CN106349233B - 3, 4-diphenyl-4H-1, 2, 4-triazole derivative and preparation method and application thereof - Google Patents

Abstract

The invention discloses a 3, 4-diphenyl-4H-1, 2, 4-triazole derivative, a preparation method and application thereof. Specifically, the invention relates to a 3, 4-diphenyl-4H-1, 2, 4-triazole derivative with a structure shown in a formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof, wherein the definition of each substituent in the formula (I) is the same as that in the specification. The compounds with novel structures have the activity of inhibiting the HSP90 heat shock protein, can be used for treating cancers, neurodegenerative diseases, inflammatory diseases, autoimmune diseases, ischemic brain injury and the like, and have wide application prospects.

Description

3, 4-diphenyl-4H-1, 2, 4-triazole derivative and preparation method and application thereof

Technical Field

The invention belongs to the field of drug synthesis, and particularly relates to a 3, 4-diphenyl-4H-1, 2, 4-triazole derivative, and a preparation method and application thereof.

Background

Heat shock proteins play a key role in protecting various cellular stress factors (e.g., toxic foreign substances, chemotherapy, radiation) and can prevent the misfolding of key proteins involved in maintaining normal cellular functions. Heat shock protein HSP90 plays an important role in the conformational maturation, stabilization and functionalization of a range of client proteins, many of which belong to the proto-oncogene protein family, such as Bcr-Abl, Raf-1, Akt, ErbB2, EGFR, Hif and other proteins and steroid hormone receptors. Inhibition of heat shock protein HSP90 can trigger disaggregation of the heat shock protein and client protein complex, which subsequently leads to degradation of the client protein and loss of efficacy, and can thereby inhibit the growth of tumor cells. Thus, the role of heat shock protein HSP90 has become an important target in different disease areas, especially in cancer and neurodegenerative diseases (Solit d.b., et al, Drug discov.today,2008,13(1-2), 38; taylor d.m., et al, Cell Stress Chaperones,2007,12, 2, 151; Yang z, et al, nat. med.,2007,13, 3, 348; Luo w.et al, proc. natl.acad.sci. 2007,104,9511; Macario a.j., et al, n.engl.j.med.,2005,353,1489; Dou f., etal, int.j.mol.sci.,2007,8, 51).

In addition, many HSP90 client proteins are overexpressed in cancer and often in mutated form, leading to unlimited proliferation and survival of cancer cells; moreover, it has recently been discovered that HSP90 also plays an important role in the infiltration and spread of cancer cells. Interestingly, the HSP90 protein isolated from tumor cells has a particularly higher atpase activity than that of normal cells, and therefore, it is possible to design specific compounds that can selectively inhibit HSP90 in tumor cells without affecting the function of normal cells (chilis g., et al., acschem.biol.,2006,1, Ii, 279; european b.k., et al., Nature Cell biol.,2004,6, 507; Koga f., et al., Cell cycle,2007,6, 1393).

Therefore, HSP90 is considered to be an important target for developing cancer therapeutic drugs, and inhibition of HSP90 can achieve treatment of various cancers. Since the discovery that two natural products, Geldanamycin and Radicicol, can bind to the adenosine triphosphate pocket in the N-terminal region of heat shock proteins, there has been increasing interest in the development of HSP90 inhibitors. The natural antibiotic Geldanamycin showed potential inhibition of human Cancer cell growth, but the apparent toxicity of this compound prevented its further clinical development (Whitesell l., et al, Cancer res.,1992,52, 1721; Supko j.g., et al, Cancer chemother, pharmacol.,1995,36, 305).

Currently, the FDA has not approved an HSP90 inhibitor as an anticancer drug, and HSP90 as a promising target of anticancer drug still attracts the medical community to develop a new HSP90 inhibitor.

Disclosure of Invention

In order to overcome the defects in the prior art, the inventor has intensively studied and found a 3, 4-diphenyl-4H-1, 2, 4-triazole derivative with a structure shown as a formula (I). The compounds with novel structures have the activity of inhibiting the HSP90 heat shock protein, can be used for treating cancers, neurodegenerative diseases, inflammatory diseases, autoimmune diseases, ischemic brain injury and the like, and have wide application prospects.

An object of the present invention is to provide a 3, 4-diphenyl-4H-1, 2, 4-triazole derivative which is a compound having the following formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof:

wherein:

R₁selected from hydrogen, deuterium, halogen, hydroxyl, sulfydryl, cyano, nitro, azido and C_1-8Alkyl radical, C_2-8Alkenyl radical, C_2-8Alkynyl, C_3-8Cycloalkyl, 3-8 membered heterocyclyl, 3-8 membered heterocyclyloxy, 3-8 membered heterocyclylthio, C_5-10Aryl radical, C_5-10Aryloxy radical, C_5-10Arylthio, 5-10 membered heteroaryl, 5-10 membered heteroaryloxy, 5-10 membered heteroarylthio, -C_0-8-S(O)rR₅、-C_0-8-O-R₅、-C_0-8-C(O)OR₅、-C_0-8-C(O)R₆、-C_0-8-O-C(O)R₆、-C_0-8-NR₇R₈、-C_0-8-C(O)NR₇R₈、-C_0-8-N(R₅)-C(O)R₆or-C_0-8-N(R₆)-C(O)OR₅Optionally further substituted with one or more groups selected from halogen, hydroxy, mercapto, cyano, nitro, azido, C_1-8Alkyl radical, C_2-8Alkenyl radical, C_2-8Alkynyl, C_3-8Cycloalkyl, 3-8 membered heterocyclyl, 3-8 membered heterocyclyloxy, 3-8 membered heterocyclylthio, C_5-10Aryl radical, C_5-10Aryloxy radical, C_5-10Arylthio, 5-10 membered heteroaryl, 5-10 membered heteroaryloxy, 5-10 membered heteroarylthio, -C_0-8-S(O)rR₅、-C_0-8-O-R₅、-C_0-8-C(O)OR₅、-C_0-8-C(O)R₆、-C_0-8-O-C(O)R₆、-C_0-8-NR₇R₈、-C_0-8-C(O)NR₇R₈、-C_0-8-N(R₅)-C(O)R₆or-C_0-8-N(R₆)-C(O)OR₅Substituted with the substituent(s);

R₂、R₃、R₄each independently selected from hydrogen, deuterium, halogen, hydroxyl, mercapto, cyano, nitro, azido, C_1-8Alkyl radical, C_2-8Alkenyl radical, C_2-8Alkynyl, C_3-8Cycloalkyl, 3-8 membered heterocyclyl, 3-8 membered heterocyclyloxy, 3-8 membered heterocyclylthio, C_5-10Aryl radical, C_5-10Aryloxy radical, C_5-10Arylthio, 5-10 membered heteroaryl, 5-10 membered heteroaryloxy, 5-10 membered heteroarylthio, -C_0-8-S(O)rR₅、-C_0-8-O-R₅、-C_0-8-C(O)OR₅、-C_0-8-C(O)R₆、-C_0-8-O-C(O)R₆、-C_0-8-NR₇R₈、-C_0-8-C(O)NR₇R₈、-C_0-8-N(R₅)-C(O)R₆or-C_0-8-N(R₆)-C(O)OR₅Optionally further substituted with one or more groups selected from halogen, hydroxy, mercapto, cyano, nitro, azido, C_1-8Alkyl radical, C_2-8Alkenyl radical, C_2-8Alkynyl, C_3-8Cycloalkyl, 3-8 membered heterocyclyl, 3-8 membered heterocyclyloxy, 3-8 membered heterocyclylthio, C_5-10Aryl radical, C_5-10Aryloxy radical, C_5-10Arylthio, 5-10 membered heteroaryl, 5-10 membered heteroaryloxy, 5-10 membered heteroarylthio, -C_0-8-S(O)rR₅、-C_0-8-O-R₅、-C_0-8-C(O)OR₅、-C_0-8-C(O)R₆、-C_0-8-O-C(O)R₆、-C_0-8-NR₇R₈、-C_0-8-C(O)NR₇R₈、-C_0-8-N(R₅)-C(O)R₆or-C_0-8-N(R₆)-C(O)OR₅Substituted with the substituent(s);

or, R₂And R₃、R₂And R₄Together with the carbon atom to which they are directly attached form a 6-8 membered nitrogen-containing heterocyclic group, optionally further substituted with one or moreSelected from halogen, hydroxyl, sulfydryl, carbonyl, cyano, nitro, azido and C_1-8Alkyl radical, C_2-8Alkenyl radical, C_2-8Alkynyl, C_3-8Cycloalkyl, 3-8 membered heterocyclyl, 3-8 membered heterocyclyloxy, 3-8 membered heterocyclylthio, C_5-10Aryl radical, C_5-10Aryloxy radical, C_5-10Arylthio, 5-10 membered heteroaryl, 5-10 membered heteroaryloxy, 5-10 membered heteroarylthio, -C_0-8-S(O)rR₅、-C_0-8-O-R₅、-C_0-8-C(O)OR₅、-C_0-8-C(O)R₆、-C_0-8-O-C(O)R₆、-C_0-8-NR₇R₈、-C_0-8-C(O)NR₇R₈、-C_0-8-N(R₅)-C(O)R₆or-C_0-8-N(R₆)-C(O)OR₅Substituted with the substituent(s);

R₅selected from hydrogen, C_l-8Alkyl radical, C_3-8Cycloalkyl or C_l-8An alkylcarbonyl group;

R₆、R₇、R₈each independently selected from hydrogen, C_1-8Alkyl radical, C_1-8Alkoxy radical, C_2-8Alkenyl radical, C_2-8Alkynyl, C_3-8Cycloalkyl, 3-8 membered heterocyclyl, 3-8 membered heterocyclyloxy, 3-8 membered heterocyclylthio, C_5-10Aryl radical, C_5-10Aryloxy radical, C_5-10Arylthio, 5-10 membered heteroaryl, 5-10 membered heteroaryloxy, 5-10 membered heteroarylthio, C_0-8Alkylcarbonyl group, C_0-8Alkylamino or C_0-8Alkylamido, optionally further substituted with one or more substituents selected from halogen, hydroxy, mercapto, cyano, nitro, acetamido, azido, sulfonyl, methylsulfonyl, C_1-8Alkyl radical, C_2-8Alkenyl radical, C_2-8Alkynyl, C_3-8Cycloalkyl, 3-8 membered heterocyclyl, C_1-8Alkoxy radical, C_1-8Alkoxycarbonyl, C_1-8Alkylcarbonyl group, C_1-8Alkylcarbonyloxy, 3-8 membered heterocyclyloxy, 3-8 membered heterocyclylthio, C_5-10Aryl radical, C_5-10Aryloxy radical, C_5-10An arylthio group, a 5-to 10-membered heteroaryl group,5-10 membered heteroaryloxy, 5-10 membered heteroarylthio, amino, C_1-8Alkyl monosubstituted amino or C_1-8Substituted by a substituent of alkyl disubstituted amino;

r is 0, 1 or 2.

As a further preferred embodiment, the 3, 4-diphenyl-4H-1, 2, 4-triazole derivative, a stereoisomer thereof or a pharmaceutically acceptable salt thereof, R₃、R₄Each independently selected from hydrogen. .

As a still further preferred embodiment, the 3, 4-diphenyl-4H-1, 2, 4-triazole derivative, its stereoisomer or a pharmaceutically acceptable salt thereof, R₁Selected from hydroxy or-C_0-4-C(O)NR₇R₈。

As a further preferred embodiment, the 3, 4-diphenyl-4H-1, 2, 4-triazole derivative, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, is selected from the following structures:

wherein R is₁Selected from hydroxy or-C_0-4-C(O)NR₇R₈；R₇、R₈As defined in claim 1; r₉、R₁₀Each independently selected from hydrogen, halogen, hydroxyl, sulfhydryl, cyano, nitro, azido and C_1-8Alkyl radical, C_2-8Alkenyl radical, C_2-8Alkynyl, C_3-8Cycloalkyl, 3-8 membered heterocyclyl, 3-8 membered heterocyclyloxy, 3-8 membered heterocyclylthio, C_5-10Aryl radical, C_5-10Aryloxy radical, C_5-10Arylthio, 5-10 membered heteroaryl, 5-10 membered heteroaryloxy, 5-10 membered heteroarylthio, -C_0-8-S(O)rR₅、-C_0-8-O-R₅、-C_0-8-C(O)OR₅、-C_0-8-C(O)R₆、-C_0-8-O-C(O)R₆、-C_0-8-NR₇R₈、-C_0-8-C(O)NR₇R₈、-C_0-8-N(R₅)-C(O)R₆or-C_0-8-N(R₆)-C(O)OR₅。

As a still further preferred embodiment, the 3, 4-diphenyl-4H-1, 2, 4-triazole derivative, its stereoisomer or a pharmaceutically acceptable salt thereof, R₉、R₁₀Each independently selected from hydrogen, fluoro, methyl, ethyl, allyl, cyclopropyl, methoxy, ethoxycarbonyl, acetyl, acetoxy, amino, carbamoyl or acetylamino.

As a still further preferred embodiment, the 3, 4-diphenyl-4H-1, 2, 4-triazole derivative, its stereoisomer or a pharmaceutically acceptable salt thereof, R₆、R₇、R₈Each independently selected from hydrogen, fluoro, methyl, ethyl, allyl, cyclopropyl, methoxy, acetyl, amino, carbamoyl, acetylamino, 5-membered heterocyclyl.

As a further preferred embodiment, said 3, 4-diphenyl-4H-1, 2, 4-triazole derivative, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, the 5-membered heterocyclic group is selected from the following structures:

X₁selected from oxygen or sulfur, X₂Selected from nitrogen, oxygen or sulfur.

As a most preferred embodiment, the 3, 4-diphenyl-4H-1, 2, 4-triazole derivative, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof is selected from the group consisting of:

according to the theory of chemical resonance, the following compounds are isomers of each other:

and

and

as can be seen from the above, when R is₁In the case of hydroxyl, the following structural interconversion of formula (I) may occur:

as a further preferred embodiment, the 3, 4-diphenyl-4H-1, 2, 4-triazole derivative, a stereoisomer thereof or a pharmaceutically acceptable salt thereof, R₂And R₃、R₂And R₄And the carbon atoms directly connected with the heterocyclic ring form a 7-membered nitrogen heterocyclic group, and are optionally further substituted by one or more groups selected from halogen, hydroxyl, sulfydryl, carbonyl, cyano, nitro, azido and C_1-8Alkyl radical, C_2-8Alkenyl radical, C_2-8Alkynyl, C_3-8Cycloalkyl, 3-8 membered heterocyclyl, 3-8 membered heterocyclyloxy, 3-8 membered heterocyclylthio, C_5-10Aryl radical, C_5-10Aryloxy radical, C_5-10Arylthio, 5-10 membered heteroaryl, 5-10 membered heteroaryloxy, 5-10 membered heteroarylthio, -C_0-8-S(O)rR₅、-C_0-8-O-R₅、-C_0-8-C(O)OR₅、-C_0-8-C(O)R₆、-C_0-8-O-C(O)R₆、-C_0-8-NR₇R₈、-C_0-8-C(O)NR₇R₈、-C_0-8-N(R₅)-C(O)R₆or-C_0-8-N(R₆)-C(O)OR₅Substituted with the substituent(s).

As a still further preferred embodiment, the 3, 4-diphenyl-4H-1, 2, 4-triazole derivative, its stereoisomer or a pharmaceutically acceptable salt thereof, R₂And R₃、R₂And R₄To carbon atoms directly attached theretoTogether form a 7-membered nitrogen-containing heterocyclic group, optionally further substituted with one or more groups selected from carbonyl, C_1-4Alkyl or C_3-6Cycloalkyl substituents.

As a still further preferred embodiment, the 3, 4-diphenyl-4H-1, 2, 4-triazole derivative, its stereoisomer or a pharmaceutically acceptable salt thereof, R₁Selected from hydrogen, hydroxy or-C_0-4-C(O)NR₇R₈。

As a still further preferred embodiment, the 3, 4-diphenyl-4H-1, 2, 4-triazole derivative, its stereoisomer or a pharmaceutically acceptable salt thereof, R₇、R₈Each independently selected from hydrogen, C_1-4Alkyl radical, C_3-6Cycloalkyl radical, C_1-4Alkoxy or C_0-4An alkylamino group.

As a most preferred embodiment, the 3, 4-diphenyl-4H-1, 2, 4-triazole derivative, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof is selected from the group consisting of:

in another aspect, the present invention provides a method for preparing the aforementioned 3, 4-diphenyl-4H-1, 2, 4-triazole derivative, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, which comprises the steps of:

alternatively, the first and second electrodes may be,

alternatively, the first and second electrodes may be,

optionally, according to R₁、R₂、R₃、R₄The step of further reaction according to the defined difference;

wherein Pg₁For the protecting group of a hydroxyl group, benzyl, 2-tetrahydrofuran, methoxymethyl, ethoxyethyl, C are preferred_1-8Alkyl, allyl, trimethylsilyl, triethylsilyl, triisopropylsilyl, tert-butyldimethylsilyl or tert-butyldiphenylsilyl;

Pg₂is an amino protecting group, preferably selected from benzyloxycarbonyl, t-butoxycarbonyl, 9-fluorenylmethyloxycarbonyl, trityl, trifluoroacetyl, benzyl or p-methoxyphenyl;

x is halogen, preferably chlorine; r₁、R₂、R₃、R₄、R₅、R₆、R₇、R₈And r is as defined for the compound of formula (I).

In a further aspect, the present invention provides a pharmaceutical composition comprising a therapeutically effective amount of the aforementioned 3, 4-diphenyl-4H-1, 2, 4-triazole derivative, a stereoisomer thereof or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

In a further aspect, the present invention provides an application of the aforementioned 3, 4-diphenyl-4H-1, 2, 4-triazole derivative, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or the aforementioned pharmaceutical composition in the preparation of a medicament for treating cancer, neurodegenerative diseases, inflammatory diseases, autoimmune diseases, and ischemic brain injury.

Detailed Description

Detailed description: unless stated to the contrary, the following terms used in the specification and claims have the following meanings.

“C_1-8Alkyl "refers to straight and branched alkyl groups comprising 1 to 8 carbon atoms, alkyl refers to a saturated aliphatic hydrocarbon group, C_0-8Means containing no carbon atoms or C_1-8Alkyl radicals, such as the methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1-dimethylpropyl, 1, 2-dimethylpropyl, 2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylbutyl radicalPropyl group, 1, 2-trimethylpropyl group, 1-dimethylbutyl group, 1, 2-dimethylbutyl group, 2-dimethylbutyl group, 1, 3-dimethylbutyl group, 2-ethylbutyl group, 2-methylpentyl group, 3-methylpentyl group, 4-methylpentyl group, 2, 3-dimethylbutyl group, n-heptyl group, 2-methylhexyl group, 3-methylhexyl group, 4-methylhexyl group, 5-methylhexyl group, 2, 3-dimethylpentyl group, 2, 4-dimethylpentyl group, 2-dimethylpentyl group, 3-dimethylpentyl group, 2-ethylpentyl group, 3-ethylpentyl group, n-octyl group, 2, 3-dimethylhexyl group, 2, 4-dimethylhexyl group, 2, 5-dimethylhexyl group, 2, 3-dimethylhexyl group, 2, 2-dimethylhexyl, 3-dimethylhexyl, 4-dimethylhexyl, 2-ethylhexyl, 3-ethylhexyl, 4-ethylhexyl, 2-methyl-2-ethylpentyl, 2-methyl-3-ethylpentyl or various branched isomers thereof, and the like.

Alkyl groups may be substituted or unsubstituted, and when substituted, the substituents may be substituted at any available point of attachment, preferably one or more groups independently selected from halogen, hydroxy, mercapto, cyano, nitro, azido, C_1-8Alkyl radical, C_2-8Alkenyl radical, C_2-8Alkynyl, C_3-8Cycloalkyl, 3-8 membered heterocyclyl, 3-8 membered heterocyclyloxy, 3-8 membered heterocyclylthio, C_5-10Aryl radical, C_5-10Aryloxy radical, C_5-10Arylthio, 5-10 membered heteroaryl, 5-10 membered heteroaryloxy, 5-10 membered heteroarylthio, -C_0-8-S(O)rR₅、-C_0-8-O-R₅、-C_0-8-C(O)OR₅、-C_0-8-C(O)R₆、-C_0-8-O-C(O)R₆、-C_0-8-NR₇R₈、-C_0-8-C(O)NR₇R₈、-N(R₅)-C(O)R₆or-N (R)₆)-C(O)OR₅Substituted with the substituent(s);

"cycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent, "C_3-8Cycloalkyl "refers to cycloalkyl groups comprising 3 to 8 carbon atoms, for example:

non-limiting examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, cyclooctyl, and the like.

