CA2325389A1 - Compounds for inhibiting beta-amyloid peptide release and/or its synthesis - Google Patents

Abstract

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

Description

C
_ E
DEMANDES OU BREVETS VOLUMINEUX

COMPREND PLUS D'UN TOME.
CSC! EST LE TOME 'I DE
Pour les tomes additionels, veuillez contacter le Bureau canadien des brevets THlS SECTION OF THE APPLICATiON/PATENT CONTAINS MORE
THAN ONE VOLUME
THlS !S VOLUME ~ , NOTE: For additional volumes please contact the Canadian Patent Office COMPOUNDS FOR INHIBITING BETA-AMYLOID PEPTIDE RELEASE AND/OR ITS SYNTHESIS
CROSS-REFERENCE TO RELATED APPLICATIONS
This application claims the benefit of U.S. Provisional Application No.
60I , which was converted pursuant to 37 C.F.R. ~ 1.53(b) from U.S.S.N.
09/102,507, filed 3une 22, 1998; the disclosure of which is incorporated herein by reference in its entirety.
BACKGROUND OF THE INVENTION
Field of the Invention This invention relates to compounds which inhibit ~i-amyloid peptide release and/or its synthesis, and, accordingly, have utility in treating Alzheimer's disease.
$eferences The following publications, patents and patent applications are cited in this application as superscript numbers:
1 Glenner, et al., Biochem. Biophys. Res. Commun., ~2_Q:885-890 ( 1984)

2 U.S. Patent No. 4,666,829

3 Selkoe, Neuron, x:487-498 (1991)

4 Goate, et al., Nature, ~4Q:704-706 (1990)

5 Chartier Harlan, et al., Nature, ~S :844-846 (1989) '-

6 Murrell, et al. , Science, ?e~4:97-99 ( 1991 ) Mullan, et aI . , Nature Genet. ,1:345-347 ( 1992) 8 Schenk, et al., International Patent Application Publication No. WO

94/10569, "Methods and Compositions for the Detection of Soluble ~Amyloid Peptide ", published 11 May 1994 Selkoe, Scientific American, "Amyloid Protein and Alzheimer's Disease", pp. 2-8, November, 1991 10 Tetrahedron Letters, 34(48), 7685 (1993) 11 Losse, et al., Tetrahedron, X7_:1423-1434 (1971) 12 Citron, et al., Nature, ~Q:672-674 (1992) 13 Hansen, et al., J. Immun. Meth., .x:203-210 (1989) 14 U,S. Patent No. 3,598,859 15 . Ogliaruso and Wolfe, Synthesis of Lactones and Lactams, Patai, et al. Editor, J. Wiley & Sons, New York, New York, USA, pp. 1085 et seq. (1993).

16 Ugi, et al., Tetrahedron, 5?(35):11657-11664 (1996) 17 Blade-Font, Tetrahedron Lett., x:2443 (1980). ..

18 Freidinger, et al., J. Org. Chem., .7:104-109 (1982) 19 Semple, et al., J. Med. Chem., X2:4531-4536 (1996).

20 Holladay, et al., J. Org. Chem., x:3900-3905 (1991).

21 Donaruma, et al., Organic Reactions, x.1:1-156 (1960) 22 wolff, Organic Reactions, x:307-336 (1946) 23 Krow, et al., J. Qrg. Chem., x.:5574-5580 (1996) 24 Tetrahedron, x:2433 (1979) Gracias, et al., J. Am. Chem. Soc., 17:8047-8048 {1995) 26 Milligan, et al., J. Am. Chem. Soc., .x:10449-10459 (1995) 27 Miller, et al., J. Am. Chem. Soc., x$:9606-9614 (1996) 25 28 March, Advanced Organic Chemistry, Reaction Mechanisms and Structure, 2nd Edition, McGraw-Hill Book Company, New York, New York, USA ( 1977) 29 Colombo, et al., Tetrahedron Lett., x.5(23):4031-4034 (1994) 30 Rogriguez, et al., Tetrahedron, 5:7727-7736 (1996) 31 parsons, et al., Biochem. Biophys. Res. Comm., x:108-113 (1983) 32 Watthey, et al., J. Med. Chem., x$:1511-1516 (1985) 33 Armstrong, et al. , Tetrahedron Lett. , x.:3239 ( 1994) 34 King, et al., J. Org. Chem., .x,$:3384 (1993).
35 Hu, et al., Tetrahedron Lett., .6(21):3659-3662 (1995).
36 Wada, et al., Bull. Chem. Soc. Japan, x:2833-2835 (1973) 37 Gaetzi, Chem. Abs. , ~:28690m 38 Wheeler, et al., Organic Syntheses, Coll. Vol. VI, p. 840 39 J. Med. Chem., 2$(12):1886 (1985) 40 greener, et al., U.S. Patent No. 2,938,029 41 gvans, et al., J. Am. Chem. Soc., .1.].x:4011-4030 (1990) 42 Micouin, et al., Tetrahedron; x:7719-7726 (1996) 43 Butcher, et al., Tetrahedron Lett. , ~Z(37):6685-6688 (1996) M.L. ReuppIe, et al., J. Am. Chem. Soc., x:7021 et seq. (1971) 45 p_A.S. Smith, Organic Reactions, x:337-449 (1946) "

46 K. Orito, et al., Tetrahedron, x:1017-1021 (1980) 47 Krimm, Chem. Ber., x:1057 (1958) 48 Suda, et al. , J. Chem. Soc. Chem Comm. , 949-950, ( 1994) 49 ga~on, et al., J. Chem. Soc., 1764-1767 (1975) 50 Kitagawa, et al., J. Am. Chem. Soc., 1_7:5169-5178 (1975) 1 S S 1 Akhatar, et al . , J. Org. Chem. , ~5 :5222-5225 ( 1990) 52 Nedenskov, et al., Acta Chem. Scand., x_2:1405-1410 (1958}

53 Sakakida, et al. , Bull. Chem. Soc. Japan, X4:478-480 ( 1971 ) 54 Hoffman, et al. , Tet. Lett. , x:4207-4210 ( 1989) 55 Vedejs, et al. , Tet. Lett. , ,x:3261-3264 (1992) 56 van der Steen, et al., Tetrahedron, ~7, 7503-7524 (1991) 57 Hart, et al., Chem Rev., $Q:1447-1465 (1989) 58 Lowe, et al., Bioorg. Med. Chem. Lett., 4:2877-2882 (1994) 59 McKennis, Jr., et al., J. Org. Chem. , x$:383-387 (1963) 60 Shirota, et al., J. Med. Chem. , x:1623-1627 (1977) ' 61 Overberger, et al., J. Am. Chem. Soc., $5:3431 (1963) 62 Herschmann, Helv. Chim. Acta, x:2537 (1949) 63 Overberger, et al., Macromolecules, ~:1 (1968) 64 Busacca, et al. , Tet. Lett. , x:165-168 ( 1992) 65 Croisier, et al., U.S. Patent No. 4,080,449 66 J.A. Robl, et al., Tetrahedron Lett., x(10):1593-1596 (1995) 67 Flynn, et al., J. Med. Chem., 3:2420-2423 (1993) 68 Orito, et al., Tetrahedron, ~:I017-1021 (1980) 69 Kawase, et al., J.Org. Chem., x.4:3394-3403 (1989) 70 hwe, et al., J. Med. Chem., x:3789-3811 (1994) 71 Robl, et al., Bioorg. Med. Chem. Lett., 4:1789-1794 (1994) 72 Skiles, et al., Bioorg. Med. Chem. Lett.,.~:773-778 (1993) 73 Grunewald, et al., J. Med. Chem. , .x.9(18):3539 (1996)

-7-74 Thomas, et al., J. Chem. Soc., Perkin II, 747 (1986) 75 Warshawsky, et al., Bioorg. Med. Chem. Lett., f:957-962 (1996) 76 Ben-Ishai, et al. , Tetrahedron, x:439-450 ( 1987) 77 van Niel et al., Bioorg. Med. Chem. Lett., x:1421-1426 (1995) 78 Kawase, et al., J. Org. Chem., X4:3394-3403 (1989) Edwards, et al., Can. J. Chem., x:1648-1658 (1971) 80 Milligan, et al., J. Am. Chem. Soc.,11Z:10449-10459 (1995) 81 Curran et al., Tet. Lett., x:191-194 (1995) 82 Slusarchyk, et al., Bioorg. Med. Chem. Lett.,,~:753-758 (1995) 83 Wyvratt, et al., Eur. Pat. Appl. 61187 (1982) Cornille, et al., J. Am. Chem. Soc., x.7:909-917 (1995) 85 Kolc; Coll. Czech. Chem. Comm., .4:630 (1969) 86 Dickerman, et al. , J. Org. Chem. , X4:530 (1949) 87 Dickerman, et al., J. Org. Chem., ~Q:206 (1955) 88 Dickerman, et al., J. Org. Chem., .~.~:1855 (1954) _g_ 89 Hoffman, et al., J. Org. Chem., x:3565 (1962}
90 Wasserman, et al., J. Am. Chem. Soc., x:461-2 (1981) "
91 Crombie, et al . , Tetrahedron Lett. , x(42) :5151-5154 ( 1986) 92 Yokoo, et al . , Bull, Chem. Soc. Jap. , ~ :631 ( 1956) 93 gurkholder, et al., Biog. Med. Chem. Lett., x:231 (1993) 94 Karanewsky, U.S. Patent No. 4,460,579 95 Kametani, et al., Heterocycles, ,x:831-840 (1978) 96 yanganasawa, et al. , J. Med. Chem. , 3:1984-1991 ( 1987) 97 J. Das et al . , Biorg. Med. Chem. Lett. , 4:2193-2198 ( 1994) All of the above publications, patents and patent applications are herein incorporated by reference in their entirety to the same extent as if each individual publication, patent or patent application was specifically and individually indicated to be incorporated by reference in its entirety.
State of the Art Alzheimer's Disease (AD) is a degenerative brain disorder characterized clinically by progressive loss of memory, cognition, reasoning, judgment and emotional stability that gradually leads to profound mental deterioration and ultimately death. AD is a very common cause of progressive mental failure (dementia) in aged humans and is believed to represent the fourth most common medical cause of death in the United States. AD has been observed in races and WO 99!67221 PCT/US99/14193 _9-ethnic groups worldwide and presents a major present and future public health problem. The disease is currently estimated to affect about two to three million individuals in the United States alone. AD is at present incurable. No treatment «
that effectively prevents AD or reverses its symptoms and course is currently known.
The brains of individuals with AD exhibit characteristic lesions termed senile (or amyloid) plaques, amyloid angiopathy (amyloid deposits in blood vessels) and neurofibriIlary tangles. Large numbers of these lesions, particularly amyloid plaques and neurofibrillary tangles, are generally found in several areas of the human brain important for memory and cognitive function in patients with AD.
Smaller numbers of these lesions in a more restrictive anatomical distribution are also found in the brains of most aged humans who do not have clinical AD.
Amyloid plaques and amyloid angiopathy also characterize the brains of individuals with Trisomy 21 (Down's Syndrome) and Hereditary Cerebral Hemorrhage with Amyloidosis of the Dutch Type (HCHWA-D). At present, a definitive diagnosis of AD usually requires observing the aforementioned lesions in the brain tissue of patients who have died with the disease or, rarely, in small biopsied samples of brain tissue taken during an invasive neurosurgical procedure .
The principal chemical constituent of the amyloid plaques and vascular amyloid deposits (amyloid angiopathy) characteristic of AD and the other disorders mentioned above is an approximately 4.2 kilodalton (kD) protein of about 39-43 amino acids designated the ~i-amyloid peptide (AP) or sometimes A , A P or /A4.
B-Amyloid peptide was first purified and a partial amino acid sequence was provided by Glenner, et al.l The isolation procedure and the sequence data for the first 28 amino acids are described in U.S. Patent No. 4,666,8292.

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

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

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

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

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

wherein each R2 is independently selected from the group consisting of alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, °°
cycloalkyl, aryl, heteroaryl and heterocyclic;
Z is represented by the formula -T-C(X' )(X")C(O)- where T is selected from the group consisting of a bond covalently linking Rl to -C(X')(X")-, oxygen, sulfur, and -NRS where RS is hydrogen, acyl, alkyl, substituted alkyl, aryl, heterocyclic or heteroaryl group;
RS is hydrogen, alkyl, substituted alkyl, aryl, heterocyclic or heteroaryl group;
X' and X" are independently selected from the group consisting of hydrogen, fluoro, alkyl, substituted alkyl, aryl, heteroaryl, heterocyclic, -ORS' , -SRS, -N(RS)~, -N(CO)OR'S and -N3, with the proviso that at least one of X' or X"
is other than hydrogen, hydroxy or fluoro, and with the further proviso that both X' and X" cannot both be -ORS , -SRS, -N(RS)Z, -N(CO)OR'S and -N3 ; further, neither X' and X" can be -ORS' -SRS, -N(RS),, -N(CO)OR'S or -N3 when T is other than a bond covalently linking Rl to -C(X')(X")-;
n is an integer equal to 1 or 2;
p is an integer equal to 0 or 1 such that when p is zero, the ring defined by W and -C(H)pC(=X)- is unsaturated at the carbon atom of ring attachment to Y
and when p is one, the ring is saturated at the carbon atom of ring attachment to Y, with the following provisos:
when R1 is 2-propylpentanoyl, R2 is methyl, and R15 is hydrogen, then W, together with > CH and > C=X, does not form a 2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one when R1 is 3,5-difluorobenzoyl, R2 is methyl, and R15 is hydrogen, then W, together with > CH and > C=X, does not form a 2,3-dihydro-1-methyl-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one "
when R1 is trans-cinnamyl, R2 is methyl, and R15 is hydrogen, then W, together with > CH and > C=X, does not form a 2,3-dihydro-1-(3,3-dimethyl-2-oxobutyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one when Rl is 2-(4-chlorophenoxy)-2-methylpropionyl, R2 is methyl, and R15 is hydrogen, then W, together with > CH and > C=X, does not form a 2,3-dihydro-1-methyl-5-(2-pyridyl}-1 H-1,4-benzodiazepin-2-one when R1 is a-methoxyphenylacetyl, R2 is methyl, and R15 is hydrogen, then W, together with > CH and > C=X, does not form a 2,3-dihydro-1-methyl-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one when RI is diphenylacetyl, R2 is methyl, and R15 is hydrogen, then W, together with >CH and >C=X, does not form a 2,3-dihydro-1-methyl-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one when R1 is a-methoxyphenylacetyl, R2 is methyl, and R15 is hydrogen, then W, together with > CH and > C=X, does not form a 2,3-dihydro-1-(3,3-dimethyl-2-oxobutyl)- 5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one when R1 is a-hydroxy-diphenylacetyl, R2 is methyl, and R15 is hydrogen, then W, together with > CH and > C=X, does not form a 2,3-dihydro-1-(3,3-dimethyl-2-oxobutyl)- 5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one when R1 is diphenylacetyl, R2 is methyl, and R15 is hydrogen, then W, together with > CH and > C=X, does not form a 2,3-dihydro-1-(3,3-dimethyl-2-oxobutyl)- 5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one "
when R1 is 2-(chlorophenoxy)-2-methylpropionyl, R2 is methyl, and R15 is hydrogen, then W, together with >CH and >C=X, does not form a 2,3-dihydro-1-(3,3-dimethyl-2-oxobutyl)- 5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one when R1 is diphenylacetyl, R2 is methyl, and R15 is hydrogen, then W, together with > CH and > C=X, does not form a 2,3-dihydro-1-(2-N,N-diethylaminoethyl)- 5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one when R1 is 3,5-difluorobenzoyl, R2 is methyl, and R15 is hydrogen, then W, together with > CH and > C=X, does not form a 2,3-dihydro-1-(2-N,N-diethylaminoethyl)- 5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one when R1 is trans-cinnamyl, R2 is methyl, and R15 is hydrogen, then W, together with > CH and > C=X, does not form a 2,3-dihydro-1-(2-N,N-diethylaminoethyl)- 5-(2-pyridyl}-1H-1,4-benzodiazepin-2-one when R1 is 2-(4-chlorophenoxy)-2-methylpropionyl, R2 is methyl, and R15 is hydrogen, then W, together with >CH and >C=X, does not form a 2,3-dihydro-1-(2-N,N-diethylaminoethyl)- 5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one when R1-N(R'S) is (2,5-dimethoxyphenyl)ureylenyl and R2 is methyl, then W, together with > CH and > C=X, does not form a 2,3-dihydro-1-methyl-5-pheny 1-1 H-1, 4-benzodiazepin-2-one when R1 is D,L-2-pyrrolidinone-5-yl, R2 is methyl, and R15 is hydrogen, then W, together with > CH and > C=X, does not form a 7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one. "
Accordingly, in one of its method aspects, this invention is directed to a method for inhibiting ~i-amyloid peptide release and/or its synthesis in a cell which method comprises administering to such a cell an amount of a compound or a mixture of compounds as described herein effective in inhibiting the cellular release and/or synthesis of ~i-amyloid peptide.
Because the in vivo generation of ~i-amyloid peptide is associated with the pathogenesis of ADg'9, the compounds described herein can also be employed in conjunction with a pharmaceutical composition to prophylactically and/or therapeutically prevent and/or treat AD. Accordingly, in another of its method aspects, this invention is directed to a prophylactic method for preventing the onset of AD in a patient at risk for developing AD by administering to the patient a pharmaceutical composition comprising a pharmaceutically inert carrier and an effective amount of one or more of the compounds described herein.
In yet another of its method aspects, this invention is directed to a therapeutic method for treating a patient with AD in order to inhibit further deterioration in the condition of that patient which method comprises administering to said patient a pharmaceutical composition comprising a pharmaceutically inert carrier and an effective amount of a compound or a mixture of compounds as described herein.
Preferred R' groups include, by way of example, all of the aryl (including substituted aryl), cycloalkyl, and substituted cycloalkyl groups defined for R' above as well as the following additional groups:

WO 99/67221 PC"r/US99/14193 thiophene-2-yl, 2-furanyl, cyclopropyl, cyclobutyl, 1-phenylcyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl, 2-benzofuranyl, 5-chloro-benzofuran-2-yl, 5,5-dimethyl-butyrolactone-4-yl, 4-methylsulfonyl-phenyl, cis-2-phenyl-cyclopropyl, 5-methylsulfonylthiophen-2-yl, 1,8 dimethyl-6-hydroxy-bicyclo[2.2.2]oct-2-yl, 1,4-benzodioxan-2-yl, tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, cyclohex-3-enyl, ~ 3,5-difluorophenyl, 4-methylphenyl, 2-naphthyl, 1-naphthyl, 4-chlorothiophene-yl, 4-cyanophenyl, tetrahydrofuran-2-yl, cyclohex-3-ene-yl, 1,2,3,4-tetrahydronaphth-2-yl, 1,2,3,4-tetrahydronaphth-3-yl, 4-trifluoromethyl-cyclohexyl, bicyclo[2.2. 1] hept-2-yl, bicyclo[2.2.1]hept-5-ene-2-yl, 2,2 dichloropropyl, 2,4-dichlorophenyl, cis-2-methyl-cyclopropyl, 1-(4-chlorophenyl)cyclobutyl, 2-phenylphenyl, 1,2-dihydro-1-oxo-2-phenyl-bicyclo[3.3.1]non-6-ene-3-yl and -CH=CH(~)).
Preferred R1 groups include unsubstituted aryl groups such as phenyl, 1-naphthyl, 2-naphthyl, etc.; substituted aryl groups such as monosubstituted phenyls (preferably substituents at 3 or 5 positions); disubstituted phenyls (preferably substituents at 3 and 5 positions); and trisubstituted phenyls (preferably substituents at the 3,4,5 positions). Preferably, the substituted phenyl groups do not include more than 3 substituents. Examples of substituted phenyls include, for instance, 2-chlorophenyl, 2-fluorophenyl, 2-bromophenyl, 2-hydroxyphenyl, 2-nitrophenyl, 2-methylphenyl, 2-methoxyphenyl, 2-phenoxyphenyl, 2-trifluoromethylphenyl, 4-fluorophenyl, 4-chlorophenyl, 4-bromophenyl, 4-nitrophenyl, 4-methylphenyl, 4-hydroxyphenyl, 4-methoxyphenyl, 4-ethoxyphenyl, 4-butoxyphenyl, 4-iso-propylphenyl, 4-phenoxyphenyl, 4-trifluoromethylphenyl, 4-hydroxymethylphenyl, 3-methoxyphenyl, 3-hydroxyphenyl, 3-nitrophenyl, 3-fluorophenyl, 3-chlorophenyl, 3-bromophenyl, 3-phenoxyphenyl, 3-thiomethoxyphenyi, 3-methylphenyl, 3-trifluoromethylphenyl, 3-(trifluoromethyl)-4-chlorophenyl, 3-chloro-4-cyanophenyl, 3-chloro-4-iodophenyl, 3,4-methylenedioxyphenyl, 4-azidophenyl, 4-cyanophenyl, 4-ethylphenyl, 4-iodophenyl, 4-(phenylcarbonyl)phenyl, 4-(1-othoxy)ethylphenyl, 2,3-dichlorophenyl, 2,3-difluorophenyl, 2,4-dichlorophenyl, 2,5-dimethoxyphenyl, 3,4-dichlorophenyl, 3,4-difluorophenyl, 3,4-methylenedioxyphenyl, 3,4- w dimethoxyphenyl, 3,5-difluorophenyl, 3,5-dichlorophenyl, 3,5-di-(trifluoromethyl)phenyl, 3,5-dimethoxyphenyl, 2,4-dichlorophenyl, 2,4-difluorophenyl, 2,6-difluorophenyl, 3;4,5-trifluorophenyl, 3,4,5-trimethoxyphenyl, 3,4,5-tri-(trifluoromethyl)phenyl, 2,4,6-trifluorophenyl, 2,4,6-trimethylphenyl, 2,4,6-tri-(trifluoromethyl)phenyl, 2,3,5-trifluorophenyl, 2,4,5-trifluorophenyl, 2,5-difluorophenyl, 2-fluoro-3-trifluoromethylphenyl, 4-fluoro-2-trifluoromethylphenyl, 2-fluoro-4-trifluoromethylphenyl, 4-benzyloxyphenyl, 2-chloro-6-fluorophenyl, 2-fluoro-6-chlorophenyl, 2,3,4,5,6-pentafluorophenyl, 2,5-dimethylphenyl, 4-phenylphenyl, 2-fluoro-3-trifluoromethylphenyl.
Other preferred RI groups include, by way of example, adamantyl, benzyl, 2-phenylethyl, 3-phenyl-n-propyi, 4-phenyl-n-butyl, methyl, ethyl, n-propyl, iso-propyl, iso-butyl, sec-butyl, tent-butyl, n-pentyl, iso-valeryl, n-hexyl, cyclopropyl, cyclobutyl, cyclohexyl, cyclopentyl, cyclopent-1-enyl, cyclopent-2-enyl, cyclohex-1-enyl, -CH2-cyclopropyl, -CH2-cyclobutyl, -CH2-cyclohexyl, -CH2-cyclopentyl, -CH2CH2-cyclopropyl, -CH2CH2-cyclobutyl, -CH2CH2-cyclohexyl, -CH2CH2-cyclopentyl, pyrid-2-yl, pyrid-3-yl, pyrid-4-yl, fluoropyridyls (including 5-fluoropyrid-3-yl), chloropyridyls (including 5-chloropyrid-3-yl), thien-2-yl, thien-3-yl, benzothiazol-4-yl, 2-phenylbenzoxazol-5-yl, furan-2-yl, benzofuran-2-yl, thionaphthen-2-yl, thionaphthen-3-yl, thionaphthen-4-yl, 2-chlorothiophen-5-yl, 3-methylisoxazol-5-yl, 2-(thiophenyl)thien-5-yI, 6-methoxythionaphthen-2-yl, 3-phenyl-1,2,4-thiooxadiazol-5-yl, 2-phenyloxazol-4-yl, indol-3-yl, 1-phenyl-tetrazol-5-yl, allyl,, 2-(cyclohexyl)ethyl, (CH3)2CH=CHCH2CH2CH(CH3)-,phenyl-C(O}CH2-, thien-2-yl-methyl, 2-(thien-2-yl)ethyl, 3-(thien-2-yl)-n-propyl, 2-(4-nitrophenyl)ethyl, 2-(4-methoxyphenyl)ethyi, norboran-2-yl, (4-methoxyphenyl)methyl, (2-methoxyphenyl)methyl, (3-methoxyphenyl)methyl, (3-hydroxyphenyl)methyl, (4-hydroxyphenyl)methyl, (4-methoxyphenyl}methyl, (4-methylphenyl)methyl, (4-fluorophenyl)methyl, (4-fluorophenoxy)methyl, (2,4-dichlorophenoxy)ethyl, (4-chlorophenyl)methyl, (2-chlorophenyl)methyl, (1-phenyl)ethyl, (1-(p-chlorophenyl)ethyl, (1-trifluoromethyl)ethyl, (4-methoxyphenyl)ethyl, CH30C(O)CH2-, benzylthiomethyl, 5-(methoxycarbonyl)-n-pentyl, 3-(methoxycarbonyl)-n-propyl, indan-2-yl, (2-methylbenzofuran-3-yl), methoxymethyl, CH3CH=CH-, CH3CH2CH=CH-, (4-chlorophenyl)C(O)CH2-, (4-fluorophenyl}C(O)CH2-, (4-methoxyphenyl)C(O)CH2-, 4-(fluorophenyl)-NHC(O)CH2-, 1-phenyl-n-butyl, (phenyl)2CHNHC(O)CH2CH2-, (CH3)2NC(O)CH2-, (phenyl)2CHNHC(O)CH2CH2-, methylcarbonylmethyl, (2,4-dimethylphenyl)C(O)CH2-, 4-methoxyphenyl-C(O)CH2-, phenyl-C(O)CH2-, CH3C(O)N(phenyl)-, ethenyl, methylthiomethyl, (CH3)3CNHC(O)CH2-, 4-fluorophenyl-C(O)CH2-, diphenylmethyl, phenoxymethyi, 3,4-methylenedioxyphenyl-CH2-, benzo[b]thiophen-3-yl, (CH3)3COC(O)NHCH2-, trans-styryl, H2NC(O)CH2CH2-, 2-trifluoromethylphenyl-C(O)CH2, C(O)NHCH(phenyl)CH2-, mesityl, CH3CH(=NHOH)CH2-, 4-CH3-phenyl-NHC(O)CH2CH2-, C(O)CH(phenyl)CH2-, (CH3)2CHC(O)NHCH(phenyl)-, CH3CH~OCH2-, CH30C( O)CH(CH3)(CH2)3-, 2,2,2-trifluoroethyl, 1-(trifluoromethyl)ethyl, 2-CH3-benzofuran-3-yl, 2-(2,4-dichlorophenoxy)ethyl, phenyl-S02CH2-, 3-cyclohexyl-n-propyl, CF3CH2CH2CH2- and N-pyrrolidinyl.
Still other preferred Rl groups include those set forth in the Tables below.
Each R2 is preferably (and independently for n = 2) selected from the group consisting of alkyl, substituted alkyl, alkenyl, cycloalkyl, aryl, heteroaryl and heterocyclic.
Particularly preferred R2 substituents include, by way of example, methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, tent-butyl, -CH2CH(CH2CH3)2, 2-methyl-n-butyl, 6-fluoro-n-hexyl, phenyl, benzyl, cyclohexyl, cyclopentyl, cycloheptyl, allyl, iso-but-2-enyl, 3-methylpentyl, -CH2-cyclopropyl, -CH2-cyclohexyl, -CH2CH2-cyclopropyl, -CH2CH2- "
cyclohexyl, -CH2-indol-3-yl, p-(phenyl)phenyl, o-fluorophenyl, m-fluorophenyl, p-fluorophenyl, m-methoxyphenyl, p-methoxyphenyl, phenethyl, benzyl, m-hydroxybenzyl, p-hydroxybenzyl, p-nitrobenzyl, m-trifluoromethylphenyl, p-(CH3)2NCH2CH2CH20-benzyl, p-(CH3)3COC(O)CH20-benzyl, p-(HOOCCH20)-benzyl, 2-aminopyrid-6-yl, p-(N-morpholino-CH2CH20)-benzyl, -CH2CH2C(O)NH2, -CH2-imidazol-4-yl, -CH2-(3-tetrahydrofuranyl), -CH2-thiophen-2-yl, -CH2(1-methyl)cyclopropyl, -CH2-thiophen-3-yl, thiophen-3-yl, thiophen-2-yl, -CH2-C(O)O-t-butyl, -CH2-C(CH3)3, -CH2CH(CH2CH3)2, -2-methylcyclopentyl, -cyclohex-2-enyl, -CH[CH(CH3)2]COOCH3, -CH2CH2N(CH3)2, -CH2C(CH3)=CH2, -CH2CH=CHCH3 (cis and traps), -CH20H, -CH(OH)CH3, -CH(O-t-butyl)CH3, -CH20CH3, -(CH2)4NH-Boc, -(CH2)4NH2, -CH2-pyridyl (e.g., 2-pyridyl, 3-pyridyl and 4-pyridyl), pyridyl (2-pyridyl, 3-pyridyl and 4-pyridyl), -CH2-naphthyl (e.g., I-naphthyl and 2-naphthyl), -CH2-(N-morpholino), p-(N-morpholino-CH2CH20)-benzyl, benzo[b]thiophen-2-yl, 5-chlorobenzo[b]thiophen-2-yl, 4,5,6,7-tetrahydrobenzo[b]thiophen-2-yl, benzo[b]thiophen-3-yl, S-chlorobenzo[b]thiophen-3-yl, benzo[b]thiophen-5-yl, 6-methoxynaphth-2-yl, -CH2CH2SCH3, thien-2-yl, and thien-3-yl.
Compounds of this invention include, by way of example, 3-[(N'-(4-methylbenzoyl)-D-phenylglycinyl)]amino-2,3-dihydro- I -methyl-5-phenyl-I H-1,4-benzodiazepin-2-one 3-[(N'-(4-methylbenzoyl)-L-alaninyl)]amino-2,3-dihydro-1-methy l-5-pheny l-1 H-1, 4-benzodiazepin-2-one 3-[(N'-(Diphenylacetyl)-L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1 H-1,4-benzodiazepin-2-one 3-[(N'-(2-Naphthoyl)-L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one 3-[(N'-(1-Naphthoyl}-L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1 H-1,4-benzodiazepin-2-one 3-[(N'-(5-Chloro-2-thiophenecarboxyl)-L-alaninyl)]amino-2, 3-dihydro-1-methyl-5-phenyl-1 H-1,4-benzodiazepin-2-one 3-((N'-(4-Cyanobenzoyl)-L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1 H-1,4-benzodiazepin-2-one 3-[(N'-(Tetrahydro-2-furoyl)-L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1 H-1,4-benzodiazepin-2-one 3-((N'-(3 ,5-Difluorobenzoyl)-L-alaninyl)]amino-2, 3-dihydro-1-methyl-5-phenyl-1 H-1,4-benzodiazepin-2-one 3-[(N'-(3-Cyclohexenecarboxyl)-L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one 3-((N'-(Acetyl}-L-alariinyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one 3-[(N'-( 1,2,3,4-Tetrahydro-2-naphthoyl)-L-alaninyl)]amino-2, 3-d ihydro-1-methy 1-5-pheny 1-1 H-1, 4-benzod iazep in-3-o ne 3-[(N'-(Cyclopentanecarboxyl)-L-alaninyl))amino-2,3-dihydro-1-methyl-S-phenyl-1H-1,4-benzodiazepin-2-one (S)-3-[(N'-(2-phenoxybutyryl)-L-alaninyl)]amino-2,3-dihydro-1-methy 1-5-pheny 1- I H-1,4-benzodiazepin-2-one (S)-3-[(N'-(2-Thiophenecarboxyl)-L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-I H-I ,4-benzodiazepin-2-one (S)-3-((N'-(2,3-Diphenylpropionyl)-L-alaninyl)]amino-2,3-dihydro-I-methyl-5-phenyl-IH-I ,4-benzodiazepin-2-one (S)-3-[(N'-((R, S)-(-)-a-Methoxyphenylacetyl)-L-alaninyl)]amino-2,3-dihydro-I-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one (S)-3-[(N'-(2-Furoyl)-L-alaninyl))amino-2,3-dihydro-I-methyl-5-phenyl-1 H-I ,4-benzodiazepin-2-one (S)-3-[(N'-(2-Phenoxypropionyl)-L-alaninyl)]amino-2,3-dihydro- I-methyl-5-phenyl-1 H-1,4-benzodiazepin-2-one (S)-3-[(N'-(Cyclohexanecarboxyl)-L-alaninyl)]amino-2,3-dihydro-1-methyl-S-phenyl-1H-1,4-benzodiazepin-2-one (S)-3-[(N'-(2-(4-Chlorophenoxy)-2-methylpropionyl)-L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-I ,4-benzodiazepin-2-one WO 99!67221 PCT/US99/14193 (S)-3-[(N'-(Cyclobutanecarboxyl)-L-alaninyl)]amino-2,3-dihydro-I-methyl-S-phenyl-1H-1,4-benzodiazepin-2-one (S)-3-((N'-( 1-Phenyl-I-cyclopropanecarboxyl)-L-alaninyl)]amino=2, 3-dihydro- I-methyl-5-phenyl- I H-I ,4-benzodiazepin-2-one (S)-3-[(N'-(2-Benzofurancarboxyl)-L-alaninyl)]amino-2,3-I O dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one (S)-3-[(N'-(2-Isopropyl-2-pheny!acetyl)-L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1 H-I ,4-benzodiazepin-2-one (S)-3-[(N'-(5-Chlorobenzofuran-2-carboxyl)-L-alaninyl)]amino-2, 3-dihydro-1-methyl-S-phenyl-1 H-1,4-benzodiazepin-2-one (S)-3-[(N'-(2-Ethylhexanoyl)-L-alaninyl)]amino-2,3-dihydro-I -methy I-5-phenyl-1 H- I , 4-benzod iazep in-2-one (S)-3-[(N'-(2-Methylbutyryl)-L-alaninyl)]amino-2,3-dihydro-1-methyl-S-phenyl-1H-1,4-benzodiazepin-2-one (S)-3-[(N'-((R,S)-2-Phenoxypropionyl)-L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one (S)-3-[(N'-(5,S-dimethyl-butyrolactone-4-yl)-L-aIaninyl)]amino-2, 3-dihydro-1-methyl-5-phenyl-IH-1,4-benzodiazepin-2-one (S)-3-[(N'-(2-Methyl-4,4,4-trifluorobutyryl)-L-alaninyl))amino-2,3-dihydro-I-methyl-5-phenyl-IH-1,4-benzodiazepin-2-one S-{N'-(2-phenylpropionyl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one 5-{N'-(tetrahydro-3-furoyl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one 3-[N'-(3 , 5-difluorophenyl-a-methoxyacetyl)-L-alaninyl]-amino-2 , 3-dihydro-1-methyl-5-phenyl-1 H-1,4-Benzodiazepin-2-one 3-[N'-(3,S-difluorophenyl-a-methoxyacetyl)-L-alaninyl]-amino-2, 3-dihydro-1-methyl-5-pheny 1-1 H-1,4-Benzodiazepin-2-one (S)-3-[(N'-(4-(Trifluoromethyl)cyclohexane carboxyl)-L-alaninyl)]amino-2, 3-dihydro-I -methyl-5-phenyl-1 H-1,4-benzodiazepin-2-one (S)-3-[(N'-(Bicyclo[2.2.1]heptane-2-carboxyl)-L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one °°
(S)-3-[(N'-(Bicyclo(2.2.1)hept-5-ene-2-carboxyl)-L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-I,4-benzodiazepin-2-one (S)-3-[(N'-(2,2-Dichlorocyclopropane carboxyl)-L-alaninyl)]amino-2, 3-dihydro-1-methyl-5-phenyl- I H-1,4-benzodiazepin-2-one (S)-3-[(N'-(Cycloheptanecarboxyl)-L-alaninyl)]amino-2,3-dihydro- I -methyl-S-phenyl-1 H-1,4-benzodiazepin-2-one (S)-3-[(N'-(2-Methylvaleryl)-L-alaninyl)]amino-2,3-dihydro-I-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one 3-[(N'-(2-(4-hydroxyphenoxy)propionyl)-L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one (S)-3-[(N' -(a.-(Hydroxymethyl)phenylacetyl)-L-alaniny I)] amino-2,3-dihydro-1-methyl-5-phenyl-1 H-1,4-benzodiazepin-2-one (S)-3-[(N'-(1-(2,4 Dichlorophenyl)cyclopropanecarboxyl)-L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one (S)-3-[(N'-(2-Ethylbutyryl)-L-alaninyl)Jamino-2,3-dihydro-1-methyl-5-phenyl-1 H-1,4-benzodiazepin-2-one (S)-3-[(N'-(2-Methylcyclopropanecarboxyl)-L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one (S)-3-[(N'-( 1-(4-Chlorophenyl)-1-cyclobutanecarboxyl)-L-alaninyl)]amino-2, 3-dihydro-1-methyl-5-phenyl-1 H-1,4-benzodiazepin-2-one (S)-3-[(N' -(2-Biphenylcarboxyl)-L-alaninyl)]amino-2, 3-dihydro-1-methyl-5-phenyl-1 H-1,4-benzodiazepin-2-one (S)-3-[(N'-(Pivalyl)-L-ataninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1 H-1,4-benzodiazepin-2-one (S)-3-[(N'-(trans-Cinnamyl)-L-alaninyl)]amino-2,3-dihydro-1-methy 1-5-pheny 1-1 H-1, 4-benzod iazepin-2-one (S)-3-((N'-(1,2-Dihydro-1-oxo-2-phenyl-4-isoquinolinecarboxyl)-L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1 H-1,4-benzodiazepin-2-one (S)-3-((N'-(Bicyclo (3.3.1)non-6-ene-3-carboxyl)-L-alaninyl}]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one (S)-3-[(N'-(Cyclopropanecarboxyl)-L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one (S)-3-[(N'-(3-furoyl}-L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1 H-1,4-benzodiazepin-2-one (S)-3-[(N'-(2-(4-Cyanophenoxy)-2-methyl propionyl)-L-alaninyl)]amino-2, 3-dihydro-1-methyl-5-phenyl-1 H-1,4-benzodiazepin-2-one (S)-3-((N'-(Diphenylacetyl)-L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1 H-1,4-benzodiazepin-2-one (S)-3-[(N'-(Tetrahydro-2-furoyl)-L-alaninyl)]amino-2.3-dihydro-1-methyl-5-phenyl-1 H-1,4-benzodiazepin-2-one (S)-3-[(N'-(3,5-Difluorobenzoyl)-L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1 H-1.4-benzodiazepin-2-one (S)-3-[(N'-(3-Cyclohexenecarboxyl)-L-alaninyl)]amino-2,3-d ihydro-1-methy 1-5-pheny 1-1 H-1, 4-benzodiazep in-2-one (S)-3-[(N'-( 1,2,3,4-Tetrahydro-2-naphthoyl)-L-alaninyl)]amino-2.3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one (S)-3-[(N'-(Cyclopentanecarboxyl)-L-alaninyl)]amino-2,3-dihydro-1-methyl-S-phenyl-1 H-1,4-benzodiazepin-2-one (S)-3-[(N'-(2-(4-triftuorophenyoxy)propionyl)-L-alaninyl))amino-2, 3-dihydro-I-methyl-5-phenyl-1 H-1,4-benzodiazepin-2-one °' (S)-3-[(N'-(2-(4-Biphenylyloxy)propionyl)-L-alaninyl)]amino-2, 3-dihydro-1-methyl-5-phenyl-1 H-1,4-benzodiazepin-2-one (S)-3-[(N'-(Diphenylacetyl)-L-phenylglycinyl)]amino-2,3-dihydro-I-methyl-5-phenyl-1 H- I ,4-benzodiazepin-2-one (S)-3-[(N'-(4-(methylsulfonyl)benzoyl)-L-alaninyl)]amino 2, 3-dihydro-1-methyl-5-phenyl-1 H-I ,4-benzodiazepin-2-one (S)-3-((N'-(4-chloro-a-methylphenylacetyl)-L-alaninyl)]amino-2, 3-dihydro-1-methyl-5-phenyl- I H-1,4-benzodiazepin-2-one (S)-3-[(N'-(trans-2-Phenyl-I-cyclopropanecarboxyl)-L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2~one (S)-3-[(N'-(4-chloro-a,a-dimethyiphenylacetyl)-L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one (S)-3-[(N'-(5-methylsulfonyl)thiophene-2-carboxyl)-L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one (S)-3-[(N'-( 1, 8-dimethyl-6-Hydroxy-bicyclo(2.2.2)octane-2-carboxyl)-L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl- "
1H-1,4-benzodiazepin-2-one (S}-3-[(N'-((S)-(~+)-2-hydroxy-2-phenylpropionyl)-L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1 H-1,4-benzodiazepin-2-one (S)-3-((N'-{ 1,4-Benzodioxan-2-carboxyl)-L-alaninyl)Jamino-2, 3-d ihydro-1-methyl-5-phenyl-1 H-1,4-benzodiazepin-2-one (S)-3-[(N'-(Tetrahydro-3-furoyl)-L-alaninyl)]amino-2, 3-dihydro-1-methyl-5-phenyl-1 H-1,4-benzodiazepin-2-one (S)-3-[(N'-(Acetyl)-L-phenylglycinyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one (S)-3-[(N'-(3-Cyclohexenecarboxyl)-L-phenylglycinyI)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one (S)-3-((N' -(Cyclopropanecarboxyl)-L-phenylglycinyl)Jamino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one (S)-3-[(N'-(3,5-Difluorobenzoyl)-L-phenylglycinyl}Jamino-2,3-dihydro-1-methyl-5-phenyl-1 H-1,4-benzodiazepin-2-one 3-[(N'-(L-2-pyrrolidinone-5-yl)-L-alaninyl)]amino]-2,3-dihydro-1-methyl-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one °' 3-[(N'-(trans-cinnamyl)-L-alaninyl)]amino]-2,3-dihydro-1-methyl-5-(2-pyridyl}-1 H-1,4-benzodiazepin-2-one 3-[(N'-( 1-phenyl-1-cyclopropanecarboxyl)-L-alaninyl)]amino]-2, 3-dihydro-1-methyl-5-(2-pyridyl)-1 H-1,4-benzodiazepin-2-one 3-[(N'-( 1-phenyl-1-cyclopropanecarboxyl)-L-alaninyl)]amino]-2,3-dihydro-1-(3,3-dimethyl-2-oxobutyl)-5-(2-pyridyl)-1 H-1,4-benzodiazepin-2-one (S}-3-((N'-(a-hydroxy-diphenylacetyl)-L-alaninyl)]amino-2,3-dihydro-1-methyl-5-(2-pyridyl)-1 H-1,4-benzodiazepin-2-one 3-[(N'-(3,5-difluorobenzoyl)-L-alaninyl)]amino]-2,3-dihydro-1-(3,3-dimethyl-2-oxobutyl)- 5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one 3-[(N'-(L-2-pyrrolidinone-5-yl)-L-alaninyl)]amino]-2,3-dihydro-1-(3,3-dimethyl-2-oxobutyl)- 5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one (S)-3-[(N'-(a-hydroxy-diphenylacetyl)-L-alaninyl)]amino-2,3-dihydro-1-2-(diethylamino)ethyl-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one 3-[(N'-(1-phenyl-1-cyclopropanecarboxyl)-L-alaninyl)]amino)-2,3-dihydro-I-(2-N,N-diethylaminoethyl)-5-(2-pyridyl)-1 H-1,4-benzodiazepin-2-one 3-((N'-(a-methoxyphenylacetyl)-L-alaninyl)]amino]-2,3-dihydro-1-(2-N,N-diethylaminoethyl)- 5-(2-pyridyl)-IH-1,4-benzodiazepin-2-one 3-(S)-[2-(( 1 H)-isoquinoline-3 ,4-dihydro-3-oxo)-2-methyl-acetyl]-amino-2,3-dihydro-1-methyl-5-phenyl-1 H-1,4-benzodiazepin-2-one 3-(S)-[2-(( 1 H)-isoquinoline-3 ,4-dihydro-3-oxo)-2-methyl-acetyl]-amino-2, 3-dihydro-1-methyl-5-phenyl-1 H-1,4-benzodiazepin-2-one (S)-3-[(N'-((trans-2-Phenylcyclopropyl)ureylenyl)-L-alaninyl)]amino-2, 3-dihydro-1-methyl-5-phenyl=1 H-1,4-benzodiazepin-2-one (S)-3-[(N'-((3,4-Dichlorophenyi)ureylenyl)-L-alaninyI)]amino-2, 3-dihydro-1-methyl-5-phenyl-1 H-1,4-benzodiazepin-2-one (S)-3-[(N'-((2-propenyl)ureylenyl)-L-alaninyl)]amino-2,3-dihydro-1-methy 1-S-pheny 1-1 H-1, 4-benzod iazepin-2-one (S)-3-[(N'-((R)-(-)-I-( 1-Naphthyl)ethyl)ureylenyl)-L-alaninyl)]amino-2,3-dihydro-I-methyl-5-phenyl-IH-1,4-benzodiazepin-2-one (S)-3-[(N'-((2,6-Diisopropylphenyi)ureylenyl)-L-alaninyl)]amino-2.3-dihydro-I-methyl-5-phenyl-IH-1,4-I 0 benzodiazepin-2-one (S)-3-[(N'-((3-[(Trifluoromethyl)phenyl)ureylenyl)-L-alaninyl)]amino-2.3-dihydro-I -methyl-5-phenyl-1 H-1,4-benzodiazepin-2-one (S)-3-[(N'-((Phenyl)ureylenyl)-L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one (S)-3-((N' -((4-ethoxycarbonylphenyl)ureylenyl)-L-alaninyl)]amino-2,3-dihydro-I-methyl-S-phenyl-1H-1,4-benzodiazepin-2-one (S)-3-[(N'-((2-Bromophenyl)ureylenyl)-L-alaninyl)]amino 2,3-dihydro-I-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one (S)-3-[(N'-((o-Tolyl)ureylenyl)-L-alaninyl)]amino-2,3 dihydro-1-methyl-5-phenyl-1 H-1,4-benzodiazepin-2-one (S)-3-[(N'-((2-Ethyl-6-methylphenyl)ureylenyl)-L-alaninyl)]amino-2,3-dihydro-1-methyl-~-phenyl-1H-1,4-benzodiazepin-2-one ..
(S)-3-[(N'-((2-Fluorophenyl)ureylenyl)-L-alaninyl)]amino-2, 3-dihydro-1-methyl-5-phenyl-1 H-1,4-benzodiazepin-2-one (S)-3-[(N'-((2,4-difluorophenyl)ureylenyl)-L-alaninyl)]amino-2, 3-dihydro-1-methyl-5-phenyl-1 H-1,4-benzodiazepin-2-one (S)-3-[(N'-((2-Ethoxyphenyl)ureylenyl)-L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1 H-1,4-benzodiazepin-2-one (S)-3-[(N'-((3-Acetylphenyl)ureylenyl)-L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1 H-1,4-benzodiazepin-2-one (S)-3-[(N'-((3-[(cyano)phenyl)ureylenyl)-L-alaninyl)]amino-2, 3-dihydro-1-methyl-5-phenyl-1 H-1,4-benzodiazepin-2-one (S)-3-[(N'-((Phenethyl)ureylenyl)-L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-henzodiazepin-2-one (S)-3-[(N'-((4-n-Butylphenyl)ureylenyl)-L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1 H-1,4-benzodiazepin-2-one (S)-3-[(N'-((Octyl)ureylenyl)-L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1 H-1,4-benzodiazepin-2-one (S)-3-[(N'-((4-Biphenyl)ureylenyl)-L-alaninyl)]amino-2,3-dihydro- I-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one (S)-3-[(N'-((4-Isopropylphenyl)ureylenyl)-L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-IH-I,4-benzodiazepin-2-one (S)-3-[(N'-((Hexyl)ureylenyl)-L-alaninyl)]amino-2,3-dihydro- I-methyl-5-phenyl-I H-I ,4-benzodiazepin-2-one (S)-3-[(N'-((2-Isopropylphenyl)ureylenyl)-L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-I ,4-benzodiazepin-2-one (S)-3-[(N'-((2,6-Difluorophenyl)ureylenyl)-L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-I ,4-benzodiazepin-2-one (S)-3-[(N'-((Octadecyl)ureylenyl)-L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1 H- I ,4-benzodiazepin-2-one (S)-3-[(N' -((4-(Trifluoromethoxy)phenyl)ureylenyl)-L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-IH-1,4-benzodiazepin-2-one (S)-3-[(N'-((2,4-Dichlorophenyl)ureylenyl)-L-alaninyl)]amino-2,3-dihydro- I-methyl-5-phenyl-1 H-1,4-benzodiazepin-2-one (S)-3-[(N'-((3-Ethoxycarbonylphenyl)ureylenyl)-L-alaninyl)]amino-2, 3-dihydro-1-methyl-5-phenyl-1 H-I ,4-benzodiazepin-2-one (S)-3-[(N'-((4-Chlorophenyl)ureylenyl)-L-alaninyl)]amino-2,3-dihydro-1-rriethyl-5-phenyl-1H-1,4-benzodiazepin-2-one (S)-3-[(N'-((4-butoxyphenyl)ureylenyl)-L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one (S)-3-[(N'-((4-Phenoxyphenyl)ureylenyl)-L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1 H-1,4-benzodiazepin-2-one (S)-3-[(N'-(( 1-Naphthyl)ureylenyl)-L-alaninyl)]amino-2,3-dihydro-I-methyl-5-phenyl-IH-1,4-benzodiazepin-2-one (S)-3-[(N'-((2-Biphenyl)ureylenyl)-L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-IH-1,4-benzodiazepin-2-one (S)-3-[(N'-((2-(Methylthio)phenyl)ureylenyl)-L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one (S)-3-[(N'-((2-Ethylphenyl)ureylenyl}-L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one (S)-3-((N'-((3-Methoxyphenyl)ureylenyl)-L-alaninyl)]amino-2, 3-dihydro-1-methyl-5-phenyl-1 H-1,4-benzodiazepin-2-one (S)-3-[(N'-((3,4,5-Trimethoxyphenyl)ureylenyl)-L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one (S)-3-[(N'-((2,4,6-Trimethylphenyl)ureylenyI)-L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one (S)-3-[(N'-((2-methyl-6-t-butylphenyl)ureylenyl)-L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1 H-1,4-benzodiazepin-2-one (S)-3-[(N'-((2-(2-thiophene-yl)ethyl)ureylenyl)-L-alaninyl)Jamino-2, 3-dihydro- I-methyl-5-phenyl-1 H- I ,4-benzodiazepin-2-one 3-[N'-3.5-difluorophenyl-acetamido)-L-alaninyl)-3-amino-2, 3-dihydro 1-methyl-5-phenyl-1 H-1,4-benzodiazepine 3-[N'-3,5-difluorophenyl-a-azidoacetyl)-L-alaninyl]-3-amino-2,3-dihydrol-methyl-5-phenyl-1H-1,4-benzodiazepine S-{N'-(cyclopropane carboxyl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,dJazepin-6-one 5- { N' -(2-methylhexanoy 1)-L-alaniny 1 } -amino-7-methy l-5 , 7-dihydro-6H-dibenz[b,d]azepin-6-one 5-{N'-(bicyclo[2.2.1]heptane-2-carboxyl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one 5-{N'-(N-acetyl-N-phenylglycinyl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one 5-{N'-((aminoacetoxy)-3,5-difluorophenylacetyl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6H-dibertz[b,dJazepin-6-one 3-[N'-(3,5-difluorophenyl-a-(2-aminoacetoxy)acetyl)-L-alaninyl)-amino-2, 3-dihydro-1-methyl-5-phenyl-1 H-1,4-Benzodiazepin-2-one 5-{N'-(diphenylacetyl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one 5-{N'-(acetyl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one 5-{N'-(2-phenoxyphenylacetyl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6I-I-dibenz[b,d]azepin-6-one 5-{ N' -(trans-c innamyl)-L-alaniny 1 }-amino-7-methyl-5 , 7-dihydro-6H-dibenz[b,d]azepin-6-one 5-{ N' -(tetrahydro-2-furoy 1)-L-alaninyl}-amino-7-methyl-5 , 7-dihydro-6H-dibenz[b,d]azepin-6-one S-{N'-(cyclopentanecarboxyl)L-alaninyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one 5-{N'-(2-thiophenecarboxyl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one 5-{N'-((S)-( +)-2-hydroxy-2-phenylpropionyl)-L-alaninyl}
amino-7-methyl-5 , 7-d ihydro-6H-d ibenz [b, d] azepin-6-one 5-{N'-((R)-(-)-2-hydroxy-2-phenylpropionyl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one 3-[N'-(3,5-difluorophenyl-a-hydroxy-a-methyIacetyl)-L-alaninyl]-amino-2,3-dihydro-1-methyl-5-(2-fluorophenyl)-I H- I ,4-Benzodiazepin-2-one 5-{N'-(benzenesulfonyl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one 3-[N'-(3,5-difluorophenyl-a-hydroxy-a-meihylacetyl)-L-aianinyl]-amino-2,3-dihydro-I-methyl-5-(2-fluorophenyl)-1 H-1,4-Benzodiazepin-2-one S-{N'-(3-fluorobenzenesulfonyl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one 5-(S)-(N'-((Butylureylenyl)-L-alaninyl)-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one 5-(S)-(N'-((Benzylureylenyl)-L-alaninyl)-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one 5-{N'-(benzylsulfonyl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one 5-(S)-(N'-((Ethylureylenyl)-L-alaninyl)-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d)azepin-6-one 5-(S)-(N'-((Phenethylureylenyl)-L-alaninyl)-amino-7-methyl-5,7-dihydro-6H-dibenz(b,d]azepin-6-one 5-(S)-(N'-(3 , S-difluorophenyl-a-aminoacetyl)-L-val inyl]-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one IS
-(S)-(N'-(3 , 5-difluorophenyl-a-aminoacetyl)-L-tert-leucinyl-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one 5-{N'-(butylsulfonyl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one S-{N'-(octylsulfonyl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one 5-(S)-(N'-((2-(thiophen-2-yl)ethylureylenyl)-L-alaninyl)-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one 5-(S}-(N'-(3,S-difluorophenyl-a-aminoacetyl)-L-alaninyl-amino-7-methyl-5 ,7-dihydro-6H-dibenz[b,d)azepin-6-one S-(S)-(N'-(L-valinyl)-L-alaninyl-)]amino-2,3-dihydro-1-methyl-5-phenyl-1 H-1,4-benzodiazepin-2-one S-(R/S)-(N'-(2-hydroxy-2-phenethylureylenyl)-L-alaninyl)-amino-7-methyl-5 , 7-d ihydro-6H-d ibenz [b, d] azepin-6-one 5-(S)-(N'-((hexylureylenyl)-L-alaninyl)-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one 5-(S)-(N'-((cyclohexylureylenyl)-L-alaninyl)-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one 5-(S)-(N'-((isopropylureylenyl)-L-alaninyl)-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one 5-(S)-(N'-((tert-butylureylenyl)-L-alaninyl)-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one 5-(S)-(N'-(( 1-adamantylureylenyl)-L-alaninyl)-amino-7-methyl-5,7-dihydro-6H-dibenz(b,d]azepin-6-one 5-(S)-(N'-((2-methylpropylureylenyl)-L-alaninyl)-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one 5-(S)-(N'-(R/S)-3-hydroxy-3-phenyiethylureylenyl)-L-alaninyl)-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one S-(S)-(N'-((3-methylbutylureylenyI)-L-alaninyl)-amino-7-methyl-S,7-dihydro-6H-dibenz(b,d]azepin-6-one S-(S)-((N'-(S)-I-hydroxymethyI-3-methylbutylureylenyl)-L-S alaninyl)-amino-7-methyl-S,7-dihydro-6H-dibenz(b,d]azepin-6-one S-(S)-((N'-( 1 S)-(2S)-1-hydroxymethyl-2-methylbutylureylenyl)-L-alaninyl)-amino-7-methyl-S,7-dihydro-6H-dibenz(b,d]azepin-6-one S-(S)-(N'-(3-chloropropylureylenyl)-L-alaninyl)-amino-7-methyl-S , 7-dihydro-6H-dibenz(b,d]azepin-6-one 1 S S-(S)-(N'-octylureylenyl)-L-alaninyl)-amino-7-methyl-S,7-dihydro-6H-dibenz[b,d]azepin-6-one S-(S)-(N'-1,1,3,3-tetramethylbutylureylenyl)-L-alaninyl)-amino-7-methyl-S,7-dihydro-6H-dibenz[b,d]azepin-6-one S-(S)-(N'-(R/S)-1-methylbutylureylenyl)-L-alaninyl)-amino-7-methyl-S,7-dihydro-6H-dibenz[b,d]azepin-6-one S-(S)-((N'-(R/S)-1-hydroxymethylbutylureylenyl)-L-2S alaninyl)-amino-7-methyl-S,7-dihydro-6H-dibenz[b,d]azepin-6-one S-(S)-((N'-(R/S)-1, 3-dimethylbutylureylenyl)-L-alaninyl)-amino-7-methyl-S,7-dihydro-6H-dibenz[b,d]azepin-6-one 5-(S)-((N'-(R)-1-hydroxymethyl-3-methylbutylureylenyl)-L-alaninyl)-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one S-(S)-((N'-(R/S)-2-methylbutylureylenyl)-L-alaninyl)-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one 5-(S)-(N'-morphoiinoureylenyl)-L-alaninyl)-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one 5-(S)-(N'-(2-(2-hydroxyethoxy)-ethylureylenyl_)-L-alaninyl)-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one 5-(S)-(N'-piperidinylureylenyI)-L-alaninyl)-amino-7-methyl-IS 5,7-dihydro-6H-dibenz[b,d]azepin-6-one 5-(S)-(N'-(N"-methyl-N"-butylureylenyl)-L-alaninyl)-amino-7-methy 1-5 ,7-dihydro-6H-dibenz[b,d]azepin-6-one 5-(S)-(N'-(1-(R/S)-hydroxymethylcyclopentylureylenyl)-L-alaninyl)-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one 5-(S)-(N'-(4-hydroxybutylureylenyl)-L-alaninyl)-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one 5-(S)-(N'-( 1-(R/S)-hydroxymethyl-2-methylpropylureylenyl)-L-alaninyl)-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one 5-(S)-(N'-(2-(R/S)-hydroxycyclohexylureylenyl)-L-alaninyl)-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one 5-(S)-(N'-(isopropyl-hydroxyureylenyl)-L-alaninyl)-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one 5-(S)-(N'-(benzyl-hydroxyureylenyl)-L-alaninyl)-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one S-(S)-(N'-(valinyl)-L-alaninyl-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one 5-(S)-(N'-(phenylglycinyl)-L-alaninyl-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one 5-(S)-(N'-(3,5-difluorophenyt-a-aminoacetyl)-L-alaninyl-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one 5-(S)-(N'-(3,5-difluoro phenylglycinyl)-L-alaninyl-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one 5-(S)-(N'-(threonine)-L-alaninyl-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one 5-(S)-(N'-(D-valinyl)-L-alaninyl-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one 5-(S)-(N'-(phenylglycinyl)-L-alaninyl-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one -4.6-5-(S)-(N"-(S)-phenylglycinyl)-N'-L-alaninyl]amino-1-methyl-S-phenyl-1,3,4, 5-tetrahydro-2H-1,5-benzodiazepin-2-one 5-(S)-[(N"-L-valinyl)-N'-L-alaniny I J amino-1-methy I-5-phenyl-1, 3 ,4,5-tetrahydro-2H-1,5-benzodiazepin-2-one 5-(S)-(N'-(thiomorpholinylureylenyl)-L-alaninyl)-amino-7-methyl-5.7-dihydro-6H-dibenz[b,d]azepin-6-one 5-(S)-(N'-(2(R/S)-hydroxybutylureylenyl)-L-alaninyl)-amino-7-methyl-5 , 7-dihydro-6H-dibenz[b,d] azepin-6-one 5-(S)-(N'-2,2.2-trifluoroethylureylenyl)-L-alaninyl)-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one 5-(S)-(N'-(4R/S)-cyclohexylureyienyl)-L-alaninyl)-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one 5-(S)-(N'-( 1 R)-hydroxymethyl-3-methylthiopropylureylenyl)-L-alaninyl)-amino-7-methyl-5,7-dihydro-6H-dibenz[b,dJazepin-6-one S-{N'-(2-hydroxy-2-methylpropionyl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one 5-{ N' -(2-hydroxy-2-methylbutanoy 1)-L-alaniny 1 }-amino-7-methyl-5,7-dihydro-6H-dibenz[b,djazepin-6-one 3-[N'-(2-thioacetyl-3-methyl-butanoyl)-L-alaninyl]-amino-2,3-dihydro-1-methyl-5-phenyl-1 H-1,4-benzodiazepin-2-one 5-(S)-(N'-(2-thioacetyl-3-methyl-butanoyl)-L-alaninylj-amino-7-methyl-5 , 7-dihydro-6H-dibenz[b,d] azepin-6-one 5-(S)-[N'-(L-Trifluoromethylphenylglycinyl}-L-aianinyl]-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one 5-(S)-[N'-(L-N-methyl-valinyl)-L-alaninyl]
-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one 5-(S)-(N"-(3,5-difluorophenylglycinyl)-N'-L-alaninyl)amino-2,4-dioxo-1-methyl-5-phenyl-2 , 3,4,5-tetrahydro-2H-1, 5-benzodiazepine hydrochloride 5-(S)-(N"-(3,5-difluorophenylglycinyl)-N'-L-alaninyl]amino-2,4-dioxo-1-methyl-S-phenyl-2,3,4,5-tetrahydro-2H-1,5-benzodiazepine hydrochloride 5-(S)-[N'-(Hexafluorovalinyl)-L-alaninyl]-amino-7-methyl-5, 7-dihydro-6H-dibenz[b,d]azepin-6-one 3-[N'-(2-mercapto-3-methyl-butanoyl)-L-alaninyl]-amino-2 , 3- dihydro-1-methyl-5-phenyl-1 H-1,4-benzodiazepin-2-one 5-(S)-[N'-(2-mercapto-3-methylbutanoyl}-L-alaninyl]-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one Additional examples of suitable compounds include:
5-(S)-[N'-(2-Amino-3,3,3-trifluoromethylbutyryl)-L-alaninyl]-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one 5-(S)-[N'-(2-amino -5,5,5-trifluoropentanyl)-L-alaninyl]-amino-7-methyl-5,7-dihydro-6H-dibenz(b,d)azepin-6-one 5-(S)-[N'-( 2-amino-4,4,4-trifluorobutyryl)-L-alaninyl]-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one 1-(S)-(N'-(2-Amino-3,3,3-trifluorobutyryl)-L-alaninyl]-amino-3-methyl-4,5.6,7-tetrahydro-2H-3-benzazepin-2-one I-(S)-[N'-(2-Amino-5,5,5-trifluoropentanoyl)-L-alaninyl]-amino-3-methyl-4,5,6,7-tetrahydro-2H-3-benzazepin-2-one 1-(S)-[N'-(2-Amino-4,4,4-trifluorobutyryl)-L-alaninyl]-amino-3-methyl-4,5,6,7-tetrahydro-2H-3-benzazepin-2-one 1-(S}-[N'-(2-Aminobutyryl)-L-alaninyl]-amino-3-methyl-4,5,6,7-tetrahydro-2H-3-benzazepin-2-one 1-(S)-[N'-(Hexafluorovalinyl)-L-alaninyl]-amino-3-methyl-4,5,6,7-tetrahydro-2H-3-benzazepin-2-one 1-(S)-[N'-(L-2-Aminobutyryl)-L-alaninyl]-amino-3-(2-methylpropy l)-4, 5 , 6, 7-tetrahydro-2H-3-benzazepin-2-one Preferred cyclic groups defined by W and -C(H~C(=X)- include cycloalkyl, lactone, lactam, benzazepinone, dibenzazepinone and benzodiazepine groups. In one preferred embodiment; the cyclic group defined by W and -C(H)pC(=X)-, forms a cycloalkyl group of the formula:
_cH r wherein T is selected from the group consisting of alkylene and substituted alkylene.

