Imidazole fused ring compound, pharmaceutical composition, and preparation method therefor and use thereof

Abstract

The present invention relates to a derivative containing an imidazole fused ring, a pharmaceutical composition thereof, and a preparation method therefor and the use thereof. In particular, the present invention relates to a compound as shown in general formula (I), a preparation method therefor, a pharmaceutical composition containing the compound, and the use thereof as an NK-3 receptor antagonist in the treatment and / or prevention of a series of broad diseases or disorders, such as CNS and peripheral diseases, wherein the definition of each substituent in the general formula (I) is the same as that defined in the description.

Description

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

[0001] This application claims priority to prior applications No. 202410444043.2, filed with the State Intellectual Property Office of China on April 12, 2024, entitled “Imidazole-fused-ring compounds, pharmaceutical compositions, preparation methods, and uses thereof”; and No. 202510420941.9, filed with the State Intellectual Property Office of China on April 3, 2025, entitled “Imidazole-fused-ring compounds, pharmaceutical compositions, preparation methods, and uses thereof”. The entire contents of the aforementioned prior applications are incorporated herein by reference. Technical Field

[0002] The present invention belongs to the field of medicine, and in particular relates to a class of imidazole fused ring compounds, a pharmaceutical composition containing the compound, and a preparation method and application thereof. Background Art

[0003] Tachykinin receptors are targets of a family of structurally related peptides collectively designated "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, designated neurokinin-1 (NK-1) receptor, neurokinin-2 (NK-2) receptor, and neurokinin-3 (NK-3) receptor. 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 primarily expressed in the CNS.

[0004] The NK-3 receptor, encoded by the TACR3 gene, is involved in regulating the hypothalamic-pituitary-gonadal axis. TACR3 knockout or mutant mice exhibit abnormal reproductive organ development, low sex hormone levels, and severely reduced reproductive capacity. Carrying TACR3 gene mutations can lead to abnormal gonadotropin release, resulting in sexual infantilism and infertility. A significant proportion of familial hypogonadism is caused by TACR3 gene mutations.

[0005] Kisspeptin / neurokinin B / dynorphin (KNDy) neurons participate in the gonadotropin-releasing hormone (GnRH) signaling pathway, promoting estrogen production through the GnRH neuron-pituitary-sex organ pathway. This signaling pathway is regulated by a negative feedback mechanism, thereby maintaining hormone levels within a reasonable range. KNDy neurons are also involved in thermoregulatory signaling pathways, releasing NKB ligands that bind to NK-3 receptors in the median preoptic nucleus (MPN). This regulates body temperature within a certain range by inhibiting shivering and vasoconstriction and promoting sweating and vasodilation. In menopausal women, decreased estrogen levels lead to a loss of this negative feedback mechanism, leading to overactivation of KNDy neurons and the release of large amounts of endogenous NKB ligands, which bind to NK-3 receptors in the MPN. This leads to sweating, vasodilation, and symptoms of hot flashes. Therefore, the development of antagonists targeting KNDy neurons and the MPN NK-3 receptor has the potential to be effective in treating symptoms such as hot flashes.

[0006] In the CNS, NK-3 receptors are expressed in regions including the medial prefrontal cortex, hippocampus, thalamus, and amygdala. Furthermore, NK-3 receptors are expressed on dopaminergic neurons. Activation of the NK-3 receptor has been shown to regulate the release of dopamine, acetylcholine, and serotonin, suggesting the therapeutic utility of NK-3 receptor modulators in treating a variety of conditions, including psychotic disorders, anxiety disorders, depression, schizophrenia, and obesity, pain, or inflammation.

[0007] Although a large amount of meaningful research has been conducted in this field, there is still a need to continue researching and developing more effective small molecule NK3R receptor antagonists. The present invention provides a NK3R receptor antagonist with a novel structure, and it is found that compounds with such a structure have good activity and can effectively treat a series of CNS and peripheral diseases. Summary of the Invention

[0008] The present invention provides a compound represented by formula (I), its stereoisomers, tautomers, nitrogen oxides, solvates, polymorphs, metabolites, pharmaceutically acceptable salts or prodrugs:

[0009] wherein X is selected from O or CR1R2;

[0010] R1 and R2 are the same or different and are independently selected from H, C 1-6 Alkyl or halogenated C 1-6 alkyl;

[0011] Each R a The same or different, independently selected from OH, CN, halogen, C 1-6 Alkyl or halogenated C1-6 alkyl;

[0012] R b selected from halogen;

[0013] m is selected from 0, 1, 2, 3 or 4.

[0014] According to some embodiments, X is selected from O or CH2.

[0015] According to some embodiments, each R a are the same or different and are independently selected from F, Cl or Br.

[0016] According to some embodiments, R b is selected from F, Cl or Br.

[0017] According to some embodiments, m is selected from 1.

[0018] According to some embodiments, the compound represented by formula (I) is selected from the following structures:

[0019] Among them, X, R a 、R b , m have the definitions as described herein.

[0020] According to some embodiments, the compound represented by formula (I) is selected from the following structures:

[0021] X, R a 、R b has the definitions as described herein.

[0022] According to some embodiments, the compound of formula (I) may be a specific compound represented by the following structure:

[0023] According to some embodiments, the compound of formula (I) may be a specific compound represented by the following structure:

[0024] The present invention also provides a pharmaceutical composition comprising one, two or more of the compound represented by the above formula (I), its stereoisomers, tautomers, nitrogen oxides, solvates, polymorphs, metabolites, pharmaceutically acceptable salts or prodrugs.

