AZOLO TRIAZINES AND PYRIMIDINES

AZOLO TRIAZINES ET PYRIMIDINES

English Abstract

Corticotropin releasing factor (CRF) antagonists of formula (I) or (II) and
their use in treating anxiety, depression, and other psychiatric,
neurological disorders as well as treatment of immunological, cardiovascular
or heart-related diseases and colonic hypersensitivity associated
with psychopathological disturbance and stress.

French Abstract

Cette invention concerne des inhibiteurs de facteur de libération de corticotropine, lesquels correspondent à la formule (I) ou (II). Cette invention concerne également l'utilisation de ces inhibiteurs dans le traitement de l'anxiété, de dépressions ainsi que d'autres troubles psychiatriques et neurologiques. Ces inhibiteurs peuvent également être utilisés dans le traitement de maladies immunologiques, cardio-vasculaires ou touchant le coeur, ainsi que dans le traitement de l'hypersensibilité du côlon associée à des problèmes psychopathologiques et au stress.

Claims

CLAIMS
WHAT IS CLAIMED IS:

1. Use of a compound of Formulae (1) or (2 ):
Image
and geometric isomers thereof, stereoisomeric forms
thereof, or mixtures of stereoisomeric forms
thereof, and pharmaceutically acceptable salt or
pro-drug forms thereof, wherein:

A is N;

Z is N or CR2;

Ar is selected from phenyl, naphthyl, pyridyl,
pyrimidinyl, triazinyl, furanyl, thienyl,
benzothienyl, benzofuranyl, 2,3-
dihydrobenzofuranyl, 2,3-dihydrobenzothienyl,
indanyl, 1,2-benzopyranyl, 3,4-dihydro-1,2-
benzopyranyl, and tetralinyl, each Ar
optionally substituted with 1 to 5 R4 groups
and each Ar is attached to an unsaturated
carbon atom;

-169-


R1 is independently selected at each occurrence from
H, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl,
halo, CN, C1-C4 haloalkyl, C1-C12 hydroxyalkyl,
C2-C12 alkoxyalkyl, C2-C10 cyanoalkyl, C3-C6
cycloalkyl, C4-C10 cycloalkylalkyl, NR9R10, C1-
C4 alkyl-NR9R10, NR9COR10, OR11, SH and
S (O) n R12 ;

R2 is selected from H, C1-C4 alkyl, C2-C4 alkenyl,
C2-C4 alkynyl, C3-C6 cycloalkyl, C4-C10
cycloalkylalkyl, C1-C4 hydroxyalkyl, halo, CN,
-NR6R7, NR9COR10, -NR6S (O) n R7, S(O) n NR6R7, C1-
C4 haloalkyl, -OR7, SH and -S(O)n R12;

R3 is selected from:
-H, OR7, SH, S(O)n R13, COR7, CO2R7,
OC(O)R13, NR8COR7, N(COR7)2, NR8CONR6R7,
NR8CO2R13, NR6R7, NR6aR7a, N(OR7)R6,
CONR6R7, aryl, heteroaryl and
heterocyclyl,
-C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl,
C3-C8 cycloalkyl, C5-C8 cycloalkenyl, C4-
C12 cycloalkylalkyl and C6-C10
cycloalkenylalkyl, each optionally
substituted with 1 to 3 substituents
independently selected at each occurrence
from C1-C6 alkyl, C3-C6 cycloalkyl, halo,
C1-C4 haloalkyl, cyano, OR15, SH,
S(O) n R13 , COR15, CO2R15, OC(O)R13,
NR8COR15, N(COR15)2, NR8CONR16R15,
-170-


NR8CO2R13, NR16R15, CONR16R15, aryl,
heteroaryl and heterocyclyl;

R4 is independently selected at each occurrence
from: C1-C10 alkyl, C2-C10 alkenyl, C2-
C10 alkynyl, C3-C6 cycloalkyl, C4-
C12 cycloalkylalkyl, NO2, halo, CN, C1-
C4 haloalkyl, NR6R7, NR8COR7, NR8CO2R7, COR7,
OR7, CONR6R7, CO(NOR9)R7, CO2R7, and S(O)n R7,
where each such C1-C10 alkyl, C2-C10 alkenyl,
C2-C10 alkynyl, C3-C6 cycloalkyl and C4-
C12 cycloalkylalkyl are optionally substituted
with 1 to 3 substituents independently selected
at each occurrence from C1-C4 alkyl, NO2, halo,
CN, NR6R7, NR8COR7, NR8CO2R7, COR7, OR7,
CONR6R7, CO2R7, CO(NOR9)R7, and S(O)n R7;

R6 and R7, R6a and R7a are independently selected at
each occurrence from:
-H,
-C1-C10 alkyl, C3-C10 alkenyl, C3-C10 alkynyl,
C1-C10 haloalkyl with 1-10 halogens, C2-C8
alkoxyalkyl, C3-C6 cycloalkyl, C4-
C12 cycloalkylalkyl, C5-C10 cycloalkenyl,
and C6-C14 cycloalkenylalkyl, each
optionally substituted with 1 to 3
substituents independently selected at
each occurrence from C1-C6 alkyl, C3-
C6 cycloalkyl, halo, C1-C4 haloalkyl,
cyano, OR15, SH, S(O)n R13, COR15, CO2R15,
OC(O)R13, NR8COR15, N(COR15)2,
NR8CONR16R15, NR8CO2R13, NR16R15,
CONR16R15, aryl, heteroaryl and
heterocyclyl,

-171-


-aryl, aryl(C1-C4 alkyl), heteroaryl,
heteroaryl(C1-C4 alkyl), heterocyclyl
and heterocyclyl(C1-C4 alkyl);

alternatively, NR6R7 and NR6a R7a are independently
piperidine, pyrrolidine, piperazine, N-
methylpiperazine, morpholine or thiomorpholine, each
optionally substituted with 1-3 C1-C4 alkyl groups;
R8 is independently selected at each occurrence from
H and C1-C4 alkyl;

R9 and R10 are independently selected at each
occurrence from H, C1-C4 alkyl, and C3-C6
cycloalkyl;

R11 is selected from H, C1-C4 alkyl, C1-C4
haloalkyl, and C3-C6 cycloalkyl;

R12 is C1-C4 alkyl or C1-C4 haloalkyl;

R13 is selected from C1-C4 alkyl, C1-C4 haloalkyl,
C2-C8 alkoxyalkyl, C3-C6 cycloalkyl, C4-
C12 cycloalkylalkyl, aryl, aryl(C1-C4 alkyl)-,
heteroaryl and heteroaryl(C1-C4 alkyl)-;

R14 is selected from C1-C10 alkyl, C3-C10 alkenyl,
C3-C10 alkynyl, C3-C8 cycloalkyl, and C4-
C12 cycloalkylalkyl, each optionally
substituted with 1 to 3 substituents
independently selected at each occurrence from
C1-C6 alkyl, C3-C6 cycloalkyl, halo, C1-
C4 haloalkyl, cyano, OR15, SH, S(O)n R15, COR15,
CO2R15, OC(O)R15, NR8COR15, N(COR15)2,
NR8CONR16R15, NR8CO2R15, NR16R15, CONR16R15,

-172-


and C1-C6 alkylthio, C1-C6 alkylsulfinyl and
C1-C6 alkylsulfonyl;

R15 and R16 are independently selected at each
occurrence from H, C1-C6 alkyl, C3-C10
cycloalkyl, and C4-C16 cycloalkylalkyl, except
that for S(O)n R15, R15 cannot be H;

aryl is phenyl or naphthyl, each optionally
substituted with 1 to 5 substituents
independently selected at
each occurrence from C1-C6 alkyl, C3-
C6 cycloalkyl, halo, C1-C4 haloalkyl, cyano,
OR15, SH, S(O)n R15, COR15, CO2R15, OC(O)R15,
NR8COR15, N(COR15)2, NR8CONR16R15, NR8CO2R15,
NR16R15, and CONR16R15,

heteroaryl is pyridyl, pyrimidinyl, triazinyl,
furanyl, pyranyl, quinolinyl, isoquinolinyl,
thienyl, imidazolyl, thiazolyl, indolyl,
pyrrolyl, oxazolyl, benzofuranyl, benzothienyl,
benzothiazolyl, isoxazolyl, pyrazolyl, 2,3-
dihydrobenzothienyl or 2,3-dihydrobenzofuranyl,
each being optionally substituted with 1 to 5
substituents independently selected at each
occurrence from C1-C6 alkyl, C3-C6 cycloalkyl,
halo, C1-C4 haloalkyl, cyano, OR15, SH,
S(O)n R15, -COR15, CO2R15, OC(O)R15, NR8COR15,
N(COR15)2, NR8CONR16R15, NR8CO2R15, NR16R15, and
CONR16R15;

heterocyclyl is saturated or partially saturated
heteroaryl, optionally substituted with 1 to 5
substituents independently selected at each
occurrence from C1-C6 alkyl, C3-C6 cycloalkyl,

-173-


halo, C1-C4 haloalkyl, cyano, OR15, SH,
S(O)n R15, COR15, CO2R15, OC(O)R15, NR8COR15,
N(COR15)2, NR8CONR16R15, NR8CO2R15, NR15R16, and
CONR16R15;

n is independently at each occurrence 0, 1 or 2,
with the provisos that
(1) when R1 is -(C1-C2 alkylene) -O- (C1-C2 alkyl) or
-(C1-C2 alkylene) -OH, then at least one of the
following conditions (i), (ii) and (iii) is
true:
(i) the compound is a compound of formula (2);
(ii) Ar is selected from optionally substituted
naphthyl, triazinyl, furanyl, thienyl,
benzothienyl, benzofuranyl, 2,3-
dihydrobenzofuranyl, 2,3-dihydrobenzothienyl,
indanyl, 1,2-benzopyranyl, 3,4-dihydro-1,2-
benzopyranyl, and tetralinyl;
(iii) R3 is selected from H, SH, S(O)n R13 wherein
n = 1, CO2R7 , OC(O)R13, NR8COR7, N(COR7)2,
NR8CONR6R7, NR8CO2R13, N(OR7)R6, CONR6R7, aryl
other than optionally substituted phenyl,
heteroaryl other than (a) optionally
substituted pyrazinyl, (b) optionally
substituted pyrimidyl or (c) optionally
substituted pyridazinyl, or heterocyclyl; and

(2) when R3 is C5-C8 cycloalkenyl or C6-C10
cylcoalkenylalkyl, then at least one of the
following conditions (i), (ii) and (iii) is
true:
(i) the compound is a compound of formula (2);
(ii) Ar is selected from optionally substituted
naphthyl, triazinyl, furanyl, thienyl,

-174-


benzothienyl, benzofuranyl, 2,3-
dihydrobenzofuranyl, 2,3-dihydrobenzothienyl,
indanyl, 1,2-benzopyranyl, 3,4-dihydro-1,2-
benzopyranyl, and tetralinyl;
(iii) R1 is selected from C2-C4 alkenyl, C2-C4
alkynyl, CN, C1-C4 haloalkyl, C3-C12 hydroxyalky-
l, C4-C12 alkoxyalkyl other than -(C1-C2
alkylene) -O- (C1-C2 alkyl), C2-C10 cyanoalkyl,
C3-C6 cycloalkyl, C4-C10 cycloalkylalkyl, NR9R16,
C1-C4 alkyl-NR9R10, NR9COR16, OR11, SH or S(O)n R12;

in the manufacture of a medicament for treating
affective disorder, anxiety, depression, headache,
irritable bowel syndrome, post-traumatic stress
disorder, supranuclear palsy, immune suppression,
Alzheimer's disease, gastrointestinal diseases,
anorexia nervosa or other feeding disorder, drug
addiction, drug or alcohol withdrawal symptoms,
inflammatory diseases, fertility problems, human
immunodeficiency virus infections, hemorrhagic
stress, obesity, infertility, head and spinal cord
traumas, epilepsy, stroke, ulcers, amyotrophic
lateral sclerosis, hypoglycemia or a disorder the
treatment of which can be effected or facilitated by
antagonizing CRF, including disorders induced or
facilitated by CRF, in mammals.

2. Use according to claim 1 wherein, in the
compound of Formulae (1) or (2), Ar is phenyl,
pyridyl or 2,3-dihydrobenzofuranyl, each optionally
substituted with 1 to 4 R4 substituents.

3. Use according to claim 1 wherein, in the
compound of Formulae (1) or (2), Z is CR2, Ar is
2,4-dichlorophenyl, 2,4-dimethylphenyl or 2,4,6-
-175-


trimethylphenyl, R1 and R2 are CH3, and R3 is
NR6a R7a.

4. A compound of Formulae (1) or (2):
Image
and geometric isomers thereof, stereoisomeric forms
thereof, or mixtures of stereoisomeric forms
thereof, and pharmaceutically acceptable salt or
pro-drug forms thereof wherein:

A is N;

Z is N or CR2;

Ar is selected from phenyl, naphthyl, pyridyl,
pyrimidinyl, triazinyl, furanyl, thienyl,
benzothienyl, benzofuranyl, 2,3-
dihydrobenzofuranyl, 2,3-dihydrobenzothienyl,
indanyl, 1,2-benzopyranyl, 3,4-dihydro-1,2-
benzopyranyl, and tetralinyl, each Ar
optionally substituted with 1 to 5 R4 groups
and each Ar is attached to an unsaturated
carbon atom;

-176-


R1 is independently selected at each occurrence from
H, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl,
halo, CN, C1-C4 haloalkyl, C1-C12 hydroxyalkyl,
C2-C12 alkoxyalkyl, C2-C10 cyanoalkyl, C3-C6
cycloalkyl, C4-C10 cycloalkylalkyl, NR9R10, C1-
C4 alkyl-NR9R10, NR9COR10, OR11, SH and
S (O)n R12;

R2 is selected from H, C1-C4 alkyl, C2-C4 alkenyl,
C2-C4 alkynyl, C3-C6 cycloalkyl, C4-C10
cycloalkylalkyl, C1-C4 hydroxyalkyl, halo, CN,
-NR6R7, NR9COR10, -NR6S(O)n R7, S(O)n NR6R7, C1-
C4 haloalkyl, -OR7, SH and -S(O)n R12;

R3 is selected from:
-H, OR7, SH, S(O)n R13, COR7, CO2R7,
OC(O)R13, NR8COR7, N(COR7)2, NR8CONR6R7,
NR8CO2R13, NR6R7, NR6a R7a, N(OR7)R6,
CONR6R7, aryl, heteroaryl and
heterocyclyl, or
-C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl,
C3-C8 cycloalkyl, C5-C8 cycloalkenyl, C4-
C12 cycloalkylalkyl and C6-C10
cycloalkenylalkyl, each optionally
substituted with 1 to 3 substituents
independently selected at each occurrence
from C1-C6 alkyl, C3-C6 cycloalkyl, halo,
C1-C4 haloalkyl, cyano, OR15, SH,
S(O)n R13, COR15, CO2R15, OC(O)R13,
NR8COR15, N(COR15)2, NR8CONR16R15,
-177-


NR8CO2R13, NR16R15, CONR16R15, aryl,
heteroaryl and heterocyclyl;

R4 is independently selected at each occurrence
from: C1-C10 alkyl, C2-C10 alkenyl, C2-
C10 alkynyl, C3-C6 cycloalkyl, C4-
C12 cycloalkylalkyl, NO2, halo, CN, C1-
C4 haloalkyl, NR6R7, NR8COR7, NR8CO2R7, COR7,
OR7, CONR6R7, CO(NOR9)R7, CO2R7, and S(O)n R7,
where each such C1-C10 alkyl, C2-C10 alkenyl,
C2-C10 alkynyl, C3-C6 cycloalkyl and C4-
C12 cycloalkylalkyl are optionally substituted
with 1 to 3 substituents independently selected
at each occurrence from C1-C4 alkyl, NO2, halo,
CN, NR6R7, NR8COR7, NR8CO2R7, COR7 OR7, CONR6R7,
CO2R7, CO(NOR9)R7, and S(O)n R7;

R6 and R7, R6a and R7a are independently selected at
each occurrence from:
-H,
-C1-C10 alkyl, C3-C10 alkenyl, C3-C10 alkynyl,
C1-C10 haloalkyl with 1-10 halogens, C2-C8
alkoxyalkyl, C3-C6 cycloalkyl, C4-
C12 cycloalkylalkyl, C5-C10 cycloalkenyl,
and C6-C14 cycloalkenylalkyl, each
optionally substituted with 1 to 3
substituents independently selected at
each occurrence from C1-C6 alkyl, C3-
C6 cycloalkyl, halo, C1-C4 haloalkyl,
cyano, OR15, SH, S(O)n R13, COR15, CO2R15,
OC(O)R13, NR8COR15, N(COR15)2,
NR8CONR16R15, NR8CO2R13, NR16R15,
CONR16R15, aryl, heteroaryl and
heterocyclyl,

-178-


-aryl, aryl(C1-C4 alkyl), heteroaryl,
heteroaryl(C1-C4 alkyl), heterocyclyl
and heterocyclyl(C1-C4 alkyl),
alternatively, NR6R7 and NR6a R7a are independently
piperidine, pyrrolidine, piperazine, N-
methylpiperazine, morpholine or thiomorpholine, each
optionally substituted with 1-3 C1-C4 alkyl groups;
R8 is independently selected at each occurrence from
H and C1-C4 alkyl;

R9 and R10 are independently selected at each
occurrence from H, C1-C4 alkyl, and C3-C6
cycloalkyl;

R11 is selected from H, C1-C4 alkyl, C1-C4
haloalkyl, and C3-C6 cycloalkyl;

R12 is C1-C4 alkyl or C1-C4 haloalkyl;

R13 is selected from C1-C4 alkyl, C1-C4 haloalkyl,
C2-C8 alkoxyalkyl, C3-C6 cycloalkyl, C4-
C12 cycloalkylalkyl, aryl, aryl(C1-C4 alkyl)-,
heteroaryl and heteroaryl(C1-C4 alkyl)-;

R14 is selected from C1-C10 alkyl, C3-C10 alkenyl,
C3-C10 alkynyl, C3-C8 cycloalkyl, and C4-
C12 cycloalkylalkyl, each optionally
substituted with 1 to 3 substituents
independently selected at each occurrence from
C1-C6 alkyl, C3-C6 cycloalkyl, halo, C1-
C4 haloalkyl, cyano, OR15, SH, S(O)n R15, COR15,
CO2R15, OC(O)R15, NR8COR15, N(COR15)2,
NR8CONR16R15, NR8CO2R15, NR16R15, CONR16R15,

-179-


and C1-C6 alkylthio, C1-C6 alkylsulfinyl and
C1-C6 alkylsulfonyl;

R15 and R16 are independently selected at each
occurrence from H, C1-C6 alkyl, C3-C10
cycloalkyl, and C4-C16 cycloalkylalkyl, except
that for S(O)n R15, R15 cannot be H;

aryl is phenyl or naphthyl, each optionally
substituted with 1 to 5 substituents
independently selected at
each occurrence from C1-C6 alkyl, C3-
C6 cycloalkyl, halo, C1-C4 haloalkyl, cyano,
OR15, SH, S(O)n R15, COR15, CO2R15, OC(O)R15,
NR8COR15, N(COR15)2, NR8CONR16R15, NR8CO2R15,
NR16R15, and CONR16R15;

heteroaryl is pyridyl, pyrimidinyl, triazinyl,
furanyl, pyranyl, quinolinyl, isoquinolinyl,
thienyl, imidazolyl, thiazolyl, indolyl,
pyrrolyl, oxazolyl, benzofuranyl, benzothienyl,
benzothiazolyl, isoxazolyl, pyrazolyl, 2,3-
dihydrobenzothienyl or 2,3-dihydrobenzofuranyl,
each being optionally substituted with 1 to 5
substituents independently selected at each
occurrence from C1-C6 alkyl, C3-C6 cycloalkyl,
halo, C1-C4 haloalkyl, cyano, OR15, SH,
S(O)n R15, -COR15, CO2R15, OC(O)R15, NR8COR15,
N(COR15)2, NR8CONR16R15, NR8CO2R15, NR16R15, and
CONR16R15;

heterocyclyl is saturated or partially saturated
heteroaryl, optionally substituted with 1 to 5
substituents independently selected at each
occurrence from C1-C6 alkyl, C3-C6 cycloalkyl,

-180-


halo, C1-C4 haloalkyl, cyano, OR15, SH,
S(O)n R15, COR15, CO2R15, OC(O)R15, NR8COR15,
N(COR15)2, NR8CONR16R15, NR8CO2R15, NR15R16, and
CONR16R15;

n is independently at each occurrence 0, 1 or 2,
with the provisos that:

(1) when Z is CR2, R2 is H, R3 is -OR7 or -OCOR13,
and R7 is H, then R1 is not H, OH or SH;

(2) when Z is CR2, R1 is H, SH, SCH3, CH3 or C2H5, R2
is H, and R3 is OH, H, CH3, C2H5, C6H5, n-C3H7,
i-C3H7, SH, SCH3, NHC4H9, or N(C2H5) 2, then Ar is
not phenyl, m-Cl-phenyl, or m-CH3-phenyl;

(3) when Z is CR2, R2 is H, R1 is H or C1-C4 alkyl
and Ar is pyridyl or unsubstituted
pyrimidinyl then R3 is not -NH2, -NR8COR7
wherein R7 is C1-C5 alkyl, NR8CONR6R7 wherein R6
and R7 are each independently selected from H
and C1-C5 alkyl, provided that at least one
of R6 and R7 is H, or NR6a R7a, wherein R6a and R7a
are independently selected from H and C1-C5
alkyl;

(4) when Z is CR2, and R2 is SO2NR6R7, then R3 is not
OH or SH;

(5) when Z is CR2 and R2 is -NR6SO2R7 or -SO2NR6R7,
then R3 is not OH or SH;

(6) when R1 is -(C1-C2 alkylene) -O- (C1-C2 alkyl) or
-(C1-C2 alkylene) -OH, then at least one of the
-181-



following conditions (i), (ii) and (iii) is
true:
(i) the compound is a compound of formula (2);
(ii) Ar is selected from optionally substituted
naphthyl, triazinyl, furanyl, thienyl,
benzothienyl, benzofuranyl, 2,3-
dihydrobenzofuranyl, 2,3-dihydrobenzothienyl,
indanyl, 1,2-benzopyranyl, 3,4-dihydro-l,2-
benzopyranyl, and tetralinyl;
(iii) R3 is selected from H, SH, S(O)n R13 wherein
n = 1, CO2R7, OC(O)R13, NR8COR7, N(COR7)2,
NR8CONR6R7, NR8CO2R13, N(OR7)R6, CONR6R7, aryl
other than optionally substituted phenyl,
heteroaryl other than (a) optionally
substituted pyrazinyl, (b) optionally
substituted pyrimidyl or (c) optionally
substituted pyridazinyl, or heterocyclyl;

(7) when R3 is C5-C8 cycloalkenyl or C6-C10
cylcoalkenylalkyl, then at least one of the
following conditions (i), (ii) and (iii) is
true:
(i) the compound is a compound of formula (2);
(ii) Ar is selected from optionally substituted
naphthyl, triazinyl, furanyl, thienyl,
benzothienyl, benzofuranyl, 2,3-
dihydrobenzofuranyl, 2,3-dihydrobenzothienyl,
indanyl, 1,2-benzopyranyl, 3,4-dihydro-1,2-
benzopyranyl, and tetralinyl;
(iii) R1 is selected from C2-C4 alkenyl, C2-C4
alkynyl, CN, C1-C4 haloalkyl, C3-C12 hydroxyalk-
yl, C4-C12 alkoxyalkyl other than -(C1-C2
alkylene) -O- (C1-C2 alkyl), C2-C10 cyanoalkyl,
C3-C6 cycloalkyl, C4-C10 cycloalkylalkyl, NR9R16,
C1-C4 alkyl -NR9R10, NR9COR16, OR11, SH or S(O)n R12.

-182-



5. A compound of claim 4 and geometric isomers
thereof, stereoisomeric forms thereof, or mixtures
of stereoisomeric forms thereof, and
pharmaceutically acceptable salt or pro-drug forms
thereof with the additional provisos that: (1) when
R1 is H, C1-C4 alkyl, halo, CN, C1-C12 hydroxyalkyl,
C1-C4 alkoxyalkyl or SO2(C1-C4 alkyl), R3 is NR6a R7a
and R6a is unsubstituted C1-C4 alkyl, then R7a is
not phenyl, naphthyl, thienyl, benzothienyl,
pyridyl, quinolyl, pyrazinyl, furanyl, benzofuranyl,
benzothiazolyl, indolyl or C3-C6 cycloalkyl; and (2)
R1 is H, C1-C4 alkyl, halo, CN, C1-C12 hydroxyalkyl,
C1-C4 alkoxyalkyl or SO2(C1-C4 alkyl), R3 is NR6a R7a
and R7a is unsubstituted C1-C4 alkyl, then R6a is
not phenyl, naphthyl, thienyl, benzothienyl,
pyridyl, quinolyl, pyrazinyl, furanyl, benzofuranyl,
benzothiazolyl, indolyl or C3-C6 cycloalkyl.

6. A compound of claim 4 and geometric isomers
thereof, stereoisomeric forms thereof, or mixtures
of stereoisomeric forms thereof, and
pharmaceutically acceptable salt or pro-drug forms
thereof wherein Ar is phenyl, pyridyl or 2,3-
dihydrobenzofuranyl, each optionally substituted
with 1 to 4 R4 substituents.

7. A compound of claim 6 and geometric isomers
thereof, stereoisomeric forms thereof, or mixtures
of stereoisomeric forms thereof, and
pharmaceutically acceptable salt or pro-drug forms
thereof wherein Z is CR2, Ar is 2,4-dichlorophenyl,
2,4-dimethylphenyl or 2,4,6-trimethylphenyl, R1 and
R2 are CH3, and R3 is NR6a R7a.

8. A pharmaceutical composition comprising a
pharmaceutically acceptable carrier and a
-183-



of a compound of claim 4.

9. A pharmaceutical composition comprising a
pharmaceutically acceptable carrier and a compound of claim
6.

10. A pharmaceutical composition comprising a
pharmaceutically acceptable carrier and a compound of claim
7.

11. A compound of Formula (2) of claim 4 and geometric
isomers thereof, stereoisomeric forms thereof, or mixtures
of stereoisomeric forms thereof, and pharmaceutically
acceptable salt or pro-drug forms thereof.

12. A compound of claim 11 and geometric isomers thereof,
stereoisomeric forms thereof, or mixtures of stereoisomeric
form thereof, and pharmaceutically acceptable salt or pro-
drug forms thereof wherein Ar is phenyl, pyridyl or 2,3-
dihydrobenzofuranyl and each Ar is optionally substituted
with 1 to 4 R4 substituents.

13. A compound of claim 11 and geometric isomers thereof,
stereoisomeric forms thereof, or mixtures of stereoisomeric
forms thereof, and pharmaceutically acceptable salt or pro-
drug forms thereof wherein R3 is NR6a R7a or OR7.

14. A compound of claim 11 and geometric isomers thereof,
stereoisomeric forms thereof, or mixtures of stereoisomeric
form thereof, and pharmaceutically acceptable salt or pro-
drug forms thereof wherein Ar is phenyl, pyridyl or 2,3-
dihydrobenzofuranyl, and each Ar is optionally substituted
with 1 to 4 R4 substituents, and R3 is NR6a R7a or OR7.

-184-



15. A compound of Formula (1) of claim 4 and geometric
isomers thereof, stereoisomeric forms thereof, or mixtures
of stereoisomeric forms thereof, and pharmaceutically
acceptable salt or pro-drug forms thereof wherein Z is CR2.
16. A compound of claim 15 and geometric isomers thereof,
stereoisomeric forms thereof, or mixtures of stereoisomeric
forms thereof, and pharmaceutically acceptable salt or pro-
drug forms thereof wherein Ar is phenyl, pyridyl 2,3-
dihydrobenzofuranyl and each Ar is optionally substituted
with 1 to 4 R4 substituents.

17. A compound of claim 15 and geometric isomers thereof,
stereoisomeric forms thereof, or mixtures of stereoisomeric
forms thereof, and pharmaceutically acceptable salt or pro-
drug forms thereof wherein R3 is NR6a R7a or OR7.

18. A compound of claim 17 and geometric isomers thereof,
stereoisomeric forms thereof, or mixtures of stereoisomeric
forms thereof, and pharmaceutically acceptable salt or pro-
drug forms thereof wherein R6a is independently selected

from:

-H,
-C1-C10 alkyl, C3-C10 alkenyl, C3-C10 alkynyl,
-C1-C10 haloalkyl with 1-10 halogens, C2-C8
alkoxyalkyl, C3-C6 cycloalkyl, C4-

C12 cylcoalkylalkyl, C5-C10 cycloalkenyl,
and C6-C14 cycloalkenylalkyl, each

optionally substituted with 1 to 3 substituents
independently selected at

-185-



each occurrence from C1-C6 alkyl, C3-
C6 cycloalkyl, halo, C1-C4 haloalkyl,
cyano, OR15, SH, S(O)n R13, COR15, CO2R15,
OC(O)R13, NR8COR15, N(COR15)2,
NR8CONR16R15, NR8CO2R13, NR16R15,
CONR16R15, aryl, heteroaryl and
heterocyclyl,
-aryl, aryl(C1-C4 alkyl)-, heteroaryl,
heteroaryl(C1-C4 alkyl)-, heterocyclyl and
heterocyclyl(C1-C4 alkyl)-; and
R7a is independently selected at each occurrence from:
-H,
-C5-C10 alkyl, C3-C10 alkenyl, C3-C10 alkynyl,
C1-C10 haloalkyl with 1-10 halogens, C2-C8
alkoxyalkyl, C3-C6 cycloalkyl, C4-
C12 cycloalkylalkyl, C5-C10 cycloalkenyl,
and C6-C14 cycloalkenylalkyl, each
optionally substituted with 1 to 3
substituents independently selected at
each occurrence from C1-C6 alkyl, C3-
C6 cycloalkyl, halo, C1-C4 haloalkyl,
cyano, OR15, SH, S(O)n R13, COR15, CO2R15,
OC(O)R13, NR8COR15, N(COR15)2,
NR8CONR16R15, NR8CO2R13, NR16R15,
CONR16R15, aryl, heteroaryl and
heterocyclyl,
-aryl, aryl(C1-C4 alkyl), heteroaryl,
heteroaryl(C1-C4 alkyl), heterocyclyl
and heterocyclyl(C1-C4 alkyl);

alternatively, NR6R7 and NR6a R7a are independently
piperidine, pyrrolidine, piperazine, N-
methylpiperazine, morpholine or thiomorpholine, each
optionally substituted with 1-3 C1-C4 alkyl groups.

-186-



19. A compound of C1aim 17 and geometric isomers
thereof, stereoisomeric forms thereof, or mixtures of
stereoisomeric forms thereof, and pharmaceutically
acceptable salt or pro-drug forms thereof wherein R6a
and R7a are identical and are selected from:
-C1-C4 alkyl and C3-C6 cycloalkyl, each optionally
substituted with 1 to 3 substituents
independently selected at each occurrence
from C1-C6 alkyl, C3-C6 cycloalkyl, halo, C1-
C4 haloalkyl, cyano, OR15, SH, S(O)n R13,
COR15, CO2R15, OC(O)R13, NR8COR15, N(COR15)2,
NR8CONR16R15, NR8CO2R13, NR16R15, CONR16R15,
aryl, heteroaryl and heterocyclyl, and
-aryl and heteroaryl.

20. A compound of C1aim 17 and geometric isomers
thereof, stereoisomeric forms thereof, or mixtures of
stereoisomeric forms thereof, and pharmaceutically
acceptable salt or pro-drug forms thereof wherein
R6a is selected from:
-H,
-C1-C10 alkyl, C3-C10 alkenyl, C3-C10 alkynyl,
C1-C10 haloalkyl with 1-10 halogens, C2-C8
alkoxyalkyl, C3-C6 cycloalkyl, C4-
C12 cycloalkylalkyl, C5-C10 cycloalkenyl,
and C6-C14 cycloalkenylalkyl, each
optionally substituted with 1 to 3
substituents independently selected at
each occurrence from C1-C6 alkyl, C3-
C6 cycloalkyl, halo, C1-C4 haloalkyl,
cyano, OR15, SH, S(O)n R13, COR15, CO2R15,
OC(O)R13, NR8COR15, N(COR15)2,
NR8CONR16R15, NR8CO2R13, NR16R15,
CONR16R15, aryl, heteroaryl and
heterocyclyl,

-187-



-aryl, aryl(C1-C4 alkyl), heteroaryl,
heteroaryl(C1-C4 alkyl), heterocyclyl and
heterocyclyl(C1-C4 alkyl);
R7a is
-C1-C4 alkyl, wherein each such C1-C4 alkyl is
substituted with 1-3 substituents
independently selected at each occurrence
from C1-C6 alkyl, C3-C6 cycloalkyl, halo, C1-
C4 haloalkyl, cyano, OR15, SH, S(O)n R13,
COR15, CO2R15, OC(O)R13, NR8COR15, N(COR15)2,
NR8CONR16R15, NR8CO2R13, NR16R15, CONR16R15,
aryl, heteroaryl and heterocyclyl.

21. A compound of claim 17 and geometric isomers
thereof, stereoisomeric forms thereof, or mixtures of
stereoisomeric forms thereof, and pharmaceutically
acceptable salt or pro-drug forms thereof wherein one
of R6a and R7a is selected from:
-C3-C6 cycloalkyl, each such C3-C6 cycloalkyl
optionally substituted with 1-3 substituents
independently selected at each occurrence
from C1-C6 alkyl, C3-C6 cycloalkyl, halo, C1-
C4 haloalkyl, cyano, OR15, SH, S(O)n R13,
COR15, CO2R15, OC(O)R13, NR8COR15, N(COR15)2,
NR8CONR16R15, NR8CO2R13, NR16R15, CONR16R15,
aryl, heteroaryl and heterocyclyl,
-aryl,
-heteroaryl and
-heterocyclyl,
and the other of R6a and R7a is unsubstituted C1-C4
alkyl.

22. A compound of claim 17 and geometric isomers
thereof, stereoisomeric forms thereof, or mixtures of
stereoisomeric forms thereof, and pharmaceutically

-188-



acceptable salt or pro-drug forms thereof wherein R6a
and R7a are independently H or C1-C10 alkyl, each such
C1-C10 alkyl optionally substituted with 1 to 3
substituents independently selected at each occurrence
from C1-C6 alkyl, C3-C6 cycloalkyl, halo, C1-
C4 haloalkyl, cyano, OR15, SH, S(O)n R13, COR15, CO2R15,
OC(O)R13, NR8COR15, N(COR15)2, R8CONR16R15, NR8CO2R13,
NR16R15, CONR16R15, aryl, heteroaryl and heterocyclyl.
23. A compound of claim 15 and geometric isomers
thereof, stereoisomeric forms thereof, or mixtures of
stereoisomeric forms thereof, and pharmaceutically
acceptable salt or pro-drug forms thereof wherein Ar is
phenyl, pyridyl or 2,3-dihydrobenzofuranyl, and each Ar
is optionally substituted with 1 to 4 R4 substituents,
and R3 is NR6aR7a or OR7.

24. A compound of claim 23 and geometric isomers
thereof, stereoisomeric forms thereof, or mixtures of
stereoisomeric forms thereof, and pharmaceutically
acceptable salt or pro-drug forms thereof wherein R6a
is independently selected from:
-H,
-C1-C10 alkyl, C3-C10 alkenyl, C3-C10 alkynyl,
C1-C10 haloalkyl with 1-10 halogens, C2-C8
alkoxyalkyl, C3-C6 cycloalkyl, C4-
C12 cycloalkylalkyl, C5-C10 cycloalkenyl,
and C6-C14 cycloalkenylalkyl, each
optionally substituted with 1 to 3
substituents independently selected at
each occurrence from C1-C6 alkyl, C3-
C6 cycloalkyl, halo, C1-C4 haloalkyl,
cyano, OR15, SH, S(O) nR13, COR15, CO2R15,
OC(O)R13, NR8COR15, N(COR15)2,
NR8CONR16R15, NR8CO2R13, NR16R15,
-189-



CONR16R15, aryl, heteroaryl and
heterocyclyl,
-aryl, aryl(C1-C4 alkyl)-, heteroaryl,
heteroaryl(C1-C4 alkyl), heterocyclyl and
heterocyclyl(C1-C4 alkyl);

R7a is independently selected at each occurrence from:
-H,
-C5-C10 alkyl, C3-C10 alkenyl, C3-C10 alkynyl,
C1-C10 haloalkyl with 1-10 halogens, C2-C8
alkoxyalkyl, C3-C6 cycloalkyl, C4-
C12 cycloalkylalkyl, C5-C10 cycloalkenyl,
and C6-C14 cycloalkenylalkyl, each
optionally substituted with 1 to 3
substituents independently selected at
each occurrence from C1-C6 alkyl, C3-
C6 cycloalkyl, halo, C1-C4 haloalkyl,
cyano, OR15, SH, S(O)n R13, COR15, CO2R15,
OC(O)R13, NR8COR15, N(COR15)2,
NR8CONR16R15, NR8CO2R13, NR16R15,
CONR16R15, aryl, heteroaryl and
heterocyclyl,
-aryl, aryl(C1-C4 alkyl), heteroaryl,
heteroaryl(C1-C4 alkyl), heterocyclyl
and heterocyclyl(C1-C4 alkyl),

alternatively, NR6R7 and NR6a R7a are independently
piperidine, pyrrolidine, piperazine, N-
methylpiperazine, morpholine or thiomorpholine, each
optionally substituted with 1-3 C1-C4 alkyl groups.
25. A compound of claim 23 and geometric isomers
thereof, stereoisomeric forms thereof, or mixtures of
stereoisomeric forms thereof, and pharmaceutically
acceptable salt or pro-drug forms thereof wherein R6a
and R7a are identical and are selected from:

-190-



-C1-C4 alkyl and C3-C6 cycloalkyl, each optionally
substituted with 1 to 3 substituents
independently selected at each occurrence
from C1-C6 alkyl, C3-C6 cycloalkyl, halo, C1-
C4 haloalkyl, cyano, OR15, SH, S(O)n R13, -
COR15, CO2R15, OC(O)R13, NR8COR15, N(COR15)2,
NR8CONR16R15, NR8CO2R13 , NR16R15, CONR16R15,
aryl, heteroaryl and heterocyclyl, and
-aryl and heteroaryl.

26. A compound of C1aim 23 and geometric isomers
thereof, stereoisomeric forms thereof, or mixtures of
stereoisomeric forms thereof, and pharmaceutically
acceptable salt or pro-drug forms thereof wherein R6a
and R7a are identical and are
-C1-C4 alkyl, each such C1-C4 alkyl optionally
substituted with 1 to 3 substituents
independently selected at each occurrence
from C1-C6 alkyl, C3-C6 cycloalkyl, halo, C1-
C4 haloalkyl, cyano, OR15, SH, S(O)n R13,
COR15, CO2R15, OC(O)R13, NR8COR15, N(COR15)2,
NR8CONR16R15, NR8CO2R13 , NR16R15, CONR16R15,
aryl, heteroaryl and heterocyclyl.

27. A compound of C1aim 23 and geometric isomers
thereof, stereoisomeric forms thereof, or mixtures of
stereoisomeric forms thereof, and pharmaceutically
acceptable salt or pro-drug forms thereof wherein
R6a is selected from:
-H,
-C1-C10 alkyl, C3-C10 alkenyl, C3-C10 alkynyl, C1
-C10 haloalkyl with 1-10 halogens, C2-C8
alkoxyalkyl, C3-C6 cycloalkyl, C4-
C12 cycloalkylalkyl, C5-C10 cycloalkenyl,
and C6-C14 cycloalkenylalkyl, each

-191-



optionally substituted with 1 to 3
substituents independently selected at
each occurrence from C1-C6 alkyl, C3-
C6 cycloalkyl, halo, C1-C4 haloalkyl,
cyano, OR15, SH, S(O)n R13, COR15, CO2R15,
OC(O)R13, NR8COR15, N(COR15)2,
NR8CONR16R15, NR8CO2R13, NR16R15,
CONR16R15, aryl, heteroaryl and
heterocyclyl,
-aryl, aryl(C1-C4 alkyl), heteroaryl,
heteroaryl(C1-C4 alkyl), heterocyclyl and
heterocyclyl(C1-C4 alkyl);

R7a is :
-C1-C4 alkyl wherein each such C1-C4 alkyl is
substituted with 1-3 substituents
independently selected at each occurrence
from C1-C6 alkyl, C3-C6 cycloalkyl, halo, C1-
C4 haloalkyl, cyano, OR15, SH, S(O)n R13,
COR15, CO2R15, OC(O)R13, NR8COR15, N(COR15)2,
NR8CONR16R15, NR8CO2R13, NR16R15, CONR16R15,
aryl, heteroaryl and heterocyclyl.

28. A compound of claim 23 and geometric isomers
thereof, stereoisomeric forms thereof, or mixtures of
stereoisomeric forms thereof, and pharmaceutically
acceptable salt or pro-drug forms thereof wherein one
of R6a and R7a is selected from:
-C3-C6 cycloalkyl, each such C3-C6
cycloalkyloptionally substituted with 1-3
substituents independently selected at each
occurrence from C1-C6 alkyl, C3-C6
cycloalkyl, halo, C1-C4 haloalkyl, cyano,
OR15, SH, S(O)n R13, COR15, CO2R15, OC(O)R13,
NR8COR15, N(COR15)2, NR8CONR16R15, NR8CO2R13,
NR16R15, CONR16R15, aryl, heteroaryl and
heterocyclyl,

-192-




-aryl,
-heteroaryl and
-heterocyclyl,
and the other of R6a and R7a is unsubstituted C1-C4
alkyl.

29. A compound of claim 23 and geometric isomers
thereof, stereoisomeric forms thereof, or mixtures of
stereoisomeric forms thereof, and pharmaceutically
acceptable salt or pro-drug forms thereof wherein R6a
and R7a are independently H or C1-C10 alkyl, each such
C1-C10 alkyl optionally substituted with 1 to 3
substituents independently selected at each occurrence
from C1-C6 alkyl, C3-C6 cycloalkyl, halo, C1-
C4 haloalkyl, cyano, OR15, SH, S(O)n R13, COR15, CO2R15,
OC(O)R13, NR8COR15, N(COR15)2, R8CONR16R15, NR8CO2R13,
NR16R15, CONR16R15, aryl, heteroaryl and heterocyclyl.
30. A compound of claim 15 and geometric isomers
thereof, stereoisomeric forms thereof, or mixtures of
stereoisomeric forms thereof, and pharmaceutically
acceptable salt or pro-drug forms thereof wherein
-Ar is phenyl, pyridyl or 2,3-dihydrobenzofuranyl,
and each Ar is optionally substituted with 1
to 4 R4 substituents,
-R3 is NR6a R7a or OR7 and
-R1 and R2 are independently selected from H, C1-
C4 alkyl, C3-C6 cycloalkyl, and C4-C10
cycloalkylalkyl.

31. A compound of claim 30 and geometric isomers
thereof, stereoisomeric forms thereof, or mixtures of
stereoisomeric forms thereof, and pharmaceutically
acceptable salt or pro-drug forms thereof wherein R6a
is independently selected from:
-H,

-193-



-C1-C10 alkyl, C3-C10 alkenyl, C3-C10 alkynyl,
C1-C10 haloalkyl with 1-10 halogens, C2-C8
alkoxyalkyl, C3-C6 cycloalkyl, C4-
C12 cycloalkylalkyl, C5-C10 cycloalkenyl,
and C6-C14 cycloalkenylalkyl, each
optionally substituted with 1 to 3
substituents independently selected at
each occurrence from C1-C6 alkyl, C3-
C6 cycloalkyl, halo, C1-C4 haloalkyl,
cyano, OR15, SH, S(O)n R13, COR15, CO2R15,
OC(O)R13 , NR8COR15 , N(COR15)2,
NR8CONR16R15, NR8CO2R13, NR16R15,
CONR16R15, aryl, heteroaryl and
heterocyclyl,
-aryl, aryl(C1-C4 alkyl)-, heteroaryl,
heteroaryl(C1-C4 alkyl), heterocyclyl and
heterocyclyl(C1-C4 alkyl);
R7a is independently selected at each occurrence from:
-H,
-C5-C10 alkyl, C3-C10 alkenyl, C3-C10 alkynyl,
C1-C10 haloalkyl with 1-10 halogens, C2-C8
alkoxyalkyl, C3-C6 cycloalkyl, C4-
C12 cycloalkylalkyl, C5-C10 cycloalkenyl,
and C6-C14 cycloalkenylalkyl, each
optionally substituted with 1 to 3
substituents independently selected at
each occurrence from C1-C6 alkyl, C3-
C6 cycloalkyl, halo, C1-C4 haloalkyl,
cyano, OR15, SH, S(O)n R13, COR15, CO2R15,
OC(O)R13, NR8COR15, N(COR15)2,
NR8CONR16R15, NR8CO2R13, NR16R15,
CONR16R15, aryl, heteroaryl and
heterocyclyl,

-194-



-aryl, aryl(C1-C4 alkyl), heteroaryl,
heteroaryl(C1-C4 alkyl), heterocyclyl
and heterocyclyl(C1-C4 alkyl),

alternatively, NR6R7 and NR6a R7a are independently
piperidine, pyrrolidine, piperazine, N-
methylpiperazine, morpholine or thiomorpholine, each
optionally substituted with 1-3 C1-C4 alkyl groups.
32. A compound of claim 30 and geometric isomers
thereof, stereoisomeric forms thereof, or mixtures of
stereoisomeric forms thereof, and pharmaceutically
acceptable salt or pro-drug forms thereof wherein R6a
and R7a are identical and are selected from:
-C1-C4 alkyl and C3-C6 cycloalkyl, each optionally
substituted with 1 to 3 substituents
independently selected at each occurrence
from C1-C6 alkyl, C3-C6 cycloalkyl, halo, C1-
C4 haloalkyl, cyano, OR15, SH, S(O)n R13, -
COR15, CO2R15, OC(O)R13, NR8COR15, N(COR15)2,
NR8CONR16R15, NR8CO2R13, NR16R15, CONR16R15,
aryl, heteroaryl and heterocyclyl,
-aryl and heteroaryl.

33. A compound of claim 30 and geometric isomers
thereof, stereoisomeric forms thereof, or mixtures of
stereoisomeric forms thereof, and pharmaceutically
acceptable salt or pro-drug forms thereof wherein R6a
and R7a are identical and are
-C1-C4 alkyl, each such C1-C4 alkyl optionally
substituted with 1 to 3 substituents
independently selected at each occurrence
from C1-C6 alkyl, C3-C6 cycloalkyl, halo, C1-
C4 haloalkyl, cyano, OR15, SH, S(O)n R13,
-COR15, CO2R15, OC(O)R13, NR8COR15, N(COR15)2,

-195-



NR8CONR16R15, NR8CO2R13, NR16R15, CONR16R15,
aryl, heteroaryl and heterocyclyl.

34. A compound of claim 30 and geometric isomers
thereof, stereoisomeric forms thereof, or mixtures of
stereoisomeric forms thereof, and pharmaceutically
acceptable salt or pro-drug forms thereof wherein R6a
is selected from:
-H,
-C1-C10 alkyl, C3-C10 alkenyl, C3-C10 alkynyl,
C1-C10 haloalkyl with 1-10 halogens, C2-C8
alkoxyalkyl, C3-C6 cycloalkyl, C4-
C12 cycloalkylalkyl, C5-C10 cycloalkenyl,
and C6-C14 cycloalkenylalkyl, each
optionally substituted with 1 to 3
substituents independently selected at
each occurrence from C1-C6 alkyl, C3-
C6 cycloalkyl, halo, C1-C4 haloalkyl,
cyano, OR15, SH, S(O)n R13, COR15, CO2R15,
OC(O)R13, NR8COR15, N(COR15)2,
NR8CONR16R15, NR8CO2R13, NR16R15,
CONR16R15, aryl, heteroaryl and
heterocyclyl,
-aryl, aryl(C1-C4 alkyl), heteroaryl,
heteroaryl(C1-C4 alkyl), heterocyclyl and
heterocyclyl(C1-C4 alkyl);

R7a is:
-C1-C4 alkyl wherein each such C1-C4 alkyl is
substituted with 1-3 substituents
independently selected at each occurrence
from C1-C6 alkyl, C3-C6 cycloalkyl, halo, C1-
C4 haloalkyl, cyano, OR15, SH, S(O)n R13,
COR15, CO2R15, OC(O)R13, NR8COR15, N(COR15)2,
NR8CONR16R15, NR8CO2R13, NR16R15, CONR16R15,
aryl, heteroaryl and heterocyclyl.

-196-



35. A compound of claim 30 and geometric isomers
thereof, stereoisomeric forms thereof, or mixtures of
stereoisomeric forms thereof, and pharmaceutically
acceptable salt or pro-drug forms thereof wherein one
of R6a and R7a is selected from:
-C3-C6 cycloalkyl, each such C3-C6 cycloalkyl
optionally substituted with 1-3 substituents
independently selected at each occurrence
from C1-C6 alkyl, C3-C6 cycloalkyl, halo, C1-
C4 haloalkyl, cyano, OR15, SH, S(O)n R13,
COR15, CO2R15, OC(O)R13, NR8COR15, N(COR15)2,
NR8CONR16R15, NR8CO2R13 , NR16R15, CONR16R15,
aryl, heteroaryl and heterocyclyl,
-aryl,
-heteroaryl and
-heterocyclyl,
and the other of R6a and R7a is unsubstituted C1-C4
alkyl.