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

T
-C(H) <.
CH
.~
OH
or T
-C(H}v CH
SH
wherein p is zero or one, T is selected from the group consisting of alkylene, substituted alkylene, alkenylene, substituted alkenylene, -(RZ'Z)qR'-'- and -ZRZ'-, where Z is a substituent selected from the group consisting of -O-, -S- and > NR20, each R20 is independently selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, substituted alkyl, substituted alkenyl, substituted alkynyl, aryl, heteroaryl and heterocyclic, each RZ' is independently alkylene, substituted alkylene, alkenylene and substituted alkenylene with the proviso that when Z is -O- or -S-, any unsaturation in the alkenylene and substituted alkenylene does not involve participation of the -O- or -S-, and q is an integer of from 1 to 3.
Particularly preferred alcohol or thiol substituted groups include ~R')w (R')w OH
OH
Mt Mt Ho Mr ~)w (R')w OH OH
wherein each V is independently selected from the group consisting of hydroxy, acyl, acyloxy, alkyl, substituted alkyl, alkoxy, substituted alkoxy, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, amino, substituted amino aminoacyl, alkaryl, aryl, aryloxy, carboxyl, carboxylalkyl, cyano, halo, vitro, heteroaryl, thioalkoxy, substituted thioalkoxy, trihalomethyl and the like;
each Ra is independently selected from the group consisting of alkyl, substituted alkyl, alkoxy, substituted alkoxy, amino, substituted amino carboxyl, carboxyl alkyl, cyano, halo, and the like; t is an integer from 0 to 4; and w is an integer from 0 to 3.

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

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

(R')w Mc -SS-wherein each V is independently selected from the group consisting of hydroxy, acyl, acyloxy, alkyl, substituted alkyl, alkoxy, substituted alkoxy, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, amino, substituted amino aminoacyl, alkaryl, aryl, aryloxy, carboxyl, carboxylalkyl, cyano, halo, nitro, heteroaryl, thioalkoxy, substituted thioalkoxy, trihalomethyl and the like;
each Ra is independently selected from the group consisting of alkyl, substituted alkyl, alkoxy, substituted alkoxy, amino, substituted amino carboxyl, carboxyl alkyl, cyano, halo, and the like; t is an integer from 0 to 4; and w is an integer from 0 to 3.
Preferably t is an integer from 0 to 2 and, more preferably, is an integer equal to 0 or 1.
In another preferred embodiment, the cyclic group defined by W, together with -C(H)pC(=X)-, forms a ring of the formula:

T
-C(H)p ~O
C
IC

T
-C(H)p C /S
O

T
--C(H)p /O
C
S
or T
-C(H)p S
C
S
wherein p is zero or one, T is selected from the group consisting of alkylene, substituted alkylene, alkenylene, substituted alkenylene, -(R21Z)qR21- and -where Z is a substituent selected from the group consisting of -O-, -S- and > NR20, each R20 is independently selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, substituted alkyl, substituted alkenyl, substituted alkynyl, aryl, heteroaryl and heterocyclic, each R21 is independently S alkylene, substituted alkylene, alkenylene and substituted alkenylene with the proviso that when Z is -O- or -S-, any unsaturation in the alkenylene and substituted alkenylene does not involve participation of the -O- or -S-, and q is an integer of from 1 to 3.
Particularly preferred lactone and thiolactone groups include:
Mt ~R~)w ~ ~ ~R~~w o wherein each V is independently selected from the group consisting of hydroxy, acyl, acyloxy, alkyl, substituted alkyl, alkoxy, substituted alkoxy, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, amino, substituted amino aminoacyl, alkaryl, aryl, aryloxy, carboxyl, carboxylalkyl, cyano, halo, nitro, heteroaryl, thioalkoxy, substituted thioalkoxy, trihalomethyl and the Like;
each Ra is independently selected from the group consisting of alkyl, substituted alkyl, alkoxy, substituted alkoxy, amino, substituted amino carboxyl, carboxyl alkyl, cyano, halo, and the like; t is an integer from 0 to 4; and w is an integer from 0 to 3.

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

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

Particularly preferred lactam and thiolactam groups include:
Mt ~R'~w / ~
v N ~R° N~ Re I
O
M R:) r m -Mt (R')w i R~
NwRb N
yRe M.
Mr (Rs)w (R'~w J
N
Oj ~Rb O~ Re (R ?w (R'~w ~- N
l0 , O'' ~Rb ~Re Mt Mt (R')w ~R~)w \
is NJ
O~ ~Rb .
Re Q' Mt f yRa~ I O N
N ~ I ~ Mt 20 O \R° p~N~ a R
Rc Re O N '~. . N ~-Mc 2s ~ , Mt N ~ i R~
N ~ \ N
Mt ~ j N
N_ _ O Ro.

wherein A-B is selected from the group consisting of alkylene, alkenylene, substituted alkylene, substituted alkenylene and -N=CH-; Q is oxygen or sulfur;
each V is independently selected from the group consisting of hydroxy, acyl, ..
acyloxy, alkyl, substituted alkyl, alkoxy, substituted alkoxy, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, amino, substituted amino aminoacyl, alkaryl, aryl, aryloxy, carboxyl, carboxylalkyl, cyano, halo, nitro, heteroaryl, thioalkoxy, substituted thioalkoxy, trihalomethyl and the like; each Ra is independently selected from the group consisting of alkyl, substituted alkyl, alkoxy, substituted alkoxy, amino, substituted amino carboxyl, carboxyl alkyl, cyano, halo, and the like; Rb is selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, acyl, aryl, heteroaryl, heterocyclic, and the like; Rc is selected from the group consisting of alkyl, substituted alkyl, alkenyl, substituted alkenyl, aryl, heteroaryl, heterocyclic, thioalkoxy, substituted amino, cycloalkyl, and substituted cycloalkyl; t is an integer from 0 to 4; t is an integer from 0 to 3; and w is an integer from 0 to 3.
Preferably t is an integer from 0 to 2 and, more preferably, is an integer equal to 0 or 1.
In one preferred embodiment of this invention, W is a cyclic group of the formula:
~Rs~p -_. _ ~R~~q N~
R
O
wherein _6ø_ each R6 is independently selected from the group consisting of acyl, acylamino, acyloxy, alkenyl, substituted alkenyl, alkoxy, substituted alkoxy, alkyl, substituted alkyl, alkynyl, substituted alkynyl, amino, substituted amino, aminoacyl, aryl, aryloxy, carboxyl, carboxyalkyl, cyano, cycloalkyl, substituted cycloalkyl, halo, heteroaryl, heterocyclic, nitro, thioalkoxy, substituted thioalkoxy, thioaryloxy, thioheteroaryloxy, -SO-alkyl, -SO-substituted alkyl, -SO-aryl, -SO-heteroaryl, -SOZ-alkyl; -SO~-substituted alkyl, -SOZ-aryl, and -SOZ-heteroaryl;
each R' is independently selected from the group consisting of acyl, acylamino, acyloxy, alkenyl, substituted alkenyl, alkoxy, substituted alkoxy, alkyl, substituted alkyl, alkynyl, substituted alkynyl, amino, substituted amino, aminoacyl, aryl, aryloxy, carboxyl, carboxyalkyl, cyano, cycloalkyl, substituted cycloalkyl, halo, heteroaryl, heterocyclic, nitro, thioalkoxy, substituted thioalkoxy, thioaryloxy, thioheteroaryloxy, -SO-alkyl, -SO-substituted alkyl, -SO-aryl, -SO-heteroaryl, -SO~-alkyl, -SO,-substituted alkyl, -SO,-aryl, and -SO~-heteroaryl;
R8 is selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyi, substituted alkynyl, acyl, aryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heteroaryl and heterocyclic;
p is an integer from 0 to 4; q is an integer from 0 to 4.
Preferably, R6 and R' are independently selected from the group consisting of alkoxy, substituted alkoxy, alkyl, substituted alkyl, amino, substituted amino, carboxyl, carboxyalkyl, cyano, halo, nitro, thioalkoxy and substituted thioalkoxy.
More preferably, when present, R6 and R' are fluoro.

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

wherein R6 and p are as defined herein.
In yet another preferred embodiment of this invention, W is a cyclic ring of S the formula:
O
wherein R6 and p are as defined herein.
In still another preferred embodiment of this invention, W is a cyclic ring of the formula:
~R9~9 ~Rs~p ~R9~s ~N~

O
wherein R6, Rg and p are as defined herein; and each R9 is independently selected from the group consisting of alkyl, substituted alkyl, alkenyt, substituted alkenyl, alkynyl, substituted alkynyl, aryl, cyctoalkyl, substituted cyctoalkyl, cycloalkenyl, substituted cycloalkenyl, 1 S heteroaryt and heterocyctic; and g is an integer from 0 to 2.
When present, R9 is preferably alkyl or substituted alkyl.

In another preferred embodiment of this invention, W is a cyclic ring of the formula:
~Rfi~p \
~R9~9 ~R9~9 N~

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

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

O

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

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

WO 99/67221 PG"T/US99/14193 ~Rs~c ~~N ~ I
N~

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

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

WO 99/67221 PC'T/US99/14193 T
-C(H)p , CH
NR~R~
wherein p is zero or one, T is selected from the group consisting of alkylene, substituted alkylene, alkenylene, substituted alkenylene, -(R21Z)qR21- and -, where Z is a substituent selected from the group consisting of -O-, -S- and > NR2~, each R20 is independently selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, substituted alkyl, substituted alkenyl, substituted alkynyl, aryl, heteroaryl and heterocyclic, each R21 is independently aIkylene, substituted alkylene, alkenylene and substituted alkenylene with the proviso that when Z is -O- or -S-, any unsaturation in the alkenylene and substituted alkenylene does not involve participation of the -O- or -S-, and g is an integer of from 1 to 3.
In another preferred embodiment, R'S is H, R' is alkyl or aryl, Rb is alkyl, substituted alkyl, cycloalkyl or aryl, RZ is methyl, and the compound is a compound of Formulas I, II or VI.
This invention also provides for novel pharmaceutical compositions comprising a pharmaceutically inert carrier and one or more of the compounds described in Formulas I-VI above.
Still further, this invention provides for novel compounds of Formulas I-VI:

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

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

wherein R1 is selected from the group consisting of alkyl, alkenyl, alkynyl, "
cycloalkyl, cycloalkenyl, substituted alkyl, substituted alkenyl, substituted alkynyl, substituted cycloalkyl, substituted cycloalkenyl, aryl, heteroaryl and heterocyclic;
R'is selected from the group consisting of aryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heteroaryl, heterocyclic, -CH3, -CH=CHI, -CH=CHR', -CH=CR'R', -CR'=CHZ, -CR'=CHR', -CR'=CR'R', -C=CH and -C=CR'; with the proviso that when R' is heteroaryl or heterocyclic, there is no N in R' at a position beta to the C=Q group;
Q is S or O;
R'S is selected from the group consisting of hydrogen, alkyl, substituted alkyl, aryl, heterocyclic and heteroaryl;
R'S' is selected from the group consisting of hydrogen, hydroxyl, alkyl, I S substituted alkyl, aryl, heterocyclic and heteroaryl;
W, together with -C(H)pC(=X)-, forms a cycloalkyl, cycloalkenyl, heterocyclic, substituted cycloalkyl, or substituted cycloalkenyl group wherein each of said cycloalkyl, cycloalkenyl, heterocyclic, substituted cycloalkyl or substituted cycloalkenyl group is optionally fused to form a bi- or multi-fused ring system (preferably no more than 5 fused rings) with one or more ring structures selected from the group consisting of cycioalkyl, cycloalkenyl, heterocyclic, aryl and heteroaryl group which, in turn, each of such ring structures are optionally substituted with 1 to 4 substituents selected from the group consisting of hydroxyl, keto, thioketo, , halo, alkoxy, substituted alkoxy, thioalkoxy, substituted thioalkoxy, nitro, cyano, carboxyl, carboxyl esters, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, amino, substituted amino, -NHC(O)R4, -NHS02R4, -C(O)NH2, -C(O)NHR4, -C(O)NR4R4, -S(O)R4, -S(O)2R4, -S(O)2NHR4 and -S(O)2NR4R4, where each R4 is independently selected from the group consisting of alkyl, substituted alkyl, aryl and heteroaryl;
X is selected from the group consisting of oxo (=O), thiooxo (=S), hydroxyl (-H, -OH), thiol (H,-SH) and hydro (H,H);
Y is represented by the formula:
Rz /CH ~ / 1VH
C
O
20 wherein each RZ is independently selected from the group consisting of alkyl, substituted alkyl, alkenyl, substituted alkenyI, alkynyl, substituted alkynyl, cycloalkyl, aryl, heteroaryl and heterocyclic;
Z is represented by the formula -T-C(X')(X")C(O)- where T is selected from the group consisting of a bond covalently linking Rl to -C(X')(X")-, oxygen, sulfur, and -NRS where RS is hydrogen, acyl, alkyl, substituted alkyl, aryl, heterocyclic or heteroaryl group;
RS is hydrogen, alkyl, substituted alkyl, aryl, heterocyclic or heteroaryl group;

X' and X" are independently selected from the group consisting of hydrogen, fluoro, alkyl, substituted alkyl, aryl, heteroaryl, heterocyclic, -ORS', -SRS, -N(RS)2, -N(CO)OR'S and -N3, with the proviso that at least one of X' or X"
is other than hydrogen, hydroxy or fluoro, and with the further proviso that both X' and X" cannot both be -ORS', -SRS, -N(RS)Z, -N(CO)OR'S and -N3 ; further, neither X' and X" can be -ORS , -SRS, -N(RS)z, -N(CO)OR'S or -N3 when T is other than a bond covalently linking Rl to -C(X')(X")-;
n is an integer equal to 1 or 2;
p is an integer equal to 0 or 1 such that when p is zero, the ring defined by W and -C(H)pC(=X)- is unsaturated at the carbon atom of ring attachment to Y
and when p is one, the ring is saturated at the carbon atom of ring attachment to Y, with the following provisos:
when R1 is 2-propylpentanoyl, R2 is methyl, and R15 is hydrogen, then W, together with >CH and >C=X, does not form a 2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one when R1 is 3,5-difluorobenzoyl, R2 is methyl, and R15 is hydrogen, then W, together with > CH and > C=X, does not form a 2,3-dihydro-1-methyl-5-(2-pyridyl)-1 H-1,4-benzodiazepin-2-one when R1 is trans-cinnamyl, R2 is methyl, and R15 is hydrogen, then W, together with > CH and > C=X, does not form a 2,3-dihydro-1-(3,3-dimethyl-2-oxobutyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one when R1 is 2-(4-chlorophenoxy)-2-methylpropionyl, R2 is methyl, and R15 is hydrogen, then W, together with > CH and > C=X, does not form a 2,3-dihydro-1-methyl-5-(2-pyridyl)-1 H-1,4-benzodiazepin-2-one <.
when RI is a-methoxyphenylacetyl, R2 is methyl, and R15 is hydrogen, then W, together with > CH and > C=X, does not form a 2,3-dihydro-1-methyl-5-(2-pyridyl)-IH-1,4-benzodiazepin-2-one when R1 is diphenylacetyl, R2 is methyl, and R15 is hydrogen, then W, together with >CH and >C=X, does not form a 2,3-dihydro-1-methyl-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one when R1 is a-methoxyphenylacetyl, R2 is methyl, and R15 is hydrogen, then W, together with > CH and > C=X, does not form a 2,3-dihydro-I-(3,3-dimethyl-2-oxobutyl)- 5-(2-pyridyl)-IH-1,4-benzodiazepin-2-one when Rl is a-hydroxy-diphenylacetyl, R2 is methyl, and R15 is hydrogen, then W, together with > CH and > C=X, does not form a 2,3-dihydro-1-(3,3-dimethyl-2-oxobutyl)- 5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one when R1 is diphenylacetyi, R2 is methyl, and R15 is hydrogen, then W, together with >CH and >C=X, does not form a 2,3-dihydro-1-(3,3-dimethyl-2-oxobutyl)- 5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one when Rl is 2-(chlorophenoxy)-2-methylpropionyl, R2 is methyl, and R15 is hydrogen, then W, together with > CH and > C =X, does not form a 2,3-dihydro-1-{3,3-dimethyl-2-oxobutyl)- 5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one when Rl is diphenylacetyl, R2 is methyl, and RIS is hydrogen, then W, together with > CH and > C=X, does not form a 2,3-dihydro-1-(2-N,N-diethylaminoethyl)- 5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one S when R1 is 3,5-difluorobenzoyl, R2 is methyl, and R15 is hydrogen, then W, together with >CH and >C=X, does not form a 2,3-dihydro-1-(2-N,N-diethylaminoethyl)- S-(2-pyridyl)-1H-1,4-benzodiazepin-2-one when R1 is trans-cinnamyl, R2 is methyl, and R15 is hydrogen, then W, together with >CH and >C=X, does not form a 2,3-dihydro-1-(2-N,N-diethylaminoethyl)- 5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one when R1 is 2-(4-chlorophenoxy)-2-methylpropionyl, R2 is methyl, and R15 is hydrogen, then W, together with > CH and > C=X, does not form a 2,3-dihydro-1-(2-N,N-diethylaminoethyl)- 5-(2-pyridyl}-1H-1,4-benzodiazepin-2-one when R1-N(R'S) is (2,5-dimethoxyphenyl}ureylenyl and R2 is methyl, then W, together with > CH and > C=X, does nat form a 2,3-dihydro-1-methyl-5-phenyl-1 H-1,4-benzodiazepin-2-one when R1 is D,L-2-pyrrolidinone-5-yl, R2 is methyl, and R15 is hydrogen, then W, together with > CH and > C=X, does not form a 7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one.
As is appreciated by the skilled person, compounds of the present invention exist as isomers. Herein, the Cahn-Prelog-Ingold designations of (R)- and (S)-and, for amino acid derived portions of the compounds, the L- and D-designations of stereochemistry relative to the isomers of glyceraldehyde are used to refer to specific isomers where designated. The specific isomers can be prepared by stereospecific synthesis or can be resolved and recovered by techniques known in the art. such as, chromatography on chiral stationary phases, and fractional recrystallization of addition salts formed by reagents used for that purpose.
Useful methods of resolving and recovering specific stereoisomers are known in the art and described, for example, in Stereochemistry of Organic Compounds; E.L.
Eliel and S.H. Wilen (Wiley-Interscience 1994), Enantiomers, Racemates and Resolutions, J. Jacques, A. Collet and S.J. Wilen (Wiley-Interscience 1981), and European Patent Application No. EP-A-838448, published April 29, 1998. It is to be understood that the invention extends to all of the isomeric forms of the compounds of the present invention, including the diastereomeric, enantiomeric and racemic forms of the compounds.
Preferred compounds described herein include those set forth in the tables below:

WO 99/67221 PC'T/US99/14193 R' O
H r~3 0 N---N
_~ R
N Q H
Rz WO 99/67221 PC'T/US99/14193 .

Ex. R R' R R

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

phenyl -1-19 2- methyl 2-pyridyl methyl pyrrolidinone-[ 1-21 ~ 1-phenyl methyl 2-pyridyl methyl WO 99/67221 PC'T/US99/14I93 1-22 1-phenyl 2-oxo-3,3- 2-pyridyl methyl cyclopropyl dimethylbutyl 1-23 3,5- 2-oxo-3,3- 2-pyridyl methyl difluorophenyldimethylbutyl 1-24 2- 2-oxo-3,3- 2-pyridyl methyl pyrrolidinone-dimethylbutyl 5-yl 1-26 1-phenyl 2-diethyl 2-pyridyl methyl c clo ro yl aminoeth cont'd Ex. R R R R

1-27 4-methylphenylmethyl phenyl phenyl 1-28 4-methylphenylmethyl phenyl methyl 1-29 3-pyridyl methyl phenyl methyl 1-30 2-naphthyl methyl phenyl methyl 1-31 1-naphthyl methyl phenyl methyl 1-32 4-chloro- methyl phenyl methyl thiophene-yl 1-33 4-cyanophenylmethyl phenyl methyl 1-34 tetrahydroturanmethyl phenyl methyl -2-yl 1-35 3,5-dilluoromethyl phenyl methyl phenyl 1-36 cyclohex-3-ene-methyl phenyl methyl yl 1-37 1,2,3,4- methyl phenyl methyl tetrahydro naphth-2-yl 1-38 cyclopentyl methyl phenyl methyl 1-39 4-tritluoro methyl phenyl methyl methyl c clohex cont'd Ex. R R R R

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

1-56 tetrahydrofuran-3-yl 1-57 cyclopropyl 1-59 bicyclo[2.2.1]heptan-2-- yl 1-60 tetrahydrofuran-2-y l 1-61 cyclopentyl 1-62 thio hene-2- 1 R' O

N
N
N . ~ I ~~'C z O H X X

Ex. R X X- R R ~~ R

2-1 benzyl phenyl H methyl phenyl methyl 2-2 phenyl ethyl H methyl phenyl methyl 2-4 phenyl isopropylH methyl phenyl methyl 2-5 butyl ethyl H methyl phenyl methyl 2-6 ethyl methyl H methyl phenyl methyl 2-7 2,2,2- methyl H methyl phenyl methyl trifluoro-ethy I

2-8 phenyl phenyl H methyl phenyl phenyl 2-9 4-chloro methyl H methyl phenyl methyl pheny 2-10 4-chloro methyl methyl methyl phenyl methyl phenyl -2-11 phenyl methyl hydroxylmethyl phenyl methyl 2-12 hen l hen 1 h drox meth 1 2- rid meth WO 99/67221 PCT/US99/14193 .

Ex. R X' ~ X- R' R ~ R

2-15 phenyl phenyl hydroxyl2-oxo-3,3-2-pyridylmethyl 2-17 phenyl phenyl hydroxyl2-diethyl2-pyridylmethyl amino ethyl 2-18 3,5- methyl hydroxylmethyl phenyl methyl difluoro phenyl 2-19 3,5- methyl hydroxylmethyl phenyl methyl difluoro hen 1 .S

0 H R' 0 N
R
-N x I X~ i" X2 _88_ Ex. R R' ~ X' X

2-20 phenyl methyl phenyl H

2-21 H methyl H H

2-22 propyi methyl methyl H

2-23 phenyl methyl hydroxymethylH

2-24 ethyl methyl ethyl H

2-25 methyl methyl methyl methyl 2-26 phenyl methyl phenyl H

2-27 H phenyl H H

2-28 isopropylmethyl thioacetyl H

~ 2-29 f isopropylmethyl thio H ~
~

X~ Xz ~ O
N
p - O
Ex. R X' X

2-30 phenyl methyl H

2-31 butyl methyl H

2-32 phenyl phenyl H

2-33 phenyl methyl hydroxy 2-34 phenyl hydroxyl methyl 2-35 methyl hydroxyl methyl 2-36 ethyl hydroxyl methyl 2-37 isopropyl thioacetyl H

2-39 iso ro t thiol H

RZ
O
N
N
O H
R' Ex. R R-3-1 _ methyl phenyl 3-2 2- rid ( methyl H O
N
O R " O
Ex. _ R
3-5 Methvl WO 99/67221 PCT/US99/14193 .

H
I ~N
R
Nii~,,~,.
Ra RZ I
H O N
Ex. R ~ R ~ R R R

4-1 phenyl methyl ethyl H phenoxy 4-2 phenyl methyl phenyl H methoxy 4-3 phenyl methyl methyl methyl 4-chlorophenoxy 4-4 phenyl methyl methyl H phenoxy 4-5 phenyl methyl 3,5- H methoxy difluoro phenyl 4-6 phenyl methyl 3.5- H methoxy difluoro phenyl 4-7 phenyl methyl methyl H 4-hydroxyphenoxy 4-8 phenyl methyl methyl H 4-trifluoromethoxy phenoxy 4-9 phenyl methyl methyl H 4-phenylphenoxy 4-10 2-pyridyl 2-(diethylphenyl H methoxy amino) ethyl 4-16 phenyl methyl methyl methyl 4-cyano henox WO 99/67221 PCT/LJS99/14193 .

H X
N
\N N N/R

Ex. R R' X

5-1 trans-2-phenylcyclopropylH O

5-2 3,4-dichlorophenyl H ~ O

5-3 2-propenyl H O

5-4 (1-naphthyl)ethyl H O

5-5 2,6-diisopropylphenylH O

5-6 3-[(trifluoromethyl)phenylH O

5-7 phenyl H O

5-8 (4-ethoxycarbonyl)phenylH O

5-9 2-bromophenyl H O

5-10 o-tolyl H O

5-11 2-ethyl-6-methylphenylH O

5-12 2-fluorophenyl H O

5-13 2,4-difluorophenyl H O

S-14 2-ethoxyphenyl H O

5-IS 3-acetylphenyl H O

5-16 3-[(cyano)phenyl H O

5-18 phenethyl H O

5-19 4-n-but 1 hen 1 H O

WO 99/67221 PCT/US99/14t93 Ex. R ~ R' X

5-20 octyl H O

5-21 4-biphenyl H O

5-22 4-isopropylphenyl H O

5-23 hexyl H O

S 5-24 2-isopropylphenyl H S

5-25 2,6-difluorophenyl H O

5-26 octadecy 1 H O

5-27 4-(trifluoromethoxy)phenylH O

5-28 2,4-dichlorophenyl H O

5-29 3-ethoxycarbonylphenylH O

5-30 4-chlorophenyl H O

5-31 4-butoxyphenyl H O

5-32 4-phenoxyphenyl H O

S-33 1-naphthyl H O

5-34 2-biphenyl H O

5-35 2-(methylthio)phenylH O

5-36 2-ethylphenyl H O

5-37 3-methoxyphenyl H O

5-38 3,4,5-trimethoxyphenylH O

5-39 2,4,6-trimethylphenylH O

5-40 2-methyl-6-t-butylphenylH O

5-41 2-(2-thiophene-yl H O

R, H O I
N N N\
R/
_ H O

Ex. R ~ R' 5-43 (2-thiophene-yl)ethylH

5-44 phenethyl H

5-45 butyl H

S S-4b benzyl H

5-47 ethyl H

5-48 2-hydroxy-2-phenethylH

5-49 hexyl H

5-SO cyclohexyl H

5-51 isopropyl H

5-52 t-butyl H

5-53 1-adamantyl H

5-54 2-methylpropyl H

S-55 3-hydroxy-3-phenylethylH

5-56 3-methylbutyl H

5-57 (S)-1-hydroxymethyl-3-H
methylbutyl 5-58 ( 1 S)-(2S)-1- H
hydroxymethyl-2-methylbutyl 5-59 3-chloropropyl H

5-60 octyl H

S-61 1,1,3,3-tetramethylbutylH

5-62 (R/S)-1-methylbutyl H

5-63 5-(S)-((N'-(R/S)-1- H
hydroxymethylbutyl 5-64 (R/S)-1,3-dimethylbutylH

5-65 (R)-1-hydroxymethyl-3-H
methylbutyl 5-66 (R/S)-2-methylbutyl H

5-67 morpholino H

5-68 2-(2-hydroxyethoxy)-ethylH

5-69 piperidinyl H

S-70 N"-methyl-N"-butyl H

S-71 1-(R/S)- H
hydroxymethylcyclopentyl 5-72 4-hydroxybutyl H

5-73 1-(R/S)-h drox methyl-2-H

WO 99/67221 PC'TNS99/14193 5-74 2-(R/S)-hydroxycyclohexylH

5-75 isopropyl OH

5-76 1-(benzyl) OH

5-77 thiomorpholinyl H

5-78 2(R/S)-hydroxybutyl H

5-79 2.2,2-trifluoroethylH

5-80 (4RIS)-cyclohexyl H

5-81 hydroxymethyl-3- H
meth Ithio ro 1 WO 99!67221 PCT/LJS99/14193 i5 II R
N
~N . Ni O R' Ex. R R

6-I phenyl H

6-2 3-t7uorophenyl H

6-3 be nzy t H

6-4 butyl H

6-5 octvl H

WO 99/67221 PC'T/US99/14193 .

p R p H
~N N ~ /R
N C
p R
Ex. R R' R"

7-1 3,5- NHZ isopropyl difluorophenyl 7-2 3,5- NH, t-butyl difluorophenyl 7-3 isopropyl NH, methyl 7-4 phenyl NH, methyl 7-5 3,5-difluoroNH, methyl (Isomer A) phenyl 7-6 3,5-dif7uoroNH, methyl (Isomer B) phenyl 7-8 isopropyl NH, methyl 7-9 phenyl NH, methyl 7-10 3,5- NH, methyl (Mixture difluorophenyl of isomers) 7-11 phenyl CF,C(O)NH- methyl 7-12 isopropyl NHCH3 methyl 7-13 1-trifluoro NHS methyl methyl-2,2,2-trifluoroeth O H
CH3 O .
\ N R
N !
N ~~R
N O.
H H

WO 99/67221 PC'T/US99/14193 H ~ O
N .-. N
O ~N
CJi3 1-f N
O I

Ex. R R' 7-17 phenyl NH, 7-18 iso ro NH, I

WO 99/67221 PCT/US99/14193 ' H O C
H N
v N N

~N
O
Cti~
Ex. R R' 7-19 3,5-difluoro NH,-HCl phenyl 7-20 3,5-difluoro NH,-HCI

hen 1 H O
N

_ Ex. R.

36361 1-trifluoromethyl ethyl 36362 3 .3.3-trifluoropropyl 36363 ~,~.2-trifluoroethyl O
N
HzN N
O ~3 H O Kt Ex. R

36364 1-trifluoromethyl methyl ethyl 36365 3.3,3-trifluoropropylmethyl 36366 2,2,2-trifluoroethylmethyl 36367 ethyl methyl 36368 1-(trifluoromethyl)-2,2,2-methyl trifluoroethyl 36369 ethyl isobutyl Niii,,,,.
'N
H H t O
N

Ex.
9-1 methyl N
~N..
f ~ I ~-N
\ /
Ex. R
9-2 ~ methy 1 H O
Cl~
A~ C/N\N N N
O H
15 Ex.

10-1 - 3,5_ difluoro hen lmethvl H O
R.
~N N
O
O R H O

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

Asp Ala Glu Phe Arg His Asp Ser Gly Tyr Glu Val His His Gln Lys Leu Val Phe Phe WO 99/67221 PCT/US99/14193 .

Ala Glu Asp Val Gly Ser Asn Lys Gly Ala Ile Ile Gly Leu Met Val Gly Gly Val Val Ile Ala Thr (SEQ ID NO: 1 ) or a sequence which is substantially homologous thereto.
"Alkyl" refers to monovalent alkyl groups preferably having from 1 to 20 carbon atoms, more preferably 1 to 10 carbon atoms and most preferably 1 to 6 carbon atoms. This term is exemplified by groups such as methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, n-hexyl, and the like.
"Substituted alkyl" refers to an alkyl group, preferably of from 1 to 10 carbon atoms, having from 1 to 5 substituents, and preferably 1 to 3 substituents, selected from the group consisting of alkoxy, substituted alkoxy, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, acyl, acylamino, acyloxy, amino, substituted amino aminoacyl, aminoacyloxy, oxyacylamino, cyano, halogen, hydroxyl, keto, thioketo, , carboxyl, carboxylalkyl, thiol, thioalkoxy, substituted thioalkoxy, aryl, aryloxy, heteroaryl, heteroaryloxy, heterocyclic, hydroxyamino, alkoxyamino, nitro, -SO-alkyl, -SO-substituted alkyl, -SO-aryl, -SO-heteroaryl, -S02-alkyl, -S02-substituted alkyl, -S02-aryl, -S02-heteroaryl, and mono- and di-alkylamino, mono- and di-(substituted alkyl)amino, mono- and di-arylamino, mono- and di-heteroarylamino, mono- and di-heterocyclic amino, and unsymmetric di-substituted amines having different substituents selected from alkyl, substituted alkyl, aryl, heteroaryl and heterocycIic.
"Alkylene" refers to divalent alkylene groups preferably having from 1 to 10 carbon atoms and more preferably 1 to 6 carbon atoms. This term is exemplified by groups such as methylene (-CH2-), ethylene (-CH2CH2-), the propylene isomers (e.g., -CH2CH2CH2- and -CH(CH3)CH2-) and the like.
"Substituted alkylene" refers to an alkylene group, preferably of from 1 to 10 carbon atoms, having from 1 to 3 substituents selected from the group consisting of alkoxy, substituted alkoxy, acyl, acylamino, acyloxy, amino, substituted amino aminoacyl, aminoacyloxy, oxyacylamino, , cyano, halogen, hydroxyl, keto, thioketo, , carboxyl, carboxylalkyl, thiol, thioalkoxy, substituted thioalkoxy. aryl, heteroaryl, heterocyclic, heterocyclooxy, heterocyclooxy, , I S nitro, and mono- and di-alkylamino, mono- and di-(substituted alkyl)amino, mono-and di-arylamino, mono- and di-heteroarylamino, mono- and di-heterocyclic amino, and unsymmetric di-substituted amines having different substituents selected from alkyl, substituted alkyl; aryl, heteroaryl and heterocyclic.
Additionally, such substituted alkylene groups include those where 2 substituents on the alkylene group are fused to form one or more cycloalkyl, aryl, heterocyclic or heteroaryl groups fused to the alkylene group. Preferably, such fused cycloalkyl groups contain from 1 to 3 fused ring structures.
"Alkenylene" refers to divalent alkenylene groups preferably having from 2 to 10 carbon atoms and more preferably 2 to 6 carbon atoms. This term is exemplified by groups such as ethenylene (-CH=CH-), the propenylene isomers (e.g., -CH2CH=CH- and -C(CH3)=CH-) and the like.

