Tetrahydropyridine derivative used as muscarinic receptor agonist, and use thereof in medicine

Abstract

Provided are a tetrahydropyridine derivative or a pharmaceutically acceptable salt thereof, a pharmaceutical composition containing same, a use thereof as a muscarinic receptor agonist, and a use thereof in the preparation of drugs for treating pains, central nervous system disorders, or diseases related to the pains and the central psychiatric disorders. The provided compound has the advantages of high selectivity for muscarinic receptors, no gender differences in pharmacokinetic parameters, minimal gastrointestinal adverse reactions, a wide therapeutic window, high drug safety, and a lower clinical dosage.

Description

Tetrahydropyridine derivatives as muscarinic receptor agonists and their use in medicine

[0001] This application claims priority to Chinese patent application 2024116904936 with a filing date of 2024 / 11 / 25. This application incorporates the entirety of the aforementioned Chinese patent application. TECHNICAL FIELD

[0002] The present invention provides a tetrahydropyridine derivative or a pharmaceutically acceptable salt thereof and a pharmaceutical composition containing the same, and the use thereof as a muscarinic receptor agonist and the use thereof in the preparation of a medicament for treating pain, central nervous system disorders, or diseases associated with pain, central nervous system disorders. BACKGROUND

[0003] The present invention relates to tetrahydropyridine derivatives and their use as medicaments for the treatment of disorders alleviated by activation of muscarinic receptors in a human or animal subject.

[0004] Schizophrenia affects about 0.5 to 1% of the population. The disease is characterized by symptoms that are divided into positive symptoms (e.g. hallucinations, delusions etc.), negative symptoms (e.g. social withdrawal, anhedonia etc.) and cognitive symptoms (e.g. inability to process information, poor working memory etc.) depending on the symptoms. The quality of life of patients with schizophrenia can be greatly reduced. Their risk of death is increased due to many factors such as increased suicide rate. Schizophrenia places a large burden on patients, families and society, with some schizophrenic patients potentially being incarcerated, homeless or unemployed.

[0005] Existing schizophrenia treatments rely on dopamine and serotonin receptors, as was the case with the first antipsychotic drug, chlorpromazine, discovered in 1952. Over 60 years, few new mechanism antipsychotic drugs have been launched. Current antipsychotic drugs are only effective against positive symptoms, and fail to treat negative and cognitive symptoms. Alzheimer's disease is another area of treatment. It has proven extremely difficult to develop new therapies, with a success rate of only 0.4% of molecules entering clinical development and gaining market approval. There is an urgent need for new therapeutic drugs for patients in these areas.

[0006] Activation of the muscarinic system via muscarinic receptor agonists can treat several diseases, including schizophrenia, Alzheimer's disease, Parkinson's disease, depression, movement disorders, drug addiction, pain, and neurodegenerative diseases such as tau proteinopathies or synucleinopathies. Muscarinic cholinergic receptors are G protein-coupled receptors with five distinct receptor subtypes (M1-M5), each found to have different tissue distributions 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.

[0007] In a double-blind, placebo-controlled trial of xanomeline (a muscarinic cholinergic receptor agonist with preferential activity against M1 and M4 receptor subtypes) in patients with schizophrenia, schizophrenia was alleviated. However, because it also binds to muscarinic receptors outside the brain, xanomeline has a number of serious side effects, including gastrointestinal (GI) side effects, cardiac side effects, and excessive salivation, with significant gender differences in efficacy. Dosage-limiting adverse events were problematic and led to a high discontinuation rate, ultimately resulting in the discontinuation of xanomeline development. Many companies have attempted to develop muscarinic receptor agonists for CNS disorders that avoid these unacceptable side effects, and no such agonist has yet entered the market. Past development efforts have focused on medicinal chemistry to develop more tolerable molecules, typically choosing 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 need in clinical practice to develop muscarinic agonists with fewer side effects, stable pharmacokinetic properties, and good efficacy. Summary of the Invention

[0008] This invention provides a tetrahydropyridine derivative compound as shown in formula (I), its stereoisomers, hydrates, solvates, polymorphs, active metabolites, pharmaceutically acceptable salts thereof, or prodrugs thereof:

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

[0010] R 2 It is independently selected from hydrogen atoms, methyl groups, and deuterated methyl groups.

