US2005192269A1PendingUtilityA1
Cycloalkyl, lactam, lactone and related compounds, pharmaceutical compositions comprising same, and methods for inhibiting beta-amyloid peptide release and/or its synthesis by use of such compounds
Priority: Jun 22, 1998Filed: Dec 3, 2004Published: Sep 1, 2005
Est. expiryJun 22, 2018(expired)· nominal 20-yr term from priority
Inventors:Richard ThompsonStephen WilkieDouglas Richard StackEldon VanmeterQing ShiThomas C. BrittonJames AudiaJon K. ReelThomas E. MabryBruce A. DressmanCynthia L. CwiSteven S. HenryStacey L. McdanielRussell StuckyWarren J. Porter
C07D 401/12A61P 25/28C07K 5/0821C07D 403/12C07K 5/0823A61K 38/00
54
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Claims
Abstract
Disclosed are compounds which inhibit β-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 β-amyloid peptide release and/or its synthesis as well as methods for treating Alzheimer's disease both prophylactically and therapeutically with such pharmaceutical compositions.
Claims
exact text as granted — not AI-modified1 . A method for inhibiting β-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 β-amyloid peptide wherein said compounds are represented by the following formulas:
wherein R 1 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, —CH 3 , —CH═CH 2 , —CH═CHR 1 , —CH═CR 1 R 1 , —CR 1 ═CH 2 , —CR 1 ═CHR 1 , —CR 1 ═CR 1 R 1 , —C═CH and —C═CR 1 ; 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 15 is selected from the group consisting of hydrogen, alkyl, substituted alkyl, aryl, heterocyclic and heteroaryl;
R 15 ′ 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)R 4 , —NHSO 2 R 4 , —C(O)NH 2 , —C(O)NHR 4 , —C(O)NR 4 R 4 , —S(O)R 4 , —S(O) 2 R 4 , —S(O) 2 NHR 4 and—S(O) 2 NR 4 R 4 , where each R 4 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:
wherein each R 2 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 R 1 to —C(X′)(X″)—, oxygen, sulfur, and —NR 5 where R 5 is hydrogen, acyl, alkyl, substituted alkyl, aryl, heterocyclic or heteroaryl group;
R 5′ 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, —OR 5 ′, —SR 5 , —N(R 5 ) 2 , —N(CO)OR 15 and —N 3 , 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 —OR 5′ , —SR 5 , —N(R 5 ) 2 , —N(CO)OR 15 and —N 3 ; further, neither X′ and X″ can be —OR 5 ′, —SR 5 , —N(R 5 ) 2 , —N(CO)OR 15 or —N 3 when T is other than a bond covalently linking R 1 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 >C═X, does not form a 2,3-dihydro-1-methyl-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one
when R1 is α-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 α-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 α-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-methyl-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 15 ) 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:
wherein R 1 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, —CH 3 , —CH═CH 2 , —CH═CHR 1 , —CH═CR 1 R 1 , —CR 1 ═CH 2 , —CR 1 ═CHR 1 , —CR 1 ═CR 1 R 1 , —C═CH and —C═CR 1 ; 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 15 is selected from the group consisting of hydrogen, alkyl, substituted alkyl, aryl, heterocyclic and heteroaryl;
R 15′ 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)R 4 , —NHSO 2 R 4 , —C(O)NH 2 , —C(O)NHR 4 , —C(O)NR 4 R 4 , —S(O)R 4 , —S() 2 R 4 , —S() 2 NHR 4 and —S(O) 2 NR 4 R 4 , where each R 4 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:
wherein each R 2 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 R 1 to —C(X′)(X″)—, oxygen, sulfur, and —NR 5 where R 5 is hydrogen, acyl, alkyl, substituted alkyl, aryl, heterocyclic or heteroaryl group;
R 5′ 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, —OR 5′ , —SR 5 , —N( 5 ) 2 , —N(CO)OR 15 and —N 3 , 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 —OR 5′ , —SR 5 , —N( 5 )2, —N(CO)OR 15 and —N 3 ; further, neither X′ and X″ can be —OR 5′ , —SR 5 , —N(R 5 ) 2 , —N(CO)OR 15 or —N 3 when T is other than a bond covalently linking R 1 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 Ri5 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 α-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 α-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 α-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
when R1 is 3,5-difluorobenzoyl, R2 is methyl, and R15 is hydrogen, then W, together with >CH and >C═X, does not forrn 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 15 ) 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:
wherein R 1 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, —CH 3 , —CH═CH 2 , —CH═CHR 1 , —CH═CR 1 R 1 , —CR 1 ═CH 2 , —CR 1 ═CHR 1 , —CR 1 ═CR 1 R 1 , —C═CH and —C═CR 1 ; 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 15 is selected from the group consisting of hydrogen, alkyl, substituted alkyl, aryl, heterocyclic and heteroaryl,
R 15′ 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)R 4 , —NHSO 2 R 4 , —C(O)NH 2 , —C(O)NHR 4 , —C(O)NR 4 R 4 , —S(O)R 4 , —S(O) 2 R 4 , —S(O) 2 NHR 4 and —S(O) 2 NR 4 R 4 , where each R 4 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:
wherein each R 2 is independently selected from the group consisting of alkyl, substituted allcyl, 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 R 1 to —C(X′)(X″)—, oxygen, sulfur, and —NR 5 where R 5 is hydrogen, acyl, alkyl, aryl, substituted alkyl, heterocyclic or heteroaryl group;
R 5′ 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, —OR 5′ , —SR 5 , —N(R 5 ) 2 , —N(CO)OR 15 and —N 3 , 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 —OR 5′ , —SR 5 , —N(R 5 ) 2 , —N(CO)OR 15 and —N 3 ; further, neither X′ and X″ can be —OR 5′ , —SR 5 , —N(R 5 ) 2 , —N(CO)OR 15 or —N 3 when T is other than a bond covalently linking R 1 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 >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-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 α-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 α-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
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 15 ) is (2,5dimethoxyphenyl)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.
4 . A method according to any of claims 1 - 3 wherein R 1 is aryl or heteroaryl.
5 . A method according to claim 4 wherein R 1 is selected from the group consisting of
(a) alkyl (b) phenyl, (c) a substituted phenyl group of the formula: wherein R c is selected from the group consisting of acyl, alkyl, alkoxy, alkylalkoxy, azido, substituted amino, cyano, 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.
6 . The method according to claim 4 wherein R 1 is selected from the group consisting of mono-, di- and tri-substituted phenyl groups.
7 . The method according to claim 6 wherein R 1 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.
8 . The method according to claim 6 wherein R 1 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 R 1 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 R 1 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 R 1 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, 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-dimnethylphenyl, 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, —CH 2 -cyclopropyl, —CH 2 -cyclobutyl, —CH 2 -cyclohexyl, —CH 2 -cyclopentyl, —CH 2 CH 2 -cyclopropyl, —CH 2 CH 2 -cyclobutyl, —CH 2 CH 2 -cyclohexyl, —CH 2 CH 2 -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, (CH 3 ) 2 CH═CHCH 2 CH 2 CH(CH 3 )—, C(O)CH 2 —, 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)m ethyl, (2,4-dichlorophenoxy)ethyl, (4-chlorophenyl)methyl, (2-chlorophenyl)methyl, (1-phenyl)ethyl, (1-(p-chlorophenyl)ethyl, (1-trifluoromethyl)ethyl, (4-methoxyphenyl)ethyl, CH 3 OC(O)CH 2 —, benzylthiomethyl, 5-(methoxycarbonyl)-n-pentyl, 3-(methoxycarbonyl)-n-propyl, indan-2-yl, (2-methylbenzofuran-3-yl), methoxymethyl, CH 3 CH 50 CH—, CH 3 CH 2 CH═CH—, (4-chlorophenyl)C(O)CH 2 —, (4-fluorophenyl)C(O)CH 2 —, (4-methoxyphenyl)C(O)CH 2 —, 4-(fluorophenyl)—NHC(O)CH 2 —, 1-phenyl-n-butyl, (phenyl) 2 CHNHC(O)CH 2 CH 2 —, (CH 3 ) 2 NC(O)CH 2 —, (phenyl) 2 CHNHC(O)CH 2 CH 2 —, methylcarbonylmethyl, (2,4-dimethylphenyl)C(O)CH 2 —, 4-methoxyphenyl—C(O)CH 2 —, phenyl—C(O)CH 2 —, CH 3 C(O)N(phenyl)-, ethenyl, methylthiomethyl, (CH 3 ) 3 CNHC(O)CH 2 —, 4-fluorophenyl-C(O)CH 2 —, diphenylmethyl, phenoxymethyl, 3,4-methylenedioxyphenyl-CH 2 —, benzo[b]thiophen-3-yl, (CH 3 ) 3 COC(O)NHCH 2 —, trans-styryl, H 2 NC(O)CH 2 CH 2 —, 2-trifluoromethylphenyl-C(O)CH 2 , C(O)NHCH(phenyl)CH 2 —, mesityl, CH 3 CH(═NHOH)CH 2 —, 4-CH 3 -phenyl-NHC(O)CH 2 CH 2 —, C(O)CH(phenyl)CH 2 —, (CH 3 ) 2 CHC(O)NHCH(phenyl)—, CH 3 CH 2 OCH 2 —, CH 3 OC(O)CH(CH 3 )(CH 2 ) 3 —, 2,2,2-trifluoroethyl, 1-(trifluoromethyl)ethyl, 2-CH 3 -benzofuran-3-yl, 2-(2,4-dichlorophenoxy)ethyl, SO 2 CH 2 —, 3-cyclohexyl-n-propyl, CF 3 CH 2 CH 2 CH 2 - and N-pyrrolidinyl.