WO 99/67221 PCTNS99/14193 ' "Substituted alkenylene" refers to an alkenylene group, preferably of from 2 to 10 carbon atoms, having from 1 to 3 substituents selected from the group consisting of alkoxy, substituted alkoxy, acyl, acylamino, acyloxy, amino, substituted amino aminoacyl, aminoacyloxy, oxyacylamino. , cyano, halogen, hydroxyl, keto, thioketo, , carboxyl, carboxylalkyl, thiol, thioalkoxy, substituted thioalkoxy, aryl, heteroaryl, heterocyclic, heterocyclooxy, nitro, and mono-and di-alkylamino, mono- and di-(substituted alkyl)amino, mono- and di-arylamino, mono- and di-heteroarylamino, mono- and di-heterocyclic amino, and unsymmetric di-substituted amines having different substituents selected from alkyl, substituted alkyl, aryl, heteroaryl and heterocyclic. Additionally, such substituted alkylene groups include those where 2 substituents on the alkylene group are fused to form one or more cycloalkyl, aryl, heterocyclic or heteroaryl groups fused to the alkytene group.
"Alkaryl" refers to -alkylene-aryl groups where alkyiene and aryl are as defined herein. Such alkaryl groups are exemplified by benzyl, phenethyl and the like.
"Alkoxy" refers to the group "alkyl-O-", where alkyl is as defined above.
Preferred alkoxy groups include, by way of example, methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, tent-butoxy, sec-butoxy, n-pentoxy, n-hexoxy, 1,2-dimethylbutoxy, and the like.
"Substituted alkoxy" refers to the group "substituted alkyl-O-" where substituted alkyl is as defined above.
"Alkylalkoxy" refers to the group "-alkylene-O-alkyl"where alkylene and alkyl are as defined above. Such groups include methylenemethoxy (-CH20CH3), ethylenemethoxy (-CH2CH20CH3), n-propylene-iso-propoxy (-CH2CH2CH20CH(CH3)2), methylene-t-butoxy (-CH2-O-C(CH3)3) and the like.
"Alkylthioaikoxy" refers to the group "-alkylene-S-alkyl" where alkylene and alkyl are as defined above. Such groups include methylenethiomethoxy (-CH2SCH3), ethylenethiomethoxy (-CH2CH2SCH3), n-propylene-thio-iso-propoxy (-CH2CH2CH2SCH(CH3)2), methylenethio-t-butoxy (-CH2SC(CH3)3) and the like.
"Alkenyl" refers to alkenyl groups preferably having from 2 to 10 carbon atoms and more preferably 2 to 6 carbon atoms and having at least 1 and preferably from 1-2 sites of alkenyl unsaturation. Preferred alkenyl groups include ethenyl (-CH=CH2), n-propenyl (-CH2CH=CH2), iso-propenyl (-C(CH3)=CH2), and the like.
"Substituted alkenyl" refers to an alkenyl group as defined above having from 1 to 3 substituents selected from the group consisting of alkoxy, substituted alkoxy, acyl, acylamino, acyloxy, amino, substituted amino aminoacyl, aminoacyloxy, oxyacylamino, , cyano. halogen, hydroxyl, keto, thioketo, , carboxyl, carboxylalkyl, thiol, thioalkoxy, substituted thioalkoxy. aryl, heteroaryl, heterocyciic, heterocyclooxy, nitro. -SO-alkyl, -SO-substituted alkyl, -SO-aryl, -SO-heteroaryl. -S02-alkyl, -S02-substituted alkyl, -S02-aryl, -S02-heteroaryl, and mono- and di-alkylamino, mono- and di-(substituted alkyl)amino, mono- and di-arylamino, mono- and di-heteroarylamino, mono- and di-heterocyclic amino, and unsymmetric di-substituted amines having different substituents selected from alkyl, substituted alkyl, aryl, heteroaryl and heterocyclic.
"Alkynyl" refers to alkynyl groups preferably having from 2 to 10 carbon atoms and more preferably 2 to 6 carbon atoms and having at Ieast 1 and preferably from 1-2 sites of alkynyl unsaturation. Preferred alkynyl groups include ethynyl (-CH~CH2), propargyl (-CH2C~H) and the like.
"Substituted alkynyl" refers to an alkynyl group as defined above having from 1 to 3 substituents selected from the group consisting of aIkoxy, substituted alkoxy, acyl, acylamino, acyloxy, amino, substituted amino aminoacyl, aminoacyloxy, oxyacylamino, , cyano, halogen, hydroxyl, keto, thioketo, .
carboxyl, carboxylalkyl, thiol. thioalkoxy, substituted thioalkoxy, aryl, heteroaryl, heterocyclic, heterocyclooxy, nitro, -SO-alkyl, -SO-substituted alkyl, -SO-aryl, -SO-heteroaryl, -S02-alkyl, -S02-substituted alkyl, -S02-aryl, -S02-heteroaryl, and mono- and di-alkylamino, mono- and di-(substituted alkyl)amino, mono- and di-arylamino, mono- and di-heteroarylamino, mono- and di-heterocyclic amino, and unsymmetric di-substituted amines having different substituents selected from alkyl, substituted alkyl, aryl, heteroaryl and heterocyclic.
"Acyl" refers to the groups alkyl-C(O)-, substituted alkyl-C(O)-, cycloalkyl-C(O)-, substituted cycloalkyl-C(O)-, aryl-C(O)-, heteroaryl-C(O)-and heterocyclic-C(O)- where alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, aryl, heteroaryl and heterocyclic are as defined herein.
"Acylamino" refers to the group -C(O)NRR where each R is independently hydrogen, alkyl, substituted alkyl, aryl, heteroaryl, or heterocyclic wherein alkyl, substituted alkyl, aryl, heteroaryl and heterocyclic are as defined herein.
Substituted amino" refers to the group -N(R)2, where each R is independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, cycloalkyl, substituted cycloalkyl, heteroaryl, heterocyclic and where both R groups are joined to form a heterocyclic; group. When both R groups are hydrogen, -N(R)2 is an amino group. Examples of substituted amino groups include, by way of example, mono- and di-alkylamino, mono- and di-(substituted alkyl)amino, mono- and di-arylamino, mono- and diheteroarylamino, mono and di-heterocyclic amino, and unsymmetric di-substituted amines having different substituents selected from the group consisting of alkyl, substituted alkyl, aryl, heteroaryl, heterocyclic and the like.
"Aminoacyl" refers to the group -NRC(O)R where each R is independently hydrogen, alkyl, substituted alkyl, aryl, heteroaryl, or heterocyclic wherein alkyl, substituted alkyl, aryl, heteroaryl and heterocyclic are as defined herein.
"Aminoacyloxy" refers to the group -NRC(O)OR where each R is independently hydrogen, alkyl, substituted alkyl, aryl, heteroaryl, or heterocyclic 1S wherein alkyl, substituted alkyl, aryl, heteroaryl and heterocyclic are as defined herein.
"Acyloxy" refers to the groups alkyl-C(O)O-, substituted alkyl-C(O)O-, cycloalkyl-C(O)O-, aryl-C(O)O-, heteroaryl-C(O)O-, and heterocyclic-C(O)O-wherein alkyl, substituted alkyl, cycioalkyl, aryl, heteroaryl, and heterocyclic are as defined herein.
"Aryl" refers to an unsaturated aromatic carbocyclic group of from 6 to 14 carbon atoms having a single ring (e.g., phenyl) or multiple condensed (fused) rings (e.g., naphthyl or anthryl). Preferred aryls include phenyl, naphthyl and the like. Unless otherwise constrained by the definition for the aryl substituent, such aryl groups can optionally be substituted with from 1 to 5 substituents and preferably 1 to 3 substituents selected from the group consisting of acyloxy, 1 to 5 and preferably 1 to 3 substituents selected from the group consisting of hydroxy, acyl, alkyl, alkoxy, alkenyl, alkynyl, substituted alkyl, substituted alkoxy, substituted alkenyl, substituted alkynyl, amino, substituted amino, aminoacyl, acylamino, alkaryl, aryl, aryloxy, azido, carboxyl, carboxylalkyl, cyano, halo.
nitro, heteroaryl, heteroaryloxy, heterocyclic, heterocyclooxy, aminoacyloxy, oxyacylamino, thioalkoxy, substituted thioalkoxy, thioaryloxy, thioheteroaryloxy, -SO-alkyl, -SO-substituted alkyl. -SO-aryl, -SO-heteroaryl, -S02-alkyl, -S02-substituted alkyl, -S02-aryl, -S02-heteroaryl, trihalomethyl. Preferred substituents include alkyl, alkoxy, halo, cyano, nitro, trihalomethyl, and thioalkoxy.
"Aryloxy" refers to the group aryl-O- wherein the aryl group is as defined above including optionally substituted aryl groups as also defined above.
"Carboxyalkyl" refers to the group "-C(O)Oalkyl" and "-C(O)O-substituted alkyl" where alkyl and substituted alkyl are as defined above.
"Cycloalkyl" refers to cyclic alkyl groups of from 3 to 12 carbon atoms having a single cyclic ring or multiple condensed rings. Such cycloalkyl groups include, by way of example, single ring structures such as cyclopropyl, cyclobutyl.
cyclopentyi, cyclohexyl, cycloheptyl, cyclooctyl, and the like, or multiple ring structures such as adamantanyl, bicyclo(2.2.1]heptyl, bicyclo(2.2.1)hept-5-ene-yl, bicyclo (3.3.1)non-6-ene-3-carboxyl) and the like.
"Substituted cycloalkyl" refers to cycloalkyl groups having from 1 to 5 (preferably 1 to 3) substituents selected from the group consisting of hydroxy, acyl, acyloxy, alkyl, substituted alkyl, alkoxy, substituted alkoxy, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, amino, substituted amino aminoacyl, alkaryl, aryl, aryloxy, carboxyl, carboxylalkyI, cyano, halo, nitro, heteroaryl. thioalkoxy, substituted thioalkoxy, trihalomethyl and the like.

-11'7-"Cycloalkenyl" refers to cyclic alkenyl groups of from 4 to 12 carbon atoms having at least one cyclic ring and preferably no more than four rings, which rings are optionally fused, and which include at least one point of internal unsaturation. Examples of suitable cycloalkenyl groups include, for instance, cyclobut-2-enyl, cyclopent-3-enyl, cyclooct-3-enyl and the like.
"Substituted cycloalkenyl" refers to cycloalkenyl groups having from 1 to 5 substituents selected from the group consisting of hydroxy, acyl, acyloxy, alkyl, substituted alkyl, alkoxy, substituted alkoxy, alkenyl, substituted aikenyl, alkynyl, substituted alkynyl, amino, substituted amino aminoacyl, alkaryl, aryl, aryloxy, carboxyl, carboxylalkyl, cyano, halo, nitro, heteroaryl, thioalkoxy, substituted thioalkoxy, trihalomethyl and the like.
"Halo" or "halogen" refers to fluoro, chloro, bromo and iodo and preferably is either fluoro or chloro.
"Heteroaryl" refers to an aromatic carbocyclic group of from 1 to 15 carbon atoms and 1 to 4 heteroatoms selected from oxygen, nitrogen and sulfur within at least one ring (if there is more than one ring).
Unless otherwise constrained by the definition for the heteroaryl substituent, such heteroaryl groups can be optionally substituted with from 1 to 5 substituents and preferably 1 to 3 substituents selected from the group consisting of acyloxy, 1 to S and preferably 1 to 3 substituents selected from the group consisting of hydroxy, acyl, alkyl, alkoxy, alkenyl, alkynyl, substituted alkyl, substituted alkoxy, substituted alkenyl, substituted alkynyl, amino, substituted amino, aminoacyl, acylamino, alkaryl, aryl, aryloxy, azido, carboxyl, carboxylalkyl, cyano, halo, nitro, heteroaryl, heteroaryloxy, heterocyclic.

heterocyclooxy, aminoacyloxy, oxyacylamino, thioalkoxy, substituted thioalkoxy, thioaryloxy, thioheteroaryloxy, -SO-alkyl, -SO-substituted alkyl, -SO-aryl, -SO-heteroaryl. -S02-alkyl, -S02-substituted alkyl, -S02-aryl, -S02-heteroaryl, trihalomethyl. Preferred substituents include alkyl, alkoxy, halo, cyano, nitro, trihalomethyl, and thioalkoxy. Such heteroaryl groups can have a single ring (e.g., pyridyl or furyl) or,multiple condensed rings (e.g., indolizinyl or benzothienyl). Preferred heteroaryls include pyridyl, pyrrolyl and furyl.
"Heteroaryloxy" refers to "O-heteroaryl", where heteroaryl is as defined herein.
"Heterocyclooxy" refers to "O-heterocyclic", where heterocyclic is as defined herein.
"Heterocycle" or "heterocyclic" refers to a monovalent saturated or unsaturated group having a single ring or multiple condensed rings, from 1 to carbon atoms and from 1 to 4 hetero atoms selected from nitrogen, sulfur or oxygen within the ring.
Unless otherwise constrained by the definition for the heterocyclic substituent, such heterocyclic groups can be optionally substituted with 1 to substituents selected from the group consisting of alkyl, substituted alkyl, alkoxy, substituted alkoxy, aryl, aryloxy, halo, nitro, heteroaryl, thiol, thioalkoxy, substituted thioalkoxy, thioaryloxy, trihalomethyl, and the like. Such heterocyclic groups can have a single ring or multiple condensed rings. Preferred heterocyclics include morpholino, piperidinyl, and the like.
Examples of nitrogen heterocycles and heteroaryls include, but are not limited to, pyrrole, imidazole, pyrazole, pyridine, pyrazine, pyrimidine, pyridazine, indolizine, isoindole, indole, indazole, purine, quinolizine, isoquinoline, quinoline, phthalazine, naphthylpyridine, quinoxaline, quinazoline, cinnoline, pteridine, carbazole, carboline, phenanthridine, acridine, phenanthroline, isothiazole, phenazine, isoxazole, phenoxazine, phenothiazine, imidazolidine, imidazoline, piperidine, piperazine, indoline, morpholino, piperidinyl, tetrahydrofuranyl, and the like as well as N-alkoxy-nitrogen containing heterocycles.
"Oxyacylamino" refers to the group -OC(O)NRR where each R is independently hydrogen, alkyl, substituted alkyl, aryl, heteroaryl, or heterocyclic wherein alkyl, substituted alkyl, aryl, heteroaryl and heterocyclic are as defined herein.
"Thiol" refers to the group -SH.
"Thioalkoxy" refers to the group -S-alkyl.
"Substituted thioalkoxy" refers to the group -S-substituted alkyl.
"Thioaryloxy" refers to the group aryl-S- wherein the aryl group is as defined above including optionally substituted aryl groups also defined above.
"Thioheteroaryloxy" refers to the group heteroaryl-S- wherein the heteroaryl group is as defined above including optionally substituted aryl groups as also defined above.
As to any of the above groups that contain 1 or more substituents, it is understood, of course, that such groups do not contain any substitution or substitution patterns which are sterically impractical and/or synthetically non-feasible.
"Pharmaceutically acceptable salts" refers to pharmaceutically acceptable ,.
salts of a compound of Formulas I-VI which salts are derived from a variety of organic and inorganic counter ions well known in the art and include, by way of example only, sodium, potassium, calcium, magnesium, ammonium, tetraalkylammonium, and the like; and when the molecule contains a basic functionality, salts of organic or inorganic acids, such as hydrochloride, hydrobromide, tartrate, mesylate, acetate, maleate, oxalate and the like can be used as the pharmaceutically acceptable salt.
The term "protecting group" or "blocking group" refers to any group which when bound to one or more hydroxyl, amino or carboxyl groups of the compounds (including intermediates thereof such as the aminolactams, aminolactones, etc.) prevents reactions from occurring at these groups and which protecting group can be removed by conventional chemical or enzymatic steps to reestablish the hydroxyl, amino or carboxyl group. The particular removable blocking group employed is not critical and preferred removable hydroxyl blocking groups include conventional substituents such as allyl, benzyl, acetyl, chloroacetyl, thiobenzyl, benzylidine, phenacyl, t-butyl-diphenylsilyl and any other group that can be introduced chemically onto a hydroxyl functionality and later selectively removed either by chemical or enzymatic methods in mild conditions compatible with the nature of the product.
Preferred removable amino blocking groups include conventional substituents such as t-butyoxycarbonyl (t-BOC}, benzyloxycarbonyl (CBZ), and the like which can be removed by conventional conditions compatible with the nature of the product.

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

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

wherein R1, R2, W, X, and Z are as defined above. The reaction is conventionally conducted by using at least a stoichiometric amount of carboxylic acid _1 and amine 2. This reaction is conventionally conducted for peptide synthesis and synthetic methods used therein can also be employed to prepare compound ~ which is a compound of formula I above. For example, well known coupling reagents such as carbodiimides with or without the use of well known additives such as N-hydroxysuccinimide, 1-hydroxybenzotriazole, etc. can be used to facilitate coupling. The reaction is conventionally conducted in an inert aprotic polar diluent such as dimethylformamide, dichloromethane, chloroform, acetonitrile, tetrahydrofuran and the like. Alternatively, the acid halide of compound ,~ can be employed in reaction ( 1 ) and, when so employed, it is typically employed in the presence of a suitable base to scavenge the acid generated during the reaction. Suitable bases include, by way of example, triethylamine, diisopropylethylamine, N-methylmorpholine and the like.
Various compounds as described herein can be prepared by N-substitution reactions of compound ~. Reaction of compound ,~ with an carboxylic acid derivative can also lead to various compounds as described herein. Both reactions are described below.
Carboxylic acids ~ can be prepared by several divergent synthetic routes with the particular route selected relative to the ease of compound preparation, commercial availability of starting materials, whether n :~ one or two.
A. Synthesis of Carboxylic Acids t0 When n is one, a first synthetic method involves the introduction of the Rl group to the amino acid NH2CH(R2)COOH or ester thereof.
The introduction of the Rl group onto the amino acid NH2CH(R2)COOH
or ester thereof can be accomplished in several methods. For example, conventional coupling of a halo acetic acid with a primary amine forms an amino acid as shown in reaction (2) below:

O O
Z' _ N
+ R~ NHZ ----~ R' ~ OH
Rz 4 5 6 Rz (Reaction 2}

wherein R1 and R2 are as defined above and Z is a halo group such as chloro or bromo. Alternatively, leaving groups other than halo may be employed such as triflate and the like. Additionally, suitable esters of 4 may be employed in this reaction.
As above, reaction (2) involves coupling of a suitable haloacetic acid derivative 4_ with a primary amine ~ under conditions that provide for amino acid 1. This reaction is described by, for example, Yates, et al.l4 and proceeds by combining approximately stoichiometric equivalents of haloacetic acid 4 with primary amine ~ in a suitable inert diluent such as water, dimethylsulfoxide (DMSO) and the like. The reaction employs an excess of a suitable base such as sodium bicarbonate, sodium hydroxide, etc. to scavenge the acid generated by the reaction. The reaction is preferably conducted at from about 25°C to about 100°C
until reaction completion which typically occurs within 1 to about 24 hours.
This reaction is further described in U.S. Patent No. 3,598,859, which is incorporated herein by reference in its entirety. Upon reaction completion, N-substituted amino S acid ø is recovered by conventional methods including precipitation, chromatography, filtration and the Iike.
In reaction (2), each of the reagents (haloacetic acid ~, primary amine ~
and alcohol ~) are well known in the art with a plurality of each being commercially available.
In an alternative embodiment, the R1 group can be coupled to an alanine ester (or other suitable amino acid ester) by conventional N-arylation. For example, a stoichiometric equivalent or slight excess of the amino acid ester can be dissolved in a suitable diluent such as DMSO and coupled with a halo-R1 compound, Z -R1 where Z is a halo group such as chloro or bromo and Rl is as defined above. The reaction is conducted in the presence of an excess of base such as sodium hydroxide to scavenge the acid generated by the reaction. The reaction typically proceeds at from 15°C to about 250°C and is complete in about 1 to 24 hours. Upon reaction completion. N-substituted amino acid ester is recovered by conventional methods including chromatography, filtration and the like. This ester is then hydrolyzed by conventional methods to provide for carboxylic acid 1 for use in reaction (1).
In still another alternative embodiment, the esterifted amino acids described above can be prepared by reductive amination of a suitable pyruvate ester in the manner illustrated in reaction (3) below:

O
O Z
H R, /~
R + Rt-NHZ Catalyst _OR
(Reaction 3) R O RZ
7 ~ 8 WO 99/67221 PCTlUS99/14193 ' wherein R is typically an alkyl group and Rl and R2 are as defined above.
In reaction (3), approximately stoichiometric equivalents of pyruvate ester ~ and amine $ are combined in an inert diluent such as methanol, ethanol and the like and the reaction solution treated under conditions that provide for imine formation (not shown). The imine formed is then reduced under conventional conditions by a suitable reducing agent such as sodium cyanoborohydride, H2/palladium on carbon and the like to form the N-substituted amino acid ester $. In a particularly preferred embodiment, the reducing agent is H2/palladium on carbon which is incorporated into the initial reaction medium which permits imine reduction in situ in a one pot procedure to provide for the N-substituted amino acid ester $.
The reaction is preferably conducted at from about 20°C to about 80°C at a pressure of from 1 to 10 atmospheres until the reaction is complete, which typically occurs within I to about 24 hours. Upon reaction completion. N-substituted amino acid ester $ is recovered by conventional methods including chromatography, filtration and the like.
Subsequent hydrolysis of the ester $ leads to the corresponding carboxylic acid derivative _1 which can be employed in reaction (1) above.
For compounds where n is two, conventional coupling of a second amino acid (e.g., NH2CH(R2)C(O)OR where R is typically an alkyl group) to the amino acid produced above (i.e., RiNHCH(R2)COOH) provides for esters of an analogue of carboxylic acid ~ which are then conventionally de-esterified to provide for an analogue of compound _l.

WO 99/67221 PCT/US99/14193 ' Alternatively, an ester such as H2NCH(R2)C(O)NHCH(R2)COOR where each R2 is independently as defined above and R is typically an alkyl group can first be formed by conventional peptide synthetic procedures, N-substitution can be conducted in the manner described above followed by de-esterification to provide for analogues of carboxylic acids ~ where n is two.
When n is one, a first synthetic method involves conventional coupling of an carboxylic acid derivative with a primary amine of an esterified amino acid as shown in reaction (4) below:
X. ~ i O
.f. HzN
X"
OR
Rz 9 1o Rz (Reaction 4) X' X"
~ O
R
OR

t1 S
wherein R is typically an alkyl group, and Rl, R2, X' and X" are as defined above.
Reaction (4) merely involves coupling of a suitable carboxylic acid derivative _9 with the primary amine of amino acid ester ~,Q under conditions that provide for the N-acetyl derivative ~. Alternatively, the carboxylic acid R'COOH can be used in place of compound 9 to provide intermediates useful for preparing compounds of Formula VI above. This reaction is conventionally conducted for peptide synthesis and synthetic methods used therein can also be employed to prepare the N-acetyl amino acid esters ~ of this invention. For example, well known coupling reagents such as carbodiimides with or without the use of well known additives such as N-hydroxysuccinimide, 1-hydroxybenzotriazole, etc. can be used to facilitate coupling. The reaction is conventionally conducted in an inert aprotic polar diluent such as dimethylformamide, dichloromethane, chloroform, acetonitrile, or tetrahydrofuran. Alternatively, the acid halide of compound Q can be employed in reaction (4) and, when so employed, it is typically employed in the presence of a suitable base to scavenge the acid generated during the reaction. Suitable bases include, by way of example, triethylamine, diisopropylethylamine, and N-methylmorpholine.
Reaction (4) is preferably conducted at from about 0°C to about 60°C until the reaction is complete, which typically occurs within 1 to about 24 hours.
Upon reaction completion, N-acetyl amino acid ester ~ is recovered by conventional methods including precipitation, chromatography, and filtration or alternatively is hydrolyzed to the corresponding acid without purification and/or isolation other than conventional work-up (e.g., aqueous extraction, etc.).
In reaction (4), each of the reagents (carboxylic acid derivative .Q and amino acid ester ~Q) are well known in the art with a plurality of each being commercially available.
When n is two, a further amino acid ester is coupled to the amino acid ester ~ by first de-esterifying ~ and then using well known peptide coupling chemistry with well known coupling reagents such as carbodiimides with or without the use of well known additives such as N-hydroxysuccinimide and 1-hydroxybenzotriazole,.which can be used to facilitate coupling. The reaction is conventionally conducted in an inert aprotic polar diluent such as dimethylformamide, dichloromethane. chloroform, acetonitrile, or 1 S tetrahydrofuran. De-esterification of the resulting ester provides for carboxylic acids _1 having n equal to 2.
Alternatively, carboxylic acids 1 having n equal to 2 can be prepared by first forming the ester, N-acetylating these esters and then de-esterifying the resulting product.
Carboxylic acids ~ having n equal to 1 or 2 can also be prepared by using polymer-supported forms of carbodiimide peptide coupling reagents. A polymer-supported form of EDC, for example, has been described (Tetrahedron Letters, 34(48), 7685 (1993))1. Additionally, a new carbodiimide coupling reagent, PEPC, and its corresponding polymer-supported forms have been discovered and are very useful for preparing such compounds.

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

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

Such methods are described more fully in PCT Application PCT/US97/22986, which application is incorporated herein by reference in its entirety. Briefly, PEPC is prepared by first reacting ethyl isocyanate with 1-(3-aminopropyt)pyrroIidine. The resulting urea is treated with 4-toluenesulfonyl chloride to provide PEPC. The polymer-supported form is prepared by reaction of PEPC with an appropriate resin under standard conditions to give the desired reagent.
The carboxylic acid coupling reactions employing these reagents are performed at about ambient temperature to about 45°C, for from about 3 to 120 hours. Typically, the product is isolated by washing the reaction mixture with CHC13 and concentrating the remaining organics under reduced pressure. As discussed supra, isolation of products from reactions where a polymer bound reagent has been used is greatly simplified, requiring only filtration of the reaction mixture and then concentration of the filtrate under reduced pressure.
Sulfonamidation Chemistry Sulfonamides, such as those in Formula III, can be readily prepared using known sulfonamidation reactions. These typically involve the reaction of sulfonyl chlorides with primary or secondary amines in the presence of a tertiary amine or other suitable acid scavenger (See, for Example, page 923. Morrison and Boyd, Organic Chemistry, fourth edition).
Suitable sulfonic acids can be prepared by several divergent synthetic routes with the particular route selected relative to the ease of compound preparation, and commercial availability of starting materials.
A. Synthesis of Sulfonic Acids Alkyl sulfonic acids can be prepared using means well known to those of skill in the art, as described, for example, in U.S. Patent Nos. 2,493,038 and 2,697,722, the contents of which are hereby incorporated by reference. One method for preparing alkyl sulfonic acids is by the oxidation of disulfides, which can themselves be prepared by the oxidation of thiols. Aromatic sulfonic acids can be produced by the sulfonating action of sulfuric acid, SO,, oleum or alkyl sulfonic acids on aromatic compounds using techniques well known to those of skill in the art.
Activation of Sulfonic Acids Suitable sulfonic acid derivatives can be prepared, for example, by reacting a sulfonic acid with a chlorinating reagent such as phosphorous pentachloride or sulfonyl chloride.
Preu~ration of Ureas Ureas can be prepared by any known methodology, but preferably are prepared by reacting an amine with an isocyanate, as described on page 844 of Morrison and Boyd, Organic Chemistry, Fourth Edition, Allyn and Bacon, ed., Boston (1983). Suitable isocyanates can be prepared using methods known to those of skill in the art.
Cyclic amino compounds Z employed in reaction (1) above are generally aminolactams, aminolactones, aminothiolactones and aminocycloalkyl compounds which can be represented by the formula:

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

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

In reaction (6), reductive amination of 14 with aldehyde l5 and subsequent ring closure by methods using, for example, EDC provides for aminolactam 1~.
The preparation of 6 membered lactams using this general procedure is described by Semple, et al., J. Med. Chem., ~Q:4531-4536 (1996)19.
The internal cyclization of ari amide anion with a halide or equivalent thereof can sometimes be used to particular advantage in the synthesis of smaller ring lactams where the stereochemistry of the amino-lactam center is available from the standard amino-acid pool. This approach is illustrated in reaction (7) below:
SMe N ~"6 N~.=s5 -' ?cc~:N 1 (Reacrioa 7) 1~ ~ ~ C
where R6 is as defined above.
The approach of reaction (7) is presented by Semple, et al., sttpra.l9, and Freidinger, et al., J. Org. Chem., 47:104-109 (1982)18 where a dimethyisulfonium leaving group is generated from methyl iodide treatment of an alkyl methyl sulfide ~ to provide for lactam ~$. A similar approach using a Mitsunobu reaction on an omega alcohol is found Holladay, et al. , J. Org.
Chem. , x:3900-3905 (1991)20.
In another method, lactams ~ can be prepared from cyclic ketones 1 Q
using either the well known Beckmann rearrangement (e.g., Donaruma, et al., Organic Reactions, ~:1-156 (1960))21 or the well known Schmidt reaction (Wolff, Organic Reactions, x:307-336 (1946))22 as shown in reaction (8) beiow:
~ECkr;;aut r~2r~ art~e~;~rrt cr ~c:;ric~t n_c;~crt ~_~~ ~ (Reaction 8) O
wherein L is as defined above.
Appiication of these two reactions leads to a wide variety of lactams especially lactams having two hydrogen atoms on the carbon a to the lactam carbonyl which lactams form a preferred group of lactams in the synthesis of the I S compounds described above. In these reactions, the L group can be highly variable including, for example, alkylene, substituted alkylene and hetero containing alkylene with the proviso that a heteroatom is not adjacent to the carbonyl group of compound 19. Additionally, the Beckmann rearrangement can be applied to bicyclic ketones as described in Krow, et al., J. Org. Chem., øx:5574-5580 ( 1996)23.
The preparation of lactones can be similarly conducted using peracids in a Baeyer-Villiger reaction on ketones. Alternatively, thiolactones can be prepared by cyclization of an omega -SH group to a carboxylic acid and thiolactams can be prepared by conversion of the oxo group to the thiooxo group by P2S5 or by use of the commercially available Lawesson's Reagent, Tetrahedron, .x:2433 (1979)24.

One recently reported route for lactam synthesis is a variation of the Schmidt reaction through the use of an alkyl azide, either intermolecularly or intramolecularly, through a tethered alkylazide function that attacks a ketone under acidic conditions. Gracias. et al., J. Am. Chem. Soc., ,1 X7:8047-8048 (1995)25 describes the intermolecular version whereas Milligan, et al., J. Am. Chem.
Soc., x:10449-10459 (1995)26 describes.the intramolecular version. One example of the intramolecular version is illustrated in reaction (9) below:

Q
-.~-... ,- -N= -;v Rzn ~ zo ~ZQ (Reaction 9) where R10 is exemplified by alkyl. substituted alkyl, alkoxy, substituted alkoxy, aryl, heteroaryl, cycloalkyl and heterocyclic.
In this reaction, ketone ~ is converted to an a-(w-alkyl)ketone 22 which is cyclized to form bicyclic lactam ~. Such intramolecu(ar reactions are useful in forming bicyclic lactams having 5-7 members and the lactam ring of 6-13 members. The use of heteroatoms at non-reactive sites in these rings is feasible in preparing heterobicyclic lactams.
Still another recent approach to the synthesis of lactams is described by Miller, et al. , J. Am. Chem. Soc. , X1,.$:9606-9614 ( 1996)2 and references cited and is illustrated in reaction (10) below:

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

Related chemistry to cyclize amides to form lactams is disclosed by Colombo, et al., Tetrahedron Lett., x(23):4031-4034 (1994)29 and is illustrated in reaction (11) below:
Ac~IV ~V -'~'~c.~iV
V
D
C~2~~u o CVZtQe (Reaction 11) In this reaction, proline derivative 27 is cyclized via a tributyltin-radical cyclization to provide for lactam ~$.
Some of the lactams described above contain the requisite amino group a to the lactam carbonyl whereas others did not. However, the introduction of the required amino group can be achieved by any of several routes delineated below which merely catalogue several recent literature references for this synthesis.
For example, in a first general synthetic procedure, azide or amine displacement of a leaving group a to the carbonyl group of the lactam leads to the a-aminolactams. Such general synthetic procedures are exemplified by the introduction of a halogen atom followed by displacement with phthalimide anion or azide and subsequent conversion to the amine typically by hydrogenation for the azide as described in Rogriguez, et al., Tetrahedron, x:7727-7736 (1996)30, Parsons, et al., Biochem. Biophys. Res. Comm., 1:108-113 (1983)31 and Watthey, et al., J. Med. Chem., ?$:15/1-1516 (1985)32. One particular method involves iodination and azide displacement on, for example, benzyllactams as described by Armstrong, et al., Tetrahedron Lett., x:3239 (1994)33 and by King, et al. , J. Org. Chem. , x$:3384 ( 1993)34.
Another example of this first general procedure for the synthesis of a-aminolactams from the corresponding lactam involves displacement of a triflate group by an azido group as described by Hu, et al. , Tetrahedron Lett. , x(21):3659-3662 (1995)35.
Still another example of this first general procedure uses a Mitsunobu reaction of an alcohol and a nitrogen equivalent (either -NH2 or a phthalimido group) in the presence of an azodicarboxylate and a triarylphosphine as described in Wada, et al. , Bull. Chem. Soc. Japan, ,4:2833-2835 ( 1973)36 using an open chain reagent.
Yet another example of this first general procedure involves reaction of a-chlorolactams with anilines or alkyl amines in a neat mixture at 120°C
to provide for 2-(N-aryl or N-alkyl)lactams as described by Gaetzi, Chem. Abs. , øø:28690m, 37 In a second general synthetic procedure, reaction of an enolate with an alkyl nitrite ester to prepare the a oxime followed by reduction yields the a-aminolactam compound. This general synthetic procedure is exemplified by Wheeler; et al., Organic Syntheses, Coll. Vol. VI, p. 84038 which describes the reaction of isoamyl nitrite with a ketone to prepare the desired oxime. The reduction of the oxime methyl ester (prepared from the oxime by reaction with methyl iodide) is described in the J. Med. Chem.,,~$(12):1886 (1985)39 and the reduction of a-oximino caprolactams by Raney-nickel and palladium catalysts is described by Brenner, et al., U.S. Patent No. 2,938,029.40 WO 99/67221 PC'T/US99/14193 in a third general synthetic procedure, direct reaction of an enolate with an electrophilic nitrogen transfer agent can be used. The original reaction employed toluenesulfonyl azide but was improved as described by Evans, et al. , J. Am.
Chem. Soc., x:4011-4030 (1990)41. Specifically, direct introduction of an S azido group which can be reduced to the amine by hydrogenation is described by Micouin, et al., Tetrahedron. x:771.9-7726 (1996)42. Likewise, the use of triisopropylbenzenesulfonyl azide as the azide transferring agent for reaction with an enolate is described by Evans, et al., supra. The use of triphenylphosphine to reduce the a-azidolactams to the corresponding aminolactams in the benzodiazepine series is disclosed by Butcher, et al., Tetrahedron Lett., X7(37):6685-6688 (1996).43 Lastly, diazo transfer of ~i-diketones and subsequent reduction of the diazo group to the amino group is exemplified by Hu, et al., Tetrahedron Lett., xø(21):3659-3662 (1995)35 who used Raney-nickel and hydrogen in acetic acid and acetic anhydride as the solvent.
In a fourth general procedure, N-substituted lactams are first converted to the 3-alkoxycarbonyl derivatives by reaction with a dialkyl carbonate and a base such as sodium hydride. See, for example, M.L. Reupple, et al.. J. Am. Chem.
Soc., x:7021 et seq. (1971) The resulting esters serve as starting materials for conversion to the 3-amino derivatives. This conversion is achieved via the Curtius reaction as shown in reaction (12) below:
..
w R:.
L-.V ~ ' _,...~ L - ~V.
c a where Pr is as defined above and R12 is typically hydrogen, an alkyl or an aryl group.
The Curtius reaction is described by P.A.S. Smith, Organic Reactions, 3_:337-449 (1946).45 Depending on the reaction conditions chosen, Pr = H or a protecting group such as Boc. For example, when R = H, treatment of the acid with diphenylphosphoryl azide in the presence of t-butanol provides the product wherein Pr = Boc.
The a-aminolactams employed as the cyclic amino compounds ~ in reaction (1) above include ring N-substituted lactams in addition to ring N-H lactams.
Some methods for preparing ring N-substituted lactams have been described above. More generally, however, the preparation of these compounds range from the direct introduction of the substituent after lactam formation to essentially introduction before lactam formation. The former methods typically employ a base and an primary alkyl halide although it is contemplated that a secondary alkyl halide can also be employed although yields may suffer.
Accordingly, a first general method for preparing N-substituted lactams is achieved via reaction of the lactam with base and alkyl halide (or acrylates in some cases). This reaction is quite well known and bases such as sodamide, sodium hydride, LDA, LiHMDS in appropriate solvents such as THF, DMF, etc. are employed provided that the selected base is compatible with the solvent. See for example: K. Orito, et al., Tetrahedron, 3:1017-1021 (1980)46 and J.E. Semple, et al., J. Med. Chem., x:4531-4536 (1996)19 (use of LiHMDS with either R-X
or acrylates as electrophiles).
A second general method employs reductive amination on an amino function that is then cyclized to an appropriate ester or other carbonyl function.

A third general method achieves production of the N-substitution during lactam formation. Literature citations report such production from either photolytic or thermal rearrangement of oxaziridines, particularly of N-aryl compounds. See, for example, Krimm, Chem. Ber. , x:1057 (1958)47 and Suda, S et al. , J. Chem. Soc. Chem Comm. , 949-950, ( 1994) 48 Also, the use of methyl hydroxylamine for the formation of nitrones and their rearrangement to the N-methyl derivatives is reported by Burton, et al. , J. Chem. Soc. , 1764-1767 (1975).49 Additionally, the use of the oxaziridine process in chiral synthesis has been reported by Kitagawa, et al. , J. Am. Chem. Soc. , x:5169-5178 (1975).50 A more direct route to obtain N-phenyl substituted lactams from the corresponding NH lactams through the use of t-butyltetramethylguanidine and triphenylbismuth dichloride is disclosed by Akhatar, et al., J. Org. Chem., 5:5222-5225 (1990)51 as shown in reaction (13) below.
O
y ~ (Reaction 13) O N ~ _..~ O N.J
~l Given that numerous methods are available to introduce an a-amino group onto a lactam (or lactone) ring, the following lactams (and appropriate corresponding lactones) are contemplated for use in the synthesis of compounds described above. Similar alcohol functions at the carbonyl position are derivative of either amine ring opening of cyclic epoxides, ring opening of aziridines, displacement of appropriate halides with amine or alcohol nucleophiles, or most likely reduction of appropriate ketones. These ketones are also of interest to the present invention.
Monocyciic lactams as described by Nedenskov, et al., Acta Chem. Scand., .~~:1405-1410 (1958)52 are represented by the formula:
O
NH
R~
RZ
where R1 and R2 are exemplified by alkyl, aryl or alkenyl (e.g., allyl).
Monocyclic lactams containing a second nitrogen ring atom as described by Sakakida, et al. , Bull. Chem. Soc. Japan, X4:478-480 ( 1971 )53 are represented by the formula:

NH
r R

where R is exemplified by CH3- or PhCH2-.
Monocyclic lactams having hydroxyl substitution on the ring as described ..
by Hu, et al., Tetrahedron Lett., x(21):3659-3662 (1995)35 are represented by the formula:
HO

O R
where R is exemplified by benzyl (includes both the cis and trans hydroxy lactams).
The direct preparation N-substituted lactams of 5-8 members from the corresponding ketones is described by Hoffman, et al . , Tet. Lett. , ~ :4207-(1989).54 These lactams are represented by the formula:
O
~O
-_,~ N. 9 . .
(C,~f~n ~ n = t _ Q
(~~t~n wherein R is alkyl, alkenyl, alkynyl, cycloalkyl, or benzyl.
N-Methoxylactams prepared from cyclohexanone and dimethoxyamine are described by Vedejs, et al., Tet. Lett., x:3261-3264 (1992) ss These structures are represented by the formula:

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

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

H
N ~ ., 3. Herschmann, Helv. Chim. Acta, x:2537 (1949)62 describes the synthesis of a disubstituted caprolactam from the Beckman rearrangement of menthone which is represented by the formula:
IS

N

H

4. Overberger, et al. , Macromolecules,1:1 ( 1968)63 describes the synthesis of eight-membered lactams from 3-methylcycloheptanone as shown below:
a ~ ~ o J
H N
. O H

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

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

Another tricyclic lactam series is disclosed by Flynn, et al., J. Med.
Chem., x:2420-2423 (1993)67 and references cited therein.
6. Orito, et al., Tetrahedron. x:1017-1021 (1980)68 discloses phenyl substituted benzazepinones represented by the formula:
O
/ ~ N_A
wherein R = H or CH3-;
Kawase, et al., J.Org. Chem., ,5:3394-3403 (1989)69 discloses a N-methoxy benzazepinone represented by the formula:
N
O
D.
7. Lowe, et al. , J. Med. Chem. , ,x:3789-3811 ( 1994)70 describes several synthetic pathways to substituted benzazepinones of the formula:
z NHZ
O
'q2 where R1 is substituted aryl or cyclohexyl, X is a suitable substituent and R2 can be H or alkyl. The syntheses described in Lowe are, however, adaptable to form numerous R1 substituents.

8. Robl, et al., Bioorg. Med. Chem. Lett., x:1789-1794 (1994)71 and references cited therein as well as Skiles, et al., Bioorg. Med. Chem.
Lett.,~:773-778 (1993)72 disclose benzofused lactams which contain additional heteroatoms in the lactam ring. These compounds are represented by the formula:
RZ
X
NHZ
N
R D
where X is O and R2 = H or CH3 or X = S and R~ = H. In either case, R1 =
..
H or alkyl. Also, in Skiles, the thin group of the thiolactam can be oxidized to the S02 group. These structures are also presented from Beckmann rearrangement in Grunewald. et al., J. Med. Chem., x(18):3539 (1996).73

9. Also syntheses for the benzoheterolactam series is presented in Thomas, et al., J. Chem. Soc., Perkin II, 747 (1986)74 which could lead to compounds of the formula:
~~Z
o.~N_~l P,'' where X is O or H2 and R is C02R.

10. Further examples of benzazepinones are found in Warshawsky, et al., Bioorg. Med. Chem. Lett. , x:957-962 ( 1996)75 which discloses N-R
l~Z,v a to The synthesis can be generalized to produce R = alkyl or aryl.

11. Ben-Ishai, et al., Tetrahedron, _4:439-450 (1987)76 describes syntheses which could lead to several benzolactams of the formula ~(CH~n j~~. \N-~
x ~-- o 1-fZN
wherein n = 0,1,2 and R= -CH3, PhCH2- and H.

12. van Niel et al., Bioorg. Med. Chem. Lett., x:1421-1426 (1995)77 reports the synthesis of N N
NHZ ~. ~ NHBoc O
wherein X is -OH, -NH2 or -NR6R6 where R6 is as defined above. The reported ketone is a versatile synthetic intermediate which can be modified by conventional methods such as reductive amination, reduction, etc.

13 . Kawase, et al. , J. Org. Chem. , 5:3394-3403 ( 1989)78 describes a synthetic method for the preparation of:
NHZ
a o In addition to the above, saturated bicyclic a-aminolactams are also contemplated for use in the synthesis of compounds of formulas I-VI. Such saturated bicyclic a-aminolactams are well known in the art. For example.
Edwards, et al., Can. J. Chem., x:1648-1658 (1971)78 describes several syntheses of bicyclic lactams of the formula:
O R~ O
N N N
A H
Rz R

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

rs w NJ
r ..

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

Org. Cnem., 1:1855 (1954)88 used the Schmidt and Beckmann reactions on substituted 4-piperidones to provide for lactams of the formula:
R'~N'p R ..
~..~ N.
0 -~...
O N
H
where R is acyl, alkyl, substituted alkyl, aryl, heteroaryl or heterocycIic provided that R is not an acid labile group such as t-Boc; and R' is hydrogen, alkyl, substituted alkyl, alkoxy, substituted alkoxy, aryl, aryloxy, heteroaryl, heteroaryloxy, heterocyclic, heterocyclooxy, halo, cyano, nitro, trihalomethyl, and the like.
An internal cyclization of appropriate ethylenediamine amides onto a ketone or aldehyde is described by Hoffman, et al. , J. Org. Chem. , ~ :3565 (1962)89 as follows:
R
Z R
0 ' HN ~ N
o ~ ---N O
H -N
.K
R = Methyl, Phenyl Ring expansion methodology based on ~i lactams to provide for larger ring lactams containing an aza group has twice been reported in Wasserman, et al., J.
Am. Chem. Soc. , (~:46I-2 (1981)90 and in Crombie, et al., Tetrahedron Lett. , 27(42):5151-5154 (1986).91 Dieckmann methodology has been used to prepare aza caprolactams from unsymmetrical amines such as shown below by Yokoo, et al. , Bull, Chem. Soc.
Jap. , x:631 ( 1956).92 R
~--N' R
N
COZEN ---.-COZEt 0 N
H
wherein R is as defined in this reference. The disclosure of Yokoo, et al. can be extended to cover R being alkyl, substituted alkyl, aryl, alkoxy, substituted alkoxy, heteroaryl, cycloalkyl, heterocyclic, heterocyclooxy, alkenyl, substituted alkenyl, and the like.
The synthesis of various members of the oxalactam series has been reported by Burkholder, et al., Bioorg. Med. Chem. Lett., 2:231 (1993)93 and references cited therein which oxalactams are represented by the formula:
,R IV
~0 ,N
R

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

caucling \ O agent ~ O
I / ~N T R-NHz ~ N
( OH i 0 O v NHR
O O
O
parafotmaldehyda ~ N-mettsylhyd2zine p-TosOH N N~R
C1ZCHCl-fCt~ ~ ~ ~ HZN N~~
O -Q

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

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

1. Cycliiation 2. Selective HzN N
allcyt;ation O .RI

R2 can be highly variable (e.g., alkyl, substituted alkyl, aryl, heteroaryl, heterocyclic and the like) since a number of well documented routes exist for the synthesis of nitroethylene derivatives from aldehydes and nitromethane (Henry reaction) followed by dehydration. RI is limited to groups that can undergo alkylation reactions.
The second compound series can be prepared as follows:
O
\ SH Rz NHBoc ~ , ~N +
OCHPhz OMs O O
t . Protec:ing group removal ~ Rz H2N ~ N, 2 ~ Cycfization R ~
1' 3. Selective alfcyfation (Rj}
4. Methyfhydrarine .
NHBoc o~
I \ N S R2 OCHPhz 2U ~~ O
In this synthesis, R2 can be highly variable. The starting component required to introduce R2 can be readily derived by the reduction of any known a-BOC-amino acid to the alcohol derivative followed by formation of the mesylate.
25 As noted above, the primary approaches to the preparation of lactams is the Beckmann/Schmidt ring expansion reaction using either inter- or intramolecular approaches serves to prepare lactams of various ring sizes. The intramolecular approach generates bicyclic materials with the lactam nitrogen incorporated into the ring fusion. Additional approaches set forth above involve the internal cyclization of omega-amino acids/esters where the construction of the substituent pattern takes place prior to cyclization, and internal cyclization of an electrophilic center onto a nucleophilic functional group as in the Friedel Crafts type cyclization ,.
used in the Ben-Ishal procedure for making benzazepinones. This latter procedure S is applicable to a wide variety of heteroaromatics as well as benzenoid rings, and may also be applied to non-aromatic double or triple bonds to generate a wide array of suhstituents or ring fusions.
Deoxygenation of the lactam by reagents such as diborane, LiAlH4, and the like leads to azaheterocycles (=X is dihydro).
Similarly, for X = H, OH, such compounds can be prepared by epoxidation of cycloalkenyl groups followed by oxirane opening by, e.g., ammonia. After formation of compounds of Formulas I-VI, =X being H, OH can be oxidized to provide for cycloalkylones (=X being oxo).
Additionally, the 5,7-dihydro-6H-dibenz[b,dJazepin-6-one derivatives employed in this invention can be prepared using conventional procedures and reagents. For example, an appropriately substituted N-tert-Boc-2-amino-2'-methylbiphenyl compound can be cyclized to form the corresponding 5,7-dihydro-6H-dibenz[b,dJazepin-6-one derivative by first treating the biphenyl compound with about 2.1 to about 2.5 equivalents of a strong base, such as sec-butyl lithium.
This reaction is typically conducted at a temperature ranging from about -80°C to about -60°C in an inert diluent such as THF. The resulting dianion is then treated with dry carbon dioxide at a temperature of about -78°C to afford the 5,7-dihydro-6H-diben[b,dJazepin-6-one. This procedure is described further in R. D. Clark et al., Tetrahedron, 49(7), 1351-1356 (1993) and references cited therein.

