JP2002518481A - Compounds for inhibiting the release of β-amyloid peptide and / or its synthesis - Google Patents

Abstract

(57) Abstract: A compound of formula I, which inhibits the release and / or synthesis of β-amyloid peptide and is useful for treating Alzheimer's disease. [Wherein W is type (2): , (3): Wherein Y is a group represented by the formula (II): And a compound represented by the formula: Also disclosed are pharmaceutical compositions comprising compounds that inhibit the release of and / or synthesis of β-amyloid peptide, and methods of using such pharmaceutical compositions to preventively and therapeutically treat Alzheimer's disease.

Description

DETAILED DESCRIPTION OF THE INVENTION

TECHNICAL FIELD The present invention inhibits the release of β-amyloid peptide and / or its synthesis,
Thus, it relates to compounds that have utility in treating Alzheimer's disease.

Literature The following publications, patents and patent applications are cited in this application by superscript numbers. ¹ Biochem. Biophys. Res. Commun., 120 (3): 885-890 by Glenner et al.
(1984). ² U.S. Patent No. 4,666,829 (issued May 19, 1987), GG Glenner et al., "Poly
peptide Marker for Alzheimer's Disease and Its Use for Diagnosis, " ³ Selkoe, Neuron, 6 : 487-498 (1991). ⁴ Goate et al., Nature, 349 : 704-706 (1991). ⁵ Chartier Harlan et al., Nature, 353 : 844-846 (1991). ⁶ Murrell et al., Science, 254 : 97-99 (1991). ⁷ Nature Genet., 1 : 345-347 (1992), by Mullan et al. ⁸ International patent application WO 94/10569 (published May 11, 1994) by Schenk et al.
`` Methods and Compositions for the Detection of Soluble β-Amyloid Pepti
de " ⁹ " Amyloid Protein and Alzheimer's Disease "by Selkoe, Scient
ific American, p.2-8 (November 1911). ¹⁰ U.S. Patent No. 3,598,859 to Yates et al. ¹¹ Tetrahedron Letters 1993, 34 (48), 7685. ¹² Tetrahedron Letters 1971, 8, 667-670, by RFC Brown et al. ¹³ AO King et al., J. Org. Chem. 1993, 58, 3384-3386. ¹⁴ US Provisional Patent Application No. 60 / 019,790 (filed June 14, 1996). ¹⁵ RD Clark et al., Tetrahedron 1993, 49 (7), 1351-1356. ¹⁶ Nature (1992) 360: 672-674 by Citron et al. ¹⁷ P. Seubert et al., Nature (1992) 359: 325-327. ¹⁸ Hansen et al., J. Immun. Meth. (1989) 119: 203-210. ¹⁹ Games et al., Nature (1995) 373: 523-527. ²⁰ PNAS USA (1997) 94: 1550-1555, by Johnson-Wood et al.

[0003] All of the above references, patents and patent applications are hereby incorporated by reference, as each document, patent or patent application is specifically and individually indicated to form a part of this specification. Is configured.

State of the Art Alzheimer's disease (AD) clinically causes a progressive loss of memory, cognition, reasoning, judgment, and emotional stability, gradually leading to deep dementia, and ultimately A degenerative brain disorder characterized by death. AD is a very common cause of progressive mental retardation (dementia) in older humans and is considered to be the fourth-largest common medical cause of death in the United States. AD has been observed in races and racial groups around the world and is a major present and future public health problem. The disease is estimated to affect about 2 to 3 million people in the United States alone. AD is currently incurable. It is widely known that there is no treatment that effectively prevents or reverses the symptoms and course of AD.

[0005] The brains of patients with AD exhibit characteristic lesions called senile (or amyloid) plaques, amyloid angiopathy (amyloid deposition in blood vessels) and neurofibrillary tangles. Many of these lesions, especially amyloid plaques and neurofibrillary tangles,
It is commonly found in several areas of the human brain that are important for the memory and cognitive functions of AD patients. A small number of these lesions in a more restricted anatomical distribution are also found in the majority of aged human brains without clinical AD. Amyloid plaques and amyloid angiopathy also occur in trisomy 21 (Down syndrome) and hereditary cerebral hemorrhage in Dutch-type amyloidosis (Hereditary Cerebral Hemorrhage wit)
h Amyloidosis of the Dutch Type (HCHWA-D). Currently, the definitive diagnosis of AD is usually to observe the above lesions in the brain tissue of a patient who died of the disease, or a small biopsy sample of brain tissue removed during rarely invasive neurosurgery Cost.

[0006] The major chemical constituents of amyloid plaques and vascular amyloid deposits (amyloid angiopathy), which are characteristic of AD and the other diseases mentioned above, are β-amyloid peptide (βAP) or sometimes Aβ, AβP Or about 3 called β / A4
Approximately 4.2 kilodalton (kD) protein of 9-43 amino acids. The β-amyloid peptide was first purified by Glenner et al. ¹ and a partial amino acid sequence was presented. Sequence data for the isolation method and the first 28 amino acids are described in ² U.S. Patent No. 4,666,829.

[0007] By molecular biology and protein chemical analysis, β-amyloid peptide is a small fragment of a much larger precursor protein called amyloid precursor protein (APP), usually found in many tissues of various animals, including humans. It was shown to be produced in cells inside. Knowledge of the structure of the gene encoding APP has demonstrated that β-amyloid peptide occurs as a peptide fragment that is cleaved from APP by protease enzymes. The exact biochemical mechanism, i.e., the mechanism by which β-amyloid peptide fragments are cleaved from APP and subsequently deposited as amyloid plaques in brain tissue and in the blood vessel walls of the brain and cerebral meninges,
Currently unknown.

[0008] Several lines of evidence indicate that progressive brain deposition of β-amyloid peptide plays a seminal role in AD embryology and that cognitive symptoms may be years or even 1
It has been shown that it can be 0 years ahead. See, for example, Selkoe ³ . According to the most important evidence, the 770-amino acid isoform of APP 717
Missense DNA mutations at amino acids are found in affected members but not in unaffected members of some families with genetically determined (familial) forms of AD. ( ⁴ ) by Goate et al., ⁵ by Cartier Harlan et al., And Murrell
) Et al. ⁶ ), which is called the Swedish variant. A double mutation that changes lysine ⁵⁹⁵ -methionine ⁵⁹⁶ to asparagine ⁵⁹⁵ -leucine ⁵⁹⁶ , which was found in a Swedish family, was reported in 1992 (Muren et al. ⁷ ). Genetic binding analysis has shown that these mutations, as well as certain other mutations in the APP gene, are specific molecular causes of AD in affected members of their families. In addition, a mutation at amino acid 693 of the 770 amino acid isoform of APP has been identified as the cause of β-amyloid peptide deposition disease, HCHWA-D, and the change from alanine to glycine at amino acid 692 has been identified in some patients. HCHWA in AD and others
It seems to cause a phenotype similar to -D. When AD is viewed based on genetics, the discovery of those and other mutations in APP suggests that changes in APP and subsequent β
-Demonstrates that deposition of amyloid peptide fragments can cause AD.

[0009] Despite progress in understanding the mechanisms underlying AD and other β-amyloid peptide-related diseases, there is a need for the development of methods and compositions for treating those diseases. Ideally, the method of treatment would be conveniently with a drug capable of inhibiting the release of β-amyloid peptide and / or its synthesis in vivo.

Compounds that inhibit the release of β-amyloid peptide and / or its synthesis in vivo are described in US patent application Ser. No. 08 / 996,442, filed Dec. 22, 1997;
Cycloalkyl, Lactam, Lactone and Related Compounds, Pharmaceutical Compos
itions Comprising Same, and Methods for inhibiting β-Amyloid Peptide Re
lease, and / or its Synthesis by Use of Such Compounds, "which is incorporated herein by reference. The invention relates to deoxy derivatives of such compounds.

(Summary of the Invention) The present invention inhibits the release of β-amyloid peptide and / or its synthesis,
Accordingly, the present invention relates to the discovery of a group of compounds that are useful in the treatment of patients with AD to prevent AD and / or to prevent further exacerbation of those diseases in patients susceptible to AD.

Accordingly, in one aspect of the composition, the present invention provides a compound of formula I:

Embedded image [Where W is

Embedded image

Embedded image

Embedded image And a cyclic group selected from the group consisting of Wherein ring A, together with the atoms to which it is attached, is a carbocyclic ring selected from the group consisting of aryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heteroaryl and heterocyclic; Forms a heterocyclic ring. Ring B, together with the atoms to which it is attached, is a carbocyclic or heterocyclic group selected from the group consisting of aryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heteroaryl and heterocyclic. Form a ring. Ring C, together with the atoms to which it is attached, forms heteroaryl and heterocyclic. Y is the formula:

Embedded imageIndicated by R¹Is alkyl, alkenyl, alkynyl, cycloalkyl, cycloalk
Nil, substituted alkyl, substituted alkenyl, substituted alkynyl, substituted cycloalkyl,
Substituted cycloalkenyl, aryl, heteroaryl, and heterocyclic
Selected from the group consisting of R^TwoIs alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl
, Substituted alkynyl, cycloalkyl, aryl, heteroaryl and heterosa
Selected from the group consisting of iclick. R^ThreeIs hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl,
Quinyl, substituted alkynyl, acyl, aryl, cycloalkyl, substituted cycloal
Kill, cycloalkenyl, substituted cycloalkenyl, heteroaryl and hetero
Selected from the group consisting of cyclic. Each R^FourIs independently alkyl, substituted alkyl, alkenyl, substituted alkenyl,
Rukinyl, substituted alkynyl, aryl, cycloalkyl, substituted cycloalkyl,
Cycloalkenyl, substituted cycloalkenyl, heteroaryl and heterocycle
Selected from the group consisting of Rick. R^FiveIs hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl,
Quinyl, substituted alkynyl, alkoxy, substituted alkoxy, aryl, arylo
Xy, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloa
Lucenyl, substituted amino, heteroaryl, heterocyclic, thioalkoxy
And substituted thioalkoxy. Q is oxygen, sulfur, -S (O)-, -S (O)_Two-, -C (O)-or -C (S)-
is there. Z is represented by the formula: -T-CX'X "V- (where T is oxygen, sulfur, -N
R⁶(Where R⁶Is hydrogen, acyl, alkyl, aryl, or heteroaryl
And -CX'X "-and R¹Selected from the group consisting of
Is). X 'is hydrogen, hydroxy, or fluorine; X "is hydrogen, hydroxy, or fluorine; or X' and X" are
To form an oxo group. V is selected from the group consisting of alkylene or substituted alkylene;¹And Z together form aryl, cycloalkyl, substituted cycloalkyl, cyclo
Loalkenyl, substituted cycloalkenyl, heterocyclic, or substituted
Form a cyclic. X is hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkyl
Nil, substituted alkynyl, acyl, aryl, cycloalkyl, substituted cycloalkyl
, Cycloalkyl, substituted cycloalkenyl, heteroaryl and heterocyclyl
Selected from the group consisting of clicks, or X, one R^FourAnd they combine
The atoms together form a double bond. t is an integer of 0 to 2. f is an integer of 0 to 2. n is an integer of 1 or 2. And a pharmaceutically acceptable salt thereof, wherein T is R ¹ And other than a covalent bond connecting —CX′X ″ — to X ′ and X ″,
Nor can it be hydroxy or fluorine). .

The present invention also provides a novel pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound of formula I above.

Thus, in one aspect of the method, the present invention relates to a method of inhibiting β-amyloid peptide release and / or synthesis in a cell, wherein the method comprises administering to the cell a compound of Formula I or a compound of the compound Administering the mixture in an amount effective to inhibit release and / or synthesis of β-amyloid peptide in the cells.

Since the in vivo occurrence of β-amyloid peptide is associated with the pathogenesis of AD ^8,9 , the compounds of formula I also prevent and / or therapeutically prevent AD and / or It can be used in conjunction with a pharmaceutical composition to be treated. Thus, in another aspect of the method, the present invention provides a method for treating AD in patients at risk of developing AD.
A prophylactic method of preventing the onset of, comprising administering to a patient a pharmaceutical composition comprising a pharmaceutically inert carrier and an effective amount of a compound of formula I or a mixture of such compounds.

[0016] In yet another aspect of the method, the invention relates to a therapeutic method of treating a patient with AD to inhibit further exacerbation of the patient's illness, wherein the method is pharmaceutically acceptable to the patient. Administering a pharmaceutical composition comprising a pharmaceutically acceptable carrier and an effective amount of a compound of formula I above or a mixture of such compounds.

In the above formula I, ring A and ring B may be the same or different;
These are preferably independently selected from the group consisting of aryl, cycloalkyl, cycloalkenyl, heteroaryl and heterocyclic. More preferably, ring A and ring B are independently selected from the group consisting of aryl and cycloalkyl. Even more preferably, rings A and B are independently aryl.

Particularly preferred rings A and B include, for example, phenyl, substituted phenyl (including fluoro-substituted phenyl), cyclohexyl and the like.

Preferred rings C include, for example, pyrrolidinyl, piperidinyl, morpholino and the like.

Preferred R 1 groups include non-phenyl groups such as phenyl, 1-naphthyl, 2-naphthyl and the like.
Substituted aryl group, monosubstituted phenyl (preferably substituted at the 3- or 5-position), disubstituted phenyl
Phenyl (preferably substituted at the 3- and 5-positions), and 3-substituted phenyl (preferably
(Substituted at positions 3, 4, and 5). Preferably
A substituted phenyl group contains no more than three substitutions. Examples of substituted phenyl include, for example, 2-
Chlorophenyl, 2-fluorophenyl, 2-bromophenyl, 2-hydroxyphenyl
, 2-nitrophenyl, 2-methylphenyl, 2-methoxyphenyl, 2-phenoxy
Phenyl, 2-trifluoromethylphenyl, 4-fluorophenyl, 4-chlorophen
Nyl, 4-bromophenyl, 4-nitrophenyl, 4-methylphenyl, 4-hydroxy
Phenyl, 4-methoxyphenyl, 4-ethoxyphenyl, 4-butoxyphenyl, 4-
Isopropylphenyl, 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-tri
Fluoromethylphenyl, 2,3-dichlorophenyl, 2,3-difluorophenyl, 2,3
4-dichlorophenyl, 2,5-dimethoxyphenyl, 3,4-dichlorophenyl, 3,4-di
Fluorophenyl, 3,4-methylenedioxyphenyl, 3,4-dimethoxyphenyl,
3,5-difluorophenyl, 3,5-dichlorophenyl, 3,5-di- (trifluoromethyl
) Phenyl, 3,5-dimethoxyphenyl, 2,4-difluorophenyl, 2,6-difluoro
Rophenyl, 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-tri
Fluorophenyl, 2,4,5-trifluorophenyl, 2,5-difluorophenyl, 4-
Fluoro-2-trifluoromethylphenyl, 2-fluoro-4-trifluoromethylf
Phenyl, 4-benzyloxyphenyl, 2-chloro-6-fluorophenyl, 2-fluoro
B-6-chlorophenyl, 2,3,4,5,6-pentafluorophenyl, 2,5-dimethylphen
Nil, 4-phenylphenyl, and 2-fluoro-3-trifluoromethylphenyl
Is included. Other preferred R¹Groups include, for example, 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,
So-valeryl, n-hexyl, cyclopropyl, cyclobutyl, cyclohexyl,
Cyclopentyl, cyclopenten-1-yl, cyclopenten-2-yl, cyclohexyl
Sen-1-yl, -CH_Two-Cyclopropyl, -CH_Two-Cyclobutyl, -CH_Two-Cyclohexyl
, -CH_Two-Cyclopentyl, -CH_TwoCH_Two-Cyclopropyl, -CH_TwoCH_Two-Cyclobutyl, -CH _Two CH_Two-Cyclohexyl, -CH_TwoCH_Two-Cyclopentyl, pyridin-2-yl, pyridine-3
-Yl, pyridin-4-yl, fluoropyridyl (including 5-fluoropyridin-3-yl
), Chloropyridyl (including 5-chloropyridin-3-yl), thien-2-yl, thie
-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-methylisoxazo
5-yl, 2- (thiophenyl) thien-5-yl, 6-methoxythionaphthene-2-i
, 3-phenyl-1,2,4-thiooxadiazol-5-yl, 2-phenyloxazole
-4-yl, indol-3-yl, 1-phenyl-tetraol-5-yl, allyl, 2- (
(Cyclohexyl) ethyl, (CH_Three) CH = CHCH_TwoCH_TwoCH (CH_Three)-, (CH_Three)_TwoC = CHCH_TwoCH_TwoCH (CH_Three)
-, FC (O) CH_Two-, Thien-2-yl-methyl, 2- (thien-2-yl) ethyl, 3- (thien-2
-Yl) -n-propyl, 2- (4-nitrophenyl) ethyl, 2- (4-methoxyphenyl)
Tyl, norboran-2-yl, (4-methoxyphenyl) methyl, (2-methoxyphenyl
) Methyl, (3-methoxyphenyl) methyl, (3-hydroxyphenyl) methyl, (4-
(Droxyphenyl) 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-trifluoro
(Methyl) ethyl, (4-methoxyphenyl) ethyl, CH_Three0C (O) CH_Two-, Benzylthiome
Tyl, 5- (methoxycarbonyl) -n-pentyl, 3- (methoxycarbonyl) -n-propyl
, Indan-2-yl, (2-methylbenzofuran-3-yl), methoxymethyl, CH_ThreeC
H = CH-, CH_ThreeCH_TwoCH = CH-, (4-chlorophenyl) C (O) CH_Two-, (4-fluorophenyl) C (O
) CH_Two-, (4-methoxyphenyl) C (O) CH_Two-, 4- (fluorophenyl) -NHC (O) CH_Two-, 1-
Phenyl-n-butyl, (f)_TwoCHNHC (O) CH_TwoCH_Two-, (CH_Three)_TwoNC (O) CH_Two-, (F)_TwoCHNHC (O) CH_Two CH_Two-, Methylcarbonylmethyl, (2,4-dimethylphenyl) C (O) CH_Two-, Phenyl-C
(O) CH_Two-, CH_ThreeC (O) N (f)-, ethenyl, methylthiomethyl, (CH_Three)_ThreeCNHC (O) CH_Two-
Phenylmethyl, phenoxymethyl, 3,4-methylenedioxyphenyl-CH_Two-
Nzo [b] thiophen-3-yl, (CH_Three)_ThreeCOC (O) NHCH_Two-, Trans-styryl, H_TwoNC (O) CH_Two CH_Two-, 2-trifluoromethylphenyl-C (O) CH_Two, FC (O) NHCH (f) CH_Two-, Mesityl,
CH_ThreeCH (= NHOH) CH_Two-, 4-CH_Three-f-NHC (O) CH_TwoCH_Two-, FC (O) CH (f) CH_Two-, (CH_Three)_TwoCHC (O) NHC
H (f)-, CH_ThreeCH_Two0CH_Two-, CH_Three0C (O) CH (CH_Three) (CH_Two)_Three-, 2,2,2-trifluoroethyl, 1-
(Trifluoromethyl) ethyl, 2-CH_Three-Benzofuran-3-yl, 2- (2,4-dichlorofu
Enoxy) ethyl, fSO_TwoCH_Two-, 3-cyclohexyl-n-propyl, CF_ThreeCH_TwoCH_TwoCH_Two-,
And N-pyrrolidinyl.

R^TwoIs preferably alkyl, substituted alkyl, alkenyl, cycloalkyl,
Selected from the group consisting of aryl, heteroaryl, and heterocyclic
. Particularly preferred R^TwoSubstituents include, for example, methyl, ethyl, n-propyl, iso-
-Propyl, n-butyl, iso-butyl, sec-butyl, tert-butyl,
-CH_TwoCH (CH_TwoCH_Three)_Two, 2-methyl-n-butyl, 6-fluoro-n-hex
Sil, phenyl, benzyl, cyclohexyl, cyclopentyl, cycloheptyl
, Allyl, iso-buten-2-yl, 3-methylpentyl, -CH_Two-Cyclop
Ropir, -CH_Two-Cyclohexyl, -CH_TwoCH_Two-Cyclopropyl, -CH_TwoC
H_Two-Cyclohexyl, -CH_Two-Indol-3-yl, p- (phenyl) phenyl
, O-fluorophenyl, m-fluorophenyl, p-fluorophenyl, m
-Methoxyphenyl, p-methoxyphenyl, phenethyl, benzyl, m-hydrido
Roxybenzyl, p-hydroxybenzyl, p-nitrobenzyl, m-triflu
Oromethylphenyl, p- (CH_Three) NCH_TwoCH_TwoCH_TwoO-benzyl, p- (CH_Three )_ThreeCOC (O) CH_TwoO-benzyl, p- (HOOCCH_TwoO) -benzyl, 2-amido
Nopyridin-6-yl, p- (N-morpholino-CH_TwoCH_TwoO) -benzyl, -CH _Two CH_TwoC (O) NH_Two, -CH_Two-Imidazol-4-yl, -CH_Two-(3-tetra
Hydrofuranyl), -CH_Two-Thiophen-2-yl, -CH_Two(1-methyl) sic
Ropropyl, -CH_Two-Thiophen-3-yl, thiophen-3-yl, thiof
En-2-yl, -CH_Two-C (O) Ot-butyl, -CH_Two-C (CH_Three)_Three, -C
H_TwoCH (CH_TwoCH_Three)_Two, 2-methylcyclopentyl, cyclohexen-2-yl
, -CH [CH (CH_Three)_Two] COOCH_Three, -CH_TwoCH_TwoN (CH_Three)_Two, -CH_TwoC (C
H_Three) = CH_Two, -CH_TwoCH = CHCH_Three(Cis and trans), -CH_TwoOH,
-CH (OH) CH_Three, -CH (Ot-butyl) CH_Three, -CH_TwoOCH_Three,-(CH_Two )_FourNH-Boc,-(CH_Two)_FourNH_Two, -CH_Two-Pyridyl (for example, 2-pyridyl
, 3-pyridyl, and 4-pyridyl), pyridyl (2-pyridyl, 3-pyridyl)
, And 4-pyridyl), -CH_Two-Naphthyl (eg, 1-naphthyl and
2-naphthyl), -CH_Two-(N-morpholino), p- (N-morpholino-CH_TwoC
H_TwoO) benzyl, benzo [b] thiophen-2-yl, 5-chlorobenzo [b] thio
Phen-2-yl, 4,5,6,7-tetrahydrobenzo [b] thiophen-2-i
Benzo [b] thiophen-3-yl, 5-chlorobenzo [b] thiophen-3-
Yl, benzo [b] thiophen-5-yl, 6-methoxynaphth-2-yl, -C
H_TwoCH_TwoSCH_Three, Thien-2-yl, thien-3-yl and the like.

Preferably, R ³ is selected from the group consisting of hydrogen, alkyl, substituted alkyl and cycloalkyl.

Particularly preferred R ³ substituents are, for example, hydrogen, methyl, 2-methylpropyl, hexyl, methoxycarbonylmethyl, 3,3-dimethyl-2-oxobutyl, 4-
Includes phenylbutyl, cyclopropylmethyl, 2,2,2-trifluoroethyl, cyclohexyl, and the like.

When present, R ⁴ is preferably alkyl or substituted alkyl.

R ⁵ is alkyl, substituted alkyl, aryl, substituted aryl (eg, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 2-chlorophenyl, etc.), cycloalkyl (eg, cyclohexyl, etc.), or Heteroaryl or heterocyclic (eg, piperidin-1-yl, 2-pyridyl, 2-thiazolyl, 2-thienyl, etc.) are preferred.

F is preferably 0 or 1. More preferably, f is 0. n is preferably 1.

In one embodiment of the present invention, W is of the formula:

Embedded image Wherein each R ⁶ is independently 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 ₂ - alkyl, -SO ₂ - substituted alkyl, -SO ₂ - aryl and -SO ₂ - group consisting of heteroaryl Selected from. Each R ⁷ is independently 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 ₂ - alkyl, -SO ₂ - substituted alkyl, -SO ₂ - aryl and -SO ₂ - group consisting of heteroaryl Selected from. R ⁸ is selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, acyl, aryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heteroaryl and heterocyclic. It is. p is an integer of 0-4, and q is an integer of 0-4. ] The cyclic group of these.

R ⁶ and R ⁷ are independently alkoxy, substituted alkoxy, alkyl, substituted alkyl, amino, substituted amino, carboxyl, carboxyalkyl, cyano, halo,
It is preferably selected from the group consisting of nitro, thioalkoxy and substituted thioalkoxy. More preferably, when present, R ⁶ and R ⁷ are fluoro.

Preferably, R ⁸ is selected from the group consisting of hydrogen, alkyl, substituted alkyl, acyl, aryl, cycloalkyl and substituted cycloalkyl. More preferably, R ⁸ is selected from the group consisting of hydrogen, alkyl, substituted alkyl and cycloalkyl.

Particularly preferred R ⁸ substituents are, for example, hydrogen, methyl, 2-methylpropyl, hexyl, methoxycarbonylmethyl, 3,3-dimethyl-2-oxobutyl, 4-
Includes phenylbutyl, cyclopropylmethyl, 2,2,2-trifluoroethyl, cyclohexyl, and the like.

In another preferred embodiment of the invention, W is of the formula:

Embedded image Wherein R ⁶ , R ⁷ and p are as defined herein, and r is an integer from 0 to 3. ] Is a cyclic group.

In yet another preferred embodiment of the present invention, W is of the formula:

Embedded image Wherein R ⁶ and p are as defined herein. ].

In another preferred embodiment of the invention, W is of the formula:

Embedded image Wherein R ⁶ and p are as defined herein. ] The cyclic group of these.

In yet another preferred embodiment of the present invention, W is of the formula:

Embedded image Wherein R ⁶ , R ⁸ and p are as defined herein, and each R ⁹ is independently alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, cycloalkyl , Substituted cycloalkyl,
G is an integer from 0 to 2 selected from the group consisting of cycloalkenyl, substituted cycloalkenyl, heteroaryl and heterocyclic. ] The cyclic group of these.

When present, R ⁹ is preferably alkyl or substituted alkyl.

In another preferred embodiment of the invention, W is of the formula:

Embedded image Wherein R ⁶ , R ⁸ , R ⁹ , g and p are as defined herein. ].

In yet another preferred embodiment of the present invention, W is of the formula:

Embedded image Wherein R ⁶ , R ⁸ , R ⁹ , g and p are as defined herein. ].

In yet another preferred embodiment of the present invention, W is of the formula:

Embedded image Wherein R ⁶ , R ⁸ and p are as defined herein. ].

In another preferred embodiment of the invention, W is of the formula:

Embedded image Wherein R ⁶ , R ⁸ , R ⁹ , g and p are as defined herein. ].

In another preferred embodiment of the invention, W is of the formula:

Embedded image Wherein R ⁶ , R ⁸ and p are as defined herein, and R ¹⁰ is alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl,
It is selected from the group consisting of aryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heteroaryl and heterocyclic. ].

In another preferred embodiment of the invention, W is of the formula:

Embedded image Wherein R ⁶ , R ¹⁰ and p are as defined herein and DE is alkylene, alkenylene, substituted alkylene, substituted alkynylene and —NH ＝ CH
-Selected from the group consisting of: ].

In another preferred embodiment of the invention, W is of the formula:

Embedded image Wherein R ⁶ , R ⁸ , R ⁹ , g and p are as defined herein, and Q is oxygen, sulfur, —S (O) —, —S (O) ₂ — . ].

In another preferred embodiment of the invention, W is of the formula:

Embedded image Wherein R ⁶ , R ⁸ and p are as defined herein. ].

In another preferred embodiment of the invention, W is of the formula:

Embedded image Wherein R ⁸ is as defined herein. ].

In another preferred embodiment of the invention, W is of the formula:

Embedded image Wherein R ⁸ is as defined herein. ].

In another preferred embodiment of the invention, W is of the formula:

Embedded image Wherein R ⁸ is as defined herein. ].

In another preferred embodiment of the invention, W is of the formula:

Embedded image Wherein R ⁴ and R ⁸ are as defined herein. ].

In another preferred embodiment of the invention, W is of the formula:

Embedded image Wherein R ⁴ is as defined herein. ].

In another preferred embodiment of the present invention, W is of the formula:

Embedded image Wherein R ⁴ , R ⁶ , R ⁸ and p are as defined herein. ].

In another preferred embodiment of the invention, W is of the formula:

Embedded image Wherein R ⁴ , R ⁶ , R ⁸ and p are as defined herein. ].

Compounds of the present invention include, for example, the following compounds: 5- (S)-(N ′-(2- (3,5-difluorophenyl) ethyl) -L-alaninyl) -amino-7-methyl -5,7-dihydro-6H-dibenz [b, d] azepin-6-one, 5 (S)-(N '-(2 (R) -hydroxy-2- (3,5-difluorophenyl) ethyl) -L-alaninyl
) -Amino-7-methyl-5,7-dihydro-6H-dibenz [b, d] azepin-6-one, 5 (S)-(N ′-(2 (S) -hydroxy-2- (3, 5-difluorophenyl) ethyl) -L-alaninyl
) -Amino-7-methyl-5,7-dihydro-6H-dibenz [b, d] azepin-6-one, 5 (S)-(N ′-(2 (R / S) -hydroxy-3-isopropyl (Oxy-propyl) -L-alaninyl)
-Amino-7-methyl-5,7-dihydro-6H-dibenz [b, d] azepin-6-one, 5 (S)-(N '-(2 (R / S) -hydroxy-butyl) -L -Alaninyl) -amino-7-methyl-5,7-dihydro-6H-dibenz [b, d] azepin-6-one, 5 (S)-(N '-(2 (R / S) -3-dihydroxy -Propyl) -L-alaninyl) -amino-7-methyl-
5,7-dihydro-6H-dibenz [b, d] azepin-6-one, 5 (S)-(N '-(2 (R / S) -hydroxy-3-morpholinopropyl) -L-alaninyl)- Amino-7
-Methyl-5,7-dihydro-6H-dibenz [b, d] azepin-6-one, 5 (S)-(N '-(2 (R / S) -hydroxy-tetradecyl) -L-alaninyl)- Amino-7-methyl-
5,7-dihydro-6H-dibenz [b, d] azepin-6-one, 5 (S)-(N '-(2 (R / S) -hydroxy-octyl) -L-alaninyl) -amino-7 -Methyl-5,7-
Dihydro-6H-dibenz [b, d] azepin-6-one, 5 (S)-(N '-(2 (R) -hydroxy-2- (3,4,5-trifluorophenyl) ethyl) -L -Alaninyl) -amino-7-methyl-5,7-dihydro-6H-dibenz [b, d] azepin-6-one, 5 (S)-(N '-(2 (S) -hydroxy-2- ( 3,4,5-trifluorophenyl) ethyl) -L-alaninyl) -amino-7-methyl-5,7-dihydro-6H-dibenz [b, d] azepin-6-one, 5 (S)-( N '-(2 (R) -hydroxy-2- (4- (trifluoromethyl) phenyl) ethyl) -L-alaninyl) -amino-7-methyl-5,7-dihydro-6H-dibenz [b, d Azepin-6-one, 5 (S)-(N '-(2 (S) -hydroxy-2- (4- (trifluoromethyl) phenyl) ethyl) -L-alaninyl) -amino-7-methyl- 5,7-dihydro-6H-dibenz [b, d] azepin-6-one, 5 (S)-(N '-(2 (R) -hydroxy-2- (3,5-bis- (trifluoromethyl ) Phenyl) ethyl) -L-alaninyl) -amino-7-methyl-5,7-dihydro-6H-dibenz [b, d] azepine -
6-one, 5 (S)-(N '-(2 (S) -hydroxy-2- (3,5-bis- (trifluoromethyl) phenyl) ethyl) -L-alaninyl) -amino-7-methyl -5,7-dihydro-6H-dibenz [b, d] azepine-
6-one, 5 (S)-(N '-(2 (R) -hydroxy-2- (3,3,3-trifluoro) -propyl) -L-alaninyl)
-Amino-7-methyl-5,7-dihydro-6H-dibenz [b, d] azepin-6-one, 5 (S)-(N '-(2 (S) -hydroxy-2- (3,3 , 3-Trifluoro) -propyl) -L-alaninyl)
-Amino-7-methyl-5,7-dihydro-6H-dibenz [b, d] azepin-6-one, 5- (S)-(N '-(3-methyl-2-butanone) -L-alaninyl ) -Amino-7-methyl-5,7-dihydro-6H-dibenz [b, d] azepin-6-one, 5- (S)-(N ′-(3-methyl-2- (S) -hydroxy Butyl) -L-alaninyl) -amino-7-methyl-5,7-dihydro-6H-dibenz [b, d] azepin-6-one, 3- (N '-(3-methyl-2- (S) 2-hydroxybutyl) -L-alaninyl) -amino-2,4-dioxo-1-methyl-5-phenyl-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine, 3- (N '-(2- (R / S) -3,5-difluorophenyl-2-hydroxyethyl) -L-alaninyl)-
Amino-2,4-dioxo-1-methyl-5-phenyl-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine, 5- [N '-(S) -2- (4-methyl Pentyl) amino-3-methylbutyryl-L-alaninyl] -amino-7-methyl-5,7-dihydro-6H-dibenz [b, d] azepin-6-one, 5- (S)-{N '-[ (1RS, 2SR) -1,2,3,4-tetrahydro-1-hydroxy-2-naphthyl] alaninyl} -amino-7-methyl-5,7-dihydro-6H-dibenz [b, d] azepine-6 -One, 5- (S)-{N '-[(1RS, 2RS) -1,2,3,4-tetrahydro-1-hydroxy-2-naphthyl] alaninyl} -amino-7-methyl-5,7 -Dihydro-6H-dibenz [b, d] azepin-6-one, 5- (S)-[N '-(2-a-tetralone) -L-alaninyl] -amino-7-methyl-5,7- Dihydro-6H
-Dibenz [b, d] azepin-6-one hydrochloride, 5- (S)-[N '-(1,2,3,4-tetrahydro-2-naphthyl) -L-alaninyl] -amino-7- Methyl-5,7-dihydro-6H-dibenz [b, d] azepin-6-one, 5- (S)-{N '-[(1RS, 2SR) -1-hydroxy-2-cyclohexyl] alaninyl}- Amino-7-
Methyl-5,7-dihydro-6H-dibenz [b, d] azepin-6-one, 5- (S)-[N '-(4-methylpentyl) -L-alaninyl] -amino-7-methyl- 5,7-dihydro-
6H-dibenz [b, d] azepin-6-one.

Other examples are shown in the table below. The compounds listed below have the following formula I:

Embedded image Matches. Here, W has the following structure unless otherwise specified.

Embedded image

[0053]

[Table 1]

[0054]

[Table 2]

[0055]

[Table 3]

As will be appreciated by those skilled in the art, the compounds of the present invention exist as isomers. As used herein, the (R)-and (S) -designated Cahn-Prerog-Ingold designations for the amino acid-derived moiety of the compound, the stereochemistry relative to the glyceraldehyde isomer. Chemical L- and D- designations are used to refer to the specific stereoisomer being indicated. Certain isomers may be synthesized by stereospecific synthesis or by techniques known in the art (eg, chromatographic purification on a chiral stationary phase and fractionation of the addition salt formed with the reagents used for that purpose). Crystal) and can be recovered. Useful methods for resolving and recovering specific isomers are known in the art, for example, Stereochemistry of Organ
In ic Compounds, EL Eliel and SH Wilen (Wiley-Interscience 1
994), Enantiomers, Racemates and Resolutions, J. Jacques, A. Collet and
SJ Wilen (Wiley-Interscience 1981) and European patent application EP-A-83844
No. 8 (filed on April 29, 1998). It is to be understood that the present invention extends to all isomers of the compounds of the present invention (eg, diastereomers, enantiomers and racemates of the compounds).

Prodrugs of the above compounds of Formula I (including, for example, acyls of alcohols and thiols, including the aminal of one or more amines, etc.)
It is within the scope of the present invention.

DETAILED DESCRIPTION OF THE INVENTION As noted above, the present invention relates to methods of inhibiting the release of β-amyloid peptide and / or its synthesis, and thus having utility in treating Alzheimer's disease. However, before describing the present invention in more detail, the following terms will first be defined.

The definition phrase "β-amyloid peptide" refers to 39-4 having a molecular weight of about 4.2 kD.
A three amino acid peptide is meant wherein the peptide is essentially homologous to the form of the protein described by Glenner et al. ¹ , including mutations and post-translational modifications of the normal β-amyloid peptide. In any form, β-amyloid peptide is an approximately 39-43 amino acid fragment called the β-amyloid precursor protein (APP) of a glycoprotein that spans large membranes. Its 43 amino acid sequence is: 1 Asp Ala Glu Phe Arg His Asp Ser Gly Tyr 11 Glu Val His His Gln Lys Leu Val Phe Phe 21 Ala Glu Asp Val Gly Ser Asn Lys Gly Ala 31 Ile Ile Gly Leu Met Val Gly Gly Val Val 41 Ile Ala Thr (SEQ ID NO: 1) or a sequence substantially homologous thereto.

The “alkyl” preferably has 1 to 20 carbon atoms, and more preferably has 1 to carbon atoms.
It means six monovalent alkyl groups. The term exemplifies the group methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, n-hexyl and the like.

“Substituted alkyl” refers to alkoxy, substituted alkoxy, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, acyl, acylamino, acyloxy, amino, substituted amino, aminoacyl, aminoacyloxy, oxyacylamino, cyano , Halogen, hydroxyl, carboxyl, carboxylalkyl, keto, thioketo, thiol, thioalkoxy, substituted thioalkoxy, aryl, aryloxy, heteroaryl, heteroaryloxy,
Heterocyclic, heterocyclooxy, hydroxyamino, alkoxyamino, nitro, -SO-alkyl, -SO-substituted alkyl, -SO-aryl,-
SO- heteroaryl, -SO ₂ - alkyl, -SO ₂ - substituted alkyl, -SO ₂
An alkyl group (preferably having 1 to 10 carbon atoms) having 1 to 5 substituents (preferably 1 to 3 substituents) selected from the group consisting of -aryl and -SO ₂ -heteroaryl. .

The “alkylene” preferably has 1 to 10 carbon atoms, more preferably 1 carbon atom.
Means up to 6 divalent alkylene groups. The term is methylene (-CH ₂ -),
Ethylene (—CH ₂ CH ₂ —), propylene isomer (eg, —CH ₂ CH ₂ CH ₂₎
- and _{-CH (CH 3) CH 2 -} ) to illustrate the group, such as.

“Substituted alkylene” refers to alkoxy, substituted alkoxy, cycloalkyl, substituted cycloalkyl, cycloalkoxy, substituted cycloalkoxy, acyl, acylamino, acyloxy, amino, substituted amino, aminoacyl, aminoacyloxy, cyano, halogen, hydroxyl , Carboxyl, carboxylalkyl,
Keto, thioketo, thiol, thioalkoxy, substituted thioalkoxy, aryl,
Heteroaryl, heterocyclic, heterocyclooxy, nitro, -SO-
Alkyl, -SO- substituted alkyl, -SO- aryl, -SO- heteroaryl, -SO ₂ - alkyl, -SO ₂ - substituted alkyl, -SO ₂ - aryl and -S
It means an alkylene group having 1 to 3 substituents (preferably having 1 to 10 carbon atoms) selected from the group consisting of O ₂ -heteroaryl. In addition, the substituted alkylene groups include groups wherein two substituents on the alkylene group are fused to form one or more cycloalkyl, aryl, heterocyclic or heteroaryl groups fused to the alkylene group. . The condensed cycloalkyl group preferably contains 1 to 3 condensed ring structures.

“Alkenylene” is preferably 2-10 carbon atoms, more preferably 2 carbon atoms.
It means 2 to 6 divalent alkenylene groups. This term refers to ethenylene (-CH =
CH-), a propenylene isomer (eg, -CH_TwoCH = CH- and -C (CH _Three ) = CH-).

“Substituted alkenylene” refers to alkoxy, substituted alkoxy, cycloalkyl,
Substituted cycloalkyl, cycloalkoxy, substituted cycloalkoxy, acyl, acylamino, acyloxy, amino, substituted amino, aminoacyl, aminoacyloxy, cyano, halogen, hydroxyl, carboxyl, carboxylalkyl, keto, thioketo, thiol, thioalkoxy, substituted thioalkoxy , Aryl, heteroaryl, heterocyclic, heterocyclooxy, nitro, -SO
- alkyl, -SO- substituted alkyl, -SO- aryl, -SO- heteroaryl, -SO ₂ - alkyl, -SO ₂ - substituted alkyl, -SO ₂ - aryl and -
Alkenylene group having 1 to 3 substituents (preferably having 2 to 10 carbon atoms) selected from the group consisting of SO ₂ -heteroaryl). In addition, the substituted alkylene groups can be one or more cycloalkyl, aryl, heterocyclic, or two or more substituents on the alkylene group fused to the alkylene group. Includes groups that form heteroaryl groups.

“Alkaryl” refers to an -alkylene-aryl group having preferably 1 to 8 carbon atoms in the alkylene portion and 6 to 10 carbon atoms in the aryl portion. These alkaryl groups are exemplified by benzyl, phenethyl and the like.

“Alkoxy” means an “alkyl-O—” group. Preferred alkoxy groups include, for example, methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, tert-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” means an “-alkylene-O-alkyl” group,
Such as methylene methoxy (-CH ₂ OCH _3), ethylene-methoxy _{(-CH 2 CH 2 OCH 3)} , n- propylene - iso - propoxy _{(-CH 2 CH 2 CH 2 OCH} (C
H _{3) 2),} and the like methylene -t- butoxy _{(-CH 2 -O-C (CH} 3) 3).

“Alkylthioalkoxy” means an “-alkylene-S-alkyl” group such as methylenethiomethoxy (—CH ₂ SCH ₃ ), ethylenethiomethoxy (
_{-CH 2 CH 2 SCH 3),} n- propylene - thio - iso - propoxy (-CH ₂ C
_{H 2 CH 2 SCH (CH 3} ) 2), and the like methylenethio -t- butoxy _{(-CH 2 SC (CH 3)} 3).

The “alkenyl” preferably has 2 to 10 carbon atoms, more preferably 2 carbon atoms.
Have at least one, preferably at least one, two or more alkenyl unsaturated sites
Alkenyl group. Preferred alkenyl groups are ethenyl (-CH = CH _Two ), N-propenyl (—CH_TwoCH = CH_Two), Iso-propenyl (-C (CH_Three)
= CH_Two).

“Substituted alkenyl” refers to alkoxy, substituted alkoxy, cycloalkyl, substituted cycloalkyl, cycloalkoxy, substituted cycloalkoxy, acyl, acylamino, acyloxy, amino, substituted amino, aminoacyl, aminoacyloxy, cyano, halogen, hydroxyl , Carboxyl, carboxylalkyl,
Keto, thioketo, thiol, thioalkoxy, substituted thioalkoxy, aryl,
Heteroaryl, heterocyclic, heterocyclooxy, nitro, -SO-
Alkyl, -SO- substituted alkyl, -SO- aryl, -SO- heteroaryl, -SO ₂ - alkyl, -SO ₂ - substituted alkyl, -SO ₂ - aryl and -S
An alkenyl group as defined above having 1 to 3 substituents selected from the group consisting of O ₂ -heteroaryl.

“Alkynyl” preferably has 2 to 10 carbon atoms, more preferably 2 carbon atoms.
An alkynyl group having from 6 to 6, and having at least 1, preferably from 1 to 2, alkynyl unsaturation. Preferred alkynyl groups are ethynyl (-C≡C
H), propargyl (—CH ₂ C≡CH) and the like.

“Substituted alkynyl” refers to alkoxy, substituted alkoxy, cycloalkyl, substituted cycloalkyl, cycloalkoxy, substituted cycloalkoxy, acyl, acylamino, acyloxy, amino, substituted amino, aminoacyl, aminoacyloxy, cyano, halogen, hydroxyl , Carboxyl, carboxylalkyl,
Keto, thioketo, thiol, thioalkoxy, substituted thioalkoxy, aryl,
Heteroaryl, heterocyclic, heterocyclooxy, nitro, -SO-
Alkyl, -SO- substituted alkyl, -SO- aryl, -SO- heteroaryl, -SO ₂ - alkyl, -SO ₂ - substituted alkyl, -SO ₂ - aryl, -SO ₂ -
An alkynyl group as defined above having one to three substituents selected from the group consisting of heteroaryl.

“Acyl” refers to an alkyl-C (O) — group, a substituted alkyl-C (O) — group, a cycloalkyl-C (O) — group, a substituted cycloalkyl-C (O) — group, an aryl -C (O)-
Groups, heteroaryl-C (O)-and heterocyclic-C (O)-groups wherein alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, aryl, heteroaryl and heterocyclic are referred to herein. As defined in
Means

“Acylamino” refers to a —C (O) NRR group, wherein each R is independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, aryl, heteroaryl, or heterocyclic, or both. The R groups together form a heterocyclic group, and alkyl, substituted alkyl, aryl, heteroaryl and heterocyclic are as defined herein).

“Amino” refers to the group —NH ₂ .

“Substituted amino” refers to the group —N (R) ₂ wherein each R is independently hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, cycloalkyl, substituted cycloalkyl, Or R is selected from the group consisting of heteroaryl, heterocyclic, or both R together form a heterocyclic group). When both R groups are hydrogen, the -N (R) ₂ group is an amino group. Examples of substituted amino groups are mono- and di-alkylamino, mono- and di- (substituted alkyl) amino, mono- and di-arylamino, mono- and di-heteroarylamino, mono- and di-heterocyclyl. Includes click amino and asymmetric di-substituted amines having different substituents selected from alkyl, substituted alkyl, aryl, heteroaryl and heterocyclic.

The term “amino-blocking group” or “amino-protecting
) Group "prevents undesired reactions on the amino group when it is attached to the amino group, and is removed by conventional chemical and / or enzymatic methods to regenerate the amino group. Means any group obtained. Any amino blocking group can be used in the present invention. Typically, the amino blocking group is chosen such that the resulting blocked amino group is unreactive to the particular reagents or reaction conditions used in the subsequent predetermined reaction or reactions. Examples of suitable amino blocking group, tert- butoxycarbonyl (Boc), benzyloxycarbonyl (Cbz), acetyl, 1- (1 ^'- adamantyl) -1-methyl-ethoxycarbonyl (Acm), allyloxycarbonyl (Aloc ), Benzyloxymethyl (Bom), 2-p-biphenylisopropyloxycarbonyl (Bp)
oc), tert-butyldimethylsilyl (Bsi), benzoyl (Bz), benzyl (Bn), 9-fluorenyl-methyloxycarbonyl (Fmoc), 4
-Methylbenzyl, 4-methoxybenzyl, 2-nitrophenylsulfenyl (
Nps), 3-nitro-2-pyridinesulfenyl (NPys), trifluoroacetyl (Tfa), 2,4,6-trimethoxybenzyl (Tmob), trityl (Trt) and the like. If desired, amino-blocking groups covalently linked to a solid support can also be used.

“Aminoacyl” refers to a —NRC (O) R group, where each R is independently hydrogen, alkyl, substituted alkyl, aryl, heteroaryl or heterocyclic, and includes alkyl, substituted alkyl, aryl , Heteroaryl and heterocyclic are as defined herein).

“Aminoacyloxy” refers to an —NRC (O) OR group, 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).

“Acyloxy” refers to an alkyl-C (O) O— group, a substituted alkyl-C (O) O group, a cycloalkyl-C (O) O— group, a substituted cycloalkyl-C (O) O group. , Aryl-C (O) O-, heteroaryl-C (O) O- and heterocyclic-C
An (O) O- group is meant wherein alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, aryl, heteroaryl and heterocyclic are as defined herein.

“Aryl” means an unsaturated aromatic carbocyclic group having 6 to 14 carbon atoms having a single ring (eg, phenyl) or multiple condensed rings (eg, naphthyl or anthryl). Preferred aryls include, for example, phenyl, naphthyl and the like.

Unless indicated otherwise in the definition for aryl substituents, the aryl groups may optionally be acyloxy, hydroxy, acyl, alkyl, alkoxy, alkenyl, alkynyl, substituted alkyl, substituted alkoxy, substituted alkenyl, substituted alkynyl, amino, substituted Amino, aminoacyl, acylamino, alkaryl, aryl, aryloxy, azide, carboxyl, carboxylalkyl, cyano, halo, nitro, heteroaryl, heterocyclic, aminoacyloxy,
Oxyacylamino, thioalkoxy, substituted thioalkoxy, thioaryloxy, thioheteroaryloxy, -SO-alkyl, -SO-substituted alkyl,-
SO- aryl, -SO- heteroaryl, -SO ₂ - alkyl, -SO ₂ - substituted alkyl, -SO ₂ - aryl, -SO ₂ - 1 to 5 substituents selected from the group consisting of heteroaryl and trihalomethyl May be substituted with a group. Preferred substituents include alkyl, alkoxy, halo, cyano, nitro, trihalomethyl and thioalkoxy.

“Aryloxy” means an aryl-O— group in which the aryl group is as previously described, optionally including a substituted aryl group as defined above.

“Carboxyalkyl” refers to “—C (O) O-alkyl” groups and “—C (O
A) -substituted alkyl "group wherein alkyl is as defined above.

“Cycloalkyl” means a cyclic alkyl group having 3 to 12 carbon atoms having a single ring or multiple condensed rings (including a condensed ring, a bridged ring, a spiro ring and a combination thereof). The cycloalkyl ring may be optionally fused to an aryl, heteroaryl, or heterocycle ring. These cycloalkyl groups include, for example, a monocyclic structure (eg, cyclopropyl, cyclobutyl, cyclopentyl, cyclooctyl, etc.) or a polycyclic structure (eg, adamantanyl).

“Substituted cycloalkyl” refers to alkoxy, substituted alkoxy, cycloalkyl
, Substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, acyl, a
Silamino, acyloxy, amino, substituted amino, aminoacyl, aminoacyl
Oxy, oxyacylamino, cyano, halogen, hydroxyl, carboxyl
, Carboxylalkyl, keto, thioketo, thiol, thioalkoxy, substituted thio
Oalkoxy, aryl, aryloxy, heteroaryl, heteroaryl
Xy, heterocyclic, heterocyclooxy, hydroxyamino, alkoxy
Cyamino, nitro, -SO-alkyl, -SO-substituted alkyl, -SO-aryl
, -SO-heteroaryl, -SO_Two-Alkyl, -SO_Two-Substituted alkyl, -SO _Two -Aryl and -SO_Two-1-5 selected from the group consisting of heteroaryl (
(Preferably 1 to 3) cycloalkyl groups having a substituent.

“Cycloalkenyl” means a monocyclic ring or a cyclic alkenyl group having at least one internal unsaturation and having 4 to 8 carbon atoms. Examples of suitable cycloalkenyl groups include, for example, cyclobut-2-enyl, cyclopenta-3-enyl, cyclooct-3-enyl, and the like.

“Substituted cycloalkenyl” refers to alkoxy, substituted alkoxy, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, acyl,
Acylamino, acyloxy, amino, substituted amino, aminoacyl, aminoacyloxy, oxyacylamino, cyano, halogen, hydroxyl, carboxyl, carboxylalkyl, keto, thioketo, thiol, thiolalkoxy,
Substituted thioalkoxy, aryl, aryloxy, heteroaryl, heteroaryloxy, heterocyclic, heterocyclooxy, hydroxyamino, alkoxyamino, nitro, -SO-alkyl, -SO-substituted alkyl, -SO-
Aryl, -SO- heteroaryl, -SO ₂ - alkyl, -SO ₂ - substituted alkyl, -SO ₂ - aryl and -SO ₂ - cycloalkenyl having from 1 to 5 substituents selected from the group consisting of heteroaryl Means a group.

“Halo” or “halogen” means fluoro, chloro, bromo and iodo, preferably fluoro or chloro.

“Heteroaryl” means 1 to 15 carbon atoms and 1 to 4 heteroatoms selected from oxygen, nitrogen and sulfur in at least one ring (if more than one ring).
Aromatic groups.

Unless indicated otherwise in the definition of heteroaryl substituents, the heteroaryl groups may be optionally acyloxy, hydroxyl, 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, hetero Cyclic, aminoacyloxy, oxyacylamino, thioalkoxy, substituted thioalkoxy, thioaryloxy, thioheteroaryloxy, -SO-alkyl, -SO-substituted alkyl, -SO-aryl, -SO-heteroaryl, -SO ₂ -alkyl, -S
O ₂ - substituted alkyl, -SO ₂ - aryl and -SO ₂ - may be substituted with 1 to 5 substituents selected from the group consisting of heteroaryl and trihalomethyl. These hetaryl groups may have a single ring (eg, pyridyl or furyl) or multiple condensed rings (eg, indolodinyl or benzothienyl).

“Heteroaryloxy” refers to the group “—O-heteroaryl”.

“Heterocycle” or “heterocyclic”
"Is a monovalent saturated or unsaturated group having 1 to 15 carbon atoms and having 1 to 4 heteroatoms monocyclic and polycondensed rings selected from nitrogen, sulfur or oxygen in at least one ring. means.

Unless otherwise indicated in the definition of heterocyclic substituents, the heterocyclic substituents may be alkoxy, substituted alkoxy, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, acyl, acylamino,
Acyloxy, amino, substituted amino, aminoacyl, aminoacyloxy, oxyacylamino, cyano, halogen, hydroxyl, carboxyl, carboxylalkyl, keto, thioketo, thiol, thioalkoxy, substituted thioalkoxy, aryl, aryloxy, heteroaryl, heteroaryl Oxy, heterocyclic, heterocyclooxy, hydroxyamino, alkoxyamino, nitro, -SO-alkyl, -SO-substituted alkyl, -SO-aryl, -SO-
Heteroaryl, -SO ₂ - alkyl, -SO ₂ - substituted alkyl, -SO ₂ - aryl and -SO ₂ - may be substituted with 1 to 5 substituents selected from the group consisting of heteroaryl. These heterocyclic groups may have a single ring or multiple condensed rings. Preferred heterocyclics include morpholino, piperidinyl and the like.

“Monocyclic heterocycle” means a monocyclic heterocycle group, for example, pyrrolidinyl, morpholino and the like.

“Bicyclic heterocycle” refers to a fused, heterocyclic, heterocycle wherein at least one ring contains a heteroatom and the other ring is selected from the group consisting of cycloalkyl, cycloalkenyl, aryl, heteroaryl and heterocyclic. A heterocyclic group that includes a bicyclic system, which may be spiro or bridged, is meant. Fused bicyclic heterocyclic ring systems include, for example, 3- (1,2,3,4-tetrahydroisoquinolinyl) and the like.

“Tricyclic heterocycle” means that each ring system is independently fused, spiro or bridged, wherein at least one ring has a heteroatom and the other two rings are cycloalkyl, cycloalkenyl , Aryl, heteroaryl and heterocyclic means a heterocyclic group containing a tricyclic ring. When the remaining two rings are cycloalkyl, cycloalkenyl or heterocyclic, these rings may optionally be spiro-linked.

Examples of heterocycles and heteroaryls include pyrrole, furan, imidazole, pyrazole, pyridine, pyrazine, pyrimidine, pyridazine, indolizine, isoindole, indole, indazole, purine, quinolidine, isoquinoline, quinoline, phthalazine, naphthyl Pyridine, quinoxaline, quinazoline, cinnoline, pteridine, carbazole, carbolin, phenanthridine, acridine, phenanthrin, isothiazole, phenazine, isoxazole, phenoxazoline, phenothiazoline, imidazolidine, imidazoline, piperidine, piperazine, indoline, morpholino, Including heterocycles which also contain N-alkoxy-nitrogen, such as piperidinyl, tetrahydrofuranyl, etc. It is not limited to.

“Heterocyclooxy” refers to the group “—O-heterocycle”.

“Keto” or “oxo” refers to the group “＝ O”.

“Oxyacylamino” refers to a —OC (O) NRR group, wherein each R is independently hydrogen, alkyl, substituted alkyl, aryl, heteroaryl or heterocyclic, 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” means an aryl-S— group in which the aryl group is as previously described, and optionally includes a substituted aryl group as defined above.

“Thioheteroaryloxy” means a heteroaryl-S— group in which the heteroaryl group is as previously described, and optionally also includes a hetero-substituted aryl group as defined above. I do.

“Thioketo” refers to the group “」 S ”.

The term “5,7-dihydro-6H-dibenz [b, d] azepin-6-one”
formula:

Embedded image [Where the atoms and bonds are numbered and lettered for naming, respectively. ] Means a polycyclic ε-caprolactam ring system having

The term “5,6-dihydro-4H-quino [8,1-ab] benzazepine-8 (9H)
"-On" means the formula:

Embedded image [Where the atoms and bonds are numbered and lettered for naming, respectively. ] Means a polycyclic ε-caprolactam ring system having

The term “1,3,4,7,12,12a-hexahydropyrido [2,1-b] [3] benzazepin-6 (2H) -one” has the formula:

Embedded image [Where the atoms and bonds are numbered and lettered for naming, respectively. ] Means a polycyclic ε-caprolactam ring system having

The term “4,5,6,7-tetrahydro-3,7-methano-3H-3-benzazonin-2 (1H) -one” has the formula:

Embedded image [Where the atoms and bonds are numbered and lettered for naming, respectively. ] Means a polycyclic ε-caprolactam ring system having

With respect to any of the above groups that contain one or more substituents, those groups are any substituents that are sterically impractical and / or synthetically not feasible. Or, it should be understood that no substitution pattern is contained.

“Pharmaceutically acceptable salts” are pharmaceutically acceptable salts of the compounds of Formula I, derived from a number of organic and inorganic counterions well known in the art. For example, sodium, potassium, calcium, magnesium,
Ammonium, tetraalkylammonium, etc .; and when the molecule has basic functionality, salts of organic or inorganic acids (eg, hydrochloride, hydrobromide, tartrate, methanesulfonate, Acetate, maleate, oxalate, etc.) can be used as pharmaceutically acceptable salts

The phrase “protecting group” or “blocking group” refers to a group attached to one or more hydroxyl, thiol, carboxyl or other protectable functional groups of a compound. Means any group that prevents a reaction from taking place at these groups and that can be removed by conventional chemical and enzymatic steps to regenerate unprotected functional groups. The particular removable blocking group used is not critical and preferred removable hydroxyl blocking groups are those substituted with conventional substituents (e.g., allyl, benzyl, acetyl, chloroacetyl, thiobenzyl, benzylidine, phenacyl, t-butyl-diphenyl). Silyl), and any other that can be chemically introduced onto the hydroxyl function and subsequently selectively removed by chemical or enzymatic methods under mild conditions compatible with the properties of the product Including the group of

Preferred carboxyl protecting groups include esters (eg, methyl, ethyl, propyl, t-butyl, etc.), which can be removed by mild hydrolysis reaction conditions compatible with the properties of the product.

Preparation of Compounds When n is 1, the compounds of formula I are readily prepared by conventional acylation reactions followed by reductive amination reactions, as illustrated in Scheme 1 below. Reaction formula 1

Embedded image

As shown in Scheme 1, protected amino acid 1 (where B is a protecting group) is converted to 2 (where R ⁶ , R ⁷ , R ⁸ , p, and (q is as defined above), followed by deprotection to give Intermediate 3 . One of skill in the art will recognize that amine 2 is merely typical, and
One skilled in the art will recognize that amino derivatives of any of the other ring systems described herein may be used in this reaction. Typically, the reaction is performed using conventional coupling reagents and methods, and at least a stoichiometric amount of amino acid 1 and amine 2 . For example, promote coupling by using a well-known coupling reagent such as carbodiimide, with or without well-known additives such as N-hydroxysuccinimide, 1-hydroxybenzotriazole, etc. can do. The reaction is usually performed in an inert aprotic polar diluent such as dimethylformamide, dichloromethane, chloroform, acetonitrile, tetrahydrofuran and the like.

Acid 1 can also be coupled to amine 2 prepared using a polymer-supported carbodiimide peptide coupling reagent. For example, polymer-supported EDC is described. (Tetrahedron Letters, 34 (48), 7685 (1993)) ¹¹ . In addition, novel carbodiimide coupling reagents, PEPC, and their corresponding polymer-supported types have been disclosed and are very useful for the preparation of such compounds. Polymers suitable for preparing polymer-supported coupling reagents are either commercially available or could be prepared by methods well known to those skilled in the polymer arts. Suitable polymers must have pendant side chains that retain moieties that react with the terminal amine of the carbodiimide. Such reactive moieties include chloro, bromo, iodo and methanesulfonyl. Preferably, the reactive moiety is a chloromethyl group. Further, the basic skeleton of the polymer (back
bone) must be inert to both the carbodiimide and the reaction conditions using the final polymer-bound coupling reagent.

Certain hydroxymethylated resins could be converted to chloromethylated resins useful for making polymer-supported coupling reagents. Examples of these hydroxylated resins include 4-hydroxymethylphenyl-acetamidomethyl resin (Pam Resin) available from Advanced Chemtech (Louisville, Kentucky, USA).
Contains 4-benzyloxybenzyl alcohol resin (Wang Resin) (Advanced C
hemtech 1993-1994 catalog, page 115). The hydroxymethyl groups on these resins could be converted to the desired chloromethyl groups by any of a number of methods well known to those skilled in the art. A preferred resin is chloromethylated styrene because commercially available products can be easily used.
/ Divinylbenzene resin. As the name implies, these resins are already chloromethylated and do not require chemical modification before use. These resins are known as commercial Merrifield resins and are available from Aldrich Chemical Company (Milwau).
kee, Wisconsin, USA) (see Aldrich 1994-1995 catalog, page 899)
). The production method of PEPC and its polymer-supported type is shown in the following reaction formula 1A.