36. A compound of claim 30 and geometric isomers
thereof, stereoisomeric forms thereof, or mixtures of
stereoisomeric forms thereof, and pharmaceutically
acceptable salt or pro-drug forms thereof wherein R6a
and R7a are independently H or C1-C10 alkyl, each such
C1-C10 alkyl optionally substituted with 1 to 3
substituents independently selected at each occurrence
from C1-C6 alkyl, C3-C6 cycloalkyl, halo, C1-
C4 haloalkyl, cyano, OR15, SH, S(O)n R13, COR15, CO2R15,
OC(O)R13, NR8COR15, N(COR15)2, R8CONR16R15, NR8CO2R13,
NR16R15, CONR16R15, aryl, heteroaryl and heterocyclyl.
37. A compound of claim 30 of Formula (50)



-197-




Image
and geometric isomers thereof, stereoisomeric forms
thereof, or mixtures of stereoisomeric forms thereof,
and pharmaceutically acceptable salt or pro-drug forms
thereof, selected from the group consisting of:

a compound of Formula (50) wherein R3 is -NHCH(n-Pr)2,
R4a is Cl, R4b is H, R4c is Cl, R4d is H and R4e
is H;

a compound of Formula (50) wherein R3 is -N(Et)(n-Bu),
R4a is Cl, R4b is H, R4c is Cl, R4d is H and R4e
is H;

a compound of Formula (50) wherein R3 is
-N(n-Pr)(CH2cPr), R4a is Cl, R4b is H, R4C is Cl,
R4d is H and R4e is H;

a compound of Formula (50) wherein R3 is
-N(CH2CH2OMe)2, R4a is Cl, R4b is H, R4c is Cl,
R4d is H and R4e is H;

a compound of Formula (50) wherein R3 is -NHCH(Et)(n-
Bu), R4a is Cl, R4b is H, R4c is Cl, R4d is H and
R4e is H;

-198-


a compound of Formula (50) wherein R3 is
-NHCH(Et)(CH2OMe), R4a is Cl, R4b is H, R4c is Cl,
R4d is H and R4e is H;

a compound of Formula (50) wherein R3 is
-NHCH(CH2OMe)2, R4a is Cl, R4b is H, R4c is Cl,
R4d is H and R4e is H;

a compound of Formula (50) wherein R3 is -N(Et)2, R4a
is Cl, R4b is H, R4c is C1, R4d is H and R4e is H;
a compound of Formula (50) wherein R3 is
-NHCH(CH2OEt)2, R4a is Cl, R4b is H, R4c is Cl,
R4d is H and R4e is H;

a compound of Formula (50) wherein R3 is -NHCH(Et)2,
R4a is Cl, R4b is H, R4c is Cl, R4d is H and R4e
is H;

a compound of Formula (50) wherein R3 is -N(Me)(Ph),
R4a is Cl, R4b is H, R4c is Cl, R4d is H and R4e
is H;

a compound of Formula (50) wherein R3 is -N(n-Pr)2, R4a
is Cl, R4b is H, R4C is C1, R4d is H and R4e is H;
a compound of Formula (50) wherein R3 is -NHCH(Et)(n-
Pr), R4a is Cl, R4b is H, R4c is Cl, R4d is H and
R4e is H;

a compound of Formula (50) wherein R3 is
-NHCH(CH2OMe)2, R4a is Me, R4b is H, R4c is Me,
R4d is H and R4e is Me;

a compound of Formula (50) wherein R3 is
-NHCH(CH2OMe)2, R4a is Me, R4b is H, R4c is Me,
R4d is H and R4e is H;

-199-


a compound of Formula (50) wherein R3 is
-N(CH2CH2OMe)2, R4a is Me, R4b is H, R4c is Me,
R4d is H and R4e is H;

a compound of Formula (50) wherein R3 is
-NHCH(Et)(CH2OMe), R4a is Me, R4b is H, R4c is Me,
R4d is H and R4e is H;

a compound of Formula (50) wherein R3 is -NHCH(Et)2,
R4a is Me, R4b is H, R 4c is Me, R4d is H and R4e
is H;

a compound of Formula (50) wherein R3 is -OEt, R4a is
Cl, R4b is H, R4c is Cl, R4d is H and R4e is H;
a compound of Formula (50) wherein R3 is -N(Et)2, R4a

is Me, R4b is H, R4C is Me, R4d is H and R4e is H;
a compound of Formula (50) wherein R3 is -N(CH2CN)2,
R4a is Me, R4b is H, R4c is Me, R4d is H and R4e
is H;

a compound of Formula (50) wherein R3 is
-NHCH(Me)(CH2OMe), R4a is Me, R4b is H, R4c is Me,
R4d is H and R4e is H;

a compound of Formula (50) wherein R3 is
-OCH(Et)(CH2OMe), R4a is Me, R4b is H, R4c is Me,
R4d is H and R4e is H;

a compound of Formula (50) wherein R3 is
-N(n-Pr)(CH2cPr), R4a is Me, R4b is H, R4c is Me,
R4d is H and R4e is H;

a compound of Formula (50) wherein R3 is
-NHCH(Me)(CH2N(Me)2), R4a is Me, R4b is H, R4C is
Me, R4d is H and R4e is H;

-200-


a compound of Formula (50) wherein R3 is
-N(cPr)(CH2CH2CN), R4a is Me, R4b is H, R4c is Me,
R4d is H and R4e is H;

a compound of Formula (50) wherein R3 is
-N(n-Pr)(CH2CH2CN), R4a is Me, R4b is H, R4c is
Me, R4d is H and R4e is H;

a compound of Formula (50) wherein R3 is
-N(n-Bu)(CH2CN), R4a is Me, R4b is H, R4c is Me,
R4d is H and R4e is H;

a compound of Formula (50) wherein R3 is
-NHCH(Et)(CH2OMe), R4a is Me, R4b is H, R4c is Me,
R4d is H and R4e is Me;

a compound of Formula (50) wherein R3 is -NHCH(Et)2,
R4a is Me, R4b is H, R4c is Me, R4d is H and R4e
is Me;

a compound of Formula (50) wherein R3 is
-N(CH2CH2OMe)2, R4a is Me, R4b is H, R4c is Me,
R4d is H and R4e is Me;

a compound of Formula (50) wherein R3 is
-NHCH(CH2OMe)2, R4a is Br, R4b is H, R4c is OMe,
R4d is H and R4e is H;

a compound of Formula (50) wherein R3 is
-NHCH(Et)(CH2OMe), R4a is Br, R4b is H, R4c is
OMe, R4d is H and R4e is H;

a compound of Formula (50) wherein R3 is -N(Et)2, R4a
is Me, R4b is H, R4c is Me, R4d is H and R4e is
Me;

a compound of Formula (50) wherein R3 is
-NHCH(CH2OEt)2, R4a is Me, R4b is H, R4c is Me,
R4d is H and R4e is Me;

-201-


a compound of Formula (50) wherein R3 is
-NHCH(CH2CH2OMe)(CH2OMe), R4a is Me, R4b is H, R4c
is Me, R4d is H and R4e is Me;

a compound of Formula (50) wherein R3 is morpholino,
R4a is Me, R4b is H, R4c is Me, R4d is H and R4e
is H;

a compound of Formula (50) wherein R3 is
-N(CH2CH2OMe)2, R4a is Br, R4b is H, R 4c is OMe,
R4d is H and R4e is H;

a compound of Formula (50) wherein R3 is -NHCH(Et)2,
R4a is Br, R4b is H, R4c is OMe, R4d is H and R4e
is H;

a compound of Formula (50) wherein R3 is -N(Et)2, R4a
is Br, R4b is H, R4c is OMe, R4d is H and R4e is
H;

a compound of Formula (50) wherein R3 is -NH(c-Pr), R4a
is Me, R4b is H, R4c is Me, R4d is H and R4e is H;
a compound of Formula (50) wherein R3 is
-NHCH(CH2OMe)2, R4a is CN, R4b is H, R4c is OMe,
R4d is H and R4e is H;

a compound of Formula (50) wherein R3 is
-N(c-Pr)(CH2CH2CN), R4a is Me, R4b is H, R4C is
Me, R4d is H and R4e is Me;

a compound of Formula (50) wherein R3 is -NCH(CH2OMe)2,
R4a is Me, R4b is H, R4c is Br, R4d is H and R4e
is H;

a compound of Formula (50) wherein R3 is
-NHCH(CH2OMe)(CH2CH2OMe), R4a is Me, R4b is H, R4c
is Br, R4d is H and R4e is H;

-202-


a compound of Formula (50) wherein R3 is
-NHCH(CH2OMe)2, R4a is Me, R4b is H, R4c is OMe,
R4d is Me and R4e is H;

a compound of Formula (50) wherein R3 is
-N(CH2CH2OMe)2, R4a is Me, R4b is H, R4C is OMe,
R4d is Me and R4e is H;

a compound of Formula (50) wherein R3 is -NHCH(Et)2,
R4a is Me, R4b is H, R4c is OMe, R4d is Me and R4e
is H;

a compound of Formula (50) wherein R3 is -N(Et)2, R4a
is Me, R4b is H, R4c is OMe, R4d is Me and R4e is
H;

a compound of Formula (50) wherein R3 is
-NHCH(CH2OMe)2, R4a is Cl, R4b is H, R4c is Me,
R4d is H and R4e is H;

a compound of Formula (50) wherein R3 is
-NHCH(Et)(CH2OMe), R4a is Cl, R4b is H, R4C is Me,
R4d is H and R4e is H;

a compound of Formula (50) wherein R3 is
-N(CH2CH2OMe)2, R4a is Cl, R4b is H, R4c is Me,
R4d is H and R4e is H;

a compound of Formula (50) wherein R3 is
-NHCH(CH2OMe)(CH2CH2OMe), R4a is Cl, R4b is H, R4c
is Me, R4d is H and R4e is H;

a compound of Formula (50) wherein R3 is
-N(c-Pr)(CH2CH2CN), R4a is Me, R4b is H, R4C is
OMe, R4d is Me and R4e is H;

a compound of Formula (50) wherein R3 is
-N(c-Pr)(CH2CH2CN), R4a is Cl, R4b is H, R4c is
Cl, R4d is H and R4e is H;

-203-


a compound of Formula (50) wherein R3 is
(S)-NHCH(CH2OMe)(CH2CH2OMe), R4a is Cl, R4b is H,
R4c is Cl, R4d is H and R4e is H;

a compound of Formula (50) wherein R3 is
-NHCH(CH2OMe)(CH2CH2OMe), R4a is C1, R4b is H, R4c
is Cl, R4d is H and R4e is H;

a compound of Formula (50) wherein R3 is -NHCH(Et)2,
R4a is Me, R4b is H, R4c is Br, R4d is H and R4e
is H;

a compound of Formula (50) wherein R3 is
-N(CH2CH2OMe)2, R4a is Me, R4b is H, R4c is Br,
R4d is H and R4e is H;

a compound of Formula (50) wherein R3 is
-NH(CH2OMe)(CH2-iPr), R4a is Me, R4b is H, R4c is
Me, R4d is H and R4e is H;

a compound of Formula (50) wherein R3 is
-N(CH2CH2OMe)2, R4a is Me, R4b is H, R4c is H, R4d
is H and R4e is H;

a compound of Formula (50) wherein R3 is
-N(CH2CH2OMe)2, R4a is Me, R4b is H, R4c is NMe2,
R4d is H and R4e is H;

a compound of Formula (50) wherein R3 is
-NHCH(CH2OMe)(n-Pr), R4a is Me, R4b is H, R4c is
Me, R4d is H and R4e is H;

a compound of Formula (50) wherein R3 is
-NHCH(CH2OEt)(Et), R4a is Me, R4b is H, R4c is Me,
R4d is H and R4e is H;

a compound of Formula (50) wherein R3 is
-NHCH(CH2OMe)(CH2CH2OMe), R4a is Me, R4b is H, R4c
is NMe2, R4d is H and R4e is H;

-204-


a compound of Formula (50) wherein R3 is -N(Et)2, R4a
is Me, R4b is H, R4C is Cl, R4d is H and R4e is H;

a compound of Formula (50) wherein R3 is -NHCH(Et)2,
R4a is Me, R4b is H, R4c is C1, R4d is H and R4e
is H;

a compound of Formula (50) wherein R3 is
-N(CH2CH2OMe)2, R4a is Me, R4b is H, R4c is Cl,
R4d is H and R4e is H;

a compound of Formula (50) wherein R3 is
-NHCH(CH2OMe)2, R4a is Me, R4b is H, R4C is C1,
R4d is H and R4e is H;

a compound of Formula (50) wherein R3 is -N(Et)2, R4a
is Me, R4b is H, R4C is Br, R4d is H and R4e is H;
a compound of Formula (50) wherein R3 is -N(Et)2, R4a
is Cl, R4b is H, R4c is Me, R4d is H and R4e is H;
a compound of Formula (50) wherein R3 is -NHCH(Et)2,
R4a is C1, R4b is H, R4c is Me, R4d is H and R4e
is H;

a compound of Formula (50) wherein R3 is -NHCH(Et)2,
R4a is Me, R4b is H, R4c is NMe2, R4d is H and R4e
is H;

a compound of Formula (50) wherein R3 is
(S)-NHCH(CH2OMe)(CH2CH2OMe), R4a is Me, R4b is H,
R4c is Me, R4d is H and R4e is H;

a compound of Formula (50) wherein R3 is
-NHCH(CH2OMe)(CH2CH2OMe), R4a is Me, R4b is H, R4c
is Me, R4d is H and R4e is H;

-205-


a compound of Formula (50) wherein R3 is
(S)-NHCH(CH2OMe)(CH2CH2OMe), R4a is Me, R4b is H,
R4c is Cl, R4d is H and R4e is H;

a compound of Formula (50) wherein R3 is
-NHCH(CH2OMe)(CH2CH2OMe), R4a is Me, R4b is H, R4c
is Cl, R4d is H and R4e is H;

a compound of Formula (50) wherein R3 is
-N(c-Pr)(CH2CH2CN), R4a is Me, R4b is H, R4c is
Cl, R4d is H and R4e is H;

a compound of Formula (50) wherein R3 is
-NHCH(Et)(CH2CN), R4a is Me, R4b is H, R4c is C1,
R4d is H and R4e is H;

a compound of Formula (50) wherein R3 is -N(Et)2, R4a
is Me, R4b is Me, R4c is OMe, R4d is H and R4e is
H;

a compound of Formula (50) wherein R3 is
-N(CH2CH2OMe)(CH2CH2OH), R4a is Cl, R4b is H, R4c
is Cl, R4d is H and R4e is H;

a compound of Formula (50) wherein R3 is
-N(CH2CH2OMe)2, R4a is Me, R4b is Me, R4c is OMe,
R4d is H and R4e is H;

a compound of Formula (50) wherein R3 is -NHCH(Et)2,
R4a is Me, R4b is Me, R4c is OMe, R4d is H and R4e
is H;

a compound of Formula (50) wherein R3 is -N(CH2c-Pr)
(n-Pr), R4a is Me, R4b is H, R4c is Cl, R4d is H
and R4e is H;

a compound of Formula (50) wherein R3 is -N(c-Pr)
(CH2CH2CN), R4a is Me, R4b is Me, R4c is OMe, R4d
is H and R4e is H;

-206-


a compound of Formula (50) wherein R3 is -NHCH (Et)2,
R4a is Cl, R4b is H, R4c is OMe, R4d is H and R4e
is H;

a compound of Formula (50) wherein R3 is -N(Et)2, R4a
is Cl, R4b is H, R4c is OMe, R4d is H and R4e is
H;

a compound of Formula (50) wherein R3 is
-N(CH2CH2OMe)2, R4a is Cl, R4b is H, R4C is OMe,
R4d is H and R4e is H;

a compound of Formula (50) wherein R3 is
-NHCH(Et)(CH2OMe), R4a is C1, R4b is H, R4c is
OMe, R4d is H and R4e is H;

a compound of Formula (50) wherein R3 is -N(Et)2, R4a
is C1, R4b is H, R4c is CN, R4d is H and R4e is H;
a compound of Formula (50) wherein R3 is
-N(c-Pr)(CH2CH2CN), R4a is C1, R4b is H, R4c is
OMe, R4d is H and R4e is H;

a compound of Formula (50) wherein R3 is -NHCH(CH2OH)2,
R4a is C1, R4b is H, R4c is Cl, R4d is H and R4e
is H; and

a compound of Formula (50) wherein R3 is N(CH2CH2OMe)2,
R4a is Me, R4b is H, R4c is OMe, R4d is H and R4e
is H

38. A compound of claim 30 and geometric isomers
thereof, stereoisomeric forms thereof, or mixtures
of stereoisomeric forms thereof, and
pharmaceutically acceptable salt or pro-drug forms
thereof, wherein said compound is 4-(bis-(2-
methoxyethyl)amino)-2,7-dimethyl-8-(2-methyl-4-
methoxyphenyl)-[1,5-a]-pyrazolo-1,3,5-triazine.

-207-


39. A compound of claim 30 and geometric isomers
thereof, stereoisomeric forms thereof, or mixtures
of stereoisomeric forms thereof, and
pharmaceutically acceptable salt or pro-drug forms
thereof, wherein said compound is 4-(bis-(2-
methoxyethyl)amino)-2,7-dimethyl-8-(2,5-dimethyl-4-
methoxyphenyl)-[1,5-a]-pyrazolo-1,3,5-triazine.
40. A pharmaceutical composition comprising a
pharmaceutically acceptable carrier and a compound of
claim 15.

41. A pharmaceutical composition comprising a
pharmaceutically acceptable carrier and a compound of
claim 23.

42. A pharmaceutical composition comprising a
pharmaceutically acceptable carrier and a compound of
claim 37.

43. A pharmaceutical composition comprising a
pharmaceutically acceptable carrier and a compound of
claim 38.

44. A pharmaceutical composition comprising a
pharmaceutically acceptable carrier and a compound of
claim 39.

45. Use of a compound according to claim 4, 23, 37,
38 or 39 in the manufacture of a medicament for
treating affective disorder, anxiety, depression,

-208-


headache, irritable bowel syndrome, post-traumatic
stress disorder, supranuclear palsy, immune
suppression, Alzheimer's disease, gastrointestinal
diseases, anorexia nervosa or other feeding
disorder, drug addiction, drug or alcohol withdrawal
symptoms, inflammatory diseases, fertility problems,
human immunodeficiency virus infections, hemorrhagic
stress, obesity, infertility, head and spinal cord
traumas, epilepsy, stroke, ulcers, amyotrophic
lateral sclerosis, hypoglycemia or a disorder the
treatment of which can be effected or facilitated by
antagonizing CRF, including but not limited to
disorders induced or facilitated by CRF, in mammals.
46. A compound of claim 31, and geometric isomers
thereof, stereoisomeric forms thereof, or mixtures
of stereoisomeric forms thereof, and
pharmaceutically acceptable salt or pro-drug forms
thereof, wherein:
R1 and R2 are methyl;
R3 is NHCH (Et) 2;
Ar is 2-chloro-5-fluoro-methoxyphenyl.
47. A pharmaceutical composition comprising a
pharmaceutically acceptable carrier and a compound
of claim 46.

48. Use of a compound according to claim 46 in the
manufacture of a medicament for treating affective
disorder, anxiety, depression, headache, irritable
bowel syndrome, post-traumatic stress disorder,
supranuclear palsy, immune suppression, Alzheimer's
disease, gastrointestinal diseases, anorexia nervosa
or other feeding disorder, drug addiction, drug or
alcohol withdrawal symptoms, inflammatory diseases,

-209-


fertility problems, human immunodeficiency virus
infections, hemorrhagic stress, obesity,
infertility, head and spinal cord traumas, epilepsy,
stroke, ulcers, amyotrophic lateral sclerosis,
hypoglycemia or a disorder the treatment of which
can be effected or facilitated by antagonizing CRF,
including but not limited to disorders induced or
facilitated by CRF, in mammals.

-210-

Description

CA 02259583 1999-01-04

WO 98/03510 PCT/US97/13072
TITLE
AZOLO TRIAZINES AND PYRIMIDINES

FIELD OF THE INVENTTnN

This invention relates a treatment of
psychiatric disorders and neurological diseases
including major depression, anxiety-related
disorders, post-traumatic stress disorder,
supranuclear palsy and feeding disorders as well as
treatment of immunological, cardiovascular or heart-
related diseases and colonic hypersensitivity
associated with psychopathological disturbance and
stress, by administration of certain [1,5-a]-
pyrazolo-1,3,5-triazines, [1,5-a]-1,2,3-triazolo-
1,3,5-triazines, [1,5-a]-pyrazolo-pyrimidines and
[1,5-a]-1,2,3-triazolo-pyrimidines.

BACKGROUND OF THE INVENTION
Corticotropin releasing factor (herein referred
to as CRF), a 41 amino acid peptide, is the primary
physiological regulator of proopiomelanocortin(POMC)
-derived peptide secretion from the anterior
pituitary gland [J. Rivier et al., Proc. Nat. Acad.
Sci. (USA) 80:4851 (1983); W. Vale et al., Science
213:1394 (1981)]. In addition to its endocrine role
at the pituitary gland, immunohistochemical
localization of CRF has demonstrated that the hormone
has a broad extrahypothalamic distribution in the
central nervous system and produces a wide spectrum
of autonomic, electrophysiological and behavioral
effects consistent with a neurotransmitter or
neuromodulator role in brain [W. Vale et al., Rec.
Prog. Horm. Res. 39:245 (1983); G.F. Koob, Persp.
Behav. Med. 2:39 (1985); E.B. De Souza et al., J.
-1-


CA 02259583 1999-01-04

WO 98/03510 PCT/US97/13072
Neurosci. 5:3189 (1985)). There is also evidence
that CRF plays a significant role in integrating the
response of the immune system to physiological,
psychological, and immunological stressors [J.E.
Blalock, Physiological Reviews 69:1 (1989); J.E.
Morley, Life Sci. 41 : 527 (1987)).
Clinical data provide evidence that CRF has a
role in psychiatric disorders and neurological
diseases including depression, anxiety-related
disorders and feeding disorders. A role for CRF has
also been postulated in the etiology and
pathophysiology of Alzheimer's disease, Parkinson's
disease, Huntington's disease, progressive
supranuclear palsy and amyotrophic lateral sclerosis
as they relate to the dysfunction of CRF neurons in
the central nervous system [for review see E.B. De
Souza, Hosp. Practice 23:59 (1988)].
In affective disorder, or major depression, the
concentration of CRF is significantly increased in
the cerebral spinal fluid (CSF) of drug-free
individuals [C.B. Nemeroff et al., Science 226:1342
(1984); C.M. Banki et al., Am. J. Psychiatry 144:873
(1987); R.D. France et al., Biol. Psychiatry 28:86
(1988); M. Arato et al., Biol Psychiatry 25:355
(1989)]. Furthermore, the density of CRF receptors
is significantly decreased in the frontal cortex of
suicide victims, consistent with a hypersecretion of
CRF (C.B. Nemeroff et al., Arch. Gen. Psychiatry
45:577 (1988)]. In addition, there is a blunted
adrenocorticotropin (ACTH) response to CRF (i.v.
administered) observed in depressed patients [P.W.
Gold et al., Am J. Psychiatry 141:619 (1984); F.
Holsboer et al., Psychoneuroendocrinology 9:147
(1984); P.W. Gold et al., New Eng. J. Med. 314:1129
(1986)]. Preclinical studies in rats and non-human
primates provide additional support for the

-2-


CA 02259583 1999-01-04

WO 98/03510 PCT/US97/13072
hypothesis that hypersecretion of CRF may be involved
in the symptoms seen in human depression [R.M.
Sapolsky, Arch. Gen. Psychiatry 46:1047 (1989)].
There is preliminary evidence that tricyclic
antidepressants can alter CRF levels and thus
modulate the numbers of CRF receptors in brain
[Grigoriadis et al., Neuropsychopharmacology 2:53
(1989)].
There has also been a role postulated for CRF in
the etiology of anxiety-related disorders. CRF
produces anxiogenic effects in animals and
interactions between benzodiazepine / non-
benzodiazepine anxiolytics and CRF have been
demonstrated in a variety of behavioral anxiety
models [D.R. Britton et al., Life Sci. 31:363 (1982);
C.W. Berridge and A.J. Dunn Regul. Peptides 16:83
(1986)]= Preliminary studies using the putative CRF
receptor antagonist a-helical ovine CRF (9-41) in a
variety of behavioral paradigms demonstrate that the
antagonist produces "anxiolytic-like" effects that
are qualitatively similar to the benzodiazepines
[C.W. Berridge and A.J. Dunn Horm. Behav. 21:393
(1987) , Brain Research Reviews 15:71 (1990) ] .
Neurochemical, endocrine and receptor binding studies
have all demonstrated interactions between CRF and
benzodiazepine anxiolytics providing further evidence
for the involvement of CRF in these disorders.
Chlordiazepoxide attenuates the "anxiogenic" effects
of CRF in both the conflict test [K.T. Britton et
al., Psychopharmacology 86:170 (1985); K.T. Britton
et al., Psychopharmacology 94:306 (1988)] and in the
acoustic startle test [N.R. Swerdlow et al.,
Psychopharmacology 88:147 (1986)] in rats. The
benzodiazepine receptor antagonist (Ro15-1788), which
was without behavioral activity alone in the operant
conflict test, reversed the effects of CRF in a dose-
-3-

-------------


CA 02259583 1999-01-04

WO 98/03510 PCT/US97/13072
dependent manner while the benzodiazepine inverse
agonist (FG7142) enhanced the actions of CRF [K.T.
Britton et al., Psychopharmacology 94:306 (1988)].
The mechanisms and sites of action through which
the standard anxiolytics and antidepressants produce
their therapeutic effects remain to be elucidated.
It has been hypothesized however, that they are
involved in the suppression of the CRF hypersecretion
that is observed in these disorders. Of particular
interest is that preliminary studies examining the
effects of a CRF receptor antagonist ((c- h elical
CRF9-41) in a variety of behavioral paradigms have
demonstrated that the CRF antagonist produces
"anxiolytic-like" effects qualitatively similar to
the benzodiazepines [for review see G.F. Koob and
K.T. Britton, In: Corticotropin-Releasing Factor:
Basic and Clinical Studies of a Neuropeptide, E.B. De
Souza and C.B. Nemeroff eds., CRC Press p221 (1990)].
Several publications describe corticotropin
releasing factor antagonist compounds and their use
to treat psychiatric disorders and neurological
diseases. Examples of such publications include
DuPont Merck PCT application US94/11050 , Pfizer WO
95/33750, Pfizer WO 95/34563, Pfizer WO 95/33727 and
Pfizer EP 0778 277 Al.
Insofar as is known, [1,5-a]-pyrazolo-
1,3,5-triazines, [1,5-a]-1,2,3-triazolo-1,3,5-
triazines, [1,5-a]-pyrazolo-pyrimidines and [1,5-a]-
1,2,3-tri,azolo-pyrimidines, have not been previously
reported as corticotropin releasing factor antagonist
compounds useful in the treatment of psychiatric
disorders and neurological diseases. However, there
have been publications which teach some of these
compounds for other uses.
For instance, EP 0 269 859 (Ostuka, 1988)
discloses pyrazolotriazine compounds of the formula
-4-

t


CA 02259583 1999-01-04

WO 98/03510 PCT/US97/13072
R`
N N

RZ N

R3
where R1 is OH or alkanoyl, R2 is H, OH, or SH, and R3 is
an unsaturated heterocyclic group, naphthyl or_
substituted phenyl, and states that the compounds have
xanthine oxidase inhibitory activity and are useful for
treatment of gout.

EP 0 594 149 (Ostuka, 1994) discloses
pyrazolotriazine and pyrazolopyrimidine compounds of the
formula

OH

N
A (Rl)m (R2)n
R3
N
R"
where A is CH or N, RO and R3 are H or alkyl, and R1 and
R2 are H, alkyl, alkoxyl, alkylthio, nitro, etc., and
states that the compounds inhibit androgen and are
useful in treatment of benign prostatic hypertrophy and
prostatic carcinoma.

US 3,910,907 (ICI, 1975) discloses
pyrazolotriazines of the formula:

-5-


CA 02259583 1999-01-04

WO 98/03510 PCTIUS97/13072
z
N/ N~
Y
Ri N

where Rl is CH3, C2H5 or C6H5, X is H, C6H5, m-CH3C6H4r
CN, COOEt, Cl, I or Br, Y is H, C6H5, o-CH3CgH4, or p-
CH3C6H4r and Z is OH, H, CH3, C2H5, C6H5r n-C3H7, i-C3H7,
SH, SCH3, NHC4H9, or N(C2H5) 2, and states that the
compounds are c-AMP phosphodiesterase inhibitors useful
as bronchodilators.

US 3,995,039 discloses pyrazolotriazines of
the formula:

NR2R3

N
N y
R1 N

R
where R1 is H or alkyl, R2 is H or alkyl, R3 is H, alkyl,
alkanoyl, carbamoyl, or lower alkylcarbamoyl, and R is
pyridyl, pyrimidinyl, or pyrazinyl, and states that the
compounds are useful as bronchodilators.

US 5,137,887 discloses pyrazolotriazines of
the formula

-6-


CA 02259583 1999-01-04

WO 98/03510 PCT/US97/13072
OH

N N N
R (0)n
I
N
wh.;:re R is lower alkoxy, and teaches that the compounds
are xanthine oxidase inhibitors and are useful for
treatment of gout.

US 4,892,576 discloses pyrazolotriazines of the
formula

x
R7 N
N N, ~- \ II
S N Ar
Rg N O R6

R9
where X is 0 or S, Ar is a phenyl, naphthyl, pyridyl or
thienyl group, R6-R8 are H, alkyl, etc., and Rg is H,
alkyl, phenyl, etc. The patent states that the
compounds are useful as herbicides and plant growth
regulants.

US 5,484,760 and WO 92/10098 discloses
herbicidal compositions containing, among other things,
a herbicidal compound of the formula

-7-


CA 02259583 1999-01-04

WO 98/03510 PCT/US97/13072
R; N -II A

>-
B

Rz where A can be N, B can be CR3, R3 can be phenyl or
substituted phenyl, etc., R is -N (R4 ) S02R5 or -SO2N (R6) R7
and R1 and R2 can be taken together to form

I I I I I II
N C C C or N C N C
where X, Y and Z are H, alkyl, acyl, etc. and D is 0 or
S.

US 3,910,907 and Senga et al., J. Med. Chem.,
1982, 25, 243-249, disclose triazolotriazines cAMP
phosphodiesterase inhibitors of the formula

R
I

R1 ~ N N

N where Z is H, OH, CH3, C2H5, C6H5, n-C3H-7, iso-C3H-7, SH,

SCH3, NH (n-C4H9) , or N (C2H5) 2, R is H or CH3, and R1 is
CH3 or C2H5. The reference lists eight therapeutic
areas where inhibitors of cAMP phosphodiesterase could
have utility: asthma, diabetes mellitus, female
fertility control, male infertility, psoriasis,
thrombosis, anxiety, and hypertension.

-8-


CA 02259583 1999-01-04

WO 98/03510 PCT/US97/13072
W095/35298 (Otsuka, 1995) discloses
pyrazolopyrimidines and states that they are useful as
analgesics. The compounds are represented by the
formula

R6 N ( NH ) 2
rt-- Q A R
RS
N
N \
R3
R1 N

RQ
where Q is carbonyl or sulfonyl, n is 0 or 1, A is a
single bond, alkylene or alkenylene, R1 is H, alkyl,
etc., R2 is naphthyl, cycloalkyl, heteroaryl,
substituted phenyl or phenoxy, R3 is H, alkyl or phenyl,
R4 is H, alkyl, alkoxycarbonyl, phenylalkyl, optionally
phenylthio-substituted phenyl, or halogen, R5 and R6 are
H or alkyl.
EP 0 591 528 (Otsuka,1991) discloses anti-
inflammatory use of pyrazolopyrimidines represented by
the formula

R5
R1 N N

Rq
RZ N

R3
where R1, R2, R3 and R4 are H, carboxyl, alkoxycarbonyl,
optionally substituted alkyl, cycloalkyl, or phenyl, R5

-9-


CA 02259583 1999-01-04

WO 98/03510 PCTIUS97/13072
is SR6 or NR7R8, R6 is pyridyl or optionally substituted
phenyl, and R7 and Re are H or optionally substituted
phenyl.

Springer et al, J. Med. Chem., 1976, vol. 19,
no. 2, 291-296 and Springer U.S. patents 4021,556 and
3,920,652 disclose pyrazolopyrimidines of the formula

OH

N
N

HO N
where R can be phenyl, substituted phenyl or pyridyl,
and their use to treat gout, based on their ability to
inhibit xanthine oxidase.

Joshi et al., J. Prakt. Chemie, 321, 2, 1979,
341-344, discloses compounds of the formula

R2

N
N \
R` N

C6Hg

where R1 is CF3, C2F5, or C6H4F, and R2 is CH3, C2H5, CF3,
or C6H4F.

-10-

T


CA 02259583 1999-01-04

WO 98/03510 PCT/US97/13072
Maquestiau et al., Bull. Soc. Belg., vol.101,
no. 2, 1992, pages 131-136 discloses a pyrazolo[1,5-
a]pyrimidine of the formula

N
N
OH
CN

C6H5

Ibrahim et al., Arch. Pharm. (weinheim) 320,
487-491 (1987) discloses pyrazolo[1,5-a]pyrimidines of
the formula
CH3

N
N
R
CH3 N

Ar
where R is NH2 or OH and Ar is 4-phenyl-3-cyano-2-
aminopyrid-2-yl.
Other references which disclose
azolopyrimidines inclued EP 0 511 528 (Otsuka, 1992), US
4,997,940 (Dow, 1991), EP 0 374 448 (Nissan, 1990), US
4,621,556 (ICN,1997), EP 0 531 901 (Fujisawa, 1993), US
4,567,263 (BASF, 1986), EP 0 662 477 (Isagro, 1995), DE
4 243 279 (Bayer, 1994), US 5,397,774 (Upjohn, 1995), EP
0 521 622 (Upjohn, 1993), wO 94/109017 (Upjohn, 1994),
J. Med. Chem., 24, 610-613 (1981), and J. Het. Chem.,
22, 601 (1985).

-11-


CA 02259583 1999-01-04

WO 98/03510 PCT/US97/13072
SUMMARY OF THE TNVENTT(1N

In accordance with one aspect, the present
invention provides novel compounds, pharmaceutical
compositions and methods which may be used in the
treatment of affective disorder, anxiety, depression,
irritable bowel syndrome, post-traumatic stress
disorder, supranuclear palsy, immune suppression,
Al::heimer's disease, gastrointestinal disease,
anorexia nervosa or other feeding disorder, drug or
alcohol withdrawal symptoms, drug addiction, .
inflammatory disorder, fertility problems, disorders,
the treatment of which can be effected or facilitated
by antagonizing CRF, including but not limited to
disorders induced or facilitated by CRF, or a
disorder selected from inflammatory disorders such as
rheumatoid arthritis and osteoarthritis, pain,
asthma, psoriasis and allergies; generalized anxiety
disorder; panic, phobias, obsessive-compulsive
disorder; post-traumatic stress disorder; sleep
disorders induced by stress; pain perception such as
fibromyalgia; mood disorders such as depression,
including major depression, single episode
depression, recurrent depression, child abuse induced
depression, and postpartum depression; dysthemia;
bipolar disorders; cyclothymia; fatigue syndrome;
stress-induced headache; cancer, human
immunodeficiency virus (HIV) infections;
neurodegenerative diseases such as Alzheimer's
disease, Parkinson's disease and Huntington's
disease; gastrointestinal diseases such as ulcers,
irritable bowel syndrome, Crohn's disease, spastic
colon, diarrhea, and post operative ilius and colonic
hypersensitivity associated by psychopathological
disturbances or stress; eating disorders such as
anorexia and bulimia nervosa; hemorrhagic stress;
-12-


CA 02259583 1999-01-04

WO 98/03510 PCT/US97/13072
stress-induced psychotic episodes; euthyroid sick
syndrome; syndrome of inappropriate antidiarrhetic
hormone (ADH); obesity; infertility; head traumas;
spinal cord trauma; ischemic neuronal damage (e=cJ.,
cerebral ischemia such as cerebral hippocampal
ischemia); excitotoxic neuronal damage; epilepsy;
cardiovascular and hear related disorders including
hypertension, tachycardia and congestive heart
failure; stroke; immune dysfunctions including stress
induced immune dysfunctions (e.a., stress induced
fevers, porcine stress syndrome, bovine shipping
fever, equine paroxysmal fibrillation, and
dysfunctions induced by confinement in chickens,
sheering stress in sheep or human-animal interaction
related stress in dogs); muscular spasms; urinary
incontinence; senile dementia of the Alzheimer's
type; multiinfarct dementia; amyotrophic lateral
sclerosis; chemical dependencies and addictions
(e.a., dependencies on alcohol, cocaine, heroin,
benzodiazepines, or other drugs); drug and alcohol
withdrawal symptoms; osteoporosis; psychosocial
dwarfism and hypoglycemia in a mammal.

The present invention provides novel compounds
which bind to corticotropin releasing factor
receptors, thereby altering the anxiogenic effects of
CRF secretion. The compounds of the present
invention are useful for the treatment of psychiatric
disorders and neurological diseases, anxiety-related
disorders, post-traumatic stress disorder,
supranuclear palsy and feeding disorders as well as
treatment of immunological, cardiovascular or heart-
related diseases and colonic hypersensitivity
associated with psychopathological disturbance and
stress in a mammal.

-13-


CA 02259583 1999-01-04

WO 98/03510 PCT/US97/13072
According to another aspect, the present
invention provides novel compounds of Formulae (1)
and (2) (described below) which are useful as
antagonists of the corticotropin releasing factor.
The compounds of the present invention exhibit
activity as corticotropin releasing factor
antagonists and appear to suppress CRF
hypersecretion. The present invention also includes
pharmaceutical compositions containing such compounds
of Formulae (1) and (2), and methods of using such
compounds for the suppression of CRF hypersecretion,
and/or for the treatment of anxiogenic disorders.

According to yet another aspect of the
invention, the compounds provided by this invention
(and especially labelled compounds of this invention)
are also useful as standards and reagents in
determining the ability qf a potential pharmaceutical
to bind to the CRF receptor.

DETAILED DESCRIPTION OF INVENTION
[1] The present invention comprises a method of
treating affective disorder, anxiety, depression,
headache, irritable bowel syndrome, post-traumatic
stress disorder, supranuclear palsy, immune
suppression, Alzheimer's disease, gastrointestinal
diseases, anorexia nervosa or other feeding disorder,
drug addiction, drug or alcohol withdrawal symptoms,
inflammatory diseases, cardiovascular or heart-
related diseases, fertility problems, human
immunodeficiency virus infections, hemorrhagic
stress, obesity, infertility, head and spinal cord
traumas, epilepsy, stroke, ulcers, amyotrophic
lateral sclerosis, hypoglycemia or a disorder the
treatment of which can be effected or facilitated by
-14-

T


CA 02259583 1999-01-04

WO 98/03510 PCT/US97/13072
antagonizing CRF, including but not limited to
disorders induced or facilitated by CRF, in mammals
comprising administering to the mammal a
therapeutically effective amount of a compound of
Formulae (1) or (2)

R3 R3
R14
A/ Ni \\ A N

z p
\ ~ ~ \
Rl N Rl N

Ar Ar
(1) (2)
and isomers thereof, stereoisomeric forms thereof, or
mixtures of stereoisomer'ic forms thereof, and
pharmaceutically acceptable salt or pro-drug forms
thereof, wherein:

A is N or CR;
Z is N or CR2;

Ar is selected from phenyl, naphthyl, pyridyl,
pyrimidinyl, triazinyl, furanyl, thienyl,
benzothienyl, benzofuranyl, 2,3-
dihydrobenzofuranyl, 2,3-dihydrobenzothienyl,
indanyl, 1,2-benzopyranyl, 3,4-dihydro-1,2-
benzopyranyl, tetralinyl, each Ar optionally
substituted with 1 to 5 R4 groups and each Ar is
attached to an unsaturated carbon atom;
-15-


CA 02259583 1999-01-04

WO 98/03510 PCT/US97/13072
R is independently selected at each occurrence from
H, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl,
C3-C6 cycloalkyl, C4-C7 cycloalkylalkyl, halo,
CN, Cl-C4 haloalkyl;
R1 is independently selected at each occurrence from
H, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl,
halo, CN, C1-C4 haloalkyl, C1-C12 hydroxyalkyl,
C2-C12 alkoxyalkyl, C2-C10 cyanoalkyl, C3-C6
cycloalkyl, C4-C10 cycloalkylalkyl, NR9R10, C1-
C4 alkyl-NR9R10, NR9COR10, OR11, SH or S(O)nR12;
R2 is selected from H, C1-C4 alkyl, C2-C4 alkenyl,
C2-C4 alkynyl, C3-C6 cycloalkyl, C4-C10
cycloalkylalkyl, C1-C4 hydroxyalkyl, halo, CN,
-NR6R7, NR9CORI0, -NR6S(O)nR7, S(O)nNR6R7, C1-
C4 haloalkyl, -OR7, SH or -S(0)nR12;

R3 is selected from:
-H, OR7, SH, S(O)nR13, COR7, C02R7,
OC(O)R13, NR8COR7, N(COR7)2, NR8CONR6R7,
NR8C02R13, NR6R7, NR6aR7a, N(OR7)R6,
CONR6R7, aryl, heteroaryl and heterocyclyl,
or
-C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl,
C3-C8 cycloalkyl, C5-Cg cycloalkenyl, C4-
C12 cycloalkylalkyl or C6-C10
cycloalkenylalkyl, each optionally
substituted with 1 to 3 substituents
independently selected at each occurrence
from Cl-C6 alkyl, C3-C6 cycloalkyl, halo,
C1-C4 haloalkyl, cyano, OR15, SH,
S(O) nR13, COR15, C02R15, OC (O) R13,
NR8COR15, N(COR15)2, NR8CONR16R15,
NR8C02R13, NR16R15, CONR16R15, aryl,
heteroaryl and heterocyclyl;
-16-


CA 02259583 1999-01-04

WO 98/03510 PCTIUS97/13072
R4 is independently selected at each occurrence from:
C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl,
C3-C6 cycloalkyl, C4-C12 cycloalkylalkyl, N02,
halo, CN, C1-C4 haloalkyl, NR6R7, NR8COR7,
NR8CO2R7, COR7, OR7, CONR6R7, CO (NOR9) R7, C02R7,
or S(O)nR7, where each such C1-C10 alkyl, C2-
C10 alkenyl, C2-C10 alkynyl, C3-C6 cycloalkyl
and C4-C12 cycloalkylalkyl are optionally
substituted with 1 to 3 substituents
independently selected at each occurrence.from
Cl-C4 alkyl, N02, halo, CN, NR6R7, NR8COR7,
NR8C02R7, COR7 OR7, CONR6R7, C02R7, CO (NORg) R7,
or S(O)nR7;
R6 and R7, R6a and R7a are independently selected at
each occurrence from:
-H,
-C1-C10 alkyl, C3-C10 alkenyl, C3-C10 alkynyl,
C1-C10 haloalkyl with 1-10 halogens, C2-C8
alkoxyalkyl, C3-C6 cycloalkyl, C4-
C12 cycloalkylalkyl, C5-C10 cycloalkenyl,
or C6-C14 cycloalkenylalkyl, each
optionally substituted with 1 to 3
substituents independently selected at each
occurrence from C1-C6 alkyl, C3-
C6 cycloalkyl, halo, C1-C4 haloalkyl,
cyano, OR15, SH, S(O)nR13, COR15, C02R15OC (O) R13, NR8COR15, N(COR15 ) Z,
NRBCONR16R15,
NR8C02R13, NR16R15, CONR16R15, aryl,
heteroaryl or heterocyclyl,
-aryl, aryl(C1-C4 alkyl), heteroaryl,
heteroaryl(C1-C4 alkyl), heterocyclyl or
heterocyclyl(C1-C4 alkyl);

-17-


CA 02259583 1999-01-04

WO 98/03510 PCT/US97/13072
alternatively, NR6R7 and NR6aR7a are independently
piperidine, pyrrolidine, piperazine, N-
methylpiperazine, morpholine or thiomorpholine, each
optionally substituted with 1-3 C1-C4 alkyl groups;
R8 is independently selected at each occurrence from
H or C1-C4 alkyl;

R9 and R10 are independently selected at each
occurrence from H, C1-C4 alkyl, or C3-C6
cycloalkyl;

R11 is selected from H, C1-C4 alkyl, Cl-C4 haloalkyl,
or C3-C6 cycloalkyl;
R12 is C1-C4 alkyl or C1-C4 haloalkyl;

R13 is selected from C1-C-4 alkyl; C1-C4 haloalkyl,
C2-C8 alkoxyalkyl, C3-C6 cycloalkyl, C4-
C12 cycloalkylalkyl, aryl, aryl(C1-C4 alkyl)-,
heteroaryl or heteroaryl(C1-C4 alkyl)-;

R14 is selected from C1-C10 alkyl, C3-Clp alkenyl, C3-
C10 alkynyl, C3-Cg cycloalkyl, or C4-
C12 cycloalkylalkyl, each optionally substituted
with 1 to 3 substituents independently selected
at each occurrence from C1-C6 alkyl, C3-
C6 cycloalkyl, halo, C1-C4 haloalkyl, cyano,
OR15, SH, S(O) nR15, COR15, C02R15, OC (O) R15,
NR8COR15, N(COR15)2r NR8CONR16R15, NR8C02R15,
NR16R15, CONR16R15, and C1-C6 alkylthio, C1-C6
alkylsulfinyl and Cl-C6 alkylsulfonyl;

R15 and R16 are independently selected at each
occurrence from H, C1-C6 alkyl, C3-C10
-18-

.


CA 02259583 1999-01-04

WO 98/03510 PCTIUS97/13072
cycloalkyl, C4-C16 cycloalkylalkyl, except that
for S(O)nR15, R15 cannot be H;

aryl is phenyl or naphthyl, each optionally
substituted with 1 to 5 substituents
independently selected at
each occurrence from Cl-C6 alkyl, C3-
C6 cycloalkyl, halo, Cl-C4 haloalkyl, cyano,
OR15, SH, S(0) nR15, COR15, C02R15, OC (O) R15,
NRaCOR15, N(COR15)2, NRSCONR16R15, NR8C02R15,
NR16R15, and CONR16R15;

heteroaryl is pyridyl, pyrimidinyl, triazinyl,
furanyl, pyranyl, quinolinyl, isoquinolinyl,
thienyl, imidazolyl, thiazolyl, indolyl,
pyrrolyl, oxazolyl, benzofuranyl, benzothienyl,
benzothiazolyl, isoxazolyl, pyrazolyl, 2,3-
dihydrobenzothienyl=or 2,3-dihydrobenzofuranyl,
each being optionally substituted with 1 to 5
substituents independently selected at each
occurrence from C1-C6 alkyl, C3=C6 cycloalkyl,
halo, Cl-C4 haloalkyl, cyano, OR15, SH,
S(O) nR15, -COR15, C02R15, OC (O) RIS, NR8COR15,
N(COR15)2, NR8CONR16R15, NR8C02R15, NR16R15, and
CONR16R15;

heterocyclyl is saturated or partially saturated
heteroaryl, optionally substituted with 1 to 5
substituents independently selected at each
occurrence from Cl-C6 alkyl, C3-C6 cycloalkyl,
halo, C1-C4 haloalkyl, cyano, OR15, SH,
S(O) nR15, COR15, C02R15, OC (O) R15, NR8COR15,
N(COR15)2, NR8CONR16R15, NR8C02R15, NR15R16, and
CONR16R15;

-19-


CA 02259583 1999-01-04

WO 98/03510 PCTIUS97/13072
n is independently at each occurrence 0, 1 or 2,

[2] Preferred methods of the present invention are
methods in wherein in the compound of Formulae (1) or
(2), Ar is phenyl, pyridyl or 2,3-
dihydrobenzofuranyl, each optionally substituted with
1 to 4 R4 substituents.

{3; Further preferred methods of the above invention
are methods wherein, in the compound of Formulae (1)
or (2), A is N, Z is CR2, Ar is 2,4-dichlorophenyl,
2,4-dimethylphenyl or 2,4,6-trimethylphenyl, R1 and R2
are CH3, and R3 is NR6aR7a.