After forming the 5,7-dihydro-6H-dibenz[b,d]azepin-6-one, the amide nitrogen can be readily alkylated by first treating the dibenazepinone with about 1.1 to about 1.5 equivalents of a strong base, such as sodium hydride, in an inert diluent, such as DMF. This reaction is typically conducted at a temperature ranging from about -10°C to about 80°C for about 0.5 to about 6 hours. The resulting anion is then contacted with an 'excess, preferably about 1.1 to about 3.0 equivalents, of an alkyl halide, typically an alkyl chloride, bromide or iodide.
Generally, this reaction is conducted at a temperature of about 0°C to about 100°C
for about 1 to about 48 hours.
An amino group can then be introduced at the 5-position of the 7-alkyl-5,7-dihydro-6H-diben[b,d]azepin-6-one using conventional procedures and reagents.
For example, treatment of 7-methyl-5.7-dihydro-6H-diben(b,d]azepin-6-one with an excess of butyl nitrite in the presence of a strong base, such as potassium 1,1,1,3,3,3-hexamethyldisilazane (KHMDS), affords 5-oximo-7-methyl-5,7-dihydro-6H-diben[b,d]azepin-6-one. Subsequent reduction of the oximo group by hydrogenation in the presence of a catalyst, such as palladium on carbon, then provides 5-amino-7-methyl-5,7-dihydro-6H-diben(b,d]azepin-6-one. Other conventional amination procedures, such as azide transfer followed by reduction of the azido group, may also be employed.
Similarly, various benzodiazepine derivatives suitable for use in this invention can be prepared using conventional procedures and reagents. For example, a 2-aminobenzophenone can be readily coupled to a-(isopropylthio)-N-(benzyloxycarbonyl)glycine by first forming the acid chloride of the glycine derivative with oxalyl chloride, and then coupling the acid chloride with the aminobenzophenone in the presence of a base, such as 4-methylmorpholine, to afford the 2-[ -(isopropylthio)-N-(benzyloxycarbonyl)glycinyl]-aminobenzophenone. Treatment of this compound with ammonia gas in the presence of an excess, preferably about 1.1 to about 1.5 equivalents, of mercury (II) chloride then affords the 2-(N-(a-amino}-N -(benzyloxycarbonyl)-glycinyl]aminobenzophenone. This intermediate can then be readily cyclized by treatment with glacial acetic acid and ammonium acetate to provide the 3-S (benzyloxycarbonyl)amino-2.3-dihydro-5-phenyl-1H-1,4-benzodiazepin-2-onel.
Subsequent removal of the Cbz group affords the 3-amino-2,3-dihydro-5-phenyl-1 H-1,4-benzodiazepin-2-one.
Alternatively, 2,3-dihydro-S-phenyl-1H-1,4-benzodiazepin-2-ones can be readily aminated at the 3-position using conventional azide transfer reactions followed by reduction of the resulting azido group to form the corresponding amino group. The conditions for these and related reactions are described in the examples set forth below. Additionally, 2,3-dihydro-5-phenyl-1H-1,4-benzodiazepin-2-ones are readily alkylated at the 1-position using conventional procedures and reagents. For example, this reaction is typically conducted by first treating the benzodiazepinone with about 1.1 to about 1.5 equivalents of a base, such as sodium hydride, potassium tert-butoxide, potassium 1,1.1,3,3,3-hexamethyldisilazane, cesium carbonate, in an inert diluent, such as DMF. This reaction is typically conducted at a temperature ranging from about -78°C to about 80°C for about 0.5 to about 6 hours. The resulting anion is then contacted with an excess, preferably about 1.1 to about 3.0 equivalents, of an alkyl halide, typically an alkyl chloride, bromide or iodide. Generally, this reaction is conducted at a temperature of about 0°C to about 100°C for about 1 to about 48 hours.
Additionally, the 3-amino-2,4-dioxo-2,3,4,5-tetrahydro-1H-1,5-benzodiazepines employed in this invention are typically prepared by first coupling malonic acid with a 1,2-phenylenediamine. Conditions for this reaction are well known in the art and are described, for example, in PCT Application WO 96-US8400 960603. Subsequent alkylation and amination using conventional procedures and reagents affords various 3-amino-1,5-bis(alkyl)-2,4-dioxo-2,3,4,5-tetrahydro-1H-1,5-benzodiazepines. Such procedures are described in further detail in the example set forth below. "
Accordingly, a vast number of lactams, lactones and thiolactones are available by art recognized procedures. Similarly, the art is replete with examples of aminocycloaikyl compounds for use in the synthesis of compounds of Formulas I-VI above.
In the synthesis of the compounds described herein using the synthetic methods described above, the starting materials can contain a chiral center (e.g., alanine) and, when a racemic starting material is employed, the resulting product is a mixture of R,S enantiomers. Alternatively, a chiral isomer of the starting material can be employed and, if the reaction protocol employed does not racemize this starting material, a chiral product is obtained. Such reaction protocols can involve inversion of the chiral center during synthesis.
Pharmaceutical Formulations When employed as pharmaceuticals, the compounds described herein are usually administered in the form of pharmaceutical compositions. These compounds can be administered by a variety of routes including oral, rectal, transdermal, subcutaneous, intravenous, intramuscular, and intranasal. These compounds are effective as both injectable and oral compositions. Such compositions are prepared in a manner well known in the pharmaceutical art and comprise at least one active compound.
The pharmaceutical compositions contain, as the active ingredient, one or more of the compounds described above, associated with pharmaceutically acceptable carriers. The pharmaceutical compositions can be prepared, for example, by mixing the active ingredient with an excipient, diluting the active ingredient with an excipient, or enclosing the active ingredient within a carrier such as a capsule (including microparticles, nanoparticles, and liposomes), sachet, paper or other container. When the excipient serves as a diluent, it can be a solid, semi-solid, or liquid material, which acts as a vehicle, carrier or medium for the active ingredient. Thus, the compositions can be in the form of tablets, pills, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols (as a solid or in a liquid medium), ointments containing, for example, up to 10% by weight of the active compound, soft and hard gelatin capsules, suppositories, sterile injectable solutions, and sterile packaged powders.
In preparing a formulation, it may be necessary to mill the active compound to provide the appropriate particle size prior to combining with the other ingredients. If the active compound is substantially insoluble, it ordinarily is milled to a particle size of less than 200 mesh. If the active compound is substantially water soluble, the particle size is normally adjusted by milling to provide a substantially uniform distribution in the formulation, e.g. about 40 mesh.
Some examples of suitable excipients include lactose, dextrose, sucrose, sorbitol, mannitol, starches, gum acacia, calcium phosphate, alginates, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, sterile water, syrup, and methyl cellulose. The formulations can additionally include: lubricating agents such as talc, magnesium stearate, and mineral oil; wetting agents; emulsifying and suspending agents; preserving agents such as methyl- and propylhydroxy-benzoates; sweetening agents; and flavoring agents. The compositions of the invention can be formulated so as to provide quick, sustained or delayed release of the active ingredient after administration to the patient by employing procedures known in the art.

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

WO 99/67221 PC'T/US99/14193 The tablets or pills of the present invention may be coated or otherwise compounded to provide a dosage form affording the advantage of prolonged action. For example, the tablet or pill can comprise an inner dosage and an outer dosage component, the latter being in the form of an envelope over the former.
The two components can separated by enteric Layer which serves to resist disintegration in the stomach and permit the inner component to pass intact into the duodenum or to be delayed in release. A variety of materials can be used for such enteric layers or coatings, such materials including a number of polymeric acids and mixtures of polymeric acids with such materials as shellac, cetyl alcohol, and cellulose acetate.
The liquid forms in which the compositions may be incorporated for administration orally or by injection include aqueous solutions, suitably flavored syrups, aqueous or oil suspensions, and flavored emulsions with edible oils such as cottonseed oil, sesame oil, coconut oil, or peanut oil, as well as elixirs and similar pharmaceutical vehicles.
Compositions for inhalation or insufflation include solutions and suspensions in pharmaceutically acceptable, aqueous or organic solvents, or mixtures thereof, and powders. The liquid or solid compositions may contain suitable pharmaceutically acceptable excipients as described supra. Preferably the compositions are administered by the oral or nasal respiratory route for local or systemic effect. Compositions in preferably pharmaceutically acceptable solvents may be nebulized by use of inert gases. Nebulized solutions may be breathed directly from the nebulizing device or the nebulizing device may be attached to a face masks tent, or intermittent positive pressure breathing machine.
Solution, suspension, or powder compositions may be administered, preferably orally or nasally, from devices which deliver the formulation in an appropriate manner.

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

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

WO 99!67221 PCT/US99/14193 sieve. The granules so produced are dried at 50 to 60°C and passed through a 16 mesh U.S. sieve. The sodium carboxymethyl starch, magnesium stearate, and talc, previously passed through a No. 30 mesh U.S. sieve, are then added to the granules which, after mixing, are compressed on a tablet machine to yield tablets each weighing 150 mg.
Formulation Exam~~5, Capsules, each containing 40 mg of medicament are made as follows:
Quantity Ingredient ~mgJc_~e) Active Ingredient 40.0 mg Starch ~ 109.0 mg Magnesium stearate 1.0 mg Total 150.0 mg The active ingredient, starch, and magnesium stearate are blended, passed through a No. 20 mesh U.S. sieve, and filled into hard gelatin capsules in 150 mg quantities.
Formulation Example 6 Suppositories, each containing 25 mg of active ingredient are made as follows:
Active Ingredient 25 mg Saturated fatty acid glycerides to 2,000 mg The active ingredient is passed through a No. 60 mesh U.S. sieve and suspended in the saturated fatty acid glycerides previously melted using the minimum heat necessary. The mixture is then poured into a suppository mold of nominal 2.0 g capacity and allowed to cool.
Formulation Example 7 Suspensions, each containing 50 mg of medicament per 5.0 ml dose are made as follows:
Active Ingredient 50.0 mg Xanthan gum 4.0 mg Sodium carboxymethyl cellulose (11%) Microcrystalline cellulose (89%) 50.0 mg Sucrose 1.75 g Sodium benzoate 10.0 mg Flavor and Color q.v.
Purified water to 5.0 ml The active ingredient, sucrose and xanthan gum are blended, passed through a No. 10 mesh U.S. sieve, and then mixed with a previously made solution of the microcrystalline cellulose and sodium carboxymethyl cellulose in water. The sodium benzoate, flavor, and color are diluted with some of the water and added with stirring. Sufficient water is then added to produce the required volume.

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

~cLrmulation Exam lie 10 A topical formulation may be prepared as follows:
Active Ingredient 1-10 g Emulsifying Wax 30 g Liquid Paraffin 20 g White Soft Paraffin to 100 g The white soft paraffin is heated until molten. The liquid paraffin and emulsifying wax are incorporated and stirred until dissolved. The active ingredient is added and stirring is continued until dispersed. The mixture is then cooled until solid.
Another preferred formulation employed in the methods of the present invention employs transdermal delivery devices ("patches"). Such transdermal patches may be used to provide continuous or discontinuous infusion of the compounds of the present invention in controlled amounts. The construction and use of transdermal patches for the delivery of pharmaceutical agents is well known in the art. ee. e.~., U.S. Patent 5.023,252, issued June 11, 1991, herein incorporated by reference. Such patches may be constructed for continuous, pulsatile, or on demand delivery of pharmaceutical agents.
Frequently, it will be desirable or necessary to introduce the pharmaceutical composition to the brain, either directly or indirectly. Direct techniques usually involve placement of a drug delivery catheter into the host's ventricular system to bypass the blood-brain barrier. One such implantable delivery system used for the transport of biological factors to specific anatomical regions of the body is described in U.S. Patent 5,011,472 which is herein incorporated by reference.
Indirect techniques, which are generally preferred, usually involve formulating the compositions to provide for drug Iatentiation by the conversion of hydrophilic drugs into lipid-soluble drugs. Latentiation is generally achieved through blocking of the hydroxy, carbonyl, sulfate, and primary amine groups present on the drug to render the drug more lipid soluble and amenable to transportation across the blood-brain barrier. Alternatively, the delivery of hydrophilic drugs may be enhanced by intra-arterial infusion of hypertonic solutions which can transiently open the blood-brain barrier.
Other suitable formulations for use in the present invention can be found in Remington's Pharmaceutical Sciences, Mace Publishing Company, Philadelphia, PA, 17th ed. ( 1985).
Utility The compounds and pharmaceutical compositions of the invention are useful in inhibiting (3-amyloid peptide release and/or its synthesis, and, accordingly, have utility in diagnosing and treating Alzheimer's disease in mammals including humans.
As noted above, the compounds described herein are suitable for use in a variety of drug delivery systems described above. Additionally, in order to enhance the in vivo serum half life of the administered compound, the compounds may be encapsulated, introduced into the lumen of liposomes, prepared as a colloid, or other conventional techniques may be employed which provide an extended serum half-life of the compounds. A variety of methods are available for preparing liposomes, as described in, e.g., Szoka, et al., U.S. Patent Nos.

4,235,871, 4,501,728 and 4,837,028, the contents of each of which is incorporated herein by reference.
The amount of compound administered to the patient will vary depending upon what is being administered, the purpose of the administration, such as prophylaxis or therapy, the state of the patient, the manner of administration, and the like. In therapeutic applications, compositions are administered to a patient already suffering from AD in an amount sufficient to at least partially arrest further onset of the symptoms of the disease and its complications. An amount adequate to accomplish this is defined as "therapeutically effective dose."
Amounts effective for this use will depend on the judgment of the attending clinician depending upon factors such as the degree or severity of AD in the patient, the age, weight and general condition of the patient, and the like.
Preferably, for use as therapeutics, the compounds described herein are administered at dosages ranging from about 1 to about 500 mg/kg/day.
In prophylactic applications. compositions are administered to a patient at risk of developing AD (determined for example by genetic screening or familial trait) in an amount sufficient to inhibit the onset of symptoms of the disease. An amount adequate to accomplish this is defined as a "prophylactically effective dose."
Amounts effective for this use will depend on the judgment of the attending clinician depending upon factors such as the age, weight and general condition of the patient, and the like. Preferably, for use as prophylactics, the compounds described herein are administered at dosages ranging from about 1 to about S00 mg/kg/day.
As noted above, the compounds administered to a patient are in the form of pharmaceutical compositions described above. These compositions may be sterilized by conventional sterilization techniques, or may be sterile filtered. The resulting aqueous solutions may be packaged for use as is, or lyophilized, the lyophilized preparation being combined with a sterile aqueous carrier prior to administration. The pH of the compound preparations typically will be between and l I, more preferably from S to 9 and most preferably from 7 and 8. It will be understood that use of certain of the foregoing excipients, carriers, or stabilizers will result in the formation of pharmaceutical salts.
The compounds described herein are also suitable for use in the administration of the compounds to a cell for diagnostic and drug discovery purposes.
Specifically, the compounds may be used in the diagnosis of cells releasing andlor synthesizing ~3-amyloid peptide. In addition the compounds described herein are useful for the measurement and evaluation of the activity of other candidate drugs on the inhibition of the cellular release and/or synthesis of ~3-amyloid peptide.
1 S The following synthetic and biological examples are offered to illustrate this invention and are not to be construed in any way as limiting the scope of this invention.
EXAMPLES
In the examples below, the following abbreviations have the following meanings. If an abbreviation is not defined, it has its generally accepted meaning.
BEMP - 2-tert-butylimino-2-diethylamino-1,3-dimethylperhydro-1,3,2-diazaphosphorine Boc - t-butoxycarbonyl BOP - benzotriazol-1-yloxy-tris (dimethylamino)phosphonium hexafluorophosphate bd - broad doublet bs - broad singlet d - doublet dd - doublet of doublets DIC - diisopropylcarbodiimide ., DMF - dimethylformamide DMAP - dimethylaminopyridine DMSO - dimethylsulfoxide EDC - ethyl-1-(3-dimethyaminopropyl'carbodiimide eq. - equivalents EtOAc - ethyl acetate g - grams HOBT - 1-hydroxybenzotriazole hydrate Hunig's base diisopropylethylamine -L - liter m - multiplet i M - molar S

max - maximum meq - milliequivalent mg - milligram mL - milliliter mm - millimeter mmol - millimole MOC - methoxyoxycarbonyl N - normal N/A - not available ng - nanogram nm - nanometers OD - optical density PEPC - 1-(3-(1-pyrrolidinyl)propyl)-3-ethylcarbodiimide PP-HOBT - piperidine-piperidine-1-hydroxybenzotrizole psi - pounds per square inch - phenyl q - quartet ,.

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

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

WO 99/67221 PC'T/US99/14193 The term "Advanced Chemtech" indicates that the compound or reagent is commercially available from Advanced Chemtech, Louisville, KY.
The term "Pfaltz & Bauer" indicates that the compound or reagent is commercially available from Pfaltz & Bauer, Waterbury, CT, USA.
I. Cou~g Procedures GENERAL PROCEDURE A
first EDC Coupiing Procg~re, To a 1:1 mixture of the corresponding carboxylic acid and the corresponding amino acid ester or amide in CH2C12 at O C was added 1.5 equivalents triethylamine, followed by 2.0 equivalents hydroxybenzotriazole monohydrate and then 1.25 equivalents of ethyl-3-(3-dimethylamino)propyl carbodiimide HCI. The reaction mixture was stirred overnight at room temperature and then transferred to a separatory funnel. The mixture was washed with water, saturated aqueous NaHC03, 1N HCl and saturated aqueous NaCI, and then dried over MgS04. The resulting solution was stripped free of solvent on a rotary evaporator to yield the crude product.
GENERAL PROCEDURE B
Second EDC Coupj'~g Procedure A mixture of the corresponding acid (1 eqv), N-1-hydroxybenzotriazole (1.6 eqv), the corresponding amine (1 eqv), N-methylmorpholine ( 3 eqv) and dichloromethane (or DMF for insoluble substrates) was cooled in an ice-water bath and stirred until a clear solution was obtained. EDC (1.3 eqv) was then added to the reaction mixture. The cooling bath was then allowed to warm to ambient temperature over 1-2 h and the reaction mixture was stirred overnight. The reaction mixture was then evaporated to dryness under vacuum. To the residue was added 20% aqueous potassium carbonate and the mixture was shaken throughly and then allowed to stand until the oily product solidified (overnight if necessary). The solid product was then collected by filtration, washed thoroughly <.
with 20% aqueous potassium carbonate, water, 10% HCI, and water to give the product, usually in pure state. No racemization was observed.
GENERAL PROCEDURE C
Third EDC Cou lei g Procedure The carboxylic acid was dissolved in methylene chloride. The corresponding amino acid ester or amide (1 eq.), N-methylmorpholine (5 eq.) and hydroxybenzotriazole monohydrate (1.2 eq.) were added in sequence. A cooling bath was applied to the round bottomed flask until the solution reached 0°C. At that time, 1.2 eq. of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride was added. The solution was allowed to stir overnight and come to room temperature under nitrogen pressure. The reaction mixture was worked up by washing the organic phase with saturated aqueous sodium carbonate, O.1M citric acid, and brine before drying with sodium sulfate. The solvents were then removed to yield crude product.
GENERAL PROCEDURE D
Fourth EDC Coupling Procedure A round bottom flask was charged with the corresponding carboxylic acid (1.0 eq.), hydroxybenzotriazole hydrate (1.1 eq.) and the corresponding amine (1.0 eq.) in THF under nitrogen atmosphere. An appropriate amount (1.1 eq for free amines and 2.2 eq. for hydrochloride amine salts) of base, such as Hunig's base was added to the well stirred mixture followed by EDC (1.1 eq.). After stirring from 4 to 17 hours at room temperature the solvent was removed at reduced pressure, the residue taken up in ethyl acetate (or similar solvent) and water, washed with saturated aqueous sodium bicarbonate solution, 1 N HCI, brine, dried over anhydrous sodium sulfate and the solvent removed at reduced pressure to provide the product.
GENERAL PROCEDURE E
BOP Cou~ng Proce ure To a stirred solution of N (3,5-difluorophenylacetyl)alanine (2 mmol) in DMF, cooled in an ice-water bath, was added BOP (2.4 mmol) and N
methylmorpholine (6 mmol). The reaction mixture was stirred for 50 min. and then a solution of a-amino-a-lactam (2 mmol) in DMF cooled at 0 °C was added.
The cooling bath was allowed to warm to ambient temperature over 1-2 h and the reaction mixture was then stirred overnight. A 20% aqueous potassium carbonate solution (60 mL) was added and this mixture shaken throughly. No solid formed.
The mixture was then washed with ethyl acetate (150 mL) and evaporated to dryness under vacuum to give a white solid. Water (SO mL) was then added and this mixture was shaken throughly. The precipitate that formed was collected by filtration, then washed thoroughly with water, followed by 1 mL of diethyl ether to give the product (51 mg, 0.16 mmol, 7.8%).
GENERAL PROCEDURE F
Coupling of an Acid Chloride with an Amino Acid Ester To a stirred solution of (D,L)-alanine isobutyl ester hydrochloride (4.6 mmol) in 5 ml of pyridine was added 4.6 mmol of the acid chloride. Precipitation occurred immediately. The mixture was stirred for 3.5 h, dissolved in 100 mL
of diethyl ether, washed with 10% HCl three times, brine once. 20% potassium carbonate once and brine once. The solution was dried over magnesium sulfate, filtered, and evaporated to yield the product. Other amino acid esters may also be employed in this procedure.
GENERAL PROCEDURE G

~oy~ling of a Carboxylic Acid with an Amino Acid Ester A solution of the carboxylic acid (3.3 mmol) and 1,1'-carbodiimidazole (CDI) in 20 mL THF was stirred for 2 h. (D,L)-alanine isobutyl ester hydrochloride (3.6 mmol) was added, followed by 1.5 mL (10.8 mmol) of triethylamine. The reaction mixture was stirred overnight. The reaction mixture was dissolved in 100 mL of diethyl ether, washed with 10% HCI three times, brine once, 20% potassium carbonate once and brine once. The solution was dried over magnesium sulfate, filtered, and evaporated to yield the product. Other amino acid esters may also be employed in this procedure.
GENERAL PROCEDURE H
Fifth EDC Coupling Procedure In a round bottom flask was added a carboxylic acid (1.1 eq.) in THF, an amine hydrochloride (1.0 eq.), 1-hydroxybenzotriazole hydrate (1.1 eq.). N,N-diisopropylethylamine (2.1 eq.), followed by 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC) (1.I eq.). The reaction mixture stirred at room temperature for 10-20 hours under an atmosphere of nitrogen. The mixture was diluted with EtOAc and washed with 0.1 M HCl (1 x 10 mL), saturated NaHC03 (1 x 10 mL), H20 (1 x 10 mL), and brine and dried over MgS04. The drying agent was removed by filtration and the filtrate was concentrated in vacuo.
The residue was purified by flash column chromatography on silica gel followed by trituration from EtOAc and hexanes.
GENERAL PROCEDURE I
sixth EDC Coupling Proc~r_e To a solution or suspension of the amine or amine hydrochloride (1.0 eq.) in THF (0.05-0.1 M) under N2 at 0°C was added the carboxylic acid (1.0-1.1 eq.), hydroxybenzotriazole monohydrate (l.l-1.15 eq.), Hunig's base (1.1 eq. for free amines and 1.1-2.3 eq. for hydrochloride amine salts), followed by 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.1-1.15 eq.). The cooling bath was removed and the mixture allowed to warm to room temperature for 10-24 hours. The solution or mixture was diluted with EtOAc, in a 3-5 volume multiple of the initial THF volume, and washed with 0.1-1.0 M aq. HCI
(1 or 2x), dilute NaHC03 (1 or 2x), and brine (lx). Then, the organic phase was dried over either MgS04 or Na2S04, .filtered, concentrated to provide the crude product, which was either further purified or utilized without further purification.
GENERAL PROCEDURE J
EEDQ CouDing Procedure To a solution of the amine in THF (1.0 eq., 0.05-0.08 M, final molarity) under N2 at room temperature was added the N-t-Boc protected amino acid (1.1 eq., either as a solid or in THF via cannula), followed by EEDQ (Aldrich, 1.1 eq.). The pale yellow solution was stirred at room temperature for 16-16.5 hours, then diluted with EtOAc (in a 3-5 volume multiple of the initial THF volume), and washed with 1M aq. HCl (2x), dilute aq. NaHC03 (2x), and brine (lx). The organic phase was dried over either Na2S04 or MgS04, filtered, and concentrated.
II. ~:arboxylic Acids GENERAL PROCEDURE II-A
Ester Hvdrolvsis to Free Acid Ester hydrolysis to the free acid was conducted by conventional methods.
Below are two examples of such conventional de-esterification methods.
Method A To a carboxylic ester compound in a l: l mixture of CH30H/H20 was added 2-5 equivalents of K2C03. The mixture was heated to 50°C for 0.5 to 1.5 hours until tlc showed complete reaction. The reaction was cooled to room temperature and the methanol was removed on a rotary evaporator. The pH of the remaining aqueous solution was adjusted to -2, and ethyl acetate was added to extract the product. The organic phase was then washed with saturated aqueous ..
NaCI and dried over MgS04. The solution was stripped free of solvent on a rotary evaporator to yield the product.
Method B: The amino acid ester was dissolved in dinxane/water (4:1) to which was added LiOH ( - 2 eq.) that was dissolved in water such that the total solvent after addition was about 2:1 dioxane:water. The reaction mixture was stirred until reaction completion and the dioxane was removed under reduced.
pressure. The residue was dissolved in water and washed with ether. The layers were separated and the aqueous layer was acidified to pH 2. The aqueous layer was extracted with ethyl acetate. The ethyl acetate extracts were dried over Na2S04 and the solvent was removed under reduced pressure after filtration.
The residue was purified by conventional methods (e.g., recrystallization).
GENERAL PROCEDURE II-B
Awid Chloride Pre aration A carboxylic acid is dissolved in dichloromethane and this solution is cooled to 0°C. DMF (0.5 mL, catalytic) is added, followed by the dropwise addition of oxalyl chloride (18 mL, 0.20 mol) over a 5 minute period. The reaction is stirred for 3 h and then rotoevaporated at reduced pressure to give an oil which is placed on a high vacuum pump for 1 h to afford the acid chlorides.
GENERAL PROCEDURE II-C
Schotten-Baumann Procedure The acid chloride (from General Procedure II-B} is added dropwise to a 0°C
solution of L-alanine (Aldrich) (16.7 g, 0.187 mol) in 2 N sodium hydroxide (215 mL, 0.43 mol) or another amino acid such as tert-leucine or phenyl glycine.
The reaction is stirred for 1 h at 0°C and then overnight at room temperature. The reaction is diluted with water (100 mL), then extracted with ethyl acetate (3 x 150 mL). The organic layer is then washed with brine (200 mL), dried over MgS04, ..
and rotoevaporated at reduced pressure to a residue. Recrystallization of the residue from ethyl acetate/hexanes affords the desired product in high yield.
GENERAL PROCEDURE II-D
To a solution of an arylamine in ethanol in a hydrogenation flask is added 1 equivalent of a 2-oxocarboxylic acid ester (e.g., pyruvate ester), followed by 10%
palladium on carbon (25 weight percent based on the arylamine). The reaction mixture is hydrogenated at 20 psi H2 on a Parr shaker until complete reaction is indicated by tlc (30 minutes to 16 hours). The reaction mixture is then filtered through a pad of Celite 545 (available from Aldrich Chemical Company, Inc.) and stripped free of solvent on a rotary evaporator. The crude product residue can then be further purified via chromatography.
3. Cvclic Kelqne Derivatives Jones Oxidation Procedure The compound to be oxidized is stirred in acetone and the Jones reagent is added in portions until the starting material is consumed. The reaction mixture is quenched with isopropanol and the mixture is filtered through Celite and concentrated under reduced pressure. The residue is partitioned between ethyl acetate and water and the organic portion is dried over sodium sulfate and then concentrated under reduced pressure. The crude product is purified by silica gel chromatography and/or recrystallization.

Swern Oxidation Procedure To a stirred mixture of oxalyl chloride (0.1.5 mL, 1.2 mmol) in 10 mL of dichloromethane cooled to -78°C is added DMSO (0.106 mL, 1.5 mmol) and the S mixture is stirred for 10 minutes. A solution of the alcohol (0.1828 g, 0.60 mmol) in 20 mL of chloroform is added dropwise. The reaction mixture is stirred at -78°C for 2 hours, and then 0.5 mL (3.6 mmol) of triethylamine is added.
Stirring is continued for 1 hour and then the mixture is allowed to warm to room temperature and stirring is continued at ambient temperature overnight. The mixture is then diluted with SO mL of dichloromethane, washed with brine '(3x), dried over magnesium sulfate, filtered and evaporated to dryness to give a crude product that is typically purified by column chromatography.
5. Lactams N Alkylation of Lactams To a stirred solution of a BOC-protected a-aminocaprolactam (6.87 g, 30 mmol) in DMF (150 mL) was added in portions 97% NaH (1.08g, 45 mmol).
Bubbling occurred immediately and followed by heavy precipitation. After 10 min., benzyl bromide (3.93 mL, 33 mmol) was added. The precipitate dissolved quickly and in about 10 min. a clear solution was obtained. The reaction mixture was stirred overnight and then evaporated as completely as possible on a rotovap at 30°C. Ethyl acetate (100 mL) was added to the residue and this mixture was washed with water, brine, and dried over magnesium sulfate. After filtration and concentration, a thick liquid (10 g) was obtained which was then chromatographed over silica gel with 1:3 ethyl acetate/hexane as the eluant to provide 5.51 g (58% ) of the N-benzylated product as an oil. Other lactams and alkylating agents may be used in this procedure to obtain a wide variety of N-alkylated lactams.
Various bases, such as LiN(SiMe3), may also be employed.

BOC Removal Procedure The BOC-protected compound in a 1:1-2:1 mixture of CH2C12 and trifluoroacetic acid was stirred until tlc indicated complete conversion, typically 2 hours. The solution was then stripped to dryness and the residue was taken up in ethyl acetate or CH2C12. The solution was washed with saturated aqueous NaHC03 and the aqueous phase was adjusted to a basic pH, then extracted with ethyl acetate or CH2Cl2. The organic phase was washed with saturated aqueous NaCI and dried over MgS04. The solution was stripped free of solvent on a rotary evaporator to yield the product.

S~rnthesis of A-Aminolactams The Schmidt reaction was conducted on 4-ethylcyclohexanone using hydroxyamine sulfonic acid as described in Olah, Org. Synth. Collective, Vol.
VII, page 254, to provide 5-ethylcaprolactam in 76% yield. Using the procedure described in Watthey, et al., J. Med. Chem., 1985, 28, 1511-1516, this lactam was then dichlorinated with PC15 at the a position and reduced by hydrogenation to provide four isomeric monochlorides (two racemic mixtures). The two racemic mixtures were separated from each other by column chromatography using silica gel and each racemic mixture was reacted with sodium azide to yield the corresponding azide, which was hydrogenated to provide the corresponding a-aminolactams. Other cycloalkanones may be employed in this procedure to provide a wide variety of a-aminolactams. In some cases, such as when preparing the 9-membered ring a-aminolactam, longer reaction times, higher reaction temperatures and an excess of sodium azide may be required. For example, the 9-membered ring a-aminolactam required 5 equivalents of sodium azide, a reaction temperature of 120°C and a reaction time of 4 days. Such conditions can be readily determined by those of ordinary skill in the art.

e,.rt~,P~;~ .,f 4-A ino-1 2 3 4-tetrahydroisoa,~j~lline-3-ones ~L,.~.."
The 4-amino-1,2,3,4-tetrahydroisoquinoline-3-one derivatives employed in this invention can be prepared by the following art-recognized procedures. The conditions for these reactions are further described in D. Ben-Ishai, et al., Tetrahedron, 43, 439-450 (1987). The following intermediates were prepared via this procedure:
3-amino-1,2,3,4-tetrahydroisoquinolin-3-one 4-amino-7-benzyl-1,2,3,4-tetrahydroisoquinolin-3-one 4-amino-1-phenyl-1,2,3,4-tetrahydroisoquinolin-3-one IS cis and traps-4-amino-1-phenyl-1,2,3,4-tetrahydroisoquinolin-3-one 4-amino-2-phenethyl-1,2,3,4-tetrahydroisoquinolin-3-one 4-amino-2-methy 1-1, 2 , 3 , 4-tetrahydroisoqu inolin-3-one 9-amino(fluoren-1-yl)glycine d-lactam-1,2,3,4-tetrahydroisoquinolin-3-one.
St~eR A Pr.~paration of N Bismethox~arbonvlaminoacetic Acid To one mole equivalent of glyoxylic acid in 2 liters of ethanol-free chloroform was added two mole equivalents of methyl carbamate and 0. I mole equivalent of naphthalene sulfonic acid. The reaction mixture was then brought to a reflux for 6 hours.
Water was removed using an inverse Dean Stark trap. The reaction was then cooled and the product filtered and washed with chloroform. The white solid was recrystallized from ethyl acetate/hexanes to give a white powder in 65 %
yield.
S~te~B - Coupling Procedure: To 0.0291 moles of N-bismethoxycarbonylaminoacetic acid (or the appropriate carbocyclic acid) in WO 99/67221 PC'T/US99/14193 mL of THF was added one mole equivalent of EDCCHCI, a benzylamine, HOBT, and diisopropylethylamine. The reaction was allowed to stir at room temperature for 18 hours and then poured into a separatory funnel and extracted into ethyl ..
acetate. The ethyl acetate solution was washed with 1 molar IC2C0, and then 1 molar HCI. The organic layer was dried over NazS04, filtered and solvent removed to give the crystalline benzylamide of N-bismethoxycarbonylaminoacetic acid. This material was used without further purification. Typical yields range from 40 - 55 % .
~p C-Cvclization Procedure: The benzylamide of N-bismethoxycarbonylaminoacetic acid (0.008 moles) was dissolved in 75 mL of methanesulfonic acid and allowed to stir over night at room temperature. The reaction mixture was poured over ice and extracted into ethyl acetate. The ethyl acetate extract was washed with 1 molar K,C03 and then 1 N HCI. The organic layer was dried over Na,SO,, filtered and the solvent removed to give the crystalline 4-methoxycarbonylamino-1,2,3,4-tetrahydroisoquinoline-3-one in 50-90% yield. This material was used without further purification.
~lPp D - Removal of the MethoxYoxvcarbony_ls'u_o~p~MOC): To the 4-methoxycarbonylamino-1,2,3,4-tetrahydroisoquinoline-3-one (3.4 mmoles) in 30 mL of acetonitrile was added 2 mole equivalents of trimethylsilyliodide (TMSI).
The reaction mixture was heated to 50-80°C for 3 hrs and then cooled and poured into a separatory funnel. The reaction mixture was diluted with ethyl acetate and washed with 1 molar K,C03 and then with 5 %a NaHS03. The organic layer was dried over Na~S04 and filtered. The solvent was removed under reduced pressure to give the 4-amino-1,2,3,4-tetrahydroisoquinoline-3-one derivative. Typical yields range from 50-87 % .

$xP,~ F - Alternative Procedure for Removal of the Methoxyoxvcarbonyl Group To 3.8 mmoles of the MOC-protected compound was added 10 mL of 30% HBr in acetic acid and this reaction mixture was heated to 60°C for 3 hrs.
The mixture was then cooled and hexanes were added. The hexanes layer was decanted off and the residue as placed under reduced pressure to give a tan solid.
This solid was slurried in ether and filtered to give the 4-amino-1,2,3,4-tetrahydroisoquinoline-3-one hydrobromide salt. Typical yields range from 57-88%.
Example 5-A
Synthesis of 3-Amino-1,2,3,4-tetrahydroquinolin-2-one Sodium (0.308, 1 l OM % ) was added to anhydrous ethanol (45 mL) and the reaction mixture was stirred until homogenous. Diethyl N-1 S acetylaminomalonate (2.51 g, 100 M % ) was added in one portion and this mixture was stirred for 1 h. 2-Nitrobenzyl bromide (2.Sg, 100M%) was then added in one portion and the reaction mixture was stirred for 3 h. The reaction was poured into water and extracted with ethyl acetate (3x) and then backwashed with water (3x) and brine (lx). Treatment with MgSO~, rotoevaporation, and chromatography (30% EtOAc/hexanes) yielded diethyl N-acetylamino-2-nitrobenzylmalonate in 82% yield.
Step B: Diethyl N-acetylamino-2-nitrobenzylmalonate (lg, 100M%) was dissolved in a minimum amount of EtOH. Pd/C (10%a, O.OSg) was added and the reaction mixture was subjected to 50 psi of HZ for 3 hours. The reaction was then filtered thru a pad of celite. Additional EtOH (25mL) and TsOH (catalytic amount, O.OIg) were added and this mixture was refluxed for 2 hours. The reaction was rotoevaporated to a residue and then partitioned between water and ethyl acetate. The water layer was extracted with ethyl acetate (3x) and the combined ethyl acetate extracts were washed with water (3x) and then brine (lx).
Treatment with MgS04 and rotoevaporation yielded pure 3-(N-acetylamino)-3-carboethoxy-1,2,3,4-tetrahydroquinolin-2-one (89% yield). ..
Step C: 3-(N-Acetylamino)-3-carboethoxy-1,2,3,4-tetrahydroquinolin-2-one (0.75 g, 100M%) was suspended in 6N HCl (25 mL) and the mixture was heated to 100°C for 3 hours. The reaction was cooled, rotoevaporated to a residue and then partitioned between water and ethyl acetate. The water was extracted with ethyl acetate (3x) and the combined ethyl acetate extracts were then washed with water (3x) and then brine (lx). Treatment with MgS04 followed by rotoevaporation yielded 3-(R,S)-amino-1,2,3,4-tetrahydroquinolin-2-one (72%
yield).
Example 5-B
Synthesis of 4-Amino-1-(pyrid-4-yl)-1,2,3,4-tetrahydroisoquinolin-3-one Step A: To a solution of 4-cyanopyridine (Aldrich) (0.150 moles) in 300 mL of dry ether was added 1.1 eq. of phenylmagnesium bromide (Aldrich) dropwise. The reaction was refluxed for 2 hours and then stirred overnight at room temperature. Sodium borohydride (1.0 eq.) was added dropwise as a solution in 200 mL of methanol (CAUTION -- very exothermic). The reaction was then heated to reflux for 6 hours, cooled and quenched with a saturated solution of ammonium chloride. The solution was decanted from the salt in the reaction mixture and acidified with 1N HCI. After washing the aqueous layer with ethyl acetate, the pH of aqueous layer was adjusted to about 9.0 with 1N
sodium hydroxide (cold). The aqueous layer was then extracted with ethyl acetate and the organic extracts washed with brine, dried over NazS04, filtered and concentrated to give 4-pyridyl-a-benzyl amine as a thick yellow oil.
Sten B: Following General Procedure 5-D and using 4-pyridyl-a-benzyl amine, the title compound was prepared.

Example 5-C
Synthesis of ,.
4-Amino-I-(pyrid-2-yl)-1,2,3,4-tetrahydroisoquinolin-3-one ~R~ 2-Pyridyl-a-benzyl amine was prepared by substituting 2-cyanopyridine (Aldrich) for 4-cyanopyridine in the procedure described in Example 5-B.
Step B: Following General Procedure 5-D and using 4-pyridyl-a-benzyl amine, the title compound was prepared.
Example 5-D
Synthesis of 4-Amino-1-(pyrid-3-yl)-1,2,3,4-tetrahydroisoquinolin-3-one Stet A: Following the procedure described in J. Med. Chem., 1982, 25, 1248, and using 3-benzoyl-pyridine (Aldrich), 3-pyridyl-a-benzyl amine was prepared.
Ste~B: Following General Procedure 5-D and using 3-pyridyl-a-benzyl amine, the title compound was prepared.
Example 5-E
Synthesis of 4-Amino-7-benzyl-1,2,3,4-tetrahydroisoquinolin-3-one SteR A: To a Parr bottle containing 3-benzoylbenzoic acid (0.044 moles) (Aldrich) in 150 mL of ethyl acetate and 4.5 mL of concentrated I~S04 was added 10 grams of 5 % Pd/C. The mixture was hydrogenated on a Pan apparatus under hydrogen (45 psi) overnight. The reaction mixture was then filtered through Hyflo, washing with ethyl acetate. The filtrate was dried over NazS04, filtered WO 99/67221 PC'T/US99/14193 and concentrated to give an oil. The oil was slurried in hexane and the resulting white solid was collected by filtration to afford 3-benzylbenzoic acid, which was used without further purification.
Step B: To the product from Step A (0.0119 moles) was added 150 mL of CH2C1,, one drop of DMF, 10 mL of oxalyl chloride, and the mixture was stirred at room temperature for 3 hours. After cooling to 10°C, 30 mL of NI-~,OH
(exothermic) was added and the mixture was stirred for 30 min. The reaction mixture was then concentrated and the resulting residue diluted with ethyl acetate.
The organic layer was washed with 1 N NaOH, brine, dried over Na~S04, and concentrated to give the 3-(benzyl)benzamide as a white solid, which was used without further purification.
Step C: To a solution of 3-(benzyl)benzamide (.0094 moles) from Step B
I 5 in 70 of toluene was added 8 mL of Red-Al7 (65 + wt. % solution of sodium bis(2-methoxyethoxy)aluminum hydride in toluene, Aldrich) (CAUTION --reaction very exothermic). The reaction mixture was then heated at 60°C
for 2 hours and then poured over ice. The resulting mixture was extracted with ethyl acetate and the combined extracts were washed with water and brine. The organic layer was extracted with 1N HC1 and the aqueous layer washed with ethyl acetate.
The pH of the aqueous layer was then adjusted to about 9.0 with 1N NaOH and extracted with ethyl acetate. The organic extracts were washed with water and brine and then concentrated to give 3-(benzyl)benzyl amine.
St~D: Following General Procedure 5-D and using 3-(benzyl)benzyl amine, the title compound was prepared.
Example S-F
Synthesis of WO 9916'7221 PCT/US99/14193 4-Amino-6-phenyl-1,2,3,4-tetrahydroisoquinolin-3-one step A: To a solution of 4-biphenylcarboxamide (Aldrich) (0.025 mole) in 150 mL of THF cooled to 10°C was added a solution of 1.5 eq of LAH (1M
in THF) dropwise. The reaction mixture turned from a white slurry to a green homogenous solution and then to a yellow homogeneous solution. The reaction was then quenched with 2.5 mL of 1N NaOH. The mixture was then filtered through Hyflo and extracted with ethyl acetate. The organic layer was then washed with 1 N HCI. The pH of the resulting aqueous layer was adjusted to about 9 with 1N NaOH and extracted with ethyl acetate. The organic extracts were washed with water and brine, and then dried over Na~S04, filtered and concentrated to give 4-(phenyl)benzyl amine as a white solid.
Step B: Following General Procedure 5-D and using 4-(phenyl)benzyl amine, the title compound was prepared.
' Example 5-G
Synthesis of cis- and traps-4-Amino-1-phenyl-1,2,3,4-tetrahydroisoquinolin-3-one Step A: Following General Procedure 5-D and using a-phenylbenzylamine (Aldrich), 4-amino-1-phenyl-1.2,3,4-tetrahydroisoquinolin-3-one was prepared.
den B: To a solution of 4-amino-1-phenyl-1,2,3,4-tetrahydroisoquinolin-3-one (0.00158 moles) from Step A in 20 mL of CH,CI, was added 2.0 eq. of triethylamine and Boc anhydride (1.1 eq.). The reaction was stirred overnight at room temperature and then concentrated. The residue was diluted with ethyl acetate and water. The pH of the aqueous layer was adjusted to 3.0 with sodium bisulfate and the layers were separated. The organic layer was dried over Na~SOd, filtered and concentrated. The residue was purified by LC 2000, eluting with WO 99/67221 PC'T/US99/14193 ethyl acetate/hexanes (70:30) to give a white solid containing a 1:1 mixture of cis-and traps-4-(N-Boc-amino)-1-phenyl-1,2,3,4-tetrahydroisoquinolin-3-one isomers.
This mixture was recrystailized from ethyl acetate to give the pure traps isomer and a cis isomer-enriched mixture of cis and traps isomers. This mixture was S recrystallized again from ethyl acetate/hexanes (70:30) to give the pure cis isomer.
step C: The cis isomer and the traps isomer from Step B were separately deprotected using General Procedure 8-J to give cis-4-amino-1-phenyl-1.2,3,4-tetrahydroisoquinolin-3-one and traps-4-amino-1-phenyl-I,2,3,4-tetrahydroisoquinolin-3-one.
Example 5-H
Synthesis of 4-Amino-7-phenyl-1,2,3,4-tetrahydroisoquinolin-3-one Step A: To a solution of 1-bromo-3-phenylbenzene (Aldrich) (0.0858 moles) in 300 mL of dry THF cooled to -78°C was added tert-butyl lithium (2 eq.) (1.7M in hexane) dropwise. The reaction mixture was stirred for 40 min. at -78°C and then quenched with 2 eq. of DMF (13.24 mL). The resulting mixture was stirred for 20 min. and then poured into a separatory funnel and extracted with CH,Ch. The organic extracts were washed with water, dried over Na<SO,, filtered and concentrated to give a brown oil. This oil was purified by LC

chromatography, eluting with ethyl acetate/hexanes (5:95) to give 3-biphenylcarboxaldehyde.
Step To a solution of 3-biphenylcarboxaldehyde (O.OI1 eq.) in 30 mL
of methanol was added 10 eq. of 7N NH,IMeOH and NaCNBH4 (2 eq.). A yellow gum precipitated from solution. The solution was then heated at 60°C
until gum dissolved and the solution was stirred at room temperature overnight. The reaction mixture was then concentrated and the resulting residue diluted with ice water and ethyl acetate. The organic layer was then washed with brine and extracted with SN HCI. The pH of the aqueous layer was then adjusted to 12 and the aqueous layer was extracted with cold ethyl acetate. The organic layer was dried over Na,S04, filtered and concentrated to give 3-(phenyl)benzyl amine as an s oil.
Sten C:C: Following General Procedure s-D and Using 3-(phenyl)benzyl amine, the title compound was prepared.
Example s-I
Synthesis of 4-Amino-1-benzyl-1,2,3,4-tetrahydroisoquinolin-3-one Sten A: To a solution of benzoyl chloride (0.123 moles) (Aldrich) in 600 mL of CH,CI, was added 2.0 eq. of phenethylamine (Aldrich) dropwise. The 1 s reaction mixture was stirred at room temperature for 3 hours and then poured into a separatory and extracted with CH,CI,. The organic extracts were washed with water and 1N HCI, and then dried over Na,S04, filtered and concentrated to give N-phenethyl benzamide.
Step B: Reduction of N-phenethyl benzamide using the procedure of Example s-E, Step C afforded N-benzyl-N-phenethylamine as an oil.
Step C: Following General Procedure s-D and using N-benzyl-N-phenethylamine, the title compound was prepared.
zs Example 5-J
Synthesis of 3-Amino-1-methyl-Z-indolinone Monohydrochloride Step A: (2,3-Dihydro-1-methyl-2-oxo-1H-indol-3-yl)carbamic acid methyl ester (CAS No. 110599-56-9) was prepared using the procedure described in Ben-Ishai, D.; Sataty, L; Peled, N.: Goldshare, R. Tetrahedron 1987, 43, 439-450.
, The starting materials for this preparation were N-methylaniline (CAS# 100-61-8, Eastman Kodak Co.), glyoxylic acid (CAS# 298-12-4, Aldrich), and methyl carbamate (CAS# 598-55-0, Aldrich)..
Step B: The product from Step A (333.5 mg) in 31 % HBr in AcOH (IO
mL) was heated to 50-60°C for 2 hours. The resulting orange solution was IO concentrated to a thick orange oil which was dissolved in EtOAc (15 mL) and the product extracted into 1 M aq. HCl (10 mL). The aqueous acid was neutralized with aq. NaHCO, and the product extracted into CH,CI, (10 x 10 mL). HC1 (gas) was passed through the combined CH,CI, extracts to form a purple solution. The solution was concentrated to provide the title compound (262.8 mg) as a purple I S solid.
Example 5-K
Synthesis of 3-Amino-1-methyl-4-phenyl-3,4-trans-dihydrocarbostyril/Tin 20 Complex SteQ A: - Synthesis of 4-Phenyl-3,4-dihydrocarbostyril 4-Phenyl-3,4-dihydrocarbostyril (CAS# 4888-33-9) was prepared in two steps using the procedure described by Conley, R. T.; Knopka, W. N. J. Org.
Chem. 1964, 29, 496-497. The starting materials for this preparation were 25 cinnamoyl chloride (Aldrich) and aniline (Aldrich). The title compound was purified by flash chromatography eluting with CH,CI~/EtOAc (4:1).
Sten B: - Synthesis of 1-Methyl-4-phenyl-3,4-dihydrocarbostyril To a suspension of NaH (1.2 eq., 0.537 g of 60% dispersion in mineral oil) in THF (50 mL) under N, at 0°C was added the product from Step A (1.0 eq..
2.50 g) in THF (SO mL) via cannula over a period of 5 minutes. The resulting pale yellow mixture was stirred at 0°C for 10 minutes, then MeI (2.0 eq., 1.39 mL) was added. The opaque yellow mixture was allowed to slowly (ice bath not removed) warm to ambient temperature with stirring for 15 hours. 1M Aq. HCl (50 mL) and EtOAc (250 mL) were added and the phases partitioned. The organic phase was washed with dilute NaHCO~ (1 x 100 mL), brine (1 x 100 mL), then dried over MgSO~,, filtered, concentrated, and the residue purified by flash chromatography eluting with CH=Ch/EtOAc (19:1 gradient to 15:1) to provide 1-methyl-4-phenyl-3,4-dihydrocarbostyril.
Step C: - Synthesis of 3-Azido-1-methyl-4-phenyl-3,4-trans-dihydrocarbostyril Following General Procedure 8-K. 3-azido-1-methyl-4-phenyl-3,4-trans-dihydrocarbostyril was prepared as a white solid. The product was purified by flash chromatography eluting with CH,CI,/hexanes/EtOAc 15:15:1.
Selected 'H-NMR data for the title compound (CDC13): d = 4.46 (d, 1H, J
= 10.57 Hz), 4.18 (d, 1H, J = 10.63 Hz).
Sten D: - Synthesis of 3-Amino-l-methyl-4-phenyl-3,4-trans-dihydrocarbostyrillTin Complex To a mixture of SnCh (350.7 mg} in MeOH (7 mL) under N, at 0°C was added the product from Step C (257.4 mg) in MeOH/THF (5 mL/5 mL) via cannula over a period of 1 minute. The cooling bath was removed the solution allowed to warm to ambient temperature for 8 hours (No starting material by TLC). The solution was concentrated to a yellow foam, THF (10 mL) was added and the mixture was re-concentrated and used without further purification.

