Tetrahydropyridine derivative used as muscarinic receptor agonist and application of tetrahydropyridine derivative in medicine

Abstract

The invention provides a tetrahydropyridine derivative or a pharmaceutically acceptable salt thereof, a pharmaceutical composition containing the tetrahydropyridine derivative, application of the tetrahydropyridine derivative as a muscarinic receptor agonist and application of the tetrahydropyridine derivative in preparation of drugs for treating pain and central mental system disorders or / and diseases related to the pain and the central mental system disorders. The compound provided by the invention has the advantages of high selectivity to muscarinic receptors, no sex difference of pharmacokinetic parameters, small adverse reaction to gastrointestinal tracts, higher drug safety window, higher drug safety and lower clinical dosage.

Description

Technical Field

[0001] The present invention provides a tetrahydropyridine derivative or a pharmaceutically acceptable salt thereof and a pharmaceutical composition containing the same, as well as use of the tetrahydropyridine derivative as a muscarinic receptor agonist and use of the tetrahydropyridine derivative in preparing a drug for treating pain, central nervous system disorders, or diseases related to pain and central nervous system disorders. Background Art

[0002] The present invention relates to tetrahydropyridine derivatives and their use as medicaments for treating disorders alleviated by activation of muscarinic receptors in human or animal subjects.

[0003] Schizophrenia affects about 0.5% to 1% of the population. The characteristics of the disease are divided into positive symptoms (such as hallucinations, delusions, etc.), negative symptoms (such as social isolation, lack of pleasure, etc.) and cognitive symptoms (such as inability to process information, poor working memory, etc.) according to the symptoms. The quality of life of patients with schizophrenia will be greatly reduced. Due to many factors (such as increased suicide rates), their mortality risk is increased. Schizophrenia brings a great burden to patients, their families and society. Some patients with schizophrenia may be imprisoned, homeless or unemployed.

[0004] Existing schizophrenia treatments rely on dopamine and serotonin receptors, as in the case of chlorpromazine, the first antipsychotic discovered in 1952. Few new mechanisms of action have been brought to market for schizophrenia in more than 60 years. Current antipsychotics are only effective for positive symptoms, while failing to treat negative and cognitive symptoms. Alzheimer's disease is another therapeutic area. Developing new treatments has proven extremely difficult, with a success rate of only 0.4% for molecules that enter clinical development and gain market approval. Patients in these areas are in urgent need of new therapeutics.

[0005] Activation of the muscarinic system by muscarinic receptor agonists can treat several diseases, such as schizophrenia, Alzheimer's disease, Parkinson's disease, depression, movement disorders, drug addiction, pain and neurodegeneration, such as tauopathy or synucleinopathies. Muscarinic cholinergic receptors are G protein-coupled receptors with five different receptor subtypes (M1-M5), each of which is found in the CNS with different tissue distributions. The M1 and M4 subtypes have attracted attention as therapeutic targets for various diseases. For example, the mood stabilizers lithium and valproic acid used to treat bipolar depression can affect the muscarinic system, particularly through the M4 subtype receptor.

[0006] In a double-blind placebo-controlled trial of xanomeline (a muscarinic cholinergic receptor agonist with preferential activity on M1 and M4 subtype receptors) in schizophrenia patients, schizophrenia was alleviated. However, due to its binding to muscarinic receptors outside the brain, xanomeline has many serious side effects, including gastrointestinal (GI) side effects, cardiac side effects, and excessive salivation, and large gender differences in efficacy. Dose-limiting adverse events are problematic and lead to a high discontinuation rate, which ultimately led to the discontinuation of xanomeline development. Many companies have tried but have not developed muscarinic receptor agonists for CNS disorders that avoid these unacceptable side effects, and no such agonists have entered the market. Past development efforts have focused on medicinal chemistry to develop more tolerable molecules, typically selecting M1 and M4 subtypes rather than M2 and M3 muscarinic receptor subtypes. However, M1 and M4 activation outside the brain may still lead to muscarinic-related gastrointestinal intolerance. Therefore, it is urgent to develop muscarinic agonists with minimal side effects, stable pharmacokinetic properties and good efficacy in clinical practice. Summary of the invention

[0007] The present invention provides a tetrahydropyridine derivative compound as shown in formula (I), its stereoisomers, hydrates, solvates, polymorphs, active metabolites, pharmaceutically acceptable salts or prodrugs thereof:

[0008]

[0009] Wherein: R¹ is independently selected from hydrogen atom, deuterium atom, halogen, trifluoromethyl, difluoromethyl, isopropyl, cyclopropyl, cyclobutyl ;

[0010] R 2 Independently selected from a hydrogen atom, a methyl group, and a deuterated methyl group.

[0011] The tetrahydropyridine derivative compound as shown in formula (I) preferably has a structure shown in any of the following structural formulas:

[0012] .

[0013] The compounds of the present invention are usually used in the form of free acids or free bases. Alternatively, the compounds of the present invention can be used in the form of acid or base salts. Acid addition salts of free amino compounds of the present invention can be prepared by methods known in the art and can be prepared from organic acids and inorganic acids. Suitable organic acids include maleic acid, fumaric acid, benzoic acid, ascorbic acid, succinic acid, methanesulfonic acid, acetic acid, trifluoroacetic acid, oxalic acid, propionic acid, tartaric acid, salicylic acid, citric acid, gluconic acid, lactic acid, mandelic acid, phenylacetic acid, aspartic acid, stearic acid, palmitic acid, glycolic acid, glutamic acid and benzenesulfonic acid. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, gluconate heptanoate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxyethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate, and the like. Basic salts include salts formed with carboxylate anions, and include salts formed with organic and inorganic cations such as selected from alkali metal ions, alkaline earth metal ions (e.g., lithium, sodium, potassium, magnesium, barium, calcium) and ammonium ions, and substituted derivatives thereof (e.g., dibenzylamine, benzylamine, 2-hydroxyethylamine, etc.). Therefore, the term "pharmaceutically acceptable salts" of general formula (I) should include and all acceptable salt forms.

[0014] In addition, prodrugs are also included within the scope of the present invention. A prodrug is any covalently bound carrier that releases a compound of formula (I) in vivo when the prodrug is administered to a patient. Prodrugs are generally prepared by modifying functional groups in a manner that allows the modifications to decompose, by conventional exchange or in vivo, to yield the parent compound. Prodrugs include, for example, compounds of the present invention in which a hydroxyl, amino or sulfhydryl group is bound to any group that dissociates to yield a hydroxyl, amino or sulfhydryl group when the prodrug is administered to a patient.

[0015] Therefore, representative examples of prodrugs include (but are not limited to) acetates, formates and benzoates of alcohol and amine functional groups of compounds of formula (I). In addition, in the case of carboxylic acids (-COOH), esters such as methyl esters, ethyl esters, etc. may be included. In the case of hydroxyl groups, mixed anhydrides such as methoxy, ethoxy, propoxy, tert-butoxy, etc. may be included.

[0016] For stereoisomers, the compounds of general formula (I) may have chiral centers and may exist in the form of racemates, racemic mixtures, and individual enantiomers or diastereomers. All isomeric forms are included in the present invention, including mixtures thereof. In addition, some crystalline forms of the compounds of general formula (I) may exist in the form of polymorphs, which are also included in the present invention. In addition, some of the compounds of general formula (I) may also form solvates with water or other organic solvents. Such solvates are also similarly included in the scope of the present invention.

[0017] It will be understood by those skilled in the art that any compound may contain unnatural proportions of atomic isotopes on one or more of the atoms constituting the compound. As used herein, in the specification and claims, H refers to hydrogen, and includes any stable isotope of hydrogen, i.e. 1 H and D. In the embodiments where the atom is designated as H, no work is performed to enrich the atoms of a specific isotope of hydrogen, and therefore it should be understood by those of ordinary skill in the art that such hydrogen atoms may be present at about the natural abundance concentration of hydrogen. In the tetrahydrofurancarboxamide derivatives involved in the present invention, the deuterated means that the atoms at the relevant sites of the compound contain deuterium atoms exceeding the natural ratio (i.e., exceeding the natural abundance of deuterium). Therefore, any tetrahydropyridine derivative compound shown in formula (I) containing deuterium atoms at a ratio higher than the natural abundance of deuterium at the relevant sites is within the scope of protection of the present invention. For example, it is understood that the corresponding tetrahydropyridine derivative compounds having the corresponding deuterated rate or deuterium content obtained by introducing deuterium atoms using commercially available deuterated reagents by the same or similar chemical synthesis means as shown in the embodiments of the present invention are within the scope of protection of the present invention. The chemical synthesis means and deuterated reagents herein are not limited to those exemplified in the embodiments, but should be understood to include all synthesis methods or routes that can be used in the art to obtain the compounds of the present invention, as well as all deuterated reagents that can be used in conjunction with the aforementioned synthesis methods or routes to introduce deuterium atoms into the target molecule.

[0018] Isotope-labeled compounds and salts can be used in a variety of advantageous ways, including as medicines. In some embodiments, isotope-labeled compounds and salts are deuterium (D) labeled. Deuterium (D) labeled compounds and salts are useful in treatment, with potential therapeutic advantages over non-D labeled compounds. Generally, due to the kinetic isotope effect described below, compared with non-isotope-labeled compounds and salts, deuterium (D) labeled compounds and salts can have higher metabolic stability. Higher metabolic stability is directly converted into extended half-life or reduced dosage in vivo, which will represent preferred embodiments of the present invention in most cases. Isotope-labeled compounds and salts can be prepared generally in the following manner: carry out the procedures disclosed in the synthesis scheme, examples and related descriptions, and replace non-isotope-labeled reactants with readily available isotope-labeled reactants. Deuterium (D) labeled compounds and salts can manipulate the oxidative metabolic rate of the compound by the primary kinetic isotope effect. The primary kinetic isotope effect is a change in the rate of a chemical reaction resulting from isotopic nuclear exchange, which in turn is caused by a change in the ground state energy of the covalent bonds participating in the reaction. The exchange of heavier isotopes generally results in a decrease in the ground state energy of the chemical bond and thus a reduction in rate-limiting bond breakage. If bond breakage occurs in or near a saddle point region along the coordinates of a multi-product reaction, the product distribution ratio can be substantially altered.