12 . A method according to any of claims 1 , 2 or 3 where each R 2 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 R 2 is selected from the group consisting of methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, —CH 2 CH(CH 2 CH 3 ) 2 , 2-methyl-n-butyl, 6-fluoro-n-hexyl, phenyl, benzyl, cyclohexyl, cyclopentyl, cycloheptyl, allyl, iso-but-2-enyl, 3-methylpentyl, —CH 2 -cyclopropyl, —CH 2 -cyclohexyl, —CH 2 CH 2 -cyclopropyl, —CH 2 CH 2 -cyclohexyl, —CH 2 -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-(CH 3 ) 2 NCH 2 CH 2 CH 2 O-benzyl, p-(CH 3 ) 3 COC(O)CH 2 O-benzyl, p-(HOOCCH 2 O)-benzyl, 2-aminopyrid-6-yl, p-(N-morpholino-CH 2 CH 2 O)-benzyl, —CH 2 CH 2 C(O)NH 2 , —CH 2 -imidazol4-yl, —CH 2 -(3-tetrahydrofuranyl), —CH 2 -thiophen-2-yl, —CH 2 (1-methyl)cyclopropyl, —CH 2 -thiophen-3-yl, thiophen-3-yl, thiophen-2-yl, -CH 2 -C(O)O-t-butyl, -CH 2 -C(CH 3 ) 3 , —CH 2 CH(CH 2 CH 3 ) 2 , 2-methylcyclopentyl, cyclohex-2-enyl, —CH[CH(CH 3 ) 2 ]COOCH 3 , —CH 2 CH 2 N(CH 3 ) 2 , —CH 2 C(CH 3 )═CH 2 , —CH 2 CH═CHCH 3 (cis and trans), —CH 2 OH, —CH(OH)CH 3 , —CH(O-t-butyl)CH 3 , —CH 2 OCH 3 , —(CH 2 ) 4 NH-Boc, —(CH 2 ) 4 NH 2 , —CH 2 -pyridyl, pyridyl, —CH 2 -naphthyl, —CH 2 -(N-morpholino), p-(N-morpholino—CH 2 CH 2 O)-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, —CH 2 CH 2 SCH 3 , 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:
wherein p is zero or one, T is selected from the group consisting of alkylene, substituted alkylene, alkenylene, substituted alkenylene, —(R 21 Z) q R 21 — and —ZR 21 —, where Z is a substituent selected from the group consisting of —O—, —S— and >NR 20 , each R 20 is independently selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, substituted alkyl, substituted alkenyl, substituted alkynyl, aryl, heteroaryl and heterocyclic, each R 21 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
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:
wherein p is zero or one, T is selected from the group consisting of alkylene, substituted alkylene, alkenylene, substituted alkenylene, —(R 21 Z) q R 21 — and —ZR 21 —, where Z is a substituent selected from the group consisting of —O—, —S— and >NR 20 , each R 20 is independently selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, substituted alkyl, substituted alkenyl, substituted alkynyl, aryl, heteroaryl and heterocyclic, each R 21 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.
18 . The method according to claim 17 wherein the alcohol or thiol substituted groups is selected from the group consisting of
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.
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:
wherein p is zero or one, T is selected from the group consisting of alkylene, substituted alkylene, alkenylene, substituted alkenylene, —(R 21 Z) q R 21 — and —ZR 21 —, where Z is a substituent selected from the group consisting of —O—, —S— and >NR 20 , each R 20 is independently selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, substituted alkyl, substituted alkenyl, substituted alkynyl, aryl, heteroaryl and heterocyclic, each R 21 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.
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:
wherein p is zero or one, T is selected from the group consisting of alkylene, substituted alkylene, alkenylene, substituted alkenylene, —(R 21 Z) q R 21 — and —ZR 21 —, where Z is a substituent selected from the group consisting of —O—, —S— and >NR 20 , each R 20 is independently selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, substituted alkyl, substituted alkenyl, substituted alkynyl, aryl, heteroaryl and heterocyclic, each R 21 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.
21 . The method according to claim 20 wherein the compound of Formula I is selected from the group consisting of
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.
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:
wherein p is zero or one, T is selected from the group consisting of alkylene, substituted alkylene, alkenylene, substituted alkenylene, —(R 21 Z) q R 21 — and —ZR 20 —, where Z is a substituent selected from the group consisting of —O—, —S— and >NR 20 , each R 20 is independently selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, substituted alkyl, substituted alkenyl, substituted alkynyl, aryl, heteroaryl and heterocyclic, each R 21 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.
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:
wherein p is zero or one, T is selected from the group consisting of alkylene, substituted alkylene, alkenylene, substituted alkenylene, —(R 21 Z) q R 21 — and —ZR 21 —, where Z is a substituent selected from the group consisting of —O—, —S— and >NR 20 , each R 20 is independently selected from the group consisting of alky, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, substituted alkyl, substituted alkenyl, substituted alkynyl, aryl, heteroaryl and heterocyclic, each R 21 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.
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:
wherein p is zero or one, T is selected from the group consisting of alkylene, substituted alkylene, alkenylene, substituted alkenylene, —(R 21 Z) q R 21 — and —ZR 21 —, where Z is a substituent selected from the group consisting of —O—, —S— and >NR 20 , each R 20 is independently selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, substituted alkyl, substituted alkenyl, substituted alkynyl, aryl, heteroaryl and heterocyclic, each R 21 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.
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:
wherein p is zero or one, T is selected from the group consisting of alkylene, substituted alkylene, alkenylene, substituted alkenylene, —(R 21 Z) q R 21 — and —ZR 21 —, where Z is a substituent selected from the group consisting of —O—, —S— and >NR 20 , each R 20 is independently selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, substituted alkyl, substituted alkenyl, substituted alkynyl, aryl, heteroaryl and heterocyclic, each R 21 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.
26 . The method according to claim 25 wherein the compound is selected from the group consisting of:
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:
wherein p is zero or one, T is selected from the group consisting of alkylene, substituted alkylene, alkenylene, substituted alkenylene, —(R 21 Z) q R 21 — and —ZR 21 —, where Z is a substituent selected from the group consisting of —O—, —S— and >NR 20 , each R 20 is independently selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, substituted alkyl, substituted alkenyl, substituted alkynyl, aryl, heteroaryl and heterocyclic, each R 21 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.
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:
wherein p is zero or one, T is selected from the group consisting of alkylene, substituted alkylene, alkenylene, substituted alkenylene, —(R 21 Z) q R 21 — and —ZR 21 —, where Z is a substituent selected from the group consisting of —O—, —S— and >NR 20 , each R 20 is independently selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, substituted alkyl, substituted alkenyl, substituted alkynyl, aryl, heteroaryl and heterocyclic, each. R 21 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.
