CN113087713A - Benzodiazepine derivatives, and preparation method and use thereof - Google Patents

Abstract

The invention discloses benzodiazepines of formula (I)

Derivatives, enantiomers, diastereomers, racemates and mixtures thereof, and pharmaceutically acceptable salts, crystalline hydrates and solvates thereof, and methods for preparing same, and pharmaceutical compositions for preparing an antidote for a GABAA receptor agonist, an analeptic agent after anesthesia, an antiepileptic drug, a pharmaceutical composition for treating epilepsy, a method for preparing same, and a pharmaceutical composition for treating epilepsy,The application of the medicine for resisting senile dementia, antidote for alcoholism and stimulant for treating mental loss caused by unknown reason.

Description

Benzodiazepine derivatives, and preparation method and use thereof

Reference to the prior application

The application requires that the application number submitted to the intellectual property office of China at 29.3.3.2021 is 202110330261.X, entitled' class I benzodiazepine

Derivatives and methods of their preparation and use "priority, the contents of which are incorporated herein by reference in their entirety.

Technical Field

The invention belongs to the field of pharmacy, and particularly relates to benzodiazepine

Derivatives and their use as benzodiazepines

Antidotes with excessive quasi-drugs, awakening agents after anesthesia, diagnostic agents with unknown reasons and mental loss, and the like.

Background

Gamma-aminobutyric acid (GABA) is the most prominent inhibitory neurotransmitter in the central nervous system and is widely distributed in the brain and spinal cord. GABA acts primarily by generating biological signals through binding to GABA receptors, which include two classes, the type A (GABAa) and the type C (GABAc) ionotropic receptors; another class is the type B G protein-coupled metabolic receptors (GABAb). Dinitrogen benzene

The quasi-drugs (BZDs) combine with specific BZD receptor binding sites on GABAa receptors to open chloride ion channels on cell membranes, so that chloride ions flow into cells, and the postsynaptic membrane is hyperpolarized, thereby generating central nerve inhibition.

Dinitrogen benzene

Quasi drugs are one of the most widely used drugs in human society. They are commonly used in a variety of diseases including anxiety, stress, insomnia, epilepsy, muscle spasms and alcohol withdrawal; in addition, BDZs are also used in patients under general anesthesia and conscious sedation.

Dinitrogen benzene

The quasi-drugs are also common drugs used accidentally and deliberately in excess. Benzodiazepines in patients over 17 years of age

The highest number of toxic exposures were reported for the quasi-drugs as single drugs and in combination with other drugs. Despite the ingestion of benzodiazepines only

The quasi-drug appears to cause relatively less mortality, but the morbidity and mortality from overdosing increases.

Drugs currently used to treat BDZs overdose include naloxone, methylxanthines, cholinergic agents. But competitive benzodiazepines

Antagonists are rare.

Flumazenil (FMZ) is GABA_AReceptor antagonists which bind specifically to benzodiazepines of the central nervous system

Receptor, competitive blocking of benzodiazepines

Inhibition of GABA energy signaling system. It is often used as a specific competitive antagonist of BDZs clinically. However, flumazenil has the disadvantages of fast metabolism, short in-vivo half-life, low bioavailability, poor solubility and the like, so that only injection preparations are clinically used at present. The injection has the defects of poor patient compliance, large toxic and side effects, high production cost and the like, limits the application of flumazenil, and is not beneficial to the development and development of novel clinical indications of flumazenil.

Disclosure of Invention

According to one aspect of the present invention there is provided a benzodiazepine of formula (I)

Derivatives, enantiomers, diastereomers, racemates and mixtures thereof, and pharmaceutically acceptable salts, crystalline hydrates and solvates thereof,

wherein, R is unsubstituted C6, C7, C8, C9, C10, C11, C12, C13 aryl, C13 containing 1,2 or 3 substituents, C13 aryl, unsubstituted C13, C, C7, C8, C9, C10, C11 cycloalkyl, unsubstituted C11, C11 alkoxy, C11, 7-membered, 8-membered, 9-membered, 10-membered, 11-membered, 12-membered heteroaryl, 6-membered, 7-membered, 8-membered, 9-membered, 10-membered, 11-membered, 12-membered heteroaryl containing 1,2, or 3 substituents and containing 1,2, or 3 heteroatoms selected from N, O and S, unsubstituted 5-membered, 6-membered, 7-membered, 8-membered, 9-membered, 10-membered, 11-membered, 12-membered heterocyclyl containing 1,2, or 3 substituents and containing 1,2, or 3 heteroatoms selected from N, O and S, 5-membered, 6-membered, 7-membered, 8-membered, 9-membered, 10-membered, 11-membered, 12-membered heterocyclyl.

Preferably, R is unsubstituted C6, C7, C8, C9, C10, C10 aryl, C6, C7, C8, C9, C10 aryl containing 1 to 3 substituents, unsubstituted C1, C2, C3, C4, C5, C6, C7, C8, C9, C10 straight or branched alkyl, C1 containing 1,2 or 3 substituents, C2 straight or branched alkyl containing 1,2 or 3 substituents, unsubstituted C2, c1, C2, C3, C4, C5, C6, C7, C8, C9, C10 alkylcarbonyl containing 1,2 or 3 heteroatoms selected from N, O and S, unsubstituted 6-, 7-, 8-, 9-, 10-membered heteroaryl containing 1,2 or 3 substituents and containing 1,2 or 3 heteroatoms selected from N, O and S, unsubstituted 5-, 6-, 7-, 8-, 9-, 10-membered heteroaryl containing 1,2 or 3 heteroatoms selected from N, O and S, unsubstituted 5-, 6-, 7-, 8-, 9-, 10-membered heterocyclyl containing 1,2 or 3 substituents and containing 1,2 or 3 heteroatoms selected from N, O and S, 5-, 6-, 7-, 8-, 9-, 10-membered heterocyclyl containing 1,2 or 3 substituents and containing 1,2 or 3 heteroatoms selected from N, O and S.

Further preferably, R is unsubstituted C, C aryl, unsubstituted C, C aryl containing 1 to 3 substituents, unsubstituted C, C straight or branched alkyl, C straight or branched alkyl containing 1,2 or 3 substituents, unsubstituted C, C straight or branched alkyl, unsubstituted C, C cycloalkyl, C cycloalkyl containing 1,2 or 3 substituents, unsubstituted C, C alkoxy, C alkoxy containing 1,2 or 3 substituents, unsubstituted C, C alkylcarbonyl, C, alkylcarbonyl containing 1,2 or 3 substituents, unsubstituted 6-to 8-membered heteroaryl containing 1,2 or 3 heteroatoms selected from S, a 6-membered, 7-membered, 8-membered heteroaryl group containing 1,2, or 3 substituents and containing 1,2, or 3 heteroatoms selected from N, O and S, an unsubstituted 5-membered, 6-membered, 7-membered, 8-membered heterocyclyl group containing 1,2, or 3 heteroatoms selected from N, O and S, a 5-membered, 6-membered, 7-membered, 8-membered heterocyclyl group containing 1,2, or 3 substituents and containing 1,2, or 3 heteroatoms selected from N, O and S.

Further preferably, when R is C6, C7, C8, C9, C10, C11, C12, C13, C14, C15, C16, C17, C18, C19, C20 aryl or C6, C7, C8, C9, C10, C10 aryl containing 1 to 3 substituents, each of said substituents is independently selected from C1, C2, C3 straight or branched chain alkyl, halogen, C1, C2, C3 alkoxy and cyano, wherein halogen is selected from F, Cl or Br.

Further preferably, when R is C1, C2, C3, C4, C5, C6, C7, C8, C9, C10, C11, C12, C13, C14, C15, C16, C17, C18, C19, C20 straight or branched chain alkyl containing 1,2 or 3 substituents, C20, straight or branched chain alkyl or C20, C20 straight or branched chain alkyl containing 1,2 or 3 substituents, each independently selected from halogen, C20 alkoxy and Br, wherein the substituents are selected from halogen or Br 20.

Further preferably, when R is C3, C4, C5, C6, C7, C8, C9, C10, C11, C12, C13, C14, C15, C16, C17, C18, C19, C20 cycloalkyl containing 1,2 or 3 substituents, C3-C10 cycloalkyl containing 1,2 or 3 substituents, or C3, C4, C5, C6 cycloalkyl containing 1,2 or 3 substituents, each independently selected from C1, C2, C3 linear or branched alkyl, halogen, C1, C2, C3 alkoxy and cyano, wherein halogen is selected from F, Cl or Br.

Further preferably, when R is C, C alkoxy containing 1,2 or 3 substituents, C alkoxy containing 1,2 or 3 substituents or C, C alkoxy containing 1,2 or 3 substituents, each of the substituents is independently selected from C, C straight or branched alkyl, C alkylcarbonyl, C straight or branched alkyl containing 1,2 or 3C, C cycloalkyl, halogen substituted C, wherein the halogen is selected from or Br.

Further preferably, when R is C1, C2, C3, C4, C5, C6, C7, C8, C9, C10, C11, C12, C13, C14, C15, C16 alkylcarbonyl containing 1,2 or 3 substituents, C16 alkylcarbonyl containing 1,2 or 3 substituents, each of said substituents is independently selected from C16, C16 or C16 branched alkyl group containing 1,2 or 3 substituents, C16, or C16, C16 alkyl alkoxy group.

Further preferably, when R is a 6-, 7-, 8-, 9-, 10-, 11-, 12-membered heteroaryl group containing 1,2 or 3 substituents and containing 1,2 or 3 heteroatoms selected from N, O and S, a 6-10-membered heteroaryl group containing 1,2 or 3 substituents and containing 1,2 or 3 heteroatoms selected from N, O and S, or a 6-8-membered heteroaryl group containing 1,2 or 3 substituents and containing 1,2 or 3 heteroatoms selected from N, O and S, each of said substituents is independently selected from C1, C2, C3 straight or branched chain alkyl, halogen, C1, C2, C3 alkoxy and cyano, wherein halogen is selected from F, Cl or Br.

Further preferably, when R is a 5-, 6-, 7-, 8-, 9-, 10-, 11-, 12-membered heterocyclic group containing 1,2 or 3 substituents and containing 1,2 or 3 heteroatoms selected from N, O and S, a 5-, 6-, 7-, 8-, 9-, 10-, 11-, 12-membered heterocyclic group containing 1,2 or 3 substituents and containing 1,2 or 3 heteroatoms selected from N, O and S, or a 5-, 6-, 7-, 8-membered heterocyclic group containing 1,2 or 3 substituents and containing 1,2 or 3 heteroatoms selected from N, O and S, each of said substituents is independently selected from C1, C2, C3 straight or branched chain alkyl, halogen, C1, C2, C3 alkylcarbonyl and cyano, wherein halogen is selected from F, Cl or Br.

