free amine 218. The free amine is then condensed
with an isocyanate or a carbamate to yield the desired
urea 219 .
Scheme 25d.
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F F
O
BOP, c
NHBoc
NH + HO
Huenig's Base
216 217
DMF
1, BH3-THF
2 , TFA, CH2C12
3, NaOH
218
R3-NCO or H
R3-NHC00-Ph ~N~R3
I0
Acetonitrile
219
EXAMPLES
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
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Part A: Preparation of 4-benzyl-1-(3-N-phthalimido-n-
prop-1-yl)piperidine
P1~N
4-benzylpiperidine (8.0 g , 45.6 mmol, 1eq), N-(3-
bromopropyl)-phthalimide (13.5 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 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) S 8.00-7.80 (m, 2H); 7.80-7.60 (m,
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
I~~NH~
/
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 °C 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.
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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) S 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
\ n
H H ~N
4-benzyl-1-(3-amino-n-prop-1-yl)piperidine (300 mg,
1.29 mmol, 1 eq) was dissoved in THF at 25 °C 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) b 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) .
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EXAMPLE 2
Part A: Preparation of 4-benzyl-1-carbomethoxymethyl-
1-[3-(3-cyanophenylaminocarbonylamino)prop-1-
yl]piperidinium bromide
4-benzyl-1-[3-(3-
cyanophenylaminocarbonylamino)prop-1-yl]piperidine
(50mg, 0.233 mmol, 1 eq), was dissoved in acetone at 25
°C 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 (300MHz, CD3OD) 8
8.00-7.80 (m, 1H) ; 7.65-7.45 (m, 1H); 7.45-7.33 (m,
1H); 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
Part A: Preparation of 1-(t-Butoxycarbonyl)-3-
piperidone
O i. H2, Pd/C, CH30H,
23 °C
~ ~1-' ~ 1
ii. (Boc)20, NaHC03,
H THF, 23 °C O
86%
To a deep yellow solution of 1-benzyl-3-piperidone
hydrochloride (3.00 g, 1.33 mmol, 1 equiv) in methanol
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(100 mL) was added 10 wt. o (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
mL) 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-
butoxycarbonyl)-3-piperidone (3.79 g, 86%) as a white
oily solid. 1H NMR (300 MHz, 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(O)P(OEt)2
DME, 23-80 °C
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
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 layers were separated
15 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
20 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),
8: 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.
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Part C: Preparation of 1-(t-Butoxycarbonyl)-3-
benzylpiperidine
H2, 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), 8: 7.23 (m, 2H), 7.14 (m, 3H), 3.86
(m, 2H), 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)] - 176.
Part D: 3-Benzylpiperidine hydrochloride
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/
HCl
~ HCl
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
resulting yellow solution was stirred for 1 hr, at which
time the reaction was concentrated in vacuo to provide
3-benzylpiperidine hydrochloride (308 mg, 100%) as an
amorphous solid. 1H NMR (300 MHz, CD30D), $: 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, 1H) , 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
/)
H H
/
I
OCH3
The above compound was prepared by the methods
similar to the ones employed in Example 1, part C.
1H NMR (300 MHz, CD30D), $:7.29-7.13 (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);
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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
~+
B iw 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
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) S 7.88
(d, 1H, 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-nitro-spiro[2H-isoindole-2,1'-
piperidinium] bromide
~+ O
~~+
Br
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4-Fluorobenzylpiperidine (0.94 g, 4.86 mmol, 1.0
eq), a,a'-dibromo-3-nitro-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, 1H,
J=8 Hz), 7.84 -7.80 (m, 1H), 7.75-7.69 (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).
Part C: Preparation of 4-Amino-1, 3-dihydro-4'-[4-
fluorophenylmethyl]-spiro[2H-isoindole-2,1'-
piperidinium] bromide
' 1+
V
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
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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 20o MeOH/CHC13 to yield 0.81g of a yellow foam.
NMR (300 MHz, DMSO) 8 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-
fluorophenyl-methyl]spiro[2H-isoindole-2,1'-piperdinium-
4-yl]-N'-4-fluorophenylurea bromide
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 15 cm quartz column via silica
plug. The product was eluted with 10% MeOH/CHC13 to
yield 65 mg of a yellow foam. 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),
1.91-1.62 (m, 5H)
EXAMPLE 5
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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
CClg/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 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
1000 ethyl actetate yielded 2.48 g of an orange oil.
NMR (CDC13) 8 7.40-7.10 (m, 10H); 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.
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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, 1.2 eq), and toluene (1.0
mL) were mixed and stirred overnight at room temperature
under a N2 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
1:1 hexane/ethyl acetate yielded 84 mg of product as an
25 oil. NMR (CDC13) 8 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 cmw .
Part C: Preparation of 4-benzyl-1-(3-amino-3-
phenylprop-1-yl)piperidine
The compound from part B (100 mg), 10% Pd on carbon
(120 mg), and methanol (100 mL) were carefully combined
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in a flask under a N2 atmosphere. The contents were then
submitted to 1 atm of H~ 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
/ /
H H ~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) 87.58 (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.
EXAMPLE 6
Part A: Preparation of 2-benzyloxycarbonylamino-1-
phenyl-3-butene.
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/
~H ~ w
/
To a stirred suspension of
methyltriphenylphosphonium bromide (10.72 g, 0.03 moles)
in 100 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.
i
H
W
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
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was stirred at 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.
/ O
F
H
/ OH
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.
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~2
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
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 C3pH33FNg02 . 501.
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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.
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TABLE 1*
C~~~N~ N-R3 C~~~H ~ R
O C~,~ H
H H 3 ~~ R3
0 O
a b
~, H H G H H H
C~~~ N~ N-R3 /"'~N~ N, N I~
G~ ~ R3 /~ ~ R
H H
0 O
d a
~'~~~ H IH~T.
R3
O
g
G~~ OH H H C~~ OH H H
~~~R3 ~ .~~~R3
Ph O Ph O
h i
G~N H N N.R G~,~N OH N N. G~N N N.
3 ~ R3 ~ ~ R3
p O p 0 Ph O
~ k 1
Ex # Core G R3 M+1
7 a Ph 3-C02Et-Ph 410
8 a Ph 3-I-Ph 464
9 a Ph 1-adamantyl 396
10 a Ph 3-OCH3-Ph 368
11 a Ph Ph 338
12 a Ph 4-F-Ph 356
13 a Ph 4-C02Et-Ph 410
14 a Ph 4-CN-Ph 363
b Ph 1-adamantyl 410
16 b Ph 2-F-5-CF3-Ph 438
17 b Ph 2-naphthyl 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
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25 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
30 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
35 b Ph CH(iPr)C02Et 404
36 b Ph nC8H17 388
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-cyclo 392
ropyl
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 398
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-c clopropyl410
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
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84 b 2-F-Ph 3-CN-Ph 395
85 b 3-OCH3-Ph 3-F-Ph 400
86 b 2-F-Ph 3-OCH3-Ph 400
87 b 3-OCH3-Ph 3-C02Et-Ph 454
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-Cl-Ph 3-OCH3-Ph 416
96 b 2-F-Ph 4-C02Et-Ph 442
97 b 3-F-Ph 3-OCH3-Ph 400
98 b 3-F-Ph 4-F-Ph 388
99 b 3-F-Ph 4-C02Et-Ph 442
100 b 3,4-diF-Ph 4-F-Ph 406
101 b 3-Cl-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-naphth 1 3-CN-Ph 427
107 b 1-naphth 1 4-F-Ph 420
108 b 1-naphthyl 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-adamantyl 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-adamantyl 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 388
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
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
~
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142 d Ph 3-CN-Ph 391
143 d Ph 3-CO2Et-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 ~-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-adamantyl 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 j Ph 3-CN-Ph 483
163 j Ph 3-OCH3-Ph 488
164 j 4-F-Ph 3-OCH3-Ph 506
165 j 4-F-Ph 4-F-Ph 494
166 j 4-F-Ph 1-adamantyl 534
167 1 Ph 3-OCH3-Ph 458
168 1 Ph 1-adamantyl 486
169 c imidazol-1-yl 3-OCH3-Ph 372
* All stereocenters are (+/-) unless otherwise
indicated
EXAMPLE 6a
N-(1-{2-(3S)-3-(4-fluorobenzyl)piperidinyl)methyl}-
cyclopropyl)-N'-[3-(1-methyl-1H-tetraazole-5
yl)phenyl]urea
Part A: Preparation of tert-1-{[(3S)-3-(4-
fluorobenzyl)piperidinyl]carbonyl}cyclopropylcarbamate
HBoc
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To a ice-water cooled solution of (S)-3-(4-
fluorobenzyl)piperidine (100 mg, 0.517 mmol), Boc-1-
aminocyclopropane-1-carboxylic acid (109.3 mg, 0.543
mmol) in DMF (2.2 mL) was added HATU reagent (204 mg,
0.543 mmol), followed by addition of Huenig's base
(0.142 mL, 0.815 mmol). The resulting mixture was then
warmed to room temperature and stirred for 2h. The
reaction mixture was diluted in sat. NaHC03 aq.
solution, and extracted with ethyl acetate (25 mL). The
organic layer was washed with sat. NaHC03 aq. Solution,
and brine. The organic layer was then dried in MgS04,
concentrated and used directly in the next step. Mass:
Spec(ES), 377.2 (M+H); 1H NMR (300 MHz, CDC13): 8 7.15-
7.10 (m, 2H), 6.98 (t, 2H, J = 8.8 Hz), 4.42-4.36 (m,
1H), 4.26-4.18 (m, 1H), 2.98-2.84 (m, 1H), 2.82 (s, 2H),
2.61-2.48 (m, 3H), 1.82-1.67 (m, 3H), 1.43 (S, 9H),
1.28-1.13 (m, 3H), 0.97 (bs, 1H).
Part B: Preparation of 1-[j(3S)-3-(4-
fluorophenyl)methyl]piperidinylmethyl]cyclopropanamine
To a solution of of tert-1-{[(3S)-3-(4-
fluorobenzyl)piperidinyl]carbonyl}cyclopropylcarbamate
(5.2 g, 13.8 mmol) in THF (40 mL) was dropwise added
BH3~THF solution (40 mL, 1.0 M). The resulting solution
was stirred at room temperature for additional 4.5 h.
The reaction mixture was then concentrated, and directly
treated with a 50% solution of TFA in methylene chloride
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(52 mL) for 1.0 h at RT. The solvent of the reaction
mixture was removed. The resulting residue was
suspended in water, extracted with diethyl ether (3 x 25
mL). The aq. solution was then neutralized with 1 N
NaOH solution to pH 9-10, and extracted with ether
extensively (6 X 25 mL). The combined organic layer was
then dried over NaS04 and concentrated to provide 1-
[[(3S)-3-(4-
fluorophenyl)methyl]piperidinylmethyl]cyclopropanamine.
Mass: Spec(ES), 263.3 (M+H); 1H NMR (300 MHz, CDC13):
(m, 2H), 6.99-6.93 (m, 2H), 2.91-2.2.80 (m, 2H), 2.52-
2.46 (m, 2H), 2.29 (d, 1H, J = 12.5 HZ), 2.13 (d, 1H, J
- 12.5 Hz), 1.89-1.63 (m, 8H), 0.96-0.91 (m, 1H); 0.59-
0.54 (m, 2H), 0.32-0Ø30 (m, 2H).
The material was found to have a purity of greater than
95% and was used directly in the next step without
further purification.
Part C: Preparation of N-(1-~2-(3S)-3-(4-
fluorobenzyl)piperidinyl)methyl}cyclopropyl)-N'-[3-(1-
methyl-1H-tetraazole-5-yl)phenyl]urea
F
/ N N N NN
N~ O I / \
To a solution of 1-[[(3S)-3-(4-
fluorophenyl)methyl]piperidinylmethyl]cyclopropanamine
(102 mg, 0.3893 mmol) in acetonitrile (1.55 mL) was
phenyl 3-(1-methyl-1H-tetraazole-5-yl)phenylcarbamate
(126 mg, 0.4285 mmol). The mixture was stirred RT for
4.0 h and the solevent was evaporated off. The residue
was directly purified on silica gel with elution with
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methylene chloride, and 10% methanol ethylacetate
in to
give a white solid (162mg, 90% yield); Mass: Spec(ES),
464.2 (M+H); 1H NMR (300MHz, CD30D) . 8.03 (d,2H, J
S
- 1.5 Hz), 7.54-7.53 (m, 2H), 7.46-7.44 (m, 1H), 7.21-
7.16 (m, 2H), 6.97-6.94 (m, 2H), 4.20 (s, 3H), 3.90-3.82
(m, 1H), 3.76-3.70 (m, 1H), 3.38-3.3.22 (m, 2H), 2.95-
2.80 (m, 1H), 2.78-2.60 (m, 3H), 2.18-2.05 (m, 2H),
1.95-1.78 (m, 2H), 1.30-1.20 (m, 1H), 1.15-0.98 (m, 4H).
The following compounds in Table 1a can be made by
the procedures described in Example 6a, and by other
procedures described in this application andlor by
procedures familiar to one skilled in the art.
TABLE 1a
F
H H
N N.R3
NO
Ex. # n R3 Mass spec
M+1
169a 1 O 424
/ I \
169b 1 N~NN 464
N
Me
169c 1 ~ ~ 495
0
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169d 1 OMe 525
~N w0
pJ
169e 1 OMe 469
\
HN O
169f 1 OMe 455
H2N O
1698 1 ~S Me 445.1
N /
O Me
169h 2 N-NN 478.3
,
\ N
/ Me
EXAMPLE 6b
N-f3-f (3S)-3-f (4-
Fluorophenyl)methyllpiperidinyllpropyll-N'-f4-(1-methyl
1H-tetrazol-5-yl)phenyll-urea
Part A. Preparation of N-Methyl-4-nitro-benzamide
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O.. N+.O-
O NCH
4-Nitrobenzoyl chloride (7.00 g, 38 mmol, 1 eq) was
dissolved in 50 ml of THF and added to a 2.0 M solution
of methylamine in THF (41.5 ml, 83 mmol, 2.2 eq.) at
0°C. Worked up after 3 hours by adding EtOAc and
rinsing 3X with 1N NaOH, 1X with brine. The organic
layer was dried over MgS04, then stripped to obtain 2.25
g of off-white solids as product. NMR (300 MHz, DMSO-
d6) ~ 8.80 (m, 1H), 8.33 (d, 2H, J = 7 Hz), 8.06 (d, 2H,
J = 7 Hz). 2.86 (d, 3H, J = 7 Hz).
Part B. Preparation of 1-Methyl-5-(4-nitro-phenyl)-1H-
tetrazole
O.. N+,O_
\
N ~ N~
N=N
N-Methyl-4-nitro-benzamide (2.25 g, 12.5 mmol, 1 eq.)
and PC15 (2.60 g, 12.5 mmol, 1 eq.) were melted together
under house vacuum connected to a NaOH trap behind a
safety shield. Melting occurred at 100°C. Heated at
130 °C for 1 hour then purified by kugelrohr
distillation at 0.1 mmHg at 130°C. CAUTION: THE
EXPLOSIVE PROPERTIES OF THIS COMPOUND ARE UNKNOWN). The
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iminoyl chloride (12.5 mmol 1 eq.) in DMF 10 m1 was
added to NaN3 in 10 ml of DMF at 25°C and stirred
overnight. Worked up by adding EtOAc then rinsing 3X
with H20. The organic layer was dried over MgS04, then
stripped to obtain yellow solids which were purified
over silica gel in 3:1 hexanesJEtOAc to 100% EtOAc.
Obtained 1.21 g of yellow solids as product. NMR (300
MHz, CDC13) 8 8.46 (d, 2H, J = 7Hz), 8.02 (d, 2H, J =
7Hz),4.27 (S, 3H).
Part C. Preparation of 4-(1-Methyl-1H-tetrazol-5-yl)-
phenylamine
NH2
N ~ N~
\ /
N=N
1-Methyl-5-(4-nitro-phenyl)-1H-tetrazole (470 mg), 20%
Pd(OH)~ (94 mg), and 1:1 MeOH/EtOAc (25 ml), were
hydrogenated at 50 PSI for 1 hour. The reaction was
filtered through fiberglass filter paper under nitrogen.
The filtrate was stripped to yield 383 mg of yellow
solids as product. Mass Spec detects 176 (M+H). NMR
(300 MHz, CDC13) 8 7.57 (d, 2H, J = 7Hz), 6.80 (d, 2H, J
- 7Hz), 4.14 (s, 3H), 4.03 (M, 2H).
Part D. Preparation of [4-(1-Methyl-1H-tetrazol-5-yl)-
phenyl]-carbamic acid phenyl ester
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/
H~N~O \
N ~ N~
\ /
N=N
4-(1-Methyl-1H-tetrazol-5-yl)-phenylamine (190 mg, 1.08
mmol, 1 eq.), triethylamine (0.14 ml, 1.08 mmol, 1 eq.),
in 10 ml of THF under nitrogen were cooled to 0°C. A 5
ml solution of phenyl chloroformate (0.14 ml, 1.08 mmol,
1 eq.), was added dropwise via an addition funnel.
Worked up after 16 hours by adding EtOAc then rinsing 3X
with H20. The organic layer was dried over MgSO4, then
stripped to obtain yellow solids which were purified
over silica gel in 3:1 hexanes/EtOAc to 100% EtOAc.
Obtained 93 mg of white solids as product. Mass Spec,
296 (M+H). NMR (300 MHz, DMSO-dg ) 8 10.65 (s, 2H),
7.86 (d, 2H, J = 7Hz), 7.76 (d, 2H, J = 7Hz), 7.44 (t,
2H, J = 7Hz), 7.28 (t, 2H, J = 7Hz), 4.18 s, 3H).
Part E. Preparation of N-[3-[(3S)-3-[(4-
fluorophenyl)methyl]piperidinyl]propyl]-N'-[4-(1-methyl-
1H-tetrazol-5-yl)phenyl]-urea
N-N
*HC1 O / ANN
N~N~N
H H
F
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To a stirring solution of 25 mg 3-[(3S)-3-[(4-
fluorophenyl)methyl]piperidinyl]propylamine (0.1 mmol, 1
eq) in 1 ml of dry acetonitrile was added 32.5 mg [4-(1-
methyl-1H-tetrazol-5-yl)-phenyl]-carbamic acid phenyl
ester (0.1 mmol, 1.1 eq). This mixture was stirred at
room temperature for two hours, then concentrated in-
vacuo to a pale yellow oil. This oil was purified via
radial chromatography, eluting with a 19:1 mixture of
methylene chloride and methanol, to yield a white solid.
This solid was dissolved in methylene chloride and
treated with 1 M hydrochloric acid in diethyl ether (0.1
ml, 1 eq). This mixture was stirred for 30 minutes,
then concentrated in-vacuo to a white solid. This solid
was dissolved in a 1:1 mixture of acetonitrile and
water, and lyophilized to 26 mg of a white solid as
product. NMR (300 MHz, CD30D) 8 7.72 (d, 2H, J = 9 Hz),
7.64 (d, 2H, J = 9Hz), 7.21-7.16 (m, 2H), 7.01 (dd, 2 H,
J = 8, 17 Hz), 4.17 (s, 3H), 3.59-3.54 (m, 1H), 3.40-
3.11 (m, 4H), 2.89-2.81 (m, 1H), 2.73-2.59 (m, 3H),
2.10-1.70 (m, 7H), 1.43-1.34 (m, 1H). MS (ESI~-) 452 (M
- Cl) .
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.
TABLE 2**
R5 a R5b
R5C i1 i2
I ~ N~ I~~~~ Z
R4 !O
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
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172 H 3-OCH3 CH2Ph Br H H H H H
173 H 3-CN - - C02Et H H H H
174 H 3-OCH3 CH3 I H H H H H
175 H 3-CN CH3 I H H H H H
176 H 3-CN CH2Ph Br H H H H H
177 H 3-CN - - H H H CH2Ph 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 CH2C02CH3 Br H H H H H
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 - - CH2Ph
190 F 3-CN CH3 I H H H H H
191 F 3-COCH3 - - H CH2Ph H H H
192 F 4-F-Ph - - H CH2Ph H H H
19 F 3 -OCH3 - - H CH2 H H H
3 Ph
194 H 3-OCH3 - - H H H CH2Ph H
195 H 3-CN - - H H H CH2Ph H
~ ~
**All compounds are amorphous unless otherwise indicted.
TABLE 3**
X- ~F~ z y + X- ~H~ Z
Y ~ N O 1~~~ N ~ ~ ~l0
n o
Ex # Core Y Z X
196 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 Br
207 o F 3-OCH3 Br
208 0 F 3-CN Br
209 0 ~ F 3-CN Br
Call~ compounds are amorphous unless otherwise indicted.
156

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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-
nitro-benzyl bromide (X = Br, R14 = H), Scheme 26) to
give the N-benzyl compound 166. The nitro 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 example, 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
nitro ketone 171. The nitro 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 175 (R14 = H) can be
opened with the 4-benzyl piperidine to give the
corresponding nitro benzyl alcohol which is hydrogenated
to give the aniline alcohol 176. The aniline 176 may be
treated with various isocyanates to give the urea
alcohols 174.
The 4-benzyl piperidine can also be N-alkylated
with 3-cyanobenzyl bromide (177, Scheme 28) to.give the
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cyano analog 178. The cyano group is reduced using
Raney nickel 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 182. The cyano
group of 182 is converted to the imidate 183 by
HCl/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, 128, 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 189. Reductive amination with
piperidine analogs gives the cyclohexyl methyl-1-
piperidinyl analogue 190. 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 192. Several examples using these
synthetic methods are listed in Table 3a and Table 3.1.
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SCHEME 2 6
o~
X ~~ _
14 ~ \ ~ N
R \
i / -!- N A 14 _I
N4z ~ R ' /
165 NOz
X = Cl, Br, MsO, etc. 166
B
0
C N
R14 i / H
O ~ N z
168 D E 167
0
N
R14
N~ N~ R
O
169
A: DMF/KzC03/RT or THF/RT. B:lO~Pd/C, Hz 50 psi.
C: THF/Et3N/chlorophenylformate. D:NHR/DMF/50;C.
E: R-N=C=O/THF
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SCHEME 27
O _ p I\
U
R14 ~ \ \ 14 I \ N /
' / + R ' /~
N02 N~ ~ V \N02 171
170
B
O
N ~ / O \
R14 I \ \ N
/ N N. C R14 ~ v
R ~ 1 / NH2 172
173
D
D
OH I ~ OH
\ N / \ N
R14 ~ R14 ~ _
/ N~N.R ~ ~ / NH2 176
p ~ A,B
174 p
R14 ~ \ V + N
/
N02
175
A: DMF/K2C03/RT or DMF/50;C.
B:10%Pd/C, H~ 50 psi. C:
R-N=C=0/THF. D:NaBH4/MeOH/RT
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SCHEME 28
/ \
Br \ / A w N'_
\ / +N
178
CN CN
177 / ~, B
\
N ~ / \
I ',~c N
i w
O ~ I~
N~ 179
N-R NH2
180
A: DMF/IC2C03/RT B:Raney nickel,
HZ 50 psi. C: R-N=C=O/THF.
SCHEME 29
NH NH
~ CN A' ~ ~ CN B' ~ ~ OEt C ~ ~ ~ ~ \
/ / / /
NHS
O / O / O /
182 183 184
A: R-N=C=O/THF. B:EtOH/HCl/RT
C: 4-benzylpiperidine/EtOH/RT
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SCHEME 30
OH OMs
A,B
C
' ~~' OMe
~NH2
O /
185
186
A: R-N=C=O/DMF. B:Ms-C1/THF
C:4-benzylpiperidine/DMF/RT
SCHEME 31
OH
OH
_~ b
~'NH2 ~~'NH-CBZ
187 188
F F
O
H N
N
d
~~NH-CBZ
~~~~H-CBZ
189
F 190
F
N N
a
.~~'NH2 ~ ~''~N~N \ OMe
191
192
a:Benzyl chloroformate/Na2C03/CH2C1~. b.Swern
Oac. c:NaBH(OAc)3 d:H2/10a Pd/C e:R-N=C=O/THF.
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SCE 31a
OH
OH
b
;~N~ ~
I~~NI~ CBZ
187 188
F ,~ ~ ~ F
O
N, )
N
d
,~~NI~CBZ
a ~~~'I~CBZ
18A H
19~i
~ F . / ~ F
N~ N
a O
w
~.''~N~ ' .,~~N N
194
195
aBenzyl chlomforn~abe/Na2C03/CI~Ch. b.Swern Ox.
c:NaBH(OAc)3 d:HzJlO% 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.
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EXAMPLE 218
N-[1-(ph~nylmethyl)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 KZC03 (1.38 g, 10 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 166 (Scheme 26, R14 = 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, 40% 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
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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.
A solution of aniline 167 (Scheme 26; (R14 = 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, 20o 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 K~C03 (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 NH3tgas)) 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
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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
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 KZC03
(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 10o 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) to 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, 20% 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
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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 NaBH4 (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)+ - 466.
EXAMPLE 223
N-[3-[imino-[4-(phenylmethyl)-1-piperidinyl]methyl]
phenyl]-N'-phenylurea
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 300
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
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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 CH~Cl~ (50 mL) is added 50 ml of
an aqueous solution of Na2C03 (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, CDC13) S
7.40-7.29 (m, 5 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 %)
Step b: A solution of DMSO (2.52 g, 30 mmol) in
CH~C1~ (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
CH2C1~ (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 HCl, and brine. The organic layer
is dried over Na2S04, filtered, and concentrated to give
2.5 g (9.5 mmol) of the aldehyde 189 as a white solid.
1H NMR (300 MHz, CDC13) 8 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
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H), 2.19-2.11 (m,1 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 (2.0 g, 7.7
mmol), 4-(4-fluorophenylmethyl)piperidine hydrochloride
(1.8 g, 7.8 mmol) 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% EtOAc) to give 250 mg of urea 192 as a solid. MS
esi: (M+H)+ - 454.4 (100%), HRMS (M+H)+- 454.2875.
EXAMPLE 415
N-(3-acetylphenyl)-N'-~(1R,2S)-2-ff(3S)-3-(4-
fluorophenvl)methyllpiperidin~rllmethyllcyclohexyll-urea.
Step a: To a solution of (R, R) amino alcohol 187 [J.Org.
Chem. 1996, 61, 5557-5563; J. Am. Cheat. Soc. 1996, 118,
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5502-5503] (9.5 g, 73.8 mmol) in CH2C1~ (200 mL) is
added 200 ml of an aqueous solution of Na~C03 (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) S 7.40-7.29 (m, 5 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 ) * - 2 6 4 . 3 ( 10 0 % )
Step b: A solution of DMSO (36 g, 430 mmol) in CH2C12
(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 CH2C12
(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 Na2S04, 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. 1H NMR (300 MHz, CDC13) 8
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,1 H),
2.09-2.01 ( m, 1 H), 1.86-1.75 (m, 3 H), 1.54-1.17 (m, 4
H) .
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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)3BH (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
MgS04 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) 8 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 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 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
NH40H/MeOH/CH2C12) 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
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purified by a second chromatography on silica gel
(40:60:1 EtAc/Hex/TEA) and final recrystallization from
ether to give crystalline solid. mp 115-117 °C, [off]D25 =
+16.8° (CH30H, c = 0.23 g/dL). 1H 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 (100%). Anal. Calcd for C28H36N302F: C, 72.23; H
7.70; N, 9.02. Found: C, 72.33; H, 7.91; N, 9.00.
EXAMPLE 415a
N-(3-acetylphenyl)-N'-f(1R,2S)-2-f[(3S)-3-(4-
fluorophenyl)methyllpiperidinyllmethyllcyclohexyll-urea
Hydrochloride.
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. [oG]D25 = +20.0 ° (CH30H, c = 0.23 g/dL) . 1H NMR
(400 MHz, DMSO-Dg) ~ 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), 3.47-3.31 (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
172