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:
wherein p is zero or one, T is selected from the group consisting of alkylene, substituted alkylene, alkenylene, substituted alkenylene, —(R 21 Z) q R 21 — and —ZR 21 —, where Z is a substituent selected from the group consisting of —O—, —S— and >NR 20 , each R 20 is independently selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, substituted alkyl, substituted alkenyl, substituted alkynyl, aryl, heteroaryl and heterocyclic, each R 21 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.
30 . A pharmaceutical composition comprising a pharmaceutically inert carrier and a pharmaceutically effective amount of a compound of the following formulas:
wherein R 1 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, —CH 3 , —CH═CH 2 , —CH═CHR 1 , —CH═CR 1 R 1 , —CR 1 ═CH 2 , —CR 1 ═CHR 1 , —CR 1 ═CR 1 R 1 , —C═CH and —C═CR 1 ; 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 15 is selected from the group consisting of hydrogen, alkyl, substituted alkyl, aryl, heterocyclic and heteroaryl;
R 15 ′ 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)R 4 , —NHSO 2 R 4 , —C(O)NH 2 , —C(O)NHR 4 , —C(O)NR 4 R 4 , —S(O)R 4 , —S(O) 2 R 4 , —S(O) 2 NHR 4 and —S(O) 2 NR 4 R 4 , where each R 4 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:
wherein each R 2 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 R 1 to —C(X′)(X″)—, oxygen, sulfur, and —NR 5 where R 5 is hydrogen, acyl, alkyl, aryl, substituted alkyl, heterocyclic or heteroaryl group;
R 5′ 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, —OR 5′ , —SR 5 , —N(R 5 ) 2 , —N(CO)OR 15 and —N 3 , 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 —OR 5′ , —SR 5 , —N(R 5 ) 2 , —N(CO)OR 15 and —N 3 ; further, neither X′ and X″ can be —OR 5′ , —SR 5 , ≦N(R 5 ) 2 , —N(CO)OR 15 or —N 3 when T is other than a bond covalently linking R 1 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 >C═X, does not form a 2,3-dihydro-1-methyl-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one
when R1 is α-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 α-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 α-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
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 15 ) 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.
31 . The pharmaceutical composition according to claim 30 , wherein R 1 is aryl or heteroaryl.
32 . The pharmaceutical composition according to claim 31 wherein R 1 is selected from the group consisting of
(a) alkyl, (b) phenyl, (c) a substituted phenyl group of the formula: 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 arid 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.
33 . The pharmaceutical composition according to claim 29 wherein R 1 is selected from the group consisting of mono-, di- and tri-substituted phenyl groups.
34 . The pharmaceutical composition according to claim 33 wherein R 1 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-chloro4-cyanophenyl, 3-chloro-4-iodophenyl, and 3,4-methylenedioxyphenyl.
35 . The pharmaceutical composition according to claim 33 wherein R 1 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.
36 . The pharmaceutical composition according to claim 33 wherein R 1 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 R 1 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 R 1 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, 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, —CH 2 -cyclopropyl, —CH 2 -cyclobutyl, —CH 2 -cyclohexyl, —CH 2 -cyclopentyl, —CH 2 CH 2 -cyclopropyl, —CH 2 CH 2 -cyclobutyl, —CH 2 CH 2 -cyclohexyl, —CH 2 CH 2 -cyclopentyl, pyrid-2-yl, pyrid-3-yl, pyrid4-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, (CH 3 ) 2 CH═CHCH 2 CH 2 CH(CH 3 )—, C(O)CH 2 —, 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-(-chlorophenyl)ethyl, (1-trifluoromethyl)ethyl, (4-methoxyphenyl)ethyl, CH 3 OC(O)CH 2 -, benzylthiomethyl, 5-(methoxycarbonyl)-n-pentyl, 3-(methoxycarbonyl)-n-propyl, indan-2-yl, (2-methylbenzofuran-3-yl), methoxymethyl, CH 3 CH═CH—, CH 3 CH 2 CH═CH—, (4-chlorophenyl)C(O)CH 2 -, (4-fluorophenyl)C(O)CH 2 —, (4-methoxyphenyl)C(O)CH 2 —, 4-(fluorophenyl)-NHC(O)CH 2 —, 1-phenyl-n-butyl, (phenyl) 2 CHNHC(O)CH 2 CH 2 —, (CH 3 ) 2 NC(O)CH 2 —, (phenyl) 2 CHNHC(O)CH 2 CH 2 —, ethylcarbonylmethyl, (2,4-dimethylphenyl)C(O)CH 2 —, 4-methoxyphenyl-C(O)CH 2 —, phenyl-C(O)CH 2 —, CH 3 C(O)N(phenyl)-, ethenyl, methylthiomethyl, (CH 3 ) 3 CNHC(O)CH 2 —, 4-fluorophenyl-C(O)CH 2 —, diphenylmethyl, phenoxymethyl, 3,4-methylenedioxyphenyl-CH 2 —, benzo[b]thiophen-3-yl, (CH 3 ) 3 COC(O)NHCH 2 —, trans-styryl, H 2 NC(O)CH 2 CH 2 —, 2-trifluoromethylphenyl-C(O)CH 2 , phenyl-C(O)NHCH(phenyl)CH 2 —, mesityl, CH 3 CH(═NHOH)CH 2 —, 4-CH 3 -phenyl-NHC(O)CH 2 CH 2 —, C(O)CH(phenyl)CH 2 —, (CH 3 ) 2 CHC(O)NHCH(phenyl)-, CH 3 CH 2 OCH 2 —, CH 3 OC(O)CH(CH 3 )(CH 2 ) 3 —, 2,2,2-trifluoroethyl, 1-(trifluoromethyl)ethyl, 2-CH 3 -benzofuran-3-yl, 2-(2,4-dichlorophenoxy)ethyl, SO 2 CH 2 —, 3cyclohexyl-n-propyl, CF 3 CH 2 CH 2 CH 2 — and N-pyrrolidinyl.
39 . The pharmaceutical composition according to claim 29 where each R 2 is independently selected from the group consisting of alkyl, substituted alkyl, alkenyl, cycloalkyl, aryl, heteroaryl and heterocyclic.
40 . The pharmaceutical composition according to claim 39 wherein R 2 is selected from the group consisting of methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, —CH 2 CH(CH 2 CH 3 ) 2 , 2-methyl-n-butyl, 6-fluoro-n-hexyl, phenyl, benzyl, cyclohexyl, cyclopentyl, cycloheptyl, allyl, iso-but-2-enyl, 3-methylpentyl, —CH 2 -yclopropyl, —CH 2 -cyclohexyl, —CH 2 CH 2 -cyclopropyl, —CH 2 CH 2 -yclohexyl, —CH 2 -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-(CH 3 ) 2 NCH 2 CH 2 CH 2 O-benzyl, p-(CH 3 ) 3 COC(O)CH 2 O-benzyl, p-(HOOCCH 2 O)-benzyl, 2-aminopyrid-6-yl, p-(N-morpholino-CH 2 CH 2 O)-benzyl, —CH 2 CH 2 C(O)NH 2 , —CH 2 -imidazol-4-yl, —CH 2 -(3-tetrahydrofuranyl), —CH 2 -thiophen-2-yl, —CH 2 (1-methyl)cyclopropyl, —CH 2 -thiophen-3-yl, thiophen-3-yl, thiophen-2-yl, —CH 2 -C(O)O-t-butyl, —CH 2 -C(CH 3 ) 3 ,—CH 2 CH(CH 2 CH 3 ) 2 , 2-methylcyclopentyl, cyclohex-2-enyl, —CH[CH(CH 3 ) 2 ]COOCH 3 , —CH 2 CH 2 N(CH 3 ) 2 , —CH 2 C(CH 3 )═CH 2 , —CH 2 CH CHCH 3 (cis and trans), —CH 2 OH, —CH(OH)CH 3 , —CH(O-t-butyl)CH 3 , —CH 2 OCH 3 , —(CH 2 ) 4 NH-Boc, —(CH 2 ) 4 NH 2 , —CH 2 -pyridyl, pyridyl, —CH 2 -naphthyl, —CH 2 -(N-morpholino), p-(N-morpholino-CH 2 CH 2 O)-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, —CH 2 CH 2 SCH 3 , 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:
wherein p is zero or one, T is selected from the group consisting of alkylene, substituted alkylene, alkenylene, substituted alkenylene, —(R 21 Z) q R 21 — and —ZR 21 —, where Z is a substituent selected from the group consisting of —O—, —S— and >NR 20 , each R 20 is independently selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, substituted alkyl, substituted alkenyl, substituted alkynyl, aryl, heteroaryl and heterocyclic, each R 21 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
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:
wherein p is zero or one, T is selected from the group consisting of alkylene, substituted alkylene, alkenylene, substituted alkenylene, —(R 21 Z) q R 21 — and —ZR 21 —, where Z is a substituent selected from the group consisting of —O—, —S— and >NR 20 , each R 20 is independently selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, substituted alkyl, substituted alkenyl, substituted alkynyl, aryl, heteroaryl and heterocyclic, each R 21 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.