According to the invention, benzodiazepines of formula (I)

Derivatives, enantiomers, diastereomers, racemates and mixtures thereof, as well as pharmaceutically acceptable salts, crystalline hydrates and solvates thereof, selected from the group consisting of the following compounds:

according to another aspect of the present invention, there is also provided a process for the synthesis of a compound of formula (I) according to the following reaction scheme:

1) carrying out condensation reaction on 5-fluoro-2-nitrobenzoic acid and creatine methyl ester under the catalysis of 1-ethyl- (3-dimethylaminopropyl) carbonyl diimine hydrochloride and 1-hydroxybenzotriazole to obtain N- (5-fluoro-2-nitrobenzoyl) -N-methylglycine methyl ester;

2) n- (5-fluoro-2-nitrobenzoyl) -N-methyl glycine methyl ester reduces nitro under the catalysis of palladium carbon or Raney nickel, and 7-fluoro-3, 4-dihydro-4-methyl-1H- [1, 4-cyclization is simultaneously obtained]Benzodiazepines

-2, 5-diketones;

3) 7-fluoro-3, 4-dihydro-4-methyl-1H- [1, 4%]Benzodiazepines

The (E) -2, 5-diketone is chlorinated by a chlorinating agent and then reacts with ethyl isonitrile acetate under the alkaline condition to obtain 8-fluoro-5, 6-dihydro-5-methyl-6-oxo-4H-imidazo [1, 5-alpha ]][1,4]Benzodiazepines

-3-carboxylic acid ethyl ester;

4) 8-fluoro-5, 6-dihydro-5-methyl-6-oxo-4H-imidazo [1, 5-alpha ]][1,4]Benzodiazepines

Reduction of the ester group of ethyl-3-carboxylate by sodium borohydride/Lewis acid gives 8-fluoro-3-hydroxymethyl-5, 6-dihydro-5-methyl-6H-imidazo [1,5-a][1,4]Benzodiazepines

-6-ketones;

5) 8-fluoro-3-hydroxymethyl-5, 6-dihydro-5-methyl-6H-imidazo [1,5-a][1,4]Benzodiazepines

Reacting the (6-keto) with a corresponding acid or an acid chloride to form an ester, thereby obtaining the benzodiazepine represented by the formula (I)

And (3) derivatives.

According to another aspect of the present invention there is provided a pharmaceutical composition comprising a therapeutically effective amount of a benzodiazepine of formula (I)

Derivatives, enantiomers, diastereomers, racemates thereof and mixtures thereof, and one or more of pharmaceutically acceptable salts, crystalline hydrates and solvates thereof, and at least one excipient, diluent or carrier.

According to another aspect of the present invention there is provided a benzodiazepine of formula (I)

The derivatives, enantiomers, diastereomers, racemates and mixtures thereof, pharmaceutically acceptable salts, crystal hydrates and solvates thereof, and the application of the pharmaceutical composition in preparing an antidote of a GABAA receptor agonist, a postanesthesia awakening agent, an antiepileptic drug, an anti-senile dementia drug, an alcoholism antidote and a drug of an awakening agent for treating mental loss caused by unknown reasons.

Detailed Description

Hereinafter, the present invention will be described in detail. Before the description is made, it should be understood that the terms used in the present specification and the appended claims should not be construed as limited to general and dictionary meanings, but interpreted based on the meanings and concepts corresponding to technical aspects of the present invention on the basis of the principle that the inventor is allowed to define terms appropriately for the best explanation. Accordingly, the description proposed herein is just a preferable example for the purpose of illustrations only, not intended to limit the scope of the invention, so it should be understood that other equivalents and modifications could be made thereto without departing from the spirit and scope of the invention.

The compounds described herein may contain one or more asymmetric centers and thus may exist in various isomeric forms, such as enantiomers and/or diastereomers. For example, the compounds described herein may be in the form of individual enantiomers, diastereomers, or geometric isomers, or may be in the form of mixtures of stereoisomers, including racemic mixtures and mixtures enriched in one or more stereoisomers. Isomers may be isolated from mixtures by methods known to those skilled in the art, including chiral High Performance Liquid Chromatography (HPLC) and the formation and crystallization of chiral salts; or preferred isomers may be prepared by asymmetric synthesis. The present disclosure additionally encompasses compounds described herein which are individual isomers substantially free of other isomers, and alternatively, as mixtures of various isomers, including racemic mixtures.

When a range of values is recited, it is intended to include each value and sub-range within the range. For example, "C1, C2, C3, C4, C5, C6" is intended to encompass C₁，C₂，C₃，C₄，C₅，C₆，C_1–6，C_1–5，C_1–4，C_1–3，C_1–2，C_2–6，C_2–5，C_2–4，C_2–3，C_3–6，C_3–5，C_3–4，C_4–6，C_4–5And C_5–6。

The compounds of the present disclosure may exist in isotopically labeled or enriched forms, which comprise one or more atoms having an atomic mass or mass number different from the atomic mass or mass number most abundant in nature. The isotope may be a radioactive isotope or a non-radioactive isotope. Isotopes of atoms such as hydrogen, carbon, phosphorus, sulfur, fluorine, chlorine, and iodine, including but not limited to²H，³H，¹³C，¹⁴C，¹⁵N，¹⁸O，³²P，³⁵S，¹⁸F，³⁶Cl and¹²⁵I. compounds containing other isotopes of these and/or other atoms are within the scope of the present invention.

As used herein, the term "alkyl" used by itself or as part of another group refers to straight or branched chain aliphatic hydrocarbons typically having 1-20 carbons. In one embodiment, the alkyl group is a linear or branched C1, C2, C3, C4, C5, C6, C7, C8, C9, C10 alkyl group. In another embodiment, alkyl is a straight or branched chain C1, C2, C3, C4, C5, C6 alkyl, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, isobutyl, n-pentyl, isopentyl, n-hexyl, 2-methyl-pentyl, and the like.

"cycloalkyl" as used by itself or as part of another group refers to a group that is a non-aromatic cyclic hydrocarbon group, e.g., having from 3 to 20 ring carbon atoms in a non-aromatic ring system ("C3, C4, C5, C6, C7, C8, C9, C10, C11, C12, C13, C14, C15, C16, C17, C18, C19, C20 cycloalkyl"), and zero heteroatoms. In one embodiment, a cycloalkyl group has 3 to 10 ring carbon atoms ("C3-C10 cycloalkyl") and zero heteroatoms. In one embodiment, a cycloalkyl group has 3 to 6 ring carbon atoms ("C3, C4, C5, C6 cycloalkyl") and zero heteroatoms. The cycloalkyl group may be monocyclic ("monocyclic cycloalkyl") or contain a fused, bridged or spiro ring system, such as a bicyclic system ("bicyclic cycloalkyl"), and may be saturated or may be partially unsaturated. Non-limiting exemplary cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, norbornyl, decalin, adamantyl, cyclopentenyl and cyclohexenyl. In a preferred embodiment, the term "cycloalkyl" refers to a monocyclic saturated group having from 3 to 10, more preferably from 3 to 6, ring carbon atoms.

"heterocyclyl" or "heterocycle" as used by itself or as part of another group refers to a group of 6 to 20-membered non-aromatic ring systems having ring carbon atoms and 1 to 3 ring heteroatoms, wherein each heteroatom is independently selected from N, O and S ("C6, C7, C8, C9, C10, C11, C12, C13, C14, C15, C16, C17, C18, C19, C20-membered heterocyclyl"). In heterocyclic groups containing one or more nitrogen or oxygen atoms, the point of attachment may be a carbon, nitrogen or oxygen atom, as valence permits. A heterocyclyl group can be monocyclic ("monocyclic heterocyclyl") or a fused, bridged or spiro ring system, such as a bicyclic system ("bicyclic heterocyclyl"), and can be saturated or can be partially unsaturated. Heterocyclyl bicyclic ring systems may contain one or more heteroatoms in one or both rings. "Heterocyclyl" also includes ring systems in which a heterocycle as defined above is fused to one or more cycloalkyl groups, where the point of attachment is on the cycloalkyl or heterocycle, or ring systems in which a heterocycle as defined above is fused to one or more aryl or heteroaryl groups, where the point of attachment is on the heterocycle, in which case the number of ring members continues to indicate the number of ring members in the heterocycle system.

"aryl" used alone or as part of another group refers to a monocyclic or polycyclic (e.g., bicyclic or tricyclic) 4n +2 aromatic ring system (e.g., sharing 6, 10, or 14 pi electrons in a cyclic array) having 6 to 12 ring carbon atoms and zero heteroatoms in the aromatic ring system ("C6, C7, C8, C9, C10, C11, C12 aryl"). In some embodiments, aryl is phenyl. "aryl" also includes ring systems in which an aryl ring as defined above is fused to one or more cycloalkyl or heterocyclyl groups, where the radical or point of attachment is on the aryl ring, and in this case the number of carbon atoms continues to refer to the number of carbon atoms in the aromatic ring system.

"aralkyl" used alone or as part of another group refers to an alkyl group substituted with one or more aryl groups, preferably one aryl group. When it is mentioned that an aralkyl group is optionally substituted, the alkyl portion or the aryl portion of the aralkyl group may be optionally substituted.

"heteroaryl" used alone or as part of another group refers to a group of a 5-, 6-, 7-, 8-, 9-, 10-, 11-, 12-membered monocyclic or bicyclic 4n +2 aromatic ring system (e.g., sharing 6 or 10 pi electrons in a cyclic array) having ring carbon atoms and 1-4 ring heteroatoms in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("5-, 6-, 7-, 8-, 9-, 10-, 11-, 12-membered heteroaryl"). In heteroaryl groups containing one or more nitrogen atoms, the point of attachment may be a carbon or nitrogen atom, as valence permits. Heteroaryl bicyclic ring systems may contain one or more heteroatoms in one or both rings. "heteroaryl" includes ring systems in which a heteroaryl ring as defined above is fused to one or more cycloalkyl or heterocyclyl groups, wherein the point of attachment is on the heteroaryl ring, and in this case the number of ring members continues to refer to the number of ring members in the heteroaryl ring system. "heteroaryl" also includes ring systems in which a heteroaryl ring as defined above is fused with one or more aryl groups, wherein the point of attachment is on the aryl or heteroaryl ring, and in this case the number of ring members refers to the number of ring members in the fused (aryl/heteroaryl) ring system. Bicyclic heteroaryl groups in which one ring does not contain a heteroatom (e.g., indolyl, quinolinyl, carbazolyl, and the like), the point of attachment may be on either ring, i.e., a ring with a heteroatom (e.g., 2-indolyl) or a ring that does not contain a heteroatom (e.g., 5-indolyl).

The invention also includes isotopically-labeled compounds of the invention, which are otherwise identical to those recited herein, except that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, fluorine and chlorine, such as²H、³H、¹³C、¹⁴C、¹⁵N、¹⁸O、¹⁷O、¹⁸F and³⁶Cl。

certain isotopically-labeled compounds of the present invention (e.g., via)³H and¹⁴c-labeled compounds) can be used in the identification of compound and/or stromal tissue distribution. Tritiated (i.e. by tritiation)³H) And carbon-14 (i.e.¹⁴C) Isotopes are particularly preferred for their ease of preparation and detection. In addition, via a base such as deuterium (i.e., deuterium)²H) The heavier isotope substitutions of (a) may provide certain therapeutic benefits arising from greater metabolic stability (e.g., increased in vivo half-life or reduced dosage requirements), and thus may be preferred for use in certain conditions. Isotopically labeled compounds of the present invention can generally be prepared by following procedures analogous to those disclosed in the schemes and/or in the examples below, by substituting an isotopically labeled reagent for a non-isotopically labeled reagent.

The compounds of the present invention or pharmaceutically acceptable salts thereof may exist in the form of hydrates, solvates or prodrugs thereof. Accordingly, hydrates, solvates or prodrugs of the compounds of the invention or pharmaceutically acceptable salts thereof are also included within the scope of the invention.

The term "pharmaceutically acceptable" as used herein is intended to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.

