JP2002518482A - Compounds that inhibit β-amyloid peptide release and / or its synthesis - Google Patents

Abstract

  (57) [Summary] Disclosed are compounds that inhibit β-amyloid peptide release and / or synthesis thereof, and thereby are useful in treating Alzheimer's disease. Also disclosed is a pharmaceutical composition comprising a compound that inhibits β-amyloid peptide release and / or its synthesis, and a method for the prophylactic and therapeutic treatment of Alzheimer's disease using the pharmaceutical composition.

Description

DETAILED DESCRIPTION OF THE INVENTION

CROSS REFERENCE TO RELATED APPLICATIONS The present invention relates to US patent application Ser. No. 09 / 102,728, filed Jun. 22, 1998.
No. (this application is incorporated herein by reference in its entirety).
To 37 CFR US Provisional Application No. 6 as modified in accordance with §1.53 (b)
Claims the benefits of 0 / ,.

BACKGROUND OF THE INVENTION Field of the Invention The present invention relates to inhibiting β-amyloid peptide release and / or its synthesis,
Accordingly, it relates to compounds having utility in the treatment of Alzheimer's disease.

REFERENCES The following publications, patents and patent applications are cited herein by superscript number: 1 Glenner et al., Biochem. Biophys. Res. Commun. (1984) 120: 885-890.2 U.S. Pat.No. 4,666,829, issued May 19, 1987GG Glenner et al., "Polypept
ide Marker for Alzheimer's Disease and Its Use for Diagnosis. "3 Selkoe, Neuron. (1991) 6: 487-498.4 Goate et al., Nature (1990) 349: 704-706.5 Chartier Harlan et al., Nature (1989) 353 : 844-846.6 Murrell et al., Science (1991) 254: 97-99.7 Mullan et al., Nature Genet. (1992) 1: 345-347.8 Schenk et al., International Patent Application Publication No.WO94 / 105.
69, "Methods and Compositions for the Detection of Soluble β-Amyloid Pe
ptide ", published May 11, 1994. 9 Selkoe, Scientific American," Amyoid Protein and Alzheimer's Diseas
e ", pp. 2-8, November 1991.10 Yates et al., U.S. Pat.No. 3,598,859.11 Tetrahedron Letters 1993, 34 (48), 7685.12 RFC Brown et al., Tetrahedron Letters 1971, 8, 667-670. 13 AO King et al., J. Org. Chem. 1993, 58, 3384-3386. 14 U.S. Provisional Application No. 60 / 019,790, filed on June 14, 1996. 15 RD Clark et al., Tetrahedron 1993, 49 ( 7), 1351-1356.16 Citron et al., Nature (1992) 360: 672-674.17 P. Seubert, Nature (1992) 359: 325-327.18 Hansen et al., J. Immun. Meth. (1989) 119 19 Games et al., Nature (1995) 373: 523-527. 20 Johnson-Wood et al., PNAS USA (1997) 94: 1550-1555.

[0004] All of the above publications, patents and patent applications are to the same extent as if each individual publication, patent or patent application was specifically and individually indicated to be incorporated by reference. Is incorporated herein by reference in its entirety.

The state of the art Alzheimer's disease (AD) is clinically characterized by a progressive loss of memory, cognition, reason, judgment and emotional stability, which leads to a gradual and severe mental loss and ultimately death. It is a degenerative brain disorder. AD is a progressive decrease in mental intelligence of the elderly (dementia)
And is considered the fourth most common cause of death in the United States. AD has been observed in races and ethnic groups worldwide and is a major current and future global health problem. At present, the disease affects about 2
It is estimated that it affects between million and three million people. AD is currently incurable. There is currently no known treatment that effectively prevents AD or ameliorates its symptoms and reverses its progress.

The brain of an individual suffering from AD has features called senile plaques (or amyloid plaques or amyloid plaques), amyloid vascular disorders (amyloid angiopathy) (amyloid deposition in blood vessels) and neurofibrillary tangles. Indicates a serious obstacle. Many of these disorders, particularly amyloid plaques and neurofibrillary tangles, are commonly found in several regions of the human brain that are important for memory and cognitive function in AD patients. These disorders, which show fewer and more limited anatomical distributions, are also found in many elderly human brains who are not clinically AD patients. Amyloid plaque and amyloid vasculopathy are also characteristic of the brain of patients with hereditary cerebral hemorrhage with trisomy 21 (Down's syndrome) and German amyloidosis (HCHWA-D). At present, the definitive diagnosis of AD usually involves the observation of the disorder in the brain tissue of patients who have died of the disease or, in rare cases, in small brain tissue biopsy samples taken during invasive neurosurgery. Need to be done.

[0007] The major chemical composition of amyloid plaques and vascular amyloid deposits (amyloid vasculopathy) that characterize AD and other disorders described above is described as β-amyloid peptide (βAP) or sometimes Aβ, AβP or β / A4. It is a protein of about 4.2 kilodaltons (kD) of about 39-43 amino acids. The β-amyloid peptide was first purified and a partial amino acid sequence was obtained by Glenner, et al ¹ . The isolation procedure and sequence data for this first 28 amino acids are described in US Pat.
It is described in 6,829 No. ^2.

[0008] By molecular biological and protein chemical analyses, β-amyloid peptide and amyloid precursor protein (APP), which are normally produced by cells in many tissues of various animals, including humans, It has been shown to be a much smaller fragment of the precursor protein, referred to as the fragment. Knowing the structure of the gene encoding APP, the β-amyloid peptide was converted to AP by protease enzyme (s).
It was shown to occur as a peptide fragment cleaved from P. The exact biochemical mechanism by which β-amyloid peptide fragments are cleaved from APP and deposited as amyloid plaques in brain tissue and on the walls of blood vessels in the brain and meninges is currently unknown.

[0009] Several types of evidence indicate that progressive brain deposition of β-amyloid peptide plays a fundamental role in the pathogenesis of AD, which can precede symptom recognition for years or decades. ing. See, for example, Selkoe ³ . The most important type of evidence is that the missense DNA mutation at amino acid 717 of the 770 amino acid isoform APP, termed the Swedish variant, is a result of several genetically determined (familial) forms of AD. It is found in affected members of the family,
It was a finding that was not found in unaffected members (Goate, et al. ⁴ ; Chartier Harlan, et al. ⁵ ; and Murrell, et al. ⁶ ). In 1992, a double mutation in which a lysine ⁵⁹⁵ -methionine ⁵⁹⁶ was changed to an asparagine ⁵⁹⁵ -leucine ⁵⁹⁶ (for the 695 isoform) was reported in a Swedish family (Mullan, et al. ⁷ ). ). Genetic linkage analysis has shown that these mutations and other specific mutations in the APP gene are specific molecular causes of AD in affected members of the family. In addition, a mutation at amino acid 693 of the 770 amino acid isoform APP has been identified as a cause of the β-amyloid peptide deposition disease, HCHWA-D, and, in some patients, resembling AD when the alanine at amino acid 692 is changed to glycine. It causes the trait but appears to cause HCHWA-D in other patients. The discovery of these and other APP mutations in genetically based AD cases demonstrates that mutations in APP and subsequent deposition of β-amyloid peptide fragments may be responsible for AD.

[0010] Despite advances in understanding the underlying mechanisms of diseases associated with AD and other β-amyloid peptides, there remains a need to develop methods of treating the disease (s) and compositions therefor. I do. Ideally, this method of treatment would be advantageously based on a drug capable of inhibiting the release of β-amyloid peptide and / or its in vivo synthesis.

[0011] Compounds that inhibit the release of β-amyloid peptide and / or its in vivo synthesis are described in detail in December 1997, which is hereby incorporated by reference in its entirety.
U.S. Patent Application Serial No. 08 / 996,422, filed on March 22, entitled "Cycloalkyls, Lactams, Lactones and Related Compounds, Pharmaceutical Compositions Containing the Compounds, and Release and / or Release of β-Amyloid Peptides Using the Compounds Or a method of inhibiting its synthesis ", Attorney Docket 002010-062). The invention relates to deoxy derivatives of said compounds.

SUMMARY OF THE INVENTION The present invention inhibits the release of β-amyloid peptide and / or its synthesis,
Thus, it relates to the discovery of a class of compounds useful in the prevention of AD and / or the treatment of AD patients to inhibit further exacerbation of symptoms in patients prone to AD.

Thus, in one of its compositional aspects, the present invention provides a compound of formula I: and the pharmaceutically acceptable salts thereof:

Embedded image [Where W is

Embedded image

Embedded image Wherein ring A, together with the atom to which it is attached, is aryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, Forming a carbocyclic or heterocyclic ring selected from the group consisting of heteroaryl and heterocyclic; ring B together with the atom to which it is attached is aryl, cycloalkyl, substituted cyclo Forming a carbocyclic or heterocyclic ring selected from the group consisting of alkyl, cycloalkenyl, substituted cycloalkenyl, heteroaryl and heterocyclic; ring C together with the atom to which it is attached Y forms a heteroaryl or heterocyclic ring;

Embedded image With the proviso that at least one Y is-(CHR ^{2 '} ) _a -NH-; R ¹ is alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, substituted alkyl, substituted alkenyl, substituted alkynyl, substituted cycloalkyl, R ² is selected from the group consisting of substituted cycloalkenyl, aryl, heteroaryl and heterocyclic; R ² is alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl,
Selected from the group consisting of substituted alkynyl, cycloalkyl, aryl, heteroaryl and heterocyclic; each R ^{2 ′} is hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, aryl, heteroaryl And R ³ is independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, acyl, aryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cyclo alkenyl, it is selected from the group consisting of heteroaryl and heterocyclic; each R ⁴ is alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, cycloalkyl, substituted consequent Alkyl, cycloalkenyl, substituted cycloalkenyl, are independently selected from the group consisting of heteroaryl and heterocyclic; R ⁵ is alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl,
Q is selected from the group consisting of substituted alkynyl, substituted amino, aryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heteroaryl, heterocyclic, thioalkoxy and substituted thioalkoxy; Q is oxygen, sulfur, -S (O) - or S (O) ₂ - a and; Z is the formula: -T-CX'X "C (O ) - represented by wherein, T is R ¹ and -CX'X" - connecting Covalent single bond, oxygen, sulfur and-
NR ⁶ is selected from the group consisting of R ⁶ is hydrogen, acyl, alkyl, aryl or heteroaryl group; X ′ is hydrogen, hydroxy or fluoro, and X ″ is hydrogen, hydroxy or fluoro Or X ′ and X ″ together form an oxo group; a is an integer from 2 to about 6; f is an integer from 0 to 2; m is an integer from 0 or 1; n is an integer of 1 or 2.].

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

[0015] In still another of its method aspects, the present invention relates to a method of inhibiting the release of β-amyloid peptide and / or its synthesis in a cell, wherein the cell comprises the compound of formula I or a mixture thereof. Administering an amount effective to inhibit beta-amyloid peptide release and / or synthesis in the cell.

Also, since the in vivo production of β-amyloid peptide is associated with the pathogenesis of AD ^8,9 , the compounds of formula I can be used in combination with a pharmaceutical composition for preventing and / or treating AD. Thus, in another method aspect, the present invention provides a method comprising:
A method of preventing the onset of AD in a patient at risk of developing D, comprising administering to said patient an effective amount of a pharmaceutically inert carrier and a compound of formula I or a mixture thereof. A method comprising administering the composition.

In yet another method aspect, the present invention is a therapeutic method for treating an AD patient to prevent further worsening of the patient's condition, comprising providing the patient with a pharmaceutically inert carrier and A method comprising administering a pharmaceutical composition comprising an effective amount of a compound of formula I above or a mixture thereof.

In Formula I above, Ring A and Ring B may be the same or different and are preferably independent of the group consisting of aryl, cycloalkyl, cycloalkenyl, heteroaryl and heterocyclic. Selected. More preferably, ring A and ring B are independently selected from the group consisting of aryl and cycloalkyl. More preferably, rings A and B are independently aryl.

Particularly preferred rings A and B include, by way of example, phenyl, substituted phenyl, including fluoro-substituted phenyl, cyclohexyl, and the like.

[0020] Preferred C rings include, by way of example, pyrrolidinyl, piperidinyl, morpholino, and the like.

When m is 0 (ie there is one covalent bond from R ¹ to NH), R ¹ is preferably aryl (including substituted aryl) or heteroaryl (including substituted heteroaryl) . In this embodiment, further preferred R ¹ groups are (a) phenyl, (b) a formula:

Embedded image Wherein R ^c is acyl, alkyl, alkoxy, alkylalkoxy, azide,
Selected from the group consisting of cyano, halo, hydrogen, nitro, trihalomethyl, thioalkoxy, wherein R ^b and R ^c are fused to form a heteroaryl or heterocyclic ring with the phenyl ring, The cyclic ring contains 3-8 atoms, of which 1-3 are heteroatoms independently selected from the group consisting of oxygen, nitrogen and sulfur; R ^b and R ^{b ′} are hydrogen, Independently selected from the group consisting of halo, nitro, cyano, trihalomethyl, alkoxy and thioalkoxy, provided that when R ^c is hydrogen, then R ^b and R ^{b ′} are both hydrogen, or both are hydrogen. A substituted phenyl group represented by the formula: (c) 2-naphthyl, (d) an alkyl at the fourth, fifth, sixth, seventh and / or eighth position, 2-naphthyl (e) heteroaryl substituted with 1-5 substituents selected from the group consisting of alkoxy, halo, cyano, nitro, trihalomethyl, thioalkoxy, aryl and heteroaryl, (f) alkyl , Alkoxy, aryl, aryloxy, cyano, halo, nitro, heteroaryl, thioalkoxy, thioaryloxy, substituted heteroaryl containing 1-3 substituents selected from the group consisting of Heteroaryl, not ortho to the bond to the -NH group) and (g) alkyl.

When m is 0, particularly preferred substituted phenyl R ¹ groups include 3,5-disubstituted phenyl, such as 3,5-dichlorophenyl, 3,5-difluorophenyl, 3,5
-Di (trifluoromethyl) -phenyl and the like; 3,4-disubstituted phenyl, for example, 3
, 4-Dichlorophenyl, 3,4-difluorophenyl, 3- (trifluoromethyl) -4-chlorophenyl, 3-chloro-4-cyanophenyl, 3-chloro-4
-Iodophenyl, 3,4-methylenedioxyphenyl and the like; 4-substituted phenyl, for example, 4-azidophenyl, 4-bromophenyl, 4-chlorophenyl, 4-
Cyanophenyl, 4-ethylphenyl, 4-fluorophenyl, 4-iodophenyl, 4- (phenylcarbonyl) phenyl, 4- (1-ethoxy) ethylphenyl and the like; 3,4,5-trisubstituted phenyl such as 3,4 4,5-trifluorophenyl,
Mono-, di- and tri-substituted phenyl groups, including 3,4,5-trichlorophenyl and the like are included.

When m is 0, specific R ¹ groups include 3,4-dichlorophenyl, 4-phenylfurazan-3-yl, and the like.

When m is 0, other preferred R ¹ substituents include, for example, 2-naphthyl,
Quinolin-3-yl, 2-methylquinolin-6-yl, benzothiazol-6
Yl, 5-indolyl, phenyl and the like.

When m is 1, preferred R ¹ groups include unsubstituted aryl groups such as phenyl, 1-naphthyl, 2-naphthyl and the like; substituted aryl groups such as mono-substituted phenyl (
Preferably 3- or 5-substituted); disubstituted phenyl (preferably 3- and 5-substituted); and trisubstituted phenyl (preferably 3-, 4-,
5th-substitution). Preferably, a substituted phenyl group does not contain more than two substituents. Examples of substituted phenyl include, for example, 2-chlorophenyl, 2-fluorophenyl, 2-bromophenyl, 2-hydroxyphenyl, 2-nitrophenyl, 2-methylphenyl, 2-methoxyphenyl, 2-phenoxyphenyl,
2-trifluoromethylphenyl, 4-fluorophenyl, 4-chlorophenyl, 4-bromophenyl, 4-nitrophenyl, 4-methylphenyl, 4-hydroxyphenyl, 4-methoxyphenyl, 4-ethoxyphenyl, 4-butoxyphenyl , 4-iso-propylphenyl, 4-phenoxyphenyl, 4-trifluoromethylphenyl, 4-hydroxymethylphenyl, 3-methoxyphenyl,
3-hydroxyphenyl, 3-nitrophenyl, 3-fluorophenyl, 3-chlorophenyl, 3-bromophenyl, 3-phenoxyphenyl, 3-thiomethoxyphenyl, 3-methylphenyl, 3-trifluoromethylphenyl, 2,3 −
Dichlorophenyl, 2,3-difluorophenyl, 2,4-dichlorophenyl, 2
, 5-Dimethoxyphenyl, 3,4-dichlorophenyl, 3,4-difluorophenyl, 3,4-methylenedioxyphenyl, 3,4-dimethoxyphenyl, 3,5
-Difluorophenyl, 3,5-dichlorophenyl, 3,5-di- (trifluoromethyl) phenyl, 3,5-dimethoxyphenyl, 2,4-dichlorophenyl,
, 4-Difluorophenyl, 2,6-difluorophenyl, 3,4,5-trifluorophenyl, 3,4,5-trimethoxyphenyl, 3,4,5-tri- (trifluoromethyl) phenyl, 4,6-trifluorophenyl, 2,4,6-trimethylphenyl, 2,4,6-tri- (trifluoromethyl) phenyl, 2,3,5-trifluorophenyl, 2,4,5-trifluoro Phenyl, 2,5-difluorophenyl, 2-fluoro-3-trifluoromethylphenyl, 4-fluoro-2-trifluoromethylphenyl, 2-fluoro-4-trifluoromethylphenyl,
-Benzyloxyphenyl, 2-chloro-6-fluorophenyl, 2-fluoro-6-chlorophenyl, 2,3,4,5,6-pentafluorophenyl, 2,5-dimethylphenyl, 4-phenylphenyl and 2- Fluoro-3-trifluoromethylphenyl is included.

When m is 1, other preferred R¹Groups include, for example, adamantyl, ben
Jill, 2-phenylethyl, 3-phenyl-n-propyl, 4-phenyl-n-
Butyl, methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-
Butyl, sec-butyl, tert-butyl, n-pentyl, iso-valeryl, n-
Xyl, cyclopropyl, cyclobutyl, cyclohexyl, cyclopentyl,
Clopent-1-enyl, cyclopent-2-enyl, cyclohex-1-enyl
, -CH_Two-Cyclopropyl, -CH_Two-Cyclobutyl, -CH_Two-Cyclohexyl
Sill, -CH_Two-Cyclopentyl, -CH_TwoCH_Two-Cyclopropyl, -CH_TwoCH _Two -Cyclobutyl, -CH_TwoCH_Two-Cyclohexyl, -CH_TwoCH_Two-Cyclopen
Tyl, pyrid-2-yl, pyrid-3-yl, pyrid-4-yl, fluoropyri
Jyl (including 5-fluoropyrid-3-yl), chloropyridyl (5-chloropyridin
Lid-3-yl), thien-2-yl, thien-3-yl, benzothiazo
4-yl, 2-phenylbenzoxazol-5-yl, furan-2-i
Benzofuran-2-yl, thionaphthen-2-yl, thionaphthen-3-i
Thionaphthen-4-yl, 2-chlorothiophen-5-yl, 3-methylyl
Soxazol-5-yl, 2- (thiophenyl) thien-5-yl, 6-methoxy
Cythionaphthen-2-yl, 3-phenyl-1,2,4-thiooxadiazole
-5-yl, 2-phenyloxazol-4-yl, indol-3-yl, 1
-Phenyl-tetraol-5-yl, allyl, 2- (cyclohexyl) ethyl,
(CH_Three)_TwoCH = CHCH_TwoCH_TwoCH (CH_Three)-, ΦC (O) CH_Two-, Chain-2-
Yl-methyl, 2- (thien-2-yl) ethyl, 3- (thien-2-yl) -n-
Propyl, 2- (4-nitrophenyl) ethyl, 2- (4-methoxyphenyl) ethyl
, Norboran-2-yl, (4-methoxyphenyl) methyl, (2-methoxyphenyl)
(Enyl) methyl, (3-methoxyphenyl) methyl, (3-hydroxyphenyl) meth
Tyl, (4-hydroxyphenyl) methyl, (4-methoxyphenyl) methyl, (4
-Methylphenyl) methyl, (4-fluorophenyl) methyl, (4-fluorophenyl
(Oxy) methyl, (2,4-dichlorophenoxy) ethyl, (4-chlorophenyl) meth
Tyl, (2-chlorophenyl) methyl, (1-phenyl) ethyl, (1- (p-chloro
(Phenyl) ethyl, (1-trifluoromethyl) ethyl, (4-methoxyphenyl)
Ethyl, CH_ThreeOC (O) CH_Two-, Benzylthiomethyl, 5- (methoxycarbonyl
Ru) -n-pentyl, 3- (methoxycarbonyl) -n-propyl, indan-2
-Yl, (2-methylbenzofuran-3-yl), methoxymethyl, CH_ThreeCH =
CH-, CH_ThreeCH_TwoCH = CH-, (4-chlorophenyl) C (O) CH_Two-, (4-
Fluorophenyl) C (O) CH_Two-, (4-methoxyphenyl) C (O) CH_Two−4
-(Fluorophenyl) -NHC (O) CH_Two-, 1-phenyl-n-butyl, (φ)_Two CHNHC (O) CH_TwoCH_Two−, (CH_Three)_TwoNC (O) CH_Two−, (Φ)_TwoCHNHC (O)
CH_TwoCH_Two-, Methylcarbonylmethyl, (2,4-dimethylphenyl) C (O) C
H_Two-, (4-methoxyphenyl) -C (O) CH_Two-, Phenyl-C (O) CH_Two−,
CH_ThreeC (O) N (φ)-, ethenyl, methylthiomethyl, (CH_Three)_ThreeCNHC (O) C
H_Two-, 4-fluorophenyl-C (O) CH_Two-, Diphenylmethyl, phenoxy
Methyl, 3,4-methylenedioxyphenyl-CH_Two-, Benzo [b] thiophene
-3-yl, (CH_Three)_ThreeCOC (O) NHCH_Two-, Trans-styryl, H_TwoNC (
O) CH_TwoCH_Two-, 2-trifluoromethylphenyl-C (O) CH_Two, ΦC (O) N
HCH (φ) CH_Two-, Mesityl, CH_ThreeCH (= NHOH) CH_Two-, 4-CH_Three−φ
-NHC (O) CH_TwoCH_Two-, ΦC (O) CH (φ) CH_Two−, (CH_Three)_TwoCHC (O) N
HCH (φ)-, CH_ThreeCH_TwoOCH_Two-, CH_ThreeOC (O) CH (CH_Three) (CH_Two)_Three−,
2,2,2-trifluoroethyl, 1- (trifluoromethyl) ethyl, 2-CH_Three
-Benzofuran-3-yl, 2- (2,4-dichlorophenoxy) ethyl, φSO_Two CH_Two-, 3-cyclohexyl-n-propyl, CF_ThreeCH_TwoCH_TwoCH_Two− And
N-pyrrolidinyl is included.

At present, R ² is alkyl, substituted alkyl, alkenyl, cycloalkyl,
Preferably, it is selected from the group consisting of aryl, heteroaryl and heterocyclic.

Each R ^{2 ′} is (independently) from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, cycloalkyl, aryl, heteroaryl, and heterocyclic.
Preferably, it is selected.

Particularly preferred R^TwoAnd R^{Two '}Substitution (R^{Two '}Is other than hydrogen)
Is methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-
Butyl, sec-butyl, tert-butyl, -CH_TwoCH (CH_TwoCH_Three)_Two, 2-methyl
-N-butyl, 6-fluoro-n-hexyl, phenyl, benzyl, cyclohexyl
Sil, cyclopentyl, cycloheptyl, allyl, iso-but-2-enyl, 3
-Methylpentyl, -CH_Two-Cyclopropyl, -CH_Two-Cyclohexyl, -C
H_TwoCH_Two-Cyclopropyl, -CH_TwoCH_Two-Cyclohexyl, -CH_Two− India
Yl-3-yl, p- (phenyl) phenyl, o-fluorophenyl, m-fluoro
Rophenyl, p-fluorophenyl, m-methoxyphenyl, p-methoxyphenyl
Nil, phenethyl, benzyl, m-hydroxybenzyl, p-hydroxybenzyl
, P-nitrobenzyl, m-trifluoromethylphenyl, p- (CH_Three)_TwoNC
H_TwoCH_TwoCH_TwoO-benzyl, p- (CH_Three)_ThreeCOC (O) CH_TwoO-benzyl, p-
(HOOCCH_TwoO) -benzyl, 2-aminopyrid-6-yl, p- (N-morpho
Reno-CH_TwoCH_TwoO) -benzyl, -CH_TwoCH_TwoC (O) NH_Two, -CH_Two−Imida
Zol-4-yl, -CH_Two-(3-tetrahydrofuranyl), -CH_Two-Thiophe
N-2-yl, -CH_Two(1-methyl) cyclopropyl, -CH_Two-Thiophene-3
-Yl, thiophen-3-yl, thiophen-2-yl, -CH_Two-C (O) O-
t-butyl, -CH_Two-C (CH_Three)_Three, -CH_TwoCH (CH_TwoCH_Three)_Two, -2-methyl
Cyclopentyl, -cyclohex-2-enyl, -CH [CH (CH_Three)_Two] COOC
H_Three, -CH_TwoCH_TwoN (CH_Three)_Two, -CH_TwoC (CH_Three) = CH_Two, -CH_TwoCH = CH
CH_Three(Cis and trans), -CH_TwoOH, -CH (OH) CH_Three, -CH (O-
t-butyl) CH_Three, -CH_TwoOCH_Three,-(CH_Two)_FourNH-Boc,-(CH_Two)_FourNH _Two , -CH_Two-Pyridyl (eg, 2-pyridyl, 3-pyridyl and 4-pyridyl
), Pyridyl (2-pyridyl, 3-pyridyl and 4-pyridyl), -CH_Two-Na
Phthyl (eg, 1-naphthyl and 2-naphthyl), -CH_Two-(N-morpholino)
, P- (N-morpholino-CH_TwoCH_TwoO) -benzyl, benzo [b] thiophene-2
-Yl, 5-chlorobenzo [b] thiophen-2-yl, 4,5,6,7-tetrahi
Drobenzo [b] thiophen-2-yl, benzo [b] thiophen-3-yl, 5-
Chlorobenzo [b] thiophen-3-yl, benzo [b] thiophen-5-yl, 6
-Methoxynaphth-2-yl, -CH_TwoCH_TwoSCH_Three, Thien-2-yl, Thie
-3-yl and the like.

Preferably, R ³ is selected from the group consisting of hydrogen, alkyl, substituted alkyl and cycloalkyl. In another preferred embodiment, R ³ is alkyl, substituted alkyl or aryl. More preferably, R ³ is alkyl.

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

It is presently preferred that R ⁴ is alkyl or substituted alkyl.

R ⁵ is alkyl; substituted alkyl; phenyl; substituted phenyl such as 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 2-chlorophenyl and the like; cycloalkyl such as cyclohexyl and the like; Clicks are preferred, for example 1-piperdinyl, 2-pyridyl, 2-thiazyl, 2-thienyl and the like.

Preferably, f is 0 or 1. More preferably, f is 0.

When Y is a group — (CHR ^{2 ′} ) _a —NH—, the integer a is preferably 2, 3 or 4, more preferably 2 or 4, and even more preferably a is 2 It is. In a preferred embodiment, Y has the formula: -CHR ^{₂ '-CH 2} -NH- (wherein, R ^2'
Is as defined herein), which includes the preferred embodiments described.

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

Embedded image[Wherein each R⁶Is acyl, acylamino, acyloxy, alkenyl, substituted
Kenyl, alkoxy, substituted alkoxy, alkyl, substituted alkyl, alkynyl,
Substituted alkynyl, amino, substituted amino, aminoacyl, aryl, aryloxy
Si, carboxyl, carboxyalkyl, cyano, cycloalkyl, substituted cyclo
Alkyl, halo, heteroaryl, heterocyclic, nitro, thioalkoxy
, Substituted thioalkoxy, thioaryloxy, thioheteroaryloxy,-
SO-alkyl, -SO-substituted alkyl, -SO-aryl, -SO-heteroaryl, -SO_Two-Alkyl, -SO_Two-Substituted alkyl, -SO _Two -Aryl and -SO_TwoEach independently selected from the group consisting of: -heteroaryl;⁷Is acyl, acylamino, acyloxy, alkenyl, substituted alkenyl
, Alkoxy, substituted alkoxy, alkyl, substituted alkyl, alkynyl, substituted
Ruquinyl, amino, substituted amino, aminoacyl, aryl, aryloxy,
Ruboxyl, carboxyalkyl, cyano, cycloalkyl, substituted cycloalkyl
, Halo, heteroaryl, heterocyclic, nitro, thioalkoxy,
Substituted thioalkoxy, thioaryloxy, thioheteroaryloxy, -SO-
Alkyl, -SO-substituted alkyl, -SO-aryl, -SO-heteroaryl, -SO_Two-Alkyl, -SO_Two-Substituted alkyl, -SO _Two -Aryl and -SO_TwoIndependently selected from the group consisting of: heteroaryl; R⁸Is hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkyl
Nil, substituted alkynyl, acyl, aryl, cycloalkyl, substituted cycloalkyl
, Cycloalkenyl, substituted cycloalkenyl, heteroaryl and heterosa
P is an integer of 0 to 4; q is an integer of 0 to 4].

Preferably, R ⁶ and R ⁷ are independently of the group consisting of alkoxy, substituted alkoxy, alkyl, substituted alkyl, amino, substituted amino, carboxyl, carboxyalkyl, cyano, halo, nitro, thioalkoxy and substituted thioalkoxy Selected. At present, more preferably, R ⁶ and R ⁷ are fluoro.

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

Particularly preferred R ⁸ substituents include, for example, hydrogen, methyl, 2-methylpropyl, hexyl, methoxycarbonylmethyl, 3,3-dimethyl-2-oxobutyl, 4-phenylbutyl, cyclopropylmethyl, , 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 0-3
And a cyclic group represented by the formula:

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

Embedded image Wherein R ⁶ and p are as defined in the present specification.

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 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; each R ⁹ is alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, cycloalkyl, substituted cyclo Independently selected from the group consisting of alkyl, cycloalkenyl, substituted cycloalkenyl, heteroaryl, and heterocyclic; and g is an integer from 0 to 2].

It is presently preferred that R ⁹ is 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.
Is a cyclic ring represented by

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.
Is a cyclic ring represented by

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

Embedded image Wherein R ⁶ , each R ⁸ and p are as defined in the present specification.

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

Embedded image Wherein R ⁶ , each R ⁸ , R ⁹ , g and p are as defined in the present specification.

In 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; R ¹⁰ is alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl,
Selected from the group consisting of substituted alkynyl, substituted amino, aryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heteroaryl, heterocyclic, thioalkoxy, and substituted thioalkoxy. It is.

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; DE is selected from the group consisting of alkylene, alkenylene, substituted alkylene, substituted alkenylene and —N ＝ CH— ] It is a cyclic ring shown by these.

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) — or —S (O) ₂ — There is a cyclic ring represented by

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

Embedded image Wherein R ⁶ , R ⁸ and p are as defined in the present specification.

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

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

In the above formula, preferably each R ⁶ is independently selected from the group consisting of alkyl, substituted alkyl, alkoxy and halo; each R ⁷ is independently selected from the group consisting of alkyl, substituted alkyl, alkoxy and halo is selected; each R ⁸ is alkyl, substituted alkyl, are independently selected from the group consisting of cycloalkyl and aryl; each R ⁹
Is independently selected from the group consisting of alkyl, substituted alkyl, cycloalkyl and aryl; and g, p, q and r are 0 or 1. More preferably, g, p, q and r are 0.

Compounds of the present invention include, by way of example, the following:

Embedded image That is, 5S- [N ′-(2S-hydroxy-3-methylbutyryl) -2S-aminoprop-1-yl] amino-7-methyl-5,7-dihydro-6H-dibenzo [b, d] azepin-6-one .

The products of the present invention include a mixture of R, S enantiomers at any stereochemical center. However, if a chiral product is desired, the chiral product will be L
-Preferably those corresponding to amino acid derivatives. In the formulas described herein, mixtures of R, S enantiomers at stereochemical centers may be conventionally indicated by a squiggly line. In other cases, there may be no stereochemical indication at the stereochemical center, which also means that a mixture of enantiomers is present.

Also within the scope of the invention are prodrugs of the compounds of formula I above, including the acylated forms of alcohols and thiols, the aminals of one or more amines, and the like. .

Detailed Description of the Invention As noted above, the present invention relates to compounds that inhibit the release of β-amyloid peptide and / or its synthesis, and thus have utility in the treatment of Alzheimer's disease. Before describing the present invention in further detail, the following terms will first be defined.

Definitions The term “β-amyloid peptide” refers to a 39-43 amino acid peptide with a molecular weight of about 4.2 kD, including mutant and post-translationally modified normal β-amyloid peptides, Glenner, et al. al represents a peptide that is substantially homologous to the form of the protein described by al ¹ . In either form, the β-amyloid peptide is a large transmembrane (me) called β-amyloid precursor protein (APP).
mbrane-spanning) An approximately 39-43 amino acid fragment of a glycoprotein. Part 43
-The amino acid sequence is: 1 Asp Ala Glu Phe Arg His Asp Ser Gly Tyr 11 Glu Val His His Gln Lys Leu Val Phe Phe 21 Ala Glu Asp Val Gly Ser Asn Lys Gly Ala 31 Ile Ile Gly Leu Met Val Gly Gly Val Val 41 Ile Ala Thr (SEQ ID NO: 1) or a sequence substantially homologous thereto.

“Alkyl” represents a monovalent alkyl group preferably having 1 to 20 carbon atoms, more preferably having 1 to 6 carbon atoms. Examples of this term include groups such as methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, n-hexyl and the like.

“Substituted alkyl” preferably refers to 1 to 5, preferably 1 to 3,
Coxy, substituted alkoxy, cycloalkyl, substituted cycloalkyl, cycloalk
Nil, substituted cycloalkenyl, acyl, acylamino, acyloxy, amino,
Substituted amino, aminoacyl, aminoacyloxy, oxyacylamino, cyano
, Halogen, hydroxyl, carboxyl, carboxylalkyl, keto, thio
Keto, thiol, thioalkoxy, substituted thioalkoxy, aryl, arylo
Xy, heteroaryl, heteroaryloxy, heterocyclic, heterocy
Chlooxy, hydroxyamino, alkoxyamino, nitro, -SO-alkyl
, -SO-substituted alkyl, -SO-aryl, -SO-heteroaryl, -SO _Two -Alkyl, -SO_Two-Substituted alkyl, -SO_Two-Aryl and -SO_Two-Hete
An aryl group having 1 to 10 carbon atoms having a substituent selected from the group consisting of
Represents a alkyl group.

“Alkylene” represents a divalent alkylene group preferably having 1 to 10 carbon atoms, more preferably 1 to 6 carbon atoms. Examples of this term include methylene (
—CH ₂ —), ethylene (—CH ₂ CH ₂ —), and propylene isomers (eg, —CH ₂ CH ₂ CH ₂ — and —CH (CH ₃ ) CH ₂ —).

“Substituted alkylene” is preferably alkoxy, substituted alkoxy, cycloalkyl, substituted cycloalkyl, cycloalkoxy, substituted cycloalkoxyl,
Acyl, acylamino, acyloxy, amino, substituted amino, aminoacyl, aminoacyloxy, cyano, halogen, hydroxyl, carboxyl, carboxylalkyl, keto, thioketo, thiol, thioalkoxy, substituted thioalkoxy, aryl, heteroaryl, heterocyclic, hetero Cyclooxy, nitro-SO-alkyl, -SO-substituted alkyl, -SO-aryl, -SO-
Heteroaryl, -SO ₂ - alkyl, -SO ₂ - substituted alkyl, -SO ₂ - aryl and -SO ₂ - having 1-3 substituents selected from the group consisting of heteroaryl, carbon atoms 1 to 10 Represents an alkylene group. Further, the substituted alkylene group is fused with two substituents on the alkylene group to form one or more cycloalkyl, aryl, heterocyclic or heteroaryl groups fused to the alkylene group. Includes what you are doing. Preferably, the fused cycloalkyl group contains 1 to 3 fused ring structures.

“Alkenylene” represents a divalent alkenylene group preferably having 2 to 10, more preferably 2 to 6, carbon atoms. Examples of this term include ethenylene (
-CH = CH-), the propenylene isomers (e.g., -CH ₂ CH = CH- and -
C (CH ₃₎ = CH-) has groups such as.

“Substituted alkenylene” is preferably alkoxy, substituted alkoxy, cycloalkyl, substituted cycloalkyl, cycloalkoxy, substituted cycloalkoxyl, 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 -SO ₂ - having 1-3 substituents selected from the group consisting of heteroaryl, carbon atoms 2 Represents 10 alkenylene groups. Further, the substituted alkylene group is fused with two substituents on the alkylene group to form one or more cycloalkyl, aryl, heterocyclic or heteroaryl groups fused to the alkylene group. Includes what you are doing.

“Alkaryl” preferably means that the alkylene moiety has 1 to 8 carbon atoms,
Represents an -alkylene-aryl group having 6 to 10 carbon atoms in the aryl moiety.
Examples of such alkaryl groups include benzyl, phenethyl and the like.

“Alkoxy” refers to the group alkyl-O—. Preferred alkoxy groups include
Examples include methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, tert-butoxy, sec-butoxy, n-pentoxy, n-hexoxy,
, 2-dimethylbutoxy and the like.

“Substituted alkoxy” refers to the group: substituted alkyl-O—, where substituted alkyl is as defined above.

“Alkylalkoxy” refers to the group: —alkylene-O-alkyl, which includes, by way of example, methylenemethoxy (—CH ₂ OCH ₃ ), ethylenemethoxy (—C
_{H 2 CH 2 OCH 3),} n- propylene - iso - propoxy (-CH ₂ CH ₂ CH ₂ O
CH (CH _{3) 2),} methylene -t- butoxy _{(-CH 2 -O-C (CH} 3) 3) , and the like.

“Alkylthioalkoxy” refers to the group: —alkylene-S-alkyl,
This includes by way of example, methylene thio methoxy (-CH ₂ SCH _3), ethylene thiomethoxide _{(-CH 2 CH 2 SCH 3)} , n- propylene - thio - iso - propoxy _{(-CH 2 CH 2 CH 2 SCH} ( CH _{3) 2),} methylenethio -t- butoxy _{(-CH 2 SC (CH 3)} 3) , and the like.

“Alkenyl” is an alkenyl group preferably having 2 to 10 carbon atoms, more preferably 2 to 6 carbon atoms, and having at least 1, preferably 1 to 2 alkenyl unsaturated sites. Represents Preferred alkenyl groups include ethenyl (-CH
ＣＨCH ₂ ), n-propenyl (—CH ₂ CH ＝ CH ₂ ), iso-propenyl (—C (
CH ₃ ) = CH ₂ ).

“Substituted alkenyl” refers to alkoxy, substituted alkoxy, cycloalkyl, substituted cycloalkyl, cycloalkoxy, substituted cycloalkoxyl, 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 -
Having 1 to 3 substituents selected from the group consisting of SO ₂ -heteroaryl,
Represents an alkenyl group as defined above.

“Alkynyl” is an alkynyl group preferably having 2 to 10 carbon atoms, more preferably 2 to 6 carbon atoms, and having at least 1, preferably 1 to 2 alkynyl unsaturated sites. Represents Preferred alkynyl groups include ethynyl (-C≡
CH), propargyl (—CH ₂ C≡CH) and the like.

“Substituted alkynyl” refers to alkoxy, substituted alkoxy, cycloalkyl, substituted cycloalkyl, cycloalkoxy, substituted cycloalkoxyl, 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 -
Having 1 to 3 substituents selected from the group consisting of SO ₂ -heteroaryl,
Represents an alkynyl group as defined above.

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

“Acylamino” refers to the group —C (O) NRR wherein each R is independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, aryl, heteroaryl, heterocyclic. And both R groups are joined to form a heterocyclic group wherein 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 where} each R is hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, cycloalkyl, substituted cycloalkyl, Or independently selected from the group consisting of heteroaryl and heterocyclic, or both R groups combine to form a heterocyclic group]. When both R groups are hydrogen, -N (R) ₂ is an amino group. Examples of substituted amino groups include mono- and di-alkylamino, mono- and di- (substituted alkyl) amino, mono- and di-arylamino, mono- and di-heteroarylamino, mono- and di-hetero. It includes cyclic amino and asymmetric disubstituted amines having various substituents selected from alkyl, substituted alkyl, aryl, heteroaryl and heterocyclic.

The term “amino protecting group”, when attached to an amino group, prevents undesired reactions at the amino group from occurring and is removed by conventional chemical and / or enzymatic techniques to restore the amino group. Represents any group that can be Any known amino protecting group can be used in the present invention. Typically, the amino protecting group is
The resulting protected amino group is selected to be non-reactive to the particular reagents and reaction conditions used in the following predetermined chemical reaction or series of reactions. After the reaction is completed, the amino protecting group is selectively removed to recover the amino group. Examples of suitable amino protecting groups include tert-butoxycarbonyl (Boc), benzyloxycarbonyl (Cbz), acetyl, 1- (1′-adamantyl) -1
-Methylethoxycarbonyl (Acm), allyloxycarbonyl (Aloc)
, Benzyloxymethyl (Bom), 2-p-biphenylisopropyloxycarbonyl (Bpoc), tert-butyldimethylsilyl (Bsi), benzoyl (
Bz), benzyl (Bn), 9-fluorenyl-methyloxycarbonyl (Fm
oc), 4-methylbenzyl, 4-methoxybenzyl, 2-nitrophenylsulfenyl (Nps), 3-nitro-2-pyridinesulfenyl (NPys), trifluoroacetyl (Tfa), 2,4,6-tri Methoxybenzyl (Tmob
), Trityl (Trt) and the like. If desired, amino protecting groups covalently linked to a solid support may be used.

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

“Aminoacyloxy” refers to the group —NRC (O) OR where each R is independently hydrogen, alkyl, substituted alkyl, aryl, heteroaryl or heterocyclic, wherein alkyl, Substituted alkyl, aryl, heteroaryl and heterocyclic are as defined herein.

“Acyloxy” refers to the group alkyl-C (O) O—, substituted alkyl-C (O) O.
-, Cycloalkyl-C (O) O-, substituted cycloalkyl-C (O)-, aryl-
C (O) O-, heteroaryl-C (O) O- and heterocyclic-C (O) O
Represents-where alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, aryl, heteroaryl and heterocyclic are as defined herein.

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

Unless otherwise stated by the definition for aryl substituents, such aryl groups are 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 - may have been substituted by 1-5 substituents selected from the group consisting of heteroaryl and trihalomethyl. Preferred substituents include alkyl, alkoxy, halo, cyano, nitro, trihalomethyl and thioalkoxy.

“Aryloxy” refers to the group aryl-O— wherein the aryl group is as defined above and may optionally include a substituted aryl group as defined above. .

“Carboxyalkyl” refers to the group —C (O) Oalkyl and —C (O) O
-Represents a substituted alkyl wherein alkyl is as defined above.

“Cycloalkyl” refers to a cyclic alkyl group having from 3 to 12 carbon atoms and having a single ring or fused multiple rings. Such cycloalkyl groups include, by way of example, single ring structures such as cyclopropyl, cyclobutyl, cyclopentyl, cyclooctyl and the like or multiple ring structures such as adamantanyl and the like.

“Substituted cycloalkyl” 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, -
1 to 2 selected from the group consisting of SO ₂ -aryl and -SO ₂ -heteroaryl
Represents a cycloalkyl group having 5 (preferably 1 to 3) substituents.

“Cycloalkenyl” refers to cyclic alkenyl groups having from 4 to 8 carbon atoms, having a single ring and at least one site of internal unsaturation. Examples of suitable cycloalkenyl groups include, for example, cyclobut-2-enyl, cyclopent-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, 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,
It represents a cycloalkenyl group having 1-5 substituents selected from the group consisting of heteroaryl - -SO ₂ - aryl and -SO _2.

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

“Heteroaryl” refers to 1 to 15 carbon atoms and at least one heteroatom selected from oxygen, nitrogen and sulfur in at least one ring (if one or more rings are present). Represents an aromatic group having four.

Unless otherwise stated by the definition for heteroaryl substitutions,
Heteroaryl groups are optionally acyloxy, hydroxy, acyl, alk
Kill, alkoxy, alkenyl, alkynyl, substituted alkyl, substituted alkoxy,
Substituted alkenyl, substituted alkynyl, amino, substituted amino, aminoacyl, acyl
Amino, alkaryl, aryl, aryloxy, azide, carboxyl,
Ruboxylalkyl, cyano, halo, nitro, heteroaryl, heterocyclyl
, Aminoacyloxy, oxyacylamino, thioalkoxy, substituted thioa
Lucoxy, thioaryloxy, thioheteroaryloxy, -SO-alkyl
, -SO-substituted alkyl, -SO-aryl, -SO-heteroaryl, -SO _Two -Alkyl, -SO_Two-Substituted alkyl, -SO_Two-Aryl, -SO_Two-Heteroa
1 to 5 substituents selected from the group consisting of reel and trihalomethyl.
May have been replaced. Such heteroaryl groups can be monocyclic (e.g.,
Lysyl or furyl) or fused multiple rings (eg indolizinyl or benzothienyl)
Enyl). Preferred heteroaryls include pyridyl, pyrrolyl and
Contains frills.

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

The term “heterocycle” or “heterocyclic” has a single ring or a condensed multiple ring, and has 1 to 15 carbon atoms and a ring selected from nitrogen, sulfur and oxygen. Represents a monovalent saturated or unsaturated group having 1 to 4 hetero atoms.