[0011] The tetrahydropyridine derivative compounds of formula (I) preferably have the structure shown in any of the following structural formulas:

[0012] The compounds of the present invention are generally used in the form of free acids or free bases. Alternatively, the compounds of the present invention may be used in the form of acid or base salts. Acid adducts of the free amino compounds of the present invention can be prepared using methods known in the art, and can be prepared from organic 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, ethylene glycol, glutamic acid, and benzenesulfonic acid. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, hydrogen sulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecyl sulfate, ethanesulfonate, formate, fumarate, glucono-heptate, glyceryl phosphate, gluconate, hemisulfate, heptaate, hydroiodate, 2-hydroxyethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, dihydroxynaphthalate, pectate, persulfate, 3-phenylpropionate, phosphate, picrate, neopentanoate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate, etc. Basic salts include salts formed with carboxylate anions, and also include salts formed with organic and inorganic cations such as those selected from alkali metal ions, alkaline earth metal ions (e.g., lithium, sodium, potassium, magnesium, barium, calcium), and ammonium ions, as well as their substituted derivatives (e.g., dibenzylamine, benzylamine, 2-hydroxyethylamine, etc.). Therefore, the term "pharmaceutical-acceptable salt" of general formula (I) should include all acceptable salt forms.

[0013] Furthermore, prodrugs are also included within the scope of this invention. A prodrug is any covalently bound carrier that, when administered to a patient, releases in vivo a compound accepting general formula (I). Prodrugs are typically prepared by modifying functional groups in a way that allows the modification to be resolved in vivo via conventional exchange or degradation to yield the parent compound. Prodrugs include compounds of this invention, for example, hydroxyl, amino, or thiol groups bound to any group, wherein, when administered to a patient, the group is detached to yield a hydroxyl, amino, or thiol group.

[0014] Therefore, representative examples of prodrugs include (but are not limited to) acetates (esters), formates (esters), and benzoate derivatives of compounds with alcohol and amine functional groups of general formula (I). Furthermore, in the case of carboxylic acids (-COOH), esters such as methyl esters and ethyl esters may be included. In the case of hydroxyl groups, mixed acid anhydrides such as methoxy, ethoxy, propoxy, and tert-butoxy may be included.

[0015] For stereoisomers, compounds of general formula (I) may have a chiral center and may exist as racemates, racemic mixtures, and individual enantiomers or diastereomers. All isomeric forms are included within the scope of this invention, including mixtures thereof. Furthermore, certain crystalline forms of compounds of general formula (I) may exist in polymorphic forms, which are also included in this invention. In addition, some compounds of said general formula (I) may also form solvates with water or other organic solvents. Such solvates are similarly included within the scope of this invention.

[0016] Those skilled in the art will understand that any compound may contain atomic isotopes in non-natural proportions on one or more of the atoms constituting the compound. As used in this invention, in the specification and claims, H refers to hydrogen and includes any stable isotope of hydrogen, i.e. 1 H and D. In embodiments where the atom is designated as H, no work was performed to enrich the specific isotope of hydrogen, and therefore those skilled in the art will understand that such hydrogen atoms may be present at approximately the natural abundance concentration of hydrogen. In the tetrahydrofuran carboxamide derivatives involved in this invention, deuteration means that the atom at the relevant site of the compound contains deuterium atoms in a proportion exceeding the natural proportion (i.e., exceeding the natural abundance of deuterium). Therefore, any tetrahydropyridine derivative compound of formula (I) containing deuterium atoms at the relevant site in a proportion exceeding the natural abundance of deuterium is within the scope of protection of this invention. For example, it can be understood that corresponding tetrahydropyridine derivative compounds with corresponding deuteration rates or deuterium contents obtained by introducing deuterium atoms using commercially available deuterating agents through the same or similar chemical synthesis methods shown in the embodiments of this invention are within the scope of protection of this invention. The chemical synthesis methods and deuterated reagents mentioned 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 conjunction with the aforementioned synthetic methods or routes to introduce deuterium atoms into the target molecule.