Reaction formula 1A

Embedded image

[0123] Such methods are described in U.S. Patent Application No. 60 / 019,790 No. ¹⁴ (June 14, 1996 application, the application is incorporated herein by reference) it is fully described. Easy, PEPC
Is prepared by first reacting ethyl isocyanate with 1- (3-aminopropyl) pyrrolidine. The obtained urea is treated with 4-toluenesulfonyl chloride to obtain PEPC. A polymer-supported mold is prepared by reacting PEPC with a suitable resin under standard conditions to obtain the desired reagent. The carboxylic acid coupling reaction using these reagents is carried out at about ambient to about 45 ° C. for about 3 to 120 hours. Typically, the reaction can be washed with CHCl ₃ and the residual organic layer concentrated under reduced pressure to isolate the product. As mentioned above, the isolation of the product from the reaction using the polymer binding reagent is very simple, it is only necessary to filter the reaction mixture and then concentrate the filtrate under reduced pressure. Alternatively, the acid halide of compound 1 can be used in reaction (1), and if so, is typically used in the presence of a suitable base to capture the acid generated during the reaction. . Suitable bases include, by way of example, triethylamine, diisopropylethylamine, N-methylmorpholine, and the like. The intermediate 3 is then obtained by removal of the amine protecting group using conventional methods and reagents. Intermediate 3 is then coupled with an excess of aldehyde 4 , preferably 1.1 to 2 equivalents of 4 , and an excess, preferably 1.1 to 1.5 equivalents, of a reducing agent such as sodium cyanoborohydride, of formula I Obtain the compound. Generally, the reaction is carried out in an essentially inert diluent, such as methanol, at a temperature ranging from about O <0> C to about 50 <0> C, preferably at ambient temperature for about 0.5 to 3 hours.

[0124] Alternatively, the compounds of the formula I have the formula 5:

Embedded image Wherein R ¹ , R ² , B ¹ , T, X ′ and X ″ are as defined above, are reacted with the amine 2 under the above-mentioned acylation reaction conditions. It can be prepared by deprotecting the amino protecting group (B ¹ ) using conventional reagents and methods known in the art.The compound of formula I wherein n is 2 is represented by the following reaction scheme 2. The intermediate 10 can be prepared by first coupling an amine such as 2 with the protected amino acid 9 and then deprotecting and converting the resulting intermediate 10 as described in Scheme 1 above.

Reaction formula 2

Embedded image Alternatively, when n is 2, the aldehyde or carboxylic acid unit could be coupled to the amine before the reaction using a suitable reductive amination or acylation method as described above. The resulting intermediate is then coupled with an amine such as 2 to give a precursor of the compound of formula I. Compounds of formula I could also be prepared by any of the methods described below by conventional means known to those skilled in the art.

Reductive alkylation as shown in Reaction Scheme 3 below,

Embedded image [Wherein, R ¹ , T, X ′, X ″, Y, W, and Z have the same meanings as described above and are described in detail in the above Reaction Scheme 1.] Ring opening, Reaction formula 4

Embedded image [Wherein R ¹ , Y, and W are as defined above. Or nucleophilic substitution shown in the following reaction formula 5. Reaction formula 5

Embedded image [Wherein R ¹ , Y, W and Z are as defined above, and X is a leaving group known to those skilled in the art such as halogen, tosylate, mesylate, triflate and the like. ]

The ring opening reaction of the epoxide ring results in a β-hydroxyl group (β to amine). The conditions used for such reactions are well known in the art. Similarly, a nucleophilic substitution reaction provides a convenient method for obtaining an amino acid derivative, for example, by reacting a primary amine with, for example, an α-haloacetic acid derivative (this reaction is described in International Patent Application Publication No. 22441). In any of the above Reaction Formulas 3-5, the substituent may be protected by a protecting group known to those skilled in the art, if necessary, to prevent a reaction with a reactive group.

Synthesis of Aldehyde and Carboxylic Acid Starting Materials In the aldehyde and carboxylic acid used in the above reaction, n is 1 or 2, etc.
Characteristics selected based on the availability of commercially available starting materials and the ease of compound production
It can be easily synthesized by various synthesis routes having a fixed route. A. Synthesis of aldehyde Formula used in the present invention4The aldehyde is converted to the corresponding alcohol using a conventional oxidizing agent.
Can be easily produced by oxidizing the catalyst. For example, primary alcohol
Swern oxidation of provides the corresponding aldehyde. Typically, the reaction is
Alcohol and oxalyl chloride in the presence of a quaternary amine such as ethylamine and
It is carried out by contacting with a mixture of dimethyl sulfoxide. Generally, this
Reaction in an inert diluent such as dichloromethane at an initial temperature of about -78 ° C, followed by
At ambient temperature for about 0.25 to 2 hours to give the aldehyde. Used for this reaction
Alcohols are commercially available or are prepared using conventional reagents and methods.
Can be For example, a suitable alcohol is lithium aluminum hydride
The corresponding amino acid or amino acid ester is converted using a conventional reducing agent such as
It can be produced by reduction. B. Synthesis of carboxylic acid Formula1The carboxylic acid is commercially available or can be obtained by a method well known in the art.
It can be produced by esterifying a more corresponding α-amino acid. formula Five The acid has the formulaFourIs converted to esterified α- under the above-mentioned reductive amination reaction conditions.
It can be produced by conventional coupling with the amino group of an amino acid.
Wear.

Preparation of Cyclic Compounds (eg, Benzazepinone, Dibenzazepinone, Benzodiazepine and Related Compounds) Are the cyclic compounds (eg, 2 ) and their amino-substituted derivatives used in the above reactions known in the art? Or by art-recognized methods using commercially available starting materials and reagents.

For example, 5,7-dihydro-6H-dibenz [b, d] azepin-6-one is described in R.
It can be prepared by cyclizing the chloromethylamide intermediate using the method described in Tetrahedron Letters 1971, 8, 667-670 ¹² by FC Brown et al. And the references cited therein.

In addition, a representative cyclic compound, namely 5,7-dihydro-6H-dibenz [b
Scheme 6 illustrates the synthesis of [, d] azepin-6-one. As will be readily apparent to those skilled in the art, the synthetic methods illustrated below in Scheme 6 and the reaction conditions thereof can be modified by selecting appropriate starting materials and reagents to provide suitable The production of other cyclic amines becomes possible. Reaction formula 6

Embedded image

As shown in Reaction Scheme 6, 5,7-dihydro-6H-dibenz [b, d] azepine-6
-One derivative 23 (where R ⁶ , R ⁷ , p and q are as described above)
It can be easily produced from the -bromotoluene derivative 18 and the 2-bromoaniline derivative 20 in several steps. In this synthesis method, the 2-bromotoluene derivative 18
Is converted to the corresponding 2-methylphenylboronic ester 19 first. The reaction is typically performed in an inert diluent (e.g., THF) at about -80 <0> C to about -60.
Treat 18 with about 1.0 to about 2.1 equivalents of an alkyllithium reagent, preferably sec-butyllithium or tert-butyllithium, for about 0.25 to about 1 hour at a temperature in the range of 0 ° C. By doing. The resulting lithium anion is then treated in situ with an excess (preferably 1.5 equivalents) of a trialkyl borate (eg, trimethyl borate). The reaction is first carried out at -80 ° C to -6
Perform at 0 ° C., then raise the temperature from about 0 ° C. to about 30 ° C. for about 0.5 to about 3 hours. The resulting boronic acid methyl ester is typically not isolated, but can be converted to the pinacol ester by treating the reaction mixture with an excess (preferably about 2.0 equivalents) of pinacol in situ. preferable. The reaction carried out typically about 12 hours to about 24 hours at ambient temperature, 2-methylphenyl boronic acid ester 19 (both R ^a groups are taken _{together, -C (CH 3) 2 C} (CH 3 ) _2- is preferably formed).

In another reaction, the amino group of the 2-bromoaniline derivative 20 has about 20
Converted to the N-Boc derivative 21 by treatment with 0.0 to about 1.5 equivalents of di-tert-butyl dicarbonate. Typically, the reaction is between 25 ° C and about 100 ° C.
At a temperature in the range of about 12 hours to about 48 hours to provide N-Boc-2-
The bromoaniline derivative is obtained.

As further exemplified in Reaction Scheme 6, the 2-methylphenylboronic acid ester 19 and the N-Boc-2-bromoaniline derivative 21 are then subjected to a coupling reaction to obtain a biphenyl derivative 22. This reaction typically involves the reaction of 21 with a palladium catalyst (
Tetrakis (triphenylphosphine) palladium (0) is preferred) in the presence of
It is carried out by contacting with about 1.0 to about 1.2 equivalents of 19 and about 1.0 to about 1.2 equivalents of potassium carbonate. Generally, the coupling reaction is carried out under an inert atmosphere at a temperature in the range of about 50 ° C. to about 100 ° C. for about 6 hours to about 24 hours with the diluent (
20% water / dioxane is preferred).

The biphenyl derivative 22 is then carboxylated at its 2-methyl group, followed by cyclization to form ε-caprolactam, by 5,7-dihydro-6
It is easily converted to H-dibenz [b, d] azepin-6-one 23. The carboxylation reaction typically involves 22 to about 2.0 to about 2.5 equivalents of a suitable base (e.g.,
sec-butyllithium, tert-butyllithium, etc.) and an inert diluent (
For example, in THF) at a temperature ranging from about -100C to about -20C, from about 0.5 to about 6
The reaction is performed by contacting for a time. The carboxylate is then obtained by treating the resulting dianion with an excess of anhydrous carbon dioxide.
The carboxylate is then placed in a suitable diluent (eg, methanol) for about 2
Treatment with excess hydrogen chloride at a temperature in the range of 5 ° C to about 100 ° C gives 5,7-dihydro-6H-dibenz [b, d] azepin-6-one 23. A variety of other cyclic compounds can be made by routine modifications of the above method.

A preferred synthesis for amination of representative compounds is illustrated in Scheme 7.
The improvement of Scheme 7 and subsequent reaction conditions by the selection of appropriate starting materials and reagents allows for the preparation of other amino acids suitable for use in the present invention.
It will be readily apparent to one skilled in the art. Reaction formula 7

Embedded image

As shown in Reaction Scheme 7, 5,7-dihydro-6H-dibenz [b, d] azepine-6
-One 23 is optionally N-alkylated using conventional reagents and conditions,
The 7-alkyl-5,7-dihydro-6H-dibenz [b, d] azepin-6-one derivative 24 is obtained. Typically, the reaction is first performed with an inert diluent (eg, DMF
, THF, etc., at a temperature in the range of about -78 ° C to about -50 ° C, for about 0.25 hours to about 6 hours, about 1.0 to about 1.5 equivalents of a suitable base (e.g., hydrogen). Sodium chloride,
(Bis (trimethylsilyl) amide, etc.) and 23. The resulting anion is then reacted in situ with an excess (preferably about 1.1 to about 2.0 equivalents) of an alkyl halide, substituted alkyl halide, cycloalkyl halide, etc. (typically chloride, bromide or (Iodide).
The reaction is typically carried out at a temperature in the range of about 0 ° C. to about 60 ° C. for about 1.0 to about 48 hours to give the 7-alkyl-5,7-dihydro-6H-dibenz [b, d] azepine -6
The -one derivative 24 is obtained.

The 24 was then added in excess (about 1.0 to about 2.0 equivalents of alkyl nitrite,
About 1.0-1.5 equivalents is preferred) and a 7-alkyl-5,5 by contact reaction with a suitable base such as sodium bis (trimethylsilyl) amide.
7-Dihydro-6H-dibenz [b, d] azepin-6-one 24 is oximinated. Suitable alkyl nitrites used in this reaction include, for example, butyl nitrite, isoamyl nitrite, and the like. The reaction is typically performed in an inert diluent (such as THF) at a temperature ranging from about -10 ° C to about 20 ° C for about 0.5 to about 6 hours to give the 7-alkyl-5- Oximo-5,7-dihydro-6H-dibenz [b, d] azepin-6-one derivative 25 is obtained.

[0139] The 5-amino- is then reduced by 25 reduction reactions using conventional reagents and conditions.
7-alkyl-5,7-dihydro-6H-dibenz [b, d] azepin-6-one 2
Get 6. This reduction reaction is performed by hydrogenating the oxime 25 in the presence of a catalyst (for example, Raney nickel). The reaction typically takes about 200 p
at a temperature of about 70 ° C. to about 120 ° C. under si to about 600 psi for about 8 to about 48 hours;
Performed in diluent, preferably a mixture of ethanol and ammonia (about 20: 1). Alternatively, in another preferred method, the oximes may be reduced between 10% Pd / C and about 30 to about 60 psi at a temperature in the range of about 20C to about 50C for about 4 hours. The resulting 5-amino-7-alkyl-5,7-dihydro-6H
-Dibenz [b, d] azepin-6-one 26 is purified using commonly known methods (e.g. recrystallization and / or chromatography).

Alternatively, 5,7-dihydro-6H-dibenz [b, d] azepin-6-one 2
6 with 5,5-dihydro-6H-dibenz [b, d] azepin-6-one 23
It can be produced by first producing the iodine derivative 27. In this reaction typically as described by AO King et al ^13, excess 23 (about 1.2 to about 2.
5 equivalents) in the presence of a trialkylamine (e.g., triethylamine, diisopropylethylamine, TMEDA, etc.) at a temperature in the range of about -20 <0> C to about 0 <0> C for about 3 minutes to about 30 minutes, the excess ( about 1.2 to about 2.5 is treated with trimethylsilyl iodide equivalents are preferred), and then carried out by adding from about 1.1 to about 2.0 equivalents of iodine (I _2). Typically, after the addition of iodine, the reaction is stirred at a temperature in the range of about 0 ° C to about 20 ° C for about 2 hours to about 4 hours to provide 5-iodo-5,7-dihydro-6H-dibenz [ [b, d] azepin-6-one derivative 27
Get.

Next, a substitution reaction of iodine derived from 27 using an alkali metal azide was carried out.
5-azido-5,7-dihydro-6H-dibenz [b, d] azepin-6-one,
Get 8. Typically, the reaction is carried out in an inert diluent (eg, DMF) at a temperature ranging from about 0 ° C. to about 50 ° C. for about 12 hours to about 48 hours, about 1.1 to about 1.5. The reaction is carried out by contacting with an equivalent amount of sodium azide.

The azide derivative 28 is then reduced to the corresponding amino derivative 29 using conventional methods and reagents. For example, the azido group is preferably reduced by contacting 28 with an excess (preferably about 3 equivalents) of triphenylphosphine in a diluent (eg, a mixture of THF and water is preferred). The reduction reaction is typically carried out at a temperature in the range of about 0 ° C. to about 50 ° C. for about 12 to about 48 hours to produce 5
-Amino-5,7-dihydro-6H-dibenz [b, d] azepin-6-one 29 is obtained.

The 29 amino groups are then protected or blocked using a conventional amino blocking group. Compound 29 is prepared using about 1.0 to about 1.1 equivalents of di-tert-butyl dicarbonate in the presence of an excess (preferably about 2 to about 3 equivalents) of a trialkylamine (e.g., triethylamine). Treatment. The reaction is typically performed in an inert diluent (e.g., THF) at a temperature in the range of about 0C to about 50C for 3 hours to about 24 hours to give 5- (N-Boc-amino)-. 5,7-Dihydro-6H-dibenz [b, d] azepin-6-one 30 is obtained.

Compound 30 is then optionally N-alkylated and, after deblocking of the amino group, 5-amino-7-alkyl-5,7-dihydro-6H-dibenz [b, d] azepin-6-one 26 obtain. The N-alkylation reaction typically involves 30 to about 1.
In the presence of 0 to about 1.5 equivalents of a suitable base, such as cesium carbonate, about 1.
It is carried out by treating with 0 to about 1.5 equivalents of an alkyl halide, substituted alkyl halide or cycloalkyl halide. The reaction is generally carried out in an inert diluent (such as DMF) at a temperature ranging from about 25 ° C to about 100 ° C for about 1 hour.
Perform for 2 hours to about 48 hours.

Representative alkyl halides, substituted alkyl halides and cycloalkyl halides suitable for use in this N-alkylation reaction include, for example, 1-iodo-2-methylpropane, methyl bromoacetate, 1-chloro-3 , 3-dimethyl-2
-Butanone, 1-chloro-4-phenylbutane, bromomethylcyclopropane,
1-bromo-2,2,2-trifluoroethane, bromocyclohexane, 1-bromohexane and the like.

The N-Boc protecting group was then removed using conventional methods and reagents to give 5-
Amino-7-alkyl-5,7-dihydro-6H-dibenz [b, d] azepine-6
-Get ON 26. The deblocking reaction typically involves the N-Boc compound 30 in an inert diluent (eg, 1,4-dioxane) at a temperature ranging from about 0 ° C. to about 50 ° C. for about 2 hours to about 8 hours. , Using anhydrous hydrogen chloride. The resulting 5-amino-7-alkyl-5,7-dihydro-6H-dibenz [b, d] azepin-6-one 26 is generally prepared by well-known methods (eg, recrystallization and / or chromatography). ).

5-Amino-7-alkyl-5,7-dihydro-6H-dibenz [b, d] azepin-6-one 26 can also be prepared by an azide transfer reaction, as illustrated in Scheme 8. . Reaction formula 8

Embedded image

As shown in Reaction Scheme 8, 5,7-dihydro-6H-dibenz [b, d] azepine-6
-One 23 is first N-alkylated using conventional reagents and conditions as described above to give 7-alkyl-5,7-dihydro-6H-dibenz [b, d] azepine-6.
The -one derivative 24 is obtained.

Subsequently, 7-alkyl-5,7-dihydro-6H-dibenz [b, d] azepine-
The 6-one 24 was converted to 5-azido-7-alkyl-5,7- using an azide transfer reagent.
Dihydro-6H-dibenz [b, d] azepin-6-one 31 is obtained. Typically,
The reaction is first performed in an inert diluent (e.g., THF) at about -90C to about -60C.
Catalytic reaction of 24 with an excess (preferably about 1.0 to about 1.5 equivalents) of a suitable base, such as lithium diisopropylamine, for about 0.25 to about 2.0 hours at a temperature in the range of 0 ° C. By doing it. Then, the resulting anion was added in excess (about 1.
Treatment with 1 to about 1.2 equivalents of an azide transfer reagent (e.g., 2,4,6-triisopropylbenzenesulfonyl azide (trityl azide)). The reaction is typically carried out at a temperature ranging from about -90C to about -60C, from about 0.25 to about 2.
Perform for 0 hours. The reaction mixture is then typically treated with an excess of glacial acetic acid, and the mixture is allowed to warm to ambient temperature and then to about 35 ° C to about 50 ° C for about 2 hours.
Heat for ４4 hours to give the 5-azido-7-alkyl-5,7-dihydro-6H-dibenz [b, d] azepin-6-one derivative 31. The 5-amino-7-alkyl-5,5 was then reduced by the above-mentioned reduction reaction of 31 using usual reagents and conditions.
7-Dihydro-6H-dibenz [b, d] azepin-6-one 26 is obtained.

If desired, 5-amino-7-alkyl-5,7-dihydro-6H-dibenz [
The aryl ring of b, d] azepin-6-one 26 and its analogous or related compounds can be partially or completely saturated by treatment with hydrogen in the presence of a hydrogenation catalyst. Typically, the reaction is performed by treating 26 with hydrogen at a pressure of about 10 to about 100 psi in the presence of a catalyst (eg, rhodium / carbon). The reaction is typically performed in a suitable diluent (such as, for example, ethyl acetate / acetic acid (1: 1)) at a temperature ranging from about 20 ° C. to about 100 ° C. for about 12 hours to 96 hours.

Another method of making intermediates useful in the present invention is described in US patent application Ser. No. 09 / 102,726 (
Filed June 22, 1998, `` Polycyclic α-Amino-ε-caprolactams and Related
Comppounds "), the disclosure of which is hereby incorporated by reference.

In addition, for a number of benzapinones and related compounds, see Busacca et al., Tetrahedron Lett., 33, 165-168 (1992); Crosisier et al., US Pat. No. 4,080,449; JA Robl et al., Tetrahedron Lett. . 36 (10), 1
593-1596 (1995); Flynn et al., J. Med. Chem. 36, 2420-2423 (1993); Or
Tetrahedron, 36, 1017-1021 (1980) by ito et al .; J. Org. Ch. by Kawase et al.
em. 54, 3394-3403 (1989); Robl et al., Bioorg. Med. Chem. Lett., 4, 178.
9-1794 (1994); Skiles et al., Bioorg. Med. Chem. Lett., 3, 773-778 (199).
3); Grunewald et al., J. Med. Chem., 39 (18), 3539- (1996); Warshawsky.
Bioorg. Med. Chem. Lett., 6, 957-962 (1996); Ben-Ishai et al.
Tetrahedron, 43, 439-450 (1987); Van Neil et al., Bioorg. Med. Chem.
1421-1426 (1995) and their references. These documents and patents form a part of the present specification.

Similarly, a number of benzodiazepine derivatives suitable for use in the present invention can be prepared using conventional methods and reagents. For example, first, oxalyl chloride is used to generate an acid chloride of a glycine derivative, and then the acid chloride is converted to a base (
For example, by coupling reaction with 2-aminobenzophenone in the presence of 4-methylmorpholine), 2-aminobenzophenone can be easily coupled to α- (isopropylthio) -N- (benzyloxycarbonyl) glycine. Thus, 2- [α- (isopropylthio) -N- (benzyloxycarbonyl) glycinyl] aminobenzophenone can be obtained. Excess (about 1.1 to about 1.
This compound is treated with ammonia in the presence of mercury (II) chloride of 5 equivalents to give 2- [N- (α-amino) -N ^′ -(benzyloxycarbonyl) glycinyl] aminobenzophenone. obtain. This intermediate was then readily cyclized by treatment with glacial acetic acid and ammonium acetate to give 3- (benzyloxycarbonyl) amino-2,3-dihydro-5-phenyl-1H-1,4
-Benzodiazepin-2-one can be obtained. Subsequent removal of the Cbz group gives 3-amino-2,3-dihydro-5-phenyl-1H-1,4.
-To obtain benzodiazepin-2-one.

Alternatively, 2,3-dihydro-5-phenyl-1H-1,4-benzodiazepin-2-one can be readily aminated at the 3-position using a conventional azide transfer reaction and subsequently obtained. Reduction of the resulting azide group gives the corresponding amino group. The conditions for these reactions and their related reactions are described in the Examples below. In addition, 2,3-dihydro-5-phenyl-1H-1,4-benzodiazepin-2-one is easily alkylated at position 1 using conventional methods and reagents.
For example, the reaction typically involves first converting the benzodiazepinone from about 1.0 to about 1.0.
5 equivalents of a base (e.g., sodium hydride, potassium tert-butoxide, 1,
1,1,3,3,3-Hexamethyldisilazane, cesium carbonate) in an inert diluent (for example, THF). The reaction is typically performed at a temperature ranging from about -78C to about 80C 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, alkyl bromide or alkyl iodide. Generally, the reaction is carried out at a temperature of about 0C to about 100C for about 1 to about 48 hours.

In addition, the 3-amino-2,4-dioxo-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine used in the present invention typically comprises firstly malonic acid and 1 , 2
-Prepared by a coupling reaction with 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 reactions employ a number of 3-amino-1,5-bis (alkyl) -2,4-dioxo-2,3,4,5-tetrahydro- 1H-1,5-benzodiazepine is obtained. The production methods thereof will be described in more detail in the following examples.

In the synthesis of compounds of Formula I using the synthetic methods described herein, some starting materials contain a chiral center (eg, alanine), and when using the racemic starting material The resulting product is a mixture of R, S enantiomers. Alternatively, the chiral isomer of the starting material can be used, and a chiral product is obtained if the reaction protocol employed does not racemize the starting material. The reaction protocol may involve inversion of the chiral center during the synthesis.

Thus, unless otherwise indicated, the products of the present invention are R, S enantiomeric mixtures. However, if chiral products are desired, they may be L
-Preferably corresponds to an amino acid derivative. Alternatively, the chiral product is R,
It can be obtained by purification techniques that separate the enantiomers from the S mixture to give one or the other stereoisomer.

Pharmaceutical Formulations When used as pharmaceuticals , the compounds of formula I are usually administered in the form of a pharmaceutical composition. These compounds can be administered by a variety of routes including oral, rectal, transdermal, subcutaneous, intravenous, intramuscular, and intranasal. These compounds are useful as both injectable and oral compositions. These compositions are prepared in a manner well known in the pharmaceutical art and comprise at least one active compound.

The present invention also includes pharmaceutical compositions containing one or more compounds of the above Formula I as active ingredients, together with a pharmaceutically acceptable carrier. In preparing the compositions of the present invention, the active ingredient will usually be mixed with an excipient and diluted with the excipient, or in a carrier which can take the form of capsules, sachets, papers or other containers. Encapsulate. 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 may be used as tablets, pills, powders, troches, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols (as a solid or liquid medium), ointments (eg, Up to 10% by weight of active compound), soft and hard capsules, suppositories, sterile injectable solutions and sterile packaged powders.

When preparing formulations, it is necessary to mill the active compound in order to obtain a suitable particle size before mixing with the other ingredients. If the active compound is substantially insoluble,
Usually, pulverization is performed so that the particle size is smaller than 200 mesh. If the active compound is substantially water-soluble, the particle size is usually adjusted by grinding to obtain a substantially uniform distribution (eg, about 40 mesh) in the formulation.

Examples of suitable excipients include lactose, dextrose, sucrose, sorbitol, mannitol, starch, acacia gum, calcium phosphate, alginate, tragacanth gum, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, reduced Contains sterilized water, syrup and methylcellulose. The formulation may also contain a wetting agent (eg, talc, magnesium stearate and mineral oil); a wetting agent; emulsifying and suspending agents; a preservative (eg, methyl and propyl hydroxybenzoate); a sweetening agent; May be included. After administration to a patient, the compositions of the present invention may be formulated using methods known in the art to provide a fast, sustained or delayed release of the active ingredient.

The compositions are preferably formulated in a single 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 phrase "single dose form" refers to physically discrete units suitable for human subjects and other mammals as unit doses, each unit with a suitable pharmaceutical excipient and the desired therapeutic effect. Contains a predetermined amount of active substance calculated to produce Formula I above
Uses less than about 20% by weight of the pharmaceutical composition, more preferably less than about 15% by weight (the balance being a pharmaceutically inert carrier).

The active compounds are effective over a wide range of dosages, and are generally administered in a pharmaceutically effective amount. However, the actual amount of compound to be administered will take into account environmental factors (including therapeutic conditions, the route of administration selected, the actual compound to be administered, the age, weight and response of the individual patient, the severity of the patient's symptoms, etc.). Is determined by the physician.

For preparing solid compositions such as tablets, the principal active ingredient is mixed with a pharmaceutical excipient to form a solid pre-formulated composition containing a homogeneous mixture of the compound of the invention. When these pre-formulated compositions are said to be homogeneous, the active ingredients are uniformly dispersed throughout the composition so that the composition is equally effective in unit dose form (eg, tablets, pills). And capsules). This solid pre-formulation is then subdivided into single dose forms of the type described above containing an active ingredient of the present invention (e.g., 0.1 to about 500 mg).

The tablets or pills of the present invention can be coated or otherwise mixed to give a dosage form affording the advantage of prolonged action. For example, a tablet or pill contains an inner component and an outer component, the latter taking the form of an envelope over the former. The two components are resistant to disintegration in the stomach and are separated by an enteric layer that acts to allow the internal components to pass intact to the duodenum or delay release. Numerous materials can be used for these enteric layers or coatings, including many polymeric acids and mixtures of these polymeric acids with such materials as shellac, cetyl alcohol and cellulose acetate.

Liquid dosage forms incorporating the novel compositions of the present invention for oral or injectable administration include aqueous solutions, suitably aromatized syrups, aqueous or oily suspensions, and edible oils such as Aromatizing emulsions with cottonseed oil, sesamin oil, coconut oil, or peanut oil), and also include 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. Liquid or solid compositions may include suitable pharmaceutically acceptable excipients as noted above. The compositions are preferably administered by the oral or nasal respiratory route for local or systemic effect. Compositions in preferred pharmaceutically acceptable solvents may be nebulized using an inert gas. The nebulized solution may be breathed directly from a nebulizer, a nebulizer attached to a facial mask tent, or an intermittent positive pressure respirator. The solution, suspension or powder composition is preferably administered orally or nasally in a suitable manner from the device for transporting the formulation.

The following formulation examples illustrate the pharmaceutical compositions of the present invention.

Formulation Example 1 A hard capsule containing the following ingredients is produced.

[Table 4]

The above ingredients are mixed and filled into 340 mg hard capsules.

Formulation Example 2 A tablet is produced using the following components.

[Table 5]

The ingredients are mixed and compressed to give tablets each weighing 240 mg.

Formulation Example 3 A dry powder inhalant containing the following ingredients is prepared.

[Table 6]

The active ingredient is mixed with lactose and the mixture is added to a dry powder inhaler device.

Formulation Example 4 Tablets containing 30 mg of each active ingredient are prepared as follows.

[Table 7]

The active ingredient, starch and cellulose are sieved through a No. 20 mesh US sieve and mixed well. The polyvinylpyrrolidone solutions are mixed with the resulting powder, which is then sieved through a # 16 mesh US sieve. The resulting granules are dried at 50-60 ° C and sieved through a No. 16 mesh US sieve. Then sodium carboxymethyl starch, magnesium stearate and talc, previously sieved through a No. 30 mesh US sieve, are added to the granules, mixed and compressed with a tablet machine to give tablets weighing 150 mg each.

Formulation Example 5 Capsules each containing 40 mg of a drug are produced as follows.

[Table 8]

The active ingredient, starch and magnesium stearate are mixed, sifted through a No. 20 mesh US sieve and filled to give a 150 mg quantity of hard capsules.

Formulation Example 6 Suppositories each containing 25 mg of the active ingredient are prepared as follows.

[Table 9]

The active ingredient is sieved through a No. 60 mesh US sieve and suspended in the required minimum amount of heat dissolved saturated fatty acid glycerides. The mixture is then poured into a suppository mold having a nominal 2.0 g capacity and cooled.

Formulation Example 7 A suspension containing 50 mg of each drug per 5.0 mL dose is prepared as follows.

[Table 10]

The active ingredient, sucrose and xanthan are mixed and sieved through a No. 10 mesh US sieve, then mixed with the previously prepared aqueous solution of microcrystalline cellulose and sodium carboxymethylcellulose. The sodium benzoate, flavor and color are diluted with some of the water and added with stirring. Then
Add enough water to get the required amount.

Formulation Example 8

[Table 11]

The active ingredient, starch and magnesium stearate are mixed, sifted through a 20 mesh US sieve and filled into 560 mg hard capsules.

Formulation Example 9 A subcutaneous formulation can be manufactured as follows.

[Table 12]

(If desired, up to about 5.0 mg or more of the active ingredient may be used in the formulation, depending on the solubility of the active ingredient in corn oil.)

Formulation Example 10 A topical formulation can be manufactured as follows.

[Table 13]

[0188] The white petrolatum was heated until dissolved. Mix and add liquid paraffin and emulsified wax and stir until dissolved. Add the active ingredient and continue stirring until dispersed.
The mixture is then cooled until it solidifies.

Another preferred formulation for use in the methods of the invention is one that uses a transdermal delivery means ("patch"). The transdermal patches can be used to provide the compound of the present invention continuously or discontinuously in controlled amounts.
It is well known in the art to construct and use transdermal patches for drug delivery. See, for example, U.S. Pat. No. 5,023,252 (issued Jun. 11, 1991), which forms part of this specification. The patches can be configured to deliver the medicament continuously, pulsatically, or as needed.

Sometimes, it is desirable or necessary to introduce a pharmaceutical composition directly or indirectly into the brain. Direct techniques usually involve placing a drug delivery catheter in the host's ventricular system to bypass the blood-brain barrier. One of those implantable delivery systems used to deliver biological agents to specific anatomical regions in the body is described in US Pat. No. 5,011,472, which is incorporated herein by reference. I have.

Although indirect techniques are generally preferred, they usually involve the formulation of a composition to render the drug latent by converting a hydrophilic drug into a lipid-soluble drug. . Latentation generally blocks hydroxy, carbonyl, carboxyl, sulfate, and primary amine groups on drugs to make them more soluble in lipids and to facilitate transport across the blood-brain barrier. Is achieved by Alternatively, hydrophilic drug delivery can be increased by intra-arterial injection of a hypertonic solution that can temporarily open the blood-brain barrier. Other suitable formulations for use in the present invention are Remington's Pharmaceutical Sci.
ences), Mace Publishing Company, Philadelphia, PA, 17th edition (1985).

Uses The compounds and pharmaceutical compositions of the present invention are useful for inhibiting β-amyloid peptide release and / or its synthesis, and therefore have utility in the diagnosis and treatment of Alzheimer's disease in mammals, including humans. Have.

As described above, the compounds described herein are suitable for use in the various drug delivery systems described above. In addition, the compounds may be encapsulated to increase the in vivo serum half-life of the administered compounds, introduced into the lumen of liposomes, manufactured as a colloid, or other compounds that may increase the serum half-life of the compound. It is also possible to use the usual methods. For example, U.S. Pat.Nos. 4,235,871, 4,50 by Szoka et al.
Numerous methods are available for the production of liposomes, as described in 1,728 and 4,837,028, which form part of the present specification.

The amount of the compound administered to the patient will depend on the dosage, the purpose of the administration, such as prophylaxis or therapy,
It varies depending on the condition of the patient, administration method, and the like. In the case of therapeutic applications, the composition is administered to a patient already suffering from AD in an amount sufficient to further delay the onset of symptoms of the disease and at least partially its complications. An amount adequate to achieve this end is defined as "therapeutically effective amount." The effective amount for this use is left to the discretion of the attending physician based on such factors as the degree or severity of the patient's AD, the patient's age, weight, and general condition. To use for treatment,
It is preferred that the compounds described herein be administered at a dose ranging from about 1 to about 500 mg / kg / day.

For prophylactic applications, the compositions may be administered to patients at risk of developing AD (eg,
(Determined by genetic screening or familial characteristics), administer an amount sufficient to prevent the onset of symptoms of the disease. A sufficient amount to achieve this goal is "
A prophylactically effective amount is defined. The effective amount for this use is left to the discretion of the attending physician based on such factors as the patient's age, weight and general condition. For prophylactic use, it is preferable to administer the compounds described herein at a dose ranging from about 1 to about 500 mg / kg / day.

As mentioned above, the compound administered to the patient takes the form of a pharmaceutical composition as described above. These compositions can be sterilized by conventional sterilization techniques, or can be sterile filtered. The resulting aqueous solutions can be packaged for use as is, or lyophilized, the lyophilized preparation being combined with a sterile aqueous carrier prior to administration.
The pH for the preparation of the compound is typically between 3 and 11, more preferably between 5 and 9,
7-8 are most preferred. It is understood that the use of certain excipients, carriers or stabilizers described above produces pharmaceutical salts.

The compounds described herein are also suitable for use when administering the compounds to cells for diagnostic and drug discovery purposes. Specifically, the compounds can be used to diagnose the release of β-amyloid peptide and / or its synthesis in cells. In addition, the compounds described herein are useful for measuring and evaluating the activity of other candidate drugs in inhibiting the release of β-amyloid peptide and / or its synthesis in cells.

The following synthetic and biological examples serve to illustrate the present invention and are not to be considered as limiting the scope of the invention.

[0199]

【Example】

In the following examples, 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-diazaphosphorin Boc = t-butoxycarbonyl BOP = benzotriazol-1-yloxy-tris (dimethyl-
Amino) phosphonium hexafluorophosphate bd = broad doublet bs = broad singlet bs = broad triplet CBZ = benzyloxycarbonyl d = doublet dd = doublet doublet DIC = diisopropylcarbodiimide DIPEA = diisopropylethylamine DMF = Dimethylformamide DMAP = dimethylaminopyridine DMSO = dimethylsulfoxide EDC = ethyl-1- (3-dimethylaminopropyl) carbodiimide ee = enantiomeric excess eq. = Equivalent EtOAc = Ethyl acetate g = Grams HMDS = 1,1,1,3,3,3-Hexamethyldisilazane HOBT = 1-Hydroxybenzotriazole hydrate Hunig's base = Diisopropylethylamine L = Liter LDA = Lithium diisopropyl Amide m = multiplet M = mol max = maximal meq = milliequivalent mg = milligram mL = milliliter mm = millimeter mmol = millimol N = specified ng = nanogram nm = nanometer OD = optical density 1-pyrrolidinyl) propyl) -3-ethylcarbodiimide PP-HOBT = piperidine-piperidine-1-hydroxybenzotrizole psi = pounds / square inch φ = phenyl q = quartet quint. = Quintet rpm = Rotations / minute RT = room temperature s = singlet sat. = Saturation t = triplet t-BuOK = potassium tert-butoxide TFA = trifluoroacetic acid THF = tetrahydrofuran tlc = thin layer chromatography TMSI = trimethylsilyl iodide [mu] L = microliter UV = UV

In the following examples, all temperatures are degrees Celsius (unless otherwise indicated). The compounds shown in the following examples are prepared using the following general procedures as indicated.

In the following Examples and Production Methods, the term “Aldrich” means that the compound or reagent used in the production method is Aldrich Chemical Company, Inc.
, 1001 West Saint Paul Avenue, Milwaukee, Wis. 53233 USA); the term "fluca" refers to compounds or reagents that are available from Fluk.
a Chemical Corp., 980 South 2nd Street, Ronkonkoma NY 11779 USA), indicating that it is commercially available; the term "Lancaster" refers to a compound or reagent that is available from Lancaster Synthesis, Inc., PO Box 100 Windham. , NH 0
3087 USA); indicates that the compound or reagent is commercially available from Sigma (Sigma, PO 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 "Backchem" indicates that the compound or reagent is
Biosciences (Bachem Biosciences Inc., 3700 Horizon Drive, Renaiss
ance at Gulph Mills, King of Prussia, PA 19406 USA); the term "Maybridge" refers to compounds or reagents that may be purchased from Maybridge Chemical Co. Trevillet, Tintagel, Cornwall PL34. OHW United
(TCI America), 9211 North Harborgate Street, Portlan.
d OR 97203); the term “alpha” refers to compounds or reagents that are available from the Johnson Matthey Catalog.
Company, Inc., 30 Bond Street, Ward Hill, MA 01835-0747); indicates that the compound or reagent is Calbiochem-Novabiochem Corp. 10933 North Tor
rey Pines Road, PO Box 12087, La Jolla CA 92039-2087); the term "oakwood" refers to compounds or reagents from Oakwood, Columbia, South Carolina. Indicates that it is commercially available; the term "Advanced Chemtech" indicates that the compound or reagent is commercially available from Advanced Chemtech, Louisville, KY; the term "Preflat &Bowell""Indicates that the compound or reagent is commercially available from Pflatz & Bauer, Waterbury, CT, USA.

I. Coupling Procedure The following coupling procedure could be used to prepare the compounds of the present invention.

General Procedure A First EDC Coupling Procedure To a mixture (1: 1) of the corresponding carboxylic acid and the corresponding amino acid ester or amide in CH ₂ Cl ₂ at 0 ° C., triethylamine (1.5 eq) ), Followed by hydroxybenzotriazole monohydrate (2.0 eq.), Followed by ethyl-3- (3-dimethylamino) propylcarbodiimide.HCl (1.25 eq.)
. ) Was added. The reaction mixture was stirred at room temperature overnight and then transferred to a separatory funnel. The mixture is combined with water, saturated aqueous NaHCO ₃ , 1N HCl and saturated NaCl
Washed with an aqueous solution, then dried over MgSO _4. The solvent was removed from the obtained solution by a rotary evaporator to obtain a crude product.

General Preparation B Second EDC Coupling Preparation The corresponding acid (1 eq.), N-1-hydroxybenzotriazole (1.6 e.
q. ), The corresponding amine (1 eq.), N-methylmorpholine (3 eq.) And dichloromethane (or DMF for insoluble substrates) were cooled in an ice-water bath and stirred until a clear solution was obtained. Then, EDC (1.3 eq.
) Was added to the reaction mixture. The temperature was then raised to ambient temperature using a cold bath over 1-2 hours and the reaction mixture was stirred overnight. The reaction mixture was then evaporated under vacuum until dryness. A 20% aqueous potassium carbonate solution was added to the residue, the mixture was shaken well and then allowed to stand until the oily product solidified (overnight if necessary). The solid product was then collected by filtration and 20% aqueous potassium carbonate, water, 10% H
After thorough washing with Cl and water, the product was usually obtained in a pure state. No racemization was observed.

General Preparation C Third EDC Coupling Preparation 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 successively. A cold bath was applied to the round bottom flask until the solution reached 0 ° C. Then, 1- (3-dimethylaminopropyl)
-3-Ethylcarbodiimide hydrochloride (1.2 eq.) Was added. The solution was stirred overnight and allowed to warm to room temperature under nitrogen pressure. Before drying over sodium sulfate, the reaction mixture was worked up by washing the organic phase with saturated aqueous sodium carbonate, 0.1 M citric acid and brine. Then, the solvent was removed to obtain a crude product.

General Preparation D A fourth EDC-coupled preparation round bottom flask was placed under nitrogen atmosphere with the corresponding carboxylic acid (1.0 eq.), Hydroxybenzotriazole hydrate (1.1 eq.) And the corresponding Amine (1.0
eq.) in THF. An appropriate amount (1.1 eq. For free amine, 2.2 eq. For amine hydrochloride) of base (eg Hunig's base) is added to the well-stirred mixture, followed by EDC (1.1 eq.). Was added. 4-17 at room temperature
After stirring for hours, the solvent was removed under reduced pressure, the residue was dissolved in ethyl acetate (or similar solvent) and water, washed with saturated aqueous sodium hydrogen carbonate, 1N HCl, brine, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. Removal under yielded the product.

General Preparation E BOP Coupling Preparation 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-methyl. Morpholine (6 mmol) was added. The reaction mixture was stirred for 50 minutes, then a solution of α-amino-γ-lactam (2 mmol) in DMF cooled at 0 ° C. was added. The temperature was raised to ambient temperature using a cold bath over 1-2 hours, and then the reaction mixture was stirred overnight. A 20% aqueous potassium carbonate solution (60 mL) was added, and the mixture was thoroughly washed. No solid formed. The mixture was then added to ethyl acetate (150 m
L) and evaporated under vacuum to dryness to give a white solid. Then water (5
0 mL) was added and the mixture was shaken well. The precipitate formed was collected by filtration and then washed thoroughly with water followed by diethyl ether (1 mL) to give the product (
51 mg, 0.16 mmol, 7.8%).

[0208] General Procedure F acid chloride with amino acid esters of the coupling reaction (D, L) - alanine iso-butyl ester hydrochloride To a stirred solution of pyridine (4.6mmol) (5mL), acid chloride (4.6 mmol) Was added. A precipitate formed immediately. The mixture was stirred for 3.5 hours, dissolved in diethyl ether (100 mL) and washed three times with 10% HCl, once with brine (brine), once with 20% potassium carbonate and once with brine. The solution was dried over magnesium sulfate, filtered and evaporated to give the product. Other amino acid esters may be used in this process.

[0209] General Procedure G carboxylic acid and a coupling reaction the carboxylic acid with the amino acid ester (3.3 mmol) and 1,1 ^'- carbodiimidazole (CDI
) In THF (20 mL) was stirred for 2 hours. (D, L) -alanine isobutyl ester / hydrochloric acid (3.6 mmol) was added, followed by triethylamine (1.5 mL).
, 10.8 mmol) was added. The reaction mixture was stirred overnight. The reaction mixture was dissolved in diethyl ether (100 mL), 3 times with 10% HCl, once with brine,
Washed once with 20% potassium carbonate and once with brine. The solution was dried over magnesium sulfate, filtered and evaporated to give the product. Other amino acid esters can be used in this process.

General Preparation H In a fifth round EDC-coupling manufacturing round bottom flask was placed THF, amine hydrochloride (1.0 eq.) Of carboxylic acid (1.1 eq.).
eq.), 1-hydroxybenzotriazole hydrate (1.1 eq.), N, N-
Diisopropylethylamine (2.1 eq.) Was added, followed by 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide-hydrochloric acid (EDC) (1.1 eq.). The reaction mixture was stirred at room temperature under a nitrogen atmosphere for 10-20 hours. Et mixture
Dilute with OAc and add 0.1 M HCl (1 × 10 mL), saturated NaHCO ₃ (1 × 1
0 mL), H ₂ O (1 × 10 mL) and brine and dried over MgSO ₄ . The drying agent was removed by filtration, and the filtrate was concentrated under vacuum. The residue was purified by silica gel flash column chromatography followed by trituration (from EtOAc and hexane).

General Preparation I Sixth EDC Coupling Preparation A solution of amine or amine-hydrochloric acid (1.0 eq.) In THF (0.05-0.1 M) at 0 ° C. under N ₂ at 0 ° C. Carboxylic acid (1.0-1.1 eq.), Hydroxybenzotriazole monohydrate (1.1-1.15 eq.), Hunig's base (1.1 eq. In the case of free amine and 1.1 eq. Of amine hydrochloride) In case 1.1-2.3
eq.) followed by 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide.hydrochloric acid (1.1 to 1.15 eq.). Remove the cooling bath and allow the mixture to reach room temperature.
The temperature was raised over 0 to 24 hours. The solution or mixture is diluted to 3-5 times the starting THF volume with EtOAc, and 0.1-1.0 M hydrochloric acid (1 or 2 ×), dilute NaHCO ₃ (1 or 2 ×) and brine (1 × 2 ×). 1 ×). The organic phase was then dried over MgSO ₄ or Na ₂ SO ₄ , filtered and concentrated to give the crude product,
This was used for further purification or without further purification.

General Production Method JEEDQ coupling manufacturing method A solution of the amine in THF (1.0 eq., 0.05-0.08 M, final molarity) was added with N _Two At room temperature, an Nt-Boc protected amino acid (1.1 eq., Solid or THF solution)
By cannula) followed by EEDQ (Aldrich, 1.1 eq.).
added. The pale yellow solution was stirred at room temperature for 16-16.5 h, then EtOAc
(3-5 times the starting THF volume) with 1M hydrochloric acid (2 ×), diluted NaH
CO_ThreeWashed with aqueous solution (2 ×) and brine (1 ×). Organic phase Na_TwoSO_Four
Or MgSO_Four, Filtered and concentrated.

II. Carboxylic Acids The following processes can be used to prepare carboxylic acid intermediates useful in the present invention.

General Production Method II-A Hydrolysis of Ester to Free Acid The hydrolysis of ester to free acid was carried out by a conventional method. less than,
Two examples of these conventional de-esterification methods are shown below.

Method A: K ₂ CO ₃ (2 to 5 equivalents) was added to a CH ₃ OH / H ₂ O (1: 1) mixture of a carboxylic acid ester compound. The mixture was heated to 50 ° C. for 0.5-1.5 hours until the reaction was complete by tlc. Cool the reaction to room temperature,
The methanol was removed using a rotary evaporator. The pH of the remaining aqueous solution was adjusted to ２2 and ethyl acetate was added to extract the product. The organic phase is then washed with saturated NaCl
Washed with an aqueous solution and dried over MgSO ₄ . The solution was stripped of solvent using a rotary evaporator to give the product.

Method B: An amino acid ester was dissolved in dioxane / water (4: 1), LiOH (〜2 eq.) Dissolved in water was added thereto, and the total solvent after the addition was dioxane:
Water (about 2: 1). The reaction mixture was stirred until the reaction was completed, and dioxane was removed under reduced pressure. The residue was dissolved in water and washed with ether. The phases were separated and the aqueous phase was acidified to pH2. The aqueous phase was extracted with ethyl acetate. The ethyl acetate extract was dried over Na ₂ SO ₄ , filtered and the solvent was removed under reduced pressure. The residue was purified by a usual method (for example, recrystallization).

General Preparation II-B Preparation of Acid Chloride 3,4-Difluorophenylacetic acid (30 g, 0.174 mol) (Aldrich) was dissolved in dichloromethane and the solution was cooled to 0 ° C. DMF (0.5 mL, catalytic amount) was added, followed by oxalyl chloride (18 mL, 0.20 mol) dropwise over 5 minutes. The reaction was stirred for 3 hours and then rotary evaporated under reduced pressure to give an oil which was placed under a high vacuum pump for 1 hour to give 3,4-difluorophenylacetyl chloride. Other acid chlorides can be prepared in a similar manner.

General Preparation II-C Schotten-Baumann Method 3,5-Difluorophenylacetyl chloride (from General Preparation II-B) was prepared by adding L-alanine (Aldrich) (16.7 g, 0.187 mol) at 0 ° C. It was added dropwise to a 2N sodium hydroxide (215 mL, 0.43 mol) solution. The reaction was stirred at 0 ° C. for 1 hour and then at room temperature overnight. The reaction was diluted with water (100 mL) and extracted with ethyl acetate (3 × 150 mL). The organic phase is then washed with brine (2
00 mL), dried over MgSO ₄ and rotary evaporated under reduced pressure to give a residue.
The residue was recrystallized (from ethyl acetate / hexane) to give the desired product (34.5 g).
, Yield 82%). Other acid chlorides may be used in this process to provide intermediates useful in the present invention.

General Preparation II-D Reductive Amination Procedure A solution of an arylamine in ethanol in a hydrogenation flask was charged with 1 equivalent of 2
-Oxocarboxylic acid ester (e.g. pyruvate) followed by 10% palladium on carbon (25% by weight based on arylamine). Until the reaction was complete is indicated by tlc (~ 16 hours 30 minutes), it was hydrogenated reaction with 20 psi H ₂ using a Parr shaker. Next, the reaction mixture was passed through Celite 54.
Filtered through 5 pads (available from Aldrich Chemical Company, Inc.) and stripped of solvent on a rotary evaporator. Next, the crude product residue was further purified by chromatography.

III. Cyclic Compounds The following preparations illustrate the synthesis of various cyclic compound intermediates useful for preparing the compounds of the present invention.

A. Benzazepinone Derivatives and Related Compounds General Preparation Method 1-A 1-Amino-1,3,4,5-tetrahydro-2H-benzazepin-2-one
Alkylation reaction step A : 1-ethoxycarbonylamino-1,3,4,5-tetrahydro-2H
-3-Benzazepin-2-one is described in Tetrahdron, 1987, 43 by Ben-Ishai et al.
, 430, the contents of which are incorporated herein by reference.

Step B : 1-ethoxycarbonylamino-1,3,4,5-tetrahydro-2H
-3-Benzazepin-2-one (2.0 g, 100 M%) was added to DNF (30 mL).
) And NaH (95%, 0.17 g, 100 M%) was added in one portion. The reaction mixture was stirred for 1 hour, then the appropriate alkyl iodide (300 M%) was added and the mixture was stirred for 12 hours. The reaction was poured into water and ethyl acetate (3 ×
). The ethyl acetate extract was then combined with water (3 ×) and brine (1 ×).
×). Treatment with MgSO4, rotary evaporation and chromatographic purification (30% EtOAc / hexanes) were performed to give 1-ethoxycarbonylamino-3-alkyl-1,3,4,5-tetrahydro-2H-3-benzazepine-
The 2-one was obtained in 87% yield.

Step C : 1-ethoxycarbonylamino-3-alkyl-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one (1.0 g, 100M%)
Suspended in 30% HBr / HOAc (30 mL) and heated to 100 ° C. The reaction mixture is stirred at this temperature for 5 hours, then the reaction is cooled and rotary evaporated to give 1-amino-3-alkyl-1,3,4,5-tetrahydro-2H-3-benzazepine-2 -On.hydrobromide (100% yield) was obtained.

General Production Method 1-B 3-Amino-1,3,4,5-tetrahydro-2H-1-benzazepin-2-o
Alkylation reaction step A : 3-Amino-1,3,4,5-tetrahydro-2H-1-benzazepin-2-one was prepared according to Armstrong et al., Tetrahedron Letters, 1994, 35, 3239 (the contents of which are described herein). Prepared from α-tetralone using the method described in (1) Constituting part of the book. The following compounds: 5-methyl-3-amino-1,3,4,5-tetrahydro-2H-1-benzazepin-2-one (from 4-methyl-α-tetralone (Aldrich)) and 5,5-dimethyl -3-Amino-1,3,4,5-tetrahydro-2H-1-benzazepin-2-one (derived from 4,4-dimethyl-α-tetralone (Aldrich)) is obtained by this method used in the following steps. To manufacture.

Step B : 3-Amino-1,3,4,5-tetrahydro-2H-1-benzazepin-2-one (4.43 g, 100 M%) was suspended in t-butanol (30 mL), and BOC- Anhydrous (7.5 mL, 130 m%) was added dropwise. The reaction was stirred for 2 hours and then rotary evaporated to give a residue which was chromatographed (60% ethyl acetate / hexane) to give the BOC-protected 3-.
Amino-1,3,4,5-tetrahydro-2H-1-benzazepine (87% yield) was obtained.

Step C : BOC-protected 3-amino-1,3,4,5-tetrahydro-2H-
1-Benzazepin-2-one (1.5 g, 100 M%) in DMF (20 mL)
And NaH (95%, 0.13 g, 100 M%) was added in one portion. The reaction mixture was stirred for 1 hour, then the appropriate alkyl iodide (300 M%) was added,
Stirring was continued for 12 hours. The reaction was poured into water and extracted with ethyl acetate (x3). The ethyl acetate extract was washed with water (× 3) and then with brine (1 ×). M
gSO ₄ , rotary evaporation and chromatographic purification (30% EtOAc
/ Hexane) to give the BOC-protected 3-amino-1-alkyl-1,3,4
, 5-Tetrahydro-2H-1-benzazepin-2-one (80% yield) was obtained.

Step D: The BOC-protected 3-amino-1-alkyl-1,3,4,5-
Tetrahydro-2H-1-benzodiazepin-2-one (1.0 g, 100 M%
) Was suspended in CH ₂ Cl ₂ / trifluoroacetic acid (1: 1, 30 mL) and the mixture was stirred for 4 hours. The reaction was then rotary evaporated to give 3-amino-1-
Alkyl-1,3,4,5-tetrahydro-2H-1-benzazepin-2-one (100% yield) was obtained.

Example 1-A 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 is described in Tetrahedron Letters, 1994 by Armstrong et al.
, 35, 3239, the contents of which are incorporated herein by reference.
-Methyl-α-tetralone.

Step B : 3-amino-5-methyl-1,3,4,5-tetrahydro-2H-1
-Benzazepin-2-one (9.3 g, 100 M%) was added to dioxane (300 m
1) and the solution was cooled to 0 ° C. BOC-anhydride (13.89 g,
130M%), the ice bath was removed, the solution was allowed to warm to room temperature, and stirring was continued for 16 hours. The solution was rotary evaporated to remove the dioxane, giving an off-white solid. The solid was recrystallized (from CHCl ₃ ) to give BOC-protected 3-amino-5-methyl-1,3,4,5-tetrahydro-2H-1-benzazepin-2-one (55% yield). I got

Step C: BOC-protected 3-amino-5-methyl-1,3,4,5-tetrahydro-2H-1-benzazepin-2-one (100 M%) in DMF (20 m
L), NaH (95%, 100M%) was added in one portion and the reaction mixture was stirred for 1 hour. Methyl iodide (300 M%) was added and the mixture was stirred for 12 hours. The reaction was then poured into water, extracted with ethyl acetate (3 ×), then washed again with water (3 ×), then brine (1 ×). Treatment with MgSO ₄ , rotary evaporation and chromatographic purification (5% MeOH / CH ₂ Cl ₂ )
BOC-protected 3-amino-1,5-dimethyl-1,3,4,5-tetrahydro-
2H-1-Benzazepin-2-one (75% yield) was obtained.

Step D : BOC-protected 3-amino-1,5-dimethyl-1,3,4,5-tetrahydro-2H-1-benzazepin-2-one (100 M%) was added to CH ₂ C
Suspended in l ₂ / trifluoroacetic acid (1: 1, 30 mL). The reaction mixture is
Stirred for hours. Then, the reaction solution was rotary evaporated to give 3-amino-1,5-dimethyl-1,3,4,5-tetrahydro-2H-1-benzazepin-2-one (
(100% yield).

Example 1-B 5- (L-alaninyl) amino-3,3,7-trimethyl-5,7-dihydro-6H
Synthesis of benz [b] azepin-6-one.hydrochloride Nt-Boc-L-alanine and 5-amino-3 according to General Preparation H
Using (3,7-trimethyl-5,7-dihydro-6H-benz [b] azepin-6-one.hydrochloride (Example 1-C), 5- (Nt-Boc-L-alaninyl) Amino-3,3,7-trimethyl-5,7-dihydro-6H-benz [b] azepine-6
-On was produced. According to a general production method (Example 1-C, Step B), 5- (Nt
-Boc-L-alaninyl) amino-3,3,7-trimethyl-5,7-dihydro-
5- (L-alaninyl) amino-3 using 6H-benz [b] azepin-6-one.
, 3,7-Trimethyl-5,7-dihydro-6H-benz [b] azepin-6-one.hydrochloric acid was produced.

Example 1-C Synthesis of 5-amino-3,3,7-trimethyl-5,7-dihydro-6H-benzo [b] azepin-6-one.hydrochloric acid General procedure N-alkylation of lactams Reaction Step A 97% NaH (1.08 g, 45 mmol) was added to a stirred solution of BOC-protected α-aminocaprolactam (6.87 g, 30 mmol) in DMF (150 ml).
) Was added in several portions. Foaming occurred immediately, followed by massive settling.
After 10 minutes, benzyl bromide (3.93 mL, 33 mmol) was added. The precipitate dissolved immediately and a clear solution was obtained in about 10 minutes. The reaction mixture was stirred overnight,
It was then evaporated as completely as possible on a rotary evaporator at 30 ° C. Ethyl acetate (100
mL) was added to the residue and the 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 (eluted with ethyl acetate / hexane (1: 3)) to give an oily N-benzylated product (5 g). .51 g, 58%). Other lactams and reagents can be used in this process to obtain a wide range of N-alkylated lactams. Numerous bases (eg, LiN (SiMe ₃ )) can also be used.

According to this production method, Nt-Boc-5-amino-3,3-dimethyl-5,7-
Dihydro-6H-benzo [b] azepin-6-one (General procedure 1-B followed by B
oc) and methyl iodide to give Nt-Boc-5-amino-3,
3,7-Trimethyl-5,7-dihydro-6H-benzo [b] azepin-6-one was prepared.

General Procedure BOC Removal Method Step A Vapor of anhydrous HCl gas was bubbled through a stirred solution of Nt-Boc-protected amino acid in 1,4-dioxane (0.03-0.09M) and N ₂ Under an ice bath, the mixture was cooled to -10C over 10 to 15 minutes. The solution was sealed, the cooling bath was removed, and the solution was allowed to warm to room temperature while stirring for 2-8 hours, monitoring the consumption of starting material by TLC. The solution is concentrated (eg, dissolved in CH ₂ Cl ₂ and then concentrated again,
Place in a vacuum dryer at 60-70 ° C. to remove most residual dioxane),
Used without further purification.

According to this general production method, Nt-Boc-5-amino-3,3,7-trimethyl-
The title compound was prepared using 5,7-dihydro-6H-benz [b] azepin-6-one.

Example 1-D 3- (S) -Amino-1-methyl-5-oxa-1,3,4,5-tetrahydro-2
Synthesis step A of H-1-benzazepin-2-one: 3- (S) -amino-5-oxa-1,3,5,7-tetrahydro-2
-H-l-benzazepin-2-one was obtained from N-Boc-serine (Bachem) and 2-fluoro-l-nitrobenzene (Aldrich) by RJ DeVita et al.
Organic and Midicinal Chemisty Lett. 1995, 5 (12) 1281-1286, the contents of which are incorporated herein by reference.

Step B : Following the general procedure of Step A of Example 1-C, using the product from Step A of this example, the title compound was prepared.

Example 1-E 3- (S) -Amino-1-ethyl-5-oxa-1,3,4,5-tetrahydro-2
Synthesis step A of H-1-benzazepin-2-one: 3- (S) -amino-5-oxa-1,3,4,5-tetrahydro-2
H-1-benzazepin-2-one was obtained from N-Boc-serine (Bachem) and 2-fluoro-1-nitrobenzene (Aldrich) by RJ DeVita et al., Bioorganic and Midicinal Chemisty Lett. 1995, 5 (12) 1281- 1286, the contents of which are incorporated herein by reference.

Step B : The title compound was prepared using the product of Step A of this example according to the general procedure of Step A of Example 1-C.

Example 1-F 3- (S) -Amino-1-methyl-5-thia-1,3,4,5-tetrahydro-2H
Synthesis of -1-benzodiazepin-2-one From N-Boc-cystine (Novabio) and 2-fluoro-1-nitrobenzene (Aldrich), Bioorganic and Midicinal Che by RJ DeVita et al.
misty Lett. 1995, 5 (12) 1281-1286 (this content forms a part of this specification)
Using the general procedure of Step A of Example 1-C, the title compound was prepared.

Example 1-G 7-Amino-1,3,4,7,12,12a-hexahydropyrido [2,1-b] [3]-
Synthesis of benzazepin-6 (2H) -one Step A - Synthesis of N-chloroacetyl-2-benzylpiperidine The title compound was prepared according to General Procedure F using 2-benzylpyridine. Physical data are as follows: (MW = 251.8); mass spectroscopy (MH +) 252.0.

[0243] Step B: 1, 3, 4, 7, 12,12a-hexahydropyrido [2,1-b] [3] ben
Synthesis of Zazepin-6 (2H) -one The title compound was prepared according to General Procedure G using N-chloroacetyl-2-benzylpiperidine. Physical data are as follows: ¹ H-nmr (CDCl ₃ ): δ = 1.3-1.9 (6H); 2.42 (t, 1H).
3.08 (m, 2H); 3.47 (m, 1H); 3.96 (q, 2H); 4.66 (
d, 1H); 7.2 (m, 4H). (MW = 215.3); mass spectroscopy (MH +) 216.1.