Unless otherwise stated by the definition for heterocyclic substituents, such
A telocyclic group is optionally alkoxy, substituted alkoxy, cycloalkyl, substituted
Substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, acyl, acyl
Amino, acyloxy, amino, substituted amino, aminoacyl, aminoacyloxy
Oxyacylamino, cyano, halogen, hydroxyl, carboxyl,
Ruboxylalkyl, keto, thioketo, thiol, thioalkoxy, substituted thioa
Lucoxy, aryl, aryloxy, heteroaryl, heteroaryloxy
, Heterocyclic, heterocyclooxy, hydroxyamino, alkoxya
Mino, nitro, -SO-alkyl, -SO-substituted alkyl, -SO-aryl,
-SO-heteroaryl, -SO_Two-Alkyl, -SO_Two-Substituted alkyl, -SO _Two -Aryl and -SO_Two1 to 5 selected from the group consisting of heteroaryl
May have been substituted with Such heterocyclic groups can be monocyclic or
May have fused multiple rings. Preferred heterocyclic groups are morpholino, piperidinyl
And so on.

Examples of heterocyclic and heteroaryl compounds include pyrrole, furan, imidazole, pyrazole, pyridine, pyrazine, pyrimidine, pyridazine, indolizine, isoindole, indole, indazole, purine, quinolidine, isoquinoline, quinoline, phthalazine, Naphthylpyridine, quinoxaline, quinazoline, cinnoline, pteridine, carbazole, carbolin, phenanthridine, acridine, phenanthroline, isothiazole, phenazine, isoxazole, phenoxazine, phenothiazine, imidazolidine, imidazoline, piperidine, piperazine, indoline, morpholinol, piperidinyl , Tetrahydrofuranyl, and the like, as well as N-alkoxy-nitrogens containing heterocyclic groups. Not.

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

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

“Oxyacylamino” refers to the group —OC (O) NRR wherein each R is independently hydrogen, alkyl, substituted alkyl, aryl, heteroaryl or heterocyclic, wherein alkyl is , Substituted alkyl, aryl, heteroaryl and heterocyclic are as defined herein)].

“Thiol” refers to the group —SH.

“Thioalkoxy” refers to the group —S-alkyl.

“Substituted thioalkoxy” refers to the group —S-substituted alkyl.

“Thioaryloxy” refers to the group aryl-S- wherein the aryl group is as defined above and may include a substituted aryl group as defined above.

“Thioheteroaryloxy” refers to the group heteroaryl-S- wherein the heteroaryl group is as defined above, and may include a substituted aryl group as defined above. Represents

“Thioketo” represents the group: ＝ S.

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

Embedded image [For the purposes of naming, atoms and bonds in the formulas are each numbered and lettered as described.] Represents a polycyclic ε-caprolactam ring system of the formula:

The term “5,6-dihydro-4H-quino [8,1-ab] [3] benzazepin-8 (9H) -one” has the formula:

Embedded image [For the purposes of naming, atoms and bonds in the formulas are each numbered and lettered as described.] Represents a polycyclic ε-caprolactam ring system of the formula

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

Embedded image [For the purposes of naming, atoms and bonds in the formulas are each numbered and lettered as described.] Represents a polycyclic ε-caprolactam ring system of the formula

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

Embedded image [For the purposes of naming, atoms and bonds in the formulas are each numbered and lettered as described.] Represents a polycyclic ε-caprolactam ring system of the formula:

For any of the above groups containing one or more substituents, of course,
It will be appreciated that the groups do not contain any substitutions or substitution patterns that are impractical with respect to the spatial arrangement of the atoms and / or are synthetically impossible.

The term “pharmaceutically acceptable salt” refers to a pharmaceutically acceptable salt of a compound of Formula I derived from various organic and inorganic counterions, as is well known in the art, This includes, by way of example only, sodium, potassium, calcium, magnesium, ammonium, tetraalkylammonium, and the like; organic or inorganic, if the molecule has a basic functional group. For example, salts of acids such as hydrochloride, hydrobromide, tartrate, mesylate, acetate, maleate, oxalate and the like can be used as pharmaceutically acceptable salts.

The term “protecting group” refers to the reaction of one or more hydroxyl, thiol, carboxyl groups, or other functional groups of the present compound, that occur when bound to these groups. Hindering, and also any group capable of removing this protecting group by conventional chemical or enzymatic steps and restoring the unprotected functional group. It is not important what the removable protecting group used is; preferred removable hydroxyl protecting groups include conventional substituents such as allyl, benzyl, acetyl, chloroacetyl, thiobenzyl, benzylidine (benz).
ylidine), phenacyl, t-butyl-diphenylsilyl, and can be chemically introduced into the hydroxyl function, and then selectively by chemical or enzymatic methods under mild conditions compatible with the properties of the product Include any other groups that can be removed.

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

Compound Preparation When m and n are 1, conventional reductive amination as described in Scheme 1,
The compound of formula I can then be readily prepared by acylation. Reaction formula 1

Embedded image

As shown in Scheme 1, a protected aldehyde or ketone compound 1 wherein B ¹ is a protecting group and R ^{2 ′} and a are as defined herein. With an amine compound, such as 2 wherein R ⁶ , R ⁷ , R ⁸ , p and q are as defined herein, by conventional reductive amination and deprotection After that, intermediate 3 can be obtained. In Scheme 1, amine compound 2 is merely exemplary, and those skilled in the art will recognize that any other ring system amino derivative described herein may be used in this reaction. Will. Typically, the reaction involves the amine compound 2 in excess of compound 1 , preferably 1.
1-2 equivalents of compound 1 and excess, preferably 1.1-1.5 equivalents of reducing agent,
For example, by contacting with sodium cyanoborohydride. Generally, the reaction is carried out in an essentially inert diluent, such as methanol, at about 0 C to about 50 C, preferably at room temperature, for about 0.5 to 3 hours. The amine protecting group is then removed using conventional techniques and reagents to give intermediate 3 .

The intermediate 3 is then acylated or coupled with a carboxylic acid compound, such as 4 , wherein R ¹ , T, X ′ and X ″ are as defined herein, to give the compound 5 can be obtained. in this reaction typically carried out using conventional coupling reagents and techniques, and at least the intermediate 3 and carboxylic acid compound 4 stoichiometric amounts. for example, N- hydroxysuccinimide, 1 Coupling can be promoted with known coupling reagents such as carbodiimide compounds, with or without known additives such as -hydroxybenzotriazole, etc. This reaction is conventional. Inactive non-protocols such as dimethylformamide, dichloromethane, chloroform, acetonitrile, tetrahydrofuran, etc. Conducted in sex polar diluent. Alternatively, the reaction of the acid halide of compound 4 (
It can be used in 1), and if so, it is typically used in the presence of a suitable base to exclude acids formed during the reaction. Suitable bases include, for example,
Triethylamine, diisopropylethylamine, N-methylmorpholine and the like.

Alternatively, using conventional reagents and techniques, the compound of formula 6 :

Embedded image Wherein R ¹ , R ^{2 ′} , T, X ′, X ″ and a are as defined herein, by reductive amination of the compound with an amine compound 2 5
Can be manufactured.

Equation 7 :

Embedded image Wherein, B ² is a suitable amine protecting group, R ^1, R ^{2 'and} a are as defined herein] Reductive amination of intermediate represented by an amine compound 2 The compound of formula 1 wherein n is 1 and m is 0 can be similarly prepared by deprotection using conventional techniques.

When n is 2 and both Y are of the formula: — (CHR ^{2 ′} ) _a —NH—, intermediate 3 is further converted to, for example, compound 6 or 7 using conventional reagents and techniques. Compounds of formula I can be prepared by reductive alkylation. Alternatively, Intermediate 3 can be reductively alkylated with a protected aldehyde or ketone compound 1 using the same procedure described above, and the resulting intermediate can be deprotected and acylated.

N is 2, one of Y is represented by the formula: — (CHR ^{2 ′} ) _a —NH—, and the other Y is represented by the formula: —CHR ² —C (O) NH— The compounds that are to be prepared are prepared using conventional coupling reagents and techniques as described above, using intermediate 3
Into Equation 8 :

Embedded image Wherein R ¹ , R ² , Z and m are as defined herein, by coupling with a protected carboxylic acid of formula I to give a compound of formula I it can.

Alternatively, as shown in Scheme 2, first an amine compound such as compound 2 is coupled with a protected carboxylic acid compound 9 and then, after deprotection, the resulting intermediate 10 The compound of formula I can be prepared by reductive alkylation of

Reaction formula 2

Embedded image

When n is 2, the aldehyde, ketone or carboxylic acid units may be coupled together and then appropriately reacted with an amine compound using the reductive amination or acylation technique described above. The resulting intermediate is then coupled with an amine compound, such as Compound 2 , to give a compound of Formula I.

Synthesis of Aldehyde, Ketone and Carboxylic Acid Starting Materials The aldehyde, ketone and carboxylic acid compounds used in the above reaction are:
It can be readily prepared by several different synthetic routes, the specific routes of which are: ease of compound preparation, commercial availability of starting materials, m is 0 or 1 or n is A choice can be made as to whether it is 1 or 2.

A. Synthesis of Aldehyde and Ketone Compounds The aldehyde and ketone compounds used in the present invention, for example, 1 , 6 and 7 , can be easily produced by oxidizing the corresponding alcohol compounds using a conventional oxidizing agent. For example, N-protected amino primary alcohol compounds are Swern oxidized (S
Wern oxidation yields the corresponding aldehyde compound. Typically, this reaction is carried out by contacting the alcohol compound with a mixture of oxalyl chloride and dimethyl sulfoxide in the presence of a tertiary amine compound, such as triethylamine. Generally, the reaction is carried out in an inert diluent, such as dichloromethane, at an initial temperature of about -78 ° C and then at room temperature for about 0.25 to 2 hours to give the aldehyde compound. The alcohol compound used in this reaction is commercially available or can be produced using conventional reagents and techniques. For example, an appropriate alcohol compound can be produced by reducing the corresponding amino acid or amino acid ester using a conventional reducing agent such as lithium aluminum hydride.

B. Synthesis of Carboxylic Acid Compound The carboxylic acid compound represented by Formula 8 (where m is 0) can be produced by various conventional methods. For example, as shown in Reaction Scheme 3, haloacetic acid compound 1
1 wherein Z ′ is a halo group, eg, chloro or bromo, and R ² is as defined herein, with a primary amine compound 12 wherein R ¹ is as defined herein. As defined herein) to provide amino acid compound 13 . Alternatively, leaving groups other than halo, such as triflate, may be used. In addition, a suitable ester of compound 11 can be used in this reaction.

Reaction formula 3

Embedded image As shown in Scheme 3, an appropriate haloacetic acid derivative 11 is reacted with a primary amine compound 12 under conditions that provide an amino acid compound 13 . This reaction is for example Y
ates, et al. ¹⁰ , and in a suitable inert diluent, such as water, dimethylsulfoxide (DMSO), converts a stoichiometrically nearly equivalent haloacetic acid compound 11 to a primary amine compound 12. Proceed by mixing with In this reaction, an excess amount of a suitable base such as sodium bicarbonate or sodium hydroxide is used to remove the acid generated by the reaction. The reaction is preferably carried out at a temperature from about 25 ° C. to about 100 ° C. until the reaction is complete (typically 1 to about 24 hours). This reaction is
U.S. Pat. No. 3,598,859, which is incorporated herein by reference in its entirety.
It is further described in the issue. Upon completion of the reaction, the N-substituted amino acid compound 13 is recovered by a conventional method including sedimentation, chromatography, filtration and the like.

The respective reagents used in this reaction (eg, haloacetic acid compound 11 and primary amine compound 12 ) are well known in the art and most are commercially available.

In another embodiment, the R ¹ group can be coupled to an alanine ester compound (or other suitable amino acid ester compound) by conventional N-arylation. For example, a stoichiometrically equivalent or slightly excess amino acid ester compound is dissolved in a suitable diluent, eg, DMSO, and the halo-R ¹ compound:
Z′-R ¹ , wherein Z ′ is a halo group, such as chloro or bromo, and R ¹ is as defined above. The reaction is carried out in the presence of an excess of a base, for example sodium hydroxide, to remove the acid formed by the reaction. The reaction typically proceeds at 15 ° C to about 250 ° C and is completed in about 1 to 24 hours. Upon completion of the reaction, the N-substituted amino acid ester compound is recovered by a conventional method including chromatography, filtration and the like. Next, the ester compound is hydrolyzed by a conventional method to obtain a carboxylic acid compound 8 (where m is 0).

In yet another embodiment, as shown in Scheme 4, a suitable pyruvate compound 14 wherein R is typically an alkyl group and R ² is as defined above ) With a primary amine compound 12 (wherein R ¹ is as defined herein) to form an esterification of formula 8 wherein m is 0 The produced amino acid compound can be produced.

Reaction formula 4

Embedded image The reaction shown in Scheme 4 typically involves near stoichiometric equivalence under inert diluents such as methanol, ethanol, etc., under conditions that provide for the formation of the imine compound (not shown). This is carried out by mixing the pyruvate compound 14 and the amine compound 12 . The formed imine compound is then treated under conventional conditions
Suitable reducing agents include sodium cyanoborohydride, H ₂ / palladium - reduced by such as carbon, to form an N- substituted amino acid ester compound 15. In a particularly preferred embodiment, the reducing agent is H ₂ / palladium - carbon, which was included in the initial reaction medium, reduction of the imine compound in situ in a one-pot technique, N-
It is possible to obtain a substituted amino acid ester compound 15 .

The reaction is preferably conducted at a pressure of 1 to 10 atmospheres at about 20 ° C. to about 80 ° C. until the reaction is complete (typically 1 to about 24 hours). Upon completion of the reaction, the N-substituted amino acid ester compound 15 is prepared by conventional methods including chromatography, filtration and the like.
Collect. Next, the ester compound 15 is hydrolyzed to obtain the corresponding carboxylic acid derivative 8 in which m is 0.

As described in Scheme 5, the acetic acid derivative 4 (where R ¹ , T, X ′ and X
Is a primary amine compound of an esterified amino acid, wherein R is typically an alkyl group, and R ² is as defined herein. ) To produce a carboxylic acid compound of formula 8 wherein m is 1.

Reaction formula 5

Embedded image As described in Scheme 5, for this reaction, the appropriate acetic acid derivative 4 was converted to the primary amine compound 16 of the amino acid ester under conditions providing the N-acetyl derivative 17.
Only the coupling is involved. This reaction is routinely performed as described for peptide synthesis, and uses the synthetic methods employed therein to prepare the N-
Acetyl amino acid ester compound 17 can be produced. For example, the coupling can be promoted with or without the use of well-known additives, such as N-hydroxysuccinimide, 1-hydroxybenzotriazole, and the like, using well-known coupling reagents, such as carbodiimide. This reaction is conventionally carried out in an inert aprotic polar diluent such as dimethylformamide, dichloromethane, chloroform, acetonitrile, tetrahydrofuran and the like. Alternatively, the acid halide of compound 4 can be used, and when used, typically in the presence of a suitable base to remove the acid formed during the reaction. Suitable bases include, for example,
Triethylamine, diisopropylethylamine, N-methylmorpholine and the like.

The coupling reaction between Compound 4 and Compound 16 is preferably performed at about 0 ° C. to about 60 ° C.
Until the reaction is complete (typically 1 to about 24 hours). Upon completion of the reaction, the N-acetylamino acid ester compound 17 may be recovered by conventional methods including sedimentation, chromatography, filtration, etc. Hydrolysis to the corresponding acid without separation.

Each reagent (eg, acetic acid derivative 4 and amino acid ester compound 16 ) is well known in the art and most are commercially available.

A carboxylic acid compound such as compound 4 can be coupled with an amine compound prepared using a carbodiimide peptide coupling reagent in a polymer supported form. Polymer supported EDCs are described, for example, in (Tetrahedron Letters, 3
4 (48), 7685 (1993)) ¹¹ . In addition, a novel carbodiimide coupling reagent, PEPC, and its corresponding polymer supported form has been discovered, which is very useful for the preparation of such compounds.

Suitable polymers for use in making the 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 a side chain with a moiety that is reactive with the terminal amine of the carbodiimide. Such reactive moieties include chloro, bromo, iodo and methanesulfonyl. Preferably, the reactive moiety is a chloromethyl group. In addition, the polymer backbone must be inert to both the carbodiimide and the reaction conditions using the final polymer binding coupling reagent.

[0140] Certain hydroxymethylated resins can be converted to chloromethylated resins useful for making polymer-supported coupling reagents. Examples of these hydroxylated resins include 4-hydroxymethylphenylacetamidomethyl resin (Pam Resin) available from Advanced Chemtech of Louisville, Kentucky, USA.
-There is a benzyloxybenzyl alcohol resin (Wang Resin) (Advanced Che
mtech 1993-1994 catalog, page 115). The hydroxymethyl groups on these resins can be converted to the desired chloromethyl groups by any of a number of methods well known to those skilled in the art.

A preferred resin is a chloromethylated styrene / divinylbenzene resin because of its commercial availability. As the name implies, these resins are already chloromethylated and do not need to be chemically modified before use. These resins are commercially known as Merrifield's resins and are available from Aldrich Chemical
pany of Milwaukee, Wisconsin, USA (Aldrich 1994-1995).
catalog, page 899). The process for preparing PEPC and its polymer support form is outlined in Scheme 6.

Reaction formula 6

Embedded image

This method is described on Jun. 1, 1996, which is hereby incorporated by reference in its entirety.
It is more fully described in U.S. Patent Application No. 60 / 019,790 No. ¹⁴ of 4 filed. 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. Polymeric support forms are prepared by reacting PEPC with a suitable resin under standard conditions to obtain the desired reagent.

The coupling reaction of a carboxylic acid compound using these reagents is performed at about 45 ° C. for about 3 to 120 hours from around room temperature. Typically, the product can be isolated by washing the reaction with CHCl ₃ and concentrating the remaining organics under reduced pressure. As discussed above, isolation of the product from the reaction using the polymer-bound reagent requires only filtration of the reaction mixture followed by concentration of the filtrate under reduced pressure, which is very significant. Easy.

Preparation of Cyclic Compounds (eg Benzoepinones, Dibenzoazepinones, Benzodiazepines and Related Compounds) The cyclic compounds used in the above reactions and their amino-substituted derivatives, such as compound 2, are known in the art, Alternatively, using commercially available starting materials and reagents,
It can be produced by art-recognized techniques.

For example, see RFC Brown et al., Tetrahedron Letters 1971, 8, 667-670 ¹²
And cyclization of the chloromethylamide intermediate using the techniques described in US Pat. d] Azepin-6-one can be produced.

In addition, a representative cyclic compound, namely 5,7-dihydro-6H-dibenzo [
b, d] Azepin-6-one is described in Scheme 7. As will be readily apparent to those skilled in the art, by selecting appropriate starting materials and reagents, the synthetic procedure described in Scheme 1 and the reaction conditions described below can be modified and used in the present invention. Other suitable cyclic amine compounds can be prepared.

Reaction formula 7

Embedded image

As shown in Scheme 7, a 5,7-dihydro-6H-dibenzo [b, d] azepin-6-one derivative 23 (wherein R ⁶ , R ⁷ , p and q are defined above Can be readily prepared in several steps from the 2-bromotoluene derivative 18 and the 2-bromoaniline derivative 20 . In this synthesis method,
The bromotoluene derivative 18 is first converted to the corresponding 2-methylphenylboronate ester 19 . The reaction typically involves compound 18 in an inert diluent such as THF at a temperature of about -80 ° C to about -60 ° C for about 0.25 to about 1 hour, about 1 hour.
. It is carried out by treating with 0 to about 2.1 equivalents of an alkyl lithium reagent, preferably sec-butyllithium or tert-butyllithium. The resulting lithium anion is then in situ treated with an excess, preferably 1.5 equivalents, of a trialkyl borate, such as trimethyl borate. This reaction starts at -80 ° C to about-
Perform at 60 ° C., then warm up to about 0 ° C. to about 30 ° C. for about 0.5 to about 3 hours. The resulting methyl boronate ester is typically not isolated, but preferably
The reaction mixture is treated with an excess, preferably about 2.0 equivalents, of pinacol to convert in situ to pinacol ester. Typically, the reaction is carried out at room temperature for about 12 to about 24 hours.
Performs time 2-methylphenyl boronate ester 19 (wherein, preferably, both R ^a groups -C together _{(CH 3) 2 C (CH} 3) 2 - to form a) obtained.

In another reaction, compound 20 is treated with about 1.0 to about 1.5 equivalents of di-tert-butyl-dicarbonate to convert the amino group of 2-bromoaniline derivative 20 to N-Bo.
Converted to c derivative 21 . Typically, this reaction is carried out at a temperature in the range of 25 ° C. to about 100 ° C. for about 12 to 48 hours to give the N-Boc-2-bromoaniline derivative 21 .

As further shown in Scheme 7, the 2-methylphenylboronate ester compound 19 and the N-Boc-2-bromoaniline derivative 21 can then be coupled to form a biphenyl derivative 22. . This reaction is typically palladium catalyst, preferably tetrakis presence of (triphenylphosphine) palladium (0), compound 21 of about 1.0 to about 1.2 equivalents of compound 19 and about 1.0 to about 1 Performed by contacting with 2 equivalents of potassium carbonate. Generally, the coupling reaction is carried out in a diluent, preferably 20% water / dioxane, under an inert atmosphere, at a temperature ranging from about 50C to about 100C for about 6 to 24 hours.

Next, the 2-methyl group of the biphenyl derivative 22 was carboxylated, and then cyclized to form ε-caprolactam, whereby 5,7-dihydro-6H-dibenzo [b, d] azepin-6-one was formed. Easily converted to 23 . The carboxylation reaction is typically carried out in an inert diluent, such as THF, from about -100C to about -20C.
By contacting compound 22 with about 2.0 to about 2.5 equivalents of a suitable base, such as sec-butyllithium, tert-butyllithium, and the like, for a time in the range of about 0.5 to 6 hours. The resulting dianion is then treated with an excess of anhydrous carbon dioxide to form a carboxylate. The carboxylate is then treated with an excess of hydrogen chloride in a suitable diluent, such as methanol, at a temperature in the range of about 25 ° C to about 100 ° C, to provide 5,7-dihydro-6H-dibenzo [b, d]. Azepine-6-
Get On 23 . Various other cyclic compounds can be prepared by conventional modifications of the above procedure.

A preferred synthetic procedure for aminating a representative compound is shown in Scheme 8. By selecting appropriate starting materials and reagents, it is possible to modify the synthetic procedure shown in Scheme 8 and the following reaction conditions, and to be able to produce other amino compounds suitable for use in the present invention. It will be readily apparent to the trader.

Reaction formula 8

Embedded image

As shown in Scheme 8, optionally using conventional reagents and conditions,
, 7-Dihydro-6H-dibenzo [b, d] azepin-6-one 23 is N-alkylated to give a 7-alkyl-5,7-dihydro-6H-dibenzo [b, d] azepin-6-one derivative 24 May be obtained. The reaction typically involves first, DMF,
About 0.25 in an inert diluent such as THF at a temperature ranging from about -78 ° C to about 50 ° C.
This is accomplished by contacting compound 23 with about 1.0 to 1.5 equivalents of a suitable base, such as sodium hydride, sodium bis (trimethylsilyl) amide, and the like for about 6 hours. The resulting anion is then in excess, preferably from about 1.1 to about 2.
Typically, such as 0 equivalents of alkyl, substituted alkyl, cycloalkyl halide, etc.
Treat in situ with 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, and provides 7-alkyl-5,7-dihydro-6H-dibenzo [b, d] azepine The -6-one derivative 24 is obtained.

Then, in the presence of about 1.0 to about 2.0 equivalents of alkyl nitrite, the 7-alkyl-
Contacting 5,7-dihydro-6H-dibenzo [b, d] azepin-6-one 24 with an excess, preferably about 1.0 to 1.5 equivalents of a suitable base, such as sodium bis (trimethylsilyl) amide To form an oxime. Alkyl nitrites suitable for use in the present invention include, by way of example, butyl nitrite, isoamyl nitrite, and the like. This reaction is typically carried out in an inert diluent such as THF at about -10.
C. for about 0.5 to about 6 hours at a temperature in the range of about 20.degree. C. to about 20.degree. C. to give 7-alkyl-5-oximo-5,7-dihydro-6H-dibenzo [b, d] azepin-6-one derivative 25 . obtain.

The compounds are then prepared using conventional reagents and conditions25Is reduced to 5-amino-7
-Alkyl-5,7-dihydro-6H-dibenzo [b, d] azepin-6-one 26 Get. This reduction reaction is preferably carried out by using an oxime compound25The catalyst, for example
It is carried out by hydrogenation in the presence of Raney nickel. This reaction is typically
Under hydrogen at about 200 psi to about 600 psi, a diluent, preferably ethanol and
About 8 to 48 hours at a temperature of about 70 ° C. to about 120 ° C. in a mixture of ammonia (about 20: 1)
Do it for a while. Alternatively, in another preferred approach, 10% Pd / C and about
Using hydrogen in the range of 30 to about 60 psi, at a temperature in the range of about 20 ° C to about 50 ° C, about 4
Over time, the oxime compound may be reduced. Generally, the resulting 5-amino-7
-Alkyl-5,7-dihydro-6H-dibenzo [b, d] azepin-6-one 26 Using well known techniques such as recrystallization and / or chromatography
Purify.

Alternatively, first, 5,7-dihydro-6H-dibenzo [b, d] azepine-6
-ON235-iodo derivatives of27To form 5-amino-7
-Alkyl-5,7-dihydro-6H-dibenzo [b, d] azepin-6-one 26 Can be manufactured. This reaction is typically performed by A. O. King et al.¹³Described in
Thus, an excess of trialkylamine such as triethylamine, diisopropyl
About 3 ° C. at a temperature in the range of about −20 ° C. to about 0 ° C. in the presence of tylamine, TMEDA, etc.
~ 30 min, compound23In excess, preferably from about 1.2 to about 2.5 equivalents of trime
Treated with tilsilyl iodide, then about 1.1 to about 2.0 equivalents of iodine (I_Two
) Is added. Typically, after the iodide is added, the
The reaction is stirred at a temperature in the range of about 20 ° C for about 2-4 hours, and the 5-iodo-5,7-
Dihydro-6H-dibenzo [b, d] azepin-6-one27Get.

Next, the compound is prepared using an alkali metal azide.27Replacing the iodide of origin,
5-azido-5,7-dihydro-6H-dibenzo [b, d] azepin-6-one 28 Get. Typically, the reaction is carried out at about 0 ° C. in an inert diluent such as DMF.
From about 12 to about 48 hours at a temperature ranging from about27From about 1.1 to about 1.
Performed by contacting with 5 equivalents of sodium azide.

Next, the azide derivative 28 is reduced to the corresponding amino derivative 29 using a conventional technique and reagents. For example, it is preferred to reduce the azide group by contacting compound 28 with an excess, preferably about 3 equivalents, of triphenylphosphine in a diluent, preferably a mixture of THF and water. This reduction reaction typically involves
The reaction is carried out at a temperature in the range of about 0 ° C. to about 50 ° C. for about 12 to 48 hours, and the 5-amino-5,7-
This gives dihydro-6H-dibenzo [b, d] azepin-6-one 29 .

The amino group of compound 29 is then protected using a conventional amino protecting group. Preferably, compound 29 is treated with 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, such as triethylamine. . The reaction is typically carried out with an inert diluent, such as T
Perform in HF at a temperature in the range of about 0 ° C. to about 50 ° C. for 3 to about 24 hours, and give 5- (NB
oc-amino) -5,7-dihydro-6H-dibenzo [b, d] azepine-6-
To provide an on-30.

Next, compound 30 is optionally N-alkylated and, after deprotection of the amino group,
This gives 5-amino-7-alkyl-5,7-dihydro-6H-dibenzo [b, d] azepin-6-one 26 . The N-alkylation reaction is typically from about 1.0 to
This is accomplished by treating compound 30 with about 1.0 to 1.5 equivalents of an alkyl halide, substituted alkyl halide or cycloalkyl halide in the presence of about 1.5 equivalents of a suitable base, such as cesium carbonate. The reaction is generally performed in an inert diluent such as DMF at a temperature ranging from about 25C to about 100C for about 12 to about 48 hours.

Representative alkyl, substituted alkyl and cycloalkyl halides suitable for use in this N-alkylation reaction include, by way of example, 1-iodo-2-methylpropane, methylbromoacetate, 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 techniques and reagents to give 5-amino-7-alkyl-5,7-dihydro-6H-dibenzo [b, d] azepine-6.
-Get ON 26 . This deprotection reaction is typically carried out with an inert diluent, e.g.
N-Bo in 4-dioxane at a temperature ranging from about 0C to about 50C for about 2 to about 8 hours.
c) by treating compound 30 with anhydrous hydrogen chloride. In general, the resulting 5-amino-7-alkyl-5,7-dihydro-6H-dibenzo [b, d] azepine- is obtained using well-known techniques, such as recrystallization and / or chromatography.
The 6-one 26 is purified.

In addition, 5-amino-7-alkyl-5,7-dihydro-6H-dibenzo [b, d] azepin-6-one 26 can be produced via an azide transfer reaction represented by Reaction Scheme 9. .

Reaction formula 9

Embedded image As shown in Scheme 9, 5,7-dihydro-6H-dibenzo [b, d] azepin-6-one 23 was first converted to N-
Alkylation gives 7-alkyl-5,7-dihydro-6H-dibenzo [b, d] azepin-6-one derivative 24 .

Next, 7-alkyl-5,7-dihydro-6H-dibenzo [b, d] azepin-6-one 24 is reacted with an azide transfer reagent to give 5-azido-7-alkyl-5.
, 7-Dihydro-6H-dibenzo [b, d] azepin-6-one 31 are obtained. Typically, the reaction is first carried out in an inert diluent, such as THF, from about -90 ° C to about -90 ° C.
By contacting compound 24 with an excess, preferably about 1.0 to 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 60 ° C. Do. The resulting anion is then treated with an excess, preferably from about 1.1 to about 1.2 equivalents of an azide transfer reagent, such as 2,4,6-triisopropylbenzenesulfonyl azide (trisyl azide). . The reaction is typically carried out at a temperature in the range of about -90 ° C to about -60 ° C for about 0.
Perform for 25 to about 2.0 hours. Typically, the reaction mixture is then typically treated with excess glacial acetic acid and the mixture is allowed to warm to room temperature before heating at about 35 ° C. to about 50 ° C. for about 2-4 hours to give 5-azido A -7-alkyl-5,7-dihydro-6H-dibenzo [b, d] azepin-6-one derivative 31 is obtained. Compound 31 is then reduced as described above using conventional reagents and conditions to give the 5-amino-7-alkyl-
5,7-Dihydro-6H-dibenzo [b, d] azepin-6-one 26 is obtained.

If desired, the aryl ring of 5-amino-7-alkyl-5,7-dihydro-6H-dibenzo [b, d] azepin-6-one 26 and similar or related compounds can be replaced with a hydrogenation catalyst. It may be partially or completely saturated by treatment with hydrogen in the presence. Typically, the reaction is carried out in the presence of a catalyst such as rhodium-carbon, compound 26
By treating with hydrogen at a pressure of about 10 to about 100 psi. The reaction is typically carried out in a suitable diluent such as ethyl acetate / acetic acid (1: 1) for about 2 hours.
It is carried out at a temperature in the range of 0 ° C. to about 100 ° C. for about 12 to 96 hours.

Other methods of making intermediates useful in the present invention are described in US patent application Ser. No. 09 / 102,726 filed Jun. 22, 1998 and US patent application Ser. (Attorney Docket No. 002010-345) (both of which are referred to as “polycyclic α-amino-ε-caprolactam and related compounds (Polycycl
ic α-Amino-ε-caprolactams and Related Compounds), the entire disclosure of which is incorporated herein by reference).

The synthesis of a further variety of benzapinones and related compounds is described in Bu
sacca et al., Tetrahedron Lett., 33, 165-168 (1992); Crosisier et al., U
.S. Patent No. 4,080,449; JA Robl et al., Tetrahedron Lett., 36 (10),
1593-1596 (1995); Flynn et al. J. Med.Chem. 36, 2420-2423 (1993); Orito
et al. Tetrahedron, 36, 1017-1021 (1980); Kawase et al., J. Org. Chem.,
54, 3394-3403 (1989); Lowe et al., J. Med.Chem. 37, 3789-3811 (1994);
Robl et al., Bioorg.Med.Chem.Lett., 4, 1789-1794 (1994); Skiles et al.
., Bioorg. Med. Chem. Lett., 3, 773-778 (1993); Grunewald et al., J. Med.
Chem., 39 (18), 3539- (1996); Warshawsky et al., Bioorg. Med. Chem. Let.
t., 6, 957-962 (1996); Ben-Ishai, et al., Tetrahedron, 43, 439-450 (1987)
); van Neil et al., Bioorg. Med. Chem. 5, 1421-1426 (1995); and the references cited therein. These publications and patents are incorporated herein by reference in their entirety.

Similarly, various benzodiazepine derivatives suitable for use in the present invention can be prepared using conventional techniques and reagents. For example, an acid chloride of a glycine derivative is first formed using oxayl chloride, and then the acid chloride is coupled with 2-aminobenzophenone in the presence of a base, eg, 4-methylmorpholine, to give 2-aminobenzophenone. Easy coupling of aminobenzophenone with α- (isopropylthio) -N- (benzyloxycarbonyl) glycine to give 2- [α- (isopropylthio) -N- (benzyloxycarbonyl) glycinyl] -aminobenzophenone Can be. This compound is then treated with ammonia gas in the presence of an excess, preferably about 1.1 to about 1.5 equivalents of mercury (II) chloride, to give 2- [N- (α-amino) -N′-. (Benzyloxycarbonyl) -glycinyl] aminobenzophenone is obtained. 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. 1 can be obtained. The Cbz group was then removed and 3-amino-2,3-dihydro-5-phenyl-1H-1,4-benzodiazepine-2
-Get on.

Alternatively, 2,3-dihydro-5-phenyl-1H-1, 2,3-dihydro-5-phenyl-1H-1, The third position of 4-benzodiazepin-2-one is readily aminated. Conditions for these and related reactions are set forth in the Examples below.
Further, using conventional techniques and reagents, 2,3-dihydro-5-phenyl-1
The first position of H-1,4-benzodiazepin-2-one is easily alkylated. For example, the reaction typically involves first converting benzodiazepinone in an inert diluent, such as DMF, from about 1.1 to about 1.5 equivalents of a base, such as sodium, potassium hydride.
It is carried out by treating with tert-butoxide, potassium 1,1,1,3,3,3-hexamethyldisilazane and cesium carbonate. The reaction is typically about -78
C. at a temperature in the range of from about .degree. C. to about 80.degree. C. for about 0.5 to about 6 hours. The resulting anion is then contacted with an excess, preferably from 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 from about 0C to about 100C for about 1 to about 48 hours.

Further, the 3-amino-2,4-dioxo-2,3, used in the present invention.
4,5-Tetrahydro-1H-1,5-benzodiazepine is typically prepared by first coupling malonic acid with 1,2-phenylenediamine. Conditions for this reaction are well known in the art and are described, for example, in PCT application WO 96-
It is described in US8400 960603. It is then alkylated and aminated using conventional techniques and reagents to give various 3-amino-1,5-bis (alkyl) -2,4-dioxo-2,3,4,5-tetrahydro-1H-1 , 5-benzodiazepine. This approach is illustrated in more detail in the examples described below.

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

Thus, unless stated otherwise, the products of the invention are mixtures of R, S enantiomers. However, if a chiral product is desired, the chiral product may be
-Corresponds to an amino acid derivative. Alternatively, chiral products can be obtained by purification techniques that separate the enantiomers from the R, S mixture to give one or the other stereoisomer. This technique is well known in the art.

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

The present invention also includes pharmaceutical compositions comprising one or more compounds of the above Formula I as active ingredients, together with a pharmaceutically acceptable carrier. In making the compositions of the present invention, the active ingredient will generally be mixed with an excipient, diluted with an excipient, or included in a carrier which may be in the form of a capsule, sashimi, paper or other container. . When the excipient serves as a diluent, it can be a solid, semi-solid or liquid material that acts as a vehicle, carrier or medium for the active ingredient. Thus, the compositions may be tablets, pills, powders, troches, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols (as solid or liquid media), for example Ointments, soft and hard capsules, suppositories, sterile injectable solutions and sterile packaged powders containing up to 10% by weight of active compound can be prepared.

In the manufacture of formulations, it may be necessary to mill the active compound, to a suitable particle size, and then mix it with other ingredients. If the active compound is substantially insoluble, it is usually ground to a particle size of less than 200 mesh. If the active compound is substantially water soluble, its particle size will usually be adjusted by milling to provide a substantially uniform distribution in the formulation, for example 40 mesh.

Some examples of suitable excipients include lactose, dextrose, sucrose, sorbitol, mannitol, starch, gum acacia, calcium phosphate,
Includes alginates, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, sterile water, syrup and methylcellulose. The formulation may further include lubricants such as talc, magnesium stearate and mineral oil; wetting agents; emulsifying and suspending agents; preservatives such as methylbenzoate and propylhydroxybenzoate; sweeteners; it can. The compositions of the present invention can be formulated so as to provide quick, sustained or delayed release of the active ingredient after administration to the patient using techniques known in the art.

The compositions may be administered in a dosage from about 5 to about 100 mg, more usually from about 10 to about 30 mg.
It is preferred to formulate in unit dosage form containing g active ingredient. The term "unit dosage form" is a physically discrete unit suitable as a single dosage for human patients and other mammals, with each unit calculated to produce the desired therapeutic effect. , Containing a predetermined amount of active substance together with suitable pharmaceutical excipients. Preferably, about 20% by weight of the pharmaceutical composition, more preferably about 15%
Up to% by weight of the compounds of the above formula I are used in balance with the inert pharmaceutical carrier (s).

The active compounds are effective over a wide dosage range and generally administer a pharmaceutically effective amount. However, the actual amount of compound administered will depend on the condition to be treated, the route of administration chosen, the compound actually administered, the age, weight and response of the individual patient, the severity of the patient's symptoms, and It will be appreciated that it is determined in the light of the relevant circumstances, including the degree.

For the manufacture of solid compositions, for example tablets, the principal active ingredient is mixed with a pharmaceutical excipient and a solid preform containing a homogeneous mixture of the compound of the invention.
ormulation composition). When these preformulation compositions are homogeneous, the active ingredient is dispersed homogeneously throughout the composition and the composition is readily converted into uniformly effective unit dosage forms, such as tablets, pills, and capsules. Means that it can be subdivided. This solid preformulation is then subdivided into unit dosage forms of the type described above containing, for example, 0.1 to about 500 mg of the active ingredient of the present invention.

The tablets or pills of the present invention can be coated or mixed into dosage forms that provide the advantage of prolonged action. For example, a tablet or pill can be comprised of an internally administered ingredient and an externally administered ingredient in the form of an envelope surrounding it. The two components may be separated by an enteric layer that resists degradation in the stomach and allows the internal components to enter the duodenum intact or delay their release. A variety of materials can be used for such enteric layers or coatings, including a number of polymeric acids and materials such as shellac, cetyl alcohol and cellulose acetate. A mixture of acids is included.

Liquid dosage forms which can contain the novel compositions of the present invention for oral administration or for administration by injection include aqueous solutions, syrups with suitable aromas, aqueous or oily suspensions,
And flavored emulsions including edible oils such as cottonseed oil, sesame oil, coconut oil or peanut oil and 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 can be nebulized using an inert gas. The nebulized solution can be sucked in directly from the spray device or the spray device can be
face masks tent) or intermittent positive pressure breathing apparatus. Solution, suspension or powder compositions may be administered, preferably orally or nasally, from devices which deliver the formulation in an appropriate manner.

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

Formulation Example 1 A hard gelatin capsule containing the following ingredients is prepared: The above ingredients are mixed and 340 mg is filled into hard gelatin capsules.

Formulation Example 2 Tablets are prepared using the following ingredients: The ingredients are mixed and a tablet weighing 240 mg each is compressed.

Formulation Example 3 A dry powder inhalation formulation containing the following ingredients is prepared: The active ingredient is mixed with lactose and the mixture is added to a dry powder inhaler.

Formulation Example 4 Each tablet containing 30 mg of the active ingredient is prepared as follows: The active ingredients, starch and cellulose were no. Pass through a 20 mesh US sieve and mix well. The solution of polyvinylpyrrolidone is mixed with the resulting powder, which is then passed through a 16 mesh US sieve. The granules thus produced are treated at 50 ° C to 6 ° C.
Dry at 0 ° C. and pass through a 16 mesh US sieve. Then, in advance, No. Add sodium carboxymethyl starch, magnesium stearate and talc which had been passed through a 30 mesh US sieve to the granules, mix and compress with a tablet machine, each 1
A tablet weighing 50 mg is obtained.

Formulation Example 5 Each capsule containing 40 mg of drug is prepared as follows: Mix the active ingredient, starch and magnesium stearate, Fill 150 mg quantity into hard gelatin capsules through 20 mesh US sieve.

Formulation Example 6 Each suppository containing 25 mg of the active ingredient is prepared as follows: The active ingredient was no. Pass through a 60 mesh US sieve and suspend in pre-melted saturated fatty acid glyceride with minimal heating required. The mixture is then poured into a suppository mold of nominal 2.0 g capacity and cooled.

Formulation Example 7 Each suppository containing 50 mg of drug per 5.0 mL dose is prepared as follows: Mix the active ingredient, sucrose and xanthan gum. Pass through a 10 mesh US sieve and then mix with the previously prepared aqueous solution of microcrystalline cellulose and sodium carboxymethylcellulose. The sodium benzoate, flavor and color are diluted with water and added with stirring. Then enough water is added to produce the required amount.

Formulation Example 8 Mix the active ingredient, starch and magnesium stearate, Pass through a 20 mesh US sieve and fill 560 mg amount into hard gelatin capsules.

Formulation Example 9 A subcutaneous formulation can be prepared as follows: (Depending on the solubility of the active ingredient in the corn oil, if desired, about 5.0
mg or more of the active ingredient can be used in the formulation).

Formulation Example 10 A topical formulation can be manufactured as follows: Heat and melt the white soft paraffin. Add liquid paraffin and emulsified wax and stir to dissolve. The active ingredient is added and the stirring is continued to diffuse. The mixture is then cooled and solidified.

Another preferred formulation for use in the methods of the invention uses a transdermal delivery device ("patch"). Such transdermal patches can be used to provide continuous or intermittent infusions of a controlled amount of a compound of the present invention. The construction and use of transdermal patches for the delivery of pharmaceutical substances is well known in the art. For example, US Pat. No. 5,023, issued June 11, 1991, which is incorporated herein by reference.
See No. 252. Such patches provide continuous, pulsatile (pu)
lsatile) or can be built for on-demand delivery.

It will often be desirable or necessary to introduce the pharmaceutical composition directly or indirectly into the brain. Direct techniques usually involve placing a drug delivery catheter in the host's ventricular system, bypassing the blood-brain barrier. One implantable delivery system used to transport biological agents to specific anatomical regions of the body is described in US Pat.
011,472.

Generally preferred indirect techniques generally involve formulating the composition to provide a drug latency by conversion of the hydrophilic drug to a lipophilic drug. Latency is generally achieved by protecting the hydroxy, carbonyl, sulfate, and primary amine groups present on a drug, making the drug more lipophilic, and allowing transport across the blood-brain barrier. To
Alternatively, the delivery of hydrophilic drugs may be enhanced by intra-arterial infusion of a hypertonic solution that can temporarily open the blood-brain barrier.

Another suitable formulation for use in the present invention is Remington's Pharmaceutic.
al Sciences, Mace Publishing Company, Philadelphia, PA, 17th ed. (1985)
Can be found in

Utility The compounds and pharmaceutical compositions of the present invention provide for the release and / or release of β-amyloid peptide.
Or to inhibit its synthesis, and thus has utility in diagnosing and treating Alzheimer's disease in mammals, including humans.

As noted above, the compounds described herein are suitable for use in the various drug delivery systems described above. In addition, to increase the in vivo serum half-life of the administered compound, the compound can be encapsulated, introduced into the liposome lumen, prepared as a colloid, or using other conventional techniques to increase the serum half-life of the compound. Good. For example, Szoka, et a, each of which is incorporated herein by reference.
l., U.S. Pat. Nos. 4,235,871, 4,501,728 and 4,8.
As described in 37,028, various methods can be used for preparing liposomes.

The amount of the compound administered to the patient will vary depending on the substance being administered, the purpose of the administration, such as prophylaxis or therapy, the condition of the patient, the manner of administration, and the like. For therapeutic applications, a patient already suffering from AD is administered an amount of the composition sufficient to at least partially inhibit the further onset of the disease and its complications. An amount sufficient to accomplish this is defined as "therapeutically effective amount." The effective dosage for this use is
It will depend on the judgment of the attending physician depending on factors such as the degree or severity of the patient's AD, the patient's age, weight and overall condition. For use as therapeutics, it is preferable to administer an amount of a compound described herein in the range of about 1 to about 500 mg / kg / day.

In prophylactic applications, patients at risk of developing AD (eg, as determined by genetic screening or a familial trait) will inhibit the onset of symptoms of the disease. The composition is administered in an amount sufficient to An amount sufficient to accomplish this is defined as a "prophylactically effective amount." Effective dosages for this use will depend on the judgment of the attending physician, depending on factors such as the patient's age, weight and overall condition. For use as a prophylactic, about 1 to about 500 m
It is preferred to administer an amount of a compound described herein in the range of g / kg / day.

As described above, the compound administered to the patient is in the form of a pharmaceutical composition as described above. These compositions may be sterilized by conventional sterilization techniques, or may be sterile filtered.
Package or freeze-dry the obtained aqueous solution as it is,
The lyophilized preparation may be administered after mixing with a sterile aqueous carrier. The pH of the compound preparation is typically between 3 and 11, more preferably between 5 and 9, most preferably between 7 and 8. It will be appreciated that certain of the aforementioned excipients, carriers or stabilizers may be used to form a pharmaceutical salt.

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

The invention will now be illustrated by the following synthetic and biological examples, which should not be construed as limiting the scope of the invention in any way.