[0017] Isotope-labeled compounds and salts can be used in a variety of advantageous ways, including as pharmaceuticals. In some embodiments, the isotope-labeled compounds and salts are deuterium (D)-labeled. Deuterium (D)-labeled compounds and salts are therapeutically useful, possessing potential therapeutic advantages over unlabeled compounds. Generally, due to the kinetic isotope effect described below, deuterium (D)-labeled compounds and salts can exhibit higher metabolic stability compared to unlabeled compounds and salts. Higher metabolic stability directly translates to prolonged in vivo half-life or reduced dose, which in most cases will represent preferred embodiments of the invention. Isotope-labeled compounds and salts can generally be prepared by performing the procedures disclosed in the synthetic schemes, examples, and related descriptions, replacing the unlabeled reactants with readily available isotope-labeled reactants. Deuterium (D)-labeled compounds and salts can manipulate the oxidative metabolic rate of said compounds through primary kinetic isotope effects. Primary kinetic isotope effects are rate changes in chemical reactions resulting from isotopic nuclear exchange, which in turn is caused by changes in the ground-state energy of the covalent bonds involved in the reaction. Exchange with heavier isotopes typically lowers the ground-state energy of chemical bonds and thus reduces the rate-limiting bond breaking. If bond breaking occurs in or near a saddle point region along the coordinates of a multi-product reaction, it can substantially alter the product distribution ratio.

[0018] Based on the specific embodiments disclosed below according to the present invention, 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.

[0019] The present invention further provides the use of a tetrahydropyridine derivative compound of formula (I), its stereoisomers, hydrates, solvates, polymorphs, active metabolites, pharmaceutically acceptable salts thereof, or prodrugs thereof in the preparation of muscarinic agonists.

[0020] The present invention further provides the use of a tetrahydropyridine derivative compound of 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 caused by muscarinic disorders.

[0021] The present invention further provides the use of a tetrahydropyridine derivative compound of 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 diseases of pain or central nervous system disorders.

[0022] The present invention further provides a pharmaceutical composition comprising a therapeutically effective amount of a tetrahydropyridine derivative compound of formula (I), its stereoisomer, hydrate, solvate, polymorph, active metabolite, pharmaceutically acceptable salt thereof or a prodrug thereof, and a pharmaceutically acceptable carrier.

[0023] The compounds of the present invention, or their pharmaceutically acceptable salts, in pure form or suitable pharmaceutical compositions, can be administered in any acceptable mode of administration to a similarly effective agent. The pharmaceutical compositions of the present invention can be prepared by combining the compounds of the present invention with suitable pharmaceutically acceptable carriers, diluents, or excipients, and can be formulated into solid, semi-solid, liquid, or gaseous formulations, such as tablets, capsules, powders, granules, ointments, solutions, suppositories, injections, inhalers, gels, microspheres, and aerosols. Typical routes of administration of the pharmaceutical compositions include (but are not limited to) oral, topical, transdermal, inhalation, non-enteric, sublingual, buccal, rectal, vaginal, and intranasal administration. As used herein, the term non-enteric includes subcutaneous injection, intravenous, intramuscular, intrasternal injection, or infusion techniques. The pharmaceutical compositions of the present invention are formulated to allow the bioavailability of the contained clean components after administration to a patient. The composition to be administered to an individual or patient may be in the form of one or more dose units, wherein, for example, a tablet may be a single dose unit, while a container containing the compound of the invention in aerosol form may hold multiple dose units. The actual methods for preparing the dosage form are known to, or will be 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, in order to treat the disease or condition of interest according to the teachings of the invention.

[0024] The pharmaceutical compositions of the present invention can be in solid or liquid form. On one hand, the carrier is a microparticle, so that the composition is in the form of, for example, tablets or powders. 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. When intended for oral administration, the pharmaceutical composition is preferably in solid or liquid form, wherein semi-solid, semi-liquid, suspension, and gel forms are included in forms considered solid or liquid herein. For oral solid compositions, the pharmaceutical composition can be formulated into 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 carboxymethyl cellulose, ethyl cellulose, microcrystalline cellulose, yellow tartar glue, or gelatin; excipients, such as starch, lactose, or dextrin; disintegrants, such as alginate, sodium alginate, Primogel, corn starch, etc.; lubricants, such as magnesium stearate or hydrogenated vegetable oil (Sterotex); flow aids, such as colloidal silica; sweeteners, such as sucrose or saccharin; flavoring agents, such as peppermint, methyl salicylate, or sweet orange flavoring; and coloring agents.