[0025] According to some embodiments, the pharmaceutical composition may optionally further comprise at least one pharmaceutically acceptable excipient.

[0026] According to some embodiments, the pharmaceutical composition may optionally further comprise at least one additional active ingredient; specifically, the pharmaceutical composition may further comprise one or more active ingredients other than the compound of formula (I), its stereoisomers, tautomers, nitrogen oxides, solvates, polymorphs, pharmaceutically acceptable salts, metabolites, and prodrugs.

[0027] In the pharmaceutical composition, the dosage of the compound of formula (I), its stereoisomers, tautomers, nitrogen oxides, solvates, polymorphs, metabolites, pharmaceutically acceptable salts or prodrugs may be a therapeutically effective amount.

[0028] According to the present invention, the pharmaceutical composition of the present invention can be prepared into a dosage form suitable for administration by methods known in the art.

[0029] The present invention also provides the use of the compound represented by the above formula (I), one, two or more of its stereoisomers, tautomers, nitrogen oxides, solvates, polymorphs, metabolites, pharmaceutically acceptable salts or prodrugs, or the pharmaceutical composition in the preparation of a drug;

[0030] According to the present invention, the drug is a NK3 receptor antagonist.

[0031] According to the present invention, the medicament is used for preventing and / or treating diseases mediated by NK3 receptors.

[0032] In some embodiments, the medicament can be used to prevent and / or treat depression, anxiety, psychosis, schizophrenia, psychotic disorders, bipolar disorder, cognitive disorders, 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 disease-related diseases.

[0033] 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 (e.g., follicular maturation arrest, atresia, anovulation, dysmenorrhea, dysfunctional uterine bleeding, infertility), androgen-producing tumors (masculinizing ovarian tumors or adrenal tumors), menorrhagia, and adenomyosis.

[0034] The airway-related diseases include chronic obstructive pulmonary disease, asthma, airway hyperresponsiveness, bronchoconstriction and cough.

[0035] In some embodiments, the drug is used to treat and / or prevent diseases related to menopausal syndrome, wherein the menopausal syndrome includes symptoms such as hot flashes, sweating, palpitations, dizziness and obesity.

[0036] In some embodiments, the medicament is for treating and / or preventing vasomotor disorders.

[0037] In some embodiments, the vasomotion disorder is selected from moderate and / or severe vasomotion disorder.

[0038] In some embodiments, the vasomotor disorder is associated with perimenopause, menopause, or postmenopause.

[0039] In some embodiments, the vasomotor symptoms are associated with breast cancer treatment, oophorectomy, or ovarian suppression.

[0040] In some embodiments, the vasomotor symptoms are vasomotor symptoms induced by adjuvant endocrine therapy in female breast cancer patients (breast cancer VMS).

[0041] The present invention also provides a method for treating and / or preventing NK3 receptor-mediated conditions or diseases, comprising administering to a subject a therapeutically effective amount of a compound of formula (I), one, two or more of its stereoisomers, tautomers, nitrogen oxides, solvates, polymorphs, metabolites, pharmaceutically acceptable salts or prodrugs, or a pharmaceutical composition thereof.

[0042] In some embodiments, the condition or disease is depression, anxiety, psychosis, schizophrenia, psychotic disorders, bipolar disorder, cognitive disorders, 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 disease-related diseases.

[0043] 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 (e.g., follicular maturation arrest, atresia, anovulation, dysmenorrhea, dysfunctional uterine bleeding, infertility), androgen-producing tumors (masculinizing ovarian tumors or adrenal tumors), menorrhagia, and adenomyosis.

[0044] The airway-related diseases include chronic obstructive pulmonary disease, asthma, airway hyperresponsiveness, bronchoconstriction and cough.

[0045] In some embodiments, the condition or disease is a disease associated with menopausal syndrome, wherein the menopausal syndrome includes symptoms such as hot flashes, sweating, palpitations, dizziness, and obesity.

[0046] In some embodiments, the condition or disease is a vasomotor disorder.

[0047] In some embodiments, the vasomotion disorder is selected from moderate and / or severe vasomotion disorder.

[0048] In some embodiments, the vasomotor disorder is associated with perimenopause, menopause, or postmenopause.

[0049] In some embodiments, the vasomotor symptoms are associated with breast cancer treatment, oophorectomy, or ovarian suppression.

[0050] In some embodiments, the vasomotor symptoms are vasomotor symptoms induced by adjuvant endocrine therapy in female breast cancer patients (breast cancer VMS).

[0051] Preferably, the subject is a warm-blooded animal, more preferably a human. Beneficial effects

[0052] Through structural optimization, the present invention creatively obtains a class of structurally novel compounds (particularly compound 001), which not only have good NK-3 receptor inhibitory effects, but also have significantly improved physicochemical properties and pharmacokinetic properties, significantly enhanced in vivo efficacy, and good safety.

[0053] Definition of terms

[0054] Unless otherwise specified, all technical terms used in the present invention have the same meaning as commonly understood by those skilled in the art to which the present invention belongs. All patents and publications related to the present invention are incorporated herein by reference in their entirety.

[0055] The term "comprising" is an open expression, that is, including the contents specified in the present invention, but not excluding other contents.

