JP2002518451A - Cyclic amino acid compound and pharmaceutical composition thereof, and method of inhibiting release of β-amyloid peptide and / or synthesis thereof using the compound - Google Patents

Abstract

  (57) [Summary] The present invention relates to compounds that inhibit the release of β-amyloid peptide and / or its synthesis, and thus have utility in treating Alzheimer's disease. The present invention also relates to pharmaceutical compositions comprising compounds that inhibit the release of and / or synthesis of β-amyloid peptide, and methods of treating Alzheimer's disease using these pharmaceutical compositions prophylactically and therapeutically. Also concerns.

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. Pat. No. 4,666,829 (issued May 19, 1987). 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. 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.

[0010] 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) (Atony Docket No. 002010-062) `` Cycloalkyl, Lactam, Lactone and Relate
d Compounds, Pharmaceutical Compositions Comprising Same, and Methods fo
r inhibit β-Amyloid Peptide Release, and / or its Synthesis by Use of
Such Compounds, "which is incorporated herein by reference. The present invention relates to novel N-terminal cyclic amino acid derivatives of these 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 or formula Ia:

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, heteroaryl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, 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 image Indicated by R ¹ , together with R ^′ and the carbon and nitrogen atoms respectively attached thereto, is a nitrogen-containing heterocyclic or heterocyclic or heteroaryl group of the formula Ia or Ia To form R ^″ is selected from the group consisting of hydrogen, alkyl, substituted alkyl and aryl. Each R ² is independently selected from the group consisting of alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, aryl, heteroaryl, and heterocyclic. Each R ³ independently comprises hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, acyl, aryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heteroaryl, and heterocyclic. Selected from the group. 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, alkoxy, substituted alkoxy, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, substituted amino, aryl, aryloxy, cycloalkyl, substituted cycloalkyl, cycloalkenyl,
It is selected from the group consisting of substituted cycloalkenyl, heteroaryl, heterocyclic, thioalkoxy and substituted thioalkoxy. Q is selected from the group consisting of oxygen, sulfur, -S (O)-, -S (O) _2- , -C (O)-and -C (S)-. X is selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, acyl, aryl, cycloalkyl, substituted cycloalkyl, cycloalkyl, substituted cycloalkenyl, heteroaryl and heterocyclic Alternatively, X, one R ⁴ and the atoms to which they are attached together form a double bond. Each f is independently an integer of 0 to 2. n is an integer of 1 or 2. And a pharmaceutically acceptable salt thereof.

The present invention also provides novel pharmaceutical compositions comprising a pharmaceutically acceptable carrier and a compound of Formula I or Ia as described above.

Accordingly, 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, the method comprising administering to the cell a compound of the above formula I / Ia or a compound thereof. Administering a mixture of compounds 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 / Ia also prevent and / or therapeutically prevent AD. And / or used in conjunction with a pharmaceutical composition to be treated. Thus, in another aspect of the method, the present invention relates to a prophylactic method of preventing the development of AD in a patient at risk of developing AD, the method comprising administering to the patient a pharmaceutically acceptable inactive agent. Administering a pharmaceutical composition comprising an effective amount of a carrier and a compound of Formula I / Ia or a mixture of such compounds.

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 possible carrier and an effective amount of a compound of formula I / Ia or a mixture thereof.

In the above formula I or Ia, ring A and ring B may be the same or different and are independently selected from the group consisting of aryl, cycloalkyl, cycloalkenyl, heteroaryl and heterocyclic Preferably.
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.

R ¹ is preferably a heterocycle defined by R ^′ and a nitrogen atom and a carbon atom bonded thereto, each being, for example, a monocyclic nitrogen-containing heterocycle (the ring may be optionally hydroxyl, keto , Thioketo, alkyl, substituted alkyl, alkoxy, substituted alkoxy, amino,
Substituted amino, aryl, aryloxy, cyano, cycloalkyl, substituted cycloalkyl, halo, heteroaryl, heteroaryloxy, nitro, thiol,
Substituted with 1 to 3 substituents selected from the group consisting of thioalkoxy, substituted thioalkoxy, thioaryloxy, thioheteroaryloxy, etc.)
A bicyclic heterocycle (where the second cyclic group is aryl, cycloalkyl,
Selected from the group consisting of cycloalkenyl, heteroaryl and heterocyclic, and wherein the bicyclic groups include fused bicyclic, bridged bicyclic and spiro bicyclic;
Further each ring is optionally hydroxyl, keto, thioketo, alkyl, substituted alkyl, alkoxy, substituted alkoxy, amino, substituted amino, aryl, aryloxy, cyano, cycloalkyl, substituted cycloalkyl, halo, heteroaryl, heteroaryloxy, A nitro, thiol, thioaroxy, substituted thioalkoxy, thioaryloxy and thioheteroaryloxy substituted with 1 to 3 substituents selected from the group consisting of: The second and / or third cyclic groups are independently
Selected from the group consisting of aryl, cycloalkyl, cycloalkenyl, heteroaryl, and heterocyclic, and wherein the tricyclic groups include fused tricyclic, bridged tricyclic, spiro tricyclic, and combinations thereof; Is optionally hydroxyl, keto, thioketo, alkyl, substituted alkyl, alkoxy, substituted alkoxy, amino, substituted amino, aryl, aryloxy, cyano, cycloalkyl, substituted cycloalkyl, halo, heteroaryl, heteroaryloxy, nitro, thiol , Substituted with 1 to 3 substituents selected from the group consisting of thioalkoxy, substituted thioalkoxy, thioaryloxy, thioheteroaryloxy, etc.).

R ¹ is defined by R ^′ and the nitrogen and carbon atoms attached thereto. Particularly preferred nitrogen-containing heterocycles are, for example, pyrrolidinyl,
4-hydroxypyrrolidinyl, azetidinyl, thiazolidinyl, piperidinyl,
Piperazinyl, dihydroindolyl (eg, 2,3-dihydroindol-2-yl), tetrahydroquinolinyl (eg, 1,2,3,4-tetrahydroquinolin-2-yl, 1,2,3) , 4-tetrahydroquinolin-1-yl, 1,2,3,4-tetrahydroquinolin-3-yl), morpholinyl, thiomorpholinyl, 4-halopyrrolidinyl, 3-phenylpyrrolidinyl, 4-aminopyrrolidinyl, 3- Methoxypyrrolidinyl, 4,4-dimethylpyrrolidinyl, 5.5
-Dimethylthiazolindin-4-yl, 2,3,4,5-
Includes tetrahydrooxazol-4-yl, perhydroindol-2-yl and the like.

R ¹ is defined by R ^′ and the nitrogen and carbon atoms attached thereto, and each preferred nitrogen-containing heteroaryl group is, for example, a monocyclic heteroaryl (the groups optionally being hydroxyl , Alkyl,
Substituted alkyl, alkoxy, substituted alkoxy, amino, substituted amino, aryl,
1-3 selected from the group consisting of aryloxy, cyano, cycloalkyl, substituted cycloalkyl, halo, heteroaryl, heteroaryloxy, nitro, thiol, thioalkoxy, substituted thioalkoxy, thioaryloxy and thioheteroaryloxy Bicyclic heteroaryl, wherein the second cyclic group is aryl, cycloalkyl,
Selected from the group consisting of cycloalkenyl, heteroaryl and heterocyclic, and wherein the bicyclic groups include fused bicyclic and bridged bicyclic, each ring optionally having hydroxyl, alkyl, substituted alkyl, alkoxy, substituted Alkoxy, amino, substituted amino, aryl, aryloxy, cyano, cycloalkyl,
Substituted cycloalkyl, halo, heteroaryl, heteroaryloxy, nitro,
Thiol, thiolalkoxy, substituted thiolalkoxy, thioaryloxy and thioheteroaryloxy are substituted with 1 to 3 substituents selected from the group consisting of a cycloalkyl group, A cycloalkenyl or heterocyclic group, a keto group and a thioketo group); and a tricyclic hetaryl, wherein the second and / or third cyclic groups are independently aryl, cycloalkyl, cycloalkenyl, Selected from the group consisting of heteroaryl and heterocyclic, and wherein the tricyclic groups include fused tricyclic, bridged tricyclic, spiro tricyclic, and any combination thereof, further wherein each ring is optionally hydroxyl, Alkyl, substituted alkyl, alkoxy, substituted alkoxy, aryl, aryloxy , Cyano, cycloalkyl, substituted cycloalkyl, halo, heteroaryl, heteroaryloxy, nitro, thiol, thioalkoxy, substituted thioalkoxy, thioaryloxy and thioheteroaryloxy. Substituted with substituents, and the second / third cyclic group is a cycloalkyl group, a cycloalkenyl group or a heterocyclic group, a keto group and a thioketo group).

R ¹ is defined by R ^′ and the nitrogen and carbon atoms attached thereto. Particularly preferred heteroaryls are each, for example, pyridinyl, 2-quinoxalinyl, indolyl, N-methylindolyl, 3- Amino-2-pyrazinyl, 3-amino-5,6-dichloro-2-pyrazinyl, 4-methoxyindolyl,
3-isoquinolinyl and the like.

R ² is alkyl, substituted alkyl, alkenyl, cycloalkyl, aryl,
It is preferably selected from the group consisting of heteroaryl and heterocyclic.

Particularly preferred R^TwoSubstituents include, for example, methyl, ethyl, n-propyl, isop
Propyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, -C
H_TwoCH (CH_TwoCH_Three)_Two, 2-methyl-n-butyl, 6-fluoro-n-hexyl
, Phenyl, benzyl, cyclohexyl, cyclopentyl, cycloheptyl,
Ryl, iso-but-2-enyl, 3-methylpentyl, -CH_Two-Cyclopropyl
, -CH_Two-Cyclohexyl, -CH_TwoCH_Two-Cyclopropyl, -CH_TwoCH_Two
-Cyclohexyl, -CH_Two-Indol-3-yl, p- (phenyl) phenyl
, O-fluorophenyl, m-fluorophenyl, p-fluorophenyl, m-
Methoxyphenyl, p-methoxyphenyl, phenethyl, benzyl, m-hydro
Xybenzyl, p-hydroxybenzyl, p-nitrobenzyl, m-trifluoro
Lomethylphenyl, p- (CH_Three) NCH_TwoCH_TwoCH_TwoO-benzyl, p- (CH_Three)_Three COC (O) CH_TwoO-benzyl, p- (HOOCCH_TwoO) -benzyl, 2-amino
Pyridin-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, cyclohex-2-enyl
, -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 (e.g., 1-naphthyl and 2-
Naphthyl), -CH_Two-(N-morpholino), p- (N-morpholino-CH_TwoCH_TwoO
) -Benzyl, benzo [b] thiophen-2-yl, 5-chlorobenzo [b] thiof
Hen-2-yl, 4,5,6,7-tetrahydrobenzo [b] thiophen-2-yl
Benzo [b] thiophen-3-yl, 5-chlorobenzo [b] thiophen-3-i
Benzo [b] thiophen-5-yl, 6-methoxynaphth-2-yl, -CH _Two CH_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 hydrogen, alkyl, substituted alkyl, phenyl, substituted phenyl (eg,
2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 2-chlorophenyl, etc.), cycloalkyl (eg, cyclohexyl), or heteroaryl or heterocyclic (eg, 1-piperidinyl, 2-pyridyl, 2- Thiazyl, 2-thienyl, etc.) are preferred.

F is preferably 0 or 1. f is 0, and when f is 0, it is more preferable that a methylene group or a methenylene group is defined.

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.

R ⁸ is preferably 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,
Q is oxygen, sulfur, -S (O)-, -S (O) _2- , -C (O)-or -C (S)-. ].

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 present 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 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 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 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:

Embedded image 5- (S) - [(N '- Homopuroriru) -L- alaninyl] amino-7-methyl-5,
7-dihydro-6H-dibenzo [b, d] azepin-6-one;

[0058]

Embedded image 5- (S)-[L-prolyl-L-alaninyl] amino-7-methyl-5,7-dihydro-6H-dibenzo [b, d] azepin-6-one;

[0059]

Embedded image 5- (S) - [(N '- octahydroindolyl-2 oil) -L- alaninyl]
Amino-7-methyl-5,7-dihydro-6H-dibenzo [b, d] azepine-6
on;

[0060]

Embedded image 5- (S)-[L- (4- (3-methylbutyl) prolyl) -L-alaninyl] amino-7-methyl-5,7-dihydro-6H-dibenzo [b, d] azepin-6-one;

[0061]

Embedded image ^{5- (S) - [N '} - picolinyl -L- alaninyl] amino-7-methyl-5,7
Dihydro-6H-dibenzo [b, d] azepin-6-one;

[0062]

Embedded image 5- (S)-[N ^' -(1,2,3,4-tetrahydroisoquinoline-1-oil)-
L-alaninyl] amino-7-methyl-5,7-dihydro-6H-dibenzo [b, d
Azepin-6-one;

[0063]

Embedded image 5- (S)-[N ^' -(decahydroquinolyl-2-oil) -L-alaninyl] amino-7-methyl-5,7-dihydro-6H-dibenzo [b, d] azepin-6-one;

[0064]

Embedded image 5- [N ^' -(decahydroquinolyl-2-oil) -L-alaninyl] amino-7
-Methyl-5,7-dihydro-6H-dibenzo [b, d] azepin-6-one;

[0065]

Embedded image 5- {N ^' -[(S) -indolyl-2-oil] -L-alaninyl} amino-7-
Methyl-5,7-dihydro-6H-dibenzo [b, d] azepin-6-one;

[0066]

Embedded image 5- (S)-{N ^' -[(S) -indolyl-2-oil] -L-alaninyl} amino-7-methyl-5,7-dihydro-6H-dibenzo [b, d] azepine-6- on;

[0067]

Embedded image 5- (S)-[N ^' -(L-trans-4-hydroxyprolyl) -L-alaninyl
] Amino-7-methyl-5,7-dihydro-6H-dibenzo [b, d] azepine-6
-On;

[0068]

Embedded image 5- (S)-[N ^' -(1,2,3,4-tetrahydroquinolyl) -2-oil) -L-
Alaninyl] amino-7-methyl-5,7-dihydro-6H-dibenzo [b, d] azepin-6-one;

[0069]

Embedded image 5- (S)-[N ^' -(3,3-dimethylindolyl-2-oil) -L-alaninyl] amino-7-methyl-5,7-dihydro-6H-dibenzo [b, d] azepine-
6-one;

[0070]

Embedded image 5- {N ^' -((S) -2-methylindolyl-2-oil] -L-alaninyl} amino-7-methyl-5,7-dihydro-6H-dibenzo [b, d] azepine-6- on;

[0071]

Embedded image 5- (S)-{N ^' -[(S) -2-methylindolyl-2-oil] -L-alaninyl} amino-7-methyl-5,7-dihydro-6H-dibenzo [b, d] Azepine-
6-one;

[0072]

Embedded image 5- [N ^' -(indole-2-oil) -L-alaninyl] amino-7-methyl-5,7-dihydro-6H-dibenzo [b, d] azepin-6-one;

[0073]

Embedded image 1- (S)-[N ^' -(3,3-dimethylindolyl-2-oil) -L-alaninyl] amino-7-methyl-4,5,6,7-tetrahydro-2H-3-benzazepine -2-one;

[0074]

Embedded image 1- (S)-{N ^' -(1,2,3,4-tetrahydroquinolyl-2-oil) -L-
[Alaninyl] amino-3-methyl-4,5,6,7-tetrahydro-2H-3-benzazepin-2-one;

3-[(N ^′ -(3-pyridinoyl) -L-alaninyl] amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one;

5- {N ^′ -(2-piperidinecarboxyl) -L-alaninyl] amino-7-methyl-5,7-dihydro-6H-dibenzo [b, d] -azepin-6-one (both enantiomers ),and

[0077]

Embedded image 5- [N ^' -(quinolyl-2-oil) -L-alaninyl] amino-7-methyl-
5,7-dihydro-6H-dibenzo [b, d] -azepin-6-one.

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. Jacques1, A. Collet an
d SJ Wilen (Wiley-Interscience 1981) and European Patent Application EP-A-8384
No. 48 (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 or Ia (including, for example, acyl forms of alcohols and thiols, aminal forms of one or more amines, and the like) are also within the scope of the 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, 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:

[Table 1] Alternatively, it is 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 of methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, n-hexyl, decyl, dodecyl, hexadecyl 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 20 carbon atoms) having 1 to 5 substituents (preferably 1 to 3 substituents) selected from the group consisting of -aryl and -SO ₂ -heteroaryl. .

“Alkylene” is preferably 1 to 20 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 20 carbon atoms, more preferably having 1 to 6 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” means a divalent alkenylene group preferably having 2 to 20 carbon atoms, more preferably having 2 to 6 carbon atoms. The term ethylene (-CH = C
H-), the propenylene isomers (e.g., -CH ₂ CH = CH- and -C (CH ₃₎
= 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 selected from the group consisting of SO ₂ -heteroaryl) (preferably having 2 to 20 carbon atoms, more preferably having 2 to 6 carbon atoms)
Means In addition, those substituted alkenylene groups are alkenylene (
alkylene) groups, wherein two substituents are fused to form one or more cycloalkyl, aryl, heterocyclic or heteroaryl groups fused to an alkylene group.

“Alkaryl” refers to an alkylene moiety having preferably 1 to 20 carbon atoms, more preferably 1 to 6 carbon atoms, and an aryl moiety having 6 to 10 carbon atoms.
It means an alkylene-aryl group. These alkaryl groups are exemplified by benzyl, phenethyl and the like.

“Alkoxy” means an “alkyl-O—” group wherein “alkyl” is as defined above. 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” means a “substituted alkyl-O—” group wherein substituted alkyl is as defined above.

“Alkylalkoxy” refers to an “-alkylene-O-alkyl” group, wherein
Alkylene and alkyl means a is) as defined above, 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} (CH 3) 2),
Including methylene -t- butoxy _{(-CH 2 -O-C (CH} 3) 3).

“Alkylthioalkoxy” means an “-alkylene-S-alkyl” group wherein alkylene and alkyl are as defined above, for example, methylenethiomethoxy (—CH ₂ SCH ₃ ) , ethylene thiomethoxide (-CH ₂ C
H ₂ SCH _3), n- propylene - thio - iso - propoxy (-CH ₂ CH ₂ CH ₂
SCH (CH _{3) 2),} and the like methylenethio -t- butoxy _{(-CH 2 SC (CH 3)} 3).

“Alkenyl” is preferably 2-20 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” is preferably 2-10 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 the group —NRC (O) R, where each R is independently hydrogen, alkyl, substituted alkyl, aryl, heteroaryl or heterocyclic, wherein alkyl, substituted alkyl, aryl , Heteroaryl and heterocyclic are as defined herein).

“Aminoacyloxy” refers to 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 the definition for aryl substituents indicates otherwise, the aryl groups may be optionally 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.

The term “cycloalkyl” refers to a cycloalkyl having 3 to 20 carbon atoms (preferably having 3 to 12 carbon atoms) having a single ring or a polycyclic ring (including a condensed ring, a bridged ring, a spiro ring and a combination thereof). Means a cyclic alkyl group. 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.

The term “cycloalkenyl” refers to a monocyclic or polycyclic ring (including a condensed ring, a bridged ring, a spiro ring and a combination thereof) and 4 to 20 carbon atoms (4 to 12 carbon atoms) having at least one internal unsaturation. (Preferably having 3 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 otherwise indicated 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.

The heteroaryl groups may have a single ring (eg, pyridyl or furyl) or multiple rings (including fused and bridged ring structures) (eg, indolodinyl or benzothienyl).

“Monocyclic heteroaryl” means a monocyclic heteroaryl group, and is exemplified by, for example, pyridyl, pyrrolyl and pyrimidine.

“Bicyclic heteroaryl” refers to a fused ring wherein at least one ring comprises a heteroatom and the other ring is selected from the group consisting of cycloalkyl, cycloalkenyl, aryl, heteroaryl and heterocyclic. A heteroaryl group consisting of a bicyclic ring, which may be substituted or bridged.

“Tricyclic heteroaryl” means that each ring system is independently fused or bridged, wherein at least one of the rings contains a heteroatom and the other two rings are cycloalkyl. It means a heteroaryl group consisting of a tricyclic ring selected from the group consisting of alkyl, cycloalkenyl, aryl, heteroaryl and heterocyclic. If the remaining two rings are cycloalkyl, cycloalkenyl or heterocyclic, these rings may optionally be spiro-linked.

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

“Heterocycle” or “heterocyclic”
"Means a monovalent saturated or unsaturated group having 1 to 15 carbon atoms and a monocyclic or polycondensed ring having 1 to 4 heteroatoms selected from nitrogen, sulfur or oxygen in the ring. .

