COMPOUNDS FOR INHIBITING BETA-AMYLOID PEPTIDE RELEASE AND/OR ITS SYNTHESIS

COMPOSES D'INHIBITION DE LA LIBERATION DU PEPTIDE .BETA.-AMYLOIDE ET/OU DE SA SYNTHESE

English Abstract

Disclosed are compounds which inhibit .beta.-amyloid peptide release and/or
its synthesis, and, accordingly, have utility in treating Alzheimer's disease.
Also disclosed are pharmaceutical compositions that include a compound which
inhibits .beta.-amyloid peptide release and/or its synthesis as well as
methods for treating Alzheimer's disease both prophylactically and
therapeutically with such pharmaceutical compositions.

French Abstract

L'invention concerne des composés inhibant la libération du peptide .beta.-amyloïde et/ou sa synthèse et présentant par conséquent une utilité dans le traitement de la maladie d'Alzheimer. L'invention concerne également des compositions pharmaceutiques comprenant un composé inhibant la libération du peptide .beta.-amyloïde et/ou sa synthèse ainsi que des méthodes de traitement de la maladie d'Alzheimer à la fois de façon prophylactique et thérapeutique à l'aide de ces compositions pharmaceutiques.

Claims

-525-
Claims:
1. A method for inhibiting .beta.-amyloid peptide release
and/or its synthesis in a cell which method comprises administering
to such a cell an amount of a compound or a mixture of compounds
effective in inhibiting the cellular release and/or synthesis of
.beta.-amyloid peptide wherein said compounds are represented by the
following formulas:
<IMG>

-526-
<IMGS>

-527-
<IMG>
Formula VI
wherein R1 is selected from the group consisting of alkyl,
alkenyl, alkynyl, cycloalkyl, cycloalkenyl, substituted alkyl,
substituted alkenyl, substituted alkynyl, substituted cycloalkyl,
substituted cycloalkenyl, aryl, heteroaryl and heterocyclic:
R'is selected from the group consisting of aryl, cycloalkyl,
substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl,
heteroaryl, heterocyclic, -CH3, -CH=CH2, -CH=CHR1,- CH=CR1R1.
-CR1=CH2, -CR1=CHR2, -CR1=CR1R1. -C=CH and
-C=CR1: with the proviso that when R' is heteroaryl or
heterocyclic, there is no N in R' at a position beta to the C=Q
group;
Q is S or O:
R15 is selected from the group consisting of hydrogen, alkyl.
substituted alkyl, aryl, heterocyclic and heteroaryl;

-528-
R15' is selected from the group consisting of hydrogen.
hydroxyl, alkyl. substituted alkyl, aryl, heterocyclic and heteroaryl;
W, together with -C(H)pC(=X)-, forms a cycloalkyl,
cycloalkenyl. heterocyclic, substituted cycloalkyl, or substituted
cycloalkenyl group wherein each of said cycloalkyl, cycloalkenyl,
heterocyclic, substituted cycloalkyl or substituted cycloalkenyl
group is optionally fused to form a bi- or multi-fused ring system
(preferably no more than 5 fused rings) with one or more ring
structures selected from the group consisting of cycloalkyl,
cycloalkenyl. heterocyclic, aryl and heteroaryl group which, in
turn, each of such ring structures are optionally substituted with 1 to
4 substituents selected from the group consisting of hydroxyl, halo,
alkoxy, substituted alkoxy, thioalkoxy, substituted thioalkoxy, nitro.
cyano, carboxyl, carboxyl esters, alkyl, substituted alkyl, alkenyl.
substituted alkenyl, alkynyl, substituted alkynyl, amino, substituted
amino. -NHC(O)R4. -NHSO2R4. -C(O)NH2. -C(O)NHR4, - C(O)NR4R4.
-S(O)R4, -S(O)2R4, -S(O)2NHR4 and -S(O)2NR4R4.
where each R4 is independently selected from the group consisting
of alkyl, substituted alkyl, aryl and heteroaryl;
X is selected from the group consisting of oxo (=O), thiooxo
(=S), hydroxyl (-H, -OH), thiol (H,-SH) and hydro (H,H);
Y is represented by the formula:

-529-
<IMG>
wherein each R2 is independently selected from the group consisting
of alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl,
substituted alkynyl, cycloalkyl, aryl, heteroaryl and heterocyclic;
Z is represented by the formula -T-C(X')(X")C(O)- where T
is selected from the group consisting of a bond covalently linking
R1 to -C(X')(X")-, oxygen, sulfur, and -NR5 where R5 is
hydrogen, acyl, alkyl, substituted alkyl, aryl. heterocyclic or
heteroaryl group;
R5' is hydrogen. alkyl, substituted alkyl, aryl, heterocyclic
or heteroaryl group:
X' and X" are independently selected from the group
consisting of hydrogen, fluoro, alkyl, substituted alkyl, aryl,
heteroaryl. heterocyclic, -OR5~, -SR5, -N(R5)2, -N(CO)OR15 and
- N3, with the proviso that at least one of X' or X" is other than
hydrogen, hydroxy or fluoro, and with the further proviso that both
X' and X" cannot both be -OR5', -SR5. -N(R5)2, -N(CO)OR15 and
- N3 ; further, neither X' and X" can be -OR5,. -SR5. -N(R5)2,
- N(CO)OR15 or -N3 when T is other than a bond covalently linking
R1 to -C(X')(X")-;
n is an integer equal to 1 or 2;
p is an integer equal to 0 or 1 such that when p is zero, the
ring defined by W and -C(H)p C(=X)- is unsaturated at the carbon

-530-
atom of ring attachment to Y and when p is one, the ring is
saturated at the carbon atom of ring attachment to Y.
with the following provisos:
when R1 is 2-propylpentanoyl, R2 is methyl, and R15 is
hydrogen, then W, together with >CH and >C=X, does not form
a 2,3-dihydro-1-methyl-5-phenyl-1H-1.4-benzodiazepin-2-one
when R1 is 3.5-difluorobenzoyl. R2 is methyl, and R15 is
hydrogen, then W, together with > CH and > C=X, does not form
a 2,3-dihydro-1-methyl-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one
when R1 is trans-cinnamyl. R2 is methyl, and R15 is
hydrogen, then W. together with > CH and > C=X, does not form
a 2.3-dihydro-1-(3.3-dimethyl-2-oxobutyl)-5-(2-pyridyl)-1H-1.4-benzodiazepin-2-
one
when R1 is 2-(4-chlorophenoxy)-2-methylpropionyl. R2 is
methyl, and R15 is hydrogen, then W, together with > CH and
>C=X, does not form a 2,3-dihydro-1-methyl-5-(2-pyridyl)-1H-1,4-benzodiazepin-
2-one
when R1 is .alpha.-methoxyphenylacetyl, R2 is methyl. and R15
is hydrogen, then W. together with > CH and > C=X, does not
form a 2,3-dihydro-1-methyl-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one

-531-
when R1 is diphenylacetyl, R2 is methyl, and R15 is
hydrogen, then W, together with > CH and > C=X, does not form
a 2,3-dihydro-1-methyl-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one
when R1 is .alpha.-methoxyphenylacetyl, R2 is methyl, and R15
is hydrogen, then W, together with > CH and > C=X, does not
form a 2.3-dihydro-1-(3,3-dimethyl-2-oxobutyl)- 5-(2-pyridyl)-1H-
1,4-benzodiazepin-2-one
when R1 is .alpha.-hydroxy-diphenylacetyl, R2 is methyl, and
R15 is hydrogen, then W, together with > CH and > C=X, does
not form a 2.3-dihydro-1-(3,3-dimethyl-2-oxobutyl)- 5-(2-pyridyl)-
1H-1,4-benzodiazepin-2-one
when R1 is diphenylacetyl, R2 is methyl, and R15 is
hydrogen, then W. together with > CH and > C=X. does not form
a 2,3-dihydro-1-(3.3-dimethyl-2-oxobutyl)- 5-(2-pyridyl)-1H-1,4-
benzodiazepin-2-one
when R1 is 2-(chlorophenoxy)-2-methylpropionyl. R2 is
methyl, and R15 is hydrogen, then W, together with > CH and
>C=X, does not form a 2.3-dihydro-1-(3.3-dimethyl-2-oxobutyl)-
5-(2-pyridyl)-1H-1.4-benzodiazepin-2-one
when R1 is diphenylacetyl, R2 is methyl, and R15 is
hydrogen, then W, together with > CH and > C = X, does not form
a 2.3-dihydro-1-(2-N.N-diethylaminoethyl)- 5-(2-pyridyl)-1H-1,4-
benzodiazepin-2-one

-532-
when R1 is 3,5-difluorobenzoyl, R2 is methyl. and R15 is
hydrogen, then W. together with > CH and > C=X, does not form
a 2,3-dihydro-1-(2-N.N-diethylaminoethyl)- 5-(2-pyridyl)-1H-1.4-
benzodiazepin-2-one
when R1 is trans-cinnamyl. R2 is methyl, and R15 is
hydrogen, then W, together with >CH and >C=X, does not form
a 2,3-dihydro-1-(2-N,N-diethylaminoethyl)- 5-(2-pyridyl)-1H-1.4-
benzodiazepin-2-one
when R1 is 2-(4-chlorophenoxy)-2-methylpropionyl. R2 is
methyl, and R15 is hydrogen, then W, together with > CH and
>C=X, does not form a 2.3-dihydro-1-(2-N.N-diethylaminoethyl)-
5-(2-pyridyl)-1H-1.4-benzodiazepin-2-one
when R1-N(R15) is (2.5-dimethoxyphenyl)ureylenyl and R2
is methyl, then W, together with > CH and > C=X, does not form
a 2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one
when R1 is D.L-2-pyrrolidinone-5-yl. R2 is methyl, and R15
is hydrogen. then W, together with > CH and > C=X. does not
form a 7-methyl-5,7-dihydro-6H-dibenz[b.d]azepin-6-one.
2. A method for preventing the onset of AD in a human patient
at risk for developing AD which method comprises administering to
said patient a pharmaceutical composition comprising a
pharmaceutically inert carrier and an effective amount of a
compound or a mixture of compounds of the following formulas:

-533-
<IMGS>

-534-
<IMGS>

-535-
<IMGS>

-536-
wherein R1 is selected from the group consisting of alkyl.
alkenyl, alkynyl, cycloalkyl, cycloalkenyl, substituted alkyl.
substituted alkenyl. substituted alkynyl, substituted cycloalkyl.
substituted cycloalkenyl, aryl, heteroaryl and heterocyclic:
R'is selected from the group consisting of aryl, cycloalkyl.
substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl,
heteroaryl, heterocyclic, -CH3, -CH=CH2, -CH=CHR1,
-CH=CR1R1, -CR1=CH2, -CR1=CHR1, -CR1=CR1R1, -C=CH and
-C=CR1: with the proviso that when R' is heteroaryl or
heterocyclic, there is no N in R' at a position beta to the C=Q
group;
Q is S or O:
R15 is selected from the group consisting of hydrogen, alkyl,
substituted alkyl, aryl, heterocyclic and heteroaryl;
R15' is selected from the group consisting of hydrogen,
hydroxyl, alkyl, substituted alkyl, aryl, heterocyclic and heteroaryl;
W. together with -C(H)p C(=X)-, forms a cycloalkyl,
cycloalkenyl, heterocyclic, substituted cycloalkyl, or substituted
cycloalkenyl group wherein each of said cycloalkyl, cycloalkenyl.
heterocyclic, substituted cycloalkyl or substituted cycloalkenyl
group is optionally fused to form a bi- or multi-fused ring system
(preferably -no more than 5 fused rings) with one or more ring
structures selected from the group consisting of cycloalkyl,
cycloalkenyl, heterocyclic, aryl and heteroaryl group which, in
turn, each of such ring structures are optionally substituted with 1 to
4 substituents selected from the group consisting of hydroxyl, halo,
alkoxy, substituted alkoxy, thioalkoxy, substituted thioalkoxy, vitro,
cyano, carboxyl, carboxyl esters, alkyl, substituted alkyl, alkenyl,
substituted alkenyl, alkynyl, substituted alkynyl, amino, substituted

-537-
amino. -NHC(O)R4. -NHSO2R4, -C(O)NH2, -C(O)NHR4,
-C(O)NR4R4, -S(O)R4, -S(O)2R4. -S(O)2NHR4 and -S(O)2NR4R4,
where each R4 is independently selected from the group consisting
of alkyl, substituted alkyl, aryl and heteroaryl;
X is selected from the group consisting of oxo (=O), thiooxo
(=S), hydroxyl (-H, -OH), thiol (H,-SH) and hydro (H,H):
Y is represented by the formula:
<IMG>
wherein each R2 is independently selected from the group consisting
of alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl,
substituted alkynyl, cycloalkyl, aryl, heteroaryl and heterocyclic:
Z is represented by the formula -T-C(X')(X")C(O)- where T
is selected from the group consisting of a bond covalently linking
R1 to -C(X')(X")-, oxygen, sulfur, and -NR5 where R5 is
hydrogen, acyl, alkyl, substituted alkyl, aryl, heterocyclic or
heteroaryl group:

-538-
R5' is hydrogen, alkyl, substituted alkyl, aryl. heterocyclic
or heteroaryl group:
X' and X" are independently selected from the group
consisting of hydrogen, fluoro, alkyl, substituted alkyl, aryl.
heteroaryl, heterocyclic, -OR5', -SR5, -N(RS)2, -N(CO)OR15
and - N3, with the proviso that at least one of X' or X" is other than
hydrogen, hydroxy or fluoro, and with the further proviso that both
X' and X" cannot both be -OR5', -SR5, -N(R5)2, -N(CO)OR15
and - N3 ; further, neither X' and X" can be -OR5', -SR5, -N(R5)2,
-N(CO)OR15 or -N3 when T is other than a bond covalently linking
R1 to -C(X')(X")-:
n is an integer equal to 1 or 2;
p is an integer equal to 0 or 1 such that when p is zero, the
ring defined by W and -C(H)p C(=X)- is unsaturated at the carbon
atom of ring attachment to Y and when p is one, the ring is
saturated at the carbon atom of ring attachment to Y,
with the following provisos:
when R1 is 2-propylpentanoyl, R2 is methyl, and R15 is
hydrogen, then W, together with >CH and >C=X, does not form
a 2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one
when R1 is 3,5-difluorobenzoyl, R2 is methyl, and R15 is
hydrogen, then W, together with > CH and > C = X, does not form
a 2,3-dihydro-1-methyl-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one
when R1 is trans-cinnamyl, R2 is methyl, and R15 is hydrogen.
then W, together with > CH and > C =X, does not form a

-539-
2.3-dihydro-1-(3,3-dimethyl-2-oxobutyl)-5-(2-pyridyl)-1H-1,4-
benzodiazepin-2-one
when R1 is 2-(4-chlorophenoxy)-2-methylpropionyl, R2 is
methyl, and R15 is hydrogen, then W, together with > CH and
>C=X, does not form a 2,3-dihydro-1-methyl-5-(2-pyridyl)-1H-
1.4-benzodiazepin-2-one
when R1 is .alpha.-methoxyphenylacetyl, R2 is methyl, and R15 is
hydrogen, then W, together with >CH and >C=X, does not form
a 2,3-dihydro-1-methyl-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one
when R1 is diphenylacetyl, R2 is methyl, and R15 is hydrogen.
then W, together with > CH and > C = X, does not form a
2.3-dihydro-1-methyl-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one
when R1 is .alpha.-methoxyphenylacetyl. R2 is methyl, and R15 is
hydrogen, then W, together with > CH and > C=X. does not form
a 2,3-dihydro-1-(3,3-dimethyl-2-oxobutyl)-5-(2-pyridyl)-1H-1,4-
benzodiazepin-2-one
when R1 is .alpha.-hydroxy-diphenylacetyl, R2 is methyl, and R15 is
hydrogen. then W, together with >CH and >C=X, does not form
a 2,3-dihydro-1-(3,3-dimethyl-2-oxobutyl)-5-(2-pyridyl)-1H-1,4-
benzodiazepin-2-one
when R1 is diphenylacetyl, R2 is methyl, and R15 is hydrogen.
then W, together with > CH and > C=X. does not form a

-540-
2,3-dihydro-1-(3,3-dimethyl-2-oxobutyl)-5-(2-pyridyl)-1H-1,4-
benzodiazepin-2-one
when R1 is 2-(chlorophenoxy)-2-methylpropionyl, R2 is
methyl, and R15 is hydrogen, then W, together with >CH and
>C=X, does not form a 2,3-dihydro-1-(3,3-dimethyl-2-oxobutyl)-
5-(2-pyridyl)-1H-1.4-benzodiazepin-2-one
when R1 is diphenylacetyl, R2 is methyl, and R15 is hydrogen,
then W, together with >CH and >C=X, does not form a
2.3-dihydro-1-(2-N,N-diethylaminoethyl)-5-(2-pyridyl)-1H-1,
4-benzodiazepin-2-one
when R1 is 3,5-ditluorobenzoyl, R2 is methyl, and R15 is
hydrogen, then W, together with >CH and >C=X. does not form
a 2,3-dihydro-1-(2-N,N-diethylaminoethyl)-5-(2-pyridyl)-1H-1,
4-benzodiazepin-2-one
when R1 is trans-cinnamyl, R2 is methyl, and R15 is hydrogen.
then W, together with >CH and >C=X, does not form a
2,3-dihydro-1-(2-N,N-diethylaminoethyl)-5-(2-pyridyl)-1H-1,
4-benzodiazepin-2-one
when R1 is 2-(4-chlorophenoxy)-2-methylpropionyl, R2 is
methyl, and R15 is hydrogen, then W, together with > CH and
>C=X, does not form a 2,3-dihydro-1-(2-N,N-diethylaminoethyl)-
5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one

-541-
when R1-N(R15) is (2,5-dimethoxyphenyl)ureylenyl and R2 is
methyl, then W, together with >CH and >C=X, does not form a
2,3-dihydro-1-methyl-5-phenyl-1H-1.4-benzodiazepin-2-one
when R1 is D,L-2-pyrrolidinone-5-yl, R2 is methyl, and R15 is
hydrogen, then W, together with >CH and >C=X, does not form
a 7-methyl-5,7-dihydro-6H-dibenz[b.d]azepin-6-one.
3. A method for treating a human patient with AD in order to
inhibit further deterioration in the condition of that patient which
method comprises administering to said patient a pharmaceutical
composition comprising a pharmaceutically inert carrier and an
effective amount of a compound or a mixture of compounds of the
following formulas:
<IMG>

-542-
<IMGS>

-543-
<IMGS>

-544-
<IMGS>
wherein R1 is selected from the group consisting of alkyl,
alkenyl, alkynyl, cycloalkyl, cycloalkenyl, substituted alkyl,
substituted alkenyl, substituted alkynyl, substituted cycloalkyl.
substituted cycloalkenyl, aryl, heteroaryl and heterocyclic:

-545-
R'is selected from the group consisting of aryl, cycloalkyl,
substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl,
heteroaryl, heterocyclic, -CH3, -CH=CH2, -CH=CHR1,
-CH=CR1R1, -CR1=CH2, -CR1=CHR1, -CR1=CR1R1, -C=CH and
-C=CR1; with the proviso that when R' is heteroaryl or
heterocyclic, there is no N in R' at a position beta to the C=Q
group;
Q is S or O;
R15 is selected from the group consisting of hydrogen, alkyl,
substituted alkyl, aryl, heterocyclic and heteroaryl,
R15 is selected from the group consisting of hydrogen,
hydroxyl, alkyl, substituted alkyl, aryl, heterocyclic and heteroaryl,
W, together with -C(H)p C(=X)-, forms a cycloalkyl,
cycloalkenyl, heterocyclic, substituted cycloalkyl, or substituted
cycloalkenyl group wherein each of said cycloalkyl, cycloalkenyl,
heterocyclic, substituted cycloalkyl or substituted cycloalkenyl
group is optionally fused to form a bi- or multi-fused ring system
(preferably no more than 5 fused rings) with one or more ring
structures selected from the group consisting of cycloalkyl,
cycloalkenyl, heterocyclic, aryl and heteroaryl group which, in
turn, each of such ring structures are optionally substituted with 1 to
4 substituents selected from the group consisting of hydroxyl, halo.
alkoxy, substituted alkoxy, thioalkoxy, substituted thioalkoxy, vitro,
cyano, carboxyl, carboxyl esters, alkyl, substituted alkyl, alkenyl,
substituted alkenyl, alkynyl, substituted alkynyl, amino, substituted
amino, -NHC(O)R4, -NHSO2R4, -C(O)NH2, -C(O)NHR4,
-C(O)NR4R4, -S(O)R4, -S(O)2R4, -S(O)2NHR4 and -S(O)NR4R4,
where each R4 is independently selected from the group consisting
of alkyl, substituted alkyl, aryl and heteroaryl;

-546-
X is selected from the group consisting of oxo (=O), thiooxo
(=S), hydroxyl (-H, -OH), thiol (H,-SH) and hydro (H,H);
Y is represented by the formula:
<IMG>
wherein each R2 is independently selected from the group
consisting of alkyl, substituted alkyl, alkenyl, substituted alkenyl,
alkynyl, substituted alkynyl, cycloalkyl, aryl, heteroaryl and
heterocyclic;
Z is represented by the formula -T-C(X')(X")C(O)- where T
is selected from the group consisting of a bond covalently linking
R1 to -C(X')(X")-, oxygen, sulfur, and -NR5 where R5 is
hydrogen, acyl, alkyl, aryl, substituted alkyl, heterocyclic or
heteroaryl group;
R5' is hydrogen, alkyl, substituted alkyl, aryl, heterocyclic
or heteroaryl group;
X' and X" are independently selected from the group
consisting of hydrogen, fluoro, alkyl, substituted alkyl, aryl,

-547-
heteroaryl, heterocyclic. -OR5', -SR5, -N(R5)2, -N(CO)OR15 and
-N3, with the proviso that at least one of X' or X" is other than
hydrogen, hydroxy or fluoro, and with the further proviso that both
X' and X" cannot both be -OR5' , -SR5, -N(R5)2, -N(CO)OR15 and
-N3 ; further, neither X' and X" can be -OR5' , -SR5, -N(R5)2,
-N(CO)OR15 or -N3 when T is other than a bond covalently linking
R1 to -C(X')(X")-;
n is an integer equal to 1 or 2;
p is an integer equal to 0 or 1 such that when p is zero, the
ring defined by W and -C(H)p C(=X)- is unsaturated at the carbon
atom of ring attachment to Y and when p is one, the ring is
saturated at the carbon atom of ring attachment to Y,
with the following provisos:
when R1 is 2-propylpentanoyl, R2 is methyl, and R15 is
hydrogen, then W, together with >CH and >C=X, does not form
a 2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one
when R1 is 3,5-difluorobenzoyl, R2 is methyl, and R15 is
hydrogen, then W, together with >CH and >C=X, does not form
a 2,3-dihydro-1-methyl-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one
when R1 is trans-cinnamyl, R2 is methyl, and R15 is
hydrogen, then W, together with >CH and >C=X, does not form
a 2,3-dihydro-1-(3,3-dimethyl-2-oxobutyl)-5-(2-pyridyl)-1H-1,4-
benzodiazepin-2-one
when R1 is 2-(4-chlorophenoxy)-2-methylpropionyl, R2 is
methyl, and R15 is hydrogen, then W, together with >CH and

-548-
>C=X, does not form a 2,3-dihydro-1-methyl-5-(2-pyridyl)-1H-
1,4-benzodiazepin-2-one
when R1 is .alpha.-methoxyphenylacetyl, R2 is methyl, and R15
is hydrogen, then W, together with > CH and > C=X, does not
form a 2,3-dihydro-1-methyl-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one
when R1 is diphenylacetyl, R2 is methyl, and R15 is
hydrogen, then W, together with > CH and > C = X, does not form
a 2,3-dihydro-1-methyl-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one
when R1 is .alpha.-methoxyphenylacetyl, R2 is methyl, and R15
is hydrogen, then W, together with > CH and > C=X, does not
form a 2.3-dihydro-1-(3,3-dimethyl-2-oxobutyl)-5-(2-pyridyl)-1H-
1,4-benzodiazepin-2-one
when R1 is .alpha.-hydroxy-diphenylacetyl, R2 is methyl, and
R15 is hydrogen, then W, together with > CH and > C=X, does
not form a 2,3-dihydro-1-(3,3-dimethyl-2-oxobutyl)-5-(2-pyridyl)-
1H-1,4-benzodiazepin-2-one
when R1 is diphenylacetyl, R2 is methyl, and R15 is
hydrogen, then W, together with > CH and > C =X, does not form
a 2,3-dihydro-1-(3,3-dimethyl-2-oxobutyl)- 5-(2-pyridyl)-1H-1,4-
benzodiazepin-2-one
when R1 is 2-(chlorophenoxy)-2-methylpropionyl, R2 is
methyl, and R15 is hydrogen, then W, together with > CH and

-549-
>C=X, does not form a 2,3-dihydro-1-(3,3-dimethyl-2-oxobutyl)-
5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one
when R1 is diphenylacetyl, R2 is methyl, and R15 is
hydrogen, then W, together with >CH and >C=X, does not form
a 2.3-dihydro-1-(2-N,N-diethylaminoethyl)-5-(2-pyridyl)-1H-1,4-
benzodiazepin-2-one
when R1 is 3,5-difluorobenzoyl, R2 is methyl, and R15 is
hydrogen, then W, together with > CH and > C = X, does not form
a 2,3-dihydro-1-(2-N,N-diethylaminoethyl)-5-(2-pyridyl)-1H-1,4-
benzodiazepin-2-one
when R1 is trans-cinnamyl, R2 is methyl, and R15 is
hydrogen, then W, together with > CH and > C=X, does not form
a 2,3-dihydro-1-(2-N,N-diethylaminoethyl)-5-(2-pyridyl)-1H-1,4-
benzodiazepin-2-one
when R1 is 2-(4-chlorophenoxy)-2-methylpropionyl, R2 is
methyl, and R15 is hydrogen. then W, together with > CH and
>C=X, does not form a 2,3-dihydro-1-(2-N,N-diethylaminoethyl)-
5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one
when R1-N(R15) is (2,5-dimethoxyphenyl)ureylenyl and R2
is methyl, then W, together with >CH and >C=X, does not form
a 2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one

-550-
when R1 is D,L-2-pyrrolidinone-5-yl, R2 is methyl, and R15
is hydrogen, then W, together with > CH and > C=X, does not
form a 7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one.
4. A method according to any of Claims 1-3 wherein R1
is aryl or heteroaryl.
5. A method according to Claim 4 wherein R1 is
selected from the group consisting of
(a) alkyl
(b) phenyl,
(c) a substituted phenyl group of the formula:
<IMG>
wherein R c is selected from the group consisting of acyl,
alkyl, alkoxy, alkylalkoxy, azido, substituted amino, cyano, halo,
hydrogen, nitro, trihalomethyl, thioalkoxy.

-551-
and wherein R b and R c are fused to form a heteroaryl or
heterocyclic ring with the phenyl ring wherein the heteroaryl or
heterocyclic ring contains from 3 to 8 atoms of which from 1 to 3
are heteroatoms independently selected from the group consisting of
oxygen, nitrogen and sulfur
R b and R b are independently selected from the group
consisting of hydrogen, halo, vitro, cyanc, trihalomethyl, alkoxy,
and thioalkoxy with the proviso that when R c is hydrogen, then R b
and R b are either both hydrogen or both substituents other than
hydrogen,
(d) 2-naphthyl,
(e) 2-naphthyl substituted at the 4, 5, 6, 7 and/or 8 positions
with 1 to 5 substituents selected from the group consisting alkyl.
alkoxy, halo, cyano, vitro, trihalomethyl, thioalkoxy, aryl, and
heteroaryl,
(f) heteroaryl, and
(g) substituted heteroaryl containing 1 to 3 substituents
selected from the group consisting of alkyl, alkoxy, aryl, aryloxy.
cyano, halo, vitro, heteroaryl, thioalkoxy, thioaryloxy provided that
said substituents are not ortho to the heteroaryl attachment to
the - NH group.
6. The method according to Claim 4 wherein R1 is
selected from the group consisting of mono-, di- and tri-substituted
phenyl groups.
7. The method according to Claim 6 wherein R1 is a
disubstituted phenyl selected from the group consisting of
3,5-dichlorophenyl, 3,5-difluorophenyl, 3,5-di(trifluoromethyl)-phenyl.

-552-
3,4-dichiorophenyl, 3,4-difluorophenyl, 3-(trifluoromethyl)-4-
chlorophenyl, 3-chloro-4-cyanophenyl, 3-chloro-4-iodophenyl, and
3,4-methylenedioxyphenyl.
8. The method according to Claim 6 wherein R1 is a
monosubstituted phenyl selected from the group consisting of
4-azidophenyl, 4-bromophenyl, 4-chlorophenyl, 4-cyanophenyl,
4-ethylphenyl, 4-fluorophenyl, 4-iodophenyl, 4-(phenylcarbonyl)-
phenyl, and 4-(1-ethoxy)ethylphenyl.
9. The method according to Claim 6 wherein R1 is a
trisubstituted phenyl selected from the group consisting of
3,4,5-trifluorophenyl and 3,4,5-trichlorophenyl.
10. The method according to Claim 4 wherein R1 is
selected from the group consisting of 2-naphthyl, quinolin-3-yl,
2-methylquinolin-6-yl, benzothiazol-6-yl, 5-indolyl, and phenyl.
11. A method according to any of Claims 1, 2 or 3
wherein R1 is selected from the group consisting of phenyl,
1-naphthyl, 2-naphthyl, 2-chlorophenyl, 2-fluorophenyl.
2-bromophenyl. 2-hydroxyphenyl, 2-nitrophenyl, 2-methylphenyl,
2-methoxyphenyl, 2-phenoxyphenyl, 2-trifluoromethylphenyl,
4-fluorophenyl, 4-chlorophenyl, 4-bromophenyl, 4-nitrophenyl,
4-methylphenyl, 4-hydroxyphenyl, 4-methoxyphenyl, 4-ethoxyphenyl,
4-butoxyphenyl, 4-iso-propylphenyl, 4-phenoxyphenyl,
4-trifluoromethylphenyl, 4-hydroxymethylphenyl, 3-methoxyphenyl,
3-hydroxyphenyl, 3-nitrophenyl, 3-fluorophenyl, 3-chlorophenyl,
3-bromophenyl, 3-phenoxyphenyl, 3-thiomethoxyphenyl,

-553-
3-methylphenyl, 3-trifluoromethylphenyl, 2,3-dichlorophenyl,
2,3-difluorophenyl, 2,4-dichlorophenyl, 2,5-dimethoxyphenyl,
3,4-dichlorophenyl, 3,4-difluorophenyl, 3,4-methylenedioxyphenyl,
3,4-dimethoxyphenyl, 3,5-difluorophenyl, 3,5-dichlorophenyl,
3.5-di-(trifluoromethyl)phenyl, 3,5-dimethoxyphenyl,
2,4-dichlorophenyl, 2,4-difluorophenyl, 2,6-difluorophenyl,
3,4,5-trifluorophenyl, 3,4,5-trimethoxyphenyl, 3,4,5-tri-
(trifluoromethyl)phenyl, 2,4,6-trifluorophenyl,
2,4,6-trimethylphenyl, 2,4,6-tri-(trifluoromethyl)phenyl,
2,3,5-trifluorophenyl, 2,4,5-trifluorophenyl, 2,5-difluorophenyl,
2-fluoro-3-trifluoromethylphenyl, 4-fluoro-2-trifluoromethylphenyl,
2-fluoro-4-trifluoromethylphenyl, 4-benzyloxyphenyl, 2-chloro-6-
fluorophenyl, 2-fluoro-6-chlorophenyl, 2,3,4,5,6-
pentafluorophenyl, 2,5-dimethylphenyl, 4-phenylphenyl, 2-fluoro-3-
tritluoromethylphenyl, adamantyl, benzyl, 2-phenylethyl,
3-phenyl-n-propyl, 4-phenyl-n-butyl, methyl, ethyl, n-propyl, iso-propyl,
iso-butyl, sec-butyl, tert-butyl, n-pentyl, iso-valeryl, n-hexyl,
cyclopropyl, cyclobutyl, cyclohexyl, cyclopentyl, cyclopent-1-enyl.
cyclopent-2-enyl, cyclohex-1-enyl, -CH2-cyclopropyl,
-CH2-cyclobutyl, -CH2-cyclohexyl, -CH2-cyclopentyl,
-CH2CH2-cyclopropyl, -CH2CH2-cyclobutyl,
-CH~CH'-cyclohexyl, -CH2CH2-cyclopentyl, pyrid-2-yl, pyrid-3-
yl, pyrid-4-yf. tluoropyridyls, chioropyridyls, thien-2-yl, thien-3-yl,
benzothiazol-4-yl, 2-phenylbenzoxazol-5-yl, furan-2-yl, benzofuran-2-yl,
thionaphthen-2-yl, thionaphthen-3-yl, thionaphthen-4-yl,
2-chlorothiophen-5-yl, 3-methylisoxazol-5-yl. 2-(thiophenyl)thien-5-
yl, 6-methoxythionaphthen-2-yl, 3-phenyl-1,2,4-thiooxadiazol-5-yl,
2-phenyloxazol-4-yl, indol-3-yl, 1-phenyl-tetrazol-5-yl, allyl,
2-(cyclohexyl)ethyl, (CH3)2CH=CHCH2CH2CH(CH3)-, C(O)CH2-.

-554-
thien-2-yl-methyl, 2-(thien-2-yl)ethyl, 3-(thien-2-yl)-n-propyl, 2-(4-
nitrophenyl)ethyl. 2-(4-methoxyphenyl)ethyl, norboran-2-yl,
(4-methoxyphenyl)methyl, (2-methoxyphenyl)methyl,
(3-methoxyphenyl)methyl. (3-hydroxyphenyl)methyl,
(4-hydroxyphenyl)methyl. (4-methoxyphenyl)methyl,
(4-methylphenyl)methyl, (4-fluorophenyl)methyl,
(4-fluorophenoxy)methyl, (2.4-dichlorophenoxy)ethyl,
(4-chlorophenyl)methyl, (2-chlorophenyl)methyl. (1-phenyl)ethyl,
(1-(p-chlorophenyl)ethyl, (1-trifluoromethyl)ethyl,
(4-methoxyphenyl)ethyl, CH3OC(O)CH2-, benzylthiomethyl,
5-(methoxycarbonyl)-n-pentyl, 3-(methoxycarbonyl)-n-propyl,
indan-2-yl, (2-methylbenzofuran-3-yl), methoxymethyl,
CH3CH=CH-. CH3CH2CH=CH-. (4-chlorophenyl)C(O)CH2-,
(4-fluorophenyl)C(O)CH2-, (4-methoxyphenyl)C(O)CH2-,
4-(fluorophenyl)-NHC(O)CH2-, 1-phenyl-n-butyl,
(phenyl)2CHNHC(O)CH2CH2-. (CH3)2NC(O)CH2-,
(phenyl)2CHNHC(O)CH2CH2-. methylcarbonylmethyl,
(2,4-dimethylphenyl)C(O)CH2-, 4-methoxyphenyl-C(O)CH2-,
phenyl-C(O)CH2-. CH3C(O)N(phenyl)-, ethenyl,
methylthiomethyl, (CH3)3CNHC(O)CH2-, 4-fluorophenyl-
C(O)CH2-, diphenylmethyl, phenoxymethyl, 3,4-
methylenedioxyphenyl-CH2-, benzo[b)thiophen-3-yl,
(CH3)3COC(O)NHCH2-, trans-styryl, H2NC(O)CH2CH2-, 2-
trifluoromethylphenyl-C(O)CH2, C(O)NHCH(phenyl)CH2-,
mesityl, CH3CH(=NHOH)CH2-, 4-CH3-phenyl-
NHC(O)CH2CH2-, C(O)CH(phenyl)CH2-,
(CH3)2CHC(O)NHCH(phenyl)-, CH3CH2OCH2-,
CH3OC(O)CH(CH3)(CH2)3-, 2,2,2-trifluoroethyl.
1-(trifluoromethyl)ethyl. 2-CH3-benzofuran-3-yl.

-555-
2-(2,4-dichlorophenoxy)ethyl, SO2CH2-. 3-cyclohexyl-n-propyl,
CF3CH2CH2CH2- and N-pyrrolidinyl.
12. A method according to any of Claims 1, 2 or 3 where
each R2 is independently selected from the group consisting of
alkyl, substituted alkyl, alkenyl, cycloalkyl, aryl, heteroaryl and
heterocyclic.
13. The method according to Claim 12 wherein R2 is
selected from the croup consisting of methyl, ethyl, n-propyl,
iso-propyl, n-butyl, iso-butyl, sec-butyl, ten-butyl,
-CH2CH(CH2CH3)2, 2-methyl-n-butyl, 6-fluoro-n-hexyl, phenyl,
benzyl, cyclohexyl, cyclopentyl, cycloheptyl, allyl, iso-but-2-enyl,
3-methylpentyl. -CH2-cyclopropyl, -CH2-cyclohexyl,
-CH2CH2-cyclopropyl, -CH2CH2-cyclohexyl, -CH2-indol-3-yl,
p-(phenyl)phenyl. o-fluorophenyl, m-fluorophenyl, p-fluorophenyl,
m-methoxyphenyl, p-methoxyphenyl, phenethyl, benzyl,
m-hydroxybenzyl, p-hydroxybenzyl, p-nitrobenzyl,
m-trifluoromethylphenyl, p-(CH3)2NCH2CH2CH2O-benzyl,
p-(CH3)3COC(O)CH2O-benzyl, p-(HOOCCH2O)-benzyl,
2-aminopyrid-6-yl, p-(N-morpholino-CH2CH2O)-benzyl,
-CH2CH2C(O)NH2, -CH2-imidazol-4-yl,
-CH2-(3-tetrahydrofuranyl), -CH2-thiophen-2-yl.
-CH2(1-methyl)cyclopropyl, -CH2-thiophen-3-yl, thiophen-3-yl,
thiophen-2-yl, -CH2-C(O)O-t-butyl, -CH2-C(CH3)3,
-CH2CH(CH2CH3)2, 2-methylcyclopentyl, cyclohex-2-enyl,
-CH[CH(CH3)2]COOCH3, -CH2CH2N(CH3)2,
-CH2C(CH3)=CH2, -CH2CH=CHCH3 (cis and trans), -CH2OH,
-CH(OH)CH3, -CH(O-t-butyl)CH3, -CH2OCH3, -(CH2)4NH-Boc,

-556-
-(CH2)4NH2. -CH2-pyridyl, pyridyl. -CH2-naphthyl,
-CH2-(N-morpholino), p-(N-morpholino-CH2CH2O)-benzyl,
benzo[b]thiophen-2-yl, 5-chlorobenzo[b]thiophen-2-yl,
4,5,6,7-tetrahydrobenzo[b]thiophen-2-yl, benzo[b]thiophen-3-yl.
5-chlorobenzo[b]thiophen-3-yl, benzo[b]thiophen-5-yl,
6-methoxynaphth-2-yl, -CH2CH2SCH3, thien-2-yl, and thien-3-yl.
14. A method according to any of Claims 1. 2 or 3
wherein the cyclic groups defined by W and -C(H)p C(=X)- is
selected from the group consisting of lactones, lactams,
thiolactones, thiolactams, heterocyclic and cycloalkyl groups.
15. The method according to Claim 14 wherein the cyclic
group defined by W and -C(H)p C(=X)-, forms a lactam or
thiolactam ring of the formula:
<IMGS>

-557-
wherein p is zero or one, T is selected from the group consisting of
alkylene, substituted alkylene, alkenylene, substituted alkenylene,
-(R21Z)q R21- and -ZR21-, where Z is a substituent selected from
the group consisting of -O-, -S- and > NR20, each R20 is
independently selected from the group consisting of alkyl, alkenyl,
alkynyl, cycloalkyl, cycloalkenyl, substituted alkyl, substituted
alkenyl, substituted alkynyl. aryl, heteroaryl and heterocyclic, each
R21 is independently alkylene, substituted alkylene, alkenylene and
substituted alkenylene with the proviso that when Z is -O- or -S-,
any unsaturation in the alkenylene and substituted alkenylene does
not involve participation of the -O- or -S-, and q is an integer of
from 1 to 3.
16. The method according to Claim 15 wherein the
lactam ring is selected from the group consisting of

-558-
<IMGS>

-559-
<IMGS>

-560-
wherein A-B is selected from the group consisting of alkylene,
alkenylene. substituted alkylene, substituted alkenylene and
-N=CH-: Q is oxygen or sulfur: each V is independently selected
from the group consisting of hydroxy, acyl, acyloxy, alkyl,
substituted alkyl, alkoxy, substituted alkoxy, alkenyl, substituted
alkenyl, alkynyl, substituted alkynyl, amino, substituted amino,
aminoacyl, alkaryl, aryl, aryloxy, carboxyl, carboxylalkyl, cyano,
halo, nitro. heteroaryl, thioalkoxy, substituted thioalkoxy, and
trihalomethyl; each R a is independently selected from the group
consisting of alkyl, substituted alkyl, alkoxy, substituted alkoxy,
amino, substituted amino, carboxyl, carboxyl alkyl, cyano, and
halo: R b is selected from the group consisting of alkyl, substituted
alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl,
acyl, aryl, heteroaryl, and heterocyclic, R c is selected from the
group consisting of alkyl, substituted alkyl, alkenyl, substituted
alkenyl, aryl, heteroaryl, heterocyclic, thioalkoxy, substituted
amino, cycloalkyl, and substituted cycloalkyl; t is an integer from 0
to 4: t is an integer from 0 to 3: and w is an integer from 0 to 3.
17. The method according to Claim 14 wherein the cyclic
group defined by W, together with -C(H)p C(=X)- is a ring of the
formula:
<IMG>

-561-
<IMGS>

-562-
wherein p is zero or one. T is selected from the group consisting of
alkylene, substituted alkylene, alkenylene, substituted alkenylene,
-(R21Z)q R21- and -ZR21, where Z is a substituent selected from
the group consisting of -O-, -S- and > NR20, each R20 is
independently selected from the group consisting of alkyl, alkenyl,
alkynyl, cycloalkyl, cycloalkenyl, substituted alkyl, substituted
alkenyl, substituted alkynyl, aryl, heteroaryl and heterocyclic, each
R21 is independently alkylene, substituted alkylene, alkenylene and
substituted alkenylene with the proviso that when Z is -O- or -S-,
any unsaturation in the alkenylene and substituted alkenylene does
not involve participation of the -O- or -S-, and q is an integer of
from 1 to 3.

-563-
18. The method according to Claim 17 wherein the alcohol or
thiol substituted groups is selected from the group consisting of
<IMGS>
wherein each V is independently selected from the group consisting
of hydroxy, acyl, acyloxy, alkyl, substituted alkyl, alkoxy,
substituted alkoxy, alkenyl, substituted alkenyl, alkynyl, substituted
alkynyl, amino, substituted amino, aminoacyl, alkaryl, aryl,

-564-
aryloxy, carboxyl, carboxylalkyl, cyano, halo, nitro, heteroaryl.
thioalkoxy, substituted thioalkoxy, and trihalomethyl; each R a is
independently selected from the group consisting of alkyl,
substituted alkyl, alkoxy, substituted alkoxy, amino, substituted
amino, carboxyl, carboxyl alkyl, cyano, and halo: t is an integer
from 0 to 4; and w is an integer from 0 to 3.
19. The method according to Claim 14 wherein the cyclic
group defined by W, together with -C(H)p C(=X)-, forms a ring of
the formula:
<IMG>

-565-
wherein p is zero or one. T is selected from the group consisting of
alkylene, substituted alkylene. alkenylene, substituted alkenylene.
-(R21Z)q R21- and -ZR21, where Z is a substituent selected from
the group consisting of -O-, -S- and > NR20. each R20 is
independently selected from the group consisting of alkyl, alkenyl,
alkynyl. cycloalkyl, cycloalkenyl, substituted alkyl, substituted
alkenyl, substituted alkynyl, aryl, heteroaryl and heterocyclic, each
R21 is independently alkylene, substituted alkylene. alkenylene and
substituted alkenylene with the proviso that when Z is -O- or -S-,
any unsaturation in the alkenylene and substituted alkenylene does
not involve participation of the -O- or -S-, and q is an integer of
from 1 to 3.

-566-
20. The method according to Claim 14 wherein the cyclic
group defined by W, together with -C(H)p C(=X)-, forms a ring of
the formula:
<IMG>
wherein p is zero or one, T is selected from the group consisting of
alkylene, substituted alkylene, alkenylene, substituted alkenylene.
-(R21Z)q R21- and -ZR21, where Z is a substituent selected from
the group consisting of -O-, -S- and > NR20, each R20 is
independently selected from the group consisting of alkyl. alkenyl,
alkynyl, cycloalkyl, cycloalkenyl. substituted alkyl. substituted
alkenyl, substituted alkynyl, aryl, heteroaryl and heterocyclic, each
R21 is independently alkylene. substituted alkylene, alkenylene and
substituted alkenylene with the proviso that when Z is -O- or -S-.
any unsaturation in the alkenylene and substituted alkenylene does
not involve participation of the -O- or -S-, and q is an integer of
from 1 to 3.

-567-
21. The method according to Claim 20 wherein the
compound of Formula I is selected from the group consisting of
<IMGS>
wherein each V is independently selected from the group consisting
of hydroxy, acyl, acyloxy, alkyl, substituted alkyl, alkoxy,
substituted alkoxy, alkenyl, substituted alkenyl, alkynyl, substituted
alkynyl, amino, substituted amino, aminoacyl, alkaryl, aryl,
aryloxy, carboxyl. carboxylalkyl, cyano, halo, nitro, heteroaryl,
thioalkoxy, substituted thioalkoxy, and trihalomethyl; each R a is
independently selected from the group consisting of alkyl,
substituted alkyl, alkoxy, substituted alkaxy, amino, substituted
amino, carboxyl, carboxyl alkyl, cyano, and halo; t is an integer
from 0 to 4; and w is an integer from 0 to 3.
22. The method according to Claim 14 wherein the cyclic
group defined by W , together with -C(H)p C( = X)-, forms a ring of
the formula:

-568-
<IMG>
wherein p is zero or one, T is selected from the group consisting of
alkylene, substituted alkylene, alkenylene, substituted alkenylene.
-(R21Z)q R21- and -ZR21, where Z is a substituent selected from
the group consisting of -O-. -S- and > NR20, each R20 is
independently selected from the group consisting of alkyl, alkenyl.
alkynyl, cycloalkyl, cycloalkenyl, substituted alkyl, substituted
alkenyl, substituted alkynyl, aryl, heteroaryl and heterocyclic, each
R21 is independently alkylene, substituted alkylene, alkenylene and
substituted alkenylene with the proviso that when Z is -O- or -S-,
any unsaturation in the alkenylene and substituted alkenylene does
not involve participation of the -O- or -S-, and q is an integer of
from 1 to 3.

-569-
23. The method according to Claim 14 wherein the cyclic
group defined by W, together with -C(H)p C(=X)-, forms a ring of
the formula:
<IMG>
wherein p is zero or one, T is selected from the group consisting of
alkylene, substituted alkylene, alkenylene, substituted alkenylene,
-(R21Z)q R21- and -ZR21-, where Z is a substituent selected from
the group consisting of -O-, -S- and > NR20, each R20 is
independently selected from the group consisting of alkyl, alkenyl,
alkynyl, cycloalkyl, cycloalkenyl, substituted alkyl, substituted
alkenyl, substituted alkynyl, aryl, heteroaryl and heterocyclic, each
R21 is independently alkylene, substituted alkylene. alkenylene and

-570-
substituted alkenylene with the proviso that when Z is -O- or -S-,
any unsaturation in the alkenylene and substituted alkenylene does
not involve participation of the -O- or -S-, and q is an integer of
from 1 to 3.
24. The method according to Claim 14 wherein the cyclic
group defined by W, together with -C(H)p C(=X)-, forms a ring of
the formula:
<IMG>
wherein p is zero or one, T is selected from the group consisting of
alkylene. substituted alkylene, alkenylene, substituted alkenylene.
-(R21Z)q R21- and -ZR21-, where Z is a substituent selected from
the group consisting of -O-, -S- and > NR20, each R20 is
independently selected from the group consisting of alkyl, alkenyl,
alkynyl, cycloalkyl, cycloalkenyl, substituted alkyl, substituted
alkenyl, substituted alkynyl, aryl, heteroaryl and heterocyclic, each
R21 is independently alkylene, substituted alkylene, alkenylene and
substituted alkenylene with the proviso that when Z is -O- or -S-.

-571-
any unsaturation in the alkenylene and substituted alkenylene does
not involve participation of the -O- or -S-, and q is an integer of
from 1 to 3.
25. The method according to Claim 14 wherein the cyclic
group defined by W, together with -C(H)p C(=X)-, forms a ring of
the formula:
<IMG>
wherein p is zero or one, T is selected from the group consisting of
alkylene, substituted alkylene, alkenylene, substituted alkenylene, -
(R21Z)q R21- and -ZR21, where Z is a substituent selected from
the group consisting of -O-. -S- and > NR20, each R20 is
independently selected from the group consisting of alkyl, alkenyl,
alkynyl, cycloalkyl, cycloalkenyl, substituted alkyl, substituted
alkenyl, substituted alkynyl, aryl, heteroaryl and heterocyclic, each
R21 is independently alkylene, substituted alkylene, alkenylene and

-572-
substituted alkenylene with the proviso that when Z is -O- or -S-,
any unsaturation in the alkenylene and substituted alkenylene does
not involve participation of the -O- or -S-, and q is an integer of
from 1 to 3.
26. The method according to Claim 25 wherein the
compound is selected from the group consisting of:
<IMGS>
27. The method according to Claim 14 wherein the cyclic
group defined by W, together with -C(H)p C(=X)-, forms a ring of
the formula:

-573-
<IMG>
wherein p is zero or one, T is selected from the group consisting of
alkylene, substituted alkylene, alkenylene, substituted alkenylene.
-(R21Z)q R21- and -ZR21 , where Z is a substituent selected from

the group consisting of -O-, -S- and > NR20, each R20 is
independently selected from the group consisting of alkyl, alkenyl,
alkynyl. cycloalkyl, cycloalkenyl, substituted alkyl, substituted
alkenyl, substituted alkynyl, aryl, heteroaryl and heterocyclic, each
R21 is independently alkylene, substituted alkylene, alkenylene and
substituted alkenylene with the proviso that when Z is -O- or -S-,
any unsaturation in the alkenylene and substituted alkenylene does
not involve participation of the -O- or -S-, and q is an integer of
from 1 to 3.

-574-
28. The method according to Claim 14 wherein the cyclic
group defined by W, together with -C(H) p C(=X)-, forms a ring of
the formula:
<IMG>
wherein p is zero or one. T is selected from the group consisting of
alkylene, substituted alkylene, alkenylene, substituted alkenylene,
-(R21Z)q R21- and -ZR21-, where Z is a substituent selected from
the group consisting of -O-, -S- and > NR20, each R20 is
independently selected from the group consisting of alkyl, alkenyl,
alkynyl, cycloalkyl, cycloalkenyl, substituted alkyl, substituted
alkenyl, substituted alkynyl, aryl, heteroaryl and heterocyclic, each
R21 is independently alkylene, substituted alkylene, alkenylene and
substituted alkenylene with the proviso that when Z is -O- or -S-,
any unsaturation in the alkenylene and substituted alkenylene does
not involve participation of the -O- or -S-, and q is an integer of
from 1 to 3.

-575-
29. The method according to Claim 14 wherein the cyclic
group defined by W, together with -C(H)p C(=X)-, forms a ring of
the formula:
<IMG>
wherein p is zero or one, T is selected from the group consisting of
alkylene. substituted alkylene, alkenylene, substituted alkenylene,
-(R21Z)q R21- and -ZR21-, where Z is a substituent selected from
the group consisting of -O-, -S- and >NR20, each R20 is
independently selected from the group consisting of alkyl, alkenyl,
alkynyl, cycloalkyl, cycloalkenyl, substituted alkyl, substituted
alkenyl, substituted alkynyl, aryl, heteroaryl and heterocyclic, each
R21 is independently alkylene, substituted alkylene, alkenylene and
substituted alkenylene with the proviso that when Z is -O- or -S-,
any unsaturation in the alkenylene and substituted alkenylene does

-576-
not involve participation of the -O- or -S-, and q is an integer of
from 1 to 3.
30. A pharmaceutical composition comprising a
pharmaceutically inert carrier and a pharmaceutically effective
amount of a compound of the following formulas:
<IMG>

-577-
<IMGS>

-578-
<IMGS>
wherein R1 is selected from the group consisting of alkyl,
alkenyl, alkynyl, cycloalkyl, cycloalkenyl, substituted alkyl,
substituted alkenyl, substituted alkynyl, substituted cycloalkyl,
substituted cycloalkenyl, aryl, heteroaryl and heterocyclic:

-579-
R'is selected from the group consisting of aryl, cycloalkyl,
substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl,
heteroaryl, heterocyclic. -CH3, -CH=CH2, -CH=CHR1,
-CH=CR1R1, -CR1=CH2, -CR1=CHR1, -CR1=CR1R1, -C=CH and
-C=CR1; with the proviso that when R' is heteroaryl or
heterocyclic, there is no N in R' at a position beta to the C=Q
group;
Q is S or O;
R15 is selected from the group consisting of hydrogen, alkyl,
substituted alkyl, aryl, heterocyclic and heteroaryl;
R15' is selected from the group consisting of hydrogen,
hydroxyl, alkyl, substituted alkyl, aryl, heterocyclic and heteroaryl;
W, together with -C(H)p C(=X)-, forms a cycloalkyl,
cycloalkenyl, heterocyclic, substituted cycloalkyl, or substituted
cycloalkenyl group wherein each of said cycloalkyl. cycloalkenyl,
heterocyclic, substituted cycloalkyl or substituted cycloalkenyl
group is optionally fused to form a bi- or multi-fused ring system
(preferably no more than 5 fused rings) with one or more ring
structures selected from the group consisting of cycloalkyl,
cycloalkenyl. heterocyclic, aryl and heteroaryl group which, in
turn, each of such ring structures are optionally substituted with 1 to
4 substituents selected from the group consisting of hydroxyl, halo,
alkoxy, substituted alkoxy, thioalkoxy, substituted thioalkoxy, nitro,
cyano, carboxyl, carboxyl esters, alkyl, substituted alkyl, alkenyl,
substituted alkenyl, alkynyl, substituted alkynyl, amino, substituted
amino,-NHC(O)R4, -NHSO2R4, -C(O)NH2, -C(O)NHR4,
-C(O)NR4R4, -S(O)R4, -S(O)2R4, -S(O)2NHR4 and -S(O)2NR4R4,
where each R4 is independently selected from the group consisting
of alkyl, substituted alkyl, aryl and heteroaryl;

-580-
X is selected from the group consisting of oxo (=O), thiooxo
(=S), hydroxyl (-H, -OH), thiol (H,-SH) and hydro (H,H);
Y is represented by the formula:
<IMG>
wherein each R2 is independently selected from the group consisting
of alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl,
substituted alkynyl, cycloalkyl, aryl, heteroaryl and heterocyclic;
Z is represented by the formula -T-C(X')(X")C(O)- where T
is selected from the group consisting of a bond covalently linking
R1 to -C(X')(X")-, oxygen, sulfur, and -NR5 where R5 is
hydrogen, acyl, alkyl, aryl, substituted alkyl, heterocyclic or
heteroaryl group:
R5' is hydrogen, alkyl, substituted alkyl, aryl, heterocyclic
or heteroaryl group;
X' and X" are independently selected from the group
consisting of hydrogen, fluoro, alkyl, substituted alkyl, aryl,
heteroaryl, heterocyclic, -OR5', -SR5, -N(R5)2, -N(CO)OR15 and -

-581-
N3, with the proviso that at least one of X' or X" is other than
hydrogen, hydroxy or fluoro, and with the further proviso that both
X' and X" cannot both be -OR5', -SR5, -N(R5)2, -N(CO)OR15 and
-N3 ; further, neither X' and X" can be -OR5', -SR5, -N(R5)2,
-N(CO)OR15 or -N3 when T is other than a bond covalently linking
R1 to -C(X')(X")-;
n is an integer equal to 1 or 2;
p is an integer equal to 0 or 1 such that when p is zero, the
ring defined by W and -C(H)p C(=X)- is unsaturated at the carbon
atom of ring attachment to Y and when p is one, the ring is
saturated at the carbon atom of ring attachment to Y,
with the following provisos:
when R1 is 2-propylpentanoyl, R2 is methyl, and R15 is
hydrogen, then W, together with >CH and >C=X, does not form
a 2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one
when R1 is 3.5-difluorobenzoyl, R2 is methyl, and R15 is
hydrogen, then W, together with >CH and >C=X, does not form
a 2,3-dihydro-1-methyl-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one
when R1 is trans-cinnamyl, R2 is methyl, and R15 is
hydrogen, then W, together with >CH and >C=X, does not form
a 2,3-dihydro-1-(3,3-dimethyl-2-oxobutyl)-5-(2-pyridyl)-1H-1,4-
benzodiazepin-2-one
when R1 is 2-(4-chlorophenoxy)-2-methylpropionyl, R2 is
methyl, and R15 is hydrogen, then W, together with >CH and

-582-
>C=X, does not form a 2,3-dihydro-1-methyl-5-(2-pyridyl)-1H-
1,4-benzodiazepin-2-one
when R1 is .alpha.-methoxyphenylacetyl, R2 is methyl, and R15
is hydrogen, then W, together with >CH and >C=X, does not
form a 2.3-dihydro-1-methyl-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one
when R1 is diphenylacetyl, R2 is methyl, and R15 is
hydrogen, then W, together with >CH and >C=X, does not form
a 2,3-dihydro-1-methyl-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one
when R1 is .alpha.-methoxyphenylacetyl, R2 is methyl, and R15
is hydrogen, then W, together with >CH and >C=X, does not
form a 2.3-dihydro-1-(3,3-dimethyl-2-oxobutyl)- 5-(2-pyridyl)-1H-
1.4-benzodiazepin-2-one
when R1 is .alpha.-hydroxy-diphenylacetyl, R2 is methyl, and
R15 is hydrogen, then W, together with >CH and >C=X, does
not form a 2.3-dihydro-1-(3,3-dimethyl-2-oxobutyl)- 5-(2-pyridyl)-
1H-1,4-benzodiazepin-2-one
when R1 is diphenylacetyl, R2 is methyl, and R15 is
hydrogen, then W, together with >CH and >C=X, does not form
a 2,3-dihydro-1-(3,3-dimethyl-2-oxobutyl)- 5-(2-pyridyl)-1H-1,4-
benzodiazepin-2-one
when R1 is 2-(chlorophenoxy)-2-methylpropionyl, R2 is
methyl, and R15 is hydrogen, then W, together with >CH and

-583-
>C=X, does not form a 2,3-dihydro-1-(3,3-dimethyl-2-oxobutyl)-
5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one
when R1 is diphenylacetyl, R2 is methyl, and R15 is
hydrogen, then W, together with >CH and >C=X, does not form
a 2,3-dihydro-1-(2-N,N-diethylaminoethyl)- 5-(2-pyridyl)-1H-1,4-
benzodiazepin-2-one
when R1 is 3,5-difluorobenzoyl, R2 is methyl, and R15 is
hydrogen, then W, together with >CH and >C=X, does not form
a 2,3-dihydro-1-(2-N,N-diethylaminoethyl)- 5-(2-pyridyl)-1H-1,4-
benzodiazepin-2-one
when R1 is trans-cinnamyl, R2 is methyl, and R15 is
hydrogen, then W, together with >CH and >C=X, does not form
a 2,3-dihydro-1-(2-N,N-diethylaminoethyl)- 5-(2-pyridyl)-1H-1,4-
benzodiazepin-2-one
when R1 is 2-(4-chlorophenoxy)-2-methylpropionyl, R2 is
methyl, and R15 is hydrogen, then W, together with >CH and
>C=X, does not form a 2,3-dihydro-1-(2-N.N-diethylaminoethyl)-
5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one
when R1-N(R15) is (2,5-dimethoxyphenyl)ureylenyl and R2
is methyl, then W, together with >CH and >C=X, does not form
a 2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one

-584-
when R1 is D,L-2-pyrrolidinone-5-yl, R2 is methyl, and R15
is hydrogen, then W, together with >CH and >C = X, does not
form a 7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one.
31. The pharmaceutical composition according to Claim
30, wherein R1 is aryl or heteroaryl.
32. The pharmaceutical composition according to Claim
31 wherein R1 is selected from the group consisting of
(a) alkyl,
(b) phenyl,

-585-
(c) a substituted phenyl group of the formula:
<IMG>
wherein R c is selected from the group consisting of acyl,
alkyl, alkoxy, alkylalkoxy, azido, cyano, substituted amino, halo,
hydrogen, nitro, trihalomethyl, thioalkoxy,
and wherein R b and R c are fused to form a heteroaryl or
heterocyclic ring with the phenyl ring wherein the heteroaryl or
heterocyclic ring contains from 3 to 8 atoms of which from 1 to 3
are heteroatoms independently selected from the group consisting of
oxygen, nitrogen and sulfur
R b and R b are independently selected from the group
consisting of hydrogen, halo, nitro, cyano, trihalomethyl, alkoxy,

-586-
and thioalkoxy with the proviso that when R c is hydrogen, then R b
and R b are either both hydrogen or both substituents other than
hydrogen,
(d) 2-naphthyl,
(e) 2-naphthyl substituted at the 4, 5, 6, 7 and/or 8 positions
with 1 to 5 substituents selected from the group consisting alkyl,
alkoxy. halo, cyano, nitro, trihalomethyl, thioalkoxy, aryl, and
heteroaryl,
(f) heteroaryl, and
(g) substituted heteroaryl containing 1 to 3 substituents
selected from the group consisting of alkyl, alkoxy, aryl, aryloxy,
cyano, halo, nitro, heteroaryl, thioalkoxy, thioaryloxy provided that
said substituents are not ortho to the heteroaryl attachment to the
-NH group.
33. The pharmaceutical composition according to Claim
29 wherein R1 is selected from the group consisting of mono-,
di-and tri-substituted phenyl groups.
34. The pharmaceutical composition according to Claim
33 wherein R1 is a disubstituted phenyl selected from the group
consisting of 3,5-dichlorophenyl, 3,5-difluorophenyl,
3,5-di(trifluoromethyl)-phenyl, 3,4-dichlorophenyl, 3,4-difluorophenyl,
3-(trifluoromethyl)-4-chlorophenyl, 3-chloro-4-cyanophenyl,
3-chloro-4-iodophenyl, and 3,4-methylenedioxyphenyl.
35. The pharmaceutical composition according to Claim
33 wherein R1 is a monosubstituted phenyl selected from the group
consisting of 4-azidophenyl, 4-bromophenyl, 4-chlorophenyl.