45 . The pharmaceutical composition according to claim 44 wherein the alcohol or thiol substituted groups is selected from the group consisting of
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.
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:
wherein p is zero or one, T is selected from the group consisting of alkylene, substituted alkylene, alkenylene, substituted alkenylene, (R 21 Z) q R 21 — and —ZR 21 —, where Z is a substituent selected from the group consisting of —O—, —S— and >NR 20 , each R 20 is independently selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, substituted alkyl, substituted alkenyl, substituted alkynyl, aryl, heteroaryl and heterocyclic, each R 21 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.
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:
wherein p is zero or one, T is selected from the group consisting of alkylene, substituted alkylene, alkenylene, substituted alkenylene, —(R 21 Z) q R 21 — and —ZR 21 —, where Z is a substituent selected from the group consisting of —O—, —S— and >NR 20 , each R 20 is independently selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, substituted alkyl, substituted alkenyl, substituted alkynyl. aryl, heteroaryl and heterocyclic, each R 21 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
wherein each V is independently selected from the group consisting of hydroxy, acyl, acyloxy, alky, 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:
wherein p is zero or one, T is selected from the group consisting of alkylene, substituted alkylene, alkenylene, substituted alkenylene, —(R 21 Z) q R 21 — and —ZR 21 —, were Z is a substituent selected from the group consisting of —O—, —S— and >NR 20 , each R 20 is independently selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, substituted alkyl, substituted alkenyl, substituted alkynyl, aryl, heteroaryl and heterocyclic, each R 21 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) p C(═X)—, forms a ring of the formula:
wherein p is zero or one, T is selected from the group consisting of alkylene, substituted alkylene, alkenylene, substituted alkenylene, —(R 21 Z) q R 21 — and —ZR 21 —, where Z is a substituent selected from the group consisting of —O—, —S— and >NR 20 , each R 20 is independently selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, substituted alkyl, substituted alkenyl, substituted alkynyl, aryl, heteroaryl and heterocyclic, each R 21 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:
wherein p is zero or one, T is selected from the group consisting of alkylene, substituted alkylene, alkenylene, substituted alkenylene, —(R 21 Z) q R 21 — and —ZR 21 —, where Z is a substituent selected from the group consisting of —O—, —S— and >NR 20 , each R 20 is independently selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, substituted alkyl, substituted alkenyl, substituted alkynyl, aryl, heteroaryl and heterocyclic, each R 21 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) p C(═X)—, forms a ring of the formula:
wherein p is zero or one, T is selected from the group consisting of alkylene, substituted alkylene, alkenylene, substituted alkenylene, —(R 21 Z) q R 21 — and —ZR 21 —, where Z is a substituent selected from the group consisting of —O—, —S— and >NR 20 , each R 20 is independently selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, substituted alkyl, substituted alkenyl, substituted alkynyl, aryl, heteroaryl and heterocyclic, each R 21 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:
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:
wherein p is zero or one, T is selected from the group consisting of alkylene, substituted alkylene, alkenylene, substituted alkenylene, —(R 21 Z) q R 21 — and —ZR 21 —, where Z is a substituent selected from the group consisting of —O—, —S— and >NR 20 , each R 20 is independently selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, substituted alkyl, substituted alkenyl, substituted alkynyl, aryl, heteroaryl and heterocyclic, each R 21 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:
wherein p is zero or one, T is selected from the group consisting of alkylene, substituted alkylene, alkenylene, substituted alkenylene, —(R 21 Z) q R 21 — and —ZR 21 —, where Z is a substituent selected from the group consisting of —O—, —S— and >NR 20 , each R 20 is independently selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, substituted alkyl, substituted alkenyl, substituted alkynyl, aryl, heteroaryl and heterocyclic, each R 21 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:
wherein p is zero or one, T is selected from the group consisting of alkylene, substituted alkylene, alkenylene, substituted alkenylene, —(R 21 Z) q R 21 — and —ZR 21 —, where Z is a substituent selected from the group consisting of —O—, —S— and >NR 20 , each R 20 is independently selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, substituted alkyl, substituted alkenyl, substituted alkynyl, aryl, heteroaryl and heterocyclic, each R 21 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;
wherein p is zero or one, T is selected from the group consisting of alkylene, substituted alkylene, alkenylene, substituted alkenylene, —(R 21 Z) q R 21 — and —ZR 21 —, where Z is a substituent selected from the group consisting of —O—, —S— and >NR 20 , each R 20 is independently selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, substituted alkyl, substituted alkenyl, substituted alkynyl, aryl, heteroaryl and heterocyclic, each R 21 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:
wherein R 1 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, —CH 3 , —CH═CH 2 , —CH═CHR 1 , —CH═CR 1 R 1 , —CR 1 ═CH 2 , —CR 1 ═CHR 1 , —CR 1 ═CR 1 R 1 , —C ═CH and —C═CR 1 ; 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 15 is selected from the group consisting of hydrogen, alkyl, substituted alkyl, aryl, heterocyclic and heteroaryl;
R 15′ 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)R 4 , —NHSO 2 R 4 , —C(O)NH 2 , —C(O)NHR 4 , —C(O)NR 4 R 4 , —S(O)R 4 , —S(O) 2 R 4 , —S(O) 2 NHR 4 and —S(O) 2 NR 4 R 4 , where each R 4 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:
wherein each R 2 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 R 1 to —C(X′)(X″)—, oxygen, sulfur, and —NR 5 where R 5 is hydrogen, acyl, alkyl, substituted alkyl, aryl, heterocyclic or heteroaryl group;
R 5′ 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, —OR 5′ , —SR 5 , —N(R 5 ) 2 , —N(CO)OR 15 and —N 3 , 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 —OR 5′ , —SR 5 , —N(R 5 ) 2 , —N(CO)OR 15 and —N 3 ; further, neither X′ and X″ can be —OR 5′ , —SR 5 , —N(R 5 ) 2 , —N(CO)OR 15 or —N 3 when T is other than a bond covalently linking R 1 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 >C═X, does not form a 2,3-dihydro-1-methyl-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one
when R1 is α-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 α-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 α-hydroxy-diphenylacetyl, R2 is methyl, and
R5 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
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 transcinnamyl, 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 15 ) 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 R 1 is aryl or heteroaryl.
60 . The compound according to claim 59 wherein R 1 is selected from the group consisting of
(a) alkyl (b) phenyl, (c) a substituted phenyl group of the formula: 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 R 1 is selected from the group consisting of mono-, di- and tri-substituted phenyl groups.