(4] The present invention comprises compounds of
Formulae (1) or (2) :

R3 R3 R14
~
A~ N~\\ A) N_N
z O
. \ \ \ \
R1 N R1 N

Ar Ar
(2)
and isomers thereof, stereoisomeric forms thereof, or
mixtures of stereoisomeric forms thereof, and
pharmaceutically acceptable salt or pro-drug forms
thereof wherein:
A is N or CR;

-20-

T


CA 02259583 1999-01-04

WO 98/03510 PCTIUS97/13072
Z is N or CR2;

Ar is selected from phenyl, naphthyl, pyridyl,
pyrimidinyl, triazinyl, furanyl, thienyl,
benzothienyl, benzofuranyl, 2,3-
dihydrobenzofuranyl, 2,3-dihydrobenzothienyl,
indanyl, 1,2-benzopyranyl, 3,4-dihydro-1,2-
benzopyranyl, tetralinyl, each Ar optionally
substituted with 1 to 5 R4 groups and each Ar is
attached to an unsaturated carbon atom;

R is independently selected at each occurrence from
H, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl,
C3-C6 cycloalkyl, C4-C7 cycloalkylalkyl, halo,
CN, C1-C4 haloalkyl;

R1 is independently seleQted at each occurrence from
H, C1-C4 alkyl, C2-C4 alkenyl., C2-C4 alkynyl,
halo, CN, C1-C4 haloalkyl, C1-C12 hydroxyalkyl,
C2-CI2 alkoxyalkyl, C2-C10 cyanoalkyl, C3-C6
cycloalkyl, C4-Clp cycloalkylalkyl, NRgRlO, Cl-
C4 alkyl-NRgR10, NR9CORI0, OR11, SH or S(O)nR12;

R2 is selected from H, C1-C4 alkyl, C2-C4 alkenyl,
C2-C4 alkynyl, C3-C6 cycloalkyl, C4-C10
cycloalkylalkyl, Cl-C4 hydroxyalkyl, halo, CN,
-NR6R7, NR9COR10, -NR6S(0)nR7, S(0)nNR6R7, C1-
C4 haloalkyl, -OR7, SH or -S(O)nR12;
R3 is selected from:
-H, OR7, SH, S(0) nR13, COR7, C02R7,
OC (0) R13, NR8COR7, N(COR7 ) 2, NR8CONR6R7,
NR8C02R13, NR6R7, NR6aR7a, N(OR7)R6,
CONR6R7, aryl, heteroaryl and
heterocyclyl, or

-21-


CA 02259583 1999-01-04

WO 98/03510 PCT/US97/13072
-C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl,
C3-C8 cycloalkyl, C5-C8 cycloalkenyl, C4-
C12 cycloalkylalkyl or C6-C10
cycloalkenylalkyl, each optionally
substituted with 1 to 3 substituents
independently selected at each occurrence
from C1-C6 alkyl, C3-C6 cycloalkyl, halo,
C1-C4 haloalkyl, cyano, OR15, SH,
S(O) nR13, COR15, C02R15, OC (O) R13,
NR8COR15, N(COR15)2, NR8CONR16R15,
NR8C02R13f NR16R15, CONR16R15, aryl,.
heteroaryl and heterocyclyl;

R4 is independently selected at each occurrence from:
C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl,
C3-C6 cycloalkyl, C4-C12 cycloalkylalkyl, N02,
halo, CN, C1-C4 haloalkyl, NR6R7, NR8COR7,
NR8C02R7, COR7, OR7,, CONR6R7, CO (NOR9) R7, C02R7,
or S(O)nR7, where each such C1-C10 alkyl, C2-
C10 alkenyl, C2-C10 alkynyl, C3-C6 cycloalkyl
and C4-C12 cycloalkylalkyl are optionally
substituted with 1 to 3 substituents
independently selected at each occurrence from
C1-C4 alkyl, N02, halo, CN, NR6R7, NR8COR7,
NR8CO2R7, COR7 OR7, CONR6R7, C02R7, CO (NOR9) R7,
or S (O) nR7 ;

R6 and R7, R6a and R7a are independently selected at
each occurrence from:
-H,
-C1-C10 alkyl, C3-C10 alkenyl, C3-C10 alkynyl,
C1-C10 haloalkyl with 1-10 halogens, C2-C8
alkoxyalkyl, C3-C6 cycloalkyl, C4-
C12 cycloalkylalkyl, C5-C10 cycloalkenyl,
or C6-C14 cycloalkenylalkyl, each
optionally substituted with 1 to 3

-22-
t


CA 02259583 1999-01-04

WO 98/03510 PCT/US97/13072
substituents independently selected at each
occurrence from C1-C6 alkyl, C3-
C6 cycloalkyl, halo, C1-C4 haloalkyl,
cyano, OR15, SH, S(O)nR13, COR15, C02R15,
OC(0)R13, NR8COR15, N(COR15)2r NR8CONR16R15,
NR8C02R13, NR16R15' CONR16R15, aryl,
heteroaryl or heterocyclyl,
-aryl, aryl(C1-C4 alkyl), heteroaryl,
heteroaryl(C1-C4 alkyl), heterocyclyl or
heterocyclyl(C1-C4 alkyl),
alternatively, NR6R7 and NR6aR7a are independently
piperidine, pyrrolidine, piperazine, N-
methylpiperazine, morpholine or thiomorpholine, each
optionally substituted with 1-3 C1-C4 alkyl groups;
R8 is independently selected at each occurrence from
H or C1-C4 alkyl;

R9 and R10 are independently selected at each
occurrence from H, C1-C4 alkyl, or C3-C6
cycloalkyl;

R11 is selected from H, C1-C4 alkyl, C1-C4 haloalkyl,
or C3-C6 cycloalkyl;
R12 is C1-C4 alkyl or C1-C4 haloalkyl;

R13 is selected from Cl-C4 alkyl, C1-C4 haloalkyl,
C2-C8 alkoxyalkyl, C3-C6 cycloalkyl, C4-
C12 cycloalkylalkyl, aryl, aryl(C1-C4 alkyl)-,
heteroaryl or heteroaryl(Cl-C4 alkyl)-;

R14 is selected from C1-Clp alkyl, C3-Clp alkenyl, C3-
Clp alkynyl, C3-C8 cycloalkyl, or C4-
C12 cycloalkylalkyl, each optionally substituted
with 1 to 3 substituents independently selected
-23-


CA 02259583 1999-01-04

WO 98/03510 PCT/US97/13072
at each occurrence from Cl-C6 alkyl, C3-
C6 cycloalkyl, halo, Cl-C4 haloalkyl, cyano,
OR15, SH, S(O)nR15, COR15, C02R15, OC(O)R15,
NR8COR15, N(COR15)2, NR8CONR16R15, NR8C02R155 NR16R15, CONR16R15, and C1-C6
alkylthio, C1-C6
alkylsulfinyl and C1-C6 alkylsulfonyl;

R15 and R16 are independent.ly selected at each
occurrence from H, C1-C6 alkyl, C3-C10
cycloalkyl, C4-C16 cycloalkylalkyl, except that
for S(O)nR15, R15 cannot be H;

aryl is phenyl or naphthyl, each optionally
substituted with 1 to 5 substituents
independently selected at
each occurrence from Cl-C6 alkyl, C3-
C6 cycloalkyl, halo, Cl-C4 haloalkyl, cyano,
OR15, SH, S(0) nR15, ,COR15, C02R15, OC (O) R15,
NR8COR15, N(COR15)2, NR8CONR16R15, NR8CO2R15,
NR16R15, and CONR16R15;

heteroaryl is pyridyl, pyrimidinyl, triazinyl,
furanyl, pyranyl, quinolinyl, isoquinolinyl,
thienyl, imidazolyl, thiazolyl, indolyl,
pyrrolyl, oxazolyl, benzofuranyl, benzothienyl,
benzothiazolyl, isoxazolyl, pyrazolyl, 2,3-
dihydrobenzothienyl or 2,3-dihydrobenzofuranyl,
each being optionally substituted with 1 to 5
substituents independently selected at each
occurrence from C1-C6 alkyl, C3-C6 cycloalkyl,
halo, Cl-C4 haloalkyl, cyano, OR15, SH,
S(O) nR15, -COR15, C02R15, OC (O) R1S, NR8COR15,
N(COR15)2, NR8CONR16R15, NR8C02R15, NR16R15, and
CONR16R15;

-24-

T


CA 02259583 1999-01-04

WO 98/03510 PCT/US97/13072
heterocyclyl is saturated or partially saturated
heteroaryl, optionally substituted with 1 to 5
substituents independently selected at each
occurrence from C1-C6 alkyl, C3-C6 cycloalkyl,
halo, Cl-C4 haloalkyl, cyano, OR15, SH,
S(0) nR15, COR15, C02R15, OC (O) R15, NR8COR15,
N(COR15)2, NR8CONR16R15, NR8C02R15, NR15R16, and
CONR16R15;

n is independently at each occurrence 0, 1 or 2,
with the provisos that:

(1) when A is N, Z is CR2, R2 is H, R3 is -OR7 or
-OCOR13, and R7 is H, then R1 is not H, OH or
SH;

(2) when A is N, Z is CR2, R1 is CH3 or C2H5, R2 is H,
and R3 is OH, H, CH3, C2H5, C6H5, n-C3H7, i-C3H7,
SH, SCH3, NHC4H9, or N(C2H5)2, then Ar is not
phenyl or m-CH3-phenyl;

(3) when A is N, Z is CR2, R2 is H, and Ar is
pyridyl, pyrimidinyl or pyrazinyl, and R3 is
NR6aR7a, then R6a and R7a are not H or alkyl;

(4) when A is N, Z is CR2, and R2 is S02NR6R7, then R3
is not OH or SH;

(5) when A is CR and Z is CR2, then R2 is not-NR6SO2R7
or -S02NR6R7%

(6) when A is N, Z is CR2 and R2 is -NR6SO2R7 or
-S02NR6R7, then R3 is not OH or SH;
(7) when A is N, Z is CR2, R1 is methyl or ethyl, R2
is H, and R3 is H, OH, CH3, C2H5, C6H5, n-C3H7,
-25-


CA 02259583 1999-01-04

WO 98/03510 PCTIUS97/13072
iso-C3H7, SH, SCH3, NH (n-C4H9) , or N(C2H5) 2, then
Ar is not unsubstituted phenyl or m-methylphenyl;

(8) when A is CR, Z is CR2, R2 is H, phenyl or alkyl,
R3 is NR8COR7 and Ar is phenyl or phenyl
substituted with phenylthio, then R7 is not aryl,
aryl(C1-C4 alkyl), heteroaryl, heteroaryl(C1-C4
alkyl), heterocyclyl or heterocycly(C1-C4 alkyl);

(9) when A is CR, Z is CR2, R2 is H or alkyl, Ar is
phenyl, and R3 is SR13 or NR6aR7a, then R13 is not
aryl or heteroaryl and R6a and R7a are not H or
aryl; or

(10) when A is CH, Z is CR2, R1 is OR11, R2 is H, R3 is
OR7, and R7 and R11 are both H, then Ar is not
phenyl, p-Br-phenyl, p-Cl-phenyl, p-NHCOCH3-
phenyl, p-CH3-phenyl, pyridyl or naphthyl;

(11) when A is CH, Z is CR2, R2 is H, Ar is
unsubstituted phenyl, and R3 is CH3, C2H5, CF3 or
C6H4F, then R1 is not CF3 or C2F5;

(12) when A is CR, R is H, Z is CR2, R2 is OH, and R1
and R3 are H, then Ar is not phenyl;

(13) when A is CR, R is H, Z is CR2, R2 is OH or
NH2, R1 and R3 are CH3, then Ar is not 4-
phenyl-3-cyano-2-aminopyrid-2-yl.
[51 Preferred compounds of the above invention are
compounds of Formulae (1) and-(2) and isomers
thereof, stereoisomeric forms thereof, or mixtures of
stereoisomeric forms thereof, and pharmaceutically
acceptable salt or pro-drug forms thereof with the
additional provisos that: (1) when A is N, Rl is H,
C1-C4 alkyl, halo, CN, C1-C12 hydroxyalkyl, C1-C4

-26-

,


CA 02259583 1999-01-04

WO 98/03510 PCT/US97/13072
alkoxyalkyl or S02(Cl-C4 alkyl), R3 is NR6aR7a and
R6a is unsubstituted C1-C4 alkyl, then R7a is not
phenyl, naphthyl, thienyl, benzothienyl, pyridyl,
quinolyl, pyrazinyl, furanyl, benzofuranyl,
benzothiazolyl, indolyl or C3-C6 cycloalkyl; and (2)
A is N, R1 is H, Cl-C4 alkyl, halo, CN, C1-C12
hydroxyalkyl, C1-C4 alkoxyalkyl or S02(Cl-C4 alkyl),
R3 is NR6aR7a and R7a is unsubstituted C1-C4 alkyl,
then R6a is not phenyl, naphthyl, thienyl,
benzothienyl, pyridyl, quinolyl, pyrazinyl, furanyl,
benzofuranyl, benzothiazolyl, indolyl or C3-C6-
cycloalkyl.

[6] Preferred compounds of the above invention also
include compounds of Formulae (1) and (2) and isomers
thereof, stereoisomeric forms thereof, or mixtures of
stereoisomeric forms thereof, and pharmaceutically
acceptable salt or pro-drug forms thereof wherein Ar
is phenyl, pyridyl or 2,3-dihydrobenzofuranyl, each
optionally substituted with 1 to 4 R4 substituents.
[7]. Preferred compounds of the above invention also
include compounds of Formulae (1) and (2) and isomers
thereof, stereoisomeric forms thereof, or mixtures of
stereoisomeric forms thereof, and pharmaceutically
acceptable salt or pro-drug forms thereof wherein A
is N, Z is CR2, Ar is 2,4-dichiorophenyl, 2,4-
dimethylphenyl or 2,4,6-trimethylphenyl, R1 and R2 are
CH3, and R3 is NR6aR7a.
[11] More preferred compounds of the above invention are
compounds and isomers thereof, stereoisomeric forms
thereof, or mixtures of stereoisomeric forms thereof,
and pharmaceutically acceptable salt or pro-drug forms
thereof wherein A is N.

-27-


CA 02259583 1999-01-04

WO 98/03510 PCT/US97/13072
[12] More preferred compounds of the above invention
also include compounds and isomers thereof,
stereoisomeric forms thereof, or mixtures of
stereoisomeric forms thereof, and pharmaceutically
acceptable salt or pro-drug forms thereof.

[13] More preferred compounds of the above invention
also include compounds and isomers thereof,
stereoisomeric forms thereof, or mixtures of
stereoisomeric forms thereof, and pharmaceutically
acceptable salt or pro-drug forms thereof wherein Ar is
phenyl, pyridyl or 2,3-dihydrobenzofuranyl and each Ar
is optionally substituted with 1 to 4 R4 substituents.

[14] More preferred compounds of the above invention
also include compounds and isomers thereof,
stereoisomeric forms thereof, or mixtures of
stereoisomeric forms thereof, and pharmaceutically
acceptable salt or pro-drug forms thereof wherein R3 is
NR6aR7a or OR7.

[15] More preferred compounds of the above invention
also include compounds and isomers thereof,
stereoisomeric forms thereof, or mixtures of
stereoisomeric forms thereof, and pharmaceutically
acceptable salt or pro-drug forms thereof wherein Ar is
phenyl, pyridyl or 2,3-dihydrobenzofuranyl, and each Ar
is optionally substituted with 1 to 4 R4 substituents,
and R3 is NR6aR7a or OR7.
[16] More preferred compounds of the above invention
also include compounds and isomers thereof,
stereoisomeric forms thereof, or mixtures of
stereoisomeric forms thereof, and pharmaceutically
acceptable salt or pro-drug forms thereof wherein Z is
CR2.

-28-


CA 02259583 1999-01-04

WO 98/03510 PCTIUS97/13072
[17] More preferred compounds of the above invention
also include compounds and isomers thereof,
stereoisomeric forms thereof, or mixtures of
stereoisomeric forms thereof, and pharmaceutically
acceptable salt or pro-drug forms thereof wherein Ar is
phenyl, pyridyl or 2,3-dihydrobenzofuranyl and each Ar
is optionally substituted with 1 to 4 R4 substituents.

[18] More preferred compounds of the above invention
also include compounds and isomers thereof,
stereoisomeric forms thereof, or mixtures of
stereoisomeric forms thereof, and pharmaceutically
acceptable salt or pro-drug forms thereof wherein R3 is
NR6aR7a or OR7.

[19] More preferred compounds of the above invention
also include compounds amd isomers thereof,
stereoisomeric forms thereof, or mixtures of
stereoisomeric forms thereof, and pharmaceutically
acceptable salt or pro-drug forms thereof wherein
R6a is independently selected from:
-H,
-C1-C10 alkyl, C3-C10 alkenyl, C3-C10 alkynyl,
C1-C10 haloalkyl with 1-10 halogens, C2-C8
alkoxyalkyl, C3-C6 cycloalkyl, C4-
C12 cycloalkylalkyl, C5-C10 cycloalkenyl,
or C6-C14 cycloalkenylalkyl, each
optionally substituted with 1 to 3
substituents independently selected at each
occurrence from Cl-C6 alkyl, C3-
C6 cycloalkyl, halo, C1-C4 haloalkyl,
cyano, OR15, SH, S(O)nR13, COR15, C02R15,
OC (O) R13, NR8COR15, N(COR15) 2r NR8CONR16R15,
NR8C02R13, NR16R15, CONR16R15, aryl,
heteroaryl or heterocyclyl,

-2 9-


CA 02259583 1999-01-04

WO 98/03510 PCT/US97/13072
-aryl, aryl(C1-C4 alkyl)-, heteroaryl, heteroaryl(C1-
C4 alkyl)-, heterocyclyl or heterocyclyl(C1-C4
alkyl) -; and
R7a is independently selected at each occurrence from:
-H,
-C5-C10 alkyl, C3-C10 alkenyl, C3-C10 alkynyl,
C1-C10 haloalkyl with 1-10 halogens, C2-C8
alkoxyalkyl, C3-C6 cycloalkyl, C4-
C12 cycloalkylalkyl, C5-C10 cycloalkenyl,
or C6-C14 cycloalkenylalkyl, each
optionally substituted with 1 to 3-
substituents independently selected at each
occurrence from C1-C6 alkyl, C3-
C6 cycloalkyl, halo, C1-C4 haloalkyl,
cyano, OR15, SH, S(0)nR13, COR15, C02R151
OC (0) R13, NR8COR15, N(COR15) 2, NR8CONR16R15,
NR8C02R13, NR16R15, CONR16R15, aryl,
heteroaryl or heterocyclyl,
-aryl, aryl(C1-C4 alkyl), heteroaryl,
heteroaryl(C1-C4 alkyl), heterocyclyl or
heterocyclyl(C1-C4 alkyl);
alternatively, NR6R7 and NR6aR7a are independently
piperidine, pyrrolidine, piperazine, N-
methylpiperazine, morpholine or thiomorpholine, each
optionally substituted with 1-3 C1-C4 alkyl groups.
[20] More preferred compounds of the above invention
also include compounds and isomers thereof,
stereoisomeric forms thereof, or mixtures of
stereoisomeric forms thereof, and pharmaceutically
acceptable salt or pro-drug forms thereof wherein R6a
and R7a are identical and are selected from:
-C1-C4 alkyl or C3-C6 cycloalkyl, each optionally
substituted with 1 to 3 substituents
independently selected at each occurrence from

-30-


CA 02259583 1999-01-04

WO 98/03510 PCTIUS97/13072
Cl-C6 alkyl, C3-C6 cycloalkyl, halo, C1-C4
haloalkyl, cyano, OR15, SH, S(O) nR13, -COR15,
C02R15, OC (O) R13, NR8COR15, N(COR25) 2,
NR8CONR16R15, NR8CO2R13, NR16R15, CONR16R15,
aryl, heteroaryl or heterocyclyl, and
-aryl or heteroaryl.

[21] More preferred compounds of the above invention
also include compounds and isomers thereof,
stereoisomeric forms thereof, or mixtures of
stereoisomeric forms thereof, and pharmaceutically
acceptable salt or pro-drug forms thereof wherein
R6a is selected from:
-H,
-C1-C10 alkyl, C3-C10 alkenyl, C3-C10 alkynyl,
C1-C10 haloalkyl with 1-10 halogens, C2-C8
alkoxyalkyl, C3-C6 cycloalkyl, C4-
C12 cycloalkylalkyl, C5-C10 cycloalkenyl,
or C6-C14 cycloalkenylalkyl, each
optionally substituted with 1 to 3
substituents independently selected at each
occurrence from C1-C6 alkyl, C3-
C6 cycloalkyl, halo, C1-C4 haloalkyl,
cyano, OR15, SH, S(O)nR13, COR15, C02R15,
OC (O) R13, NR8COR15, N(COR15) 2, NR8CONR16R15,
NR8C02R13, NR16R15, CONR16R15, aryl,
heteroaryl or heterocyclyl,
-aryl, aryl(C1-C4 alkyl), heteroaryl,
heteroaryl(C1-C4 alkyl), heterocyclyl or
heterocyclyl(C1-C4 alkyl);
R7a is selected from:
-C1-C4 alkyl and each such Cl-C4 alkyl is
substituted with 1-3 substituents
independently selected at each occurrence from
C1-C6 alkyl, C3-C6 cycloalkyl, halo, C1-C4
haloalkyl, cyano, OR15, SH, S(O) nR13, COR15,
-31-


CA 02259583 1999-01-04

WO 98/03510 PCTIUS97/13072
C02R15, OC (O) R13, NR8COR15, N(COR15) 2,
NR8CONR16R15, NR8C02R13, NR16R15, CONR16R15,
aryl, heteroaryl or heterocyclyl.

[221 More preferred compounds of the above invention
also include compounds and isomers thereof,
stereoisomeric forms thereof, or mixtures of
stereoisomeric forms thereof, and pharmaceutically
acceptable salt or pro-drug forms thereof wherein
one of R6a and R7a is selected from:
-C3-C6 cycloalkyl, each such C3-C6 cycloalkyl
optionally substituted with 1-3 substituents
independently selected at each occurrence from
C1-C6 alkyl, C3-C6 cycloalkyl, halo, C1-C4
haloalkyl, cyano, OR15, SH, S(O) nR13, COR15,
C02R15, OC (O) R13, NR8COR15, N(COR15) 2,
NR8CONR16R15, NR8CO2R13, NR16R15, CONR16R15,
aryl, heteroaryl or heterocyclyl,
-aryl,
-heteroaryl or
-heterocyclyl,
and the other of R6a and R7a is unsubstituted C1-C4
alkyl.
[23] More preferred compounds of the above invention
also include compounds and isomers thereof,
stereoisomeric forms thereof, or mixtures of
stereoisomeric forms thereof, and pharmaceutically
acceptable salt or pro-drug forms thereof wherein
R6a and R7a are independently H or C1-Clp alkyl,
each such C1-Cip alkyi optionally substituted with
1 to 3 substituents independently selected at each
occurrence from C1-C6 alkyl, C3-C6 cycloalkyl,
halo, C1-C4 haloalkyl, cyano, OR15, SH, S(O)nR13,
COR15, C02R15, OC (O) R13, NR8COR15, N(COR15) 2,

-32-


CA 02259583 1999-01-04

WO 98/03510 PCT/US97/13072
R8CONR16R15, NR8C02R13, NR16R15, CONR16R15, aryl,
heteroaryl or heterocyclyl.

[24] More preferred compounds of the above invention
also include compounds and isomers thereof,
stereoisomeric forms thereof, or mixtures of
stereoisomeric forms thereof, and pharmaceutically
acceptable salt or pro-drug forms thereof wherein Ar is
pnenyl, pyridyl or 2,3-dihydrobenzofuranyl, and each Ar
is optionally substituted with 1 to 4 R4 substituents,
and R3 is NR6aR7a or OR7.

[25] More preferred compounds of the above invention
also include compounds and isomers thereof,
stereoisomeric forms thereof, or mixtures of
stereoisomeric forms thereof, and pharmaceutically
acceptable salt or pro-drug forms thereof wherein
R6a is independently selected from:
-H,
-C1-C10 alkyl, C3-C10 alkenyl, C3-C10 alkynyl,
C1-Clp haloalkyl with 1-10 halogens, C2-C8
alkoxyalkyl, C3-C6 cycloalkyl, C4-
C12 cycloalkylalkyl, C5-C10 cycloalkenyl,
or C6-C14 cycloalkenylalkyl, each
optionally substituted with 1 to 3
substituents independently selected at each
occurrence from C1-C6 alkyl, C3-
C6 cycloalkyl, halo, C1-C4 haloalkyl,
cyano, OR15, SH, S(O)nR13, COR15, C02R15,
OC (O) R13, NR8COR15, N(COR15) 2, NR8CONR16R15f
NR8C02R13, NR16R15, CONR16R15, aryl,
heteroaryl or heterocyclyl,
-aryl, aryl(C1-C4 alkyl)-, heteroaryl,
heteroaryl(C1-C4 alkyl), heterocyclyl or
heterocyclyl(C1-C4 alkyl);

-33-


CA 02259583 1999-01-04

WO 98/03510 PCT/US97/13072
R7a is independently selected at each occurrence from:
-H,
-C5-Clp alkyl, C3-C10 alkenyl, C3-C10 alkynyl,
C1-C10 haloalkyl with 1-10 halogens, C2-C8
alkoxyalkyl, C3-C6 cycloalkyl, C4-
C12 cycloalkylalkyl, C5-C10 cycloalkenyl,
or C6-C14 cycloalkenylalkyl, each
optionally substituted with 1 to 3
substituents independently selected at each
occurrence from C1-C6 alkyl, C3-
C6 cycloalkyl, halo, C1-C4 haloalkyl,
cyano, OR15, SH, S(O)nR13, COR15, C02R15,
OC (0) R13, NR8COR15, N(COR15) Z, NR8CONR16R15,
NR8C02R13, NR16R15, CONR16R15, aryl,
heteroaryl or heterocyclyl,
-aryl, aryl(C1-C4 alkyl), heteroaryl,
heteroaryl(C1-C4 alkyl), heterocyclyl or
heterocyclyl(CZ-C4 alkyl),

alternatively, NR6R7 and NR6aR7a are independently
piperidine, pyrrolidine, piperazine, N-
methylpiperazine, morpholine or thiomorpholine, each
optionally substituted with 1-3 C1-C4 alkyl groups.

(26] More preferred compounds of the above invention
also include compounds and isomers thereof,
stereoisomeric forms thereof, or mixtures of
stereoisomeric forms thereof, and pharmaceutically
acceptable salt or pro-drug forms thereof wherein R6a
and R7a are identical and are selected from:
-C1-C4 alkyl or C3-C6 cycloalkyl, each optionally
substituted with 1 to 3 substituents
independently selected at each occurrence from
C1-C6 alkyl, C3-C6 cycloalkyl, halo, C1-C4
haloalkyl, cyano, OR15, SH, S(O) nR13, -COR15,
-34-


CA 02259583 1999-01-04

WO 98/03510 PCTIUS97/13072
C02R15, OC (0) R13, NR8COR15, N(COR15) 2,
NR8CONR16R15, NR8C02R13, NR16R15, CONR16R15,
aryl, heteroaryl or heterocyclyl, and
-aryl or heteroaryl.
[27] More preferred compounds of the above invention
also include compounds and isomers thereof,
stereoisomeric forms thereof, or mixtures of
stereoisomeric forms thereof, and pharmaceutically
acceptable salt or pro-drug forms thereof wherein R6a
and R7a are identical and are -
-C1-C4 alkyl, each such C1-C4 alkyl
optionally substituted with 1 to 3
substituents independently selected at each
occurrence from C1-C6 alkyl, C3-C6 cycloalkyl,
halo, C1-C4 haloalkyl, cyano, OR15, SH,
S(O) nR13, -COR15, C02R15, OC (O) R13, NR8COR15,
N(COR15) 2, NR8CONR16R15, NR8C02R13, NR16R15,
CONR16R15, aryl, heteroaryl or heterocyclyl.
[28] More preferred compounds of the above invention
also include compounds and isomers thereof,
stereoisomeric forms thereof, or mixtures of
stereoisomeric forms thereof, and pharmaceutically
acceptable salt or pro-drug forms thereof wherein
R6a is selected from:
-H,
-C1-Clp alkyl, C3-Clp alkenyl, C3-Clp alkynyl,
C1-Clp haloalkyl with 1-10 halogens, C2-C8
alkoxyalkyl, C3-C6 cycloalkyl, C4-
C12 cycloalkylalkyl, C5-Clp cycloalkenyl,
or C6-C14 cycloalkenylalkyl, each
optionally substituted with 1 to 3
substituents independently selected at each
occurrence from C1-C6 alkyl, C3-
C6 cycloalkyl, halo, C1-C4 haloalkyl,
-35-


CA 02259583 1999-01-04

WO 98/03510 PCT/US97/13072
cyano, OR15, SH, S(O)nR13, COR15, C02R15,
OC (0) R13, NR8COR15, N(COR15) 2, NR8CONR16R15,
NR8C02R13/ NR16R15, CONR16R15, aryl,
heteroaryl or heterocyclyl,
-aryl, aryl(C1-C4 alkyl), heteroaryl,
heteroaryl(C1-C4 alkyl), heterocyclyl or
heterocyclyl(C1-C4 alkyl);
R7a is.
-C1-C4 alkyl and each such C1-C4 alkyl is
substituted with 1-3 substituents
independently selected at each occurrence from
C1-C6 alkyl, C3-C6 cycloalkyl, halo, C1-C4
haloalkyl, cyano, OR15, SH, S(O) nR13, COR15,
C02R15, OC (O) R13, NR8COR15, N(COR15)2,
NR8CONR16R15, NR8C02R13, NR16R15, CONR16R15,
aryl, heteroaryl or heterocyclyl.

[29] More preferred compounds of the above invention
also include compounds and isomers thereof,
stereoisomeric forms thereof, or mixtures of
stereoisomeric forms thereof, and pharmaceutically
acceptable salt or pro-drug forms thereof wherein one of
R6a and R7a is selected from:
-C3-C6 cycloalkyl, each such C3-C6 cycloalkyl
optionally substituted with 1-3 substituents
independently selected at each occurrence from
C1-C6 alkyl, C3-C6 cycloalkyl, halo, C1-C4
haloalkyl, cyano, OR15, SH, S(O)nR13, COR15,
C02R15, OC (O) R13, NR8COR15, N(COR15) 2,
NR8CONR16R15, NR8C02R13, NR16R15, CONR16R15,
aryl, heteroaryl or heterocyclyl,
-aryl,
-heteroaryl or
-heterocyclyl,
and the other of R6a and R7a is unsubstituted C1-C4
alkyl.

-36-

T


CA 02259583 1999-01-04

WO 98/03510 PCT/US97/13072
[30] More preferred compounds of the above invention
also include compounds and isomers thereof,
stereoisomeric forms thereof, or mixtures of
stereoisomeric forms thereof, and pharmaceutically
acceptable salt or pro-drug forms thereof wherein
R6a and R7a are independently H or Cl-Clp alkyl,
each such C1-C10 alkyl optionally substituted with
1 to 3 substituents independently selected at each
occurrence from Cl-C6 alkyl, C3-C6 cycloalkyl,
halo, C1-C4 haloalkyl, cyano, OR15, SH, S(O)nRi3,
COR15, C02R15, OC (O) R13, NR8COR15, N(COR15)2,
R8CONR16R15, NR8C02R13, NR16R15, CONR16R15, aryl,
heteroaryl or heterocyclyl.
[31] More preferred compounds of the above invention
also include compounds and isomers thereof,
stereoisomeric forms thereof, or mixtures of
stereoisomeric forms thereof, and pharmaceutically
acceptable salt or pro-drug forms thereof wherein
-Ar is phenyl, pyridyl or 2,3-dihydrobenzofuranyl,
and each Ar is optionally substituted with 1
to 4 R4 substituents,
-R3 is NR6aR7a or OR7 and
-Rl and R2 are independently selected from H, Cl-C4
alkyl, C3-C6 cycloalkyl, C4-C10
cycloalkylalkyl.

[32] More preferred compounds of the above invention
also include compounds and isomers thereof,
stereoisomeric forms thereof, or mixtures of
stereoisomeric forms thereof, and pharmaceutically
acceptable salt or pro-drug forms thereof wherein
R6a is independently selected from:
-H,

-37-


CA 02259583 1999-01-04

WO 98/03510 PCT/US97/13072
-C1-C10 alkyl, C3-C10 alkenyl, C3-C10 alkynyl,
C1-C10 haloalkyl with 1-10 halogens, C2-C8
alkoxyalkyl, C3-C6 cycloalkyl, C4-
C12 cycloalkylalkyl, C5-C10 cycloalkenyl,
or C6-C14 cycloalkenylalkyl, each
optionally substituted with 1 to 3
substituents independently selected at each
occurrence from C1-C6 alkyl, C3-
C6 cycloalkyl, halo, C1-C4 haloalkyl,

cyano, OR15, SH, S(O)nR13, COR15, C02R15OC (O) R13, NR8COR1S, N(COR15) 2,
NR8CONR16R15,
NR8C02R13, NR16R15' CONR16R15, aryl,
heteroaryl or heterocyclyl,
-aryl, aryl(C1-C4 alkyl)-, heteroaryl, heteroaryl(Ci-
Cq alkyl), heterocyclyl or heterocyclyl(C1-C4
alkyl) ;
R7a is independently selected at each occurrence from:
-H,
-C5-C10 alkyl, C3-C10 alkenyl, C3-Clp alkynyl,
C1-C10 haloalkyl with 1-10 halogens, C2-C8
alkoxyalkyl, C3-C6 cycloalkyl, C4-
C12 cycloalkylalkyl, C5-C10 cycloalkenyl,
or C6-C14 cycloalkenylalkyl, each
optionally substituted with 1 to 3
substituents independently selected at each
occurrence from C1-C6 alkyl, C3-
C6 cycloalkyl, halo, C1-C4 haloalkyl,
cyano, OR15, SH, S(O)nR13, COR15, C02R15,
OC(O)R13, NR8COR15, N(COR15)2, NR8CONR16R15,
NR8C02R13, NR16R15, CONR16R15, aryl,
heteroaryl or heterocyclyl,
-aryl, aryl(C1-C4 alkyl), heteroaryl,
heteroaryl(C1-C4 alkyl), heterocyclyl or
heterocyclyl(C1-C4 alkyl),

-38-

T


CA 02259583 1999-01-04

WO 98/03510 PCTIUS97/13072
alternatively, NR6R7
and NR6aR7a are independently
piperidine, pyrrolidine, piperazine, N-
methylpiperazine, morpholine or thiomorpholine, each
optionally substituted with 1-3 C1-C4 alkyl groups.
[33] More preferred compounds of the above invention
also include compounds and isomers thereof,
stereoisomeric forms thereof, or mixtures of
stereoisomeric forms thereof, and pharmaceutically
acceptable salt or pro-drug forms'thereof wherein R6a
and R7a are identical and are selected from:
-C1-C4 alkyl or C3-C6 cycloalkyl, each optionally
substituted with 1 to 3 substituents
independently selected at each occurrence from
Ci-C6 alkyl, C3-C6 cycloalkyl, halo, C1-C4
haloalkyl, cyano, OR15, SH, S(O) nR13, -COR15,
C02R15, OC (O) R13, NR8COR15, N(COR15) 2,
NR8CONR16R15, NR8C02R13, NR16R15, CONR16R15,
aryl, heteroaryl or heterocyclyl, and
-aryl or heteroaryl.

[34] More preferred compounds of the above invention
also include compounds and isomers thereof,
stereoisomeric forms thereof, or mixtures of
stereoisomeric forms thereof, and pharmaceutically
acceptable salt or pro-drug forms thereof wherein R6a
and R7a are identical and are
-C1-C4 alkyl, each such C1-C4 alkyl
optionally substituted with 1 to 3
substituents independently selected at each
occurrence from C1-C6 alkyl, C3-C6 cycloalkyl,
halo, C1-C4 haloalkyl, cyano, OR15, SH,
S(O) nR13, -COR15, C02R15, OC (O) R13, NRBCOR15,
N(COR15)2, NR8CONR16R15, NR8C02R13, NR16R15,
CONR16R15, aryl, heteroaryl or heterocyclyl.

-39-


CA 02259583 1999-01-04

WO 98/03510 PCT/US97/13072
(35] More preferred compounds of the above invention
also include compounds and isomers thereof,
stereoisomeric forms thereof, or mixtures of
stereoisomeric forms thereof, and pharmaceutically
acceptable salt or pro-drug forms thereof wherein
R6a is selected from:
-H,
-C1-C10 alkyl, C3-C10 alkenyl, C3-C10 alkynyl,
C1-C10 haloalkyl with 1-10 halogens, C2-C8
alkoxyalkyl, C3-C6 cycloalkyl, C4-
C12 cycloalkylalkyl, C5-C10 cycloalkenyl,
or C6-C14 cycloalkenylalkyl, each
optionally substituted with 1 to 3
substituents independently selected at each
occurrence from Cl-C6 alkyl, C3-
C6 cycloalkyl, halo, C1-C4 haloalkyl,
cyano, OR15, SH, S(O)nR13, COR15, C02R15,
OC(O)R13, NR8COR15, N(COR15)2, NR8CONR16R15,
NR8C02R13, NR16R15, CONR16R15, aryl,
heteroaryl or heterocyclyl,
-aryl, aryl(C1-C4 alkyl), heteroaryl,
heteroaryl(Cl-C4 alkyl), heterocyclyl or
heterocyclyl(C1-C4 alkyl);
R7a is:
-C1-C4 alkyl and each such Cl-C4 alkyl is
substituted with 1-3 substituents
independently selected at each occurrence from
C1-C6 alkyl, C3-C6 cycloalkyl, halo, C1-C4
haloalkyl, cyano, OR15, SH, S(O) nR13, COR15,
C02R15, OC (O) R13, NR8COR15, N(COR15)2,
NR8CONR16R15, NR8C02R13, NR16R15,. CONR16R15,
aryl, heteroaryl or heterocyclyl.

(36] More preferred compounds of the above invention
also include compounds and isomers thereof,

-40-


CA 02259583 1999-01-04

WO 98/03510 PCT/US97/13072
stereoisomeric forms thereof, or mixtures of
stereoisomeric forms thereof, and pharmaceutically
acceptable salt or pro-drug forms thereof wherein one.of
R6a and R7a is selected from:
-C3-C6 cycloalkyl, each such C3-C6 cycloalkyl
optionally substituted with 1-3 substituents
independently selected at each occurrence from
C1-C6 alkyl, C3-C6 cycloalkyl, halo, C1-C4
haloalkyl, cyano, OR15, SH, S(O)nR13, COR15,
C02R15, OC (O) R13, NR8COR15, N(COR15) 2,
NR8CONR16R15, NR8C02R13, NR16R15, CONR16R15,
aryl, heteroaryl or heterocyclyl,
-aryl,
-heteroaryl or
-heterocyclyl,
and the other of R6a and R7a is unsubstituted C1-C4
alkyl.

[37] More preferred compounds of the above invention
also include compounds and isomers thereof,
stereoisomeric forms thereof, or mixtures of
stereoisomeric forms thereof, and pharmaceutically
acceptable salt or pro-drug forms thereof wherein
R6a and R7a are independently H or C1-C10 alkyl,
each such Cl-C10 alkyl optionally substituted with
1 to 3 substituents independently selected at each
occurrence from C1-C6 alkyl, C3-C6 cycloalkyl,
halo, C1-C4 haloalkyl, cyano, OR15, SH, S(O)nR13,
COR15, C02R15, OC (O) R13, NR8COR15, N(COR15) 2,
R8CONR16R15f NR8C02R13, NR16R15, CONR16R15, aryl,
heteroaryl or heterocyclyl.

[38] Specifically preferred compounds of the above
invention are compounds of Formula (50)

-41-


CA 02259583 1999-01-04

WO 98/03510 PCTIUS97/13072
R3
N N N
~
N
4eR R4a
4dR R4b
R4c

FORMULA (50)

and isomers thereof, stereoisomeric forms thereof, or
mixtures of stereoisomeric forms thereof, and
pharmaceutically acceptable salt or pro-drug forms
thereof, selected from the group consisting of:

a compound of Formula (50) wherein R3 is -NHCH(n-Pr)2,
R4a is Cl, R4b is H, R4c is Cl, R4d is H and R4e is
H;

a compound of Formula (50) wherein R3 is -N(Et)(n-Bu),
R4a is Cl, R4b is H, R4c is Cl, R4d is H and R4e is
H;

a compound of Formula (50) wherein R3 is -(n-
Pr)(CH2cPr), R4a is Cl, R4b is H, R4C is C1, R4d is
H and R4e is H;

a compound of Formula (50) wherein R3 is -N(CH2CH2OMe)2,
R4a is Cl, R4b is H, R4c is C1, R4d is H and R4e is
H;
a compound of Formula (50) wherein R3 is -NHCH(Et)(n-
Bu), R4a is Cl, R4b is H, R4c is Cl, R4d is H and
R4e is H;

a compound of Formula (50) wherein R3 is
-NHCH(Et)(CH2OMe), R4a is Cl, R4b is H, R4c is Cl,
R4d is H and R4e is H;

-42-

,


CA 02259583 1999-01-04

WO 98/03510 PCT/US97/13072
a compound of Formula (50) wherein R3 is -NHCH(CH2OMe)2,
R4a is Cl, R4b is H, R4c is Cl, R4d is H and R4e is
H;

a compound of Formula (50) wherein R3 is -N(Et)2, R4a is
Cl, R4b is H, R4c is C1, R4d is H and R4e is H;

a compound of Formula (50) wherein R3 is -NHCH(CH2OEt)2,
R4a is Cl, R4b is H, R4c is Cl, R4d is H and R4e is
H;

a compound of Formula (50) wherein R3 is -NHCH(Et)2, R4a
is Cl, R4b is H, R4c is Cl, R4d is H and R4e is H;
a compound of Formula (50) wherein R3 is -N(Me)(Ph), R4a
is Cl, R4b is H, R4c is C1, R4d is H and R4e is H;
a compound of Formula (50) wherein R3 is -N(n-Pr)2, R4a
is Cl, R4b is H, R4c is Cl, R4d is H and R4e is H;

a compound of Formula (50) wherein R3 is -NHCH(Et)(n-
pr), R4a is Cl, R4b.is H, R4c is Cl. R4d is H and
R4e is H;

a compound of Formula (50) wherein R3 is -NHCH(CH2OMe)2,
R4a is Me, R4b is H, R4c is Me, R4d is H and R4e is
Me;

a compound of Formula (50) wherein R3 is -NHCH(CH2OMe)2,
R4a is Me, R4b is H, R4c is Me, R4d is H and R4e is
H;

a compound of Formula (50) wherein R3 is -N(CH2CH2OMe)2,
R4a is Me, R4b is H, R4c is Me, R4d is H and R4e is
H;

a compound of Formula (50) wherein R3 is
-NHCH(Et)(CH2OMe), R4a is Me, R4b is H, R4c is Me,
R4d is H and R4e is H;
a compound of Formula (50) wherein R3 is -NHCH(Et)2, R4a
is Me, R4b is H. R4c is Me, R4d is H and R4e is H;
a compound of Formula (50) wherein R3 is -OEt, R4a is
Cl, R4b is H, R4c is Cl, R4d is H and R4e is H;
-43-


CA 02259583 1999-01-04

WO 98/03510 PCT/US97/13072
a compound of Formula (50) wherein R3 is -N(Et)2, R4a is
Me, R4b is H, R4c is Me, R4d is H and R4e is H;

a compound of Formula (50) wherein R3 is -N(CH2CN)2, R4a
is Me, R4b is H, R4C is Me, R4d is H and R4e is H;
a compound of Formula (50) wherein R3 is
-NHCH(Me)(CH2OMe), R4a is Me, R4b is H, R4c is Me,
R4d is H and R4e is H;
a compound of Formula (50) wherein R3 is
-OCH(Et)(CH2OMe), R4a is Me, R4b is H, R4C is Me,
R4d is H and R4e is H;

a compound of Formula (50) wherein R3 is -N(n-
Pr)(CH2cPr), R4a is Me, R4b is H, R4c is Me, R4d is
H and R4e is H;

a compound of Formula (50) wherein R3 is
-NHCH (Me) (CH2N (Me) 2) , R4a is Me, R4b is H, R4c is
Me, R4d is H and R 4e is H;

a compound of Formula (50) wherein R3 is
-N (cPr) (CH2CH2CN) , R4a is Me, R4b is H, R4c is Me,
R4d is H and R4e is H;

a compound of Formula (50) wherein R3 is -N(n-
Pr)(CH2CH2CN), R4a is Me, R4b is H, R4c is Me, R4d
is H and R4e is H;
a compound of Formula (50) wherein R3 is -N(n-
Bu)(CH2CN), R4a is Me, R4b is H, R4c is Me, R4d is
H and R4e is H;

a compound of Formula (50) wherein R3 is
-NHCH(Et)(CH2OMe), R4a is Me, R4b is H, R4c is Me,
R4d is H and R4e is Me;

a compound of Formula (50) wherein R3 is -NHCH(Et)2, R4a
is Me, R4b is H, R4c is Me, R4d is H and R4e is Me;
a compound of Formula (50) wherein R3 is -N(CH2CH2OMe)2,
R4a is Me, R4b is H, R4c is Me, R4d is H and R4e is
Me;

-44-

T


CA 02259583 1999-01-04

WO 98/03510 PCT/US97/13072
a compound of Formula (50) wherein R3 is -NHCH(CH20Me)2,
R4a is Br, R4b is H, R4c is OMe, R4d is H and R4e
is H;

a compound of Formula (50) wherein R3 is
-NHCH(Et)(CH2OMe), R4a is Br, R4b is H, R4c is OMe,
R4d is H and R4e is H;

a compound of Formula (50) wherein R3 is -N(Et)2, R4a is
Me, R4b is H, R4c is Me, R4d is H and R4e is Me;

a compound of Formula (50) wherein R3 is -NHCH(CH2OEt)2,
R4a is Me, R4b is H, R4c is Me, R4d is H and R4e is
Me;
a compound of Formula (50) wherein R3 is
-NHCH(CH2CH2OMe)(CH2OMe)2, R4a is Me, R4b is H, R4c
is Me, R4d is H and R4e is Me;

a compound of Formula (50) wherein R3 is morpholino, R4a
is Me, R4b is H, R4c is Me, R4d is H and R4e is H;
a compound of Formula (50) wherein R3 is -N(CH2CH2OMe)2,
R4a is Br, R4b is H, R4c is OMe, R4d is H and R4e
is H;

a compound of Formula (50) wherein R3 is -NHCH(Et)2, R4a
is Br, R4b is H, R4c is OMe, R4d is H and R4e is H;
a compound of Formula (50) wherein R3 is -N(Et)2, R4a is
Br, R4b is H, R4c is OMe, R4d is H and R4e is H;
a compound of Formula (50) wherein R3 is -NH(c-Pr), R4a
is Me, R4b is H, R4c is Me, R4d is H and R4e is H;
a compound of Formula (50) wherein R3 is -NHCH(CH2OMe)2,
R4a is CN, R4b is H, R4c is OMe, R4d is H and R4e
is H;

a compound of Formula (50) wherein R3 is -N(c-
Pr)(CH2CH2CN), R4a is Me, R4b is H, R4c is Me, R4d
is H and R4e is Me;

a compound of Formula (50) wherein R3 is -NCH(CH2OMe)2,
R4a is Me, R4b is H, R4c is Br, R4d is H and R4e is
H;

-45-


CA 02259583 1999-01-04

WO 98/03510 PCT/US97/13072
a compound of Formula (50) wherein R3 is
-NHCH(CH2OMe)(CH2CH2OMe), R4a is Me, R4b is H, R4c
is Br, R4d is H and R4e is H;
a compound of Formula (50) wherein R3 is -NHCH(CH2OMe)2,
R4a is Me, R4b is H, R4c is OMe, R4d is Me and R4e
is H;

a compound of Formula (50) wherein R3 is -N(CH2CH2OMe)2,
R4a is Me, R4b is H, R4c is OMe, R4d is Me and R4e
is H;

a compound of Formula (50) wherein R3 is -NHCH(Et)2, R4a
is Me, R4b is H, R4c is OMe, R4d is Me and R4e is
H;

a compound of Formula (50) wherein a compound of Formula
(50) wherein R3 is -N(Et)2, R4a is Me, R4b is H,
R4c is OMe, R4d is Me and R4e is H;

a compound of Formula (50) wherein R3 is -NHCH(CH2OMe)2,
R4a is Cl, R4b is H, R4c is Me, R4d is H and R4e is
H;
a compound of Formula (50) wherein R3 is
-NHCH(Et)(CH2OMe), R4a is Cl, R4b is H, R4c is Me,
R4d is H and R4e is H;

a compound of Formula (50) wherein R3 is -N(CH2CH2OMe)2,
R4a is Cl, R4b is H, R4c is Me, R4d is H and R4e is
H;

a compound of Formula (50) wherein R3 is
-NHCH(CH2OMe)(CH2CH2OMe), R4a is Cl, R4b is H, R4c
is Me, R4d is H and R4e is H;

a compound of Formula (50) wherein R3 is -N(c-
Pr) (CH2CH.2CN) , R4a is Me, R4b is H, R4c is OMe, R4d
is Me and R4e is H;

a compound of Formula (50) wherein R3 is -N(c-
Pr)(CH2CH2CN), R4a is Cl, R4b is H, R4c is Cl, R4d
is H and R4e is H;

-46-

, . .... .... T
T


CA 02259583 1999-01-04

WO 98/03510 PCTIUS97/13072
a compound of Formula (50) wherein R3 is (S)-
NHCH(CH2OMe)(CH2CH2OMe), R4a is Cl, R4b is H, R4c
is Cl, R4d is H and R4e is H;

a compound of Formula (50) wherein R3 is
-NHCH(CH2OMe)(CH2CH2OMe), R4a is Cl, R4b is H, R4c
is Cl, R4d is H and R4e is H;

a compound of Formula (50) wherein R3 is -NHCH(Et)2, R4a
is Me, R4b is H, R4c is Br, R4d is H and R4e is H;
a compound of Formula (50) wherein R3 is -N(CH2CH2OMe)2,
R4a is Me, R4b is H, R4c is Br, R4d is H and R4e is
H;
a compound of Formula (50) wherein R3 is
-NH (CH2OMe) (CH2-iPr) , R4a is Me, R4b is H, R4c is
Me, R4d is H and R4e is H;

a compound of Formula (50) wherein R3 is -N(CH2CH2OMe)2,
R4a is Me, R4b is H, R4c is H, R4d is H and R4e is
H;

a compound of Formula (50) wherein R3 is -N(CH2CH2OMe)2,
R4a is Me, R4b is H, R4c is NMe2, R4d is H and R4e
is H;

a compound of Formula (50) wherein R3 is
-NHCH(CH2OMe)(n-Pr), R4a is Me, R4b is H, R4c is
Me, R4d is H and R4e is H;

a compound of Formula (50) wherein R3 is
-NHCH(CH2OEt)(Et), R4a is Me, R4b is H, R4c is Me,
R4d is H and R4e is H;
a compound of Formula (50) wherein R3 is
-NHCH(CH2OMe)(CH2CH2OMe), R4a is Me, R4b is H, R4c
is NMe2, R4d is H and R4e is H;

a compound of Formula (50) wherein R3 is -N(Et)2, R4a is
Me, R4b is H, R4c is Cl, R4d is H and R4e is H;

a compound of-Formula (50) wherein R3 is -NHCH(Et)2, R4a
is Me, R4b is H, R4c is Cl, R4d is H and R4e is H;

-47-


CA 02259583 1999-01-04

WO 98/03510 PCT/US97/13072
a compound of Formula (50) wherein R3 is -N(CH2CH2OMe)2,
R4a is Me, R4b is H, R4c is Cl, R4d is H and R4e is
H;

a compound of Formula (50) wherein R3 is -NHCH(CH2OMe)2,
R4a is Me, R4b is H, R4c is C1, R4d is H and R4e is
H;

a compound of Formula (50) wherein R3 is -N(Et)2, R4a is
Me, R4b is H, R4c is Br, R4d is H and R4e is H;

a compound of Formula (50) wherein R3 is -N(Et)2, R4a is
Cl, R4b is H, R4c is Me, R4d is H and R4e is H;

a compound of Formula (50) wherein R3 is -NHCH(Et)2, R4a
is C1, R4b is H, R4c is Me, R4d is H and R4e is H;
a compound of Formula (50) wherein R3 is -NHCH(Et)2, R4a
is Me, R4b is H, R4c is NMe2, R4d is H and R4e is
H;

a compound of Formula (50) wherein R3 is (S)-
NHCH(CH2OMe)(CH2CH2OMe), R4a is Me, R4b is H, R4c
is Me, R4d is H and R4e is H;
a compound of Formula (50) wherein R3 is
-NHCH(CH2OMe)(CH2CH2OMe), R4a is Me, R4b is H, R4c
is Me, R4d is H and R4e is H;

a compound of Formula (50) wherein R3 is (S)-
NHCH(CH2OMe)(CH2CH2OMe), R4a is Me, R4b is H, R4c
is Cl, R4d is H and R4e is H;

a compound of Formula (50) wherein R3 is
-NHCH(CH2OMe)(CH2CH2OMe), R4a is Me, R4b is H, R4c
is Cl, R4d is H and R4e is H;

a compound of Formula (50) wherein R3 is -N(c-
Pr)(CH2CH2CN), R4a is Me, R4b is H, R4c is Cl, R4d
is H and R4e is H;

a compound of Formula (50) wherein R3 is -NH(Et)(CH2CN),
R4a is Me, R4b is H, R4c is Cl, R4d is H and R4e is
H;

-48-

T


CA 02259583 1999-01-04

WO 98/03510 PCT/US97/13072
a compound of Formula (50) wherein R3 is -N(Et)2, R4a is
Me, R4b is Me, R4c is OMe, R4d is H and R4e is H;

a compound of Formula (50) wherein R3 is
-N(CH2CH2OMe)(CH2CH2OH), R4a is Cl, R4b is H, R4c
is Cl, R4d is H and R4e is H;

a compound of Formula (50) wherein R3 is -N(CH2CH2OMe)2,
R4a is Me, R4b is Me, R4c is OMe, R4d is H and R4e
is H;

a compound of Formula (50) wherein R3 is -NHCH(Et)2, R4a
is Me, R4b is Me, R4c is OMe, R4d is H and R4e is
H;
a compound of Formula (50) wherein R3 is -N(CH2c-Pr) (n-
Pr), R4a is Me, R4b is H, R4c is Cl, R4d is H and
R4e is H;

a compound of Formula (50) wherein R3 is -N(c-Pr)
(CH2CH2CN), R4a is Me, R4b is Me, R4C is OMe, R4d
is H and R4e is H;

a compound of Formula (50) wherein R3 is -NHCH (Et)2,
R4a is Cl, R4b is H, R4c is OMe, R4d is H and R4e
is H;

a compound of Formula (50) wherein R3 is -N(Et)2, R4a is
Cl, R4b is H, R4c is OMe, R4d is H and R4e is H;
a compound of Formula (50) wherein R3 is -N(CH2CH2OMe)2,
R4a is Cl, R4b is H, R4c is OMe, R4d is H and R4e
is H;

a compound of Formula (50) wherein R3 is
-NHCH(Et)(CH2OMe), R4a is Cl, R4b is H, R4c is OMe,
R4d., is H and R4e is H;

a compound of Formula (50) wherein R3 is -N(Et)2, R4a is
C1, R4b is H, R4c is CN, R4d is H and R4e is H;

a compound of Formula (50) wherein R3 is -N(c-
Pr) (CH2CH2CN) , R4a is Cl, R4b is H, R4c is OMe, R4d
is H and R4e is H;

-49-


CA 02259583 1999-01-04

WO 98/03510 PCT/US97/13072
a compound of Formula (50) wherein R3 is -NHCH(CH20H)2,
R4a is Cl, R4b is H, R4c is Cl, R4d is H and R4e is
H; and

a compound of Formula (50) wherein R3 is N(CH2CH2OMe)2,
R4a is Me, R4b is H, R4c is OMe, R4d is H and R4e
is H.