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(m, 7 H), 1.30-1.00 (m, 4 H). Anal. Calcd for
C28H37N302FC1~H20~THFp.25: C, 64.73; H 7.68; N, 7.81.
Found: C, 64.89; H, 7.41; N, 7.81.
EXAMPLE 415b
N-(3-acetylphenyl)-N'-f(1R,2S)-2-ff(3S)-3-(4-
fluorophenyl)methyllpiperidinyllmethyllcyclohexyll-urea
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]D25 = +16.9 ° (CH30H, c = 0.23 g/dL) . Anal. Calcd
for C34H42N3O5FS: 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
173

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R16 i ~ R16
N.E ~ / N'E
14 ~/ ~Z~O ,R3 14 ~~~Z~O ,R3
R ~~ ~ ~ H R ~~ ~ H
p q
R16 ~ ~ R16 ~ ~ + ~CH3
N,E ' / N'E
O ~ ~ O
14 / ~Z~ ,R3 R14 ~~Z~ ~R3
R ~~ ~ ~ H ~~ ~ H
Ex Core R16 E Z R14 R3 MS
#
_ M+H
1-(phenylmethyl)-
218 p H CH2 (1) H 4-piperidinyl] 497
NH
2,5-
219 p H CH2 (1) H difluorophenyl 436
NH
2,5-
220 p H CH2 (2) H difluorophenyl 450
CH2NH
2,5-
221 p H , (1) H difluorophenyl 464
~~~, NH
O
2,5-
222 p H ~ (1) H difluorophenyl 466
~~~ NH
OH
phenyl
223 p H C=NH (2) H 413
NH
1-(phenylmethyl)-
224 p H CH2 (2) H 4-piperidinyl] 497
NH
2- ( 4-
225 p H CH2 (1) H fluorophenyl)- 446
NH ethyl
3-hydroxypropyl
226 p H CH2 (1) H 382
NH
174

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2- ( 1-
227 p H CH2 (1) H piperidinyl)- 435
NH ethyl
2-
228 p H CH2 (1) H (dimethylamino)et395
NH hyl
4-(phenylmethyl)
229 p H CH2 (1) H -1-piperazine 483
NH
4-(phenylmethyl)
230 p H CH2 (1) H -1-piperidine 482
NH
(1,3-benzodioxol-
231 p H CH2 (1) H 5-ylmethyl) 458
NH
2,2-
232 p H CH2 (1) H (diphenyl)ethyl 504
NH
4- ( 4-
233 p H CH2 (1) H Chlorophenyl)-4-518
NH hydroxy-1-
piperidine
4-phenyl-4-
234 p H CH2 (1) H hydroxy-1- 484
NH piperidine
4-phenyl-1-
235 p H CH2 (1) H piperidine 468
NH
(1H)-indazol-5-yl
236 p H CH2 (1) H 440
NH
(1H)-indazol-6-yl
237 p H CH2 (1) H 440
NH
phenylmethyl
238 p H CH2 (1) H 414
NH
1,3-benzodioxol-
239 p H CH2 (1) H 5-yl 444
NH
(3-4) 1-(phenylmethyl)-
240 p H CH2 (1) 4-piperidinyl] 541
NH
175

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(3-4) 2-(4-
241 p H CH2 (1) fluorophenyl)- 490
NH ~ ethyl
(3-4) 4-((2-
242 p H CH2 (1) phenyl)ethyl) 541
-1-
NH ~ piperazine
(3-4) (1H)-indazol-5-yl
243 p H CH2 (1) 484
NH O
(3-4) (1H)-indazol-6-yl
244 p H CH2 (1) 484
NH O
(3-4) benzothiazol-6-yl
245 p H CH2 (1) 501
NH
f2_ (4_
246 p H CH2 (1) (4) fluorophenyl)- 462
NH OH ethyl
1-(phenylmethyl)-
247 p H CH2 (1) (4) 4-piperidinyl] 513
NH OH
(3-4) 3-phenylpropyl
248 p H CH2 (1) 486
NH O
(1H)-indazol-5-yl
249 p H CH2 (2) H 440
NH
f2_(4_
250 p H CH2 (2) H fluorophenyl)- 446
NH ethyl
2,5-
251 p H bond (1) H difluorophenyl 422
NH
Phenyl
252 p H CH2 (1) H 400
NH
4-methoxyphenyl
253 p H CH2 (1) H 430
NH
176

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3-methoxyphenyl
254 p H CH2 (1) H 430
NH
3-methoxyphenyl
255 q 4-F CH2 (2) H 454
NH
3-acetylphenyl
256 q 4-F CH2 (2) H 466
NH
3-methoxyphenyl
257 r H CH2 (1) H 430
NH
3-cyanophenyl
258 p H CH2 (2) H 425
NH
3-cyanophenyl
259 p H CH2 (3) H 425
NH
4-methoxyphenyl
260 p H CH2 (3) H 430
NH
2-phenylethyl
261 p H CH2 (3) H 428
NH
3-carboethoxy-
262 p H CH2 (1) H phenyl 472
NH
3-cyanophenyl
263 p H CH2 (1) H 425
NH
phenyl
264 p 4-F CH2 (1) H 418
NH
phenyl
265 p H CH2 (1) H 490
N-
Benzyl
3-cyanophenyl
266 p H CH2 (1) H 515
N-
Benzyl
2-phenylethyl
267 p H CH2 (1) H 428
NH
(3-4) 3-cyanophenyl
268 p H CH2 (1) 469
NH
177

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(3-4) 3-carboethoxy-
269 p H CH2 (1) phenyl 516
NH O
(3-4) 4-carboethoxy-
270 p H CH2 (1) phenyl 516
NH
phenyl
271 p H CH2 (1) (4) 416
NH OH
3-cyanophenyl
272 p H CH2 (1) (4) 441
NH OH
(4) 3-methoxyphenyl
273 p H CH2 (1) 524
NH O~~
~O
S
-O~ CHs
(4) Trans-2-phenyl-
274 p H CH2 (1) cyclopropyl 534
NH O~~ e0
S
-O~ CHs
(3) 3-cyanophenyl
275 p H CH2 (1) 483
NH C02Me
(3) 3-methoxyphenyl
276 p H CH2 (1) 488
NH C02Me
(4) 3-cyanophenyl
277 p H CH2 (1) 519
NH O~~ ~O
S
-O~ CHs
(3) 3-methoxyphenyl
278 p H CH2 (1) 460
NH ~OH
178

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(3) 3-cyanophenyl
279 p H CH2 (1) 455
NH ~OH
(4) 3-cyanophenyl
280 p 4-F CH2 (1) 501
NH C02Me
(5) 3-cyanophenyl
280a p 4-F CH2 (1) 501
NH C02Me
(5) 3-cyanophenyl
280b p 4-F CH2 (1) 500
NH CONMe
(5) 3-cyanophenyl
280c p 4-F CH2 (1) 486
NH CONH2
(5) 3-(1-
280d P 4-F CH2 (1) hydroxyethyl)- 520
NH C02Me phenyl
(5) phenyl
280e r H CH2 (1) 458
NH C02Me
(5) phenyl
280f P 4-F CH2 (1) 462
NH C02H
(5) 3-cyanophenyl
2808 r H CH2 (1) 483
NH C02Me
(5) 3-methoxyphenyl
280h r H CH2 (1) 488
NH C02Me
(5) 3-acetylphenyl
2801 r H CH2 (1) 500
NH C02Me
(5) 3-acetylphenyl
280j p 4-F CH2 (1) 518
HCl(sal ~ C02Me
t)
179

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(5) 3-cyanophenyl
280k p 4-F CH2 (1) 501
HCl(salNH C02Me
t)
(4) phenyl
281 p 4-F CH2 (1) 476
NH C02Me
(5) phenyl
281a p 4-F CH2 (1) 476
NH C02Me
(5) phenyl
281b p 4-F CH2 (1) 475
NH CONMe
(5) phenyl
281c p 4-F CH2 (1) 461
NH CONH2
3-methoxyphenyl
282 p 4-F CH2 (1) (4) 506
NH
C02Me
3-methoxyphenyl
282a p 4-F CH2 (1) (5) 506
NH
C02Me
(5) 3-methoxyphenyl
282b p 4-F CH2 (1) 505
NH CONMe
(5) 3-acetylphenyl
282c p 4-F CH2 (1) 518
NH C02Me
(5) 3-acetylphenyl
282d p 4-F CH2 (1) 517
NH CONMe
(5) 3-acetylphenyl
282e p 4-F CH2 (1) 503
NH CONH2
(4) 3-cyanophenyl
283 p 4-F CH2 (1) 473
NH ~.OH
3-cyanophenyl
284 p 4-F CH2 (1) (3-4) 493
NH fused
Phenyl
180

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3-methoxyphenyl
285 p 4-F CH2 (1) (3-4) 498
NH fused
Phenyl
3-cyanophenyl
286 p 4-F CH2 (1) (4) 562
NH
-CONPh
3-cyanophenyl
286a p 4-F CH2 (1) (5) 562
NH
-CONPh
3-acetylphenyl
286b p 4-F CH2 (1) (5) 579
NH
-CONPh
(4) 3-methoxyphenyl
287 p 4-F CH2 (1) 478
NH OOH
(4) 3-cyanophenyl
288 p 4-F CH2 (1) 500
NH CONMe
(4) 3-cyanophenyl
288a p 4-F CH2 (1) 500
HCl(salNH CONMe
t)
(5) 3-acetylphenyl
288b p 4-F CH2 (1) 517
HC1(sal~ CONMe
t)
(5) 3-acetylphenyl
288c p 4-F CH2 (1) 574
NH CON
(CH2)2
NMe2
(5) 3-acetylphenyl
288d p 4-F CH2 (1) 557
NH CON
(CH2)2
NMe2
(5) 3-acetylphenyl
288e p 4-F CH2 (1) 453
NH CON
C3H5
(5) 3-acetylphenyl
288f p 4-F CH2 (1) 531
NH CON
C3 H5
(5) 3-methoxyphenyl
2888 p 4-F CH2 (1) 519
NH CONMe2
181

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(5) 3-acetylphenyl
288h p 4-F CH2 (1) 531
NH CONMe2
(5) 3-acetylphenyl
2881 p 4-F CH2 (1) 580
NH CON(2-
pyridin
y1)
(5) 3-methoxyphenyl
288j p 4-F CH2 (1) 568
NH CONMe2
2,5-
289 p H CH2 (1) H difluorophenyl 450
CH2NH
3-cyanophenyl
290 p H CH2 (1) H 439
CH2NH
3-carboethoxy-
291 p H CH2 (1) H phenyl 486
CH2NH
3-methoxyphenyl
292 p H CH2 (1) H 444
CH2NH
4-methoxyphenyl
293 p H CH2 (1) H 444
CH2NH
3-methoxyphenyl
294 p H ~ (1) H 460
~~~ NH
OH
3-methoxyphenyl
295 r H (1) H 460
~~~~ NH
OH
3-cyanophenyl
296 p H ~ (1) H 455
~~~ NH
OH
3-carboethoxy-
297 p H ~ (1) H phenyl 502
~~~ NH
OH
182

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phenyl
298 p H ~ (1) H 430
~~~ NH
OH
(5) phenyl
299 p 4-F CH2 (1) 448
NH ~OH
phenyl
300 p H ~~~~ (1) H 443
NH
NOH
phenyl
301 p H ~ (2) H 428
~~, NH
O
phenyl
302 p H ~ (2) H 430
~~~ NH
OH
phenyl
303 p 4-F ~ (1) H 448
~~~ NH
OH
3-methoxyphenyl
304 p 4-F ~ (1) H 478
~~~ NH
OH
3-cyanophenyl
305 p 4-F ~ (1) H 473
~~~ NH
OH
(3-4) 3-cyanophenyl
306 p H ~ (1) 499
~~~ NH
OH
O
3-cyanophenyl
307 p H CH2-CH2 (1) H 439
NH
3-cyanophenyl
308 p 4-F CH2-CH2 (1) H 457
NH
183

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3-methoxyphenyl
309 p H CH2-CH2(1) H 444
NH
3-methoxyphenyl
310 p 4-F CH2CH2 (1) H 462
NH
3-methoxyphenyl
311 r H CH2-CH2(1) H 444
NH
3-acetylphenyl
312 p 4-F CH2-CH2(1) H 474
NH
4-fluorophenyl
313 p 4-F CH2-CH2(1) H 450
NH
1-adamantyl
314 p 4-F CH2-CH2(1) H 490
NH
(3-4) 3-cyanophenyl
315 s H CH2 (1) 483
NH O~ (M+)
3-cyanophenyl
316 s H CH2 (1) (4) 455
NH OH (M+)
3-cyanophenyl
317 s H CH2 (1) (4) 539
NH 0-
(M+)
(2-THP)
184

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TABLE 3.1
Ris
N Ris
HN~NHR3 U
O ~ N
HN~NHR3
Ris
O
b
N-
HN~NHR3
O
MS
Ex Core R16 Stereo- Salt
# 3 +
M+H
chemistry Form
400 a H 1,2 trans - 3-methoxylphenyl 436
racemic
401 a 4-F 1,2 trans - 3-methoxylphenyl 454
racemic
402 a H 1,2 cis - 3-methoxylphenyl 436
racemic
403 a 4-F 1,2 trans - 3-cyanophenyl 449
racemic
403a a 4-F 1,2 trans - 3-acetylphenyl 466
racemic
403b a 4-F 1,2 trans - 3-nitrophenyl 469
racemic
403c a 4-F 1,2 trans - 4-nitrophenyl 469
racemic
403d a 4-F 1,2 trans - 4-pyridinyl 425
racemic
403e a 4-F 1,2 trans HC1 3-acetylphenyl 466
racemic
403f a 4-F 1,2 trans - (1H)-indazol-5-yl 464
racemic
404 a 4-F 1S,2R - 3-acetylphenyl 466
185

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405 a 4-F 1S,2R - 3-cyanophenyl 449
406 a 4-F 1S,2R - 3-methoxylphenyl 454
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-methoa~yphenyl 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 HC1 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 HC1 3-acetylphenyl 466
186

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417 b 4-F 1R,2S,3S - 3-cyanophenyl 449
418 b 4-F 1R,2S,3R - 3-cyanophenyl 449
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)-indol-6-yl 463
429 b 4-F 1R,2S,3S - (1H)-2,3- 491
dimethylindol-5-yl
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-fluorophenyl467
433 b 4-F 1R,2S,3S - 3-acetyl-4- 484
fluorophenyl
434 b 4-F 1R,2S,3S - 3,5-diacetylphenyl 508
435 b 4-F 1R,2S,3S - 3-(1-hydroxyethyl)- 468
phenyl
436 b 4-F 1R,2S,3S - 4-methyl-thiazol-2-yl445
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-2-yl432
439 b 4-F 1R,2S,3S - 4-chlorol-benzthiazol-515
2-yl
440 b 4-F 1R,2S,3S - thiazol-2-yl 431
441 b 4-F 1R,2S,3S - 5-methyl-isoxazol-3-yl429
187

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442 b 4-F 1R,2S,3S - 1-methyl-pyrazol-3-yl428
443 b 4-F 1R,2S,3S - 4-(1,2,4-triazol-1- 491
yl)phenyl
443a b 4-F 1R,2R,3S - 4-(1,2,4-triazol-1- 491
yl)phenyl
444 b 4-F 1R,2S,3S - (1H)-3-chloro-indazol-499
5-yl
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-indazol-464
1-yl
463 b 4-F 1R,2S,3S - 3-chlorophenyl 458
464 b 4-F 1R,2S,3S - 3-fluoro-4- 456
methylphenyl
188

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465 b 4-F 1R,2S,3S - 3-cyano-4-(1- 515
pyrazolyl)phenyl
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-dimetho~cyphenyl484
470 b 4-F 1R,2S,3S - 2,5-dimethoxyphenyl 484
471 b 4-F 1R,2S,3S - 2-methoxy-5- 468
methylphenyl
472 b 4-F 1R,2S,3S - 2-methyl-5- 456
fluorophenyl
473 b 4-F 1R,2S,3S - 3,5-bis((1H)-1- 588
methyltetrazol-5-
yl)phenyl
474 b 4-F 1R,2S,3S - (3-((1H)-1- 506
methyltetrazol-5-
1)phenyl
475 b 4-F 1R,2S,3S - (4- 517
(carboethoxymethyl)thi
azol-2-yl
476 b 4-F 1R,2S,3S - 5-bromothiazol-2-yl 509
477 b 4-F 1R,2S,3S - 4,5-di(4- 619
fluorophenyl)thiazol-
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 CF3C02H indanon-6-yl 478
481 b 4-F 1R,2S,3S CF3CO2H indanon-4-yl 478
482 b 4-F 1R,2S,3S CF3C02H 4-(isopropyl)phenyl 466
483 b 4-F 1R,2S,3S CF3C02H 3-nitro-4-methylphenyl483
484 b 4-F 1R,2S,3S CF3C02H trans-2- 464
phenylcycloprop-1-yl
485 b 4-F 1R,2S,3S CF3C02H 2,4-difluorophenyl 460
486 b 4-F 1R,2S,3S CF3C02H 2,5-difluorophenyl 460
487 b 4-F 1R,2S,3S CF3C02H 2,4-dichlorophenyl 492
488 b 4-F 1R,2S,3S CF3C02H 2,5-dichlorophenyl 492
189

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489 b 4-F 1R,2S,3S CF3C02H 2-methoxyphenyl 454
490 b 4-F 1R,2S,3S CF3C02H 2,4-dimethoxy-phenyl484
491 b 4-F 1R,2S,3S CF3C02H 2,5-dimethoxyphenyl 484
492 b 4-F 1R,2S,3S CF3C02H 2- 492
trifluoromethylyphenyl
493 b 4-F 1R,2S,3S CF3C02H 2-methylphenyl 438
494 b 4-F 1R,2S,3S CF3C02H 3-trifluoromethyly- 492
phenyl
495 b 4-F 1R,2S,3S CF3C02H 3-methylphenyl 438
496 b 4-F 1R,2S,3S CF3C02H 4-methoxyphenyl 454
497 b 4-F 1R,2S,3S CF3C02H 4-carboethoxy-phenyl496
498 b 4-F 1R,2S,3S CF3C02H 4-trifluoromethyly- 492
phenyl
499 b 4-F 1R,2S,3S CF3C02H 4-methylphenyl 438
500 b 4-F 1R,2S,3S CF3C02H 2-fluorophenyl 442
501 b 4-F 1R,2S,3S CF3C02H 2-chloropheny 458
502 b 4-F 1R,2S,3S CF3C02H 2-nitrophenyl 469
503 b 4-F 1R,2S,3S CF3C02H 2,4-dichlorophenyl 563
504 b 4-F 1R,2S,3S CF3C02H 3-nitrophenyl 469
505 b 4-F 1R,2S,3S CF3C02H 3,5-di 560
(trifluoromethyly)-
phenyl
506 b 4-F 1R,2S,3S CF3C02H 2,4-dimethylyphenyl 452
507 b 4-F 1R,2S,3S CF3C02H 2,4-dimethoxy-5- 518
chlorophenyl
508 b 4-F 1R,2S,3S CF3C02H 3,4,5-trimethoxyphenyl514
509 b 4-F 1R,2S,3S CF3C02H 3,5-dimethylphenyl 452
510 b 4-F 1R,2S,3S CF3C02H 3-trifluoromethyl-4-526
chlorophenyl
511 b 4-F 1R,2S,3S CF3C02H 4-phenoxyphenyl 516
512 b 4-F 1R,2S,3S CF3C02H 4-ethoxyphenyl 468
513 b 4-F 1R,2S,3S CF3C02H 4-thiomethylphenyl 470
190