[0056] Unless otherwise indicated, numerical ranges recited in this specification and claims are equivalent to reciting at least each specific integer value therein. For example, the numerical range "1-6" is equivalent to reciting each integer value in the numerical range "1-6", namely 1, 2, 3, 4, 5, and 6. It should be understood that when used herein in describing one or more substituents, "a plurality" should refer to an integer ≥ 2, such as 2, 3, 4, 5, 6, 7, 8, 9, or 10.

[0057] The term "halogen" or "halo" refers to fluorine (F), chlorine (Cl), bromine (Br), or iodine (I).

[0058] Unless otherwise stated, the definition of a term herein also applies to groups containing the term, for example, the definition of alkyl also applies to the alkyl group in alkoxy, alkylamino, dialkylamino, etc.

[0059] In general, the term "substituted" means that one or more hydrogen atoms in a given structure are replaced by a specified substituent. Furthermore, when a group is substituted with one or more of the substituents, the substituents are independent of each other, that is, the one or more substituents may be different 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 structural formula can be substituted by one or more substituents selected from the specified group, the substituents may be the same or different at each position. The substituents may include, but are not limited to, =O, =S, hydrogen, deuterium, cyano, nitro, amino, hydroxyl, thiol, halogen, alkyl, haloalkyl, alkoxy, carboxyl, cycloalkyl, cycloalkyloxy, heterocyclyl, heterocyclylalkyl, aryl, arylalkyl, aryloxy, heteroaryl, heteroarylalkyl, heteroaryloxy, and the like.

[0060] In addition, it should be noted that the description "… independently selected from" as employed in the present application should be interpreted broadly, unless explicitly indicated otherwise, and means that each individual described is independent of the other, and can be independently selected from the same or different specific group. In more detail, the description "… independently selected from" can mean that the specific options expressed between the same symbols in different groups do not influence each other; or that the specific options expressed between the same symbols in the same group do not influence each other.

[0061] The term "optionally" (or "optionally", "optional") in the general formula definitions herein means the atom to which this term pertains is optionally substituted with 0, 1, 2, 3, 4, or 5 substituents. For example, the description "optionally substituted with one, two, or more R" means that the atom can be unsubstituted (no substitution) or can be optionally substituted with one, two, or more R.

[0062] Throughout various portions of the specification, substituents of compounds disclosed herein are presented by reciting a genus of groups or ranges. In particular, it is specifically intended that the present application include each and every individual subcombination of the members of the genus or range. For example, the term "C 1-6 "Alkyl" specifically refers to independently disclosed C1 alkyl, C2 alkyl, C3 alkyl, C4 alkyl, C5 alkyl, or C6 alkyl.

[0063] The term "C 1-6 "Alkyl" means straight and branched chain alkyl groups having 1, 2, 3, 4, 5, or 6 carbon atoms. The alkyl groups can optionally be substituted with one or more substituents described herein. In some embodiments, the alkyl group contains 1-6 carbon atoms; in other embodiments, the alkyl group contains 1-3 carbon atoms. Examples of the alkyl group include, but are not limited to, methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, isobutyl, sec-butyl, t-butyl, isopentyl, 2-methylbutyl, 1-methylbutyl, 1-ethylpropyl, 1,2-dimethylpropyl, neopentyl, 1,1-dimethylpropyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 2-ethylbutyl, 1-ethylbutyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl, 2,3-dimethylbutyl, 1,3-dimethylbutyl, or 1,2-dimethylbutyl, and the like or their isomers.

[0064] "Stereoisomers" refer to compounds which have the same chemical constitution, but differ in the arrangement of atoms or groups in space. Stereoisomers include enantiomers, diastereomers, conformers (rotamers), geometric isomers (cis / trans) isomers, atropisomers, and the like.

[0065] "Enantiomer" refers to two isomers of a compound which are non-superimposable mirror images of each other.

[0066] "Diastereomer" refers to two or more stereoisomers having at least two asymmetric centers and which are not mirror images of one another. Diastereomers have different physical properties, such as melting points, boiling points, spectral properties, and reactivities. Mixtures of diastereomers can be separated by high resolution analytical techniques such as electrophoresis and chromatography, e.g., HPLC.

[0067] Any asymmetric atom (e.g., carbon, etc.) of a compound disclosed herein can exist in racemic or enantiomeric enrichment, e.g., (R)-, (S)-, or (R,S)-configurational forms. In certain embodiments, each asymmetric atom has at least 0% enantiomeric excess in the (R)- or (S)- configuration, 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.

[0068] Any mixture of stereoisomers can be separated into their individual enantiomers or geometric isomers on the basis of their physical differences by means known to those skilled in the art, such as

[0069] The term "tautomer" refers to structural isomers that exist in equilibrium with one another through a low energy barrier. If tautomerism is possible (as in solution), a chemical equilibrium of the tautomers can be achieved. For example, proton tautomers (also known as prototropic tautomers) include interconversions by proton migration, such as keto-enol isomerization and imine-enamine isomerization. Valence tautomers include interconversions by reorganization of some bonding electrons. A specific example of keto-enol tautomerism is the interconversion of the pentane-2,4-dione and 4-hydroxypent-3-en-2-one tautomers. Another example of tautomerism is phenol-keto tautomerism. A specific example of phenol-keto tautomerism is the interconversion of the pyridin-4-ol and pyridin-4(lH)-one tautomers. Unless otherwise specified, all tautomeric forms of the compounds of the application are within the scope of the application.