Step C: 7-oximo-1,3,4,7,12,12a-hexahydropyrido [ 2,
Synthesis of 1-b] [3] benzazepin-6 (2H) -one 1,3,7,12,12a-Hexahydropyrido [2,1-b] [3 The title compound was prepared using benzazepine-6 (2H) -one (from Step B above). Physical data are as follows: (MW = 244.3); mass spectroscopy (MH +) 245.0.

Step D: Synthesis of 7-Amino-1,3,7,12,12a-hexahydropyrido [2,1-b ] [3] benzazepin-6 (2H) -one General procedure 3A (Step According to C), 7-oximo-1,3,7,12,12a-
The title compound was prepared using hexahydropyrido [2,1-b] [3] benzazepin-6 (2H) -one (from Step C above). Physical data are as follows: ¹ H-nmr (CDCl ₃ ): δ = 1.3-1.9 (6H); 2.42 (t, 1H).
3.08 (m, 2H); 3.47 (m, 1H); 3.96 (q, 2H); 4.66 (
d, 1H); 7.2 (m, 4H). (MW = 230.3); mass spectroscopy (MH +) 231.1.

[0246] Example 1H 1- (N ^'-L- alaninyl) amino-4,5,6,7-tetrahydro-3,7-methano-3H-3- Benzazonin (benzazonin) -2 (1H) - Synthesis of ON Step A: Synthesis of N-chloroacetyl-3-phenylpiperidine According to General Preparation F, using 3-phenylpyridine · hydrochloric acid (Aldrich),
The title compound was prepared.

Step B: 4,5,6,7-tetrahydro-3,7-methano-3H-3-benzazo
Synthesis of Zonin-2 (1H) -one The title compound was prepared according to General Procedure G using N-chloroacetyl-3-phenylpiperidine. Physical data are as follows: ¹ H-nmr (CDCl ₃ ): δ = 1.32-1.57 (2H); 2.08 (m, 2)
H); 2.81 (t, 1H); 3.13 (bs, 1H); 3.37 (m, 2H);
36 (M, 2H); 4.50 (d, 1H). (MW = 201.3); mass spectroscopy (MH +) 202.1.

Step C: 1-oximo-4,5,6,7-tetrahydro-3,7-methano-3H-
Synthesis of 3-benzazonin-2 (1H) -one The title compound was prepared using the product from Step B above according to General Preparation 3A (Step B).

Step D: 1-amino-4,5,6,7-tetrahydro-3,7-methano-3H-3
Synthesis of -Benzazonin-2 (1H) -one The title compound was prepared using the product from Step C above according to General Preparation 3A (Step C). Physical data are as follows: ¹ H-nmr (CDCl ₃ ): δ = 2.86 (t, 1H); 3.17 (bs, 1H).
3.39 (dd, 1H); 4.40 (d, 1H); 4.50 (d, 1H); 5.39
(S, 1H). (MW = 216.3); mass spectroscopy (MH +) 217.4.

[0250] Step ^{E: 1- (N '-Boc-} L- alaninyl) amino-4,5,6,7-tetra
Synthesis of hydro-3,7-methano-3H-3-benzazonin-2 (1H) -one Using N-tert-Boc-L-alanine (Aldrich) and the product from step D above according to General Preparation Method D. To give the title compound. Physical data are as follows: (MW = 387.48); mass spectroscopy (MH +) 388.1.

[0251] Step E: 1- (N ^'-L- alaninyl) amino-4,5,6,7-tetrahydro -
Synthesis of 3,7-methano-3H-3-benzazonin-2 (1H) -one The title compound was prepared using the product from Step E according to General Procedure E. Physical data are as follows: ¹ H-nmr (CDCl ₃ ): δ = 2.85 (t, 1H); 3.16 (bs, 1H)
3.40 (dd, 1H); 3.67 (m, 1H); 4.35 (d, 1H); 4.56
(D, 1H); 6.40 (d, 1H). (MW = 287.4); mass spectroscopy (MH +) 288.1.

Example 2-A Synthesis of 5-Amino-5,7-dihydro-6H -dibenz [a, c] cyclohepten-6 -ol.hydrochloric acid Step A: 5-oximo-5,7-dihydro-6H- dibenz [a, c] Shikurohepu
Synthesis round bottom flask Ten-6-one, 5,7-dihydro -6h- dibenz [a, c] cycloheptene -
6-one (1.0 g, 4.81 mmol) (CAS # 1139-82-8, Tetrahedron Lett
ers, 28, 23 (1987), pp. 2633-2636 (prepared as described in this specification) and butyl nitrite (0.673 mL, 5.77 mm).
It was filled with Et ₂ O of the ol) (Aldrich). The solution was cooled to 0 ° C and saturated HC
The solution was treated dropwise using l (g) / Et ₂ O solution. After 5 hours at 0 ° C., the resulting precipitate was filtered, rinsed with cold Et ₂ O, and dried in vacuo to give the title compound as a colorless solid. The NMR data are as follows: ¹ H-nmr (CDCl ₃ ): δ = 7.26-7.74 (m, 8H); 3.84 (m
, 2H). _{C 15 H 11 NO 2 (MW} = 237.26), mass spectroscopy (MH +) 238. Elemental analysis (C ₁₅ H ₁₁ as NO _2); theoretical value: C, 75.93, H, 4.67 ,
N, 5.90; Found: C, 75.67, H, 4.83, N, 5.67.

Step B 5-Amino-5,7-dihydro-6H-dibenz [a, c] cyclohepte
Down-6-ol hydrochloride The above isolated compound (0.489 g, 2.04 mmol) was dissolved in THF,
It was added dropwise to a well-stirred mixture of LAH (10.2 mL, 10.2 mmol) in THF. After heating to reflux for 25 hours under a N ₂ atmosphere, the solution was quenched and worked up according to the Fieser method. The solid obtained was rinsed with saturated NH ₃ / CHCl ₃ , the filtrate was evaporated and the title product was purified by chromatography (SiO ₂ , CHCl ₃ ). _{C 15 H 15 NO (MW =} 225.90); mass spectroscopy (MH +) 226. Elemental analysis (C ₁₅ as H ₁₁ NO); theoretical: C, 79.97, H, 6.71 , N
, 6.22; found: C, 80.19, H, 6.71, N, 5.91.

Example 2-B Preparation of 5- [L-alaninyl] amino-5,7-dihydro-6H-dibenz [a, c] cyclohepten-6-one Boc-L-alanine according to General Preparation D above. (Aldrich) and 5-amino-5,7-dihydro-6H-dibenz [a, c] cyclohepten-6-ol.
A tan foam was produced using hydrochloric acid (Example 2-A).

The resulting alcohol was oxidized as follows. To a stirred mixture of oxalyl chloride (0.15 mL, 1.2 mmol) in dichloromethane (10 mL) cooled to -78 C, DMSO (0.106 mL, 1.5 mmol) was added and the mixture was stirred for 10 minutes. A solution of the alcohol (0.1828 g, 0.60 mmol) in chloroform (20 mL) was added dropwise. The reaction mixture was stirred at -78 <0> C for 2 hours, then triethylamine (0.5 mL, 3.6 mmol) was added. Continue stirring for one hour,
The mixture was then allowed to warm to room temperature and continued stirring at ambient temperature overnight. The mixture is then diluted with dichloromethane (50 mL), washed with brine (3 ×), dried over magnesium sulfate, filtered and evaporated to dryness to give a crude product, which is typically chromatographed. Purification was performed.

The Boc group was removed using 2.0M HCl / dioxane. The title compound was isolated as an orange foam. C ₁₈ H ₁₈ N ₂ O ₂ HCl (MW = 330.4); mass spectroscopy (MH +
295).

C. Dibenzazepinone Derivatives and Related Compounds General Preparation 3-A 5-Amino-7-alkyl-5,7-dihydro-6H-dibenz [b, d] azepine
Step A for producing -6-one derivative : According to the general procedure of Step A of Example 1-C, 5,7-dihydro-6
Using H-dibenz [b, d] azepin-6-one and alkyl iodide,
Alkyl-5,7-dihydro-6H-dibenz [b, d] azepin-6-one was prepared.

Step B : 7-alkyl-5,7-dihydro-6H-dibenz [b, d] azepin-6-one (1 eq.) Was dissolved in THF, and isoamyl nitrite (1.2 eq.) Was added. Was. The mixture was cooled to 0 ° C. in an ice bath. NaHMDS (1.1 eq.,
1M THF) was added dropwise. After stirring for 1 hour or until the reaction was complete, the mixture was concentrated, then acidified with 1N HCl and extracted with EtOAc. The organics were dried and concentrated to give a crude product, which was purified by silica gel chromatography.

Step C : The obtained oxime was dissolved in EtOH / NH ₃ (20: 1) and placed in a pressure vessel (bomb) using Raney nickel and hydrogen (500 psi).
Hydrogenated at 0 ° C. for 10 hours. The resulting mixture was filtered and concentrated to give an oil,
This was purified by silica gel chromatography to give the title compound.

General Preparation 3-B Fluoro-substituted 5,7-dihydro-6H-dibenz [b, d] azepin-6-one
Tetrahedron by conductor manufacturing Robin D.Clark and Jahangir, 49 Vol, No. 7, P1351-1356,
A modified version of the 1993 ¹⁵ process was used. Specifically, appropriately substituted Nt-Boc-2
- amino-2 ^'- methyl-biphenyl was dissolved in THF, cooled to -78 ° C..
s-Butyllithium (1.3 M in cyclohexane, 2.2 eq.) was added slowly, keeping the temperature below -65 ° C. The resulting mixture was heated to −25 ° C. and stirred at that temperature for 1 hour. The mixture was cooled to -78C. Dry CO ₂ was bubbled through the mixture for 30 seconds. The mixture was warmed to ambient temperature and then carefully quenched with water. The mixture is concentrated under reduced pressure and then pN with 1N HCl
Adjusted to H3. The mixture was extracted with EtOAc and the organics were dried and concentrated to give a crude. The crude was dissolved in methanol and the solution was saturated with HCl. The mixture was heated at reflux for 12 hours and then cooled. Concentrating the mixture to obtain the crude lactam,
It was purified by chromatography or crystallization.

General Preparation Method 3-C 5-Amino-7-methyl-5,7-dihydro-6H-dibenz [b, d] azepine-
To a 6-one split round bottom flask was added the methanol of the racemic free base of the amine (1.0 eq.), Followed by di-p-toluoyl-D-tartaric acid monohydrate (
1.0 eq.). The mixture was concentrated in vacuo to give a residue, redissolved in the appropriate amount of methanol and stirred in an open system at room temperature (8-72 hours). The solid was removed by filtration. The enantiomeric excess was determined by chiral HPLC (Chiralcel ODR) (eluent, 15% acetonitrile and 85% H ₂ O, combined with 0.1% trifluoroacetic acid;
Flow rate 1.0 mL / min, 35 ° C.). The split di-p-toluoyl-D-tartrate was then combined with EtOAc and saturated N until the pH reached 9-10.
Dissolved in aHCO ₃ . The phases were separated and washed again and the organic phase with saturated NaHCO _3, H ₂ O and brine. The organic phase was dried over MgSO ₄ and the desiccant was removed by filtration. The filtrate was concentrated under vacuum. The free amine was dissolved in MeOH and HCl (1
2M, 1.0 eq.). The salt is concentrated under vacuum and the resulting film is
Triturated with tOAc. The HCl salt was filtered and rinsed with EtOAc. ee was determined by chiral HPLC.

Example 3-A 5-Amino-7-methyl-5,7-dihydro-6H-dibenz [b, d] azepine-
Synthesis step 6-one-hydrochloric acid A - 7-Methyl-5,7-dihydro-6H-dibenz [b, d] azepine-
Synthesis of 6-one Round bottom flask with sodium hydride (0.295 g, 7.46 mmol) in DMF
(9.0 mL), and 5,7-dihydro-6H-dibenz [b, d] azepine-
6-one (1.3 g, 6.22 mmol) (CAS # 20011-90-9, Te by Brown et al.
Treahedron letters , No. 8, 667-670 (1971) and references therein (manufactured as described in part of this specification). 1 at 60 ° C
After stirring for an hour, the solution was treated with methyl iodide (1.16 mL, 18.6 mmol),
Stirring was continued for 17 hours protected from light. After cooling, the reaction was diluted with _{CH 2 Cl 2 / H 2 O} , washed with NaHSO ₄ solution, H ₂ O, and dried over Na ₂ SO _4. Evaporation and purification by flash chromatography (SiO ₂ , CHCl ₃ ) afforded the title compound (0.885 g, 63%) as a colorless solid. NMR data are as follows: ¹ H-nmr (CDCl ₃ ): δ = 7.62 (d, 2H), 7.26-7.47 (m
, 6H), 3.51 (m, 2H), 3.32 (s, 3H). C ₁₅ H ₁₃ NO (MW = 223.27); mass spectroscopy (MH ⁺ ) 223. Elemental analysis (as C ₁₅ H ₁₃ NO): theoretical value: C, 80.69; H, 5.87 ; N
, 6.27, found: C, 80.11; H, 5.95; N, 6.23.

Step B -Synthesis of 7-methyl-5-oximo-5,7-dihydro-6H-dibenz [b , d] azepin-6-one The title compound isolated above (0.700 g, 3.14 mmol) ) With toluene (2
0 mL) and treated with butyl nitrite (0.733 mL, 6.28 mmol). The reaction temperature was reduced to 0 ° C. and the solution was KHMDS (9.42 mL, 0.5 M).
And treated under N ₂ atmosphere. After stirring for 1 hour, the reaction was quenched with a saturated solution of NaHSO ₄ , diluted with CH ₂ Cl ₂ and separated. The organic phase is dried over Na ₂ SO ₄ and the title compound is purified by chromatography (SiO ₂ , CHCl ₃ / MeOH (98
: 2)) to give a colorless solid (0.59 g, 80%). _{C 15 H 12 N 2 O 2} (MW = 252.275); mass spectroscopy (MH ⁺⁾ 252. Elemental analysis (as _{C 15 H 12 N 2 O 2} ): theoretical value: C, 71.42; H, 4.79 ;
N, 11.10, found: C, 71.24; H, 4.69; N, 10.87.

Step C— 5-Amino-7-methyl-5,7-dihydro-6H-dibenz [b,
d] Synthesis of azepin-6- one.hydrochloric acid The oxime (0.99 g, 3.92 mmol) isolated above was treated with 1 in a Parr apparatus.
Hydrogenated (35 psi) in 3A ethanol over 0% Pd / C (0.46 g). After 32 hours, the reaction mixture was filtered through a plug of celite and the filtrate was evaporated to give a foam, which was treated with a saturated solution of HCl (g) in Et ₂ O. The resulting colorless solid was filtered, rinsed with cold Et ₂ O and dried in vacuo to give the title compound (0.66 g, 61
%). NMR data are as follows: ¹ H-nmr (DMSO-d ₆ ): δ = 9.11 (bs, 3H), 7.78-7.4.
1 (m, 8H), 4.83 (s, 1H), 3.25 (s, 3H). _{C 15 H 14 N 2 O ·} HCl (MW = 274.753); mass spectroscopy (MH ⁺ free base) 238. Elemental analysis (as _{C 15 H 14 N 2 O ·} HCl): theoretical value: C, 65.57; H, 5
.50; N, 10.19, found: C, 65.27; H, 5.67; N, 10.13.
.

Example 3-B Preparation of (S)-and (R) -5- (L-alaninyl) amino-7-methyl-5,7-dihydro-6H-dibenz [b, d] azepin-6-one Synthesis Step A- (S)-and (R) -5- (N-Boc-L-alaninyl) amino-7
Synthesis of -methyl-5,7-dihydro-6H-dibenz [b, d] azepin-6-one Boc-L-alanine (0.429 g, 2.26 mmol) (Aldrich) was dissolved in THF, and HOBt. Hydrate (0.305 g, 2.26 mmol) and 5-amino-7-methyl-5,7-dihydro-6H-dibenz [b, d] azepin-6-one (0.45 g, 1.89 mmol) ( Processed using Example 3-A). The temperature was reduced to 0 ° C. and the reaction mixture was quenched with EDC (0.449 g, 2.26 mmol) (Al
It was treated with Drich), and stirred 17 hours under N _2. The reaction mixture is evaporated and the residue is
Diluted with tOAc / H ₂ O, washed with 1.0 N HCl, saturated NaHCO ₃ , brine and dried over Na ₂ SO ₄ . The diastereomers were separated on a Chiralcel OD column (eluent, 10% IPA / heptane; 1.5 mL / min). Isomer 1: retention time 3.37 minutes. The NMR data are as follows: ¹ H-nmr (CDCl ₃ ): δ = 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: [α] ₂₀ = −96 @ 589 nm (c = 1, MeOH). _{C 23 H 27 N 3 O 4} (MW = 409.489); mass spectroscopy (MH ⁺⁾ 409. Elemental analysis (as _{C 23 H 27 N 3 O 4} ): theoretical value: 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. The NMR data are as follows: ¹ H-nmr (CDCl ₃ ): δ = 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: [α] ₂₀ = 69 @ 589 nm (c = 1, MeOH). _{C 23 H 27 N 3 O 4} (MW = 409.489); mass spectroscopy (MH ⁺⁾ 409. Elemental analysis (as _{C 23 H 27 N 3 O 4} ): theoretical value: C, 67.46; H, 6.64 ;
N, 10.26; Found: C, 67.40; H, 6.62; N, 10.02.

Step B— (S) — and (R) -5- (L-alaninyl) amino-7-methyl-5,7 -dihydro -6H -dibenz [b, d] azepin-6-one hydrochloric acid The compound (each separated isomer) isolated in Part A of Synthesis is dissolved in dioxane, and excess H
Treated with Cl (gas). After stirring for 17 hours, evaporation and drying in vacuo, the title compound was isolated as a colorless solid. Isomer 1: C ₁₈ H ₁₉ N ₃ O ₂ .HCl (MW = 345.832); mass spectroscopy (MH ⁺ free base) 309. Optical rotation: [α] ₂₀ = −55 @ 589 nm (c = 1, MeOH). Isomer 2: C ₁₈ H ₁₉ N ₃ O ₂ .HCl (MW = 345.832); mass spectroscopy (MH ⁺ free base) 309. Optical rotation: [α] ₂₀ = 80 @ 589 nm (c = 1, MeOH).

Example 3-C of (S)-and (R) -5- (L-valinyl) amino-7-methyl-5,7-dihydro-6H-dibenz [b, d] azepin-6-one Synthesis Step A- (S)-and (R) -5- (N-Boc-L-valinyl) amino-7-
Synthesis of Methyl-5,7-dihydro-6H-dibenz [b , d] azepin-6-one Boc-L-valine (0.656 g, 3.02 mmol) (Aldrich) in THF
HOBt hydrate (0.408 g, 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 3-A). The temperature was reduced to 0 ° C. and the reaction mixture was treated with EDC (0.601 g, 3.02 mmol) (Aldrich) and 1 N ₂ under N _2.
Stir for 7 hours. The reaction mixture was evaporated, the residue was diluted with EtOAc / H ₂ O,
Washed with 1.0 N HCl, saturated NaHCO ₃ , brine and dried over Na ₂ SO ₄ . The diastereomers were separated on a Chiralcel OD column (eluent, 10% IPA / heptane; 1.5 mL / min). Isomer 1: retention time 3.23 minutes. Optical rotation: [α] ₂₀ = −120 @ 589 nm (c = 1, MeOH). _{C 25 H 31 N 3 O 4} (MW = 437.544); mass spectroscopy (MH ⁺⁾ 438. Isomer 2: Retention time 6.64 minutes. Optical rotation: [α] ₂₀ = 50 @ 589 nm (c = 1, MeOH). _{C 25 H 31 N 3 O 4} (MW = 437.544); mass spectroscopy (MH ⁺⁾ 438.

Step B— (S) — and (R) -5- (L-valinyl) amino-7-methyl-5,
Synthesis of 7-dihydro-6H-dibenz [b, d] azepin-6-one.hydrochloric acid The compound isolated in Part A (each separated isomer) was dissolved in dioxane, and excess H was added.
Treated with Cl (gas). After stirring for 17 hours, evaporation and drying in vacuo, the title compound was isolated as a colorless solid. Isomer _{1: C 20 H 23 N 3} O 2 · HCl (MW = 373.88); mass spectroscopy (MH ⁺ free base) 338. Optical rotation: [α] ₂₀ = −38 @ 589 nm (c = 1, MeOH). Isomer _{2: C 20 H 23 N 3} O 2 · HCl (MW = 373.88); mass spectroscopy (MH ⁺ free base) 338. Optical rotation: [α] ₂₀ = 97 @ 589 nm (c = 1, MeOH).

Example 3-D (S)-and (R) -5- (L-tert-leucine) amino-7-methyl-5,7
Synthesis of -dihydro-6H- dibenz [b, d] azepin-6-one Step A- (S)-and (R) -5- (N-Boc-L-tert-leucinyl) amino-7-methyl-5 , 7-Dihydro-6H-dibenz [b, d] azepine-6-
Synthesis of Boc-L-tert-leucine (0.698 g, 3.02 mmol) (Fluka) in THF was dissolved in THF, and HOBt hydrate (0.408 g, 3.02 mmol), D
IPEA (1.05 mL, 6.05 mmol) and 5-amino-7-methyl-5
, 7-Dihydro-6H-dibenz [b, d] azepin-6-one.hydrochloric acid (0.75 g
, 2.75 mmol) (Example 3-A). The temperature was reduced to 0 ° C. and the reaction mixture was treated with EDC (0.601 g, 3.02 mmol) (Aldrich) and stirred under N ₂ for 17 hours. The reaction mixture was evaporated and the residue was taken up in EtOAc / H ₂ O
And washed with 1.0 N HCl, saturated NaHCO ₃ , brine and dried over Na ₂ SO ₄ . These diastereomers are applied to a chiral cell OD column (eluate, 10%
(IPA / heptane; 1.5 mL / min). Isomer 1: retention time 3.28 minutes. Optical rotation: [α] ₂₀ = −128 @ 589 nm (c = 1, MeOH). _{C 26 H 33 N 3 O 4} (MW = 451.571); mass spectroscopy (MH ⁺⁾ 452. Isomer 2: retention time 5.52 minutes. Optical rotation: [α] ₂₀ = 26 @ 589 nm (c = 1, MeOH). _{C 26 H 33 N 3 O 4} (MW = 451.571); mass spectroscopy (MH ⁺⁾ 452.

Step B— (S) — and (R) -5- (L-tert-leucinyl) amino-7-
Methyl-5,7-dihydro-6H-dibenz [b , d] azepin-6-one.
The compound isolated in Synthesis Part A (each separated isomer) is dissolved in dioxane and excess H
Treated with Cl (gas). After stirring for 17 hours, evaporation and drying in vacuo, the title compound was isolated as a colorless solid. Isomer 1: C ₂₁ H ₂₅ N ₃ O ₂ .HCl (MW = 387.91); mass spectroscopy (MH ⁺ free base) 352. Optical rotation: [α] ₂₀ = −34 @ 589 nm (c = 1, MeOH). Isomer 2: C ₂₁ H ₂₅ N ₃ O ₂ .HCl (MW = 387.91); mass spectroscopy (MH ⁺ free base) 352. Optical rotation: [α] ₂₀ = 108 @ 589 nm (c = 1, MeOH).

Example 3-E Synthesis of 5- (N-Boc-amino) -5,7-dihydro-6H, 7H-dibenz [b, d] azepin-6-one Step A- 5-iodo-5, 7-dihydro-6H-dibenz [b, d] azepine-
Synthesis of 6-one 5,7-dihydro-6H-dibenz [b, d] azepin-6-one (1.0 g, 4.
77 mmol) (Example 3-A) and Et ₃ N (2.66mL, 19.12mm
ol) in CH ₂ Cl ₂ at −15 ° C. for 5.0 min.
(6 mL, 9.54 mmol). After stirring for 15 minutes, I ₂ (1.81 g, 7.
16 mmol) was added in one portion and the reaction was warmed to 5-10 ° C. over 3 hours. The reaction was quenched with saturated NaHCO ₃ , diluted with CH ₂ Cl ₂ and separated. The organics were washed with Na ₂ SO ₃ and NaHSO ₃ and dried over MgSO ₄ . After filtration, the organic matter was concentrated to about 20 mL, and further diluted with hexane (20 mL). The title compound was isolated by filtration as a tan precipitate.

Step B— 5-Azido-5,7-dihydro-6H-dibenz [b, d] azepine-
Synthesis of iodine isolates 6 on was dissolved in DMF, and treated with NaN ₃ (1.2 eq). 2
After stirring at 3 ° C. for 17 hours, the mixture was diluted with EtOAc / H ₂ O, separated, washed with brine and dried over MgSO ₄ . Triturate the title compound as a tan powder (
(From hot EtOAc).

Step C- 5- (N-Boc-amino) -5,7-dihydro-6H, 7H-diben
Synthesis of [b, d] azepin-6-one The azides were dissolved in THF / H ₂ O and stirred at 23 ° C. for 17 hours in the presence of Ph ₃ P (3.0 equivalents). The reaction was diluted and separated with 50% HOAc / toluene, the aqueous phase was extracted with toluene and evaporated to give an oily residue. The pH was adjusted to 7.0 with 1N NaOH, and the resulting HOAc salt was collected and dried in vacuo. Finally, in THF to those compounds, and treated with Boc anhydride (1.05 eq) and Et ₃ N (2.1 eq). After stirring at 23 ° C. for 5 hours, the reaction solution was filtered to isolate the title compound as a colorless powder.

Example 3-F 5-Amino-7- (2-methylpropyl) -5,7-dihydro-6H-dibenz [b
Synthesis of [, d] azepin-6-one-hydrochloric acid Step A- 5- (N-Boc-amino) -7- (2-methylpropyl) -5,7-
Synthesis of dihydro-6H-dibenz [b, d] azepin-6-one 5- (N-Boc-amino) -5,7-dihydro-6H-dibenz [b, d] azepin-6-one (0.2 g) , 0.617 mmol) (Example 3-E) in DMF was treated with Cs ₂ CO ₃ (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 was continued for 17 hours. After cooling to 23 ° C., the mixture was washed with CH ₂
Diluted with Cl _2, washed with several portions of brine and dried over Na ₂ SO _4. The title compound was purified by chromatography (SiO ₂ , CHCl ₃ / MeOH (9: 1)). _{C 23 H 28 N 2 O 3} (MW = 380.41); mass spectroscopy (MH ⁺⁾ 381. Elemental analysis (as _{C 23 H 28 N 2 O 3} ): theoretical value: C, 72.61; H, 7.42 ;
N, 7.36; Found: C, 72.31; H, 7.64; N, 7.17.

Step B— 5-Amino-7- (2-methylpropyl) -5,7-dihydro-6H
Synthesis of -dibenz [b, d] azepin-6-one.hydrochloride The compound isolated in Part A was deprotected in dioxane saturated with HCl gas.
After evaporation and drying in vacuo, the title compound was isolated as a slightly colored solid.

Example 3-G 5-Amino-7- (methoxyacetyl) -5,7-dihydro-6H-dibenz [b,
d] Synthesis of azepin-6-one.hydrochloric acid Step A- 5- (N-Boc-amino) -7- (methoxyacetyl) -5,7-di
Synthesis of hydro-6H-dibenz [b, d] azepin-6-one 5- (N-Boc-amino) -5,7-dihydro-6H-dibenz [b, d] azepin-6-one (1.03 g) (3.08 mmol) (Example 3-E) in DMF was treated with Cs ₂ CO ₃ (1.10 g, 3.39 mmol) and warmed to 60 ° C.
To the reaction mixture was added bromomethyl acetate (0.321 mL, 3.39 mmol) (
Aldrich) was added and stirring continued for 17 hours. After cooling to 23 ° C., the mixture was washed with CH ₂ C
diluted with l _2, washed with several portions of brine and dried over Na ₂ SO _4. The title compound was purified by chromatography (SiO ₂ , CHCl ₃ ). _{C 22 H 24 N 2 O 5} (MW = 396.44); mass spectroscopy (MH ⁺⁾ 397. Elemental analysis (as _{C 22 H 24 N 2 O 5} ): theoretical value: C, 66.65; H, 6.10 ;
N, 7.07, found: C, 66.28; H, 5.72; N, 6.50.

Step B— 5-Amino-7- (methoxyacetyl) -5,7-dihydro-6H-
Synthesis of dibenz [b, d] azepin-6-one.hydrochloride The compound isolated in Part A was deprotected in dioxane saturated with HCl gas.
After evaporation and drying in vacuo, the title compound was isolated as a colorless solid. _{C 17 H 16 N 2 O 3} · HCl (MW = 332.78); mass spectroscopy (MH ⁺ free base) 297.

Example 3-H 5-Amino-7- (3,3-dimethyl-2-butanonyl) -5,7-dihydro-6H
Synthesis of dibenz [b, d] azepin-6-one.hydrochloric acid Step A- 5- (N-Boc-amino) -7- (3,3-dimethylbutanonyl)-
Synthesis of 5,7-dihydro-6H-dibenz [b, d] azepin-6-one 5- (N-Boc-amino) -5,7-dihydro-6H-dibenz [b, d] azepin-6-one in DMF (0.2g, 0.617mmol) (example 3-E), it was treated with _{Cs 2 CO 3 (0.3g, 0.925mmol} ), warmed to 60 ° C..
To the reaction mixture was added 1-chloro-3,3-dimethyl-2-butanone (0.096 mL,
(0.74 mmol) (Aldrich) was added and stirring continued for 17 hours. After cooling to 23 ° C., the mixture was diluted with CH ₂ Cl ₂ , washed with several portions of brine and dried over Na ₂ SO ₄ . The title compound was isolated as a colorless solid. _{C 25 H 30 N 2 O 5} (MW = 422.522); mass spectroscopy (MH ⁺⁾ 423.

Step B— 5-Amino-7- (3,3-dimethyl-2-butanonyl) -5,7-di
Synthesis of hydro-6H-dibenz [b, d] azepin-6-one.hydrochloric acid The compound isolated in Part A was deprotected in dioxane saturated with HCl gas.
After evaporation and drying in vacuo, the title compound was isolated as a colorless solid.

Example 3-I L-alaninyl-5-amino-7-methyl-5,7-dihydro-6H-dibenz [
b, d] -Azepin-6-one · hydrochloric acid Synthesis step A: Nt-Boc-L-alanine and 5-amino-7-methyl-5,7-dihydro-6H-dibenz according to general preparation method D. Using [b, d] azepin-6-one, Nt-Boc-L-alaninyl-5-amino-7-methyl-5,
7-Dihydro-6H-dibenz [b, d] -azepin-6-one was prepared.

Step B: Following the general procedure of Step B of Example 1-C, Nt-Boc-L-
Alaninyl-5-amino-7-methyl-5,7-dihydro-6H-dibenz [b,
The title compound was prepared using d] -azepin-6-one. Other substitution Nt-
Boc-L-alaninyl-5-amino-7-methyl-5,7-dihydro-6H-
Dibenz [b, d] -azepin-6-one can also be produced by this production method.

Example 3-J L-valinyl-5-amino-7-methyl-5,7-dihydro-6H-dibenz [b
Step A: Synthesis of N, t-Boc-L-valine and 5-amino-7-methyl-5,7-dihydro-6H-dibenz [, d] -azepin-6-one.hydrochloride Using [b, d] azepin-6-one, Nt-Boc-L-valinyl-5-amino-7-methyl-5,7-
Dihydro-6H-dibenz [b, d] -azepin-6-one was prepared.

Step B: Following the general procedure of Step B of Example 1-C, Nt-Boc-L-
Valinyl-5-amino-7-methyl-5,7-dihydro-6H-dibenz [b, d]
The title compound was prepared using -azepin-6-one. Other substituted Nt-Bo
c-L-valinyl-5-amino-7-methyl-5,7-dihydro-6H-dibenz [b, d] -azepin-6-one can also be produced by this production method.

Example 3-K Synthesis of 5-amino-7-phenbutyl-5,7-dihydro-6H-dibenz [b, d] azepin-6-one 5,7-dihydro according to General Preparation 3-A -6H-dibenz [b, d] azepin-6-one ( Tetrahedron Letters , 8, 667-670 (1971) by Brown et al. And references therein, the contents of which are incorporated herein by reference). Produced as described in)
The title compound was prepared using and 1-chloro-4-phenylbutane.

Example 3-L 5-amino-7-cyclopropylmethyl-5,7-dihydro-6H-dibenz [b
Synthesis of 5,7-dihydro-6H-dibenz [b, d] azepin-6-one (Brown et al., Tetrahedron Letters , 8, No. 667-). The title compound was prepared using 670 (1971) and the references therein (prepared as described herein) and (bromomethyl) cyclopropane (Aldrich).

[0286] Example 3-M 5-amino-7- (2 ^{', 2',} 2 ^'- trifluoroethyl) -5,7-dihydro -6H
Synthesis of -dibenz [b, d] azepin-6-one 5,7-dihydro-6H-dibenz [b, d] azepin-6-one (Brown et al., Tetrahedron Letters , 8). No., 667-670 (1971) and references therein (prepared as described herein), and 1-bromo-2,2,2-trifluoroethane (Aldrich). ) Was used to produce the title compound.

Example 3-N Synthesis of 5-amino-7-cyclohexyl-5,7-dihydro-6H-dibenz [b, d] azepin-6-one 5,7-dihydro according to General Preparation 3-A -6H-dibenz [b, d] azepin-6-one (Brown et al., Tetrahedron Letters , 8, 667-670 (1971) and references therein, the contents of which are incorporated herein by reference. ) And bromocyclohexane (Aldrich) to give the title compound.

Example 3-O 5- (L-alaninyl) amino-9-fluoro-7-methyl-5,7-dihydro-
Synthesis of 6H-dibenz [b, d] azepin-6-one.hydrochloric acidStep A: 2-Bromo-5-fluorotoluene was stirred in THF at -78 ° C.
Was. Slowly add s-BuLi (1.05 eq., 1.3 M cyclohexane solution)
The mixture was stirred for 45 minutes. Add trimethyl borate (1.5 eq.)
The mixture was warmed to ambient temperature. After stirring for 1 hour, pinacol (2 eq.) Was added.
I got it. The mixture was stirred for 16 hours and then concentrated under reduced pressure. The resulting residue is CH _Two Cl_TwoIn water and filtered through celite. Concentrate the filtrate to an oil
Obtained and inactivated silica gel chromatography (eluent, Et_ThreeN
) To give the arylboronic ester.

Step B: 2-bromoaniline (1 eq.) And di-t-butyl dicarbonate (1.
1 eq.) At 80 ° C. for 20 hours. The resulting mixture was cooled and distilled directly using hose vacuum to give Nt-Boc-2-bromoaniline.

Step C : Nt-2-bromoaniline (Step 2, 1 eq.), Their arylboronic esters (Step 1, 1.1 eq.), K ₂ CO ₃ (1.1 eq.) And tetrakis ( (Triphenylphosphine) palladium (0) (0.02 eq.) Was stirred in 20% water / dioxane under nitrogen. The solution was heated at reflux for 10 hours. The mixture was cooled then concentrated. The obtained residue was partitioned between water and chloroform. The organics were dried and concentrated to give an oil which was chromatographed on silica gel (C
H ₂ Cl ₂ / hexane (1: 1) was purified by use).

Step D: According to General Production Method 3-B, using substituted biphenyl from Step 3
9-Fluoro-5,7-dihydro-6H-dibenz [b, d] azepin-6-one was prepared.

Step E : 9-fluoro-5,7-dihydro-6H-dibenz [b, d] azepin-6-one (1 eq., Step 4), cesium carbonate (1.1 eq., Aldrich) and iodide Methyl (1.1 eq., Aldrich) was stirred in dry DMF at ambient temperature for 16 hours. The mixture was concentrated under reduced pressure to give a residue, which was partitioned between EtOAc and water. The organics were dried and concentrated to give an oil which was purified by silica gel chromatography to give 9-fluoro-7-methyl-5,7-dihydro-6.
H-dibenz [b, d] azepin-6-one was obtained.

Step F: 9-Fluoro-7- from General Production Method 3-A, Step B and Step 5
According to methyl-5,7-dihydro-6H-dibenz [b, d] azepin-6-one
5-amino-9-fluoro-7-methyl-5,7-dihydro-6H-dibenz [b
[d] azepin-6-one was prepared.

Step G: According to the preparation method of Example 3-I, 5-amino-9-fluoro-7-methyl-5,7-dihydro-6H-dibenz [b, d] azepin-6-one from Step 6 Was used to produce the title compound.

Example 3-P Synthesis of 5- (L-alaninyl) amino-13-fluoro-7-methyl-5,7-dihydro-6H-dibenz [b, d] azepin-6-one.hydrochloric acid Example Following the procedure for 3-O, the title compound was prepared using 2-bromo-4-fluoroaniline (Step 2, Lancaster) and o-tolylboronic acid (Step 3, Aldrich).

Example 3-Q Synthesis of 5- (L-alaninyl) amino-10-fluoro-7-methyl-5,7-dihydro-6H-dibenz [b, d] azepin-6-one.hydrochloride Example The title compound was produced according to the method of 3-O using 2-bromo-4-fluorotoluene (Step 1).

Example 3-R 5- (L-alaninyl) amino-7-cyclopropylmethyl-5,7-dihydro-
Synthesis of 6H-dibenz [b, d] azepin-6-one.hydrochloric acid According to the preparation method of Example 3-I, 5-amino-7-cyclopropylmethyl-5,7
The title compound was prepared using -dihydro-6H-dibenz [b, d] azepin-6-one (Example 3-L).

Example 3-S Synthesis of 5- (L-alaninyl) amino-7-phenbutyl-5,7-dihydro-6H-dibenz [b, d] azepin-6-one.hydrochloride of Example 3-I The title compound was prepared according to the manufacturing method using 5-amino-7-phenbutyl-5,7-dihydro-6H-dibenz [b, d] azepin-6-one (Example 3-K).

Example 3-T 5- (L-valinyl) amino-7-cyclopropylmethyl-5,7-dihydro-6
Synthesis of H-dibenz [b, d] azepin-6-one.hydrochloric acid According to the preparation method of Example 3-J, 5-amino-7-cyclopropylmethyl-5,7
The title compound was prepared using -dihydro-6H-dibenz [b, d] azepin-6-one (Example 3-L).

Example 3-U Synthesis of 5- (L-valinyl) amino-7-phenbutyl-5,7-dihydro-6H-dibenz [b, d] azepin-6-one.hydrochloride of Example 3-J The title compound was prepared according to the manufacturing method using 5-amino-7-phenbutyl-5,7-dihydro-6H-dibenz [b, d] azepin-6-one (Example 3-U).

Example 3-V 5- (L-valinyl) amino-7-hexyl-5,7-dihydro-6H-dibenz [
Synthesis process of [b, d] azepin-6-one.hydrochloride A: According to general production method 3-A, 5,7-dihydro-6H-dibenz [b,
d] Azepin-6-one ( Tetrahedron Letters , 8, No. 667-670 by Brown et al. (19
71) and the references therein (prepared as described in this specification) and 1-bromohexane (Aldrich) using 5-amino-7-
Hexyl-5,7-dihydro-6H-dibenz [b, d] azepin-6-one was prepared.

Step B: According to the preparation method of Example 3-J, 5-amino-7-hexyl-5,7-
The title compound was prepared using dihydro-6H-dibenz [b, d] azepin-6-one.

Example 3-W 5- (L-valinyl) amino-10-fluoro-7-methyl-5,7-dihydro-
Synthesis of 6H-dibenz [b, d] azepin-6-one.hydrochloric acid According to the method of Example 3-J, 5-amino-10-fluoro-7-methyl-5,
The title compound was prepared using 7-dihydro-6H-dibenz [b, d] azepin-6-one (as prepared in Example 3-Q).

Example 3-X 5- (L-valinyl) amino-13-fluoro-7-methyl-5,7-dihydro-
Synthesis of 6H-dibenz [b, d] azepin-6-one.hydrochloric acid According to the production method of Example 3-J, 5-amino-13-fluoro-7-methyl-5,
The title compound was prepared using 7-dihydro-6H-dibenz [b, d] azepin-6-one (as prepared in Example 3-P).

Example 3-Y 5- (L-valinyl) amino-13-fluoro-7-methyl-5,7-dihydro-
Synthesis of 6H-dibenz [b, d] azepin-6-one.hydrochloric acid According to the preparation method of Example 3-J, 5-amino-9-fluoro-7-methyl-5,7
The title compound was prepared using -dihydro-6H-dibenz [b, d] azepin-6-one (as prepared in Example 3-O).

Example 3-Z (5-amino-7-methyl-1,2,3,4,5,7-hexahydro-6H-
Synthesis of dicyclohexyl [b, d] azepin-6-one 5-Amino-7-methyl-5,7-dihydro-6H-dibenz [b, d] azepin-6-one.hydrochloride (Example 3-A) , Dissolved in an EtOAc / HOAc (1: 1) mixture. 5% Rh / C was added and the mixture was stirred at 60 ° C. under hydrogen (60 psi). After 3 days, the mixture was filtered and the filtrate was concentrated to give an oil which was purified by SC
Purification by X-cation exchange chromatography provided the title compound.

Example 3-AA Synthesis of 5- (S) -amino-7-methyl-5,7-dihydro-6H-dibenz [b, d] azepin-6-one.hydrochloric acid According to General Preparation Method 3-C 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 monohydrate (1.0 eq.) Using 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 9.97 minutes. Unwanted enantiomer 2: retention time 8.62 minutes. The NMR data are as follows: ¹ H-nmr (CDCl ₃ ): δ = 9.39 (s, 2H), 7.75-7.42 (m
, 8H), 4.80 (s, 1H), 3.30 (s, 3H). C ₁₅ H ₁₅ ClN ₂ O (MW = 274.75); mass spectroscopy (MH ⁺ ) 239.1
. Elemental analysis (as _{C 15 H 15 ClN 2 O 3} ): theoretical value: C, 66.57; H, 5.5
N; 10.20; Found: C, 65.51; H, 5.61; N, 10.01.

Example 3-AB 9-Amino-5,6-dihydro-4H-quino [8,1-ab] [3] benzazepine-
8 (9H) - degassed on-synthesis process A 8-phenylquinoline synthetic 8-bromo quinoline hydrochloride (1.0g, 4.81mmol) (Aldrich) in dioxane _{(50mL) / H 2 O (} 10mL) The solution was washed with phenylboronic acid (0.6
4 g, 5.29 mmol) (Aldrich), Pd (Ph ₃ P) ₄ (0.050 g, 0.04
mmol) and _{K 2 CO 3 (0.73g, 5.29mmol} ) was treated with.
After refluxing under a N ₂ atmosphere for 4 hours, the reaction was cooled, diluted with EtOAc and separated. Dried over Na ₂ SO ₄ and chromatographed on SiO ₂ (hexane / EtOA)
c (95: 5)) After purification, the title compound was isolated as a colorless oil. The physical data is as follows. ¹ H-nmr (CDCl ₃ ): δ = 8.97 (d, 1H), 8.22 (dd, 1H)
, 7.87-7.39 (m, 9H). _{C 15 H 11 N (MW =} 205); mass spectroscopy (MH ⁺⁾ 206.

Step B Synthesis of 8-phenyl-1,2,3,4-tetrahydroquinoline
Hydrogenated according to the procedure described in CS Perkin I (1980), 1933-1938. The physical data is as follows. ¹ H-nmr (CDCl ₃ ): δ = 7.46 (m, 3H), 7.38 (m, 2H),
6.98 (m, 2H), 6.70 (m, 1H), 3.27 (t, 2H), 2.86 (t,
2H), 1.96 (m, 2H). _{C 15 H 15 N (MW =} 209); mass spectroscopy (MH ⁺⁾ 210.

Step C 1-Chloromethylacetyl-8-phenyl -1,2,3,4-tetrah
The product (1.0 g, 4.78 mmol) from the synthesis step B of droquinoline was added to CH ₂ Cl ₂ (20 mL).
/ H ₂ O (10 mL) and NaHCO ₃ (0.602 g, 7.18 mmol)
Followed by chloroacetyl chloride (0.478 mL, 5.26 mm
ol). After stirring at 23 ° C. for 17 hours, the reaction was diluted with CH ₂ Cl ₂ , washed with saturated aqueous NaHCO ₃ , dried over Na ₂ SO ₄ ,
Purification by iO ₂ chromatography (CHCl ₃ / hexane (9: 1)) was performed. The title compound was isolated as a colorless solid. The physical data is as follows. C ₁₇ H ₁₆ ClNO (MW = 286.77); mass spectroscopy (MH ⁺ ) 287. Elemental analysis (as C ₁₇ H ₁₆ ClNO): theoretical value: C, 71.45; H, 5.64
N, 4.90; Found: C, 71.63; H, 5.60; N, 4.87.

Step D 5,6-Dihydro-4H-quino [8,1-a, b] [3] benzazepine-
The product (0.89 g, 3.11 mmol) from the synthesis step C of 8 (9H) -one was converted to AlCl ₃ (0.87 g).
, 6.54 mmol) at 23 ° C. and the mixture was heated at 100 ° C. for 5-7 minutes. After vigorous gas evolution, the melted mixture was cooled and extracted with CH ₂ Cl ₂ / NaHCO ₃ (sat.) In several portions. The combined organic phases were dried over Na ₂ SO ₄ and the title compound was purified by chromatography (SiO ₂ , CHCl ₃ / hexane (9: 1)) to give a colorless oil which solidified on standing. . The physical data is as follows. _{C 17 H 15 NO (MW =} 249.312); mass spectroscopy (MH ⁺⁾ 250. Elemental analysis (as C ₁₇ H ₁₅ NO): theoretical value: C, 81.90; H, 6.06 ; N
5.62; Found: C, 81.75; H, 6.11; N, 5.86.

Step E 9-oximo-5,6-dihydro-4H-quino [8,1-a, b] [3] be
Synthesis of Ndazepin-8 (9H) -one The product from step D (0.490 g, 1.97 mmol) was dissolved in THF and butyl nitrite (0.46 mL, 3.93 mmol) and the KHMDS (0. .5
M, 4.52 mL, 2.26 mmol). After stirring for 1 hour, the reaction was quenched with cold 1N HCl, extracted with EtOAc, the combined organic phases were dried over Na ₂ SO ₄ and chromatographed on SiO ₂ (CHCl ₃ / hexane (9: 1)). ). The product was isolated as a colorless solid. The physical data is as follows. _{C 17 H 14 N 2 O 2} (MW = 278.3); mass spectroscopy (MH ⁺⁾ 279. Elemental analysis (as _{C 17 H 14 N 2 O 2} · 0.3317mmol H 2 O): Calculated:
H, 5.19; N, 9.85; Found: C, 71.85; H, 5.8.
09; N, 9.59.

Step F 9-Amino-5,6-dihydro-4H-quino [8,1-a, b] [3] ben
The product (0.360 g, 1.29 mmol) from synthesis step E of zuazepin-8 (9H) -one was added to EtOH (50 mL).
) / NH ₃ (anhydrous) (5.0 mL) over Ra / Ni (0.05 g) at 100 ° C.
The hydrogenation reaction was performed at 500 psi for 10 hours. The catalyst was removed by filtration, and the obtained filtrate was purified by SiO ₂ chromatography (CHCl ₃ / MeOH (98: 2)) to isolate the title compound as a colorless oil, which solidified on standing. The physical data is as follows. _{C 17 H 16 N 2 O (} MW = 264.326); mass spectroscopy (MH ⁺⁾ 266. Elemental analysis (as _{C 17 H 16 N 2 O)} : theory: C, 77.25; H, 6.10 ;
N, 10.60; Found: C, 77.23; H, 6.15; N, 10.49.

[0314] Example 3-AC 9- (N ^'-L- alaninyl) amino-5,6-dihydro--4H- Kino [8, 1-ab
] [3] benzazepine -8 (9H) - Synthesis Step A 9- (N ^'-Boc-L- alaninyl) on-hydrochloride-amino-5,6-dihydro -4H
Synthesis of quino [8,1-ab] [3] benzazepin-8 (9H) -one Following general procedure D, N-Boc-alanine (Aldrich) and 9-amino-
5,6-dihydro-4H-quino [8,1-ab] [3] benzazepine-8 (9H)-
The title compound was prepared using ON (Example 3-AB). The physical data is as follows. _{C 25 H 29 N 3 O 4} (MW = 435.521); mass spectroscopy (MH ⁺⁾ 436. Elemental analysis (as C ₂₅ H ₂₉ N ₃ O ₄ .0.4102 mol H ₂ O): theoretical value: C
H, 6.79; N, 9.49; Found: C, 67.83; H, 6.9.
1; N, 9.29.

[0315] Step B 9- (N ^'-L- alaninyl) amino-5,6-dihydro--4H- Kino [
Synthesis of 8,1-ab] [3] benzazepin-8 (9H) -one.hydrochloride The title compound was prepared using the product from Step A according to General Preparation Method E. The physical data is as follows. _{C 20 H 21 N 3 O 2} · HCl (MW = 371.6); mass spectroscopy (free base MH ⁺⁾ 335.

Example 3-AD 5- [L-alaninyl] amino-7- (2-methylpropyl) -5,7-dihydro-
Synthesis of 6H-dibenz [b, d] azepin-6-one-hydrochloric acid According to the above general process D, N-Boc-L-alanine (Aldrich) and 5-
Amino-7- (2-methylpropyl) -5,7-dihydro-6H-dibenz [b, d]
The title compound as a tan foam was prepared using azepin-6-one.hydrochloric acid (Example 3-F). The resulting Boc group was removed using 2.0M HCl / dioxane. After evaporation and drying in vacuo, the title compound was isolated as a slightly colored solid. C ₂₁ H ₂₄ N ₃ O ₂ .HCl (MW = 386); mass spectroscopy (MH ^{+ of the} free base) 351.

Example 3-AE 5- [L-alaninyl] amino-5,7-dihydro-6H, 7H-dibenz [b, d]
Synthesis of azepin-6-one.hydrochloric acid Step A5-amino-5,7-dihydro-6H, 7H-dibenz [b, d] azepi
Synthesis of N-6-one ・ hydrochloric acid 5- (N-Boc-amino) -5,7-dihydro-6H, 7H-dibenz [b, d]
Azepin-6-one (Example 3-E) was prepared using 2.0 M HCl / dioxane.
Processed. After stirring at 23 ° C. for 17 hours, after filtration and drying under vacuum,
The title compound was isolated. C₁₄H₁₂N_TwoO.HCl (MW = 260.72); mass spectroscopy (MH of free base) ⁺ ) 225. Elemental analysis (C₁₄H₁₂N_TwoO.HCl): Theory: C, 64.50; H, 5
.03; N, 10.74; Found: C, 64.35; H, 4.99; N, 10.51.
.

Step B Synthesis of 5- [N-Boc-L-alaninyl] amino-5,7-dihydro-6H, 7H-dibenz [b, d] azepin-6-one The separated compound was Boc-L-alanine (Aldr
ich). The title compound was used without further purification. _{C 22 H 25 N 4 O 4} (MW = 395.45); mass spectroscopy (MH ⁺⁾ 396. Elemental analysis (as _{C 22 H 25 N 4 O 4} ): theoretical value: C, 66.82; H, 6.37 ;
N, 10.63; Found: C, 65.53; H, 6.16; N, 10.38.

Step C 5- [L-alaninyl] amino-5,7-dihydro-6H, 7H-diben
Synthesis of z [b, d] azepin-6-one.hydrochloride The compound isolated above was deprotected using HCl / dioxane. 1 at 23 ° C
After stirring for 7 hours and drying in vacuo, the title compound was used without further purification.

D. Benzodiazepine Derivatives and Related Compounds General Preparation 4-A benzodiazepine N-1-methylated benzodiazepine (1 eq.) In DMF (0.1 M) was added at 0 ° C.
Treated with potassium t-butoxy (1.0 eq., 1.0 M in THF). 0 ° C
After stirring for 30 minutes, iodomethane (1.3 eq.) Was added, and stirring was continued for 25 minutes. The mixture was diluted with dichloromethane and washed with water and brine. Organic phase N
Dry over a ₂ SO ₄ , filter and concentrate. The crude product was then purified by trituration (using ether / hexane (1: 1)) or HPLC chromatography (eluent, ethyl acetate / hexane).

General Preparation 4-B Cbz Removal Procedure A flask was filled with Cbz -protected 3-aminobenzodiazepine (1 eq.). To this was added HBr (34 eq .; 30% acetic acid solution). Within 20 minutes, all of the starting material had dissolved. The reaction was stirred at ambient temperature for 5 hours. Addition of ether to the orange solution precipitated the amine HBr salt. The mixture was decanted. This step of ether addition and decantation was repeated three times to remove acetic acid and benzyl bromide. Toluene was added and the mixture was concentrated under vacuum. This step was repeated again. The HBr salt was partitioned between ethyl acetate and 1M K ₂ CO _3. The aqueous phase was re-extracted with ethyl acetate. Combine organics and wash with brine, N
It was dried over a ₂ SO ₄ , filtered and concentrated.

General Preparation 4-C Boc Removal A solution of Boc-protected amine (1 eq.) In dichloromethane (0.15M) 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 temperature for 20 minutes to 1 hour. The mixture was concentrated under vacuum to remove excess trifluoroacetic acid. The residue was dissolved in dichloromethane, saturated NaHCO ₃ aqueous solution or 1M K ₂ CO _3, and brine.
The organic phase was dried over Na ₂ SO ₄ , filtered and concentrated.

General Preparation Method Azide Transfer Reaction Using 4-D KHMDS The azide derivative was synthesized by John W. Butcher et al., Tet. Lett., 37, 6685-6688 (1996).
(The contents constitute a part of the present specification).

General Preparation Method 4- Azide Transfer Reaction Using LDA -Diisopropylamine (1.1 eq.) Cooled to 78 ° C. in dry THF (1
mL) solution while maintaining the reaction temperature at -78 ° C.
M hexane solution) (1.1 eq.) Was added dropwise. The reaction mixture was stirred at −78 ° C. for 30 minutes, then lactam (0.471 mM) was added dropwise as a solution in dry THF (1 mL). The reaction mixture was stirred at -78 ° C for 30 minutes, then a pre-cooled solution of trisyl azide (1.2 eq.) Was added as a solution in dry THF (1 mL). The reaction mixture was then stirred at 40 ° C. for 20 minutes, then acetic acid (4.0 eq.
). The reaction mixture was then allowed to stir at 40 ° C. for 2 hours. The reaction was then poured into EtOAc, washed with water, sodium bicarbonate and brine, then dried over sodium sulfate, filtered and concentrated. The residue was purified by LC2000 chromatography.

General Preparation Method 4- Reduction Reaction of Azide Group: The reaction described in John W. Butcher et al., Tet. Lett., 37, 6685-6688 (1996), the contents of which are incorporated herein by reference. The azide group was reduced to the corresponding primary amine using the procedure.

General Preparation Amide or lactone using 4-G sodium hydride or potassium tert-butoxide
N-alkylation of tam Dry sodium D or potassium tert-butoxide (1.1 eq.)
An appropriate amide (0.0042 mol) was added to a MF (15 mL) slurry in DMF (
10 mL) as a solution. The alkyl iodide was then added, producing a thick slurry. The reaction became less concentrated over time and upon completion by TLC, the reaction became homogeneous. The reaction mixture was poured on ice and extracted with ethyl acetate. The organic phase was washed with water, followed by brine. The organic phase was then dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by HPLC (LC2000; eluent, ethyl acetate / hexane system).

General Preparation 4- N-Alkylation of Amides or Lactams with HHMHMDS KHMDS was added dropwise to the appropriate amide or lactam THF cooled to -78 ° C and the reaction mixture was added at -78 ° C for 30 minutes. Stirred for minutes. Then, while maintaining the temperature at -70 ° C, alkyl iodide was added dropwise. Then, the cooling bath was removed, the reaction solution was heated to room temperature, and stirring was continued for 2 hours. Then the reaction mixture was poured on ice and extracted into ethyl acetate. The organic extract was washed with water followed by brine. The organic phase was then dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by HPLC (LC20
00; eluate, ethyl acetate / hexane system).

General Production Method 4-I N-Alkylation Reaction of Amide or Lactam Using Cesium Carbonate To a solution of amide or lactam in DMF was added cesium carbonate (1.05 eq.) And alkyl iodide (1.1 eq.). added. The mixture was stirred at room temperature overnight, then the reaction mixture was diluted with ethyl acetate and washed with water followed by brine. The organic phase was dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by HPLC (LC2000; eluent, ethyl acetate / hexane system).

General Preparation 4-J BOC Removal Procedure The N-Boc protected compound was added to CH ₂ Cl ₂ / 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, water, washed with saturated sodium bicarbonate, dried over Na ₂ SO _4, filtered and concentrated to give free amine.

General Preparation Method 4-K Azide Transfer Method This azide transfer method is described in Evans, DA; Britton, TC; Ellman, JA; Dorow, R.
L. J. Am. Chem. Soc. 1990, 112. 4011-4030, the contents of which are incorporated herein by reference. T of lactam substrate (1.0 eq.)
In HF solution (~0.1M), N ₂ under at _{-78 ℃ KN (TMS) 2 (} 1.1eq., 0.
(5M toluene solution, Aldrich) was added dropwise over 2-10 minutes. A slight exotherm was observed with an internal thermometer, and the resulting solution was stirred for 5-15 minutes while re-cooling to -78 ° C. Then, trisyl azide (1.1-1.5 eq., CAS No. 36982-84-0, previously cooled to −78 ° C. or room temperature, cited in the above-mentioned reference to Evans (the content of which is incorporated herein by reference) Part of the product)
-0.5M) was added via cannula over 0.5-5 minutes. Again, generally a slight exotherm was recorded. The resulting solution was stirred for 5-10 minutes while recooling to -78 ° C. Next, AcOH (4.5-4.6 eq., Glacial acetic acid) was added, and the cooling bath was removed.
The mixture was allowed to warm to room temperature with stirring for 12-16 hours. T at the start of the mixture
Dilute with 2 to 5 volumes of HF with EtOAc and dilute aqueous NaHCO ₃ (1-2
×), 0.1 to 1.0 M hydrochloric acid (0 to 2 ×) and brine (1 ×). Then dry the organic phase over MgSO _4, filtered and concentrated to give the crude product.

General Preparation 4- Reduction of Azide to L- Amine A mixture of azide / anhydrous EtOH (0.03-0.07M) and 10% Pd / C (〜1 / 3 by weight of azide) was added to Parr during device, H ₂ under (35～45Psi
), Shaking at room temperature for 3-6 hours. The catalyst was removed by filtration through a plug of celite, rinsed with anhydrous EtOH, and the filtrate was concentrated to give the crude amine product.

General Production Method 4-Methylation reaction of amide using cesium carbonate This production method is described in PCT application WO96-40655 by Claremon, DA et al. (The contents of which are incorporated in the present specification). This is an improved method. 2,4-dioxo-2,3,4,
To a mixture of 5-tetrahydro-1H-1,5-benzodiazepine (CAS number 49799-48-6) in DMF (1.0 eq., 0.7 M) was added Cs ₂ CO ₃ (2.2 e) at room temperature under N ₂ at room temperature.
q.) and the appropriate alkyl iodide (2.2 eq.). Mix the mixture at room temperature for 5.
Stir for 5-16 hours. The mixture was partitioned with saturated NaHCO ₃ and EtOAc. The aqueous phase was extracted with EtOAc (1 to 2 ×), dried over Na ₂ SO ₄ the combined EtOAc extracts were filtered and concentrated to give the crude product.

[0333] General Procedure 4-N BOC Removal Method under N _2, for 10 to 15 minutes, the 1,4-dioxane stirred solution of N-t-Boc protected amino acid was cooled to in an ice bath to 10 ° C., anhydrous HCl gas vapor was vented. The solution was sealed, the cold bath was removed, and the solution was allowed to warm to room temperature with stirring for 2-8 hours, monitoring the consumption of starting material by TLC. The solution was concentrated (and dissolved, for example, in CH ₂ Cl ₂ , then concentrated again and placed in a vacuum oven at 60-70 ° C. to remove most of the residual dioxane) and used without further purification. Was.

Example 4-A Synthesis of 3-Amino-1,3-dihydro-5- (1-piperidinyl) -2H-1,4-benzodiazepin-2-one Step A -1,2,2-dihydro-3H- 1-methyl-5- (1-piperidinyl)-
Preparation of 1,4-benzodiazepin-2-one A solution of phosphorus pentachloride (1.2 eq.) In dichloromethane was added to 1-methyl-1,2,3,
4-tetrahydro-3H-1,4-benzodiazepine-2,5-dione (Showell,
It was added to a solution of J. Med. Chem., 1994, 37, 719 by GA et al., The contents of which are incorporated herein, in dichloromethane. The resulting yellowish-orange solution was stirred at ambient temperature for 2.5 hours; the solvent was removed under vacuum. The orange residue was redissolved in dichloromethane, cooled to 0 ° C. and treated with a solution of piperidine (2 eq.) And triethylamine (2 eq.) In dichloromethane. The cooling bath was removed and the reaction was stirred for 18 hours. The reaction mixture was washed with saturated aqueous NaHCO ₃ (re-extracted with dichloromethane) and brine. The organic phase was dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified by HPLC (eluent, methanol / dichloromethane (4-10% gradient)) to give the title intermediate as a yellow solid (mp: 103-105 ° C). _{C 15 H 19 N 3 O (} MW = 257.37); mass spectroscopy (MH ⁺⁾ 257. Elemental analysis (as _{C 15 H 19 N 3 O)} : theory: C, 70.01; H, 7.44 ;
N, 16.33; Found: C, 69.94; H, 7.58; N, 16.23.

