Tetrahydropyridine derivatives used as muscarinic receptor agonists and their medical applications

Abstract

The present invention provides a tetrahydropyridine derivative or a pharmaceutically acceptable salt thereof, and a pharmaceutical composition containing the same, as well as its use as a muscarinic receptor agonist and its use in the preparation of a medicament for treating pain, central nervous system disorders, or diseases associated with pain and central nervous system disorders. The compound provided by the present invention has the advantages of high selectivity for muscarinic receptors, no gender difference in pharmacokinetic parameters, small gastrointestinal adverse reactions, a higher drug safety window, higher drug safety, and a lower clinical dosage.

Description

Technical Field

[0001] The present invention provides a tetrahydropyridine derivative or a pharmaceutically acceptable salt thereof, a pharmaceutical composition containing the same, and uses thereof as a muscarinic receptor agonist and in the preparation of 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 drugs for treating disorders alleviated by activation of muscarinic receptors in human or animal subjects.

[0003] Schizophrenia affects approximately 0.5% to 1% of the population. The disease is characterized, according to symptoms, into positive symptoms (such as hallucinations, delusions, etc.), negative symptoms (such as social isolation, anhedonia, etc.), and cognitive symptoms (such as inability to process information, poor working memory, etc.). The quality of life of patients with schizophrenia is greatly reduced. Due to many factors (such as increased suicide rate), their risk of mortality increases. Schizophrenia imposes a significant burden on patients, families, and society, and some schizophrenic patients may be incarcerated, homeless, or unemployed.

[0004] Existing treatments for schizophrenia rely on dopamine and serotonin receptors, as in the case of chlorpromazine, the first antipsychotic drug discovered in 1952. For more than 60 years, few antipsychotic drugs with new mechanisms have been marketed. Current antipsychotics are only effective against positive symptoms and fail to treat negative and cognitive symptoms. Alzheimer's disease is another treatment area. It has been proven extremely difficult to develop new therapies, and the success rate of molecules entering clinical development and obtaining market approval is only 0.4%. Patients in these areas are in urgent need of new therapeutic drugs.

[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 tauopathies or synucleinopathies. Muscarinic cholinergic receptors are G protein-coupled receptors with five different receptor subtypes (M1-M5), each of which is found to have a different tissue distribution in the CNS. 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 for M1 and M4 subtypes) in patients with schizophrenia, the schizophrenia was alleviated. However, since it also binds to muscarinic receptors outside the brain, xanomeline has many serious side effects, including gastrointestinal (GI) side effects, cardiac side effects, and excessive salivation, and there are large gender differences in efficacy. Dose-limiting adverse events are problematic and lead to a high discontinuation rate, ultimately resulting in the discontinuation of the development of xanomeline. Many companies have tried but have not developed a muscarinic receptor agonist for CNS disorders that avoids these unacceptable side effects, and no such agonist has entered the market. Past development efforts have focused on medicinal chemistry to develop more tolerable molecules, typically by selecting M1 and M4 subtypes rather than M2 and M3 muscarinic receptor subtypes. However, activation of M1 and M4 outside the brain can still lead to muscarinic-related gastrointestinal intolerance. Therefore, there is an urgent clinical need to develop muscarinic agonists with low side effects, stable pharmacokinetic properties, and good efficacy. SUMMARY OF THE INVENTION

[0007] The present invention provides a compound of the tetrahydropyridine derivative class represented by formula (I), its stereoisomers, hydrates, solvates, polymorphs, active metabolites, pharmaceutically acceptable salts thereof or prodrugs thereof:

[0008]

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

[0010] R 2 is independently selected from a hydrogen atom, a methyl group, a deuterated methyl group.

[0011] The compound of the tetrahydropyridine derivative class represented by formula (I) preferably has a structure represented by any of the following structural formulas:

[0012] .

[0013] The compounds of the present invention are generally used in the form of free acids or free bases. Optionally, the compounds of the present invention can be used in the form of acid or base salts. The acid addition salts of the free amino compounds of the present invention can be prepared by methods well 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 adipates, alginates, ascorbates, aspartates, benzenesulfonates, benzoates, bisulfates, borates, butyrates, camphorates, camphorsulfonates, citrates, cyclopentanepropionates, digluconates, dodecyl sulfates, ethanesulfonates, formates, fumarates, glucoheptanoates, glycerophosphates, gluconates, hemisulfates, heptanoates, hexanoates, hydroiodides, 2-hydroxyethanesulfonates, lactates, lactobionates, laurates, lauryl sulfates, malates, maleates, malonates, methanesulfonates, 2-naphthalenesulfonates, nicotinates, nitrates, oleates, oxalates, palmitates, pamoates, pectates, persulfates, 3-phenylpropionates, phosphates, picrates, pivalates, propionates, stearates, succinates, sulfates, tartrates, thiocyanates, p-toluenesulfonates, undecanoates, valerates, etc. 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 their substituted derivatives (e.g., dibenzylamine, benzylamine, 2-hydroxyethylamine, etc.). Thus, the term "pharmaceutically acceptable salts" of general formula (I) shall 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 bonded carrier that releases a compound of general formula (I) in vivo when the prodrug is administered to a patient. Prodrugs are generally prepared by modifying a functional group in such a way that the modification can be cleaved by conventional means or decomposed in vivo to give the parent compound. Prodrugs include, for example, compounds of the present invention in which a hydroxyl, amino, or mercapto group is bonded to any group that detaches when the prodrug is administered to a patient to give a hydroxyl, amino, or mercapto group.