[0019] According to the specific embodiments disclosed below, those skilled in the art can use the same or similar principles and methods to prepare the specific compounds involved in the tetrahydropyridine derivative compounds represented by the general formula (I) of the present invention.

[0020] The present invention further provides a use of a tetrahydropyridine derivative compound as shown in formula (I), its stereoisomers, hydrates, solvates, polymorphs, active metabolites, pharmaceutically acceptable salts or prodrugs thereof in the preparation of muscarinic agonists.

[0021] The present invention further provides a use of a tetrahydropyridine derivative compound as shown in formula (I), its stereoisomers, hydrates, solvates, polymorphs, active metabolites, pharmaceutically acceptable salts or prodrugs thereof in the preparation of a drug for treating diseases causing muscarinic disorders.

[0022] The present invention further provides a tetrahydropyridine derivative compound as shown in formula (I), its stereoisomers, hydrates, solvates, polymorphs, active metabolites, pharmaceutically acceptable salts or prodrugs thereof for use in the preparation of a drug for treating any one or more diseases of pain and central nervous system disorders.

[0023] The present invention further provides a pharmaceutical composition comprising a therapeutically effective amount of a tetrahydropyridine derivative compound as shown in formula (I), its stereoisomers, hydrates, solvates, polymorphs, active metabolites, pharmaceutically acceptable salts or prodrugs thereof, and a pharmaceutically acceptable carrier.

[0024] The pure form of the compound of the present invention or its pharmaceutically acceptable salt or a suitable pharmaceutical composition can be administered by any acceptable mode of administering a medicament with similar effects. The pharmaceutical composition of the present invention can be prepared by combining the compound of the present invention with a suitable pharmaceutically acceptable carrier, diluent or excipient, and can be formulated into solid, semisolid, liquid or gaseous preparations, such as tablets, capsules, powders, granules, ointments, solutions, suppositories, injections, inhalants, gels, microspheres and aerosols. Typical routes of administering the pharmaceutical composition include, but are not limited to, oral, topical, transdermal, inhaled, parenteral, sublingual, buccal, rectal, vaginal and intranasal administration. As used herein, the term parenteral includes subcutaneous injection, intravenous, intramuscular, intrasternal injection or infusion technology. The pharmaceutical composition of the present invention is formulated to allow the clean ingredients contained therein to be bioavailable after the composition is administered to the patient. The composition to be administered to an individual or patient is in the form of one or more dosage units, where, for example, a tablet can be a single dosage unit, while a container containing the compound of the invention in aerosol form can accommodate multiple dosage units. The actual method of preparing such dosage forms is known to or will become known to those skilled in the art. The composition to be administered will in any case contain a therapeutically effective amount of the compound of the invention or a pharmaceutically acceptable salt thereof, so as to treat the disease or condition of interest according to the teachings of the present invention.

[0025] The pharmaceutical composition of the present invention can be in solid or liquid form. On the one hand, the carrier is a microparticle, so that the composition is in the form of a tablet or powder, for example. The carrier can be a liquid, and the composition is, for example, an oral syrup, an injectable liquid, or an aerosol suitable for, for example, inhalation administration. When oral administration is desired, the pharmaceutical composition is preferably in solid or liquid form, wherein semi-solid, semi-liquid, suspension and gel forms are included in the forms considered as solid or liquid herein. For oral solid compositions, the pharmaceutical composition can be formulated into forms such as powders, granules, compressed tablets, pills, capsules, chewable tablets, powder tablets, etc. Such solid compositions typically contain one or more inert diluents or edible carriers. In addition, one or more of the following substances may be present: binders, such as carboxymethylcellulose, ethylcellulose, microcrystalline cellulose, xanthan gum or gelatin; excipients, such as starch, lactose or dextrin; disintegrants, such as alginic acid, sodium alginate, Primogel, corn starch, etc.; lubricants, such as magnesium stearate or hydrogenated vegetable oil (Sterotex); glidants, such as colloidal silicon dioxide; sweeteners, such as sucrose or saccharin; flavorings, such as mint, methyl salicylate or orange flavoring; and coloring agents.

[0026] In the preparation of compositions for oral administration, any common pharmaceutical medium can be used, such as water, glycols, oils, alcohols, etc. in the case of oral liquid compositions (such as suspensions, syrups, free agents, emulsions and solutions): or in the case of solid compositions, solid carriers such as starch, sugar, kaolin, lubricants, adhesives, disintegrants, etc. For parenteral compositions, the carrier will generally include at least sterile water in the majority, but other ingredients such as solubilizers, emulsifiers or other adjuvants may also be added thereto. Injectable solutions may be prepared, wherein the carrier includes physiological saline solution, glucose solution or a mixture of the two. Injectable suspensions may also be prepared, in which case appropriate liquid carriers, suspending agents, etc. may be used. Also included are solid form preparations that are expected to be converted into liquid form preparations shortly before use, such as powders for reconstruction.

[0027] When the pharmaceutical composition is in capsule form, such as a gelatin capsule, in addition to the above-mentioned types of materials, it may also contain a liquid carrier, such as polyethylene glycol or oil. The pharmaceutical composition may be in liquid form, such as a tincture, syrup, solution, emulsion or suspension. This liquid may be taken orally, or delivered by injection, as two examples. When oral administration is desired, the preferred composition contains one or more of a sweetener, a preservative, a dye / colorant and a flavor enhancer in addition to the compounds of the present invention. In the composition intended to be administered by injection, one or more of a surfactant, a preservative, a wetting agent, a dispersant, a suspending agent, a buffer, a stabilizer and an isotonic agent may be included.

[0028] Whether it is a solution, suspension or other similar form of the liquid pharmaceutical composition of the present invention, it can include one or more of the following adjuvants: sterile diluents, such as water for injection, physiological saline solution, preferably physiological saline, Ringer's solution, isotonic sodium chloride, fixed oils (such as synthetic mono- or diglycerides, which can be used as solvents or suspension media), polyethylene glycol, glycerol, propylene glycol and other solvents; antibacterial agents, such as benzyl alcohol or methyl paraben; antioxidants, such as ascorbic acid or sodium bisulfite; chelating agents, such as ethylenediaminetetraacetic acid; buffers, such as acetates, citrates or phosphates, and agents for adjusting tension, such as sodium oxide or dextrose. Parenteral preparations can be packaged in ampoules, disposable syringes or multiple dose vials made of glass or plastic. Physiological saline is a preferred adjuvant. Injectable pharmaceutical compositions are preferably sterile.

[0029] The liquid pharmaceutical composition of the present invention intended for parenteral administration or oral administration should contain a certain amount of the compound of the present invention so that a suitable dose can be obtained. The pharmaceutical composition of the present invention may be intended to be administered topically, in which case the carrier preferably comprises a solution, emulsion, ointment or gel matrix. For example, this matrix may comprise one or more of the following: paraffin oil, lanolin, polyethylene glycol, beeswax, mineral oil, diluents (e.g., water and alcohol), and emulsifiers and stabilizers. Thickeners may be present in the pharmaceutical composition for topical administration. If transdermal administration is intended, the composition may include a transdermal patch or an iontophoresis device.

[0030] The pharmaceutical composition of the present invention can be administered rectally, for example in the form of a suppository, which will melt in the rectum and release the drug. Compositions for rectal administration may contain an oily base as a suitable non-irritating excipient. Such bases include, but are not limited to, lanolin, cocoa butter, and polyethylene glycol.

[0031] The pharmaceutical composition of the present invention may include various materials that change the physical form of a solid or liquid dosage unit. For example, the composition may include a material that forms a coating shell around the active ingredient. The material that forms the coating shell is generally inert and may be selected from, for example, sugar, shellac, and other enteric coating agents. Alternatively, the active ingredient may be encapsulated in a gelatin capsule.

[0032] Pharmaceutical compositions of the invention in solid or liquid form may include an agent that binds to a compound of the invention and thereby aids in the delivery of the compound. Suitable agents having this capability include monoclonal or polyclonal antibodies, proteins or liposomes.

[0033] The pharmaceutical composition of the present invention can be composed of dosage units that can be administered in the form of an aerosol. The term aerosol is used to represent a variety of systems from colloidal types to systems consisting of pressurized packaging. Delivery can be carried out by liquefied or compressed gas, or by a suitable pump system that distributes the active ingredient. The aerosol of the compound of the present invention can be delivered in a single-phase, two-phase or three-phase system to deliver the active ingredient. The delivery of the aerosol includes necessary containers, starters, valves, sub-containers, etc., which together can form a kit. A person skilled in the art can determine a preferred aerosol without too much experimentation.

[0034] The pharmaceutical composition of the present invention can be made using methods well known in the pharmaceutical field. For example, a pharmaceutical composition to be administered by injection can be prepared by combining the compound of the present invention with sterile distilled water to form a solution. A surfactant can be added to facilitate the formation of a uniform solution or suspension. A surfactant is a compound that non-covalently interacts with the compound of the present invention, thereby promoting the dissolution or uniform suspension of the compound in an aqueous delivery system. A solution can be formed by combining the compound of the present invention with an acceptable solvent or solvent, such as water, Ringer's solution, and isotonic sodium chloride solution. A sterile injectable preparation can be a sterile injectable oil-in-water microemulsion in which the active ingredient is dissolved in the oil phase. The injection or microemulsion can be injected into the patient's bloodstream by local mass injection. Alternatively, it is best to administer the solution and microemulsion in a manner that can maintain a constant circulating concentration of the disclosed compound.