Step B- 1,2-Dihydro-3H-1-methyl-3-oxyimido-5- (1
Preparation of -piperidinyl ) -1,4-benzodiazepin-2-one -1,2-dihydro-3H-1-methyl-5- (1-piperidinyl) -at 20 ° C.
To a toluene solution of 1,4-benzodiazepin-2-one (1 eq.) Was added tert-
Butoxy potassium (2.5 eq.) Was added in two portions. After stirring at −20 ° C. for 20 minutes, isoamyl nitrite (1.2 eq., Aldrich) was added to the red reaction mixture. The reaction was stirred at −20 ° C. for 5 hours, during which time the reaction was checked by TLC. The cooling bath was removed and the reaction was quenched with 0.5M citric acid. After stirring for 10 minutes,
Diethyl ether was added. The suspension was stirred overnight at ambient temperature and then filtered, washing with ether. The resulting cream colored solid has a melting point of 197-
200 ° C. The NMR data for the E / Z isomer are as follows: ¹ H-nmr (300 MHz, CDCl ₃ ): δ = 7.64 (1H, bs), 7.4
8 (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 15 H 18 N 4 O 2} (MW = 286.37); mass spectroscopy 286.

Step C- 1,2-Dihydro-3H-1-methyl-3- [O- (ethylaminoca
Rubonyl) oximido] -5- (1-Piperidinyl) -1,4-benzodi
Preparation of azepin-2-one A THF mixture of 1,2-dihydro-3H-1-methyl-3-oxyimido-5- (1-piperidinyl) -1,4-benzodiazepin-2-one (1 eq.) Treatment with isocyanate (1.7 eq.) And triethylamine (0.6 eq.). The mixture was heated to 64 ° C. for 4 hours. The mixture is concentrated and the residue is purified by HPLC
(Eluent, 5% methanol / dichloromethane). The NMR data for the E / Z isomer are as follows: ¹ H-nmr (300 MHz, CDCl ₃ ): δ = 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 18 H 23 N 5 O 3} (MW = 357.46); mass spectroscopy 357.

Step D- 3-Amino-1,3-dihydro-2H-1-methyl-5- (1-pipe
Preparation of (ridinyl) -1,4-benzodiazepin-2-one 1,2-dihydro-3H-1-methyl-3- [O- (ethylaminocarbonyl) oxymido] -5- (1-piperidinyl) -1,4 -Benzodiazepin-2-one (1
eq.) was hydrogenated (43 psi) over 5% palladium on carbon (0.15 eq.) in methanol for 3.25 hours. The reaction was filtered through celite and concentrated under vacuum. The residue was dissolved in dichloromethane and filtered through celite twice. The filtrate was concentrated and the resulting foam was used immediately.

Example 4-B 3- (L-alaninyl) amino-2,3-dihydro-1-methyl-5-phenyl-
Synthesis of 1H-1,4-benzodiazepin-2-one Step A- (S) -3-amino-1,3-dihydro-1-methyl-5-phenyl
-2H-1,4-benzodiazepin-2-one, (1S) -7,7-dimethyl-2-
Preparation of oxobicyclo [2.2.1] heptane-1-methanesulfonate Starting according to J. Org. Chem. 1987, 52, 955 by Reider, PJ et al., The contents of which are hereby incorporated by reference. 3-amino-1,3-dihydro-1-
Methyl-5-phenyl-2H-1,4-benzodiazepin-2-one Bock, MG
The title compound was prepared using J. Org. Chem. 1987, 52, 3232, which is incorporated herein by reference.

Step B- 3- [N ^′ -(tert-butylcarbamate) -L-alaninyl]
Mino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodia
Preparation of Zepin-2-one (S) -3-Amino-1,3-dihydro-1-methyl-5-phenyl-2H-1,
4-Benzodiazepin-2-one, (1S) -7,7-dimethyl-2-oxobicyclo [2.2.1] heptane-1-methanesulfonate was added to dichloromethane and 1
The free base was obtained by partitioning with M potassium carbonate. Then, the free base was subjected to a coupling reaction with N-Boc-alanine according to General Production Method D. _{C 24 H 28 N 4 O 4} (MW = 436.56); mass spectroscopy 436. Elemental analysis (as _{C 24 H 28 N 4 O 4} ): theoretical value: C, 66.03; H, 6.47 ;
N, 12.84; Found: C, 65.79; H, 6.68; N, 12.80.

Step C- 3- (L-alaninyl) amino-2,3-dihydro-1-methyl-5
Preparation of phenyl-1H-1,4-benzodiazepin-2-one Following the general production method 4-C, 3- [N ^′ -(tert-butylcarbamate) -L-
[Alaninyl] amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,
The title compound was obtained as a white foam using 4-benzodiazepin-2-one. Elemental analysis (as _{C 19 H 19 N 4 O 2} ): theoretical value: C, 69.21; H, 6.64 ;
N, 15.37; Found: C, 70.11; H, 6.85; N, 15.01.

Example 4-C 3- (L-alaninyl) amino-7-chloro-2,3-dihydro-1-methyl-5
Synthesis of -phenyl-1H-1,4-benzodiazepin-2-one Step A- 3- (Benzyloxycarbonyl) amino-7-chloro-2,3-di
Hydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-o
Preparation of 3- (benzyloxycarbonyl) amino-7-chloro-2,3-dihydro-5
A solution of -phenyl-1H-1,4-benzodiazepin-2-one (1 eq .; Neosystem) in DMF was cooled to 0 ° C. and treated with potassium tert-butoxide (1 eq .; 1.0 M THF solution). did. The resulting yellow solution is treated at 0 ° C. with 3
Stirred for 0 min, then quenched with methyl iodide (1.3 eq.). After stirring for an additional 25 minutes, the reaction was diluted with dichloromethane and washed with water and brine. The organic phase was dried over Na ₂ SO _4, filtered, and concentrated. The residue was purified by HPLC chromatography (eluent, gradient 20 → 30% ethyl acetate / hexane). _{C 24 H 20 ClN 3 O 3} (MW = 433.92); mass spectroscopy 433. Elemental analysis (as _{C 24 H 20 ClN 3 O 3} ): theoretical value: C, 66.44; H, 4.6
5; N, 9.68; Found: C, 66.16; H, 4.50; N, 9.46.

Step B- 3-Amino-7-chloro-1,3-dihydro-1-methyl-5-f
Preparation of enyl-2H-1,4-benzodiazepin-2-one According to General Production Method 4-B, 3- (benzyloxycarbonyl) amino-7-chloro-1,3-dihydro-1-methyl-5-phenyl- Use 1H-1,4-benzodiazepin-2-one to produce the title intermediate as a white foam, which is obtained in Step C
Used immediately.

[0343] process C- 3- [N ^'-tert- butyl carbamate) -L- alaninyl] A
Mino-7-chloro-1,3-dihydro-1-methyl-5-phenyl-2H-1,4
Preparation of -benzodiazepin-2-one According to general procedure D, N-Boc-L-alanine and 3-amino-7-chloro-1,3-dihydro-1-methyl-5-phenyl-2H-1,4- The title intermediate was prepared as a white foam using benzodiazepin-2-one. _{C 24 H 28 ClN 4 O 4} (MW = 471.18); mass spectroscopy 471. Elemental analysis (as _{C 24 H 28 ClN 4 O 4} ): theoretical value: C, 61.21; H, 5.7
8; N, 11.90; Found: C, 61.24; H, 5.59; N, 11.67.

Step D- 3- (L-alaninyl) amino-7-chloro-1,3-dihydro-1
- in accordance with the manufacturer General Procedure 4-C of methyl-5-phenyl-2H-1,4-benzodiazepin-2-one, 3- [N ^'-tert- butyl carbamate) -L-
The title intermediate as a white foam was prepared using [alaninyl] amino-7-chloro-1,3-dihydro-1-methyl-5-phenyl-2H-1,4-benzodiazepin-2-one. The crude material was used immediately.

Example 4-D 3- (L-alaninyl) amino-7-bromo-2,3-dihydro-1-methyl-5
Synthesis of-(2-fluorophenyl) -1H-1,4-benzodiazepin-2-one Step A- 3- (Benzyloxycarbonyl) amino-7-bromo-2,3-di
Hydro-1-methyl-5- (2-fluorophenyl) -1H-1,4-benzodia
Preparation of Zepin-2-one According to General Production Method 4-A, 3- (benzyloxycarbonyl) amino-7-bromo-2,3-dihydro-5- (2-fluorophenyl) -1H-1,4-benzodiazepine The title intermediate of a white foam was prepared using -2-one (Neosystem). _{C 24 H 19 BrFN 3 O 3} (MW = 496.36); mass spectroscopy 497. Elemental analysis _{(C 24 H 19 BrFN 3 O} 3): theoretical value: C, 58.08; H, 3.86 ;
N, 8.47; Found: C, 57.90; H, 4.15; N, 8.20.

Step B- 3-Amino-7-bromo-1,3-dihydro-1-methyl-5- (2
Preparation of -fluorophenyl) -2H-1,4-benzodiazepin-2-one 3- (benzyloxycarbonyl) amino-7-bromo-2,3-dihydro-1-methyl-5 according to General Preparation Method 4-B. -(2-fluorophenyl) -1H-1,4
A white foam was obtained using -benzodiazepin-2-one, which was used immediately in step C.

Step C- 3- [N ^' -(tert-butylcarbamate) -L-alaninyl]
Preparation of mino-7-bromo-1,3-dihydro-1-methyl-5- (2-fluorophenyl ) -2H-1,4-benzodiazepin-2-one N-Boc-L- Alanine (Novo) and 3-
The title intermediate was prepared as a white foam using amino-7-bromo-1,3-dihydro-1-methyl-5- (2-fluorophenyl) -2H-1,4-benzodiazepin-2-one. . _{C 24 H 26 BrFN 4 O 4} (MW = 533.12); mass spectroscopy 533.2. Elemental analysis (as _{C 24 H 26 BrFN 4 O 4} ): theoretical value: C, 54.04; H, 4 .
N; 10.50; Found: C, 53.75; H, 4.92; N, 10.41.

Step D- 3- (L-alaninyl) amino-7-bromo-1,3-dihydro-1
-Methyl-5- (2-fluorophenyl) -2H-1,4-benzodiazepine-2
Preparation of -one 3- [N ^′ -(tert-butylcarbamate) -L-
[Alaninyl] amino-7-bromo-1,3-dihydro-1-methyl-5- (2-fluorophenyl) -2H-1,4-benzodiazepin-2-one to give the title intermediate in a white foam Manufactured. The crude was used immediately.

[0349] Example 4-E 3- (N ^'- methyl -L- alaninyl) amino-2,3-dihydro-1-methyl-5
- phenyl-1H-1,4-benzodiazepin-2-one synthesis step A- 3- [N ^'- (tert- butylcarbamate) ^-N' - methyl -L-
[Alaninyl] amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,
Preparation of 4-benzodiazepin-2-one According to General Preparation D, (S) -3-amino-1,3-dihydro-1-methyl-5-
The title intermediate as a white solid was prepared using phenyl-2H-1,4-benzodiazepin-2-one (Example 8-B) and N-tert-Boc-N-methylalanine (Sigma). _{C 25 H 30 N 4 O 4} (MW = 450.2); mass spectroscopy (M + 1) 451.2. Elemental analysis (as _{C 25 H 30 N 4 O 4} ): theoretical value: C, 66.65; H, 6.71 ;
N, 12.44; Found: C, 66.66; H, 6.89; N, 12.21.

[0350] Step B- 3- (N ^'- methyl -L- alaninyl) amino-2,3-dihydro-1
Preparation of -methyl-5-phenyl-1H-1,4-benzodiazepin-2-one Following the general production method 4-C, 3- [N ^′ -(tert-butylcarbamate) -N ^′
-Methyl-L-alaninyl] amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one was used to produce the title intermediate as a white foam. _{C 20 H 22 N 4 O 2} (MW = 350.46); mass spectroscopy (M + 1) 351.4. Elemental analysis (as _{C 20 H 22 N 4 O 2} ): theoretical value: C, 68.55; H, 6.33 ;
N, 15.99; Found: C, 68.36; H, 6.20; N, 15.79.

Example 4-F 3- (L-alaninyl) amino-7-chloro-2,3-dihydro-1-methyl-5
Synthesis of-(2-chlorophenyl) -1H-1,4-benzodiazepin-2-one Step A- 3- (Benzyloxycarbonyl) amino-7-chloro-2,3-di
Hydro-1-methyl-5- (2-chlorophenyl) -1H-1,4-benzodiaze
Preparation of pin-2-one 3- (benzyloxycarbonyl) amino-7-chloro-2,3-dihydro-5- (2-chlorophenyl) -1H-1,4-benzodiazepine- Using 2-one (Neosystem), the title intermediate as a white solid (melting point: 23
2-233 ° C)).

(Equation 1)

Step B- 3-Amino-7-chloro-1,3-dihydro-1-methyl-5- (2
Preparation of-(chlorophenyl) -2H-1,4-benzodiazepin-2-one According to General Production Method 4-B, 3- (benzyloxycarbonyl) amino-7-chloro-2,3-dihydro-1-methyl-5- (2-chlorophenyl) -1H-1,4-
Use benzodiazepin-2-one to give the title intermediate as a white foam, which was used immediately in Step C.

Step C- 3- [N ^' -(tert-butylcarbamate) -L-alaninyl]
Mino-7-chloro-1,3-dihydro-1-methyl-5- (2-chlorophenyl)
Preparation of -2H-1,4-benzodiazepin-2-one According to General Preparation D, N-Boc-L-alanine and 3-amino-7-chloro-1,3-dihydro-1-methyl-5- (2 -Chlorophenyl) -2H-1,4-
The title intermediate was prepared as a white foam using benzodiazepin-2-one. _{C 24 H 26 Cl 2 N 4} O 4 (MW = 505.44); mass spectroscopy 505.2.

Step D- 3- (L-alaninyl) amino-7-chloro-1,3-dihydro-1
-Methyl-5- (2-chlorophenyl) -2H-1,4-benzodiazepine-2-
According manufacturing General Procedure 4-C ON, 3- [N ^'- (tert- butylcarbamate) -L-
Producing the title intermediate as a white foam using [alaninyl] amino-7-chloro-1,3-dihydro-1-methyl-5- (2-chlorophenyl) -2H-1,4-benzodiazepin-2-one did. The crude was used immediately.

Example 4-G Synthesis of 3- (L-alaninyl) amino-5-cyclohexyl-2,3-dihydro-1-methyl-1H-1,4-benzodiazepin-2-one Step A- 3- ( Production of (benzyloxycarbonyl ) amino-5-cyclohexyl- 2,3-dihydro-1-methyl-1H-1,4-benzodiazepin-2-one 3- (benzyloxycarbonyl) amino- The title intermediate (mp: 205-206 ° C) as a white solid was prepared using 5-cyclohexyl-2,3-dihydro-1H-1,4-benzodiazepin-2-one (Neosystem). _{C 24 H 27 N 3 O 3} (MW = 405.54); mass spectroscopy 405. ¹ H-nmr (300 MHz, CDCl ₃ ): δ = 7.54 (1H, d, J = 7.5.
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), 2.7
7 (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- 3-Amino-5-cyclohexyl-1,3-dihydro-1-methyl
Preparation of -2H-1,4-benzodiazepin-2-one According to General Production Method 4-B, 3- (benzyloxycarbonyl) amino-5-cyclohexyl-2,3-dihydro-1-methyl-1H-1,4 -Benzodiazepine-
The 2-one was used to give the title intermediate as a white foam, which was used immediately in Step C. C ₁₆ H ₂₁ N ₃ O (MW + H = 271.1763); mass spectroscopy 272.176
6.

Step C- 3- [N ^' -(tert-butylcarbamate) -L-alaninyl] a
Mino-5-cyclohexyl-1,3-dihydro-1-methyl-2H-1,4-ben
Preparation of zodiazepin-2-one According to general procedure D, N-Boc-L-alanine and 3-amino-5-cyclohexyl-1,3-dihydro-1-methyl-2H-1,4-benzodiazepine-
The title intermediate of a white foam was prepared using 2-one. _{C 24 H 34 N 4 O 4} (MW = 442.62); mass spectroscopy (M + H) 443.2.

Step D- 3- (L-alaninyl) amino-5-cyclohexyl-1,3-diphenyl
Preparation of Dro-1-methyl-2H-1,4-benzodiazepin-2-one According to General Production Method 4-C, 3- [N ^′ -(tert-butylcarbamate) -L-
[Alaninyl] amino-5-cyclohexyl-1,3-dihydro-1-methyl-2H
The title intermediate was prepared as a white foam using -1,4-benzodiazepin-2-one. The crude was used immediately. _{C 19 H 26 N 4 O 2} (M + H = 343.2136); mass spectroscopy 343.2139
.

Example 4-H 3- (L-alaninyl) amino-2,3-dihydro-1-methyl-7-nitro-5
Synthesis of -phenyl-1H-1,4-benzodiazepin-2-one Step A- 2- [N- (α-isopropylthio) -N ^′ -(benzyloxycarbo
Nyl) glycinyl] amino-5-nitrobenzophenone α- (isopropylthio) -N- (benzyloxycarbonyl) glycine (1 eq
, Zoller, V .; Ben-Ishai, D. Tetrahedron 1975, 31, 863 (the contents of which are part of this specification) are cooled to 0 ° C. in dry THF, and oxalyl chloride (
1 eq.) And DMF (3 drops). After stirring at 0 ° C. for 15 minutes, the cooling bath was removed and stirring continued at ambient temperature for 40 minutes. The solution was recooled to 0 ° C. A solution of 2-amino-5-nitrobenzophenone (0.9 eq .; Acros) and 4-methylmorpholine (2.0 eq.) In dry THF was added to the acid chloride via cannula. The cooling bath was removed and the reaction was stirred at ambient temperature for 5 hours. The reaction was diluted with dichloromethane and washed with 0.5M citric acid, saturated aqueous NaHCO ₃ and brine. The organic phase was dried over Na ₂ SO _4, filtered, and concentrated. Preparative L for residue
Purification by C2000 (eluent, ethyl acetate / hexane 15% → 20% gradient) gave an off-white foam. _{C 26 H 25 N 3 O 6} S (MW = 507.61); mass spectroscopy 507.9. Elemental analysis (as _{C 26 H 25 N 3 O 6} S): Theoretical value: C, 61.53; H, 4.96
N, 8.28; Found: C, 61.70; H, 4.99; N, 8.22.

Step B- 2- [N- (α-amino) -N ^′ -(benzyloxycarbonyl) glycyi
Production of [nyl] amino-5-nitrobenzophenone Ammonia gas was added to a THF solution of 2- [N- (α-isopropylthio) -N ^′ -(benzyloxycarbonyl) glycinyl] amino-5-nitrobenzophenone (1 eq.). Bubble at 0 ° C. After 35 minutes, mercury (II) chloride (1.1 eq.) Was added. The ice bath was removed and ammonia gas was continued to bubble into the suspension for 4 hours. The bubbler was removed and the reaction continued to stir for 16 hours. The mixture was filtered through celite while washing with THF. The filtrate was concentrated under vacuum. The crude solid was used in Step C without further purification.

Step C- 3- (benzyloxycarbonyl) amino-2,3-dihydro-7-
Preparation of nitro-5-phenyl-1,4-benzodiazepin-2-one 2- [N- (α-amino) -N ^′ -(benzyloxycarbonyl) glycinyl] amino-5-nitrobenzophenone (1 eq.) Acetic acid and ammonium acetate (
(4.7 eq.). The suspension was stirred at ambient temperature for 21 hours. After concentrating the reaction under vacuum, the residue was partitioned between ethyl acetate and 1N NaOH. The aqueous phase was re-extracted with ethyl acetate. The combined organics were washed with brine, dried over Na ₂ SO ₄ and concentrated. The residue was purified by flash chromatography (eluent, 2 → 3% gradient of isopropyl alcohol / dichloromethane). _{C 23 H 18 N 4 O 5} (MW = 430.45); mass spectroscopy (M + H) 431.2. Elemental analysis (as _{C 23 H 18 N 4 O 5} ): theoretical value: C, 64.18; H, 4.22 ;
N, 13.02; Found: C, 64.39; H, 4.30; N, 13.07.

Step D- 3- (benzyloxycarbonyl) amino-2,3-dihydro-1-
Methyl-7-nitro-5-phenyl-1H-1,4-benzodiazepin-2-o
According to the general production method 4-A, 3- (benzyloxycarbonyl) amino-2,3-
Dihydro-7-nitro-5-phenyl-1H-1,4-benzodiazepine-2-
Using ON, the title intermediate was prepared as a yellow foam. _{C 24 H 20 N 4 O 5} (MW = 444.48); mass spectroscopy (M + H) 445.2. Elemental analysis (as _{C 24 H 20 N 4 O 5} ): theoretical value: C, 64.86; H, 4.54 ;
N, 12.60; Found: C, 65.07; H, 4.55; N, 12.46.

Step E- 3-Amino-1,3-dihydro-1-methyl-7-nitro-5-f
Preparation of phenyl-2H-1,4-benzodiazepin-2-one According to the general production method 4-B, 3- (benzyloxycarbonyl) amino-2,3-
The title intermediate was prepared as a yellow foam using dihydro-1-methyl-7-nitro-5-phenyl-1H-1,4-benzodiazepin-2-one, which was used immediately in Step F.

Step F- 3- [N ^' -(tert-butylcarbamate) -L-alaninyl] a
Mino-2,3-dihydro-1-methyl-7-nitro-5-phenyl-1H-1,4
Preparation of -Benzodiazepin-2-one N-Boc-L-alanine and 3-amino-1,3-
The title intermediate was prepared as a yellow solid using dihydro-1-methyl-7-nitro-5-phenyl-2H-1,4-benzodiazepin-2-one. _{C 24 H 27 N 5 O 6} (MW = 481.56); mass spectroscopy (M + H) 482.3. Elemental analysis (as _{C 24 H 27 N 5 O 6} ): theoretical value: C, 59.88; H, 5.61 ;
N, 14.55; Found: C, 60.22; H, 5.75; N, 13.91.

Step G- 3- (L-alaninyl) amino- 2,3-dihydro-1-methyl-7
Preparation of -Nitro-5-phenyl-1H-1,4-benzodiazepin-2-one 3- [N ^′ -(tert-butylcarbamate) -L-
The title intermediate of a yellow foam was prepared using [alaninyl] amino-2,3-dihydro-1-methyl-7-nitro-5-phenyl-1H-1,4-benzodiazepin-2-one. The crude was used immediately.

Example 4-I Synthesis of 3- (L-alaninyl) amino-2,3-dihydro-1-methyl-5- (2-fluorophenyl) -1H-1,4-benzodiazepin-2-one A- 3-Amino-1,3-dihydro-1-methyl-5- (2-fluorophenyl
(Henyl) -2H-1,4-benzodiazepin-2-one. Filled with 1H-1,4-benzodiazepin-2-one (1 eq .; Example 4-D, step A) and 10% palladium on carbon. Methanol was added, the flask was placed under a balloon of H _2. The reaction was stirred for 21 hours. The mixture was filtered through celite while washing with methanol. The filtrate was concentrated to give a white solid. C ₁₆ H ₁₄ FN ₃ O (MW = 283.33); mass spectroscopy (M + H) 284.1
.

Step B- 3- [N ^′ -(tert-butylcarbamate) -L-alaninyl] a
Preparation of mino-1,3-dihydro-1-methyl-5- (2-fluorophenyl) -2H-1,4- benzodiazepin-2 -one N-Boc-L-alanine and 3- Amino-1,3-
The title intermediate was prepared as a white solid using dihydro-1-methyl-5- (2-fluorophenyl) -2H-1,4-benzodiazepin-2-one. C ₂₄ H ₂₇ FN ₄ O ₄ (MW = 454.50); mass spectroscopy (M + H) 455.4
. Elemental analysis (as _{C 24 H 27 FN 4 O 4} ): theoretical value: C, 63.44; H, 5.95
N, 12.33; Found: C, 63.64; H, 6.08; N, 12.16.

Step C- 3- (L-alaninyl) amino-7-bromo-1,3-dihydro-1
-Methyl-5- (2-fluorophenyl) -2H-1,4-benzodiazepine-2
Preparation of -one 3- [N ^′ -(tert-butylcarbamate) -L-
The title intermediate as a white foam was prepared using [alaninyl] amino-1,3-dihydro-1-methyl-5- (2-fluorophenyl) -2H-1,4-benzodiazepin-2-one. The crude was used immediately.

Example 4-J Synthesis of 3- (L-alaninyl) amino-2,3-dihydro-1-methyl-5- (3-fluorophenyl) -1H-1,4-benzodiazepin-2-one Preparation of A- 2-amino- ^3′ -fluorobenzophenone A THF solution of 3-bromofluorobenzene (1 eq.) Was cooled to −78 ° C. under nitrogen, and tert-butyllithium (2.05 eq., 1.6 M) was added. (Pentane solution) at a flow rate of 40 mL / hour. The internal temperature was not allowed to rise above -74 ° C. Anthranilonitrile (0.6 eq.)
The orange solution was stirred at -78 C for 30 minutes before adding the THF solution of. The reaction was heated to 0 ° C. and stirred for 2 hours. 3N HCl was added to the mixture and stirring was continued for 30 minutes. The reaction was diluted with ethyl acetate and the phases were separated. The aqueous phase was re-extracted three times with ethyl acetate. The combined extracts were washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated. HPLC of the residue (eluent, hexane / ethyl acetate (93: 7))
And purified. _{C 13 H 10 FNO (MW =} 215.24); mass spectroscopy (M + H) 216.3. ¹ H-NMR (300 MHz, CDCl ₃ ) δ 7.44 to 7.19 (6H, m),
6.74 (1H, d, J = 8.0 Hz), 6.61 (1H, dd, J = 0.94, 7.
9 Hz), 6.10 (2H, bs).

Step B- 2- [N- (α-isopropylthio) -N ^′ -(benzyloxycarbo
Nyl) glycinyl] amino- ^3′ -fluorobenzophenone α- (isopropylthio) -N- (benzyloxycarbonyl) glycine (1 eq
, Zoller, V .; Ben-Ishai, D. Tetrahedron 1975, 31, 863 (prepared according to part of this specification) in dry THF was cooled to 0 ° C and oxalyl chloride ( 1 eq.) And DMF (3 drops). After stirring at 0 ° C. for 15 minutes, the cooling bath was removed and stirring continued at ambient temperature for 40 minutes. The solution was recooled to 0 ° C.
A solution of 2-amino- ^3' -fluorobenzophenone (0.9 eq.) And 4-methylmorpholine (2.0 eq.) In dry THF was added to the acid chloride via cannula.
The cooling bath was removed and the reaction was stirred at ambient temperature for 5 hours. The reaction was diluted with dichloromethane and washed with 0.5M citric acid, saturated aqueous NaHCO ₃ and brine.
The organic phase was dried over Na ₂ SO _4, filtered, and concentrated. Preparative LC2000 residue
(Eluent, 15% → 20% gradient of ethyl acetate / hexane) to give an off-white foam. C ₂₆ H ₂₅ N ₂ O ₄ S (MW = 480.60); mass spectroscopy (M + NH ₄ ⁺ ) 49
8.3 ¹ H-nmr (300 MHz, CDCl ₃ ): δ 11.39 (1H, s), 8.
59 (1H, d, J = 6.0 Hz), 7.63-7.55 (2H, m), 7.48-
7.27 (9H, m), 7.14 (1H, dt, J = 1.2, 8.4 Hz), 5.9
4 (1H, d, J = 7.2 Hz), 5.58 (1H, d, J = 8.7 Hz), 5.1
7 (2H, ABq, J = 14.7 Hz), 3.25 (1H, seq, J = 6.6H)
z), 1.44 (3H, d, J = 6.0 Hz), 1.28 (3H, d, J = 6.6H)
z).

Step C- 2- [N- (α-amino) -N ^′ -(benzyloxycarbonyl) glycyi
Sulfonyl] ^{amino-3 '-} production of fluorobenzophenone 2- [N- (α- isopropylthio) ^-N' - (benzyloxycarbonyl) glycinyl] ^{amino-3 '-} (. 1 eq) in THF solution of fluoro benzophenone, ammonia Gas was blown in at 0 ° C. After 35 minutes, mercury (II) chloride (1.1 eq.) Was added. The ice bath was removed and ammonia gas was continued to bubble into the suspension for 4 hours. The bubbler was removed and the reaction continued to stir for 16 hours. The mixture was filtered through celite while washing with THF. The filtrate was concentrated under vacuum. The crude solid was used in Step D without further purification.

Step D- Preparation of 3- (benzyloxycarbonyl) amino-2,3-dihydro-5- ( 3-fluorophenyl) -1H-1,4-benzodiazepin-2-one 2- [N- (α -Amino) -N ^' -(benzyloxycarbonyl) glycinyl] amino- ^3' -fluorobenzophenone (1 eq.) Was treated with glacial acetic acid and ammonium acetate (4.7 eq.). The suspension was stirred at ambient temperature for 21 hours. After concentrating the reaction under vacuum, the residue was partitioned between ethyl acetate and 1N NaOH. The aqueous phase was re-extracted with ethyl acetate. The combined organics were washed with brine, dried over Na ₂ SO ₄ and concentrated. The residue was purified by flash chromatography (eluent, 2 → 3% gradient of isopropyl alcohol / dichloromethane). C ₂₃ H ₁₈ FN ₃ O ₃ (MW = 403.44); mass spectroscopy (M + H) 404.4
. Elemental analysis (as _{C 23 H 18 FN 3 O 3} · 0.5H 2 O): theory: C, 66.98
H, 4.64; N, 10.18, found: C, 67.20; H, 4.64; N, 9
.77.

Step E- 3- (benzyloxycarbonyl) amino-2,3-dihydro-1-
Methyl-5- (3-fluorophenyl) -1H-1,4-benzodiazepine-2-
According manufacturing General Procedure 4-A of one, 3- (benzyloxycarbonyl) amino-2,3
Dihydro-5- (3-fluorophenyl) -1H-1,4-benzodiazepine-2
Using -one produced the title intermediate as a yellow foam. C ₂₄ H ₂₀ FN ₃ O ₃ (MW = 417.47); mass spectroscopy (M + H) 418.3
. Elemental analysis (as _{C 24 H 20 FN 3 O 3} ): theoretical value: C, 69.06; H, 4.83
N, 10.07; Found: C, 69.33; H, 4.95; N, 9.82.

Step F- 3-Amino-1,3-dihydro-1-methyl-5- (3-fluorophenyl
Preparation of ( enyl) -2H-1,4-benzodiazepin-2-one According to the general production method 4-B, 3- (benzyloxycarbonyl) amino-2,3-
The title intermediate was prepared as a yellow foam using dihydro-1-methyl-5- (3-fluorophenyl) -1H-1,4-benzodiazepin-2-one, which was used directly in Step G. .

Step G- 3- [N ^' -(tert-butylcarbamate) -L-alaninyl]
Preparation of mino-2,3-dihydro-1-methyl-5- (3-fluorophenyl) -1H-1,4- benzodiazepin-2 -one N-Boc-L-alanine and 3- Amino-1,3-
The title intermediate was prepared as a yellow solid using dihydro-1-methyl-5- (3-fluorophenyl) -2H-1,4-benzodiazepin-2-one. C ₂₄ H ₂₇ FN ₄ O ₄ (MW = 454.50); mass spectroscopy (M + H) 455.3
. Elemental analysis (as _{C 24 H 27 FN 4 O 4} ): theoretical value: C, 63.42; H, 5.99
N, 12.33; Found: C, 63.34; H, 6.01; N, 12.08.

Step H- 3- (L-alaninyl) amino- 2,3-dihydro-1-methyl-5
Preparation of-(3-fluorophenyl) -1H-1,4- benzodiazepin-2 -one Following the general production method 4-C, 3- [N ^′ -(tert-butylcarbamate) -L-
The title intermediate of a yellow foam was prepared using [alaninyl] amino-2,3-dihydro-1-methyl-5- (3-fluorophenyl) -1H-1,4-benzodiazepin-2-one. The crude was used immediately.

Example 4-K Synthesis of 3- (L-alaninyl) amino-2,3-dihydro-1-methyl-5- (4-fluorophenyl) -1H-1,4-benzodiazepin-2-one Preparation of A- 2-amino- ^4′ -fluorobenzophenone A THF solution of 4-bromofluorobenzene (1 eq.) Was cooled to −78 ° C. under nitrogen, and tert-butyllithium (2.05 eq., 1.6 M pentane) was added. Solution) at a flow rate of 40 mL / hour. The internal temperature was not allowed to rise above -74 ° C. The orange solution was stirred at -78 ° C for 30 minutes before adding a solution of anthranilonitrile (0.6 eq.) In THF. The reaction was heated to 0 ° C. and stirred for 2 hours. 3N HCl was added to the mixture and stirring was continued for 30 minutes. The reaction was diluted with ethyl acetate and the phases were separated. The aqueous phase was re-extracted three times with ethyl acetate. The combined extracts were washed with brine, dried over Na ₂ SO _4, filtered, and concentrated. The residue is HP
Purified by LC (eluent, hexane / ethyl acetate (93: 7)). _{C 13 H 10 FNO (MW =} 215.24); mass spectroscopy (M + H) 216.3. Elemental analysis (as C ₁₃ H ₁₀ FNO): theoretical value: C, 72.55; H, 4.68 ;
N, 6.51; Found: C, 72.80; H, 4.51; N, 6.74.

Step B- 2- [N- (α-isopropylthio) -N ^′ -(benzyloxycarbo
Nyl) glycinyl] amino- ^4′ -fluorobenzophenone α- (isopropylthio) -N- (benzyloxycarbonyl) glycine (1 eq
, Zoller, V .; Ben-Ishai, D. Tetrahedron 1975, 31, 863 (prepared according to part of this specification) in dry THF was cooled to 0 ° C and oxalyl chloride ( 1 eq.) And DMF (3 drops). After stirring at 0 ° C. for 15 minutes, the cooling bath was removed and stirring continued at ambient temperature for 40 minutes. The solution was recooled to 0 ° C.
A solution of 2-amino- ^4' -fluorobenzophenone (0.9 eq.) And 4-methylmorpholine (2.0 eq.) In dry THF was added to the acid chloride via cannula.
The cooling bath was removed and the reaction was stirred at ambient temperature for 5 hours. The reaction was diluted with dichloromethane and washed with 0.5M citric acid, saturated aqueous NaHCO ₃ and brine. The organic phase was dried over Na ₂ SO _4, filtered, and concentrated. The residue was prepared using Preparative LC2000 (
Purification by eluent (15% → 20% gradient of ethyl acetate / hexane) gave an off-white foam. C ₂₆ H ₂₅ N ₂ O ₄ S (MW = 480.60); mass spectroscopy (M + NH ₄ ⁻ ) 49
8.2 ¹ H-nmr (300 MHz, CDCl ₃ ): δ = 11.28 (1H, s), 8.
56 (1H, d, J = 8.4 Hz), 7.78-7.73 (2H, m), 7.61-
7.53 (2H, m), 7.36-7.32 (5H, m), 7.20-7.14 (3
H, m), 5.98 (1H, d, J = 7.5 Hz), 5.57 (1H, d, J = 7.5 Hz).
8 Hz), 5.16 (2H, ABq, J = 14.7 Hz), 3.25 (1H, se
q, J = 6.0 Hz), 1.43 (3H, d, J = 6.3 Hz), 1.27 (3H,
d, J = 6.6 Hz).

Step C- 2- [N- (α-amino) -N ^′ -(benzyloxycarbonyl) glycyi
Sulfonyl] amino-4 ^'- production of fluorobenzophenone 2- [N- (α- isopropylthio) ^-N' - (benzyloxycarbonyl) glycinyl] amino -3 ^'- (. 1 eq) in THF solution of fluoro benzophenone, ammonia Gas was blown at 0 ° C. After 35 minutes, mercury (II) chloride (1.1 eq.) Was added. The ice bath was removed and ammonia gas was continued to bubble into the suspension for 4 hours. The bubbler was removed and the reaction continued to stir for 16 hours. The mixture was filtered through celite while washing with THF. The filtrate was concentrated under vacuum. The crude solid was used in Step D without further purification.

Step D- Preparation of 3- (benzyloxycarbonyl) amino-2,3-dihydro-5- ( 4-fluorophenyl) -1H-1,4-benzodiazepin-2-one 2- [N- (α -Amino) -N ^' -(benzyloxycarbonyl) glycinyl] amino- ^4' -fluorobenzophenone (1 eq.) Was treated with glacial acetic acid and ammonium acetate (4.7 eq.). The suspension was stirred at ambient temperature for 21 hours. After concentrating the reaction under vacuum, the residue was partitioned between ethyl acetate and 1N NaOH. The aqueous phase was re-extracted with ethyl acetate. The combined organics were washed with brine, dried over Na ₂ SO ₄ and concentrated. The residue was purified by flash chromatography (eluent, 2 → 3% gradient of isopropyl alcohol / dichloromethane). C ₂₃ H ₁₈ FN ₃ O ₃ (MW = 403.44); mass spectroscopy (M + H) 404.4
. Elemental analysis (as _{C 23 H 18 FN 3 O 3} · 1.25H 2 O): theory: C, 64.8
5; H, 4.85; Found: C, 64.80; H, 4.55.

Step E- 3- (benzyloxycarbonyl) amino-2,3-dihydro-1-
Methyl-5- (4-fluorophenyl) -1H-1,4-benzodiazepine-2-
According manufacturing General Procedure 4-A of one, 3- (benzyloxycarbonyl) amino-2,3
Dihydro-5- (4-fluorophenyl) -1H-1,4-benzodiazepine-2
Using -one produced the title intermediate as a yellow foam. _{C 24 H 20 FN 3 O 3} (MW = 417.47); mass spectroscopy (M + H) 418.2. Elemental analysis (as _{C 24 H 20 FN 3 O 3} ): theoretical value: C, 69.06; H, 4.83
N, 10.07; Found: C, 69.35; H, 4.93; N, 9.97.

Step F- 3-Amino-1,3-dihydro-1-methyl-5- (4-fluorophenyl
Preparation of ( enyl) -2H-1,4-benzodiazepin-2-one According to the general production method 4-B, 3- (benzyloxycarbonyl) amino-2,3-
The title intermediate was prepared as a yellow foam using dihydro-1-methyl-5- (4-fluorophenyl) -1H-1,4-benzodiazepin-2-one, which was used immediately in Step G. .

Step G- 3- [N ^' -(tert-butylcarbamate) -L-alaninyl]
Preparation of mino-2,3-dihydro-1-methyl-5- (3-fluorophenyl) -1H-1,4- benzodiazepin-2 -one N-Boc-L-alanine and 3- Amino-1,3-
The title intermediate was prepared as a yellow solid using dihydro-1-methyl-5- (3-fluorophenyl) -2H-1,4-benzodiazepin-2-one. C ₂₄ H ₂₇ FN ₄ O ₄ (MW = 454.50); mass spectroscopy (M + H) 455.4
. Elemental analysis (as _{C 24 H 27 FN 4 O 4} · 1.5H 2 O): theory: C, 59.86
H, 6.28; N, 11.64, found: C, 60.04; H, 5.62; N, 1
1.27.

Step H- 3- (L-alaninyl) amino- 2,3-dihydro-1-methyl-5
Preparation of-(4-fluorophenyl) -1H-1,4- benzodiazepin-2 -one Following the general production method 4-C, 3- [N ^′ -(tert-butylcarbamate) -L-
The title intermediate of a yellow foam was prepared using [alaninyl] amino-2,3-dihydro-1-methyl-5- (4-fluorophenyl) -1H-1,4-benzodiazepin-2-one. The crude was used immediately.

[0385] Example 4-L 3- (N ^'-L- alaninyl) amino-2,3-dihydro-1-isobutyl-5-phenyl-1H-1,4-benzodiazepin-2-one Synthesis Step A: 1,3-dihydro-5-phenyl-2H-1,4-benzodiazepin-2-one (J. Org. Chem. 1987, 52, 3232-3239 by MG Bock et al. Is alkylated with isobutyl iodide using General Preparation 8-G to give 1,3-dihydro-1-isobutyl-
5-phenyl-2H-1,4-benzodiazepin-2-one was prepared.

Step B: Following the general procedures 4-D and 4-F, using the product from Step A, give 3-amino-1,3-dihydro-1-isobutyl-5-phenyl-2H-1,
4-benzodiazepin-2-one was prepared.

Step C: The product from Step B and N-Boc-L-alanine (Sigma) are subjected to a coupling reaction using General Procedure D, and then Boc is removed using General Procedure 8-J. to, 3- (N ^'-L- alaninyl) amino-1,3-dihydro-1-
Isobutyl-5-phenyl-2H-1,4-benzodiazepin-2-one was obtained.

In place of isobutyl iodide in the above step A, isopropyl iodide, n-iodide
Propyl, by replacing the cyclopropylmethyl iodide and ethyl iodide, further following intermediates were prepared: 3- (N ^'-L- alaninyl) amino-1,3-dihydro-1-isopropyl -5
- phenyl-2H-1,4-benzodiazepin-2-one, 3- (N ^'-L- alaninyl) amino-1,3-dihydro-1-propyl-5-phenyl-2H-1,4-benzodiazepin-2 - one, 3- (N ^'-L- alaninyl) amino-1,3-dihydro-1-cyclopropylmethyl-5-phenyl-2H-1,4-benzodiazepin-2-one 3- ^(N' -L- (Alaninyl) amino-1,3-dihydro-1-ethyl-5-phenyl-2H-1,4-benzodiazepin-2-one.

[0389] Example 4-M 3- (N ^'-L- alaninyl) amino-1-methyl-5-phenyl-1,3,4,5
Synthesis step A of tetrahydro-2H-1,5-benzodiazepin-2-one : 1,3,4,5-tetrahydro-5-phenyl-2H-1,5-benzodiazepin-2-one (CAS number 32900-17- 7) was methylated using general procedure 4-I to give 1-methyl-5-phenyl-1,3,4,5-tetrahydro-2H-1,
5-benzodiazepin-2-one was prepared.

Step B: Following the general procedures 4-E and 4-F, using the product from Step A, 3-amino-1-methyl-5-phenyl-1,3,4,5-tetrahydro- 2
H-1,5-benzodiazepin-2-one was prepared.

Step C: The product from Step B and N-Boc-L-alanine (Sigma) are subjected to a coupling reaction using General Procedure D, followed by Boc using General Procedure 8-N. It was removed to give 3- (N ^{'-L-alaninyl)} amino-1-methyl-5-phenyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-2-one.

[0392] Example 4-N 3- (N ^'-L- alaninyl) amino-2,4-dioxo-1-methyl-5-phenyl-2,3,4,5-tetrahydro-1H-1,5- Synthesis of Benzodiazepines 3-Amino-2,4-dioxo-1-methyl-5-phenyl-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine (CAS No. 131604-75-6) was synthesized. The coupling reaction was performed with N-Boc-L-alanine (Sigma) using General Preparation Method D, followed by removal of the Boc group using General Preparation Method 4-N to obtain the title compound.

Example 4-O 3-((R) -hydrazinopropionyl) amino-2,3-dihydro-1-methyl-
Synthesis 1 part of 5-phenyl)-1H-1,4-benzodiazepin-2-one ^{- - (R) -N ',} N' - Synthesis of di -Boc-2-hydrazino-propionic acid Step A: -50 ° C. To the cooled (S)-(-)-4-benzyl-2-oxazolidanone (Aldrich) in THF was added n-butyllithium (1.1 eq., 1.6 M hexane solution). The reaction mixture was warmed to -20 ° C and then -78 ° C.
Re-cooled and propionyl chloride (1.1 eq.) Was added in one portion. The reaction mixture was stirred at -78 C for a further 15 minutes and then allowed to warm to room temperature. Then the reaction was quenched with saturated sodium bicarbonate solution and extracted with ethyl acetate. The organic extract was washed with water, followed by brine, then dried over sodium sulfate,
Filtration and concentration gave (S)-(-)-3-propionyl-4-benzyl-2-oxazolidanone.

Step B: To a THF solution of (S)-(-)-3-propionyl-4-benzyl-2-oxazolidanone was added KHMDS (1.05 eq) (Aldrich) dropwise at -78 ° C. The reaction mixture was stirred at -78 ° C for 30 minutes, then the pre-cooled di-t
A solution of tert-butyl-azodicarboxylate (Aldrich) was added via cannula. After 5 minutes, acetic acid (2.6 eq.) Was added. Then the reaction mixture was extracted with dichloromethane and the organic phase was washed with 1M potassium phosphate. Then, the organic phase was dried over sodium sulfate, filtered and concentrated to give (S)-(
-) - 3 - [(R ) -N, N '- di -BOC-2-hydrazino-propynyl] -4-benzyl-2-Okisazoridanon.

[0395]Step C: (S)-(-)-3-[(R) -N, N^'-Di-BOC-2-hydra
Dinopropionyl] -4-benzyl-2-oxozolidanone (0.49 mol)
In THF (8 mL) and water (3 mL), LiOH (1.7 eq.) And H_TwoO _Two (3.0 eq.) Was added and the reaction mixture was stirred at room temperature for 3 hours. Then,
The reaction mixture was poured into a separatory funnel and diluted with water. The aqueous mixture is diluted with ethyl acetate
And then acidified to pH 2.0 using 1N HCl and ethyl acetate
Extracted. The organic phase is then dried over sodium sulphate, filtered and the solvent is evaporated.
Let (R) -N, N^'To obtain di-BOC-2-hydrazinopropionic acid,
Was used without further purification.

Part B 3-Amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one was prepared using general procedure D to give (R) -N, N ^'- di -BO
Coupling reaction was performed with C-2-hydrazinopropionic acid. Mixture of BOC- protected compounds were CH ₂ Cl ₂ and trifluoroacetic acid by dissolving in (1: 1-2 1 mixture), to remove the BOC group. The resulting solution was stirred until tlc indicated complete conversion (typically 2 hours). Then, the solution was stripped to dryness, dissolved the residue in ethyl acetate or CH ₂ Cl _2. The solution was washed with saturated NaHCO ₃ solution, the aqueous phase was adjusted to basic pH and then extracted with ethyl acetate or CH ₂ Cl ₂ . The organic phase is saturated NaC
Washed with 1 aqueous solution and dried over MgSO ₄ . The solution was stripped of solvent on a rotary evaporator to give the title compound.

Example 4-P 3-Amino-2,4-dioxo-1,5-bis (1-methylethyl) -2,3,4,5
Synthesis step A of tetrahydro-1H-1,5-benzodiazepine : Synthesis of 2,4-dioxo-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine 2,4-dioxo-2,3, 4,5-Tetrahydro-1H-1,5-benzodiazepine (CAS No. 49799-48-6) was purchased from Claremon, D, A. et al. In PCT application WO 96/4065.
Prepared from 1,2-phenylenediamine (Aldrich) and malonic acid (Aldrich) using the process of 5 (part of this specification).

Step B: 2,4-dioxo-1,5-bis (1-methylethyl) -2,3,4,5
Synthesis of tetrahydro-1H-1,5-benzodiazepine 2,4-dioxo-1,5-bis (1-methylethyl) -2,3,4,5-tetrahydro-1H-1,5-benzodiazepine (CAS number 113021-84-4) was prepared according to general procedure 4-M using the product from step A and 2-iodopropane (Aldrich). Purified by flash chromatography (eluent, EtOAc / hexane (gradient 3: 7 to 1: 1)) followed by recrystallization (from EtOAc / hexane).

Step C: 3-azido-2,4-dioxo-1,5-bis (1-methylethyl)-
Synthesis of 2,3,4,5-tetrahydro-1H-1,5-benzodiazepine Following the general procedure 4-K, the product from step B, 3-azido-2,4-dioxo-1,5-bis ( 1-methylethyl) -2,3,4,5-tetrahydro-1H-1,
A white solid was prepared using 5-benzodiazepine (CAS number 186490-50-6). The product was purified by flash chromatography (eluent, hexane / EtOAc (4
1)) to give a pseudo-axial / pseudo-equatorial (23: 1) azide mixture. Pure pseudo-axial azide was used in the next step.

Step D: 3-Amino-2,4-dioxo-1,5-bis (1-methylethyl)-
Synthesis of 2,3,4,5-tetrahydro-1H-1,5-benzodiazepine Following general procedure 4-L, the product from step C, 3-amino-2,4-dioxo-1,5-bis ( 1-methylethyl) -2,3,4,5-tetrahydro-1H-1,
A white solid was prepared using 5-benzodiazepine (CAS number 186490-51-7). Flash chromatography (eluent, CH ₂ Cl ₂ / MeOH (98: _2-
95: 5 gradient)). The isolated pseudo-axial amine atropisomer is completely converted to the pseudo-equatorial amine atropisomer by heating in toluene at 100-105 ° C for 15 minutes, and the pseudo-equatorial amine atropisomer is converted to Used in the next step. The isomers were distinguished by ¹ H-NMR (in CDCl ₃ ). Selected ¹ H-NMR (CDCl ₃ ): pseudo-axial amine 4.40 (s, 1 H); pseudo-equatorial amine 3.96 (s, 1 H)
.

Example 4-Q 3- (R-2-thienylglycinyl) amino-2,4-dioxo-1,5-bis (1
Step A: Synthesis of N- (t-butoxycarbonyl) -R-2-thienylglycine N- (t -Butoxycarbonyl) -R-2-thienylglycine (CAS number 74462-0)
3-1) was synthesized by The Practice of Peptide Synthesis; Sp by Bodansky, M. et al.
ringer Verlag; 1994, p17 (the contents of which are incorporated herein by reference) were prepared from L-α- (2-thienyl) glycine (Sigma).

Step B: 3- [N ^' -(t-butoxycarbonyl) -R-2-thienylglycinyl] amino-2,4-dioxo-1,5-bis (1-methylethyl) -2,3 , 4,5-
Synthesis of tetrahydro-1H-1,5-benzodiazepine According to the above General Production Method J, using the product from Example 4-P and the product from Step A above, 3- [N ^′ -( (t-butoxycarbonyl) -R-2-
Thienylglycinyl] amino-2,4-dioxo-1,5-bis (1-methylethyl
) -2,3,4,5-Tetrahydro-1H-1,5-benzodiazepine was prepared.
Flash chromatography _{(eluent, CH 2 Cl 2 / EtOAc (} 9: 1~5
: 1 gradient)).

Step C: 3- (R-2-thienylglycinyl) amino-2,4-dioxo-1,
Synthesis of 5-bis (1-methylethyl) -2,3,4,5-tetrahydro-1H-1,5-benzodiazepine / hydrochloric acid Using the product from step B according to the above general production method 4-N, The title compound was prepared as a white solid.

Example 4-R 3- (L-alaninyl) amino-2,4-dioxo-1,5-bismethyl-2,3,4
Synthetic process A of 2,5-tetrahydro-1H-1,5-benzodiazepine / hydrochloric acid : 2,4-dioxo-1,5-bismethyl-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine / hydrochloric acid Synthesis of 2,4-dioxo-1,5-bismethyl-2,3,4,5-tetrahydro-1H-
1,5-Benzodiazepine (CAS number 23954-54-3) was prepared from the product from Example 4-P, Step A and iodomethane (Aldrich) according to the general procedure 4-M. After workup, a white solid precipitated while the reaction was somewhat concentrated,
This was isolated by filtration.

Step B: 3-azido-2,4-dioxo-1,5-bismethyl-2,3,4,5
-Synthesis of tetrahydro-1H-1,5-benzodiazepine / hydrochloric acid For this substrate, general production method 4-K was improved to the following method. First, the product from step A is suspended in THF at -78 ° C (not a solution), followed by KN (TM
S) ₂ solution was added and the suspension was allowed to warm to -35 ° C over 12 minutes, during which the suspension became a solution, which was recooled to -78 ° C and then described in the general procedure. Processed as 3-azido-2,4-dioxo-1,5-bismethyl-2,
The 3,4,5-tetrahydro-1H-1,5-benzodiazepine was purified by flash chromatography (eluent, CHCl ₃ / EtOAc (7: 1)) followed by trituration (from hot CHCl ₃ and hexane). Cooled to 23 ° C. The product was isolated as a white solid.

Step C: 3-Amino-2,4-dioxo-1,5-bismethyl-2,3,4,5
Synthesis of tetrahydro-1H-1,5-benzodiazepine Using the product from step B according to General Preparation 4-L, 3-amino-2,4-dioxo-1,5-bismethyl-2 as a white solid , 3,4,5-tetrahydro-1H
-1,5-benzodiazepine was prepared. The crude product was used without further purification.

Step D: 3- [N ^′ -(t-butoxycarbonyl) -L-alaninyl] amino-
2,4-dioxo-1,5-bismethyl-2,3,4,5-tetrahydro-1H-1,
Synthesis of 5-benzodiazepine According to the above General Process I, using N-Boc-L-alanine (Nova Biochem) and the product from Step C, give 3- [N ^' -(t-butoxycarbonyl)-as a white foam. [L-alaninyl] amino-2,4-dioxo-1,5-bismethyl-2,3,
4,5-Tetrahydro-1H-1,5-benzodiazepine was prepared. Flash chromatography _{(eluent, CH 2 Cl 2 / EtOAc (} 2: 1~1: 1 gradient)
).

Step E: Synthesis of 3- (L-alaninyl) amino-2,4-dioxo-1,5-bismethyl-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine / hydrochloric acid The title compound was produced as an off-white amorphous solid using the product from Step D according to Typical Preparation 4-N.

Example 4-S 3- (L-alaninyl) amino-2,4-dioxo-1,5-bis (2-methylpropyl) -2,3,4,5-tetrahydro-1H-1,5 Synthesis step A of benzodiazepine / hydrochloric acid : 2,4-dioxo-1,5-bis (2-methylpropyl) -2,3,4,
Synthesis of 5-tetrahydro-1H-1,5-benzodiazepine 2,4-dioxo-1,5-bis (2-methylpropyl) -2,3,4,5-tetrahydro-1H-1,5-benzodiazepine is generally used. Example 4 according to a typical production method 4-M
-P, product from step A and 1-iodo-2-methylpropane (Aldrich)
Manufactured from. Purification by flash chromatography (eluent, EtOAc / hexane (3: 7)) followed by recrystallization (from EtOAc / hexane).

Step B: 3-azido-2,4-dioxo-1,5-bis (2-methylpropyl)
Synthesis of -2,3,4,5-tetrahydro-1H-1,5-benzodiazepine General procedure 4-K (precipitate forms during addition of KN (TMS) ₂ but dissolves with addition of trisyl azide) And using the product from step A, 3-azido-2,4-dioxo-1,5-bis (2-methylpropyl) -2,3,4 as a white solid.
, 5-Tetrahydro-1H-1,5-benzodiazepine was prepared. The product was flash chromatographed (eluent, hexane / EtOAc (4: 1)) and a second flash chromatography (eluent, CH ₂ Cl ₂ / hexane / E)
Purified by tOAc (gradient from 10: 10: 1 to 8: 6: 1).

Step C: 3-Amino-2,4-dioxo-1,5-bis (2-methylpropyl)
Synthesis of -2,3,4,5-tetrahydro-1H-1,5-benzodiazepine According to General Preparation 4-L and using the product from Step B, 3-amino-2,4-dioxo as a white solid -1,5-bis (2-methylpropyl) -2,3,4,5-tetrahydro-1H-1,5-benzodiazepine was prepared. Flash chromatography of the product (eluent, CHCl ₃ / MeOH (gradient from 98: 2 to 95: 5))
It was purified by with 5% NH ₃ / MeOH).

Step D: 3- [N ^′ -(t-butoxycarbonyl) -L-alaninyl] amino-
Synthesis of 2,4-dioxo-1,5-bis (2-methylpropyl) -2,3,4,5-tetrahydro-1H-1,5-benzodiazepine N-Boc-L- Using alanine (Nova Biochem) and the product from Step C, a white foam of 3- [N ^′ -(t-butoxycarbonyl) -L-alaninyl] amino-2,4-dioxo-1,5-bis ( (2-Methylpropyl) -2,3,4,5-tetrahydro-1H-1,5-benzodiazepine was prepared. Flash chromatography (eluent, CH ₂ Cl ₂ / EtOAc (3:
(1-3: 2 gradient).

Step E: 3- (L-alaninyl) amino-2,4-dioxo-1,5-bis (2
-Methylpropyl) -2,3,4,5-tetrahydro-1H-1,5-benzodiazepine / hydrochloric acid Synthesis of an amorphous white solid using the product derived from step D according to the above general production method 4-N The title compound was prepared.

Example 4-T 3- (S-phenylglycinyl) amino-2,4-dioxo-1,5-bis- (2-
Synthesis step A of methylpropyl) -2,3,4,5-tetrahydro-1H-1,5-benzodiazepine / hydrochloric acid : 3- [N ^′ -(t-butoxycarbonyl) -S-phenylglycinyl]
Amino-2,4-dioxo-1,5-bis (2-methylpropyl) -2,3,4,5-
Synthesis of tetrahydro-1H-1,5-benzodiazepine Following the general procedure J above, the product from Example 4-S, Step C and Boc-
Using L-phenylglycine (Nova Biochem, CAS No. 2900-27-8), 3- [N ^′ -(t-butoxycarbonyl) -S-phenylglycinyl] amino-2,4-dioxo- as a white foam. 1,5-bis (2-methylpropyl) -2,3,4,5-tetrahydro-1H-1,5-benzodiazepine was prepared. Flash chromatography _{(eluent, CH 2 Cl 2 / EtOAc (} 9: 1~5: were purified by gradient 1).

Step B: 3- (S-phenylglycinyl) amino-2,4-dioxo-1,5-
Synthesis of bis (2-methylpropyl) -2,3,4,5-tetrahydro-1H-1,5-benzodiazepine / hydrochloric acid 3- (S-phenylglycinyl) amino-2,4-dioxo-1,5-bis (
(2-Methylpropyl) -2,3,4,5-tetrahydro-1H-1,5-benzodiazepine / hydrochloric acid was produced.

Example 4-U 3- (L-alaninyl) amino-2,4-dioxo-1,5-bis- (cyclopropylmethyl) -2,3,4,5-tetrahydro-1H-1,5 Synthesis step A of benzodiazepine / hydrochloric acid : 2,4-dioxo-1,5-bis (cyclopropylmethyl) -2,3,4
Synthesis of 2,5-tetrahydro-1H-1,5-benzodiazepine 2,4-dioxo-1,5-bis (cyclopropylmethyl) -2,3,4,5-tetrahydro-1H-1,5-benzodiazepine Prepared from the product from Example 4-P, Step A, and (bromomethyl) cyclopropane (Lancaster) according to General Procedure 4-M. Purification by flash chromatography (eluent, linear gradient from EtOAc / hexane (3: 7) to ETOAc), followed by recrystallization (from EtOAc / hexane).

Step B: Synthesis of 3-azido-2,4-dioxo-1,5-bis (cyclopropylmethyl) -2,3,4,5-tetrahydro-1H-1,5-benzodiazepine Thus, the general production method 4-K was improved to the following method. First, the product from step A is suspended in THF at -78 ° C (not a solution), followed by KN (T
MS) ₂ solution was added and the suspension was allowed to warm to -30 ° C, during which time the suspension became a solution, which was recooled to -78 ° C. Upon recooling at −78 ° C., a precipitate began to form, and thus the reaction flask containing the mixture was cooled to an internal temperature of −50 ° C.
Raised slightly on a cold bath until rising to; then the trisyl azide solution was added. The cooling bath was removed and the mixture was allowed to warm to -20 ° C, after which the mixture became a nearly homogeneous solution and AcOH was added. The mixture was then processed as described in the general recipe. 3-azido-2,4-dioxo-1,5-bis (cyclopropylmethyl)-
2,3,4,5-Tetrahydro-1H-1,5-benzodiazepine was triturated (using hot to room temperature EtOAc) followed by recrystallization (hot CHCl _3).
/ EtOAc / EtOH (5: 5: 1) to CHCl ₃ / EtOAc / −23 ° C.
(From EtOH (5: 5: 1)) and a white solid was isolated.

Step C: Synthesis of 3-amino-2,4-dioxo-1,5-bis (cyclopropylmethyl) -2,3,4,5-tetrahydro-1H-1,5-benzodiazepine General Production Method 4 According to -L, using the product from Step B, 3-amino-2,4-dioxo-1,5-bis (cyclopropylmethyl) -2,3,4,5-tetrahydro-1H- as a white solid 1,5-benzodiazepine was produced. Flash chromatography (eluent, CH ₂ Cl ₂ / MeOH (gradient from 98: _{2 to} 95: 5), 5
% NH ₃ / MeOH) followed by recrystallization (warm CH ₂ Cl ₂ / hexane (1: 1)
) ~-23 ° C. in CH ₂ Cl ₂ / hexane (1: purified by from 1)).

Step D: 3- [N ^′ -(t-butoxycarbonyl) -L-alaninyl] amino-
Synthesis of 2,4-dioxo-1,5-bis (cyclopropylmethyl) -2,3,4,5-tetrahydro-1H-1,5-benzodiazepine N-Boc-L-alanine according to the above General Production Method I (Nova Biochem) and the product from Step C using a white foam of 3- [N ^' -(t-butoxycarbonyl) -L-alaninyl] amino-2,4-dioxo-1,5-bis (cyclo (Propylmethyl) -2,3,4,5-tetrahydro-1H-1,5-benzodiazepine was prepared. Flash chromatography (eluent, CH ₂ Cl ₂ / EtOAc (3
: 1 to 2: 1 gradient)).