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

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

[0017] Those skilled in the art should understand that any compound may contain non-natural proportions of atomic isotopes on one or more atoms constituting the compound. As used in the present invention, in the specification and claims, H refers to hydrogen and includes any stable isotope of hydrogen, namely 1 H and D. In the examples where an atom is designated as H, no work has been done to enrich the specific isotope of hydrogen of the atom, and thus those of ordinary skill in the art should understand that such hydrogen atoms may be present at approximately the natural abundance concentration of hydrogen. In the tetrahydrofuranformamide derivatives involved in the present invention, the term "deuteration" means that the atoms at the relevant sites of the compound contain deuterium atoms in an amount exceeding the natural proportion (i.e., exceeding the natural abundance of deuterium). Therefore, any compound of the tetrahydropyridine derivative of formula (I) that contains deuterium atoms at a proportion higher than the natural abundance of deuterium at the relevant sites is within the scope of protection of the present invention. For example, it can be understood that the corresponding tetrahydropyridine derivative compounds with the corresponding deuteration 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 examples of the present invention are all 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 examples, but should be understood as all synthetic methods or routes that can be used in the art to obtain the compounds of the present invention, and all deuterated reagents that can be used in combination with the foregoing synthetic methods or routes to introduce deuterium atoms into the target molecule.

[0018] Isotopically labeled compounds and salts can be used in a variety of advantageous ways, including as pharmaceuticals. In some embodiments, the isotopically labeled compounds and salts are deuterium (D)-labeled. Deuterium (D)-labeled compounds and salts are therapeutically useful and have potential therapeutic advantages over non-D-labeled compounds. Generally, due to the kinetic isotope effects described below, deuterium (D)-labeled compounds and salts can have higher metabolic stability compared to non-isotopically labeled compounds and salts. Higher metabolic stability directly translates into an extended in vivo half-life or a reduced dose, which in most cases will represent a preferred embodiment of the present invention. Isotopically labeled compounds and salts can generally be prepared by carrying out the procedures disclosed in the synthetic schemes, examples, and related descriptions and replacing non-isotopically labeled reactants with readily available isotopically labeled reactants. Deuterium (D)-labeled compounds and salts can manipulate the oxidative metabolic rate of the compounds through the primary kinetic isotope effect. The primary kinetic isotope effect is a change in the rate of a chemical reaction resulting from an isotopic nuclear exchange, which in turn is caused by a change in the ground-state energy of the covalent bond participating in the reaction. Exchange of the heavier isotope generally causes a decrease in the ground-state energy of the chemical bond and thus a reduction in the cleavage of the rate-limiting bond. If bond cleavage occurs in or near the saddle-point region along the reaction coordinate of a multi-product reaction, the product distribution ratio can be substantially altered.

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

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

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

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

[0023] The present invention further provides a pharmaceutical composition, which comprises a therapeutically effective amount of a tetrahydropyridine derivative compound represented by formula (I), its stereoisomers, hydrates, solvates, polymorphs, active metabolites, its pharmaceutically acceptable salts or its prodrugs, 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 agents 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, semi-solid, liquid or gaseous forms of 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, inhalation, parenteral, sublingual, buccal, rectal, vaginal and intranasal administration. As used herein, the term parenteral includes subcutaneous injection, intravenous, intramuscular, intrasternal injection or infusion techniques. The pharmaceutical composition of the present invention is formulated to allow the active ingredient contained therein to be bioavailable after administering the composition to a patient. The composition to be administered to an individual or patient is in the form of one or more dosage units. For example, a tablet can be a single dosage unit, and a container containing the compound of the present invention in aerosol form can contain multiple dosage units. The actual methods of preparing such dosage forms are known to those skilled in the art or will be known to them. The composition to be administered will in any case contain a therapeutically effective amount of the compound of the present invention or its pharmaceutically acceptable salt 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 particulate, so that the composition is in the form of, for example, tablets or powders. The carrier can be liquid, and the composition is, for example, an oral syrup, an injectable liquid, or an aerosol suitable for, for example, inhalation administration. When intended for oral administration, the pharmaceutical composition is preferably in solid or liquid form, where semi-solid, semi-liquid, suspension and gel forms are included in the forms regarded 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 usually contain one or more inert diluents or edible carriers. In addition, one or more of the following substances may also be present: binders, such as carboxymethyl cellulose, ethyl cellulose, microcrystalline cellulose, tragacanth 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 silica; sweeteners, such as sucrose or saccharin; flavoring agents, such as peppermint, methyl salicylate or sweet orange flavoring agent; and coloring agents.

[0026] In the preparation of compositions for oral administration, any common pharmaceutical vehicle can be used. In the case of oral liquid compositions such as suspensions, syrups, elixirs, emulsions, and solutions, for example, water, glycols, oils, alcohols, etc.; or in the case of solid compositions, solid carriers such as starches, sugars, kaolin, lubricants, binders, disintegrants, etc. For parenteral compositions, the vehicle will generally comprise at least predominantly sterile water, but other ingredients such as solubilizers, emulsifiers, or additional adjuvants can also be added thereto. Injectable solutions can be prepared, wherein the vehicle comprises a physiological saline solution, a glucose solution, or a mixture of both. Injectable suspensions can also be prepared, in which case appropriate liquid vehicles, suspending agents, etc. can be employed. Also included are solid form preparations that are intended to be converted into a liquid form preparation shortly before use, such as powders for reconstitution.

[0027] When the pharmaceutical composition is in the form of a capsule, for example a gelatin capsule, in addition to substances of the above types, it can also contain a liquid vehicle such as polyethylene glycol or an oil. The pharmaceutical composition can be in liquid form, such as a tincture, syrup, solution, emulsion, or suspension. This liquid can be administered orally or by injection, as two examples. When intended to be administered orally, preferably the composition contains, in addition to the compound of the present invention, one or more of a sweetening agent, a preservative, a dye / colorant, and a flavor enhancer. In a composition intended to be administered by injection, one or more of a surfactant, a preservative, a wetting agent, a dispersing agent, a suspending agent, a buffering agent, a stabilizing agent, and an isotonic agent can be included.