[0035] Pharmaceutical compositions of the present disclosure can be in the form of sterile injection water or oil suspension for intramuscular and subcutaneous administration. The suspension can be prepared by known techniques with the above-mentioned suitable dispersants or wetting agents and suspending agents. Sterile injection preparations can also be sterile injection solutions or suspensions prepared in parenteral acceptable non-toxic diluents or solvents. In addition, sterile fixed oils can be conveniently used as solvents or suspension media. For this purpose, any blended fixed oils can be used. In addition, fatty acids can also be used to prepare injections.

[0036] For buccal or sublingual administration, the composition may take the form of tablets, lozenges, pastilles, or gels formulated in conventional manner. Such compositions may contain the active ingredient in a flavored base such as sucrose and acacia or tragacanth.

[0037] The compounds of the invention, or pharmaceutically acceptable salts thereof, are administered in a therapeutically effective amount, which will vary depending on a variety of factors, including the activity of the particular compound employed; the metabolic stability and duration of action of the compound; the age, weight, general health, sex, and diet of the patient; the mode and timing of administration; the rate of excretion; drug combinations; the severity of the particular disorder or condition; and the individual undergoing therapy.

[0038] The compounds of the present invention or their pharmaceutically acceptable salts may also be administered at the same time, before or after administering one or more other therapeutic agents. This combination therapy includes administering a single pharmaceutical administration formulation containing the compounds of the present invention and one or more other active agents, as well as administering a separate pharmaceutical administration formulation of the compounds of the present invention and each active agent. For example, the compounds of the present invention and another active agent can be administered to the patient together with a single oral administration composition (e.g., tablets or capsules), or each agent can be administered with a separate oral administration formulation. In the case of using a separate administration formulation, the compounds of the present invention and one or more additional active agents can be administered at substantially the same time (i.e., simultaneously) or at a separate staggered time (i.e., successively); combination therapy should be understood to include all of these schemes.

[0039] The compounds and salts of the present invention or their pharmaceutically acceptable compositions can also be incorporated into compositions for coating implantable medical devices such as prostheses, artificial valves, vascular grafts, stents and catheters. Therefore, on the other hand, the present invention comprises compositions for coating implantable devices, the implantable devices comprising compounds or salts of the present invention as generally described above and classes and subclasses herein and carriers suitable for coating the implantable devices. On still another hand, the present invention comprises implantable devices coated with compositions, the compositions comprising compounds or salts of the present invention as generally described above and classes and subclasses herein and carriers suitable for coating the implantable devices. The coating is typically a biocompatible polymeric material, such as a hydrogel polymer, polymethyldisiloxane, polycaprolactone, polyethylene glycol, polylactic acid, ethylene vinyl acetate and mixtures thereof. The coating can optionally be further coated with a suitable top layer of fluorosilicone, polysaccharide, polyethylene glycol, phospholipid or a combination thereof to impart controlled release properties to the composition.

[0040] As a general guide, the active compounds of the present disclosure are preferably in a unit dose form, or in a form that a patient can self-administer in a single dose. The unit dose of the compounds or compositions of the present disclosure can be expressed in tablets, capsules, cachets, bottled liquids, powders, granules, lozenges, suppositories, reconstituted powders or liquid formulations. Suitable unit doses can be 0.1-1000 mg.

[0041] The pharmaceutical composition of the present disclosure may contain one or more excipients in addition to the active compound, and the excipients are selected from the following ingredients: fillers (diluents), binders, wetting agents, disintegrants or excipients, etc. Depending on the administration method, the composition may contain 0.1 to 99% by weight of the active compound.

[0042] In some embodiments, the unit dose of the pharmaceutical composition is 0.001 mg-1000 mg.

[0043] In certain embodiments, the pharmaceutical composition contains 0.01%-99.99% of a pharmaceutically acceptable excipient based on the total weight of the composition. In certain embodiments, the pharmaceutical composition contains 0.1%-99.9% of a pharmaceutically acceptable excipient. In certain embodiments, the pharmaceutical composition contains 0.5%-99.5% of a pharmaceutically acceptable excipient. In certain embodiments, the pharmaceutical composition contains 1%-99% of a pharmaceutically acceptable excipient. In certain embodiments, the pharmaceutical composition contains 2%-98% of a pharmaceutically acceptable excipient. Tablets contain active ingredients and non-toxic pharmaceutically acceptable excipients suitable for preparing tablets for mixing. These excipients can be inert excipients, granulating agents, disintegrants, binders, and lubricants. These tablets may be uncoated or may be coated by known techniques that mask the taste of the drug or delay disintegration and absorption in the gastrointestinal tract, thereby providing a sustained release effect over a longer period of time.

[0044] The present invention relates to tetrahydropyridine derivative compounds represented by formula (I), their prodrugs and deuterated compounds thereof, and pharmaceutical compositions containing the same, as well as use of the compositions for treating, preventing or alleviating diseases caused by muscarinic receptor disorders.

[0045] The present invention relates to tetrahydropyridine derivative compounds represented by formula (I), their prodrugs and deuterated compounds thereof, pharmaceutical compositions containing the same, and methods for treating muscarinic receptor disorders using the compositions.

[0046] The present invention relates to tetrahydropyridine derivative compounds shown in formula (I), prodrugs thereof, deuterated compounds thereof, pharmaceutical compositions containing the same, and methods for treating, preventing or alleviating central nervous system disorders using the compositions. Central nervous system disorders are selected from schizophrenia, Alzheimer's disease, Huntington's disease, Parkinson's disease, Lewy body dementia, psychosis, cognitive deficits, movement disorders, mood disorders, cognitive disorders, attention disorders and addiction disorders. In certain embodiments, the central nervous system disorder is schizophrenia.

[0047] In certain embodiments, the central nervous system disorder is Alzheimer's disease.

[0048] In certain embodiments, the central nervous system disorder is Huntington's disease. In certain embodiments, the central nervous system disorder is Parkinson's disease.

[0049] In certain embodiments, the central nervous system disorder is Lewy body dementia. In certain embodiments, the central nervous system disorder is a psychotic disorder.

[0050] In certain embodiments, the central nervous system disorder is a cognitive deficit.

[0051] "Movement disorders" include, but are not limited to, Gilles de la Tourette syndrome, Friederich's ataxia, Huntington's chorea, restless legs syndrome, and other diseases or disorders, symptoms of which include excessive movement, itching, and cramps. "Emotional disorders" include major depressive disorder, dysthymia, recurrent brief depression, mild depressive disorder, bipolar disorder, mania, and anxiety. "Cognitive disorders" refer to diseases or disorders characterized by cognitive deficits (e.g., abnormal working memory, problem-solving ability, etc.). Diseases include, but are not limited to, Alzheimer's disease, Parkinson's disease, dementia (including, but not limited to, AIDS-related dementia, vascular dementia, age-related dementia, dementia associated with Lewy bodies, and idiopathic dementia), Pick's disease, proteinopathy, synucleinopathy, confusion, cognitive deficits associated with fatigue, learning disabilities, brain trauma, autism, age-related cognitive decline, and Cushing's Disease (cognitive impairment associated with autoimmune diseases). “Attention Disorder” means a disease or condition characterized by abnormal or reduced attention span. Diseases include, but are not limited to, attention deficit hyperactivity disorder (ADHD), attention deficit disorder (ADD), Dubowitz Syndrome, FG syndrome, Down syndrome, growth delay caused by insulin-like growth factor I (IGF1) deficiency, hepatic encephalopathy syndrome, and Strauss syndrome. “Addictive Disorder” means a disease or condition characterized by addiction or substance dependence as defined by the Diagnostic & Statistical Manual V (DSM-5). Such disorders are characterized by physical dependence, withdrawal, and tolerance to substances. These substances include, but are not limited to, alcohol, cocaine, amphetamines, opioids, benzodiazepines, inhalants, nicotine, barbiturates, cocaine, and marijuana. Addictive disorders also include behaviors that are compulsive or persistent despite apparent negative consequences. For example, gambling addiction (gambling addiction or compulsive gambling) is considered by those skilled in the art to be an addictive behavior that usually has devastating consequences. In some embodiments, the addictive behavior can be Internet gaming disorder (gaming addiction) as defined in DSM-5.

[0052] The present invention relates to tetrahydropyridine derivative compounds represented by formula (I), their prodrugs, and deuterated compounds thereof, and pharmaceutical compositions containing the same, as well as the use of the compositions for treating, preventing or alleviating muscarinic receptor disorder diseases. Muscarinic disorder diseases refer to any disease or condition that can be improved by activating the muscarinic system. Such diseases include diseases that have therapeutic effects by directly activating muscarinic receptors themselves or inhibiting cholinesterase.

[0053] The present invention relates to tetrahydropyridine derivative compounds represented by formula (I), their prodrugs, and deuterated compounds thereof, and pharmaceutical compositions containing the same, as well as the use of the compositions for treating, preventing or alleviating "diseases associated with schizophrenia" and "disorders associated with schizophrenia". "Diseases associated with schizophrenia" and "disorders associated with schizophrenia" include but are not limited to schizoaffective disorder, psychosis, delusional disorder, psychosis associated with Alzheimer's disease, psychosis associated with Parkinson's disease, psychotic depression, bipolar disorder, psychotic bipolar disorder or any other disease with psychotic features.