[39] More specifically preferred is 4-(bis-(2-
methoxyethyl)amino)-2,7-dimethyl-8-(2-methyl-4-
methoxyphenyl)-[1,5-a]-pyrazolo-1,3,5-triazine
and isomers thereof, stereoisomeric forms thereof, or
mixtures of stereoisomeric forms thereof, and
pharmaceutically acceptable salt or pro-drug forms
thereof.

[40] More specifically preferred is 4-(bis-(2-
methoxyethyl)amino)-2,7-dimethyl-8-(2,5-dimethyl-4-
methoxyphenyl)-[1,5-a]-pyrazolo-1,3,5-triazine and
isomers thereof, stereoisomeric forms thereof, or
mixtures of stereoisomeric forms thereof, and
pharmaceutically acceptable salt or pro-drug forms
thereof.
[41] More preferred are compounds of the above invention
are compounds and isomers thereof, stereoisomeric forms
thereof, or mixtures of stereoisomeric forms thereof,
and pharmaceutically acceptable salt or pro-drug forms
thereof wherein A is CR.

[42] More preferred compounds of the above invention
also include compounds and isomers thereof,
stereoisomeric forms thereof, or mixtures of
stereoisomeric forms thereof, and pharmaceutically
acceptable salt or pro-drug forms thereof.

-50-

,


CA 02259583 1999-01-04

WO 98/03510 PCT/US97/13072
[43] More preferred compounds of the above invention
also include compounds and isomers thereof,
stereoisomeric forms thereof, or mixtures of
stereoisomeric forms thereof, and pharmaceutically
acceptable salt or pro-drug forms thereof wherein Ar is
phenyl, pyridyl or 2,3-dihydrobenzofuranyl and each Ar
is optionally substituted with 1 to 4 R4 substituents.
[44] More preferred compounds of the above invention
also include compounds and isomers thereof,
stereoisomeric forms thereof, or mixtures of
stereoisomeric forms thereof, and pharmaceutically
acceptable salt or pro-drug forms thereof wherein R3 is
NR6aR7a or OR7.
[45] More preferred compounds of the above invention
also include compounds and isomers thereof,
stereoisomeric forms thereof, or mixtures of
stereoisomeric forms thereof, and pharmaceutically
acceptable salt or pro-drug forms thereof wherein Ar is
phenyl, pyridyl or 2,3-dihydrobenzofuranyl, and each Ar
is optionally substituted with 1 to 4 R4 substituents,
and R3 is NR6aR7a or OR7.

[46] More preferred compounds of the above invention
also include compounds and isomers thereof,
stereoisomeric forms thereof, or mixtures of
stereoisomeric forms thereof, and pharmaceutically
acceptable salt or pro-drug forms thereof wherein Z is
CR2.

[47] More preferred compounds of the above invention
also include compounds and isomers thereof,
stereoisomeric forms thereof, or mixtures of
stereoisomeric forms thereof, and pharmaceutically
acceptable salt or pro-drug forms thereof wherein Ar is
-51-


CA 02259583 1999-01-04

WO 98/03510 PCT/US97/13072
phenyl, pyridyl or 2,3-dihydrobenzofuranyl and each Ar
is optionally substituted with 1 to 4 R4 substituents.
[48] More preferred compounds of the above invention
also include compounds and isomers thereof,
stereoisomeric forms thereof, or mixtures of
stereoisomeric forms thereof, and pharmaceutically
acceptable salt or pro-drug forms thereof wherein R3 is
NR6aR7a or OR7.
[49] More preferred compounds of the above invention
also include compounds and isomers thereof,
stereoisomeric forms thereof, or mixtures of
stereoisomeric forms thereof, and pharmaceutically
acceptable salt or pro-drug forms thereof wherein Ar is
phenyl, pyridyl or 2,3-dihydrobenzofuranyl, and each Ar
is optionally substituted with 1 to 4 R4 substituents,
and R3 is NR6aR7a or OR7.

[50) More preferred compounds of the above invention
also include compounds and isomers thereof,
stereoisomeric forms thereof, or mixtures of
stereoisomeric forms thereof, and pharmaceutically
acceptable salt or pro-drug forms thereof wherein
R6a and R7a are independently H or C1-C10 alkyl,
and each such C1-C10 alkyl is optionally
substituted with 1 to 3 substituents independently
selected at each occurrence from Cl-C6 alkyl, C3-
C6 cycloalkyl, halo, C1-C4 haloalkyl, cyano, OR15,
SH, S(0) nR13, COR15, C02R15, OC (0) R13, NR8COR15,
N(COR15)2, R8CONR16R15, NR8C02R13, NR16R15,
CONR16R15, aryl, heteroaryl or heterocyclyl.

[51] More preferred compounds of the above invention
also include compounds and isomers thereof,
stereoisomeric forms thereof, or mixtures of

-52-

. .. ... _ . . . . .. . . T


CA 02259583 1999-01-04

WO 98/03510 PCT/US97/13072
stereoisomeric forms thereof, and pharmaceutically
acceptable salt or pro-drug forms thereof wherein
-Ar is phenyl, pyridyl or 2,3-dihydrobenzofuranyl,
and each Ar is optionally substituted with 1
to 4 R4 substituents,
-R3 is NR6aR7a or OR'7 and
-Rl and R2 are independently selected from H, Ci-C4
alkyl, C3-C6 cycloalkyl, C4-C10
cycloalkylalkyl.
[52] More preferred compounds of the above invention
also include compounds and isomers thereof,
stereoisomeric forms thereof, or mixtures of
stereoisomeric forms thereof, and pharmaceutically
acceptable salt or pro-drug forms thereof wherein
R6a and R7a are independently H or Cl-C10 alkyl,
and each such Cl-Cl0 alkyl is optionally
substituted with 1 to 3 substituents independently
selected at each occurrence from Cl-C6 alkyl, C3-
C6 cycloalkyl, halo, Cl-C4 haloalkyl, cyano, OR15,
SH, S(O)nR13, COR15, C02R15, OC(O)R13, NR8COR15,
N(COR15)2r R8CONR16R15, NR8C02R13, NR16R15,
CONR16R15, aryl, heteroaryl or heterocyclyl.

[53] Specifically preferred compounds of the above
invention are compounds of Formula (51)

-53-


CA 02259583 1999-01-04

WO 98/03510 PCTIUS97/13072
R3
~ N N

N
4eR R4a
4dR R4b
R4c

FORMULA (51)

and isomers thereof, stereoisomeric forms thereof, or
mixtures of stereoisomeric forms thereof, and
pharmaceutically acceptable salt or pro-drug forms
thereof selected from the group consisting of:

a compound of Formula (51) wherein R3 is -NHCH(n-Pr)2,
R4a is Me, R4b is H,' R4c is Me, R4d is H and R4e is
H;

a compound of Formula (51) wherein R3 is -NHCH(CH2OMe)2,
R4a is Me, R4b is H, R4C is Me, R4d is H and R4e is
H;

a compound of Formula (51) wherein R3 is -N(CH2CH2OMe)2,
R4a is Me, R4b is H, R4c is Me, R4d is H and R4e is
H;

a compound of Formula (51) wherein R3 is -N(c-
Pr)(CH2CH2CN), R4a is Me, R4b is H, R4c is Me, R4d
is H and R4e is H;
a compound of Formula (51) wherein R3 is -N(CH2CH2OMe)2,
R4a is Cl, R4b is H, R4c is Me, R4d is H and R4e is
H;

a compound of Formula (51) wherein R3 is -NHCH(CH2OMe)2,
R4a is Cl, R4b is H, R4c is Me, R4d is H and R4e is
H;

-54-

,


CA 02259583 1999-01-04

WO 98/03510 PCT/US97/13072
a compound of Formula (51) wherein R3 is -NHCH(Et)2, R4a
is Cl, R4b is H, R4c is Me, R4d is H and R4e is H;

a compound of Formula (51) wherein R3 is -N(Et)2, R4a is
Me, R4b is H, R4c is Me, R4d is H and R4e is H;

a compound of Formula (51) wherein R3 is -N(n-
Pr) (CH2CH2CN) , R4a is Me, R4b is H, R4c is Me, R4d
is H and R4e is H;
a compound of Formula (51) wherein R3 is -N(n-
Bu) (CH2CH2CN) , R4a is Me, R4b is H, R4c is Me, R4d
is H and R4e is H;

a compound of Formula (51) wherein R3 is -NHCH(n-
Pr) (CH2OMe) , R4a is Me, R4b is H, R4c is Me, R4d is
H and R4e is H;

a compound of Formula (51) wherein R3 is -NHCH(Et)2, R4a
is Me, R4b is H, R4c is OMe, R4d is H and R4e is H;
a compound of Formula (51) wherein R3 is -NHCH(CH2OMe)2,
R4a is Me, R4b is H,' R4c is OMe, R4d is H and R4e
is H;
a compound of Formula (51) wherein R3 is (S)
-NH (CH2CH2OMe) CH2OMe, R4a is Me, R4b is H, R4c is
Me, R4d is H and R4e is H;

a compound of Formula (51) wherein R3 is
-NH (CH2CH2OMe) CH2OMe, R4a is Me, R4b is H, R4c is
Me, R4d is H and R4e is H;

a compound of Formula (51) wherein R3 is -N(CH2CH2OMe)2,
R4a is Me, R4b is H, R4c is C1, R4d is H and R 4e is
H;

a compound of Formula (51) wherein R3 is -NH(Et), R4a is
Me, R4b is H, R4c is Me, R4d is H and R4e is H;
a compound of Formula (51) wherein R3 is -NHCH(n-Pr)2,
R4a is Me, R4b is H, R4c is Cl, R4d is H and R4e is
H;

-55-


CA 02259583 1999-01-04

WO 98/03510 PCT/US97/13072
a compound of Formula (51) wherein R3 is -NHCH(CH2OMe)2,
R4a is Me, R4b is H, R4c is Cl, R4d is H and R4e is
H;

a compound of Formula (51) wherein R3 is (S)
-NH (CH2CH2OMe) CH2OMe, R4a is Me, R4b is H, R4c is
Cl, R4d is H and R4e is H;

a compound of Formula (51) wherein R3 is
-NH(CH2CH2OMe)CH2OMe, R4a is Me, R4b is H, R4c is
Cl, R4d is H and R4e is H;

a compound of Formula (51) wherein R3 is -N(n-
Pr) (CH2CH2CN) , R4a is Me, R4b is H, R4c is OMe, R4d
is H and R4e is H;

a compound of Formula (51) wherein R3 is -N(Et)2, R4a is
Me, R4b is H, R4c is OMe, R4d is H and R4e is H;

a compound of Formula (51) wherein R3 is (S)
-NH(CH2CH2OMe)CH2OMe, R4a is Cl, R4b is H, R4c is
Me, R4d is H and R4e is H;

a compound of Formula (51) wherein R3 is
-NH(CH2CH2OMe)CH2OMe, R4a is C1, R4b is H, R4c is
Me, R4d is H and R4e is H;

a compound of Formula (51) wherein R3 is -N(Et)2, R4a is
Cl, R4b is H, R4c is Me, R4d is H and R4e is H;
a compound of Formula (51) wherein R3 is -N(c-
Pr) (CH2CH2CN) , R4a is Me, R4b is H, R4c is OMe, R4d
is H and R4e is H;

a compound of Formula (51) wherein R3 is -N(c-
Pr)(CH2CH2CN), R4a is Cl, R4b is H, R4c is Me, R4d
is H and R4e is H;

a compound of Formula (51) wherein R3 is -NHCH (n-
Pr) (CH2OMe) , R4a is Me, R4b is H, R4c is OMe, R4d
is H and R4e is H;

a compound of Formula (51) wherein R3 is -NHCH (n-
Pr) (CH2OMe) , R4a is Cl, R4b is H, R4c is Me, R4d is
H and R4e is H;

-5 6-

T


CA 02259583 1999-01-04

WO 98/03510 PCT/US97/13072
a compound of Formula (51) wherein R3 is -NHCH(Et)2, R4a
is Br, R4b is H, R4c is OMe, R4d is OMe and R4e is
H;
a compound of Formula (51) wherein R3 is -NHCH(Et)2, R4a
is Br, R4b is H, R4c is OMe, R4d is H and R4e is H;
a compound of Formula (51) wherein R3 is -N(CH2CH2OMe)2,
R4a is Br, R4b is H, R4c is OMe, R4d is H and R4e
is H;

a compound of Formula (51) wherein R3 is -NHCH(CH2OMe)2,
R 4a is Br, R4b is H, R4c is OMe, R4d is H-.and R4e
is H;

a compound of Formula (51) wherein R3 is -N(Et)2, R4a is
Me, R4b is H, R4c is C1, R4d is H and R4e is H;

a compound of Formula (51) wherein R3 is -N(Et)2, R4a is
Cl, R4b is H, R4c is OMe, R4d is OMe and R4e is H;

a compound of Formula (5k) wherein R3 is -NHCH(Et)2, R4a
is Cl, R4b is H, R4c is OMe, R4d is OMe and R4e is
H;

a compound of Formula (51) wherein R3 is -N (CH2CH2OMe) 2,
R4a is Cl, R4b is H, R4c is Cl, R4d is H and R4e is
H;
a compound of Formula (51) wherein R3 is -NHCH(CH2OMe)2,
R4a is C1, R4b is H, R4c is Cl, R4d is H and R4e is
H;

a compound of Formula (51) wherein R3 is
-N (Pr) (CH2CH2CN) , R4a is Cl, R4b is H, R4c is Cl,
R4d is H and R4e is H;

a compound of Formula (51) wherein R3 is -N(Bu)(Et), R4a
is Cl, R4b is H, R4c is Cl, R4d is H and R4e is H;
a compound of Formula (51) wherein R3 is
-NHCH(Et)CH2OMe, R4a is Cl, R4b is H, R 4c is Cl,
R4d is H and R4e is H;

-57-


CA 02259583 1999-01-04

WO 98/03510 PCT/US97/13072
a compound of Formula (51) wherein R3 is -NHCH(Et)2, R4a
is Cl, R4b is H, R4c is Cl, R4d is H and R4e is H;

a compound of Formula (51) wherein R3 is -NHCH(Et)2, R.4a
is Me, R4b is H, R4c is Me, R4d is H and R4e is H;
a compound of Formula (51) wherein R3 is -NHCH(Et)2, R4a
is Cl, R4b is H, R4c is Me, R4d is H and R4e is H;
a compound of Formula (51) wherein R3 is -NHCH(Et)2, R4a
is Me, R4b is H, R4c is Cl, Rqd is H and R4e is H;

a compound of Formula (51) wherein R3 is -NEt2, R4a is
Me, R4b is H, R4c is OMe, R4d is H and R4e is H;
and

a compound of Formula (51) wherein R3 is
-N (Pr) (CH2CH2CN) , R4a is Me, R4b is H, R4C is OMe,
R4d is H and R4e is H.

[54] More specifically preferred is 7-(3-
pentylamino)-2,5-dimethyl-3-(2-methyl-4-
methoxyphenyl)-[1,5-a]-pyrazolopyrimidine and isomers
thereof, stereoisomeric forms thereof, or mixtures of
stereoisomeric forms thereof, and pharmaceutically
acceptable salt or pro-drug forms thereof.

[55] More specifically preferred is 7-(Diethylamino)-
2,5-dimethyl-3-(2-methyl-4-methoxyphenyl-[1,5-a]-
pyrazolopyrimidine and isomers thereof,
stereoisomeric forms thereof, or mixtures of
stereoisomeric forms thereof, and pharmaceutically
acceptable salt or pro-drug forms thereof.
[56] More specifically preferred is 7-(N-(3-
cyanopropyl)-N-propylamino)-2,5-dimethyl-3-(2,4-
dimethylphenyl)-[1,5-a]-pyrazolopyrimidine and
isomers thereof, stereoisomeric forms thereof, or
mixtures of stereoisomeric forms thereof, and
-58-
r


CA 02259583 1999-01-04

WO 98/03510 PCT/US97/13072
pharmaceutically acceptable salt or pro-drug forms
thereof.

The present invention also provides
pharmaceutical compositions comprising compounds of
Formulae (1) and (2) and a pharmaceutically
acceptable carrier.

Many compounds of this invention have one or more
asymmetric centers or planes. Unless otherwise
indicated, all chiral (enantiomeric and diastereomeric)
and racemic forms are included in the present invention.
Many geometric isomers of olefins, C=N double bonds, and
the like can also be present in the compounds, and all
such stable isomers are contemplated in the present
invention. The compounds 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. All chiral,
(enantiomeric and diastereomeric) and racemic forms and
all geometric isomeric forms of a structure are
intended, unless the specific stereochemistry or isomer
form is specifically indicated.
The term "alkyl" includes both branched and
straight-chain alkyl having the specified number of
carbon atoms. Commonly used abbreviations have the
following meanings: Me is methyl, Et is ethyl, Pr is
propyl, Bu is butyl. The prefix "n" means a straight
chain alkyl. The prefix "c" means a cycloalkyl. The
prefix "(S)" means the S enantiomer and the prefix
"(R)" means the R enantiomer. Alkenyl" includes
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
-5 9-


CA 02259583 1999-01-04

WO 98/03510 PCT/US97/13072
like. "Alkynyl" includes hydrocarbon chains of either
a straight or branched configuration and one or more
triple carbon-carbon bonds which may occur in any
stable point along the chain, such as ethynyl,
propynyl and the like. "Haloalkyl" is intended to
include both branched and straight-chain alkyl having
the specified number of carbon atoms, substituted
with 1 or more halogen; "alkoxy" represents an alkyl
group of indicated number of carbon atoms attached
through an oxygen bridge; "cycloalkyl" is intended to
include saturated ring groups, including mono-,bi- or
poly-cyclic ring systems, such as cyclopropyl,
cyclobutyl, cyclopentyl, cyclohexyl, and so forth.
"Halo" or "halogen" includes fluoro, chloro, bromo,
and iodo.
The term "substituted", as used herein, means
that one or more hydrogen 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.,
=0), then 2 hydrogens on the atom are replaced.
Combinations of substituents and/or variables
are permissible only if such combinations result in
stable compounds. By "stable compound" or "stable
structure" is meant 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.
The term "appropriate amino acid protecting
group" means any group known in the art of organic
synthesis for the protection of amine or carboxylic
acid groups. Such amine protecting groups include
those listed in Greene and Wuts, "Protective Groups
in Organic Synthesis" John Wiley & Sons, New York
(1991) and "The Peptides: Analysis, Synthesis,
-60-

T


CA 02259583 2007-02-27

WO 98/03510 PCT/US97/13072
Biology, Vol. 3, Academic Press, New York (1981).

Any amine protecting group known in the
art can be used. Examples of amine protecting groups
include, but are not limited to, the following: 1)
acyl types such as formyl, trifluoroacetyl, phthalyl,
and p-toluenesulfonyl; 2) aromatic carbamate types
such as benzyloxycarbonyl (Cbz) and substituted
benzyloxycarbonyls, 1-(p-biphenyl)-1-
methylethoxycarbonyl, and
9-fluorenylmethyloxycarbonyl (Fmoc); 3) aliphatic
carbamate types such as tert-butyloxycarbonyl (Boc),
ethoxycarbonyl, diisopropylmethoxycarbonyl, and
allyloxycarbonyl; 4) cyclic alkyl carbamate types
such as cyclopentyloxycarbonyl and
adamantyloxycarbonyl; 5) alkyl types such as
triphenylmethyl and benzyl; 6) trialkylsilane such as
trimethylsilane; and 7) thiol containing types such
as phenylthiocarbonyl and dithiasuccinoyl.
The term "pharmaceutically acceptable salts"
includes acid or base salts of the compounds of
Formulae (1) and (2). 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.
Pharmaceutically acceptable salts of the
compounds of the invention 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
-61-


CA 02259583 2007-02-27

WO 98/03510 PCTIUS97/13072
Company, Easton, PA, 1985, p. 1418.

"Prodrugs" are considered to be any covalently
bonded carriers which release the active parent drug
of formula (I) or (II) in vivo when such prodrug is
administered to a mammalian subject. Prodrugs of the
compounds of formula (I) and (II) are prepared by
modifying functional groups present in the compounds
in such a way that the modifications are cleaved,
either in routine manipulation or in vivo, to the
parent compounds. Prodrugs include compounds wherein
hydroxy, amine, or sulfhydryl groups are bonded to
any group that, when administered to a mammalian
subject, cleaves to form a free hydroxyl, amino, or
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 formulas (2) and (II); and
the like.
The term "therapeutically effective amount" of a
compound of this invention means an amount effective
to antagonize abnormal level of CRF or treat the
symptoms of affective disorder, anxiety or depression
in a host.

Syntheses
Some compounds of Formula (1) may be prepared from
intermediate compounds of Formula (7), using the
procedures outlined in Scheme 1:
-62-


CA 02259583 1999-01-04

WO 98/03510 PCT/US97/13072
SCHEbE 1

Y halogenating agent or X
sulfonylating agent
N + / - base, + / - solvent N
HN N~ ~~ N N''~ ~~
Z Z
\. \
R1 \ N Rl \ N

Ar Ar
(7) Y = 0 (8)

R3
R3H, + / - base, N
~
+ / - solvent Z
R1 N
Ar
(I) A = N
Compounds of Formula (7) (where Y is 0) may be treated
with a halogenating agent or sulfonylating agent in the
presence or absence of a base in the presence or absence
of an inert solvent at reaction temperatures ranging
from -80 C to 2500C to give products of Formula (8)
(where X is halogen, alkanesulfonyloxy, arylsulfonyloxy
or haloalkane-sulfonyloxy). Halogenating agents
include, but are not limited to, SOC12, POC13, PC13,
PC15, POBr3, PBr3 or PBr5. Sulfonylating agents include,
but are not limited to, alkanesulfonyl halides or
anhydrides (such as methanesulfonyl chloride or
methanesulfonic acid anhydride), arylsulfonyl halides or
anhydrides (such as p-toluenesulfonyl chloride or
anhydride) or haloalkylsulfonyl halides or anhydrides
(preferably trifluoromethanesulfonic anhydride). Bases
may include, but are not limited to, alkali metal

-63-


CA 02259583 1999-01-04

WO 98/03510 PCTIUS97/13072
hydrides (preferably sodium hydride), alkali metal
alkoxides (1 to 6 carbons)(preferably sodium methoxide
or sodium ethoxide), alkaline earth metal hydrides,
alkali metal dialkylamides (preferably lithium di-
isopropylamide), alkali metal bis(trialkylsilyl)amides
(pref,zrably sodium bis(trimethylsilyl)amide), trialkyl
amines (preferably N,N-di-isopropyl-N-ethyl amine or
triethylamine) or aromatic amines (preferably pyridine).
Ir.trt solvents may include, but are not limited to,
lower alkanenitriles (1 to 6 carbons, preferably
acetonitrile), dialkyl ethers (preferably diethyl
ether), cyclic ethers (preferably tetrahydrofuran or
1,4-dioxane), N,N-dialkylformamides (preferably
dimethylformamide), N,N-dialkylacetamides (preferably
dimethylacetamide), cyclic amides (preferably N-
methylpyrrolidin-2-one), dialkylsulfoxides (preferably
dimethylsulfoxide), aromatic hydrocarbons (preferably
benzene or toluene) or haloalkanes of 1 to 10 carbons
and 1 to 10 halogens (preferably dichloromethane).
Preferred reaction temperatures range from -20 C to
100 C.
Compounds of Formula (8) may be reacted with
compounds of Formula R3H (where R3 is defined as above
except R3 is not SH, COR7, C02R7, aryl or heteroaryl) in
the presence or absence of a base in the presence or
absence of an inert solvent at reaction temperatures
ranging from -80 to 250 C to generate compounds of
Formula (1). Bases may include, but are not limited to,
alkali metal hydrides (preferably sodium hydride),
alkali metal alkoxides (1 to 6 carbons)(preferably
sodium methoxide or sodium ethoxide), alkaline earth
metal hydrides, alkali metal dialkylamides (preferably
lithium di-isopropylamide), alkali metal carbonates,
alkali metal bicarbonates, alkali metal
bis(trialkylsilyl)amides (preferably sodium
bis(trimethylsilyl)amide), trialkyl amines (preferably
-64-

T


CA 02259583 1999-01-04

WO 98/03510 PCT/US97/13072
N,N-di-isopropyl-N-ethyl amine) or aromatic amines
(preferably pyridine). Inert solvents may include, but
are not limited to, alkyl alcohols (1 to 8 carbons,
preferably methanol or ethanol), lower alkanenitriles (1
to 6 carbons, preferably acetonitrile), dialkyl ethers
(preferably diethyl ether), cyclic ethers (preferably
tetrahydrofuran or 1,4-dioxane), N,N-dialkylformamides
(preferably dimethylformamide), N,N-dialkylacetamides
(pceferably dimethylacetamide), cyclic amides
(preferably N-methylpyrrolidin-2-one), dialkylsulfoxides
(preferably dimethylsulfoxide), aromatic hydrocarbons
(preferably benzene or toluene) or haloalkanes of 1 to
10 carbons and 1 to 10 halogens (preferably
dichloromethane). Preferred reaction temperatures range
from 0 C to 140 C.
Scheme 2 delineates the procedures for converting
intermediate compounds of Formula (7) (where Y isS) to
some compounds of Formula (1). =

-65-


CA 02259583 1999-01-04

WO 98/03510 PCT/US97/13072
SCHEb1E 2

Y SR13
R13X, + / - base,
HN N + - solvent N N ~~
Z Z
R1 N Rl N

Ar Ar
(7) Y = S (12)
oxidizing agent,
solvent R3g~ + / - base,
+ / - solvent
S (0)nRl3 3
R
N~ N~,- N~ R3H, +/- base, N
`Z + / - solvent A N Z
Rl N
R N
Ar
Ar
(13)
(1) A = N
Compounds of Formula (7) (where Y is S) may be treated
with an alkylating agent R13X (where R13 is defined as
above, except R13 is not aryl or heteroaryl) in the
presence or absence of a base in the presence or absence
of an inert solvent at reaction temperatures ranging
from -80 C to 2500C. Bases may include, but are not
limited to, alkali metal hydrides (preferably sodium
hydride), alkali metal alkoxides (1 to 6
carbons)(preferably sodium methoxide or sodium
ethoxide), alkaline earth metal hydrides, alkali metal
dialkylamides (preferably lithium di-isopropylamide),
alkali metal carbonates, alkali metal hydroxides, alkali
metal bis(trialkylsilyl)amides (preferably sodium

-66-

T


CA 02259583 1999-01-04

WO 98/03510 PCT/US97/13072
bis(trimethylsilyl)amide), trialkyl amines (prefereably
N,N-di-isopropyl-N-ethyl amine or triethyl amine) or
aromatic amines (preferably pyridine). Inert solvents
may include, but are not limited to, alkyl alcohols (1
to 8 carbons, preferably methanol or ethanol), lower
alkanenitriles (1 to 6 carbons, preferably
acetonitrile), dialkyl ethers (preferably diethyl
ether), cyclic ethers (preferably tetrahydrofuran or
1,4-dioxane), N,N-dialkylformamides (preferably
dimethylformamide), N,N-dialkylacetamides (preferably
dimethylacetamide), cyclic amides (preferably N-
methylpyrrolidin-2-one), dialkylsulfoxides (preferably
dimethylsulfoxide), aromatic hydrocarbons (preferably
benzene or toluene) or haloalkanes of 1 to 10 carbons
and 1 to 10 halogens (preferably dichloromethane).
Preferred reaction temperatures range from -80 C to
100 C.
Compounds of Formula (12) (Formula (1) where R3 is
SR13) may then be reacted with compounds of Formula R3H
to give compounds of Formula (1), using the same
conditions and reagents as were used for the conversion
of compounds of Formula (8) to compounds of Formula (1)
as outlined for Scheme 1 above. Alternatively,
compounds of Formula (12) (Formula (1) where R3 is SR13)
may be oxidized to compounds of Formula (13) (Formula
(1) where R3 is S(0)nR13, n is 1,2) by treatment with an
oxidizing agent in the presence of an inert solvent at
temperatures ranging from -80 C to 250 C. Oxidizing
agents include, but are not limited to, hydrogen
peroxide, alkane or aryl peracids (preferably peracetic
acid or m-chloro-perbenzoic acid), dioxirane, oxone, or
sodium periodate. Inert solvents may include, but are
not limited to, alkanones (3 to 10 carbons, preferably
acetone), water, alkyl alcohols (1 to 6 carbons),
aromatic hydrocarbons (preferably benzene or toluene) or
haloalkanes of 1 to 10 carbons and 1 to 10 halogens

-67-


CA 02259583 1999-01-04

WO 98/03510 PCT/US97/13072
(preferably dichloromethane) or combinations thereof.
The choices of oxidant and solvent are known to those
skilled in the art (cf. Uemura, S., Oxidation of Sulfur,
Selenium and Tellurium, in Comprehensive Organic
Synthesis, Trost, B.M. ed., (Elmsford, NY: Pergamon
Press, 1991), 7, 762-769). Preferred reaction
temperatures range from -20 C to 100 C. Compounds of
Formula (13) (Formula (1) where R3 is S(O)nR13, n is 1,2)
may then be reacted with compounds of Formula R3H to
give compounds of Formula (1), using the same conditions
and reagents as were used for the conversion of
compounds of Formula (8) to compounds of Formula (1) as
outlined for Scheme (1) above.
Compounds of Formula (1), where R3 may be -NR8COR7,
-N(COR7 )2r -NR8CONR6R7, -NR8C02R13, -NR6R7, -NR8S02R7,
may be prepared from compounds of Formula (7), where Y
is NH, by the procedures depicted in Scheme 3.

SCHEME 3

Y R
3
alkylating, sulfonylatinq
HN N---- N or acylating agents N
Z + / - base, solvent A N Z
Rl N \ \ \
R1 N
Ar Ar
(7) Y = NH (l~

A=N;
R3 = NR6R7, NR8COR7,
N (COR7) 2, NR8CONR6R7,
NRgC02R13
Reaction of compounds of Formula (7), where Y is NH,
with alkylating agents, sulfonylating agents or
acylating agents or sequential reactions with

-68-

T


CA 02259583 1999-01-04

WO 98/03510 PCT/US97/13072
combinations thereof, in the presence or absence of a
base in an inert solvent at reaction temperatures
ranging from -80 C to 250 C may afford compounds of
Formula (1), where R3 may be -NR8COR7, -N(COR7 )2,
-NRBCONR6R7, -NR8C02R13, -NR6R7, -NR8SO2R7. Alkylating
agents may include, but are not limited to, Cl-C10 alkyl
-halides, -tosylates, -mesylates or -triflates; C1-C10
haloalkyl(1 - 10 halogens)-halides, -tosylates,
-mesylates or -triflates; C2-Cg alkoxyalkyl-halides,
-tosylates, -mesylates or -triflates; C3-C6 cycloalkyl-
halides, -tosylates, -mesylates or -triflates; C4-
C12 cycloalkylalkyl-halides, -tosylates, -mesylates or
-triflates; aryl(Cl-Cq alkyl)-halides, -tosylates,
-mesylates or -triflates; heteroaryl(Cl-C4 alkyl)-
halides, -tosylates, -mesylates or -triflates; or
heterocyclyl(Cl-C4 alkyl)-halides, -tosylates,
-mesylates or -triflates. Acylating agents may include,
but are not limited to, C1-C10 alkanoyl halides or
anhydrides, C1-C10 haloalkanoyl halides or anhydrides
with 1 - 10 halogens, C2-C8 alkoxyalkanoyl halides or
anhydrides, C3-C6 cycloalkanoyl halides or anhydrides,
C4-C12 cycloalkylalkanoyl halides or anhydrides, aroyl
halides or anhydrides, aryl(C1-Cq) alkanoyl halides or
anhydrides, heteroaroyl halides or anhydrides,
heteroaryl(Cl-C4) alkanoyl halides or anhydrides,
heterocyclylcarboxylic acid halides or anhydrides or
heterocyclyl(Cl-C4) alkanoyl halides or anhydrides.
Sulfonylating agents include, but are not limited to,
Cl-C10 alkylsulfonyl halides or anhydrides, C1-C10
haloalkylsulfonyl halides or anhydrides with 1 - 10
halogens, C2-C8 alkoxyalkylsulfonyl halides or
anhydrides, C3-C6 cycloalkylsulfonyl halides or
anhydrides, C4-C12 cycloalkylalkylsulfonyl halides or
anhydrides, arylsulfonyl halides or anhydrides, aryl(C1-
C4 alkyl)-, heteroarylsulfonyl halides or anhydrides,
heteroaryl(C1-C4 alkyl)sulfonyl halides or anhydrides,

-69-


CA 02259583 1999-01-04

WO 98/03510 PCT/US97/13072
heterocyclylsulfonyl halides or anhydrides or
heterocyclyl(C1-C4 alkyl)sulfonyi halides or anhydrides.
Bases may include, but are not limited to, alkali metal
hydrides (preferably sodium hydride), alkali metal
alkoxides (1 to 6 carbons)(preferably sodium methoxide
or sodium ethoxide), alkaline earth metal hydrides,
alkali metal dialkylamides (preferably lithium di-
isopropylamide), alkali metal carbonates, alkali metal
bis(trialkylsilyl)amides (preferably sodium
bis(trimethylsilyl)amide), trialkyl amines (prefereably
di-isopropylethyl amine) or aromatic amines (preferably
pyridine). Inert solvents may include, but are not
limited to, alkyl alcohols (1 to 8 carbons, preferably
methanol or ethanol), lower alkanenitriles (1 to 6
carbons, preferably acetonitrile), dialkyl ethers
(preferably diethyl ether), cyclic ethers (preferably
tetrahydrofuran or 1,4-dioxane), N,N-dialkylformamides
(preferably dimethylform3mide), N,N-dialkylacetamides
(preferably dimethylacetamide), cyclic amides
(preferably N-methylpyrrolidin-2-one), dialkylsulfoxides
(preferably dimethylsulfoxide) or aromatic hydrocarbons
(preferably benzene or toluene). Preferred reaction
temperatures range from 0 C to 100 C.
Scheme 4 delineates procedures, which may be
employed to prepare intermediate compounds of Formula
(7), where Y is 0, S and Z is CR2.

-70-

T


CA 02259583 1999-01-04

WO 98/03510 PCTIUS97/13072
SCHEME 4

0
R2CORb, base, NC NH2NH2 - H2O,
ArCH2CN solvent R2 solvent

Ar (3)
NH

~
Rl (5) ORc N N ~T \ R2 + / - acid NH HN
solvent R
2
H2N R1 S
Ar
(4) (6)

Y
Y=C (Rd) 2, base, EN
solvent 2
R1 N
Ar
(7) Y= 0, S; Z CR2
Compounds of the formula ArCH2CN are reacted with
compounds of the formula R2CORb, where R2 is defined
above and Rb is halogen, cyano, lower alkoxy (1 to 6
carbons) or lower alkanoyloxy (1 to 6 carbons), in the
presence of a base in an inert solvent at reaction
temperatures ranging from -78 C to 200 C to afford
compounds of Formula (3). Bases may include, but are
not limited to, alkali metal hydrides (preferably sodium
hydride), alkali metal alkoxides (1 to 6
carbons)(preferably sodium methoxide or sodium
ethoxide), alkaline earth metal hydrides, alkali metal

-71-


CA 02259583 1999-01-04

WO 98/03510 PCT/US97/13072
dialkylamides (preferably lithium di-isopropylamide),
alkali metal carbonates, alkali metal hydroxides, alkali
metal bis(trialkylsilyl)amides (preferably sodium
bis(trimethylsilyl)amide), triaikyl amines (preferably
N,N-di-isopropyl-N-ethyl amine) or aromatic amines
(preferably pyridine). Inert solvents may include, but
are not limited to, alkyl alcohols (1 to 8 carbons,
preferably methanol or ethanol), lower alkanenitriles (1
to 6 carbons, preferably acetonitrile), water, dialkyl
ethers (preferably diethyl ether), cyclic ethers
(preferably tetrahydrofuran or 1,4-dioxane), N;N-
dialkylformamides (preferably dimethylformamide), N,N-
dialkylacetamides (preferably dimethylacetamide), cyclic
amides (preferably N-methylpyrrolidin-2-one),
dialkylsulfoxides (preferably dimethylsulfoxide) or
aromatic hydrocarbons (preferably benzene or toluene).
Preferred reaction temperatures range from 0 C to 1000C.
Compounds of Formula (3) may be treated with
hydrazine-hydrate in the presence of an inert solvent at
temperatures ranging from 0 C to 200 C, preferably 70 C
to 150 C, to produce compounds of Formula (4). Inert
solvents may include, but are not limited to, water,
alkyl alcohols (1 to 8 carbons, preferably methanol or
ethanol), lower alkanenitriles (1 to 6 carbons,
preferably acetonitrile), cyclic ethers (preferably
tetrahydrofuran or 1,4-dioxane), N,N-dialkylformamides
(preferably dimethylformamide), N,N-dialkylacetamides
(preferably dimethylacetamide), cyclic amides
(preferably N-methylpyrrolidin-2-one), dialkylsulfoxides
(preferably dimethylsulfoxide) or aromatic hydrocarbons
(preferably benzene or toluene). Compounds of Formula
(4) may be reacted with compounds of Formula (5) (where
Rc is alkyl (1-6 carbons)) in the presence or absence of
an acid in the presence of an inert solvent at
temperatures ranging from 0 C to 200 C to produce
compounds of Formula (6). Acids may include, but are
-72-

T


CA 02259583 1999-01-04

WO 98/03510 PCT/US97/13072
not limited to alkanoic acids of 2 to 10 carbons
(preferably acetic acid), haloalkanoic acids (2 - 10
carbons, 1-10 halogens, such as trifluoroacetic acid),.
arylsulfonic acids (preferably p-toluenesulfonic acid or
benzenesulfonic acid), alkanesulfonic acids of 1 to 10
carbons (preferably methanesulfonic acid), hydrochloric
acid, sulfuric acid or phosphoric acid. Stoichiometric
or catalytic amounts of such acids may be used. Inert
solvents may include, but are not limited to, water,
alkanenitriles (1 to 6 carbons, preferably
acetonitrile), halocarbons of 1 to 6 carbons and 1 to 6
halogens (preferably dichloromethane or chloroform),
alkyl alcohols of 1 to 10 carbons (preferably ethanol),
dialkyl ethers (4 to 12 carbons, preferably diethyl
ether or di-isopropylether) or cyclic ethers such as
dioxan or tetrahydrofuran. Preferred temperatures range
from ambient temprature to 100 C.
Compounds of Formul~a (6) may be converted to
intermediate compounds of Formula (7) by treatment with
compounds C=Y(Rd)2 (where Y is 0 or S and Rd is halogen
(preferably chlorine), alkoxy (1 to 4 carbons) or
alkylthio (1 to 4 carbons)) in the presence or absence
of a base in an inert solvent at reaction temperatures
from -50 C to 200 C. Bases may include, but are not
limited to, alkali metal hydrides (preferably sodium
hydride), alkali metal alkoxides (1 to 6
carbons)(preferably sodium methoxide or sodium
ethoxide), alkali metal carbonates, alkali metal
hydroxides, trialkyl amines (preferably N,N-di-
isopropyl-N-ethyl amine or triethylamine) or aromatic
amines (preferably pyridine). Inert solvents may
include, but are not limited to, alkyl alcohols (1 to 8
carbons, preferably methanol or ethanol), lower
alkanenitriles (1 to 6 carbons, preferably
acetonitrile), cyclic ethers (preferably tetrahydrofuran
or 1,4-dioxane), N,N-dialkylformamides (preferably

-73-


CA 02259583 1999-01-04

WO 98/03510 PCT/US97/13072
dimethylformamide), N,N-dialkylacetamides (preferably
dimethylacetamide), cyclic amides (preferably N-
methylpyrrolidin-2-one), dialkylsulfoxides (preferably
dimethylsulfoxide) or aromatic hydrocarbons (preferably
benzene or toluene). Preferred temperatures are 0 C to
150 C.
Intermediate compounds of Formula (7), where Z is
N, may be synthesized according the methods outlined in
Scheme 5.

-74-

t


CA 02259583 1999-01-04

WO 98/03510 PCT/US97/13072
SCHF.ME 5

R4'---~ N iN
RqCH2N3, base, N
reducing agent,
solvent H2N solvent
ArCH2CN
(9) Ar
NH

1
R (5) ORc
HN'~
N + / - acid, NH HN ,,N H2N solvent RI N \ \ N

(10) Ar H Ar
(11)
Y

HN N" N\
Y=C (Rd) 2, base, Z
solvent_
R1 N

Ar
(7) Y = 0, S; Z =N
Compounds of ArCH2CN are reacted with compounds of
Formula RqCH2N3 (where Rq is a phenyl group optionally
substituted by H, alkyl (1 to 6 carbons) or alkoxy (1 to
6 carbons) in the presence or absence of a base in an
inert solvent at temperatures ranging from 0 C to 200 C
to generate compounds of Formula (9). Bases may
include, but are not limited to, alkali metal hydrides

-75-


CA 02259583 1999-01-04

WO 98/03510 PCT/US97/13072
(preferably sodium hydride), alkali metal alkoxides (1
to 6 carbons)(preferably sodium methoxide, sodium
ethoxide or potassium t-butoxide), alkaline earth metal
hydrides, alkali metal dialkylamides (preferably lithium
di-isopropylamide), alkali metal carbonates, alkali
metal hydroxides, alkali metal bis(trialkylsilyl)amides
(preferably sodium bis(trimethylsilyl)amide), trialkyl
amines (preferably N,N-di-isopropyl-N-ethyl amine or
triethylamine) or aromatic amines (preferably pyridine).
Inert solvents may include, but are not limited to,
alkyl alcohols (1 to 8 carbons, preferably methanol or
ethanol), lower alkanenitriles (1 to 6 carbons,
preferably acetonitrile), dialkyl ethers (preferably
diethyl ether), cyclic ethers (preferably
tetrahydrofuran or 1,4-dioxane), N,N-dialkylformamides
(preferably dimethylformamide), N,N-dialkylacetamides
(preferably dimethylacetamide), cyclic amides
(preferably N-methylpyrr6lidin-2-one), dialkylsulfoxides
(preferably dimethylsulfoxide) or aromatic hydrocarbons
(preferably benzene or toluene). Preferred reaction
temperatures range from ambient temperature to 100 C.
Compounds of Formula (9) may be treated with a
reducing agent in an inert solvent at -100 C to 100 C to
afford products of Formula (10). Reducing agents
include, but are not limited to, (a) hydrogen gas in
combination with noble metal catalysts such as Pd-on-
carbon, Pt02, Pt-on-carbon, Rh-on-alumina or Raney
nickel, (b) alkali metals (preferably sodium) in
combination with liquid ammonia or (c) ceric ammonium
nitrate. Inert solvents may include, but are not limited
to, alkyl alcohols (1 to 8 carbons, preferably methanol
or ethanol), lower alkanenitriles (1 to 6 carbons,
preferably acetonitrile), water, dialkyl ethers
(preferably diethyl ether), cyclic ethers (preferably
tetrahydrofuran or 1,4-dioxane), N,N-dialkylformamides
(preferably dimethylformamide), N,N-dialkylacetamides
-7 6-

T


CA 02259583 1999-01-04

WO 98/03510 PCTIUS97/13072
(preferably dimethylacetamide), cyclic amides
(preferably N-methylpyrrolidin-2-one), dialkylsulfoxides
(preferably dimethylsulfoxide) or aromatic hydrocarbons
(preferably benzene or toluene). The preferred reaction
temperatures are -50 C to 60 C. Compounds of Formula
(9) are then converted to compounds of Formula (7)
(where Z is N) via intermediates of Formula (11) using
the reagents and reaction conditions outlined in Scheme
4 for the conversion of compounds of Formula (4) to
compounds of Formula (7) (where Z is CR2).
Compounds of Formula (1) may also be`prepared
from compounds of Formula (7) (where Y is 0, S and Z is
defined above) as outlined in Scheme 6:

SCHEME 6

ii R3H, + / - acid, R3
+ dehydrating agent
HN N N + - solvent A/ N ~
Z Z
Rl Rl \N

Ar Ax
(7) Y = 0, S; Z = N, CR2 (1) A=N
Compounds of Formula (7) may be reacted with compounds
of Formula R3H in the presence of a dehydrating agent in
an inert solvent at reaction temperatures ranging from
0 C to 250 C. Dehydrating agents include, but are not
limited to, P205, molecular sieves or inorganic or
organic acids. Acids may include, but are not limited
to alkanoic acids of 2 to 10 carbons (preferably acetic
acid), arylsulfonic acids (preferably p-toluenesulfonic
acid or benzenesulfonic acid), alkanesulfonic acids of 1
to 10 carbons (preferably methanesulfonic acid),
hydrochloric acid, sulfuric acid or phosphoric acid.
Inert solvents may include, but are not limited to,
-77-


CA 02259583 1999-01-04

WO 98/03510 PCT/US97/13072
alkyl alcohols (1 to 8 carbons, preferably methanol or
ethanol), lower alkanenitriles (1 to 6 carbons,
preferably acetonitrile), dialkyl ethers (preferably
glyme or diglyme), cyclic ethers (preferably
tetrahydrofuran or 1,4-dioxane), N,N-dialkylformamides
(preferably dimethylformamide), N,N-dialkylacetamides
(preferably dimethylacetamide), cyclic amides
(preferably N-methylpyrrolidin-2-one), dialkylsulfoxides
(preferably dimethylsulfoxide), aromatic hydrocarbons
(preferably benzene or toluene) or halocarbons of 1 to
10 carbons and 1 to 10 halogens (preferably chloroform).
Preferred reaction temperatures range from ambient
temperature to 1500C.
Some compounds of Formula (1) (where A is N) may
also be prepared by the methods shown in Scheme 7:
SCHEM 7

R3C(ORe)3, R3
NH HN_-, N + / - acid,

Z solvent X N'~
z
Rl N
H Rl N
Ar
(14) Ar
(1) A = N
Intermediate compounds of Formula (14), where Z is
defined above, may be reacted with compounds of Formula
R3C(ORe)3, where Re may be alkyl (1 to 6 carbons) in the
presence or absence of an acid in an inert solvent at
temperatures ranging from 0 C to 250 C. Acids may
include, but are not limited to alkanoic acids of 2 to
10 carbons (preferably acetic acid), arylsulfonic acids
(preferably p-toluenesulfonic acid or benzenesulfonic
acid), alkanesulfonic acids of 1 to 10 carbons
(preferably methanesulfonic acid), hydrochloric acid,
sulfuric acid or phosphoric acid. Stoichiometric or

-78-

..... . ...... .T


CA 02259583 1999-01-04

WO 98/03510 PCT/US97/13072
catalytic amounts of such acids may be used. Inert
solvents may include, but are not limited to, lower
alkanenitriles (1 to 6 carbons, preferably
acetonitrile), dialkyl ethers (preferably diethyl
ether), cyclic ethers (preferably tetrahydrofuran or
1,4-dioxane), N,N-dialkylformamides (preferably
dimethylformamide), N,N-dialkylacetamides (preferably
dimethylacetamide), cyclic amides (preferably N-
methylpyrrolidin-2-one), dialkylsulfoxides (preferably
dimethylsulfoxide), aromatic hydrocarbons (preferably
benzene or toluene) or haloalkanes of 1 to 10 carbons
and 1 to 10 halogens (preferably dichloromethane).
Preferred reaction temperatures range from 50 C to
150 C.
Intermediate compounds of Formula (7) may also be
synthesized by the reactions displayed in Scheme 8.
SCHEbE e

Y

Y
A )--,- N ~N
ArM, + / - catalyst,

Z solvent Rl N Z

X R1 N
(15) Y = OH, SH NR6R7; Ar
Z = N, CR2, (7) A N
X = Br, Cl, I, B(OR"")2

Compounds of Formula (15), (where Y is OH, SH, NR6R7; Z
is defined above, X is Br, Cl, I, O3SCF3 or B(OR"")2 and
RI'll is H or alkyl (1 to 6 carbons)) may be reacted with
a compound of Formula ArM (where M is halogen, alkali
metal, ZnCl, ZnBr, ZnI, MgBr, MgCl, MgI, CeC12, CeBr2 or
copper halides) in the presence or absence of an
-79-


CA 02259583 1999-01-04

WO 98/03510 PCT/US97/13072
organometallic catalyst in the presence or absence of a
base in an inert solvents at temperatures ranging from
-100 C to 200 C. Those skilled in the art will
recognize that the reagents ArM may be generated in
situ. Organometallic catalysts include, but are not
limited to, palladium phosphine complexes (such as
Pd(PPh3)4), palladium halides or alkanoates (such as
PdC12(PPh3)2 or Pd(OAc)2) or nickel complexes (such as
NiC12(PPh3)2). Bases may include, but are not limited
to, alkali metal carbonates or trialkyl amines
(preferably N,N-di-isopropyl-N-ethyl amine or
triethylamine). Inert solvents may include, but are not
limited to, dialkyl ethers (preferably diethyl ether),
cyclic ethers (preferably tetrahydrofuran or 1,4-
dioxane), N,N-dialkylformamides (preferably
dimethylformamide), N,N-dialkylacetamides (preferably
dimethylacetamide), cyclic amides (preferably N-
methylpyrrolidin-2-one), dialkylsulfoxides (preferably
dimethylsulfoxide), aromatic hydrocarbons (preferably
benzene or toluene) or water. Preferred reaction
temperatures range from -80 C to 100 C.
The choices of M and X are known to those skilled in the
art (cf. Imamoto, T., Organocerium Reagents in
Comprehensive Organic Synthesis, Trost, B.M. ed.,
(Elmsford, NY: Pergamon Press, 1991), 1, 231-250;
Knochel, P., Organozinc, Organocadmium and Organomercury
Reagents in Comprehensive Orqanic Synthesis, Trost, B.M.
ed., (Elmsford, NY: Pergamon Press, 1991), 1, 211-230;
Knight, D.W., Coupling Reactions between sp2 Carbon
Centers, in Comprehensive Organic Synthesis, Trost, B.M.
ed., (Elmsford, NY: Pergamon Press, 1991), 3, 481-520).
Compounds of Formula (1) may also be prepared using
the methods shown in Scheme 9.
-80-

. . . . . . . . . . . .. . . ., . _._ .. . T.


