CN120817948A

CN120817948A - Imidazole fused ring compound, pharmaceutical composition, preparation method and application thereof

Info

Publication number: CN120817948A
Application number: CN202510446126.XA
Authority: CN
Inventors: 沈光远; 胡治隆; 杨方龙; 王思勤; 金磊
Original assignee: Changchun Genescience Pharmaceutical Co Ltd
Current assignee: Changchun Genescience Pharmaceutical Co Ltd
Priority date: 2024-04-12
Filing date: 2025-04-10
Publication date: 2025-10-21
Also published as: WO2025214437A1

Abstract

The invention relates to imidazole-containing condensed ring derivatives, a pharmaceutical composition thereof, a preparation method and application thereof. In particular, the present invention relates to compounds of general formula (I), wherein each substituent is as defined in the specification, processes for their preparation and pharmaceutical compositions containing them, and their use as NK-3 receptor antagonists in the treatment and/or prophylaxis of a wide range of diseases or conditions such as CNS and peripheral diseases.

Description

Imidazole condensed ring compound, pharmaceutical composition, preparation method and application thereof

The invention claims priority to the prior application of the patent application number 202410444043.2, named as imidazole condensed ring compound, pharmaceutical composition and preparation method and application thereof, which is submitted to the China national intellectual property office at the 12 th 04 th 2024, and the prior application of the patent application number 202510420941.9, named as imidazole condensed ring compound, pharmaceutical composition and preparation method and application thereof, which is submitted to the China national intellectual property office at the 03 th 2025. The entire contents of the above-mentioned prior application are incorporated by reference into the present invention.

Technical Field

The invention belongs to the field of medicines, and particularly relates to an imidazole condensed ring compound, a pharmaceutical composition containing the compound, and a preparation method and application thereof.

Background

Tachykinin receptors are targets of a family of structurally related peptides collectively termed "tachykinins" including Substance P (SP), neurokinin a (NKA), and neurokinin B (NKB). Tachykinins are synthesized in the Central Nervous System (CNS) and peripheral tissues, where they exert a variety of biological activities. Three tachykinin receptors are currently known and are designated neurokinin-1 (NK-1), neurokinin-2 (NK-2) and neurokinin-3 (NK-3) receptors. NK-1 receptors, NK-2 receptors, and NK-3 receptors have been identified in different species. NK-1 receptors and NK-2 receptors are expressed in a variety of peripheral tissues and NK-1 receptors are also expressed in the CNS, while NK-3 receptors are mainly expressed in the CNS.

NK-3 receptor is encoded by TACR gene and is involved in the regulation of hypothalamic-pituitary-gonadal axis. TACR3 knockout or mutant mice are all characterized by abnormal development of reproductive organs, low sex hormone level and severely reduced reproductive capacity. Carrying the TACR gene mutation results in abnormal gonadotrophin release in the patient, leading to sexual juvenility and infertility in the patient, and a significant portion of familial hypogonadism is due to the TACR gene mutation.

The Kisspeptin/neurokinin B/dynorphin (KNDy) neurons participate in the gonadotrophin releasing hormone (GnRH) signaling pathway, promote estrogen production through the GnRH neuron-pituitary-sexual organ pathway, and this signaling pathway is regulated by a negative feedback mechanism, thereby maintaining hormone levels in the body within a reasonable range. At the same time KNDy neurons are also associated with the thermoregulation signaling pathway, which regulates body temperature in a range by releasing NKB ligands, binding to NK-3 receptors on the median anterior nucleus, promoting perspiration and vasodilation by inhibiting trembling and vasoconstriction. Women in menopause, due to the reduced estrogen levels in the body, have a loss of negative feedback mechanisms, so that KNDy neurons are overactivated, release endogenous NKB ligands in large amounts, bind to NK-3 receptors on the metakaryotic anterior nucleus, cause sweating, vasodilation, and develop symptoms of hot flashes. Therefore, development of an antagonist against KNDy neurons and NK-3 receptor on the median anterior nucleus is expected to have positive therapeutic effects on symptoms such as hot flashes.

In the CNS, NK-3 receptors are expressed in areas including the medial prefrontal cortex, hippocampus, thalamus and amygdala. In addition, NK-3 receptors are expressed on dopaminergic neurons. Activation of the NK-3 receptor has been shown to modulate the release of dopamine, acetylcholine and serotonin, suggesting therapeutic utility for NK-3 receptor modulators for the treatment of a variety of disorders including psychotic disorders, anxiety, depression, schizophrenia, as well as obesity, pain or inflammation.

Although significant research has been conducted in this area, there is still a continuing need to develop more potent small molecule NK3R receptor antagonists, the present invention provides a novel structure of NK3R receptor antagonists and finds that compounds with such structures have good activity, which are effective in treating a range of CNS and peripheral diseases.

Disclosure of Invention

The invention provides a compound shown as a formula (I), a stereoisomer, a tautomer, a nitrogen oxide, a solvate, a polymorph, a metabolite, a pharmaceutically acceptable salt or a prodrug thereof:

wherein X is selected from O or CR ₁R₂;

R ₁、R₂, identical or different, are independently of one another selected from H, C _1-6 alkyl or halogenated C _1-6 alkyl;

Each R _a, which is the same or different, is independently selected from OH, CN, halogen, C _1-6 alkyl or halogenated C _1-6 alkyl;

r _b is selected from halogen;

m is selected from 0,1, 2, 3 or 4.

According to some embodiments, X is selected from O or CH ₂.

According to some embodiments, each R _a, the same or different, is independently selected from F, cl or Br.

According to some embodiments, R _b is selected from F, cl or Br.

According to some embodiments, m is selected from 1.

According to some embodiments, the compound of formula (I) is selected from the following structures:

Wherein X, R _a、R_b, m have the definitions as described herein.

X, R _a、R_b have the definitions as described herein.

According to some embodiments, the compound of formula (I) may be a specific compound shown in the following structure:

The invention also provides a pharmaceutical composition comprising one, two or more of the compounds represented by the above formula (I), stereoisomers, tautomers, nitrogen oxides, solvates, polymorphs, metabolites, pharmaceutically acceptable salts or prodrugs thereof.

According to some embodiments, the pharmaceutical composition may further optionally comprise at least one pharmaceutically acceptable excipient.