Step E: 3- (L-alaninyl) amino-2,4-dioxo-1,5-bis (cyclopropylmethyl) -2,3,4,5-tetrahydro-1H-1,5-benzodiazepine Synthesis of Hydrochloric Acid The title compound was produced as an off-white solid using the product from Step D according to General Procedure 4-N above.

Example 4-V 3- (L-alaninyl) amino-2,4-dioxo-1,5-bis (2,2-dimethyl
Propyl) -2,3,4,5-tetrahydro-1H-1,5-benzodiazepine / salt
Acid synthesisStep A: 2,4-dioxo-1,5-bis (2,2-dimethylpropyl) -2,3
Of 4-, 4,5-tetrahydro-1H-1,5-benzodiazepine DMSO of the product from Example 4-P, Step A (1.0 eq., 17.08 g)
(500 mL) to a stirred suspension of neopentyl iodide (43.01 g, 2.
24 eq., Aldrich) and Cs_TwoCO_Three(72.65 g, 2.3 eq., Aldrich)
Was added. The resulting mixture is heated to 75 ° C. for 30 minutes,_TwoCO_Three(3
(1.59 g, 1.0 eq.) And the mixture was stirred rapidly at 75 ° C. for 6 hours. mixture
Cool the material,_TwoO (500 mL) and EtOAc (1000 mL) were added
. Phase and the organic phase is H_TwoO (1 × 500 mL), 1M hydrochloric acid (2 × 500 m
L) and brine (1 × 500 mL). The organic phase is then _Four , Filtered, concentrated and flash chromatographed (eluent, hexane
/ EtOAc (3: 2-2: 3: gradient)) to give 2,4- as a white solid.
Dioxo-1,5-bis (2,2-dimethylpropyl) -2,3,4,5-tetrahydride
B-1H-1,5-benzodiazepine was obtained.

Step B: Synthesis of 3-azido-2,4-dioxo-1,5-bis (2,2-dimethylpropyl) -2,3,4,5-tetrahydro-1H-1,5-benzodiazepine General The product from Step A was used according to Standard Production Method 4-K to give 3-azido-2,4-dioxo-1,5-bis (2,2-dimethylpropyl) -2,3,4, 5-
Tetrahydro-1H-1,5-benzodiazepine was prepared. The product was purified by flash chromatography (eluent, hexane / CH ₂ Cl ₂ : EtOAc (10: 5
: 1 to 5: 5: 1 gradient)) and purified and separable pseudo-axial / pseudo-
An equatorial (13: 1) azide mixture was obtained. Pure pseudo-axial azide was used for the next step. Selected ¹ H-NMR (CDCl ₃ ): pseudo-axial azide 5.12 (s, 1H); pseudo-equatorial azide 4.03 (s, 1H).

Step C: Synthesis of 3-amino-2,4-dioxo-1,5-bis (2,2-dimethylpropyl) -2,3,4,5-tetrahydro-1H-1,5-benzodiazepine Using the product from step B, 3-amino-2,4-dioxo-1,5-bis (2,2-dimethylpropyl) -2,3,4, 5-
Tetrahydro-1H-1,5-benzodiazepine was prepared. Flash chromatography (eluent, CH ₂ Cl ₂ / MeOH (gradient from 98: _{2 to} 95: 5, 5
And purified by% NH ₃ / with MeOH)). ^{From 1} H-NMR, the isolated white solid was identified as a mixture of pseudo-axial and pseudo-equatorial amine atropisomers (〜4: 1). The mixture was heated in toluene to 100 ° C. for 20 minutes and then reconcentrated to give a pure pseudo-equatorial amine atropisomer as a white solid, which was used in the next step. Selected ¹ H-NMR (CDCl ₃ ): pseudo-axial azide 4.59 (s, 1 H); pseudo-equatorial azide
4.03 (s, 1H).

Step D: 3- [N ^′ -(t-butoxycarbonyl) -L-alaninyl] amino-
Synthesis of 2,4-dioxo-1,5-bis (2,2-dimethylpropyl) -2,3,4,5-tetrahydro-1H-1,5-benzodiazepine N-Boc- Using L-alanine (Nova Biochem) and the product from Step C, a white foam of 3- [N ^' -(t-butoxycarbonyl) -L-alaninyl] amino-2,4-dioxo-1,5- Bis (2,2-dimethylpropyl) -2,3,4,5-tetrahydro-1H-1,5-benzodiazepine was prepared. Flash chromatography (eluent, CH ₂ Cl ₂ / EtOAc (
(4: 1 to 5: 2 gradient).

Step E: 3- (L-alaninyl) amino-2,4-dioxo-1,5-bis (2,
Synthesis of (2-dimethylpropyl) -2,3,4,5-tetrahydro-1H-1,5-benzodiazepine / hydrochloric acid An off-white solid using the product from step D according to the above general production method 4-N. The title compound was prepared.

Example 4-W 3- (L-alaninyl) amino-2,4-dioxo-1,5-bisphenyl-2,3,
Synthesis step A of 4,5-tetrahydro-1H-1,5-benzodiazepine / hydrochloric acid : 2,4-dioxo-1,5-bisphenyl-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine This production method is an improved method of the production method described in Tetrahedron Lett. 1996, 37, 9013-9016 by Chan, DMT (the contents of which are part of the present specification). Example 4-
P, product from step A (1.0 eq., 7.50 g), Ph ₃ Bi (2.2 eq.,
41.26 g, Aldrich), Cu (OAc) ₂ (2.0 eq., 15.48 g, Aldrich)
_{), Et 3 N (2.0eq.} , The CH ₂ Cl ₂ (100mL) mixture of 8.62 g),
Stirred at room temperature under N ₂ for 6 days (tracked by TLC). The solid is washed with CH ₂ Cl ₂ / Me
Filtered through a plug of celite, rinsing with OH (3 × 75 mL). The filtrate was concentrated, heat CH ₂ Cl ₂ / MeOH: were dissolved in (9 1), the large plug (eluent on silica gel, CH ₂ Cl ₂ from _{CH 2 Cl 2 / MeOH (9} : 1) to a linear gradient, 2L
). The filtrate was concentrated and the residue was purified by flash chromatography (eluent, CH ₂ Cl ₂ from _{CH 2 Cl 2 / MeOH (9} : linear gradient to 1)) was purified by. While concentrating the fractions containing the product, 2,4-dioxo-
1,5-bisphenyl-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine crystallized and was isolated as a white solid by filtration.

Step B: 3-azido-2,4-dioxo-1,5-bisphenyl-2,3,4,
Synthesis of 5-tetrahydro-1H-1,5-benzodiazepine For this substrate, the general procedure 4-K was modified as follows. First, the product from step A is suspended in THF at -70 ° C (not a solution), followed by KN (T
MS) ₂ solution was added and the suspension was allowed to warm to -20 ° C for 10 minutes, during which time the suspension became a solution, which was recooled to -70 ° C; Processed as follows. Triturate the title compound (hot CHCl ₃ / hexane (1
: 1)) to give 3-azido-2,4-dioxo-1,
5-Bisphenyl-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine was purified.

Step C: 3-Amino-2,4-dioxo-1,5-bisphenyl-2,3,4,
Synthesis of 5-tetrahydro-1H-1,5-benzodiazepine According to General Preparation 4-L, using the product from Step B, 3-amino-2,4-dioxo-1,5-bisphenyl as a white solid -2,3,4,5-tetrahydro-1
H-1,5-benzodiazepine was produced. Flash chromatography _{(eluent, CH 2 Cl 2 / MeOH (} 98: 2~95: gradient _{5), 5% NH 3 /} Me
(With OH).

Step D: 3- [N ^′ -(t-butoxycarbonyl) -L-alaninyl] amino-
2,4-dioxo-1,5-bisphenyl-2,3,4,5-tetrahydro-1H-
Synthesis of 1,5-Benzodiazepine According to General Procedure I above, using N-Boc-L-alanine (Nova Biochem) and the product from Step C, give 3- [N ^' -(t-butoxycarbonyl) as a white foam. ) -L-alaninyl] amino-2,4-dioxo-1,5-bisphenyl-2,
3,4,5-Tetrahydro-1H-1,5-benzodiazepine was prepared. The product was purified by flash chromatography _{(eluent, CH 2 Cl 2 / EtOAc (} 4: 1~
(3: 1 gradient).

Step E: Synthesis of 3- (L-alaninyl) amino-2,4-dioxo-1,5-bisphenyl-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine / hydrochloric acid The title compound was prepared as a white amorphous solid using the product from Step D according to General Preparation 4-N.

Example 4-X Synthesis of 3-Amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one J. Org. Chem., By RG Sherrill et al. The title compound was prepared according to the method of 1995, 60, 730-734, the contents of which are incorporated herein, using glacial acetic acid and HBr gas.

Example 4-Y 3- (L-valinyl) amino-2,3-dihydro-1-methyl-5-phenyl-1
Synthesis step A of H-1,4-benzodiazepin-2-one : 3- [N ^′ -(tert-butylcarbamate) -L-valinyl] -amino-2,3-dihydro-1-methyl-5-phenyl- Synthesis of 1H-1,4-benzodiazepin-2-one (S) -3-amino-1,3-dihydro-1-methyl-5-phenyl-2H-1,
4-benzodiazepin-2-one, (1S) -7,7-dimethyl-2-oxobicyclo [2.2.1] heptane-1-methanesulfonate (Example 4-B, Step A)
The free base was obtained by partitioning with dichloromethane and 1M potassium carbonate. Then, the free amine was subjected to a coupling reaction with N-Boc-valine according to General Production Method D to obtain the title compound. _{C 26 H 32 N 4 O 4} (MW = 464.62); mass spectroscopy 464.3. Elemental analysis (as _{C 26 H 32 N 4 O 4} ): theoretical value: C, 67.22; H, 6.94 ;
N, 12.06; Found: C, 67.29; H, 6.79; N, 11.20.

Step B: 3- (L-valinyl) amino-2,3-dihydro-1-methyl-5
Synthesis of phenyl-1H-1,4-benzodiazepin-2-one According to general production method 4-C, 3- [N ^′ -(tert-butylcarbamate) -L-
Valinyl] amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4
-The title compound was prepared as a white foam using -benzodiazepin-2-one. _{C 21 H 23 N 4 O 2} (MW = 363.48); mass spectroscopy (M + H) 364.2.

Example 4-Z 3- (L-tert-leucinyl) amino-2,3-dihydro-1-methyl-5-
Synthesis Step A of Phenyl-1H-1,4-benzodiazepin-2-one : 3- [N ^′ -(tert-butylcarbamate) -L-tert-leucinyl] amino-2,3-dihydro-1-methyl-5 -Phenyl-1H-1,4-
Synthesis of benzodiazepin-2-one (S) -3-amino-1,3-dihydro-1-methyl-5-phenyl-2H-1,
4-benzodiazepin-2-one, (1S) -7,7-dimethyl-2-oxobicyclo [2.2.1] heptane-1-methanesulfonate (Example 4-B, Step A)
The free base was obtained by partitioning with dichloromethane and 1M potassium carbonate.
Then, the free amine was subjected to a coupling reaction with N-Boc-tert-leucine according to General Production Method D to obtain the title compound. _{C 27 H 35 N 4 O 4} (MW = 479.66); mass spectroscopy 479.

Step B: 3- (L-tert-leucinyl) amino-2,3-dihydro-1-
Synthesis of methyl-5-phenyl-1H-1,4-benzodiazepin-2-one According to general production method 4-C, 3- [N ^′ -(tert-butylcarbamate) -L-
tert-leucinyl] amino-2,3-dihydro-1-methyl-5-phenyl-
The title compound was prepared as a white foam using 1H-1,4-benzodiazepin-2-one. Elemental analysis (as _{C 22 H 25 N 4 O 2} · 0.5H 2 O): theory: C, 68.19;
H, 7.02; N, 14.40, found: C, 68.24; H, 7.00; N, 14
.00.

Example 4-AA 3- (L-alaninyl) amino-2,3-dihydro-1,5-dimethyl-1H-1,
Synthesis of 4-benzodiazepine 2,3-dihydro-1,5-dimethyl-1H-1,4-benzodiazepine was prepared according to general procedure 8-I (using methyl iodide), 4-D and 4-F.
The coupling reaction of this intermediate and Boc-L-alanine (Novo) was performed using General Production Method D.

The Boc-protected compound was treated with a mixture of CH ₂ Cl ₂ and trifluoroacetic acid (
(1: 1 to 2: 1) to remove the Boc group. The resulting solution was stirred until tlc indicated complete conversion (typically 2 hours). Then
The solution was stripped to dryness, dissolved the residue in ethyl acetate or Cl ₂ Cl _2. The solution was washed with saturated aqueous NaHCO _{3, the} aqueous phase was adjusted to basic pH and then extracted with ethyl acetate or CH ₂ Cl ₂ . The solvent was stripped of the organic phase on a rotary evaporator to give the title compound, which was used without further purification.

Example 4-AB 3- (L-3-thienylglycinyl) amino-2,4-dioxo-1,5-bis- (
Synthesis step A of 2,2-dimethylpropyl) -2,3,4,5-tetrahydro-1H-1,5-benzodiazepine : Synthesis of N- (t-butoxycarbonyl) -L-3-thienylglycine N- ( t-Butoxycarbonyl) -L-3-thienylglycine is converted to L-α- (3
-Thienyl) glycine (Sigma) from The Practice of P by Bodansky, M. et al.
eptide Synthesis; Springer Verlag; 1994, p17 (the content of which is part of the present specification).

Step B: 3- [N ^' -(t-butoxycarbonyl) -L-3-thienylglycinyl] amino-2,4-dioxo-1,5-bis (2,2-dimethylpropyl) -2 , 3,
Synthesis of 4,5-tetrahydro-1H-1,5-benzodiazepine According to the general process D described above, using the product from Example 4-V, Step C and the product from Step A above, 3- [N ^' -(T-butoxycarbonyl) -L-3-thienylglycinyl] amino-2,4-dioxo-1,5-bis (2,2-dimethylpropyl) -2,3,4,5-tetrahydro-1H -1,5-benzodiazepine was prepared.

Step C: 3- (L-3-thienylglycinyl] amino-2,4-dioxo-1,
5-bis (2,2-dimethylpropyl) -2,3,4,5-tetrahydro-1H-1,
Synthesis of 5-benzodiazepine The title compound was prepared using the product from Step B according to General Preparation 4-N above.

Example 4-AC of 2- (L-alaninyl) amino-3H-flueno [1.9-ef] -2,4-dihydro-1-methyl-1H-1,4-diazepin-3-one Synthesis Step A Preparation of 1- [N- (α-isopropylthio) -N ^′ -(benzyloxycarbonyl) glycinyl] amino-9-fluorenone α- (isopropylthio) -N- (benzyloxycarbonyl) glycine (1 eq)
A dry THF solution of Tetrahedron 1975, 31, 863 by Ben-Ishai, D (manufactured according to part of this specification) by Ben-Ishai, D is cooled to 0 ° C. and oxalyl chloride (1 eq. ) And DMF (3 drops). 15 at 0 ° C
After stirring for minutes, the cooling bath was removed and stirring continued at ambient temperature for 40 minutes. The solution was recooled to 0 ° C. 1-amino-9-fluorenone (0.9 eq .; Aldrich) and 4-
A solution of methyl morpholine (2.0 eq .; Aldrich) in dry THF was added to the acid chloride using a cannula. The cooling bath was removed and the reaction was stirred at ambient temperature for 5 hours. Dilute the reaction with dichloromethane and add 0.5 M citric acid, saturated NaH
Washed with aqueous CO ₃ and brine. Drying the organic phase over Na ₂ SO ₄ ,
Filtration and concentration. The residue was triturated with diethyl ether / hexane (1: 1) to give the title compound as a yellow solid. MS (C ₂₆ H calculated as _{24 N 2 O 4 S):} 461.15 (MH -), Found (46
1.3. Elemental analysis (as _{C 26 H 24 N 2 O 4} S): Theoretical value: C, 67.81; H, 5.25
N, 6.08; Found: C, 67.97; H, 5.26; N, 6.14.

Step B Production of 1- [N- (α-amino) -N ^′ -(benzyloxycarbonyl) glycinyl ] amino-9-fluorenone ^' -(Benzyloxycarbonyl) glycinyl)] amino-9-fluorenone (1 eq) in THF at 0 ° C. After 35 minutes, mercury (II) chloride (1.1 eq.) Was added. The ice bath was removed and ammonia gas continued to bubble through the suspension. The bubbler was removed and the reaction continued to stir for 16 hours. The mixture was filtered through celite washing with THF. The filtrate was concentrated under vacuum. The crude solid was used for Step C without further purification.

Step C 2- (benzyloxycarbonyl) amino-3H-fluoreno [1,9-e
f] Preparation of 2,4-dihydro-1H-1,4-diazepin-3-one 1- [N- (α-amino) -N ^′ -(benzyloxycarbonyl) glycinyl] amino-9-fluorenone (1 eq) .) With glacial acetic acid and ammonium acetate (4.7e).
q. ). The suspension was stirred at ambient temperature for 21 hours. After concentrating the reaction in vacuo, the residue was partitioned between ethyl acetate and 1N NaOH.
Washed with brine and the combined organics dried over Na ₂ SO _4, filtered, and concentrated. The residue was triturated with diethyl ether / dichloromethane (3: 1). Elemental analysis (as _{C 23 H 17 N 3 O 3} · 0.25H 2 O): theory: C, 71.22;
H, 4.55; N, 10.83, found: C, 71.50; H, 4.44; N, 10
.84.

Step D 2- (benzyloxycarbonyl) amino-3H-fluoreno [1,9-e
f] Preparation of 2,4-dihydro-1-methyl-1H-1,4- diazepin-3 -one
According to the above general production method 4-A, 2- (benzyloxycarbonyl) amino-3H
-Fluoreno [1,9-ef] -2,4-dihydro-1H-1,4-diazepine-3
The title intermediate was prepared as a yellow solid using -one. Elemental analysis (as _{C 26 H 19 N 3 O 3} ): theoretical value: C, 72.53; H, 4.82 ;
N, 10.57; Found: C, 72.37; H, 5.01; N, 10.36.

Step E 2-Amino-3H-fluoreno [1,9-ef] -2,4-dihydro-1-
Preparation of methyl-1H-1,4-diazepin-3-one 2- (benzyloxycarbonyl) amino-3H
Using fluoreno [1,9-ef] -2,4-dihydro-1-methyl-1H-1,4-diazepin-3-one to produce the title intermediate in the form of a yellow foam, Used immediately in Step F.

Step F 2- [N ^′ -(tert-butylcarbamate) -L-alaninyl] amino
-3H-fluoreno [1,9-ef] -2,4-dihydro-1-methyl-1H-1,
Preparation of 4-diazepin-3-one According to general procedure D, N-Boc-alanine (Novabiochem) and 2-amino-3H-fluoreno [1,9-ef] -2,4-dihydro-1-methyl-1H. −
The title intermediate was prepared as a yellow solid using 1,4-diazepin-3-one. MS (calculated as _{C 24 H 27 N 4 O 4} ): 435.21 (MH -): Found 435.
29.

Step G 2- (L-alaninyl) amino-3H-fluoreno [1,9-ef] -2,4
Preparation of -dihydro-1-methyl-1H-1,4-diazepin-3-one 2- [N ^′ -(tert-butylcarbamate) -L-
[Alaninyl] amino-3H-fluoreno [1,9-ef] -2,4-dihydro-1-
The title intermediate was prepared as a yellow foam using methyl-1H-1,4-diazepin-3-one.

Example 4-AD 5- (L-alaninyl) amino-7-methyl-1,2,4-triazo [4,3-d] [1
, 4] Benzodiazepin-6 (7H) -one Synthesis Step A 1,3-Dihydro-5- (ethylthio ) -1-methyl-2H-1,4-
Preparation of nzodiazepin-2-one 1-Cooled to -40 ° C to -45 ° C in a flask dried with a dryer under N _2.
Methyl-1,2,3,4-tetrahydro-3H-1,4-benzodiazepine-2,5
Dione (Showell, GA et al., J. Med. Chem. 1994, 37, 719, the contents of which are incorporated herein) (1 eq.) And pyridine (1 eq., Aldrich).
) Of CH ₂ Cl ₂ (0.16M dione)
Trifluoromethanesulfonic anhydride (1.1 eq., Aldrich) was treated dropwise. The resulting mixture (light yellow; sediment) was stirred at -40 ° C to -35 ° C for 20 minutes, then at 0 ° C (ice bath) to 10 ° C for 14.5 hours. To dissolve slowly). The resulting orange solution (some precipitates) was cooled again to 0 ° C. and treated dropwise with ethanediol (1.2 eq., Aldrich). The resulting mixture was stirred at 0-4 ° C. under N ₂ for 8 h, then CH ₂ Cl ₂
And saturated aqueous NaHCO ₃ . The aqueous phase was extracted 3 times with CH ₂ Cl _2. The combined organic extracts were dried over Na ₂ SO ₄ and concentrated in vacuo. The mixture was purified by flash chromatography was purified performed _{(eluent, CH 2 Cl 2 ~CH 2 Cl} 2 / ethyl acetate (30:70) gradient). MS (calculated as _{C 12 H 15 NOS): 235.09} (MH +): Found 235
.0. Elemental analysis (as C ₁₂ H ₁₅ NOS): theoretical value: C, 61.51; H, 6.02 ;
N, 11.96; Found: C, 61.55; H, 5.99; N, 11.74.

Step B 7-Methyl-1,2,4-triazolo [4,3-d] [1,4] benzodiaze
Preparation of pin-6 (7H) -one 1,3-dihydro-5- (ethylthio) -1-methyl-2H-1,4-benzodiazepin-2-one (1 eq.) And formic hydrazide (5.8 eq. Aldrich)
The mixture Roh n- butanol (0.1M benzodiazepines solution), N ₂ under 24 h and stirred under reflux. Further, formic acid hydrazide (1.67 eq.) Was added, and the mixture was further refluxed for 16 hours. The yellow solution was evaporated in vacuo, the residue was purified by flash chromatography was purified by performing a (CH ₂ Cl ₂ / ethyl acetate (98: 2 to 96 eluting with 4 gradient)). The product was obtained as a white solid. MS (calculated as _{C 11 H 11 N 4 O)} : 215.09 (MH +): Found 215.
3. Elemental analysis (as _{C 11 H 11 N 4 O)} : theory: C, 61.67; H, 4.71 ; N
, 26.15, found: C, 61.56; H, 4.71; N, 26.08.

Step C Preparation of 5 (5H) azido-7-methyl-1,2,4-triazolo [4,3-d] [ 1,4] benzodiazepin-6 (7H) -one General procedure 4-K According to 5H-7-methyl-1,2,4-triazolo [4,3-
The title compound was prepared as a pale yellow solid using d] [1,4] -benzodiazepin-6 (7H) -one. MS (calculated as _{C 11 H 9 N 7 O)} : 255.09: FDMS Found 255.0
. IR (CHCl ₃ solution) 2138, 2115 cm ⁻¹ .

Step D Preparation of 5 (5H) amino-7-methyl-1,2,4-triazolo [4,3-d] [ 1,4] benzodiazepin-6 (7H) -one 5 (5H) azido- 7-methyl-1,2,4-triazolo [4,3-d] [1,4] benzodiazepine -6 (7H) - a on-ethyl acetate (0.1 M) mixture, N ₂ under 10
% Pd-carbon (0.4 eq., Engelhard). Flush the reaction vessel with H _2, stirring was continued for 3 hours under H ₂ balloon. The vessel was flushed with N ₂ and the contents were washed with ethyl acetate while washing with Celite 5
Filtered through 75. The filtrate was concentrated under vacuum to give a white powder. MS (calculated as _{C 11 H 12 N 5 O)} : 230.10 (MH +): Found 230.
One.

[0452] Step E 5 (5H) - [N '-tert- butyl carbamate) -L- alaninyl] amino-7-methyl-1,2,4-triazolo [4,3-d] [1,4] benzodiazepines
Preparation of 1-6 (7H) -one 5 (5H) amino-7-methyl-1,2,4-triazolo [
The title intermediate was prepared as a white foam using 4,3-d] [1,4] benzodiazepin-6 (7H) -one and N-Boc-alanine (Novabiochem). MS (calculated as _{C 19 H 25 N 6 O 4} ): 401.19 (MH +): Found 401
.1. Elemental analysis (as _{C 19 H 24 N 6 O 4} ): theoretical value: C, 55.74; H, 6.15 ;
N, 20.53; Found: C, 56.06; H, 6.42; N, 20.20.

Step F 5 (5H)-(L-alaninyl) amino-7-methyl-1,2,4-tria
Preparation of Zolo [4,3-d] [1,4] benzodiazepin-6 (7H) -one 5 (5H)-[N ^' -(tert-butylcarbamate) according to General Preparation Method 4-C.
-L-alaninyl] amino-7-methyl-1,2,4-triazolo [4,3-d] [1,
4] Benzodiazepin-6 (7H) -one was used to produce the title compound as a white foam. MS (C ₁₄ calculated as _{H 17 N 6 O 2):} 301.14 (MH +): Found 301
.1.

Example 4-AE Preparation of 3- (L-alaninyl) amino-2,3-dihydro-1-methyl-5-piperidinyl-1H-1,4-benzodiazepin-2-one Step A 3- [N ^' -Tert-butylcarbamate) -L-alaninyl] amino
-2,3-dihydro-1-methyl-5- (1-piperidinyl) -1H-1,4-ben
Preparation of zodiazepin-2-one According to the above General Production Method D, 3-amino-1,3-dihydro-1-methyl-5- (
1-piperidinyl) -2H-1,4-benzodiazepin-2-one (Example 4-A
) And N-Boc-alanine (Nova Biochem) to produce the title intermediate as a white foam. MS (calculated as _{C 23 H 33 N 5 O 4} ): 444.26 (MH +): Found 444
.4. Elemental analysis (as _{C 23 H 33 N 5 O 4} · 0.5H 2 O): theory: C, 61.04; H
N, 15.47; N, 15.47; Found: C, 61.09; H, 7.29; N, 15.
21.

Step B Preparation of 3- (L-alaninyl) amino-2,3-dihydro-1-methyl-5- ( 1-piperidinyl) -1H-1,4-benzodiazepin-2-one General production method 4- In accordance with C, 3- [N ^'-tert- butyl carbamate) -L-
[Alaninyl] amino-2,3-dihydro-1-methyl-5- (1-piperidinyl)-
The title intermediate was prepared using 1H-1,4-benzodiazepin-2-one.

Example 4-AF Preparation of 3- (L-alaninyl) amino-2,3-dihydro-5-isopropyl-1-methyl-1H-1,4-benzodiazepin-2-one Step A 3- (benzyl (Oxycarbonyl) amino-2,3-dihydro-5-i
Preparation of Sopropyl-1H-1,4-benzodiazepin-2-one 2- (benzotriazol-1-yl) -N- (benzyloxycarbonyl) glycine (1.1 equivalents, J. Org. Chem. By Katrizky, AR et al. . 1990, 55, 2206 (the contents of which are incorporated herein), a THF slurry (0.3 M) was cooled to 0 ° C. and treated dropwise with oxalyl chloride (1.1 equivalents). . DMF (0.1 equivalent) was added dropwise to the slurry, and stirring was continued at 0 ° C. for 1 hour. 1- (2-Aminopropylphenyl) -2-methyl-1-propanone cooled to 0 ° C. (1.0 equivalent; Synthesis 1991, 56 by Robl, JA, the contents of which are incorporated herein by reference). ) And N-methylmorpholine (2.2 eq) in THF (1M in propanone) were added via cannula. After the addition was complete, the reaction was warmed to ambient temperature. The mixture was filtered and the filter cake was washed with THF. The filtrate was transferred to a three-neck flask and treated with ammonia gas for 15 minutes using a dispersion tube. Methanol (0.3M propanone solution) was added and ammonia was continued to bubble through the solution for 1 hour. The reaction was concentrated, diluted with ethyl acetate and concentrated again.
This operation was repeated again. The residue was diluted with ethyl acetate and washed twice with 1N NaOH. The aqueous wash was re-extracted with ethyl acetate. The combined organics were washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated. Acetic acid was added and concentrated under vacuum. The syrup was dissolved in acetic acid (0.6M propanone solution) and treated with ammonium acetate (4.0 equivalents). The reaction was stirred at ambient temperature for 18 hours. The resulting solid was filtered, washed with H ₂ O. MS (calculated as _{C 20 H 22 N 3 O 3} ): 352.17: Found 352.5.

Step B 3- (benzyloxycarbonyl) amino-2,3-dihydro-5-i
Preparation of Sopropyl-1-methyl-1H-1,4-benzodiazepin-2-one According to General Production Method 4-A, 3- (benzyloxycarbonyl) amino-2,3-
The title compound was prepared as a white solid using dihydro-5-isopropyl-1H-1,4-benzodiazepin-2-one. MS (calculated as _{C 21 H 24 N 3 O 3} ): 366.18 (MH +): Found 366
.2. Elemental analysis (as _{C 21 H 23 N 3 O 3} · 0.25H 2 O): theory: C, 68.18;
H, 6.40; N, 11.36, found: C, 68.36; H, 6.28; N, 11
.48.

Step C 3-Amino-2,3-dihydro-5-isopropyl-1-methyl-1
Production of H-1,4-benzodiazepin-2-one According to the general production method 4-B, 3- (benzyloxycarbonyl) amino-2,3-
Dihydro-5-isopropyl-1-methyl-1H-1,4-benzodiazepine
The title compound was prepared as a white foam using 2-one. MS (calculated as _{C 13 H 18 N 3 O)} : 232.14 (MH +): Found 232.
19.

Step D 3- [N ^' -(tert-butylcarbamate) -L-alaninyl] amido
No-2,3-dihydro-5-isopropyl-1-methyl-1H-1,4-benzodi
Preparation of azepin-2-one According to General Preparation Method D, 3-amino-2,3-dihydro-5-isopropyl-1
The title compound was prepared as a white solid using -methyl-1H-1,4-benzodiazepin-2-one and N-Boc-alanine (Novabiochem). MS (calculated as _{C 21 H 31 N 4 O 4} ): 403.23 (MH +): Found 403
.46.

Step E 3- (L-alaninyl) amino-2,3-dihydro-5-isopropyl
Preparation of -1-methyl-1H-1,4-benzodiazepin-2-one According to the general production method 4-C, 3- [N ^′ -(tert-butylcarbamate) -L-
[Alaninyl] amino-2,3-dihydro-5-isopropyl-1-methyl-1H-
The title compound was prepared as a white foam using 1,4-benzodiazepin-2-one. MS (calculated as _{C 16 H 23 N 4 O 2} ): 303.18 (MH +): Found 303
.21. Elemental analysis (as _{C 16 H 23 N 4 O 2} · 0.3H 2 O): theory: C, 62.44; H
N, 18.20; Found: C, 62.58; H, 7.10; N, 17.
79.

Example 4-AG Preparation of 3- (L-alaninyl) amino-2,3-dihydro-5-n-propyl-1-methyl-1H-1,4-benzodiazepin-2-one Step A 1- Preparation of (2-aminophenyl) -1-butanone A solution of anthranilonitrile (1 equivalent, Aldrich) in diethyl ether (2.4 M) was cooled to 0 ° C. and propylmagnesium chloride (
2.5 eq, Aldrich, 2.0 M Et ₂ O solution) were added dropwise over 1 hour. After adding 25% of the Grignard reagent, another 1/10 volume of E ₂ O was added. The cooling bath was removed and the suspension continued stirring for 5 hours. Return the reaction to 0 ° C. and add 3N HCl
Was carefully quenched. The cooling bath was removed and stirring continued for 30 minutes. The mixture is N
Add aOH solid to make it basic. The contents are extracted three times with ethyl acetate,
Brine was added to break up the suspension. The combined extracts were washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated. The crude residue was purified by chromatography (eluted with hexane / ethyl acetate (95: 5)). MS (calculated as _{C 10 H 13 NO): 163.10} (MH +): Found 163.
18. Elemental analysis (as _{C 10 H 13 NO · 0.2H 2} O): theory: C, 72.00; H,
8.10; N, 8.40, found: C, 72.36; H, 8.25; N, 8.76.

Step B 3- (benzyloxycarbonyl) amino-2,3-dihydro-5-i
Preparation of Sopropyl-1H-1,4-benzodizepin-2-one 2- (benzotriazol-1-yl) -N- (benzyloxycarbonyl) glycine (1.1 equivalents, J. Org. Chem. By Katrizky, AR et al. A THF slurry (0.3 M) of 1990, 55, 2206, the contents of which is part of this specification, was cooled to 0 ° C. and treated dropwise with oxalyl chloride (1.1 eq). . DMF (0.1 eq) was added to the slurry and stirring was continued at 0 ° C. for 1 hour. 1 cooled to 0 ° C
-(2-aminopropylphenyl) -1-butanone and N-methylmorpholine (
(2.2 eq) in THF (1 M butanone solution) was added via cannula. After the addition was complete, the reaction was warmed to ambient temperature. The mixture was filtered and the filter cake was washed with THF. The filtrate was transferred to a three-neck flask and treated with ammonia gas for 15 minutes using a dispersion tube. Methanol (0.3 M butanone solution) was added and ammonia was continued to bubble through the solution for 1 hour. Concentrate the reaction,
Diluted with ethyl acetate and concentrated again. This operation was repeated again. The residue was diluted with ethyl acetate and washed twice with 1N NaOH. The aqueous wash was re-extracted with ethyl acetate. The combined organics were washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated. Acetic acid was added and concentrated under vacuum. Add the syrup to acetic acid (0.6M
(Butanone solution) and treated with ammonium acetate (4.0 equivalents). The reaction was stirred at ambient temperature for 18 hours. The resulting solid was filtered, washed with H ₂ O. MS (calculated as _{C 20 H 22 N 3 O 3} ): 352.17: Found 352.4.

Step C 3- (benzyloxycarbonyl) amino-2,3-dihydro-5-n
Preparation of propyl-1-methyl-1H-1,4-benzodiazepin-2-one According to General Production Method 4-A, 3- (benzyloxycarbonyl) amino-2,3-
The title compound was prepared as a white solid using dihydro-5-n-propyl-1H-1,4-benzodiazepin-2-one. MS (calculated as _{C 21 H 24 N 3 O 3} ): 366.18 (MH +): Found 366
.2.

Step D 3-Amino-2,3-dihydro-5-n-propyl-1-methyl-1
Production of H-1,4-benzodiazepin-2-one According to the general production method 4-B, 3- (benzyloxycarbonyl) amino-2,3-
Dihydro-5-n-propyl-1-methyl-1H-1,4-benzodiazepine
The title compound was prepared as a white foam using 2-one. This compound was used immediately in Step E.

Step E 3- [N ^′ -(tert-butylcarbamate) -L-alaninyl] ami
No-2,3-dihydro-5-n-propyl-1-methyl-1H-1,4-benzodi
Preparation of azepin-2-one According to General Preparation Method D, 3-amino-2,3-dihydro-5-n-propyl-1
The title compound was prepared as a white solid using -methyl-1H-1,4-benzodiazepin-2-one and N-Boc-alanine (Novabiochem). MS (calculated as _{C 21 H 31 N 4 O 4} ): 403.23 (MH +): Found 403
.4.

Step F 3- (L-alaninyl) amino-2,3-dihydro-5-n-propyl
Preparation of -1-methyl-1H-1,4-benzodiazepin-2-one According to the general production method 4-C, 3- [N ^′ -(tert-butylcarbamate) -L-
[Alaninyl] amino-2,3-dihydro-5-n-propyl-1-methyl-1H-
The title compound was prepared as a white foam using 1,4-benzodiazepin-2-one.

Example 4-AH Synthesis Step A of 3- (L-alaninyl) amino-4-n-butyl-3,4-dihydro-1-methyl-1H-1,4-benzodiazepine-2,5-dione 4-n-butyl-3,4-dihydro-1-methyl-1H-1,4-ben
Preparation of zodiazepine-2,5-dione 3,4-dihydro-1-methyl-1H-1,4-benzodiazepine-2,5-dione (Tett. Lett. 1994, 50 (30), 9051 (this content is A solution of dry dimethylformamide (30 mL), which forms part of the specification, under nitrogen at 0 ° C. with 1 equivalent of t.
-Potassium butoxy (Aldrich, 1.0 M THF solution) was treated dropwise. 0 ° C
After 45 minutes, iodobutane was introduced with a syringe over several minutes. The reaction mixture was stirred at ambient temperature for 75 minutes, diluted with dichloromethane and then saturated with water and sodium chloride. The organic solution was dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give a yellow oil. Purification by flash chromatography (silica gel, eluted with ethyl acetate / hexane (7/1)) gave a colorless oil (9
(0% yield) of pure material. C ₁₄ H ₁₈ N ₂ O ₂ (MW = 246.3) Elemental analysis (as C ₁₄ H ₁₈ N ₂ O ₂ ): Theory: C, 68.27; H, 7.37;
N, 11.37; Found: C, 68.53; H, 7.11; N, 11.41.

Step B 3-Azido-4-n-butyl-3,4-dihydro-1-methyl-1H
Preparation of -1,4-benzodiazepine-2,5-dione Following the general production method 4-K, 4-n-butyl-3,4-dihydro-1-methyl-
The title intermediate was prepared as a waxy solid using 1H-1,4-benzodiazepine-2,5-dione. C ₁₄ H ₁₇ N ₅ O ₂ (MW = 287.3); precision mass FAB ⁺ theoretical value 288.1
461, found 288.1449.

Step C 3-Amino-4-n-butyl-3,4-dihydro-1-methyl-1H
Preparation of -1,4-benzodiazepine-2,5-dione Azide (see Step B above) (0.4 mmol) in 10% ethyl acetate
The reaction was treated with Pd / C (Englehard) (170 mg), and the hydrogenation reaction was carried out overnight at a hydrogen-filled balloon static pressure connected to the reaction thrusco with a syringe and a septum.
The catalyst was removed by filtration and the filtrate was concentrated in vacuo to give a yellow oil. This is chromatographed (silica gel, 1 mil chromatotron plate (
Purified by mil Chromatotron plate, dichloromethane / methanol (95/5) [7N ammonia]). Elemental analysis (as _{C 14 H 19 N 3 O 2} ): theoretical value: C, 64.35; H, 7.33 ;
N, 16.08; Found: C, 64.58; H, 7.19; N, 15.94.

Step D 3- (n-tert-butylcarbamate-L-alaninyl) amino-4
-N-butyl-3,4-dihydro-1-methyl-1H-1,4-benzyldiazepine
Preparation of -2,5-dione Following general procedure D, using N-Boc-alanine and the aminobenzodiazepinedione from step C above gave the title intermediate as an amorphous white solid. Elemental analysis (as _{C 22 H 32 N 4 O 5} ): theoretical value: C, 61.09; H, 7.46 ;
N, 12.95; Found: C, 60.83; H, 7.51; N, 12.69.

Step E 3- (L-aralanyl) amino-4-n-butyl-3,4-dihydro-1
Preparation of -Methyl-1,4-benzodiazepine-2,5-dione Following general procedure 4-C and using the Boc-protected intermediate from step D above, the title intermediate was obtained as a white solid. C ₁₇ H ₂₄ N ₄ O ₃ (MW = 332.4), precision mass FAB ⁺ theoretical value MW = 33
3.1927, found MW = 333.1924.

Example 4-AI Preparation of 3- (L-alaninyl) amino-1,3-dihydro-5-ethylthio-1-methyl-2H-1,4-benzodiazepin-2-one Step A 1,3- Dihydro-5-ethylthio-1-methyl-2H-1,4-ben
Preparation of zodiazepin-2-one In a round bottom flask dried in a dryer under nitrogen, 3,4-dihydro-1-methyl-
1H-1,4-benzodiazepine-2,5-dione (1.0 mmol) (Tett. Let
t. 1994, 50 (30), 9051) in dry dichloromethane (Aldrich Sure Seal (Sure S)
eal)) was treated with anhydrous pyridine (mallinkrodt)) (1.1 equivalents). The reaction was cooled to −51 ° C. in a dry ice / acetone bath and trifluoromethanesulfonic anhydride (1.1 eq, Aldrich, stoppered ampoule) was treated dropwise with a syringe over 30 minutes. The reaction mixture was stirred for 20 minutes while maintaining the reaction temperature between -47C and -35C. The temperature was brought to 0 ° C in 1-2 minutes and then kept at that temperature for 1 hour. Ethanediol (3.4 eq) was introduced by syringe and the mixture was stirred overnight while immersed in a Dewar bottle filled with ice water. The temperature had risen to 16 ° C. by morning. The reaction mixture was partitioned between dichloromethane and aqueous sodium bicarbonate. The aqueous phase is further extracted three times with dichloromethane,
The extracts were combined, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give a yellow oil. Purification was performed by flash chromatography (silica gel, dichloromethane / ethyl acetate (100/1, 95/5, 90/10 and 85/1).
Elution with 5 gradients)) was effective. Crystallization on standing afforded the title compound as a colorless oil. Elemental analysis (as _{C 12 H 14 N 2 OS)} : theoretical value: C, 61.51; H, 6.02 ;
N, 11.96; Found: C, 61.55; H, 5.99; N, 11.74.

Step B 3-Azido-1,3-dihydro-5-ethylthio-1-methyl-2H
Preparation of -1,4-benzodiazepin-2-one The title compound as a white solid was prepared according to General Preparation 4-K using the ethylthionebenzodiazepine intermediate from Step A above. Elemental analysis (as _{C 12 H 13 N 5 OS)} : theoretical value: C, 52.35; H, 4.76 ;
N, 25.44; Found: C, 52.63; H, 4.67; N, 25.39.

Step C 3-Amino-1,3-dihydro-5-ethylthio-1-methyl-2H
Production of -1,4-benzodiazepin-2-one Azide (derived from the above step B) to which tetrahydrofuran (13
mL) solution was added in one portion with excess (2.8 eq) of solid triphenylphosphine. The reaction was stirred at room temperature under nitrogen for 20 hours, then extracted with ethyl acetate. The solution was extracted three times with 1N HCl, and the combined extracts were combined with 5N Na
OH was added to make it basic. This was extracted three times with ethyl acetate, the extracts were combined, saturated with saturated sodium chloride, dried over anhydrous sodium sulfate, filtered and concentrated on a rotary evaporator under vacuum. The resulting oil was used immediately. C ₁₂ H ₁₅ N ₃ OS (MW = 249.3), precise mass FAB ⁺ theoretical value 250.1
014, found 250.1011.

Step D 3- (N-tert-butylcarbamate-L-alaninyl) amino-
1,3-dihydro-5-ethylthio-1-methyl-2H-1,4-benzodiazepi
Preparation of 2 -N-one Following general procedure D, using N-Boc-alanine and the aminobenzodiazepin-2-one from step C above, the title compound was obtained as an amorphous white solid. Elemental analysis (as _{C 20 H 28 N 4 O 4} S): Theoretical value: C, 57.12; H, 6.71
N, 13.32; Found: C, 56.85; H, 6.77; N, 13.12.

Step E 3- (L-alaninyl) amino-4-n-butyl-3,4-dihydro-
Preparation of 1-methyl-1,4-benzodiazepine-2,5-dione Following general procedure 4-C and using the Boc-protected intermediate from step D above, the title intermediate was obtained as a colorless oil. . C ₁₅ H ₂₀ N ₄ O ₂ S (MW = 32.4), FAB ⁺ precision mass theoretical value 321
.1385, found 321.1388.

Example 4-AJ Synthesis of 3-L-alaninyl-amino-5-phenyl-1-methyl-2H-1,5-diazepin-2-one Step A: Preparation of 1-phenyl-4-piperidinone Hermant RM et al., J. Am. Chem. Soc., 1990, 112, 1212-1221 (
The title compound was prepared using aniline (Aldrich) and methyl acrylate (Aldrich).

Step B: Preparation of 5-phenyl-2H-1,5-diazepin-2-one Step A (12.54 g, 71.56 mmol) was added to glacial acetic acid (60 mL) and concentrated sulfuric acid (30 mL) at 0 ° C. , Sodium azide (5.12 g, 78.7 mmol) was added in four portions of 1.024 g over 4 hours. The resulting pale yellow oil was allowed to warm to room temperature for 17 hours while stirring under nitrogen. Pour the mixture onto ice,
Neutralized to pH 7 using 5M aqueous NaOH. The product is treated with dichloromethane (
2 × 400 mL), the combined organic extracts were dried over sodium sulfate, filtered and concentrated to a light yellow oil. Flash chromatography purification (eluting with a gradient of EtOAc to EtOAc / hexane (95: 5)) provided the title intermediate (12.37 g, 91%) as a pale yellow solid. _{C 11 H 14 N 2 O (} MW = 190.25), mass spectroscopy (MH +) 191.4. Elemental analysis (as _{C 11 H 14 N 2 O)} : theory: C, 69.45; H, 7.42 ; N
, 14.72, found: C, 69.74; H, 7.23; N, 15.00.

Step C: Preparation of 5-phenyl-1-methyl-2H-1,5-diazepin-2-one The product from Step B, methyl iodide and tert were prepared according to General Preparation 4-G.
-The title intermediate was prepared using potassium butoxy. HPLC purification (EtOA
eluted with c) to give the product as a white solid. _{C 12 H 16 N 2 O (} MW = 204.27), mass spectroscopy (MH ⁺⁾ 205.2. Elemental analysis (as _{C 12 H 16 N 2 O)} : theory: C, 70.56; H, 7.90 ; N
, 13.71, found: C, 70.65; H, 7.70; N, 13.95.

Step D: Preparation of 3-azido-5-phenyl-1-methyl-2H-1,5-diazepin-2-one Using the product from Step C according to General Preparation 4-E, An intermediate was prepared. HPLC purification (eluted with EtOAc / hexane (60:40)) and a second HPLC purification (eluted with dichloromethane / methanol (98: 2)) gave the product as a pale yellow solid. _{C 12 H 15 N 5 O (} MW = 245), mass spectroscopy (MH ⁺⁾ 246.4.

Step E: Preparation of 3-Amino-5-phenyl-1-methyl-2H-1,5-diazepin-2-one Using the product from Step D according to General Preparation 4-F, The title intermediate was prepared as an oil which solidified on standing. C ₁₂ H ₁₇ N ₃ O (MW = 219), mass spectroscopy (MH ⁺ ) 220.3. Elemental analysis (as _{C 12 H 17 N 3 O)} : theory: C, 65.73; H, 7.81 ; N
, 19.16, found: C, 65.94; H, 7.37; N, 18.85.

Step F: 3- [N ^′ -(t-butoxycarbonyl) -L-alaninyl] amino-
Preparation of 5-phenyl-1-methyl-2H-1,5-diazepin-2-one Following general procedure D, using the product from step E and Boc-L-alanine (Novabiochem), the title intermediate was used. Manufactured. HPLC purification (eluting with EtOAc / hexane (1: 1)) provided the title compound as a white solid. Exact mass analysis (calculated as _{C 20 H 31 N 4 O 4} ): theory, 391.2345, found, 391.2342.

Step G: 3- (L-alaninyl) amino-5-phenyl-1-methyl-2H-
Preparation of 1,5-Diazepin-2-one The title intermediate was prepared using the product from Step F according to General Preparation 4-N. HPLC purification (eluting with dichloromethane / methanol (95: 5)) gave the title intermediate. Exact mass analysis (C ₁₅ calculated as H ₂₃ N ₄ O _2): theory, 291.1821; found, 291.1816.

Example 4-K 3-((S) -phenylglycinyl) amino-5-phenyl-1-methyl-2H-2
Synthesis step of A , 3,4,5-tetrahydro-1,5-benzodiazepin-2-one A : 3- [N ^′ -(t-butoxycarbonyl)-(S) -phenylglycinyl
] Amino-1-methyl-5-phenyl-1,3,4,5-tetrahydro-2H-1,
Preparation of 5-benzodiazepin-2-one According to a modification of general procedure J, the product from step B of Example 4-M and Bo
The title intermediate was prepared using c-L-phenylglycine (Novabiochem). The improvement is that the reaction was stirred for only 6 hours. HPLC analysis (eluting with hexane / EtOAc (80/20)) gave the separated diastereomers; Isomer 1 (eluting first) and Isomer 2 (eluting second). C ₂₉ H ₃₂ N ₄ O ₄ (MW = 500.60), mass spectroscopy for isomer 1: MH ⁺ 501.2; MH ⁻ 499.3; mass spectroscopy for isomer 2: MH ⁺ 501.
.2; MH ^- 499.3.

Step B : Preparation of 3-((S) -phenylglycinyl) amino-1-methyl-5-phenyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-2-one The title intermediate was prepared using the product from Step A (Isomers 1 and 2 separately obtained in reaction order) according to General Preparation 4-N. HPLC purification (eluting with dichloromethane / methanol (95/5)) provided the title intermediate as a pale yellow oil. C ₂₄ H ₂₄ N ₄ O ₂ (MW = 400.48), mass spectroscopy for isomer 1: MH ⁺ 401.3; MH ^- 399.2; mass spectroscopy for isomer 2: MH ⁺ 401
.2; MH ^- 399.3.

Example 4-AL 3- (L-norvalinyl) amino-2,4-dihydro-1,5-bismethyl-2,3,
Synthesis step A of 4,5-tetrahydro-1H-1,5-benzodiazepine : 3- [N ^′ -(t-butoxycarbonyl) -L-norvalinyl] amino-2,4-dioxo-1,5-bismethyl-2 , 3,4,5-tetrahydro-1H-
Preparation of 1,5-benzodiazepine According to general procedure D, the product from step C of Example 4-R and Boc-L-
The title intermediate was prepared using norvaline (BACHEM). HPLC
Purification (eluting with EtOAc / hexane (60:40)) provided the title intermediate as a white solid. _{C 21 H 30 N 4 O 5} (MW = 418.49). Elemental analysis (as _{C 21 H 30 N 4 O 5} · hemihydrate): Calculated: C, 59.00; H,
7.39; N, 13.10, found: C, 59.35; H, 7.58; N, 12.8.
6. Precise mass (calculated as C ₂₁ H ₃₁ N ₄ O ₅ ): theoretical 419.2294, found 419.2289.

Step B: Preparation of 3- (L-norvalinyl) amino-2,4-dioxo-1,5-bismethyl-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine General Production Method 4 The title compound was prepared according to -N using the product from step A and used without further purification. _{C 16 H 220 N 4 O 3} (MW = 318.38). Exact mass (calculated as _{C 16 H 23 N 4 O 3} ): theory 319.1770, found 319.1774.

Example 4-AM Synthesis of 3- (L-norvalinyl) amino-2,4-dihydro-1-methyl-5-phenyl-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine Step A: 3- [N ^' -(t-butoxycarbonyl) -L-norvalinyl] amino-2,4-dioxo-1-methyl-5-phenyl-2,3,4,5-tetrahydro-
Preparation of 1H-1,5-benzodiazepine According to General Production Method D, 3-amino-2,4-dioxo-1-methyl-5-phenyl-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine (CAS 1316
No. 04-75-6) and Boc-L-norvaline (Bachem) to prepare the title intermediate. HPLC purification (eluting with EtOAc / hexane (1: 1)) produced the title intermediate as a white solid. _{C 26 H 32 N 4 O 5} (MW = 480.57); mass spectroscopy, MH ⁺ 481.2. Elemental analysis (C ₂₆ H ₃₂ calculated as N ₄ O _5): theoretical value: C, 64.98; H, 6.7
1; N, 11.66; Found: C, 64.87; H, 6.83; N, 11.53.

Step B: 3- (L-norvalinyl) amino-2,4-dioxo-1-methyl-
Preparation of 5-phenyl-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine The title intermediate was prepared using the product from Step A according to General Preparation 4-N. HPLC analysis (eluting with dichloromethane / methanol (9: 1)) gave the title intermediate as an off-white solid. C ₂₁ H ₂₄ N ₄ O ₃ (MW = 380.45); mass spectroscopy, MH ⁺ 381.1. Exact mass (calculated as C ₂₁ H ₂₅ N ₄ O ₃ ): calc. 381.1889, found 381.1928.

Example 4-AN Synthesis of 3- (L-alaninyl) amino-1,5-bismethyl-2H-2,3,4,5-tetrahydro-1,5-benzodiazepin-2-one Step A: N , N ^'-.. preparation of dimethyl-1,2-phenylenediamine Stetter, Chem by H. Ber, by 1953, 86, 161 and Cheeseman GW.
The title intermediate was prepared from a low melting solid, 1,2-phenylenediamine (Aldrich), according to the process described in J. Chem. Soc., 1955, 3308, the contents of which are incorporated by reference. Manufactured. _{C 8 H 12 N 2 (MW} = 136); mass spectroscopy, MH ⁺ 136.1. Precise mass analysis (calculated as C ₈ H ₁₃ N ₂ ): theoretical 137.179, found 137.11081.

Step B: 1,5-bismethyl-2,3,4,5-tetrahydro-2H-1,5-
Preparation of Benzodiazepin-2-one A solution of the product from step A (400 mg, 2.94 mmol) in 5 M hydrochloric acid was added
Acrylic acid (0.202 mL, 3.23 mmol, Aldrich) was added and the mixture was heated to reflux for 18 hours. The black mixture was cooled, then poured on ice and the pH was adjusted to 10 using 5M aqueous NaOH. The product is converted to CH ₂ C
l ₂ (200 mL), water (100 mL) and brine (100 mL)
Washed using. The organic phase was dried over Na ₂ SO _4, filtered and concentrated to give black oil. HPLC purification (eluting with hexane / EtOAc (1: 1)) provided the title intermediate (364 mg) as a brown oil. _{C 11 H 14 N 2 O (} MW = 190.25); mass spectroscopy, MH ⁺ 191.4. Elemental analysis (calculated as _{C 11 H 14 N 2 O)} : theory: C, 69.45; H, 7.42
N, 14.72; Found: C, 69.26; H, 7.40; N, 14.64.

Step C: 3-azido-1,5-bismethyl-2,3,4,5-tetrahydro-2
Preparation of H-1,5-benzodiazepin-2-one The title intermediate was prepared using the product from Step B according to General Preparation 4-E. HPLC purification (eluted with hexane / EtOAc (7: 3))
The title intermediate was obtained as a light brown oil. _{C 11 H 13 N 5 O (} MW = 231.26); mass spectroscopy, MH ⁺ 232.2. Exact mass analysis (C ₁₁ H ₁₃ N calculated as ₅ O): theory 232.1198, found 232.1196.

Step D: 3-Amino-1,5-bismethyl-2,3,4,5-tetrahydro-2
Preparation of H-1,5-benzodiazepin-2-one The title intermediate was prepared according to General Preparation 4-F using the product from Step C and used without chromatographic purification. . _{C 11 H 15 N 3 O (} MW = 205.26); mass spectroscopy, MH ⁺ 206.2. Precise mass (calculated as C ₁₁ H ₁₅ N ₃ O): theoretical value 206.1293, measured value
206.1295.

Step E: 3- [N ^' -(t-butoxycarbonyl) -L-alaninyl] amino-
Preparation of 1,5-bismethyl-2,3,4,5-tetrahydro-2H-1,5-benzodiazepin-2-one Following general procedure D, the product from step D and Boc-L-alanine (Novabiochem) Was used to produce the title intermediate. HPLC purification (eluting with EtOAc / hexane (6: 4)) provided the title intermediate as a white foamy solid. _{C 19 H 28 N 4 O 4} (MW = 376.45); mass spectroscopy, MH ⁺ 377.4, M
H ^- 375.3. Elemental analysis (calculated as _{C 19 H 28 N 4 O 4} ): theoretical value: C, 60.62; H, 7.5
0; N, 14.88; Found: C, 60.58; H, 7.42; N, 14.38.

Step F: 3- (L-alaninyl) amino-1,5-bismethyl-2,3,4,5-
Preparation of Tetrahydro-2H-1,5-benzodiazepin-2-one The title intermediate was prepared using the product from Step E according to General Preparation 4-N. HPLC purification (eluted with EtOAc / hexane (6: 4))
The title intermediate was obtained as a thick yellow oil. _{C 14 H 20 N 4 O 2} (MW = 276.34); mass spectroscopy, MH ⁺ 277.2.

The following preparations can be used to make the following additional intermediates for use in the present invention.

General Preparation CH The intermediates shown in Table C-1 were synthesized in parallel using the following preparation. Step A: 3- (tert-butoxycarbonyl) amino-2,3-dihydro-
5-phenyl-1H-1,4-benzodiazepin-2-one (CA No. 125: 33692)
: 100 mg, 0.28 mmol) in anhydrous DMF (1 mL) and a solution of potassium bis (trimethylsilyl) amide (0.30 mmol) in toluene (0.5 M, 6 M).
00 μL) solution was added. Neat alkyl halide (0.56 mmol; Table C)
-1 indicated) was immediately added once and the reaction mixture was allowed to stand overnight. If an alkyl chloride was used, sodium iodide (1 equivalent) was added to the reaction mixture. After concentration under reduced pressure, the crude reaction residue was diluted with dichloromethane (2 mL) and a saturated aqueous solution of hydrogencarbonate (2 mL).
mL) and then passed through an Extralut QE cartridge (EM Science; Gibbstown, NJ) with dichloromethane (10 mL). The filtrate obtained is concentrated under reduced pressure and the crude product is further purified by automated semi-preparative HP
LC (YMC 20 × 50 mm silica column; gradient elution; ethyl acetate / dichloromethane: 0-5% (5.5 minutes), 5-20% (3.5 minutes), 20-100% (2 minutes)
, 100% (4 min); flow rate, 25 mL / min). The product is IEX
MS showed the expected M + 1 peak, which was used without further purification and identification.

Step B: The product obtained from Step A was treated with 15% TFA / dichloromethane (5 m
L) Dissolved in the solution and allowed to stand for 16 hours. After concentration under reduced pressure, the TFA salts were dissolved in methanol and placed directly on SCX (1 g). The column is treated with methanol (
2 mL, 3 ×) and the product was washed with a 2.0 M ammonia / methanol solution (6 m
L) to elute from the column. After concentration under reduced pressure, the product was identified by IEX MS and used without further purification.

Step C: HOBT.H ₂ O was added to the crude product (1.05 equivalents) obtained in Step B.
(1.05 equivalents) of a DMF solution (0.3 mM), Nt-BOC-L-alanine (
1.0 equivalent) of a THF solution (0.3 mM) and 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide (1.05 equivalent) in THF (0.3 mM) were added successively. After standing for 24 hours, the reaction mixture was concentrated, and the residue was concentrated in 10% methanol /
Redissolved in dichloromethane solution (2 mL). This solution was then washed with an SCX column (1 g) (Varian Sample Preparation (Va
rian Sample Preparation)) and further filtered using the same solvent (8 mL). For Example CV, a Si column (1 g) (Varian Sample Preparation) was used. The filtrate was concentrated to about 1/3 of its original volume under a stream of nitrogen and then AG 1-8X anion exchange resin (BioRad; Hercules, CA; column was pre-incubated with 1N NaOH, water and Methanol (washed with methanol) (500 mg) and additional methanol (10 mL)
And passed through. The obtained filtrate was concentrated under reduced pressure, identified by IEX MS,
The crude product was used without further purification.

Step D: The crude product obtained from Step C was dissolved in a 15% TFA / dichloromethane solution (5 mL) and allowed to stand for 16 hours. After concentration under reduced pressure, the TFA salt was dissolved in methanol and placed directly on an SCX column (1 g). The column was washed with methanol (2 mL, 3 ×) and the product was eluted from the column with a 2.0 M ammonia / methanol solution (6 mL). After concentration under reduced pressure, the product was identified by IEX MS and used without further purification. The intermediates produced by this method are shown in Table CA.

Table CA Intermediates

[Table 14]

[Table 15]

[Table 16]

Example C-AA (S) -3- (L-phenylglycinyl) amino-2,3-dihydro-1-methyl-
Synthesis of 5-phenyl-1H-1,4-benzodiazepin-2-oneStep A: (S) -3- (N^'-(Tert-butoxycarbonyl) -L-phenyl
(Glycinyl) amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,
Synthesis of 4-benzodiazepin-2-one Triethylamine (519 μL, 3.8 mmol) and (S) -3-amino-
5-phenyl-2-oxo-1,4-benzodiazepine (1.0 g, 3.8 mmol
l) (J. Org. Chem., 1987, 52, 3232-3239 by M. G. Bock et al.
Is a part of the present specification)) in anhydrous dichloromethane (100 mL) solution,
At −20 ° C., N-Boc-L-phenylglycine fluoride (Carpiano et al.
 Org. Chem., 1991, 56, 2611-2614) was added in one portion. The reaction mixture is
Stirred for minutes and quenched with saturated aqueous bicarbonate (10 mL). Phase separated, yes
The organic phase is washed successively with saturated aqueous bicarbonate, water and brine, then sulfuric acid.
Dried with sodium. The crude products were purified by silica gel chromatography (10
~ 50% ethyl acetate / hexane) and purified using hydroscopic
A white foam (1.3 g, 69%) was obtained. The NMR data is as follows:¹H-NMR (300 MHz, CDCl_Three): Δ = 1.35 (brs, 9H), 3
.41 (s, 3H), 5.30-5.45 (m, 2H), 5.75-5.95 (m,
1H), 7.15-7.75 (m, 15H). IR (CDCl_Three): 1709.7, 1676.6, 1489, 1166.3 cm ^-1 . IEX MS (M + l): 498.0.