-587-
4-cyanophenyl, 4-ethylphenyl, 4-fluorophenyl, 4-iodophenyl,
4-(phenylcarbonyl)-phenyl, and 4-(1-ethoxy)ethylphenyl.
36. The pharmaceutical composition according to Claim
33 wherein R1 is a trisubstituted phenyl selected from the group
consisting of 3,4,5-trifluorophenyl and 3,4,5-trichlorophenyl.
37. The pharmaceutical composition according to Claim
29 wherein R1 is selected from 2-naphthyl, quinolin-3-yl,
2-methylquinolin-6-yl, benzothiazol-6-yl, 5-indolyl, and phenyl.
38. The pharmaceutical composition according to Claim
32 wherein R1 is selected from the group consisting of phenyl,
1-naphthyl, 2-naphthyl, 2-chlorophenyl, 2-fluorophenyl,
2-bromophenyl, 2-hydroxyphenyl, 2-nitrophenyl, 2-methylphenyl,
2-methoxyphenyl, 2-phenoxyphenyl, 2-trifluoromethylphenyl,
4-fluorophenyl, 4-chlorophenyl, 4-bromophenyl,
xxxxxx 4-nitrophenyl, 4-methylphenyl, 4-hydroxyphenyl, 4-methoxyphenyl,
4-ethoxyphenyl, 4-butoxyphenyl, 4-iso-propylphenyl,
4-phenoxyphenyl, 4-trifluoromethylphenyl, 4-hydroxymethylphenyl,
3-methoxyphenyl, 3-hydroxyphenyl, 3-nitrophenyl, 3-fluorophenyl,
3-chlorophenyl, 3-bromophenyl, 3-phenoxyphenyl,
3-thiomethoxyphenyl, 3-methylphenyl, 3-trifluoromethylphenyl,
2,3-dichlorophenyl, 2,3-difluorophenyl, 2,4-dichlorophenyl,
2,5-dimethoxyphenyl, 3,4-dichlorophenyl. 3.4-difluorophenyl,
3,4-methylenedioxyphenyl, 3,4-dimethoxyphenyl,
3,5-difluorophenyl, 3,5-dichlorophenyl,
3,5-di-(trifluoromethyl)phenyl, 3,5-dimethoxyphenyl,
2,4-dichlorophenyl, 2,4-difluorophenyl, 2,6-difluorophenyl,

-588-
3,4,5-trifluorophenyl, 3,4.5-trimethoxyphenyl,
3,4,5-tri-(trifluoromethyl)phenyl, 2,4,6-trifluorophenyl,
2,4,6-trimethylphenyl, 2,4,6-tri-(trifluoromethyl)phenyl,
2,3,5-trifluorophenyl, 2,4,5-trifluorophenyl, 2,5-difluorophenyl,
2-fluoro-3-trifluoromethylphenyl, 4-fluoro-2-trifluoromethylphenyl,
2-fluoro-4-trifluoromethylphenyl, 4-benzyloxyphenyl, 2-chloro-6-
fluorophenyl, 2-fluoro-6-chlorophenyl, 2,3,4,5,6-
pentafluorophenyl, 2,5-dimethylphenyl, 4-phenylphenyl, 2-fluoro-3-
trifluoromethylphenyl, adamantyl, benzyl, 2-phenylethyl, 3-phenyl-
n-propyl, 4-phenyl-n-butyl, methyl, ethyl, n-propyl, iso-propyl,
iso-butyl, sec-butyl, tent-butyl, n-pentyl, iso-valeryl, n-hexyl,
cyclopropyl, cyclobutyl, cyclohexyl, cyclopentyl, cyclopent-1-enyl,
cyclopent-2-enyl, cyclohex-1-enyl, -CH2-cyclopropyl,
-CH2-cyclobutyl, -CH2-cyclohexyl, -CH2-cyclopentyl,
-CH2CH2-cyclopropyl. -CH2CH2-cyclobutyl, -CH2CH2-cyclohexyl,
-CH2CH2-cyclopentyl, pyrid-2-yl, pyrid-3-yl, pyrid-4-yl,
fluoropyridyls, chloropyridyls, thien-2-yl, thien-3-yl, benzothiazol-4-yl,
2-phenylbenzoxazol-5-yl, furan-2-yl, benzofuran-2-yl.
thionaphthen-2-yl, thionaphthen-3-yl, thionaphthen-4-yl,
2-chlorothiophen-5-yl, 3-methylisoxazol-5-yl, 2-(thiophenyl)thien-5-yl,
6-methoxythionaphthen-2-yl, 3-phenyl-1,2,4-thiooxadiazol-5-yl,
2-phenyloxazol-4-yl, indol-3-yl, 1-phenyl-tetrazol-5-yl, allyl,
2-(cyclohexyl)ethyl, (CH3)2CH=CHCH2CH2CH(CH3)-,
C(O)CH2-, thien-2-yl-methyl, 2-(thien-2-yl)ethyl, 3-(thien-2-yl)-n-
propyl, 2-(4-nitrophenyl)ethyl. 2-(4-methoxyphenyl)ethyl,
norboran-2-yl,
(4-methoxyphenyl)methyl, (2-methoxyphenyl)methyl,
(3-methoxyphenyl)methyl, (3-hydroxyphenyl)methyl.
(4-hydroxyphenyl)methyl, (4-methoxyphenyl)methyl,

-589-
(4-methylphenyl)methyl, (4-fluorophenyl)methyl,
(4-fluorophenoxy)methyl. (2,4-dichlorophenoxy)ethyl,
(4-chlorophenyl)methyl, (2-chlorophenyl)methyl, (1-phenyl)ethyl,
(1-(p-chlorophenyl)ethyl, (1-trifluoromethyl)ethyl,
(4-methoxyphenyl)ethyl, CH3OC(O)CH2-, benzylthiomethyl,
5-(methoxycarbonyl)-n-pentyl, 3-(methoxycarbonyl)-n-propyl.
indan-2-yl, (2-methylbenzofuran-3-yl), methoxymethyl,
CH3CH=CH-, CH3CH2CH=CH-, (4-chlorophenyl)C(O)CH2-.
(4-fluorophenyl)C(O)CH2-, (4-methoxyphenyl)C(O)CH2-,
4-(fluorophenyl)-NHC(O)CH2-. 1-phenyl-n-butyl,
(phenyl)2CHNHC(O)CH2CH2-, (CH3)2NC(O)CH2-,
(phenyl)2CHNHC(O)CH2CH2-, ethylcarbonylmethyl,
(2,4-dimethylphenyl)C(O)CH2-, 4-methoxyphenyl-C(O)CH2-,
phenyl-C(O)CH2-. CH3C(O)N(phenyl)-, ethenyl,
methylthiomethyl, (CH3)3CNHC(O)CH2-. 4-fluorophenyl-
C(O)CH2-, diphenylmethyl, phenoxymethyl,
3.4-methylenedioxyphenyi-CH2-, benzo[b]thiophen-3-yl.
(CH3)3COC(O)NHCH2-, trans-styryl, H2NC(O)CH2CH2-.
2-trifluoromethylphenyl-C(O)CH2, phenyl-
C(O)NHCH(phenyl)CH2-, mesityl, CH3CH(=NHOH)CH2-.
4-CH3-phenyl-NHC(O)CH2CH2-, C(O)CH(phenyl)CH2-,
(CH3)2CHC(O)NHCH(phenyl)-, CH3CH2OCH2-,
CH3OC(O)CH(CH3)(CH2)3-, 2,2,2-trifluoroethyl,
1-(trifluoromethyl)ethyl, 2-CH3-benzofuran-3-yl,
2-(2,4-dichlorophenoxy)ethyl, SO2CH2-, 3-cyclohexyl-n-propyl,
CF3CH2CH2CH2- and N-pyrrolidinyl.
39. The pharmaceutical composition according to Claim
29 where each R2 is independently selected from the group

-590-
consisting of alkyl, substituted alkyl, alkenyl, cycloalkyl, aryl,
heteroaryl and heterocyclic.
40. The pharmaceutical composition according to Claim
39 wherein R2 is selected from the group consisting of methyl,
ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, tert-butyl,
-CH2CH(CH2CH3)2, 2-methyl-n-butyl, 6-fluoro-n-hexyl, phenyl,
benzyl, cyclohexyl, cyclopentyl, cycloheptyl, allyl, iso-but-2-enyl,
3-methylpentyl, -CH2-cyclopropyl, -CH2-cyclohexyl.
-CH2CH2-cyclopropyl, -CH2CH2-cyclohexyl, -CH2-indol-3-yl,
p-(phenyl)phenyl, o-fluorophenyl, m-fluorophenyl, p-fluorophenyl,
m-methoxyphenyl, p-methoxyphenyl, phenethyl, benzyl,
m-hydroxybenzyl, p-hydroxybenzyl, p-nitrobenzyl,
m-trifluoromethylphenyl, p-(CH3)2NCH2CH2CH2O-benzyl,
p-(CH3)3COC(O)CH2O-benzyl, p-(HOOCCH2O)-benzyl.
2-aminopyrid-6-yl, p-(N-morpholino-CH2CH2O)-benzyl,
-CH2CH2C(O)NH2, -CH2-imidazol-4-yl.
-CH2-(3-tetrahydrofuranyl), -CH2-thiophen-2-yl.
-CH2(1-methyl)cyclopropyl, -CH2-thiophen-3-y1, thiophen-2-yl, thiophen-2-yl,
-CH2-C(O)O-t-butyl. -CH2-C(CH3)3,-CH2CH(CH2CH3)2,
2-methylcyclopentyl, cyclohex-2-enyl. -CH[CH(CH3)2]COOCH3.
-CH2CH2N(CH3)2,
-CH2C(CH3)=CH2, -CH2CH=CHCH3 (cis and trans), -CH2OH,
-CH(OH)CH3, -CH(O-t-butyl)CH3, -CH2OCH3, -(CH2)4NH-Boc,
-(CH2)4NH2. -CH2-pyridyl, pyridyl, -CH2-naphthyl.
-CH2-(N-morpholino), p-(N-morpholino-CH2CH2O)-benzyl,
benzo[b]thiophen-2-yl, 5-chlorobenzo[b]thiophen-2-yl,
4,5,6,7-tetrahydrobenzo[b]thiophen-2-yl, benzo(b]thiophen-3-yl,
5-chlorobenzo(b]thiophen-3-yl, benzo[b]thiophen-5-yl,

-591-
6-methoxynaphth-2-yl, -CH2CH2SCH3, thien-2-yl, and thien-3-yl.
41. The pharmaceutical composition according to Claim
29 wherein the cyclic groups defined by W and -C(H) p C(=X)- is
selected from the group consisting of lactones, lactams,
thiolactones, thiolactams, heterocyclic and cycloalkyl groups.
42. The pharmaceutical composition according to Claim
41 wherein the cyclic group defined by W and -C(H) p C(=X)-,
forms a lactam or thiolactam ring of the formula:

-592-
<IMGS>

-593-
wherein p is zero or one, T is selected from the group consisting of
alkylene, substituted alkylene, alkenylene, substituted alkenylene,
-(R21Z)q R21- and -ZR21 , where Z is a substituent selected from
the group consisting of -O-, -S- and > NR20, each R20 is
independently selected from the group consisting of alkyl, alkenyl,
alkynyl, cycloalkyl, cycloalkenyl, substituted alkyl, substituted
alkenyl, substituted alkynyl, aryl, heteroaryl and heterocyclic, each
R21 is independently alkylene, substituted alkylene, alkenylene and
substituted alkenylene with the proviso that when Z is -O- or -S-,
any unsaturation in the alkenylene and substituted alkenylene does
not involve participation of the -O- or -S-, and q is an integer of
from 1 to 3.
43. The method according to Claim 42 wherein the
lactam ring is selected from the group consisting of
<IMGS>

-594-
<IMGS>

-595-
<IMGS>

-596-
wherein A-B is selected from the group consisting of alkylene,
alkenylene, substituted alkylene, substituted alkenylene and
-N=CH-; Q is oxygen or sulfur; each V is independently selected
from the group consisting of hydroxy, acyl, acyloxy, alkyl,
substituted alkyl, alkoxy, substituted alkoxy, alkenyl, substituted
alkenyl, alkynyl, substituted alkynyl, amino, substituted amino,
aminoacyl, alkaryl, aryl, aryloxy, carboxyl, carboxylalkyl, cyano,
halo, nitro, heteroaryl, thioalkoxy, substituted thioalkoxy, and
trihalomethyl; each R a is independently selected from the group
consisting of alkyl, substituted alkyl, alkoxy, substituted alkoxy,
amino, substituted amino, carboxyl, carboxyl alkyl, cyano, and
halo; R b is selected from the group consisting of alkyl, substituted
alkyl, alkenyl, substituted alkenyl. alkynyl, substituted alkynyl,
acyl, aryl, heteroaryl, and heterocyclic; R c is selected from the
group consisting of alkyl, substituted alkyl, alkenyl, substituted
alkenyl, aryl, heteroaryl, heterocyclic, thioalkoxy, substituted
amino, cycloalkyl, and substituted cycloalkyl; t is an integer from 0
to 4; t is an integer from 0 to 3; and w is an integer from 0 to 3.
44. The pharmaceutical composition according to Claim
41 wherein the cyclic group defined by W, together with
-C(H) p C(=X)- is a ring of the formula:

-597-
<IMG>
or
<IMG>
wherein p is zero or one, T is selected from the group consisting of
alkylene, substituted alkylene, alkenylene, substituted alkenylene,
-(R21Z)q R21- and -ZR21-, where Z is a substituent selected from
the group consisting of -O-, -S- and > NR20, each R20 is
independently selected from the group consisting of alkyl, alkenyl,
alkynyl, cycloalkyl, cycloalkenyl, substituted alkyl, substituted
alkenyl, substituted alkynyl, aryl, heteroaryl and heterocyclic, each
R21 is independently alkylene, substituted alkylene, alkenylene and
substituted alkenylene with the proviso that when Z is -O- or -S-,
any unsaturation in the alkenylene and substituted alkenylene does
not involve participation of the -O- or -S-, and q is an integer of
from 1 to 3.

-598-
45. The pharmaceutical composition according to Claim
44 wherein the alcohol or thiol substituted groups is selected from
the group consisting of
<IMGS>
wherein each V is independently selected from the group consisting
of hydroxy, acyl, acyloxy, alkyl, substituted alkyl, alkoxy,
substituted alkoxy, alkenyl, substituted alkenyl, alkynyl, substituted
alkynyl, amino, substituted amino, aminoacyl, alkaryl, aryl,
aryloxy, carboxyl, carboxylalkyl, cyano, halo, nitro, heteroaryl,
thioalkoxy, substituted thioalkoxy, and trihalomethyl; each R a is
independently selected from the group consisting of alkyl,
substituted alkyl, alkoxy, substituted alkoxy, amino, substituted
amino, carboxyl, carboxyl alkyl, cyano, and halo; t is an integer
from 0 to 4; and w is an integer from 0 to 3.

-599-
46. The pharmaceutical composition according to Claim
41 wherein the cyclic group defined by W, together
with - C(H)p C(=X)-, forms a ring of the formula:
<IMG>
wherein p is zero or one, T is selected from the group consisting of
alkylene, substituted alkylene, alkenylene, substituted alkenylene,
-(R21Z)q R21- and -ZR21-, where Z is a substituent selected from
the group consisting of -O-, -S- and > NR20, each R20 is
independently selected from the group consisting of alkyl, alkenyl,
alkynyl, cycloalkyl, cycloalkenyl, substituted alkyl, substituted
alkenyl, substituted alkynyl, aryl, heteroaryl and heterocyclic, each
R21 is independently alkylene, substituted alkylene, alkenylene and
substituted alkenylene with the proviso that when Z is -O- or -S-,
any unsaturation in the alkenylene and substituted alkenylene does

-600-
not involve participation of the -O- or -S-, and q is an integer of
from 1 to 3.
47. The pharmaceutical composition according to Claim
41 wherein the cyclic group defined by W, together
with - C(H)p C(=X)-, forms a ring of the formula:
<IMG>

-601-
wherein p is zero or one, T is selected from the group consisting of
alkylene, substituted alkylene, alkenylene, substituted alkenylene,
-(R21Z)q R21- and -ZR21 , where Z is a substituent selected from
the group consisting of -O-, -S- and > NR20, each R20 is
independently selected from the group consisting of alkyl, alkenyl,

-602-
alkynyl, cycloalkyl, cycloalkenyl, substituted alkyl, substituted
alkenyl, substituted alkynyl, aryl, heteroaryl and heterocyclic, each
R21 is independently alkylene, substituted alkylene, alkenylene and
substituted alkenylene with the proviso that when Z is -O- or -S-,
any unsaturation in the alkenylene and substituted alkenylene does
not involve participation of the -O- or -S-, and q is an integer of
from 1 to 3.
48. The pharmaceutical composition according to Claim
47 wherein the compound is selected from the group consisting of
<IMGS>

-603-
wherein each V is independently selected from the group consisting
of hydroxy, acyl, acyloxy, alkyl, substituted alkyl, alkoxy,
substituted alkoxy, alkenyl, substituted alkenyl, alkynyl, substituted
alkynyl, amino, substituted amino, aminoacyl, alkaryl, aryl,
aryloxy, carboxyl, carboxylalkyl, cyano, halo, nitro, heteroaryl,
thioalkoxy, substituted thioalkoxy, and trihalomethyl; each R a is
independently selected from the group consisting of alkyl,
substituted alkyl, alkoxy, substituted alkoxy, amino, substituted
amino, carboxyl, carboxyl alkyl, cyano, and halo; t is an integer
from 0 to 4; and w is an integer from 0 to 3.
49. The pharmaceutical composition according to Claim
41 wherein the cyclic group defined by W, together with
-C(H)p C(=X)-, forms a ring of the formula:
<IMG>
wherein p is zero or one, T is selected from the group consisting of
alkylene, substituted alkylene, alkenylene, substituted alkenylene,
-(R21Z)q R21- and -ZR21-, where Z is a substituent selected from

-604-
the group consisting of -O-, -S- and > NR20, each R20 is
independently selected from the group consisting of alkyl, alkenyl,
alkynyl, cycloalkyl, cycloalkenyl, substituted alkyl, substituted
alkenyl, substituted alkynyl, aryl, heteroaryl and heterocyclic, each
R21 is independently alkylene, substituted alkylene, alkenylene and
substituted alkenylene with the proviso that when Z is -O- or -S-,
any unsaturation in the alkenylene and substituted alkenylene does
not involve participation of the -O- or -S-, and q is an integer of
from 1 to 3.
50. The pharmaceutical composition according to Claim
41 wherein the cyclic group defined by W, together with
-C(H)pC(=X)-, forms a ring of the formula:
<IMG>
wherein p is zero or one, T is selected from the group consisting of
alkylene, substituted alkylene, alkenylene, substituted alkenylene,
-(R21Z)q R21- and -ZR21-, where Z is a substituent selected from
the group consisting of -O-, -S- and > NR20, each R20 is
independently selected from the group consisting of alkyl, alkenyl,

-605-
alkynyl, cycloalkyl, cycloalkenyl, substituted alkyl, substituted
alkenyl, substituted alkynyl, aryl, heteroaryl and heterocyclic, each
R21 is independently alkylene, substituted alkylene, alkenylene and
substituted alkenylene with the proviso that when Z is -O- or -S-,
any unsaturation in the alkenylene and substituted alkenylene does
not involve participation of the -O- or -S-, and q is an integer of
from 1 to 3.
51. The pharmaceutical composition according to Claim
41 wherein the cyclic group defined by W, together with
-C(H)p C(=X)-, forms a ring of the formula:
<IMG>
wherein p is zero or one, T is selected from the group consisting of
alkylene, substituted alkylene, alkenylene, substituted alkenylene,
-(R21Z)q R21- and -ZR21-, where Z is a substituent selected from
the group consisting of -O-, -S- and > NR20, each R20 is

-606-
independently selected from the group consisting of alkyl, alkenyl,
alkynyl, cycloalkyl, cycloalkenyl, substituted alkyl, substituted
alkenyl, substituted alkynyl, aryl, heteroaryl and heterocyclic, each
R21 is independently alkylene, substituted alkylene, alkenylene and
substituted alkenylene with the proviso that when Z is -O- or -S-,
any unsaturation in the alkenylene and substituted alkenylene does
not involve participation of the -O- or -S-, and q is an integer of
from 1 to 3.
52. The pharmaceutical composition according to Claim
41 wherein the cyclic group defined by W, together with
-C(H)pC(=X)-, forms a ring of the formula:
<IMG>

-607-
wherein p is zero or one, T is selected from the group consisting of
alkylene, substituted alkylene, alkenylene, substituted alkenylene,
-(R21Z)q R21- and -ZR21-, where Z is a substituent selected from
the group consisting of -O-, -S- and > NR20, each R20 is
independently selected from the group consisting of alkyl, alkenyl,
alkynyl, cycloalkyl, cycloalkenyl, substituted alkyl, substituted
alkenyl, substituted alkynyl, aryl, heteroaryl and heterocyclic, each
R21 is independently alkylene, substituted alkylene, alkenylene and
substituted alkenylene with the proviso that when Z is -O- or -S-,
any unsaturation in the alkenylene and substituted alkenylene does
not involve participation of the -O- or -S-, and q is an integer of
from 1 to 3.
53. The pharmaceutical composition according to Claim
52 wherein the compound is selected from the group consisting of:

-608-
<IMGS>
54. The pharmaceutical composition according to Claim
41 wherein the cyclic group defined by W, together with
-C(H)p C(=X)-, forms a ring of the formula:
<IMG>
wherein p is zero or one, T is selected from the group consisting of
alkylene, substituted alkylene, alkenylene, substituted alkenylene,
(R21Z)q R21- and -ZR21-, where Z is a substituent selected from
the group consisting of -O-, -S- and > NR20, each R20 is
independently selected from the group consisting of alkyl, alkenyl,
alkynyl, cycloalkyl, cycloalkenyl, substituted alkyl, substituted
alkenyl, substituted alkynyl, aryl, heteroaryl and heterocyclic, each

-609-
R21 is independently alkylene, substituted alkylene, alkenylene and
substituted alkenylene with the proviso that when Z is -O- or -S-,
any unsaturation in the alkenylene and substituted alkenylene does
not involve participation of the -O- or -S-, and q is an integer of
from 1 to 3.
55. The pharmaceutical composition according to Claim
41 wherein the cyclic group defined by W, together with
-C(H)p C(=X)-, forms a ring of the formula:
<IMG>
wherein p is zero or one, T is selected from the group consisting of
alkylene, substituted alkylene, alkenylene, substituted alkenylene,
-(R21Z)q R21- and -ZR21-, where Z is a substituent selected from
the group consisting of -O-, -S- and > NR20, each R20 is
independently selected from the group consisting of alkyl, alkenyl,
alkynyl, cycloalkyl, cycloalkenyl, substituted alkyl, substituted

-610-
alkenyl, substituted alkynyl, aryl, heteroaryl and heterocyclic, each
R21 is independently alkylene, substituted alkylene, alkenylene and
substituted alkenylene with the proviso that when Z is -O- or -S-,
any unsaturation in the alkenylene and substituted alkenylene does
not involve participation of the -O- or -S-, and q is an integer of
from 1 to 3.
56. The pharmaceutical composition according to Claim
41 wherein the cyclic group defined by W, together with
-C(H)p C(=X)-, forms a ring of the formula:
<IMG>
wherein p is zero or one, T is selected from the group consisting of
alkylene, substituted alkylene, alkenylene, substituted alkenylene,

-611-
-(R21Z)q R21- and -ZR21-, where Z is a substituent selected from
the group consisting of -O-, -S- and > NR20, each R20 is
independently selected from the group consisting of alkyl, alkenyl,
alkynyl, cycloalkyl, cycloalkenyl, substituted alkyl, substituted
alkenyl, substituted alkynyl, aryl, heteroaryl and heterocyclic, each
R21 is independently alkylene, substituted alkylene, alkenylene and
substituted alkenylene with the proviso that when Z is -O- or -S-,
any unsaturation in the alkenylene and substituted alkenylene does
not involve participation of the -O- or -S-, and q is an integer of
from 1 to 3.
57. The pharmaceutical composition according to Claim
41 wherein the cyclic group defined by W, together with
-C(H)p C(=X)-, forms a ring of the formula:
<IMG>

-612-
wherein p is zero or one, T is selected from the group consisting of
alkylene, substituted alkylene, alkenylene, substituted alkenylene,
-(R21Z)q R21- and -ZR21-, where Z is a substituent selected from
the group consisting of -O-, -S- and > NR20, each R20 is
independently selected from the group consisting of alkyl, alkenyl,
alkynyl, cycloalkyl, cycloalkenyl, substituted alkyl, substituted
alkenyl, substituted alkynyl, aryl, heteroaryl and heterocyclic, each
R21 is independently alkylene, substituted alkylene, alkenylene and
substituted alkenylene with the proviso that when Z is -O- or -S-,
any unsaturation in the alkenylene and substituted alkenylene does
not involve participation of the -O- or -S-, and q is an integer of
from 1 to 3.
58. A compound of the following formulas:
<IMG>

-613-
<IMGS>

-614-
<IMGS>

-615-
wherein R1 is selected from the group consisting of alkyl,
alkenyl, alkynyl, cycloalkyl, cycloalkenyl, substituted alkyl,
substituted alkenyl, substituted alkynyl, substituted cycloalkyl,
substituted cycloalkenyl, aryl, heteroaryl and heterocyclic;
R'is selected from the group consisting of aryl, cycloalkyl,
substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl,
heteroaryl, heterocyclic. -CH3, -CH=CH2, -CH=CHR1,
-CH=CR1R1, -CR1=CH2, -CR1=CHR1, -CR1=CR1R1, -C=CH and
-C=CR1; with the proviso that when R' is heteroaryl or
heterocyclic, there is no N in R' at a position beta to the C=Q
group;
Q is S or O;
R15 is selected from the group consisting of hydrogen, alkyl,
substituted alkyl, aryl, heterocyclic and heteroaryl;
R15' is selected from the group consisting of hydrogen,
hydroxyl, alkyl, substituted alkyl, aryl, heterocyclic and heteroaryl;
W, together with -C(H)p C(=X)-, forms a cycloalkyl,
cycloalkenyl, heterocyclic, substituted cycloalkyl, or substituted
cycloalkenyl group wherein each of said cycloalkyl, cycloalkenyl,
heterocyclic, substituted cycloalkyt or substituted cycloalkenyl
group is optionally fused to form a bi- or multi-fused ring system
(preferably no more than 5 fused rings) with one or more ring
structures selected from the group consisting of cycloalkyt,
cycloalkenyl, heterocyclic, aryl and heteroaryl group which, in
turn, each of such ring structures are optionally substituted with 1 to
4 substituents selected from the group consisting of hydroxyl, halo,
alkoxy, substituted alkoxy, thioalkoxy, substituted thioalkoxy, nitro,
cyano, carboxyl, carboxyl esters, alkyl, substituted alkyl, alkenyl,
substituted alkenyl, alkynyl, substituted alkynyl, amino, substituted

-616-
amino, -NHC(O)R4, -NHSO2R4, -C(O)NH2, -C(O)NHR4,
-C(O)NR4R4, -S(O)R4, -S(O)2R4, -S(O)2NHR4 and -S(O)2NR4R4,
where each R4 is independently selected from the group consisting
of alkyl, substituted alkyl, aryl and heteroaryl;
X is selected from the group consisting of oxo (=O), thiooxo
(=S), hydroxyl (-H, -OH), thiol (H,-SH) and hydro (H,H);
Y is represented by the formula:
<IMG>
wherein each R2 is independently selected from the group consisting
of alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl,
substituted alkynyl, cycloalkyl, aryl, heteroaryl and heterocyclic;
Z is represented by the formula -T-C(X')(X")C(O)- where T
is selected from the group consisting of a bond covalently linking
R1 to -C(X')(X")-, oxygen, sulfur, and -NR5 where R5 is
hydrogen, acyl, alkyl, substituted alkyl, aryl, heterocyclic or
heteroaryl group;

-617-
R5' is hydrogen, alkyl, substituted alkyl, aryl, heterocyclic
or heteroaryl group;
X' and X" are independently selected from the group
consisting of hydrogen, fluoro, alkyl, substituted alkyl, aryl,
heteroaryl, heterocyclic, -OR5', -SR5, -N(R5)2, -N(CO)OR15 and
-N3, with the proviso that at least one of X' or X" is other than
hydrogen, hydroxy or fluoro, and with the further proviso that both
X' and X" cannot both be -OR5', -SR5, -N(R5)2, -N(CO)OR15 and
-N3 ; further, neither X' and X" can be -OR5' -SR5, -N(R5)z.
-N(CO)OR15 or -N3 when T is other than a bond covalently linking
R1 to -C(X')(X")-;
n is an integer equal to 1 or 2;
p is an integer equal to 0 or 1 such that when p is zero, the
ring defined by W and -C(H)p C(=X)- is unsaturated at the carbon
atom of ring attachment to Y and when p is one, the ring is
saturated at the carbon atom of ring attachment to Y,
with the following provisos:
when R1 is 2-propylpentanoyl, R2 is methyl, and R15 is
hydrogen, then W, together with >CH and >C = X, does not form
a 2,3-dihydro-1-methyl-5-phenyl-1H-1.4-benzodiazepin-2-one
when R1 is 3,5-difluorobenzoyl, R2 is methyl, and R15 is
hydrogen, then W, together with >CH and >C=X, does not form
a 2,3-dihydro-1-methyl-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one
when R1 is trans-cinnamyl, R2 is methyl, and R15 is
hydrogen, then W, together with >CH and >C=X, does not form

-618-
a 2,3-dihydro-1-(3,3-dimethyl-2-oxobutyl)-5-(2-pyridyl)-1H-1,4-
benzodiazepin-2-one
when R1 is 2-(4-chlorophenoxy)-2-methylpropionyl, R2 is
methyl, and R15 is hydrogen, then W, together with >CH and
>C=X, does not form a 2,3-dihydro-1-methyl-5-(2-pyridyl)-1H-
1,4-benzodiazepin-2-one
when R1 is .alpha.-methoxyphenylacetyl, R2 is methyl, and R15
is hydrogen, then W, together with >CH and >C=X, does not
form a 2,3-dihydro-1-methyl-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one
when R1 is diphenylacetyl. R2 is methyl, and R15 is
hydrogen, then W, together with >CH and >C=X, does not form
a 2,3-dihydro-1-methyl-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one
when R1 is .alpha.-methoxyphenylacetyl, R2 is methyl, and R15
is hydrogen, then W, together with >CH and >C=X, does not
form a 2,3-dihydro-1-(3,3-dimethyl-2-oxobutyl)-5-(2-pyridyl)-1H-
1,4-benzodiazepin-2-one
when R1 is .alpha.-hydroxy-diphenylacetyl, R2 is methyl, and
R15 is hydrogen, then W, together with >CH and >C=X, does
not form a 2,3-dihydro-1-(3,3-dimethyl-2-oxobutyl)-5-(2-pyridyl)-
1H-1,4-benzodiazepin-2-one
when R1 is diphenylacetyl, R2 is methyl, and R15 is
hydrogen, then W , together with >CH and >C=X, does not form

-619-
a 2,3-dihydro-1-(3,3-dimethyl-2-oxobutyl)-5-(2-pyridyl)-1H-1,4-
benzodiazepin-2-one
when R1 is 2-(chlorophenoxy)-2-methylpropionyl, R2 is
methyl, and R15 is hydrogen, then W, together with >CH and
>C=X, does not form a 2,3-dihydro-1-(3,3-dimethyl-2-oxobutyl)-
5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one
when R1 is diphenylacetyl, R2 is methyl, and R15 is
hydrogen, then W, together with >CH and >C=X, does not form
a 2,3-dihydro-1-(2-N,N-diethylaminoethyl)- 5-(2-pyridyl)-1H-1,4-
benzodiazepin-2-one
when R1 is 3.5-difluorobenzoyl, R2 is methyl, and R15 is
hydrogen, then W, together with >CH and >C=X, does not form
a 2,3-dihydro-1-(2-N,N-diethylaminoethyl)- 5-(2-pyridyl)-1H-1,4-
benzodiazepin-2-one
when R1 is trans-cinnamyl, R2 is methyl, and R15 is
hydrogen, then W, together with >CH and >C=X, does not form
a 2,3-dihydro-1-(2-N,N-diethylaminoethyl)- 5-(2-pyridyl)-1H-1,4-
benzodiazepin-2-one
when R1 is 2-(4-chlorophenoxy)-2-methylpropionyl, R2 is
methyl, and R15 is hydrogen, then W, together with >CH and
>C=X, does not form a 2,3-dihydro-1-(2-N,N-diethylaminoethyl}-
5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one

-620-
when R1-N(R15) is (2,5-dimethoxyphenyl)ureylenyl and R2
is methyl, then W, together with >CH and >C=X, does not form
a 2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one
when R1 is D,L-2-pyrrolidinone-5-yl, R2 is methyl, and R15
is hydrogen, then W, together with >CH and >C=X, does not
form a 7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one.
59. The compound according to Claim 58 wherein R1 is
aryl or heteroaryl.
60. The compound according to Claim 59 wherein R1 is
selected from the group consisting of
(a) alkyl
(b) phenyl,
(c) a substituted phenyl group of the formula:
<IMG>

-621-
wherein R c is selected from the group consisting of acyl,
alkyl, alkoxy, alkylalkoxy, azido, cyano, substituted amino, halo,
hydrogen, nitro, trihalomethyl, thioalkoxy,
and wherein R b and R c are fused to form a heteroaryl or
heterocyclic ring with the phenyl ring wherein the heteroaryl or
heterocyclic ring contains from 3 to 8 atoms of which from 1 to 3
are heteroatoms independently selected from the group consisting of
oxygen, nitrogen and sulfur
R b and R b are independently selected from the group
consisting of hydrogen, halo, nitro, cyano, trihalomethyl, alkoxy,
and thioalkoxy with the proviso that when R c is hydrogen, then R b
and R b are either both hydrogen or both substituents other than
hydrogen,
(d) 2-naphthyl,
(e) 2-naphthyl substituted at the 4, 5, 6, 7 and/or 8 positions
with 1 to 5 substituents selected from the group consisting alkyl,
alkoxy, halo, cyano, nitro, trihalomethyl, thioalkoxy, aryl, and
heteroaryl,
(f) heteroaryl, and
(g) substituted heteroaryl containing 1 to 3 substituents
selected from the group consisting of alkyl, alkoxy, aryl, aryloxy,
cyano, halo, nitro, heteroaryl, thioalkoxy, thioaryloxy provided that
said substituents are not ortho to the heteroaryl attachment to the
-NH group.
61. The compound according to Claim 57 wherein R1 is
selected from the group consisting of mono-, di- and tri-substituted
phenyl groups.

-622-
62. The compound according to Claim 61 wherein R1 is
a disubstituted phenyl selected from the group consisting of
3,5-dichlorophenyl, 3,5-difluorophenyl, 3,5-di(trifluoromethyl)-phenyl,
3,4-dichlorophenyl, 3,4-difluorophenyl, 3-(trifluoromethyl)-4-chlorophenyl,
3-chloro-4-cyanophenyl, 3-chloro-4-iodophenyl, and
3,4-methylenedioxyphenyl.
63. The compound according to Claim 61 wherein R1 is
a monosubstituted phenyl selected from the group consisting of
4-azidophenyl, 4-bromophenyl, 4-chlorophenyl, 4-cyanophenyl,
4-ethylphenyl, 4-fluorophenyl, 4-iodophenyl, 4-(phenylcarbonyl)-phenyl,
and 4-(1-ethoxy)ethylphenyl.
64. The compound according to Claim 61 wherein R1 is
a trisubstituted phenyl selected from the group consisting of
3,4,5-trifluorophenyl and 3,4,5-trichlorophenyl.
65. The compound according to Claim 58 wherein R1 is
selected from 2-naphthyl, quinolin-3-yl, 2-methylquinolin-6-yl,
benzothiazol-6-yl, 5-indolyl, and phenyl.
66. The compound according to Claim 61 wherein R1 is
selected from the group consisting of phenyl, 1-naphthyl,
2-naphthyl, n-butyl, 2-chlorophenyl, 2-fluorophenyl, 2-bromophenyl,
2-hydroxyphenyl, 2-nitrophenyl, 2-methylphenyl, 2-methoxyphenyl,
2-phenoxyphenyl, 2-trifluoromethylphenyl, 4-fluorophenyl,
4-chlorophenyl, 4-bromophenyl, 4-nitrophenyl, 4-methylphenyl,
4-hydroxyphenyl, 4-methoxyphenyl, 4-ethoxyphenyl,
4-butoxyphenyl, 4-iso-propylphenyl, 4-phenoxyphenyl,

-623-
4-trifluoromethylphenyl, 4-hydroxymethylphenyl,
3-methoxyphenyl,
3-hydroxyphenyl, 3-nitrophenyl, 3-fluorophenyl, 3-chlorophenyl,
3-bromophenyl, 3-phenoxyphenyl, 3-thiomethoxyphenyl,
3-methylphenyl, 3-trifluoromethylphenyl, 2,3-dichlorophenyl,
2,3-difluorophenyl, 2,4-dichlorophenyl, 2,5-dimethoxyphenyl,
3,4-dichlorophenyl, 3,4-difluorophenyl, 3,4-methylenedioxyphenyl,
3,4-dimethoxyphenyl, 3,5-difluorophenyl, 3,5-dichlorophenyl,
3,5-di-(trifluoromethyl)phenyl, 3,5-dimethoxyphenyl,
2,4-dichlorophenyl, 2,4-difluorophenyl, 2,6-difluorophenyl,
3,4,5-trifluorophenyl, 3,4,5-trimethoxyphenyl,
3,4,5-tri-(trifluoromethyl)phenyl, 2,4,6-trifluorophenyl,
2,4,6-trimethylphenyl, 2,4,6-tri-(trifluoromethyl)phenyl,
2,3,5-trifluorophenyl, 2,4,5-trifluorophenyl, 2,5-difluorophenyl,
2-fluoro-3-trifluoromethylphenyl, 4-fluoro-2-trifluoromethylphenyl,
2-fluoro-4-trifluoromethylphenyl, 4-benzyloxyphenyl,
2-chloro-6-fluorophenyl, 2-fluoro-6-chlorophenyl,
2,3,4,5,6-pentafluorophenyl, 2,5-dimethylphenyl, 4-phenylphenyl,
2-fluoro-3-trifluoromethylphenyl, adamantyl, benzyl,
2-phenylethyl, 3-phenyl-n-propyl, 4-phenyl-n-butyl, methyl, ethyl,
n-propyl, iso-propyl, iso-butyl, sec-butyl, tert-butyl, n-pentyl,
iso-valeryl, n-hexyl, cyclopropyl, cyclobutyl, cyclohexyl, cyclopentyl,
cyclopent-1-enyl, cyclopent-2-enyl, cyclohex-1-enyl,
-CH2-cyclopropyl, -CH2-cyclobutyl, -CH2-cyclohexyl, -CH2-cyclopentyl,
-CH2CH2-cyclopropyl, -CH2CH2-cyclobutyl,
-CH2CH2-cyclohexyl, -CH2CH2-cyclopentyl, pyrid-2-yl, pyrid-3-yl,
pyrid-4-yl, fluoropyridyls, chloropyridyls, thien-2-yl, thien-3-yl,
benzothiazol-4-yl, 2-phenylbenzoxazol-5-yl, furan-2-yl, benzofuran-2-yl,
thionaphthen-2-yl, thionaphthen-3-yl, thionaphthen-4-yl,

-624-
2-chlorothiophen-5-yl, 3-methylisoxazol-5-yl, 2-(thiophenyl)thien-5-yl,
6-methoxythionaphthen-2-yl, 3-phenyl-1,2,4-thiooxadiazol-5-yl,
2-phenyloxazol-4-yl, indol-3-yl, 1-phenyl-tetrazol-5-yl, allyl,
2-(cyclohexyl)ethyl, (CH3)2CH=CHCH2CH2CH(CH3)-,
C(O)CH2-, thien-2-yl-methyl, 2-(thien-2-yl)ethyl, 3-(thien-2-yl)-n-propyl,
2-(4-nitrophenyl)ethyl, 2-(4-methoxyphenyl)ethyl,
norboran-2-yl, (4-methoxyphenyl)methyl,
(2-methoxyphenyl)methyl, (3-methoxyphenyl)methyl, (3-hydroxy
phenyl)methyl, (4-hydroxyphenyl)methyl,
(4-methoxyphenyl)methyl, (4-methylphenyl)methyl,
(4-fluorophenyl)methyl, (4-fluorophenoxy)methyl,
(2,4-dichlorophenoxy)ethyl, (4-chlorophenyl)methyl,
(2-chlorophenyl)methyl, (1-phenyl)ethyl, (1-(p-chlorophenyl)ethyl,
(1-trifluoromethyl)ethyl, (4-methoxyphenyl)ethyl, CH3OC(O)CH2-,
benzylthiomethyl, 5-(methoxycarbonyl)-n-pentyl,
3-(methoxycarbonyl)-n-propyl, indan-2-yl, (2-methylbenzofuran-3-yl),
methoxymethyl, CH3CH=CH-, CH3CH2CH=CH-,
(4-chlorophenyl)C(O)CH2-,(4-fluorophenyl)C(O)CH2-, (4-methoxy
phenyl)C(O)CH2-, 4-(fluorophenyl)-NHC(O)CH2-, 1-phenyl-n-butyl,
(phenyl)2CHNHC(O)CH2CH2-, (CH3)2NC(O)CH2-,
(phenyl)2CHNHC(O)CH2CH2-, methylcarbonylmethyl,
(2,4-dimethylphenyl)C(O)CH2-, 4-methoxyphenyl-C(O)CH2-,
phenyl-C(O)CH2-, CH3C(O)N(phenyl)-, ethenyl, methylthiomethyl,
(CH3)3CNHC(O)CH2-, 4-fluorophenyl-C(O)CH2-,
diphenylmethyl, phenoxymethyl, 3,4-methylenedioxyphenyl-CH2-,
benzo[b]thiophen-3-yl, (CH3)3COC(O)NHCH2-, trans-styryl,
H2NC(O)CH2CH2-, 2-trifluoromethylphenyl-C(O)CH2,
phenylC(O)NHCH(phenyl)CH2-, mesityl, CH3CH(=NHOH)CH2-,
4-CH3-phenyl-NHC(O)CH2CH2-, phenyl-C(O)CH(phenyl)CH2-,

-625-
(CH3)2CHC(O)NHCH(phenyl)-, CH3CH2OCH2-,
CH3OC(O)CH(CH3)(CH2)3-, 2,2,2-trifluoroethyl,
1-(trifluoromethyl)ethyl, 2-CH3-benzofuran-3-yl,
2-(2,4-dichlorophenoxy)ethyl, SO2CH2-, 3-cyclohexyl-n-propyl,
CF3CH2CH2CH2- and N-pyrrolidinyl.
67. The compound according to Claim 58 where each R2
is independently selected from the group consisting of alkyl,
substituted alkyl, alkenyl, cycloalkyl, aryl, heteroaryl and
heterocyclic.
68. The compound according to Claim 58 wherein R2 is
selected from the group consisting of methyl, ethyl, n-propyl,
iso-propyl, n-butyl, iso-butyl, sec-butyl, tert-butyl,
-CH2CH(CH2CH3)2, 2-methyl-n-butyl, 6-fluoro-n-hexyl, phenyl,
benzyl, cyclohexyl, cyclopentyl, cycloheptyl, allyl, iso-but-2-enyl,
3-methylpentyl, -CH2-cyclopropyl, -CH2-cyclohexyl,
-CH2CH2-cyclopropyl, -CH2CH2-cyclohexyl, -CH2-indol-3-yl,
p-(phenyl)phenyl, o-fluorophenyl, m-fluorophenyl, p-fluorophenyl,
m-methoxyphenyl, p-methoxyphenyl, phenethyl, benzyl,
m-hydroxybenzyl, p-hydroxybenzyl, p-nitrobenzyl,
m-trifluoromethylphenyl, p-(CH3)2NCH2CH2CH2O-benzyl,
p-(CH3)3COC(O)CH2O-benzyl, p-(HOOCCH2O)-benzyl,
2-aminopyrid-6-yl, p-(N-morpholino-CH2CH2O)-benzyl,
-CH2CH2C(O)NH2, -CH2-imidazol-4-yl,
-CH2-(3-tetrahydrofuranyl), -CH2-thiophen-2-yl,
-CH2(1-methyl)cyclopropyl, -CH2-thiophen-3-yl, thiophen-3-yl,
thiophen-2-yl, -CH2-C(O)O-t-butyl, -CH2-C(CH3)3, -CH2CH(CH2CH3)2,
2-methylcyclopentyl, cyclohex-2-enyl, -CH[CH(CH3)2]COOCH3,

-626-
-CH2CH2N(CH3)2, -CH2C(CH3)=CH2, -CH2CH=CHCH3 (cis
and trans), -CH2OH, -CH(OH)CH3, -CH(O-t-butyl)CH3,
-CH2OCH3, -(CH2)4NH-Boc, -(CH2)4NH2, -CH2-pyridyl, pyridyl,
-CH2-naphthyl, -CH2-(N-morpholino), p-(N-morpholino-
CH2CH2O)-benzyl, benzo[b]thiophen-2-yl,
5-chlorobenzo[b]thiophen-2-yl, 4,5,6,7-tetrahydrobenzo[b]thiophen-2-yl,
benzo[b]thiophen-3-yl, 5-chlorobenzo[b]thiophen-3-yl,
benzo[b]thiophen-5-yl, 6-methoxynaphth-2-yl, -CH2CH2SCH3,
thien-2-yl, and thien-3-yl.
69. The compound according to Claim 58 wherein the
cyclic groups defined by W and -C(H)p C(=X)- is selected from the
group consisting of lactones, lactams, thiolactones, thiolactams,
heterocyclic and cycloalkyl groups.
70. The compound according to Claim 69 wherein the
cyclic group defined by W and -C(H)p C(=X)-, forms a lactam or
thiolactam ring of the formula:
<IMG>

-627-
or
<IMG>
wherein p is zero or one, T is selected from the group consisting of
alkylene, substituted alkylene, alkenylene, substituted alkenylene,
-(R21Z)q R21- and -ZR21-, where Z is a substituent selected from

-628-
the group consisting of -O-, -S- and > NR20, each R20 is
independently selected from the group consisting of alkyl, alkenyl,
alkynyl, cycloalkyl, cycloalkenyl, substituted alkyl, substituted
alkenyl, substituted alkynyl, aryl, heteroaryl and heterocyclic, each
R21 is independently alkylene, substituted alkylene, alkenylene and
substituted alkenylene with the proviso that when Z is -O- or -S-,
any unsaturation in the alkenylene and substituted alkenylene does
not involve participation of the -O- or -S-, and q is an integer of
from 1 to 3.

-629-
71. The method according to Claim 70 wherein the lactam ring
is selected from the group consisting of
<IMGS>

-630-
<IMGS>

-631-
<IMGS>

-632-
wherein A-B is selected from the group consisting of alkylene,
alkenylene, substituted alkylene, substituted alkenylene and
-N=CH-; Q is oxygen or sulfur; each V is independently selected
from the group consisting of hydroxy, acyl, acyloxy, alkyl,
substituted alkyl, alkoxy, substituted alkoxy, alkenyl, substituted
alkenyl, alkynyl, substituted alkynyl, amino, substituted amino,

-633-
aminoacyl, alkaryl, aryl, aryloxy, carboxyl, carboxylalkyl, cyano,
halo, nitro, heteroaryl, thioalkoxy, substituted thioalkoxy, and
trihalomethyl; each R a is independently selected from the group
consisting of alkyl, substituted alkyl, alkoxy, substituted alkoxy,
amino, substituted amino, carboxyl, carboxyl alkyl, cyano, and
halo; R b is selected from the group consisting of alkyl, substituted
alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl,
acyl, aryl, heteroaryl, and heterocyclic; R c is selected from the
group consisting of alkyl, substituted alkyl, alkenyl, substituted
alkenyl, aryl, heteroaryl, heterocyclic, thioalkoxy, substituted
amino, cycloalkyl, and substituted cycloalkyl; t is an integer from 0
to 4; t is an integer from 0 to 3; and w is an integer from 0 to 3.
72. The compound according to Claim 69 wherein the cyclic
group defined by W, together with -C(H)p C(=X)- is a ring of the
formula:
<IMG>
or

-634-
<IMG>
wherein p is zero or one, T is selected from the group consisting of
alkylene, substituted alkylene, alkenylene, substituted alkenylene,
-(R21Z)q R21 - and -ZR21-, where Z is a substituent selected from
the group consisting of -O-, -S- and > NR20, each R20 is
independently selected from the group consisting of alkyl, alkenyl,
alkynyl, cycloalkyl, cycloalkenyl, substituted alkyl, substituted
alkenyl, substituted alkynyl, aryl, heteroaryl and heterocyclic, each
R21 is independently alkylene, substituted alkylene, alkenylene and
substituted alkenylene with the proviso that when Z is -O- or -S-,
any unsaturation in the alkenylene and substituted alkenylene does
not involve participation of the -O- or -S-, and q is an integer of
from 1 to 3.
73. The compound according to Claim 57 wherein the
alcohol or thiol substituted groups is selected from the group
consisting of

-635-
<IMGS>
wherein each V is independently selected from the croup consisting
of hydroxy, acyl, acyloxy, alkyl, substituted alkyl, alkoxy,
substituted alkoxy, alkenyl, substituted alkenyl, alkynyl, substituted
alkynyl, amino, substituted amino, aminoacyl, alkaryl, aryl,
aryloxy, carboxyl. carboxylalkyl, cyano, halo, nitro, heteroaryl,
thioalkoxy, substituted thioalkoxy, and trihalomethyl; each R a is
independently selected from the group consisting of alkyl,
substituted alkyl, alkoxy, substituted alkoxy, amino, substituted
amino, carboxyl, carboxyl alkyl, cyano, and halo; t is an integer
from 0 to 4; and w is an integer from 0 to 3.

-636-
74. The compound according to Claim 58 wherein the cyclic
group defined by W, together with -C(H)p C(=X)-, forms a ring of
the formula:
<IMG>
wherein p is zero or one, T is selected from the group consisting of
alkylene, substituted alkylene, alkenylene, substituted alkenylene. -
(R21Z)q R21- and -ZR21, where Z is a substituent selected from
the group consisting of -O-. -S- and > NR20, each R20 is
independently selected from the group consisting of alkyl, alkenyl,
alkynyl, cycloalkyl, cycloalkenyl, substituted alkyl, substituted
alkenyl, substituted alkynyl, aryl, heteroaryl and heterocyclic, each
R21 is independently alkylene, substituted alkylene, alkenylene and
substituted alkenylene with the proviso that when Z is -O- or -S-,
any unsaturation in the alkenylene and substituted alkenylene does
not involve participation of the -O- or -S-, and q is an integer of
from 1 to 3.
75. The compound according to Claim 69 wherein the cyclic
group defined by W, together with -C(H)p C(=X)-, forms a ring of
the formula:

-637-
<IMG>
wherein p is zero or one, T is selected from the group consisting of
alkylene, substituted alkylene, alkenylene, substituted alkenylene. -
(R21Z)q R21- and -ZR21, where Z is a substituent selected from
the group consisting of -O-, -S- and > NR20, each R20 is
independently selected from the group consisting of alkyl, alkenyl,
alkynyl, cycloalkyl, cycloalkenyl, substituted alkyl, substituted
alkenyl, substituted alkynyl, aryl, heteroaryl and heterocyclic, each
R21 is independently alkylene, substituted alkylene, alkenylene and
substituted alkenylene with the proviso that when Z is -O- or -S-,
any unsaturation in the alkenylene and substituted alkenylene does
not involve participation of the -O- or -S-, and q is an integer of
from 1 to 3.
76. The compound according to Claim 69 wherein the
compound is selected from the group consisting of

-638-
<IMGS>
wherein each V is independently selected from the group consisting
of hydroxy, acyl, acyloxy, alkyl, substituted alkyl, alkoxy,
substituted alkoxy, alkenyl, substituted alkenyl, alkynyl, substituted
alkynyl, amino, substituted amino, aminoacyl, alkaryl, aryl,
aryloxy, carboxyl, carboxylalkyl, cyano, halo, nitro, heteroaryl,
thioalkoxy, substituted thioalkoxy, and trihalomethyl: each R a is
independently selected from the group consisting of alkyl,
substituted alkyl, alkoxy, substituted alkoxy, amino. substituted
amino, carboxyl, carboxyl alkyl, cyano, and halo; t is an integer
from 0 to 4; and w is an integer from 0 to 3.
77. The compound according to Claim 69 wherein the cyclic
group defined by W, together with -C(H)p C(=X)-, forms a ring of
the formula:

-639-
<IMG>
wherein p is zero or one, T is selected from the group consisting of
alkylene, substituted alkylene, alkenylene, substituted alkenylene, -
(R21Z)q R21- and -ZR21, where Z is a substituent selected from
the group consisting of -O-, -S- and > NR20, each R20 is
independently selected from the group consisting of alkyl, alkenyl,
alkynyl, cycloalkyl, cycloalkenyl, substituted alkyl, substituted
alkenyl, substituted alkynyl. aryl, heteroaryl and heterocyclic. each
R21 is independently alkylene, substituted alkylene, alkenylene and
substituted alkenylene with the proviso that when Z is -O- or -S-,
any unsaturation in the alkenylene and substituted alkenylene does
not involve participation of the -O- or -S-, and q is an integer of
from 1 to 3.
78. The compound according to Claim 69 wherein the cyclic
group defined by W, together with -C(H)p C(=X)-, forms a ring of
the formula:
<IMG>

-640-
wherein p is zero or one, T is selected from the group consisting of
alkylene, substituted alkylene, alkenylene, substituted alkenylene,
-(R21Z)q R21- and -ZR21, where Z is a substituent selected from
the group consisting of -O-, -S- and > NR20, each R20 is
independently selected from the group consisting of alkyl, alkenyl,
alkynyl, cycloalkyl, cycloalkenyl, substituted alkyl, substituted
alkenyl, substituted alkynyl, aryl, heteroaryl and heterocyclic, each
R21 is independently alkylene, substituted alkylene, alkenylene and
substituted alkenylene with the proviso that when Z is -O- or -S-,
any unsaturation in the alkenylene and substituted alkenylene does
not involve participation of the -O- or -S-, and q is an integer of
from 1 to 3.
79. The compound according to Claim 69 wherein the cyclic
group defined by W, together with -C(H)p C(=X)-, forms a ring of
the formula:
<IMG>

-641-
wherein p is zero or one, T is selected from the group consisting of
alkylene, substituted alkylene, alkenylene, substituted alkenylene,
-(R21Z)q R21- and -ZR21-, where Z is a substituent selected from
the group consisting of -O-, -S- and > NR20, each R20 is
independently selected from the group consisting of alkyl, alkenyl,
alkynyl, cycloalkyl, cycloalkenyl, substituted alkyl, substituted
alkenyl, substituted alkynyl, aryl, heteroaryl and heterocyclic, each
R21 is independently alkylene, substituted alkylene, alkenylene and
substituted alkenylene with the proviso that when Z is -O- or -S-,
any unsaturation in the alkenylene and substituted alkenylene does
not involve participation of the -O- or -S-, and q is an integer of
from 1 to 3.
80. The compound according to Claim 69 wherein the cyclic
group defined by W, together with -C(H)p C(=X)-, forms a ring of
the formula:

-642-
wherein p is zero or one, T is selected from the group consisting of
alkylene, substituted alkylene, alkenylene, substituted alkenylene,
-(R21Z)q R21- and -ZR21-, where Z is a substituent selected from
the group consisting of -O-, -S- and > NR20, each R20 is
independently selected from the group consisting of alkyl, alkenyl,
alkynyl, cycloalkyl, cycloalkenyl, substituted alkyl, substituted
alkenyl, substituted alkynyl, aryl, heteroaryl and heterocyclic, each
R21 is independently alkylene, substituted alkylene, alkenylene and
substituted alkenylene with the proviso that when Z is -O- or -S-,
any unsaturation in the alkenylene and substituted alkenylene does
not involve participation of the -O- or -S-, and q is an integer of
from 1 to 3.
81. The compound according to Claim 80 wherein the
compound is selected from the group consisting of:
<IMGS>

-643-
82. The compound according to Claim 69 wherein the cyclic
group defined by W, together with -C(H)p C(=X)-, forms a ring of
the formula:
<IMGS>

-644-
wherein p is zero or one, T is selected from the group consisting of
alkylene, substituted alkylene, alkenylene, substituted alkenylene,
(R21Z)q R21- and -ZR21, where Z is a substituent selected from
the group consisting of -O-, -S- and > NR20, each R20 is
independently selected from the group consisting of alkyl, alkenyl,
alkynyl, cycloalkyl, cycloalkenyl, substituted alkyl, substituted
alkenyl, substituted alkynyl, aryl, heteroaryl and heterocyclic, each
R21 is independently alkylene, substituted alkylene, alkenylene and
substituted alkenylene with the proviso that when Z is -O- or -S-.

-645-
any unsaturation in the alkenylene and substituted alkenylene does
not involve participation of the -O- or -S-, and q is an integer of
from 1 to 3.
83. The compound according to Claim 69 wherein the cyclic
group defined by W, together with -C(H)p C(=X)-, forms a ring of
the formula:
<IMG>

-646-
wherein p is zero or one, T is selected from the group consisting of
alkylene, substituted alkylene, alkenylene, substituted alkenylene. -
(R21Z)q R21- and -ZR21, where Z is a substituent selected from
the group consisting of -O-, -S- and > NR20, each R20 is
independently selected from the group consisting of alkyl, alkenyl,
alkynyl, cycloalkyl, cycloalkenyl, substituted alkyl, substituted
alkenyl, substituted alkynyl, aryl, heteroaryl and heterocyclic, each
R21 is independently alkylene, substituted alkylene, alkenylene and
substituted alkenylene with the proviso that when Z is -O- or -S-,
any unsaturation in the alkenylene and substituted alkenylene does
not involve participation of the -O- or -S-, and q is an integer of
from 1 to 3.
84. A compound selected from the group consisting of:
3-[(N'-(4-methylbenzoyl)-D-phenylglycinyl)]amino-2.3-
dihydro-1-methyl-5-phenyl-1 H-1,4-benzodiazepin-2-one

-647-
3-[(N'-(4-methylbenzoyl)-L-alaninyl)]amino-2,3-
dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one
3-[(N'-(Diphenylacetyl)-L-alaninyl)]amino-2,3-dihydro-
1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one
3-[(N'-(2-Naphthoyl)-L-alaninyl)]amino-2,3-dihydro-1-
methyl-5-phenyl-1H-1,4-benzodiazepin-2-one
3-[(N'-(1-Naphthoyl)-L-alaninyl)]amino-2,3-dihydro-1-
methyl-5-phenyl-1H-1.4-benzodiazepin-2-one
3-[(N'-(5-Chloro-2-thiophenecarboxyl)-L-
alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-
benzodiazepin-2-one
3-[(N'-(4-Cyanobenzoyl)-L-alaninyl)]amino-2,3-
dihydro-1-methyl-5-phenyl-1 H-1,4-benzodiazepin-2-one
3-[(N'-(Tetrahydro-2-furoyl)-L-alaninyl)]amino-2,3-
dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one
3-[(N'-(3,5-Difluorobenzoyl)-L-alaninyl)]amino-2,3-
dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one
3-[(N'-(3-Cyclohexenecarboxyl)-L-alaninyl)]amino-2,3-
dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one

-648-
3-[(N'-(Acetyl)-L-alaninyl)]amino-2,3-dihydro-1-
methyl-5-phenyl-1 H-1,4-benzodiazepin-2-one
3-[(N'-(1,2,3,4-Tetrahydro-2-naphthoyl)-L-alaninyl)]
amino-2, 3-dihydro-1-methyl-5-phenyl-1 H-1,
4-benzodiazepin-2-one
3-[(N'-(Cyclopentanecarboxyl)-L-alaninyl)]amino-2,
3-dihydro-1 -methyl-5-phenyl-1H-1 ,4-benzodiazepin-2-one
(S)-3-[(N'-(2-phenoxybutyryl)-L-alaninyl)]amino-2,
3-dihydro-1-methyl-5-pheny l- 1 H-1,4-benzodiazepin-2-one
(S)-3-[(N'-(2-Thiophenecarboxyl)-L-alaninyl)]amino-2,
3-dihydro-1-methyl-5-phenyl-1 H-1 ,4-benzodiazepin-2-one
(S)-3-[(N'-(2, 3-Diphenylpropionyl)-L-alaninyl)]amino-2,
3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one
(S}-3-[(N'-((R, S)-(-)-.alpha.-Methoxyphenylacetyl)-L-alaninyl)]
amino-2,3-dihydro-1-methyl-5-phenyl-1 H-1,
4-benzodiazepin-2-one
(S)-3-[(N'-(2-Furoyl)-L-alaninyl)]amino-2,3-dihydro-1-
methyl-5-phenyl-1H-1,4-benzodiazepin-2-one

-649-
(S)-3-[(N'-(2-Phenoxypropionyl)-L-alaninyl)]amino-2,
3-dihydro-1-methyl-5-phenyl-1 H-1,4-benzodiazepin-2-one
(S)-3-[(N'-(Cyclohexanecarboxyl)-L-alaninyl)]amino-2,

3-dihydro-1-methyl-5-phenyl-1 H-1,4-benzodiazepin-2-one
(S)-3-[(N'-(2-(4-Chlorophenoxy)-2-methylpropionyl)
-L-alaninyl)]amino-2.3-dihydro-1-methyl-5-phenyl-1 H-1,
4-benzodiazepin-2-one
(S)-3-[(N'-(Cyclobutanecarboxyl)-L-alaninyl)]amino-2,
3-dihydro-1-methyl-5-phenyl-1 H-1,4-benzodiazepin-2-one
(S)-3-[(N'-(1-Phenyl-1-cyclopropanecarboxyl)-L-alaninyl)]
amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,
4-benzodiazepin-2-one
(S)-3-[(N'-(2-Benzofurancarboxyl)-L-alaninyl)]amino-2-,
3-dihydro-1-methyl-5-phenyl-1H-1 ,4-benzodiazepin-2-one
(S)-3-[(N'-(2-Isopropyl-2-phenylacetyl)-L-alaninyl)]
amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,
4-benzodiazepin-2-one
(S)-3-[(N'-(S-Chlorobenzofuran-2-carboxyl)-L-

-650-
alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,
4-benzodiazepin-2-one
(S)-3-[(N'-(2-Ethylhexanoyl)-L-alaninyl)]amino-2,
3-dihydro-1-methyl-5-phenyl-1 H-1, 4-benzodiazepin-2-one
(S)-3-[(N'-(2-Methylbutyryl)-L-alaninyl}]amino-2,
3- dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one
(S}-3-[(N'-((R,S}-2-Phenoxypropionyl)-L-alaninyl)]
amino-2, 3-dihydro-1-methyl-5-phenyl-1 H-1,
4-benzodiazepin-2-one
(S)-3-[(N'-(5.5-dimethyl-butyrolactone-4-yl)
-L- alaninyl)]amino-2, 3-dihydro-1-methyl-5-phenyl-1 H-1,
4-benzodiazepin-2-one
(S)-3-[(N'-(2-Methyl-4,4,4-trifluorobutyryl)
-L- alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,
4-benzodiazepin-2-one
5-{N' -(2-phenylpropionyl}-L-alaninyl }-amino-7-methyl-5,
7-dihydro-6H-dibenz[b,d]azepin-6-one
5-{N'-(tetrahydro-3-furoyl)-L-alaninyl}-amino-7-methyl-5,
7-dihydro-6H-dibenz[b,d]azepin-6-one

-651-
3-[N'-(3,5-difluorophenyl-.alpha.-methoxyacetyl)-L-alaninyl]-
amino-2, 3-dihydro-1-methyl-5-phenyl-1 H-1,
4-Benzodiazepin-2-one
3-[N'-(3,5-difluorophenyl-.alpha.-methoxyacetyl)-L-alaninyl]-
amino-2 , 3-dihydro-1-methyl-5-phenyl-1 H-1,
4-Benzodiazepin-2-one
(S}-3-((N'-(4-(Trifluoromethyl)cyclohexane carboxyl)
-L- alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,
4-benzodiazepin-2-one
(S)-3-[(N'-(Bicyclo(2.2.1 ]heptane-2-carboxyl)
-L- alaninyl)]amino-2.3-dihydro-1-methyl-5-phenyl-1 H-1,
4-benzodiazepin-2-one
(S)-3-[(N'-(Bicyclo(2.2.1 )hept-5-ene-2-carboxyl)
-L- alaninyl)] amino-2.3-dihydro-1-methyl-5-phenyl-1 H-1,
4-benzodiazepin-2-one
(S)-3-((N'-(2,2-Dichlorocyclopropane carboxyl)
-L- alaninyl)] amino-2, 3-dihydro-1-methyl-5-phenyl-1 H-1,
4-benzodiazepin-2-one
(S)-3-[(N'-(Cycloheptanecarboxyl)-L-alaninyl)]amino-2,
3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2- one

-652-
(S)-3-[(N'-(2-Methylvaleryl)-L-alaninyl)]amino-2,
3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one
3-[(N'-(2-(4-hydroxyphenoxy)propionyl)-L-alaninyl)]
amino-2,3-dihydro-1-methyl-5-phenyl-1 H-1,
4-benzodiazepin-2-one
(S)-3-[(N'-(.alpha.-(Hydroxymethyl)phenylacetyl)-L-alaninyl)]
amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,
4-benzodiazepin-2-one
(S)-3-[(N'-( 1-(2,4
Dichlorophenyl)cyclopropanecarboxyl)-L-alaninyl)]
amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,
4-benzodiazepin-2-one
(S)-3-[(N'-(2-Ethylbutyryl)-L-alaninyl)]amino-2,
3-dihydro-1-methyl-5-phenyl- 1H-1.4-benzodiazepin-2-one
(S)-3-[(N'-(2-Methylcyclopropanecarboxyl)-L-ananinyl)]
amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,
4-benzodiazepin-2-one
(S)-3-[(N'-( 1-(4-Chlorophenyl)-1-cyclobutanecarboxyl)
-L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,
4-benzodiazepin-2-one
(S)-3-[(N'-(2-Biphenylcarboxyl)-L-alaninyl)]amino-2,
3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one

-653-
(S)-3-[(N'-(Pivalyl)-L-alaninyl)]amino-2,3-dihydro-1-
methyl-5-phenyl-1 H-1,4-benzodiazepin-2-one
(S)-3-[(N'-(trans-Cinnamyl)-L-alaninyl)]amino-2,
3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one
(S)-3-[(N'-( 1,2-Dihydro-1-oxo-2-phenyl-4-
isoquinolinecarboxyl)-L-alaninyl)]amino-2,3-dihydro-1-
methyl-5-phenyl-1 H-1,4-benzodiazepin-2-one
(S)-3-[(N'-(Bicyclo (3.3.1)non-6-ene-3-carboxyl)
-L- alaninyl)]amino-2.3-dihydro-1-methyl-5-phenyl-1 H-1,
4-benzodiazepin-2-one
(S)-3-[(N'-(Cyclopropanecarboxyl)-L-alaninyl)]amino-2,
3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one

(S)-3-[(N'-(3-furoyl)-L-alaninyl)]amino-2,3-dihydro-1-
methyl-5-phenyl-1 H-1,4-benzodiazepin-2-one
(S)-3-[(N'-(2-(4-Cyanophenoxy)-2-methyl propionyl)
-L- alaninyl)] amino-2, 3-dihydro-1-methyl-5-phenyl-1 H- 1,
4- benzodiazepin-2-one
(S)-3-[(N' -(Diphenylacetyl)-L -alaninyl)]amino-2,
3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one