According to some embodiments, the pharmaceutical composition may optionally further comprise at least one additional active ingredient, in particular, the pharmaceutical composition may further comprise one or more active ingredients other than a compound as shown in formula (I), a stereoisomer, a tautomer, a nitroxide, a solvate, a polymorph, a pharmaceutically acceptable salt, a metabolite, a prodrug thereof.

In the pharmaceutical composition, the dosage of the compound shown as the formula (I), the stereoisomer, the tautomer, the nitrogen oxide, the solvate, the polymorph, the metabolite, the pharmaceutically acceptable salt or the prodrug can be a therapeutically effective amount.

According to the present invention, the pharmaceutical composition of the present invention may be formulated into a dosage form suitable for administration by methods known in the art.

The invention also provides the use of one, two or more of the compounds shown in the formula (I), stereoisomers, tautomers, nitrogen oxides, solvates, polymorphs, metabolites, pharmaceutically acceptable salts or prodrugs thereof or the pharmaceutical composition in preparing medicaments;

according to the invention, the medicament is an NK3 receptor antagonist.

According to the invention, the medicament is for the prevention and/or treatment of diseases mediated by NK3 receptors.

In some embodiments, the medicament may be used for the prevention and/or treatment of depression, anxiety, psychosis, schizophrenia, psychotic disorders, bipolar disorders, cognitive disorders, parkinson's disease, alzheimer's disease, attention Deficit Hyperactivity Disorder (ADHD), pain, convulsions, obesity, inflammatory disorders, emesis, preeclampsia, airway related disorders, reproductive disorders, contraception and sex hormone dependent disorders or gynecological disorders.

Such sex hormone dependent diseases include, but are not limited to, benign Prostatic Hyperplasia (BPH), prostatic hyperplasia, metastatic prostate cancer, testicular cancer, breast cancer, ovarian cancer, androgen dependent acne, male pattern baldness, endometriosis, adolescent abnormalities, uterine fibrosis, uterine fibroids, hormone dependent cancer, hyperandrogenism, hirsutism, maleation, polycystic ovary syndrome (PCOS), premenstrual dysphoric disorder (PMDD), HAIR-AN syndrome (hyperandrogenism, insulin resistance and acanthosis nigricans), ovarian follicular cell hyperplasia (HAIR-AN with yellow body follicular cell proliferation in the ovarian interstitium), other manifestations of elevated intra-ovarian androgen concentrations (e.g., follicular maturation arrest, occlusion, anovulation, dysmenorrhoea, dysfunctional uterine bleeding, infertility), androgen producing tumors (maleated ovarian tumor or adrenal tumor), menorrhoea.

The airway-related diseases include chronic obstructive pulmonary disease, asthma, airway hyperreactivity, bronchoconstriction, and cough.

In some embodiments, the medicament is for the treatment and/or prevention of a disorder associated with climacteric syndrome, said climacteric syndrome comprising symptoms such as hot flashes, sweating, palpitations, dizziness, and obesity.

In some embodiments, the medicament is for treating and/or preventing vasomotor symptoms.

In some embodiments, the vasomotor symptoms are selected from moderate and/or severe vasomotor symptoms.

In some embodiments, the vasomotor symptoms are associated with perimenopause, menopause, or postmenopause.

In some embodiments, the vasomotor symptoms are associated with treatment of breast cancer, ovariectomy, or treatment of inhibition of ovarian function.

In some embodiments, the vasomotor symptoms are vasomotor symptoms (breast cancer VMS) caused by a female breast cancer patient receiving supplemental endocrine therapy.

The present invention also provides a method for treating and/or preventing an NK3 receptor-mediated disorder or disease, comprising administering to a subject a therapeutically effective amount of one, two or more of a compound of formula (I), a stereoisomer, tautomer, nitroxide, solvate, polymorph, metabolite, pharmaceutically acceptable salt or prodrug thereof, or a pharmaceutical composition.

In some embodiments, the disorder or disease is depression, anxiety, psychosis, schizophrenia, psychotic disorders, bipolar disorders, cognitive disorders, parkinson's disease, alzheimer's disease, attention Deficit Hyperactivity Disorder (ADHD), pain, convulsions, obesity, inflammatory disorders, emesis, preeclampsia, airway related disorders, reproductive disorders, contraception, and sex hormone dependent disorders or gynecological disorders.

In some embodiments, the condition or disease is a disorder associated with climacteric syndrome, which includes symptoms such as hot flashes, sweating, palpitations, dizziness, and obesity.

In some embodiments, the disorder or disease is vasomotor symptoms.

Preferably, the subject is a warm-blooded animal, more preferably a human.

Advantageous effects

Through structural optimization, the novel compound (particularly compound 001) is creatively obtained, and has the advantages of good NK-3 receptor inhibition effect, obvious improvement of physicochemical property and pharmacokinetic property, obvious improvement of in-vivo efficacy and good safety.

Definition of terms

Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. All patents and publications referred to herein are incorporated by reference in their entirety.

The term "comprising" is an open-ended expression, i.e. including what is indicated by the invention, but not excluding other aspects.

The numerical ranges recited in the specification and claims are equivalent to at least each specific integer number recited therein unless otherwise stated. For example, a numerical range "1-6" corresponds to each of the integer numbers 1,2, 3, 4, 5, 6 in the numerical range "1-6". It will be understood that "plurality" as used herein in describing one or more substituents shall mean an integer of ≡2, such as 2, 3, 4, 5, 6, 7, 8, 9 or 10.

The term "halogen" or "halo" refers to fluorine (F), chlorine (Cl), bromine (Br) or iodine (I).

Unless otherwise indicated, the definition of a term herein applies equally to a group containing the term, e.g., the definition of alkyl applies to alkyl in alkoxy, alkylamino, dialkylamino, and the like.

In general, the term "substituted" means that one or more hydrogen atoms in a given structure are replaced with a specific substituent. Further, when the group is substituted with 1 or more of the substituents, the substituents are independent of each other, that is, the 1 or more substituents may be different from each other or the same. Unless otherwise indicated, a substituent group may be substituted at each substitutable position of the substituted group. When more than one position in a given formula can be substituted with one or more substituents selected from a particular group, then the substituents may be the same or different at each position. Wherein the substituents may be, but are not limited to, =o, =s, hydrogen, deuterium, cyano, nitro, amino, hydroxyl, mercapto, halogen, alkyl, haloalkyl, alkoxy, carboxyl, cycloalkyl, cycloalkyloxy, heterocyclyl, heterocyclylalkyl, aryl, arylalkyl, aryloxy, heteroaryl, heteroarylalkyl, heteroaryloxy, and the like.