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 rings (including fused rings, bridged rings, spiro rings and combinations thereof). Preferred heterocyclics include morpholino, piperidinyl and the like.

“Nitrogen-containing heterocycle” means the above heterocyclic groups (including saturated and unsaturated heterocyclic groups) wherein at least one heteroatom of the heterocyclic group is nitrogen.

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

“Bicyclic heterocycle” refers to a fused, heterocyclic, heterocyclic ring wherein at least one ring comprises 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” means a “> C ＝ O” group.

“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, optionally including 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 a "> C = S" group.

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

Embedded image [Where the atoms and bonds are each numbered and printed for naming purposes. ] 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 each numbered and printed for naming purposes. ] 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 each numbered and printed for naming purposes. ] 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 each numbered and printed for naming purposes. ] Means a polycyclic ε-caprolactam ring system having

For 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 salt” is a pharmaceutically acceptable salt of a compound of Formula I or Ia, which salt comprises a number of organic and inorganic counters well known in the art. Derived from ions, including, for example, sodium, potassium, calcium, magnesium, ammonium, tetraalkylammonium, and the like; and when the molecule has basic functionality, salts of organic or inorganic acids (eg, hydrochloric acid). Salts, hydrobromide, tartrate, methanesulfonate, acetate, maleate, oxalate, etc.) can be used as pharmaceutically acceptable salts

The phrase “protecting group” or “blocking group” refers to a compound attached to one or more amino, hydroxyl, thiol, carboxyl or other protectable functional groups of a compound. A group that prevents a reaction from taking place at these groups and in which protecting groups can be removed by conventional chemical and enzymatic steps to regenerate unprotected functional groups. I do. 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, compounds of formula I (and related compounds of formula Ia)
Is easily produced by a usual acylation reaction as exemplified in the following reaction formula 1.

Embedded image

As shown in Scheme 1, protected carboxylic acid 1 (B ¹ is an amino protecting group and R ² is as defined herein) can be converted to a conventional acyl group well known in peptide chemistry. Depending on the oxidation reaction conditions, amine compounds such as 2 (wherein R ⁶ , R ⁷ , R ⁸ ,
(p and q are as defined herein), and after deprotection, intermediate 3 can be obtained.

In Scheme 1, amine 2 is merely representative, and one skilled in the art can use any amino derivative of any of the other ring systems described herein in this reaction to provide a compound of Formula I Would be able to obtain Similarly, amino acid 4 can be substituted with an unsaturated heterocyclic or heteroaryl amino acid (eg, picolinic acid (pyridin-2-
Yl carboxylic acid) to give compounds of formula Ia.

The intermediate 3 is then acylated using a cyclic amino acid (eg, 4 ), wherein R ^′ , R ^″ and R ¹ are as defined herein, or A ring reaction can be performed. If necessary, it can be blocked using a blocking group capable of removing the amino group of the cyclic amino acid 4 (for example, BOC, CBZ, etc.).

Both acylation reactions are typically carried out using conventional coupling reagents and methods, and, in the case of the first acylation reaction, stoichiometric amounts of intermediate 2 and carboxylic acid 1, and In the case of the acylation reaction, the intermediate 3 and the carboxylic acid 4 are used. For example, use of well-known coupling reagents such as carbodiimide to promote the coupling reaction with or without the use of well-known additives (such as N-hydroxysuccinimide, 1-hydroxybenzotriazole). It is possible. The reaction is usually performed in an inert aprotic polar diluent (dimethylformamide, dichloromethane, chloroform, acetonitrile, tetrahydrofuran, etc.). Alternatively, the acid halides of compounds 1 and / or 4 can be used in the acylation reaction of reaction formula (1), and when they are used, typically to remove the acid formed during the reaction. Use in the presence of a suitable base. Suitable bases include, for example, triethylamine, diisopropylethylamine, N-methylmorpholine and the like.

Alternatively, compound 5 can be reacted with amine 2 and formula 6 under the usual acylation reaction conditions described above.
:

Embedded image Wherein R ^′ , R ^″ , R ¹ and R ² are as described herein.

When n is 2, a second acylation reaction is performed simply by coupling the compound of formula I with Intermediate 3 , followed by removal of the blocking group, and then under normal acylation conditions cyclic The compound of the present invention can be produced by coupling reaction with amino acid 4 . Alternatively, a triamino acid analog of compound 6 can be prepared, which can then be coupled with amine 2 according to conventional reaction conditions as described above to give a compound of formula I or Ia.

Synthesis of Amino Acid Starting Materials Amino acids 1 and 4 used in the above reactions are well known in the art, and many of these amino acids are commercially available. In addition, when n is 1 or 2,
These amino acids can be readily prepared by a number of divergent synthetic routes having selected particular routes that are relatively chosen in terms of the difficulty of preparing the compound, the commercial availability of starting materials, and the like.

Amino acids (eg, 1 and 4 ) can also be prepared using a carbodiimide peptide coupling reagent in a polymeric supported form. Polymer-supported forms of EDC have been described, for example, (Tetrahedron Letters, 34 (48), 7685 (1993)) ¹¹ .
In addition, a novel carbodiimide coupling reagent, PEPC, and its corresponding polymeric support forms have been discovered, which are very useful for the preparation of such compounds.

Polymers suitable for use in preparing polymer-supported coupling reagents are either commercially available or can be prepared by methods well known to those skilled in the polymer art. . Suitable polymers must have pendant side chains that possess moieties that react with the terminal amines of the carbodiimide. Those reactive moieties include chloro, bromo, iodo and methanesulfonyl. The reactive moiety is preferably a chloromethyl group. In addition, the polymer backbone must be inert both to the carbodiimide and to the reaction conditions using the final polymer coupled with the coupling reagent.

[0155] Certain hydroxymethylated resins can be converted to chloromethylated resins useful for the production of polymer-supported coupling reagents. Examples of these hydroxylated resins include 4-hydroxymethylphenylacetamidomethyl resin (Pam resin) and 4-benzyloxybenzyl alcohol resin (Wang resin) available from Advanced Chemtech of Louisville, Kentucky, USA (Advanced Chemtech 199
See 3-1994 catalog, p115). The hydroxymethyl group of these resins can be converted to the desired chloromethyl group by any of a number of methods well known to those skilled in the art.

[0156] Preferred resins include chloromethylated styrene / divinylbenzene resins because they are readily available commercially. As the name suggests, these resins are already chloromethylated and do not require chemical modification before use. These resins are commercially known as Merrifield resins and are available from the Aldrich Chemical Company of Milwaukee, Wisconsin, USA (see Aldrich, catalog 1994-1995, p899). The method for producing PEPC and its polymer-supported form is outlined in Reaction Scheme 2.

Embedded image

[0157] These methods are described in U.S. Patent Application No. 60 / 019,790 ¹⁴ No. (1996, June 14 filed) are well described by in its application to constitute a part of this specification. Briefly, 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. The polymeric support form 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 performed at about ambient temperature to about 45 ° C. for about 3 to 120 hours. Typically, the product is a reaction of CHCl ₃
And the remaining organics can be isolated by concentration under reduced pressure. As noted above, isolation of the product from the reaction using the polymer-bound reagent is very simple, requiring only filtration of the reaction mixture and then concentration of the filtrate under reduced pressure. is there.

Preparation of Cyclic Compounds (eg, Benzoazepinone, Dibenzoazepinone, Benzodiazepine and Related Compounds) The cyclic compounds (eg, 2 ) and their amino-substituted derivatives used in the above reactions are known in the art, Alternatively, it can be prepared by art-recognized methods using commercially available starting materials and reagents.

For example, 5,7-dihydro-6H-dibenzo [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, representative cyclic compounds, ie, 5,7-dihydro-6H-divezo [b,
Reaction Scheme 3 illustrates the synthesis of d] azepin-6-one. As will be readily apparent to one of ordinary skill in the art, the synthetic methods illustrated below in Scheme 3 and the reaction conditions thereof can be improved by selecting appropriate starting materials and reagents to provide suitable methods for use in the present invention. The production of other cyclic amines becomes possible.

Embedded image

As shown in Reaction Scheme 3, 5,7-dihydro-6H-dibenzo [b, d] azepine-6
-One derivative 23 (where R⁶, R⁷, P and q are as defined above), 2
Several steps from -bromotoluene derivative 18 and 2-bromoaniline derivative 20
And can be easily manufactured. In this synthesis method, the 2-bromotoluene derivative 18
Is converted to the corresponding 2-methylphenylboronic ester 19 first. this
The reaction is typically carried out in an inert diluent (e.g., THF) from about -80 <0> C to about -60.
At a temperature in the range of from about 0.25 to about 1 hour at about 1.0 to about 2.1 equivalents of
Kill lithium reagent (sec-butyl lithium or tert-butyl lithium
(Preferably). Then, the obtained lithium ani
Excess trialkyl borate in situ (preferably 1.5 equivalents)
(For example, trimethyl borate [(CH_ThreeO)_ThreeB]). This reaction first
Perform at -80 ° C to -60 ° C, then to about 0 ° C to about 30 ° C for about 0.5 hour to about 3 hours.
Let the temperature rise for hours. The resulting boronic acid methyl ester is typically not isolated,
Mix in situ with excess (preferably about 2.0 equivalents) pinacol.
Preferably, the compound is converted to pinacol ester by processing.
The reaction is typically carried out at ambient temperature for about 12 hours to about 24 hours to give 2-methylphene.
Nylboronic ester 19 (both R^aThe groups together form -C (CH_Three)_TwoC (CH _Three )_Two-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 3, 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-dibenzo [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-dibenzo [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 4.
The improvement of Scheme 4 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.

Embedded image

As shown in Reaction Scheme 4, 5,7-dihydro-6H-dibenzo [b, d] azepine-6
-One 23 is optionally N-alkylated using conventional reagents and conditions,
The 7-alkyl-5,7-dihydro-6H-dibenzo [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 performed at a temperature in the range of about 0 ° C. to about 60 ° C. for about 1.0 to about 48 hours to provide the 7-alkyl-5,7-dihydro-6H-dibenzo [b, d] azepine -6
The -one derivative 24 is obtained. However, if a substituted alkyl halide or cycloalkyl halide is used in this reaction, it is understood that the 7-substituent will be a substituted alkyl or cycloalkyl in place of the alkyl group referred to herein.

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-dibenzo [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-dibenzo [b, d] azepin-6-one derivative 25 is obtained.

The 5-amino-reaction was then carried out by a reduction reaction of 25 using the usual reagents and conditions.
7-alkyl-5,7-dihydro-6H-dibenzo [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
-Dibenzo [b, d] azepin-6-one 26 is purified using commonly known methods (eg, recrystallization and / or chromatography).

Alternatively, 5,7-dihydro-6H-dibenzo [b, d] azepin-6-one 2
6 with 5,5-dihydro-6H-dibenzo [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-dibenzo [ [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-dibenzo [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-dibenzo [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-dibenzo [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-dibenzo [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-dibenzo [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-dibenzo [b, d] azepin-6-one 26 is usually purified by well-known methods (eg, recrystallization and / or chromatography). ).

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

Embedded image

As shown in Reaction Scheme 5, 5,7-dihydro-6H-dibenzo [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-dibenzo [b, d] azepine-6.
The -one derivative 24 is obtained.

Then, 7-alkyl-5,7-dihydro-6H-dibenzo [b, d] azepine-
The 6-one 24 was converted to 5-azido-7-alkyl-5,7- using an azide transfer reagent.
Dihydro-6H-dibenzo [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 ~ 4 hours to obtain the 5-azido-7-alkyl-5,7-dihydro-6H-dibenzo [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-dibenzo [b, d] azepin-6-one 26 is obtained.

If desired, 5-amino-7-alkyl-5,7-dihydro-6H-dibenzo [
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 for making intermediates useful in the present invention is described in US patent application Ser. No. 09 / 102,726 (
Filed June 22, 1998, Atony Docket No. 002010-125, `` Polycyclic α-Am
ino-ε-caprolactams and Related Compounds), the disclosure of which is hereby incorporated by reference.

In addition, for a number of benzapinones and their related compounds, see Tetrahedron Lett. By Busacca et al., 33, 165-168 (1992); US Patent No. 4,080,449 by Crosisier et al .; Tetrahedron Lett by JA Robl et al. . 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.

The synthesis of alternative ring structures is shown in the examples below.

In synthesizing compounds of Formula I or Ia using the synthetic methods described herein,
Some starting materials contain a chiral center (eg, alanine), and if a racemic starting material is used, 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 or Ia 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 or Ia 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 cellulose. 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
Or the compound of Ia uses no more than about 20% by weight of the pharmaceutical composition, more preferably no more than about 15% by weight (the balance being a pharmaceutically active 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 present 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 are 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 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 (eg, 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 2]

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

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

[Table 3]

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 4]

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

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

[Table 5]

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 6]

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 7]

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 glyceride. 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 produced as follows.

[Table 8]

The active ingredient, sucrose and xanthan are mixed and sieved through a # 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 9]

The active ingredient, starch and magnesium stearate are mixed, sieved through a No. 20 mesh US sieve and filled into 425.0 mg hard capsules.

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

[Table 10]

(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 11]

[0219] 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.

While 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. . Latency is generally achieved by blocking hydroxy, carbonyl, sulfate, and primary amine groups on the drug to make it more soluble in lipids and to facilitate transport across the blood-brain barrier. Achieved. 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 Sciences), Mace Publishing Co.
mpany, Philadelphia, PA, 17th edition (1985).

Uses The compounds and pharmaceutical compositions of the present invention are useful for inhibiting beta-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 noted 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 noted above, the compound administered to the patient will take 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 examples and biological examples serve to illustrate the invention and are not to be considered as limiting the scope of the invention.

EXAMPLES In the following examples, the following abbreviations have the following meanings. If an abbreviation is not defined, it has its generally accepted meaning. 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 DMSO = dimethylsulfoxide EDC = ethyl-1- (3-dimethylaminopropyl) carbodiimide 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 = max mg = milligram mL = milliliter mm = millimeter mmol = millimol N = defined ng = nanogram nm = nanometer OD = optical density PEPC = 1- (3- (1-pyrrolidinyl) Propyl) -3-ethylcarbodiimide psi = pounds per square inch φ = phenyl q = quadruple quint. = Quintet rpm = rotation / min RT = room temperature s = singlet sat. = Saturation t = triplet 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 Process The following process can be used to prepare the compounds of the present invention, in which an amine compound (eg, amino acid ester or amine compound 2 above) is used.
Is reacted with a carboxylic acid compound.

General Preparation A First EDC Coupling Preparation A mixture of the corresponding carboxylic acid and the corresponding amine, amine hydrochloride, amino acid ester or amide (1: 1) in CH ₂ Cl ₂ at 0 ° C. with triethylamine (
1.5 eq. ) Followed by hydroxybenzotriazole monohydrate (2.0 eq)
. ), Followed by ethyl-3- (3-dimethylamino) propylcarbodiimide-HC
l (1.25 eq.) was added. The reaction mixture was stirred at room temperature overnight and then transferred to a separatory funnel. The mixture was washed with water, saturated aqueous NaHCO ₃ , 1N HCl and saturated aqueous NaCl, and 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 dichloromethane. The corresponding amine, amino acid ester or amide (1 eq.), N-methylmorpholine (5 eq.) And hydroxybenzotriazole monohydrate (1.2 eq.) Were added successively. Solution at 0 ° C
A cold bath was applied to the round bottom flask until the temperature reached. Thereafter, 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 A stirred solution of carboxylic acid (2 mmol) in DMF cooled in an ice-water bath was added with BO
P (2.4 mmol) and N-methylmorpholine (6 mmol) were added. The reaction mixture was stirred for 50 minutes and then cooled at 0 ° C. to α-amino-γ-lactam (
(2 mmol) in DMF 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. 20% potassium carbonate aqueous solution (6
0 mL) was added and the mixture was washed thoroughly. No solid formed. Then the mixture was washed with ethyl acetate (150 mL) and evaporated under vacuum to dryness to give a white solid. Then water (50 mL) was added and the mixture was shaken well. The precipitate formed was collected by filtration and then water followed by diethyl ether (1.
(mL) to give the product (51 mg, 0.16 mmol, 7.8%).

[0239] pyridine General Procedure F acid chloride coupling reaction an amine of amino acid ester, an amino acid ester or amide (4.6 mmol) (5 m
To the stirred solution of L), carboxylic 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, once with 20% potassium carbonate and once with brine. The solution was dried over magnesium sulfate, filtered and evaporated to give the product.

[0240] 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 A fifth EDC coupling preparation round bottom flask was charged with THF of carboxylic acid (1.1 eq.), Amine hydrochloride (1.0 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 make carboxylic acid intermediates useful in the present invention.

General Production Method II-A Hydrolysis of Ester to Free Acid The hydrolysis of the 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 (し た 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 A carboxylic acid (0.174 mol) was dissolved in dichloromethane and the solution was added at 0 ° C.
Cooled down. DMF (0.5 mL, catalytic amount) was added, followed by oxalyl chloride (
18 mL, 0.20 mol) was added dropwise over 5 minutes. The reaction was stirred for 3 hours,
Rotary evaporation under reduced pressure then gave an oil which was placed under a high vacuum pump for 1 hour to give the corresponding acid chloride.

General Preparation II-C The Schotten-Baumann Method Carboxylic Chloride (from General Preparation II-B) was converted to an amino acid (0.18) at 0 ° C.
(7 mol) in 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 solution was added to water (
100 mL) and extracted with ethyl acetate (3 × 150 mL). The organic phase is then washed with brine (200 mL), dried over MgSO _4, to yield a residue rotary evaporated under reduced pressure. The residue was recrystallized (from ethyl acetate / hexane) to give the desired product (34.5 g, 82% yield).

The following preparations illustrate the synthesis of cyclic intermediates useful for preparing the compounds of the present invention.

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

A. Benzoazepinone Derivatives and Related Compounds General Preparation Method 1-A 1-Amino-1,3,4,5-tetrahydro-2H-benzoazepin-2-one
Alkylation reaction step A : 1-ethoxycarbonylamino-1,3,4,5-tetrahydro-2H
-3-Benzoazepin-2-one is described in Tetrahdron, 1987, 43 by Ben-Ishai et al.
, 430.

Step B : 1-ethoxycarbonylamino-1,3,4,5-tetrahydro-2H
-3-Benzoazepin-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 rotavaped to give 1-amino-3-alkyl-1,3,4,5-tetrahydro-2H-3-benzazepine- The 2-one hydrobromide salt (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 the method described by Armstrong et al. In Tetrahedron Letters, 1994, 35, 3239. From α-tetralone. 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 used in the following step. It is manufactured by a manufacturing method.

Step B : 3-Amino-1,3,4,5-tetrahydro-2H-1-benzazepin-2-one (4.43 g, 100M%) was suspended in t-butanol (30 mL), and BOC was added. -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).

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
-Benzoazepin-2-one is described in Tetrahedron Letters, 1994 by Armstrong et al.
, 35, 3239, using 4-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 the BOC-protected 3-amino-5-methyl-1,3,4,5-tetrahydro-2H-1-benzazepin-2-one (55% yield). ) 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. The reaction was then rotary evaporated and 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 -benzo [b] azepin-6-one.hydrochloride 5-amino-3,3,7-trimethyl-5,7- according to the method of Example 2-I
The title compound was prepared using dihydro-6H-benzo [b] azepin-6-one.hydrochloride (Example 1-C).

Example 1-C Synthesis of 5-amino-3,3,7-trimethyl-5,7-dihydro-6H-benzo [b] azepin-6-one.hydrochloric acid Step A : General procedure N of lactam -Alkylation reaction To a stirred solution of BOC-protected α-aminocaprolactam (6.87 g, 30 mmol) in DMF (150 ml) was added 97% NaH (1.08 g, 45 mmol).
) 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.

Step B : General Preparation BOC Removal Method Anhydrous HCl gas vapor was bubbled through a stirred solution of Nt-Boc-protected amino acid in 1,4-dioxane (0.03-0.09M), ₂ below, and cooled over a period of 10-15 minutes until -10 ° C. in an ice bath. 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 the present general production method, Nt-Boc-5-amino-3,3,7-trimethyl-
The title compound was prepared using 5,7-dihydro-6H-benzo [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-benzoazepin-2-one: 3- (S) -amino-5-oxa-1,3,5,7-tetrahydro-2
-H-1-benzazepin-2-one was obtained from N-Boc-serine (Bachem) and 2-fluoro-1-nitrobenzene (Aldrich) in Bioorganic and Midicinal Chemisty Lett. 1995, 5 by RJ DeVita et al. (12) Manufactured using the method of 1281-1286.

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-Benzoazepin-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. Manufactured using the method of -1286.

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.
The title compound was prepared using the method of misty Lett. 1995, 5 (12) 1281-1286, followed by the general procedure of Step A of Example 1-C.