CA 02413421 2002-12-19
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514 b 4-F 1R,2S,3S CF3C02H 2-naphthyl 474
515 b 4-F 1R,2S,3S CF3C02H 4-acetylphenyl 466
516 b 4-F 1R,2S,3S CF3C02H 2,6-dichloro-pyridin-493
4-yl
517 b 4-F 1R,2S,3S CF3C02H 5-indan-4-yl 464
518 b 4-F 1R,2S,3S CF3C02H 4-chloronaphth-1-yl 508
519 b 4-F 1R,2S,3S CF3C02H 3-fluoro-4- 472
methoxyphenyl
520 b 4-F 1R,2S,3S CF3C02H 4-(methylsulfonyl)- 502
phenyl)
521 b 4-F 1R,2S,3S CF3C02H 3-(methylsulfonyl)- 502
phenyl
522 b 4-F 1R,2S,3S CF3C02H 2-((1H)-pyrrol-1- 489
yl)phenyl
523 b 4-F 1R,2S,3S CF3C02H 1,3-benzodioxol-5-yl468
524 b 4-F 1R,2S,3S CF3C02H 1-acetylindolin-6-yl507
525 b 4-F 1R,2S,3S CF3C02H 4-(6- 571
methylbenzothiazol-2-
1)phenyl
526 b 4-F 1R,2S,3S CF3C02H 4-((2,2- 523
- dimethylpropanoyl)amin
o)phen 1
527 b 4-F 1R,2S,3S CF3C02H 4-(1-methyltetrazol-5-506
yl)phenyl
528 b 4-F 1R,2S,3S CF3C02H 4-(1-morpholino)phenyl509
529 b 4-F 1R,2S,3S CF3C02H quinolin-8-yl 475
530 b 4-F 1R,2S,3S CF3C02H 3-hydroxyphenyl 440
531 b 4-F 1R,2S,3S CF3C02H 4-(acetylamino)-phenyl481
532 b 4-F 1R,2S,3S CF3C02H 4-hydroxyphenyl 440
533 b 4-F 1R,2S,3S CF3C02H 3-hydro~cy-4- 470
methoxyphenyl
534 b 4-F 1R,2S,3S CF3C02H 3-(acetylamino)-phenyl481
535 b 4-F 18,25,35 CF3C02H 4-fluoro-3- 456
methylphenyl
536 b 4-F 18,2S,35 CF3C02H 3-methoxy-4- 468
methylphenyl
537 b 4-F 1R,2S,3S CF3C02H 4-chloro-3- 472
methylphenyl
538 b 4-F 1R,2S,3S CF3C02H 4-(N- 481
methylcarboacamide)phen
y1
191

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539 b 4-F 1R,2S,3S CF3C02H 1-adamantyl 482
540 b 4-F 1R,2S,3S CF3C02H quinolin-5-yl 475
541 b 4-F 1R,2S,3S CF3C02H quinolin-6-yl 475
542 b 4-F 1R,2S,3S CF3C02H 1,4-benzodioxan-6-yl482
543 b 4-F 1R,2S,3S CF3C02H isoquinolin-5-yl 475
544 b 4-F 1R,2S,3S CF3C02H 4-(sulfonamide)-phenyl503
545 b 4-F 1R,2S,3S CF3C02H benzotriazol-5-yl 465
546 b 4-F 1R,2S,3S CF3C02H 2-hydroxy-4- 454
methylphenyl
547 b 4-F 1R,2S,3S CF3C02H 3-hydroxy-4- 454
methylphenyl
548 b 4-F 1R,2S,3S CF3C02H 2-methyl-benzothiazol-495
5-yl
549 b 4-F 1R,2S,3S CF3C02H (4-methoxylphenyl)- 468
methyl
550 b 4-F 1R,2S,3S CF3C02H (4-fluorophenyl)- 456
methyl
551 b 4-F 1R,2S,3S CF3C02H (4-methylphenyl)- 452
methyl
552 b 4-F 1R,2S,3S CF3C02H (1R)-1-(phenyl)ethyl452
553 b 4-F 1R,2S,3S CF3C02H 1-acetylindolin-5-yl507
554 b 4-F 1R,2S,3S CF3C02H 5,6,7,8- 478
tetrahydronaphth-1-yl
555 b 4-F 1R,2S,3S CF3C02H 3-acetyl-4- 482
hydroxyphenyl
556 b 4-F 1R,2S,3S CF3C02H 4-(piperidin-1- 507
yl)phenyl
557 b 4-F 1R,2S,35 CF3C02H cyclohexyl 430
558 b 4-F 1R,2S,3S CF3C02H 2-methoxyphenyl 468
559 b 4-F 1R,2S,3S CF3C02H 2,6-dimethylphenyl 452
560 b 4-F 1R,2S,3S CF3C02H 2-ethylphenyl 452
561 b 4-F 1R,2S,3S CF3C02H 2,4,6-trimethylphenyl466
562 b 4-F 1R,2S,3S CF3C02H 2,5-dimethoxyphenyl 484
563 b 4-F 1R,2S,3S CF3C02H t-butyl 404
192

CA 02413421 2002-12-19
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564 b 4-F 1R,2S,3S CF3C02H i-propyl 390
565 b 4-F 1R,2S,3S CF3C02H Ethoxycarbonyl-methyl)434
566 b 4-F 1R,2S,3S CF3C02H 2-trifluoromethoxy- 508
phenyl
567 b 4-F 1R,2S,3S CF3C02H (1R,S)-1-- 462
(methoxycarbonyl)-2-
methyl-prop 1
568 b 4-F 1R,2S,3S CF3C02H [(1S)-1- 510
(methoxycarbonyl)-2-
henylethyl
569 b 4-F 1R,2S,3S CF3C02H 2,4,4-trimethyl-2- 460
pentyl
570 b 4-F 1R,2S,3S CF3C02H 2-phenylethyl 452
571 b 4-F 1R,2S,3S CF3C02H 3-acetylphenyl 466
572 b 4-F 1R,2S,3S CF3C02H 2-carbomethoa~y-phenyl482
573 b 4-F 1R,2S,3S CF3C02H (1S)-1-(phenyl)ethyl452
574 b 4-F 1R,2S,3S CF3C02H 4-(phenyl)phenyl 500
575 b 4-F 1R,2S,3S CF3C02H 1-naphthyl 474
576 b 4-F 1R,2S,3S CF3C02H 2-(phenyl)phenyl 500
577 b 4-F 1R,2S,3S CF3C02H Phenylmethoxy 454
578 b 4-F 1R,2S,3S CF3C02H 3,4-dimethoxyphenyl 484
579 b 4-F 1R,2S,3S CF3C02H (3H)-2- 520
ethylquinazolin-4-on-
3-yl
580 b 4-F 1R,2S,3S CF3C02H 3-pyridinyl 425
581 b 4-F 1R,2S,3S CF3C02H 6-methoxy-3-pyridinyl455
582 b 4-F 1R,2S,3S CF3C02H 2-methylquinolin-8-yl489
583 b 4-F 1R,2S,3S CF3C02H 2-methylnaphth-1-yl 488
584 b 4-F 1R,2S,3S CF3C02H 4-((1H)-1-propyl- 534
tetrazol-5-yl)phenyl
585 b 4-F 1R,2S,3S CF3C02H 3-aminophenyl 439
586 b 4-F 1R,2S,3S - 3-(acetylamino)-phenyl481
587 b 4-F 1R,2S,3S CF3C02H 3-(N-methylcarbamoyl)-481
phenyl
588 b 4-F 1R,2S,3S CF3C02H 2-nitro-4- 499
methoxyphenyl
193

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589 b 4-F 1R,2S,3S CF3C02H 8-hydroxyquinolin-5-yl491
590 b 4-F 1R,2S,3S CF3C02H 3-methylpyridin-2-yl439
591 b 4-F 1R,2S,3S CF3C02H isoquinolin-1-yl 475
Example 318
0
N ~0
Part A: Preparation of 1-t-butyloxycarbonyl-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 Bicarbonate (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 = 97.9%. NMR (300 MHz, CDC13)8 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).
194

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O O
O
)H + OH
erythro threo
Part B: Preparation of erythro-and threo-cis-4-
benzyl-1-t-butoxycarbonyl-oc-ethylpiperidinemethanol
1-t-butyloxycarbonyl-4-benzylpiperidine (5.0 g,
18.2 mmol, 1.0 eq.) was dissolved in Et20 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 Et20. 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 = 11.20 and 0.91 g of a colorless oil as
isomer B, yield = 15.0%.
Isomer A NMR (300 MHz, CDC13)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).
195

CA 02413421 2002-12-19
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Isomer B NMR (300 MHz, CDC13)$ 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); 2.60-2.40 (m, 2H); 1.90-1.00 (m, 9H); 1.44 (s,
9H); 0.96 (t, 3H, J = 7 Hz).
O
' N- \
O
H
erythro
Part C: Structure determination of Isomer B via
cyclization to 40G, 60~, 7oG-4-benzyl-7-ethyl-8-oxa-1-
azabicyclo[4.3.0]nonane-9-one
Isomer B (60 mg, 0.18 mmol, 2 eq.) was dissolved in DMF
at 25 °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 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 = 640. Product
structure confirmed by N.O.E. NMR (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) .
196

CA 02413421 2002-12-19
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)H
Part D: Preparation of erythro-cis-4-benzyl-OC-
ethylpiperidinemethanol
Erythro-cis-4-benzyl-1-t-butoxycarbonyl-oc-
ethylpiperidinemethanol(isomer B from part B)(815 mg,
2.44 mmol, 1 eq.) was dissolved in 8 mL of ethanol at 25
°C under N2. NaOH (391 mg, 9.78 mmol, 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) 8
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
-- ~N
>H o v
Part E: Preparation of erythro-cis-4-benzyl-oc-
ethyl-1-(3-N-phthalimido-n-prop-1-yl)piperidinemethanol
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Erythro-cis-4-benzyl-oc-ethylpiperidinemethanol
(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 200% EtOAc then 4:1 chloroform/MeOH. Obtained 200
mg. Yield = 57%.
NMR (300 MHz, CDC13) S 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) .
~NH~
)H
Part F: Preparation of erythro-cis-1-(3-amino-n-
prop-1-yl)-4-benzyl-oc-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 N2.
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
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was removed in vacuo to yield an oil which was stirred
in Et20. The triturated solids were filtered and the
filtrate solvent was removed in vacuo to yield 120 mg of
an oil. Yield = 870. NMR (300 MHz, CDC13) 8 7.27 (t,
2H, J = 7 Hz); 7.17 (d, 1H, J = 7 Hz); 7.13 (d, 2H, J =
7 Hz); 3.70-3.30 (m, 2H); 3.20-3.00 (m, 2H); 3.00-2.70
(m, 2H); 2.70-2.40 (m, 2H); 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 ) .
0
0
H H H
.~ ~N~N O + ~ ~N~ H O
H
)H )~N
O /
O
Part G: preparation of erythro-cis-1-[3-(3-
acetylphenylaminocarbonylamino)-n-prop-1-yl]-4-benzyl-oG-
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-OG-
ethylpiperidinemethanol (120 mg, 0.41 mmol, 1 eq.) was
dissolved in 5 mL of THF at 25 °C under N~ 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
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CA 02413421 2002-12-19
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chloroform/MeOH. Isolated mono-addition product
(product A) along with an additional bis-addition
product (product B). Proud A yielded 81 mg of an oil.
Yield = 43%. Product B yielded 43 mg of an oil.
Product A NMR (300 MHz, CDC13) 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, = Hz); 6.30-6.05 (m,
J 7
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 (m, 2H); 1.80-1.40 (m, 5H);1.30 -1.05 (m, 2H);
0.94 (t, 3H, = Hz).
J 7
Product B NMR (300 MHz, CDC13) 8 10.80-10.60 (m, 1H);
8.20-8.00 (m, 1H); 7.91 (bs, 1H); 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, 10H); 1.00-0.80 (m, 3H)
Product A was separated into its enantiomers employing a
Daicel Chiral Pack AD column, eluting with 0.10
diethylamine in methanol. (-)-isomer [oG]D25 (c = 0.300
g/dL, MeOH) - -14.9°. (+) -isomer [oc]D~5 (c = 0.290 g/dL,
MeOH) - +20.2°.
The following compounds can be synthesized by the
methods discussed previously:
TABLE 3b.
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CA 02413421 2002-12-19
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O 61 / ~3R3 6 / ~ R3
O 1 ' 3
~N~N 2 N~N 2
N H H N' ' H H
OH OH
/ R2 / R2
R1 ~ R1
a
5
3 O 61 \ , 3R
R ~3
O 1 \ 3 \'
~N 2 ~N~N 2
N H N H H
H O
NH
1
R2 O ~ R3
R1 ~ /
R1
5 4
6 / / R3
O 1 ' ~ 3
~N~N 2
N H H
_ O~NH
1
/ R2 O ~ / R3
R1
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
324 a,b H (CH3)2CH --- 3-COCH3 466
325 a,b H CH3CH2CH2CH2 --- 3-COCH3 480
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326 a,b H (CH3)2CHCH2 --- 3-COCH3 480
327 d,e H CH3CH2 --- 3-COCH3 613
328 d,e H CH3CH2CH2 --- 3-COCH3 627
329 d,e H (CH3)2CH --- 3-COCH3 627
330 d,e H CH3CH2CH2CH2 --- 3-COCH3 641
331 d,e H (CH3)2CHCH2 --- 3-COCH3 641
EXAMPLE 332
Part A Preparation of N-cyano-N'-3-
methoxyphenylcarbamimidic acid, phenyl ester
,N
i N~ ~
w ~ o~N w ~ 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-
d6) 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 " -cyano-N'-(3-f4-(4-
fluorobenzyl)piperidinelpropyl-N-(3-
methoxyphenyl)auanidine
~N
~I I
N~N~N ~
~I
202

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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
N2 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, CDC13) 8
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) .
20
EXAMPLE 334
Part A: Preparation of f(Methylthio)(3-
acetylphenyl amino)lmethylenepropanedinitrile
N' ,~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 N~ 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-d6) 8 10.66
203

CA 02413421 2002-12-19
WO 01/98270 PCT/USO1/19752
(m, 1H); 7.90 - 7.80 (m, 2H); 7.60 - 7.50 (m, 2H); 2.60
(s, 3H); 2.54 (s, 3H).
Part B: Preparation of 2-[(3-acetylanilino)({3-[4-
(4-fluorobenzyl)-1-piperidinyl]propyl}
amino)methylene]malononitrile
N'~ , N
/ NON 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) S 7.82
(d,
1H, J = 7 Hz) ; 3 1H) ; 7.51 (t, 1H, J= 7 Hz) ;
7.7 (s, 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
O
H
/S N
3 0 02N
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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% ethyl acetatelhexanes, to yield 0.63 g
of a yellow powder as product. Yield = 65%. NMR (300
MHz, CDC13) S 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
H H
N N N
F
O~N
To a suspension of N-[1-(methylthio)-2-
nitroethenyl]-3-acetylbenzenamine (0.30 g, 1.19 mmol,
2.00 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,
CDC13) $ 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),
205

CA 02413421 2002-12-19
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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:
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Table 3c
H H F ~ \ ~ H H
F / N~/\~N~N.R3 / ~,~..r N~N~N'.R3
Z Z
b
F \ F \
/ a"~~N H H I / d..vN \ Z 'R3
.,,~N~N.R H H
II 3
c Z d
F
/ ~~~~N H H
/ N II N.R
3
z
Core Z R3 Mass
Spec
M+1
332 a N-CN 3-methoxyphenyl 424
333 a N-CN 3-acetylphenyl 460
334 a C(CN)2 3-acetylphenyl 460
335 a CHN02 3-acetylphenyl 455
336 b N-CN 3-acetylphenyl 436
337 b C(CN)2 3-acetylphenyl 460
338 b NCONH2 3-acetylphenyl 454
339 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-tetrazol-476
5-yl)phenyl
345 b C(CN)2 3-(1-methyl-1H-tetrazol-500
5-yl)phenyl
346 b NCONH2 3-(1-methyl-1H-tetrazol-494
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5-yl)phenyl
347 b N-CN 2,4-dimethoxy-phenyl 454
348 b N-CN 5-acetyl-2-methoxy- 466
phenyl
349 d N-CN 3-(1-methyl-1H-tetrazol-488
5-yl)phenyl
350 c N-CN phenyl 448
351 c N-CN 3-acetylphenyl 490
352 c N-CN 3-cyanopneyl 473
353 c N-CN 2,4-dimethoxyphenyl 508
354 c N-CN 2,5-dimethoxyphenyl 508
355 c N-CN 5-acetyl-2-methoxy- 520
phenyl
356 c N-CN 2,4-dimethylphenyl 476
357 c N-CN 4-(1-methyl-1H-tetrazol-530
5-yl)phenyl
358 c N-CN 4-(1-propyl-1H-tetrazol-558
5-yl)phenyl
359 c N-CN 5,6,7,8-tetrahydro- 502
naphthy-2-yl-phenyl
360 c N-CN 4-(4-morpholinyl)-phenyl533
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-metho~cy- 544
phenyl
369 c CHN02 3-acetylphenyl 509
370 a CHN02 3-acetylphenyl 560
371 a N-CN 3,5-diacetylphenyl 583
372 a N-CN 3-acetylphenyl 541
373 a N-CN 4-(1-propyl-1H-tetrazol-581
5-yl)phenyl
The following examples were synthesized using the
methods outlined in Schemes 31a and 25c.
EXAMPLE 606
208

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N-f2,4,4-Trimethyl-2-pentyll-N'-f(1R,2S)-2-ff(3S)
3-(4-fluorophenyl)methyl)pi~eridinyllmethyllcyclohexyl
urea
,, / \ F
A solution of amine 194 (Scheme 31a, see also
Example 415, step d) (6 mg, 0.02 mmol) in 1 mL of THF is
treated with 2,4,4-trimethyl-2-pentyl isocyanate (3 ~.,I,L,
0.03 mmol) at room temperature for 1 h. PS-trisamine
(33 mg, 0.15 mmol, Argonaut Technologies Inc.) was added
and stirred for 1 h. The reaction mixture was filtered
and the polymer was washed with CH2C12, and the combined
filtrate was concentrated under vacuum. The residue is
further purified by HPLC, using a VYDAC C18 prepacked
column (10 mm, 22 x 250 mm) and UV detection at 214 nm,
elution with MeCN-H20-TFA (90:10:0.1-10:90:0.1), flow
rate 15 mL/min, to afford 5.6 mg of the urea product as
a solid. 1H NMR (300 MHz, DMDO-D6) 8.33 (bs, 1 H), 7.23-
7.10 (m, 5 H), 6.75-6.72 (d, 1H, J = 7 Hz, 1 H), 5.75
5.70 (d, J = 8 Hz, 1H), 3.40 (m, 1 H), 3.18 (m, 1 H),
3.05 (m, 1 H), 2.95 (m, 1 H), 2.75 (m, 1 H), 2.60 (m, 1
H), 2.45 (m, 1 H), 2.00 (bs, 1 H), 1.90-1.55 (m, 10 H),
1.22 (s, 6 H) , 1.20-1.05 (m, 6 H) , 0.92 (s, 9 H) . MS
esi: (M+H)+ - 460
EXAMPLE 607
N-f(1S)-2-HVdroxy-1-phenylethyll-N'-f(1R,2S)-2-
1 f (3S) -3- (4
fluorophenyl)methyl)pi~eridinyllmethyllcyclohexyll-urea
209

CA 02413421 2002-12-19
WO 01/98270 PCT/USO1/19752
F
N, )
'/H~N ''°'~OH
O
Part A. Preparation of phenyl (1R)-2-hydroxy-
1-phenylethyl carbamate
H
\ O~N ''°'~OH
O
To a mixture of 137.2 mg of R-(-)-2-phenylglycinol
(1.0 mmol) and 250 mg polyvinyl-pyridine (Aldrich, 25%
crosslinked) in 3 mL THF were added 188 ~,L (1.5 mmol)
phenyl chloroformate. The reaction mixture was mixed at
room temperature for overnight. To this mixture were
then added 500 mg (2 mmols) PS-trisamine and the
reaction mixed for additional 3 h. The reaction mixture
was then filtered and the volatiles evaporated to give
the title compound. MS esi: (M+H)+ - 258. This
compound is used for next step without purification.
Part B. preparation of N-f(1R) -2-hydroxy-1-
phenylethyll-N'-(1R,2S)-2-ff(3S)-3-(4-
fluorophenyl)methyl)piperidinyllmethyllcyclohexyll-urea
210

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WO 01/98270 PCT/USO1/19752
F
N'
./
,,
°' OOH
O
Amine 194 (Scheme 31a, see also Example 415, step
d) (6 mg, 0.02 mmol) and the product from Part A (25.8
mg, 0.1 mmol, ca 5 eq.) were mixed and then stirred
overnight. PS-trisamine (44 mg, 0.2 mmol, Argonaut
Technologies Inc.) was added and stirred for 8 h. The
reaction mixture was filtered and the polymer was washed
with CH2C12, and the combined filtrate was concentrated
under vacuum. The residue is further purified by HPLC,
using a VYDAC C18 prepacked column (10 mm, 22 x 250 mm)
and W detection at 214 nm, elution with MeCN-H20-TFA
(90:10:0.1-10:90:0.1), flow rate 15 mL/min, to afford
2.6 mg of urea 607 as a solid. MS esi: (M+H)+ - 468.
EXAMPLE 615
N"-Cyano-N-(2-ethoxyethyl)-N'-llR,2S)-2-ff(3S)-3-(4-
fluorophenyl)methyl)piperidinyllmethyllcyclohexyll-
auanidine
\ l F
N
~~NH
N/'H-~O~
CN
Part A. Preparation of N-cyano-N'-3-
ethoxyeth~rlcarbamimidic acid, phenyl ester
NC,
n
~O N O
H
211

CA 02413421 2002-12-19
WO 01/98270 PCT/USO1/19752
2-Ethoxyethylamine (0.315 mL, 3 mmol, 1 eq.), and
diphenylcyanocarbonimidate (715 mg, 3 mmol, 1 eq.) were
mixed and refluxed in acetonitrile for overnight. The
solvent was removed in vacuo, and the residue was
subjected to flash chromatography, eluting with 50%
Ethyl acetate/hexane, to yield 467 mg product as a white
solid. MS esi: (M+H)+ - 234.
Part B. Preparation of N"-cyano-N-(2-ethox~rethyl)-
N'-(1R,2S)-2-ff(3S)-3-(4-
fluorophenyl)methyl)piperidinyllmethyllcyclohexyll-
ctuanidine
Amine 194 (Scheme 31a) (15 mg, 0.05 mmol) and the
product from Part A (117 mg, 0.5 mmol, 10 eq.) were
mixed then stirred overnight. The reaction was stripped
and the residue then purified in silica gel in 100%
ethyl acetate followed by 9:1 ethyl acetate/methanol.
The product was further purified by HPLC, using a VYDAC
C18 prepacked column (10 mm, 22 x 250 mm) and W
detection at 214 nm, elution with MeCN-H20-TFA
(90:10:0.1-10:90:0.1), flow rate 15 mLlmin, to afford
13.6 mg of pure product as a white solid. 1H NMR (300
MHz, CD30D) 7.20 (m, 2 H), 7.05 (m, 2 Hj, 3.62-3.35 (m,
11 H), 3.15 (m, 1 H), 3.10-2.8 (m, 2 H), 2.70-2.50 (m, 3
H), 2.10-2.65 (m, 8 H), 1.45-1.10 (m, 5 H), 1.10 (t, J =
8 Hz, 3 H). MS esi: (M+H)+ - 444.
The following compounds can be prepared by
procedures described previously.
Table 3d
212