CA 02259583 1999-01-04

WO 98/03510 PCT/US97/13072
R3 SCFIEME 9

N
R3
A N~, Z ArM, + - catalyst, A~ N~N
~ ..~ solvent ~\Z
R1 N ~ ~=~
X R1 N
Ar
(16) X = Br, Cl, Z, (1)
B(OR"")2r 03SCF3

Compounds of Formula (16), where A, Z, R1 and R3 are
defined above and X is Br, Cl, I, 03SCF3 or B(OR"")z and
R"" is H or alkyl (1 to 6 carbons)) may be reacted with
a compound of Formula ArM (where M is halogen, alkali
metal, ZnCl, ZnBr, ZnI, MgBr, MgCl, MgI, CeCl2, CeBr2 or
copper halides) in the presence or absence of an
organometallic catalyst in the presence or absence of a
base in an inert solvents at temperatures ranging from
-100 C to 2000C. Those skilled in the art will
recognize that the reagents ArM may be generated in situ
(see the above references in Comnrehensive Organic
Svnthesis). Organometallic catalysts include, but are
not limited to, palladium phosphine complexes (such as
Pd(PPh3)4), palladium halides or alkanoates (such as
PdC12(PPh3)2 or Pd(OAc)2) or nickel complexes (such as
NiC12(PPh3)2). Bases may include, but are not limited
to, alkali metal carbonates or trialkyl amines
(preferably N,N-di-isopropyl-N-ethyl amine or
triethylamine). Inert solvents may include, but are not
limited to, dialkyl ethers (preferably diethyl ether),
cyclic ethers (preferably tetrahydrofuran or 1,4-
dioxane), N,N-dialkylformamides (preferably
dimethylformamide), N,N-dialkylacetamides (preferably
dimethylacetamide), cyclic amides (preferably N-
methylpyrrolidin-2-one), dialkylsulfoxides (preferably
dimethylsulfoxide), aromatic hydrocarbons (preferably

-81-


CA 02259583 1999-01-04

WO 98/03510 PCT/US97/13072
benzene or toluene) or water. Preferred reaction
temperatures range from -80 C to 100 C.
Intermediate compounds of Formula (7)(where Y is 0,
S, NH, Z is CR2 and R1, R2 and Ar are defined as above)
may be prepared as illustrated in Scheme 10.

SCHEIME 10

Y
O N
NH2NH2 (C=Y) NH2 H2N rj/
N +/ - base or acid, R2
R2 solvent
H2N
Ar
(3) Ar
(17)
Y

R1C (OR ) 3, N
+ / - acid, HN \\
solvent \ :~
JZ
R1 N
Ar
(7) Y = 0, S, NH; Z = CR2,
Compounds of Formula (3) may be reacted with compounds
of Formula H2NNH(C=Y)NH2, where Y is 0, S or NH, in the
presence or absence of a base or acid in an inert
solvent at temperatures from 0 C to 250 C to produce
compounds of Formula (17). Acids may include, but are
not limited to alkanoic acids of 2 to 10 carbons
(preferably acetic acid), arylsulfonic acids (preferably
p-toluenesulfonic acid or benzenesulfonic acid),
alkanesulfonic acids of 1 to 10 carbons (preferably
methanesulfonic acid), hydrochloric acid, sulfuric acid
or phosphoric acid. Stoichiometric or catalytic amounts

-82-

T


CA 02259583 1999-01-04

WO 98/03510 PCT/US97/13072
of such acids may be used. Bases may include, but are
not limited to, alkali metal hydrides (preferably sodium
hydride), alkali metal alkoxides (1 to 6
carbons)(preferably sodium methoxide or sodium
ethoxide), alkaline earth metal hydrides, alkali metal
dialkylamides (preferably lithium di-isopropylamide),
alkali metal bis(trialkylsilyl)amides (preferably sodium
bis(trimethylsilyl)amide), trialkyl amines (preferably
N,N-di-isopropyl-N-ethyl amine or triethylamine) or
aromatic amines (preferably pyridine). Inert solvents
may include, but are not limited to, alkyl alcohols (1
to 6 carbons), lower alkanenitriles (1 to 6 carbons,
preferably acetonitrile), dialkyl ethers (preferably
diethyl ether), cyclic ethers (preferably
tetrahydrofuran or 1,4-dioxane), N,N-dialkylformamides
(preferably dimethylformamide), N,N-dialkylacetamides
(preferably dimethylacetamide), cyclic amides
(preferably N-methylpyrrolidin-2-one), dialkylsulfoxides
(preferably dimethylsulfoxide), aromatic hydrocarbons
(preferably benzene or toluene) or haloalkanes of 1 to
10 carbons and 1 to 10 halogens (preferably
dichloromethane).
Preferred reaction temperatures range from 0 C to
150 C. Compounds of Formula (17) may then be reacted
with compounds of Formula R3C(ORe)3, where Re may be
alkyl (1 to 6 carbons) in the presence or absence of an
acid in an inert solvent at temperatures ranging from
0 C to 250 C. Acids may include, but are not limited to
alkanoic acids of 2 to 10 carbons (preferably acetic
acid), arylsulfonic acids (preferably p-toluenesulfonic
acid or benzenesulfonic acid), alkanesulfonic acids of 1
to 10 carbons (preferably methanesulfonic acid),
hydrochloric acid, sulfuric acid or phosphoric acid.
Stoichiometric or catalytic amounts of such acids may be
used. Inert solvents may include, but are not limited
to, lower alkanenitriles (1 to 6 carbons, preferably
-83-


CA 02259583 1999-01-04

WO 98/03510 PCTIUS97/13072
acetonitrile), dialkyl ethers (preferably diethyl
ether), cyclic ethers (preferably tetrahydrofuran or
1,4-dioxane), N,N-dialkylformamides (preferably
dimethylformamide), N,N-dialkylacetamides (preferably
dimethylacetamide), cyclic amides (preferably N-
methylpyrrolidin-2-one), dialkylsulfoxides (preferably
dimethylsulfoxide), aromatic hydrocarbons (preferably
benzene or toluene) or haloalkanes of 1 to 10 carbons
and 1 to 10 halogens (preferably dichloromethane).
Preferred reaction temperatures range from 50 C to
150 C.
In Scheme 11, the procedures which may be used to
convert compounds of Formula (1), where R3 is COR7,
C02R7, NR8COR7 and CONR6R7, to other compounds of Formula
(1) , where R3 is CH (OH) R7, CH2OH, NR8CH2R7 and CH2NR6R7
by treatment with a reducing agent in an inert solvent
at temperatures ranging from -80 C to 250 C.

SCHEI~ 11
R3
R3
A ) N reducing agent,
Z solvent A ) N "-"N

Z 00. R1 \N \
~ R1 N

Ar
(1) R3 = COR7, C02R7,
CONR6R7 (1) R3 = C( OH ) R~ ,
CH2OH,
CH2NR6R7

Reducing agents include, but are not limited to, alkali
metal or alkaline earth metal borohydrides (preferably
lithium or sodium borohydride), borane, dialkylboranes
(such as di-isoamylborane), alkali metal aluminum
hydrides (preferably lithium aluminum hydride), alkali
metal (trialkoxy)aluminum hydrides, or dialkyl aluminum
-84-

T


CA 02259583 1999-01-04

WO 98/03510 PCT/US97/13072
hydrides (such as di-isobutylaluminum hydride). Inert
solvents may include, but are not limited to, alkyl
alcohols (1 to 6 carbons), dialkyl ethers (preferably
diethyl ether), cyclic ethers (preferably
tetrahydrofuran or 1,4-dioxane), aromatic hydrocarbons
(preferably benzene or toluene). Preferred reaction
temperatures range from -80 C to 100 C.
In Scheme 12, the procedures are shown which may be
used to convert compounds of Formula (1), where R3 is
COR7 or C02R7, to other compounds of Formula (1), where
R3 is C(OH)(R7 )2 by treatment with a reagent of Formula
R7M in an inert solvent at temperatures ranging from
-80 C to 250 C.

SCSEME 12
R3
R3
A) N
\\ reducing agent, ;ro _-,p
Z solvent A N
R 1
R N
Ar
Ar
(1) R3 = COR7, CO2R7, (1) R3 = C(O$) (R7 ) 2
M is halogen, alkali metal, ZnCl, ZnBr, ZnI, MgBr, MgCl,
MgI, CeC12, CeBr2 or copper halides. Inert solvents may
include, but are not limited to, dialkyl ethers
(preferably diethyl ether), cyclic ethers (preferably
tetrahydrofuran) or aromatic hydrocarbons (preferably
benzene or toluene). Preferred reaction temperatures
range from -80 C to 100 C.
Compounds of Formula (1), where R3 may be -NR8COR7,
-N(COR7 )2, -NR8CONR6R7, -NR8CO2R13, -NR6R7, -NR8SO2R7,
may be synthesized as depicted in Scheme 13.

-85-


CA 02259583 1999-01-04

WO 98/03510 PCT/US97/13072
SCHEME 13

0
NC
R1 NH2
(18) R R
+ / - base, Ni N
= solvent

N Rl
HNZ
Ar
(19)
H2N

Ar
(4) Z = CR2
(10) Z = N

R3
alkylating, sulfonylatinq
or acylating agents
N
+ / - base,solvent A N~
Z
Rl N

Ar
(1)
A = CR
R3 =NR6R7 , NRBCOR7,
N(COR7)2,
NR8CONR6R7,
NR8C02R13

Reaction of compounds of Formula (18), where R and R1
are defined above, with compounds of Formula (4) or (10)
in the presence or absence of base in an inert solvent
may produce compounds of Formula (19) at temperatures
-86-

T


CA 02259583 1999-01-04

WO 98/03510 PCT/US97/13072
ranging from -50 C to 2500C. Bases may include, but are
not limited to, alkali metal hydrides (preferably sodium
hydride), alkali metal alkoxides (1 to 6
carbons)(preferably sodium methoxide or sodium
.5 ethoxide), alkaline earth metal hydrides, alkali metal
dialkylamides (preferably lithium di-isopropylamide),
alkali metal carbonates, alkali metal
bis(trialkylsilyl)amides (preferably sodium
bis(trimethylsilyl)amide), trialkyl amines (prefereably
di-isopropylethyl amine) or aromatic amines (preferably
pyridine). Inert solvents may include, but are not
limited to, alkyl alcohols (1 to 8 carbons, preferably
methanol or ethanol), lower alkanenitriles (1 to 6
carbons, preferably acetonitrile), dialkyl ethers
(preferably diethyl ether), cyclic ethers (preferably
tetrahydrofuran or 1,4-dioxane), N,N-dialkylformamides
(preferably dimethylformamide), N,N-dialkylacetamides
(preferably dimethylacetamide), cyclic amides
(preferably N-methylpyrrolidin-2-one), dialkylsulfoxides
(preferably dimethylsulfoxide) or aromatic hydrocarbons
(preferably benzene or toluene). Preferred reaction
temperatures range from 0 C to 1000C.
Compounds of Formula (19) may then be reacted with
alkylating agents, sulfonylating agents or acylating
agents or sequential reactions with combinations
thereof, in the presence or absence of a base in an
inert solvent at reaction temperatures ranging from
-80 C to 250 C may afford compounds of Formula (1),
where R3 may be -NR8COR7, -N(COR7)2, -NR8CONR6R7,
-NR8C02R13, -NR6R7f -NR8S02R7. Alkylating agents may
include, but are not limited to, C1-CIO alkyl -halides,
-tosylates, -mesylates or -triflates; C1-C10 haloalkyl(1
- 10 halogens)-halides, -tosylates, -mesylates or
-triflates; C2-C8 alkoxyalkyl-halides, -tosylates,
-mesylates or -triflates; C3-C6 cycloalkyl-halides,
-tosylates, -mesylates or -triflates; C4-

-87-


CA 02259583 1999-01-04

WO 98/03510 PCT/US97/13072
C12 cycloalkylalkyl-halides, -tosylates, -mesylates or
-triflates; aryl(C1-C4 alkyl)-halides, -tosylates,
-mesylates or -triflates; heteroaryl(Cl-C4 alkyl)-
halides, -tosylates, -mesylates or -triflates; or
heterocyclyl(C1-C4 alkyl)-halides, -tosylates,
-mesylates or -triflates. Acylating agents may include,
but are not limited to, C1-C10 alkanoyl halides or
anhydrides, C1-C10 haloalkanoyl halides or anhydrides
with 1 - 10 halogens, C2-C8 alkoxyalkanoyl halides or
anhydrides, C3-C6 cycloalkanoyl halides or anhydrides,
C4-C12 cycloalkylalkanoyl halides or anhydrides, aroyl
halides or anhydrides, aryl(C1-Cq) alkanoyl halides or
anhydrides, heteroaroyl halides or anhydrides,
heteroaryl(C1-Cq) alkanoyl halides or anhydrides,
heterocyclylcarboxylic acid halides or anhydrides or
heterocyclyl(C1-C4) alkanoyl halides or anhydrides.
Sulfonylating agents include, but are not limited to,
C1-C10 alkylsulfonyl halides or anhydrides, C1-C10
haloalkylsulfonyl halides or anhydrides with 1 - 10
halogens, C2-C8 alkoxyalkylsulfonyl halides or
anhydrides, C3-C6 cycloalkylsulfonyl halides or
anhydrides, C4-C12 cycloalkylalkylsulfonyl halides or
anhydrides, arylsulfonyl halides or anhydrides, aryl(C1-
C4 alkyl)-, heteroarylsulfonyl halides or anhydrides,
heteroaryl(C1-C4 alkyl)sulfonyl halides or anhydrides,
heterocyclylsulfonyl halides or anhydrides or
heterocyclyl(C1-C4 alkyl)sulfonyl halides or anhydrides.
Bases may include, but are not limited to, alkali metal
hydrides.(preferably sodium hydride), alkali metal
alkoxides (1 to 6 carbons)(preferably sodium methoxide
or sodium ethoxide), alkaline earth metal hydrides,
alkali metal dialkylamides (preferably lithium di-
isopropylamide), alkali metal carbonates, alkali metal
bis(trialkylsilyl)amides (preferably sodium
bis(trimethylsilyl)amide), trialkyl amines (prefereably
di-isopropylethyl amine) or aromatic amines (preferably
-88-

T


CA 02259583 1999-01-04

WO 98/03510 PCT/US97/13072
pyridine). Inert solvents may include, but are not
limited to, alkyl alcohols (1 to 8 carbons, preferably
methanol or ethanol), lower alkanenitriles (1 to 6
carbons, preferably acetonitrile), dialkyl ethers
(preferably diethyl ether), cyclic ethers (preferably
tetrahydrofuran or 1,4-dioxane), N,N-dialkylformamides
(preferably dimethylformamide), N,N-dialkylacetamides
(preferably dimethylacetamide), cyclic amides
(p.:eferably N-methylpyrrolidin-2-one), dialkylsulfoxides
(preferably dimethylsulfoxide) or aromatic hydrocarbons
(preferably benzene or toluene). Preferred reaction
temperatures range from 0 C to 100 C.
Compounds of Formula (1), where A is CR and R is
defined above, may be synthesized by the methods
depicted in Scheme 14.

-89-


CA 02259583 1999-01-04

WO 98/03510 PCT/US97/13072
SCHEME 14

0 0

HN/ N 3R Ayk Rl R3
Z R

N
H N (20) A N~
2 + / - base, Z
Ar solvent
Rl
(4) Z = CR2
(10) Z = N (1) Ar
A = CR

O
Re02
R1
R3S, + / - base,
R + / - solvent
(21)
+ / - base,
solvent
OH X

N N halogenating agent N~
or sulfonylating agent
Z Z
+ / base,
+ / - solvent \
Rl R1 N
Ar Ar
(22) (23)
Compounds of Formula (4) or (10) may be treated with
compounds of Formula (20), where R1 and R3 are defined
above in the presence or absence of base in an inert
solvent at temperatures ranging from 0 C to 2500C to
give compounds of Formula (1), where A is CR and R is
defined above. Bases may include, but are not limited

-90-

T


CA 02259583 1999-01-04

WO 98/03510 PCT/US97/13072
to, alkali metal hydrides (preferably sodium hydride),
alkali metal alkoxides (1 to 6 carbons)(preferably
sodium methoxide or sodium ethoxide), alkaline earth
metal hydrides, alkali metal dialkylamides (preferably
lithium di-isopropylamide), alkali metal carbonates,
alkali metal bis(trialkylsilyl)amides (preferably sodium
bis(trimethylsilyl)amide), trialkyl amines (preferably
di-isopropylethyl amine) or aromatic amines (preferably
pY_idine). Inert solvents may include, but are not
limited to, alkyl alcohols (1 to 8 carbons, preferably
methanol or ethanol), lower alkanenitriles (1 to 6
carbons, preferably acetonitrile), dialkyl ethers
(preferably diethyl ether), cyclic ethers (preferably
tetrahydrofuran or 1,4-dioxane), N,N-dialkylformamides
(preferably dimethylformamide), N,N-dialkylacetamides
(preferably dimethylacetamide), cyclic amides
(preferably N-methylpyrrolidin-2-one), dialkylsulfoxides
(preferably dimethylsulfoxide) or aromatic hydrocarbons
(preferably benzene or toluene). Preferred reaction
temperatures range from 0 C to 100 C. Alternatively,
compounds of Formula (1) where A is CR and R is defined
above, may be synthesized through intermediates (22) and
(23).
Compounds of Formula (4) or (10) may be treated
with compounds of Formula (21), where R1 is defined
above and Re is alkyl (1 - 6 carbons), in the presence
or absence of base in an inert solvent at temperatures
ranging from 0 C to 250 C to give compounds of Formula
(1), where A is CR and R is defined above. Bases may
include, but are not limited to, alkali metal hydrides
(preferably sodium hydride), alkali metal alkoxides (1
to 6 carbons)(preferably sodium methoxide or sodium
ethoxide), alkaline earth metal hydrides, alkali metal
dialkylamides (preferably lithium di-isopropylamide),
alkali metal carbonates, alkali metal
bis(trialkylsilyl)amides (preferably sodium
-91-


CA 02259583 1999-01-04

WO 98/03510 PCTlUS97/13072
bis(trimethylsilyl)amide), trialkyl amines (prefereably
di-isopropylethyl amine) or aromatic amines (preferably
pyridine). Inert solvents may include, but are not
limited to, alkyl alcohols (1 to 8 carbons, preferably'
methanol or ethanol), lower alkanenitriles (1 to 6
carbons, preferably acetonitrile), dialkyl ethers
(preferably diethyl ether), cyclic ethers (preferably
tetrahydrofuran or 1,4-dioxane), N,N-dialkylformamides
(preferably dimethylformamide), N,N-dialkylacetamides
(preferably dimethylacetamide), cyclic amides
(preferably N-methylpyrrolidin-2-one), dialkylsulfoxides
(preferably dimethylsulfoxide) or aromatic hydrocarbons
(preferably benzene or toluene). Preferred reaction
temperatures range from 0 C to 100 C. Compounds of
Formula (22) may be treated with a halogenating agent or
sulfonylating agent in the presence or absence of a base
in the presence or absence of an inert solvent at
reaction temperatures ranging from -80 C to 250 C to
give products of Formula (23) (where X is halogen,
alkanesulfonyloxy, arylsulfonyloxy or haloalkane-
sulfonyloxy). Halogenating agents include, but are not
limited to, SOC12, POC13, PC13, PC15, POBr3, PBr3 or
PBrs. Sulfonylating agents include, but are not limited
to, alkanesulfonyl halides or anhydrides (such as
methanesulfonyl chloride or methanesulfonic acid
anhydride), arylsulfonyl halides or anhydrides (such as
p-toluenesulfonyl chloride or anhydride) or
haloalkylsulfonyl halides or anhydrides (preferably
trifluoromethanesulfonic anhydride). Bases may include,
but are not limited to, alkali metal hydrides
(preferably sodium hydride), alkali metal alkoxides (1
to 6 carbons)(preferably sodium methoxide or sodium
ethoxide), alkaline earth metal hydrides, alkali metal
dialkylamides (preferably lithium di-isopropylamide),
alkali metal bis(trialkylsilyl)amides (preferably sodium
bis(trimethylsilyl)amide), trialkyl amines (preferably
-92-

r


CA 02259583 1999-01-04

WO 98/03510 PCT/US97/13072
N,N-di-isopropyl-N-ethyl amine or triethylamine) or
aromatic amines (preferably pyridine). Inert solvents
may include, but are not limited to, lower
alkanenitriles (1 to 6 carbons, preferably
acetonitrile), dialkyl ethers (preferably diethyl
ether), cyclic ethers (preferably tetrahydrofuran or
1,4-dioxane), N,N-dialkylformamides (preferably
dimethylformamide), N,N-dialkylacetamides (preferably
di,nethylacetamide), cyclic amides (preferably N-
methylpyrrolidin-2-one), dialkylsulfoxides (preferably
dimethylsulfoxide), aromatic hydrocarbons (preferably
benzene or toluene) or haloalkanes of 1 to 10 carbons
and 1 to 10 halogens (preferably dichloromethane).
Preferred reaction temperatures range from -20 C to
100 C.
Compounds of Formula (23) may be reacted with
compounds of Formula R3H (where R3 is defined as above
except R3 is not SH, COR7, C02R7, aryl or heteroaryl) in
the presence or absence of a base in the presence or
absence of an inert solvent at reaction temperatures
ranging from -80 C to 2500C to generate compounds of
Formula (1). Bases may include, but are not limited to,
alkali metal hydrides (preferably sodium hydride),
alkali metal alkoxides (1 to 6 carbons)(preferably
sodium methoxide or sodium ethoxide), alkaline earth
metal hydrides, alkali metal dialkylamides (preferably
lithium di-isopropylamide), alkali metal carbonates,
alkali metal bicarbonates, alkali metal
bis(trialkylsilyl)amides (preferably sodium
bis(trimethylsilyl)amide), trialkyl amines (preferably
N,N-di-isopropyl-N-ethyl amine) or aromatic amines
(preferably pyridine). Inert solvents may include, but
are not limited to, alkyl alcohols (1 to 8 carbons,
preferably methanol or ethanol), lower alkanenitriles (1
to 6 carbons, preferably acetonitrile), dialkyl ethers
(preferably diethyl ether), cyclic ethers (preferably
-93-


CA 02259583 1999-01-04

WO 98/03510 PCT/US97/13072
tetrahydrofuran or 1,4-dioxane), N,N-dialkyiformamides
(preferably dimethylformamide), N,N-dialkylacetamides
(preferably dimethylacetamide), cyclic amides
(preferably N-methylpyrrolidin-2-one), dialkylsulfoxid-es
(preferably dimethylsulfoxide), aromatic hydrocarbons
(preferably benzene or toluene) or haloalkanes of 1 to
carbons and 1 to 10 halogens (preferably
dichloromethane). Preferred reaction temperatures range
from 0 C to 140 C.
10 Some compounds of Formula (1) may also be prepared
using the methods shown in Scheme 15.

-94-

1


CA 02259583 1999-01-04

WO 98/03510 PCT/US97/13072
SCIiFbJ$ 15
0
CN

RO j--r N$2NH2, Z~ (C_Y) ~2 ,
+ / - a(2 4) Ar - acid,
solvant aolvent
Y
HN
OH H2N N" \
OH
H2N

(25) Ar H2N

. (26) Y = 0, SAr
For A = N: For A= CR:
1) R1C (=NH) OR. 1) Rl (C--O) CFiR (C=Y) OR,
+/- acid, solvent +/- baso or acid,
2) Y=C(Rd)Z solvent
+/- baso, solvent
R1C(ORQ)3
+/- solvent

YH R3
N JN \ N
A)\ N~ see text A \\
OH ~ Z
1/ ` ' ` 1 \ \
R N R N
Ar Ar
27)Y = 0, S (1) Z = CR2
A compound of Formula (24) (Rc is a lower alkyl group
and Ar is defined as above) may be reacted with
hydrazine in the presence or absence of an inert solvent
to afford an intermediate of Formula (25), where Ar is
defined as above. The conditions employed are similar to
those used for the preparation of intermediate of
Formula (4) from compound of Formula (3) in Scheme 4.
Compounds of Formula (25), where A is N, may be reacted
with reagents of the formula R1C(=NH)ORe, where R1 is
-95-


CA 02259583 1999-01-04

WO 98/03510 PCTIUS97/13072
defined above and Re is a lower alkyl group) in the
presence or absence of an acid in an inert solvent,
followed by reaction with a compound of formula
YisC(Rd)2 (where Y is 0 or S and Rd is halogen
(preferably chlorine), alkoxy (1 to 4 carbons) or
alkylthio (1 to 4 carbons)) in the presence or absence
of a base in an inert solvent to give compounds of
Formula (27) (where A is N and Y is 0, S). The
conditions for these transformations are the same as
those employed for the conversions of compound of
Formula (4) to compound of Formula (7) in Scheme 4.
Alternatively, compounds of Formula (25), where A
is CR, may be reacted with compounds of the formula
R1(C=0)CHR(C=Y)ORc (where R1 and R are defined as above
and Rc is a lower alkyl group) to give a compound of
Formula (27) (where A is CR) using conditions similar to
those employed for the conversion of compounds of
Formula (21) to compounds, of Formula (22) in Scheme 14.
Intermediates of Formula (27) (where Y is 0) may be
treated with halogenating agents or sulfonylating agents
in the presence or absence of a base in an inert
solvent, followed by reaction with R3H or R2H in the
presence or absence of a base in an inert solvent to
give compounds of Formula (1) (where Z is CR2).
It will be recognized by those skilled in the art
that various combinations of halogenating agents,
sulfonylating agents, R3H or R2H may be used in
different orders of reaction sequences in Scheme 15 to
afford compounds of Formula (1). For example, in some
cases, it may be desirable to react compounds with
stoichiometric amounts of halogenating agents or
sulfonylating agents, react with R2H (or R3H), then
repeat the reaction with halogenating agents or
sulfonylating agents and react with R3H (or R2H) to give
compounds of Formula (1). The reaction conditions and
reagents used for these conversions are similar to the
-96-

1


CA 02259583 1999-01-04

WO 98/03510 PCTIUS97/13072
ones employed for the conversion of intermediate
compounds of Formulae (22) to (23) to (1) in Scheme 14
(for A is CR) or the conversion of intermediate
compounds of Formulae (7) to (8) to (1) in Scheme 1
(where A is N).
Alternatively, compounds of Formula (27) (where Y
is S) may be converted to compounds of Formula (1) in
Scheme 15. Intermediate compounds of Formula (27) may
be alkylated with a compound RfX (where Rf is lower
alkyl and X is halogen, alkanesulfonyloxy or
haloalkanesulfonyloxy) in an inert solvent, (then
optionally oxidized with an oxidizing agent in an inert
solvent) and then reacted with R3H in the presence or
absence of a base in an inert solvent to give a compound
of Formula (1). The conditions and reagents employed
are similar to those used in the conversion of
intermediate compounds of Formulae (7) to (12) (or to
(13)) to compounds of Formula (1) in Scheme 2.
Compounds of Formula (1) may be prepared from
compounds of Formula (24), using an alternate route as
depicted in Scheme 15. Compounds of Formula (24) may be
converted to compounds of Formula (27) via reaction with
compounds of formula NH2NH(C=NH)NH2 in the presence or
absence of an acid in an inert solvent, followed by
reaction with compounds R1C(ORc)3 (where R. is lower
alkyl and R1 is defined as above), using the conditions
employed for the conversion of compounds of Formulae (3)
to (17) to (7) in Scheme 10.
Some compounds of Formula (2) may be prepared by
the methods illustrated in Scheme 16.

-97-


CA 02259583 1999-01-04

WO 98/03510 PCT/US97/13072
SCHEME 16

YE YH
~
R14X, +/- base 14
~
solvent A O
O om- Ri \N Rl ~ N

Ar Ar
27b) Y= O, S ( 28)Y = 0, S
see text

3
R3 R14X, R
1 ~
N +j- base, 14
N Z solvent N

R1 \ N
Ar Am
(1) Z = COH (2)

Compounds of Formula (27b) may be treated with various
alkylating agents R14X (where R14 is defined above and X
is halogen, alkanesulfonyloxy or haloalkanesulfonyloxy)
in the presence or absence of a base in an inert solvent
to afford structures of Formula (28). Compounds of
Formula (28) (Y is 0) may then be converted to compounds
of Formula (2) by treatment with halogenating agents or
sulfonylating agents in the presence or absence of a
base in an inert solvent, followed by reaction with R3H
in the presence or absence of a base in an inert solvent
to give compounds of Formula (2). The reaction
conditions used for these conversions are similar to the
-98-
r


CA 02259583 1999-01-04

WO 98/03510 PCTIUS97/13072
ones employed for the conversion of intermediate
compounds (22) to (23) to (1) in Scheme 14 (for A is CR)
or the conversion of intermediate compounds of Formulae
(7) to (8) to (1) in Scheme 1 (where A is N).
Alternatively, compounds of Formula (28) (Y is S) may be
alkylated with a compound RfX (where Rf is lower alkyl
and X is halogen, alkanesulfonyloxy or
haloalkanesulfonyloxy) in an inert solvent, (then
op-..ionally oxidized with an oxidizing agent in an inert
solvent) and then reacted with R3H in the presence or
absence of a base in an inert solvent to give a compound
of Formula (1). The conditions and reagents employed
are similar to those used in the conversion of
intermediate compounds of Formulae (7) to (12) (or to
(13)) to compounds of Formula (1) in Scheme 2.
Compounds of Formula (1), where Z is COH, may be
converted to compounds of Formula (2) as illustrated in
Scheme 16. Treatment with various alkylating agents
R14X (where R14 is defined above and X is halogen,
alkanesulfonyloxy or haloalkanesulfonyloxy) in the
presence or absence of a base in an inert solvent to
afford structures (2). It will be recognized by one
skilled in the art that the methods used in Scheme 16
may also be used to prepare compounds of Formula (1)
where Z is COR7.
For Scheme 16, the terms "base" and " inert
solvent" may have the meanings given below. Bases may
include, but are not limited to, alkali metal hydrides
(preferably sodium hydride), alkali metal alkoxides (1
to 6 carbons)(preferably sodium methoxide or sodium
ethoxide), alkaline earth metal hydrides, alkali metal
dialkylamides (preferably lithium di-isopropylamide),
alkali metal bis(trialkylsilyl)amides (preferably sodium
bis(trimethylsilyl)amide), trialkyl amines (preferably
N,N-di-isopropyl-N-ethyl amine or triethylamine) or
aromatic amines (preferably pyridine). Inert solvents
-99-


CA 02259583 1999-01-04

WO 98/03510 PCT/US97/13072
may include, but are not limited to, lower
alkanenitriles (.1 to 6 carbons, preferably
acetonitrile), dialkyl ethers (preferably diethyl
ether), cyclic ethers (preferably tetrahydrofuran or
1,4-dioxane), N,N-dialkylformamides (preferably
dimethylformamide), N,N-dialkylacetamides (preferably
dimethylacetamide), cyclic amides (preferabiy N-
methylpyrrolidin-2-one), dialkylsulfoxides (preferably
din.iethylsulfoxide), aromatic hydrocarbons (preferably
benzene or toluene) or haloalkanes of 1 to 10 carbons
and 1 to 10 halogens (preferably dichloromethane).
Preferred reaction temperatures range from -20 C to
1000C.

FXAMPT,F.S
Analytical data were recorded for the compounds
described below using the.following general procedures.
Proton NMR spectra were recorded on an IBM-Bruker FT-NMR
(300 MHz); chemical shifts were recorded in ppm (S) from
an internal tetramethysilane standard in
deuterochloroform or deuterodimethylsulfoxide as
specified below. Mass spectra (MS) or high resolution
mass spectra (HRMS) were recorded on a Finnegan MAT 8230
spectrometer (using chemi-ionization (CI) with NH3 as
the carrier gas or gas chromatography (GC) as specified
below) or a Hewlett Packard 5988A model spectrometer.
Melting points were recorded on a Buchi Model 510
melting point apparatus and are uncorrected. Boiling
points are uncorrected. All pH determinations during
workup were made with indicator paper.
Reagents were purchased from commercial sources
and, where necessary, purified prior to use according to
the general procedures outlined by D. Perrin and W.L.F.
Armarego, Purification of Laboratory Chemicals, 3rd ed.,
(New York: Pergamon Press, 1988). Chromatography was
-100-

T


CA 02259583 1999-01-04

WO 98/03510 PCT/US97/13072
performed on silica gel using the solvent systems
indicated below, For mixed solvent systems, the volume
ratios are given. Otherwise, parts and percentages are
by weight.
The following examples are provided to describe
the invention in further detail. These examples,
which set forth the best mode presently contemplated
for carrying out the invention, are intended to
illustrate and not to limit the invention.
EXAMPLE 1
Preparation of
2,7-dimethyl-8-(2,4-dimethylphenyl)[1,5-a]
-pyrazolo-[1,3,5]-triazin-4(3H)-one
(Formula 7, where Y is 0, R1 is CH3, Z is C-CH3r
Ar is 2,4-dimethylphenyl)
A. 1-Cyano-l-(2,4-dimethylphenyl)propan-2-one
Sodium pellets (9.8g, 0.43 mol) were added
portionwise to a solution of 2,4-
dimethylphenylacetonitrile (48 g, 0.33 mol) in ethyl
acetate (150 mL) at ambient temperature. The reaction
mixture was heated to reflux temperature and stirred for
16 hours. The resulting suspension was cooled to room
temperature and filtered. The collected precipitate was
washed with copious amounts of ether and then air-dried.
The solid was dissolved in water and a LN HC1 solution
was added until the pH = 5-6. The mixture was extracted
with ethyl acetate (3 X 200 mL); the combined organic
layers were dried over MgSO4 and filtered. Solvent was
removed in vacUo to afford a white solid (45.7g, 74%
yield) : NMR (CDC13,300 MHz) :; CI-MS: 188 (M + H).
B. 5-Amino-4-(2,4-dimethylphenyl)-3-methylpyrazole
-101-


CA 02259583 1999-01-04

WO 98/03510 PCT/US97/13072
A mixture of 1-cyano-l-(2,4-dimethylphenyl)propan-
2-one (43.8g, 0.23 mol), hydrazine-hydrate (22 mL, 0.46
mol), glacial acetic acid (45 mL, 0.78 mol) and toluene
(500 mL) were stirred at reflux temperature for 18 hours
in an apparatus fitted with a Dean-Stark trap. The
reaction mixture was cooled to ambient temperature and
solvent was removed in vacuo. The residue was dissolved
in 6N HC1 and the resulting solution was extracted with
ether three times. A concentrated ammonium hydroxide
solution was added to the aqueous layer until pH = 11.
The resulting semi-solution was extracted three times
with ethyl acetate. The combined organic layers were
dried over MgSO4 and filtered. Solvent was removed in
vacuo to give a pale brown viscous oil (34.6g, 75%
yield) : NMR (CDC13,300 MHz) : 7.10 (s, 1H), 7.05 (d, 2H,
J=1), 2.37 (s, 3H), 2.10 (s, 3H); CI-MS: 202 (M + H).
C. 5-Acetamidino-4-(2,4-dimethylphenyl)-3-
methylpyrazole, acetic acid salt
Ethyl acetamidate hydrochloride (60g, 0.48 mol) was
added quickly to a rapidly stirred mixture of potassium
carbonate (69.5g, 0.50 mol), dichloromethane (120 mL)
and water (350 mL). The layers were separated and the
aqueous layer was extracted with dichloromethane (2 X
120 mL). The combined organic layers were dried over
MgSO4 and filtered. Solvent was removed by simple
distillation and the pot residue, a clear pale yellow
liquid, (35.0 g) was used without further purification.
Glacial aetic acid (9.7 mL, 0.17 mol) was added to
a stirred mixture of 5-amino-4-(2,4-dimethylphenyl)-3-
methylpyrazole ( 34g, 0.17 mol), ethyl acetamidate (22g,
0.25 mol) and acetonitrile (500 mL). The resulting
reaction mixture was stirred at room temperature for 3
days; at the end of which time, it was concentrated in
vacuo to about one-third of its original volume. The
resulting suspension was filtered and the collected
-102-

T


CA 02259583 1999-01-04

WO 98/03510 PCT/US97/13072
solid was washed with copious amounts of ether. The
white solid was dried in vacuo (31.4g, 61% yield): NMR
(DMSO-d6,300 MHz): 7.00 (s, 1H), 6.90 (dd, 2H, J=7, 1),
2.28 (s, 3H), 2.08 (s, 3H), 2.00 (s, 3H), 1.90 (s, 3H),
1.81 (s, 3H); CI-MS: 243 (M + H).

D. 2,7-dimethyl-8-(2,4-dimethylphenyl)[1,5-a]-
pyrazolo-[1,3,5]-triazin-4(3H)-one
Sodium pellets (23g, 1 mol) were added portionwise
to ethanol (500 mL) with vigorous stirring. After all
the sodium reacted, 5-acetamidino-4-(2,4-
dimethylphenyl)-3-methylpyrazole, acetic acid salt
(31.2g, 0.1 mol) and diethyl carbonate ( 97 mL, 0.8 mol)
were added. The resulting reaction mixture was heated
to reflux temperature and stirred for 18 hours. The mix
was cooled to room temperature and solvent was removed
in vacuo. The residue was dissolved in water and a 1N
HC1 solution was added slowly until pH = 5-6. The
aqueous layer was extracted with ethyl acetate three
times; the combined organic layers were dried over MgSO4
and filtered. Solvent was removed in vacuo to give a
pale tan solid (26g, 98% yield) : NMR (CDC13,300 MHz) :
7.15(s, 1H), 7.09 (s, 2H), 2.45 (s, 3H), 2.39 (s, 3H),
2.30 (s, 3H); CI-MS: 269 (M + H).
EXAMPLE 2
Preparation of
5-methyl-3-(2,4,6-trimethyiphenyl)[1,5-a]-
[1,2,3]-triazolo-[1,3,5]-triazin-7(6H)-one
(Formula 7, where Y is 0, R1 is CH3, Z is N,
Ar is 2,4,6-trimethylphenyl)

A. 1-Phenylmethyl-4-(2,4,6-trimethylphenyl)-5-
aminotriazole
A mixture of 2,4,6-trimethylbenzyl cyanide (1.Og,
6.3 mmol), benzyl azide (0.92g, 6.9 mmol) and potassium
-103-


CA 02259583 1999-01-04

WO 98/03510 PCT/US97/13072
t-butoxide (0.78g, 6.9 mmol) in tetrahydrofuran (lOmL)
was stirred at ambient temperature for 2.5 days. The
resulting suspension was diluted with water and
extracted three times with ethyl acetate. The combined
organic layers were dried over MgSO4 and filtered.
Solvent was removed in vacuo to give a brown oil.
Trituration with ether and filtration afforded a yellow
solid (1.12g, 61%- yield): NMR (CDC13,300 MHz):7.60-7.30
(m, 5H), 7.30-7.20 (m, 2H), 5.50 (s, 2H), 3.18 (br s,
2H), 2.30 (s, 3H), 2.10 (s, 6H); CI-MS: 293 (M + H).
B. 4-(2,4,6-Trimethylphenyl)-5-aminotriazole
Sodium (500 mg, 22 mmol) was added with stirring to
a mixture of liquid ammonia (30 mL) and 1-phenylmethyl-
4-(2,4,6-trimethylphenyl)-5-aminotriazole (1.1g, 3.8
mmol). The reaction mixture was stirred until a dark
green color persisted. An ammonium chloride solution
mL) was added and the mixture was stirred while warming
to ambient temperature over 16 hours. The residue was
treated with a 1M HC1 solution and filtered. The
aqueous layer was basified with a concentrated ammonium
hydroxide solution (pH = 9) and then extracted with
ethyl acetate three times. The combined organic layers
were dried over MgSO4 and filtered. Solvent was removed
in vacuo to give a yellow solid (520 mg), which was
homogeneous by thin layer chromatography (ethyl
acetate):
NMR (CDC13,300 MHz): 6.97 (s, 2H), 3.68-3.50 (br.s, 2H),
2.32 (s, 3H), 2.10 (s, 6H); CI-MS: 203 (M + H).
C. 4-(2,4,6-Trimethylphenyl)-5-acetamidinotriazole,
acetic acid salt
A mixture of 4-(2,4,6-trimethylphenyl)-5-
aminotriazole (400 mg, 1.98 mmol), ethyl acetamidate
261 mg, 3 mmol) and glacial acetic acid (0.1 mL, 1.98
mmol) in acetonitrile (6 mL) was stirred at ambient
-104-
T


CA 02259583 1999-01-04

WO 98/03510 PCT/US97/13072
temperature for 4 hours. The resulting suspension was
filtered and the collected solid was washed with copious
amounts of ether. Drying in vacuo afforded a white
solid (490 mg, 82% yield): NMR (DMSO-d6,300 MHz):7.90-
7.70 (br s, 0.5H), 7.50-7.20 (br. s, 0.5H), 6.90 (s,
2H), 6.90 (s, 2H),= 3.50-3.10 (br s, 3H), 2.30-2.20 (br
s, 3H), 2.05 (d, 1H, J = 7), 1.96 (s, 6H), 1.87 (s, 6H) ;
CI-MS: 244 (M + H).

D. 5-methyl-3-(2,4,6-trimethylphenyl)[1,5-a]-
[ 1, 2, 3]-triazolo- [ 1, 3, 5]-triazin-7 ( 4H) -one
Sodium (368 mg, 16.2 mmol) was added with stirring
to ethanol (10 mL) at room temperature. After the
sodium had reacted, 4-(2,4,6-trimethylphenyl)-5-
acetamidino-triazole, acetic acid salt (490 mg, 1.6
mmol) and diethyl carbonate (1.6 mL, 13 mmol) were
added. The reaction mixture was stirred at reflux
temperature for 5 hours, then cooled to room
temperature. The reaction mixture was diluted with
water; a 1N HC1 solution was added until pH = 5-6 and
three extractions with ethyl acetate were performed.
The combined organic layers were dried over MgSO4 and
filtered. Solvent was removed in vacuo to give a yellow
residue. Trituration with ether and filtration afforded
a yellow solid (300 mg, 69o yield) : NMR (CDC13,300 MHz)
6.98 (s, 2H), 2.55 (s, 3H), 2.35 (s, 3H), 2.10 (s, 6H);
CI-MS: 270 (M + H).

EXAMPLE 3
Preparation of 4-(di(carbomethoxy)methyl)-
2,7-dimethyl-8-(2,4-dimethylphenyl)[1,5-a]-pyrazolo-
1,3,5-triazine
(Formula 1, where R3 is CH (CHC02CH3) 2, R1 is CH3, Z is C-
CH3, Ar is 2,4-dimethylphenyl)

-105-


CA 02259583 1999-01-04

WO 98/03510 PCT/US97/13072
A. 4-chloro-2,7-dimethyl-8-(2,4-dichlorophenyl)[1,5-
a]- pyrazolotriazine
A mixture of 2,7-dimethyl-8-(2,4-
dimethylphenyl) [1, 5-a]
-pyrazolo-1,3,5-triazin-4-one (Example 1, 1.38g, 4.5
mmol), N,N-dimethylaniline (1 mL, 8 mmol) and phosphorus
oxychloride (10 mL) was stirred at reflux temperature
for 48 hours. The excess phosphorus oxychloride was
removed in vacuo. The residue was poured onto ice-
water, stirred briefly and extracted quickly with ethyl
acetate three times. The combined organic layers were
washed with ice water, then dried over MgSO4 and
filtered. Solvent was removed in vacuo to give a brown
oil. Flash column chromatography (ethyl
acetate:hexanes::1:4) gave one fraction (Rf = 0.5)
Solvent was removed in vacuo to afford a yellow oil
(1.Og, 68% yield): NMR (CDC13,300 MHz): 7.55 (d, lH, J
1 ), 7 . 3 8 (dd, 1H, J = 7, 1), 7.30 (d, 1H, J = 7), 2.68
(s, 3H), 2.45 (s, 3H) ; CI-MS: 327 (M + H).
B. 4-(di(carbomethoxy)methyl)-2,7-dimethyl-8-(2,4-
dimethylphenyl)[1,5-a]-pyrazolo-1,3,5-triazine
Sodium hydride ( 60 % in oil, 80 mg, 2 mmol) was
washed with hexanes twice, decanted after each washing
and taken up in anhydrous tetrahydrofuran (THF, 1 mL).
A solution of diethyl malonate (0.32g, 2 mmol) in THF (2
mL) was added dropwise over 5 min, during which time
vigorous gas evolution ensued. A solution of 4-chloro-
2,7-dimethyl-8-(2,4-dichlorophenyl)[1,5-a]-
pyrazolotriazine (0.5g, 1.75 mmol) in THF (2 mL)
was added and the reaction mixture was then stirred
under a nitrogen atmosphere for 48 hours. The resulting
suspension was poured onto water and extracted three
times with ethyl acetate. The combined organic layers
were washed once with brine, dried over MgSO4 and
filtered. Solvent was removed in vacuo to give a brown
-106-


CA 02259583 1999-01-04

WO 98/03510 PCT/US97/13072
oil. Column chromatography (ethyl acetate:hexanes::1:9)
afforded, after removal of solvent in vacuo, a pale
yellow solid (Rf = 0.2, 250 mg, 35¾ yield): mp 50-52 C;
NMR (CDC13, 300 MHz): 12.35 (br.s, 1H, 7.15-7.00 (m,
3H), 4.40 (q, 2H, J = 7), 4.30 (q, 2H, J = 7), 2.4,
2.35, 2.3, 2.2, 2.1 (5 s, 12H), 1.4 (t, 3H, J = 7),
1.35-1.25 (m, 3H); CI-HRMS: Calcd: 411.2032, Found:
411.2023.

EXAMPLE 6
Preparation of 4-(1,3-dimethoxy-2-propylamino)-
2,7-dimethyl-8-(2,4-dichlorophenyl)[1,5-a]-pyrazolo-
I, 3, 5-triazine
(Formula 1, where R3 is NHCH(CH2OCH3)2, R1 is CH3, Z is
C-CH3, Ar is 2,4-dichiorophenyl)

A. 4-chloro-2,7-dimethyl-8-(2,4-dichlorophenyl)[1,5-
a]- pyrazolotriazine
A mixture of 2,7-dimethyl-8-(2,4
dimethylphenyl)[1,5-a]-pyrazolo-1,3,5-triazin-4-one
(Example 1, 1.38g, 4.5 mmol), N,N-dimethylaniline (1 mL,
8 mmol) and phosphorus oxychloride (10 mL) was stirred
at reflux temperature for 48 hours. The excess
phosphorus oxychloride was removed in vacuo. The
residue was poured onto ice-water, stirred briefly and
extracted quickly with ethyl acetate three times. The
combined organic layers were washed with ice water, then
dried over MgSO4 and filtered. Solvent was removed in
vacuo to give a brown oil. Flash column chromatography
(ethyl acetate:hexanes::1:4) gave one fraction (Rf =
0.5) Solvent was removed in vacuo to afford a yellow
oil (1 .Og, 68% yield) : NMR (CDC13,300 MHz) : 7.55 (d, 1H,
J= 1), 7.38 (dd, 1H, J = 7,1 ), 7.30 (d, 1H, J = 7),
2.68 (s, 3H), 2.45 (s, 3H); CI-MS: 327 (M + H).
-107-


CA 02259583 1999-01-04

WO 98/03510 PCTIUS97/13072
B. 4-(1,3-dimethoxy-2-propylamino)-2,7-dimethyl-8-
(2,4- dichlorophenyl)[1,5-a]-pyrazolo-1,3,5-triazine
A mixture of 4-chloro-2,7-dimethyl-8-(2,4-
dichlorophenyl)[1,5-a]-pyrazolo-1,3,5-triazine (Part A,
570 mg, 1.74 mmol), 1,3-dimethoxypropyl-2-aminopropane
(25mg, 2.08 mmol) and ethanol (10 mL) was stirred at
ambient temperature for 18 hours. The reaction mixture
was poured onto water (25 mL) and extracted three times
wi'=h ethyl acetate. The combined organic layers were
dried over MgSO4 and filtered. Solvent was removed in
vacuo. Column chromatography (CH2C12:CH30H::50:1)
afforded one fraction. Removal of solvent in vacuo gave
a solid (250 mg, 35% yield): mp 118-120 C; NMR
(CDC13,300 MHz) : 7.50 (s, 1H), 7.28 (dd, 2H, J= 8, 1) ,
6.75 (d, 1H, J = 8), 4.70-4.58 (m, 1H), 3.70-3.55 (m,
4H), 3.43 (s, 6H), 2.50 (s, 3H), 2.35 (s, 3H); CI-HRMS:
Calcd: 409.1072, Found: 409.1085; Analysis Calcd. for
C18H21C12N502: C, 52.69, H,, 5.17, N, 17.07, Cl, 17.28;
Found: C, 52.82, H, 5.06, N, 16.77, Cl, 17.50.
Using the above procedures and modifications known
to one skilled in the art of organic synthesis, the
following additional examples of Tables 1-4 may be
prepared.
The examples delineated in TABLE 1 may be prepared
by the methods outlined in Examples 1, 2, 3 or 6.
Commonly used abbreviations are: Ph is phenyl, Pr is
propyl, Me is methyl, Et is ethyl, Bu is butyl, Ex is
Example.

-108-

,


CA 02259583 1999-01-04

WO 98/03510 PCT/US97/13072
TABLE 1

R3
N )", N, N\
Z
N
Ar
6a C-Me NHCH(CH2OMe)2 2,4-C12-Ph 118-120
7b C-Me NHCHPr2 2,4-C12-ph 114-116
8c C-Me NEtBu 2,4-C12-Ph oil
gd C-Me NPr(CH2-c-C3H5) 2,4-C12-Ph oil
l0e C-Me N(CH2CH2OMe)2 2,4-C12-Ph oil
ilf C-Me NH-3-heptyl 2,4-C12-Ph 90-92
129 C-Me NHCH(Et)=CH2OMe 2,4-C12-Ph 179-181
13h C-Me NEt2 2,4-C12-Ph 133-134
141 C-Me NHCH(CH2OEt)2 2,4-C12-Ph oil
15i C-Me NH-3-pentyl 2,4-C12-Ph 139-140
16k C-Me NMePh 2,4-C12-Ph 60-62
171 C-Me NPr2 2,4-C12-Ph oil.
18m C-Me NH-3-hexyl 2,4-C12-Ph 130-132
19 C-Me morpholino 2,4-C12-Ph
20 C-Me N(CH2Ph)CH2CH2OMe 2,4-C12-Ph
21 C-Me NHCH(CH2Ph)CH2OMe 2,4-C12-Ph
22 C-Me NH-4-tetrahydropyranyl 2,4-C12-Ph
23 C-Me NH-cyclopentyl 2,4-C12-Ph
24 C-Me 1,2,3,4-tetrahydro- 2,4-C12-Ph
isoquinolinyl
25 C-Me CH2-(1,2,3,4-tetrahydro- 2,4-C12-Ph
isoquinolinyl)
26n C-Me OEt 2,4-C12-Ph 141-143
27 C-Me OCH(Et)CH2OMe 2,4-C12-Ph

-109-


CA 02259583 1999-01-04

WO 98/03510 PCT/US97/13072
28 C-Me OCH2Ph 2,4-C12-Ph
29 C-Me 0-3-pentyl 2,4-C12-Ph
30 C-Me SEt 2,4-C12-Ph
31 C-Me S(0)Et 2,4-C12-Ph
32 C-Me S02Et 2,4-C12-Ph
33 C-Me CH(C02Et)2 2,4-C12-Ph
34 C-Me C (Et) (C02Et) 2 2,4-C12-Ph
35 C-Me CH(Et)CH2OH 2,4-C12-Ph
36 C-Me CH(Et)CH2OMe 2,4-C12-Ph
37 C-Me CONMe2 2,4-C12-Ph
38 C-Me COCH3 2,4-C12-Ph
39 C-Me CH(OH)CH3 2,4-C12-Ph
40 C-Me C(OH)Ph-3-pyridyl 2,4-C12-Ph
41 C-Me Ph 2,4-C12-Ph
42 C-Me 2-CF3-Ph 2,4-C12-Ph
43 C-Me 2-Ph-Ph 2,4-C12-Ph
44 C-Me 3-pentyl 2,4-C12-Ph
45 C-Me cyclobutyl 2,4-C12-Ph
46 C-Me 3-pyridyl 2,4-C12-Ph
47 C-Me CH(Et)CH2CONMe2 2,4-C12-Ph
48 C-Me CH(Et)CH2CH2NMe2 2,4-C12-Ph
490 C-Me NHCH(CH2OMe)2 2,4,6-Me3-Ph 125-127
50 C-Me NHCHPr2 2,4,6-Me3-Ph
51 C-Me NEtBu 2,4,6-Me3-Ph
52 C-Me NPr(CH2-c-C3H5) 2,4,6-Me3-Ph
53ae C-Me N(CH2CH2OMe)2 2,4,6-Me3-Ph 123-124
54 C-Me NH-3-heptyl 2,4,6-Me3-Ph
55ac C-Me NHCH(Et)CH2OMe 2,4,6-Me3-Ph 145-146
56ah C-Me NEt2 2,4,6-Me3-Ph 88-90
57ai C-Me NHCH(CH2OEt)2 2,4,6-Me3-Ph 132-134
58ad C-Me NH-3-pentyl 2,4,6-Me3-Ph 134-135
59 C-Me NMePh 2,4,6-Me3-Ph
60 C-Me NPr2 2,4,6-Me3-Ph
61 C-Me NH-3-hexyl 2,4,6-Me3-Ph
62 C-Me morpholino 2,4,6-Me3-Ph
63 C-Me N(CH2Ph)CH2CH2OMe 2,4,6-Me3-Ph
-110-
.