In addition, unless explicitly stated otherwise, the description means ". As used in the present invention, independently selected" is to be construed broadly, to mean that each individual described is independent of the other, and may be independently selected from the same or different specific groups. In more detail, the description means "..independently selected" may mean that specific options expressed between the same symbols in different groups do not affect each other, or that specific options expressed between the same symbols in the same groups do not affect each other.

The term "optional" (or "optionally", "optionally") in the definition of the general formula of the present application means that the situation is substituted with 0, one or more substituents, e.g. "optionally substituted with one, two or more R" means that it may be unsubstituted (unsubstituted) or optionally substituted with one, two or more R.

In the various parts of the present specification, substituents of the presently disclosed compounds are disclosed in terms of the type or scope of groups. It is specifically noted that the present invention includes each individual subcombination of the individual members of these group classes and ranges. For example, the term "C _1-6 alkyl" particularly refers to independently disclosed C ₁ alkyl, C ₂ alkyl, C ₃ alkyl, C ₄ alkyl, C ₅ alkyl, or C ₆ alkyl.

The term "C _1-6 alkyl" denotes straight and branched alkyl groups having 1,2, 3, 4, 5 or 6 carbon atoms. Wherein the alkyl group may be optionally substituted with one or more substituents described herein. In some embodiments, the alkyl groups contain 1 to 6 carbon atoms, and in still other embodiments, the alkyl groups contain 1 to 3 carbon atoms. Examples of such alkyl groups include, but are not limited to, methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl, 2-methylbutyl, 1-ethylpropyl, 1, 2-dimethylpropyl, neopentyl, 1-dimethylpropyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 2-ethylbutyl, 1-ethylbutyl, 3-dimethylbutyl, 2-dimethylbutyl, 1-dimethylbutyl, 2, 3-dimethylbutyl, 1, 3-dimethylbutyl, or 1, 2-dimethylbutyl, and the like, or isomers thereof.

"Stereoisomers" refer to compounds having the same chemical structure but different arrangements of atoms or groups in space. Stereoisomers include enantiomers, diastereomers, conformational isomers (rotamers), geometric isomers (cis/trans), atropisomers, and the like.

"Enantiomer" refers to two isomers of a compound that do not overlap but are in mirror image relationship to each other.

"Diastereoisomers" refers to stereoisomers which have two or more chiral centers and whose molecules are not mirror images of each other. Diastereomers have different physical properties, such as melting point, boiling point, spectral properties, and reactivity. The diastereomeric mixture may be separated by high resolution analytical procedures such as electrophoresis and chromatography, e.g., HPLC.

Any asymmetric atom (e.g., carbon, etc.) of the disclosed compounds may exist in racemic or enantiomerically enriched form, such as in the (R) -, (S) -or (R, S) -configuration. In certain embodiments, each asymmetric atom has at least 0% enantiomeric excess, at least 60% enantiomeric excess, at least 70% enantiomeric excess, at least 80% enantiomeric excess, at least 90% enantiomeric excess, at least 95% enantiomeric excess, or at least 99% enantiomeric excess in the (R) -or (S) -configuration.

The resulting mixture of any stereoisomers may be separated into pure or substantially pure geometric isomers, enantiomers, diastereomers, e.g., by chromatography and/or fractional crystallization, depending on the differences in the physicochemical properties of the components.

The term "tautomer" refers to structural isomers having different energies that can be interconverted by a low energy barrier (low energy barrier). If tautomerism is possible (e.g., in solution), chemical equilibrium of the tautomers can be achieved. For example, proton tautomer (proton tautomer) (also known as proton transfer tautomer (prototro pictautomer)) includes interconversions by proton transfer, such as keto-enol isomerisation and imine-enamine isomerisation. Valence tautomers (valen cetautomer) include interconversions by recombination of some of the bond-forming electrons. Specific examples of keto-enol tautomerism are tautomerism of pentane-2, 4-dione and 4-hydroxypent-3-en-2-one tautomer. Another example of tautomerism is phenol-ketone tautomerism. One specific example of phenol-ketone tautomerism is the interconversion of pyridin-4-ol and pyridin-4 (1H) -one tautomers. Unless otherwise indicated, all tautomeric forms of the compounds of the invention are within the scope of the invention.

The term "pharmaceutically acceptable" refers to molecular entities and compositions that are physiologically tolerable and do not generally produce allergies or similar inappropriate reactions, such as gastrointestinal discomfort, dizziness, etc., when administered to humans.

The term "carrier" refers to a diluent, adjuvant, excipient, or matrix with which the compound is administered. These pharmaceutical carriers can be sterile liquids, such as water and oils, including those of petroleum, animal, vegetable or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil and the like. Water and aqueous solutions saline solutions and aqueous dextrose and glycerol solutions are preferably employed as carriers, particularly injectable solutions.

The term "prodrug" as used herein means a compound that is converted in vivo to a compound of formula (I). Such conversion is effected by hydrolysis of the prodrug in the blood or enzymatic conversion to the parent structure in the blood or tissue. The prodrug of the invention can be esters, and in the prior invention, the esters can be phenyl esters, aliphatic (C _1-24) esters, acyloxymethyl esters, carbonic esters, carbamates and amino acid esters as the prodrugs. For example, one compound of the invention may contain a hydroxyl group, i.e., it may be acylated to provide the compound in a prodrug form. Other prodrug forms include phosphates, such as those obtained by phosphorylation of a hydroxyl group on the parent.

The term "metabolite" as used herein refers to a product obtained by metabolizing a specific compound or salt thereof in vivo. The metabolites of a compound may be identified by techniques well known in the art and their activity may be characterized by employing the assay methods as described herein. Such products may be obtained by oxidation, reduction, hydrolysis, amidization, deamination, esterification, degreasing, enzymatic cleavage, etc. of the administered compound. Accordingly, the present invention includes metabolites of compounds, including metabolites produced by contacting a compound of the present invention with a mammal for a period of time sufficient.