Step B: (S) -3- (L-phenylglycinyl) amino-2,3-dihydro-
Synthesis of 1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one (S) -3- (N ^′ -(tert-butoxycarbonyl) -L-phenylglycinyl) amino-2,3- Dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one (1.27 g, 2.55 mmol) was added in one portion to a stirred solution of 15% TFA in dichloromethane (50 mL). After stirring for 1 hour, the reaction mixture was concentrated under reduced pressure, and the residue was dissolved in dichloromethane (100 mL). The solution was washed twice with saturated sodium bicarbonate, once with brine, and then dried over sodium sulfate. The crude product is subjected to silica gel chromatography (eluent, 5 to 10
% Methanol / dichloromethane) to give a very light green foam (743
mg, 73%). NMR data are as follows: ¹ H-NMR (300 MHz, CDCl ₃ ): δ = 2.05 (brs, 1H);
3.45 (s, 3H), 5.51 (d, J = 8.39 Hz, 1H), 7.15-7.
70 (m, 14H), 8.60 (d, J = 830 Hz, 1H). ^{_{IR (CDCl 3): 1673.3,1601.1,1506.1cm -1}} . IEX MS (M + l): 399.2.

Example C-AB 3- (L-alaninyl) amino-2,3-dihydro-1- (2-oxo-2-phenylethyl) -5-phenyl-1H-1,4-benzodiazepine-2- Synthesis step A of 3- (benzoxycarbonyl) amino-2,3-dihydro-1- (2-
Synthesis of (oxo-2-phenylethyl) -5-phenyl-1H-1,4-benzodiazepin-2-one 3- (benzoxycarbonyl) amino-2,3-dihydro-5-phenyl-1H
-1,4-benzodiazepin-2-one (Tetrahedron Let by Bock, MG et al.)
t. 1987, 28, 939 (the contents of which are incorporated herein); 4.0 g, 10.4
mmol) in anhydrous DMF (40 mL) at 0 ° C. was added potassium tert-butoxide (1.51 g, 13.5 mmol) in one portion. The reaction mixture was stirred for 20 minutes and α-bromoacetophenone (Lancaster; Windham, NH; 2.9 g, 1
4.6 mmol) was added. The reaction mixture was warmed to room temperature over 30 minutes and then diluted with water (100 mL) and dichloromethane (200 mL). The phases were separated. The organic phase was extracted with water and dried over sodium sulfate. The crude product was purified by silica gel chromatography (eluent, 0-5% ethyl acetate / dichloromethane) to give an off-white foam (4.2 g, 81%). The NMR data are as follows: ¹ H-NMR (300 MHz, CDCl ₃ ): δ = 5.16 (s, 2H), 5.34 (
s, 2H), 5.50 (d, J = 8.33 Hz, 1H), 6.70 (d, J = 8.28)
Hz, 1H), 7.20-7.70 (m, 12H), 7.91 (d, J = 7.54H)
z, 2H). IR (CHCl ₃ ): 1706.4, 1685.3, 1505.9, 1489.1,
1450.3, 1244.7 cm ^-1 . IEX MS (M + l): 504.3.

Step B: Synthesis of 3-amino-2,3-dihydro-1- (2-oxo-2-phenylethyl) -5-phenyl-1H-1,4-benzodiazepin-2-one (Xycarbonyl) amino-2,3-dihydro-1- (2-oxo-2
-Phenylethyl) -5-phenyl-1H-1,4-benzodiazepin-2-one (3.7 g, 7.36 mmol) in anhydrous dichloromethane (100 mL) was cooled at 0 ° C. under nitrogen. Next, vapor of anhydrous HBr gas was passed through the solution for 1 hour. The bubbler was removed, and the reaction solution was heated to room temperature under nitrogen. After stirring for 1 hour, the reaction was concentrated in vacuo, and the residue was dissolved in dichloromethane (20 mL). The crude HBr salt of the product was precipitated from solution with anhydrous ether (300 mL) and collected by filtration to give a pale yellow solid. After washing with ether, the solid was dissolved in dichloromethane and saturated sodium bicarbonate. The phases were separated and the organic phase was extracted with saturated sodium bicarbonate. The aqueous phases were then combined and re-extracted twice with dichloromethane. The combined organic phases were extracted once with water and dried over sodium sulfate. After concentration under vacuum, the product was an orange foam (2.27 g), which was used without further purification. NMR data are as follows: ¹ H-NMR (300 MHz, CDCl ₃ ): δ = 2.60 (brs, 2H), 4
.72 (s, 1H), 5.34 (s, 2H), 7.10-7.70 (m, 12H),
7.91 (d, J = 7.60 Hz, 2H). IEX MS (M + l): 370.2.

Step C: 3- (N ^′ -(tert-butoxycarbonyl) -L-alaninyl) amino-2,3-dihydro-1- (2-oxo-2-phenylethyl) -5-phenyl-1H- Synthesis of 1,4-benzodiazepin-2-one HOBt-H ₂ O (697 mg, 5.16 mmol), N, N-diisopropylethylamine (900 μL, 5.16 mmol) and Nt-Boc-L-alanine (975 mg, 5.16 mmol) in anhydrous THF (20 mL).
1- (3-dimethylaminopropyl) -3-ethylcarbodiimide-hydrochloric acid (E
DCI; 986 mg, 5.16 mmol) was added in one portion. After stirring for 5 minutes,
Amino-2,3-dihydro-1- (2-oxo-2-phenylethyl) -5-phenyl-1H-1,4-benzodiazepin-2-one (2.0 g, 5.43 mmol
) In anhydrous THF (20 mL) was added via syringe and the reaction mixture was allowed to warm to room temperature and stirred overnight. Dilute the reaction mixture with dichloromethane (200 mL) and add 1
Successively extracting with 0% citric acid, saturated sodium bicarbonate, water and brine,
Then dried over sodium sulfate. The crude product was purified by silica gel chromatography (eluent, 10% to 30% ethyl acetate / dichloromethane) to give a white foam (2.59 g, 93%). NMR data are as follows: ¹ H-NMR (300 MHz, CDCl ₃ ): δ = 1.30-1.60 (m, 12
H), 4.35 (brs, 1H), 5.00-5.50 (m, 3H), 5.65-5
.70 (m, 1H), 7.15-7.65 (m, 12H), 7.70-7.80 (m
, 1H), 7.85-7.95 (m, 1H). IR (CHCl ₃ ): 1705.8, 1678.8, 1488.7, 1450.2
, 1230.4, 1164.4 cm ^-1 . IEX MS (M + l): 541.2.

Step D: 3- (L-alaninyl) amino-2,3-dihydro-1- (2-oxo-2-phenylethyl) -5-phenyl-1H-1,4-benzodiazepine-2-
Synthesis of 3- (N ^′ -(tert-butoxycarbonyl) -L-alaninyl) amino-2,
3-dihydro-1- (2-oxo-2-phenylethyl) -5-phenyl-1H-
1,4-benzodiazepin-2-one (2.5 g, 4.63 mmol) was added to 15% T
One portion was added to a stirred solution of FA / dichloromethane (100 mL). After stirring for 2 hours, the reaction mixture was concentrated under reduced pressure, and the residue was dissolved in dichloromethane (150 mL). The solution was washed twice with saturated sodium bicarbonate, once with brine, and then dried over sodium sulfate. The crude product was purified using silica gel chromatography (eluent, 1-10% methanol / dichloromethane) to give the title compound as a white foam (1.91 g, 94%). The NMR data are as follows: ¹ H-NMR (300 MHz, CDCl ₃ ): δ = 1.30-1.50 (m, 3H
), 1.80-2.20 (brs, 2H), 3.55-3.75 (m, 1H), 5.
20-5.45 (m, 2H), 5.67 (t, J = 7.48 Hz, 1H), 7.20
−7.65 (m, 12H), 7.90 (d, J = 7.7 Hz, 2H), 8.80 (d
d, J ₁ = 25.09 Hz, J ₂ = 8.33 Hz, 1H). IEX MS (M + l): 441.2.

Example C-AC 3- (L-alaninyl) amino-2,3-dihydro-1- (4,4,4-trifluorobutyl) -5-phenyl-1H-1,4-benzodiazepine-2 -A synthesis step A: 3- (benzoxycarbonyl) amino-2,3-dihydro-1- (4,
Synthesis of 4,4-trifluorobutyl) -5-phenyl-1H-1,4-benzodiazepin-2-one 3- (benzoxycarbonyl) amino-2,3-dihydro-5-phenyl-1H
Anhydrous D of -1,4-benzodiazepin-2-one (3.7 g, 9.61 mmol)
To a solution of MF (40 mL) was added potassium tert-butoxide (1.6 g, 14.
4 mmol) was added in one portion. The reaction mixture was stirred for 20 minutes and 4,4,4-trifluoro-1-bromobutane (Lancaster; Windham, NH; 2.6 g, 13.4 m)
mol) was added. The reaction mixture was allowed to warm to room temperature over 30 minutes and then water (
100 mL) and dichloromethane (200 mL). The phases were separated. The organic phase was extracted with water and dried over sodium sulfate. The crude product was purified by silica gel chromatography (eluent, 0-3% ethyl acetate / dichloromethane) to give an off-white foam (1.52 g, 32%). The NMR data is as follows: ¹ H-NMR (300 MHz, CDCl ₃ ): δ = 1.50-2.10 (m, 4H
), 3.70-3.90 (m, 1H), 4.35-4.55 (m, 1H), 5.15
(S, 2H), 5.33 (d, J = 8.47 Hz, 1H), 6.67 (d, J = 8.
40Hz, 1H), 7.2-7.70 (m, 14H). IR (CHCl ₃ ): 1720.4, 1683.0, 1604.8, 1505.5
, 1451.1, 1323.9, 1254.5, 1148.4 cm ^-1 . IEX MS (M + l): 496.3.

Step B: Synthesis of 3-amino-2,3-dihydro-1- (4,4,4-trifluorobutyl) -5-phenyl-1H-1,4-benzodiazepin-2-one Benzoxycarbonyl) amino-2,3-dihydro-1- (4,4,4-trifluorobutyl) -5-phenyl-1H-1,4-benzodiazepin-2-one (
A solution of 1.42 g (2.87 mmol) in anhydrous dichloromethane (50 mL) was cooled to 0 ° C. under nitrogen. Anhydrous HBr gas vapor was slowly bubbled through the solution for 1 hour. The bubbler was removed and the reaction was warmed to room temperature under nitrogen. After stirring for 1 hour,
The reaction was concentrated under vacuum and the residue was redissolved in dichloromethane (10 mL). The crude HBr salt of the product was precipitated from solution using anhydrous ether (90 mL),
Collected by filtration. After washing with ether, the HBr salt was dissolved in dichloromethane and saturated sodium bicarbonate. The phases were separated and the organic phase was extracted with saturated sodium bicarbonate. The aqueous phases were then combined and re-extracted twice with dichloromethane. The combined organic phases were extracted once with water and dried over sodium sulfate. After concentration under vacuum, the product was obtained as a white foam (1.06 g, 100%), which was used without further purification. The NMR data is as follows: ¹ H-NMR (300 MHz, CDCl ₃ ): δ = 1.60-2.10 (m, 4H
), 2.76 (brs, 2H), 3.75-3.85 (m, 1H), 4.40-4.
60 (m, 2H), 7.20-7.70 (m, 9H). IEX MS (M + l): 362.1.

Step C: 3- (N ^' -(tert-butoxycarbonyl) -L-alaninyl)-
Amino-2,3-dihydro-1- (4,4,4-trifluoro-butyl) -5-phenyl-1H-1,4-benzodiazepin-2-one Synthesis _{HOBt-H 2 O (373mg,} 2.76mmol ), N, N-diisopropylethylamine (481 μL, 2.76 mmol) and Nt-Boc-L-alanine (522 mg, 2.76 mmol) in anhydrous THF (10 mL).
1- (3-dimethylaminopropyl) -3-ethylcarbodiimide-hydrochloric acid (E
DCI; 527 mg, 2.76 mmol) was added in one portion. After stirring for 5 minutes,
Amino-2,3-dihydro-1- (4,4,4-trifluorobutyl) -5-phenyl-1H-1,4-benzodiazepin-2-one (1.05 g, 2.91 mmol
)) In anhydrous THF (10 mL) was added via syringe and the reaction mixture was allowed to warm to room temperature and stirred overnight. Dilute the reaction mixture with dichloromethane (100 mL) and add 1
Successively extracting with 0% citric acid, saturated sodium bicarbonate, water and brine,
Then dried over sodium sulfate. The crude product was purified by silica gel chromatography (eluent, 10% to 30% ethyl acetate / dichloromethane) to give a white foam (1.28 g, 83%). The NMR data are as follows: ¹ H-NMR (300 MHz, CDCl ₃ ): δ = 1.40-2.10 (m, 16
H), 3.70-3.85 (m, 1H), 4.30-4.55 (m, 2H), 5.1
0 (brs, 1H), 5.45-5.55 (m, 1H), 7.25-7.80 (m,
10H). IR (CHCl ₃ ): 1676.6, 1605.2, 1488.6, 1450.9
1393.2, 1338.7, 1324.9, 1253.8, 115.4 cm ^-1
. IEX MS (M + l): 533.1.

Step D: 3- (L-alaninyl) amino-2,3-dihydro-1- (4,4,4-
Synthesis of trifluorobutyl) -5-phenyl-1H-1,4-benzodiazepin-2-one 3- (N ^′ -(tert-butoxycarbonyl) -L-alaninyl) amino-2,
3-dihydro-1- (4,4,4-trifluorobutyl) -5-phenyl-1H-1
, 4-benzodiazepin-2-one (1.21 g, 2.27 mmol) in 15% T
One portion was added to the FA / dichloromethane stirring solution (50 mL). After stirring for 2 hours, the reaction mixture was concentrated under reduced pressure, and the residue was dissolved in dichloromethane (100 mL).
The solution was washed twice with saturated sodium bicarbonate solution, once with brine, and then dried over sodium sulfate. The crude product was purified by silica gel chromatography (eluent, 1-5% methanol / dichloromethane) to give a pale pink foam (6
70 mg, 68%). NMR data are as follows: ¹ H-NMR (300 MHz, CDCl ₃ ): δ = 1.43 (t, J = 7.0 Hz)
, 3H), 1.60-2.20 (m, 7H), 3.60-3.85 (m, 2H), 4
.35-4.55 (m, 1H), 5.51 (dd, J 1 = 8.36Hz, J 2 = 2.4
8 Hz, 1 H), 7.20-7.70 (m, 9 H), 8.80 (dd, J ₁ = 27.
_{73Hz, J 2 = 8.34Hz, 1H} ). IEX MS (M + l): 433.2.

Example C-AE Synthesis of 3-[(L-alaninyl) amino] -2,3-dihydro-1-methyl-5- (2-pyridyl) -1H-1,4-benzodiazepin-2-one Step A: 3-Amino-2,3-dihydro-1-methyl-5- (2-pyridyl)
Synthesis of -1H-1,4-benzodiazepin-2-one The title compound was synthesized according to the method described in Synth. Commun., 26 (4), Synthesized as follows.

Step B: 3-[(N-tert-butoxycarbonyl-L-alaninyl) amino] -2,3-dihydro-1-methyl-5- (2-pyridyl) -1H-1,4-benzodiazepine- Synthesis of 2-one L-Boc-alanine (1.74 g, 9.20 mmol), HOBt monohydrate (1.24 g, 9.20 mmol), diisopropylethylamine (1.6 mL)
, 9.20 mmol) and CH ₂ Cl ₂ (30 mL) solution were purged with nitrogen and cooled in an ice bath. To the cold solution was added 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide-hydrochloric acid (1.76 g, 9.20 mmol) followed by CH ₂
Was dissolved in Cl ₂ (15mL) 3- amino-2,3-dihydro-1-methyl-5-
(2-pyridyl) -1H-1,4-benzodiazepin-2-one (2.45 g, 9.
20 mmol) was added. The cooling bath was removed and the solution was stirred at room temperature overnight. The reaction mixture was extracted with H ₂ O, 0.1N aqueous citric acid, 5% aqueous NaHCO ₃ and brine. The remaining CH ₂ Cl ₂ solution was dried (MgSO ₄ ) and concentrated to give a tan foam. Crystallization (from CH ₂ Cl ₂ / EtOAc) afforded the title compound as white crystals (mp: 228-229 ° C.) (3.47 g, 86% yield). Elemental analysis (as _{C 23 H 27 N 5 O 4} ): theoretical value: C, 63.14; H, 6.22 ;
N, 16.01; Found: C, 63.25; H, 6.15; N, 15.95. MS (FD ^<+> ) 437 m / z.

Step C : 3-[(L-alaninyl) amino] -2,3-dihydro-1-methyl-
Synthesis of 5- (2-pyridyl) -1H-1,4-benzodiazepin-2-one 3-[(N-tert-butoxycarbonyl-L-alaninyl) amino] -2,3
-Dihydro-1-methyl-5- (2-pyridyl) -1H-1,4-benzodiazepin-2-one (3.42 g, 7.82 mmol) in CH ₂ Cl ₂ (90 mL) cooled in an ice bath And treated with TFA (13.2 mL, 172 mmol). The cooling bath was removed and the solution was stirred at room temperature for 4 hours. The reaction mixture was washed with a 1M aqueous solution of K ₂ CO _{3 and the} aqueous solution was re-extracted with CH ₂ Cl ₂ . The combined extracts were washed with H ₂ O, dried (MgSO ₄ ) and concentrated to give the title compound as an off-white foam (1
.75 g, 66% yield). MS (IS ^<+> ) 338 (m / e). ¹ H NMR (CDCl ₃ ): δ = 8.76-8.86 (1H, m), 8.63 (1H,
m), 8.17 (1H, m), 7.82 (2H, m), 7.60 (1H, m), 7.41
(3H, m), 5.60 (1H, m), 3.63 (1H, m), 3.49 (3H, s)
, 1.66 (2H, wide), 1.45 (3H, m).

Example C-AF 3-[(L-alaninyl) amino] -2,3-dihydro-1- (2-N, N-diethylaminoethyl) -5- (2-pyridyl) -1H-1, Synthesis step A of 4-benzodiazepin-2-one : 3-amino-2,3-dihydro-1- (2-N, N-diethylaminoethyl) -5- (2-pyridyl) -1H-1,4-benzodiazepine Synthesis of -2-one The title compound was synthesized as described in Synth. Commun., 26 (4), 721-727 (1996), the contents of which are part of this specification.

[0516]Step B: 3-[(N-tert-butoxycarbonyl-L-alaninyl) ami
[No] -2,3-dihydro-1- (2-N, N-diethylaminoethyl) -5- (2-pi
Synthesis of (Risyl) -1H-1,4-benzodiazepin-2-one L-Boc-alanine (1.80 g, 9.50 mmol), HOBt.monohydration
(1.28 g, 9.50 mmol), diisopropylethylamine (1.65 m
L, 9.50 mmol) and CH_TwoCl_Two(40 mL) purge the solution with nitrogen,
Cool in an ice bath. To the cold solution was added 1- (3-dimethylaminopropyl) -3-e
Tilcarbodiimide-hydrochloric acid (1.82 g, 9.50 mmol) was added, followed by CH _Two Cl_Two(25 mL) dissolved in 3-amino-2,3-dihydro-1- (2-N, N
-Diethylaminoethyl) -5- (2-pyridyl) -1H-1,4-benzodiazepi
2-N-one (3.34 g, 9.50 mmol) was added. Remove the cold bath and allow the solution to
Stirred overnight at warm. The reaction mixture is_TwoO, 5% NaHCO_ThreeAqueous solution and brine
Extracted. Remaining CH_TwoCl_TwoDry the solution (MgSO_Four) And concentrate to tan
A foam was obtained. Column chromatography (eluent, 2% MeOH / CH_TwoCl_Two -10% MeOH / CH_TwoCl_Two) To give the title compound as a yellow foam (3.5)
3 g, 71% yield). MS (FD⁺) 522 m / z. HNMR (CDCl_Three): Δ = 8.62 (1H, d), 8.11 (1H, m), 7.
80 (2H, m), 7.59 (2H, m), 7.32-7.45 (2H, m), 5.5
4 (1H, m), 5.02-5.18 (1H, m), 4.38 (1H, m), 4.2
0 (1H, m), 3.83 (1H, m), 2.62 (2H, t), 2.44 (4H,
m), 1.40-1.56 (12H, m), 0.88 (6H, m).

Step C : 3-[(L-alaninyl) amino] -2,3-dihydro-1- (2-N,
Synthesis of N-diethylaminoethyl) -5- (2-pyridyl) -1H-1,4-benzodiazepin-2-one The title compound was synthesized using the production method described in Example C-AE, Step C. 3-[(
N-tert-butoxycarbonyl-L-alaninyl) amino] -2,3-dihydro-1- (2-N, N-diethylaminoethyl) -5- (2-pyridyl) -1H-1,
A solution of 4-benzodiazepin-2-one (3.52 g, 6.73 mmol) in TFA
(11.4 mL, 148 mmol) to give a pale yellow foam (2.61 g, 92% yield). MS (IS ^<+> ) 423 (m / e). H NMR (CDCl ₃ ): δ = 8.78-8.93 (1H, m), 8.62 (1H,
d), 8.11 (1H, m), 7.80 (2H, m), 7.58 (2H, m), 7.3
9 (2H, m), 5.58 (1H, m), 4.22 (1H, m), 3.88 (1H, m)
m), 3.61 (1H, m), 2.67 (2H, t), 2.49 (4H, m), 1.
73 (2H, broad), 1.42 (3H, m), 0.91 (6H, m).

Example C-AG 3-[(L-alaninyl) amino] -2,3-dihydro-1- (3,3-dimethyl-2
-Oxobutyl) -5- (2-pyridyl) -1H-1,4-benzodiazepine-2-
Synthesis step A of 3-amino-2,3-dihydro-1- (3,3-dimethyl-2-oxobutyl) -5- (2-pyridyl) -1H-1,4-benzodiazepin-2-one Synthesis The title compound was synthesized as described in Synth. Commun., 26 (4), 721-727 (1996), the contents of which are part of this specification.

[0519]Step B: 3-[(N-tert-butoxycarbonyl-L-alaninyl) ami
[No] -2,3-dihydro-1- (3,3-dimethyl-2-oxobutyl) -5- (2-
Synthesis of pyridyl) -1H-1,4-benzodiazepin-2-one L-Boc-alanine (1.57 g, 8.33 mmol), HOBt / monohydration
(1.13 g, 8.33 mmol), diisopropylethylamine (1.45 m
L, 8.33 mmol) and CH_TwoCl_Two(40 mL) purge the solution with nitrogen,
Cool in an ice bath. To the cold solution was added 1- (3-dimethylaminopropyl) -3-e
Tilcarbodiimide-hydrochloric acid (1.60 g, 8.33 mmol) was added, followed by CH _Two Cl_Two(25 mL) dissolved in 3-amino-2,3-dihydro-1- (3,3-di
Methyl-2-oxobutyl) -5- (2-pyridyl) -1H-1,4-benzodiaze
Pin-2-one (2.92 g, 8.33 mmol) was added. Remove the cold bath and pour the solution
Stirred at room temperature overnight. The reaction mixture is_TwoO, 0.1N citric acid aqueous solution, 5% Na
HCO_ThreeExtracted with aqueous solution and brine. Remaining CH_TwoCl_TwoDry the solution (Mg
SO_Four) And concentrated to give a yellow foam. Column chromatography (eluent)
, 20% EtOAc / hexane to 60% EtOAc / hexane).
The title compound (4.19 g, 96% yield) was obtained as a pale yellow foam. MS (FD⁺) 521 m / z. HNMR (CDCl_Three): Δ = 8.65 (1H, t), 8.17 (1H, t), 7.
90 (1H, t), 7.71-7.85 (1H, m), 7.54 (1H, m), 7.4
4 (1H, t), 7.37 (1H, d), 7.24-7.32 (1H, m), 7.1
4 (1H, m), 5.67 (1H, dd), 5.18 (1H, wide), 4.93−
5.07 (1H, m), 4.50-4.64 (1H, m), 4.38 (1H, wide
), 1.42-1.51 (12H, m), 1.26 (9H, d).

Step C : 3-[(L-alaninyl) amino] -2,3-dihydro-1- (3,3-
Synthesis of dimethyl-2-oxobutyl) -5- (2-pyridyl) -1H-1,4-benzodiazepin-2-one The title compound was synthesized using the production method described in Example C-AE, Step C. 3-[(
N-tert-butoxycarbonyl-L-alaninyl) amino] -2,3-dihydro-1- (3,3-dimethyl-2-oxobutyl) -5- (2-pyridyl) -1H-
The 1,4-benzodiazepin-2-one (4.18 g, 8.01 mmol) solution was added to T
Treatment with FA (13.6 mL, 176 mmol) gave an off-white foam (3.
14 g, yield 93%). MS (IS ^<+> ) 422 (m / e). H NMR (CDCl ₃ ): δ = 8.85-8.99 (1H, m), 8.68 (1H,
d), 8.20 (1H, t), 7.87 (1H, t), 7.58 (1H, t), 7.4
2 (2H, m), 7.30 (1H, t), 7.17 (1H, d), 5.72 (1H,
m), 5.08 (1H, d), 4.60 (1H, d), 3.66 (1H, m), 1.
47 (3H, m), 1.28 (9H, m).

Example C-AH Synthesis of 3-[(L-alaninyl) amino] -2,3-dihydro-1-methyl-5- (2-thiazyl) -1H-1,4-benzodiazepin-2-one Step A: 3-Amino-2,3-dihydro-1-methyl-5- (2-thiazyl)
Synthesis of -1H-1,4-benzodiazepin-2-one The title compound was converted to 2- (2-aminobenzoyl) thiazole (Tetrahedron, 51 (3
), 773-786, (1995)) to Synth. Commun., 26 (4
), 721-727 (1996) (the contents of which are part of the present specification). MS (IS ^<+> ) 273 (m / e). ¹ H-NMR (CDCl ₃ ): δ = 7.83-7.94 (2H, m), 7.61 (1
H, t), 7.50 (1H, d), 7.34 (2H, m), 4.60 (1H, s), 3.
46 (3H, s), 1.97 (2H, wide).

[0522]Step B: 3-[(N-tert-butoxycarbonyl-L-alaninyl) ami
[No] -2,3-dihydro-1-methyl-5- (2-thiazyl) -1H-1,4-ben
Synthesis of zodiazepin-2-one L-Boc-alanine (1.85 g, 9.77 mmol), HOBt monohydrate
(1.32 g, 9.77 mmol), diisopropylethylamine (1.70 m
L, 9.77 mmol) and CH_TwoCl_Two(30 mL) purge the solution with nitrogen,
Cool in an ice bath. To the cold solution was added 1- (3-dimethylaminopropyl) -3-e
Tilcarbodiimide-hydrochloric acid (1.87 g, 9.77 mmol) was added, followed by CH _Two Cl_Two3-Amino-2,3-dihydro-1-methyl-5 dissolved in (20 mL)
-(2-thiazyl) -1H-1,4-benzodiazepin-2-one (2.66 g, 9
.77 mmol) was added. The cooling bath was removed and the solution was stirred at room temperature overnight. Reaction mixing
H_TwoO, 0.1N citric acid aqueous solution, 5% NaHCO_ThreeIn aqueous solution and brine
Extracted. Remaining CH_TwoCl_TwoDry the solution (MgSO_Four) And concentrate to light yellow foam
I got a body. Crystallization (from EtOAc / hexane) gave the title compound as white crystals (
Melting point: 196-197 ° C) (3.22 g, yield 74%). Elemental analysis (C_{twenty one}H_{twenty five}N_FiveO_FourS): Theoretical: C, 56.87; H, 5.68
N, 15.79; Found: C, 56.74; H, 5.75; N, 15.55. MS (IS^-) 444 m / e.

Step C : 3-[(L-alaninyl) amino] -2,3-dihydro-1-methyl-
Synthesis of 5- (2-thiazyl) -1H-1,4-benzodiazepin-2-one The title compound was synthesized using the production method described in Example C-AE, Step C.

Example C-AI 3-[(L-alaninyl) amino] -2,3-dihydro-1-methyl-5- (thiophen-2-yl) -1H-1,4-benzodiazepin-2-one Synthesis Step A of 3-Amino-2,3-dihydro-1-methyl-5- (2-thiophen-2-yl) -1H-1,4-benzodiazepin-2-one (2-Aminobenzoyl) thiophene (Collct. Czech. Che
m. Commun., 34 (2), 468-478 (1969) (the contents of which are incorporated herein by reference).
Starting from Synth. Commun., 26 (4), 721-727 (1996) (
The contents were synthesized in the same manner as in the production method described in the present specification). MS (IS ^<+> ) 272 (m / e). ¹ H-NMR (CDCl ₃ ): δ = 7.68 (1H, d), 7.60 (1H, t),
7.48 (1H, m), 7.35 (2H, d), 7.28 (1H, m), 7.15 (
1H, d), 7.05 (1H, d), 4.50 (1H, wide), 3.45 (3H
, S), 2.26 (2H, wide).

Step B: 3-[(N-tert-butoxycarbonyl-L-alaninyl) amino] -2,3-dihydro-1-methyl-5- (2-thiophenyl) -1H-1,4-
Synthesis of benzodiazepin-2-one The title compound was synthesized by a method similar to that described in Example C-AH, step B. MS (IS ^<+> ) 443 (m / e). ¹ H-NMR (CDCl ₃ ): δ = 7.69 (1H, d), 7.61 (2H, m)
, 7.48 (1H, d), 7.27-7.42 (2H, m), 7.18 (1H, m)
, 7.05 (1H, m), 5.51 (1H, d), 5.13 (1H, wide), 4.
36 (1H, wide), 3.44 (3H, s), 1.38-1.57 (12H, m
).

Step C : 3-[(L-alaninyl) amino] -2,3-dihydro-1-methyl-
Synthesis of 5- (2-thiophen-2-yl) -1H-1,4-benzodiazepin-2-one The title compound was synthesized by a method similar to that described in General Production Method C-AE, Step C. MS (IS ^<+> ) 343 (m / e). ¹ H-NMR (CDCl ₃ ): δ = 8.55 (1H, d), 7.68 (1H, d)
, 7.59 (1H, m), 7.48 (1H, d), 7.36 (1H, d), 7.31
(1H, d), 7.16 (1H, m), 7.04 (1H, t), 5.54 (1H,
d) 3.58 (1H, m), 3.45 (3H, s), 1.41 (3H, d).

Example 5-A 3- (L-alaninyl) amino-2,3-dihydro-1-methyl-5-phenyl-
Synthesis of 1H-1-benzazepin-2-one Step A- 1- 1-Phenyl-1- [2-N- (α-isopropylthio) -N ^′ -(
Preparation of benzyloxycarbonyl) glycinyl] aminophenyl] ethylene α- (isopropylthio) -N- (benzyloxycarbonyl) glycine (1 eq
, Zoller, V .; Ben-Ishai, D. Tetrahedron 1975, 31, 863 (prepared according to part of this specification) in dry THF was cooled to 0 ° C and oxalyl chloride ( 1 eq.) And DMF (3 drops). After stirring at 0 ° C. for 15 minutes, the cooling bath was removed and stirring continued at ambient temperature for 40 minutes. The solution was recooled to 0 ° C.
1-phenyl-1- (2-aminophenyl) ethylene (0.9 eq .; Arienti, A.
Tetrahedron 1997, 53, 3795, the contents of which are incorporated herein by reference.
)) And 4-methylmorpholine (2.0 eq.) In dry THF were added to the acid chloride via cannula. The cooling bath was removed and the reaction was stirred at ambient temperature for 5 hours. The reaction was diluted with dichloromethane and washed with 0.5M citric acid, saturated aqueous NaHCO ₃ and brine. The organic phase was dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified by flash chromatography (CH ₂ Cl ₂ , then CH ₂ Cl ₂ / ethyl acetate (
90:10) to give a pale yellow oil. _{C 27 H 28 N 2 O 3} S (MW = 460.60); mass spectroscopy (MH ⁺⁾ 461.4. Elemental analysis (as _{C 27 H 28 N 2 O 3} S): Theoretical value: C, 70.41; H, 6.13
N, 6.08; Found: C, 70.42; H, 6.05; N, 6.05.

Step B 3- (benzyloxycarbonyl) amino-2,3-dihydro-5-fe
Preparation of nil-1H-1-benzazepin-2-one 1-phenyl-1- [2-N- (α-isopropylthio) -N ^′ -(benzyloxycarbonyl) glycinylaminophenyl] ethylene (1 eq) acetonitrile the solution under N _2, mercury (II) (1.0 eq, Aldrich) chloride and treated with. After the mercury (II) chloride had dissolved, a white precipitate formed immediately. 2.5 of the mixture
The mixture was heated to reflux for an hour, further added with mercury (II) chloride (0.05 equivalent), and refluxed for 1 hour. The reaction was cooled to ambient temperature and filtered while washing the mercury salt with dichloromethane. The filtrate was concentrated under vacuum, the resulting residue was dissolved in dichloromethane and filtered to remove further mercury salts. The filtrate was washed with water. The aqueous phase was re-extracted five times with dichloromethane. The organics were combined and allowed to stand overnight; more mercury salts were filtered. The filtrate was dried over Na ₂ SO _4, filtered, and concentrated in vacuo. Performing a crude oil was purified by flash chromatography (eluting with _{CH 2 Cl 2 ~CH 2 Cl 2} / ethyl acetate (82:18) gradient) to give a tan solid. The solid was further triturated with diethyl ether to give a white solid. _{C 24 H 20 N 2 O 3} (MW = 384.43); mass spectroscopy (MH ⁺⁾ 385.1. Elemental analysis (as _{C 24 H 20 N 2 O 3} · 0.5H 2 O): theory: C, 73.27;
H, 5.38; N, 7.12, found: C, 73.41; H, 5.13; N, 7.3.
0.

Step C 3- (Benzyloxycarbonyl) amino-2,3-dihydro-1-methyl
Preparation of 5- (5-phenyl-1H-benzazepin-2-one) According to General Production Method 4-A, 3- (benzyloxycarbonyl) amino-2,3-
The title intermediate was prepared as a white solid using dihydro-5-phenyl-1H-1-benzazepin-2-one. _{C 25 H 22 N 2 O 3} (MW = 398.4); mass spectroscopy (MH ⁺⁾ 399.2. Elemental analysis (as _{C 25 H 22 N 2 O 3} ): theoretical value: C, 75.36; H, 5.57 ;
N, 7.03; Found: C, 75.21; H, 5.57; N, 7.13.

Step D 3-Amino-2,3-dihydro-1-methyl-5-phenyl-2H-1
Preparation of benzazepin-2-one 3- (benzyloxycarbonyl) amino-2,3-
The title intermediate as an amber oil was prepared using dihydro-1-methyl-5-phenyl-1H-1-benzazepin-2-one, which was used immediately in Step E.

Step E 3- [N ^′ -(tert-butylcarbamate) -L-alaninyl] amino
-2,3-dihydro-1-methyl-5-phenyl-1H-1-benzazepine 2
Preparation of -one Following general procedure D, using N-Boc-alanine and 3-amino-1,3-dihydro-1-methyl-5-phenyl-2H-1-benzazepin-2-one as a white solid The title intermediate was prepared. _{C 25 H 29 N 3 O 4} (MW = 435.57); mass spectroscopy (MH ⁺⁾ 436.3. ¹ H-NMR (300 MHz, CDCl ₃ ): δ = 7.54 (2H, d, J = 4.
6Hz), 7.52-7.25 (18H, m), 5.90 (1H, d, J = 5.3H)
z), 5.88 (1H, d, J = 5.3 Hz), 5.1 (1H, bs), 4.9 (1
H, bs), 4.60 (2H, m), 4.31 (2H, m), 3.48 (6H, s)
), 1.48 (9H, s), 1.46 (9H, s), 1.43 (3H, d, J = 4.
5 Hz), 1.40 (3H, d, J = 4.1 Hz).

Step F 3- (L-alaninyl) amino-2,3-dihydro-1-methyl-5-f
Preparation of enyl-1H-1-benzazepin-2-one According to General Production Method 4-C, 3- [N ^′ -(tert-butylcarbamate) -L-
[Alaninyl] amino-2,3-dihydro-1-methyl-5-phenyl-1H-1-
The title intermediate was prepared as a white foam using benzozepin-2-one. Further purification was unnecessary. _{C 20 H 21 N 3 O 2} (MW = 335.40); mass spectroscopy (MH ⁺⁾ 336.2. Elemental analysis (as _{C 20 H 21 N 3 O 2} ): theoretical value: C, 71.62; H, 6.31 ;
N, 12.53; Found: C, 71.78; H, 6.54; N, 12.22.

Example 5-B 3- (L-alaninyl) amino-2,3,4,5-tetrahydro-1-methyl-5
Synthetic process A of phenyl-1H-1-benzazepin-2-one 3-amino-2,3,4,5-tetrahydro-1-methyl-5-fe
Preparation of nil-2H-1-benzazepin-2-one 3- (benzyloxycarbonyl) amino-2,3-dihydro-1-methyl-5
-Phenyl-1H-1-benzazepin-2-one (Example 5-A, steps AC)
The methanol solution under N ₂ of), 10% palladium - was treated with carbon (0.4 eq). The reaction vessel was placed under a balloon of hydrogen and stirred for 3 hours. The reaction flask was thoroughly slushed with nitrogen, and the reaction mixture was filtered through celite and washed with CH ₂ Cl ² . The filtrate was concentrated to obtain a white foam. _{C 17 H 18 N 2 O (} MW = 266.37); mass spectroscopy (MH ⁺⁾ 267.1. Elemental analysis (as _{C 17 H 18 N 2 O)} : theory: C, 76.66; H, 6.81 ;
N, 10.52; Found: C, 76.56; H, 6.83; N, 10.38.

Step B 3- [N ^′ -(tert-butylcarbamate) -L-alaninyl] amino
-2,3,4,5-tetrahydro-1-methyl-5-phenyl-1H-1-benz
Preparation of azepin 2-one Following general procedure D, N-Boc-alanine and 3-amino-2,3,4,5
-Tetrahydro-1-methyl-5-phenyl-2H-1-benzazepine-2-
Using ON produced the title intermediate in a white foam. _{C 25 H 31 N 3 O 4} (MW = 437.59); mass spectroscopy (MH ⁺⁾ 438.2. Elemental analysis (as _{C 25 H 31 N 3 O 4} ): theoretical value: C, 68.63; H, 7.14 ;
N, 9.60; Found: C, 68.93; H, 7.13; N, 9.49.

Step C 3- (L-alaninyl) amino-2,3,4,5-tetrahydro-1-methyl
Preparation of l-5-phenyl-1H-1-benzazepin-2-one According to General Production Method 4-C, 3- [N ^′ -(tert-butylcarbamate) -L-
[Alaninyl] amino-2,3,4,5-tetrahydro-1-methyl-5-phenyl-
The title intermediate was prepared as a white foam using 1H-1-benzazepin-2-one. Further purification was unnecessary. _{C 20 H 23 N 3 O 2} (MW = 337.46); mass spectroscopy (MH ⁺⁾ 338.2. Elemental analysis (as _{C 20 H 23 N 3 O 2} ): theoretical value: C, 71.19; H, 6.87 ;
N, 12.45; Found: C, 71.38; H, 6.83; N, 12.51.

Example 5-C 3- (L-alaninyl) amino-2,3,4,5-tetrahydro-1-methyl-5
Synthetic process A of phenyl-1H-1-benzazepin-2-one 3-amino-2,3,4,5-tetrahydro-1-methyl-5-fe
Preparation of nil-2H-1-benzazepin-2-one A flask containing freshly condensed liquid ammonia (300 mL) was charged with -70.
At C, lithium metal (4.1 eq) was added. The dark blue slurry was heated to −45 ° C. and cooled previously to 3- (benzyloxycarbonyl) amino-2,3-dihydro-1-methyl-5-phenyl-1H-1-benzazepin-2-one (imp. Treated with the distilled THF (30 ml) solution of Example 4-AC, steps AC). 1
After 0 minutes, a solution of tert-butanol (4.0 equivalents) in distilled THF was added. After an additional 10 minutes, the reaction was quenched with ammonium chloride. The cooling bath was removed and the ammonia was evaporated overnight. The contents were partitioned with CH ₂ Cl ₂ and saturated aqueous NaHCO _3. The organic phase was washed with brine, dried over Na ₂ SO _4, filtered, and concentrated. Liquid chromatography (CH ₂ Cl ₂ / MeOH (99: 1 to 90:10)
) And purified by). _{C 17 H 18 N 2 O (} MW = 266.37); mass spectroscopy (MH ⁺⁾ 267.0.

Step B 3- [N ^′ -(tert-butylcarbamate) -L-alaninyl] amino
-2,3,4,5-tetrahydro-1-methyl-5-phenyl-1H-1-benz
Preparation of azepin 2-one Following general procedure D, N-Boc-alanine and 3-amino-2,3,4,5
-Tetrahydro-1-methyl-5-phenyl-2H-1-benzazepine-2-
Using ON produced the title intermediate in a white foam. _{C 25 H 31 N 3 O 4} (MW = 437.59); mass spectroscopy (M + H) 438.2. Elemental analysis (as _{C 25 H 31 N 3 O 4} ): theoretical value: C, 68.63; H, 7.14 ;
N, 9.60; Found: C, 68.70; H, 7.15; N, 9.54.

Step C 3- (L-alaninyl) amino-2,3,4,5-tetrahydro-1-methyl
Preparation of l-5-phenyl-1H-1-benzazepin-2-one According to General Production Method 4-C, 3- [N ^′ -(tert-butylcarbamate) -L-
[Alaninyl] amino-2,3,4,5-tetrahydro-1-methyl-5-phenyl-
The title intermediate was prepared as a white foam using 1H-1-benzazepin-2-one. Further purification was unnecessary. _{C 20 H 23 N 3 O 2} (MW = 337.46); mass spectroscopy (M + H) 338.2. Elemental analysis (as _{C 20 H 23 N 3 O 2} ): theoretical value: C, 71.19; H, 6.87 ;
N, 12.45; Found: C, 71.32; H, 6.57; N, 12.24.

E. Cyclic Ketone Derivatives General Method 6-A Jones Oxidation Method The compound to be oxidized was stirred in acetone and Jones reagent was added in portions until the starting material was consumed. The reaction mixture was quenched with isopropanol and the mixture was filtered through Celite and concentrated under reduced pressure. The residue was partitioned between ethyl acetate and water,
The organic layer was dried over sodium sulfate and then concentrated under reduced pressure. The crude product was purified by silica gel chromatography and / or recrystallization.

General Method 6-B Swern Oxidation Method Oxalyl chloride (0.1.5 ml, 1.2 mm
ol), DMSO (0.106 mL, 1.5 mmol) was added and the mixture was stirred for 10 minutes. A solution of the alcohol (0.1828 g, 0.60 mmol) in 20 mL of chloroform was added dropwise. The reaction mixture was stirred at -78 ° C for 2 hours, and then 0.5 mL (3.6 mm
ol). Stirring was continued for 1 hour, then the mixture was warmed to room temperature and kept stirring at ambient temperature overnight. The mixture is then diluted with 50 mL of dichloromethane, washed with brine (3x), dried over magnesium sulfate, filtered, and evaporated to dryness to give the crude product, which is typically a column Purified by chromatography.

F. Dibenzazepinone Derivatives and Related Compounds General Method 7-A Preparation of 5-Amino-7-alkyl-5,7-dihydro-6H-dibenz [b, d] azepin-6-one Derivatives Step A According to general method 5-A, using 5,7-dihydro-6H-dibenz [b, d] azepin-6-one and an alkyl halide, 7-alkyl-5,7-dihydro-6H-dibenz [ [b, d] azepin-6-one was prepared. Step B 7-Alkyl-5,7-dihydro-6H-dibenz [b, d] azepin-6-one (1 eq.) Was dissolved in THF and isoamylnitrile (1.2 eq.) Was added. The mixture was cooled to O 0 C in an ice bath. NaHMDS (1.1 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 HCl and extracted with EtOAc. The organic layer was dried and concentrated to give a crude product, which was purified by silica gel chromatography. Step C Dissolve the resulting oxime in EtOH / NH ₃ (20: 1) and add Raney nickel and hydrogen (50
(0 psi) in a bomb at 100 ° C. for 10 hours. The resulting mixture was filtered and concentrated to give an oil, which was purified by silica gel chromatography to give the title compound.

General Method 7-B Preparation of fluoro-substituted 5,7-dihydro-6H-dibenz [b, d] azepin-6-one derivatives Robin D. Clark et al. (Tetrahedron, Vol. 49, No. 7, pp. 1351-1356, 1993, the contents of which are incorporated herein by reference. Specifically, appropriately substituted Nt-Boc-2-amino-2'-methylbiphenyl was dissolved in THF and cooled to -78 ° C. s-Butyllithium (1.3M, 2.2 eq. in cyclohexane) at -65 ° C
Gradually added to remain below. The resulting mixture was warmed to -25 ° C and stirred at that temperature for 1 hour. The mixture was cooled to -78 ° C. The mixture dried C0 ₂ for 30 sec vented (bubbled). The mixture was warmed to ambient temperature and then carefully quenched with water. The mixture was concentrated under reduced pressure and then adjusted to pH 3 with 1H HCl. Mixture E
Extraction with tOAc, drying of the organic layer and concentration gave a crude material. The crude was dissolved in methanol and the solution was saturated with HCl. The mixture was heated at reflux for 12 hours and then cooled. The mixture was concentrated to give the crude lactam, which was purified by chromatography or crystallization.

General Method 7-C Resolution of 5-amino-7-methyl-5,7-dihydro-6H-dibenz [b, d] azepin-6-one Racemic free base amine in methanol in a round bottom flask (1.0 eq.) Followed by di-p-toluoyl-D-tartaric acid monohydrate (1.0 eq.). The mixture was concentrated under reduced pressure to give a residue, redissolved in an appropriate amount of methanol and stirred at room temperature while open to the atmosphere (8-72 hours). The solid was removed by filtration. 0.1% enantiomeric excess
Chiral HPLC using 85% H ₂ 0 and 15% acetonitrile containing trifluoroacetic acid
(Chiracel ODR) (flow rate 1.0 mL / min, 35 ° C.). Then, the divided
-p- toluoyl -D- tartaric acid salt was dissolved in EtOAc, it was added saturated NaHCO ₃ until a pH 9-10. Saturating the organic layer again was separated layers NaHC0 _3, H ₂ 0, and brine. The organic layer was dried over MgSO _4, and removed by filtration of the drying agent. The filtrate was concentrated under reduced pressure.
The free amine was dissolved in MeOH and HCl (12M, 1.0 eq.) Was added. The salt was concentrated under reduced pressure and the resulting film was triturated with EtOAc. The HCl salt was filtered and rinsed with EtOAc. ee was measured 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 7-methyl-5,7-dihydro Synthesis of -6H-dibenz [b, d] azepin-6-one A round bottom flask was charged with sodium hydride (0.295 g, 7.46 mmol) in 9.0 ml of DMF and charged with 5,7-dihydro-6H-dibenz [b , d] Azepin-6-one (1.3 g, 6.22 mmol) (CAS
# 20011-90-9, according to Brown et al., Tetrahedron Letters, No. 8, 667-670, (1971) and references described therein (the contents of which are incorporated herein by reference). Prepared). After stirring for 1 hour at 60 ° C., the solution was methyl iodide (1.1
(6 ml, 18.6 mmol) and kept stirring for 17 hours protected from light. Cool, then CH ₂ C
diluted with l ₂ / H ₂ 0, washed with NaHS0 ₄ solution, H ₂ O, then dried over Na ₂ SO _4. The title compound of evaporation and flash chromatography (Si0 _2, CHCl ₃₎ by a colorless solid 0.8
85 g (63%) were obtained. NMR data are as follows: ¹ H-nmr (CDCl ₃ ): δ = 7.62 (d. 2H), 7.26-7.47 (m, 6H), 3.51 (m, 2H), 3.32
(s, 3H). C ₁₅ H ₁₃ NO (MW = 223.27); mass spectrometry (MH +) 223. Elemental analysis: C ₁₅ H ₁₃ NO theoretical; C, 80.69 H, 5.87 N, 6.27. , 80.11 H
, 5.95 N, 6.23.

Step B Synthesis of 7-Methyl-5-oximo-5,7-dihydro-6H-dibenz [b, d] azepin-6-one The above isolated compound (0.700 g, 3.14 mmol) was dissolved in 20 mL of toluene. And butyl nitrite
(0.733 ml, 6.28 mmol). The reaction temperature was lowered to 0 ° C., N ₂ atmosphere under solution KH
Treated with MDS (9.42 ml, 0.5 M). After stirring for 1 hour, quenched with saturated NaHS0 ₄ solution, diluted with CH ₂ Cl _2, and separated. The organic layer was dried over Na ₂ SO _4, the title compound was purified was purified by _{(Si0 2, 98 2 CHCl 3} / MeOH), to give a colorless solid 0.59 g (80%). C ₁₅ H ₁₂ N ₂ 0 ₂ (MW = 252.275); Mass spectrometry (MH +) 252. Elemental analysis: Theoretical value of C ₁₅ H ₁₂ N ₂ 0 ₂ ; C, 71.42 H, 4.79 N, 11.10 Actual value : C, 71.
24 H, 4.69 N, 10.87. Step C Synthesis of 5-Amino-7-methyl-5,7-dihydro-6H-dibenz [b, d] azepin-6-one hydrochloride The above isolated oxime (0.99 g, 3.92) mmol) was hydrogenated at 35 psi over 10% Pd / C in 3A ethanol (0.46 g) using a Parr apparatus. After 32 hours, the reaction mixture was filtered through a plug of Celite, evaporate the filtrate and foam was treated with a saturated solution of HCl (g) in Et ₂ O. The obtained colorless solid was filtered, rinsed with cold Et ₂ O, and dried under reduced pressure to obtain 0.66 g (61%) of the title compound. NMR data are as follows: ¹ H-nmr (DMSOd6): δ = 9.11 (bs, 3H), 7.78-7.41 (m, 8H), 4.83 (s, 1H), 3.25
(s, 3H). C ₁₅ H ₁₄ N ₂ 0. HCl (MW = 274.753); Mass spectrometry (MH + free base) 238. Elemental analysis: C ₁₅ H ₁₄ N ₂ 0. Theoretical value of HCl; C, 65.57 H , 5.50 N, 10.19. Found: C,
65.27 H, 5.67 N, 10.13.

Example 7-B (S)-and (R) -5- (L-alaninyl) -amino-7-methyl-5,7-dihydro-6H-dibenz [
b, d] Synthesis of azepin-6-one Step A (S)-and (R) -5- (N-Boc-L-alaninyl) -amino-7-methyl-5,7-dihydro-6H-
Synthesis of dibenz [b, d] azepin-6-one Boc-L-alanine (0.429 g, 2.26 mmol) (Aldrich) was dissolved in THF and HOBt (0.305
g, 2.26 mmol) and 5-amino-7-methyl-5,7-dihydro-6H-dibenz [b, d] azepin-6-one (0.45 g, 1.89 mmol) (Example 7-A). . Lower the temperature to O ° C,
The reaction mixture EDC was treated with (0.449 g, 2.26 mmol) ( Alrich), and stirred for 17 hours under N _2. The reaction mixture was evaporated, the residue was diluted with EtOAc / H ₂ O, 1.0N HCl, saturated NaH
C0 _3, washed with brine and dried over Na ₂ SO _4. Chiralcel O using 10% IPA / heptane
Diastereomers were separated on a D column at 1.5 ml / min. Isomer 1: retention time 3.37 min. NMR data are as follows: ¹ H-nmr (CDCl ₃ ): δ = 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: [α] ₂₀ = -96 ＠ 589 nm (c = 1, MeOH). C ₂₃ H _{27 N 3 0 4 (MW =} 409.489); mass spectroscopy (MH +) 409. elemental analysis:. theoretical value of _{C 23 H 27 N 3 0 4} ; 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 are as follows: ¹ H-nmr (CDCl ₃ ): δ = 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: [α] ₂₀ = 69 ＠ 589 nm (c = 1, _{. MeOH) C 23 H 27 N} 3 0 4 (MW = 409.489), mass spectrometry (MH +) 409. elemental analysis:. theoretical value of _{C 23 H 27 N 3 0 4} ; C, 67.46 H, 6.64 N, 10.26 Found Values: C, 67.4
0 H, 6.62 N, 10.02

Step B (S)-and (R) -5- (L-alaninyl) -amino-7-methyl-5,7-dihydro-6H-dibenz [
Synthesis of b, d] azepin-6-one hydrochloride The compound isolated in step A (separately for each isomer) is dissolved in dioxane and excess HCl (
g). Stir for 17 hours, then evaporate and dry under reduced pressure to isolate the title compound as a colorless solid. Isomer 1: C ₁₈ H ₁₉ N ₃ O ₂ .HCl (MW 345.832); mass spectrometry (MH + free base) 309. Optical rotation: [α] ₂₀ = 55 ＠ 589 nm (c = 1, MeOH). _{2: C 18 H 19 N 3} 0 2 .HCl (MW = 345.832); mass spectroscopy (MH + free base) 309. Optical _{Rotation: [α] 20 = 80 @} 589 nm (c = 1, MeOH).

General Method 8-G N-Alkylation of Amides or Lactams with Sodium or Potassium tert-Butoxide Sodium or Potassium tert-Butoxide (1.1 eq) in 15 mL of Dry DMF
To the slurry of was added the appropriate amide (0.0042 mol) as a solution in 10 mL DMF. Next, alkyl iodide was added to obtain a thick slurry. The thickness of the reaction decreased over time, and the reaction became homogeneous when TLC was completed. The reaction mixture was poured over ice and extracted in ethyl acetate. The organic layer was washed with water and then with brine.
Next, the organic layer was dried over sodium sulfate, filtered, and then concentrated under reduced pressure. The residue was purified by HPLC (LC 2000) eluting with ethyl acetate / hexane system.

General Method 8-I N-Alkylation of Amides or Lactams with Cesium Carbonate To a solution of the amide or lactam in DMF was added cesium carbonate (1.05 eq) and alkyl iodide (1.1 eq). The mixture was stirred at room temperature overnight, then the reaction mixture was diluted with ethyl acetate and washed with water and then brine. The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by HPLC (LC2000) eluting with ethyl acetate / hexane system.

General Method 8-J BOC Removal Method To the N-Boc protected compound at room temperature was added CH ₂ Cl ₂ / TFA (4: 1). The reaction mixture was stirred at room temperature for 3 hours and then concentrated. The residue was extracted with dichloromethane, washed with water, saturated sodium bicarbonate, dried over Na ₂ SO _4, filtered and then concentrated to give the free amine.

General Method AA Reductive Amination In a hydrogenation flask, a solution of the arylamine in ethanol was added to an equivalent of 2-oxocarboxylic acid ester (eg, pyruvate) followed by 10% palladium
/ Carbon (25% by weight based on arylamine). Reaction completion is indicated by tlc (30
Using a separatory 16 h) Parr shaker and hydrogenated at 20 psi H _2. The reaction mixture was then filtered through a pad of Celite 545 (available from Aldrich Chemical Company, Inc.) and the solvent was removed on a rotary evaporator. The crude product residue was then further purified by chromatography.

General Method AB First Transesterification Technique 1-5 equivalents of the desired alcohol solution was added to 1 equivalent of sodium hydride in toluene. After off-gassing of the gas was released, the transesterifying compound dissolved in toluene was added. After 0.5 h, the reaction was heated to 40 ° C. and placed under house vacuum (〜20 mm Hg) or the solution was bubbled with nitrogen while heating at 90 ° C.
The reaction was followed by a tlc, and when the reaction was complete, the solution was cooled and water or 1M HCl
The reaction was stopped with a smaller scale and the reaction was diluted with ethyl acetate. The organic layer was extracted with saturated aqueous NaHCO _3, then with saturated aqueous NaCl, and dried over MgSO _4. The solvent was stripped from the solution on a rotary evaporator, and the crude product residue was further purified by chromatography. Alternatively, the reaction mixture was worked up by evaporating the solvent and directly chromatographing the crude mixture. This method is expensive and / or particularly useful in the case of high boiling alcohols.

General Methods AC Second Transesterification Technique The compound to be transesterified was placed in a large excess of the desired alcohol. A catalytic amount of dry NaH was added and the reaction was followed by a tlc until no more starting material was detected. Stop the reaction with a few milliliters of 1N HCl, stir for a few minutes, then add saturated aqueous NaHC
0 ₃ was added. The organic layer was washed with saturated aqueous NaCl, and dried over MgSO _4. The solvent was stripped from the solution on a rotary evaporator, and the crude product residue was further purified by chromatography.

General Methods AD Tertiary Transesterification Technique The compound to be transesterified was placed in a large excess of the desired alcohol. A catalytic amount of dry NaH was added and the reaction was followed by a tlc until no more starting material was detected. Stop the reaction with a few milliliters of 1N HCl, stir for a few minutes, then add saturated aqueous NaHC
0 ₃ was added. The volume of the reaction mixture was reduced on a rotary evaporator until excess alcohol was removed, then the remaining residue was taken up in ethyl acetate and more water was added. The organic layer was washed with saturated aqueous NaCl, and dried over MgSO _4. The solvent was stripped from the solution on a rotary evaporator, and the crude product residue was further purified by chromatography. This method is used especially for low-boiling, inexpensive alcohols that are miscible with water.

General Method AE O-Alkylation Technique Prepared by reductive amination with carboxylic acid compounds (eg, general method AA to obtain N-aryl amino acid esters, in DMF followed by hydrolysis with method AF in DMF) ) Was added with 1.5 equivalents of K ₂ CO ₃ , followed by 1 equivalent of an alkylating agent (eg, tert-butyl bromoacetate). The reaction was stirred at room temperature for 2 hours, then quenched with water and extracted into ethyl acetate. The organic layer was washed with saturated aqueous NaHCO _3, water, and saturated aqueous NaCl, then dried over MgSO _4. The solvent was stripped from the solution on a rotary evaporator to give a crude product.

General Method AF Ester Hydrolysis to the Free Acid Carboxylic acid ester compounds in a 1: 1 mixture of CH ₃ 0H / H ₂₀ (eg, general method for obtaining N-aryl amino acid esters Reductive by AA Prepared by amination
) Was added with 2-5 equivalents of K ₂ CO ₃ . The mixture was heated to 50 ° C. for 0.5-1.5 hours until tlc indicated the reaction was complete. 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 22 and ethyl acetate was added to extract the product. The organic layer was washed with saturated aqueous NaCl, and dried over MgSO _4. The solvent was stripped from the solution on a rotary evaporator to give a crude product.

General Method AG N-Heteroarylation of Alanine A solution of 1.1 equivalents of L-alanine and 2 equivalents of NaOH in DMSO was stirred at room temperature for 1 hour, then 1 equivalent of 2-chlorobenzothiazole was added. Was. The mixture was heated to 100 ° C. for 4 hours, then cooled to room temperature and poured on ice. The pH of the resulting aqueous solution was adjusted to 22, and the precipitated solid was removed by filtration. This solid was then dissolved in 1N NaOH and the resulting solution was filtered through a pad of Celite 545. The pH of the filtrate was adjusted to 22 and the white precipitate was removed by filtration and washed with water to give a crude product.

General Method AH EDC Coupling To a 1: 1 mixture of the desired acid and alcohol in CH ₂ Cl ₂ at O ° C., 1.5 equivalents of triethylamine, then 2.0 equivalents of hydroxybenzotriazole monohydrate, then , 1.25 equivalents of ethyl-3- (3-dimethylamino) -propylcarbodiimide HCl (EDC
) Was added. The reaction was stirred overnight at room temperature and then transferred to a separatory funnel, washed with water, saturated aqueous NaHCO _3, 1N HCl, and saturated aqueous NaCl, then dried over MgSO _4. The solvent was stripped from the solution on a rotary evaporator to give a crude product.

General Methods AI Oxime or Amine Coupling Technique Trichlorophenyl ester of carboxylic acid (1 eq) was stirred in DMF or THF. Oxime or amine (1.2 eq) was added and the mixture was stirred at ambient temperature for 1-4 hours. If an amine hydrochloride was used, a suitable base such as N, N-diisopropylethylamine (1.2 eq) was also added. The obtained mixture was concentrated under reduced pressure to obtain a crude product,
Use this without purification or use silica gel chromatography and / or
Or purified by crystallization.

General Methods AJ Alkylation Technique The amine (1 eq), α-bromoester (1.1 eq), and the appropriate base (such as triethylamine) (2 eq) were stirred in chloroform. The resulting solution was heated to reflux for 4-12 hours. After cooling, the mixture was diluted with chloroform and washed with water. The organic layer was dried (sodium sulfate) and concentrated under reduced pressure. The crude product was purified by silica gel chromatography.

General Methods AK Oxime or Alcohol Coupling Technique The carboxylic acid (1 eq) was stirred in a suitable solvent (such as THF, dioxane, or DMF). Alcohol or oxime (1-5 eq) was added. EDC hydrochloride (1.2 eq) and hydroxybenzotriazole hydrate (1 eq) were added. The appropriate base (such as 4-methylmorpholine or triethylamine) (0-1 eq) was added. Catalyst amount (0.1 eq)
4-Dimethylaminopyridine was added. The mixture was stirred at ambient temperature under a dry nitrogen gas atmosphere. After 20 hours, the mixture was concentrated under reduced pressure. The resulting concentrate was partitioned between ethyl acetate and water. The organic layer was separated and washed with aqueous sodium bicarbonate and brine. The organic layer was dried (sodium sulfate) and concentrated under reduced pressure. The crude product was used without further purification or was further purified by silica gel chromatography and / or crystallization.

General Methods AL EDC Coupling The carboxylic acid was dissolved in methylene chloride. Amino acids (1 eq.), N-methylmorpholine (5 eq.), And hydroxybenzotriazole monohydrate (1.2 eq.) Were added sequentially. A cooling bath was applied to the round bottom flask until the solution reached O <0> C. At that time, 1.2 e
q. 1- (3-Dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (EDC) was added. The solution was stirred overnight and brought to room temperature under nitrogen pressure. The reaction mixture was worked up by washing the organic phase with saturated aqueous sodium carbonate, 0.1 M citric acid, and brine, and then dried over sodium sulfate. Then, the solvent was removed to obtain a crude product. Pure product was obtained by flash chromatography using a suitable solvent.