62 . The compound according to claim 61 wherein R 1 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 R 1 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 R 1 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 R 1 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 R 1 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-methoxyphenyl, 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, —CH 2 -cyclopropyl, —CH 2 -cyclobutyl, —CH 2 -cyclohexyl, —CH 2 -cyclopentyl, —CH 2 CH 2 -cyclopropyl, —CH 2 CH 2 -cyclobutyl, —CH 2 CH 2 -cyclohexyl, —CH 2 CH 2 -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, (CH 3 ) 2 CH ═CHCH 2 CH 2 CH(CH 3 )—, C(O)CH 2 —, 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, CH 3 OC(O)CH 2 -, benzylthiomethyl, 5-(methoxycarbonyl)-n-pentyl, 3-(methoxycarbonyl)-n-propyl, indan-2-yl, (2-methylbenzofuran-3-yl), methoxymethyl, CH 3 CH═CH—, CH 3 CH 2 CH═CH—, (4-chlorophenyl)C(O)CH 2 —, (4-fluorophenyl)C(O)CH 2 -, (4-methoxy phenyl)C(O)CH 2 —, 4-(fluorophenyl)-NHC(O)CH 2 —, 1-phenyl-n-butyl, (phenyl) 2 CHNHC(O)CH 2 CH 2 -, (CH 3 ) 2 NC(O)CH 2 -, (phenyl) 2 CHNHC(O)CH 2 CH 2 -, methylcarbonylmethyl, (2,4-dimethylphenyl)C(O)CH 2 —, 4-methoxyphenyl-C(O)CH 2 —, phenyl-C(O)CH 2 —, CH 3 C(O)N(phenyl)-, ethenyl, methylthiomethyl, (CH 3 ) 3 CNHC(O)CH 2 —, 4-fluorophenyl-C(O)CH 2 —, diphenylmethyl, phenoxymethyl, 3,4-methylenedioxyphenyl-CH 2 —, benzo[b]thiophen-3-yl, (CH 3 ) 3 COC(O)NHCH 2 —, trans-styryl, H 2 NC(O)CH 2 CH 2 —, 2-trifluoromethylphenyl-C(O)CH 2 , phenylC(O)NHCH(phenyl)CH 2 —, mesityl, CH 3 CH(═NHOH)CH 2 —, 4—CH 3 -phenyl-NHC(O)CH 2 CH 2 —, phenyl-C(O)CH(phenyl)CH 2 —, (CH 3 ) 2 CHC(O)NHCH(phenyl)-, CH 3 CH 2 OCH 2 —, CH 3 OC(O)CH(CH 3 )(CH 2 ) 3 —, 2,2,2-trifluoroethyl, 1-(trifluoromethyl)ethyl, 2—CH 3 -benzofuran-3-yl, 2-(2,4-dichlorophenoxy)ethyl, SO 2 CH 2 —, 3-cyclohexyl-n-propyl, CF 3 CH 2 CH 2 CH 2 — and N-pyrrolidinyl.
67 . The compound according to claim 58 where each R 2 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 R 2 is selected from the group consisting of methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, —CH 2 CH(CH 2 CH 3 ) 2 , 2-methyl-n-butyl, 6-fluoro-n-hexyl, pheniyl, benzyl, cyclohexyl, cyclopentyl, cycloheptyl, allyl, iso-but-2-enyl, 3-methylpentyl, —CH 2 -cyclopropyl, —CH 2 -cyclohexyl, —CH 2 CH 2 -cyclopropyl, —CH 2 CH 2 -cyclohexyl, —CH 2 -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-(CH 3 ) 2 NCH 2 CH 2 CH 2 O-benzyl, p-(CH 3 ) 3 COC(O)CH 2 Q-benzyl, p-(HOOCCH 2 O)-benzyl, 2-aminopyrid-6-yl, p-(N-morpholino-CH 2 CH 2 O)-benzyl, —CH 2 CH 2 C(O)NH 2 , —CH 2 -imidazol4-yl, —CH 2 -(3-tetrahydrofuiranyl), —CH 2 -thiophen-2-yl, —CH 2 (1-methyl)cyclopropyl, —CH 2 -thiophen-3-yl, thiophen-3-yl, thiophen-2-yl, —CH 2 -C(O)O-t-butyl, —CH 2 -C(CH 3 ) 3 , —CH 2 CH(CH 2 CH 3 ) 2 , 2-methylcyclopentyl, cyclohex-2-enyl, —CH[CH(CH 3 ) 2 ]COOCH 3 , —CH 2 CH 2 N(CH 3 ) 2 , —CH 2 C(CH 3 ) ═CH 2 , —CH 2 CH═CHCH 3 (cis and trans), —CH 2 QH, —CH(OH)CH 3 , —CH(O-t-butyl)CH 3 , —CH 2 OCH 3 , —(CH 2 ) 4 NH-Boc, —(CH 2 ) 4 NH 2 , —CH 2 -pyridyl, pyridyl, —CH 2 -naphthyl, —CH 2 -(N-morpholino), p-(N-morpholino-CH 2 CH 2 O)-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, —CH 2 CH 2 SCH 3 , 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 (═X)—, forms a lactam or thiolactam ring of the formula:
wherein p is zero or one, T is selected from the group consisting of alkylene, substituted alkylene, alkenylene, substituted alkenylene, —(R 21 Z) q R 21 — and —ZR 21 —, where Z is a substituent selected from the group consisting of —O—, —S— and >NR 20 , each R 20 is independently selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, substituted alkyl, substituted alkenyl, substituted alkynyl, aryl, heteroaryl and heterocyclic, each R 21 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.
71 . The method according to claim 70 wherein the lactam ring is selected from the group consisting of
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.
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:
wherein p is zero or one, T is selected from the group consisting of alkylene, substituted alkylene, alkenylene, substituted alkenylene, —(R 21 Z) q R 21 — and —ZR 21 —, where Z is a substituent selected from the group consisting of —O—, —S— and >NR 20 , each R 20 is independently selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, substituted alkyl, substituted alkenyl, substituted alkynyl, aryl, heteroaryl and heterocyclic, each R 21 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
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.
74 . The compound according to claim 58 wherein the cyclic group defined by W, together with —C(H) p (═X)—, forms a ring of the formula:
wherein p is zero or one, T is selected from the group consisting of alkylene, substituted alkylene, alkenylene, substituted alkenylene, —(R 21 Z) q R 21 — and —ZR 21 —, where Z is a substituent selected from the group consisting of —O—, —S— and >NR 20 , each R 20 is independently selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, substituted alkyl, substituted alkenyl, substituted alkynyl, aryl, heteroaryl and heterocyclic, each R 21 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 (═X)—, forms a ring of the formula:
wherein p is zero or one, T is selected from the group consisting of alkylene, substituted alkylene, alkenylene, substituted alkenylene, —(R 21 Z)R 21 — and —ZR 21 —, where Z is a substituent selected from the group consisting of —O—, —S— and >NR 20 , each R ° is independently selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, substituted alkyl, substituted alkenyl, substituted alkynyl, aryl, heteroaryl and heterocyclic, each R 21 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
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 (═X)—, forms a ring of the formula:
wherein p is zero or one, T is selected from the group consisting of alkylene, substituted alkylene, alkenylene, substituted alkenylene, —(R 21 Z) q R 21 — and —ZR 21 —, where Z is a substituent selected from the group consisting of —O—, —S— and >NR 20 , each R ° is independently selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, substituted alkyl, substituted alkenyl, substituted alkynyl, aryl, heteroaryl and heterocyclic, each R 21 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 (═X)—, forms a ring of the formula:
wherein p is zero or one, T is selected from the group consisting of alkylene, substituted alkylene, alkenylene, substituted alkenylene, —(R 21 Z) q R 21 — and —ZR 21 —, where Z is a substituent selected from the group consisting of —O—, —S— and >NR 20 , each R 20 is independently selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, substituted alkyl, substituted alkenyl, substituted alkynyl, aryl, heteroaryl and heterocyclic, each R 21 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 (═X)—, forms a ring of the formula:
wherein p is zero or one, T is selected from the group consisting of alkylene, substituted alkylene, alkenylene, substituted alkenylene, —(R 21 Z) q R 21 — and —ZR 21 —, where Z is a substituent selected from the group consisting of —O—, —S— and >NR 20 , each R 20 is independently selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, substituted alkyl, substituted alkenyl, substituted alkynyl, aryl, heteroaryl and heterocyclic, each R 21 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 defmed by W, together with —C(H) p C(═X)—, forms a ring of the formula:
wherein p is zero or one, T is selected from the group consisting of alkylene, substituted alkylene, alkenylene, substituted alkenylene, —(R 21 Z) q R 21 — and —ZR 21 —, where Z is a substituent selected from the group consisting of —O—, —S— and >NR 20 , each R 20 is independently selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, substituted alkyl, substituted alkenyl, substituted alkynyl, aryl, heteroaryl and heterocyclic, each R 21 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:
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:
wherein p is zero or one, T is selected from the group consisting of alkylene, substituted alkylene, alkenylene, substituted alkenylene, —(R 21 Z) q R 21 — and —ZR 21 —, where Z is a substituent selected from the group consisting of —O—, —S— and >NR 20 , each R 20 is independently selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, substituted alkyl, substituted alkenyl, substituted alkynyl, aryl, heteroaryl and heterocyclic, each R 21 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.