[0028] Regardless of whether the liquid pharmaceutical composition of the present invention is in the form of a solution, suspension, or other similar form, 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 di-glycerides, which can be used as solvents or suspending media), polyethylene glycol, glycerol, propylene glycol, and other solvents; antibacterial agents such as benzyl alcohol or methylparaben; antioxidants such as ascorbic acid or sodium bisulfite; chelating agents such as ethylenediaminetetraacetic acid; buffering agents such as acetate, citrate, or phosphate, and agents for adjusting tonicity such as sodium chloride or dextrose. Parenteral preparations can be enclosed in ampoules, disposable syringes, or multi-dose vials made of glass or plastic. Physiological saline is the preferred adjuvant. Injectable pharmaceutical compositions are preferably sterile.

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

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

[0031] The pharmaceutical compositions of the present invention may include various substances that modify the physical form of solid or liquid dosage units. For example, such compositions may include substances that form a coating shell around the active ingredient. The substances that form the coating shell are generally inert and may be selected from, for example, sugars, shellac and other enteric coating agents. Alternatively, the active ingredient may be encapsulated in a gelatin capsule.

[0032] The pharmaceutical compositions of the present invention in solid or liquid form may include a reagent that binds to the compound of the present invention and thus aids in the delivery of the compound. Suitable reagents having this ability include monoclonal or polyclonal antibodies, proteins or liposomes.

[0033] The pharmaceutical compositions of the present invention may consist of dosage units that can be administered in the form of an aerosol. The term "aerosol" is used to denote a variety of systems ranging from colloidal species to systems consisting of a pressurized package. Delivery may be effected by a liquefied or compressed gas, or by a suitable pump system for dispensing the active ingredient. The aerosol of the compound of the present invention may be delivered as a single-phase, two-phase or three-phase system to deliver the active ingredient. The delivery of the aerosol includes the necessary container, actuator, valve, sub-container, etc., which together may form a kit. A person skilled in the art can determine the preferred aerosol without undue experimentation.

[0034] The pharmaceutical compositions of the present invention can be prepared using methods well known in the pharmaceutical art. For example, a pharmaceutical composition intended for administration by injection can be prepared by combining a 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 a compound of the present invention with an acceptable vehicle or solvent such as water, Ringer's solution, and isotonic sodium chloride solution. A sterile injectable preparation can be a sterile water-in-oil microemulsion in which the active ingredient is dissolved in the oil phase. The injectable solution or microemulsion can be injected into the bloodstream of a patient by local bolus injection. Alternatively, the solution and microemulsion are preferably administered in a manner that maintains a constant circulating concentration of the disclosed compound.

[0035] The pharmaceutical compositions of the present disclosure can be in the form of a sterile injectable aqueous or oily suspension for intramuscular and subcutaneous administration. The suspension can be formulated with those suitable dispersing or wetting agents and suspending agents as known in the art. A sterile injectable preparation can also be a sterile injectable solution or suspension prepared in a parenterally acceptable non-toxic diluent or solvent. In addition, a sterile fixed oil can be conveniently used as a solvent or suspending medium. For this purpose, any compatible fixed oil can be used. In addition, fatty acids can also be used to prepare injectables.

[0036] For buccal or sublingual administration, the composition can take the form of tablets, lozenges, troches, or gels formulated in a conventional manner. Such compositions can contain an active ingredient in a flavoring base such as sucrose and gum arabic or tragacanth.

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

[0038] The compounds of the present invention or their pharmaceutically acceptable salts can also be administered simultaneously with, before, or after the administration of one or more other therapeutic agents. Such combination therapies include administering a single pharmaceutical dosage form containing a compound of the present invention and one or more other active agents, as well as administering the compound of the present invention and the individual active agents in their own separate pharmaceutical dosage forms. For example, a compound of the present invention and another active agent can be administered to a patient together in a single oral dosage composition (e.g., a tablet or capsule), or each agent can be administered in a separate oral dosage form. In the case of using separate dosage forms, the compound of the present invention and one or more additional active agents can be administered substantially at the same time (i.e., simultaneously) or at separate staggered times (i.e., sequentially); combination therapy is understood to include all such regimens.

[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. Thus, on the other hand, the present invention encompasses a composition for coating an implantable device, the implantable device including a compound or salt of the present invention as generally described above, the classes and subclasses herein, and a carrier suitable for coating the implantable device. In yet another aspect, the present invention encompasses an implantable device coated with a composition, the composition including a compound or salt of the present invention as generally described above, the classes and subclasses herein, and a carrier suitable for coating the implantable device. The coating is typically a biocompatible polymeric material such as a hydrogel polymer, polydimethylsiloxane, 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 unit dose form, or in a form in which the patient can self-administer in a single dose. The expression of the unit dose of the compounds or compositions of the present disclosure can be tablets, capsules, cachets, vials of medicine, powders, granules, lozenges, suppositories, reconstituted powders, or liquid preparations. Suitable unit doses can be 0.1 - 1000 mg.

[0041] In addition to the active compound, the pharmaceutical compositions of the present disclosure can contain one or more excipients selected from the following components: fillers (diluents), binders, wetting agents, disintegrants, or excipients, etc. Depending on the different administration methods, the composition can 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, based on the total weight of the composition, the pharmaceutical composition contains 0.01% - 99.99% of a pharmaceutically acceptable excipient. 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 an active ingredient and non-toxic pharmaceutically acceptable excipients suitable for mixing to prepare tablets. These excipients can be inert excipients, granulating agents, disintegrants, binders, and lubricants. These tablets can be uncoated or coated by known techniques that mask the taste of the drug or delay disintegration and absorption in the gastrointestinal tract, thus providing a sustained-release effect over a longer period.

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

[0045] The present invention relates to tetrahydropyridine derivative compounds of formula (I), their prodrugs, their deuterated compounds, and pharmaceutical compositions containing the same, and a method for using such compositions to treat muscarinic receptor disorders.