Polycyclic cycloalkyl groups include spiro, fused and bridged cycloalkyl groups. "spirocycloalkyl" refers to polycyclic groups that share a single carbon atom (called a spiro atom) between single rings, which may contain one or more double bonds, but none of the rings have a completely conjugated pi-electron system. Spirocycloalkyl groups are classified according to the number of spiro atoms shared between rings into mono-, di-or multi-spirocycloalkyl groups, non-limiting examples of which include:

"fused cyclic alkyl" refers to an all-carbon polycyclic group in which each ring in the system shares an adjacent pair of carbon atoms with other rings in the system, wherein one or more of the rings may contain one or more double bonds, but none of the rings has a fully conjugated pi-electron system. And may be classified as bicyclic, tricyclic, tetracyclic, or polycyclic fused ring alkyl groups depending on the number of constituent rings, non-limiting examples of fused ring alkyl groups including:

"bridged cycloalkyl" refers to an all-carbon polycyclic group in which any two rings share two carbon atoms not directly connected, and these may contain one or more double bonds, but none of the rings have a completely conjugated pi-electron system. Depending on the number of constituent rings, may be classified as bicyclic, tricyclic, tetracyclic, or polycyclic bridged cycloalkyl groups, non-limiting examples of which include:

the cycloalkyl ring may be fused to an aryl, heteroaryl or heterocycloalkyl ring, where the ring to which the parent structure is attached is cycloalkyl, non-limiting examples of which include indanyl, tetrahydronaphthyl, benzocycloheptanyl, and the like.

Cycloalkyl groups may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more groups independently selected from halogen, hydroxy, mercapto, cyano, nitro, azido, C_1-8Alkyl radical, C_2-8Alkenyl radical, C_2-8Alkynyl, C_3-8Cycloalkyl, 3-8 membered heterocyclyl, 3-8 membered heterocyclyloxy, 3-8 membered heterocyclylthio, C_5-10Aryl radical, C_5-10Aryloxy radical, C_5-10Arylthio, 5-10 membered heteroaryl, 5-10 membered heteroaryloxy, 5-10 membered heteroarylthio, -C_0-8-S(O)rR₅、-C_0-8-O-R₅、-C_0-8-C(O)OR₅、-C_0-8-C(O)R₆、-C_0-8-O-C(O)R₆、-C_0-8-NR₇R₈、-C_0-8-C(O)NR₇R₈、-N(R₅)-C(O)R₆or-N (R)₆)-C(O)OR₅Substituted with the substituent(s);

"Heterocyclyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent in which one or more ring atoms are selected from nitrogen, oxygen, or heteroatoms of S (O) r (where r is an integer 0, 1, 2), but does not include the ring portion of-O-O-, -O-S-, or-S-S-, and the remaining ring atoms are carbon. "3-8 membered heterocyclic group" means a cyclic group containing 3 to 8 ring atoms, "3-6 membered heterocyclic group" means a cyclic group containing 3 to 6 ring atoms, and 3-8 membered heterocyclic group is preferably 3-6 membered heterocyclic group, further preferably 6 membered heterocyclic group.

Non-limiting examples of monocyclic heterocyclyl groups include pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, and the like.

Polycyclic heterocyclic groups include spiro, fused and bridged heterocyclic groups. "spiroheterocyclyl" refers to a polycyclic heterocyclic group in which one atom (referred to as a spiro atom) is shared between monocyclic rings, and in which one or more ring atoms are selected from nitrogen, oxygen, or a heteroatom of S (O) r (where r is an integer of 0, 1, 2), and the remaining ring atoms are carbon. These may contain one or more double bonds, but none of the rings has a completely conjugated pi-electron system. Spirocycloalkyl groups are classified into a single spiroheterocyclyl group, a double spiroheterocyclyl group, or a multiple spiroheterocyclyl group according to the number of spiro atoms shared between rings. Non-limiting examples of spirocycloalkyl groups include:

"fused heterocyclyl" refers to a polycyclic heterocyclic group in which each ring in the system shares an adjacent pair of atoms with the other rings in the system, and one or more of the rings may contain one or more double bonds, but none of the rings has a fully conjugated pi-electron system, in which one or more of the ring atoms is selected from nitrogen, oxygen, or a heteroatom of S (O) r (where r is an integer 0, 1, 2), and the remaining ring atoms are carbon. And may be classified as bicyclic, tricyclic, tetracyclic, or polycyclic fused heterocycloalkyl depending on the number of rings comprising, non-limiting examples of fused heterocyclic groups include:

"bridged heterocyclyl" refers to polycyclic heterocyclic groups in which any two rings share two atoms not directly attached, which may contain one or more double bonds, but none of the rings have a fully conjugated pi-electron system in which one or more ring atoms are selected from nitrogen, oxygen, or heteroatoms of S (O) r (where r is an integer 0, 1, 2), the remaining ring atoms being carbon. Depending on the number of constituent rings, may be classified as bicyclic, tricyclic, tetracyclic, or polycyclic bridged cycloalkyl groups, non-limiting examples of which include:

the heterocyclyl ring may be fused to an aryl, heteroaryl or cycloalkyl ring, wherein the ring to which the parent structure is attached is heterocyclyl, non-limiting examples of which include:

the heterocyclic group may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more groups independently selected from halogen, hydroxy, mercapto, cyano, nitro, azido, C_1-8Alkyl radical, C_2-8Alkenyl radical, C_2-8Alkynyl, C_3-8Cycloalkyl, 3-8 membered heterocyclyl, 3-8 membered heterocyclyloxy, 3-8 membered heterocyclylthio, C_5-10Aryl radical, C_5-10Aryloxy radical, C_5-10Arylthio, 5-10 membered heteroaryl, 5-10 membered heteroaryloxy, 5-10 membered heteroarylthio, -C_0-8-S(O)rR₅、-C_0-8-O-R₅、-C_0-8-C(O)OR₅、-C_0-8-C(O)R₆、-C_0-8-O-C(O)R₆、-C_0-8-NR₇R₈、-C_0-8-C(O)NR₇R₈、-N(R₅)-C(O)R₆or-N (R)₆)-C(O)OR₅Substituted with the substituent(s);

"aryl" refers to an all-carbon monocyclic or fused polycyclic (i.e., rings which share adjacent pairs of carbon atoms) group, a polycyclic (i.e., rings which carry adjacent pairs of carbon atoms) group having a conjugated pi-electron system, and a "C" group_5-10Aryl "means an all-carbon aryl group having 5 to 10 carbons, and" 5-to 10-membered aryl "means an all-carbon aryl group having 5 to 10 carbons, such as phenyl and naphthyl. The aryl ring may be fused to a heteroaryl, heterocyclyl or cycloalkyl ring, wherein the ring attached to the parent structure is an aryl ring, non-limiting examples of which include:

aryl groups may be substituted or unsubstituted, and when substituted, the substituents are preferably one or more groups independently selected from halogen, hydroxy, mercapto, cyano, nitro, azido, C_1-8Alkyl radical, C_2-8Alkenyl radical, C_2-8Alkynyl, C_3-8Cycloalkyl, 3-8 membered heterocyclyl, 3-8 membered heterocyclyloxyA group, 3-8 membered heterocyclylthio, C_5-10Aryl radical, C_5-10Aryloxy radical, C_5-10Arylthio, 5-10 membered heteroaryl, 5-10 membered heteroaryloxy, 5-10 membered heteroarylthio, -C_0-8-S(O)rR₅、-C_0-8-O-R₅、-C_0-8-C(O)OR₅、-C_0-8-C(O)R₆、-C_0-8-O-C(O)R₆、-C_0-8-NR₇R₈、-C_0-8-C(O)NR₇R₈、-N(R₅)-C(O)R₆or-N (R)₆)-C(O)OR₅Substituted with the substituent(s);

"heteroaryl" refers to a heteroaromatic system containing 1 to 4 heteroatoms including nitrogen, oxygen, and S (O) r (where r is an integer of 0, 1, 2), 5-7 membered heteroaryl refers to a heteroaromatic system containing 5-7 ring atoms, and 5-10 membered heteroaryl refers to a heteroaromatic system containing 5-10 ring atoms, such as furyl, thienyl, pyridyl, pyrrolyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, imidazolyl, tetrazolyl, and the like. The heteroaryl ring may be fused to an aryl, heterocyclyl or cycloalkyl ring, wherein the ring joined together with the parent structure is a heteroaryl ring, non-limiting examples of which include:

heteroaryl groups may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more groups independently selected from halogen, hydroxy, mercapto, cyano, nitro, azido, C_1-8Alkyl radical, C_2-8Alkenyl radical, C_2-8Alkynyl, C_3-8Cycloalkyl, 3-8 membered heterocyclyl, 3-8 membered heterocyclyloxy, 3-8 membered heterocyclylthio, C_5-10Aryl radical, C_5-10Aryloxy radical, C_5-10Arylthio, 5-10 membered heteroaryl, 5-10 membered heteroaryloxy, 5-10 membered heteroarylthio, -C_0-8-S(O)rR₅、-C_0-8-O-R₅、-C_0-8-C(O)OR₅、-C_0-8-C(O)R₆、-C_0-8-O-C(O)R₆、-C_0-8-NR₇R₈、-C_0-8-C(O)NR₇R₈、-N(R₅)-C(O)R₆or-N (R)₅)-C(O)OR₅Substituted with the substituent(s);

"alkenyl" means an alkyl group as defined above consisting of at least two carbon atoms and at least one carbon-carbon double bond, C_2-8Alkenyl means a straight-chain or branched alkenyl group having 2 to 8 carbons, preferably a straight-chain or branched alkenyl group having 2 to 4 carbons. Such as ethenyl, 1-propenyl, 2-propenyl, 1-, 2-or 3-butenyl, and the like.

The alkenyl group may be substituted or unsubstituted, and when substituted, the substituents are preferably one or more groups independently selected from halogen, hydroxy, mercapto, cyano, nitro, azido, C_1-8Alkyl radical, C_2-8Alkenyl radical, C_2-8Alkynyl, C_3-8Cycloalkyl, 3-8 membered heterocyclyl, 3-8 membered heterocyclyloxy, 3-8 membered heterocyclylthio, C_5-10Aryl radical, C_5-10Aryloxy radical, C_5-10Arylthio, 5-10 membered heteroaryl, 5-10 membered heteroaryloxy, 5-10 membered heteroarylthio, -C_0-8-S(O)rR₅、-C_0-8-O-R₅、-C_0-8-C(O)OR₅、-C_0-8-C(O)R₆、-C_0-8-O-C(O)R₆、-C_0-8-NR₇R₈、-C_0-8-C(O)NR₇R₈、-N(R₅)-C(O)R₆or-N (R)₆)-C(O)OR₅Substituted with the substituent(s);

"alkynyl" means an alkyl group as defined above consisting of at least two carbon atoms and at least one carbon-carbon triple bond, C_2-8Alkynyl means a straight or branched chain alkynyl group having 2 to 8 carbons, preferably a straight or branched chain alkynyl group having 2 to 4 carbons. For example, ethynyl, 1-propynyl, 2-propynyl, 1-, 2-or 3-butynyl and the like.

Alkynyl groups may be substituted or unsubstituted, and when substituted, the substituents are preferably one or more groups independently selected from halogen, hydroxy, mercapto, cyano, nitro, azideBase, C_1-8Alkyl radical, C_2-8Alkenyl radical, C_2-8Alkynyl, C_3-8Cycloalkyl, 3-8 membered heterocyclyl, 3-8 membered heterocyclyloxy, 3-8 membered heterocyclylthio, C_5-10Aryl radical, C_5-10Aryloxy radical, C_5-10Arylthio, 5-10 membered heteroaryl, 5-10 membered heteroaryloxy, 5-10 membered heteroarylthio, -C_0-8-S(O)rR₅、-C_0-8-O-R₅、-C_0-8-C(O)OR₅、-C_0-8-C(O)R₆、-C_0-8-O-C(O)R₆、-C_0-8-NR₇R₈、-C_0-8-C(O)NR₇R₈、-N(R₅)-C(O)R₆or-N (R)₆)-C(O)OR₅Substituted with the substituent(s);

"alkoxy" refers to-O- (alkyl) wherein alkyl is as defined above. C_1-8Alkoxy means an alkyloxy group having 1 to 8 carbons, preferably an alkyloxy group having 1 to 4 carbons, and non-limiting examples include methoxy, ethoxy, propoxy, butoxy and the like.

Alkoxy groups may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more groups independently selected from halogen, hydroxy, mercapto, cyano, nitro, azido, C_1-8Alkyl radical, C_2-8Alkenyl radical, C_2-8Alkynyl, C_3-8Cycloalkyl, 3-8 membered heterocyclyl, 3-8 membered heterocyclyloxy, 3-8 membered heterocyclylthio, C_5-10Aryl radical, C_5-10Aryloxy radical, C_5-10Arylthio, 5-10 membered heteroaryl, 5-10 membered heteroaryloxy, 5-10 membered heteroarylthio, -C_0-8-S(O)rR₅、-C_0-8-O-R₅、-C_0-8-C(O)OR₅、-C_0-8-C(O)R₆、-C_0-8-O-C(O)R₆、-C_0-8-NR₇R₈、-C_0-8-C(O)NR₇R₈、-N(R₅)-C(O)R₆or-N (R)₆)-C(O)OR₅Substituted with the substituent(s);

"Cycloalkoxy" means-O- (unsubstituted cycloalkyl) wherein cycloalkyl is as definedAs described above. C_3-8Cycloalkoxy means cycloalkyloxy having 3 to 8 carbons, preferably cycloalkyloxy having 3 to 6 carbons, and non-limiting examples include cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy and the like.

Cycloalkoxy groups may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more groups independently selected from halogen, hydroxy, mercapto, cyano, nitro, azido, C_1-8Alkyl radical, C_2-8Alkenyl radical, C_2-8Alkynyl, C_3-8Cycloalkyl, 3-8 membered heterocyclyl, 3-8 membered heterocyclyloxy, 3-8 membered heterocyclylthio, C_5-10Aryl radical, C_5-10Aryloxy radical, C_5-10Arylthio, 5-10 membered heteroaryl, 5-10 membered heteroaryloxy, 5-10 membered heteroarylthio, -C_0-8-S(O)rR₅、-C_0-8-O-R₅、-C_0-8-C(O)OR₅、-C_0-8-C(O)R₆、-C_0-8-O-C(O)R₆、-C_0-8-NR₇R₈、-C_0-8-C(O)NR₇R₈、-N(R₅)-C(O)R₆or-N (R)₆)-C(O)OR₅Substituted with the substituent(s);

"halogen-substituted C_1-8Alkyl "refers to a 1-8 carbon alkyl group optionally substituted with fluorine, chlorine, bromine, iodine atoms for hydrogen on the alkyl, preferably a 1-4 carbon alkyl group optionally substituted with fluorine, chlorine, bromine, iodine atoms for hydrogen on the alkyl, for example, difluoromethyl, dichloromethyl, dibromomethyl, trifluoromethyl, trichloromethyl, tribromomethyl, and the like.

"halogen-substituted C_1-8Alkoxy "hydrogen on alkyl is optionally substituted by fluorine, chlorine, bromine, iodine atoms 1-8 carbon alkoxy groups, preferably hydrogen on alkyl is optionally substituted by fluorine, chlorine, bromine, iodine atoms 1-4 carbon alkoxy groups. For example, difluoromethoxy, dichloromethoxy, dibromomethoxy, trifluoromethoxy, trichloromethoxy, tribromomethoxy and the like.

"halogen" means fluorine, chlorine, bromine or iodine.

“C_1-8Alkoxycarbonyl "means C_1-8Alkoxy radicalCarbonyl radicals substituted by radicals, preferably C_1-4Alkoxy-substituted carbonyl, non-limiting examples include methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, n-butoxycarbonyl, isobutoxycarbonyl, tert-butoxycarbonyl, sec-butoxycarbonyl, and the like.

“C_1-8Alkylcarbonyl "means C_1-8Alkyl-substituted carbonyl, preferably C_1-4Non-limiting examples of alkyl-substituted carbonyl groups include acetyl, propionyl, isopropionyl, n-butyryl, isobutyryl, t-butyryl, sec-butyryl, n-pentanoyl, 1-dimethylpropionyl, 1, 2-dimethylpropionyl, 2-dimethylpropionyl, 1-ethylpropionyl, 2-methylbutyryl, 3-methylbutyryl and the like.

“C_1-8Alkylcarbonyloxy "means C_1-8Alkyl-substituted carbonyloxy, preferably C_1-4Non-limiting examples of alkyl-substituted carbonyloxy include methoxycarbonyloxy, ethylcarbonyloxy, propylcarbonyloxy, isopropylcarbonyloxy, n-butylcarbonyloxy, isobutylcarbonyloxy, tert-butylcarbonyloxy or sec-butylcarbonyloxy.

“C_1-8Alkyl monosubstituted amino "refers to C_1-8Alkyl-substituted amino groups, preferably C_1-4Non-limiting examples of alkyl-substituted amino groups include methylamino, ethylamino, propylamino, isopropylamino, n-butylamino, isobutylamino, tert-butylamino, or sec-butylamino, and the like.

“C_1-8Alkyl disubstituted amino "means two C_1-8Alkyl-substituted amino group, preferably two C_1-4Non-limiting examples of alkyl-substituted amino groups include dimethylamino, diethylamino, dipropylamino, diisopropylamino, di-n-butylamino, diisobutylamino, di-t-butylamino, di-s-butylamino, and the like.

-C_0-8-S(O)rR₅preferably-C_0-4-S(O)rR₅；

-C_0-8-O-R₅preferably-C_0-4-O-R₅；

-C_0-8-C(O)OR₅preferably-C_0-,4-C(O)OR₅；

-C_0-8-C(O)R₆preferably-C_0-4-C(O)R₆；

-C_0-8-O-C_0-8-C(O)R₆preferably-C_0-8-O-C_0-4-C(O)R₆Further preferred is-C_0-4-O-C_0-4-C(O)R₆；

-C_0-8-NR₇R₈preferably-C_0-4-NR₇R₈；

-C_0-8-C(O)NR₇R₈preferably-C_0-4-C(O)NR₇R₈Further preferred is-C (O) NR₇R₈；

-C_0-8-N(R₅)-C_0-8-C(O)R₆preferably-C_0-8-N(R₅)-C_0-4-C(O)R₆Further preferred is-C_0-4-N(R₅)-C_0-4-C(O)R₆；

-C_0-8-N(R₆)-C(O)OR₅preferably-C_0-4-N(R₆)-C(O)OR₅。

"optional" or "optionally" means that the subsequently described event or circumstance may, but need not, occur, and that the description includes instances where the event or circumstance occurs or does not. For example, "a heterocyclic group optionally substituted with an alkyl" means that an alkyl may, but need not, be present, and the description includes the case where the heterocyclic group is substituted with an alkyl and the heterocyclic group is not substituted with an alkyl.

"substituted" means that one or more, preferably up to 5, more preferably 1 to 3, hydrogen atoms in the group are independently substituted with a corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions, and that the person skilled in the art is able to determine (experimentally or theoretically) possible or impossible substitutions without undue effort. For example, amino or hydroxyl groups having free hydrogen may be unstable in combination with carbon atoms having unsaturated (e.g., olefinic) bonds.

"pharmaceutical composition" means a mixture containing one or more compounds described herein or a physiologically/pharmaceutically acceptable salt or prodrug thereof in admixture with other chemical components, as well as other components such as physiologically/pharmaceutically acceptable carriers and excipients. The purpose of the pharmaceutical composition is to facilitate administration to an organism, facilitate absorption of the active ingredient and exert biological activity.

The present invention will be described more fully with reference to the following examples, but the present invention is not limited thereto, and the present invention is not limited to the examples.

The structure of the compounds of the invention is determined by Nuclear Magnetic Resonance (NMR) or/and liquid mass chromatography (LC-MS). NMR chemical shifts (δ) are given in parts per million (ppm). NMR was measured using a Bruker AVANCE-400 NMR spectrometer using deuterated dimethyl sulfoxide (DMSO-d)₆) Deuterated methanol (CD)₃OD) and deuterated chloroform (CDCl)₃) Internal standard is Tetramethylsilane (TMS).

LC-MS was measured using an Agilent 1200 Infinity Series Mass spectrometer. HPLC was carried out using an Agilent 1200DAD high pressure liquid chromatograph (Sunfire C18150X 4.6mm column) and a Waters 2695-2996 high pressure liquid chromatograph (Gimini C18150X 4.6mm column).

The thin layer chromatography silica gel plate adopts a tobacco yellow sea HSGF254 or Qingdao GF254 silica gel plate, the specification adopted by TLC is 0.15 mm-0.20 mm, and the specification adopted by the thin layer chromatography separation and purification product is 0.4 mm-0.5 mm. The column chromatography generally uses 200-300 mesh silica gel of the Tibet Huanghai silica gel as a carrier.

The starting materials in the examples of the present invention are known and commercially available, or may be synthesized using or according to methods known in the art.

All reactions of the present invention are carried out under a dry nitrogen or argon atmosphere with continuous magnetic stirring, and the solvent is a dry solvent, unless otherwise specified.