Example 1-G 7-Amino-1,3,4,7,12,12a-hexahydropyrido [2,1-b] [3]-
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.

[0274] Step B: 1, 3, 4, 7, 12,12a-hexahydropyrido [2,1-b] [3] ben
Synthesis of Zoazepin-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] [1,3,7,12,12a-hexahydropyrido [2,1-b] [ 3] The title compound was prepared using benzazepin-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 Preparation Method 3A ( According to step C), the 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.

[0277] 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 The title compound was prepared according to General Preparation Method F using 3-phenylpyridine · hydrochloric acid (Aldrich).

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.

[0281] 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.

[0282] 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 -dibenzo [a, c] cyclohepten-6 -ol.hydrochloric acid Step A: 5-Oxymo-5,7-dihydro-6H- Dibenzo [a, c] cyclohep
Synthesis of Ten-6-one In a round bottom flask, 5,7-dihydro-6h-dibenzo [a, c] cycloheptene-
6-one (1.0 g, 4.81 mmol) (CAS # 1139-82-8, Tetrahedron Lett
ers, 28, 23 (1987), pp. It was prepared as described in 2633-2636) and butyl nitrite (0.673mL, met of Et ₂ O 5.77 mmol) (Aldrich). The solution was cooled to 0 ° C. and treated dropwise with a saturated HCl (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-dibenzo [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-dibenzo [a, c] cyclohepten-6-one Boc-L-alanine according to General Preparation D above. (Aldrich) and 5
-Amino-5,7-dihydro-6H-dibenzo [a, c] cyclohepten-6-ol.hydrochloric acid (Example 2-A) was used to produce a tan foam.

The obtained 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. Dibenzoazepinone derivatives and related compounds General production method 3-A 5-Amino-7-alkyl-5,7-dihydro-6H-dibenzo [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-dibenzo [b, d] azepin-6-one and alkyl iodide, 7-
Alkyl-5,7-dihydro-6H-dibenzo [b, d] azepin-6-one was prepared.

Step B : 7-Alkyl-5,7-dihydro-6H-dibenzo [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-dibenzo [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-dibenzo [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-dibenzo [b, d] azepine-
Synthesis Step A of 6-one-hydrochloric acid A - 7-Methyl-5,7-dihydro-6H-dibenzo [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-dibenzo [b, d] azepine-
6-one (1.3 g, 6.22 mmol) (CAS # 20011-90-9, Te by Brown et al.
trahedron letters , No. 8, 667-670 (1971) and the preparations described therein. After stirring at 60 ° C. for 1 hour, the solution was diluted with methyl iodide (1.1).
(6 mL, 18.6 mmol) and continued stirring 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, N
a ₂ SO ₄ dried. Evaporate and flash chromatography (SiO ₂ , C
HCl ₃ ) to give 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-dibenzo [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-dibenzo [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 of (S)-and (R) -5- (L-alaninyl) amino-7-methyl-5,7-dihydro-6H-dibenzo [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-dibenzo [b, d] azepin-6-one Boc-L-alanine (0.429 g, 2.26 mmol) (Aldrich) was dissolved in THF, and HOBt.water Hydrate (0.305 g, 2.26 mmol) and 5
-Amino-7-methyl-5,7-dihydro-6H-dibenzo [b, d] azepine-6
Treated with -one (0.45 g, 1.89 mmol) (Example 3-A). The temperature was reduced to 0 ° C. and the reaction mixture was EDC (0.449 g, 2.26 mmol)
(Aldrich) and stirred under N ₂ for 17 hours. The reaction mixture is evaporated, the residue diluted with _{EtOAc / H 2 O, 1.0N 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 -dibenzo [b, d] azepin-6-one hydrochloric acid 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 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 Synthesis of (S)-and (R) -5- (L-valinyl) amino-7-methyl-5,7-dihydro-6H-dibenzo [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-dibenzo [b , d] azepin-6-one Boc-L-valine (0.656 g, 3.02 mmol) (Aldrich) was converted to T
Dissolved in HF, HOBt hydrate (0.408 g, 3.02 mmol), DIPE
A (1.05 mL, 6.05 mmol) and 5-amino-7-methyl-5,7-
Dihydro-6H-dibenzo [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)
Stirred under N ₂ for 17 hours. The reaction mixture is evaporated, the residue diluted with _{EtOAc / H 2 O, 1.0N HCl} , saturated NaHCO _3, brine, and dried over Na ₂ SO _4. These diastereomers are applied to a chiral cell OD column (eluate, 10% I
PA / 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-dibenzo [b, d] azepin-6-one.hydrochloric acid The compound isolated in Part A (each separated isomer) was dissolved in dioxane, and excess H was dissolved.
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- dibenzo [b, d] azepin-6-one Step A- (S)-and (R) -5- (N-Boc-L-tert-leucinyl) amino-7-methyl-5 , 7-Dihydro-6H-dibenzo [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-dibenzo [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 stirred under N ₂ for 17 hours. The reaction mixture was evaporated and the residue was washed with EtOAc /
Dilute with H ₂ O, wash with 1.0 N HCl, saturated NaHCO ₃ , brine and dry 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-dibenzo [b , d] azepin-6 -one.hydrochloric acid
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-dibenzo [b, d] azepin-6-one Step A- 5-Iodo-5, 7-dihydro-6H-dibenzo [b, d] azepine-
Synthesis of 6-one 5,7-dihydro-6H-dibenzo [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-dibenzo [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 zo [b, d] azepin-6-one These 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-dibenzo [b
Synthesis of [, d] azepin-6-one-hydrochloric acid Step A- 5- (N-Boc-amino) -7- (2-methylpropyl) -5,7-
Synthesis of dihydro-6H-dibenzo [b, d] azepin-6-one 5- (N-Boc-amino) -5,7-dihydro-6H-dibenzo [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 -dibenzo [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-dibenzo [b,
d] Synthesis of azepin-6-one.hydrochloric acid Step A- 5- (N-Boc-amino) -7- (methoxyacetyl) -5,7-di
Synthesis of hydro-6H-dibenzo [b, d] azepin-6-one 5- (N-Boc-amino) -5,7-dihydro-6H-dibenzo [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 cooled to C
Diluted with H ₂ Cl ₂ , washed several times with 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 dibenzo [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 dibenzo [b, d] azepin-6-one.hydrochloric acid Step A-5- (N-Boc-amino) -7- (3,3-dimethylbutanonyl)-
5,7-dihydro-6H-dibenzo [b, d] Synthesis of azepin-6-one 5- (N-Boc-amino) -5,7-dihydro-6H-dibenzo [b, d] azepi
A solution of 1-6-one (0.2 g, 0.617 mmol) (Example 3-E) in DMF was prepared.
, Cs_TwoCO_Three(0.3 g, 0.925 mmol) and warmed to 60 ° C.
To the reaction mixture was added 1-chloro-3,3-dimethyl-2-butanone (0.096 mL,
(0.74 mmol) (Aldrich) was added and stirring continued for 17 hours. Up to 23 ° C
After cooling with CH_TwoCl_TwoAnd washed several times with brine, _Two SO_FourAnd dried. The title compound was isolated as a colorless solid. C_{twenty five}H₃₀N_TwoO_Five(MW = 422.522); mass spectroscopy (MH⁺) 423.

Step B— 5-Amino-7- (3,3-dimethyl-2-butanonyl) -5,7-di
Synthesis of hydro-6H-dibenzo [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-dibenzo [
b, d] -Azepin-6-one.hydrochloric acid Synthesis step A: Nt-Boc-L-alanine and 5-amino-7-methyl-5,7-dihydro-6H-dibenzo according to general production method D Using [b, d] azepin-6-one, Nt-Boc-L-alaninyl-5-amino-7-methyl-5,
7-Dihydro-6H-dibenzo [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-dibenzo [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-
Dibenzo [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-dibenzo [b
Synthetic process A of N, t] -azepin-6-one.hydrochloride : According to general preparation method D, Nt-Boc-L-valine and 5-amino-7-methyl-5,7-dihydro-6H-dibenzo [ Using [b, d] azepin-6-one, Nt-Boc-L-valinyl-5-amino-7-methyl-5,7-
Dihydro-6H-dibenzo [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-dibenzo [b, d]
The title compound was prepared using -azepin-6-one. Other substituted Nt-Bo
cL-Valinyl-5-amino-7-methyl-5,7-dihydro-6H-dibenzo [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-dibenzo [b, d] azepin-6-one 5,7-dihydro according to General Preparation 3-A -6H-dibenzo [b, d] azepin-6-one (prepared as described in Tetrahedron Letters , 8, 667-670 (1971) by Brown et al. And references therein) and 1-chloro-4-phenyl The title compound was prepared using butane.

Example 3-L 5-Amino-7-cyclopropylmethyl-5,7-dihydro-6H-dibenzo [b
Synthesis of 5,7-dihydro-6H-dibenzo [b, d] azepin-6-one (Brown et al., Tetrahedron Letters , 8, 8, 667-). 670 (1971) and the references therein) and (bromomethyl) cyclopropane (
(Aldrich) to produce the title compound.

[0317] Example 3-M 5-amino-7- (2 ^{', 2',} 2 ^'- trifluoroethyl) -5,7-dihydro -6H
Synthesis of -Dibenzo [b, d] azepin-6-one 5,7-dihydro-6H-dibenzo [b, d] azepin-6-one (Brown et al., Tetrahedron Letters , 8), according to General Procedure 3-A. No. 667-670 (1971) and the references therein) and 1-bromo-2,2,2-trifluoroethane (Aldrich) were used to prepare the title compound.

Example 3-N Synthesis of 5-amino-7-cyclohexyl-5,7-dihydro-6H-dibenzo [b, d] azepin-6-one 5,7-dihydro according to General Preparation 3-A -6H-dibenzo [b, d] azepin-6-one (produced as described in Brown et al., Tetrahedron Letters , 8, 667-670 (1971) and references therein) and bromocyclohexane (Aldrich). Was used to produce the title compound.

Example 3-O 5- (L-alaninyl) amino-9-fluoro-7-methyl-5,7-dihydro-
Synthesis of 6H-dibenzo [b, d] azepin-6-one.hydrochloric acidStep 1: 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 2: 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 3 : 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 4: According to General Production Method 3-B, using substituted biphenyl derived from Step 3,
9-Fluoro-5,7-dihydro-6H-dibenzo [b, d] azepin-6-one was prepared.

Step 5 : 9-fluoro-5,7-dihydro-6H-dibenzo [b, d] azepin-6-one (1 eq., Step 4), cesium carbonate (1.1 eq., Aldrich)
And methyl iodide (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 Ac 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-6H-dibenzo [b, d] azepin-6-one. I got

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

Step 7: According to the process of Example 3-I, 5-amino-9-fluoro-7-methyl-5,7-dihydro-6H-dibenzo [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-dibenzo [b, d] azepin-6-one.hydrochloride Example The title compound was prepared according to the method of 3-O 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-dibenzo [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-dibenzo [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-dibenzo [b, d] azepin-6-one (Example 3-L).

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

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

Example 3-U Synthesis of 5- (L-valinyl) amino-7-phenbutyl-5,7-dihydro-6H-dibenzo [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-dibenzo [b, d] azepin-6-one (Example 3-U).

Example 3-V 5- (L-valinyl) amino-7-hexyl-5,7-dihydro-6H-dibenzo [
Synthesis process of b, d] azepin-6-one.hydrochloric acid A: According to general production method 3-A, 5,7-dihydro-6H-dibenzo [b,
d] Azepin-6-one ( Tetrahedron Letters , 8, No. 667-670 by Brown et al. (19
71) and the references therein) and 1-bromohexane (Aldrich) using 5-amino-7-hexyl-5,7-dihydro-6H-
Dibenzo [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-dibenzo [b, d] azepin-6-one.

Example 3-W 5- (L-valinyl) amino-10-fluoro-7-methyl-5,7-dihydro-
Synthesis of 6H-dibenzo [b, d] azepin-6-one.hydrochloric acid According to the production method of Example 3-J, 5-amino-10-fluoro-7-methyl-5,
The title compound was prepared using 7-dihydro-6H-dibenzo [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-dibenzo [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-dibenzo [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-dibenzo [b, d] azepin-6-one.hydrochloric acid According to the production method of Example 3-J, 5-amino-9-fluoro-7-methyl-5,7
The title compound was prepared using -dihydro-6H-dibenzo [b, d] azepin-6-one (as prepared in Example 3-O).

Example 3-Z Synthesis of (5-Amino-7-methyl-1,2,3,4,5,7-hexahydro-6H-dicyclohexyl [b, d] azepin-6-one 7-Methyl-5,7-dihydro-6H-dibenzo [b, d] azepin-6-one.hydrochloric acid (Example 3-A) was dissolved in a mixture of EtOAc / HOAc (1: 1), 5% Rh. / C was added and the mixture was stirred under hydrogen (60 psi) at 60 ° C. 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-dibenzo [b, d] azepin-6-one.hydrochloric acid According to General Preparation Method 3-C Racemic 5-amino-7-methyl-5,7-dihydro-6H-dibenzo [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 (1.0 g, 4.81 mmol) in dioxane _{(Aldrich) (50mL) / H 2 O} (10mL) The solution is treated with phenylboronic acid (
0.64 g, 5.29 mmol) (Aldrich), Pd (Ph ₃ P) ₄ (0.050
g, 0.04 mmol) and K ₂ CO ₃ (0.73 g, 5.29 mmol). After refluxing under a N ₂ atmosphere for 4 hours, the reaction was cooled, diluted with EtOAc and separated. After drying over Na ₂ SO ₄ and purification on SiO ₂ chromatography (hexane / EtOAc (95: 5)), 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 The product from Step A (0.99 g, 4.82 mmol) was purified by the method of Hornel, M. et al.
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-tetrahi
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] benzoazepine-
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 nzoazepin-8 (9H) -one The product from Step D (0.490 g, 1.97 mmol) is 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
Synthesis of zoazepin-8 (9H) -one The product from step E (0.360 g, 1.29 mmol) 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.

[0345] Example 3-AC 9- (N ^'-L- alaninyl) amino-5,6-dihydro--4H- Kino [8, 1-ab
] [3] benzazepine -8 (9H) - on-hydrochloride synthesis process A 9- (N ^'-Boc-L- alaninyl) 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) -one (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.

[0346] 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-dibenzo [b, d] azepin-6-one-hydrochloric acid According to the above general production method D, N-Boc-L-alanine (Aldrich) and 5-amino-7- (2-methylpropyl) -5, 7-dihydro-6H-dibenzo [b
The title compound as a tan foam was prepared using [, d] azepin-6-one.hydrochloride (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-dibenzo [b, d]
Synthesis of azepin-6-one.hydrochloric acid Step A5-amino-5,7-dihydro-6H, 7H-dibenzo [b, d] azepi
Synthesis of N-6-one ・ hydrochloric acid 5- (N-Boc-amino) -5,7-dihydro-6H, 7H-dibenzo [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-dibenzo [b, d] azepin-6-one The separated compound was subjected to a coupling reaction with Boc-L-alanine (Aldrich). 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 zo [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 (0.15 M) 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).
It manufactured using the manufacturing method of a.

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 Method 4- Reduction of the Azide Group The azide group was reduced to the corresponding primary amine using the method described in John W. Butcher et al., Tet. Lett., 37, 6685-6688 (1996). did.

General Procedure 4-G Amide or lactone using 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 Method 4- N-Alkylation Reaction of Amide or Lactam Using 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. A lactam substrate (1.0 eq.) In THF (〜0.1 M) was added under N ₂ at −78.
A solution of KN (TMS) ₂ (1.1 eq., 0.5 M toluene solution, Aldrich) was added dropwise at 2O <0> C over 2 to 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 to 1.5 eq., CAS
No. 36982-84-0, THF prepared as described in the Evans reference cited above (
-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) 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 of Amides Using Cesium Carbonate This method is an improved method of the production method described in PCT application WO96-40655 by Claremon, DA et al. 2,4-dioxo-2,3,4,5-tetrahydro of DMF-1H-1,5-benzodiazepine (CAS No. 49799-48-6) (1.0eq., 0.7M) to the mixture, N ₂ under At room temperature, Cs ₂ CO ₃ (2.2 eq.) And the appropriate alkyl iodide (2.2
eq.). The mixture was stirred at room temperature for 5.5-16 hours. Mix the mixture with EtOA
and saturated NaHCO ₃ . The aqueous phase was extracted with EtOAc (1-2 ×),
The tOAc extracts were combined, dried over Na ₂ SO ₄ , filtered and concentrated to give a crude product.

General Preparation 4-N BOC Removal Method An N-t-Boc protected amino acid stirred in a stirred solution of 1,4-dioxane in an ice bath at −10 ° C. for 10-15 minutes under N _{2 was} dried in 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,
GA; Bourrain, S .; Neduvelil, JG; Flether, SR; Baker, R .;
Watt, AP; FletcherA. E .; Freedman, SB; Kemp, JA; Marshall,
GR; Patel, S .; Smith, AJ; Matassa, VG, J. Med. Chem., 19
94, 37, 719) in dichloromethane solution. 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. Remove the cold bath and add 1
Stir for 8 hours. The reaction mixture was washed with saturated aqueous NaHCO ₃ (re-extracted with dichloromethane) and brine. The organic phase is dried over Na ₂ SO ₄ , filtered,
Concentrated. The residue was subjected to HPLC (eluent, methanol / dichloromethane (4 to 10%
Purification by gradient)) afforded 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 19
7-200 ° 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 Reider, PJ; Davis, P .; Hughes, DL; J.O by Grabowski, EJJ
According to rg. Chem. 1987, 52, 955, 3-amino-1,3-dihydro-1-methyl-5-phenyl-2H-1,4-benzodiazepin-2-one Bock,
MG; DiPardo, RM; Evans, BE; Rittle, KE; Veber, DF; Frei
dinger, RM; hirshfield, J .; Springer, JP, J. Org. Chem. 1987,
52, 3232) to give the title compound.

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.

[0374] 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.

[0380] 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.

[0381] 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)). _{C 24 H 19 Cl 2 N 3} O 3 (MW = 468.36); mass spectroscopy 468.

Embedded image

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- ( Preparation of (benzyloxycarbonyl ) amino-5-cyclohexyl- 2,3-dihydro-1-methyl-1H-1,4-benzodiazepin-2-one According to General Production Method 4-A, 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]
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) in dry THF was cooled to 0 ° C. and treated with 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. 2-amino-5-nitrobenzophenone (0.9 eq.
Acros) and 4-methylmorpholine (2.0 eq.) In dry TH
The F solution was added to the acid chloride via cannula. Remove the cooling bath and allow the reaction to
Stirred for hours. Dilute the reaction with dichloromethane and add 0.5M citric acid, saturated N
Washed with aHCO ₃ aqueous solution and brine. The organic phase was dried over Na ₂ SO _4, filtered, and concentrated. The residue was purified by preparative LC2000 (eluent, ethyl acetate / hexane 15% → 20% gradient) to give 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) in dry THF was cooled to 0 ° C. and treated with 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. Dilute the reaction with dichloromethane and add 0.5 M citric acid, saturated NaHC
Washed with aqueous O ₃ and brine. The organic phase was dried over Na ₂ SO _4, filtered, and concentrated. The residue was purified by preparative LC2000 (eluent, ethyl acetate / hexane 15).
% → 20% gradient) 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- 3 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] a
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) in dry THF was cooled to 0 ° C. and treated with 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 purified by preparative LC2000 (eluent, 15% ethyl acetate / hexane →
(20% gradient) to give an off-white foam. C ₂₆ H ₂₅ N ₂ O ₄ S (MW = 480.60); mass spectroscopy (M + NH ₄ ⁻ ) 49
8.2 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- 3 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] a
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.

[0416] 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 (prepared according to the procedure of MG Bock et al. In J. Org. Chem. 1987, 52, 3232-3239) was prepared according to general procedure 4 Alkylating with isobutyl iodide using -G;
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, 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 4-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.

[0420] 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 and 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 the general procedure of Step B of Example 1-C. to remove the Boc using method, 3- (N ^'-L- alaninyl) amino-1
-Methyl-5-phenyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-2-one was obtained.

[0423] 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. (S)-(−)-4-benzyl-2-oxazolidanone (Aldrich) in THF cooled to n-butyllithium (1.1 eq., 1.6 eq.).
M hexane solution). The reaction mixture was allowed to warm to −20 ° C. and then −
It was recooled to 78 ° C 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, filtered and concentrated to give (S)-(-)-3-propionyl-4-benzyl-2-oxazolidanone.