In the present invention, reference to a compound also includes isotopically-labeled compounds, which are identical to those shown in formula I, but for the fact 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 naturally occurring. Examples of isotopes that can be incorporated into compounds of the invention include H, C, N, O, S, F and isotopes of Cl, such as ²H、³H、¹³C、¹¹C、¹⁴C、¹⁵N、¹⁸O、¹⁷O、³²P、³⁵S、¹⁸F and ³⁶ Cl, respectively. The compounds of the invention, prodrugs thereof, or pharmaceutically acceptable salts of the compounds or prodrugs, which contain the isotopes described above and/or other isotopes of other atoms, are within the scope of this invention. Certain isotopically-labeled compounds of the present invention, for example, compounds incorporating radioisotopes such as ³ H and ¹⁴ C, are useful in drug and/or substrate tissue distribution assays. Tritium (i.e., ³ H) and carbon 14 (i.e., ¹⁴ C) isotopes are particularly preferred for ease of preparation and detectability. Furthermore, substitution with heavier isotopes such as deuterium, i.e., ² H or D, may afford certain therapeutic advantages resulting from greater metabolic stability (e.g., increased in vivo half-life or reduced dosage requirements) and may therefore be preferred in certain circumstances. The compounds of the invention as claimed may be specifically limited to substitution with deuterium or tritium. Furthermore, the presence of hydrogen in a substituent is not listed solely by the term deuterium or tritium and is not meant to exclude deuterium or tritium, but may equally well comprise deuterium or tritium.

In the description of the present specification, a description referring to terms "one embodiment," "some embodiments," "examples," "specific examples," or "some examples," etc., means that a particular feature, structure, material, or characteristic described in connection with the embodiment or example is included in at least one embodiment or example of the present invention. In this specification, schematic representations of the above terms are not necessarily directed to the same embodiment or example. Furthermore, the particular features, structures, materials, or characteristics described may be combined in any suitable manner in any one or more embodiments or examples. Furthermore, the different embodiments or examples described in this specification and the features of the different embodiments or examples may be combined and combined by those skilled in the art without contradiction.

Detailed Description

The invention is further described below in connection with examples, which are not intended to limit the scope of the invention.

The structure of the compounds of the present invention is determined by Nuclear Magnetic Resonance (NMR) or/and liquid chromatography-mass spectrometry (LC-MS). NMR chemical shifts (δ) are given in parts per million (ppm). NMR was performed using BrukerAVANCE-400 nuclear magnetic resonance apparatus with deuterated dimethyl sulfoxide (DMSO-d ₆), deuterated methanol (CD ₃ OD) and deuterated chloroform (CDCl ₃) as the measurement solvents and Tetramethylsilane (TMS) as the internal standard.

The LC-MS was measured using an Agilent 1200INFINITYSERIES mass spectrometer. HPLC was performed using Agilent 1200DAD high pressure liquid chromatograph (Sunfire C18150X 4.6mm column) and Waters2695-2996 high pressure liquid chromatograph (GiminiC 18150X 4.6mm column).

The thin layer chromatography silica gel plate uses a smoke table 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. Column chromatography generally uses a tobacco stand yellow sea silica gel of 200-300 meshes 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 invention were carried out under continuous magnetic stirring under dry nitrogen or argon atmosphere, with the solvent being a dry solvent and the reaction temperature being in degrees celsius, without specific explanation.

Example 1

Preparation of (R) -1- (3- (3-chloro-1, 2, 4-thiadiazol-5-yl) -7- (4-fluorobenzoyl) -8-methyl-5, 6, 7-8-tetrahydroimidazo [1,5-a ] pyrazin-1-yl) pyrrolidin-2-one (001)

Preparation of first step (3-methylpyrazin-2-yl) methyl carbamic acid tert-butyl ester 001b

2-Bromo-3-methylpyrazine 001a (5 g,28.9 mmol) was dissolved in dry dioxane/water=10/1 (80 mL), and tert-butyl ((trifluoro-4-borane) methyl) carbamate potassium salt (8.26 g,34.68 mmol), pdCl ₂ (dppf) (211 mg,0.29 mmol) and cesium carbonate (18.83 g,57.8 mmol) were added. The reaction solution was stirred at 80 ℃ for 16 hours. After the completion of the reaction, the reaction mixture was concentrated. The resulting concentrate was purified by silica gel column chromatography (petroleum ether/ethyl acetate=3/1) to give tert-butyl (3-methylpyrazin-2-yl) methylcarbamate 001b (5.5 g, pale yellow solid) in 85% yield.

MS m/z(ESI):224.3(M+1)。

Preparation of hydrochloride of (3-methylpyrazin-2-yl) methylamine 001c in the second step

Tert-butyl (3-methylpyrazin-2-yl) methylcarbamate 001b (5.5 g,24.63 mmol) was dissolved in 2NHCl dioxane (50 mL). The reaction solution was stirred at 25 ℃ for 3 hours. After the completion of the reaction, the reaction mixture was concentrated to give (3-methylpyrazin-2-yl) methylamine 001c hydrochloride (3.95 g, pale yellow solid) in 100% yield.

MS m/z(ESI):124.1(M+1)。

Preparation of 3-chloro-5- (1-ethoxyvinyl) -1,2, 4-thiadiazole 001e

3, 5-Dichloro-1, 2, 4-thiadiazole 001d (5 g,32.26 mmol) was dissolved in dry DMF (80 mL) and ditolylphosphoropalladium dichloride (1.13 g,1.61 mmol) and tributyl (1-ethoxyethylene) tin (11.65 g,25.8 mmol) were added at room temperature. The reaction solution was heated to 80 ℃ under nitrogen and stirred for 16 hours. After the completion of the reaction, the reaction mixture was cooled to room temperature, quenched with aqueous potassium fluoride (100 mL), the solid was removed by filtration, the filtrate was extracted with ethyl acetate (100 mL. Times.2), and the organic phase was washed with brine, dried, and concentrated. The resulting concentrate was purified by silica gel column chromatography (PE/ea=3/1) to give 3-chloro-5- (1-ethoxyvinyl) -1,2, 4-thiadiazole 001e (5 g, pale yellow oil) in 81% yield.