General Method AM Triflate Substituted To a 0 ° C. solution of iso-butyl R-(+)-lactate in CH ₂ Cl ₂ was added 1.1 equivalents of trifluoromethanesulfonic anhydride. After stirring at room temperature for 20 minutes, 1.1 equivalents of 2,6-
Lutidine was added and stirring continued for 10 minutes. This solution was then transferred to a flask containing 1 equivalent of arylamine and 1 equivalent of N, N-diisopropylethylamine in CH ₂ Cl ₂ or CH ₃ NO ₂ at 0 ° C. The reaction was left overnight at room temperature, then the solvent was stripped from the solution on a rotary evaporator. Dissolve the residue in ethyl acetate,
Washed with 5% citric acid, then saturated aqueous NaCl, dried over magnesium sulfate or sodium sulfate, then stripped the solvent from the solution on a rotary evaporator to give the crude product, which was then purified by chromatography.

General Method AN BOC Removal Add the BOC-protected compound to a 1: 1 mixture of CH ₂ Cl ₂ and trifluoroacetic acid and stir, typically for 2 h, until tlc indicates complete conversion did. Then
The solution was stripped and dried, the residue was taken up in ethyl acetate and extracted with dilute HCl.
The acid reactant was neutralized and extracted with ethyl acetate. Wash the organic phase with saturated aqueous NaCl, Mg
And dried over S0 _4. The solvent was stripped from the solution on a rotary evaporator to give a crude product.

General Method Synthesis of AO Pyruvate To a mixture of pyruvate (8.8 g, 0.1 mol) (Aldrich) in 100 mL of benzene,
-Butanol (14.82 g, 0.2 mol) and a catalytic amount of p-toluenesulfonic acid were added. The mixture was then refluxed using a Dean Stark device. After 4 hours, 1.8 g of water (0.1 mo
l) was isolated and the reaction appeared to be complete. Benzene and iso-butanol were removed on a rotary evaporator. nmr [ ¹ H-Nmr (CDCl ₃ ): δ = 4.0 (d, 2H
), 2.5 (s, 3H), 2.0 (m, 1H), 1.0 (d, 6H)] to further purify the residue (14 g, 0.1 mol), which was mainly iso-butyl pyruvate. Used without. Iso-butanol can be replaced with other alcohols (e.g., ethanol, isopropanol)
, n-butanol, benzyl alcohol, etc.) to produce other pyruvate esters as well.

General Method AP Aromatic Nucleophilic Substitution of Fluorobenzene A mixture of 1.82 g (10 mmol) of D, L-alanine iso-butyl ester hydrochloride, 10 g of fluorobenzene (10 mmol) and 3 g of anhydrous potassium carbonate in 10 mL of DMSO Was stirred at 120 ° C. for 2-5 hours. Next, the reaction mixture was cooled to room temperature and diluted with 100 mL of ethyl acetate.
The ethyl acetate extract was washed with water (3x), dried over MgSO _4, then evaporated to dryness to give the crude product which was further purified by column chromatography this.

General Method AQ Fourth Transesterification Technique The ester to be transesterified was dissolved in a large excess of alcohol and 0.3 equivalent of titanium (IV) isopropoxide (Aldrich) was added. Following the reaction, t
An lc was performed and then the volatiles were removed under reduced pressure. The resulting crude was then chromatographed to give the desired product.

General Method Synthesis of AR N-BOC aniline To a solution of aniline in THF at O 0 C, 1 equivalent of di-tert-butyl dicarbonate (Aldrich) in THF, then 1.5 equivalents of 1ON aqueous hydroxide Sodium was added dropwise. 1 at room temperature
After stirring for 6 hours or, if necessary, heating at 80 ° C. for 3 hours, the reaction mixture is diluted with ether, washed with NaHCO ₃ , brine, dried over sodium sulfate and potassium carbonate and concentrated under reduced pressure. Followed by chromatography to give N-BOC aniline.

General Methods AS Oxime Ester Formation Trichlorophenyl ester (1 eq.) Was stirred in DMF or THF. Oxime
(1.2 eq.) Was added and the mixture was stirred at ambient temperature for 1-4 hours. The resulting mixture was concentrated under reduced pressure, and the residue was purified by silica gel chromatography and / or crystallization.

IV. Preparation of Epoxides General Procedure EA First Epoxide Opening Method 5- (S)-[L-alaninyl] -amino-7-methyl-5,7- in methanol (0.1 M) A solution of dihydro-6H-dibenz [b, d] azepin-6-one hydrochloride (1 eq., Ex. 7B) was added to diisopropylethylamine (1.5-2 eq., Aldrich) and the appropriate .)
Processed. The resulting mixture was stirred at room temperature for 96 hours, then concentrated under reduced pressure.
The obtained oil was dissolved in methylene chloride and washed with water. The aqueous layer was re-extracted with methylene chloride, then the combined organic extracts were dried over Na ₂ SO _4, filtered, then concentrated. The crude product was purified by flash chromatography.

General Method EB Second Epoxide Ring Opening Method 5- (S)-[L-alaninyl] -amino-7-methyl-5,7-dihydro- in methanol (0.1 M)
A solution of 6H-dibenz [b, d] azepin-6-one hydrochloride (1 eq., Ex. 7B) is treated with diisopropylethylamine (1-3 eq., Aldrich) and the appropriate epoxide (1.5-2 eq.) did. The resulting mixture was heated to 50 ° C. for 48 hours, then cooled to room temperature and concentrated under reduced pressure. The obtained oil was dissolved in methylene chloride and washed with water. The aqueous layer was re-extracted with methylene chloride, then the combined organic extracts were dried over Na ₂ SO _4, filtered, and concentrated. The crude product was purified by flash chromatography.

Example EB Synthesis of N- (2 (R / S) -Hydroxy-2- (3,5-difluorophenyl) ethyl) -L-alanine 2- (3,5-difluoro (Phenyl) -1,2-epoxyethane (Example EC1) and L-alanine methyl ester hydrochloride (Bachem), followed by 3:
The title compound was isolated by flash chromatography using 1-1: 1 (gradient) hexane / ethyl acetate. _{C 12 H 15 F 2 N0 3} (MW = 259.25); mass spectroscopy ^{(MH +) 260.2 1 H NMR} (CD 3 0D, 250 MHz, δ) 7.04-6.75 (m, 3H), 4.78-4.64 (m, 1H) , 3.71 (
s, 3H), 3.49-3.29 (m, 1H), 2.84-2.60 (m, 2H) .1.31 (d, J = 5.6Hz, 3H).

General Method EC Preparation of Epoxides The appropriate aldehyde (1 e) in 1: 1 methylene chloride / 50% aqueous sodium hydroxide (0.15 M)
) was treated with tetrabutylammonium iodide (0.1 eq., Aldrich) and trimethylsulfonium iodide (1.2 eq., Aldrich). 24 of the resulting mixture
Heated to 50 ° C. for hours, then cooled to room temperature and washed with water. The aqueous layer was re-extracted with methylene chloride, then the combined organic extracts were dried over Na ₂ SO _4, filtered, and concentrated. The crude product was purified by flash chromatography.

Example EC1 Synthesis of 2- (3,5-difluorophenyl) -l, 2-epoxyethane Following general procedure EC, using 3,5-difluorobenzaldehyde (Aldrich), 20:
1 The title compound was isolated by flash chromatography using pentane / diethyl ether. C ₈ H ₆ F ₂₀ (MW = 156.13); mass spectrometry 156.0 ¹ H NMR (CDCl ₃ , 300 MHz, δ), 6.84-6.70 (m, 3H), 3.84-3.82 (m, 1H), 3.16-
3.12 (m, 1H), 2.73-2.70 (m, 1H).

Example EC2 Synthesis of 2- (3,4,5-trifluorophenyl) -1,2-epoxyethane Following general procedure EC, 3,4,5-trifluorobenzaldehyde (Strem) was used.
The title compound was isolated by flash chromatography using 0: 1 pentane / diethyl ether. C ₈ H ₅ F ₃₀ (MW = 174.12); mass spectrometry 174.1 ¹ H NMR (CDCl ₃ , 300 MHz, δ) 6.94-6.89 (m, 2H), 3.81-3.79 (m, 1H), 3.15-3
.12 (m, 1H), 2.69-2.67 (m, 1H).

Example EC3 Synthesis of 2- (3,4,5-trifluorophenyl) -1,2-epoxyethane Following general procedure EC, 4- (trifluoromethyl) -benzaldehyde (Aldrich) was used. The title compound was isolated by flash chromatography using 1: 1 pentane / diethyl ether. C ₉ H ₇ F ₃₀ (MW = 188.15); mass spectrometry 188.0 ¹ H NMR (CDCl ₃ , 300 MHz, δ) 7.61 (d, J = 7.9 Hz, 2H), 7.40 (d, J = 7.9 Hz, 2H )
, 3.93-3.90 (m, 1H), 3.20-3.17 (m, 1H), 2,78-2.75 (m, 1H).

Example EC4 Synthesis of 2- (3,5-bis- (trifluoromethyl) phenyl) -1,2-epoxyethane 3,5-bis- (trifluoromethyl) -benzaldehyde according to General Procedure EC (Lan
The title compound was isolated by flash chromatography using a caster) with 10: 1 pentane / diethyl ether. C _1O H ₆ F ₆₀ (MW = 256.15); mass spectrometry 257 ¹ H NMR (CDCl ₃ , 300 MHz, δ) 7.82 (s, 1H), 7.74 (s, 2H), 4.00-3.98 (m, 1H
), 3.25-3.22 (m, 1H), 2.80-2.77 (m, 1H).

General Methods ED Deprotection of SEM protected alcohol The appropriate SEM protected alcohol was stirred in 5% HCl in methanol at room temperature for 17 hours. The reaction solution was poured into aqueous saturated NaHCO _3, and extracted with dichloromethane. The organic layer was concentrated under reduced pressure to obtain a deprotected product.

V. Synthesis of Intermediates Intermediate A 5- (S)-(N ′-(3-methyl-2- (S)-(2-trimethylsilylethyloxy) -methyloxybutyl) -L-alaninyl) Synthesis of 1-amino-7-methyl-5,7-dihydro-6H-dibenz [b, d] azepin-6-one Step A Methyl-2- (S)-(2-trimethylsilylethyloxy-) methyloxy-3 Preparation of -methylbutanoate Methyl-2- (S) -hydroxy-3-methylbutanoate in dichloromethane (1.0 eq
A solution of J. Org. Chem. (1997), 62 (7), 2292-2297, which is incorporated herein by reference, was stirred with diisopropylethylamine (2.0 eq) under nitrogen. Two
-Trimethylsilylethoxymethyl chloride (3 eq; Aldrich) was added dropwise via syringe. The solution was stirred at room temperature for 17 hours. The solution was washed with 1.0N HCl and the aqueous layer was back extracted with dichloromethane. The organic layers were combined, dried over Na ₂ SO _4, then the solvent was removed under reduced pressure. The residue was purified by radial chromatography using 20% ethyl acetate in hexane to give the title intermediate as a clear oil. ¹ H NMR data is as follows: ¹ H NMR (400 MHz, CDCl ₃ ) δ 4.71 (2H s), δ 3.89 (1 H d, J = 5.7 Hz), δ 3.7
2 (3H s), δ 3.72-3.57 (2H m), δ 2.10-2.03 (1H m), δ 0.97-0.86 (8H m),
_{δ 0.10 (9H s) C 12} H 26 0 4 Si (MW = 262.42);. mass spectrometry (M +) 262.

Step B Preparation of 3-Methyl-2- (S) -2- (trimethylsilyl) ethyloxy-methyloxybutanal Methyl-2- (S)-(2-trimethylsilylethyloxy) methyloxybutyl- in toluene A solution of 3-methylbutanoate (1.0 eq) was cooled to -78 ° C under a nitrogen gas atmosphere. DIBAL-H (Aldrich, 1.0 M in toluene, 1.5 eq) was added dropwise at -78 ° C.
The reaction was stirred at -78 ° C for 20 minutes and quenched with methanol. -78 mixture
Stirred at C for an additional 30 minutes and added 10% Rochelle saline solution. The reaction was warmed to room temperature and stirred for 17 hours. The layers were separated and the organic layer was concentrated under reduced pressure. The residue was purified by radial chromatography using 20% ethyl acetate in hexane to give the title intermediate as a clear oil. ¹ H NMR data is as follows: ¹ H NMR (400 MHz, CDCl ₃ ) δ 9.61 (1H s), δ 4.79-4.72 (1H m), δ 4.69-4.6
3 (2H m), δ 3.71-3.56 (2H m), δ 2.16-2.01 (1H m), δ 1.23 (2H br s),
δ 1.20-0.82 (6H m), δ 0.03 (9H s) C 11 H 24 0 3 Si (MW = 232.40);. mass spectrometry (MH +) 233.

Step C Preparation of N- (3-methyl-2- (S)-(2-trimethylsilylethyloxy) -methyloxybutyl) -L-alanine, methyl ester 3-methyl-2- (S)-( 2-trimethylsilylethyloxy) methyloxybutanal
(1.0 eq) was stirred in methanol with L-alanine, methyl ester (0.8 eq; Bachem) at room temperature. Sodium cyanoborohydride (0.5 eq) was added to the solution and the reaction was stirred for 17 hours. It was made alkaline by addition of aqueous saturated NaHCO ₃ solution to the reaction.
The mixture was extracted with dichloromethane, dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by radial chromatography using 20% ethyl acetate in hexane to give the title intermediate as a clear oil. C ₁₅ H ₃₃ NO ₄ Si (MW = 319.50); Mass spectrometry (MH +) 320 Elemental analysis: Theoretical value of C ₁₅ H ₃₃ NO ₄ Si: C 56.39, H 10.41, N 4.38. Actual value: C 56.1
5. H 10.14, N 4.42.Step D 5- (S)-(N '-(3-methyl-2- (S)-(2-trimethylsilylethyloxy) methyloxybutyl) -L-alaninyl) -amino- 7-methyl-5,7-dihydro-6H-dibenz [b
, d] Preparation of azepin-6-one N- (3-methyl-2- (S)-(2-trimethylsilylethyloxy) methyloxybutyl) -L-alanine according to General Method II-A, Method B, The acid was prepared using the methyl ester. Using the residue and following general method D, 5- (S) -amino-7-methyl-5,7-dihydro-
The title intermediate was obtained using 6H-dibenz [b, d] azepin-6-one hydrochloride (Example 7A). _{C 29 H 43 N 3 0 4} Si (MW = 525.77), mass spectrometry (MH +) 526. Elemental _{analysis: C 29 H 43 N 3 0} 4 Si of theory:. C 66.25, H 8.24, N 7.99 Found: C 66.10
, H 8.13, N 8.13.

Intermediate B 3- (N ′-(3-methyl-2- (S)-(2-trimethylsilylethyloxy) methyloxybutyl
Synthesis of) -L-alaninyl) -amino-2,4-dioxo-1-methyl-5-phenyl-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine General Method II-A, Method According to B, N- (3-methyl-2- (S)-(2-trimethylsilylethyloxy) methyloxybutyl) -L-alanine, methyl ester (intermediate A, step C: 1
eq) was used to produce the free acid. Using the residue and following general procedure D, 3-amino-2
The title intermediate was prepared using 1,4-dioxo-1-methyl-5-phenyl-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine (CAS No. 131604-75-6). _{C 30 H 44 N 4 0 5} Si (MW = 568.79), mass spectrometry (MH +) 569. Elemental analysis:. Theoretical value of _{C 30 H 44 N 4 0 5} Si; C 63.35, H 7.80, N 9.85 Found: C 63.
24, H 7.48, N 9.89.

Synthesis of Intermediate C N- (2- (R / S) -3,5-Difluorophenyl-2-hydroxyethyl) -L-alanine 3: 1 Butanol / N- (2- (R / S) -3,5-difluorophenyl
The title intermediate was prepared using (-2-hydroxyethyl) -L-alanine (Example EB). ^{The 1} H NMR data are as follows: ¹ H NMR (400 MHz, CD ₃ OD) δ 7.04-7.01 (2H m), δ 6.89-6.79 (1H m), δ 4.97-
4.83 (1H m), δ4.00 (1H q, J = 7.0 Hz), δ3.27-3.08 (2H m), δ1.54 (3H d,
_{J = 2.8 Hz) C 11 H} 13 F 2 N0 3 (MW = 245.23); mass spectroscopy (MH +) 246.

Example 6 5- (S)-(N ′-(2- (3,5-difluorophenyl) ethyl) -L-alaninyl) -amino-7-methyl-5,7-dihydro-6H-dibenz Synthesis of [b, d] azepin-6-one 3,5-difluorophenylacetaldehyde containing sodium cyanoborohydride (0.6 eq., Aldrich) in methanol (CAS 109346-94-3: Elliott, Michael et al
Pestic. Sci. (1987), 18 (4), 239-44, the contents of which are incorporated herein, 1.4 eq) and 5- (S)-[L-alaninyl] -amino-7. A solution of -methyl-5,7-dihydro-6H-dibenz [b, d] azepin-6-one hydrochloride (1 eq., Example 7B) was stirred at room temperature for 1.5 hours. The solution was removed under reduced pressure, the residue 1: 1 was dissolved in aqueous saturated NaHCO ₃ / diethyl ether mixture. The layers were separated and the aqueous layer was back-extracted with diethyl ether. The organic layers were combined and concentrated under reduced pressure. The residue was purified by flash column chromatography using 50% ethyl acetate in hexane to give the title compound. _{C 26 H 25 F 2 N 3} 0 2 (MW = 449.50); mass spectroscopy (MH +) 450. Elemental analysis: Calculated for _{C 26 H 25 F 2 N 3} 0 2; C 69.47, H 5.61, N 9.35, F 8.45. Found: C 69.55, H 5.63, N 9.21, F 8.30.

Examples 7 and 8 5 (S)-(N ′-(2 (R) -hydroxy-2- (3,5-difluorophenyl) ethyl) -L-alaninyl
) -Amino-7-methyl-5,7-dihydro-6H-dibenz [b, d] azepin-6-one and (S)-(N ′-(2 (S) -hydroxy- (3,5- Difluorophenyl) ethyl) -L-alaninyl)-
Synthesis of amino-7-methyl-5,7-dihydro-6H-dibenz [b, d] azepin-6-one Following general procedure EB, 2- (3,5-difluorophenyl) -1,2-epoxyethane Using (Example EC1), the title compound was obtained as pure diastereomer after flash chromatography using 1: 1 hexane / ethyl acetate. . Ex 7 (less polar by _{TLC): C 26 H 25 F} 2 N 3 0 3 (MW = 465.50): mass spectrometry (MH +) 466.2 Elemental _{analysis: C 26 H 25 F 2 N} 3 0 3: C, 67.09 ; H, 5.41; N, 9.03. Found: C, 67.06; H,
5.67, N, 8.75. Ex. 8 (more polar with TLC): C ₂₆ H ₂₅ F ₂ N ₃ 0 ₃ (MW = 465.50); Mass spectrometry (MH +) 466.2 Elemental analysis: C ₂₆ H ₂₅ F ₂ N ₃ 0 ₃ : C, 67.09; H, 5.41; N, 9.03. Found: C, 67.04: H,
5.46. N, 8.89.

Example 9 5 (S)-(N ′-(2 (R / S) -hydroxy-3-isopropyloxy-propyl) -L-alaninyl)
Synthesis of -Amino-7-methyl-5,7-dihydro-6H-dibenz [b, d] azepin-6-one Following general procedure EB, using isopropyl glycidyl ether (Aldrich), 95:
The title compound was obtained as a diastereomer mixture after flash chromatography using 5 ethyl acetate / methanol. _{C 24 H 31 N 3 0 4} (MW = 425.53); mass spectroscopy (MH +) 426.2 Elemental _{analysis: C 24 H 31 N 3 0} 4:. C, 67.74; H, 7.34; N, 9.87 Found: C, 67.90 ; H, 7.40; N, 9.60.

Example 10 5 (S)-(N ′-(2 (R / S) -hydroxy-butyl) -L-alaninyl) -amino-7-methyl-5,7-dihydro-6H-benz [b Synthesis of, d] azepin-6-one Following general procedure EB, using 1,2-epoxybutane (Aldrich), 9: 1 ethyl acetate /
The title compound was obtained as a mixture of diastereomers after flash chromatography with methanol. _{C 22 H 27 N 3 0 3} (MW = 381.48); mass spectroscopy (MH +) 382.4 Elemental _{analysis: C 22 H 27 N 3 0} 3:. C, 69.27; H, 7.13; N, 11.02 Found: C, 69.51 ; H,
7.14; N, 10.76.

Example 11 5 (S)-(N ′-(2 (R / S), 3-dihydroxy-propyl) -L-alaninyl) -amino-7-methyl-
Synthesis of 5,7-dihydro-6H-dibenz [b, d] azepin-6-one Diastereomer mixture after flash chromatography using glycidol (Aldrich) and 7: 3 ethyl acetate / methanol according to general method EB To give the title compound. _{C 21 H 25 N 3 0 4} (MW = 383.45); mass spectroscopy (MH +) 384.3 Elemental _{analysis: C 21 H 25 N 3 0} 4:. C, 65.78; H, 6.57; N, 10.96 Found: C, 64.13 , H,
6.17; N, 9.84.

Example 12 5 (S)-(N ′-(2 (R / S) -hydroxy-3-morpholinopropyl) -L-alaninyl) -amino-7
Synthesis of 1-methyl-5,7-dihydro-6H-dibenz [b, d] azepin-6-one 9-acetic acid using 3-morpholino-1,2-epoxypropane (Transworld) according to general procedure EB The title compound was obtained as a mixture of diastereomers after flash chromatography using ethyl / methanol. _{C 25 H 32 N 4 0 4} (MW = 452.56); mass spectroscopy (MH +) 453.2 Elemental _{analysis: C 25 H 32 N 4 0} 4 of theory:. C, 66.35; H, 7.13; N, 12.38 Found: C,
65.45; H, 7.21; N, 11.37.

Example 13 5 (S)-(N ′-(2 (R / S) -hydroxy-tetradecyl) -L-alaninyl) -amino-7-methyl-
Synthesis of 5,7-dihydro-6H-dibenz [bd] azepin-6-one Following general procedure EB, using 1,2-epoxytetradecane (Aldrich) and flash chromatography using 100% ethyl acetate, diastereomeric mixture The title compound was isolated as _{C 32 H 47 N 3 0 3} (MW = 521.75); mass spectroscopy (MH +) 522.4 Elemental _{analysis: C 32 H 47 N 3 0} 3 of theory:. C, 73.67; H, 9.08, N, 8.05 Found: C, 7
3.77; H, 8.16; N, 8.11.

Example 14 5 (S)-(N ′-(2 (R / S) -hydroxy-octyl) -L-alaninyl) -amino-7-methyl-5,7-
Synthesis of dihydro-6H-dibenz [b, d] azepin-6-one Titled as a diastereomeric mixture after flash chromatography using 1,2-epoxyoctane (Aldrich) using 100% ethyl acetate according to general procedure EB. The compound was isolated. _{C 26 H 35 N 3 0 3} (MW = 437.58); mass spectroscopy (MH +) 438.2 Elemental _{analysis: C 26 H 35 N 3 0} 3 of theory:. C, 71.37; H, 8.06, N, 9.60 Found: C, 67
.61; H, 7.28; N, 8.93.

Examples 15 and 16 5 (S)-(N '-(2 (R) -hydroxy-2- (3,4,5-trifluorophenyl) ethyl) -L-alaninyl) -amino-7- Methyl-5,7-dihydro-6H-dibenz [b, d] azepin-6-one and
(S)-(N '-(2 (S) -hydroxy-2- (3,4,5-trifluorophenyl) ethyl) -L-alaninyl) -amino-7-methyl-5,7-dihydro-6H Synthesis of -dibenz [bd] azepin-6-one Following general procedure EB, 2- (3,4,5-trifluorophenyl) -1,2-epoxyethane (
Using Example EC2), the title compound was isolated as a pure diastereomer after flash chromatography using 100% ethyl acetate. Ex. 15 (less polar at TLC): C ₂₆ H ₂₄ F ₃ N ₃ 0 ₃ (MW = 483.49); mass spectrometry (MH +) 484.
5 Elemental _{analysis: C 26 H 24 F 3 N} 3 0 3 of theory:. C, 64.59; H, 5.00; N, 8.69 Found: C,
Ex. 16 (more polar by TLC): C ₂₆ H ₂₄ F ₃ N ₃ 0 ₃ (MW = 483.49); mass spectrometry (MH +) 484.
5 Elemental analysis: C ₂₆ H ₂₄ F ₃ N ₃ 0 ₃ Theoretical: C, 64.59; H, 5.00; N, 8.69.
64.71; H, 4.93; N, 8.74.

Examples 17 and 18 5 (S)-(N ′-(2 (R) -hydroxy-2- (4- (trifluoromethyl) phenyl) ethyl) -L-alaninyl) -amino-7-methyl -5,7-dihydro-6H-dibenz [b, d] azepin-6-one and 5 (S)-(N '-(2 (S) -hydroxy-2- (4- (trifluoromethyl) phenyl ) Ethyl) -L-alaninyl) -amino-7-methyl-5,7-dihydro-6H-dibenz [b, d] azepin-6-one Following general procedure EB, 2- (4- (trifluoro The title compound was isolated as a pure diastereomer after flash chromatography using 100% ethyl acetate using (methyl) phenyl) -1,2-epoxyethane (Example EC3). Ex. 17 (less polar at TLC): C ₂₇ H ₂₆ F ₃ N ₃ 0 ₃ (MW = 497.52), mass spectrometry (MH +) 498.
3 Elemental analysis: C ₂₇ H ₂₆ F ₃ N ₃ 0 ₃ Theoretical value: C, 65.18, H, 5.27, N, 8.45.
.. 64.60; H. 5.31; N , 8.32 Ex 18 ( more polar and more in _{TLC): C 27 H 26 F} 3 N 3 0 3 (MW = 497.52); mass spectroscopy (MH +) 498.
3 Elemental analysis: Calculated for _{C 27 H 26 F 3 N 3} 0 3:. C, 65.18; H, 5.27; N, 8.45 Found: C,
66.12; H, 5.46; N, 8.77.

Examples 19 and 20 5 (S)-(N '-(2 (R) -hydroxy-2- (3,5-bis- (trifluoromethyl) phenyl) ethyl) -L-alaninyl) -amino -7-methyl-5,7-dihydro-6H-dibenz [b, d] azepine-
6-one and 5 (S)-(N '-(2 (S) -hydroxy-2- (3,5-bis- (trifluoromethyl) phenyl) ethyl) -L-alaninyl) -amino-7- Methyl-5,7-dihydro-6H-dibenz [b, d] azepine-
Synthesis of 6-one Flash chromatography using 100% ethyl acetate using 2- (3,5-bis- (trifluoromethyl) phenyl) -1,2-epoxyethane (Example EC4) according to general method EB. The title compound was later isolated as a pure diastereomer. Ex. 19 (less polar at TLC): C ₂₈ H ₂₅ F ₆ N ₃ 0 ₃ (MW = 565.52); mass spectrometry (MH +) 566.
5 Elemental _{analysis: C 28 H 25 F 6 N} 3 0 3 of theory:. C, 59.47, H, 4.46 N, 7.43 Found:. C,
Ex. 20 (more polar by TLC): C ₂₈ H ₂₅ F ₆ N ₃ 0 ₃ (MW = 565.52); mass spec (MH +) 566.
5 Elemental _{analysis: C 28 H 25 F 6 N} 3 0 3 of theory: C, 59.47: H, 4.46 , N. 7.43 Found:. C,
59.51; H, 4.40; N. 7.26.

Examples 21 and 22 5 (S)-(N '-(2 (R) -hydroxy-2- (3,3,3-trifluoro) -propyl) -L-alaninyl)
-Amino-7-methyl-5,7-dihydro-6H-dibenz [b, d] azepin-6-one and 5 (S)-(N '-(2 (S) -hydroxy-2- (3,3 , 3-Trifluoro) -propyl) -L-alaninyl)
Synthesis of -Amino-7-methyl-5,7-dihydro-6H-dibenz [b, d] azepin-6-one Following general procedure EA, 3,3,3-trifluoro-1,2-epoxypropane ( Lancaster)
The title compound was isolated as a pure diastereomer after flash chromatography using 100% ethyl acetate. Ex. 21 (less polar at TLC): C ₂₁ H ₂₂ F ₃ N ₃ 0 ₃ (MW = 421.42); mass spectrometry (MH +) 422.
1 Elemental analysis: C ₂₁ H ₂₂ F ₃ N ₃ 0 ₃ Theoretical: C, 59.85; H, 5.26; N, 9.97. Found: C,
Ex. 22 (more polar at TLC): C ₂₁ H ₂₂ F ₃ N ₃ 0 ₃ (MW = 421.42); mass spec (MH +) 422.
1 Elemental _{analysis: C 2l H 22 F 3 N} 3 0 3 of theory:. C, 59.85; H, 5.26; N, 9.97 Found: C.,
59.42; H, 5.37; N, 9.85.

Example 23 5- (S)-(N ′-(3-methyl-2-butanone) -L-alaninyl) -amino-7-methyl-5,7-dihydro-6H-dibenz [b, d Synthesis of] azepin-6-one 5- (S)-[L-alaninyl] -amino-7-methyl-5,7-dihydro-6H in dichloromethane
A solution of -dibenz [b, d] azepin-6-one hydrochloride (Example 7B, 1.0 eq) was added at 0 ° C with DIEA (
2 eq). Bromo-3-methyl-2-butanone in dichloromethane (2 e
q; Org. Syn., 1988, Coll. Vol6, p193, the contents of which are incorporated herein by reference.
) Was added dropwise from the addition funnel. The reaction mixture was warmed to room temperature and continued stirring for 17 hours. The stirring was stopped and the solvent was removed under reduced pressure to give a yellow oil. This oil was purified by silica gel radial chromatography using ethyl acetate as eluent to give the title compound. ^{The 1} H NMR data is as follows: ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.64 (1 H d, J = 7.8 Hz), δ 7.59-7.22 (8H m), δ
5.30 (1H d, J = 7.8 Hz), δ3.81 (1H d, J = 19.1 Hz), δ3.39 (1H d, J = 19.1 Hz)
), δ3.29 (3H s), δ3.07 (1H q, J = 6.8 Hz), δ2.63-2.54 (1H m) δ1.22 (3
H d, J = 7.1 Hz) , δ1.15-1.02 (6H m). C 23 H 27 N 3 0 3 (MW = 393.48), mass spectrometry (MH +) 394.

Example 24 5- (S)-(N ′-(3-methyl-2- (S) -hydroxybutyl) -L-alaninyl) -amino-7-methyl-5,7-dihydro-6H- Synthesis of dibenz [b, d] azepin-6-one 5- (S)-(N ′-(3-methyl-2- (S)-(2-trimethylsilylethyloxy) methyloxybutyl ) -L-Alaninyl) -amino-7-methyl-5,7-dihydro-
The title compound was prepared using 6H-dibenz [b, d] azepin-6-one (intermediate A). _{C 23 H 29 N 3 0 3} (MW = 395.51); mass spectroscopy (MH +) 396. Elemental analysis:. Theoretical value of _{C 23 H 29 N 3 0 3} ; C 69.85, H 7.39, N 10.62 Found: C 69.74
, H 7.45, N 10.52.

Example 25 3- (N ′-(3-methyl-2- (S) -2- (hydroxybutyl) -L-alaninyl) -amino-2,4-dioxo-1-methyl-5-phenyl Synthesis of -2,3,4,5-tetrahydro-1H-1,5-benzodiazepine According to the above general method ED, 3- (N ′-(3-methyl-2- (S) -2- (trimethylsilyl) ethyl (Oxymethyloxybutyl) -L-alaninyl) -amino-2,4-dioxo-1-methyl-5-
The title compound was prepared using phenyl-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine (Intermediate B). _{C 24 H 30 N 4 0 4} (MW = 438.53); mass spectroscopy (MH +) 439. Elemental analysis:. Theoretical value of _{C 24 H 3O N 4 0 4} ; C 65.73, H 6.90, N 12.78 Found: C 63.76 ,
H 6.81, N 12.22

Example 26 3- (N ′-(2- (R / S) -3,5-difluorophenyl-2-hydroxyethyl) -L-alaninyl)-
Synthesis of amino-2,4-dioxo-1-methyl-5-phenyl-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine 3-amino-2,4-dioxo -1-methyl-5-phenyl-2,3,4,5-
Tetrahydro-1H-1,5-benzodiazepine (CAS No. 131604-75-6) and N- (2- (R /
The title compound was prepared using S) -3,5-difluorophenyl-2-hydroxyethyl) -L-alanine (Intermediate C). _{C 27 H 26 F 2 N 4} 0 4 (MW = 508.52); mass spectroscopy (MH +) 509. Elemental analysis:. Theoretical value of _{C 27 H 26 F 2 N 4} 0 4; C 63.77, H 5.15, N 11.02 Found Value: C 63
.57, H 5.65, N 9.74.

Example 27 5- (S)-{N ′-[(1RS, 2SR) -1,2,3,4-tetrahydro-1-hydroxy-2-naphthyl] alaninyl} -amino-7-methyl- Synthesis of 5,7-dihydro-6H-dibenz [b, d] azepin-6-one Step A Synthesis of 1,2,3,4-tetrahydro-naphthalen-1,2-dione-2-oxime To a mixture of t-BuOK (1.2 eq.) In THF was added isoamylnitrile in THF (1.2
eq.) and α-tetralone (Aldrich) (1.0 eq.) were added dropwise. The reaction mixture was warmed to room temperature and stirred at room temperature for 2 hours. The reaction mixture was dried and stripped, mixed with ice-cold HCl (1M), extracted with EtOAc, washed with brine, dried over MgSO _4, filtered,
It was then concentrated. The residue was purified by flash chromatography (silica gel, 2: 1 hexane / EtOAc) to give the title compound. C ₁₀ H ₉ NO ₂ (MW = 175.186); Mass spectrometry (MH ⁺ ) 176. Elemental analysis: C ₁₀ H ₉ NO ₂ theoretical: C, 68.56 H, 5.18 N, 8.00; found: C, 68.81
H, 5.20 N 7.98.Step B Synthesis of (1,2,3,4-tetrahydro-1-hydroxy-2-naphthyl) -amine The compound (1.0 eq.) Produced in Step A above was dissolved in THF, and 0 Cooled to ° C. THF (1
LAH in M) (2.0 eq.) Was added slowly. The reaction mixture was warmed to room temperature. The reaction mixture was stirred overnight at room temperature. The reaction mixture was cooled in an ice bath, then worked up with EtOH and saturated sodium potassium tartrate solution and extracted with CH ₂ Cl _2, washed with brine and dried over Na ₂ SO _4. The residue was purified by acid / base extraction to give the title compound. C ₁₀ H ₁₃ NO (MW = 163.219); mass spectrometry (MH +) 164.

Step C Synthesis of N ′-(1,2,3,4-tetrahydro-1-hydroxy-2-naphthyl) -alanine ethyl ester Ethyl-D-lactate (Fluka) and B The title compound was prepared using the compound prepared in the above. _{C 15 H 21 N0 3 (MW} = 263.335);. Mass spectrometry (MH ⁺⁾ 264 Step D N- (3a, 4,5,9b- tetrahydronaphth [2,1-d] oxazol -2 (3H) - On )
- (. 1 eq) Synthesis 0 ℃ alanine ethyl ester, under nitrogen, to a solution of the compound prepared in Part C in _{CH 2 Cl 2, CH 2 Cl} 2
Et ₃ N (1 eq.) And carbonyldiimidazole (1 eq.) In were added and the mixture was stirred for 3 hours. Further, add 1 eq. Of carbonyldiimidazole in CH ₂ Cl ₂ and add
Stirred for hours. The reaction mixture was stirred at room temperature for 3 hours. Add water, stir for 15 minutes, C
And extracted with H ₂ Cl _2, washed with water, dried over Na ₂ SO _4, filtered, then concentrated. The residue was purified by flash chromatography (silica gel, 2: 1 hexane / EtOAc),
The title compound was obtained. C ₁₆ H ₁₉ NO ₄ (MW = 289.329); mass spectrometry (MH ⁺ ) 290.

Step E N- (3a, 4,5,9b-tetrahydronaphthal [2,1-d] oxazol-2 (3H) -one)-
Synthesis of alanine According to General Method 11-A and Method B, the title compound was prepared using the compound prepared in D above.
Manufactured. C₁₄H_FifteenNO_Four (MW = 261.276), mass spectrometry (MH +) 262. Step F 5- (S)-{N '-[(3a RS, 9a SR) -3a, 4,5,9b-tetrahydronaphtha [2,1-d ] Oh
Xazol-2 (3H) -one] -alaninyl} -amino-7-methyl-5,7-dihydro-6H-dibe
Synthesis of benzo [b, d] azepin-6-one The compound prepared in E above and 5- (S) -amino-7-methyl-5,
Labeled with 7-dihydro-6H-dibenz [b, d] azepin-6-one hydrochloride (Example 7A)
The mixture was prepared by flash chromatography (silica gel, 5% MeOH / CH)._TwoCl _Two ). C₂₉H₂₇N_Three0_Four(MW = 481.549); mass spectrometry (MH⁺482. Elemental analysis: C₂₉H₂₇N_Three0_FourTheory of: C, 72.33 H, 5.65 N, 8.73; Found: C, 72.44
 H, 5.90 N 8.55.

Step G 5-S- {N ′-[(1RS, 2SR) -1,2,3,4-tetrahydro-1-hydroxy-2-naphthyl
] Alaninyl} amino-7-methyl-5,7-dihydro -6H- dibenz [b, d] azepin-6-one Synthesis of F EtOH / H ₂ 0 the compound prepared in (2: 1) 2N in The mixture was heated under reflux with NaOH for 20 minutes. The reaction mixture was dried and stripped, extracted with EtOAc, washed with water, then dried over Na ₂ SO _4. To give the title compound as a mixture of four diastereomers by evaporation and SCX column purification _{[5% MeOH (7N NH 3} ) / CH 2 Cl 2]. _{. C 28 H 29 N 3 0} 3 (MW = 455.555); mass spectroscopy (MH ⁺⁾ 456 Elemental _{analysis: C 28 H 29 N 3 0} 3: C, 73.82 H, 6.42 N, 9.22; Found: C, 73.87 H, 6.30
N 9.46. 4 single isomers, HPLC (reverse phase, H ₂ 0 / CH ₃ CN containing 0.1% TFA), SCX column purification [5%
MeOH (7N NH ₃ ) / CH ₂ Cl ₂ ] and chromatography [silica gel, 5% MeOH (7N NH ₃ ) /
CH ₂ Cl ₂ ]: Isomer 1: ¹ H-nmr (CDCl ₃ ): δ = 8.20 [d, 1H, (-CONH-)] Isomer 2: ¹ H-nmr (CDCl ₃ ): δ = 8.38 [d, 1H, (-CONH-)] isomer 3: ¹ H-nmr (CDCl ₃ ): δ = 8.60 [d, 1H, (-CONH-)] isomer 4: ¹ H-nmr ( CDCl ₃ ): δ = 9.03 [d, 1H, (-CONH-)]

Example 28 5- (S)-{N ′-[(1RS, 2RS) -1,2,3,4-tetrahydro-1-hydroxy-2-naphthyl] arani
Synthesis of nil} -amino-7-methyl-5,7-dihydro-6H-dibenz [b, d] azepin-6-one
Step A N-[(1RS, 2RS) -1,2,3,4-tetrahydro-1-hydroxy-2-naphthyl] -ara
Synthesis of Nin Ethyl Ester According to general method AM, ethyl-D-lactate (Fluka) and N-[(1RS, 2RS) -1,2,3
, 4-Tetrahydro-1-hydroxy-2-naphthyl] -amine (Liebigs Ann. Chem. 1992,
 pp 273, the contents of which are incorporated herein by reference) to produce the title compound.
. C_FifteenH_{twenty one}NO_Three (MW = 263.335), mass spectrometry (MH⁺264. Step B N-[(1RS, 2RS) -1,2,3,4-tetrahydro-1-hydroxy-2-naphthyl] -ara
Synthesis of Nin lithium salt Compound prepared in A above according to General Method II-A, Method B (but without post treatment)
The reaction mixture was stripped and dried using to afford the title compound. C₁₃H₁₆NO_ThreeLi (MW = 241.241); mass spectrometry (MH⁺242. Step C 5- (S)-{N '-[(1RS, 2RS) -1,2,3,4-tetrahydro-1-hydroxy-2-naphthy
Ru] -Alaninyl} -amino-7-methyl-5,7-dihydro-6H-dibenz [b, d] azepine-6-
Synthesis of ONThe compound prepared in B above and 5- (S) -amino-7-methyl-5,
Using 7-dihydro-6H-dibenz [b, d] azepin-6-one hydrochloride (Example 7A), three
The title compound was prepared as a mixture of diastereomers of this, which was purified by HPLC (reverse phase, CH _Three CN / H_Two0% in 0.1% TFA) and SCX column [5% MeOH (7N NH_Three) / CH_TwoCl_Two]
The isomers were obtained: Isomer 1:¹H-nmr (CDCl_Three): δ = 8.70 [d, 1H, (-CONH-)]; C₂₈H₂₉N_Three0_Three (MW = 455.
555); mass spectrometry (MH⁺456. Isomer 2:¹H-nmr (CDCl_Three): δ = 9.31 [d, 1H, (-CONH-)]; C₂₈H₂₉N_Three0_Three (MW = 455.
555); mass spectrometry (MH⁺) 456 Elemental analysis: C₂₈H₂₉N_Three0_ThreeTheoretical value for: C, 73.82 H, 6.42
N, 9.22; Found: C, 74.05 H, 6.51 N 8.96. Mixture of isomers 2 and 3:¹H-nmr (CDCl_Three): δ = 9.31 [d, (-CONH-)], 8
.95 [d, (-CONH-)]; C₂₈H₂₉N_Three0_Three(MW = 455.555); mass spectrometry (MH⁺) 456; Elemental analysis:
1/4 H_TwoC including 0₂₈H₂₉N_Three0_ThreeTheory of: C, 73.09 H, 6.48 N, 9.14; Found: C, 7
3.08 H. 6.77 N 8.79.

Example 29 5- (S)-[N ′-(2-α-tetralone) -L-alaninyl] -amino-7-methyl-5,7-dihydro-6
Synthesis of H-dibenz [b, d] azepin-6-one hydrochloride According to General Method 6-A, 5- (S)-{N ′-[(1RS, 2RS) -1,2,3,4- Tetrahydro-1-hydroxy-2-naphthyl] -L-alaninyl} -amino-7-methyl-5,7-dihydro-6H-dibenz [b, d] azepin-6-one and isomers obtained from Example 29 The free base of the title compound is prepared as a mixture of two diastereomers using a mixture of 2 and 3,
This was treated with HCl / dioxane, respectively, to give the hydrochloride isomer 1 and isomer 2. Isomer 1: Exact Mass analysis: Calculated for _{C 28 H 28 N 3 0 3} = 454.2131, Found 454.2135; Elemental _{analysis: C 28 H 27 N 3 0} 3 of theory including 1/2 dioxane: C. 67.46 H, 6.05 N, 7.8
. 7; Found: C, 67.06 H, 5.74 N 7.49 Isomer 2: Exact Mass analysis: Calculated for _{C 28 H 28 N 3 0 3} = 454.2131; Found 454.2126; Elemental analysis: C ₂₈ containing 1 dioxane H ₂₉ N ₃ 0 ₃ of theory: C, 66.48 H, 6.29 N , 7.27;
Found: C, 66.32 H, 5.97 N 7.42.

Example 30 5- (S)-[N ′-(1,2,3,4-tetrahydro-2-naphthyl) -L-alaninyl] -amino-7-methyl-5,7-dihydro-6H Of 5-Dibenz [b, d] azepin-6-one 5- (S)-(L-alaninyl) -amino-7-methyl-5,7-dihydro-6H-dibenz [b, d] azepin-6- ON (Example 7-B) (1.00 eq.), Β-tetralone (Aldrich) (1.00 eq.),
And a mixture of titanium (IV) isopropoxide (Aldrich) (1.25 eq.) Was stirred at room temperature for 1 hour and then diluted with MeOH. NaBH ₃ CN (0.67 eq.) Was added, and the mixture was stirred at room temperature overnight. Add water, dilute with EtOAc, filter and then concentrate to give a residue.
This was applied to an SCX column [3% MeOH (7N NH ₃ ) / CH ₂ Cl ₂ ] and flash chromatography [
Purification on silica gel, 3% MeOH (7N NH ₃ ) / CH ₂ Cl ₂ ] gave the title compound. _{. C 28 H 29 N 3 0} 2 (MW = 439.556); mass spectroscopy ^{(MH +) 440 1 H-} nmr (CDCl 3): δ = 9.50 (m, 1H), 7.60-7.11 (m, 12H), 5.28 -5.20 (m, 1H), 3.
39-2.86 (m, 8H), 2.15-2.10 (m, 1H), 1.56-1.21 (m, 6H).

Example 31 5- (S)-{N ′-[(1RS, 2SR) -1-hydroxy-2-cyclohexyl] alaninyl} -amino-7-
Synthesis of methyl-5,7-dihydro-6H-dibenz [b, d] azepin-6-one According to the method of Example 28, the title compound was prepared using cis-2-aminocyclohexanol hydrochloride (ACROS). . .. Exact Mass _{spectrometry: C 24 H 31 N 3 0} 3 of theory: 408.2287 Found 408.2283 Elemental _{analysis: C 24 H 29 N 3 0} 3 of theory: C, 70.74 H, 7.17 N , 10.31; Found: C, 70.
72 H, 7.23 N 10.41.

Example 32 5- (S)-[N ′-(4-methylpentyl) -L-alaninyl] -amino-7-methyl-5,7-dihydro-
Synthesis of 6H-dibenz [b, d] azepin-6-one 5- (S)-(L-alaninyl) -amino-7-methyl-5,7-dihydro-6H-dibenz in MeOH
b, d] azepin-6-one (Example 7-B) (2.00 eq.) was added to a few drops of HCl-MeOH, 4-methyl-1-pentanal (1.00 eq.) (Tetrahedron Letter, No. 31, 1975, pp2647 (
This content was made according to the method described in (2), and molecular sieves were added. NaBH ₃ CN (0.67 eq.) Was added. HCl-MeOH was added to maintain the pH of the reaction mixture at 5-6. The reaction mixture was stirred at room temperature. The reaction mixture was basified, extracted with EtOAc, dried over Na ₂ SO _4. Concentration and flash chromatography [silica _{gel, 5% MeOH (7N NH 3} ) / CH 2 Cl 2] to give the title compound. Exact Mass _{spectrometry: C 24 H 32 N 3 0} 2 of theory:. 394.2495; found 394.2499 Elemental _{Analysis: 4/5 H C 24 H 31 N} 3 0 2 of theory containing ₂ 0: C, 70.66 H, 8.07 N, 10.30; Found: C, 70.25 H, 7.58 N 10.64.

Example 33 Cell Screening to Detect Inhibitors of β-Amyloid Production The compounds of formula I above were assayed for their ability to inhibit β-amyloid production in cell lines harboring the Swedish mutation. This screening assay
Are described in International Patent Publication 94/10569 ⁸ and ¹² of the method described by Citron et al.,
Cells stably transfected with the gene for amyloid precursor protein 751 (APP751) containing a double mutation from Lys ₆₅₁ Met ₆₅₂ to Asn ₆₅₁ Leu ₆₅₂ (numbered APP751) (K293 = human kidney cell line) )It was used. This mutation is commonly referred to as the Swedish mutation and is described in “293 75
1 SWE "Corning 96-wells in Dulbecco's minimal essential medium (Sigma, St. Louis, MO) plus 10% fetal calf serum at a rate of 2-4 x 10 ⁴ cells / well. Plated on plate. Cell number is important to achieve β-amyloid ELISA (ELISA) results within the linear range of the assay (approximately 0.2-2.5 ng / ml).

After overnight incubation at 37 ° C. in an incubator equilibrated with 10% carbon dioxide, the medium was removed during the 2 h pretreatment and the compound of formula I (drug) (2
(00 μL / well) and the cells were incubated as described above. The drug stock should be such that the concentration of dimethylsulfoxide at the final drug concentration used in the process does not exceed 0.5%, in practice usually 0.1%.
Prepared in 100% dimethyl sulfoxide.

At the end of the pretreatment period, the media was again removed, replaced with media containing the new drug as described above, and the cells were incubated for an additional 2 hours. After treatment, plates were centrifuged in a Beckman GPR (1200 rpm) for 5 minutes at room temperature to pellet cell debris from the conditioned media. From each well, conditioned media or appropriate dilutions (100 [mu] L), antibody 266 against β- amyloid peptide amino acids 13-28 described in International Patent Publication 94/10569 ⁸ [P. Seubert
According to Nature (1992) 359: 325-327] and transferred to ELISA plates previously coated with ^17, and stored overnight at 4 ° C.. The next day, amino acid 1 of β-amyloid peptide
3D6 [Nature (1992) 359: 325-327 by P. Seubert]
The amount of β-amyloid peptide produced was determined by performing an ELISA test using ¹⁷ .

[0612] The cytotoxic effects of these compounds were determined by a modification of the method of Hansen et al ^18. 3- (4,5-dimethylthiazole-2) was added to the cells remaining in the tissue culture plate.
-Yl) -2,5-diphenyltetrazolium bromide (MTT) (Sigma, St. Louis, MO) (25 μL) (5 mg / mL) was added, and the final concentration was 1 mg.
/ ML. The cells were incubated at 37 ° C. for 1 hour and the MTT lysis buffer (2
0% w / v sodium dodecyl sulfate 50% dimethylformamide, pH 4.
The cell activity was stopped by adding an equivalent amount of 7). Complete extraction was achieved by shaking at room temperature overnight. The difference between OD _{562 nm} and OD _{650 nm} as an indicator of cell viability, molecular devices UV _max microplate recorder (Molecular Device's UV _max micropla
te reader).

The results of the β-amyloid peptide ELISA method were fitted to a standard curve and expressed as β-amyloid peptide (ng / mL). To normalize for cytotoxicity, these results were divided by the MTT results and expressed as a percentage of the results obtained from the no drug control. All results are the average and standard deviation of at least 6 replicate assays.

Using this assay, test compounds were assayed for activity in inhibiting β-amyloid peptide production in cells. The results of this assay showed that when using 10 μg / mL, the compound of formula I inhibited the production of β-amyloid peptide by at least 30% compared to the control.

Example 34 In Vivo Inhibition of β-Amyloid Release and / or Synthesis Thereof This example illustrates in vivo inhibition of β-amyloid release and / or its synthesis of compounds of the present invention. For these experiments, PDAPP mice (age:
3-4 months) [Nature 1 373: 523-527 (1995) by Games et al.] ¹⁹ .
Depending on the compound tested, the compound will usually be formulated in a range of 1-10 mg / mL. Due to the low solubility factor of these compounds, they are available in a variety of vehicles, such as corn oil (Safeway, South San Francisco, CA); corn oil in 10% ethanol; 2-hydroxypropyl-β-cyclodextrin (Research Biochemicals).・ International (Research Biochemicals International, Natic
k MA); and carboxy-methyl-cellulose (Sigma, St. Louis MO)
It can be formulated together with.

Mice were injected subcutaneously with a 26 gauge needle, 3 hours later the animals were euthanized with CO ₂ anesthesia and the blood was coated with a 0.5 M EDTA (pH 8.0) solution in 1 cc 25G 5/8 ”tuberculin. The blood was collected by cardiac puncture using a syringe / needle, and the blood was placed in a Becton-Dickinson vacutainer tube containing EDTA and centrifuged (1500 × g) at 5 ° C. for 15 minutes. The mouse brain was then removed and the cortex and hippocampus dissected and placed on ice.

[0617] 1. Brain Assays To produce hippocampus and cortical tissue for enzyme-linked immunosorbent assays (ELISAs), each brain region was treated with 10 volumes of ice-cold guanidine buffer (5.0 M guanidine-HCl, 50 mM Tris-HCl, pH 8. In 0), homogenized using a Contes motorized pestle (Fisher, Pittsburgh, PA). The homogenate was gently shaken on a rotating platform at room temperature for 3-4 hours and stored at -20 ° C until the determination of β-amyloid.

The brain homogenate was added to ice-cold casein buffer [0.25% casein, phosphate buffered saline (PBS), 0.05% sodium azide, 20 μg / ml.
Aprotinin, 5 mM EDTA, pH 8.0, 10 μg / ml leupeptin], thereby reducing the final concentration of guanidine to 0.5 M, followed by centrifugation (16, 000xg). If necessary, the sample is further diluted by the addition of casein buffer supplemented with guanidine / hydrochloric acid (0.5 M) to achieve the optimal range for ELISA measurement. The β-amyloid standard solution (1 to
40, or 1-42 amino acids) was made so that the final composition was equal to 0.5 M guanidine in the presence of 0.1% bovine serum albumin (BSA).

The total β-amyloid sandwich ELISA method, which quantifies both β-amyloid (aa 1-40) and β-amyloid (aa 1-42), comprises two monoclonal antibodies (mAb) against β-amyloid. Consists of Capture antibody 266 [Nature (1992) 359: 325-327 by P. Seubert] ¹⁷ is specific for amino acids 13-28 of β-amyloid. Amino acid 1 of β-amyloid
Antibody 3D6 [PNAS USA by Johnson-Wood et al. (1997
) 94: 1550-1555] ²⁰ is biotinylated and the reporter (repo
rter) works as an antibody. The 3D6 biotinylation process uses the N-type immunoglobulin except that a 100 mM sodium bicarbonate buffer (pH 8.5) is used.
The protocol for the product of manufacture (Pierce, Rockford IL) for HS-biotin labeling is used. The 3D6 antibody uses a secreted amyloid precursor protein (APP)
) Or full-length APP and only β-amyloid species with an amino-terminal aspartic acid are detected. The assay has a lower limit of sensitivity: ~ 50 pg / ml (11P
M) and does not show cross-reactivity to endogenous mouse β-amyloid peptide at concentrations up to 1 ng / ml.

In a sandwich-type ELISA setup to quantify β-amyloid (aa 1-42) levels, mAb21F12 [PNAS USA (1997) 94 by Johnson-Wood et al.
: 1550-1555] ^20, which recognizes amino acids 33-42 of β-amyloid, is used as the capture antibody. Biotinylated 3D6 is a reporter antibody with a lower limit of sensitivity in this assay: １２５125 pg / ml (28 PM).

The 266 and 21F12 captured mABs are coated at 10 μg / ml in 96-well immunoassay plates (Costar, Cambridge, Mass.) At room temperature overnight. The plate is then aspirated and 0.25% human serum albumin in PBS
Protect with buffer for at least 1 hour at room temperature, then store dry at 4 ° C. until use. Prior to using the plate, wash buffer (Tris-buffered saline, 0.05% Twee
n Rehydrate with 20). Add samples and standards to the plate and incubate at 4 ° C overnight. The plates were washed three or more times with wash buffer during each step of the assay. Casein incubation buffer (0.25% casein, PBS,
Biotinylated 3D6 diluted to 0.5 μg / ml in 0.05% Tween 20, pH 7.4) is incubated in the wells for 1 hour at room temperature. Avidin-HRP (Vector, Burl) diluted 1: 4000 in casein incubation buffer
ingame CA) is added to the wells at room temperature over 1 hour. Colorimetric substrate, Slow TM
Add B-ELISA (Pierce, Cambridge MA) and react for 15 minutes, then 2N
H ₂ SO _{4 is} added to stop the enzyme reaction. The reaction product is quantified by measuring the difference in absorbance at 450 nm and 650 nm using a molecular device V _max (Menlo Park CA).

[0622] 2. Blood assay EDTA plasma was diluted with a standard diluent (sodium phosphate / H ₂ O (monobasic) (0.2 g).
m / l), sodium phosphate 7H ₂ O (dibasic) (2.16 gm / l), thimerosal (0.5 gm / l), sodium chloride (8.5 gm / l)
, Triton X-405 (0.5 ml), globulin-free bovine serum albumin (6.0 g / l; and water). The brain assays were performed using the total β-amyloid assay described above (266 capture / 3D6 reporter), except that the standard diluent was used instead of the casein diluent described above. Assay samples and standards in the product diluent.

Other formulation components than those described above can also be used for oral and intravenous delivery to humans. For oral delivery, the compound is mixed with 100% corn oil, or 80% corn oil, 19.5% oleic acid and 0.5
% Labrafil can be mixed in a solution containing% labrafil. The compound can be mixed with the above solutions at concentrations ranging from 1 mg / mL to 10 mg / mL. The compound in solution is preferably administered orally to humans at a dose of 5 mL / body weight (kg). For IV derivatives, the compound is preferably mixed with a solution of 3% ethanol, 3% solutol HS-15 and 94% brine. The compound is preferably mixed with the above solution at a concentration of 0.25 mg / mL to 5 mg / mL. The compound in solution is administered at a dose of 2 mL / body weight (kg
It is preferred to orally administer IV in humans in).

From the foregoing description, various modifications and variations in the compositions and methods will be made by those skilled in the art. It is intended to include all such modifications that fall within the scope of the claims.