Step B: KHMDS (1.05 eq) (Aldrich) was added to a THF solution of (S)-(-)-3-propionyl-4-benzyl-2-oxazolidanone at -78 ° C.
Was added dropwise. The reaction mixture was stirred at -78 ° C for 30 minutes, then a pre-cooled solution of di-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, (S) - (-) - 3 - [(R) -N, N '- di -BOC-2-hydrazino-propynyl] -
4-Benzyl-2-oxazolidanone was obtained.

[0426]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 is 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 process 5

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). 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; produced from L-α- (2-thienyl) glycine (Sigma) by the production method described in 1994, p17.

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 No. 23954-54-3) was prepared from the product from Example 4-P, Step A and iodomethane (Aldrich) according to General Procedure 4-M. After work-up, a white solid precipitated during some concentration of the reaction, which 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, prepared from the product from step A and 1-iodo-2-methylpropane (Aldrich). 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 (TM
S) 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, so the reaction flask containing the mixture was raised somewhat on a cold bath until the internal temperature rose to −50 ° C .; 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. It was then processed as described in the general procedure. 3
-Azido-2,4-dioxo-1,5-bis (cyclopropylmethyl) -2,3,4,
5-Tetrahydro-1H-1,5-benzodiazepine was triturated (hot Et
OAc from room temperature EtOAc), followed by recrystallization (hot CHCl ₃ / EtO
Ac / EtOH (5: 5: 1) to CHCl ₃ / EtOAc / EtOH at −23 ° C.
(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 the above General Production Method 4-N.

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., Al
Dritch). The resulting mixture is heated to 75 ° C. for 30 minutes, _Two CO_Three(31.59 g, 1.0 eq.) And the mixture is stirred rapidly at 75 ° C. for 6 hours
did. The mixture is cooled and H_TwoO (500 mL) and EtOAc (1000 mL
) Was added. Phase and the organic phase is H_TwoO (1 × 500 mL), 1M hydrochloric acid (2
× 500 mL) and brine (1 × 500 mL). Then the organic phase
To MgSO_Four, Filtered, concentrated and flash chromatographed (eluent
, Hexane / EtOAc (gradient 3: 2 to 2: 3) to give a white solid
2,4-dioxo-1,5-bis (2,2-dimethylpropyl) -2,3,4,5-te
Trahydro-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 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. Example 4-P, Product from Step A (1.0 eq., 7
.50 g), Ph ₃ Bi (2.2 eq., 41.26 g, Aldrich), Cu (OA
c) ₂ (2.0 eq., 15.48 g, Aldrich), Et ₃ N (2.0 eq., 8.
A mixture of 62 g) of CH ₂ Cl ₂ (100 mL) was stirred at room temperature under N ₂ for 6 days (tracked by TLC). The solid was filtered through a plug of celite, rinsing with CH ₂ Cl ₂ / MeOH (3 × 75 mL). The filtrate is concentrated and hot CH ₂ Cl ₂ / M
Dissolve in MeOH (9: 1) and add a large plug of silica gel (eluent, CH ₂ Cl ₂ to C
Filtered through a linear gradient ( ₂ L) through H ₂ Cl ₂ / MeOH (9: 1). The filtrate is concentrated and the residue is flash chromatographed (eluent, CH ₂ Cl ₂ to CH ₂ C
l ₂ / MeOH: was purified by linear gradient) to (9 1). 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 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 4-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.

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)
, Zoller, V; prepared according to Tetrahedron 1975, 31, 863 by Ben-Ishai, D), cooled to 0 ° C, oxalyl chloride (1 eq.) And DMF (1 eq.).
3 drops). After stirring at 0 ° C. for 15 minutes, the cooling bath was removed and 40 minutes at ambient temperature.
Stirring was continued for minutes. The solution was recooled to 0 ° C. A solution of 1-amino-9-fluorenone (0.9 eq .; Aldrich) and 4-methylmorpholine (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. 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 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 Preparation of 1- [N- (α-amino) -N ^′ -(benzyloxycarbonyl) glycinyl ] amino-9-fluorenone Ammonia gas was added to 1- [N- (α-isopropylthio) -N ^' -(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
-Zeon (Showell, GA; Bourrain, S .; Neduveil, JG; Fletcher, SR
; Baker, R .; Watt. AP; Fletcher, AE; Freedman, SB; Kemp, JA;
J. Med. C by Marshall, GR, Patel, S .; Smith, AJ; Matassa, VG
hem. 1994, 37, 719) (1 eq.) and pyridine (1 eq., Aldrich).
A rapidly stirred solution of CH ₂ Cl ₂ (0.16 M dione) was treated dropwise with trifluoromethanesulfonic anhydride (1.1 eq., Aldrich). The resulting mixture (pale yellow; sediment) was heated at -40 ° C to -35 ° C for 20 minutes.
The mixture was then stirred at 0 ° C. (ice bath) to 10 ° C. for 14.5 hours (Note: the ice in the Dewar bottle slowly melts overnight). 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. for 8 hours under N ₂ ,
Partition between H ₂ Cl ₂ and saturated aqueous NaHCO ₃ . The aqueous phase is washed with CH ₂ Cl ₂
Extracted times. 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) in n-butanol (0.1 M benzodiazepine solution) under N ₂
Stirred under reflux for 24 hours. Further, formic hydrazide (1.67 eq.) Was added,
Reflux was continued for another 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.

[0483] 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 procedure 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, Katrizky, AR; Urogdi, L .; Mayence J. Org. C, by A.
hem. 1990, 55, 2206) in THF (0.3 M) was cooled to 0 ° C. and treated dropwise with oxalyl chloride (1.1 eq). DMF (0.1 equivalent) was added dropwise to the slurry, and stirring was continued at 0 ° C. for 1 hour. THF of 1- (2-aminopropylphenyl) -2-methyl-1-propanone (1.0 eq; Synthesis 1991, 56 by Robl, JA) and N-methylmorpholine (2.2 eq) cooled to 0 ° C.
The (1M propanone solution) 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 (0.3M 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 is diluted with ethyl acetate,
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] ami
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 equivalent, Aldrich). , 2.0M Et ₂ O solution) was 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.
Carefully quenched with 3N HCl. The cooling bath was removed and stirring continued for 30 minutes. The mixture was made basic by addition of solid NaOH. The contents were extracted three times with ethyl acetate and 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 is purified by chromatography (eluted with hexane / ethyl acetate (95: 5)).
Was done. 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, Katrizky, AR; Urogdi, L .; Mayence J. Org. Ch., By A.
em. 1990, 55, 2206) in THF (0.3 M) 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. TH of 1- (2-aminopropylphenyl) -1-butanone and N-methylmorpholine (2.2 equivalents) cooled to 0 ° C.
The F (1M butanone solution) 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. The reaction was concentrated, diluted with ethyl acetate,
Concentrated again. This operation was repeated again. The residue is diluted with ethyl acetate and
Washed twice with N 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 (0.6 M butanone solution) and treated with ammonium acetate (4.0 eq). The reaction is allowed to run at ambient temperature for 18 hours.
Stirred for 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 Dry dimethylformamide of 3,4-dihydro-1-methyl-1H-1,4-benzodiazepine-2,5-dione (Tett. Lett. 1994, 50 (30), 9051) (30m
L) The solution was prepared by adding 1 equivalent of potassium t-butoxide (Aldrich, 1.
(0M THF solution) was added dropwise. After 45 minutes at 0 ° C., 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. Flash chromatography purification (silica gel, ethyl acetate / hexane (7/1
) To give the pure material as a colorless oil (90% yield). 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 Ssuresil (S
ure Seal)) 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 added in 3 portions.
The mixture was dropped with a syringe over 0 minutes. The reaction mixture was stirred for 20 minutes while maintaining the reaction temperature between -47C and -35C. The temperature was reduced to 0 ° C in 1-2 minutes,
It was then kept at that temperature for one 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 diluted with dichloromethane
Extracted once, combined the extracts, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give a yellow oil. Purification was effective by flash chromatography (silica gel, dichloromethane / ethyl acetate (eluting with a gradient of 100/1, 95/5, 90/10 and 85/15)). 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 3-L-alaninyl-5-phenyl-1-methyl-2H-1,5-diazepine
Synthesis Step A of 2-one : Preparation of 1-phenyl-4-piperidinone (CAS 19125-34-9) Hermant, RM et al., J. Am. By method, 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 ^'- dimethyl-1,2-phenylenediamine (CAS 3213-79-4
) Production by Stetter, H. by Chem. Ber., 1953, 86, 161 and by Cheeseman. GW
According to the method described in the literature of J. Chem. Soc., 1955, 3308, 1,2-
The title intermediate was prepared from phenylenediamine (Aldrich). _{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.

[0522]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.
The mixture was heated to reflux for 18 hours. Cool the black mixture and then put it on ice
Pour and adjust the pH to 10 using 5M NaOH aqueous solution. The product is CH _Two Cl_Two(200 mL), water (100 mL) and brine (100 mL).
). The organic phase is Na_TwoSO_Four, Filtered and concentrated to a black oil
A product was obtained. HPLC purification (eluted with hexane / EtOAc (1: 1))
This provided the title intermediate (364 mg) as a brown oil. C₁₁H₁₄N_TwoO (MW = 190.25); mass spectroscopy, MH⁺ 191.4. Elemental analysis (C₁₁H₁₄N_TwoCalculated as O): Theoretical: 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 Preparations CH The intermediates shown in Table C-1 were synthesized in parallel using the following preparations. 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 from 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 12]

[Table 13]

[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) (M. Bock et al., J. Org. Chem., 1987, 52,
3232-3239) in anhydrous dichloromethane (100 mL) 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 was stirred for 15 minutes and quenched with saturated aqueous bicarbonate (10 mL).
I did. Separate the phases and continue the organic phase with saturated aqueous bicarbonate, water and brine.
And then dried over sodium sulfate. Silica gel chromatography
Purify using matography (10-50% ethyl acetate / hexane)
A hydroscopic 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 (Beck, MG et al., Tetr
ahedron Lett. 1987, 28, 939; 4.0 g, 10.4 mmol
l) in anhydrous DMF (40 mL) at 0 ° C in 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)
, 14.6 mmol). 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. Silica gel chromatography of the crude product (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 mmol) was added. The reaction mixture was allowed to warm to room temperature over 30 minutes,
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, 0-3% 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 as described in Synth. Commun., 26 (4), 721-727 (1996).

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).

[0547]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).

[0550]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 (Tetrahedr).
on, 51 (3), 773-786, (1995)) and synthesized in the same manner as in the method described in Synth. did. 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).

[0553]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 (Collect. Cz
ech. Chem. Commun., 34 (2), 468-478 (1969)) to Synth. Commun., 26 (4), 721-.
727 (1996). 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-Phenyl-1- [2-N- (α-isopropylthio) -N ^′ -(
Preparation of benzyloxycarbonyl) glycinyl] aminophenyl] ethylene α- (isopropylthio) -N- (benzyloxycarbonyl) glycine (1 eq
., Zoller, V .; Ben-Isai, d. Tetrahedron 1
975, 31, 863) was cooled to 0 ° C. and treated with 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 .; Arien
ti, A .; Biggi, f .; Maggi, R .; Marzi, E .; Maggi, P
Rastelli, M .; Sartori, G .; Tarantola, f. Tetrahedron 1997, 53, 3795) and 4-methylmorpholine (2.0 eq.) In dry THF were added via cannula to the acid chloride. 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 elution with 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 nyl-1H-1-benzazepin-2-one 1-phenyl-1- [2-N- (α-isopropylthio) -N ^′ -(benzyloxycarbonyl) glycinylaminophenyl] ethylene (1 eq) The acetonitrile solution was treated with mercury (II) chloride (1.0 eq, Aldrich) under N ₂ . After the mercury (II) chloride had dissolved, a white precipitate formed immediately. The mixture is
Heat to reflux for 0.5 h, add more mercury (II) chloride (0.05 eq) and add
Reflux was continued for hours. 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 the 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
Preparation of 2-one Following general procedure D, using N-Boc-alanine and 3-amino-1,3-dihydro-1-methyl-5-phenyl-2H-1-benzazepin-2-one, give white The title intermediate was prepared as a solid. _{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 Preparation 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
Synthesis Step 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-benzo
Preparation of azepin-2-one According to 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 Following the 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-benzoazepin-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
Synthesis Step 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 pre-cooled 3- (benzyloxycarbonyl) amino-2,3-dihydro-1-methyl-5-phenyl-1H-1-benzazepin-2-one ( 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-benzo
Preparation of azepin-2-one According to 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 Following the 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-benzoazepin-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.

Example 6 5- (S)-[N ^′ -(L-prolyl) -L-alaninyl] amino-7-methyl-5,7
- dihydro -6H- dibenzo [b, d] azepin-6-one Step ^{A N-L- (N '-tert} -Boc-L- prolyl) alanine methyl es
Synthesis of Ter N-tert-Boc-L-proline (Aldrich) (5.00 g, 23 m
mol) was dissolved in THF (300 mL) under N _2. L-alanine methyl ester / hydrochloric acid (3.53 g, 25 mmol), HOBT (3.38 g, 25 mmol)
), EDC (4.79 g, 25 mmol) and DIPEA (3.23 g, 25 m
mol) was added. The reaction mixture was stirred overnight at room temperature. The reaction mixture was stripped to dryness, dissolved in EtOAc, saturated NaHSO4, diluted NaH
Washed with CO ₃ and brine and dried over Na ₂ SO ₄ . Removal of solvent gave the title compound as a white solid (6.10 g, 88%). _{C 14 H 24 N 2 O 5} (MW = 300.4); mass spectroscopy (MH ⁺⁾ 301.

Step B. ^{N-L- (N '-tert-} Boc-L- prolyl) Synthesis Step A above compound prepared in alanine (5.98 g, 20 mmol) was dissolved in 1,4-dioxane (154 mL). LiOH.H ₂ O (0.84 g, 20 mmol) in H ₂ O (25 ml) was added. The reaction was stirred at room temperature for 1.5 hours. The reaction mixture was adjusted to pH = 3 with saturated aqueous NaHSO ₄ and then evaporated to remove most of the 1,4-dioxane. The residue is EtOAc
And dried over Na ₂ SO ₄ . The solvent was removed to give the title compound (4) as a white solid.
.98 g, 87%). _{C 13 H 22 N 2 O 5} (MW = 286.37); mass spectroscopy (MH ⁺⁾ 287.

Step C. 5- (S)-[N ^' -(N ^" -tert-Boc-L-prolyl) -L-A
Laninyl] amino-7-methyl-5,7-dihydro-6H-dibenzo [b, d] azene
Pin-6-one synthesized above step a solution of the compound prepared in B of (0.50 g, 1.74 mmol) and N ₂ TH under
Dissolved in F (46 ml). 5- (S) -amino-7-methyl-5,7-dihydro-6H-dibenzo [b, d] azepin-6-one.hydrochloric acid (Example 3-A) (0.44)
g, 1.59 mmol), HOBT (0.24 g, 1.75 mmol), EDC (
0.34 g, 1.75 mmol) and DIPEA (0.23 g, 1.75 mmol)
) Was added. The reaction mixture was stirred overnight at room temperature. The reaction mixture was stripped to dryness, dissolved in EtOAc, saturated NaHSO _4, then washed with dilute NaHCO ₃ and brine, and dried over Na ₂ SO _4. Removal of the solvent afforded the title compound as a white solid (0.76 g, 94%). _{C 28 H 30 N 2 O 7} (MW = 506.60); mass spectroscopy (MH ⁺⁾ 507.

Step D 5- (S)-[N ^′ -(L-prolyl) -L-alaninyl] amino-7-methyl
Synthesis of le-5,7-dihydro-6H-dibenzo [b, d] azepin-6-one The compound prepared above (0.70 g, 1.38 mmol) was treated with 1,4 M HCl in 1,
Dissolved in a 4-dioxane solution (40 mL) and stirred at room temperature overnight. The reaction mixture was evaporated to dryness, SCX column [3% (MeOH in 7N NH ₃₎ /
CH ₂ Cl ₂ ] to afford the title compound as a white solid (0.53 g, 95%).
I got _{C 23 H 26 N 4 O 3} (MW = 406.483); mass spectroscopy (MH ⁺⁾ 407. Exact mass (calculated as _{C 23 H 26 N 4 O 3} ): 407.2083 (MH +); Found: 407.2079. Elemental analysis (as _{C 23 H 26 N 4 O 3} · 1 / 2H 2 O): theory: C, 66.48;
H, 6.56; N, 13.49, found: C, 66.60; H, 6.38; N, 13
.35.

Example 7 5- (S)-[N ^′ -(L-homoprolyl) -L-alaninyl] amino-7-methyl-
5,7-dihydro -6H- dibenzo [b, d] Synthesis of azepin-6-one Step ^{A N-L- (N '-tert} -Boc-L- Homopuroriru) alanine methyl
Synthesis of Ester N-tert-Boc-L-Homoproline (Bachem-CA) (0.80 g,
3.49 mmol) was dissolved in THF (170 mL) while keeping under N2. L-alanine methyl ester / hydrochloric acid (0.54 g, 3.84 mmol), HOB
T (0.52 g, 3.84 mmol), EDC (0.74 g, 3.84 mmol) and DIPEA (0.50 g, 3.84 mmol) were added. The reaction mixture was stirred overnight at room temperature. The reaction mixture was stripped to dryness, EtOAc
And washed with saturated aqueous NaHSO ₄ , dilute NaHCO ₃ and brine,
a ₂ SO ₄ dried. The solvent was removed and the title compound as a white solid (1.06 g, 9
7%). _{C 15 H 26 N 2 O 5} (MW = 314.43); mass spectroscopy (MH ⁺⁾ 315.

[0575] Step ^{B N-L- (N '-tert} -Boc-L- Homopuroriru) Synthesis Step A above compound prepared in alanine (0.79 g, 2.5 mmol) in 1,4-dioxane (19 mL) Dissolved. Then, LiOH.H ₂ O (0.10 g, 2.5 m
was added H ₂ O (3mL) in mol). The reaction mixture was stirred at room temperature for 1.5 hours. The reaction mixture was adjusted to pH = 3 with saturated aqueous NaHSO ₄ and evaporated to remove most of the 1,4-dioxane. Etch the residue
Extracted with OAc and dried over Na ₂ SO ₄ . Removal of the solvent gave the title compound as a white solid (0.71 g, 94%). _{C 14 H 24 N 2 O 5} (MW = 300.40); mass spectroscopy (MH ⁺⁾ 301.

Step C 5- (S)-[N ^′ -(N ^″ -tert-Boc-L-homoprolyl) -L-
Alaninyl] amino-7-methyl-5,7-dihydro-6H-dibenzo [b, d] a
Zepin-6-one compound prepared in Preparation B above for (0.38 g, 1.27 mmol) while maintaining under N _2, was dissolved in THF (36 mL). 5- (S) -amino-7-methyl-5,7-
Dihydro-6H-dibenzo [b, d] azepin-6-one (Example 3-A) (0.3
0 g, 1.27 mmol), HOBT (0.17 g, 1.27 mmol) and E
DC (0.24 g, 1.27 mmol) was added. The reaction mixture was stripped to dryness, dissolved in EtOAc, saturated aqueous NaHSO _4, and washed with dilute NaHCO ₃ and brine, and dried over Na ₂ SO _4. Evaporation and flash chromatography purification (5% MeOH / CH ₂ Cl ₂ ) gave the title compound as a white solid (0.61 g, 92%). _{C 29 H 32 N 2 O 7} (MW = 520.63); mass spectroscopy (MH ⁺⁾ 521.

Step D 5- (S)-[N ^′ -(L-homoprolyl) -L-alaninyl] amino-7-
Preparation of methyl-5,7-dihydro-6H-dibenzo [b , d] azepin-6-one The compound (0.61 g, 1.17 mmol) prepared in Step C above was treated with 4M HCl.
Was dissolved in 1,4-dioxane (30 mL) and stirred at room temperature overnight. The reaction mixture was stripped to dryness, washed with Et ₂ O, SCX column [3%
Purification using (7N MeOH in _{NH 3) / CH 2 Cl 2} ], to give the title compound as a white solid (0.41g, 83%). _{C 24 H 28 N 4 O 3} (MW = 420.510); mass spectroscopy (MH ⁺⁾ 421. Elemental analysis (as _{C 24 H 28 N 4 O 3} ): theoretical value: C, 68.55; H, 6.71 ;
N, 13.32; Found: C, 68.26; H, 6.73; N, 13.20.