MS m/z(ESI):191.0(M+1)。

Preparation of fourth step 3-chloro-1, 2, 4-thiadiazole-5-carboxylic acid ethyl ester 001f

An aqueous solution (50 mL) of sodium periodate (22.44 g,104.9 mmol) was added to a solution (100 mL) of 3-chloro-5- (1-ethoxyvinyl) -1,2, 4-thiadiazole 001e (5.0 g,26.23 mmol) in dioxane, and after the reaction solution was stirred for 5 minutes, potassium permanganate (1.24 g,7.87 mmol) was added to the reaction solution, and the reaction solution was stirred overnight at room temperature. After the reaction, the reaction mixture was extracted with ethyl acetate (100 mL. Times.3), and the organic phases were combined, washed with brine, dried, and concentrated. The resulting concentrate was purified by silica gel column chromatography (PE/ea=3/1) to give ethyl 3-chloro-1, 2, 4-thiadiazole-5-carboxylate 001f (1.6 g, colorless oil) in 32% yield.

MS m/z(ESI):193.0(M+1)。

Fifth step preparation of 3-chloro-N- ((3-methylpyrazin-2-yl) methyl) -1,2, 4-thiadiazole-5-carboxamide 001g

Ethyl 3-chloro-1, 2, 4-thiadiazole-5-carboxylate 001f (2.8 g,14.54 mmol) was dissolved in dry DMF (40 mL) and (3-methylpyrazin-2-yl) methylamine 001c hydrochloride (3.18 g,15.99 mmol) and TBD (3.04 g,21.8 mmol) were added at room temperature. The reaction solution was stirred at room temperature for 2 hours. After completion of the reaction, the mixture was extracted with saturated brine (50 mL) and ethyl acetate (50 mL. Times.3), and the organic phase was washed with brine, dried and concentrated. The resulting concentrate was purified by silica gel column chromatography (petroleum ether/ethyl acetate=1/1) to give 001g (2.1 g, white solid) of the product 3-chloro-N- ((3-methylpyrazin-2-yl) methyl) -1,2, 4-thiadiazole-5-carboxamide in 54% yield.

MS m/z(ESI):270.0(M+1)。

Sixth step preparation of 3-chloro-5- (8-methylimidazo [1,5-a ] pyrazin-3-yl) -1,2, 4-thiadiazole for 001h

3-Chloro-N- ((3-methylpyrazin-2-yl) methyl) -1,2, 4-thiadiazole-5-carboxamide 001g (1.2 g,2.25 mmol) was dissolved in phosphorus oxychloride (15 mL). The reaction solution was heated to 100 ℃ under nitrogen and stirred for 24 hours. After the completion of the reaction, the reaction mixture was concentrated, extracted with saturated aqueous sodium hydrogencarbonate and ethyl acetate, and the organic phase was washed with brine, dried and concentrated. The resulting concentrate was purified by silica gel column chromatography (dichloromethane/methanol=95/5) to give the product 3-chloro-5- (8-methylimidazo [1,5-a ] pyrazin-3-yl) -1,2, 4-thiadiazole (900 mg, yellow oil) in 80% yield.

MS m/z(ESI):252.0(M+1)。

Seventh step preparation of 3-chloro-5- (8-methyl-5, 6,7, 8-tetrahydroimidazo [1,5-a ] pyrazin-3-yl) -1,2, 4-thiadiazole 001i

3-Chloro-5- (8-methylimidazo [1,5-a ] pyrazin-3-yl) -1,2, 4-thiadiazole 001h (900 mg,3.58 mmol) was dissolved in a solution of dichloromethane/acetic acid=1/1 (20 mL), and sodium cyanoborohydride (674 mg,10.73 mmol) was added portionwise under ice-bath. The reaction solution was stirred at room temperature for 2 hours. After the completion of the reaction, the reaction mixture was concentrated, extracted with saturated aqueous sodium hydrogencarbonate and methylene chloride, and the organic phase was washed with brine, dried and concentrated. The resulting concentrate was purified by silica gel column chromatography (dichloromethane/methanol=10/1) to give 3-chloro-5- (8-methyl-5, 6,7, 8-tetrahydroimidazo [1,5-a ] pyrazin-3-yl) -1,2, 4-thiadiazole 001i (700 mg, pale yellow oil) in 77% yield.

MS m/z(ESI):256.1(M+1)。

Eighth step preparation of (3- (3-chloro-1, 2, 4-thiadiazol-5-yl) -8-methyl-5, 6-dihydroimidazo [1,5-a ] pyrazin-7 (8H) -yl) (4-fluorophenyl) methanone 001j

3-Chloro-5- (8-methyl-5, 6,7, 8-tetrahydroimidazo [1,5-a ] pyrazin-3-yl) -1,2, 4-thiadiazole 001i (700 mg,2.74 mmol) is dissolved in dichloromethane (10 mL), triethylamine (381 mg,8.21 mmol) is added, and parafluorobenzoyl chloride (521 mg,3.28 mmol) is added dropwise under ice-bath. After the completion of the dropwise addition, the reaction solution was stirred at room temperature for 2 hours. After the reaction, the reaction mixture was washed with brine, dried and concentrated. The resulting concentrate was purified by silica gel column chromatography (petroleum ether/ethyl acetate=4/1) to give the product (3- (3-chloro-1, 2, 4-thiadiazol-5-yl) -8-methyl-5, 6-dihydroimidazo [1,5-a ] pyrazin-7 (8H) -yl) (4-fluorophenyl) methanone 001j (500 mg, pale yellow oil) in 48% yield.

MS m/z(ESI):378.0(M+1)。

Preparation of (1-bromo-3- (3-chloro-1, 2, 4-thiadiazol-5-yl) -8-methyl-5, 6-dihydroimidazo [1,5-a ] pyrazin-7 (8H) -yl) (4-fluorophenyl) methanone 001k

(3- (3-Chloro-1, 2, 4-thiadiazol-5-yl) -8-methyl-5, 6-dihydroimidazo [1,5-a ] pyrazin-7 (8H) -yl) (4-fluorophenyl) methanone 001j (500 mg,1.32 mmol) was dissolved in ethanol (10 mL), and NBS (353 mg,1.99 mmol) was added. The reaction solution was stirred at room temperature for 2 hours. After the reaction, the reaction mixture was concentrated, extracted with water and ethyl acetate, and the organic phase was washed with brine, dried, and concentrated. The resulting concentrate was purified by silica gel column chromatography (petroleum ether/ethyl acetate=4/1) to give the product (1-bromo-3- (3-chloro-1, 2, 4-thiadiazol-5-yl) -8-methyl-5, 6-dihydroimidazo [1,5-a ] pyrazin-7 (8H) -yl) (4-fluorophenyl) methanone 001k (350 mg), yield 58%.