[0025] In preparing 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 (e.g., suspensions, syrups, free radicals, emulsions, and solutions); or solid carriers such as starch, sugar, kaolin, lubricants, binders, disintegrants, etc., in the case of solid compositions. For parenteral compositions, the carrier will typically consist of at least predominantly sterile water, but other components such as solubilizers, emulsifiers, or additional adjuvants may be added. Injectable solutions can be prepared in which the carrier includes physiological saline, glucose solution, or a mixture of both. Injectable suspensions can also be prepared, in which case appropriate liquid carriers, suspending agents, etc., can be used. Solid formulations intended to be converted into liquid form shortly before use are also included, such as powders for reconstitution.

[0026] When the pharmaceutical composition is in capsule form, such as a gelatin capsule, it may contain a liquid carrier, such as polyethylene glycol or oil, in addition to the substances described above. The pharmaceutical composition may be in liquid form, such as a tincture, syrup, solution, emulsion, or suspension. This liquid may be administered orally or by injection, as two examples. When intended for oral administration, the composition preferably contains one or more of the following in addition to the compounds of the present invention: a sweetener, a preservative, a dye / coloring agent, and a flavor enhancer. In compositions intended for injection, one or more of the following may be included: a surfactant, a preservative, a wetting agent, a dispersant, a suspending agent, a buffer, a stabilizer, and an isotonic agent.

[0027] Regardless of whether it is a solution, suspension, or other similar form, the liquid pharmaceutical composition of the present invention may include one or more of the following adjuvants: a sterile diluent, such as water for injection, physiological saline solution, preferably physiological saline, Ringer's solution, isotonic sodium chloride, non-volatile oils (e.g., synthetic mono- or diglycerides, which can be used as solvents or suspension media), polyethylene glycol, glycerol, propylene glycol, etc.; an antibacterial agent, such as benzyl alcohol or methylparaben; an antioxidant, such as ascorbic acid or sodium bisulfite; a chelating agent, such as ethylenediaminetetraacetic acid; a buffer, such as acetate, citrate, or phosphate; and a tonic agent, such as sodium oxide or dextran. Enteral preparations may be packaged in ampoules, disposable syringes, or multi-dose vials made of glass or plastic. Physiological saline is a preferred adjuvant. Injectable pharmaceutical compositions are preferably sterile.

[0028] Liquid pharmaceutical compositions of the present invention intended for oral or intestinal administration should contain an amount of the compounds of the present invention to achieve a suitable dosage. Pharmaceutical compositions of the present invention may be intended for topical administration, 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 pharmaceutical compositions intended for topical administration. If intended for transdermal administration, the composition may comprise a transdermal patch or an iontophoresis device.

[0029] The pharmaceutical compositions of this invention can be administered rectally, for example in suppository form, where they melt in the rectum and release the drug. The compositions for rectal administration may contain an oily matrix as a suitable non-irritating excipient. The matrix includes (but is not limited to) lanolin, cocoa butter, and polyethylene glycol.

[0030] The pharmaceutical compositions of the present invention may include various substances in physical form that alter the dosage units of solids or liquids. For example, the composition may include a substance that forms a coating around the active ingredient. The substance forming the coating is generally inert and may be selected from, for example, sugars, shellac, and other enteric coatings. Alternatively, the active ingredient may be encapsulated in a gelatin capsule.

[0031] Pharmaceutical compositions of the present invention in solid or liquid form may include an agent that binds to and thereby facilitates the delivery of the compound. Suitable agents with this capability include monoclonal or polyclonal antibodies, proteins, or liposomes.

[0032] The pharmaceutical compositions of the present invention can consist of dosage units that can be administered in aerosol form. The term aerosol is used to refer to a variety of systems, ranging from gel-like forms to systems consisting of pressurized packaging. Delivery can be carried out by liquefied or compressed gas, or by a suitable pump system dispensing the active ingredient. The aerosols of the compounds of the present invention can be delivered in a single-phase, two-phase, or three-phase system to deliver the active ingredient. Aerosol delivery includes necessary containers, initiators, valves, sub-containers, etc., which together form a kit. Preferred aerosols can be determined by those skilled in the art without extensive experimentation.