Example 8 5- (S)-[N^'-(DL-homoprolyl) -L-alaninyl] amino-7-methyl
Production of -5,7-dihydro-6H-dibenzo [b, d] azepin-6-oneStep A Synthesis of N-tert-Boc-DL-homoproline DL-pipecolinic acid / hydrochloric acid (Aldrich) (1.00
g, 6.0 mmol) with NaHCO_ThreeSolution (NaHCO_Three1.51 g, 18 mmo
l; H_TwoO: 25 mL). Add 1,4-dioxane (15 mL)
The reaction was then stirred at 0 ° C. Di-tert-butyl dicarbonate (1.44 g,
6.6 mmol) of 1,4-dioxane (10 mL) was added and the reaction
The solution was stirred overnight at room temperature. Thereafter, the solvent was stripped, then water and CH _Two Cl_TwoWas added. The aqueous phase is NaHSO_FourAdjust to pH = 3 with CH_TwoCl _Two , Extracted with brine, washed with brine, Na_TwoSO_FourAnd dried. Remove the solvent
This afforded the title compound as a white solid (0.32 g, 23%). C₁₁H₁₉NO_Four(MW = 229.31); mass spectroscopy (MH⁺) 230.

[0579] Step ^{B N-L- (N '-t} -Boc-DL- Homopuroriru) alanine methyl es
Synthesis N-tert-Boc-DL- homoproline (0.32 g, 1.4 mmol) in ether while maintaining under N _2, was dissolved in THF (50 mL). L-alanine methyl ester / hydrochloric acid (0.21 g, 1.5 mmol), HOBT (0.21 g, 1.5 mmol)
l), EDC (0.30 g, 1.5 mmol) and DIPEA (0.27 mL,
(1.5 mmol) was added. The resulting mixture was stirred at room temperature overnight, after which the reaction mixture was stripped to dryness, dissolved in EtOAc and saturated NaHS
Washed with aqueous O ₄ , dilute NaHCO ₃ and brine. The resulting organic phase Na ₂
And dried over SO _4. The solvent was removed and the title compound as a white solid (0.43 g, 98%
) Got. _{C 15 H 26 N 2 O 5} (MW = 314.43); mass spectroscopy (MH ⁺⁾ 315.

[0580] Step ^{C N-L- (N '-tert} -Boc-DL- Homopuroriru) If alanine
The compound prepared in formation above step B (0.430g, 1.37mmol) was dissolved in 1,4-dioxane (10.5 mL). Then, LiOH.H ₂ O (0.057 g)
, H ₂ O a (1.7 mL) was added a 1.37 mmol), the reaction mixture was stirred for 1.5 hours at room temperature. PH The reaction mixture with saturated aqueous NaHSO ₄ =
Adjusted to 3 and the resulting reaction mixture was evaporated to remove most of the 1,4-dioxane. The residue was extracted with EtOAc, dried over Na ₂ SO _4. Removal of the solvent gave the title compound (0.400 g, 95%). _{C 14 H 24 N 2 O 5} (MW = 300.40); mass spectroscopy (MH ⁺⁾ 301.

Step D 5- (S)-[N ^′ -(N ^″ -tert-Boc-DL-homoprolyl) -L
-Alaninyl] amino-7-methyl-5,7-dihydro-6H-dibenzo [b, d]
Azepin-6-one compounds synthesized were prepared by the above C of (0.40 g, 1.3 mmol) while the maintaining under N _2, was dissolved in THF (38 mL). Then, 5- (S) -amino-7-methyl-5
, 7-Dihydro-6H-dibenzo [b, d] azepin-6-one (Example 3-A) (
0.36 g, 1.3 mmol), HOBT (0.18 g, 1.3 mmol) and E
DC (0.25 g, 1.3 mmol) and DIPEA (0.23 mL, 1.3 mm)
ol) and the resulting reaction mixture was stripped to dryness, EtO
It was dissolved in Ac, saturated aqueous NaHSO _4, and washed with dilute NaHCO ₃ and brine, and dried over Na ₂ SO _4. Evaporate and perform flash chromatography purification (5% MeOH / CH ₂ Cl ₂ ) to give the title compound as a white solid (0.64 g,
95%). _{C 29 H 32 N 2 O 7} (MW = 520.63); mass spectroscopy (MH ⁺⁾ 521.

Step E 5- (S)-[N ^′ -(DL-homoprolyl) -L-alaninyl] amino-7
Preparation of -Methyl-5,7-dihydro-6H-dibenzo [b, d] azepin-6-one The compound (0.64 g, 1.2 mmol) prepared in Step D above was treated with 1,4-dioxane (4M HCl). 30 mL) and then stirred at room temperature overnight. 7N
In MeOH NH ₃ was added. Evaporate and flash chromatographic purification (5% MeOH / CH ₂ Cl ₂ ) to give the title compound (0.44 g, 87%).
I got _{C 24 H 28 N 4 O 3} (MW = 420.510); mass spectroscopy (MH ⁺⁾ 421. Elemental analysis (as _{C 24 H 28 N 4 O 3} · 1 / 2H 2 O): theory: C, 67.11;
H, 6.82; N, 13.05, found: C, 66.78; H, 6.42; N, 12
.71.

Example 9 5- (S)-[N ^′ -(1,2,3,4-tetrahydroisoquinoline-1-oil) -L
-Alaninyl] amino-7-methyl-5,7-dihydro-6H-dibenzo [b, d]
Azepin-6-one synthesis step ^{A N- (N '-tert-Boc} -1,2,3,4- tetrahydroisoquinolinyl
Synthesis of 1-oil) -L-alanine methyl ester N-tert-Boc-1,2,3,4-tetrahydroisoquinoline-1-carboxylic acid (J. Med. Chem., 1993, 36, 3) , p315) (5.00 g, 18 mmol)
) Was dissolved in THF (240 mL) while keeping under N ₂ . L-alanine methyl ester / hydrochloric acid (2.77 g, 20 mmol), HOBT (2.70 g, 20 m
mol), EDC (3.83 g, 20 mmol) and DIPEA (2.58 g,
20 mmol) was added and the resulting mixture was stirred at room temperature overnight. The reaction mixture was stripped to dryness, dissolved in EtOAc, saturated aqueous NaHSO _4, then washed with dilute NaHCO ₃ and brine, then dried over Na ₂ SO _4. Removal of the solvent gave the title compound (6.40 g, 98%). _{C 19 H 26 N 2 O 5} (MW = 362.423); mass spectroscopy (MH ⁺⁾ 363.

[0584] Step ^{B N- (N '-tert-Boc} -1,2,3,4- tetrahydroisoquinolinyl
Synthesis of 1-oil) -L-alanine The compound (6.09 g, 17 mmol) produced in the above step A was dissolved in 1,4-dioxane (127 mL). Then, LiOH.H ₂ O (0.71 g, 17 mm
ol) of H ₂ O (20 mL) was added and the resulting reaction mixture was stirred at room temperature for 1.5 hours. The reaction mixture was adjusted to pH = 3 with saturated aqueous NaHSO ₄ and then the reaction mixture was evaporated to remove most of the 1,4-dioxane. The residue was extracted with EtOAc, dried over Na ₂ SO _4. Removal of solvent gave the title compound (5.79 g, 98%). _{C 18 H 24 N 2 O 5} (MW = 348.44); mass spectroscopy (MH ⁺⁾ 349.

[0585]Step C 5- (S)-[N ^' -(N ^" -tert-Boc-1,2,3,4-tetrahydrid
Loisoquinoline-1-oil) -L-alaninyl] amino-7-methyl-5,7-
Synthesis of dihydro-6H-dibenzo [b, d] azepin-6-one The compound (0.56 g, 1.61 mmol) prepared in B above was converted to N_TwoKeep the bottom
Were dissolved in THF (46 mL). Then, 5- (S) -amino-7-methyl-
5,7-dihydro-6H-dibenzo [b, d] azepin-6-one.hydrochloric acid (Example 3
-A) (0.40 g, 1.46 mmol), HOBT (0.22 g, 1.61 mmol)
l) and EDC (0.31 g, 1.61 mmol) and DIPEA (0.28
mL, 1.61 mmol) was added and the reaction mixture was stirred at room temperature overnight. That
The reaction mixture was stripped to dryness, dissolved in EtOAc and saturated NaHS
O_FourAqueous solution, diluted NaHCO_ThreeAnd washed with brine, then Na_TwoSO_Fourso
Dried. Evaporate and purify by flash chromatography (5% MeOH / CH _Two Cl_Two) To give the title compound (0.84 g, 100%). C₃₃H₃₆N_FourO_Five(MW = 568.73); mass spectroscopy (MH⁺) 569.

Step D 5- (S)-[N ^′ -(1,2,3,4-tetrahydroisoquinoline-1-oy
) -L-alaninyl] amino-7-methyl-5,7-dihydro-6H -dibenzo [ b, d] azepin-6-one The compound prepared in step C above (0.84 g, 1.5 mmol). Was dissolved in 4M HCl in 1,4-dioxane (50 mL) and then stirred at room temperature for 2 hours. Evaporate and purify by flash chromatography [SCX, 4% (M in 7N NH ₃ )
MeOH) / CH ₂ Cl ₂ ) to afford the title compound as a white solid (0.65 g, 93%).
) Got. Flash chromatography (silica gel, 5% MeOH / CH ₂ C)
According to l ₂ ), two isomers were isolated from the title compound. Isomer 1: C ₂₈ H ₂₈ N ₄ O ₃ (MW = 468.554); mass spectroscopy (MH ⁺ )
469. Elemental analysis (as _{C 28 H 28 N 4 O 3} · 1 / 2H 2 O): theory: C, 70.42;
H, 6.13; N, 11.73, found: C, 70.60; H, 5.72; N, 11
.79. Isomer 2: C ₂₈ H ₂₈ N ₄ O ₃ (MW = 468.554); mass spectroscopy (MH ⁺ )
469. Elemental analysis (as _{C 28 H 28 N 4 O 3} ): theoretical value: C, 71.78; H, 6.02 ;
N, 11.96; Found: C, 71.72; H, 5.91; N, 11.79.

Example 10 5- (S)-[N ^′ -(octahydroindolyl-2-oil) -L-alaninyl] amino-7-methyl-5,7-dihydro-6H-dibenzo [b, d ] Azepin-6-one Synthesis Step A 5- (S)-[N ^′ -(N ^″ -tert-Boc-octahydroindolyl)
-2-oil) -L-alaninyl] amino-7-methyl-5.7-dihydro-6H
Synthesis of dibenzo [b, d] azepin-6-one According to General Preparation D, N-tert-Boc-octahydroindolyl-2-
Carboxylic acid (Bachem) and (S) -5- (L-alaninyl) amino-7-methyl-5,7-dihydro-6H-dibenzo [b, d] azepin-6-one (Example 3-B
) Was used to produce the title compound. _{C 32 H 40 N 4 O 5} (MW = 560.691); mass spectroscopy (MH ⁺⁾ 561.

Step B 5- (S)-[N ^′ -(octahydroindolyl-2-oil) -L-arani
Nyl] amino-7-methyl-5,7-dihydro-6H-dibenzo [b, d] azepine
According to the synthetic General Procedure 4-N of the 6-one, using the compound prepared in the above step A, was passed through an SCX column _{[4% MeOH (7N NH 3} ) / CH 2 Cl 2], the title compound Manufactured. _{C 27 H 32 N 4 O 3} (MW = 460.575); mass spectroscopy (MH ⁺⁾ 461. Elemental analysis (as _{C 27 H 32 N 4 O 3} · 1 / 2H 2 O): theory: C, 69.05;
H, 7.10; N, 11.93, found: C, 68.66; H, 7.05; N, 11
.79.

Example 11 5- {N ^′ -[cis-4- (3-methylbutyl) -L-prolyl] -L-alaninyl}
Amino-7-methyl-5,7-dihydro-6H-dibenzo [b, d] azepine-6
ON Synthesis Step A 5- {N ^′ -[cis-4- (3-methylbutyl) -N ^″ -tert-Boc
-L-Prolyl] -L-alaninyl} amino-7-methyl-5,7-dihydro-6
Synthesis of H-dibenzo [b, d] azepin-6-one Following General Procedure D, cis-4- (3-methylbutyl) -N- (tert-Bo
c-L-proline (J. Am. Chem. Soc., 20, 16, 1998, p. 3899) and 5
-(L-alaninyl) amino-7-methyl-5,7-dihydro-6H-dibenzo [b
The title compound was prepared using [, d] azepin-6-one (Example 3-B). _{C 33 H 44 N 4 O 5} (MW = 576.81); mass spectroscopy (MH ⁺⁾ 577.

Step B 5- {N ^' -[cis-4- (3-methylbutyl) -L-prolyl] -L-ara
Ninyl} amino-7-methyl-5,7-dihydro-6H-dibenzo [b, d] azepi
According to General Preparation 4-N, using the compound prepared in Step A above, the title compound of the free base was prepared, which was subjected to flash chromatography [4% MeOH].
(7N NH ₃ ) / CH ₂ Cl ₂ ]. _{C 28 H 36 N 4 O 3} (MW = 476.617); mass spectroscopy (MH ⁺⁾ 477. Elemental analysis (as _{C 28 H 36 N 4 O 3} ): theoretical value: C, 70.56; H, 7.61 ;
N, 11.75; Found: C, 70.66; H, 7.45; N, 11.55.

Example 12 5- {N ^′ -[trans-4- (3-methylbutyl) -L-prolyl] -L-alaninyl} amino-7-methyl-5,7-dihydro-6H-dibenzo [b, d] azepine-
Synthesis step A of 6-one 5- {N ^′ -[trans-4- (3-methylbutyl) -N ^″ -tert-B
oc-L-prolyl] -L-alaninyl} amino-7-methyl-5,7-dihydro
Synthesis of -6H-dibenzo [b, d] azepin-6-one Following General Procedure D, trans-4- (3-methylbutyl) -N- (tert-
Boc-L-proline (J. Am. Chem. Soc., 20, 16, 1998, p3899) and 5- (L-alaninyl) amino-7-methyl-5,7-dihydro-6H-dibenzo [b The title compound was prepared using [, d] azepin-6-one (Example 3-B). _{C 33 H 44 N 4 O 5} (MW = 576.81); mass spectroscopy (MH ⁺⁾ 577.

Step B 5- {N ^' -[trans-4- (3-methylbutyl) -L-prolyl] -L-
Alaninyl} amino-7-methyl-5,7-dihydro-6H-dibenzo [b, d] a
Synthesis of Zepin-6-one The title compound of the free base was prepared according to General Preparation 4-N using the compound prepared in Step A above and flash chromatography [4% MeOH].
(7N NH ₃ ) / CH ₂ Cl ₂ ]. Precision mass spectroscopy (calculated as C ₂₈ H ₃₇ N ₄ O ₃ ): 477.2866;
477.22871. Elemental analysis (as _{C 28 H 37 N 4 O 3} · 1H 2 O): theory: C, 67.99; H,
7.76; N, 11.33, found: C, 67.82; H, 7.60; N, 11.2.
6.

Example 13 5- (S)-[N ^′ -(decahydroquinolyl-2-oil) -L-alaninyl] amino-7-methyl-5,7-dihydro-6H-dibenzo [b, d] Synthesis process A of azepin-6-one Synthesis of decahydroquinoline-2-carboxylic acid / hydrochloric acid An acetic acid mixture of PtO ₂ (25% by weight) and 2-quinoline carboxylic acid (Aldrich) is hydrogenated at room temperature under 60 psi overnight. The reaction was performed. The reaction mixture was stripped to dryness. Concentrated HCl was added and stripped to dryness to give the title compound as a white solid. C ₁₀ H ₁₇ NO ₂ (free base, MW = 183.26); mass spectroscopy (MH ⁺ ) 1
84.

Step B Synthesis of N-tert-Boc-decahydroquinoline-2-carboxylic acid The compound prepared above (1.0 equivalent) was treated with tert-butyl alcohol and 2
Dissolved in N NaOH. Di-tert-butyl dicarbonate (1.2 eq) was added,
Stirred at room temperature for 8.5 hours. The reaction mixture was evaporated then extracted with EtOAc. The aqueous phase was acidified with 2N HCl, extracted with EtOAc and dried.
Evaporation of the solvent gave the title compound. _{C 15 H 25 NO 4 (MW} = 283.41); mass spectroscopy (MH ⁺⁾ 284.

Step C 5- (S)-[N ^' -(N ^" -tert-Boc-decahydroquinolyl-2"
-Oil) -L-alaninyl] amino-7-methyl-5,7-dihydro-6H-di
Synthesis of Benzo [b, d] azepin-6-one The compound prepared above and (S) -5- (L-alaninyl) amino-7-methyl-5,7-dihydro-6H- Dibenzo [b, d] azepine-
The title compound was prepared using 6-one (Example 3-B). _{C 33 H 42 N 4 O 5} (MW = 574.79); mass spectroscopy (MH ⁺⁾ 575.

Step D 5- (S)-[N ^' -(decahydroquinolyl-2-oil) -L-alaninyl ] amino-7-methyl-5,7-dihydro -6H -dibenzo [b, d] azepine -6
- in accordance with the general method of Step B of Example 1-C ON, using the above compounds, to produce the title compound free base, the ones flash chromatography [silica, 4%
Purification by _{MeOH (7N NH 3) / CH} 2 Cl 2], to obtain a mixture of the two. Mixture 1: C ₂₈ H ₃₄ N ₄ O ₃ (MW = 474.602); mass spectroscopy (MH ⁺ )
475. Elemental analysis (as _{C 28 H 34 N 4 O 3} · 1 / 2H 2 O): theory: C, 69.54;
H, 7.31; N, 11.59, found: C, 69.40; H, 7.68; N, 11
.46. Mixture 2: C ₂₈ H ₃₄ N ₄ O ₃ (MW = 474.602); mass spectroscopy (MH ⁺ )
475. Elemental analysis (as _{C 28 H 34 N 4 O 3} · 1 / 3H 2 O): theory: C, 69.97;
H, 7.29; N, 11.66, found: C, 70.09; H, 6.96; N, 11
.52.

Example 14 5- [N ^′ -(decahydroquinolyl-2-oil) -L-alaninyl] amino-7-
Synthesis Step A of Methyl-5,7-dihydro-6H-dibenzo [b, d] azepin-6-one 5- [N ^′ -(N ^″ -tert-Boc-decahydroquinolyl-2-oy)
Synthesis of l) -L-alaninyl] amino-7-methyl-5,7-dihydro-6H -dibenzo [ b, d] azepin-6-one N-tert-Boc-decahydroquinoline- 2-carboxylic acid (Example 3-B above) and 5- (L-alaninyl) amino-7-methyl-
5,7-dihydro-6H-dibenzo [b, d] azepin-6-one (Example 3-B)
Was used to produce the title compound. _{C 33 H 42 N 4 O 5} (MW = 574.79); mass spectroscopy (MH ⁺⁾ 575.

Step B 5- [N ^' -(decahydroquinolyl-2-oil) -L-alaninyl] amido
No-7-methyl-5,7-dihydro-6H-dibenzo [ b, d] azepin-6-one
Following the general method of Step B of Example 1-C, and using the above compounds, to produce the title compound free base by flash chromatography [silica this thing, 4%
Purification by _{MeOH (7N NH 3) / CH} 2 Cl 2], to obtain a mixture of the two. Mixture 1: C ₂₈ H ₃₄ N ₄ O ₃ (MW = 474.602); mass spectroscopy (MH ⁺ )
475. Elemental analysis (as _{C 28 H 34 N 4 O 3} · 2 / 3H 2 O): theory: C, 69.10;
H, 7.33; N, 11.52, found: C, 68.96; H, 7.06; N, 11
.46. Mixture 2: C ₂₈ H ₃₄ N ₄ O ₃ (MW = 474.602); mass spectroscopy (MH ⁺ )
475. Elemental analysis (as _{C 28 H 34 N 4 O 3} · 1 / 2H 2 O): theory: C, 69.54;
H, 7.31; N, 11.59, found: C, 69.42; H, 7.30; N, 11
.43. Exact mass (calculated for C ₂₈ H ₃₄ N ₄ O ₃ ): 475.2709 (MH ⁺ ); found: 475.2729.

Example 15 5- {N ^′ -[(S) -indolyl-2-oil] -L-alaninyl} amino-7-methyl-5,7-dihydro-6H-dibenzo [b, d] azepine- Synthesis Step A of 6-one Synthesis of N-tert-Boc- (S) -2-indolinecarboxylic acid (S)-(−)-Indoline-2-carboxylic acid (Aldrich) (1 equivalent) and DIEA (1 equivalent) the CH ₂ Cl ₂ mixture) was stirred at 0 ° C.. Di-tert-carbonate
-Butyl CH ₂ Cl ₂ was added and stirred at 0 ° C. for 2 hours. The reaction mixture was concentrated, acidified with NaHSO _4, extracted with EtOAc, dried and washed with brine. Evaporate and flash chromatographic purification (silica, 10% MeO
H / CH ₂ Cl ₂ ) to give the title compound. _{C 14 H 17 NO 4 (MW} = 263.32); mass spectroscopy (MH ⁺⁾ 264.