MS m/z(ESI):458.0(M+1)。

Tenth step preparation of 1- (3- (3-chloro-1, 2, 4-thiadiazol-5-yl) -7- (4-fluorobenzoyl) -8-methyl-5, 6,7, 8-tetrahydroimidazo [1,5-a ] pyrazin-1-yl) pyrrolidin-2-one 001l

(1-Bromo-3- (3-chloro-1, 2, 4-thiadiazol-5-yl) -8-methyl-5, 6-dihydroimidazo [1,5-a ] pyrazin-7 (8H) -yl) (4-fluorophenyl) methanone 001k (350 mg,0.77 mmol), pyrrolidin-2-one (72 mg,0.84 mmol), cesium carbonate (499 mg,1.53 mmol), cesium fluoride (116 mg,0.77 mmol), (1S, 2S) -N1, N2-dimethylcyclohexane-1, 2-diamine (109 mg,0.77 mol) and cuprous iodide (146 mg,0.77 mol) were dissolved in dioxane (15 mL), and the reaction mixture was placed in a sealed tube, replaced three times with nitrogen and reacted under nitrogen protection with stirring under heating at 110℃for 16 hours. After the completion of the reaction, the reaction solution was concentrated. The resulting concentrate was purified by silica gel column chromatography (petroleum ether/ethyl acetate=4/1) to give 001l (70 mg) of the product 1- (3- (3-chloro-1, 2, 4-thiadiazol-5-yl) -7- (4-fluorobenzoyl) -8-methyl-5, 6,7, 8-tetrahydroimidazo [1,5-a ] pyrazin-1-yl) pyrrolidin-2-one (yield 20%).

MS m/z(ESI):461.1(M+1)。

Preparation of (R) -1- (3- (3-chloro-1, 2, 4-thiadiazol-5-yl) -7- (4-fluorobenzoyl) -8-methyl-5, 6, 7-8-tetrahydroimidazo [1,5-a ] pyrazin-1-yl) pyrrolidin-2-one 001

1- (3- (3-Chloro-1, 2, 4-thiadiazol-5-yl) -7- (4-fluorobenzoyl) -8-methyl-5, 6,7, 8-tetrahydroimidazo [1,5-a ] pyrazin-1-yl) pyrrolidin-2-one 001l (70 mg,0.15 mmol) is subjected to chiral resolution (Apparatus：SFC 150.Column:Daicel CHIRALCEL OJ,250mm*30mm I.D.,10μm.Mobile phase：CO₂/MeOH[0.2％NH₃(7M Solution in MeOH)]＝70/30.Flow rate:120g/min.Wave length:UV 214nm.Temperature:35℃) to give the product (R) -1- (3- (3-chloro-1, 2, 4-thiadiazol-5-yl) -7- (4-fluorobenzoyl) -8-methyl-5, 6, 7-8-tetrahydroimidazo [1,5-a ] pyrazin-1-yl) pyrrolidin-2-one 001 (20 mg), yield 29%.

MS m/z(ESI):461.0(M+1)。

HPLC:100%(214nm),100%(254nm)。

¹H NMR(400MHz,CDCl₃)δ7.60-7.43(m,2H),7.21-7.10(m,2H),5.04(d,1H),4.27-4.15(m,2H),3.64(s,1H),3.45(s,1H),2.52(s,2H),2.35-2.04(m,2H),1.65-1.60(m,2H),1.36(s,3H).

With reference to the above example under similar conditions, the compounds in Table 1 below were prepared, whose structure characterization data are shown in Table 1

TABLE 1

Biological evaluation

Test example 1 determination of the Activity of the Compounds of the invention on human NK-3 receptors

The method is used for determining antagonism of the compounds in the invention on the activity of the human NK-3 receptor protein expressed in the human NK-3R/HEK293 stably transformed cell line.

1. Test material and instrument

1.1 Medium

F12(Gibco,Cat#11765-047);

FBS(Corning,Cat#35-076-CV);

Geneticin(Invitrogen,Cat#10131);

Penicillin/Streptomycin(Invitrogen,Cat#15140)。

1.2 Reagents

Fluo-4 Direct(Invitrogen,Cat#F10471);

HBSS(Gibco,Cat#14025076);

HEPES(Gibco,Cat#15630080);

Bonine SerumAlbumin(Sgima,Cat#B2064-100G)。

1.3 Instrument consumables

384well Poly-D-Lysine protein coatingplate(Greiner,Cat#781946);

FLIPR(Molecular Devices);

Vi-cell XR Cell ViabilityAnalyzer(Beckman Coulter);

Incubator(Thermo)。

2. Experimental procedure

2.1 Human NK-3R/HEK293 stably transformed cell lines were inoculated on 384-well cell culture plates at a density of 12000 cells/well/25. Mu.L and cultured overnight at 37℃with 5% CO ₂;

2.2 freezing and thawing to 20X ComponentA to room temperature, diluting to 2X working concentration by using an Assay Buffer, and standing at room temperature for later use;

2.3 cell culture plates were equilibrated at room temperature for 10 min, medium removed, added 20. Mu. LAssay Buffer and 20. Mu.L 2X ComponentA,200g, centrifuged at room temperature for 3-5sec,37℃and incubated for 2 h;

2.4 diluting the compound 3 times in a 3834 PP_DMSO plate by using DMSO, transferring the compound 240nl/well each to a working plate by using Echo 550, 200g, room temperature for 1min, adding 40 mu lAssay Buffer to the working plate, 200g, room temperature for 1min, uniformly mixing at 2500rpm of an oscillator for 20min, 200g, room temperature for 1min for later use;

2.5 preparing 2.5nM Neurokinin B TFA (6X) by using an Assay Buffer, and taking 50 mu L to 3657 plates for later use;

2.6 taking out the cell culture plate, standing at room temperature for 10min, adding 10 mu L of the diluted compound in the step 2.4 into the corresponding hole, and standing at 25 ℃ for 30min;

2.7 data were collected by adding FLIPR TETRA to 10. Mu.L of the diluted compound of step 2.5 to the corresponding wells.