-654-
(S)-3-[(N'-(Tetrahydro-2-furoyl)-L-alaninyl)]amino-2,3-
dihydro-1-methy 1-5-phenyl-1H-1,4-benzodiazepin-2-one
(S)-3-[(N'-(3,5-Difluorobenzoyl)-L-alaninyl)]amino-2,3-
dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one
(S)-3-[(N'-(3-Cyclohexenecarboxyl)-L-alaninyl)]amino-
2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-
one
(S)-3-[(N'-(1,2,3,4-Tetrahydro-2-naphthoyl)-L-
alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-
benzodiazepin-2-one
(S)-3-[(N'-(Cyclopentanecarboxyl)-L-alaninyl)]amino-
2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-
one
(S)-3-[(N'-(2-(4-trifluorophenyoxy)propionyl)-L-
alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-
benzodiazepin-2-one
(S)-3-[(N'-(2-(4-Biphenylyloxy)propionyl)-L-
alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-
benzodiazepin-2-one
(S)-3-[(N'-(Diphenylacetyl)-L-phenylglycinyl)]amino-
2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-
one

-655-
(S)-3-[(N'-(4-(methylsulfonyl)benzoyl)-L-
alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-
benzodiazepin-2-one
(S)-3-[(N'-(4-chloro-.alpha.-methylphenylacetyl)-L-
alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-
benzodiazepin-2-one
(S)-3-[(N'-(trans-2-Phenyl-1-cyclopropanecarboxyl)-L-
alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-
benzodiazepin-2-one
(S)-3-[(N'-(4-chloro-.alpha.,.alpha.-dimethylphenylacetyl)-L-
alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-
benzodiazepin-2-one
(S)-3-[(N'-(5-methylsulfonyl)thiophene-2-carboxyl)-L
alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-
benzodiazepin-2-one
(S)-3-[(N'-(1,8-dimethyl-6-Hydroxy-
bicyclo(2.2.2)octane-2-carboxyl)-L-alaninyl)]amino-2,3-
dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one
(S)-3-[(N'-((S)-(+)-2-hydroxy-2-phenylpropionyl)-L-
alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-
benzodiazepin-2-one

-656-
(S)-3-[(N'-(1,4-Benzodioxan-2-carboxyl)-L-
alaninyl)]amino-2.3-dihydro-1-methyl-5-phenyl-1H-1,4-
benzodiazepin-2-one
(S)-3-[(N'-(Tetrahydro-3-furoyl)-L-alaninyl)]amino-2,3-
dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one
(S)-3-[(N'-(Acetyl)-L-phenylglycinyl)]amino-2,3-
dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one
(S)-3-[(N'-(3-Cyclohexenecarboxyl)-L-
phenylglycinyl)]amino-2,3-dihydro-1-methyl-5-phenyl-
1H-1,4-benzodiazepin-2-one
(S)-3-[(N'-(Cyclopropanecarboxyl)-L-
phenylglycinyl)]amino-2,3-dihydro-1-methyl-5-phenyl-
1H-1,4-benzodiazepin-2-one
(S)-3-[(N'-(3,5-Difluorobenzoyl)-L-
phenylglycinyl)]amino-2,3-dihydro-1-methyl-5-phenyl-
1H-1,4-benzodiazepin-2-one
3-[(N'-(L-2-pyrrolidinone-5-yl)-L-alaninyl)]amino]-2,3-
dihydro-1-methyl-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-
one
3-[(N'-(trans-cinnamyl)-L-alaninyl)]amino)-2,3-dihydro-
1-methyl-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one

-657-
3-[(N'-(1-phenyl-1-cyclopropanecarboxyl)-L-
alaninyl)]amino]-2,3-dihydro-1-methyl-5-(2-pyridyl)-
1H-1,4-benzodiazepin-2-one
3-[(N'-(1-phenyl-1-cyclopropanecarboxyl)-L-
alaninyl)]amino]-2,3-dihydro-1-(3,3-dimethyl-2-
oxobutyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one
(S)-3-[(N'-(.alpha.-hydroxy-diphenylacetyl)-L-
alaninyl)]amino-2,3-dihydro-1-methyl-5-(2-pyridyl)-1H-
1,4-benzodiazepin-2-one
3-[(N'-(3,5-difluorobenzoyl)-L-alaninyl)]amino]-2,3-
dihydro-1-(3,3-dimethyl-2-oxobutyl)-5-(2-pyridyl)-1H-
1,4-benzodiazepin-2-one
3-[(N'-(L-2-pyrrolidinone-5-yl)-L-alaninyl)]amino]-2,3-
dihydro-1-(3,3-dimethyl-2-oxobutyl)-5-(2-pyridyl)-1H-
1,4-benzodiazepin-2-one
(S)-3-[(N'-(.alpha.-hydroxy-diphenylacetyl)-L-
alaninyl)]amino-2,3-dihydro-1-2-(diethylamino)ethyl-5-
(2-pyridyl)-1H-1,4-benzodiazepin-2-one
3-[(N'-(1-phenyl-1-cyclopropanecarboxyl)-L-
alaninyl)]amino]-2,3-dihydro-1-(2-N,N-
diethylaminoethyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-
2-one

-658-
3-[(N'-(.alpha.-methoxyphenylacetyl)-L-alaninyl)]amino]-2,3-
dihydro-1-(2-N.N-diethylaminoethyl)-5-(2-pyridyl)-1H-
1,4-benzodiazepin-2-one
3-(S)-[2-((1H)-isoquinoline-3,4-dihydro-3-oxo)-2-
methyl-acetyl]-amino-2.3-dihydro-1-methyl-5-phenyl-
1H-1.4-benzodiazepin-2-one
3-(S)-[2-((1H)-isoquinoline-3,4-dihydro-3-oxo)-2-
methyl-acetyl]-amino-2,3-dihydro-1-methyl-5-phenyl-
1H-1.4-benzodiazepin-2-one
(S)-3-[(N'-((trans-2-Phenylcyclopropyl)ureylenyl)-L-
alaninyl)]amino-2.3-dihydro-1-methyl-5-phenyl-1H-1,4-
benzodiazepin-2-one
(S)-3-[(N'-((3.4-Dichlorophenyl)ureylenyl)-L-
alaninyl)]amino-2.3-dihydro-1-methyl-5-phenyl-1H-1.4-
benzodiazepin-2-one
(S)-3-[(N'-((2-propenyl)ureylenyl)-L-alaninyl)]amino-
2,3-dihydro-1-methyl-5-phenyl-1H-1.4-benzodiazepin-2-
one
(S)-3-((N'-((R)-(-)-1-(1-Naphthyl)ethyl)ureylenyl)-L-
alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1.4-
benzodiazepin-2-one

-659-
(S)-3-[(N'-((2,6-Diisopropylphenyl)ureylenyl)-L-
alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-
benzodiazepin-2-one
(S)-3-[(N'-((3-[(Trifluoromethyl)phenyl)ureylenyl)-L-
alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-
benzodiazepin-2-one
(S)-3-[(N'-((Phenyl)ureylenyl)-L-alaninyl)]amino-2.3-
dihydro-1-methyl-5-phenyl-1H-1.4-benzodiazepin-2-one
(S)-3-[(N'-((4-ethoxycarbonylphenyl)ureylenyl)-L-
alaninyl)]amino-2.3-dihydro-1-methyl-5-phenyl-1H-1,4-
benzodiazepin-2-one
(S)-3-[(N'-((2-Bromophenyl)ureylenyl)-L-
alaninyl)]amino-2.3-dihydro-1-methyl-5-phenyl-1H-1.4-
benzodiazepin-2-one
(S)-3-[(N'-((o-Tolyl)ureylenyl)-L-alaninyl)]amino-2,3-
dihydro-1-methyl-5-phenyl-1H-1.4-benzodiazepin-2-one
(S)-3-[(N'-((2-Ethyl-6-methylphenyl)ureylenyl)-L-
alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-
benzodiazepin-2-one
(S)-3-[(N'-((2-Fluorophenyl)ureylenyl)-L-
alaninyl)]amino-2.3-dihydro-1-methyl-5-phenyl-1H-1,4-
benzodiazepin-2-one

-660-
(S)-3-[(N'-((2.4-difluorophenyl)ureylenyl)-L-
alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1.4-
benzodiazepin-2-one
(S)-3-[(N'-((2-Ethoxyphenyl)ureylenyl)-L-
alaninyl)]amino-2, 3-dihydro-1-methyl-5-phenyl-1H-1,4-
benzodiazepin-2-one
(S)-3-[(N'-((3-Acetylphenyl)ureylenyl)-L-
alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-
benzodiazepin-2-one
(S)-3-[(N'-((3-[(cyano)phenyl)ureylenyl)-L-
alaninyl)]amino-2.3-dihydro-1-methyl-5-phenyl-1H-1,4-
benzodiazepin-2-one
(S)-3-[(N'-((Phenethyl)ureylenyl)-L-alaninyl)]amino-2,3-
dihydro-1-methyl-5-phenyl-1H-1.4-benzodiazepin-2-one
(S)-3-[(N'-((4-n-Butylphenyl)ureylenyl)-L-
alaninyl)]amino-2.3-dihydro-1-methyl-5-phenyl-1H-1.4-
benzodiazepin-2-one
(S)-3-[(N'-((Octyl)ureylenyl)-L-alaninyl)]amino-2.3-
dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one

-661-
(S)-3-[(N'-((4-Biphenyl)ureylenyl)-L-alaninyl)]amino-
2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one
(S)-3-[(N'-((4-Isopropylphenyl)ureylenyl)-L-
alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-
benzodiazepin-2-one
(S)-3-[(N'-((Hexyl)ureylenyl)-L-alaninyl)]amino-2,3-
dihydro-1-methyl-5-phenyl-1H-1.4-benzodiazepin-2-one
(S)-3-[(N'-((2-Isopropylphenyl)ureylenyl)-L-
alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-
benzodiazepin-2-one
(S)-3-[(N'-((2,6-Difluorophenyl)ureylenyl) -L-
alaninyl)]amino-2.3-dihydro-1-methyl-5-phenyl-1H-1,4-
benzodiazepin-2-one
(S)-3-((N'-((Octadecyl)ureylenyl)-L-alaninyl)]amino-
2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one
(S)-3-[(N'-((4-(Trifluoromethoxy)phenyl)ureylenyl)-L-
alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-
benzodiazepin-2-one
(S)-3-[(N'-((2,4-Dichlorophenyl)ureylenyl)-L-
alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1.4-
benzodiazepin-2-one

-662-
(S)-3-[(N'-((3-Ethoxycarbonylphenyl)ureylenyl)-L-
alaninyl)]amino-2.3-dihydro-1-methyl-5-phenyl-1H-1,4-
benzodiazepin-2-one
(S)-3-[(N'-((4-Chlorophenyl)ureylenyl)-L-
alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-
benzodiazepin-2-one
(S)-3-((N'-((4-butoxyphenyl)ureylenyl)-L-
alaninyl)}amino-2.3-dihydro-1-methyl-5-phenyl-1H-1,4-
benzodiazepin-2-one
(S)-3-[(N'-((4-Phenoxyphenyl)ureylenyl)-L-
alaninyl)]amino-2.3-dihydro-1-methyl-5-phenyl-1H-1,4-
benzodiazepin-2-one
(S)-3-[(N'-((1-Naphthyl)ureylenyl)-L-alaninyl)]amino-
2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one
(S)-3-[(N'-((2-Biphenyl)ureylenyl)-L-alaninyl)]amino-
2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one
(S)-3-[(N'-((2-(Methylthio)phenyl)ureylenyl)-L-
alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1.4-
benzodiazepin-2-one

-663-
(S)-3-[(N'-((2-Ethylphenyl)ureylenyl)-L-
alaninyl)]amino-2.3-dihydro-1-methyl-5-phenyl-1H-1,4-
benzodiazepin-2-one
(S)-3-[(N'-((3-Methoxyphenyl)ureylenyl)-L-
alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-
benzodiazepin-2-one
(S)-3-[(N'-((3,4,5-Trimethoxyphenyl)ureylenyl)-L-
alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-
benzodiazepin-2-one
(S)-3-[(N'-((2,4,6-Trimethylphenyl)ureylenyl)-L-
alaninyl)]amino-2.3-dihydro-1-methyl-5-phenyl-1H-1,4-
benzodiazepin-2-one
(S)-3-[(N'-((2-methyl-6-t-butylphenyl)ureylenyl)-L-
alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1.4-
benzodiazepin-2-one
(S)-3-[(N'-((2-(2-thiophene-yl)ethyl)ureylenyl)-L-
alaninyl)]amino-2.3-dihydro-1-methyl-5-phenyl-1H-1,4-
benzodiazepin-2-one
3-[N'-3.5-difluorophenyl-acetamido)-L-alaninyl]-3-
amino-3.3-dihydrol-methyl-5-phenyl-1H-1.4-
benzodiazepine

-664-
3-(N'-3,5-difluorophenyl-.alpha.-azidoacetyl)-L-alaninyl]-3-
amino-2,3-dihydrol-methyl-5-phenyl-1H-1,4-
benzodiazepine
5-{N'-(cyclopropane carboxyl)-L-alaninyl}-amino-7-
methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one
5-{N'-(2-methylhexanoyl)-L-alaninyl}-amino-7-methyl-
5,7-dihydro-6H-dibenz[b.d]azepin-6-one
5-{N'-(bicyclo[2.2.1]heptane-2-carboxyl)-L-alaninyl}-
amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one
5-{N'-(N-acetyl-N-phenylglycinyl)-L-alaninyl}-amino-7-
methyl-5.7-dihydro-6H-dibenz[b.d]azepin-6-one
5-{N'-((aminoacetoxy)-3.5-difluorophenylacetyl)-L-
alaninyl}-amino-7-methyl-5,7-dihydro-6H-
dibenz[b,d]azepin-6-one
3-[N'-(3,5-difluorophenyl-.alpha.-(2-aminoacetoxylacetyl)-L-
alaninyl]-amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-
Benzodiazepin-2-one
5-{N'-(diphenylacetyl)-L-alaninyl}-amino-7-methyl-5.7-
dihydro-6H-dibenz[b.d]azepin-6-one

-665-
5-{N'-(acetyl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-
6H-dibenz[b,d]azepin-6-one
5-{N'-(2-phenoxyphenylacetyl)-L-alaninyl}-amino-7-
methyl-5.7-dihydro-6H-dibenz[b,d]azepin-6-one
5-{N'-(trans-cinnamyl)-L-alaninyl}-amino-7-methyl-5,7-
dihydro-6H-dibenz[b,d]azepin-6-one
5-{N'-(tetrahydro-2-furoyl)-L-alaninyl}-amino-7-methyl-
5.7-dihydro-6H-dibenz[b,d]azepin-6-one
5-{N'-(cyclopentanecarboxyl)L-alaninyl}-amino-7-
methyl-5,7-dihydro-6H-dibenz[b.d]azepin-6-one
5-{N'-(2-thiophenecarboxyl)-L-alaninyl}-amino-7
methyl-5.7-dihydro-6H-dibenz[b.d]azepin-6-one
5-{N'-((S)-(+)-2-hydroxy-2-phenylpropionyl)-L-
alaninyl}-amino-7-methyl-5,7-dihydro-6H-
dibenz[b.d]azepin-6-one
5-{N'-((R)-(-)-2-hydroxy-2-phenylpropionyl)-L-
alaninyl}-amino-7-methyl-5,7-dihydro-6H-
dibenz[b,d]azepin-6-one
3-[N'-(3.5-difluorophenyl-.alpha.-hydroxy-.alpha.-methylacetyl)-L-
alaninyl]-amino-2,3-dihydro-1-methyl-5-(2-
fluorophenyl)-1H-1,4-Benzodiazepin-2-one

-666-
5-{N'-(benzenesulfonyl)-L-alaninyl}-amino-7-methyl-
5,7-dihydro-6H-dibenz[b,d]azepin-6-one
3-[N'-(3,5-difluorophenyl-.alpha.-hydroxy-.alpha.-methylacetyl)-L-
alaninyl]-amino-2,3-dihydro-1-methyl-5-(2-
fluorophenyl)-1H-1,4-Benzodiazepin-2-one
5-{N'-(3-fluorobenzenesulfonyl)-L-alaninyl}-amino-7-
methyl-5.7-dihydro-6H-dibenz[b.d]azepin-6-one
5-(S)-(N'-((Butylureylenyl)-L-alaninyl)-amino-7-methyl-
5,7-dihydro-6H-dibenz[b,d]azepin-6-one
5-(S)-(N'-((Benzylureylenyl)-L-alaninyl)-amino-7-
methyl-5.7-dihydro-6H-dibenz[b.d]azepin-6-one
5-{N'-(benzylsulfonyl)-L-alaninyl}-amino-7-methyl-5.7-
dihydro-6H-dibenz[b.d]azepin-6-one
5-(S)-(N'-((Ethylureylenyl)-L-alaninyl)-amino-7-methyl-
5.7-dihydro-6H-dibenz[b,d]azepin-6-one
5-(S)-(N'-((Phenethylureylenyl)-L-alaninyl)-amino-7-
methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one
5-(S)-(N'-(3.5-difluorophenyl-.alpha.-aminoacetyl)-L-
valinyl)-amino-7-methyl-5,7-dihydro-6H-
dibenz[b,d]azepin-6-one

-667-
5-(S)-(N'-(3,5-difluorophenyl-.alpha.-aminoacetyl)-L-tert-
leucinyl-amino-7-methyl-5,7-dihydro-6H-
dibenz[b,d]azepin-6-one
5-{N'-(butylsulfonyl)-L-alaninyl}-amino-7-methyl-5.7-
dihydro-6H-dibenz[b.d]azepin-6-one
5-{N'-(octylsulfonyl)-L-alaninyl}-amino-7-methyl-
5,7-dihydro-6H-dibenz[b,d]azepin-6-one
5-(S)-(N'-((2-(thiophen-2-yl)ethylureylenyl)-L-
alaninyl)-amino-7-methyl-5,7-dihydro-6H-
dibenz[b,d]azepin-6-one
5-(S)-(N'-(3,5-difluorophenyl-.alpha.-aminoacetyl)-L-
alaninyl-amino-7-methyl-5,7-dihydro-6H-
dibenz[b,d]azepin-6-one
5-(S)-(N'-(L-valinyl)-L-alaninyl-)]amino-2.3-dihydro-1-
methyl-5-phenyl-1H-1.4-benzodiazepin-2-one
5-(R/S)-(N'-(2-hydroxy-2-phenethylureylenyl)-L-
alaninyl)-amino-7-methyl-5.7-dihydro-6H-
dibenz[b,d]azepin-6-one
5-(S)-(N'-((hexylureylenyl)-L-alaninyl)-amino-7-methyl-
5.7-dihydro-6H-dibenz[b.d]azepin-6-one

-668-
5-(S)-(N'-((cyclohexylureylenyl)-L-alaninyl)-amino-7-
methyl-5.7-dihydro-6H-dibenz[b,d]azepin-6-one
5-(S)-(N'-((isopropylureylenyl)-L-alaninyl)-amino-7-
methyl-5.7-dihydro-6H-dibenz[b,d]azepin-6-one
5-(S)-(N'-((tert-butylureylenyl)-L-alaninyl)-amino-7-
methyl-5.7-dihydro-6H-dibenz[b.d]azepin-6-one
5-(S)-(N'-((1-adamantylureylenyl)-L-alaninyl)-amino-7-
methyl-5,7-dihydro-6H-dibenz[b.d]azepin-6-one
5-(S)-(N'-((2-methylpropylureylenyl)-L-alaninyl)-amino-
7-methyl-5.7-dihydro-6H-dibenz[b.d]azepin-6-one
5-(S)-(N'-(R/S)-3-hydroxy-3-phenylethylureylenyl)-L-
alaninyl)-amino-7-methyl-5.7-dihydro-6H-
dibenz[b,d]azepin-6-one
5-(S)-(N'-((3-methylbutylureylenyl)-L-alaninyl)-amino-
7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one
5-(S)-((N'-(S)-1-hydroxymethyl-3-
methylbutylureylenyl)-L-alaninyl)-amino-7-methyl-5.7-
dihydro-6H-dibenz[b,d]azepin-6-one
5-(S)-((N'-(1S)-(2S)-1-hydroxymethyl-2-
methylbutylureylenyl)-L-alaninyl)-amino-7-methyl-5.7-
dihydro-6H-dibenz[b,d]azepin-6-one

-669-
5-(S)-(N'-(3-chloropropylureylenyl)-L-alaninyl)-amino-
7-methyl-5.7-dihydro-6H-dibenz[b,d]azepin-6-one
5-(S)-(N'-octylureylenyl)-L-alaninyl)-amino-7-methyl-
5,7-dihydro-6H-dibenz[b,d]azepin-6-one
5-(S)-(N'-1,1,3,3-tetramethylbutylureylenyl)-L-
alaninyl)-amino-7-methyl-5.7-dihydro-6H-
dibenz[b,d]azepin-6-one
5-(S)-(N'-(R/S)-1-methylbutylureylenyl)-L-alaninyl)-
amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one
5-(S)-((N'-(R/S)-1-hydroxymethylbutylureylenyl)-L-
alaninyl)-amino-7-methyl-5.7-dihydro-6H-
dibenz[b,d]azepin-6-one
5-(S)-((N'-(R/S)-1,3-dimethylbutylureylenyl)-L-
alaninyl)-amino-7-methyl-5,7-dihydro-6H-
dibenz[b.d]azepin-6-one
S-(S)-((N'-(R)-1-hydroxymethyl-3-
methylbutylureylenyl)-L-alaninyl)-amino-7-methyl-5.7-
dihydro-6H-dibenz[b,d)azepin-6-one
5-(S)-((N'-(R/S)-2-methylbutylureylenyl)-L-alaninyl)-
amino-7-methyl-5.7-dihydro-6H-dibenz[b,d]azepin-6-one

-670-
5-(S)-(N'-morpholinoureylenyl)-L-alaninyl)-amino-7-
methyl-5.7-dihydro-6H-dibenz[b,d]azepin-6-one
5-(S)-(N'-(2-(2-hydroxyethoxy)-ethylureylenyl)-L-
alaninyl)-amino-7-methyl-5,7-dihydro-6H-
dibenz[b,d]azepin-6-one
5-(S)-(N'-piperidinylureylenyl)-L-alaninyl)-amino-7-
methyl-5.7-dihydro-6H-dibenz[b,d]azepin-6-one
5-(S)-(N'-(N"-methyl-N"-butylureylenyl)-L-alaninyl)-
amino-7-methyl-5,7-dihydro-6H-dibenz(b,d]azepin-6-one
5-(S)-(N'-(1-(R/S)-hydroxymethylcyclopentylureylenyl)-
L-alaninyl)-amino-7-methyl-5.7-dihydro-6H-
dibenz[b.d]azepin-6-one
5-(S)-(N'-(4-hydroxybutylureylenyl)-L-alaninyl)-amino-
7-methyl-5.7-dihydro-6H-dibenz[b,d]azepin-6-one
5-(S)-(N'-(1-(RlS)-hydroxymethyl-2-
methylpropylureylenyl)-L-alaninyl)-amino-7-methyl-5,7-
dihydro-6H-dibenz[b.d]azepin-6-one
5-(S)-(N'-(2-(R/S)-hydroxycyclohexylureylenyl)-L-
alaninyl)-amino-7-methyl-5,7-dihydro-6H-
dibenz[b,d]azepin-6-one

-671-
5-(S)-(N'-(isopropyl-hydroxyureylenyl)-L-alaninyl)-
amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one
5-(S)-(N'-(benzyl-hydroxyureylenyl)-L-alaninyl)-amino-
7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one
5-(S)-(N'-(valinyl)-L-alaninyl-amino-7-methyl-5,7-
dihydro-6H-dibenz[b.d]azepin-6-one
5-(S)-(N'-(phenylglycinyl)-L-alaninyl-amino-7-methyl-
5,7-dihydro-6H-dibenz[b,d]azepin-6-one
5-(S)-(N'-(3,5-difluorophenyl-.alpha.-aminoacetyl)-L-
alaninyl-amino-7-methyl-5.7-dihydro-6H-
dibenz[b,d]azepin-6-one
5-(S)-(N'-(3.5-difluoro phenylglycinyl)-L-alaninyl-
amino-7-methyl-5,7-dihydro-6H-dibenz[b.d]azepin-6-one
5-(S)-(N'-(threonine)-L-alaninyl-amino-7-methyl-5,7-
dihydro-6H-dibenz[b,d]azepin-6-one
5-(S)-(N'-(D-valinyl)-L-alaninyl-amino-7-methyl-5.7-
dihydro-6H-dibenz[b,d]azepin-6-one
5-(S)-(N'-(phenylglycinyl)-L-alaninyl-amino-7-methyl-
5,7-dihydro-6H-dibenz[b,d]azepin-6-one

-672-
5-(S)-(N"-(S)-phenylglycinyl)-N'-L-alaninyl]amino-1-
methyl-5-phenyl-1.3,4,5-tetrahydro-2H-1,5-
benzodiazepin-2-one
5-(S)-[(N"-L-valinyl)-N'-L-alaninyl]amino-1-methyl-5-
phenyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-2-one
5-(S)-(N'-(thiomorpholinylureylenyl)-L-alaninyl)-amino-
7-methyl-5,7-dihydro-6H-dibenz[b.d]azepin-6-one
5-(S)-(N'-(2(R/S)-hydroxybutylureylenyl)-L-alaninyl)-
amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one
5-(S)-(N'-2,2,2-trifluoroethylureylenyl)-L-alaninyl)-
amino-7-methyl-5,7-dihydro-6H-dibenz[b.d]azepin-6-one
5-(S)-(N'-(4R/S)-cyclohexylureylenyl)-L-alaninyl)-
amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one
5-(S)-(N'-(1R)-hydroxymethyl-3-
methylthiopropylureylenyl)-L-
alaninyl)-amino-7-methyl-5.7-dihydro-6H-
dibenz[b,d]azepin-6-one

-673-
5-{N'-(2-hydroxy-2-methylpropionyl)-L-alaninyl}-
amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one
5-{N'-(2-hydroxy-2-methylbutanoyl)-L-alaninyl}-amino-
7-methyl-5.7-dihydro-6H-dibenz[b,d]azepin-6-one
3-[N'-(2-thioacetyl-3-methyl-butanoyl)-L-alaninyl]-
amino-2.3-dihydro-1-methyl-5-phenyl-1H-1,4-
benzodiazepin-2-one
5-(S)-[N'-(2-thioacetyl-3-methyl-butanoyl)-L-alaninyl]-
amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one
5-(S)-[N'-(L-Trifluoromethylphenylglycinyl)-L-alaninyl]
-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one
5-(S)-[N'-(L-N-methyl-valinyl)-L-alaninyl]
-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one
5-(S)-(N"-(3.5-difluorophenylglycinyl)-N'-L-
alaninyl]amino-2.4-dioxo-1-methyl-5-phenyl-2.3,4,5-
tetrahydro-2H-1,5-benzodiazepine hydrochloride
5-(S)-(N"-(3,5-difluorophenylglycinyl)-N'-L-
alaninyl]amino-2,4-dioxo-1-methyl-5-phenyl-2,3,4,5-
tetrahydro-2H-1.5-benzodiazepine hydrochloride

-674-
5-(S)-[N'-(Hexafluorovalinyl)-L-alaninyl]-amino-7-
methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one
3-[N'-(2-mercapto-3-methyl-butanoyl)-L-alaninyl]-
amino-2,3-dihydro-1-methyl-5-phenyl-1 H- 1,
4-benzodiazepin-2-one
and
5-(S)-[N'-(2-mercapto-3-methylbutanoyl)-L-alaninyl]-
amino-7-methyl-5.7-dihydro-6H-dibenz[b,d]azepin-6-one.
85. The compound of claim 58, wherein the compound is of
Formula I.
86. The compound of claim 85, wherein each R15 is H.
87. The compound of claim 86, wherein the cyclic group
defined by W and -C(H)pC(=X)-, forms a lactam ring
of the formula:

-675-
<IMGS>

-676-
wherein p is zero or one, T is selected from the group consisting of
alkylene, substituted alkylene, alkenylene, substituted alkenylene,
-(R21Z)q R21- and -ZR21 , where Z is a substituent selected from
the group consisting of -O-, -S- and >NR20, each R20 is
independently selected from the group consisting of alkyl, alkenyl,
alkynyl, cycloalkyl, cycloalkenyl, substituted alkyl, substituted
alkenyl, substituted alkynyl, aryl, heteroaryl and heterocyclic, each
R21 is independently alkylene, substituted alkylene, alkenylene and
substituted alkenylene with the proviso that when Z is -O- or -S-,
any unsaturation in the alkenylene and substituted alkenylene does
not involve participation of the -O- or -S-, and q is an integer of
from 1 to 3.
88. The compound of claim 87 wherein the lactam ring is
selected from the group consisting of

-677-
<IMGS>

-678-
<IMGS>

-679-
<IMG>
wherein A-B is selected from the group consisting of alkylene.
alkenylene, substituted alkylene, substituted alkenylene
and-N=CH-; Q is oxygen or sulfur; each V is independently selected
from the group consisting of hydroxy, acyl, acyloxy, alkyl,
substituted alkyl, alkoxy, substituted alkoxy, alkenyl, substituted
alkenyl, alkynyl, substituted alkynyl. amino, substituted amino.

-680-
aminoacyl, alkaryl, aryl. aryloxy, carboxyl, carboxylalkyl, cyano,
halo, nitro, heteroaryl, thioalkoxy, substituted thioalkoxy, and
trihalomethyl: each Ra is independently selected from the group
consisting of alkyl, substituted alkyl, alkoxy, substituted alkoxy,
amino, substituted amino, carboxyl, carboxyl alkyl, cyano, and
halo; Rb is selected from the group consisting of alkyl, substituted
alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl,
acyl, aryl, heteroaryl, and heterocyclic: Rc is selected from the
group consisting of alkyl, substituted alkyl, alkenyl, substituted
alkenyl, aryl, heteroaryl, heterocyclic, thioalkoxy, substituted
amino, cycloalkyl, and substituted cycloalkyl; t is an integer from 0
to 4; t is an integer from 0 to 3; and w is an integer from 0 to 3.
89. The compound of claim 88, wherein R1 is selected from
the group consisting of
(a) alkyl
(b) phenyl.
(c) a substituted phenyl group of the formula:
<IMG>

-681-
wherein Rc is selected from the group consisting of acyl, alkyl,
alkoxy, alkylalkoxy, azido. cyano, halo, hydrogen, substituted
amino, nitro, trihalomethyl, thioalkoxy,
and wherein Rb and Rc are fused to form a heteroaryl or
heterocyclic ring with the phenyl ring wherein the heteroaryl or
heterocyclic ring contains from 3 to 8 atoms of which from 1 to 3
are heteroatoms independently selected from the group consisting of
oxygen, nitrogen and sulfur
Rb and Rb are independently selected from the group consisting
of hydrogen, halo, nitro, cyano, trihalomethyl, alkoxy, and
thioalkoxy with the proviso that when Rc is hydrogen, then Rb and
Rb are either both hydrogen or both substituents other than
hydrogen.
(d) 2-naphthyl.
(e) 2-naphthyl substituted at the 4, 5, 6, 7 and/or 8 positions
with 1 to 5 substituents selected from the group consisting alkyl,
alkoxy, halo, cyano, nitro, trihalomethyl, thioalkoxy, aryl, and
heteroaryl.
(f) heteroaryl, and
(g) substituted heteroaryl containing 1 to 3 substituents selected
from the group consisting of alkyl, alkoxy, aryl, aryloxy, cyano,
halo, nitro, heteroaryl, thioalkoxy, thioaryloxy provided that said
substituents are not ortho to the heteroaryl attachment to the -NH
group.
90. The compound of claim 89 wherein R1 is selected from
the group consisting of phenyl, 1-naphthyl, 2-naphthyl, n-butyl,
2-chlorophenyl, 2-fluorophenyl, 2-bromophenyl, 2-hydroxyphenyl,

-682-
2-nitrophenyl, 2-methylphenyl. 2-methoxyphenyl,
2-phenoxyphenyl,
2-trifluoromethylphenyl, 4-fluorophenyl, 4-chlorophenyl,
4-bromophenyl, 4-nitrophenyl, 4-methylphenyl, 4-hydroxyphenyl.
4-methoxyphenyl, 4-ethoxyphenyl, 4-butoxyphenyl,
4-iso-propylphenyl, 4-phenoxyphenyl, 4-trifluoromethylphenyl,
4-hydroxymethylphenyl, 3-methoxyphenyl,
3-hydroxyphenyl, 3-nitrophenyl, 3-fluorophenyl, 3-chlorophenyl,
3-bromophenyl. 3-phenoxyphenyl, 3-thiomethoxyphenyl.
3-methylphenyl, 3-trifluoromethylphenyl, 2,3-dichlorophenyl, 2,
3-difluorophenyl. 2,4-dichlorophenyl, 2,5-dimethoxyphenyl, 3.
4-dichlorophenyl. 3,4-difluorophenyl, 3,4-methylenedioxyphenyl,
3,4-dimethoxyphenyl, 3,5-difluorophenyl, 3,5-dichlorophenyl. 3,
5-di-(trifluoromethyl)phenyl, 3.5-dimethoxyphenyl, 2,
4-dichlorophenyl, 2,4-difluorophenyl 2,6-difluorophenyl. 3,4,
5-trifluorophenyl. 3,4.5-trimethoxyphenyl, 3,4,
5-tri-(trifluoromethyl)phenyl, 2,4.6-trifluorophenyl, 2,4.
6-trimethylphenyl, 2.4,6-tri-(trifluoromethyl)phenyl, 2,3,
5-trifluorophenyl, 2.4,5-trifluorophenyl, 2,5-difluorophenyl. 2-fluoro-
3-trifluoromethylphenyl. 4-fluoro-2-trifluoromethylphenyl. 2-fluoro-
4-trifluoromethylphenyl, 4-benzyloxyphenyl, 2-chloro-6-
fluorophenyl, 2-fluoro-6-chlorophenyl, 2,3,4,5.
6-pentafluorophenyl. 2.5-dimethylphenyl,
4-phenylphenyl. 2-fluoro-3-trifluoromethylphenyl, adamantyl.
benzyl. 2-phenylethyl, 3-phenyl-n-propyl, 4-phenyl-n-butyl, methyl,
ethyl, n-propyl, iso-propyl, iso-butyl, sec-butyl, tert-butyl,
n-pentyl, iso-valeryl, n-hexyl, cyclopropyl, cyclobutyl, cyclohexyl,
cyclopentyl, cyclopent-1-enyl, cyclopent-2-enyl, cyclohex-1-enyl, -
CH2-cyclopropyl. -CH2-cyclobutyl, -CH2-cyclohexyl. -CH2-

-683-
cyclopentyl. -CH2CH2-cyclopropyl, -CH2CH2-cyclobutyl,
CH2CH2-cyclohexyl, -CH2CH2-cyclopentyl, pyrid-2-yl, pyrid-3- yl,
pyrid-4-yl, fluoropyridyls, chloropyridyls, thien-2-yl, thien-3-yl,
benzothiazol-4-yl, 2-phenylbenzoxazol-5-yl. furan-2-yl, benzofuran-2-yl,
thionaphthen-2-yl, thionaphthen-3-yl, thionaphthen-4-yl,
2-chlorothiophen-5-yl, 3-methylisoxazol-5-yl, 2-(thiophenyl)thien-5-yl,
6-methoxythionaphthen-2-yl, 3-phenyl-1,2,4-thiooxadiazol-5-yl,
2-phenyloxazol-4-yl, indol-3-yl, 1-phenyl-tetrazol-5-yl, allyl,
2-(cyclohexyl)ethyl, (CH3)2CH=CHCH2CH2CH(CH3),-C
(O)CH2-, thien-2-yl-methyl, 2-(thien-2-yl)ethyl, 3-(thien-2-yl)-n-
propyl, 2-(4-nitrophenyl)ethyl, 2-(4-methoxyphenyl)ethyl,
norboran-2-yl, (4-methoxyphenyl)methyl,
(2-methoxyphenyl)methyl, (3-methoxyphenyl)methyl, (3-hydroxy
phenyl)methyl. (4-hydroxyphenyl)methyl,
(4-methoxyphenyl)methyl, (4-methylphenyl)methyl,
(4-fluorophenyl)methyl, (4-fluorophenoxy)methyl, (2,
(4-dichlorophenoxy)ethyl, (4-chlorophenyl)methyl,
(2-chlorophenyl)methyl, (1-phenyl)ethyl, (1-(p-chlorophenyl)ethyl,
(1-trifluoromethyl)ethyl, (4-methoxyphenyl)ethyl. CH3OC(O)
CH2-benzylthiomethyl, 5-(methoxycarbonyl)-n-pentyl,
3-(methoxycarbonyl)-n-propyl, indan-2-yl, (2-methylbenzofuran-3-yl),
methoxymethyl, CH3CH=CH-, CH3CH2CH=CH-,
(4-chlorophenyl)C(O)CH2-,(4-fluorophenyl)C(O)CH2-, (4-methoxy
phenyl)C(O)CH2-, 4-(fluorophenyl)-NHC(O)CH2-, 1-phenyl-n-
butyl, (phenyl)2CHNHC(O)CH2CH2-, (CH3)2NC(O)CH2-(phenyl)2
CHNHC(O)CH2CH2-, methylcarbonylmethyl, (2.4-
dimethylphenyl)C(O)CH2-, 4-methoxyphenyl-C(O)CH2-, phenyl-
C(O)CH2-, CH3C(O)N(phenyl)-, ethenyl, methylthiomethyl,
(CH3)3CNHC(O)CH2-, 4-fluorophenyl-C(O)CH2-,

-684-
diphenylmethyl, phenoxymethyl. 3.4-methylenedioxyphenyl-CH2-,
benzo[b]thiophen-3-yl, (CH3)3COC(O)NHCH2-, traps-styryl,
H2NC(O)CH2CH2-. 2-trifluoromethylphenyl-C(O)CH2,
phenylC(O)NHCH(phenyl)CH2-, mesityl, CH3CH(=NHOH)
Ch2-,4-CH3-phenyl-NHC(O)CH2CH2-, phenyl-C(O)CH(phenyl)
CH2,(CH3)2CHC(O)NHCH(phenyl)-, CH3CH2OCH2-,
CH3OC(O)CH(CH3)(CH2)3-. 2,2.2-trifluoroethyl,
1-(trifluoromethyl)ethyl, 2-CH3-benzofuran-3-yl: 2-(2,
4-dichlorophenoxy)ethyl, SO2CH2-, 3-cyclohexyl-n-propyl,
CF3CH2CH2CH2- and N-pyrrolidinyl.
91. The compound of Claim 90 where each R2 is
independently selected from the group consisting of alkyl,
substituted alkyl, alkenyl, cycloalkyl, aryl, heteroaryl and
heterocyclic.
92. The compound of Claim 91 wherein R2 is selected from
the group consisting of methyl, ethyl, n-propyl. iso-propyl, n-butyl.
iso-butyl, sec-butyl, tert-butyl, -CH2CH(CH2CH3)2, 2-methyl-n-
butyl, 6-fluoro-n-hexyl, phenyl, benzyl, cyclohexyl, cyclopentyl.
cycloheptyl, allyl, iso-but-2-enyl. 3-methylpentyl, -CH2-
cyclopropyl. -CH2-cyclohexyl, -CH2CH2-cyclopropyl, -CH2CH2-
cyclohexyl, -CH2-indol-3-yl, p-(phenyl)phenyl, o-fluorophenyl,
m-fluorophenyl, p-fluorophenyl, m-methoxyphenyl, p-methoxyphenyl,
phenethyl, benzyl, m-hydroxybenzyl, p-hydroxybenzyl,
p-nitrobenzyl, m-trifluoromethylphenyl, p-(CH3)2NCH2CH2CH2O
benzyl, p-(CH3)3COC(O)CH2O-benzyl, p-(HOOCCH2O)-benzyl,
2-aminopyrid-6-yl, p-(N-morpholino-CH2CH2O)-benzyl, -
CH2CH2C(O)NH2, -CH2-imidazol-4-yl, -CH2-(3-

-685-
tetrahydrofuranyl), -CH2-thiophen-2-yl, -CH2(1-methyl)
cyclopropyl, -CH2-thiophen-3-yl. thiophen-3-yl, thiophen-2-yl,
-CH2-C(O)O-t-butyl. -CH2-C(CH3)3, -CH2CH(CH2CH3)2,
2-methylcyclopentyl, cyclohex-2-enyl, -CH[CH(CH3)2]COOCH3,
CH2CH2N(CH3)2, -CH2C(CH3)=CH2, -CH2CH=CHCH3 (cis
and trans). -CH2OH. -CH(OH)CH3, -CH(O-t-butyl)CH3, -
CH2OCH3. -(CH2)4NH-Boc, -(CH2)4NH2, -CH2-pyridyl, pyridyl,
-CH2-naphthyl. -CH2-(N-morpholino), p-(N-morpholino-
CH2CH2O)-benzyl, benzo[b]thiophen-2-yl,
5-chlorobenzo[b]thiophen-2-yl. 4,5,6,7-tetrahydrobenzo[b]thiophen-2-
yl, benzo[b]thiophen-3-yl, 5-chlorobenzo[b]thiophen-3-yl,
benzo[b]thiophen-5-yl, 6-methoxynaphth-2-yl. -CH2CH2SCH3.
thien-2-yl, and thien-3-yl.
93. The compound of Claim 92 wherein Rb is selected from
the group consisting of alkyl, substituted alkyl, cycloalkyl and aryl.
94. The compound of Claim 93 wherein R2 is methyl.
95. The compound of Claim 94 wherein R1 is alkyl.
96. The compound of Claim 95 wherein Rb is alkyl.
97. The compound of Claim 58 wherein the compounds are
compounds of Formula VI.
9g. The compounds of Claim 97 wherein each R15 is H.
99. The compounds of Claim 98 wherein the cyclic group

-686-
defined by W and -C(H)pC(=X)-, forms a lactam ring of the
formula:
<IMG>
or
<IMG>

-687-
wherein p is zero or one, T is selected from the group consisting of
alkylene, substituted alkylene, alkenylene, substituted alkenylene,
(R21Z)qR21- and -ZR21 , where Z is a substituent selected from
the group consisting of -O-. -S- and > NR20, each R20 is
independently selected from the group consisting of alkyl, alkenyl,
alkynyl, cycloalkyl. cycloalkenyl, substituted alkyl, substituted
alkenyl, substituted alkynyl, aryl, heteroaryl and heterocyclic, each
R21 is independently alkylene, substituted alkylene, alkenylene and
substituted alkenylene with the proviso that when Z is -O- or -S-,
any unsaturation in the alkenylene and substituted alkenylene does
not involve participation of the -O- or -S-, and q is an integer of
from 1 to 3.
100. The compound of claim 87 wherein the lactam ring is
selected from the group consisting of

-688-
<IMGS>

-689-
<IMGS>

-690-
<IMGS>
and
<IMGS>
wherein A-B is selected from the group consisting of alkylene,
alkenylene, substituted alkylene, substituted alkenylene and -
N=CH-; Q is oxygen or sulfur: each V is independently selected
from the group consisting of hydroxy, acyl, acyloxy, alkyl,
substituted alkyl, alkoxy, substituted alkoxy, alkenyl, substituted
alkenyl, alkynyl, substituted alkynyl, amino, substituted amino,
aminoacyl, alkaryl, aryl, aryloxy, carboxyl, carboxylalkyl, cyano,
halo, nitro, heteroaryl, thioalkoxy, substituted thioalkoxy, and
trihalomethyl; each Ra is independently selected from the group
consisting of alkyl, substituted alkyl, alkoxy, substituted alkoxy,
amino, substituted amino, carboxyl, carboxyl alkyl, cyano, and
halo; Rb is selected from the group consisting of alkyl, substituted
alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl,
acyl, aryl, heteroaryl, and heterocyclic; Rc is selected from the
group consisting of alkyl, substituted alkyl, alkenyl, substituted

-691-
alkenyl, aryl, heteroaryl, heterocyclic. substituted amino,
cycloalkyl, and substituted cycloalkyl; t is an integer from 0 to 4; t
is an integer from 0 to 3; and w is an integer from 0 to 3.
101. The compound of Claim 100 wherein R1 is selected
from the group consisting of
(a) alkyl
(b) phenyl,
(c) a substituted phenyl group of the formula:
<IMG>
wherein Rc is selected from the group consisting of acyl, alkyl,
alkoxy, alkylalkoxy, azido, cyano, halo, hydrogen, substituted
amino, nitro, trihalomethyl, thioalkoxy,
and wherein Rb and Rc are fused to form a heteroaryl or
heterocyclic ring with the phenyl ring wherein the heteroaryl or
heterocyclic ring contains from 3 to 8 atoms of which from 1 to 3
are heteroatoms independently selected from the group consisting of
oxygen, nitrogen and sulfur

-692-
Rb and Rb are independently selected from the group consisting
of hydrogen. halo, nitro. cyano, trihalomethyl, alkoxy, and
thioalkoxy with the proviso that when Rc is hydrogen, then Rb and
Rb are either both hydrogen or both substituents other than
hydrogen,
(d) 2-naphthyl,
(e) 2-naphthyl substituted at the 4, 5, 6, 7 and/or 8 positions
with 1 to 5 substituents selected from the group consisting alkyl,
alkoxy, halo, cyano, nitro, trihalomethyl, thioalkoxy, aryl, and
heteroaryl,
(f) heteroaryl, and
(g) substituted heteroaryl containing 1 to 3 substituents selected
from the group consisting of alkyl, alkoxy, aryl, aryloxy, cyano,
halo, nitro, heteroaryl, thioalkoxy, thioaryloxy provided that said
substituents are not ortho to the heteroaryl attachment to the -NH
group.
102. The compound of Claim 101 wherein R1 is selected
from the group consisting of phenyl, 1-naphthyl, 2-naphthyl,
n-butyl, 2-chlorophenyl, 2-fluorophenyl, 2-bromophenyl,
2-hydroxyphenyl, 2-nitrophenyl, 2-methylphenyl, 2-methoxyphenyl,
2-phenoxyphenyl, 2-trifluoromethylphenyl, 4-fluorophenyl,
4-chlorophenyl, 4-bromophenyl, 4-nitrophenyl. 4-methylphenyl,
4-hydroxyphenyl, 4-methoxyphenyl, 4-ethoxyphenyl,
4-butoxyphenyl, 4-iso-propylphenyl, 4-phenoxyphenyl,
4-trifluoromethylphenyl, 4-hydroxymethylphenyl.
3-methoxyphenyl. 3-hydroxyphenyl, 3-nitrophenyl, 3-fluorophenyl,
3-chlorophenyl, 3-bromophenyl, 3-phenoxyphenyl,

-693-
3-thiomethoxyphenyl, 3-methylphenyl. 3-trifluoromethylphenyl,
2,3-dichlorophenyl, 2,3-difluorophenyl, 2,4-dichlorophenyl,
2,5-dimethoxyphenyl, 3,4-dichlorophenyl. 3,4-difluorophenyl,
3,4-methylenedioxyphenyl, 3,4-dimethoxyphenyl,
3.5-difluorophenyl, 3,5-dichlorophenyl,
3,5-di-(trifluoromethyl)phenyl, 3.5-dimethoxyphenyl,
2,4-dichlorophenyl, 2,4-difluorophenyl, 2,6-difluorophenyl,
3,4,5-trifluorophenyl, 3,4,5-trimethoxyphenyl,
3,4,5-tri-(trifluoromethyl)phenyl. 2,4,6-trifluorophenyl,
2,4,6-trimethylphenyl, 2,4,6-tri-(trifluoromethyl)phenyl,
2,3,5-trifluorophenyl, 2,4,5-trifluorophenyl, 2,5-difluorophenyl,
2-fluoro-3-trifluoromethylphenyl, 4-fluoro-2-trifluoromethylphenyl,
2-fluoro-4-trifluoromethylphenyl, 4-benzyloxyphenyl,
2-chloro-6-fluorophenyl, 2-fluoro-6-chlorophenyl,
2,3.4.5,6-pentafluorophenyl. 2,5-dimethylphenyl, 4-phenylphenyl,
2-fluoro-3-trifluoromethylphenyl, adamantyl, benzyl,
2-phenylethyl. 3-phenyl-n-propyl, 4-phenyl-n-butyl, methyl, ethyl,
n-propyl, iso-propyl, iso-butyl, sec-butyl, tent-butyl, n-pentyl,
iso-valeryl, n-hexyl, cyclopropyl, cyclobutyl, cyclohexyl, cyclopentyl.
cyclopent-1-enyl, cyclopent-2-enyl, cyclohex-1-enyl, -CH2-
cyclopropyl, -CH2-cyclobutyl, -CH2-cyclohexyl, -CH2-cyclopentyl,
-CH2CH2-cyclopropyl, -CH2CH2-cyclobutyl, -CH2CH2-cyclohexyl,
-CH2CH2-cyclopentyl, pyrid-2-yl, pyrid-3-yl, pyrid-4-yl,
fluoropyridyls, chloropyridyls, thien-2-yl, thien-3-yl,
benzothiazol-4-yl, 2-phenylbenzoxazol-5-yl, furan-2-yl, benzofuran-2-yl,
thionaphthen-2-yl, thionaphthen-3-yl, thionaphthen-4-yl,
2-chlorothiophen-5-yl, 3-methylisoxazol-5-yl, 2-(thiophenyl)thien-5-yl,
6-methoxythionaphthen-2-yl, 3-phenyl-1,2,4-thiooxadiazol-5-yl,
2-phenyloxazol-4-yl, indol-3-yl, 1-phenyl-tetrazol-5-y1, allyl,

-694-
2-(cyclohexyl)ethyl, (CH3)2CH=CHCH2CH2CH(CH3),
C(O)CH2-, thien-2-yl-methyl, 2-(thien-2-yl)ethyl, 3-(thien-2-yl)-n-
propyl, 2-(4-nitrophenyl)ethyl, 2-(4-methoxyphenyl)ethyl,
norboran-2-yl, (4-methoxyphenyl)methyl,
(2-methoxyphenyl)methyl, (3-methoxyphenyl)methyl, (3-hydroxy
phenyl)methyl, (4-hydroxyphenyl)methyl,
(4-methoxyphenyl)methyl, (4-methylphenyl)methyl,
(4-fluorophenyl)methyl, (4-fluorophenoxy)methyl,
(2,4-dichlorophenoxy)ethyl, (4-chlorophenyl)methyl,
(2-chlorophenyl)methyl, (1-phenyl}ethyl,
(1-(p-chlorophenyl)ethyl, (1-trifluoromethyl)ethyl,
(4-methoxyphenyl)ethyl, CH3OC(O)CH2-, benzylthiomethyl,
5-(methoxycarbonyl)-n-pentyl, 3-(methoxycarbonyl)-n-propyl,
indan-2-yl, (2-methylbenzofuran-3-yl), methoxymethyl,
CH3CH=CH-, CH3CH2CH=CH-, (4-chlorophenyl)C(O)CH2-,
(4-fluorophenyl)C(O)CH2-, (4-methoxy phenyl)C(O)CH2-,
4-(fluorophenyl)-NHC(O)CH2-, 1-phenyl-n-butyl,
(phenyl)2CHNHC(O)CH2CH2-, (CH3)2NC(O)CH2-,
(phenyl)2CHNHC(O)CH2CH2-, methylcarbonylmethyl,
(2,4-dimethylphenyl)C(O)CH2-, 4-methoxyphenyl-C(O)CH2-,
phenyl-C(O)CH2-, CH3C(O)N(phenyl)-, ethenyl,
methylthiomethyl, (CH3)3CNHC(O)CH2-, 4-fluorophenyl-
C(O)CH2-, diphenylmethyl, phenoxymethyl, 3,4-
methylenedioxyphenyl-CH2-, benzo[b]thiophen-3-yl,
(CH3)3COC(O)NHCH2-, trans-styryl, H2NC(O)CH2CH2-,
2-trifluoromethylphenyl-C(O)CH2, phenylC(O)NHCH(phenyl)CH2-
mesityl, CH3CH(=NHOH)CH2-, 4-CH3-phenyl-
NHC(O)CH2CH2-, phenyl-C(O)CH(phenyl)CH2-,

-695-
(CH3)2CHC(O)NHCH(phenyl)-, CH3CH2OCH2-,
CH3OC(O)CH(CH3)(CH2)3-, 2,2,2-trifluoroethyl,
1-(trifluoromethyl)ethyl, 2-CH3-benzofuran-3-yl,
2-(2,4-dichlorophenoxy)ethyl, SO2CH2-, 3-cyclohexyl-n-propyl,
CF3CH2CH2CH2- and N-pyrrolidinyl.
103. The compound according to Claim 102 where each R2
is independently selected from the group consisting of alkyl,
substituted alkyl, alkenyl, cycloalkyl, aryl, heteroaryl and
heterocyclic.
104. The compound according to Claim 103 wherein R2 is
selected from the group consisting of methyl, ethyl, n-propyl,
iso-propyl, n-butyl, iso-butyl, sec-butyl, tert-butyl,
-CH2CH(CH2CH3)2, 2-methyl-n-butyl, 6-fluoro-n-hexyl, phenyl,
benzyl, cyclohexyl, cyclopentyl, cycloheptyl, allyl, iso-but-2-enyl,
3-methylpentyl, -CH2-cyclopropyl, -CH2-cyclohexyl.
-CH2CH2-cyclopropyl. -CH2CH2-cyclohexyl, -CH2-indol-3-yl,
p-(phenyl)phenyl, o-fluorophenyl, m-fluorophenyl, p-fluorophenyl,
m-methoxyphenyl, p-methoxyphenyl, phenethyl, benzyl,
m-hydroxybenzyl, p-hydroxybenzyl, p-nitrobenzyl,
m-trifluoromethylphenyl, p-(CH3)2NCH2CH2CH2O-benzyl,
p-(CH3)3COC(O)CH2O-benzyl, p-(HOOCCH2O)-benzyl,
2-aminopyrid-6-yl, p-(N-morpholino-CH2CH2O)-benzyl.
-CH2CH2C(O)NH2, -CH2-imidazol-4-yl,
-CH2-(3-tetrahydrofuranyl), -CH2-thiophen-2-yl, -CH2(1-
methyl)cyclopropyl, -CH2-thiophen-3-yl, thiophen-3-yl, thiophen-2-yl,
-CH2-C(O)O-t-butyl, -CH2-C(CH3)3, -CH2CH(CH2CH3)2,
2-methylcyclopentyl, cyclohex-2-enyl, -CH[CH(CH3)2]COOCH3, -

-696-
CH2CH2N(CH3}2,-CH2C(CH3)=CH2, -CH2CH=CHCH3 (cis
and trans}, -CH2OH, -CH(OH)CH3. -CH(O-t-butyl)CH3, -
CH2OCH3, -(CH2)4NH-Boc, -(CH2)4NH2, -CH2-pyridyl, pyridyl,
-CH2-naphthyl, -CH2-(N-morpholino), p-(N-morpholino-
CH2CH2O)-benzyl, benzo[b]thiophen-2-yl,
5-chlorobenzo[b]thiophen-2-yl, 4,5,6,7-tetrahydrobenzo[b]thiophen-2-
yl, benzo[b]thiophen-3-yl, 5-chlorobenzo[b)thiophen-3-yl,
benzo[b]thiophen-5-yl, 6-methoxynaphth-2-yl, -CH2CH2SCH3.
thien-2-yl, and thien-3-yl.
105. The compound of Claim 104 wherein Rb is selected
from the group consisting of alkyl, substituted alkyl, cycloalkyl and
aryl.
106. The compound of Claim 105 wherein R2 is methyl.
107. The compound of Claim 106 wherein R1 is alkyl.
108. The compound of Claim 107 wherein Rb is alkyl.
109. The compound of Claim 58 wherein the compound is a
compound of Formula II.
110. The compound of Claim 109 wherein T is a bond and
X' and X" are independently selected from the group consisting of
H, hydroxyl, alkyl, substituted alkyl and aryl.
111. The compound of Claim 110 wherein each R15 is H.

-697-
112. The compound of Claim 111 the cyclic group defined by
W and -C(H)pC( = X)- forms a lactam ring of the formula:
<IMG>
or
<IMG>
wherein p is zero or one, T is selected from the group consisting'of
alkylene, substituted alkylene, alkenylene, substituted alkenylene,
(R21Z)qR21- and -ZR21 , where Z is a substituent selected from

-698-
the group consisting of -O-, -S- and > NR20, each R20 is
independently selected from the group consisting of alkyl, alkenyl,
alkynyl, cycloalkyl, cycloalkenyl, substituted alkyl; substituted
alkenyl, substituted alkynyl, aryl, heteroaryl and heterocyclic, each
R21 is independently alkylene, substituted alkylene, alkenylene and
substituted alkenylene with the proviso that when Z is -O- or -S-,any
unsaturation in the alkenylene and substituted alkenylene does
not involve participation of the -O- or -S-, and q is an integer of
from 1 to 3.
113. The compound of claim 112 wherein the lactam ring is
selected from the group consisting of
<IMG>

-699-
<IMGS>

-700-
<IMGS>

-701-
wherein A-B is selected from the group consisting of alkylene,
alkenylene, substituted alkylene, substituted alkenylene and -
N=CH-; Q is oxygen or sulfur; each V is independently selected
from the group consisting of hydroxy, acyl, acyloxy, alkyl,
substituted alkyl, alkoxy, substituted alkoxy, alkenyl, substituted
alkenyl, alkynyl, substituted alkynyl, amino, substituted amino,
aminoacyl, alkaryl, aryl, aryloxy, carboxyl, carboxylalkyl, cyano,
halo, nitro, heteroaryl, thioalkoxy, substituted thioalkoxy, and
trihalomethyl; each Ra is independently selected from the group
consisting of alkyl, substituted alkyl, alkoxy, substituted alkoxy,
amino, substituted amino, carboxyl, carboxyl alkyl, cyano, and
halo; Rb is selected from the group consisting of alkyl, substituted
alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl,
acyl, aryl, heteroaryl, and heterocyclic; Rc is selected from the
group consisting of alkyl, substituted alkyl, alkenyl, substituted
alkenyl, aryl, heteroaryl, heterocyclic, substituted amino,
cycloalkyl, and substituted cycloalkyl; t is an integer from 0 to 4; t
is an integer from 0 to 3; and w is an integer from 0 to 3.
114. The compound of Claim 113 wherein R1 is selected
from the group consisting of
(a) alkyl,
(b) phenyl,
(c) a substituted phenyl group of the formula:

-702-
<IMG>
wherein Rc is selected from the group consisting of acyl, alkyl,
alkoxy, alkylalkoxy, azido, cyano, halo, hydrogen, substituted
amino, nitro, trihalomethyl, thioalkoxy,
and wherein Rb and Rc are fused to form a heteroaryl or
heterocyclic ring with the phenyl ring wherein the heteroaryl or
heterocyclic ring contains from 3 to 8 atoms of which from 1 to 3
are heteroatoms independently selected from the group consisting of
oxygen, nitrogen and sulfur
Rb and Rb are independently selected from the group consisting
of hydrogen, halo, nitro, cyano, trihalomethyl, alkoxy, and
thioalkoxy with the proviso that when Rc is hydrogen, then Rb and
Rb are either both hydrogen or both substituents other than
hydrogen,
(d) 2-naphthyl,
(e) 2-naphthyl substituted at the 4, 5, 6, 7 and/or 8 positions
with 1 to 5 substituents selected from the group consisting alkyl,
alkoxy, halo, cyano, nitro, trihalomethyl, thioalkoxy, aryl, and
heteroaryl,
(f) heteroaryl, and
(g) substituted heteroaryl containing 1 to 3 substituents selected
from the group consisting of alkyl, alkoxy, aryl, aryloxy, cyano,
halo, nitro, heteroaryl, thioalkoxy, thioaryloxy provided that said

-703-
substituents are not ortho to the heteroaryl attachment to the -NH
group.
115. The compound of Claim 114 wherein R1 is selected
from the group consisting of phenyl, 1-naphthyl, 2-naphthyl,
n-butyl, 2-chlorophenyl, 2-fluorophenyl, 2-bromophenyl,
2-hydroxyphenyl, 2-nitrophenyl, 2-methylphenyl, 2-methoxyphenyl,
2-phenoxyphenyl, 2-trifluoromethylphenyl, 4-fluorophenyl,
4-chlorophenyl, 4-bromophenyl, 4-nitrophenyl, 4-methylphenyl,
4-hydroxyphenyl, 4-methoxyphenyl, 4-ethoxyphenyl,
4-butoxyphenyl, 4-iso-propylphenyl, 4-phenoxyphenyl,
4-trifluoromethylphenyl, 4-hydroxymethylphenyl,
3-methoxyphenyl, 3-hydroxyphenyl, 3-nitrophenyl, 3-fluorophenyl,
3-chlorophenyl, 3-bromophenyl, 3-phenoxyphenyl,
3-thiomethoxyphenyl, 3-methylphenyl, 3-trifluoromethylphenyl,
2,3-dichlorophenyl, 2,3-difluorophenyl, 2,4-dichlorophenyl,
2,5-dimethoxyphenyl, 3,4-dichlorophenyl, 3,4-difluorophenyl,
3,4-methylenedioxyphenyl, 3,4-dimethoxyphenyl,
3,5-difluorophenyl, 3,5-dichlorophenyl,
3,5-di-(trifluoromethyl)phenyl, 3,5-dimethoxyphenyl,
2,4-dichlorophenyl, 2,4-difluorophenyl, 2,6-difluorophenyl,
3,4,5-trifluorophenyl, 3,4,5-trimethoxyphenyl,
3,4,5-tri-(trifluoromethyl)phenyl, 2,4,6-trifluorophenyl,
2,4,6-trimethylphenyl, 2,4,6-tri-(trifluoromethyl)phenyl,
2,3,5-trifluorophenyl, 2,4,5-trifluorophenyl, 2,5-difluorophenyl,
2-fluoro-3-trifluoromethylphenyl, 4-fluoro-2-trifluoromethylphenyl,
2-fluoro-4-trifluoromethylphenyl, 4-benzyloxyphenyl,
2-chloro-6-fluorophenyl, 2-fluoro-6-chlorophenyl,
2,3,4,5,6-pentafluorophenyl, 2,5-dimethylphenyl, 4-phenylphenyl,

-704-
2-fluoro-3-trifluoromethylphenyl, adamantyl, benzyl,
2-phenylethyl, 3-phenyl-n-propyl, 4-phenyl-n-butyl, methyl, ethyl,
n-propyl, iso-propyl, iso-butyl, sec-butyl, tert-butyl, n-pentyl,
iso-valeryl, n-hexyl, cyclopropyl, cyclobutyl, cyclohexyl, cyclopentyl,
cyclopent-1-enyl, cyclopent-2-enyl, cyclohex-1-enyl,
-CH2-cyclopropyl, -CH2-cyclobutyl, -CH2-cyclohexyl, -CH2-cyclopentyl,
-CH2CH2-cyclopropyl, -CH2CH2-cyclobutyl, -CH2CH2-cyclohexyl,
-CH2CH2-cyclopentyl, pyrid-2-yl, pyrid-3-yl, pyrid-4-yl,
fluoropyridyls, chloropyridyls, thien-2-yl, thien-3-yl,
benzothiazol-4-yl, 2-phenylbenzoxazol-5-yl, furan-2-yl, benzofuran-2-yl,
thionaphthen-2-yl, thionaphthen-3-yl, thionaphthen-4-yl,
2-chlorothiophen-5-yl, 3-methylisoxazol-5-yl, 2-(thiophenyl)thien-5-yl,
6-methoxythionaphthen-2-yl, 3-phenyl-1,2,4-thiooxadiazol-5-yl,
2-phenyloxazol-4-yl, indol-3-yl, 1-phenyl-tetrazol-5-yl, allyl,
2-(cyclohexyl)ethyl, (CH3)2CH=CHCH2CH2CH(CH3)-,
C(O)CH2-, thien-2-yl-methyl, 2-(thien-2-yl)ethyl, 3-(thien-2-yl)-n-propyl,
2-(4-nitrophenyl)ethyl, 2-(4-methoxyphenyl)ethyl,
norboran-2-yl, (4-methoxyphenyl)methyl,
(2-methoxyphenyl)methyl, (3-methoxyphenyl)methyl, (3-hydroxy
phenyl)methyl, (4-hydroxyphenyl)methyl,
(4-methoxyphenyl)methyl, (4-methylphenyl)methyl,
(4-fluorophenyl)methyl, (4-fluorophenoxy)methyl,
(2,4-dichlorophenoxy)ethyl, (4-chlorophenyl)methyl,
(2-chlorophenyl)methyl, (1-phenyl)ethyl, (1-(p-chlorophenyl)ethyl,
(1-trifluoromethyl)ethyl, (4-methoxyphenyl)ethyl, CH3OC(O)CH2-,
benzylthiomethyl, 5-(methoxycarbonyl)-n-pentyl,
3-(methoxycarbonyl)-n-propyl, indan-2-yl, (2-methylbenzofuran-3-yl,
methoxymethyl, CH3CH=CH-, CH3CH2CH=CH-,

-705-
(4-chlorophenyl)C(O)CH2-, (4-fluorophenyl)C(O)CH2-, (4-methoxy
phenyl)C(O)CH2-, 4-(fluorophenyl)-NHC(O)CH2-, 1-phenyl-n-butyl,
(phenyl)2CHNHC(O)CH2CH2-, (CH3)2NC(O)CH2-,
(phenyl)2CHNHC(O)CH2CH2-, methylcarbonylmethyl,
(2,4-dimethylphenyl)C(O)CH2-, 4-methoxyphenyl-C(O)CH2-,
phenyl-C(O)CH2-, CH3C(O)N(phenyl)-, ethenyl,
methylthiomethyl, (CH3)3CNHC(O)CH2-, 4-fluorophenyl- C(O)CH2-,
diphenylmethyl, phenoxymethyl,
3,4-methylenedioxyphenyl-CH2-, benzo[b]thiophen-3-yl,
(CH3)3COC(O)NHCH2-, trans-styryl, H2NC(O)CH2CH2-,
2-trifluoromethylphenyl-C(O)CH2, phenylC(O)NHCH(phenyl)CH2-,
mesityl, CH3CH(=NHOH)CH2-, 4-CH3-phenyl-NHC(O)CH2CH2-,
phenyl-C(O)CH(phenyl)CH2-,
(CH3)2CHC(O)NHCH(phenyl)-, CH3CH2OCH2-,
CH3OC(O)CH(CH3)(CH2)3-, 2,2,2-trifluoroethyl,
1-(trifluoromethyl)ethyl, 2-CH3-benzofuran-3-yl,
2-(2,4-dichlorophenoxy)ethyl, SO2CH2-, 3-cyclohexyl-n-propyl,
CF3CH2CH2CH2- and N-pyrrolidinyl.
116. The compound according to Claim 115 where each R2
is independently selected from the group consisting of alkyl,
substituted alkyl, alkenyl, cycloalkyl, aryl, heteroaryl and
heterocyclic.
117. The compound according to Claim 116 wherein R2 is
selected from the group consisting of methyl, ethyl, n-propyl,
iso-propyl, n-butyl, iso-butyl, sec-butyl, tert-butyl,
-CH2CH(CH2CH3)2, 2-methyl-n-butyl, 6-fluoro-n-hexyl, phenyl,
benzyl, cyclohexyl, cyclopentyl, cycloheptyl, allyl, iso-but-2-enyl,

-706-
3-methylpentyl, -CH2-cyclopropyl, -CH2-cyclohexyl,
-CH2CH2-cyclopropyl, -CH2CH2-cyclohexyl, -CH2-indol-3-yl,
p-(phenyl)phenyl, o-fluorophenyl, m-fluorophenyl, p-fluorophenyl,
m-methoxyphenyl, p-methoxyphenyl, phenethyl, benzyl,
m-hydroxybenzyl, p-hydroxybenzyl, p-nitrobenzyl,
m-trifluoromethylphenyl, p-(CH3)2NCH2CH2CH2O-benzyl,
p-(CH3)3COC(O)CH2O-benzyl, p-(HOOCCH2O)-benzyl,
2-aminopyrid-6-yl, p-(N-morpholino-CH2CH2O)-benzyl,
-CH2CH2C(O)NH2, -CH2-imidazol-4-yl,
-CH2-(3-tetrahydrofuranyl), -CH2-thiophen-2-yl,
-CH2(1-methyl)cyclopropyl, -CH2-thiophen-3-yl, thiophen-3-yl,
thiophen-2-yl, -CH2-C(O)O-t-butyl, -CH2-C(CH3)3,
-CH2CH(CH2CH3)2, 2-methylcyclopentyl, cyclohex-2-enyl,
-CH[CH(CH3)2]COOCH3, -CH2CH2N(CH3)2,
-CH2C(CH3)=CH2, -CH2CH=CHCH3 (cis and trans), -CH2OH,
-CH(OH)CH3, -CH(O-t-butyl)CH3, -CH2OCH3, -(CH2)4NH-Boc,
-(CH2)4NH2, -CH2-pyridyl, pyridyl, -CH2-naphthyl,
-CH2-(N-morpholino), p-(N-morpholino-CH2CH2O)-benzyl,
benzo[b]thiophen-2-yl, 5-chlorobenzo[b]thiophen-2-yl,
4,5.6,7-tetrahydrobenzo[b]thiophen-2-yl, benzo[b]thiophen-3-yl,
5-chlorobenzo[b]thiophen-3-yl, benzo[b)thiophen-5-yl,
6-methoxynaphth-2-yl, -CH2CH2SCH3, thien-2-yl, and thien-3-yl.
118. The compound of Claim 117 wherein Rb is selected
from the group consisting of alkyl, substituted alkyl, cycloalkyl and
aryl.
119. The compound of Claim 118 wherein R2 is methyl.