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

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

WO 99/67221 PCTNS99/14l93 Selected 'H-NMR data for the title compound (CDCl3): d = 4.45 (d, 1H, J
= 11.1 Hz), 4.24 (d, 1H, J = 11.2 Hz).
Step C: - Synthesis of 3-Amino-1-tert butoxycarbonyl-4-phenyl-3,4-S trans-dihydrocarbostyril/Tin Complex To a mixture of SnCIZ (450.6 mg) in MeOH (9 mL) under N, at 0°C
was added the product from Part D (433.0 mg) in MeOH (15 mL) via cannula over a period of 1 minute. The cooling bath was removed the solution allowed to warm to ambient temperature for 17 hours. The solution was concentrated to an amorphous yellow solid and used without further purification.
Example S-N
Synthesis of 1 S (S)-3-Amino-1-benzyl-d-valerolactam Ste~A: - Synthesis of L-(+)-Ornithine Methyl Ester Hydrochloride Into a stirred suspension of L-(+)-ornithine hydrochloride (Aldrich) in methanol was bubbled anhydrous hydrochloric acid gas until the solution was saturated. The reaction mixture was capped with a rubber septum and stirring was continued overnight at room temperature. The solvent was then stripped under reduced pressure and the residue triturated with ether. The resulting solid was dried under reduced pressure to afford L-(+)-ornithine methyl ester hydrochloride as a white solid (97% yield).

Step B: - Synthesis of (S)-3-Amino-d-valerolactam Sodium spheres in oil (2.0 eq.) (Aldrich) were washed with hexanes (2x) and methanol (2.3 mL/mmol) was slowly added. The reaction mixture was stirred under nitrogen until the sodium dissolved and then L-(+)-ornithine methyl ester hydrochloride ( 1 eq. ) in methanol (2.3 mL/mmol) was added dropwise. The reaction mixture was stirred for 16 hours and then diluted with diethyl ether (5 mL/mmol) and filtered to remove the solids. The solvent was then removed under reduced pressure and the residue was heated at 70°C for 3 hours under reduced pressure. The residue was then triturated with dichloromethane/ether, the solvent decanted and the resulting residue dried under reduced pressure to afford (S)-amino-d-valerolactam (44% yield).
Step C: - Synthesis of N-Boc-(S)-3-Amino-d-valerolactam (S)-3-Amino-d-valerolactam (1 eq.) was dissolved in dioxane and the solution was chilled to 0°C. BOC-anhydride (1.3 eq.) was added and the ice bath was removed allowing the solution to come to room temperature and stirring was continued for 16 hours. The solution was rotary evaporated to afford N-Boc-(S)-amino-d-valerolactam.
Step D: - Synthesis of (S)-3-Amino-1-benzyl-d-valerolactam Following General Procedure 5-A and using N-Boc-(S)-3-amino-d-valerolactam and benzyl bromide provided N-Boc-(S)-3-amino-1-benzyl-d-valerolactam. Removal of the Boc group using General Procedure 5-B afford the title compound.
Example 5-O
Synthesis of 4-Amino-2-aza-2-benzyl-3-oxo-bicyclo[3.2.1]octane Hydrochloride Step a: - Synthesis of 2-Aza-3-oxo-bicyclo[3.2.1]octane and 3-Aza-2-oxo-bicyclo[3.2.1]octane (9:1 Mixture) To (")-norcamphor {Aldrich) in 1 mL/mmole of acetic acid was added 1.5 eq. of hydroxylamine-O-sulfonic acid. The reaction mixture was heated to reflux under nitrogen for 1 hour and then saturated sodium carbonate and dilute sodium hydroxide were added. The resulting mixture was extracted with dichloromethane and the organic extracts washed with brine, dried over sodium sulfate, and the solvent removed under reduced pressure. Purification of the <.
residue by column chromatography afforded a 9:1 mixture of 2-aza-3-oxo-bicyclo[3.2.1]octane and 3-aza-2-oxo-bicycio[3.2.1]octane.
Step - Synthesis of 2-Aza-2-benzyl-3-oxo-bicyclo[3.2.1]octane Following General Procedure 5-A and using the product for Step A and benzyl bromide, 2-aza-2-benzyl-3-oxo-bicyclo[3.2.1 )octane was prepared.
Step C: - Synthesis of 2-Aza-2-benzyl-4-oximino-3-oxo-bicyclo[3.2.1]octane To a solution of 2-aza-2-benzyl-3-oxo-bicyclo[3.2.1]octane in THF was added 2.5 eq. of 1M t-BuOK/THF (Aldrich) and the resulting mixture was stirred for 30 minutes. Isoamyl nitrite (1.5 eq.) was then added dropwise and the reaction mixture was stirred overnight. To the reaction mixture was added 3N HC1 and this mixture was extracted with ethyl acetate and the organic extracts washed with water, dried, and concentrated under reduced pressure. The residue was triturated with ether/hexanes, the solvents decanted and the residue dried under reduced pressure to afford 2-aza-2-benzyl-4-oximino-3-oxo-bicyclo[3.2.1]octane as a tan liquid (41 % yield). This procedure is further described in Y. Kim, Tetrahedron Lett. 30(21 ), 2833-2636 ( 1989).
Step D: - Synthesis of 2-Aza-2-benzyl-4-amino-3-oxo-bicyclo[3.2.1]octane A solution of 2-aza-2-benzyl-4-oximino-3-oxo-bicyclo[3.2.1]octane in 10 mL/mmole of ethanol and 5.8 mL/mmole of 3N HCl containing 0.5 g/mmole of 10% Pd/C was saturated with hydrogen gas to 45 psi. The mixture was shaken for 3 hours and then filtered through a layer of Celite. The filtrate was dried over sodium sulfate and concentrated under reduced pressure to afford the title compound as a solid (86% yield). This procedure is further described in E.
Reimann, Arch. Pharm. 310, 102-109 (1977).
6. Benzazepinone Derivatives and Related omp Alkylation of 1-Amino-1.3 .4.5-tetrahvdro-2H-3-benzazeQin-~-one Step A: 1-Ethoxycarbonylamino-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one was prepared according to the procedure of Ben-Ishai et ai., Tetrahedron, 1987, 43, 430.
Steo BB: 1-Ethoxycarbonylamino-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one 1 S (2.0 g, 100 M % ) was dissolved in DMF (30 mL) and NaH (95 % , 0.17 g, 100M % ) was added in one portion. The reaction mixture was stirred for 1 hour and then the appropriate alkyl iodide (300M%) was added and the mixture was stirred for 12 hours. The reaction was poured into water and extracted with ethyl acetate (3x). The ethyl acetate extracts were then washed with water (3x) and brine (lx). Treatment with MgS04, rotoevaporation, and chromatography (30%
EtOAc/hexanes) yielded 1-ethoxycarbonylamino-3-alkyl-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one in 87% yield.
Ste~C: 1-Ethoxycarbony!amino-3-alkyl-1,3,4, 5-tetrahydro-2H-3-benzazepin-2-one ( 1.Og, 100M % ) was suspended in 30 mL of 30 % HBr/HOAc and heated to 100°C. The reaction mixture was stirred for S hours at this temperature and then the reaction was cooled and rotoevaporated to yield 1-amino-3-alkyl-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one as the hydrobromide salt (100% yield).

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

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

Step D: BOC-protected 3-amino-1.5-dimethyl-1.3,4,5-tetrahydro-2H-1-benzazepin-2-one ( 100 M % ) was suspended in 30 mL of 1:1 CH,CI,/triflouroacetic acid. The reaction mixture was stirred for 4 hours. The ., reaction was then rotoevaporated to yield 3-amino-1.5-dimethyl-1,3,4,5-tetrahydro-2H-1-benzazepin-2-one (100% yield).
Example 6-B
Synthesis of 5-(L-Alaninyl)-amino-3,3,7-trimethyl-5,7-dihydro-6H-benz[b]azepin-6-one Hydrochloride Following the procedure of Example 7-I and using 5-amino-3,3,7-trimethyl-5,7-dihydro-6H-bent[b]azepin-6-one hydrochloride (Example 6-C), the title compound was prepared.
Example 6-C
Synthesis of 5-Amino-3,3, 7-trimethyl-5, 7-dihydro-6H-benz[b]azepin-6-one Hydrochloride Sten A:A: Following General Procedure 5-A and using N-t-Boc-5-amino-3,3-dimethyl-5,7-dihydro-6H-bent[b)azepin-6-one (General Procedure 6-B, followed by Boc protection) and methyl iodide, N-t-Boc-5-amino-3,3,?-trimethyl-5,7-dihydro-6H-bent[b]azepin-6-one was prepared.
Step B: Following General Procedure 8-N and using N-t-Boc-5-amino-3,3,7-trimethyl-5,7-dihydro-6H-benz(b)azepin-6-one, the title compound was prepared.
Example 6-D
Synthesis of 3-(S)-Amino-1-methyl-5-oxa-1,3,4,5-tetrahydro-2H-1-benzazepin-2-one Step A: 3-(S)-Amino-S-oxa-1,3,4,5-tetrahydro-2H-1-benzazepin-2-one was prepared from N-Boc-serine (Bachem) and 2-fluoro-1-nitrobenzene (Aldrich) using the method of R. J. DeVita et al., Bioorganic and Medicinal Chemistry Lett.
1995.
5(12) 1281-1286.
Step Following General Procedure 5-A and using the product from Step A, the title compound was prepared.
Example 6-E
Synthesis of 3-(S)-Amino-1-ethyl-5-oxa-1,3,4,5-tetrahydro-2H-1-benzazepin-2-one Ste~a A: 3-(S)-Amino-5-oxa-1,3,4,5-tetrahydro-2H-1-benzazepin-2-one was prepared from N-Boc-serine (Bachem) and 2-fluoro-1-nitrobenzene (Aldrich) using the method of R. J. DeVita et al., Bioorganic and Medicinal Chemistry Lett.
1995, 5(12) 1281-1286.
Step B: Following General Procedure 5-A and using the product from Step A, the title compound was prepared.
Example 6-F
Synthesis of 3-(S)-Amino-1-methyl-5-this-1,3,4,5-tetrahydro-2H-1-benzazepin-2-one The title compound was prepared from N-Boc-cystine (Novabio) and 2-fluoro-1-nitrobenzene (Aldrich) using the method of R. J. DeVita et al., Bioorganic and Medicinal Chemistry Lett. 1995, 5(12) 1281-1286, followed by General Procedure 5-A.
7. Dibenzazepinone Derivatives and Related Comb?funds Preparation of 5-Amino-7-alkyl-5,7-dihydro 6H-dibenzLb.d]azenin-6-one Derivatives Step A: Following General Procedure 5-A and using 5,7-dihydro-bH-dibenz(b,d]azepin-6-one and an alkyl halide, the 7-alkyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one was prepared.
Step B: The 7-alkyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one (1 eq.) was dissolved in THF and isoamylnitrite (1.2 eq.) was added. The mixture was cooled to 0°C in an ice bath. NaHMDS (1.I eq., 1M in THF) was added dropwise.
After stirring for 1 hour or until the reaction was complete, the mixture was concentrated then acidified with 1N HC1 and extracted with EtOAc. The organic portion was dried and concentrated to yield a crude product which was purified by silica gel chromatography.
step C: The resulting oxime was dissolved in EtOH/NH3 (20:1) and hydrogenated in a bomb using Raney nickel and hydrogen (500 psi) at 100°C for 10 hours. The resulting mixture was filtered and concentrated to provide an oil which was purified by silica gel chromatography to yield the title compound.

Preparation of Fluoro-substituted 5,7-dihydro-6H-dibenz(~.d]azepin-6-one Derivatives A modification of the procedure of Robin D. Clark and Jahangir, Tetrahedron, Vol. 49, No. 7, pp. 1351-1356, 1993 was used. Specifically, an appropriately substituted N-t-Boc-2-amino-2'-methylbiphenyl was dissolved in THF and cooled to -78°C. s-Butyl lithium (1.3M in cyclohexane, 2.2 eq.) was added slowly so that the temperature remained below -65°C. The resulting mixture was allowed to warm to -25°C and was stirred at that temperature for 1 hour. The mixture was cooled to -78°C. Dry CO2 was bubbled through the mixture for 30 seconds. The mixture was allowed to warm to ambient temperature then was carefully quenched with water. The mixture was concentrated under reduced pressure then was adjusted to pH 3 with 1N HC1. The mixture was extracted with EtOAc and the organic portion was dried and concentrated to yield a crude material. The crude material was dissolved in methanol and the solution was saturated with HCI. The mixture was heated at reflux for 12 hours then was allowed to cool. The mixture was concentrated to provide crude lactam which was purified by chromatography or crystallization.

Resolution of 5-Amino-7-methyl-5 .7-dihydro-6H-dibenz[b.dJazepin-6-one In a round bottom flask was added the racemic freebase amine (1.0 eq.) in methanol followed by di p-toluoyl-D-tartaric acid monohydrate (1.0 eq.). The mixture was concentrated in vacuo to a residue and redissolved in a moderate volume of methanol and allowed to stir at room temperature open to the atmosphere (8-72 hours). The solid was removed by filtration. The enantiomeric excess was determined by chiral HPLC (Chiracel ODR) using 15 %a acetonitrile and 85 % HBO with 0.1 % trifluoroacetic acid and a flow rate of 1.0 mL/min at 35°C. The resolved di p-toluoyl-D-tartaric salt was then dissolved in EtOAc and saturated NaHC03 until pH 9-10 was reached. The layers were separated and the organic layer was washed again with saturated NaHC43, H20, and brine. The organic layer was dried over MgS04 and the drying agent was removed by filtration. The filtrate was concentrated in vacuo. The free amine was dissolved in MeOH and HCl (12M, 1.0 eq.) was added. The salt was concentrated in vacuo , and the resulting film was triturated with EtOAc. The HCl salt was filtered and S rinsed with EtOAc. The ee was determined by chiral HPLC.
Example 7-A
Synthesis of 5-Amino-7-methyl-5, 7-dihydro 6H-dibenz[b,d]azepin-6-one Hydrochloride Step A - synthesis of 7-Methyl-5.7-dihvdro-6H-dibenz[b.dJazepin-6-one A round bottom flask was charged with sodium hydride (0.295 g, 7.46 mmol) in 9.0 ml of DMF and treated with 5,7-dihydro-6H-dibenz[b,d]azepin-6-one (1.3 g, 6.22 mmol) (CAS # 20011-90-9, prepared as described in Brown, et.
IS al., Tetrahedron Letters, No. 8. 667-670, (1971) and references cited therein).
After stirring at 60°C for 1 h. the solution was treated with methyl iodide (1.16 ml, 18.6 mmol) and stirring continued for 17 h with the exclusion of light.
After cooling, the reaction was diluted with CH,Ch/H:O, washed with NaHSO~
solution, H=O, and dried over Na,SO,. Evaporation and flash chromatography (SiO,, CHC13) gave 0.885 g (63%) of the title compound as a colorless solid.
NMR data was as follows:
'H-nmr (CDC13): d = 7.62 (d, 2H), 7.26-7.47 (m, 6H), 3.51 (m, 2H), 3.32 (s, 3H).
C'SH'3N0 (MW = 223.27); mass spectroscopy (MH+) 223.
~ Anal. Calcd for C,SH,3N0; C, 80.69 H, 5.87 N, 6.27. Found: C, 80.11 H,5.95N,6.23.
' Step B - Synthesis of 7-Methyl-5-oximo-5~ -dihvdro-6H-dibenz(b~J~~zepin-6-~ne The compound isolated above (0.700 g, 3.14 mmol) was dissolved in 20 ml of toluene and treated with butyl nitrite (0.733 ml, 6.28 mmol). The reaction temperature was lowered to 0°C and the solution was treated with KHMDS
(9.42 ..
ml, 0.5 M) under N, atmosphere. After stirring for 1 h the reaction was quenched with a saturated solution of NaHS04, diluted with CH,CI~ and separated. The organic layer was dried over Na,SOa and the title compound purified by chromatography (SiO,, 98:2 CHCh/MeOH) giving 0.59 ~ (80 %) as a colorless solid.
C,SH,~N~O~ (MW = 252.275); mass spectroscopy (MH+) 252.
Anal. Calcd for C,SH,zN,O,; C, 71.42 H, 4.79 N, 11.10. Found: C, 71.24.
H, 4.69 N, 10.87.
Step C - Synthesis of 5-Amino-7-Meth -S ~-di ydro 6H
dibenz(b dlazenin-6-one Hydrochtr,T;.tP
The oxime isolated above (0.99 g, 3.92 mmol) was hydrogenated in a Parr apparatus at 35 psi over 10 % Pd/C (0.46 g) in 3A ethanol. After 32 h the reaction mixture was filtered through a plug of celite, the filtrate evaporated to a foam and treated with a saturated solution of HCl (g) in Et,O. The resulting colorless solid was filtered, rinsed with cold Et~O and vacuum dried to give 0.66 g (61 % ) of the title compound.
NMR data was as follows:
'H-nmr (DMSOd6): d = 9.11 (bs, 3H), 7.78-7.41(m, 8H), 4.83 (s, 1H), 3.25 (s, 3H).
C,SH,~N,O HCI (MW = 274.753); mass spectroscopy (MH+ free base) 238.
Anal. Calcd for C,SH,.,N~O . HCI; C, 65.57 H, 5.50 N, 10.19 Found: C, 65.27 H, 5.67 N, 10.13.
Example 7-B

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

Anal. Calcd for C,,H~,N30~; C, 67.46 H, 6.64 N, 10.26. Found: C, 67.40 H, 6.62 N, 10.02 Step B - Svnthesis of lS)- and l~~L-Alaninvll-amino-7 methsn ~.7-dihvdro-6H-diben~
[~i~~.enin-6-one ~ydrochloride The compounds isolated in Part A (each isomer separately) were dissolved in dioxane and treated with excess HCl (g). After stirring for 17 hours, the title compounds were isolated as colorless solids after evaporation and vacuum drying.
Isomer 1:
C,8H,9N,O,.HCI (MW = 345.832); mass spectroscopy (MH+ free base) 309.
Optical Rotation: [aj,o = - 55 ~ 589 nm (c = l, MeOH).
Isomer 2:
C,8H,9N~O,.HC1 (MW = 345.832); mass spectroscopy (MH+ free base) 309.
Optical Rotation: [a),~, = 80 ~ 589 nm (c = l, MeOH).
Example 7-C
Synthesis of (S)- and (R)-5-(L-Valinyl)-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one Step A - Synthesis of lS)- and (R)-5-(N-Boc-L-Valinyll-amino 7-m~thyl-5.7-dihydro-6H-dibenz[b dlazepin-6-one Boc-L-Valine (0.656 g, 3.02 mmol) (Aldrich) was dissolved in THF and treated with HOBt hydrate (0.408, 3.02 mmol), Dipea ( 1.05 ml, 6.05 mrnol) and 5-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one hydrochloride (0.75 g, 2.75 mmol)(Example 7-A). The temperature was lowered to 0°C and the reaction mixture treated with EDC (0.601 g, 3.02 mmol)(Alrich) and stirred 17 hours under N,. The reaction mixture was evaporated, the residue diluted with EtOAc/HZO, washed 1.0 N HC1, sat. NaHC03, brine and dried over Na,SOa. The diastereomers were separated on a Chiralcel OD column using 10% IPA/heptane at 1.5 ml/minute.
Isomer 1: Retention time 3.23 minutes.
Optical Rotation: ja]ZO = - 120 Q 589 nm (c = 1, MeOH).
C,SH;,N30~ (MW = 437.544); mass spectroscopy (MH+) 438 Isomer 2: Retention time 6.64 minutes.
Optical Rotation: [a]ZO = 50 Qa 589 nm (c = 1, MeOH).
C,SH3,N,Oy (MW = 437.544); mass spectroscopy (MH+) 438 Step B - Synthesis of (S1- and ($ -).-~-5-(L-Valin~)-amino-7-met~yl-S.7-dihvdro-6H-dibenzj~]~oin-6-one Hydrochloride The compounds isolated in Part A (each isomer separately) were dissolved in dioxane and treated with excess HCl (g). After stirring for 17 hours, the title 1 S compounds were isolated as colorless solids after evaporation and vacuum drying.
Isomer l:
C,oH,3N,O,.HC1 (MW = 373.88); mass spectroscopy (MH+ free base) 338.
Optical Rotation: [a]ZO = - 38 Qa 589 nm (c = 1, MeOH).
Isomer 2:
Czali"N,O~.HCI (MW = 373.88); mass spectroscopy (MH+ free base) 338.
Optical Rotation: [a]zo = 97 ~a 589 nm (c = 1, MeOH).
Example 7-D
Synthesis of (S)- and (R)-5-(L-tent-Leucine)-amino-7-methyl 5,7-dihydro-6H-dibenz(b,d]azepin-6-one Step A - Synthesis of (S)- and (R)-5-lN-Boc-L-tert-LeucirLyl)-amino-7-meth - .7-di vdro-6H-dibenz[b.d]azepin-6-one Boc-L-tert-Leucine (0.698 g, 3.02 mmol) (Fluka) was dissolved in THF
and treated with HOBt hydrate (0.408, 3.02 mmol), Dipea (1.05 ml, 6.05 mmol) and 5-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d)azepin-6-one hydrochloride (0.75 g, 2.75 mmol)(Example 7-A). The temperature was lowered to 0°C
and the reaction mixture treated with EDC (0.601 g, 3.02 mmol) (Alrich) and stirred 17 hours under N,. The reaction mixture was evaporated, the residue diluted with EtOAc/H~O, washed 1.0 N HCI, sat. NaHC03, brine and dried over Na~SO,. The diastereomers were separated on a Chiralcel OD column using 10% IPA/heptane at 1.5 ml/minute.
Isomer 1: Retention time 3.28minutes.
Optical Rotation: [a)," _ - 128 ~ 589 nm (c = 1, MeOH).
C,6H~31V30~ (MW = 451.571 ); mass spectroscopy (MH + ) 452 Isomer 2: Retention time 5.52 minutes.
Optical Rotation: [a)_~ = 26 Qa 589 nm (c = 1, MeOH).
C26H33N3~4 (MW = 451.571 ); mass spectroscopy (MH + ) 452 Step B - S~thesis of (S)- and (R)-5-(L-tert-Leuci~,vl)-amino-7-methyl-5 7-dihvdro-6H-djbenz~(b ~,j~pin-6-one Hydrochloride The compounds isolated in Part A (each isomer separately) were dissolved in dioxane and treated with excess HC1 (g). After stirring for 17 hours, the title compounds were isolated as colorless solids after evaporation and vacuum drying.
Isomer 1:
C,,H~SN30,.HC1 (MW = 387.91); mass spectroscopy (MH+ free base) 352.

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

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

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

C"H,bNzO~ HCl (MW = 332.78): mass spectroscopy (MH+ free base) 297.
Example 7-H
Synthesis of 5-Amino-7-(3,3-dimethyl-2-butanonyl) 5,7-dihydro-6H-dibenz(b,d]azepin-6-one Hydrochloride Step A- Synthesis of 5-(N-Boc-Aminp~ 7-(,3.3-dimet 1-butanonyl)-5.7dihydro-6H-dibenz jj~.d]~z p~~-6-one A solution of 5-(N-Boc-amino)-5.7-dihydro-6H-dibenz[b,d]azepin-6-one (0.2 g, 0.617 mmol) (Example 7-E) in DMF was treated with CSzC03 (0.3 g, 0.925 mmol) and warmed to 60°C. To the reaction mixture was added 1-chloro-3,3-dimethyl-2-butanone (0.096 ml, 0.74 mmol) (Aldrich) and stirring continued for 17 h. After cooling to 23 °C, the mixture was diluted with CH,Ch, washed with several portions of brine and dried over Na~SO~. The title compound was isolated as a colorless solid.
C,SH3~N,0~ (MW = 422.522); mass spectroscopy (MH+) 423 Step B - Synthesis of 5-Amino-7-(3.3-dimeth, 1-~ onyl_l-5.7-dijtvdro-6H-dibenzjb.d]~~~,pin-6-one Hydrochloride The compound isolated in Part A was deprotected in dioxane saturated with gaseous HCI. The title compound was isolated as a colorless solid after evaporation and vacuum drying.
Example 7-I
Synthesis of L-Alaninyl-5-amino-7-methyl-5,7-dihydro-6H-dibenz(b,d]azepin-6-one Hydrochloride Step A: Following General Procedure D and using N-t-Boc-L-alanine and 5-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one, N-t-Boc-L-alaninyl-5-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d)azepin-6-one was prepared.
Step B: Following General Procedure 8-N and using the N-t-Boc-L-alaninyl-5-amino-7-methyl-5.7-dihydro-6H-dibenz(b,d)azepin-6-one, the title compound was prepared. Other substituted N-t-Boc-L-alaninyl-5-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d)azepin-6-ones can also be prepared by this procedure.
Example 7-J
Synthesis of L-Vaiinyl-5-amino-7-methyl-5, 7-dihydro-6H-dibenz(b,d)azepin-6-one Hydrochloride St~~ A: Following General Procedure D and using N-t-Boc-L-valine and 5-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d)azepin-6-one, N-t-Boc-L-vaiinyl-5-amino-7-methyl-5,7-dihydro-6H-dibenz(b,d)azepin-6-one was prepared.
Step B: Following General Procedure 8-N and using the N-t-Boc-L-valinyl-5-amino-7-methyl-5.7-dihydro-6H-dibenz(b,d)azepin-6-one, the title compound was prepared. Other substituted N-t-Boc-L-valinyl-5-amino-7-methyl-5,7-dihydro-6H-dibenz(b.d)azepin-6-ones can also be prepared by this procedure.
Example 7-K
Synthesis of 5-Amino-7-phenbutyl-5,7-dihydro-6H-dibenz(b,d]azepin-6-one Following General Procedure 7-A and using 5,7-dihydro-6H-dibenz(b,d)azepin-6-one (prepared as described in Brown, et. al. , Tetrahedron Letters, No. 8, 667-670, (1971) and references cited therein) and 1-chloro-4-phenylbutane (Aldrich), the title compound was prepared.

Example 7-L
Synthesis of 5-Amino-7-cyclopropymethyl-5, 7-dihydro- , 6H-dibenz[b,d]azepin-6-one Following General Procedure 7-A and using 5,7-dihydro-6H-dibenz[b,d]azepin-6-one (prepared as described in Brown, et. al., Tetrahedron Letters, No. 8, 667-670, ( 1971 ) and references cited therein) and (bromomethyl)cyclopropane (Aldrich), the title compound was prepared.
Example 7-M
Synthesis of 5-Amino-7-(2,2,2-trifluoroethyl)-5, 7-dihydro-6H-dibenz(b,d]azepin-6-one Following General Procedure 7-A and using 5,7-dihydro-6H-dibenz[b,d]azepin-6-one (prepared as described in Brown, et. al., Tetrahedron Letters, No. 8, 667-670, (1971) and references cited therein) and 1-bromo-2,2.2-trifluoroethane (Aldrich), the title compound was prepared.
Example 7-N
Synthesis of 5-Amino-7-cyclohexyl-5,7-dihydro-- 6H-dibenz(b,d]azepin-6-one Following General Procedure 7-A and using 5.7-dihydro-6H-dibenz[b,d]azepin-6-one (prepared as described in Brown, et. al., Tetrahedron Letters, No. 8, 667-670, (1971) and references cited therein) and bromocyclohexane (Aldrich), the title compound was prepared.
Example 7-O
Synthesis of 5-(L-Alaninyl)amino-9-fluoro-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one Hydrochloride Ste~l: 2-Bromo-5-fluorotoluene was stirred in THF at -78C. s-BuLi ..
(1.05 eq., 1.3 M in cyclohexane) was slowly added and the mixture was stirred for S 45 minutes. Trimethyiborate (1.5 eq) was added and the mixture was allowed to warm to ambient temperature. After stirring for 1 hour, pinacol (2 eq.) was added. The mixture was stirred for 16 hours then was concentrated under reduced pressure. The resulting residue was slurried in CH,CI, and filtered through Celite.
The filtrate was concentrated to yield an oil which was purified by chromatography on deactivated silica gel (Et3N) to yield the arylboronate ester.
Ste~2-. 2-Bromoaniline (1 eq.) and di-t-butyl-dicarbonate (1.1 eq.) were stirred at 80°C for 20 hours. The resulting mixture was allowed to cool and was directly distilled using house vacuum to provide N-t-Boc-2-bromoaniline.
Ste~3~. N-t-Boc-2-bromoaniline (Step 2, 1 eq.), the arylboronate ester (Step 1. 1.1 eq.), K,CO, ( 1.1 eq. ) and tetrakis(triphenylphosphine)palladium(0) (0.02 eq) were stirred in 20% water/dioxane under nitrogen. The solution was heated at reflux for 10 hours. The mixture was allowed to cool then was concentrated. The resulting residue was partitioned between water and chloroform. The organic portion was dried and concentrated to yield an oil which was purified by silica gel chromatography using 1:1 CH~CI,/hexanes.
Step 4: Following General Procedure 7-B and using the substituted biphenyl from step 3, the 9-fluoro-5,7-dihydro-6H-dibenz[b,d]azepin-6-one was prepared.
Step 5: 9-Fluoro-5,7-dihydro-6H-dibenz[b,d]azepin-6-one (1 eq., Step 4), cesium carbonate (1.1 eq., Aldrich) and methyl iodide (1.1 eq., Aldrich) were stirred in dry DMF at ambient temperature for 16 hours. The mixture was concentrated under reduced pressure to provide a residue which was partitioned between EtOAc and water. The organic portion was dried and concentrated to yield an oil which was purified by silica gel chromatography to 9-fluoro-7-methyl-S 5,7-dihydro-6H-dibenz[b,d)azepin-6-one.
Ste~L Following General Procedure 7-A, Step R and 9-fluoro-7-methyl-5,7-dihydro-6H-dibenz(b,d)azepin-6-one from Step 5, 5-amino-9-fluoro-7-methyl-5,7-dihydro-6H-dibenz[b.d)azepin-6-one was prepared.
Step 7: Following the procedure of Example 7-I and using 5-amino-9-fluoro-7-methyl-5.7-dihydro-6H-dibenz[b,d)azepin-6-one from Step 6, the title compound was prepared.
I S Example 7-P
Synthesis of 5-(L-Alaninyl)amino-13-fluoro-7-methyi 5,7-dihydro-6H-dibenz[b,d)azepin-6-one Hydrochloride Following the procedure of Example 7-O and using 2-bromo-4-fluoroaniline (Step 2, Lancaster) and o-tolylboronic acid (Step 3, Aldrich), the title compound was prepared.
Example 7-Q
Synthesis of 5-(L-Alaninyl)amino-14-fluoro-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one Hydrochloride Following the procedure of Example 7-O and using 2-bromo-4-fluorotoluene (Step 1), the title compound was prepared.

Example 7-R
Synthesis of 5-(L-Alanyl)-amino-7-cyclopropylmethyl 5,7-dihydro-6H-dibenz[b,d]azepin-6-one Hydrochloride Following the procedure of Example 7-I and using 5-amino-7-cyclopropylmethyl-5,7-dihydro-6H-dibenz(b,d]azepin-6-one (Example. 7-L), the title compound was prepared.
Example 7-S
Synthesis of 5-(L-Alaninyl)amino-7-phenbutyl 5,7-dihydro-6H-dibenz(b,d]azepin-6-one Hydrochloride Following the procedure of Example 7-I and using 5-amino-7-phenbutyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one (Example 7-K), the title compound was prepared.
Example 7-T
Synthesis of 5-(L-Valinyl)amino-7-cyclopropylmethyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one Hydrochloride Following the procedure of Example 7-J and using 5-amino-7-cyclopropylmethyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one (Example 7-L), the title compound was prepared.
Example 7-U
Synthesis of 5-(L-Valinyl)amino-7-phenbutyl S,7-dihydro-6H-dibenz[b,d]azepin-6-one Hydrochloride Following the procedure of Example 7-J and using 5-amino-7-phenbutyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one (Example 7-U), the title compound was prepared.
Example 7-V
Synthesis of 5-(L-Valinyl)amino-7-hexyl-5, 7-dihydro-6H-dibenz[b,d]azepin-6-one Hydrochloride Step A: Following General Procedure 7-A and using 5,7-dihydro-6H-dibenz[b,d]azepin-6-one (prepared as described in Brown, et. al., Tetrahedron Letters, No. 8, 667-670, (1971) and references cited therein) and 1-bromohexane (Aldrich), 5-amino-7-hexyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one was prepared.
Stem $: Following the procedure of Example 7-J and using 5-amino-7-hexyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one, the title compound was prepared.
Example 7-W
Synthesis of 5-(L-Valinyl)amino-10-fluoro-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one Hydrochloride Following the procedure of Example 7-J and using S-amino-10-fluoro-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one (as prepared in Example 7-Q}, the title compound was prepared.
Example 7-X
Synthesis of 5-(L-Valinyl)amino-13-fluoro-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one Hydrochloride WO 99/67221 PCT/US99/14I93' Following the procedure of Example 7-J and using the 5-amino-13-fluoro-7-methyl-5,7-dihydro-6H-dibenz(b,d]azepin-6-one (as prepared in Example 7-P), the title compound was prepared. , Example 7-Y
Synthesis of 5-(L-Valinyl)amino-13-fluoro-7-methyl 5,7-dihydro-6H-dibenz[b,d)azepin-6-one Hydrochloride Following the procedure of Example 7-J and using the 5-amino-9-fluoro-7-methyl-5,7-dihydro-6H-dibenz(b,d]azepin-6-one (as prepared in Example 7-O), the title compound was prepared.
Example 7-Z
Synthesis of (5-Amino-7-methyl-1,2,3,4,5,7-hexahydro-6H-dicyclohexyl[b,d)azepin-6-one The 5-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one hydrochloride (Example 7-A) was dissolved in a 1:1 mixture of EtOAc/HOAc.
5% lth/C was added and the mixture was stirred at 60°C under 60 psi of hydrogen. After 3 days, the mixture was filtered and the filtrate was concentrated to provide an oil which was purified by SCX-canon exchange chromatography to yield the title compound.
Example 7-AA
Synthesis of 5-(S)-Amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one Hydrochloride Following General Procedure 7-C using racemic 5-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one (1.0 eq.) and di p-toluoyl-D-tartaric acid WO 99/67221 PCT/US99/14193 ' monohydrate (1.0 eq.) in methanol, the title compound was prepared as a solid.
The product was collected by filtration. Enantiomeric excess was determined by chiral HPLC.
Desired enantiomer 1: retention time of 9.97 minutes.
Undesired enantiomer 2: retention time of 8.62 minutes.
NMR data was as follows:
'H-nmr (CDC13): d = 9.39 (s, 2H), 7.75-7.42 (m. 8H), 4.80 (s, 1H), 3.30 (s, 3H).
C,SH,SC1N,0 (MW = 274.75); mass spectroscopy (MH+) 239.1.
Anal Calcd for C,SH,SC1N,0,; C, 65.57; H, 5.50; N, 10.20; Found: C, 65.51, H, 5.61; N, 10.01.
8. Be podia enine Derivatives and Relay Com oundc N-1-Methylation of Benzodiaze inee A solution of benzodiazepine (1 eq.) in DMF (0.1 M concentration) at 0°C
was treated with potassium tert-butoxide ( 1.0 eq.. 1.0 M solution in THF).
After stirring for 30 minutes at 0°C, iodomethane (1.3 eq.) was added and stirring continued for 25 minutes. The mixture was diluted with methylene chloride and washed with water and brine. The organic phase was dried over Na2S04, filtered, and concentrated. The crude product was then either purified by trituration with 1:1 ether/hexanes or chromatographed via HPLC using ethyl acetate/hexanes as the eluent.

(~bz Removal Procedure A flask was charged with the Cbz-protected 3-aminobenzodiazepine (1 eq.).
To this was added HBr (34 eq.; 30% solution in acetic acid). Within 20 minutes WO 99/67221 PCT/US99/14193 ' all of the starting material dissolves. The reaction was stirred for 5 hours at ambient temperature. Ether was added to the orange solution causing the HBr amine salt to precipitate. The mixture was decanted. This process of adding ether and decanting was repeated thrice in an effort to remove acetic acid and benzyl bromide. Toluene was added and the mixture concentrated in vacuo. This step was also repeated. The HBr salt was partitioned between ethyl acetate and 1 M
K2C03. The aqueous layer was back-extracted with ethyl acetate. The combined organics were washed with brine, dried over Na2S04, filtered, and concentrated.

Boc Removal Procedure A solution of Boc-protected amine (1 eq.) in methylene chloride (0.15 M
concentration) was cooled to 0°C and treated with trifluoroacetic acid (30 eq.).
After 10 minutes at 0°C, the cooling bath was removed and stirring continued at ambient for 20 minutes to 1 hour. The mixture was concentrated in vacuo to remove excess trifluoroacetic acid. The residue was dissolved in methylene chloride and washed with saturated aqueous NaHC03 or 1 M K2C03 and brine.
The organic layer was dried over Na2S04, filtered, and concentrated.

The azido derivative was prepared using the procedure described in John W.
Butcher et al., Tet. Lett., 37, 6685-6688 (1996).

Azide Transfer Reaction Using LDA
To a solution of diisopropylamine (1.1 eq.) in 1 mL of dry THF cooled to -78°C was added n-butyl lithium (1.6M in hexane) (1.1 eq.) dropwise maintaining the reaction temperature at -78°C. The reaction mixture was stirred for 30 min. at -78°C and then the lactam (0.471 mM) was added dropwise as a solution in 1 mL
of drv THF. The reaction mixture was stirred at -78°C for 30 min. and then a pre-cooled solution of trisyl azide (1.2 eq.) was added as a solution in 1 mL
of dry THF. The reaction mixture was stirred at -78°C for 20 min. and then quenched with acetic acid (4.0 eq.). The reaction mixture was then stirred at 40°C for 2 hrs. The reaction was then poured into EtOAc and washed with water, sodium bicarbonate and brine, and then dried over sodium sulfate, filtered and concentrated. The residue was purified by LC 2000 chromatography.

Azido Group Reduction The azido group was reduced to the corresponding primary amine using the procedure described in John W . Butcher et al. , Tet. Lett. , 37, 6685-6688 ( 1996).

N-Alkylation of Amides or Lactams Using Sodium Hydride or Potassium tert-Butoxide To a slurry of sodium hydride or potassium tent-butoxide (1.1 eq) in 15 mL of dry DMF was added the appropriate amide (0.0042 moles) as a solution in 10 mL
of DMF. The alkyl iodide was then added and a thick slurry resulted. The reaction became less thick-as time elapsed and when complete by TLC the reaction had become homogeneous. The reaction mixture was poured over ice and extracted into ethyl acetate. The organic layer was washed with water.
followed by brine. The organic layer was then dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by HPLC (LC
2000), eluting with an ethyl acetate/hexane system.

WO 99!67221 PCTNS99/14193 N-Alkylation of To the appropriate amide or lactam in THF cooled to -78°C was added KHMDS dropwise and the reaction mixture was stirred for 30 min. at -78°C. The alkyl iodide was then added dropwise while maintaining the temperature at -70°C.
The cooling bath was then removed and reaction was allowed to warm to room temperature and stirring was continued for 2 hours. The reaction mixture was then poured over ice and extracted into ethyl acetate. The organic extracts were washed with water, followed by brine. The organic layer was then dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by HPLC (LC 2000), eluting with an ethyl acetatelhexane system.

N-Alkylation of Amides or Lactams Using Cesium Carbonate To a solution of the amide or lactam in DMF was added cesium carbonate (1.05 eq) and an alkyl iodide (1.1 eq). The mixture was allowed to stir overnight at room temperature and then the reaction mixture was diluted with ethyl acetate and washed with water, followed by brine. The organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by HPLC (LC 2000), eluting with an ethyl acetate/hexane system.

BOC Removal Procedure To an N-Boc protected compound was added CH2C12/TFA (4:1) at room temperature. The reaction mixture was stirred at room temperature for 3 hours and then concentrated. The residue was extracted into dichloromethane and washed with water, saturated sodium bicarbonate, dried over Na2S04, filtered and concentrated to give the free amine.

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

Azide Reduction to ari Amine A mixture of the azide in absolute EtOH (0.03-0.07 M) and 10%a Pd/C ( -1/3 by weight of the azide) was shaken in a Parr apparatus under H2 (35-45 psi) at room temperature for 3-6 hours. The catalyst was removed by filtration through a plug of Celite, rinsing with absolute EtOH, and the filtrate concentrated to provide the crude amine product.

Amide AIkYlation Using cesium Carbonate This procedure is a modification of the procedure described in Claremon, D.
A.; et al, PCT Application: WO 96-US8400 960603. To a mixture of 2,4-dioxo-2,3,4.5-tetrahydro-1H-1,5-benzodiazepine (CAS No. 49799-48-6) in DMF (1.0 eq., 0.7 M) under N2 at room temperature was added Cs2C03 (2.2 eq.) and the appropriate alkyl halide (2.2 eq.). The mixture was stirred at room temperature for 5.5-16 hours. The mixture was partitioned between EtOAc and sat. NaHC03.
The aqueous layer was extracted with EtOAc (1-2x) and the combined EtOAc extracts were dried over Na,S04, filtered, and concentrated to provide the crude product.