[0033] The pharmaceutical compositions of the present invention can be prepared using methods well-known in the pharmaceutical industry. For example, a pharmaceutical composition intended for injection can be prepared by combining the compounds of the present invention with sterile distilled water to form a solution. Surfactants can be added to facilitate the formation of a homogeneous solution or suspension. Surfactants are compounds that non-covalently interact with the compounds of the present invention, thereby promoting the dissolution or homogeneous suspension of the compounds in an aqueous delivery system. A solution can be formed by combining the compounds of the present invention with an acceptable solvent such as water, Ringer's solution, or isotonic sodium chloride solution. The sterile injectable formulation can be a sterile injectable oil-in-water microemulsion in which the active ingredient is dissolved in the oil phase, which can be injected into the patient's bloodstream by local large-volume injection. Alternatively, it is preferable to administer the solution and microemulsion in a manner that maintains a constant circulating concentration of the compounds of the present invention.

[0034] The pharmaceutical compositions disclosed herein may be in the form of sterile injectable aqueous or oil suspensions for intramuscular and subcutaneous administration. These suspensions may be formulated using suitable dispersants or wetting agents and suspending agents as described above, according to known techniques. The sterile injectable formulations may also be sterile injectable solutions or suspensions prepared in parenteral-acceptable, non-toxic diluents or solvents. Furthermore, sterile fixative oils may be conveniently used as solvents or suspension media. For this purpose, any blended fixative oil may be used. Additionally, fatty acids may also be used to prepare injectable formulations.

[0035] For buccal or sublingual administration, the composition can be in the form of tablets, lozenges, candy lozenges, or gels formulated in a conventional manner. Such compositions may contain flavoring bases such as sucrose and active ingredients from gum arabic or astragalus gum.

[0036] The compounds of the present invention or their pharmaceutically acceptable salts are administered in therapeutically effective amounts, 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 patient's age, weight, general health status, sex, and diet; the administration pattern and timing; the rate of excretion; the combination of drugs; the severity of the particular disease or symptom; and the individual receiving the therapy.

[0037] The compounds of the present invention or pharmaceutically acceptable salts thereof may also be administered concurrently with, before, or after administration of one or more other therapeutic agents. This combination therapy includes administration of a single pharmaceutical formulation containing the compound of the present invention and one or more other active agents, as well as administration of separate pharmaceutical formulations containing the compound of the present invention and each active agent individually. For example, the compound of the present invention and another active agent may be administered to the patient as a single oral composition (e.g., tablets or capsules), or each agent may be administered as a separate oral formulation. In the case of using separate formulations, the compound of the present invention and one or more additional active agents may be administered substantially at the same time (i.e., simultaneously) or at separately staggered times (i.e., sequentially); combination therapy should be understood to include all of these options.

[0038] The compounds and salts of the present invention, or pharmaceutically acceptable compositions thereof, can also be incorporated into compositions for coating implantable medical devices such as prostheses, artificial valves, vascular grafts, stents, and catheters. Thus, in another aspect, the present invention comprises compositions for coating implantable devices comprising the compounds or salts of the present invention as generally described above, as well as the classes and subclasses herein, and carriers suitable for coating said implantable devices. Still in another aspect, the present invention comprises implantable devices coated with compositions comprising the compounds or salts of the present invention as generally described above, as well as the classes and subclasses herein, and carriers suitable for coating said 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 may optionally be further coated with a suitable topcoat of fluorosilicone, polysaccharide, polyethylene glycol, phospholipid, or combinations thereof to impart controlled-release properties to the composition.

[0039] As a general guideline, the active compounds disclosed herein are preferably administered in unit dose form, or in a manner that allows the patient to self-administer a single dose. The unit dose of the disclosed compounds or compositions may be expressed as tablets, capsules, sachets, bottled liquids, powders, granules, lozenges, suppositories, regenerated powders, or liquid formulations. Suitable unit doses may range from 0.1 to 1000 mg.

[0040] In addition to the active compound, the pharmaceutical compositions disclosed herein may contain one or more excipients, wherein the excipients are selected from the following components: fillers (diluents), binders, wetting agents, disintegrants, or excipients, etc. Depending on the method of administration, the composition may contain 0.1 to 99% by weight of the active compound.