-707-
120. The compound of Claim 119 wherein R1 is alkyl.
121. The compound of Claim 120 wherein Rb is alkyl.
122. A compound selected from the group consisting of
5-(S)-[N'-(2-Amino-3,3,3-trifluoromethylbutyryl)-L-alaninyl]-
amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one
5-(S)-[N'-(2-amino -5,5,5-trifluoropentanyl)-L-alaninyl]-amino-7-
methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one
5-(S)-[N'-(2-amino-4,4,4-trifluorobutyryl)-L-alaninyl]-amino-7-
methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one
1-(S)-[N'-(2-Amino-3,3.3-trifluorobutyryl)-L-alaninyl]-amino-3-
methyl-4,5,6,7-tetrahydro-2H-3-benzazepin-2-one
1-(S)-[N'-(2-Amino-5,5,5-trifluoropentanoyl)-L-alaninyl]-amino-3-
methyl-4,5,6,7-tetrahydro-2H-3-benzazepin-2-one
1-(S)-[N'-(2-Amino-4,4,4-trifluorobutyryl)-L-alaninyl]-amino-3-
methyl-4,5,6,7-tetrahydro-2H-3-benzazepin-2-one
1-(S)-[N'-(2-Aminobutyryl)-L-alaninyl]-amino-3-methyl-4,5,6,7-
tetrahydro-2H-3-benzazepin-2-one
1-(S)-[N'-(Hexafluorovalinyl)-L-alaninyl]-amino-3-methyl-4,5,6,7-
tetrahydro-2H-3-benzazepin-2-one

-708-
1-(S)-[N'-(L-2-Aminobutyryl)-L-alaninyl]-amino-3-(2-methylpropyl)
-4,5,6,7-tetrahydro-2H-3-benzazepin-2-one,
and
5-[N'-(S)-2-(4-methylpentyl)amino-3-methylbutyryl-L-alaninyl]-
amino-7-methyl-5,7-dihydro-6H-dibenz(b,d]azepin-6-one.
123. The compound of claim 60 wherein R1 is selected from
the group consisting of methyl, ethyl, n-propyl, iso-propyl,
iso-butyl, sec-butyl, n-butyl, n-pentyl and isovaleryl.

Description

CA 02325389 2000-09-21
C
_ E
DEMANDES OU BREVETS VOLUMINEUX
LA PRESENTS PART1E DE CETTE DEMANDS OU CE BREVET
COMPREND PLUS D'UN TOME.
CSC! EST LE TOME 'I DE
Pour les tomes additionels, veuillez contacter le Bureau canadien des
brevets
JUMBO APPL1CATIONS/PATENTS
THlS SECTION OF THE APPLICATiON/PATENT CONTAINS MORE
THAN ONE VOLUME
THlS !S VOLUME ~ ,
NOTE: For additional volumes please contact the Canadian Patent Office

CA 02325389 2000-09-21
WO 99/67221 PCT/US99/14193
-1-
COMPOUNDS FOR INHIBITING BETA-AMYLOID PEPTIDE RELEASE AND/OR ITS SYNTHESIS
CROSS-REFERENCE TO RELATED APPLICATIONS
This application claims the benefit of U.S. Provisional Application No.
60I , which was converted pursuant to 37 C.F.R. ~ 1.53(b) from U.S.S.N.
09/102,507, filed 3une 22, 1998; the disclosure of which is incorporated
herein by
reference in its entirety.
BACKGROUND OF THE INVENTION
Field of the Invention
This invention relates to compounds which inhibit ~i-amyloid peptide
release and/or its synthesis, and, accordingly, have utility in treating
Alzheimer's
disease.
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77 van Niel et al., Bioorg. Med. Chem. Lett., x:1421-1426 (1995)
78 Kawase, et al., J. Org. Chem., X4:3394-3403 (1989)
Edwards, et al., Can. J. Chem., x:1648-1658 (1971)
80 Milligan, et al., J. Am. Chem. Soc.,11Z:10449-10459 (1995)
81 Curran et al., Tet. Lett., x:191-194 (1995)
82 Slusarchyk, et al., Bioorg. Med. Chem. Lett.,,~:753-758 (1995)
83 Wyvratt, et al., Eur. Pat. Appl. 61187 (1982)
Cornille, et al., J. Am. Chem. Soc., x.7:909-917 (1995)
85 Kolc; Coll. Czech. Chem. Comm., .4:630 (1969)
86 Dickerman, et al. , J. Org. Chem. , X4:530 (1949)
87 Dickerman, et al., J. Org. Chem., ~Q:206 (1955)
88 Dickerman, et al., J. Org. Chem., .~.~:1855 (1954)

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89 Hoffman, et al., J. Org. Chem., x:3565 (1962}
90 Wasserman, et al., J. Am. Chem. Soc., x:461-2 (1981) "
91 Crombie, et al . , Tetrahedron Lett. , x(42) :5151-5154 ( 1986)
92 Yokoo, et al . , Bull, Chem. Soc. Jap. , ~ :631 ( 1956)
93 gurkholder, et al., Biog. Med. Chem. Lett., x:231 (1993)
94 Karanewsky, U.S. Patent No. 4,460,579
95 Kametani, et al., Heterocycles, ,x:831-840 (1978)
96 yanganasawa, et al. , J. Med. Chem. , 3:1984-1991 ( 1987)
97 J. Das et al . , Biorg. Med. Chem. Lett. , 4:2193-2198 ( 1994)
All of the above publications, patents and patent applications are herein
incorporated by reference in their entirety to the same extent as if each
individual
publication, patent or patent application was specifically and individually
indicated
to be incorporated by reference in its entirety.
State of the Art
Alzheimer's Disease (AD) is a degenerative brain disorder characterized
clinically by progressive loss of memory, cognition, reasoning, judgment and
emotional stability that gradually leads to profound mental deterioration and
ultimately death. AD is a very common cause of progressive mental failure
(dementia) in aged humans and is believed to represent the fourth most common
medical cause of death in the United States. AD has been observed in races and

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ethnic groups worldwide and presents a major present and future public health
problem. The disease is currently estimated to affect about two to three
million
individuals in the United States alone. AD is at present incurable. No
treatment «
that effectively prevents AD or reverses its symptoms and course is currently
known.
The brains of individuals with AD exhibit characteristic lesions termed
senile (or amyloid) plaques, amyloid angiopathy (amyloid deposits in blood
vessels) and neurofibriIlary tangles. Large numbers of these lesions,
particularly
amyloid plaques and neurofibrillary tangles, are generally found in several
areas of
the human brain important for memory and cognitive function in patients with
AD.
Smaller numbers of these lesions in a more restrictive anatomical distribution
are
also found in the brains of most aged humans who do not have clinical AD.
Amyloid plaques and amyloid angiopathy also characterize the brains of
individuals with Trisomy 21 (Down's Syndrome) and Hereditary Cerebral
Hemorrhage with Amyloidosis of the Dutch Type (HCHWA-D). At present, a
definitive diagnosis of AD usually requires observing the aforementioned
lesions
in the brain tissue of patients who have died with the disease or, rarely, in
small
biopsied samples of brain tissue taken during an invasive neurosurgical
procedure .
The principal chemical constituent of the amyloid plaques and vascular
amyloid deposits (amyloid angiopathy) characteristic of AD and the other
disorders
mentioned above is an approximately 4.2 kilodalton (kD) protein of about 39-43
amino acids designated the ~i-amyloid peptide (AP) or sometimes A , A P or
/A4.
B-Amyloid peptide was first purified and a partial amino acid sequence was
provided by Glenner, et al.l The isolation procedure and the sequence data for
the
first 28 amino acids are described in U.S. Patent No. 4,666,8292.

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Molecular biological and protein chemical analyses have shown that the ~i-
amyloid peptide is a small fragment of a much larger precursor protein termed
the
amyloid precursor protein (APP), that is normally produced by cells in many "
tissues of various animals, including humans. Knowledge of the structure of
the
gene encoding APP has demonstrated that ~3-amyloid peptide arises as a peptide
fragment that is cleaved from APP by protease enzyme(s). The precise
biochemical mechanism by which the ~i-amyloid peptide fragment is cleaved from
APP and subsequently deposited as amyloid plaques in the cerebral tissue and
in
the walls of the cerebral and meningeal blood vessels is currently unknown.
Several lines of evidence indicate that progressive cerebral deposition of ~i-
amyloid peptide plays a seminal role in the pathogenesis of AD and can precede
cognitive symptoms by years or decades. See, for example, Selkoe . The most
important line of evidence is the discovery that missense DNA mutations at
amino
acid 717 of the 770-amino acid isoform of APP can be found in affected members
but not unaffected members of several families with a genetically determined
(familial) form of AD (Goate, et al 4: Chartier Harlan, et a1.5; and Murrell,
et
a1.6) and is referred to as the Swedish variant. A double mutation changing
lysine595-methionine596 to asparagine595-leucine596 (with reference to the 695
isoform) found in a Swedish family was reported in 1992 (Mullan, et al ~).
Genetic linkage analyses have demonstrated that these mutations, as well as
certain
other mutations in the APP gene, are the specific molecular cause of AD in the
affected members of such families. In addition, a mutation at amino acid 693
of
the 770-amino acid isoform of APP has been identified as the cause of the ~-
amyloid peptide deposition disease, HCHWA-D, and a change from alanine to
glycine at amino acid 692 appears to cause a phenotype that resembles AD is
some
patients but HCHWA-D in others. The discovery of these and other mutations in
APP in genetically based cases of AD prove that alteration of APP and
subsequent
deposition of its ~3-amyloid peptide fragment can cause AD.

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Despite the progress which has been made in understanding the underlying
mechanisms of AD and other p-amyloid peptide related diseases, there remains a
need to develop methods and compositions for treatment of the disease(s).
Ideally,
the treatment methods would advantageously be based on drugs that are capable
of
inhibiting ~i-amyloid peptide release and/or its synthesis in vivo.
SUMMARY OF THE INVENTION
This invention is directed to the discovery of a class of compounds which
inhibit ~3-amyloid peptide release andlor its synthesis and, therefore, are
useful in
the prevention of AD in patients susceptible to AD and/or in the treatment of
patients with AD in order to inhibit further deterioration in their condition.
The
class of compounds having the described properties are defined by Formulas I-
VI
below:
Rts~ R~s
R~ ~ C ~ Y H
~ ~n ~ )p W
Q
X
Formula I

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R~s
R~ Z ~ Y H
~n ~ )p
X
Formula II
Ris
R~-SO - ~ Y ( H)
2 L ~n p
IS
X
Formula III
R~s R~s R~s
RI Z ~ ~ C ~ Y H
~n ~ )p
Q
Formula IV

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X
C R~s
y CH)
W C N ~ ~n (
O _
Formula V
C(H)p
X
Ris
N ~Y)n (CH)P W
Q
Formula VI
X
wherein R1 is selected from the group consisting of aryl, alkyl, alkenyl,
alkynyl, cycloalkyl, cycloalkenyl, substituted alkyl, substituted alkenyl,
substituted
alkynyl, substituted cycloalkyl, substituted cycloalkenyl, aryl, heteroaryl
and
heterocyclic;
R'is selected from the group consisting of aryl, cycloalkyl, substituted
cycloalkyl, cycloalkenyl, substituted cycioalkenyl, heterocyclic, heteroaryl,
heterocyclooxy, -CH3, -CH=CH,, -CH=CHR', -CH=CR'R', -CR'=CHI,
CR'=CHR', -CR'=CR'R', -C=CH and -C=CR'; with the proviso that when R'
is heteroaryl or heterocyclic, there is no N in R' at a position beta to the
C=Q
group;
QisSorO;
R'5 is selected from the group consisting of hydrogen, alkyl, substituted
alkyl, aryl, heterocyclic and heteroaryl;

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R'S' is selected from the group consisting of hydrogen, hydroxyl, alkyl,
substituted alkyl, aryl, heterocyclic and heteroaryl;
W, together with -C(H)pC(=X)-, forms a cycloalkyl, cycloalkenyl, w
heterocyclic, substituted cycloalkyl, or substituted cycloalkenyl group
wherein
each of said cycloalkyl, cycloalkenyl, heterocyclic, substituted cycloalkyl or
substituted cycloalkenyl group is optionally fused to form a bi- or mufti-
fused ring
system (preferably no more than 5 fused rings) with one or more ring
structures
selected from the group consisting of cycloalkyl, cycloalkenyl, heterocyclic,
aryl
and heteroaryl group which, in turn, each of such ring structures are
optionally
substituted with 1 to 4 substituents selected from the group consisting of
hydroxyl,
keto, thioketo, , halo, alkoxy, substituted alkoxy, thioalkoxy, substituted
thioalkoxy, nitro, cyano, carboxyl, carboxyl esters, alkyl, substituted alkyl,
alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, amino, substituted
amino, -NHC(O)R4, -NHS02R4, -C(O)NH2, -C(O)NHR4, -C(O)NR4R4, -
S(O)R4, -S(O)2R4, -S(O)2NHR4 and -S(O)2NR4R4, where each R4 is
independently selected from the group consisting of alkyl, substituted alkyl,
aryl
and heteroaryl;
X is selected from the group consisting of oxo (=O), thiooxo (=S),
hydroxyl (-H,-OH), thiol (H,-SH) and hydro (H,H);
Y is represented by the formula:
Rz
NCH ~ C / NH '
O

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wherein each R2 is independently selected from the group consisting of alkyl,
substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl,
°°
cycloalkyl, aryl, heteroaryl and heterocyclic;
Z is represented by the formula -T-C(X' )(X")C(O)- where T is selected
from the group consisting of a bond covalently linking Rl to -C(X')(X")-,
oxygen,
sulfur, and -NRS where RS is hydrogen, acyl, alkyl, substituted alkyl, aryl,
heterocyclic or heteroaryl group;
RS is hydrogen, alkyl, substituted alkyl, aryl, heterocyclic or heteroaryl
group;
X' and X" are independently selected from the group consisting of
hydrogen, fluoro, alkyl, substituted alkyl, aryl, heteroaryl, heterocyclic, -
ORS' , -
SRS, -N(RS)~, -N(CO)OR'S and -N3, with the proviso that at least one of X' or
X"
is other than hydrogen, hydroxy or fluoro, and with the further proviso that
both
X' and X" cannot both be -ORS , -SRS, -N(RS)Z, -N(CO)OR'S and -N3 ; further,
neither X' and X" can be -ORS' -SRS, -N(RS),, -N(CO)OR'S or -N3 when T is
other than a bond covalently linking Rl to -C(X')(X")-;
n is an integer equal to 1 or 2;
p is an integer equal to 0 or 1 such that when p is zero, the ring defined by
W and -C(H)pC(=X)- is unsaturated at the carbon atom of ring attachment to Y
and when p is one, the ring is saturated at the carbon atom of ring attachment
to
Y,
with the following provisos:
when R1 is 2-propylpentanoyl, R2 is methyl, and R15 is hydrogen, then
W, together with > CH and > C=X, does not form a 2,3-dihydro-1-methyl-5-
phenyl-1H-1,4-benzodiazepin-2-one

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when R1 is 3,5-difluorobenzoyl, R2 is methyl, and R15 is hydrogen, then
W, together with > CH and > C=X, does not form a 2,3-dihydro-1-methyl-5-(2-
pyridyl)-1H-1,4-benzodiazepin-2-one "
when R1 is trans-cinnamyl, R2 is methyl, and R15 is hydrogen, then W,
together with > CH and > C=X, does not form a 2,3-dihydro-1-(3,3-dimethyl-2-
oxobutyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one
when Rl is 2-(4-chlorophenoxy)-2-methylpropionyl, R2 is methyl, and R15
is hydrogen, then W, together with > CH and > C=X, does not form a 2,3-
dihydro-1-methyl-5-(2-pyridyl}-1 H-1,4-benzodiazepin-2-one
when R1 is a-methoxyphenylacetyl, R2 is methyl, and R15 is hydrogen,
then W, together with > CH and > C=X, does not form a 2,3-dihydro-1-methyl-
5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one
when RI is diphenylacetyl, R2 is methyl, and R15 is hydrogen, then W,
together with >CH and >C=X, does not form a 2,3-dihydro-1-methyl-5-(2-
pyridyl)-1H-1,4-benzodiazepin-2-one
when R1 is a-methoxyphenylacetyl, R2 is methyl, and R15 is hydrogen,
then W, together with > CH and > C=X, does not form a 2,3-dihydro-1-(3,3-
dimethyl-2-oxobutyl)- 5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one
when R1 is a-hydroxy-diphenylacetyl, R2 is methyl, and R15 is hydrogen,
then W, together with > CH and > C=X, does not form a 2,3-dihydro-1-(3,3-
dimethyl-2-oxobutyl)- 5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one

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when R1 is diphenylacetyl, R2 is methyl, and R15 is hydrogen, then W,
together with > CH and > C=X, does not form a 2,3-dihydro-1-(3,3-dimethyl-2-
oxobutyl)- 5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one "
when R1 is 2-(chlorophenoxy)-2-methylpropionyl, R2 is methyl, and R15
is hydrogen, then W, together with >CH and >C=X, does not form a 2,3-
dihydro-1-(3,3-dimethyl-2-oxobutyl)- 5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one
when R1 is diphenylacetyl, R2 is methyl, and R15 is hydrogen, then W,
together with > CH and > C=X, does not form a 2,3-dihydro-1-(2-N,N-
diethylaminoethyl)- 5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one
when R1 is 3,5-difluorobenzoyl, R2 is methyl, and R15 is hydrogen, then
W, together with > CH and > C=X, does not form a 2,3-dihydro-1-(2-N,N-
diethylaminoethyl)- 5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one
when R1 is trans-cinnamyl, R2 is methyl, and R15 is hydrogen, then W,
together with > CH and > C=X, does not form a 2,3-dihydro-1-(2-N,N-
diethylaminoethyl)- 5-(2-pyridyl}-1H-1,4-benzodiazepin-2-one
when R1 is 2-(4-chlorophenoxy)-2-methylpropionyl, R2 is methyl, and R15
is hydrogen, then W, together with >CH and >C=X, does not form a 2,3-
dihydro-1-(2-N,N-diethylaminoethyl)- 5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one
when R1-N(R'S) is (2,5-dimethoxyphenyl)ureylenyl and R2 is methyl, then
W, together with > CH and > C=X, does not form a 2,3-dihydro-1-methyl-5-
pheny 1-1 H-1, 4-benzodiazepin-2-one

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when R1 is D,L-2-pyrrolidinone-5-yl, R2 is methyl, and R15 is hydrogen,
then W, together with > CH and > C=X, does not form a 7-methyl-5,7-dihydro-
6H-dibenz[b,d]azepin-6-one. "
Accordingly, in one of its method aspects, this invention is directed to a
method for inhibiting ~i-amyloid peptide release and/or its synthesis in a
cell which
method comprises administering to such a cell an amount of a compound or a
mixture of compounds as described herein effective in inhibiting the cellular
release and/or synthesis of ~i-amyloid peptide.
Because the in vivo generation of ~i-amyloid peptide is associated with the
pathogenesis of ADg'9, the compounds described herein can also be employed in
conjunction with a pharmaceutical composition to prophylactically and/or
therapeutically prevent and/or treat AD. Accordingly, in another of its method
aspects, this invention is directed to a prophylactic method for preventing
the onset
of AD in a patient at risk for developing AD by administering to the patient a
pharmaceutical composition comprising a pharmaceutically inert carrier and an
effective amount of one or more of the compounds described herein.
In yet another of its method aspects, this invention is directed to a
therapeutic method for treating a patient with AD in order to inhibit further
deterioration in the condition of that patient which method comprises
administering
to said patient a pharmaceutical composition comprising a pharmaceutically
inert
carrier and an effective amount of a compound or a mixture of compounds as
described herein.
Preferred R' groups include, by way of example, all of the aryl (including
substituted aryl), cycloalkyl, and substituted cycloalkyl groups defined for
R'
above as well as the following additional groups:

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thiophene-2-yl, 2-furanyl, cyclopropyl, cyclobutyl, 1-phenylcyclopropyl,
cyclopentyl, cyclohexyl, cycloheptyl, 2-benzofuranyl, 5-chloro-benzofuran-2-
yl,
5,5-dimethyl-butyrolactone-4-yl, 4-methylsulfonyl-phenyl, cis-2-phenyl-
cyclopropyl, 5-methylsulfonylthiophen-2-yl, 1,8 dimethyl-6-hydroxy-
bicyclo[2.2.2]oct-2-yl, 1,4-benzodioxan-2-yl, tetrahydrofuran-2-yl,
tetrahydrofuran-3-yl, cyclohex-3-enyl, ~ 3,5-difluorophenyl, 4-methylphenyl, 2-
naphthyl, 1-naphthyl, 4-chlorothiophene-yl, 4-cyanophenyl, tetrahydrofuran-2-
yl,
cyclohex-3-ene-yl, 1,2,3,4-tetrahydronaphth-2-yl, 1,2,3,4-tetrahydronaphth-3-
yl,
4-trifluoromethyl-cyclohexyl, bicyclo[2.2. 1] hept-2-yl, bicyclo[2.2.1]hept-5-
ene-2-
yl, 2,2 dichloropropyl, 2,4-dichlorophenyl, cis-2-methyl-cyclopropyl, 1-(4-
chlorophenyl)cyclobutyl, 2-phenylphenyl, 1,2-dihydro-1-oxo-2-phenyl-
bicyclo[3.3.1]non-6-ene-3-yl and -CH=CH(~)).
Preferred R1 groups include unsubstituted aryl groups such as phenyl, 1-
naphthyl, 2-naphthyl, etc.; substituted aryl groups such as monosubstituted
phenyls
(preferably substituents at 3 or 5 positions); disubstituted phenyls
(preferably
substituents at 3 and 5 positions); and trisubstituted phenyls (preferably
substituents at the 3,4,5 positions). Preferably, the substituted phenyl
groups do
not include more than 3 substituents. Examples of substituted phenyls include,
for
instance, 2-chlorophenyl, 2-fluorophenyl, 2-bromophenyl, 2-hydroxyphenyl, 2-
nitrophenyl, 2-methylphenyl, 2-methoxyphenyl, 2-phenoxyphenyl, 2-
trifluoromethylphenyl, 4-fluorophenyl, 4-chlorophenyl, 4-bromophenyl, 4-
nitrophenyl, 4-methylphenyl, 4-hydroxyphenyl, 4-methoxyphenyl, 4-
ethoxyphenyl, 4-butoxyphenyl, 4-iso-propylphenyl, 4-phenoxyphenyl, 4-
trifluoromethylphenyl, 4-hydroxymethylphenyl, 3-methoxyphenyl, 3-
hydroxyphenyl, 3-nitrophenyl, 3-fluorophenyl, 3-chlorophenyl, 3-bromophenyl, 3-
phenoxyphenyl, 3-thiomethoxyphenyi, 3-methylphenyl, 3-trifluoromethylphenyl,
3-(trifluoromethyl)-4-chlorophenyl, 3-chloro-4-cyanophenyl, 3-chloro-4-
iodophenyl, 3,4-methylenedioxyphenyl, 4-azidophenyl, 4-cyanophenyl, 4-

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ethylphenyl, 4-iodophenyl, 4-(phenylcarbonyl)phenyl, 4-(1-othoxy)ethylphenyl,
2,3-dichlorophenyl, 2,3-difluorophenyl, 2,4-dichlorophenyl, 2,5-
dimethoxyphenyl,
3,4-dichlorophenyl, 3,4-difluorophenyl, 3,4-methylenedioxyphenyl, 3,4- w
dimethoxyphenyl, 3,5-difluorophenyl, 3,5-dichlorophenyl, 3,5-di-
(trifluoromethyl)phenyl, 3,5-dimethoxyphenyl, 2,4-dichlorophenyl, 2,4-
difluorophenyl, 2,6-difluorophenyl, 3;4,5-trifluorophenyl, 3,4,5-
trimethoxyphenyl, 3,4,5-tri-(trifluoromethyl)phenyl, 2,4,6-trifluorophenyl,
2,4,6-
trimethylphenyl, 2,4,6-tri-(trifluoromethyl)phenyl, 2,3,5-trifluorophenyl,
2,4,5-
trifluorophenyl, 2,5-difluorophenyl, 2-fluoro-3-trifluoromethylphenyl, 4-
fluoro-2-
trifluoromethylphenyl, 2-fluoro-4-trifluoromethylphenyl, 4-benzyloxyphenyl, 2-
chloro-6-fluorophenyl, 2-fluoro-6-chlorophenyl, 2,3,4,5,6-pentafluorophenyl,
2,5-
dimethylphenyl, 4-phenylphenyl, 2-fluoro-3-trifluoromethylphenyl.
Other preferred RI groups include, by way of example, adamantyl, benzyl,
2-phenylethyl, 3-phenyl-n-propyi, 4-phenyl-n-butyl, methyl, ethyl, n-propyl,
iso-
propyl, iso-butyl, sec-butyl, tent-butyl, n-pentyl, iso-valeryl, n-hexyl,
cyclopropyl,
cyclobutyl, cyclohexyl, cyclopentyl, cyclopent-1-enyl, cyclopent-2-enyl,
cyclohex-
1-enyl, -CH2-cyclopropyl, -CH2-cyclobutyl, -CH2-cyclohexyl, -CH2-cyclopentyl,
-CH2CH2-cyclopropyl, -CH2CH2-cyclobutyl, -CH2CH2-cyclohexyl, -CH2CH2-
cyclopentyl, pyrid-2-yl, pyrid-3-yl, pyrid-4-yl, fluoropyridyls (including 5-
fluoropyrid-3-yl), chloropyridyls (including 5-chloropyrid-3-yl), thien-2-yl,
thien-
3-yl, benzothiazol-4-yl, 2-phenylbenzoxazol-5-yl, furan-2-yl, benzofuran-2-yl,
thionaphthen-2-yl, thionaphthen-3-yl, thionaphthen-4-yl, 2-chlorothiophen-5-
yl, 3-
methylisoxazol-5-yl, 2-(thiophenyl)thien-5-yI, 6-methoxythionaphthen-2-yl, 3-
phenyl-1,2,4-thiooxadiazol-5-yl, 2-phenyloxazol-4-yl, indol-3-yl, 1-phenyl-
tetrazol-5-yl, allyl,, 2-(cyclohexyl)ethyl, (CH3)2CH=CHCH2CH2CH(CH3)-
,phenyl-C(O}CH2-, thien-2-yl-methyl, 2-(thien-2-yl)ethyl, 3-(thien-2-yl)-n-
propyl,
2-(4-nitrophenyl)ethyl, 2-(4-methoxyphenyl)ethyi, norboran-2-yl, (4-
methoxyphenyl)methyl, (2-methoxyphenyl)methyl, (3-methoxyphenyl)methyl, (3-

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hydroxyphenyl)methyl, (4-hydroxyphenyl)methyl, (4-methoxyphenyl}methyl, (4-
methylphenyl)methyl, (4-fluorophenyl)methyl, (4-fluorophenoxy)methyl, (2,4-
dichlorophenoxy)ethyl, (4-chlorophenyl)methyl, (2-chlorophenyl)methyl, (1-
phenyl)ethyl, (1-(p-chlorophenyl)ethyl, (1-trifluoromethyl)ethyl, (4-
methoxyphenyl)ethyl, CH30C(O)CH2-, benzylthiomethyl, 5-(methoxycarbonyl)-
n-pentyl, 3-(methoxycarbonyl)-n-propyl, indan-2-yl, (2-methylbenzofuran-3-yl),
methoxymethyl, CH3CH=CH-, CH3CH2CH=CH-, (4-chlorophenyl)C(O)CH2-,
(4-fluorophenyl}C(O)CH2-, (4-methoxyphenyl)C(O)CH2-, 4-(fluorophenyl)-
NHC(O)CH2-, 1-phenyl-n-butyl, (phenyl)2CHNHC(O)CH2CH2-,
(CH3)2NC(O)CH2-, (phenyl)2CHNHC(O)CH2CH2-, methylcarbonylmethyl,
(2,4-dimethylphenyl)C(O)CH2-, 4-methoxyphenyl-C(O)CH2-, phenyl-C(O)CH2-,
CH3C(O)N(phenyl)-, ethenyl, methylthiomethyl, (CH3)3CNHC(O)CH2-, 4-
fluorophenyl-C(O)CH2-, diphenylmethyl, phenoxymethyi, 3,4-
methylenedioxyphenyl-CH2-, benzo[b]thiophen-3-yl, (CH3)3COC(O)NHCH2-,
trans-styryl, H2NC(O)CH2CH2-, 2-trifluoromethylphenyl-C(O)CH2,
C(O)NHCH(phenyl)CH2-, mesityl, CH3CH(=NHOH)CH2-, 4-CH3-phenyl-
NHC(O)CH2CH2-, C(O)CH(phenyl)CH2-, (CH3)2CHC(O)NHCH(phenyl)-,
CH3CH~OCH2-, CH30C( O)CH(CH3)(CH2)3-, 2,2,2-trifluoroethyl, 1-
(trifluoromethyl)ethyl, 2-CH3-benzofuran-3-yl, 2-(2,4-dichlorophenoxy)ethyl,
phenyl-S02CH2-, 3-cyclohexyl-n-propyl, CF3CH2CH2CH2- and N-pyrrolidinyl.
Still other preferred Rl groups include those set forth in the Tables below.
Each R2 is preferably (and independently for n = 2) selected from the
group consisting of alkyl, substituted alkyl, alkenyl, cycloalkyl, aryl,
heteroaryl
and heterocyclic.
Particularly preferred R2 substituents include, by way of example, methyl,
ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, tent-butyl,

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-CH2CH(CH2CH3)2, 2-methyl-n-butyl, 6-fluoro-n-hexyl, phenyl, benzyl,
cyclohexyl, cyclopentyl, cycloheptyl, allyl, iso-but-2-enyl, 3-methylpentyl,
-CH2-cyclopropyl, -CH2-cyclohexyl, -CH2CH2-cyclopropyl, -CH2CH2- "
cyclohexyl, -CH2-indol-3-yl, p-(phenyl)phenyl, o-fluorophenyl,
m-fluorophenyl, p-fluorophenyl, m-methoxyphenyl, p-methoxyphenyl, phenethyl,
benzyl, m-hydroxybenzyl, p-hydroxybenzyl, p-nitrobenzyl,
m-trifluoromethylphenyl, p-(CH3)2NCH2CH2CH20-benzyl,
p-(CH3)3COC(O)CH20-benzyl, p-(HOOCCH20)-benzyl, 2-aminopyrid-6-yl, p-
(N-morpholino-CH2CH20)-benzyl, -CH2CH2C(O)NH2, -CH2-imidazol-4-yl, -
CH2-(3-tetrahydrofuranyl), -CH2-thiophen-2-yl, -CH2(1-methyl)cyclopropyl, -
CH2-thiophen-3-yl, thiophen-3-yl, thiophen-2-yl, -CH2-C(O)O-t-butyl, -CH2-
C(CH3)3, -CH2CH(CH2CH3)2, -2-methylcyclopentyl, -cyclohex-2-enyl, -
CH[CH(CH3)2]COOCH3, -CH2CH2N(CH3)2, -CH2C(CH3)=CH2, -
CH2CH=CHCH3 (cis and traps), -CH20H, -CH(OH)CH3, -CH(O-t-butyl)CH3, -
CH20CH3, -(CH2)4NH-Boc, -(CH2)4NH2, -CH2-pyridyl (e.g., 2-pyridyl, 3-
pyridyl and 4-pyridyl), pyridyl (2-pyridyl, 3-pyridyl and 4-pyridyl), -CH2-
naphthyl (e.g., I-naphthyl and 2-naphthyl), -CH2-(N-morpholino), p-(N-
morpholino-CH2CH20)-benzyl, benzo[b]thiophen-2-yl, 5-chlorobenzo[b]thiophen-
2-yl, 4,5,6,7-tetrahydrobenzo[b]thiophen-2-yl, benzo[b]thiophen-3-yl, S-
chlorobenzo[b]thiophen-3-yl, benzo[b]thiophen-5-yl, 6-methoxynaphth-2-yl, -
CH2CH2SCH3, thien-2-yl, and thien-3-yl.
Compounds of this invention include, by way of example,
3-[(N'-(4-methylbenzoyl)-D-phenylglycinyl)]amino-2,3-
dihydro- I -methyl-5-phenyl-I H-1,4-benzodiazepin-2-one
3-[(N'-(4-methylbenzoyl)-L-alaninyl)]amino-2,3-dihydro-1-
methy l-5-pheny l-1 H-1, 4-benzodiazepin-2-one

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3-[(N'-(Diphenylacetyl)-L-alaninyl)]amino-2,3-dihydro-1-
methyl-5-phenyl-1 H-1,4-benzodiazepin-2-one
3-[(N'-(2-Naphthoyl)-L-alaninyl)]amino-2,3-dihydro-1-
methyl-5-phenyl-1H-1,4-benzodiazepin-2-one
3-[(N'-(1-Naphthoyl}-L-alaninyl)]amino-2,3-dihydro-1-
methyl-5-phenyl-1 H-1,4-benzodiazepin-2-one
3-[(N'-(5-Chloro-2-thiophenecarboxyl)-L-alaninyl)]amino-
2, 3-dihydro-1-methyl-5-phenyl-1 H-1,4-benzodiazepin-2-one
3-((N'-(4-Cyanobenzoyl)-L-alaninyl)]amino-2,3-dihydro-1-
methyl-5-phenyl-1 H-1,4-benzodiazepin-2-one
3-[(N'-(Tetrahydro-2-furoyl)-L-alaninyl)]amino-2,3-dihydro-
1-methyl-5-phenyl-1 H-1,4-benzodiazepin-2-one
3-((N'-(3 ,5-Difluorobenzoyl)-L-alaninyl)]amino-2, 3-dihydro-
1-methyl-5-phenyl-1 H-1,4-benzodiazepin-2-one
3-[(N'-(3-Cyclohexenecarboxyl)-L-alaninyl)]amino-2,3-
dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one
3-((N'-(Acetyl}-L-alariinyl)]amino-2,3-dihydro-1-methyl-5-
phenyl-1H-1,4-benzodiazepin-2-one
3-[(N'-( 1,2,3,4-Tetrahydro-2-naphthoyl)-L-alaninyl)]amino-
2, 3-d ihydro-1-methy 1-5-pheny 1-1 H-1, 4-benzod iazep in-3-o ne

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3-[(N'-(Cyclopentanecarboxyl)-L-alaninyl))amino-2,3-
dihydro-1-methyl-S-phenyl-1H-1,4-benzodiazepin-2-one
(S)-3-[(N'-(2-phenoxybutyryl)-L-alaninyl)]amino-2,3-
dihydro-1-methy 1-5-pheny 1- I H-1,4-benzodiazepin-2-one
(S)-3-[(N'-(2-Thiophenecarboxyl)-L-alaninyl)]amino-2,3-
dihydro-1-methyl-5-phenyl-I H-I ,4-benzodiazepin-2-one
(S)-3-((N'-(2,3-Diphenylpropionyl)-L-alaninyl)]amino-2,3-
dihydro-I-methyl-5-phenyl-IH-I ,4-benzodiazepin-2-one
(S)-3-[(N'-((R, S)-(-)-a-Methoxyphenylacetyl)-L-
alaninyl)]amino-2,3-dihydro-I-methyl-5-phenyl-1H-1,4-
benzodiazepin-2-one
(S)-3-[(N'-(2-Furoyl)-L-alaninyl))amino-2,3-dihydro-I-
methyl-5-phenyl-1 H-I ,4-benzodiazepin-2-one
(S)-3-[(N'-(2-Phenoxypropionyl)-L-alaninyl)]amino-2,3-
dihydro- I-methyl-5-phenyl-1 H-1,4-benzodiazepin-2-one
(S)-3-[(N'-(Cyclohexanecarboxyl)-L-alaninyl)]amino-2,3-
dihydro-1-methyl-S-phenyl-1H-1,4-benzodiazepin-2-one
(S)-3-[(N'-(2-(4-Chlorophenoxy)-2-methylpropionyl)-L-
alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-I ,4-
benzodiazepin-2-one

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(S)-3-[(N'-(Cyclobutanecarboxyl)-L-alaninyl)]amino-2,3-
dihydro-I-methyl-S-phenyl-1H-1,4-benzodiazepin-2-one
(S)-3-((N'-( 1-Phenyl-I-cyclopropanecarboxyl)-L-
alaninyl)]amino=2, 3-dihydro- I-methyl-5-phenyl- I H-I ,4-
benzodiazepin-2-one
(S)-3-[(N'-(2-Benzofurancarboxyl)-L-alaninyl)]amino-2,3-
I O dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one
(S)-3-[(N'-(2-Isopropyl-2-pheny!acetyl)-L-alaninyl)]amino-
2,3-dihydro-1-methyl-5-phenyl-1 H-I ,4-benzodiazepin-2-one
(S)-3-[(N'-(5-Chlorobenzofuran-2-carboxyl)-L-
alaninyl)]amino-2, 3-dihydro-1-methyl-S-phenyl-1 H-1,4-
benzodiazepin-2-one
(S)-3-[(N'-(2-Ethylhexanoyl)-L-alaninyl)]amino-2,3-dihydro-
I -methy I-5-phenyl-1 H- I , 4-benzod iazep in-2-one
(S)-3-[(N'-(2-Methylbutyryl)-L-alaninyl)]amino-2,3-dihydro-
1-methyl-S-phenyl-1H-1,4-benzodiazepin-2-one
(S)-3-[(N'-((R,S)-2-Phenoxypropionyl)-L-alaninyl)]amino-
2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one

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(S)-3-[(N'-(5,S-dimethyl-butyrolactone-4-yl)-L-
aIaninyl)]amino-2, 3-dihydro-1-methyl-5-phenyl-IH-1,4-
benzodiazepin-2-one
(S)-3-[(N'-(2-Methyl-4,4,4-trifluorobutyryl)-L-
alaninyl))amino-2,3-dihydro-I-methyl-5-phenyl-IH-1,4-
benzodiazepin-2-one
S-{N'-(2-phenylpropionyl)-L-alaninyl}-amino-7-methyl-5,7-
dihydro-6H-dibenz[b,d]azepin-6-one
5-{N'-(tetrahydro-3-furoyl)-L-alaninyl}-amino-7-methyl-5,7-
dihydro-6H-dibenz[b,d]azepin-6-one
3-[N'-(3 , 5-difluorophenyl-a-methoxyacetyl)-L-alaninyl]-
amino-2 , 3-dihydro-1-methyl-5-phenyl-1 H-1,4-
Benzodiazepin-2-one
3-[N'-(3,S-difluorophenyl-a-methoxyacetyl)-L-alaninyl]-
amino-2, 3-dihydro-1-methyl-5-pheny 1-1 H-1,4-
Benzodiazepin-2-one
(S)-3-[(N'-(4-(Trifluoromethyl)cyclohexane carboxyl)-L-
alaninyl)]amino-2, 3-dihydro-I -methyl-5-phenyl-1 H-1,4-
benzodiazepin-2-one

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(S)-3-[(N'-(Bicyclo[2.2.1]heptane-2-carboxyl)-L-
alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-
benzodiazepin-2-one °°
(S)-3-[(N'-(Bicyclo(2.2.1)hept-5-ene-2-carboxyl)-L-
alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-I,4-
benzodiazepin-2-one
(S)-3-[(N'-(2,2-Dichlorocyclopropane carboxyl)-L-
alaninyl)]amino-2, 3-dihydro-1-methyl-5-phenyl- I H-1,4-
benzodiazepin-2-one
(S)-3-[(N'-(Cycloheptanecarboxyl)-L-alaninyl)]amino-2,3-
dihydro- I -methyl-S-phenyl-1 H-1,4-benzodiazepin-2-one
(S)-3-[(N'-(2-Methylvaleryl)-L-alaninyl)]amino-2,3-dihydro-
I-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one
3-[(N'-(2-(4-hydroxyphenoxy)propionyl)-L-alaninyl)]amino-
2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one
(S)-3-[(N' -(a.-(Hydroxymethyl)phenylacetyl)-L-
alaniny I)] amino-2,3-dihydro-1-methyl-5-phenyl-1 H-1,4-
benzodiazepin-2-one
(S)-3-[(N'-(1-(2,4 Dichlorophenyl)cyclopropanecarboxyl)-L-
alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-
benzodiazepin-2-one

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(S)-3-[(N'-(2-Ethylbutyryl)-L-alaninyl)Jamino-2,3-dihydro-1-
methyl-5-phenyl-1 H-1,4-benzodiazepin-2-one
(S)-3-[(N'-(2-Methylcyclopropanecarboxyl)-L-
alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-
benzodiazepin-2-one
(S)-3-[(N'-( 1-(4-Chlorophenyl)-1-cyclobutanecarboxyl)-L-
alaninyl)]amino-2, 3-dihydro-1-methyl-5-phenyl-1 H-1,4-
benzodiazepin-2-one
(S)-3-[(N' -(2-Biphenylcarboxyl)-L-alaninyl)]amino-2, 3-
dihydro-1-methyl-5-phenyl-1 H-1,4-benzodiazepin-2-one
(S)-3-[(N'-(Pivalyl)-L-ataninyl)]amino-2,3-dihydro-1-methyl-
5-phenyl-1 H-1,4-benzodiazepin-2-one
(S)-3-[(N'-(trans-Cinnamyl)-L-alaninyl)]amino-2,3-dihydro-
1-methy 1-5-pheny 1-1 H-1, 4-benzod iazepin-2-one
(S)-3-((N'-(1,2-Dihydro-1-oxo-2-phenyl-4-
isoquinolinecarboxyl)-L-alaninyl)]amino-2,3-dihydro-1-
methyl-5-phenyl-1 H-1,4-benzodiazepin-2-one
(S)-3-((N'-(Bicyclo (3.3.1)non-6-ene-3-carboxyl)-L-
alaninyl}]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-
benzodiazepin-2-one

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(S)-3-[(N'-(Cyclopropanecarboxyl)-L-alaninyl)]amino-2,3-
dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one
(S)-3-[(N'-(3-furoyl}-L-alaninyl)]amino-2,3-dihydro-1-
methyl-5-phenyl-1 H-1,4-benzodiazepin-2-one
(S)-3-[(N'-(2-(4-Cyanophenoxy)-2-methyl propionyl)-L-
alaninyl)]amino-2, 3-dihydro-1-methyl-5-phenyl-1 H-1,4-
benzodiazepin-2-one
(S)-3-((N'-(Diphenylacetyl)-L-alaninyl)]amino-2,3-dihydro-
1-methyl-5-phenyl-1 H-1,4-benzodiazepin-2-one
(S)-3-[(N'-(Tetrahydro-2-furoyl)-L-alaninyl)]amino-2.3-
dihydro-1-methyl-5-phenyl-1 H-1,4-benzodiazepin-2-one
(S)-3-[(N'-(3,5-Difluorobenzoyl)-L-alaninyl)]amino-2,3-
dihydro-1-methyl-5-phenyl-1 H-1.4-benzodiazepin-2-one
(S)-3-[(N'-(3-Cyclohexenecarboxyl)-L-alaninyl)]amino-2,3-
d ihydro-1-methy 1-5-pheny 1-1 H-1, 4-benzodiazep in-2-one
(S)-3-[(N'-( 1,2,3,4-Tetrahydro-2-naphthoyl)-L-
alaninyl)]amino-2.3-dihydro-1-methyl-5-phenyl-1H-1,4-
benzodiazepin-2-one
(S)-3-[(N'-(Cyclopentanecarboxyl)-L-alaninyl)]amino-2,3-
dihydro-1-methyl-S-phenyl-1 H-1,4-benzodiazepin-2-one

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(S)-3-[(N'-(2-(4-triftuorophenyoxy)propionyl)-L-
alaninyl))amino-2, 3-dihydro-I-methyl-5-phenyl-1 H-1,4-
benzodiazepin-2-one °'
(S)-3-[(N'-(2-(4-Biphenylyloxy)propionyl)-L-
alaninyl)]amino-2, 3-dihydro-1-methyl-5-phenyl-1 H-1,4-
benzodiazepin-2-one
(S)-3-[(N'-(Diphenylacetyl)-L-phenylglycinyl)]amino-2,3-
dihydro-I-methyl-5-phenyl-1 H- I ,4-benzodiazepin-2-one
(S)-3-[(N'-(4-(methylsulfonyl)benzoyl)-L-alaninyl)]amino
2, 3-dihydro-1-methyl-5-phenyl-1 H-I ,4-benzodiazepin-2-one
(S)-3-((N'-(4-chloro-a-methylphenylacetyl)-L-
alaninyl)]amino-2, 3-dihydro-1-methyl-5-phenyl- I H-1,4-
benzodiazepin-2-one
(S)-3-[(N'-(trans-2-Phenyl-I-cyclopropanecarboxyl)-L-
alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-
benzodiazepin-2~one
(S)-3-[(N'-(4-chloro-a,a-dimethyiphenylacetyl)-L-
alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-
benzodiazepin-2-one
(S)-3-[(N'-(5-methylsulfonyl)thiophene-2-carboxyl)-L-
alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-
benzodiazepin-2-one

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(S)-3-[(N'-( 1, 8-dimethyl-6-Hydroxy-bicyclo(2.2.2)octane-2-
carboxyl)-L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl- "
1H-1,4-benzodiazepin-2-one
(S}-3-[(N'-((S)-(~+)-2-hydroxy-2-phenylpropionyl)-L-
alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1 H-1,4-
benzodiazepin-2-one
(S)-3-((N'-{ 1,4-Benzodioxan-2-carboxyl)-L-alaninyl)Jamino-
2, 3-d ihydro-1-methyl-5-phenyl-1 H-1,4-benzodiazepin-2-one
(S)-3-[(N'-(Tetrahydro-3-furoyl)-L-alaninyl)]amino-2, 3-
dihydro-1-methyl-5-phenyl-1 H-1,4-benzodiazepin-2-one
(S)-3-[(N'-(Acetyl)-L-phenylglycinyl)]amino-2,3-dihydro-1-
methyl-5-phenyl-1H-1,4-benzodiazepin-2-one
(S)-3-[(N'-(3-Cyclohexenecarboxyl)-L-
phenylglycinyI)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-
1,4-benzodiazepin-2-one
(S)-3-((N' -(Cyclopropanecarboxyl)-L-
phenylglycinyl)Jamino-2,3-dihydro-1-methyl-5-phenyl-1H-
1,4-benzodiazepin-2-one
(S)-3-[(N'-(3,5-Difluorobenzoyl)-L-phenylglycinyl}Jamino-
2,3-dihydro-1-methyl-5-phenyl-
1 H-1,4-benzodiazepin-2-one

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3-[(N'-(L-2-pyrrolidinone-5-yl)-L-alaninyl)]amino]-2,3-
dihydro-1-methyl-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one °'
3-[(N'-(trans-cinnamyl)-L-alaninyl)]amino]-2,3-dihydro-1-
methyl-5-(2-pyridyl}-1 H-1,4-benzodiazepin-2-one
3-[(N'-( 1-phenyl-1-cyclopropanecarboxyl)-L-
alaninyl)]amino]-2, 3-dihydro-1-methyl-5-(2-pyridyl)-1 H-1,4-
benzodiazepin-2-one
3-[(N'-( 1-phenyl-1-cyclopropanecarboxyl)-L-
alaninyl)]amino]-2,3-dihydro-1-(3,3-dimethyl-2-oxobutyl)-
5-(2-pyridyl)-1 H-1,4-benzodiazepin-2-one
(S}-3-((N'-(a-hydroxy-diphenylacetyl)-L-alaninyl)]amino-
2,3-dihydro-1-methyl-5-(2-pyridyl)-1 H-1,4-benzodiazepin-2-
one
3-[(N'-(3,5-difluorobenzoyl)-L-alaninyl)]amino]-2,3-
dihydro-1-(3,3-dimethyl-2-oxobutyl)- 5-(2-pyridyl)-1H-1,4-
benzodiazepin-2-one
3-[(N'-(L-2-pyrrolidinone-5-yl)-L-alaninyl)]amino]-2,3-
dihydro-1-(3,3-dimethyl-2-oxobutyl)- 5-(2-pyridyl)-1H-1,4-
benzodiazepin-2-one

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(S)-3-[(N'-(a-hydroxy-diphenylacetyl)-L-alaninyl)]amino-
2,3-dihydro-1-2-(diethylamino)ethyl-5-(2-pyridyl)-1H-1,4-
benzodiazepin-2-one
3-[(N'-(1-phenyl-1-cyclopropanecarboxyl)-L-
alaninyl)]amino)-2,3-dihydro-I-(2-N,N-diethylaminoethyl)-
5-(2-pyridyl)-1 H-1,4-benzodiazepin-2-one
3-((N'-(a-methoxyphenylacetyl)-L-alaninyl)]amino]-2,3-
dihydro-1-(2-N,N-diethylaminoethyl)- 5-(2-pyridyl)-IH-1,4-
benzodiazepin-2-one
3-(S)-[2-(( 1 H)-isoquinoline-3 ,4-dihydro-3-oxo)-2-methyl-
acetyl]-amino-2,3-dihydro-1-methyl-5-phenyl-1 H-1,4-
benzodiazepin-2-one
3-(S)-[2-(( 1 H)-isoquinoline-3 ,4-dihydro-3-oxo)-2-methyl-
acetyl]-amino-2, 3-dihydro-1-methyl-5-phenyl-1 H-1,4-
benzodiazepin-2-one
(S)-3-[(N'-((trans-2-Phenylcyclopropyl)ureylenyl)-L-
alaninyl)]amino-2, 3-dihydro-1-methyl-5-phenyl=1 H-1,4-
benzodiazepin-2-one
(S)-3-[(N'-((3,4-Dichlorophenyi)ureylenyl)-L-
alaninyI)]amino-2, 3-dihydro-1-methyl-5-phenyl-1 H-1,4-
benzodiazepin-2-one

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(S)-3-[(N'-((2-propenyl)ureylenyl)-L-alaninyl)]amino-2,3-
dihydro-1-methy 1-S-pheny 1-1 H-1, 4-benzod iazepin-2-one
(S)-3-[(N'-((R)-(-)-I-( 1-Naphthyl)ethyl)ureylenyl)-L-
alaninyl)]amino-2,3-dihydro-I-methyl-5-phenyl-IH-1,4-
benzodiazepin-2-one
(S)-3-[(N'-((2,6-Diisopropylphenyi)ureylenyl)-L-
alaninyl)]amino-2.3-dihydro-I-methyl-5-phenyl-IH-1,4-
I 0 benzodiazepin-2-one
(S)-3-[(N'-((3-[(Trifluoromethyl)phenyl)ureylenyl)-L-
alaninyl)]amino-2.3-dihydro-I -methyl-5-phenyl-1 H-1,4-
benzodiazepin-2-one
(S)-3-[(N'-((Phenyl)ureylenyl)-L-alaninyl)]amino-2,3-
dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one
(S)-3-((N' -((4-ethoxycarbonylphenyl)ureylenyl)-L-
alaninyl)]amino-2,3-dihydro-I-methyl-S-phenyl-1H-1,4-
benzodiazepin-2-one
(S)-3-[(N'-((2-Bromophenyl)ureylenyl)-L-alaninyl)]amino
2,3-dihydro-I-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one
(S)-3-[(N'-((o-Tolyl)ureylenyl)-L-alaninyl)]amino-2,3
dihydro-1-methyl-5-phenyl-1 H-1,4-benzodiazepin-2-one

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(S)-3-[(N'-((2-Ethyl-6-methylphenyl)ureylenyl)-L-
alaninyl)]amino-2,3-dihydro-1-methyl-~-phenyl-1H-1,4-
benzodiazepin-2-one ..
(S)-3-[(N'-((2-Fluorophenyl)ureylenyl)-L-alaninyl)]amino-
2, 3-dihydro-1-methyl-5-phenyl-1 H-1,4-benzodiazepin-2-one
(S)-3-[(N'-((2,4-difluorophenyl)ureylenyl)-L-
alaninyl)]amino-2, 3-dihydro-1-methyl-5-phenyl-1 H-1,4-
benzodiazepin-2-one
(S)-3-[(N'-((2-Ethoxyphenyl)ureylenyl)-L-alaninyl)]amino-
2,3-dihydro-1-methyl-5-phenyl-1 H-1,4-benzodiazepin-2-one
(S)-3-[(N'-((3-Acetylphenyl)ureylenyl)-L-alaninyl)]amino-
2,3-dihydro-1-methyl-5-phenyl-1 H-1,4-benzodiazepin-2-one
(S)-3-[(N'-((3-[(cyano)phenyl)ureylenyl)-L-alaninyl)]amino-
2, 3-dihydro-1-methyl-5-phenyl-1 H-1,4-benzodiazepin-2-one
(S)-3-[(N'-((Phenethyl)ureylenyl)-L-alaninyl)]amino-2,3-
dihydro-1-methyl-5-phenyl-1H-1,4-henzodiazepin-2-one
(S)-3-[(N'-((4-n-Butylphenyl)ureylenyl)-L-alaninyl)]amino-
2,3-dihydro-1-methyl-5-phenyl-1 H-1,4-benzodiazepin-2-one
(S)-3-[(N'-((Octyl)ureylenyl)-L-alaninyl)]amino-2,3-dihydro-
1-methyl-5-phenyl-1 H-1,4-benzodiazepin-2-one

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(S)-3-[(N'-((4-Biphenyl)ureylenyl)-L-alaninyl)]amino-2,3-
dihydro- I-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one
(S)-3-[(N'-((4-Isopropylphenyl)ureylenyl)-L-alaninyl)]amino-
2,3-dihydro-1-methyl-5-phenyl-IH-I,4-benzodiazepin-2-one
(S)-3-[(N'-((Hexyl)ureylenyl)-L-alaninyl)]amino-2,3-
dihydro- I-methyl-5-phenyl-I H-I ,4-benzodiazepin-2-one
(S)-3-[(N'-((2-Isopropylphenyl)ureylenyl)-L-alaninyl)]amino-
2,3-dihydro-1-methyl-5-phenyl-1H-I ,4-benzodiazepin-2-one
(S)-3-[(N'-((2,6-Difluorophenyl)ureylenyl)-L-
alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-I ,4-
benzodiazepin-2-one
(S)-3-[(N'-((Octadecyl)ureylenyl)-L-alaninyl)]amino-2,3-
dihydro-1-methyl-5-phenyl-1 H- I ,4-benzodiazepin-2-one
(S)-3-[(N' -((4-(Trifluoromethoxy)phenyl)ureylenyl)-L-
alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-IH-1,4-
benzodiazepin-2-one
(S)-3-[(N'-((2,4-Dichlorophenyl)ureylenyl)-L-
alaninyl)]amino-2,3-dihydro- I-methyl-5-phenyl-1 H-1,4-
benzodiazepin-2-one

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(S)-3-[(N'-((3-Ethoxycarbonylphenyl)ureylenyl)-L-
alaninyl)]amino-2, 3-dihydro-1-methyl-5-phenyl-1 H-I ,4-
benzodiazepin-2-one
(S)-3-[(N'-((4-Chlorophenyl)ureylenyl)-L-alaninyl)]amino-
2,3-dihydro-1-rriethyl-5-phenyl-1H-1,4-benzodiazepin-2-one
(S)-3-[(N'-((4-butoxyphenyl)ureylenyl)-L-alaninyl)]amino-
2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one
(S)-3-[(N'-((4-Phenoxyphenyl)ureylenyl)-L-alaninyl)]amino-
2,3-dihydro-1-methyl-5-phenyl-1 H-1,4-benzodiazepin-2-one
(S)-3-[(N'-(( 1-Naphthyl)ureylenyl)-L-alaninyl)]amino-2,3-
dihydro-I-methyl-5-phenyl-IH-1,4-benzodiazepin-2-one
(S)-3-[(N'-((2-Biphenyl)ureylenyl)-L-alaninyl)]amino-2,3-
dihydro-1-methyl-5-phenyl-IH-1,4-benzodiazepin-2-one
(S)-3-[(N'-((2-(Methylthio)phenyl)ureylenyl)-L-
alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-
benzodiazepin-2-one
(S)-3-[(N'-((2-Ethylphenyl)ureylenyl}-L-alaninyl)]amino-2,3-
dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one
(S)-3-((N'-((3-Methoxyphenyl)ureylenyl)-L-alaninyl)]amino-
2, 3-dihydro-1-methyl-5-phenyl-1 H-1,4-benzodiazepin-2-one

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(S)-3-[(N'-((3,4,5-Trimethoxyphenyl)ureylenyl)-L-
alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-
benzodiazepin-2-one
(S)-3-[(N'-((2,4,6-Trimethylphenyl)ureylenyI)-L-
alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-
benzodiazepin-2-one
(S)-3-[(N'-((2-methyl-6-t-butylphenyl)ureylenyl)-L-
alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1 H-1,4-
benzodiazepin-2-one
(S)-3-[(N'-((2-(2-thiophene-yl)ethyl)ureylenyl)-L-
alaninyl)Jamino-2, 3-dihydro- I-methyl-5-phenyl-1 H- I ,4-
benzodiazepin-2-one
3-[N'-3.5-difluorophenyl-acetamido)-L-alaninyl)-3-amino-
2, 3-dihydro 1-methyl-5-phenyl-1 H-1,4-benzodiazepine
3-[N'-3,5-difluorophenyl-a-azidoacetyl)-L-alaninyl]-3-
amino-2,3-dihydrol-methyl-5-phenyl-1H-1,4-benzodiazepine
S-{N'-(cyclopropane carboxyl)-L-alaninyl}-amino-7-methyl-
5,7-dihydro-6H-dibenz[b,dJazepin-6-one
5- { N' -(2-methylhexanoy 1)-L-alaniny 1 } -amino-7-methy l-5 , 7-
dihydro-6H-dibenz[b,d]azepin-6-one

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5-{N'-(bicyclo[2.2.1]heptane-2-carboxyl)-L-alaninyl}-amino-
7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one
5-{N'-(N-acetyl-N-phenylglycinyl)-L-alaninyl}-amino-7-
methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one
5-{N'-((aminoacetoxy)-3,5-difluorophenylacetyl)-L-
alaninyl}-amino-7-methyl-5,7-dihydro-6H-
dibertz[b,dJazepin-6-one
3-[N'-(3,5-difluorophenyl-a-(2-aminoacetoxy)acetyl)-L-
alaninyl)-amino-2, 3-dihydro-1-methyl-5-phenyl-1 H-1,4-
Benzodiazepin-2-one
5-{N'-(diphenylacetyl)-L-alaninyl}-amino-7-methyl-5,7-
dihydro-6H-dibenz[b,d]azepin-6-one
5-{N'-(acetyl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6H-
dibenz[b,d]azepin-6-one
5-{N'-(2-phenoxyphenylacetyl)-L-alaninyl}-amino-7-methyl-
5,7-dihydro-6I-I-dibenz[b,d]azepin-6-one
5-{ N' -(trans-c innamyl)-L-alaniny 1 }-amino-7-methyl-5 , 7-
dihydro-6H-dibenz[b,d]azepin-6-one
5-{ N' -(tetrahydro-2-furoy 1)-L-alaninyl}-amino-7-methyl-5 , 7-
dihydro-6H-dibenz[b,d]azepin-6-one

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S-{N'-(cyclopentanecarboxyl)L-alaninyl}-amino-7-methyl-
5,7-dihydro-6H-dibenz[b,d]azepin-6-one
5-{N'-(2-thiophenecarboxyl)-L-alaninyl}-amino-7-methyl-
5,7-dihydro-6H-dibenz[b,d]azepin-6-one
5-{N'-((S)-( +)-2-hydroxy-2-phenylpropionyl)-L-alaninyl}
amino-7-methyl-5 , 7-d ihydro-6H-d ibenz [b, d] azepin-6-one
5-{N'-((R)-(-)-2-hydroxy-2-phenylpropionyl)-L-alaninyl}-
amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one
3-[N'-(3,5-difluorophenyl-a-hydroxy-a-methyIacetyl)-L-
alaninyl]-amino-2,3-dihydro-1-methyl-5-(2-fluorophenyl)-
I H- I ,4-Benzodiazepin-2-one
5-{N'-(benzenesulfonyl)-L-alaninyl}-amino-7-methyl-5,7-
dihydro-6H-dibenz[b,d]azepin-6-one
3-[N'-(3,5-difluorophenyl-a-hydroxy-a-meihylacetyl)-L-
aianinyl]-amino-2,3-dihydro-I-methyl-5-(2-fluorophenyl)-
1 H-1,4-Benzodiazepin-2-one
S-{N'-(3-fluorobenzenesulfonyl)-L-alaninyl}-amino-7-
methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one
5-(S)-(N'-((Butylureylenyl)-L-alaninyl)-amino-7-methyl-5,7-
dihydro-6H-dibenz[b,d]azepin-6-one

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5-(S)-(N'-((Benzylureylenyl)-L-alaninyl)-amino-7-methyl-
5,7-dihydro-6H-dibenz[b,d]azepin-6-one
5-{N'-(benzylsulfonyl)-L-alaninyl}-amino-7-methyl-5,7-
dihydro-6H-dibenz[b,d]azepin-6-one
5-(S)-(N'-((Ethylureylenyl)-L-alaninyl)-amino-7-methyl-5,7-
dihydro-6H-dibenz[b,d)azepin-6-one
5-(S)-(N'-((Phenethylureylenyl)-L-alaninyl)-amino-7-methyl-
5,7-dihydro-6H-dibenz(b,d]azepin-6-one
5-(S)-(N'-(3 , S-difluorophenyl-a-aminoacetyl)-L-val inyl]-
amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one
IS
-(S)-(N'-(3 , 5-difluorophenyl-a-aminoacetyl)-L-tert-leucinyl-
amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one
5-{N'-(butylsulfonyl)-L-alaninyl}-amino-7-methyl-5,7-
dihydro-6H-dibenz[b,d]azepin-6-one
S-{N'-(octylsulfonyl)-L-alaninyl}-amino-7-methyl-
5,7-dihydro-6H-dibenz[b,d]azepin-6-one
5-(S)-(N'-((2-(thiophen-2-yl)ethylureylenyl)-L-alaninyl)-
amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one
5-(S}-(N'-(3,S-difluorophenyl-a-aminoacetyl)-L-alaninyl-
amino-7-methyl-5 ,7-dihydro-6H-dibenz[b,d)azepin-6-one