The term "pharmaceutically acceptable salts" refers to salts of the compounds of the present invention, prepared from the compounds of the present invention found to have particular substituents, with relatively nontoxic acids or bases. When compounds of the present invention contain relatively acidic functional groups, base addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of a base in neat solution or in a suitable inert solvent. Pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic ammonia or magnesium salts or similar salts. When compounds of the invention contain relatively basic functional groups, acid addition salts (i.e., pharmaceutically acceptable salts) can be obtained by contacting the neutral form of such compounds with a sufficient amount of an acid in neat solution or in a suitable inert solvent, examples of which include salts of inorganic acids including, for example, hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, bicarbonate, phosphoric acid, monohydrogen phosphate, dihydrogen phosphate, sulfuric acid, bisulfate, hydroiodic acid, phosphorous acid, and the like; such organic acids include, for example, benzoic acid, 2-hydroxyethanesulfonic acid, sulfamic acid, benzenesulfonic acid, phenylacetic acid, mandelic acid, malonic acid, propionic acid, oxalic acid, sulfanilic acid, p-toluenesulfonic acid, polygalacturonic acid, fumaric acid, pantothenic acid, fumaric acid, glutamic acid, succinic acid, methanesulfonic acid, tartaric acid, ascorbic acid, phthalic acid, maleic acid, citric acid, malic acid, glucoheptose, gluconic acid, isethionic acid, lactic acid, lactose, dodecylsulfonic acid, pamoic acid, salicylic acid, suberic acid, phosphorous acid, and the like; glycolic acid, acetic acid, ethanesulfonic acid, isobutyric acid, stearic acid and the like; also included are salts of amino acids such as arginine and the like, and salts of organic acids such as glucuronic acid and the like. Certain specific compounds of the invention may contain both basic and acidic functionalities and thus may be converted to any base or acid addition salt. The parent form of the compound differs from the various salt forms by certain physical properties, such as solubility in polar solvents.

The term "pharmaceutically acceptable carrier" refers to any formulation or carrier medium capable of delivering an effective amount of an active agent of the present invention, without interfering with the biological activity of the active agent, and without toxic side effects to the host or patient, and representative carriers include water, oils, vegetables and minerals, cream bases, lotion bases, ointment bases, and the like. These include suspending agents, viscosity enhancers, skin penetration enhancers, and the like. Their preparation is known to those skilled in the cosmetic or topical pharmaceutical field.

The term "effective amount" or "therapeutically effective amount" with respect to a drug or pharmacologically active agent refers to a sufficient amount of the drug or agent that is non-toxic but achieves the desired effect. For oral dosage forms of the invention, an "effective amount" of one active agent in a composition is the amount required to achieve the desired effect when combined with another active agent in the composition. The determination of an effective amount varies from person to person, depending on the age and general condition of the recipient and also on the particular active substance, and an appropriate effective amount in an individual case can be determined by a person skilled in the art according to routine tests.

The pharmaceutical composition according to the present invention comprises a therapeutically effective amount of a compound represented by formula (I), and one or more of stereoisomers, pharmaceutically acceptable salts, prodrugs, solvates, hydrates, and crystal forms thereof, and at least one excipient, diluent, or carrier.

Typical formulations are prepared by mixing a compound of formula (I) of the invention with a carrier, diluent or excipient. Suitable carriers, diluents or excipients are well known to those skilled in the art and include materials such as carbohydrates, waxes, water soluble and/or swellable polymers, hydrophilic or hydrophobic materials, gelatin, oils, solvents, water and the like.

The particular carrier, diluent or excipient employed will depend upon the mode of use and the purpose of the compound of the invention. The solvent is generally selected based on the solvent that one of skill in the art would consider safe and effective for administration to mammals. Generally, safe solvents are non-toxic aqueous solvents such as water, as well as other non-toxic solvents that are soluble or miscible with water. Suitable aqueous solvents include one or more of water, ethanol, propylene glycol, polyethylene glycol (e.g., PEG400, PEG300), and the like. The formulation may also include one or more buffers, stabilizers, surfactants, wetting agents, lubricants, emulsifiers, suspending agents, preservatives, antioxidants, opacifiers, glidants, processing aids, colorants, sweeteners, flavoring agents or other known additives to make or use the drug in an acceptable form.

When the compound of formula (I) according to the present invention is used in combination with at least one other drug, the two drugs or more may be used separately or in combination, preferably in the form of a pharmaceutical composition. The compounds or pharmaceutical compositions of the invention according to formula (I) can be administered to a subject separately or together in any known oral, intravenous, rectal, vaginal, transdermal, other topical or systemic administration form.

These pharmaceutical compositions may also contain one or more buffering agents, stabilizing agents, surfactants, wetting agents, lubricating agents, emulsifying agents, suspending agents, preservatives, antioxidants, opacifiers, glidants, processing aids, colorants, sweeteners, flavoring agents or other known additives to allow the pharmaceutical composition to be manufactured or used in an acceptable form.

The route of oral administration is preferred for the medicaments of the invention. Solid dosage forms for oral administration may include capsules, tablets, powders or granules. In solid dosage forms, the compounds or pharmaceutical compositions of the present invention are mixed with at least one inert excipient, diluent or carrier. Suitable excipients, diluents or carriers include substances such as sodium citrate or dicalcium phosphate, or starches, lactose, sucrose, mannitol, silicic acid and the like; binders such as carboxymethyl cellulose, alginate, gelatin, polyvinyl pyrrolidone, sucrose, gum arabic, etc.; humectants such as glycerin, etc.; disintegrating agents such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, specific complex silicate, sodium carbonate, etc.; solution retarding agents such as paraffin, etc.; absorption accelerators such as quaternary ammonium compounds and the like; adsorbents such as kaolin, bentonite, etc.; lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and the like. In the case of capsules and tablets, the dosage form may also include buffering agents. Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using lactose and high molecular weight polyethylene glycols and the like as excipients.

Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups and elixirs. In addition to the compounds of the present invention or compositions thereof, the liquid dosage forms may contain inert diluents commonly used in the art, such as water or other solvents; solubilizers and emulsifiers such as ethanol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1, 3-butylene glycol, dimethylformamide; oils (e.g., cottonseed oil, groundnut oil, corn germ oil, olive oil, castor oil, sesame oil, etc.); glycerol; tetrahydrofurfuryl alcohol; fatty acid esters of polyethylene glycol and sorbitan; or mixtures of several of these substances, and the like.

In addition to these inert diluents, the compositions can also include excipients such as one or more of wetting agents, emulsifying agents, suspending agents, sweetening, flavoring, and perfuming agents.

For suspensions, in addition to the compounds or combinations of the present invention, carriers such as suspending agents, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol, sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar, tragacanth, or mixtures of several of these, may be included.

The compounds or pharmaceutical compositions of the present invention may be administered in other topical dosage forms including creams, powders, sprays and inhalants. The medicament may be mixed under sterile conditions with a pharmaceutically acceptable excipient, diluent or carrier, and any preservatives, buffers or propellants which may be required. Ophthalmic formulations, ophthalmic ointments, powders and solutions are also intended to be within the scope of the present invention.

The following examples are given by way of illustration of embodiments of the invention and are not to be construed as limiting the invention, and it will be understood by those skilled in the art that modifications may be made without departing from the spirit and scope of the invention. Unless otherwise specified, reagents and equipment used in the following examples are commercially available products.

Example 1: (8-fluoro-5, 6-dihydro-5-methyl-6-oxo-4H-imidazo [1, 5-a)][1,4]Benzodiazepines

Preparation of (E) -3-yl) methylnicotinate (FY0348)

(8-fluoro-5, 6-dihydro-5-methyl-6-oxo-4H-imidazo [1, 5-a)][1,4]Benzodiazepines

The synthetic route of the (3-yl) methylnicotinate is shown in the following reaction formula.

Step a: preparation of N- (5-fluoro-2-nitrobenzoyl) -N-methylglycine methyl ester

Weighing 5-fluoro-2-nitrobenzoic acid (20g, 108mmol), 1-ethyl- (3-dimethylaminopropyl) carbonyldiimine hydrochloride (EDCI, 25g, 130mmol) and 1-hydroxybenzotriazole (HOBT, 18g, 130mmol), placing in a reaction bottle (500ml), adding dichloromethane (200ml), stirring for dissolving, and activating at room temperature for 30 min; sarcosine methyl ester hydrochloride (15g, 108mmol) and triethylamine (22g, 216mmol) were separately weighed and dissolved in dichloromethane (200ml), and then the solution was sequentially added to a reaction flask and reacted at room temperature for 12 hours. The sample was subjected to TLC to detect the reaction, and the starting material spot was completely disappeared to terminate the reaction. Quenching the reaction solution with water/dichloromethane (V: V ═ 1:1, 200ml × 2), combining the organic phases, drying over anhydrous sodium sulfate, and concentrating under reduced pressure to obtain a brown yellow oil a; performing column chromatography on the a, and taking dichloromethane-ethyl acetate-8: 1(V: V) as an eluent to obtain a light yellow oily substance b; dissolving the oily matter b in an ethyl acetate/petroleum ether mixed solution, carrying out ultrasonic treatment for 30min, separating out a large amount of solid, and carrying out suction filtration to obtain about 22g of light yellow solid, wherein the yield is as follows: 76 percent.¹H NMR (400MHz, DMSO-d6) delta 8.34(m,1H, ArH),7.59(m,1H, ArH),7.40 and 7.24(br,1H, ArH),4.31 and 4.10(br,2H, CH₂) 3.72 and 3.64(br,3H, CH)₃) 3.04 and 2.89(br,3H, CH)₃) HRMS (ESI, m/z) calculated value C₁₁H₁₁FN₂O₅[(M+H)⁺]271.06; experimental value 271.06.

Step b: 7-fluoro-3, 4-dihydro-4-methyl-1H- [1, 4%]Benzodiazepines

Preparation of (E) -2, 5-diketones

Weighing 10g (37mmol) of N- (5-fluoro-2-nitrobenzoyl) -N-methylglycine methyl ester and 1.5g (15% × g) of Raney nickel, putting into a 500ml high-pressure reaction kettle, adding 300ml of methanol for dissolving, and introducing H₂And reacting at 120 ℃ for 8h under the environment of 5atm pressure. Sampling TLC detection, and completely disappearing the raw material point. Taking out the reaction solution, heating at 60 ℃ for 30min to dissolve precipitated solid, removing Raney nickel by suction filtration, concentrating partial solvent in mother liquor under reduced pressure, performing ultrasonic treatment for 30min to precipitate white solid, and performing suction filtration to obtain about 6.7g of white solid, wherein the yield is as follows: 87 percent.¹H NMR(400MHz,DMSO-d6)δ(ppm):10.45(s,1H,NH),7.44(dd,J＝9.3,3.1Hz,1H,ArH),7.37(ddd,J＝8.8,8.0,3.1Hz,1H,ArH),7.10(dd,J＝8.9,4.9Hz,1H,ArH),3.84(s,2H,CH₂),3.08(s,3H,CH₃) HRMS (ESI, m/z) calculated value C₁₀H₉FN₂O₂[(M+H)+]209.08; experimental value 209.08.

Step c: step d: 8-fluoro-5, 6-dihydro-5-methyl-6-oxo-4H-imidazo [1, 5-alpha ]][1,4]Benzodiazepines

Preparation of ethyl (3-carboxylate)

2g (9.6mmol) of 7-fluoro-3, 4-dihydro-4-methyl-1H- [1,4]Benzodiazepines

The-2, 5-diketone is placed in a 150ml reaction flask, 2ml of N is added,n-dimethylformamide and 50ml of dichloromethane were stirred at 0 ℃ for 10min, 1.5g (11.5mmol) of oxalyl chloride were added dropwise and the mixture was refluxed at 50 ℃ for 3 h. The reaction mixture was concentrated under reduced pressure, and the concentrated solution was concentrated under reduced pressure with methylene chloride (10ml) several times to remove residual oxalyl chloride, and then dissolved in N, N-dimethylformamide for use.

4.7g (14.4mmol) of cesium carbonate was weighed into a 150ml reaction flask, 30ml of N, N-dimethylformamide was added thereto and stirred to dissolve, and 1.3g (11.5mmol) of ethyl isonitrile acetate was further added to the reaction flask. And (3) cooling the system to 0 ℃ by ice-water bath, dropwise adding the solution into a reaction bottle, and reacting for 4 hours by ice-water bath. The reaction solution was quenched with water/dichloromethane (30 ml. times.2), and the organic phases were combined and dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a brown oil. The oil was subjected to column chromatography, eluting with petroleum ether: the product was isolated in 610mg ethyl acetate as eluent, yield: 21 percent. 1H NMR (400MHz, chloroform-d) (ppm): δ 7.92(s,1H, CH),7.78(dd, J ═ 8.7,2.9Hz,1H, ArH),7.44(br,1H, ArH),7.36(br,1H, ArH),5.16(d,2H, CH), and so on₂),4.44(d,2H,CH₂),3.24(s,3H,CH₃),1.44(t,J＝7.1Hz,3H,CH₃) HRMS (ESI, m/z) calculated value C₁₅H₁₄FN₃O₃[(M+H)+]304.11; experimental value 304.11.