An argon atmosphere or nitrogen atmosphere means that the reaction flask is connected to a balloon of argon or nitrogen with a volume of about 1L. The hydrogen atmosphere refers to a reaction flask connected with a hydrogen balloon with a volume of about 1L.

The solutions in the examples are aqueous solutions unless otherwise specified. The reaction temperature was room temperature. The room temperature is the most suitable reaction temperature and is 20-30 ℃.

Example one

5- (2, 4-Dihydrox-5-isopropylbenzene) -N-ethyl-4- (4-methyl-2, 3,4, 5-tetrahydrobenzo [ b ] [1,4] oxazepin-8-yl) -4H-1,2, 4-triazole-3-carboxamide

The method comprises the following steps: 2- (hydroxymethyl) -5-nitrophenol

Adding dried tetrahydrofuran (100mL) into a compound 2-hydroxy-4-nitrobenzoic acid (15g, 82mmol), slowly dropwise adding a borane dimethyl sulfide solution (82mL, 820mmol) with the concentration of 10M under ice bath, and after dropwise adding, heating to room temperature for reacting for 16 h. Cooling to 0 deg.C, slowly adding methanol dropwise to quench. The mixture was refluxed for 1h at 70 ℃ and concentrated, then ethyl acetate was added, washed with brine, dried and concentrated to give 2- (hydroxymethyl) -5-nitrophenol (13.5g) in 97.5% yield.

MS m/z(ESI):168.1。

Step two: 2-hydroxy-4-nitrobenzaldehyde

The compound 2- (hydroxymethyl) -5-nitrophenol (13g,77mmol) and manganese dioxide (26.7g,308mmol) were added to ethyl acetate (250mL) and heated to 80 ℃ for 16 h. Filtration, concentration of the filtrate and column chromatography (1: 3, v/v) of the crude product afforded 2-hydroxy-4-nitrobenzaldehyde (10.5g) in 81.7% yield.

MS m/z(ESI):166.1。

Step three: 2- ((methylamino) methyl) -5-nitrophenol

Compound 2-hydroxy-4-nitrobenzaldehyde 1c (7g,42mmol) was dissolved in methanol (200mL) and a 2M solution of methylamine in tetrahydrofuran (31mL,63mmol) and zinc chloride (5.7g,42mmol) were slowly added dropwise over an ice bath. After the temperature is raised to room temperature and the reaction is carried out for 2h, sodium cyanoborohydride (5.3g,84mmol) is added in batches, the reaction is continued for 36h, ethyl acetate is added after the concentration and the drying, the washing with water is carried out, the yield of the 2- ((methylamino) methyl) -5-nitrophenol (7.2g) is 94.4 percent after the drying and the concentration.

MS m/z(ESI):183.1。

Step four: 2-chloro-N- (2-hydroxy-4-nitrobenzyl) -N-methylacetamide

Compound 2- ((methylamino) methyl) -5-nitrophenol (7.2g,34.6mmol) and triethylamine (14mL,103mmol) were dissolved in dichloromethane (50mL), and after chloroacetyl chloride (5.2mL,69mmol) was slowly added dropwise in an ice bath, the reaction was carried out at room temperature for 1 h. Dilute with dichloromethane, wash with 1M dilute hydrochloric acid, 1M sodium bicarbonate solution and saturated brine, respectively, dry and concentrate to give the crude product 2-chloro-N- (2-hydroxy-4-nitrophenyl) -N-methylacetamide (11 g).

MS m/z(ESI):193.1。

Step five: 4-methyl-8-nitro-4, 5-dihydrobenzo [ f ] [1,4] oxazepin-3 (2H) -one

2-chloro-N- (2-hydroxy-4-nitrophenyl) -N-methylacetamide (11g, 42.5mmol, crude), potassium carbonate (11.8g, 85mmol) and potassium iodide (3.5g, 21.3mmol) were added N, N-dimethylformamide (60 mL). After 16h reaction at rt, filtration and concentration of the filtrate to dryness, the crude product was isolated by column chromatography (dichloromethane/methanol ═ 30:1, v/v) to give 4-methyl-8-nitro-4, 5-dihydrobenzo [ f ] [1,4] oxazepin-3 (2h) -one (5.1g) in 54% yield.

MS m/z(ESI):193.1；

¹H NMR(400MHz,DMSO-d6,ppm):δ7.85-7.82(dd,J＝2.0,8.0Hz,1H),7.68(d,J＝2.0,1H),7.55-7.53(d,J＝8.4,1H),4.89(s,2H),4.82(s,2H),3.0(s,3H)。

Step six: 4-methyl-8-nitro-2, 3,4, 5-tetrahydrobenzo [ f ] [1,4] oxazepine

4-methyl-8-nitro-4, 5-dihydrobenzo [ f ] [1,4] oxazepin-3 (2H) -one (5g, 22.5mmol) was dissolved in tetrahydrofuran (50mL) and a 10M solution of borane dimethylsulfide (22.5mL,225mmol) was slowly added dropwise. After the dropwise addition, the mixture is heated to 80 ℃ for reaction for 16 h. Cooling to 0 deg.C, slowly adding methanol dropwise to quench. Heating to 80 ℃, refluxing for 1h, concentrating, adding dichloromethane, washing with brine, drying, and concentrating to obtain 4-methyl-8-nitro-2, 3,4, 5-tetrahydrobenzo [ f ] [1,4] oxazepine (4.1g), wherein the yield is 87.5%.

MS m/z(ESI):209.2。

Step seven: 4-methyl-2, 3,4, 5-tetrahydrobenzo [ f ] [1,4] oxazepin-8-amine

4-methyl-8-nitro-2, 3,4, 5-tetrahydrobenzo [ f ] [1,4] oxazepine (4g, 19.2mmol) was dissolved in methanol (40mL) and dry palladium on carbon (400mg) was added. The reaction is carried out for 2h under hydrogen at room temperature, filtration is carried out, and the filtrate is concentrated to obtain 4-methyl-2, 3,4, 5-tetrahydrobenzo [ f ] [1,4] oxazepin-8-amine (3.2g), with the yield of 93.5%.

MS m/z(ESI):179.2。

Step eight: 2, 4-Dihydrox-5-isopropyl-N- (4-methyl-2, 3,4, 5-tetrahydrobenzo [ f ] [1,4] oxazepin-8-yl) benzenesulf onamide

4-methyl-2, 3,4, 5-tetrahydrobenzo [ f ] [1,4] oxazepin-8-amine (3.2g, 18mmol) was dissolved in N, N-dimethylformamide (50mL), and sulfinyl bis ((2, 4-diphenolhydroxy-5-isopropylbenzene) methylsulfane) (7.9g, 18mmol) was added and reacted at room temperature for 16 h. Concentration, dilution with ethyl acetate, washing with water, drying with brine and concentration to obtain a crude product, which is separated by column chromatography (petroleum ether/ethyl acetate ═ 1:1 to dichloromethane/methanol ═ 30:1 to dichloromethane/methanol ═ 10:1, v/v) to give 2, 4-diphenolhydroxy-5-isopropyl-N- (4-methyl-2, 3,4, 5-tetrahydrobenzo [ f ] [1,4] oxazepin-8-yl) benzenethioamide (3.1g) with a yield of 46.4%.

MS m/z(ESI):373.1。

Step nine: 5- (2, 4-Dihydrox-5-isopropylbenzene) -N-ethyl-4- (4-methyl-2, 3,4, 5-tetrahydrobenzo [ f ] [1,4] oxazepin-8-yl) -4H-1,2, 4-triazole-3-carboxamide

Adding the compound 2, 4-diphenol hydroxy-5-isopropyl-N- (4-methyl-2, 3,4, 5-tetrahydrobenzo [ f ] [1,4] oxazepin-8-yl) benzenethioamide (500mg,1.34mmol), 2-hydrazino-2-oxo-N-propylacetamide (229mg,1.75mmol), mercuric chloride (1.1g,4.03mmol) and pyridine (0.325mL,4.03mmol) into anhydrous dioxane (12mL), heating to 80 ℃ by microwave for 20min, adding ethyl acetate for dilution, filtering to remove solid, washing filtrate with saturated sodium bicarbonate solution, washing with brine, drying, filtering, concentrating, and performing column chromatography on the crude product (dichloromethane/methanol ═ 30:1 to dichloromethane/methanol ═ 8:1, v/v) to obtain a crude product, purification by reverse phase chromatography (acetonitrile/water 0 to acetonitrile/water 40%, v/v) gave 5- (2, 4-diphenolhydroxy-5-isopropylbenzene) -N-ethyl-4- (4-methyl-2, 3,4, 5-tetrahydrobenzo [ f ] [1,4] oxazepin-8-yl) -4-hydro-1, 2, 4-triazole-3-carboxamide (142mg) in 23.4% yield.

MS m/z(ESI):452.5；

¹H NMR(400MHz,DMSO-d₆,ppm):δ10.45(s,1H),9.73(s,1H),8.96-8.93(t,J＝6.0,1H),7.27-7.25(d,J＝7.6,1H),6.97-6.96(m,2H),6.64(s,1H),6.34(s,1H),3.99-3.97(m,2H),3.67(s,1H),3.21-3.14(m,2H),2.98-2.91(m,1H),2.88-2.87(m,2H),1.07-1.03(t,J＝7.2,3H),0.84(s,3H),0.82(s,3H)。

Example two

4- (4-cyclohexyl-3-oxo-2, 3,4, 5-tetrahydrobenzo [ f ] [1,4] oxazepin-8-yl) -5- (2, 4-diphenolhydroxy-5-isopropylbenzene) -N-ethyl-4-hydro-1, 2, 4-triazole-3-carboxamide

The method comprises the following steps: 2- ((cyclopropylamine) methyl) -5-nitrophenol

The compound 2-hydroxy-4-nitrobenzaldehyde (1.8g,10.8mmol) was dissolved in methanol (50mL), and cyclopropylamine (800mg,14mmol) and acetic acid (650mg,10.8mmol) were added. After reacting for 0.5h at room temperature, sodium cyanoborohydride (1.35g,21.6mmol) is added in batches, the reaction is continued for 3h, dichloromethane is added after concentration, the mixture is washed by saturated sodium bicarbonate, washed by salt water, dried and concentrated, and the yield of 2- ((cyclopropylamine) methyl) -5-nitrophenol (2.1g) is 93.6%.

MS m/z(ESI):209.2。

Step two: 2-chloro-N-cyclopropyl-N- (2-hydroxy-4-nitrobenzyl) acetamide

Compound 2- ((cyclopropylamine) methyl) -5-nitrophenol (1.6g,7.7mmol) and triethylamine (2.2mL,15.4mmol) were dissolved in dichloromethane (50mL), and after chloroacetyl chloride (1.16mL,15.4mmol) was slowly added dropwise in an ice bath, the reaction was carried out at room temperature for 2 h. The mixture was diluted with dichloromethane, washed with 1M dilute hydrochloric acid and saturated brine, respectively, dried, and concentrated to give a crude product, 2-chloro-N- (2-hydroxy-4-nitrophenyl) -N-methylacetamide (2.2g), in 100% yield.

MS m/z(ESI):219.3。

Step three: 4-cyclohexyl-8-nitro-4, 5-dihydrobenzo [ f ] [1,4] oxazepin-3 (2H) -one

2-chloro-N-cyclopropyl-N- (2-hydroxy-4-nitrophenyl) -N-acetamide (2.2g, 7.7mmol, crude), potassium carbonate (2.1g, 15.4mmol) and potassium iodide (1.28g, 7.7mmol) were added N, N-dimethylformamide (20 mL). After 16h reaction at rt, filtration was carried out, the filtrate was concentrated to dryness and the crude product was isolated by column chromatography (1:1 petroleum ether/ethyl acetate to 1:3 petroleum ether/ethyl acetate, v/v) to give 4-cyclohexyl-8-nitro-4, 5-dihydrobenzo [ f ] [1,4] oxazepin-3 (2h) -one (1.6g) in 83% yield.

MS m/z(ESI):219.1。

Step four: 8-amino-4-cyclohexyl-4, 5-dihydrobenzo [ f ] [1,4] oxazepin-3 (2H) -one

4-cyclohexyl-8-nitro-4, 5-dihydrobenzo [ f ] [1,4] oxazepin-3 (2H) -one 2d (1.6g, 6.45mmol) was dissolved in methanol (20mL) and dry palladium on charcoal (160mg) was added. The reaction is carried out for 16h under hydrogen at room temperature, filtration is carried out, and the filtrate is concentrated to obtain 8-amino-4-cyclohexyl-4, 5-dihydrobenzo [ f ] [1,4] oxazepine-3 (2H) -one (1.4g), with the yield of 99%.

MS m/z(ESI):219.3。

Step five: n- (4-cyclohexyl-3-oxo-2, 3,4, 5-tetrahydrobenzo [ f ] [1,4] oxazepin-8-yl) -2, 4-dihydroxyl-5-isopropyl-benzenesulfenamide

8-amino-4-cyclohexyl-4, 5-dihydrobenzo [ f ] [1,4] oxazepin-3 (2H) -one (1.3g, 6mmol) was dissolved in N, N-dimethylformamide (40mL), and sulfinyl bis ((2, 4-diphenol hydroxy-5-isopropylbenzene) methylsulfane) (2.6g, 6mmol) was added and reacted at room temperature for 2 h. Concentration and isolation of the crude product by column chromatography (5: 1 petroleum ether/ethyl acetate to 1:2, v/v) gave N- (4-cyclohexyl 3-oxo-2, 3,4, 5-tetrahydrobenzo [ f ] [1,4] oxazepin-8-yl) -2, 4-diphenolhydroxy-5-isopropyl-benzenethioamide (1.5g) in 61.1% yield.

MS m/z(ESI):413.2。

Step six: 4- (4-cyclohexyl-3-oxo-2, 3,4, 5-tetrahydrobenzo [ f ] [1,4] oxazepin-8-yl) -5- (2, 4-diphenolhydroxy-5-isopropylbenzene) -N-ethyl-4-hydro-1, 2, 4-triazole-3-carboxamide

Adding the compound N- (4-cyclohexyl-3-oxo-2, 3,4, 5-tetrahydrobenzo [ f ] [1,4] oxazepin-8-yl) -2, 4-diphenol hydroxy-5-isopropyl-benzenethioamide (500mg,1.21mmol), 2-hydrazino-2-oxo-N-propylacetamide (190mg,1.45mmol), mercuric chloride (987mg,3.63mmol) and pyridine (0.3mL,3.63mmol) into anhydrous dioxane (12mL), heating to 80 deg.C with microwave for 20min, filtering, concentrating the filtrate, dissolving with ethyl acetate, washing with 1M hydrochloric acid aqueous solution, 1M sodium sulfide aqueous solution and saturated saline, drying, concentrating, adding methanol into the crude product, pulping to obtain 4- (4-cyclohexyl-3-oxo-2, 3,4, 5-Tetrahydrobenzo [ f ] [1,4] oxazepin-8-yl) -5- (2, 4-diphenol hydroxy-5-isopropylbenzene) -N-ethyl-4-hydro-1, 2, 4-triazole-3-carboxamide (107mg) in 17.9% yield.

MS m/z(ESI):492.3；

¹H NMR(400MHz,DMSO-d₆,ppm):δ10.59(s,1H),9.76(s,1H),8.95-8.92(t,J＝5.2,1H),7.36-7.34(d,J＝7.6,1H),6.97-6.94(m,2H),6.59(s,1H),6.35(s,1H),4.74(s,2H),4.70(s,2H),3.21-3.14(m,2H),2.96-2.89(m,1H),2.85-2.79(m,1H),2.31(s,3H),1.07-1.03(t,J＝7.2,3H),0.88(s,3H),0.87(s,3H)。

EXAMPLE III

5- (2, 4-Dihydrox-5-isopropylbenzene) -N- (3-oxo-2, 3,4, 5-tetrahydrobenzo [ f ] [1,4] oxazepin-8-yl) -N-ethyl-4 hydro-1, 2, 4-triazole-3-carboxamide

The method comprises the following steps: 2- (((2, 4-dimethoxybenzyl) amino) methyl) -5-nitrophenol

The compound 2-hydroxy-4-nitrobenzaldehyde (4g,23.9mmol) was dissolved in methanol (100mL) and 2, 4-dimethoxybenzylamine (4.8g,28.7mmol) and acetic acid (1.44g,23.9mmol) were added. After reacting at room temperature for 0.5h, sodium cyanoborohydride (3g,47.8mmol) is added in portions, the reaction is continued for 2h, dichloromethane is added after concentration, the mixture is washed by saturated sodium bicarbonate and saturated common salt, dried and concentrated, and crude product is pulped (dichloromethane/petroleum ether ═ 1:10) to obtain 2- (((2, 4-dimethoxybenzyl) amino) methyl) -5-nitrophenol (6.5g) with the yield of 85.3%.

MS m/z(ESI):319.1。

Step two: 2-chloro-N- (2, 4-dimethoxybenzyl) -N- (2-hydroxy-4-nitrobenzyl) acetamide

The compound 2- (((2, 4-dimethoxybenzyl) amino) methyl) -5-nitrophenol (6.5g,20.4mmol) and triethylamine (5.7mL,40.8mmol) were dissolved in dichloromethane (100mL), and after chloroacetyl chloride (3.1mL,40.8mmol) was slowly added dropwise under ice bath, the reaction was carried out at room temperature for 1 h. Dilute with dichloromethane, wash with 1M dilute hydrochloric acid and saturated brine, dry, and concentrate to give the crude product 2-chloro-N- (2, 4-dimethoxybenzyl) -N- (2-hydroxy-4-nitrobenzyl) acetamide (7.8g) in 96.8% yield.

MS m/z(ESI):329.2。

Step three: 4- (2, 4-Dimethoxybenzyl) -8-nitro-4, 5-dihydrobenzo [ f ] [1,4] oxazepin-3 (2H) -one

2-chloro-N- (2, 4-dimethoxybenzyl) -N- (2-hydroxy-4-nitrobenzyl) acetamide (7.8g, 19.8mmol, crude), potassium carbonate (5.5g, 39.6mmol) and potassium iodide (3.3g, 19.8mmol) was added N, N-dimethylformamide (80 mL). After 16h reaction at room temperature, filtration and concentration of the filtrate gave 4- (2, 4-dimethoxybenzyl) -8-nitro-4, 5-dihydrobenzo [ f ] [1,4] oxazepin-3 (2H) -one (6.9g) in 97.5% yield.

MS m/z(ESI):319.1。

Step four: 8-Nitro-4, 5-dihydrobenzo [ f ] [1,4] oxazepin-3 (2H) -one

4- (2, 4-dimethoxybenzyl) -8-nitro-4, 5-dihydrobenzo [ f ] [1,4] oxazepin-3 (2H) -one (6.9g, 19.3mmol) is dissolved in trifluoroacetic acid (30mL), heated by microwave to 60 ℃ for 20min, concentrated, dissolved by adding dichloromethane, washed by saturated sodium bicarbonate and saturated salt water, dried and concentrated, and separated by crude column chromatography (dichloromethane/methanol ═ 50:1, v/v) to give 8-nitro-4, 5-dihydrobenzo [ f ] [1,4] oxazepin-3 (2H) -one (3.5g) with a yield of 87.3%.

MS m/z(ESI):179.2。

Step five: 8-amino-4, 5-dihydrobenzo [ f ] [1,4] oxazepin-3 (2H) -one

8-Nitro-4, 5-dihydrobenzo [ f ] [1,4] oxazepin-3 (2H) -one (1g, 4.8mmol) was dissolved in a mixed solution of methanol and tetrahydrofuran (methanol/tetrahydrofuran ═ 1:1, v/v, 50mL), and Raney nickel (200mg) was added. The reaction is carried out for 2h under hydrogen at room temperature, filtration is carried out, and the filtrate is concentrated to obtain 8-amino-4, 5-dihydrobenzo [ f ] [1,4] oxazepin-3 (2H) -one (720mg) with the yield of 84.1 percent.

MS m/z(ESI):179.2。

Step six: 2, 4-Dihydrox-5-isopropyl-N- (3-oxo-2, 3,4, 5-tetrahydrobenzo [ f ] [1,4] oxazepin-8-yl) benzenesulf onamide

8-amino-4, 5-dihydrobenzo [ f ] [1,4] oxazepin-3 (2H) -one (406mg, 2.28mmol) was dissolved in N, N-dimethylformamide (20mL), and sulfinylbis ((2, 4-diphenolhydroxy-5-isopropylbenzene) methylsulfan) (500mg, 1.14mmol) was added and reacted at room temperature for 2 h. Concentration and isolation of the crude product by column chromatography (dichloromethane/methanol ═ 40:1, v/v) gave 2, 4-diphenolhydroxy-5-isopropyl-N- (3-oxo-2, 3,4, 5-tetrahydrobenzo [ f ] [1,4] oxazepin-8-yl) benzenesulphonamide (320mg) in 37.7% yield.