──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. ⁷ Identification symbol FI Theme coat ゛ (Reference) C07D 223/16 C07D 223/16 4C086 243/10 243/10 243/12 243/12 243/24 243/24 267/14 267/14 281/10 281/10 401/04 401/04 409/04 409/04 409/12 409/12 417/04 417/04 471/04 121 471/04 121 471/06 471/06 471/08 471/08 487/04 151 487/04 151 (81) Designated country EP (AT, BE, CH, CY, DE, DK, ES, FI, FR, GB, GR, IE, IT, LU, MC, NL, PT, SE), OA (BF, BJ, CF, CG, CI, CM, GA, GN, GW, ML, MR, NE, SN, TD, TG), AP (GH, GM, KE) , LS, MW, SD, SL, SZ, UG, ZW), EA (AM, AZ, BY, G, KZ, MD, RU, TJ, TM), AL, AM, AT, AU, AZ, BA, BB, BG, BR, BY, CA, CH, CN, CU, CZ, DE, DK, EE, ES , FI, GB, GD, GE, GH, GM, HR, HU, ID, IL, IN, IS, JP, KE, KG, KP, KR, KZ, LC, LK, LR, LS, LT, LU, LV, MD, MG, MK, MN, MW, MX, NO, NZ, PL, PT, RO, RU, SD, SE, SG, SI, SK, SL, TJ, TM, TR, TT, UA, UG , US, UZ, VN, YU, ZA, ZW (72) James E. Odia United States 46278 Lakeside Woods Circle No. 6449 Lakeside Woods Circle, Indianapolis, Indiana (72) Inventor Warren Jay Porter United States 46260 No. 8037 (72), Reaver Road, Indianapolis, Indiana Inventor Richard Sea Thompson United States 46041 No. 763, North County Road, 900 West, Frankfort, Indiana, United States 46041 (72) Inventor Stephen Sea Wilkie United States 46268 Quetico Drive, Indianapolis, Indiana No. 8229 (72) Inventor Douglas Earl Stack USA 46038 Fishers, Indiana Overcrest Drive No. 9755 (72) Inventor Shikin United States 46033 Carmel, Indiana Pen Eagle Drive 13138 No. F term (reference) 4C036 AB03 AB05 AB08 AB13 AB17 AB20 4C050 AA01 BB04 CC11 EE02 FF02 GG03 HH01 4C056 AA03 AB01 AC03 AD03 AE03 FA06 FA08 FA13 FB05 4C063 AA01 BB01 BB07 ACOA DDCC CC DD DDCC CC AA09 BB14 CC0 9 DD01 EE02 HH01 JJ01 KK02 LL04 PP01 4C086 AA01 AA02 AA03 BC32 BC56 BC92 CB11 MA01 MA04 NA14 ZA16

Claims (38)

[Claims] 1. A method for inhibiting the release and / or synthesis of β-amyloid peptide in a cell, the method comprising an amount of a β-amyloid peptide effective in inhibiting the release and / or synthesis of the β-amyloid peptide in the cell. , Formula I: [Wherein W is Embedded image Embedded image And a cyclic group selected from the group consisting of Wherein ring A, together with the atoms to which it is attached, is a carbocyclic ring selected from the group consisting of aryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heteroaryl and heterocyclic; Forms a heterocyclic ring. Ring B, together with the atoms to which it is attached, is a carbocyclic or heterocyclic group selected from the group consisting of aryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heteroaryl and heterocyclic. Form a ring. Ring C, together with the atoms to which it is attached, forms heteroaryl and heterocyclic. Y is the formula: Indicated by R ¹ is alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, substituted alkyl, substituted alkenyl, substituted alkynyl, substituted cycloalkyl,
It is selected from the group consisting of substituted cycloalkenyl, aryl, heteroaryl, and heterocyclic. R ² is selected from the group consisting of alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, aryl, heteroaryl and heterocyclic. R ³ is selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, acyl, aryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heteroaryl and heterocyclic. It is. Each R ⁴ is independently alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, cycloalkyl, substituted cycloalkyl,
It is selected from the group consisting of cycloalkenyl, substituted cycloalkenyl, heteroaryl and heterocyclic. R ⁵ is hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, alkoxy, substituted alkoxy, aryl, aryloxy, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, substituted amino, heteroaryl , Heterocyclic, thioalkoxy and substituted thioalkoxy. Q is oxygen, sulfur, -S (O)-, -S (O) _2- , -C (O)-or -C (S)-. Z is represented by the formula: -T-CX'X "V- (where T is oxygen, sulfur, -N
R ⁶ (where R ⁶ is hydrogen, acyl, alkyl, aryl, or heteroaryl), and a bond consisting of —CX′X ″ — and a bond covalently bonding R ¹ . X "is hydrogen, hydroxy, or fluorine, or X 'and X" together form an oxo group. V is selected from the group consisting of alkylene or substituted alkylene Or R ¹ and Z together form an aryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heterocyclic, or substituted heterocyclic, where X is hydrogen, alkyl, substituted Alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, acyl, aryl, cycloalkyl, substituted cycle Alkyl, Shikuroarukeru, substituted cycloalkenyl, or selected from the group consisting of heteroaryl and heterocyclic, or X, one of R ⁴ and the atoms to which they are attached are taken together to form a double bond T is an integer of 0 to 2. f is an integer of 0 to 2. n is an integer of 1 or 2.] or a mixture of the compounds and a pharmaceutically acceptable salt thereof. which comprises administering to such cells (although, T is R ¹ and -CX'X "- when it is other than a covalent bond linking the, X 'and X" is a both hydroxy or fluorine obtain Absent). 2. A method for preventing the onset of Alzheimer's disease in a human patient at risk for developing Alzheimer's disease, comprising an effective amount of a compound of the formula I: Wherein W is Embedded image Embedded image And a cyclic group selected from the group consisting of Wherein ring A, together with the atoms to which it is attached, is a carbocyclic ring selected from the group consisting of aryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heteroaryl and heterocyclic; Forms a heterocyclic ring. Ring B, together with the atoms to which it is attached, is a carbocyclic or heterocyclic group selected from the group consisting of aryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heteroaryl and heterocyclic. Form a ring. Ring C, together with the atoms to which it is attached, forms heteroaryl and heterocyclic. Y is the formula: Indicated by R ¹ is alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, substituted alkyl, substituted alkenyl, substituted alkynyl, substituted cycloalkyl,
It is selected from the group consisting of substituted cycloalkenyl, aryl, heteroaryl, and heterocyclic. R ² is selected from the group consisting of alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, aryl, heteroaryl and heterocyclic. R ³ is selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, acyl, aryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heteroaryl and heterocyclic. It is. Each R ⁴ is independently alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, cycloalkyl, substituted cycloalkyl,
It is selected from the group consisting of cycloalkenyl, substituted cycloalkenyl, heteroaryl and heterocyclic. R ⁵ is hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, alkoxy, substituted alkoxy, aryl, aryloxy, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, substituted amino, heteroaryl , Heterocyclic, thioalkoxy and substituted thioalkoxy. Q is oxygen, sulfur, -S (O)-, -S (O) _2- , -C (O)-or -C (S)-. Z is represented by the formula: -T-CX'X "V- (where T is oxygen, sulfur, -N
R ⁶ (where R ⁶ is hydrogen, acyl, alkyl, aryl, or heteroaryl), and a bond consisting of —CX′X ″ — and a bond covalently bonding R ¹ . X "is hydrogen, hydroxy, or fluorine, or X 'and X" together form an oxo group. V is selected from the group consisting of alkylene or substituted alkylene Or R ¹ and Z together form an aryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heterocyclic, or substituted heterocyclic, where X is hydrogen, alkyl, substituted Alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, acyl, aryl, cycloalkyl, substituted cycle Alkyl, Shikuroarukeru, substituted cycloalkenyl, or selected from the group consisting of heteroaryl and heterocyclic, or X, one of R ⁴ and the atoms to which they are attached are taken together to form a double bond T is an integer of 0 to 2 f is an integer of 0 to 2 n is an integer of 1 or 2] or a mixture of the compounds and a pharmaceutically acceptable salt thereof, And a method comprising administering to the patient a pharmaceutical composition comprising a pharmaceutically inert carrier (provided that when T is other than a covalent bond linking R ¹ and —CX′X ″ —, X ′ And X "cannot both be hydroxy or fluorine). 3. A method of treating a human Alzheimer's disease patient to prevent the condition from further worsening, comprising treating the patient with an effective amount of a compound of the formula I: Wherein W is Embedded image Embedded image And a cyclic group selected from the group consisting of Wherein ring A, together with the atoms to which it is attached, is a carbocyclic ring selected from the group consisting of aryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heteroaryl and heterocyclic; Forms a heterocyclic ring. Ring B, together with the atoms to which it is attached, is a carbocyclic or heterocyclic group selected from the group consisting of aryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heteroaryl and heterocyclic. Form a ring. Ring C, together with the atoms to which it is attached, forms heteroaryl and heterocyclic. Y is the formula: Indicated by R ¹ is alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, substituted alkyl, substituted alkenyl, substituted alkynyl, substituted cycloalkyl,
It is selected from the group consisting of substituted cycloalkenyl, aryl, heteroaryl, and heterocyclic. R ² is selected from the group consisting of alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, aryl, heteroaryl and heterocyclic. R ³ is selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, acyl, aryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heteroaryl and heterocyclic. It is. Each R ⁴ is independently alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, cycloalkyl, substituted cycloalkyl,
It is selected from the group consisting of cycloalkenyl, substituted cycloalkenyl, heteroaryl and heterocyclic. R ⁵ is hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, alkoxy, substituted alkoxy, aryl, aryloxy, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, substituted amino, heteroaryl , Heterocyclic, thioalkoxy and substituted thioalkoxy. Q is oxygen, sulfur, -S (O)-, -S (O) _2- , -C (O)-or -C (S)-. Z is represented by the formula: -T-CX'X "V- (where T is oxygen, sulfur, -N
R ⁶ (where R ⁶ is hydrogen, acyl, alkyl, aryl, or heteroaryl), and a bond consisting of —CX′X ″ — and a bond covalently bonding R ¹ . X "is hydrogen, hydroxy, or fluorine, or X 'and X" together form an oxo group. V is selected from the group consisting of alkylene or substituted alkylene Or R ¹ and Z together form an aryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heterocyclic, or substituted heterocyclic, where X is hydrogen, alkyl, substituted Alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, acyl, aryl, cycloalkyl, substituted cycle Alkyl, Shikuroarukeru, substituted cycloalkenyl, or selected from the group consisting of heteroaryl and heterocyclic, or X, one of R ⁴ and the atoms to which they are attached are taken together to form a double bond T is an integer of 0 to 2 f is an integer of 0 to 2 n is an integer of 1 or 2] or a mixture of the compounds and a pharmaceutically acceptable salt thereof, And a method comprising administering to the patient a pharmaceutical composition comprising a pharmaceutically inert carrier (provided that when T is other than the covalent bond linking R ¹ and -CX'X "-, X 'and X "can be hydroxy or fluorine.) 4. The method according to claim 1, wherein n is 1. 5. The method according to claim 1, wherein ring A and ring B are independently selected from the group consisting of aryl, cycloalkyl, cycloalkenyl, heteroaryl and heterocyclic. A compound as described. 6. The compound according to claim 5, wherein Ring A and Ring B are independently aryl. 7. R¹Is phenyl, 1-naphthyl, 2-naphthyl, 2-chlorophen
Nyl, 2-fluorophenyl, 2-bromophenyl, 2-hydroxyphenyl, 2-nitro
Rophenyl, 2-methylphenyl, 2-methoxyphenyl, 2-phenoxyphenyl,
2-trifluoromethylphenyl, 4-fluorophenyl, 4-chlorophenyl, 4-butane
Lomophenyl, 4-nitrophenyl, 4-methylphenyl, 4-hydroxyphenyl,
4-methoxyphenyl, 4-ethoxyphenyl, 4-butoxyphenyl, 4-isopropyl
Phenyl, 4-phenoxyphenyl, 4-trifluoromethylphenyl, 4-hydro
Xymethylphenyl, 3-methoxyphenyl, 3-hydroxyphenyl, 3-nitroph
Phenyl, 3-fluorophenyl, 3-chlorophenyl, 3-bromophenyl, 3-pheno
Xyphenyl, 3-thiomethoxyphenyl, 3-methylphenyl, 3-trifluoromethyl
Tylphenyl, 2,3-dichlorophenyl, 2,3-difluorophenyl, 2,4-dichloro
Phenyl, 2,5-dimethoxyphenyl, 3,4-dichlorophenyl, 3,4-difluorophenyl
Phenyl, 3,4-methylenedioxyphenyl, 3,4-dimethoxyphenyl, 3,5-difur
Orophenyl, 3,5-dichlorophenyl, 3,5-di- (trifluoromethyl) phenyl
, 3,5-dimethoxyphenyl, 2,4-difluorophenyl, 2,6-difluorophenyl
, 3,4,5-trifluorophenyl, 3,4,5-trimethoxyphenyl, 3,4,5-tri- (to
(Trifluoromethyl) phenyl, 2,4,6-trifluorophenyl, 2,4,6-trimethyl
Phenyl, 2,4,6-tri- (trifluoromethyl) phenyl, 2,3,5-trifluorophenyl
Phenyl, 2,4,5-trifluorophenyl, 2,5-difluorophenyl, 2-fluoro-3
-Trifluoromethylphenyl, 4-fluoro-2-trifluoromethylphenyl, 2-
Fluoro-4-trifluoromethylphenyl, 4-benzyloxyphenyl, 2-chloro
B-6-fluorophenyl, 2-fluoro-6-chlorophenyl, 2,3,4,5,6-pentaful
Orophenyl, 2,5-dimethylphenyl, 4-phenylphenyl, adamantyl,
Benzyl, 2-phenylethyl, 3-phenyl-n-propyl, 4-phenyl-n-butyl,
Chill, ethyl, n-propyl, iso-propyl, iso-butyl, sec-butyl, tert-
Butyl, n-pentyl, iso-valeryl, n-hexyl, cyclopropyl, cyclobut
Tyl, cyclohexyl, cyclopentyl, cyclopent-1-enyl, cyclopen
Ta-2-enyl, cyclohex-1-enyl, -CH_Two-Cyclopropyl, -CH_Two-Cyclobuti
, -CH_Two-Cyclohexyl, -CH_Two-Cyclopentyl, -CH_TwoCH_Two-Cyclopropyl, -C
H_TwoCH_Two-Cyclobutyl, -CH_TwoCH_Two-Cyclohexyl, -CH_TwoCH_Two-Cyclopentyl, pyri
Zin-2-yl, pyridin-3-yl, pyridin-4-yl, fluoropyridyl (5-fur
Olopyridin-3-yl), chloropyridyl (including 5-chloropyridin-3-yl)
M), thien-2-yl, thien-3-yl, benzothiazol-4-yl, 2-phenylbe
Nnzoxazol-5-yl, furan-2-yl, benzofuran-2-yl, thionaphthene-
2-yl, thionaphthen-3-yl, thionaphthen-4-yl, 2-chlorothiophen-5-
Yl, 3-methylisoxazol-5-yl, 2- (thiophenyl) thien-5-yl, 6-methyl
Toxithionaphthen-2-yl, 3-phenyl-1,2,4-thiooxadiazol-5-yl
, 2-phenyloxazol-4-yl, indol-3-yl, 1-phenyl-tetrao
5-yl, allyl, 2- (cyclohexyl) ethyl, (CH_Three)_TwoCH = CHCH_TwoCH_TwoCH (CH_Three)-
, ΦC (O) CH_Two-, Thien-2-yl-methyl, 2- (thien-2-yl) ethyl, 3- (thien-2
-Yl) -n-propyl, 2- (4-nitrophenyl) ethyl, 2- (4-methoxyphenyl)
Tyl, norboran-2-yl, (4-methoxyphenyl) methyl, (2-methoxyphenyl
) Methyl, (3-methoxyphenyl) methyl, (3-hydroxyphenyl) methyl, (4-
(Droxyphenyl) 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-methoxy
Nyl) ethyl, CH_Three0C (O) CH_Two-, Benzylthiomethyl, 5- (methoxycarbonyl) -n-
Pentyl, 3- (methoxycarbonyl) -n-propyl, indan-2-yl, (2-methyl
Benzofuran-3-yl), methoxymethyl, CH_ThreeCH = CH-, CH_ThreeCH_TwoCH = CH-, (4-chloro
Phenyl) C (O) CH_Two-, 4- (fluorophenyl) -NHC (O) CH_Two-, 1-phenyl-n-butyl
, (Φ)_TwoCHNHC (O) CH_TwoCH_Two-, (CH_Three)_TwoNC (O) CH_Two-, (Φ)_TwoCHNHC (O) CH_TwoCH_Two-, Methylka
Rubonylmethyl, (2,4-dimethylphenyl) C (O) CH_Two-, 4-methoxyphenyl-C (O) C
H_Two-, Phenyl-C (O) CH_Two-, CH_ThreeC (O) N (φ)-, ethenyl, methylthiomethyl, (CH_Three) _Three CNHC (O) CH_Two-, 4-Fluorophenyl-C (O) CH_Two-, Diphenylmethyl, phenoxy
Methyl, 3,4-methylenedioxyphenyl-CH_Two-, Benzo [b] thiophen-3-yl, (
CH_Three)_ThreeCOC (O) NHCH_Two-, Trans-styryl, H_TwoNC (O) CH_TwoCH_Two-, 2-trifluoromethyl
Phenyl-C (O) CH_Two, ΦC (O) NHCH (φ) CH_Two-, Mesityl, CH_ThreeCH (= NHOH) CH_Two-, 4-CH_Three-
φ-NHC (O) CH_TwoCH_Two-, ΦC (O) CH (φ) CH_Two-, (CH_Three)_TwoCHC (O) NHCH (φ)-, CH_ThreeCH_Two0CH_Two-,
CH_Three0C (O) CH (CH_Three) (CH_Two)_Three-, 2,2,2-trifluoroethyl, 1- (trifluoromethyl)
Ethyl, 2-CH_Three-Benzofuran-3-yl, 2- (2,4-dichlorophenoxy) ethyl, φS
O_TwoCH_Two-, 3-cyclohexyl-n-propyl, CF_ThreeCH_TwoCH_TwoCH_Two-, And N-pyrrolidinyl
4. The method according to claim 1, wherein the method is selected from the group consisting of: 8. The method according to claim 1, wherein R ² is independently selected from the group consisting of alkyl, substituted alkyl, alkenyl, cycloalkyl, aryl, heteroaryl and heterocyclic. Method. 9. R ² is methyl, ethyl, n- propyl, iso - propyl, n
- butyl, iso - butyl, sec- butyl, tert- butyl, -CH ₂ CH (C
H ₂ CH _{3) 2,} 2- methyl -n- butyl, 6-fluoro -n- hexyl, phenyl, benzyl, cyclohexyl, cyclopentyl, cycloheptyl, allyl, iso - but-2-enyl, 3-methylpentyl, - CH ₂ - cyclopropyl, -CH ₂ - cyclohexyl, -CH ₂ CH ₂ - cyclopropyl, -CH ₂ CH ₂ - cyclohexyl, -CH ₂ - indol-3-yl, p-(phenyl) phenyl, o- fluorophenyl , M-fluorophenyl, p-fluorophenyl, m-methoxyphenyl, p-methoxyphenyl, phenethyl, benzyl, m-hydroxybenzyl, p-hydroxybenzyl, p-nitrobenzyl, m-trifluoromethylphenyl, p- ( CH ₃ ) NCH ₂ CH ₂ CH ₂ O-benzyl, p- (CH ₃ ) ₃ COC (O) C
H ₂ O-benzyl, p- (HOOCCH ₂ O) - benzyl, 2- Aminopiriji 6-
Yl, p-(N-morpholino -CH ₂ CH ₂ O) - _{benzyl, -CH 2 CH 2 C (O} ) N
H _2, -CH ₂ - imidazol-4-yl, -CH ₂ - (3- tetrahydrofuranyl
), - CH ₂ - thiophen-2-yl, -CH ₂ (1-methyl) cyclopropyl, -
CH ₂ - thiophen-3-yl, thiophen-3-yl, _{thiophen-2-yl, -CH 2 -C (O) O} -t- _{butyl, -CH 2 -C (CH 3)} 3, -CH 2 CH (CH ₂
CH _{3) 2,} 2-methylcyclopentyl, cyclohex-2-enyl, -CH [CH
_{(CH 3) 2] COOCH 3} , -CH 2 CH 2 N (CH 3) 2, -CH 2 C (CH 3) = CH 2,
-CH ₂ CH = CHCH ₃ (cis and _{trans), - CH 2 OH, -CH} (OH)
CH _3, -CH (O-t- _{butyl) CH 3, -CH 2 OCH 3} , - (CH 2) 4 NH-Bo
_{c, - (CH 2) 4} NH 2, -CH 2 - pyridyl, pyridyl, -CH ₂ - naphthyl, -
CH ₂ - (N-morpholino), p-(N-morpholino -CH ₂ CH ₂ O) benzyl, benzo [b] thiophen-2-yl, 5-chlorobenzo [b] thiophen-2-yl,
4,5,6,7-tetrahydrobenzo [b] thiophen-2-yl, benzo [b] thiophen-3-yl, 5-chlorobenzo [b] thiophen-3-yl, benzo [b] thiophen-5-yl 6-methoxy naphth-2-yl, -CH ₂ CH ₂ SCH _3,
The method according to claim 8, wherein the method is selected from the group consisting of thien-2-yl and thien-3-yl. 10. The method according to claim 1, wherein R ³ is selected from the group consisting of hydrogen, alkyl, substituted alkyl and cycloalkyl. 11. R ³ is hydrogen, methyl, 2-methylpropyl, hexyl, methoxycarbonylmethyl, 3,3-dimethyl-2-oxobutyl, 4-phenylbutyl, cyclopropylmethyl, 2,2,2-trifluoro The method according to claim 10, wherein the method is selected from the group consisting of ethyl and cyclohexyl. 12. The method according to claim 1, wherein R ⁴ is hydrogen, alkyl or substituted alkyl. 13. The method according to claim 1, wherein R ⁵ is selected from the group consisting of alkyl, substituted alkyl, phenyl, substituted phenyl, cycloalkyl, heteroaryl and heterocyclic. 14. The compound according to claim 5, wherein the compound is 5- (S)-(N ′-(2- (3,5-difluorophenyl) ethyl) -L-alaninyl) -amino-7-methyl-5,7-dihydro- 6H-dibenz [b, d] azepin-6-one, 5 (S)-(N '-(2 (R) -hydroxy-2- (3,5-difluorophenyl) ethyl) -L-alaninyl
) -Amino-7-methyl-5,7-dihydro-6H-dibenz [b, d] azepin-6-one, 5 (S)-(N ′-(2 (S) -hydroxy-2- (3, 5-difluorophenyl) ethyl) -L-alaninyl
) -Amino-7-methyl-5,7-dihydro-6H-dibenz [b, d] azepin-6-one, 5 (S)-(N ′-(2 (R / S) -hydroxy-3-isopropyl (Oxy-propyl) -L-alaninyl)
-Amino-7-methyl-5,7-dihydro-6H-dibenz [b, d] azepin-6-one, 5 (S)-(N '-(2 (R / S) -hydroxy-butyl) -L -Alaninyl) -amino-7-methyl-5,7-dihydro-6H-dibenz [b, d] azepin-6-one, 5 (S)-(N '-(2 (R / S) -3-dihydroxy -Propyl) -L-alaninyl) -amino-7-methyl-
5,7-dihydro-6H-dibenz [b, d] azepin-6-one, 5 (S)-(N '-(2 (R / S) -hydroxy-3-morpholinopropyl) -L-alaninyl)- Amino-7
-Methyl-5,7-dihydro-6H-dibenz [b, d] azepin-6-one, 5 (S)-(N '-(2 (R / S) -hydroxy-tetradecyl) -L-alaninyl)- Amino-7-methyl-
5,7-dihydro-6H-dibenz [b, d] azepin-6-one, 5 (S)-(N '-(2 (R / S) -hydroxy-octyl) -L-alaninyl) -amino-7 -Methyl-5,7-
Dihydro-6H-dibenz [b, d] azepin-6-one, 5 (S)-(N '-(2 (R) -hydroxy-2- (3,4,5-trifluorophenyl) ethyl) -L -Alaninyl) -amino-7-methyl-5,7-dihydro-6H-dibenz [b, d] azepin-6-one, 5 (S)-(N '-(2 (S) -hydroxy-2- ( 3,4,5-trifluorophenyl) ethyl) -L-alaninyl) -amino-7-methyl-5,7-dihydro-6H-dibenz [b, d] azepin-6-one, 5 (S)-( N '-(2 (R) -hydroxy-2- (4- (trifluoromethyl) phenyl) ethyl) -L-alaninyl) -amino-7-methyl-5,7-dihydro-6H-dibenz [b, d Azepin-6-one, 5 (S)-(N '-(2 (S) -hydroxy-2- (4- (trifluoromethyl) phenyl) ethyl) -L-alaninyl) -amino-7-methyl- 5,7-dihydro-6H-dibenz [b, d] azepin-6-one, 5 (S)-(N '-(2 (R) -hydroxy-2- (3,5-bis- (trifluoromethyl ) Phenyl) ethyl) -L-alaninyl) -amino-7-methyl-5,7-dihydro-6H-dibenz [b, d] azepine -
6-one, 5 (S)-(N '-(2 (S) -hydroxy-2- (3,5-bis- (trifluoromethyl) phenyl) ethyl) -L-alaninyl) -amino-7-methyl -5,7-dihydro-6H-dibenz [b, d] azepine-
6-one, 5 (S)-(N '-(2 (R) -hydroxy-2- (3,3,3-trifluoro) -propyl) -L-alaninyl)
-Amino-7-methyl-5,7-dihydro-6H-dibenz [b, d] azepin-6-one, 5 (S)-(N '-(2 (S) -hydroxy-2- (3,3 , 3-Trifluoro) -propyl) -L-alaninyl)
-Amino-7-methyl-5,7-dihydro-6H-dibenz [b, d] azepin-6-one, 5- (S)-(N '-(3-methyl-2-butanone) -L-alaninyl ) -Amino-7-methyl-5,7-dihydro-6H-dibenz [b, d] azepin-6-one, 5- (S)-(N ′-(3-methyl-2- (S) -hydroxy Butyl) -L-alaninyl) -amino-7-methyl-5,7-dihydro-6H-dibenz [b, d] azepin-6-one, 3- (N '-(3-methyl-2- (S) 2-hydroxybutyl) -L-alaninyl) -amino-2,4-dioxo-1-methyl-5-phenyl-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine, 3- (N '-(2- (R / S) -3,5-difluorophenyl-2-hydroxyethyl) -L-alaninyl)-
Amino-2,4-dioxo-1-methyl-5-phenyl-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine, 5- [N '-(S) -2- (4-methyl Pentyl) amino-3-methylbutyryl-L-alaninyl] -amino-7-methyl-5,7-dihydro-6H-dibenz [b, d] azepin-6-one, 5- (S)-{N '-[ (1RS, 2SR) -1,2,3,4-tetrahydro-1-hydroxy-2-naphthyl] alaninyl} -amino-7-methyl-5,7-dihydro-6H-dibenz [b, d] azepine-6 -One, 5- (S)-{N '-[(1RS, 2RS) -1,2,3,4-tetrahydro-1-hydroxy-2-naphthyl] alaninyl} -amino-7-methyl-5,7 -Dihydro-6H-dibenz [b, d] azepin-6-one, 5- (S)-[N '-(2-α-tetralone) -L-alaninyl] -amino-7-methyl-5,7- Dihydro-6
H-dibenz [b, d] azepin-6-one hydrochloride, 5- (S)-[N '-(1,2,3,4-tetrahydro-2-naphthyl) -L-alaninyl] -amino-7 -Methyl-5,7-dihydro-6H-dibenz [b, d] azepin-6-one, 5- (S)-{N '-[(1RS, 2SR) -1-hydroxy-2-cyclohexyl] alaninyl} -Amino-7-
Methyl-5,7-dihydro-6H-dibenz [b, d] azepin-6-one, 5- (S)-[N '-(4-methylpentyl) -L-alaninyl] -amino-7-methyl- 5,7-dihydro-
4. The method according to claim 1, wherein the method is selected from the group consisting of 6H-dibenz [b, d] azepin-6-one. 15. A pharmaceutically acceptable carrier and a pharmaceutically effective amount of Formula I: Wherein W is Embedded image Embedded image And a cyclic group selected from the group consisting of Wherein ring A, together with the atoms to which it is attached, is a carbocyclic ring selected from the group consisting of aryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heteroaryl and heterocyclic; Forms a heterocyclic ring. Ring B, together with the atoms to which it is attached, is a carbocyclic or heterocyclic group selected from the group consisting of aryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heteroaryl and heterocyclic. Form a ring. Ring C, together with the atoms to which it is attached, forms heteroaryl and heterocyclic. Y is the formula: Indicated by R ¹ is alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, substituted alkyl, substituted alkenyl, substituted alkynyl, substituted cycloalkyl,
It is selected from the group consisting of substituted cycloalkenyl, aryl, heteroaryl, and heterocyclic. R ² is selected from the group consisting of alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, aryl, heteroaryl and heterocyclic. R ³ is selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, acyl, aryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heteroaryl and heterocyclic. It is. Each R ⁴ is independently alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, cycloalkyl, substituted cycloalkyl,
It is selected from the group consisting of cycloalkenyl, substituted cycloalkenyl, heteroaryl and heterocyclic. R ⁵ is hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, alkoxy, substituted alkoxy, aryl, aryloxy, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, substituted amino, heteroaryl , Heterocyclic, thioalkoxy and substituted thioalkoxy. Q is oxygen, sulfur, -S (O)-, -S (O) _2- , -C (O)-or -C (S)-. Z is represented by the formula: -T-CX'X "V- (where T is oxygen, sulfur, -N
R ⁶ (where R ⁶ is hydrogen, acyl, alkyl, aryl, or heteroaryl), and a bond consisting of —CX′X ″ — and a bond covalently bonding R ¹ . X "is hydrogen, hydroxy, or fluorine, or X 'and X" together form an oxo group. V is selected from the group consisting of alkylene or substituted alkylene Or R ¹ and Z together form an aryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heterocyclic, or substituted heterocyclic, where X is hydrogen, alkyl, substituted Alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, acyl, aryl, cycloalkyl, substituted cycle Alkyl, Shikuroarukeru, substituted cycloalkenyl, or selected from the group consisting of heteroaryl and heterocyclic, or X, one of R ⁴ and the atoms to which they are attached are taken together to form a double bond T is an integer of 0 to 2. f is an integer of 0 to 2. n is an integer of 1 or 2.] or a mixture of the compounds and a pharmaceutically acceptable salt thereof. a pharmaceutical composition comprising (although, T is R ¹ and -CX'X "- when it is other than a covalent bond linking the, X 'and X" can not represent or both hydroxy or fluorine). 16. The pharmaceutical composition according to claim 15, wherein n is 1. 17. The pharmaceutical composition according to claim 15, wherein Ring A and Ring B are independently selected from the group consisting of aryl, cycloalkyl, cycloalkenyl, heteroaryl and heterocyclic. 18. The pharmaceutical composition according to claim 17, wherein Ring A and Ring B are independently aryl. 19. R¹Is phenyl, 1-naphthyl, 2-naphthyl, 2-chloroph
Phenyl, 2-fluorophenyl, 2-bromophenyl, 2-hydroxyphenyl, 2-diphenyl
Trophenyl, 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-isopro
Pyrphenyl, 4-phenoxyphenyl, 4-trifluoromethylphenyl, 4-hydr
Roxymethylphenyl, 3-methoxyphenyl, 3-hydroxyphenyl, 3-nitro
Phenyl, 3-fluorophenyl, 3-chlorophenyl, 3-bromophenyl, 3-phenyl
Nonoxyphenyl, 3-thiomethoxyphenyl, 3-methylphenyl, 3-trifluoro
Methylphenyl, 2,3-dichlorophenyl, 2,3-difluorophenyl, 2,4-dichloro
Rophenyl, 2,5-dimethoxyphenyl, 3,4-dichlorophenyl, 3,4-difluoro
Phenyl, 3,4-methylenedioxyphenyl, 3,4-dimethoxyphenyl, 3,5-diphenyl
Fluorophenyl, 3,5-dichlorophenyl, 3,5-di- (trifluoromethyl) phenyl
3,3-dimethoxyphenyl, 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-trimethyl
Phenyl, 2,4,6-tri- (trifluoromethyl) phenyl, 2,3,5-trifluoro
Phenyl, 2,4,5-trifluorophenyl, 2,5-difluorophenyl, 2-fluoro
-3-trifluoromethylphenyl, 4-fluoro-2-trifluoromethylphenyl,
2-fluoro-4-trifluoromethylphenyl, 4-benzyloxyphenyl, 2-
Loro-6-fluorophenyl, 2-fluoro-6-chlorophenyl, 2,3,4,5,6-pentaf
Fluorophenyl, 2,5-dimethylphenyl, 4-phenylphenyl, 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
Tyl, cyclohexyl, cyclopentyl, cyclopent-1-enyl, cyclopen
Ta-2-enyl, cyclohex-1-enyl, -CH_Two-Cyclopropyl, -CH_Two-Cyclobuti
, -CH_Two-Cyclohexyl, -CH_Two-Cyclopentyl, -CH_TwoCH_Two-Cyclopropyl, -C
H_TwoCH_Two-Cyclobutyl, -CH_TwoCH_Two-Cyclohexyl, -CH_TwoCH_Two-Cyclopentyl, pyri
Zin-2-yl, pyridin-3-yl, pyridin-4-yl, fluoropyridyl (5-fur
Olopyridin-3-yl), chloropyridyl (including 5-chloropyridin-3-yl)
M), thien-2-yl, thien-3-yl, benzothiazol-4-yl, 2-phenylbe
Nnzoxazol-5-yl, furan-2-yl, benzofuran-2-yl, thionaphthene-
2-yl, thionaphthen-3-yl, thionaphthen-4-yl, 2-chlorothiophen-5-
Yl, 3-methylisoxazol-5-yl, 2- (thiophenyl) thien-5-yl, 6-methyl
Toxithionaphthen-2-yl, 3-phenyl-1,2,4-thiooxadiazol-5-yl
, 2-phenyloxazol-4-yl, indol-3-yl, 1-phenyl-tetrao
5-yl, allyl, 2- (cyclohexyl) ethyl, (CH_Three)_TwoCH = CHCH_TwoCH_TwoCH (CH_Three)-
, ΦC (O) CH_Two-, Thien-2-yl-methyl, 2- (thien-2-yl) ethyl, 3- (thien-2
-Yl) -n-propyl, 2- (4-nitrophenyl) ethyl, 2- (4-methoxyphenyl)
Tyl, norboran-2-yl, (4-methoxyphenyl) methyl, (2-methoxyphenyl
) Methyl, (3-methoxyphenyl) methyl, (3-hydroxyphenyl) methyl, (4-
(Droxyphenyl) 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-methoxy
Nyl) ethyl, CH_Three0C (O) CH_Two-, Benzylthiomethyl, 5- (methoxycarbonyl) -n-
Pentyl, 3- (methoxycarbonyl) -n-propyl, indan-2-yl, (2-methyl
Benzofuran-3-yl), methoxymethyl, CH_ThreeCH = CH-, CH_ThreeCH_TwoCH = CH-, (4-chloro
Phenyl) C (O) CH_Two-, 4- (fluorophenyl) -NHC (O) CH_Two-, 1-phenyl-n-butyl
, (Φ)_TwoCHNHC (O) CH_TwoCH_Two-, (CH_Three)_TwoNC (O) CH_Two-, (Φ)_TwoCHNHC (O) CH_TwoCH_Two-, Methylka
Rubonylmethyl, (2,4-dimethylphenyl) C (O) CH_Two-, 4-methoxyphenyl-C (O) C
H_Two-, Phenyl-C (O) CH_Two-, CH_ThreeC (O) N (φ)-, ethenyl, methylthiomethyl, (CH_Three) _Three CNHC (O) CH_Two-, 4-Fluorophenyl-C (O) CH_Two-, Diphenylmethyl, phenoxy
Methyl, 3,4-methylenedioxyphenyl-CH_Two-, Benzo [b] thiophen-3-yl, (
CH_Three)_ThreeCOC (O) NHCH_Two-, Trans-styryl, H_TwoNC (O) CH_TwoCH_Two-, 2-trifluoromethyl
Phenyl-C (O) CH_Two, ΦC (O) NHCH (φ) CH_Two-, Mesityl, CH_ThreeCH (= NHOH) CH_Two-, 4-CH_Three-
φ-NHC (O) CH_TwoCH_Two-, ΦC (O) CH (φ) CH_Two-, (CH_Three)_TwoCHC (O) NHCH (φ)-, CH_ThreeCH_Two0CH_Two-,
CH_Three0C (O) CH (CH_Three) (CH_Two)_Three-, 2,2,2-trifluoroethyl, 1- (trifluoromethyl)
Ethyl, 2-CH_Three-Benzofuran-3-yl, 2- (2,4-dichlorophenoxy) ethyl, φS
O_TwoCH_Two-, 3-cyclohexyl-n-propyl, CF_ThreeCH_TwoCH_TwoCH_Two-, And N-pyrrolidinyl
The pharmaceutical composition according to claim 15, which is selected from the group consisting of: 20. The pharmaceutical composition according to claim 15, wherein R ² is independently selected from the group consisting of alkyl, substituted alkyl, alkenyl, cycloalkyl, aryl, heteroaryl, and heterocyclic. 21. R ² is methyl, ethyl, n- propyl, iso - propyl,
n- butyl, iso - butyl, sec- butyl, tert- butyl, -CH ₂ CH (
CH ₂ CH _{3) 2,} 2- methyl -n- butyl, 6-fluoro -n- hexyl, phenyl, benzyl, cyclohexyl, cyclopentyl, cycloheptyl, allyl, iso - but-2-enyl, 3-methylpentyl, - CH ₂ - cyclopropyl, -C
H ₂ - cyclohexyl, -CH ₂ CH ₂ - cyclopropyl, -CH ₂ CH ₂ - cyclohexyl, -CH ₂ - indol-3-yl, p-(phenyl) phenyl, o- fluorophenyl, m- fluorophenyl, p - fluorophenyl, m- methoxyphenyl, p- methoxyphenyl, phenethyl, benzyl, m- hydroxybenzyl, p- hydroxybenzyl, p- nitrobenzyl, m- _{trifluoromethylphenyl, p- (CH 3) NCH 2} CH 2 CH ₂ O-benzyl, p- (CH ₃ ) ₃ COC (
O) CH ₂ O-benzyl, p- (HOOCCH ₂ O) - benzyl, 2-Aminopiriji 6-yl, p-(N-morpholino -CH ₂ CH ₂ O) - benzyl, -CH ₂ CH ₂ C
_{(O) NH 2, -CH 2} - imidazol-4-yl, -CH ₂ - (3- tetrahydrofuranyl), - CH ₂ - thiophen-2-yl, -CH ₂ (1-methyl) cyclopropyl, -CH ₂ -thiophen-3-yl, thiophen-3-yl, thiophen-2
- _{yl, -CH 2 -C (O) O} -t- _{butyl, -CH 2 -C (CH 3)} 3, -CH 2 CH (
CH ₂ CH _{3) 2,} 2- methylcyclopentyl, cyclohex-2-enyl, -CH
_{[CH (CH 3) 2]} COOCH 3, -CH 2 CH 2 N (CH 3) 2, -CH 2 C (CH 3) = C
_{H 2, -CH 2 CH = CHCH} 3 ( cis and _{trans), - CH 2 OH, -CH} (
_{OH) CH 3, -CH (O} -t- _{butyl) CH 3, -CH 2 OCH 3} , - (CH 2) 4 NH
_{-Boc, - (CH 2) 4} NH 2, -CH 2 - pyridyl, pyridyl, -CH ₂ - naphthyl, -CH ₂ - (N-morpholino), p-(N-morpholino -CH ₂ CH ₂ O) benzyl , Benzo [b] thiophen-2-yl, 5-chlorobenzo [b] thiophen-2-
Yl, 4,5,6,7-tetrahydrobenzo [b] thiophen-2-yl, benzo [b
] Thiophen-3-yl, 5-chlorobenzo [b] thiophen-3-yl, benzo [
b] thiophen-5-yl, 6-methoxy-naphth-2-yl, -CH ₂ CH ₂ SC
_{3. The} composition according to claim 2, wherein the group is selected from the group consisting of H3, thien-2-yl and thien-3-yl.
0. The pharmaceutical composition according to 0. 22. The pharmaceutical composition according to claim 15, wherein R ³ is selected from the group consisting of hydrogen, alkyl, substituted alkyl and cycloalkyl. 23. R ³ is hydrogen, methyl, 2-methylpropyl, hexyl, methoxycarbonylmethyl, 3,3-dimethyl-2-oxobutyl, 4-phenylbutyl, cyclopropylmethyl, 2,2,2-trifluoro 23. The pharmaceutical composition according to claim 22, which is selected from the group consisting of ethyl and cyclohexyl. 24. The pharmaceutical composition according to claim 15, wherein R ⁴ is hydrogen, alkyl or substituted alkyl. 25. The pharmaceutical composition according to claim 15, wherein R ⁵ is selected from the group consisting of alkyl, substituted alkyl, phenyl, substituted phenyl, cycloalkyl, heteroaryl, and heterocyclic. (26) the compound, wherein 5- (S)-(N '-(2- (3,5-difluorophenyl) ethyl) -L-alaninyl) -amino-7-methyl-5,7-dihydro- 6H-dibenz [b, d] azepin-6-one, 5 (S)-(N '-(2 (R) -hydroxy-2- (3,5-difluorophenyl) ethyl) -L-alaninyl
) -Amino-7-methyl-5,7-dihydro-6H-dibenz [b, d] azepin-6-one, 5 (S)-(N ′-(2 (S) -hydroxy-2- (3, 5-difluorophenyl) ethyl) -L-alaninyl
) -Amino-7-methyl-5,7-dihydro-6H-dibenz [b, d] azepin-6-one, 5 (S)-(N ′-(2 (R / S) -hydroxy-3-isopropyl (Oxy-propyl) -L-alaninyl)
-Amino-7-methyl-5,7-dihydro-6H-dibenz [b, d] azepin-6-one, 5 (S)-(N '-(2 (R / S) -hydroxy-butyl) -L -Alaninyl) -amino-7-methyl-5,7-dihydro-6H-dibenz [b, d] azepin-6-one, 5 (S)-(N '-(2 (R / S) -3-dihydroxy -Propyl) -L-alaninyl) -amino-7-methyl-
5,7-dihydro-6H-dibenz [b, d] azepin-6-one, 5 (S)-(N '-(2 (R / S) -hydroxy-3-morpholinopropyl) -L-alaninyl)- Amino-7
-Methyl-5,7-dihydro-6H-dibenz [b, d] azepin-6-one, 5 (S)-(N '-(2 (R / S) -hydroxy-tetradecyl) -L-alaninyl)- Amino-7-methyl-
5,7-dihydro-6H-dibenz [b, d] azepin-6-one, 5 (S)-(N '-(2 (R / S) -hydroxy-octyl) -L-alaninyl) -amino-7 -Methyl-5,7-
Dihydro-6H-dibenz [b, d] azepin-6-one, 5 (S)-(N '-(2 (R) -hydroxy-2- (3,4,5-trifluorophenyl) ethyl) -L -Alaninyl) -amino-7-methyl-5,7-dihydro-6H-dibenz [b, d] azepin-6-one, 5 (S)-(N '-(2 (S) -hydroxy-2- ( 3,4,5-trifluorophenyl) ethyl) -L-alaninyl) -amino-7-methyl-5,7-dihydro-6H-dibenz [b, d] azepin-6-one, 5 (S)-( N '-(2 (R) -hydroxy-2- (4- (trifluoromethyl) phenyl) ethyl) -L-alaninyl) -amino-7-methyl-5,7-dihydro-6H-dibenz [b, d Azepin-6-one, 5 (S)-(N '-(2 (S) -hydroxy-2- (4- (trifluoromethyl) phenyl) ethyl) -L-alaninyl) -amino-7-methyl- 5,7-dihydro-6H-dibenz [b, d] azepin-6-one, 5 (S)-(N '-(2 (R) -hydroxy-2- (3,5-bis- (trifluoromethyl ) Phenyl) ethyl) -L-alaninyl) -amino-7-methyl-5,7-dihydro-6H-dibenz [b, d] azepine -
6-one, 5 (S)-(N '-(2 (S) -hydroxy-2- (3,5-bis- (trifluoromethyl) phenyl) ethyl) -L-alaninyl) -amino-7-methyl -5,7-dihydro-6H-dibenz [b, d] azepine-
6-one, 5 (S)-(N '-(2 (R) -hydroxy-2- (3,3,3-trifluoro) -propyl) -L-alaninyl)
-Amino-7-methyl-5,7-dihydro-6H-dibenz [b, d] azepin-6-one, 5 (S)-(N '-(2 (S) -hydroxy-2- (3,3 , 3-Trifluoro) -propyl) -L-alaninyl)
-Amino-7-methyl-5,7-dihydro-6H-dibenz [b, d] azepin-6-one, 5- (S)-(N '-(3-methyl-2-butanone) -L-alaninyl ) -Amino-7-methyl-5,7-dihydro-6H-dibenz [b, d] azepin-6-one, 5- (S)-(N ′-(3-methyl-2- (S) -hydroxy Butyl) -L-alaninyl) -amino-7-methyl-5,7-dihydro-6H-dibenz [b, d] azepin-6-one, 3- (N '-(3-methyl-2- (S) 2-hydroxybutyl) -L-alaninyl) -amino-2,4-dioxo-1-methyl-5-phenyl-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine, 3- (N '-(2- (R / S) -3,5-difluorophenyl-2-hydroxyethyl) -L-alaninyl)-
Amino-2,4-dioxo-1-methyl-5-phenyl-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine, 5- [N '-(S) -2- (4-methyl Pentyl) amino-3-methylbutyryl-L-alaninyl] -amino-7-methyl-5,7-dihydro-6H-dibenz [b, d] azepin-6-one, 5- (S)-{N '-[ (1RS, 2SR) -1,2,3,4-tetrahydro-1-hydroxy-2-naphthyl] alaninyl} -amino-7-methyl-5,7-dihydro-6H-dibenz [b, d] azepine-6 -One, 5- (S)-{N '-[(1RS, 2RS) -1,2,3,4-tetrahydro-1-hydroxy-2-naphthyl] alaninyl} -amino-7-methyl-5,7 -Dihydro-6H-dibenz [b, d] azepin-6-one, 5- (S)-[N '-(2-α-tetralone) -L-alaninyl] -amino-7-methyl-5,7- Dihydro-6
H-dibenz [b, d] azepin-6-one hydrochloride, 5- (S)-[N '-(1,2,3,4-tetrahydro-2-naphthyl) -L-alaninyl] -amino-7 -Methyl-5,7-dihydro-6H-dibenz [b, d] azepin-6-one, 5- (S)-{N '-[(1RS, 2SR) -1-hydroxy-2-cyclohexyl] alaninyl} -Amino-7-
Methyl-5,7-dihydro-6H-dibenz [b, d] azepin-6-one, 5- (S)-[N '-(4-methylpentyl) -L-alaninyl] -amino-7-methyl- 5,7-dihydro-
The pharmaceutical composition according to claim 15, which is selected from the group consisting of 6H-dibenz [b, d] azepin-6-one. 27. A compound of formula I: [Wherein, W is Embedded image Embedded image And a cyclic group selected from the group consisting of Wherein ring A, together with the atoms to which it is attached, is a carbocyclic ring selected from the group consisting of aryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heteroaryl and heterocyclic; Forms a heterocyclic ring. Ring B, together with the atoms to which it is attached, is a carbocyclic or heterocyclic group selected from the group consisting of aryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heteroaryl and heterocyclic. Form a ring. Ring C, together with the atoms to which it is attached, forms heteroaryl and heterocyclic. Y is the formula: Indicated by R ¹ is alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, substituted alkyl, substituted alkenyl, substituted alkynyl, substituted cycloalkyl,
It is selected from the group consisting of substituted cycloalkenyl, aryl, heteroaryl, and heterocyclic. R ² is selected from the group consisting of alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, aryl, heteroaryl and heterocyclic. R ³ is selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, acyl, aryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heteroaryl and heterocyclic. It is. Each R ⁴ is independently alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, cycloalkyl, substituted cycloalkyl,
It is selected from the group consisting of cycloalkenyl, substituted cycloalkenyl, heteroaryl and heterocyclic. R ⁵ is hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, alkoxy, substituted alkoxy, aryl, aryloxy, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, substituted amino, heteroaryl , Heterocyclic, thioalkoxy and substituted thioalkoxy. Q is oxygen, sulfur, -S (O)-, -S (O) _2- , -C (O)-or -C (S)-. Z is represented by the formula: -T-CX'X "V- (where T is oxygen, sulfur, -N
R ⁶ (where R ⁶ is hydrogen, acyl, alkyl, aryl, or heteroaryl), and a bond consisting of —CX′X ″ — and a bond covalently bonding R ¹ . X "is hydrogen, hydroxy, or fluorine, or X 'and X" together form an oxo group. V is selected from the group consisting of alkylene or substituted alkylene Or R ¹ and Z together form an aryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heterocyclic, or substituted heterocyclic, where X is hydrogen, alkyl, substituted Alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, acyl, aryl, cycloalkyl, substituted cycle Alkyl, Shikuroarukeru, substituted cycloalkenyl, or selected from the group consisting of heteroaryl and heterocyclic, or X, one of R ⁴ and the atoms to which they are attached are taken together to form a double bond T is an integer of 0 to 2. f is an integer of 0 to 2. n is an integer of 1 or 2.] and a pharmaceutically acceptable salt thereof, wherein T is R ¹ and -CX '
When other than a covalent bond linking X "-, neither X 'nor X" can be hydroxy or fluorine. 28. The compound according to claim 27, wherein n is 1. 29. The compound of claim 27, wherein Ring A and Ring B are preferably independently selected from the group consisting of aryl, cycloalkyl, cycloalkenyl, heteroaryl, and heterocyclic. 30. The compound of claim 27, wherein Ring A and Ring B are independently aryl. 31. R¹Is phenyl, 1-naphthyl, 2-naphthyl, 2-chloroph
Phenyl, 2-fluorophenyl, 2-bromophenyl, 2-hydroxyphenyl, 2-diphenyl
Trophenyl, 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-isopro
Pyrphenyl, 4-phenoxyphenyl, 4-trifluoromethylphenyl, 4-hydr
Roxymethylphenyl, 3-methoxyphenyl, 3-hydroxyphenyl, 3-nitro
Phenyl, 3-fluorophenyl, 3-chlorophenyl, 3-bromophenyl, 3-phenyl
Nonoxyphenyl, 3-thiomethoxyphenyl, 3-methylphenyl, 3-trifluoro
Methylphenyl, 2,3-dichlorophenyl, 2,3-difluorophenyl, 2,4-dichloro
Rophenyl, 2,5-dimethoxyphenyl, 3,4-dichlorophenyl, 3,4-difluoro
Phenyl, 3,4-methylenedioxyphenyl, 3,4-dimethoxyphenyl, 3,5-diphenyl
Fluorophenyl, 3,5-dichlorophenyl, 3,5-di- (trifluoromethyl) phenyl
3,3-dimethoxyphenyl, 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-trimethyl
Phenyl, 2,4,6-tri- (trifluoromethyl) phenyl, 2,3,5-trifluoro
Phenyl, 2,4,5-trifluorophenyl, 2,5-difluorophenyl, 2-fluoro
-3-trifluoromethylphenyl, 4-fluoro-2-trifluoromethylphenyl,
2-fluoro-4-trifluoromethylphenyl, 4-benzyloxyphenyl, 2-
Loro-6-fluorophenyl, 2-fluoro-6-chlorophenyl, 2,3,4,5,6-pentaf
Fluorophenyl, 2,5-dimethylphenyl, 4-phenylphenyl, 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
Tyl, cyclohexyl, cyclopentyl, cyclopent-1-enyl, cyclopen
Ta-2-enyl, cyclohex-1-enyl, -CH_Two-Cyclopropyl, -CH_Two-Cyclobuti
, -CH_Two-Cyclohexyl, -CH_Two-Cyclopentyl, -CH_TwoCH_Two-Cyclopropyl, -C
H_TwoCH_Two-Cyclobutyl, -CH_TwoCH_Two-Cyclohexyl, -CH_TwoCH_Two-Cyclopentyl, pyri
Zin-2-yl, pyridin-3-yl, pyridin-4-yl, fluoropyridyl (5-fur
Olopyridin-3-yl), chloropyridyl (including 5-chloropyridin-3-yl)
M), thien-2-yl, thien-3-yl, benzothiazol-4-yl, 2-phenylbe
Nnzoxazol-5-yl, furan-2-yl, benzofuran-2-yl, thionaphthene-
2-yl, thionaphthen-3-yl, thionaphthen-4-yl, 2-chlorothiophen-5-
Yl, 3-methylisoxazol-5-yl, 2- (thiophenyl) thien-5-yl, 6-methyl
Toxithionaphthen-2-yl, 3-phenyl-1,2,4-thiooxadiazol-5-yl
, 2-phenyloxazol-4-yl, indol-3-yl, 1-phenyl-tetrao
5-yl, allyl, 2- (cyclohexyl) ethyl, (CH_Three)_TwoCH = CHCH_TwoCH_TwoCH (CH_Three)-
, FC (O) CH_Two-, 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-
(Droxyphenyl) 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-methoxy
Nyl) ethyl, CH_Three0C (O) CH_Two-, Benzylthiomethyl, 5- (methoxycarbonyl) -n-
Pentyl, 3- (methoxycarbonyl) -n-propyl, indan-2-yl, (2-methyl
Benzofuran-3-yl), methoxymethyl, CH_ThreeCH = CH-, CH_ThreeCH_TwoCH = CH-, (4-chloro
Phenyl) C (O) CH_Two-, 4- (fluorophenyl) -NHC (O) CH_Two-, 1-phenyl-n-butyl
, (F)_TwoCHNHC (O) CH_TwoCH_Two-, (CH_Three)_TwoNC (O) CH_Two-, (F)_TwoCHNHC (O) CH_TwoCH_Two-, Methylcal
Bonylmethyl, (2,4-dimethylphenyl) C (O) CH_Two-, 4-methoxyphenyl-C (O) CH_Two -, Phenyl-C (O) CH_Two-, CH_ThreeC (O) N (f)-, ethenyl, methylthiomethyl, (CH_Three)_ThreeCN
HC (O) CH_Two-, 4-Fluorophenyl-C (O) CH_Two-, Diphenylmethyl, phenoxymethi
, 3,4-methylenedioxyphenyl-CH_Two-, Benzo [b] thiophen-3-yl, (CH_Three) _Three COC (O) NHCH_Two-, Trans-styryl, H_TwoNC (O) CH_TwoCH_Two-, 2-trifluoromethylfe
Nyl-C (O) CH_Two, FC (O) NHCH (f) CH_Two-, Mesityl, CH_ThreeCH (= NHOH) CH_Two-, 4-CH_Three-f-NHC (
O) CH_TwoCH_Two-, FC (O) CH (f) CH_Two-, (CH_Three)_TwoCHC (O) NHCH (f)-, CH_ThreeCH_Two0CH_Two-, CH_Three0C (O) CH
(CH_Three) (CH_Two)_Three-, 2,2,2-trifluoroethyl, 1- (trifluoromethyl) ethyl, 2-
CH_Three-Benzofuran-3-yl, 2- (2,4-dichlorophenoxy) ethyl, fSO_TwoCH_Two-, 3-
Cyclohexyl-n-propyl, CF_ThreeCH_TwoCH_TwoCH_Two-, And the group consisting of N-pyrrolidinyl
28. The compound according to claim 27 selected from: 32. Each R ² is independently alkyl, substituted alkyl, alkenyl,
28. The compound according to claim 27, wherein the compound is selected from the group consisting of cycloalkyl, aryl, heteroaryl, and heterocyclic. 33. R ² is methyl, ethyl, n-propyl, iso-propyl,
n- butyl, iso - butyl, sec- butyl, tert- butyl, -CH ₂ CH (
CH ₂ CH _{3) 2,} 2- methyl -n- butyl, 6-fluoro -n- hexyl, phenyl, benzyl, cyclohexyl, cyclopentyl, cycloheptyl, allyl, iso - but-2-enyl, 3-methylpentyl, - CH ₂ - cyclopropyl, -C
H ₂ - cyclohexyl, -CH ₂ CH ₂ - cyclopropyl, -CH ₂ CH ₂ - cyclohexyl, -CH ₂ - indol-3-yl, p-(phenyl) phenyl, o- fluorophenyl, m- fluorophenyl, p - fluorophenyl, m- methoxyphenyl, p- methoxyphenyl, phenethyl, benzyl, m- hydroxybenzyl, p- hydroxybenzyl, p- nitrobenzyl, m- _{trifluoromethylphenyl, p- (CH 3) NCH 2} CH 2 CH ₂ O-benzyl, p- (CH ₃ ) ₃ COC (
O) CH ₂ O-benzyl, p- (HOOCCH ₂ O) - benzyl, 2-Aminopiriji 6-yl, p-(N-morpholino -CH ₂ CH ₂ O) - benzyl, -CH ₂ CH ₂ C
_{(O) NH 2, -CH 2} - imidazol-4-yl, -CH ₂ - (3- tetrahydrofuranyl), - CH ₂ - thiophen-2-yl, -CH ₂ (1-methyl) cyclopropyl, -CH ₂ -thiophen-3-yl, thiophen-3-yl, thiophen-2
- _{yl, -CH 2 -C (O) O} -t- _{butyl, -CH 2 -C (CH 3)} 3, -CH 2 CH (
CH ₂ CH _{3) 2,} 2- methylcyclopentyl, cyclohex-2-enyl, -CH
_{[CH (CH 3) 2]} COOCH 3, -CH 2 CH 2 N (CH 3) 2, -CH 2 C (CH 3) = C
_{H 2, -CH 2 CH = CHCH} 3 ( cis and _{trans), - CH 2 OH, -CH} (
_{OH) CH 3, -CH (O} -t- _{butyl) CH 3, -CH 2 OCH 3} , - (CH 2) 4 NH
_{-Boc, - (CH 2) 4} NH 2, -CH 2 - pyridyl, pyridyl, -CH ₂ - naphthyl, -CH ₂ - (N-morpholino), p-(N-morpholino -CH ₂ CH ₂ O) benzyl , Benzo [b] thiophen-2-yl, 5-chlorobenzo [b] thiophen-2-
Yl, 4,5,6,7-tetrahydrobenzo [b] thiophen-2-yl, benzo [b
] Thiophen-3-yl, 5-chlorobenzo [b] thiophen-3-yl, benzo [
b] thiophen-5-yl, 6-methoxy-naphth-2-yl, -CH ₂ CH ₂ SC
H _3, thien-2-yl, selected from the group consisting of 3-yl, claim 3
3. The compound according to 2. 34. The compound according to claim 27, wherein R ³ is selected from the group consisting of hydrogen, alkyl, substituted alkyl and cycloalkyl. 35. R ³ is hydrogen, methyl, 2-methylpropyl, hexyl, methoxycarbonylmethyl, 3,3-dimethyl-2-oxobutyl, 4-phenylbutyl, cyclopropylmethyl, 2,2,2 35. The compound according to claim 34, wherein the compound is selected from the group consisting of ethyl and cyclohexyl. 36. The method of claim 2, wherein R ⁴ is hydrogen, alkyl or substituted alkyl.
8. The compound according to 7. 37. The compound according to claim 27, wherein R ⁵ is selected from the group consisting of alkyl, substituted alkyl, phenyl, substituted phenyl, cycloalkyl, heteroaryl, and heterocyclic. 38. The compound, wherein 5- (S)-(N ′-(2- (3,5-difluorophenyl) ethyl) -L-alaninyl) -amino-7-methyl-5,7-dihydro- 6H-dibenz [b, d] azepin-6-one, 5 (S)-(N '-(2 (R) -hydroxy-2- (3,5-difluorophenyl) ethyl) -L-alaninyl
) -Amino-7-methyl-5,7-dihydro-6H-dibenz [b, d] azepin-6-one, 5 (S)-(N ′-(2 (S) -hydroxy-2- (3, 5-difluorophenyl) ethyl) -L-alaninyl
) -Amino-7-methyl-5,7-dihydro-6H-dibenz [b, d] azepin-6-one, 5 (S)-(N ′-(2 (R / S) -hydroxy-3-isopropyl (Oxy-propyl) -L-alaninyl)
-Amino-7-methyl-5,7-dihydro-6H-dibenz [b, d] azepin-6-one, 5 (S)-(N '-(2 (R / S) -hydroxy-butyl) -L -Alaninyl) -amino-7-methyl-5,7-dihydro-6H-dibenz [b, d] azepin-6-one, 5 (S)-(N '-(2 (R / S) -3-dihydroxy -Propyl) -L-alaninyl) -amino-7-methyl-
5,7-dihydro-6H-dibenz [b, d] azepin-6-one, 5 (S)-(N '-(2 (R / S) -hydroxy-3-morpholinopropyl) -L-alaninyl)- Amino-7
-Methyl-5,7-dihydro-6H-dibenz [b, d] azepin-6-one, 5 (S)-(N '-(2 (R / S) -hydroxy-tetradecyl) -L-alaninyl)- Amino-7-methyl-
5,7-dihydro-6H-dibenz [b, d] azepin-6-one, 5 (S)-(N '-(2 (R / S) -hydroxy-octyl) -L-alaninyl) -amino-7 -Methyl-5,7-
Dihydro-6H-dibenz [b, d] azepin-6-one, 5 (S)-(N '-(2 (R) -hydroxy-2- (3,4,5-trifluorophenyl) ethyl) -L -Alaninyl) -amino-7-methyl-5,7-dihydro-6H-dibenz [b, d] azepin-6-one, 5 (S)-(N '-(2 (S) -hydroxy-2- ( 3,4,5-trifluorophenyl) ethyl) -L-alaninyl) -amino-7-methyl-5,7-dihydro-6H-dibenz [b, d] azepin-6-one, 5 (S)-( N '-(2 (R) -hydroxy-2- (4- (trifluoromethyl) phenyl) ethyl) -L-alaninyl) -amino-7-methyl-5,7-dihydro-6H-dibenz [b, d Azepin-6-one, 5 (S)-(N '-(2 (S) -hydroxy-2- (4- (trifluoromethyl) phenyl) ethyl) -L-alaninyl) -amino-7-methyl- 5,7-dihydro-6H-dibenz [b, d] azepin-6-one, 5 (S)-(N '-(2 (R) -hydroxy-2- (3,5-bis- (trifluoromethyl ) Phenyl) ethyl) -L-alaninyl) -amino-7-methyl-5,7-dihydro-6H-dibenz [b, d] azepine -
6-one, 5 (S)-(N '-(2 (S) -hydroxy-2- (3,5-bis- (trifluoromethyl) phenyl) ethyl) -L-alaninyl) -amino-7-methyl -5,7-dihydro-6H-dibenz [b, d] azepine-
6-one, 5 (S)-(N '-(2 (R) -hydroxy-2- (3,3,3-trifluoro) -propyl) -L-alaninyl)
-Amino-7-methyl-5,7-dihydro-6H-dibenz [b, d] azepin-6-one, 5 (S)-(N '-(2 (S) -hydroxy-2- (3,3 , 3-Trifluoro) -propyl) -L-alaninyl)
-Amino-7-methyl-5,7-dihydro-6H-dibenz [b, d] azepin-6-one, 5- (S)-(N '-(3-methyl-2-butanone) -L-alaninyl ) -Amino-7-methyl-5,7-dihydro-6H-dibenz [b, d] azepin-6-one, 5- (S)-(N ′-(3-methyl-2- (S) -hydroxy Butyl) -L-alaninyl) -amino-7-methyl-5,7-dihydro-6H-dibenz [b, d] azepin-6-one, 3- (N '-(3-methyl-2- (S) 2-Hydroxybutyl) -L-alaninyl) -amino-2,4-
Dioxo-1-methyl-5-phenyl-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine, 3- (N '-(2- (R / S) -3,5-difluorophenyl- 2-hydroxyethyl) -L-alaninyl)-
Amino-2,4-dioxo-1-methyl-5-phenyl-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine, ☆ 5- [N '-(S) -2- (4- Methylpentyl) amino-3-methylbutyryl-L-alaninyl] -amino-7-methyl-5,7-dihydro-6H-dibenz [b, d] azepin-6-one, 5- (S)-{N'- [(1RS, 2SR) -1,2,3,4-tetrahydro-1-hydroxy-2-naphthyl] alaninyl} -amino-7-methyl-5,7-dihydro-6H-dibenz [b, d] azepine- 6-one, 5- (S)-{N '-[(1RS, 2RS) -1,2,3,4-tetrahydro-1-hydroxy-2-naphthyl] alaninyl} -amino-7-methyl-5, 7-dihydro-6H-dibenz [b, d] azepin-6-one, 5- (S)-[N '-(2-a-tetralone) -L-alaninyl] -amino-7-methyl-5,7 -Dihydro-6H
-Dibenz [b, d] azepin-6-one hydrochloride, 5- (S)-[N '-(1,2,3,4-tetrahydro-2-naphthyl) -L-alaninyl] -amino-7- Methyl-5,7-dihydro-6H-dibenz [b, d] azepin-6-one, 5- (S)-{N '-[(1RS, 2SR) -1-hydroxy-2-cyclohexyl] alaninyl}- Amino-7-
Methyl-5,7-dihydro-6H-dibenz [b, d] azepin-6-one, 5- (S)-[N '-(4-methylpentyl) -L-alaninyl] -amino-7-methyl- 5,7-dihydro-
28. The compound according to claim 27 selected from the group consisting of 6H-dibenz [b, d] azepin-6-one.