[0041] In some embodiments, the unit dose of the pharmaceutical composition is 0.001 mg to 1000 mg.

[0042] In some embodiments, the pharmaceutical composition contains 0.01% to 99.99% pharmaceutically acceptable excipients based on the total weight of the composition. In some embodiments, the pharmaceutical composition contains 0.1% to 99.9% pharmaceutically acceptable excipients. In some embodiments, the pharmaceutical composition contains 0.5% to 99.5% pharmaceutically acceptable excipients. In some embodiments, the pharmaceutical composition contains 1% to 99% pharmaceutically acceptable excipients. In some embodiments, the pharmaceutical composition contains 2% to 98% pharmaceutically acceptable excipients. The tablets contain the active ingredient and non-toxic, pharmaceutically acceptable excipients suitable for tablet preparation for mixing. These excipients may be inert excipients, granulating agents, disintegrants, binders, and lubricants. These tablets may be uncoated or coated using known techniques that mask the taste of the drug or delay disintegration and absorption in the gastrointestinal tract, thus providing sustained release over a longer period.

[0043] This invention relates to tetrahydropyridine derivatives of formula (I), their precursor drugs and their deuterated compounds, and pharmaceutical compositions containing them, as well as the use of such compositions to treat, prevent or alleviate diseases caused by muscarinic receptor disorders.

[0044] The present invention relates to tetrahydropyridine derivatives of formula (I), their precursor drugs and their deuterated compounds, and pharmaceutical compositions containing the same, as well as methods of using the composition to treat muscarinic receptor disorders.

[0045] This invention relates to tetrahydropyridine derivatives of formula (I), their prodrugs and deuterated compounds, and pharmaceutical compositions containing them, as well as methods of using the compositions to treat, prevent, or alleviate central nervous system disorders. Central nervous system disorders are selected from schizophrenia, Alzheimer's disease, Huntington's disease, Parkinson's disease, Lewy body dementia, psychosis, cognitive deficits, motor disorders, mood disorders, cognitive impairments, attention deficits, and addiction disorders. In some embodiments, the central nervous system disorder is schizophrenia.

[0046] In some embodiments, the central nervous system disorder is Alzheimer's disease.

[0047] In some embodiments, the central nervous system disorder is Huntington's disease. In some embodiments, the central nervous system disorder is Parkinson's disease.

[0048] In some embodiments, the central nervous system disorder is Lewy body dementia. In some embodiments, the central nervous system disorder is psychosis.

[0049] In some embodiments, the central nervous system disorder is a cognitive deficit.

[0050] "Motor disorders" include, but are not limited to, Tourette syndrome, Friederich ataxia, Huntington's disease, restless legs syndrome, and other disorders or conditions with symptoms including hyperkinesis, itching, and spasms. "Mood disorders" include major depressive disorder, dysphoric mood, recurrent transient depression, mild depressive disorder, bipolar disorder, mania, and anxiety disorders. "Cognitive impairment" refers to disorders or conditions characterized by cognitive deficits (e.g., abnormal working memory, problem-solving abilities, etc.). These 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, proteinopathies, connulopathies, confusion, fatigue-related cognitive deficits, learning disabilities, traumatic brain injury, autism, age-related cognitive decline, and Cushing's disease (cognitive impairment associated with an autoimmune disease). "Attention deficit disorder" refers to a disorder or condition characterized by an abnormal or reduced duration of attention. Disorders include, but are not limited to, Attention Deficit Hyperactivity Disorder (ADHD), Attention Deficit Disorder (ADD), Dubowitz Syndrome, FG Syndrome, Down Syndrome, growth retardation due to insulin-like growth factor I (IGF1) deficiency, hepatic encephalopathy syndrome, and Strauss Syndrome. "Addiction disorder" refers to a disorder or condition characterized by addiction or substance dependence as defined in the Diagnostic and Statistical Manual of Man and on the Medical Standards for Aging (DSM-5). Such disorders are characterized by physical dependence on, withdrawal from, and tolerance to a substance. These substances include, but are not limited to, alcohol, cocaine, amphetamines, opioids, benzodiazepines, inhalers, nicotine, barbiturates, cocaine, and cannabis. Addiction disorders also include compulsive or persistent behaviors that the patient engages in despite obvious negative consequences. For example, gambling addiction (gambling disorder or compulsive gambling) is considered by those skilled in the art to be an addictive behavior that typically has devastating consequences. In some embodiments, the addictive behavior may be Internet gaming disorder (gaming addiction) as defined in DSM-5.