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F I i ,,,..~N
H H
..~N Z N~R3
Ex. 2 R3 Mass Spec
# M+1
601 O t-butyl 404
602 O i-proryl 390
603 O C2H50COCH2 434
604 O CH3 462
CH3'
C02CH3
605 O Ph~~ 510
C02CH3
606 O H CCH3CH3 460
3 ~I L
H3C~~3
607 O Ph~~ 468
HO'
608 O NH2COCH~ 405
6 0 0 CH3 OCH~ CH2 4 0 6
9
610 O CZHSOCHZCH2 420
611 NCN C2H50COCH2 458
612 N(CN)2 CH30CH2CH2 454
613 NCN PhOCH2CH2 492
614 NCN CHgOCH2CH~ 430
615 NCN C2H50CH2CH2 444
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
213

CA 02413421 2002-12-19
WO 01/98270 PCT/USO1/19752
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 1a-44.
TABLE 4*
G/~N~ ~ R3 G/~N~N N_R G/~N~N~N'R.3
H H p 3 H H
1a 2a 3a
C~.,~N~ ~~ R~ C'~Nw/~,.N N_R C~~N~N~N,R3
H H p 3 H H
1b 2b 3b
~N~N~I~T'R3 G~N~N~N R3 G~N~N~N'R3
G H H ~ H H
5 6 7
G/~N~ G/~N ~N~
G ~ H
i H
N'R3 ~'~R3 ~~R3
8a ~ 9a ~ 10
C~,~N~ C~,~N G~N
i H - I 1 H H
~N.R3 ~N.R3 ~N.R3
8b ~ 9b ~ 11
J H ~ H
HNY~R3 HNY~R3
12a ~ 13a
H ~ H
HN~N_R3 HN~~'R3
12b ~ 13b
214