[0046] The present invention relates to tetrahydropyridine derivative compounds of formula (I), their prodrugs, their deuterated compounds, and pharmaceutical compositions containing the same, and a method for using such compositions to treat, prevent, or alleviate central nervous system disorders. The 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 impairments, attention disorders, and addictive 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 psychosis.

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

[0051] "Movement disorders" include, but are not limited to, Gilles de la Tourette syndrome, Friederich ataxia, Huntington's disease, restless legs syndrome, and other diseases or disorders, the symptoms of which include excessive movement, itching, and spasms. "Mood disorders" include major depressive disorder, dysthymia, recurrent brief depression, minor depressive disorder, bipolar disorder, mania, and anxiety disorders. "Cognitive disorders" refer to diseases or disorders characterized by cognitive deficits (e.g., having 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, Lewy body-related dementia, and idiopathic dementia), Pick's disease, proteopathy, synucleinopathy, confusion, fatigue-related cognitive deficits, learning disorders, traumatic brain injury, autism, age-related cognitive decline, and Cushing's Disease (cognitive impairment related to autoimmune diseases). "Attention disorders" refer to diseases or conditions characterized by abnormal or reduced attention duration. 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 disorders" refer to diseases or conditions characterized by addiction or substance dependence as defined in the Diagnostic & Statistical Manual V (DSM-5). Such disorders are characterized by physical dependence on substances, withdrawal, and tolerance. 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 a patient is compelled or continues to engage in despite obvious negative consequences. For example, gambling addiction (compulsive gambling or pathological 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 the DSM-5.

[0052] The present invention relates to tetrahydropyridine derivative compounds represented by formula (I), their prodrugs, their deuterated compounds, pharmaceutical compositions containing the same, and the use of such compositions for treating, preventing or alleviating muscarinic receptor disorder diseases. Muscarinic disorder diseases refer to any disease or disorder that is improved by activating the muscarinic system. Such diseases include those in which therapeutic effects are produced by directly activating the muscarinic receptor itself or inhibiting cholinesterase.

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

[0054] This invention relates to tetrahydropyridine derivative compounds represented by formula (I), their prodrugs, their deuterated compounds, pharmaceutical compositions containing them, and the use of such 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, herpes zoster neuralgia, general neuralgia, epilepsy, epileptic conditions, neurodegenerative disorders, mental disorders, anxiety, depression, bipolar disorder, myotonia, arrhythmia, movement disorders, neuroendocrine disorders, ataxia, multiple sclerosis and irritable bowel syndrome, central neuropathic pain, incontinence, pathological cough, visceral pain, osteoarthritis pain, postherpetic neuralgia, diabetic neuropathy, radiculopathy, sciatica, back pain, non-specific 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., central neuropathic pain after stroke), whiplash-associated disorders, fragility fractures, spinal fractures, ankylosing spondylitis, pemphigus, Raynaud's disease, scleroderma, systemic lupus erythematosus, epidermolysis bullosa, gout, juvenile idiopathic arthritis, melorheostosis, polymyalgia rheumatica, pyoderma gangrenosum, chronic widespread pain, diffuse idiopathic skeletal hyperostosis, disc degeneration / herniation pain, radiculopathy, facet joint syndrome, failed back surgery syndrome, burns, carpal tunnel syndrome, Paget's disease pain, spinal stenosis, discitis, transverse myelitis, Ehlers-Danlos syndrome, Fabry disease, mastocytosis, neurofibromatosis, ocular neuropathic pain, sarcoidosis, spondylolysis, 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 motility disorders or methods for reducing their severity.

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

[0056] The compounds provided by the present invention have the advantages of high selectivity for M receptors, no gender differences in pharmacokinetic parameters, small gastrointestinal adverse reactions, a higher drug safety window, higher drug safety, and lower clinical drug doses. Therefore, the compounds of the present invention have better pharmaceutics properties.

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

[0058] Unless otherwise specified, the compounds of the present invention are named manually or by chemical structure software, and commercially available compounds use the supplier's catalog names.

[0059] On the basis of conforming to common knowledge in the art, the above preferred conditions can be combined arbitrarily to obtain various preferred examples of the present invention. Detailed Description of the Invention

[0060] Certain preferred embodiments of the present invention are illustratively shown in the following non-limiting examples. For the experimental methods without specific conditions noted in the following examples, they are carried out according to conventional methods and conditions, or selected according to the product specifications. The raw materials can be obtained commercially, 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 synthesis route is as follows:

[0064]

[0065] Preparation of Intermediate 2:

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

[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 h. Water was added and the mixture was extracted with EA, dried and concentrated under reduced pressure. Purification by flash silica gel column chromatography, eluting with ethyl acetate - petroleum ether, gave Intermediate 3 (5.9 g).

[0069] Preparation of Intermediate 4:

[0070] Intermediate 3 (2.3 g, 7.5 mmol) was dissolved in acetone (15 ml), and methyl iodide (1.5 ml, 30 mmol) was added dropwise to the reaction solution. The reaction mixture was stirred at room temperature for 18 h, and a solid precipitated from the solution. It was filtered and dried to give 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, and the reaction mixture was stirred at 0 °C for 1 h. It was concentrated under reduced pressure, water was added, and it was extracted with EA. The organic phases were combined and concentrated under reduced pressure. Purification by flash silica gel column chromatography, eluting with a gradient of ethyl acetate - methanol, gave Compound 1 (1.9 g). 1 H NMR (400 MHz, DMSO-d6) δ 7.01 (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)pentane-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 h. Water was added and the mixture was extracted with EA, dried and concentrated under reduced pressure. It was purified by flash silica gel column chromatography, eluting with ethyl acetate - petroleum ether to obtain Intermediate 5 (5.2 g).