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S-(S)-(N'-(L-valinyl)-L-alaninyl-)]amino-2,3-dihydro-1-
methyl-5-phenyl-1 H-1,4-benzodiazepin-2-one
S-(R/S)-(N'-(2-hydroxy-2-phenethylureylenyl)-L-alaninyl)-
amino-7-methyl-5 , 7-d ihydro-6H-d ibenz [b, d] azepin-6-one
5-(S)-(N'-((hexylureylenyl)-L-alaninyl)-amino-7-methyl-5,7-
dihydro-6H-dibenz[b,d]azepin-6-one
5-(S)-(N'-((cyclohexylureylenyl)-L-alaninyl)-amino-7-
methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one
5-(S)-(N'-((isopropylureylenyl)-L-alaninyl)-amino-7-methyl-
5,7-dihydro-6H-dibenz[b,d]azepin-6-one
5-(S)-(N'-((tert-butylureylenyl)-L-alaninyl)-amino-7-methyl-
5,7-dihydro-6H-dibenz[b,d]azepin-6-one
5-(S)-(N'-(( 1-adamantylureylenyl)-L-alaninyl)-amino-7-
methyl-5,7-dihydro-6H-dibenz(b,d]azepin-6-one
5-(S)-(N'-((2-methylpropylureylenyl)-L-alaninyl)-amino-7-
methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one
5-(S)-(N'-(R/S)-3-hydroxy-3-phenyiethylureylenyl)-L-
alaninyl)-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-
6-one

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S-(S)-(N'-((3-methylbutylureylenyI)-L-alaninyl)-amino-7-
methyl-S,7-dihydro-6H-dibenz(b,d]azepin-6-one
S-(S)-((N'-(S)-I-hydroxymethyI-3-methylbutylureylenyl)-L-
S alaninyl)-amino-7-methyl-S,7-dihydro-6H-dibenz(b,d]azepin-
6-one
S-(S)-((N'-( 1 S)-(2S)-1-hydroxymethyl-2-
methylbutylureylenyl)-L-alaninyl)-amino-7-methyl-S,7-
dihydro-6H-dibenz(b,d]azepin-6-one
S-(S)-(N'-(3-chloropropylureylenyl)-L-alaninyl)-amino-7-
methyl-S , 7-dihydro-6H-dibenz(b,d]azepin-6-one
1 S S-(S)-(N'-octylureylenyl)-L-alaninyl)-amino-7-methyl-S,7-
dihydro-6H-dibenz[b,d]azepin-6-one
S-(S)-(N'-1,1,3,3-tetramethylbutylureylenyl)-L-alaninyl)-
amino-7-methyl-S,7-dihydro-6H-dibenz[b,d]azepin-6-one
S-(S)-(N'-(R/S)-1-methylbutylureylenyl)-L-alaninyl)-amino-
7-methyl-S,7-dihydro-6H-dibenz[b,d]azepin-6-one
S-(S)-((N'-(R/S)-1-hydroxymethylbutylureylenyl)-L-
2S alaninyl)-amino-7-methyl-S,7-dihydro-6H-dibenz[b,d]azepin-
6-one
S-(S)-((N'-(R/S)-1, 3-dimethylbutylureylenyl)-L-alaninyl)-
amino-7-methyl-S,7-dihydro-6H-dibenz[b,d]azepin-6-one

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5-(S)-((N'-(R)-1-hydroxymethyl-3-methylbutylureylenyl)-L-
alaninyl)-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-
6-one
S-(S)-((N'-(R/S)-2-methylbutylureylenyl)-L-alaninyl)-amino-
7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one
5-(S)-(N'-morphoiinoureylenyl)-L-alaninyl)-amino-7-methyl-
5,7-dihydro-6H-dibenz[b,d]azepin-6-one
5-(S)-(N'-(2-(2-hydroxyethoxy)-ethylureylenyl_)-L-alaninyl)-
amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one
5-(S)-(N'-piperidinylureylenyI)-L-alaninyl)-amino-7-methyl-
IS 5,7-dihydro-6H-dibenz[b,d]azepin-6-one
5-(S)-(N'-(N"-methyl-N"-butylureylenyl)-L-alaninyl)-amino-
7-methy 1-5 ,7-dihydro-6H-dibenz[b,d]azepin-6-one
5-(S)-(N'-(1-(R/S)-hydroxymethylcyclopentylureylenyl)-L-
alaninyl)-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-
6-one
5-(S)-(N'-(4-hydroxybutylureylenyl)-L-alaninyl)-amino-7-
methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one
5-(S)-(N'-( 1-(R/S)-hydroxymethyl-2-methylpropylureylenyl)-
L-alaninyl)-amino-7-methyl-5,7-dihydro-6H-
dibenz[b,d]azepin-6-one

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5-(S)-(N'-(2-(R/S)-hydroxycyclohexylureylenyl)-L-alaninyl)-
amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one
5-(S)-(N'-(isopropyl-hydroxyureylenyl)-L-alaninyl)-amino-7-
methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one
5-(S)-(N'-(benzyl-hydroxyureylenyl)-L-alaninyl)-amino-7-
methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one
S-(S)-(N'-(valinyl)-L-alaninyl-amino-7-methyl-5,7-dihydro-
6H-dibenz[b,d]azepin-6-one
5-(S)-(N'-(phenylglycinyl)-L-alaninyl-amino-7-methyl-5,7-
dihydro-6H-dibenz[b,d]azepin-6-one
5-(S)-(N'-(3,5-difluorophenyt-a-aminoacetyl)-L-alaninyl-
amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one
5-(S)-(N'-(3,5-difluoro phenylglycinyl)-L-alaninyl-amino-7-
methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one
5-(S)-(N'-(threonine)-L-alaninyl-amino-7-methyl-5,7-
dihydro-6H-dibenz[b,d]azepin-6-one
5-(S)-(N'-(D-valinyl)-L-alaninyl-amino-7-methyl-5,7-
dihydro-6H-dibenz[b,d]azepin-6-one
5-(S)-(N'-(phenylglycinyl)-L-alaninyl-amino-7-methyl-5,7-
dihydro-6H-dibenz[b,d]azepin-6-one

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-4.6-
5-(S)-(N"-(S)-phenylglycinyl)-N'-L-alaninyl]amino-1-methyl-
S-phenyl-1,3,4, 5-tetrahydro-2H-1,5-benzodiazepin-2-one
5-(S)-[(N"-L-valinyl)-N'-L-alaniny I J amino-1-methy I-5-
phenyl-1, 3 ,4,5-tetrahydro-2H-1,5-benzodiazepin-2-one
5-(S)-(N'-(thiomorpholinylureylenyl)-L-alaninyl)-amino-7-
methyl-5.7-dihydro-6H-dibenz[b,d]azepin-6-one
5-(S)-(N'-(2(R/S)-hydroxybutylureylenyl)-L-alaninyl)-amino-
7-methyl-5 , 7-dihydro-6H-dibenz[b,d] azepin-6-one
5-(S)-(N'-2,2.2-trifluoroethylureylenyl)-L-alaninyl)-amino-7-
methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one
5-(S)-(N'-(4R/S)-cyclohexylureyienyl)-L-alaninyl)-amino-7-
methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one
5-(S)-(N'-( 1 R)-hydroxymethyl-3-methylthiopropylureylenyl)-
L-alaninyl)-amino-7-methyl-5,7-dihydro-6H-
dibenz[b,dJazepin-6-one
S-{N'-(2-hydroxy-2-methylpropionyl)-L-alaninyl}-amino-7-
methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one

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5-{ N' -(2-hydroxy-2-methylbutanoy 1)-L-alaniny 1 }-amino-7-
methyl-5,7-dihydro-6H-dibenz[b,djazepin-6-one
3-[N'-(2-thioacetyl-3-methyl-butanoyl)-L-alaninyl]-amino-
2,3-dihydro-1-methyl-5-phenyl-1 H-1,4-benzodiazepin-2-one
5-(S)-(N'-(2-thioacetyl-3-methyl-butanoyl)-L-alaninylj-
amino-7-methyl-5 , 7-dihydro-6H-dibenz[b,d] azepin-6-one
5-(S)-[N'-(L-Trifluoromethylphenylglycinyl}-L-aianinyl]-
amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one
5-(S)-[N'-(L-N-methyl-valinyl)-L-alaninyl]
-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one
5-(S)-(N"-(3,5-difluorophenylglycinyl)-N'-L-alaninyl)amino-
2,4-dioxo-1-methyl-5-phenyl-2 , 3,4,5-tetrahydro-2H-1, 5-
benzodiazepine hydrochloride
5-(S)-(N"-(3,5-difluorophenylglycinyl)-N'-L-alaninyl]amino-
2,4-dioxo-1-methyl-S-phenyl-2,3,4,5-tetrahydro-2H-1,5-
benzodiazepine hydrochloride
5-(S)-[N'-(Hexafluorovalinyl)-L-alaninyl]-amino-7-methyl-5,
7-dihydro-6H-dibenz[b,d]azepin-6-one
3-[N'-(2-mercapto-3-methyl-butanoyl)-L-alaninyl]-amino-
2 , 3- dihydro-1-methyl-5-phenyl-1 H-1,4-benzodiazepin-2-one

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5-(S)-[N'-(2-mercapto-3-methylbutanoyl}-L-alaninyl]-amino-
7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one
Additional examples of suitable compounds include:
5-(S)-[N'-(2-Amino-3,3,3-trifluoromethylbutyryl)-L-alaninyl]-
amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one
5-(S)-[N'-(2-amino -5,5,5-trifluoropentanyl)-L-alaninyl]-amino-7-
methyl-5,7-dihydro-6H-dibenz(b,d)azepin-6-one
5-(S)-[N'-( 2-amino-4,4,4-trifluorobutyryl)-L-alaninyl]-amino-7-
methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one
1-(S)-(N'-(2-Amino-3,3,3-trifluorobutyryl)-L-alaninyl]-amino-3-
methyl-4,5.6,7-tetrahydro-2H-3-benzazepin-2-one
I-(S)-[N'-(2-Amino-5,5,5-trifluoropentanoyl)-L-alaninyl]-amino-3-
methyl-4,5,6,7-tetrahydro-2H-3-benzazepin-2-one
1-(S)-[N'-(2-Amino-4,4,4-trifluorobutyryl)-L-alaninyl]-amino-3-
methyl-4,5,6,7-tetrahydro-2H-3-benzazepin-2-one
1-(S}-[N'-(2-Aminobutyryl)-L-alaninyl]-amino-3-methyl-4,5,6,7-
tetrahydro-2H-3-benzazepin-2-one
1-(S)-[N'-(Hexafluorovalinyl)-L-alaninyl]-amino-3-methyl-4,5,6,7-
tetrahydro-2H-3-benzazepin-2-one

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1-(S)-[N'-(L-2-Aminobutyryl)-L-alaninyl]-amino-3-(2-
methylpropy l)-4, 5 , 6, 7-tetrahydro-2H-3-benzazepin-2-one
Preferred cyclic groups defined by W and -C(H~C(=X)- include
cycloalkyl, lactone, lactam, benzazepinone, dibenzazepinone and benzodiazepine
groups. In one preferred embodiment; the cyclic group defined by W and -
C(H)pC(=X)-, forms a cycloalkyl group of the formula:
_cH r
20
wherein T is selected from the group consisting of alkylene and substituted
alkylene.

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A preferred cycloalkyl group is represented by the formula:
rw.
wherein each V is independently selected from the group consisting of hydroxy,
acyl, acyloxy, alkyl, substituted alkyl, alkoxy, substituted alkoxy, alkenyl,
substituted alkenyl, alkynyl, substituted alkynyl, amino, substituted amino,
aminoacyl, alkaryl, aryl, aryloxy, carboxyl, carboxylalkyl, cyano, halo,
nitro,
heteroaryl, thioalkoxy, substituted thioalkoxy, trihalomethyl and the like;
each Ra
is independently selected from the group consisting of alkyl, substituted
alkyl,
alkoxy, substituted alkoxy, amino, substituted amino carboxyl, carboxyl alkyl,
cyano, halo, and the like; t is an integer from 0 to 4; and w is an integer
from 0 to
3.
Preferably t is an integer from 0 to 2 and, more preferably, is an integer
equal to 0 or 1.
In another preferred embodiment, the cyclic group defined by W, together
with -C(H)pC(=X)- is a ring of the formula:

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-S 1-
T
-C(H) <.
CH
.~
OH
or
T
-C(H}v
CH
SH
wherein p is zero or one, T is selected from the group consisting of alkylene,
substituted alkylene, alkenylene, substituted alkenylene, -(RZ'Z)qR'-'- and -
ZRZ'-,
where Z is a substituent selected from the group consisting of -O-, -S- and
> NR20, each R20 is independently selected from the group consisting of alkyl,
alkenyl, alkynyl, cycloalkyl, cycloalkenyl, substituted alkyl, substituted
alkenyl,
substituted alkynyl, aryl, heteroaryl and heterocyclic, each RZ' is
independently
alkylene, substituted alkylene, alkenylene and substituted alkenylene with the
proviso that when Z is -O- or -S-, any unsaturation in the alkenylene and

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substituted alkenylene does not involve participation of the -O- or -S-, and q
is an
integer of from 1 to 3.
Particularly preferred alcohol or thiol substituted groups include
~R')w
(R')w
OH
OH
Mt
Mt Ho
Mr
~)w (R')w
OH OH
wherein each V is independently selected from the group consisting of hydroxy,
acyl, acyloxy, alkyl, substituted alkyl, alkoxy, substituted alkoxy, alkenyl,
substituted alkenyl, alkynyl, substituted alkynyl, amino, substituted amino
aminoacyl, alkaryl, aryl, aryloxy, carboxyl, carboxylalkyl, cyano, halo,
vitro,
heteroaryl, thioalkoxy, substituted thioalkoxy, trihalomethyl and the like;
each Ra
is independently selected from the group consisting of alkyl, substituted
alkyl,
alkoxy, substituted alkoxy, amino, substituted amino carboxyl, carboxyl alkyl,
cyano, halo, and the like; t is an integer from 0 to 4; and w is an integer
from 0 to
3.

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Preferably t is an integer from 0 to 2 and, more preferably, is an integer
equal to 0 or 1.
Yet another preferred embodiment of the cyclic group defined by W,
together with -C(H)pC(=X)-, is a ring of the formula:
-C(H)p
C
O
IS
or
T
-C(H)p
~C
S

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wherein p is zero or one, T is selected from the group consisting of alkylene,
substituted alkylene, alkenylene, substituted alkenylene. -(RZ'Z)qR2'- and -
ZRZ'_,
where Z is a substituent selected from the group consisting of -O-, -S- and
> NR2~, each R2~ is independently selected from the group consisting of alkyl,
alkenyl, alkynyl, cycloalkyl, cycloalkenyl, substituted alkyl, substituted
alkenyl,
substituted alkynyl, aryl, heteroaryl and heterocyclic, each R21 is
independently
1 S alkylene, substituted alkylene, alkenylene and substituted alkenylene with
the
proviso that when Z is -O- or -S-, any unsaturation in the alkenylene and
substituted alkenylene does not involve participation of the -O- or -S-, and q
is an
integer of from 1 to 3.
Particularly preferred cyclic ketone and thioketone groups inciude:
(R')w
Mt
2s ~ ~
0
(R')w Mc
0 0

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-SS-
wherein each V is independently selected from the group consisting of hydroxy,
acyl, acyloxy, alkyl, substituted alkyl, alkoxy, substituted alkoxy, alkenyl,
substituted alkenyl, alkynyl, substituted alkynyl, amino, substituted amino
aminoacyl, alkaryl, aryl, aryloxy, carboxyl, carboxylalkyl, cyano, halo,
nitro,
heteroaryl, thioalkoxy, substituted thioalkoxy, trihalomethyl and the like;
each Ra
is independently selected from the group consisting of alkyl, substituted
alkyl,
alkoxy, substituted alkoxy, amino, substituted amino carboxyl, carboxyl alkyl,
cyano, halo, and the like; t is an integer from 0 to 4; and w is an integer
from 0 to
3.
Preferably t is an integer from 0 to 2 and, more preferably, is an integer
equal to 0 or 1.
In another preferred embodiment, the cyclic group defined by W, together
with -C(H)pC(=X)-, forms a ring of the formula:
25

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T
-C(H)p
~O
C
IC
0
T
-C(H)p
C /S
O

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T
--C(H)p
/O
C
S
or
T
-C(H)p
S
C
S
wherein p is zero or one, T is selected from the group consisting of alkylene,
substituted alkylene, alkenylene, substituted alkenylene, -(R21Z)qR21- and -
ZR21-

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where Z is a substituent selected from the group consisting of -O-, -S- and
> NR20, each R20 is independently selected from the group consisting of alkyl,
alkenyl, alkynyl, cycloalkyl, cycloalkenyl, substituted alkyl, substituted
alkenyl,
substituted alkynyl, aryl, heteroaryl and heterocyclic, each R21 is
independently
S alkylene, substituted alkylene, alkenylene and substituted alkenylene with
the
proviso that when Z is -O- or -S-, any unsaturation in the alkenylene and
substituted alkenylene does not involve participation of the -O- or -S-, and q
is an
integer of from 1 to 3.
Particularly preferred lactone and thiolactone groups include:
Mt
~R~)w ~ ~ ~R~~w
o
0 0
wherein each V is independently selected from the group consisting of hydroxy,
acyl, acyloxy, alkyl, substituted alkyl, alkoxy, substituted alkoxy, alkenyl,
substituted alkenyl, alkynyl, substituted alkynyl, amino, substituted amino
aminoacyl, alkaryl, aryl, aryloxy, carboxyl, carboxylalkyl, cyano, halo,
nitro,
heteroaryl, thioalkoxy, substituted thioalkoxy, trihalomethyl and the Like;
each Ra
is independently selected from the group consisting of alkyl, substituted
alkyl,
alkoxy, substituted alkoxy, amino, substituted amino carboxyl, carboxyl alkyl,
cyano, halo, and the like; t is an integer from 0 to 4; and w is an integer
from 0 to
3.

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Preferably t is an integer from 0 to 2 and, more preferably, is an integer
equal to 0 or 1.
In another preferred embodiment, the cyclic group defined by W and
-C(H)pC(=X)-, forms a lactam ring of the formula:
T
-C(H)p
NRZo
C
O
or a thiolactam ring of the formula:

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T
-C(H)p
NR~
C
i)
S
to
wherein p is zero or one, T is selected from the group consisting of alkylene,
substituted alkylene, alkenylene, substituted alkenylene, -(R21Z)qR21- and -
ZR21-
, where Z is a substituent selected from the group consisting of -O-, -S- and
> NR20, each R20 is independently selected from the group consisting of alkyl,
alkenyl, alkynyl, cycloalkyl, cycloalkenyl, substituted alkyl, substituted
alkenyl,
substituted alkynyl, aryl, heteroaryl and heterocyclic, each R21 is
independently
alkylene, substituted alkylene, alkenylene and substituted alkenylene with the
proviso that when Z is -O- or -S-, any unsaturation in the alkenylene and
substituted alkenylene does not involve participation of the -O- or -S-, and q
is an
integer of from 1 to 3.

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Particularly preferred lactam and thiolactam groups include:
Mt
~R'~w
/ ~
v
N ~R° N~ Re
I
O
M R:)
r
m -
Mt
(R')w i
R~
NwRb N
yRe
0
M.
Mr

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(Rs)w (R'~w
J
N
Oj ~Rb O~ Re
(R ?w (R'~w
~- N
l0 , O'' ~Rb
~Re
Mt Mt
(R')w
~R~)w \
is NJ
O~ ~Rb .
Re
Q' Mt f
yRa~ I O N
N ~ I ~ Mt
20 O \R° p~N~ a
R
Rc
Re
O N '~. . N ~-Mc
2s ~ , Mt N ~ i
0
R~
N ~ \ N
Mt ~ j
N
N_ _ O Ro.

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wherein A-B is selected from the group consisting of alkylene, alkenylene,
substituted alkylene, substituted alkenylene and -N=CH-; Q is oxygen or
sulfur;
each V is independently selected from the group consisting of hydroxy, acyl,
..
acyloxy, alkyl, substituted alkyl, alkoxy, substituted alkoxy, alkenyl,
substituted
alkenyl, alkynyl, substituted alkynyl, amino, substituted amino aminoacyl,
alkaryl,
aryl, aryloxy, carboxyl, carboxylalkyl, cyano, halo, nitro, heteroaryl,
thioalkoxy,
substituted thioalkoxy, trihalomethyl and the like; each Ra is independently
selected from the group consisting of alkyl, substituted alkyl, alkoxy,
substituted
alkoxy, amino, substituted amino carboxyl, carboxyl alkyl, cyano, halo, and
the
like; Rb is selected from the group consisting of hydrogen, alkyl, substituted
alkyl,
alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, acyl, aryl,
heteroaryl,
heterocyclic, and the like; Rc is selected from the group consisting of alkyl,
substituted alkyl, alkenyl, substituted alkenyl, aryl, heteroaryl,
heterocyclic,
thioalkoxy, substituted amino, cycloalkyl, and substituted cycloalkyl; t is an
integer from 0 to 4; t is an integer from 0 to 3; and w is an integer from 0
to 3.
Preferably t is an integer from 0 to 2 and, more preferably, is an integer
equal to 0 or 1.
In one preferred embodiment of this invention, W is a cyclic group of the
formula:
~Rs~p -_. _ ~R~~q
N~
R
O
wherein

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_6ø_
each R6 is independently selected from the group consisting of acyl,
acylamino, acyloxy, alkenyl, substituted alkenyl, alkoxy, substituted alkoxy,
alkyl,
substituted alkyl, alkynyl, substituted alkynyl, amino, substituted amino,
aminoacyl, aryl, aryloxy, carboxyl, carboxyalkyl, cyano, cycloalkyl,
substituted
cycloalkyl, halo, heteroaryl, heterocyclic, nitro, thioalkoxy, substituted
thioalkoxy, thioaryloxy, thioheteroaryloxy, -SO-alkyl, -SO-substituted alkyl, -
SO-
aryl,
-SO-heteroaryl, -SOZ-alkyl; -SO~-substituted alkyl, -SOZ-aryl, and -SOZ-
heteroaryl;
each R' is independently selected from the group consisting of acyl,
acylamino, acyloxy, alkenyl, substituted alkenyl, alkoxy, substituted alkoxy,
alkyl,
substituted alkyl, alkynyl, substituted alkynyl, amino, substituted amino,
aminoacyl, aryl, aryloxy, carboxyl, carboxyalkyl, cyano, cycloalkyl,
substituted
cycloalkyl, halo, heteroaryl, heterocyclic, nitro, thioalkoxy, substituted
thioalkoxy, thioaryloxy, thioheteroaryloxy, -SO-alkyl, -SO-substituted alkyl, -
SO-
aryl,
-SO-heteroaryl, -SO~-alkyl, -SO,-substituted alkyl, -SO,-aryl, and -SO~-
heteroaryl;
R8 is selected from the group consisting of hydrogen, alkyl, substituted
alkyl, alkenyl, substituted alkenyl, alkynyi, substituted alkynyl, acyl, aryl,
cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl,
heteroaryl and heterocyclic;
p is an integer from 0 to 4; q is an integer from 0 to 4.
Preferably, R6 and R' are independently selected from the group consisting
of alkoxy, substituted alkoxy, alkyl, substituted alkyl, amino, substituted
amino,
carboxyl, carboxyalkyl, cyano, halo, nitro, thioalkoxy and substituted
thioalkoxy.
More preferably, when present, R6 and R' are fluoro.

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10
R8 is preferably selected from the group consisting of hydrogen, alkyl,
substituted alkyl, acyl, aryl, cycloalkyl and substituted cycloalkyl. More
preferably, Rg is selected from the group consisting of hydrogen, alkyl,
substituted
alkyl and cycloalkyl.
Particularly preferred R8 substituents include, by way of example,
hydrogen, methyl, 2-methypropyl, hexyl, methoxycarbonylmethyl, 3,3-dimethyl-
2-oxobutyl, 4-phenylbutyl, cyclopropylmethyl, 2,2,2-trifluoroethyl,
cyclohexyl,
and the like.
In another preferred embodiment of this invention, W is a cyclic group of
the formula:
(R')r
\ /
N
O
wherein R°, R', and p are as defined herein and r is an integer from 0
to 3.
In still another preferred embodiment of this invention, W is a cyclic group
of the formula:
(
O

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wherein R6 and p are as defined herein.
In yet another preferred embodiment of this invention, W is a cyclic ring of
S the formula:
O
wherein R6 and p are as defined herein.
In still another preferred embodiment of this invention, W is a cyclic ring
of the formula:
~R9~9
~Rs~p
~R9~s
~N~
R8
O
wherein R6, Rg and p are as defined herein; and
each R9 is independently selected from the group consisting of alkyl,
substituted alkyl, alkenyt, substituted alkenyl, alkynyl, substituted alkynyl,
aryl,
cyctoalkyl, substituted cyctoalkyl, cycloalkenyl, substituted cycloalkenyl,
1 S heteroaryt and heterocyctic; and g is an integer from 0 to 2.
When present, R9 is preferably alkyl or substituted alkyl.

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In another preferred embodiment of this invention, W is a cyclic ring of the
formula:
~Rfi~p \
~R9~9 ~R9~9
N~
R8
O
wherein R6, R8, R9, g and p are as defined herein.
In yet another preferred embodiment of this invention, W is a cyclic ring of
the formula:
~R9~9
~R9~s
N~
R8
O
wherein R6, Rg, Ry, g and p are as defined herein.
In still another preferred embodiment of this invention, W is a cyclic ring
of the formula:
R8 ~Rs~P
O N \ /
N~
R8
O

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wherein R6, each R8 end p are as defined herein.
In another preferred embodiment of this invention, W is a cyclic ring of the
formula:
18 ..- 1R6)P
N \
N~Re
R9)9
wherein R6, each R8, R9, g and p are as defined herein.
In another preferred embodiment of this invention, W is a cyclic ring of the
formula:
Rio ~Rs)P
N~ \
N~
Ra
O
wherein R6, Rg and p are as defined herein; and
R'° is selected from the group consisting of alkyl, substituted
alkyl,
alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, substituted amino,
aryl,
cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl,
heteroaryl, heterocyclic, thioalkoxy and substituted thioalkoxy.
In another preferred embodiment of this invention, W is a cyclic ring of the
formula:

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Rio ~Rs~p
~I
N~E
I
N-D
wherein R6, R'° and p are as defined herein; and
D-E is selected from the group consisting of alkylene, alkenylene,
substituted alkylene, substituted alkenylene and -N=CH-.
In another preferred embodiment of this invention, W is a cyclic ring of the
formula:
~Rs~p
~R9~9 Q ~ I
N~
Ra
O
wherein R6, R8, Rv, g and p are as defined herein; and
Q is oxygen, sulfur, -S(O)- or -S(O~,-.
In another preferred embodiment of this invention, W is a cyclic ring of the
formula:

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~Rs~c
~~N ~ I
N~
R8
O
wherein R6, R8 and p are as defined herein.
In another preferred embodiment of this invention, W is a cyclic ring of the
formula:
N~
Rs
O
wherein Rg is as defined herein.
In the above formulae, preferably each R6 is independently selected from
the group consisting of alkyl, substituted alkyl, alkoxy and halo; each R' is
independently selected from the group consisting of alkyl, substituted alkyl,
alkoxy
and halo; each R8 is independently selected from the group consisting of
alkyl,
substituted alkyl, cycloalkyl and aryl; each R9 is independently selected from
the
group consisting of alkyl, substituted alkyl, cycloalkyl and aryl; and g, p, q
and r
are 0 or I. More preferably, g, p, q and r are 0.
In another preferred embodiment, the cyclic group defined by W, together
with -C(H)pC(=X)-, forms a ring of the formula:

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T
C~l"~w NRZo
CHZ
wherein p is zero or one, T is selected from the group consisting of alkylene,
substituted alkylene, alkenylene, substituted alkenylene, -(R21Z)qR21- and -
ZR21-
where Z is a substituent selected from the group consisting of -O-, -S- and
> NR2~, each R20 is independently selected from the group consisting of alkyl,
alkenyl, alkynyl, cycloalkyl, cycloaikenyl, substituted alkyl, substituted
alkenyl,
substituted alkynyl, aryl, heteroaryl and heterocyclic, each R21 is
independently
alkylene, substituted alkylene, alkenylene and substituted alkenylene with the
proviso that when Z is -O- or -S-, any unsaturation in the alkenylene and
substituted alkenylene does not involve participation of the -O- or -S-, and q
is an
integer of from 1 to 3.
A still further preferred embodiment is directed to a ring group defined by
W, together with -C(H)pC(=X; , of the formula:

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T
-C(H)p ,
CH
NR~R~
wherein p is zero or one, T is selected from the group consisting of alkylene,
substituted alkylene, alkenylene, substituted alkenylene, -(R21Z)qR21- and -
ZR21-
, where Z is a substituent selected from the group consisting of -O-, -S- and
> NR2~, each R20 is independently selected from the group consisting of alkyl,
alkenyl, alkynyl, cycloalkyl, cycloalkenyl, substituted alkyl, substituted
alkenyl,
substituted alkynyl, aryl, heteroaryl and heterocyclic, each R21 is
independently
aIkylene, substituted alkylene, alkenylene and substituted alkenylene with the
proviso that when Z is -O- or -S-, any unsaturation in the alkenylene and
substituted alkenylene does not involve participation of the -O- or -S-, and g
is an
integer of from 1 to 3.
In another preferred embodiment, R'S is H, R' is alkyl or aryl, Rb is alkyl,
substituted alkyl, cycloalkyl or aryl, RZ is methyl, and the compound is a
compound of Formulas I, II or VI.
This invention also provides for novel pharmaceutical compositions
comprising a pharmaceutically inert carrier and one or more of the compounds
described in Formulas I-VI above.
Still further, this invention provides for novel compounds of Formulas I-
VI:

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Rts~ Rts
R' ~ C ~ Y H
L Jn ( )p
Q
Formula I
Rts
R' Z ~ Y H
C In ( )p
X
Formula II
Rts
Rt-SO,- ~ Y H
.. L In ( )p
Formula BI I
X

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Ris Rts Ris
R~ Z N N C N [Y]~ ( H)P
Q
X
Formula IV
C Ris
~ y -(CH)p W
C N ~ ~n
W
O
C(H)P Formula V
X
Ris
R,
N LY~n (CH)F W
Q
Formula VI

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wherein R1 is selected from the group consisting of alkyl, alkenyl, alkynyl, "
cycloalkyl, cycloalkenyl, substituted alkyl, substituted alkenyl, substituted
alkynyl,
substituted cycloalkyl, substituted cycloalkenyl, aryl, heteroaryl and
heterocyclic;
R'is selected from the group consisting of aryl, cycloalkyl, substituted
cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heteroaryl, heterocyclic, -
CH3,
-CH=CHI, -CH=CHR', -CH=CR'R', -CR'=CHZ, -CR'=CHR', -CR'=CR'R', -
C=CH and -C=CR'; with the proviso that when R' is heteroaryl or heterocyclic,
there is no N in R' at a position beta to the C=Q group;
Q is S or O;
R'S is selected from the group consisting of hydrogen, alkyl, substituted
alkyl, aryl, heterocyclic and heteroaryl;
R'S' is selected from the group consisting of hydrogen, hydroxyl, alkyl,
I S substituted alkyl, aryl, heterocyclic and heteroaryl;
W, together with -C(H)pC(=X)-, forms a cycloalkyl, cycloalkenyl,
heterocyclic, substituted cycloalkyl, or substituted cycloalkenyl group
wherein
each of said cycloalkyl, cycloalkenyl, heterocyclic, substituted cycloalkyl or
substituted cycloalkenyl group is optionally fused to form a bi- or multi-
fused ring
system (preferably no more than 5 fused rings) with one or more ring
structures
selected from the group consisting of cycioalkyl, cycloalkenyl, heterocyclic,
aryl
and heteroaryl group which, in turn, each of such ring structures are
optionally
substituted with 1 to 4 substituents selected from the group consisting of
hydroxyl,
keto, thioketo, , halo, alkoxy, substituted alkoxy, thioalkoxy, substituted
thioalkoxy, nitro, cyano, carboxyl, carboxyl esters, alkyl, substituted alkyl,
alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, amino, substituted
amino, -NHC(O)R4, -NHS02R4, -C(O)NH2, -C(O)NHR4, -C(O)NR4R4, -
S(O)R4, -S(O)2R4, -S(O)2NHR4 and -S(O)2NR4R4, where each R4 is

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independently selected from the group consisting of alkyl, substituted alkyl,
aryl
and heteroaryl;
X is selected from the group consisting of oxo (=O), thiooxo (=S),
hydroxyl (-H, -OH), thiol (H,-SH) and hydro (H,H);
Y is represented by the formula:
Rz
/CH ~ / 1VH
C
O
20 wherein each RZ is independently selected from the group consisting of
alkyl,
substituted alkyl, alkenyl, substituted alkenyI, alkynyl, substituted alkynyl,
cycloalkyl, aryl, heteroaryl and heterocyclic;
Z is represented by the formula -T-C(X')(X")C(O)- where T is selected
from the group consisting of a bond covalently linking Rl to -C(X')(X")-,
oxygen,
sulfur, and -NRS where RS is hydrogen, acyl, alkyl, substituted alkyl, aryl,
heterocyclic or heteroaryl group;
RS is hydrogen, alkyl, substituted alkyl, aryl, heterocyclic or heteroaryl
group;

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X' and X" are independently selected from the group consisting of
hydrogen, fluoro, alkyl, substituted alkyl, aryl, heteroaryl, heterocyclic, -
ORS', -
SRS, -N(RS)2, -N(CO)OR'S and -N3, with the proviso that at least one of X' or
X"
is other than hydrogen, hydroxy or fluoro, and with the further proviso that
both
X' and X" cannot both be -ORS', -SRS, -N(RS)Z, -N(CO)OR'S and -N3 ; further,
neither X' and X" can be -ORS , -SRS, -N(RS)z, -N(CO)OR'S or -N3 when T is
other than a bond covalently linking Rl to -C(X')(X")-;
n is an integer equal to 1 or 2;
p is an integer equal to 0 or 1 such that when p is zero, the ring defined by
W and -C(H)pC(=X)- is unsaturated at the carbon atom of ring attachment to Y
and when p is one, the ring is saturated at the carbon atom of ring attachment
to
Y,
with the following provisos:
when R1 is 2-propylpentanoyl, R2 is methyl, and R15 is hydrogen, then
W, together with >CH and >C=X, does not form a 2,3-dihydro-1-methyl-5-
phenyl-1H-1,4-benzodiazepin-2-one
when R1 is 3,5-difluorobenzoyl, R2 is methyl, and R15 is hydrogen, then
W, together with > CH and > C=X, does not form a 2,3-dihydro-1-methyl-5-(2-
pyridyl)-1 H-1,4-benzodiazepin-2-one
when R1 is trans-cinnamyl, R2 is methyl, and R15 is hydrogen, then W,
together with > CH and > C=X, does not form a 2,3-dihydro-1-(3,3-dimethyl-2-
oxobutyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one

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when R1 is 2-(4-chlorophenoxy)-2-methylpropionyl, R2 is methyl, and R15
is hydrogen, then W, together with > CH and > C=X, does not form a 2,3-
dihydro-1-methyl-5-(2-pyridyl)-1 H-1,4-benzodiazepin-2-one <.
when RI is a-methoxyphenylacetyl, R2 is methyl, and R15 is hydrogen,
then W, together with > CH and > C=X, does not form a 2,3-dihydro-1-methyl-
5-(2-pyridyl)-IH-1,4-benzodiazepin-2-one
when R1 is diphenylacetyl, R2 is methyl, and R15 is hydrogen, then W,
together with >CH and >C=X, does not form a 2,3-dihydro-1-methyl-5-(2-
pyridyl)-1H-1,4-benzodiazepin-2-one
when R1 is a-methoxyphenylacetyl, R2 is methyl, and R15 is hydrogen,
then W, together with > CH and > C=X, does not form a 2,3-dihydro-I-(3,3-
dimethyl-2-oxobutyl)- 5-(2-pyridyl)-IH-1,4-benzodiazepin-2-one
when Rl is a-hydroxy-diphenylacetyl, R2 is methyl, and R15 is hydrogen,
then W, together with > CH and > C=X, does not form a 2,3-dihydro-1-(3,3-
dimethyl-2-oxobutyl)- 5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one
when R1 is diphenylacetyi, R2 is methyl, and R15 is hydrogen, then W,
together with >CH and >C=X, does not form a 2,3-dihydro-1-(3,3-dimethyl-2-
oxobutyl)- 5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one
when Rl is 2-(chlorophenoxy)-2-methylpropionyl, R2 is methyl, and R15
is hydrogen, then W, together with > CH and > C =X, does not form a 2,3-
dihydro-1-{3,3-dimethyl-2-oxobutyl)- 5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one

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when Rl is diphenylacetyl, R2 is methyl, and RIS is hydrogen, then W,
together with > CH and > C=X, does not form a 2,3-dihydro-1-(2-N,N-
diethylaminoethyl)- 5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one
S when R1 is 3,5-difluorobenzoyl, R2 is methyl, and R15 is hydrogen, then
W, together with >CH and >C=X, does not form a 2,3-dihydro-1-(2-N,N-
diethylaminoethyl)- S-(2-pyridyl)-1H-1,4-benzodiazepin-2-one
when R1 is trans-cinnamyl, R2 is methyl, and R15 is hydrogen, then W,
together with >CH and >C=X, does not form a 2,3-dihydro-1-(2-N,N-
diethylaminoethyl)- 5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one
when R1 is 2-(4-chlorophenoxy)-2-methylpropionyl, R2 is methyl, and R15
is hydrogen, then W, together with > CH and > C=X, does not form a 2,3-
dihydro-1-(2-N,N-diethylaminoethyl)- 5-(2-pyridyl}-1H-1,4-benzodiazepin-2-one
when R1-N(R'S) is (2,5-dimethoxyphenyl}ureylenyl and R2 is methyl, then
W, together with > CH and > C=X, does nat form a 2,3-dihydro-1-methyl-5-
phenyl-1 H-1,4-benzodiazepin-2-one
when R1 is D,L-2-pyrrolidinone-5-yl, R2 is methyl, and R15 is hydrogen,
then W, together with > CH and > C=X, does not form a 7-methyl-5,7-dihydro-
6H-dibenz[b,d]azepin-6-one.
As is appreciated by the skilled person, compounds of the present invention
exist as isomers. Herein, the Cahn-Prelog-Ingold designations of (R)- and (S)-
and, for amino acid derived portions of the compounds, the L- and D-
designations
of stereochemistry relative to the isomers of glyceraldehyde are used to refer
to
specific isomers where designated. The specific isomers can be prepared by

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stereospecific synthesis or can be resolved and recovered by techniques known
in
the art. such as, chromatography on chiral stationary phases, and fractional
recrystallization of addition salts formed by reagents used for that purpose.
Useful
methods of resolving and recovering specific stereoisomers are known in the
art
and described, for example, in Stereochemistry of Organic Compounds; E.L.
Eliel
and S.H. Wilen (Wiley-Interscience 1994), Enantiomers, Racemates and
Resolutions, J. Jacques, A. Collet and S.J. Wilen (Wiley-Interscience 1981),
and
European Patent Application No. EP-A-838448, published April 29, 1998. It is
to
be understood that the invention extends to all of the isomeric forms of the
compounds of the present invention, including the diastereomeric, enantiomeric
and racemic forms of the compounds.
Preferred compounds described herein include those set forth in the tables
below:

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TABLE 1-I
R' O
H r~3 0
N---
N
_~ R
N Q H
Rz

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Ex. R R' R R
1-1 2-thiophene-ylmethyl phenyl methyl
1-2 2-furanyl methyl phenyl methyl
1-3 cyclobutyl methyl phenyl methyl
1-4 1-phenyl methyl phenyl methyl
cyclopropyl
1-S cyclohexyl methyl phenyl methyl
1-6 2-benzofuranylmethyl phenyl methyl
1-7 5-chloro methyl phenyl methyl
benzofuran-2-yl
1-8 5,5-dimethyl-methyl phenyl methyl
butyrolactone-
4-yl
1-9 3-furoyl methyl phenyl methyl
1-10 4-methyl methyl phenyl methyl
sulfonyl
phenyl
1-11 cis-2-phenylmethyl phenyl methyl
1-12 5-methyl methyl phenyl methyl
sulfonyl
thiophen-2-yl
1-13 1,8-dimethyl-6-methyl phenyl methyl
hydroxy-
bicyclo[2.2.2]0
ct-2-yl
1-14 1,4-benzo methyl phenyl methyl
dioxan-2-yl
1-15 tetrahydro methyl phenyl methyl
furan-3-yl
1-16 cyclohex-3-ene-methyl phenyl phenyl
yl
1-17 cyclopropyl methyl phen I
y
1-18 3,5-difluoromethyl phenyl phen
l
Y
phenyl
-
1-19 2- methyl 2-pyridyl methyl
pyrrolidinone-
[ 1-21 ~ 1-phenyl methyl 2-pyridyl methyl

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1-22 1-phenyl 2-oxo-3,3- 2-pyridyl methyl
cyclopropyl dimethylbutyl
1-23 3,5- 2-oxo-3,3- 2-pyridyl methyl
difluorophenyldimethylbutyl
1-24 2- 2-oxo-3,3- 2-pyridyl methyl
pyrrolidinone-dimethylbutyl
5-yl
1-26 1-phenyl 2-diethyl 2-pyridyl methyl
c clo ro yl aminoeth
1
TABLE 1-1
cont'd
Ex. R R R R
1-27 4-methylphenylmethyl phenyl phenyl
1-28 4-methylphenylmethyl phenyl methyl
1-29 3-pyridyl methyl phenyl methyl
1-30 2-naphthyl methyl phenyl methyl
1-31 1-naphthyl methyl phenyl methyl
1-32 4-chloro- methyl phenyl methyl
thiophene-yl
1-33 4-cyanophenylmethyl phenyl methyl
1-34 tetrahydroturanmethyl phenyl methyl
-2-yl
1-35 3,5-dilluoromethyl phenyl methyl
phenyl
1-36 cyclohex-3-ene-methyl phenyl methyl
yl
1-37 1,2,3,4- methyl phenyl methyl
tetrahydro
naphth-2-yl
1-38 cyclopentyl methyl phenyl methyl
1-39 4-tritluoro methyl phenyl methyl
methyl
c clohex
1

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TABLE 1-1
cont'd
Ex. R R R R
1-40 bicyclo[2.2.1]methyl phenyl methyl
hept-2-yl
1-41 bicyclo[2.2.1]methyl phenyl methyl
hept-5-ene-2-yl
1-42 2,2-dichloromethyl phenyl methyl
cyclopropyl
1-43 cycloheptyl methyl phenyl methyl
1-44 1-(2,4-dichloromethyl phenyl methyl
phenyl}-
cyclopropyl
1-45 cis-2-methylmethyl phenyl methyl
cyclopropyl
1-46 1-(4-chloro methyl phenyl methyl
pheny 1 )
cyclobutyl
1-47 2-phenylphenylmethyl phenyl methyl
1-48 1,2-dihydro-1-methyl phenyl methyl
oxo-2-phenyl-
4-isoquinolinyl
1-49 bicyclo[3.3.1]nmethyl phenyl methyl
on-6-ene-3-yl
1-50 cyclopropyl methyl phenyl methyl
1-51 tetrahydro methyl phenyl methyl
furan-2-y
1
1-52 3,5-diftuoromethyl phenyl methyl
phenyl
1-53 cyclohex-3-ene-methyl phenyl methyl
yl
1-54 1,2,3,4- methyl phenyl methyl
tetrahydro
naphth-3-yl
1-55 c clo ent meth 1 hen 1 meth
1 1

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TABLE I-2
S
H O \
R
N
N\
N
O
H O
Ex. R
1-56 tetrahydrofuran-3-yl
1-57 cyclopropyl
1-59 bicyclo[2.2.1]heptan-2-
- yl
1-60 tetrahydrofuran-2-y
l
1-61 cyclopentyl
1-62 thio hene-2- 1

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TABLE 2-1
R'
O
H F13 O
N
N
N . ~ I ~~'C z
O H X X
R2
15
Ex. R X X- R R ~~ R
2-1 benzyl phenyl H methyl phenyl methyl
2-2 phenyl ethyl H methyl phenyl methyl
2-4 phenyl isopropylH methyl phenyl methyl
2-5 butyl ethyl H methyl phenyl methyl
2-6 ethyl methyl H methyl phenyl methyl
2-7 2,2,2- methyl H methyl phenyl methyl
trifluoro-
ethy I
2-8 phenyl phenyl H methyl phenyl phenyl
2-9 4-chloro methyl H methyl phenyl methyl
pheny
1
2-10 4-chloro methyl methyl methyl phenyl methyl
phenyl -
2-11 phenyl methyl hydroxylmethyl phenyl methyl
2-12 hen l hen 1 h drox meth 1 2- rid meth
1 1 1

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Ex. R X' ~ X- R' R ~ R
2-15 phenyl phenyl hydroxyl2-oxo-3,3-2-pyridylmethyl
2-17 phenyl phenyl hydroxyl2-diethyl2-pyridylmethyl
amino
ethyl
2-18 3,5- methyl hydroxylmethyl phenyl methyl
difluoro
phenyl
2-19 3,5- methyl hydroxylmethyl phenyl methyl
difluoro
hen 1
.S
TABLE Z-2
0 H R' 0
N
R
-N x
I X~ i" X2
0 H

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Ex. R R' ~ X' X
2-20 phenyl methyl phenyl H
2-21 H methyl H H
2-22 propyi methyl methyl H
2-23 phenyl methyl hydroxymethylH
2-24 ethyl methyl ethyl H
2-25 methyl methyl methyl methyl
2-26 phenyl methyl phenyl H
2-27 H phenyl H H
2-28 isopropylmethyl thioacetyl H
~ 2-29 f isopropylmethyl thio H ~
~

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TABLE 2-3
X~ Xz ~ O
N
p - O
Ex. R X' X
2-30 phenyl methyl H
2-31 butyl methyl H
2-32 phenyl phenyl H
2-33 phenyl methyl hydroxy
1
2-34 phenyl hydroxyl methyl
2-35 methyl hydroxyl methyl
2-36 ethyl hydroxyl methyl
2-37 isopropyl thioacetyl H
2-38 H - H H
2-39 iso ro t thiol H

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TABLE 3-1
RZ
O
N
N
O H
R'
Ex. R R-
3-1 _ methyl
phenyl
3-2 2- rid ( methyl

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TABLE 3-2
H O
N
O R " O
Ex. _ R
3-5 Methvl

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TABLE 4-1
H
I ~N
R
Nii~,,~,.
Ra RZ I
H O N
Ex. R ~ R ~ R R R
4-1 phenyl methyl ethyl H phenoxy
4-2 phenyl methyl phenyl H methoxy
4-3 phenyl methyl methyl methyl 4-chlorophenoxy
4-4 phenyl methyl methyl H phenoxy
4-5 phenyl methyl 3,5- H methoxy
difluoro
phenyl
4-6 phenyl methyl 3.5- H methoxy
difluoro
phenyl
4-7 phenyl methyl methyl H 4-hydroxyphenoxy
4-8 phenyl methyl methyl H 4-
trifluoromethoxy
phenoxy
4-9 phenyl methyl methyl H 4-phenylphenoxy
4-10 2-pyridyl 2-(diethylphenyl H methoxy
amino)
ethyl
4-16 phenyl methyl methyl methyl 4-cyano
henox

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TABLE 5-1
H X
N
\N N N/R
15
Ex. R R' X
5-1 trans-2-phenylcyclopropylH O
5-2 3,4-dichlorophenyl H ~ O
5-3 2-propenyl H O
5-4 (1-naphthyl)ethyl H O
5-5 2,6-diisopropylphenylH O
5-6 3-[(trifluoromethyl)phenylH O
5-7 phenyl H O
5-8 (4-ethoxycarbonyl)phenylH O
5-9 2-bromophenyl H O
5-10 o-tolyl H O
5-11 2-ethyl-6-methylphenylH O
5-12 2-fluorophenyl H O
5-13 2,4-difluorophenyl H O
S-14 2-ethoxyphenyl H O
5-IS 3-acetylphenyl H O
5-16 3-[(cyano)phenyl H O
5-18 phenethyl H O
5-19 4-n-but 1 hen 1 H O

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Ex. R ~ R' X
5-20 octyl H O
5-21 4-biphenyl H O
5-22 4-isopropylphenyl H O
5-23 hexyl H O
S 5-24 2-isopropylphenyl H S
5-25 2,6-difluorophenyl H O
5-26 octadecy 1 H O
5-27 4-(trifluoromethoxy)phenylH O
5-28 2,4-dichlorophenyl H O
5-29 3-ethoxycarbonylphenylH O
5-30 4-chlorophenyl H O
5-31 4-butoxyphenyl H O
5-32 4-phenoxyphenyl H O
S-33 1-naphthyl H O
5-34 2-biphenyl H O
5-35 2-(methylthio)phenylH O
5-36 2-ethylphenyl H O
5-37 3-methoxyphenyl H O
5-38 3,4,5-trimethoxyphenylH O
5-39 2,4,6-trimethylphenylH O
5-40 2-methyl-6-t-butylphenylH O
5-41 2-(2-thiophene-yl H O
TABLE 5-2
R, H O I
N N N\
R/
_ H O

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Ex. R ~ R'
5-43 (2-thiophene-yl)ethylH
5-44 phenethyl H
5-45 butyl H
S S-4b benzyl H
5-47 ethyl H
5-48 2-hydroxy-2-phenethylH
5-49 hexyl H
5-SO cyclohexyl H
5-51 isopropyl H
5-52 t-butyl H
5-53 1-adamantyl H
5-54 2-methylpropyl H
S-55 3-hydroxy-3-phenylethylH
5-56 3-methylbutyl H
5-57 (S)-1-hydroxymethyl-3-H
methylbutyl
5-58 ( 1 S)-(2S)-1- H
hydroxymethyl-2-
methylbutyl
5-59 3-chloropropyl H
5-60 octyl H
S-61 1,1,3,3-tetramethylbutylH
5-62 (R/S)-1-methylbutyl H
5-63 5-(S)-((N'-(R/S)-1- H
hydroxymethylbutyl
5-64 (R/S)-1,3-dimethylbutylH
5-65 (R)-1-hydroxymethyl-3-H
methylbutyl
5-66 (R/S)-2-methylbutyl H
5-67 morpholino H
5-68 2-(2-hydroxyethoxy)-ethylH
5-69 piperidinyl H
S-70 N"-methyl-N"-butyl H
S-71 1-(R/S)- H
hydroxymethylcyclopentyl
5-72 4-hydroxybutyl H
5-73 1-(R/S)-h drox methyl-2-H

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5-74 2-(R/S)-hydroxycyclohexylH
5-75 isopropyl OH
5-76 1-(benzyl) OH
5-77 thiomorpholinyl H
5-78 2(R/S)-hydroxybutyl H
5-79 2.2,2-trifluoroethylH
5-80 (4RIS)-cyclohexyl H
5-81 hydroxymethyl-3- H
meth Ithio ro 1

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TABLE 6-1
i5
0 H
II R
N
~N . Ni
0
O R'
Ex. R R
6-I phenyl H
6-2 3-t7uorophenyl H
6-3 be nzy t H
6-4 butyl H
6-5 octvl H

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TABLE 7-1
p R p
H
~N N ~ /R
N C
p
R
Ex. R R' R"
7-1 3,5- NHZ isopropyl
difluorophenyl
7-2 3,5- NH, t-butyl
difluorophenyl
7-3 isopropyl NH, methyl
7-4 phenyl NH, methyl
7-5 3,5-difluoroNH, methyl
(Isomer A) phenyl
7-6 3,5-dif7uoroNH, methyl
(Isomer B) phenyl
7-8 isopropyl NH, methyl
7-9 phenyl NH, methyl
7-10 3,5- NH, methyl
(Mixture difluorophenyl
of
isomers)
7-11 phenyl CF,C(O)NH- methyl
7-12 isopropyl NHCH3 methyl
7-13 1-trifluoro NHS methyl
methyl-2,2,2-
trifluoroeth
1

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TABLE 7-2
15
O H
CH3 O .
\ N R
N !
N ~~R
N O.
H H

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TABLE 7-3
H ~ O
N .-. N
O ~N
CJi3 1-f
N
O I
CH3
Ex. R R'
7-17 phenyl NH,
7-18 iso ro NH,
I

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TABLE 7-4
H O C
H N
v N N
Q CH3 H
~N
O
Cti~
Ex. R R'
7-19 3,5-difluoro NH,-HCl
phenyl
7-20 3,5-difluoro NH,-HCI
hen 1

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TABLE 7-5
H O
N
H2N
_
O CH3
Ex. R.
36361 1-trifluoromethyl
ethyl
36362 3 .3.3-trifluoropropyl
36363 ~,~.2-trifluoroethyl

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TABLE 7-6
O
N
HzN N
O ~3 H O Kt
1S
Ex. R
36364 1-trifluoromethyl methyl
ethyl
36365 3.3,3-trifluoropropylmethyl
36366 2,2,2-trifluoroethylmethyl
36367 ethyl methyl
36368 1-(trifluoromethyl)-2,2,2-methyl
trifluoroethyl
36369 ethyl isobutyl

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TABLE 8-1
H 0
N ICH3
Niii,,,,.
'N
H H t
15

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TABLE 9-1
0
0
O
N
15
Ex.
9-1 methyl

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TABLE 9-2
0 0
N
~N..
f ~ I ~-N
\ /
Ex. R
9-2 ~ methy 1

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TABLE 10-1
H O
Cl~
A~ C/N\N N N
O H
15 Ex.
10-1 - 3,5_
difluoro hen lmethvl
TABLE 10-2
H O
R.
~N N
O
O R H O

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I>rx. IR IR' i
10-2

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Also included within the scope of this invention are prodrugs of the
compounds of Formulas I-VI described above including acylated forms of
alcohols
and thiols, aminals of one or more amines, and the like, as well as acid
addition
salts of amines. This invention is not intended to encompass subject matter
disclosed and claimed in co-pending U.S.S.N. 08/996,422, the contents of which
are hereby incorporated ~by reference in its entirety.
DETAILED DESCRIPTION OF THE INVENTION
As above, this invention relates to compounds that inhibit ~3-amyloid
peptide release and/or its synthesis, and, accordingly, have utility in
treating
Alzheimer's disease. However, prior to describing this invention in further
detail,
the following terms will first be defined.
Definitions
The term " /3-amyloid peptide" refers to a 39-43 amino acid peptide having
a molecular weight of about 4.2 kD, which peptide is substantially homologous
to
the form of the protein described by Glenner, et al.l including mutations and
post-
translational modifications of the normal ~i-amyloid peptide. In whatever
form,
the (3-amyloid peptide is an approximate 39-43 amino acid fragment of a large
membrane-spanning glycoprotein, referred to as the ~3-amyloid precursor
protein
(APP). Its 43-amino acid sequence is:
1
Asp Ala Glu Phe Arg His Asp Ser Gly Tyr
Glu Val His His Gln Lys Leu Val Phe Phe

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Ala Glu Asp Val Gly Ser Asn Lys Gly Ala
Ile Ile Gly Leu Met Val Gly Gly Val Val
Ile Ala Thr (SEQ ID NO: 1 )
or a sequence which is substantially homologous thereto.
"Alkyl" refers to monovalent alkyl groups preferably having from 1 to 20
carbon atoms, more preferably 1 to 10 carbon atoms and most preferably 1 to 6
carbon atoms. This term is exemplified by groups such as methyl, ethyl, n-
propyl,
iso-propyl, n-butyl, iso-butyl, n-hexyl, and the like.
"Substituted alkyl" refers to an alkyl group, preferably of from 1 to 10
carbon atoms, having from 1 to 5 substituents, and preferably 1 to 3
substituents,
selected from the group consisting of alkoxy, substituted alkoxy, cycloalkyl,
substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, acyl,
acylamino,
acyloxy, amino, substituted amino aminoacyl, aminoacyloxy, oxyacylamino,
cyano, halogen, hydroxyl, keto, thioketo, , carboxyl, carboxylalkyl, thiol,
thioalkoxy, substituted thioalkoxy, aryl, aryloxy, heteroaryl, heteroaryloxy,
heterocyclic, hydroxyamino, alkoxyamino, nitro, -SO-alkyl, -SO-substituted
alkyl,
-SO-aryl, -SO-heteroaryl, -S02-alkyl, -S02-substituted alkyl, -S02-aryl,
-S02-heteroaryl, and mono- and di-alkylamino, mono- and di-(substituted
alkyl)amino, mono- and di-arylamino, mono- and di-heteroarylamino, mono- and
di-heterocyclic amino, and unsymmetric di-substituted amines having different

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substituents selected from alkyl, substituted alkyl, aryl, heteroaryl and
heterocycIic.
"Alkylene" refers to divalent alkylene groups preferably having from 1 to
10 carbon atoms and more preferably 1 to 6 carbon atoms. This term is
exemplified by groups such as methylene (-CH2-), ethylene (-CH2CH2-), the
propylene isomers (e.g., -CH2CH2CH2- and -CH(CH3)CH2-) and the like.
"Substituted alkylene" refers to an alkylene group, preferably of from 1 to
10 carbon atoms, having from 1 to 3 substituents selected from the group
consisting of alkoxy, substituted alkoxy, acyl, acylamino, acyloxy, amino,
substituted amino aminoacyl, aminoacyloxy, oxyacylamino, , cyano, halogen,
hydroxyl, keto, thioketo, , carboxyl, carboxylalkyl, thiol, thioalkoxy,
substituted
thioalkoxy. aryl, heteroaryl, heterocyclic, heterocyclooxy, heterocyclooxy, ,
I S nitro, and mono- and di-alkylamino, mono- and di-(substituted alkyl)amino,
mono-
and di-arylamino, mono- and di-heteroarylamino, mono- and di-heterocyclic
amino, and unsymmetric di-substituted amines having different substituents
selected from alkyl, substituted alkyl; aryl, heteroaryl and heterocyclic.
Additionally, such substituted alkylene groups include those where 2
substituents
on the alkylene group are fused to form one or more cycloalkyl, aryl,
heterocyclic
or heteroaryl groups fused to the alkylene group. Preferably, such fused
cycloalkyl groups contain from 1 to 3 fused ring structures.
"Alkenylene" refers to divalent alkenylene groups preferably having from 2
to 10 carbon atoms and more preferably 2 to 6 carbon atoms. This term is
exemplified by groups such as ethenylene (-CH=CH-), the propenylene isomers
(e.g., -CH2CH=CH- and -C(CH3)=CH-) and the like.

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"Substituted alkenylene" refers to an alkenylene group, preferably of from
2 to 10 carbon atoms, having from 1 to 3 substituents selected from the group
consisting of alkoxy, substituted alkoxy, acyl, acylamino, acyloxy, amino,
substituted amino aminoacyl, aminoacyloxy, oxyacylamino. , cyano, halogen,
hydroxyl, keto, thioketo, , carboxyl, carboxylalkyl, thiol, thioalkoxy,
substituted
thioalkoxy, aryl, heteroaryl, heterocyclic, heterocyclooxy, nitro, and mono-
and
di-alkylamino, mono- and di-(substituted alkyl)amino, mono- and di-arylamino,
mono- and di-heteroarylamino, mono- and di-heterocyclic amino, and unsymmetric
di-substituted amines having different substituents selected from alkyl,
substituted
alkyl, aryl, heteroaryl and heterocyclic. Additionally, such substituted
alkylene
groups include those where 2 substituents on the alkylene group are fused to
form
one or more cycloalkyl, aryl, heterocyclic or heteroaryl groups fused to the
alkytene group.
"Alkaryl" refers to -alkylene-aryl groups where alkyiene and aryl are as
defined herein. Such alkaryl groups are exemplified by benzyl, phenethyl and
the
like.
"Alkoxy" refers to the group "alkyl-O-", where alkyl is as defined above.
Preferred alkoxy groups include, by way of example, methoxy, ethoxy, n-
propoxy, iso-propoxy, n-butoxy, tent-butoxy, sec-butoxy, n-pentoxy, n-hexoxy,
1,2-dimethylbutoxy, and the like.
"Substituted alkoxy" refers to the group "substituted alkyl-O-" where
substituted alkyl is as defined above.
"Alkylalkoxy" refers to the group "-alkylene-O-alkyl"where alkylene and
alkyl are as defined above. Such groups include methylenemethoxy (-CH20CH3),

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ethylenemethoxy (-CH2CH20CH3), n-propylene-iso-propoxy (-
CH2CH2CH20CH(CH3)2), methylene-t-butoxy (-CH2-O-C(CH3)3) and the like.
"Alkylthioaikoxy" refers to the group "-alkylene-S-alkyl" where alkylene
and alkyl are as defined above. Such groups include methylenethiomethoxy (-
CH2SCH3), ethylenethiomethoxy (-CH2CH2SCH3), n-propylene-thio-iso-propoxy
(-CH2CH2CH2SCH(CH3)2), methylenethio-t-butoxy (-CH2SC(CH3)3) and the
like.
"Alkenyl" refers to alkenyl groups preferably having from 2 to 10 carbon
atoms and more preferably 2 to 6 carbon atoms and having at least 1 and
preferably from 1-2 sites of alkenyl unsaturation. Preferred alkenyl groups
include
ethenyl (-CH=CH2), n-propenyl (-CH2CH=CH2), iso-propenyl (-
C(CH3)=CH2), and the like.
"Substituted alkenyl" refers to an alkenyl group as defined above having
from 1 to 3 substituents selected from the group consisting of alkoxy,
substituted
alkoxy, acyl, acylamino, acyloxy, amino, substituted amino aminoacyl,
aminoacyloxy, oxyacylamino, , cyano. halogen, hydroxyl, keto, thioketo, ,
carboxyl, carboxylalkyl, thiol, thioalkoxy, substituted thioalkoxy. aryl,
heteroaryl,
heterocyciic, heterocyclooxy, nitro. -SO-alkyl, -SO-substituted alkyl, -SO-
aryl, -
SO-heteroaryl. -S02-alkyl, -S02-substituted alkyl, -S02-aryl, -S02-heteroaryl,
and mono- and di-alkylamino, mono- and di-(substituted alkyl)amino, mono- and
di-arylamino, mono- and di-heteroarylamino, mono- and di-heterocyclic amino,
and unsymmetric di-substituted amines having different substituents selected
from
alkyl, substituted alkyl, aryl, heteroaryl and heterocyclic.
"Alkynyl" refers to alkynyl groups preferably having from 2 to 10 carbon
atoms and more preferably 2 to 6 carbon atoms and having at Ieast 1 and

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preferably from 1-2 sites of alkynyl unsaturation. Preferred alkynyl groups
include ethynyl (-CH~CH2), propargyl (-CH2C~H) and the like.
"Substituted alkynyl" refers to an alkynyl group as defined above having
from 1 to 3 substituents selected from the group consisting of aIkoxy,
substituted
alkoxy, acyl, acylamino, acyloxy, amino, substituted amino aminoacyl,
aminoacyloxy, oxyacylamino, , cyano, halogen, hydroxyl, keto, thioketo, .
carboxyl, carboxylalkyl, thiol. thioalkoxy, substituted thioalkoxy, aryl,
heteroaryl,
heterocyclic, heterocyclooxy, nitro, -SO-alkyl, -SO-substituted alkyl, -SO-
aryl, -
SO-heteroaryl, -S02-alkyl, -S02-substituted alkyl, -S02-aryl,
-S02-heteroaryl, and mono- and di-alkylamino, mono- and di-(substituted
alkyl)amino, mono- and di-arylamino, mono- and di-heteroarylamino, mono- and
di-heterocyclic amino, and unsymmetric di-substituted amines having different
substituents selected from alkyl, substituted alkyl, aryl, heteroaryl and
heterocyclic.
"Acyl" refers to the groups alkyl-C(O)-, substituted alkyl-C(O)-,
cycloalkyl-C(O)-, substituted cycloalkyl-C(O)-, aryl-C(O)-, heteroaryl-C(O)-
and
heterocyclic-C(O)- where alkyl, substituted alkyl, cycloalkyl, substituted
cycloalkyl, aryl, heteroaryl and heterocyclic are as defined herein.
"Acylamino" refers to the group -C(O)NRR where each R is independently
hydrogen, alkyl, substituted alkyl, aryl, heteroaryl, or heterocyclic wherein
alkyl,
substituted alkyl, aryl, heteroaryl and heterocyclic are as defined herein.
Substituted amino" refers to the group -N(R)2, where each R is
independently selected from the group consisting of hydrogen, alkyl,
substituted
alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl,
cycloalkyl,
substituted cycloalkyl, heteroaryl, heterocyclic and where both R groups are
joined

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to form a heterocyclic; group. When both R groups are hydrogen, -N(R)2 is an
amino group. Examples of substituted amino groups include, by way of example,
mono- and di-alkylamino, mono- and di-(substituted alkyl)amino, mono- and di-
arylamino, mono- and diheteroarylamino, mono and di-heterocyclic amino, and
unsymmetric di-substituted amines having different substituents selected from
the
group consisting of alkyl, substituted alkyl, aryl, heteroaryl, heterocyclic
and the
like.
"Aminoacyl" refers to the group -NRC(O)R where each R is independently
hydrogen, alkyl, substituted alkyl, aryl, heteroaryl, or heterocyclic wherein
alkyl,
substituted alkyl, aryl, heteroaryl and heterocyclic are as defined herein.
"Aminoacyloxy" refers to the group -NRC(O)OR where each R is
independently hydrogen, alkyl, substituted alkyl, aryl, heteroaryl, or
heterocyclic
1S wherein alkyl, substituted alkyl, aryl, heteroaryl and heterocyclic are as
defined
herein.
"Acyloxy" refers to the groups alkyl-C(O)O-, substituted alkyl-C(O)O-,
cycloalkyl-C(O)O-, aryl-C(O)O-, heteroaryl-C(O)O-, and heterocyclic-C(O)O-
wherein alkyl, substituted alkyl, cycioalkyl, aryl, heteroaryl, and
heterocyclic are
as defined herein.
"Aryl" refers to an unsaturated aromatic carbocyclic group of from 6 to 14
carbon atoms having a single ring (e.g., phenyl) or multiple condensed (fused)
rings (e.g., naphthyl or anthryl). Preferred aryls include phenyl, naphthyl
and the
like. Unless otherwise constrained by the definition for the aryl substituent,
such
aryl groups can optionally be substituted with from 1 to 5 substituents and
preferably 1 to 3 substituents selected from the group consisting of acyloxy,
1 to 5
and preferably 1 to 3 substituents selected from the group consisting of
hydroxy,

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acyl, alkyl, alkoxy, alkenyl, alkynyl, substituted alkyl, substituted alkoxy,
substituted alkenyl, substituted alkynyl, amino, substituted amino, aminoacyl,
acylamino, alkaryl, aryl, aryloxy, azido, carboxyl, carboxylalkyl, cyano,
halo.
nitro, heteroaryl, heteroaryloxy, heterocyclic, heterocyclooxy, aminoacyloxy,
oxyacylamino, thioalkoxy, substituted thioalkoxy, thioaryloxy,
thioheteroaryloxy,
-SO-alkyl, -SO-substituted alkyl. -SO-aryl,
-SO-heteroaryl, -S02-alkyl, -S02-substituted alkyl, -S02-aryl,
-S02-heteroaryl, trihalomethyl. Preferred substituents include alkyl, alkoxy,
halo,
cyano, nitro, trihalomethyl, and thioalkoxy.
"Aryloxy" refers to the group aryl-O- wherein the aryl group is as defined
above including optionally substituted aryl groups as also defined above.
"Carboxyalkyl" refers to the group "-C(O)Oalkyl" and "-C(O)O-substituted
alkyl" where alkyl and substituted alkyl are as defined above.
"Cycloalkyl" refers to cyclic alkyl groups of from 3 to 12 carbon atoms
having a single cyclic ring or multiple condensed rings. Such cycloalkyl
groups
include, by way of example, single ring structures such as cyclopropyl,
cyclobutyl.
cyclopentyi, cyclohexyl, cycloheptyl, cyclooctyl, and the like, or multiple
ring
structures such as adamantanyl, bicyclo(2.2.1]heptyl, bicyclo(2.2.1)hept-5-ene-
yl,
bicyclo (3.3.1)non-6-ene-3-carboxyl) and the like.
"Substituted cycloalkyl" refers to cycloalkyl groups having from 1 to 5
(preferably 1 to 3) substituents selected from the group consisting of
hydroxy,
acyl, acyloxy, alkyl, substituted alkyl, alkoxy, substituted alkoxy, alkenyl,
substituted alkenyl, alkynyl, substituted alkynyl, amino, substituted amino
aminoacyl, alkaryl, aryl, aryloxy, carboxyl, carboxylalkyI, cyano, halo,
nitro,
heteroaryl. thioalkoxy, substituted thioalkoxy, trihalomethyl and the like.