83 . The compound according to claim 69 wherein the cyclic group defined by W, together with —C(H) p (═X)—, forms a ring of the formula:
wherein p is zero or one, T is selected from the group consisting of alkylene, substituted alkylene, alkenylene, substituted alkenylene, —(R 21 Z) q R 21 — and —ZR 21 —, where Z is a substituent selected from the group consisting of —O—, —S— and >NR 20 , each R 20 is independently selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, substituted alkyl, substituted alkenyl, substituted alkynyl, aryl, heteroaryl and heterocyclic, each R 21 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-1H-1,4-benzodiazepin-2-one 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-1H-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 3-[(N′-(Acetyl)-L-alaninyl)]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-dihydro-1-methyl-5-phenyl-1H-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-phenyl-1H-1,4-benzodiazepin-2-one (S)-3-[(N′-(2-Thiophenecarboxyl)-L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-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)-(−)-α-Methoxyphenylacetyl)-L-alaninyi)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-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 (S)-3-[(N′-(2-Phenoxypropionyl)-L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one (S)-3-[(N′-(Cyclohexanecarboxyl)-L-alaninyl)]amino-2,3-dihydro-1-methyl-5-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-1,4-benzodiazepin-2-one (S)-3-[(N′-(Cyclobutanecarboxyl)-L-alaninyl)]amino-2,3dihydro-1-methyl-5-phenyl-1H-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′-(5-Chlorobenzofuran-2-carboxyl)-L-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-1H-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-1H-1,4-benzodiazepin-2-one (S)-3-[(N′-(5,5-dimethyl-butyrolactone-4-yl)-L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one (S)-3-[(N′-(2-Methyl-4,4,4-trifiuorobutyryl)-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 3-[N′-(3,5-difluorophenyl-α-methoxyacetyl)-L-alaninyl]-amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-Benzodiazepin-2-one 3-[N′-(3,5-difluorophenyl-α-methoxyacetyl)-L-alaninyl]-amino-2,3-dihydro-1-methyl-5-phenyl-1H-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-1H-1,4-bemzodiazepin-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-1,4-benzodiazepin-2-one (S)-3-[(N′-(2,2-Dichlorocyclopropane carboxyl)-L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-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 (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-1H-1,4-benzodiazepin-2-one (S)-3-[(N′-(α-(Hydroxymethyl)phenylacetyl)-L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one (S)-3-[(N′-(1-(2,4Dichlorophenyl)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-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-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 (S)-3-[(N′-(Pivalyl)-L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one (S)-3-[(N′-(trans-Cinnmayl)-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-phenyl4-isoquinolinecarboxyl)-L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-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 (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-1H-1,4-benzodiazepin-2-one (S)-3-[(N′-(2-(4-Cyanophenoxy)-2-methyl propionyl)-L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-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 (S)-3-[(N′-(Tetrahydro-2-furoyl)-L-alaninyl)]amino-2,3-dihydro-1-methyl-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 (S)-3-[(N′-(4-(methylsulfonyl)benzoyl)-L-alaninyl)]amino-2,3dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one (S)-3-[(N′-(4-chloro-α-methylphenylacetyl)-L-alaninyl)]amino-2,3-dihydro-1-nethyl-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-α,α-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 (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-pheny 1-1H-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-2,3dihydro-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-alaniny)]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-methyl-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one 3-[(N′-(1-phenyl-1-cyclopropanecarboxyl)-L-alaninyl)]amino]-2,3dihydro-1-(3,3-dimethyl-2-oxobutyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one (S)-3-[(N′-α-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′-(α-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 3-[(N′-(α-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 (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-2,3dihydro-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 (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 (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-methyl1-5-phenyl-l1H-1,4-benzodiazepin-2-one (S)-3-[(N′-((2-Isopropylphenyl)ureylenyl)-L-alaninyl)]amino-2,3-ihydro-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-benizodiazepin-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 (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-Chloropbenyl)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-2,3dihydro-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 (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-2,3-dihydro 1-methyl-5-phenyl-1H-1,4-benzodiazepine 3-[N′-3,5-difluorophenyl-α-azidoacetyl)-L-alaninyl]-3-amino-2,3-dihydro-1-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′-(3,5difluorophenyl-α-(2-aminoacetoxy)acetyl)-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 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-dihydio-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}-amnino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one 3-[N′-(3,5-difluorophenyl-α-hydroxy-α-methylacetyl)-L-alaninyl]-amino-2,3-dihydro-1-methyl-5-(2-fluorophenyl)-1H-1,4-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-α-hydroxy-α-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-α-aminoacetyl)-L-valinyl)-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one 5-(S)-(N′-(3,5-difluorophenyl-α-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-α-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 5-(S)-(N′-((cyclohexylureylenyl)-L-alaninyl)-amino-7-methyl-5,7dihydro-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 S-(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-benz[b,d]azepin-6-one S-(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-dihydro6H-dibenz[b,d]azepin-6-one 5-(S)-((N′-(S)-(2S)-1-hydroxymethyl-2-methylbutylureylenyl)-L-alaninyl)-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one 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-5,7dihydro-6H-dibenz[b,d]azepin-6-one 5-(S)-(N′-(R/S)-1-methylbutylureylenyl)-L-alaninyl)-amino-7-methyl-5,7-dihydro-6Hdibenz[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 5-(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 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-5,7dihydro-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 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 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-α-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-5,7dihydro-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 5-(S)-(N″-(S)-phenylglycinyl)-N′-L-alaninyl]amino-1-methy 1-5-phenyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-2-one S-(S)-[(N″-L-valinyl)-N′-L-alaninyl]amino-1-methyl-S-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-5,7dihydro-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 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 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-1H-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 R 15 is H.
87 . The compound of claim 86 , wherein the cyclic group defined by W and —C(H) p (═X)—, forms a lactam ring of the formula:
wherein p is zero or one, T is selected from the group consisting of alkylene, substituted alkylene, alkenylene, substituted alkenylene, —(R 21 Z) q R 21 — and —ZR 21 —, where Z is a substituent selected from the group consisting of —O—, —S— and >NR 20 , each R 20 is independently selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, substituted alkyl, substituted alkenyl, substituted alkynyl, aryl, heteroaryl and heterocyclic, each R 21 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
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.
89 . The compound of claim 88 , wherein R 1 is selected from the group consisting of
(a) alkyl (b) phenyl, (c) a substituted phenyl group of the formula: wherein R c is selected from the group consisting of acyl, alkyl, alkoxy, alkylalkoxy, azido, cyano, halo, hydrogen, substituted amino, 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, ttihalomethyl, 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.
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, 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, 2,5dimethoxyphenyl, 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, —CH 2 -cyclopropyl, —CH 2 -cyclobutyl, —CH 2 -cyclohexyl, —CH 2 -cyclopentyl, —CH 2 CH 2 -cyclopropyl, —CH 2 CH 2 -cyclobutyl, —CH 2 CH 2 -cyclohexyl, —CH 2 CH 2 -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-phenyloxazol4-yl, indol-3-yl, 1-phenyl-tetrazol-5-yl, allyl, 2-(cyclohexyl)ethyl, (CH 3 ) 2 CH═CHCH 2 CH 2 CH(CH 3 )—, C(O)CH 2 —, 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, CH 3 OC(O)CH 2 —, benzylthiomethyl, 5-(methoxycarbonyl)-n-pentyl, 3-(methoxycarbonyl)-n-propyl, indan-2-yl, (2-methylbenzofuran-3-yl), methoxymethyl, CH 3 CH═CH—, CH 3 CH 2 CH═CH—, (4-chlorophenyl)C(O)CH 2 —, (4-fluotophenyl)C(O)CH 2 —, (4-methoxy phenyl)C(O)CH 2 —, 4-(fluorophenyl)-NHC(O)CH 2 —, 1-phenyl-n-butyl, (phenyl) 2 CHNHC(O)CH 2 CH 2 —, (CH 3 ) 2 NC(O)CH 2 —, (phenyl) 2 CHNHC(O)CH 2 CH 2 —, methylcarbonylmethyl, (2,4-dimethylphenyl)C(O)CH 2 —, 4-methoxyphenyl-C(O)CH 2 —, phenyl-C(O)CH 2 —, CH 3 C(O)N(phenyl)-, ethenyl, methylthiomethyl, (CH 3 ) 3 CNHC(O)CH 2 —, 4-fluorophenyl-C(O)CH 2 —, diphenylmethyl, phenoxymethyl, 3,4-methylenedioxyphenyl-CH 2 —, benzo[b]thiophen-3-yl, (CH 3 ) 3 COC(O)NHCH 2 —, trans-styryl, H 2 NC(O)CH 2 CH 2 —, 2-trifluoromethylphenyl-C(O)CH 2 , phenylC(O)NHCH(phenyl)CH 2 —, mesityl, CH 3 CH(═NHOH)CH 2 —, 4—CH 3 -phenyl-NHC(O)CH 2 CH 2 —, phenyl-C(O)CH(phenyl)CH 2 —, (CH 3 ) 2 CHC(O)NHCH(phenyl)-, CH 3 CH 2 OCH 2 —, CH 3 OC(O)CH(CH 3 )(CH 2 ) 3 —, 2,2,2-trifluoroethyl, 1-(trifluoromethyl)ethyl, 2—CH 3 -benzofuran-3-yl, 2-(2,4-dichlorophenoxy)ethyl, SO 2 CH 2 —, 3-cyclohexyl-n-propyl, CF 3 CH 2 CH 2 CH 2 — and N-pyrrolidinyl.