Step e: 8-fluoro-3-hydroxymethyl-5, 6-dihydro-5-methyl-6H-imidazo [1,5-a][1,4]Benzodiazepines

Preparation of (E) -6-ketones

3g (9.9mmol) of 8-fluoro-5, 6-dihydro-5-methyl-6-oxo-4H-imidazo [1, 5-alpha ] are weighed out][1,4]Benzodiazepines

Ethyl-3-carboxylate, 0.958g (25mmol) of sodium borohydride, 2.19g (19.8mmol) of calcium chloride were placed in a 250ml reaction flask, 40ml of anhydrous tetrahydrofuran and 40ml of methanol were added as a solvent, and the reaction was refluxed at 68 ℃ overnight. Sampling TLC detection, and completely disappearing the raw material point. AddingAdding 5ml saturated ammonium chloride, stirring at room temperature for 30min, adding 20ml methanol to dissolve the precipitated product, vacuum filtering, and removing insoluble solid. The mother liquor was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a white solid. The white solid was purified by column chromatography, dichloromethane: methanol 10: 1 is eluent, 2.2g of product is obtained, yield: 88 percent. 1H NMR (400MHz, DMSO-d6) Δ 8.12(s,1H, CH),7.68(dd, J ═ 8.8,4.6Hz,1H, Ar), 7.63-7.44 (m,2H, ArH, ArH),5.06 and 4.36(br,2H, CH, H)₂),4.47(d,J＝5.2Hz,2H,CH₂),3.04(s,3H,CH₃) HRMS (ESI, m/z) calculated value C₁₃H₁₂FN₃O₂[(M+H)⁺]262.09; experimental value 262.09.

Step f: (8-fluoro-5, 6-dihydro-5-methyl-6-oxo-4H-imidazo [1, 5-a)][1,4]Benzodiazepines

Preparation of (E) -3-yl) methylnicotinate (FY0348)

200mg (0.8mmol) of 8-fluoro-3-hydroxymethyl-5, 6-dihydro-5-methyl-6H-imidazo [1,5-a ] are weighed out][1,4]Benzodiazepines

-6-ketone was placed in a 50mL reaction flask, suspended in 20mL dichloromethane, and 202mg (2.0mmol) triethylamine was added; after stirring in an ice-water bath for 10min to lower the temperature of the system to 0 ℃, a solution of 214mg (1.2mmol) of nicotinoyl chloride hydrochloride in methylene chloride was added dropwise. After the reaction was over night, TCL was sampled to detect the reaction, and the reaction was terminated when the starting material spot was completely disappeared. The reaction was quenched with water/dichloromethane (20ml × 2), the organic phase was collected, extracted again with saturated sodium bicarbonate/dichloromethane (20ml × 2), dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a yellow oil. Dissolving the yellow oily substance in ethyl acetate/petroleum ether, performing ultrasonic treatment for 10min to precipitate a light yellow solid, performing suction filtration, and drying to obtain 220mg of the light yellow solid, wherein the yield is as follows: 86 percent.

1H NMR (400MHz, chloroform-d) delta (ppm)):9.24(s,1H,CH),8.77(d,J＝4.7Hz,1H,CH),8.32(d,J＝8.0Hz,1H,CH),7.89(s,1H,CH),7.76(dd,J＝8.8,2.8Hz,1H,ArH),7.39(m,2H,CH,ArH,),7.35–7.29(m,1H,ArH),5.45(br,2H,CH₂),4.54(d,J＝46.0Hz,2H,CH₂),3.25(s,3H,CH₃) HRMS (ESI, m/z) calculated value C₁₉H₁₅FN₄O₃[(M+H)+]367.12; experimental value 367.12.

Example 2: 8-fluoro-5, 6-dihydro-5-methyl-6-oxo-4H-imidazo [1,5-a][1,4]Benzodiazepines

Preparation of 3-methyl acetate (FY0226)

With reference to the preparation method and conditions of example 1, 8-fluoro-3-hydroxymethyl-5, 6-dihydro-5-methyl-6H-imidazo [1,5-a ]][1,4]Benzodiazepines

Esterification and condensation are carried out on-6-ketone and acetyl chloride which are used as raw materials to obtain 136mg of white solid, and the yield is as follows: 75 percent. 1H NMR (400MHz, chloroform-d) delta (ppm):7.88(s,1H, CH),7.73(dd, J ═ 8.8,2.9Hz,1H, ArH),7.38(s,1H, ArH), 7.35-7.28 (m,1H, ArH),5.14(s,2H, CH), and so on₂),4.44(s,2H,CH₂),3.20(s,3H.CH₃),2.07(s,3H,CH₃) HRMS (ESI, m/z) calculated value C₁₅H₁₄FN₃O₃[(M+H)+]304.10; experimental value 304.10.

Example 3: preparation of methyl 8-fluoro-5, 6-dihydro-5-methyl-6-oxo-4H-imidazo [1,5-a ] [1,4] benzodiazepine-3-cyclopropanecarboxylate (FY0230)

With reference to the preparation method and conditions of example 1, 8-fluoro-3-hydroxymethyl-5, 6-dihydro-5-methyl-6H-imidazo [1,5-a ]][1,4]Benzodiazepines

Esterification condensation is carried out on the-6-ketone and the cyclopropane formyl chloride which are used as raw materials to obtain about 115g of white solid with the yield of 35 percent. 1H NMR (400MHz, chloroform-d) delta (ppm) 7.87(s,1H, CH),7.74(dd, J ═ 8.9,2.7Hz,1H, ArH),7.38(dd, J ═ 8.5,4.7Hz,1H, ArH),7.35-7.27(m,1H, ArH),5.17(d,2H, CH, H₂),4.43(d,2H,CH₂),3.20(s,3H,CH₃),1.65(dt,J＝7.9,3.5Hz,1H,CH),1.05–0.95(m,2H,CH₂),0.87(dd,J＝7.5,3.3Hz,2H,CH₂) HRMS (ESI, m/z) calculated value C₁₇H₁₆FN₃O₃[(M+H)+]330.13; experimental value 330.13.

Example 4: 8-fluoro-5, 6-dihydro-5-methyl-6-oxo-4H-imidazo [1,5-a][1,4]Benzodiazepines

Preparation of methyl (3-cyclobutanecarboxylate) (FY0232)

With reference to the preparation method and conditions of example 1, 8-fluoro-3-hydroxymethyl-5, 6-dihydro-5-methyl-6H-imidazo [1,5-a ]][1,4]Benzodiazepines

Esterification and condensation are carried out on-6-ketone and cyclobutylformyl chloride which are used as raw materials to obtain 80mg of white solid, and the yield is as follows: 29 percent. 1H NMR (400MHz, chloroform-d) delta (ppm) 7.87(s,1H, CH),7.73(dd, J ═ 8.8,2.9Hz,1H, ArH),7.38(dd, J ═ 8.8,4.6Hz,1H, ArH),7.34-7.27(m,1H, ArH),5.15(d,2H, CH, ppm)₂),4.44(d,2H,CH₂),3.21(s,3H,CH₃),3.18–3.11(m,1H,CH),2.23(ddd,J＝31.7,12.3,8.7Hz,4H,CH₂,CH₂),2.00–1.83(m,2H,CH₂) HRMS (ESI, m/z) calculated value C₁₈H₁₈FN₃O₃[(M+H)+]344.15; experimental value 344.15.

Example 5: 8-fluoro-5, 6-dihydro-5-methyl-6-oxo-4H-imidazo [1,5-a][1,4]Benzodiazepines

Synthesis of (FY0305) methyl cyclohexanecarboxylate

With reference to the preparation method and conditions of example 1, 8-fluoro-3-hydroxymethyl-5, 6-dihydro-5-methyl-6H-imidazo [1,5-a ]][1,4]Benzodiazepines

Esterification condensation is carried out on-6-ketone and cyclohexyl formyl chloride which are used as raw materials to obtain about 120mg of white solid, and the yield is as follows: 41 percent. 1H NMR (400MHz, chloroform-d) delta (ppm) 7.88(s,1H, CH),7.73(dd, J ═ 8.5,2.4Hz,1H, ArH),7.38(dd, J ═ 8.8,4.6Hz,1H, ArH),7.31(td, J ═ 9.7,8.5,2.8Hz,1H, ArH),5.14(d,2H, CH, H, and H, respectively)₂),4.44(d,,2H,CH₂),3.21(s,3H,CH₃),2.32(ddd,J＝14.7,11.3,3.5Hz,1H,CH),1.88(d,J＝13.6Hz,2H,CH₂),1.72(d,J＝11.8Hz,2H,CH₂),1.62(d,J＝5.6Hz,1HCH₂-H),1.48–1.35(m,2H,CH₂),1.21(q,J＝12.4Hz,3H,CH₂,CH₂H) calculation of HRMS (ESI, m/z) C₂₀H₂₂FN₃O₃[(M+H)+]372.12; experimental value 372.12.

Example 6: preparation of methyl 8-fluoro-5, 6-dihydro-5-methyl-6-oxo-4H-imidazo [1,5-a ] [1,4] benzodiazepine-3-tetrahydro-2H-pyran-4-carboxylate (FY0306)

With reference to the preparation method and conditions of example 1, 8-fluoro-3-hydroxymethyl-5, 6-dihydro-5-methyl-6H-imidazo [1,5-a ]][1,4]Benzodiazepines

Esterification condensation is carried out on the raw materials of-6-ketone and tetrahydropyran-4-formyl chloride to obtain white solid of about 100mg,yield: 34 percent. 1H NMR (400MHz, chloroform-d) delta (ppm): 7.93(s,1H, CH),7.75(dd, J ═ 8.8,2.9Hz,1H, ArH),7.40(dd, J ═ 8.8,4.6Hz,1H, ArH),7.35-7.29(m,1H, ArH),5.18(d,2H),4.45(d,2H),3.94(dt, J ═ 11.5,3.7Hz,2H, CH, and so on)₂),3.39(td,J＝11.4,2.7Hz,2H,CH₂),3.22(s,3H,CH₃),2.57(ddd,J＝11.0,6.7,4.3Hz,1H,CH),1.87-1.73(m,4H,CH₂,CH₂) HRMS (ESI, m/z) calculated value C₁₉H₂₀FN₃O₄[(M+H)+]374.15; experimental value 374.15.

Example 7: 8-fluoro-5, 6-dihydro-5-methyl-6-oxo-4H-imidazo [1,5-a][1,4]Benzodiazepines

Preparation of methyl (FY0308) 3-cyclopentanecarboxylate

With reference to the preparation method and conditions of example 1, 8-fluoro-3-hydroxymethyl-5, 6-dihydro-5-methyl-6H-imidazo [1,5-a ]][1,4]Benzodiazepines

Esterification condensation is carried out on-6-ketone and cyclopentyl formyl chloride which are used as raw materials to obtain white solid of about 150mg, and the yield is as follows: 53 percent. 1H NMR (400MHz, chloroform-d) δ (ppm)7.91(s,1H, CH),7.74(dd, J ═ 8.8,2.9Hz,1H, ArH),7.39(dd, J ═ 8.8,4.6Hz,1H, ArH),7.32(ddd, J ═ 8.8,7.2,2.9Hz,1H, ArH),5.16(d,2H, CH), c, d, c, H₂),4.45(d,2H,CH₂),3.21(s,3H,CH₃),2.81–2.70(m,1H,CH),1.93–1.84(m,2H,CH₂),1.82-1.73(m,2H,CH₂),1.68(dd,J＝7.0,3.5Hz,2H,CH₂),1.56(dd,J＝7.1,4.6Hz,2H,CH₂) HRMS (ESI, m/z) calculated value C₁₉H₂₀FN₃O₃[(M+H)+]358.16; experimental value 358.16.