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"Cycloalkenyl" refers to cyclic alkenyl groups of from 4 to 12 carbon
atoms having at least one cyclic ring and preferably no more than four rings,
which rings are optionally fused, and which include at least one point of
internal
unsaturation. Examples of suitable cycloalkenyl groups include, for instance,
cyclobut-2-enyl, cyclopent-3-enyl, cyclooct-3-enyl and the like.
"Substituted cycloalkenyl" refers to cycloalkenyl groups having from 1 to 5
substituents selected from the group consisting of hydroxy, acyl, acyloxy,
alkyl,
substituted alkyl, alkoxy, substituted alkoxy, alkenyl, substituted aikenyl,
alkynyl,
substituted alkynyl, amino, substituted amino aminoacyl, alkaryl, aryl,
aryloxy,
carboxyl, carboxylalkyl, cyano, halo, nitro, heteroaryl, thioalkoxy,
substituted
thioalkoxy, trihalomethyl and the like.
"Halo" or "halogen" refers to fluoro, chloro, bromo and iodo and
preferably is either fluoro or chloro.
"Heteroaryl" refers to an aromatic carbocyclic group of from 1 to 15
carbon atoms and 1 to 4 heteroatoms selected from oxygen, nitrogen and sulfur
within at least one ring (if there is more than one ring).
Unless otherwise constrained by the definition for the heteroaryl
substituent, such heteroaryl groups can be optionally substituted with from 1
to 5
substituents and preferably 1 to 3 substituents selected from the group
consisting of
acyloxy, 1 to S and preferably 1 to 3 substituents selected from the group
consisting of hydroxy, acyl, alkyl, alkoxy, alkenyl, alkynyl, substituted
alkyl,
substituted alkoxy, substituted alkenyl, substituted alkynyl, amino,
substituted
amino, aminoacyl, acylamino, alkaryl, aryl, aryloxy, azido, carboxyl,
carboxylalkyl, cyano, halo, nitro, heteroaryl, heteroaryloxy, heterocyclic.

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heterocyclooxy, aminoacyloxy, oxyacylamino, thioalkoxy, substituted
thioalkoxy,
thioaryloxy, thioheteroaryloxy, -SO-alkyl, -SO-substituted alkyl, -SO-aryl,
-SO-heteroaryl. -S02-alkyl, -S02-substituted alkyl, -S02-aryl,
-S02-heteroaryl, trihalomethyl. Preferred substituents include alkyl, alkoxy,
halo,
cyano, nitro, trihalomethyl, and thioalkoxy. Such heteroaryl groups can have a
single ring (e.g., pyridyl or furyl) or,multiple condensed rings (e.g.,
indolizinyl or
benzothienyl). Preferred heteroaryls include pyridyl, pyrrolyl and furyl.
"Heteroaryloxy" refers to "O-heteroaryl", where heteroaryl is as defined
herein.
"Heterocyclooxy" refers to "O-heterocyclic", where heterocyclic is as
defined herein.
"Heterocycle" or "heterocyclic" refers to a monovalent saturated or
unsaturated group having a single ring or multiple condensed rings, from 1 to
15
carbon atoms and from 1 to 4 hetero atoms selected from nitrogen, sulfur or
oxygen within the ring.
Unless otherwise constrained by the definition for the heterocyclic
substituent, such heterocyclic groups can be optionally substituted with 1 to
5
substituents selected from the group consisting of alkyl, substituted alkyl,
alkoxy,
substituted alkoxy, aryl, aryloxy, halo, nitro, heteroaryl, thiol, thioalkoxy,
substituted thioalkoxy, thioaryloxy, trihalomethyl, and the like. Such
heterocyclic
groups can have a single ring or multiple condensed rings. Preferred
heterocyclics
include morpholino, piperidinyl, and the like.
Examples of nitrogen heterocycles and heteroaryls include, but are not
limited to, pyrrole, imidazole, pyrazole, pyridine, pyrazine, pyrimidine,

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pyridazine, indolizine, isoindole, indole, indazole, purine, quinolizine,
isoquinoline, quinoline, phthalazine, naphthylpyridine, quinoxaline,
quinazoline,
cinnoline, pteridine, carbazole, carboline, phenanthridine, acridine,
phenanthroline, isothiazole, phenazine, isoxazole, phenoxazine, phenothiazine,
imidazolidine, imidazoline, piperidine, piperazine, indoline, morpholino,
piperidinyl, tetrahydrofuranyl, and the like as well as N-alkoxy-nitrogen
containing heterocycles.
"Oxyacylamino" refers to the group -OC(O)NRR where each R is
independently hydrogen, alkyl, substituted alkyl, aryl, heteroaryl, or
heterocyclic
wherein alkyl, substituted alkyl, aryl, heteroaryl and heterocyclic are as
defined
herein.
"Thiol" refers to the group -SH.
"Thioalkoxy" refers to the group -S-alkyl.
"Substituted thioalkoxy" refers to the group -S-substituted alkyl.
"Thioaryloxy" refers to the group aryl-S- wherein the aryl group is as
defined above including optionally substituted aryl groups also defined above.
"Thioheteroaryloxy" refers to the group heteroaryl-S- wherein the
heteroaryl group is as defined above including optionally substituted aryl
groups as
also defined above.
As to any of the above groups that contain 1 or more substituents, it is
understood, of course, that such groups do not contain any substitution or

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substitution patterns which are sterically impractical and/or synthetically
non-feasible.
"Pharmaceutically acceptable salts" refers to pharmaceutically acceptable ,.
salts of a compound of Formulas I-VI which salts are derived from a variety of
organic and inorganic counter ions well known in the art and include, by way
of
example only, sodium, potassium, calcium, magnesium, ammonium,
tetraalkylammonium, and the like; and when the molecule contains a basic
functionality, salts of organic or inorganic acids, such as hydrochloride,
hydrobromide, tartrate, mesylate, acetate, maleate, oxalate and the like can
be
used as the pharmaceutically acceptable salt.
The term "protecting group" or "blocking group" refers to any group
which when bound to one or more hydroxyl, amino or carboxyl groups of the
compounds (including intermediates thereof such as the aminolactams,
aminolactones, etc.) prevents reactions from occurring at these groups and
which
protecting group can be removed by conventional chemical or enzymatic steps to
reestablish the hydroxyl, amino or carboxyl group. The particular removable
blocking group employed is not critical and preferred removable hydroxyl
blocking groups include conventional substituents such as allyl, benzyl,
acetyl,
chloroacetyl, thiobenzyl, benzylidine, phenacyl, t-butyl-diphenylsilyl and any
other
group that can be introduced chemically onto a hydroxyl functionality and
later
selectively removed either by chemical or enzymatic methods in mild conditions
compatible with the nature of the product.
Preferred removable amino blocking groups include conventional
substituents such as t-butyoxycarbonyl (t-BOC}, benzyloxycarbonyl (CBZ), and
the like which can be removed by conventional conditions compatible with the
nature of the product.

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Preferred carboxyl protecting groups include esters such as methyl, ethyl,
propyl, t-butyl etc. which can be removed by mild hydrolysis conditions
compatible with the nature of the product.

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Compound Pre aration
Amidation Chemistry
Compounds including amide linkages can be readily prepared by
conventional amidation of a carboxyl acid as shown in reaction (1) below
where,
for the sake of illustration, n is one:
Rz
Rf ~Z ~ NH 1
O
~W
HZN-CH
C
X
i
'N -CH
R' ~ ~''~ NH
O C (Reaction 1 )
X

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10
wherein R1, R2, W, X, and Z are as defined above. The reaction is
conventionally conducted by using at least a stoichiometric amount of
carboxylic
acid _1 and amine 2. This reaction is conventionally conducted for peptide
synthesis and synthetic methods used therein can also be employed to prepare
compound ~ which is a compound of formula I above. For example, well known
coupling reagents such as carbodiimides with or without the use of well known
additives such as N-hydroxysuccinimide, 1-hydroxybenzotriazole, etc. can be
used
to facilitate coupling. The reaction is conventionally conducted in an inert
aprotic
polar diluent such as dimethylformamide, dichloromethane, chloroform,
acetonitrile, tetrahydrofuran and the like. Alternatively, the acid halide of
compound ,~ can be employed in reaction ( 1 ) and, when so employed, it is
typically employed in the presence of a suitable base to scavenge the acid
generated during the reaction. Suitable bases include, by way of example,
triethylamine, diisopropylethylamine, N-methylmorpholine and the like.
Various compounds as described herein can be prepared by N-substitution
reactions of compound ~. Reaction of compound ,~ with an carboxylic acid

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derivative can also lead to various compounds as described herein. Both
reactions
are described below.
Carboxylic acids ~ can be prepared by several divergent synthetic routes
with the particular route selected relative to the ease of compound
preparation,
commercial availability of starting materials, whether n :~ one or two.
A. Synthesis of Carboxylic Acids
t0 When n is one, a first synthetic method involves the introduction of the Rl
group to the amino acid NH2CH(R2)COOH or ester thereof.
The introduction of the Rl group onto the amino acid NH2CH(R2)COOH
or ester thereof can be accomplished in several methods. For example,
conventional coupling of a halo acetic acid with a primary amine forms an
amino
acid as shown in reaction (2) below:

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O O
Z' _ N
+ R~ NHZ ----~ R' ~ OH
Rz 4 5 6 Rz
(Reaction 2}
15
wherein R1 and R2 are as defined above and Z is a halo group such as chloro or
bromo. Alternatively, leaving groups other than halo may be employed such as
triflate and the like. Additionally, suitable esters of 4 may be employed in
this
reaction.
As above, reaction (2) involves coupling of a suitable haloacetic acid
derivative 4_ with a primary amine ~ under conditions that provide for amino
acid
1. This reaction is described by, for example, Yates, et al.l4 and proceeds by
combining approximately stoichiometric equivalents of haloacetic acid 4 with
primary amine ~ in a suitable inert diluent such as water, dimethylsulfoxide
(DMSO) and the like. The reaction employs an excess of a suitable base such as
sodium bicarbonate, sodium hydroxide, etc. to scavenge the acid generated by
the

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reaction. The reaction is preferably conducted at from about 25°C to
about 100°C
until reaction completion which typically occurs within 1 to about 24 hours.
This
reaction is further described in U.S. Patent No. 3,598,859, which is
incorporated
herein by reference in its entirety. Upon reaction completion, N-substituted
amino
S acid ø is recovered by conventional methods including precipitation,
chromatography, filtration and the Iike.
In reaction (2), each of the reagents (haloacetic acid ~, primary amine ~
and alcohol ~) are well known in the art with a plurality of each being
commercially available.
In an alternative embodiment, the R1 group can be coupled to an alanine
ester (or other suitable amino acid ester) by conventional N-arylation. For
example, a stoichiometric equivalent or slight excess of the amino acid ester
can be
dissolved in a suitable diluent such as DMSO and coupled with a halo-R1
compound, Z -R1 where Z is a halo group such as chloro or bromo and Rl is as
defined above. The reaction is conducted in the presence of an excess of base
such
as sodium hydroxide to scavenge the acid generated by the reaction. The
reaction
typically proceeds at from 15°C to about 250°C and is complete
in about 1 to 24
hours. Upon reaction completion. N-substituted amino acid ester is recovered
by
conventional methods including chromatography, filtration and the like. This
ester
is then hydrolyzed by conventional methods to provide for carboxylic acid 1
for
use in reaction (1).
In still another alternative embodiment, the esterifted amino acids described
above can be prepared by reductive amination of a suitable pyruvate ester in
the
manner illustrated in reaction (3) below:

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O
O Z
H R, /~
R + Rt-NHZ Catalyst _OR
(Reaction 3)
R O RZ
7 ~ 8

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wherein R is typically an alkyl group and Rl and R2 are as defined above.
In reaction (3), approximately stoichiometric equivalents of pyruvate ester
~ and amine $ are combined in an inert diluent such as methanol, ethanol and
the
like and the reaction solution treated under conditions that provide for imine
formation (not shown). The imine formed is then reduced under conventional
conditions by a suitable reducing agent such as sodium cyanoborohydride,
H2/palladium on carbon and the like to form the
N-substituted amino acid ester $. In a particularly preferred embodiment, the
reducing agent is H2/palladium on carbon which is incorporated into the
initial
reaction medium which permits imine reduction in situ in a one pot procedure
to
provide for the N-substituted amino acid ester $.
The reaction is preferably conducted at from about 20°C to about
80°C at a
pressure of from 1 to 10 atmospheres until the reaction is complete, which
typically occurs within I to about 24 hours. Upon reaction completion. N-
substituted amino acid ester $ is recovered by conventional methods including
chromatography, filtration and the like.
Subsequent hydrolysis of the ester $ leads to the corresponding carboxylic
acid derivative _1 which can be employed in reaction (1) above.
For compounds where n is two, conventional coupling of a second amino
acid (e.g., NH2CH(R2)C(O)OR where R is typically an alkyl group) to the amino
acid produced above (i.e., RiNHCH(R2)COOH) provides for esters of an
analogue of carboxylic acid ~ which are then conventionally de-esterified to
provide for an analogue of compound _l.

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Alternatively, an ester such as H2NCH(R2)C(O)NHCH(R2)COOR where
each R2 is independently as defined above and R is typically an alkyl group
can
first be formed by conventional peptide synthetic procedures, N-substitution
can be
conducted in the manner described above followed by de-esterification to
provide
for analogues of carboxylic acids ~ where n is two.
When n is one, a first synthetic method involves conventional coupling of
an carboxylic acid derivative with a primary amine of an esterified amino acid
as
shown in reaction (4) below:
X. ~ i O
.f. HzN
X"
OR
Rz 9 1o Rz
(Reaction 4)
X' X"
~ O
R
OR
O R2
t1

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S
wherein R is typically an alkyl group, and Rl, R2, X' and X" are as defined
above.
Reaction (4) merely involves coupling of a suitable carboxylic acid
derivative _9 with the primary amine of amino acid ester ~,Q under conditions
that
provide for the N-acetyl derivative ~. Alternatively, the carboxylic acid
R'COOH can be used in place of compound 9 to provide intermediates useful for
preparing compounds of Formula VI above. This reaction is conventionally
conducted for peptide synthesis and synthetic methods used therein can also be
employed to prepare the N-acetyl amino acid esters ~ of this invention. For
example, well known coupling reagents such as carbodiimides with or without
the
use of well known additives such as N-hydroxysuccinimide, 1-
hydroxybenzotriazole, etc. can be used to facilitate coupling. The reaction is
conventionally conducted in an inert aprotic polar diluent such as
dimethylformamide, dichloromethane, chloroform, acetonitrile, or
tetrahydrofuran. Alternatively, the acid halide of compound Q can be employed
in
reaction (4) and, when so employed, it is typically employed in the presence
of a
suitable base to scavenge the acid generated during the reaction. Suitable
bases
include, by way of example, triethylamine, diisopropylethylamine, and N-
methylmorpholine.
Reaction (4) is preferably conducted at from about 0°C to about
60°C until
the reaction is complete, which typically occurs within 1 to about 24 hours.
Upon
reaction completion, N-acetyl amino acid ester ~ is recovered by conventional
methods including precipitation, chromatography, and filtration or
alternatively is

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hydrolyzed to the corresponding acid without purification and/or isolation
other
than conventional work-up (e.g., aqueous extraction, etc.).
In reaction (4), each of the reagents (carboxylic acid derivative .Q and amino
acid ester ~Q) are well known in the art with a plurality of each being
commercially available.
When n is two, a further amino acid ester is coupled to the amino acid ester
~ by first de-esterifying ~ and then using well known peptide coupling
chemistry
with well known coupling reagents such as carbodiimides with or without the
use
of well known additives such as N-hydroxysuccinimide and 1-
hydroxybenzotriazole,.which can be used to facilitate coupling. The reaction
is
conventionally conducted in an inert aprotic polar diluent such as
dimethylformamide, dichloromethane. chloroform, acetonitrile, or
1 S tetrahydrofuran. De-esterification of the resulting ester provides for
carboxylic
acids _1 having n equal to 2.
Alternatively, carboxylic acids 1 having n equal to 2 can be prepared by
first forming the ester, N-acetylating these esters and then de-esterifying
the
resulting product.
Carboxylic acids ~ having n equal to 1 or 2 can also be prepared by using
polymer-supported forms of carbodiimide peptide coupling reagents. A polymer-
supported form of EDC, for example, has been described (Tetrahedron Letters,
34(48), 7685 (1993))1. Additionally, a new carbodiimide coupling reagent,
PEPC, and its corresponding polymer-supported forms have been discovered and
are very useful for preparing such compounds.

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Polymers suitable for use in making a polymer-supported coupling reagent
are either commercially available or may be prepared by methods well known to
those of skill in the polymer arts. A suitable polymer must possess pendant
sidechains bearing moieties reactive with the terminal amine of the
carbodiimide.
S Such reactive moieties include chloro, bromo, iodo and methanesulfonyl.
Preferably, the reactive moiety is a chloromethyl group. Additionally, the
polymer backbone must be inert to both the carbodiimide and reaction
conditions
under which the ultimate polymer-bound coupling reagents will be used.
Certain hydroxymethylated resins may be converted into chloromethylated
resins useful for the preparation of polymer-supported coupling reagents.
Examples of these hydroxylated resins include the 4-
hydroxymethylphenylacetamidomethyl resin (Pam Resin) and 4-benzyloxybenzyl
alcohol resin (Wang Resin) available from Advanced Chemtech of Louisville,
Kentucky, USA (see Advanced Chemtech 1993-1994 catalog, page 115). The
hydroxymethyl groups of these resins may be converted into the desired
chloromethyl groups by any of a number of methods well known to the skilled
artisan.
Preferred resins are the chloromethylated styrene/divinylbenzene resins
because of their ready commercial availability. As the name suggests, these
resins
are already chloromethylated and require no chemical modification prior to
use.
These resins are commercially known as Merrifield's resins and are available
from
Aldrich Chemical Company of Milwaukee, Wisconsin. USA (see Aldrich 1994-
1995 catalog, page 899). Methods for the preparation of PEPC and its polymer-
supported forms are outlined in the following scheme.

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~NCo
. ti N
O
~~a .
1 .o
w
~~ w.= c = N
LG
Fun~ai~cee Reain
'"'~ O ~ art mare ~olyr~
] $ ana lC a C. 8t ! ar OSO~cliz
~N N-C =,y
p C.

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Such methods are described more fully in PCT Application
PCT/US97/22986, which application is incorporated herein by reference in its
entirety. Briefly, PEPC is prepared by first reacting ethyl isocyanate with 1-
(3-
aminopropyt)pyrroIidine. The resulting urea is treated with 4-toluenesulfonyl
chloride to provide PEPC. The polymer-supported form is prepared by reaction
of
PEPC with an appropriate resin under standard conditions to give the desired
reagent.
The carboxylic acid coupling reactions employing these reagents are
performed at about ambient temperature to about 45°C, for from about 3
to 120
hours. Typically, the product is isolated by washing the reaction mixture with
CHC13 and concentrating the remaining organics under reduced pressure. As
discussed supra, isolation of products from reactions where a polymer bound
reagent has been used is greatly simplified, requiring only filtration of the
reaction
mixture and then concentration of the filtrate under reduced pressure.
Sulfonamidation Chemistry
Sulfonamides, such as those in Formula III, can be readily prepared
using known sulfonamidation reactions. These typically involve the reaction of
sulfonyl chlorides with primary or secondary amines in the presence of a
tertiary
amine or other suitable acid scavenger (See, for Example, page 923. Morrison
and
Boyd, Organic Chemistry, fourth edition).
Suitable sulfonic acids can be prepared by several divergent synthetic
routes with the particular route selected relative to the ease of compound
preparation, and commercial availability of starting materials.
A. Synthesis of Sulfonic Acids

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Alkyl sulfonic acids can be prepared using means well known to those of
skill in the art, as described, for example, in U.S. Patent Nos. 2,493,038 and
2,697,722, the contents of which are hereby incorporated by reference. One
method for preparing alkyl sulfonic acids is by the oxidation of disulfides,
which
can themselves be prepared by the oxidation of thiols. Aromatic sulfonic acids
can
be produced by the sulfonating action of sulfuric acid, SO,, oleum or alkyl
sulfonic
acids on aromatic compounds using techniques well known to those of skill in
the
art.
Activation of Sulfonic Acids
Suitable sulfonic acid derivatives can be prepared, for example, by
reacting a sulfonic acid with a chlorinating reagent such as phosphorous
pentachloride or sulfonyl chloride.
Preu~ration of Ureas
Ureas can be prepared by any known methodology, but preferably
are prepared by reacting an amine with an isocyanate, as described on page 844
of
Morrison and Boyd, Organic Chemistry, Fourth Edition, Allyn and Bacon, ed.,
Boston (1983). Suitable isocyanates can be prepared using methods known to
those of skill in the art.
Cyclic amino compounds Z employed in reaction (1) above are generally
aminolactams, aminolactones, aminothiolactones and aminocycloalkyl compounds
which can be represented by the formula:

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W'
..
/Q
C
X
wherein X is as defined above, Q is preferably selected from the group
consisting of -O-, -S-, > NR6, and > CR~RB where each of R6, R~ and R8 are
independently selected from the group consisting of hydrogen, alkyl,
substituted
alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl,
heteroaryl
and heterocyclic with the proviso that if Q is -O-. -S- or > NR6, then X is
oxo or
dihydro, and W together with Q, C=X and CH forms a lactone, thiolactone,
lactam, cyclic ketone, cyclic alcohol. a heterocycle. and the like.
The aminolactams, aminolactones and aminothiolactones of the formulas
above can be prepared by use or adaptation of known chemical syntheses which
syntheses are well described in the literature. See, e.g., Ogliaruso and
Wolfe.
Synthesis of Lactones and Lactams. Patai, et al. Editor, J. Wiley & Sons, New
York, New York, USA, pp. 1085 et seq. (1993)15.
Specifically, 3-amino substituted lactams ~ with S, 6 or 7 ring atoms may
be prepared by the direct cyclization of a suitable a, omega-diamino acid
ester ~
as shown in reaction (5) below:

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O
--L -----,,. ~ ~
L
~~V1~-~ r ..
(Reaction 5)
wherein L is a linking group (typically an alkylene group) of from 2-4 atoms,
Pr is
a suitable protecting group such as t-butoxycarbonyl, carbobenzyloxy, or the
like
and R9 is an alkoxy or aryloxy group such as methoxy, ethoxy,
p-nitrophenoxy, N succinimidoxy, and the like. The reaction may be carried out
in a solvent such as water, methanol, ethanol, pyridine, and the like. Such
reactions are exemplified by cyclization of a lysine ester to a caprolactam as
described by Ugi, et al., Tetrahedron, ?(35):11657-11664 (1996)16.
Alternatively, such a cyclization can also be conducted in the presence of
dehydrating agents such as alumina or silica to form lactams as described by
Blade-Font, Tetrahedron Lett., 2_x:2443 (1980)17.
The preparation of aminolactams alkylated on the amino group of the cyclic
lactam is described by Freidinger, et al. , J. Org. Chern. , 47:104-109 (
1982)18 and
illustrated in reaction (6) below:
O
CE"' 6 t ~ S2t,:::y ifc't
R
ar;~iraacrt FLfiY
~"""~r
~2N ~~ O 2 Cyc:iz3~crt L (Reaction 6)
L ~ ~r
wherein L and R6 are as defined above.

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In reaction (6), reductive amination of 14 with aldehyde l5 and subsequent
ring closure by methods using, for example, EDC provides for aminolactam 1~.
The preparation of 6 membered lactams using this general procedure is
described
by Semple, et al., J. Med. Chem., ~Q:4531-4536 (1996)19.
The internal cyclization of ari amide anion with a halide or equivalent
thereof can sometimes be used to particular advantage in the synthesis of
smaller
ring lactams where the stereochemistry of the amino-lactam center is available
from the standard amino-acid pool. This approach is illustrated in reaction
(7)
below:
SMe
N ~"6 N~.=s5
-' ?cc~:N 1 (Reacrioa 7)
1~ ~ ~ C
where R6 is as defined above.
The approach of reaction (7) is presented by Semple, et al., sttpra.l9, and
Freidinger, et al., J. Org. Chem., 47:104-109 (1982)18 where a
dimethyisulfonium leaving group is generated from methyl iodide treatment of
an
alkyl methyl sulfide ~ to provide for lactam ~$. A similar approach using a
Mitsunobu reaction on an omega alcohol is found Holladay, et al. , J. Org.
Chem. ,
x:3900-3905 (1991)20.
In another method, lactams ~ can be prepared from cyclic ketones 1 Q
using either the well known Beckmann rearrangement (e.g., Donaruma, et al.,

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Organic Reactions, ~:1-156 (1960))21 or the well known Schmidt reaction
(Wolff, Organic Reactions, x:307-336 (1946))22 as shown in reaction (8) beiow:
~ECkr;;aut r~2r~ art~e~;~rrt
cr
~c:;ric~t n_c;~crt ~_~~ ~ (Reaction 8)
O
wherein L is as defined above.
Appiication of these two reactions leads to a wide variety of lactams
especially lactams having two hydrogen atoms on the carbon a to the lactam
carbonyl which lactams form a preferred group of lactams in the synthesis of
the
I S compounds described above. In these reactions, the L group can be highly
variable including, for example, alkylene, substituted alkylene and hetero
containing alkylene with the proviso that a heteroatom is not adjacent to the
carbonyl group of compound 19. Additionally, the Beckmann rearrangement can
be applied to bicyclic ketones as described in Krow, et al., J. Org. Chem.,
øx:5574-5580 ( 1996)23.
The preparation of lactones can be similarly conducted using peracids in a
Baeyer-Villiger reaction on ketones. Alternatively, thiolactones can be
prepared
by cyclization of an omega -SH group to a carboxylic acid and thiolactams can
be
prepared by conversion of the oxo group to the thiooxo group by P2S5 or by use
of the commercially available Lawesson's Reagent, Tetrahedron, .x:2433
(1979)24.

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One recently reported route for lactam synthesis is a variation of the
Schmidt reaction through the use of an alkyl azide, either intermolecularly or
intramolecularly, through a tethered alkylazide function that attacks a ketone
under
acidic conditions. Gracias. et al., J. Am. Chem. Soc., ,1 X7:8047-8048
(1995)25
describes the intermolecular version whereas Milligan, et al., J. Am. Chem.
Soc.,
x:10449-10459 (1995)26 describes.the intramolecular version. One example of
the intramolecular version is illustrated in reaction (9) below:
0 O
Q
-.~-... ,- -N= -;v
Rzn ~ zo
~ZQ (Reaction 9)
where R10 is exemplified by alkyl. substituted alkyl, alkoxy, substituted
alkoxy,
aryl, heteroaryl, cycloalkyl and heterocyclic.
In this reaction, ketone ~ is converted to an a-(w-alkyl)ketone 22 which is
cyclized to form bicyclic lactam ~. Such intramolecu(ar reactions are useful
in
forming bicyclic lactams having 5-7 members and the lactam ring of 6-13
members. The use of heteroatoms at non-reactive sites in these rings is
feasible in
preparing heterobicyclic lactams.
Still another recent approach to the synthesis of lactams is described by
Miller, et al. , J. Am. Chem. Soc. , X1,.$:9606-9614 ( 1996)2 and references
cited
and is illustrated in reaction (10) below:

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Ru
Pr, .-
...___.," ..
FtZN ~N.
d . P r d A /~ R
where R6 and Pr are as defined above and Rl 1 is exemplified by halo, alkyl,
substituted alkyl, alkoxy, substituted alkoxy, aryl, heteroaryl, cycloalkyl
and
heterocyclic wherein the aryl, heteroaryl, cycloalkyl and heterocyclic group
is
optionally fused to the lactam ring structure.
Specifically, in reaction (10), lactam ~ø is formed from an appropriate
unsaturated amide (e.g., 24) through a ruthenium or molybdenum complexes
catalyzed olefin metathesis reaction to form unsaturated lactam ~ which can be
used herein without further modification. However, the unsaturation in ~
permits
a myriad of techniques such as hydroboration, Sharpless or Jacobsen
epoxidations,
Sharpless dihydroxylations, Diels-Alder additions, dipolar cycloaddition
reactions
and many more chemistries to provide for a wide range of substituents on the
lactam ring. Moreover, subsequent transformations of the formed substitution
leads to other additional substituents (e.g., mesylation
of an alcohol followed by nucleophilic substitution reactions). See, for
example,
March, et al. for a recitation of numerous such possible reactions 2g
Saturated
2S amides used in this reaction are conventional with amide 24 being
commercially
available.

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Related chemistry to cyclize amides to form lactams is disclosed by
Colombo, et al., Tetrahedron Lett., x(23):4031-4034 (1994)29 and is
illustrated
in reaction (11) below:
Ac~IV ~V -'~'~c.~iV
V
D
C~2~~u o CVZtQe (Reaction 11)
In this reaction, proline derivative 27 is cyclized via a tributyltin-radical
cyclization to provide for lactam ~$.
Some of the lactams described above contain the requisite amino group a to
the lactam carbonyl whereas others did not. However, the introduction of the
required amino group can be achieved by any of several routes delineated below
which merely catalogue several recent literature references for this
synthesis.
For example, in a first general synthetic procedure, azide or amine
displacement of a leaving group a to the carbonyl group of the lactam leads to
the
a-aminolactams. Such general synthetic procedures are exemplified by the
introduction of a halogen atom followed by displacement with phthalimide anion
or
azide and subsequent conversion to the amine typically by hydrogenation for
the
azide as described in Rogriguez, et al., Tetrahedron, x:7727-7736 (1996)30,
Parsons, et al., Biochem. Biophys. Res. Comm., 1:108-113 (1983)31 and
Watthey, et al., J. Med. Chem., ?$:15/1-1516 (1985)32. One particular method

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involves iodination and azide displacement on, for example, benzyllactams as
described by Armstrong, et al., Tetrahedron Lett., x:3239 (1994)33 and by
King,
et al. , J. Org. Chem. , x$:3384 ( 1993)34.
Another example of this first general procedure for the synthesis of a-
aminolactams from the corresponding lactam involves displacement of a triflate
group by an azido group as described by Hu, et al. , Tetrahedron Lett. ,
x(21):3659-3662 (1995)35.
Still another example of this first general procedure uses a Mitsunobu
reaction of an alcohol and a nitrogen equivalent (either -NH2 or a phthalimido
group) in the presence of an azodicarboxylate and a triarylphosphine as
described
in Wada, et al. , Bull. Chem. Soc. Japan, ,4:2833-2835 ( 1973)36 using an open
chain reagent.
Yet another example of this first general procedure involves reaction of a-
chlorolactams with anilines or alkyl amines in a neat mixture at 120°C
to provide
for 2-(N-aryl or N-alkyl)lactams as described by Gaetzi, Chem. Abs. ,
øø:28690m, 37
In a second general synthetic procedure, reaction of an enolate with an
alkyl nitrite ester to prepare the a oxime followed by reduction yields the a-
aminolactam compound. This general synthetic procedure is exemplified by
Wheeler; et al., Organic Syntheses, Coll. Vol. VI, p. 84038 which describes
the
reaction of isoamyl nitrite with a ketone to prepare the desired oxime. The
reduction of the oxime methyl ester (prepared from the oxime by reaction with
methyl iodide) is described in the J. Med. Chem.,,~$(12):1886 (1985)39 and the
reduction of a-oximino caprolactams by Raney-nickel and palladium catalysts is
described by Brenner, et al., U.S. Patent No. 2,938,029.40

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in a third general synthetic procedure, direct reaction of an enolate with an
electrophilic nitrogen transfer agent can be used. The original reaction
employed
toluenesulfonyl azide but was improved as described by Evans, et al. , J. Am.
Chem. Soc., x:4011-4030 (1990)41. Specifically, direct introduction of an
S azido group which can be reduced to the amine by hydrogenation is described
by
Micouin, et al., Tetrahedron. x:771.9-7726 (1996)42. Likewise, the use of
triisopropylbenzenesulfonyl azide as the azide transferring agent for reaction
with
an enolate is described by Evans, et al., supra. The use of triphenylphosphine
to
reduce the a-azidolactams to the corresponding aminolactams in the
benzodiazepine series is disclosed by Butcher, et al., Tetrahedron Lett.,
X7(37):6685-6688 (1996).43 Lastly, diazo transfer of ~i-diketones and
subsequent
reduction of the diazo group to the amino group is exemplified by Hu, et al.,
Tetrahedron Lett., xø(21):3659-3662 (1995)35 who used Raney-nickel and
hydrogen in acetic acid and acetic anhydride as the solvent.
In a fourth general procedure, N-substituted lactams are first converted to
the 3-alkoxycarbonyl derivatives by reaction with a dialkyl carbonate and a
base
such as sodium hydride. See, for example, M.L. Reupple, et al.. J. Am. Chem.
Soc., x:7021 et seq. (1971) The resulting esters serve as starting materials
for
conversion to the 3-amino derivatives. This conversion is achieved via the
Curtius
reaction as shown in reaction (12) below:
..
w R:.
L-.V ~ '
_,...~ L - ~V.
c
a

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where Pr is as defined above and R12 is typically hydrogen, an alkyl or an
aryl
group.
The Curtius reaction is described by P.A.S. Smith, Organic Reactions,
3_:337-449 (1946).45 Depending on the reaction conditions chosen, Pr = H or a
protecting group such as Boc. For example, when R = H, treatment of the acid
with diphenylphosphoryl azide in the presence of t-butanol provides the
product
wherein Pr = Boc.
The a-aminolactams employed as the cyclic amino compounds ~ in reaction
(1) above include ring N-substituted lactams in addition to ring N-H lactams.
Some methods for preparing ring N-substituted lactams have been described
above. More generally, however, the preparation of these compounds range from
the direct introduction of the substituent after lactam formation to
essentially
introduction before lactam formation. The former methods typically employ a
base and an primary alkyl halide although it is contemplated that a secondary
alkyl
halide can also be employed although yields may suffer.
Accordingly, a first general method for preparing N-substituted lactams is
achieved via reaction of the lactam with base and alkyl halide (or acrylates
in some
cases). This reaction is quite well known and bases such as sodamide, sodium
hydride, LDA, LiHMDS in appropriate solvents such as THF, DMF, etc. are
employed provided that the selected base is compatible with the solvent. See
for
example: K. Orito, et al., Tetrahedron, 3:1017-1021 (1980)46 and J.E. Semple,
et al., J. Med. Chem., x:4531-4536 (1996)19 (use of LiHMDS with either R-X
or acrylates as electrophiles).
A second general method employs reductive amination on an amino
function that is then cyclized to an appropriate ester or other carbonyl
function.

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A third general method achieves production of the N-substitution during
lactam formation. Literature citations report such production from either
photolytic or thermal rearrangement of oxaziridines, particularly of N-aryl
compounds. See, for example, Krimm, Chem. Ber. , x:1057 (1958)47 and Suda,
S et al. , J. Chem. Soc. Chem Comm. , 949-950, ( 1994) 48 Also, the use of
methyl
hydroxylamine for the formation of nitrones and their rearrangement to the N-
methyl derivatives is reported by Burton, et al. , J. Chem. Soc. , 1764-1767
(1975).49 Additionally, the use of the oxaziridine process in chiral synthesis
has
been reported by Kitagawa, et al. , J. Am. Chem. Soc. , x:5169-5178 (1975).50
A more direct route to obtain N-phenyl substituted lactams from the
corresponding NH lactams through the use of t-butyltetramethylguanidine and
triphenylbismuth dichloride is disclosed by Akhatar, et al., J. Org. Chem.,
5:5222-5225 (1990)51 as shown in reaction (13) below.
O
y ~ (Reaction 13)
O N ~ _..~ O N.J
~l

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Given that numerous methods are available to introduce an a-amino group
onto a lactam (or lactone) ring, the following lactams (and appropriate
corresponding lactones) are contemplated for use in the synthesis of compounds
described above. Similar alcohol functions at the carbonyl position are
derivative
of either amine ring opening of cyclic epoxides, ring opening of aziridines,
displacement of appropriate halides with amine or alcohol nucleophiles, or
most
likely reduction of appropriate ketones. These ketones are also of interest to
the
present invention.
Monocyciic lactams as described by Nedenskov, et al., Acta Chem. Scand.,
.~~:1405-1410 (1958)52 are represented by the formula:
O
NH
R~
RZ
where R1 and R2 are exemplified by alkyl, aryl or alkenyl (e.g., allyl).
Monocyclic lactams containing a second nitrogen ring atom as described by
Sakakida, et al. , Bull. Chem. Soc. Japan, X4:478-480 ( 1971 )53 are
represented by
the formula:
0
NH
r
R

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where R is exemplified by CH3- or PhCH2-.
Monocyclic lactams having hydroxyl substitution on the ring as described ..
by Hu, et al., Tetrahedron Lett., x(21):3659-3662 (1995)35 are represented by
the formula:
HO
H2N N
O R
where R is exemplified by benzyl (includes both the cis and trans hydroxy
lactams).
The direct preparation N-substituted lactams of 5-8 members from the
corresponding ketones is described by Hoffman, et al . , Tet. Lett. , ~ :4207-
4210
(1989).54 These lactams are represented by the formula:
O
~O
-_,~ N. 9 . .
(C,~f~n ~ n = t _ Q
(~~t~n
wherein R is alkyl, alkenyl, alkynyl, cycloalkyl, or benzyl.
N-Methoxylactams prepared from cyclohexanone and dimethoxyamine are
described by Vedejs, et al., Tet. Lett., x:3261-3264 (1992) ss These
structures
are represented by the formula:

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N ..
O.
C'~s
Substituted 3-aminoazetidinone derivatives prepared by a variety of routes
including those described by van der Steen, et al. , Tetrahedron, 4Z, 7503-
7524
(1991)56, Hart, et al., Chem Rev., $Q:1447-1465 (1989)57 and references cited
therein are represented by the formula:
Rz
N
~ ~Rz
where Rl and R2 are independently selected from alkyl, substituted alkyl,
alkenyl,
substituted alkenyl, aryl, heteroaryl, heterocyclic or are fused to form a
cyclic
group.
Ring substituted lactams are described by Lowe, et al. , Bioorg. Med.
Chem. Lett. , _4:2877-2882 (1994)58 and are represented by the formula:
R3
R2
H2N N
p ,R r

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wherein R2 and R3 are exemplified by aryl and substituted aryl and Rl is
exemplified by alkyl or hydrogen.
The synthesis of substituted 3-aminopyrrolidones from a-bromoketones is
described by McKennis, Jr. , et al. , J. Org. Chem. , .x$:383-387 ( 1963)59.
These
compounds are represented by the formula:
NHZ
d
Rt~ or ~~, Rt O
Rz
where R1 is aryl or heteroaryl and R2 corresponds to any substituent for which
the
corresponding amine R2-NH2 exists.
Additional references for the synthesis of a aminolactams are as follows:
1. Shirota, et al., J. Med. Chem., ZQ:1623-1627 (1977)60 which describes
the synthesis of
CH3
CH3
HzN N
O H
2. Overberger, et al. , J. Am. Chem. Soc. , $,~ :3431 ( 1963)61 which
describes the preparation of optically active -methylcaprolactam of the
formula:

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H
N ~ .,
3. Herschmann, Helv. Chim. Acta, x:2537 (1949)62 describes the
synthesis of a disubstituted caprolactam from the Beckman rearrangement of
menthone which is represented by the formula:
IS
N
H
4. Overberger, et al. , Macromolecules,1:1 ( 1968)63 describes the
synthesis of eight-membered lactams from 3-methylcycloheptanone as shown
below:
a ~ ~ o J
H N
. O H

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S. The synthesis of benzolactams (benzazepinones) has been reported by
Busacca, et al.. Tet. Lett., x:165-168 (1992)64:
O

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S
by Croisier, et al., U.S. Patent No. 4,080,44965
O
and by J.A. Robl. et al. , Tetrahedron Lett. , ~( 10):1593-1596 ( 1995)66 who
employed an internal Friedel-Crafts like cyclization to prepare the tricyclic
benzyllactams shown below where Pht is the phthalimido protecting group:
E.'Q OE!
~ / -~ / \ / \ /
rr;t-cv ..._...
N ~ht-.V ~N H2~V N
O
CO~c: COyc; C
9~
IO

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Another tricyclic lactam series is disclosed by Flynn, et al., J. Med.
Chem., x:2420-2423 (1993)67 and references cited therein.
6. Orito, et al., Tetrahedron. x:1017-1021 (1980)68 discloses phenyl
substituted benzazepinones represented by the formula:
O
/ ~ N_A
wherein R = H or CH3-;
Kawase, et al., J.Org. Chem., ,5:3394-3403 (1989)69 discloses a N-
methoxy benzazepinone represented by the formula:
N
O
D.
7. Lowe, et al. , J. Med. Chem. , ,x:3789-3811 ( 1994)70 describes several
synthetic pathways to substituted benzazepinones of the formula:
z
NHZ
O
'q2

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where R1 is substituted aryl or cyclohexyl, X is a suitable substituent and R2
can
be H or alkyl. The syntheses described in Lowe are, however, adaptable to form
numerous R1 substituents.
8. Robl, et al., Bioorg. Med. Chem. Lett., x:1789-1794 (1994)71 and
references cited therein as well as Skiles, et al., Bioorg. Med. Chem.
Lett.,~:773-
778 (1993)72 disclose benzofused lactams which contain additional heteroatoms
in
the lactam ring. These compounds are represented by the formula:
RZ
X
NHZ
N
R D
where X is O and R2 = H or CH3 or X = S and R~ = H. In either case, R1 =
..
H or alkyl. Also, in Skiles, the thin group of the thiolactam can be oxidized
to the
S02 group. These structures are also presented from Beckmann rearrangement in
Grunewald. et al., J. Med. Chem., x(18):3539 (1996).73
9. Also syntheses for the benzoheterolactam series is presented in Thomas,
et al., J. Chem. Soc., Perkin II, 747 (1986)74 which could lead to compounds
of
the formula:
~~Z
o.~N_~l
P,''

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where X is O or H2 and R is C02R.
10. Further examples of benzazepinones are found in Warshawsky, et al.,
Bioorg. Med. Chem. Lett. , x:957-962 ( 1996)75 which discloses
N-R
l~Z,v a
to
The synthesis can be generalized to produce R = alkyl or aryl.
11. Ben-Ishai, et al., Tetrahedron, _4:439-450 (1987)76
describes syntheses which could lead to several benzolactams of the formula
~(CH~n
j~~. \N-~
x ~-- o
1-fZN
wherein n = 0,1,2 and R= -CH3, PhCH2- and H.
12. van Niel et al., Bioorg. Med. Chem. Lett., x:1421-1426 (1995)77
reports the synthesis of

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Q H3C O
N N
NHZ ~. ~ NHBoc
O
wherein X is -OH, -NH2 or -NR6R6 where R6 is as defined above. The reported
ketone is a versatile synthetic intermediate which can be modified by
conventional
methods such as reductive amination, reduction, etc.
13 . Kawase, et al. , J. Org. Chem. , 5:3394-3403 ( 1989)78 describes a
20
synthetic method for the preparation of:
NHZ
a o
OCH3
In addition to the above, saturated bicyclic a-aminolactams are also
contemplated for use in the synthesis of compounds of formulas I-VI. Such
saturated bicyclic a-aminolactams are well known in the art. For example.
Edwards, et al., Can. J. Chem., x:1648-1658 (1971)78 describes several
syntheses of bicyclic lactams of the formula:
O R~ O
N N N
A H
Rz
R

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Similarly, Milligan, et al., J. Am. Chem. Soc., X17:10449-10459 (1995)8
and references cited therein report the synthesis of lactams of the formula:
wherein R1 and R2 are H or -CH3, ring A can have from 6-13 members and ring
B can have from 5 - 7 members. R can be alkyl, aryl, cycloalkyl, and the like.
The introduction of a heteroatom into the saturated cyclic structure fused to
the lactam ring is disclosed by Curran et al., Tet. Lett., x:191-194 (1995)81
who
1 S describe a synthetic method which can be used to obtain a lactam of the
formula:
O
NH
N
NH.z
by Slusarchyk, et al., Bioorg. Med. Chem. Lett., x:753-758 (1995)82 who
describe syntheses which could lead to a lactam of the formula:
~S
HZ~'V
O
and by Wyvratt, et al. , Eur. Pat. Appl. 61187 ( 1982)83 who describe a lactam
of
the formula:

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rs
w NJ
r ..
0
s
Lactams having further heteroatom(s) in the cyclic lactam structure (in
addition to the nitrogen of the amido group of the lactam) are described by
Cornille. et al. , J. Am. Chem. Soc. , ~ 17:909-917 ( 1995)84 who describe
lactams
of the formula:
O
N
h2N
O
J. Kolc, Coll. Czech. Chem. Comm., x:630 (1969)85 who describes lysines
suitable for cyclization to lactams which have a hetero lactam ring atom as
shown
by the formula:
l-f2N X X
'-"' ""'~ O ~ _ _
~ N
N~2 H
wherein X=O, S and NR where R is, for example, alkyl, substituted alkyl, aryl,
heteroaryl, heterocyclic, heterocyclooxy, and the like.
Similarly, each of Dickerman, et al., J. Org. Chem., x:530 (1949}86,
Dickerman, et al., J. Org. Chem., 2:206 (1955)87, and Dickerman, et al., J.

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Org. Cnem., 1:1855 (1954)88 used the Schmidt and Beckmann reactions on
substituted 4-piperidones to provide for lactams of the formula:
R'~N'p R ..
~..~ N.
0 -~...
O N
H
where R is acyl, alkyl, substituted alkyl, aryl, heteroaryl or heterocycIic
provided
that R is not an acid labile group such as t-Boc; and R' is hydrogen, alkyl,
substituted alkyl, alkoxy, substituted alkoxy, aryl, aryloxy, heteroaryl,
heteroaryloxy, heterocyclic, heterocyclooxy, halo, cyano, nitro,
trihalomethyl, and
the like.
An internal cyclization of appropriate ethylenediamine amides onto a
ketone or aldehyde is described by Hoffman, et al. , J. Org. Chem. , ~ :3565
(1962)89 as follows:
R
Z R
0 '
HN ~ N
o ~ ---
N O
H -N
.K
R = Methyl, Phenyl
Ring expansion methodology based on ~i lactams to provide for larger ring
lactams containing an aza group has twice been reported in Wasserman, et al.,
J.
Am. Chem. Soc. , (~:46I-2 (1981)90 and in Crombie, et al., Tetrahedron Lett. ,
27(42):5151-5154 (1986).91

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Dieckmann methodology has been used to prepare aza caprolactams from
unsymmetrical amines such as shown below by Yokoo, et al. , Bull, Chem. Soc.
Jap. , x:631 ( 1956).92
R
~--N' R
N
COZEN ---.-
COZEt 0 N
H
wherein R is as defined in this reference. The disclosure of Yokoo, et al. can
be
extended to cover R being alkyl, substituted alkyl, aryl, alkoxy, substituted
alkoxy, heteroaryl, cycloalkyl, heterocyclic, heterocyclooxy, alkenyl,
substituted
alkenyl, and the like.
The synthesis of various members of the oxalactam series has been reported
by Burkholder, et al., Bioorg. Med. Chem. Lett., 2:231 (1993)93 and references
cited therein which oxalactams are represented by the formula:
,R IV
~0
,N
R

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wherein R' is as defined in the reference and R can be alkyl, substituted
alkyl,
aryl, alkoxy, substituted alkoxy, heteroaryl, cycloalkyl, heterocyclic,
heterocyclooxy, aikenyl, substituted alkenyl, and the like.
The synthesis of thialactams (generally oxalactams can be made by the
same methodology) has been reported by Freidinger, et al. , J. Org. Chem. ,
47:104-109 ( 1982) 18 who prepared thialactams of the formula:
I.~ZN
p
This reference provides a series of procedures having broad application for
synthesis of lactams, permitting R in the above formula to be derived from any
amine (alkyl, aryl, heteroaryl, etc.) with the restriction being that the R-
group
does not contain any functional groups reactive with formaldehyde (e.g.,
primary
and secondary amines). The general synthetic scheme provided by Freidlinger,
et
al. is:
H
~--N
~-N
O S 0 S
caucling
\ O agent ~ O
I / ~N T R-NHz ~ N
( OH i
0 O v NHR
O O
O
parafotmaldehyda ~ N-mettsylhyd2zine
p-TosOH N N~R
C1ZCHCl-fCt~ ~ ~ ~ HZN N~~
O -Q

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The coupling agent is any standard reagent used in the formation of typical
peptide or amide bonds, for example, carbodiimide reagents. See, also,
Karanewsky, U.S. Patent No. 4,460,57994 and Kametani, et al., Heterocycles,
S x:831-840 (1978).95
The Friedinger procedure can be extended to afford disubstituted
thialactams of the following structure:
~~vr~Z
i
FfzN ~N~ ~~"
~l z
p C
S1-f ~a ~ ~ ~:.clirtg p S RZ
agent
. ON ~ ~ N N..
O O Pr / \ ~ O Ri
O
In practical terms, R2 will be limited to aryl and heteroaryl groups and
sterically hindered alkyl groups such as t-butyl. Rl can be highly variable
and is
limited only by subsequent reaction steps.
Still further is the Kametani procedure which provides for lactams as
follows:
O
SH ~ H r? p-TosOH O S ~ Rz
~N ; ~ 2 benzene
N.
N ffpT O -------~ / \ _N
O O O
-- O

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In principle, the Kametani procedure allows for a wide selection of R1 and
S R2 groups limited primarily by stability to the reaction conditions.
See, for example, Yanganasawa, et al., J. Med. Chem. , ~Q:1984-1991
(.1987)96 and J. Das et al . , Biorg. Med. Chem. Lett. , 4:2193-2198 ( 1994)97
which
describes general methods for the synthesis of isomeric 7-membered thialactams
of
the following structure:
S
~ R
HZN lI N' HZN N
O Rt p ~Rt
The first synthetic route is:
SH RZ
1: V-rt;ethy- S
AZ morpholirte Nhz
- Boc;~N OH l ~ '-""'~"'
N02 2. Reduction gocHN OH
O O
R2
1. Cycliiation
2. Selective HzN N
allcyt;ation
O .RI

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R2 can be highly variable (e.g., alkyl, substituted alkyl, aryl, heteroaryl,
heterocyclic and the like) since a number of well documented routes exist for
the
synthesis of nitroethylene derivatives from aldehydes and nitromethane (Henry
reaction) followed by dehydration. RI is limited to groups that can undergo
alkylation reactions.
The second compound series can be prepared as follows:
O
\ SH Rz NHBoc
~ , ~N +
OCHPhz OMs
O O
t . Protec:ing group
removal ~ Rz
H2N ~ N,
2 ~ Cycfization R ~
1' 3. Selective alfcyfation (Rj}
4. Methyfhydrarine .
NHBoc
o~
I \ N S R2
OCHPhz
2U ~~ O
In this synthesis, R2 can be highly variable. The starting component
required to introduce R2 can be readily derived by the reduction of any known
a-
BOC-amino acid to the alcohol derivative followed by formation of the
mesylate.
25 As noted above, the primary approaches to the preparation of lactams is the
Beckmann/Schmidt ring expansion reaction using either inter- or intramolecular
approaches serves to prepare lactams of various ring sizes. The intramolecular
approach generates bicyclic materials with the lactam nitrogen incorporated
into
the ring fusion. Additional approaches set forth above involve the internal

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cyclization of omega-amino acids/esters where the construction of the
substituent
pattern takes place prior to cyclization, and internal cyclization of an
electrophilic
center onto a nucleophilic functional group as in the Friedel Crafts type
cyclization ,.
used in the Ben-Ishal procedure for making benzazepinones. This latter
procedure
S is applicable to a wide variety of heteroaromatics as well as benzenoid
rings, and
may also be applied to non-aromatic double or triple bonds to generate a wide
array of suhstituents or ring fusions.
Deoxygenation of the lactam by reagents such as diborane, LiAlH4, and
the like leads to azaheterocycles (=X is dihydro).
Similarly, for X = H, OH, such compounds can be prepared by
epoxidation of cycloalkenyl groups followed by oxirane opening by, e.g.,
ammonia. After formation of compounds of Formulas I-VI, =X being H, OH can
be oxidized to provide for cycloalkylones (=X being oxo).
Additionally, the 5,7-dihydro-6H-dibenz[b,dJazepin-6-one derivatives
employed in this invention can be prepared using conventional procedures and
reagents. For example, an appropriately substituted N-tert-Boc-2-amino-2'-
methylbiphenyl compound can be cyclized to form the corresponding 5,7-dihydro-
6H-dibenz[b,dJazepin-6-one derivative by first treating the biphenyl compound
with about 2.1 to about 2.5 equivalents of a strong base, such as sec-butyl
lithium.
This reaction is typically conducted at a temperature ranging from about -
80°C to
about -60°C in an inert diluent such as THF. The resulting dianion is
then treated
with dry carbon dioxide at a temperature of about -78°C to afford the
5,7-dihydro-
6H-diben[b,dJazepin-6-one. This procedure is described further in R. D. Clark
et
al., Tetrahedron, 49(7), 1351-1356 (1993) and references cited therein.

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After forming the 5,7-dihydro-6H-dibenz[b,d]azepin-6-one, the amide
nitrogen can be readily alkylated by first treating the dibenazepinone with
about
1.1 to about 1.5 equivalents of a strong base, such as sodium hydride, in an
inert
diluent, such as DMF. This reaction is typically conducted at a temperature
ranging from about -10°C to about 80°C for about 0.5 to about 6
hours. The
resulting anion is then contacted with an 'excess, preferably about 1.1 to
about 3.0
equivalents, of an alkyl halide, typically an alkyl chloride, bromide or
iodide.
Generally, this reaction is conducted at a temperature of about 0°C to
about 100°C
for about 1 to about 48 hours.
An amino group can then be introduced at the 5-position of the 7-alkyl-5,7-
dihydro-6H-diben[b,d]azepin-6-one using conventional procedures and reagents.
For example, treatment of 7-methyl-5.7-dihydro-6H-diben(b,d]azepin-6-one with
an excess of butyl nitrite in the presence of a strong base, such as potassium
1,1,1,3,3,3-hexamethyldisilazane (KHMDS), affords 5-oximo-7-methyl-5,7-
dihydro-6H-diben[b,d]azepin-6-one. Subsequent reduction of the oximo group by
hydrogenation in the presence of a catalyst, such as palladium on carbon, then
provides 5-amino-7-methyl-5,7-dihydro-6H-diben(b,d]azepin-6-one. Other
conventional amination procedures, such as azide transfer followed by
reduction of
the azido group, may also be employed.
Similarly, various benzodiazepine derivatives suitable for use in this
invention can be prepared using conventional procedures and reagents. For
example, a 2-aminobenzophenone can be readily coupled to a-(isopropylthio)-N-
(benzyloxycarbonyl)glycine by first forming the acid chloride of the glycine
derivative with oxalyl chloride, and then coupling the acid chloride with the
2-
aminobenzophenone in the presence of a base, such as 4-methylmorpholine, to
afford the 2-[ -(isopropylthio)-N-(benzyloxycarbonyl)glycinyl]-
aminobenzophenone. Treatment of this compound with ammonia gas in the

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presence of an excess, preferably about 1.1 to about 1.5 equivalents, of
mercury
(II) chloride then affords the 2-(N-(a-amino}-N -(benzyloxycarbonyl)-
glycinyl]aminobenzophenone. This intermediate can then be readily cyclized by
treatment with glacial acetic acid and ammonium acetate to provide the 3-
S (benzyloxycarbonyl)amino-2.3-dihydro-5-phenyl-1H-1,4-benzodiazepin-2-onel.
Subsequent removal of the Cbz group affords the 3-amino-2,3-dihydro-5-phenyl-
1 H-1,4-benzodiazepin-2-one.
Alternatively, 2,3-dihydro-S-phenyl-1H-1,4-benzodiazepin-2-ones can be
readily aminated at the 3-position using conventional azide transfer reactions
followed by reduction of the resulting azido group to form the corresponding
amino group. The conditions for these and related reactions are described in
the
examples set forth below. Additionally, 2,3-dihydro-5-phenyl-1H-1,4-
benzodiazepin-2-ones are readily alkylated at the 1-position using
conventional
procedures and reagents. For example, this reaction is typically conducted by
first
treating the benzodiazepinone with about 1.1 to about 1.5 equivalents of a
base,
such as sodium hydride, potassium tert-butoxide, potassium 1,1.1,3,3,3-
hexamethyldisilazane, cesium carbonate, in an inert diluent, such as DMF. This
reaction is typically conducted at a temperature ranging from about -
78°C to about
80°C for about 0.5 to about 6 hours. The resulting anion is then
contacted with an
excess, preferably about 1.1 to about 3.0 equivalents, of an alkyl halide,
typically
an alkyl chloride, bromide or iodide. Generally, this reaction is conducted at
a
temperature of about 0°C to about 100°C for about 1 to about 48
hours.
Additionally, the 3-amino-2,4-dioxo-2,3,4,5-tetrahydro-1H-1,5-
benzodiazepines employed in this invention are typically prepared by first
coupling
malonic acid with a 1,2-phenylenediamine. Conditions for this reaction are
well
known in the art and are described, for example, in PCT Application WO 96-
US8400 960603. Subsequent alkylation and amination using conventional

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procedures and reagents affords various 3-amino-1,5-bis(alkyl)-2,4-dioxo-
2,3,4,5-
tetrahydro-1H-1,5-benzodiazepines. Such procedures are described in further
detail in the example set forth below. "
Accordingly, a vast number of lactams, lactones and thiolactones are
available by art recognized procedures. Similarly, the art is replete with
examples
of aminocycloaikyl compounds for use in the synthesis of compounds of Formulas
I-VI above.
In the synthesis of the compounds described herein using the synthetic
methods described above, the starting materials can contain a chiral center
(e.g.,
alanine) and, when a racemic starting material is employed, the resulting
product
is a mixture of R,S enantiomers. Alternatively, a chiral isomer of the
starting
material can be employed and, if the reaction protocol employed does not
racemize
this starting material, a chiral product is obtained. Such reaction protocols
can
involve inversion of the chiral center during synthesis.
Pharmaceutical Formulations
When employed as pharmaceuticals, the compounds described herein are
usually administered in the form of pharmaceutical compositions. These
compounds can be administered by a variety of routes including oral, rectal,
transdermal, subcutaneous, intravenous, intramuscular, and intranasal. These
compounds are effective as both injectable and oral compositions. Such
compositions are prepared in a manner well known in the pharmaceutical art and
comprise at least one active compound.
The pharmaceutical compositions contain, as the active ingredient, one or
more of the compounds described above, associated with pharmaceutically
acceptable carriers. The pharmaceutical compositions can be prepared, for

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example, by mixing the active ingredient with an excipient, diluting the
active
ingredient with an excipient, or enclosing the active ingredient within a
carrier
such as a capsule (including microparticles, nanoparticles, and liposomes),
sachet,
paper or other container. When the excipient serves as a diluent, it can be a
solid,
semi-solid, or liquid material, which acts as a vehicle, carrier or medium for
the
active ingredient. Thus, the compositions can be in the form of tablets,
pills,
powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions,
solutions,
syrups, aerosols (as a solid or in a liquid medium), ointments containing, for
example, up to 10% by weight of the active compound, soft and hard gelatin
capsules, suppositories, sterile injectable solutions, and sterile packaged
powders.
In preparing a formulation, it may be necessary to mill the active
compound to provide the appropriate particle size prior to combining with the
other ingredients. If the active compound is substantially insoluble, it
ordinarily is
milled to a particle size of less than 200 mesh. If the active compound is
substantially water soluble, the particle size is normally adjusted by milling
to
provide a substantially uniform distribution in the formulation, e.g. about 40
mesh.
Some examples of suitable excipients include lactose, dextrose, sucrose,
sorbitol, mannitol, starches, gum acacia, calcium phosphate, alginates,
tragacanth,
gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone,
cellulose, sterile water, syrup, and methyl cellulose. The formulations can
additionally include: lubricating agents such as talc, magnesium stearate, and
mineral oil; wetting agents; emulsifying and suspending agents; preserving
agents
such as methyl- and propylhydroxy-benzoates; sweetening agents; and flavoring
agents. The compositions of the invention can be formulated so as to provide
quick, sustained or delayed release of the active ingredient after
administration to
the patient by employing procedures known in the art.

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The compositions are preferably formulated in a unit dosage form, each
dosage containing from about 5 to about 100 mg, more usually about 10 to about
30 mg, of the active ingredient. The term "unit dosage forms" refers to
physically
discrete units suitable as unitary dosages for human subjects and other
mammals,
each unit containing a predetermined quantity of active material calculated to
produce the desired therapeutic effect, in association with a suitable
pharmaceutical excipient. Preferably, the compound of Formulas I-VI above is
employed at no more than about 20 weight percent of the pharmaceutical
composition, more preferably no more- than about 15 weight percent, with the
balance being pharmaceutically inert carrier(s).
The active compound is effective over a wide dosage range and is generally
administered in a pharmaceutically effective amount. It will be understood,
however, that the amount of the compound actually administered will be
determined by a physician, in the light of the relevant circumstances,
including the
condition to be treated, the chosen route of administration, the actual
compound
administered, the age, weight, and response of the individual patient, and the
severity of the patient's symptoms.
For preparing solid compositions such as tablets, the principal active
ingredient is mixed with a pharmaceutical excipient to form a solid
preformulation
composition containing a homogeneous mixture of a compound of the present
invention. When referring to these preformulation compositions as homogeneous,
it is meant that the active ingredient is dispersed evenly throughout the
composition so that the composition may be readily subdivided into equally
effective unit dosage forms such as tablets, pills and capsules. This solid
preformulation is then subdivided into unit dosage forms of the type described
above containing from, for example, 0.1 to about 500 mg of the active
ingredient
of the present invention.