[0070] The term "pharmaceutically acceptable" refers to molecular entities and compositions that are physiologically tolerable and do not typically produce an allergic or similar untoward reaction, such as gastrointestinal upset, dizziness, and the like, when administered to a human.

[0071] The term "carrier" refers to a diluent, adjuvant, excipient, or medium 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 saline solutions and aqueous dextrose and glycerol solutions are preferably used as carriers, particularly for injectable solutions.

[0072] The term "prodrug" as used in the present invention refers to a compound that is converted into a compound represented by formula (I) in vivo. Such conversion is affected by the hydrolysis of the prodrug in the blood or by enzyme conversion to the parent structure in the blood or tissue. The prodrug compound of the present invention can be an ester. In the existing invention, esters that can be used as prodrugs include phenyl esters, aliphatic (C 1-24 ) esters, acyloxymethyl esters, carbonates, carbamates, and amino acid esters. For example, a compound of the present invention containing a hydroxyl group can be acylated to produce a prodrug form of the compound. Other prodrug forms include phosphate esters, such as these phosphate ester compounds, which are obtained by phosphorylating a hydroxyl group on the parent compound.

[0073] As used herein, the term "metabolite" refers to a product resulting from the in vivo metabolism of a specific compound or salt thereof. Metabolites of a compound can be identified using techniques known in the art, and their activity can be characterized using assays such as those described herein. Such products can be obtained by administering the compound through oxidation, reduction, hydrolysis, amidation, deamidation, esterification, defatting, enzymatic cleavage, and the like. Accordingly, the present invention encompasses metabolites of the compound, including metabolites produced by contacting a compound of the invention with a mammal for a sufficient period of time.

[0074] In the present invention, the compounds referred to also include isotopically labeled compounds, which are the same as those shown in Formula I, but in which one or more atoms are replaced by atoms 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 the compounds of the present invention include isotopes of H, C, N, O, S, F, and Cl, such as 2 H. 3 H. 13 C. 11 C. 14 C. 15 N. 18 O. 17 O. 32 P. 35 S. 18 F and 36Cl. Compounds of the invention, prodrugs thereof, or pharmaceutically acceptable salts of said compounds or prodrugs containing the aforementioned isotopes and / or other isotopes of other atoms are within the scope of the invention. Certain isotopically labeled compounds of the invention, for example, those incorporating radioactive isotopes (such as 3 H and 14 C) compounds can be used in drug and / or substrate tissue distribution assays. 3 H) and carbon 14 (i.e. 14 C) isotopes are particularly preferred due to their ease of preparation and detectability. 2 Substitution with hydrogen (H or D) may provide certain therapeutic advantages (e.g., increased in vivo half-life or reduced dosage requirements) derived from greater metabolic stability and may therefore be preferred in certain circumstances. The compounds of the present invention as claimed in the claims may be specifically limited to substitution with deuterium or tritium. Furthermore, the absence of separate listing of the term deuterium or tritium for hydrogen present in a substituent does not exclude deuterium or tritium, but rather may also include deuterium or tritium.

[0075] In the description of this specification, the reference terms "one embodiment", "some embodiments", "example", "specific example", or "some examples" mean that the specific features, structures, materials or characteristics described in conjunction with the embodiment or example are included in at least one embodiment or example of the present invention. In this specification, the schematic representations of the above terms do not necessarily refer to the same embodiment or example. Moreover, the specific features, structures, materials or characteristics described can be combined in any one or more embodiments or examples in a suitable manner. In addition, those skilled in the art can combine and combine different embodiments or examples described in this specification and features of different embodiments or examples without contradiction. DETAILED DESCRIPTION

[0076] The present invention is further described below with reference to the following examples, but these examples are not intended to limit the scope of the present invention.

[0077] The structures of the compounds of the present invention are determined by nuclear magnetic resonance (NMR) and / or liquid chromatography-mass spectrometry (LC-MS). NMR chemical shifts (δ) are given in parts per million (ppm). NMR measurements were performed using a Bruker AVANCE-400 NMR spectrometer, using deuterated dimethyl sulfoxide (DMSO-d6), deuterated methanol (CD3OD), and deuterated chloroform (CDCl3) as the solvents, with tetramethylsilane (TMS) as the internal standard.

[0078] LC-MS determination was performed using Agilent 1200 Infinity Series Mass Spectrometer. HPLC determination was performed using Agilent 1200 DAD high pressure liquid chromatograph (Sunfire C18 150x4.6mm column) and Waters 2695-2996 high pressure liquid chromatograph (Gimini C18 150x4.6mm column).

[0079] Thin layer chromatography silica gel plate was used Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plate, TLC used specification was 0.15mm-0.20mm, thin layer chromatography separation and purification product used specification was 0.4mm-0.5mm. Column chromatography generally used Yantai Huanghai silica gel 200-300 mesh silica gel as carrier.

[0080] The starting materials in the embodiments of the present application are known and commercially available, or can be synthesized using or according to methods known in the art.

[0081] Unless otherwise specified, all reactions of the present application were carried out under continuous magnetic stirring, under dry nitrogen or argon atmosphere, with dry solvents, and the reaction temperature unit was degree Celsius.