Example 8: 8-fluoro-5, 6-dihydro-5-methyl-6-oxo-4H-imidazo [1,5-a][1,4]Benzodiazepines

Preparation of methyl (3-phenyl) formate (FY0313)

With reference to the preparation method and conditions of example 1, 8-fluoro-3-hydroxymethyl-5, 6-dihydro-5-methyl-6H-imidazo [1,5-a ]][1,4]Benzodiazepines

Esterification condensation is carried out on-6-ketone and benzoyl chloride as raw materials to obtain light yellow solid 200mg, and the yield is as follows: 68 percent. 1H NMR (400MHz, chloroform-d) delta (ppm): 8.04(dd, J ═ 8.3,1.2Hz,2H, ArH),7.90(s,1H, CH),7.73(dd, J ═ 8.8,2.9Hz,1H, ArH), 7.58-7.49 (m,1H, ArH), 7.45-7.35 (m,3H, ArH), 7.33-7.28 (m,1HArH),5.42(d,2H, CH, H₂),4.51(d,2H,CH₂),3.21(s,3H,CH₃) HRMS (ESI, m/z) calculated value C₂₀H₁₆FN₃O₃[(M+H)+]366.11; experimental value 366.11.

Example 9: 8-fluoro-5, 6-dihydro-5-methyl-6-oxo-4H-imidazo [1,5-a][1,4]Benzodiazepines

Preparation of methyl-3-hexanoate (FY0319)

With reference to the preparation method and conditions of example 1, 8-fluoro-3-hydroxymethyl-5, 6-dihydro-5-methyl-6H-imidazo [1,5-a ]][1,4]Benzodiazepines

Esterification condensation is carried out on the-6-ketone and the caproyl chloride which are used as raw materials to obtain white solid of about 140mg with the yield of 49 percent. 1H NMR (400MHz, DMSO-d6) delta (ppm): 8.25(s,1H, CH),7.75(dd, J ═ 8.9,5.1Hz,1H, ArH), 7.67-7.57 (m,2H, ArH),5.10(dr,2H, CH), and so on₂),4.51(d,2H,CH₂),3.08(s,3H,CH₃),2.30(t,J＝7.4Hz,2H,CH₂),1.57–1.43(m,2H,CH₂),1.27–1.18(m,4H,CH₂,CH₂),0.86–0.78(m,3H,CH₃) HRMS (ESI, m/z) calculated value C₂₀H₁₆FN₃O₃[(M+H)+]360.17; experimental value 360.17.

Example 10: (8-fluoro-5, 6-dihydro-5-methyl-6-oxo-4H-imidazo [1, 5-a)][1,4]Benzodiazepines

Preparation of (E) -3-yl) methyl, malonic ester (FY0324)

With reference to the preparation method and conditions of example 1, 8-fluoro-3-hydroxymethyl-5, 6-dihydro-5-methyl-6H-imidazo [1,5-a ]][1,4]Benzodiazepines

Carrying out esterification condensation on-6-ketone and malonyl chloride serving as raw materials to obtain 150mg of white solid, wherein the yield is as follows: 52 percent. 1H NMR (400MHz, chloroform-d) delta (ppm):7.89(s,1H, CH),7.68(dd, J ═ 8.6,2.8Hz,1H, ArH),7.36(dd, J ═ 8.7,4.5Hz,1H, ArH),7.28(t, J ═ 8.0Hz,1H, ArH),5.21(s,2H, CH, ar ═ H), and pharmaceutically acceptable salts thereof₂),4.57(s,2H,CH₂),4.40(d,2H,CH₂),3.16(s,3H,CH₃),2.10(s,3H,CH₃) HRMS (ESI, m/z) calculated value C₁₇H₁₆FN₃O₅[(M+H)+]362.09; experimental value 362.09.

Example 11: 8-fluoro-5, 6-dihydro-5-methyl-6-oxo-4H-imidazo [1,5-a][1,4]Benzodiazepines

Preparation of (3-4-methylpentanoate) (FY0332)

Reference example 1 preparation method and conditionsWith 8-fluoro-3-hydroxymethyl-5, 6-dihydro-5-methyl-6H-imidazo [1,5-a][1,4]Benzodiazepines

Esterification and condensation are carried out on the raw materials of-6-ketone and 4-methyl valeryl chloride to obtain 170mg of white solid with the yield of 60 percent. 1H NMR (400MHz, chloroform-d) delta (ppm) 8.02(s,1H, CH),7.75(dd, J ═ 8.8,2.9Hz,1H, ArH),7.42(dd, J ═ 8.9,4.6Hz,1H, ArH),7.36-7.29(m,1H, ArH),5.18(d,2H, CH, H₂),4.45(d,2H,CH₂),3.22(s,3H,CH₃),2.40-2.29(m,2H,CH₂),1.62-1.43(m,3H,CH₂,CH),0.87(d,J＝6.3Hz,6H,CH₃,CH₃) HRMS (ESI, m/z) calculated value C₁₉H₂₂FN₃O₃[(M+H)+]360.17; experimental value 360.17.

Example 12: 8-fluoro-5, 6-dihydro-5-methyl-6-oxo-4H-imidazo [1,5-a][1,4]Dinitrogen benzene

Preparation of methyl (3-3, 5-dimethylbenzoate) (FY0333)

With reference to the preparation method and conditions of example 1, 8-fluoro-3-hydroxymethyl-5, 6-dihydro-5-methyl-6H-imidazo [1,5-a ]][1,4]Benzodiazepines

Esterification and condensation are carried out on-6-ketone and 3, 5-dimethylbenzoyl chloride which are used as raw materials to obtain 220mg of white solid, and the yield is as follows: 70 percent. 1H NMR (400MHz, chloroform-d) delta (ppm) 8.13(s,1H, CH),7.77(dd, J ═ 8.8,2.9Hz,1H, ArH),7.69(s,2H, ArH),7.45(dd, J ═ 8.4,5.0Hz,1H, ArH), 7.37-7.33 (m,1H, ArH),7.20(s,1H, ArH),5.46(d,2H, CH, H)₂) 4.65 and 4.47(bs,2H, CH)₂),3.24(s,3H,CH₃),2.35(s,6H,CH₃,CH₃) HRMS (ESI, m/z) calculated value C₂₂H₂₀FN₃O₃[(M+H)+]394.13; experimental value 394.13.

Example 13: preparation of methyl 8-fluoro-5, 6-dihydro-5-methyl-6-oxo-4H-imidazo [1,5-a ] [1,4] benzodiazepine-3-3, 5-difluorobenzoate (FY0334)

With reference to the preparation method and conditions of example 1, 8-fluoro-3-hydroxymethyl-5, 6-dihydro-5-methyl-6H-imidazo [1,5-a ]][1,4]Benzodiazepines

Esterification and condensation are carried out on-6-ketone and 3, 5-difluorobenzoyl chloride which are used as raw materials to obtain 260mg, and the yield is as follows: 81 percent. 1H NMR (400MHz, chloroform-d) delta (ppm) 8.03(s,1H, CH),7.76(dd, J ═ 8.8,2.9Hz,1H, ArH), 7.65-7.50 (m,2H, ArH),7.43(dd, J ═ 8.8,4.6Hz,1H, ArH),7.38-7.31(m,1H, ArH),7.05-6.96(m,1H, ArH),5.45(d,2H, CH-d)₂),4.52(d,2H,CH₂),3.24(s,3H,CH₃) HRMS (ESI, m/z) calculated value C₂₀H₁₄F3N₃O₃[(M+H)+]402.11; experimental value 402.11.

Example 14: 8-fluoro-5, 6-dihydro-5-methyl-6-oxo-4H-imidazo [1,5-a][1,4]Benzodiazepines

Preparation of methyl (E) -3- (4-chlorophenoxy) acetate (FY0335)

With reference to the preparation method and conditions of example 1, 8-fluoro-3-hydroxymethyl-5, 6-dihydro-5-methyl-6H-imidazo [1,5-a ]][1,4]Benzodiazepines

Esterification and condensation are carried out on-6-ketone and (4-chlorophenoxy) acetyl chloride as raw materials to obtain 220mg of white solid, and the yield is as follows: and 64 percent. 1H NMR (400MHz, chloroform-d) delta (ppm) 7.95(s,1H, CH),7.75(dd, J-8.8, 2.9Hz,1H, ArH),7.40(dd, J-8.8, 4.6Hz,1H, ArH),7.34(dd, J-7.1, 2.9 Hz),1H,ArH),7.24-7.15(m,2H,ArH),6.81(s,2H,ArH),5.30(d,2H,CH₂),4.63(s,2H,CH₂),4.43(d,J＝27.1Hz,2H,CH₂),3.18(s,3H,CH₃) HRMS (ESI, m/z) calculated value C₂₁H₁₇ClFN₃O₄[(M+H)+]430.10; experimental value 430.10.

Example 15: 8-fluoro-5, 6-dihydro-5-methyl-6-oxo-4H-imidazo [1,5-a][1,4]Benzodiazepines

Preparation of-3-Methylmethylsuccinate (FY0336)

With reference to the preparation method and conditions of example 1, 8-fluoro-3-hydroxymethyl-5, 6-dihydro-5-methyl-6H-imidazo [1,5-a ]][1,4]Benzodiazepines

Esterification condensation is carried out on-6-ketone and 3-methoxycarbonyl propionyl chloride which are taken as raw materials to obtain 180mg of white solid, and the yield is as follows: 60 percent. 1H NMR (400MHz, chloroform-d) delta (ppm) 7.82(s,1H, CH),7.67(dd, J ═ 8.8,2.8Hz,1H, ArH),7.33(dd, J ═ 8.7,4.5Hz,1H, ArH),7.26(dd, J ═ 7.0,2.5Hz,1H, ArH),5.13(s,2H, CH, H₂),4.37(d,2H,CH₂),3.60(s,3H,CH₃),3.14(s,3H,CH₃),2.58(t,J＝5.7Hz,4H,CH₂,CH₂) HRMS (ESI, m/z) calculated value C₁₈H₁₈FN₃O₅[(M+H)+]376.12; experimental value 376.12.

Example 16: 8-fluoro-5, 6-dihydro-5-methyl-6-oxo-4H-imidazo [1,5-a][1,4]Benzodiazepines

Preparation of methyl (3-3-phenylpropionate) (FY0339)

With reference to the preparation method and conditions of example 1, 8-fluoro-3-hydroxymethyl-5, 6-dihydro-5-methyl-6H-imidazo [1,5-a ]][1,4]Benzodiazepines

Esterification condensation is carried out on-6-ketone and hydrocinnamoyl chloride which are used as raw materials to obtain 100mg, and the yield is as follows: 32 percent. 1H NMR (400MHz, chloroform-d) δ (ppm) 7.82(s,1H, CH),7.68(dd, J ═ 8.8,2.8Hz,1H, ArH),7.31(d, J ═ 4.5Hz,1H, ArH),7.26(dd, J ═ 7.1,2.8Hz,1H, ArH),7.19-7.13(m,2H, ArH),7.09(t, J ═ 7.3Hz,3H, ArH),5.10(s,2H, CH, δ (ppm), 1.2H NMR (H), c, H, c₂),4.30(d,2H,CH₂),3.08(s,3H,CH₃),2.87(t,J＝7.7Hz,2H,CH₂),2.60(t,J＝7.7Hz,2H,CH₂) HRMS (ESI, m/z) calculated value C₂₂H₂₀FN₃O₃[(M+H)+]394.14; experimental value 394.14.