[0079] Preparation of Intermediate 6:

[0080] Intermediate 5 (2.0 g, 7.5 mmol) was dissolved in acetone (15 ml), and methyl iodide (1.5 ml, 30 mmol) was added dropwise to the reaction solution. The reaction mixture was stirred at room temperature for 18 h, and a solid precipitated from the solution. It 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, and the reaction mixture was stirred at 0 °C for 1 h, concentrated under reduced pressure, water was added, and it was extracted with EA. The organic phases were combined and concentrated under reduced pressure. It was purified by flash silica gel column chromatography, eluting with a gradient of ethyl acetate - methanol to obtain Compound 2 (1.8 g). Deuterium incorporation rate: 98.8%. 1 H NMR (400 MHz, DMSO-d6) δ 7.09 (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 h. Water was added and the mixture was extracted with EA, dried and concentrated under reduced pressure. It was purified by flash silica gel column chromatography, eluting with ethyl acetate - petroleum ether to obtain Intermediate 7 (8.5 g).

[0089] Preparation of Intermediate 8:

[0090] Intermediate 7 (2.9 g, 7.5 mmol) was dissolved in acetone (15 ml). Methyl iodide (1.5 ml, 30 mmol) was added dropwise to the reaction solution. The reaction mixture was stirred at room temperature for 18 h. A solid precipitated from the solution, was 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 h, concentrated under reduced pressure, water was added, and it was extracted with EA. The organic phases were combined and concentrated under reduced pressure. It was purified by flash silica gel column chromatography, eluting with a gradient of ethyl acetate - methanol to obtain Compound 3 (1.8 g). 1 H NMR (400 MHz, DMSO - d6) δ 7.08 (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 h. Water was added and the mixture was extracted with EA, dried and concentrated under reduced pressure. Purification by flash silica gel column chromatography, eluting with ethyl acetate - petroleum ether, gave Intermediate 11 (4.8 g).

[0099] Preparation of Intermediate 12:

[0100] Intermediate 11 (2.1 g, 7.5 mmol) was dissolved in acetone (15 ml), and methyl iodide (1.5 ml, 30 mmol) was added dropwise to the reaction solution. The reaction mixture was stirred at room temperature for 18 h, and a solid precipitated from the solution. It was filtered and dried to give 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), and sodium borohydride (0.45 g, 12 mmol) was added. The reaction mixture was stirred at 0 °C for 1 h, concentrated under reduced pressure, water was added, and it was extracted with EA. The organic phases were combined and concentrated under reduced pressure. Purification by flash silica gel column chromatography, eluting with a gradient of ethyl acetate - methanol, gave Compound 4 (1.7 g). 1 H NMR (400 MHz, DMSO-d6) δ 7.05 (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 h. Water was added and the mixture was extracted with EA, dried and concentrated under reduced pressure. Purification by flash silica gel column chromatography, eluting with ethyl acetate - petroleum ether, gave Intermediate 18 (4.8 g).

[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 h, and a solid precipitated from the solution. It was filtered and dried to obtain Intermediate 19 (2.3 g).

[0111] Preparation of Compound 5:

[0112] Intermediate 19 (2.5 g, 6 mmol) was dissolved in absolute ethanol (60 ml), and sodium borohydride (0.45 g, 12 mmol) was added. The reaction mixture was stirred at 0 °C for 1 h, concentrated under reduced pressure, water was added, and it was extracted with EA. The organic phases were combined and concentrated under reduced pressure. Purification by flash silica gel column chromatography, eluting with a gradient of ethyl acetate - methanol, gave Compound 5 (1.8 g). 1 H NMR (400 MHz, DMSO-d6) δ 7.35 (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 h. Water was added and the mixture was extracted with EA, dried and concentrated under reduced pressure. It was purified by flash 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 methyl iodide (1.5 ml, 30 mmol) was added dropwise to the reaction solution. The reaction mixture was stirred at room temperature for 18 h, and a solid precipitated from the solution. It 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, and the reaction mixture was stirred at 0 °C for 1 h, concentrated under reduced pressure, water was added, and it was extracted with EA. The organic phases were combined and concentrated under reduced pressure. It was purified by flash silica gel column chromatography, eluted with a gradient of ethyl acetate - methanol, and purified. Compound 6 (1.7 g) was obtained. 1 H NMR (400 MHz, DMSO-d6) δ 7.38 (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). Methyl iodide-d3 (1.5 ml, 30 mmol) was added dropwise to the reaction solution. The reaction mixture was stirred at room temperature for 18 h. A solid precipitated from the solution, 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 absolute ethanol (60 ml). Sodium borohydride (0.45 g, 12 mmol) was added. The reaction mixture was stirred at 0 °C for 1 h, concentrated under reduced pressure, water was added, and the mixture was extracted with EA. The organic phases were combined and concentrated under reduced pressure. Purification was carried out by flash silica gel column chromatography with gradient elution of ethyl acetate - methanol to obtain Compound 7 (2 g). Deuterium incorporation rate: 99.1%. 1 H NMR (400 MHz, DMSO-d6) δ 7.09 (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] For the preparation process of Intermediate 14, refer to the preparation of Intermediate 6, with the difference that methyl iodide was replaced by methyl iodide-d3 to obtain Intermediate 14 (2.2 g).

[0137] Preparation of Compound 8:

[0138] Intermediate 14 (2.5 g, 6 mmol) was dissolved in absolute ethanol (60 ml). Sodium borohydride (0.45 g, 12 mmol) was added. The reaction mixture was stirred at 0 °C for 1 h, concentrated under reduced pressure, water was added, and the mixture was extracted with EA. The organic phases were combined and concentrated under reduced pressure. Purification was carried out by flash silica gel column chromatography with gradient elution of ethyl acetate - methanol to obtain Compound 8 (1.9 g).

[0139] Deuterium ratio: 98.6%. 1 H NMR (400 MHz, DMSO-d6) δ 7.08 (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] For the preparation process of Intermediate 15, refer to the preparation of Intermediate 8. The difference is that methyl iodide is replaced with deuterated methyl iodide to obtain Intermediate 15 (2.2 g).