[0082] Example 1

[0083] 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)

[0084] Preparation of tert-butyl (3-methylpyrazin-2-yl)methylcarbamate 001b

[0085] Dissolve 2-bromo-3-methylpyrazine 001a (5 g, 28.9 mmol) in dry dioxane / water = 10 / 1 (80 mL), add ((trifluoro-4-borane) methyl) tert-butyl carbamate potassium salt (8.26 g, 34.68 mmol), PdCl2(dppf) (211 mg, 0.29 mmol) and cesium carbonate (18.83 g, 57.8 mmol). The reaction solution was stirred at 80°C for 16 hours. After the reaction was completed, the reaction solution was concentrated. The obtained concentrate was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 3 / 1) to obtain tert-butyl (3-methylpyrazin-2-yl)methylcarbamate 001b (5.5 g, light yellow solid), with a yield of 85%.

[0086] MS m / z (ESI): 224.3 (M+1).

[0087] Preparation of hydrochloride salt of (3-methylpyrazin-2-yl)methanamine 001c

[0088] Tert-butyl (3-methylpyrazin-2-yl)methylcarbamate 001b (5.5 g, 24.63 mmol) was dissolved in 2N HCl in dioxane (50 mL). The reaction was stirred at 25 °C for 3 hours. After the reaction was completed, the reaction was concentrated to give hydrochloride salt of (3-methylpyrazin-2-yl)methanamine 001c (3.95 g, light yellow solid) with a yield of 100%.

[0089] MS m / z (ESI): 124.1 (M+1).

[0090] Preparation of 3-chloro-5-(1-ethoxyvinyl)-1,2,4-thiadiazole 001e

[0091] 3,5-Dichloro-1,2,4-thiadiazole 001d (5 g, 32.26 mmol) was dissolved in dry DMF (80 mL), and bis(triphenylphosphine)palladium dichloride (1.13 g, 1.61 mmol) and tributyl(1-ethoxyvinyl)tin (11.65 g, 25.8 mmol) were added at room temperature. The reaction was heated to 80 °C under nitrogen protection and stirred for 16 hours. After the reaction was completed, the reaction was cooled to room temperature, quenched with aqueous potassium fluoride solution (100 mL), and filtered to remove the solid. The filtrate was extracted with ethyl acetate (100 mL x 2), washed with brine, dried, and concentrated. The obtained concentrate was purified by silica gel column chromatography (PE / EA = 3 / 1) to give product 3-chloro-5-(1-ethoxyvinyl)-1,2,4-thiadiazole 001e (5 g, light yellow oil) with a yield of 81%.

[0092] MS m / z (ESI): 191.0 (M+1).

[0093] Preparation of ethyl 3-chloro-1,2,4-thiadiazole-5-carboxylate 001f

[0094] A solution of sodium periodate (22.44 g, 104.9 mmol) in water (50 mL) was added to a solution of 3-chloro-5-(l-ethoxyvinyl)-l,2,4-thiadiazole 001e (5.0 g, 26.23 mmol) in dioxane (100 mL) at room temperature. After the solution was stirred for 5 min, potassium permanganate (1.24 g, 7.87 mmol) was added to the solution, which was stirred at room temperature overnight. After the reaction was completed, the solution was extracted with ethyl acetate (100 mL x 3), the organic phase was combined, washed with brine, dried, and concentrated. The obtained concentrate was purified by silica gel column chromatography (PE / EA = 3 / 1) to give 3-chloro-l,2,4-thiadiazole-5-carboxylic acid ethyl ester 001f (1.6 g, colorless oil) in a yield of 32%.

[0095] MS m / z (ESI): 193.0 (M+l).

[0096] Fifth Step Preparation of 3-chloro-N-((3-methylpyrazin-2-yl)methyl)-l,2,4- thiadiazole-5-carboxamide 001g

[0097] 3-chloro-l,2,4-thiadiazole-5-carboxylic acid ethyl ester 001f (2.8 g, 14.54 mmol) was dissolved in dry DMF (40 mL), and (3-methylpyrazin-2-yl)methanamine 001c hydrochloride (3.18 g, 15.99 mmol) and TBD (3.04 g, 21.8 mmol) were added at room temperature. The solution was stirred at room temperature for 2 h. After the reaction was completed, the solution was extracted with saturated brine (50 mL) and ethyl acetate (50 mL x 3), the organic phase was washed with brine, dried, and concentrated. The obtained concentrate was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 1) to give the product 3-chloro-N-((3-methylpyrazin-2-yl)methyl)-l,2,4-thiadiazole-5-carboxamide 001g (2.1 g, white solid) in a yield of 54%.

[0098] MS m / z (ESI): 270.0 (M+l).

[0099] Sixth Step Preparation of 3-chloro-5-(8-methylimidazo[l,5-a]pyrazin-3-yl)-l,2,4- thiadiazole 001h

[0100] To a solution of 3-chloro-N-((3-methylpyrazin-2-yl)methyl)-l,2,4-thiadiazole-5- carboxamide 001g (1.2 g, 2.25 mmol) in phosphorus oxychloride (15 mL) was heated to 100 °C under nitrogen for 24 h. After the reaction was completed, the reaction was concentrated and extracted with saturated aqueous sodium bicarbonate and ethyl acetate. The organic phase was washed with brine, dried and concentrated. The resulting concentrate was purified by column chromatography on silica gel (dichloromethane / methanol = 95 / 5) to give the product 3-chloro-5-(8-methylimidazo[l,5-a]pyrazin-3-yl)-l,2,4-thiadiazole 001h (900 mg, yellow oil) in 80% yield.