CA 02259583 1999-01-04

WO 98/03510 PCT/US97/13072
64 C-Me NHCH(CH2Ph)CH2OMe 2,4,6-Me3-Ph
65 C-Me NH-4-tetrahydropyranyl 2,4,6-Me3-Ph
66 C-Me NH-cyclopentyl 2,4,6-Me3-Ph
67 C-Me 1,2,3,4-tetrahydro- 2,4,6-Me3-Ph
isoquinolinyl
68 C-Me CH2-(1,2,3,4-tetrahydro- 2,4,6-Me3-Ph
isoquinolinyl)
69 C-Me OEt 2,4,6-Me3-Ph
70 C-Me OCH(Et)CH2OMe 2,4,6-Me3-Ph
71 C-Me OCH2Ph 2,4,6-Me3-Ph
72 C-Me 0-3-pentyl 2,4,6-Me3-Ph
73 C-Me SEt 2,4,6-Me3-Ph
74 C-Me S(O)Et 2, 4, 6-Me3-Ph
75 C-Me S02Et 2,4,6-Me3-Ph
76 C-Me CH(C02Et)2 2,4,6-Me3-Ph
77 C-Me C(Et)(C02Et)2 2,4,6-Me3-Ph
78 C-Me CH(Et)CH20H 2,4,6-Me3-Ph
79 C-Me CH(Et)GH2OMe 2,4,6-Me3-Ph
80 C-Me CONMe2 2,4,6-Me3-Ph
81 C-Me COCH3 2,4,6-Me3-Ph
82 C-Me CH(OH)CH3 2,4,6-Me3-Ph
83 C-Me C(OH)Ph-3-pyridyl 2,4,6-Me3-Ph
84 C-Me Ph 2,4,6-Me3-Ph
85 C-Me 2-CF3-Ph 2,4,6-Me3-Ph
86 C-Me 2-Ph-Ph 2,4,6-Me3-Ph
87 C-Me 3-pentyl 2,4,6-Me3-Ph
88 C-Me cyclobutyl 2,4,6-Me3-Ph
89 C-Me 3-pyridyl 2,4,6-Me3-Ph
90 C-Me CH(Et)CH2CONMe2 2,4,6-Me3-Ph
91 C-Me CH(Et)CH2CH2NMe2 2,4,6-Me3-Ph
92P C-Me NHCH(CH2OMe)2 2,4-Me2-Ph 44-45
93q C-Me N(CH2CH2OMe)2 2,4-Me2-Ph oil
94r C-Me NHCH(Et)CH2OMe 2,4-Me2-Ph 102-104
95S C-Me NH-3-pentyl 2,4-Me2-Ph 102-104
96t C-Me NEt2 2,4-Me2-Ph oil
97U C-Me N(CH2CN)2 2,4-Me2-Ph 148-150
-111-


CA 02259583 1999-01-04

WO 98/03510 PCTIUS97/13072

98 C-Me NHCH(Me)CH2OMe 2,4-Me2-Ph 102-104
99W C-Me OCH(Et)CH2OMe 2,4-Me2-ph oil
100X C-Me NPr-c-C3H5 2,4-Me2-Ph oil
lOly C-Me NHCH(Me)CH2NMe2 2,4-Me2-Ph 47-48
102Z C-Me N(c-C3H5)CH2CH2CN 2,4-Me2-Ph 117-118
103aa C-Me N(Pr)CH2CH2CN 2,4-Me2-Ph oil
104ab C-Me N(Bu)CH2CH2CN 2,4-Me2-Ph oil
105 C-Me NHCHPr2 2,4-Me2-Ph
10v C-Me NEtBu 2,4-Me2-Ph
107 C-Me NPr(CH2-c-C3HS) 2,4-Me2-Ph
108 C-Me NH-3-heptyl 2,4-Me2-Ph
109 C-Me NEt2 2,4-Me2-Ph
110 C-Me NHCH(CH2OEt)2 2,4-Me2-Ph
111 C-Me NH-3-pentyl 2,4-Me2-Ph
112 C-Me NMePh 2,4-Me2-Ph
113 C-Me NPr2 2,4-Me2-Ph
114 C-Me NH-3-hexyl 2,4-Me2-Ph
115 C-Me morpholino 2,4-Me2-Ph
116 C-Me N(CH2Ph)CH2CH2OMe 2,4-Me2-Ph
117 C-Me NHCH(CH2Ph)CH2OMe 2,4-Me2-Ph
118 C-Me NH-4-tetrahydropyranyl 2,4-Me2-Ph
119 C-Me NH-cyclopentyl 2,4-Me2-Ph
120 C-Me 1,2,3,4-tetrahydro- 2,4-Me2-Ph
isoquinolinyl
121 C-Me CH2-(1,2,3,4-tetrahydro- 2,4-Me2-Ph
isoquinolinyl)
122 C-Me OEt 2,4-Me2-Ph
123 C-Me OCH(Et)CH2OMe 2,4-Me2-Ph
124 C-Me OCH2Ph 2,4-Me2-Ph
125 C-Me 0-3-pentyl 2,4-Me2-Ph
126 C-Me SEt 2,4-Me2-Ph
127 C-Me S(O)Et 2,4-Me2-Ph
128 C-Me SO2Et 2,4-Me2-Ph
3 C-Me CH(C02Et)2 2,4-Me2-Ph 50-52
129 C-Me C(Et)(C02Et)2 2,4-Me2-Ph

-112-

T


CA 02259583 1999-01-04

WO 98/03510 PCT/US97/13072
130 C-Me CH(Et)CH2OH 2,4-Me2-Ph
131 C-Me CH(Et)CH2OMe 2,4-Me2-Ph
132 C-Me CH(Et)CH2OEt 2,4-Me2-Ph
133 C-Me CONMe2 2,4-Me2-Ph
134 C-Me COCH3 2,4-Me2-Ph
135 C-Me CH(OH)CH3 2,4-Me2-Ph
136 C-Me C(OH)Ph-3-pyridyl 2,4-Me2-Ph
137 C-Me Ph 2,4-Me2-Ph
13S-. C-Me 2-CF3-Ph 2,4-Me2-Ph
139 C-Me 2-Ph-Ph 2,4-Me2-Ph
140 C-Me 3-pentyl 2,4-Me2-Ph
141 C-Me cyclobutyl 2,4-Me2-Ph
142 C-Me 3-pyridyl 2,4-Me2-Ph
143 C-Me CH(Et)CH2CONMe2 2,4-Me2-Ph
144 C-Me CH(Et)CH2CH2NMe2 2,4-Me2-Ph
145bc C-Me NHCH(CH2OMe)2 2-Me-4-MeO-Ph 45-46
146bd C-Me N(CH2CH2OMe)2 2-Me-4-MeO-Ph oil
147be C-Me NHCH(Et)CH2OMe 2-Me-4-MeO-Ph 86-88
148bf C-Me N(Pr)CH2CH2CN 2-Me-4-MeO-Ph oil
149 C-Me OCH(Et)CH2OMe 2-Me-4-MeO-Ph
150af C-Me NHCH(CH2OMe)2 2-Br-4-MeO-Ph 88-90
151a1 C-Me N(CH2CH2OMe)2 2-Br-4-MeO-Ph oil
152ag C-Me NHCH(Et)CH2OMe 2-Br-4-MeO-Ph 95-97
153 C-Me N(Pr)CH2CH2CN 2-Br-4-MeO-Ph
154 C-Me OCH(Et)CH2OMe 2-Br-4-MeO-Ph
155 C-Me NHCH(CH2OMe)2 2-Me-4-NMe2-Ph
156 C-Me N(CH2CH2OMe)2 2-Me-4-NMe2-Ph oil
157 C-Me NHCH(Et)CH2OMe 2-Me-4-NMe2-Ph
158 C-Me N(Pr)CH2CH2CN 2-Me-4-NMe2-Ph
159 C-Me OCH(Et)CH2OMe 2-Me-4-NMe2-Ph
160 C-Me NHCH(CH2OMe)2 2-Br-4-NMe2-Ph
161 C-Me N(CH2CH2OMe)2 2-Br-4-NMe2-Ph
162 C-Me NHCH(Et)CH2OMe 2-Br-4-NMe2-Ph
163 C-Me N(Pr)CH2CH2CN 2-Br-4-NMe2-Ph
164 C-Me OCH(Et)CH2OMe 2-Br-4-NMe2-Ph
165 C-Me NHCH(CH2OMe)2 2-Br-4-i-Pr-Ph
-113-


CA 02259583 1999-01-04

WO 98/03510 PCT/US97/13072
166 C-Me N(CH2CH2OMe)2 2-Br-4-i-Pr-Ph
167 C-Me NHCH(Et)CH2OMe 2-Br-4-i-Pr-Ph
168 C-Me N(Pr)CH2CH2CN 2-Br-4-i-Pr-Ph
169 C-Me OCH(Et)CH2OMe 2-Br-4-i-Pr-Ph
170 C-Me NHCH(CH2OMe)2 2-Br-4-Me-Ph
171 C-Me N(CH2CH2OMe)2 2-Br-4-Me-Ph
172 C-Me NHCH(Et)CH2OMe 2-Br-4-Me-Ph
173 C-Me N(Pr)CH2CH2CN 2-Br-4-Me-Ph
174 C-Me OCH(Et)CH2OMe 2-Br-4-Me-Ph
175ar C-Me NHCH(CH2OMe)2 2-Me-4-Br-Ph 108-109
176 C-Me N(CH2CH2OMe)2 2-Me-4-Br-Ph

177 C-Me NHCH(Et)CH2OMe 2-Me-4-Br-Ph
178 C-Me N(Pr)CH2CH2CN 2-Me-4-Br-Ph
179 C-Me OCH(Et)CH2OMe 2-Me-4-Br-Ph
180 C-Me NHCH(CH2OMe)2 2-C1-4,6-Me2-Ph
181 C-Me N(CH2CH2OMe)2 2-C1-4,6-Me2-Ph
182 C-Me NHCH(CH2OMe)2 4-Br-2,6-(Me)2-Ph
183 C-Me N(CH2CH-2OMe)2 4-Br-2,6-(Me)2-Ph
184 C-Me NHCH(CH2OMe)2 4-i-Pr-2-SMe-Ph
185 C-Me N(CH2CH2OMe)2 4-i-Pr-2-SMe-Ph
186 C-Me NHCH(CH2OMe)2 2-Br-4-CF3-Ph
187 C-Me N(CH2CH2OMe)2 2-Br-4-CF3-Ph
188 C-Me NHCH(CH2OMe)2 2-Br-4,6-(MeO)2-Ph
189 C-Me N(CH2CH2OMe)2 2-Br-4,6-(MeO)2-Ph
190 C-Me NHCH(CH2OMe)2 2-C1-4,6-(MeO)2-Ph
191 C-Me N(CH2CH2OMe)2 2-C1-4,6-(Me0)2-Ph
192 C-Me NHCH(CH2OMe)2 2,6-(Me)2-4-SMe-Ph
193 C-Me N(CH2CH2OMe)2 2,6-(Me)2-4-SMe-Ph
194 C-Me NHCH(CH2OMe)2 4-(COMe)-2-Br-Ph
195 C-Me N(CH2CH2OMe)2 4-(COMe)-2-Br-Ph
196 C-Me NHCH(CH2OMe)2 2,4,6-Me3-pyrid-3-yl
197 C-Me N(CH2CH2OMe)2 2,4,6-Me3-pyrid-3-yl
198 C-Me NHCH(CH2OMe)2 2,4-(Br)2-Ph
199 C-Me N(CH2CH2OMe)2 2,4-(Br)2-Ph
200 C-Me NHCH(CH2OMe)2 4-i-Pr-2-SMe-Ph
201 C-Me N(CH2CH2OMe)2 4-i-Pr-2-SMe-Ph
-114-

r


CA 02259583 1999-01-04

WO 98/03510 PCT/US97/13072
202 C-Me NHCH(CH2OMe)2 4-i-Pr-2-SO2Me-Ph
203 C-Me N(CH2CH2OMe)2 4-i-Pr-2-SO2Me-Ph
204 C-Me NHCH(CH2OMe)2 2,6-(Me)2-4-SMe-Ph
205 C-Me N(CH2CH2OMe)2 2,6-(Me)2-4-SMe-Ph
206 C-Me NHCH(CH2OMe)2 2,6-(Me)2-4-SO2Me-Ph
207 C-Me N(CH2CH2OMe)2 2,6-(Me)2-4-SO2Me-Ph
208 C-Me NHCH(CH2OMe)2 2-I-4-i-Pr-Ph
209 C-Me N(CH2CH2OMe)2 2-I-4-i-Pr-Ph
21CG C-Me NHCH(CH2OMe)2 2-Br-4-N(Me)2-6-MeO-Ph
211 C-Me N(CH2CH2OMe)2 .2-Br-4-N(Me)2-6-MeO-Ph
212 C-Me NHCH(CH2OMe)2 2,4-[SMe]2-Ph
213 C-Me N(CH2CH2OMe)2 2,4-[SMe)2-Ph
214 C-Me NHCH(CH2OMe)2 2,4-[S02Me]2-Ph
215 C-Me N(CH2CH2OMe)2 2,4-[S02Me)2-Ph
216 C-Me NHCH(CH2OMe)2 4-i-Pr-2-SMe-Ph
217 C-Me N(CH2CH2OMe)2 4-i-Pr-2-SMe-Ph
218 C-Me NHCH(CH2OMe)2 4-i-Pr-2-SO2Me-Ph
219 C-Me N (CH2CH2OMe) 2 4-i-Pr-2-SO2Me-Ph
220 C-Me NHCH(CH2OMe)2 2-N(Me)2-4-Me-Ph
221 C-Me N(CH2CH2OMe)2 2-N(Me)2-4-Me-Ph
222 C-Me NHCH(CH2OMe)2 2-MeS-4,6-(Me)2-Ph
223 C-Me N(CH2CH2OMe)2 2-MeS-4,6-(Me)2-Ph
224 C-Me NHCH(CH2OMe)2 2-(CH3CO)-4,6-(Me)2-Ph
225 C-Me N(CH2CH2OMe)2 2-(CH3CO)-4,6-(Me)2-Ph

226 H NHCH(CH2OMe)2 2,4-Me2-Ph
227 H NHCH(CH2OMe)2 2,4-Me2-Ph
228 CF3 N(CH2CH2OMe)2 2,4-Me2-Ph
229 CF3 N(CH2CH2OMe)2 2,4-Me2-Ph
230 N NHCH(CH2OMe)2 =2,4,6-Me3-Ph
231 N NHCHPr2 2,4,6-Me3-Ph
232 N NEtBu 2,4,6-Me3-Ph
233 N NPr(CH2-c-C3H5) 2,4,6-Me3-Ph
234 N N(CH2CH2OMe)2 2,4,6-Me3-Ph
235 N NH-3-heptyl 2,4,6-Me3-Ph
236 N NHCH(Et)CH2OMe 2,4,6-Me3-Ph
237 N NEt2 2,4,6-Me3-Ph
-115-


CA 02259583 1999-01-04

WO 98/03510 PCT/US97/13072
238 N NHCH (CH2OEt ) 2 2, 4, 6-ctile3-Ph
239 N NF[-3-pentyl 2,4,6-Me3-Ph
240 N NMePh 2,4,6-Me3-Ph
241 N NPr2 2,4,6-Me3-Ph
242 N NH-3-hexyl 2,4,6-Me3-Ph
243 N morpholino 2,4,6-Me3-Ph
244 N N(CH2Ph)CH2CH2OMe 2,4,6-Me3-Ph
245 N NHCH(CH2Ph)CH2OMe 2,4,6-Me3-Ph
24~ N NH-4-tetrahydropyranyl 2,4,6-Me3-Ph
247 N NH-cyclopentyl 2,4,6-Me3-Ph
248 N 1,2,3,4-tetrahydro- 2,4,6-Me3-Ph
isoquinolinyl
249 N CH2-(1,2,3,4-tetrahydro- 2,4,6-Me3-Ph
isoquinolinyl)
250 N OEt 2,4,6-Me3-Ph
251 N OCH(Et)CH2OMe 2,4,6-Me3-Ph
252 N OCH2Ph 2,4,6-Me3-Ph
253 N O-3-pentyl 2,4,6-Me3-Ph
254 N SEt 2,4,6-Me3-Ph
255 N S(O)Et 2,4,6-Me3-Ph
256 N S02Et 2,4,6-Me3-Ph
257 N CH(C02Et)2 2,4,6-Me3-Ph
258 N C(Et)(C02Et)2 2,4,6-Me3-Ph
259 N CH(Et)CH20H 2,4,6-Me3-Ph
260 N CH(Et)CH2OMe 2,4,6-Me3-Ph
261 N CONMe2 2,4,6-Me3-Ph
262 N COCH3 2,4,6-Me3-Ph
263 N CH(OH)CH3 2,4,6-Me3-Ph
264 N C(OH)Ph-3-pyridyl 2,4,6-Me3-Ph
265 N Ph 2,4,6-Me3-Ph
266 N 2-CF3-Ph 2,4,6-Me3-Ph
267 N 2-Ph-Ph 2,4,6-Me3-Ph
268 N 3-pentyl 2,4,6-Me3-Ph
269 N cyclobutyl 2,4,6-Me3-Ph

270 N 3-pyridyl 2,4,6-Me3-Ph
271 N CH(Et)CH2CONMe2 2,4,6-Me3-Ph

-116-


CA 02259583 1999-01-04

WO 98/03510 PCT/US97/13072
272 N CH(Et)CH2CH2NMe2 2,4,6-Me3-Ph
273 N NHCH(CH2OMe)2 2,4-Me2-Ph
274 N NHCHPr2 2,4-Me2-Ph
275 N NEtBu 2,4-Me2-Ph
276 N NPr(CH2-c-C3H5) 2,4-Me2-Ph
277 N N(CH2CH2OMe)2 2,4-Me2-Ph
278 N NH-3-heptyl 2,4-Me2-Ph
279 N NHCH(Et)CH2OMe 2,4-Me2-Ph
28;; N NEt2 2,4-Me2-Ph
281 N NHCH(CH2OEt)2 2,4-Me2-Ph
282 N NH-3-pentyl 2,4-Me2-Ph
283 N NMePh 2,4-Me2-Ph
284 N NPr2 2,4-Me2-Ph
285 N NH-3-hexyl 2,4-Me2-Ph
286 N morpholino 2,4-Me2-Ph
287 N N(CH2Ph)CH2CH2OMe 2,4-Me2-Ph
288 N NHCH(CH2Ph)CH2OMe 2,4-Me2-Ph
289 N NH-4-tetrahydropyranyl 2,4-Me2-Ph
290 N NH-cyclopentyl 2,4-Me2-Ph
291 N 1,2,3,4-tetrahydro- 2,4-Me2-Ph
isoquinolinyl
292 N CH2-(1,2,3,4-tetrahydro- 2,4-Me2-Ph

isoquinolinyl)
293 N OEt 2,4-Me2-Ph
294 N OCH(Et)CH2OMe 2,4-Me2-Ph
295 N OCH2Ph 2,4-Me2-Ph
296 N 0-3-pentyl 2,4-Me2-Ph
297 N SEt 2,4-Me2-Ph
298 N S(O)Et 2,4-Me2-Ph
299 N S02Et 2,4-Me2-Ph
300 N CH(C02Et)2 2,4-Me2-Ph
301 N C(Et)(C02Et)2 2,4-Me2-Ph
302 N CH(Et)CH2OH 2,4-Me2-Ph
303 N CH(Et)CH2OMe 2,4-Me2-Ph
304 N CONMe2 2,4-Me2-Ph
305 N COCH3 2,4-Me2-Ph
-117-


CA 02259583 1999-01-04

WO 98/03510 PCT/US97/13072
306 N CH(OH)CH3 2,4-Me2-Ph
307 N C(OH)Ph-3-pyridyl 2,4-Me2-Ph
308 N Ph 2,4-Me2-Ph
309 N 2-CF3-Ph 2,4-Me2-Ph
310 N 2-Ph-Ph 2,4-Me2-Ph
311 N 3-pentyl 2,4-Me2-Ph
312 N cyclobutyl 2,4-Me2-Ph
313 N 3-pyridyl 2,4-Me2-Ph
311 N CH(Et)CH2CONMe2 2,4-Me2-Ph
315 N CH(Et)CH2CH2NMe2 2,4-Me2-Ph

316an C-Me NEt2 2-Br-4-Me0-Ph oil
317am C-Me NH-3-pentyl 2-Br-4-MeO-Ph oil
318aj C-Me NHCH(CH2CH2OMe)CH2OMe 2,4,6-Me3-Ph 101-103
319ao C-Me NH(c-C3H5) 2,4-Me2-Ph oil
320ak C-Me morpholino 2,4,6-Me3-Ph 139-141
321ap C-Me NHCH(CH2OMe)2 2-CN-4-Me-Ph 152-153
322aq C-Me N(c-C3H5)CH2CH2CN 2,4,6-Me3-Ph 149-151
324aS C-Me NHCH(CH2CH2OMe)CH2OMe 2-Me-4-Br-Ph 115-117
325at C-Me NHCH(CH2OMe)2 2,5-Me2-4-MeO-Ph 55-57
326au C-Me N(CH2CH2OMe)2 2,5-Me2-4-Me0-Ph 72
327d C-Me NH-3-pentyl 2,5-Me2-4-MeO-Ph 45-47
328aW C-Me NEt2 2,5-Me2-4-Me0-Ph oil
329aX C-Me NHCH(CH2OMe)2 2-C1-4-MePh 80-81
330ay C-Me NCH(Et)CH2OMe 2-C1-4-MePh 77-79
331dz C-Me N(CH2CH2OMe)2 2-C1-4-MePh oil
332ba C-Me (S)-NHCH(CH2CH2OMe)CH2OMe 2-Cl-4-MePh 139-140
333bb C-Me N(c-C3H5)CH2CH2CN 2,5-Me2-4-MeOPh 120-122
334bg C-Me NEt2 2-Me-4-MeOPh oil
335bh C-Me OEt 2-Me-4-MeOPh oil
336bi C-Me (S)-NHCH(CH2CH2OMe)CH2OMe 2-Me-4-MeOPh oil
337b7 C-Me N(c-C3H5)CH2CH2CN 2-Me-4-MeOPh 129
338bk C-Me NHCH(CH2CH2OEt)2 2-Me-4-MeOPh amorph.
339 C-Me N(c-C3H5)CH2CH2CN 2,4-C12-Ph 109-110
340 C-Me (S)-NHCH(CH2CH2OMe)CH2OMe 2,4-C12-Ph 93-94

341 C-Me NH-3-pentyl 2-Me-4-BrPh 118-119
342 C-Me N(CH2CH2OMe)2 2-Me-4-BrPh oil
-118-

T


CA 02259583 1999-01-04

WO 98/03510 PCT/US97/13072
343 C-Me NHCH(CH2-iPr)CH2OMe 2,4-Me2-Ph oil
344 C-Me NHCH (P r) C H 2 OMe 2,4-Me2-Ph 94-95
345 C-Me NHCH(Et)CH2OEt 2,4-Me2-Ph 76-77
346 C-Me NHCH(CH2OMe)CH2CH2OMe 2-Me-4-Me2NPh oil
347 C-Me NEt2 2-Me-4-ClPh oil
348 C-Me NH-3-pentyl 2-Me-4-C1Ph 122-124
349 C-Me N (CH2CH2OMe) 2 2-Me-4-C1Ph oil
350 C-Me NHCH(CH20Me)2 2-Me-4-C1Ph 122-123
351, C-Me NEt2 2-Me-4-C1Ph oil
352 C-Me NEt2 2-Cl-4-MePh oil
353 C-Me NH-3-pentyl 2-Cl-4-MePh 120-121
354 C-Me NHCH(CH2OMe)2 2-C1-4-MeOPh
355b1 C-Me N(CH2CH2OMe)2 2-Cl-4-MeOPh oil
356bm C-Me NHCH(Et)CH20Me 2-C1-4-MeOPh 108-110
357bn C-Me N(c-Pr)CH2CH2CN 2-C1-4-MeOPh 127-129
358bo C-Me NEt2 2-Cl-4-MeOPh oil
359bp C-Me NH-3-pentyl 2-C1-4-MeOPh 77-79
360 C-Me NHCH(Et)CK2CH2OMe 2-C1-4-Me0Ph
361 C-Me NHCH(Me)CH2CH2OMe 2-C1-4-MeOPh
362 C-Me NHCH(Et)CH2CH2OMe 2-Br-4-MeOPh
363 C-Me NHCH(Me)CH2CH2OMe 2-Br-4-MeOPh
364 C-Me NHCH(Et)CH2CH2OMe 2-Me-4-MeOPh
365 C-Me NHCH(Me)CH2CH2OMe 2-Me-4-MeOPh
366 C-Me NHCH(CH2OMe)2 2-C1-4,5-(MeO)2Ph
367 C-Me N(CH2CH2OMe)2 2-C1-4,5-(Me0)2Ph
368 C-Me NHCH(Et)CH2OMe 2-C1-4,5-(MeO)2Ph
369 C-Me N(c-Pr)CH2CH2CN 2-C1-4,5-(MeO)2Ph
370 C-Me NEt2 2-C1-4,5-(MeO)2Ph
371 C-Me NH-3-pentyl 2-Cl-4,5-(MeO)2Ph
372 C-Me NHCH(Et)CH2CH2OMe 2-Cl-4,5-(MeO)2Ph
373 C-Me NHCH(Me)CH2CH2OMe 2-C1-4,5-(Me0)2Ph
374bq C-Me NHCH(CH2OMe)2 2-Br-4,5-(MeO)2Ph 137-138
375 C-Me N(CH2CH2OMe)2 2-Br-4,5-(MeO)2Ph
376br C-Me NHCH(Et)CH2OMe 2-Br-4,5-(MeO)2Ph 147-148
377 C-Me N(c-Pr)CH2CH2CN 2-Br-4,5-(MeO)2Ph
378bs C-Me NEt2 2-Br-4,5-(MeO)2Ph 52-58
-119-


CA 02259583 1999-01-04

WO 98/03510 PCT/US97/13072
379 C-Me NH-3-pentyl 2-Br-4,5-(MeO)2Ph
380 C-Me NHCH(Et)CH2CH2OMe 2-Br-4,5-(MeO)2Ph
381 C-Me NHCH(Me)CH2CH2OMe 2-Br-4,5-(MeO)2Ph
382 C-Me NHCH(CH2OMe)2 2-C1-4,6-(MeO)2Ph
383 C-Me N(CH2CH2OMe)2 2-C1-4,6-(Me0)2Ph
384 C-Me NHCH(Et)CH2OMe 2-C1-4,6-(MeO)2Ph
385 C-Me N(c-Pr)CH2CH2CN 2-C1-4,6-(Me0)2Ph
386 C-Me NEt2 2-C1-4,6-(Me0)2Ph
38"i C-Me NH-3-pentyl 2-C1-4,6-(MeO)2Ph
388 C-Me NHCH(Et)CH2CH2OMe 2-C1-4,6-(Me0)22h
389 C-Me NHCH(Me)CH2CH2OMe 2-C1-4,6-(Me0)2Ph
390 C-Me NHCH(CH2OMe)2 2-Me-4,6-(MeO)2Ph
391 C-Me N(CH2CH2OMe)2 2-Me-4,6-(MeO)2Ph
392 C-Me NHCH(Et)CH2OMe 2-Me-4,6-(MeO)2Ph
393 C-Me N(c-Pr)CH2CH2CN 2-Me-4,6-(MeO)2Ph
395 C-Me NEt2 2-Me-4,6-(MeO)2Ph
396 C-Me NH-3-pentyl 2-Me-4,6-(MeO)2Ph
397 C-Me NHCH(Et)CH2CH2OMe 2-Me-4,6-(MeO)2Ph
398 C-Me NHCH(Me)CH2CH2OMe 2-Me-4,6-(Me0)2Ph
399 C-Me N(c-Pr)CH2CH2CN 2-Br-4,6-(MeO)2Ph
400 C-Me NEt2 2-Br-4,6-(MeO)2Ph
401 C-Me NH-3-pentyl 2-Br-4,6-(MeO)2Ph
402 C-Me NHCH(Et)CH2CH2OMe 2-Br-4,6-(MeO)2Ph
403 C-Me NHCH(Me)CH2CH2OMe 2-Br-4,6-(MeO)2Ph
404 C-Me NHCH(Et)CH2CH2OMe 2-Me-4-MeOPh
405 C-Me NHCH(Me)CH2CH2OMe 2-Me-4-MeOPh
406 C-Me NHCH(CH2OMe)2 2-MeO-4-MePh
407 C-Me N(CH2CH2OMe)2 2-MeO-4-MePh
408 C-Me NHCH(Et)CH2OMe 2-MeO-4-MePh
409 C-Me N(c-Pr)CH2CH2CN 2-MeO-4-MePh
410 C-Me NEt2 2-MeO-4-MePh
411 C-Me NH-3-pentyl 2-MeO-4-MePh
412 C-Me NHCH(Et)CH2CH2OMe 2-MeO-4-MePh
413 C-Me NHCH(Me)CH2CH2OMe 2-MeO-4-MePh
414 C-Me NHCH(CH2OMe)2 2-MeO-4-MePh
415 C-Me N(CH2CH2OMe)2 2-MeO-4-MePh
-120-

1


CA 02259583 1999-01-04

WO 98/03510 PCT/US97/13072
416 C-Me NHCH(Et)CH2OMe 2-Me0-4-MePh
417 C-Me N(c-Pr)CH2CH2CN 2-Me0-4-MePh
418 C-Me NEt2 2-Me0-4-MePh
419 C-Me NH-3-pentyl 2-Me0-4-MePh
420 C-Me NHCH(Et)CH2CH2OMe 2-Me0-4-MePh
421 C-Me NHCH(Me)CH2CH2OMe 2-Me0-4-MePh
423bt C-Me NHCH(CH2oMe)2 2-Me0-4-C1Ph oil
424 C-Me N(CH2CH2OMe)2 2-Me0-4-C1Ph
42:5 C-Me NHCH(Et)CH2OMe 2-Me0-4-C1Ph
426 C-Me N(c-Pr)CH2CH2CN 2-Me0-4-ClPh
427 C-Me NEt2 2-Me0-4-C1Ph
428 C-Me NH-3-pentyl 2-MeO-4-ClPh
429 C-Me NHCH(Et)CH2CH2OMe 2-Me0-4-C1Ph
430 C-Me NHCH(Me)CH2CH2OMe 2-Me0-4-ClPh
NOTES FOR TABLE 1:
a) Analysis Calcd: C, 52.69, H, 5.17, N, 17.07, Cl,
17.28; Found: C, 52.'82, H, 5.06, N, 16.77, Cl,
17.50.
b) CI-HRMS: Calcd: 406.1565, Found: 405.1573 (M + H);
Analysis Calcd: C: 59.11; H: 6.20; N: 17.23; Cl:
17.45; Found: C: 59.93; H: 6.34; N: 16.50; Cl:
16.95;
NMR (CDC13, 300 MHz) : 0.95 (t, J = 8, 4H), 1.30-
1.40 (m, 4H), 1.50-1.75 (m, 4H), 2.35 (s, 3H), 2.48
(s, 3H), 4.30-4.45 (m, 1H), 6.15 (d, J= 8, 1H),
7.30 (s, 2H), 7.50 (s, 1H)
c) CI-HRMS: Calcd: 392.1409, Found: 392.1388 (M + H);
NMR (CDC13, 300 MHz) : 1.00 (t, J =8, 3H), 1.35 (t,
J = 8, 3H), 1.41 (q, J = 8, 2H), 1.65-1.85 (m, 2H),
2.30 (s, 3H), 2.40 (s, 3H), 3.85-4.20 (m, 4H), 7.30
( s , 2H) , 7 . 50 (s, 1H) .
d) CI-HRMS: Calcd: 404.1409, Found: 404.1408 (M + H);
NMR(CDC13, 300 MHz): 0.35-0.45 (m, 2H), 0.52-0.62
(m, 2H), 0.98 (t, J= 8, 3H), 1.70-1.90 (m, 2H),

-121-


CA 02259583 1999-01-04

WO 98/03510 PCT/US97/13072
2.30 (s, 3H), 2.40 (s, 3H), 3.85-4.02 (m, 2H),
4.02-4.20 (m, 2H), 7.30 (s, 2H), 7.50 (s, 1H)
e) CI-HRMS: Calcd: 424.1307, Found: 424.1307 (M + H):
NMR (CDC13, 300 MHz): 2.28 (s, 3H), 2.40 (s, 3H),
3.40 (s, 6H), 3.75 (t, J = 8, 4H), 4.20-4.45 (m,
4H), 7.30 (s, 2H), 7.50 (s, 1H).
f) CI-HRMS: Calcd: 406.1565, Found: 406.1578 (M + H);
NMR (CDC13, 300 MHz) : 0.90 (t, J = 8, 3H), 1.00 (t,
J = 8, 3H), 1.28-1.45 (m, 4H), 1.50-1.80 (m, 4H),
2.35 (s, 3H), 2.50 (s, 3H), 4 .20-4 .35 (m, 1H),
6.10-6.23 (m, 1H), 7.30 (s, 2H), 7.50 (s, 1H).
g) CI-HRMS: Calcd: 394.1201, Found: 394.1209 (M + H);
NMR (CDC13, 300 MHz) : 1.02 (t, J = 8, 3H), 1. 65-
1. 90 (m, 2H)', 2.35 (s, 3H), 2.48 (s, 3H), 3.40 (s,
3H), 3.50-3.60 (m, 2H), 4.35-4.45 (brs, 1H), 6.50-
6.60 (m, 1H), 7.30 (s, 2H), 7.50 (s, 1H).
h) CI-HRMS: Calcd: 364.1096, Found: 364.1093 (M + H);
Analysis: Calcd: Cf 56.05; H: 5.27; N: 19.23; Cl:
19.46; Found: C: 55.96; H: 5.24; N. 18.93; Cl:
19.25;
NMR (CDC13, 300 MHz) : 1.35 (t, J = 8, 6H), 2.30 (3,
3H), 2.40 (s, 3H), 3.95-4.15 (m, 4H), 7.30 (s, 2H),
7.50 (d, J = 1, 1H).
i) CI-HRMS: Calcd: 438.1464, Found: 438.1454 (M + H);
NMR (CDC13, 300 MHz) : 1.22 (t, J = 8, 6H), 2.35 (s,
3H), 2.47 (s, 3H), 3.39 (q, J = 8, 4H) , 3.65 (dd, J
= 8, 1, 2H), 3.73 (dd, J = 8, 1, 2H), 4. 55-4 . 65 (m,
1H), 6.75 (d, J = 8, 1H), 7.30 (d, J = 1, 2H), 7.50
(s, 1H).
j) CI-HRMS: Calcd: 378.1252, Found: 378.1249 (M + H);
Analysis: Calcd: C: 57.15; H: 5.61; N: 18.51; Cl:
18.74; Found: C: 57.56; H: 5.65; N: 18.35; Cl:
18.45;
NMR (CDC13, 300 MHz): 1.00 (t, J = 8, 6H), 1.55-
1.70 (m, 2H), 1.70-1.85 (m, 2H), 2.35 (s, 3H), 2.50
-122-


CA 02259583 1999-01-04

WO 98/03510 PCT/US97/13072
(s, 3H), 4.15-4.25 (m, 1H), 6.18 (d, J = 8, 1H),
7.30 (s, 2H) , 7. 50 (s, 1H)
k) CI-HRMS: Calcd: 398.0939, Found: 398.0922 (M + H);
Analysis: Calcd: C: 60.31; H: 4.30; N: 17.58; Cl:
17.80; Found: C: 60.29; H: 4.59; N: 17.09; Cl:
17.57;
NMR (CDC13, 300 MHz) : 2.05 (s, 3H), 2.50 (s, 3H),
3.78 (s, 3H), 7.20-7.45 (m, 7H), 7.50 (d, J= 1,
1H).
1) CI-HRMS: Calcd: 392.1409, Found: 392.1391 (M + H);
NMR (CDC13, 300 MHz) : 0.98 (t, J = 8, 6H)-, 1.70-
1.85 (m, 4H), 2.30 (s, 3H), 2.40 (s, 3H), 3.80-4.10
(m, 4H), 7.30 (s, 2H), 7.50 (d, J = 1, 1H).
m) CI-HRMS: Calcd: 392.1409, Found: 392.1415 (M + H);
Analysis: Calcd: C: 58.17; H: 5.92; N: 17.85; Cl:
18.07; Found: C: 58.41; H: 5.85: N: 18.10; Cl:
17.75;
NMR (CDC13, 300 MHz)=: 0.90-1.05 (m, 6H), 1.35-1.55
(m, 2H), 1 . 55-1 .85 (m, 4H), 2.35 (s, 3H), 2.48 (s,
3H), 4.20-4.35 (m, 1H), 6.15 (d, J = 8, 1H), 7.30
(s, 2H), 7.50 (d, J = 1, 1H).
n) CI-HRMS: Calcd: 337.0623, Found: 337.0689 (M + H);
Analysis: Calcd: C: 53.43; H: 4.18; N: 16.62; Cl:
21.03, Found: C: 53.56; H: 4.33; N: 16.56; Cl:
20.75;
NMR (CDC13, 300 MHz) : 1.60 (t, J = 8, 3H), 2.40 (s,
3H), 2.55 (s, 3H), 4.80 (q, J= 8, 2H), 7.30 (d, J
= 8, 1H), 7.35 (dd, J = 8, 1, 1H), 7.55 (d, J = 1,
1H).
o) CI-HRMS: Calcd: 383.2321, Found: 383.2309 (M + H);
NMR (CDC13, 300 MHz) : 2.00 (s, 6H), 2.20 (s, 3H),
2.30 (s, 3H), 2.45 (s, 3H), 3.45 (s, 6H), 3.61 (dd,
J= 8, 8, 2H), 3.70 (dd, J = 8, 8, 2H), 4.60-4.70
(m, 1H), 6.70 (d, J = 8, 1H), 6.94 (s, 2H).
p) CI-HRMS: Calcd: 370.2243, Found: 370.2246 (M + H);
-123-


CA 02259583 1999-01-04

WO 98/03510 PCT/US97/13072
Analysis: Calcd: C: 65.02; H: 7.38; N: 18.96;
Found: C: 65.22; H: 7.39; N: 18.71;
NMR (CDC13, 300 MHz) : 2.18 (s, 3H), 2.30 (s, 3H),
2.45 (s, 3H), 3.45 (s, 6H), 3.60 (dd, J = 8, 8,
2H), 3.69 (dd, J = 8, 8, 2H), 4.60-4.70 (m, 1H),
6.70 (d, J 8, 1H), 7.05 (d, J = 8, 1H), 7.07 (d,
J = 8, 1H) , 7. 10 (s, 1H) .
q) CI-HRMS: Calcd: 384.2400, Found: 384.2393 (M + H);
NMR (CDC13, 300 MHz): 2.16 (s, 3H), 2.25 (s, 3H),
2.35 (s, 3H), 2.39 (s, 3H), 3.40 (s, 6H), 3.77 (t,
J= 8, 4H), 4.20-4.45 (m, 4H), 7.02 (d, J= 8, 1H)
7.05 (s, 1H), 7.10 (d, J= 7, 1H).
r) CI-HRMS: Calcd: 354.2294, Found: 354.2271 (M + H);
Analysis: Calcd: C: 67.96; H: 7.71; N: 19.81;
Found: C: 67.56; H: 7.37; N: 19.60;
NMR (CDC13, 300 MHz) : 1.03 (t, J = 8, 3H), 1.65-
1.88 (m, 2H), 2.17 (s, 3H), 2.30 (s, 3H), 2.35 (s,
3H), 2.45 (s, 3H), 3.40 (s, 3H), 3.50-3.62 (m, 2H),
4.30-4.45 (m, 1H), 6.51 (d, J= 8, 1H), 7.04 (d, J
= 8, 1H), 7.10 (d, J=8, 1H), 7.12 (s, 1H).
s) CI-HRMS: Calcd: 338.2345, Found: 338.2332 (M + H);
Analysis: Calcd: C: 71.18; H: 8.06; N: 20.75;
Found: C: 71.43; H: 7.80; N: 20.70;
NMR (CDC13, 300 MHz) : 1.00 (t, J = 8, 6H), 1.55-
1.70 (m, 2H), 1.70-1.85 (m, 2H), 2.19 (s, 3H), 2.30
(s, 3H), 2.35 (s, 3H), 2.46 (s, 3H), 4.15-4.26 (m,
1H), 6.17 (d, J= 8, 1H), 7.06 (d, J= 8, 1H), 7.10
(d, J= 1, 1H), 7.13 (s, 1H).
t) CI-HRMS: Calcd: 324.2188, Found: 324.2188 (M + H);
NMR (CDC13, 300 MHz) : 1.25 (t, J = 8, 6H) , 2.16 (s,
3H), 2.28 (s, 3H), 2.35 (s, 3H), 2.40 (s, 3H),
3.95-4.20 (m, 4H), 7.05 (dd, J = 8, 1, 1H), 7.07
(s, 1H), 7.10 (d, J = 1, 1H)
u) CI-HRMS: Calcd: 346.1780, Found: 346.1785 (M + H);
Analysis: Calcd: C: 66.07; H: 5.54; N: 28.39;
Found: C: 66.07; H: 5.60; N: 27.81;

-124-

T


CA 02259583 1999-01-04

WO 98/03510 PCT/US97/13072
NMR (CDC13, 300 MHz) : 2.15 (s, 3H), 2.32 (s, 3H)
2.17 (s, 3H), 2.52 (s, 3H), 5.25-5.35 (m, 4H), 7.08
(s, 2H), 7.15 (s, 1H).
v) CI-HRMS: Calcd: 340.2137, Found: 340.2137 (M + H);
Analysis: Calcd: C: 67.23; H: 7.42; N: 20.63;
Found:C: 67.11; H: 7.39; N: 20.26;
NMR (CDC13, 300 MHz): 1.40 (d, J = 8, 3H), 2.16 (s,
3H), 2.32 (s, 3H), 2.35 (s, 3H), 2.47 (s, 3H), 3.42
(s, 3H), 3.50-3.60 (m, 2H), 4.50-4.15 (m, 1H), 6.56
(d, J= 8, 1H), 7.00-7.15 (m, 3H).
w) CI-HRMS: Calcd: 355.2134, Found: 355.2134 (M + H);
NMR (CDC13, 300 MHz): 1.05 (t, J = 8, 3H), 1.85-
2.00 (m, 2H), 2.17 (s, 3H), 2.36 (s, 6H), 2.50 (s,
3H), 3.41 (s, 3H), 3.45 (dd, J= 8, 3, 1H), 3.82
(dd, J = 8, 1, 1H) , 5. 70-5 .80 (m, 1H), 7.00-7.20
(m, 3H).
x) CI-HRMS: Calcd: 364.2501, Found: 364.2501 (M + H);
NMR (CDC13, 300 MHz)': 0.35-0.43 (m, 2H), 0.50-0.60
(m, 2H), 0.98 (t, J= 8, 3H), 1.20-1 . 30 (m, 1H),
1.72-1.90 (m, 2H), 2.18 (s, 3H) 2.28 (s, 3H), 2.35
(s, 3H), 2.40 (s, 3H), 3. 88-4 . 03 (m, 2H), 4. 03-4 .20
(m, 2H), 7.00-7.15 (m, 3H).
y) CI-HRMS: Calcd: 353.2454, Found: 353.2454 (M + H);
Analysis: Calcd: C: 68.15; H: 8.02; N: 23.84;
Found: C: 67.43; H: 7.81; N: 23.45;
NMR (CDC13, 300 MHz): 1.38 (d, J = 8, 3H), 2.18 (s,
3H), 2.30-2.40 (m, 12H), 2.47 93, 3H), 2.60-2.75
(m, 2H), 4.30-4.50 (m, 1H), 6.60-6.70 (m, 1H),
7.00-7.15 (m, 3H).
z) CI-HRMS: Calcd: 361.2140, Found: 361.2128 (M + H);
NMR (CDC13, 300 MHz): 0.75-0.83 (m, 2H), 1.00-1.10
(m, 2H), 2.17 (s, 3H), 2.30 (s, 3H), 2.36 (s, 3H),
2.47 (s, 3H), 2.85 (t, J = 8, 2H), 3.30-3.40 (m,
1H), 4.40-4.55 (m, 2H), 7.00-7.18 (m, 3H).
aa) CI-HRMS: Calcd: 363.2297, Found: 363.2311 (M + H);
-125-


CA 02259583 1999-01-04

WO 98/03510 PCT/US97/13072
NMR (CDC13, 300 MHz): 1.01 (t, 3H, J=8), 1.75-1.90
(m,2H), 2.15 (s,3H), 2.19 (s, 3H), 2.35 (s, 3H),
2. 40 (s, 3H) , 2. 40 (s, 3H) , 2. 98 (t, 2H, J = 8) ,
3.97-4.15 (m, 2H) , 4.15-4.30 (m, 2H) , 7.03(d, 1H,
1H), 7.08 (d, 1H, J = 8), 7.10 (s, 1H).
ab) CI-HRMS: Calcd: 363.2297, Found: 363.2295 (M + H);
NMR (CDC13, 300 MHz): 1.01 (t, 3H, J = 8), 1.35-
1.55 (m, 2H), 1.75-1.90 (m, 2H), 2.15 (s, 3H), 2.30
(s, 3H), 2.36 (s, 3H), 2.46 (s, 3H), 4.10-4.30 (m,
2H), 4.95-5.10 (br s, 2H), 7.05 (d, 1H, J = 8),
7.10 (d, 1H, J = 8), 7.15 ( s, 1H).
ac) CI-HRMS: Calcd: 368.2450, Found: 368.2436;
Analysis: Calcd: C, 68.62, H, 7.95, N, 19.06;
Found: C, 68.73, H, 7.97, N, 19.09; NMR (CDC13, 300
MHz): 1.05 (t, J = 8, 3H), 1.70-1.90 (m, 2H), 2.01
(d, J = 3, 6H), 2.20 (s, 3H), 2.30 (s, 3H), 2.46,
2.465 (s, s, 3H), 3.42, 3.48 (s, s, 3H), 3.53-3.63
(m, 2H), 4 . 35-4 . 45 (m, 1H), 6.73 (d, J = 8, 1H),
6.97 (s, 2H).
(ad) CI- HRMS: Calcd: 352.2501, Found: 352.2500 (M +
H): Analysis: Calcd: C: 71.76; H: 8.33; N: 19.92,
Found: C: 71.55; H: 8.15; N: 19.28;
NMR (CDC13, 300 MHz) : 1. 01 (t, J = 8, 6H), 1.58
-1.70 (m, 2H), 1.70-1.85 (m, 2H), 2.02 (s, 6H),
2.19 (s, 3H), 2.45 (s, 3H), 4.12-4.28 (m, 1H), 6.18
(d, J= 8, 1H), 6.95 (s, 2H).
(ae) CI- HRMS: Calcd: 398.2556, Found: 398.2551 (M +
H); Analysis: Calcd: C: 66.47; H: 7.86; N: 17.62,
Found: C: 66.74; H: 7.79; N: 17.70;
NMR (CDC13, 300 MHz) : 2.00 (s, 6H), 2.12 (s, 3H),
2.30 (s, 3H), 2.37 (s, 3H), 3.40 (s, 6H), 3.78 (t,
J= 8, 4H), 4.25-4.40 (m, 4H), 6.93 (s, 2H).
(af) CI-HRMS: Calcd: 450.1141, Found: 450.1133 (M + H);
Analysis: Calcd: C: 50.67; H: 5.37; N: 15.55; Br:
17.74; Found: C: 52.36; H: 5.84; N: 14.90; Br:
17.44;