The antagonistic activity of the compounds of the present invention on human NK-3 receptor was determined by the above experiments, the inhibition curves of the compounds of the present invention were obtained and the concentration (IC ₅₀) of the corresponding compounds of the reference antagonist, which inhibited 50%, was determined, and the specific IC ₅₀ values are shown in Table 2.

TABLE 2 IC ₅₀ values for the antagonistic Activity of the Compounds of the invention on human NK-3 receptors

Compounds of formula (I)	IC₅₀(nM)
		Fezolinetant	125.7
Compound A	10.31
		001	6.72
002	16.95
		003	8.48
004	17.46

Conclusion of experiment:

The above data shows that the compounds of the present embodiments are potent NK-3 receptor antagonists.

Test example 2, rat pharmacokinetic test of the Compounds of the invention

1. Purpose of experiment

The pharmacokinetic behavior of the compound of the invention in rats was studied and its pharmacokinetic profile was evaluated.

2. Experimental protocol

2.1 Experimental drugs

The compounds of the examples of the present invention and the control compounds.

2.2 Laboratory animals

Healthy adult SD female rats.

2.3 Pharmaceutical formulation

A proper amount of sample is weighed, a 5% DMSO+10% Solutol+85% Saline formula is used, the gastric administration group is subjected to ultrasonic preparation to prepare a 0.2mg/mL suspension, and the intravenous administration group is prepared to prepare a 0.2mg/mL suspension.

2.4 Administration of drugs

SD rats were administered by gavage and by intravenous injection at a dose of 2mg/kg and 1mg/kg by intravenous injection after a night fast.

3. Operation of

Blood is collected for 0.1mL before and after 5min, 15min, 30min, 1h, 2h, 4h, 8h and 24h, and placed in an anticoagulant tube containing EDTA-K2 anticoagulant, and centrifuged within 30min to obtain blood plasma. The whole blood sample was placed on wet ice prior to centrifugation. All collected plasma samples were stored on dry ice or in a freezer until analyzed and detected. Animals were returned to feeding/free drinking after 4 hours post dosing.

The LC/MS method was used to determine the amount of test compound in the plasma of rats after gavage administration, and the pharmacokinetic parameters of the test compound are shown in table 3.

TABLE 3 pharmacokinetic parameters of the compounds of the invention

Conclusion of experiment:

the data show that the compound of the invention has better absorption of the rat gastric lavage drug substitution, and the exposure and the bioavailability are obviously increased, namely, the drug substitution absorption effect of the compound is obviously improved through structural optimization.

Test example 3 Simian pharmacokinetic testing of Compounds of the invention

1. Purpose of experiment

The pharmacokinetic behavior of the compound of the invention in vivo in cynomolgus monkeys is studied, and the pharmacokinetic characteristics are evaluated.

2. Experimental protocol

2.1 Experimental drugs

The compounds of the examples of the present invention and control compounds.

2.2 Laboratory animals

Healthy adult female cynomolgus monkeys.

2.3 Pharmaceutical formulation

2.4 Administration of drugs

The cynomolgus monkey is respectively administrated by stomach infusion and intravenous injection after being fasted overnight, the dose of the stomach infusion is 2mg/kg, and the dose of the intravenous injection is 1mg/kg.

3. Operation of

The LC/MS method was used to determine the amount of test compound in the plasma of female cynomolgus monkeys after gavage administration, and the pharmacokinetic parameters of the test compound are shown in table 4.

TABLE 4 pharmacokinetic parameters of the compounds of the invention

Conclusion of experiment:

The data show that the compound of the invention has better gastric lavage drug absorption in female cynomolgus monkeys, prolonged half-life and obviously improved drug absorption effect.

Test example 4 rat in vitro brain model test of the Compound of the invention

1. Purpose of experiment

The compounds of the invention were studied for their ability to penetrate the Blood Brain Barrier (BBB) in vitro in rats and their ability to penetrate the CNS was assessed.

2. Experimental protocol

2.1 Experimental drugs

The compounds of the examples of the present invention and control compounds.

2.2 Experimental model

MDR1-MDCKII model.

3. Operation of

The test sample was diluted from dimethylsulfoxide stock to a concentration of 2 μm (dimethylsulfoxide < 1%) with transport buffer (HBSS with 10mM Hepes, ph 7.4) and applied to the top or basolateral side of the cell monolayer. Permeation assays of test compounds from a direction to B direction or from B direction to a direction are performed in duplicate. Digoxin is detected at 10 μm in the A-B direction, and also can be detected in the B-A direction, with nadolol and metoprolol being detected at 2 μm in the A-B direction, in duplicate. Plates were incubated for 2.5 hours in a CO ₂ incubator at 37+ -1deg.C with 5% CO ₂ at saturated humidity without shaking. In addition, the outflow rate of each compound was also measured. The test and control were quantified by LC-MS/MS analysis based on the peak area ratio of analyte/IS.

Following the transport assay, cell monolayer integrity was determined using a fluorescein rejection assay. The buffer was removed from the apical and basolateral chambers, and then 75. Mu.L of 100. Mu.M fluorescein and 250. Mu.L of transport buffer were added to the transport buffer and apical and basolateral chambers, respectively. The dishes were incubated at 37℃with 5% CO ₂ and saturated humidity for 30 minutes without shaking. After 30 minutes incubation, 20 μl of the rissin yellow sample was extracted from the top, and then 60 μl of transport buffer was added. Then 80. Mu.L of a sample of Lexifaxine was extracted from the outside of the substrate. Relative Fluorescence Units (RFU) of fluorescein were measured at 425/528nm (excitation/emission) using an Envision plate reader. The experimental results are shown in table 5.

TABLE 5 pharmacokinetic parameters of the compounds of the invention

Conclusion of experiment:

the data show that the compound of the invention has obvious brain penetrating effect and is superior to that of the control compound A.

The structure of the compound A in the invention is as follows:

The embodiments of the technical solution of the present application have been described above by way of example. It should be understood that the protection scope of the present application is not limited to the above embodiments. Any modification, equivalent replacement, improvement, etc. made by those skilled in the art within the spirit and principles of the present application should be included in the scope of the present application as defined in the appended claims.