Example 17: 8-fluoro-5, 6-dihydro-5-methyl-6-oxo-4H-imidazo [1,5-a][1,4]Benzodiazepines

Preparation of methyl (3-3, 3-dimethylbutyrate) (FY0340)

With reference to the preparation method and conditions of example 1, 8-fluoro-3-hydroxymethyl-5, 6-dihydro-5-methyl-6H-imidazo [1,5-a ]][1,4]Benzodiazepines

Esterification and condensation are carried out on the raw materials of-6-ketone and 3, 3-dimethylbutyrylchloride to obtain white solid with the yield of 49 percent. 1H NMR (400MHz, chloroform-d) delta (ppm) 7.87(s,1H, CH),7.74(dd, J ═ 8.8,2.9Hz,1H, ArH),7.37(dd, J ═ 8.8,4.6Hz,1H, ArH),7.34-7.27(m,1H, ArH),5.14(d,2H, CH, H₂),4.44(br,2H,CH₂),3.22(s,3H,CH₃),2.22(s,2H,CH₂),0.99(s,9H,CH₃,CH₃,CH₃) HRMS (ESI, m/z) calculated value C₁₉H₂₂FN₃O₃[(M+H)+]360.16; experimental value 360.16.

Example 18: 8-fluoro-5, 6-dihydro-5-methyl-6-oxo-4H-imidazo [1,5-a][1,4]Benzodiazepines

Preparation of (E) -3-2-Chloropropionate (FY0341)

With reference to the preparation method and conditions of example 1, 8-fluoro-3-hydroxymethyl-5, 6-dihydro-5-methyl-6H-imidazo [1,5-a ]][1,4]Benzodiazepines

Esterification and condensation are carried out on the-6-ketone and the 2-chloropropionyl chloride which are taken as raw materials to obtain 150mg of white solid with the yield of 60 percent. 1H NMR (400MHz, chloroform-d) δ (ppm) 7.85(s,1H, CH),7.66(dd, J ═ 8.8,2.9Hz,1H, ArH),7.34(dd, J ═ 8.8,4.6Hz,1H, ArH),7.26(td, J ═ 8.9,8.3,3.1Hz,1H, ArH),5.19(d,2H, CH),7.66(dd, J ═ 8.8,2.9Hz,1H, ArH), and c, d, c, d₂),4.36(m,3H,CH₂,CH),3.15(s,3H,CH₃),1.61(d,J＝7.0Hz,3H,CH₃) HRMS (ESI, m/z) calculated value C₁₆H₁₅ClFN₃O₃[(M+H)+]352.07; experimental value 352.07.

Example 19: 8-fluoro-5, 6-dihydro-5-methyl-6-oxo-4H-imidazo [1,5-a][1,4]Benzodiazepines

Preparation of methyl (3-2-methylpentanoate) (FY0342)

With reference to the preparation method and conditions of example 1, 8-fluoro-3-hydroxymethyl-5, 6-dihydro-5-methyl-6H-imidazo [1,5-a ]][1,4]Benzodiazepines

Esterification condensation of-6-ketone and 2-methyl valeryl chloride as raw materials to obtain white solidBody 120mg, yield: 42 percent. 1H NMR (400MHz, chloroform-d) delta (ppm) 7.83(s,1H, CH),7.68(d, J ═ 8.8Hz,1H, ArH),7.35(dd, J ═ 8.8,4.6Hz,1H, ArH),7.31-7.23(m,1H, ArH),5.09(s,2H, CH) (ppm)₂),4.40(d,2H,CH₂),3.16(s,3H,CH₃),2.50-2.33(m,1H,CH),1.39-1.12(m,4H,CH₂,CH₂),1.07(d,J＝6.9Hz,3H,CH₃),0.81(t,J＝7.2Hz,3H,CH₃) HRMS (ESI, m/z) calculated value C₁₉H₂₂FN₃O₃[(M+H)+]360.16; experimental value 360.16.

Example 20: 8-fluoro-5, 6-dihydro-5-methyl-6-oxo-4H-imidazo [1,5-a][1,4]Benzodiazepines

Preparation of methyl (3-2- (((2S, 5S) -5-isopropyl-2-methylcyclohexyl) oxy) acetate (FY0343)

With reference to the preparation method and conditions of example 1, 8-fluoro-3-hydroxymethyl-5, 6-dihydro-5-methyl-6H-imidazo [1,5-a ]][1,4]Benzodiazepines

Esterification and condensation are carried out on the raw materials of-6-ketone and (-) -menthoxy acetyl chloride to obtain white solid 200mg with the yield of 56 percent. 1H NMR (400MHz, chloroform-d) delta (ppm) 7.88(d,1H, CH),7.79-7.72(m,1H, ArH),7.38(dd, J ═ 8.3,4.3Hz,1H, ArH),7.35-7.29(m,1H, ArH),5.24(s,2H, CH)₂),4.47(d,2H,CH₂),4.14(q,2H,CH₂),3.23(d,J＝1.9Hz,3H,CH₃),3.15(td,1H,CH),2.30-2.21(m,1H,CH),2.02(d,1H,CH),1.63(s,2H,CH₂),1.42-1.17(m,3H,CH₃),1.00-0.70(m,11H,CH,CH₂,CH₂,CH₃,CH₃) HRMS (ESI, m/z) calculated value C₂₅H₃₂FN₃O₄[(M+H)+]458.25; experimental value 458.25.

Example 21: 8-fluoro-5, 6-dihydro-5-methyl-6-oxo-4H-imidazo [1,5-a][1,4]Benzodiazepines

Preparation of methyl (3-2-chloro-4-fluorobenzoate) (FY0346)

With reference to the preparation method and conditions of example 1, 8-fluoro-3-hydroxymethyl-5, 6-dihydro-5-methyl-6H-imidazo [1,5-a ]][1,4]Benzodiazepines

Esterification and condensation are carried out on the raw materials of-6-ketone and 2-chloro-4-fluorobenzoyl chloride to obtain 290mg of white solid with the yield of 87%. 1H NMR (400MHz, chloroform-d) delta (ppm) 7.97(dd, J-8.8, 6.1Hz,1H, ArH),7.90(s,1H, CH),7.76(dd, J-8.8, 2.9Hz,1H, ArH),7.39(dd, J-8.8, 4.6Hz,1H, ArH),7.35-7.29(m,1H, ArH),7.19(dd, J-8.5, 2.5Hz,1H, ArH),7.02(ddd, J-8.8, 7.6,2.5Hz, 1H), 5.43(s,2H, CH, H₂),4.53(d,2H,CH₂),3.24(s,3H,CH₃) HRMS (ESI, m/z) calculated value C₂₀H₁₄ClF₂N₃O₃[(M+H)+]418.08; experimental value 418.08.

Example 22: 8-fluoro-5, 6-dihydro-5-methyl-6-oxo-4H-imidazo [1,5-a][1,4]Benzodiazepines

Preparation of methyl (3-2-chloronicotinate) (FY0349)

With reference to the preparation method and conditions of example 1, 8-fluoro-3-hydroxymethyl-5, 6-dihydro-5-methyl-6H-imidazo [1,5-a ]][1,4]Benzodiazepines

Esterification condensation is carried out on the-6-ketone and the 2-chloronicotinoyl chloride which are used as raw materials to obtain 210mg of white solid, and the yield is as follows: 75 percent. 1H NMR (400MHz, chloroform-d) delta (ppm):8.52(dd,J＝4.8,1.9Hz,1H,ArH),8.24(dd,J＝7.7,2.0Hz,1H,ArH),7.91(s,1H,CH),7.76(dd,J＝8.8,2.9Hz,1H,ArH),7.40(dd,J＝8.8,4.6Hz,1H,ArH),7.35–7.30(m,2H,ArH,,ArH),5.46(s,2H,CH₂),4.54(d,2H,CH₂),3.25(s,3H,CH₃) HRMS (ESI, m/z) calculated value C₁₉H₁₄ClFN₄O₃[(M+H)+]401.06; experimental value 401.06.

Example 23: 8-fluoro-5, 6-dihydro-5-methyl-6-oxo-4H-imidazo [1,5-a][1,4]Benzodiazepines

Preparation of methyl (3-4-methoxybenzoate) (FY0350)

With reference to the preparation method and conditions of example 1, 8-fluoro-3-hydroxymethyl-5, 6-dihydro-5-methyl-6H-imidazo [1,5-a ]][1,4]Benzodiazepines

Esterification and condensation are carried out on the-6-ketone and the p-methoxybenzoyl chloride which are used as raw materials to obtain 200mg of white solid with the yield of 63 percent. 1H NMR (400MHz, chloroform-d) δ (ppm):8.01(d, J ═ 8.9Hz,2H, ArH),7.92(s,1H, CH),7.75(dd, J ═ 8.8,2.9Hz,1H, ArH),7.39(dd, J ═ 8.7,4.6Hz,1H, ArH),7.36-7.29(m,1H, ArH),6.90(d, J ═ 8.9Hz,2H, ArH),5.40(br,2H, CH), 8.9 (c₂),4.53(d,2H,CH₂),3.85(s,3H,CH₃),3.22(s,3H,CH₃) HRMS (ESI, m/z) calculated value C₂₁H₁₈FN₃O₄[(M+H)+]396.14; experimental value 396.14.

Example 24: 8-fluoro-5, 6-dihydro-5-methyl-6-oxo-4H-imidazo [1,5-a][1,4]Benzodiazepines

Preparation of (E) -3-4-Bromobenzoic acid methyl ester (FY0402)

With reference to the preparation method and conditions of example 1, 8-fluoro-3-hydroxymethyl-5, 6-dihydro-5-methyl-6H-imidazo [1,5-a ]][1,4]Benzodiazepines

Esterification condensation is carried out on-6-ketone and 4-bromobenzoyl chloride as raw materials to obtain 210mg of white solid, and the yield is as follows: 68 percent. 1H NMR (400MHz, chloroform-d) δ (ppm) 7.96-7.85 (m,3H, CH, ArH),7.74(dd, J ═ 8.8,2.9Hz,1H, ArH),7.55(d, J ═ 8.6Hz,2H, ArH),7.39(dd, J ═ 8.8,4.6Hz,1H, ArH),7.31(td, J ═ 8.8,8.0,2.9Hz,1H, ArH),5.40(br,2H, CH, ppm), 7.96-7.85 (m,3H, CH, ArH, rh),7.74(dd, J ═ 8.8,4.6Hz,1H, ArH),7.31(₂),3.21(s,3H,CH₃) HRMS (ESI, m/z) calculated value C₂₀H₁₅BrFN₃O[(M+H)+]444.04; experimental value 444.04.

Example 25: 8-fluoro-5, 6-dihydro-5-methyl-6-oxo-4H-imidazo [1,5-a][1,4]Benzodiazepines

Preparation of (E) -3-pentanoic acid methyl ester (LZ-03)

With reference to the preparation method and conditions of example 1, 8-fluoro-3-hydroxymethyl-5, 6-dihydro-5-methyl-6H-imidazo [1,5-a ]][1,4]Benzodiazepines

Esterification condensation is carried out on-6-ketone and n-valeryl chloride which are used as raw materials to obtain 230mg of white solid, and the yield is as follows: 83 percent. 1H NMR (400MHz, chloroform-d) delta (ppm) 7.84(s,1H, CH),7.73(dd, J ═ 8.8,2.9Hz,1H, ArH),7.36(dd, J ═ 8.8,4.6Hz,1H, ArH),7.33-7.26(m,1H, ArH),5.15(br,2H, CH, H₂),4.43(d,2H,CH₂),3.20(s,3H,CH₃),2.38-2.27(m,2H,CH₂),1.65-1.52(m,2H,CH₂),1.34-1.21(m,2H,CH₂),0.87(t,J＝7.3Hz,3H,CH₃) HRMS (ESI, m/z) calculated value C₁₈H₂₀FN₃O₃[(M+H)+],346.16；Experimental value 346.16.