Step B 5- {N ^' -[N ^" -tert -Boc- (S) -indolyl- 2-oil] -L-alaninyl} amino-7-methyl-5,7-dihydro-6H-dibenzo Synthesis of [b, d] azepin-6-one The compound prepared above and 5- (L-alaninyl) amino-7-methyl-5,7-dihydro-6H-dibenzo [b, d The title compound was prepared using azepin-6-one (Example 3-B). _{C 32 H 34 N 4 O 5} (MW = 554.70); mass spectroscopy (MH ⁺⁾ 555.

Step C 5- {N ^' -[(S) -indolyl-2-oil] -L-alaninyl} amino
Of -7-methyl-5,7-dihydro-6H-dibenzo [b, d] azepin-6-one
Following the general procedure of Step B of Synthesis Example 1-C, the above compound was used to prepare the title compound as the free base, which was subjected to flash chromatography (silica, 4%
Purification by MeOH / CH ₂ Cl ₂ ) afforded the title compound. Exact mass (calculated as _{C 27 H 26 N 4 O 3} ): 455.2083 (MH +); Found: 455.2080. ¹ Hnmr (CDCl ₃ ): δ = 3.35 (s, 1.5H), 3.34 (s, 1.5)
H) 1.68-1.41 (m, 3H).

Example 16 5- (S)-{N ^′ -[(S) -indolyl-2-oil] -L-alaninyl} amino-
Synthesis step A of 5 -methyl-5,7-dihydro-6H-dibenzo [b, d] azepin-6-one 5- (S)-{N ^' -[N ^" -tert-Boc- (S)- Indolyl-2-
Oil] -L-alaninyl} amino-7-methyl-5,7-dihydro-6H-dibe
Synthesis of Nzo [b, d] azepin-6-one According to General Preparation Method D, N-tert-Boc- (S) -2-indolinecarboxylic acid (Example 15-A above) and (S) -5- (L-alaninyl) amino-7-methyl-5,7-dihydro-6H-dibenzo [b, d] azepin-6-one (Example 3
The title compound was prepared using B). _{C 32 H 34 N 4 O 5} (MW = 554.70); mass spectroscopy (MH ⁺⁾ 555.

Step B 5- (S)-{N ^′ -[(S) -indolyl-2-oil] -L-alaninyl}
Amino-7-methyl-5,7-dihydro-6H-dibenzo [b, d] azepine-6
According to the general procedure of Step B of Example 1-C, the above compound was used to prepare the title compound as the free base, which was purified by flash chromatography (silica, 4%
Purification by MeOH / CH ₂ Cl ₂ ) afforded the title compound. Exact mass (calculated as _{C 27 H 26 N 4 O 3} ): 455.2083 (MH +); Found: 455.2070. ¹ H nmr (CDCl ₃ ): δ = 3.35 (s, 3H), 1.43 (d, 3H).

Example 17 5- [N ^′ -(L-trans-4-hydroprolyl) -L-alaninyl] amino-7
Synthesis step A of 5 -methyl-5,7-dihydro-6H-dibenzo [b, d] azepin-6-one 5- [N ^' -(N ^" -tert-Boc-L-trans-4-hydroxy
Prolyl) -L-alaninyl} amino-7-methyl-5,7-dihydro-6H-di
Synthesis of Benzo [b, d] azepin-6-one Following General Procedure D, Na-tert-Boc-L-trans-4-hydroxyproline (Novabiochem) and 5- (L-alaninyl) amino-7- Methyl-5,7-dihydro-6H-dibenzo [b, d] azepin-6-one (Example 3
The title product was prepared using B). C ₂₈ H ₃₄ N ₄ O ₆ (MW = 522.66); mass spectroscopy (M ⁺ CH ₃ COO ⁻ )
581.

Step B 5- [N ^' -(L-trans-4-hydroxyprolyl) -L-alaninyl ] amino-7-methyl-5,7-dihydro -6H -dibenzo [b, d] azepine-6
- in accordance with the general method of Step B of Example 1-C ON, using the above compounds, to produce the title compound free base, this one was purified by reverse phase HPLC and SCX column, the two diastereoisomers The stereomeric title compound was obtained. Isomer 1: Exact mass (calculated as C ₂₃ H ₂₆ N ₄ O ₄ ): 423.2032 (MH ⁺ ); Found: 423.2009. ¹ Hnmr (CDCl ₃ ): δ = 3.35 (s, 1.5H), 3.50 (s, 3H)
), 1.42 (d, 3H). Isomer 2: (calculated as _{C 23 H 26 N 4 O 4} ) exact mass: 423.2032 (MH ^+); Found: 423.2012. ¹ Hnmr (CDCl ₃ ): δ = 3.35 (s, 1.5H), 3.50 (s, 3H)
), 1.45 (d, 3H).

Example 18 5- (S)-[N ^′ -(1,2,3,4-tetrahydroquinolyl-2-oil) -L-alaninyl] amino-7-methyl-5,7-dihydro- Synthesis step A of 6H-dibenzo [b, d] azepin-6-one Synthesis of 1,2,3,4-tetrahydroquinoline-2-carboxylic acid PtO ₂ (25% by weight) and 2-quinolinecarboxylic acid (Aldrich) Was subjected to a hydrogenation reaction at room temperature under 60 psi overnight. The reaction mixture was stripped to dryness to give the title compound. _{C 10 H 11 NO 2 (MW} = 177.22); mass spectroscopy (MH ⁺⁾ 178.

Step B N-tert-Boc-1,2,3,4-tetrahydroquinoline-2-ca
Synthesis of Rubonic Acid The compound prepared above (1.0 equivalent) was treated with tert-butyl alcohol and 2
Dissolved in N NaOH. Di-tert-butyl dicarbonate (1.2 eq) was added,
Stirred at room temperature overnight. The reaction mixture was evaporated and extracted with EtOAc. The aqueous phase was acidified with 2N HCl, extracted with EtOAc and dried. Let it evaporate,
Purification by flash chromatography (silica, 10% MeOH / CH ₂ Cl ₂ ) provided the title compound. _{C 15 H 19 NO 4 (MW} = 277.35); mass spectroscopy (MH ⁺⁾ 278.

Step C 5- (S)-[N ^' -(N ^" -tert-Boc-1,2,3,4-tetrahydrid
Roquinolyl-2-oil) -L-alaninyl] amino-7-methyl-5,7-dihi
Synthesis of Dro-6H-dibenzo [b, d] azepin-6-one The compound prepared above and (S) -5- (L-alaninyl) amino-7-methyl-5,7- according to General Preparation Method D. Dihydro-6H-dibenzo [b, d] azepine-
The title compound was prepared using 6-one (Example 3-B), which was purified by flash chromatography (silica, 10% MeOH / CH ₂ Cl ₂ ).
The title compound was prepared. _{C 33 H 36 N 4 O 6} (MW = 568.73); mass spectroscopy (MH ⁺⁾ 569.

Step D 5- (S)-[N ^' -(1,2,3,4-tetrahydroquinolyl-2-oil)
Synthesis of -L-alaninyl] amino-7-methyl-5,7-dihydro-6H-dibenzo [b, d] azepin-6-one The above compound was used according to the general procedure of Step B of Example 1-C. To give the title compound as a mixture of the two diastereomers, which is the free base, which was flash chromatographed [silica, 3% MeOH (7N NH ₃ ) / CH ₂ Cl ₂ ].
To give two diastereomers. Isomer 1: C ₂₈ H ₂₈ N ₄ O ₃ (MW = 468.60); mass spectroscopy (MH ⁺ ) 4
69. ¹ Hnmr (CDCl ₃ ): δ = 3.34 (s, 3H), 1.40 (d, 3H). Isomer 2: Exact mass (calculated as C ₂₈ H ₂₈ N ₄ O ₃ ): 469.2239 (MH ⁺ ); Found: 469.2234. ¹ H nmr (CDCl ₃ ): δ = 3.34 (s, 3H), 1.42 (d, 3H).

Example 19 5- (S)-[N ^′ -(3,3-dimethylindolyl-2-oil) -L-alaninyl]
Amino-7-methyl-5,7-dihydro-6H-dibenzo [b, d] azepine-6
ON Synthesis Step A [N-tert-Boc- (S) -3,3-dimethylindoline] -2-ca
Synthesis of Ethyl Rubonate Ethyl (S) -3,3-dimethylindoline-2-carboxylate (WO96358
05) (1 equivalent), DIEA (1 equivalent) and di-tert-butyl dicarbonate (1 equivalent).
.2 equiv.) Of CH ₂ Cl ₂ mixture was stirred from 0 ° C. to room temperature for 3 days. Evaporation and flash chromatography purification (silica, EtOAc / hexanes (1: 7 by volume)) gave the title compound. _{C 18 H 25 NO 4 (MW} = 319.399); mass spectroscopy (MH ⁺⁾ 320.

Step B N-tert-Boc- (S) -3,3-dimethylindoline-2-cal
Synthesis of Bonic Acid 5% NaOH, MeOH, THF and a catalytic amount of T
Mix with BABr and heat to reflux for 4 hours. After evaporation of most of the solvent, ether was added. The aqueous phase was acidified with concentrated HCl, extracted with EtOAc, washed with brine and dried. Removal of the solvent gave the title compound. _{C 16 H 21 NO 4 (MW} = 291.345); mass spectroscopy ^(M-H) - 290.

Step C 5- (S)-[N ^′ -(N ^″ -tert-Boc-3,3-dimethylindori)
Ru-2-oil) -L-alaninyl] amino-7-methyl-5,7-dihydro-6
Synthesis of H-Dibenzo [b, d] azepin-6-one The compound prepared above according to General Preparation Method D and (S) -5- (L-alaninyl) amino-7-methyl-5,7-dihydro- 6H-dibenzo [b, d] azepine-
The title compound was prepared using 6-one (Example 3-B). _{C 34 H 38 N 4 O 6} (MW = 582.76); mass spectroscopy (MH ⁺⁾ 583.

Step D 5- (S)-[N ^′ -(3,3-dimethylindolyl-2-oil) -LA
Laninyl] amino-7-methyl-5,7-dihydro-6H-dibenzo [b, d] azene
Synthesis of Pin-6-one Following the general procedure of Step B of Example 1-C, the above compound was used to prepare the title compound of the free base, which was purified by flash chromatography (silica, 4%
MeOH / CH ₂ Cl ₂ ) to give the title compound. Isomer 1: Exact mass (calculated as C ₂₉ H ₃₀ N ₄ O ₃ ): 483.2396 (MH ⁺ ); Found: 483.2401. ¹ Hnmr (CDCl ₃ ): δ = 3.36 (s, 3H), 1.58 (s, 3H),
1.45 (d, 3H), 1.13 (s, 3H). Isomer 2: Exact mass (calculated as C ₂₉ H ₃₀ N ₄ O ₃ ): 483.2396 (MH ⁺ ); Found: 483.2397. ¹ Hnmr (CDCl ₃ ): δ = 3.33 (s, 3H), 1.57 (s, 3H),
1.46 (d, 3H), 1.09 (s, 3H).

Example 20 5- {N ^′ -[(S) -2-methylindolyl-2-oil] -L-alaninyl} amino-7-methyl-5,7-dihydro-6H-dibenzo [b, d] Synthesis process A of azepin-6-one A cis-L-3- (1,1-dimethylethyl) -9,9a-dihydro-1H,
Synthesis of 3H-oxazolo [3,4-a] indol-1-one (S)-(−)-Indoline-2-carboxylic acid (Aldrich) (1 equivalent), pivalic aldehyde (7.1 equivalent) and molecular The sieve CH ₃ CN mixture was heated to reflux overnight. The reaction mixture was filtered and stripped to dryness to give the title compound. _{C 14 H 17 NO 2 (MW} = 231.293); mass spectroscopy (MH ⁺⁾ 232.

Step B cis- (S) -3- (1,1-dimethylethyl) -9,9a-dihydro-9a
Synthesis of -methyl-1H, 3H-oxazolo [ 3,4 -a] indol-1-one THF of the compound prepared above (1.0 equivalent) was cooled to -78 ° C. LDA
(1.2 equivalents, 2.0 M heptane / THF / ethylbenzene) was added dropwise and -78.
Stir at 45 ° C. for 45 minutes. The reaction mixture was warmed to 0 ° C. Saturated NH ₄ Cl
The solution and EtOAc were added. The EtOAc phase was washed with NaHCO ₃ and brine, then dried. The solvent was removed to produce the title compound. _{C 15 H 19 NO 2 (MW} = 245.320); mass spectroscopy (M ⁺ H) ⁺ 246.

Step C Synthesis of (S) -2-methylindoline-2-carboxylic acid The compound prepared above was dissolved in MeOH / H ₂ O (volume ratio 6: 1). Silica gel (230-400 mesh, 100% by weight) was added. The reaction mixture was stirred at room temperature over the weekend. The reaction mixture was stripped to dryness. Me
OH was added and filtered. The filtrate was evaporated to give the title compound. _{C 10 H 11 NO 2 (MW} = 177.202); mass spectroscopy (M ⁺ H) + 178.

Step D N-tert-Boc- (S) -2-methylindoline-2-carboxylic acid
The compound prepared above (1 equivalent) was dissolved in CH ₂ Cl ₂ . DIEA (1 equivalent) and di-tert-butyl dicarbonate (1 equivalent) were added and stirred at 0 ° C. for 3 hours. EtOAc and saturated NaHSO ₄ were added. The EtOAc phase was washed with brine and dried. Evaporate and flash chromatographic purification (silica, 5
% MeOH / CH ₂ Cl ₂ ) to give the title compound. _{C 15 H 19 NO 4 (MW} = 277.318); mass spectroscopy (M ⁺ H) + 278.

Step E 5- {N ^′ -[N ^″ -tert-Boc- (S) -2-methylindolyl-
2-Oil] -L-alaninyl} amino-7-methyl-5,7-dihydro-6H-
Synthesis of dibenzo [b, d] azepin-6-one Following general procedure D, the compound prepared above and 5- (L-alaninyl) amino-7-methyl-5,7-dihydro-6H-dibenzo [b, The title compound was prepared using d] azepin-6-one (Example 3-B). _{C 33 H 36 N 4 O 5} (MW = 568.670); mass spectroscopy (MH ⁺⁾ 569.

Step F 5- {N ^' -[(S) -2-methylindolyl-2-oil] -L-alanini
} Amino-7-methyl-5,7-dihydro-6H-dibenzo [b, d] azepine-
Synthesis of 6-one Following the general procedure of Step B of Example 1-C, the above compound was used to prepare the title compound as the free base, which was purified by flash chromatography (silica, 4%
MeOH / CH ₂ Cl ₂ ) to give the title compound. Exact mass (calculated for C ₂₈ H ₂₉ N ₄ O ₃ ): 469.2239 (MH ⁺ ); found: 469.2233. ¹ Hnmr (CDCl ₃ ): δ = 3.34 (s, 3H), 1.57 (s, 1.5H)
), 1.56 (s, 1.5H), 1.46 (d, 1.5H), 1.41 (d, 1.5H)
).

Example 21 5- (S)-{N ^′ -[(S) -2-methylindolyl-2-oil] -L-alaninyl
} Amino-7-methyl-5,7-dihydro-6H-dibenzo [b, d] azepine-6
-On Synthesis Step A 5- (S)-{N ^′ -[N ^″ -tert-Boc- (S) -2-methylindo
Ryl-2-oil] -L-alaninyl} amino-7-methyl-5,7-dihydro-
Synthesis of 6H-dibenzo [b, d] azepin-6-one According to General Preparation Method D, N-tert-Boc- (S) -2-methylindoline-
2-carboxylic acid (Example 20-D above) and (S) -5- (L-alaninyl) amino-7-methyl-5,7-dihydro-6H-dibenzo [b, d] azepin-6-one ( The title compound was prepared using Example 3-B). _{C 33 H 36 N 4 O 5} (MW = 568.670); mass spectroscopy (MH ⁺⁾ 569.

Step B 5- {N ^' -[(S) -2-methylindolyl-2-oil] -L-alanini
} Amino-7-methyl-5,7-dihydro-6H-dibenzo [b, d] azepine-
Synthesis of 6-one Following the general procedure of Step B of Example 1-C, the above compound was used to prepare the title compound as the free base, which was purified by flash chromatography (silica, 4%
MeOH / CH ₂ Cl ₂ ) to give the title compound. Exact mass (calculated as _{C 28 H 29 N 4 O 3} ): 469.2239 (MH +); Found: 469.2260. ¹ Hnmr (CDCl ₃ ): δ = 3.34 (s, 3H), 1.57 (s, 3H),
1.42 (d, 3H).

Example 22 5- [N ^′ -(indole-2-oil) -L-alaninyl] amino-7-methyl-
Synthesis of 5,7-dihydro-6H-dibenzo [b, d] azepin-6-one Following general procedure D, indole-2-carboxylic acid (Aldrich) and 5
-(L-alaninyl) amino-7-methyl-5,7-dihydro-6H-dibenzo [b
The title compound was prepared using [, d] azepin-6-one (Example 3-B). Exact mass (calculated as _{C 27 H 24 N 4 O 3} ): 453.1926 (M + H +); Found: 453.1917. ¹ Hnmr (CDCl ₃ ): δ = 3.53 (s, 1.5H), 3.51 (s, 1.5)
H), 1.83 (d, 1.5H), 1.67 (d, 1.5H).

Example 23 1- (S)-[N ^′ -(3,3-dimethylindolyl-2-oil) -L-alaninyl]
Synthesis step A 1- (S)-[N ^′ -(N ^″ -tert-Boc-3) of amino-3-methyl-4,5,6,7-tetrahydro-2H-3-benzazepin-2-one , 3-dimethylindori
Ru-2-oil) -L-alaninyl] amino-3-methyl-4,5,6,7-tetra
Synthesis of hydro-2H-3-benzazepin-2-one Following general procedure D, N-tert-Boc- (S) -3,3-dimethylindoline-2-carboxylic acid (Example 19-B above) and Using (N) -1- (S)-(L-alaninyl) amino-3-methyl-4,5,6,7-tetrahydro-2H-3-benzazepin-2-one, HPLC (metasil (Metasil) ) AQC1
8 columns, flow rate: 10 ml / min; 1: 214 nm; eluent: CH ₃ CN / 0.01
% HCl), the single diastereomer which was the first eluting diastereomer was isolated. C ₃₀ H ₃₈ N ₄ O ₅ (MW = 534.72); mass spectroscopy (M + H ⁺ ) 535.

Step B 1- (S)-[N ^′ -(3,3-dimethylindolyl-2-oil) -LA
Laninyl] amino-3-methyl-4,5,6,7 -tetrahydro-2H-3-benzo
Synthesis of Azepin-2-one According to the method of Step B of Example 1-C, using the compound prepared above, the title compound of the free base was produced, and this was subjected to flash chromatography (silica,
_{5% MeOH (7N NH 3)} / CH 2 Cl 2] Purification was performed to give the title compound. Isomer 1: Exact mass (calculated as C ₂₅ H ₃₁ N ₄ O ₃ ): 435.2396 (MH ⁺ ); Found: 435.2404. ¹ H nmr (CDCl ₃ ): δ = 3.02 (s, 3H), 1.58 (s, 3H)
, 1.50 (d, 3H), 1.11 (s, 3H). Isomer 2: Exact mass (calculated as C ₂₅ H ₃₁ N ₄ O ₃ ): 435.2396 (MH ⁺ ); Found: 435.2382. ¹ H nmr (CDCl ₃ ): δ = 3.02 (s, 3H), 1.58 (s, 3H)
, 1.50 (d, 3H), 1.10 (s, 3H).

Example 24 1- (S)-[N ^′ -(1,2,3,4-tetrahydroquinolyl-2-oil) -L-alaninyl] amino-3-methyl-4,5,6, Synthesis Step A of 1- (S)-[N ^′ -(N ^″ -tert-Boc-1,2,3,4 -tetrahydrid) of 7-tetrahydro-2H-3-benzazepin-2 -one
Roquinolyl-2-oil) -L-alaninyl] amino-3-methyl-4,5,6,7
Synthesis of -tetrahydro-2H-3-benzazepin-2-one N-tert-Boc-1,2,3,4-tetrahydroquinoline-2-carboxylic acid (Example 18-B above) according to General Preparation Method D And (N)-(S) -1- (L-
(Alaninyl) amino-3-methyl-4,5,6,7-tetrahydro-2H-3-benzazepin-2-one using HPLC (Metasil AQC
18 columns, flow rate: 10 ml / min; 1: 214 nm; CH ₃ CN / 0.01% H
The first diastereomer, the single diastereomer, was isolated from (1) eluting with Cl) to produce the title compound. _{C 29 H 36 N 4 O 5} (MW = 520.69); mass spectroscopy (M ⁺ H ⁺⁾ 521.