BOC Removal Procedure A stream of anhydrous HCl gas was passed through a stirred solution of the N-t-Boc protected amino acid in 1.4-dioxane (0.03-0.09 M), chilled in a ice bath to -10°C under N2, for 10-15 minutes. The solution was capped, the cooling bath removed, and the solution was allowed to warm to room temperature with stirring for 2-8 hours, monitoring by TLC for the consumption of starting material. The solution was concentrated (and in some instances dissolved in CH2Cl2 then re-concentrated and placed in vacuum oven at 60-70°C to remove most of the residual dioxane) and used without further purification.
Example 8-A
Synthesis of 3-Amino-1,3-dihydro-5-(1-piperidinyl)-2H-1,4-benzodiazepin-2-one Step A - Preparation of 1.2-Dihydro-3H-Lm~~y~l-~ e~~l)-1.4-benzodiazenin-2-one A solution of phosphorous pentachloride (1.2 eq) in methylene chloride was added dropwise to a solution of 1-methyl-1,2,3,4-tetrahydro-3H-1.4-benzodiazepin-2,5-dione (Showell, G. A.; Bourrain. S.: Neduvelil, J. G.;
Fletcher, S. R.; Baker, R.; Watt, A. P.; Fletcher, A. E.; Freedman, S. B.;
Kemp, J. A.; Marshall, G. R.; Patel, S.; Smith, A. J.; Matassa. V. G. J. Med. Chem.
1994, 37, 719. ) in methylene chloride. The resultant yellowish-orange solution was stirred at ambient temperature for 2.5 hours; the solvent was removed in vacuo. The orange residue was redissolved in methylene chloride, cooled to 0 EC, and treated with a solution of piperidine (2 eq) and triethylamine (2 eq) in methylene chloride. The cooling bath was removed and the reaction stirred for hours. The reaction mixture was washed with saturated aqueous NaHC03 (back-extracted with methylene chloride) and brine. The organic phase was dried over Na,SO~, filtered, and concentrated. The residue was purified via HPLC eluting with a gradient of 4 to 10 % methanolJmethylene chloride affording the title intermediate as a yellow solid having a melting point of 103-105°C.
C,SH,9N~0 (MW 257.37); mass spectroscopy 257.
Anal. Calcd for C,SH,yN,O: C, 70.01; 1-i, 7.44; N, 16.33. Found: C, 69.94; H, 7.58; N. 16.23.
Step B - Preparation of 1 2-Dihydro-3H-1-methyl-3-oximid~ -(1-p~peridin~,)-1 4-be podia epin-~-one Potassium tert-butoxide (2.5 eq) was added in two portions to a -20°C
solution of 1,2-dihydro-3H-1-methyl-5-(1-piperidinyl)-1.4-benzodiazepin-2-one (1 eq) in toluene). After stirring at - 20°C for 20 min, isoamyl nitrite (1.2 eq.;
Aldrich) was added to the red reaction mixture. The reaction was stirred at -20 °C
for 5 hours at which time the reaction was done by TLC. The cooling bath was removed and the reaction quenched with 0.5 M citric acid. After stirring for minutes, diethyl ether was added. The suspension was stirred at ambient temperature overnight then filtered washing with ether. The resultant cream colored solid had a melting point of 197-200°C. ' 'H NMR data of the E/Z isomers was as follows:

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

Example 8-B
Synthesis of 3-(L-Alaninyl)-amino-2,3-dihydro- , 1-methyl-S-phenyl-1 H-1,4-benzodiazepin-2-one Step A - Preparation of (~l-3-amino-1 3-dih~Q~,-metl~y~ S phen3rl-2H-1 4-benzodiazePin-2-one (1S)-7 7-dimethyl-2-oxobicysloj~~,]~gp~anP_ 1-methanesulfonate The title intermediate was prepared according to Reider, P. J.; Davis, P.;
Hughes, D. L.; Grabowski, E. J. J. J. Org. Chem. 1987, 52. 955 using 3-amino-1,3-dihydro-1-methyl-5-phenyl-2H-1,4-benzodiazepin-2-one (Bock M. G.;
DiPardo, R. M.; Evans, B. E.; Rittle, K. E.; Veber, D. F.; Freidinger, R. M.;
Hirshfield, J.; Springer, J. P. J. Org. Chem. 1987, 52, 3232.) as the starting material.
Step B - Preparation of 3-jN~tert-Butvlcarbamate)-L-alaninvll-amino-~ 3-dil~,ydro- -methyL~,~~nvl-1H-1 4-benzodiazepin-2-Q~
(S)-3-Amino-1, 3-dihydro-1-methyl-S-phenyl-2H-1.4-benzodiazepin-2-one, (1S)-7,7-dirnethyl-2-oxobicyclo[2.2.1]heptane-1-methanesulfonate was free based by partitioning between methylene chloride and 1 M potassium carbonate. The free amine was then coupled with N-Boc-alanine following General Procedure D.
C,~HZgNaO, (MW = 436.56); mass spectroscopy 436.
Anal. Calc. for C,4H,gN,Oy: C, 66.03; H, 6.47; N, 12.84. Found: C, 65.79; H, 6.68; N. 12.80.
Step C - Preparation of 3-(L-AlaninyjZamino-2 3-dihvdro-1-meth~t ~-phenyl-1 H-1.4-benzodiazepin-2-one WO 99!67221 PCT/US99/14193 Following General Procedure 8-C using 3-[N'-(tert-butylcarbamate)-L-alaninylj-amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one, the title compound was prepared as a white foam.
Anal. Calc. for C,9H,9N,0,: C, 69.21; H, 6.64; N, 15.37. Found: C, 70.11; H, 6.85; N, 15.01.
Example 8-C
Synthesis of 3-(L-Alaninyl)-amino-7-chloro-2,3-dihydro-1-methyl-S-phenyl-1H-1,4-benzodiazepin-2-one Step A - Preparation of 3-lBenzy~, carbo~yl)-amino-7-chloro-dihvdro-1-meth3rl-~p~vl-1 H-1.4-ben~~ ia~Pnin-2 one A solution of 3-(benzyloxycarbonyl)-amino-7-chloro-2,3-dihydro-5-phenyl-1H-1,4-Benzodiazepin-2-one ( 1 eq: Neosystem) in DMF was cooled to 0°C
and treated with potassium tent-butoxide ( 1 eq; 1.OM solution in THF). The resultant yellow solution was stirred at 0°C for 30 minutes then quenched with methyl iodide (1.3 eq). After stirring an addition 25 minutes the reaction was diluted with methylene chloride and washed with water and brine. The organic phase was dried over Na,S04, filtered, and concentrated. The residue was purified via HPLC
chromatography eluting with a gradient of 20630% ethyl acetate/hexanes.
C,4H~~,C1N303 (MW = 433.92); mass spectroscopy 433.
Anal. calcd for C,,,HZ~C1N303: C, 66.44; H, 4.65; N, 9.68. Found: C, 66.16;H,4.50:N,9.46.
Step B - Preparation of 3-Amin -7-chloro-1 3-dihydro-1-m~,~-5-enyl-2H-1.4-benzodiazepin-2-one Following General Procedure 8-B using 3-(benzyloxycarbonyl)-amino-7-chloro-2,3-dihydro-1-methyl-S-phenyl-1H-1,4-benzodiazepin-2-one, the title intermediate was prepared as a white foam which was used immediately in Step C.

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

Anal. calcd for C,.,H,9BrFN303: C. 58.08; H, 3.86; N, 8.47. Found: C, 57.90; H, 4.15; N, 8.20.
Step B - Preparation of 3-Amino-7-bromo-1.3-dihydro-1-methyl-5-«_ fJuoroQh~yll-2H-1.4-benzodiazenin-2-one Following General Procedure 8-B using 3-(benzyloxycarbonyl)-amino-7-bromo-2,3-dihydro-1-methyl-5-(2-fluorophenyl)-1H-1,4-benzodiazepin-2-one, the title intermediate was prepared as a white foam which was used immediately in Step C.
Step C - Preparation of 3-[N'-ltert-Butvlcarbamate)-L-alar,;n~O-amino-7-bromo-1 3-dihvdro-1-met~~~l-5-(2-fluorophenvl)-2H-1.4-benzodiazenin-2-one Following General Procedure D using N-Boc-L-alanine (Novo) and 3-amino-7-bromo-1,3-dihydro-1-methyl-5-(2-fluorophenyl)-2H-1,4-benzodiazepin-2-one, the title intermediate was prepared as a white foam.
C~~H,6BrFN,Oa (MW = 533.12): mass spectroscopy 533.2.
Anal. calcd for C,.,H,6BrFN~O,,: C. 54.04; H, 4.9I: N, 10.50. Found: C, 53.75; H, 4.92; N. 10.41.
Step D - Preparation of ~ (, -Alaniny~l-amino-7-br2yo-11 i3-dih, d methyl-S-(2-fluorophen I)-v 2H-li4-benzodiazepin-2-one Following General Procedure 8-C using 3-[N'-(tent-butylcarbamate)-L-alaniny l]-amino-7-bromo-1.3-dihydro-1-methyl-5-(2-fluorophenyl}-2H-1.4-benzodiazepin-2-one, the title intermediate was prepared as a white foam. The crude material was used immediately.
Example 8-E
Synthesis of WO 99167221 PCT/US99t14193 3-(N-Methyl-L-alaninyl)-amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one Step A - ~~paration of 3-[~T~tert-Butvlcarbamate)-N'-methyl-L-alaniny,)Lamino-2.3-dihydro-1-methL-5-phenyl-1 H-1.4-benzodiazepin-2-one Following General Procedure D and using (S)-3-amino-1,3-dihydro-I-methyl-5-phenyl-2H-1,4-benzodiazepin-2-one (Example 8-B) and N-tent-Boc-N-methyl-alanine (Sigma), the title intermediate was obtained as a white solid.
C,SH3oN4O4 (MW = 450.2): mass spectroscopy (M+1) 451.2.
Anal. calcd for C~SH3oN,,04: C, 66.65; H, 6.71; N, 12.44. Found: C, 66.66; H, 6.89; N, 12.21.
Step A - ~gparation of 3-(N'-Meth3~l-L-alaninyl)-amino-2.3-dih ro-methyl-5-phenyl-1H-I .4-benzodiazepin-2-one Following General Procedure 8-C and using 3-[N'-(tert-butylcarbamate)-N-methyl-L-alaninyl]-amino-2.3-dihydro-1-methyl-5-phenyl-1 H-1,4-benzodiazepin-2-one, the title intermediate was prepared as a white foam.
C,oH~,N40, (MW = 350.46): mass spectroscopy (M + 1 ) 351.4.
Anal. calcd for C,oH~~N.~O,: C, 68.55; H, 6.33; N, 15.99. Found, C, 68.36: H, 6.20; N, 15.79.
Example 8-F
Synthesis of 3-(L-Alaninyl)amino-7-chloro-2,3-dihydro-1-methyl-5-(2-chlorophenyl)-1H-1,4-benzodiazepin-2-one Step A - Preparation of 3-l~enzvloxycarbon~)-amino-7-chloro-2.3-dihXdro-1-methy~2-chlorophenvl)-1 H-1.4-benzodiazepin-Following General Procedure 8-A using 3-(benzyloxycarbonyl)-amino-7-chloro-2,3-dihydro-5-(2-chlorophenyl)-1H-1,4-benzodiazepin-2-one (Neosystem), the title intermediate was prepared as a white solid having a melting point of 233°C.
C24HI9C12N303 (MW = 468.36); mass spectroscopy 468.
'H NMR (300 MHz, CDC13): d = 7.67 (1H, m), 7.52 (1H, dd, J=2.4, 8.7 Hz), 7.42-7.26 (9H, m), 7.07 (1H, d, J=2.4 Hz), 6.70 (1H, d, J=8.3 Hz), 5.35 (1H, d, J=8.4 Hz), 5.14 (2H, ABq, J=19.6 Hz), 3.47 (3H, s).
"C NMR (75 MHz. CDCl3): d = 166.66, 165.65, 155.72, 140.52, IO 136.99, 136.0, 132.87, 131.99. 131.47, 131.40, 131.38, 131.16, 130.54, 130.06, 128.45, 128.08, 128.03, 127.72, 127.22, 123.28, 122.01, 68.95, 67.02, 35.32.
Step B - ~~~naration of 3 Amino 7 chloro-1 3-dihvdro-1-methyl-5-(2-~hloro,~h~Ll~'-~u-~ 4-benzodiaze ' - -one 1 S Following General Procedure 8-B using 3-(benzyloxycarbonyl)-amino-7-chloro-2,3-dihydro-1-methyl-5-(2-chlorophenyl)-1H-1,4-benzodiazepin-2-one, the title intermediate was prepared as a white foam which was used immediately in Step C.
20 Step C - s;~~ration of 3 IN' (tert But~carbamate)-L-alaninvll-amino 7 chloro 1 3 dihvdro-1-methyl-S-«-~hloro envl)-~H-I 4-benzodia~enin-2-one Following General Procedure D using N-Boc-L-alanine and 3-amino-7-chloro-1,3-dihydro-1-methyl-5-(2-chlorophenyl)-2H-1,4-benzodiazepin-2-one, the 25 title intermediate was prepared as a white foam.
C~4H,6C1,N40a (MW = 505.44); mass spectroscopy 505.2.
Step D - ~1'Laration of 3 (L Alaninvll amino-7-chloro-1 3-dihvdro1-1-~~,~1 5 (2 chloro~hem~,L?H-1 4-benzod~a~enin-2-one Following General Procedure 8-C using 3-[N'-(tent-butylcarbamate)-L-alaninyl)-amino-7-chloro-1, 3-dihydro-1-methyl-5-(2-chlorophenyl)-2H-1,4-benzodiazepin-2-one, the title intermediate was prepared as a white foam. The w crude material was used immediately.
Example 8-G
Synthesis of 3-(L-Alaninyl)amino-5-cyclohexyl-2,3-dihydro-1-methyl-1H-1,4-Benzodiazepin-2-one Step A - py~paration of ~-~RPn~L~loxvcarbony],)-amino-5-cyclohexvl-2 .3-di~y~ro-1-methy]I-1 H-1.4-benzodiazenin-2-one Following General Procedure 8-A using 3-(benzyloxycarbonyl)-amino-5-cyclohexyl-2,3-dihydro-1H-1,4-benzodiazepin-2-one (Neosystem), the title intermediate was prepared as a white solid having a melting point of 205-206°C.
C,4H,,N~O, (MW = 405.54); mass spectroscopy 405.
'H NMR (300 MHz, CDC13): d = 7.54 (1H, d, J=7.9 Hz). 7.48 (1H, d, J=7.7 Hz), 7.36-7.26 (7H, m), 6.54 (1H, d, J= 8.3 Hz), 5.15 (1H, d, J=8.0 Hz). 5.09 (2H, ABq, J=17.1 Hz), 3.39 (3H, s), 2.77 (1H, m), 2.01 (1H, bd, J=13.6 Hz), 1.85 (1H, bd, J=12.4 Hz), 1.68-1.49 (4H, m), 1.34-1.02 (4H, m).
Step B - PreDaraLlOn of '~-Amino-5-cXclohexyl-1 3-dihydro-1-meth ~~l-7N-1 d-hen~odiazeQ n- -one Following General Procedure 8-B using 3-(benzyloxycarbonyl)-amino-S-cyclohexyl-2,3-dihydro-1-methyl-1H-1.4-benzodiazepin-2-one, the title intermediate was prepared as a white foam which was used immediately in Step C.
C,6H,,N30 (MW+H = 272.1763); mass spectroscopy 272.1766 Step C - Prgparation of 3-[N'-(tent-Buty~carba ate)-L-alaninvll-amino-5-cyclohexyl-1 3-dihydro-1-methy -12H1.4-CA 02325389 2000-09-21 .
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Claims (123)

Claims:

1. A method for inhibiting .beta.-amyloid peptide release and/or its synthesis in a cell which method comprises administering to such a cell an amount of a compound or a mixture of compounds effective in inhibiting the cellular release and/or synthesis of .beta.-amyloid peptide wherein said compounds are represented by the following formulas:
Formula VI
wherein R1 is selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, substituted alkyl, substituted alkenyl, substituted alkynyl, substituted cycloalkyl, substituted cycloalkenyl, aryl, heteroaryl and heterocyclic:
R'is selected from the group consisting of aryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heteroaryl, heterocyclic, -CH3, -CH=CH2, -CH=CHR1,- CH=CR1R1.
-CR1=CH2, -CR1=CHR2, -CR1=CR1R1. -C=CH and -C=CR1: with the proviso that when R' is heteroaryl or heterocyclic, there is no N in R' at a position beta to the C=Q
group;
Q is S or O:
R15 is selected from the group consisting of hydrogen, alkyl.
substituted alkyl, aryl, heterocyclic and heteroaryl;

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

wherein each R2 is independently selected from the group consisting of alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, aryl, heteroaryl and heterocyclic;
Z is represented by the formula -T-C(X')(X")C(O)- where T
is selected from the group consisting of a bond covalently linking R1 to -C(X')(X")-, oxygen, sulfur, and -NR5 where R5 is hydrogen, acyl, alkyl, substituted alkyl, aryl. heterocyclic or heteroaryl group;
R5' is hydrogen. alkyl, substituted alkyl, aryl, heterocyclic or heteroaryl group:
X' and X" are independently selected from the group consisting of hydrogen, fluoro, alkyl, substituted alkyl, aryl, heteroaryl. heterocyclic, -OR5~, -SR5, -N(R5)2, -N(CO)OR15 and - N3, with the proviso that at least one of X' or X" is other than hydrogen, hydroxy or fluoro, and with the further proviso that both X' and X" cannot both be -OR5', -SR5. -N(R5)2, -N(CO)OR15 and - N3 ; further, neither X' and X" can be -OR5,. -SR5. -N(R5)2, - N(CO)OR15 or -N3 when T is other than a bond covalently linking R1 to -C(X')(X")-;
n is an integer equal to 1 or 2;
p is an integer equal to 0 or 1 such that when p is zero, the ring defined by W and -C(H)p C(=X)- is unsaturated at the carbon atom of ring attachment to Y and when p is one, the ring is saturated at the carbon atom of ring attachment to Y.
with the following provisos:
when R1 is 2-propylpentanoyl, R2 is methyl, and R15 is hydrogen, then W, together with >CH and >C=X, does not form a 2,3-dihydro-1-methyl-5-phenyl-1H-1.4-benzodiazepin-2-one when R1 is 3.5-difluorobenzoyl. R2 is methyl, and R15 is hydrogen, then W, together with > CH and > C=X, does not form a 2,3-dihydro-1-methyl-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one when R1 is trans-cinnamyl. R2 is methyl, and R15 is hydrogen, then W. together with > CH and > C=X, does not form a 2.3-dihydro-1-(3.3-dimethyl-2-oxobutyl)-5-(2-pyridyl)-1H-1.4-benzodiazepin-2-one when R1 is 2-(4-chlorophenoxy)-2-methylpropionyl. R2 is methyl, and R15 is hydrogen, then W, together with > CH and >C=X, does not form a 2,3-dihydro-1-methyl-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one when R1 is .alpha.-methoxyphenylacetyl, R2 is methyl. and R15 is hydrogen, then W. together with > CH and > C=X, does not form a 2,3-dihydro-1-methyl-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one when R1 is diphenylacetyl, R2 is methyl, and R15 is hydrogen, then W, together with > CH and > C=X, does not form a 2,3-dihydro-1-methyl-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one when R1 is .alpha.-methoxyphenylacetyl, R2 is methyl, and R15 is hydrogen, then W, together with > CH and > C=X, does not form a 2.3-dihydro-1-(3,3-dimethyl-2-oxobutyl)- 5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one when R1 is .alpha.-hydroxy-diphenylacetyl, R2 is methyl, and R15 is hydrogen, then W, together with > CH and > C=X, does not form a 2.3-dihydro-1-(3,3-dimethyl-2-oxobutyl)- 5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one when R1 is diphenylacetyl, R2 is methyl, and R15 is hydrogen, then W. together with > CH and > C=X. does not form a 2,3-dihydro-1-(3.3-dimethyl-2-oxobutyl)- 5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one when R1 is 2-(chlorophenoxy)-2-methylpropionyl. R2 is methyl, and R15 is hydrogen, then W, together with > CH and >C=X, does not form a 2.3-dihydro-1-(3.3-dimethyl-2-oxobutyl)-5-(2-pyridyl)-1H-1.4-benzodiazepin-2-one when R1 is diphenylacetyl, R2 is methyl, and R15 is hydrogen, then W, together with > CH and > C = X, does not form a 2.3-dihydro-1-(2-N.N-diethylaminoethyl)- 5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one when R1 is 3,5-difluorobenzoyl, R2 is methyl. and R15 is hydrogen, then W. together with > CH and > C=X, does not form a 2,3-dihydro-1-(2-N.N-diethylaminoethyl)- 5-(2-pyridyl)-1H-1.4-benzodiazepin-2-one when R1 is trans-cinnamyl. R2 is methyl, and R15 is hydrogen, then W, together with >CH and >C=X, does not form a 2,3-dihydro-1-(2-N,N-diethylaminoethyl)- 5-(2-pyridyl)-1H-1.4-benzodiazepin-2-one when R1 is 2-(4-chlorophenoxy)-2-methylpropionyl. R2 is methyl, and R15 is hydrogen, then W, together with > CH and >C=X, does not form a 2.3-dihydro-1-(2-N.N-diethylaminoethyl)-5-(2-pyridyl)-1H-1.4-benzodiazepin-2-one when R1-N(R15) is (2.5-dimethoxyphenyl)ureylenyl and R2 is methyl, then W, together with > CH and > C=X, does not form a 2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one when R1 is D.L-2-pyrrolidinone-5-yl. R2 is methyl, and R15 is hydrogen. then W, together with > CH and > C=X. does not form a 7-methyl-5,7-dihydro-6H-dibenz[b.d]azepin-6-one.

2. A method for preventing the onset of AD in a human patient at risk for developing AD which method comprises administering to said patient a pharmaceutical composition comprising a pharmaceutically inert carrier and an effective amount of a compound or a mixture of compounds of the following formulas:

wherein R1 is selected from the group consisting of alkyl.
alkenyl, alkynyl, cycloalkyl, cycloalkenyl, substituted alkyl.
substituted alkenyl. substituted alkynyl, substituted cycloalkyl.
substituted cycloalkenyl, aryl, heteroaryl and heterocyclic:
R'is selected from the group consisting of aryl, cycloalkyl.
substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heteroaryl, heterocyclic, -CH3, -CH=CH2, -CH=CHR1, -CH=CR1R1, -CR1=CH2, -CR1=CHR1, -CR1=CR1R1, -C=CH and -C=CR1: with the proviso that when R' is heteroaryl or heterocyclic, there is no N in R' at a position beta to the C=Q
group;
Q is S or O:
R15 is selected from the group consisting of hydrogen, alkyl, substituted alkyl, aryl, heterocyclic and heteroaryl;
R15' is selected from the group consisting of hydrogen, hydroxyl, alkyl, substituted alkyl, aryl, heterocyclic and heteroaryl;
W. together with -C(H)p C(=X)-, forms a cycloalkyl, cycloalkenyl, heterocyclic, substituted cycloalkyl, or substituted cycloalkenyl group wherein each of said cycloalkyl, cycloalkenyl.
heterocyclic, substituted cycloalkyl or substituted cycloalkenyl group is optionally fused to form a bi- or multi-fused ring system (preferably -no more than 5 fused rings) with one or more ring structures selected from the group consisting of cycloalkyl, cycloalkenyl, heterocyclic, aryl and heteroaryl group which, in turn, each of such ring structures are optionally substituted with 1 to 4 substituents selected from the group consisting of hydroxyl, halo, alkoxy, substituted alkoxy, thioalkoxy, substituted thioalkoxy, vitro, cyano, carboxyl, carboxyl esters, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, amino, substituted amino. -NHC(O)R4. -NHSO2R4, -C(O)NH2, -C(O)NHR4, -C(O)NR4R4, -S(O)R4, -S(O)2R4. -S(O)2NHR4 and -S(O)2NR4R4, where each R4 is independently selected from the group consisting of alkyl, substituted alkyl, aryl and heteroaryl;
X is selected from the group consisting of oxo (=O), thiooxo (=S), hydroxyl (-H, -OH), thiol (H,-SH) and hydro (H,H):
Y is represented by the formula:

wherein each R2 is independently selected from the group consisting of alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, aryl, heteroaryl and heterocyclic:
Z is represented by the formula -T-C(X')(X")C(O)- where T
is selected from the group consisting of a bond covalently linking R1 to -C(X')(X")-, oxygen, sulfur, and -NR5 where R5 is hydrogen, acyl, alkyl, substituted alkyl, aryl, heterocyclic or heteroaryl group:

R5' is hydrogen, alkyl, substituted alkyl, aryl. heterocyclic or heteroaryl group:
X' and X" are independently selected from the group consisting of hydrogen, fluoro, alkyl, substituted alkyl, aryl.
heteroaryl, heterocyclic, -OR5', -SR5, -N(RS)2, -N(CO)OR15 and - N3, with the proviso that at least one of X' or X" is other than hydrogen, hydroxy or fluoro, and with the further proviso that both X' and X" cannot both be -OR5', -SR5, -N(R5)2, -N(CO)OR15 and - N3 ; further, neither X' and X" can be -OR5', -SR5, -N(R5)2, -N(CO)OR15 or -N3 when T is other than a bond covalently linking R1 to -C(X')(X")-:
n is an integer equal to 1 or 2;
p is an integer equal to 0 or 1 such that when p is zero, the ring defined by W and -C(H)p C(=X)- is unsaturated at the carbon atom of ring attachment to Y and when p is one, the ring is saturated at the carbon atom of ring attachment to Y, with the following provisos:

when R1 is 2-propylpentanoyl, R2 is methyl, and R15 is hydrogen, then W, together with >CH and >C=X, does not form a 2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one when R1 is 3,5-difluorobenzoyl, R2 is methyl, and R15 is hydrogen, then W, together with > CH and > C = X, does not form a 2,3-dihydro-1-methyl-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one when R1 is trans-cinnamyl, R2 is methyl, and R15 is hydrogen.
then W, together with > CH and > C =X, does not form a 2.3-dihydro-1-(3,3-dimethyl-2-oxobutyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one when R1 is 2-(4-chlorophenoxy)-2-methylpropionyl, R2 is methyl, and R15 is hydrogen, then W, together with > CH and >C=X, does not form a 2,3-dihydro-1-methyl-5-(2-pyridyl)-1H-1.4-benzodiazepin-2-one when R1 is .alpha.-methoxyphenylacetyl, R2 is methyl, and R15 is hydrogen, then W, together with >CH and >C=X, does not form a 2,3-dihydro-1-methyl-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one when R1 is diphenylacetyl, R2 is methyl, and R15 is hydrogen.
then W, together with > CH and > C = X, does not form a 2.3-dihydro-1-methyl-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one when R1 is .alpha.-methoxyphenylacetyl. R2 is methyl, and R15 is hydrogen, then W, together with > CH and > C=X. does not form a 2,3-dihydro-1-(3,3-dimethyl-2-oxobutyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one when R1 is .alpha.-hydroxy-diphenylacetyl, R2 is methyl, and R15 is hydrogen. then W, together with >CH and >C=X, does not form a 2,3-dihydro-1-(3,3-dimethyl-2-oxobutyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one when R1 is diphenylacetyl, R2 is methyl, and R15 is hydrogen.
then W, together with > CH and > C=X. does not form a 2,3-dihydro-1-(3,3-dimethyl-2-oxobutyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one when R1 is 2-(chlorophenoxy)-2-methylpropionyl, R2 is methyl, and R15 is hydrogen, then W, together with >CH and >C=X, does not form a 2,3-dihydro-1-(3,3-dimethyl-2-oxobutyl)-5-(2-pyridyl)-1H-1.4-benzodiazepin-2-one when R1 is diphenylacetyl, R2 is methyl, and R15 is hydrogen, then W, together with >CH and >C=X, does not form a 2.3-dihydro-1-(2-N,N-diethylaminoethyl)-5-(2-pyridyl)-1H-1, 4-benzodiazepin-2-one when R1 is 3,5-ditluorobenzoyl, R2 is methyl, and R15 is hydrogen, then W, together with >CH and >C=X. does not form a 2,3-dihydro-1-(2-N,N-diethylaminoethyl)-5-(2-pyridyl)-1H-1, 4-benzodiazepin-2-one when R1 is trans-cinnamyl, R2 is methyl, and R15 is hydrogen.
then W, together with >CH and >C=X, does not form a 2,3-dihydro-1-(2-N,N-diethylaminoethyl)-5-(2-pyridyl)-1H-1, 4-benzodiazepin-2-one when R1 is 2-(4-chlorophenoxy)-2-methylpropionyl, R2 is methyl, and R15 is hydrogen, then W, together with > CH and >C=X, does not form a 2,3-dihydro-1-(2-N,N-diethylaminoethyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one when R1-N(R15) is (2,5-dimethoxyphenyl)ureylenyl and R2 is methyl, then W, together with >CH and >C=X, does not form a 2,3-dihydro-1-methyl-5-phenyl-1H-1.4-benzodiazepin-2-one when R1 is D,L-2-pyrrolidinone-5-yl, R2 is methyl, and R15 is hydrogen, then W, together with >CH and >C=X, does not form a 7-methyl-5,7-dihydro-6H-dibenz[b.d]azepin-6-one.

3. A method for treating a human patient with AD in order to inhibit further deterioration in the condition of that patient which method comprises administering to said patient a pharmaceutical composition comprising a pharmaceutically inert carrier and an effective amount of a compound or a mixture of compounds of the following formulas:

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

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

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

when R1 is 2-propylpentanoyl, R2 is methyl, and R15 is hydrogen, then W, together with >CH and >C=X, does not form a 2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one when R1 is 3,5-difluorobenzoyl, R2 is methyl, and R15 is hydrogen, then W, together with >CH and >C=X, does not form a 2,3-dihydro-1-methyl-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one when R1 is trans-cinnamyl, R2 is methyl, and R15 is hydrogen, then W, together with >CH and >C=X, does not form a 2,3-dihydro-1-(3,3-dimethyl-2-oxobutyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one when R1 is 2-(4-chlorophenoxy)-2-methylpropionyl, R2 is methyl, and R15 is hydrogen, then W, together with >CH and >C=X, does not form a 2,3-dihydro-1-methyl-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one when R1 is .alpha.-methoxyphenylacetyl, R2 is methyl, and R15 is hydrogen, then W, together with > CH and > C=X, does not form a 2,3-dihydro-1-methyl-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one when R1 is diphenylacetyl, R2 is methyl, and R15 is hydrogen, then W, together with > CH and > C = X, does not form a 2,3-dihydro-1-methyl-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one when R1 is .alpha.-methoxyphenylacetyl, R2 is methyl, and R15 is hydrogen, then W, together with > CH and > C=X, does not form a 2.3-dihydro-1-(3,3-dimethyl-2-oxobutyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one when R1 is .alpha.-hydroxy-diphenylacetyl, R2 is methyl, and R15 is hydrogen, then W, together with > CH and > C=X, does not form a 2,3-dihydro-1-(3,3-dimethyl-2-oxobutyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one when R1 is diphenylacetyl, R2 is methyl, and R15 is hydrogen, then W, together with > CH and > C =X, does not form a 2,3-dihydro-1-(3,3-dimethyl-2-oxobutyl)- 5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one when R1 is 2-(chlorophenoxy)-2-methylpropionyl, R2 is methyl, and R15 is hydrogen, then W, together with > CH and >C=X, does not form a 2,3-dihydro-1-(3,3-dimethyl-2-oxobutyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one when R1 is diphenylacetyl, R2 is methyl, and R15 is hydrogen, then W, together with >CH and >C=X, does not form a 2.3-dihydro-1-(2-N,N-diethylaminoethyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one when R1 is 3,5-difluorobenzoyl, R2 is methyl, and R15 is hydrogen, then W, together with > CH and > C = X, does not form a 2,3-dihydro-1-(2-N,N-diethylaminoethyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one when R1 is trans-cinnamyl, R2 is methyl, and R15 is hydrogen, then W, together with > CH and > C=X, does not form a 2,3-dihydro-1-(2-N,N-diethylaminoethyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one when R1 is 2-(4-chlorophenoxy)-2-methylpropionyl, R2 is methyl, and R15 is hydrogen. then W, together with > CH and >C=X, does not form a 2,3-dihydro-1-(2-N,N-diethylaminoethyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one when R1-N(R15) is (2,5-dimethoxyphenyl)ureylenyl and R2 is methyl, then W, together with >CH and >C=X, does not form a 2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one when R1 is D,L-2-pyrrolidinone-5-yl, R2 is methyl, and R15 is hydrogen, then W, together with > CH and > C=X, does not form a 7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one.

4. A method according to any of Claims 1-3 wherein R1 is aryl or heteroaryl.

5. A method according to Claim 4 wherein R1 is selected from the group consisting of (a) alkyl (b) phenyl, (c) a substituted phenyl group of the formula:

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, vitro, cyanc, trihalomethyl, alkoxy, and thioalkoxy with the proviso that when R c is hydrogen, then R b and R b are either both hydrogen or both substituents other than hydrogen, (d) 2-naphthyl, (e) 2-naphthyl substituted at the 4, 5, 6, 7 and/or 8 positions with 1 to 5 substituents selected from the group consisting alkyl.
alkoxy, halo, cyano, vitro, trihalomethyl, thioalkoxy, aryl, and heteroaryl, (f) heteroaryl, and (g) substituted heteroaryl containing 1 to 3 substituents selected from the group consisting of alkyl, alkoxy, aryl, aryloxy.
cyano, halo, vitro, heteroaryl, thioalkoxy, thioaryloxy provided that said substituents are not ortho to the heteroaryl attachment to the - NH group.

6. The method according to Claim 4 wherein R1 is selected from the group consisting of mono-, di- and tri-substituted phenyl groups.

7. The method according to Claim 6 wherein R1 is a disubstituted phenyl selected from the group consisting of 3,5-dichlorophenyl, 3,5-difluorophenyl, 3,5-di(trifluoromethyl)-phenyl.

3,4-dichiorophenyl, 3,4-difluorophenyl, 3-(trifluoromethyl)-4-chlorophenyl, 3-chloro-4-cyanophenyl, 3-chloro-4-iodophenyl, and 3,4-methylenedioxyphenyl.

8. The method according to Claim 6 wherein R1 is a monosubstituted phenyl selected from the group consisting of 4-azidophenyl, 4-bromophenyl, 4-chlorophenyl, 4-cyanophenyl, 4-ethylphenyl, 4-fluorophenyl, 4-iodophenyl, 4-(phenylcarbonyl)-phenyl, and 4-(1-ethoxy)ethylphenyl.

9. The method according to Claim 6 wherein R1 is a trisubstituted phenyl selected from the group consisting of 3,4,5-trifluorophenyl and 3,4,5-trichlorophenyl.

10. The method according to Claim 4 wherein R1 is selected from the group consisting of 2-naphthyl, quinolin-3-yl, 2-methylquinolin-6-yl, benzothiazol-6-yl, 5-indolyl, and phenyl.

11. A method according to any of Claims 1, 2 or 3 wherein R1 is selected from the group consisting of phenyl, 1-naphthyl, 2-naphthyl, 2-chlorophenyl, 2-fluorophenyl.
2-bromophenyl. 2-hydroxyphenyl, 2-nitrophenyl, 2-methylphenyl, 2-methoxyphenyl, 2-phenoxyphenyl, 2-trifluoromethylphenyl, 4-fluorophenyl, 4-chlorophenyl, 4-bromophenyl, 4-nitrophenyl, 4-methylphenyl, 4-hydroxyphenyl, 4-methoxyphenyl, 4-ethoxyphenyl, 4-butoxyphenyl, 4-iso-propylphenyl, 4-phenoxyphenyl, 4-trifluoromethylphenyl, 4-hydroxymethylphenyl, 3-methoxyphenyl, 3-hydroxyphenyl, 3-nitrophenyl, 3-fluorophenyl, 3-chlorophenyl, 3-bromophenyl, 3-phenoxyphenyl, 3-thiomethoxyphenyl, 3-methylphenyl, 3-trifluoromethylphenyl, 2,3-dichlorophenyl, 2,3-difluorophenyl, 2,4-dichlorophenyl, 2,5-dimethoxyphenyl, 3,4-dichlorophenyl, 3,4-difluorophenyl, 3,4-methylenedioxyphenyl, 3,4-dimethoxyphenyl, 3,5-difluorophenyl, 3,5-dichlorophenyl, 3.5-di-(trifluoromethyl)phenyl, 3,5-dimethoxyphenyl, 2,4-dichlorophenyl, 2,4-difluorophenyl, 2,6-difluorophenyl, 3,4,5-trifluorophenyl, 3,4,5-trimethoxyphenyl, 3,4,5-tri-(trifluoromethyl)phenyl, 2,4,6-trifluorophenyl, 2,4,6-trimethylphenyl, 2,4,6-tri-(trifluoromethyl)phenyl, 2,3,5-trifluorophenyl, 2,4,5-trifluorophenyl, 2,5-difluorophenyl, 2-fluoro-3-trifluoromethylphenyl, 4-fluoro-2-trifluoromethylphenyl, 2-fluoro-4-trifluoromethylphenyl, 4-benzyloxyphenyl, 2-chloro-6-fluorophenyl, 2-fluoro-6-chlorophenyl, 2,3,4,5,6-pentafluorophenyl, 2,5-dimethylphenyl, 4-phenylphenyl, 2-fluoro-3-tritluoromethylphenyl, adamantyl, benzyl, 2-phenylethyl, 3-phenyl-n-propyl, 4-phenyl-n-butyl, methyl, ethyl, n-propyl, iso-propyl, iso-butyl, sec-butyl, tert-butyl, n-pentyl, iso-valeryl, n-hexyl, cyclopropyl, cyclobutyl, cyclohexyl, cyclopentyl, cyclopent-1-enyl.
cyclopent-2-enyl, cyclohex-1-enyl, -CH2-cyclopropyl, -CH2-cyclobutyl, -CH2-cyclohexyl, -CH2-cyclopentyl, -CH2CH2-cyclopropyl, -CH2CH2-cyclobutyl, -CH~CH'-cyclohexyl, -CH2CH2-cyclopentyl, pyrid-2-yl, pyrid-3-yl, pyrid-4-yf. tluoropyridyls, chioropyridyls, thien-2-yl, thien-3-yl, benzothiazol-4-yl, 2-phenylbenzoxazol-5-yl, furan-2-yl, benzofuran-2-yl, thionaphthen-2-yl, thionaphthen-3-yl, thionaphthen-4-yl, 2-chlorothiophen-5-yl, 3-methylisoxazol-5-yl. 2-(thiophenyl)thien-5-yl, 6-methoxythionaphthen-2-yl, 3-phenyl-1,2,4-thiooxadiazol-5-yl, 2-phenyloxazol-4-yl, indol-3-yl, 1-phenyl-tetrazol-5-yl, allyl, 2-(cyclohexyl)ethyl, (CH3)2CH=CHCH2CH2CH(CH3)-, C(O)CH2-.

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

2-(2,4-dichlorophenoxy)ethyl, SO2CH2-. 3-cyclohexyl-n-propyl, CF3CH2CH2CH2- and N-pyrrolidinyl.

12. A method according to any of Claims 1, 2 or 3 where each R2 is independently selected from the group consisting of alkyl, substituted alkyl, alkenyl, cycloalkyl, aryl, heteroaryl and heterocyclic.

13. The method according to Claim 12 wherein R2 is selected from the croup consisting of methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, ten-butyl, -CH2CH(CH2CH3)2, 2-methyl-n-butyl, 6-fluoro-n-hexyl, phenyl, benzyl, cyclohexyl, cyclopentyl, cycloheptyl, allyl, iso-but-2-enyl, 3-methylpentyl. -CH2-cyclopropyl, -CH2-cyclohexyl, -CH2CH2-cyclopropyl, -CH2CH2-cyclohexyl, -CH2-indol-3-yl, p-(phenyl)phenyl. o-fluorophenyl, m-fluorophenyl, p-fluorophenyl, m-methoxyphenyl, p-methoxyphenyl, phenethyl, benzyl, m-hydroxybenzyl, p-hydroxybenzyl, p-nitrobenzyl, m-trifluoromethylphenyl, p-(CH3)2NCH2CH2CH2O-benzyl, p-(CH3)3COC(O)CH2O-benzyl, p-(HOOCCH2O)-benzyl, 2-aminopyrid-6-yl, p-(N-morpholino-CH2CH2O)-benzyl, -CH2CH2C(O)NH2, -CH2-imidazol-4-yl, -CH2-(3-tetrahydrofuranyl), -CH2-thiophen-2-yl.
-CH2(1-methyl)cyclopropyl, -CH2-thiophen-3-yl, thiophen-3-yl, thiophen-2-yl, -CH2-C(O)O-t-butyl, -CH2-C(CH3)3, -CH2CH(CH2CH3)2, 2-methylcyclopentyl, cyclohex-2-enyl, -CH[CH(CH3)2]COOCH3, -CH2CH2N(CH3)2, -CH2C(CH3)=CH2, -CH2CH=CHCH3 (cis and trans), -CH2OH, -CH(OH)CH3, -CH(O-t-butyl)CH3, -CH2OCH3, -(CH2)4NH-Boc, -(CH2)4NH2. -CH2-pyridyl, pyridyl. -CH2-naphthyl, -CH2-(N-morpholino), p-(N-morpholino-CH2CH2O)-benzyl, benzo[b]thiophen-2-yl, 5-chlorobenzo[b]thiophen-2-yl, 4,5,6,7-tetrahydrobenzo[b]thiophen-2-yl, benzo[b]thiophen-3-yl.
5-chlorobenzo[b]thiophen-3-yl, benzo[b]thiophen-5-yl, 6-methoxynaphth-2-yl, -CH2CH2SCH3, thien-2-yl, and thien-3-yl.

14. A method according to any of Claims 1. 2 or 3 wherein the cyclic groups defined by W and -C(H)p C(=X)- is selected from the group consisting of lactones, lactams, thiolactones, thiolactams, heterocyclic and cycloalkyl groups.

15. The method according to Claim 14 wherein the cyclic group defined by W and -C(H)p C(=X)-, forms a lactam or thiolactam ring of the formula:

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

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

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

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

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 alkaxy, amino, substituted amino, carboxyl, carboxyl alkyl, cyano, and halo; t is an integer from 0 to 4; and w is an integer from 0 to 3.

22. The method according to Claim 14 wherein the cyclic group defined by W , together with -C(H)p C( = X)-, forms a ring of the formula:

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

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

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

any unsaturation in the alkenylene and substituted alkenylene does not involve participation of the -O- or -S-, and q is an integer of from 1 to 3.

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

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

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

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

30. A pharmaceutical composition comprising a pharmaceutically inert carrier and a pharmaceutically effective amount of a compound of the following formulas:
wherein R1 is selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, substituted alkyl, substituted alkenyl, substituted alkynyl, substituted cycloalkyl, substituted cycloalkenyl, aryl, heteroaryl and heterocyclic:

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

X is selected from the group consisting of oxo (=O), thiooxo (=S), hydroxyl (-H, -OH), thiol (H,-SH) and hydro (H,H);
Y is represented by the formula:
wherein each R2 is independently selected from the group consisting of alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, aryl, heteroaryl and heterocyclic;
Z is represented by the formula -T-C(X')(X")C(O)- where T
is selected from the group consisting of a bond covalently linking R1 to -C(X')(X")-, oxygen, sulfur, and -NR5 where R5 is hydrogen, acyl, alkyl, aryl, substituted alkyl, heterocyclic or heteroaryl group:
R5' is hydrogen, alkyl, substituted alkyl, aryl, heterocyclic or heteroaryl group;
X' and X" are independently selected from the group consisting of hydrogen, fluoro, alkyl, substituted alkyl, aryl, heteroaryl, heterocyclic, -OR5', -SR5, -N(R5)2, -N(CO)OR15 and -N3, with the proviso that at least one of X' or X" is other than hydrogen, hydroxy or fluoro, and with the further proviso that both X' and X" cannot both be -OR5', -SR5, -N(R5)2, -N(CO)OR15 and -N3 ; further, neither X' and X" can be -OR5', -SR5, -N(R5)2, -N(CO)OR15 or -N3 when T is other than a bond covalently linking R1 to -C(X')(X")-;
n is an integer equal to 1 or 2;
p is an integer equal to 0 or 1 such that when p is zero, the ring defined by W and -C(H)p C(=X)- is unsaturated at the carbon atom of ring attachment to Y and when p is one, the ring is saturated at the carbon atom of ring attachment to Y, with the following provisos:
when R1 is 2-propylpentanoyl, R2 is methyl, and R15 is hydrogen, then W, together with >CH and >C=X, does not form a 2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one when R1 is 3.5-difluorobenzoyl, R2 is methyl, and R15 is hydrogen, then W, together with >CH and >C=X, does not form a 2,3-dihydro-1-methyl-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one when R1 is trans-cinnamyl, R2 is methyl, and R15 is hydrogen, then W, together with >CH and >C=X, does not form a 2,3-dihydro-1-(3,3-dimethyl-2-oxobutyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one when R1 is 2-(4-chlorophenoxy)-2-methylpropionyl, R2 is methyl, and R15 is hydrogen, then W, together with >CH and >C=X, does not form a 2,3-dihydro-1-methyl-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one when R1 is .alpha.-methoxyphenylacetyl, R2 is methyl, and R15 is hydrogen, then W, together with >CH and >C=X, does not form a 2.3-dihydro-1-methyl-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one when R1 is diphenylacetyl, R2 is methyl, and R15 is hydrogen, then W, together with >CH and >C=X, does not form a 2,3-dihydro-1-methyl-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one when R1 is .alpha.-methoxyphenylacetyl, R2 is methyl, and R15 is hydrogen, then W, together with >CH and >C=X, does not form a 2.3-dihydro-1-(3,3-dimethyl-2-oxobutyl)- 5-(2-pyridyl)-1H-1.4-benzodiazepin-2-one when R1 is .alpha.-hydroxy-diphenylacetyl, R2 is methyl, and R15 is hydrogen, then W, together with >CH and >C=X, does not form a 2.3-dihydro-1-(3,3-dimethyl-2-oxobutyl)- 5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one when R1 is diphenylacetyl, R2 is methyl, and R15 is hydrogen, then W, together with >CH and >C=X, does not form a 2,3-dihydro-1-(3,3-dimethyl-2-oxobutyl)- 5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one when R1 is 2-(chlorophenoxy)-2-methylpropionyl, R2 is methyl, and R15 is hydrogen, then W, together with >CH and >C=X, does not form a 2,3-dihydro-1-(3,3-dimethyl-2-oxobutyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one when R1 is diphenylacetyl, R2 is methyl, and R15 is hydrogen, then W, together with >CH and >C=X, does not form a 2,3-dihydro-1-(2-N,N-diethylaminoethyl)- 5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one when R1 is 3,5-difluorobenzoyl, R2 is methyl, and R15 is hydrogen, then W, together with >CH and >C=X, does not form a 2,3-dihydro-1-(2-N,N-diethylaminoethyl)- 5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one when R1 is trans-cinnamyl, R2 is methyl, and R15 is hydrogen, then W, together with >CH and >C=X, does not form a 2,3-dihydro-1-(2-N,N-diethylaminoethyl)- 5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one when R1 is 2-(4-chlorophenoxy)-2-methylpropionyl, R2 is methyl, and R15 is hydrogen, then W, together with >CH and >C=X, does not form a 2,3-dihydro-1-(2-N.N-diethylaminoethyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one when R1-N(R15) is (2,5-dimethoxyphenyl)ureylenyl and R2 is methyl, then W, together with >CH and >C=X, does not form a 2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one when R1 is D,L-2-pyrrolidinone-5-yl, R2 is methyl, and R15 is hydrogen, then W, together with >CH and >C = X, does not form a 7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one.

31. The pharmaceutical composition according to Claim 30, wherein R1 is aryl or heteroaryl.

32. The pharmaceutical composition according to Claim 31 wherein R1 is selected from the group consisting of (a) alkyl, (b) phenyl, (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.

33. The pharmaceutical composition according to Claim 29 wherein R1 is selected from the group consisting of mono-, di-and tri-substituted phenyl groups.

34. The pharmaceutical composition according to Claim 33 wherein R1 is a disubstituted phenyl selected from the group consisting of 3,5-dichlorophenyl, 3,5-difluorophenyl, 3,5-di(trifluoromethyl)-phenyl, 3,4-dichlorophenyl, 3,4-difluorophenyl, 3-(trifluoromethyl)-4-chlorophenyl, 3-chloro-4-cyanophenyl, 3-chloro-4-iodophenyl, and 3,4-methylenedioxyphenyl.

35. The pharmaceutical composition according to Claim 33 wherein R1 is a monosubstituted phenyl selected from the group consisting of 4-azidophenyl, 4-bromophenyl, 4-chlorophenyl.

4-cyanophenyl, 4-ethylphenyl, 4-fluorophenyl, 4-iodophenyl, 4-(phenylcarbonyl)-phenyl, and 4-(1-ethoxy)ethylphenyl.

36. The pharmaceutical composition according to Claim 33 wherein R1 is a trisubstituted phenyl selected from the group consisting of 3,4,5-trifluorophenyl and 3,4,5-trichlorophenyl.

37. The pharmaceutical composition according to Claim 29 wherein R1 is selected from 2-naphthyl, quinolin-3-yl, 2-methylquinolin-6-yl, benzothiazol-6-yl, 5-indolyl, and phenyl.