Example 26: 8-fluoro-5, 6-dihydro-5-methyl-6-oxo-4H-imidazo [1,5-a][1,4]Benzodiazepines

Preparation of methyl (LZ-04) 3-2, 2-dimethylbutyrate

With reference to the preparation method and conditions of example 1, 8-fluoro-3-hydroxymethyl-5, 6-dihydro-5-methyl-6H-imidazo [1,5-a ]][1,4]Benzodiazepines

Esterification and condensation are carried out on the raw materials of-6-ketone and 2, 2-dimethylbutyrylchloride to obtain 240mg of white solid with the yield of 84%. 1H NMR (400MHz, chloroform-d) delta (ppm) 7.89(s,1H, CH),7.76(dd, J ═ 8.8,2.9Hz,1H, ArH),7.40(dd, J ═ 8.8,4.6Hz,1H, ArH),7.33(dd, J ═ 7.2,2.9Hz,1H, ArH),5.16(br,2H, CH, H₂),4.47(d,2H,CH₂),3.23(s,3H,CH₃),1.56(d,J＝7.5Hz,2H,CH₂),1.15(s,6H,CH₃,CH₃),0.77(t,J＝7.5Hz,3H,CH₃) HRMS (ESI, m/z) calculated value C₁₉H₂₂FN₃O₃[(M+H)+]360.17; experimental value 360.17.

Example 27: 8-fluoro-5, 6-dihydro-5-methyl-6-oxo-4H-imidazo [1,5-a][1,4]Benzodiazepines

Preparation of methyl (3-2-naphthoate) (JB-02)

With reference to the preparation method and conditions of example 1, 8-fluoro-3-hydroxymethyl-5, 6-dihydro-5-methyl-6H-imidazo [1,5-a ]][1,4]Benzodiazepines

Esterification and condensation are carried out on-6-ketone and 1-naphthoyl chloride which are used as raw materials to obtain 250mg of white solid, and the yield is as follows: 75 percent. 1H NMR (400MHz, chloroform-d) δ (ppm) 8.93(dd, J ═ 8.7,1.1Hz,1H, ArH),8.25(dd, J ═ 7.3,1.3Hz,1H, ArH),8.05-7.98(m,1H, ArH),7.93-7.83(m,2H, ArH),7.74(dd, J ═ 8.8,2.9Hz,1H, ArH),7.60(ddd, J ═ 8.5,6.8,1.5Hz,1H, ArH),7.57-7.42(m,2H, ArH),7.38(dd, J ═ 8.9,4.6Hz,1H, ArH), 7.35-7.25 (m,1H, ArH, 51.51, CH(s), CH (CH, 51, and s) (m, H, and H) in a suitable solvent, and a suitable carrier for use in the₂),4.69–4.42(m,2H,CH₂),3.22(s,3H,CH₃) HRMS (ESI, m/z) calculated value C₂₄H₁₈FN₃O₃[(M+H)+]416.14; experimental value 416.14.

Example 28: 8-fluoro-5, 6-dihydro-5-methyl-6-oxo-4H-imidazo [1,5-a][1,4]Benzodiazepines

Preparation of methyl (3-2-acetoxy) acetate (FY0330)

With reference to the preparation method and conditions of example 1, 8-fluoro-3-hydroxymethyl-5, 6-dihydro-5-methyl-6H-imidazo [1,5-a ]][1,4]Benzodiazepines

Esterification and condensation are carried out on-6-ketone and acetoxyacetyl chloride which are used as raw materials to obtain 120mg of white solid, and the yield is as follows: 42 percent. 1H NMR (400MHz, chloroform-d) δ (ppm) 7.89(s,1H, CH),7.68(dd, J ═ 8.6,2.8Hz,1H, ArH),7.36(dd, J ═ 8.7,4.5Hz,1H, ArH),7.28(t, J ═ 8.0Hz,1H, ArH),5.21(s,2H, CH): 7.89 (dd, J ═ 8.0Hz,1H, ArH), and c₂),4.57(s,2H,CH₂),4.40(d,2H,CH₂),3.16(s,3H,CH₃),2.10(s,3HCH₃) HRMS (ESI, m/z) calculated value C₁₇H₁₆FN₃O₅[(M+H)+]362.10; experimental value 362.10.

Example 29: 8-fluoro-5, 6-dihydro-5-methyl-6-oxo-4H-imidazo [1,5-a][1,4]Benzodiazepines

Preparation of methyl (3-2-methylbutyrate) (FY0310)

With reference to the preparation method and conditions of example 1, 8-fluoro-3-hydroxymethyl-5, 6-dihydro-5-methyl-6H-imidazo [1,5-a ]][1,4]Benzodiazepines

Esterification and condensation are carried out on the raw materials of-6-ketone and 2-methylbutyryl chloride to obtain 80mg with the yield of 29 percent. 1HNMR (400MHz, chloroform-d) delta (ppm):7.98(s,1H, CH),7.74(dd, J ═ 8.8,2.9Hz,1H, ArH),7.41(dd, J ═ 8.8,4.6Hz,1H, ArH), 7.37-7.28 (m,1H, ArH),5.16(s,2H, CH, H₂),4.45(d,2H,CH₂),3.22(s,3H,CH₃),2.40(q,J＝6.9Hz,1H,CH),1.26(d,J＝14.7Hz,2H,CH₂),1.12(d,J＝7.0Hz,3H,CH₃),0.86(t,J＝7.4Hz,3H,CH₃) HRMS (ESI, m/z) calculated value C₁₈H₂₀FN₃O₃[(M+H)+]346.14; experimental value 346.14.

Example 30: 8-fluoro-5, 6-dihydro-5-methyl-6-oxo-4H-imidazo [1,5-a][1,4]Benzodiazepines

Preparation of methyl (3-3-methylbenzoate) (FY0423)

With reference to the preparation method and conditions of example 1, 8-fluoro-3-hydroxymethyl-5, 6-dihydro-5-methyl-6H-imidazo [1,5-a ]][1,4]Benzodiazepines

Esterification condensation is carried out on-6-ketone and m-methyl benzoyl chloride as raw materials to obtain white solid 200mg, and the yield is as follows: 66 percent. 1H NMR (400MHz, DMSO-d6) delta (ppm:8.24(s,1H, CH), 7.77-7.68 (m,3H, ArH,), 7.63-7.53(m,2H,ArH,,ArH,),7.42(d,J＝7.5Hz,1H,ArH,),7.36(t,J＝7.5Hz,1H,ArH,),5.33(s,2H,CH₂),4.54(d,2H,CH₂),3.06(s,3H,CH₃),2.32(s,3H,CH₃) HRMS (ESI, m/z) calculated value C₂₁H₁₈FN₃O₃[(M+H)+]380.14; experimental value 380.14.

Example 31: 8-fluoro-5, 6-dihydro-5-methyl-6-oxo-4H-imidazo [1,5-a][1,4]Benzodiazepines

Preparation of methyl (3-3-cyanobenzoate) (FY0424)

With reference to the preparation method and conditions of example 1, 8-fluoro-3-hydroxymethyl-5, 6-dihydro-5-methyl-6H-imidazo [1,5-a ]][1,4]Benzodiazepines

Esterification and condensation are carried out on the raw materials of-6-ketone and 3-cyanobenzoyl chloride to obtain 180mg of white solid with the yield of 67 percent. 1H NMR (400MHz, chloroform-d) δ (ppm) 8.34(t, J ═ 1.7Hz,1H, ArH), 8.29-8.24 (m,1H, ArH),7.98(s,1H, CH),7.82(dt, J ═ 7.7,1.4Hz,1H, ArH),7.75(dd, J ═ 8.8,2.9Hz,1H, ArH),7.56(t, J ═ 8.1Hz,1H, ArH),7.40(dd, J ═ 8.8,4.6Hz,1H, ArH),7.32(ddd, J ═ 8.8,7.1,2.9Hz,1H, ArH),5.45(br,2H, CH), 5.45(br,2H, CH, and H), and c₂),4.52(br,2H,CH₂),3.24(s,3H,CH₃) HRMS (ESI, m/z) calculated value C₂₁H₁₅FN₄O₃[(M+H)+]391.12; experimental value 391.12.

Example 32: 8-fluoro-5, 6-dihydro-5-methyl-6-oxo-4H-imidazo [1,5-a][1,4]Benzodiazepines

Preparation of (E) -3-methyl-1-acetylpiperidine-4-carboxylic acid methyl ester (FY0309)

With reference to the preparation method and conditions of example 1, 8-fluoro-3-hydroxymethyl-5, 6-dihydro-5-methyl-6H-imidazo [1,5-a ]][1,4]Benzodiazepines

Esterification condensation is carried out on the-6-ketone and the N-acetylpiperidine-4-acyl chloride which are used as raw materials to obtain a white solid of about 180mg with the yield of 45 percent. 1H NMR (400MHz, DMSO-d6) delta (ppm) 8.21(s,1H, CH),7.71(dd, J ═ 8.5,4.5Hz,1H, ArH), 7.62-7.52 (m,2H, ArH, ArH),5.08(br,2H, CH)₂),4.47(br,2H,CH₂) 4.15 and 3.69(br,2H, CH)₂),3.30(s,1H,CH),3.04(s,3H,CH₃),2.66–2.54(m,2H,CH₂),1.93(s,3H,CH₃),1.82–1.72(m,2H,CH₂),1.51–1.41(m,1H,CH₂-H),1.36–1.26(m,1H,CH₂H) calculation of HRMS (ESI, m/z) C₂₁H₂₃FN₄O₄[(M+H)+]415.182; experimental value 415.18.

Example 33: nerve cell proliferation inhibition assay

Human neuroblastoma cells (SH-SY5Y) have the advantages of low cell differentiation, rapid propagation, similar cell morphology, physiological and biochemical functions to normal nerve cells and the like, so SH-SY5YX cells have better characteristics on the inhibition of the cell proliferation of the GABAa antagonist. Based on the above, the inventors carried out activity tests on partial compounds of the present invention and flumazenil standards, respectively. The experimental method is as follows:

test cells: SH-SY 5Y; grouping experiments: staurosporine positive control (cell + media +10uM STSP), DMSO solvent control (cell + media + 0.5% DMSO), and media blank control; preparing a compound working solution: according to the requirements, test compounds are diluted into 10mM stock solution by cosolvent DMSO, diluted by 100% DMSO in a gradient manner, and diluted into 5X working solution by culture medium for standby. Cell culture and experimental methods: when the culture dish is 80-90% full of cells, 0.25% pancreatin is used for digesting the cells, then the cells are resuspended by using a new culture medium, and the cells are passaged according to a proper proportion. 1 day before the experiment, cells were seeded at 3000 cells/well into 96-well cellsPlates were seeded with 80uL of cell suspension per well and the plates were placed at 37 ℃ in 5% CO₂Incubate overnight. On the day of the experiment, 20uL of compound working solution with final concentration of 100uM, 50uM and 10uM was added to each well according to the experimental requirements, 2 multiple wells were set at each concentration, and 5% CO was added at 37 deg.C₂Incubate the incubator for 72 hours in the dark. After the incubation is finished, adding CCK8 into the cell plate according to 10 uL/hole, placing at 37℃,

5％CO₂Incubate in the incubator for 4 hours. The absorbance at a wavelength of 450nm was measured on Envision, and the inhibition ratio was calculated. Value inhibition (%) - (ODs-OD)_NC)/(OD_STSP-OD_NC) X 100% of where, OD_SAbsorbance (test compound) for the sample well; OD_NCAs negative well absorbance (cell + medium + DMSO; OD_STSPAbsorbance values for STSP wells (cells + media +10uM STSP). The results are shown in Table 1.