EXAMPLES In the following examples, the abbreviations below have the following meanings. If an abbreviation is not defined, it shall have its generally accepted meaning.

BEMP = 2-tert-butylimino-2-diethylamino-1,3-dimethylperhydro-1,3,2
-Diazaphosphorin (2-tert-butylimino-2-diethylamino-1,3-dimethylperhydro-1,3,2-diazaphosp
horine) Boc = t-butoxycarbonyl BOP = benzotriazol-1-yloxy-tris (dimethylamino) phosphonium hexafluorophosphate bd = broad doublet bs = broad singlet d = two Doublet dd = doublet of doublets DIC = diisopropylcarbodiimide DMF = dimethylformamide DMAP = dimethylaminopyridine DMSO = dimethylsulfoxide EDC = ethyl-1- (3-dimethylaminopropyl) carbodiimide eq. = equivalents EtOAc = ethyl acetate g = grams HOBT = 1-hydroxybenzotriazole hydrate Hunig's base = diisopropylethylamine L = liter m = multiplet M = molarity max = maximum meq = milliequivalent (Milliequivalent) mg = milligram mL = milliliter mm = millimeter mmol = millimol MO = Methoxyoxycarbonyl N = specified N / A = not available ng = nanogram nm = nanometer OD = optical density PEPC = 1- (3- (1-pyrrolidinyl) propyl) -3-ethylcarbodiimide PP-HOBT = Piperidine-piperidine-1-hydroxybenzotrizole psi = pounds per square inch φ = phenyl q = quartet quint. = Quintet rpm = rotations / minute s = singlet t = Triplet TFA = trifluoroacetic acid THF = tetrahydrofuran tlc = thin-layer chromatography μL = microliter UV = UV

In the following examples, all temperatures are in degrees Celsius (unless otherwise noted). The compounds described in the following examples are prepared using the following general procedure.

[0211] In the following examples and procedures, the term "Aldrich" refers to a compound or reagent used in this procedure if the compound or reagent used is Aldrich Chemical Company, Inc., 1001 West Saint Pau.
l indicates that it is commercially available from Avenue, Milwaukee, WI 53233 USA; the term "Fl
uka "means that the compound or reagent is not available from Fluka Chemical Corp., 980 South 2nd Street,
Indicates commercially available from Ronkonkoma NY 11779 USA; term "Lancaster"
Means that the compound or reagent is Lancaster Synthesis, Inc., PO Box 100 Windham,
The term "Sigma" indicates that the compound or reagent is commercially available from Sigma, PO Box 14508, St. Louis MO 63178 USA; the term "Chemservice" indicates that the compound or reagent is commercially available from NH 03087 USA. Or the reagent is from Chemservice Inc.,
Indicates that the compound or reagent is commercially available from Westchester, PA; the term "Bachem" refers to compounds or reagents that are available from Bachem Biosciences Inc., 3700 Horizon Drive, Renaissance at G
indicates that it is commercially available from ulph Mills, King of Prussia, PA 19406 USA;
The term "Maybridge" is used when a compound or reagent is identified as Maybridge Chemical Co. Trevillet.
t, Tintagel, Cornwall PL34 OHW indicates that it is commercially available from United Kingdom; and the term "TCI" refers to compounds or reagents that are available from TCI America, 9211 North
rborgate Street, Portland OR 97203, indicating that the term "A
lfa "indicates that the compound or reagent is a Johnson Matthey Catalog Company, Inc. 30 Bon
d Street, Ward Hill, MA 01835-0747, indicating that the term "N
ovabiochem "means that the compound or reagent is a Calbiochem-Novabiochem Corp. 10933 No
rth Torrey Pines Road, PO Box 12087, La Jolla CA 92039-2087; indicates that the term "Oakwood" refers to a compound or reagent that is commercially available from Oakwood Produc.
ts, Inc., 1741 Old Dunbar Rd., West Columbia, SC 29169; indicates that the term "Advanced Chemtech" means that the compound or reagent is
Emtech, Louisville, KY; commercially available; term "Pfaltz & Baue
r "indicates that the compound or reagent is commercially available from Pfaltz & Bauer, Waterbury, CT, USA; and the term" Fluorochem "indicates that the compound or reagent is
orochem Ltd. Wesley St. Old Glossop, Derbyshire SK13 9RY, United Kingdom
(For sales offices in the United States, see Oakwood Products, Inc., supra).

I. Coupling Procedure The following coupling procedure can be used to prepare the compounds of the present invention: General Procedure A First EDC Coupling Procedure The corresponding carboxylic acid compound and the corresponding carboxylic acid compound in CH ₂ Cl ₂ at 0 ° C. To a 1: 1 mixture of amino acid ester compounds or amide compounds was added 1.5 equivalents of triethylamine, then 2.0 equivalents of hydroxybenzotriazole monohydrate and then 1.25 equivalents of ethyl-3- (3-dimethyl Amino) propyl carbodiimide
HCl was added. The reaction mixture was stirred overnight at room temperature and then transferred to a separating funnel. The mixture was washed with water, saturated aqueous NaHCO ₃ , 1N HCl and saturated aqueous NaCl, and then dried over MgSO ₄ . The resulting solution was stripped on a rotary evaporator to remove the solvent and obtain a crude product.

General Procedure B Second EDC Coupling Procedure The corresponding acid compound (1 equivalent), N-1-hydroxybenzotriazole (1.
6 equivalents), corresponding amine compound (1 equivalent), N-methylmorpholine (3 equivalents)
And a mixture of dichloromethane (or DMF for insoluble substrates) was cooled in an ice-water bath and stirred to give a clear solution. The reaction mixture was then added to EDC (1
. 3 eq.). The cooling bath was then allowed to warm to room temperature over 1-2 hours and the reaction mixture was stirred overnight. The reaction mixture was then evaporated to dryness under reduced pressure. A 20% aqueous potassium carbonate solution was added to the residue and the mixture was shaken thoroughly and allowed to stand until the oily product solidified (overnight if necessary). The solid product was then collected by filtration and washed well with 20% aqueous potassium carbonate, water, 10% HCl and water to give the product, usually pure. No racemization was observed.

General Procedure C Third EDC Coupling Procedure The carboxylic acid compound was dissolved in methylene chloride. The corresponding amino acid ester compound or amide compound (1 equivalent), N-methylmorpholine (5 equivalents) and hydroxybenzotriazole monohydrate (1.2 equivalents) were added in that order. A cooling bath was applied to the round bottom flask and the solution was brought to 0 ° C. At this point, 1.2 equivalents of 1- (3
-Dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride was added. The solution was stirred overnight and brought to room temperature under nitrogen pressure. A saturated aqueous solution of sodium carbonate, 0.
After washing the organic layer with 1 M citric acid and brine, the reaction mixture was worked up by drying over sodium sulfate. Then the solvent was removed to get the crude product.

General Procedure D Fourth EDC Coupling Procedure In a round bottom flask, under nitrogen atmosphere, the corresponding carboxylic acid compound (1
. 0 eq), hydroxybenzotriazole hydrate (1.1 eq) and the corresponding amine compound (1.0 eq). Add the appropriate amount (1.1 equivalents for free amine compound, hydrochloride amine salt) to the well stirred mixture.
For salts), 2.2 equivalents) of a base, for example Hunig's base, is added and then E
DC (1.1 eq) was added. After stirring at room temperature for 4-17 hours, the solvent was removed under reduced pressure, the residue was taken up in ethyl acetate (or similar solvent) and water, washed with saturated aqueous sodium bicarbonate, 1N HCl, brine and anhydrous sulfuric acid. Drying over sodium and removing the solvent under reduced pressure gave the product.

General Procedure E BOP Coupling Procedure To a stirred solution of N- (3,5-difluorophenylacetyl) alanine (2 mmol) in DMF cooled in an ice-water bath was added BOP (2.4 mmol) and N- Methyl morpholine (6 mmol) was added. After stirring the reaction mixture for 50 minutes, a solution of α-amino-γ-lactam (2 mmol) in DMF cooled at 0 ° C. was added. After allowing the cooling bath to warm to room temperature over 1-2 hours, the reaction mixture was stirred overnight. 20
% Potassium carbonate aqueous solution (60 mL) was added and the mixture was shaken well. No solids were formed. The mixture was then washed with ethyl acetate (150 mL),
Evaporate to dryness under reduced pressure 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 washed well with water and then 1 mL of diethyl ether to give the product (51 mg, 0.16 mmol
, 7.8%).

General Procedure F Coupling of acid chloride compound and amino acid ester compound (D, L) -alanine isobutyl ester hydrochloride (4.6 mm) in 5 mL of pyridine
ol) was added 4.6 mmol of the acid chloride compound. A precipitate formed immediately. The mixture was stirred for 3.5 hours, dissolved in 100 mL of diethyl ether,
Washed three times with 0% 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. Other amino acid ester compounds may be used in this procedure.

General Procedure G Coupling of Carboxylic Acid Compound and Amino Acid Ester Compound A solution of the carboxylic acid compound (3.3 mmol) and 1,1′-carbodiimidazole (CDI) in 20 mL of THF was stirred for 2 hours. (D, L) -alanine isobutyl ester hydrochloride (3.6 mmol) followed by 1.5 mL of triethylamine (10.
8 mmol) was added. The reaction mixture was stirred overnight. The reaction mixture was dissolved in 100 mL of diethyl ether 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. Other amino acid ester compounds may be used in this procedure.

General Procedure H Fifth EDC Coupling Procedure In a round bottom flask, carboxylic acid compound (1.1 eq), amine hydrochloride (1.0 eq), 1-hydroxybenzotriazole in THF Hydrate (1.1 eq), N, N-diisopropylethylamine (2.1 eq) were added, followed by 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (EDC) (1.1 eq) ) Was added. The reaction mixture was stirred at room temperature under a nitrogen atmosphere for 10-20 hours. Dilute the mixture with EtOAc and add 0.1M HC
1 (1 × 10 mL), saturated NaHCO ₃ (1 × 10 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 reduced pressure. The residue was purified by flash column chromatography on silica gel, then triturated from EtOAc and hexane.

General Procedure I Sixth EDC Coupling Procedure A solution or suspension of an amine compound or amine hydrochloride (1.0 eq) in THF (0.05-0.1 M) at 0 ° C. under N ₂ A carboxylic acid compound (1.0 to 1.
1 equivalent), hydroxybenzotriazole monohydrate (1.1-1.15 equivalents),
Hunig's base (1.1 equivalents for free amine compound, 1.1-2.3 equivalents for amine hydrochloride) was added, followed by 1- (3-dimethylaminopropyl)-.
3-Ethylcarbodiimide hydrochloride (1.1-1.15 eq) was added. The cooling bath was removed and the mixture was warmed to room temperature for 10-24 hours. The solution or mixture is diluted with 3-5 times the volume of initial EtOAc in EtOAc and 0.1-1.0 M
Washed with aqueous HCl (1 or 2 ×), diluted NaHCO ₃ (1 or 2 ×) and brine (1 ×). The organic layer was then dried over MgSO ₄ or Na ₂ SO ₄ , filtered and concentrated to give the crude product, which was used with or without further purification.

General Procedure J EEDQ Coupling Procedure A solution of an amine compound in THF at room temperature under N ₂ (1.0 eq, 0.05-0.
08M, final molarity), add an Nt-Boc protected amino acid (1.1 equivalents, as a solid or via cannula in THF), then add EEDQ (
Aldrich, 1.1 eq.). The pale yellow solution was stirred at room temperature for 16-16.5 hours, then diluted with EtOAc (3-5 times the original THF volume) and diluted with 1M
HCl aqueous solution (2 ×), diluted NaHCO ₃ aqueous solution (2 ×) and brine (1 ×
). The organic layer was dried over Na ₂ SO ₄ or MgSO _4, filtered, and concentrated.

II. Carboxylic acid compound A carboxylic acid intermediate useful in the present invention can be produced by the following method. General Procedure II-A Hydrolysis of Ester Compound to Free Acid Compound The hydrolysis of the ester compound to the free acid compound was performed by a conventional method. The following are two examples of such conventional deesterification methods. Method A: Add _{2 to} the carboxylic ester compound in a 1: 1 mixture of CH ₃ OH / H ₂ O
5 was added of K ₂ CO ₃ equivalents. 0.5-until tlc indicates the reaction is complete
The mixture was heated to 50 ° C. for 1.5 hours. The reaction was cooled to room temperature and the methanol was removed on a rotary evaporator. The pH of the remaining aqueous solution was adjusted to ２2, ethyl acetate was added and the product was extracted. The organic phase was then washed with a saturated aqueous solution of NaCl and dried over MgSO ₄ . The solution was stripped off on a rotary evaporator to remove the solvent and the product was obtained.

Method B: The amino acid ester compound was dissolved in dioxane / water (4: 1), LiOH dissolved in water (当 2 equivalents) was added thereto, and after the addition, the entire solvent was dioxane: water about 2: 1. I tried to be. 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 layers were separated and the aqueous layer was acidified to pH2. This aqueous layer was extracted with ethyl acetate. The ethyl acetate extract was dried over Na ₂ SO ₄ , filtered off the solvent and removed under reduced pressure. The residue was purified by conventional methods (eg recrystallization).

General Procedure II-B Preparation of Acid Chloride Compound 3,5-Difluorophenylacetic acid (30 g, 0.174 mol) (Aldrich) was dissolved in dichloromethane and the solution was cooled to 0 ° C. DMF (0.5 mL, catalyst)
After the addition of oxalyl chloride (18 mL, 0.20 mol) was added dropwise over 5 minutes. After stirring the reaction for 3 hours, it was rotary evaporated under reduced pressure (rotoevap).
otrate) to give an oil which was placed under a high vacuum pump for 1 hour to give 3,5-difluorophenylacetyl chloride as a pale yellow oil. Similarly, other acid chloride compounds can be produced.

General Procedure II-C The procedure of Schotten-Baumann 3,5-Difluorophenylacetyl chloride (obtained from General Procedure II-B) was prepared using L in 2N sodium hydroxide (215 mL, 0.43 mol). -Alanine (Aldrich) (16.7 g, 0.187 mol) was added dropwise to a 0 ° C solution. The reaction was stirred at 0 ° C. for 1 hour and then at room temperature overnight. Add the reaction to water (100 mL
) And extracted with ethyl acetate (3 x 150 mL). Then the organic layer was washed with brine (200 mL), dried over MgSO _4, and the residue was rotary evaporated under reduced pressure. The residue was recrystallized from ethyl acetate / hexane to give the desired product (34.5 g, 82% yield). Other acid chloride compounds may be used in this procedure to produce intermediates useful in the present invention.

General Procedure II-D Reductive Amination A solution of the arylamine compound in ethanol in a hydrogenation flask was charged with 1 equivalent of 2-
Oxocarboxylic acid ester compounds (eg pyruvate), then 10%
Palladium-carbon (25% by weight based on the arylamine compound) was added. until completion of the reaction is indicated by tlc (30 minutes to 16 hours), the reaction was hydrogenated at 20psi of H ₂ in a Parr shaker. The reaction mixture was then filtered through celite 545 bed (available from Aldrich Chemical Company, Inc.) and the solvent was stripped off on a rotary evaporator. The crude product residue was then further purified by chromatography.

The following procedure illustrates the synthesis of carboxylic acid intermediates useful in preparing compounds of the present invention.

Example A Synthesis of N- (phenylacetyl) -L-alanine Using general procedure II-C, a solid with a melting point of 102-104 ° C. was obtained from phenylacetyl chloride (Aldrich) and L-alanine (Aldrich). The title compound was prepared as a product. NMR data were as follows: ¹ H-nmr (CDCl ₃ ): δ = 9.14 (br s, 1H), 7.21-7.40 (m,
5H), 6.20 (d, J = 7.0 Hz, 1H), 4.55 (m, 1H), 3.61 (s, 2H)
), 1.37 (d, J = 7.1 Hz, 3H). ¹³ C-nmr (CDCl ₃ ): δ = 176.0, 171.8, 134.0, 129.4,
127.5, 48.3, 43.2, 17.9.

Example B Synthesis of N- (3,5-difluorophenylacetyl) -L-alanine Using General Procedure II-C, 3,5-difluorophenylacetyl chloride (General Procedure II-B) The title compound was prepared from L-alanine (Aldrich). NMR data were as follows: ¹ H-nmr (CD ₃ OD): δ = 8.32 (brs, 0.3H), 6.71 (m, 2H),
6.60 (m, 1H), 4.74 (br s, 1.7H), 4.16 (m, 1H), 3.36 (s,
2H), 1.19 (d, J = 7.3 Hz, 3H). ¹³ C-nmr (CD ₃ OD): δ = 175.9, 172.4, 164.4 (dd, J =
13.0, 245.3 Hz), 141.1, 113.1 (dd, J = 7.8, 17.1 Hz),
102.9 (t, J = 25.7 Hz), 49.5, 42.7, 17.5.

Example C Synthesis of N- (Cyclopentylacetyl) -L-phenylglycine Step A Preparation of N- (cyclopentylacetyl) -L-phenylglycine Methyl Ester According to General Procedure A above, cyclopentylacetic acid (Aldrich) and 83-86 ° C. using phenylglycine methyl ester hydrochloride (Novabiochem)
The title compound was prepared as a solid. The reaction was monitored by tlc on silica gel (Rf = 0.28 in 25% ethyl acetate / hexane).
Purified by recrystallization from hexane. NMR data were as follows: ¹ H-nmr (CDCl ₃ ): δ = 7.35 (s, 5H), 6.44 (bd, 1H), 5.6.
(D, 1H), 3.72 (s, 3H), 2.24 (bs, 3H), 1.9-1.4 (m, 6H), 1
.2-1.05 (m, 2H). ¹³ C-nmr (CDCl ₃ ): δ = 172.3, 171.7, 136.7, 129.0,
128.6, 127.3, 56.2, 52.7, 42.5, 36.9, 32.40, 32.38,
24.8. C ₁₆ H ₂₁ NO ₃ (MW = 275.35); mass spectrum analysis (M + Na) 29
8.

Step B Preparation of N- (cyclopentylacetyl) -L-phenylglycine According to general procedure II-A above, N- (cyclopentylacetyl) -L-phenylglycine methyl ester (obtained in step A) is obtained. Using, melting point 155
The title compound was prepared as a solid at 158 ° C. This reaction is carried out on silica gel
c (Rf = 0.10 in 10% methanol / dichloromethane).
18). NMR data were as follows: ¹ H-nmr (CDCl ₃ ): δ = 8.60 (d, J = 7.8 Hz, 1H), 7.45 (
m, 5H0, 5.41 (d, J = 7.2 Hz, 1H), 2.20 (m, 3H), 1.8-1.1
(M, 8H). ¹³ C-nmr (CDCl ₃ ): δ = 172.3, 172.0, 137.5, 128.7,
128.1, 127.8, 56.2, 40.9, 36.8, 31.8, 24.5. C ₁₅ H ₁₉ NO ₃ (MW = 261.32); mass spectrum analysis (M + Na) 28
4.

Example D Synthesis of N- (Cyclopentylacetyl) -L-alanine Step A Preparation of N- (cyclopentylacetyl) -L-alanine Methyl Ester According to General Procedure A above, cyclopentyl acetic acid (Aldrich) and L- The title compound was prepared using alanine methyl ester hydrochloride (Sigma) as a solid, mp 43-46 ° C. Purified by recrystallization from ethyl acetate / hexane. NMR data were as follows: ¹ H-nmr (CDCl ₃ ): δ = 6.38 (d, 1H), 4.50 (m, 1H), 3.6.
5 (s, 3H), 2.13 (bs, 3H), 1.80-1.00 (m (d at 1.30, including 3H
), 11H). ¹³ C-nmr (CDCl ₃ ): δ = 173.7, 172.5, 52.1, 47.6, 42
.3,36.8,32.15,32.14,18.0. C ₁₁ H ₁₉ NO ₃ (MW = 213.28); mass spectrometry (MH ⁺ ) 214.

Step B Preparation of N- (Cyclopentylacetyl) -L-alanine According to general procedure II-A, using N- (cyclopentylacetyl) -L-alanine methyl ester (obtained in step A), The title compound was prepared. The reaction was monitored by tlc on silica gel (Rf = 0.18 in 10% methanol / dichloromethane). NMR data were as follows: ¹ H-nmr (DMSO-d ₆ ): δ = 12.45 (bs, 1H), 8.12 (d, J =
7.2Hz, 1H), 4.24 (quintet, J = 7.2Hz, 1H), 2.14 (m, 3H), 1
0.8-1.4 (m, 6H), 1.29 (d, J = 7.2 Hz, 3H), 1.2-1.0 (m, 3
H). ¹³ C-nmr (DMSO-d ₆ ): δ = 174.6, 171.9, 47.3, 41.1,
36.7, 31.8, 24.5, 17.2. _{C 10 H 17 NO 3 (MW} = 199.25); mass spectroscopy (MH ⁺⁾ N / A.

Example E Synthesis of N- (cyclopropylacetyl) -L-alanine Step A Preparation of N- (cyclopropylacetyl) -L-alanine methyl ester According to General Procedure A above, cyclopropylacetic acid (Aldrich) The title compound was prepared as an oil using and L-alanine methyl ester hydrochloride (Sigma). The reaction was monitored by tlc on silica gel (Rf = 0.15 in 25% ethyl acetate / hexane) and flash column chromatography (
25% ethyl acetate / hexane as eluent). NMR data were as follows: ¹ H-nmr (CDCl ₃ ): δ = 6.60 (d, 1H), 4.55 (m, 1H), 3.6.
9 (s, 3H), 2.10 (m, 2H), 1.34 (d, 3H), 0.95 (m, 1H), 0.5
8 (m, 2H), 0.15 (m, 2H). ¹³ C-nmr (CDCl ₃ ): δ = 173.7, 172.3, 52.3, 47.7, 41
0.0, 18.2, 6.7, 4.27, 4.22. _{C 9 H 15 NO 3 (MW} = 185.22); mass spectroscopy (MH ⁺⁾ N / A.

Step B—Preparation of N- (Cyclopentylacetyl) -L-alanine According to general procedure II-A above, N- (cyclopropylacetyl) -L-alanine methyl ester (obtained in step A) is The title compound was prepared as an oil. The reaction was monitored by tlc on silica gel (10%
Rf = 0.27 in methanol / dichloromethane). NMR data were as follows: ¹ H-nmr (DMSO-d ₆ ): δ = 8.18 (d, 1H), 4.25 (m, 1H),
2.08 (m, 2H), 1.30 (d, 3H), 1.00 (m, 1H), 0.50 (m, 2H),
0.19 (m, 2H). ¹³ C-nmr (DMSO-d ₆ ): δ = 174.6, 171.7, 47.4, 17.3,
7.6, 4.12, 4.06. _{C 8 H 13 NO 3 (MW} = 199.25); mass spectroscopy (MH ⁺⁾ N / A.

Example F Synthesis of N- (cyclopropylacetyl) -L-phenylglycine Step A—Preparation of N- (cyclopropylacetyl) -L-glycine methyl ester According to General Procedure A above, cyclopropylacetic acid ( (Aldrich) and L-phenylglycine methyl ester to give the title compound as a solid, mp 74-76 ° C. The reaction was monitored by tlc on silica gel (50
% In ethyl acetate / hexane, Rf = 0.61), purified by recrystallization from ethyl acetate / hexane. NMR data were as follows: ¹ H-nmr (CDCl ₃ ): δ = 7.35 (m, 5H), 6.97 (bd, J = 7.2H).
z, 1H), 5.59 (d, J = 7.8 Hz, 1H), 3.71 (s, 3H), 2.17 (m,
2H), 1.05-0.95 (m, 1H), 0.62 (m, 2H), 0.20 (m, 2H). ¹³ C-nmr (CDCl ₃ ): δ = 171.9, 174.6, 136.6, 129.0,
128.5, 127.2, 56.1, 52.7, 41.0, 6.9, 4.37, 4.33. _{C 14 H 17 NO 3 (MW} = 247.30); mass spectroscopy (MH ⁺⁾ N / A.

Step B—Preparation of N- (Cyclopentylacetyl) -L-phenylglycine According to general procedure II-A above, N- (cyclopropylacetyl) -L-phenylglycinemethyl (obtained in step A) Using ester, melting point 152-
The title compound was prepared as a solid at 157 ° C. This reaction is carried out on silica gel
c (Rf = 0.2 in 10% methanol / dichloromethane).
3) Purified by recrystallization from ethyl acetate / hexane. NMR data were as follows: ¹ H-nmr (CDCl ₃ ): δ = 8.47 (d, J = 7.69 Hz, 1H), 7.35
(M, 5H), 5.34 (d, J = 7.69 Hz, 1H), 2.10 (m, 2H), 0.90 (
m, 1H), 0.40 (m, 2H), 0.10 (m, 2H). ¹³ C-nmr (CDCl ₃ ): δ = 172.3, 171.8, 137.6, 128.7,
56.2, 7.7, 4.0. C ₁₃ H ₁₅ NO ₃ (MW = 233.27); mass spectrometry (MH ⁺ ) N / A.

Example H Synthesis of N- (2-biphenyl) -D, L-alanine 2-aminobiphenyl (2 g, 11.8 mmol, Aldrich), triethylamine (1.2 eq) and ethyl 2-bromopropionate (1.1 equivalents, Aldrich
) Was mixed and heated to 85 ° C. with stirring. After 7 days, the mixture was diluted with chloroform and washed with water. The organic portion was dried and concentrated to give an oil, which was purified by silica gel chromatography (1: 1 CH ₂ Cl ₂ / hexane). The resulting oil was dissolved in a 1: 2 mixture of water / dioxane (200 mL),
LiOH (2 eq) was added. After 2 hours, the mixture was concentrated to give an oil, which was dissolved in water. The aqueous solution was washed with ether, adjusted to pH 3 with 5N HCl, and extracted with ethyl acetate. The organic portion was dried and concentrated to give an oil, which was purified by silica gel chromatography (EtOAc) to give the title compound.

Example I Synthesis of N- (Phenyl-furazan-3-yl) -D, L-alanine According to general procedure II-D, 4-phenyl-furazan-3-ylamine (
The ethyl ester compound was prepared using Maybridge) and ethyl pyruvate (Aldrich). General Procedure II-A, method B (LiOH / H ₂ O / dioxane)
The title compound was prepared using this ethyl ester compound according to the procedure described below.

Example L Synthesis of S-(+)-3,5-difluoromandelic acid Step A- Preparation of methyl S- (±) -3,5-difluoromandelic acid 3 in CH ₂ Cl ₂ (100 mL) , 5-Difluorobenzaldehyde (Aldrich
)), ZnCl ₂ (6.7 g, 21.1 mmol) was added to form a slurry. Trimethylsilyl cyanide (21) dissolved in CH ₂ Cl ₂ (100 mL)
. (0 g, 211.2 mmol) was slowly added to the 0 ° C. slurry. The resulting solution was stirred at room temperature for 4 hours. Then the reaction mixture was diluted with water and the organic layer was separated. The organic layers were combined and concentrated to a residue. This residue was washed with MeOH (200 m
L), and anhydrous HCl gas was bubbled through the solution for 10 minutes.
After stirring at room temperature for 18 hours, the solution was concentrated to a solid. This solid is CH ₂
Dissolved in Cl ₂ / H ₂ O and the aqueous layer was extracted with CH ₂ Cl ₂ . The organic layers were combined, washed with brine, dried over anhydrous MgSO ₄ and concentrated to a solid (37.4 g, 87.
6%). mp = 77-78 ° C. ¹ H NMR (300 MHz, CDCl ₃ ): δ = 6.97 (dd, J = 9.6 Hz,
J = 1.79 Hz, 2H), 6.74 (dt, J = 8.82, J = 2.28 Hz, 1H), 5
.14 (d, J = 4.64 Hz, 1H), 3.78 (s, 3H), 3.54 (d, J = 5.
1Hz, 1H).

Step B—Preparation of Methyl S-(+)-3,5-Difluoromandelate Methyl (±) -3,5-difluoromandelate was prepared by preparative chiral HPLC.
To give a white solid with a melting point of 70-71 ° C. C₉H₈F_TwoO_Three(MW = 202.17); Mass spectrum analysis Actual value (M + NH_Four ⁺ ) 220.0. Elemental analysis (C₉H₈F_TwoO_ThreeAs) calculated: C, 53.47; H, 3.99. Measured value
: C, 53.40; H, 3.89.

Step C—Preparation of S-(+)-3,5-difluoromandelic acid Methyl S-(+)-3,5-difluoromandelicate in 74% aqueous THF
(1 equivalent) was cooled to 0 ° C. and treated with lithium hydroxide. After 40 minutes at 0 ° C., TLC indicated the reaction was complete. The contents are transferred to a separator, and CH ₂ Cl ₂ and N
Partitioned into a saturated aqueous solution of aHCO ₃ . The aqueous layer was acidified with 0.5N NaHSO ₄ and extracted three times with ethyl acetate. The combined extracts were washed with brine, dried over Na ₂ SO _4, filtered, and concentrated to a white solid mp 119 to 122 ° C.. ¹ H NM
R was consistent with known 3,5-difluoromandelic acid.

Example N Synthesis of (R) -N, N′-di-BOC-2-hydrazinopropionic acid Step A: (S)-(−)-4-benzyl in THF cooled to −50 ° C. -2-
To oxazolidanone (Aldrich) was added dropwise 1.1 equivalents of n-butyllithium (1.6 M in hexane). After warming the reaction mixture to -20 ° C,
Cooled to 78 ° C. and added propionyl chloride (1.1 eq) in one portion. The reaction mixture was stirred at -78 ° C for a further 15 minutes and then allowed to warm to room temperature. The reaction was then quenched with saturated sodium bicarbonate solution and extracted with ethyl acetate. The organic extract was washed with water, then brine, then dried over sodium sulfate, filtered,
Concentration gave (S)-(-)-3-propionyl-4-benzyl-2-oxazolidanone.

Step B: To a solution of (S)-(−)-3-propionyl-4-benzyl-2-oxazolidanone in THF at −78 ° C. was added LiHMDS (1.05 eq) (Aldrich
) Was added dropwise. After stirring the reaction mixture at -78 ° C for 30 minutes, a previously cooled solution of di-tert-butyl-azodicarboxylate (Aldrich) was added via cannula. After 5 minutes, 2.6 equivalents of acetic acid were added. The reaction mixture was then extracted with dichloromethane, and the organic layer was washed with 1M potassium phosphate. The organic layer was then dried over sodium sulfate, filtered, and concentrated to give (S)-(-)-3-[(R) -N,
N′-Di-BOC-2-hydrazinopropionyl] -4-benzyl-2-oxazolidanone was obtained.

Step C: To the product of Step B (1.0 g, 2.16 mM) in THF (34 mL) and water (13 mL) cooled to 0 ° C. was added H ₂ O ₂ (0.734 mL, 6.4 m).
M) and a 30% solution of LiOH (57 mg, 2.37 mM) were added. The reaction mixture was stirred at room temperature for 1.5 hours before being quenched with 1.5N Na ₂ SO ₃ (15 mL). A saturated solution of sodium bicarbonate (48 mL) was added and the mixture was partitioned between dichloromethane and water. The aqueous layer was acidified with 10% citric acid and extracted with dichloromethane. The organic layer was dried over Na ₂ SO ₄ , filtered and concentrated to give the title compound (3
(90 mg, 60%) as a colorless vitreous material, which was used without further purification.

Example O Synthesis of 3,5-difluorophenyl-α-oxoacetic acid Step A: 1-Bromo according to the procedure described in J. Org. Chem., 45 (14), 2883-2887 (1980). -3,5-difluorobenzene (Aldrich) to ethyl 3,5-
Difluorophenyl-α-oxoacetate was prepared. Step B: Ethyl 3,5-difluorophenyl-α-oxoacetate is hydrolyzed using general procedure II-A (method B) to give 3,5-difluorophenyl-
α-oxoacetic acid was obtained.

Example P Synthesis of Cyclopentyl-α-hydroxyacetic Acid Using the procedure described in Gibby, WA; Gubler, CJ Biochemical Medicine 1982, 27, 15-25, cyclopentylmethanal (CAS No. 872-53-
7, Wiley) to give the title compound (CAS No. 6053-71-0) in two steps.

Example Q Synthesis of N- (3,4-dichlorophenyl) alanine US Pat. No. 3,598, the entire disclosure of which is incorporated herein by reference.
N- (3,4-dichlorophenyl) alanine was produced using the method described in U.S. Pat. Specifically, a solution of 3,4-dichloroaniline (1 equivalent) (Aldrich) in isopropanol (about 500 mL per mole of 3,4-dichloroaniline) was mixed with water (about 0.06 mL per mL of isopropanol) and 2-chloroaniline. Propionic acid (2 equivalents) (Aldrich) is added. The mixture was warmed to 40 ° C., and sodium bicarbonate (0.25 eq) was added continuously and then heated to reflux for 4-5 days.
After cooling, the reaction mixture is poured into water and unreacted 3,4-dichloroaniline is removed by filtration. The filtrate is acidified to pH 3-4 with concentrated hydrochloric acid and the resulting precipitate is filtered, washed and dried to give the title compound. mp = 148-149 ° C.

Example R Synthesis of N- (3,5-difluorophenyl) alanine According to the procedures described in US Pat. 2-chloropropionic acid (Aldr
ich) to produce N- (3,5-difluorophenyl) alanine.

Example S Synthesis of α-Fluoro-3,5-difluorophenylacetic acid Step A—Synthesis of methyl 3,5-difluoromandelic A solution of 3,5-difluoromandelic acid (Fluorochem) in methanol
1 gas was bubbled for 10 minutes. The reaction was refluxed overnight. The mixture was then concentrated under reduced pressure and the residue was taken up in ethyl acetate and washed with saturated NaHCO ₃ and brine. The organic layer was dried over Na ₂ SO _4, filtered, and concentrated to give the title intermediate as a white solid. _{C 9 H 8 F 2 O 3} (MW = 202.17); mass spectroscopy 202. ¹ H NMR (300 MHz, CDCl ₃ ): δ = 7.00 (2H, d, J = 6.58)
Hz), 6.76 (1H, t, J = 8.86 Hz), 5.16 (1H, d, J = 5.29 Hz)
), 3.81 (3H, s), 3.54 (1H, d, J = 5.39 Hz).

Step B—Synthesis of Methyl α-Fluoro-3,5-difluorophenylacetate Diethylaminosulfur trifluoride (DAST) in methylene chloride (DAST)
(1.1 eq.) Was cooled to 0 ° C. and a previously cooled solution of methyl 3,5-difluoromandelate (1 eq.) In methylene chloride was added. The transfer flask was rinsed with a small amount of methylene chloride. After 15 minutes, the cooling bath was removed and the reaction mixture was stirred at room temperature for another 40 minutes. The mixture was poured on ice and the layers were separated. The organic phase was washed with saturated NaHCO ₃ and brine. The organic layer was dried over Na ₂ SO _4, filtered, and concentrated. The residue was purified by HPLC (eluted with 7% ethyl acetate / hexane) to give the title intermediate as a yellow oil. _{C 9 H 7 F 3 O 2} (MW = 204.16); mass spectroscopy 204. Elemental analysis (C ₉ H ₇ F ₃ as O ₂₎ Calculated: C, 52.95; H, 3.46 . Found: C, 52.80; H, 3.73.

Step C—Synthesis of α-Fluoro-3,5-difluorophenylacetic acid The title intermediate was prepared according to General Procedure II-A, Method B using methyl α-fluoro-3,5-difluorophenylacetate. Was prepared as a white solid with a melting point of 100-102 <0> C. _{C 8 H 5 F 3 O 2} (MW = 190.13); mass spectroscopy 190. Elemental analysis (C ₈ H ₅ F ₃ as O ₂₎ Calculated: C, 50.54; H, 2.65 . Found: C, 50.47; H, 2.79.

Additionally, various other amino acid derivatives suitable for use in the present invention are
Disclosed in CT Publication Nos. WO 98/22430 and WO 98/22493, both published May 28, 1998, the entire disclosures of which are incorporated herein by reference. Have been.

III. Cyclic Compounds The following procedure describes the synthesis of various cyclic compound intermediates useful for preparing the compounds of the present invention. A. Benzoazepinone Derivatives and Related Compounds General Procedure 6-A Alkylation of 1-amino-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one Step A: Ben-Ishai et al., Tetrahedron, 1987, 43, 430, 1-ethoxycarbonylamino-1,3,4,5-tetrahydro-2H-3-
Benzoazepin-2-one was produced.

Step B: 1-ethoxycarbonylamino-1,3,4,5-tetrahydro-2
H-3-Benzazepin-2-one (2.0 g, 100 M%) was added to DMF (30 m
L) and NaH (95%, 0.17 g, 100 M%) was added in one portion. After stirring the reaction mixture for 1 hour, the appropriate alkyl iodide (300 M%) was added and the mixture was stirred for 12 hours. The reaction was poured into water and extracted with ethyl acetate (3x). The ethyl acetate extract was then washed with water (3x) and brine (1x). Over MgSO _4, treated with a rotary evaporator and chromatography (30% EtOAc / hexane), 1-ethoxy-3- alkyl-1,3,4,
5-Tetrahydro-2H-3-benzazepin-2-one was obtained with a yield of 87%.

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

General Procedure 6-B Alkylation of 3-Amino-1,3,4,5-tetrahydro-2H-1-benzazepin-2-one Step A: Armstrong et al. Tetrahedron Letters, 1994, 35, Using the method described in 3239, 3-amino-1,3,4,5-tetrahydro-2H-1-benzoazepin-2-one was prepared from α-tetralone. The following compounds are used in subsequent steps as prepared by this procedure: 5-Methyl-3-amino-1,3,4,5-tetrahydro-2H-1-benzazepin-2-one (4- Methyl-α-tetralone (from Aldrich); and 5,5-dimethyl-3-amino-1,3,4,5-tetrahydro-2H-1-benzazepin-2-one (4,4-dimethyur α-tetralone (4,4-dimethyul-
α-tetralone) (from Aldrich)).

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

Step C: BOC protected 3-amino-1,3,4,5-tetrahydro-2
H-1-benzoazepin-2-one (1.5 g, 100 M%) was added to DMF (20 m
L) and NaH (95%, 0.13 g, 100 M%) was added in one portion. After stirring the reaction mixture for 1 hour, the appropriate alkyl iodide (300 M%) was added and stirring was continued for 12 hours. The reaction was poured into water and extracted with ethyl acetate (3x). The ethyl acetate extract was washed with water (3 ×) and then with brine (1 ×). M
MgSO _4, rotary evaporated and then treated with chromatography (30% EtOAc / hexane), 3-amino-1-alkyl-1,3,4,5-tetrahydro-2H-1-benzazepine-protected BOC -2-one was obtained in a yield of 80%.

Step D: BOC-protected 3-amino-1-alkyl-1,3,4,5-tetrahydro-2H-1-benzazepin-2-one (1.0 g, 100 M%) in CH ₂ The suspension was suspended in 30 mL of Cl ₂ / trifluoroacetic acid (1: 1) 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 was obtained (yield 1).
00%).

Example 6-A Synthesis of 3-Amino-1,5-dimethyl-1,3,4,5-tetrahydro-2H-1-benzazepin-2-one Step A: Armstrong et al. Tetrahedron Letters, 1994, 35, 3239, from 4-methyl-α-tetralone to 3-amino-5-methyl-1.
, 3,4,5-Tetrahydro-2H-1-benzazepin-2-one was prepared.

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
L) and the solution was cooled to 0 ° C. BOC anhydride (13.89 g, 13
0M%) was added, the ice bath was removed, the solution was allowed to come to room temperature and stirring was continued for 16 hours. The solution was rotary evaporated to remove dioxane and give an off-white solid. This solid was recrystallized from CHCl ₃ to give BOC protected 3-amino-5.
-Methyl-1,3,4,5-tetrahydro-2H-1-benzazepin-2-one was obtained in a 55% yield.

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

Step D: BOC protected 3-amino-1,5-dimethyl-1,3,4,5-
Tetrahydro-2H-1-benzazepin-2-one (100 M%) was converted to CH ₂ C
The suspension was suspended in 30 mL of l ₂ / trifluoroacetic acid (1: 1). The reaction mixture was stirred for 4 hours. The reaction was then rotary evaporated to give 3-amino-1,5-dimethyl-1,3,4,5-tetrahydro-2H-1-benzazepin-2-one (
Yield 100%).

Example 6-B 5- (L-alaninyl) -amino-3,3,7-trimethyl-5,7-dihydro-6
Synthesis of H-benzo [b] azepin-6-one hydrochloride According to the procedure of Example 7-1, 5-amino-3,3,7-trimethyl-5,7
The title compound was prepared using -dihydro-6H-benzo [b] azepin-6-one hydrochloride (Example 6-C).

Example 6-C Synthesis of 5-amino-3,3,7-trimethyl-5,7-dihydro-6H-benzo [b] azepin-6-one hydrochloride Step A: General procedure 5-A Nt-Boc-5-amino-3,
Using 3-dimethyl-5,7-dihydro-6H-benzo [b] azepin-6-one (general procedure 6-B followed by Boc protection) and methyl iodide,
-Boc-5-amino-3,3,7-trimethyl-5,7-dihydro-6H-benzo [b] azepin-6-one was prepared. Step B: Nt-Boc-5-amino-3, according to general procedure 8-N
The title compound was prepared using 3,7-trimethyl-5,7-dihydro-6H-benzo [b] azepin-6-one.

Example 6-D 3- (S) -Amino-1-methyl-5-oxa-1,3,4,5-tetrahydro-2
Synthesis of H-1-benzoazepin-2-one Step A: RJ DeVita et al., Bioorganic and Medicinal Chemistry Lett
1995, 5 (12) 1281-1286, using N-Boc-serine (Bachem) and 2-fluoro-1-nitrobenzene (Aldrich) to give 3- (S) -amino-5-.
Oxa-1,3,4,5-tetrahydro-2H-1-benzazepin-2-one was prepared. Step B: The title compound was prepared using the product of Step A according to General Procedure 5-A.

Example 6-E 3- (S) -Amino-1-ethyl-5-oxa-1,3,4,5-tetrahydro-2
Synthesis of H-1-benzoazepin-2-one Step A: RJ DeVita et al., Bioorganic and Medicinal Chemistry Lett
1995, 5 (12) 1281-1286, using N-Boc-serine (Bachem) and 2-fluoro-1-nitrobenzene (Aldrich) to give 3- (S) -amino-5-.
Oxa-1,3,4,5-tetrahydro-2H-1-benzazepin-2-one was prepared. Step B: The title compound was prepared using the product of Step A according to General Procedure 5-A.

Example 6-F 3- (S) -Amino-1-methyl-5-thia-1,3,4,5-tetrahydro-2H
Synthesis of -1-benzazepin-2-one RJ DeVita et al., Bioorganic and Medicinal Chemistry Lett. 1995, 5
(12) The title compound was prepared from N-Boc-cystine (Novabio) and 2-fluoro-1-nitrobenzene (Aldrich) using the method of 1281-1286 followed by general procedure 5-A.

Example 6-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 were as follows: (MW = 251.8); mass spectrometry (MH +) 252.0.

Step B—Synthesis of 1,3,4,7,12,12a-Hexahydropyrido [2,1-b] [3] benzazepin-6 (2H) -one According to general procedure G, The title compound was prepared using N-chloroacetyl-2-benzylpiperidine. Physical data were 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, 1)
H); 7.2 (m, 4H). (MW = 215.3); mass spectrometry (MH +) 216.1.

Step C-7-Oximo-1,3,4,7,12,12a-Hexahydropyrido [2
Synthesis of 1,1-b] [3] Benzoazepin-6 (2H) -one According to general formula A (step B), 1,3,4,7,12,1 (obtained in step B)
The title compound was prepared using 2a-hexahydropyrido [2,1-b] [3] benzazepin-6 (2H) -one. Physical data were as follows: (MW = 244.3); mass spectrometry (MH +) 245.0.

Step D—7-Amino-1,3,4,7,12,12a-hexahydropyrido [2,
Synthesis of 1-b] [3] Benzoazepin-6 (2H) -one 7-oximo-1 (obtained in step C) according to general procedure A (step C).
, 3,4,7,12,12a-Hexahydropyrido [2,1-b] [3] benzazepine-
The title compound was prepared using 6 (2H) -one. Physical data were 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, 1)
H); 7.2 (m, 4H). (MW = 230.3); mass spectral analysis (MH +) 231.1.

Example 6-H Synthesis of 1- (N′-L-alaninyl) amino-4,5,6,7-tetrahydro-3,7-methano-3H-3-benzoazonin-2 (1H) -one Step A—Synthesis of N-Chloroacetyl-3-phenylpiperidine The title compound was prepared according to General Procedure F using 3-phenylpyridine hydrochloride (Aldrich).

Step B—Synthesis of 4,5,6,7-Tetrahydro-3,7-methano-3H-3-benzoazonin-2 (1H) -one According to general procedure G, N-chloroacetyl-3- The title compound was prepared using phenylpiperidine. Physical data were as follows: ¹ H-nmr (CDCl ₃ ): d = 1.32-1.57 (2H); 2.08 (m, 2H)
); 2.81 (t, 1H); 3.13 (bs, 1H); 3.37 (m, 2H); 4.36 (
m, 2H); 4.50 (d, 1H). (MW = 201.3); mass spectral analysis (MH +) 202.1.

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

Step D- 1-amino-4,5,6,7-tetrahydro-3,7-methano-3H-
Synthesis of 3-benzoazonin-2 (1H) -one The title compound was prepared using the product of Step C according to General Procedure A (Step C). Physical data were 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 spectrum analysis (MH +) 217.4.

Step E-1 Synthesis of 1- (N′-Boc-L-alaninyl) amino-4,5,6,7-tetrahydro-3,7-methano-3H-3-benzoazonin-2 (1H) -one The title compound was prepared according to general procedure D using N-tert-Boc-L-alanine (Aldrich) and the product of step D. Physical data were as follows: (MW = 387.48); mass spectrometry (MH +) 388.1.