38. The pharmaceutical composition according to Claim 32 wherein R1 is selected from the group consisting of phenyl, 1-naphthyl, 2-naphthyl, 2-chlorophenyl, 2-fluorophenyl, 2-bromophenyl, 2-hydroxyphenyl, 2-nitrophenyl, 2-methylphenyl, 2-methoxyphenyl, 2-phenoxyphenyl, 2-trifluoromethylphenyl, 4-fluorophenyl, 4-chlorophenyl, 4-bromophenyl, xxxxxx 4-nitrophenyl, 4-methylphenyl, 4-hydroxyphenyl, 4-methoxyphenyl, 4-ethoxyphenyl, 4-butoxyphenyl, 4-iso-propylphenyl, 4-phenoxyphenyl, 4-trifluoromethylphenyl, 4-hydroxymethylphenyl, 3-methoxyphenyl, 3-hydroxyphenyl, 3-nitrophenyl, 3-fluorophenyl, 3-chlorophenyl, 3-bromophenyl, 3-phenoxyphenyl, 3-thiomethoxyphenyl, 3-methylphenyl, 3-trifluoromethylphenyl, 2,3-dichlorophenyl, 2,3-difluorophenyl, 2,4-dichlorophenyl, 2,5-dimethoxyphenyl, 3,4-dichlorophenyl. 3.4-difluorophenyl, 3,4-methylenedioxyphenyl, 3,4-dimethoxyphenyl, 3,5-difluorophenyl, 3,5-dichlorophenyl, 3,5-di-(trifluoromethyl)phenyl, 3,5-dimethoxyphenyl, 2,4-dichlorophenyl, 2,4-difluorophenyl, 2,6-difluorophenyl, 3,4,5-trifluorophenyl, 3,4.5-trimethoxyphenyl, 3,4,5-tri-(trifluoromethyl)phenyl, 2,4,6-trifluorophenyl, 2,4,6-trimethylphenyl, 2,4,6-tri-(trifluoromethyl)phenyl, 2,3,5-trifluorophenyl, 2,4,5-trifluorophenyl, 2,5-difluorophenyl, 2-fluoro-3-trifluoromethylphenyl, 4-fluoro-2-trifluoromethylphenyl, 2-fluoro-4-trifluoromethylphenyl, 4-benzyloxyphenyl, 2-chloro-6-fluorophenyl, 2-fluoro-6-chlorophenyl, 2,3,4,5,6-pentafluorophenyl, 2,5-dimethylphenyl, 4-phenylphenyl, 2-fluoro-3-trifluoromethylphenyl, adamantyl, benzyl, 2-phenylethyl, 3-phenyl-n-propyl, 4-phenyl-n-butyl, methyl, ethyl, n-propyl, iso-propyl, iso-butyl, sec-butyl, tent-butyl, n-pentyl, iso-valeryl, n-hexyl, cyclopropyl, cyclobutyl, cyclohexyl, cyclopentyl, cyclopent-1-enyl, cyclopent-2-enyl, cyclohex-1-enyl, -CH2-cyclopropyl, -CH2-cyclobutyl, -CH2-cyclohexyl, -CH2-cyclopentyl, -CH2CH2-cyclopropyl. -CH2CH2-cyclobutyl, -CH2CH2-cyclohexyl, -CH2CH2-cyclopentyl, pyrid-2-yl, pyrid-3-yl, pyrid-4-yl, fluoropyridyls, chloropyridyls, thien-2-yl, thien-3-yl, benzothiazol-4-yl, 2-phenylbenzoxazol-5-yl, furan-2-yl, benzofuran-2-yl.
thionaphthen-2-yl, thionaphthen-3-yl, thionaphthen-4-yl, 2-chlorothiophen-5-yl, 3-methylisoxazol-5-yl, 2-(thiophenyl)thien-5-yl, 6-methoxythionaphthen-2-yl, 3-phenyl-1,2,4-thiooxadiazol-5-yl, 2-phenyloxazol-4-yl, indol-3-yl, 1-phenyl-tetrazol-5-yl, allyl, 2-(cyclohexyl)ethyl, (CH3)2CH=CHCH2CH2CH(CH3)-, C(O)CH2-, thien-2-yl-methyl, 2-(thien-2-yl)ethyl, 3-(thien-2-yl)-n-propyl, 2-(4-nitrophenyl)ethyl. 2-(4-methoxyphenyl)ethyl, norboran-2-yl, (4-methoxyphenyl)methyl, (2-methoxyphenyl)methyl, (3-methoxyphenyl)methyl, (3-hydroxyphenyl)methyl.
(4-hydroxyphenyl)methyl, (4-methoxyphenyl)methyl, (4-methylphenyl)methyl, (4-fluorophenyl)methyl, (4-fluorophenoxy)methyl. (2,4-dichlorophenoxy)ethyl, (4-chlorophenyl)methyl, (2-chlorophenyl)methyl, (1-phenyl)ethyl, (1-(p-chlorophenyl)ethyl, (1-trifluoromethyl)ethyl, (4-methoxyphenyl)ethyl, CH3OC(O)CH2-, benzylthiomethyl, 5-(methoxycarbonyl)-n-pentyl, 3-(methoxycarbonyl)-n-propyl.
indan-2-yl, (2-methylbenzofuran-3-yl), methoxymethyl, CH3CH=CH-, CH3CH2CH=CH-, (4-chlorophenyl)C(O)CH2-.
(4-fluorophenyl)C(O)CH2-, (4-methoxyphenyl)C(O)CH2-, 4-(fluorophenyl)-NHC(O)CH2-. 1-phenyl-n-butyl, (phenyl)2CHNHC(O)CH2CH2-, (CH3)2NC(O)CH2-, (phenyl)2CHNHC(O)CH2CH2-, ethylcarbonylmethyl, (2,4-dimethylphenyl)C(O)CH2-, 4-methoxyphenyl-C(O)CH2-, phenyl-C(O)CH2-. CH3C(O)N(phenyl)-, ethenyl, methylthiomethyl, (CH3)3CNHC(O)CH2-. 4-fluorophenyl-C(O)CH2-, diphenylmethyl, phenoxymethyl, 3.4-methylenedioxyphenyi-CH2-, benzo[b]thiophen-3-yl.
(CH3)3COC(O)NHCH2-, trans-styryl, H2NC(O)CH2CH2-.
2-trifluoromethylphenyl-C(O)CH2, phenyl-C(O)NHCH(phenyl)CH2-, mesityl, CH3CH(=NHOH)CH2-.
4-CH3-phenyl-NHC(O)CH2CH2-, C(O)CH(phenyl)CH2-, (CH3)2CHC(O)NHCH(phenyl)-, CH3CH2OCH2-, CH3OC(O)CH(CH3)(CH2)3-, 2,2,2-trifluoroethyl, 1-(trifluoromethyl)ethyl, 2-CH3-benzofuran-3-yl, 2-(2,4-dichlorophenoxy)ethyl, SO2CH2-, 3-cyclohexyl-n-propyl, CF3CH2CH2CH2- and N-pyrrolidinyl.

39. The pharmaceutical composition according to Claim 29 where each R2 is independently selected from the group consisting of alkyl, substituted alkyl, alkenyl, cycloalkyl, aryl, heteroaryl and heterocyclic.

40. The pharmaceutical composition according to Claim 39 wherein R2 is selected from the group consisting of methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, -CH2CH(CH2CH3)2, 2-methyl-n-butyl, 6-fluoro-n-hexyl, phenyl, benzyl, cyclohexyl, cyclopentyl, cycloheptyl, allyl, iso-but-2-enyl, 3-methylpentyl, -CH2-cyclopropyl, -CH2-cyclohexyl.
-CH2CH2-cyclopropyl, -CH2CH2-cyclohexyl, -CH2-indol-3-yl, p-(phenyl)phenyl, o-fluorophenyl, m-fluorophenyl, p-fluorophenyl, m-methoxyphenyl, p-methoxyphenyl, phenethyl, benzyl, m-hydroxybenzyl, p-hydroxybenzyl, p-nitrobenzyl, m-trifluoromethylphenyl, p-(CH3)2NCH2CH2CH2O-benzyl, p-(CH3)3COC(O)CH2O-benzyl, p-(HOOCCH2O)-benzyl.
2-aminopyrid-6-yl, p-(N-morpholino-CH2CH2O)-benzyl, -CH2CH2C(O)NH2, -CH2-imidazol-4-yl.
-CH2-(3-tetrahydrofuranyl), -CH2-thiophen-2-yl.
-CH2(1-methyl)cyclopropyl, -CH2-thiophen-3-y1, thiophen-2-yl, thiophen-2-yl, -CH2-C(O)O-t-butyl. -CH2-C(CH3)3,-CH2CH(CH2CH3)2, 2-methylcyclopentyl, cyclohex-2-enyl. -CH[CH(CH3)2]COOCH3.
-CH2CH2N(CH3)2, -CH2C(CH3)=CH2, -CH2CH=CHCH3 (cis and trans), -CH2OH, -CH(OH)CH3, -CH(O-t-butyl)CH3, -CH2OCH3, -(CH2)4NH-Boc, -(CH2)4NH2. -CH2-pyridyl, pyridyl, -CH2-naphthyl.
-CH2-(N-morpholino), p-(N-morpholino-CH2CH2O)-benzyl, benzo[b]thiophen-2-yl, 5-chlorobenzo[b]thiophen-2-yl, 4,5,6,7-tetrahydrobenzo[b]thiophen-2-yl, benzo(b]thiophen-3-yl, 5-chlorobenzo(b]thiophen-3-yl, benzo[b]thiophen-5-yl, 6-methoxynaphth-2-yl, -CH2CH2SCH3, thien-2-yl, and thien-3-yl.

41. The pharmaceutical composition according to Claim 29 wherein the cyclic groups defined by W and -C(H) p C(=X)- is selected from the group consisting of lactones, lactams, thiolactones, thiolactams, heterocyclic and cycloalkyl groups.

42. The pharmaceutical composition according to Claim 41 wherein the cyclic group defined by W and -C(H) p C(=X)-, forms a lactam or thiolactam ring of the formula:

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

43. The method according to Claim 42 wherein the lactam ring is selected from the group consisting of 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:

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

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

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

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, alkyl, substituted alkyl, alkoxy, substituted alkoxy, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, amino, substituted amino, aminoacyl, alkaryl, aryl, aryloxy, carboxyl, carboxylalkyl, cyano, halo, nitro, heteroaryl, thioalkoxy, substituted thioalkoxy, and trihalomethyl; each R a is independently selected from the group consisting of alkyl, substituted alkyl, alkoxy, substituted alkoxy, amino, substituted amino, carboxyl, carboxyl alkyl, cyano, and halo; t is an integer from 0 to 4; and w is an integer from 0 to 3.

49. The pharmaceutical composition according to Claim 41 wherein the cyclic group defined by W, together with -C(H)p C(=X)-, forms a ring of the formula:

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

50. The pharmaceutical composition according to Claim 41 wherein the cyclic group defined by W, together with -C(H)pC(=X)-, forms a ring of the formula:

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

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

52. The pharmaceutical composition according to Claim 41 wherein the cyclic group defined by W, together with -C(H)pC(=X)-, forms a ring of the formula:

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

53. The pharmaceutical composition according to Claim 52 wherein the compound is selected from the group consisting of:

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

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

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

57. The pharmaceutical composition according to Claim 41 wherein the cyclic group defined by W, together with -C(H)p C(=X)-, forms a ring of the formula:

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

58. A compound of the following formulas:

wherein R1 is selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, substituted alkyl, substituted alkenyl, substituted alkynyl, substituted cycloalkyl, substituted cycloalkenyl, aryl, heteroaryl and heterocyclic;
R'is selected from the group consisting of aryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heteroaryl, heterocyclic. -CH3, -CH=CH2, -CH=CHR1, -CH=CR1R1, -CR1=CH2, -CR1=CHR1, -CR1=CR1R1, -C=CH and -C=CR1; with the proviso that when R' is heteroaryl or heterocyclic, there is no N in R' at a position beta to the C=Q
group;
Q is S or O;
R15 is selected from the group consisting of hydrogen, alkyl, substituted alkyl, aryl, heterocyclic and heteroaryl;
R15' is selected from the group consisting of hydrogen, hydroxyl, alkyl, substituted alkyl, aryl, heterocyclic and heteroaryl;
W, together with -C(H)p C(=X)-, forms a cycloalkyl, cycloalkenyl, heterocyclic, substituted cycloalkyl, or substituted cycloalkenyl group wherein each of said cycloalkyl, cycloalkenyl, heterocyclic, substituted cycloalkyt or substituted cycloalkenyl group is optionally fused to form a bi- or multi-fused ring system (preferably no more than 5 fused rings) with one or more ring structures selected from the group consisting of cycloalkyt, cycloalkenyl, heterocyclic, aryl and heteroaryl group which, in turn, each of such ring structures are optionally substituted with 1 to 4 substituents selected from the group consisting of hydroxyl, halo, alkoxy, substituted alkoxy, thioalkoxy, substituted thioalkoxy, nitro, cyano, carboxyl, carboxyl esters, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, amino, substituted amino, -NHC(O)R4, -NHSO2R4, -C(O)NH2, -C(O)NHR4, -C(O)NR4R4, -S(O)R4, -S(O)2R4, -S(O)2NHR4 and -S(O)2NR4R4, where each R4 is independently selected from the group consisting of alkyl, substituted alkyl, aryl and heteroaryl;
X is selected from the group consisting of oxo (=O), thiooxo (=S), hydroxyl (-H, -OH), thiol (H,-SH) and hydro (H,H);
Y is represented by the formula:

wherein each R2 is independently selected from the group consisting of alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, aryl, heteroaryl and heterocyclic;
Z is represented by the formula -T-C(X')(X")C(O)- where T
is selected from the group consisting of a bond covalently linking R1 to -C(X')(X")-, oxygen, sulfur, and -NR5 where R5 is hydrogen, acyl, alkyl, substituted alkyl, aryl, heterocyclic or heteroaryl group;

R5' is hydrogen, alkyl, substituted alkyl, aryl, heterocyclic or heteroaryl group;
X' and X" are independently selected from the group consisting of hydrogen, fluoro, alkyl, substituted alkyl, aryl, heteroaryl, heterocyclic, -OR5', -SR5, -N(R5)2, -N(CO)OR15 and -N3, with the proviso that at least one of X' or X" is other than hydrogen, hydroxy or fluoro, and with the further proviso that both X' and X" cannot both be -OR5', -SR5, -N(R5)2, -N(CO)OR15 and -N3 ; further, neither X' and X" can be -OR5' -SR5, -N(R5)z.
-N(CO)OR15 or -N3 when T is other than a bond covalently linking R1 to -C(X')(X")-;
n is an integer equal to 1 or 2;
p is an integer equal to 0 or 1 such that when p is zero, the ring defined by W and -C(H)p C(=X)- is unsaturated at the carbon atom of ring attachment to Y and when p is one, the ring is saturated at the carbon atom of ring attachment to Y, with the following provisos:
when R1 is 2-propylpentanoyl, R2 is methyl, and R15 is hydrogen, then W, together with >CH and >C = X, does not form a 2,3-dihydro-1-methyl-5-phenyl-1H-1.4-benzodiazepin-2-one when R1 is 3,5-difluorobenzoyl, R2 is methyl, and R15 is hydrogen, then W, together with >CH and >C=X, does not form a 2,3-dihydro-1-methyl-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one when R1 is trans-cinnamyl, R2 is methyl, and R15 is hydrogen, then W, together with >CH and >C=X, does not form a 2,3-dihydro-1-(3,3-dimethyl-2-oxobutyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one when R1 is 2-(4-chlorophenoxy)-2-methylpropionyl, R2 is methyl, and R15 is hydrogen, then W, together with >CH and >C=X, does not form a 2,3-dihydro-1-methyl-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one when R1 is .alpha.-methoxyphenylacetyl, R2 is methyl, and R15 is hydrogen, then W, together with >CH and >C=X, does not form a 2,3-dihydro-1-methyl-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one when R1 is diphenylacetyl. R2 is methyl, and R15 is hydrogen, then W, together with >CH and >C=X, does not form a 2,3-dihydro-1-methyl-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one when R1 is .alpha.-methoxyphenylacetyl, R2 is methyl, and R15 is hydrogen, then W, together with >CH and >C=X, does not form a 2,3-dihydro-1-(3,3-dimethyl-2-oxobutyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one when R1 is .alpha.-hydroxy-diphenylacetyl, R2 is methyl, and R15 is hydrogen, then W, together with >CH and >C=X, does not form a 2,3-dihydro-1-(3,3-dimethyl-2-oxobutyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one when R1 is diphenylacetyl, R2 is methyl, and R15 is hydrogen, then W , together with >CH and >C=X, does not form 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(R15) is (2,5-dimethoxyphenyl)ureylenyl and R2 is methyl, then W, together with >CH and >C=X, does not form a 2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one when R1 is D,L-2-pyrrolidinone-5-yl, R2 is methyl, and R15 is hydrogen, then W, together with >CH and >C=X, does not form a 7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one.

59. The compound according to Claim 58 wherein R1 is aryl or heteroaryl.

60. The compound according to Claim 59 wherein R1 is selected from the group consisting of (a) alkyl (b) phenyl, (c) a substituted phenyl group of the formula:

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

61. The compound according to Claim 57 wherein R1 is selected from the group consisting of mono-, di- and tri-substituted phenyl groups.

62. The compound according to Claim 61 wherein R1 is a disubstituted phenyl selected from the group consisting of 3,5-dichlorophenyl, 3,5-difluorophenyl, 3,5-di(trifluoromethyl)-phenyl, 3,4-dichlorophenyl, 3,4-difluorophenyl, 3-(trifluoromethyl)-4-chlorophenyl, 3-chloro-4-cyanophenyl, 3-chloro-4-iodophenyl, and 3,4-methylenedioxyphenyl.

63. The compound according to Claim 61 wherein R1 is a monosubstituted phenyl selected from the group consisting of 4-azidophenyl, 4-bromophenyl, 4-chlorophenyl, 4-cyanophenyl, 4-ethylphenyl, 4-fluorophenyl, 4-iodophenyl, 4-(phenylcarbonyl)-phenyl, and 4-(1-ethoxy)ethylphenyl.

64. The compound according to Claim 61 wherein R1 is a trisubstituted phenyl selected from the group consisting of 3,4,5-trifluorophenyl and 3,4,5-trichlorophenyl.

65. The compound according to Claim 58 wherein R1 is selected from 2-naphthyl, quinolin-3-yl, 2-methylquinolin-6-yl, benzothiazol-6-yl, 5-indolyl, and phenyl.

66. The compound according to Claim 61 wherein R1 is selected from the group consisting of phenyl, 1-naphthyl, 2-naphthyl, n-butyl, 2-chlorophenyl, 2-fluorophenyl, 2-bromophenyl, 2-hydroxyphenyl, 2-nitrophenyl, 2-methylphenyl, 2-methoxyphenyl, 2-phenoxyphenyl, 2-trifluoromethylphenyl, 4-fluorophenyl, 4-chlorophenyl, 4-bromophenyl, 4-nitrophenyl, 4-methylphenyl, 4-hydroxyphenyl, 4-methoxyphenyl, 4-ethoxyphenyl, 4-butoxyphenyl, 4-iso-propylphenyl, 4-phenoxyphenyl, 4-trifluoromethylphenyl, 4-hydroxymethylphenyl, 3-methoxyphenyl, 3-hydroxyphenyl, 3-nitrophenyl, 3-fluorophenyl, 3-chlorophenyl, 3-bromophenyl, 3-phenoxyphenyl, 3-thiomethoxyphenyl, 3-methylphenyl, 3-trifluoromethylphenyl, 2,3-dichlorophenyl, 2,3-difluorophenyl, 2,4-dichlorophenyl, 2,5-dimethoxyphenyl, 3,4-dichlorophenyl, 3,4-difluorophenyl, 3,4-methylenedioxyphenyl, 3,4-dimethoxyphenyl, 3,5-difluorophenyl, 3,5-dichlorophenyl, 3,5-di-(trifluoromethyl)phenyl, 3,5-dimethoxyphenyl, 2,4-dichlorophenyl, 2,4-difluorophenyl, 2,6-difluorophenyl, 3,4,5-trifluorophenyl, 3,4,5-trimethoxyphenyl, 3,4,5-tri-(trifluoromethyl)phenyl, 2,4,6-trifluorophenyl, 2,4,6-trimethylphenyl, 2,4,6-tri-(trifluoromethyl)phenyl, 2,3,5-trifluorophenyl, 2,4,5-trifluorophenyl, 2,5-difluorophenyl, 2-fluoro-3-trifluoromethylphenyl, 4-fluoro-2-trifluoromethylphenyl, 2-fluoro-4-trifluoromethylphenyl, 4-benzyloxyphenyl, 2-chloro-6-fluorophenyl, 2-fluoro-6-chlorophenyl, 2,3,4,5,6-pentafluorophenyl, 2,5-dimethylphenyl, 4-phenylphenyl, 2-fluoro-3-trifluoromethylphenyl, adamantyl, benzyl, 2-phenylethyl, 3-phenyl-n-propyl, 4-phenyl-n-butyl, methyl, ethyl, n-propyl, iso-propyl, iso-butyl, sec-butyl, tert-butyl, n-pentyl, iso-valeryl, n-hexyl, cyclopropyl, cyclobutyl, cyclohexyl, cyclopentyl, cyclopent-1-enyl, cyclopent-2-enyl, cyclohex-1-enyl, -CH2-cyclopropyl, -CH2-cyclobutyl, -CH2-cyclohexyl, -CH2-cyclopentyl, -CH2CH2-cyclopropyl, -CH2CH2-cyclobutyl, -CH2CH2-cyclohexyl, -CH2CH2-cyclopentyl, pyrid-2-yl, pyrid-3-yl, pyrid-4-yl, fluoropyridyls, chloropyridyls, thien-2-yl, thien-3-yl, benzothiazol-4-yl, 2-phenylbenzoxazol-5-yl, furan-2-yl, benzofuran-2-yl, thionaphthen-2-yl, thionaphthen-3-yl, thionaphthen-4-yl, 2-chlorothiophen-5-yl, 3-methylisoxazol-5-yl, 2-(thiophenyl)thien-5-yl, 6-methoxythionaphthen-2-yl, 3-phenyl-1,2,4-thiooxadiazol-5-yl, 2-phenyloxazol-4-yl, indol-3-yl, 1-phenyl-tetrazol-5-yl, allyl, 2-(cyclohexyl)ethyl, (CH3)2CH=CHCH2CH2CH(CH3)-, C(O)CH2-, thien-2-yl-methyl, 2-(thien-2-yl)ethyl, 3-(thien-2-yl)-n-propyl, 2-(4-nitrophenyl)ethyl, 2-(4-methoxyphenyl)ethyl, norboran-2-yl, (4-methoxyphenyl)methyl, (2-methoxyphenyl)methyl, (3-methoxyphenyl)methyl, (3-hydroxy phenyl)methyl, (4-hydroxyphenyl)methyl, (4-methoxyphenyl)methyl, (4-methylphenyl)methyl, (4-fluorophenyl)methyl, (4-fluorophenoxy)methyl, (2,4-dichlorophenoxy)ethyl, (4-chlorophenyl)methyl, (2-chlorophenyl)methyl, (1-phenyl)ethyl, (1-(p-chlorophenyl)ethyl, (1-trifluoromethyl)ethyl, (4-methoxyphenyl)ethyl, CH3OC(O)CH2-, benzylthiomethyl, 5-(methoxycarbonyl)-n-pentyl, 3-(methoxycarbonyl)-n-propyl, indan-2-yl, (2-methylbenzofuran-3-yl), methoxymethyl, CH3CH=CH-, CH3CH2CH=CH-, (4-chlorophenyl)C(O)CH2-,(4-fluorophenyl)C(O)CH2-, (4-methoxy phenyl)C(O)CH2-, 4-(fluorophenyl)-NHC(O)CH2-, 1-phenyl-n-butyl, (phenyl)2CHNHC(O)CH2CH2-, (CH3)2NC(O)CH2-, (phenyl)2CHNHC(O)CH2CH2-, methylcarbonylmethyl, (2,4-dimethylphenyl)C(O)CH2-, 4-methoxyphenyl-C(O)CH2-, phenyl-C(O)CH2-, CH3C(O)N(phenyl)-, ethenyl, methylthiomethyl, (CH3)3CNHC(O)CH2-, 4-fluorophenyl-C(O)CH2-, diphenylmethyl, phenoxymethyl, 3,4-methylenedioxyphenyl-CH2-, benzo[b]thiophen-3-yl, (CH3)3COC(O)NHCH2-, trans-styryl, H2NC(O)CH2CH2-, 2-trifluoromethylphenyl-C(O)CH2, phenylC(O)NHCH(phenyl)CH2-, mesityl, CH3CH(=NHOH)CH2-, 4-CH3-phenyl-NHC(O)CH2CH2-, phenyl-C(O)CH(phenyl)CH2-, (CH3)2CHC(O)NHCH(phenyl)-, CH3CH2OCH2-, CH3OC(O)CH(CH3)(CH2)3-, 2,2,2-trifluoroethyl, 1-(trifluoromethyl)ethyl, 2-CH3-benzofuran-3-yl, 2-(2,4-dichlorophenoxy)ethyl, SO2CH2-, 3-cyclohexyl-n-propyl, CF3CH2CH2CH2- and N-pyrrolidinyl.

67. The compound according to Claim 58 where each R2 is independently selected from the group consisting of alkyl, substituted alkyl, alkenyl, cycloalkyl, aryl, heteroaryl and heterocyclic.

68. The compound according to Claim 58 wherein R2 is selected from the group consisting of methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, -CH2CH(CH2CH3)2, 2-methyl-n-butyl, 6-fluoro-n-hexyl, phenyl, benzyl, cyclohexyl, cyclopentyl, cycloheptyl, allyl, iso-but-2-enyl, 3-methylpentyl, -CH2-cyclopropyl, -CH2-cyclohexyl, -CH2CH2-cyclopropyl, -CH2CH2-cyclohexyl, -CH2-indol-3-yl, p-(phenyl)phenyl, o-fluorophenyl, m-fluorophenyl, p-fluorophenyl, m-methoxyphenyl, p-methoxyphenyl, phenethyl, benzyl, m-hydroxybenzyl, p-hydroxybenzyl, p-nitrobenzyl, m-trifluoromethylphenyl, p-(CH3)2NCH2CH2CH2O-benzyl, p-(CH3)3COC(O)CH2O-benzyl, p-(HOOCCH2O)-benzyl, 2-aminopyrid-6-yl, p-(N-morpholino-CH2CH2O)-benzyl, -CH2CH2C(O)NH2, -CH2-imidazol-4-yl, -CH2-(3-tetrahydrofuranyl), -CH2-thiophen-2-yl, -CH2(1-methyl)cyclopropyl, -CH2-thiophen-3-yl, thiophen-3-yl, thiophen-2-yl, -CH2-C(O)O-t-butyl, -CH2-C(CH3)3, -CH2CH(CH2CH3)2, 2-methylcyclopentyl, cyclohex-2-enyl, -CH[CH(CH3)2]COOCH3, -CH2CH2N(CH3)2, -CH2C(CH3)=CH2, -CH2CH=CHCH3 (cis and trans), -CH2OH, -CH(OH)CH3, -CH(O-t-butyl)CH3, -CH2OCH3, -(CH2)4NH-Boc, -(CH2)4NH2, -CH2-pyridyl, pyridyl, -CH2-naphthyl, -CH2-(N-morpholino), p-(N-morpholino-CH2CH2O)-benzyl, benzo[b]thiophen-2-yl, 5-chlorobenzo[b]thiophen-2-yl, 4,5,6,7-tetrahydrobenzo[b]thiophen-2-yl, benzo[b]thiophen-3-yl, 5-chlorobenzo[b]thiophen-3-yl, benzo[b]thiophen-5-yl, 6-methoxynaphth-2-yl, -CH2CH2SCH3, thien-2-yl, and thien-3-yl.

69. The compound according to Claim 58 wherein the cyclic groups defined by W and -C(H)p C(=X)- is selected from the group consisting of lactones, lactams, thiolactones, thiolactams, heterocyclic and cycloalkyl groups.

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

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

73. The compound according to Claim 57 wherein the alcohol or thiol substituted groups is selected from the group consisting of wherein each V is independently selected from the croup consisting of hydroxy, acyl, acyloxy, alkyl, substituted alkyl, alkoxy, substituted alkoxy, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, amino, substituted amino, aminoacyl, alkaryl, aryl, aryloxy, carboxyl. carboxylalkyl, cyano, halo, nitro, heteroaryl, thioalkoxy, substituted thioalkoxy, and trihalomethyl; each R a is independently selected from the group consisting of alkyl, substituted alkyl, alkoxy, substituted alkoxy, amino, substituted amino, carboxyl, carboxyl alkyl, cyano, and halo; t is an integer from 0 to 4; and w is an integer from 0 to 3.

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

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

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

76. The compound according to Claim 69 wherein the compound is selected from the group consisting of wherein each V is independently selected from the group consisting of hydroxy, acyl, acyloxy, alkyl, substituted alkyl, alkoxy, substituted alkoxy, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, amino, substituted amino, aminoacyl, alkaryl, aryl, aryloxy, carboxyl, carboxylalkyl, cyano, halo, nitro, heteroaryl, thioalkoxy, substituted thioalkoxy, and trihalomethyl: each R a is independently selected from the group consisting of alkyl, substituted alkyl, alkoxy, substituted alkoxy, amino. substituted amino, carboxyl, carboxyl alkyl, cyano, and halo; t is an integer from 0 to 4; and w is an integer from 0 to 3.

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

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

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

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

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

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

81. The compound according to Claim 80 wherein the compound is selected from the group consisting of:

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

any unsaturation in the alkenylene and substituted alkenylene does not involve participation of the -O- or -S-, and q is an integer of from 1 to 3.

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

84. A compound selected from the group consisting of:
3-[(N'-(4-methylbenzoyl)-D-phenylglycinyl)]amino-2.3-dihydro-1-methyl-5-phenyl-1 H-1,4-benzodiazepin-2-one 3-[(N'-(4-methylbenzoyl)-L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one 3-[(N'-(Diphenylacetyl)-L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one 3-[(N'-(2-Naphthoyl)-L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one 3-[(N'-(1-Naphthoyl)-L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1.4-benzodiazepin-2-one 3-[(N'-(5-Chloro-2-thiophenecarboxyl)-L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one 3-[(N'-(4-Cyanobenzoyl)-L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1 H-1,4-benzodiazepin-2-one 3-[(N'-(Tetrahydro-2-furoyl)-L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one 3-[(N'-(3,5-Difluorobenzoyl)-L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one 3-[(N'-(3-Cyclohexenecarboxyl)-L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one 3-[(N'-(Acetyl)-L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1 H-1,4-benzodiazepin-2-one 3-[(N'-(1,2,3,4-Tetrahydro-2-naphthoyl)-L-alaninyl)]
amino-2, 3-dihydro-1-methyl-5-phenyl-1 H-1, 4-benzodiazepin-2-one 3-[(N'-(Cyclopentanecarboxyl)-L-alaninyl)]amino-2, 3-dihydro-1 -methyl-5-phenyl-1H-1 ,4-benzodiazepin-2-one (S)-3-[(N'-(2-phenoxybutyryl)-L-alaninyl)]amino-2, 3-dihydro-1-methyl-5-pheny l- 1 H-1,4-benzodiazepin-2-one (S)-3-[(N'-(2-Thiophenecarboxyl)-L-alaninyl)]amino-2, 3-dihydro-1-methyl-5-phenyl-1 H-1 ,4-benzodiazepin-2-one (S)-3-[(N'-(2, 3-Diphenylpropionyl)-L-alaninyl)]amino-2, 3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one (S}-3-[(N'-((R, S)-(-)-.alpha.-Methoxyphenylacetyl)-L-alaninyl)]
amino-2,3-dihydro-1-methyl-5-phenyl-1 H-1, 4-benzodiazepin-2-one (S)-3-[(N'-(2-Furoyl)-L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one (S)-3-[(N'-(2-Phenoxypropionyl)-L-alaninyl)]amino-2, 3-dihydro-1-methyl-5-phenyl-1 H-1,4-benzodiazepin-2-one (S)-3-[(N'-(Cyclohexanecarboxyl)-L-alaninyl)]amino-2, 3-dihydro-1-methyl-5-phenyl-1 H-1,4-benzodiazepin-2-one (S)-3-[(N'-(2-(4-Chlorophenoxy)-2-methylpropionyl) -L-alaninyl)]amino-2.3-dihydro-1-methyl-5-phenyl-1 H-1, 4-benzodiazepin-2-one (S)-3-[(N'-(Cyclobutanecarboxyl)-L-alaninyl)]amino-2, 3-dihydro-1-methyl-5-phenyl-1 H-1,4-benzodiazepin-2-one (S)-3-[(N'-(1-Phenyl-1-cyclopropanecarboxyl)-L-alaninyl)]
amino-2,3-dihydro-1-methyl-5-phenyl-1H-1, 4-benzodiazepin-2-one (S)-3-[(N'-(2-Benzofurancarboxyl)-L-alaninyl)]amino-2-, 3-dihydro-1-methyl-5-phenyl-1H-1 ,4-benzodiazepin-2-one (S)-3-[(N'-(2-Isopropyl-2-phenylacetyl)-L-alaninyl)]
amino-2,3-dihydro-1-methyl-5-phenyl-1H-1, 4-benzodiazepin-2-one (S)-3-[(N'-(S-Chlorobenzofuran-2-carboxyl)-L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1, 4-benzodiazepin-2-one (S)-3-[(N'-(2-Ethylhexanoyl)-L-alaninyl)]amino-2, 3-dihydro-1-methyl-5-phenyl-1 H-1, 4-benzodiazepin-2-one (S)-3-[(N'-(2-Methylbutyryl)-L-alaninyl}]amino-2, 3- dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one (S}-3-[(N'-((R,S}-2-Phenoxypropionyl)-L-alaninyl)]
amino-2, 3-dihydro-1-methyl-5-phenyl-1 H-1, 4-benzodiazepin-2-one (S)-3-[(N'-(5.5-dimethyl-butyrolactone-4-yl) -L- alaninyl)]amino-2, 3-dihydro-1-methyl-5-phenyl-1 H-1, 4-benzodiazepin-2-one (S)-3-[(N'-(2-Methyl-4,4,4-trifluorobutyryl) -L- alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1, 4-benzodiazepin-2-one 5-{N' -(2-phenylpropionyl}-L-alaninyl }-amino-7-methyl-5, 7-dihydro-6H-dibenz[b,d]azepin-6-one 5-{N'-(tetrahydro-3-furoyl)-L-alaninyl}-amino-7-methyl-5, 7-dihydro-6H-dibenz[b,d]azepin-6-one 3-[N'-(3,5-difluorophenyl-.alpha.-methoxyacetyl)-L-alaninyl]-amino-2, 3-dihydro-1-methyl-5-phenyl-1 H-1, 4-Benzodiazepin-2-one 3-[N'-(3,5-difluorophenyl-.alpha.-methoxyacetyl)-L-alaninyl]-amino-2 , 3-dihydro-1-methyl-5-phenyl-1 H-1, 4-Benzodiazepin-2-one (S}-3-((N'-(4-(Trifluoromethyl)cyclohexane carboxyl) -L- alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1, 4-benzodiazepin-2-one (S)-3-[(N'-(Bicyclo(2.2.1 ]heptane-2-carboxyl) -L- alaninyl)]amino-2.3-dihydro-1-methyl-5-phenyl-1 H-1, 4-benzodiazepin-2-one (S)-3-[(N'-(Bicyclo(2.2.1 )hept-5-ene-2-carboxyl) -L- alaninyl)] amino-2.3-dihydro-1-methyl-5-phenyl-1 H-1, 4-benzodiazepin-2-one (S)-3-((N'-(2,2-Dichlorocyclopropane carboxyl) -L- alaninyl)] amino-2, 3-dihydro-1-methyl-5-phenyl-1 H-1, 4-benzodiazepin-2-one (S)-3-[(N'-(Cycloheptanecarboxyl)-L-alaninyl)]amino-2, 3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2- one (S)-3-[(N'-(2-Methylvaleryl)-L-alaninyl)]amino-2, 3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one 3-[(N'-(2-(4-hydroxyphenoxy)propionyl)-L-alaninyl)]
amino-2,3-dihydro-1-methyl-5-phenyl-1 H-1, 4-benzodiazepin-2-one (S)-3-[(N'-(.alpha.-(Hydroxymethyl)phenylacetyl)-L-alaninyl)]
amino-2,3-dihydro-1-methyl-5-phenyl-1H-1, 4-benzodiazepin-2-one (S)-3-[(N'-( 1-(2,4 Dichlorophenyl)cyclopropanecarboxyl)-L-alaninyl)]
amino-2,3-dihydro-1-methyl-5-phenyl-1H-1, 4-benzodiazepin-2-one (S)-3-[(N'-(2-Ethylbutyryl)-L-alaninyl)]amino-2, 3-dihydro-1-methyl-5-phenyl- 1H-1.4-benzodiazepin-2-one (S)-3-[(N'-(2-Methylcyclopropanecarboxyl)-L-ananinyl)]
amino-2,3-dihydro-1-methyl-5-phenyl-1H-1, 4-benzodiazepin-2-one (S)-3-[(N'-( 1-(4-Chlorophenyl)-1-cyclobutanecarboxyl) -L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1, 4-benzodiazepin-2-one (S)-3-[(N'-(2-Biphenylcarboxyl)-L-alaninyl)]amino-2, 3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one (S)-3-[(N'-(Pivalyl)-L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1 H-1,4-benzodiazepin-2-one (S)-3-[(N'-(trans-Cinnamyl)-L-alaninyl)]amino-2, 3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one (S)-3-[(N'-( 1,2-Dihydro-1-oxo-2-phenyl-4-isoquinolinecarboxyl)-L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1 H-1,4-benzodiazepin-2-one (S)-3-[(N'-(Bicyclo (3.3.1)non-6-ene-3-carboxyl) -L- alaninyl)]amino-2.3-dihydro-1-methyl-5-phenyl-1 H-1, 4-benzodiazepin-2-one (S)-3-[(N'-(Cyclopropanecarboxyl)-L-alaninyl)]amino-2, 3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one (S)-3-[(N'-(3-furoyl)-L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1 H-1,4-benzodiazepin-2-one (S)-3-[(N'-(2-(4-Cyanophenoxy)-2-methyl propionyl) -L- alaninyl)] amino-2, 3-dihydro-1-methyl-5-phenyl-1 H- 1, 4- benzodiazepin-2-one (S)-3-[(N' -(Diphenylacetyl)-L -alaninyl)]amino-2, 3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one (S)-3-[(N'-(Tetrahydro-2-furoyl)-L-alaninyl)]amino-2,3-dihydro-1-methy 1-5-phenyl-1H-1,4-benzodiazepin-2-one (S)-3-[(N'-(3,5-Difluorobenzoyl)-L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one (S)-3-[(N'-(3-Cyclohexenecarboxyl)-L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one (S)-3-[(N'-(1,2,3,4-Tetrahydro-2-naphthoyl)-L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one (S)-3-[(N'-(Cyclopentanecarboxyl)-L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one (S)-3-[(N'-(2-(4-trifluorophenyoxy)propionyl)-L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one (S)-3-[(N'-(2-(4-Biphenylyloxy)propionyl)-L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one (S)-3-[(N'-(Diphenylacetyl)-L-phenylglycinyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one (S)-3-[(N'-(4-(methylsulfonyl)benzoyl)-L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one (S)-3-[(N'-(4-chloro-.alpha.-methylphenylacetyl)-L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one (S)-3-[(N'-(trans-2-Phenyl-1-cyclopropanecarboxyl)-L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one (S)-3-[(N'-(4-chloro-.alpha.,.alpha.-dimethylphenylacetyl)-L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one (S)-3-[(N'-(5-methylsulfonyl)thiophene-2-carboxyl)-L
alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one (S)-3-[(N'-(1,8-dimethyl-6-Hydroxy-bicyclo(2.2.2)octane-2-carboxyl)-L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one (S)-3-[(N'-((S)-(+)-2-hydroxy-2-phenylpropionyl)-L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one (S)-3-[(N'-(1,4-Benzodioxan-2-carboxyl)-L-alaninyl)]amino-2.3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one (S)-3-[(N'-(Tetrahydro-3-furoyl)-L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one (S)-3-[(N'-(Acetyl)-L-phenylglycinyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one (S)-3-[(N'-(3-Cyclohexenecarboxyl)-L-phenylglycinyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one (S)-3-[(N'-(Cyclopropanecarboxyl)-L-phenylglycinyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one (S)-3-[(N'-(3,5-Difluorobenzoyl)-L-phenylglycinyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one 3-[(N'-(L-2-pyrrolidinone-5-yl)-L-alaninyl)]amino]-2,3-dihydro-1-methyl-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one 3-[(N'-(trans-cinnamyl)-L-alaninyl)]amino)-2,3-dihydro-1-methyl-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one 3-[(N'-(1-phenyl-1-cyclopropanecarboxyl)-L-alaninyl)]amino]-2,3-dihydro-1-methyl-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one 3-[(N'-(1-phenyl-1-cyclopropanecarboxyl)-L-alaninyl)]amino]-2,3-dihydro-1-(3,3-dimethyl-2-oxobutyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one (S)-3-[(N'-(.alpha.-hydroxy-diphenylacetyl)-L-alaninyl)]amino-2,3-dihydro-1-methyl-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one 3-[(N'-(3,5-difluorobenzoyl)-L-alaninyl)]amino]-2,3-dihydro-1-(3,3-dimethyl-2-oxobutyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one 3-[(N'-(L-2-pyrrolidinone-5-yl)-L-alaninyl)]amino]-2,3-dihydro-1-(3,3-dimethyl-2-oxobutyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one (S)-3-[(N'-(.alpha.-hydroxy-diphenylacetyl)-L-alaninyl)]amino-2,3-dihydro-1-2-(diethylamino)ethyl-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one 3-[(N'-(1-phenyl-1-cyclopropanecarboxyl)-L-alaninyl)]amino]-2,3-dihydro-1-(2-N,N-diethylaminoethyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one 3-[(N'-(.alpha.-methoxyphenylacetyl)-L-alaninyl)]amino]-2,3-dihydro-1-(2-N.N-diethylaminoethyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one 3-(S)-[2-((1H)-isoquinoline-3,4-dihydro-3-oxo)-2-methyl-acetyl]-amino-2.3-dihydro-1-methyl-5-phenyl-1H-1.4-benzodiazepin-2-one 3-(S)-[2-((1H)-isoquinoline-3,4-dihydro-3-oxo)-2-methyl-acetyl]-amino-2,3-dihydro-1-methyl-5-phenyl-1H-1.4-benzodiazepin-2-one (S)-3-[(N'-((trans-2-Phenylcyclopropyl)ureylenyl)-L-alaninyl)]amino-2.3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one (S)-3-[(N'-((3.4-Dichlorophenyl)ureylenyl)-L-alaninyl)]amino-2.3-dihydro-1-methyl-5-phenyl-1H-1.4-benzodiazepin-2-one (S)-3-[(N'-((2-propenyl)ureylenyl)-L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1.4-benzodiazepin-2-one (S)-3-((N'-((R)-(-)-1-(1-Naphthyl)ethyl)ureylenyl)-L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1.4-benzodiazepin-2-one (S)-3-[(N'-((2,6-Diisopropylphenyl)ureylenyl)-L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one (S)-3-[(N'-((3-[(Trifluoromethyl)phenyl)ureylenyl)-L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one (S)-3-[(N'-((Phenyl)ureylenyl)-L-alaninyl)]amino-2.3-dihydro-1-methyl-5-phenyl-1H-1.4-benzodiazepin-2-one (S)-3-[(N'-((4-ethoxycarbonylphenyl)ureylenyl)-L-alaninyl)]amino-2.3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one (S)-3-[(N'-((2-Bromophenyl)ureylenyl)-L-alaninyl)]amino-2.3-dihydro-1-methyl-5-phenyl-1H-1.4-benzodiazepin-2-one (S)-3-[(N'-((o-Tolyl)ureylenyl)-L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1.4-benzodiazepin-2-one (S)-3-[(N'-((2-Ethyl-6-methylphenyl)ureylenyl)-L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one (S)-3-[(N'-((2-Fluorophenyl)ureylenyl)-L-alaninyl)]amino-2.3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one (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-methyl-5-phenyl-1H-1.4-benzodiazepin-2-one (S)-3-[(N'-((2-Isopropylphenyl)ureylenyl)-L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one (S)-3-[(N'-((2,6-Difluorophenyl)ureylenyl) -L-alaninyl)]amino-2.3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one (S)-3-((N'-((Octadecyl)ureylenyl)-L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one (S)-3-[(N'-((4-(Trifluoromethoxy)phenyl)ureylenyl)-L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one (S)-3-[(N'-((2,4-Dichlorophenyl)ureylenyl)-L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1.4-benzodiazepin-2-one (S)-3-[(N'-((3-Ethoxycarbonylphenyl)ureylenyl)-L-alaninyl)]amino-2.3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one (S)-3-[(N'-((4-Chlorophenyl)ureylenyl)-L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one (S)-3-((N'-((4-butoxyphenyl)ureylenyl)-L-alaninyl)}amino-2.3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one (S)-3-[(N'-((4-Phenoxyphenyl)ureylenyl)-L-alaninyl)]amino-2.3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one (S)-3-[(N'-((1-Naphthyl)ureylenyl)-L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one (S)-3-[(N'-((2-Biphenyl)ureylenyl)-L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one (S)-3-[(N'-((2-(Methylthio)phenyl)ureylenyl)-L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1.4-benzodiazepin-2-one (S)-3-[(N'-((2-Ethylphenyl)ureylenyl)-L-alaninyl)]amino-2.3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one (S)-3-[(N'-((3-Methoxyphenyl)ureylenyl)-L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one (S)-3-[(N'-((3,4,5-Trimethoxyphenyl)ureylenyl)-L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one (S)-3-[(N'-((2,4,6-Trimethylphenyl)ureylenyl)-L-alaninyl)]amino-2.3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one (S)-3-[(N'-((2-methyl-6-t-butylphenyl)ureylenyl)-L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1.4-benzodiazepin-2-one (S)-3-[(N'-((2-(2-thiophene-yl)ethyl)ureylenyl)-L-alaninyl)]amino-2.3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one 3-[N'-3.5-difluorophenyl-acetamido)-L-alaninyl]-3-amino-3.3-dihydrol-methyl-5-phenyl-1H-1.4-benzodiazepine 3-(N'-3,5-difluorophenyl-.alpha.-azidoacetyl)-L-alaninyl]-3-amino-2,3-dihydrol-methyl-5-phenyl-1H-1,4-benzodiazepine 5-{N'-(cyclopropane carboxyl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one 5-{N'-(2-methylhexanoyl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b.d]azepin-6-one 5-{N'-(bicyclo[2.2.1]heptane-2-carboxyl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one 5-{N'-(N-acetyl-N-phenylglycinyl)-L-alaninyl}-amino-7-methyl-5.7-dihydro-6H-dibenz[b.d]azepin-6-one 5-{N'-((aminoacetoxy)-3.5-difluorophenylacetyl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one 3-[N'-(3,5-difluorophenyl-.alpha.-(2-aminoacetoxylacetyl)-L-alaninyl]-amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-Benzodiazepin-2-one 5-{N'-(diphenylacetyl)-L-alaninyl}-amino-7-methyl-5.7-dihydro-6H-dibenz[b.d]azepin-6-one 5-{N'-(acetyl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one 5-{N'-(2-phenoxyphenylacetyl)-L-alaninyl}-amino-7-methyl-5.7-dihydro-6H-dibenz[b,d]azepin-6-one 5-{N'-(trans-cinnamyl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one 5-{N'-(tetrahydro-2-furoyl)-L-alaninyl}-amino-7-methyl-5.7-dihydro-6H-dibenz[b,d]azepin-6-one 5-{N'-(cyclopentanecarboxyl)L-alaninyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b.d]azepin-6-one 5-{N'-(2-thiophenecarboxyl)-L-alaninyl}-amino-7 methyl-5.7-dihydro-6H-dibenz[b.d]azepin-6-one 5-{N'-((S)-(+)-2-hydroxy-2-phenylpropionyl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b.d]azepin-6-one 5-{N'-((R)-(-)-2-hydroxy-2-phenylpropionyl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one 3-[N'-(3.5-difluorophenyl-.alpha.-hydroxy-.alpha.-methylacetyl)-L-alaninyl]-amino-2,3-dihydro-1-methyl-5-(2-fluorophenyl)-1H-1,4-Benzodiazepin-2-one 5-{N'-(benzenesulfonyl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one 3-[N'-(3,5-difluorophenyl-.alpha.-hydroxy-.alpha.-methylacetyl)-L-alaninyl]-amino-2,3-dihydro-1-methyl-5-(2-fluorophenyl)-1H-1,4-Benzodiazepin-2-one 5-{N'-(3-fluorobenzenesulfonyl)-L-alaninyl}-amino-7-methyl-5.7-dihydro-6H-dibenz[b.d]azepin-6-one 5-(S)-(N'-((Butylureylenyl)-L-alaninyl)-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one 5-(S)-(N'-((Benzylureylenyl)-L-alaninyl)-amino-7-methyl-5.7-dihydro-6H-dibenz[b.d]azepin-6-one 5-{N'-(benzylsulfonyl)-L-alaninyl}-amino-7-methyl-5.7-dihydro-6H-dibenz[b.d]azepin-6-one 5-(S)-(N'-((Ethylureylenyl)-L-alaninyl)-amino-7-methyl-5.7-dihydro-6H-dibenz[b,d]azepin-6-one 5-(S)-(N'-((Phenethylureylenyl)-L-alaninyl)-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one 5-(S)-(N'-(3.5-difluorophenyl-.alpha.-aminoacetyl)-L-valinyl)-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one 5-(S)-(N'-(3,5-difluorophenyl-.alpha.-aminoacetyl)-L-tert-leucinyl-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one 5-{N'-(butylsulfonyl)-L-alaninyl}-amino-7-methyl-5.7-dihydro-6H-dibenz[b.d]azepin-6-one 5-{N'-(octylsulfonyl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one 5-(S)-(N'-((2-(thiophen-2-yl)ethylureylenyl)-L-alaninyl)-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one 5-(S)-(N'-(3,5-difluorophenyl-.alpha.-aminoacetyl)-L-alaninyl-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one 5-(S)-(N'-(L-valinyl)-L-alaninyl-)]amino-2.3-dihydro-1-methyl-5-phenyl-1H-1.4-benzodiazepin-2-one 5-(R/S)-(N'-(2-hydroxy-2-phenethylureylenyl)-L-alaninyl)-amino-7-methyl-5.7-dihydro-6H-dibenz[b,d]azepin-6-one 5-(S)-(N'-((hexylureylenyl)-L-alaninyl)-amino-7-methyl-5.7-dihydro-6H-dibenz[b.d]azepin-6-one 5-(S)-(N'-((cyclohexylureylenyl)-L-alaninyl)-amino-7-methyl-5.7-dihydro-6H-dibenz[b,d]azepin-6-one 5-(S)-(N'-((isopropylureylenyl)-L-alaninyl)-amino-7-methyl-5.7-dihydro-6H-dibenz[b,d]azepin-6-one 5-(S)-(N'-((tert-butylureylenyl)-L-alaninyl)-amino-7-methyl-5.7-dihydro-6H-dibenz[b.d]azepin-6-one 5-(S)-(N'-((1-adamantylureylenyl)-L-alaninyl)-amino-7-methyl-5,7-dihydro-6H-dibenz[b.d]azepin-6-one 5-(S)-(N'-((2-methylpropylureylenyl)-L-alaninyl)-amino-7-methyl-5.7-dihydro-6H-dibenz[b.d]azepin-6-one 5-(S)-(N'-(R/S)-3-hydroxy-3-phenylethylureylenyl)-L-alaninyl)-amino-7-methyl-5.7-dihydro-6H-dibenz[b,d]azepin-6-one 5-(S)-(N'-((3-methylbutylureylenyl)-L-alaninyl)-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one 5-(S)-((N'-(S)-1-hydroxymethyl-3-methylbutylureylenyl)-L-alaninyl)-amino-7-methyl-5.7-dihydro-6H-dibenz[b,d]azepin-6-one 5-(S)-((N'-(1S)-(2S)-1-hydroxymethyl-2-methylbutylureylenyl)-L-alaninyl)-amino-7-methyl-5.7-dihydro-6H-dibenz[b,d]azepin-6-one 5-(S)-(N'-(3-chloropropylureylenyl)-L-alaninyl)-amino-7-methyl-5.7-dihydro-6H-dibenz[b,d]azepin-6-one 5-(S)-(N'-octylureylenyl)-L-alaninyl)-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one 5-(S)-(N'-1,1,3,3-tetramethylbutylureylenyl)-L-alaninyl)-amino-7-methyl-5.7-dihydro-6H-dibenz[b,d]azepin-6-one 5-(S)-(N'-(R/S)-1-methylbutylureylenyl)-L-alaninyl)-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one 5-(S)-((N'-(R/S)-1-hydroxymethylbutylureylenyl)-L-alaninyl)-amino-7-methyl-5.7-dihydro-6H-dibenz[b,d]azepin-6-one 5-(S)-((N'-(R/S)-1,3-dimethylbutylureylenyl)-L-alaninyl)-amino-7-methyl-5,7-dihydro-6H-dibenz[b.d]azepin-6-one S-(S)-((N'-(R)-1-hydroxymethyl-3-methylbutylureylenyl)-L-alaninyl)-amino-7-methyl-5.7-dihydro-6H-dibenz[b,d)azepin-6-one 5-(S)-((N'-(R/S)-2-methylbutylureylenyl)-L-alaninyl)-amino-7-methyl-5.7-dihydro-6H-dibenz[b,d]azepin-6-one 5-(S)-(N'-morpholinoureylenyl)-L-alaninyl)-amino-7-methyl-5.7-dihydro-6H-dibenz[b,d]azepin-6-one 5-(S)-(N'-(2-(2-hydroxyethoxy)-ethylureylenyl)-L-alaninyl)-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one 5-(S)-(N'-piperidinylureylenyl)-L-alaninyl)-amino-7-methyl-5.7-dihydro-6H-dibenz[b,d]azepin-6-one 5-(S)-(N'-(N"-methyl-N"-butylureylenyl)-L-alaninyl)-amino-7-methyl-5,7-dihydro-6H-dibenz(b,d]azepin-6-one 5-(S)-(N'-(1-(R/S)-hydroxymethylcyclopentylureylenyl)-L-alaninyl)-amino-7-methyl-5.7-dihydro-6H-dibenz[b.d]azepin-6-one 5-(S)-(N'-(4-hydroxybutylureylenyl)-L-alaninyl)-amino-7-methyl-5.7-dihydro-6H-dibenz[b,d]azepin-6-one 5-(S)-(N'-(1-(RlS)-hydroxymethyl-2-methylpropylureylenyl)-L-alaninyl)-amino-7-methyl-5,7-dihydro-6H-dibenz[b.d]azepin-6-one 5-(S)-(N'-(2-(R/S)-hydroxycyclohexylureylenyl)-L-alaninyl)-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one 5-(S)-(N'-(isopropyl-hydroxyureylenyl)-L-alaninyl)-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one 5-(S)-(N'-(benzyl-hydroxyureylenyl)-L-alaninyl)-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one 5-(S)-(N'-(valinyl)-L-alaninyl-amino-7-methyl-5,7-dihydro-6H-dibenz[b.d]azepin-6-one 5-(S)-(N'-(phenylglycinyl)-L-alaninyl-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one 5-(S)-(N'-(3,5-difluorophenyl-.alpha.-aminoacetyl)-L-alaninyl-amino-7-methyl-5.7-dihydro-6H-dibenz[b,d]azepin-6-one 5-(S)-(N'-(3.5-difluoro phenylglycinyl)-L-alaninyl-amino-7-methyl-5,7-dihydro-6H-dibenz[b.d]azepin-6-one 5-(S)-(N'-(threonine)-L-alaninyl-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one 5-(S)-(N'-(D-valinyl)-L-alaninyl-amino-7-methyl-5.7-dihydro-6H-dibenz[b,d]azepin-6-one 5-(S)-(N'-(phenylglycinyl)-L-alaninyl-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one 5-(S)-(N"-(S)-phenylglycinyl)-N'-L-alaninyl]amino-1-methyl-5-phenyl-1.3,4,5-tetrahydro-2H-1,5-benzodiazepin-2-one 5-(S)-[(N"-L-valinyl)-N'-L-alaninyl]amino-1-methyl-5-phenyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-2-one 5-(S)-(N'-(thiomorpholinylureylenyl)-L-alaninyl)-amino-7-methyl-5,7-dihydro-6H-dibenz[b.d]azepin-6-one 5-(S)-(N'-(2(R/S)-hydroxybutylureylenyl)-L-alaninyl)-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one 5-(S)-(N'-2,2,2-trifluoroethylureylenyl)-L-alaninyl)-amino-7-methyl-5,7-dihydro-6H-dibenz[b.d]azepin-6-one 5-(S)-(N'-(4R/S)-cyclohexylureylenyl)-L-alaninyl)-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one 5-(S)-(N'-(1R)-hydroxymethyl-3-methylthiopropylureylenyl)-L-alaninyl)-amino-7-methyl-5.7-dihydro-6H-dibenz[b,d]azepin-6-one 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-1 H- 1, 4-benzodiazepin-2-one and 5-(S)-[N'-(2-mercapto-3-methylbutanoyl)-L-alaninyl]-amino-7-methyl-5.7-dihydro-6H-dibenz[b,d]azepin-6-one.