MS m/z(ESI):373.1。

Step seven: 5- (2, 4-Dihydrox-5-isopropylbenzene) -N- (3-oxo-2, 3,4, 5-tetrahydrobenzo [ f ] [1,4] oxazepin-8-yl) -N-ethyl-4 hydro-1, 2, 4-triazole-3-carboxamide

The compound 2, 4-dihydroxyl-5-isopropyl-N- (3-oxo-2, 3,4, 5-tetrahydrobenzo [ f ] [1,4] oxazepin-8-yl) benzenethioamide (180mg,0.483mmol), 2-hydrazino-2-oxo-N-propylacetamide (76mg,0.58mmol), mercuric chloride (394mg,1.45mmol) and pyridine (0.12mL,1.45mmol) were added to anhydrous dioxane (10mL), microwave heated to 80 ℃ for 20min, filtered, the filtrate was concentrated and the crude product was purified by reverse phase chromatography (acetonitrile/water 0 to acetonitrile/water 28%, v/v) to give 5- (2, 4-dihydroxyl-5-isopropylbenzene) -N- (3-oxo-2, 3,4, 5-Tetrahydrobenzo [ f ] [1,4] oxazepin-8-yl) -N-ethyl-4 h-1,2, 4-triazole-3-carboxamide (43mg) in 19.7% yield.

MS m/z(ESI):452.2；

¹H NMR(400MHz,CD₃OD,ppm):δ7.42-7.40(d,J＝8.0,1H),7.17(d,J＝2.0,1H),7.11-7.09(dd,J＝2.0,8.0,1H),6.69(s,1H),6.33(s,1H),4.66(s,2H),4.46(s,2H),3.33-3.31(m,2H),3.06-3.00(m,1H),1.21-1.18(t,J＝7.2,3H),0.92(s,3H),0.91(s,3H)。

Example four

5- (2, 4-Dihydrox-5-isopropyl) -N- (4-methyl-3-oxo-2, 3,4, 5-tetrahydrobenzo [ f ] [1,4] oxazepin-8-yl) -N-ethyl-4 hydro-1, 2, 4-triazole-3-carboxamide

The method comprises the following steps: 4-methyl-8-nitro-4, 5-dihydrobenzo [ f ] [1,4] oxazepin-3 (2H) -one

8-Nitro-4, 5-dihydrobenzo [ f ] [1,4] oxazepin-3 (2H) -one was dissolved in N, N-dimethylformamide (20mL), and cesium carbonate (3.8g, 11.6mmol) and iodomethane (1.8mL, 2.9mmol) were added. Reacting for 16h at room temperature, filtering, concentrating the filtrate, and separating a crude product by column chromatography (dichloromethane) to obtain 4-methyl-8-nitro-4, 5-dihydrobenzo [ f ] [1,4] oxazepine-3 (2H) -one (800mg) with the yield of 62.5%.

MS m/z(ESI):193.1。

Step two: 8-amino-4-methyl-4, 5-dihydrobenzo [ f ] [1,4] oxazepin-3 (2H) -one

4-methyl-8-nitro-4, 5-dihydrobenzo [ f ] [1,4] oxazepin-3 (2H) -one (800mg, 3.6mmol) was dissolved in methanol (50mL) and dry palladium on charcoal (80mg) was added. The reaction is carried out for 4h under hydrogen at room temperature, filtration and concentration of the filtrate are carried out to obtain 8-amino-4-methyl-4, 5-dihydrobenzo [ f ] [1,4] oxazepin-3 (2H) -one (650mg) with the yield of 93.9 percent.

MS m/z(ESI):193.1。

Step three: 2, 4-dihydroxyl-5-isopropyl-N- (4-methyl-3-oxo-2, 3,4, 5-tetrahydrobenzo [ f ] [1,4] oxazepin-8-yl) benzenesulf onamide

8-amino-4-methyl-4, 5-dihydrobenzo [ f ] [1,4] oxazepin-3 (2H) -one (600mg, 3.12mmol) was dissolved in N, N-dimethylformamide (15mL), and sulfinyl bis ((2, 4-diphenolhydroxy-5-isopropylbenzene) methylsulfane) (1.37g, 3.12mmol) was added and reacted at room temperature for 2 h. Concentration and isolation of the crude product by column chromatography (petroleum ether/ethyl acetate ═ 2:1 to dichloromethane/methanol ═ 50:1, v/v) gave 2, 4-diphenolhydroxy-5-isopropyl-N- (4-methyl-3-oxo-2, 3,4, 5-tetrahydrobenzo [ f ] [1,4] oxazepin-8-yl) benzenesulphonamide (1g) in 82.9% yield.

MS m/z(ESI):387.3。

Step four: 5- (2, 4-Dihydrox-5-isopropyl) -N- (4-methyl-3-oxo-2, 3,4, 5-tetrahydrobenzo [ f ] [1,4] oxazepin-8-yl) -N-ethyl-4 hydro-1, 2, 4-triazole-3-carboxamide

Adding a compound 2, 4-diphenol hydroxyl-5-isopropyl-N- (4-methyl-3-oxo-2, 3,4, 5-tetrahydrobenzo [ f ] [1,4] oxazepin-8-yl) benzenethioamide (1g,2.59mmol), 2-hydrazino-2-oxo-N-propylacetamide (441mg,3.36mmol), mercuric chloride (2.11g,7.76mmol) and pyridine (0.62mL,7.76mmol) into anhydrous dioxane (30mL), heating to 80 ℃ by microwave for 20min, filtering, concentrating the filtrate, dissolving the crude product by adding dichloromethane, washing with ethylene diamine tetraacetic acid aqueous solution and saturated saline solution, drying and concentrating, pulping the crude product by methanol to obtain 5- (2, 4-diphenol hydroxyl-5-isopropyl) -N- (4-methyl-3-oxo-2, 3,4, 5-Tetrahydrobenzo [ f ] [1,4] oxazepin-8-yl) -N-ethyl-4 h-1,2, 4-triazole-3-carboxamide (250mg) in 20.8% yield.

MS m/z(ESI):466.1；

¹H NMR(400MHz,DMSO-d6,ppm):δ10.49(s,1H),9.73(s,1H),8.95-8.92(t,J＝6.0,1H),7.32-7.30(d,J＝8.0,1H),6.99(d,J＝2.0,1H),6.94-6.92(dd,J＝2.0,8.0,1H),6.59(s,1H),6.34(s,1H),4.77(s,2H),4.72(s,2H),3.21-3.15(m,2H),2.99(s,3H),2.97-2.89(m,1H),1.07-1.04(t,J＝7.2,3H),0.85(s,3H),0.83(s,3H)。

EXAMPLE five

5- (2, 4-Dihydrox-5-isopropyl) -N-ethyl- (4-oxo-2, 3,4, 5-tetrahydrobenzo [ b ] [1,4] oxazepin-8-yl-4 hydro-1, 2, 4-triazole-3-carboxamide and 5- (2, 4-Dihydrox-5-isopropyl) -N-ethyl- (4-oxo-2, 3,4, 5-tetrahydrobenzo [ b ] [1,4] oxazepin-7-yl-4 hydro-1, 2, 4-triazole-3-carboxamide

The method comprises the following steps: 3- (2-Nitrophenoxy) propionic acid

2-Nitrophenol 5a (10g,71.9mmol) was dissolved in 1M aqueous sodium hydroxide (100mL) and 3-bromopropionic acid (16.5g,118mmol) was added. The reaction was heated to 70 ℃ for 14h, neutralized with 1M aqueous dilute hydrochloric acid (PH 6-7), extracted with ethyl acetate, dried and concentrated, and the crude product was isolated by column chromatography (3: 1 petroleum ether/ethyl acetate to 1:2, v/v) to give 3- (2-nitrophenoxy) propionic acid (4g) in 31% yield.

MS m/z(ESI):182.1。

Step two: 3- (2-aminophenoxy) propionic acid

3- (2-Nitrophenoxy) propionic acid (4g, 19.1mmol) was dissolved in ethanol (40mL) and dry palladium on carbon (300mg) was added. The reaction was carried out under hydrogen at room temperature for 14 hours, followed by filtration and concentration of the filtrate to give 3- (2-aminophenoxy) propionic acid 5c (3.2g) in a yield of 93.3%.

MS m/z(ESI):182.1。

Step three: 2, 3-dihydrobenzo [ b ] [1,4] oxazepin-4 (5H) -one

3- (2-aminophenoxy) propionic acid (2g,11mmol) and dicyclohexylcarbodiimide (2.5g,12.1mmol) were added to anhydrous dichloromethane (200mL) and reacted at room temperature for 16h, concentrated and the crude product was isolated by column chromatography (petroleum ether/ethyl acetate ═ 6:1 to petroleum ether/ethyl acetate ═ 2:1, v/v) to give 2, 3-dihydrobenzo [ b ] [1,4] oxazepin-4 (5 h) -one (1.5g) in 83.3% yield.

¹H NMR(400MHz,DMSO-d₆,ppm):δ9.71(s,1H),7.08-7.00(m,5H),4.37-4.34(t,J＝6.0,2H),2.70-2.67(t,J＝6.0,2H)。

Step four: 8-nitro-2, 3-dihydrobenzo [ b ] [1,4] oxazepin-4 (5H) -one and 7-nitro-2, 3-dihydrobenzo [ b ] [1,4] oxazepin-4 (5H) -one

2, 3-Dihydrobenzo [ b ] [1,4] oxazepin-4 (5H) -one (1g,6.13mmol) was dissolved in trifluoroacetic acid (30mL), and potassium nitrate (1.86g,18.39mmol) was added under ice bath to react at room temperature for 2 h. After concentration, water was added thereto, the mixture was neutralized with an aqueous sodium bicarbonate solution, extracted with ethyl acetate, and the organic phase was washed with saturated brine, dried and concentrated to give a mixture (880mg) of 8-nitro-2, 3-dihydrobenzo [ b ] [1,4] oxazepin-4 (5-hydro) -one and 7-nitro-2, 3-dihydrobenzo [ b ] [1,4] oxazepin-4 (5-hydro) -one in a yield of 68.9%.

MS m/z(ESI):179.2。

Step five: 8-amino-2, 3-dihydrobenzo [ b ] [1,4] oxazepin-4 (5H) -one and 7-amino-2, 3-dihydrobenzo [ b ] [1,4] oxazepin-4 (5H) -one

A mixture of 8-nitro-2, 3-dihydrobenzo [ b ] [1,4] oxazepin-4 (5H) -one and 7-nitro-2, 3-dihydrobenzo [ b ] [1,4] oxazepin-4 (5H) -one (500mg, 2.4mmol) was dissolved in methanol (10mL) and dry palladium on charcoal (100mg) was added. The reaction was carried out under hydrogen at room temperature for 16h, filtered, and the filtrate was concentrated to give a mixture (380mg) of 8-amino-2, 3-dihydrobenzo [ b ] [1,4] oxazepin-4 (5H) -one and 7-amino-2, 3-dihydrobenzo [ b ] [1,4] oxazepin-4 (5H) -one, with a yield of 88.8%.

MS m/z(ESI):179.2。

Step six: 2, 4-dihydroxyl-5-isopropyl-N- (4-oxo-2, 3,4, 5-tetrahydrobenzo [ b ] [1,4] oxazepin-8-yl) benzenethioamide and 2, 4-dihydroxyl-5-isopropyl-N- (4-oxo-2, 3,4, 5-tetrahydrobenzo [ b ] [1,4] oxazepin-7-yl) benzenethioamide

A mixture of 8-amino-2, 3-dihydrobenzo [ b ] [1,4] oxazepin-4 (5H) -one and 7-amino-2, 3-dihydrobenzo [ b ] [1,4] oxazepin-4 (5H) -one (300mg,1.68mmol) was dissolved in N, N-dimethylformamide (10mL), sulfinylbis ((2, 4-diphenolhydroxy-5-isopropylbenzene) methylsulfate) (370mg, 0.84mmol) was added and reacted at room temperature for 16 h. Concentration and separation of the crude product by column chromatography (petrol ether/ethyl acetate ═ 1:1, v/v) gave 2, 4-diphenolhydroxy-5-isopropyl-N- (4-oxo-2, 3,4, 5-tetrahydrobenzo [ b ] [1,4] oxazepin-8-yl) benzenesulphonamide and a mixture of 2, 4-diphenolhydroxy-5-isopropyl-N- (4-oxo-2, 3,4, 5-tetrahydrobenzo [ b ] [1,4] oxazepin-7-yl) benzenesulphonamide (180mg), 57.5% yield.

MS m/z(ESI):373.1。

Step seven: 5- (2, 4-Dihydrox-5-isopropyl) -N-ethyl- (4-oxo-2, 3,4, 5-tetrahydrobenzo [ b ] [1,4] oxazepin-8-yl-4 hydro-1, 2, 4-triazole-3-carboxamide and 5- (2, 4-Dihydrox-5-isopropyl) -N-ethyl- (4-oxo-2, 3,4, 5-tetrahydrobenzo [ b ] [1,4] oxazepin-7-yl-4 hydro-1, 2, 4-triazole-3-carboxamide

Adding a mixture (180mg,0.48mmol) of 2, 4-dihydroxyl-5-isopropyl-N- (4-oxo-2, 3,4, 5-tetrahydrobenzo [ b ] [1,4] oxazepin-8-yl) benzenethioamide and 2, 4-dihydroxyl-5-isopropyl-N- (4-oxo-2, 3,4, 5-tetrahydrobenzo [ b ] [1,4] oxazepin-7-yl) benzenethioamide, 2-hydrazino-2-oxo-N-propylacetamide (76mg,0.58mmol), mercuric chloride (394mg,1.45mmol) and pyridine (0.12mL,1.45mmol) into anhydrous dioxane (10mL), heating to 80 ℃ by microwave for 20min, filtering, concentrating the filtrate, adding dichloromethane to dissolve the crude product, washing with dilute aqueous hydrochloric acid and saturated brine, drying and concentrating, purifying the crude product by reverse phase chromatography (acetonitrile/water 0 to acetonitrile/water 32%, v/v) to give 5- (2, 4-dihydroxyhydroxy-5-isopropyl) -N-ethyl- (4-oxo-2, 3,4, 5-tetrahydrobenzo [ b ] [1,4] oxazepin-8-yl-4 h-ydro-1, 2, 4-triazole-3-carboxamide (32mg) in 14.7% yield of 5- (2, 4-dihydroxyhydroxy-5-isopropyl) -N-ethyl- (4-oxo-2, 3,4, 5-tetrahydrobenzo [ b ] [1,4] oxazepin-7-yl-4 h-1,2, 4-triazole-3-carboxamide (9mg) in 4.1% yield.

5- (2, 4-Dihydrox-5-isopropyl) -N-ethyl- (4-oxo-2, 3,4, 5-tetrahydrobenzo [ b ] [1,4] oxazepin-8-yl-4H-1, 2, 4-triazole-3-carboxamide.

MS m/z(ESI):452.2

¹H NMR(400MHz,DMSO-d₆,ppm):δ10.46(s,1H),9.95(s,1H),9.74(s,1H),8.95-8.92(t,J＝6.0,1H),7.10-7.08(d,J＝8.4,1H),7.04-7.03(d,J＝2.0,1H),6.98-6.95(dd,J＝2.4,8.4,1H),6.67(s,1H),6.34(s,1H),4.34-4.31(t,J＝5.6,2H),3.22-3.15(m,2H),2.99-2.92(m,1H),2.76-2.74(t,J＝5.6,2H),1.07-1.04(t,J＝7.2,3H),0.91(s,3H),0.89(s,3H)。

5- (2, 4-Dihydrox-5-isopropyl) -N-ethyl- (4-oxo-2, 3,4, 5-tetrahydrobenzo [ b ] [1,4] oxazepin-7-yl-4H-1, 2, 4-triazole-3-carboxamide.

MS m/z(ESI):452.2；

¹H NMR(400MHz,DMSO-d₆,ppm):δ10.53(s,1H),9.86(s,1H),9.78(s,1H),8.99-8.96(t,J＝6.0,1H),7.06-7.04(d,J＝8.4,1H),7.04-7.03(d,J＝2.0,1H),6.99-6.97(dd,J＝2.4,8.4,1H),6.63(s,1H),6.35(s,1H),4.38-4.35(t,J＝5.2,2H),3.22-3.15(m,2H),2.99-2.92(m,1H),2.77-2.74(t,J＝5.2,2H),1.08-1.04(t,J＝7.2,3H),0.90(s,3H),0.88(s,3H)。

EXAMPLE six

N- (4- (3- (2, 4-dihydroxy-5-isopropylphenyl) -5-carbonyl-1, 5-dihydro-4H-1, 2, 4-triazol-4-yl) benzyl) -5-methyl-1, 3, 4-oxadiazole-2-carboxamide

Step one, 2- (4-nitrobenzyl) isoindoline-1, 3-dione

1- (bromomethyl) -4-nitrobenzene (5.5g, 25.5mmol) was dissolved in N, N-dimethylformamide (30ml), and potassium phthalimide phthalate (9.5g, 51.3mmol) was added. The reaction mixture was stirred at room temperature for 3 hours, then water (250ml) was added. Filtration gave a solid which was rinsed with water (15ml x 3) and the solid dried to give 2- (4-nitrobenzyl) isoindoline-1, 3-dione (9.5g crude) which was taken directly to the next step.

¹H NMR(400MHz,CD₃OD,ppm):δ8.23(d,2H),7.92(dd,2H),7.85(dd,2H),7.62(d,2H),4.96(s,2H)。

Step two, namely (4-nitrophenyl) methylamine

2- (4-nitrobenzyl) isoindoline-1, 3-dione (5g, 17mmol) was dissolved in tetrahydrofuran (30ml) and hydrazine hydrate (4g, 68mmol, 85% aq) was added at room temperature and the reaction heated to 80 ℃ for 12 h. Then directly concentrated to remove the solvent, then water (200ml), ethyl acetate (50ml x 2) was added, the organic phase was extracted, dried over anhydrous sodium sulfate and concentrated to give (4-nitrophenyl) methylamine (1.5g, 52% yield).

¹H NMR(400MHz,DMSO-d₆,ppm):δ8.17(d,2H),7.60(d,2H),3.81(s,2H),1.90-2.05(br,2H)。

Step three (4-nitrobenzyl) carbamic acid tert-butyl ester

(4-Nitrophenyl) methylamine (1.4g, 9.2mmol) was dissolved in dichloromethane (35ml), and triethylamine (2.8g, 27.6mmol) was added at room temperature, followed by dropwise addition of di-tert-butyl dicarbonate (3.0g, 13.8 mmol). The reaction was heated to reflux for 3 hours and then concentrated to remove the solvent to give the crude product. The crude product was purified on a silica gel column to give tert-butyl (4-nitrobenzyl) carbamate (2.3g, 100% yield).

¹H NMR(400MHz,CDCl₃,ppm):δ8.12(d,2H),7.37(d,2H)，4.85-5.00(br,1H),4.35(d,2H)，1.40(s,9H)。

Step four (4-aminobenzyl) carbamic acid tert-butyl ester

Palladium on carbon (200mg) was added to a solution of tert-butyl (4-nitrobenzyl) carbamate (2.4g, 9.5mmol) in ethanol (40ml) under nitrogen. The reaction mixture was reacted in a hydrogen (1atm) atmosphere at room temperature for 3 hours. The catalyst was removed by filtration and the organic phase evaporated to dryness to give tert-butyl (4-aminobenzyl) carbamate (1.94g, 91% yield).

¹H NMR(400MHz,DMSO-d₆,ppm):δ7.14(m，1H)，6.78(d,2H),6.49(d,2H),4.91(s,2H),3.91(d,2H)，1.37(s,9H)。

Step five (4- ((phenoxycarbonyl) amino) benzyl) carbamic acid tert-butyl ester

Phenyl chloroformate (1.09ml, 8.7mmol) was added dropwise to a solution of tert-butyl (4-aminobenzyl) carbamate (1.94g, 8.7mmol) in dichloromethane (30ml) at 0 ℃ under nitrogen. The reaction was stirred for 5 minutes under nitrogen at 0 ℃ and then pyridine (0.85ml, 10.5mmol) was added dropwise to the reaction system, followed by stirring again for 30 minutes under nitrogen at 0 ℃. Water (50ml) was added to the reaction system, the organic phase was separated, dried over anhydrous sodium sulfate and evaporated to dryness to give a crude (2.9g) of tert-butyl (4- ((phenoxycarbonyl) amino) benzyl) carbamate which was used directly in the next step.

MS m/z(ESI):343.1。

Step six tert-butyl 4- (hydrazine-1-carboxamido) benzyl) carbamate

Hydrazine hydrate (10ml, 85% aqueous solution) was added to a solution of tert-butyl (4- ((phenoxycarbonyl) amino) benzyl) carbamate (2.9g, 8.5mmol) in dioxane (20 ml). The reaction was heated to 80 ℃ for 3 hours and the solvent was evaporated to dryness to give the crude product. The crude product was washed with water (20ml x 3) to give crude product, which was dried under an oil pump to give tert-butyl 4- (hydrazine-1-carboxamido) benzyl) carbamate (2g, 84%).