Step B 1- (S)-[N ^′ -(1,2,3,4-tetrahydroquinolyl-2-oil)
-L-alaninyl] amino-3-methyl-4,5,6,7-tetrahydro-2H-3
According to the method of Step B of Example 1-C, the title compound of the free base was prepared according to the method of Step B of Example 1-C, and this was subjected to flash chromatography (silica,
_{5% MeOH (7N NH 3)} / CH 2 Cl 2] Purification was performed to give the title compound of two diastereomeric mixtures. Exact mass (calculated as _{C 24 H 28 N 4 O 3} ): 421.2239 (MH +); Found: 421.2219. ¹ Hnmr (CDCl ₃ ): δ = 3.02 (s, 3H), 1.51-1.42 (m
, 3H).

The title compound of the hydrochloride salt was prepared by reverse phase HPLC separation. Isomer _{1: C 24 H 28 N 4} O 3 (MW = 420.510); mass spectroscopy (M ⁺ H) ⁺ 421. ¹ H nmr (DMSO-d ₆ ): δ = 2.90 (s, 3H), 1.30 (d, 3)
H). Mixture of isomer 1 and isomer 2: exact mass (calculated as C ₂₄ H ₂₈ N ₄ O ₃ ):
421.2239 (MH ^<+> ); found: 421.2226. ¹ H nmr (DMSO-d ₆ ): δ = 2.89 (s, 3H), 1.38-1.2
8 (m, 3H).

Example 25 3-[(N ^′ -(3-pyridinoyl) -L-alaninyl)] amino-2,3-dihydro-
Synthesis of 1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one According to one or more of the general procedures described above, 3-pyridinecarboxylic acid and 3 as described in Example 4-B above. The title compound was prepared using-[(L-alaninyl)] amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one. The molecular weight measured by mass spectroscopy (FD) was 442 (M + H).

Example 26 Synthesis of 3- {N ^′ -(2-piperidinecarboxyl) -L-alaninyl} amino-7-methyl-5,7-dihydro-6H-dibenzo [b, d] azepin-2-one Following one or more of the general procedures described above, 2-piperidinecarboxylic acid and 5- (L-alaninyl) amino-7-methyl-5,5 as described in Example 3-B.
The title compound was prepared using 7-dihydro-6H-dibenzo [b, d] azepin-6-one.

Example 27 3- [N ^′ -(quinolyl-2-oil) -L-alaninyl} amino-7-methyl-5,
Synthesis of 7-dihydro-6H-dibenzo [b, d] azepin-6-one Following general procedures, quinaldic acid (Aldrich) and 5- (L-alaninyl) amino-7-methyl-5,7-dihydro-6H -Dibenzo [b, d] azepine-
The title compound was prepared using 6-one (Example 3-B). Elemental analysis (calculated as _{C 28 H 24 N 4 O 3} ): theoretical value: C, 72.40; H, 5.2
1; N, 12.06; found: C, 72.23; H, 5.20; N, 11.79. Exact mass (calculated for C ₂₈ H ₂₄ N ₄ O ₃ ) (MH ⁺ ): 465.1926; found: 465.1918.

Example 28 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 with 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 removed again, 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
Nature (1992) 359: 325-327] and stored overnight at 4 ° C. The next day, amino acids 1 to 3 of the β-amyloid peptide
Labeled antibody 3D6 against 5 [P Nature by Seubert (1992) 359:. 325-327 ] 1 7 performs ELISA assay was used to measure the amount of production was β- amyloid peptide.

[0634] 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 β-amyloid peptide production inhibitory activity 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 29 In Vivo Inhibition of β-Amyloid Release and / or Its Synthesis In Vivo This example illustrates the 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, and 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 were dissected and placed on ice.

[0640] 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] is specific for amino acids 13-28 of β-amyloid. Amino acids 1 of β-amyloid
Antibody 3D6 [PNAS USA (1997) by Johnson-Wood et al.
94: 1550-1555] are biotinylated and reporters for those assays.
) Work as an antibody. The 3D6 biotinylation process uses the immunoglobulin NHS except that a 100 mM sodium bicarbonate buffer (pH 8.5) is used.
-Use the protocol of the product of manufacture (Pierce, Rockford IL) for biotin labeling. The 3D6 antibody does not recognize secreted amyloid precursor protein (APP) or full-length APP and detects only β-amyloid species with an amino-terminal aspartic acid. The assay has a lower limit of sensitivity: ~ 50 pg / ml (11 PM)
And shows no 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] (which recognizes 33-42 amino acids of β-amyloid).
Are used as capture antibodies. 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 a 96-well immunoassay plate (Costar, Cambridge, MA) 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).

[0644] 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 changes 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 Continuation of front page (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, KG, KZ, MD, RU, TJ, TM), AE, 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, Indianapolis, Indiana No. 6449 (72) Inventor Bruce A. Dresman United States 46202 Indianapolis, Indiana No. 1430 North New Jersey Shikin United States 46033 Carmel, Indiana, Pen Eagle Drive # 13138 F-term (reference) 4C084 AA02 BA32 NA14 ZA161 ZA162 ZC801 ZC802 4H045 AA10 AA30 BA11 BA51 EA21 EA50 F A30 HA02

Claims (65)