85. The compound of claim 58, wherein the compound is of Formula I.

86. The compound of claim 85, wherein each R15 is H.

87. The compound of claim 86, wherein the cyclic group defined by W and -C(H)pC(=X)-, forms a lactam ring of the formula:

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

88. The compound of claim 87 wherein the lactam ring is selected from the group consisting of wherein A-B is selected from the group consisting of alkylene.
alkenylene, substituted alkylene, substituted alkenylene and-N=CH-; Q is oxygen or sulfur; each V is independently selected from the group consisting of hydroxy, acyl, acyloxy, alkyl, substituted alkyl, alkoxy, substituted alkoxy, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl. amino, substituted amino.

aminoacyl, alkaryl, aryl. aryloxy, carboxyl, carboxylalkyl, cyano, halo, nitro, heteroaryl, thioalkoxy, substituted thioalkoxy, and trihalomethyl: each Ra is independently selected from the group consisting of alkyl, substituted alkyl, alkoxy, substituted alkoxy, amino, substituted amino, carboxyl, carboxyl alkyl, cyano, and halo; Rb is selected from the group consisting of alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, acyl, aryl, heteroaryl, and heterocyclic: Rc is selected from the group consisting of alkyl, substituted alkyl, alkenyl, substituted alkenyl, aryl, heteroaryl, heterocyclic, thioalkoxy, substituted amino, cycloalkyl, and substituted cycloalkyl; t is an integer from 0 to 4; t is an integer from 0 to 3; and w is an integer from 0 to 3.

89. The compound of claim 88, wherein R1 is selected from the group consisting of (a) alkyl (b) phenyl.
(c) a substituted phenyl group of the formula:
wherein Rc is selected from the group consisting of acyl, alkyl, alkoxy, alkylalkoxy, azido. cyano, halo, hydrogen, substituted amino, nitro, trihalomethyl, thioalkoxy, and wherein Rb and Rc are fused to form a heteroaryl or heterocyclic ring with the phenyl ring wherein the heteroaryl or heterocyclic ring contains from 3 to 8 atoms of which from 1 to 3 are heteroatoms independently selected from the group consisting of oxygen, nitrogen and sulfur Rb and Rb are independently selected from the group consisting of hydrogen, halo, nitro, cyano, trihalomethyl, alkoxy, and thioalkoxy with the proviso that when Rc is hydrogen, then Rb and Rb are either both hydrogen or both substituents other than hydrogen.
(d) 2-naphthyl.
(e) 2-naphthyl substituted at the 4, 5, 6, 7 and/or 8 positions with 1 to 5 substituents selected from the group consisting alkyl, alkoxy, halo, cyano, nitro, trihalomethyl, thioalkoxy, aryl, and heteroaryl.
(f) heteroaryl, and (g) substituted heteroaryl containing 1 to 3 substituents selected from the group consisting of alkyl, alkoxy, aryl, aryloxy, cyano, halo, nitro, heteroaryl, thioalkoxy, thioaryloxy provided that said substituents are not ortho to the heteroaryl attachment to the -NH
group.

90. The compound of claim 89 wherein R1 is selected from the group consisting of phenyl, 1-naphthyl, 2-naphthyl, n-butyl, 2-chlorophenyl, 2-fluorophenyl, 2-bromophenyl, 2-hydroxyphenyl, 2-nitrophenyl, 2-methylphenyl. 2-methoxyphenyl, 2-phenoxyphenyl, 2-trifluoromethylphenyl, 4-fluorophenyl, 4-chlorophenyl, 4-bromophenyl, 4-nitrophenyl, 4-methylphenyl, 4-hydroxyphenyl.
4-methoxyphenyl, 4-ethoxyphenyl, 4-butoxyphenyl, 4-iso-propylphenyl, 4-phenoxyphenyl, 4-trifluoromethylphenyl, 4-hydroxymethylphenyl, 3-methoxyphenyl, 3-hydroxyphenyl, 3-nitrophenyl, 3-fluorophenyl, 3-chlorophenyl, 3-bromophenyl. 3-phenoxyphenyl, 3-thiomethoxyphenyl.
3-methylphenyl, 3-trifluoromethylphenyl, 2,3-dichlorophenyl, 2, 3-difluorophenyl. 2,4-dichlorophenyl, 2,5-dimethoxyphenyl, 3.
4-dichlorophenyl. 3,4-difluorophenyl, 3,4-methylenedioxyphenyl, 3,4-dimethoxyphenyl, 3,5-difluorophenyl, 3,5-dichlorophenyl. 3, 5-di-(trifluoromethyl)phenyl, 3.5-dimethoxyphenyl, 2, 4-dichlorophenyl, 2,4-difluorophenyl 2,6-difluorophenyl. 3,4, 5-trifluorophenyl. 3,4.5-trimethoxyphenyl, 3,4, 5-tri-(trifluoromethyl)phenyl, 2,4.6-trifluorophenyl, 2,4.
6-trimethylphenyl, 2.4,6-tri-(trifluoromethyl)phenyl, 2,3, 5-trifluorophenyl, 2.4,5-trifluorophenyl, 2,5-difluorophenyl. 2-fluoro-3-trifluoromethylphenyl. 4-fluoro-2-trifluoromethylphenyl. 2-fluoro-4-trifluoromethylphenyl, 4-benzyloxyphenyl, 2-chloro-6-fluorophenyl, 2-fluoro-6-chlorophenyl, 2,3,4,5.
6-pentafluorophenyl. 2.5-dimethylphenyl, 4-phenylphenyl. 2-fluoro-3-trifluoromethylphenyl, adamantyl.
benzyl. 2-phenylethyl, 3-phenyl-n-propyl, 4-phenyl-n-butyl, methyl, ethyl, n-propyl, iso-propyl, iso-butyl, sec-butyl, tert-butyl, n-pentyl, iso-valeryl, n-hexyl, cyclopropyl, cyclobutyl, cyclohexyl, cyclopentyl, cyclopent-1-enyl, cyclopent-2-enyl, cyclohex-1-enyl, -CH2-cyclopropyl. -CH2-cyclobutyl, -CH2-cyclohexyl. -CH2-cyclopentyl. -CH2CH2-cyclopropyl, -CH2CH2-cyclobutyl, CH2CH2-cyclohexyl, -CH2CH2-cyclopentyl, pyrid-2-yl, pyrid-3- yl, pyrid-4-yl, fluoropyridyls, chloropyridyls, thien-2-yl, thien-3-yl, benzothiazol-4-yl, 2-phenylbenzoxazol-5-yl. furan-2-yl, benzofuran-2-yl, thionaphthen-2-yl, thionaphthen-3-yl, thionaphthen-4-yl, 2-chlorothiophen-5-yl, 3-methylisoxazol-5-yl, 2-(thiophenyl)thien-5-yl, 6-methoxythionaphthen-2-yl, 3-phenyl-1,2,4-thiooxadiazol-5-yl, 2-phenyloxazol-4-yl, indol-3-yl, 1-phenyl-tetrazol-5-yl, allyl, 2-(cyclohexyl)ethyl, (CH3)2CH=CHCH2CH2CH(CH3),-C
(O)CH2-, thien-2-yl-methyl, 2-(thien-2-yl)ethyl, 3-(thien-2-yl)-n-propyl, 2-(4-nitrophenyl)ethyl, 2-(4-methoxyphenyl)ethyl, norboran-2-yl, (4-methoxyphenyl)methyl, (2-methoxyphenyl)methyl, (3-methoxyphenyl)methyl, (3-hydroxy phenyl)methyl. (4-hydroxyphenyl)methyl, (4-methoxyphenyl)methyl, (4-methylphenyl)methyl, (4-fluorophenyl)methyl, (4-fluorophenoxy)methyl, (2, (4-dichlorophenoxy)ethyl, (4-chlorophenyl)methyl, (2-chlorophenyl)methyl, (1-phenyl)ethyl, (1-(p-chlorophenyl)ethyl, (1-trifluoromethyl)ethyl, (4-methoxyphenyl)ethyl. CH3OC(O) CH2-benzylthiomethyl, 5-(methoxycarbonyl)-n-pentyl, 3-(methoxycarbonyl)-n-propyl, indan-2-yl, (2-methylbenzofuran-3-yl), methoxymethyl, CH3CH=CH-, CH3CH2CH=CH-, (4-chlorophenyl)C(O)CH2-,(4-fluorophenyl)C(O)CH2-, (4-methoxy phenyl)C(O)CH2-, 4-(fluorophenyl)-NHC(O)CH2-, 1-phenyl-n-butyl, (phenyl)2CHNHC(O)CH2CH2-, (CH3)2NC(O)CH2-(phenyl)2 CHNHC(O)CH2CH2-, methylcarbonylmethyl, (2.4-dimethylphenyl)C(O)CH2-, 4-methoxyphenyl-C(O)CH2-, phenyl-C(O)CH2-, CH3C(O)N(phenyl)-, ethenyl, methylthiomethyl, (CH3)3CNHC(O)CH2-, 4-fluorophenyl-C(O)CH2-, diphenylmethyl, phenoxymethyl. 3.4-methylenedioxyphenyl-CH2-, benzo[b]thiophen-3-yl, (CH3)3COC(O)NHCH2-, traps-styryl, H2NC(O)CH2CH2-. 2-trifluoromethylphenyl-C(O)CH2, phenylC(O)NHCH(phenyl)CH2-, mesityl, CH3CH(=NHOH) Ch2-,4-CH3-phenyl-NHC(O)CH2CH2-, phenyl-C(O)CH(phenyl) CH2,(CH3)2CHC(O)NHCH(phenyl)-, CH3CH2OCH2-, CH3OC(O)CH(CH3)(CH2)3-. 2,2.2-trifluoroethyl, 1-(trifluoromethyl)ethyl, 2-CH3-benzofuran-3-yl: 2-(2, 4-dichlorophenoxy)ethyl, SO2CH2-, 3-cyclohexyl-n-propyl, CF3CH2CH2CH2- and N-pyrrolidinyl.

91. The compound of Claim 90 where each R2 is independently selected from the group consisting of alkyl, substituted alkyl, alkenyl, cycloalkyl, aryl, heteroaryl and heterocyclic.

92. The compound of Claim 91 wherein R2 is selected from the group consisting of methyl, ethyl, n-propyl. iso-propyl, n-butyl.
iso-butyl, sec-butyl, tert-butyl, -CH2CH(CH2CH3)2, 2-methyl-n-butyl, 6-fluoro-n-hexyl, phenyl, benzyl, cyclohexyl, cyclopentyl.
cycloheptyl, allyl, iso-but-2-enyl. 3-methylpentyl, -CH2-cyclopropyl. -CH2-cyclohexyl, -CH2CH2-cyclopropyl, -CH2CH2-cyclohexyl, -CH2-indol-3-yl, p-(phenyl)phenyl, o-fluorophenyl, m-fluorophenyl, p-fluorophenyl, m-methoxyphenyl, p-methoxyphenyl, phenethyl, benzyl, m-hydroxybenzyl, p-hydroxybenzyl, p-nitrobenzyl, m-trifluoromethylphenyl, p-(CH3)2NCH2CH2CH2O
benzyl, p-(CH3)3COC(O)CH2O-benzyl, p-(HOOCCH2O)-benzyl, 2-aminopyrid-6-yl, p-(N-morpholino-CH2CH2O)-benzyl, -CH2CH2C(O)NH2, -CH2-imidazol-4-yl, -CH2-(3-tetrahydrofuranyl), -CH2-thiophen-2-yl, -CH2(1-methyl) cyclopropyl, -CH2-thiophen-3-yl. thiophen-3-yl, thiophen-2-yl, -CH2-C(O)O-t-butyl. -CH2-C(CH3)3, -CH2CH(CH2CH3)2, 2-methylcyclopentyl, cyclohex-2-enyl, -CH[CH(CH3)2]COOCH3, CH2CH2N(CH3)2, -CH2C(CH3)=CH2, -CH2CH=CHCH3 (cis and trans). -CH2OH. -CH(OH)CH3, -CH(O-t-butyl)CH3, -CH2OCH3. -(CH2)4NH-Boc, -(CH2)4NH2, -CH2-pyridyl, pyridyl, -CH2-naphthyl. -CH2-(N-morpholino), p-(N-morpholino-CH2CH2O)-benzyl, benzo[b]thiophen-2-yl, 5-chlorobenzo[b]thiophen-2-yl. 4,5,6,7-tetrahydrobenzo[b]thiophen-2-yl, benzo[b]thiophen-3-yl, 5-chlorobenzo[b]thiophen-3-yl, benzo[b]thiophen-5-yl, 6-methoxynaphth-2-yl. -CH2CH2SCH3.
thien-2-yl, and thien-3-yl.

93. The compound of Claim 92 wherein Rb is selected from the group consisting of alkyl, substituted alkyl, cycloalkyl and aryl.

94. The compound of Claim 93 wherein R2 is methyl.

95. The compound of Claim 94 wherein R1 is alkyl.

96. The compound of Claim 95 wherein Rb is alkyl.

97. The compound of Claim 58 wherein the compounds are compounds of Formula VI.

9g. The compounds of Claim 97 wherein each R15 is H.

99. The compounds of Claim 98 wherein the cyclic group defined by W and -C(H)pC(=X)-, forms a lactam ring of the formula:
or wherein p is zero or one, T is selected from the group consisting of alkylene, substituted alkylene, alkenylene, substituted alkenylene, (R21Z)qR21- and -ZR21 , where Z is a substituent selected from the group consisting of -O-. -S- and > NR20, each R20 is independently selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl. cycloalkenyl, substituted alkyl, substituted alkenyl, substituted alkynyl, aryl, heteroaryl and heterocyclic, each R21 is independently alkylene, substituted alkylene, alkenylene and substituted alkenylene with the proviso that when Z is -O- or -S-, any unsaturation in the alkenylene and substituted alkenylene does not involve participation of the -O- or -S-, and q is an integer of from 1 to 3.

100. The compound of claim 87 wherein the lactam ring is selected from the group consisting of and wherein A-B is selected from the group consisting of alkylene, alkenylene, substituted alkylene, substituted alkenylene and -N=CH-; Q is oxygen or sulfur: each V is independently selected from the group consisting of hydroxy, acyl, acyloxy, alkyl, substituted alkyl, alkoxy, substituted alkoxy, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, amino, substituted amino, aminoacyl, alkaryl, aryl, aryloxy, carboxyl, carboxylalkyl, cyano, halo, nitro, heteroaryl, thioalkoxy, substituted thioalkoxy, and trihalomethyl; each Ra is independently selected from the group consisting of alkyl, substituted alkyl, alkoxy, substituted alkoxy, amino, substituted amino, carboxyl, carboxyl alkyl, cyano, and halo; Rb is selected from the group consisting of alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, acyl, aryl, heteroaryl, and heterocyclic; Rc is selected from the group consisting of alkyl, substituted alkyl, alkenyl, substituted alkenyl, aryl, heteroaryl, heterocyclic. substituted amino, cycloalkyl, and substituted cycloalkyl; t is an integer from 0 to 4; t is an integer from 0 to 3; and w is an integer from 0 to 3.

101. The compound of Claim 100 wherein R1 is selected from the group consisting of (a) alkyl (b) phenyl, (c) a substituted phenyl group of the formula:
wherein Rc is selected from the group consisting of acyl, alkyl, alkoxy, alkylalkoxy, azido, cyano, halo, hydrogen, substituted amino, nitro, trihalomethyl, thioalkoxy, and wherein Rb and Rc are fused to form a heteroaryl or heterocyclic ring with the phenyl ring wherein the heteroaryl or heterocyclic ring contains from 3 to 8 atoms of which from 1 to 3 are heteroatoms independently selected from the group consisting of oxygen, nitrogen and sulfur Rb and Rb are independently selected from the group consisting of hydrogen. halo, nitro. cyano, trihalomethyl, alkoxy, and thioalkoxy with the proviso that when Rc is hydrogen, then Rb and Rb are either both hydrogen or both substituents other than hydrogen, (d) 2-naphthyl, (e) 2-naphthyl substituted at the 4, 5, 6, 7 and/or 8 positions with 1 to 5 substituents selected from the group consisting alkyl, alkoxy, halo, cyano, nitro, trihalomethyl, thioalkoxy, aryl, and heteroaryl, (f) heteroaryl, and (g) substituted heteroaryl containing 1 to 3 substituents selected from the group consisting of alkyl, alkoxy, aryl, aryloxy, cyano, halo, nitro, heteroaryl, thioalkoxy, thioaryloxy provided that said substituents are not ortho to the heteroaryl attachment to the -NH
group.

102. The compound of Claim 101 wherein R1 is selected from the group consisting of phenyl, 1-naphthyl, 2-naphthyl, n-butyl, 2-chlorophenyl, 2-fluorophenyl, 2-bromophenyl, 2-hydroxyphenyl, 2-nitrophenyl, 2-methylphenyl, 2-methoxyphenyl, 2-phenoxyphenyl, 2-trifluoromethylphenyl, 4-fluorophenyl, 4-chlorophenyl, 4-bromophenyl, 4-nitrophenyl. 4-methylphenyl, 4-hydroxyphenyl, 4-methoxyphenyl, 4-ethoxyphenyl, 4-butoxyphenyl, 4-iso-propylphenyl, 4-phenoxyphenyl, 4-trifluoromethylphenyl, 4-hydroxymethylphenyl.
3-methoxyphenyl. 3-hydroxyphenyl, 3-nitrophenyl, 3-fluorophenyl, 3-chlorophenyl, 3-bromophenyl, 3-phenoxyphenyl, 3-thiomethoxyphenyl, 3-methylphenyl. 3-trifluoromethylphenyl, 2,3-dichlorophenyl, 2,3-difluorophenyl, 2,4-dichlorophenyl, 2,5-dimethoxyphenyl, 3,4-dichlorophenyl. 3,4-difluorophenyl, 3,4-methylenedioxyphenyl, 3,4-dimethoxyphenyl, 3.5-difluorophenyl, 3,5-dichlorophenyl, 3,5-di-(trifluoromethyl)phenyl, 3.5-dimethoxyphenyl, 2,4-dichlorophenyl, 2,4-difluorophenyl, 2,6-difluorophenyl, 3,4,5-trifluorophenyl, 3,4,5-trimethoxyphenyl, 3,4,5-tri-(trifluoromethyl)phenyl. 2,4,6-trifluorophenyl, 2,4,6-trimethylphenyl, 2,4,6-tri-(trifluoromethyl)phenyl, 2,3,5-trifluorophenyl, 2,4,5-trifluorophenyl, 2,5-difluorophenyl, 2-fluoro-3-trifluoromethylphenyl, 4-fluoro-2-trifluoromethylphenyl, 2-fluoro-4-trifluoromethylphenyl, 4-benzyloxyphenyl, 2-chloro-6-fluorophenyl, 2-fluoro-6-chlorophenyl, 2,3.4.5,6-pentafluorophenyl. 2,5-dimethylphenyl, 4-phenylphenyl, 2-fluoro-3-trifluoromethylphenyl, adamantyl, benzyl, 2-phenylethyl. 3-phenyl-n-propyl, 4-phenyl-n-butyl, methyl, ethyl, n-propyl, iso-propyl, iso-butyl, sec-butyl, tent-butyl, n-pentyl, iso-valeryl, n-hexyl, cyclopropyl, cyclobutyl, cyclohexyl, cyclopentyl.
cyclopent-1-enyl, cyclopent-2-enyl, cyclohex-1-enyl, -CH2-cyclopropyl, -CH2-cyclobutyl, -CH2-cyclohexyl, -CH2-cyclopentyl, -CH2CH2-cyclopropyl, -CH2CH2-cyclobutyl, -CH2CH2-cyclohexyl, -CH2CH2-cyclopentyl, pyrid-2-yl, pyrid-3-yl, pyrid-4-yl, fluoropyridyls, chloropyridyls, thien-2-yl, thien-3-yl, benzothiazol-4-yl, 2-phenylbenzoxazol-5-yl, furan-2-yl, benzofuran-2-yl, thionaphthen-2-yl, thionaphthen-3-yl, thionaphthen-4-yl, 2-chlorothiophen-5-yl, 3-methylisoxazol-5-yl, 2-(thiophenyl)thien-5-yl, 6-methoxythionaphthen-2-yl, 3-phenyl-1,2,4-thiooxadiazol-5-yl, 2-phenyloxazol-4-yl, indol-3-yl, 1-phenyl-tetrazol-5-y1, allyl, 2-(cyclohexyl)ethyl, (CH3)2CH=CHCH2CH2CH(CH3), C(O)CH2-, thien-2-yl-methyl, 2-(thien-2-yl)ethyl, 3-(thien-2-yl)-n-propyl, 2-(4-nitrophenyl)ethyl, 2-(4-methoxyphenyl)ethyl, norboran-2-yl, (4-methoxyphenyl)methyl, (2-methoxyphenyl)methyl, (3-methoxyphenyl)methyl, (3-hydroxy phenyl)methyl, (4-hydroxyphenyl)methyl, (4-methoxyphenyl)methyl, (4-methylphenyl)methyl, (4-fluorophenyl)methyl, (4-fluorophenoxy)methyl, (2,4-dichlorophenoxy)ethyl, (4-chlorophenyl)methyl, (2-chlorophenyl)methyl, (1-phenyl}ethyl, (1-(p-chlorophenyl)ethyl, (1-trifluoromethyl)ethyl, (4-methoxyphenyl)ethyl, CH3OC(O)CH2-, benzylthiomethyl, 5-(methoxycarbonyl)-n-pentyl, 3-(methoxycarbonyl)-n-propyl, indan-2-yl, (2-methylbenzofuran-3-yl), methoxymethyl, CH3CH=CH-, CH3CH2CH=CH-, (4-chlorophenyl)C(O)CH2-, (4-fluorophenyl)C(O)CH2-, (4-methoxy phenyl)C(O)CH2-, 4-(fluorophenyl)-NHC(O)CH2-, 1-phenyl-n-butyl, (phenyl)2CHNHC(O)CH2CH2-, (CH3)2NC(O)CH2-, (phenyl)2CHNHC(O)CH2CH2-, methylcarbonylmethyl, (2,4-dimethylphenyl)C(O)CH2-, 4-methoxyphenyl-C(O)CH2-, phenyl-C(O)CH2-, CH3C(O)N(phenyl)-, ethenyl, methylthiomethyl, (CH3)3CNHC(O)CH2-, 4-fluorophenyl-C(O)CH2-, diphenylmethyl, phenoxymethyl, 3,4-methylenedioxyphenyl-CH2-, benzo[b]thiophen-3-yl, (CH3)3COC(O)NHCH2-, trans-styryl, H2NC(O)CH2CH2-, 2-trifluoromethylphenyl-C(O)CH2, phenylC(O)NHCH(phenyl)CH2-mesityl, CH3CH(=NHOH)CH2-, 4-CH3-phenyl-NHC(O)CH2CH2-, phenyl-C(O)CH(phenyl)CH2-, (CH3)2CHC(O)NHCH(phenyl)-, CH3CH2OCH2-, CH3OC(O)CH(CH3)(CH2)3-, 2,2,2-trifluoroethyl, 1-(trifluoromethyl)ethyl, 2-CH3-benzofuran-3-yl, 2-(2,4-dichlorophenoxy)ethyl, SO2CH2-, 3-cyclohexyl-n-propyl, CF3CH2CH2CH2- and N-pyrrolidinyl.

103. The compound according to Claim 102 where each R2 is independently selected from the group consisting of alkyl, substituted alkyl, alkenyl, cycloalkyl, aryl, heteroaryl and heterocyclic.

104. The compound according to Claim 103 wherein R2 is selected from the group consisting of methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, -CH2CH(CH2CH3)2, 2-methyl-n-butyl, 6-fluoro-n-hexyl, phenyl, benzyl, cyclohexyl, cyclopentyl, cycloheptyl, allyl, iso-but-2-enyl, 3-methylpentyl, -CH2-cyclopropyl, -CH2-cyclohexyl.
-CH2CH2-cyclopropyl. -CH2CH2-cyclohexyl, -CH2-indol-3-yl, p-(phenyl)phenyl, o-fluorophenyl, m-fluorophenyl, p-fluorophenyl, m-methoxyphenyl, p-methoxyphenyl, phenethyl, benzyl, m-hydroxybenzyl, p-hydroxybenzyl, p-nitrobenzyl, m-trifluoromethylphenyl, p-(CH3)2NCH2CH2CH2O-benzyl, p-(CH3)3COC(O)CH2O-benzyl, p-(HOOCCH2O)-benzyl, 2-aminopyrid-6-yl, p-(N-morpholino-CH2CH2O)-benzyl.
-CH2CH2C(O)NH2, -CH2-imidazol-4-yl, -CH2-(3-tetrahydrofuranyl), -CH2-thiophen-2-yl, -CH2(1-methyl)cyclopropyl, -CH2-thiophen-3-yl, thiophen-3-yl, thiophen-2-yl, -CH2-C(O)O-t-butyl, -CH2-C(CH3)3, -CH2CH(CH2CH3)2, 2-methylcyclopentyl, cyclohex-2-enyl, -CH[CH(CH3)2]COOCH3, -CH2CH2N(CH3}2,-CH2C(CH3)=CH2, -CH2CH=CHCH3 (cis and trans}, -CH2OH, -CH(OH)CH3. -CH(O-t-butyl)CH3, -CH2OCH3, -(CH2)4NH-Boc, -(CH2)4NH2, -CH2-pyridyl, pyridyl, -CH2-naphthyl, -CH2-(N-morpholino), p-(N-morpholino-CH2CH2O)-benzyl, benzo[b]thiophen-2-yl, 5-chlorobenzo[b]thiophen-2-yl, 4,5,6,7-tetrahydrobenzo[b]thiophen-2-yl, benzo[b]thiophen-3-yl, 5-chlorobenzo[b)thiophen-3-yl, benzo[b]thiophen-5-yl, 6-methoxynaphth-2-yl, -CH2CH2SCH3.
thien-2-yl, and thien-3-yl.

105. The compound of Claim 104 wherein Rb is selected from the group consisting of alkyl, substituted alkyl, cycloalkyl and aryl.

106. The compound of Claim 105 wherein R2 is methyl.

107. The compound of Claim 106 wherein R1 is alkyl.

108. The compound of Claim 107 wherein Rb is alkyl.

109. The compound of Claim 58 wherein the compound is a compound of Formula II.

110. The compound of Claim 109 wherein T is a bond and X' and X" are independently selected from the group consisting of H, hydroxyl, alkyl, substituted alkyl and aryl.

111. The compound of Claim 110 wherein each R15 is H.

112. The compound of Claim 111 the cyclic group defined by W and -C(H)pC( = X)- forms a lactam ring of the formula:
or wherein p is zero or one, T is selected from the group consisting'of alkylene, substituted alkylene, alkenylene, substituted alkenylene, (R21Z)qR21- and -ZR21 , where Z is a substituent selected from the group consisting of -O-, -S- and > NR20, each R20 is independently selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, substituted alkyl; substituted alkenyl, substituted alkynyl, aryl, heteroaryl and heterocyclic, each R21 is independently alkylene, substituted alkylene, alkenylene and substituted alkenylene with the proviso that when Z is -O- or -S-,any unsaturation in the alkenylene and substituted alkenylene does not involve participation of the -O- or -S-, and q is an integer of from 1 to 3.

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 Ra is independently selected from the group consisting of alkyl, substituted alkyl, alkoxy, substituted alkoxy, amino, substituted amino, carboxyl, carboxyl alkyl, cyano, and halo; Rb is selected from the group consisting of alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, acyl, aryl, heteroaryl, and heterocyclic; Rc is selected from the group consisting of alkyl, substituted alkyl, alkenyl, substituted alkenyl, aryl, heteroaryl, heterocyclic, substituted amino, cycloalkyl, and substituted cycloalkyl; t is an integer from 0 to 4; t is an integer from 0 to 3; and w is an integer from 0 to 3.

114. The compound of Claim 113 wherein R1 is selected from the group consisting of (a) alkyl, (b) phenyl, (c) a substituted phenyl group of the formula:

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

115. The compound of Claim 114 wherein R1 is selected from the group consisting of phenyl, 1-naphthyl, 2-naphthyl, n-butyl, 2-chlorophenyl, 2-fluorophenyl, 2-bromophenyl, 2-hydroxyphenyl, 2-nitrophenyl, 2-methylphenyl, 2-methoxyphenyl, 2-phenoxyphenyl, 2-trifluoromethylphenyl, 4-fluorophenyl, 4-chlorophenyl, 4-bromophenyl, 4-nitrophenyl, 4-methylphenyl, 4-hydroxyphenyl, 4-methoxyphenyl, 4-ethoxyphenyl, 4-butoxyphenyl, 4-iso-propylphenyl, 4-phenoxyphenyl, 4-trifluoromethylphenyl, 4-hydroxymethylphenyl, 3-methoxyphenyl, 3-hydroxyphenyl, 3-nitrophenyl, 3-fluorophenyl, 3-chlorophenyl, 3-bromophenyl, 3-phenoxyphenyl, 3-thiomethoxyphenyl, 3-methylphenyl, 3-trifluoromethylphenyl, 2,3-dichlorophenyl, 2,3-difluorophenyl, 2,4-dichlorophenyl, 2,5-dimethoxyphenyl, 3,4-dichlorophenyl, 3,4-difluorophenyl, 3,4-methylenedioxyphenyl, 3,4-dimethoxyphenyl, 3,5-difluorophenyl, 3,5-dichlorophenyl, 3,5-di-(trifluoromethyl)phenyl, 3,5-dimethoxyphenyl, 2,4-dichlorophenyl, 2,4-difluorophenyl, 2,6-difluorophenyl, 3,4,5-trifluorophenyl, 3,4,5-trimethoxyphenyl, 3,4,5-tri-(trifluoromethyl)phenyl, 2,4,6-trifluorophenyl, 2,4,6-trimethylphenyl, 2,4,6-tri-(trifluoromethyl)phenyl, 2,3,5-trifluorophenyl, 2,4,5-trifluorophenyl, 2,5-difluorophenyl, 2-fluoro-3-trifluoromethylphenyl, 4-fluoro-2-trifluoromethylphenyl, 2-fluoro-4-trifluoromethylphenyl, 4-benzyloxyphenyl, 2-chloro-6-fluorophenyl, 2-fluoro-6-chlorophenyl, 2,3,4,5,6-pentafluorophenyl, 2,5-dimethylphenyl, 4-phenylphenyl, 2-fluoro-3-trifluoromethylphenyl, adamantyl, benzyl, 2-phenylethyl, 3-phenyl-n-propyl, 4-phenyl-n-butyl, methyl, ethyl, n-propyl, iso-propyl, iso-butyl, sec-butyl, tert-butyl, n-pentyl, iso-valeryl, n-hexyl, cyclopropyl, cyclobutyl, cyclohexyl, cyclopentyl, cyclopent-1-enyl, cyclopent-2-enyl, cyclohex-1-enyl, -CH2-cyclopropyl, -CH2-cyclobutyl, -CH2-cyclohexyl, -CH2-cyclopentyl, -CH2CH2-cyclopropyl, -CH2CH2-cyclobutyl, -CH2CH2-cyclohexyl, -CH2CH2-cyclopentyl, pyrid-2-yl, pyrid-3-yl, pyrid-4-yl, fluoropyridyls, chloropyridyls, thien-2-yl, thien-3-yl, benzothiazol-4-yl, 2-phenylbenzoxazol-5-yl, furan-2-yl, benzofuran-2-yl, thionaphthen-2-yl, thionaphthen-3-yl, thionaphthen-4-yl, 2-chlorothiophen-5-yl, 3-methylisoxazol-5-yl, 2-(thiophenyl)thien-5-yl, 6-methoxythionaphthen-2-yl, 3-phenyl-1,2,4-thiooxadiazol-5-yl, 2-phenyloxazol-4-yl, indol-3-yl, 1-phenyl-tetrazol-5-yl, allyl, 2-(cyclohexyl)ethyl, (CH3)2CH=CHCH2CH2CH(CH3)-, C(O)CH2-, thien-2-yl-methyl, 2-(thien-2-yl)ethyl, 3-(thien-2-yl)-n-propyl, 2-(4-nitrophenyl)ethyl, 2-(4-methoxyphenyl)ethyl, norboran-2-yl, (4-methoxyphenyl)methyl, (2-methoxyphenyl)methyl, (3-methoxyphenyl)methyl, (3-hydroxy phenyl)methyl, (4-hydroxyphenyl)methyl, (4-methoxyphenyl)methyl, (4-methylphenyl)methyl, (4-fluorophenyl)methyl, (4-fluorophenoxy)methyl, (2,4-dichlorophenoxy)ethyl, (4-chlorophenyl)methyl, (2-chlorophenyl)methyl, (1-phenyl)ethyl, (1-(p-chlorophenyl)ethyl, (1-trifluoromethyl)ethyl, (4-methoxyphenyl)ethyl, CH3OC(O)CH2-, benzylthiomethyl, 5-(methoxycarbonyl)-n-pentyl, 3-(methoxycarbonyl)-n-propyl, indan-2-yl, (2-methylbenzofuran-3-yl, methoxymethyl, CH3CH=CH-, CH3CH2CH=CH-, (4-chlorophenyl)C(O)CH2-, (4-fluorophenyl)C(O)CH2-, (4-methoxy phenyl)C(O)CH2-, 4-(fluorophenyl)-NHC(O)CH2-, 1-phenyl-n-butyl, (phenyl)2CHNHC(O)CH2CH2-, (CH3)2NC(O)CH2-, (phenyl)2CHNHC(O)CH2CH2-, methylcarbonylmethyl, (2,4-dimethylphenyl)C(O)CH2-, 4-methoxyphenyl-C(O)CH2-, phenyl-C(O)CH2-, CH3C(O)N(phenyl)-, ethenyl, methylthiomethyl, (CH3)3CNHC(O)CH2-, 4-fluorophenyl- C(O)CH2-, diphenylmethyl, phenoxymethyl, 3,4-methylenedioxyphenyl-CH2-, benzo[b]thiophen-3-yl, (CH3)3COC(O)NHCH2-, trans-styryl, H2NC(O)CH2CH2-, 2-trifluoromethylphenyl-C(O)CH2, phenylC(O)NHCH(phenyl)CH2-, mesityl, CH3CH(=NHOH)CH2-, 4-CH3-phenyl-NHC(O)CH2CH2-, phenyl-C(O)CH(phenyl)CH2-, (CH3)2CHC(O)NHCH(phenyl)-, CH3CH2OCH2-, CH3OC(O)CH(CH3)(CH2)3-, 2,2,2-trifluoroethyl, 1-(trifluoromethyl)ethyl, 2-CH3-benzofuran-3-yl, 2-(2,4-dichlorophenoxy)ethyl, SO2CH2-, 3-cyclohexyl-n-propyl, CF3CH2CH2CH2- and N-pyrrolidinyl.

116. The compound according to Claim 115 where each R2 is independently selected from the group consisting of alkyl, substituted alkyl, alkenyl, cycloalkyl, aryl, heteroaryl and heterocyclic.

117. The compound according to Claim 116 wherein R2 is selected from the group consisting of methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, -CH2CH(CH2CH3)2, 2-methyl-n-butyl, 6-fluoro-n-hexyl, phenyl, benzyl, cyclohexyl, cyclopentyl, cycloheptyl, allyl, iso-but-2-enyl, 3-methylpentyl, -CH2-cyclopropyl, -CH2-cyclohexyl, -CH2CH2-cyclopropyl, -CH2CH2-cyclohexyl, -CH2-indol-3-yl, p-(phenyl)phenyl, o-fluorophenyl, m-fluorophenyl, p-fluorophenyl, m-methoxyphenyl, p-methoxyphenyl, phenethyl, benzyl, m-hydroxybenzyl, p-hydroxybenzyl, p-nitrobenzyl, m-trifluoromethylphenyl, p-(CH3)2NCH2CH2CH2O-benzyl, p-(CH3)3COC(O)CH2O-benzyl, p-(HOOCCH2O)-benzyl, 2-aminopyrid-6-yl, p-(N-morpholino-CH2CH2O)-benzyl, -CH2CH2C(O)NH2, -CH2-imidazol-4-yl, -CH2-(3-tetrahydrofuranyl), -CH2-thiophen-2-yl, -CH2(1-methyl)cyclopropyl, -CH2-thiophen-3-yl, thiophen-3-yl, thiophen-2-yl, -CH2-C(O)O-t-butyl, -CH2-C(CH3)3, -CH2CH(CH2CH3)2, 2-methylcyclopentyl, cyclohex-2-enyl, -CH[CH(CH3)2]COOCH3, -CH2CH2N(CH3)2, -CH2C(CH3)=CH2, -CH2CH=CHCH3 (cis and trans), -CH2OH, -CH(OH)CH3, -CH(O-t-butyl)CH3, -CH2OCH3, -(CH2)4NH-Boc, -(CH2)4NH2, -CH2-pyridyl, pyridyl, -CH2-naphthyl, -CH2-(N-morpholino), p-(N-morpholino-CH2CH2O)-benzyl, benzo[b]thiophen-2-yl, 5-chlorobenzo[b]thiophen-2-yl, 4,5.6,7-tetrahydrobenzo[b]thiophen-2-yl, benzo[b]thiophen-3-yl, 5-chlorobenzo[b]thiophen-3-yl, benzo[b)thiophen-5-yl, 6-methoxynaphth-2-yl, -CH2CH2SCH3, thien-2-yl, and thien-3-yl.

118. The compound of Claim 117 wherein Rb is selected from the group consisting of alkyl, substituted alkyl, cycloalkyl and aryl.

119. The compound of Claim 118 wherein R2 is methyl.

120. The compound of Claim 119 wherein R1 is alkyl.

121. The compound of Claim 120 wherein Rb is alkyl.

122. A compound selected from the group consisting of 5-(S)-[N'-(2-Amino-3,3,3-trifluoromethylbutyryl)-L-alaninyl]-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one 5-(S)-[N'-(2-amino -5,5,5-trifluoropentanyl)-L-alaninyl]-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one 5-(S)-[N'-(2-amino-4,4,4-trifluorobutyryl)-L-alaninyl]-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one 1-(S)-[N'-(2-Amino-3,3.3-trifluorobutyryl)-L-alaninyl]-amino-3-methyl-4,5,6,7-tetrahydro-2H-3-benzazepin-2-one 1-(S)-[N'-(2-Amino-5,5,5-trifluoropentanoyl)-L-alaninyl]-amino-3-methyl-4,5,6,7-tetrahydro-2H-3-benzazepin-2-one 1-(S)-[N'-(2-Amino-4,4,4-trifluorobutyryl)-L-alaninyl]-amino-3-methyl-4,5,6,7-tetrahydro-2H-3-benzazepin-2-one 1-(S)-[N'-(2-Aminobutyryl)-L-alaninyl]-amino-3-methyl-4,5,6,7-tetrahydro-2H-3-benzazepin-2-one 1-(S)-[N'-(Hexafluorovalinyl)-L-alaninyl]-amino-3-methyl-4,5,6,7-tetrahydro-2H-3-benzazepin-2-one 1-(S)-[N'-(L-2-Aminobutyryl)-L-alaninyl]-amino-3-(2-methylpropyl) -4,5,6,7-tetrahydro-2H-3-benzazepin-2-one, and 5-[N'-(S)-2-(4-methylpentyl)amino-3-methylbutyryl-L-alaninyl]-amino-7-methyl-5,7-dihydro-6H-dibenz(b,d]azepin-6-one.

123. The compound of claim 60 wherein R1 is selected from the group consisting of methyl, ethyl, n-propyl, iso-propyl, iso-butyl, sec-butyl, n-butyl, n-pentyl and isovaleryl.