Claims

1. A compound represented by general formula (I), its stereoisomers, tautomers, nitrogen oxides, solvates, polymorphs, metabolites, pharmaceutically acceptable salts or prodrugs:

wherein X is selected from O or CR ₁ R ₂ ;

R ₁ and R ₂ are the same or different and are independently selected from H, C _1-6 alkyl or halogenated C _1-6 alkyl;

Each _Ra is the same or different and is independently selected from OH, CN, halogen, _C1-6 alkyl or halogenated _C1-6 alkyl;

R _b is selected from halogen;

m is selected from 0, 1, 2, 3 or 4.

2. The compound according to claim 1, its stereoisomers, tautomers, N-oxides, solvates, polymorphs, metabolites, pharmaceutically acceptable salts or prodrugs, wherein X is selected from O or CH ₂ ;

Preferably, each _Ra is the same or different and is independently selected from F, Cl or Br;

Preferably, R _b is selected from F, Cl or Br;

Preferably, m is selected from 1.

3. The compound according to claim 1 or 2, its stereoisomers, tautomers, nitrogen oxides, solvates, polymorphs, metabolites, pharmaceutically acceptable salts or prodrugs, characterized in that the compound represented by formula (I) is selected from the following structures:

wherein X, _Ra , _Rb , and m have the definitions as described in any one of claims 1-2.

4. The compound according to any one of claims 1 to 3, its stereoisomers, tautomers, nitrogen oxides, solvates, polymorphs, metabolites, pharmaceutically acceptable salts or prodrugs, characterized in that the compound represented by formula (I) is selected from the following structures:

X, _Ra , and _Rb have the definitions as defined in any one of claims 1-2.

5. The compound according to any one of claims 1 to 4, its stereoisomers, tautomers, nitrogen oxides, solvates, polymorphs, metabolites, pharmaceutically acceptable salts or prodrugs, characterized in that the compound represented by formula (I) is selected from the following structures:

6. The compound according to any one of claims 1 to 5, its stereoisomers, tautomers, nitrogen oxides, solvates, polymorphs, metabolites, pharmaceutically acceptable salts or prodrugs, characterized in that the compound represented by formula (I) is selected from the following structures:

7. A pharmaceutical composition comprising one, two or more of the compound of formula (I) according to any one of claims 1 to 6, its stereoisomers, tautomers, nitrogen oxides, solvates, polymorphs, metabolites, pharmaceutically acceptable salts or prodrugs;

Preferably, the pharmaceutical composition further comprises one or more pharmaceutically acceptable excipients.

8. Use of the compound of formula (I) according to any one of claims 1 to 6, one, two or more of its stereoisomers, tautomers, nitrogen oxides, solvates, polymorphs, metabolites, pharmaceutically acceptable salts or prodrugs, or the pharmaceutical composition according to claim 7 in the preparation of a medicament for preventing and/or treating diseases mediated by NK-3 receptors.

9. Use of the compound of formula (I) according to any one of claims 1 to 6, one or more of its stereoisomers, tautomers, nitrogen oxides, solvates, polymorphs, metabolites, pharmaceutically acceptable salts or prodrugs, or the pharmaceutical composition according to claim 7 in the preparation of a medicament for preventing and/or treating depression, anxiety, psychosis, schizophrenia, psychotic disorders, bipolar disorder, cognitive impairment, Parkinson's disease, Alzheimer's disease, attention deficit hyperactivity disorder (ADHD), pain, convulsions, obesity, inflammatory diseases, vomiting, preeclampsia, airway-related diseases, reproductive disorders, contraception and sex hormone-dependent diseases, gynecological diseases, and menopausal syndrome-related diseases;

Preferably, the sex hormone-dependent diseases include but are not limited to benign prostatic hyperplasia (BPH), prostatic hyperplasia, metastatic prostate cancer, testicular cancer, breast cancer, ovarian cancer, androgen-dependent acne, male pattern baldness, endometriosis, puberty abnormalities, uterine fibrosis, uterine fibroids, hormone-dependent cancers, hyperandrogenism, hirsutism, virilization, polycystic ovary syndrome (PCOS), premenstrual dysphoric disorder (PMDD), HAIR-AN syndrome (hyperandrogenism, insulin resistance and acanthosis nigricans), ovarian theca cell hyperplasia (HAIR-AN with luteinizing theca cell hyperplasia in the ovarian stroma), other manifestations of high intraovarian androgen concentrations (such as follicular maturation arrest, atresia, anovulation, dysmenorrhea, dysfunctional uterine bleeding, infertility), androgen-producing tumors (masculinizing ovarian tumors or adrenal tumors), menorrhagia and adenomyosis;

Preferably, the airway-related diseases include chronic obstructive pulmonary disease, asthma, airway hyperresponsiveness, bronchoconstriction and cough;

Preferably, the menopausal syndrome includes symptoms such as hot flashes, sweating, palpitations, dizziness and obesity;

Preferably, the medicament is for treating and/or preventing vasomotor disorders;

Preferably, the vasomotor symptoms are selected from moderate and/or severe vasomotor symptoms;

Preferably, the vasomotor symptoms are associated with perimenopause, menopause or postmenopause;

Preferably, the vasomotor symptoms are associated with breast cancer treatment, oophorectomy or ovarian suppression treatment;

Preferably, the vasomotor syndrome is vasomotor syndrome (breast cancer VMS) caused by female breast cancer patients receiving adjuvant endocrine therapy.

10. A method for treating and/or preventing a disease, comprising administering to a subject a therapeutically effective amount of a compound of formula (I) according to any one of claims 1 to 6, one or more of its stereoisomers, tautomers, nitrogen oxides, solvates, polymorphs, metabolites, pharmaceutically acceptable salts or prodrugs, or the pharmaceutical composition according to claim 7, wherein the disease is depression, anxiety, psychosis, schizophrenia, psychotic disorder, bipolar disorder, cognitive disorder, Parkinson's disease, Alzheimer's disease, attention deficit hyperactivity disorder (ADHD), pain, convulsions, obesity, inflammatory diseases, vomiting, preeclampsia, airway-related diseases, reproductive disorders, contraception, and sex hormone-dependent diseases or gynecological diseases;

Preferably, the disease is a disease related to menopausal syndrome, and the menopausal syndrome includes symptoms such as hot flashes, sweating, palpitations, dizziness and obesity;

Preferably, the disease is vasomotor disease;

Preferably, the vasomotor disorder is associated with perimenopause, menopause or postmenopause;