[0101] MS m / z (ESI): 252.0 (M+l).

[0102] Seventh step: Preparation of 3-chloro-5-(8-methyl-5,6,7,8-tetrahydroimidazo[l,5- a]pyrazin-3-yl)-l,2,4-thiadiazole 001i

[0103] To a solution of 3-chloro-5-(8-methylimidazo[l,5-a]pyrazin-3-yl)-l,2,4-thiadiazole 001h (900 mg, 3.58 mmol) in dichloromethane / acetic acid = 1 / 1 (20 mL) was added sodium cyanoborohydride (674 mg, 10.73 mmol) portionwise under ice bath. The reaction was stirred at room temperature for 2 h. After the reaction was completed, the reaction was concentrated and extracted with saturated aqueous sodium bicarbonate and dichloromethane. The organic phase was washed with brine, dried and concentrated. The resulting concentrate was purified by column chromatography on silica gel (dichloromethane / methanol = 10 / 1) to give 3-chloro-5-(8-methyl-5,6,7,8-tetrahydroimidazo[l,5-a]pyrazin-3-yl)-l,2,4- thiadiazole 001i (700 mg, yellowish oil) in 77% yield.

[0104] MS m / z (ESI): 256.1 (M+l).

[0105] Eighth step: Preparation of (3-(3-chloro-l,2,4-thiadiazol-5-yl)-8-methyl-5,6- dihydroimidazo[l,5-a]pyrazin-7(8H)-yl)(4-fluorophenyl)methanone 001j

[0106] To a solution of 3-chloro-5-(8-methyl-5,6,7,8-tetrahydroimidazo[l,5- a]pyrazin-3-yl)-l,2,4-thiadiazole 001i (700 mg, 2.74 mmol) in dichloromethane (10 mL) was added triethylamine (831 mg, 8.21 mmol) and p-fluorobenzoyl chloride (521 mg, 3.28 mmol) dropwise at ice bath. After the addition was completed, the reaction was stirred at room temperature for 2 hours. After the reaction was completed, the reaction 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-l,2,4-thiadiazol-5-yl)-8-methyl-5,6-dihydroimidazo[l,5- a]pyrazin-7(8H)-yl)(4-fluorophenyl)methanone 001j (500 mg, yellowish oil) in 48% yield.

[0107] MS m / z (ESI): 378.0 (M+l).

[0108] Ninth step: Preparation of l-bromo-3-(3-chloro-l,2,4-thiadiazol-5-yl)-8-methyl- 5,6-dihydroimidazo[l,5-a]pyrazin-7(8H)-yl)(4-fluorophenyl)methanone 001k

[0109] To a solution of (3-(3-chloro-l,2,4-thiadiazol-5-yl)-8-methyl-5,6- dihydroimidazo[l,5-a]pyrazin-7(8H)-yl)(4-fluorophenyl)methanone 001j (500 mg, 1.32 mmol) in ethanol (10 mL) was added NBS (353 mg, 1.99 mmol). The reaction was stirred at room temperature for 2 hours. After the reaction was completed, the reaction was concentrated, extracted with water and ethyl acetate, 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 l-bromo-3-(3-chloro-l,2,4-thiadiazol-5-yl)-8-methyl-5,6-dihydroimidazo[l,5- a]pyrazin-7(8H)-yl)(4-fluorophenyl)methanone 001k (350 mg) in 58% yield.

[0110] MS m / z (ESI): 458.0 (M+l).

[0111] Tenth step: Preparation of l-(3-(3-chloro-l,2,4-thiadiazol-5-yl)-7-(4- fluorobenzoyl)-8-methyl-5,6,7,8-tetrahydroimidazo[l,5-a]pyrazin-l-yl)pyrrolidin-2- one 0011

[0112] (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 copper iodide (146 mg, 0.77 mol) were dissolved in dioxane (15 mL), the reaction mixture was put into a sealed tube, replaced with nitrogen three times, and heated with stirring at 110 °C for 16 hours under nitrogen protection. After the reaction was completed, the reaction solution was concentrated. The obtained concentrate was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 4 / 1) to obtain 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 0011 (70 mg) with a yield of 20%.

[0113] MS m / z (ESI): 461.1 (M+1).

[0114] Tenth step 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

[0115] 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 0011 (70 mg, 0.15 mmol) was subjected to chiral resolution (Apparatus: SFC 150. Column: Daicel CHIRALCEL OJ, 250 mm*30 mm I.D., 10 μm. Mobile phase: CO2 / MeOH [0.2% NH3(7M Solution in MeOH)] = 70 / 30. Flow rate: 120 g / min. Wave length: UV 214 nm. Temperature: 35 °C) to obtain 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) with a yield of 29%.

[0116] MS m / z (ESI): 461.0 (M+1).

[0117] HPLC: 100% (214 nm), 100% (254 nm).

[0118] 1 H NMR (400 MHz, CDC13) δ 7.60 - 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).

[0119] The following compounds in Table 1 were prepared according to the similar procedures described in the above examples, and their structure characterization data are shown in Table 1.