Step F-1 Synthesis of 1- (N′-L-alaninyl) amino-4,5,6,7-tetrahydro-3,7-methano-3H-3-benzoazonin-2 (1H) -one General The title compound was prepared according to Procedure E using the product of Step E. Physical data were 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 spectrometry (MH +) 288.1.

B. Dibenzoazepinone Derivatives and Related Compounds General Procedure 7-A Preparation of 5-Amino-7-alkyl-5,7-dihydro-6H-dibenzo [b, d] azepin-6-one Derivatives Step A: General Procedure 5 5, A-dihydro-6H-dibenzo [
b, d] azepin-6-one and an alkyl halide to give a 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 equivalent) was dissolved in THF and isoamyl nitrite (1.2 equivalent) was added. The mixture was cooled to 0 ° C. in an ice bath. NaHMDS (1.1 equivalents, T
1M in HF) was added dropwise. After stirring for 1 hour or until the reaction was complete, the mixture was concentrated then acidified with 1N HCl and extracted with EtOAc. The organic portion was dried and concentrated to give the crude product, which was purified by silica gel chromatography.

Step C: Dissolve the resulting oxime compound in EtOH / NH ₃ (20: 1) and use Raney nickel and hydrogen (500 psi) in a bomb to give 10
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 Procedure 7-B Preparation of Fluoro-Substituted 5,7-Dihydro-6H-dibenzo [b, d] azepin-6-one Derivatives Robin D. Clark and Jahangir, Tetrahedron, Vol. 49, No. 7, pp. 1351-135
6, 1993 Modified and used ¹⁵ methods. Specifically, a suitable substituted Nt-Boc-
2-Amino-2'-methylbiphenyl was dissolved in THF and cooled to -78 ° C. S-butyllithium (1.3 M in cyclohexane, 2.2 equiv.) Was added slowly keeping the temperature below -65 <0> C. The resulting mixture was allowed to warm to -25 ° C and was stirred at this temperature for 1 hour. The mixture was cooled to -78C. Dry CO ₂ was bubbled through the mixture for 30 seconds. After warming the mixture to room temperature,
Quenched carefully with water. The mixture was concentrated under reduced pressure, and then concentrated with 1N HCl.
Adjusted to H3. The mixture was extracted with EtOAc, the organic portion was dried and concentrated to give a crude material. This crude material was dissolved in methanol and the solution was saturated with HCl. The mixture was heated under reflux for 12 hours and then cooled. Concentrate the mixture,
A crude lactam was obtained, which was purified by chromatography or crystallization.

General Procedure 7-C 5-Amino-7-methyl-5,7-dihydro-6H-dibenzo [b, d] azepine-
Separation of 6-one In a round bottom flask, place the free base amine (1.0 equivalent) of the racemate in methanol.
) And then di-p-toluoyl-D-tartaric acid monohydrate (1.0 equivalent).
The mixture is concentrated under reduced pressure and the residue is redissolved in a moderate volume of methanol and
Stirred (8-72 hours) open to the atmosphere at warm. Solid
The form was removed by filtration. Chiral HPLC (Chiracel ODR) (0.1%
15% acetonitrile and 85% H with trifluoroacetic acid_TwoFlow rate using O
1.0 mL / min, 35 ° C.) to determine the enantiomeric excess. Then minutes
The cleaved di-p-toluoyl-D-tartrate is taken up in EtOAc and saturated NaHCO _Three And adjusted to pH 9-10. Separate the layers and separate the organic layer with saturated NaHCO_Three, H_Two
Washed again with O and brine. Organic layer_FourAnd desiccant is filtered
Removed by The filtrate was concentrated under reduced pressure. Free amine compound to MeOH
Dissolve and add HCl (12M, 1.0 eq). The salt is concentrated under reduced pressure to give
The film was triturated with EtOAc. The HCl salt is filtered and EtO
I rinsed with Ac. The ee was measured by chiral HPLC.

Example 7-A 5-Amino-7-methyl-5,7-dihydro-6H-dibenzo [b, d] azepine-
Synthesis of 6-one hydrochloride Step A-7-Methyl-5,7-dihydro-6H-dibenzo [b, d] azepine-
Synthesis of 6-one A round bottom flask was charged with sodium hydride (0.295 g, 7
. 46 mmol) and 5,7-dihydro-6H-dibenzo [b, d] azepine-6-
ON (1.3 g, 6.22 mmol) (CAS # 2011-90-9, Brown, et a
l., Tetrahedron Letters, No. 8, 667-670, (1971) and manufactured as described therein. After stirring at 60 ° C. for 1 hour, the solution was treated with methyl iodide (1.16 mL, 18.6 mmol) and stirring continued in the dark for 17 hours. After cooling, the reaction was diluted with CH ₂ Cl ₂ / H ₂ O, washed with NaHSO ₄ solution, water and dried over Na ₂ SO ₄ . Evaporation and flash chromatography (S
to give the title compound 0.885g (63%) as a colorless solid by iO _2, CHCl _3). NMR data were as follows: ¹ H-nmr (CDCl ₃ ): δ = 7.62 (d, 2H), 7.26-7.47 (m, 6
H), 3.51 (m, 2H), 3.32 (s, 3H). _{C 15 H 13 NO (MW =} 223.27); mass spectroscopy (MH +) 223. Elemental analysis (C ₁₅ H ₁₃ as NO); Calculated: C, 80.69 H, 5.87 N , 6.
27. Found: C, 80.11 H, 5.95 N, 6.23.

Step B— 7-Methyl-5-oximo-5,7-dihydro-6H-dibenzo [b
Synthesis of [, d] azepin-6-one The above isolated compound (0.700 g, 3.14 mmol) was treated with 20 mL of toluene.
And treated with butyl nitrite (0.733 mL, 6.28 mmol). The reaction temperature was lowered down to 0 ° C., N ₂ atmosphere, a solution of KHMDS (9.42mL, 0.5
M). 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 layer was dried over Na ₂ SO ₄ and the title compound was purified by chromatography (SiO ₂ , 98: 2 CHCl ₃ / MeOH) to give 0.59 g (80%) of a colorless solid. _{C 15 H 12 N 2 O 2} (MW = 252.275); mass spectroscopy (MH +) 25
2. Elemental analysis (C ₁₅ H ₁₂ N ₂ as O _2); Calculated: C, 71.42 H, 4.79 N , 1
1.10. 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 hydrochloride The oxime compound isolated above (0.99 g, 3.92 mmol) was catalyzed with 10% Pd / C (0.46 g) in 3A ethanol using Parr 35 in the device
Hydrogenated at psi. After 32 hours, the reaction mixture was filtered through a celite plug and the filtrate evaporated to a foam and 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 under reduced pressure to give 0.66 g (61%) of the title compound. NMR data were as follows: ¹ H-nmr (DMSOd6): δ = 9.11 (bs, 3H), 7.78-7.41 (
m, 8H), 4.83 (s, 1H), 3.25 (s, 3H). C ₁₅ H ₁₄ N ₂ O HCl (MW = 274.753); mass spectrometry (MH +
Free base) 238. Elemental analysis (C ₁₅ H ₁₄ N as ₂ O HCl); Calcd: C, 65.57 H, 5.50
N, 10.19 Found: C, 65.27 H, 5.67 N, 10.13.

Example 7-B (S)-and (R) -5- (L-alaninyl) -amino-7-methyl-5,7-dihydro-6H-dibenzo [b, d] azepin-6-one Step A- (S)-and (R) -5- (N-Boc-L-alaninyl) -amino-7-methyl-5,7-dihydro-6H-dibenzo [b, d] azepine-6 Synthesis of Boc-L-alanine (0.429 g, 2.26 mmol) (Aldrich) was dissolved in THF and HOBt hydrate (0.305 g, 2.26 mmol) and 5-amino-7 were synthesized.
-Methyl-5,7-dihydro-6H-dibenzo [b, d] azepin-6-one (0.
45 g, 1.89 mmol) (Example 7-A). Lower the temperature to 0 ° C,
The reaction mixture was treated with EDC (0.449 g, 2.26 mmol) (Aldrich) and N ₂
Stirred under for 17 hours. The reaction mixture was evaporated and the residue was taken up in EtOAc / H ₂
Diluted with O, washed with 1.0 N HCl, saturated NaHCO ₃ , brine, Na ₂ S
Dried over O ₄ . Chiralcel using 10% IPA / heptane at 1.5 mL / min
Diastereomers were separated on an OD column.

Isomer I: retention time 3.37 minutes NMR data were as follows: ¹ H-nmr (CDCl ₃ ): δ = 7.62-7.33 (m, 9H), 5.26 (D, 1
H), 5.08 (m, 1H), 4.34 (m, 1H), 3.35 (s, 3H), 1.49 (s, 9)
H), 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 +) 40
9. Elemental analysis (as _{C 23 H 27 N 3 O 4} ); Calculated: C, 67.46 H, 6.64 N , 1
0.26. Found: C, 68.42 H, 7.02 N, 9.81. Isomer 2: Retention time 6.08 min NMR data was 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 +) 40
9. Elemental analysis (as _{C 23 H 27 N 3 O 4} ); Calculated: C, 67.46 H, 6.64 N , 1
0.26. 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 hydrochloride The compound isolated in Part A was dissolved in dioxane (each isomer separately) and treated with excess HCl (g). After stirring for 17 hours, evaporated and dried under reduced pressure to isolate the title compound as a colorless solid. Isomer 1: C ₁₈ H ₁₉ N ₃ O ₂ .HCl (MW = 345.832); mass spectrum analysis (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 spectrum analysis (MH
+ Free base) 309. Optical rotation: [α] ₂₀ = 80 ＠ 589 nm (c = 1, MeOH).

Example 7-C (S)-and (R) -5- (L-valinyl) -amino-7-methyl-5,7-dihydro-6H-dibenzo [b, d] azepin-6-one Step A- (S)-and (R) -5- (N-Boc-L-valinyl) -amino-
Synthesis of 7-methyl-5,7-dihydro-6H-dibenzo [b, d] azepin-6-one Boc-L-valine (0.656 g, 3.02 mmol) (Aldrich) was dissolved in THF and HOBt water was added. Hydrate (0.408, 3.02 mmol) Dipea (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 7-A). ). The temperature was reduced to 0 ° C. and the reaction mixture was poured into EDC (0.60
1 g, 3.02 mmol) (Aldrich) and stirred under N ₂ for 17 hours. The reaction mixture was evaporated and the residue was diluted with EtOAc / H ₂ O, 1.0N HCl,
Washed with saturated NaHCO ₃ , brine and dried over Na ₂ SO ₄ . Diastereomers were separated on a Chiralcel OD column using 10% IPA / heptane at 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 = 437.5544); mass spectrum analysis (MH +) 43
8. 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 = 437.5544); mass spectrum analysis (MH +) 43
8.

Step B— (S) — and (R) -5- (L-valinyl) -amino-7-methyl-
Synthesis of 5,7-dihydro-6H-dibenzo [b, d] azepin-6-one hydrochloride The compound isolated in Part A (each isomer separately) was dissolved in dioxane and excess HCl (g ). After stirring for 17 hours, evaporated and dried under reduced pressure to isolate the title compound 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 7-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) with TH
FOB, HOBt hydrate (0.408, 3.02 mmol), Dipea (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 7-A). The temperature was reduced to 0 ° C. and the reaction mixture was added to EDC (
0.601 g, was treated with 3.02mmol) (Aldrich), and stirred for 17 hours under N _2. The reaction mixture was evaporated and the residue was diluted with EtOAc / H ₂ O, 1.0N
HCl, saturated NaHCO ₃ , brine and dried over Na ₂ SO ₄ . Chiralc
Diastereomers were separated on an el OD column using 10% IPA / heptane at 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 spectrum analysis (MH +) 45
2. 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 spectrum analysis (MH +) 45
2.

Step B— (S) — and (R) -5- (L-tert-leucyl) -amino-7-methyl-5,7-dihydro-6H-dibenzo [b, d] azepin-6-one Synthesis of Hydrochloride The compound isolated in Part A (each isomer separately) was dissolved in dioxane and treated with excess HCl (g). After stirring for 17 hours, evaporated and dried under reduced pressure to isolate the title compound as a colorless solid. Isomer 1: C ₂₁ H ₂₅ N ₃ O ₂ .HCl (MW = 387.91); mass spectrometry (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 spectrometry (MH +
Free base) 352. Optical rotation: [α] ₂₀ = 108 ＠ 589 nm (c = 1, MeOH).

Example 7-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,
. 77 mmol) (Example 7-A) and Et ₃ N (2.66mL, 19.12mmol
The solution) in CH ₂ Cl _2, stirred for 5.0 minutes at -15 ℃, TMSI (1.36m
L, 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 degrees over 3 hours.
The reaction was quenched with saturated Na ₂ SO ₃ , diluted with CH ₂ Cl ₂ and separated. The organic layer was washed with Na ₂ SO ₃ and NaHSO ₃ and dried over MgSO ₄ . After filtration, the organic layer was concentrated to about 20 mL and diluted with 20 mL of hexane. The title compound was isolated by filtration as a tan precipitate.

Step B— 5-Azido-5,7-dihydro-6H-dibenzo [b, d] azepine-
The iodide isolated on 6-one synthesized was dissolved in DMF, and treated with 1.2 equivalents of NaN _3. After stirring at 23 ° C. for 17 hours, the mixture was diluted with EtOAc / H ₂ O, separated, washed with brine and dried over MgSO ₄ . Transfer the title compound to hot Et
Triturated from OAc as a tan powder.

Step C—Synthesis of 5- (N-Boc-amino) -5,7-dihydro-6H, 7H-dibenzo [b, d] azepin-6-one The azide was dissolved in THF / H ₂ O. The mixture was stirred at 23 ° C. for 17 hours in the presence of 3.0 equivalents of Ph ₃ P. The reaction was diluted with 50% HOAc / toluene, separated, and the aqueous layer was extracted with toluene and evaporated to give an oily residue. 1N NaOH was added thereto to adjust the pH to 7.0, and the obtained HOAc salt was collected and dried under reduced pressure. Finally, TH
The compound was treated with Boc anhydride in F (1.05 eq) and Et ₃ N (2.1 eq). After stirring at 23 ° C. for 5 hours, the reaction was filtered and the title compound was isolated as a colorless powder.

Example 7-F 5-Amino-7- (2-methylpropyl) -5,7-dihydro-6H-dibenzo [b
Synthesis of [, d] azepin-6-one hydrochloride 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 in DMF
A solution of [, d] azepin-6-one (0.2 g, 0.617 mmol) (Example 7-E) 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, 0.1 mL).
(678 mmol) was added and stirring was continued for 17 hours. After cooling to 23 ° C., the mixture was diluted with CH 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 / MeOH 9: 1). _{C 23 H 28 N 2 O 3} (MW = 380.41); mass spectroscopy (MH +) 381
. Elemental analysis (C ₂₃ H ₂₈ N ₂ as O _3); Calculated: 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. Evaporate and dry under vacuum to isolate the title compound as a slightly colored solid.

Example 7-G 5-Amino-7- (methoxyacetyl) -5,7-dihydro-6H-dibenzo [b,
d] Synthesis of azepin-6-one hydrochloride 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 in DMF
, d] azepin-6-one (1.03, 3.08 mmol) (Example 7-E)
Cs_TwoCO_Three(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) (Aldri
ch) and stirring was continued for 17 hours. After cooling to 23 ° C., the mixture was _Two Cl_TwoAnd washed several times with brine, Na_TwoSO_FourAnd dried. Chromatography
Fee (SiO_Two, CHCl_Three) To purify the title compound. C_{twenty two}H_{twenty four}N_TwoO_Five(MW = 396.44); mass spectrum analysis (MH +) 397
. Elemental analysis (C_{twenty two}H_{twenty four}N_TwoO_FiveCalculated 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. Evaporated and dried under reduced pressure to isolate the title compound as a colorless solid. C ₁₇ H ₁₆ N ₂ O ₃ HCl (MW = 332.78); mass spectrometry (MH +
Free base) 297.

Example 7-H 5-Amino-7- (3,3-dimethyl-2-butanonyl) -5,7-dihydro-6H
Synthesis of -Dibenzo [b, d] azepin-6-one hydrochloride Step A-5- (N-Boc-amino) -7- (3,3-dimethyl-butanonyl)
Synthesis of -5,7-dihydro-6H-dibenzo [b, d] azepin-6-one 5- (N-Boc-amino) -5,7-dihydro-6H-dibenzo [b in DMF
A solution of [, d] azepin-6-one (0.2 g, 0.617 mmol) (Example 7-E)
To Cs_TwoCO_Three(0.3 g, 0.925 mmol) and warmed to 60 ° C.
. 1-chloro-3,3-dimethyl-2-butanone (0.096
mL, 0.74 mmol) (Aldrich) was added and stirring was continued for 17 hours. 23 ℃
After cooling in_TwoCl_TwoAnd washed several times with brine, Na _Two SO_FourAnd dried. The title compound was isolated as a colorless solid. C_{twenty five}H₃₀N_TwoO_Four(MW = 422.522); mass spectrum analysis (MH +) 42
3.

Step B—Synthesis of 5-Amino-7- (3,3-dimethyl-2-butanonyl) -5,7-dihydro-6H-dibenzo [b, d] azepin-6-one hydrochloride In Part A The isolated compound was deprotected in dioxane saturated with HCl gas. Evaporated and dried under reduced pressure to isolate the title compound as a colorless solid.

Example 7-I L-alaninyl-5-amino-7-methyl-5,7-dihydro-6H-dibenzo [
Synthesis of [b, d] azepin-6-one hydrochloride Step A: According to general procedure D, Nt-Boc-L-alanine and 5
-Amino-7-methyl-5,7-dihydro-6H-dibenzo [b, d] azepine-6
-N-t-Boc-L-alaninyl-5-amino-7-methyl-5
, 7-Dihydro-6H-dibenzo [b, d] azepin-6-one was prepared. Step B: According to General Procedure 8-N, Nt-Boc-L-alaninyl-
5-amino-7-methyl-5,7-dihydro-6H-dibenzo [b, d] azepine-
The title compound was prepared using 6-one. With this approach, other substitutions NtB
oc-L-alaninyl-5-amino-7-methyl-5,7-dihydro-6H-dibenzo [b, d] azepin-6-one can also be prepared.

Example 7-J L-valinyl-5-amino-7-methyl-5,7-dihydro-6H-dibenzo [b
Synthesis of [, d] azepin-6-one hydrochloride Step A: According to general procedure D, Nt-Boc-L-valine and 5-
Amino-7-methyl-5,7-dihydro-6H-dibenzo [b, d] azepine-6
With on, Nt-Boc-L-valinyl-5-amino-7-methyl-5,
7-Dihydro-6H-dibenzo [b, d] azepin-6-one was prepared. Step B: Nt-Boc-L-valinyl-5 according to general procedure 8-N
-Amino-7-methyl-5,7-dihydro-6H-dibenzo [b, d] azepine-6
The title compound was prepared using -one. With this approach, other substituted Nt-Bo
c-L-valinyl-5-amino-7-methyl-5,7-dihydro-6H-dibenzo [b, d] azepin-6-one can also be prepared.

Example 7-K Synthesis of 5-amino-7-phenbutyl-5,7-dihydro-6H-dibenzo [b, d] azepin-6-one According to General Procedure 7-A, 5,7- Dihydro-6H-dibenzo [b, d] azepin-6-one (Brown, et al., Tetrahedron Letters, No 8, 667-670, (1971)
) And 1-chloro-4-phenylbutane (Aldrich) to give the title compound.

Example 7-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, No. 8) according to general procedure 7-A. , 667-670, (1971
) And (bromomethyl) cyclopropane (Aldrich) to prepare the title compound.

Example 7-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) according to General Procedure 7-A Letters, No 8, 667-670, (1971
) And 1-bromo-2,2,2-trifluoroethane (Aldrich) to give the title compound.

Example 7-N Synthesis of 5-amino-7-cyclohexyl-5,7-dihydro-6H-dibenzo [b, d] azepin-6-one 5,7- according to general procedure 7-A Dihydro-6H-dibenzo [b, d] azepin-6-one (Brown, et al., Tetrahedron Letters, No 8, 667-670, (1971)
) And bromocyclohexane (Aldr)
ich) to give the title compound.

Example 7-O 5- (L-alaninyl) amino-9-fluoro-7-methyl-5,7-dihydro-
Synthesis of 6H-dibenzo [b, d] azepin-6-one hydrochloride Step 1: 2-bromo-5-fluorotoluene is stirred in THF at -78 ° C.
Was. Slowly add s-BuLi (1.05 eq, 1.3 M in cyclohexane).
The mixture was stirred for 45 minutes. Add trimethyl borate (1.5 eq) and mix
The thing was warmed up to room temperature. After stirring for 1 hour, pinacol (2 equivalents) was added.
. The mixture was stirred for 16 hours and concentrated under reduced pressure. The residue obtained is CH _Two Cl_TwoAnd filtered through celite. Concentrate the filtrate and remove the oil
This was chromatographed on inert silica gel (Et._ThreeN)
To obtain an aryl boronate ester compound.

Step 2: 2-Bromoaniline (1 eq.) And di-t-butyl-dicarbonate (1.1 eq.) Were stirred at 80 ° C. for 20 hours. The resulting mixture was cooled and directly distilled using house vacuum to give Nt-Boc-2-bromoaniline.

Step 3: Nt-Boc-2-bromoaniline (Step 2, 1 equivalent), Arylboronate ester compound (Step 1, 1.1 equivalent), K ₂ CO ₃ (1.1 equivalent)
And tetrakis (triphenylphosphine) palladium (0) (0.02 equiv.) Were stirred in 20% water / dioxane under nitrogen. The solution was heated at reflux for 10 hours. After cooling the mixture, it was concentrated. The resulting residue was partitioned between water and chloroform. The organic portion was dried and concentrated to give an oil, which was purified by silica gel chromatography using 1: 1 CH ₂ Cl ₂ / hexane.

Step 4: According to General Procedure 7-B, using the substituted biphenyl obtained in Step 3, 9-fluoro-5,7-dihydro-6H-dibenzo [b, d] azepine-6.
-On was produced.

Step 5: 9-Fluoro-5,7-dihydro-6H-dibenzo [b, d] azepin-6-one (1 equivalent, step 4), cesium carbonate (1.1 equivalent, Aldrich) and methyl ioda The id (1.1 eq, Aldrich) was stirred in dry DMF at room temperature for 16 hours. The mixture was concentrated under reduced pressure to give a residue, which was partitioned between EtOAc and water. The organic portion was 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] azepine-6-. Got on.

Step 6: According to General Procedure 7-A, Step B, 9-fluoro-7-methyl-5,7-dihydro-6H-dibenzo [b, d] azepine-6 obtained in Step 5 With on, 5-amino-9-fluoro-7-methyl-5,7-dihydro-6H
-Dibenzo [b, d] azepin-6-one was prepared.

Step 7: According to the procedure of Example 7-I, 5-amino-9 obtained in Step 6
-Fluoro-7-methyl-5,7-dihydro-6H-dibenzo [b, d] azepine-
The title compound was prepared using 6-one.

Example 7-P Synthesis of 5- (L-alaninyl) amino-13-fluoro-7-methyl-5,7-dihydro-6H-dibenzo [b, d] azepin-6-one hydrochloride Example According to the method of 7-O, 2-bromo-4-fluoroaniline (Step 2)
The title compound was prepared using o-tolylboronic acid (Step 3, Aldrich).

Example 7-Q Synthesis of 5- (L-alaninyl) amino-10-fluoro-7-methyl-5,7-dihydro-6H-dibenzo [b, d] azepin-6-one hydrochloride Example According to the method of 7-O, 2-bromo-4-fluorotoluene (Step 1)
Was used to produce the title compound.

Example 7-R 5- (L-alanyl) -amino-7-cyclopropylmethyl-5,7-dihydro-
Synthesis of 6H-dibenzo [b, d] azepin-6-one hydrochloride According to the procedure of Example 7-1, 5-amino-7-cyclopropylmethyl-5
The title compound was prepared using, 7-dihydro-6H-dibenzo [b, d] azepin-6-one (Example 7-L).

Example 7-S Synthesis of 5- (L-alaninyl) amino-7-phenbutyl-5,7-dihydro-6H-dibenzo [b, d] azepin-6-one hydrochloride of Example 7-I Following the procedure, the title compound was prepared using 5-amino-7-phenbutyl-5,7-dihydro-6H-dibenzo [b, d] azepin-6-one (Example 7-K).

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

Example 7-U Synthesis of 5- (L-valinyl) amino-7-phenbutyl-5,7-dihydro-6H-dibenzo [b, d] azepin-6-one hydrochloride of Example 7-J Following the procedure, the title compound was prepared using 5-amino-7-phenbutyl-5,7-dihydro-6H-dibenzo [b, d] azepin-6-one (Example 7-U).

Example 7-V 5- (L-valinyl) amino-7-hexyl-5,7-dihydro-6H-dibenzo [
Synthesis of b, d] azepin-6-one hydrochloride Step A: According to general procedure 7-A, 5,7-dihydro-6H-dibenzo [
b, d] azepin-6-one (Brown, et al., Tetrahedron Letters, No 8, 667-
670, (1971) and 1-bromohexane (Aldrich) and 5-amino-7-hexyl-5,7-dihydro-6H-dibenzo [b, d] azepine using 1-bromohexane (Aldrich). -6-one was produced. Step B: Following the procedure of Example 7-J, 5-amino-7-hexyl-5,
The title compound was prepared using 7-dihydro-6H-dibenzo [b, d] azepin-6-one.

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

Example 7-X 5- (L-valinyl) amino-13-fluoro-7-methyl-5,7-dihydro-
Synthesis of 6H-dibenzo [b, d] azepin-6-one hydrochloride According to the procedure of Example 7-J, 5-amino-13-fluoro-7-methyl-
The title compound was prepared using 5,7-dihydro-6H-dibenzo [b, d] azepin-6-one (prepared in Example 7-P).

Example 7-Y 5- (L-valinyl) amino-13-fluoro-7-methyl-5,7-dihydro-
Synthesis of 6H-dibenzo [b, d] azepin-6-one hydrochloride According to the procedure of Example 7-J, 5-amino-9-fluoro-7-methyl-5
The title compound was prepared using, 7-dihydro-6H-dibenzo [b, d] azepin-6-one (prepared in Example 7-O).

Example 7-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 hydrochloride (Example 7-A) was dissolved in a 1: 1 mixture of EtOAc / HOAc, 5% Rh / C. Was added and the mixture was stirred at 60 ° C. under 60 psi of hydrogen.
After days, the mixture was filtered and the filtrate was concentrated to give an oil, which was purified by SCX cation exchange chromatography to give the title compound.

Example 7-AA Synthesis of 5- (S) -amino-7-methyl-5,7-dihydro-6H-dibenzo- [b, d] azepin-6-one hydrochloride General Procedure 7-C The racemic 5-amino-7 in methanol
-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) to give the title compound as a solid. The product was collected by filtration. Chiral H
The enantiomeric excess was measured by PLC. Desired enantiomer 1: retention time 9.97 minutes. Undesired enantiomer 2: retention time 8.62 minutes. NMR data were as follows: ¹ H-nmr (CDCl ₃ ): δ = 9.39 (s, 2H), 7.75-7.42 (m, 8)
H), 4.80 (s, 1H), 3.30 (s, 3H). C ₁₅ H ₁₅ ClN ₂ O (MW = 274.75); mass spectrometry (MH ⁺ ) 23
9.1. Elemental analysis (C ₁₅ H ₁₅ ClN as ₂ O _3); Calculated: C, 65.57; H, 5.50
N, 10.20; Found: C, 65.51; H, 5.61; N, 10.01.

Example 7-AB 9-Amino-5,6-dihydro-4H-quino [8,1-ab] [3] benzazepine-
8 (9H) - one Synthesis dioxane synthetic steps A- 8-phenylquinoline hydrochloride (50mL) / H ₂ degassed 8-bromoquinoline in O (10mL) (1.0g, 4.81mmol ) (Aldrich The solution of phenylboronic acid (0.
64 g, 5.29 mmol) (Aldrich), Pd (Ph ₃ P) ₄ (0.050 g, 0.04 m
mol) and K ₂ CO ₃ (0.73g, was treated with 5.29 mmol). After refluxing for 4 hours under N ₂ atmosphere, the reaction was cooled, diluted with EtOAc, and separated. Na ₂ S
Dry over O ₄ and chromatograph on SiO ₂ (95: 5 hexane / EtOAc)
The title compound was isolated as a colorless oil. Physical data were 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 According to the procedure described in Honel, M., et. Al., JCS Perkin I, (1980), 1933-1938. The product of Step A (0.99 g, 4.82 mmol) was hydrogenated. Physical data were as follows: ¹ H-nmr (CDCl ₃ ): δ = 7.46 (m, 3H), 7.38 (m, 2H), 6.9.
8 (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—Synthesis of 1-Chloromethylacetyl-8-phenyl-1,2,3,4-tetrahydroquinoline The product of Step B (1.0 g, 4.78 mmol) was converted to CH ₂ Cl ₂ (20 mL). / H ₂
Dissolved in O (20 mL) and treated with NaHCO ₃ (0.602 g, 7.18 mmol) followed by chloroacetyl chloride (0.478 mL, 5.26 mmol). 23
After stirring at 17 ° C. for 17 hours, the reaction was diluted with CH ₂ Cl ₂ , washed with saturated NaHCO ₃ , dried over Na ₂ SO ₄ and purified by SiO ₂ chromatography (CHCl ₃ / hexane 9: 1). . The product was isolated as a colorless solid. Physical data were as follows: C ₁₇ H ₁₆ ClNO (MW = 286.77); mass spectrometry (MH +) 28
7. Elemental analysis (C ₁₇ H ₁₆ as ClNO); Calculated: 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-ab] [3] benzazepine-
Synthesis of 8 (9H) -one At 23 ° C., the product of Step C (0.89 g, 3.11 mmol) was added to AlCl ₃
(0.87 g, 6.54 mmol) and the mixture was heated neat at 100 ° C. for 5-7 minutes. After vigorous evolution of gas, the molten mixture was cooled and extracted several times with CH ₂ Cl ₂ / NaHCO ₃ (sat.). The organic layers are collected, dried over Na ₂ SO ₄ and chromatographed (SiO ₂ , CHCl ₃ / hexane 9: 1)
The title compound was purified by purification to give a colorless oil which solidified on standing. Physical data were as _{follows: C 17 H 15 NO (MW} = 249.312); mass spectroscopy (MH +) 250
. Elemental analysis (C ₁₇ as H ₁₅ NO); Calculated: 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-ab] [3]
Synthesis of Benzoazepin-8 (9H) -one The product of Step D (0.490 g, 1.97 mmol) was dissolved in THF and butyl nitrite (0.46 mL, 3.93 mmol) and the KHMDS (0 .5M;
52 mL, 2.26 mmol). After stirring for 1 hour, the reaction was quenched with cold 1N HCl and extracted with EtOAc. The organic layers were combined, dried over Na ₂ SO ₄ and the product was purified by SiO ₂ chromatography (CHCl ₃ / MeOH, 99: 1). The title compound was isolated as a colorless solid. Physical data were as _{follows: C 17 H 14 N 2 O} 2 (MW = 278.3); mass spectroscopy (MH +) 279. Elemental analysis _{(C 17 H 14 N 2 O} 2 .0.3317 mole H as ₂ O); Calculated: C, 71.
82 H, 5.19 N, 9.85. Found: C, 71.85 H, 5.09 N, 9.59.

Step F—Synthesis of 9-Amino-5,6-dihydro-4H-quino [8,1-ab] [3] benzazepin-8 (9H) -one The product of Step E (0.360 g, 1.29 mmol) was added to EtOH (50 mL) /
Catalyzed with Ra / Ni (0.05 g) in NH ₃ (anhydrous) (5.0 mL),
Hydrogenated at 500C and 500 psi for 10 hours. The catalyst was removed by filtration and the resulting filtrate was subjected to SiO ₂ chromatography (CHCl ₃ / MeOH, 98: 2) to give the title compound as a colorless oil which solidified on standing. Physical data were as _{follows: C 17 H 16 N 2 O} (MW = 264.326); mass spectroscopy (MH +) 26
6. Elemental analysis (as _{C 17 H 16 N 2 O)} ; Calculated: C, 77.25 H, 6.10 N , 1
0.60. Found: C, 77.23 H, 6.15 N, 10.49.

Example 7-AC 9- (N'-L-alaninyl) amino-5,6-dihydro-4H-quino [8,1-ab
] [3] Synthesis of benzazepin-8 (9H) -one hydrochloride Step A-9- (N'-Boc-L-alaninyl) amino-5,6-dihydro-4
Synthesis of H-quino [8,1-ab] [3] benzazepin-8 (9H) -one According to 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 (obtained in Example 7-AC). Physical data were as _{follows: C 25 H 29 N 3 O} 4 (MW = 435.521); mass spectroscopy (MH +) 43
6. Elemental analysis _{(C 25 H 29 N 3 O} 4 .0.4102 mole H ₂ as O); Calculated: C, 67.
79H, 6.79N, 9.49; Found: C, 67.83H, 6.91N, 9.29.

Step B—Synthesis of 9- (N′-L-alaninyl) amino-5,6-dihydro-4H-quino [8,1-ab] [3] benzazepin-8 (9H) -one Hydrochloride The title compound was prepared using the product of Step A according to General Procedure E. Physical data were as _{follows: C 20 H 21 N 3 O} 2 HCl (MW = 371.6); mass spectroscopy (MH + free base) 335.

C. Benzodiazepine Derivatives and Related Compounds General Procedure 8-A N-1-Methylation of Benzodiazepines A solution of benzodiazepine (1 equiv.) In DMF at 0 ° C. (0.1 M concentration) was treated with potassium tert-butoxide (1.0 equiv., THF). 1.0 M solution in). After stirring at 0 ° C. for 30 minutes, iodomethane (1.3 equivalents) was added and stirring was continued for 25 minutes.
Continued for minutes. The mixture was diluted with methylene chloride and washed with water and brine. The organic layer was dried over Na ₂ SO _4, filtered, and concentrated. The crude product was then purified by trituration with ether: hexane (1: 1) or chromatographed on HPLC using ethyl acetate / hexane as eluent.

General Procedure 8-B Cbz Removal Procedure Cbz-protected 3-aminobenzodiazepine (1 equivalent) was placed in a flask. To this was added HBr (34 eq; 30% solution in acetic acid). All starting materials dissolved within 20 minutes. The reaction was stirred at room temperature for 5 hours. Ether was added to the orange solution to precipitate HBr.amine salt. This mixture was decanted. This ether addition and decantation step was repeated three times to remove acetic acid and benzyl bromide in an effort. Toluene was added and the mixture was concentrated under reduced pressure. This step was repeated. The HBr salt was partitioned between ethyl acetate and 1M K ₂ CO _3. The aqueous layer was back-extracted with ethyl acetate. The organic layers were combined, washed with brine, dried over Na ₂ SO _4, filtered, and concentrated.

General Procedure 8-C Boc Removal Procedure A solution of a Boc protected amine (1 equivalent) in methylene chloride (0.1 equivalent)
(5M concentration) was cooled to 0 ° C. and treated with trifluoroacetic acid (30 eq). After 10 minutes at 0 ° C., the cooling bath was removed and stirring continued at room temperature for 20 minutes to 1 hour. The mixture was concentrated under reduced pressure to remove excess trifluoroacetic acid. The residue was dissolved in methylene chloride and washed with saturated aqueous NaHCO ₃ or 1M K ₂ CO ₃ and brine. The organic layer was dried over Na ₂ SO _4, filtered, and concentrated.

General Procedure 8-D Azide Transfer Reaction Using KHMDS An azide derivative was prepared using the procedure described in John W. Butcher et al., Tet. Lett., 37, 6685-6688 (1996). .

General Procedure 8-E. Azide Transfer Reaction Using LDA n-Butyllithium (1.6 M in hexane) (1 M) was added to a solution of diisopropylamine (1.1 eq) in .1 eq) were added dropwise while maintaining the reaction temperature at -78 ° C. The reaction mixture was stirred at -78 ° C for 30 minutes, then lactam (0.471 mM) was added dropwise as a solution in 1 mL of dry THF. The reaction mixture was stirred at −78 ° C. for 30 minutes, and was previously cooled,
A solution of trisyl azide (1.2 eq) was added as a solution in 1 mL of dry THF. The reaction mixture was stirred at -78 C for 20 minutes before being quenched with acetic acid (4.0 eq). Then the reaction mixture was stirred at 40 ° C. for 2 hours. The reaction is then
After pouring into tOAc and washing with water, sodium bicarbonate and brine, dried over sodium sulfate, filtered and concentrated. The residue was purified by LC2000 chromatography.

General Procedure 8-F Reduction of Azide Group The azide group was converted to the corresponding primary using the procedure described in John W. Butcher et al., Tet. Lett., 37, 6685-6688 (1996). Reduced to amine.

General Procedure 8-G N-Alkylation of Amides or Lactam Compounds Using Sodium or Potassium tert-Butoxide To a slurry of sodium or potassium tert-butoxide (1.1 eq) in 15 mL of dry DMF , An appropriate amide compound (0.0042 mol)
Added as a solution in 10 mL of F. Then, alkyl iodide was added to obtain a thick slurry. Over time, the thickness of the reaction decreased and the reaction was homogeneous when TLC indicated the reaction was complete. The reaction mixture was poured on ice and extracted with ethyl acetate. The organic layer was washed with water and then with brine. The organic layer was then dried over sodium sulfate, filtered, and concentrated under reduced pressure. HPLC (LC20
00), the residue was purified by elution with an ethyl acetate / hexane system.

General Procedure 8-H N-alkylation of amide or lactam compound using KHMDS
S was added dropwise and the reaction mixture was stirred at -78 C for 30 minutes. Then the temperature was reduced to -70.
The alkyl iodide was added dropwise while maintaining the temperature. The cooling bath was then removed and the reaction was allowed to warm to room temperature, so stirring was continued for 2 hours. Then the reaction mixture was poured onto ice and extracted into ethyl acetate. The organic extract was washed with water and then with brine. The organic layer was then dried over sodium sulfate, filtered, and concentrated under reduced pressure. HPLC (LC
2000), and the residue was purified by elution with an ethyl acetate / hexane system.

General Procedure 8-I N-Alkylation of Amide or Lactam Compound Using Cesium Carbonate To a solution of the amide or lactam compound in DMF was added cesium carbonate (1.05 equivalents) and alkyl iodide (1.1 equivalents). ) Was added. After stirring the mixture at room temperature overnight, the reaction mixture was diluted with ethyl acetate and washed with water and then brine. The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure. HPLC (
LC2000), eluting with an ethyl acetate / hexane system and purifying the residue.

General Procedure 8-J Boc Removal Procedure To the N-Boc protected compound was added 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, washed with water, saturated sodium bicarbonate, dried over Na ₂ SO _4, filtered to give the free amine compound and concentrated.

General Procedure 8-K Azide Transfer Procedure This azide transfer procedure is described in Evans, DA; Britton, TC; Ellman, JA; D
orow, RLJ Am. Chem. Soc. 1990, 112, 4011-4030. Under N _2, to a solution of -78 ° C. lactam substrates in THF (1.0 eq) (~0.1M), KN (TMS ) 2 ( in toluene 0.5M, 1.1 eq, Aldri
The solution of ch) was added dropwise over 2-10 minutes. A slight exotherm was often observed on the internal thermometer, and the resulting solution was re-cooled to -78 ° C with stirring for 5-15 minutes. Then trisyl azide (1.1-1.5 equivalents, CAS No. 36982-84-0, pre-cooled to -78 ° C in THF at room temperature, as described in the Evans literature reference above). (As prepared) (） 0.5M) was added via cannula over 0.5-5 minutes. Generally, a slight exotherm occurred again.
The resulting solution was re-cooled to -78 C with stirring for 5-10 minutes. Then Ac
OH (4.5-4.6 equivalents, glacial acetic acid) was added, the cooling bath was removed and the mixture was added to 12-
The mixture was warmed to room temperature with stirring for 16 hours. The mixture is diluted with 2-5 volumes of the initial THF volume of EtOAc, diluted aqueous NaHCO ₃ (1-2 ×), 0 ×
. Washed with 1-1.0 M aqueous HCl (0-2 ×) and brine (1 ×). The organic layer was then dried over MgSO _4, filtered to give the crude product were concentrated.

General Procedure 8-L Reduction of Azide to Amine Compound Azide (0.03-0.07M) in anhydrous EtOH and 10% Pd / C (
The mixture of azide weight of ~ 1/3), in a Parr apparatus, H ₂ (35~45psi)
Shake 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 Procedure 8-M Alkylation of Amide Compounds Using Cesium Carbonate This procedure is described in Claremon, DA; et al. PCT Application No. WO 96-US840.
This is a modification of the technique described in US Pat. No. 0,960,603. A mixture of 2,4-dioxo-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine (CAS No. 49799-48-6) in DMF at room temperature under N ₂ (1.0 eq.
0.7M), Cs ₂ CO ₃ (2.2 equivalents) and a suitable alkyl halide (2.
2 eq.). The mixture was stirred at room temperature for 5.5-16 hours. Mixtures with E
Partitioned between tOAc and saturated NaHCO ₃ . The aqueous layer was extracted with EtOAc (1-2 ×) and the combined EtOAc extracts were dried over Na ₂ SO ₄ , filtered and concentrated to give the crude product.

General Procedure 8-N BOC Removal Procedure A stirred solution of Nt-Boc protected amino acid (0.03-0.09 M) in 1,4-dioxane cooled to −10 ° C. in an ice bath under N _2. ), A stream of anhydrous HCl was applied to 10-1.
Passed for 5 minutes. The solution was capped, the cooling bath was removed, and the solution was allowed to warm to room temperature with stirring for 2-8 hours, so TLC monitored the consumption of starting material. The solution is concentrated (optionally dissolved in CH ₂ Cl ₂ and then re-concentrated at 60-70 ° C.
In a vacuum oven to remove most of the remaining dioxane) and used without further purification.

Example 8-A Synthesis of 3-Amino-1,3-dihydro-5- (1-piperidinyl) -2H-1,4-benzodiazepin-2-one Step A- 1,2-Dihydro-3H- 1-methyl-5- (1-piperidinyl)-
Preparation of 1,4-benzodiazepin-2-one A solution of phosphorus pentachloride (1.2 equivalents) in methylene chloride is prepared by adding 1-methyl-1,2,3,4-tetrahydro-3H-1,4 in methylene chloride. -Benzodiazepine-2,5-dione (Showell, GA; Bourrain, S .; Neduvelil, JG; Fletc
her, SR; Baker, R .; Watt, AP; Fletcher, AE; Freedman, SB; Ke
mp, JA; Marshall, GR; Patel, S .; Smith, AJ; Matassa, VGJ
Med. Chem. 1994, 37, 719). The resulting yellowish orange solution was stirred at room temperature for 2.5 hours; the solvent was removed under reduced pressure. The orange residue was redissolved in methylene chloride, cooled to 0 ° C. and treated with a solution of piperidine (2 eq) and triethylamine (2 eq) in methylene chloride. The cooling bath was removed and the reaction was stirred for 18 hours. The reaction mixture was washed with a saturated aqueous solution of NaHCO ₃ (back extracted with methylene chloride) and washed with brine. Organic layer N
Dried over a ₂ SO ₄ , filtered and concentrated. The residue was purified by HPLC, eluting with a 4-10% gradient of methanol / methylene chloride, to give the title intermediate:
Obtained as a yellow solid with a melting point of 103-105 ° C. _{C 15 H 19 N 3 O (} MW257.37); mass spectroscopy 257. Elemental analysis (C ₁₅ H ₁₉ as N ₃ O); Calculated: 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-oximid-5- (1-
Preparation of 1,2-Dihydro-3H-1-methyl-3-oximido-5- (1-piperidinyl) -1,4
-benzodiazepin-2-one) 1,2-dihydro-3H-1-methyl-5- (1-piperidinyl) in toluene
To a solution of -1,4-benzodiazepin-2-one (1 equivalent) at -20 ° C was added potassium te.
rt-butoxide (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, at which point the reaction was complete according to 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 room temperature, then filtered,
Washed with ether. The resulting cream colored solid had a melting point of 197-200 ° C. ¹ H NMR data for the E / Z isomer were as follows: ¹ H NMR (300 MHz, CDCl ₃ ): δ = 7.64 (1H, bs), 7.48
(2H, d, J = 7.4 Hz), 7.35-7.20 (6H, m), 6.75 (1H, bs)
3.8-3.2 (8H, m), 3.46 (3H, s), 3.42 (3H, s), 1.90-1
.40 (12H, m). _{C 15 H 18 N 4 O 2} (MW = 286.37); mass spectroscopy 286.

Step C- 1,2-Dihydro-3H-1-methyl-3- [O- (ethylaminocarbonyl) oxymido] -5- (1-piperidinyl) -1,4-benzodiazepine-
Preparation of 2-one 1,2-dihydro-3H-1-methyl-3-oximid-5- (1-
A mixture of (piperidinyl) -1,4-benzodiazepin-2-one (1 eq) was treated with ethyl isocyanate (1.7 eq) and triethylamine (0.6 eq). The mixture was heated to 64 ° C. for 4 hours. The mixture is concentrated and the residue is
Purified by HPLC, eluting with 5% methanol / methylene chloride. ¹ H NMR data for the E / Z isomer were as follows: ¹ H NMR (300 MHz, CDCl ₃ ): δ = 7.50 (2H, dd, J = 8.4,
1.5Hz), 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), 3.2
5 (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—Preparation of 3-Amino-1,3-dihydro-2H-1-methyl-5- (1-piperidinyl) -1,4-benzodiazepin-2-one 1,2-dihydro-3H-1 -Methyl-3- [O- (ethylaminocarbonyl) oxymido] -5- (1-piperidinyl) -1,4-benzodiazepin-2-one (1
Catalyzed with 5% palladium on carbon (0.15 eq) in methanol to give 4
Hydrogenated at 3 psi for 3.25 hours. The reaction was filtered through celite and concentrated under reduced pressure. The residue was taken up in methylene chloride and filtered a second time through celite. The filtrate was concentrated, and the obtained foam was used as it was.