[Claims] 1. Compounds of formula I or Ia, and pharmaceutically acceptable salts thereof. Embedded image [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, heteroaryl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, 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 , together with R ^′ and the carbon and nitrogen atoms respectively attached thereto, is a nitrogen-containing heterocyclic or heterocyclic or heteroaryl group of the formula Ia or Ia To form R ^″ is selected from the group consisting of hydrogen, alkyl, substituted alkyl and aryl. Each R ² is independently selected from the group consisting of alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, aryl, heteroaryl, and heterocyclic. Each R ³ independently comprises hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, acyl, aryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heteroaryl, and heterocyclic. Selected from the group. 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, alkoxy, substituted alkoxy, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, substituted amino, aryl, aryloxy, cycloalkyl, substituted cycloalkyl, cycloalkenyl,
It is selected from the group consisting of substituted cycloalkenyl, heteroaryl, heterocyclic, thioalkoxy and substituted thioalkoxy. Q is selected from the group consisting of oxygen, sulfur, -S (O)-, -S (O) _2- , -C (O)-and -C (S)-. X is selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, acyl, aryl, cycloalkyl, substituted cycloalkyl, cycloalkyl, substituted cycloalkenyl, heteroaryl and heterocyclic Alternatively, X, one R ⁴ and the atoms to which they are attached together form a double bond. Each f is independently an integer of 0 to 2. n is an integer of 1 or 2. ] 2. The compound according to claim 1, wherein n is 1. 3. The compound according to claim 1, wherein ring A and ring B are preferably independently selected from the group consisting of aryl, cycloalkyl, cycloalkenyl, heteroaryl and heterocyclic. 4. The compound of claim 3, wherein ring A and ring B are independently aryl. 5. The compound according to claim 1, wherein R ^″ is hydrogen. 6. The compound according to claim 5, wherein R ¹ , R ^′ and the nitrogen and carbon atoms bonded thereto form a heterocyclic ring. 7. The heterocyclic ring may be a monocyclic nitrogen-containing heterocycle (the rings may optionally be hydroxyl, keto, thioketo, alkyl, substituted alkyl, alkoxy, substituted alkoxy, amino,
Substituted amino, aryl, aryloxy, cyano, cycloalkyl, substituted cycloalkyl, halo, heteroaryl, heteroaryloxy, nitro, thiol,
A bicyclic heterocycle (where the second cyclic group is selected from the group consisting of thioalkoxy, substituted thioalkoxy, thioaryloxy, and thioheteroaryloxy); Aryl, cycloalkyl,
Selected from the group consisting of cycloalkenyl, heteroaryl and heterocyclic, and wherein the bicyclic groups include fused bicyclic, bridged bicyclic and spiro bicyclic;
Further each ring is optionally hydroxyl, keto, thioketo, alkyl, substituted alkyl, alkoxy, substituted alkoxy, amino, substituted amino, aryl, aryloxy, cyano, cycloalkyl, substituted cycloalkyl, halo, heteroaryl, heteroaryloxy, Nitro, thiol, thioaroxy, substituted thioalkoxy, thioaryloxy and thioheteroaryloxy substituted with 1 to 3 substituents); and tricyclic heterocycle (where And / or the third cyclic group is independently:
Selected from the group consisting of aryl, cycloalkyl, cycloalkenyl, heteroaryl, and heterocyclic, and wherein the tricyclic groups include fused tricyclic, bridged tricyclic, spiro tricyclic, and combinations thereof; Is optionally hydroxyl, keto, thioketo, alkyl, substituted alkyl, alkoxy, substituted alkoxy, amino, substituted amino, aryl, aryloxy, cyano, cycloalkyl, substituted cycloalkyl, halo, heteroaryl, heteroaryloxy, nitro, thiol Thioalkoxy, substituted thioalkoxy, thioaryloxy and thioheteroaryloxy, which are substituted with 1 to 3 substituents selected from the group consisting of: Item 7. The compound according to Item 6. 8. The heterocyclic ring is pyrrolidinyl, 4-hydroxypyrrolidinyl, azetidinyl, thioazolidinyl, piperidinyl, piperazinyl,
Dihydroindolyl (eg, 2,3-dihydroindol-2-yl), tetrahydroquinolinyl (eg, 1,2,3,4-tetrahydroquinolin-2-yl), morpholinyl, thiomorpholinyl, 4-halopyrrolidinyl, 3 8. The composition according to claim 7, wherein the compound is selected from the group consisting of -phenylpyrrolidinyl, 4-aminopyrrolidinyl, 3-methoxypyrrolidinyl, 4,4-dimethylpyrrolidinyl, and 5,5-dimethylthiazolidine-4-yl. A compound as described. 9. The compound according to claim 5, wherein R ¹ , R ^′ and the nitrogen and carbon atoms bonded thereto form a heteroaryl ring. 10. A heteroaryl ring is a monocyclic heteroaryl, wherein those groups are optionally hydroxyl, alkyl,
Substituted alkyl, alkoxy, substituted alkoxy, amino, substituted amino, aryl,
1-3 selected from the group consisting of aryloxy, cyano, cycloalkyl, substituted cycloalkyl, halo, heteroaryl, heteroaryloxy, nitro, thiol, thioalkoxy, substituted thioalkoxy, thioaryloxy and thioheteroaryloxy Bicyclic heteroaryl (wherein the second cyclic group is aryl, cycloalkyl,
Selected from the group consisting of cycloalkenyl, heteroaryl and heterocyclic, and wherein the bicyclic groups include fused bicyclic and bridged bicyclic, each ring optionally having hydroxyl, alkyl, substituted alkyl, alkoxy, substituted Alkoxy, amino, substituted amino, aryl, aryloxy, cyano, cycloalkyl,
Substituted cycloalkyl, halo, heteroaryl, heteroaryloxy, nitro,
Substituted with 1 to 3 substituents selected from the group consisting of thiol, thioalkoxy, substituted thioalkoxy, thioaryloxy and thioheteroaryloxy, and the second cyclic group is a cycloalkyl group, a cycloalkenyl Or heterocyclic, keto and thioketo groups); and tricyclic heteroaryl, wherein the second and / or third cyclic groups are independently
Selected from the group consisting of aryl, cycloalkyl, cycloalkenyl, heteroaryl, and heterocyclic, and wherein the tricyclic groups include fused tricyclic, bridged tricyclic, spiro tricyclic, and any combination thereof; Further, each ring is optionally hydroxyl, alkyl, substituted alkyl, alkoxy, substituted alkoxy,
1 to 1 selected from the group consisting of aryl, aryloxy, cyano, cycloalkyl, substituted cycloalkyl, halo, heteroaryl, heteroaryloxy, nitro, thiol, thioalkoxy, substituted thioalkoxy, thioaryloxy and thioheteroaryloxy Substituted with three substituents, and additionally the second and / or third cyclic group is a cycloalkyl, cycloalkenyl or heterocyclic group, a keto group and a thioketo group) 10. The compound according to claim 9, which is selected. 11. The heteroaryl group is pyridinyl, 2-quinoxalinyl,
11. The method according to claim 10, wherein the group is selected from the group consisting of indolyl, N-methylindolyl, 3-amino-2-pyrazinyl, 3-amino-5,6-dichloro-2-pyrazinyl, 4-methoxyindolyl and 3-isoquinolinyl. A compound as described. 12. The compound of claim 1, wherein R ² is independently selected from the group consisting of alkyl, substituted alkyl, alkenyl, cycloalkyl, aryl, heteroaryl, and heterocyclic. 13. 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 1
3. The compound according to 2. 14. The compound according to claim 1, wherein R ³ is selected from the group consisting of hydrogen, alkyl, substituted alkyl and cycloalkyl. 15. R ³ is hydrogen, methyl, 2-methylpropyl, hexyl,
15. The compound according to claim 14, wherein the compound is selected from the group consisting of methoxycarbonylmethyl, 3,3-dimethyl-2-oxobutyl, 4-phenylbutyl, cyclopropylmethyl, 2,2,2-trifluoroethyl, and cyclohexyl. 16. The compound according to claim 1, wherein R ⁴ is hydrogen, alkyl or substituted alkyl. 17. The compound according to claim 16, wherein R ⁴ is alkyl. 18. The compound according to claim 1, wherein R ⁵ is selected from the group consisting of alkyl, substituted alkyl, phenyl, substituted phenyl, cycloalkyl, heteroaryl, and heterocyclic. 19. The compound according to claim 18, wherein R ⁵ is alkyl. 20. 5- (S)-[N ^′ -(L-prolyl) -L-alaninyl] amino-7-methyl-5,7-dihydro-6H-dibenzo [b, d] azepin-one; -(S)-[N ^' -(L-homoprolyl) -L-alaninyl] amino-7-methyl-5,7-dihydro-6H-dibenzo [b, d] azepin-one; 5- (S)-[ N ^' -(DL-homoprolyl) -L-alaninyl] amino-7-methyl-5,7-dihydro-6H-dibenzo [b, d] azepin-one; 5- (S)-[N ^' -(1, 2,3,4-tetrahydroisoquinoline-1-oil)-
L-alaninyl] amino-7-methyl-5,7-dihydro-6H-dibenzo [b, d
] Azepin-one; 5- (S)-[N ^' -(octahydro-indolyl-2-oil) -L-alaninyl
] Amino-7-methyl-5,7-dihydro-6H-dibenzo [b, d] azepin-one; 5- {N ^' -[cis-4- (3-methylbutyl) -L-prolyl] -L-alaninyl
} Amino-7-methyl-5,7-dihydro-6H-dibenzo [b, d] azepin-one; 5- {N ^' -[trans-4- (3-methylbutyl) -L-prolyl] -L-alaninyl } A compound selected from the group consisting of amino-7-methyl-5,7-dihydro-6H-dibenzo [b, d] azepin-one; and pharmaceutical salts thereof. 21. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a pharmaceutically effective amount of a compound of claim 1 or a mixture of those compounds. 22. The pharmaceutical composition according to claim 21, wherein n is 1. 23. The pharmaceutical composition according to claim 21, wherein Ring A and Ring B are independently selected from the group consisting of aryl, cycloalkyl, cycloalkenyl, heteroaryl and heterocyclic. 24. The pharmaceutical composition according to claim 23, wherein Ring A and Ring B are independently aryl. 25. The pharmaceutical composition according to claim 21, wherein R ^″ is hydrogen. 26. The pharmaceutical composition according to claim 25, wherein R ¹ , R ^′ and the nitrogen and carbon atoms bonded thereto form a heterocyclic ring. 27. The heterocyclic ring is a monocyclic nitrogen-containing heterocycle (the rings optionally include hydroxyl, keto, thioketo, alkyl, substituted alkyl, alkoxy, substituted alkoxy, amino,
Substituted amino, aryl, aryloxy, cyano, cycloalkyl, substituted cycloalkyl, halo, heteroaryl, heteroaryloxy, nitro, thiol,
A bicyclic heterocycle (where the second cyclic group is selected from the group consisting of thioalkoxy, substituted thioalkoxy, thioaryloxy, and thioheteroaryloxy); Aryl, cycloalkyl,
Selected from the group consisting of cycloalkenyl, heteroaryl and heterocyclic, and wherein the bicyclic groups include fused bicyclic, bridged bicyclic and spiro bicyclic;
Further each ring is optionally hydroxyl, keto, thioketo, alkyl, substituted alkyl, alkoxy, substituted alkoxy, amino, substituted amino, aryl, aryloxy, cyano, cycloalkyl, substituted cycloalkyl, halo, heteroaryl, heteroaryloxy, Nitro, thiol, thioaroxy, substituted thioalkoxy, thioaryloxy and thioheteroaryloxy substituted with 1 to 3 substituents); and tricyclic heterocycle (where And / or the third cyclic group is independently:
Selected from the group consisting of aryl, cycloalkyl, cycloalkenyl, heteroaryl, and heterocyclic, and wherein the tricyclic groups include fused tricyclic, bridged tricyclic, spiro tricyclic, and combinations thereof; Is optionally hydroxyl, keto, thioketo, alkyl, substituted alkyl, alkoxy, substituted alkoxy, amino, substituted amino, aryl, aryloxy, cyano, cycloalkyl, substituted cycloalkyl, halo, heteroaryl, heteroaryloxy, nitro, thiol Thioalkoxy, substituted thioalkoxy, thioaryloxy and thioheteroaryloxy, which are substituted with 1 to 3 substituents selected from the group consisting of: Item 29. The pharmaceutical composition according to Item 26. 28. The heterocyclic ring is pyrrolidinyl, 4-hydroxypyrrolidinyl, azetidinyl, thioazolidinyl, piperidinyl, piperazinyl, dihydroindolyl (eg, 2,3-dihydroindol-2-yl), tetrahydroquinolinyl (E.g., 1,2,3,4-tetrahydroquinolin-2-yl), morpholinyl, thiomorpholinyl, 4-halopyrrolidinyl, 3-phenylpyrrolidinyl, 4-aminopyrrolidinyl, 3-methoxypyrrolidinyl, 4-
28. The pharmaceutical composition according to claim 27, which is selected from the group consisting of dimethylpyrrolidinyl and 5,5-dimethylthiazolidin-4-yl. 29. The pharmaceutical composition according to claim 25, wherein R ¹ , R ^′ and the nitrogen and carbon atoms attached thereto form a heteroaryl ring. 30. A heteroaryl ring is a monocyclic heteroaryl wherein those groups are optionally hydroxyl, alkyl,
Substituted alkyl, alkoxy, substituted alkoxy, amino, substituted amino, aryl,
1-3 selected from the group consisting of aryloxy, cyano, cycloalkyl, substituted cycloalkyl, halo, heteroaryl, heteroaryloxy, nitro, thiol, thioalkoxy, substituted thioalkoxy, thioaryloxy and thioheteroaryloxy Bicyclic heteroaryl (wherein the second cyclic group is aryl, cycloalkyl,
Selected from the group consisting of cycloalkenyl, heteroaryl and heterocyclic, and wherein the bicyclic groups include fused bicyclic and bridged bicyclic, each ring optionally having hydroxyl, alkyl, substituted alkyl, alkoxy, substituted Alkoxy, amino, substituted amino, aryl, aryloxy, cyano, cycloalkyl,
Substituted cycloalkyl, halo, heteroaryl, heteroaryloxy, nitro,
Substituted with 1 to 3 substituents selected from the group consisting of thiol, thioalkoxy, substituted thioalkoxy, thioaryloxy and thioheteroaryloxy, and the second cyclic group is a cycloalkyl group, a cycloalkenyl Or heterocyclic, keto and thioketo groups); and tricyclic heteroaryl, wherein the second and / or third cyclic groups are independently
Selected from the group consisting of aryl, cycloalkyl, cycloalkenyl, heteroaryl, and heterocyclic, and wherein the tricyclic groups include fused tricyclic, bridged tricyclic, spiro tricyclic, and any combination thereof; Further, each ring is optionally hydroxyl, alkyl, substituted alkyl, alkoxy, substituted alkoxy,
1 to 1 selected from the group consisting of aryl, aryloxy, cyano, cycloalkyl, substituted cycloalkyl, halo, heteroaryl, heteroaryloxy, nitro, thiol, thioalkoxy, substituted thioalkoxy, thioaryloxy and thioheteroaryloxy Substituted with three substituents, and additionally the second and / or third cyclic group is a cycloalkyl, cycloalkenyl or heterocyclic group, a keto group and a thioketo group) 30. The pharmaceutical composition according to claim 29, which is selected. 31. A heteroaryl group is pyridinyl, 2-quinoxalinyl,
31. The method according to claim 30, which is selected from the group consisting of indolyl, N-methylindolyl, 3-amino-2-pyrazinyl, 3-amino-5,6-dichloro-2-pyrazinyl, 4-methoxyindolyl and 3-isoquinolinyl. A pharmaceutical composition as described. 32. The pharmaceutical composition according to claim 21, wherein R ² is independently selected from the group consisting of alkyl, substituted alkyl, alkenyl, 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} (O
_{H) 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, pharmaceutical composition according to claim 32 of the claims. 34. The pharmaceutical composition according to claim 21, 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,
35. The pharmaceutical composition according to claim 34, wherein the composition is selected from the group consisting of methoxycarbonylmethyl, 3,3-dimethyl-2-oxobutyl, 4-phenylbutyl, cyclopropylmethyl, 2,2,2-trifluoroethyl, and cyclohexyl. object. 36. The pharmaceutical composition according to claim 21, wherein R ⁴ is hydrogen, alkyl or substituted alkyl. 37. The pharmaceutical composition according to claim 36, wherein R ⁴ is alkyl. 38. The pharmaceutical composition according to claim 21, wherein R ⁵ is selected from the group consisting of alkyl, substituted alkyl, phenyl, substituted phenyl, cycloalkyl, heteroaryl, and heterocyclic. 39. The pharmaceutical composition according to claim 38, wherein R ⁵ is alkyl. 40. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a pharmaceutically effective amount of a compound, wherein the compound comprises: 5- (S)-[N ^′ -(L-prolyl) -L-alaninyl] amino-7-methyl-5,
7-dihydro-6H-dibenzo [b, d] azepin-one; 5- (S)-[N ^' -(L-homoprolyl) -L-alaninyl] amino-7-methyl-5,7-dihydro-6H- Dibenzo [b, d] azepin-one; 5- (S)-[N ^' -(DL-homoprolyl) -L-alaninyl] amino-7-methyl-5,7-dihydro-6H-dibenzo [b, d] Azepin-one; 5- (S)-[N ^' -(1,2,3,4-tetrahydroisoquinolin-1-oil)-
L-alaninyl] amino-7-methyl-5,7-dihydro-6H-dibenzo [b, d
] Azepin-one; 5- (S)-[N ^' -(octahydro-indolyl-2-oil) -L-alaninyl
] Amino-7-methyl-5,7-dihydro-6H-dibenzo [b, d] azepin-one; 5- {N ^' -[cis-4- (3-methylbutyl) -L-prolyl] -L-alaninyl
} Amino-7-methyl-5,7-dihydro-6H-dibenzo [b, d] azepin-one; 5- {N ^' -[trans-4- (3-methylbutyl) -L-prolyl] -L-alaninyl } A pharmaceutical composition selected from the group consisting of amino-7-methyl-5,7-dihydro-6H-dibenzo [b, d] azepin-one; and pharmaceutical salts thereof. 41. A method for inhibiting the release of and / or the synthesis of β-amyloid peptide in a cell, comprising the steps of: administering a compound of the formula I or Ia according to claim 1 or a mixture of these compounds in a cell. Administering to the cells an amount effective to inhibit the release and / or synthesis of β-amyloid peptide. 42. A method for preventing the onset of AD in a patient at risk of developing AD, comprising providing the patient with a pharmaceutically acceptable carrier and an effective amount.
A method comprising administering a pharmaceutical composition comprising a compound of formula I or Ia or a mixture of such compounds according to claim 1. 43. A method of treating a patient with AD to prevent the disease from further worsening, comprising providing the patient with a pharmaceutically acceptable carrier and an effective amount of an effective amount. A method comprising administering a pharmaceutical composition comprising a compound of formula I or Ia or a mixture of said compounds. 44. The method of claim 41, 42 or 43, wherein n is 1. 45. Ring A and ring B are independently aryl, cycloalkyl,
44. The method according to claim 41, 42 or 43, which is preferably selected from the group consisting of cycloalkenyl and heteroaryl and heterocyclic. 46. The method of claim 45, wherein Ring A and Ring B are independently aryl. 47. The method of claim 41, 42 or 43, wherein R ^″ is hydrogen. 48. The method of claim 47, wherein R ¹ , R ^′ and the nitrogen and carbon atoms attached thereto form a heterocyclic ring. 49. The heterocyclic ring is a monocyclic nitrogen-containing heterocycle (the rings optionally include hydroxyl, keto, thioketo, alkyl, substituted alkyl, alkoxy, substituted alkoxy, amino,
Substituted amino, aryl, aryloxy, cyano, cycloalkyl, substituted cycloalkyl, halo, heteroaryl, heteroaryloxy, nitro, thiol,
A bicyclic heterocycle (where the second cyclic group is selected from the group consisting of thioalkoxy, substituted thioalkoxy, thioaryloxy, and thioheteroaryloxy); Aryl, cycloalkyl,
Selected from the group consisting of cycloalkenyl, heteroaryl and heterocyclic, and wherein the bicyclic groups include fused bicyclic, bridged bicyclic and spiro bicyclic;
Further each ring is optionally hydroxyl, keto, thioketo, alkyl, substituted alkyl, alkoxy, substituted alkoxy, amino, substituted amino, aryl, aryloxy, cyano, cycloalkyl, substituted cycloalkyl, halo, heteroaryl, heteroaryloxy, Nitro, thiol, thioaroxy, substituted thioalkoxy, thioaryloxy and thioheteroaryloxy substituted with 1 to 3 substituents); and tricyclic heterocycle (where And / or the third cyclic group is independently:
Selected from the group consisting of aryl, cycloalkyl, cycloalkenyl, heteroaryl, and heterocyclic, and wherein the tricyclic groups include fused tricyclic, bridged tricyclic, spiro tricyclic, and combinations thereof; Is optionally hydroxyl, keto, thioketo, alkyl, substituted alkyl, alkoxy, substituted alkoxy, amino, substituted amino, aryl, aryloxy, cyano, cycloalkyl, substituted cycloalkyl, halo, heteroaryl, heteroaryloxy, nitro, thiol Thioalkoxy, substituted thioalkoxy, thioaryloxy and thioheteroaryloxy, which are substituted with 1 to 3 substituents selected from the group consisting of: Item 48. The method according to Item 48. 50. The heterocyclic ring is pyrrolidinyl, 4-hydroxypyrrolidinyl, azetidinyl, thioazolidinyl, piperidinyl, piperazinyl, dihydroindolyl (eg, 2,3-dihydroindol-2-yl), tetrahydroquinolinyl (E.g., 1,2,3,4-tetrahydroquinolin-2-yl), morpholinyl, thiomorpholinyl, 4-halopyrrolidinyl, 3-phenylpyrrolidinyl, 4-aminopyrrolidinyl, 3-methoxypyrrolidinyl, 4-
50. The method of claim 49, wherein the method is selected from the group consisting of dimethylpyrrolidinyl and 5,5-dimethylthiazolidin-4-yl. 51. The method of claim 47, wherein R ¹ , R ^′ and the nitrogen and carbon atoms attached thereto form a heteroaryl ring. 52. A heteroaryl ring is a monocyclic heteroaryl wherein those groups are optionally hydroxyl, alkyl,
Substituted alkyl, alkoxy, substituted alkoxy, amino, substituted amino, aryl,
1-3 selected from the group consisting of aryloxy, cyano, cycloalkyl, substituted cycloalkyl, halo, heteroaryl, heteroaryloxy, nitro, thiol, thioalkoxy, substituted thioalkoxy, thioaryloxy and thioheteroaryloxy Bicyclic heteroaryl (wherein the second cyclic group is aryl, cycloalkyl,
Selected from the group consisting of cycloalkenyl, heteroaryl and heterocyclic, and wherein the bicyclic groups include fused bicyclic and bridged bicyclic, each ring optionally having hydroxyl, alkyl, substituted alkyl, alkoxy, substituted Alkoxy, amino, substituted amino, aryl, aryloxy, cyano, cycloalkyl,
Substituted cycloalkyl, halo, heteroaryl, heteroaryloxy, nitro,
Substituted with 1 to 3 substituents selected from the group consisting of thiol, thioalkoxy, substituted thioalkoxy, thioaryloxy and thioheteroaryloxy, and the second cyclic group is a cycloalkyl group, a cycloalkenyl Or heterocyclic, keto and thioketo groups); and tricyclic heteroaryl, wherein the second and / or third cyclic groups are independently
Selected from the group consisting of aryl, cycloalkyl, cycloalkenyl, heteroaryl, and heterocyclic, and wherein the tricyclic groups include fused tricyclic, bridged tricyclic, spiro tricyclic, and any combination thereof; Further, each ring is optionally hydroxyl, alkyl, substituted alkyl, alkoxy, substituted alkoxy,
1 to 1 selected from the group consisting of aryl, aryloxy, cyano, cycloalkyl, substituted cycloalkyl, halo, heteroaryl, heteroaryloxy, nitro, thiol, thioalkoxy, substituted thioalkoxy, thioaryloxy and thioheteroaryloxy Substituted with three substituents, and additionally the second and / or third cyclic group is a cycloalkyl, cycloalkenyl or heterocyclic group, a keto group and a thioketo group) 52. The method of claim 51, which is selected. 53. A heteroaryl group is pyridinyl, 2-quinoxalinyl,
53. The method according to claim 52, wherein the group is selected from the group consisting of indolyl, N-methylindolyl, 3-amino-2-pyrazinyl, 3-amino-5,6-dichloro-2-pyrazinyl, 4-methoxyindolyl and 3-isoquinolinyl. The described method. 54. The method of claim 41, 42 or 43, wherein R ² is independently selected from the group consisting of alkyl, substituted alkyl, alkenyl, cycloalkyl, aryl, heteroaryl and heterocyclic. 55. 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, method according to claim 54 of the claims. 56. The method according to claim 41, 42 or 43, wherein R ³ is selected from the group consisting of hydrogen, alkyl, substituted alkyl and cycloalkyl. 57. R ³ is hydrogen, methyl, 2-methylpropyl, hexyl,
57. The method of claim 56, wherein the method is selected from the group consisting of methoxycarbonylmethyl, 3,3-dimethyl-2-oxobutyl, 4-phenylbutyl, cyclopropylmethyl, 2,2,2-trifluoroethyl, and cyclohexyl. 58. The method of claim 41, 42 or 43, wherein R ⁴ is hydrogen, alkyl or substituted alkyl. 59. The method of claim 58, wherein R ⁴ is alkyl. 60. The method of claim 41, 42 or 43, wherein R ⁵ is selected from the group consisting of alkyl, substituted alkyl, phenyl, substituted phenyl, cycloalkyl, heteroaryl and heterocyclic. 61. The method according to claim 60, wherein R ⁵ is alkyl. 62. The compound according to formula I or Ia, wherein 5- (S)-[N ^′ -(L-prolyl) -L-alaninyl] amino-7-methyl-5,
7-dihydro-6H-dibenzo [b, d] azepin-one; 5- (S)-[N ^' -(L-homoprolyl) -L-alaninyl] amino-7-methyl-5,7-dihydro-6H- Dibenzo [b, d] azepin-one; 5- (S)-[N ^' -(DL-homoprolyl) -L-alaninyl] amino-7-methyl-5,7-dihydro-6H-dibenzo [b, d] Azepin-one; 5- (S)-[N ^' -(1,2,3,4-tetrahydroisoquinolin-1-oil)-
L-alaninyl] amino-7-methyl-5,7-dihydro-6H-dibenzo [b, d
] Azepin-one; 5- (S)-[N ^' -(octahydro-indolyl-2-oil) -L-alaninyl
] Amino-7-methyl-5,7-dihydro-6H-dibenzo [b, d] azepin-one; 5- {N ^' -[cis-4- (3-methylbutyl) -L-prolyl] -L-alaninyl
} Amino-7-methyl-5,7-dihydro-6H-dibenzo [b, d] azepin-one; 5- {N ^' -[trans-4- (3-methylbutyl) -L-prolyl] -L-alaninyl 44. The method according to claim 41, 42 or 43, wherein the method is selected from the group consisting of: amino-7-methyl-5,7-dihydro-6H-dibenzo [b, d] azepin-one; and pharmaceutical salts thereof. 63. 5- (S)-[N ^′ -(decahydroquinolyl-2-oil) -L
-Alaninyl] amino-7-methyl-5,7-dihydro-6H-dibenzo [b, d]
Azepin-6-one; 5- [N ^' -(decahydroquinolyl-2-oil) -L-alaninyl] amino-7
-Methyl-5,7-dihydro-6H-dibenzo [b, d] azepin-6-one; 5- {N ^' -[(S) -indolyl-2-oil] -L-alaninyl} amino-7-
Methyl-5,7-dihydro-6H-dibenzo [b, d] azepin-6-one; 5- (S)-{N ^' -[(S) -indolyl-2-oil] -L-alaninyl} amino- 7-methyl-5,7-dihydro-6H-dibenzo [b, d] azepin-6-one; 5- [N ^' -(L-trans-4-hydroxyprolyl) -L-alaninyl] amino-7- Methyl-5,7-dihydro-6H-dibenzo [b, d] azepin-6-one; 5- (S)-[N ^' -(1,2,3,4-tetrahydroquinolyl-2-oil)- L-
Alaninyl] amino-7-methyl-5,7-dihydro-6H-dibenzo [b, d] azepin-6-one; 5- (S)-[N ^' -(3,3-dimethylindolyl-2-oil ) -L-alaninyl] amino-7-methyl-5,7-dihydro-6H-dibenzo [b, d] azepine-
6-one; 5- {N ^′ -[(S) -2-methylindolyl-2-oil] -L-alaninyl} amino-7-methyl-5,7-dihydro-6H-dibenzo [b, d] Azepin-6-one; 5- (S)-{N ^' -[(S) -2-methylindolyl-2-oil] -L-alaninyl} amino-7-methyl-5,7-dihydro-6H- Dibenzo [b, d] azepine-
6-one; 5- [N ^′ -(indole-2-oil) -L-alaninyl] amino-7-methyl-5,7-dihydro-6H-dibenzo [b, d] azepin-6-one; 1- (S)-[N ^' -(3,3-dimethylindolyl-2-oil) -L-alaninyl] amino-3-methyl-4,5,6,7-tetrahydro-2H-3-benzazepine-2 -One; 1- (S)-[N ^' -(1,2,3,4-tetrahydroquinolyl-2-oil) -L-
Alaninyl] amino-3-methyl-4,5,6,7-tetrahydro-2H-3-benzazepin-2-one; 3- [N ^′ -(3-pyridinoyl) -L-alaninyl] amino-2,3 -Dihydro-
1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one; 5- {N ^′ -(2-piperidinecarboxyl) -L-alaninyl} amino-7-methyl-5,7-dihydro-6H -Dibenzo [b, d] azepin-6-one (both enantiomers); 5- [N ^' -(quinolyl-2-oil) -L-alaninyl] amino-7-methyl-
A compound selected from the group consisting of 5,7-dihydro-6H-dibenzo [b, d] azepin-6-one; and pharmaceutically acceptable salts thereof. 64. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a pharmaceutically acceptable amount of a compound, said compound comprising 5- (S)-[N ^′ -(decahydroquinolyl- 2-Oil) -L-alaninyl] amino-7-methyl-5,7-dihydro-6H-dibenzo [b, d] azepin-6-one; 5- [N ^' -(decahydroquinolyl-2-oil) -L-alaninyl] amino-7
-Methyl-5,7-dihydro-6H-dibenzo [b, d] azepin-6-one; 5- {N ^' -[(S) -indolyl-2-oil] -L-alaninyl} amino-7-
Methyl-5,7-dihydro-6H-dibenzo [b, d] azepin-6-one; 5- (S)-{N ^' -[(S) -indolyl-2-oil] -L-alaninyl} amino- 7-methyl-5,7-dihydro-6H-dibenzo [b, d] azepin-6-one; 5- [N ^' -(L-trans-4-hydroxyprolyl) -L-alaninyl] amino-7- Methyl-5,7-dihydro-6H-dibenzo [b, d] azepin-6-one; 5- (S)-[N ^' -(1,2,3,4-tetrahydroquinolyl-2-oil)- L-
Alaninyl] amino-7-methyl-5,7-dihydro-6H-dibenzo [b, d] azepin-6-one; 5- (S)-[N ^' -(3,3-dimethylindolyl-2-oil ) -L-alaninyl] amino-7-methyl-5,7-dihydro-6H-dibenzo [b, d] azepine-
6-one; 5- {N ^′ -[(S) -2-methylindolyl-2-oil] -L-alaninyl} amino-7-methyl-5,7-dihydro-6H-dibenzo [b, d] Azepin-6-one; 5- (S)-{N ^' -[(S) -2-methylindolyl-2-oil] -L-alaninyl} amino-7-methyl-5,7-dihydro-6H- Dibenzo [b, d] azepine-
6-one; 5- [N ^′ -(indole-2-oil) -L-alaninyl] amino-7-methyl-5,7-dihydro-6H-dibenzo [b, d] azepin-6-one; 1- (S)-[N ^' -(3,3-dimethylindolyl-2-oil) -L-alaninyl] amino-3-methyl-4,5,6,7-tetrahydro-2H-3-benzazepine-2 -One; 1- (S)-[N ^' -(1,2,3,4-tetrahydroquinolyl-2-oil) -L-
Alaninyl] amino-3-methyl-4,5,6,7-tetrahydro-2H-3-benzazepin-2-one; 3- [N ^′ -(3-pyridinoyl) -L-alaninyl] amino-2,3 -Dihydro-
1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one; 5- {N ^′ -(2-piperidinecarboxyl) -L-alaninyl} amino-7-methyl-5,7-dihydro-6H -Dibenzo [b, d] azepin-6-one (both enantiomers); 5- [N ^' -(quinolyl-2-oil) -L-alaninyl] amino-7-methyl-
A pharmaceutical composition selected from the group consisting of 5,7-dihydro-6H-dibenzo [b, d] azepin-6-one; and pharmaceutically acceptable salts thereof. 65. The compound is 5- (S)-[N ^′ -(decahydroquinolyl-2-oil) -L-alaninyl] amino-7-methyl-5,7-dihydro-6H-dibenzo [b, d] azepin-6-one; 5- [N ^' -(decahydroquinolyl-2-oil) -L-alaninyl] amino-7
-Methyl-5,7-dihydro-6H-dibenzo [b, d] azepin-6-one; 5- {N ^' -[(S) -indolyl-2-oil] -L-alaninyl} amino-7-
Methyl-5,7-dihydro-6H-dibenzo [b, d] azepin-6-one; 5- (S)-{N ^' -[(S) -indolyl-2-oil] -L-alaninyl} amino- 7-methyl-5,7-dihydro-6H-dibenzo [b, d] azepin-6-one; 5- [N ^' -(L-trans-4-hydroxyprolyl) -L-alaninyl] amino-7- Methyl-5,7-dihydro-6H-dibenzo [b, d] azepin-6-one; 5- (S)-[N ^' -(1,2,3,4-tetrahydroquinolyl-2-oil)- L-
Alaninyl] amino-7-methyl-5,7-dihydro-6H-dibenzo [b, d] azepin-6-one; 5- (S)-[N ^' -(3,3-dimethylindolyl-2-oil ) -L-alaninyl] amino-7-methyl-5,7-dihydro-6H-dibenzo [b, d] azepine-
6-one; 5- {N ^′ -[(S) -2-methylindolyl-2-oil] -L-alaninyl} amino-7-methyl-5,7-dihydro-6H-dibenzo [b, d] Azepin-6-one; 5- (S)-{N ^' -[(S) -2-methylindolyl-2-oil] -L-alaninyl} amino-7-methyl-5,7-dihydro-6H- Dibenzo [b, d] azepine-
6-one; 5- [N ^′ -(indole-2-oil) -L-alaninyl] amino-7-methyl-5,7-dihydro-6H-dibenzo [b, d] azepin-6-one; 1- (S)-[N ^' -(3,3-dimethylindolyl-2-oil) -L-alaninyl] amino-3-methyl-4,5,6,7-tetrahydro-2H-3-benzazepine-2 -One; 1- (S)-[N ^' -(1,2,3,4-tetrahydroquinolyl-2-oil) -L-
Alaninyl] amino-3-methyl-4,5,6,7-tetrahydro-2H-3-benzazepin-2-one; 3- [N ^′ -(3-pyridinoyl) -L-alaninyl] amino-2,3 -Dihydro-
1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one; 5- {N ^′ -(2-piperidinecarboxyl) -L-alaninyl} amino-7-methyl-5,7-dihydro-6H -Dibenzo [b, d] azepin-6-one (both enantiomers); 5- [N ^' -(quinolyl-2-oil) -L-alaninyl] amino-7-methyl-
44. The method of claim 41, 42 or 43, wherein the method is selected from the group consisting of: 5,7-dihydro-6H-dibenzo [b, d] azepin-6-one; and pharmaceutically acceptable salts thereof.