-126-

T


CA 02259583 1999-01-04

WO 98/03510 PCT/US97/13072
NMR (CDC13, 300 MHz) : 2.32 (s, 3H), 2.57 (s, 3H),
3.42 (s, 6H), 3.60 (q, J = 8, 2H), 3.69 (q, J= 8,
2H), 3.82 (s, 3H), 4.60-4.70 (m, 1H), 6.73 (d, J
8, 1H), 6.93 (dd, J= 8, 1, 1H), 7.22 (d, J = 8,
1H).
ag) CI-HRMS: Calcd: 434.1192, Found: 434.1169 (M + H);
Analysis: Calcd: C: 52.54; H: 5.58; N: 16.12; Br:
18.40; Found: C: 52.57; H: 5.60; N: 15.98; Br:
18.22;
NMR (CDC13, 300 MHz): 1.00-1.07 (m, 3H), 1.65-1.85
(m, 2H), 2.35 (s, 3H), 2.46, 2.47 (s, s, 3H), 3.40,
3.45 (s, s, 3H), 3.83 (s, 3H), 4.35-4.45 (m, 1H),
6.55 (d, J= 8, 1H), 6.92 (dd, J= 8, 1, 1H), 7.20-
7.30 (m, 2H).
ah) CI-HRMS: Calcd: 337.2266, Found: 337.2251 (M + H);
Analysis: Calcd: C: 70.18; H: 8.06; N: 20.75;
Found: C: 70.69; H: 7.66; N: 20.34;
NMR (CDC13, 300 MHz): 1.35'(t, J = 8, 6H), 2.01 (s,
6H), 2.15 (s, 3H), 2.30 (s, 3H), 2.38 (s, 3H), 4.07
(q, J = 8, 4H), 6.93 (s, 2H).
ai) CI-HRMS: Calcd: 412.2713, Found: 412.2687 (M + H);
Analysis: Calcd: C: 67.13; H: 8.08; N: 17.02;
Found : C: 67.22; H: 7.85; N: 17.13;
NMR (CDC13, 300 MHz):1.24 (t, J = 8, 6H), 2.00 (s,
6H), 2.20 (s, 3H), 2.30 (s, 3H), 2.43 (s, 3H), 3.60
(q, J = 8, 4H), 3.66 (dd, J = 8, 3, 2H), 3.75 (dd,
J= 8, 3, 2H), 4.55-4.65 (m, 1H), 6.75 (d, J = 8,
1H), 6.95 (s, 2H).
aj) CI-HRMS: Calcd: 398.2556, Found: 398.2545 (M + H);
Analysis: Calcd: C: 66.47; H: 7.86; N: 17.62;
Found: C: 66.87; H: 7.62; N: 17.75;
NMR (CDC13, 300 MHz): 1.95-2.10 (m, 8H), 2.20 (s,
3H), 2.32 (s, 3H), 2.44 (s, 3H), 3.38 (s, 3H), 3.42
(s, 3H), 3.50-3.70 (m, 4H), 4.58-4.70 (m, 1H), 6.87
(d, J = 8, 1H), 6.95 (s, 2H).
ak) CI-HRMS: Calcd: 338.1981, Found: 338.1971 (M + H);
-127-


CA 02259583 1999-01-04

WO 98/03510 PCT/US97/13072
Analysis: Calcd: C: 67.63; H: 6.87; N: 20.06;
Found: C: 67.67; H: 6.82; N: 20.31;
NMR (CDC13, 300 MHz): 2.15 (s, 3H), 2.29 (s, 3H),
2.35 (s, 3H), 2.43 (s, 3H), 3.90 (t, J = 8, 4H),
4.35-4.45 (m, 4H), 7.00-7.15 (m, 3H).
al) CI-HRMS: Calcd: 464.1297, Found: 464.1297 (M + H);
NMR (CDC13, 300 MHz) : 2.28 (s, 3H), 2.40 (s, 3H),
3.40 (s, 6H), 3.75 (t, J = 8, 4H), 3.83 (s, 3H),
4.20-4.50 (m, 4H), 6.93 (dd, J= 8, 1, 1H), 7.20
(s, 1H) , 7.24 (d, J = 1, 1H) .
am) CI-HRMS: Calcd: 418.1242, Found: 418.1223 (M + H);
NMR (CDC13, 300 MHz) : 1.00 (t, d, J = 8, 1, 6H),
1.55-1.75 (m, 4H), 2.34 (s, 3H), 2.49 (s, 3H), 2.84
(s, 3H), 4.15-4.27 (m, 1H), 6.19 (d, J = 8, 1H),
6.93 (dd, J = 8, 1, 1H), 7. 21-7 . 30 (m, 2H).
an) CI-HRMS: Calcd: 404.1086, Found: 404.1079(M + H);
NMR (CDC13, 300 MHz): 1.35 (t, J = 8, 6H), 2.28 (s,
3H), 2.40 (s, 3H), 3.83 (s, 3H), 3.90-4.08 (m, 2H),
4.08-4.20 (m, 2H), 6.92 (dd, J= 8, 1, 1H), 7.20-
7.25 (m, 2H).
ao) CI-HRMS: Calcd: 308.1875, Found: 308.1872 (M + H);
NMR (CDC13, 300 MHz): 0.75-0.80 (m, 2H), 0.93-1.00
(m, 2H), 2.16 (s, 3H), 2.28 (s, 3H), 2.35 (s, 3H),
2.53 (s, 3H), 3.00-3.10 (m, 1H), 6.50-6.55 (m, 1H),
7.00-7.15 (m, 3H).
ap) CI-HRMS: Calcd: 397.1988, Found: 397.1984 (M + H);
NMR (CDC13, 300 MHz): 2.43 (s, 3H), 2.50 (s, 3H),
3.43 (s, 3H), 3.61 (dd, J = 8, 8, 2H), 3.69 (dd,J =
8, 8, 2H), 3.88 (s, 3H), 4.58-4.70 (m, 1H), 6.75
(d, J = 8, 1H), 7.20 (dd, J = 8, 1, 1H), 7.25 (d, J
= 1, 1H) , 7 .40 (s, 1H) .
aq) CI-HRMS: Calcd: 375.2297, Found: 375.2286 (M + H);
Analysis: Calcd: C: 70.56; H: 7.01; N: 22.44;
Found: C: 70.49; H: 6.99; N: 22.45;
NMR (CDC13, 300 MHz): 0.79-0.85 (m, 2H), 1.00-1.05
(m, 1H), 2.00 (s, 6H), 2.19 (s, 3H), 2.32 (s, 3H),
-128-

T


CA 02259583 1999-01-04

WO 98/03510 PCT/US97/13072
2.44 (s, 3H), 2.84 (t, J= 8, 2H), 3.30-3.40 (m,
1H) , 4.50 (t, J = 8, 2H) , 6. 95 (s, 2H) .
ar) CI-HRMS: Calcd: 434.1192, Found: 434.1189 (M + H);
Analysis: Calcd: C: 52.54; H: 5.58; N: 16.12; Br:
18.40; Found: C: 52.75; H: 5.59; N: 16.09; Br:
18.67;
NMR (CDC13, 300 MHz): 2.19 (s, 3H), 2.30 (s, 3H),
2.47 (s, 3H), 3.43 (s, 6H), 3.60 (dd, J = 8, 8,
2H), 3.70 (dd, J = 8,8, 2H), 4.58-4.70 (m, 1H),
6.71 (d, J = 8, 1H), 7.08 (d, J = 8, 1H), 7.37 (dd,
J= 8, 1, 1H) , 7. 45 (d, J = 1, 1H) .
as) CI-HRMS: Calcd: 448.1348, Found: 448.1332(M + H);
Analysis: Calcd: C: 53.58; H: 5.85; N: 16.62; Br:
17.82; Found: C: 53.68; H: 5.74; N: 15.52; Br:
13 . 03;
NMR (CDC13, 300 MHz): 1.95-2.10 (m, 2H), 2.20 (s,
3H), 2.30 (s, 3H), 2.47 (s, 3H), 3.38 (s, 3H), 3.41
(s, 3H), 3. 50-3. 67 (m, 4H), 4.55-4 . 70 (m, 1H), 6.89
(d, J= 8, 1H), 7.05 (d, J= 8, 1H), 7.35 (dd, J
8, 1, 1H), 7.47 (d, J = 1, 1H).
at) CI-HRMS: Calcd: 400.2349, Found: 400.2348 (M + H);
Analysis: Calcd: C: C: 63.14; H: 7.32; N: 17.53;
Found: C:63.40; H: 7.08; N: 17.14;
NMR (CDC13, 300 MHz): 2.16 (s, 3H), 2.20 (s, 3H),
2.30 (s, 3H), 2.46 (s, 3H), 3.42 (s, 6H), 3.60 (q,
J = 8, 2H), 3.70 (q, J = 8, 2H), 3.85 (s, 3H),
4.59-4.70 (m, 1H), 6.70 (d, J= 8, 1H), 6.76 (s,
1H), 6.96 (s, 1H).
au) CI-HRMS: Calcd: 414.2505, Found: 414.2493 (M + H);
NMR (CDC13, 300 MHz): 2.15 (s, 3H), 2.19 (s, 3H),
2.25 (s, 3H), 2.40 (s, 3H), 3.40 (s, 6H), 3.76 (t,
J = 8, 4H), 3.84 (s, 3H), 4.20-4 . 45 (m, 4H), 6.77
(s, 1H), 6.93 (s, 1H).
av) CI-HRMS: Calcd: 368.2450, Found: 368.2447 (M + H);
NMR (CDC13, 300 MHz): 1.00 (t, J = 8, 6H), 1.55-
1.85 (m, 4H), 2.19 (s, 3H), 2.20 (s, 3H), 2.30 (s,

-129-


CA 02259583 1999-01-04

WO 98/03510 PCT/US97/13072
3H), 2.47 (s, 3H), 3.88 (s, 3H), 4.10-4.30 (m, 1H),
6. 15 (d, J = 8, 1H) , 6. 78 (s, 1H) , 6.98 (s, 1H).
aw) CI-HRMS: Calcd: 353.2216, Found: 353.2197 (M + H);
NMR (CDC13, 300 MHz) : 1.35 (t, J= 8, 6H), 2.17 (s,
3H), 2.19 (s, 3H), 2.28 (s, 3H), 2.40 (s, 3H), 3.85
(s, 3H), 3. 90-4 .20 (m, 4H), 6.78 (s, 1H), 6.95 (s,
1H).
ax) CI-HRMS: Calcd: 390.1697, Found: 390.1688 (M + H);
Analysis: Calcd: C: 58.53; H: 6.20; N: 17.96; Cl:
9.09; Found: C: 58.95; H: 6.28; N: 17.73; Cl: 9.15;
NMR (CDC13, 300 MHz): 2.35 (s, 3H), 2.37 -(s, 3H),
2. 48 (s, 3H) , 3. 42 (s, 6H) , 3.60 (dd, J = 8, 8, 2H)
3.68 (dd, J = 8, 8, 2H), 4.59-4.72 (m, 1H), 6.72
(d, J = 8, 1H), 7.12 (d, J = 8, 1H), 7.23 (d, J
8, 1H), 7.32 (s, 1H).
ay) CI-HRMS: Calcd: 374.1748, Found: 374.1735 (M + H);
Analysis: Calcd: C: 61.04; H: 6.47; N: 18.73; Cl:
9.48; Found: C: 61..47; H: 6.54; N: 18.23; Cl: 9.61;
NMR (CDC13,300 MHz): 1.01 (t, J = 8, 3H), 1.62-
1.88 (m, 4H), 2.35 (s, 3H), 2.37 (s, 3H), 2.48 (d,
J= 1, 3H), 3.40, 3.45 (s, s, 3H), 3.50-3.64 (m,
2H), 4.38-4 . 47 (m, 1H), 6.53 (d, J= 8, 1H), 7.12
(d, J = 8, 1H), 7.07 (d, J= 8, 1H), 7.12 (s, 1H).
az) CI-HRMS: Calcd: 404.1853, Found: 404.1839 (M + H);
NMR (CDC13, 300 MHz): 2.29 (s, 3H), 2.38 (s, 3H),
2.40 (s, 3H), 3.40 (s, 6H), 3.76 (t, J = 8, 4H),
4.20-4.45 (m, 4H), 7.11 (d, J = 8, 1H), 7.22 (d, J
= 8, 1H), 7.31 (s, 1H).
ba) CI-HRMS: Calcd: 404.1853, Found: 404.1859 (M + H);
Analysis: C: 59.47; H: 6.50; N: 17.34; Cl: 8.79;
Found: C: 59.73; H: 6.46; N: 17.10; Cl: 8.73;
NMR (CDC13, 300 MHz): 1.95-2.08 (m, 2H), 2.35 (s,
3H), 2.38 (s, 3H), 2.46 (s, 3H), 3.38 (s, 3H), 3.41
(s, 3H), 3 .50-3 . 65 (m, 4H), 4 .56-4 .70 (m, iH) , 6.85
(d, J 8, IH) , 7.12 (d, J= 8, 1H), 7.45 (d, J
8, 1H), 7.32 (s, 1H)

-130-
T


CA 02259583 1999-01-04

WO 98/03510 PCT/US97/13072
bb) CI-HRMS: Calcd: 391.2246, Found: 391.2258 (M + H);
Analysis: C: 67.67; H: 6.71; N: 21.52; Found: C:
67.93; H: 6.70; N: 21.48;
NMR (CDC13, 300 MHz): 0.76-0.84 (m, 2H), 0.84-0.91
(m, 2H), 1. 00-1 . 08 (m, 2H), 2.15 (s, 3H), 2.20 (s,
3H), 2.29 (s, 3H), 2.45 (s, 3H), 2.85 (t, J= 8,
2H), 3 .28-3 .30 (m, 1H), 3.85 (s, 3H), 6.78 (s, 1H),
6.95 (s, 1H).
bcr CI-HRMS: Calcd: 386.2192, Found: 386.2181 (M + H);
Analysis: C: 62.32; H: 7.06; N: 18.17; Found: C:
62.48; H: 6.83; N: 18.15;
NMR (CDC13, 300 MHz): 7.1 (d, 1H, J= 8), 6.9 (d,
1H, J = 1), 6.8 (dd, 1H, J = 8, 1) , 6.7 (br. d, 1H,
J= 8), 4.7-4.6 (m, 1H), 3.85 (s, 3H), 3.70-3.55
(m, 4H), 3.45 (s, 6H), 2.5 (s, 3H) , 2.3 (s, 3H),
2.15 (s, 3H).
bd) CI-HRMS: Calcd: 400.2349, Found: 400.2336 (M + H);
NMR (CDC13, 300 MHz) : 7.1 (d, 1H, J = 7), 6.85 (d,
1H, J = 1), 6.75 (dd, 1H, J 7,1), 4.45-4.25
(br.s, 4H), 3.75 (t, 4H, J 7), 3.4 (s, 6H), 2.4
(s, 3H), 2.25 (s, 3H), 2.15 (s, 3H).
be) CI-HRMS: Calcd: 370.2243, Found: 370.2247 (M + H);
Analysis: C: 65.02; H: 7.38; N: 18.96; Found: C:
65.28; H: 7.27; N: 18.71;
NMR (CDC13, 300 MHz) : 7.1 (d, 1H, J = 8), 6.85 (d,
1H, J = 1), 6.8 (dd, 1H, J = 8, 1) , 6.5 (br. d, 1H,
J= 1), 4.5-4.3 (m, 1H), 3.85 (s, 3H), 3.65-3.5 (m,
2H), 3. 4(s, 2H), 2.5 (s, 3H), 2.3 (s, 3H), 2.2 (s,
3H), 1. 9-1 .7 (m, 2H), 1.05 (t, 3H, J= 7) .
bf) CI-HRMS: Calcd: 379.2246, Found: 379.2248 (M + H);
NMR (CDC13, 300 MHz) : 7.1 (d, 1H, J = 8), 6.85 (d,
1H, J = 1), 6.8 (dd, 1H, J 8, 1) , 4. 3-4 . 0 (m, 4H),
3.85 (s, 3H), 3.0 (t, 2H, J 7), 2.45 (s, 3H), 2.3
(s, 3H), 2.2 (s, 3H), 1.9-1.8 ( m, 2H), 1.0 (t, 3H,
J = 7).
bg) CI-HRMS: Calcd: 340.2137, Found: 340.2122 (M + H);
-131-


CA 02259583 1999-01-04

WO 98/03510 PCT/US97/13072
NMR (CDC13, 300 MHz) : 7. 1(d, 1H, J = 8), 6.85 (d,
1H, J= 1), 6.75 (dd, ZH, J = 8, 1) , 4.2-4.0 (br.m,
4H), 3.85 (s, 3H, 2.4 (s, 3H), 2.3 ( s, 3H), 2.2
(s, 3H), 1.35 (t, 6H, J = 7).
bh) CI-HRMS: Calcd: 313.1665, Found: 313.6664 (M + H).
bi) CI-HRMS: Calcd: 400.2349, Found: 400.2346 (M + H);
NMR (CDC13, 300 MHz) : 7.1 (d, 1H, J = 7), 6.9-6.75
(m, 3H), 4. 7-4 .55 (m, 1H), 3.8 (s, 3H), 3, 7-3. 5(m,
4H), 3.45 (s, 3H), 3.35 (s, 3H), 2.5 (s, 3H), 2.3
(s, 3H), 2.2 (s, 3H), 2. 1-1 . 95 (m, 2H).
bj) CI-HRMS: Calcd: 377.2090, Found: 377.2092 (M + H);
Analysis: C: 67.00; H: 6.44; N: 22.32; Found: C:
67.35; H: 6.44; N: 22.23;
NMR (CDC13, 300 MHz) : 7 . 1 ( d , 1H, J = 8 ), 6. 9(d,
1H, J= 1), 6.8 (dd, 1H, J = 8, 1) , 4. 55-4 . 4 (m,
2H), 3.85 (s, 3H), 3.4-3.3 (m, 1H), 2.85 (t, 2H, J
= 7), 2.5 (s, 3H), 2.3 (s, 3H), 2.2 (s, 3H), 1.1-
1.0 (m, 2H) , 0. 85-0-. 75 (m, 2H)
bk) CI-HRMS: Calcd: 413.2427, Found: 413.2416 (M + H);
NMR (CDC13, 300Hz) : 7.1 (d, 1H, J = 8), 6.85 (d,
1H, J = 1), 6.75 (dd, 1H, J = 8,1), 4.6 (m, 1H),
3.85 (s, 3H), 3.75-3.6(m, 4H), 3.6 (q, 4H, J = 7),
2.5 (s, 3H), 2.3 s, 3H), 2.2 (s, 3H), 1.25 (t, 6H,
J = 7).
bl) CI-HRMS: Calcd: 420.1802, Found: 420.1825(M + H);
bm) CI-HRMS: Calcd: 390.1697, Found: 390.1707(M + H);
bn) CI-HRMS: Calcd: 397.1465, Found: 397.1462(M + H);
bo) CI-HRMS: Calcd: 360.1513, Found: 360.1514(M + H);
bp) CI-HRMS: Calcd: 374.1748, Found: 374.1737(M + H);
bq) CI-HRMS: Calcd: 479.1155, Found: 479.1154(M + H);
br) CI-HRMS: Calcd: 463.1219, Found: 463.1211(M + H);
Analysis Calcd: C: 51.96, H: 5.23, N, 15.15, Br:
17.28; Found: C: 52.29, H: 5.62, N: 14.79, Br:
17.47
bs) CI-HRMS: Calcd: 433.1113, Found: 433.1114(M, 79Br);
bt) NH3-CI MS: Calcd: 406, Found: 406 (M + H)+;

-132-

i


CA 02259583 1999-01-04

WO 98/03510 PCT/US97/13072
NMR (CDC13, 300 MHz) : S 7.28 (d, J=lOHz, 1H), 7.03
( d , J=8Hz, 1H), 6.96 ( s , 1H), 6. 7(d, J=9, 1H),
4.63 (m, 1H), 3.79 (s, 3H), 3.6 (m, 4H), 3.42 (s,
6H), 2.47 (s, 3H), 2.32 (s, 3H).

EXAMPLE 431
Preparation of 2,4,7-dimethyl-8-(4-methoxy-2-
methylphenyl)[1,5-aJ-pyrazolo-1,3,5-triazine
(Formula 1, where R3 is CH3, R1 is CH3, Z is C-CH3, Ar is
2,4-dimethylphenyl)
5-Acetamidino-4-(4-methoxy-2-methylphenyl)-3-
methylpyrazole, acetic acid salt ( 602 mg, 2 mmol) was
mixed with a saturated NaHCO3 solution (10 mL). The
aqueous mixture was extracted with EtOAc three times.
The combined organic layers were dried over MgSO4,
filtered and concentrated in vacuo. The residue was
taken up in toluene (10 mL) and trimethyl orthoacetate
0.36 g, 3 mmol) was added to the suspension. The
reaction mixture was heated to reflux temperature under
a nitrogen atmosphere and stirred for 16 hours. After
being cooled to ambient temperature, the reaction
mixture was concentrated in vacuo to give an oily solid.
Column chromatography (CHC13:MeOH::9:1) afforded, after
removal of solvent in vacuo, a yellow viscous oil (Rf =
0.6, 210 mg, 37% yield): NMR (CDC13, 300 MHz): 7.15 (d,
1H, J = 8 ), 6. 9(d, 1H, J = 1), 6.85 (dd, 1H, J = 8, 1) ,
3.85 (s, 3H), 2.95 (s, 3H), 2.65 (s, 3H), 2.4 (s, 3H),
2.15 (s, 3H); CI-HRMS: Calcd: 283.1559, Found:
283.1554 (M + H).


-133-


CA 02259583 1999-01-04

WO 98/03510 PCTIUS97/13072
EXAMPLE 432
7-hydroxy-5-methyl-3-(2-chloro-
4-methylphenyl)pyrazolo[1,5-a]pyrimidine
(Formula 1 where A is CH, R1 is Me, R3 is OH,
Z is C-Me, Ar is 2-chloro-4-methylphenyl)

5-Amino-4-(2-chloro-4-methylphenyl)-3-
methylpyrazole (1.86 g, 8.4 mmol) was dissolved in
glacial acetic acid (30 mL) with stirring. Ethyl
acetoacetate (1.18 mL, 9.2 mmol) was then added dropwise
to the resulting solution. The reaction mixture was
then heated to reflux temperature and stirred for 16
hours, then cooled to room temperature. Ether (100 mL)
was added and the resulting precipitate was collected by
filtration. Drying in vacuo afforded a white solid (
1.0 g, 42% yield): NMR (CDC13, 300Hz): 8.70 (br.s 1H),
7.29 ( s, 1H), 7.21-7.09 ( m, 2H), 5.62 (s, 1H), 2.35
(s, 6H), 2.29 (s, 3H) ; C-I-MS: 288 (M+H).

EXAMPLE 433
7-chloro-5-methyl-3-(2-chloro-
4-methylphenyl)pyrazolo[1,5-a]pyrimidine
(Formula 1 where A is CH, R1 is Me, R3 is Cl,
Z is C-Me, Ar is 2-chloro-4-methylphenyl)
A mixture of 7-hydroxy-5-methyl-3-(2-chloro-4-
methylphenyl)-pyrazolo[1,5-a]pyrimidine (1.0 g, 3.5
mmol), phosphorus oxychloride (2.7 g, 1.64 mL, 17.4
mmol), N,N-diethylaniline (0.63 g, 0.7 mL, 4.2 mmol) and
toluene (20 mL) was stirred at reflux temperature for 3
hours, then it was cooled to ambient temperature. The
volatiles were removed in vacuo. Flash chromatography
(EtOAc:hexane::l:2) on the residue gave 7-chloro-5-
methyl-3-(2-chloro-4-methylphenyl)-pyrazolo[1,5-
a]pyrimidine (900 mg, 84% yield) as a yellow oil: NMR
-134-

T


CA 02259583 1999-01-04

WO 98/03510 PCT/US97/13072
(CDC13, 300Hz): 7.35 (s, 1H), 7.28-7.26 (m, 1H), 71.6
d, 1H, J= 7), 6.80 (s, 1H), 2.55 (s, 3H), 2.45 (s, 3H),
2.40 (s, 3H); CI- MS: 306 (M+H).

EXAMPLE 434
7-(pentyl-3-amino)-5-methyl-3-(2-chloro-
4-methylphenyl)pyrazolo[1,5-a]pyrimidine
(Formula 1 where A is CH, Rl is Me, R3 is pentyl-3-
amino, Z is C-Me, Ar is 2-chloro-4-methylphenyl)
A solution of 3-pentylamine (394mg, 6.5 mmol) and
7-chloro-5-methyl-3-(2-chloro-4-
methylphenyl)pyrazolo[1,5-a]pyrimidine (200 mg, 0.65
mmol) in dimethylsulfoxide (DMSO, 10 mL) was stirred at
150 C for 2 hours; then it was cooled to ambient
temperature. The reaction mixture was then poured onto
water (100 mL) and mixed`. Three extractions with
dichloromethane, washing the combined organic layers
with brine, drying over MgSO4, filtration and removal of
solvent in vacuo produced a yellow solid. Flash
chromatography (EtOAc:hexanes::1:4) afforded a white
solid (140 mg, 60% yield): mp 139-141 C; NMR (CDC13,
300Hz) : 7.32 (s, 1H), 7.27 (d, 1H, J = 8), 7.12 (d, 1H, J
= 7), 6.02 (d, 1H, J = 9), 5.78 ( s, 1H), 3.50-3.39 (m,
1H), 2.45 (s, 3H), 2.36 (s, 6H), 1.82-1.60 (m, 4H), 1.01
(t, 6H, J = 8); Analysis Calcd for C20H25C1N4: C, 67.31,
H, 7.06, N, 15.70, Cl: 9.93; Found: C, 67.32, H, 6.95,
N, 15.50, Cl, 9.93.
The examples delineated in TABLE 2 may be prepared by
the methods outlined in Examples 1A, 1B, 432, 433, 434.
Commonly used abbreviations are: Ph is phenyl, Pr is
propyl, Me is methyl, Et is ethyl, Bu is butyl, Ex is
Example, EtOAc is ethyl acetate.
-135-


CA 02259583 1999-01-04

WO 98/03510 PCTIUS97/13072
TABLE 2

R3
~ N,,N\
Z
\

Ar
&r ma_t~1
435b C-Me N(CH2CH2OMe)2 2,4-C12-Ph 71-73
436c C-Me N(Bu)Et 2,4-C12-Ph 86-87
437d C-Me NHCH(Et)CH2OMe 2,4-C12-Ph 110-111
438e C-Me N(Pr)CH2CH2CN 2,4-C12-Ph 83-85
439f C-Me NH-3-pentyl 2,4-C12-Ph 175-176
440g C-Me NHCH(CH20Me)2 2,4-C12-Ph 107
441h C-Me NHCH(Et)2 2,4-Me2-Ph oil
4421 C-Me NHCH(CH2OMe)2 2,4-Me2-Ph 103-105
443J C-Me N(CH2CH2OMe)2 2,4-Me2-Ph 87-89
444k C-Me N(c-Pr)CH2CH2CN 2,4-Me2-Ph 133(dec)
4451 C-Me N(CH2CH2OMe)2 2-C1,4-MePh 77-78
446m C-Me NHCH(CH2OMe)2 2-C1,4-MePh 131-133
447n C-Me NHCH(Et)2 2-C1,4-MePh 139-141
448 C-Me NEt2 2,4-Me2-Ph 92-94
449P C-Me N(Pr)CH2CH2CN 2,4-Me2-Ph 143-144
4504 C-Me N(Bu)CH2CH2CN 2,4-Me2-Ph 115-117
451r C-Me NHCH(Et)CHZOMe 2,4-Me2-Ph oil
4523 C-Me NHCH(Et)2 2-Me,4-MeOPh 104-106
453t C-Me NHCH(CH2OMe)2 2-Me,4-MeOPh 115-116
454u C-Me N(CH2CH2OMe)2 2-Me,4-MeOPh oil
455 C-Me (S)-NHCH(CH2CH2OMe)- 2-Me,4-MeOPh oil
(CH2OMe)
456W C-Me (S)-NHCH(CH2CH2OMe)- 2,4-Me2-Ph oil
(CH2OMe)

136-
T


CA 02259583 1999-01-04

WO 98/03510 PCT/US97/13072
457X C-Me N(CH2CH2OMe)2 2-Me,4-C1Ph oil
458Y C-Me NHEt 2,4-Me2-Ph oil
459Z C-Me NHCH(Et)2 2-Me,4-Clph 94-96
460aa C-Me NHCH(CH2OMe)2 2-Me,4-C1Ph 113-114
461ab C-Me N(Ac)Et 2,4-Me2-Ph oil
462ac C-Me (S)-NHCH(CH2CH2OMe)- 2-Me,4-ClPh oil
(CH2OMe)
463ad C-Me N(Pr)CH2CH2CN 2-Me,4-MeOPh 118-119
464ae C-Me NEt2 2-Me,4-MeOPh 97-99
465af C-Me (S)-NHCH(CH2CH2OMe)- 2-C1,4-MePh 101-103
(CH2OMe)

466ag C-Me NEt2 2-Cl,4-MePh 129-130
467ah C-Me N(c-Pr)CH2CH2CN 2-Me,4-MeOPh 177-178
468ai C-Me N(c-Pr)CH2CH2CN 2-Cl,4-MePh 162-163
469aj C-Me NHCH(Et)CH2OMe 2-Me,4-MeOPh oil
470ak C-Me NHCH(Et)CH2OMe 2-Cl,4-MePh 111-113
471 C-Me NHCH(CH2OMe)2 2-C1-4-MeOPh
472 C-Me N(CH2CH2OMe)2 2-Cl-4-MeOPh
473 C-Me NHCH(Et)CH2OMe 2-Cl-4-MeOPh
474 C-Me N(c-Pr)CH2CH2CN 2-Cl-4-MeOPh
475 C-Me NEt2 2-C1-4-MeOPh
476 C-Me NH-3-pentyl 2-Cl-4-MeOPh
477 C-Me NHCH(Et)CH2CH2OMe 2-Cl-4-MeOPh
478 C-Me NHCH(Me)CH2CH2OMe 2-Cl-4-MeOPh
479 C-Me NHCH(Et)CH2CH2OMe 2-Br-4-MeOPh
480 C-Me NHCH(Me)CH2CH2OMe 2-Br-4-MeOPh
481 C-Me NHCH(Et)CH2CH2OMe 2-Me-4-MeOPh
482 C-Me NHCH(Me)CH2CH2OMe 2-Me-4-MeOPh
483 C-Me NHCH(CH2OMe)2 2-Cl-4,5-(Me0)2Ph
484 C-Me N(CH2CH2OMe)2 2-Cl-4,5-(Me0)2Ph
485 C-Me NHCH(Et)CH2OMe 2-Cl-4,5-(MeO)2Ph
486 C-Me N(c-Pr)CH2CH2CN 2-Cl-4,5-(MeO)2Ph
487 C-Me NEt2 2-Cl-4,5-(Me0)2Ph 99-101
488 C-Me NH-3-pentyl 2-Cl-4,5-(MeO)2Ph 169-170
489 C-Me NHCH(Et)CH2CH2OMe 2-Cl-4,5-(Me0)2Ph

-137-


CA 02259583 1999-01-04

WO 98/03510 PCT/US97/13072
490 C-Me NHCH(Me)CH2CH2OMe 2-C1-4,5-(MeO)2Ph
491 C-Me NHCH(CH20Me)2 2-Br-4,5-(MeO)2Ph 90-93
492 C-Me N(CH2CH2OMe)2 2-Br-4,5-(MeO)2Ph 110
493 C-Me NHCH(Et)CH2OMe 2-Br-4,5-(Me0)2Ph

494 C-Me N(c-Pr)CH2CH2CN 2-Br-4,5-(Me0)2Ph
495 C-Me NEt2 2-Br-4,5-(Me0)2Ph
496 C-Me NH-3-pentyl 2-Br-4,5-(Me0)2Ph
497 C-Me NHCH(Et)CH2CH2OMe 2-Br-4,5-(Me0)2Ph
49S C-Me NHCH(Me)CH2CH2OMe 2-Br-4,5-(MeO)2Ph
499 C-Me NHCH(CH2OMe)2 2-C1-4,6-(Me0)2Ph
500 C-Me N(CH2CH2OMe)2 2-C1-4,6-(MeO)2Ph
501 C-Me NHCH(Et)CH2OMe 2-C1-4,6-(MeO)2Ph
502 C-Me N(c-Pr)CH2CH2CN 2-C1-4,6-(Me0)2Ph
503 C-Me NEt2 2-C1-4,6-(Me0)2Ph
504 C-Me NH-3-pentyl 2-C1-4,6-(Me0)2Ph
505 C-Me NHCH(Et)CH2CH2OMe 2-C1-4,6-(MeO)2Ph
506 C-Me NHCH(Me)CH2CH2OMe 2-C1-4,6-(Me0)2Ph
507 C-Me NHCH(CH2OMe)2 2-Me-4,6-(MeO)2Ph
508 C-Me N(CH2CH2OMe)2 2-Me-4,6-(Me0)2Ph
509 C-Me NHCH(Et)CH2OMe 2-Me-4,6-(MeO)2Ph
510 C-Me N(c-Pr)CH2CH2CN 2-Me-4,6-(Me0)2Ph
511 C-Me NEt2 2 -Me-4, 6- (MeO) 2Ph
512 C-Me NH-3-pentyl 2-Me-4,6-(Me0)2Ph
513 C-Me NHCH(Et)CH2CH2OMe 2-Me-4,6-(MeO)2Ph

514 C-Me NHCH(Me)CH2CH2OMe 2-Me-4, 6- (MeO) 2Ph
515 C-Me N(c-Pr)CH2CH2CN 2-Br-4,6-(Me0)2Ph
516 C-Me NEt2 2-Br-4,6-(MeO)2Ph
517 C-Me NH-3-pentyl 2-Br-4,6-(MeO)2Ph
518 C-Me NHCH(Et)CH2CH2OMe 2-Br-4, 6- (MeO) 2Ph
519 C-Me NHCH(Me)CH2CH2OMe 2-Br-4,6-(MeO)2Ph
520 C-Me NHCH(Et)CH2CH2OMe 2-Me-4-MeOPh
521 C-Me NHCH(Me)CH2CH2OMe 2-Me-4-MeOPh
522 C-Me NHCH(CH2OMe)2 2-MeO-4-MePh
523 C-Me N(CH2CH2OMe)2 2-MeO-4-MePh
524 C-Me NHCH(Et)CH2OMe 2-MeO-4-MePh
525 C-Me N(c-Pr)CH2CH2CN 2-MeO-4-MePh
-138-

1


CA 02259583 1999-01-04

WO 98/03510 PCT/US97/13072
526 C-Me NEt2 2-Me0-4-MePh
527 C-Me NH-3-pentyl 2-MeO-4-MePh
528 C-Me NHCH(Et)CH2CH2OMe 2-MeO-4-MePh
529 C-Me NHCH(Me)CH2CH2OMe 2-Me0-4-MePh
530 C-Me NHCH(CH2OMe)2 2-Me0-4-MePh
531 C-Me N (CH2CH2OMe) 2 2-MeO-4-MePh
532 C-Me NHCH(Et)CH2OMe 2-MeO-4-MePh
533 C-Me N(c-Pr)CH2CH2CN 2-Me0-4-MePh
534 C-Me NEt2 2-Me0-4-MePh

535 C-Me NH-3-pentyl 2-Me0-4-MePh
536 C-Me NHCH(Et)CH2CH2OMe 2-MeO-4-MePh
537 C-Me NHCH(Me)CH2CH2OMe 2-Me0-4-MePh
538 C-Me NHCH(CH2OMe)2 2-Me0-4-C1Ph
539 C-Me N(CH2CH2OMe)2 2-Me0-4-C1Ph
540 C-Me NHCH(Et)CH20Me 2-MeO-4-ClPh
541 C-Me N(c-Pr)CH2CH2CN 2-Me0-4-C1Ph
542 C-Me NEt2 2-Me0-4-C1Ph
543 C-Me NH-3-pentyl 2-Me0-4-C1Ph
544 C-Me NHCH(Et)CH2CH2OMe 2-Me0-4-C1Ph
545 C-Me NHCH(Me)CH2CH2OMe 2-MeO-4-ClPh
NOTES FOR TABLE 2:

b) CI-HRMS: Calcd: 423.1355; Found: 423.1337 (M + H).
c) Analysis: Calcd: C, 61.38, H, 6.18, N, 14.32:
Found: C, 61.54, H, 6.12, N, 14.37.
d) Analysis: Calcd: C: 58.02, H, 5.65, N, 14.24;
Found: C, 58.11, H, 5.52, N, 14.26.
e) Analysis: Calcd: C, 59.71, H, 5.26, N, 14.85;
Found: C, 59.94, H, 5.09, N, 17.23.
f) Analysis: Calcd: C, 60.48, H, 5.89, N, 14.85,
Found: C, 60.62, H, 5.88, N, 14.82.
h) CI-HRMS: Calcd: 337.2388; Found: 337.2392 (M + H).
i) Analysis: Calcd: C, 68.45, H, 7.669, N, 15.21,
Found: C, 68.35, H, 7.49 N, 14.91.
-139-


CA 02259583 1999-01-04

WO 98/03510 PCT/US97/13072
j) Analysis: Calcd: C, 69.08, H, 7.915, N, 14.65,
Found: C, 68.85, H, 7.83, N, 14.54.
k) Analysis: Calcd: C, 73.51, H, 7.01, N, 19.48,
Found: C, 71.57, H, 7.15, N, 19.12.
1) CI-HRMS: Calcd: 403.1899; Found: 403.1901 (M + H).
m) Analysis: Calcd: C, 61.77, H, 6.49, N, 14.41, Cl.
9.13; Found: C, 61.90, H, 6.66, N, 13.62, Cl, 9.25.
n) Analysis: Calcd: C, 67.31, H, 7.06, N, 15.70, Cl.
9.93; Found: C, 67.32, H, 6.95, N, 15.50, Cl, 9.93.
o) Analysis: Calcd: C, 74.50, H, 8.14, N, 17.38,
Found: C, 74.43, H, 7.59, N, 17.16. -
p) Analysis: Calcd: C, 73.10, H, 7.54, N, 19.37,
Found: C, 73.18, H, 7.59, N, 18.81.
q) Analysis: Calcd: C, 73.57, H, 7.78, N, 18.65,
Found: C, 73.55, H, 7.79, N, 18.64.
r) CI-HRMS: Calcd: 353.2333; Found: 353.2341 (M + H).
s) Analysis: Calcd: C, 71.56, H, 8.02, N, 15.90,
Found: C, 71 . 45, H, = 7.99, N, 15.88.
t) Analysis: Calcd: C, 65.60, H, 7.34, N, 14.57,
Found: C, 65.42, H, 7.24, N, 14.37.
u) CI-HRMS: Calcd: 399.2398; Found: 399.2396 (M + H).
v) CI-HRMS: Calcd: 399.2398; Found: 399.2396 (M + H).
w) CI-HRMS: Calcd: 383.2450; Found: 383.2447 (M + H).
x) CI-HRMS: Calcd: 403.1887; Found: 403.1901 (M + H).
y) CI-HRMS: Calcd: 295.1919; Found: 295.1923 (M + H).
z) Analysis: Calcd: C, 67.31, H, 7.06, N, 15.70,
Found: C, 67.12, H, 6.86, N, 15.53.
aa) Analysis: Calcd: C, 61.77, H, 6.49, N, 14.41, Cl,
9.13; Found: C, 62.06, H, 6.37, N, 14.25, Cl, 9.12.
ab) CI-HRMS: Calcd: 337.2017; Found: 337.2028 (M + H).
ac) CI-HRMS: Calcd: 403.1893; Found: 403.1901 (M + H).
ad) Analysis: Calcd: C, 70.00, H, 7.22, N, 18.55,
Found: C, 70.05, H, 7.22, N, 18.36.
ae) Analysis: Calcd: C, 70.98, H, 7.74, N, 16.55,
Found: C, 71.15, H,7.46, N, 16.56.

-140-

t


CA 02259583 1999-01-04

WO 98/03510 PCT/US97/13072
ag) Analysis: Calcd: C, 66.59, H, 6.76, N, 16.34,
Found: C, 66.69, H,6.82, N, 16.20.
ah) Analysis: Calcd: C, 70.38, H, 6.71, N, 18.65,
Found: C, 70.35, H,6.82, N, 18.83.
ai) Analysis: Calcd: C, 66.39, H, 5.85, N, 18.44, Cl,
9.33;
Found: C, 66.29, H, 5.51, N, 18.36, Cl, 9.31.
aj) CI-HRMS: Calcd: 369.2278; Found: 369.2291 (M + H).
ak) Analysis: Calcd: C, 64.42, H, 6.77, N, 15.02,
Found: C, 64.59, H,6.51, N, 14.81.

The examples delineated in TABLE 3 may be prepared by
the methods outlined in Examples 1, 2, 3 or 6. Commonly
used abbreviations are: Ph is phenyl, Pr is propyl, Me
is methyl, Et is ethyl, Bu is butyl, Ex is Example.
TABLE 3
R3
N / N,.. N
Z
Ar
Ex. a s.1 ~r ms~c~
546a C-Me NHCH(Et)2 2-Me-4-Me2N-Ph 164-166
547b C-Me S-NHCH(CH2CH2OMe) 2,4-Me2-Ph oil
-CH2oMe
548c C-Me S-NHCH(CH2CH2OMe) 2-Me-4-Cl-Ph oil
-CH2OMe
549d C-Me N(c-Pr)CH2CH2CN 2-Me-4-C1-Ph 115-116
-141-


CA 02259583 1999-01-04

WO 98/03510 PCT/US97/13072

550e C-Me NHCH(Et)CH2CN 2-Me-4-C1-Ph 131-132
551f C-Me N(Et)2 2,3-Me2-4-OMe-Ph oil
552g C-Me N(CH2CH2OMe)CH2CH2OH 2,4-C12-Ph oil
553h C-Me N(CH2CH2OMe)2 2,3-Me2-4-OMe-Ph oil
5541 C-Me NHCH(Et)2 2,3-Me2-4-OMePh 123-124
555i C-Me N(CH2-c-Pr)Pr 2-Me-4-Cl-Ph oil
556k C-Me N(c-Pr)CH2CH2CN 2,3-Me2-4-OMePh 158-160
557 C-Me N(c-Pr)Et 2-C1-4-OMePh
558 C-Me N(c-Pr)Me 2-C1-4-OMePh
559 C-Me N(c-Pr)Pr 2-Cl-4-OMePh
560 C-Me N(c-Pr)Bu 2-C1-4-OMePh
5611 C-Me N(Et)2 2-C1-4-CN-Ph 115-117
562 C-Me N(c-Pr)2 2-C1-4-OMe 127-129
563m C-Me NHCH(CH2OH)2 2,4-C12-Ph 128-129
564 C-Me N(c-Pr)Et 2-Br-4,5-(MeO)2Ph
565 C-Me N(c-Pr)Me 2-Br-4,5-(MeO)2Ph
566 C-Me NH-c-Pr 2-Me-4-MeOPh 126-128
567 C-Me NHCH(Et)CH2OH 2-Me-4-MeOPh 60-62
568 C-Me NMe2 2-Br-4,5-(Me0)2Ph
569 C-Me NHCH(Et)2 2-Me-4-MeOPh 103-105
570 C-Me N(c-Pr)Et 2-Me-4-MeOPh 173-174
571 C-Me NH-2-pentyl 2,4-C12-Ph 118-120
572 C-Me NHCH(Et)CH2CN 2,4-C12-Ph 141-142
573 C-Me NHCH(Pr)CH2OMe 2,4-C12-Ph 87-88
574 C-Me NHCH(CH2-iPr)CH2OMe 2,4-C12-Ph amorphous
575 C-Me NH-2-butyl 2,4-Me2-Ph oil
576 C-Me NH-2-pentyl 2,4-Me2-Ph oil
577 C-Me NH-2-hexyl 2,4-Me2-Ph oil
578 C-Me NHCH(i -Pr)Me 2,4-Me2-Ph oil
579 C-Me NHCH(Me)CH2-iPr 2,4-Me2-Ph oil
580 C-Me NHCH(Me)-c-C6H11 2,4-Me2-Ph oil
581 C-Me NH-2-indanyl 2,4-Me2-Ph oil
582 C-Me NH-1-indanyl 2,4-Me2-Ph oil
583 C-Me NHCH(Me)Ph 2,4-Me2-Ph oil
584 C-Me NHCH(Me)CH2-(4-C1Ph) 2,4-Me2-Ph oil
-142-
T


CA 02259583 1999-01-04

WO 98/03510 PCTIUS97/13072

585 C-Me NHCH(Me)CH2COCH3 2,4-Me2-Ph oil
586 C-Me NHCH(Ph)CH2Ph 2,4-Me2-Ph oil
587 C-Me NHCH (Me) (CH2) 3NEt2 2,4-Me2-Ph oil
588 C-Me NH-(2-Ph-c-C3H4) 2,4-Me2-Ph oil
589 C-Me NHCH(Et)CH2CN 2,4-Me2-Ph 119-120
590 C-Me NH-3-hexyl 2,4-Me2-Ph oil
591n C-Me NEt2 2-Me0-4-C1Ph oil
592 C-Me NHCH(Et)2 2-MeO-4-C1Ph oil
59=P C-Me NHCH(Et)CH2OMe 2-Me0-4-C1Ph oil
594 C-Me NMe2 2-Me0-4-C1Ph oil
595q C-Me NHCH(Et)2 2-OMe-4-MePh oil
596r C-Me NEt2 2-OMe-4-MePh oil
597S C-c-Pr NHCH(CH2OMe)2 2,4-C12-Ph oil
598 C-Me N(c-Pr)Et 2,4-Me2-Ph
599 C-Me N(c-Pr)Et 2,4-C12-Ph
600 C-Me N(c-Pr)Et 2,4,6-Me3-Ph
601 C-Me N(c-Pr)Et 2-Me-4-Cl-Ph
602 C-Me N(c-Rr)Et 2-Cl-4-Me-Ph
603 C-Me NHCH(c-Pr)2 2,4-C12-Ph
604 C-Me NHCH(c-Pr)2 2,4-Me2-Ph
605 C-Me NHCH(c-Pr)2 2-Me-4-Cl-Ph
606 C-Me NHCH(c-Pr)2 2-Cl-4-Me-Ph
607 C-Me NHCH(c-Pr)2 2-Me-4-OMe-Ph
608 C-Me NHCH(c-Pr)2 2-Cl-4-OMe-Ph
609 C-Me NHCH(CH2OMe)2 2-C1-5-F-OMePh
610 C-Me NEt2 2-C1-5-F-OMePh
611 C-Me N(c-Pr)CH2CH2CN 2-C1-5-F-OMePh
612 C-Me NHCH(Et)2 2-C1-5-F-OMePh
613 C-Me N(CH2CH2OMe)2 2-C1-5-F-OMePh
614 C-Me NEt2 2,6-Me2-pyrid-3-yl
615 C-Me N(c-Pr)CH2CH2CN 2,6-Me2-pyrid-3-y1
616 C-Me NHCH(Et)2 2,6-Me2-pyrid-3-yl
617 C-Me N(CH2CH2OMe)2 2,6-Me2-pyrid-3-yl
618 C-OH NHCH(CH2OMe)2 2,4-Me2-Ph
619 C-OH NEt2 2,4-Me2-Ph
620 C-OH N(c-Pr)CH2CH2CN 2,4-Me2-Ph
-143-


CA 02259583 1999-01-04

WO 98/03510 PCT/US97/13072
621 C-OH NHCH(Et)2 2,4-Me2-Ph
623 C-OH N(CH2CH2OMe)2 2,4-Me2-Ph
624 C-NEt2 NHCH(CH2OMe)2 2,4-Me2-Ph
625 C-NEt2 NEt2 2,4-Me2-Ph
626 C-NEt2 N(c-Pr)CH2CH2CN 2,4-Me2-Ph
627 C-NEt2 NHCH(Et)2 2,4-Me2-Ph
628 C-NEt2 N(CH2CH2OMe)2 2,4-Me2-Ph
629 C-Me NHCH(Et)2 2-Me-4-CN-Ph
63;i C-Me N(CH2CH2OMe)2 2-Me-4-CN-Ph

Notes for Table 3:
a) CI-HRMS: Ca1cd:367.2610, Found: 367.2607 (M + H);
b) CI-HRMS: Ca1cd:384.2400, Found: 384.2393 (M + H);
c) CI-HRMS: Calcd:404.1853, Found: 404.1844 (M + H);
d) CI-HRMS: Calcd:381.1594, Found: 381.1596 (M + H);
Analysis: Calcd: C: 63.07, H, 5.57, N, 22.07, Cl,
9.32;
Found: C: 63.40, H, 5.55, N, 21.96, Cl: 9.15
e) CI-HRMS: Calcd:369.1594, Found: 369.1576 (M + H);
f) CI-HRMS: Calcd:354.2216, Found: 354.2211 (M + H);
g) CI-HRMS: Calcd:410.1072, Found: 410.1075 (M + H);
h) CI-HRMS: Calcd:414.2427, Found: 414.2427(M + H);
i) CI-HRMS: Calcd:368.2372, Found: 368.2372(M + H);
j) CI-HRMS: Calcd:384.1955, Found: 384.1947(M + H);
k) CI-HRMS: Calcd:391.2168, Found: 391.2160(M + H);
1) CI-HRMS: Calcd:335.1984, Found: 335.1961(M + H);
m) CI-HRMS: Calcd:382.0759, Found: 382.0765(M + H);
n) NH3-CI MS: Calcd: 360, Found: 360 (M + H)+
o) NH3-CI MS: Calcd: 374, Found: 374 (M + H)+;
NMR (CDC13, 300 MHz) :8 7.29 (d, J=8.4Hz, 1H), 7.04
(dd, J=1.8,8Hz, 1H), 6.96 (d, J=1.8Hz, 1H), 6.15
(d, J=10, 1H), 4.19 (m, 1H), 3.81 (s, 3H), 2.47 (s,
3H), 2.32 (s, 3H), 1.65 (m, 4H), 0.99 (t, J=7.32Hz,
6H)
p) NH3-CI MS: Calcd: 390, Found: 390 (M + H)+;
-144-
r


CA 02259583 1999-01-04

WO 98/03510 PCTIUS97/13072
NMR (CDC13, 300 MHz) : S 7.28 (d, J=8Hz, 1H), 7.03
(d, J=8Hz, 1H), 6.96 (s, 1H), 6.52 (d, J=9Hz, 1H),
4.36 (m, 1H), 3.8 (s, 3H), 3.55 (m, 2H), 3.39 (s,
3H), 2.47 (s, 3H), 2.32 (s, 3H), 1.76 (m, 2H), 1.01
(t, J=7.32Hz, 3H).
q) CI-HRMS: Calcd: 354.2294, Found: 354.2279 (M + H)+
r) CI-HRMS: Calcd: 340.2137, Found: 340.2138 (M + H)+
s) CI-HRMS: Calcd: 436.1307, Found: 436.1296 (M + H)+
The examples delineated in TABLE 4 may be prepared by
the methods outlined in Examples 1A; 1B, 432, 433, 434.
Commonly used abbreviations are: Ph is phenyl, Pr is
propyl, Me is methyl, Et is ethyl, Bu is butyl, Ex is
Example, EtOAc is ethyl acetate.
TABLE 4

R3

N,,N
Z
Ar
E~.. Z a~ ar ma1~1
631 C-Me NHCH(Et)2 2-Br-4,5-(Me0)2Ph 160-161
632 C-Me NHCH(Et)2 2-Br-4-MeOPh 110-111
633 C-Me N(CH2CH2OMe)2 2-Br-4-MeOPh 74-76
634 C-Me NHCH(CH20Me)2 2-Br-4-MeOPh 128-130
-145-


CA 02259583 1999-01-04

WO 98/03510 PCT/US97/13072

635 C-Me N(Et)2 2-Me-4-C1Ph 113-114
636 C-Me N(c-Pr)Et 2,4-C12Ph
637 C-Me N(c-Pr)Et 2,4-Me2Ph
638 C-Me N(c-Pr)Et 2,4,6-Me3Ph
639 C-Me N(c-Pr)Et 2-Me-4-MeOPh
640 C-Me N(c-Pr)Et 2-C1-4-MeOPh
641 C-Me N(c-Pr)Et 2-C1-4-MePh
642 C-Me N(c-Pr)Et 2-Me-4-C1Ph
643 C-Me NHCH(c-Pr)2 2,4-C12-Ph
644 C-Me NHCH(c-Pr)2 2,4-Me2-Ph
645 C-Me NHCH(c-Pr)2 2-Me-4-C1-Ph
646 C-Me NHCH(c-Pr)2 2-C1-4-Me-Ph
647 C-Me NHCH(c-Pr)2 2-Me-4-OMe-Ph
648 C-Me NHCH(c-Pr)2 2-C1-4-OMe-Ph
649 C-Me NHCH(CH2OMe)2 2-C1-5-F-OMePh
650 C-Me NEt2 2-C1-5-F-OMePh
651 C-Me N(c-Pr)CH2CH2CN 2-C1-5-F-OMePh
652 C-Me NHCH(=Et)2 2-C1-5-F-OMePh
653 C-Me N(CH2CH2OMe)2 2-C1-5-F-OMePh
654 C-Me NEt2 2,6-Me2-pyrid-3-yl
655 C-Me N(c-Pr)CH2CH2CN 2,6-Me2-pyrid-3-yl
656 C-Me NHCH(Et)2 2,6-Me2-pyrid-3-yl
657 C-Me N(CH2CH2OMe)2 2,6-Me2-pyrid-3-yl
658 C-OH NHCH(CH2OMe)2 2,4-Me2-Ph
659 C-OH NEt2 2,4-Me2-Ph
660 C-OH N(c-Pr)CH2CH2CN 2,4-Me2-Ph
661 C-OH NHCH(Et)2 2,4-Me2-Ph
662 C-OH N(CH2CH2OMe)2 2,4-Me2-Ph
663 C-NEt2 NHCH(CH2OMe)2 2,4-Me2-Ph
664 C-NEt2 NEt2 2,4-Me2-Ph
665 C-NEt2 N(c-Pr)CH2CH2CN 2,4-Me2-Ph
666 C-NEt2 NHCH(Et)2 2,4-Me2-Ph
667 C-NEt2 N(CH2CH2OMe)2 2,4-Me2-Ph
668 C-Me NHCH(Et)2 2-Me-4-CN-Ph
669 C-Me N(CH2CH2OMe)2 2-Me-4-CN-Ph
-146-


CA 02259583 1999-01-04

WO 98/03510 PCTIUS97/13072
The examples in Tables 5 or 6 may be prepared by
the methods illustrated in Examples 1A, 1B, 2, 3, 6,
431, 432, 433, 434 or by appropriate combinations
thereof. Commonly used abbreviations are: Ph is phenyl,
Pr is propyl, Me is methyl, Et is ethyl, Bu is butyl, Ex
is Example.