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The tablets or pills of the present invention may be coated or otherwise
compounded to provide a dosage form affording the advantage of prolonged
action. For example, the tablet or pill can comprise an inner dosage and an
outer
dosage component, the latter being in the form of an envelope over the former.
The two components can separated by enteric Layer which serves to resist
disintegration in the stomach and permit the inner component to pass intact
into the
duodenum or to be delayed in release. A variety of materials can be used for
such
enteric layers or coatings, such materials including a number of polymeric
acids
and mixtures of polymeric acids with such materials as shellac, cetyl alcohol,
and
cellulose acetate.
The liquid forms in which the compositions may be incorporated for
administration orally or by injection include aqueous solutions, suitably
flavored
syrups, aqueous or oil suspensions, and flavored emulsions with edible oils
such as
cottonseed oil, sesame oil, coconut oil, or peanut oil, as well as elixirs and
similar
pharmaceutical vehicles.
Compositions for inhalation or insufflation include solutions and
suspensions in pharmaceutically acceptable, aqueous or organic solvents, or
mixtures thereof, and powders. The liquid or solid compositions may contain
suitable pharmaceutically acceptable excipients as described supra. Preferably
the
compositions are administered by the oral or nasal respiratory route for local
or
systemic effect. Compositions in preferably pharmaceutically acceptable
solvents
may be nebulized by use of inert gases. Nebulized solutions may be breathed
directly from the nebulizing device or the nebulizing device may be attached
to a
face masks tent, or intermittent positive pressure breathing machine.
Solution,
suspension, or powder compositions may be administered, preferably orally or
nasally, from devices which deliver the formulation in an appropriate manner.

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The following formulation examples illustrate the pharmaceutical
compositions of the present invention.
Formulat
Hard gelatin capsules containing the following ingredients are prepared:
Quantity
Ingredient (mg/ca sn ulel
Active Ingredient 30.0
Starch 305.0
Magnesium stearate 5.0
The above ingredients are mixed and filled into hard gelatin capsules in 340
mg quantities.
I S Formulation Example 2
A tablet formula is prepared using the ingredients below:
Quantity
r ~ t ~e/table_t)
Active Ingredient 25.0
Cellulose, microcrystalline 200.0
Colloidal silicon dioxide 10.0
Stearic acid 5.0
The components are blended and compressed to form tablets, each
weighing 240 mg.

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A dry powder inhaler formulation is prepared containing the following
components:
Ingr, ediet,~ Weig t
Active Ingredient
Lactose 95
The active ingredient is mixed with the lactose and the mixture is added to
a dry powder inhaling appliance.
Formu~tion Example 4 Tablets, each containing 30 mg of active ingredient,
are prepared as follows:
Quantity
~g~gdient
ffmQltablet)
IS
Active Ingredient 30.0 mg
Starch 45.0 mg
Microcrystalline cellulose 35.0 mg
Polyvinylpyrrolidone
(as 10 % solution in sterile water) 4.0 mg
Sodium carboxymethyl starch 4.5 mg
Magnesium stearate 0.5 mg
Talc 1.
Total 120 mg
The active ingredient, starch and cellulose are passed through a No. 20
mesh U.S. sieve and mixed thoroughly. The solution of polyvinyl-pyrrolidone is
mixed with the resultant powders, which are then passed through a 16 mesh U.S.

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sieve. The granules so produced are dried at 50 to 60°C and passed
through a 16
mesh U.S. sieve. The sodium carboxymethyl starch, magnesium stearate, and
talc, previously passed through a No. 30 mesh U.S. sieve, are then added to
the
granules which, after mixing, are compressed on a tablet machine to yield
tablets
each weighing 150 mg.
Formulation Exam~~5,
Capsules, each containing 40 mg of medicament are made as follows:
Quantity
Ingredient ~mgJc_~e)
Active Ingredient 40.0 mg
Starch ~ 109.0 mg
Magnesium stearate 1.0 mg
Total 150.0 mg
The active ingredient, starch, and magnesium stearate are blended, passed
through a No. 20 mesh U.S. sieve, and filled into hard gelatin capsules in 150
mg
quantities.
Formulation Example 6
Suppositories, each containing 25 mg of active ingredient are made as follows:
Active Ingredient 25 mg
Saturated fatty acid glycerides to 2,000 mg

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The active ingredient is passed through a No. 60 mesh U.S. sieve and
suspended in the saturated fatty acid glycerides previously melted using the
minimum heat necessary. The mixture is then poured into a suppository mold of
nominal 2.0 g capacity and allowed to cool.
Formulation Example 7
Suspensions, each containing 50 mg of medicament per 5.0 ml dose are made
as follows:
Active Ingredient 50.0 mg
Xanthan gum 4.0 mg
Sodium carboxymethyl cellulose (11%)
Microcrystalline cellulose (89%) 50.0 mg
Sucrose 1.75 g
Sodium benzoate 10.0 mg
Flavor and Color q.v.
Purified water to 5.0 ml
The active ingredient, sucrose and xanthan gum are blended, passed through a
No. 10 mesh U.S. sieve, and then mixed with a previously made solution of the
microcrystalline cellulose and sodium carboxymethyl cellulose in water. The
sodium benzoate, flavor, and color are diluted with some of the water and
added
with stirring. Sufficient water is then added to produce the required volume.

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Quantity
~redient (mg/ca sp ulel_ <,
Active Ingredient 15.0 mg
Starch 407.0 mg
Magnesium stearate 3.0 m~
Total 425.0 mg
The active ingredient, starch, and magnesium stearate are blended, passed
through a No. 20 mesh U.S. sieve, and filled into hard gelatin capsules in 560
mg
quantities.
I S Formulation Example 9
A subcutaneous formulation may be prepared as follows:
n di Quantitv
Active Ingredient 1.0 mg
corn oil 1 ml
(Depending on the solubility of the active ingredient in corn oil, up to about
5.0 mg or more of the active ingredient may be employed in this formulation,
if
desired).

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~cLrmulation Exam lie 10
A topical formulation may be prepared as follows:
Active Ingredient 1-10 g
Emulsifying Wax 30 g
Liquid Paraffin 20 g
White Soft Paraffin to 100 g
15
The white soft paraffin is heated until molten. The liquid paraffin and
emulsifying wax are incorporated and stirred until dissolved. The active
ingredient is added and stirring is continued until dispersed. The mixture is
then
cooled until solid.
Another preferred formulation employed in the methods of the present
invention employs transdermal delivery devices ("patches"). Such transdermal
patches may be used to provide continuous or discontinuous infusion of the
compounds of the present invention in controlled amounts. The construction and
use of transdermal patches for the delivery of pharmaceutical agents is well
known
in the art. ee. e.~., U.S. Patent 5.023,252, issued June 11, 1991, herein
incorporated by reference. Such patches may be constructed for continuous,
pulsatile, or on demand delivery of pharmaceutical agents.
Frequently, it will be desirable or necessary to introduce the pharmaceutical
composition to the brain, either directly or indirectly. Direct techniques
usually
involve placement of a drug delivery catheter into the host's ventricular
system to
bypass the blood-brain barrier. One such implantable delivery system used for
the

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transport of biological factors to specific anatomical regions of the body is
described in U.S. Patent 5,011,472 which is herein incorporated by reference.
Indirect techniques, which are generally preferred, usually involve
formulating the compositions to provide for drug Iatentiation by the
conversion of
hydrophilic drugs into lipid-soluble drugs. Latentiation is generally achieved
through blocking of the hydroxy, carbonyl, sulfate, and primary amine groups
present on the drug to render the drug more lipid soluble and amenable to
transportation across the blood-brain barrier. Alternatively, the delivery of
hydrophilic drugs may be enhanced by intra-arterial infusion of hypertonic
solutions which can transiently open the blood-brain barrier.
Other suitable formulations for use in the present invention can be found in
Remington's Pharmaceutical Sciences, Mace Publishing Company, Philadelphia,
PA, 17th ed. ( 1985).
Utility
The compounds and pharmaceutical compositions of the invention are useful
in inhibiting (3-amyloid peptide release and/or its synthesis, and,
accordingly, have
utility in diagnosing and treating Alzheimer's disease in mammals including
humans.
As noted above, the compounds described herein are suitable for use in a
variety of drug delivery systems described above. Additionally, in order to
enhance the in vivo serum half life of the administered compound, the
compounds
may be encapsulated, introduced into the lumen of liposomes, prepared as a
colloid, or other conventional techniques may be employed which provide an
extended serum half-life of the compounds. A variety of methods are available
for
preparing liposomes, as described in, e.g., Szoka, et al., U.S. Patent Nos.

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4,235,871, 4,501,728 and 4,837,028, the contents of each of which is
incorporated herein by reference.
The amount of compound administered to the patient will vary depending
upon what is being administered, the purpose of the administration, such as
prophylaxis or therapy, the state of the patient, the manner of
administration, and
the like. In therapeutic applications, compositions are administered to a
patient
already suffering from AD in an amount sufficient to at least partially arrest
further onset of the symptoms of the disease and its complications. An amount
adequate to accomplish this is defined as "therapeutically effective dose."
Amounts effective for this use will depend on the judgment of the attending
clinician depending upon factors such as the degree or severity of AD in the
patient, the age, weight and general condition of the patient, and the like.
Preferably, for use as therapeutics, the compounds described herein are
administered at dosages ranging from about 1 to about 500 mg/kg/day.
In prophylactic applications. compositions are administered to a patient at
risk
of developing AD (determined for example by genetic screening or familial
trait)
in an amount sufficient to inhibit the onset of symptoms of the disease. An
amount
adequate to accomplish this is defined as a "prophylactically effective dose."
Amounts effective for this use will depend on the judgment of the attending
clinician depending upon factors such as the age, weight and general condition
of
the patient, and the like. Preferably, for use as prophylactics, the compounds
described herein are administered at dosages ranging from about 1 to about S00
mg/kg/day.
As noted above, the compounds administered to a patient are in the form of
pharmaceutical compositions described above. These compositions may be
sterilized by conventional sterilization techniques, or may be sterile
filtered. The

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resulting aqueous solutions may be packaged for use as is, or lyophilized, the
lyophilized preparation being combined with a sterile aqueous carrier prior to
administration. The pH of the compound preparations typically will be between
3
and l I, more preferably from S to 9 and most preferably from 7 and 8. It will
be
understood that use of certain of the foregoing excipients, carriers, or
stabilizers
will result in the formation of pharmaceutical salts.
The compounds described herein are also suitable for use in the administration
of the compounds to a cell for diagnostic and drug discovery purposes.
Specifically, the compounds may be used in the diagnosis of cells releasing
andlor
synthesizing ~3-amyloid peptide. In addition the compounds described herein
are
useful for the measurement and evaluation of the activity of other candidate
drugs
on the inhibition of the cellular release and/or synthesis of ~3-amyloid
peptide.
1 S The following synthetic and biological examples are offered to illustrate
this
invention and are not to be construed in any way as limiting the scope of this
invention.
EXAMPLES
In the examples below, the following abbreviations have the following
meanings. If an abbreviation is not defined, it has its generally accepted
meaning.
BEMP - 2-tert-butylimino-2-diethylamino-1,3-
dimethylperhydro-1,3,2-diazaphosphorine
Boc - t-butoxycarbonyl
BOP - benzotriazol-1-yloxy-tris (dimethylamino)phosphonium
hexafluorophosphate
bd - broad doublet
bs - broad singlet

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d - doublet
dd - doublet of doublets
DIC - diisopropylcarbodiimide .,
DMF - dimethylformamide
DMAP - dimethylaminopyridine
DMSO - dimethylsulfoxide
EDC - ethyl-1-(3-dimethyaminopropyl'carbodiimide
eq. - equivalents
EtOAc - ethyl acetate
g - grams
HOBT - 1-hydroxybenzotriazole hydrate
Hunig's base diisopropylethylamine
-
L - liter
m - multiplet
i M - molar
S
max - maximum
meq - milliequivalent
mg - milligram
mL - milliliter
mm - millimeter
mmol - millimole
MOC - methoxyoxycarbonyl
N - normal
N/A - not available
ng - nanogram
nm - nanometers
OD - optical density
PEPC - 1-(3-(1-pyrrolidinyl)propyl)-3-ethylcarbodiimide
PP-HOBT - piperidine-piperidine-1-hydroxybenzotrizole

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psi - pounds per square inch
- phenyl
q - quartet ,.
quint. - quintet
S rpm - rotations per minute
s - singlet
t - triplet
TFA - trifluoroacetic acid
THF - tetrahydrofuran
tlc - thin layer chromatography
L - microliter
UV - ultra-violet
In the examples below, all temperatures are in degrees Celcius (unless
otherwise indicated). The compounds set forth in the examples below were
prepared using the following general procedures as indicated.
The term "Aldrich" indicates that the compound or reagent used in the
procedure is commercially available from Aldrich Chemical Company. Inc., 1001
West Saint Paul Avenue, Milwaukee, WI 53233 USA.
The term "Fluka" indicates that the compound or reagent is commercially
available from Fluka Chemical Corp., 980 South 2nd Street, Ronkonkoma NY
11779 USA.
The term "Lancaster" indicates that the compound or reagent is commercially
available from Lancaster Synthesis, Inc., P.O. Box 100 Windham, NH 03087
USA.

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The term "Sigma" indicates that the compound or reagent is commercially
available from Sigma, P.O. Box 14508, St. Louis MO 63178 USA;
The term "Chemservice" indicates that the compound or reagent is
commercially available from Chemservice, Inc., Westchester, PA.
The term "Bachem" indicates that the compound or reagent is commercially
available from Bachem Biosciences Inc., 3700 Horizon Drive, Renaissance at
Gulph Mills, King of Prussia, PA 19406 USA.
The term "Maybridge" indicates that the compound or reagent is commercially
available from Maybridge Chemical Co. Trevillett, Tintagel, Cornwall PL34
OHW United Kingdom.
The term "TCI" indicates that the compound or reagent is commercially
available from TCI America, 9211 North Harborgate Street, Portland OR 97203.
The term "Alfa" indicates that the compound or reagent is commercially
available from Johnson Matthey Catalog Company, Inc. 30 Bond Street, Ward
Hill, MA 01835-0747.
The term "Novabiochem" indicates that the compound or reagent is
commercially available from Calbiochem-Novabiochem Corp. 10933 North Torrey
Pines Road, P.O. Box 12087, La Jolla CA 92039-2087.
The term "Oakwood" indicates that the compound or reagent is commercially
available from Oakwood, Columbia, South Carolina.

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The term "Advanced Chemtech" indicates that the compound or reagent is
commercially available from Advanced Chemtech, Louisville, KY.
The term "Pfaltz & Bauer" indicates that the compound or reagent is
commercially available from Pfaltz & Bauer, Waterbury, CT, USA.
I. Cou~g Procedures
GENERAL PROCEDURE A
first EDC Coupiing Procg~re,
To a 1:1 mixture of the corresponding carboxylic acid and the corresponding
amino acid ester or amide in CH2C12 at O C was added 1.5 equivalents
triethylamine, followed by 2.0 equivalents hydroxybenzotriazole monohydrate
and
then 1.25 equivalents of ethyl-3-(3-dimethylamino)propyl carbodiimide HCI. The
reaction mixture was stirred overnight at room temperature and then
transferred to
a separatory funnel. The mixture was washed with water, saturated aqueous
NaHC03, 1N HCl and saturated aqueous NaCI, and then dried over MgS04. The
resulting solution was stripped free of solvent on a rotary evaporator to
yield the
crude product.
GENERAL PROCEDURE B
Second EDC Coupj'~g Procedure
A mixture of the corresponding acid (1 eqv), N-1-hydroxybenzotriazole (1.6
eqv), the corresponding amine (1 eqv), N-methylmorpholine ( 3 eqv) and
dichloromethane (or DMF for insoluble substrates) was cooled in an ice-water
bath
and stirred until a clear solution was obtained. EDC (1.3 eqv) was then added
to
the reaction mixture. The cooling bath was then allowed to warm to ambient
temperature over 1-2 h and the reaction mixture was stirred overnight. The
reaction mixture was then evaporated to dryness under vacuum. To the residue

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was added 20% aqueous potassium carbonate and the mixture was shaken
throughly and then allowed to stand until the oily product solidified
(overnight if
necessary). The solid product was then collected by filtration, washed
thoroughly <.
with 20% aqueous potassium carbonate, water, 10% HCI, and water to give the
product, usually in pure state. No racemization was observed.
GENERAL PROCEDURE C
Third EDC Cou lei g Procedure
The carboxylic acid was dissolved in methylene chloride. The corresponding
amino acid ester or amide (1 eq.), N-methylmorpholine (5 eq.) and
hydroxybenzotriazole monohydrate (1.2 eq.) were added in sequence. A cooling
bath was applied to the round bottomed flask until the solution reached
0°C. At
that time, 1.2 eq. of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide
hydrochloride
was added. The solution was allowed to stir overnight and come to room
temperature under nitrogen pressure. The reaction mixture was worked up by
washing the organic phase with saturated aqueous sodium carbonate, O.1M citric
acid, and brine before drying with sodium sulfate. The solvents were then
removed to yield crude product.
GENERAL PROCEDURE D
Fourth EDC Coupling Procedure
A round bottom flask was charged with the corresponding carboxylic acid (1.0
eq.), hydroxybenzotriazole hydrate (1.1 eq.) and the corresponding amine (1.0
eq.) in THF under nitrogen atmosphere. An appropriate amount (1.1 eq for free
amines and 2.2 eq. for hydrochloride amine salts) of base, such as Hunig's
base
was added to the well stirred mixture followed by EDC (1.1 eq.). After
stirring
from 4 to 17 hours at room temperature the solvent was removed at reduced
pressure, the residue taken up in ethyl acetate (or similar solvent) and
water,
washed with saturated aqueous sodium bicarbonate solution, 1 N HCI, brine,
dried

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over anhydrous sodium sulfate and the solvent removed at reduced pressure to
provide the product.
GENERAL PROCEDURE E
BOP Cou~ng Proce ure
To a stirred solution of N (3,5-difluorophenylacetyl)alanine (2 mmol) in
DMF, cooled in an ice-water bath, was added BOP (2.4 mmol) and N
methylmorpholine (6 mmol). The reaction mixture was stirred for 50 min. and
then a solution of a-amino-a-lactam (2 mmol) in DMF cooled at 0 °C was
added.
The cooling bath was allowed to warm to ambient temperature over 1-2 h and the
reaction mixture was then stirred overnight. A 20% aqueous potassium carbonate
solution (60 mL) was added and this mixture shaken throughly. No solid formed.
The mixture was then washed with ethyl acetate (150 mL) and evaporated to
dryness under vacuum to give a white solid. Water (SO mL) was then added and
this mixture was shaken throughly. The precipitate that formed was collected
by
filtration, then washed thoroughly with water, followed by 1 mL of diethyl
ether
to give the product (51 mg, 0.16 mmol, 7.8%).
GENERAL PROCEDURE F
Coupling of an Acid Chloride with an Amino Acid Ester
To a stirred solution of (D,L)-alanine isobutyl ester hydrochloride (4.6 mmol)
in 5 ml of pyridine was added 4.6 mmol of the acid chloride. Precipitation
occurred immediately. The mixture was stirred for 3.5 h, dissolved in 100 mL
of
diethyl ether, washed with 10% HCl three times, brine once. 20% potassium
carbonate once and brine once. The solution was dried over magnesium sulfate,
filtered, and evaporated to yield the product. Other amino acid esters may
also be
employed in this procedure.
GENERAL PROCEDURE G

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~oy~ling of a Carboxylic Acid with an Amino Acid Ester
A solution of the carboxylic acid (3.3 mmol) and 1,1'-carbodiimidazole (CDI)
in 20 mL THF was stirred for 2 h. (D,L)-alanine isobutyl ester hydrochloride
(3.6
mmol) was added, followed by 1.5 mL (10.8 mmol) of triethylamine. The reaction
mixture was stirred overnight. The reaction mixture was dissolved in 100 mL of
diethyl ether, washed with 10% HCI three times, brine once, 20% potassium
carbonate once and brine once. The solution was dried over magnesium sulfate,
filtered, and evaporated to yield the product. Other amino acid esters may
also be
employed in this procedure.
GENERAL PROCEDURE H
Fifth EDC Coupling Procedure
In a round bottom flask was added a carboxylic acid (1.1 eq.) in THF, an
amine hydrochloride (1.0 eq.), 1-hydroxybenzotriazole hydrate (1.1 eq.). N,N-
diisopropylethylamine (2.1 eq.), followed by 1-(3-dimethylaminopropyl)-3-
ethylcarbodiimide hydrochloride (EDC) (1.I eq.). The reaction mixture stirred
at
room temperature for 10-20 hours under an atmosphere of nitrogen. The mixture
was diluted with EtOAc and washed with 0.1 M HCl (1 x 10 mL), saturated
NaHC03 (1 x 10 mL), H20 (1 x 10 mL), and brine and dried over MgS04. The
drying agent was removed by filtration and the filtrate was concentrated in
vacuo.
The residue was purified by flash column chromatography on silica gel followed
by trituration from EtOAc and hexanes.
GENERAL PROCEDURE I
sixth EDC Coupling Proc~r_e
To a solution or suspension of the amine or amine hydrochloride (1.0 eq.) in
THF (0.05-0.1 M) under N2 at 0°C was added the carboxylic acid (1.0-
1.1 eq.),
hydroxybenzotriazole monohydrate (l.l-1.15 eq.), Hunig's base (1.1 eq. for
free
amines and 1.1-2.3 eq. for hydrochloride amine salts), followed by 1-(3-

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dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.1-1.15 eq.). The
cooling bath was removed and the mixture allowed to warm to room temperature
for 10-24 hours. The solution or mixture was diluted with EtOAc, in a 3-5
volume multiple of the initial THF volume, and washed with 0.1-1.0 M aq. HCI
(1
or 2x), dilute NaHC03 (1 or 2x), and brine (lx). Then, the organic phase was
dried over either MgS04 or Na2S04, .filtered, concentrated to provide the
crude
product, which was either further purified or utilized without further
purification.
GENERAL PROCEDURE J
EEDQ CouDing Procedure
To a solution of the amine in THF (1.0 eq., 0.05-0.08 M, final molarity)
under N2 at room temperature was added the N-t-Boc protected amino acid (1.1
eq., either as a solid or in THF via cannula), followed by EEDQ (Aldrich, 1.1
eq.). The pale yellow solution was stirred at room temperature for 16-16.5
hours,
then diluted with EtOAc (in a 3-5 volume multiple of the initial THF volume),
and
washed with 1M aq. HCl (2x), dilute aq. NaHC03 (2x), and brine (lx). The
organic phase was dried over either Na2S04 or MgS04, filtered, and
concentrated.
II. ~:arboxylic Acids
GENERAL PROCEDURE II-A
Ester Hvdrolvsis to Free Acid
Ester hydrolysis to the free acid was conducted by conventional methods.
Below are two examples of such conventional de-esterification methods.
Method A To a carboxylic ester compound in a l: l mixture of CH30H/H20
was added 2-5 equivalents of K2C03. The mixture was heated to 50°C for
0.5 to
1.5 hours until tlc showed complete reaction. The reaction was cooled to room

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temperature and the methanol was removed on a rotary evaporator. The pH of the
remaining aqueous solution was adjusted to -2, and ethyl acetate was added to
extract the product. The organic phase was then washed with saturated aqueous
..
NaCI and dried over MgS04. The solution was stripped free of solvent on a
rotary evaporator to yield the product.
Method B: The amino acid ester was dissolved in dinxane/water (4:1) to
which was added LiOH ( - 2 eq.) that was dissolved in water such that the
total
solvent after addition was about 2:1 dioxane:water. The reaction mixture was
stirred until reaction completion and the dioxane was removed under reduced.
pressure. The residue was dissolved in water and washed with ether. The layers
were separated and the aqueous layer was acidified to pH 2. The aqueous layer
was extracted with ethyl acetate. The ethyl acetate extracts were dried over
Na2S04 and the solvent was removed under reduced pressure after filtration.
The
residue was purified by conventional methods (e.g., recrystallization).
GENERAL PROCEDURE II-B
Awid Chloride Pre aration
A carboxylic acid is dissolved in dichloromethane and this solution is cooled
to 0°C. DMF (0.5 mL, catalytic) is added, followed by the dropwise
addition of
oxalyl chloride (18 mL, 0.20 mol) over a 5 minute period. The reaction is
stirred
for 3 h and then rotoevaporated at reduced pressure to give an oil which is
placed
on a high vacuum pump for 1 h to afford the acid chlorides.
GENERAL PROCEDURE II-C
Schotten-Baumann Procedure
The acid chloride (from General Procedure II-B} is added dropwise to a
0°C
solution of L-alanine (Aldrich) (16.7 g, 0.187 mol) in 2 N sodium hydroxide
(215
mL, 0.43 mol) or another amino acid such as tert-leucine or phenyl glycine.
The

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reaction is stirred for 1 h at 0°C and then overnight at room
temperature. The
reaction is diluted with water (100 mL), then extracted with ethyl acetate (3
x 150
mL). The organic layer is then washed with brine (200 mL), dried over MgS04,
..
and rotoevaporated at reduced pressure to a residue. Recrystallization of the
residue from ethyl acetate/hexanes affords the desired product in high yield.
GENERAL PROCEDURE II-D
To a solution of an arylamine in ethanol in a hydrogenation flask is added 1
equivalent of a 2-oxocarboxylic acid ester (e.g., pyruvate ester), followed by
10%
palladium on carbon (25 weight percent based on the arylamine). The reaction
mixture is hydrogenated at 20 psi H2 on a Parr shaker until complete reaction
is
indicated by tlc (30 minutes to 16 hours). The reaction mixture is then
filtered
through a pad of Celite 545 (available from Aldrich Chemical Company, Inc.)
and
stripped free of solvent on a rotary evaporator. The crude product residue can
then be further purified via chromatography.
3. Cvclic Kelqne Derivatives
GENERAL PROCEDURE 3-A
Jones Oxidation Procedure
The compound to be oxidized is stirred in acetone and the Jones reagent is
added in portions until the starting material is consumed. The reaction
mixture is
quenched with isopropanol and the mixture is filtered through Celite and
concentrated under reduced pressure. The residue is partitioned between ethyl
acetate and water and the organic portion is dried over sodium sulfate and
then
concentrated under reduced pressure. The crude product is purified by silica
gel
chromatography and/or recrystallization.

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GENERAL PROCEDURE 3-B
Swern Oxidation Procedure
To a stirred mixture of oxalyl chloride (0.1.5 mL, 1.2 mmol) in 10 mL of
dichloromethane cooled to -78°C is added DMSO (0.106 mL, 1.5 mmol) and
the
S mixture is stirred for 10 minutes. A solution of the alcohol (0.1828 g, 0.60
mmol)
in 20 mL of chloroform is added dropwise. The reaction mixture is stirred at -
78°C for 2 hours, and then 0.5 mL (3.6 mmol) of triethylamine is added.
Stirring
is continued for 1 hour and then the mixture is allowed to warm to room
temperature and stirring is continued at ambient temperature overnight. The
mixture is then diluted with SO mL of dichloromethane, washed with brine
'(3x),
dried over magnesium sulfate, filtered and evaporated to dryness to give a
crude
product that is typically purified by column chromatography.
5. Lactams
GENERAL PROCEDURE 5-A
N Alkylation of Lactams
To a stirred solution of a BOC-protected a-aminocaprolactam (6.87 g, 30
mmol) in DMF (150 mL) was added in portions 97% NaH (1.08g, 45 mmol).
Bubbling occurred immediately and followed by heavy precipitation. After 10
min., benzyl bromide (3.93 mL, 33 mmol) was added. The precipitate dissolved
quickly and in about 10 min. a clear solution was obtained. The reaction
mixture
was stirred overnight and then evaporated as completely as possible on a
rotovap
at 30°C. Ethyl acetate (100 mL) was added to the residue and this
mixture was
washed with water, brine, and dried over magnesium sulfate. After filtration
and
concentration, a thick liquid (10 g) was obtained which was then
chromatographed
over silica gel with 1:3 ethyl acetate/hexane as the eluant to provide 5.51 g
(58% )
of the N-benzylated product as an oil. Other lactams and alkylating agents may
be

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used in this procedure to obtain a wide variety of N-alkylated lactams.
Various
bases, such as LiN(SiMe3), may also be employed.
GENERAL PROCEDURE 5-B
BOC Removal Procedure
The BOC-protected compound in a 1:1-2:1 mixture of CH2C12 and
trifluoroacetic acid was stirred until tlc indicated complete conversion,
typically 2
hours. The solution was then stripped to dryness and the residue was taken up
in
ethyl acetate or CH2C12. The solution was washed with saturated aqueous
NaHC03 and the aqueous phase was adjusted to a basic pH, then extracted with
ethyl acetate or CH2Cl2. The organic phase was washed with saturated aqueous
NaCI and dried over MgS04. The solution was stripped free of solvent on a
rotary evaporator to yield the product.
GENERAL PROCEDURE 5-C
S~rnthesis of A-Aminolactams
The Schmidt reaction was conducted on 4-ethylcyclohexanone using
hydroxyamine sulfonic acid as described in Olah, Org. Synth. Collective, Vol.
VII, page 254, to provide 5-ethylcaprolactam in 76% yield. Using the procedure
described in Watthey, et al., J. Med. Chem., 1985, 28, 1511-1516, this lactam
was then dichlorinated with PC15 at the a position and reduced by
hydrogenation
to provide four isomeric monochlorides (two racemic mixtures). The two racemic
mixtures were separated from each other by column chromatography using silica
gel and each racemic mixture was reacted with sodium azide to yield the
corresponding azide, which was hydrogenated to provide the corresponding a-
aminolactams. Other cycloalkanones may be employed in this procedure to
provide a wide variety of a-aminolactams. In some cases, such as when
preparing
the 9-membered ring a-aminolactam, longer reaction times, higher reaction
temperatures and an excess of sodium azide may be required. For example, the 9-

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membered ring a-aminolactam required 5 equivalents of sodium azide, a reaction
temperature of 120°C and a reaction time of 4 days. Such conditions can
be
readily determined by those of ordinary skill in the art.
GENERAL PROCEDURE 5-D
e,.rt~,P~;~ .,f 4-A ino-1 2 3 4-tetrahydroisoa,~j~lline-3-ones
~L,.~.."
The 4-amino-1,2,3,4-tetrahydroisoquinoline-3-one derivatives employed in
this invention can be prepared by the following art-recognized procedures. The
conditions for these reactions are further described in D. Ben-Ishai, et al.,
Tetrahedron, 43, 439-450 (1987). The following intermediates were prepared via
this procedure:
3-amino-1,2,3,4-tetrahydroisoquinolin-3-one
4-amino-7-benzyl-1,2,3,4-tetrahydroisoquinolin-3-one
4-amino-1-phenyl-1,2,3,4-tetrahydroisoquinolin-3-one
IS cis and traps-4-amino-1-phenyl-1,2,3,4-tetrahydroisoquinolin-3-one
4-amino-2-phenethyl-1,2,3,4-tetrahydroisoquinolin-3-one
4-amino-2-methy 1-1, 2 , 3 , 4-tetrahydroisoqu inolin-3-one
9-amino(fluoren-1-yl)glycine d-lactam-1,2,3,4-tetrahydroisoquinolin-3-one.
St~eR A Pr.~paration of N Bismethox~arbonvlaminoacetic Acid To one
mole equivalent of glyoxylic acid in 2 liters of ethanol-free chloroform was
added
two mole equivalents of methyl carbamate and 0. I mole equivalent of
naphthalene
sulfonic acid. The reaction mixture was then brought to a reflux for 6 hours.
Water was removed using an inverse Dean Stark trap. The reaction was then
cooled and the product filtered and washed with chloroform. The white solid
was
recrystallized from ethyl acetate/hexanes to give a white powder in 65 %
yield.
S~te~B - Coupling Procedure: To 0.0291 moles of N-
bismethoxycarbonylaminoacetic acid (or the appropriate carbocyclic acid) in
200

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mL of THF was added one mole equivalent of EDCCHCI, a benzylamine, HOBT,
and diisopropylethylamine. The reaction was allowed to stir at room
temperature
for 18 hours and then poured into a separatory funnel and extracted into ethyl
..
acetate. The ethyl acetate solution was washed with 1 molar IC2C0, and then 1
molar HCI. The organic layer was dried over NazS04, filtered and solvent
removed to give the crystalline benzylamide of N-bismethoxycarbonylaminoacetic
acid. This material was used without further purification. Typical yields
range
from 40 - 55 % .
~p C-Cvclization Procedure: The benzylamide of N-
bismethoxycarbonylaminoacetic acid (0.008 moles) was dissolved in 75 mL of
methanesulfonic acid and allowed to stir over night at room temperature. The
reaction mixture was poured over ice and extracted into ethyl acetate. The
ethyl
acetate extract was washed with 1 molar K,C03 and then 1 N HCI. The organic
layer was dried over Na,SO,, filtered and the solvent removed to give the
crystalline 4-methoxycarbonylamino-1,2,3,4-tetrahydroisoquinoline-3-one in 50-
90% yield. This material was used without further purification.
~lPp D - Removal of the MethoxYoxvcarbony_ls'u_o~p~MOC): To the 4-
methoxycarbonylamino-1,2,3,4-tetrahydroisoquinoline-3-one (3.4 mmoles) in 30
mL of acetonitrile was added 2 mole equivalents of trimethylsilyliodide
(TMSI).
The reaction mixture was heated to 50-80°C for 3 hrs and then cooled
and poured
into a separatory funnel. The reaction mixture was diluted with ethyl acetate
and
washed with 1 molar K,C03 and then with 5 %a NaHS03. The organic layer was
dried over Na~S04 and filtered. The solvent was removed under reduced pressure
to give the 4-amino-1,2,3,4-tetrahydroisoquinoline-3-one derivative. Typical
yields range from 50-87 % .

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$xP,~ F - Alternative Procedure for Removal of the Methoxyoxvcarbonyl
Group To 3.8 mmoles of the MOC-protected compound was added 10 mL of
30% HBr in acetic acid and this reaction mixture was heated to 60°C for
3 hrs.
The mixture was then cooled and hexanes were added. The hexanes layer was
decanted off and the residue as placed under reduced pressure to give a tan
solid.
This solid was slurried in ether and filtered to give the 4-amino-1,2,3,4-
tetrahydroisoquinoline-3-one hydrobromide salt. Typical yields range from 57-
88%.
Example 5-A
Synthesis of
3-Amino-1,2,3,4-tetrahydroquinolin-2-one
Sodium (0.308, 1 l OM % ) was added to anhydrous ethanol (45 mL)
and the reaction mixture was stirred until homogenous. Diethyl N-
1 S acetylaminomalonate (2.51 g, 100 M % ) was added in one portion and this
mixture
was stirred for 1 h. 2-Nitrobenzyl bromide (2.Sg, 100M%) was then added in one
portion and the reaction mixture was stirred for 3 h. The reaction was poured
into
water and extracted with ethyl acetate (3x) and then backwashed with water
(3x)
and brine (lx). Treatment with MgSO~, rotoevaporation, and chromatography
(30% EtOAc/hexanes) yielded diethyl N-acetylamino-2-nitrobenzylmalonate in
82% yield.
Step B: Diethyl N-acetylamino-2-nitrobenzylmalonate (lg, 100M%) was
dissolved in a minimum amount of EtOH. Pd/C (10%a, O.OSg) was added and the
reaction mixture was subjected to 50 psi of HZ for 3 hours. The reaction was
then
filtered thru a pad of celite. Additional EtOH (25mL) and TsOH (catalytic
amount, O.OIg) were added and this mixture was refluxed for 2 hours. The
reaction was rotoevaporated to a residue and then partitioned between water
and
ethyl acetate. The water layer was extracted with ethyl acetate (3x) and the

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combined ethyl acetate extracts were washed with water (3x) and then brine
(lx).
Treatment with MgS04 and rotoevaporation yielded pure 3-(N-acetylamino)-3-
carboethoxy-1,2,3,4-tetrahydroquinolin-2-one (89% yield). ..
Step C: 3-(N-Acetylamino)-3-carboethoxy-1,2,3,4-tetrahydroquinolin-2-
one (0.75 g, 100M%) was suspended in 6N HCl (25 mL) and the mixture was
heated to 100°C for 3 hours. The reaction was cooled, rotoevaporated to
a residue
and then partitioned between water and ethyl acetate. The water was extracted
with ethyl acetate (3x) and the combined ethyl acetate extracts were then
washed
with water (3x) and then brine (lx). Treatment with MgS04 followed by
rotoevaporation yielded 3-(R,S)-amino-1,2,3,4-tetrahydroquinolin-2-one (72%
yield).
Example 5-B
Synthesis of
4-Amino-1-(pyrid-4-yl)-1,2,3,4-tetrahydroisoquinolin-3-one
Step A: To a solution of 4-cyanopyridine (Aldrich) (0.150 moles) in 300
mL of dry ether was added 1.1 eq. of phenylmagnesium bromide (Aldrich)
dropwise. The reaction was refluxed for 2 hours and then stirred overnight at
room temperature. Sodium borohydride (1.0 eq.) was added dropwise as a
solution in 200 mL of methanol (CAUTION -- very exothermic). The reaction
was then heated to reflux for 6 hours, cooled and quenched with a saturated
solution of ammonium chloride. The solution was decanted from the salt in the
reaction mixture and acidified with 1N HCI. After washing the aqueous layer
with
ethyl acetate, the pH of aqueous layer was adjusted to about 9.0 with 1N
sodium
hydroxide (cold). The aqueous layer was then extracted with ethyl acetate and
the
organic extracts washed with brine, dried over NazS04, filtered and
concentrated
to give 4-pyridyl-a-benzyl amine as a thick yellow oil.
Sten B: Following General Procedure 5-D and using 4-pyridyl-a-benzyl
amine, the title compound was prepared.

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Example 5-C
Synthesis of ,.
4-Amino-I-(pyrid-2-yl)-1,2,3,4-tetrahydroisoquinolin-3-one
~R~ 2-Pyridyl-a-benzyl amine was prepared by substituting 2-
cyanopyridine (Aldrich) for 4-cyanopyridine in the procedure described in
Example 5-B.
Step B: Following General Procedure 5-D and using 4-pyridyl-a-benzyl
amine, the title compound was prepared.
Example 5-D
Synthesis of
4-Amino-1-(pyrid-3-yl)-1,2,3,4-tetrahydroisoquinolin-3-one
Stet A: Following the procedure described in J. Med. Chem., 1982, 25,
1248, and using 3-benzoyl-pyridine (Aldrich), 3-pyridyl-a-benzyl amine was
prepared.
Ste~B: Following General Procedure 5-D and using 3-pyridyl-a-benzyl
amine, the title compound was prepared.
Example 5-E
Synthesis of
4-Amino-7-benzyl-1,2,3,4-tetrahydroisoquinolin-3-one
SteR A: To a Parr bottle containing 3-benzoylbenzoic acid (0.044 moles)
(Aldrich) in 150 mL of ethyl acetate and 4.5 mL of concentrated I~S04 was
added
10 grams of 5 % Pd/C. The mixture was hydrogenated on a Pan apparatus under
hydrogen (45 psi) overnight. The reaction mixture was then filtered through
Hyflo, washing with ethyl acetate. The filtrate was dried over NazS04,
filtered

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and concentrated to give an oil. The oil was slurried in hexane and the
resulting
white solid was collected by filtration to afford 3-benzylbenzoic acid, which
was
used without further purification.
Step B: To the product from Step A (0.0119 moles) was added 150 mL of
CH2C1,, one drop of DMF, 10 mL of oxalyl chloride, and the mixture was stirred
at room temperature for 3 hours. After cooling to 10°C, 30 mL of NI-
~,OH
(exothermic) was added and the mixture was stirred for 30 min. The reaction
mixture was then concentrated and the resulting residue diluted with ethyl
acetate.
The organic layer was washed with 1 N NaOH, brine, dried over Na~S04, and
concentrated to give the 3-(benzyl)benzamide as a white solid, which was used
without further purification.
Step C: To a solution of 3-(benzyl)benzamide (.0094 moles) from Step B
I 5 in 70 of toluene was added 8 mL of Red-Al7 (65 + wt. % solution of sodium
bis(2-methoxyethoxy)aluminum hydride in toluene, Aldrich) (CAUTION --
reaction very exothermic). The reaction mixture was then heated at 60°C
for 2
hours and then poured over ice. The resulting mixture was extracted with ethyl
acetate and the combined extracts were washed with water and brine. The
organic
layer was extracted with 1N HC1 and the aqueous layer washed with ethyl
acetate.
The pH of the aqueous layer was then adjusted to about 9.0 with 1N NaOH and
extracted with ethyl acetate. The organic extracts were washed with water and
brine and then concentrated to give 3-(benzyl)benzyl amine.
St~D: Following General Procedure 5-D and using 3-(benzyl)benzyl
amine, the title compound was prepared.
Example S-F
Synthesis of

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4-Amino-6-phenyl-1,2,3,4-tetrahydroisoquinolin-3-one
step A: To a solution of 4-biphenylcarboxamide (Aldrich) (0.025 mole) in
150 mL of THF cooled to 10°C was added a solution of 1.5 eq of LAH (1M
in
THF) dropwise. The reaction mixture turned from a white slurry to a green
homogenous solution and then to a yellow homogeneous solution. The reaction
was then quenched with 2.5 mL of 1N NaOH. The mixture was then filtered
through Hyflo and extracted with ethyl acetate. The organic layer was then
washed with 1 N HCI. The pH of the resulting aqueous layer was adjusted to
about
9 with 1N NaOH and extracted with ethyl acetate. The organic extracts were
washed with water and brine, and then dried over Na~S04, filtered and
concentrated to give 4-(phenyl)benzyl amine as a white solid.
Step B: Following General Procedure 5-D and using 4-(phenyl)benzyl
amine, the title compound was prepared.
' Example 5-G
Synthesis of
cis- and traps-4-Amino-1-phenyl-1,2,3,4-tetrahydroisoquinolin-3-
one
Step A: Following General Procedure 5-D and using a-phenylbenzylamine
(Aldrich), 4-amino-1-phenyl-1.2,3,4-tetrahydroisoquinolin-3-one was prepared.
den B: To a solution of 4-amino-1-phenyl-1,2,3,4-tetrahydroisoquinolin-
3-one (0.00158 moles) from Step A in 20 mL of CH,CI, was added 2.0 eq. of
triethylamine and Boc anhydride (1.1 eq.). The reaction was stirred overnight
at
room temperature and then concentrated. The residue was diluted with ethyl
acetate and water. The pH of the aqueous layer was adjusted to 3.0 with sodium
bisulfate and the layers were separated. The organic layer was dried over
Na~SOd,
filtered and concentrated. The residue was purified by LC 2000, eluting with

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ethyl acetate/hexanes (70:30) to give a white solid containing a 1:1 mixture
of cis-
and traps-4-(N-Boc-amino)-1-phenyl-1,2,3,4-tetrahydroisoquinolin-3-one
isomers.
This mixture was recrystailized from ethyl acetate to give the pure traps
isomer
and a cis isomer-enriched mixture of cis and traps isomers. This mixture was
S recrystallized again from ethyl acetate/hexanes (70:30) to give the pure cis
isomer.
step C: The cis isomer and the traps isomer from Step B were separately
deprotected using General Procedure 8-J to give cis-4-amino-1-phenyl-1.2,3,4-
tetrahydroisoquinolin-3-one and traps-4-amino-1-phenyl-I,2,3,4-
tetrahydroisoquinolin-3-one.
Example 5-H
Synthesis of
4-Amino-7-phenyl-1,2,3,4-tetrahydroisoquinolin-3-one
Step A: To a solution of 1-bromo-3-phenylbenzene (Aldrich) (0.0858
moles) in 300 mL of dry THF cooled to -78°C was added tert-butyl
lithium (2 eq.)
(1.7M in hexane) dropwise. The reaction mixture was stirred for 40 min. at -
78°C and then quenched with 2 eq. of DMF (13.24 mL). The resulting
mixture
was stirred for 20 min. and then poured into a separatory funnel and extracted
with
CH,Ch. The organic extracts were washed with water, dried over Na<SO,,
filtered and concentrated to give a brown oil. This oil was purified by LC
2000
chromatography, eluting with ethyl acetate/hexanes (5:95) to give 3-
biphenylcarboxaldehyde.
Step To a solution of 3-biphenylcarboxaldehyde (O.OI1 eq.) in 30 mL
of methanol was added 10 eq. of 7N NH,IMeOH and NaCNBH4 (2 eq.). A yellow
gum precipitated from solution. The solution was then heated at 60°C
until gum
dissolved and the solution was stirred at room temperature overnight. The
reaction mixture was then concentrated and the resulting residue diluted with
ice

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water and ethyl acetate. The organic layer was then washed with brine and
extracted with SN HCI. The pH of the aqueous layer was then adjusted to 12 and
the aqueous layer was extracted with cold ethyl acetate. The organic layer was
dried over Na,S04, filtered and concentrated to give 3-(phenyl)benzyl amine as
an
s oil.
Sten C:C: Following General Procedure s-D and Using 3-(phenyl)benzyl
amine, the title compound was prepared.
Example s-I
Synthesis of
4-Amino-1-benzyl-1,2,3,4-tetrahydroisoquinolin-3-one
Sten A: To a solution of benzoyl chloride (0.123 moles) (Aldrich) in 600
mL of CH,CI, was added 2.0 eq. of phenethylamine (Aldrich) dropwise. The
1 s reaction mixture was stirred at room temperature for 3 hours and then
poured
into a separatory and extracted with CH,CI,. The organic extracts were washed
with water and 1N HCI, and then dried over Na,S04, filtered and concentrated
to
give N-phenethyl benzamide.
Step B: Reduction of N-phenethyl benzamide using the procedure of
Example s-E, Step C afforded N-benzyl-N-phenethylamine as an oil.
Step C: Following General Procedure s-D and using N-benzyl-N-
phenethylamine, the title compound was prepared.
zs
Example 5-J
Synthesis of
3-Amino-1-methyl-Z-indolinone Monohydrochloride

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Step A: (2,3-Dihydro-1-methyl-2-oxo-1H-indol-3-yl)carbamic acid methyl
ester (CAS No. 110599-56-9) was prepared using the procedure described in Ben-
Ishai, D.; Sataty, L; Peled, N.: Goldshare, R. Tetrahedron 1987, 43, 439-450.
,
The starting materials for this preparation were N-methylaniline (CAS# 100-61-
8,
Eastman Kodak Co.), glyoxylic acid (CAS# 298-12-4, Aldrich), and methyl
carbamate (CAS# 598-55-0, Aldrich)..
Step B: The product from Step A (333.5 mg) in 31 % HBr in AcOH (IO
mL) was heated to 50-60°C for 2 hours. The resulting orange solution
was
IO concentrated to a thick orange oil which was dissolved in EtOAc (15 mL) and
the
product extracted into 1 M aq. HCl (10 mL). The aqueous acid was neutralized
with aq. NaHCO, and the product extracted into CH,CI, (10 x 10 mL). HC1 (gas)
was passed through the combined CH,CI, extracts to form a purple solution. The
solution was concentrated to provide the title compound (262.8 mg) as a purple
I S solid.
Example 5-K
Synthesis of
3-Amino-1-methyl-4-phenyl-3,4-trans-dihydrocarbostyril/Tin
20 Complex
SteQ A: - Synthesis of 4-Phenyl-3,4-dihydrocarbostyril
4-Phenyl-3,4-dihydrocarbostyril (CAS# 4888-33-9) was prepared in two
steps using the procedure described by Conley, R. T.; Knopka, W. N. J. Org.
Chem. 1964, 29, 496-497. The starting materials for this preparation were
25 cinnamoyl chloride (Aldrich) and aniline (Aldrich). The title compound was
purified by flash chromatography eluting with CH,CI~/EtOAc (4:1).
Sten B: - Synthesis of 1-Methyl-4-phenyl-3,4-dihydrocarbostyril

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To a suspension of NaH (1.2 eq., 0.537 g of 60% dispersion in mineral oil)
in THF (50 mL) under N, at 0°C was added the product from Step A (1.0
eq..
2.50 g) in THF (SO mL) via cannula over a period of 5 minutes. The resulting
pale yellow mixture was stirred at 0°C for 10 minutes, then MeI (2.0
eq., 1.39
mL) was added. The opaque yellow mixture was allowed to slowly (ice bath not
removed) warm to ambient temperature with stirring for 15 hours. 1M Aq. HCl
(50 mL) and EtOAc (250 mL) were added and the phases partitioned. The organic
phase was washed with dilute NaHCO~ (1 x 100 mL), brine (1 x 100 mL), then
dried over MgSO~,, filtered, concentrated, and the residue purified by flash
chromatography eluting with CH=Ch/EtOAc (19:1 gradient to 15:1) to provide 1-
methyl-4-phenyl-3,4-dihydrocarbostyril.
Step C: - Synthesis of 3-Azido-1-methyl-4-phenyl-3,4-trans-
dihydrocarbostyril
Following General Procedure 8-K. 3-azido-1-methyl-4-phenyl-3,4-trans-
dihydrocarbostyril was prepared as a white solid. The product was purified by
flash chromatography eluting with CH,CI,/hexanes/EtOAc 15:15:1.
Selected 'H-NMR data for the title compound (CDC13): d = 4.46 (d, 1H, J
= 10.57 Hz), 4.18 (d, 1H, J = 10.63 Hz).
Sten D: - Synthesis of 3-Amino-l-methyl-4-phenyl-3,4-trans-
dihydrocarbostyrillTin Complex
To a mixture of SnCh (350.7 mg} in MeOH (7 mL) under N, at 0°C was
added the product from Step C (257.4 mg) in MeOH/THF (5 mL/5 mL) via
cannula over a period of 1 minute. The cooling bath was removed the solution
allowed to warm to ambient temperature for 8 hours (No starting material by
TLC). The solution was concentrated to a yellow foam, THF (10 mL) was added
and the mixture was re-concentrated and used without further purification.

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Example 5-L
Synthesis of
3-Amino-1-methyl-4-phenyl-3,4-cis-dihydrocarbostyril
Step A: - Synthesis of 3-Amino-1-methyl-4-phenyl-3,4-trans-
dihydrocarbostyril
3-Amino-1-methyl-4-phenyl-3,4-trans-dihydrocarbostyril was prepared
following General Procedure 8-F using 3-azido-1-methyl-4-phenyl-3,4-trans-
dihydrocarbostyril from Example 5-K, Step C. The product was purified by L.C.
2000 eluting with EtOAc/hexanes (4:1) to yield a white solid.
Selected'H-NMR data for the title compound (CDCI3): d = 4.03 (d, 1H, J
= 12.8 Hz), 3.92 (d, 1H, J = 12.7 Hz}.
Step B: - Synthesis of 3-(4-Chlorobenzylimine)-1-methyl-4-phenyl-
3,4-trans-dihydrocarbostyril
To a solution of the product from Step A (1 eq., 239.6 mg) in CI~CIZ (10
mL) under N, at ambient temperature was added 4-chlorobenzaldehyde (1.05 eq.,
140 mg, Aldrich), Et3N (1.4 eq., 185 mL), and MgSO,, (3.6 eq., 411 mg). The
resultant mixture was stirred at room temperature for 73 hours. The solids
were
removed by filtration through a plug of Celite, rinsing with CH,Ch, and the
filtrate concentrated to provide 3-(4-chlorobenzylimine)-1-methyl-4-phenyl-3,4-
trans-dihydrocarbostyril as a thick white foam.
Step - Synthesis of 3-Amino-1-methyl-4-phenyl-3,4-cis-
dihydrocarbostyril
To a solution of diisopropylamine (1.05 eq., 0.132 mL) in THF (5 mL)
under N~ at -78°C was added a solution of n-BuLi (1.05 eq., 0.588 mL of
a 1.6
M solution in hexanes) and the result solution was stirred for 30 minutes. To
this
solution was added the product from Step B (1.0 eq., 336 mg) in THF (2 mL) via
cannula. The solution was allowed to warm to 0°C, then quenched with 1
M aq.

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HCl (3 mL) and allowed to warm to room temperature with stirring overnight.
The product was extracted into HBO and washed with EtOAc ( 1 x), then the
aqueous acid was basified with 1 M aq. K,C03 and the product extracted into
EtOAc. The EtOAc extract was dried over Na,SO~, filtered, and concentrated to
give 3-amino-1-methyl-4-phenyl-3,4-cis-dihydrocarbostyril.
Selected 'H-NMR data for the.title compound (CDC13): d = 4.31 (d, 1H, J
= 6.6 Hz).
Example 5-M
Synthesis of
3-Amino-1-tert butoxycarbonyl-4-phenyl-
3,4-traps-dihydrocarbostyril/Tin Complex
Siep A: - Synthesis of 1-tert Butoxycarbonyl-4-phenyl-3,4-
dihydrocarbostyril
l5 1-tert-Butoxycarbonyl-4-phenyl-3,4-dihydrocarbostyril was prepared from
the product of Example 5-K, Step A (CAS# 4888-33-9) by the Boc procedure for
aryl amides described by Grehn, L.: Gunnarsson, K.: Ragnarsson. U. Acta
Chemica Scandinavica B 1986, 40, 745-750; employing (Boc~,O (Aldrich) and
catalytic DMAP (Aldrich) in acetonitrile. The product was purified by flash
chromatography eluting with CH,Ch gradient to CH,C1,/EtOAc (19:1) and isolated
as a pale yellow oil.
Step B - Synthesis of 3-Azido-1-tert-butoxycarbonyl-4-phenyl-3,4-
traps-dihydrocarbostyril
Following General Procedure 8-K using the product from Step A, the title
compound was prepared as a 12.4:1 mixture of translcis isomers which were
separated by flash chromatography eluting with hexanes/Et,O (6:1 gradient to
4:1 )
in the first column and hexanes/EtOAc (12:1) in a secot:d column. The pure
traps
isomer was used in Step C.

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Selected 'H-NMR data for the title compound (CDCl3): d = 4.45 (d, 1H, J
= 11.1 Hz), 4.24 (d, 1H, J = 11.2 Hz).
Step C: - Synthesis of 3-Amino-1-tert butoxycarbonyl-4-phenyl-3,4-
S trans-dihydrocarbostyril/Tin Complex
To a mixture of SnCIZ (450.6 mg) in MeOH (9 mL) under N, at 0°C
was
added the product from Part D (433.0 mg) in MeOH (15 mL) via cannula over a
period of 1 minute. The cooling bath was removed the solution allowed to warm
to ambient temperature for 17 hours. The solution was concentrated to an
amorphous yellow solid and used without further purification.
Example S-N
Synthesis of
1 S (S)-3-Amino-1-benzyl-d-valerolactam
Ste~A: - Synthesis of L-(+)-Ornithine Methyl Ester Hydrochloride
Into a stirred suspension of L-(+)-ornithine hydrochloride (Aldrich) in
methanol was bubbled anhydrous hydrochloric acid gas until the solution was
saturated. The reaction mixture was capped with a rubber septum and stirring
was
continued overnight at room temperature. The solvent was then stripped under
reduced pressure and the residue triturated with ether. The resulting solid
was
dried under reduced pressure to afford L-(+)-ornithine methyl ester
hydrochloride
as a white solid (97% yield).
2S
Step B: - Synthesis of (S)-3-Amino-d-valerolactam
Sodium spheres in oil (2.0 eq.) (Aldrich) were washed with hexanes (2x)
and methanol (2.3 mL/mmol) was slowly added. The reaction mixture was stirred
under nitrogen until the sodium dissolved and then L-(+)-ornithine methyl
ester

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hydrochloride ( 1 eq. ) in methanol (2.3 mL/mmol) was added dropwise. The
reaction mixture was stirred for 16 hours and then diluted with diethyl ether
(5
mL/mmol) and filtered to remove the solids. The solvent was then removed under
reduced pressure and the residue was heated at 70°C for 3 hours under
reduced
pressure. The residue was then triturated with dichloromethane/ether, the
solvent
decanted and the resulting residue dried under reduced pressure to afford (S)-
3-
amino-d-valerolactam (44% yield).
Step C: - Synthesis of N-Boc-(S)-3-Amino-d-valerolactam
(S)-3-Amino-d-valerolactam (1 eq.) was dissolved in dioxane and the
solution was chilled to 0°C. BOC-anhydride (1.3 eq.) was added and the
ice bath
was removed allowing the solution to come to room temperature and stirring was
continued for 16 hours. The solution was rotary evaporated to afford N-Boc-(S)-
3-
amino-d-valerolactam.
Step D: - Synthesis of (S)-3-Amino-1-benzyl-d-valerolactam
Following General Procedure 5-A and using N-Boc-(S)-3-amino-d-
valerolactam and benzyl bromide provided N-Boc-(S)-3-amino-1-benzyl-d-
valerolactam. Removal of the Boc group using General Procedure 5-B afford the
title compound.
Example 5-O
Synthesis of
4-Amino-2-aza-2-benzyl-3-oxo-bicyclo[3.2.1]octane Hydrochloride
Step a: - Synthesis of 2-Aza-3-oxo-bicyclo[3.2.1]octane and 3-Aza-
2-oxo-bicyclo[3.2.1]octane (9:1 Mixture)
To (")-norcamphor {Aldrich) in 1 mL/mmole of acetic acid was
added 1.5 eq. of hydroxylamine-O-sulfonic acid. The reaction mixture was
heated
to reflux under nitrogen for 1 hour and then saturated sodium carbonate and
dilute

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sodium hydroxide were added. The resulting mixture was extracted with
dichloromethane and the organic extracts washed with brine, dried over sodium
sulfate, and the solvent removed under reduced pressure. Purification of the
<.
residue by column chromatography afforded a 9:1 mixture of 2-aza-3-oxo-
bicyclo[3.2.1]octane and 3-aza-2-oxo-bicycio[3.2.1]octane.
Step - Synthesis of 2-Aza-2-benzyl-3-oxo-bicyclo[3.2.1]octane
Following General Procedure 5-A and using the product for Step A and
benzyl bromide, 2-aza-2-benzyl-3-oxo-bicyclo[3.2.1 )octane was prepared.
Step C: - Synthesis of 2-Aza-2-benzyl-4-oximino-3-oxo-
bicyclo[3.2.1]octane
To a solution of 2-aza-2-benzyl-3-oxo-bicyclo[3.2.1]octane in THF was
added 2.5 eq. of 1M t-BuOK/THF (Aldrich) and the resulting mixture was stirred
for 30 minutes. Isoamyl nitrite (1.5 eq.) was then added dropwise and the
reaction
mixture was stirred overnight. To the reaction mixture was added 3N HC1 and
this mixture was extracted with ethyl acetate and the organic extracts washed
with
water, dried, and concentrated under reduced pressure. The residue was
triturated
with ether/hexanes, the solvents decanted and the residue dried under reduced
pressure to afford 2-aza-2-benzyl-4-oximino-3-oxo-bicyclo[3.2.1]octane as a
tan
liquid (41 % yield). This procedure is further described in Y. Kim,
Tetrahedron
Lett. 30(21 ), 2833-2636 ( 1989).
Step D: - Synthesis of 2-Aza-2-benzyl-4-amino-3-oxo-
bicyclo[3.2.1]octane
A solution of 2-aza-2-benzyl-4-oximino-3-oxo-bicyclo[3.2.1]octane in 10
mL/mmole of ethanol and 5.8 mL/mmole of 3N HCl containing 0.5 g/mmole of
10% Pd/C was saturated with hydrogen gas to 45 psi. The mixture was shaken for
3 hours and then filtered through a layer of Celite. The filtrate was dried
over

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sodium sulfate and concentrated under reduced pressure to afford the title
compound as a solid (86% yield). This procedure is further described in E.
Reimann, Arch. Pharm. 310, 102-109 (1977).
6. Benzazepinone Derivatives and Related omp
GENERAL PROCEDURE 6-A
Alkylation of
1-Amino-1.3 .4.5-tetrahvdro-2H-3-benzazeQin-~-one
Step A: 1-Ethoxycarbonylamino-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one
was prepared according to the procedure of Ben-Ishai et ai., Tetrahedron,
1987,
43, 430.
Steo BB: 1-Ethoxycarbonylamino-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one
1 S (2.0 g, 100 M % ) was dissolved in DMF (30 mL) and NaH (95 % , 0.17 g,
100M % ) was added in one portion. The reaction mixture was stirred for 1 hour
and then the appropriate alkyl iodide (300M%) was added and the mixture was
stirred for 12 hours. The reaction was poured into water and extracted with
ethyl
acetate (3x). The ethyl acetate extracts were then washed with water (3x) and
brine (lx). Treatment with MgS04, rotoevaporation, and chromatography (30%
EtOAc/hexanes) yielded 1-ethoxycarbonylamino-3-alkyl-1,3,4,5-tetrahydro-2H-3-
benzazepin-2-one in 87% yield.
Ste~C: 1-Ethoxycarbony!amino-3-alkyl-1,3,4, 5-tetrahydro-2H-3-benzazepin-
2-one ( 1.Og, 100M % ) was suspended in 30 mL of 30 % HBr/HOAc and heated to
100°C. The reaction mixture was stirred for S hours at this temperature
and then
the reaction was cooled and rotoevaporated to yield 1-amino-3-alkyl-1,3,4,5-
tetrahydro-2H-3-benzazepin-2-one as the hydrobromide salt (100% yield).

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GENERAL PROCEDURE 6-B
Alkylation of
3-Amino-1.3.4.5-tetrah3~dro_2H-1-benzazepin-2-one
Step A: 3-Amino-1,3,4,5-tetrahydro-2H-1-benzazepin-2-one was prepared
from a-tetralone using the methods described in Armstrong et al. Tetrahedron
Letters, 1994, 35, 3239. The following compounds were as prepared by this
procedure for use in the following steps:
5-methyl-3-amino-1,3,4,5-tetrahydro-2H-1-benzazepin-2-one (from 4-methyl-
a-tetralone (Aldrich)); and
5,5-dimethyl-3-amino-1,3,4,5-tetrahydro-2H-1-benzazepin-2-one (from 4,4-
dimethyl-a-tetralone (Aldrich)).
Step B: 3-Amino-1,3,4,5-tetrahydro-2H-1-benzazepin-2-one (4.43 g,
100M % ) was suspended in t-butanol (30mL) and BOC-anhydride (7.5 mL,
130M%) was added dropwise. The reaction mixture was stirred for 2 hours and
then it was rotoevaporated to a residue which was chromatographed with 60%
ethyl acetate/hexanes to yield BOC-protected 3-amino-1,3,4,5-tetrahydro-2H-1-
benzazepin-2-one in 87% yield.
: BOC-protected 3-amino-1.3,4,5-tetrahydro-2H-1-benzazepin-2-one
( 1.5 g, 100M % ) was dissolved in DMF (20mL) and NaH (95 % , 0.13g, 100M % )
was added in one portion. The reaction mixture was stirred for 1 hour and then
the appropriate alkyl iodide (300M%) was added and stirring was continued for
12
hours. The reaction was poured into water and extracted with ethyl acetate
(3x).
The ethyl acetate extracts were washed with water (3x) and then brine (lx).
Treatment with MgS04, rotoevaporation, and chromatography (30%
EtOAc/hexanes) yielded a BOC-protected 3-amino-1-alkyl-1,3,4,5-tetrahydro-2H-
1-benzazepin-2-one in 80% yield.

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Step D: The BOC-protected 3-amino-1-alkyl-1,3,4,5-tetrahydro-2H-1-
benzazepin-2-one ( 1.Og, 100M % ) was suspended in 30 mL of 1:1
CH2Cl2/triflouroacetic acid and the mixture was stirred for 4 hours. The
reaction ,
was then rotoevaporated to yield the 3-amino-1-alkyl-1,3,4,5-tetrahydro-2H-1-
benzazepin-2-one (100% yield).
Example 6-A
Synthesis of
3-Amino-1,5-dimethyl-1,3,4,5-tetrahydro-2H-1-benzazepin-2-one
Step A: 3-Amino-5-methyl-1,3,4,5-tetrahydro-2H-1-benzazepin-2-one was
prepared from 4-methyl-a-tetralone using the methods described in Armstrong et
al. Tetrahedron Letters, 1994, 35, 3239.
Step B: 3-Amino-5-methyl-1,3,4,5-tetrahydro-2H-1-benzazepin-2-one
(9.38 100M%) was dissolved in dioxane (300mL) and the solution was chilled to
0°C. BOC-anhydride (13.898 130M%) was added and the ice bath was
removed
allowing the solution to come to room temperature and stirring was continued
for
16 hours. The solution was rotary evaporated to remove dioxane to provide an
off
white solid. This solid was recrystallized from CHC13 to yield BOC-protected 3-
amino-5-methyl-1,3,4,5-tetrahydro-2H-1-benzazepin-2-one in 55% yield.
Step: BOC-protected 3-amino-5-methyl-1,3,4,5-tetrahydro-2H-1-
benzazepin-2-one (100 M%) was dissolved in DMF (20mL) and NaH (95%, 100
M % ) was added in one portion and the reaction mixture was stirred for 1
hour.
Methyl iodide (300 M % ) was added and this mixture was stirred for 12 hours.
The reaction was then poured into water and extracted with ethyl acetate (3x)
then
backwashed with water (3x) and then brine (lx). Treatment with MgSOa,
rotoevaporation, and chromatography (5 % MeOH/CH,CI:) yielded BOC-protected
3-amino-1,5-dimethyl-1,3,4,5-tetrahydro-2H-1-benzazepin-2-one in 75% yield.