MS m/z(ESI):281.1。

Step seven: (E) - (4- (2- (2, 4-bis (benzyloxy) -5-isopropylphenylmethylene) hydrazine-1-carboxamido) benzyl) carbamic acid tert-butyl ester

Tert-butyl 4- (hydrazine-1-carboxamido) benzyl) carbamate (1.3g,3.57mmol) and 5-isopropyl-2, 4-dimethoxybenzaldehyde (1g,3.57mmol) were dissolved in ethanol (50mL), acetic acid (0.1mL) was added, the mixture was heated to 90 ℃ for reaction for 2h, and the mixture was concentrated to give crude tert-butyl (E) - (4- (2- (2, 4-bis (benzyloxy) -5-isopropylphenylmethylene) hydrazine-1-carboxamido) benzyl) carbamate (2.2g), which was used directly in the next reaction.

MSm/z(ESI):623.3。

Step eight: (4- (3- (2, 4-bis (benzyloxy) -5-isopropylphenyl) -5-carbonyl-1, 5-dihydro-4H-1, 2, 4-triazol-4-yl) benzyl) carbamic acid tert-butyl ester

Crude tert-butyl (E) - (4- (2- (2, 4-bis (benzyloxy) -5-isopropylphenylmethylene) hydrazine-1-carboxamido) benzyl) carbamate (2.2g, 3.53mmol) was dissolved in ethanol (40mL) and tripotassium hexacyanoferrate (2.33g,7.07mmol) and sodium hydroxide (424mg, 10.6mmol) were added. After heating to 100 ℃ for 8H, the reaction was concentrated and the crude product was isolated by column chromatography (dichloromethane/methanol ═ 30:1, v/v) to give tert-butyl (4- (3- (2, 4-bis (benzyloxy) -5-isopropylphenyl) -5-carbonyl-1, 5-dihydro-4H-1, 2, 4-triazol-4-yl) benzyl) carbamate (1.55g) in 71% yield.

MS m/z(ESI):621.3。

Step nine: 4- (4- (aminomethyl) phenyl) -5- (2, 4-bis (benzyloxy) -5-isopropylphenyl) -2, 4-dihydro-3H-1, 2, 4-triazol-3-one

Dissolving crude tert-butyl (4- (3- (2, 4-bis (benzyloxy) -5-isopropylphenyl) -5-carbonyl-1, 5-dihydro-4H-1, 2, 4-triazol-4-yl) benzyl) carbamate (800mg, 1.29mmol) in dichloromethane (20mL), adding trifluoroacetic acid (2mL) to react at room temperature for 3H, concentrating the reaction solution, adding dichloromethane to dissolve the crude product, washing the organic phase with an aqueous sodium bicarbonate solution and saturated brine respectively, drying and concentrating to obtain 4- (4- (aminomethyl) phenyl) -5- (2, 4-bis (benzyloxy) -5-isopropylphenyl) -2, 4-dihydro-3H-1, 2, 4-triazol-3-one (650mg) in 96.9% yield.

MS m/z(ESI):521.1。

Step ten of 5-methyl-1, 3, 4-oxadiazole-2-carboxylic acid ethyl ester

Oxalyl chloride monoethyl ester (10g, 74mmol) was added dropwise to a solution of 5-methyl-2H-tetrazole (6.25g, 74mmol) and triethylamine (7.5g, 74mmol) in toluene (80ml) at 0 ℃ under nitrogen. The reaction was stirred for 30 minutes at 0 ℃ under nitrogen, the solid was removed by filtration and the solid was rinsed with cold toluene (10ml x 2). The above solution was added dropwise to toluene (20ml) under nitrogen protection at 50 ℃ and the temperature was maintained at 50 ℃, after the addition was completed, the mixture was heated at 70 ℃ for 1 hour, then cooled to room temperature, washed with saturated brine, dried over anhydrous sodium sulfate, and the organic phase was directly passed through a column to obtain ethyl 5-methyl-1, 3, 4-oxadiazole-2-carboxylate (6.8g, 59% yield).

¹H NMR(400MHz,CDCl₃,ppm):δ4.51(m,2H),2.65(s,3H),1.46(m,3H)。

Step eleven potassium 5-methyl-1, 3, 4-oxadiazole-2-carboxylate

Aqueous KOH (5ml, 780mg, 13.5mmol) was added dropwise to a solution of ethyl 5-methyl-1, 3, 4-oxadiazole-2-carboxylate (2.1g, 13.5mmol) in ethanol (50ml) at 0 ℃. Then stirred at 0 ℃ for 1 hour, filtered to give a solid, which was washed with ethanol (20ml) to give potassium 5-methyl-1, 3, 4-oxadiazole-2-carboxylate (1.6g, 72% yield).

¹H NMR(400MHz,DMSO-d₆,ppm):δ2.43(s，3H)。

Step twelve, 5-methyl-1, 3, 4-oxadiazole-2-carbonyl chloride

Potassium 5-methyl-1, 3, 4-oxadiazole-2-carboxylate (500mg, 3mmol) was dissolved in dichloromethane (10mL) and oxalyl chloride (0.76mL, 9mmol) and N, N-dimethylformamide (0.025mL) were added under ice bath. After reacting for 2h at room temperature, the reaction solution was concentrated and the crude product was used directly in the next reaction.

Step thirteen: n- (4- (3- (2, 4-bis (benzyloxy) -5-isopropylphenyl) -5-carbonyl-1, 5-dihydro-4H-1, 2, 4-triazol-4-yl) benzyl) -5-methyl-1, 3, 4-oxadiazole-2-carboxamide

Crude 4- (4- (aminomethyl) phenyl) -5- (2, 4-bis (benzyloxy) -5-isopropylphenyl) -2, 4-dihydro-3H-1, 2, 4-triazol-3-one (650mg, 1.25mmol) was dissolved in dichloromethane (10mL), triethylamine (0.5mL, 3.75mmol) and 5-methyl-1, 3, 4-oxadiazole-2-carbonyl chloride (660mg, 3mmol) were added, the reaction mixture was reacted at room temperature for 1H, the reaction mixture was concentrated, and the crude product was isolated by column chromatography (dichloromethane/methanol ═ 30:1, v/v) to give N- (4- (3- (2, 4-bis (benzyloxy) -5-isopropylphenyl) -5-carbonyl-1, 5-dihydro-4H-1, 2, 4-triazol-4-yl) benzyl) -5-methyl-1, 3, 4-oxadiazole-2-carboxamide (405mg) in 51.4% yield.

MS m/z(ESI):631.3。

Fourteen steps: n- (4- (3- (2, 4-dihydroxy-5-isopropylphenyl) -5-carbonyl-1, 5-dihydro-4H-1, 2, 4-triazol-4-yl) benzyl) -5-methyl-1, 3, 4-oxadiazole-2-carboxamide

N- (4- (3- (2, 4-bis (benzyloxy) -5-isopropylphenyl) -5-carbonyl-1, 5-dihydro-4H-1, 2, 4-triazol-4-yl) benzyl) -5-methyl-1, 3, 4-oxadiazole-2-carboxamide (400mg, 0.63mmol) was dissolved in ethanol (10mL) and dry palladium on charcoal (40mg) was added. The reaction was carried out under hydrogen at room temperature for 2 hours, and the reaction mixture was filtered, and the filtrate was concentrated to give N- (4- (3- (2, 4-dihydroxy-5-isopropylphenyl) -5-carbonyl-1, 5-dihydro-4H-1, 2, 4-triazol-4-yl) benzyl) -5-methyl-1, 3, 4-oxadiazole-2-carboxamide (61mg) in 24.4% yield.

MS m/z(ESI):451.1；

¹H NMR(400MHz,DMSO-d6,ppm):δ11.91(br,1H),9.81(s,1H),9.61(s,1H),9.39(s,1H),7.30-7.29(d,J＝6.4,2H),7.13-7.12(d,J＝6.4,2H),6.85(s,1H),6.26(s,1H),4.43(s,2H),2.98-2.96(m,1H),2.57(s,3H),0.99(s,3H),0.98(s,3H)。

EXAMPLE seven

5- (2, 4-dihydroxy-5-isopropylphenyl) -N-methoxy-4- (4-methyl-2, 3,4, 5-tetrahydrobenzo [ b ] [1,4] oxazepin-8-yl) -4H-1,2, 4-triazole-3-carboxamide

The method comprises the following steps: 5- (2, 4-dihydroxy-5-isopropylphenyl) -N-methoxy-4- (4-methyl-2, 3,4, 5-tetrahydrobenzo [ b ] [1,4] oxazepin-8-yl) -4H-1,2, 4-triazole-3-carboxamide

2, 4-dihydroxy-5-isopropyl-N- (4-methyl-2, 3,4, 5-tetrahydrobenzo [ b ] [1,4] oxazepin-8-yl) benzothioamide (100mg,0.27mmol), 2-hydrazino-N-methoxy-2-carboacetamide (47 mg,0.35mmol), mercuric chloride (219mg,0.81mmol) and pyridine (0.09mL,0.81mmol) were added to N, N-dimethylformamide (5mL), microwave heated to 80 ℃ for 20min, filtered to remove solids, the filtrate was concentrated, and the crude product was purified by reverse phase chromatography (acetonitrile/water ═ 0 to acetonitrile/water 25%, v/v) to give compound 9(1.4mg) in 1.2% yield.

MS m/z(ESI):454.1；

¹H NMR(400MHz,CD₃OD,ppm):δ7.25-7.25(d,J＝8.0,1H),6.94-6.91(m,2H),6.67(s,1H),6.19(s,1H),4.01-4.00(m,2H),3.75(m,2H),3.65(s,3H),2.96-2.95(m,2H),2.95-2.94(m,1H),2.37(s,3H),0.87(s,3H),0.85(s,3H)。

Example eight

5- (2, 4-dihydroxy-5-isopropylphenyl) -N-ethyl-4- (2-oxo-2, 3,4, 5-tetrahydro-1-H-benzo [ b ] azepin-7-yl) -4H-1,2, 4-triazole-3-carboxamide

Step one, ethyl 2-ethylamino-2-oxoacetate

Triethylamine (7.78g,76.9mmol) and ethylamine hydrochloride (2.98g,36.6mmol) were dissolved in dichloromethane (100mL) at 0 deg.C, and oxalyl chloride monoethyl ester (5.0g,36.6mmol) was slowly added dropwise to the reaction system and reacted at zero degrees for 2 hours. After completion of the reaction, the reaction mixture was filtered, diluted with dichloromethane, washed with saturated sodium bicarbonate solution, and then washed with brine. The organic phase was dried over anhydrous sodium sulfate, filtered and spin-dried to give ethyl 2-ethylamino-2-oxoacetate (5 g).

MS m/z(ESI):146(M+1)。

Step two N-ethyl-2-hydrazino-2-oxoamide

Ethyl 2-ethylamino-2-oxoacetate (5.0g,34.5mmol) was dissolved in ethanol (100mL) at room temperature, followed by addition of hydrazine hydrate (80%, 10.8g,172mmol), heating under reflux overnight, and after completion of the reaction, the system was cooled to room temperature. Ethanol was removed by rotation under reduced pressure, the residue was diluted with petroleum ether/ethyl acetate (1:1, V/V,30mL), a white solid was precipitated, filtered, and dried under air to give N-ethyl-2-hydrazino-2-oxoamide (2.0g) in 44% yield.

MS m/z(ESI):132(M+1)。

Step three, 7-nitro-1, 3,4, 5-tetrahydro-2H-benzo [ b ] azepine-2-ketone

1,3,4, 5-tetrahydro-2H-benzo [ b ] azepin-2-one (2.10g,13mmol) is dissolved in concentrated sulfuric acid (10mL) at 0 ℃, and then concentrated nitric acid (1.1mL,15.6mmol) is added dropwise to the reaction solution for half an hour of reaction. After the reaction is finished, the reaction solution is poured into ice water, filtered, the solid is washed by petroleum ether/ethyl acetate (40mL, V/V:1:1), and dried in the air to obtain 7-nitro-1, 3,4, 5-tetrahydro-2H-benzo [ b ] azepine-2-ketone (2.10g), and the yield is 78%.

MS m/z(ESI):207(M+1)；

¹H NMR(400M,DMSO-d₆,ppm)δ10.08(s,1H),8.19(d,J＝2.8Hz,1H),8.11(dd,J₁＝2.8Hz,J₂＝8.4Hz,1H),7.15(d J＝8.4Hz,1H),2.82(t,J＝7.2Hz,2H),2.24(t,J＝7.2Hz,2H),2.16(t,J＝7.2Hz,2H)。

Step four, 7-amido-1, 3,4, 5-tetrahydro-2H-benzo [ b ] azepine-2-ketone

7-Nitro-1, 3,4, 5-tetrahydro-2H-benzo [ b ] azepin-2-one (1.60g,10mmol) was dissolved in tetrahydrofuran (60mL) and methanol (20mL) at room temperature, palladium on carbon (0.16g) was added, and the mixture was stirred at room temperature under a hydrogen atmosphere overnight. After the reaction, the mixture was filtered, washed with ethyl acetate, and the solvent was dried by spinning under reduced pressure to give 7-amino-1, 3,4, 5-tetrahydro-2H-benzo [ b ] azepin-2-one (1.0g) in 78% yield.

MS m/z(ESI):177(M+1)。

Step five, 2, 4-dihydroxy-5-isopropylbenzenedithioic acid

4-isopropyl-1, 3-benzenediol (25g,164.3mmol) and potassium ethylxanthate (29g,180.7mmol) were added to N, N-dimethylformamide (300mL), and the mixture was heated to 100 ℃ for 16 hours. After cooling to room temperature, concentration, addition of water and extraction with ethyl acetate, the aqueous phase was acidified (PH 2-3) with 0.1M dilute hydrochloric acid solution, extracted with ethyl acetate, and the organic phase was washed with saturated brine, dried, filtered and concentrated to give 2, 4-dihydroxy-5-isopropylbenzenedithioic acid (30g) in 80% yield.

MS m/z(ESI):267(M+K⁺)。

Step six sulfinylbis ((2, 4-dihydroxy-5-isopropylphenyl) methanethioketone)

2, 4-dihydroxy-5-isopropylbenzenedithioic acid (2.0g,8.77mmol) was dissolved in anhydrous ether (40mL) at 0 ℃ and carbon dioxide gas was introduced into the system for 10 minutes. Then thionyl chloride (2.08g,17.5mmol) was added dropwise to the reaction system, after the dropwise addition was completed, stirring was continued for 1 hour, filtration was performed, the solid was washed with anhydrous ether, and drying was performed in the air to obtain sulfinylbis ((2, 4-dihydroxy-5-isopropylphenyl) methanethione) (1.50g), with a yield of 80%.

Step seven, 2, 4-dihydroxy-5-isopropyl-N- (2-oxo-2, 3,4, 5-tetrahydro-1H-benzo [ b ] azepin-7-yl) benzothioamide

Sulfinylbis ((2, 4-dihydroxy-5-isopropylphenyl) methanethione) (1.8g,4.11mmol) was dissolved in N, N-dimethylformamide (25mL) at room temperature, and then 7-amino-1, 3,4, 5-tetrahydro-2H-benzo [ b ] azepin-2-one (1.45g,8.22mmol) was added to the reaction system, followed by stirring at room temperature for one hour. The reaction was diluted with ethyl acetate (50mL) and washed with brine, and the organic phase was dried over anhydrous sodium sulfate, filtered and spun dry. The crude product was purified by column chromatography (petroleum ether/ethyl acetate (V/V):1/1- - -dichloromethane/methanol (V/V):25/1) to give 2, 4-dihydroxy-5-isopropyl-N- (2-oxo-2, 3,4, 5-tetrahydro-1H-benzo [ b ] azepin-7-yl) benzothioamide (1.30g) in 70% yield.

MS m/z(ESI):371(M+1)。

Step eight 5- (2, 4-dihydroxy-5-isopropylphenyl) -N-ethyl-4- (2-oxo-2, 3,4, 5-tetrahydro-1-H-benzo [ b ] azepin-7-yl) -4H-1,2, 4-triazole-3-amide

2, 4-dihydroxy-5-isopropyl-N- (2-oxo-2, 3,4, 5-tetrahydro-1H-benzo [ b ] azepin-7-yl) benzothioamide (0.70g,1.89mmol), N-ethyl-2-hydrazino-2-oxoamide (0.37g,2.84mmol), mercuric chloride (0.62g,2.27mmol), pyridine (0.30g,3.78mmol) and dioxane (15mL) were added sequentially to a 30mL microwave tube and heated at 80 ℃ for 20 minutes with microwave. Cooled to room temperature, filtered, washed with ethyl acetate, the organic phase washed with brine, dried over anhydrous sodium sulfate, filtered, dried and the crude product purified by column chromatography (dichloromethane/methanol: V/V:25/1) and then further purified by reverse phase to give 5- (2, 4-dihydroxy-5-isopropylphenyl) -N-ethyl-4- (2-oxo-2, 3,4, 5-tetrahydro-1-H-benzo [ b ] azepin-7-yl) -4H-1,2, 4-triazole-3-amide (130mg) in 7.1% yield.

MS m/z(ESI):450(M+1)；

¹H NMR(400M,CD₃OD,ppm)δ7.32(d,J＝2.4Hz,1H),7.26(dd,J₁＝2.4Hz,J₂＝8.4Hz,1H),δ7.14(d,J＝8.4Hz,1H),6.74(s,1H),6.35(s,1H),3.35(q,J＝7.2Hz,2H),3.06-3.08(m,1H),2.81(t,J＝7.2Hz,2H),2.39(t,J＝7.2Hz,2H),2.25(m,2H),1.20(t,J＝7.2Hz,3H),0.93(s,3H),0.91(s,3H)。

Example nine

5- (2, 4-dihydroxy-5-isopropylphenyl) -N-ethyl-4- (1-methyl-2-oxo-2, 3,4, 5-tetrahydro-1-H-benzo [ b ] azepin-7-yl) -4H-1,2, 4-triazole-3-carboxamide

Step one, 1-methyl-7-nitro-1, 3,4, 5-tetrahydro-2H-benzo [ b ] azepine-2-ketone

7-Nitro-1, 3,4, 5-tetrahydro-2H-benzo [ b ] azepin-2-one (4.0g,19.4mmol) was dissolved in N, N-dimethylformamide (30mL) at room temperature, followed by addition of cesium carbonate (9.50g,29.1mmol) and iodomethane (13.78g,97mmol) in that order and stirring at room temperature overnight. The reaction solution was diluted with ethyl acetate (120mL), washed with brine, the organic phase was dried over anhydrous sodium sulfate, filtered, dried, and the crude product was purified by column chromatography (petroleum ether/ethyl acetate: V/V:10/1- - -5/1) to give 1-methyl-7-nitro-1, 3,4, 5-tetrahydro-2H-benzo [ b ] azepin-2-one (2.80g, 63% yield).

MSm/z(ESI):221(M+1)。

Step two, 1-methyl-7-amino-1, 3,4, 5-tetrahydro-2H-benzo [ b ] azepine-2-ketone

1-methyl-7-nitro-1, 3,4, 5-tetrahydro-2H-benzo [ b ] azepin-2-one (2.80g,12.7mmol) was dissolved in ethanol (30mL) at room temperature, palladium on carbon (0.33g) was added, and the mixture was stirred at room temperature overnight. After the reaction, the mixture was filtered through celite, washed with ethyl acetate, and the solvent was dried by spinning under reduced pressure to give 1-methyl-7-amino-1, 3,4, 5-tetrahydro-2H-benzo [ b ] azepin-2-one (2.20g) in 91% yield.

MS m/z(ESI):191(M+1)。

Step three, 2, 4-dihydroxy-5-isopropyl-N- (1-methyl-2-oxo-2, 3,4, 5-tetrahydro-1H-benzo [ b ] azepin-7-yl) benzothioamide

Sulfinylbis ((2, 4-dihydroxy-5-isopropylphenyl) methanethione) (1.7g,3.88mmol) was dissolved in N, N-dimethylformamide (20mL) at room temperature, and then 1-methyl-7-amino-1, 3,4, 5-tetrahydro-2H-benzo [ b ] azepin-2-one (0.88g,4.66mmol) was added to the reaction system, followed by stirring at room temperature for one hour. The reaction was diluted with ethyl acetate (50mL) and washed with brine, and the organic phase was dried over anhydrous sodium sulfate, filtered and spun dry. The crude product was purified by column chromatography (petroleum ether/ethyl acetate (V/V):2/1- - -dichloromethane/methanol (V/V):25/1) to give 2, 4-dihydroxy-5-isopropyl-N- (1-methyl-2-oxo-2, 3,4, 5-tetrahydro-1H-benzo [ b ] azepin-7-yl) benzothioamide (1.40g) in 93% yield.