[0146] Preparation of Compound 9:

[0147] Intermediate 15 (3.2 g, 6 mmol) was dissolved in absolute 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, extracted with EA, the organic phases were combined and concentrated under reduced pressure. Purification was carried out by flash silica gel column chromatography with gradient elution of ethyl acetate - methanol. Compound 9 (2 g) was obtained. Deuterium ratio: 99.3%. 1 H NMR (400 MHz, DMSO - d6) δ 7.10 (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 h. Water was added and the mixture was extracted with EA, dried and concentrated under reduced pressure. Purification by flash silica gel column chromatography, eluting with ethyl acetate - petroleum ether, gave Intermediate 9 (4.7 g).

[0154] Preparation of Intermediate 16:

[0155] Intermediate 9 (2.0 g, 7.5 mmol) was dissolved in acetone (15 ml), and deuterated iodomethane (1.5 ml, 30 mmol) was added dropwise to the reaction solution. The reaction mixture was stirred at room temperature for 18 h, and a solid precipitated from the solution. It 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, and the reaction mixture was stirred at 0 °C for 1 h, concentrated under reduced pressure, water was added, and it was extracted with EA. The organic phases were combined and concentrated under reduced pressure. Purification by flash silica gel column chromatography, eluting with a gradient of ethyl acetate - methanol, gave Compound 10 (1.6 g). Deuteration rate: 98.6%. 1 H NMR (400 MHz, DMSO-d6) δ 7.33 (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 / z 283.2 [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] For the preparation process of Intermediate 17, refer to the preparation of Intermediate 12. The difference is that methyl iodide is replaced with deuterated methyl iodide to obtain Intermediate 17 (2.0 g).

[0164] Preparation of Compound 11:

[0165] Intermediate 17 (2.5 g, 6 mmol) was dissolved in absolute 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, extracted with EA, the organic phases were combined and concentrated under reduced pressure. Purification was carried out by rapid silica gel column chromatography with gradient elution of ethyl acetate - methanol to obtain Compound 11 (1.8 g). Deuterium incorporation rate: 98.9%. 1 H NMR (400 MHz, DMSO-d6) δ 7.04 (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 / z 301.1 [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] For the preparation process of Intermediate 22, refer to the preparation of Intermediate 19. The difference is that methyl iodide is replaced with deuterated methyl iodide to obtain Intermediate 22 (2.4 g).

[0172] Preparation of Compound 12:

[0173] Intermediate 22 (2.5 g, 6 mmol) was dissolved in absolute ethanol (60 ml), sodium borohydride (0.45 g, 12 mmol) was added, and the reaction mixture was stirred at 0 °C for 1 hr, concentrated under reduced pressure, water was added, extracted with EA, the organic phases were combined and concentrated under reduced pressure. Purified by flash silica gel column chromatography, eluted with ethyl acetate - methanol gradient. Compound 12 (1.9 g) was obtained. Deuteration rate: 99.1%. 1 H NMR (400 MHz, DMSO-d6) δ 7.25 (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 / z 297.2 [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] For the preparation process of Intermediate 23, refer to the preparation of Intermediate 21, with the difference that methyl iodide was replaced with deuterated methyl iodide to obtain Intermediate 23 (2.3 g).

[0180] Preparation of Compound 13:

[0181] Intermediate 23 (2.6 g, 6 mmol) was dissolved in absolute ethanol (60 ml), sodium borohydride (0.45 g, 12 mmol) was added, and the reaction mixture was stirred at 0 °C for 1 hr, concentrated under reduced pressure, water was added, extracted with EA, the organic phases were combined and concentrated under reduced pressure. Purified by flash silica gel column chromatography, eluted with ethyl acetate - methanol gradient. Compound 13 (1.8 g) was obtained. Deuteration rate: 99.1%. 11H NMR (400 MHz, DMSO-d6) δ 7.38 (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 of DCM. Under N2 protection, the temperature was lowered to -78 °C, and a DCM solution of DMSO (14.63 g, 187.26 mmol) was added, and the mixture was stirred for 15 min. Ethyl 5 - hydroxypentanoate (9.1 g, 62.42 mmol) was dissolved in 50 ml of DCM and added dropwise to the above solution, and the mixture was stirred for 10 min. Triethylamine (37.90 g, 374.51 mmol) was added dropwise. Under N2 protection, the reaction was stirred at -78 °C, and TLC was used to detect the completion of the reaction. Saturated ammonium chloride solution was added, and the mixture was extracted with ethyl acetate and purified by flash silica gel column chromatography with gradient elution of ethyl acetate - petroleum ether to obtain Intermediate 24 (6.2 g).

[0188] Preparation of Intermediate 25:

[0189] Intermediate 24 (9 g, 61.32 mmol) was dissolved in 60 ml of DCM. The temperature was lowered 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 the mixture was stirred for 16 hr. Saturated sodium bicarbonate solution was added to the reaction solution, and the mixture was extracted with ethyl acetate and purified by flash silica gel column chromatography with gradient elution of ethyl acetate - petroleum ether 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 of THF. The temperature was lowered to 0 °C under N2 protection, and LiBH4 (1.5 g, 66.6 mmol) was added. The temperature was slowly raised to 15 °C, and the reaction was stirred for 30 h. The reaction solution was added to saturated ammonium chloride solution, extracted with ethyl acetate, and purified by flash silica gel column chromatography with gradient elution of ethyl acetate - petroleum ether to obtain Intermediate 26 (3.3 g). ESI-MS m / z 139.1 [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 h. Water was added and the mixture was extracted with EA, dried, and concentrated under reduced pressure. It was purified by flash silica gel column chromatography with elution of ethyl acetate - petroleum ether to obtain Intermediate 27 (5.1 g).