[0054] The present invention relates to tetrahydropyridine derivative compounds represented by formula (I), their prodrugs, and deuterated compounds thereof, and pharmaceutical compositions containing the same, as well as the use of the compositions for treating, preventing or alleviating intestinal pain, neuropathic pain, musculoskeletal pain, inflammatory pain, cancer pain, idiopathic pain, postoperative pain, visceral pain, acute pain, subacute and chronic pain, nociceptive pain, neuropathic pain, inflammatory pain, plastic pain, arthritis, migraine, cluster headache, trigeminal neuralgia, herpetic neuralgia, general neuralgia, epilepsy, epileptic symptoms, neurodegenerative diseases, mental disorders, anxiety in subjects. , depression, bipolar disorder, myotonia, arrhythmias, movement disorders, neuroendocrine disorders, ataxia, central neuropathic pain in multiple sclerosis and irritable bowel syndrome, incontinence, pathological cough, visceral pain, osteoarthritis pain, postherpetic neuralgia, diabetic neuropathy, radicular pain, sciatica, back pain, nonspecific chronic back pain, headache, neck pain, moderate pain, severe pain, intractable pain, nociceptive pain, breakthrough pain, postoperative pain (e.g., joint replacement pain, soft tissue surgery pain, hernia repair pain, bunionectomy pain, or abdominoplasty pain), cancer pain, including Chronic cancer pain and breakthrough cancer pain, stroke (e.g., post-stroke central neuropathic pain), whiplash-related conditions, fragility fractures, spinal fractures, ankylosing spondylitis, pemphigus, Raynaud's disease, scleroderma, systemic lupus erythematosus, epidermolysis bullosa, gout, juvenile idiopathic arthritis, oleaginous bone disease, polymyalgia rheumatica, pyoderma gangrenosum, chronic widespread pain, diffuse idiopathic skeletal hyperosteogeny, disc degeneration / herniation pain, radiculopathy, facet joint syndrome, failed back surgery syndrome, burns, carpal tunnel syndrome, Paget's disease pain, spinal stenosis, spondylitis, transverse Myelitis, Ehlers-Danlos syndrome, Fabry disease, mastocytosis, neurofibromatosis, ocular neuropathic pain, sarcoidosis, spondylolisthesis, spondylolisthesis, chemotherapy-induced oral mucositis, Charcot neuropathic osteoarthropathy, temporomandibular joint disorder, painful arthroplasty, non-cardiac chest pain, pudendal, renal colic, biliary tract disease, vascular leg ulcer, pain in Parkinson's disease, pain in Alzheimer's disease, cerebral ischemia, traumatic brain injury, amyotrophic lateral sclerosis, stress-induced angina, exercise-induced angina, palpitations, hypertension, or gastrointestinal dysmotility or methods of reducing the severity thereof.

[0055] In addition to being useful for human treatment, certain compounds and formulations disclosed herein may also be used for veterinary treatment of companion animals, wild animals, and farm animals, including mammals, rodents, etc. Additional examples of animals include horses, dogs, and cats.

[0056] The compound provided by the present invention has the advantages of high selectivity for M receptors, no gender difference in pharmacokinetic parameters, small gastrointestinal adverse reactions, higher drug safety window, higher drug safety, and lower clinical dosage. Therefore, the compound of the present invention has better drugability.

[0057] Unless otherwise specified, the reagents and starting materials used in the present invention are commercially available.

[0058] Unless otherwise specified, the compounds of the present invention were named manually or using chemical structure software, and commercially available compounds were named according to supplier catalog names.

[0059] On the basis of being in accordance with the common sense in the art, the above-mentioned preferred conditions can be arbitrarily combined to obtain the preferred embodiments of the present invention. DETAILED DESCRIPTION

[0060] Certain preferred embodiments of the present invention are illustratively shown in the following non-limiting examples. The experimental methods in the following examples without specifying specific conditions are selected according to conventional methods and conditions, or according to the commercial specifications. The raw materials can be obtained from commercial sources, or prepared by methods known in the art, or prepared according to the methods described herein.

[0061] Example 1.

[0062] 3-((5,5,5-trifluoropentyl)oxy)-4-(1-methyl-1,2,5,6-tetrahydropyridin-3-yl)-1,2,5-thiadiazole

[0063] The synthetic route is as follows:

[0064]

[0065] Preparation of Intermediate 2:

[0066] Sulfur monochloride (48ml, 600mmol) was dissolved in DMF (100ml), α-amino-α-(3-pyridyl)acetonitrile (34g, 200mmol) was slowly added to the solution, and the reaction mixture was stirred at room temperature for 18hr. After adding water (400ml), the aqueous phase was extracted with ether and the ether phase was removed with α-amino-α-(3-pyridyl)acetonitrile. 50% potassium hydroxide solution was added to the aqueous phase until pH 9~10. The aqueous phase was extracted with ether twice and the ether phase was dried and concentrated under reduced pressure. Purification was performed by rapid silica gel column chromatography, eluted with ethyl acetate-dichloromethane, and purified. Intermediate 2 (18.6g) was obtained.

[0067] Preparation of intermediate 3:

[0068] Intermediate 2 (4.9 g, 25 mmol) was dissolved in anhydrous tetrahydrofuran and added dropwise to a mixed solution of 5,5,5-trifluoropentan-1-ol (10.6 g, 75 mmol), sodium hydride (1.8 g, 75 mmol) and anhydrous tetrahydrofuran. The reaction mixture was stirred at room temperature for 2 hours. Water was added and the mixture was extracted with EA, dried and concentrated under reduced pressure. Purification was performed by rapid silica gel column chromatography, eluted with ethyl acetate-petroleum ether, and purified. Intermediate 3 (5.9 g) was obtained.

[0069] Preparation of intermediate 4:

[0070] Intermediate 3 (2.3 g, 7.5 mmol) was dissolved in acetone (15 ml), iodomethane (1.5 ml, 30 mmol) was added dropwise to the reaction solution, and the reaction mixture was stirred at room temperature for 18 hours. A solid precipitated from the solution, filtered and dried to obtain intermediate 4 (2.4 g).

[0071] Preparation of compound 1:

[0072] Intermediate 4 (2.7 g, 6 mmol) was dissolved in anhydrous ethanol (60 ml), sodium borohydride (0.45 g, 12 mmol) was added, the reaction mixture was stirred at 0°C for 1 hr, concentrated under reduced pressure, water was added, EA was extracted, the organic phases were combined, and concentrated under reduced pressure. Purification was performed by rapid silica gel column chromatography, ethyl acetate-methanol gradient elution, and purification was performed to obtain compound 1 (1.9 g). 1 H NMR(400MHz, DMSO-d6)δ7.01(brs,1H),4.44(m,2H),3.25(s,2H),2.50-2.44(m,2H),2.40-2.31(m,5H),2.30-2.19(m,2H),1.84-1.81(m, 2H),1.63-1.46(m,2H)ppm.ESI-MS m / z 322.1[M+1]+.

[0073] Example 2.

[0074] 3-((4-(methyl-d3)pentyl-4,5,5,5-d4)oxy)-4-(1-methyl-1,2,5,6-tetrahydropyridin-3-yl)-1,2,5-thiadiazole

[0075] The synthetic route is as follows:

[0076]

[0077] Preparation of intermediate 5:

[0078] Intermediate 2 (4.9 g, 25 mmol) was dissolved in anhydrous tetrahydrofuran and added dropwise to a mixed solution of 4-(methyl-d3)pentan-4,5,5,5-d4-1-ol (9.2 g, 75 mmol), sodium hydride (1.8 g, 75 mmol) and anhydrous tetrahydrofuran. The reaction mixture was stirred at room temperature for 2 hours. Water was added and the mixture was extracted with EA, dried and concentrated under reduced pressure. Purification was performed by rapid silica gel column chromatography, eluted with ethyl acetate-petroleum ether, and purified. Intermediate 5 (5.2 g) was obtained.

[0079] Preparation of intermediate 6:

[0080] Intermediate 5 (2.0 g, 7.5 mmol) was dissolved in acetone (15 ml), iodomethane (1.5 ml, 30 mmol) was added dropwise to the reaction solution, and the reaction mixture was stirred at room temperature for 18 hours. A solid precipitated from the solution, which was filtered and dried to obtain Intermediate 6 (2.1 g).

[0081] Preparation of compound 2:

[0082] Intermediate 6 (2.5 g, 6 mmol) was dissolved in anhydrous ethanol (60 ml), sodium borohydride (0.45 g, 12 mmol) was added, the reaction mixture was stirred at 0°C for 1 hour, concentrated under reduced pressure, water was added, EA was extracted, the organic phases were combined, and concentrated under reduced pressure. Purification was performed by rapid silica gel column chromatography, ethyl acetate-methanol gradient elution, and purification was performed. Compound 2 (1.8 g) was obtained. Deuteration rate: 98.8%. 1 H NMR(400MHz,DMSO-d6)δ7.09(brs,1H),4.38(m,2H),3.25(s,2H),2.60-2.48 (m,2H),2.46-2.31(m,5H),1.85-1.79(m,2H),1.65-1.47(m,2H)ppm.ESI-MS m / z 289.2[M+1] + .

[0083] Example 3.