MSm/z(ESI):385(M+1)。

Step four, 5- (2, 4-dihydroxy-5-isopropylphenyl) -N-ethyl-4- (1-methyl-2-oxo-2, 3,4, 5-tetrahydro-1-H-benzo [ b ] azepin-7-yl) -4H-1,2, 4-triazole-3-amide

2, 4-dihydroxy-5-isopropyl-N- (1-methyl-2-oxo-2, 3,4, 5-tetrahydro-1H-benzo [ b ] azepin-7-yl) benzothioamide (0.16g,0.42mmol), N-ethyl-2-hydrazino-2-oxoamide (0.065g,0.50mmol), mercuric chloride (0.34g,1.26mmol), pyridine (0.05g,0.63mmol) and dioxane (5mL) were added sequentially to a 10mL microwave tube and heated at 80 ℃ for 20 minutes. Cooling to room temperature, filtration, washing with ethyl acetate, washing of the organic phase with brine, drying over anhydrous sodium sulfate, filtration, spin-drying, purification of the crude product by column chromatography (petroleum ether/ethyl acetate (V/V):25/1) and further purification by reverse phase to give 5- (2, 4-dihydroxy-5-isopropylphenyl) -N-ethyl-4- (1-methyl-2-oxo-2, 3,4, 5-tetrahydro-1-H-benzo [ b ] azepin-7-yl) -4H-1,2, 4-triazole-3-amide (15mg) in 7.5% yield.

MS m/z(ESI):464(M+1)；

¹H NMR(400M,CD₃OD,ppm)δ7.45(d,J＝8.4Hz,1H),7.36(dd,J₁＝2.4Hz,J₂＝8.4Hz,1H),δ7.29(d,J＝2.4Hz,1H),6.74(s,1H),6.35(s,1H),3.36(s,3H),3.34(q,J＝7.2Hz,2H),3.02-3.09(m,1H),2.75(t,J＝7.2Hz,2H),2.36(t,J＝7.2Hz,2H),2.19(m,2H),1.20(t,J＝7.2Hz,3H),0.94(s,3H),0.92(s,3H)。

Example ten

5- (2, 4-dihydroxy-5-isopropylphenyl) -N-ethyl-4- (1-methyl-2-oxo-2, 3,4, 5-tetrahydro-1-H-benzo [ b ] azepin-8-yl) -4H-1,2, 4-triazole-3-amide

Step one, 1-methyl-1, 3,4, 5-tetrahydro-2H-benzo [ b ] azepine-2-ketone

1,3,4, 5-tetrahydro-2H-benzo [ b ] azepin-2-one (2.0g,12.4mmol) was dissolved in N, N-dimethylformamide (30mL) at room temperature, and then cesium carbonate (8.08g,24.8mmol) and iodomethane (8.81g,62mmol) were added in that order and stirred at room temperature overnight. The reaction was diluted with ethyl acetate (120mL), washed with brine, and the organic phase was dried over anhydrous sodium sulfate, filtered, and spun-dried to give 1-methyl-1, 3,4, 5-tetrahydro-2H-benzo [ b ] azepin-2-one (2.0g, crude product).

MS m/z(ESI):176(M+1)。

Step two, 1-methyl-8-nitro-1, 3,4, 5-tetrahydro-2H-benzo [ b ] azepine-2-one

1-methyl-1, 3,4, 5-tetrahydro-2H-benzo [ b ] azepin-2-one (1.75g,1mmol) was dissolved in concentrated sulfuric acid (10mL) at 0 ℃, and then concentrated nitric acid (2g,20mmol) was added dropwise to the reaction solution and reacted for ten minutes. After the reaction, the reaction solution was poured into ice water, extracted with ethyl acetate, and the organic phase was dried over anhydrous sodium sulfate, filtered, and spin-dried to obtain a mixture of 1-methyl-8-nitro-1, 3,4, 5-tetrahydro-2H-benzo [ b ] azepin-2-one and 1-methyl-7-nitro-1, 3,4, 5-tetrahydro-2H-benzo [ b ] azepin-2-one (1.70g, crude product).

MSm/z(ESI):221(M+1)。

Step three, 1-methyl-8-amino 1,3,4, 5-tetrahydro-2H-benzo [ b ] azepine-2-ketone

A mixture of 1-methyl-8-nitro-1, 3,4, 5-tetrahydro-2H-benzo [ b ] azepin-2-one and 1-methyl-7-nitro-1, 3,4, 5-tetrahydro-2H-benzo [ b ] azepin-2-one (1.70g, yellow oil, crude) was dissolved in methanol (20mL) at room temperature, followed by addition of palladium on carbon (0.17g) and stirring overnight at room temperature under hydrogen atmosphere. Filtering, washing with ethyl acetate, and spin-drying to obtain a mixture (1.0g, crude product) of 1-methyl-8-amino 1,3,4, 5-tetrahydro-2H-benzo [ b ] azepine-2-one and 1-methyl-7-amino 1,3,4, 5-tetrahydro-2H-benzo [ b ] azepine-2-one, with a yield of 68%.

MS m/z(ESI):191(M+1)。

Step four of 2, 4-dihydroxy-5-isopropyl-N- (1-methyl-2-oxo-2, 3,4, 5-tetrahydro-1H-benzo [ b ] azepin-8-yl) benzothioamide

Sulfinylbis ((2, 4-dihydroxy-5-isopropylphenyl) methanethione) (0.63g,1.45mmol) was dissolved in N, N-dimethylformamide (10mL) at room temperature, and then a mixture of 1-methyl-8-amino-1, 3,4, 5-tetrahydro-2H-benzo [ b ] azepin-2-one and 1-methyl-7-amino-1, 3,4, 5-tetrahydro-2H-benzo [ b ] azepin-2-one (0.55g,2.89mmol) was added to the reaction system, followed by stirring at room temperature for one hour. The reaction was diluted with ethyl acetate (30mL) and washed with brine, and the organic phase was dried over anhydrous sodium sulfate, filtered and spun dry. The crude product was purified by column chromatography (petroleum ether/ethyl acetate: V/V:2/1- - -dichloromethane/methanol: V/V:25/1) to give a mixture of 2, 4-dihydroxy-5-isopropyl-N- (1-methyl-2-oxo-2, 3,4, 5-tetrahydro-1H-benzo [ b ] azepin-8-yl) benzothioamide and 2, 4-dihydroxy-5-isopropyl-N- (1-methyl-2-oxo-2, 3,4, 5-tetrahydro-1H-benzo [ b ] azepin-7-yl) benzothioamide (0.55g, crude product).

Step five, 5- (2, 4-dihydroxy-5-isopropylphenyl) -N-ethyl-4- (1-methyl-2-oxo-2, 3,4, 5-tetrahydro-1-H-benzo [ b ] azepine-8-yl) -4H-1,2, 4-triazole-3-amide

A mixture (0.30g,0.78mmol) of 2, 4-dihydroxy-5-isopropyl-N- (1-methyl-2-oxo-2, 3,4, 5-tetrahydro-1H-benzo [ b ] azepin-8-yl) benzothioamide and 2, 4-dihydroxy-5-isopropyl-N- (1-methyl-2-oxo-2, 3,4, 5-tetrahydro-1H-benzo [ b ] azepin-7-yl) benzothioamide, N-ethyl-2-hydrazino-2-oxoamide (0.15g,1.17mmol), mercuric chloride (0.63g,2.34mmol), pyridine (0.12g,1.56mmol) and dioxane (15mL) were added sequentially to a 30mL microwave tube, microwave heating at 80 deg.C for 20 min. Cooled to room temperature, filtered, washed with ethyl acetate, the organic phase washed with brine, dried over anhydrous sodium sulfate, filtered, dried and the crude product purified by column chromatography (petroleum ether/ethyl acetate: V/V:1/1) and then further purified by reverse phase to give 5- (2, 4-dihydroxy-5-isopropylphenyl) -N-ethyl-4- (1-methyl-2-oxo-2, 3,4, 5-tetrahydro-1-H-benzo [ b ] azepin-8-yl) -4H-1,2, 4-triazole-3-amide (25mg) in 12% yield.

MS m/z(ESI):464(M+1)；

¹H NMR(400M,CD₃OD,ppm)δ7.46(d,J＝8.4Hz,1H),7.37(dd,J₁＝2.4Hz,J₂＝8.4Hz,1H),7.30(d,J＝2.4Hz,1H),6.75(s,1H),6.35(s,1H),3.34(q,J＝7.2Hz,2H),3.02-3.09(m,1H),2.75(t,J＝7.2Hz,2H),2.37(t,J＝7.2Hz,2H),2.19(m,2H),1.21(t,J＝7.2Hz,3H),0.94(s,3H),0.93(s,3H)。

EXAMPLE eleven

7- (3- (2, 4-dihydroxy-5-isopropylphenyl) -4H-1,2, 4-triazol-4-yl) -1,3,4, 5-tetrahydro-2H-benzo [ b ] azepine-2-one

Step one, 7- (3- (2, 4-dihydroxy-5-isopropylphenyl) -4H-1,2, 4-triazole-4-yl) -1,3,4, 5-tetrahydro-2H-benzo [ b ] azepine-2-ketone

To a microwave tube (10mL) were added ethyl 5- (2, 4-dihydroxy-5-isopropylphenyl) -4- (2-oxo-2, 3,4, 5-tetrahydro-1-H-benzo [ b ] azepin-7-yl) -4H-1,2, 4-triazole-3-carboxylate (0.05g,0.11mmol), potassium carbonate (0.061g,0.44mmol) and ethanol (5mL) in this order, and the mixture was heated in an oil bath at 80 ℃ for 15 hours. Cooled to room temperature, spun dry, the residue was taken up in ethyl acetate, washed with brine, the organic phase was dried over anhydrous sodium sulfate, filtered, spun dry and the crude product was purified on a large plate to give 7- (3- (2, 4-dihydroxy-5-isopropylphenyl) -4H-1,2, 4-triazol-4-yl) -1,3,4, 5-tetrahydro-2H-benzo [ b ] azepin-2-one (4mg) in 9.5% yield.

MSm/z(ESI):379(M+1)；

¹HNMR(400M,CD₃OD,ppm)δ8.62(s,1H),7.27(d,J＝2.0Hz,1H),7.21(dd,J₁＝2.0Hz,J₂＝8.4Hz,1H),7.08(d,J＝8.4Hz,1H),6.75(s,1H),6.26(s,1H),3.03-3.11(m,1H),2.82(t,J＝7.2Hz,2H),2.35(t,J＝7.2Hz,2H),2.23-2.26(m,2H),0.97(s,3H),0.95(s,3H)。

Example twelve

N-methoxy-5- (2-hydroxy-5-isopropyl-4-methoxyphenyl) -4- (1-methyl-2-oxo-2, 3,4, 5-tetrahydro-1H-benzo [ b ] azepin-7-yl) -4H-1,2, 4-triazole-3-amide

Step one, 2-methoxy amido-2-oxo acetic acid ethyl ester

Triethylamine (2.5mL,1.796mmol) and methoxyamine hydrochloride (500mg,5.988mmol) were dissolved in dichloromethane (5mL) at 0 deg.C, and oxalyl chloride monoethyl ester (0.8mL,7.185mmol) was slowly added dropwise to the reaction system and reacted at zero degrees for 2 hours. After completion of the reaction, the reaction mixture was filtered, diluted with dichloromethane, washed with saturated sodium bicarbonate solution, and then washed with brine. The organic phase was dried over anhydrous sodium sulfate, filtered and spin-dried to give ethyl 2-methoxyamino-2-oxoacetate (812mg), yield 91%.

MS m/z(ESI):148(M+1)。

Step two, N-methoxy-2-hydrazino-2-oxoamide

Ethyl 2-methoxyamino-2-oxoacetate (812mg,5.520mmol) was dissolved in ethanol (10mL) at room temperature, then hydrazine hydrate (80%, 1.8mL,27.60mmol) was added, and the mixture was heated under reflux overnight, after completion of the reaction, the system was cooled to room temperature. Ethanol was removed by rotation under reduced pressure, the residue was diluted with petroleum ether/ethyl acetate (30mL, V/V:1:1), a white solid was precipitated, filtered, and dried under air to give N-methoxy-2-hydrazino-2-oxoamide (187mg) in 25% yield.

MS m/z(ESI):134(M+1)。

Step three, 7-nitro-1, 3,4, 5-tetrahydro-2H-benzo [ b ] azepine-2-ketone

1,3,4, 5-tetrahydro-2H-benzo [ b ] azepin-2-one (2.10g,13mmol) is dissolved in concentrated sulfuric acid (10mL) at 0 ℃, and then concentrated nitric acid (1.1mL,15.6mmol) is added dropwise to the reaction solution for half an hour of reaction. After the reaction is finished, the reaction solution is poured into ice water, filtered, the solid is washed by petroleum ether/ethyl acetate (40mL, V/V:1:1), and dried in the air to obtain 7-nitro-1, 3,4, 5-tetrahydro-2H-benzo [ b ] azepine-2-ketone (2.10g), and the yield is 78%.

MS m/z(ESI):207(M+1)；

¹H NMR(400M,DMSO-d₆,ppm)δ10.08(s,1H),8.19(d,J＝2.8Hz,1H),8.11(dd,J₁＝2.8Hz,J₂＝8.4Hz,1H),7.15(d J＝8.4Hz,1H),2.82(t,J＝7.2Hz,2H),2.24(t,J＝7.2Hz,2H),2.16(t,J＝7.2Hz,2H)。

Step four, 7-amido-1, 3,4, 5-tetrahydro-2H-benzo [ b ] azepine-2-ketone

7-Nitro-1, 3,4, 5-tetrahydro-2H-benzo [ b ] azepin-2-one (1.60g,10mmol) was dissolved in tetrahydrofuran (60mL) and methanol (20mL) at room temperature, palladium on carbon (0.16g) was added, and the mixture was stirred at room temperature under a hydrogen atmosphere overnight. After the reaction, the mixture was filtered, washed with ethyl acetate, and the solvent was dried by spinning under reduced pressure to give 7-amino-1, 3,4, 5-tetrahydro-2H-benzo [ b ] azepin-2-one (1.0g) in 78% yield.

MS m/z(ESI):177(M+1)。

Step five, 2, 4-dihydroxy-5-isopropylbenzenedithioic acid

4-isopropyl-1, 3-benzenediol (25g,164.3mmol) and potassium ethylxanthate (29g,180.7mmol) were added to N, N-dimethylformamide (300mL), and the mixture was heated to 100 ℃ for 16 hours. After cooling to room temperature, concentration, addition of water and extraction with ethyl acetate, the aqueous phase was acidified (PH 2-3) with 0.1M dilute hydrochloric acid solution, extracted with ethyl acetate, and the organic phase was washed with saturated brine, dried, filtered and concentrated to give 2, 4-dihydroxy-5-isopropylbenzenedithioic acid (30g) in 80% yield.

MS m/z(ESI):267(M+K⁺)。

Step six sulfinylbis ((2, 4-dihydroxy-5-isopropylphenyl) methanethioketone)

2, 4-dihydroxy-5-isopropylbenzenedithioic acid (2.0g,8.77mmol) was dissolved in anhydrous ether (40mL) at 0 ℃ and carbon dioxide gas was introduced into the system for 10 minutes. Then thionyl chloride (2.08g,17.5mmol) was added dropwise to the reaction system, after the dropwise addition was completed, stirring was continued for 1 hour, filtration was performed, the solid was washed with anhydrous ether, and drying was performed in the air to obtain sulfinylbis ((2, 4-dihydroxy-5-isopropylphenyl) methanethione) (1.50g), with a yield of 80%.

Step seven, 2, 4-dihydroxy-5-isopropyl-N- (2-oxo-2, 3,4, 5-tetrahydro-1H-benzo [ b ] azepin-7-yl) benzothioamide

Sulfinylbis ((2, 4-dihydroxy-5-isopropylphenyl) methanethione) (1.8g,4.11mmol) was dissolved in N, N-dimethylformamide (25mL) at room temperature, and then 7-amino-1, 3,4, 5-tetrahydro-2H-benzo [ b ] azepin-2-one (1.45g,8.22mmol) was added to the reaction system, followed by stirring at room temperature for one hour. The reaction was diluted with ethyl acetate (50mL) and washed with brine, and the organic phase was dried over anhydrous sodium sulfate, filtered and spun dry. The crude product was purified by column chromatography (petroleum ether/ethyl acetate (V/V):1/1- - -dichloromethane/methanol (V/V):25/1) to give 2, 4-dihydroxy-5-isopropyl-N- (2-oxo-2, 3,4, 5-tetrahydro-1H-benzo [ b ] azepin-7-yl) benzothioamide (1.30g) in 70% yield.

MS m/z(ESI):371(M+1)。

Step eight, 5- (2, 4-dihydroxy-5-isopropylphenyl) -N-methoxy-4- (2-oxo-2, 3,4, 5-tetrahydro-1-H-benzo [ b ] azepin-7-yl) -4H-1,2, 4-triazole-3-amide

2, 4-dihydroxy-5-isopropyl-N- (2-oxo-2, 3,4, 5-tetrahydro-1H-benzo [ b ] azepin-7-yl) benzothioamide (120mg,0.3239mmol), N-methoxy-2-hydrazino-2-oxoamide (60mg,0.4858mmol), mercuric chloride (252mg,0.9716mmol), pyridine (72mg,0.9716mmol) and dioxane (2mL) were added sequentially to a 10mL microwave tube and heated at 80 ℃ for 20 minutes with microwaves. Cooled to room temperature, filtered, washed with ethyl acetate, the organic phase washed with brine, dried over anhydrous sodium sulfate, filtered, dried and the crude product purified by column chromatography (dichloromethane/methanol (V/V):25/1) and then further purified by reverse phase to give 5- (2, 4-dihydroxy-5-isopropylphenyl) -N-methoxy-4- (2-oxo-2, 3,4, 5-tetrahydro-1-H-benzo [ b ] azepin-7-yl) -4H-1,2, 4-triazole-3-amide (12mg) in 7% yield.

MS m/z(ESI):452(M+1)；

¹H NMR(400M,DMSO-d6,ppm)δ12.33(s,1H),10.56(s,1H),9.78(s,1H),9.75(s,1H),7.29(s,1H),7.20(d,J＝8.4Hz,1H),7.01(d,J＝8.4Hz,1H),6.68(s,1H),6.35(s,1H),3.60(s,3H),2.92-2.96(m,1H),2.66(t,J＝7.2Hz,2H),2.19(t,J＝7.2Hz,2H),2.05-2.11(m,2H),0.86(d,J＝6.8Hz,6H)。

EXAMPLE thirteen

5- (2, 4-dihydroxy-5-isopropylphenyl) -4- (2-oxo-2, 3,4, 5-tetrahydro-1-H-benzo [ b ] azepin-7-yl) -4H-1,2, 4-triazole-3-hydrazide

Step one, (E) -2, 4-dihydroxy-5-isopropyl-N- (2-oxo-2, 3,4, 5-tetrahydro-1H-benzo [ b ] azepine-7-yl) benzohydrazone amide

2, 4-dihydroxy-5-isopropyl-N- (2-oxo-2, 3,4, 5-tetrahydro-1H-benzo [ b ] azepin-7-yl) benzothioamide (0.35g,0.95mmol), hydrazine hydrate (80 wt%, 0.24g,4.73mmol) and dioxane (6mL) were added sequentially to a 50mL round bottom flask at room temperature and refluxed for 2 hours. The reaction solution was cooled to room temperature, diluted with ethyl acetate, washed with a saturated sodium bicarbonate solution and a saturated brine solution in this order, and the organic phase was dried over anhydrous sodium sulfate, filtered, and dried to give (E) -2, 4-dihydroxy-5-isopropyl-N- (2-oxo-2, 3,4, 5-tetrahydro-1H-benzo [ b ] azepin-7-yl) benzohydrazone amide (300mg) in 86% yield.

MSm/z(ESI):369(M+1)。

Step two, ethyl 5- (2, 4-dihydroxy-5-isopropylphenyl) -4- (2-oxo-2, 3,4, 5-tetrahydro-1-H-benzo [ b ] azepin-7-yl) -4H-1,2, 4-triazole-3-carboxylate

Under the protection of nitrogen, (E) -2, 4-dihydroxy-5-isopropyl-N- (2-oxo-2, 3,4, 5-tetrahydro-1H-benzo [ b ] azepin-7-yl) benzohydrazone amide (0.15g,0.41mmol) was dissolved in tetrahydrofuran (5mL), a tetrahydrofuran solution of oxalyl chloride monoethyl ester (0.055g,0.41mmol) was added dropwise to the reaction system at-78 deg.C, diisopropylethylamine (0.079g,0.62mmol) was added dropwise after the addition, and the reaction was stirred at-78 deg.C to room temperature. After the reaction, the reaction solution was diluted with ethyl acetate, washed with saturated sodium bicarbonate solution and brine in this order, and the organic phase was dried over anhydrous sodium sulfate, filtered and dried to obtain ethyl 5- (2, 4-dihydroxy-5-isopropylphenyl) -4- (2-oxo-2, 3,4, 5-tetrahydro-1-H-benzo [ b ] azepin-7-yl) -4H-1,2, 4-triazole-3-carboxylate (170mg) in 92% yield.