Table 5
R3
R14
~ N
N N
N
Ar
Lx.. B2g
670 Me NHCH(CH2OMe)2 2,4-C12-Ph
671 Me NHCHPr2 2,4-C12-Ph
672 Me NEtBu 2,4-C12-Ph
673 Me NPr(CH2-c-C3H5) 2,4-C12-Ph
674 Me N(CH2CH2OMe)2 2,4-C12-Ph
675 Me NH-3-heptyl 2,4-C12-Ph
676 Me NHCH(Et)CH2OMe 2,4-C12-Ph
677 Me NEt2 2,4-C12-Ph
678 Me NHCH(CH2OEt)2 2,4-C12-Ph
679 Me NH-3-pentyl 2,4-C12-Ph
680 Me NMePh 2,4-C12-Ph
681 Me NPr2 2,4-C12-Ph
682 Me NH-3-hexyl 2,4-C12-Ph
683 Me morpholino 2,4-C12-Ph
-147-


CA 02259583 1999-01-04

WO 98/03510 PCT/US97/13072
684 Me N(CH2Ph)CH2CH2OMe 2,4-C12-Ph
685 Me NHCH(CH2Ph)CH2OMe 2,4-C12-Ph
686 Me NH-4-tetrahydropyranyl 2,4-C12-Ph
687 Me NH-cyclopentyl 2,4-C12-Ph
688 Me OEt 2,4-C12-Ph
689 Me OCH(Et)CH2OMe 2,4-C12-Ph
690 Me OCH2Ph 2,4-C12-Ph
691 Me 0-3-pentyl 2,4-C12-Ph
692 Me SEt 2,4-C12-Ph
693 Me S(O)Et 2,4-C12-Ph
694 Me S02Et 2,4-C12-Ph
695 Me Ph 2,4-C12-Ph
696 Me 2-CF3-Ph 2,4-C12-Ph
697 Me 2-Ph-Ph 2,4-C12-Ph
698 Me 3-pentyl 2,4-C12-Ph
699 Me cyclobutyl 2,4-C12-Ph
700 Me 3-pyridyl 2,4-C12-Ph
701 Me CH(Et)CH2CONMe2 2,4-C12-Ph
702 Me CH(Et)CH2CH2NMe2 2,4-C12-Ph
703 Me NHCH(CH2OMe)2 2,4,6-Me3-Ph
704 Me NHCHPr2 2,4,6-Me3-Ph
705 Me NEtBu 2,4,6-Me3-Ph
706 Me NPr(CH2-c-C3H5) 2,4,6-Me3-Ph
707 Me N(CH2CH2OMe)2 2,4,6-Me3-Ph
708 Me NH-3-heptyl 2,4,6-Me3-Ph
709 Me NHCH(Et)CH2OMe 2,4,6-Me3-Ph
710 Me NEt2 2,4,6-Me3-Ph
711 Me NHCH(CH2OEt)2 2,4,6-Me3-Ph
712 Me NH-3-pentyl 2,4,6-Me3-Ph

713 Me NMePh 2,4,6-Me3-Ph
714 Me NPr2 2,4,6-Me3-Ph
715 Me NH-3-hexyl 2,4,6-Me3-Ph
716 Me morpholino 2,4,6-Me3-Ph
717 Me N(CH2Ph)CH2CH2oMe 2,4,6-Me3-Ph
718 Me NHCH(CH2Ph)CH20Me 2,4,6-Me3-Ph
719 Me NH-4-tetrahydropyranyl 2,4,6-Me3-Ph
-148-


CA 02259583 1999-01-04

WO 98/03510 PCT/US97/13072
720 Me NH-cyclopentyl 2,4,6-Me3-Ph
721 Me OEt 2,4,6-Me3-Ph
722 Me OCH(Et)CH2OMe 2,4,6-Me3-Ph
723 Me OCH2Ph 2,4,6-Me3-Ph
724 Me 0-3-pentyl 2,4,6-Me3-Ph
725 Me SEt 2,4,6-Me3-Ph
726 Me S(O)Et 2,4,6-Me3-Ph
727 Me S02Et 2,4,6-Me3-Ph
728 Me CH(C02Et)2 2,4,6-Me3-Ph
729 Me C (Et) (C02Et) 2 2,4,6-Me3-Ph
730 Me CH(Et)CH2OH 2,4,6-Me3-Ph
731 Me CH(Et)CH2OMe 2,4,6-Me3-Ph
732 Me CONMe2 2,4,6-Me3-Ph
733 Me COCH3 2,4,6-Me3-Ph
734 Me CH(OH)CH3 2,4,6-Me3-Ph
735 Me C(OH)Ph-3-pyridyl 2,4,6-Me3-Ph
736 Me Ph 2,4,6-Me3-Ph
737 Me 2-Phl-Ph 2,4,6-Me3-Ph
738 Me 3-pentyl 2,4,6-Me3-Ph
739 Me cyclobutyl 2,4,6-Me3-Ph
740 Me 3-pyridyl 2,4,6-Me3-Ph
741 Me CH(Et)CH2CONMe2 2,4,6-Me3-Ph
742 Me CH(Et)CH2CH2NMe2 2,4,6-Me3-Ph
743 Me NHCH(CH2OMe)2 2,4-Me2-Ph
744 Me N(CH2CH2OMe)2 2,4-Me2-Ph
745 Me NHCH(Et)CH2OMe 2,4-Me2-Ph
746 Me NH-3-pentyl 2,4-Me2-Ph
747 Me NEt2 2,4-Me2-Ph
748 Me N(CH2CN)2 2,4-Me2-Ph
749 Me NHCH(Me)CH2OMe 2,4-Me2-Ph
750 Me OCH(Et)CH2OMe 2,4-Me2-Ph
751 Me NPr-c-C3H5 2,4-Me2-Ph
752 Me NHCH(Me)CH2NMe2 2,4-Me2-Ph
753 Me N(c-C3H5)CH2CH2CN 2,4-Me2-Ph
754 Me N(Pr)CH2CH2CN 2,4-Me2-Ph
755 Me N(Bu)CH2CH2CN 2,4-Me2-Ph
-149-


CA 02259583 1999-01-04

WO 98/03510 PCT/US97/13072
756 Me NHCHPr2 2,4-Me2-ph
757 Me NEtBu 2,4-Me2-Ph
758 Me NPr(CH2-c-C3H5) 2,4-Me2-Ph
759 Me NH-3-heptyl 2,4-Me2-Ph
760 Me NEt2 2,4-Me2-Ph
761 Me NHCH(CH2OEt)2 2,4-Me2-Ph
762 Me NH-3-pentyl 2,4-Me2-Ph
763 Me NMePh 2,4-Me2-Ph
764 Me NPr2 2,4-Me2-Ph
765 Me NH-3-hexyl 2,4-Me2-Ph
766 Me morpholino 2,4-Me2-Ph
767 Me N(CH2Ph)CH2CH2OMe 2,4-Me2-Ph
768 Me NHCH(CH2Ph)CH2OMe 2,4-Me2-Ph
769 Me NH-4-tetrahydropyranyl 2,4-Me2-Ph
770 Me NH-cyclopentyl 2,4-Me2-Ph
771 Me NHCH(CH2OMe)2 2-Me-4-MeO-Ph
772 Me N(CH2CH2OMe)2 2-Me-4-MeO-Ph
773 Me NHCH(Et)CH2OMe 2-Me-4-MeO-Ph
774 Me N(Pr)CH2CH2CN 2-Me-4-MeO-Ph
775 Me OCH(Et)CH2OMe 2-Me-4-MeO-Ph
776 Me NHCH(CH2OMe)2 2-Br-4-MeO-Ph
777 Me N(CH2CH2OMe)2 2-Br-4-MeO-Ph
778 Me NHCH(Et)CH2OMe 2-Br-4-MeO-Ph
779 Me N(Pr)CH2CH2CN 2-Br-4-MeO-Ph
780 Me OCH(Et)CH2OMe 2-Br-4-Me0-Ph
781 Me NHCH(CH2OMe)2 2-Me-4-NMe2-Ph
782 Me N(CH2CH2OMe)2 2-Me-4-NMe2-Ph
783 Me NHCH(Et)CH2OMe 2-Me-4-NMe2-Ph
784 Me N(Pr)CH2CH2CN 2-Me-4-NMe2-Ph
785 Me OCH(Et)CH2OMe 2-Me-4-NMe2-Ph
786 Me NHCH(CH2OMe)2 2-Br-4-NMe2-Ph
787 Me N(CH2CH2OMe)2 2-Br-4-NMe2-Ph
788 Me NHCH(Et)CH2OMe 2-Br-4-NMe2-Ph
789 Me N(Pr)CH2CH2CN 2-Br-4-NMe2-Ph
790 Me OCH(Et)CH2OMe 2-Br-4-NMe2-Ph
791 Me NHCH(CH2OMe)2 2-Br-4-i-Pr-Ph
-150-

1


CA 02259583 1999-01-04

WO 98/03510 PCT/US97/13072
792 Me N(CH2CH2OMe)2 2-Br-4-i-Pr-Ph
793 Me NHCH(Et)CH2OMe 2-Br-4-i-Pr-Ph
794 Me N(Pr)CH2CH2CN 2-Br-4-i-Pr-Ph
795 Me OCH(Et)CH2OMe 2-Br-4-i-Pr-Ph
796 Me NHCH(CH2OMe)2 2-Br-4-Me-Ph
797 Me N(CH2CH2OMe)2 2-Br-4-Me-Ph
798 Me NHCH(Et)CH2OMe 2-Br-4-Me-Ph
799 Me N(Pr)CH2CH2CN 2-Br-4-Me-Ph
8CiT Me OCH(Et)CH2OMe 2-Br-4-Me-Ph
801 Me NHCH(CH2OMe)2 2-Me-4-Br-Ph
802 Me N(CH2CH2OMe)2 2-Me-4-Br-Ph
803 Me NHCH(Et)CH2OMe 2-Me-4-Br-Ph
804 Me N(Pr)CH2CH2CN 2-Me-4-Br-Ph
805 Me OCH(Et)CH2OMe 2-Me-4-Br-Ph
806 Me NHCH(CH2OMe)2 2-C1-4,6-Me2-Ph
807 Me N(CH2CH2OMe)2 2-C1-4,6-Me2-Ph
808 Me NHCH(CH2OMe)2 4-Br-2,6-(Me)2-Ph
809 Me N(CH2CH2OMe)2 4-Br-2,6-(Me)2-Ph
810 Me NHCH(CH2OMe)2 4-i-Pr-2-SMe-Ph
811 Me N(CH2CH2OMe)2 4-i-Pr-2-SMe-Ph
812 Me NHCH(CH2OMe)2 2-Br-4-CF3-Ph
813 Me N(CH2CH2OMe)2 2-Br-4-CF3-Ph
814 Me NHCH(CH2OMe)2 2-Br-4,6-(MeO)2-Ph
815 Me N(CH2CH2OMe)2 2-Br-4,6-(MeO)2-Ph
816 Me NHCH(CH2OMe)2 2-C1-4,6-(MeO)2-Ph
817 Me N(CH2CH2OMe)2 2-C1-4,6-(Me0)2-Ph
818 Me NHCH(CH2OMe)2 2,6-(Me)2-4-SMe-Ph
819 Me N(CH2CH2OMe)2 2,6-(Me)2-4-SMe-Ph
820 Me NHCH(CH2OMe)2 4-(COMe)-2-Br-Ph
821 Me N(CH2CH2OMe)2 4-(COMe)-2-Br-Ph
822 Me NHCH(CH2OMe)2 2,4,6-Me3-pyrid-3-yl
823 Me N(CH2CH2OMe)2 2,4,6-Me3-pyrid-3-yl
824 Me NHCH(CH2OMe)2 2,4-(Br)2-Ph
825 Me N(CH2CH2OMe)2 2,4-(Br)2-Ph
826 Me NHCH(CH2OMe)2 4-i-Pr-2-SMe-Ph
827 Me N(CH2CH2OMe)2 4-i-Pr-2-SMe-Ph
-151-


CA 02259583 1999-01-04

WO 98/03510 PCT/US97/13072
828 Me NHCH(CH2OMe)2 4-i-Pr-2-SO2Me-Ph
829 Me N(CH2CH2OMe)2 4-i-Pr-2-S02Me-Ph
830 Me NHCH(CH2OMe)2 2,6-(Me)2-4-SMe-Ph
831 Me N(CH2CH2OMe)2 2,6-(Me)2-4-SMe-Ph
832 Me NHCH(CH2OMe)2 2,6-(Me)2-4-SO2Me-Ph
833 Me N(CH2CH2OMe)2 2,6-(Me)2-4-S02Me-Ph
834 Me NHCH(CH2OMe)2 2-I-4-i-Pr-Ph
835 Me N(CH2CH2OMe)2 2-I-4-i-Pr-Ph
835, Me NHCH(CH2OMe)2 2-Br-4-N(Me)2-6-MeO-Ph
837 Me N(CH2CH2OMe)2 2-Br-4-N(Me)2-6-MeO-Ph
838 Me NEt2 2-Br-4-MeO-Ph
839 Me NH-3-pentyl 2-Br-4-Me0-Ph
840 Me NHCH(CH2OMe)2 2-CN-4-Me-Ph
841 Me N(c-C3H5)CH2CH2CN 2,4,6-Me3-Ph
842 Me NHCH(CH2CH2OMe)CH2OMe 2-Me-4-Br-Ph
843 Me NHCH(CH2OMe)2 2,5-Me2-4-MeO-Ph
844 Me N(CH2CH2OMe)2 2,5-Me2-4-MeO-Ph
845 Me NH-3-pentyl 2,5-Me2-4-MeO-Ph
846 Me NEt2 2,5-Me2-4-MeO-Ph
847 Me NHCH(CH2OMe)2 2-C1-4-MePh
848 Me NCH(Et)CH2OMe 2-C1-4-MePh
849 Me N(CH2CH2OMe)2 2-C1-4-MePh
850 Me (S)-NHCH(CH2CH2OMe)CH2OMe 2-C1-4-MePh
851 Me N(c-C3H5)CH2CH2CN 2,5-Me2-4-MeOPh
852 Me NEt2 2-Me-4-MeOPh
853 Me OEt 2-Me-4-MeOPh
854 Me (S)-NHCH(CH2CH2OMe)CH2OMe 2-Me-4-MeOPh
855 Me N(c-C3H5)CH2CH2CN 2-Me-4-MeOPh
856 Me NHCH(CH2CH2OEt)2 2-Me-4-MeOPh
857 Me N(c-C3H5)CH2CH2CN 2,4-C12-Ph
858 Me NEt2 2-Me-4-C1Ph
859 Me NH-3-pentyl 2-Me-4-C1Ph
860 Me N(CH2CH2OMe)2 2-Me-4-C1Ph
861 Me NHCH(CH2OMe)2 2-Me-4-C1Ph
862 Me NEt2 2-Me-4-C1Ph
863 Me NEt2 2-C1-4-MePh
-152-


CA 02259583 1999-01-04

WO 98/03510 PCTIUS97/13072
864 Me NH-3-pentyl 2-C1-4-MePh
865 Me NHCH(CH2OMe)2 2-Cl-4-MeOPh
866 Me N(CH2CH2OMe)2 2-Cl-4-MeOPh
867 Me NHCH(Et)CH2OMe 2-Cl-4-MeOPh
868 Me N(c-Pr)CH2CH2CN 2-C1-4-MeOPh
869 Me NEt2 2-C1-4-MeOPh
870 Me NH-3-pentyl 2-Cl-4-MeOPh
871 Me NHCH(Et)CH2CH2OMe 2-Cl-4-MeOPh
87Z Me NHCH(Me)CH2CH2OMe 2-Cl-4-MeOPh
873 Me NHCH(Et)CH2CH2OMe 2-Br-4-MeOPh
874 Me NHCH(Me)CH2CH2OMe 2-Br-4-MeOPh
875 Me NHCH(Et)CH2CH2OMe 2-Me-4-MeOPh
876 Me NHCH(Me)CH2CH2OMe 2-Me-4-MeOPh
877 Me NHCH(CH2OMe)2 2-C1-4,5-(MeO)2Ph
878 Me N(CH2CH2OMe)2 2-C1-4,5-(MeO)2Ph
879 Me NHCH(Et)CH2OMe 2-C1-4,5-(MeO)2Ph
880 Me N(c-Pr)CH2CH2CN 2-C1-4,5-(MeO)2Ph
881 Me NEt2 2-C1-4,5-(MeO)2Ph
882 Me NH-3-pentyl 2-C1-4,5-(Me0)2Ph
883 Me NHCH(Et)CH2CH2OMe 2-C1-4,5-(MeO)2Ph
884 Me NHCH(Me)CH2CH2OMe 2-C1-4,5-(MeO)2Ph
885 Me NHCH(CH2OMe)2 2-Br-4,5-(MeO)2Ph
886 Me N(CH2CH2OMe)2 2-Br-4,5-(MeO)2Ph
887 Me NHCH(Et)CH2OMe 2-Br-4,5-(MeO)2Ph
888 Me N(c-Pr)CH2CH2CN 2-Br-4,5-(MeO)2Ph
889 Me NEt2 2-Br-4,5-(MeO)2Ph
890 Me NH-3-pentyl 2-Br-4,5-(MeO)2Ph
891 Me NHCH(CH2OMe)2 2-C1-4,6-(MeO)2Ph
892 Me N(CH2CH2OMe)2 2-C1-4,6-(Me0)2Ph
893 Me NEt2 2-C1-4,6-(MeO)2Ph
894 Me NH-3-pentyl 2-C1-4,6-(MeO)2Ph
895 Me NHCH(CH2OMe)2 2-Me-4,6-(Me0)2Ph
896 Me N(CH2CH2OMe)2 2-Me-4,6-(MeO)2Ph
897 Me NHCH(Et)CH2OMe 2-Me-4,6-(MeO)2Ph
898 Me NEt2 2-Me-4,6-(MeO)2Ph
899 Me NH-3-pentyl 2-Me-4,6-(MeO)2Ph
-153-


CA 02259583 1999-01-04

WO 98/03510 PCT/US97/13072
900 Me NHCH(Et)CH2CH2OMe 2-Me-4-MeOPh
901 Me NHCH(Me)CH2CH2OMe 2-Me-4-MeOPh
902 Me NHCH(CH2OMe)2 2-Me0-4-MePh
903 Me N(CH2CH2OMe)2 2-Me0-4-MePh
904 Me NHCH(Et)CH2OMe 2-Me0-4-MePh
905 Me N(c-Pr)CH2CH2CN 2-Me0-4-MePh
906 Me NEt2 2-Me0-4-MePh
907 Me NH-3-pentyl 2-Me0-4-MePh
90d Me NHCH(Et)CH2CH2OMe 2-Me0-4-MePh
909 Me NHCH(Me)CH2CH2OMe 2-Me0-4-MePh
910 Me NHCH(CH2OMe)2 2-MeO-4-MePh
911 Me N(CH2CH2OMe)2 2-MeO-4-MePh
912 Me NHCH(Et)CH2OMe 2-Me0-4-MePh
913 Me N(c-Pr)CH2CH2CN 2-Me0-4-MePh
914 Me NEt2 2-MeO-4-MePh
915 Me NH-3-pentyl 2-MeO-4-MePh
916 Me NHCH(CH2OMe)2 2-Me0-4-C1Ph
917 Me N(CH2CH2OMe)2 2-MeO-4-ClPh
918 Me NHCH(Et)CH2OMe 2-MeO-4-ClPh
919 Me NEt2 2-MeO-4-ClPh
920 Me NH-3-pentyl 2-Me0-4-C1Ph
-154-

T


CA 02259583 1999-01-04

WO 98/03510 PCTIUS97/13072
Table 6

R3
R14
N

N
Ar

921 Me NHCH(CH2OMe)2 2,4-C12-Ph
922 Me NHCHPr2 2,4-C12-Ph
923 Me NEtBu 2,4-C12-Ph
924 Me NPr(CH2-c-C3H5) 2,4-C12-Ph
925 Me N(CH2CH2OMe)2 2,4-C12-Ph
926 Me NH-3-heptyl 2,4-C12-Ph
927 Me NHCH(Et)CH2OMe 2,4-C12-Ph
928 Me NEt2 2,4-C12-Ph
929 Me NHCH(CH2OEt)2 2,4-C12-Ph
930 Me NH-3-pentyl 2,4-C12-Ph
931 Me NMePh 2,4-C12-Ph
932 Me NPr2 2,4-C12-Ph
933 Me NH-3-hexyl 2,4-C12-Ph
934 Me morpholino 2,4-C12-Ph
935 Me N(CH2Ph)CH2CH2OMe 2,4-C12-Ph
936 Me NHCH(CH2Ph)CH2OMe 2,4-C12-Ph
937 Me NH-4-tetrahydropyranyl 2,4-C12-Ph
938 Me NH-cyclopentyl 2,4-C12-Ph
939 Me OEt 2,4-C12-Ph
940 Me OCH(Et)CH2OMe 2,4-C12-Ph
941 Me OCH2Ph 2,4-C12-Ph
942 Me 0-3-pentyl 2,4-C12-Ph
943 Me SEt 2,4-C12-Ph
-155-


CA 02259583 1999-01-04

WO 98/03510 PCT/US97/13072
944 Me S(O)Et 2,4-C12-Ph
945 Me S02Et 2,4-C12-Ph
946 Me Ph 2,4-C12-Ph
947 Me 2-CF3-Ph 2,4-C12-Ph

948 Me 2-Ph-Ph 2,4-C12-Ph
949 Me 3-pentyl 2,4-C12-Ph
950 Me cyclobutyl 2,4-C12-Ph
951 Me 3-pyridyl 2,4-C12-Ph
952 Me CH(Et)CH2CONMe2 2,4-C12-Ph
953 Me CH(Et)CH2CH2NMe2 2,4-C12-Ph
954 Me NHCH(CH2OMe)2 2,4,6-Me3-Ph
955 Me NHCHPr2 2,4,6-Me3-Ph
956 Me NEtBu 2,4,6-Me3-Ph
957 Me NPr(CH2-c-C3H5) 2,4,6-Me3-Ph
958 Me N(CH2CH2OMe)2 2,4,6-Me3-Ph
959 Me NH-3-heptyl 2,4,6-Me3-Ph
960 Me NHCH(Et)CH2OMe 2,4,6-Me3-Ph
961 Me NEt2 2,4,6-Me3-Ph
962 Me NHCH(CH2OEt)2 2,4,6-Me3-Ph
963 Me NH-3-pentyl 2,4,6-Me3-Ph
964 Me NMePh 2,4,6-Me3-Ph
965 Me NPr2 2,4,6-Me3-Ph
966 Me NH-3-hexyl 2,4,6-Me3-Ph
967 Me morpholino 2,4,6-Me3-Ph

968 Me N(CH2Ph)CH2CH2OMe 2,4,6-Me3-Ph
969 Me NHCH(CH2Ph)CH2OMe 2,4,6-Me3-Ph
970 Me NH-4-tetrahydropyranyl 2,4,6-Me3-Ph
971 Me NH-cyclopentyl 2,4,6-Me3-Ph
972 Me OEt 2,4,6-Me3-Ph
973 Me OCH(Et)CH2OMe 2,4,6-Me3-Ph
974 Me OCH2Ph 2,4,6-Me3-Ph
975 Me 0-3-pentyl 2,4,6-Me3-Ph
976 Me SEt 2,4,6-Me3-Ph
977 Me S(O)Et 2,4,6-Me3-Ph
978 Me S02Et 2,4,6-Me3-Ph
979 Me CH(C02Et)2 2,4,6-Me3-Ph
-156-

T


CA 02259583 1999-01-04

WO 98/03510 PCT/US97/13072
980 Me C (Et) (C02Et) 2 2,4,6-Me3-Ph
981 Me CH(Et)CH2OH 2,4,6-Me3-Ph
982 Me CH(Et)CH2OMe 2,4,6-Me3-Ph
983 Me CONMe2 2,4,6-Me3-Ph
984 Me COCH3 2,4,6-Me3-Ph
985 Me CH(OH)CH3 2,4,6-Me3-Ph
986 Me C(OH)Ph-3-pyridyl 2,4,6-Me3-Ph
987 Me Ph 2,4,6-Me3-Ph
988 Me 2-Ph-Ph 2,4,6-Me3-Ph
989 Me 3-pentyl 2,4,6-Me3-Ph
990 Me cyclobutyl 2,4,6-Me3-Ph
991 Me 3-pyridyl 2,4,6-Me3-Ph
992 Me CH(Et)CH2CONMe2 2,4,6-Me3-Ph
993 Me CH(Et)CH2CH2NMe2 2,4,6-Me3-Ph
994 Me NHCH(CH2OMe)2 2,4-Me2-Ph
995 Me N(CH2CH2OMe)2 2,4-Me2-Ph
996 Me NHCH(Et)CH2OMe 2,4-Me2-Ph
997 Me NH-3-pentyl 2,4-Me2-Ph
998 Me NEt2 2,4-Me2-Ph
999 Me N(CH2CN)2 2,4-Me2-Ph
1000 Me NHCH(Me)CH2OMe 2,4-Me2-Ph
1001 Me OCH(Et)CH2OMe 2,4-Me2-Ph
1002 Me NPr-c-C3H5 2,4-Me2-Ph
1003 Me NHCH(Me)CH2NMe2 2,4-Me2-Ph
1004 Me N(c-C3H5)CH2CH2CN 2,4-Me2-Ph
1005 Me N(Pr)CH2CH2CN 2,4-Me2-Ph
1006 Me N(Bu)CH2CH2CN 2,4-Me2-Ph
1007 Me NHCHPr2 2,4-Me2-Ph
1008 Me NEtBu 2,4-Me2-Ph
1009 Me NPr(CH2-c-C3H5) 2,4-Me2-Ph
1010 Me NH-3-heptyl 2,4-Me2-Ph
1011 Me NEt2 2,4-Me2-Ph
1012 Me NHCH(CH2OEt)2 2,4-Me2-Ph
1013 Me NH-3-pentyl 2,4-Me2-Ph
1014 Me NMePh 2,4-Me2-Ph
1015 Me NPr2 2,4-Me2-Ph
-157-


CA 02259583 1999-01-04

WO 98/03510 PCT/US97/13072
1016 Me NH-3-hexyl 2,4-Me2-Ph
1017 Me morpholino 2,4-Me2-Ph
1018 Me N(CH2Ph)CH2CH2OMe 2,4-Me2-Ph
1019 Me NHCH(CH2Ph)CH2OMe 2,4-Me2-Ph
1020 Me NH-4-tetrahydropyranyl 2,4-Me2-Ph
1021 Me NH-cyclopentyl 2,4-Me2-Ph
1022 Me NHCH(CH2OMe)2 2-Me-4-Me0-Ph
1023 Me N(CH2CH2OMe)2 2-Me-4-Me0-Ph
1024 Me NHCH(Et)CH2OMe 2-Me-4-Me0-Ph
1025 Me N(Pr)CH2CH2CN 2-Me-4-Me0-Ph
1026 Me OCH(Et)CH2OMe 2-Me-4-Me0-Ph
1027 Me NHCH(CH2OMe)2 2-Br-4-Me0-Ph
1028 Me N(CH2CH2OMe)2 2-Br-4-MeO-Ph
1029 Me NHCH(Et)CH2OMe 2-Br-4-MeO-Ph
1030 Me N(Pr)CH2CH2CN 2-Br-4-MeO-Ph
1031 Me OCH(Et)CH2OMe 2-Br-4-MeO-Ph
1032 Me NHCH(CH2OMe)2 2-Me-4-NMe2-Ph
1033 Me N(CH2CH2OMe)2 2-Me-4-NMe2-Ph
1034 Me NHCH(Et)CH2OMe 2-Me-4-tNMe2-Ph
1035 Me N(Pr)CH2CH2CN 2-Me-4-NMe2-Ph
1036 Me OCH(Et)CH2OMe 2-Me-4-NMe2-Ph
1037 Me NHCH(CH2OMe)2 2-Br-4-NMe2-Ph
1038 Me N(CH2CH2OMe)2 2-Br-4-NMe2-Ph
1039 Me NHCH(Et)CH2OMe 2-Br-4-NMe2-Ph
1040 Me N(Pr)CH2CH2CN 2-Br-4-NMe2-Ph
1041 Me OCH(Et)CH2OMe 2-Br-4-NMe2-Ph
1042 Me NHCH(CH2OMe)2 2-Br-4-i-Pr-Ph
1043 Me N(CH2CH2OMe)2 2-Br-4-i-Pr-Ph
1044 Me NHCH(Et)CH2OMe 2-Br-4-i-Pr-Ph
1045 Me N(Pr)CH2CH2CN 2-Br-4-i-Pr-Ph
1046 Me OCH(Et)CH2OMe 2-Br-4-i-Pr-Ph
1047 Me NHCH(CH2OMe)2 2-Br-4-Me-Ph
1048 Me N (CH2CH2OMe) 2 2-Br-4-Me-Ph
1049 Me NHCH(Et)CH2OMe 2-Br-4-Me-Ph
1050 Me N(Pr)CH2CH2CN 2-Br-4-Me-Ph
1051 Me OCH(Et)CH2OMe 2-Br-4-Me-Ph
-158-

1


CA 02259583 1999-01-04

WO 98/03510 PCT/US97/13072
1052 Me NHCH(CH2OMe)2 2-Me-4-Br-Ph
1053 Me N(CH2CH2OMe)2 2-Me-4-Br-Ph
1054 Me NHCH(Et)CH2OMe 2-Me-4-Br-Ph
1055 Me N(Pr)CH2CIi2CN 2-Me-4-Br-Ph

1056 Me OCH(Et)CH2OMe 2-Me-4-Br-Ph
1057 Me NHCH(CH2OMe)2 2-C1-4,6-Me2-Ph
1058 Me N(CH2CH2OMe)2 2-C1-4,6-Me2-Ph
1059 Me NHCH(CH2OMe)2 4-Br-2,6-(Me)2-Ph
1060 Me N (CH2CH2OMe) 2 4-Br-2, 6- (Me) 2-Ph
1061 Me NHCH(CH2OMe)2 4-i-Pr-2-SMe-Ph
1062 Me N(CH2CH2OMe)2 4-i-Pr-2-SMe-Ph
1063 Me NHCH(CH2OMe)2 2-Br-4-CF3-Ph
1064 Me N(CH2CH2OMe)2 2-Br-4-CF3-Ph
1065 Me NHCH(CH2OMe)2 2-Br-4,6-(Me0)2-Ph
1066 Me N(CH2CH2OMe)2 2-Br-4,6-(Me0)2-Ph
1067 Me NHCH(CH2OMe)2 2-C1-4,6-(MeO)2-Ph
1068 Me N (CH2CH2OMe) 2 2-C1-4,6-(Me0)2-Ph
1069 Me NHCH(CH2OMe)2 2,6-(Me)2-4-SMe-Ph
1070 Me N(CH2CH2OMe)2 2,6-(Me)2-4-SMe-Ph
1071 Me NHCH(CH2OMe)2 4-(COMe)-2-Br-Ph
1072 Me N(CH2CH2OMe)2 4-(COMe)-2-Br-Ph
1073 Me NHCH(CH2OMe)2 2,4,6-Me3-pyrid-3-yl
1074 Me N(CH2CH2OMe)2 2,4,6-Me3-pyrid-3-yl
1075 Me NHCH(CH2OMe)2 2,4-(Br)2-Ph
1076 Me N(CH2CH2OMe)2 2,4-(Br)2-Ph
1077 Me NHCH(CH2OMe)2 4-i-Pr-2-SMe-Ph
1078 Me N(CH2CH2OMe)2 4-i-Pr-2-SMe-Ph
1079 Me NHCH(CH2OMe)2 4-i-Pr-2-SO2Me-Ph
1080 Me N(CH2CH2OMe)2 4-i-Pr-2-S02Me-Ph
1081 Me NHCH(CH2OMe)2 2,6-(Me)2-4-SMe-Ph
1082 Me N(CH2CH2OMe)2 2,6-(Me)2-4-SMe-Ph
1083 Me NHCH(CH2OMe)2 2,6-(Me)2-4-SO2Me-Ph
1084 Me N(CH2CH2OMe)2 2,6-(Me)2-4-SO2Me-Ph
1085 Me NHCH(CH2OMe)2 2-1-4-i-Pr-Ph
1086 Me N(CH2CH2OMe)2 2-I-4-i-Pr-Ph
1087 Me NHCH(CH2OMe)2 2-Br-4-N(Me)2-6-Me0-Ph
-159-


CA 02259583 1999-01-04

WO 98/03510 PCT/US97/13072
1088 Me N(CH2CH2OMe)2 2-Br-4-N(Me)2-6-Me0-Ph
1089 Me NEt2 2-Br-4-MeO-Ph
1090 Me NH-3-pentyl 2-Br-4-MeO-Ph
1091 Me NHCH(CH2OMe)2 2-CN-4-Me-Ph
1092 Me N(c-C3H5)CH2CH2CN 2,4,6-Me3-Ph
1093 Me NHCH(CH2CH2OMe)CH2OMe 2-Me-4-Br-Ph
1094 Me NHCH(CH2OMe)2 2,5-Me2-4-Me0-Ph
1095 Me N(CH2CH2OMe)2 2,5-Me2-4-Me0-Ph
1096 Me NH-3-pentyl 2,5-Me2-4-Me0-Ph
1097 Me NEt2 2,5-Me2-4-Me0-Ph
1098 Me NHCH(CH2OMe)2 2-C1-4=MePh
1099 Me NCH(Et)CH2OMe 2-C1-4-MePh
1100 Me N(CH2CH2OMe)2 2-C1-4-MePh
1101 Me (S)-NHCH(CH2CH2OMe)CH2OMe 2-C1-4-MePh
1102 Me N(c-C3H5)CH2CH2CN 2,5-Me2-4-MeOPh
1103 Me NEt2 2-Me-4-MeOPh
1104 Me OEt 2-Me-4-MeOPh
1105 Me (S)-NHCH(CH2CH2OMe)CH2OMe 2-Me-4-MeOPh
1106 Me N(c-C3H5)CH2CH2CN 2-Me-4-MeOPh
1107 Me NHCH(CH2CH2OEt)2 2-Me-4-MeOPh
1108 Me N(c-C3H5)CH2CH2CN 2,4-C12-Ph
1109 Me NEt2 2-Me-4-C1Ph
1110 Me NH-3-pentyl 2-Me-4-C1Ph
1111 Me N(CH2CH2OMe)2 2-Me-4-C1Ph
1112 Me NHCH(CH2OMe)2 2-Me-4-C1Ph
1113 Me NEt2 2-Me-4-ClPh
1114 Me NEt2 2-C1-4-MePh
1115 Me NH-3-pentyl 2-C1-4-MePh
1116 Me NHCH(CH20Me)2 2-C1-4-MeOPh
1117 Me N(CH2CH2OMe)2 2-C1-4-MeOPh
1118 Me NHCH(Et)CH2OMe 2-C1-4-MeOPh
1119 Me N(c-Pr)CH2CH2CN 2-C1-4-MeOPh
1120 Me NEt2 2-C1-4-MeOPh
1121 Me NH-3-pentyl 2-C1-4-MeOPh
1123 Me NHCH(Et)CH2CH2OMe 2-C1-4-MeOPh
1124 Me NHCH(Me)CH2CH2OMe 2-C1-4-Me0Ph
-160-

T


CA 02259583 1999-01-04

WO 98/03510 PCT/US97/13072
1125 Me NHCH(Et)CH2CH2OMe 2-Br-4-MeOPh
1126 Me NHCH(Me)CH2CH2OMe 2-Br-4-MeOPh
1127 Me NHCH(Et)CH2CH2OMe 2-Me-4-MeOPh
1128 Me NHCH(Me)CH2CH2OMe 2-Me-4-MeOPh
1129 Me NHCH(CH2OMe)2 2-C1-4,5-(Me0)2Ph
1130 Me N(CH2CH2OMe)2 2-C1-4,5-(Me0)2Ph
1131 Me NHCH(Et)CH2OMe 2-C1-4,5-(Me0)2Ph
1132 Me N(c-Pr)CH2CH2CN 2-C1-4,5-(Me0)2Ph
1133 Me NEt2 2-C1-4,5-(Me0)2Ph
1134 Me NH-3-pentyl 2-C1-4,5-(Me0)2Ph
1135 Me NHCH(Et)CH2CH2OMe 2-C1-4,5-(Me0)2Ph
1136 Me NHCH(Me)CH2CH2OMe 2-C1-4,5-(Me0)2Ph
1137 Me NHCH(CH2OMe)2 2-Br-4,5-(Me0)2Ph
1138 Me N(CH2CH2OMe)2 2-Br-4,5-(MeO)2Ph
1139 Me NHCH(Et)CH2OMe 2-Br-4,5-(MeO)2Ph
1140 Me N(c-Pr)CH2CH2CN 2-Br-4,5-(MeO)2Ph
1141 Me NEt2 2-Br-4,5-(Me0)2Ph
1142 Me NH-3-pentyl 2-Br-4,5-(MeO)2Ph
1143 Me NHCH(CH2OMe)2 2-C1-4,6-(Me0)2Ph
1144 Me N(CH2CH2OMe)2 2-C1-4,6-(MeO)2Ph
1145 Me NEt2 2-C1-4,6-(MeO)2Ph
1146 Me NH-3-pentyl 2-C1-4,6-(Me0)2Ph
1147 Me NHCH(CH2OMe)2 2-Me-4,6-(MeO)2Ph
1148 Me IN(CH2CH2OMe)2 2-Me-4,6-(MeO)2Ph
1149 Me NHCH(Et)CH2OMe 2-Me-4,6-(MeO)2Ph
1150 Me NEt2 2-Me-4,6-(MeO)2Ph
1151 Me NH-3-pentyl 2-Me-4,6-(MeO)2Ph
1152 Me NHCH(Et)CH2CH2OMe 2-Me-4-MeOPh
1153 Me NHCH(Me)CH2CH2OMe 2-Me-4-MeOPh
1154 Me NHCH(CH2OMe)2 2-MeO-4-MePh
1155 Me N(CH2CH2OMe)2 2-MeO-4-MePh
1156 Me NHCH(Et)CH2OMe 2-MeO-4-MePh
1157 Me N(c-Pr)CH2CH2CN 2-MeO-4-MePh
1158 Me NEt2 2-MeO-4-MePh
1159 Me NH-3-pentyl 2-MeO-4-MePh
1160 Me NHCH(Et)CH2CH2OMe 2-MeO-4-MePh
-161-


CA 02259583 1999-01-04

WO 98/03510 PCTIUS97/13072
1161 Me NHCH(Me)CH2CH2OMe 2-MeO-4-MePh
1162 Me NHCH(CH20Me)2 2-MeO-4-MePh
1163 Me N(CH2CH2OMe)2 2-MeO-4-MePh
1164 Me NHCH(Et)CH2OMe 2-MeO-4-MePh
1165 Me N(c-Pr)CH2CH2CN 2-MeO-4-MePh
1166 Me NEt2 2-MeO-4-MePh
1167 Me NH-3-pentyl 2-MeO-4-MePh
1168 Me NHCH(CH2OMe)2 2-Me0-4-C1Ph
1169 Me N(CH2CH2OMe)2 2-Me0-4-C1Ph
1170 Me NHCH(Et)CH2OMe 2-Me0-4-C1Ph
1171 Me NEt2 2-Me0-4-C1Ph
1172 Me NH-3-pentyl 2-Me0-4-C1Ph

LTtilitv
CRF-R1 Receptor Binding Assay for the Evaluation of
Biological Activity

The following is a description of the
isolation of cell membranes containing cloned human CRF-
Ri receptors for use in the standard binding assay as
well as a description of the assay itself.
Messenger RNA was isolated from human hippocampus.
The mRNA was reverse transcribed using oligo (dt) 12-18
and the-coding region was amplified by PCR from start to
stop codons The resulting PCR fragment was cloned into
the EcoRV site of pGEMV, from whence the insert was
reclaimed using XhoI + XbaI and cloned into the XhoI +
XbaI sites of vector pm3ar ( which contains a CMV
promoter, the SV40 't' splice and early poly A signals,
an Epstein-Barr viral origin of replication, and a
-162-

i


CA 02259583 1999-01-04

WO 98/03510 PCTIUS97/13072
hygromycin selectable marker). The resulting expression
vector, called phchCRFR was transfected in 293EBNA cells
and cells retaining the episome were selected in the
presence of 400 M hygromycin. Cells surviving 4 weeks
of selection in hygromycin were pooled, adapted to
growth in suspension and used to generate membranes for
the binding assay described below. Individual aliquots
containing approximately 1 x 108 of the suspended cells
were then centrifuged to form a pellet and frozen.
For the binding assay a frozen pellet described
above containing 293EBNA cells transfected with hCRFR1
receptors is homogenized in 10 ml of ice cold tissue
buffer ( 50 mM HEPES buffer pH 7.0, containing 10 mM
MgCl2, 2 mM EGTA, 1 g/l aprotinin, 1 g/ml leupeptin
and 1 g/ml pepstatin). The homogenate is centrifuged
at 40,000 x g for 12 min and the resulting pellet
rehomogenized in 10 ml of tissue buffer. After another
centrifugation at 40,000=x g for 12 min, the pellet is
resuspended to a protein concentration of 360 g/ml to
be used in the assay.
Binding assays are performed in 96 well plates;
each well having a 300 l capacity. To each well is
added 50 l of test drug dilutions (final concentration
of drugs range from 10-10 - 10-5 M), 100 l of 125I_
ovine-CRF (125I-o-CRF) (final concentration 150 pM) and
150 l of the cell homogenate described above. Plates
are then allowed to incubate at room temperature for 2
hours before filtering the incubate over GF/F filters
(presoaked with 0.3% polyethyleneimine) using an
appropriate cell harvester. Filters are rinsed 2 times
with ice cold assay buffer before removing individual
filters and assessing them for radioactivity on a gamma
counter.
Curves of the inhibition of 125I-o-CRF binding to
cell membranes at various dilutions of test drug are
analyzed by the iterative curve fitting program LIGAND

-163-


CA 02259583 1999-01-04

WO 98/03510 PCT/US97/13072
[P.J. Munson and D. Rodbard, Anal. Biochern. 107:220
(1980), which provides Ki values for inhibition which
are then used to assess biological activity.
A compound is considered to be active if it has
a Ki value of less than about 10000 nM for the
inhibition of CRF.

Inhibition of CRF-Stim lat d Ad nvlate yc~asP
AcCivitv

Inhibition of CRF-stimulated.adenylate cyclase
activity can be performed as described by G.
Battaglia et al. Synapse 1:572 (1987). Briefly,
assays are carried out at 37 C for 10 min in 200 ml
of buffer containing 100 mM Tris-HC1 (pH 7.4 at 37
C), 10 mM MgCl2, 0.4 mM EGTA, 0.1% BSA, 1 mM
isobutylmethylxanthine (IBMX), 250 units/mi
phosphocreatine kinase, 5 mM creatine phosphate, 100
mM guanosine 5'-triphosphate, 100 nM oCRF, antagonist
peptides (concentration range 10-9 to 10-6m) and 0.8
mg original wet weight tissue (approximately 40-60 mg
protein). Reactions are initiated by the addition of
1 mM ATP/32P)ATP (approximately 2-4 mCi/tube) and
terminated by the addition of 100 ml of 50 mM Tris-
HCL, 45 mM ATP and 2% sodium dodecyi sulfate. In
order to monitor the recovery of cAMP, 1 l of
[3H]cAMP (approximately 40,000 dpm) is added to each
tube prior to separation. The separation of
[32P]cAMP from [32P]ATP is performed by sequential
elution over Dowex and alumina columns.
In vivo Biological Assay
The in vivo activity of the compounds of the
present invention can be assessed using any one of
the biological assays available and accepted within
the art. Illustrative of these tests include the
-164-


CA 02259583 1999-01-04

WO 98/03510 PCT/US97/13072
Acoustic Startle Assay, the Stair Climbing Test, and
the Chronic Administration Assay. These and other
models useful for the testing of compounds of the
present invention have been outlined in C.W. Berridge
and A.J. Dunn Brain Research Reviews 15:71 (1990).
Compounds may be tested in any species of rodent or
small mammal.

Compounds of this invention have utility in the
treatment of inbalances associated. with abnormal
levels of corticotropin releasing factor in patients
suffering from depression, affective disorders,
and/or anxiety.
Compounds of this invention can be administered
to treat these abnormalities by means that produce
contact of the active agent with the agent's site of
action in the body of a mammal. The compounds can be
administered by any conve=ntional-means available for
use in conjunction with pharmaceuticals either as
individual therapeutic agent or in combination of
therapeutic agents. They can be administered alone,
but will generally be administered with a
pharmaceutical carrier selected on the basis of the
chosen route of administration and standard
pharmaceutical practice.
The dosage administered will vary depending on
the use and known factors such as pharmacodynamic
character of the particular agent, and its mode and
route of administration; the recipient's age, weight,
and health; nature and extent of symptoms; kind of
concurrent treatment; frequency of treatment; and
desired effect. For use in the treatment of said
diseases or conditions, the compounds of this
invention can be orally administered daily at a
dosage of the active ingredient of 0.002 to 200 mg/kg
of body weight. Ordinarily, a dose of 0.01 to 10
-165-


CA 02259583 1999-01-04

WO 98/03510 PCT/US97/13072
mg/kg in divided doses one to four times a day, or in
sustained release formulation will be effective in
obtaining the desired pharmacological effect.
Dosage forms (compositions) suitable for
administration contain from about 1 mg to about 100
mg of active ingredient per unit. In these
pharmaceutical compositions, the active ingredient
will ordinarily be present in an amount of about 0.5
to 95% by weight based on the total weight of the
composition.
The active ingredient can be administered orally
is solid dosage forms, such as capsules, tablets and
powders; or in liquid forms such as elixirs, syrups,
and/or suspensions. The compounds of this invention
can also be administered parenterally in sterile
liquid dose formulations.
Gelatin capsules can be used to contain the
active ingredient and a suitable carrier such as but
not limited to lactose, starch, magnesium stearate,
steric acid, or cellulose derivatives. 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 time. Compressed tablets
can be sugar-coated or film-coated to mask any
unpleasant taste, or used to protect the active
ingredients from the atmosphere, or to allow
selective disintegration of the tablet in the
gastrointestinal tract.
Liquid dose forms for oral administration can
contain coloring or flavoring agents to increase
patient acceptance.
In general, water, pharmaceutically acceptable
oils, saline, aqueous dextrose (glucose), and related
sugar solutions and glycols, such as propylene glycol
or polyethylene glycol, are suitable carriers for
-166-
1


CA 02259583 1999-01-04

WO 98/03510 PCTIUS97/13072
parenteral solutions. Solutions for parenteral
administration preferably contain a water soluble
salt of the active ingredient, suitable stabilizing
agents, and if necessary, butter substances.
Antioxidizing agents, such as sodium bisulfite,
sodium sulfite, or ascorbic acid, either alone or in
combination, are suitable stabilizing agents. Also
used are citric acid and its salts, and EDTA. In
addition, parenteral solutions can contain
preservatives such as benzalkonium chloride, methyl-
or propyl-paraben, and chlorobutanol.
Suitable pharmaceutical carriers are described
in "Remington's Pharmaceutical Sciences", A. Osol, a
standard reference in the field.
Useful pharmaceutical dosage-forms for
administration of the compounds of this invention can
be illustrated as follows:

Capsules
A large number of units capsules are prepared
by filling standard two-piece hard gelatin capsules
each with 100 mg of powdered active ingredient, 150
mg lactose, 50 mg cellulose, and 6 mg magnesium
stearate.
Soft Gelatin Capsules
A mixture of active ingredient in a digestible
oil such as soybean, cottonseed oil, or olive oil is
prepared, and injected by means of a positive
displacement was pumped into gelatin to form soft
gelatin capsules containing 100 mg of the active
ingredient. The capsules were washed and dried.

Tablets
A large number of tablets are prepared by
conventional procedures so that the dosage unit was

-167-


CA 02259583 1999-01-04

WO 98/03510 PCTIUS97/13072
100 mg active ingredient, 0.2 mg of colloidal silicon
dioxide, 5 mg of magnesium stearate, 275 mg of
microcrystalline cellulose, 11 mg of starch, and 98.8
mg lactose. Appropriate coatings may be applied to
increase palatability or delayed adsorption.

The compounds of this invention may also be used
as reagents or standards in the biochemical study of
neurological function, dysfunction, and disease.
Although the present invention has been
described and exemplified in terms of certain
preferred embodiments, other embodiments will be
apparent to those skilled in the art. The invention
is, therefore, not limited to the particular
embodiments described and exemplified, but is capable
of modification or variation without departing from
the spirit of the invention, the full scope of which
is delineated by the appended claims.

-168-
T

Representative Drawing