[0194] Preparation of Intermediate 28:

[0195] Intermediate 27 (2.1 g, 7.5 mmol) was dissolved in acetone (15 ml), and methyl iodide (1.5 ml, 30 mmol) was added dropwise to the reaction solution. The reaction mixture was stirred at room temperature for 18 h, and a solid precipitated from the solution. It 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), and sodium borohydride (0.45 g, 12 mmol) was added. The reaction mixture was stirred at 0 °C for 1 h, concentrated under reduced pressure, water was added, and it was extracted with EA. The organic phases were combined and concentrated under reduced pressure. It was purified by flash silica gel column chromatography with gradient elution of ethyl acetate - methanol to obtain Compound 14 (1.5 g). 1 1H NMR (400 MHz, DMSO-d6) δ 7.20 (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] Dissolve Intermediate 27 (2.1 g, 7.5 mmol) in acetone (15 ml). Dropwise add deuterated iodomethane (1.5 ml, 30 mmol) to the reaction solution. Stir the reaction mixture at room temperature for 18 h. A solid precipitates from the solution. Filter and dry to obtain Intermediate 29 (2.6 g).

[0203] Preparation of Compound 15:

[0204] Dissolve Intermediate 29 (2.6 g, 6 mmol) in absolute ethanol (60 ml). Add sodium borohydride (0.45 g, 12 mmol). Stir the reaction mixture at 0 °C for 1 h. Concentrate under reduced pressure, add water, extract with EA. Combine the organic phases and concentrate under reduced pressure. Purify by flash silica gel column chromatography with gradient elution of ethyl acetate - methanol. Obtain Compound 15 (2.1 g). 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 control compound Xanomeline with reference to the above examples:

[0206] 。

[0207] Effect Example 1 In vitro radioligand binding assay

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

[0209] Test procedure:

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

[0211] 2. The expression of mAChR in each CHO cell line was analyzed by binding [³H]-N-methylscopolamine ([³H]-NMS).

[0212] 3. The pERK assay was performed using the example compounds and the control compound at different times (2.5 - 60 minutes). 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 the activation of signaling linked to a variety of G protein-coupled receptors (GPCRs) and β-arrestin.

[0213] 4. The cells were serum starved for 5 to 6 hours. The curves were normalized relative to the maximum response to fetal bovine serum (FBS) medium corresponding to a 5-minute stimulation. Five minutes of incubation with the test article was selected for the dose-response pERK assay (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). The differences in drug potency were evaluated by comparing the EC50 values, and the differences in compound efficacy were analyzed by the maximum response (Emax). The EC 50 and Emax values are shown in Table 1.

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

[0216]

[0217] The experimental results show that as an M1 and M4 receptor agonist, xanomeline has good M1 agonist activity but general M4 agonist activity. The compounds of all examples have better M1 and M4 agonist activities than the control compound xanomeline. In particular, the M1 agonist activities of compounds 5, 14, and 15 in the examples are all more than 3 times that of xanomeline. The maximum response of compounds 5 and 14 to activate the M1 receptor, Emax, is 100%, higher than the Emax value of 90% for xanomeline's M1 agonist activity. The M4 agonist activities of compounds 2 and 14 are more than 3 times that of xanomeline. The maximum response of compounds 2 and 14 to activate the M1 receptor, Emax, is 100% and 99% respectively, higher than the Emax value of 87% for xanomeline's M4 agonist activity. Moreover, the selectivity of all M1 and M4 agonist activities is better than that of the control compound xanomeline, indicating the clinical advantages of the compounds in the examples, such as lower administration doses and fewer gastrointestinal side effects in clinical use.

[0218] Effect Example 2 Pharmacokinetic Evaluation

[0219] Using Sprague-Dawley (SD) rats as the test animals, the LC / MS / MS method was applied to determine the drug concentrations in plasma at different time points after intragastric administration of the compounds in the examples. The pharmacokinetic behavior of the compounds of the present disclosure in Sprague-Dawley (SD) rats was studied to evaluate their pharmacokinetic characteristics.

[0220] 1) Test drugs

[0221] Compounds 1, 2, 6, 14, 15 in the examples and xanomeline.

[0222] 2) Test animals

[0223] Thirty-six Sprague-Dawley (SD) rats, 6 in each group, with half males and half females. After fasting overnight without water deprivation, they were administered intragastrically.

[0224] 3) Drug preparation

[0225] Weighed a certain amount of the compounds in the examples respectively, and added the administration solvent: citric acid + 5% DMSO + 10% Solutol + 85% normal saline (pH 6.0) to prepare a homogeneous solution of 7.5 mg / mL.

[0226] 4) Administration

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

[0228] 5) Operation

[0229] At 0, 0.25, 0.5, 1.0, 2.0, 4.0, 6.0, 8.0, 12.0, and 24.0 hours after drug administration, 0.2 mL of blood was collected from the orbital sinus, placed in an EDTA-K2 anticoagulant test tube, centrifuged at 10000 rpm for 1 minute (4 °C), the plasma was separated within 1 hour, and stored at -20 °C for later measurement. The process from blood collection to centrifugation was carried out under ice bath conditions. Food was given 2 hours after drug administration.

[0230] Determination of the content of the compound to be measured in the plasma of SD rats after administration of different concentrations of the drug: Plasma samples of SD rats at each time point after administration were diluted 10-fold with an acetonitrile solution containing an internal standard, vortex-mixed, and centrifuged at 3700 rpm for 10 minutes. After the supernatant was mixed with water at a ratio of 1:1, 0.5 μL of the supernatant was taken for LC / MS / MS analysis.

[0231] 6) Results of pharmacokinetic parameters

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

[0233]

[0234] The experimental results showed that there were significant gender differences in the metabolic parameters of the control compound Xanomeline. The drug concentration C of Xanomeline in female rats max was 5.6 times that in males, and the drug concentration AUC of female rats 0-t was 4.7 times that in males. The gender differences in the metabolic parameters of all the compounds in the examples were within 2-fold, and there were no obvious gender differences. All the test compounds had higher exposure levels compared with the control compound Xanomeline. In particular, for compound 15 in male rats, C max was 4.8 times that of Xanomeline, and the AUC of male rats 0-t was 3.7 times that of Xanomeline. The experimental results showed that the compounds in the examples had better metabolic parameters, with no gender differences in the metabolic parameters, a wider range of applicable populations, a wider drug safety window, and higher drug safety in clinical use.