Example 8-B Synthesis of 3- (L-alaninyl) -amino-2,3-dihydro-1-methyl-5-phenyl-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; Grabowski, EJJJ Org.
Chem. 1987, 52, 955, 3-amino-1,3-dihydro-1-methyl-5-phenyl-2H-1,4-benzodiazepin-2-one (Bock MG; DiP
ardo, RM; Evans, BE; Rittle, KE; Veber, DF; Freidinger, R. M
The title intermediate was prepared using Hirshfield, J .; Springer, JPJ Org. Chem. 1987, 52, 3232.) as the starting material.

Step B- 3- [N '-(tert-butylcarbamate) -L-alaninyl] -amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepine-2- Preparation of ON (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 by partitioning between methylene chloride and 1M potassium carbonate Free base. The free amine compound was then coupled with N-Boc-alanine according to General Procedure D. _{C 24 H 28 N 4 O 4} (MW = 436.56); mass spectroscopy 436. Elemental analysis (C ₂₄ H ₂₈ N ₄ as O _4); Calculated: 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-
Preparation of 5-phenyl-1H-1,4-benzodiazepin-2-one Following general procedure 8-C, 3- [N ′-(tert-butylcarbamate) -L-
[Alaninyl] -amino-2,3-dihydro-1-methyl-5-phenyl-1H-1
The title compound was prepared as a white foam using, 4-benzodiazepin-2-one. Elemental analysis (C ₁₉ H ₁₉ N ₄ as O _2); Calculated: C, 69.21; H, 6.64 ; N,
15.37. Found: C, 70.11; H, 6.85; N, 15.01.

Example 8-C 3- (L-alaninyl) -amino-7-chloro-2,3-dihydro-1-methyl-
Synthesis of 5-phenyl-1H-1,4-benzodiazepin-2-one Step A-3- (benzyloxycarbonyl) -amino-7-chloro-2,3-
Dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepine-2-
Preparation of ON 3- (benzyloxycarbonyl) -amino-7-chloro-2,3- in DMF
A solution of dihydro-5-phenyl-1H-1,4-benzodiazepin-2-one (1 equivalent; Neosystem) was cooled to 0 ° C. and potassium tert-butoxide (1 equivalent; T
(1.0 M solution in HF). The resulting yellow solution was stirred at 0 ° C. for 30 minutes before being quenched with methyl iodide (1.3 eq). After stirring for an additional 25 minutes, the reaction was diluted with methylene chloride 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 (eluting with a 20 → 30% gradient of ethyl acetate / hexane). _{C 24 H 20 ClN 3 O 3} (MW = 433.92); mass spectroscopy 433. Elemental analysis (C ₂₄ H ₂₀ ClN ₃ as O _3); Calculated: C, 66.44; H, 4.65
N, 9.68. Found: C, 66.16; H, 4.50; N, 9.46.

Step B—Preparation of 3-Amino-7-chloro-1,3-dihydro-1-methyl-5-phenyl-2H-1,4-benzodiazepin-2-one According to general procedure 8-B, 3- (benzyloxycarbonyl) -amino-7
The title intermediate was prepared as a white foam using -chloro-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one, which was used as is in Step C. .

Step C- 3- [N'-tert-butylcarbamate) -L-alaninyl] -amino-7-chloro-1,3-dihydro-1-methyl-5-phenyl-2H-1,4-benzodiazepine Preparation of -2-one According to general procedure D, N-Boc-L-alanine and 3-amino-7-
The title intermediate was prepared as a white foam using chloro-1,3-dihydro-1-methyl-5-phenyl-2H-1,4-benzodiazepin-2-one. C ₂₄ H ₂₈ ClN ₄ O ₄ (MW = 471.18); mass spectrum analysis 471 elemental analysis (as C ₂₄ H ₂₈ ClN ₄ O ₄ ); calculated values: C, 61.21; H, 5.78
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
Preparation of -methyl-5-phenyl-2H-1,4-benzodiazepin-2-one According to general procedure 8-C, 3- [N'-tert-butylcarbamate) -L-
The title intermediate was prepared as a white foam using [alaninyl] -amino-7-chloro-1,3-dihydro-1-methyl-5-phenyl-2H-1,4-benzodiazepin-2-one. The crude material was used as is.

Example 8-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-
Preparation of dihydro-1-methyl-5- (2-fluorophenyl) -1H-1,4-benzodiazepin-2-one 3- (benzyloxycarbonyl) -amino-7 according to general procedure 8-A.
The title intermediate was prepared as a white foam using -bromo-2,3-dihydro-5- (2-fluorophenyl) -1H-1,4-benzodiazepin-2-one (Neosystem). _{C 24 H 19 BrFN 3 O 3} (MW = 496.36); mass spectroscopy 497. Elemental analysis (C ₂₄ H ₁₉ as BrFN ₃ O _3); Calculated: C, 58.08; H, 3.8
6; 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 according to general procedure 8-B.
-Bromo-2,3-dihydro-1-methyl-5- (2-fluorophenyl) -1H
The title intermediate was prepared as a white foam using -1,4-benzodiazepin-2-one and used directly in Step C.

Step C- 3- [N '-(tert-butylcarbamate) -L-alaninyl] -amino-7-bromo-1,3-dihydro-1-methyl-5- (2-fluorophenyl)
Preparation of -2H-1,4-benzodiazepin-2-one According to general procedure D, N-Boc-L-alanine (Novo) and 3-amino-7-bromo-1,3-dihydro-1-methyl- 5- (2-fluorophenyl)
The title intermediate was prepared as a white foam using -2H-1,4-benzodiazepin-2-one. _{C 24 H 26 BrFN 4 O 4} (MW = 533.12); mass spectroscopy 533.2
. Elemental analysis (C ₂₄ H ₂₆ BrFN ₄ as O _4); Calculated: C, 54.04; H, 4.91
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-
Preparation of 2-one According to general procedure 8-C, 3- [N '-(tert-butylcarbamate) -L-
[Alaninyl] -amino-7-bromo-1,3-dihydro-1-methyl-5- (2-
The title intermediate was prepared as a white foam using (fluorophenyl) -2H-1,4-benzodiazepin-2-one. The crude material was used as is.

Example 8-E 3- (N′-methyl-L-alaninyl) -amino-2,3-dihydro-1-methyl-
Synthesis of 5-phenyl-1H-1,4-benzodiazepin-2-one Step A-3- [N '-(tert-butylcarbamate) -N'-methyl-L-alaninyl] -amino-2,3-dihydro -1-methyl-5-phenyl-1H-1,4
Preparation of -benzodiazepin-2-one According to general procedure D, (S) -3-amino-1,3-dihydro-1-methyl-5-phenyl-2H-1,4-benzodiazepin-2-one (implemented Example 8-B)
And N-tert-Boc-N-methyl-alanine (Sigma) provided the title intermediate as a white solid. _{C 25 H 30 N 4 O 4} (MW = 450.2); mass spectroscopy (M + 1) 451.
2. Elemental analysis (C ₂₅ H ₃₀ N ₄ as O _4); Calculated: C, 66.65; H, 6.71 ; N,
12.44. Found: C, 66.66; H, 6.89; N, 12.21.

Step A- 3- (N'-methyl-L-alaninyl) -amino-2,3-dihydro-
Preparation of 1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one According to general procedure 8-C, 3- [N ′-(tert-butylcarbamate) -N ′
The title intermediate was prepared as a white foam using -methyl-L-alaninyl] -amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one. _{C 20 H 22 N 4 O 2} (MW = 350.46); mass spectroscopy (M + 1) 351
.4. Elemental analysis (C ₂₀ as H ₂₂ N ₄ O _2); Calculated: C, 68.55; H, 6.33 ; N,
15.99. Found: C, 68.36; H, 6.20; N, 15.79.

Example 8-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-
Preparation of dihydro-1-methyl-5- (2-chlorophenyl) -1H-1,4-benzodiazepin-2-one According to general procedure 8-A, 3- (benzyloxycarbonyl) -amino-7
Prepare the title intermediate as a white solid, mp 232-233 ° C, using -chloro-2,3-dihydro-5- (2-chlorophenyl) -1H-1,4-benzodiazepin-2-one (Neosystem). did. _{C 24 H 19 Cl 2 N 3} O 3 (MW = 468.36); mass spectroscopy 468. ¹ H NMR (300 MHz, CDCl ₃ ): δ = 7.67 (1H, m), 7.52 (1
H, dd, J = 2.4,8.7 Hz), 7.42-7.26 (9H, m), 7.07 (1H, d
, J = 2.4 Hz), 6.70 (1H, d, J = 8.3 Hz), 5.35 (1H, d, J = 8.3 Hz).
4 Hz), 5.14 (2H, ABq, J = 19.6 Hz), 3.47 (3H, s). ¹³ C NMR (75 MHz, CDCl ₃ ); δ = 166.66, 165.65, 155
.72,140.52,136.99,136.0,132.87,131.99,131.
47, 131.40, 131.38, 131.16, 130.54, 130.06, 128.
45,128.08,128.03,127.72,127.22,123.28,122.
01,68.95,67.02,35.32.

Step B- 3-Amino-7-chloro-1,3-dihydro-1-methyl-5- (2
Preparation of-(chlorophenyl) -2H-1,4-benzodiazepin-2-one 3- (benzyloxycarbonyl) -amino-7 according to general procedure 8-B.
-Chloro-2,3-dihydro-1-methyl-5- (2-chlorophenyl) -1H-
The title intermediate was prepared as a white foam using 1,4-benzodiazepin-2-one and used directly in Step C.

Step C- 3- [N '-(tert-butylcarbamate) -L-alaninyl] -amino-7-chloro-1,3-dihydro-1-methyl-5- (2-chlorophenyl)-
Preparation of 2H-1,4-benzodiazepin-2-one According to general procedure D, N-Boc-L-alanine and 3-amino-7-
Chloro-1,3-dihydro-1-methyl-5- (2-chlorophenyl) -2H-1,
The title intermediate was prepared as a white foam using 4-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
Preparation of -one 3- [N '-(tert-butylcarbamate) -L-
[Alaninyl] -amino-7-chloro-1,3-dihydro-1-methyl-5- (2-
The title intermediate was prepared as a white foam using (chlorophenyl) -2H-1,4-benzodiazepin-2-one. The crude material was used as is.

Example 8-G Synthesis of 3- (L-alaninyl) amino-5-cyclohexyl-2,3-dihydro-1-methyl-1H-1,4-benzodiazepin-2-one Step A-3- ( (Benzyloxycarbonyl) -amino-5-cyclohexyl-
Preparation of 2,3-dihydro-1-methyl-1H-1,4-benzodiazepin-2-one Following general procedure 8-A, 3- (benzyloxycarbonyl) -amino-5
The title intermediate was prepared using -cyclohexyl-2,3-dihydro-1H-1,4-benzodiazepin-2-one (Neosystem) as a white solid, mp 205-206 ° C. _{C 24 H 27 N 3 O 3} (MW = 405.54); mass spectroscopy 405. ¹ H NMR (300 MHz, CDCl ₃ ): δ = 7.54 (1 H, d, J = 7.9 H)
z), 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, A
Bq, J = 17.1 Hz), 3.39 (3H, s), 2.77 (1H, m), 2.01 (1
H, bd, J = 13.6 Hz), 1.85 (1H, bd, J = 12.4 Hz), 1.66-1
.49 (4H, m), 1.34-1.02 (4H, m).

Step B—Preparation of 3-Amino-5-cyclohexyl-1,3-dihydro-1-methyl-2H-1,4-benzodiazepin-2-one According to general procedure 8-B, 3- (benzyloxycarbonyl) -amino-5
The title intermediate was prepared as a white foam using -cyclohexyl-2,3-dihydro-1-methyl-1H-1,4-benzodiazepin-2-one, which was used directly in Step C. C ₁₆ H ₂₁ N ₃ O (MW + H = 272.1763); mass spectrum analysis 272.1
766.

Step C- 3- [N '-(tert-butylcarbamate) -L-alaninyl] -amino-5-cyclohexyl-1,3-dihydro-1-methyl-2H-1,4-benzodiazepine-2- Preparation of ON According to general procedure D, N-Boc-L-alanine and 3-amino-5-
The title intermediate was prepared as a white foam using cyclohexyl-1,3-dihydro-1-methyl-2H-1,4-benzodiazepin-2-one. _{C 24 H 34 N 4 O 4} (MW = 442.62); mass spectroscopy (M + H) 443
.2.

Step D—Preparation of 3- (L-alaninyl) amino-5-cyclohexyl-1,3-dihydro-1-methyl-2H-1,4-benzodiazepin-2-one According to General Procedure 8-C , 3- [N '-(tert-butylcarbamate) -L-
[Alaninyl] -amino-5-cyclohexyl-1,3-dihydro-1-methyl-2
The title intermediate was prepared as a white foam using H-1,4-benzodiazepin-2-one. The crude material was used as is. _{C 19 H 26 N 4 O 2} (M + H = 343.2136); mass spectroscopy Found 3
43.2139.

Example 8-H 3- (L-alaninyl) amino-2,3-dihydro-1-methyl-7-nitro-5
Synthesis of -phenyl-1H-1,4-benzodiazepin-2-one Step A Preparation of 2- [N- (α-isopropylthio) -N ′-(benzyloxycarbonyl) -glycinyl] -amino-5-nitrobenzophenone A solution of α- (isopropylthio) -N- (benzyloxycarbonyl) glycine (1 equivalent; prepared according to Zoller, V .; Ben-Ishai, D. Tetrahedron 1975, 31, 863.) in dry THF at 0 ° C. Oxalyl chloride (1 equivalent)
And 3 drops of DMF. After stirring at 0 ° C. for 15 minutes, the cooling bath was removed and stirring continued at room temperature for 40 minutes. The solution was cooled back to 0 ° C. 2- in dry THF
A solution of amino-5-nitrobenzophenone (0.9 eq; Acros) and 4-methylmorpholine (2.0 eq) was cannulated to the acid chloride compound.
The cooling bath was removed and the reaction was stirred at room temperature for 5 hours. The reaction was diluted with methylene chloride and washed with 0.5 M citric acid, saturated aqueous NaHCO ₃ and brine. The organic phase was dried over Na ₂ SO _4, filtered, and concentrated. The residue was prepared by LC20
Purification by 00 (eluting with a 15 → 20% gradient of ethyl acetate / hexane) gave an off-white foam. _{C 26 H 25 N 3 O 6} S (MW = 507.61); mass spectroscopy Found 507
.9. Elemental analysis (C ₂₆ H ₂₅ N ₃ O as ₆ S); Calculated: C, 61.53; H, 4.96 ;
N, 8.28. Found: C, 61.70; H, 4.99; N, 8.22.

Step B—Preparation of 2- [N- (α-amino) -N ′-(benzyloxycarbonyl) -glycinyl] -amino-5-nitrobenzophenone 2- [N- (α) in THF at 0 ° C. Ammonia gas was bubbled through a solution of -isopropylthio) -N '-(benzyloxycarbonyl) -glycinyl] -amino-5-nitrobenzophenone (1 equivalent). After 35 minutes, mercury (II) chloride (1.1 equivalent)
Was added. The ice bath was removed and the suspension was bubbled with ammonia gas for 4 hours. The bubble device was removed and the reaction continued to stir for 16 hours. The mixture was filtered through celite and washed with THF. The filtrate was concentrated under reduced pressure. In step C,
The crude solid was used without further purification.

Step C- 3- (benzyloxycarbonyl) -amino-2,3-dihydro-7
Production of -nitro-5-phenyl-1H-1,4-benzodiazepin-2-one 2- [N- (α-amino) -N ′-(benzyloxycarbonyl) -glycinyl]-
Amino-5-nitrobenzophenone (1 eq) was treated with glacial acetic acid and ammonium acetate (4.7 eq). The suspension was stirred at room temperature for 21 hours. After concentrating the reaction under reduced pressure, the residue was partitioned between ethyl acetate and 1N NaOH. The aqueous layer was back-extracted with ethyl acetate. Combine the organic layers, wash with brine, dry over Na ₂ SO ₄ ,
Filtered and concentrated. The residue was purified by flash chromatography (eluting with a 2 → 3% gradient of isopropyl alcohol / methylene chloride). C ₂₃ H ₁₈ N ₄ O ₅ (MW = 430.45); Mass spectrum analysis Actual value (M + H
) 431.2. Elemental analysis (C ₂₃ H ₁₈ N ₄ as O _5); Calculated: 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-benzodiazepine-2-
Preparation of 3- (benzyloxycarbonyl) -amino-2 according to general procedure 8-A.
, 3-Dihydro-7-nitro-5-phenyl-1H-1,4-benzodiazepine-
The title intermediate was prepared as a yellow foam using 2-one. C ₂₄ H ₂₀ N ₄ O ₅ (MW = 444.48); Mass spectrum analysis Actual value (M + H
) 445.2. Elemental analysis (C ₂₄ H ₂₀ N ₄ as O _5); Calculated: C, 64.86; H, 4.54 ; N,
12.60. Found: C, 65.07; H, 4.55; N, 12.46.

Step E—Preparation of 3-Amino-1,3-dihydro-1-methyl-7-nitro-5-phenyl-2H-1,4-benzodiazepin-2-one According to general procedure 8-B, 3- (benzyloxycarbonyl) -amino-2
The title intermediate was prepared as a yellow foam using 2,3-dihydro-1-methyl-7-nitro-5-phenyl-1H-1,4-benzodiazepin-2-one, which was used as such in Step F. .

Step F-3- [N '-(tert-butylcarbamate) -L-alaninyl] -amino-2,3-dihydro-1-methyl-7-nitro-5-phenyl-1H-1,4-
Preparation of Benzodiazepin-2-one According to general procedure D, N-Boc-L-alanine and 3-amino-1,
The title intermediate was prepared as a yellow solid using 3-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 spectrum analysis Actual value (M + H
) 482.3. Elemental analysis (C ₂₄ H ₂₇ N ₅ as O _6); Calculated: 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-
Preparation of 7-nitro-5-phenyl-1H-1,4-benzodiazepin-2-one Following general procedure 8-C, 3- [N ′-(tert-butylcarbamate) -L-
The title intermediate was prepared as a yellow foam using [alaninyl] -amino-2,3-dihydro-1-methyl-7-nitro-5-phenyl-1H-1,4-benzodiazepin-2-one. The crude material was used as is.

Example 8-I Synthesis of 3- (L-alaninyl) amino-2,3-dihydro-1-methyl-5- (2-fluorophenyl) -1H-1,4-benzodiazepin-2-one A-Production of 3-amino-1,3-dihydro-1-methyl-5- (2-fluorophenyl) -2H-1,4-benzodiazepin-2-one 3- (benzyloxycarbonyl) -amino-7- Bromo-2,3-dihydro-
1-methyl-5- (2-fluorophenyl) -1H-1,4-benzodiazepine
The 2-one (1 equivalent; Example 8-D, Step A) and 10% palladium-carbon were charged to the flask. Methanol was added, the flask was placed in a balloon (balloon) under H _2. The reaction was stirred for 21 hours. The mixture was filtered through celite and washed with methanol. The filtrate was concentrated to a white solid. C ₁₆ H ₁₄ FN ₃ O (MW = 283.33); mass spectrum analysis measured value (M + H
) 284.1.

Step B- 3- [N '-(tert-butylcarbamate) -L-alaninyl] -amino-1,3-dihydro-1-methyl-5- (2-fluorophenyl) -2H-1,4
Preparation of -benzodiazepin-2-one According to general procedure D, N-Boc-L-alanine and 3-amino-1,
The title intermediate was obtained as a white solid using 3-dihydro-1-methyl-5- (2-fluorophenyl) -2H-1,4-benzodiazepin-2-one. C ₂₄ H ₂₇ FN ₄ O ₄ (MW = 454.50); Mass spectrum analysis Actual value (M +
H) 455.4. Elemental analysis (C ₂₄ as H ₂₇ FN ₄ O _4); Calculated: 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-
Preparation of 2-one According to general procedure 8-C, 3- [N '-(tert-butylcarbamate) -L-
The title intermediate was prepared as a white foam using [alaninyl] -amino-1,3-dihydro-1-methyl-5- (2-fluorophenyl) -2H-1,4-benzodiazepin-2-one. The crude material was used as is.

Example 8-J Synthesis of 3- (L-alaninyl) -amino-2,3-dihydro-1-methyl-5- (3-fluorophenyl) -1H-1,4-benzodiazepin-2-one Step A—Preparation of 2-Amino-3′-fluorobenzophenone A solution of 3-bromofluorobenzene (1 equivalent) in THF was added under nitrogen at −78.
C. and cooled at a rate of 40 mL / hr of tert-butyllithium (2.05 equivalents,
(1.6 M solution in pentane). The internal temperature did not rise above -74 ° C. After stirring the orange solution at −78 ° C. for 30 minutes, anthranilonitrile (
anthranilonitrile, 0.6 eq.) was added as a solution in THF. Reactant 0
The mixture was stirred for 2 hours. 3N HCl was added to the mixture and stirring was continued for 30 minutes.
Continued for minutes. The reaction was diluted with ethyl acetate and the layers were separated. The aqueous layer was back extracted three times with ethyl acetate. The combined extracts were washed with brine, dried over Na ₂ SO _4, filtered, and concentrated. The residue was subjected to HPLC (hexane / ethyl acetate (93: 7)
(Eluted with). C ₁₃ H ₁₀ FNO (MW = 215.24); Mass spectrum analysis Actual value (M + H
) 216.3. _{^{1 H NMR (300MHz, CDCl 3}} ) d 7.44-7.19 (6H, m), 6.
74 (1H, dd, J = 8.0 Hz), 6.61 (1H, dd, J = 0.94, 7.9 Hz),
6.10 (2H, bs).

Step B—Preparation of 2- [N- (α-isopropylthio) -N ′-(benzyloxycarbonyl) -glycinyl] -amino-3′-fluorobenzophenone α- (isopropylthio)-in dry THF A solution of N- (benzyloxycarbonyl) glycine (1 equivalent; produced according to Zoller, V, Ben-Ishai, D. Tetrahedron 1975, 31, 863.) is cooled to 0 ° C and oxalyl chloride (1 equivalent).
And 3 drops of DMF. After stirring at 0 ° C. for 15 minutes, the cooling bath was removed and stirring continued at room temperature for 40 minutes. The solution was cooled back to 0 ° C. 2- in dry THF
A solution of amino-3'-fluorobenzophenone (0.9 eq) and 4-methylmorpholine (2.0 eq) was added to the acid chloride compound via cannula. The cooling bath was removed and the reaction was stirred at room temperature for 5 hours. The reaction was diluted with methylene chloride and washed with 0.5 M citric acid, saturated aqueous NaHCO ₃ and brine.
The organic phase was dried over Na ₂ SO _4, filtered, and concentrated. Preparing the residue with LC2000
(Eluted with a 15 → 20% gradient of ethyl acetate / hexane) to give an off-white foam. C ₂₆ H ₂₅ N ₂ O ₄ S (MW = 480.60); mass spectrum analysis measured value (M +
NH ₄ ⁺⁾ 498.3. ¹ H NMR (300 MHz, CDCl ₃ ) d 11.39 (1 H, s), 8.59 (1
H, 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), 5.94 (1H, d, J = 7.2H)
z), 5.58 (1H, d, J = 8.7 Hz), 5.17 (2H, ABq, J = 14.7H)
z), 3.25 (1H, sep, J = 6.6 Hz), 1.44 (3H, d, J = 6.0 Hz), 1
.28 (3H, d, J = 6.6 Hz).

Step C—Preparation of 2- [N- (α-amino) -N ′-(benzyloxycarbonyl) -glycinyl] -amino-3′-fluorobenzophenone 2- [N- ( α-Isopropylthio) -N ′-(benzyloxycarbonyl) -glycinyl] -amino-3′-fluorobenzophenone (1 equivalent)
Ammonia gas was bubbled into the above solution. After 35 minutes, mercury (II) chloride (1.1)
Equivalent). The ice bath was removed and the suspension was bubbled with ammonia gas for 4 hours. The bubbler was removed and the reaction continued to stir for 16 hours. The mixture was filtered through celite and washed with THF. The filtrate was concentrated under reduced pressure. The crude solid was used in Step D without further purification.

Step D-3- (benzyloxycarbonyl) -amino-2,3-dihydro-5
Preparation of-(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 room temperature for 21 hours. After concentrating the reaction under reduced pressure, the residue was partitioned between ethyl acetate and 1N NaOH. The aqueous layer was back-extracted with ethyl acetate. The organic layers were combined, washed with brine, dried over Na ₂ SO _4, filtered, and concentrated. The residue was purified by flash chromatography (eluting with a 2 → 3% gradient of isopropyl alcohol / methylene chloride). C ₂₃ H ₁₈ FN ₃ O ₃ (MW = 403.44); mass spectrum analysis measured value (M +
H) 404.4. Elemental analysis _{(C 23 H 18 FN 3 O} 3 · 0.5H as ₂ O); Calculated: 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
Preparation of 3-one 3- (benzyloxycarbonyl) -amino-2 according to general procedure 8-A.
The title intermediate was prepared as a yellow foam using 2,3-dihydro-5- (3-fluorophenyl) -1H-1,4-benzodiazepin-2-one. C ₂₄ H ₂₀ FN ₃ O ₃ (MW = 417.47); Mass spectrum analysis Actual value (M +
H) 418.3. Elemental analysis (as _{C 24 H 20 FN 3 O 3} ); Calculated: C, 69.06; H, 4.83 ;
N, 10.07. Found: C, 69.33; H, 4.95; N, 9.82.

Step F—Preparation of 3-Amino-1,3-dihydro-1-methyl-5- (3-fluorophenyl) -2H-1,4-benzodiazepin-2-one According to General Procedure 8-B , 3- (benzyloxycarbonyl) -amino-2
The title intermediate was prepared as a yellow foam using, 3-dihydro-1-methyl-5- (3-fluorophenyl) -1H-1,4-benzodiazepin-2-one and used directly in Step G.

Step G- 3- [N '-(tert-butylcarbamate) -L-alaninyl] -amino-2,3-dihydro-1-methyl-5- (3-fluorophenyl) -1H-1,4
Preparation of -benzodiazepin-2-one According to general procedure D, N-Boc-L-alanine and 3-amino-1,
The title intermediate was prepared as a yellow solid using 3-dihydro-1-methyl-5- (3-fluorophenyl) -2H-1,4-benzodiazepin-2-one. C ₂₄ H ₂₇ FN ₄ O ₄ (MW = 454.50); Mass spectrum analysis Actual value (M +
H) 455.3. Elemental analysis (C ₂₄ H ₂₇ FN ₄ as O _4); Calculated: 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-
Preparation of 5- (3-fluorophenyl) -1H-1,4-benzodiazepin-2-one According to general procedure 8-C, 3- [N ′-(tert-butylcarbamate) -L-
The title intermediate was prepared as a yellow foam using [alaninyl] -amino-2,3-dihydro-1-methyl-5- (3-fluorophenyl) -1H-1,4-benzodiazepin-2-one. The crude material was used as is.

Example 8-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 solution of 4-bromofluorobenzene (1 equivalent) in THF was added under nitrogen at -78.
C. and cooled to tert-butyllithium (2.05 eq, 1.6 M solution in pentane)
At a rate of 40 mL / hour. The internal temperature did not rise above -74 ° C. The organic solution was stirred at −78 ° C. for 30 minutes, and acetonitrile (0.6 equivalent) was added to TH.
Added as a solution in F. The reaction was warmed 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 layers were separated. The aqueous layer was back 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 H
Purified by PLC (eluted with hexane / ethyl acetate (93: 7)). C ₁₃ H ₁₀ FNO (MW = 215.24); Mass spectrum analysis Actual value (M + H
) 216.3. Elemental analysis (C ₁₃ H ₁₀ as FNO); Calculated: C, 72.55; H, 4.68 ; N,
6.51. Found: C, 72.80; H, 4.51; N, 6.74.

Step B—Preparation of 2- [N- (α-isopropylthio) -N ′-(benzyloxycarbonyl) -glycinyl] -amino-4′-fluorobenzophenone α- (isopropylthio)-in dry THF A solution of N- (benzyloxycarbonyl) glycine (1 equivalent; prepared according to Zoller, V .; Ben-Ishai, D. Tetrahedron 1975, 31, 863.) is cooled to 0 ° C and oxalyl chloride (1 equivalent).
And 3 drops of DMF. After stirring at 0 ° C. for 15 minutes, the cooling bath was removed and stirring continued at room 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 compound via cannula.
The cooling bath was removed and the reaction was stirred at room temperature for 5 hours. The reaction was diluted with methylene chloride and washed with 0.5M citric acid, saturated aqueous NaHCO ₃ and brine. The organic layer was dried over Na ₂ SO _4, filtered, and concentrated. Preparative LC for residue
Purification by 2000 (eluting with a 15 → 20% gradient of ethyl acetate / hexane) gave an off-white foam. C ₂₆ H ₂₅ N ₂ O ₄ S (MW = 480.60); mass spectrum analysis measured value (M +
NH ₄ ⁺⁾ 498.2. ¹ H NMR (300 MHz, CDCl ₃ ) d 11.28 (1 H, s), 8.56 (1
H, 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 (3H, m), 5.98 (1H,
d, J = 7.5 Hz), 5.57 (1H, d, J = 7.8 Hz), 5.16 (2H, ABq,
J = 14.7 Hz), 3.25 (1 H, sep, J = 6.0 Hz), 1.43 (3 H, d, J
= 6.3 Hz), 1.27 (3H, d, J = 6.6 Hz).

Step C—Preparation of 2- [N- (α-amino) -N ′-(benzyloxycarbonyl) -glycinyl] -amino-4′-fluorobenzophenone 2- [N- ( α-Isopropylthio) -N ′-(benzyloxycarbonyl) -glycinyl] -amino-3′-fluorobenzophenone (1 equivalent)
Ammonia gas was bubbled into the above solution. After 35 minutes, mercury (II) chloride (1.1)
Equivalent). The ice bath was removed and the suspension was bubbled with ammonia gas for 4 hours. The bubble device was removed and the reaction continued to stir for 16 hours. The mixture was filtered through celite and washed with THF. The filtrate was concentrated under reduced pressure. The crude solid was used in Step D without further purification.

Step D- 3- (benzyloxycarbonyl) amino-2,3-dihydro-5- (
Preparation of 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 room temperature for 21 hours. After concentrating the reaction under reduced pressure, the residue was partitioned between ethyl acetate and 1N NaOH. The aqueous layer was back-extracted with ethyl acetate. The organic layers were combined, washed with brine, dried over Na ₂ SO _4, filtered, and concentrated. The residue was purified by flash chromatography (eluting with a 2 → 3% gradient of isopropyl alcohol / methylene chloride). C ₂₃ H ₁₈ FN ₃ O ₃ (MW = 403.44); mass spectrum analysis measured value (M +
H) 404.4. Elemental analysis _{(C 23 H 18 FN 3 O} 3 · 1.25H as ₂ O); Calculated: C, 64.85
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
Preparation of 3-one 3- (benzyloxycarbonyl) -amino-2 according to general procedure 8-A.
The title intermediate was prepared as a yellow foam using 1,3-dihydro-5- (4-fluorophenyl) -1H-1,4-benzodiazepin-2-one. C ₂₄ H ₂₀ FN ₃ O ₃ (MW = 417.47); Mass spectrum analysis Actual value (M +
H) 418.2. Elemental analysis (as _{C 24 H 20 FN 3 O 3} ); Calculated: C, 69.06; H, 4.83 ;
N, 10.07. Found: C, 69.35; H, 4.93; N, 9.97.

Step F—Preparation of 3-Amino-1,3-dihydro-1-methyl-5- (4-fluorophenyl) -2H-1,4-benzodiazepin-2-one According to General Procedure 8-B , 3- (benzyloxycarbonyl) -amino-2
The title intermediate was prepared as a yellow foam using 3,3-dihydro-1-methyl-5- (4-fluorophenyl) -1H-1,4-benzodiazepin-2-one and used directly in Step G.

Step G- 3- [N '-(tert-butylcarbamate) -L-alaninyl] -amino-2,3-dihydro-1-methyl-5- (4-fluorophenyl) -1H-1,4
Preparation of -benzodiazepin-2-one According to general procedure D, N-Boc-L-alanine and 3-amino-1,
The title intermediate was prepared as a yellow solid using 3-dihydro-1-methyl-5- (4-fluorophenyl) -2H-1,4-benzodiazepin-2-one. C ₂₄ H ₂₇ FN ₄ O ₄ (MW = 454.50); Mass spectrum analysis Actual value (M +
H) 455.4. Elemental analysis _{(C 24 H 27 FN 4 O} 4 · 1.5H as ₂ O); Calculated: C, 59.86;
H, 6.28; N, 11.64. Found: C, 60.04; H, 5.62; N, 11.27.
.

Step H-3- (L-alaninyl) -amino-2,3-dihydro-1-methyl-
Preparation of 5- (4-fluorophenyl) -1H-1,4-benzodiazepin-2-one According to general procedure 8-C, 3- [N ′-(tert-butylcarbamate) -L-
The title intermediate was prepared as a yellow foam using [alaninyl] -amino-2,3-dihydro-1-methyl-5- (4-fluorophenyl) -1H-1,4-benzodiazepin-2-one. The crude material was used as is.

Example 8-L Synthesis of 3- (N'-L-alaninyl) amino-2,3-dihydro-1-isobutyl-5-phenyl-1H-1,4-benzodiazepin-2-one Step A: Using general procedure 8-G, 1,3-dihydro-5-phenyl-2
H-1,4-benzodiazepin-2-one (MG Bock et al., J. Org. Chem.
1987, 52, 3232-3239) was alkylated with isobutyl iodide to give 1,3-dihydro-1-isobutyl-5-phenyl-2H-1,4-benzodiazepin-2-one.

Step B: Following the general procedure 8-D and 8-F, using the product of Step A, give 3-amino-1,3-dihydro-1-isobutyl-5-phenyl-2H-1,
4-benzodiazepin-2-one was prepared.

Step C: After coupling the product of Step B and N-Boc-L-alanine (Sigma) using general procedure D, the Boc group is removed using general procedure 8-J. , 3- (N'-L-alaninyl) amino-1,3-dihydro-1-isobutyl-5-phenyl-2H-1,4-benzodiazepin-2-one. Isopropyl iodide instead of isobutyl iodide in the above step A, n-
The following further intermediates were prepared using propyl iodide, cyclopropylmethyl iodide and ethyl iodide: 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-benzodiazepine-2- On 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.

Example 8-M 3- (N′-L-alaninyl) amino-1-methyl-5-phenyl-1,3,4,5-
Synthesis of tetrahydro-2H-1,5-benzodiazepin-2-one Step A: Using general procedure 8-I, 1,3,4,5-tetrahydro-5-phenyl-2H-1,5-benzodiazepine- 2-on (CAS No. 32900)
-17-7) was methylated to give 1-methyl-5-phenyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-2-one.

Step B: Following the general procedure 8-E and 8-F, using the product of Step A, give 3-amino-1-methyl-5-phenyl-1,3,4,5-tetrahydro- 2
H-1,5-benzodiazepin-2-one was prepared.

Step C: After coupling the product of Step B and N-Boc-L-alanine (Sigma) using general procedure D, the Boc group is removed using general procedure 8-N. , 3- (N'-L-alaninyl) amino-1-methyl-5-phenyl-1,3
, 4,5-Tetrahydro-2H-1,5-benzodiazepin-2-one was obtained.

Example 8-N 3- (N′-L-alaninyl) amino-2,4-dioxo-1-methyl-5-phenyl-2,3,4,5-tetrahydro-1H-1,5- Synthesis of Benzodiazepines Using general procedure D, 3-amino-2,4-dioxo-1-methyl-5-phenyl-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine (CAS
No. 131604-75-6) was coupled with N-Boc-L-alanine (Sigma) and the Boc group was removed using general procedure 8-N to give the title compound.

Example 8-O 3-((R) -hydrazinopropionyl) amino-2,3-dihydro-1-methyl-
Synthesis of 5-phenyl) -1H-1,4-benzodiazepin-2-one Using general procedure D, 3-amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4- Benzodiazepin-2-one is converted to (R) -N, N'-di-BO
Coupling with C-2-hydrazinopropionic acid (Example N). Removal of the Boc group using general procedure 5-B gave the title compound.

Example 8-P 3-Amino-2,4-dioxo-1,5-bis- (1-methylethyl) -2,3,4,
Synthesis of 5-tetrahydro-1H-1,5-benzodiazepine Step A: -2,4-dioxo-2,3,4,5-tetrahydro-1H-1,5-
Synthesis of Benzodiazepines Claremon, DA; et al, PCT Application: WO 96-US8400 96060
Using the technique of 3, 2,4-dioxo-2,3,4,5-tetrahydro-1H-1,
5-benzodiazepine (CAS No. 49799-48-6) was prepared from 1,2-phenylenediamine (Aldrich) and malonic acid (Aldrich).

Step B: -2,4-dioxo-1,5-bis- (1-methylethyl) -2,3,4
Synthesis of 2,5-tetrahydro-1H-1,5-benzodiazepine Following the general procedure 8-M, the product of Step A and 2-iodopropane (Al
drich) using 2,4-dioxo-1,5-bis- (1-methylethyl) -2,3.
, 4,5-tetrahydro-1H-1,5-benzodiazepine (CAS No. 113)
021-84-4). Flash chromatography (EtOAc /
Purified by hexane (elution with a gradient of 3: 7 to 1: 1) and then recrystallized from EtOAc / hexane.

Step C: Synthesis of 3-azido-2,4-dioxo-1,5-bis- (1-methylethyl) -2,3,4,5-tetrahydro-1H-1,5-benzodiazepine General According to Technical Procedure 8-K, using the product of Step B as a white solid, 3
-Azido-2,4-dioxo-1,5-bis- (1-methylethyl) -2,3,4,5
-Tetrahydro-1H-1,5-benzodiazepine (CAS No. 186490)
-50-6). The product was flash chromatographed (hexane /
(Eluted with EtOAc (4: 1)) to give a separable 23: 1 mixture of pseudo-axial / pseudo-equatorial azide. Pure pseudoaxial azide was used in the next step.

Step D: Synthesis of 3-Amino-2,4-dioxo-1,5-bis- (1-methylethyl) -2,3,4,5-tetrahydro-1H-1,5-benzodiazepine General According to Technical Procedure 8-L, use the product of Step C as a white solid
-Amino-2,4-dioxo-1,5-bis- (1-methylethyl) -2,3,4,5
-Tetrahydro-1H-1,5-benzodiazepine (CAS No. 186490)
-51-7). Flash chromatography (CH ₂ Cl ₂ / MeO
H (98: 2 → 95: 5 gradient). The isolated pseudoaxial amine atropisomer is completely converted to the pseudoequatorial amine atropisomer by heating in toluene at 100-105 ° C for 15 minutes, and the pseudoequatorial amine atropisomer is converted in the next step Using.
The isomers were distinguished by ¹ H-NMR in CDCl ₃ . Selective ¹ H-NMR
(CDCl ₃ ): pseudo-axial amine 4.40 (s, 1H); pseudo-equatorial amine 3.96 (s, 1H).

Example 8-Q 3- (R-2-thienylglycinyl) amino-2,4-dioxo-1,5-bis- (
Synthesis of 1-methylethyl) -2,3,4,5-tetrahydro-1H-1,5-benzodiazepine hydrochloride Step A: Synthesis of -N- (t-butoxycarbonyl) -R-2-thienylglycine Bodansky, M. et al; The Practice of Peptide Synthesis; Springer Verlag
L-α- (2-thienyl) glycine (Sigma) by the method described in 1994, p.
From N- (t-butoxycarbonyl) -R-2-thienylglycine (CAS No.
. 74462-03-1) was produced.

Step B: 3- [N ′-(t-butoxycarbonyl) -R-2-thienylglycinyl] -amino-2,4-dioxo-1,5-bis- (1-methylethyl)- Two, three,
Synthesis of 4,5-tetrahydro-1H-1,5-benzodiazepine According to General Procedure J above, using the product of Example 8-P and the product of Step A above, 3- [N 'as a white foam. -(T-butoxycarbonyl) -R-2-thienylglycinyl] -amino-2,4-dioxo-1,5-bis- (1-methylethyl) -2,3,4,5-tetrahydro-1H- 1,5-benzodiazepine was produced. Purification by flash chromatography (eluting with CH ₂ Cl ₂ / EtOAc (9: 1 → 5: 1 gradient)).

Step C: 3- (R-2-thienylglycinyl) amino-2,4-dioxo-
1,5-bis- (1-methylethyl) -2,3,4,5-tetrahydro-1H-1,5
-Synthesis of benzodiazepine hydrochloride The title compound was prepared as a white solid using the product of Step B according to General Procedure 8-N above.

Example 8-R 3- (L-alaninyl) -amino-2,4-dioxo-1,5-bis-methyl-2,
Synthesis of 3,4,5-tetrahydro-1H-1,5-benzodiazepine hydrochloride Step A: -2,4-dioxo-1,5-bis-methyl-2,3,4,5-tetrahydro-1H-1 Synthesis of 2,5-Dioxo-1,5-bis-methyl-2,2- (4-dioxo-1,5-bis-methyl) 3,4,5
-Tetrahydro-1H-1,5-benzodiazepine (CAS No. 23954-
54-3) was produced. A white solid product precipitated upon partial concentration of the reaction after the operation and was isolated by filtration.

Step B: 3-Azido-2,4-dioxo-1,5-bis-methyl-2,3,4
Synthesis of 5,5-Tetrahydro-1H-1,5-benzodiazepine For this substrate, General Procedure 8-K was modified as follows. First, the process
The product of A was suspended (not a solution) in THF at −78 ° C. and then KN (TMS) _Two The solution was added and the suspension was allowed to warm to -35 ° C over 12 minutes.
In the meantime, the suspension becomes a solution, which is cooled again to −78 ° C .;
Treated as described in the method. Flash chromatography (CHCl_Three/ Et
Eluting with OAc (7: 1)) followed by hot CHCl_ThreeFrom tricure with hexane
To give 3-azido-2,4-dioxo-1,5-bis-methyl-2,3,4,5-
Purify tetrahydro-1H-1,5-benzodiazepine and cool to -23 ° C
. The product was isolated as a white solid.

Step C: 3-Amino-2,4-dioxo-1,5-bis-methyl-2,3,4
Synthesis of 5,5-Tetrahydro-1H-1,5-benzodiazepine According to general procedure 8-L, using the product of Step B as a white solid, 3
-Amino-2,4-dioxo-1,5-bis-methyl-2,3,4,5-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-bis-methyl-2,3,4,5-tetrahydro -1
Synthesis of H-1,5-benzodiazepine According to General Procedure I above, using N-Boc-L-alanine (Novabiochem) and the product of Step C, 3- [N '-(t-butoxy) as a white foam. Carbonyl) -L-alaninyl] -amino-2,4-dioxo-1,5-bis-methyl-2
, 3,4,5-Tetrahydro-1H-1,5-benzodiazepine was prepared. Purification by flash chromatography (eluting with CH ₂ Cl ₂ / EtOAc (gradient 2: 1 → 1: 1)).

Step E: 3- (L-alaninyl) -amino-2,4-dioxo-1,5-bis-methyl-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine hydrochloride The title compound was prepared as an off-white amorphous solid using the product of Step D according to General Procedure 8-N above.

Example 8-S 3- (L-alaninyl) amino-2,4-dioxo-1,5-bis- (2-methylpropyl) -2,3,4,5-tetrahydro-1H-1, Synthesis of 5-benzodiazepine hydrochloride Step A: -2,4-dioxo-1,5-bis- (2-methylpropyl) -2,3,
Synthesis of 4,5-tetrahydro-1H-1,5-benzodiazepine Using general procedure 8-M, using Example 8-P, the product of step A and 1-iodo-2-methylpropane (Aldrich). 2,2,4-Dioxo-1,5-bis- (2-methylpropyl) -2,3,4,5-tetrahydro-1H-1,5-benzodiazepine was prepared. Flash chromatography (EtOAc / hexane (
Elution with a gradient of 3: 7 → 1: 1), followed by purification by recrystallization from EtOAc / hexane.

Step B: Synthesis of 3-azido-2,4-dioxo-1,5-bis- (2-methylpropyl) -2,3,4,5-tetrahydro-1H-1,5-benzodiazepine General According to Technical Procedure 8-K (precipitate formed upon addition of KN (TMS) ₂ but dissolved upon addition of trisyl azide), the product of Step A was used as a white solid to give 3-azido-2,4- Dioxo-1,5-bis- (2-methylpropyl) -2,3,
4,5-Tetrahydro-1H-1,5-benzodiazepine was prepared. Flash chromatography (eluted with hexane / EtOAc (4: 1)), second flash chromatography (CH ₂ Cl ₂ / hexane / EtOAc (10:10; 1)
→ 8: 6: 1 gradient) to purify the product.

Step C: Synthesis of 3-Amino-2,4-dioxo-1,5-bis- (2-methylpropyl) -2,3,4,5-tetrahydro-1H-1,5-benzodiazepine General According to Technical Procedure 8-L, using the product of Step B as a white solid
-Amino-2,4-dioxo-1,5-bis- (2-methylpropyl) -2,3,4,
5-Tetrahydro-1H-1,5-benzodiazepine was prepared. Flash chromatography (CH ₂ Cl ₂ / MeOH (concentration gradient from 98: 2 to 95: 5, M
eluting with 5% NH _{3 in} MeOH).

Step D: -3- [N '-(t-butoxycarbonyl) -L-alaninyl] -amino-2,4-dioxo-1,5-bis- (2-methylpropyl) -2,3, Synthesis of 4,5-tetrahydro-1H-1,5-benzodiazepine According to General Procedure I above, using N-Boc-L-alanine (Novabiochem) and the product of Step C as a white foam, 3- [N '-(T-butoxycarbonyl) -L-alaninyl] -amino-2,4-dioxo-1,5-bis- (2-methylpropyl) -2,3,4,5-tetrahydro-1H-1,5 -Preparation of benzodiazepine. Flash chromatography (CH ₂ Cl ₂ / EtOAc (3: 1 →
Elution with a 3: 2 concentration gradient).