MS m/z(ESI):451(M+1)。

Step three, 5- (2, 4-dihydroxy-5-isopropylphenyl) -4- (2-oxo-2, 3,4, 5-tetrahydro-1-H-benzo [ b ] azepine-7-yl) -4H-1,2, 4-triazole-3-hydrazide

Ethyl 5- (2, 4-dihydroxy-5-isopropylphenyl) -4- (2-oxo-2, 3,4, 5-tetrahydro-1-H-benzo [ b ] azepin-7-yl) -4H-1,2, 4-triazole-3-carboxylate (0.15g,0.33mmol), hydrazine hydrate (0.098g,1.67mmol) and ethanol (10mL) were added sequentially to a microwave tube (10mL) and heated in an oil bath at 80 ℃ for 2 hours. Cooled to room temperature, dried by spinning, and the crude product was purified by reverse phase column chromatography to give 5- (2, 4-dihydroxy-5-isopropylphenyl) -4- (2-oxo-2, 3,4, 5-tetrahydro-1-H-benzo [ b ] azepin-7-yl) -4H-1,2, 4-triazole-3-hydrazide (40mg) in 28% yield.

MS m/z(ESI):437(M+1)；

¹HNMR(400M,DMSO-d₆,ppm)δ10.7(s,1H),10.17(s,1H),9.80(s,1H),9.75(s,1H),7.30(d,J＝2.4Hz,1H),7.21(dd,J₁＝2.4Hz,J₂＝8.4Hz,1H),δ7.01(d,J＝8.4Hz,1H),6.66(s,1H),6.36(s,1H),4.53(d,J＝3.6Hz,2H),2.90-2.97(m,1H),2.66(t,J＝6.8Hz,2H),2.20(t,J＝6.8Hz,2H),2.06-2.11(m,2H),0.86(s,3H),0.84(s,3H)。

Example fourteen

N' - ((tert-butyl) -5- (2, 4-dihydroxy-5-isopropylphenyl) -4- (2-oxo-2, 3,4, 5-tetrahydro-1H-benzo [ b ] azepin-7-yl) -4H-1,2, 4-triazole-3-hydrazide

Step one, ethyl 2- (2- (tert-butylhydrazino) -2-oxoacetate

Triethylamine (3.74g,36.8mmol) and tert-butylhydrazine hydrochloride (2.20g,17.6mmol) were dissolved in dichloromethane (25mL) at 0 deg.C, and oxalyl chloride monoethyl ester (2.0g,14.7mmol) was slowly added dropwise to the reaction system and reacted at zero deg.C for 2 hours. After completion of the reaction, the reaction mixture was diluted with dichloromethane, washed with saturated sodium bicarbonate solution, and then washed with brine. The organic phase was dried over anhydrous sodium sulfate, filtered and spin-dried to give ethyl 2- (2- (tert-butylhydrazino) -2-oxoacetate (2g) in 72% yield.

MS m/z(ESI):189(M+1)。

Step two, N' - ((tert-butyl) -5- (2, 4-dihydroxy-5-isopropylphenyl) -4- (2-oxo-2, 3,4, 5-tetrahydro-1H-benzo [ b ] azepin-7-yl) -4H-1,2, 4-triazole-3-hydrazide

(E) -2, 4-dihydroxy-5-isopropyl-N- (2-oxo-2, 3,4, 5-tetrahydro-1H-benzo [ b ] azepin-7-yl) benzohydrazone amide (0.15g,0.408mmol), ethyl 2- (2- (tert-butylhydrazino) -2-oxoacetate (0.15g,0.816 mmol), acetic acid (0.003g,0.0408mmol) and ethanol (5mL) were added sequentially to a microwave tube (10mL), heated in an oil bath for 15 hours at 80 deg.C, cooled to room temperature, spun dry, the residue dissolved with ethyl acetate, then washed sequentially with saturated sodium carbonate solution and brine, the organic phase dried over anhydrous sodium sulfate, filtered, spun dry, the crude product was purified first on a large plate (dichloromethane/methanol (V/V):25/1), then, the reaction mixture was purified by reverse phase column chromatography to give N' - ((tert-butyl) -5- (2, 4-dihydroxy-5-isopropylphenyl) -4- (2-oxo-2, 3,4, 5-tetrahydro-1H-benzo [ b ] azepin-7-yl) -4H-1,2, 4-triazole-3-hydrazide (5mg) in 2.5% yield.

MSm/z(ESI):493(M+1)；

¹HNMR(400M,CD₃OD,ppm)δ7.34(d,J＝2.4Hz,1H),7.30(dd,J₁＝2.4Hz,J₂＝8.4Hz,1H),7.16(d,J＝8.4Hz,1H),6.77(s,1H),6.35(s,1H),3.02-3.09(m,1H),2.81(t,J＝7.2Hz,2H),2.37(t,J＝7.2Hz,2H),2.23-2.26(m,2H),1.09(3,9H),0.94(s,3H),0.92(s,3H)。

Example fifteen

N- (2- (4- (3- (2, 4-dihydroxy-5-isopropylphenyl) -5- (ethylcarbamoyl) -4H-1,2, 4-triazol-4-yl) phenyl) propan-2-yl) -5-methyl-1, 3, 4-oxadiazole-2-amide

Step one, 2-methyl-2- (4-nitrophenyl) methyl propionate

2- (4-Nitrophenyl) acetic acid (2.0g,0.011mmol) and 18-crown-6 (0.58g,0.022mmol) were dissolved in N, N-dimethylformamide (40mL) under ice-bath, then sodium hydrogen (60%, 1.76g,44mmol) was added to the reaction system, stirred for half an hour, then iodomethane (9.37g,66mmol) was added to the reaction system, and stirred at room temperature for 14 hours. After the reaction, a saturated ammonium chloride solution was added to quench the reaction, followed by extraction with diethyl ether, washing the organic phase with saturated brine, drying the organic phase with anhydrous sodium sulfate, filtering, and spin-drying to obtain methyl 2-methyl-2- (4-nitrophenyl) propionate (2.50 g).

MS m/z(ESI):224(M+1)。

Step two, 2-methyl-2- (4-nitrophenyl) propionic acid

Methyl 2-methyl-2- (4-nitrophenyl) propionate (1.0g,4.48mmol) was dissolved in methanol (5mL) and tetrahydrofuran (5mL) at room temperature, and then an aqueous solution (2mL) of sodium hydroxide (0.36g,8.97mmol) was added dropwise to the reaction system, followed by stirring at room temperature for 14 hours. After the reaction was completed, the solvent was dried by spinning, and dilute hydrochloric acid (1N) was added to the residue to precipitate a red solid, which was filtered and dried in the air to obtain 2-methyl-2- (4-nitrophenyl) propionic acid (0.70g) in 74% yield.

MS m/z(ESI):210(M+1)；

¹HNMR(400M,DMSO,ppm)δ8.20(d,J＝9.2Hz,2H),7.62(d,J＝9.2Hz,2H),1.52(s,6H)。

Step three, 2-methyl-2- (4-nitrophenyl) propylamine

2-methyl-2- (4-nitrophenyl) propionic acid (0.20g,0.96mmol) and triethylamine (0.12g,1.20mmol) were dissolved in N, N-dimethylformamide (6mL) under ice-bath, and diphenyl phosphorazidate (0.26g,0.96mmol) was added to the reaction system under nitrogen protection, followed by stirring for two hours under ice-bath. After the reaction was completed, the reaction solution was diluted with ethyl acetate, washed with brine, and the organic phase was dried over anhydrous sodium sulfate, filtered, and dried by spinning. The residue was then dissolved in toluene (10mL), diluted hydrochloric acid (5N,2mL) was added, and the mixture was heated at 100 ℃ for two hours. After the reaction is finished, the reaction product is cooled to room temperature, then the pH value of the system is adjusted to 8-9 by sodium hydroxide, ethyl acetate is used for extraction, an organic phase is dried by anhydrous sodium sulfate, filtered and dried in a rotary mode to obtain 2-methyl-2- (4-nitrophenyl) propylamine (0.12g), and the yield is 70%.

MS m/z(ESI):181(M+1)。

Step four, 5-methyl-N- (2- (4-nitrophenyl) propan-2-yl) -1,3, 4-oxadiazole-2-amide

Potassium 5-methyl-1, 3, 4-oxadiazole-2-carboxylate (0.20g,1.20mmol) was suspended in acetonitrile (10mL) under ice-bath, oxalyl chloride (0.15g,1.20mmol) was added dropwise to the reaction system, and N, N-dimethylformamide (0.1mL) was added thereto, followed by stirring for one hour under ice-bath. After completion of the reaction, the reaction mixture was directly added dropwise to a tetrahydrofuran solution of 2-methyl-2- (4-nitrophenyl) propylamine (0.108g,0.60mmol) and N-methylmorpholine (0.36g,3.60mmol) while cooling on ice, and the mixture was stirred for two hours while cooling on ice. After the reaction, the reaction mixture was diluted with ethyl acetate, washed with saturated brine, and the organic phase was dried with anhydrous sulfuric acid, filtered, and spin-dried, and the crude product was purified on a large plate (petroleum ether/ethyl acetate (V/V):1/1) to give 5-methyl-N- (2- (4-nitrophenyl) propan-2-yl) -1,3, 4-oxadiazole-2-amide (0.07g) in 20% yield.

MS m/z(ESI):291(M+1)。

Step five, N- (2- (4-aminophenyl) propane-2-yl) -5-methyl-1, 3, 4-oxadiazole-2-amide

5-methyl-N- (2- (4-nitrophenyl) propan-2-yl) -1,3, 4-oxadiazole-2-amide (0.07g,0.24mmol) was dissolved in ethanol (15mL) at room temperature, palladium on carbon (0.02g) was added, and the mixture was stirred at room temperature under a hydrogen atmosphere overnight. After completion of the reaction, the reaction mixture was filtered, washed with ethyl acetate, and the solvent was evaporated under reduced pressure to give N- (2- (4-aminophenyl) propan-2-yl) -5-methyl-1, 3, 4-oxadiazole-2-amide (0.04g) in a yield of 63%.

MS m/z(ESI):261(M+1)。

Step six, N- (2- (4- (2, 4-dihydroxy-5-isopropylphenylthioamine) phenyl) propane-2-yl) -5-methyl-1, 3, 4-oxadiazole-2-amide

Sulfinylbis ((2, 4-dihydroxy-5-isopropylphenyl) methanethione) (0.067g,0.54mmol) was dissolved in N, N-dimethylformamide (5mL) at room temperature, and then N- (2- (4-aminophenyl) propan-2-yl) -5-methyl-1, 3, 4-oxadiazole-2-amide (0.04g,0.154mmol) was added to the reaction system, followed by stirring at room temperature for 14 hours. The reaction was diluted with ethyl acetate (40mL) and washed with brine, and the organic phase was dried over anhydrous sodium sulfate, filtered and spun dry. The crude product was purified on a large plate (dichloromethane/methanol: V/V:20/1) to give N- (2- (4- (2, 4-dihydroxy-5-isopropylphenylthioamino) phenyl) propan-2-yl) -5-methyl-1, 3, 4-oxadiazole-2-amide (0.04g) in 57% yield.

MS m/z(ESI):455(M+1)。

Step seven, N- (2- (4- (3- (2, 4-dihydroxy-5-isopropylphenyl) -5- (ethylcarbamyl) -4H-1,2, 4-triazol-4-yl) phenyl) propan-2-yl) -5-methyl-1, 3, 4-oxadiazole-2-amide

N- (2- (4- (2, 4-dihydroxy-5-isopropylphenylthioamino) phenyl) propan-2-yl) -5-methyl-1, 3, 4-oxadiazole-2-amide (0.04g,0.088mmol), N-ethyl-2-hydrazino-2-oxoamide (0.015g,0.114mmol), mercuric chloride (0.072g,0.264mmol), pyridine (0.010g,0.132mmol) and dioxane (3mL) were added sequentially to a 10mL microwave tube and heated at 80 ℃ for 20 minutes with a microwave. Cooled to room temperature, filtered, washed with ethyl acetate, the organic phase washed with dilute hydrochloric acid, washed with saturated sodium bicarbonate solution, washed with brine, dried over anhydrous sodium sulfate, filtered, spun-dried and the crude product purified by reverse phase column chromatography to give N- (2- (4- (3- (2, 4-dihydroxy-5-isopropylphenyl) -5- (ethylcarbamyl) -4H-1,2, 4-triazol-4-yl) phenyl) propan-2-yl) -5-methyl-1, 3, 4-oxadiazole-2-amide (8mg) in 17% yield.

MS m/z(ESI):534(M+1)；

¹H NMR(400M,DMSO-d₆,ppm)δ10.70(s,1H),9.81(s,1H),9.26(s,1H),8.96(t,J＝6.4Hz,1H),7.47(d,J＝8.8Hz,2H),7.31(d,J＝8.8Hz,2H),6.52(s,1H),6.36(s,1H),3.17(m,2H),2.86-2.93(m,1H),2.57(s,3H),1.70(s,6H),1.03(t,J＝7.2Hz,3H),0.80(s,3H),0.78(s,3H)。

Example sixteen

N- (4- (3- (2, 4-dihydroxy-5-isopropylphenyl) -5- (ethylcarbamyl) -4H-1,2, 4-triazol-4-yl) benzyl-5-methyl-1, 3, 4-oxadiazole-2-amide

Step one, 5-methyl-N- (4-nitrophenyl) 1,3, 4-oxadiazole-2-amide

Ethyl 5-methyl-1, 3, 4-oxadiazole-2-carboxylate (0.10g,0.51mmol), p-nitrobenzylamine (0.10g,0.66mmol) and N, N-dimethylformamide (3mL) were added sequentially to a microwave tube (10mL) and heated at 130 ℃ for 1.5 hours. After the reaction, the reaction mixture was cooled to room temperature, diluted with ethyl acetate, washed in a saturated laboratory, and the organic phase was dried over anhydrous sodium sulfate, filtered, and spin-dried, and the crude product was purified on a large plate (petroleum ether/methanol (V/V):1/1) to obtain 5-methyl-N- (4-nitrophenyl) 1,3, 4-oxadiazole-2-amide (0.11g) in a yield of 33%.

MS m/z(ESI):263(M+1)。

Step two, N- (4-aminophenyl) -5-methyl-1, 3, 4-oxadiazole-2-amide

5-methyl-N- (4-nitrophenyl) 1,3, 4-oxadiazole-2-amide (0.11g,0.42mmol) was dissolved in ethanol (10mL) at room temperature, palladium on carbon (0.02g) was added, and the mixture was stirred overnight at room temperature under a hydrogen atmosphere. After the reaction, the reaction mixture was filtered, washed with ethyl acetate, and the solvent was dried by spinning under reduced pressure to give N- (4-aminophenyl) -5-methyl-1, 3, 4-oxadiazole-2-amide (0.08g) in a yield of 82%.

MS m/z(ESI):233(M+1)。

Step three, N- (4- (2, 4-dihydroxy-5-isopropylphenylthioamine) benzyl) -5-methyl-1, 3, 4-oxadiazole-2-amide

Sulfinylbis ((2, 4-dihydroxy-5-isopropylphenyl) methanethione) (0.057g,0.129mmol) was dissolved in N, N-dimethylformamide (3mL) at room temperature, and then N- (4-aminophenyl) -5-methyl-1, 3, 4-oxadiazole-2-amide (0.03g,0.129mmol) was added to the reaction system, followed by stirring at room temperature for two hours. The reaction was diluted with ethyl acetate (50mL) and washed with brine, and the organic phase was dried over anhydrous sodium sulfate, filtered and spun dry. The crude product was purified on a large plate (dichloromethane/methanol: V/V:20/1) to give N- (4- (2, 4-dihydroxy-5-isopropylphenylthioamine) benzyl) -5-methyl-1, 3, 4-oxadiazole-2-amide (0.05g) in 91% yield.

MS m/z(ESI):427(M+1)。

Step four, N- (4- (3- (2, 4-dihydroxy-5-isopropylphenyl) -5- (ethylamine formyl) -4H-1,2, 4-triazole-4-yl) benzyl-5-methyl-1, 3, 4-oxadiazole-2-amide

N- (4- (2, 4-dihydroxy-5-isopropylphenylthioamine) benzyl) -5-methyl-1, 3, 4-oxadiazole-2-amide (0.1g,0.24mmol), N-ethyl-2-hydrazino-2-oxoamide (0.04g,0.30mmol), mercuric chloride (0.20g,0.72mmol), pyridine (0.028g,0.36mmol) and dioxane (3mL) were added in this order to a 10mL microwave tube and heated at 80 ℃ for 20 minutes with a microwave. Cooling to room temperature, filtering, washing with ethyl acetate, washing the organic phase with dilute hydrochloric acid, washing with saturated sodium bicarbonate solution, washing with brine, drying over anhydrous sodium sulfate, filtering, spin-drying, and purifying the crude product by reverse phase column chromatography to obtain N- (4- (3- (2, 4-dihydroxy-5-isopropylphenyl) -5- (ethylcarbamyl) -4H-1,2, 4-triazol-4-yl) benzyl-5-methyl-1, 3, 4-oxadiazole-2-amide (30mg) in 17% yield.

MS m/z(ESI):506(M+1)；

¹H NMR(400M,CD₃OD,ppm)δ7.41(d,J＝8.4Hz,2H),7.23(d,J＝8.4Hz,2H),6.55(s,1H),6.19(s,1H),4.52(s,2H),3.19(q,J＝7.2Hz,2H),2.82-2.90(m,1H),2.52(s,3H),1.06(t,J＝7.2Hz,3H),0.75(s,3H),0.73(s,3H)。

Example seventeen

5- (2, 4-Dihydrox-5-isopropylbenzene) -N-ethyl-4- (5-methyl-2, 3,4, 5-tetrahydrobenzo [ b ] [1,4] oxazepin-8-yl) -4H-1,2, 4-triazole-3-carboxamide

Step one, 3- (3-chloropropyl) -6-nitrobenzo [ d ] oxazol-2 (3H) -one

The compound 6-nitrobenzo [ d ] oxazol-2 (3H) -one (5g, 27.76mmol), potassium carbonate (6.52g, 47.19mmol) was added to acetone (300mL), 1-bromo-2-chloroethane (14.86g, 94.38mmol) was slowly added dropwise, and after completion of the addition, the reaction was warmed to 55 ℃ for 16 hours. Cooled to room temperature, concentrated to a smaller volume, water (100mL) and ethyl acetate (150mL) were added, the organic phase was separated and washed with brine, dried and concentrated to give the crude product, which was slurried (ethyl acetate/n-hexane: 5/95,100mL) to give 3- (3-chloropropyl) -6-nitrobenzo [ d ] oxazol-2 (3H) -one (7g) in 98% yield.

MS m/z(ESI):227.1。

Step two, potassium 2- ((3-chloropropyl) (ethoxycarbonyl) amine) -5-nitrobenzoate

Potassium hydroxide (1.33g, 23.77mmol) was dissolved in ethanol (120mL), and the compound 3- (3-chloropropyl) -6-nitrobenzo [ d ] oxazol-2 (3H) -one 18a (6.1g, 23.77mmol) was added and reacted at room temperature for 2 hours. Concentration gave potassium 2- ((3-chloropropyl) (ethoxycarbonyl) amine) -5-nitrophenyl glycolate (7.4g) in 91% yield.

Step three, 8-nitro-3, 4-dihydrobenzo [ b ] [1,4] oxazepine-5 (2H) -carboxylic acid ethyl ester

The compound potassium 2- ((3-chloropropyl) (ethoxycarbonyl) amine) -5-nitrobenzoate (7.4g, 21.71mmol) was dissolved in N, N-dimethylformamide (100mL) and the reaction was allowed to warm to 80 ℃ for 2 hours. Cooling to room temperature, pouring water (200mL), extracting with ethyl acetate (60mL x 3), washing the organic phase with water and brine in sequence, drying, concentrating to obtain a crude product, and recrystallizing with ethyl acetate to obtain ethyl 8-nitro-3, 4-dihydrobenzo [ b ] [1,4] oxazepine-5 (2H) -carboxylate (4.5g) with a yield of 78%.

MS m/z(ESI):237.3。

Step four, 8-nitro-2, 3,4, 5-tetrahydrobenzo [ b ] [1,4] oxazepine

The compound ethyl 8-nitro-3, 4-dihydrobenzo [ b ] [1,4] oxazepine-5 (2H) -carboxylate (2g, 7.51mmol) was dissolved in 2-methoxyethanol (80mL), heated to 80 deg.C, and 1N potassium hydroxide solution (39mL) was added dropwise, after completion of the addition, and reacted at 100 deg.C for 3 hours. Cooling to room temperature, adding water (200mL), extracting with ethyl acetate (100 mL. times.3), washing the organic phase with water and brine in sequence, drying, and concentrating to obtain 8-nitro-2, 3,4, 5-tetrahydrobenzo [ b ] [1,4] oxazepine (1.4g) with a yield of 96%.