[0235] Effect Example 3 In vivo pharmacodynamic evaluation of the compound in the treatment of schizophrenia

[0236] 1. Experimental method

[0237] Animals: CD-1 mice, housed separately. Fed and watered ad libitum, fed with standard rodent feed, the room humidity was maintained at about 50%, and the light-dark cycle was 12 h. The mice were fed adaptively for one week before the experiment, and all behavioral experiments were completed between 9:00 and 12:00. All animal experiments were carried out in strict accordance with the principles of animal use ethics of the International Health Research Agency.

[0238] Animal grouping: 70 CD-1 mice were randomly divided into 7 groups of 10 mice each, namely the negative control group (blank control), the model group, the positive drug group (Xanomeline), and the groups of Compounds No. 1, 2, 5, and 14, as shown in Table 3.

[0239] Table 3: Experimental grouping and dosing regimen

[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 the experimental drug was converted according to the body surface area ratio. The gavage volume for each group was 10 mL / Kg, the dosing dose was 20 mpk, and continuous gavage was performed for 10 days, BID. See Table 3 for details.

[0243] Detection of animal symptoms and cognitive function: The first day of modeling was recorded as D1. After 7 days (D7) of modeling and 10 days (D17) of treatment with the test drug, the open field test and forced swimming test were performed on all mice in sequence according to the groups for the same period of time.

[0244] 1) Open field test: It consisted of 4 gray observation boxes without a top with specifications of 50 cm x 50 cm x 40 cm, 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, and the Smart system automatically recorded the movement trajectory and distance of the rats for 30 minutes of free movement. Each observation box was divided into 9 areas of 3×3, which were set as the peripheral area and the central area. The exploratory behavior and spontaneous activity of the 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 the mice, and the activity distance in the peripheral area and the last 20 minutes (10 minutes - 20 minutes was T2, and the last 10 minutes was T3) represented the spontaneous activity of the mice.

[0245] 2) Forced swimming test: Warm water was poured into a glass beaker with a height of 40 cm and a diameter of 25 cm. During the experiment, each mouse was placed in the warm water and forced to swim for 5 minutes, and the cumulative immobile time (with the criterion that the mouse could float in the water without struggling) was recorded, and the percentage of immobile time was calculated to study the negative symptoms of schizophrenia.

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

[0247] Statistical analysis: Use SPSS 18.0 software for statistics. The data are expressed as mean ± standard deviation and analyzed by one-way ANOVA (SNK-q) and paired t-test. P < 0.05 indicates that the difference is statistically significant.

[0248] 2. Results and analysis

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

[0250] There were statistically significant differences in the peripheral activity distance, total activity distance, T1, T2, and T3 activity distances of each group of mice before drug intervention (P < 0.01). Further comparison results showed that there were statistically significant differences in the peripheral activity distance, total activity distance, and activity distances in the three time periods between the 6 model groups of mice in the model group, positive drug group, and example compound group and the negative control group (P < 0.05 or P < 0.01); indicating that the model was successfully established.

[0251] After drug intervention, there were statistically significant differences in the peripheral activity distance and total activity distance of each group compared with those before drug intervention. Compared with the negative control group, the peripheral activity distance and total activity distance of the model group were significantly increased (P < 0.01); compared with the model group, the peripheral activity distance and total activity distance of the positive drug group and the example compound were significantly decreased (P < 0.01). The results of paired t-test before and after drug intervention showed that there was no statistically significant difference in the data of the model group before and after drug administration (P > 0.05). For the positive drug group and the example compound, there were statistically significant differences in the peripheral activity distance and total activity distance after drug intervention compared with those before intervention (P < 0.01). The reduction degree of the 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 the activity distances of each group of rats in different areas of the open field test 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 the forced swimming time of each group

[0256] Compared with the negative control group, the percentage of immobility time of the 6 groups of rats in the model group, positive drug group, and compound group of the examples was significantly increased before drug intervention, suggesting that the model was successfully established.

[0257] After 10 days of treatment with Xanomeline and the compound of the example respectively, compared with the model group, there was a significant difference in reducing the percentage of immobility time in the forced swimming test in the positive drug group. Compared with the model group, there was a significant difference in reducing the percentage of immobility time in the forced swimming test in the compound group of the example (P<0.01). The compound group of the example was superior to Xanomeline in reducing the percentage of immobility time in the forced swimming test. The gastrointestinal drug-related adverse reactions of diarrhea and vomiting in the Xanomeline group were severe, while the drug-related adverse reactions in the compound group of the example were mild or had no effect. See Table 5.

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

[0259]

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

[0261] From the above experimental results, it can be seen that the compound of the example can effectively relieve the symptoms of schizophrenia in the schizophrenia model animals. The compound group of the example has a more significant curative effect in treating schizophrenia, which is superior to the positive control compound Xanomeline. The drug-related gastrointestinal adverse reactions in the compound group of the example are mild or have no effect, overcoming the clinical defects of Xanomeline. During the clinical trial, Xanomeline was forced to terminate due to severe gastrointestinal adverse reactions. The compound of the example of the present invention has better in vivo and in vitro curative effects, high selectivity for M receptors, no gender difference 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 and can be embodied in other specific forms without departing from its essential attributes. Therefore, it is expected that all aspects are illustrative rather than restrictive, referring to the appended claims rather than the foregoing embodiments, citing references only for the additional claims rather than the above examples, and all changes falling within the meaning and scope of the equivalence of the claims are thus expected 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 case of inconsistencies, the present disclosure, including the definitions, will prevail.

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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