[0084] 3-((4,5,5,5-tetrafluoro-4-(trifluoromethyl)pentyl)oxy)-4-(1-methyl-1,2,5,6-tetrahydropyridin-3-yl)-1,2,5-thiadiazole

[0085] The synthetic route is as follows:

[0086]

[0087] Preparation of intermediate 7:

[0088] Intermediate 2 (4.9 g, 25 mmol) was dissolved in anhydrous tetrahydrofuran and added dropwise to a mixed solution of 4,5,5,5-tetrafluoro-4-(trifluoromethyl)pentan-1-ol (17.1 g, 75 mmol), sodium hydride (1.8 g, 75 mmol) and anhydrous tetrahydrofuran. The reaction mixture was stirred at room temperature for 2 hours. Water was added and the mixture was extracted with EA, dried and concentrated under reduced pressure. Purification was performed by rapid silica gel column chromatography, eluted with ethyl acetate-petroleum ether, and purified. Intermediate 7 (8.5 g) was obtained.

[0089] Preparation of intermediate 8:

[0090] Intermediate 7 (2.9 g, 7.5 mmol) was dissolved in acetone (15 ml), iodomethane (1.5 ml, 30 mmol) was added dropwise to the reaction solution, and the reaction mixture was stirred at room temperature for 18 hours. A solid precipitated from the solution, filtered, and dried to obtain intermediate 8 (2.2 g).

[0091] Preparation of compound 3:

[0092] Intermediate 8 (3.2 g, 6 mmol) was dissolved in anhydrous ethanol (65 ml), sodium borohydride (0.45 g, 12 mmol) was added, the reaction mixture was stirred at 0°C for 1 hr, concentrated under reduced pressure, water was added, EA was extracted, the organic phases were combined, and concentrated under reduced pressure. Purification was performed by rapid silica gel column chromatography, ethyl acetate-methanol gradient elution, and purification was performed to obtain compound 3 (1.8 g). 1 H NMR(400MHz,DMSO-d6)δ7.08(brs,1H),4.40(m,2H),3.26(s,2H),2.61-2.47 (m,2H),2.45-2.30(m,5H),1.83-1.75(m,2H),1.68-1.35(m,2H)ppm.ESI-MS m / z 408.1[M+1] + .

[0093] Example 4.

[0094] 3-((3-(1-fluorocyclopropyl)propoxy)-4-(1-methyl-1,2,5,6-tetrahydropyridin-3-yl)-1,2,5-thiadiazole

[0095] The synthetic route is as follows:

[0096]

[0097] Preparation of intermediate 11:

[0098] Intermediate 2 (4.9 g, 25 mmol) was dissolved in anhydrous tetrahydrofuran and added dropwise to a mixed solution of 3-(1-fluorocyclopropyl)propan-1-ol (8.9 g, 75 mmol), sodium hydride (1.8 g, 75 mmol) and anhydrous tetrahydrofuran. The reaction mixture was stirred at room temperature for 2 hours. Water was added and the mixture was extracted with EA, dried and concentrated under reduced pressure. Purification was performed by rapid silica gel column chromatography, eluted with ethyl acetate-petroleum ether, and purified. Intermediate 11 (4.8 g) was obtained.

[0099] Preparation of intermediate 12:

[0100] Intermediate 11 (2.1 g, 7.5 mmol) was dissolved in acetone (15 ml), iodomethane (1.5 ml, 30 mmol) was added dropwise to the reaction solution, and the reaction mixture was stirred at room temperature for 18 hours. A solid precipitated from the solution, which was filtered and dried to obtain intermediate 12 (2.1 g).

[0101] Preparation of compound 4:

[0102] Intermediate 12 (2.5 g, 6 mmol) was dissolved in anhydrous ethanol (60 ml), sodium borohydride (0.45 g, 12 mmol) was added, the reaction mixture was stirred at 0°C for 1 hr, concentrated under reduced pressure, water was added, EA was extracted, the organic phases were combined, and concentrated under reduced pressure. Purification was performed by rapid silica gel column chromatography, ethyl acetate-methanol gradient elution, and purification was performed to obtain compound 4 (1.7 g). 1 H NMR(400MHz,DMSO-d6)δ7.05 (brs,1H),4.39(m,2H),3.28(s,2H),2.53-2.45(m,2H),2.41-2.29(m,5H),1.86-1.79(m,2H),1.59-1.45 (m, 2H),1.33-0.61(m,4H)ppm.ESI-MS m / z 298.1[M+1] + .

[0103] Example 5.

[0104] 3-((4-(Cyclopropyl)butoxy)-4-(1-methyl-1,2,5,6-tetrahydropyridin-3-yl)-1,2,5-thiadiazole

[0105] The synthetic route is as follows:

[0106]

[0107] Preparation of intermediate 18:

[0108] Intermediate 2 (4.9 g, 25 mmol) was dissolved in anhydrous tetrahydrofuran and added dropwise to a mixed solution of 4-(cyclopropyl)butan-1-ol (8.6 g, 75 mmol), sodium hydride (1.8 g, 75 mmol) and anhydrous tetrahydrofuran. The reaction mixture was stirred at room temperature for 2 hours. Water was added and the mixture was extracted with EA, dried and concentrated under reduced pressure. Purification was performed by rapid silica gel column chromatography, eluted with ethyl acetate-petroleum ether, and purified. Intermediate 18 (4.8 g) was obtained.

[0109] Preparation of intermediate 19:

[0110] Intermediate 18 (2.1 g, 7.5 mmol) was dissolved in acetone (15 ml), and iodomethane (1.5 ml, 30 mmol) was added dropwise to the reaction solution. The reaction mixture was stirred at room temperature for 18 hours, and a solid precipitated from the solution. The solid was filtered and dried to obtain intermediate 19 (2.3 g).

[0111] Preparation of compound 5:

[0112] Sodium borohydride (0.45 g, 12 mmol) was added to intermediate 19 (2.5 g, 6 mmol) in anhydrous ethanol (60 ml), and the reaction mixture was stirred at 0°C for 1 hr, concentrated under reduced pressure, added with water, extracted with EA, and the organic phases were combined and concentrated under reduced pressure. Purification was performed by rapid silica gel column chromatography with ethyl acetate-methanol gradient elution to obtain compound 5 (1.8 g). 1 H NMR (400MHz, DMSO-d6) δ7.35(brs,1H),4.40(m,2H),3.29(s,2H),2.52-2.44(m,2H),2.43-2.29(m,5H),1.85-1.77(m,2H),1.61-1.43 (m, 4H),1.22-0.61(m,5H)ppm.ESI-MS m / z 294.2[M+1] + .

[0113] Example 6.

[0114] 3-((4-(1-fluorocyclopropyl)butoxy)-4-(1-methyl-1,2,5,6-tetrahydropyridin-3-yl)-1,2,5-thiadiazole

[0115] The synthetic route is as follows:

[0116]

[0117] Preparation of intermediate 20:

[0118] Intermediate 2 (4.9 g, 25 mmol) was dissolved in anhydrous tetrahydrofuran and added dropwise to a mixed solution of 4-(1-fluorocyclopropyl)butan-1-ol (9.9 g, 75 mmol), sodium hydride (1.8 g, 75 mmol) and anhydrous tetrahydrofuran. The reaction mixture was stirred at room temperature for 2 hours. Water was added and the mixture was extracted with EA, dried and concentrated under reduced pressure. Purification was performed by rapid silica gel column chromatography, eluted with ethyl acetate-petroleum ether, and purified. Intermediate 20 (5.1 g) was obtained.

[0119] Preparation of intermediate 21:

[0120] Intermediate 19 (2.1 g, 7.5 mmol) was dissolved in acetone (15 ml), and iodomethane (1.5 ml, 30 mmol) was added dropwise to the reaction solution. The reaction mixture was stirred at room temperature for 18 hours, and a solid precipitated from the solution. The solid was filtered and dried to obtain intermediate 21 (2.1 g).

[0121] Preparation of compound 6:

[0122] Intermediate 21 (2.6 g, 6 mmol) was dissolved in anhydrous ethanol (60 ml), sodium borohydride (0.45 g, 12 mmol) was added, the reaction mixture was stirred at 0°C for 1 hr, concentrated under reduced pressure, water was added, EA was extracted, the organic phases were combined, and concentrated under reduced pressure. Purification was performed by rapid silica gel column chromatography, ethyl acetate-methanol gradient elution, and purification was performed to obtain compound 6 (1.7 g). 1 H NMR(400MHz,DMSO-d6)δ7.38 (brs,1H),4.41(m,2H),3.30(s,2H),2.53-2.45(m,2H),2.44-2.28(m,5H),1.86-1.74(m,2H),1.65-1.42 (m,4H),1.31-0.63(m,4H)ppm.ESI-MS m / z 312.2[M+1] + .

[0123] Example 7.

[0124] 3-((5,5,5-trifluoropentyl)oxy)-4-(1-(methyl-d3)-1,2,5,6-tetrahydropyridin-3-yl)-1,2,5-thiadiazole

[0125] The synthetic route is as follows:

[0126]

[0127] Preparation of intermediate 13:

[0128] Intermediate 3 (2.3 g, 7.5 mmol) was dissolved in acetone (15 ml), deuterated iodomethane (1.5 ml, 30 mmol) was added dropwise to the reaction solution, and the reaction mixture was stirred at room temperature for 18 hours. A solid precipitated from the solution, which was filtered and dried to obtain intermediate 13 (2.5 g).

[0129] Preparation of compound 7:

[0130] Intermediate 13 (2.7 g, 6 mmol) was dissolved in anhydrous ethanol (60 ml), sodium borohydride (0.45 g, 12 mmol) was added, the reaction mixture was stirred at 0°C for 1 hr, concentrated under reduced pressure, water was added, EA was extracted, the organic phases were combined, and concentrated under reduced pressure. Purification was performed by rapid silica gel column chromatography, ethyl acetate-methanol gradient elution, and purification was performed. Compound 7 (2 g) was obtained. Deuteration rate: 99.1%. 1 H NMR(400MHz,DMSO-d6)δ7.09(brs,1H),4.46(m,2H),3.24(s,2H),2.52-2.45(m,2H),2.43-2.37(m,2H),2.32-2.18 (m, 2H),1.86-1.80(m,2H),1.64-1.47(m,2H)ppm.ESI-MS m / z 325.1[M+1] + .