SH-SY5Y cell proliferation inhibition assay results for compounds of Table 1

Example 34: test for antagonizing diazepam-induced mouse dyskinesia by compound

The test is divided into a blank control group (a solvent control group) and a pathological model group (a model blank group and a model test group), wherein the pathological model is constructed by giving 10mg/kg diazepam to a mouse in a subcutaneous injection mode (sc) and inducing the movement disorder of the mouse; flumazenil (10mg/kg) as a positive agent for an analeptic; the test samples were administered by intraperitoneal (ip) injection at a dose of 10mg/kg, and were observed for 15min, 30min, and 60min, and the mouse muscle tone values were recorded during the experiment to characterize the antagonism, and the data are listed in table 2 below.

Table 2 test results of antagonism of diazepam in mouse dyskinesia

Claims (8)

1. Benzodiazepines of formula (I)

Derivatives, enantiomers, diastereomers, racemates and mixtures thereof, and pharmaceutically acceptable salts, crystalline hydrates and solvates thereof,

wherein, R is unsubstituted C6, C7, C8, C9, C10, C10, C11, C12 aryl, C12 containing 1,2 or 3 substituents, C12, C6, C7, C8, C9 cycloalkyl, unsubstituted C9, C9 alkoxy, C9, 7-membered, 8-membered, 9-membered, 10-membered, 11-membered, 12-membered heteroaryl, 6-membered, 7-membered, 8-membered, 9-membered, 10-membered, 11-membered, 12-membered heteroaryl containing 1,2, or 3 substituents and containing 1,2, or 3 heteroatoms selected from N, O and S, unsubstituted 5-membered, 6-membered, 7-membered, 8-membered, 9-membered, 10-membered, 11-membered, 12-membered heterocyclyl containing 1,2, or 3 substituents and containing 1,2, or 3 heteroatoms selected from N, O and S, 5-membered, 6-membered, 7-membered, 8-membered, 9-membered, 10-membered, 11-membered, 12-membered heterocyclyl.

2. Benzodiazepines according to claim 1

Derivatives, enantiomers, diastereomers, racemates and mixtures thereof, and pharmaceutically acceptable salts, crystal hydrates and solvates thereof, wherein R is unsubstituted C, C aryl, C aryl having 1 to 3 substituents, unsubstituted C, C straight-chain or branched alkyl, C straight-chain or branched alkyl having 1,2 or 3 substituents, unsubstituted C-C cycloalkyl, C-C cycloalkyl having 1,2 or 3 substituents, unsubstituted C, C alkoxy, C, C10 alkoxy, unsubstituted C1, C2, C3, C4, C5, C6, C7, C8, C9, C10 alkylcarbonyl, C1, C2, C3, C4, C5, C6, C7, C8, C9, C10 alkylcarbonyl containing 1,2 or 3 heteroatoms selected from N, O and SAn unsubstituted 6-, 7-, 8-, 9-, 10-membered heteroaryl group containing 1,2 or 3 substituents and containing 1,2 or 3 heteroatoms selected from N, O and S, an unsubstituted 5-, 6-, 7-, 8-, 9-, 10-membered heterocyclyl group containing 1,2 or 3 heteroatoms selected from N, O and S, a 5-, 6-, 7-, 8-, 9-, 10-membered heterocyclyl group containing 1,2 or 3 substituents and containing 1,2 or 3 heteroatoms selected from N, O and S.

3. Benzodiazepines according to claim 1

Derivatives, enantiomers, diastereomers, racemates and mixtures thereof, and pharmaceutically acceptable salts, crystal hydrates and solvates thereof, wherein R is unsubstituted C6, C7, C8, C9 aryl, C9 aryl containing 1 to 3 substituents, unsubstituted C9, C9 straight-chain or branched alkyl, C9 containing 1,2 or 3 substituents, C9 straight-chain or branched alkyl, unsubstituted C9, C9 cycloalkyl, C9 containing 1,2 or 3 substituents, C9 cycloalkyl, unsubstituted C9, C36, C1, C2, C3, C4, C5, C6 alkylcarbonyl with 2 or 3 substituents, unsubstituted 6-, 7-, 8-membered heteroaryl with 1,2 or 3 heteroatoms selected from N, O and S, 6-, 7-, 8-membered heteroaryl with 1,2 or 3 substituents and with 1,2 or 3 heteroatoms selected from N, O and S, unsubstituted 5-, 6-, 7-, 8-membered heterocyclyl with 1,2 or 3 heteroatoms selected from N, O and S, 5-, 6-, 7-, 8-membered heterocyclyl with 1,2 or 3 substituents and with 1,2 or 3 heteroatoms selected from N, O and S.

4. Benzodiazepines according to claim 1

Derivatives, enantiomers, diastereomers, racemates and mixtures thereof, and pharmaceutically acceptable salts, crystal hydrates and solvates thereof, wherein when R is C6, C7, C8, C9, C10, C10, C11, C12, C13, C14, C15, C16, C17, C18, C19, C20 aryl having 1 to 3 substituents, or C6, C7, C8, C9, C10 aryl having 1 to 3 substituents, each independently selected from C1, C2, C3 straight or branched chain alkyl, halogen, C1, C2, C3 alkoxy and cyano, wherein halogen is selected from F, Cl or Br;

further preferably, when R is C1, C2, C3, C4, C5, C6, C7, C8, C9, C10, C11, C12, C13, C14, C15, C16, C17, C18, C19, C20 straight or branched chain alkyl containing 1,2 or 3 substituents, C20, straight or branched chain alkyl or C20, C20 straight or branched chain alkyl containing 1,2 or 3 substituents, each independently selected from halogen, C20 alkoxy and Br 20, wherein the substituents are selected from halogen or Br 20;

further preferably, when R is C3, C4, C5, C6, C7, C8, C9, C10, C11, C12, C13, C14, C15, C16, C17, C18, C19, C20 cycloalkyl containing 1,2 or 3 substituents, C3, C4, C5, C6, C7, C8, C9, C10 cycloalkyl containing 1,2 or 3 substituents, or C3, C4, C5, C6 cycloalkyl containing 1,2 or 3 substituents, each of said substituents is independently selected from C1, C2, C3 straight or branched alkyl, halogen, C1, C2, C3 alkoxy and cyano, wherein halogen is selected from F, Cl or Br;

further preferably, when R is C, C alkoxy containing 1,2 or 3 substituents, C alkoxy containing 1,2 or 3 substituents or C, C alkoxy containing 1,2 or 3 substituents, each of the substituents is independently selected from C, C straight or branched alkyl, C alkylcarbonyl, C cycloalkyl containing 1,2 or 3C, C straight or branched alkyl groups, halogen substituted C, C aryl groups, wherein halogen is selected from or Br;

further preferably, when R is C1, C2, C3, C4, C5, C6, C7, C8, C9, C10, C11, C12, C13, C14, C15, C16 alkylcarbonyl containing 1,2 or 3 substituents, C16 alkylcarbonyl containing 1,2 or 3 substituents, each of said substituents is independently selected from C16, C16 or C16 branched alkyl group containing 1,2 or 3 substituents, C16 alkyl alkoxy group;

further preferably, when R is a 6-, 7-, 8-, 9-, 10-, 11-, 12-membered heteroaryl group containing 1,2 or 3 substituents and containing 1,2 or 3 heteroatoms selected from N, O and S, a 6-, 7-, 8-, 9-, 10-, 11-, 12-membered heteroaryl group containing 1,2 or 3 substituents and containing 1,2 or 3 heteroatoms selected from N, O and S, or a 6-, 7-, 8-, 9-, 10-membered heteroaryl group containing 1,2 or 3 substituents and containing 1,2 or 3 heteroatoms selected from N, O and S, each of said substituents is independently selected from C1, C2, C3 straight or branched chain alkyl, halogen, C1, C2, C3 alkoxy and cyano, wherein halogen is selected from F, Cl or Br;

further preferably, when R is a 5-, 6-, 7-, 8-, 9-, 10-, 11-, 12-membered heterocyclic group containing 1,2 or 3 substituents and containing 1,2 or 3 heteroatoms selected from N, O and S, a 5-, 6-, 7-, 8-, 9-, 10-, 11-, 12-membered heterocyclic group containing 1,2 or 3 substituents and containing 1,2 or 3 heteroatoms selected from N, O and S, or a 5-, 6-, 7-, 8-membered heterocyclic group containing 1,2 or 3 substituents and containing 1,2 or 3 heteroatoms selected from N, O and S, each of said substituents is independently selected from C1, C2, C3 straight or branched chain alkyl, halogen, C1, C2, C3 alkylcarbonyl and cyano, wherein halogen is selected from F, Cl or Br.

5. Benzodiazepines according to claim 1

Derivatives, enantiomers, diastereomers, racemates and mixtures thereof, as well as pharmaceutically acceptable salts, crystalline hydrates and solvates thereof, characterized in that said derivatives are selected from the group consisting of:

6. benzodiazepines according to any one of claims 1 to 5

A process for the synthesis of derivatives, their enantiomers, diastereomers, racemates and mixtures thereof, as well as pharmaceutically acceptable salts, crystalline hydrates and solvates thereof, according to the following reaction scheme:

1) carrying out condensation reaction on 5-fluoro-2-nitrobenzoic acid and creatine methyl ester under the catalysis of 1-ethyl- (3-dimethylaminopropyl) carbonyl diimine hydrochloride and 1-hydroxybenzotriazole to obtain N- (5-fluoro-2-nitrobenzoyl) -N-methylglycine methyl ester;

2) n- (5-fluoro-2-nitrobenzoyl) -N-methyl glycine methyl ester reduces nitro under the catalysis of palladium carbon or Raney nickel, and 7-fluoro-3, 4-dihydro-4-methyl-1H- [1, 4-cyclization is simultaneously obtained]Benzodiazepines

-2, 5-diketones;

3) 7-fluoro-3, 4-dihydro-4-methyl-1H- [1, 4%]Benzodiazepines

The (E) -2, 5-diketone is chlorinated by a chlorinating agent and then reacts with ethyl isonitrile acetate under the alkaline condition to obtain 8-fluoro-5, 6-dihydro-5-methyl-6-oxo-4H-imidazo [1, 5-alpha ]][1,4]Benzodiazepines

-3-carboxylic acid ethyl ester;

4) 8-fluoro-5, 6-dihydro-5-methyl-6-oxo-4H-imidazo [1, 5-alpha ]][1,4]Benzodiazepines

Reduction of the ester group of ethyl-3-carboxylate by sodium borohydride/Lewis acid gives 8-fluoro-3-hydroxymethyl-5, 6-dihydro-5-methyl-6H-imidazo [1,5-a][1,4]Benzodiazepines

-6-ketones;

5) 8-fluoro-3-hydroxymethyl-5, 6-dihydro-5-methyl-6H-imidazo [1,5-a][1,4]Benzodiazepines

Reacting the (6-keto) with a corresponding acid or an acid chloride to form an ester, thereby obtaining the benzodiazepine represented by the formula (I)

And (3) derivatives.

7. A pharmaceutical composition comprising a therapeutically effective amount of a benzodiazepine according to any one of claims 1 to 5

Derivatives, enantiomers, diastereomers, racemates thereof and mixtures thereof, and one or more of pharmaceutically acceptable salts, crystalline hydrates and solvates thereof, and at least one excipient, diluent or carrier.

8. Benzodiazepines according to any one of claims 1 to 5

The use of derivatives, their enantiomers, diastereomers, racemates and mixtures thereof, as well as their pharmaceutically acceptable salts, crystalline hydrates and solvates and of a pharmaceutical composition according to claim 7 for the preparation of antidotes for GABAA receptor agonists, postanesthesia wake-up agents, antiepileptics, anti-alzheimer's disease agents, antidotes for alcoholism, or wake-up-promoting agents for the treatment of loss of consciousness due to unknown cause.