[0120] Table 1

[0121] Biological evaluation

[0122] Test 1, determination of the activity of the compounds of the present application on human NK-3 receptor

[0123] This method is used to determine the antagonistic effect of the compounds in the present application on the activity of human NK-3 receptor protein expressed in human NK-3R / HEK293 stable cell strain.

[0124] 1. Test materials and instruments

[0125] 1.1 Culture medium

[0126] F12 (Gibco, Cat# 11765-047);

[0127] FBS (Corning, Cat# 35-076-CV);

[0128] Geneticin (Invitrogen, Cat# 10131);

[0129] Penicillin / Streptomycin (Invitrogen, Cat# 15140).

[0130] 1.2 Reagents

[0131] Fluo-4 Direct (Invitrogen, Cat# F10471);

[0132] HBSS (Gibco, Cat# 14025076);

[0133] HEPES (Gibco, Cat# 15630080);

[0134] Bonine Serum Albumin (Sgima, Cat# B2064-100G).

[0135] 1.3 Instrument Consumables

[0136] 384 well Poly-D-Lysine protein coating plate (Greiner, Cat# 781946);

[0137] FLIPR (Molecular Devices);

[0138] Vi-cell XR Cell Viability Analyzer (Beckman Coulter);

[0139] Incubator (Thermo).

[0140] 2、Experimental Procedure

[0141] 2.1 Human NK-3R / HEK293 stable cell line was seeded in 384-well cell culture plate at a density of 12000 cells / well / 25 μL, incubated at 37°C, 5% CO2 overnight;

[0142] 2.2 Freeze-thaw 20X Component A to room temperature, dilute it to 2X working concentration with Assay Buffer, and wait at room temperature;

[0143] 2.3 Equilibrate the cell culture plate at room temperature for 10 minutes, remove the culture medium, add 20 μL Assay Buffer and 20 μL 2X Component A, 200g, centrifuge at room temperature for 3-5 seconds, incubate at 37°C for 2 hours;

[0144] 2.4 Dilute the compounds in 384PP_DMSO plate with DMSO by 3-fold, then transfer 240 nl / well of the compounds to the working plate using Echo 550, 200g, room temperature, 1 min; add 40 μl Assay Buffer to the working plate, 200g, room temperature, 1 min, then mix on a shaker at 2500 rpm for 20 min, and 200g, room temperature, 1 min before use;

[0145] 2.5 Prepare 2.5 nM Neurokinin B TFA (6X) in Assay Buffer, transfer 50 μL to a 3657 plate and set aside;

[0146] 2.6 Remove the cell culture plate and let it stand at room temperature for 10 minutes. Add 10 μL of the compound diluted in step 2.4 to the corresponding wells and let it stand at 25°C for 30 minutes.

[0147] 2.7 Use FLIPR Tetra to add 10 μL of the compound diluted in step 2.5 to the corresponding experimental wells and collect data.

[0148] The antagonistic activity of the compounds of the present invention on human NK-3 receptor was determined by the above experiments, the inhibition curve of the compounds of the present invention was obtained and the concentration of the compound that inhibited 50% of the reference antagonist (IC 50 ), specific IC 50 See Table 2 for values.

[0149] Table 2 IC values ​​of the compounds of the present invention for antagonistic activity against human NK-3 receptor 50 value

[0150] Experimental conclusion:

[0151] The above data show that the compounds of the present invention are potent NK-3 receptor antagonists.

[0152] Test Example 2: Pharmacokinetics of the Compounds of the Invention in Rats

[0153] 1. Experimental Purpose

[0154] The pharmacokinetic behavior of the compound of the present invention in rats was studied to evaluate its pharmacokinetic characteristics.

[0155] 2. Experimental plan

[0156] 2.1 Experimental drugs

[0157] Examples of the present invention and comparative compounds.

[0158] 2.2 Experimental animals

[0159] Healthy adult female SD rats.

[0160] 2.3 Drug preparation

[0161] An appropriate amount of sample was weighed and ultrasonically prepared into a 0.2 mg / mL suspension using a formula of 5% DMSO + 10% Solutol + 85% Saline for the oral administration group and a 0.2 mg / mL suspension for the intravenous administration group.

[0162] 2.4 Dosing

[0163] SD rats were dosed by gavage and intravenous injection respectively after overnight fasting, the gavage dose was 2 mg / kg, and the intravenous injection dose was 1 mg / kg.

[0164] 3. Operation

[0165] Blood samples of 0.1 mL were taken before dosing and at 5 min, 15 min, 30 min, 1 h, 2 h, 4 h, 8 h and 24 h after dosing, and placed in an anticoagulant tube containing EDTA-K2 anticoagulant, and the plasma was obtained by centrifugation within 30 minutes. The whole blood samples were placed on wet ice before centrifugation. All collected plasma samples were stored on dry ice or in a refrigerated freezer until analysis. The animals were fed / watered freely after 4 hours after dosing.

[0166] The content of the test compound in the plasma of rats after gavage was determined by LC / MS / MS method, and the pharmacokinetic parameters of the test compound were shown in Table 3.

[0167] Table 3 Pharmacokinetic parameters of the compound in the application

[0168] Experimental conclusion:

[0169] The above data show that the gavage pharmacokinetic absorption of the compound of the application in rats is good, and the exposure and bioavailability are significantly increased, that is, the pharmacokinetic absorption effect of the compound is significantly improved by structural optimization.