91 . The compound of claim 90 where each R 2 is independently selected from the group consisting of alkyl, substituted alkyl, alkenyl, cycloalkyl, aryl, heteroaryl and heterocyclic.
92 . The compound of claim 91 wherein R 2 is selected from the group consisting of methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, —CH 2 CH(CH 2 CH 3 ) 2 , 2-methyl-n-butyl, 6-fluoro-n-hexyl, phenyl, benzyl, cyclohexyl, cyclopentyl, cycloheptyl, allyl, iso-but-2-enyl, 3-methylpentyl, —CH 2 -cyclopropyl, —CH 2 -cyclohexyl, —CH 2 CH 2 -cyclopropyl, —CH 2 CH 2 -cyclohexyl, —CH 2 -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-(CH 3 ) 2 NCH 2 CH 2 CH 2 O-benzyl, p-(CH 3 ) 3 COC(O)CH 2 O-benzyl, p-(HOOCCH 2 O)-benzyl, 2-aminopyrid-6-yl, p-(N-morpholino—CH 2 CH 2 O)-benzyl, —CH 2 CH 2 C(O)NH 2 , —CH 2 -imidazol4-yl, —CH 2 -(3-tetrahydrofuranyl), —CH 2 -thiophen-2-yl, —CH 2 (1-methyl)cyclopropyl, —CH 2 -thiophen-3-yl, thiophen-3-yl, thiophen-2-yl, —CH 2 -C(O)O-t-butyl, —CH 2 -C(CH 3 ) 3 , —CH 2 CH(CH 2 CH 3 ) 2 , 2-methylcyclopentyl, cyclohex-2-enyl, —CH[CH(CH 3 ) 2 ]COOCH 3 , —CH 2 CH 2 N(CH 3 ) 2 , —CH 2 C(CH 3 )═CH 2 , —CH 2 CH═CHCH 3 (cis and trans), —CH 2 OH, —CH(OH)CH 3 , —CH(O-t-butyl)CH 3 , —CH 2 OCH 3 , —(CH 2 ) 4 NH-Boc, —(CH 2 ) 4 NH 2 , —CH 2 -pyridyl, pyridyl, —CH 2 -naphthyl, —CH 2 -(N-morpholino), p-(N-morpholino-CH 2 CH 2 O)-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, —CH 2 CH 2 SCH 3 , 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.
98 . The compounds of claim 97 wherein each R15 is H.
99 . The compounds of claim 98 wherein the cyclic group defined by W and —C(H) p (═X)—, forms a lactam ring of the formula:
wherein p is zero or one, T is selected from the group consisting of alkylene, substituted alkylene, alkenylene, substituted alkenylene, —(R 21 Z) q R 21 — and —ZR 21 —, where Z is a substituent selected from the group consisting of —O—, —S— and >NR 20 , each R 20 is independently selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, substituted alkyl, substituted alkenyl, substituted alkynyl, aryl, heteroaryl and heterocyclic, each R 21 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
wherein A-B is selected from the group consisting of alkylene, alkenylene, substituted alkylene, substituted alkenylene and —N═CH—; Q is oxygen or sulfuir; 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, 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 R 1 is selected from the group consisting of
(a) alkyl (b) phenyl, (c) a substituted phenyl group of the formula: wherein R c is selected from the group consisting of acyl, alkyl, alkoxy, alkylalkoxy, azido, cyano, halo, hydrogen, substituted amino, 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.
102 . The compound of claim 101 wherein R 1 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-dirnethoxyphenyl, 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, IS 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, —CH 2 -cyclopropyl, —CH 2 -cyclobutyl, —CH 2 -cyclohexyl, —CH 2 -cyclopentyl, —CH 2 CH 2 -cyclopropyl, —CH 2 CH 2 -cyclobutyl, —CH 2 CH 2 -cyclohexyl, —CH 2 CH 2 -cyclopentyl, pyrid-2-yl, pyrid-3-yl, pyrid-4-yl, fluoropyridyls, chloropyridyls, thien-2-yl, thien-3-yl, benzothiazol4-yl, 2-phenylbenzoxazol-5-yl, furan-2-yl, benzofuiran-2-yl, thionaphthen-2-yl, thionaphthen-3-yl, thionaphthen4-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-phenyloxazol4-yl, indol-3-yl, 1-phenyl-tetrazol-5-yl, allyl, 2-(cyclohexyl)ethyl, (CH 3 ) 2 CH═CHCH 2 CH 2 CH(CH 3 )—, C(O)CH 2 —, 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, CH 3 OC(O)CH 2 —, benzylthiomethyl, 5-(methoxycarbonyl)-n-pentyl, 3-(methoxycarbonyl)-n-propyl, indan-2-yl, (2-methylbenzofuran-3-yl), methoxymethyl, CH 3 CH═CH—, CH 3 CH 2 CH═CH—, (4-chlorophenyl)C(O)CH 2 —, (4-fluorophenyl)C(O)CH 2 —, (4-methoxy phenyl)C(O)CH 2 —, 4-(fluorophenyl)-NHC(O)CH 2 —, 1-phenyl-n-butyl, (phenyl) 2 CHNHC(O)CH 2 CH 2 —, (CH 3 ) 2 NC(O)CH 2 —, (phenyl) 2 CHNHC(O)CH 2 CH 2 —, methylcarbonylmethyl, (2,4-dimethylphenyl)C(O)CH 2 —, 4-methoxyphenyl-C(O)CH 2 —, phenyl-C(O)CH 2 —, CH 3 C(O)N(phenyl)-, ethenyl, methylthiomethyl, (CH 3 ) 3 CNHC(O)CH 2 —, 4-fluorophenyl-C(O)CH 2 —, diphenylmethyl, phenoxymethyl, 3,4-methylenedioxyphenyl-CH 2 —, benzo[b]thiophen-3-yl, (CH 3 ) 3 COC(O)NHCH 2 —, trans-styryl, H 2 NC(O)CH 2 CH 2 —, 2-trifluoromethylphenyl-C(O)CH 2 , phenylC(O)NHCH(phenyl)CH 2 -mesityl, CH 3 CH(═NHOH)CH 2 —, 4—CH 3 -phenyl-NHC(O)CH 2 CH 2 —, phenyl-C(O)CH(phenyl)CH 2 —, (CH 3 ) 2 CHC(O)NHCH(phenyl)-, CH 3 CH 2 OCH 2 —, CH 3 OC(O)CH(CH 3 )(CH 2 ) 3 —, 2,2,2-trifluoroethyl, 1-(trifluoromethyl)ethyl, 2—CH 3 -benzofuran-3-yl, 2-(2,4-dichlorophenoxy)ethyl, SO 2 CH 2 —, 3-cyclohexyl-n-propyl, CF 3 CH 2 CH 2 CH 2 - and N-pyrrolidinyl.