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G~ ~ H G
N N _
1
H
I~R3 HN~'I~R3
14 O 15 0
G/~ G/
~ ~ H
H HN~~ R3
~~~ R3
16a 0 17a 0
HN ~
R3 ~ R3
16b O 17b 0
G~ ~ H R
N N _ 1
~N. 1 HNYN.
R3 R3
18 0 19 0
G~~ G~~N~'
~ ~ R
~
N 3
R3 IvI-
H H N
20a H H
21a
C~~~t~ N~ N-R3 C~~~~ ~ R3
H H H H
20b 21b
~~I~ ~~~/Q"'
~ ~
R2 .R2
N R N N
N_ 1 H H
Rl H H
22 23
G/~N~ N N. R ~;~~N~ N N_ /~N~ N N.
3 ~ R3 G Y R3
24 25 0 26 0
G/~N H N N. R C~,~N H N N. R G~N OH N N_R3
3 ~ 3
Me O Me 0 Me O
27 28 29
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G H H H C~y~ H H H ~ H H H
'~N N N. N~N N.R3 G N~N~N.R3
Y R3 YY
iPrO iPrO iPrO
30 31 32
G/~N H N N. R C~~N H N N. R ~N OH N N.
3 ~ ~ 3 G R
'~ Y
iBuO iBuO iBuO
33 34 35
G/~N H N N. R C~~N H N N. R ~N H N N.
3 ~ ~ 3 R
G ~ Y 3
Ph O Ph O Ph 0
36 37 3g
OH H ~ ~~ OH H ~ ~N H H
R3 ~ R3 G~, ~ R3
Ph O Ph O Ph O
39 40 41
H I~ ~~,~ H H g~ R l-~N OH H IH'I.
R3 ~ 3 G ~ R3
Ph O Ph 0 Ph 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-NHMe-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
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22 4-F-Ph 3-OCF3-Ph
23 4-F-Ph 3-SCH3-Ph
24 4-F-Ph 3-SOCH3-Ph
25 4-F-Ph 3-S02CH3-Ph
26 4-F-Ph 3-OH-Ph
27 4-F-Ph 3-CH20H-Ph
28 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
37 4-F-Ph 3-CH2C02Me-Ph
38 4-F-Ph 3-(1- i eridinyl)-Ph
39 4-F-Ph 3-(1-pyrrolidinyl)-Ph
40 4-F-Ph 3-(2-imidazolyl)-Ph
41 4-F-Ph 3-(1-imidazolyl)-Ph
42 4-F-Ph 3-(2-thiazolyl)-Ph
43 4-F-Ph 3-(3- razolyl)-Ph
44 4-F-Ph 3-(1-pyrazol 1)-Ph
45 4-F-Ph 3-(1-tetrazol 1)-Ph
46 4-F-Ph 3-(5-tetrazolyl)-Ph
47 4-F-Ph 3-(2-pyridyl)-Ph
48 4-F-Ph 3-(2-thienyl)-Ph
49 4-F-Ph 3-(2-furanyl)-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
57 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
67 4-F-Ph 4-S02NH2-Ph
68 4-F-Ph 4-S02NHMe-Ph
69 4-F-Ph 4-CF3-Ph
70 4-F-Ph 4-OCH3-Ph
71 4-F-Ph 4-OPla.-Ph
72 4-F-Ph 4-OCF3-Ph
73 4-F-Ph 4-SCH3-Ph
74 4-F-Ph 4-SOCH3-Ph
75 4-F-Ph 4-S02CH3-Ph
76 4-F-Ph 4-OH-Ph
77 4-F-Ph 4-CH20H-Ph
78 4-F-Ph 4-CHOHCH3-Ph
79 4-F-Ph 4-COH(CH3)2-Ph
80 4-F-Ph 4-CH3-Ph
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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- iperidinyl)-Ph
88 4-F-Ph 4-(1-pyrrolidinyl)-Ph
89 4-F-Ph 4-(2-imidazolyl)-Ph
90 4-F-Ph 4-(1-imidazolyl)-Ph
91 4-F-Ph 4-(2-thiazolyl)-Ph
92 4-F-Ph 4-(3- razolyl)-Ph
93 4-F-Ph 4-(1-pyrazolyl)-Ph
94 4-F-Ph 4-(1-tetrazolyl)-Ph
95 4-F-Ph 4-(5-tetrazolyl)-Ph
96 4-F-Ph 4-(2-pyrid 1)-Ph
97 4-F-Ph 4-(2-thien 1)-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
206 4-F-Ph 2-F-Ph
107 4-F-Ph 2-C1-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
113 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
132 4-F-Ph 2-Ph-Ph
133 4-F-Ph 2-CH2Ph-Ph
134 4-F-Ph 2-CH2C02Me-Ph
135 4-F-Ph 2-(1-piperidinyl)-Ph
136 4-F-Ph 2-(1-pyrrolidinyl)-Ph
137 4-F-Ph 2-(2-imidazolyl)-Ph
138 4-F-Ph 2-(1-imidazolyl)-Ph
139 ~ 4-F-Ph 2-(2-thiazolyl)-Ph
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140 4-F-Ph 2-(3-pyrazolyl)-Ph
141 4-F-Ph 2-(1- razol 1)-Ph
142 4-F-Ph 2-(1-tetrazolyl)-Ph
143 4-F-Ph 2-(5-tetrazolyl)-Ph
144 4-F-Ph 2-(2-pyridyl)-Ph
145 4-F-Ph 2-(2-thienyl)-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-Cl-2-Me0-Ph
160 4-F-Ph 5-Cl-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-naphthyl
168 4-F-Ph 2-naphthyl
169 4-F-Ph 2-thienyl
170 4-F-Ph 3-thienyl
171 4-F-Ph 2-furanyl
172 4-F-Ph 3-furanyl
173 4-F-Ph 2-pyridyl
174 4-F-Ph 3- yridyl
175 4-F-Ph 4- yridyl
176 4-F-Ph 2-indolyl
177 4-F-Ph 3-indolyl
178 4-F-Ph 5-indolyl
179 4-F-Ph 6-indolyl
180 4-F-Ph 3-indazolyl
181 4-F-Ph 5-indazolyl
182 4-F-Ph 6-indazolyl
183 4-F-Ph 2-imidazolyl
184 4-F-Ph 3-pyrazolyl
185 4-F-Ph 2-thiazolyl
186 4-F-Ph 5-tetrazolyl
187 4-F-Ph 2-benzimidazol 1
188 4-F-Ph 5-benzimidazolyl
189 4-F-Ph 2-benzothiazolyl
190 4-F-Ph 5-benzothiazolyl
191 4-F-Ph 2-benzoxazolyl
192 4-F-Ph 5-benzoxazolyl
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
219

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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-Cl-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-Cl-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
238 2-F-Ph 3,4-diCl-Ph
239 2-F-Ph 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-thienyl
243 2-F-Ph 2-furanyl
244 2-F-Ph 2-pyridyl
245 2-F-Ph 4-pyridyl
246 2-F-Ph 2-imidazolyl
247 2-F-Ph 3-pyrazolyl
248 2-F-Ph 2-thiazol 1
249 2-F-Ph 5-tetrazolyl
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
220

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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
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-diF-Ph 2-thienyl
298 2,4-diF-Ph 2-furanyl
299 2,4-diF-Ph 2-pyridyl
300 2,4-diF-Ph 4-pyridyl
301 2,4-diF-Ph 2-imidazolyl
302 2,4-diF-Ph 3-pyrazolyl
303 2,4-diF-Ph 2-thiazolyl
304 2,4-diF-Ph 5-tetrazolyl
305 2,4-diF-Ph 1-adamantyl
306 4-Cl-Ph ph
307 4-Cl-Ph 3-CN-Ph
308 4-C1-Ph 3-COCH3-Ph
309 4-C1-Ph 3-C02Me-Ph
310 4-C1-Ph 3-C02Et-Ph
311 4-C1-Ph 3-C02H-Ph
312 4-C1-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
221

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317 4-C1-Ph 3-N02-Ph
318 4-C1-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-C1-Ph 3-S02NH2-Ph
323 4-Cl-Ph 3-S02NHMe-Ph
324 4-Cl-Ph 3-CF3-Ph
325 4-Cl-Ph 3-OCH3-Ph
326 4-Cl-Ph 3-OPh-Ph
327 4-C1-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-C1-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-Cl-Ph 3-iPr-Ph
339 4-Cl-Ph 3-tBu-Ph
340 4-C1-Ph 3-Ph-Ph
341 4-C1-Ph 3-CH2Ph-Ph
342 4-Cl-Ph 3-CH2C02Me-Ph
343 4-C1-Ph 3-(1-piperidinyl)-Ph
344 4-C1-Ph 3-(1-pyrrolidinyl)-Ph
345 4-C1-Ph 3-(2-imidazolyl)-Ph
346 4-C1-Ph 3-(1-imidazolyl)-Ph
347 4-C1-Ph 3-(2-thiazolyl)-Ph
348 4-C1-Ph 3-(3-pyrazolyl)-Ph
349 4-C1-Ph 3-(1-pyrazolyl)-Ph
350 4-C1-Ph 3-(1-tetrazolyl)-Ph
351 4-C1-Ph 3-(5-tetrazolyl)-Ph
352 4-C1-Ph 3-(2-p ridyl)-Ph
353 4-C1-Ph 3-(2-thienyl)-Ph
354 4-C1-Ph 3-(2-furanyl)-Ph
355 4-C1-Ph 4-CN-Ph
356 4-C1-Ph 4-COCH3-Ph
357 4-Cl-Ph 4-C02Me-Ph
358 4-C1-Ph 4-C02Et-Ph
359 4-Cl-Ph 4-C02H-Ph
360 4-C1-Ph 4-CONH2-Ph
361 4-Cl-Ph 4-CONHMe-Ph
362 4-C1-Ph 4-CONHPh-Ph
363 4-Cl-Ph 4-NHCONH2-Ph
364 4-Cl-Ph 4-F-Ph
365 4-C1-Ph 4-CI-Ph
366 4-Cl-Ph 4-Br-Ph
367 4-Cl-Ph 4-N02-Ph
368 4-C1-Ph 4-NH2-Ph
369 4-Cl-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
222

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376 4-Cl-Ph 4-OPh-Ph
377 4-Cl-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-Cl-Ph 4-CHOHCH3-Ph
384 4-Cl-Ph 4-COH(CH3)2-Ph
385 4-C1-Ph 4-CH3-Ph
386 4-C1-Ph 4-C2H5-Ph
387 4-C1-Ph 4-iPr-Ph
388 4-Cl-Ph 4-tBu-Ph
389 4-C1-Ph 4-Ph-Ph
390 4-C1-Ph 4-CH2Ph-Ph
391 4-Cl-Ph 4-CH2C02Me-Ph
392 4-C1-Ph 4-(1-piperidin 1)-Ph
393 4-C1-Ph 4-(1- rrolidinyl)-Ph
394 4-C1-Ph 4-(2-imidazolyl)-Ph
395 4-Cl-Ph 4-(1-imidazolyl)-Ph
396 4-C1-Ph 4-(2-thiazol 1)-Ph
397 4-C1-Ph 4-(3-pyrazolyl)-Ph
398 4-C1-Ph 4-(1-pyrazolyl)-Ph
399 4-Cl-Ph 4-(1-tetrazolyl)-Ph
400 4-Cl-Ph 4-(5-tetrazolyl)-Ph
401 4-Cl-Ph 4-(2-pyridyl)-Ph
402 4-Cl-Ph 4-(2-thienyl)-Ph
403 4-C1-Ph 4-(2-furanyl)-Ph
404 4-Cl-Ph 2-CN-Ph
405 4-Cl-Ph 2-COCH3-Ph
406 4-C1-Ph 2-C02Me-Ph
407 4-C1-Ph 2-C02Et-Ph
408 4-C1-Ph 2-C02H-Ph
409 4-Cl-Ph 2-CONH2-Ph
410 4-Cl-Ph 2-CONHMe-Ph
411 4-CI-Ph 2-F-Ph
412 4-Cl-Ph 2-Cl-Ph
413 4-Cl-Ph 2-Br-Ph
414 4-CI-Ph 2-N02-Ph
415 4-C1-Ph 2-NH2-Ph
416 4-C1-Ph 2-NHMe-Ph
417 4-C1-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-C1-Ph 2-OPh-Ph
424 4-C1-Ph 2-OCF3-Ph
425 4-C1-Ph 2-SCH3-Ph
426 4-C1-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
4_3_3 4-C1-Ph 2-CH3-Ph
434 ~ 4-C1-Ph 2-C2H5-Ph
223

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435 4-Cl-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-C1-Ph 2-CH2C02Me-Ph
440 4-C1-Ph 2-(1-piperidinyl)-Ph
441 4-C1-Ph 2-(1-pyrrolidinyl)-Ph
442 4-Cl-Ph 2-(2-imidazolyl)-Ph
443 4-Cl-Ph 2-(1-imidazolyl)-Ph
444 4-Cl-Ph 2-(2-thiazolyl)-Ph
445 4-Cl-Ph 2-(3-pyrazolyl)-Ph
446 4-C1-Ph 2-(1-pyrazolyl)-Ph
447 4-Cl-Ph 2-(1-tetrazolyl)-Ph
448 4-C1-Ph 2-(5-tetrazolyl)-Ph
449 4-Cl-Ph 2-(2-pyridyl)-Ph
450 4-C1-Ph 2-(2-thienyl)-Ph
451 4-C1-Ph 2-(2-furanyl)-Ph
452 4-Cl-Ph 2,4-diF-Ph
453 4-Cl-Ph 2,5-diF-Ph
454 4-C1-Ph 2,6-diF-Ph
455 4-C1-Ph 3,4-diF-Ph
456 4-C1-Ph 3,5-diF-Ph
457 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-Cl-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-Cl-Ph 5-C1-2-Me0-Ph
465 4-Cl-Ph 5-Cl-2-Me-Ph
466 4-Cl-Ph 2-F-5-Me-Ph
467 4-C1-Ph 2-F-5-N02-Ph
468 4-Cl-Ph 3,4-OCH20-Ph
469 4-C1-Ph 3,4-OCH2CH20-Ph
470 4-Cl-Ph 2-Me0-4-Me-Ph
471 4-C1-Ph 2-Me0-5-Me-Ph
472 4-C1-Ph 1-naphthyl
473 4-C1-Ph 2-naphthyl
474 4-C1-Ph 2-thienyl
475 4-Cl-Ph 3-thienyl
476 4-C1-Ph 2-furanyl
477 4-C1-Ph 3-furanyl
478 4-C1-Ph 2-pyridyl
479 4-Cl-Ph 3-pyridyl
480 4-Cl-Ph 4-pyridyl
481 4-C1-Ph 2-indolyl
482 4-C1-Ph 3-indolyl
483 4-C1-Ph 5-indolyl
484 4-C1-Ph 6-indolyl
485 4-C1-Ph 3-indazolyl
486 4-C1-Ph 5-indazol 1
487 4-C1-Ph 6-indazolyl
488 4-C1-Ph 2-imidazol 1
489 4-C1-Ph 3-pyrazolyl
490 4-Cl-Ph 2-thiazolyl
491 4-Cl-Ph 5-tetrazolyl
492 4-Cl-Ph 2-benzimidazolyl
493 ~ 4-C1-Ph 5-benzimidazolyl
224

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494 4-Cl-Ph 2-benzothiazolyl
495 4-Cl-Ph 5-benzothiazol 1
496 4-C1-Ph 2-benzoxazolyl
497 4-C1-Ph 5-benzoxazolyl
498 4-Cl-Ph 1-adamantyl
499 4-C1-Ph 2-adamantyl
500 4-C1-Ph t-Bu
501 2-C1-Ph 3-CN-Ph
502 2:-C1-Ph 3-COCH3-Ph
503 2-Cl-Ph 3-C02Me-Ph
504 2-Cl-Ph 3-C02Et-Ph
505 2-Cl-Ph 3-C02H-Ph
506 2-Cl-Ph 3-CONH2-Ph
507 2-Cl-Ph 3-F-Ph
508 2-Cl-Ph 3-Cl-Ph
509 2-C1-Ph 3-NH2-Ph
510 2-Cl-Ph 3-S02NH2-Ph
511 2-Cl-Ph 3-CF3-Ph
512 2-Cl-Ph 3-OCH3-Ph
513 2-Cl-Ph 3-OEt-Ph
514 2-Cl-Ph 3-OCF3-Ph
515 2-C1-Ph 3-S02CH3-Ph
516 2-C1-Ph 3-OH-Ph
517 2-Cl-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-C1-Ph 4-C02Me-Ph
522 2-C1-Ph 4-C02Et-Ph
523 2-C1-Ph 4-C02H-Ph
524 2-Cl-Ph 4-CONH2-Ph
525 2-Cl-Ph 4-F-Ph
526 2-Cl-Ph 4-C1-Ph
527 2-Cl-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-C1-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-C1-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-Cl-Ph 2,5-diCl-Ph
543 2-Cl-Ph 3,4-diCl-Ph
544 2-Cl-Ph 3,5-diCl-Ph
545 2-C1-Ph 3,4-OCH20-Ph
546 2-Cl-Ph 3,4-OCH2CH20-Ph
547 2-C1-Ph 2-thienyl
548 2-Cl-Ph 2-furanyl
549 2-Cl-Ph 2-pyridyl
550 2-C1-Ph 4-p ridyl
551 2-C1-Ph 2-imidazol 1
~52 2-Cl-Ph 3-pyrazolyl
225

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553 2-C1-Ph 2-thiazolyl
554 2-Cl-Ph 5-tetrazolyl
555 2-C1-Ph 1-adamantyl
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 4-0Et-Ph
587 2,4-diCl-Ph 4-OCF3-Ph
588 2,4-diCl-Ph 4-S02CH3-Ph
589 2,4-diCl-Ph ' 4-0H-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-thienyl
603 2,4-diCl-Ph 2-furanyl
604 2,4-diCl-Ph 2-p ridyl
605 2,4-diCl-Ph 4- ridyl
606 2,4-diCl-Ph 2-imidazolyl
607 2,4-diCl-Ph 3-pyrazolyl
608 2,4-diCl-Ph 2-thiazolyl
609 2,4-diCl-Ph 5-tetrazolyl
610 2,4-diCl-Ph 1-adamantyl
611 3-OCH3-Ph 3-CN-Ph
226

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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-thienyl
658 3-OCH3-Ph 2-furanyl
659 3-OCH3-Ph 2-pyridyl
660 3-OCH3-Ph 4-pyridyl
661 3-OCH3-Ph 2-imidazolyl
662 3-OCH3-Ph 3-pyrazolyl
663 3-OCH3-Ph 2-thiazolyl
664 3-OCH3-Ph 5-tetrazol 1
665 3-OCH3-Ph 1-adamantyl
666 2-thienyl 3-CN-Ph
667 2-thienyl 3-COCH3-Ph
668 2-thienyl 3-F-Ph
669 2-thien 1 3-Cl-Ph
I 670 ~ 2-thienyl ( 3-NH2-Ph
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671 2-thienyl 3-OCH3-Ph
672 2-thienyl _ 3-OH-Ph
673 2-thienyl 4-CN-Ph
674 2-thienyl 4-COCH3-Ph
675 2-thienyl 4-F-Ph
676 2-thienyl 4-C1-Ph
677 2-thienyl 4-NH2-Ph
678 2-thienyl 4-OCH3-Ph
679 2-thienyl 4-OH-Ph
680 2-thienyl 3,4-diF-Ph
681 2-thienyl 3,5-diF-Ph
682 2-thienyl 3,4-diCl-Ph
683 2-thienyl 3,5-diCl-Ph
684 2-thienyl 3,4-OCH20-Ph
685 2-thienyl 3,4-OCH2CH20-Ph
686 3-thienyl 3-CN-Ph
687 3-thienyl 3-COCH3-Ph
688 3-thienyl 3-F-Ph
689 3-thienyl 3-Cl-Ph
690 3-thienyl 3-NH2-Ph
691 3-thienyl 3-OCH3-Ph
692 3-thienyl 3-OH-Ph
693 3-thien 1 4-CN-Ph
694 3-thien 1 4-COCH3-Ph
695 3-thienyl 4-F-Ph
696 3-thienyl 4-C1-Ph
697 3-thienyl 4-NH2-Ph
698 3-thienyl 4-OCH3-Ph
699 3-thienyl 4-OH-Ph
700 3-thienyl 3,4-diF-Ph
701 3-thienyl 3,5-diF-Ph
702 3-thienyl 3,4-diCl-Ph
703 3-thienyl 3,5-diCl-Ph
704 3-thienyl 3,4-OCH20-Ph
705 3-thienyl 3,4-OCH2CH20-Ph
706 2-furanyl 3-CN-Ph
707 2-furanyl 3-COCH3-Ph
708 2-furanyl 3-F-Ph
709 2-furanyl 3-C1-Ph
710 2-furanyl 3-NH2-Ph
711 2-furanyl 3-OCH3-Ph
712 2-furanyl 3-OH-Ph
713 2-furanyl 4-CN-Ph
714 2-furanyl 4-COCH3-Ph
715 2-furanyl 4-F-Ph
716 2-furanyl 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-furanyl 3,4-OCH2CH20-Ph
726 3-furanyl 3-CN-Ph
727 3-furanyl 3-COCH3-Ph
728 3-furanyl 3-F-Ph
729 3-furanyl 3-Cl-Ph
228

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730 3-furanyl 3-NH2-Ph
73l 3-furanyl 3-OCH3-Ph
732 3-furanyl 3-OH-Ph
733 3-furanyl 4-CN-Ph
734 3-furanyl 4-COCH3-Ph
735 3-furanyl 4-F-Ph
736 3-furanyl 4-Cl-Ph
737 3-furanyl 4-NH2-Ph
738 3-furanyl 4-OCH3-Ph
739 3-furan 1 4-OH-Ph
740 3-furanyl 3,4-diF-Ph
741 3-furanyl 3,5-diF-Ph
742 3-furanyl 3,4-diCl-Ph
743 3-furanyl 3,5-diCl-Ph
744 3-furanyl 3,4-OCH20-Ph
745 3-furanyl 3,4-OCH2CH20-Ph
746 2- yridyl 3-CN-Ph
747 2-pyridyl 3-COCH3-Ph
748 2-pyrid 1 3-F-Ph
749 2-pyridyl 3-Cl-Ph
750 2- ridyl 3-NH2-Ph
751 2- yridyl 3-OCH3-Ph
752 2-pyridyl 3-OH-Ph
753 2-pyridyl 4-CN-Ph
754 2-pyridyl 4-COCH3-Ph
755 2-pyrid 1 4-F-Ph
756 2-pyridyl 4-C1-Ph
757 2-pyridyl 4-NH2-Ph
758 2-pyrid 1 4-OCH3-Ph
759 2- yridyl 4-OH-Ph
760 2-pyrid 1 3,4-diF-Ph
761 2-pyridyl 3,5-diF-Ph
762 2-pyridyl 3,4-diCl-Ph
763 2-pyrid 1 3,5-diCl-Ph
764 2-pyridyl 3,4-OCH20-Ph
765 2-p ridyl 3,4-OCH2CH20-Ph
766 3-pyridyl 3-CN-Ph
767 3-pyridyl 3-COCH3-Ph
768 3-pyridyl 3-F-Ph
769 3- yrid 1 3-C1-Ph
770 3- yrid 1 3-NH2-Ph
771 3-pyridyl 3-OCH3-Ph
772 3-pyridyl 3-OH-Ph
773 3-pyridyl 4-CN-Ph
774 3-pyrid 1 4-COCH3-Ph
775 3-pyridyl 4-F-Ph
776 3-p ridyl 4-C1-Ph
777 3- ridyl 4-NH2-Ph
778 3-pyridyl 4-OCH3-Ph
779 3-p ridyl 4-OH-Ph
780 3-pyridyl 3,4-diF-Ph
781 3-pyridyl 3,5-diF-Ph
782 3-pyridyl 3,4-diCl-Ph
783 3-pyridyl 3,5-diCl-Ph
784 3-pyridyl 3,4-OCH20-Ph
785 3-pyridyl 3,4-OCH2CH20-Ph
786 4-pyridyl 3-CN-Ph
787 4-pyridyl 3-COCH3-Ph
788 4-pyridyl 3-F-Ph
229

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789 4-pyridyl 3-Cl-Ph
790 4-pyridyl 3-NH2-Ph
791 4-pyridyl 3-OCH3-Ph
792 4-pyridyl 3-OH-Ph
793 4-pyridyl 4-CN-Ph
794 4-pyridyl 4-COCH3-Ph
795 4-pyridyl 4-F-Ph
796 4-pyridyl 4-C1-Ph
797 4-p ridyl 4-NH2-Ph.
798 4-pyridyl 4-OCH3-Ph
799 4-pyridyl 4-OH-Ph
800 4-pyridyl 3,4-diF-Ph
801 4-pyridyl 3,5-diF-Ph
802 4-p ridyl 3,4-diCl-Ph
803 4-pyridyl 3,5-diCl-Ph
804 4-pyrid 1 3,4-OCH20-Ph
805 4-pyrid 1 3,4-OCH2CH20-Ph
806 3-indolyl 3-CN-Ph
807 3-indolyl 3-COCH3-Ph
808 3-indolyl 3-F-Ph
809 3-indol 1 3-C1-Ph
810 3-indol 1 3-NH2-Ph
811 3-indolyl 3-OCH3-Ph
812 3-indolyl 3-OH-Ph
813 3-indolyl 4-CN-Ph
814 3-indolyl 4-COCH3-Ph
815 3-indolyl 4-F-Ph
816 3-indolyl 4-Cl-Ph
817 3-indolyl 4-NH2-Ph
818 3-indol 1 4-OCH3-Ph
819 3-indolyl 4-OH-Ph
820 3-indolyl 3,4-diF-Ph
821 3-indolyl 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-indolyl 3,4-OCH2CH20-Ph
826 5-indolyl 3-CN-Ph
827 5-indolyl 3-COCH3-Ph
828 5-indolyl 3-F-Ph
829 5-indolyl 3-Cl-Ph
830 5-indolyl 3-NH2-Ph
831 5-indolyl 3-OCH3-Ph
832 5-indolyl 3-OH-Ph
833 5-indolyl 4-CN-Ph
834 5-indolyl 4-COCH3-Ph
835 5-indolyl 4-F-Ph
836 5-indolyl 4-C1-Ph
837 5-indolyl 4-NH2-Ph
838 5-indolyl 4-OCH3-Ph
839 5-indolyl 4-OH-Ph
840 5-indolyl 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-indolyl 3,4-OCH20-Ph
845 5-indolyl 3,4-OCH2CH20-Ph
846 5-indazolyl 3-CN-Ph
847 5-indazolyl 3-COCH3-Ph
230

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848 5-indazolyl 3-F-Ph
849 5-indazolyl 3-C1-Ph
850 5-indazolyl 3-NH2-Ph
851 5-indazolyl 3-OCH3-Ph
852 5-indazolyl 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-C1-Ph
857 5-indazolyl 4-NH2-Ph
858 5-indazolyl 4-OCH3-Ph
859 5-indazol 1 4-OH-Ph
860 5-indazolyl 3,4-diF-Ph
861 5-indazolyl 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-benzimidazolyl 3-CN-Ph
867 5-benzimidazolyl 3-COCH3-Ph
868 5-benzimidazolyl 3-F-Ph
869 5-benzimidazol 1 3-C1-Ph
870 5-benzimidazolyl 3-NH2-Ph
871 5-benzimidazolyl 3-OCH3-Ph
872 5-benzimidazolyl 3-OH-Ph
873 5-benzimidazolyl 4-CN-Ph
874 5-benzimidazolyl 4-COCH3-Ph
875 5-benzimidazol 1 4-F-Ph
876 5-benzimidazolyl 4-C1-Ph
877 5-benzimidazolyl 4-NH2-Ph
878 5-benzimidazolyl 4-OCH3-Ph
879 5-benzimidazolyl 4-OH-Ph
880 5-benzimidazol 1 3,4-diF-Ph
881 5-benzimidazolyl 3,5-diF-Ph
882 5-benzimidazolyl 3,4-diCl-Ph
883 5-benzimidazolyl 3,5-diCl-Ph
884 5-benzimidazolyl 3,4-OCH20-Ph
885 5-benzimidazolyl 3,4-OCH2CH20-Ph
886 5-benzothiazolyl 3-CN-Ph
887 5-benzothiazolyl 3-COCH3-Ph
888 5-benzothiazolyl 3-F-Ph
889 5-benzothiazolyl 3-Cl-Ph
890 5-benzothiazolyl 3-NH2-Ph
891 5-benzothiazolyl 3-OCH3-Ph
892 5-benzothiazolyl 3-OH-Ph
893 5-benzothiazolyl 4-CN-Ph
894 5-benzothiazolyl 4-COCH3-Ph
895 5-benzothiazolyl 4-F-Ph
896 5-benzothiazolyl 4-C1-Ph
897 5-benzothiazolyl 4-NH2-Ph
898 5-benzothiazolyl 4-OCH3-Ph
899 5-benzothiazolyl 4-OH-Ph
900 5-benzothiazolyl 3,4-diF-Ph
901 5-benzothiazolyl 3,5-diF-Ph
902 5-benzothiazolyl 3,4-diCl-Ph
903 5-benzothiazolyl 3,5-diCl-Ph
904 5-benzothiazolyl 3,4-OCH20-Ph
905 5-benzothiazolyl 3,4-OCH2CH20-Ph
906 5-benzoxazolyl 3-CN-Ph
23l

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907 5-benzoxazolyl 3-COCH3-Ph
908 5-benzoxazolyl 3-F-Ph
909 5-benzoxazolyl 3-Cl-Ph
910 5-benzoxazolyl 3-NH2-Ph
911 5-benzoxazolyl 3-OCH3-Ph
912 5-benzoxazol 1 3-OH-Ph
913 5-benzoxazolyl 4-CN-Ph
914 5-benzoxazolyl 4-COCH3-Ph
:915 5-benzoxazol 1 4-F-Ph
916 5-benzoxazolyl 4-Cl-Ph
917 5-benzoxazol 1 4-NH2-Ph
918 5-benzoxazolyl 4-OCH3-Ph
919 5-benzoxazolyl 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-benzoxazolyl 3,5-diCl-Ph
924 5-benzoxazolyl 3,4-OCH20-Ph
925 5-benzoxazolyl 3,4-OCH2CH20-Ph
TABLE 6*
O 3 O 3 O 3
HN~ N-R HN~ N R HN~ N-R
_ H F H ~.. H
R 4 R 4 R 4
0 3 O O
HN~ H R ~~ N R3 HN~ N R3
C ~ ~ H ~ H
Cl
R14 4 4
R R
0
C1 ~ HN~N~R3
v H
1
OI1 0II
HN~H R3 ~ HNnH Rs
C1
i
14 O 14
/~ I' 3
7 ~'V/~~ HN ~H R g
HN~H R3 HN~H R3
F 21
4
232

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0
1 HN~N'R3
/ " H
F F
~~ ~R ~ R3
i~~~~N
F 14 R14
F F
R~ Q R14
C1 ~~N.R3 15
13 H
C1 C
~ 3 17 ~ R3
N HN- 'H R R14 , HN H
Cl~~~~~ C
C1
R~ R14
16 18
1 O
~ HNJ~N.R3
H
C1
O
N HN N'R3 R14 ~ _Rs
H 2 0 F\~~~~ ~ H
F
F
R14 R14
19 21
~ 3
HN" H R
F
~~N.R13 R14 ~~N.R3
H 23 C1 ~ H
R14 24 R14
22
233

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H HN- 'N-R3 H ~ .R3
H i~',,~~~ HIV H
C1
H HN~IV-R3
R14 H R14
F
25 / 27
R14
~\ J~~N HN~H-R'3 2 6 Cl HN H R
R14 F HN_ _N'R3 3 0 14
H R
28
~14
H HN_ _N'R3 29 C1 H HN~~R3
H H
R14 R
F H ~ Rs
HN~I~ 3 3
31 H
R
3
HN H.R 32 C1 HN,~H R3
36
R14 F 3 R14
3 4 HN H R
H ~ _R3
HN H R14
C1 H ~ Rs
35 HN
R14
F H R3 14
37 HN H 39 R
R14
38
~.~N.R3 HN- _IdR3 C1 ~NR3
H _ H '~~~~~~ _HN ~H
R14 R14 R14
40 41 42
234

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0 3 O ~ O 3
N HN,~N.R 1 ~ N ~~N.R3 F 1 ~ N ~~H.R
~ H ~~~~ ~ H 14
R14~ F R14~ R \ /
43 45
44
_ ~ O O
N HN N~R'3 Cl ' ~ N ~ HN~N~R.3 F 1 ~ N HN~N~R3
Cl 14 H 14 H F ~ 14 H
R \ / R \ / R
\ /
46 47 48
O 3 O O
F ~ ~N HN~H~F' C1 I ~ N ~ J~N.R3 C1 1 \ N ~~N'R3
14 H
F R \ / C1 R14 \ / C1 R14 H
\ /
49
50 51
F O 3 Cl O
O
F ~ N HN~N~R C1~~\~~N HN~N'R.3 C1'~~,.~~~N HN~N'R3
14 H ' ~ H
R \ / R14 F 14 H
\ / R
\ /
52 53 54
O O
N HN~N~R3 F t ~ N HN~N~R3 \ N HN~N~R3
14 H \~~~ H
R \ / R14 F R14 H
\ / \ /
55 56 57
O
F I ~ HN~N~R3 F ~ ~ N HN~H~I'3 \ ~ 3
i
N HN N~R'
H F 14 ~ /
Cl R14 R \ / F i4 H
\ / R
F \ /
58 59
0 ~ 0 s
C1 1 ~ N HN~N~R3 1 ~ N HN~H~R CZ ~ N ~~N,R3
14 H C 1 R14 ~ s' H
R \ / C1 i4
\ / R
\ /
61 62 63
Entry R3 R14
1 Ph CN
2 Ph F
3 Ph C1
4 Ph CH20H
235

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Ph OH
6 Ph NH2
7 Ph C02Me
8 Ph C02Et
9 Ph CONH2
Ph NHPh
11 Ph NHMe
12 Ph OMe
13 Ph C(O)(2-imidazolyl)
14 Ph C(0)(4-imidazolyl)
Ph C(O)(2-thiazolyl)
16 Ph C(0)(4-thiazolyl)
17 Ph C(O)(2-oxazolyl)
18 Ph C(O)(4-oxazolyl)
19 Ph C{O){3-pyrazolyl)
Ph C(0)(4-pyrazolyl)
21 Ph C(O)(5-tetrazolyl)
22 Ph C(0)(2-pyridyl)
23 Ph C(0)(3-pyridyl)
24 Ph C(O)(4-pyridyl)
Ph C(0)(2-thienyl)
26 Ph C(O){3-thienyl)
27 Ph C(0)(2-furanyl)
28 Ph C(O)(3-furanyl)
29 Ph 2-thienyl
Ph 3-thienyl
31 Ph 2-furanyl
32 Ph 3-furanyl
33 Ph 2-pyridyl
34 Ph 3-pyridyl
Ph 4-pyridyl
36 Ph 1-imidazolyl
37 Ph 2-imidazolyl
38 Ph 4-imidazolyl
39 Ph 1-pyrazolyl
Ph 3-pyrazolyl
41 Ph 4-pyrazolyl
42 Ph 2-thiazolyl
43 Ph 4-thiazolyl
44 Ph 5-tetrazolyl
Ph 2-oxazolyl
46 Ph 4-oxazolyl
47 Ph C(0)N(2-imidazolyl)
48 Ph C(0)N(4-imidazolyl)
49 Ph C(O)N(2-thiazolyl)
Ph C(0)N(4-thiazolyl)
236

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51 Ph C(0)N(2-oxazolyl)
52 Ph C(O)N{4-oxazolyl)
53 Ph C(O)N(3-pyrazolyl)
54 Ph C(OjN(4-pyrazolyl)
55 Ph C(0)N(2-pyridyl)
56 Ph C(0)N(3-pyridyl)
57 Ph C{0)N(4-pyridyl)
.
58 Ph C(O)N(2-thienyl)
59 Ph C(0)N(3-thienyl)
60 Ph C(O)N(2-furanyl)