[0170] Test Example 3, pharmacokinetic test of the compound of the application in monkeys

[0171] 1. Experimental purpose

[0172] The pharmacokinetic behavior of the compound of the application in stone crab monkeys was studied, and the pharmacokinetic characteristics were evaluated.

[0173] 2. Experimental scheme

[0174] 2.1 Experimental drugs

[0175] The compound of the application and the control compound.

[0176] 2.2 Experimental animals

[0177] Healthy adult female stone crab monkeys.

[0178] 2.3 Drug preparation

[0179] An appropriate amount of sample was weighed, and a 5% DMSO+10% Solutol+85% Saline formulation was used, and the gavage group was prepared into a 0.2 mg / mL suspension by ultrasonic treatment; the intravenous administration group was prepared into a 0.2 mg / mL suspension.

[0180] 2.4 Administration

[0181] The stone monkeys were given intragastrical administration and intravenous injection respectively after overnight fasting, the intragastrical administration dose was 2 mg / kg, and the intravenous injection dose was 1 mg / kg.

[0182] 3. Operation

[0183] Blood, 0.1 mL, was collected before administration and at 5 min, 15 min, 30 min, 1 h, 2 h, 4 h, 8 h and 24 h after administration, and was placed in an anticoagulant tube containing EDTA-K2 anticoagulant, and plasma was obtained by centrifugation within 30 minutes. The whole blood sample was placed on wet ice before centrifugation. All collected plasma samples were stored on dry ice or in a refrigerated refrigerator until analysis. The animals were given food / water freely 4 hours after administration.

[0184] LC / MS / MS method was used to determine the content of the test compound in the plasma of female stone monkeys after intragastrical administration, and the pharmacokinetic parameters of the test compound are shown in Table 4.

[0185] Table 4 Pharmacokinetic parameters of the compound in the application

[0186] Experimental conclusion:

[0187] The above data show that the compound of the application has good pharmacokinetic absorption after intragastrical administration in female stone monkeys, the half-life is prolonged, and the pharmacokinetic absorption effect is obviously improved.

[0188] Test Example 4, in-vitro brain entry model test of the compound of the application in rats

[0189] 1. Experimental purpose

[0190] The ability of the compound of the application to penetrate the blood-brain barrier (BBB) in rats in vitro was studied to evaluate its ability to penetrate the CNS.

[0191] 2. Experimental scheme

[0192] 2.1 Experimental reagents

[0193] The compound of the application and the control compound.

[0194] 2.2 Experimental model

[0195] MDR1-MDCK II model.

[0196] 3. Operation

[0197] Test articles were diluted from dimethyl sulfoxide stock to 2 μM (dimethyl sulfoxide <1%) concentration with transport buffer (HBSS with 10 mM Hepes, pH 7.4) and applied to the apical or basolateral side of the cell monolayer. Permeation of test compounds was determined in duplicate from A to B direction or B to A direction. Digoxin was tested at 10 μM in A-B direction and also in B-A direction, nadolol and metoprolol were tested at 2 μM in A-B direction in duplicate. Plates were incubated in a 37 ± 1 °C CO2incubator for 2.5 hours, 5% CO2at saturated humidity without shaking. In addition, efflux rates were determined for each compound. Test articles and controls were quantified by LC-MS / MS analysis based on the peak area ratio of analyte / IS.

[0198] After the transport experiment, cell monolayer integrity was determined using the Lucifer Yellow exclusion assay. Buffer was removed from the apical and basolateral compartments and 75 μL of 100 μM Lucifer Yellow and 250 μL of transport buffer were added to the apical and basolateral compartments, respectively. The plates were incubated for 30 minutes at 37 °C, 5% CO2and saturated humidity without shaking. After 30 minutes of incubation, 20 μL of Lucifer Yellow sample was removed from the apical side and 60 μL of transport buffer was added. Then, 80 μL of Lucifer Yellow sample was removed from the basolateral side. The relative fluorescence units (RFU) of Lucifer Yellow were measured using an Envision plate reader at 425 / 528 nm (excitation / emission). The results of the experiment are shown in Table 5.

[0199] Table 5 Pharmacokinetic parameters of the compounds in the present application

[0200] Experimental conclusion:

[0201] The above data show that the compound of the present application has obvious brain penetration effect, which is better than that of the control compound A.

[0202] The structure of compound A described in the present application is as follows:

[0203] The above has exemplarily described the embodiments of the technical scheme of the present application. 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 principle of the present application shall be included in the protection scope of the claims of the present application.

Claims

1. A compound represented by general formula (I), its stereoisomers, tautomers, nitrogen oxides, solvates, polymorphs, metabolites, pharmaceutically acceptable salts or prodrugs: in, X is selected from O or CR1R2; R1 and R2 are the same or different and are independently selected from H, C 1-6 Alkyl or halogenated C 1-6 alkyl; Each R a The same or different, independently selected from OH, CN, halogen, C 1-6 Alkyl or halogenated C 1-6 alkyl; R b selected from halogen; m is selected from 0, 1, 2, 3 or 4.

2. The compound according to claim 1, its stereoisomers, tautomers, nitrogen oxides, solvates, polymorphs, metabolites, pharmaceutically acceptable salts or prodrugs, characterized in that: X is selected from O or CH2; Preferably, each R a The same or different, independently selected from F, Cl or Br; Preferably, R b 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: Among them, X, R a 、R b , m has the definition 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, R a 、R b It has the definition as described 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 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 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 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.

Images