[0131] Example 8.

[0132] 3-((4-(methyl-d3)pentyl-4,5,5,5-d4)oxy)-4-(1-(methyl-d3)-1,2,5,6-tetrahydropyridin-3-yl)-1,2,5-thiadiazole

[0133] The synthetic route is as follows:

[0134]

[0135] Preparation of intermediate 14

[0136] The preparation process of intermediate 14 is similar to that of intermediate 6, except that iodomethane is replaced with deuterated iodomethane to obtain intermediate 14 (2.2 g).

[0137] Preparation of compound 8:

[0138] Intermediate 14 (2.5 g, 6 mmol) was dissolved in anhydrous ethanol (60 ml), sodium borohydride (0.45 g, 12 mmol) was added, the reaction mixture was stirred at 0°C for 1 hr, concentrated under reduced pressure, water was added, EA was extracted, the organic phases were combined, and concentrated under reduced pressure. Purification was performed by rapid silica gel column chromatography, ethyl acetate-methanol gradient elution, and purification was performed to obtain compound 8 (1.9 g).

[0139] Deuterium substitution rate: 98.6%. 1 H NMR(400MHz,DMSO-d6)δ7.08(brs,1H), 4.37(m,2H), 3.23(s,2H), 2.61-2.49 (m,2H), 2.45-2.36(m,2H), 1.83-1.78(m,2H), 1.66-1.45(m,2H)ppm.ESI-MS m / z 292.2[M+1] + .

[0140] Example 9.

[0141] 3-((4,5,5,5-tetrafluoro-4-(trifluoromethyl)pentyl)oxy)-4-(1-(methyl-d3)-1,2,5,6-tetrahydropyridin-3-yl)-1,2,5-thiadiazole

[0142] The synthetic route is as follows:

[0143]

[0144] Preparation of intermediate 15

[0145] The preparation process of intermediate 15 is similar to that of intermediate 8, except that iodomethane is replaced with deuterated iodomethane to obtain intermediate 15 (2.2 g).

[0146] Preparation of compound 9:

[0147] Intermediate 15 (3.2 g, 6 mmol) was dissolved in anhydrous ethanol (60 ml), sodium borohydride (0.45 g, 12 mmol) was added, the reaction mixture was stirred at 0°C for 1 hr, concentrated under reduced pressure, water was added, EA was extracted, the organic phases were combined, and concentrated under reduced pressure. Purification was performed by rapid silica gel column chromatography, ethyl acetate-methanol gradient elution, and purification was performed. Compound 9 (2 g) was obtained. Deuteration rate: 99.3%. 1 H NMR(400MHz,DMSO-d6)δ7.10(brs,1H), 4.42(m,2H), 3.28(s,2H), 2.63-2.47(m,2H), 2.44-2.35(m,2H), 1.84-1.77(m,2H), 1.69-1.37 (m,2H)ppm. ESI-MS m / z 411.1[M+1] + .

[0148] Example 10.

[0149] 3-((3-(Cyclopropyl)propoxy)-4-(1-(methyl-d3)-1,2,5,6-tetrahydropyridin-3-yl)-1,2,5-thiadiazole

[0150] The synthetic route is as follows:

[0151]

[0152] Preparation of intermediate 9:

[0153] Intermediate 2 (4.9 g, 25 mmol) was dissolved in anhydrous tetrahydrofuran and added dropwise to a mixed solution of 3-(cyclopropyl)propan-1-ol (7.5 g, 75 mmol), sodium hydride (1.8 g, 75 mmol) and anhydrous tetrahydrofuran. The reaction mixture was stirred at room temperature for 2 hours. Water was added and the mixture was extracted with EA, dried and concentrated under reduced pressure. Purification was performed by rapid silica gel column chromatography, eluted with ethyl acetate-petroleum ether, and purified. Intermediate 9 (4.7 g) was obtained.

[0154] Preparation of intermediate 16:

[0155] Intermediate 9 (2.0 g, 7.5 mmol) was dissolved in acetone (15 ml), deuterated iodomethane (1.5 ml, 30 mmol) was added dropwise to the reaction solution, and the reaction mixture was stirred at room temperature for 18 hours. A solid precipitated from the solution, which was filtered and dried to obtain intermediate 16 (2.2 g).

[0156] Preparation of compound 10:

[0157] Intermediate 16 (2.4 g, 6 mmol) was dissolved in anhydrous ethanol (60 ml), sodium borohydride (0.45 g, 12 mmol) was added, the reaction mixture was stirred at 0°C for 1 hr, concentrated under reduced pressure, water was added, EA was extracted, the organic phases were combined, and concentrated under reduced pressure. Purification was performed by rapid silica gel column chromatography, ethyl acetate-methanol gradient elution, and purification was performed. Compound 10 (1.6 g) was obtained. Deuteration rate: 98.6%. 1 H NMR(400MHz, DMSO-d6)δ7.33(brs,1H),4.41(m,2H),3.31(s,2H),2.54-2.45(m,2H),2.42-2.34(m,2H),1.85-1.76(m, 2H),1.59-1.42(m,2H),1.24-0.62(m,5H)ppm.ESI-MS m / z283.2[M+1] + .

[0158] Example 11.

[0159] 3-((3-(1-fluorocyclopropyl)propoxy)-4-(1-(methyl-d3)-1,2,5,6-tetrahydropyridin-3-yl)-1,2,5-thiadiazole

[0160] The synthetic route is as follows:

[0161]

[0162] Preparation of intermediate 17:

[0163] The preparation process of intermediate 17 is similar to that of intermediate 12, except that iodomethane is replaced by deuterated iodomethane to obtain intermediate 17 (2.0 g).

[0164] Preparation of compound 11:

[0165] Intermediate 17 (2.5 g, 6 mmol) was dissolved in anhydrous ethanol (60 ml), sodium borohydride (0.45 g, 12 mmol) was added, the reaction mixture was stirred at 0°C for 1 hr, concentrated under reduced pressure, water was added, EA was extracted, the organic phases were combined, and concentrated under reduced pressure. Purification was performed by rapid silica gel column chromatography, ethyl acetate-methanol gradient elution, and purification was performed. Compound 11 (1.8 g) was obtained. Deuteration rate: 98.9%. 1 H NMR(400MHz, DMSO-d6)δ7.04(brs,1H),4.38(m,2H),3.29(s,2H),2.55-2.46(m,2H),2.42-2.35(m,2H),1.87-1.78(m, 2H),1.60-1.44(m,2H),1.35-0.60(m,4H)ppm.ESI-MS m / z301.1[M+1] + .

[0166] Example 12.

[0167] 3-((4-(Cyclopropyl)butoxy)-4-(1-(methyl-d3)-1,2,5,6-tetrahydropyridin-3-yl)-1,2,5-thiadiazole

[0168] The synthetic route is as follows:

[0169]

[0170] Preparation of intermediate 22:

[0171] The preparation process of intermediate 22 is similar to that of intermediate 19, except that iodomethane is replaced with deuterated iodomethane to obtain intermediate 22 (2.4 g).

[0172] Preparation of compound 12:

[0173] Intermediate 22 (2.5 g, 6 mmol) was dissolved in anhydrous ethanol (60 ml), sodium borohydride (0.45 g, 12 mmol) was added, the reaction mixture was stirred at 0°C for 1 hr, concentrated under reduced pressure, water was added, EA was extracted, the organic phases were combined, and concentrated under reduced pressure. Purification was performed by rapid silica gel column chromatography, ethyl acetate-methanol gradient elution, and purification was performed. Compound 12 (1.9 g) was obtained. Deuteration rate: 99.1%. 1 H NMR(400MHz, DMSO-d6)δ7.25(brs,1H),4.42(m,2H),3.30(s,2H),2.54-2.45(m,2H),2.43-2.37(m,2H),1.86-1.77(m, 2H),1.63-1.42(m,4H),1.25-0.63(m,5H)ppm.ESI-MS m / z297.2[M+1] + .

[0174] Example 13.

[0175] 3-((4-(1-fluorocyclopropyl)butoxy)-4-(1-(methyl-d3)-1,2,5,6-tetrahydropyridin-3-yl)-1,2,5-thiadiazole

[0176] The synthetic route is as follows:

[0177]

[0178] Preparation of intermediate 23:

[0179] The preparation process of intermediate 23 is similar to that of intermediate 21, except that iodomethane is replaced with deuterated iodomethane to obtain intermediate 23 (2.3 g).

[0180] Preparation of compound 13:

[0181] Intermediate 23 (2.6 g, 6 mmol) was dissolved in anhydrous ethanol (60 ml), sodium borohydride (0.45 g, 12 mmol) was added, the reaction mixture was stirred at 0°C for 1 hr, concentrated under reduced pressure, water was added, EA was extracted, the organic phases were combined, and concentrated under reduced pressure. Purification was performed by rapid silica gel column chromatography, ethyl acetate-methanol gradient elution, and purification was performed. Compound 13 (1.8 g) was obtained. Deuteration rate: 99.1%. 1H NMR(400MHz, DMSO-d6)δ7.38(brs,1H),4.40(m,2H),3.33(s,2H),2.55-2.45(m,2H),2.43-2.33(m,2H),1.85-1.76(m, 2H),1.68-1.39(m,4H),1.32-0.65(m,4H)ppm.ESI-MS m / z 315.2[M+1] + .

[0182] Example 14.