61 Ph C(0)N(3-furanyl)
62 Ph C(0)N(2-pyrrolyl)
63 Ph C(O)N(3-pyrrolyl)
64 Ph CH2(1-imidazolyl)
65 Ph CH2(1-(1,2,3-triazolyl))
66 Ph CH2{2-(1,2,3-triazolyl))
67 Ph CH2(1-(1,2,4-triazolyl))
68 Ph CH2 (1-pyrazolyl)
69 3-CN-Ph CN
70 3-CN-Ph F
71 3-CN-Ph C1
72 3-CN-Ph CH20H
73 3-CN-Ph OH
74 3-CN-Ph NH2
75 3-CN-Ph C02Me
76 3-CN-Ph C02Et
77 3-CN-Ph C0NH2
78 3-CN-Ph NHPh
79 3-CN-Ph NHMe
80 3-CN-Ph OMe
81 3-CN-Ph C(0)(2-imidazolyl)
82 3-CN-Ph C(0)(4-imidazolylj
83 3-CN-Ph C(0)(2-thiazolyl)
84 3-CN-Ph C(O)(4-thiazolyl)
85 3-CN-Ph C(0)(2-oxazolyl)
86 3-CN-Ph C(O){4-oxazolyl)
87 3-CN-Ph C(0)(3-pyrazolylj
88 3-CN-Ph C(O)(4-pyrazolyl)
89 3-CN-Ph C(0)(5-tetrazolyl)
90 3-CN-Ph C(O)(2-pyridyl)
91 3-CN-Ph C(O)(3-pyridyl)
92 3-CN-Ph C(O)(4-pyridyl)
93 3-CN-Ph C(0)(2-thienyl)
94 3-CN-Ph C{O)(3-thienyl)
95 3-CN-Ph C(0)(2-furanyl)
96 3-CN-Ph C(0)(3-furanylj
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97 3-CN-Ph 2-thienyl
98 3-CN-Ph 3-thienyl
99 3-CN-Ph 2-furanyl
100 3-CN-Ph 3-furanyl
101 3-CN-Ph 2-pyridyl
102 3-CN-Ph 3-pyridyl
103 3-CN-Ph 4-pyridyl
104 3-CN-Ph 1-imidazolyl
105 3-CN-Ph 2-imidazolyl
106 3-CN-Ph 4-imidazolyl
107 3-CN-Ph 1-pyrazolyl
108 3-CN-Ph 3-pyrazolyl
109 3-CN-Ph 4-pyrazolyl
110 3-CN-Ph 2-thiazolyl
111 3-CN-Ph 4-thiazolyl
112 3-CN-Ph 5-tetrazolyl
113 3-CN-Ph 2-oxazolyl
114 3-CN-Ph 4-oxazolyl
115 3-CN-Ph C(O)N(2-imidazolyl)
116 3-CN-Ph C(O)N(4-imidazolyl)
117 3-CN-Ph C(0)N(2-thiazolyl)
118 3-CN-Ph C(0)N(4-thiazolyl)
119 3-CN-Ph C(O)N(2-oxazolyl)
120 3-CN-Ph C(0)N(4-oacazolyl)
121 3-CN-Ph C(0)N(3-pyrazolyl)
122 3-CN-Ph C(0)N(4-pyrazolyl)
123 3-CN-Ph C(0)N(2-pyridyl)
124 3-CN-Ph C(O)N(3-pyridyl)
125 3-CN-Ph C(O)N(4-pyridyl)
126 3-CN-Ph C(0)N(2-thienyl)
127 3-CN-Ph C(0)N(3-thienyl)
128 3-CN-Ph C(O)N(2-furanyl)
129 3-CN-Ph C(O)N(3-furanyl)
130 3-CN-Ph C(0)N(2-pyrrolyl)
131 3-CN-Ph C(O)N(3-pyrrolyl)
132 3-CN-Ph CH2(1-imidazolyl)
133 3-CN-Ph CH2(1-(1,2,3-triazolyl))
134 3-CN-Ph CH2(2-(1,2,3-triazolyl))
135 3-CN-Ph CH2(1-(1,2,4-triazolyl))
136 3-CN-Ph CH2(1-pyrazolyl)
137 3-OMe-Ph CN
138 3-OMe-Ph F
139 3-OMe-Ph C1
140 3-OMe-Ph CH20H
141 3-OMe-Ph OH
142 3-OMe-Ph NH2
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143 3-OMe-Ph C02Me
144 3-OMe-Ph C02Et
145 3-OMe-Ph CONA2
146 3-OMe-Ph NHPh
147 3-OMe-Ph NHMe
148 3-OMe-Ph OMe
149 3-OMe-Ph C(O)(2-imidazolyl)
150 3-OMe-Ph C(O)(4-imidazolyl)
151 3-OMe-Ph C(O)(2-thiazolyl)
152 3-OMe-Ph C(O)(4-thiazolyl)
153 3-OMe-Ph C(O)(2-oxazolyl)
154 3-OMe-Ph C(O)(4-oxazolyl)
155 3-OMe-Ph C(O)(3-pyrazolyl)
156 3-OMe-Ph C(O)(4-pyrazolyl)
157 3-OMe-Ph C(0)(5-tetrazolyl)
158 3-OMe-Ph C(O)(2-pyridyl)
159 3-OMe-Ph C(O)(3-pyridyl)
160 3-OMe-Ph C(O)(4-pyridyl)
161 3-OMe-Ph C(O)(2-thienyl)
162 3-OMe-Ph C(O)(3-thienyl)
263 3-OMe-Ph C(O)(2-furanyl)
164 3-OMe-Ph C(0)(3-furanyl)
165 3-OMe-Ph 2-thienyl
166 3-OMe-Ph 3-thienyl
167 3-OMe-Ph 2-furanyl
168 3-OMe-Ph 3-furanyl
169 3-OMe-Ph 2-pyridyl
170 3-OMe-Ph 3-pyridyl
171 3-OMe-Ph 4-pyridyl
172 3-OMe-Ph 1-imidazolyl
173 3-OMe-Ph 2-imidazolyl
174 3-OMe-Ph 4-imidazolyl
175 3-OMe-Ph 1-pyrazolyl
176 3-OMe-Ph 3-pyrazolyl
177 3-OMe-Ph 4-pyrazolyl
178 3-OMe-Ph 2-thiazolyl
179 3-OMe-Ph 4-thiazolyl
180 3-OMe-Ph 5-tetrazolyl
281 3-OMe-Ph 2-oxazolyl
182 3-OMe-Ph 4-oxazolyl
183 3-OMe-Ph C(0)N(2-imidazolyl)
184 3-OMe-Ph C(O)N(4-imidazolyl)
185 3-OMe-Ph C(O)N(2-thiazolyl)
186 3-OMe-Ph C(O)N(4-thiazolyl)
187 3-OMe-Ph C(O)N(2-oxazolyl)
188 3-OMe-Ph C(O)N(4-oxazolyl)
239

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189 3-OMe-Ph C(O)N(3-pyrazolyl)
190 3-OMe-Ph C(O)N(4-pyrazolyl)
191 3-OMe-Ph C(O)N(2-pyridyl)
192 3-OMe-Ph C(O)N(3-pyridyl)
193 3-OMe-Ph C(O)N(4-pyridyl)
194 3-OMe-Ph C(0)N(2-thienyl)
195 3-OMe-Ph C(O)N(3-thienyl)
196 3-OMe-Ph C(O)N(2-furanyl)
197 3-OMe-Ph C(O)N(3-furanyl)
198 3-OMe-Ph C(O)N(2-pyrrolyl)
199 3-OMe-Ph C{O)N(3-pyrrolyl)
200 3-OMe-Ph CH2{1-imidazolyl)
201 3-OMe-Ph CH2{1-(1,2,3-triazolyl)j
202 3-OMe-Ph CH2(2-(1,2,3-triazolyl))
203 3-OMe-Ph CH2(1-(1,2,4-triazolyl))
204 3-OMe-Ph CH2(1-pyrazolyl)
205 3-C(O)Me-Ph CN
206 3-C(O)Me-Ph F
207 3-C(OjMe-Ph Cl
208 3-C(O)Me-Ph CH20H
209 3-C(O)Me-Ph OH
210 3-C (0j Me-Ph NH2
211 3-C{O)Me-Ph C02Me
212 3-C(O)Me-Ph C02Et
213 3-C(O)Me-Ph CONH2
214 3-C(O)Me-Ph NHPh
215 3-C(O)Me-Ph NHMe
216 3-C(O)Me-Ph OMe
217 3-C(0)Me-Ph C(0)(2-imidazolyl)
218 3-C(0)Me-Ph C(O)(4-imidazolyl)
219 3-C(O)Me-Ph C(O)(2-thiazolyl)
220 3-C(0)Me-Ph C(0)(4-thiazolyl)
221 3-C(0)Me-Ph C(O)(2-oxazolyl)
222 3-C(0)Me-Ph C(O)(4-oxazolyl)
223 3-C(0)Me-Ph C(O)(3-pyrazolyl)
224 3-C(0)Me-Ph C(O)(4-pyrazolyl)
225 3-C(O)Me-Ph C(O)(5-tetrazolyl)
226 3-C{0)Me-Ph C{O)(2-pyridyl)
227 3-C(0)Me-Ph C(O)(3-pyridyl)
228 3-C(0)Me-Ph C(O)(4-pyridyl)
229 3-C(0)Me-Ph C(O)(2-thienyl)
230 3-C(0)Me-Ph C{Oj(3-thienyl)
231 3-C(O)Me-Ph C(0)(2-furanyl)
232 3-C(O)Me-Ph C(O){3-furanyl)
233 3-C{O)Me-Ph 2-thienyl
234 3-C(0)Me-Ph 3-thienyl
240

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235 3-C(O)Me-Ph 2-furanyl
236 3-C(O)Me-Ph 3-furanyl
237 3-C{O)Me-Ph 2-pyridyl
238 3-C(O)Me-Ph 3-pyridyl
239 3-C(O)Me-Ph 4-pyridyl
240 3-C(O)Me-Ph 1-imidazolyl
241 3-C(O)Me-Ph 2-imidazolyl
242 3-C(O)Me-Ph 4-imidazolyl
243 3-C(O)Me-Ph 1-pyrazolyl
244 3-C{O)Me-Ph 3-pyrazolyl
245 3-C(O)Me-Ph 4-pyrazolyl
246 3-C(O)Me-Ph 2-thiazolyl
247 3-C(O)Me-Ph 4-thiazolyl
248 3-C(O)Me-Ph 5-tetrazolyl
249 3-C(O)Me-Ph 2-oxazolyl
250 3-C(O)Me-Ph 4-oxazolyl
251 3-C(O)Me-Ph C(O)N(2-imidazolyl)
252 3-C(O)Me-Ph C(O)N(4-imidazolyl)
253 3-C(O)Me-Ph C(O)N(2-thiazolyl)
254 3-C(O)Me-Ph C(O)N(4-thiazolyl)
255 3-C{O)Me-Ph C(O)N(2-oxazolyl)
256 3-C(O)Me-Ph C(O)N(4-oxazolyl)
257 3-C(O)Me-Ph C(O)N(3-pyrazolyl)
258 3-C(O)Me-Ph C(O)N(4-pyrazolyl)
259 3-C(O)Me-Ph C(O)N(2-pyridyl)
260 3-C(O)Me-Ph C(O)N(3-pyridyl)
261 3-C(O)Me-Ph C(O)N{4-pyridyl)
262 3-C(O)Me-Ph C(O)N(2-thienyl)
263 3-C(O)Me-Ph C(O)N(3-thienyl)
264 3-C(O)Me-Ph C(O)N(2-furanyl)
265 3-C(O)Me-Ph C(O)N(3-furanyl)
266 3-C(O)Me-Ph C(O)N(2-pyrrolyl)
267 3-C(O)Me-Ph C(O)N(3-pyrrolyl)
268 3-C(O)Me-Ph CH2(1-imidazolyl)
269 3-C(O)Me-Ph CH2(1-(1,2,3-triazolyl))
270 3-C(O)Me-Ph CH2(2-(1,2,3-triazolyl))
271 3-C(O)Me-Ph CH2(1-(1,2,4-triazolyl))
272 3-C(O)Me-Ph CH2(1-pyrazolyl)
273 4-F-Ph CN
274 4-F-Ph F
275 4-F-Ph C1
276 4-F-Ph CH20H
277 4-F-Ph OH
278 4-F-Ph NH2
279 4-F-Ph C02Me
280 4-F-Ph C02Et
241

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281 4-F-Ph CONH2
282 4-F-Ph NHPh
283 4-F-Ph NHMe
284 4-F-Ph OMe
285 4-F-Ph C(O)(2-imidazolyl)
286 4-F-Ph C(O)(4-imidazolyl)
287 4-F-Ph C(O)(2-thiazolyl)
288 4-F-Ph C(O)(4-thiazolyl)
289 4-F-Ph C(O)(2-oxazolyl)
290 4-F-Ph C(O)(4-oxazolyl)
291 4-F-Ph C(O)(3-pyrazolyl)
292 4-F-Ph C (O) (4-pyrazolyl)
293 4-F-Ph C(O)(5-tetrazolyl)
294 4-F-Ph C(O)(2-pyridyl)
295 4-F-Ph C(O)(3-pyridyl)
296 4-F-Ph C (O) (4-pyridyl)
297 4-F-Ph C(O)(2-thienyl)
298 4-F-Ph C(O)(3-thienyl)
299 4-F-Ph C(O)(2-furanyl)
300 4-F-Ph C(O)(3-furanyl)
301 4-F-Ph 2-thienyl
302 4-F-Ph 3-thienyl
303 4-F-Ph 2-furanyl
304 4-F-Ph 3-furanyl
305 4-F-Ph 2-pyridyl
306 4-F-Ph 3-pyridyl
307 4-F-Ph 4-pyridyl
308 4-F-Ph 1-imidazolyl
309 4-F-Ph 2-imidazolyl
310 4-F-Ph 4-imidazolyl
311 4-F-Ph 1-pyrazolyl
312 4-F-Ph 3-pyrazolyl
313 4-F-Ph 4-pyrazolyl
314 4-F-Ph 2-thiazolyl
315 4-F-Ph 4-thiazolyl
316 4-F-Ph 5-tetrazolyl
317 4-F-Ph 2-oxazolyl
328 4-F-Ph 4-oxazolyl
319 4-F-Ph C(O)N(2-imidazolyl)
320 4-F-Ph C(O)N(4-imidazolyl)
321 4-F-Ph C(O)N(2-thiazolyl)
322 4-F-Ph C(O)N(4-thiazolyl)
323 4-F-Ph C(O)N(2-oxazolyl)
324 4-F-Ph C(O)N(4-oxazolyl)
325 4-F-Ph C(O)N(3-pyrazolyl)
326 4-F-Ph C(O)N(4-pyrazolyl)
242

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327 4-F-Ph C(0)N(2-pyridyl)
328 4-F-Ph C(O)N(3-pyridyl)
329 4-F-Ph C(O)N(4-pyridyl)
330 4-F-Ph C(O)N(2-thienyl)
331 4-F-Ph C(0)N(3-thienyl)
332 4-F-Ph C(O)N(2-furanyl)
333 4-F-Ph C(O)N(3-furanyl)
334 4-F-Ph C(O)N(2-pyrrolyl)
335 4-F-Ph C(O)N(3-pyrrolyl)
336 4-F-Ph CH2(1-imidazolyl)
337 4-F-Ph CH2(1-(1,2,3-triazolyl))
338 4-F-Ph CH2(2-(1,2,3-triazolyl))
339 4-F-Ph CH2(1-(1,2,4-triazolyl))
340 I 4-F-Ph CH2(1-pyrazolyl)
243

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Table 7.
G O G 1 H H G 1 O
N ~N ~LN.R3 N ~ N ~ N. R3 N.~'~/~N ~LN. R3
R ~OH H H R1 OH O Rl OH H H
2a 3a
1a
O 1 H H 1 O
G N~N~N.R2 G N~N~N.R3 G N~N~N-R3
Rl OH H H Rl OH O R1 OH H H
1b 2b 3b
O H H O
.R NON N. N~ ~ ~R3
G N'/~N N 3 G~~ ~ R3 G~~ N N
R R
Rl OH H H 1 OH O 1 OH H H
7
G ~ G
N N H G N" H
H
R1 OH HN~N.R3 R OOH HN~N.R3 Rl OH ~T~N'R3
O 9a O 10 O
8a
G N~ G N H G N~ H
,H
R1 OH ~~N~R3 Rl OH ~~N R3 Rl OH ~~N R3
8b O 9b O 11 O
G ~ ~ G
N H ~N~ H G N
~ H
R1 OH ~~N~R3 Rl OH HN~.N.R3 Ri 'OH HN N'R
p ~ 3
12a 13a O 12b O
G N~ H
R1 OH_ ~' ~N R
3
13b O
244

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G N~ H G N~ H
Rl OH HN~N R3 Rl OH HN~N~R3
14 0 15 0
G ~ G
N~ H N~ H
R1 OH ~~N'g,3 R1 OH HN~N R3
16a O 17a 0
G N~ H G N~ H
Rl OH ~~N R. R1 OH ~~N R3
3
16b 0 17b 0
G N~ H G N~ H
Rl OH ~~N R3 Rl OH ~~N~R3
18 O 19 O
G ~ O G ~, O
N N~LN.R3 N .nN~N.R3
R ~ H H
1 OH 20a H H R1 OH 21a
O O
G N~N~N.Rg G N.,~r~" ~L -R3
N N
R ~OH 2 Ob H H R ~OH 21b H H
0 O
N~ J~ .R2 N~'~~,~.~N.R~
Rl N N G
H H R H H
R1 OH 22 1 OH 23
245

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G 1 OH H H OH H H OH H H
N~N~N.R3 G N~N~N R3 G N~N~N'R.3
R1 OH 0 Rl OH 2 5 O Rl OH 2 6 O
24
G , OH H H ~ OH H H OH H H
N~N~N.R3 G N~N~N.Rg G N'~N~N-R3
R OH Me O R OH Me O R OH Me O
1 2~ 1 28 1 29
OH H H OH H H
G N OH N N G N~N N.R N'~N~N~R3
G
r0 R3 Rl OH ipr0 3 R ~OH lPrO
R1 OH 31 1 3 2
G 1 OH H H 1 OH H H OH H H
N~N~N.R3 G N~N~N R3 G N~N~N'R.3
R1 OH iBuO Rl OH iBuO Rl OH iBuO
33 34 35
G 1 OH H H ~ OH H H OH H H
N~N~N.R3 G N~N~N.R3 G N~N~N R3
Rl OH Ph O Rl OH Ph 0 R1 OH Ph O
36 3~ 38
G 1 OH H H 1 OH H H OH H H
N~N~N.R3 G N~N~N R3 G N~N~Ny,3
Rl OH ph O R1 OH ph O Rl OHphJ O
39 40 41
G H H 1 OH H H OH H H
N N N. G N~N O N R3 G N~N~N R3
R3 O
R1 OH Ph O R1 OH Ph R1 OH Ph
42 43 44
246

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G N ~ ~ G N ~ I H N
H G ~ H
R ~OH ~ ~ N R3 Rl OH HN ~ N ~ R3 Rl OH ~ N R
3
45 46 O 47 O
R1 = a) H, b) methyl, c) ethyl, d) n-propyl, e) allyl,
f) n-butyl, g) n-pentyl, and h) n-hexyl.
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
5 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
20 4-F-Ph 3-Cl-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-NHMe-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
26 4-F-Ph 3-OH-Ph
27 4-F-Ph 3-CH20H-Ph
28 4-F-Ph 3-CHOHCH3-Ph
29 4-F-Ph 3-COH(CH3)2-Ph
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
4-F-Ph 3-Ph-Ph
36 4-F-Ph 3-CH2Ph-Ph
37 4-F-Ph 3-CH2C02Me-Ph
38 4-F-Ph 3-(1-pi eridinyl)-Ph
39 4-F-Ph 3-(1-pyrrolidinyl)-Ph
4-F-Ph 3-(2-imidazolyl)-Ph
41 4-F-Ph 3-(1-imidazolyl)-Ph
42 4-F-Ph 3-(2-thiazolyl)-Ph
43 4-F-Ph 3-(3-pyrazolyl)-Ph
44 4-F-Ph 3-(1-pyrazolyl)-Ph
247

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45 4-F-Ph 3-(1-tetrazolyl)-Ph
46 4-F-Ph 3-(5-tetrazolyl)-Ph
47 4-F-Ph 3-(2-pyridyl)-Ph
48 4-F-Ph 3-(2-thienyl)-Ph
49 4-F-Ph 3-(2-furanyl)-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
57 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
67 4-F-Ph 4-S02NH2-Ph
68 4-F-Ph 4-S02NHMe-Ph
69 4-F-Ph 4-CF3-Ph
70 4-F-Ph 4-OCH3-Ph
71 4-F-Ph 4-OPh-Ph
72 4-F-Ph 4-OCF3-Ph
73 4-F-Ph 4-SCH3-Ph
74 4-F-Ph 4-SOCH3-Ph
75 4-F-Ph 4-S02CH3-Ph
76 4-F-Ph 4-OH-Ph
77 4-F-Ph 4-CH20H-Ph
78 4-F-Ph 4-CHOHCH3-Ph
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-piperidinyl)-Ph
88 4-F-Ph 4-(1-pyrrolidinyl)-Ph
89 4-F-Ph 4-(2-imidazolyl)-Ph
90 4-F-Ph 4-(1-imidazolyl)-Ph
91 4-F-Ph 4-(2-thiazolyl)-Ph
92 4-F-Ph 4-(3-pyrazolyl)-Ph
93 4-F-Ph 4-(1-pyrazolyl)-Ph
94 4-F-Ph 4-(1-tetrazolyl)-Ph
95 4-F-Ph 4-(5-tetrazolyl)-Ph
96 4-F-Ph 4-(2-pyridyl)-Ph
97 4-F-Ph 4-(2-thienyl)-Ph
98 4-F-Ph 4-(2-furanyl)-Ph
9 9 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
248

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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-C1-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
123 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
132 4-F-Ph 2-Ph-Ph
133 4-F-Ph 2-CH2Ph-Ph
134 4-F-Ph 2-CH2C02Me-Ph
135 4-F-Ph 2-(1-piperidinyl)-Ph
136 4-F-Ph 2-(1-pyrrolidinyl)-Ph
137 4-F-Ph 2-(2-imidazolyl)-Ph
138 4-F-Ph 2-(1-imidazolyl)-Ph
139 4-F-Ph 2-(2-thiazolyl)-Ph
140 4-F-Ph 2-(3-pyrazolyl)-Ph
141 4-F-Ph 2-(1-pyrazolyl)-Ph
142 4-F-Ph 2-(1-tetrazolyl)-Ph
143 4-F-Ph 2-(5-tetrazolyl)-Ph
144 4-F-Ph 2-(2-p ridyl)-Ph
145 4-F-Ph 2-(2-thienyl)-Ph
146 4-F-Ph 2-(2-furanyl)-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-Cl-2-Me0-Ph
160 4-F-Ph 5-Cl-2-Me-Ph
161 4-F-Ph 2-F-5-Me-Ph
162 ~ 4-F-Ph 2-F-5-N02-Ph
249

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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-naphth 1
168 4-F-Ph 2-naphthyl
169 4-F-Ph 2-thien 1
170 4-F-Ph 3-thienyl
171 4-F-Ph 2-furanyl
172 4-F-Ph 3-furanyl
173 4-F-Ph 2-pyridyl
174 4-F-Ph 3-pyrid 1
175 4-F-Ph 4-pyridyl
176 4-F-Ph 2-indolyl
177 4-F-Ph 3-indolyl
178 4-F-Ph 5-indolyl
179 4-F-Ph 6-indolyl
180 4-F-Ph 3-indazolyl
181 4-F-Ph 5-indazolyl
182 4-F-Ph 6-indazolyl
183 4-F-Ph 2-imidazol 1
184 4-F-Ph 3-pyrazol 1
185 4-F-Ph 2-thiazolyl
186 4-F-Ph 5-tetrazolyl
187 4-F-Ph 2-benzimidazolyl
188 4-F-Ph 5-benzimidazolyl
189 4-F-Ph 2-benzothiazolyl
190 4-F-Ph 5-benzothiazolyl
191 4-F-Ph 2-benzoxazolyl
192 4-F-Ph 5-benzoxazolyl
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
2 04 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
250

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222 2-F-Ph 4-NH2-Ph
223 2-F-Ph 4-S02NH2-Ph
224 2-F-Ph 4-CF3-Ph
22S 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
238 2-F-Ph 3,4-diCl-Ph
239 2-F-Ph 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- ridyl
245 2-F-Ph 4- yridyl
246 2-F-Ph 2-imidazolyl
247 2-F-Ph 3-pyrazolyl
248 2-F-Ph 2-thiazolyl
249 2-F-Ph 5-tetrazolyl
250 2-F-Ph 1-adamantyl
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
251

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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
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-diF-Ph 2-thienyl
298 2,4-diF-Ph 2-furanyl
299 2,4-diF-Ph 2-pyridyl
300 2,4-diF-Ph 4-pyridyl
301 2,4-diF-Ph 2-imidazol 1
302 2,4-diF-Ph 3- yrazolyl
303 2,4-diF-Ph 2-thiazolyl
304 2,4-diF-Ph 5-tetrazolyl
305 2,4-diF-Ph 1-adamantyl
306 4-Cl-Ph Ph
307 4-C1-Ph 3-CN-Ph
308 4-Cl-Ph 3-COCH3-Ph
309 4-Cl-Ph 3-C02Me-Ph
310 4-Cl-Ph 3-C02Et-Ph
311 4-C1-Ph 3-C02H-Ph
312 4-C1-Ph 3-CONH2-Ph
313 4-C1-Ph 3-CONHMe-Ph
314 4-Cl-Ph 3-F-Ph
315 4-Cl-Ph 3-C1-Ph
316 4-Cl-Ph 3-Br-Ph
317 4-C1-Ph 3-N02-Ph
318 4-C1-Ph 3-NH2-Ph
319 4-Cl-Ph 3-NHMe-Ph
320 4-C1-Ph 3-NMe2-Ph
321 4-C1-Ph 3-NHCOCH3-Ph
322 4-C1-Ph 3-S02NH2-Ph
323 4-C1-Ph 3-S02NHMe-Ph
324 4-C1-Ph 3-CF3-Ph
325 4-C1-Ph 3-OCH3-Ph
326 4-C1-Ph 3-OPh-Ph
327 4-C1-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-C1-Ph 3-OH-Ph
332 4-C1-Ph 3-CH20H-Ph
333 4-Cl-Ph 3-CHOHCH3-Ph
334 4-Cl-Ph 3-COH(CH3)2-Ph
335 4-Cl-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-Cl-Ph 3-tBu-Ph
252

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340 4-C1-Ph 3-Ph-Ph
341 4-C1-Ph 3-CH2Ph-Ph
342 4-Cl-Ph 3-CH2C02Me-Ph
343 4-C1-Ph 3-(1-piperidinyl)-Ph
344 4-C1-Ph 3-(1-pyrrolidinyl)-Ph
345 4-Cl-Ph 3-(2-imidazol 1)-Ph
346 4-C1-Ph 3-(1-imidazolyl)-Ph
347 4-C1-Ph 3-(2-thiazolyl)-Ph
348 4-C1-Ph 3-(3- razolyl)-Ph
349 4-CI-Ph 3-(1-pyrazolyl)-Ph
350. 4-C1-Ph 3-(1-tetrazol 1)-Ph
351 4-C1-Ph 3-(5-tetrazol 1)-Ph
352 4-C1-Ph 3-(2-pyridyl)-Ph.
353 4-C1-Ph 3-(2-thien 1)-Ph
354 4-C1-Ph 3-(2-furanyl)-Ph
355 4-Cl-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-Cl-Ph 4-CONHPh-Ph
3&3 4-C1-Ph 4-NHCONH2-Ph
364 4-C1-Ph 4-F-Ph
365 4-C1-Ph 4-C1-Ph
366 4-Cl-Ph 4-Br-Ph
367 4-C1-Ph 4-N02-Ph
368 4-C1-Ph 4-NH2-Ph
369 4-Cl-Ph 4-NHMe-Ph
370 4-C1-Ph 4-NMe2-Ph
371 4-Cl-Ph 4-NHCOCH3-Ph
372 4-C1-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-C1-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-Cl-Ph 4-S02CH3-Ph
381 4-Cl-Ph 4-OH-Ph
382 4-Cl-Ph 4-CH20H-Ph
383 4-Cl-Ph 4-CHOHCH3-Ph
384 4-C1-Ph 4-COH(CH3)2-Ph
385 4-Cl-Ph 4-CH3-Ph
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-piperidin 1)-Ph
393 4-C1-Ph 4-(1-pyrrolidin 1)-Ph
394 4-Cl-Ph 4-(2-imidazolyl)-Ph
395 4-C1-Ph 4-(1-imidazolyl)-Ph
396 4-C1-Ph 4-(2-thiazolyl)-Ph
397 4-Cl-Ph 4-(3-pyrazolyl)-Ph
398 ~ 4-C1-Ph 4-(1-pyrazolyl)-Ph
253

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399 4-C1-Ph 4-(1-tetrazolyl)-Ph
400 4-C1-Ph 4-(5-tetrazol 1)-Ph
401 4-C1-Ph 4-(2-pyridyl)-Ph
402 4-C1-Ph 4-(2-thienyl)-Ph
403 4-C1-Ph 4-(2-furanyl)-Ph
404 4-C1-Ph 2-CN-Ph
405 4-C1-Ph 2-COCH3-Ph
406 4-Cl-Ph 2-C02Me-Ph
407 4-C1-Ph 2-C02Et-Ph
408 4-C1-Ph 2-C02H-Ph
409 4-C1-Ph 2-CONH2-Ph
410 4-Cl-Ph 2-CONHMe-Ph
411 4-C1-Ph 2-F-Ph
412 4-Cl-Ph 2-C1-Ph
413 4-C1-Ph 2-Br-Ph
414 4-C1-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-Cl-Ph 2-CF3-Ph
422 4-Cl-Ph 2-OCH3-Ph
423 4-C1-Ph 2-OPh-Ph
424 4-C1-Ph 2-OCF3-Ph
425 4-C1-Ph 2-SCH3-Ph
426 4-C1-Ph 2-SOCH3-Ph
427 4-C1-Ph 2-S02CH3-Ph
428 4-C1-Ph 2-0H-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-Cl-Ph 2-CHOHPh-Ph
433 4-Cl-Ph 2-CH3-Ph
434 4-Cl-Ph 2-C2H5-Ph
435 4-Cl-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-Cl-Ph 2-(1-piperidinyl)-Ph
441 4-C1-Ph 2-(1-pyrrolidinyl)-Ph
442 4-C1-Ph 2-(2-imidazolyl)-Ph
443 4-C1-Ph 2-(1-imidazolyl)-Ph
444 4-C1-Ph 2-(2-thiazolyl)-Ph
445 4-C1-Ph 2-(3-pyrazolyl)-Ph
446 4-C1-Ph 2-(1-pyrazolyl)-Ph
447 4-C1-Ph 2-(1-tetrazolyl)-Ph
448 4-Cl-Ph 2-(5-tetrazolyl)-Ph
449 4-C1-Ph 2-(2-pyridyl)-Ph
450 4-C1-Ph 2-(2-thienyl)-Ph
451 4-C1-Ph 2-(2-furanyl)-Ph
452 4-C1-Ph 2,4-diF-Ph
453 4-C1-Ph 2,5-diF-Ph
454 4-C1-Ph 2,6-diF-Ph
455 4-C1-Ph 3,4-diF-Ph
456 4-Cl-Ph 3,5-diF-Ph
457 4-C1-Ph 2,4-diCl-Ph
254

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458 4-Cl-Ph 2,5-diCl-Ph
459 4-C1-Ph 2,6-diCl-Ph
460 4-Cl-Ph 3,4-diCl-Ph
461 4-Cl-Ph 3,5-diCl-Ph
462 4-Cl-Ph 3,4-diCF3-Ph
463 4-Cl-Ph 3,5-diCF3-Ph
464 4-C1-Ph 5-Cl-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-Cl-Ph 3,4-OCH20-Ph
469 4-Cl-Ph 3,4-OCH2CH20-Ph
470 4-Cl-Ph 2-Me0-4-Me-Ph
471 4-Cl-Ph 2-Me0-5-Me-Ph
472 4-C1-Ph 1-naphthyl
473 4-Cl-Ph 2-na hthyl
474 4-Cl-Ph 2-thienyl
475 4-C1-Ph 3-thien 1
476 4-C1-Ph 2-furanyl
477 4-Cl-Ph 3-furanyl
478 4-C1-Ph 2-p ridyl
479 4-C1-Ph 3- ridyl
480 4-C1-Ph 4-pyridyl
481 4-Cl-Ph 2-indolyl
482 4-C1-Ph 3-indolyl
483 4-C1-Ph 5-indol 1
484 4-Cl-Ph 6-indolyl
485 4-C1-Ph 3-indazol 1
486 4-C1-Ph 5-indazolyl
487 4-C1-Ph 6-indazol 1
488 4-C1-Ph 2-imidazolyl
489 4-Cl-Ph 3-pyrazolyl
490 4-C1-Ph 2-thiazol 1
491 4-C1-Ph 5-tetrazolyl
492 4-Cl-Ph 2-benzimidazolyl
493 4-C1-Ph 5-benzimidazolyl
494 4-C1-Ph 2-benzothiazolyl
495 4-Cl-Ph 5-benzothiazolyl
496 4-Cl-Ph 2-benzoxazolyl
497 4-C1-Ph 5-benzoxazolyl
498 4-C1-Ph 1-adamantyl
499 4-C1-Ph 2-adamantyl
500 4-C1-Ph t-Bu
501 2-C1-Ph 3-CN-Ph
502 2-C1-Ph 3-COCH3-Ph
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-C1-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-C1-Ph 3-OCH3-Ph
513 2-C1-Ph 3-OEt-Ph
514 2-Cl-Ph 3-OCF3-Ph
515 2-C1-Ph 3-S02CH3-Ph
516 2-C1-Ph 3-OH-Ph
255

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517 2-Cl-Ph 3-CH3-Ph
518 2-C1-Ph 3-C2H5-Ph
519 2-Cl-Ph 4-CN-Ph
520 2-Cl-Ph 4-COCH3-Ph
521 2-C1-Ph 4-C02Me-Ph
522 2-C1-Ph 4-C02Et-Ph
523 2-C1-Ph 4-C02H-Ph
524 2-Cl-Ph 4-CONH2-Ph
525 2-C1-Ph 4-F-Ph
526 2-C1-Ph 4-C1-Ph
527 2-Cl-Ph 4-NH2-Ph
528 2-C1-Ph 4-S02NH2-Ph
529 2-C1-Ph 4-CF3-Ph
530 2-C1-Ph 4-OCH3-Ph
531 2-Cl-Ph 4-OEt-Ph
532 2-C1-Ph 4-OCF3-Ph
533 2-Cl-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-C1-Ph 2,4-diCl-Ph
542 2-Cl-Ph 2,5-diCl-Ph
543 2-Cl-Ph 3,4-diCl-Ph
544 2-Cl-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-furanyl
549 2-C1-Ph 2-pyridyl
550 2-C1-Ph 4-pyridyl
551 2-Cl-Ph 2-imidazolyl
552 2-Cl-Ph 3-pyrazolyl
553 2-C1-Ph 2-thiazolyl
554 2-C1-Ph 5-tetrazolyl
555 2-C1-Ph 1-adamantyl
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
256

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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-Cl-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-thienyl
603 2,4-diCl-Ph 2-furanyl
604 2,4-diCl-Ph 2-pyridyl
605 2,4-diCl-Ph 4-pyridyl
606 2,4-diCl-Ph 2-imidazolyl
607 2,4-diCl-Ph 3-pyrazolyl
608 2,4-diCl-Ph 2-thiazolyl
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-Cl-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
257

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635 3-OCH3-Ph 4-F-Ph
636 3-OCH3-Ph 4-Cl-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 3,4-0CH2CH20-Ph
657 3-OCH3-Ph 2-thienyl
658 3-OCH3-Ph 2-turan 1
659 3-OCH3-Ph 2-pyridyl
660 3-OCH3-Ph 4- yridyl
661 3-OCH3-Ph 2-imidazolyl
662 3-OCH3-Ph 3-pyrazolyl
663 3-OCH3-Ph 2-thiazolyl
664 3-OCH3-Ph 5-tetrazolyl
665 3-OCH3-Ph 1-adamantyl
666 2-thienyl 3-CN-Ph
667 2-thienyl 3-COCH3-Ph
668 2-thienyl 3-F-Ph
669 2-thienyl 3-Cl-Ph
670 2-thienyl 3-NH2-Ph
671 2-thienyl 3-OCH3-Ph
672 2-thienyl 3-OH-Ph