Step E: 3- (L-alaninyl) -amino-2,4-dioxo-1,5-bis- (2-methylpropyl) -2,3,4,5-tetrahydro-1H-1, Synthesis of 5-benzodiazepine hydrochloride The title compound was prepared as an amorphous white solid using the product of Step D according to General Procedure 8-N above.

Example 8-T 3- (S-phenylglycinyl) amino-2,4-dioxo-1,5-bis- (2-
Synthesis of methylpropyl) -2,3,4,5-tetrahydro-1H-1,5-benzodiazepine hydrochloride Step A: -3- [N '-(t-butoxycarbonyl) -S-phenylglycinyl
] -Amino-2,4-dioxo-1,5-bis- (2-methylpropyl) -2,3,4,
Synthesis of 5-tetrahydro-1H-1,5-benzodiazepine According to General Procedure J above, the product of Example 8-S, Step C and Boc-
Using L-phenylglycine (Novabiochem, CAS No. 2900-27-8) as a white foam, 3- [N '-(t-butoxycarbonyl) -S-phenylglycinyl] -amino-2,4-dioxo. -1,5-Bis- (2-methylpropyl) -2,3,4,5-tetrahydro-1H-1,5-benzodiazepine was prepared. Purification by flash chromatography (eluting with CH ₂ Cl ₂ / EtOAc (9: 1 → 5: 1 gradient)).

Step B: -3- (S-phenylglycinyl) -amino-2,4-dioxo-1,
5-bis- (2-methylpropyl) -2,3,4,5-tetrahydro-1H-1,5-
Synthesis of Benzodiazepine Hydrochloride According to General Procedure 8-N above, using the product of Step A, 3- (S-phenylglycinyl) -amino-2,4-dioxo-1, 5
-Bis- (2-methylpropyl) -2,3,4,5-tetrahydro-1H-1,5-benzodiazepine hydrochloride was prepared.

Example 8-U 3- (L-alaninyl) amino-2,4-dioxo-1,5-bis- (cyclopropylmethyl) -2,3,4,5-tetrahydro-1H-1,5 Synthesis of benzodiazepine hydrochloride Step A:-2,4-dioxo-1,5-bis- (cyclopropylmethyl) -2,
Synthesis of 3,4,5-tetrahydro-1H-1,5-benzodiazepine According to general procedure 8-M, use Example 8-P, the product of Step A and (bromomethyl) cyclopropane (Lancaster) to give 2 , 4-dioxo-1,5-bis-
(Cyclopropylmethyl) -2,3,4,5-tetrahydro-1H-1,5-benzodiazepine was prepared. Flash chromatography (EtOAc / hexane (
3: 7 eluted with pure EtOAc) and then purified by recrystallization from EtOAc / hexane.

Step B:-3-azido-2,4-dioxo-1,5-bis- (cyclopropyl
Synthesis of methyl) -2,3,4,5-tetrahydro-1H-1,5-benzodiazepine For this substrate, the general procedure 8-K was modified as follows. First, the process
The product of A was suspended (not a solution) in THF at −78 ° C. and then KN (TMS) _Two The solution was added and the suspension was warmed to -30 ° C, during which time the suspension became
This was recooled to -78 ° C. Upon re-cooling to -78 ° C, a precipitate forms
Started, partially raise the reaction flask containing this mixture above the cooling bath.
The internal temperature was raised to -50 ° C; then the trisyl azide solution was added. Cooling bath
And the mixture is warmed to -20 ° C., resulting in a nearly homogenous solution.
Was added to AcOH. Thereafter, processing was performed as described in the general procedure. high temperature~
Triturate with EtOAc at room temperature, then CHCl at hot to -23 ° C_Three/ E
Recrystallization from tOAc / EtOH (5: 5: 1) gave 3-azido-2,4-dioxo.
So-1,5-bis- (cyclopropylmethyl) -2,3,4,5-tetrahydro-1H
The -1,5-benzodiazepine was purified and isolated as a white solid.

Step C: Synthesis of 3-Amino-2,4-dioxo-1,5-bis- (cyclopropylmethyl) -2,3,4,5-tetrahydro-1H-1,5-benzodiazepine General Following the procedure 8-L, use the product of Step B as a white solid
-Amino-2,4-dioxo-1,5-bis- (cyclopropylmethyl) -2,3,4
, 5-Tetrahydro-1H-1,5-benzodiazepine was prepared. Flash chromatography (CH ₂ Cl ₂ / MeOH (concentration gradient from 98: 2 to 95: 5, M
CH ₅ Cl ₂ /5% NH _{3 in} MeOH).
It was purified by recrystallization from hexane (1: 1).

Step D: -3- [N '-(t-butoxycarbonyl) -L-alaninyl] -amino-2,4-dioxo-1,5-bis- (cyclopropylmethyl) -2,3,4 , 5-
Synthesis of Tetrahydro-1H-1,5-benzodiazepine According to General Procedure I above, using N-Boc-L-alanine (Novabiochem) and the product of Step C as a white foam, 3- [N ′-(t -Butoxycarbonyl) -L-alaninyl] -amino-2,4-dioxo-1,5-bis- (cyclopropylmethyl) -2,3,4,5-tetrahydro-1H-1,5-benzodiazepine was prepared. . Flash chromatography (CH ₂ Cl ₂ / EtOAc (3: 1)
→ 2: 1 concentration gradient).

Step E: 3- (L-alaninyl) -amino-2,4-dioxo-1,5-bis- (cyclopropylmethyl) -2,3,4,5-tetrahydro-1H-1,5 Synthesis of benzodiazepine hydrochloride The title compound was prepared as an off-white solid using the product of Step D according to General Procedure 8-N above.

Example 8-V 3- (L-alaninyl) -amino-2,4-dioxo-1,5-bis- (2,2-dimethylpropyl) -2,3,4,5-tetrahydro-1H Synthesis of -1,5-benzodiazepine hydrochloride Step A: -2,4-dioxo-1,5-bis- (2,2-dimethylpropyl)-
Synthesis of 2,3,4,5-tetrahydro-1H-1,5-benzodiazepine Stirring the product of Example 8-P, Step A (1.0 eq, 17.08 g) in DMSO (500 mL) at room temperature. Add neopentyl iodide (43.01 g, 2
. 24 eq, Aldrich) and Cs ₂ CO ₃ (72.65g, 2.3 eq, Aldrich
) Was added. The resulting mixture was heated to 75 ° C. for 30 minutes, then additional Cs ₂ CO ₃ (31.59 g, 1.0 equiv) was added and the mixture was stirred at 75 ° C. for 6 hours at high speed. The mixture was cooled and H ₂ O (500 mL) and EtOAc (1
000 mL) was added. Separate the phases and separate the organic phase from H ₂ O (1 × 500 mL), 1M
Washed with aqueous HCl (2 × 500 mL) and brine (1 × 500 mL). The organic phase is then dried over MgSO ₄ , filtered, concentrated and purified by flash chromatography (eluting with hexane / EtOAc (3: 2 → 2: 3 gradient)) to give 2,4-dioxo-1 , 5-bis- (2,2-dimethylpropyl) -2,
3,4,5-Tetrahydro-1H-1,5-benzodiazepine was obtained as a white solid.

Step B: of 3-azido-2,4-dioxo-1,5-bis- (2,2-dimethylpropyl) -2,3,4,5-tetrahydro-1H-1,5-benzodiazepine Synthesis According to General Procedure 8-K, use the product of Step A as a white solid
-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 (hexane / CH ₂ Cl ₂ / EtOAc (10
: 5: 1 → 5: 5: 1 gradient) to obtain a separable, 13: 1 mixture of pseudo-axial azide / pseudo-equatorial azide. Pure pseudoaxial azide was used in the next step. Selective ¹ H-NMR (
CDCl ₃ ): pseudo-axial azide 5.12 (s, 1H); pseudo-equatorial azide 4.03 (s, 1H).

Step C:-of 3-amino-2,4-dioxo-1,5-bis- (2,2-dimethylpropyl) -2,3,4,5-tetrahydro-1H-1,5-benzodiazepine Synthesis According to General Procedure 8-L, use the product of Step B as a white solid
-Amino-2,4-dioxo-1,5-bis- (2,2-dimethylpropyl) -2,3
, 4,5-Tetrahydro-1H-1,5-benzodiazepine was prepared. Purified by flash chromatography (CH ₂ Cl ₂ / MeOH (98: 2 → 95: 5 gradient, containing 5% NH _{3 in} MeOH)). The isolated white solid product was identified by ¹ H-NMR as a quasi-axialamine atropisomer and a ４4: 1 mixture of quasi-equatorial amine atropisomers.
The mixture was heated to 100 ° C. in toluene for 20 minutes and then re-concentrated to give pure pseudoequatorial amine atropisomer as a white solid for the next step. Selective ¹ H-NMR (CDCl ₃ ): pseudo axial amine 4.59 (s, 1 H); pseudo equatorial amine 4.03 (s, 1 H)
1H).

Step D: 3- [N ′-(t-butoxycarbonyl) -L-alaninyl] -amino-2,4-dioxo-1,5-bis- (2,2-dimethylpropyl) -2, 3,4,5
Synthesis of -tetrahydro-1H-1,5-benzodiazepine According to general procedure I above, using N-Boc-L-alanine (Novabiochem) and the product of step C as a white foam, 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 produced. Flash chromatography (CH ₂ Cl ₂ / EtOAc (4:
Elution with a concentration gradient of 1 → 5: 2).

Step E: 3- (L-alaninyl) -amino-2,4-dioxo-1,5-bis- (2,2-dimethylpropyl) -2,3,4,5-tetrahydro-1H- Synthesis of 1,5-benzodiazepine hydrochloride The title compound was prepared as an off-white solid using the product of Step D according to General Procedure 8-N above.

Example 8-W 3- (L-alaninyl) amino-2,4-dioxo-1,5-bis-phenyl-2,
Synthesis of 3,4,5-tetrahydro-1H-1,5-benzodiazepine hydrochloride Step A: -2,4-dioxo-1,5-bis-phenyl-2,3,4,5-tetrahydro-1H-1 This method is a modification of the method described in Chan, DMT Tetrahedron Lett. 1996, 37, 9013-9016. Example 8-P in CH ₂ Cl ₂ (100 mL)
Step A product (1.0 eq, 7.50 g), Ph ₃ Bi (2.2 eq, 41.
26 g, Aldrich), Cu (OAc) ₂ (2.0 eq, 15.48 g, Aldrich) E
A mixture of t ₃ N (2.0 eq, 8.62 g) was stirred at room temperature under N ₂ for 6 days (T
Monitored by LC). The solid was removed by filtration through a plug of celite and rinsed with CH ₂ Cl ₂ / MeOH (3 × 75 mL). The filtrate was concentrated, thermal _{(hot) CH 2 Cl 2 /} MeOH: were dissolved in (9 1), a large silica gel filtered through a plug _{(CH 2 Cl 2 / MeOH (} 9: Elution with 1,2L)) was. The filtrate is concentrated and flash chromatographed (pure CH ₂ Cl ₂ → CH ₂ Cl ₂ /
The residue was purified by elution with a gradient of MeOH (9: 1). The fractions containing the product are concentrated to give 2,4-dioxo-1,5-bis-phenyl-2,
3,4,5-Tetrahydro-1H-1,5-benzodiazepine crystallized and was isolated by filtration as a white solid.

Step B: 3-Azido-2,4-dioxo-1,5-bis-phenyl-2,3,
Synthesis of 4,5-tetrahydro-1H-1,5-benzodiazepine For this substrate, General Procedure 8-K was modified as follows. First, the product of Step A is suspended (not a solution) in THF at −70 ° C., and then KN (TMS) ₂
The solution is added and the suspension is allowed to warm to −20 ° C. over 10 minutes, during which time the suspension becomes a solution, which is recooled to −70 ° C .; then described in General Procedure Processed as follows. Purify the title compound by trituration with hot CHCl ₃ / hexane (1: 1) to give 3-azido-2,4-dioxo-1,5-bis-phenyl-2,3,4,5-tetrahydro-1H. -1,5-Benzodiazepine was obtained as a white solid.

Step C: 3-Amino-2,4-dioxo-1,5-bis-phenyl-2,3,
Synthesis of 4,5-Tetrahydro-1H-1,5-benzodiazepine Following general procedure 8-L, using the product of Step B as a white solid, 3
-Amino-2,4-dioxo-1,5-bis-phenyl-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine was prepared. Flash chromatography (CH ₂ Cl ₂ / MeOH (98: 2 → 95: 5 gradient, 5% in MeOH)
NH ₃ ).

Step D: -3- [N '-(t-butoxycarbonyl) -L-alaninyl] -amino-2,4-dioxo-1,5-bis-phenyl-2,3,4,5-tetrahydro −
Synthesis of 1H-1,5-benzodiazepine According to General Procedure I above, using N-Boc-L-alanine (Novabiochem) and the product of Step C as a white foam, 3- [N ′-(t-butoxy). Carbonyl) -L-alaninyl] -amino-2,4-dioxo-1,5-bis-phenyl-
2,3,4,5-Tetrahydro-1H-1,5-benzodiazepine was prepared. Purification by flash chromatography (eluting with CH ₂ Cl ₂ / EtOAc (4: 1 → 3: 1 gradient)).

Step E: 3- (L-alaninyl) -amino-2,4-dioxo-1,5-bis-phenyl-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine hydrochloride The title compound was prepared as a white amorphous solid using the product of Step D according to General Procedure 8-N above.

Example 8-X Synthesis of 3-Amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one RG Sherrill et al., J. Org. Chem. , 1995, 60, 730-734, using glacial acetic acid and HBr gas to give the title compound.

Example 8-Y 3- (L-valinyl) -amino-2,3-dihydro-1-methyl-5-phenyl-
Synthesis of 1H-1,4-benzodiazepin-2-one Step A-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 8-B, step A)
Was partitioned between methylene chloride and 1M potassium carbonate to form the free base (be fr
ee based). The free amine compound is then converted to N-Boc according to General Procedure D.
-Coupling with valine to give the title compound. _{C 26 H 32 N 4 O 4} (MW464.62); mass spectroscopy 464.3. Elemental analysis (C ₂₆ H ₃₂ N ₄ as O _4); Calculated: 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 procedure 8-C, 3- [N '-(tert-butylcarbamate) -L-
[Alaninyl] -amino-2,3-dihydro-1-methyl-5-phenyl-1H-1
The title compound was prepared as a white foam using, 4-benzodiazepin-2-one. _{C 21 H 23 N 4 O 2} (MW363.48); mass spectroscopy (M + H) 364.
2.

Example 8-Z Synthesis of 3- (L-tert-leucyl) -amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one Step A- 3- [N '-(tert-butyl carbamate) -L-tert-leucinyl]
Synthesis of -amino-2,3-dihydro-1-methyl-5-phenyl-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 8-B, Step A) was treated with methylene chloride. Partitioned into 1M potassium carbonate to free base. The free amine compound was then coupled with N-Boc-tert-leucine according to General Procedure D to give the title compound. _{C 27 H 35 N 4 O 4} (MW479.66); mass spectroscopy 479.

Step B—Synthesis of 3- (L-tert-leucinyl) -amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one General Procedure 8- According to C, 3- [N '-(tert-butylcarbamate) -L-
[tert-leucinyl] -amino-2,3-dihydro-1-methyl-5-phenyl-1
The title compound was prepared as a white foam using H-1,4-benzodiazepin-2-one. Elemental analysis _{(C 22 H 25 N 4 O} 4 · 0.5H as ₂ O); Calculated: C, 68.19; H,
7.02; N, 14.40. Found: C, 68.24; H, 7.00; N, 14.00.

Example 8-AA 3- (L-alaninyl) -amino-2,3-dihydro-1,5-dimethyl-1H-1
Synthesis of 2,4-benzodiazepine According to general procedure 8-I (using methyl iodide), 8-D and 8-F, 2,3-dihydro-1,5-dimethyl-1H-1,4-benzodiazepine was prepared. Manufactured. This intermediate is coupled with Boc-L-alanine (Novo) using general procedure D and then deprotected using general procedure 5-B to give the title compound.
It was used without further purification.

Example 8-AB 3- (L-3-thienylglycinyl) amino-2,4-dioxo-1,5-bis- (
Synthesis of 2,2-dimethylpropyl) -2,3,4,5-tetrahydro-1H-1,5-benzodiazepine Step A: Synthesis of -N- (t-butoxycarbonyl) -L-3-thienylglycine Bodansky, M. et al; The Practice of Peptide Synthesis; Springer Verlag
L-α- (3-thienyl) glycine (Sigma) by the method described in 1994, p.
)) To give N- (t-butoxycarbonyl) -L-3-thienylglycine.

Step B: -3- [N '-(t-butoxycarbonyl) -L-3-thienylglycinyl] -amino-2,4-dioxo-1,5-bis- (2,2-dimethylpropyl ) −
Synthesis of 2,3,4,5-tetrahydro-1H-1,5-benzodiazepine According to General Procedure D above, using the product of Example 8-V, Step C and the product of 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
Synthesis of -1,5-benzodiazepine The title compound was prepared using the product of Step B according to General Procedure 8-N above.

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

General Procedures CH The following procedures were used to synthesize the intermediates shown in Table C-1 in parallel: Step A: 3- (tert-Butoxycarbonyl) amino- in 1 mL of anhydrous DMF To a solution of 2,3-dihydro-5-phenyl-1H-1,4-benzodiazepin-2-one (CA No. 125: 33692: 100 mg, 0.28 mmol) was added 0.5 M potassium bis (trimethylsilyl) in toluene. Amide (0.30 mmol)
Of the solution was added. Immediately neat alkyl halide (0.5
6 mmol; those listed in Table C-1) were added in one portion and the reaction mixture was allowed to stand overnight. If an alkyl chloride was used, one equivalent of sodium iodide was added to the reaction mixture. After concentration under reduced pressure, the crude reaction residue was separated from methylene chloride (2m
L) and a saturated aqueous solution of bicarbonate (2 mL), and then methylene chloride 10m
L and passed through a 5 g Extralut QE cartridge (EM Science; Gibbstown, NJ). The filtrate obtained is concentrated under reduced pressure and the crude product is prepared for semi-preparation (semi-p
reparative) HPLC (YMC 20 × 50 mm silica column; concentration gradient elution;
0-5% (5.5 minutes), 5-20% (3.5 minutes), 20-100% (2 minutes), 1
Further purification using 00% (4 min) ethyl acetate / methylene chloride, flow rate 25 mL / min). The product showed the expected M + 1 peak by IEX MS, which was used without further purification and characterization.

Step B: The product obtained in Step A was dissolved in 5 mL of a 15% TFA / methylene chloride solution and allowed to stand for 16 hours. After concentration under reduced pressure, the TFA salt was dissolved in methanol and loaded directly on a 1 g SCX column. 2 mL of methanol
And the product was eluted from the column with 6 mL of a 2.0 M ammonia / methanol solution. After concentration under reduced pressure, the product was characterized by IEX MS and used without further purification.

Step C: The crude product obtained in Step B (1.05 eq) was added with H in DMF
0.3 mM stock solution of OBt.H ₂ O (1.05 eq), NtB in THF
A 0.3 mM stock solution of OC-L-alanine (1.0 eq.) And 1-
A 0.3 mM stock solution of (3-dimethylaminopropyl) -3-ethylcarbodiimide (1.05 eq) was added in order. After standing for 24 hours, the reaction mixture was concentrated,
The residue was dissolved in 2 mL of a 10% methanol / methylene chloride solution. The solution was then washed with 1 g SCX (Varian Samp) previously washed (methanol).
le Preparation) column, and filtered using 8 mL of the same solvent. In Example C-V, a 1 g Si column (Varian Sample Preparation) was used. The filtrate was concentrated to about 1/3 of the original volume under a nitrogen stream, and then methanol
AG 1-8 × anion exchange resin (BioRad; Hercules, California;
The column was passed through a plug (500 mg) that had been previously washed with 1 N NaOH, water and methanol. The resulting filtrate was concentrated under reduced pressure and the crude product was used without further purification after being characterized by IEX MS.

Step D: The crude product obtained in Step C was dissolved in 5 mL of a 15% TFA / methylene chloride solution and allowed to stand for 16 hours. After concentration under reduced pressure, the TFA salt was dissolved in methanol and loaded directly on a 1 g SCX column. The column was washed three times with 2 mL portions of methanol, and the product was eluted from the column with 6 mL of a 2.0 M ammonia / methanol solution. After concentration under reduced pressure, the product was characterized by IEX MS and used without further purification. The intermediates produced by this method are shown in Table CA below.

Table CA Intermediates

[Table 1]

[0458]

[Table 2]

[Table 3]

[0459]

[Table 4]

[Table 5]

Example C-AA (S) -3- (L-phenylglycinyl) amino-2,3-dihydro-1-methyl-
Synthesis of 5-phenyl-1H-1,4-benzodiazepin-2-one Step A: (S) -3- (N ′-(tert-butoxycarbonyl) -L-phenylglycinyl) amino-2,3-dihydro -1-methyl-5-phenyl-1H-1,4
Synthesis of benzodiazepin-2-one Triethylamine (51%) in 100 mL of anhydrous methylene chloride at 20 ° C
9 μL, 3.8 mmol) and (S) -3-amino-5-phenyl-2-oxo-
1,4-benzodiazepine (1.0 g, 3.8 mmol) (MG Bock et al., J.O.
rg. Chem. 1987, 52, 3232-3239) was added to the solution of N-Bo.
c-L-phenylglycine fluoride (Carpino et al, J. Org. Chem. 1991,
56, 2611-2614) at once. The reaction mixture was stirred for 15 minutes and quenched with saturated aqueous bicarbonate (10 mL). The layers were separated and the organic layer was washed successively with a saturated aqueous solution of bicarbonate, water and brine, then dried over sodium sulfate. The crude product was purified using silica gel chromatography (10-50% ethyl acetate / hexane) to give 1.3 g (69%) of a hygroscopic white foam. NMR data were as follows: ¹ H NMR (300 MHz, CDCl ₃ ): δ = 1.35 (brs, 9H), 3.4.
1 (s, 3H), 5.30-5.45 (m, 2H), 5.75-5.95 (m, 1H), 7.1
5-7.75 (m, 15H). ^{_{IR (CDCl 3): 1709.7,1676.6,1489,1166.3cm -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 treated with 15 in methylene chloride.
It was added all at once to 50 mL of a stirred solution of% TFA. After stirring for 1 hour, the reaction mixture was concentrated under reduced pressure, and the residue was dissolved in 100 mL of methylene chloride. The solution was washed twice with saturated sodium bicarbonate, once with brine, and then dried over sodium sulfate. The crude product is purified using silica gel column chromatography (5-10% methanol / methylene chloride) to give a very pale green foam 74.
3 mg (73%) were obtained. NMR data were as follows: ¹ H NMR (CDCl ₃ ): δ = 2.05 (br s, 1 H), 3.45 (s, 3 H),
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, 1506.1 cm ⁻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 of On Step A: 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 in 40 mL of anhydrous DMF at 0 ° C.
-Dihydro-5-phenyl-1H-1,4-benzodiazepin-2-one (Bock,
MG et al, Tetrahedron Lett. 1987, 28, 939; 4.0 g, 10.4 mmol)
To a solution of was added potassium tert-butoxide (1.51 g, 13.5 mmol) in one portion. The reaction mixture is stirred for 20 minutes, and α-bromoacetophenone (Lancaster;
Windham, NH; 2.9 g, 14.6 mmol) was added. The reaction mixture was allowed to warm to room temperature over 30 minutes and was diluted with 100 mL of water and 200 mL of methylene chloride. The layers were separated. The organic layer was extracted with water and dried over sodium sulfate. The crude product was purified by silica gel column chromatography (0-5% ethyl acetate / methylene chloride) to give 4.2 g (81%) of an off-white foam. NMR data were 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, 1
H), 7.20-7.70 (m, 12H), 7.91 (d, J = 7.54 Hz, 2H). IR (CHCl ₃ ): 1706.04, 1685.3, 1505.9, 1489.1, 1
450.3, 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 Anhydrous methylene chloride 3- (benzoxycarbonyl) amino-2,3-dihydro-1- (2-oxo-2-phenylethyl) -5-phenyl- in 100 mL
A solution of 1H-1,4-benzodiazepin-2-one (3.7 g, 7.36 mmol) was cooled to 0 ° C. under nitrogen. Then, a stream of anhydrous HBr was bubbled through the solution for 1 hour. The bubbler was removed and the reaction was allowed to warm to room temperature under nitrogen. After stirring for 1 hour, the reaction was concentrated under reduced pressure and the residue was washed with methylene chloride 2
Redissolved in 0 mL. HBr of the crude product using 300 mL of anhydrous ether
The salt precipitated from solution and was collected by filtration as a pale yellow solid. After washing with ether, the solid was dissolved in methylene chloride and saturated sodium bicarbonate. The layers were separated and the organic layer was extracted with saturated sodium bicarbonate. The aqueous layers were then combined and back extracted twice with methylene chloride. Combine the organic layers and extract once with water,
Dried over sodium sulfate. After concentration under reduced pressure, 2.27 g of the product was obtained as an orange foam, which was used without further purification. NMR data were as follows: ¹ H NMR (300 MHz, CDCl ₃ ): δ = 2.60 (brs, 2H), 4.7.
2 (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-
Synthesis of 1H-1,4-benzodiazepin-2-one HOBt-H ₂ O (697 mg, 5.16 mmol) in 20 mL of anhydrous THF at 0 ° C.
l), N, N-diisopropylethylamine (900 μL, 5.16 mmol) and Nt-BOC-L-alanine (975 mg, 5.16 mmol) in a solution of 1- (
3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (EDCI;
986 mg, 5.16 mmol) were added in one portion. After stirring for 5 minutes, anhydrous THF
3-Amino-2,3-dihydro-1- (2-oxo-2-phenylethyl) -5-phenyl-1H-1,4-benzodiazepin-2-one in 20 mL (2.0 g,
(5.43 mmol) was added via syringe and the reaction mixture was allowed to warm to room temperature and was stirred overnight. Dilute the reaction mixture with 200 mL of methylene chloride and add 10%
After successive extraction with citric acid, saturated sodium bicarbonate, water and brine, it was dried over sodium sulfate. Purify the crude product using silica gel chromatography (10-30% ethyl acetate / methylene chloride), 2.59 g of a white foam
(93%). NMR data were as follows: ¹ H NMR (300 MHz, CDCl ₃ ): δ = 1.30-1.60 (m, 12H),
4.35 (br s, 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, 12
30.4, 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 in one portion to 100 mL of a stirring solution of 15% TFA / methylene chloride. After stirring for 2 hours, the reaction mixture was concentrated under reduced pressure, and the residue was dissolved in 150 mL of methylene chloride. The solution was washed twice with saturated sodium bicarbonate, once with brine, and then dried over sodium sulfate. Purify the crude product using silica gel column chromatography (1-10% methanol / methylene chloride) to give the title compound 1.
91 g (94%) were obtained as a white foam. NMR data were 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), 5.20-5.4
5 (m, 2H), 5.67 (t, J = 7.48 Hz, 1H), 7.20-7.65 (m, 1
2H), 7.90 (d, J = 7.7 Hz, 2H), 8.80 (dd, J ₁ = 25.09 Hz,
J ₂ = 8.33Hz, 1H). EX 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 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 in 40 mL of anhydrous DMF at 0 ° C.
-Dihydro-5-phenyl-1H-1,4-benzodiazepin-2-one (3.
7 g, 9.61 mmol) in a solution of potassium tert-butoxide (1.6 g, 14,
4 mmol) were 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 and then 100 mL of water
And diluted with 200 mL of methylene chloride. The layers were separated. The organic layer was extracted with water and dried over sodium sulfate. The crude product was purified by silica gel column chromatography (0-3% ethyl acetate / methylene chloride) to give 1.52 g (32%) of an off-white foam. NMR data were 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 = 8.40 Hz, 1H), 7.2
-7.70 (m, 14H). IR (CHCl ₃ ): 1720.4,1683.0,1604.8,1505.5,14
51.1, 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 Anhydrous methylene 3- (benzoxycarbonyl) amino- in 50 mL of chloride
2,3-dihydro-1- (4,4,4-trifluorobutyl) -5-phenyl-1H
A solution of -1,4-benzodiazepin-2-one (1.42 g, 2.87 mmol) was cooled to 0 C under nitrogen. An anhydrous stream of HBr was bubbled slowly through the solution for 1 hour. The bubbler was removed and the reaction was allowed to warm to room temperature under nitrogen. After stirring for 1 hour, the reaction was concentrated under reduced pressure and the residue was washed with methylene chloride 1
Redissolved in 0 mL. The crude product HBr salt was precipitated from solution with 90 mL of anhydrous ether and collected by filtration. After washing with ether, the HBr
The salt was dissolved in methylene chloride and saturated sodium bicarbonate. Separate the layers,
The organic layer was extracted with saturated sodium bicarbonate. The aqueous layers were then combined and back extracted twice with methylene chloride. The organic layers were combined, extracted once with water, and dried over sodium sulfate. After concentration under reduced pressure, 1.06 g (100%) of the product was obtained as a white foam, which was used without further purification. NMR data were 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, 2
H), 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-trifluorobutyl) -5-phenyl-1
Synthesis of H-1,4-benzodiazepin-2-one HOBt-H ₂ O (373 mg, 2.76 mmol) in 10 mL of anhydrous THF at 0 ° C.
l), a solution of N, N-diisopropylethylamine (481 μL, 2.76 mmol) and Nt-BOC-L-alanine (522 mg, 2.76 mmol) was added with 1- (
3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (EDCI;
(527 mg, 2.76 mmol) were added in one portion. After stirring for 5 minutes, anhydrous THF
3-Amino-2,3-dihydro-1- (4,4,4-trifluorobutyl) -5-phenyl-1H-1,4-benzodiazepin-2-one in 10 mL (1.05 g,
(2.91 mmol) was added via syringe and the reaction mixture was allowed to warm to room temperature and was stirred overnight. Dilute the reaction mixture with 100 mL of methylene chloride and add 10%
After successive extraction with citric acid, saturated sodium bicarbonate, water and brine, it was dried over sodium sulfate. Purify the crude product using silica gel chromatography (10% -30% ethyl acetate / methylene chloride) and obtain 1.28 g of a white foam
(83%). NMR data were as follows: ¹ H NMR (300 MHz, CDCl ₃ ): δ = 1.40-2.10 (m, 16H).
3.70-3.85 (m, 1H), 4.30-4.55 (m, 2H), 5.10 (brs
, 1H), 5.45-5.55 (m, 1H), 7.25-7.80 (m, 10H). IR (CDCl ₃ ): 1676.6,1605.2,1488.6,1450.9,13
93.2, 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) was added to 15% TFA /
It was added all at once to 50 mL of a stirred solution of methylene chloride. After stirring for 2 hours, the reaction mixture was concentrated under reduced pressure, and the residue was dissolved in 100 mL of methylene chloride. 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 column chromatography (1-5% methanol / methylene chloride) to give 670 mg (68%) of a pale pink foam. NMR data were as follows: ¹ H NMR (300 MHz, CDCl ₃ ): δ = 1.43 (t, J = 7.0 Hz, 3)
H), 1.60-2.20 (m, 7H), 3.60-3.85 (m, 2H), 4.35-4.5
5 (m, 1H), 5.51 (dd, J 1 = 8.36Hz, J 2 = 2.48Hz, 1H), 7.2
0-7.70 (m, 9H), 8.80 (dd, J ₁ = 27.73 Hz, J ₂ = 8.34 Hz,
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]-
Synthesis of 2,3-dihydro-1-methyl-5- (2-pyridyl) -1H-1,4-benzodiazepin-2-one L-Boc-alanine (1.74 g, 9.20 mmol), HOBt monohydrate Things (1
. 24 g, 9.20 mmol), diisopropylethylamine (1.6 mL, 9.2)
0 mmol) and CH ₂ Cl ₂ (30 mL) were purged with nitrogen and cooled in an ice bath. To the cooled solution of 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (1.76 g, 9.20 mmol), followed by CH ₂ Cl ₂ (15
3-amino-2,3-dihydro-1-methyl-5- (2-pyridyl) -1H-1,4-benzodiazepin-2-one (2.45 g, 9.20 mmol) dissolved in
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 a tan foam. The title compound was crystallized from CH ₂ Cl ₂ / EtOAc to give 3.47 g of white crystals.
(86% yield). Melting point 228-229 [deg.] C. Elemental analysis (C ₂₃ H ₂₇ N ₅ as O _4); Calculated: 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] -2,2 in CH ₂ Cl ₂ (90 mL). 3-dihydro-1-methyl-5- (2-pyridyl) -1H-
A solution of 1,4-benzodiazepin-2-one (3.42 g, 7.82 mmol) was 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 1M aqueous K ₂ CO _{3 and the} aqueous layer was back-extracted with CH ₂ Cl ₂ . The extracts were combined, washed with H ₂ O and dried (M
gSO ₄ ) and concentrated to give 1.75 g (66% yield) of the title compound as an off-white foam. 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,
Broad), 1.45 (3H, 3).

Example C-AF 3-[(L-alaninyl) amino] -2,3-dihydro-1- (2-N, N-diethylaminoethyl) -5- (2-pyridyl) -1H-1, Synthesis of 4-benzodiazepin-2-one Step A: 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).

Step B: 3-[(N-tert-butoxycarbonyl-L-alaninyl) amino]-
Synthesis of 2,3-dihydro-1- (2-N, N-diethylaminoethyl) -5- (2-pyridyl) -1H-1,4-benzodiazepin-2-one L-Boc-alanine (1.80 g, 9.50 mmol), HOBt monohydrate (1
. 28 g, 9.50 mmol), diisopropylethylamine (1.65 mL, 9,
A solution of 50 mmol) and CH ₂ Cl ₂ (40 mL) was purged with nitrogen and cooled in an ice bath. To the cooled solution of 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (1.82 g, 9.50 mmol), followed by CH ₂ Cl ₂ (25 mL)
3-amino-2,3-dihydro-1- (2-N, N-diethylaminoethyl) -5- (2-pyridyl) -1H-1,4-benzodiazepin-2-one (
(3.34 g, 9.50 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, 5% NaHCO ₃ solution and brine. The remaining CH ₂ Cl ₂ solution was dried (MgSO ₄ ) and concentrated to a tan foam. Column chromatography (2% MeOH / CH ₂ Cl ₂ → 10% M
The title compound was isolated by MeOH / CH ₂ Cl ₂ ) and 3.53 g (71
% Yield). MS (FD ^<+> ) 522 (m / z). ¹ H NMR (CDCl ₃ ): δ = 8.62 (1H, d), 8.11 (1H, m), 7.80
(2H, m), 7.59 (2H, m), 7.32-7.45 (2H, m), 5.54 (1H, m
), 5.02-5.18 (1H, m), 4.38 (1H, m), 4.20 (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 procedure 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-1,4-
A solution of benzodiazepin-2-one (3.52 g, 6.73 mmol) was added to TFA (1
(1.4 mL, 148 mmol) to give 2.61 g (92% yield) of the title compound as a pale yellow foam. MS (IS ^<+> ) 423 (m / e). ¹ 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), 7.39 (2H, m)
), 5.58 (1H, m), 4.22 (1H, m), 3.88 (1H, 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 of on 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).

Step B: 3-[(N-tert-butoxycarbonyl-L-alaninyl) amino]-
Synthesis of 2,3-dihydro-1- (3,3-dimethyl-2-oxobutyl) -5- (2-pyridyl) -1H-1,4-benzodiazepin-2-one L-Boc-alanine (1.57 g) , 8,33 mmol), HOBt monohydrate (1
. 13 g, 8.33 mmol), diisopropylethylamine (1.45 mL, 8.3 mmol).
33 mmol) and CH ₂ Cl ₂ (40 mL) were purged with nitrogen and cooled in an ice bath. The cooled solution of 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (1.60 g, 8.33 mmol), followed by 3-amino-2,3-dissolved in CH ₂ Cl ₂ (25 mL) Dihydro-1- (3,3-dimethyl-2-oxobutyl) -5- (2-pyridyl) -1H-1,4-benzodiazepin-2-one (2
. (92 g, 8.33 mmol). 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. Dry the remaining CH ₂ Cl ₂ solution (MgSO ₄ )
And concentrated to a yellow foam. Column chromatography of the title compound (20%
EtOAc / hexane → 60% EtOAc / hexane) to give 4.19 g (96% yield) of a pale yellow foam. MS (FD ^<+> ) 521 (m / z). ¹ H NMR (CDCl ₃ ): δ = 8.65 (1H, t), 8.17 (1H, t), 7.90
(1H, t), 7.71-7.85 (1H, m), 7.54 (1H, m), 7.44 (1H, t
), 7.37 (1H, d), 7.24-7.32 (1H, m), 7.14 (1H, m), 5.67
(1H, dd), 5.18 (1H, broad), 4.93-5.07 (1H, m), 4.50
-4.64 (1H, m), 4.38 (1H, broad), 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 procedure 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-1,4
-A solution of benzodiazepin-2-one (4.18 g, 8.01 mmol) in TFA (
13.6 mL, 176 mmol) to give 3.14 g (93% yield) of the title compound as an off-white foam. MS (IS ^<+> ) 422 (m / e). ¹ 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), 7.42 (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 2- (2-aminobenzoyl) thiazole (Tetrahedron, 51 (3), 773-786, (19
95), Synth. Commun., 26 (4), 721-727 (1996).
The title compound was synthesized in the same manner as described in (1). MS (IS ^<+> ) 273 (m / e). ¹ H NMR (CDCl ₃ ): δ = 7.83-7.94 (2H, m), 7.61 (1H, t
), 7.50 (1H, d), 7.34 (2H, m), 4.60 (1H, s), 3.46 (3H, s)
), 1.97 (2H, broad).

Step B: 3-[(N-tert-butoxycarbonyl-L-alaninyl) amino]-
Synthesis of 2,3-dihydro-1-methyl-5- (2-thiazyl) -1H-1,4-benzodiazepin-2-one L-Boc-alanine (1.85 g, 9.77 mmol), HOBt monohydrate Things (1
. 32 g, 9.77 mmol), diisopropylethylamine (1.70 mL, 9.
77 mmol) and CH ₂ Cl ₂ solution of (30 mL) was purged with nitrogen and cooled in an ice bath. To the cooled solution of 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (1.87 g, 9.77 mmol), followed by CH ₂ Cl ₂ (20 mL)
3-amino-2,3-dihydro-1-methyl-5- (2-thiazyl)-dissolved in
A solution of 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. The reaction mixture was washed with H ₂
Extracted with O, 0.1 N aqueous citric acid, 5% aqueous NaHCO ₃ and brine. The remaining CH ₂ Cl ₂ solution was dried (MgSO ₄ ) and concentrated to a pale yellow foam. The title compound was crystallized from EtOAc / hexane to give 3.22 g of white crystals (7.
4% yield). Melting point 196-197 [deg.] C. Elemental analysis _{(C 21 H 25 N 5 O} 4 as S); Calculated: 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 procedure 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 Step A: Synthesis of 3-amino-2,3-dihydro-1-methyl-5- (2-thiophen-2-yl) -1H-1,4-benzodiazepin-2-one 2- (2-amino Benzoyl) thiophene (Collect. Czech. Chem. Commun., 3
4 (2), 468-478, prepared as described in (1969)) and Synth. Commun., 26 (4
), 721-727 (1996) to synthesize the title compound. 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, broad), 3.45 (3H, s), 2.26 (2H, broad).

Step B: 3-[(N-tert-butoxycarbonyl-L-alaninyl) amino]-
Synthesis of 2,3-dihydro-1-methyl-5- (thiophen-2-yl) -1H-1,4-benzodiazepin-2-one Compounds were synthesized. 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, broad), 4.36 (1H, broad), 3.
44 (3H, s), 1.38-1.57 (12H, m).

Step C: 3-[(L-alaninyl) amino] -2,3-dihydro-1-methyl-
Synthesis of 5- (thiophen-2-yl) -1H-1,4-benzodiazepin-2-one The title compound was synthesized in the same manner as described in Example 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 1 5- [N ′-(2S-hydroxy-3-methylbutyryl) -2S-aminopropyl]
Amino-7-methyl-5,7-dihydro-6H-dibenzo [b, d] azepine-6
Synthesis of ON Step A- Synthesis of N-Boc-L-Alaninal (Synthesis of N-Boc-L-Alaninal) Methylene chloride (50 mL) was added to a flask equipped with an addition funnel, and -7 was added.
After cooling to 8 ° C, 1.6 mL of oxalyl chloride (18.3 mmol, 2.
4 eq.). When this was stirred for 5 minutes, 1.8 mL (25.4 mmol, 3.3 eq) of dimethyl sulfoxide dissolved in CH ₂ Cl ₂ (20 mL) was added over 5 minutes. This was stirred for a further 5 minutes before N ₂ in CH ₂ Cl ₂ (20 mL).
1.4 g (7.8 mmol, 1.0 equiv) of -Boc-L-alaninol (Aldrich) were added. After stirring the reaction mixture for 5 minutes, 6.5 mL of triethylamine (4
(6.6 mmol, 6.0 equiv) was added and the reaction was warmed to room temperature for 10 minutes. The reaction was quenched with 200 mL of 0.1N HCl aqueous solution, which was added to CH ₂ Cl ₂ 2 × 1
Extracted with 00 mL. The combined organic layers were washed with 100 mL of saturated NaHCO ₃ , then with 100 mL of saturated NaCl, dried over Na ₂ SO ₄ and removed under reduced pressure. The remaining oil was passed through a silica gel plug using ethyl acetate (EtOAc). Removal of the solvent under reduced pressure gave 1.14 g (85%) of the desired product. NMR data were as follows: ¹ H NMR (300 MHz, CDCl ₃ ): δ = 9.56 (s, 1 H, CHO), 5.
06 (bs, 1H, NH) , 4.24 (bq, 1H, CH), 1.45 (s, 9H, C (CH 3) 3), 1.33 (d, 3H, J = 7.2Hz, CHCH _3). M ⁺ (ion spray) calculated (as C ₈ H ₁₅ NO ₃ ): 173.2, found:
174.2 (M + 1H).

Step B- 5- [N '-(tert-butyloxycarbonyl) -2S-aminopropyl
Ru] -Amino-7-methyl-5,7-dihydro-6H-dibenzo [b, d] azepine
Synthesis of -6-one 5-Amino-7-methyl-5,7-dihydro-6H- in 50 mL of methanol
620 mg (2.6 mmol, 1.0 equivalent) of dibenzo [b, d] azepin-6-one (
To the solution of Example 7-A) was added 653 mg (3.8 mmol) of N-Boc-L-alaninal.
, 1.4 equivalents) (Step A) and then 74 mg of sodium cyanoborohydride
(1.2 mmol, 0.5 equiv) was added. After stirring for 1 hour at room temperature, the solvent was removed.
Removed. The solid obtained was dissolved in 50 mL of methylene chloride and NaHCO _Three Wash with 50 mL of saturated aqueous solution. Re-extract the aqueous layer with 50 mL of methylene chloride
did. Combine the organic solvents and add Na_TwoSO_FourAnd removed under reduced pressure. Crude production
The product was purified by flash chromatography (hexane: ethyl acetate 1: 1).
Purification afforded 309 mg (30%) of the desired product. The NMR data was as follows:¹1 H NMR (300 MHz, CDCl_Three): Δ = 7.64-7.31 (m, 8H, good
Aromatic (Hs), 4.04 (bs, 1H, CHN), 3.73 (bs, 1H, CHC)
H_Three), 3.34 (s, 3H, NCH_Three), 2.78 (dd, 1H, J = 4.9, 12.0 Hz,
CHHN), 2.48 (dd, 1H, J = 6.8, 12.0 Hz, CHHN), 1.43 (s
, 9H, CCH_Three), 1.17 (d, 3H, J = 6.8 Hz, CHCH_Three). M⁺(Ion spray) calculated value (C_{twenty three}H₂₉N_ThreeO_ThreeAs): 395.5, measured
: 396.1 (M + 1H).

Step C—Synthesis of 5- (2S-aminopropyl) -amino-7-methyl-5,7-dihydro-6H-dibenzo [b, d] azepin-6-one 5- [N in 30 mL of dioxane '-(Tert-butyloxycarbonyl) -2S-
Aminopropyl] amino-7-methyl-5,7-dihydro-6H-dibenzo [b, d
] Azepin-6-one 317 mg (0.8 mmol) (step B) in a solution of HCl (
g) was bubbled for 15 minutes. After stirring at room temperature for 17 hours, the solvent was removed under reduced pressure to give 248 mg (94%) of a white solid. It was used without further purification. The NMR data were as follows: ¹ H NMR (300 MHz, CD ₃ OD) 7.73-7.45 (m, 8H, aromatic
Hs), 3.76 (m, 1 H, CHCH ₃ ), 3.38 (m, 5 H, NCH ₃ and CH ₂ N),
1.46 (d, 3H, J = 6.4Hz, CHCH 3). M ⁺ (ion spray) calculated (as C ₁₈ H ₂₁ N ₃ O): 295.4, found:
296.4 (M + 1H).