MS m/z(ESI):195.3。

Step five, 5-methyl-8-nitro-2, 3,4, 5-tetrahydrobenzo [ b ] [1,4] oxazepine

8-Nitro-2, 3,4, 5-tetrahydrobenzo [ b ] [1,4] oxazepine (650mg,3.35mmol) was dissolved in methanol (20 mL). Formaldehyde (150mg,5.02mmol) and zinc chloride (547mg,4.02mmol) were added successively, stirred at room temperature for half an hour, sodium cyanoborohydride (316mg,5.02mmol) was added in portions, the reaction was stirred at room temperature for 16 hours, and LC-MS monitored that the conversion of the starting material was completely stopped. The reaction was concentrated and the residue was dissolved in ethyl acetate (20mL) and washed with saturated sodium bicarbonate solution followed by brine. The organic phase was dried, filtered and concentrated to give the crude 5-methyl-8-nitro-2, 3,4, 5-tetrahydrobenzo [ b ] [1,4] oxazepine (550mg) in 79% yield.

MS m/z(ESI):209.2。

Step six, 5-methyl-2, 3,4, 5-tetrahydrobenzo [ b ] [1,4] oxazepin-8-amine

5-methyl-8-nitro-2, 3,4, 5-tetrahydrobenzo [ b ] [1,4] oxazepine (0.5g, 2.4mmol) was dissolved in ethanol (20mL) and palladium on carbon (0.05g, 10% w/w) was added. The hydrogenation was carried out at room temperature under standard atmospheric pressure for 2 hours, after completion of the reaction, the catalyst was filtered off, and the filtrate was concentrated to give 5-methyl-2, 3,4, 5-tetrahydrobenzo [ b ] [1,4] oxazepin-8-amine (0.4g) in 93% yield.

MS m/z(ESI):179.2。

Seventhly, 2, 4-diphenol hydroxyl-5-isopropyl-N- (5-methyl-2, 3,4, 5-tetrahydrobenzo [ b ] [1,4] oxazepin-8-yl) benzenesulf amide

5-methyl-2, 3,4, 5-tetrahydrobenzo [ b ] [1,4] oxazepin-8-amine (0.4g, 2.24mmol) was dissolved in N, N-dimethylformamide (20mL), and sulfinyl bis ((2, 4-diphenolhydroxy-5-isopropylbenzene) methylsulfane) (1g, 2.24mmol) was added and reacted at room temperature for 16 hours. The reaction solution was diluted with ethyl acetate, washed with water, washed with brine, dried and concentrated to give a crude product, which was separated by column chromatography (petroleum ether/ethyl acetate from 100:0 to 50:50, v/v) to give 2, 4-diphenolhydroxy-5-isopropyl-N- (5-methyl-2, 3,4, 5-tetrahydrobenzo [ b ] [1,4] oxazepin-8-yl) benzenethioamide (0.58g) in 70% yield.

MS m/z(ESI):373.1。

Step eight, 5- (2, 4-diphenol hydroxyl-5-isopropyl benzene) -N-ethyl-4- (5-methyl-2, 3,4, 5-tetrahydrobenzo [ b ] [1,4] oxazepin-8-yl) -4H-1,2, 4-triazole-3-carboxamide

Adding the compound 2, 4-diphenol hydroxyl-5-isopropyl-N- (5-methyl-2, 3,4, 5-tetrahydrobenzo [ b ] [1,4] oxazepin-8-yl) benzenethioamide (550mg,1.48mmol), 2-hydrazino-2-oxo-N-propyl acetamide (232mg,1.77mmol), mercuric chloride (1.2g,4.43mmol) and pyridine (350mg,4.43mmol) into anhydrous dioxane (10mL), heating to 80 ℃ by microwave for 20 minutes, adding ethyl acetate for dilution, filtering to remove solid, washing filtrate with saturated sodium bicarbonate solution, washing with brine, drying, filtering, concentrating, and subjecting the crude product to column chromatography (dichloromethane/methanol from 100:0 to 90: 10, v/v) to obtain 5- (2, 4-diphenol hydroxyl-5-isopropyl benzene) -N-ethyl-4-) (5, 4-diphenol-hydroxyl-5-isopropyl benzene) -N-ethyl-4-) (5-tetrahydrobenzo [ b ] [ 1.7 ] and 4.6mmol) 5-methyl-2, 3,4, 5-tetrahydrobenzo [ b ] [1,4] oxazepin-8-yl) -4H-1,2, 4-triazole-3-carboxamide (80mg) in 12% yield.

MS m/z(ESI):452.5；

¹H NMR(400MHz,DMSO-d₆,ppm):δ10.90(s,1H),9.78(s,1H),8.90-8.87(m,1H),6.90–6.82(m,3H),6.59(s,1H),6.36(s,1H),4.07-4.05(m,2H),3.22-3.14(m,4H),2.95-3.90(m,1H),2.87(s,3H),2.10-1.96(m,2H),1.07-1.03(m,3H),0.86(s,3H),0.84(s,3H)。

EXAMPLE eighteen

N-acetyl-N- (4- (3- (2, 4-dihydroxy-5-isopropylphenyl) -5-carbonyl-1, 5-dihydro-4H-1, 2, 4-triazol-4-yl) benzyl) -5-methyl-1, 3, 4-oxadiazole-2-carboxamide

Step one, N- (4-nitrobenzyl) -5-methyl-1, 3, 4-oxadiazole-2-formamide

Ethyl 5-methyl-1, 3, 4-oxadiazole-2-carboxylate (300mg, 1.9mmol) was dissolved in ethanol (20ml) and p-nitrobenzylamine (p-nitroaniline hydrochloride (500mg, 2.6mmol) was added to a saturated sodium bicarbonate solution, followed by extraction with ethyl acetate and evaporation of the organic phase to dryness to give p-nitrobenzylamine) was added. The reaction was heated to reflux for 12 hours and then cooled to room temperature. Filtration gave a solid which was then recrystallized from ethanol to give N- (4-nitrobenzyl) -5-methyl-1, 3, 4-oxadiazole-2-carboxamide in 66% yield.

¹H NMR(400MHz,DMSO-d₆,ppm):δ9.90(br,1H),8.20(d,J＝6.4,2H),7.60(d,J＝6.4,2H),4.57(d,J＝6.4,2H),2.59(s,3H)。

Step two, N- (4-aminobenzyl) -5-methyl-1, 3, 4-oxadiazole-2-formamide

N- (4-nitrobenzyl) -5-methyl-1, 3, 4-oxadiazole-2-carboxamide (178mg, 0.68mmol) was dissolved in methanol (20ml) and Pd/C (20mg) was added under nitrogen. The reaction was reacted under hydrogen (1atm) for 4 hours. The catalyst was removed by filtration, and the organic phase was evaporated to dryness to give N- (4-aminobenzyl) -5-methyl-1, 3, 4-oxadiazole-2-carboxamide in a yield of 96%.

¹H NMR(400MHz,DMSO-d₆,ppm):δ9.58(br,1H),6.96(d,J＝6.4,2H),6.47(d,J＝6.4,2H),4.99(br,2H),4.25(d,J＝6.4,2H),2.56(s,3H)。

Step three, (4- ((5-methyl-1, 3, 4-oxadiazole-2-formamide) methyl) phenyl) carbamic acid phenyl ester

Phenyl chloroformate (67mg, 0.43mmol) was added dropwise to a solution of N- (4-aminobenzyl) -5-methyl-1, 3, 4-oxadiazole-2-carboxamide (100mg, 0.43mmol) in tetrahydrofuran (10ml) at 0 ℃ under nitrogen. The reaction was stirred for 5 minutes under nitrogen at 0 ℃ and then pyridine (41mg, 0.51mmol) was added dropwise to the reaction system, followed by stirring again for 30 minutes under nitrogen at 0 ℃. Water (20ml) was added to the reaction system, the organic phase was separated, dried over anhydrous sodium sulfate and evaporated to dryness to give a crude (156mg) of phenyl (4- ((5-methyl-1, 3, 4-oxadiazole-2-carboxamide) methyl) phenyl) carbamate, which was used directly in the next step.

MS m/z(ESI):353.1。

Step four, N- (4- (hydrazine-formamido) benzyl) -5-methyl-1, 3, 4-oxadiazole-2-formamide

Hydrazine hydrate (71mg, 1.7mmol, 95% aqueous solution) was added to a solution of phenyl (4- ((5-methyl-1, 3, 4-oxadiazole-2-carboxamide) methyl) phenyl) carbamate (156mg, 0.48mmol) in dioxane (10 ml). The reaction was heated to 120 ℃ for 3 hours and the solvent was evaporated to dryness to give the crude product. The crude product was washed with water (10ml x 3) to give a crude product which was dried under an oil pump to give N- (4- (hydrazino-formylamino) benzyl) -5-methyl-1, 3, 4-oxadiazole-2-carboxamide (100mg) which was used directly in the next step.

MS m/z(ESI):291.1。

Step five (E) -N- (4- (2- (2, 4-bis (benzyloxy) -5-isopropylphenylmethylene) hydrazine-1-carboxamido) benzyl) -5-methyl-1, 3, 4-oxadiazole-2-carboxamide

The compound N- (4- (hydrazino-formylamino) benzyl) -5-methyl-1, 3, 4-oxadiazole-2-carboxamide (100mg,0.44mmol) and 5-isopropyl-2, 4-dimethoxybenzaldehyde (158mg,0.44mmol) were dissolved in ethanol (10mL), acetic acid (2d) was added, the temperature was raised to 90 ℃ for reaction for 2h, and the mixture was concentrated to give crude (E) -N- (4- (2- (2, 4-bis (benzyloxy) -5-isopropylbenzylidene) hydrazine-1-formylamino) benzyl) -5-methyl-1, 3, 4-oxadiazole-2-carboxamide (175m g) which was used directly in the next reaction.

MSm/z(ESI):633.3。

Step six (Z) -Ethyl N-acetyl-2- ((4- (3- (2, 4-bis (benzyloxy) -5-isopropylphenyl) -5-carbonyl-1, 5-dihydro-4H-1, 2, 4-triazol-4-yl) benzyl) amino) -2-carbonylacetylhydrazone carboxylate

Crude (E) -N- (4- (2- (2, 4-bis (benzyloxy) -5-isopropylphenylmethylene) hydrazine-1-carboxamido) benzyl) -5-methyl-1, 3, 4-oxadiazole-2-carboxamide (30mg, 0.047mmol) was dissolved in ethanol (10mL), and tripotassium hexacyanoferrate (44g,0.142mmol) and sodium hydroxide (7mg, 0.142mmol) were added. After heating to 100 ℃ for 8H, the reaction mixture was concentrated and the crude product was isolated by column chromatography (dichloromethane/methanol ═ 30:1, v/v) to give ethyl (Z) -N-acetyl-2- ((4- (3- (2, 4-bis (benzyloxy) -5-isopropylphenyl) -5-carbonyl-1, 5-dihydro-4H-1, 2, 4-triazol-4-yl) benzyl) amino) -2-carbonylacetyl hydrazone acid (30mg) in 100% yield.

MS m/z(ESI):677.3。

Step seven, N-acetyl-N- (4- (3- (2, 4-bis (benzyloxy) -5-isopropylphenyl) -5-carbonyl-1, 5-dihydro-4H-1, 2, 4-triazol-4-yl) benzyl) -5-methyl-1, 3, 4-oxadiazole-2-carboxamide

Ethyl (Z) -N-acetyl-2- ((4- (3- (2, 4-bis (benzyloxy) -5-isopropylphenyl) -5-carbonyl-1, 5-dihydro-4H-1, 2, 4-triazol-4-yl) benzyl) amino) -2-carbonylacetylhydrazone ate (30mg, 0.037mmol) was dissolved in acetic anhydride (5ml), and the reaction solution was heated to 80 ℃ for 10 hours. Then evaporated to dryness to give a crude product which was isolated by column chromatography (dichloromethane/methanol ═ 5:1, v/v) to give N-acetyl-N- (4- (3- (2, 4-bis (benzyloxy) -5-isopropylphenyl) -5-carbonyl-1, 5-dihydro-4H-1, 2, 4-triazol-4-yl) benzyl) -5-methyl-1, 3, 4-oxadiazole-2-carboxamide (15mg) in 60% yield.

MS m/z(ESI):673.3。

Step eight N-acetyl-N- (4- (3- (2, 4-dihydroxy-5-isopropylphenyl) -5-carbonyl-1, 5-dihydro-4H-1, 2, 4-triazol-4-yl) benzyl) -5-methyl-1, 3, 4-oxadiazole-2-carboxamide

N-acetyl-N- (4- (3- (2, 4-bis (benzyloxy) -5-isopropylphenyl) -5-carbonyl-1, 5-dihydro-4H-1, 2, 4-triazol-4-yl) benzyl) -5-methyl-1, 3, 4-oxadiazole-2-carboxamide (18mg, 0.022mmol) was dissolved in methanol (5ml) and Pd/C (5mg) was added under nitrogen. The reaction was reacted under hydrogen (1atm) for 2 hours. The catalyst was removed by filtration and the organic phase was evaporated to dryness to give N-acetyl-N- (4- (3- (2, 4-dihydroxy-5-isopropylphenyl) -5-carbonyl-1, 5-dihydro-4H-1, 2, 4-triazol-4-yl) benzyl) -5-methyl-1, 3, 4-oxadiazole-2-carboxamide in 90% yield.

MS m/z(ESI):493.3；

¹H NMR(400MHz,CD₃OD,ppm):δ7.48(d,J＝8.0,2H),7.28(d,J＝8.0,2H),6.90(s,1H),6.25(s,1H),4.60(s,2H),3.05-2.95(m,1H),2.65(s,3H),2.63(s,3H),0.92(d,J＝8.0,6H)。

Biological evaluation

1. Enzymatic Activity assay for HSP90 inhibitory Compounds

Enzymatic activity of HSP90 inhibitory compounds was detected using Fluorescence Polarization (Fluorescence Polarization) competitive binding methods. The reaction solution, HSP90 protein, FITC-labeled geldanamycin were added to 384-well plates, and HSP90 inhibitory compounds were added at different concentrations to different wells, and after reaction for 3 hours at room temperature, the parallel and perpendicular light readings, as well as the respective background absorbances, were measured using a BioTek plate reader. The calculation method of mP (milli-polarization) is as follows:

mP＝1000*[(Is-IsB)-(Ip-IpB)]/[(Is-IsB)+(Ip-IpB)]。

calculating the half inhibition concentration IC by adopting a 4-parameter nonlinear regression method according to each concentration inhibition rate₅₀。

The biochemical activities of the inventive compound and the control compound (STA9090) were determined by the above assay, and the IC was determined₅₀The values are given in the following table.

Example numbering	IC50(HSP90/BIO)(nM)
		Example one	5
Example two	13
		EXAMPLE III	10
Example four	7.7
		EXAMPLE five (5-1)	7
EXAMPLE five (5-2)	9
		EXAMPLE seven	25
Example eight	13.7
		Example nine	8
Example ten	4
		EXAMPLE eleven	117
Example twelve	32
		EXAMPLE thirteen	12
Example fourteen	17
		Example fifteen	14
Example sixteen	30
		Example seventeen	4
EXAMPLE eighteen	13
		Control Compound (STA9090)	26

And (4) conclusion: the compounds of the embodiment of the invention have obvious inhibition effect on the activity of HSP90 enzyme.

2. Cellular activity assay for HSP90 inhibitory compounds

Applications of

Luminescence method cell viability assay kit (

Luminescent Cell Viability Assay) to detect the inhibitory effect of drugs on the proliferation and growth of tumor cells. The method mainly comprises the following steps: a number of cells in logarithmic growth phase were seeded in 96-well culture plates. After 24 hours of adherent growth, drugs with different concentrations are added, each concentration is provided with a plurality of holes, and simultaneously, a solvent control with corresponding concentration is arranged. The tumor cells were then incubated at 37 ℃ with 5% CO₂Culturing for 72h under the condition. The plates and their contents were allowed to equilibrate to room temperature for about 30 minutes and added

Reagents, mix contents on a shaker for 2 minutes to induce cell lysis. The plates were further incubated at room temperature for 10-45 minutes, and the fluorescence signal value was measured with a microplate reader (BioTek SynergyH 1).

Calculating the half inhibition concentration IC by adopting a nonlinear regression method according to each concentration inhibition rate₅₀。

The biochemical activities of the inventive compound and the control compound (STA9090) were determined by the above assay, and the IC was determined₅₀The values are given in the following table.

Example numbering	IC50(BT474)(nM)
		Example one	6.6
Example two	7.3
		EXAMPLE III	23
Example four	5.4
		EXAMPLE five (5-1)	6.33
EXAMPLE five (5-2)	19.67
		Example eight	5.2
Example nine	6.7
		Example ten	7.7
EXAMPLE eleven	386
		Example twelve	264
EXAMPLE thirteen	79
		Example fourteen	54
Example fifteen	3.4
		Example sixteen	10.5
Example seventeen	3.3
		EXAMPLE eighteen	32
Control Compound (STA9090)	6.3

And (4) conclusion: the compounds of the embodiment of the invention have obvious inhibition effect on the activity of BT474 cells.

Finally, it should be noted that the above-mentioned embodiments are only for illustrating the technical solutions of the present invention and not for limiting the present invention, and although the present invention has been described in detail with reference to the preferred embodiments, it should be understood by those skilled in the art that modifications or equivalent substitutions may be made to the technical solutions of the present invention without departing from the spirit and scope of the technical solutions of the present invention, which should be covered by the claims of the present invention.

Claims (8)

1. A 3, 4-diphenyl-4H-1, 2, 4-triazole derivative having the structure of formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof:

wherein:

R₁is-C (O) NR₇R₈；

R₃Selected from hydrogen;

R₂and R₄Together with the carbon atom to which they are directly attached form a 7-membered nitrogen-containing heterocyclic group, optionally further substituted by one or more groups selected from carbonyl, C_1-8Alkyl or C_3-8Cycloalkyl, substituted with a substituent;

R₇、R₈each independently selected from hydrogen or C_1-4An alkyl group.

2. The 3, 4-diphenyl-4H-1, 2, 4-triazole derivative having the structure of formula (I), or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, as claimed in claim 1, wherein R is₇、R₈Each independently selected from hydrogen, ethyl.

3. The 3, 4-diphenyl-4H-1, 2, 4-triazole derivative having the structure of formula (I), or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, as claimed in claim 1, wherein R is₂And R₄Together with the carbon atom to which they are directly attached form a 7-membered nitrogen-containing heterocyclic group, optionally further substituted by one or more groups selected from carbonyl, C_1-4Alkyl or C_3-6Cycloalkyl substituents.

4. The 3, 4-diphenyl-4H-1, 2, 4-triazole derivative having the structure of formula (I), or a stereoisomer thereof or a pharmaceutically acceptable salt thereof, according to claim 1, which is selected from the following compounds:

5. a process for the preparation of a 3, 4-diphenyl-4H-1, 2, 4-triazole derivative having the structure of formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, according to any one of claims 1-4, which comprises the steps of:

alternatively, the first and second electrodes may be,

alternatively, the first and second electrodes may be,

optionally, according to R₁、R₂、R₃、R₄The step of further reaction according to the defined difference;

wherein Pg₁Is a hydroxy protecting group;

Pg₂is an amino protecting group;

x is halogen;

R₁、R₂、R₃、R₄as defined in claim 1.

6. According to claim 5The preparation method of the 3, 4-diphenyl-4H-1, 2, 4-triazole derivative with the structure of formula (I), the stereoisomer or the pharmaceutically acceptable salt thereof is characterized in that Pg₁Selected from benzyl, 2-tetrahydrofuran, methoxymethyl, ethoxyethyl, C_1-8Alkyl, allyl, trimethylsilyl, triethylsilyl, triisopropylsilyl, tert-butyldimethylsilyl or tert-butyldiphenylsilyl;

Pg₂selected from benzyloxycarbonyl, t-butoxycarbonyl, 9-fluorenylmethyloxycarbonyl, trityl, trifluoroacetyl, benzyl or p-methoxyphenyl;

x is chlorine.

7. A pharmaceutical composition comprising a therapeutically effective amount of a 3, 4-diphenyl-4H-1, 2, 4-triazole derivative having the structure of formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof, according to any one of claims 1-4, and a pharmaceutically acceptable carrier.

8. Use of a 3, 4-diphenyl-4H-1, 2, 4-triazole derivative having the structure of formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof, according to any one of claims 1-4, or a pharmaceutical composition thereof according to claim 7, in the manufacture of a medicament for the treatment of HSP 90-associated cancer, neurodegenerative disease, inflammatory disease, autoimmune disease, ischemic brain injury.