673 2-thienyl 4-CN-Ph
674 2-thienyl 4-COCH3-Ph
675 2-thienyl 4-F-Ph
676 2-thienyl 4-C1-Ph
677 2-thienyl 4-NH2-Ph
678 2-thienyl 4-OCH3-Ph
679 2-thienyl 4-OH-Ph
680 2-thienyl 3,4-diF-Ph
681 2-thienyl 3,5-diF-Ph
682 2-thienyl 3,4-diCl-Ph
683 2-thienyl 3,5-diCl-Ph
684 2-thienyl 3,4-OCH20-Ph
685 2-thienyl 3,4-OCH2CH20-Ph
686 3-thienyl 3-CN-Ph
687 3-thienyl 3-COCH3-Ph
688 3-thienyl 3-F-Ph
689 3-thienyl 3-Cl-Ph
690 3-thienyl 3-NH2-Ph
691 3-thienyl 3-OCH3-Ph
692 3-thienyl 3-OH-Ph
693 3-thienyl 4-CN-Ph
258

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694 3-thienyl 4-COCH3-Ph
695 3-thienyl 4-F-Ph
696 3-thienyl 4-Cl-Ph
697 3-thienyl 4-NH2-Ph
698 3-thienyl 4-OCH3-Ph
699 3-thienyl 4-OH-Ph
700 3-thien 1 3,4-diF-Ph
701 3-thienyl 3,5-diF-Ph
702 3-thienyl 3,4-diCl-Ph
703 3-thien 1 3,5-diCl-Ph
704 3-thienyl 3,4-OCH20-Ph
705 3-thienyl 3,4-OCH2CH20-Ph
706 2-furanyl 3-CN-Ph
707 2-furanyl 3-COCH3-Ph
708 2-furanyl 3-F-Ph
709 2-furanyl 3-C1-Ph
710 2-furanyl 3-NH2-Ph
711 2-furanyl 3-OCH3-Ph
712 2-furanyl 3-OH-Ph
713 2-furanyl 4-CN-Ph
714 2-furan 1 4-COCH3-Ph
715 2-furan 1 4-F-Ph
716 2-furanyl 4-Cl-Ph
717 2-furanyl 4-NH2-Ph
718 2-furanyl 4-OCH3-Ph
719 2-furanyl 4-OH-Ph
720 2-furanyl 3,4-diF-Ph
721 2-furanyl 3,5-diF-Ph
722 2-furanyl 3,4-diCl-Ph
723 2-furan 1 3,5-diCl-Ph
724 2-furanyl 3,4-OCH20-Ph
725 2-furanyl 3,4-OCH2CH20-Ph
726 3-furanyl 3-CN-Ph
727 3-furanyl 3-COCH3-Ph
728 3-furanyl 3-F-Ph
729 3-furan 1 3-Cl-Ph
730 3-furanyl 3-NH2-Ph
731 3-furanyl 3-OCH3-Ph
732 3-furanyl 3-OH-Ph
733 3-furanyl 4-CN-Ph
734 3-furanyl 4-COCH3-Ph
735 3-furanyl 4-F-Ph
736 3-furanyl 4-C1-Ph
737 3-furanyl 4-NH2-Ph
738 3-furanyl 4-OCH3-Ph
739 3-furanyl 4-OH-Ph
740 3-furanyl 3,4-diF-Ph
741 3-furanyl 3,5-diF-Ph
742 3-furanyl 3,4-diCl-Ph
743 3-furanyl 3,5-diCl-Ph
744 3-furanyl 3,4-OCH20-Ph
745 3-furanyl 3,4-OCH2CH20-Ph
746 2-pyridyl 3-CN-Ph
747 2-pyridyl 3-COCH3-Ph
748 2-pyridyl 3-F-Ph
749 2-pyridyl 3-C1-Ph
750 2- ridyl 3-NH2-Ph
751 2- ridyl 3-OCH3-Ph
752 2-pyridyl 3-OH-Ph
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753 2-pyridyl 4-CN-Ph
754 2-pyridyl 4-COCH3-Ph
755 2-pyridyl 4-F-Ph
756 2-p ridyl 4-Cl-Ph
757 2-p ridyl 4-NH2-Ph
758 2- yrid 1 4-OCH3-Ph
759 2-p ridyl 4-OH-Ph
760 2-pyridyl 3,4-diF-Ph
761 2- yrid 1 3,5-diF-Ph
762 2-p rid 1 3,4-diCl-Ph
763 2- yridyl 3,5-diCl-Ph
764 2- yrid 1 3,4-OCH20-Ph
765 2-pyridyl 3,4-OCH2CH20-Ph
766 3-pyridyl 3-CN-Ph
767 3-pyridyl 3-COCH3-Ph
768 3-p ridyl 3-F-Ph
769 3-pyridyl 3-C1-Ph
770 3-pyridyl 3-NH2-Ph
771 3-pyridyl 3-OCH3-Ph
772 3-pyridyl 3-OH-Ph
773 3-p ridyl 4-CN-Ph
774 3-p rid 1 4-COCH3-Ph
775 3-pyridyl 4-F-Ph
776 3-pyridyl 4-C1-Ph
777 3-pyridyl 4-NH2-Ph
778 3-pyridyl 4-OCH3-Ph
779 3-pyridyl 4-OH-Ph
780 3- yridyl 3,4-diF-Ph
781 3-pyridyl 3,5-diF-Ph
782 3- yridyl 3,4-diCl-Ph
783 3-pyridyl 3,5-diCl-Ph
784 3-pyridyl 3,4-OCH20-Ph
785 3-pyridyl 3,4-OCH2CH20-Ph
786 4-pyridyl 3-CN-Ph
787 4-pyrid 1 3-COCH3-Ph
788 4-pyridyl 3-F-Ph
789 4-pyridyl 3-C1-Ph
790 4-pyridyl 3-NH2-Ph
791 4-pyridyl 3-OCH3-Ph
792 4-pyridyl 3-OH-Ph
793 4-pyridyl 4-CN-Ph
794 4-pyridyl 4-COCH3-Ph
795 4-pyridyl 4-F-Ph
796 4-pyridyl 4-Cl-Ph
797 4-pyridyl 4-NH2-Ph
798 4-pyridyl 4-OCH3-Ph
799 4-pyridyl 4-OH-Ph
800 4-pyridyl 3,4-diF-Ph
801 4-pyridyl 3,5-diF-Ph
802 4-pyridyl 3,4-diCl-Ph
803 4-pyridyl 3,5-diCl-Ph
804 4- yridyl 3,4-OCH20-Ph
805 4-pyridyl 3,4-OCH2CH20-Ph
806 3-indolyl 3-CN-Ph
807 3-indolyl 3-COCH3-Ph
808 3-indolyl 3-F-Ph
809 3-indolyl 3-C1-Ph
810 3-indolyl 3-NH2-Ph
811 3-indolyl 3-OCH3-Ph
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812 3-indolyl 3-OH-Ph
813 3-indolyl 4-CN-Ph
814 3-indolyl 4-COCH3-Ph
815 3-indolyl 4-F-Ph
816 3-indolyl 4-C1-Ph
817 3-indolyl 4-NH2-Ph
818 3-indolyl 4-OCH3-Ph
819 3-indolyl 4-OH-Ph
820 3-indolyl 3,4-diF-Ph
821 3-indolyl 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-indolyl 3,4-OCH2CH20-Ph
826 5-indolyl 3-CN-Ph
827 5-indolyl 3-COCH3-Ph
828 5-indolyl 3-F-Ph
829 5-indolyl 3-Cl-Ph
830 5-indolyl 3-NH2-Ph
831 5-indolyl 3-OCH3-Ph
832 5-indolyl 3-OH-Ph
833 5-indolyl 4-CN-Ph
834 5-indol 1 4-COCH3-Ph
835 5-indolyl 4-F-Ph
836 5-indolyl 4-C1-Ph
837 5-indolyl 4-NH2-Ph
838 5-indolyl 4-OCH3-Ph
839 5-indolyl 4-OH-Ph
840 5-indolyl 3,4-diF-Ph
841 5-indolyl 3,5-diF-Ph
842 5-indolyl 3,4-diCl-Ph
843 5-indolyl 3,5-diCl-Ph
844 5-indolyl 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-indazolyl 3-F-Ph
849 5-indazolyl 3-C1-Ph
850 5-indazolyl 3-NH2-Ph
851 5-indazolyl 3-OCH3-Ph
852 5-indazolyl 3-OH-Ph
853 5-indazol 1 4-CN-Ph
854 5-indazolyl 4-COCH3-Ph
855 5-indazolyl 4-F-Ph
856 5-indazolyl 4-C1-Ph
857 5-indazolyl 4-NH2-Ph
858 5-indazolyl 4-OCH3-Ph
859 5-indazolyl 4-OH-Ph
860 5-indazolyl 3,4-diF-Ph
861 5-indazolyl 3,5-diF-Ph
862 5-indazolyl 3,4-diCl-Ph
863 5-indazolyl 3,5-diCl-Ph
864 5-indazolyl 3,4-OCH20-Ph
865 5-indazolyl 3,4-OCH2CH20-Ph
866 5-benzimidazolyl3-CN-Ph
867 5-benzimidazolyl3-COCH3-Ph
868 5-benzimidazolyl3-F-Ph
_869 5-benzimidazol 3-C1-Ph
1
870 5-benzimidazolyl3-NH2-Ph
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871 5-benzimidazolyl3-OCH3-Ph
872 5-benzimidazol 3-OH-Ph
1
873 5-benzimidazolyl4-CN-Ph
874 5-benzimidazolyl4-COCH3-Ph
875 5-benzimidazolyl4-F-Ph
876 5-benzimidazol 4-C1-Ph
1
877 5-benzimidazolyl4-NH2-Ph
878 5-benzimidazolyl4-OCH3-Ph
879 5-benzimidazol 4-OH-Ph
1
880 5-benzimidazolyl3,4-diF-Ph
881 5-benzimidazol 3,5-diF-Ph
1
882 5-benzimidazolyl3,4-diCl-Ph
883 5-benzimidazolyl3,5-diCl-Ph
884 5-benzimidazol 3,4-OCH20-Ph
1
885 5-benzimidazolyl3,4-OCH2CH20-Ph
886 5-benzothiazolyl3-CN-Ph
887 5-benzothiazolyl3-COCH3-Ph
888 5-benzothiazolyl3-F-Ph
889 5-benzothiazolyl3-C1-Ph
890 5-benzothiazolyl3-NH2-Ph
891 5-benzothiazolyl3-OCH3-Ph
892 5-benzothiazolyl3-OH-Ph
893 5-benzothiazol 4-CN-Ph
1
894 5-benzothiazolyl4-COCH3-Ph
895 5-benzothiazolyl4-F-Ph
896 5-benzothiazol 4-C1-Ph
1
897 5-benzothiazolyl4-NH2-Ph
898 5-benzothiazolyl4-OCH3-Ph
899 5-benzothiazol 4-OH-Ph
1
900 5-benzothiazolyl3,4-diF-Ph
901 5-benzothiazol 3,5-diF-Ph
1
902 5-benzothiazolyl3,4-diCl-Ph
903 5-benzothiazolyl3,5-diCl-Ph
904 5-benzothiazolyl3,4-OCH20-Ph
905 5-benzothiazolyl3,4-OCH2CH20-Ph
906 5-benzoxazolyl 3-CN-Ph
907 5-benzoxazolyl 3-COCH3-Ph
908 5-benzoxazolyl 3-F-Ph
909 5-benzoxazolyl 3-C1-Ph
910 5-benzoxazolyl 3-NH2-Ph
911 5-benzoxazolyl 3-OCH3-Ph
912 5-benzoxazolyl 3-OH-Ph
913 5-benzoxazolyl 4-CN-Ph
914 5-benzoxazolyl 4-COCH3-Ph
915 5-benzoxazolyl 4-F-Ph
916 5-benzoxazolyl 4-C1-Ph
917 5-benzoxazolyl 4-NH2-Ph
918 5-benzoxazolyl 4-OCH3-Ph
919 5-benzoxazolyl 4-OH-Ph
920 5-benzoxazolyl 3,4-diF-Ph
921 5-benzoxazolyl 3,5-diF-Ph
922 5-benzoxazolyl 3,4-diCl-Ph
923 5-benzoxazolyl 3,5-diCl-Ph
924 5-benzoxazolyl 3,4-OCH20-Ph
925 ~ 5-benzoxazolyl 3,4-OCH2CH20-Ph
Utility
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The utility of the compounds in accordance with the
present invention as modulators of chemokine receptor
activity may be demonstrated by methodology known in the
art, such as the assays for CCR-2 and CCR-3 ligand
binding, as disclosed by Ponath et al., J. Exp. Med.,
183, 2437-2448 (1996) and Uguccioni et al., J. Clin.
Invest., 100, 1137-1143 (1997). Cell lines for
expressing the receptor of interest include those
naturally expressing the chemokine receptor, such as
EOL-3 or THP-1, those induced to express the chemokine
receptor by the addition of chemical or protein agents,
such as HL-60 or AML14.3D10 cells treated with, for
example, butyric acid with interleukin-5 present, or a
cell engineered to express a recombinant chemokine
receptor, such as CHO or HEK-293. Finally, blood or
tissue cells, for example human peripheral blood
eosinophils, isolated using methods as described by
Hansel et al., J. Immunol. Methods, 145, 105- 110
(1991), can be utilized in such assays. In particular,
the compound of the present invention have activity in
binding to the CCR-3 receptor in the aforementioned
assays. As used herein, "activity" is intended to mean
a compound demonstrating an IC50 of 10 ~.tM or lower in
concentration when measured in the aforementioned
assays. Such a result is indicative of the intrinsic
activity of the compounds as modulators of chemokine
receptor activity. A general binding protocol is
described below.
CCR3-Receptor Binding Protocol
Millipore filter plates (#MABVN1250) are treated
with 5 [ug/ml protamine in phosphate buffered saline, pH
7.2, fox ten minutes at room temperature. Plates are
washed three times with phosphate buffered saline anal
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incubated with phosphate buffered saline for thirty
minutes at room temperature. For binding, 50 [..l.l of
binding buffer (0.5o bovine serum albumen, 20 mM HEPES
buffer and 5 mM magnesium chloride in RPMI 1640 media)
with or without a test concentration of a compound
present at a known concentration is combined with 50 ~.l
of 125-I labeled human eotaxin (to give a final
concentration of 150 pM radioligand) and 50 ~,l of cell
suspension in binding buffer containing 5x105 total
cells. Cells used for such binding assays can include
cell lines transfected with a gene expressing CCR3 such
as that described by Daugherty et al. (2996), isolated
human eosinophils such as described by Hansel et al.
(2991) or the AML14.3D10 cell line after differentiation
with butyric acid as described by Tiffany et al. (1998).
The mixture of compound, cells and radioligand are
incubated at room temperature for thirty minutes.
Plates are placed onto a vacuum manifold, vacuum
applied, and plates washed three times with binding
buffer with 0.5M NaCl added. The plastic skirt is
removed from the plate, the plate allowed to air dry,
the wells punch out and CPM counted. The percent
inhibition of binding is calculated using the total
count obtained in the absence of any competing compound
or chemokine ligand and the background binding
determined by addition of 100 nM eotaxin in place of the
test compound.
The utility of the compounds in accordance with the
present invention as inhibitors of the migration of
eosinophils or cell lines expressing the chemokine
receptors may be demonstrated by methodology known in
the art, such as the chemotaxis assay disclosed by Bacon
et al., Brit. J. Pharmacol., 95, 966-974 (1988). In
particular, the compound of the present invention have
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activity in inhibition of the migration of eosinophils
in the aforementioned assays. As used herein,
"activity" is intended to mean a compound demonstrating
an IC50 of 10 [~.M or lower in concentration when measured
in the aforementioned assays. Such a result is
indicative of the intrinsic activity of the compounds as
modulators of chemokine receptor activity. A human
eosinophil chemotaxis assay protocol is described below.
Human Eosinophil Chemotaxis Assay
Neuroprobe MBA96 96-well chemotaxis chambers with
Neuroprobe polyvinylpyrrolidone-free polycarbonate PFD5
5-micron filters in place are warmed in a 37°C incubator
prior to assay. Freshly isolated human eosinophils,
isolated according to a method such as that described by
Hansel et al. (1991), are suspended in RPMI 1640 with
0.1% bovine serum albumin at 1 x 106 cells/ml and warmed
in a 37°C incubator prior to assay. A 20 nM solution of
human eotaxin in RPMI 1640 with 0.1o bovine serum
albumin is warmed in a 37°C incubator prior to assay.
The eosinophil suspension and the 20 nM eotaxin solution
are each mixed 1:1 with prewarmed RPMI 1640 with 0.1%
bovine serum albumin with or without a dilution of a ~,
test compound that is at two fold the desired final
concentration. These mixtures are warmed in a 37°C
incubator prior to assay. The filter is separated from
the prewarmed Neuroprobe chemotaxis chamber and the
eotaxin/compound mixture is placed into a Polyfiltronics
MPC 96 well plate that has been placed in the bottom
part of the Neuro Probe chemotaxis chamber. The
approximate volume is 370 microliters and there should
be a positive meniscus after dispensing. The filter is
replaced above the 96 well plate, the rubber gasket is
attached to the bottom of the upper chamber, and the
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chamber assembled. A 200 ~,1 volume of the cell
suspension/compound mixture is added to the appropriate
wells of the upper chamber. The upper chamber is
covered with a plate sealer, and the assembled unit
placed in a 37°C incubator for 45 minutes. After
incubation, the plate sealer is removed and all
remaining cell suspension is aspirated off. The chamber
is disassembled and, while holding the filter by the
sides at a 90-degree angle, unmigrated cells are washed
away using a gentle stream of phosphate buffered saline
dispensed from a squirt bottle and then the filter wiped
with a rubber tipped squeegee. The filter is allowed to
completely dry and immersed completely in Wright Giemsa
stain for 30-45 seconds. The filter is rinsed with
distilled water fox 7 minutes, rinsed once with water
briefly, and allowed to dry. Migrated cells are
enumerated by microscopy.
Mammalian chemokine receptors provide a target for
interfering with or promoting immune cell function in a
mammal, such as a human. Compounds that inhibit or
promote chemokine receptor function are particularly
useful for modulating immune cell function for
therapeutic purposes. Accordingly, the present
invention is directed to compounds which are useful in
the prevention and/or treatment of a wide variety of
inflammatory, infectious, and immunoregulatory disorders
and diseases, including asthma and allergic diseases,
infection by pathogenic microbes (which, by definition,
includes viruses), as well as autoimmune pathologies
such as the rheumatoid arthritis and atherosclerosis.
For example, an instant compound which inhibits one
or more functions of a mammalian chemokine receptor
(e. g., a human chemokine receptor) may be administered
to inhibit (i.e., reduce or prevent) inflammation or
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infectious disease. As a result, one or more
inflammatory process, such as leukocyte emigration,
adhesion, chemotaxis, exocytosis (e. g., of enzymes,
histamine) or inflammatory mediator release, is
inhibited. For example, eosinophilic infiltration to
inflammatory sites (e. g., in asthma or allergic
rhinitis) can be inhibited according to the present
method. In particular, the compound of the following
examples has activity in blocking the migration of cells
expressing the CCR-3 receptor using the appropriate
chemokines in the aforementioned assays. As used
herein, "activity" is intended to mean a compound
demonstrating an IC50 of 10 E1M or lower in concentration
when measured in the aforementioned assays. Such a
result is also indicative of the intrinsic activity of
the compounds as modulators of chemokine receptor
activity.
Similarly, an instant compound which promotes one
or more functions of the mammalian chemokine receptor
(e. g., a human chemokine) as administered to stimulate
(induce or enhance) an immune or inflammatory response,
such as leukocyte emigration, adhesion, chemotaxis,
exocytosis (e. g., of enzymes, histamine) or inflammatory
mediator release, resulting in the beneficial
stimulation of inflammatory processes. For example,
eosinophils can be recruited to combat parasitic
infections. In addition, treatment of the
aforementioned inflammatory, allergic and autoimmune
diseases can also be contemplated for an instant
compound which promotes one or more functions of the
mammalian chemokine receptor if one contemplates the
delivery of sufficient compound to cause the loss of
receptor expression on cells through the induction of
chemokine receptor internalization or the delivery of
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compound in a manner that results in the misdirection of
the migration of cells.
In addition to primates, such as humans, a variety
of other mammals can be treated according to the method
of the present invention. For instance, mammals,
including but not limited to, cows, sheep, goats,
horses, dogs, cats, guinea pigs, rats or other bovine,
ovine, equine, canine, feline, rodent or murine species
can be treated. However, the method can also be
practiced in other species, such as avian species. The
subject treated in the methods above is a mammal, male
or female, in whom modulation of chemokine receptor
activity is desired. "Modulation" as used herein is
intended to encompass antagonism, agonism, partial
25 antagonism andlor partial agonism.
Diseases or conditions of human or other species
which can be treated with inhibitors of chemokine
receptor function, include, but are not limited to:
inflammatory or allergic diseases and conditions,
including respiratory allergic diseases such as asthma,
allergic rhinitis, hypersensitivity lung diseases,
hypersensitivity pneumonitis, eosinophilic cellulitis
(e. g., Well's syndrome), eosinophilic pneumonias (e. g.,
Loeffler's syndrome, chronic eosinophilic pneumonia),
eosinophilic fasciitis (e. g., Shulman's syndrome),
delayed-type hypersensitivity, interstitial lung
diseases (ILD) (e.g., idiopathic pulmonary fibrosis, or
ILD associated with rheumatoid arthritis, systemic lupus
erythematosus, ankylosing spondylitis, systemic
sclerosis, Sjogren's syndrome, polymyositis or
dermatomyositis); systemic anaphylaxis or
hypersensitivity responses, drug allergies (e.g., to
penicillin, cephalosporins), eosinophilia-myalgia
syndrome due to the ingestion of contaminated
tryptophan, insect sting allergies; autoimmune diseases,
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such as rheumatoid arthritis, psoriatic arthritis,
multiple sclerosis, systemic lupus erythematosus,
myasthenia gravis, juvenile onset diabetes;
glomerulonephritis, autoimmune thyroiditis, Behcet's
disease; graft rejection (e. g., in transplantation),
including allograft rejection or graft-versus-host
disease; inflammatory bowel diseases, such as Crohn's
disease and ulcerative colitis; spondyloarthropathies;
scleroderma; psoriasis (including T-cell mediated
psoriasis) and inflammatory dermatoses such as an
dermatitis, eczema, atopic dermatitis, allergic contact
dermatitis, urticaria; vasculitis (e. g., necrotizing,
cutaneous, and hypersensitivity vasculitis);
eosinophilic myositis, eosinophilic fasciitis; cancers
with leukocyte infiltration of the skin or organs.
Other diseases or conditions in which undesirable
inflammatory responses are to be inhibited can be
treated, including, but not limited to, reperfusion
injury, atherosclerosis, certain hematologic
malignancies, cytokine-induced toxicity (e. g., septic
shock, endotoxic shock), polymyositis, dermatomyositis.
Infectious diseases or conditions of human or other
species which can be treated with inhibitors of
chemokine receptor function, include, but are not
limited to, HIV.
Diseases or conditions of humans or other species
which can be treated with promoters of chemokine
receptor function, include, but are not limited to:
immunosuppression, such as that in individuals with
immunodeficiency syndromes such as AIDS or other viral
infections, individuals undergoing radiation therapy,
chemotherapy, therapy for autoimmune disease or drug
therapy (e. g., corticosteroid therapy), which causes
immunosuppression; immunosuppression due to congenital
deficiency in receptor function or other causes; and
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infections diseases, such as parasitic diseases,
including, but not limited to helminth infections, such
as nematodes (round worms); (Trichuriasis, Enterobiasis,
Ascariasis, Hookworm, Strongyloidiasis, Trichinosis,
filariasis); trematodes (flukes) (Schistosomiasis,
Clonorchiasis), cestodes (tape worms) (Echinococcosis,
Taeniasis saginata, Cysticercosis); visceral worms,
visceral larva migraines (e. g., Toxocara), eosinophilic
gastroenteritis (e. g., Anisaki sp., Phocanema sp.),
cutaneous larva migraines (Ancylostona braziliense,
Ancylostoma caninum). The compounds of the present
invention are accordingly useful in the prevention and
treatment of a wide variety of inflammatory, infectious
and immunoregulatory disorders and diseases. In
addition, treatment of the aforementioned inflammatory,
allergic and autoimmune diseases can also be
contemplated for promoters of chemokine receptor
function if one contemplates the delivery of sufficient
compound to cause the loss of receptor expression on
cells through the induction of chemokine receptor
internalization or delivery of compound in a manner that
results in the misdirection of the migration of cells.
In another aspect, the instant invention may be
used to evaluate the putative specific agonists or