Step D-5- [N '-(2S-hydroxy-3-methylbutyryl) -2S-aminopropyl] amino-7-methyl-5,7-dihydro-6H-dibenzo [b, d] azepine-6 Synthesis of -one 4: 1 tetrahydrofuran (THF): dimethylformamide (DMF) 2
240 mg (0.8 mmol, 1. mmol) of 5- (2S-aminopropyl) -amino-7-methyl-5,7-dihydro-6H-dibenzo [b, d] azepin-6-one in 5 mL.
(0 equivalent) (125 mg of 2S-2-hydroxy-3-methylbutyric acid)
(1.1 mmol, 1.3 equivalents), N-ethyl-N ′-(3-dimethylaminopropyl
) -Carbodiimide 184 mg (1.0 mmol, 1.2 equiv), 1-hydroxybenzotriazole hydrate 139 mg (0.9 mmol, 1.1 equiv) and diisopropylethylamine 0.5 mL (2.9 mmol, 3.5 equiv) Was added. The reaction mixture was stirred at room temperature for 20 hours. The solvent was removed and the remaining oil was washed with CH ₂ Cl ₂ 30
It was diluted with mL and washed with 25 mL of 0.1N HCl aqueous solution. The aqueous layer was washed with CH ₂ Cl ₂
Back-extracted with 25 mL. The organic layers were combined, dried over Na ₂ SO ₄ and removed under reduced pressure. The crude product was purified by flash column chromatography (ethyl acetate) to give 38 mg (12%) of the desired product as a white solid. NMR data were as follows: ¹ H NMR (300 MHz, CDCl ₃ ): δ = 7.62-7.37 (m, 8H, aromatic Hs), 6.67 (d, 1H, J = 9). 4.0Hz, NHCO) 4.61 (m, 1H, CH
CH ₃ ), 4.40 (bs, 1H, CHNH), 4.13 (d, 1H, J = 3.8 Hz, CH
OH), 3.38 (s, 3H, NCH ₃ ), 2.95 (m, 2H, CH ₂ NH), 2.10 (m,
_{1H, CH (CH 3) 2} ), 1.26 (d, 3H, J = 6.4Hz, CHCH 3), 1.06 (d
, 3H, J = 6.8 Hz, CH (CH ₃ ) ₂ ), 0.93 (d, 3H, J = 6.8 Hz, CH (C
H ₃ ) ₂ ). M ⁺ (ion spray) Calculated (as _{C 23 H 29 N 3 O 3} ): 395.5, Found: 396.1 (M + 1H). Element (as _{C 23 H 29 N 3 O 3} ) analysis; Calcd: C, 69.85; H, 7.39 ; N,
10.62. Found: C, 69.63; H, 7.44; N, 10.32.

Further, the procedures described herein, as well as art-recognized starting materials,
Using reagents and techniques, the compound moiety represented by the formula: -NH-W has the following structure (
Wherein X, Y and Z, if undefined, represent an aryl ring substituent) can be prepared.

[0490]

Embedded image

Embedded image

[0490]

Embedded image

Embedded image

[0492]

Embedded image

Embedded image

[0493]

Embedded image

Embedded image

[0494]

Embedded image

Embedded image

[0495]

Embedded image

Embedded image

[0496]

Embedded image

Embedded image

[0497]

Embedded image

Embedded image

[0498]

Embedded image

Embedded image

[0499]

Embedded image

Embedded image

[0500]

Embedded image

Embedded image

[0501]

Embedded image

Embedded image

[0502]

Embedded image

Embedded image

[0503]

Embedded image

Embedded image

[0504]

Embedded image

Example 2 Screening of Cells 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 a Swedish mutation. In this screening assay, as described in International Patent Application Publication No. 94/10569 ⁸ and Citron et al. ^16, (
Cells stably transfected with the gene for amyloid precursor protein 751 (APP751) having a double mutation from Lys ₆₅₁ Met ₆₅₂ to Asn ₆₅₁ Leu ₆₅₂ (with APP751 numbering) (K293 = human kidney cell line) Was used. This mutation is commonly referred to as the Swedish mutation and is described in "293 75
1 SWE "at 2-4 × 10 ⁴ cells / well in Dulbecco's minimal essential medium (Sigma, St. Louis, MO) supplemented with 10% fetal calf serum.
Plated in 96 well plates. Within the linear range of this assay (about 0
. 2 to 2.5 ng / mL) to achieve β-amyloid ELISA results.
Cell number is important.

After overnight incubation at 37 ° C. in an incubator equilibrated with 10% carbon dioxide, the pretreatment step of 2 hours removes the medium and 200 μL per well of a compound of formula I (drug) Medium was replaced and the cells were incubated as described above. At the final drug concentration used in the treatment, the dimethylsulfoxide concentration does not exceed 0.5%, and in fact usually equals 0.1%,
A drug stock solution was prepared in 100% dimethyl sulfoxide.

At the end of the pretreatment step, the medium was removed again, replaced with fresh drug-containing medium as described above, and the cells were incubated for a further 2 hours. After processing, using Beckman GPR,
Plates are centrifuged at 1200 rpm for 5 minutes at room temperature and cell debris from conditioned medium
Was pelleted. From each well, the conditioned media or appropriate dilutions 100 [mu] L, are described in International Patent Application Publication No. 94/10569 Patent ^8, beta
-Antibody 266 against amino acids 13-28 of the amyloid peptide [P. Seubert,
ELISA pre-coated with Nature (1992) 359: 325-327]
Transferred to plate and stored at 4 ° C. overnight. The next day, labeled antibody 3D6 against amino acids 1-5 of the β-amyloid peptide [P. Seubert, Nature (1992) 359:
325-327], and an ELISA assay using ¹⁷ was performed to measure the amount of β-amyloid peptide produced.

The method of Hansen, et al. ¹⁸ with modifications was used to determine the cytotoxic effect of the compounds. For the cells remaining on the tissue culture plate, 3- (4,5-dimethylthiazol-2-yl) -2,5-diphenyltetrazolium bromide (MTT) (
(Sigma, St. Louis, MO) stock solution (5 mg / mL) was added to a final concentration of 1 mg / mL. Cells were incubated for 1 hour at 37 ° C. and cell activity was stopped by adding an equal volume of MTT lysis buffer (20% w / v sodium dodecyl sulfate in 50% dimethylformamide, pH 4.7). Shake overnight at room temperature to extract completely. The difference between OD _{562 nm} and OD _{650 nm} was measured with a Molecular Device's UV _max microplate reader and used as an index of cell viability.

The results of the β-amyloid peptide ELISA were fitted to a standard curve and expressed as β-amyloid peptide (ng / mL). To normalize cytotoxicity, these results were divided by the MTT results and expressed as a percentage of the results from drug-free controls. All results are the mean and standard deviation of at least 6 replicate assays.

Using this assay, test compounds were assayed for inhibitory activity of β-amyloid peptide production in cells. From the results of this assay, the compound of formula I
When used at 0 μg / mL, β-up to at least 30% compared to control.
It is shown to inhibit amyloid peptide production.

Example 3 In Vivo Inhibition of β-Amyloid Release and / or Synthesis This example describes how compounds of the invention can be tested for in vivo inhibition of β-amyloid release and / or synthesis. In these experiments, ages 3-4
Using a PDAPP mouse of the month [Games et al, (1995) Nature 373:. 523-527] 1 9. Compounds are usually formulated in the range of 1-10 mg / mL, depending on which compound is being tested. Due to the low solubility of this compound, various vehicles, such as corn oil (Safeway, South San Francisco, CA); 10% in corn oil
Ethanol; 2-hydroxypropyl-β-cyclodextrin (Research Bio
chemicals International, Natick MA); and carboxy-methyl-cellulose (Sigma Chemical Co., St. Louis MO).

Mice were subcutaneously dosed with a 26 gauge needle, and after 3 hours, the animals were euthanized with CO ₂ anesthesia and coated with 0.5 M EDTA solution (pH 8.0).
The heart is punctured using a cc 25G 5/8 "tuberculin syringe / needle and blood is collected. The blood is placed in a Becton-Dickinson vacutainer tube containing EDTA and centrifuged at 1500 xg for 15 minutes at 5 ° C. The mouse brain is then removed, the cortex and hippocampus are dissected and placed on ice.

[0513] 1. Brain Assay To prepare hippocampus and cortical tissue for enzyme-linked immunosorbent assays (ELISAs), each brain region was ice-cold guanidine buffer (5.0 M guanidine-HCl, using Kontes motorized pestle (Fisher, Pittsburgh PA) Homogenize to 10 volumes of 50 mM Tris-HCl, pH 8.0. The homogenate is gently shaken on a rotating table at room temperature for 3 to 4 hours until the β-amyloid is determined.
Stored at -20 ° C.

The brain homogenate was added to an 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]
After dilution, thereby reducing the final concentration of guanidine to 0.5 M, the mixture was centrifuged at 4 ° C. for 20 minutes at 16,000 × g. If necessary, the sample is further diluted by adding casein buffer supplemented with 0.5 M guanidine hydrochloride to bring it to the optimal range for ELISA measurements. A β-amyloid standard (1-40 or 1-42 amino acids) was prepared and the final composition was adjusted to 0.1% in the presence of 0.1% bovine serum albumin (BSA).
Equivalent to 5M guanidine.

A total β-amyloid sandwich ELISA, quantifying both β-amyloid (aa 1-40) and β-amyloid (aa 1-42), was obtained from two monoclonal antibodies (mAb) against β-amyloid. Be composed. The capture antibody, 266 [P. Seubert, Nature (1992) 359: 325-327], is specific for amino acids 13-28 of β-amyloid. An antibody specific for amino acids 1-5 of β-amyloid, 3D6 [Johnson-Wood et al., PNAS USA (1997) 94: 1550-1555] ²⁰ is biotinylated and serves as a reporter antibody in the assay. This 3
The D6 biotinylation procedure consists of a 100 mM sodium bicarbonate buffer (pH 8.5).
Utilizes the manufacturer's (Pierce, Rockford IL) protocol for NHS-biotin labeling of immunoglobulins except using The 3D6 antibody does not recognize secreted amyloid precursor protein (APP) or full-length APP,
Only β-amyloid species having an amino-terminal aspartic acid are detected. This assay has a lower sensitivity of 〜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 ELISA configuration that quantifies the amount of β-amyloid (aa 1-42), mAb 21F (recognizing amino acids 33-42 of β-amyloid) was used.
12 [Johnson-Wood et al., PNAS USA (1997) 94: 1550-1555] is used as the capture antibody. Also, biotinylated 3D6 has a concentration of ~ 125 pg / mL (28 pM).
Is the reporter antibody for this assay with a lower sensitivity of

The 266 and 21F12 captured mAbs are coated at 10 μg / mL into a 96-well immunoassay plate (Costar, Cambidge MA) at room temperature overnight.
The plate is then aspirated and incubated at room temperature for at least 1 hour with 0,0 in PBS buffer.
After protection with 25% human serum albumin, store dry at 4 ° C. until use.
Rehydrate the plate with wash buffer (Tris-buffered saline, 0.05% Tween 20) before use. Add sample and control to plate and incubate at 4 ° C. overnight. The plate is washed three or more times with wash buffer between each step of the assay. Biotinylated 3D6 was placed in casein incubation buffer (0.25% casein, PBS, 0.05% Tween 20, pH 7.4) in 0.5.
Dilute to μg / mL and incubate in well for 1 hour at room temperature. Avidin-HRP (Vect) diluted 1: 4000 in casein incubation buffer
or Burlingame CA) at room temperature for 1 hour. Sl, a colorimetric substrate
After adding ow TMB-ELISA (Pierce, Cambridge MA) and reacting for 15 minutes,
The enzyme reaction is stopped by adding 2N H ₂ SO ₄ . Molecular Devices Vmax (Molecul
The reaction product is quantified by measuring the difference in absorbance at 450 nm and 650 nm using ar Devices, Menlo Park CA).

[0518] 2. 1. Blood assay Sample diluent (0.2 gm / L sodium phosphate monohydrate (monovalent base);
16 gm / L sodium phosphate heptahydrate (divalent base), 0.5 gm / L thimerosal, 8.5 gm / L sodium chloride, 0.5 mL Triton X-405,
Bovine serum albumin without 6.0 g / L globulin; and
Dilute TA plasma 1: 1. Using the total β-amyloid assay described above for the brain assay (266 capture / 3D6 reporter) except for using the sample diluent instead of the casein diluent described, the samples in this sample diluent were Assay a control.

Other formulations may also be used for oral and intravenous delivery to mammals. For oral delivery, the compounds of the invention can be formulated with 100% corn oil, or 80% corn oil, 19.5% oleic acid and 0% oleic acid.
. It can be mixed in a solution containing 5% labrafil. The compound of the present invention may be mixed with the above solution at a concentration ranging from 1 mg / mL to 10 mg / mL. Preferably, the compound in solution is administered orally to the mammal at a dose volume of 5 mL / kg body weight. For IV delivery, the compounds of the invention are preferably mixed with a solution of 3% ethanol, 3% solutol HS-15 and 94% saline. Preferably, the compound of the present invention is mixed with the above solution in a concentration range of 0.25 mg / mL to 5 mg / mL. For IV administration, 2 mL / kg body weight of the compound of the invention in solution
It is preferred to administer to mammals in a dosage volume of.

From the above description, those skilled in the art will be able to make various modifications and alterations to the compositions and methods of the present invention. All such modifications arising from within the scope of the claims are intended to be included within the scope of the claims.

──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. ⁷ Identification symbol FI theme coat ゛ (Reference) C07D 243/12 C07D 243/12 243/14 243/14 243/24 243/24 401/04 401/04 409 / 04 409/04 409/12 409/12 417/04 417/04 471/06 471/06 471/08 471/08 487/04 152 487/04 152 // (C07D 471/06 (C07D 471/06 223 : 00 223: 00 221: 00) 221: 00) (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 No. 6449 Lakeside Woods Circle, Indianapolis, Indiana Richard Sea Thompson United States 46041 I No. 763, North County Road, 900 West, Frankfort, Diana (72) Inventor Stephen Sea Wilkie United States 46268 Quetico Drive, Indianapolis, Indiana No. 8229 (72) Inventor Thomas Sea Britton United States 46033 Royal Oak Lane, Carmel, Indiana 4700 (72) Inventor Warren Jay Porter United States 46260 Indianapolis, Indiana, River No. 8037 (72) Inventor George W. Huffman United States 46032 Indiana Carmel, Maple Crest Drive No. 12 (72) Inventor Lee H. Latimer No. 56, Sheridan Road, Oakland, California 94618 F-term (reference) 4C050 AA01 AA07 BB04 CC11 DD10 EE02 FF02 GG03 HH01 4C063 AA01 BB02 BB09 CC19 CC25 CC28 CC29 CC34 CC43 CC52 CC58 CC62 CC67 CC75 CC92 DD12 DD19 EE01 4C065 AA07 AA09 AA18 BB14 CC09 DD01 EE02 HH01 JJ01 KK02 LL04 PP01 PP03 A02A03 BC03

Claims (83)