[0183] 3-((5,5-difluoropentyl)oxy)-4-(1-methyl-1,2,5,6-tetrahydropyridin-3-yl)-1,2,5-thiadiazole

[0184] The synthetic route is as follows:

[0185]

[0186] Preparation of intermediate 24:

[0187] Oxalyl chloride (15.85 g, 124.84 mmol) was dissolved in 100 ml DCM, N2 protected, cooled to -78 °C, DMSO (14.63 g, 187.26 mmol) in DCM solution was added, and the reaction was stirred for 15 min. Ethyl 5-hydroxyvalerate (9.1 g, 62.42 mmol) was dissolved in 50 ml DCM, added dropwise to the above solution, and stirred for 10 min. Triethylamine (37.90 g, 374.51 mmol) was added dropwise, N2 protected, -78 °C stirred, and the reaction was complete after TLC detection. Saturated ammonium chloride solution was added, extracted with ethyl acetate, and purified by rapid silica gel column chromatography, ethyl acetate-petroleum ether gradient elution, and intermediate 24 (6.2 g) was obtained.

[0188] Preparation of intermediate 25:

[0189] Intermediate 24 (9 g, 61.32 mmol) was dissolved in 60 ml DCM, cooled to -78 °C, and bis(2-methoxyethyl)aminosulfur trifluoride (16.28 g, 73.58 mmol) was added. The temperature was slowly raised to 50 °C and stirred for 16 hours. Saturated sodium bicarbonate solution was added to the reaction solution, extracted with ethyl acetate, and purified by rapid silica gel column chromatography with ethyl acetate-petroleum ether gradient elution to obtain intermediate 25 (4.6 g).

[0190] Preparation of intermediate 26:

[0191] Intermediate 25 (4 g, 22.2 mmol) was dissolved in 30 ml THF, cooled to 0°C, protected by N2, and LiBH4 (1.5 g, 66.6 mmol) was added. The temperature was slowly raised to 15°C and stirred for 30 hours. Saturated ammonium chloride solution was added to the reaction solution, extracted with ethyl acetate, and purified by rapid silica gel column chromatography, eluted with ethyl acetate-petroleum ether gradient to obtain intermediate 26 (3.3 g). ESI-MS m / z139.1[M+1] + .

[0192] Preparation of intermediate 27:

[0193] Intermediate 2 (4.9 g, 25 mmol) was dissolved in anhydrous tetrahydrofuran and added dropwise to a mixed solution of intermediate 26 (10.4 g, 75 mmol), sodium hydride (1.8 g, 75 mmol) and anhydrous tetrahydrofuran. The reaction mixture was stirred at room temperature for 2 hours. Water was added and the mixture was extracted with EA, dried and concentrated under reduced pressure. Purification was performed by rapid silica gel column chromatography, eluted with ethyl acetate-petroleum ether, and purified. Intermediate 27 (5.1 g) was obtained.

[0194] Preparation of intermediate 28:

[0195] Intermediate 27 (2.1 g, 7.5 mmol) was dissolved in acetone (15 ml), and iodomethane (1.5 ml, 30 mmol) was added dropwise to the reaction solution. The reaction mixture was stirred at room temperature for 18 hours, and a solid precipitated from the solution, which was filtered and dried to obtain intermediate 28 (2.1 g).

[0196] Preparation of compound 14:

[0197] Intermediate 28 (2.6 g, 6 mmol) was dissolved in anhydrous ethanol (60 ml), sodium borohydride (0.45 g, 12 mmol) was added, the reaction mixture was stirred at 0°C for 1 hr, concentrated under reduced pressure, water was added, EA was extracted, the organic phases were combined, and concentrated under reduced pressure. Purification was performed by rapid silica gel column chromatography, ethyl acetate-methanol gradient elution, and purification was performed to obtain compound 14 (1.5 g). 1 H NMR(400MHz, DMSO-d6) δ7.20 (brs, 1H),5.83(m,1H),4.44(m,2H),3.45(s,2H),2.57-2.52(m,2H),2.48-2.31(m,5H),1.89-1.81(m, 2H),1.63-1.46(m,2H)ppm.ESI-MS m / z 304.1[M+1] + .

[0198] Example 15.

[0199] 3-((5,5-difluoropentyl)oxy)-4-(1-(methyl-d3)-1,2,5,6-tetrahydropyridin-3-yl)-1,2,5-thiadiazole

[0200]

[0201] Preparation of intermediate 29:

[0202] Intermediate 27 (2.1 g, 7.5 mmol) was dissolved in acetone (15 ml), deuterated iodomethane (1.5 ml, 30 mmol) was added dropwise to the reaction solution, and the reaction mixture was stirred at room temperature for 18 hours. A solid precipitated from the solution, which was filtered and dried to obtain intermediate 29 (2.6 g).

[0203] Preparation of compound 15:

[0204] Intermediate 29 (2.6 g, 6 mmol) was dissolved in anhydrous ethanol (60 ml), sodium borohydride (0.45 g, 12 mmol) was added, the reaction mixture was stirred at 0°C for 1 hr, concentrated under reduced pressure, water was added, EA was extracted, the organic phases were combined, and concentrated under reduced pressure. Purification was performed by rapid silica gel column chromatography, ethyl acetate-methanol gradient elution, and purification was performed. Compound 15 (2.1 g) was obtained. Deuteration rate: 99.1%. 1 H NMR(400MHz, DMSO-d6)δ7.21(brs,1H),5.84(m,1H),4.45(m,2H),3.43(s,2H),2.58-2.53 (m,2H),2.42-2.31(m,2H),1.90-1.81(m,2H),1.60-1.46(m,2H)ppm.ESI-MS m / z 307.1[M+1] + .

[0205] Prepare the reference compound Xanomeline with reference to the above examples:

[0206] .

[0207] Effect Example 1 In vitro radioligand binding assay

[0208] The example compounds and control compounds were tested for their agonist ability on Flp-In™ Chinese hamster ovary (CHO) cells stably expressing muscarinic acetylcholine receptor (mAChR) human M1-M5 (hM1-hM5). The Flp-In™ cell line expresses the target protein from the Flp-In expression vector. Targeted integration of the Flp-In™ expression vector ensures high-level expression of mAChR hM1-hM5.

[0209] Test steps:

[0210] 1. All test compounds and the control compound Xanomeline were dissolved in dimethyl sulfoxide (DMSO) and the solution was stored at a concentration of 10 mM.

[0211] 2. Analyze the expression of mAChR in each CHO cell line by combining [³H]-N-methylscopolamine ([³H]-NMS).

[0212] 3. pERK assay was performed at different times (2.5-60 minutes) using example compounds and control compounds. Extracellular signal-related kinase (ERK1 / 2 or p42 / 44) is a kinase in the mitogen-activated protein kinase (MAPK) family. Phosphorylation of ERK (pERK) can be used as a common endpoint measure for activation of signal transduction linked to a variety of G protein-coupled receptors (GPCRs) and β-arrestin.

[0213] 4. Cells were serum starved for 5 to 6 hours. Curves were normalized to the maximum response corresponding to a 5-minute stimulation in fetal bovine serum (FBS) medium. A 5-minute incubation with the test article was selected for dose-response pERK assays (n=2).

[0214] 5. pERK dose response experiments were performed to test the agonist ability of the example compounds in CHO cells stably expressing hM2, hM3 and hM5 (n=3). These pERK dose response experiments were repeated to test the agonist ability of the example compounds in CHO cells stably expressing hM1 and hM4 (n=4). Differences in drug potency were evaluated by comparing EC50 values, and differences in compound efficacy were analyzed by maximum response (Emax), EC 50 The Emax values ​​are shown in Table 1.

[0215] Table 1: Agonistic effects of the example compounds on stably expressed muscarinic acetylcholine receptor (mAChR) human M1-M5 (hM1-hM5)

[0216]

[0217] The experimental results show that Xanomeline, as an agonist of M1 and M4 receptors, has good M1 agonist activity and general M4 agonist activity. All the example compounds have better M1 and M4 agonist activity than the control compound Xanomeline, especially the example compounds 5, 14 and 15 have M1 receptor agonist activity more than 3 times that of Xanomeline, and the maximum reaction of compound 5 and 14 to agonize M1 receptor maximum reaction Emax value is 100%, which is 90% higher than the M1 agonist Emax value of Xanomeline. The M4 agonist activity of compound 2 and 14 is more than 3 times that of Xanomeline, and the maximum reaction of compound 2 and 14 to agonize M1 receptor maximum reaction Emax value is 100% and 99%, which is 87% higher than the M4 agonist Emax value of Xanomeline. In addition, all M1 and M4 agonist activity selectivity is better than the control compound Xanomeline, indicating the clinical use of the example compounds, clinical advantages of lower dosage and lower gastrointestinal side effects.

[0218] Effect Example 2 Pharmacokinetic Evaluation

[0219] SD rats were used as test animals, and the drug concentration in plasma at different time points after oral administration of the example compounds to Sprague-Dawley (SD) rats was determined by LC / MS / MS method. The pharmacokinetic behavior of the disclosed compounds in Sprague-dawley (SD) rats was studied, and their pharmacokinetic characteristics were evaluated.

[0220] 1) Experimental drugs

[0221] Example compounds 1, 2, 6, 14, 15 and Xanomeline.

[0222] 2) Experimental animals

[0223] Thirty-six Sprague-Dawley (SD) rats were used, with 6 rats in each group, half of which were male and half were female. After fasting overnight but not water, the rats were given drugs by gavage.

[0224] 3) Drug preparation

[0225] A certain amount of the example compounds were weighed respectively, and a dosing solvent was added: citric acid + 5% DMSO + 10% Solutol + 85% saline (pH 6.0) to prepare a 7.5 mg / mL uniform solution.