antagonists of a G protein coupled receptor. The
present invention is directed to the use of these
compounds in the preparation and execution of screening
assays for compounds that modulate the activity of
chemokine receptors. Furthermore, the compounds of this
invention are useful in establishing or determining the
binding site of other compounds to chemokine receptors,
e.g., by competitive inhibition or as a reference in an
assay to compare its known activity to a compound with
an unknown activity. When developing new assays or
protocols, compounds according to the present invention
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could be used to test their effectiveness.
Specifically, such compounds may be provided in a
commercial kit, for example, for use in pharmaceutical
research involving the aforementioned diseases. The
compounds of the instant invention are also useful for
the evaluation of putative specific modulators of the
chemokine receptors. In addition, one could utilize
compounds of this invention to examine the specificity
of G protein coupled receptors that are not thought to
be chemokine receptors, either by serving as examples of
compounds which do not bind or as structural variants of
compounds active on these receptors which may help
define specific sites of interaction.
Combined therapy to prevent and treat inflammatory,
infectious and immunoregulatory disorders and diseases,
including asthma and allergic diseases, as well as
autoimmune pathologies such as rheumatoid arthritis and
atherosclerosis, and those pathologies noted above is
illustrated by the combination of the compounds of this
invention and other compounds which are known for such
utilities. For example, in the treatment or prevention
of inflammation, the present compounds may be used in
conjunction with an anti-inflammatory or analgesic agent
such as an opiate agonist, a lipoxygenase inhibitor, a
cyclooxygenase-2 inhibitor, an interleukin inhibitor,
such as an interleukin-1 inhibitor, a tumor necrosis
factor inhibitor, an NMDA antagonist, an inhibitor or
nitric oxide or an inhibitor of the synthesis of nitric
oxide, a non-steroidal anti-inflammatory agent, a
phosphodiesterase inhibitor, or a cytokine-suppressing
anti-inflammatory agent, for example with a compound
such as acetaminophen, aspirin, codeine, fentaynl,
ibuprofen, indomethacin, ketorolac, morphine, naproxen,
phenacetin, piroxicam, a steroidal analgesic,
sufentanyl, sunlindac, interferon alpha and the like.
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Similarly, the instant compounds may be administered
with a pain reliever; a potentiator such as caffeine, an
H2-antagonist, simethicone, aluminum or magnesium
hydroxide; a decongestant such as phenylephrine,
phenylpropanolamine, pseudophedrine, oxymetazoline,
ephinephrine, naphazoline, xylometazoline,
propylhexedrine, or levodesoxy-ephedrine; and
antitussive such as codeine, hydrocodone, caramiphen,
carbetapentane, or dextramethorphan; a diuretic; and a
sedating or non-sedating antihistamine. Likewise,
compounds of the present invention may be used in
combination with other drugs that are used in the
treatment/prevention/suppression or amelioration of the
diseases or conditions for which compound of the present
invention are useful. Such other drugs may be
administered, by a route and in an amount commonly used
therefore, contemporaneously or sequentially with a
compound of the present invention. When a compound of
the present invention is used contemporaneously with one
or more other drugs, a pharmaceutical composition
containing such other drugs in addition to the compound
of the present invention is preferred. Accordingly, the
pharmaceutical compositions of the present invention
include those that also contain one or more other active
ingredients, in addition to a compound of the present
invention. Examples of other active ingredients that
may be combined with a compound of the present
invention, either administered separately or in the same
pharmaceutical compositions, include, but are not
limited to: (a) integrin antagonists such as those for
selectins, ICAMs and VLA-4; (b) steroids such as
beclomethasone, methylprednisolone, betamethasone,
prednisone, dexamethasone, and hydrocortisone; (c)
immunosuppressants such as cyclosporin, tacrolimus,
rapamycin and other FK-506 type immunosuppressants; (d)
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antihistamines (H1-histamine antagonists) such as
bromopheniramine, chlorpheniramine, dexchlorpheniramine,
triprolidine, clemastine, diphenhydramine,
diphenylpyraline, tripelennamine, hydroxyzine,
methdilazine, promethazine, trimeprazine, azatadine,
cyproheptadine, antazoline, pheniramine pyrilamine,
astemizole, terfenadine, loratadine, cetirizine,
fexofenadine, descarboethoxyloratadine, and the like;
(e) non-steroidal anti-asthmatics such as b2-agonists
(terbutaline, metaproterenol, fenoterol, isoetharine,
albuteral, bitolterol, and pirbuterol), theophylline,
cromolyn sodium, atropine, ipratropium bromide,
leukotriene antagonists (zafirlukast, montelukast,
pranlukast, iralukast, pobilukast, SKB-102,203),
leukotriene biosynthesis inhibitors (zileuton, BAY-
1005); (f) non-steroidal antiinflammatory agents
(NSATDs) such as propionic acid derivatives
(alminoprofen, benxaprofen, bucloxic acid, carprofen,
fenbufen, fenoprofen, fluprofen, flurbiprofen,
ibuprofen, indoprofen, ketoprofen, miroprofen, naproxen,
oxaprozin, pirprofen, pranoprofen, suprofen, tiaprofenic
acid, and tioxaprofen), acetic acid derivatives
(indomethacin, acemetacin, alclofenac, clidanac,
diclofenac, fenclofenac, fenclozic acid, fentiazac,
furofenac, ibufenac, isoxepac, oxpinac, sulindac,
tiopinac, tolmetin, zidometacin, and zomepirac), fenamic
acid derivatives (flufenamic acid, meclofenamic acid,
mefenamic acid, niflumic acid and tolfenamic acid),
biphenylcarboxylic acid derivatives (diflunisal and
flufenisal), oxicams (isoxicam, piroxicam, sudoxicam and
tenoxican), salicylates (acetyl salicylic acid,
sulfasalazine) and the pyrazolones (apazone,
bezpiperylon, feprazone, mofebutazone, oxyphenbutazone,
phenylbutazone); (g) cyclooxygenase-2 (COX-2)
inhibitors; (h) inhibitors of phosphodiesterase type IV
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(PDE-IV); (I) other antagonists of the chemokine
receptors; (j) cholesterol lowering agents such as HMG-
COA reductase inhibitors (lovastatin, simvastatin and
pravastatin, fluvastatin, atorvsatatin, and other
statins), sequestrants (cholestyramine and colestipol),
nicotonic acid, fenofibric acid derivatives
(gemfibrozil, clofibrat, fenofibrate and benzafibrate),
and probucol; (k) anti-diabetic agents such as insulin,
sulfonylureas, biguanides (metformin), a-glucosidase
inhibitors (acarbose) and glitazones (troglitazone ad
pioglitazone); (1) preparations of interferons
(interferon alpha-2a, interferon-2B, interferon alpha-
N3, interferon beta-1a, interferon beta-1b, interferon
gamma-1b); (m) antiviral compounds such as efavirenz,
nevirapine, indinavir, ganciclovir, lamivudine,
famciclovir, and zalcitabine; (o) other compound such as
5-aminosalicylic acid an prodrugs thereof,
antimetabolites such as azathioprine and 6-
mercaptopurine, and cytotoxic cancer chemotherapeutic
agents. The weight ratio of the compound of the present
invention to the second active ingredient may be varied
and will depend upon the effective doses of each
ingredient. Generally, an effective dose of each will
be used. Thus, for example, when a compound of the
present invention is combined with an NSAID the weight
ratio of the compound of the present invention to the
NSAID will generally range from about 1000:1 to about
1:1000, preferably about 200:1 to about 1:200.
Combinations of a compound of the present invention and
other active ingredients will generally also be within
the aforementioned range, but in each case, an effective
dose of each active ingredient should be used.
The compounds are administered to a mammal in a
therapeutically effective amount. By "therapeutically
effective amount" it is meant an amount of a compound of
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Formula I that, when administered alone or in
combination with an additional therapeutic agent to a
mammal, is effective to prevent or ameliorate the
thromboembolic disease condition or the progression of
the disease.
Dosage and Formulation
The compounds of this invention can be
administered in such oral dosage forms as tablets,
capsules (each of which includes sustained release or
timed release formulations), pills, powders, granules,
elixirs, tinctures, suspensions, syrups, and emulsions.
They may also be administered in intravenous (bolus or
infusion), intraperitoneal, subcutaneous, or
intramuscular form, all using dosage forms well known to
those of ordinary skill in the pharmaceutical arts.
They can be administered alone, but generally will be
administered with a pharmaceutical carrier selected on
the basis of the chosen route of administration and
standard pharmaceutical practice.
The dosage regimen for the compounds of the present
invention will, of course, vary depending upon known
factors, such as the pharmacodynamic characteristics of
the particular agent and its mode and route of
administration; the species, age, sex, health, medical
condition, and weight of the recipient; the nature and
extent of the symptoms; the kind of concurrent
treatment; the frequency of treatment; the route of
administration, the renal and hepatic function of the
patient,and the effect desired. A physician or
veterinarian can determine and prescribe the effective
amount of the drug required to prevent, counter, or
arrest the progress of the thromboembolic disorder.
By way of general guidance, the daily oral dosage
of each active ingredient, when used for the indicated
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effects, will range between about 0.001 to 1000 mg/kg of
body weight, preferably between about 0.01 to 100 mg/kg
of body weight per day, and most preferably between
about 1.0 to 20 mg/kg/day. Intravenously, the most
preferred doses will range from about 1 to about 10
mg/kg/minute during a constant rate infusion. Compounds
of this invention may be administered in a single daily
dose, or the total daily dosage may be administered in
divided doses of two, three, or four times daily.
Compounds of this invention can be administered in
intranasal form via topical use of suitable intranasal
vehicles, or via transdermal routes, using transdermal
skin patches. when administered in the form of a
transdermal delivery system, the dosage administration
will, of course, be continuous rather than intermittent
throughout the dosage regimen.
The compounds are typically administered in
admixture with suitable pharmaceutical diluents,
excipients, or carriers (collectively referred to
herein as pharmaceutical carriers) suitably selected
with respect to the intended form of administration,
that is, oral tablets, capsules, elixirs, syrups and
the like, and consistent with conventional
pharmaceutical practices.
For instance, for oral administration in the form
of a tablet or capsule, the active drug component can
be combined with an oral, non-toxic, pharmaceutically
acceptable, inert carrier such as lactose, starch,
sucrose, glucose, methyl callulose, magnesium stearate,
dicalcium phosphate, calcium sulfate, mannitol,
sorbitol and the like; for oral administration in
liquid form, the oral drug components can be combined
with any oral, non-toxic, pharmaceutically acceptable
inert carrier such as ethanol, glycerol, water, and the
like. Moreover, when desired or necessary, suitable
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binders, lubricants, disintegrating agents, and
coloring agents can also be incorporated into the
mixture. Suitable binders include starch, gelatin,
natural sugars such as glucose or beta-lactose, corn
sweeteners, natural and synthetic gums such as acacia,
tragacanth, or sodium alginate, carboxymethylcellulose,
polyethylene glycol, waxes, and the like. Lubricants
used in these dosage forms include sodium oleate,
sodium stearate, magnesium stearate, sodium benzoate,
sodium acetate, sodium chloride, and the like.
Disintegrators include, without limitation, starch,
methyl cellulose, agar, bentonite, xanthan gum, and the
like.
The compounds of the present invention can also be
administered in the form of liposome delivery systems,
such as small unilamellar vesicles, large unilamellar
vesicles, and multilamellar vesicles. Liposomes can be
formed from a variety of phospholipids, such as
cholesterol, stearylamine, or phosphatidylcholines.
Compounds of the present invention may also be
coupled with soluble polymers as targetable drug
carriers. Such polymers can include
polyvinylpyrrolidone, pyran copolymer,
polyhydroxypropylmethacrylamide-phenol,
polyhydroxyethylaspartamidephenol, or
polyethyleneoxide-polylysine substituted with palmitoyl
residues. Furthermore, the compounds of the present
invention may be coupled to a class of biodegradable
polymers useful in achieving controlled release of a
drug, for example, polylactic acid, polyglycolic acid,
copolymers of polylactic and polyglycolic acid,
polyepsilon caprolactone, polyhydroxy butyric acid,
polyorthoesters, polyacetals, polydihydropyrans,
polycyanoacylates, and crosslinked or amphipathic block
copolymers of hydrogels.
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Dosage forms (pharmaceutical compositions) suitable
for administration may contain from about 1 milligram to
about 100 milligrams of active ingredient per dosage
unit. In these pharmaceutical compositions the active
ingredient will ordinarily be present in an amount of
about 0.5-95% by weight based on the total weight of the
composition.
Gelatin capsules may contain the active ingredient
and powdered carriers, such as lactose, starch,
cellulose derivatives, magnesium stearate, stearic acid,
and the like. Similar diluents can be used to make
compressed tablets. Both tablets and capsules can be
manufactured as sustained release products to provide
for continuous release of medication over a period of
hours. Compressed tablets can be sugar coated or film
coated to mask any unpleasant taste and protect the
tablet from the atmosphere, or enteric coated for
selective disintegration in the gastrointestinal tract.
Liquid dosage forms for oral administration can
contain coloring and flavoring to increase patient
acceptance.
In general, water, a suitable oil, saline, aqueous
dextrose (glucose), and related sugar solutions and
glycols such as propylene glycol or polyethylene glycols
are suitable carriers for parenteral solutions.
Solutions for parenteral administration preferably
contain a water soluble salt of the active ingredient,
suitable stabilizing agents, and if necessary, buffer
substances. Antioxidizing agents such as sodium
bisulfate, sodium sulfite, or ascorbic acid, either
alone or combined, are suitable stabilizing agents.
Also used are citric acid and its salts and sodium EDTA.
In addition, parenteral solutions can contain
preservatives, such as benzalkonium chloride, methyl- or
propyl-paraben, and chlorobutanol.
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Suitable pharmaceutical carriers. are described in
Reminaton's Pharmaceutical Sciences, Mack Publishing
Company, a standard reference text in this field.
Representative useful pharmaceutical dosage-forms
for administration of the compounds of this invention
can be illustrated as follows:
Capsules
A large number of unit capsules can be prepared
by filling standard two-piece hard gelatin capsules each
with 100 milligrams of powdered active ingredient, 150
milligrams of lactose, 50 milligrams of cellulose, and 6
milligrams magnesium stearate.
Soft Gelatin Capsules
A mixture of active ingredient in a digestable
oil such as soybean oil, cottonseed oil or olive oil may
be prepared and injected by means of a positive
displacement pump into gelatin to form soft gelatin
capsules containing 100 milligrams of the active
ingredient. The capsules should be washed and dried.
Tablets
Tablets may be prepared by conventional
procedures so that the dosage unit is 100 milligrams of
active ingredient, 0.2 milligrams of colloidal silicon
dioxide, 5 milligrams of magnesium stearate, 275
milligrams of microcrystalline cellulose, 11 milligrams
of starch and 98.8 milligrams of lactose. Appropriate
coatings may be applied to increase palatability or
delay absorption.
Ink ectable
A parenteral composition suitable for
administration by injection may be prepared by stirring
1.5o by weight of active ingredient in 10% by volume
propylene glycol and water. The solution should be made
isotonic with sodium chloride and sterilized.
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Suspension
.An aqueous suspension can be prepared for oral
administration so that each 5 mL contain 100 mg of
finely divided active ingredient, 200 mg of sodium
carboxymethyl cellulose, 5 mg of sodium benzoate, 1.0 g
of sorbitol solution, U.S.P., and 0.025 mL of vanillin.
Where the compounds of this invention are combined
with other anticoagulant agents, for example, a daily
dosage may be about 0.1 to 100 milligrams of the
compound of Formula I and about 1 to 7.5 milligrams of
the second anticoagulant, per kilogram of patient body
weight. For a tablet dosage form, the compounds of this
invention generally may be present in an amount of about
5 to 10 milligrams per dosage unit, and the second anti-
coagulant in an amount of about 2 to 5 milligrams per
dosage unit.
V~here two or more of the foregoing second
therapeutic agents are administered with the compound of
Formula I, generally the amount of each component in a
typical daily dosage and typical dosage form may be
reduced relative to the usual dosage of the agent when
administered alone, in view of the additive or
synergistic effect of the therapeutic agents when
administered in combination.
Particularly when provided as a single dosage unit,
the potential exists for a chemical interaction between
the combined active ingredients. For this reason, when
the compound of Formula I and a second therapeutic agent
are combined in a single dosage unit they are formulated
such that although the active ingredients are combined
in a single dosage unit, the physical contact between
.the active ingredients is minimized (that is, reduced).
For example, one active ingredient may be enteric
coated. By enteric coating one of the active
ingredients, it is possible not only to minimize the
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contact between the combined active ingredients, but
also, it is possible to control the release of one of
these components in the gastrointestinal tract such that
one of these components is not released in the stomach
but rather is released in the intestines. One of the
active ingredients may also be coated with a material
which effects a sustained-release throughout the
gastrointestinal tract and also serves to minimize
physical contact between the combined active
ingredients. Furthermore, the sustained-released
component can be additionally enteric coated such that
the release of this component occurs only in the
intestine. Still another approach would involve the
formulation of a combination product in which the one
component is coated with a sustained and/or enteric
release polymer, and the other component is also coated
with a polymer such as a lowviscosity grade of
hydroxypropyl methylcellulose (HPMC) or other
appropriate materials as known in the art, in order to
further separate the active components. The polymer
coating serves to form an additional barrier to
interaction with the other component.
These as well as other ways of minimizing contact
between the components of combination products of the
present invention, whether administered in a single
dosage form or administered in separate forms but at the
same time by the same manner, will be readily apparent
to those skilled in the art, once armed with the present
disclosure.
As will be appreciated by one of skill in the art,
numerous modifications and variations of the present
invention are possible in light of the above teachings.
It is therefore to be understood that within the scope
of the appended claims, the invention may be practiced
otherwise than as specifically described herein.
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Representative Drawing