[Claims] 1. A method of inhibiting β-amyloid peptide release and / or synthesis thereof in a cell, wherein the cell comprises an effective amount of a compound of formula I effective to inhibit the cell β-amyloid peptide release and / or synthesis. : Wherein W is Embedded image Wherein ring A, taken together with the atom to which it is attached, is aryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, Forming a carbocyclic or heterocyclic ring selected from the group consisting of heteroaryl and heterocyclic; ring B together with the atom to which it is attached is aryl, cycloalkyl, substituted cyclo Forming a carbocyclic or heterocyclic ring selected from the group consisting of alkyl, cycloalkenyl, substituted cycloalkenyl, heteroaryl, and heterocyclic; ring C together with the atom to which it is attached Y forms a heteroaryl or heterocyclic ring; Y is of the formula: And with the proviso at least one of Y - (CHR ^{2 ')} a _a -NH-; R ¹ is alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, substituted alkyl, substituted alkenyl, substituted alkynyl, substituted cycloalkyl, R ² is selected from the group consisting of substituted cycloalkenyl, aryl, heteroaryl and heterocyclic; R ² is alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl,
Selected from the group consisting of substituted alkynyl, cycloalkyl, aryl, heteroaryl and heterocyclic; each R ^{2 ′} is hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, aryl, heteroaryl And R ³ is independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, acyl, aryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cyclo alkenyl, it is selected from the group consisting of heteroaryl and heterocyclic; each R ⁴ is alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, cycloalkyl, substituted consequent Alkyl, cycloalkenyl, substituted cycloalkenyl, are independently selected from the group consisting of heteroaryl and heterocyclic; R ⁵ is alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl,
Q is selected from the group consisting of substituted alkynyl, substituted amino, aryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heteroaryl, heterocyclic, thioalkoxy and substituted thioalkoxy; Q is oxygen, sulfur, -S (O) - or S (O) ₂ - a and; Z is the formula: -T-CX'X "C (O ) - represented by wherein, T is R ¹ and -CX'X" - connecting Covalent single bond, oxygen, sulfur and-
NR ⁶ is selected from the group consisting of R ⁶ is hydrogen, acyl, alkyl, aryl or heteroaryl group; X ′ is hydrogen, hydroxy or fluoro, and X ″ is hydrogen, hydroxy or fluoro Or X ′ and X ″ together form an oxo group; a is an integer from 2 to 6; f is an integer from 0 to 2; m is an integer from 0 or 1; Is an integer of 1 or 2.] or a pharmaceutically acceptable salt thereof, or a mixture thereof. 2. A method of preventing the onset of AD in a human patient at risk of developing AD, comprising the step of providing the patient with a pharmaceutically inert carrier and an effective amount of Formula I: Wherein W is Embedded image Wherein ring A, taken together with the atom to which it is attached, is aryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, Forming a carbocyclic or heterocyclic ring selected from the group consisting of heteroaryl and heterocyclic; ring B together with the atom to which it is attached is aryl, cycloalkyl, substituted cyclo Forming a carbocyclic or heterocyclic ring selected from the group consisting of alkyl, cycloalkenyl, substituted cycloalkenyl, heteroaryl, and heterocyclic; ring C together with the atom to which it is attached Y forms a heteroaryl or heterocyclic ring; Y is of the formula: And with the proviso at least one of Y - (CHR ^{2 ')} a _a -NH-; R ¹ is alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, substituted alkyl, substituted alkenyl, substituted alkynyl, substituted cycloalkyl, R ² is selected from the group consisting of substituted cycloalkenyl, aryl, heteroaryl and heterocyclic; R ² is alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl,
Selected from the group consisting of substituted alkynyl, cycloalkyl, aryl, heteroaryl and heterocyclic; each R ^{2 ′} is hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, aryl, heteroaryl And R ³ is independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, acyl, aryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cyclo alkenyl, it is selected from the group consisting of heteroaryl and heterocyclic; each R ⁴ is alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, cycloalkyl, substituted consequent Alkyl, cycloalkenyl, substituted cycloalkenyl, are independently selected from the group consisting of heteroaryl and heterocyclic; R ⁵ is alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl,
Q is selected from the group consisting of substituted alkynyl, substituted amino, aryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heteroaryl, heterocyclic, thioalkoxy and substituted thioalkoxy; Q is oxygen, sulfur, -S (O) - or S (O) ₂ - a and; Z is the formula: -T-CX'X "C (O ) - represented by wherein, T is R ¹ and -CX'X" - connecting Covalent single bond, oxygen, sulfur and-
NR ⁶ is selected from the group consisting of R ⁶ is hydrogen, acyl, alkyl, aryl or heteroaryl group; X ′ is hydrogen, hydroxy or fluoro, and X ″ is hydrogen, hydroxy or fluoro Or X ′ and X ″ together form an oxo group; a is an integer from 2 to 6; f is an integer from 0 to 2; m is an integer from 0 or 1; Is an integer of 1 or 2.] or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the mixture thereof. 3. A method of treating a human AD patient to prevent further exacerbation of the condition, comprising administering to said patient a pharmaceutically inert carrier and an effective amount of a compound of formula I: Wherein W is Embedded image Wherein ring A, taken together with the atom to which it is attached, is aryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, Forming a carbocyclic or heterocyclic ring selected from the group consisting of heteroaryl and heterocyclic; ring B together with the atom to which it is attached is aryl, cycloalkyl, substituted cyclo Forming a carbocyclic or heterocyclic ring selected from the group consisting of alkyl, cycloalkenyl, substituted cycloalkenyl, heteroaryl, and heterocyclic; ring C together with the atom to which it is attached Y forms a heteroaryl or heterocyclic ring; Y is of the formula: And with the proviso at least one of Y - (CHR ^{2 ')} a _a -NH-; R ¹ is alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, substituted alkyl, substituted alkenyl, substituted alkynyl, substituted cycloalkyl, R ² is selected from the group consisting of substituted cycloalkenyl, aryl, heteroaryl and heterocyclic; R ² is alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl,
Selected from the group consisting of substituted alkynyl, cycloalkyl, aryl, heteroaryl and heterocyclic; each R ^{2 ′} is hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, aryl, heteroaryl And R ³ is independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, acyl, aryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cyclo alkenyl, it is selected from the group consisting of heteroaryl and heterocyclic; each R ⁴ is alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, cycloalkyl, substituted consequent Alkyl, cycloalkenyl, substituted cycloalkenyl, are independently selected from the group consisting of heteroaryl and heterocyclic; R ⁵ is alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl,
Q is selected from the group consisting of substituted alkynyl, substituted amino, aryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heteroaryl, heterocyclic, thioalkoxy and substituted thioalkoxy; Q is oxygen, sulfur, -S (O) - or S (O) ₂ - a and; Z is the formula: -T-CX'X "C (O ) - represented by wherein, T is R ¹ and -CX'X" - connecting Covalent single bond, oxygen, sulfur and-
NR ⁶ is selected from the group consisting of R ⁶ is hydrogen, acyl, alkyl, aryl or heteroaryl group; X ′ is hydrogen, hydroxy or fluoro, and X ″ is hydrogen, hydroxy or fluoro Or X ′ and X ″ together form an oxo group; a is an integer from 2 to 6; f is an integer from 0 to 2; m is an integer from 0 or 1; Is an integer of 1 or 2.] or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the mixture thereof. 4. The method according to claim 1, wherein a is 2. 5. Rings A and B are preferably aryl, cycloalkyl,
5. The method of claim 4, wherein the method is independently selected from the group consisting of cycloalkenyl, heteroaryl, and heterocyclic. 6. The method of claim 5, wherein rings A and B are independently aryl. 7. The method of claim 4, wherein m is 0. 8. The method according to claim 7, wherein R ¹ is aryl or heteroaryl. 9. R ¹ is (a) phenyl, (b) a compound represented by the formula: Wherein R ^c is acyl, alkyl, alkoxy, alkylalkoxy, azide,
Selected from the group consisting of cyano, halo, hydrogen, nitro, trihalomethyl, thioalkoxy, wherein R ^b and R ^c are fused to form a heteroaryl or heterocyclic ring with the phenyl ring, The cyclic ring contains 3-8 atoms, of which 1-3 are heteroatoms independently selected from the group consisting of oxygen, nitrogen and sulfur; R ^b and R ^{b ′} are hydrogen, Independently selected from the group consisting of halo, nitro, cyano, trihalomethyl, alkoxy and thioalkoxy, provided that when R ^c is hydrogen, then R ^b and R ^{b ′} are both hydrogen, or both are hydrogen. A substituted phenyl group represented by the formula: (c) 2-naphthyl, (d) an alkyl at the fourth, fifth, sixth, seventh and / or eighth position 2- (naphthyl) substituted with 1-5 substituents selected from the group consisting of alkoxy, halo, cyano, nitro, trihalomethyl, thioalkoxy, aryl and heteroaryl, (e) heteroaryl, (f) Substituted heteroaryl containing 1 to 3 substituents selected from the group consisting of alkyl, alkoxy, aryl, aryloxy, cyano, halo, nitro, heteroaryl, thioalkoxy, thioaryloxy, provided that the substituent is 9. The method of claim 8, wherein the heteroaryl is selected from the group consisting of: (g) not ortho to the bond to the -NH group) and (g) alkyl. 10. The method according to claim 8, wherein R ¹ is selected from the group consisting of mono-, di- and tri-substituted phenyl groups. 11. R ¹ is 3,5-dichlorophenyl, 3,5-difluorophenyl, 3,5-di (trifluoromethyl) -phenyl, 3,4-dichlorophenyl,
3,4-difluorophenyl, 3- (trifluoromethyl) -4-chlorophenyl, 3-chloro-4-cyanophenyl, 3-chloro-4-iodophenyl and 3
The method according to claim 10, which is a disubstituted phenyl selected from the group consisting of, 4-methylenedioxyphenyl. 12. R ¹ is 4-azidophenyl, 4-bromophenyl, 4-chlorophenyl, 4-cyanophenyl, 4-ethylphenyl, 4-fluorophenyl, 4-iodophenyl, 4- (phenylcarbonyl) -phenyl And 4- (1
-Ethoxy) ethylphenyl is a monosubstituted phenyl selected from the group consisting of:
The method according to claim 10. 13. R ¹ is 3,4,5-trifluorophenyl and 3,4,5
2. A trisubstituted phenyl selected from the group consisting of trichlorophenyl.
The method according to 0. 14. The method according to claim 8, wherein R ¹ is selected from 2-naphthyl, quinolin-3-yl, 2-methylquinolin-6-yl, benzothiazol-6-yl, 5-indolyl and phenyl. Method. 15. The method of claim 4, wherein m is 1. 16. R¹Is phenyl, 1-naphthyl, 2-naphthyl, 2-chloro
Rophenyl, 2-fluorophenyl, 2-bromophenyl, 2-hydroxyphen
Nil, 2-nitrophenyl, 2-methylphenyl, 2-methoxyphenyl, 2-
Phenoxyphenyl, 2-trifluoromethylphenyl, 4-fluorophenyl
, 4-chlorophenyl, 4-bromophenyl, 4-nitrophenyl, 4-methyl
Phenyl, 4-hydroxyphenyl, 4-methoxyphenyl, 4-ethoxyfe
Nyl, 4-butoxyphenyl, 4-iso-propylphenyl, 4-phenoxyf
Phenyl, 4-trifluoromethylphenyl, 4-hydroxymethylphenyl, 3
-Methoxyphenyl, 3-hydroxyphenyl, 3-nitrophenyl, 3-fur
Orophenyl, 3-chlorophenyl, 3-bromophenyl, 3-phenoxyfe
Nyl, 3-thiomethoxyphenyl, 3-methylphenyl, 3-trifluoromethyl
Phenyl, 2,3-dichlorophenyl, 2,3-difluorophenyl, 2,4-
Dichlorophenyl, 2,5-dimethoxyphenyl, 3,4-dichlorophenyl, 3
, 4-Difluorophenyl, 3,4-methylenedioxyphenyl, 3,4-dimethoate
Xyphenyl, 3,5-difluorophenyl, 3,5-dichlorophenyl, 3,5
-Di- (trifluoromethyl) phenyl, 3,5-dimethoxyphenyl, 2,4-
Dichlorophenyl, 2,4-difluorophenyl, 2,6-difluorophenyl,
3,4,5-trifluorophenyl, 3,4,5-trimethoxyphenyl, 3,4,5
-Tri- (trifluoromethyl) phenyl, 2,4,6-trifluorophenyl, 2
, 4,6-Trimethylphenyl, 2,4,6-tri- (trifluoromethyl) phenyl
2,3,5-trifluorophenyl, 2,4,5-trifluorophenyl, 2,5
-Difluorophenyl, 2-fluoro-3-trifluoromethylphenyl, 4-
Fluoro-2-trifluoromethylphenyl, 2-fluoro-4-trifluoro
Methylphenyl, 4-benzyloxyphenyl, 2-chloro-6-fluorophen
Nil, 2-fluoro-6-chlorophenyl, 2,3,4,5,6-pentafluorophenyl
Phenyl, 2,5-dimethylphenyl, 4-phenylphenyl, 2-fluoro-3
-Trifluoromethylphenyl, adamantyl, benzyl, 2-phenylethyl
, 3-phenyl-n-propyl, 4-phenyl-n-butyl, methyl, ethyl,
n-propyl, iso-propyl, iso-butyl, n-butyl, sec-butyl, ter
t-butyl, n-pentyl, iso-valeryl, n-hexyl, cyclopropyl,
Cyclobutyl, cyclohexyl, cyclopentyl, cyclopent-1-enyl,
Cyclopent-2-enyl, cyclohex-1-enyl, -CH_Two-Cyclopro
Pill, -CH_Two-Cyclobutyl, -CH_Two-Cyclohexyl, -CH_Two-Cyclope
Ethylene, -CH_TwoCH_Two-Cyclopropyl, -CH_TwoCH_Two-Cyclobutyl, -CH _Two CH_Two-Cyclohexyl, -CH_TwoCH_Two-Cyclopentyl, pyrid-2-yl,
Pyrid-3-yl, pyrid-4-yl, fluoropyridyl (5-fluoropyrido
-3-yl), chloropyridyl (including 5-chloropyrid-3-yl),
Thien-2-yl, thien-3-yl, benzothiazol-4-yl, 2-fe
Nilbenzoxazol-5-yl, furan-2-yl, benzofuran-2-i
Thionaphthen-2-yl, thionaphthen-3-yl, thionaphthen-4-i
2-chlorothiophen-5-yl, 3-methylisoxazol-5-yl
, 2- (thiophenyl) thien-5-yl, 6-methoxythionaphthen-2-yl
, 3-phenyl-1,2,4-thiooxadiazol-5-yl, 2-phenyl
Oxazol-4-yl, indol-3-yl, 1-phenyl-tetraol
-5-yl, allyl, 2- (cyclohexyl) ethyl, (CH_Three)_TwoCH = CHCH_Two
CH_TwoCH (CH_Three)-, ΦC (O) CH_Two-, Thien-2-yl-methyl, 2- (thiene
2- (2-yl) ethyl, 3- (thien-2-yl) -n-propyl, 2- (4-nitto
Rophenyl) ethyl, 2- (4-methoxyphenyl) ethyl, norborane-2-i
, (4-methoxyphenyl) methyl, (2-methoxyphenyl) methyl, (3-meth
(Toxiphenyl) methyl, (3-hydroxyphenyl) methyl, (4-hydroxyphenyl) methyl
(Enyl) methyl, (4-methoxyphenyl) methyl, (4-methylphenyl) methyl
, (4-fluorophenyl) methyl, (4-fluorophenoxy) methyl, (2,4-
Dichlorophenoxy) ethyl, (4-chlorophenyl) methyl, (2-chlorophenyl
) Methyl, (1-phenyl) ethyl, (1- (p-chlorophenyl) ethyl, (1-
(Trifluoromethyl) ethyl, (4-methoxyphenyl) ethyl, CH_ThreeOC (O) C
H_Two-, Benzylthiomethyl, 5- (methoxycarbonyl) -n-pentyl, 3- (
(Methoxycarbonyl) -n-propyl, indan-2-yl, (2-methylbenzo
Furan-3-yl), methoxymethyl, CH_ThreeCH = CH-, CH_ThreeCH_TwoCH = C
H-, (4-chlorophenyl) C (O) CH_Two-, (4-fluorophenyl) C (O) C
H_Two-, (4-methoxyphenyl) C (O) CH_Two-, 4- (fluorophenyl) -NH
C (O) CH_Two-, 1-phenyl-n-butyl, (φ)_TwoCHNHC (O) CH_TwoCH_Two−
, (CH_Three)_TwoNC (O) CH_Two−, (Φ)_TwoCHNHC (O) CH_TwoCH_Two-, Methylcarbo
Nylmethyl, (2,4-dimethylphenyl) C (O) CH_Two-, 4-methoxyphenyl
-C (O) CH_Two-, Phenyl-C (O) CH_Two-, CH_ThreeC (O) N (φ)-, ethenyl
, Methylthiomethyl, (CH_Three)_ThreeCNHC (O) CH_Two-, 4-fluorophenyl-
C (O) CH_Two-, Diphenylmethyl, phenoxymethyl, 3,4-methylenedi
Xyphenyl-CH_Two-, Benzo [b] thiophen-3-yl, (CH_Three)_ThreeCOC (O
) NHCH_Two-, Trans-styryl, H_TwoNC (O) CH_TwoCH_Two-, 2-triflu
Oromethylphenyl-C (O) CH_Two, ΦC (O) NHCH (φ) CH_Two−, Mesityl,
CH_ThreeCH (= NHOH) CH_Two-, 4-CH_Three-Φ-NHC (O) CH_TwoCH_Two−, Φ
C (O) CH (φ) CH_Two−, (CH_Three)_TwoCHC (O) NHCH (φ)-, CH_ThreeCH_TwoOC
H_Two-, CH_ThreeOC (O) CH (CH_Three) (CH_Two)_Three-, 2,2,2-trifluoroethyl
, 1- (trifluoromethyl) ethyl, 2-CH_Three-Benzofuran-3-yl, 2
-(2,4-dichlorophenoxy) ethyl, φSO_TwoCH_Two-, 3-cyclohexyl
-N-propyl, CF_ThreeCH_TwoCH_TwoCH_TwoThe group consisting of-and N-pyrrolidinyl
16. The method of claim 15, wherein the method is selected from: 17. The method of claim 4, wherein each R ² is independently selected from the group consisting of alkyl, substituted alkyl, alkenyl, cycloalkyl, aryl, heteroaryl, and heterocyclic. 18. R^TwoIs methyl, ethyl, n-propyl, iso-propyl,
n-butyl, iso-butyl, sec-butyl, tert-butyl, -CH_TwoCH (CH_TwoC
H_Three)_Two, 2-methyl-n-butyl, 6-fluoro-n-hexyl, phenyl,
Benzyl, cyclohexyl, cyclopentyl, cycloheptyl, allyl, iso-butyl
To-2-enyl, 3-methylpentyl, -CH_Two-Cyclopropyl, -CH_Two−
Clohexyl, -CH_TwoCH_Two-Cyclopropyl, -CH_TwoCH_Two-Cyclohexyl
, -CH_Two-Indol-3-yl, p- (phenyl) phenyl, o-fluorophenyl
Phenyl, m-fluorophenyl, p-fluorophenyl, m-methoxyphenyl
, P-methoxyphenyl, phenethyl, benzyl, m-hydroxybenzyl, p
-Hydroxybenzyl, p-nitrobenzyl, m-trifluoromethylphenyl
, P- (CH_Three)_TwoNCH_TwoCH_TwoCH_TwoO-benzyl, p- (CH_Three)_ThreeCOC (O) CH_Two O-benzyl, p- (HOOCCH_TwoO) -benzyl, 2-aminopyrid-6-i
, P- (N-morpholino-CH_TwoCH_TwoO) -benzyl, -CH_TwoCH_TwoC (O) NH _Two , -CH_Two-Imidazol-4-yl, -CH_Two-(3-tetrahydrofuranyl)
, -CH_Two-Thiophen-2-yl, -CH_Two(1-methyl) cyclopropyl, -C
H_Two-Thiophen-3-yl, thiophen-3-yl, thiophen-2-yl,
-CH_Two-C (O) Ot-butyl, -CH_Two-C (CH_Three)_Three, -CH_TwoCH (CH_TwoC
H_Three)_Two, -2-methylcyclopentyl, -cyclohex-2-enyl, -CH [C
H (CH_Three)_Two] COOCH_Three, -CH_TwoCH_TwoN (CH_Three)_Two, -CH_TwoC (CH_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-Bo
c,-(CH_Two)_FourNH_Two, -CH_Two-Pyridyl, pyridyl, -CH_Two-Naphthyl,-
CH_Two-(N-morpholino), p- (N-morpholino-CH_TwoCH_TwoO) -benzyl,
Benzo [b] thiophen-2-yl, 5-chlorobenzo [b] thiophen-2-yl
4,5,6,7-tetrahydrobenzo [b] thiophen-2-yl, benzo [b] thi
Offen-3-yl, 5-chlorobenzo [b] thiophen-3-yl, benzo [b]
Thiophene-5-yl, 6-methoxynaphth-2-yl, -CH_TwoCH_TwoSCH_Three
, Thien-2-yl and Thien-3-yl.
18. The method according to 17. 19. The method of claim 4, wherein R ^{2 '} is independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, cycloalkyl, aryl, heteroaryl, and heterocyclic. 20. R ^{2 ′} is hydrogen, 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) 2 NCH} 2 CH ₂ CH ₂ O-benzyl, p- (CH ₃ ) ₃ COC (
O) CH ₂ O-benzyl, p- (HOOCCH ₂ O) - benzyl, 2-aminopyrido-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, -C
_{H [CH (CH 3) 2} ] COOCH 3, -CH 2 CH 2 N (CH 3) 2, -CH 2 C (CH 3) =
_{CH 2, -CH 2 CH = CHCH} 3 ( cis and _{trans), - CH 2 OH, -CH} (
_{OH) CH 3, -CH (O} -t- _{butyl) CH 3, -CH 2 OCH 3} , - (CH 2) 4 NH
_{-Boc, - (CH 2) 4} NH 2, -CH 2 - pyridyl, pyridyl, -CH ₂ - naphthyl, -CH ₂ - (N-morpholino), p-(N-morpholino -CH ₂ CH ₂ O) - Benzyl, benzo [b] thiophen-2-yl, 5-chlorobenzo [b] thiophen-2
-Yl, 4,5,6,7-tetrahydrobenzo [b] thiophen-2-yl, benzo [
b] thiophen-3-yl, 5-chlorobenzo [b] thiophen-3-yl, benzo [b] thiophen-5-yl, 6-methoxynaphth-2-yl, -CH ₂ CH ₂ S
CH ₃ , selected from the group consisting of thien-2-yl and thien-3-yl,
The method according to claim 19. 21. The method of claim 4, wherein R ³ is selected from the group consisting of hydrogen, alkyl, substituted alkyl, and cycloalkyl. 22. R ³ is hydrogen, methyl, 2-methylpropyl, hexyl, methoxycarbonylmethyl, 3,3-dimethyl-2-oxobutyl, 4-phenylbutyl, cyclopropylmethyl, 2,2,2-trifluoro 22. The method of claim 21, wherein the method is selected from the group consisting of ethyl and cyclohexyl. 23. The method according to claim 4, wherein R ⁴ is hydrogen, alkyl or substituted alkyl. 24. R ⁵ is alkyl, substituted alkyl, substituted amino, phenyl,
5. The method of claim 4, wherein the method is selected from the group consisting of substituted phenyl, cycloalkyl, heteroaryl, heterocyclic, and thioalkoxy. 25. A pharmaceutically acceptable carrier and a pharmaceutically effective amount of Formula I: [Wherein W is embedded image Embedded image Wherein ring A, taken together with the atom to which it is attached, is aryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, Forming a carbocyclic or heterocyclic ring selected from the group consisting of heteroaryl and heterocyclic; ring B together with the atom to which it is attached is aryl, cycloalkyl, substituted cyclo Forming a carbocyclic or heterocyclic ring selected from the group consisting of alkyl, cycloalkenyl, substituted cycloalkenyl, heteroaryl, and heterocyclic; ring C together with the atom to which it is attached Y forms a heteroaryl or heterocyclic ring; Y is of the formula: And with the proviso at least one of Y - (CHR ^{2 ')} a _a -NH-; R ¹ is alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, substituted alkyl, substituted alkenyl, substituted alkynyl, substituted cycloalkyl, R ² is selected from the group consisting of substituted cycloalkenyl, aryl, heteroaryl and heterocyclic; R ² is alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl,
Selected from the group consisting of substituted alkynyl, cycloalkyl, aryl, heteroaryl and heterocyclic; each R ^{2 ′} is hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, aryl, heteroaryl And R ³ is independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, acyl, aryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cyclo alkenyl, it is selected from the group consisting of heteroaryl and heterocyclic; each R ⁴ is alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, cycloalkyl, substituted consequent Alkyl, cycloalkenyl, substituted cycloalkenyl, are independently selected from the group consisting of heteroaryl and heterocyclic; R ⁵ is alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl,
Q is selected from the group consisting of substituted alkynyl, substituted amino, aryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heteroaryl, heterocyclic, thioalkoxy and substituted thioalkoxy; Q is oxygen, sulfur, -S (O) - or S (O) ₂ - a and; Z is the formula: -T-CX'X "C (O ) - represented by wherein, T is R ¹ and -CX'X" - connecting Covalent single bond, oxygen, sulfur and-
Selected from the group consisting of NR ^6, wherein R ⁶ is hydrogen, acyl, alkyl, aryl or heteroaryl group; X ′ is hydrogen, hydroxy or fluoro; Or X ′ and X ″ together form an oxo group; a is an integer from 2 to 6; f is an integer from 0 to 2; m is an integer from 0 or 1; Is an integer of 1 or 2.] or a pharmaceutically acceptable salt thereof. 26. The pharmaceutical composition according to claim 25, wherein a is 2. 27. The pharmaceutical composition according to claim 25, wherein rings A and B are preferably independently selected from the group consisting of aryl, cycloalkyl, cycloalkenyl, heteroaryl and heterocyclic. 28. The pharmaceutical composition according to claim 27, wherein rings A and B are independently aryl. 29. The pharmaceutical composition according to claim 25, wherein m is 0. 30. The method of claim 29, wherein R ¹ is aryl or heteroaryl.
A pharmaceutical composition according to claim 1. 31. R ¹ is (a) phenyl, (b) a compound represented by the formula: Wherein R ^c is acyl, alkyl, alkoxy, alkylalkoxy, azide,
Selected from the group consisting of cyano, halo, hydrogen, nitro, trihalomethyl, thioalkoxy, wherein R ^b and R ^c are fused to form a heteroaryl or heterocyclic ring with the phenyl ring, The cyclic ring contains 3-8 atoms, of which 1-3 are heteroatoms independently selected from the group consisting of oxygen, nitrogen and sulfur; R ^b and R ^{b ′} are hydrogen, Independently selected from the group consisting of halo, nitro, cyano, trihalomethyl, alkoxy and thioalkoxy, provided that when R ^c is hydrogen, then R ^b and R ^{b ′} are both hydrogen, or both are hydrogen. A substituted phenyl group represented by the formula: (c) 2-naphthyl, (d) an alkyl at the fourth, fifth, sixth, seventh and / or eighth position 2- (naphthyl) substituted with 1-5 substituents selected from the group consisting of alkoxy, halo, cyano, nitro, trihalomethyl, thioalkoxy, aryl and heteroaryl, (e) heteroaryl, (f) Substituted heteroaryl containing 1 to 3 substituents selected from the group consisting of alkyl, alkoxy, aryl, aryloxy, cyano, halo, nitro, heteroaryl, thioalkoxy, thioaryloxy, provided that the substituent is 31. The pharmaceutical composition of claim 30, wherein the heteroaryl is selected from the group consisting of: (g) not ortho to the bond to the -NH group) and (g) alkyl. 32. The pharmaceutical composition according to claim 30, wherein R ¹ is selected from the group consisting of mono-, di- and tri-substituted phenyl groups. 33. R ¹ is 3,5-dichlorophenyl, 3,5-difluorophenyl, 3,5-di (trifluoromethyl) -phenyl, 3,4-dichlorophenyl,
3,4-difluorophenyl, 3- (trifluoromethyl) -4-chlorophenyl, 3-chloro-4-cyanophenyl, 3-chloro-4-iodophenyl and 3
33. The pharmaceutical composition according to claim 32, which is a disubstituted phenyl selected from the group consisting of, 4-methylenedioxyphenyl. 34. R ¹ is 4-azidophenyl, 4-bromophenyl, 4-chlorophenyl, 4-cyanophenyl, 4-ethylphenyl, 4-fluorophenyl, 4-iodophenyl, 4- (phenylcarbonyl) -phenyl And 4- (1
-Ethoxy) ethylphenyl is a monosubstituted phenyl selected from the group consisting of:
A pharmaceutical composition according to claim 32. 35. When R ¹ is 3,4,5-trifluorophenyl and 3,4,5-
4. A tri-substituted phenyl selected from the group consisting of trichlorophenyl.
3. The pharmaceutical composition according to 2. 36. The method according to claim 30, wherein R ¹ is selected from 2-naphthyl, quinolin-3-yl, 2-methylquinolin-6-yl, benzothiazol-6-yl, 5-indolyl and phenyl. Pharmaceutical composition. 37. The pharmaceutical composition according to claim 25, wherein m is 1. 38. R¹Is phenyl, 1-naphthyl, 2-naphthyl, 2-chloro
Rophenyl, 2-fluorophenyl, 2-bromophenyl, 2-hydroxyphen
Nil, 2-nitrophenyl, 2-methylphenyl, 2-methoxyphenyl, 2-
Phenoxyphenyl, 2-trifluoromethylphenyl, 4-fluorophenyl
, 4-chlorophenyl, 4-bromophenyl, 4-nitrophenyl, 4-methyl
Phenyl, 4-hydroxyphenyl, 4-methoxyphenyl, 4-ethoxyfe
Nyl, 4-butoxyphenyl, 4-iso-propylphenyl, 4-phenoxyf
Phenyl, 4-trifluoromethylphenyl, 4-hydroxymethylphenyl, 3
-Methoxyphenyl, 3-hydroxyphenyl, 3-nitrophenyl, 3-fur
Orophenyl, 3-chlorophenyl, 3-bromophenyl, 3-phenoxyfe
Nyl, 3-thiomethoxyphenyl, 3-methylphenyl, 3-trifluoromethyl
Phenyl, 2,3-dichlorophenyl, 2,3-difluorophenyl, 2,4-
Dichlorophenyl, 2,5-dimethoxyphenyl, 3,4-dichlorophenyl, 3
, 4-Difluorophenyl, 3,4-methylenedioxyphenyl, 3,4-dimethoate
Xyphenyl, 3,5-difluorophenyl, 3,5-dichlorophenyl, 3,5
-Di- (trifluoromethyl) phenyl, 3,5-dimethoxyphenyl, 2,4-
Dichlorophenyl, 2,4-difluorophenyl, 2,6-difluorophenyl,
3,4,5-trifluorophenyl, 3,4,5-trimethoxyphenyl, 3,4,5
-Tri- (trifluoromethyl) phenyl, 2,4,6-trifluorophenyl, 2
, 4,6-Trimethylphenyl, 2,4,6-tri- (trifluoromethyl) phenyl
2,3,5-trifluorophenyl, 2,4,5-trifluorophenyl, 2,5
-Difluorophenyl, 2-fluoro-3-trifluoromethylphenyl, 4-
Fluoro-2-trifluoromethylphenyl, 2-fluoro-4-trifluoro
Methylphenyl, 4-benzyloxyphenyl, 2-chloro-6-fluorophen
Nil, 2-fluoro-6-chlorophenyl, 2,3,4,5,6-pentafluorophenyl
Phenyl, 2,5-dimethylphenyl, 4-phenylphenyl, 2-fluoro-3
-Trifluoromethylphenyl, adamantyl, benzyl, 2-phenylethyl
, 3-phenyl-n-propyl, 4-phenyl-n-butyl, methyl, ethyl,
n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, ter
t-butyl, n-pentyl, iso-valeryl, n-hexyl, cyclopropyl,
Cyclobutyl, cyclohexyl, cyclopentyl, cyclopent-1-enyl,
Cyclopent-2-enyl, cyclohex-1-enyl, -CH_Two-Cyclopro
Pill, -CH_Two-Cyclobutyl, -CH_Two-Cyclohexyl, -CH_Two-Cyclope
Ethylene, -CH_TwoCH_Two-Cyclopropyl, -CH_TwoCH_Two-Cyclobutyl, -CH _Two CH_Two-Cyclohexyl, -CH_TwoCH_Two-Cyclopentyl, pyrid-2-yl,
Pyrid-3-yl, pyrid-4-yl, fluoropyridyl (5-fluoropyrido
-3-yl), chloropyridyl (including 5-chloropyrid-3-yl),
Thien-2-yl, thien-3-yl, benzothiazol-4-yl, 2-fe
Nilbenzoxazol-5-yl, furan-2-yl, benzofuran-2-i
Thionaphthen-2-yl, thionaphthen-3-yl, thionaphthen-4-i
2-chlorothiophen-5-yl, 3-methylisoxazol-5-yl
, 2- (thiophenyl) thien-5-yl, 6-methoxythionaphthen-2-yl
, 3-phenyl-1,2,4-thiooxadiazol-5-yl, 2-phenyl
Oxazol-4-yl, indol-3-yl, 1-phenyl-tetraol
-5-yl, allyl, 2- (cyclohexyl) ethyl, (CH_Three)_TwoCH = CHCH_Two
CH_TwoCH (CH_Three)-, ΦC (O) CH_Two-, Thien-2-yl-methyl, 2- (thiene
2- (2-yl) ethyl, 3- (thien-2-yl) -n-propyl, 2- (4-nitto
Rophenyl) ethyl, 2- (4-methoxyphenyl) ethyl, norborane-2-i
, (4-methoxyphenyl) methyl, (2-methoxyphenyl) methyl, (3-meth
(Toxiphenyl) methyl, (3-hydroxyphenyl) methyl, (4-hydroxyphenyl) methyl
(Enyl) methyl, (4-methoxyphenyl) methyl, (4-methylphenyl) methyl
, (4-fluorophenyl) methyl, (4-fluorophenoxy) methyl, (2,4-
Dichlorophenoxy) ethyl, (4-chlorophenyl) methyl, (2-chlorophenyl
) Methyl, (1-phenyl) ethyl, (1- (p-chlorophenyl) ethyl, (1-
(Trifluoromethyl) ethyl, (4-methoxyphenyl) ethyl, CH_ThreeOC (O) C
H_Two-, Benzylthiomethyl, 5- (methoxycarbonyl) -n-pentyl, 3- (
(Methoxycarbonyl) -n-propyl, indan-2-yl, (2-methylbenzo
Furan-3-yl), methoxymethyl, CH_ThreeCH = CH-, CH_ThreeCH_TwoCH = C
H-, (4-chlorophenyl) C (O) CH_Two-, (4-fluorophenyl) C (O) C
H_Two-, (4-methoxyphenyl) C (O) CH_Two-, 4- (fluorophenyl) -NH
C (O) CH_Two-, 1-phenyl-n-butyl, (φ)_TwoCHNHC (O) CH_TwoCH_Two−
, (CH_Three)_TwoNC (O) CH_Two−, (Φ)_TwoCHNHC (O) CH_TwoCH_Two-, Methylcarbo
Nylmethyl, (2,4-dimethylphenyl) C (O) CH_Two-, 4-methoxyphenyl
-C (O) CH_Two-, Phenyl-C (O) CH_Two-, CH_ThreeC (O) N (φ)-, ethenyl
, Methylthiomethyl, (CH_Three)_ThreeCNHC (O) CH_Two-, 4-fluorophenyl-
C (O) CH_Two-, Diphenylmethyl, phenoxymethyl, 3,4-methylenedi
Xyphenyl-CH_Two-, Benzo [b] thiophen-3-yl, (CH_Three)_ThreeCOC (O
) NHCH_Two-, Trans-styryl, H_TwoNC (O) CH_TwoCH_Two-, 2-triflu
Oromethylphenyl-C (O) CH_Two, ΦC (O) NHCH (φ) CH_Two−, Mesityl,
CH_ThreeCH (= NHOH) CH_Two-, 4-CH_Three-Φ-NHC (O) CH_TwoCH_Two−, Φ
C (O) CH (φ) CH_Two−, (CH_Three)_TwoCHC (O) NHCH (φ)-, CH_ThreeCH_TwoOC
H_Two-, CH_ThreeOC (O) CH (CH_Three) (CH_Two)_Three-, 2,2,2-trifluoroethyl
, 1- (trifluoromethyl) ethyl, 2-CH_Three-Benzofuran-3-yl, 2
-(2,4-dichlorophenoxy) ethyl, φSO_TwoCH_Two-, 3-cyclohexyl
-N-propyl, CF_ThreeCH_TwoCH_TwoCH_TwoThe group consisting of-and N-pyrrolidinyl
38. The pharmaceutical composition of claim 37, wherein the composition is selected from: 39. The pharmaceutical composition according to claim 25, wherein each R ² is independently selected from the group consisting of alkyl, substituted alkyl, alkenyl, cycloalkyl, aryl, heteroaryl, and heterocyclic. 40. R^TwoIs methyl, ethyl, n-propyl, iso-propyl,
n-butyl, iso-butyl, sec-butyl, tert-butyl, -CH_TwoCH (CH_TwoC
H_Three)_Two, 2-methyl-n-butyl, 6-fluoro-n-hexyl, phenyl,
Benzyl, cyclohexyl, cyclopentyl, cycloheptyl, allyl, iso-butyl
To-2-enyl, 3-methylpentyl, -CH_Two-Cyclopropyl, -CH_Two−
Clohexyl, -CH_TwoCH_Two-Cyclopropyl, -CH_TwoCH_Two-Cyclohexyl
, -CH_Two-Indol-3-yl, p- (phenyl) phenyl, o-fluorophenyl
Phenyl, m-fluorophenyl, p-fluorophenyl, m-methoxyphenyl
, P-methoxyphenyl, phenethyl, benzyl, m-hydroxybenzyl, p
-Hydroxybenzyl, p-nitrobenzyl, m-trifluoromethylphenyl
, P- (CH_Three)_TwoNCH_TwoCH_TwoCH_TwoO-benzyl, p- (CH_Three)_ThreeCOC (O) CH_Two O-benzyl, p- (HOOCCH_TwoO) -benzyl, 2-aminopyrid-6-i
, P- (N-morpholino-CH_TwoCH_TwoO) -benzyl, -CH_TwoCH_TwoC (O) NH _Two , -CH_Two-Imidazol-4-yl, -CH_Two-(3-tetrahydrofuranyl)
, -CH_Two-Thiophen-2-yl, -CH_Two(1-methyl) cyclopropyl, -C
H_Two-Thiophen-3-yl, thiophen-3-yl, thiophen-2-yl,
-CH_Two-C (O) Ot-butyl, -CH_Two-C (CH_Three)_Three, -CH_TwoCH (CH_TwoC
H_Three)_Two, 2-methylcyclopentyl, cyclohex-2-enyl, -CH [CH (
CH_Three)_Two] COOCH_Three, -CH_TwoCH_TwoN (CH_Three)_Two, -CH_TwoC (CH_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, pyridyl, -CH_Two-Naphthyl, -CH_Two -(N-morpholino), p- (N-morpholino-CH_TwoCH_TwoO) -benzyl, benzo
[b] thiophen-2-yl, 5-chlorobenzo [b] thiophen-2-yl, 4,
5,6,7-tetrahydrobenzo [b] thiophen-2-yl, benzo [b] thiophene
N-3-yl, 5-chlorobenzo [b] thiophen-3-yl, benzo [b] thiof
Hen-5-yl, 6-methoxynaphth-2-yl, -CH_TwoCH_TwoSCH_Three, Chie
40. The method according to claim 39, wherein the group is selected from the group consisting of n-2-yl and thien-3-yl.
The pharmaceutical composition according to any one of the preceding claims. 41. The pharmaceutical composition according to claim 25, wherein R ^{2 ′} is independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, cycloalkyl, aryl, heteroaryl, and heterocyclic. 42. R ^{2 ′} is hydrogen, 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) 2 NCH} 2 CH ₂ CH ₂ O-benzyl, p- (CH ₃ ) ₃ COC (
O) CH ₂ O-benzyl, p- (HOOCCH ₂ O) - benzyl, 2-aminopyrido-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, -C
_{H [CH (CH 3) 2} ] COOCH 3, -CH 2 CH 2 N (CH 3) 2, -CH 2 C (CH 3) =
_{CH 2, -CH 2 CH = CHCH} 3 ( cis and _{trans), - CH 2 OH, -CH} (
_{OH) CH 3, -CH (O} -t- _{butyl) CH 3, -CH 2 OCH 3} , - (CH 2) 4 NH
_{-Boc, - (CH 2) 4} NH 2, -CH 2 - pyridyl, pyridyl, -CH ₂ - naphthyl, -CH ₂ - (N-morpholino), p-(N-morpholino -CH ₂ CH ₂ O) - Benzyl, benzo [b] thiophen-2-yl, 5-chlorobenzo [b] thiophen-2
-Yl, 4,5,6,7-tetrahydrobenzo [b] thiophen-2-yl, benzo [
b] thiophen-3-yl, 5-chlorobenzo [b] thiophen-3-yl, benzo [b] thiophen-5-yl, 6-methoxynaphth-2-yl, -CH ₂ CH ₂ S
CH ₃ , selected from the group consisting of thien-2-yl and thien-3-yl,
42. The pharmaceutical composition according to claim 41. 43. The pharmaceutical composition according to claim 25, wherein R ³ is selected from the group consisting of hydrogen, alkyl, substituted alkyl and cycloalkyl. 44. A compound according to claim 14, wherein R ³ is hydrogen, methyl, 2-methylpropyl, hexyl, methoxycarbonylmethyl, 3,3-dimethyl-2-oxobutyl, 4-phenylbutyl, cyclopropylmethyl, 2,2,2-trifluoro 44. The pharmaceutical composition according to claim 43, wherein the composition is selected from the group consisting of ethyl and cyclohexyl. 45. The pharmaceutical composition according to paragraph 25, wherein R ⁴ is hydrogen, alkyl or substituted alkyl. 46. R ⁵ is alkyl, substituted alkyl, substituted amino, phenyl,
26. The pharmaceutical composition according to claim 25, wherein the composition is selected from the group consisting of substituted phenyl, cycloalkyl, heteroaryl, heterocyclic and thioalkoxy. 47. A compound of formula I: Wherein W is Embedded image Wherein ring A, taken together with the atom to which it is attached, is aryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, Forming a carbocyclic or heterocyclic ring selected from the group consisting of heteroaryl and heterocyclic; ring B together with the atom to which it is attached is aryl, cycloalkyl, substituted cyclo Forming a carbocyclic or heterocyclic ring selected from the group consisting of alkyl, cycloalkenyl, substituted cycloalkenyl, heteroaryl, and heterocyclic; ring C together with the atom to which it is attached Y forms a heteroaryl or heterocyclic ring; Y is of the formula: And with the proviso at least one of Y - (CHR ^{2 ')} a _a -NH-; R ¹ is alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, substituted alkyl, substituted alkenyl, substituted alkynyl, substituted cycloalkyl, R ² is selected from the group consisting of substituted cycloalkenyl, aryl, heteroaryl and heterocyclic; R ² is alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl,
Selected from the group consisting of substituted alkynyl, cycloalkyl, aryl, heteroaryl and heterocyclic; each R ^{2 ′} is hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, aryl, heteroaryl And R ³ is independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, acyl, aryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cyclo alkenyl, it is selected from the group consisting of heteroaryl and heterocyclic; each R ⁴ is alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, cycloalkyl, substituted consequent Alkyl, cycloalkenyl, substituted cycloalkenyl, are independently selected from the group consisting of heteroaryl and heterocyclic; R ⁵ is alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl,
Q is selected from the group consisting of substituted alkynyl, substituted amino, aryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heteroaryl, heterocyclic, thioalkoxy and substituted thioalkoxy; Q is oxygen, sulfur, -S (O) - or S (O) ₂ - a and; Z is the formula: -T-CX'X "C (O ) - represented by wherein, T is R ¹ and -CX'X" - connecting Covalent single bond, oxygen, sulfur and-
NR ⁶ is selected from the group consisting of R ⁶ is hydrogen, acyl, alkyl, aryl or heteroaryl group; X ′ is hydrogen, hydroxy or fluoro, and X ″ is hydrogen, hydroxy or fluoro Or X ′ and X ″ together form an oxo group; a is an integer from 2 to 6; f is an integer from 0 to 2; m is an integer from 0 or 1; Is an integer of 1 or 2.] and a pharmaceutically acceptable salt thereof. 48. The compound of claim 47, wherein a is 2. 49. The compound according to claim 47, wherein rings A and B are preferably independently selected from the group consisting of aryl, cycloalkyl, cycloalkenyl, heteroaryl and heterocyclic. 50. The compound of claim 49, wherein rings A and B are independently aryl. 51. The compound according to claim 47, wherein m is 0. 52. The method of claim 51, wherein R ¹ is aryl or heteroaryl.
The compound according to the above. 53. R ¹ is (a) phenyl, (b) a formula: Wherein R ^c is acyl, alkyl, alkoxy, alkylalkoxy, azide,
Selected from the group consisting of cyano, halo, hydrogen, nitro, trihalomethyl, thioalkoxy, wherein R ^b and R ^c are fused to form a heteroaryl or heterocyclic ring with the phenyl ring, The cyclic ring contains 3-8 atoms, of which 1-3 are heteroatoms independently selected from the group consisting of oxygen, nitrogen and sulfur; R ^b and R ^{b ′} are hydrogen, Independently selected from the group consisting of halo, nitro, cyano, trihalomethyl, alkoxy and thioalkoxy, provided that when R ^c is hydrogen, then R ^b and R ^{b ′} are both hydrogen, or both are hydrogen. A substituted phenyl group represented by the formula: (c) 2-naphthyl, (d) an alkyl at the fourth, fifth, sixth, seventh and / or eighth position 2- (naphthyl) substituted with 1-5 substituents selected from the group consisting of alkoxy, halo, cyano, nitro, trihalomethyl, thioalkoxy, aryl and heteroaryl, (e) heteroaryl, (f) Substituted heteroaryl containing 1 to 3 substituents selected from the group consisting of alkyl, alkoxy, aryl, aryloxy, cyano, halo, nitro, heteroaryl, thioalkoxy, thioaryloxy, provided that the substituent is 53. The compound of claim 52, wherein the heteroaryl is selected from the group consisting of: (g) not ortho to the bond to the -NH group) and (g) alkyl. 54. The compound according to claim 52, wherein R ¹ is selected from the group consisting of mono-, di- and trisubstituted phenyl groups. 55. R ¹ is 3,5-dichlorophenyl, 3,5-difluorophenyl, 3,5-di (trifluoromethyl) -phenyl, 3,4-dichlorophenyl,
3,4-difluorophenyl, 3- (trifluoromethyl) -4-chlorophenyl, 3-chloro-4-cyanophenyl, 3-chloro-4-iodophenyl and 3
55. The compound of claim 54, which is a disubstituted phenyl selected from the group consisting of, 4-methylenedioxyphenyl. 56. R ¹ is 4-azidophenyl, 4-bromophenyl, 4-chlorophenyl, 4-cyanophenyl, 4-ethylphenyl, 4-fluorophenyl, 4-iodophenyl, 4- (phenylcarbonyl) -phenyl And 4- (1
-Ethoxy) ethylphenyl is a monosubstituted phenyl selected from the group consisting of:
A compound according to claim 54. 57. R ¹ is 3,4,5-trifluorophenyl and 3,4,5-
6. A trisubstituted phenyl selected from the group consisting of trichlorophenyl.
5. The compound according to 4. 58. The method of claim 52, wherein R ¹ is selected from 2-naphthyl, quinolin-3-yl, 2-methylquinolin-6-yl, benzothiazol-6-yl, 5-indole and phenyl. Compound. 59. The compound of claim 53, wherein R ¹ is selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, isobutyl, sec-butyl, n-butyl, n-pentyl and isovaleryl. 60. The compound of claim 47, wherein m is 1. 61. R¹Is phenyl, 1-naphthyl, 2-naphthyl, 2-chloro
Rophenyl, 2-fluorophenyl, 2-bromophenyl, 2-hydroxyphen
Nil, 2-nitrophenyl, 2-methylphenyl, 2-methoxyphenyl, 2-
Phenoxyphenyl, 2-trifluoromethylphenyl, 4-fluorophenyl
, 4-chlorophenyl, 4-bromophenyl, 4-nitrophenyl, 4-methyl
Phenyl, 4-hydroxyphenyl, 4-methoxyphenyl, 4-ethoxyfe
Nyl, 4-butoxyphenyl, 4-iso-propylphenyl, 4-phenoxyf
Phenyl, 4-trifluoromethylphenyl, 4-hydroxymethylphenyl, 3
-Methoxyphenyl, 3-hydroxyphenyl, 3-nitrophenyl, 3-fur
Orophenyl, 3-chlorophenyl, 3-bromophenyl, 3-phenoxyfe
Nyl, 3-thiomethoxyphenyl, 3-methylphenyl, 3-trifluoromethyl
Phenyl, 2,3-dichlorophenyl, 2,3-difluorophenyl, 2,4-
Dichlorophenyl, 2,5-dimethoxyphenyl, 3,4-dichlorophenyl, 3
, 4-Difluorophenyl, 3,4-methylenedioxyphenyl, 3,4-dimethoate
Xyphenyl, 3,5-difluorophenyl, 3,5-dichlorophenyl, 3,5
-Di- (trifluoromethyl) phenyl, 3,5-dimethoxyphenyl, 2,4-
Dichlorophenyl, 2,4-difluorophenyl, 2,6-difluorophenyl,
3,4,5-trifluorophenyl, 3,4,5-trimethoxyphenyl, 3,4,5
-Tri- (trifluoromethyl) phenyl, 2,4,6-trifluorophenyl, 2
, 4,6-Trimethylphenyl, 2,4,6-tri- (trifluoromethyl) phenyl
2,3,5-trifluorophenyl, 2,4,5-trifluorophenyl, 2,5
-Difluorophenyl, 2-fluoro-3-trifluoromethylphenyl, 4-
Fluoro-2-trifluoromethylphenyl, 2-fluoro-4-trifluoro
Methylphenyl, 4-benzyloxyphenyl, 2-chloro-6-fluorophen
Nil, 2-fluoro-6-chlorophenyl, 2,3,4,5,6-pentafluorophenyl
Phenyl, 2,5-dimethylphenyl, 4-phenylphenyl, 2-fluoro-3
-Trifluoromethylphenyl, adamantyl, benzyl, 2-phenylethyl
, 3-phenyl-n-propyl, 4-phenyl-n-butyl, methyl, ethyl,
n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, ter
t-butyl, n-pentyl, iso-valeryl, n-hexyl, cyclopropyl,
Cyclobutyl, cyclohexyl, cyclopentyl, cyclopent-1-enyl,
Cyclopent-2-enyl, cyclohex-1-enyl, -CH_Two-Cyclopro
Pill, -CH_Two-Cyclobutyl, -CH_Two-Cyclohexyl, -CH_Two-Cyclope
Ethylene, -CH_TwoCH_Two-Cyclopropyl, -CH_TwoCH_Two-Cyclobutyl, -CH _Two CH_Two-Cyclohexyl, -CH_TwoCH_Two-Cyclopentyl, pyrid-2-yl,
Pyrid-3-yl, pyrid-4-yl, fluoropyridyl (5-fluoropyrido
-3-yl), chloropyridyl (including 5-chloropyrid-3-yl),
Thien-2-yl, thien-3-yl, benzothiazol-4-yl, 2-fe
Nilbenzoxazol-5-yl, furan-2-yl, benzofuran-2-i
Thionaphthen-2-yl, thionaphthen-3-yl, thionaphthen-4-i
2-chlorothiophen-5-yl, 3-methylisoxazol-5-yl
, 2- (thiophenyl) thien-5-yl, 6-methoxythionaphthen-2-yl
, 3-phenyl-1,2,4-thiooxadiazol-5-yl, 2-phenyl
Oxazol-4-yl, indol-3-yl, 1-phenyl-tetraol
-5-yl, allyl, 2- (cyclohexyl) ethyl, (CH_Three)_TwoCH = CHCH_Two
CH_TwoCH (CH_Three)-, ΦC (O) CH_Two-, Thien-2-yl-methyl, 2- (thiene
2- (2-yl) ethyl, 3- (thien-2-yl) -n-propyl, 2- (4-nitto
Rophenyl) ethyl, 2- (4-methoxyphenyl) ethyl, norborane-2-i
, (4-methoxyphenyl) methyl, (2-methoxyphenyl) methyl, (3-meth
(Toxiphenyl) methyl, (3-hydroxyphenyl) methyl, (4-hydroxyphenyl) methyl
(Enyl) methyl, (4-methoxyphenyl) methyl, (4-methylphenyl) methyl
, (4-fluorophenyl) methyl, (4-fluorophenoxy) methyl, (2,4-
Dichlorophenoxy) ethyl, (4-chlorophenyl) methyl, (2-chlorophenyl
) Methyl, (1-phenyl) ethyl, (1- (p-chlorophenyl) ethyl, (1-
(Trifluoromethyl) ethyl, (4-methoxyphenyl) ethyl, CH_ThreeOC (O) C
H_Two-, Benzylthiomethyl, 5- (methoxycarbonyl) -n-pentyl, 3- (
(Methoxycarbonyl) -n-propyl, indan-2-yl, (2-methylbenzo
Furan-3-yl), methoxymethyl, CH_ThreeCH = CH-, CH_ThreeCH_TwoCH = C
H-, (4-chlorophenyl) C (O) CH_Two-, (4-fluorophenyl) C (O) C
H_Two-, (4-methoxyphenyl) C (O) CH_Two-, 4- (fluorophenyl) -NH
C (O) CH_Two-, 1-phenyl-n-butyl, (φ)_TwoCHNHC (O) CH_TwoCH_Two−
, (CH_Three)_TwoNC (O) CH_Two−, (Φ)_TwoCHNHC (O) CH_TwoCH_Two-, Methylcarbo
Nylmethyl, (2,4-dimethylphenyl) C (O) CH_Two-, 4-methoxyphenyl
-C (O) CH_Two-, Phenyl-C (O) CH_Two-, CH_ThreeC (O) N (φ)-, ethenyl
, Methylthiomethyl, (CH_Three)_ThreeCNHC (O) CH_Two-, 4-fluorophenyl-
C (O) CH_Two-, Diphenylmethyl, phenoxymethyl, 3,4-methylenedi
Xyphenyl-CH_Two-, Benzo [b] thiophen-3-yl, (CH_Three)_ThreeCOC (O
) NHCH_Two-, Trans-styryl, H_TwoNC (O) CH_TwoCH_Two-, 2-triflu
Oromethylphenyl-C (O) CH_Two, ΦC (O) NHCH (φ) CH_Two−, Mesityl,
CH_ThreeCH (= NHOH) CH_Two-, 4-CH_Three-Φ-NHC (O) CH_TwoCH_Two−, Φ
C (O) CH (φ) CH_Two−, (CH_Three)_TwoCHC (O) NHCH (φ)-, CH_ThreeCH_TwoOC
H_Two-, CH_ThreeOC (O) CH (CH_Three) (CH_Two)_Three-, 2,2,2-trifluoroethyl
, 1- (trifluoromethyl) ethyl, 2-CH_Three-Benzofuran-3-yl, 2
-(2,4-dichlorophenoxy) ethyl, φSO_TwoCH_Two-, 3-cyclohexyl
-N-propyl, CF_ThreeCH_TwoCH_TwoCH_TwoThe group consisting of-and N-pyrrolidinyl
60. The compound of claim 59, wherein the compound is selected from: 62. The compound of claim 47, wherein each R ² is independently selected from the group consisting of alkyl, substituted alkyl, alkenyl, cycloalkyl, aryl, heteroaryl, and heterocyclic. 63. R^TwoIs methyl, ethyl, n-propyl, iso-propyl,
n-butyl, iso-butyl, sec-butyl, tert-butyl, -CH_TwoCH (CH_TwoC
H_Three)_Two, 2-methyl-n-butyl, 6-fluoro-n-hexyl, phenyl,
Benzyl, cyclohexyl, cyclopentyl, cycloheptyl, allyl, iso-butyl
To-2-enyl, 3-methylpentyl, -CH_Two-Cyclopropyl, -CH_Two−
Clohexyl, -CH_TwoCH_Two-Cyclopropyl, -CH_TwoCH_Two-Cyclohexyl
, -CH_Two-Indol-3-yl, p- (phenyl) phenyl, o-fluorophenyl
Phenyl, m-fluorophenyl, p-fluorophenyl, m-methoxyphenyl
, P-methoxyphenyl, phenethyl, benzyl, m-hydroxybenzyl, p
-Hydroxybenzyl, p-nitrobenzyl, m-trifluoromethylphenyl
, P- (CH_Three)_TwoNCH_TwoCH_TwoCH_TwoO-benzyl, p- (CH_Three)_ThreeCOC (O) CH_Two O-benzyl, p- (HOOCCH_TwoO) -benzyl, 2-aminopyrid-6-i
, P- (N-morpholino-CH_TwoCH_TwoO) -benzyl, -CH_TwoCH_TwoC (O) NH _Two , -CH_Two-Imidazol-4-yl, -CH_Two-(3-tetrahydrofuranyl)
, -CH_Two-Thiophen-2-yl, -CH_Two(1-methyl) cyclopropyl, -C
H_Two-Thiophen-3-yl, thiophen-3-yl, thiophen-2-yl,
-CH_Two-C (O) Ot-butyl, -CH_Two-C (CH_Three)_Three, -CH_TwoCH (CH_TwoC
H_Three)_Two, 2-methylcyclopentyl, cyclohex-2-enyl, -CH [CH (
CH_Three)_Two] COOCH_Three, -CH_TwoCH_TwoN (CH_Three)_Two, -CH_TwoC (CH_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, pyridyl, -CH_Two-Naphthyl, -CH_Two -(N-morpholino), p- (N-morpholino-CH_TwoCH_TwoO) -benzyl, benzo
[b] thiophen-2-yl, 5-chlorobenzo [b] thiophen-2-yl, 4,
5,6,7-tetrahydrobenzo [b] thiophen-2-yl, benzo [b] thiophene
N-3-yl, 5-chlorobenzo [b] thiophen-3-yl, benzo [b] thiof
Hen-5-yl, 6-methoxynaphth-2-yl, -CH_TwoCH_TwoSCH_Three, Chie
62. The method according to claim 61, wherein the member is selected from the group consisting of n-2-yl and thien-3-yl.
A compound as described. 64. The compound of claim 47, wherein R ^{2 ′} is independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, cycloalkyl, aryl, heteroaryl, and heterocyclic. 65. When R ^{2 ′} is hydrogen, 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) 2 NCH} 2 CH ₂ CH ₂ O-benzyl, p- (CH ₃ ) ₃ COC (
O) CH ₂ O-benzyl, p- (HOOCCH ₂ O) - benzyl, 2-aminopyrido-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, -C
_{H [CH (CH 3) 2} ] COOCH 3, -CH 2 CH 2 N (CH 3) 2, -CH 2 C (CH 3) =
_{CH 2, -CH 2 CH = CHCH} 3 ( cis and _{trans), - CH 2 OH, -CH} (
_{OH) CH 3, -CH (O} -t- _{butyl) CH 3, -CH 2 OCH 3} , - (CH 2) 4 NH
_{-Boc, - (CH 2) 4} NH 2, -CH 2 - pyridyl, pyridyl, -CH ₂ - naphthyl, -CH ₂ - (N-morpholino), p-(N-morpholino -CH ₂ CH ₂ O) - Benzyl, benzo [b] thiophen-2-yl, 5-chlorobenzo [b] thiophen-2
-Yl, 4,5,6,7-tetrahydrobenzo [b] thiophen-2-yl, benzo [
b] thiophen-3-yl, 5-chlorobenzo [b] thiophen-3-yl, benzo [b] thiophen-5-yl, 6-methoxynaphth-2-yl, -CH ₂ CH ₂ S
CH ₃ , selected from the group consisting of thien-2-yl and thien-3-yl,
65. The compound of claim 64. 66. The compound of claim 47, wherein R ³ is selected from the group consisting of hydrogen, alkyl, substituted alkyl, and cycloalkyl. 67. R ³ is hydrogen, methyl, 2-methylpropyl, hexyl, methoxycarbonylmethyl, 3,3-dimethyl-2-oxobutyl, 4-phenylbutyl, cyclopropylmethyl, 2,2,2 67. The compound of claim 66, wherein the compound is selected from the group consisting of ethyl and cyclohexyl. 68. The compound according to claim 47, wherein R ⁴ is hydrogen, alkyl or substituted alkyl. 69. R ⁵ is alkyl, substituted alkyl, substituted amino, phenyl,
50. The compound of claim 47, wherein the compound is selected from the group consisting of substituted phenyl, cycloalkyl, heteroaryl, heterocyclic, and thioalkoxy. 70. When W is the formula (a): Wherein each R ⁶ is 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 - heteroarylalkyl - aryl and -SO ₂ Independently selected; each R ⁷ is 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 -S
Independently selected from the group consisting of O ₂ -heteroaryl; R ⁸ is hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, acyl, aryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted P is an integer of 0 to 4; q is an integer of 0 to 4]; a cyclic ring represented by the formula: Formula 25 Wherein R ⁶ , R ⁷ and p are as defined above, and r is an integer from 0 to 3; (c) a cyclic group represented by the formula: Wherein R ⁶ and p are as defined above; (d) a cyclic group of the formula: Wherein R ⁶ and p are as defined above; (e) a cyclic ring of the formula: Wherein R ⁶ , R ⁸ and p are as defined above; each R ⁹ is alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, cycloalkyl, substituted cycloalkyl, cycloalkyl, Independently selected from the group consisting of alkenyl, substituted cycloalkenyl, heteroaryl, and heterocyclic; and g is an integer from 0 to 2]. (F) a cyclic ring represented by the formula: Wherein R ⁶ , R ⁸ , R ⁹ , g and p are as defined above; (g) a cyclic ring represented by the formula: [Wherein R ⁶ , each R ⁸ and p are as defined above]; (h) a cyclic ring represented by the following formula: Wherein R ⁶ , each R ⁸ , R ⁹ , g and p are as defined above; (i) a cyclic ring represented by the formula: Wherein R ⁶ , R ⁸ and p are as defined above; R ¹⁰ is alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl,
Selected from the group consisting of substituted alkynyl, substituted amino, aryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heteroaryl, heterocyclic, thioalkoxy, and substituted thioalkoxy. (J) Formula: Wherein R ⁶ , R ¹⁰ and p are as defined above; DE is selected from the group consisting of alkylene, alkenylene, substituted alkylene, substituted alkenylene and —N ＝ CH—. (K) a cyclic ring represented by the following formula: Wherein R ⁶ , R ⁸ , R ⁹ , g and p are as defined above; Q is oxygen, sulfur, —S (O) — or —S (O) ₂ —. A cyclic ring represented by the following formula (l): Wherein R ⁶ , R ⁸ and p are as defined above; (m) a cyclic ring represented by the formula: Wherein, R ⁸ is as defined above] ring cyclic represented by; is selected from the group consisting of A compound according to claim 48. 71. Each R ⁶ is independently selected from the group consisting of alkyl, substituted alkyl, alkoxy and halo; each R ⁷ is independently selected from the group consisting of alkyl, substituted alkyl, alkoxy and halo; R ⁸ is independently selected from the group consisting of alkyl, substituted alkyl, cycloalkyl and aryl; each R ⁹ is independently selected from the group consisting of alkyl, substituted alkyl, cycloalkyl and aryl; and g, p, 71. The compound of claim 70, wherein q and r are 0 or 1. 72. The compound of claim 71, wherein g, p, q and r are 0. 73. The compound according to claim 71, wherein m is 1. 74. R¹Is phenyl, 1-naphthyl, 2-naphthyl, 2-chloro
Rophenyl, 2-fluorophenyl, 2-bromophenyl, 2-hydroxyphen
Nil, 2-nitrophenyl, 2-methylphenyl, 2-methoxyphenyl, 2-
Phenoxyphenyl, 2-trifluoromethylphenyl, 4-fluorophenyl
, 4-chlorophenyl, 4-bromophenyl, 4-nitrophenyl, 4-methyl
Phenyl, 4-hydroxyphenyl, 4-methoxyphenyl, 4-ethoxyfe
Nyl, 4-butoxyphenyl, 4-iso-propylphenyl, 4-phenoxyf
Phenyl, 4-trifluoromethylphenyl, 4-hydroxymethylphenyl, 3
-Methoxyphenyl, 3-hydroxyphenyl, 3-nitrophenyl, 3-fur
Orophenyl, 3-chlorophenyl, 3-bromophenyl, 3-phenoxyfe
Nyl, 3-thiomethoxyphenyl, 3-methylphenyl, 3-trifluoromethyl
Phenyl, 2,3-dichlorophenyl, 2,3-difluorophenyl, 2,4-
Dichlorophenyl, 2,5-dimethoxyphenyl, 3,4-dichlorophenyl, 3
, 4-Difluorophenyl, 3,4-methylenedioxyphenyl, 3,4-dimethoate
Xyphenyl, 3,5-difluorophenyl, 3,5-dichlorophenyl, 3,5
-Di- (trifluoromethyl) phenyl, 3,5-dimethoxyphenyl, 2,4-
Dichlorophenyl, 2,4-difluorophenyl, 2,6-difluorophenyl,
3,4,5-trifluorophenyl, 3,4,5-trimethoxyphenyl, 3,4,5
-Tri- (trifluoromethyl) phenyl, 2,4,6-trifluorophenyl, 2
, 4,6-Trimethylphenyl, 2,4,6-tri- (trifluoromethyl) phenyl
2,3,5-trifluorophenyl, 2,4,5-trifluorophenyl, 2,5
-Difluorophenyl, 2-fluoro-3-trifluoromethylphenyl, 4-
Fluoro-2-trifluoromethylphenyl, 2-fluoro-4-trifluoro
Methylphenyl, 4-benzyloxyphenyl, 2-chloro-6-fluorophen
Nil, 2-fluoro-6-chlorophenyl, 2,3,4,5,6-pentafluorophenyl
Phenyl, 2,5-dimethylphenyl, 4-phenylphenyl, 2-fluoro-3
-Trifluoromethylphenyl, adamantyl, benzyl, 2-phenylethyl
, 3-phenyl-n-propyl, 4-phenyl-n-butyl, methyl, ethyl,
n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, ter
t-butyl, n-pentyl, iso-valeryl, n-hexyl, cyclopropyl,
Cyclobutyl, cyclohexyl, cyclopentyl, cyclopent-1-enyl,
Cyclopent-2-enyl, cyclohex-1-enyl, -CH_Two-Cyclopro
Pill, -CH_Two-Cyclobutyl, -CH_Two-Cyclohexyl, -CH_Two-Cyclope
Ethylene, -CH_TwoCH_Two-Cyclopropyl, -CH_TwoCH_Two-Cyclobutyl, -CH _Two CH_Two-Cyclohexyl, -CH_TwoCH_Two-Cyclopentyl, pyrid-2-yl,
Pyrid-3-yl, pyrid-4-yl, fluoropyridyl (5-fluoropyrido
-3-yl), chloropyridyl (including 5-chloropyrid-3-yl),
Thien-2-yl, thien-3-yl, benzothiazol-4-yl, 2-fe
Nilbenzoxazol-5-yl, furan-2-yl, benzofuran-2-i
Thionaphthen-2-yl, thionaphthen-3-yl, thionaphthen-4-i
2-chlorothiophen-5-yl, 3-methylisoxazol-5-yl
, 2- (thiophenyl) thien-5-yl, 6-methoxythionaphthen-2-yl
, 3-phenyl-1,2,4-thiooxadiazol-5-yl, 2-phenyl
Oxazol-4-yl, indol-3-yl, 1-phenyl-tetraol
-5-yl, allyl, 2- (cyclohexyl) ethyl, (CH_Three)_TwoCH = CHCH_Two
CH_TwoCH (CH_Three)-, ΦC (O) CH_Two-, Thien-2-yl-methyl, 2- (thiene
2- (2-yl) ethyl, 3- (thien-2-yl) -n-propyl, 2- (4-nitto
Rophenyl) ethyl, 2- (4-methoxyphenyl) ethyl, norborane-2-i
, (4-methoxyphenyl) methyl, (2-methoxyphenyl) methyl, (3-meth
(Toxiphenyl) methyl, (3-hydroxyphenyl) methyl, (4-hydroxyphenyl) methyl
(Enyl) methyl, (4-methoxyphenyl) methyl, (4-methylphenyl) methyl
, (4-fluorophenyl) methyl, (4-fluorophenoxy) methyl, (2,4-
Dichlorophenoxy) ethyl, (4-chlorophenyl) methyl, (2-chlorophenyl
) Methyl, (1-phenyl) ethyl, (1- (p-chlorophenyl) ethyl, (1-
(Trifluoromethyl) ethyl, (4-methoxyphenyl) ethyl, CH_ThreeOC (O) C
H_Two-, Benzylthiomethyl, 5- (methoxycarbonyl) -n-pentyl, 3- (
(Methoxycarbonyl) -n-propyl, indan-2-yl, (2-methylbenzo
Furan-3-yl), methoxymethyl, CH_ThreeCH = CH-, CH_ThreeCH_TwoCH = C
H-, (4-chlorophenyl) C (O) CH_Two-, (4-fluorophenyl) C (O) C
H_Two-, (4-methoxyphenyl) C (O) CH_Two-, 4- (fluorophenyl) -NH
C (O) CH_Two-, 1-phenyl-n-butyl, (φ)_TwoCHNHC (O) CH_TwoCH_Two−
, (CH_Three)_TwoNC (O) CH_Two−, (Φ)_TwoCHNHC (O) CH_TwoCH_Two-, Methylcarbo
Nylmethyl, (2,4-dimethylphenyl) C (O) CH_Two-, 4-methoxyphenyl
-C (O) CH_Two-, Phenyl-C (O) CH_Two-, CH_ThreeC (O) N (φ)-, ethenyl
, Methylthiomethyl, (CH_Three)_ThreeCNHC (O) CH_Two-, 4-fluorophenyl-
C (O) CH_Two-, Diphenylmethyl, phenoxymethyl, 3,4-methylenedioxy
Cyphenyl-CH_Two-, Benzo [b] thiophen-3-yl, (CH_Three)_ThreeCOC (O)
NHCH_Two-, Trans-styryl, H_TwoNC (O) CH_TwoCH_Two-, 2-trifluoro
Romethylphenyl-C (O) CH_Two, ΦC (O) NHCH (φ) CH_Two-, Mesityl, C
H_ThreeCH (= NHOH) CH_Two-, 4-CH_Three-Φ-NHC (O) CH_TwoCH_Two−, ΦC (
O) CH (φ) CH_Two−, (CH_Three)_TwoCHC (O) NHCH (φ)-, CH_ThreeCH_TwoOCH_Two
-, CH_ThreeOC (O) CH (CH_Three) (CH_Two)_Three-2,2,2-trifluoroethyl, 1
-(Trifluoromethyl) ethyl, 2-CH_Three-Benzofuran-3-yl, 2- (2
, 4-dichlorophenoxy) ethyl, φSO_TwoCH_Two-, 3-cyclohexyl-n-
Propyl, CF_ThreeCH_TwoCH_TwoCH_TwoSelected from the group consisting of-and N-pyrrolidinyl
74. The compound of claim 73, wherein 75. The compound of claim 74, wherein each R ² is independently selected from the group consisting of alkyl, substituted alkyl, alkenyl, cycloalkyl, aryl, heteroaryl, and heterocyclic. 76. R^TwoIs methyl, ethyl, n-propyl, iso-propyl,
n-butyl, iso-butyl, sec-butyl, tert-butyl, -CH_TwoCH (CH_TwoC
H_Three)_Two, 2-methyl-n-butyl, 6-fluoro-n-hexyl, phenyl,
Benzyl, cyclohexyl, cyclopentyl, cycloheptyl, allyl, iso-butyl
To-2-enyl, 3-methylpentyl, -CH_Two-Cyclopropyl, -CH_Two−
Clohexyl, -CH_TwoCH_Two-Cyclopropyl, -CH_TwoCH_Two-Cyclohexyl
, -CH_Two-Indol-3-yl, p- (phenyl) phenyl, o-fluorophenyl
Phenyl, m-fluorophenyl, p-fluorophenyl, m-methoxyphenyl
, P-methoxyphenyl, phenethyl, benzyl, m-hydroxybenzyl, p
-Hydroxybenzyl, p-nitrobenzyl, m-trifluoromethylphenyl
, P- (CH_Three)_TwoNCH_TwoCH_TwoCH_TwoO-benzyl, p- (CH_Three)_ThreeCOC (O) CH_Two O-benzyl, p- (HOOCCH_TwoO) -benzyl, 2-aminopyrid-6-i
, P- (N-morpholino-CH_TwoCH_TwoO) -benzyl, -CH_TwoCH_TwoC (O) NH _Two , -CH_Two-Imidazol-4-yl, -CH_Two-(3-tetrahydrofuranyl)
, -CH_Two-Thiophen-2-yl, -CH_Two(1-methyl) cyclopropyl, -C
H_Two-Thiophen-3-yl, thiophen-3-yl, thiophen-2-yl,
-CH_Two-C (O) Ot-butyl, -CH_Two-C (CH_Three)_Three, -CH_TwoCH (CH_TwoC
H_Three)_Two, 2-methylcyclopentyl, cyclohex-2-enyl, -CH [CH (
CH_Three)_Two] COOCH_Three, -CH_TwoCH_TwoN (CH_Three)_Two, -CH_TwoC (CH_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, pyridyl, -CH_Two-Naphthyl, -CH_Two -(N-morpholino), p- (N-morpholino-CH_TwoCH_TwoO) -benzyl, benzo
[b] thiophen-2-yl, 5-chlorobenzo [b] thiophen-2-yl, 4,
5,6,7-tetrahydrobenzo [b] thiophen-2-yl, benzo [b] thiophene
N-3-yl, 5-chlorobenzo [b] thiophen-3-yl, benzo [b] thiof
Hen-5-yl, 6-methoxynaphth-2-yl, -CH_TwoCH_TwoSCH_Three, Chie
76. The method according to claim 75, wherein the member is selected from the group consisting of n-2-yl and thien-3-yl.
A compound as described. 77. R^{2 '}Is methyl, ethyl, n-propyl, iso-propyl,
n-butyl, iso-butyl, sec-butyl, tert-butyl, -CH_TwoCH (CH_TwoC
H_Three)_Two, 2-methyl-n-butyl, 6-fluoro-n-hexyl, phenyl,
Benzyl, cyclohexyl, cyclopentyl, cycloheptyl, allyl, iso-butyl
To-2-enyl, 3-methylpentyl, -CH_Two-Cyclopropyl, -CH_Two−
Clohexyl, -CH_TwoCH_Two-Cyclopropyl, -CH_TwoCH_Two-Cyclohexyl
, -CH_Two-Indol-3-yl, p- (phenyl) phenyl, o-fluorophenyl
Phenyl, m-fluorophenyl, p-fluorophenyl, m-methoxyphenyl
, P-methoxyphenyl, phenethyl, benzyl, m-hydroxybenzyl, p
-Hydroxybenzyl, p-nitrobenzyl, m-trifluoromethylphenyl
, P- (CH_Three)_TwoNCH_TwoCH_TwoCH_TwoO-benzyl, p- (CH_Three)_ThreeCOC (O) CH_Two O-benzyl, p- (HOOCCH_TwoO) -benzyl, 2-aminopyrid-6-i
, P- (N-morpholino-CH_TwoCH_TwoO) -benzyl, -CH_TwoCH_TwoC (O) NH _Two , -CH_Two-Imidazol-4-yl, -CH_Two-(3-tetrahydrofuranyl)
, -CH_Two-Thiophen-2-yl, -CH_Two(1-methyl) cyclopropyl, -C
H_Two-Thiophen-3-yl, thiophen-3-yl, thiophen-2-yl,
-CH_Two-C (O) Ot-butyl, -CH_Two-C (CH_Three)_Three, -CH_TwoCH (CH_TwoC
H_Three)_Two, 2-methylcyclopentyl, cyclohex-2-enyl, -CH [CH (
CH_Three)_Two] COOCH_Three, -CH_TwoCH_TwoN (CH_Three)_Two, -CH_TwoC (CH_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, pyridyl, -CH_Two-Naphthyl, -CH_Two -(N-morpholino), p- (N-morpholino-CH_TwoCH_TwoO) -benzyl, benzo
[b] thiophen-2-yl, 5-chlorobenzo [b] thiophen-2-yl, 4,
5,6,7-tetrahydrobenzo [b] thiophen-2-yl, benzo [b] thiophene
N-3-yl, 5-chlorobenzo [b] thiophen-3-yl, benzo [b] thiof
Hen-5-yl, 6-methoxynaphth-2-yl, -CH_TwoCH_TwoSCH_Three, Chie
74. The method of claim 73, wherein the member is selected from the group consisting of n-2-yl and thien-3-yl
A compound as described. 78. The compound of para 77, wherein R ^{2 '} is independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, cycloalkyl, aryl, heteroaryl, and heterocyclic. 79. The compound of claim 75, wherein R ³ is selected from the group consisting of alkyl, substituted alkyl and aryl. 80. The compound of claim 77, wherein R ³ is selected from the group consisting of alkyl, substituted alkyl and aryl. 81. The compound of para 78, wherein R ^{2 '} is methyl. 82. The compound of para 81, wherein R ¹ is alkyl. 83. The compound of para 82, wherein R ³ is alkyl.