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Step D: BOC-protected 3-amino-1.5-dimethyl-1.3,4,5-tetrahydro-2H-1-
benzazepin-2-one ( 100 M % ) was suspended in 30 mL of 1:1
CH,CI,/triflouroacetic acid. The reaction mixture was stirred for 4 hours. The
.,
reaction was then rotoevaporated to yield 3-amino-1.5-dimethyl-1,3,4,5-
tetrahydro-2H-1-benzazepin-2-one (100% yield).
Example 6-B
Synthesis of
5-(L-Alaninyl)-amino-3,3,7-trimethyl-
5,7-dihydro-6H-benz[b]azepin-6-one Hydrochloride
Following the procedure of Example 7-I and using 5-amino-3,3,7-
trimethyl-5,7-dihydro-6H-bent[b]azepin-6-one hydrochloride (Example 6-C), the
title compound was prepared.
Example 6-C
Synthesis of
5-Amino-3,3, 7-trimethyl-5, 7-dihydro-
6H-benz[b]azepin-6-one Hydrochloride
Sten A:A: Following General Procedure 5-A and using N-t-Boc-5-amino-3,3-
dimethyl-5,7-dihydro-6H-bent[b)azepin-6-one (General Procedure 6-B, followed
by Boc protection) and methyl iodide, N-t-Boc-5-amino-3,3,?-trimethyl-5,7-
dihydro-6H-bent[b]azepin-6-one was prepared.
Step B: Following General Procedure 8-N and using N-t-Boc-5-amino-
3,3,7-trimethyl-5,7-dihydro-6H-benz(b)azepin-6-one, the title compound was
prepared.
Example 6-D
Synthesis of

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3-(S)-Amino-1-methyl-5-oxa-1,3,4,5-
tetrahydro-2H-1-benzazepin-2-one
Step A: 3-(S)-Amino-S-oxa-1,3,4,5-tetrahydro-2H-1-benzazepin-2-one was
prepared from N-Boc-serine (Bachem) and 2-fluoro-1-nitrobenzene (Aldrich)
using
the method of R. J. DeVita et al., Bioorganic and Medicinal Chemistry Lett.
1995.
5(12) 1281-1286.
Step Following General Procedure 5-A and using the product from Step
A, the title compound was prepared.
Example 6-E
Synthesis of
3-(S)-Amino-1-ethyl-5-oxa-1,3,4,5-
tetrahydro-2H-1-benzazepin-2-one
Ste~a A: 3-(S)-Amino-5-oxa-1,3,4,5-tetrahydro-2H-1-benzazepin-2-one was
prepared from N-Boc-serine (Bachem) and 2-fluoro-1-nitrobenzene (Aldrich)
using
the method of R. J. DeVita et al., Bioorganic and Medicinal Chemistry Lett.
1995,
5(12) 1281-1286.
Step B: Following General Procedure 5-A and using the product from Step
A, the title compound was prepared.
Example 6-F
Synthesis of
3-(S)-Amino-1-methyl-5-this-1,3,4,5-
tetrahydro-2H-1-benzazepin-2-one
The title compound was prepared from N-Boc-cystine (Novabio) and 2-
fluoro-1-nitrobenzene (Aldrich) using the method of R. J. DeVita et al.,

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Bioorganic and Medicinal Chemistry Lett. 1995, 5(12) 1281-1286, followed by
General Procedure 5-A.
7. Dibenzazepinone Derivatives and Related Comb?funds
GENERAL PROCEDURE 7-A
Preparation of
5-Amino-7-alkyl-5,7-dihydro
6H-dibenzLb.d]azenin-6-one Derivatives
Step A: Following General Procedure 5-A and using 5,7-dihydro-bH-
dibenz(b,d]azepin-6-one and an alkyl halide, the 7-alkyl-5,7-dihydro-6H-
dibenz[b,d]azepin-6-one was prepared.
Step B: The 7-alkyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one (1 eq.) was
dissolved in THF and isoamylnitrite (1.2 eq.) was added. The mixture was
cooled
to 0°C in an ice bath. NaHMDS (1.I eq., 1M in THF) was added dropwise.
After stirring for 1 hour or until the reaction was complete, the mixture was
concentrated then acidified with 1N HC1 and extracted with EtOAc. The organic
portion was dried and concentrated to yield a crude product which was purified
by
silica gel chromatography.
step C: The resulting oxime was dissolved in EtOH/NH3 (20:1) and
hydrogenated in a bomb using Raney nickel and hydrogen (500 psi) at
100°C for
10 hours. The resulting mixture was filtered and concentrated to provide an
oil
which was purified by silica gel chromatography to yield the title compound.
GENERAL PROCEDURE 7-B
Preparation of
Fluoro-substituted 5,7-dihydro-6H-
dibenz(~.d]azepin-6-one Derivatives

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A modification of the procedure of Robin D. Clark and Jahangir,
Tetrahedron, Vol. 49, No. 7, pp. 1351-1356, 1993 was used. Specifically, an
appropriately substituted N-t-Boc-2-amino-2'-methylbiphenyl was dissolved in
THF and cooled to -78°C. s-Butyl lithium (1.3M in cyclohexane, 2.2
eq.) was
added slowly so that the temperature remained below -65°C. The
resulting
mixture was allowed to warm to -25°C and was stirred at that
temperature for 1
hour. The mixture was cooled to -78°C. Dry CO2 was bubbled through the
mixture for 30 seconds. The mixture was allowed to warm to ambient temperature
then was carefully quenched with water. The mixture was concentrated under
reduced pressure then was adjusted to pH 3 with 1N HC1. The mixture was
extracted with EtOAc and the organic portion was dried and concentrated to
yield
a crude material. The crude material was dissolved in methanol and the
solution
was saturated with HCI. The mixture was heated at reflux for 12 hours then was
allowed to cool. The mixture was concentrated to provide crude lactam which
was
purified by chromatography or crystallization.
GENERAL PROCEDURE 7-C
Resolution of
5-Amino-7-methyl-5 .7-dihydro-6H-dibenz[b.dJazepin-6-one
In a round bottom flask was added the racemic freebase amine (1.0 eq.) in
methanol followed by di p-toluoyl-D-tartaric acid monohydrate (1.0 eq.). The
mixture was concentrated in vacuo to a residue and redissolved in a moderate
volume of methanol and allowed to stir at room temperature open to the
atmosphere (8-72 hours). The solid was removed by filtration. The enantiomeric
excess was determined by chiral HPLC (Chiracel ODR) using 15 %a acetonitrile
and 85 % HBO with 0.1 % trifluoroacetic acid and a flow rate of 1.0 mL/min at
35°C. The resolved di p-toluoyl-D-tartaric salt was then dissolved in
EtOAc and
saturated NaHC03 until pH 9-10 was reached. The layers were separated and the
organic layer was washed again with saturated NaHC43, H20, and brine. The

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organic layer was dried over MgS04 and the drying agent was removed by
filtration. The filtrate was concentrated in vacuo. The free amine was
dissolved
in MeOH and HCl (12M, 1.0 eq.) was added. The salt was concentrated in vacuo ,
and the resulting film was triturated with EtOAc. The HCl salt was filtered
and
S rinsed with EtOAc. The ee was determined by chiral HPLC.
Example 7-A
Synthesis of
5-Amino-7-methyl-5, 7-dihydro
6H-dibenz[b,d]azepin-6-one Hydrochloride
Step A - synthesis of 7-Methyl-5.7-dihvdro-6H-dibenz[b.dJazepin-6-one
A round bottom flask was charged with sodium hydride (0.295 g, 7.46
mmol) in 9.0 ml of DMF and treated with 5,7-dihydro-6H-dibenz[b,d]azepin-6-
one (1.3 g, 6.22 mmol) (CAS # 20011-90-9, prepared as described in Brown, et.
IS al., Tetrahedron Letters, No. 8. 667-670, (1971) and references cited
therein).
After stirring at 60°C for 1 h. the solution was treated with methyl
iodide (1.16
ml, 18.6 mmol) and stirring continued for 17 h with the exclusion of light.
After
cooling, the reaction was diluted with CH,Ch/H:O, washed with NaHSO~
solution, H=O, and dried over Na,SO,. Evaporation and flash chromatography
(SiO,, CHC13) gave 0.885 g (63%) of the title compound as a colorless solid.
NMR data was as follows:
'H-nmr (CDC13): d = 7.62 (d, 2H), 7.26-7.47 (m, 6H), 3.51 (m, 2H),
3.32 (s, 3H).
C'SH'3N0 (MW = 223.27); mass spectroscopy (MH+) 223.
~ Anal. Calcd for C,SH,3N0; C, 80.69 H, 5.87 N, 6.27. Found: C, 80.11
H,5.95N,6.23.
' Step B - Synthesis of 7-Methyl-5-oximo-5~ -dihvdro-6H-
dibenz(b~J~~zepin-6-~ne

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The compound isolated above (0.700 g, 3.14 mmol) was dissolved in 20 ml
of toluene and treated with butyl nitrite (0.733 ml, 6.28 mmol). The reaction
temperature was lowered to 0°C and the solution was treated with KHMDS
(9.42 ..
ml, 0.5 M) under N, atmosphere. After stirring for 1 h the reaction was
quenched
with a saturated solution of NaHS04, diluted with CH,CI~ and separated. The
organic layer was dried over Na,SOa and the title compound purified by
chromatography (SiO,, 98:2 CHCh/MeOH) giving 0.59 ~ (80 %) as a colorless
solid.
C,SH,~N~O~ (MW = 252.275); mass spectroscopy (MH+) 252.
Anal. Calcd for C,SH,zN,O,; C, 71.42 H, 4.79 N, 11.10. Found: C, 71.24.
H, 4.69 N, 10.87.
Step C - Synthesis of 5-Amino-7-Meth -S ~-di ydro 6H
dibenz(b dlazenin-6-one Hydrochtr,T;.tP
The oxime isolated above (0.99 g, 3.92 mmol) was hydrogenated in a Parr
apparatus at 35 psi over 10 % Pd/C (0.46 g) in 3A ethanol. After 32 h the
reaction mixture was filtered through a plug of celite, the filtrate
evaporated to a
foam and treated with a saturated solution of HCl (g) in Et,O. The resulting
colorless solid was filtered, rinsed with cold Et~O and vacuum dried to give
0.66 g
(61 % ) of the title compound.
NMR data was as follows:
'H-nmr (DMSOd6): d = 9.11 (bs, 3H), 7.78-7.41(m, 8H), 4.83 (s, 1H),
3.25 (s, 3H).
C,SH,~N,O HCI (MW = 274.753); mass spectroscopy (MH+ free base)
238.
Anal. Calcd for C,SH,.,N~O . HCI; C, 65.57 H, 5.50 N, 10.19 Found: C,
65.27 H, 5.67 N, 10.13.
Example 7-B

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Synthesis of
(S)- and (R)-5-(L-Alaninyl)-amino-7-methyl-
5,7-dihydro-6H-dibenz[b,d]azepin-6-one "
Step A - Synthesis of (S)- and Rl-5-(N-Boc-L-Alaniny_Il-amigo 7_
~ methyl-5.7-dihvdro-6H-dibenzfb djazepin-6-one_
Boc-L-Alanine (0.429 g, 2.26 mmol) (Aldrich) was dissolved in THF and
treated with HOBt hydrate (0.305 g, 2.26 nlmol), and 5-amino-7-methyl-5.7-
dihydro-6H-dibenz[b,d]azepin-6-one (0.45 g, 1.89 mmol) (Example 7-A). The
temperature was lowered to 0°C and the reaction mixture treated with
EDC (0.449
g, 2.26 mmol) (Aldrich) and stirred 17 hours under N~. The reaction mixture
was
evaporated, the residue diluted with EtOAc/H~O, washed 1.0 N HC1, sat.
NaHC03, brine and dried over Na,S04. The diastereomers were separated on a
Chiralcel OD column using 10% IPA/heptane at 1.5 mllminute.
Isomer 1: Retention time 3.37 minutes.
NMR data was as follows:
'H-nmr (CDCI,): d = 7.62-7.33 (m, 9H), 5.26 (d, 1H), 5.08 (m, 1H),
4.34 (m, 1H), 3.35 (s, 3H), 1.49 (s, 9H), 1.40 (d, 3H).
Optical Rotation: [a],o = - 96 Q 589 nm (c = 1, MeOH).
C~3H,,N,04 (MW = 409.489); mass spectroscopy (MH+) 409.
Anal. Calcd for C~3H~,Nz04; C, 67.46 H, 6.64 N, 10.26. Found: C. 68.42
H, 7.02 N. 9.81.
Isomer 2: Retention time 6.08 minutes.
NMR data was as follows:
'H-nmr {CDCl3): d = 7.74 (bd,1H), 7.62-7.32 (m, 8H), 5.28 (d, 1H), 4.99
(m, 1H). 4.36 (m, 1H), 3.35 (s. 3H), 1.49 (s, 9H), 1.46 (d, 3H).
Optical Rotation: [a]~o = 69 Q 589 nm (c = 1, MeOH).
C,3H=,N,04 (MW = 409.489); mass spectroscopy (MH+) 409.

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Anal. Calcd for C,,H~,N30~; C, 67.46 H, 6.64 N, 10.26. Found: C, 67.40
H, 6.62 N, 10.02
Step B - Svnthesis of lS)- and l~~L-Alaninvll-amino-7 methsn
~.7-dihvdro-6H-diben~
[~i~~.enin-6-one ~ydrochloride
The compounds isolated in Part A (each isomer separately) were dissolved
in dioxane and treated with excess HCl (g). After stirring for 17 hours, the
title
compounds were isolated as colorless solids after evaporation and vacuum
drying.
Isomer 1:
C,8H,9N,O,.HCI (MW = 345.832); mass spectroscopy (MH+ free base)
309.
Optical Rotation: [aj,o = - 55 ~ 589 nm (c = l, MeOH).
Isomer 2:
C,8H,9N~O,.HC1 (MW = 345.832); mass spectroscopy (MH+ free base)
309.
Optical Rotation: [a),~, = 80 ~ 589 nm (c = l, MeOH).
Example 7-C
Synthesis of
(S)- and (R)-5-(L-Valinyl)-amino-7-methyl-
5,7-dihydro-6H-dibenz[b,d]azepin-6-one
Step A - Synthesis of lS)- and (R)-5-(N-Boc-L-Valinyll-amino 7-
m~thyl-5.7-dihydro-6H-dibenz[b dlazepin-6-one
Boc-L-Valine (0.656 g, 3.02 mmol) (Aldrich) was dissolved in THF and
treated with HOBt hydrate (0.408, 3.02 mmol), Dipea ( 1.05 ml, 6.05 mrnol) and
5-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one hydrochloride (0.75 g,
2.75 mmol)(Example 7-A). The temperature was lowered to 0°C and the
reaction
mixture treated with EDC (0.601 g, 3.02 mmol)(Alrich) and stirred 17 hours
under N,. The reaction mixture was evaporated, the residue diluted with

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EtOAc/HZO, washed 1.0 N HC1, sat. NaHC03, brine and dried over Na,SOa. The
diastereomers were separated on a Chiralcel OD column using 10% IPA/heptane at
1.5 ml/minute.
Isomer 1: Retention time 3.23 minutes.
Optical Rotation: ja]ZO = - 120 Q 589 nm (c = 1, MeOH).
C,SH;,N30~ (MW = 437.544); mass spectroscopy (MH+) 438
Isomer 2: Retention time 6.64 minutes.
Optical Rotation: [a]ZO = 50 Qa 589 nm (c = 1, MeOH).
C,SH3,N,Oy (MW = 437.544); mass spectroscopy (MH+) 438
Step B - Synthesis of (S1- and ($ -).-~-5-(L-Valin~)-amino-7-met~yl-S.7-
dihvdro-6H-dibenzj~]~oin-6-one Hydrochloride
The compounds isolated in Part A (each isomer separately) were dissolved
in dioxane and treated with excess HCl (g). After stirring for 17 hours, the
title
1 S compounds were isolated as colorless solids after evaporation and vacuum
drying.
Isomer l:
C,oH,3N,O,.HC1 (MW = 373.88); mass spectroscopy (MH+ free base)
338.
Optical Rotation: [a]ZO = - 38 Qa 589 nm (c = 1, MeOH).
Isomer 2:
Czali"N,O~.HCI (MW = 373.88); mass spectroscopy (MH+ free base)
338.
Optical Rotation: [a]zo = 97 ~a 589 nm (c = 1, MeOH).
Example 7-D
Synthesis of
(S)- and (R)-5-(L-tent-Leucine)-amino-7-methyl
5,7-dihydro-6H-dibenz(b,d]azepin-6-one

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Step A - Synthesis of (S)- and (R)-5-lN-Boc-L-tert-LeucirLyl)-amino-
7-meth - .7-di vdro-6H-dibenz[b.d]azepin-6-one
Boc-L-tert-Leucine (0.698 g, 3.02 mmol) (Fluka) was dissolved in THF
and treated with HOBt hydrate (0.408, 3.02 mmol), Dipea (1.05 ml, 6.05 mmol)
and 5-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d)azepin-6-one hydrochloride
(0.75 g, 2.75 mmol)(Example 7-A). The temperature was lowered to 0°C
and the
reaction mixture treated with EDC (0.601 g, 3.02 mmol) (Alrich) and stirred 17
hours under N,. The reaction mixture was evaporated, the residue diluted with
EtOAc/H~O, washed 1.0 N HCI, sat. NaHC03, brine and dried over Na~SO,. The
diastereomers were separated on a Chiralcel OD column using 10% IPA/heptane at
1.5 ml/minute.
Isomer 1: Retention time 3.28minutes.
Optical Rotation: [a)," _ - 128 ~ 589 nm (c = 1, MeOH).
C,6H~31V30~ (MW = 451.571 ); mass spectroscopy (MH + ) 452
Isomer 2: Retention time 5.52 minutes.
Optical Rotation: [a)_~ = 26 Qa 589 nm (c = 1, MeOH).
C26H33N3~4 (MW = 451.571 ); mass spectroscopy (MH + ) 452
Step B - S~thesis of (S)- and (R)-5-(L-tert-Leuci~,vl)-amino-7-
methyl-5 7-dihvdro-6H-djbenz~(b ~,j~pin-6-one
Hydrochloride
The compounds isolated in Part A (each isomer separately) were dissolved
in dioxane and treated with excess HC1 (g). After stirring for 17 hours, the
title
compounds were isolated as colorless solids after evaporation and vacuum
drying.
Isomer 1:
C,,H~SN30,.HC1 (MW = 387.91); mass spectroscopy (MH+ free base)
352.

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Optical Rotation: [a]ZO = - 34 Q 589 nm (c = 1, MeOH).
Isomer 2:
CZ~HzsN30z.HC1 (MW = 387.91); mass spectroscopy (MH+ free base)
S 352.
Optical Rotation: [a]ZO = 108y 589 nm (c = 1, MeOH).
Example 7-E
Synthesis of
5-(N-Boc-Amino)-5,7-dihydro-6H,7H-dibenz[b,d]azepin-6-one
Step A - Synthesis of 5-Iodo-5.7-dihvdro-6H-dibelL[~,]spin-6-one
A solution of 5,7-dihydro-6H-dibenz[b,d]azepin-6-one (1.0 g, 4.77 mmol)
(Example 7-A) and Et3N ( 2.66 ml, 19.12 mmol) were stirred for 5.0 minutes at -
15°C in CH,Chand treated with TMSI (1.36 ml, 9.54 mmol). After stirring
for
15 minutes I, ( 1.81 g, 7.16 nunol) was added in a single portion and the
reaction
allowed to warm to 5-10°C over 3 h. The reaction was quenched with sat.
Na,SO,, diluted with CH,Ch and separated. The organics were washed with
Na,SO~ and NaHSO, and dried over MgSO,. After filtration, ttte organics were
concentrated to approximately 20 ml and diluted with an additional 20 ml of
hexanes. The title compound was isolated as a tan precipitate by filtration.
Step B - Synthesis of 5-Azido-5.7-dihvdro-6H-diber~[b-d]azPnin-6-
The iodide isolate above was dissolved in DMF and treated with 1.2
equivalents of NaN,. After stirring 17 h at 23°C the mixture was
diluted with
EtOAc/H,O, separated. washed with brine and dried over MgSO.,. The title
compound was triturated from hot EtOAc as a tan powder.

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Step C - ~vnthesis of 5-lN-Boc-Amino)~7-dihydro-6H.7H-
dibe b.d]azepin-6-one
The azide was dissolved in THF/H,O and stirred at 23 °C for 17 h
in the
presence of 3.0 equivalents of PhzP. The reaction was diluted with 54
S HOAc/toluene, separated, the aqueous layer extracted with toluene and
evaporated
to an aiIy residue. This was taken to ~pH 7.0 by the addition of 1 N NaOH, the
resulting HOAc salt was collected and vacuum dried. Finally, the compound was
treated with Boc anhydride (1.05 equivalents) and Et3N (2.1 equivalents) in
THF.
After stirring for S h at 23 °C the reaction was filtered and the title
compound
isolated as a colorless powder.
Example 7-F
Synthesis of
5-Amino-7-(2-methylpropyl)-5,7-dihydro-
6H-dibenz[b,d]azepin-6-one Hydrochloride
Step A - ynthesis of 5-(N-Boc-Aminol-7-l2-me ~ Iv_nrop~ Iv )-5.7-
di]~ydro-6H-~ibe~,jb.d]azepin-6-one
A solution of S-(N-Boc-amino)-5.7-dihydro-6H-dibenz[b,d]azepin-6-one
(0.2g, 0.617 mmol) (Example 7-E) in DMF was treated with CSrC03 (0.22 g,
0.678 mmol) and warmed to 60°C. To the reaction mixture was added 1-
iodo-2-
methylpropane (0.078 ml, 0.678 mmol) and stirring continued for 17 h. After
cooling to 23 °C the mixture was diluted with CH,Ch, washed with
several
portions of brine and dried over Na,SO,. The title compound was purified by
chromatography (SiO,, CHCI3/MeOH 9:1 ).
C,3HZgN,O~ (MW = 380.41); mass spectroscopy (MH+) 381
Anal. Calcd for C,3H,RN,O,: C, 72.61 H, 7.42 N, 7.36. Found: C, 72.31
H, 7.64 N, 7.17.

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Step B - Synthesis of 5-Amino-7-l2-methvlQropvl -5 7-di dro-6H-
dibenzjb.djaze~f~-one Hydrochloride
The compound isolated in Part A was deprotected in dioxane saturated with
gaseous HCI. The title compound was isolated as a slightly colored solid after
S evaporation and vacuum drying.
Example 7-G
Synthesis of
5-Amino-7-(methoxyacetyl)-5, 7-dihydro-
6H-dibenz[b,d]azepin-6-one Hydrochloride
Step A- Synthesis of 5-(N-Boc-AminoL echo xyl -) 5-7-
dihvdro-6H-dibenz[b ,~,l~pin-6-one
A solution of S-(N-Boc-amino)-5,7-dihydro-6H-dibenz[b,d]azepin-6-one
(1.03, 3.08 mmol) (Example 7-E} in DMF was treated with Cs,C03 (1.10 g, 3.39
mmol) and warmed to 60°C. To the reaction mixture was added bromomethyl
acetate (0.321 ml, 3.39 nunol) (Aldrich) and stirring continued for 17 h.
After
cooling to 23 °C the mixture was diluted with CH,Ch, washed with
several
portions of brine and dried over Na,SO~. The title compound was purified by
chromatography (SiO,, CHCI,).
C"H~4N,OS (MW = 396.44); mass spectroscopy (MH+) 397
Anal. Calcd for C"H~.,N~OS; C, 66.65 H, 6.10 N, 7.07. Found: C, 66.28
H, 5.72 N, 6.50.
Step B - Synthesis of 5-Amino-7-(methox ac vl)-57-dihvdro-6H-
diber~z(b.dja_~epin-6-one Hydrochloride
The compound isolated in Part A was deprotected in dioxane saturated with
gaseous HCI. The title compound was isolated as a colorless solid after
evaporation and vacuum drying.

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C"H,bNzO~ HCl (MW = 332.78): mass spectroscopy (MH+ free base)
297.
Example 7-H
Synthesis of
5-Amino-7-(3,3-dimethyl-2-butanonyl)
5,7-dihydro-6H-dibenz(b,d]azepin-6-one Hydrochloride
Step A- Synthesis of 5-(N-Boc-Aminp~ 7-(,3.3-dimet 1-butanonyl)-
5.7dihydro-6H-dibenz jj~.d]~z p~~-6-one
A solution of 5-(N-Boc-amino)-5.7-dihydro-6H-dibenz[b,d]azepin-6-one
(0.2 g, 0.617 mmol) (Example 7-E) in DMF was treated with CSzC03 (0.3 g,
0.925 mmol) and warmed to 60°C. To the reaction mixture was added 1-
chloro-
3,3-dimethyl-2-butanone (0.096 ml, 0.74 mmol) (Aldrich) and stirring continued
for 17 h. After cooling to 23 °C, the mixture was diluted with CH,Ch,
washed
with several portions of brine and dried over Na~SO~. The title compound was
isolated as a colorless solid.
C,SH3~N,0~ (MW = 422.522); mass spectroscopy (MH+) 423
Step B - Synthesis of 5-Amino-7-(3.3-dimeth, 1-~ onyl_l-5.7-
dijtvdro-6H-dibenzjb.d]~~~,pin-6-one Hydrochloride
The compound isolated in Part A was deprotected in dioxane saturated with
gaseous HCI. The title compound was isolated as a colorless solid after
evaporation and vacuum drying.
Example 7-I
Synthesis of
L-Alaninyl-5-amino-7-methyl-5,7-dihydro-
6H-dibenz(b,d]azepin-6-one Hydrochloride

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Step A: Following General Procedure D and using N-t-Boc-L-alanine and
5-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one, N-t-Boc-L-alaninyl-5-
amino-7-methyl-5,7-dihydro-6H-dibenz[b,d)azepin-6-one was prepared.
Step B: Following General Procedure 8-N and using the N-t-Boc-L-
alaninyl-5-amino-7-methyl-5.7-dihydro-6H-dibenz(b,d)azepin-6-one, the title
compound was prepared. Other substituted N-t-Boc-L-alaninyl-5-amino-7-methyl-
5,7-dihydro-6H-dibenz[b,d)azepin-6-ones can also be prepared by this
procedure.
Example 7-J
Synthesis of
L-Vaiinyl-5-amino-7-methyl-5, 7-dihydro-
6H-dibenz(b,d)azepin-6-one Hydrochloride
St~~ A: Following General Procedure D and using N-t-Boc-L-valine and
5-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d)azepin-6-one, N-t-Boc-L-vaiinyl-5-
amino-7-methyl-5,7-dihydro-6H-dibenz(b,d)azepin-6-one was prepared.
Step B: Following General Procedure 8-N and using the N-t-Boc-L-
valinyl-5-amino-7-methyl-5.7-dihydro-6H-dibenz(b,d)azepin-6-one, the title
compound was prepared. Other substituted N-t-Boc-L-valinyl-5-amino-7-methyl-
5,7-dihydro-6H-dibenz(b.d)azepin-6-ones can also be prepared by this
procedure.
Example 7-K
Synthesis of
5-Amino-7-phenbutyl-5,7-dihydro-6H-dibenz(b,d]azepin-6-one
Following General Procedure 7-A and using 5,7-dihydro-6H-
dibenz(b,d)azepin-6-one (prepared as described in Brown, et. al. , Tetrahedron
Letters, No. 8, 667-670, (1971) and references cited therein) and 1-chloro-4-
phenylbutane (Aldrich), the title compound was prepared.

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Example 7-L
Synthesis of
5-Amino-7-cyclopropymethyl-5, 7-dihydro- ,
6H-dibenz[b,d]azepin-6-one
Following General Procedure 7-A and using 5,7-dihydro-6H-
dibenz[b,d]azepin-6-one (prepared as described in Brown, et. al., Tetrahedron
Letters, No. 8, 667-670, ( 1971 ) and references cited therein) and
(bromomethyl)cyclopropane (Aldrich), the title compound was prepared.
Example 7-M
Synthesis of
5-Amino-7-(2,2,2-trifluoroethyl)-5, 7-dihydro-
6H-dibenz(b,d]azepin-6-one
Following General Procedure 7-A and using 5,7-dihydro-6H-
dibenz[b,d]azepin-6-one (prepared as described in Brown, et. al., Tetrahedron
Letters, No. 8, 667-670, (1971) and references cited therein) and 1-bromo-
2,2.2-
trifluoroethane (Aldrich), the title compound was prepared.
Example 7-N
Synthesis of
5-Amino-7-cyclohexyl-5,7-dihydro-
- 6H-dibenz(b,d]azepin-6-one
Following General Procedure 7-A and using 5.7-dihydro-6H-
dibenz[b,d]azepin-6-one (prepared as described in Brown, et. al., Tetrahedron
Letters, No. 8, 667-670, (1971) and references cited therein) and
bromocyclohexane (Aldrich), the title compound was prepared.
Example 7-O
Synthesis of

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5-(L-Alaninyl)amino-9-fluoro-7-methyl-
5,7-dihydro-6H-dibenz[b,d]azepin-6-one Hydrochloride
Ste~l: 2-Bromo-5-fluorotoluene was stirred in THF at -78C. s-BuLi ..
(1.05 eq., 1.3 M in cyclohexane) was slowly added and the mixture was stirred
for
S 45 minutes. Trimethyiborate (1.5 eq) was added and the mixture was allowed
to
warm to ambient temperature. After stirring for 1 hour, pinacol (2 eq.) was
added. The mixture was stirred for 16 hours then was concentrated under
reduced
pressure. The resulting residue was slurried in CH,CI, and filtered through
Celite.
The filtrate was concentrated to yield an oil which was purified by
chromatography on deactivated silica gel (Et3N) to yield the arylboronate
ester.
Ste~2-. 2-Bromoaniline (1 eq.) and di-t-butyl-dicarbonate (1.1 eq.) were
stirred at 80°C for 20 hours. The resulting mixture was allowed to cool
and was
directly distilled using house vacuum to provide N-t-Boc-2-bromoaniline.
Ste~3~. N-t-Boc-2-bromoaniline (Step 2, 1 eq.), the arylboronate ester
(Step 1. 1.1 eq.), K,CO, ( 1.1 eq. ) and
tetrakis(triphenylphosphine)palladium(0)
(0.02 eq) were stirred in 20% water/dioxane under nitrogen. The solution was
heated at reflux for 10 hours. The mixture was allowed to cool then was
concentrated. The resulting residue was partitioned between water and
chloroform. The organic portion was dried and concentrated to yield an oil
which
was purified by silica gel chromatography using 1:1 CH~CI,/hexanes.
Step 4: Following General Procedure 7-B and using the substituted
biphenyl from step 3, the 9-fluoro-5,7-dihydro-6H-dibenz[b,d]azepin-6-one was
prepared.
Step 5: 9-Fluoro-5,7-dihydro-6H-dibenz[b,d]azepin-6-one (1 eq., Step 4),
cesium carbonate (1.1 eq., Aldrich) and methyl iodide (1.1 eq., Aldrich) were

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stirred in dry DMF at ambient temperature for 16 hours. The mixture was
concentrated under reduced pressure to provide a residue which was partitioned
between EtOAc and water. The organic portion was dried and concentrated to
yield an oil which was purified by silica gel chromatography to 9-fluoro-7-
methyl-
S 5,7-dihydro-6H-dibenz[b,d)azepin-6-one.
Ste~L Following General Procedure 7-A, Step R and 9-fluoro-7-methyl-
5,7-dihydro-6H-dibenz(b,d)azepin-6-one from Step 5, 5-amino-9-fluoro-7-methyl-
5,7-dihydro-6H-dibenz[b.d)azepin-6-one was prepared.
Step 7: Following the procedure of Example 7-I and using 5-amino-9-
fluoro-7-methyl-5.7-dihydro-6H-dibenz[b,d)azepin-6-one from Step 6, the title
compound was prepared.
I S Example 7-P
Synthesis of
5-(L-Alaninyl)amino-13-fluoro-7-methyi
5,7-dihydro-6H-dibenz[b,d)azepin-6-one Hydrochloride
Following the procedure of Example 7-O and using 2-bromo-4-
fluoroaniline (Step 2, Lancaster) and o-tolylboronic acid (Step 3, Aldrich),
the title
compound was prepared.
Example 7-Q
Synthesis of
5-(L-Alaninyl)amino-14-fluoro-7-methyl-
5,7-dihydro-6H-dibenz[b,d]azepin-6-one Hydrochloride
Following the procedure of Example 7-O and using 2-bromo-4-
fluorotoluene (Step 1), the title compound was prepared.

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Example 7-R
Synthesis of
5-(L-Alanyl)-amino-7-cyclopropylmethyl
5,7-dihydro-6H-dibenz[b,d]azepin-6-one Hydrochloride
Following the procedure of Example 7-I and using 5-amino-7-
cyclopropylmethyl-5,7-dihydro-6H-dibenz(b,d]azepin-6-one (Example. 7-L), the
title compound was prepared.
Example 7-S
Synthesis of
5-(L-Alaninyl)amino-7-phenbutyl
5,7-dihydro-6H-dibenz(b,d]azepin-6-one Hydrochloride
Following the procedure of Example 7-I and using 5-amino-7-phenbutyl-
5,7-dihydro-6H-dibenz[b,d]azepin-6-one (Example 7-K), the title compound was
prepared.
Example 7-T
Synthesis of
5-(L-Valinyl)amino-7-cyclopropylmethyl-
5,7-dihydro-6H-dibenz[b,d]azepin-6-one Hydrochloride
Following the procedure of Example 7-J and using 5-amino-7-
cyclopropylmethyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one (Example 7-L), the
title compound was prepared.
Example 7-U
Synthesis of
5-(L-Valinyl)amino-7-phenbutyl
S,7-dihydro-6H-dibenz[b,d]azepin-6-one Hydrochloride

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Following the procedure of Example 7-J and using 5-amino-7-phenbutyl-
5,7-dihydro-6H-dibenz[b,d]azepin-6-one (Example 7-U), the title compound was
prepared.
Example 7-V
Synthesis of
5-(L-Valinyl)amino-7-hexyl-5, 7-dihydro-
6H-dibenz[b,d]azepin-6-one Hydrochloride
Step A: Following General Procedure 7-A and using 5,7-dihydro-6H-
dibenz[b,d]azepin-6-one (prepared as described in Brown, et. al., Tetrahedron
Letters, No. 8, 667-670, (1971) and references cited therein) and 1-
bromohexane
(Aldrich), 5-amino-7-hexyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one was
prepared.
Stem $: Following the procedure of Example 7-J and using 5-amino-7-
hexyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one, the title compound was prepared.
Example 7-W
Synthesis of
5-(L-Valinyl)amino-10-fluoro-7-methyl-
5,7-dihydro-6H-dibenz[b,d]azepin-6-one Hydrochloride
Following the procedure of Example 7-J and using S-amino-10-fluoro-7-
methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one (as prepared in Example 7-Q},
the
title compound was prepared.
Example 7-X
Synthesis of
5-(L-Valinyl)amino-13-fluoro-7-methyl-
5,7-dihydro-6H-dibenz[b,d]azepin-6-one Hydrochloride

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Following the procedure of Example 7-J and using the 5-amino-13-fluoro-
7-methyl-5,7-dihydro-6H-dibenz(b,d]azepin-6-one (as prepared in Example 7-P),
the title compound was prepared. ,
Example 7-Y
Synthesis of
5-(L-Valinyl)amino-13-fluoro-7-methyl
5,7-dihydro-6H-dibenz[b,d)azepin-6-one Hydrochloride
Following the procedure of Example 7-J and using the 5-amino-9-fluoro-7-
methyl-5,7-dihydro-6H-dibenz(b,d]azepin-6-one (as prepared in Example 7-O),
the
title compound was prepared.
Example 7-Z
Synthesis of
(5-Amino-7-methyl-1,2,3,4,5,7-hexahydro-
6H-dicyclohexyl[b,d)azepin-6-one
The 5-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one
hydrochloride (Example 7-A) was dissolved in a 1:1 mixture of EtOAc/HOAc.
5% lth/C was added and the mixture was stirred at 60°C under 60 psi of
hydrogen. After 3 days, the mixture was filtered and the filtrate was
concentrated
to provide an oil which was purified by SCX-canon exchange chromatography to
yield the title compound.
Example 7-AA
Synthesis of
5-(S)-Amino-7-methyl-5,7-dihydro-
6H-dibenz[b,d]azepin-6-one Hydrochloride
Following General Procedure 7-C using racemic 5-amino-7-methyl-5,7-
dihydro-6H-dibenz[b,d]azepin-6-one (1.0 eq.) and di p-toluoyl-D-tartaric acid

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monohydrate (1.0 eq.) in methanol, the title compound was prepared as a solid.
The product was collected by filtration. Enantiomeric excess was determined by
chiral HPLC.
Desired enantiomer 1: retention time of 9.97 minutes.
Undesired enantiomer 2: retention time of 8.62 minutes.
NMR data was as follows:
'H-nmr (CDC13): d = 9.39 (s, 2H), 7.75-7.42 (m. 8H), 4.80 (s, 1H), 3.30
(s, 3H).
C,SH,SC1N,0 (MW = 274.75); mass spectroscopy (MH+) 239.1.
Anal Calcd for C,SH,SC1N,0,; C, 65.57; H, 5.50; N, 10.20; Found: C,
65.51, H, 5.61; N, 10.01.
8. Be podia enine Derivatives and Relay Com oundc
GENERAL PROCEDURE 8-A
N-1-Methylation of Benzodiaze inee
A solution of benzodiazepine (1 eq.) in DMF (0.1 M concentration) at
0°C
was treated with potassium tert-butoxide ( 1.0 eq.. 1.0 M solution in THF).
After
stirring for 30 minutes at 0°C, iodomethane (1.3 eq.) was added and
stirring
continued for 25 minutes. The mixture was diluted with methylene chloride and
washed with water and brine. The organic phase was dried over Na2S04,
filtered,
and concentrated. The crude product was then either purified by trituration
with
1:1 ether/hexanes or chromatographed via HPLC using ethyl acetate/hexanes as
the eluent.
GENERAL PROCEDURE 8-B
(~bz Removal Procedure
A flask was charged with the Cbz-protected 3-aminobenzodiazepine (1 eq.).
To this was added HBr (34 eq.; 30% solution in acetic acid). Within 20 minutes

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all of the starting material dissolves. The reaction was stirred for 5 hours
at
ambient temperature. Ether was added to the orange solution causing the HBr
amine salt to precipitate. The mixture was decanted. This process of adding
ether
and decanting was repeated thrice in an effort to remove acetic acid and
benzyl
bromide. Toluene was added and the mixture concentrated in vacuo. This step
was also repeated. The HBr salt was partitioned between ethyl acetate and 1 M
K2C03. The aqueous layer was back-extracted with ethyl acetate. The combined
organics were washed with brine, dried over Na2S04, filtered, and
concentrated.
GENERAL PROCEDURE 8-C
Boc Removal Procedure
A solution of Boc-protected amine (1 eq.) in methylene chloride (0.15 M
concentration) was cooled to 0°C and treated with trifluoroacetic acid
(30 eq.).
After 10 minutes at 0°C, the cooling bath was removed and stirring
continued at
ambient for 20 minutes to 1 hour. The mixture was concentrated in vacuo to
remove excess trifluoroacetic acid. The residue was dissolved in methylene
chloride and washed with saturated aqueous NaHC03 or 1 M K2C03 and brine.
The organic layer was dried over Na2S04, filtered, and concentrated.
GENERAL PROCEDURE 8-D
The azido derivative was prepared using the procedure described in John W.
Butcher et al., Tet. Lett., 37, 6685-6688 (1996).
GENERAL PROCEDURE 8-E
Azide Transfer Reaction Using LDA
To a solution of diisopropylamine (1.1 eq.) in 1 mL of dry THF cooled to -
78°C was added n-butyl lithium (1.6M in hexane) (1.1 eq.) dropwise
maintaining
the reaction temperature at -78°C. The reaction mixture was stirred for
30 min. at

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-78°C and then the lactam (0.471 mM) was added dropwise as a solution
in 1 mL
of drv THF. The reaction mixture was stirred at -78°C for 30 min. and
then a
pre-cooled solution of trisyl azide (1.2 eq.) was added as a solution in 1 mL
of dry
THF. The reaction mixture was stirred at -78°C for 20 min. and then
quenched
with acetic acid (4.0 eq.). The reaction mixture was then stirred at
40°C for 2
hrs. The reaction was then poured into EtOAc and washed with water, sodium
bicarbonate and brine, and then dried over sodium sulfate, filtered and
concentrated. The residue was purified by LC 2000 chromatography.
GENERAL PROCEDURE 8-F
Azido Group Reduction
The azido group was reduced to the corresponding primary amine using the
procedure described in John W . Butcher et al. , Tet. Lett. , 37, 6685-6688 (
1996).
GENERAL PROCEDURE 8-G
N-Alkylation of Amides or Lactams
Using Sodium Hydride or Potassium tert-Butoxide
To a slurry of sodium hydride or potassium tent-butoxide (1.1 eq) in 15 mL of
dry DMF was added the appropriate amide (0.0042 moles) as a solution in 10 mL
of DMF. The alkyl iodide was then added and a thick slurry resulted. The
reaction became less thick-as time elapsed and when complete by TLC the
reaction had become homogeneous. The reaction mixture was poured over ice and
extracted into ethyl acetate. The organic layer was washed with water.
followed
by brine. The organic layer was then dried over sodium sulfate, filtered and
concentrated under reduced pressure. The residue was purified by HPLC (LC
2000), eluting with an ethyl acetate/hexane system.
GENERAL PROCEDURE 8-H

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N-Alkylation of
To the appropriate amide or lactam in THF cooled to -78°C was
added
KHMDS dropwise and the reaction mixture was stirred for 30 min. at -
78°C. The
alkyl iodide was then added dropwise while maintaining the temperature at -
70°C.
The cooling bath was then removed and reaction was allowed to warm to room
temperature and stirring was continued for 2 hours. The reaction mixture was
then poured over ice and extracted into ethyl acetate. The organic extracts
were
washed with water, followed by brine. The organic layer was then dried over
sodium sulfate, filtered and concentrated under reduced pressure. The residue
was
purified by HPLC (LC 2000), eluting with an ethyl acetatelhexane system.
GENERAL PROCEDURE 8-I
N-Alkylation of Amides or Lactams Using Cesium Carbonate
To a solution of the amide or lactam in DMF was added cesium carbonate
(1.05 eq) and an alkyl iodide (1.1 eq). The mixture was allowed to stir
overnight
at room temperature and then the reaction mixture was diluted with ethyl
acetate
and washed with water, followed by brine. The organic layer was dried over
sodium sulfate, filtered and concentrated under reduced pressure. The residue
was
purified by HPLC (LC 2000), eluting with an ethyl acetate/hexane system.
GENERAL PROCEDURE 8-J
BOC Removal Procedure
To an N-Boc protected compound was added CH2C12/TFA (4:1) at room
temperature. The reaction mixture was stirred at room temperature for 3 hours
and then concentrated. The residue was extracted into dichloromethane and
washed with water, saturated sodium bicarbonate, dried over Na2S04, filtered
and
concentrated to give the free amine.

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GENERAL PROCEDURE 8-K
Azide Transfer Pro~e~i~re
This azide transfer procedure is a modification of the procedure described in
Evans, D. A.: Britton, T. C.; Ellman. J. A.; Dorow. R. L. J. Am. Chem. Soc.
1990, 112, 4011-4030. To a solution of the lactam substrate (1.0 eq.) in THF
( ~0.1 M) under N2 at -78°C was added a solution of KN(TMSy1 (I.1 eq.
of 0.5
M in Toluene, Aldrich) dropwise over a period of 2-10 minutes. A slight
exotherm was often observed by an internal thermometer, and the resulting
solution was stirred for 5-15 minutes, while re-cooling to -78°C. Then,
trisyl
azide (1.1-1.~ eq., CAS No. 36982-84-0, prepared as described by references in
the Evans reference above) in THF (-0.5 M), either precooled to -78°C
or at
room temperature, was added via cannula over a period of 0.5-5 minutes. Again,
a slight exotherm was generally noted. The resulting solution was stirred for
from
5-10 minutes. while re-cooling to -78°C. Then, AcOH (4.5-4.6 eq.,
glacial) was
added, the cooling bath removed and the mixture allowed to warm to room
temperature with stirring for 12-16 hours. The mixture was diluted with EtOAc,
in a 2-5 volume multiple of the initial THF volume, and washed with dilute aq.
NaHC03 (1-2x), 0.1-1.0 M aq. HCl (0-2x), and brine (Ix). The organic phase
was then dried over MgS04, filtered, concentrated to provide the crude
product.
GENERAL PROCEDURE 8-L
Azide Reduction to ari Amine
A mixture of the azide in absolute EtOH (0.03-0.07 M) and 10%a Pd/C ( -1/3
by weight of the azide) was shaken in a Parr apparatus under H2 (35-45 psi) at
room temperature for 3-6 hours. The catalyst was removed by filtration through
a
plug of Celite, rinsing with absolute EtOH, and the filtrate concentrated to
provide
the crude amine product.
GENERAL PROCEDURE 8-M

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Amide AIkYlation Using cesium Carbonate
This procedure is a modification of the procedure described in Claremon, D.
A.; et al, PCT Application: WO 96-US8400 960603. To a mixture of 2,4-dioxo-
2,3,4.5-tetrahydro-1H-1,5-benzodiazepine (CAS No. 49799-48-6) in DMF (1.0
eq., 0.7 M) under N2 at room temperature was added Cs2C03 (2.2 eq.) and the
appropriate alkyl halide (2.2 eq.). The mixture was stirred at room
temperature
for 5.5-16 hours. The mixture was partitioned between EtOAc and sat. NaHC03.
The aqueous layer was extracted with EtOAc (1-2x) and the combined EtOAc
extracts were dried over Na,S04, filtered, and concentrated to provide the
crude
product.
GENERAL PROCEDURE 8-N
BOC Removal Procedure
A stream of anhydrous HCl gas was passed through a stirred solution of the
N-t-Boc protected amino acid in 1.4-dioxane (0.03-0.09 M), chilled in a ice
bath to
-10°C under N2, for 10-15 minutes. The solution was capped, the cooling
bath
removed, and the solution was allowed to warm to room temperature with
stirring
for 2-8 hours, monitoring by TLC for the consumption of starting material. The
solution was concentrated (and in some instances dissolved in CH2Cl2 then re-
concentrated and placed in vacuum oven at 60-70°C to remove most of the
residual dioxane) and used without further purification.
Example 8-A
Synthesis of
3-Amino-1,3-dihydro-5-(1-piperidinyl)-2H-1,4-benzodiazepin-2-one
Step A - Preparation of 1.2-Dihydro-3H-Lm~~y~l-~ e~~l)-
1.4-benzodiazenin-2-one
A solution of phosphorous pentachloride (1.2 eq) in methylene chloride
was added dropwise to a solution of 1-methyl-1,2,3,4-tetrahydro-3H-1.4-

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benzodiazepin-2,5-dione (Showell, G. A.; Bourrain. S.: Neduvelil, J. G.;
Fletcher, S. R.; Baker, R.; Watt, A. P.; Fletcher, A. E.; Freedman, S. B.;
Kemp,
J. A.; Marshall, G. R.; Patel, S.; Smith, A. J.; Matassa. V. G. J. Med. Chem.
1994, 37, 719. ) in methylene chloride. The resultant yellowish-orange
solution
was stirred at ambient temperature for 2.5 hours; the solvent was removed in
vacuo. The orange residue was redissolved in methylene chloride, cooled to 0
EC, and treated with a solution of piperidine (2 eq) and triethylamine (2 eq)
in
methylene chloride. The cooling bath was removed and the reaction stirred for
18
hours. The reaction mixture was washed with saturated aqueous NaHC03 (back-
extracted with methylene chloride) and brine. The organic phase was dried over
Na,SO~, filtered, and concentrated. The residue was purified via HPLC eluting
with a gradient of 4 to 10 % methanolJmethylene chloride affording the title
intermediate as a yellow solid having a melting point of 103-105°C.
C,SH,9N~0 (MW 257.37); mass spectroscopy 257.
Anal. Calcd for C,SH,yN,O: C, 70.01; 1-i, 7.44; N, 16.33. Found: C,
69.94; H, 7.58; N. 16.23.
Step B - Preparation of 1 2-Dihydro-3H-1-methyl-3-oximid~ -(1-
p~peridin~,)-1 4-be podia epin-~-one
Potassium tert-butoxide (2.5 eq) was added in two portions to a -
20°C
solution of 1,2-dihydro-3H-1-methyl-5-(1-piperidinyl)-1.4-benzodiazepin-2-one
(1
eq) in toluene). After stirring at - 20°C for 20 min, isoamyl nitrite
(1.2 eq.;
Aldrich) was added to the red reaction mixture. The reaction was stirred at -
20 °C
for 5 hours at which time the reaction was done by TLC. The cooling bath was
removed and the reaction quenched with 0.5 M citric acid. After stirring for
10
minutes, diethyl ether was added. The suspension was stirred at ambient
temperature overnight then filtered washing with ether. The resultant cream
colored solid had a melting point of 197-200°C. '
'H NMR data of the E/Z isomers was as follows:

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'H NMR (300 MHz, CDC13): d = 7.64 (1H, bs), 7.48 (2H, d, J=7.4 Hz),
7.35-7.20 (6H, m), 6.75 (1H, bs), 3.8-3.2 (8H, m), 3.46 (3H, s), 3.42 (3H, s),
1.90-1.40 (12H, m).
C,SH'8Na02 (MW = 286.37); mass spectroscopy 286.
Step C - Preparation of 1.2-dih_vdro-3 -1-met yl-3-[O-
lethylaminocarbom 1)oximido]-5-ll-pi ridinYl_l-1.4-
benzodiazepin-2 =one
A mixture of 1,2-dihydro-3H-1-methyl-3-oximido-5-(1-piperidinyl)-1,4-
benzodiazepin-2-one (1 eq) in THF was treated with ethyl isocyanate (1.7 eq)
and
triethylamine (0.6 eq). The mixture was heated to 64°C for 4 hours. The
mixture
was concentrated and the residue purified by HPLC eluting with 5 %
methanol/methylene chloride.
'H NMR data of the E/Z isomers was as follows:
'H NMR (300 MHz. CDCI,): d = 7.50 (2H, dd, J=8.4, 1.5 Hz), 7.35-
7.22 (6H, m), 6.42 (1H, bt), 6.20 (1H, bt), 3.7-3.4 (8H, m), 3.46 (3H, s),
3.44
(3H, s), 3.25 (4H, m). 1.9-1.4 ( 12H, m), 1.12 (3H, t, J =6.3 Hz), 1.10 (3H,
t,
J=6.3 Hz).
C,8H~3N50, (MW = 357.46); mass spectroscopy 357.
Step D - Per paration of 3-Amino-1.3-dihydro-2H-1-meth l-Y 5-l_1-
eridinyll-1.4-benzodiazenin-2-one
The 1.2-dihydro-3H-1-methyl-3-[O-(ethylaminocarbonyl)oximido]-5-(1-
piperidinyl)-1,4-benzodiazepin-2-one ( 1 eq) was hydrogenated in methanol over
5 % palladium on carbon (0.15 eq) at 43 psi for 3.25 hours. The reaction was
filtered through celite and concentrated in vacuo. The residue was taken up in
methylene chloride and filtered a second time through celite. The filtrate was
concentrated and the resultant foam was used immediately.

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Example 8-B
Synthesis of
3-(L-Alaninyl)-amino-2,3-dihydro- ,
1-methyl-S-phenyl-1 H-1,4-benzodiazepin-2-one
Step A - Preparation of (~l-3-amino-1 3-dih~Q~,-metl~y~ S phen3rl-
2H-1 4-benzodiazePin-2-one (1S)-7 7-dimethyl-2-
oxobicysloj~~,]~gp~anP_ 1-methanesulfonate
The title intermediate was prepared according to Reider, P. J.; Davis, P.;
Hughes, D. L.; Grabowski, E. J. J. J. Org. Chem. 1987, 52. 955 using 3-amino-
1,3-dihydro-1-methyl-5-phenyl-2H-1,4-benzodiazepin-2-one (Bock M. G.;
DiPardo, R. M.; Evans, B. E.; Rittle, K. E.; Veber, D. F.; Freidinger, R. M.;
Hirshfield, J.; Springer, J. P. J. Org. Chem. 1987, 52, 3232.) as the starting
material.
Step B - Preparation of 3-jN~tert-Butvlcarbamate)-L-alaninvll-
amino-~ 3-dil~,ydro- -methyL~,~~nvl-1H-1 4-
benzodiazepin-2-Q~
(S)-3-Amino-1, 3-dihydro-1-methyl-S-phenyl-2H-1.4-benzodiazepin-2-one,
(1S)-7,7-dirnethyl-2-oxobicyclo[2.2.1]heptane-1-methanesulfonate was free
based
by partitioning between methylene chloride and 1 M potassium carbonate. The
free
amine was then coupled with N-Boc-alanine following General Procedure D.
C,~HZgNaO, (MW = 436.56); mass spectroscopy 436.
Anal. Calc. for C,4H,gN,Oy: C, 66.03; H, 6.47; N, 12.84. Found: C,
65.79; H, 6.68; N. 12.80.
Step C - Preparation of 3-(L-AlaninyjZamino-2 3-dihvdro-1-meth~t
~-phenyl-1 H-1.4-benzodiazepin-2-one

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Following General Procedure 8-C using 3-[N'-(tert-butylcarbamate)-L-
alaninylj-amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one, the
title compound was prepared as a white foam.
Anal. Calc. for C,9H,9N,0,: C, 69.21; H, 6.64; N, 15.37. Found: C,
70.11; H, 6.85; N, 15.01.
Example 8-C
Synthesis of
3-(L-Alaninyl)-amino-7-chloro-2,3-dihydro-
1-methyl-S-phenyl-1H-1,4-benzodiazepin-2-one
Step A - Preparation of 3-lBenzy~, carbo~yl)-amino-7-chloro-
dihvdro-1-meth3rl-~p~vl-1 H-1.4-ben~~ ia~Pnin-2
one
A solution of 3-(benzyloxycarbonyl)-amino-7-chloro-2,3-dihydro-5-phenyl-
1H-1,4-Benzodiazepin-2-one ( 1 eq: Neosystem) in DMF was cooled to 0°C
and
treated with potassium tent-butoxide ( 1 eq; 1.OM solution in THF). The
resultant
yellow solution was stirred at 0°C for 30 minutes then quenched with
methyl
iodide (1.3 eq). After stirring an addition 25 minutes the reaction was
diluted with
methylene chloride and washed with water and brine. The organic phase was
dried over Na,S04, filtered, and concentrated. The residue was purified via
HPLC
chromatography eluting with a gradient of 20630% ethyl acetate/hexanes.
C,4H~~,C1N303 (MW = 433.92); mass spectroscopy 433.
Anal. calcd for C,,,HZ~C1N303: C, 66.44; H, 4.65; N, 9.68. Found: C,
66.16;H,4.50:N,9.46.
Step B - Preparation of 3-Amin -7-chloro-1 3-dihydro-1-m~,~-5-
enyl-2H-1.4-benzodiazepin-2-one
Following General Procedure 8-B using 3-(benzyloxycarbonyl)-amino-7-
chloro-2,3-dihydro-1-methyl-S-phenyl-1H-1,4-benzodiazepin-2-one, the title
intermediate was prepared as a white foam which was used immediately in Step
C.

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Step C - ~paration of 3-iN-tert-Butylcarbamatel-L-alaninyl_]-amino-
7-chloro-1 3-dihydro-1-methyl-S-phenvl-2H-1.4-
benzodiazep~n-2-one
Following General Procedure D using N-Boc-L-alanine and 3-amino-7-
chloro-1,3-dihydro-1-methyl-S-phenyl-2H-1,4-benzodiazepin-2-one, the title
intermediate was prepared as a white foam.
C24H~gC1N~O4 (MW = 471.18); mass spectroscopy 471
Anal. calcd for C,~H~RC1N,0;: C, 61.21; H, 5.78; N, 11.90. Found: C,
61.24: H, 5.59; N, 11.67.
Step D - p~p~ration of 3-(L-Alaniny,~,)amino-7-chloro-1.3-dihydro-1
methyl-5-phenyl-2H-1.4-benzodiazenin-2-one
Following General Procedure 8-C using 3-[N-tert-butylcarbamate)-L-
alaninyl]-amino-7-chloro- l , 3-dihydro-1-methyl-5-phenyl-2H-1.4-benzodiazepin-
2-
one, the title intermediate was prepared as a white foam. The crude material
was
used immediately.
Example 8-D
Synthesis of
3-(L-Alaniny))amino-7-bromo-2,3-dihydro-
1-methyl-5-(2-fluorophenyl)-1H-1,4-benzodiazepin-2-one
Step A - Preparation of 3-(Benzyloxycarbonyl)-amino-7-bromo-2,3-
dihydro-1-methyl-5-(2-fluorophenyl)-1H-1,4-benzodiazepin-
2-one
Following General Procedure 8-A using 3-(benzyloxycarbonyl)-amino-7-
bromo-2,3-dihydro-5-(2-fluorophenyl)-1H-1.4-benzodiazepin-2-one (Neosystem),
the title intermediate was prepared as a white foam.
C,~H,9BrFN30, (MW = 496.36); mass spectroscopy 497.

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Anal. calcd for C,.,H,9BrFN303: C. 58.08; H, 3.86; N, 8.47. Found: C,
57.90; H, 4.15; N, 8.20.
Step B - Preparation of 3-Amino-7-bromo-1.3-dihydro-1-methyl-5-«_
fJuoroQh~yll-2H-1.4-benzodiazenin-2-one
Following General Procedure 8-B using 3-(benzyloxycarbonyl)-amino-7-
bromo-2,3-dihydro-1-methyl-5-(2-fluorophenyl)-1H-1,4-benzodiazepin-2-one, the
title intermediate was prepared as a white foam which was used immediately in
Step C.
Step C - Preparation of 3-[N'-ltert-Butvlcarbamate)-L-alar,;n~O-
amino-7-bromo-1 3-dihvdro-1-met~~~l-5-(2-fluorophenvl)-
2H-1.4-benzodiazenin-2-one
Following General Procedure D using N-Boc-L-alanine (Novo) and 3-
amino-7-bromo-1,3-dihydro-1-methyl-5-(2-fluorophenyl)-2H-1,4-benzodiazepin-2-
one, the title intermediate was prepared as a white foam.
C~~H,6BrFN,Oa (MW = 533.12): mass spectroscopy 533.2.
Anal. calcd for C,.,H,6BrFN~O,,: C. 54.04; H, 4.9I: N, 10.50. Found: C,
53.75; H, 4.92; N. 10.41.
Step D - Preparation of ~ (, -Alaniny~l-amino-7-br2yo-11 i3-dih, d
methyl-S-(2-fluorophen I)-v 2H-li4-benzodiazepin-2-one
Following General Procedure 8-C using 3-[N'-(tent-butylcarbamate)-L-
alaniny l]-amino-7-bromo-1.3-dihydro-1-methyl-5-(2-fluorophenyl}-2H-1.4-
benzodiazepin-2-one, the title intermediate was prepared as a white foam. The
crude material was used immediately.
Example 8-E
Synthesis of

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3-(N-Methyl-L-alaninyl)-amino-2,3-dihydro-
1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one
Step A - ~~paration of 3-[~T~tert-Butvlcarbamate)-N'-methyl-L-
alaniny,)Lamino-2.3-dihydro-1-methL-5-phenyl-1 H-1.4-
benzodiazepin-2-one
Following General Procedure D and using (S)-3-amino-1,3-dihydro-I-
methyl-5-phenyl-2H-1,4-benzodiazepin-2-one (Example 8-B) and N-tent-Boc-N-
methyl-alanine (Sigma), the title intermediate was obtained as a white solid.
C,SH3oN4O4 (MW = 450.2): mass spectroscopy (M+1) 451.2.
Anal. calcd for C~SH3oN,,04: C, 66.65; H, 6.71; N, 12.44. Found: C,
66.66; H, 6.89; N, 12.21.
Step A - ~gparation of 3-(N'-Meth3~l-L-alaninyl)-amino-2.3-dih ro-
methyl-5-phenyl-1H-I .4-benzodiazepin-2-one
Following General Procedure 8-C and using 3-[N'-(tert-butylcarbamate)-N-
methyl-L-alaninyl]-amino-2.3-dihydro-1-methyl-5-phenyl-1 H-1,4-benzodiazepin-2-
one, the title intermediate was prepared as a white foam.
C,oH~,N40, (MW = 350.46): mass spectroscopy (M + 1 ) 351.4.
Anal. calcd for C,oH~~N.~O,: C, 68.55; H, 6.33; N, 15.99. Found, C,
68.36: H, 6.20; N, 15.79.
Example 8-F
Synthesis of
3-(L-Alaninyl)amino-7-chloro-2,3-dihydro-
1-methyl-5-(2-chlorophenyl)-1H-1,4-benzodiazepin-2-one
Step A - Preparation of 3-l~enzvloxycarbon~)-amino-7-chloro-2.3-
dihXdro-1-methy~2-chlorophenvl)-1 H-1.4-benzodiazepin-

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Following General Procedure 8-A using 3-(benzyloxycarbonyl)-amino-7-
chloro-2,3-dihydro-5-(2-chlorophenyl)-1H-1,4-benzodiazepin-2-one (Neosystem),
the title intermediate was prepared as a white solid having a melting point of
232-
233°C.
C24HI9C12N303 (MW = 468.36); mass spectroscopy 468.
'H NMR (300 MHz, CDC13): d = 7.67 (1H, m), 7.52 (1H, dd,
J=2.4, 8.7 Hz), 7.42-7.26 (9H, m), 7.07 (1H, d, J=2.4 Hz), 6.70 (1H, d, J=8.3
Hz), 5.35 (1H, d, J=8.4 Hz), 5.14 (2H, ABq, J=19.6 Hz), 3.47 (3H, s).
"C NMR (75 MHz. CDCl3): d = 166.66, 165.65, 155.72, 140.52,
IO 136.99, 136.0, 132.87, 131.99. 131.47, 131.40, 131.38, 131.16, 130.54,
130.06,
128.45, 128.08, 128.03, 127.72, 127.22, 123.28, 122.01, 68.95, 67.02, 35.32.
Step B - ~~~naration of 3 Amino 7 chloro-1 3-dihvdro-1-methyl-5-(2-
~hloro,~h~Ll~'-~u-~ 4-benzodiaze ' - -one
1 S Following General Procedure 8-B using 3-(benzyloxycarbonyl)-amino-7-
chloro-2,3-dihydro-1-methyl-5-(2-chlorophenyl)-1H-1,4-benzodiazepin-2-one, the
title intermediate was prepared as a white foam which was used immediately in
Step C.
20 Step C - s;~~ration of 3 IN' (tert But~carbamate)-L-alaninvll-
amino 7 chloro 1 3 dihvdro-1-methyl-S-«-~hloro envl)-
~H-I 4-benzodia~enin-2-one
Following General Procedure D using N-Boc-L-alanine and 3-amino-7-
chloro-1,3-dihydro-1-methyl-5-(2-chlorophenyl)-2H-1,4-benzodiazepin-2-one, the
25 title intermediate was prepared as a white foam.
C~4H,6C1,N40a (MW = 505.44); mass spectroscopy 505.2.
Step D - ~1'Laration of 3 (L Alaninvll amino-7-chloro-1 3-dihvdro1-1-
~~,~1 5 (2 chloro~hem~,L?H-1 4-benzod~a~enin-2-one

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Following General Procedure 8-C using 3-[N'-(tent-butylcarbamate)-L-
alaninyl)-amino-7-chloro-1, 3-dihydro-1-methyl-5-(2-chlorophenyl)-2H-1,4-
benzodiazepin-2-one, the title intermediate was prepared as a white foam. The
w
crude material was used immediately.
Example 8-G
Synthesis of
3-(L-Alaninyl)amino-5-cyclohexyl-2,3-dihydro-
1-methyl-1H-1,4-Benzodiazepin-2-one
Step A - py~paration of ~-~RPn~L~loxvcarbony],)-amino-5-cyclohexvl-
2 .3-di~y~ro-1-methy]I-1 H-1.4-benzodiazenin-2-one
Following General Procedure 8-A using 3-(benzyloxycarbonyl)-amino-5-
cyclohexyl-2,3-dihydro-1H-1,4-benzodiazepin-2-one (Neosystem), the title
intermediate was prepared as a white solid having a melting point of 205-
206°C.
C,4H,,N~O, (MW = 405.54); mass spectroscopy 405.
'H NMR (300 MHz, CDC13): d = 7.54 (1H, d, J=7.9 Hz). 7.48 (1H, d,
J=7.7 Hz), 7.36-7.26 (7H, m), 6.54 (1H, d, J= 8.3 Hz), 5.15 (1H, d, J=8.0
Hz). 5.09 (2H, ABq, J=17.1 Hz), 3.39 (3H, s), 2.77 (1H, m), 2.01 (1H, bd,
J=13.6 Hz), 1.85 (1H, bd, J=12.4 Hz), 1.68-1.49 (4H, m), 1.34-1.02 (4H, m).
Step B - PreDaraLlOn of '~-Amino-5-cXclohexyl-1 3-dihydro-1-meth ~~l-
7N-1 d-hen~odiazeQ n- -one
Following General Procedure 8-B using 3-(benzyloxycarbonyl)-amino-S-
cyclohexyl-2,3-dihydro-1-methyl-1H-1.4-benzodiazepin-2-one, the title
intermediate was prepared as a white foam which was used immediately in Step
C.
C,6H,,N30 (MW+H = 272.1763); mass spectroscopy 272.1766
Step C - Prgparation of 3-[N'-(tent-Buty~carba ate)-L-alaninvll-
amino-5-cyclohexyl-1 3-dihydro-1-methy -12H1.4-

CA 02325389 2000-09-21 .
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