103 . The compound according to claim 102 where each R 2 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 R 2 is selected from the group consisting of methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, —CH 2 CH(CH 2 CH 3 ) 2 , 2-methyl-n-butyl, 6-fluoro-n-hexyl, phenyl, benzyl, cyclohexyl, cyclopentyl, cycloheptyl, allyl, iso-but-2-enyl, 3-methylpentyl, —CH 2 -cyclopropyl, —CH 2 -cyclohexyl, —CH 2 CH 2 -cyclopropyl, —CH 2 CH 2 -cyclohexyl, —CH 2 -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-(CH 3 ) 2 NCH 2 CH 2 CH 2 O-benzyl, p-(CH 3 ) 3 COC(O)CH 2 O-benzyl, p-(HOOCCH 2 O)-benzyl, 2-aminopyrid-6-yl, p-(N-morpholino-CH 2 CH 2 O)-benzyl, —CH 2 CH 2 C(O)NH 2 , —CH 2 -imidazol4-yl, —CH 2 -(3-tetrahydrofuranyl), —CH 2 -thiophen-2-yl, —CH 2 (1-methyl)cyclopropyl, —CH 2 -thiophen-3-yl, thiophen-3-yl, thiophen-2-yl, —CH 2 -C(O)O-t-butyl, —CH 2 -C(CH 3 ) 3 , —CH 2 CH(CH 2 CH 3 ) 2 , 2-methylcyclopentyl, cyclohex-2-enyl, —CH[CH(CH 3 ) 2 ]COOCH 3 , —CH 2 CH 2 N(CH 3 ) 2 , —CH 2 C(CH 3 )═CH 2 , —CH 2 CH═CHCH 3 (cis and trans), —CH 2 OH, —CH(OH)CH 3 , —CH(O-t-butyl)CH 3 , —CH 2 OCH 3 , —(CH 2 ) 4 NH-Boc, —(CH 2 ) 4 NH 2 , —CH 2 -pyridyl, pyridyl, —CH 2 -naphthyl, —CH 2 -(N-morpholino), p-(N-morpholino-CH 2 CH 2 O)-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, —CH 2 CH 2 SCH 3 , 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.
112 . The compound of claim 111 the cyclic group defined by W and —C(H) p C(═X)— forms a lactam ring of the formula:
wherein p is zero or one, T is selected from the group consisting of alkylene, substituted alkylene, alkenylene, substituted alkenylene, —(R 21 Z) q R 21 — and —ZR 21 —, where Z is a substituent selected from the group consisting of —O—, —S— and >NR 20 , each R 20 is independently selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, substituted alkyl, substituted alkenyl, substituted alkynyl, aryl, heteroaryl and heterocyclic, each R 21 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
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, 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 R 1 is selected from the group consisting of
(a) alkyl, (b) phenyl, (c) a substituted phenyl group of the formula: wherein R c is selected from the group consisting of acyl, alkyl, alkoxy, alkylalkoxy, azido, cyano, halo, hydrogen, substituted amino, 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.
115 . The compound of claim 114 wherein R 1 is selected from the group consisting of phenyl, 1-naphthyl, 2-naphthyl, n-butyl, 2chlorophenyl, 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, 2chloro-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, —CH 2 -cyclopropyl, —CH 2 -cyclobutyl, —CH 2 -cyclohexyl, —CH 2 -cyclopentyl, —CH 2 CH 2 -cyclopropyl, —CH 2 CH 2 -cyclobutyl, —CH 2 CH 2 -cyclohexyl, —CH 2 CH 2 -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, (CH 3 ) 2 CH═CHCH 2 CH 2 CH(CH 3 )—, C(O)CH 2 —, 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, CH 3 OC(O)CH 2 —, benzylthiomethyl, 5-(methoxycarbonyl)-n-pentyl, 3-(methoxycarbonyl)-n-propyl, indan-2-yl, (2-methylbenzofuran-3-yl), methoxymethyl, CH 3 CH═CH—, CH 3 CH 2 CH═CH—, (4-chlorophenyl)C(O)CH 2 —, (4-fluorophenyl)C(O)CH 2 —, (4-methoxy phenyl)C(O)CH 2 —, 4-(fluorophenyl)-NHC(O)CH 2 —, 1-phenyl-n-butyl, (phenyl) 2 CHNHC(O)CH 2 CH 2 —, (CH 3 ) 2 NC(O)CH 2 —, (phenyl) 2 CHNHC(O)CH 2 CH 2 —, methylcarbonylmethyl, (2,4-dimethylphenyl)C(O)CH 2 —, 4-methoxyphenyl-C(O)CH 2 —, phenyl-C(O)CH 2 —, CH 3 C(O)N(phenyl)-, ethenyl, methylthiomethyl, (CH 3 ) 3 CNHC(O)CH 2 —, 4-fluorophenyl-C(O)CH 2 —, diphenylmethyl, phenoxymethyl, 3,4-methylenedioxyphenyl-CH 2 —, benzo[b]thiophen-3-yl, (CH 3 ) 3 COC(O)NHCH 2 —, trans-styryl, H 2 NC(O)CH 2 CH 2 —, 2-trifluoromethylphenyl-C(O)CH 2 , phenylC(O)NHCH(phenyl)CH 2 -mesityl, CH 3 CH(═NHOH)CH 2 —, 4—CH 3 -phenyl-NHC(O)CH 2 CH 2 —, phenyl-C(O)CH(phenyl)CH 2 —, (CH 3 ) 2 CHC(O)NHCH(phenyl)-, CH 3 CH 2 OCH 2 —, CH 3 OC(O)CH(CH 3 )(CH 2 ) 3 —, 2,2,2-trifluoroethyl, 1-(trifluoromethyl)ethyl, 2—CH 3 -benzofuran-3-yl, 2-(2,4-dichlorophenoxy)ethyl, SO 2 CH 2 —, 3-cyclohexyl-n-propyl, CF 3 CH 2 CH 2 CH 2 — and N-pyrrolidinyl.
116 . The compound according to claim 115 where each R 2 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 R 2 is selected from the group consisting of methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, —CH 2 CH(CH 2 CH 3 ) 2 , 2-methyl-n-butyl, 6-fluoro-n-hexyl, phenyl, benzyl, cyclohexyl, cyclopentyl, cycloheptyl, allyl, iso-but-2-enyl, 3-methylpentyl, —CH 2 -cyclopropyl, —CH 2 -cyclohexyl, —CH 2 CH 2 -cyclopropyl, —CH 2 CH 2 -cyclohexyl, —CH 2 -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-(CH 3 ) 2 NCH 2 CH 2 CH 2 O-benzyl, p-(CH 3 ) 3 COC(O)CH 2 Q-benzyl, p-(HOOCCH 2 O)-benzyl, 2-aminopyrid-6-yl, p-(N-morpholino-CH 2 CH 2 O)-benzyl, —CH 2 CH 2 C(O)NH 2 , —CH 2 -imidazol4-yl, —CH 2 -(3-tetrahydrofuranyl), —CH 2 -thiophen-2-yl, —CH 2 (1-methyl)cyclopropyl, —CH 2 -thiophen-3-yl, thiophen-3-yl, thiophen-2-yl, —CH 2 -C(O)O-t-butyl, —CH 2 -C(CH 3 ) 3 , —CH 2 CH(CH 2 CH 3 ) 2 , 2-methylcyclopentyl, cyclohex-2-enyl, —CH[CH(CH 3 ) 2 ]COOCH 3 , —CH 2 CH 2 N(CH 3 ) 2 , —CH 2 C(CH 3 )═CH 2 , —CH 2 CH═CHCH 3 (cis and trans), —CH 2 OH, —CH(OH)CH 3 , —CH(O-t-butyl)CH 3 , —CH 2 OCH 3 , —(CH 2 ) 4 NH-Boc, —(CH 2 ) 4 NH 2 , —CH 2 -pyridyl, pyridyl, —CH 2 -naphthyl, —CH 2 -(N-morpholino), p-(N-morpholino-CH 2 CH 2 O)-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, —CH 2 CH 2 SCH 3 , 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.
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-methyl4,5,6,7-tetrahydro-2H-3-benzazepin-2-one 1-(S)-[N′-(2-Aminobutyryl)-L-alaninyl]-amino-3-methyl4,5,6,7-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 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 R 1 is selected from the group consisting of methyl, ethyl, n-propyl, iso-propyl, iso-butyl, sec-butyl, n-butyl, n-pentyl and isovaleryl.Cited by (0)
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