[0226] 4) Drug administration

[0227] The dosage was 75 mg / kg and the administration volume was 10.0 mL / kg.

[0228] 5) Operation

[0229] Before administration and 0.25, 0.5, 1.0, 2.0, 4.0, 6.0, 8.0, 12.0, and 24.0 hours after administration, 0.2 mL of blood was collected from the eye sockets and placed in EDTA-K2 anticoagulant tubes. The blood was centrifuged at 10,000 rpm for 1 minute (4°C), and the plasma was separated within 1 hour and stored at -20°C for testing. The blood collection and centrifugation process was operated under ice bath conditions. Food was taken 2 hours after administration.

[0230] Determination of the content of the test compound in the plasma of SD rats after administration of different concentrations of the drug: Take the plasma samples of SD rats at different times after administration, dilute 10 times with acetonitrile solution containing internal standard, vortex mix, and centrifuge at 3700 rpm for 10 minutes. After the supernatant is mixed with water in a ratio of 1:1, take 0.5 μL of the supernatant for LC / MS / MS analysis.

[0231] 6) Pharmacokinetic parameter results

[0232] Table 2: Pharmacokinetic parameters of the example compounds in male and female SD rats

[0233]

[0234] The experimental results showed that there were significant differences in the metabolic parameters of the control compound Xanomeline between males and females. max The drug concentration AUC in female rats was 5.6 times that in male rats. 0-t The difference in metabolic parameters between male and female was within 2 times of that in male. There was no significant gender difference. All tested compounds had higher exposure than the control compound Xanomeline. In particular, compound 15 had a higher exposure in male rats C max It is 4.8 times that of Xanomeline, AUC in male rats 0-t The experimental results show that the example compound has better metabolic parameters, and there is no gender difference in metabolic parameters, and the clinical use population is wider, the drug safety window is wider, and the drug safety is higher.

[0235] Effect Example 3 In vivo evaluation of the efficacy of the compounds in the example in treating schizophrenia

[0236] 1. Experimental Methods

[0237] Animals: CD-1 mice were housed in separate cages. They were allowed to eat and drink freely and were fed with standard rodent diet. The humidity in the room was maintained at about 50%, and the light-dark cycle was 12 hours. The mice were fed adaptively for one week before the experiment. All behavioral experiments were completed between 9:00 and 12:00. All animal experiments strictly followed the ethical principles of animal use of international health research institutions.

[0238] Animal grouping: 70 CD-1 mice were randomly divided into 7 groups, 10 mice in each group, including negative control group (blank control), model group, positive drug group (Xanomeline), and compound number 1, 2, 5, and 14 groups, see Table 3.

[0239] Table 3: Trial groups and dosing regimens

[0240]

[0241] Preparation of schizophrenia model: The negative control group was injected with normal saline (1 mL / kg) every morning for 7 days, and the other 6 groups were injected with an equal amount of ketamine (30 mg / kg) for 7 days to establish a ketamine-induced schizophrenia animal model.

[0242] Drug administration: The dosage of experimental drugs was calculated based on the body surface area ratio. The gavage volume of each group was 10 mL / Kg, the dosage was 20 mpk, and the gavage was continued BID for 10 consecutive days. See Table 3 for details.

[0243] Animal symptoms and cognitive function testing: The first day of modeling was recorded as D1. After 7 days of modeling (D7) and 10 days of drug intervention (D17), all mice were subjected to open field test and forced swimming test for the same time according to different groups.

[0244] 1) Open field test: It consists of 4 gray observation boxes with a size of 50cm x 50cm x 40cm without a roof, a camera and a Smart3.0 animal behavior video analysis system. During the experiment, 4 mice were placed in the observation box at the same time. The Smart system automatically recorded the movement trajectory and distance of the rats, and the free movement time was 30 minutes. Each observation box was divided into 9 areas of 3×3, which were set as peripheral areas and central areas. The exploratory behavior and autonomous activities of mice in different areas and different time periods were analyzed to study the positive symptoms of schizophrenia. The activity distance in the central area and the first 10 minutes (T1) represented the exploratory behavior of mice, and the activity distance in the peripheral area and the last 20 minutes (10min-20min is T2, and the last 10min is T3) represented the autonomous activities of mice.

[0245] 2) Forced swimming test: Pour warm water into a glass beaker 40 cm high and 25 cm in diameter. During the experiment, each mouse was placed in warm water and forced to swim for 5 minutes. The cumulative immobility time (the mouse was able to float in the water without struggling) was recorded and the percentage of immobility time was calculated for studying the negative symptoms of schizophrenia.

[0246] 3) Adverse reaction record: 0.5-3 hours after the first administration on the first and third days, observe the adverse reactions of diarrhea and vomiting in mice. Record and evaluate the overall gastrointestinal adverse reactions of animals: severe +++, moderate ++, mild +, no effect -.

[0247] Statistical analysis: SPSS 18.0 software was used for statistical analysis, and the data were expressed as mean ± standard deviation. The differences were statistically significant when P < 0.05.

[0248] 2. Results and Analysis

[0249] 1. Comparison of activity distances of each group

[0250] There were statistically significant differences in peripheral activity distance, total activity distance, and activity distances at T1, T2, and T3 among the groups of mice before drug intervention (P<0.01). Further comparison results showed that there were statistically significant differences in peripheral activity distance, total activity distance, and activity distances at three time periods between the model group, positive drug group, and example compound groups and the negative control group (P<0.05 or P<0.01), indicating that the model was successfully established.

[0251] The differences in peripheral activity distance and total activity distance after drug intervention in each group were statistically significant compared with those before drug intervention. Compared with the negative control group, the peripheral activity distance and total activity distance in the model group were significantly increased (P<0.01); compared with the model group, the peripheral activity distance and total activity distance in the positive drug group and the example compound were significantly reduced (P<0.01). The paired t-test results before and after drug intervention showed that there was no statistically significant difference in the data before and after drug administration in the model group (P>0.05), and the peripheral activity distance and total activity distance after drug intervention in the positive drug group and the example compound were statistically significant compared with those before intervention (P<0.01). The reduction degree of peripheral activity distance and total activity distance in the example compound group after drug intervention was better than that of the positive control drug Xanomeline, as shown in Table 4.

[0252] Table 4: Comparison of activity distances in different areas of the open field test in each group of rats before and after drug intervention

[0253]

[0254] Note: SNK-q pairwise comparison: compared with the negative control group, **P<0.01; compared with the model group, ##P<0.01. Paired t test: compared with before drug intervention, △P<0.05, △△P<0.01.

[0255] 2. Comparison of forced swimming time among groups

[0256] Compared with the negative control group, the percentage of immobility time of the rats in the model group, positive drug group, and example compound group before drug intervention increased significantly, indicating that the model was successfully established.

[0257] After 10 days of treatment with Xanomeline and Example compounds, the positive drug group showed significant difference in reducing the percentage of immobility time in forced swimming compared with the model group, and the Example compound group showed significant difference in reducing the percentage of immobility time in forced swimming compared with the model group (P<0.01). The Example compound group was better than Xanomeline in reducing the percentage of immobility time in forced swimming. The degree of diarrhea and vomiting of Xanomeline's major gastrointestinal drug-related adverse reactions was severe, while the Example compound group had mild or no effect. See Table 5.

[0258] Table 5: Comparison of the forced swimming test and gastrointestinal adverse reactions in rats of each group after drug intervention

[0259]

[0260] Note: Pairwise comparison of SNK-q: compared with the negative control group, **P<0.01; compared with the model group, #P<0.05, ##P<0.01.

[0261] It can be seen from the above experimental results that the Example compounds can effectively alleviate the symptoms of schizophrenia-like symptoms in schizophrenia model animals. The Example compound group has a more significant therapeutic effect on schizophrenia, which is better than the positive control compound Xanomeline. The Example compound group has mild or no drug-related gastrointestinal adverse reactions, which overcomes the clinical defects of Xanomeline. During the clinical trial, Xanomeline was forced to terminate due to severe gastrointestinal adverse reactions. The Example compounds of the present invention have better in vivo and in vitro efficacy, high selectivity for M receptors, no gender differences in pharmacokinetic parameters, small gastrointestinal adverse reactions, a higher drug safety window, and higher drug safety.

[0262] For those skilled in the art, the present disclosure is not limited to the foregoing illustrative embodiments, but can be embodied in other specific forms without departing from its essential attributes. It is therefore intended that all aspects be considered as illustrative and not restrictive, that reference is made to the embodiments of the appended claims rather than to the foregoing embodiments, that references are made only to the appended claims rather than to the foregoing examples, and that all changes that come within the meaning and scope of equivalents of the claims are therefore intended to be included herein.

[0263] All patents, patent applications, and literature references cited in this specification are hereby incorporated by reference in their entirety. In the event of inconsistency, the present disclosure, including the definitions, will control.

Claims

1. A compound or a pharmaceutically acceptable salt thereof, wherein the compound is represented by any of the following structural formulas: , , , , , , , , , , , , , , .

2. A pharmaceutical composition comprising an effective amount of the compound according to claim 1 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.

3. Use of the pharmaceutical composition according to claim 2 or the compound according to claim 1 or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating, preventing or alleviating diseases related to muscarinic receptor disorders.

4. The related disease according to claim 3 is selected from pain or mental system disorders.

5. The related disease according to claim 3 is selected from intestinal pain, neuropathic pain, musculoskeletal pain, inflammatory pain, cancer pain, idiopathic pain, postoperative pain or visceral pain.

6. The related disease according to claim 3 is selected from schizophrenia, Alzheimer's disease, Huntington's disease, Parkinson's disease, Lewy body dementia, psychosis or cognitive impairment.

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