[0051] This invention relates to tetrahydropyridine derivatives of formula (I), their prodrugs and deuterated compounds, and pharmaceutical compositions containing them, as well as the use of these compositions for the treatment, prevention, or relief of muscarinic receptor disorders. Muscarinic disorders are any disease or condition that improves by activating the muscarinic system. Such diseases include those where direct activation of the muscarinic receptor itself or inhibition of cholinesterase has produced a therapeutic effect.

[0052] This invention relates to tetrahydropyridine derivatives of formula (I), their prodrugs and their deuterated compounds, and pharmaceutical compositions containing them, as well as the use of these compositions to treat, prevent, or alleviate "schizophrenia-related disorders" and "schizophrenia-related disorders." "Schizophrenia-related disorders" and "schizophrenia-related disorders" include, but are not limited to, schizoaffective disorder, psychosis, delusional disorder, Alzheimer's disease-related psychosis, Parkinson's disease-related psychosis, psychotic depression, bipolar disorder, psychotic bipolar disorder, or any other disorder with psychotic characteristics.

[0053] This relates to tetrahydropyridine derivatives of formula (I), their prodrugs and deuterated compounds, and pharmaceutical compositions containing them, as well as the use of such compositions for the treatment, prevention, or relief of 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, and anxiety in subjects. Depression, bipolar disorder, myotonia, arrhythmia, 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, bunion removal pain, or abdominoplasty pain), cancer pain, including Includes chronic cancer pain and fulminant cancer pain, stroke (e.g., post-stroke neuropathic pain), whiplash injury-related conditions, fragility fractures, spinal fractures, ankylosing spondylitis, pemphigus, Raynaud's disease, scleroderma, systemic lupus erythematosus, epidermolysis bullosa, gout, juvenile idiopathic arthritis, osteogenesis imperfecta, polymyalgia rheumatica, pyoderma gangrenosa, chronic extensive pain, diffuse idiopathic osteophyte formation, intervertebral disc degeneration / hernia 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, vertebral detachment, vertebral displacement, chemotherapy-induced stomatitis, Charcot neuropathic osteoarthritis, temporomandibular joint disorder, painful arthroplasty, non-cardiac chest pain, genital pain, renal colic, biliary tract disease, vascular leg ulcers, pain from Parkinson's disease, pain from Alzheimer's disease, cerebral ischemia, traumatic brain injury, amyotrophic lateral sclerosis, stress-induced angina, exercise-induced angina, palpitations, hypertension, or methods to reduce the severity of gastrointestinal motility disorders.

[0054] In addition to their use in human treatment, some of the compounds and formulations disclosed herein can also be used for veterinary treatment of pets, wild animals, and farm animals, including mammals, rodents, etc. Other examples of animals include horses, dogs, and cats.

[0055] The compounds provided by this invention have advantages such as high selectivity for M receptors, no gender difference in pharmacokinetic parameters, few gastrointestinal adverse reactions, a longer drug safety window, higher drug safety, and lower clinical dosage. Therefore, the compounds of this invention have better pharmaceutical properties.

[0056] Unless otherwise specified, all reagents and raw materials used in this invention are commercially available.

[0057] Unless otherwise specified, the compounds of this invention are named manually or using chemical structure software, and commercially available compounds are named according to the supplier's catalog.

[0058] Based on common knowledge in the field, the above-mentioned preferred conditions can be combined arbitrarily to obtain various preferred embodiments of the present invention. Detailed Implementation

[0059] Certain preferred embodiments of the present invention are illustrated in the following non-limiting examples. Experimental methods not specifically described in the following examples are performed according to conventional methods and conditions, or as selected according to the trade instructions. Raw materials may be commercially available, or prepared by methods known in the art, or according to the methods described herein.

[0060] Example 1.

[0061] 3-((5,5,5-trifluoropentyl)oxy)-4-(1-methyl-1,2,5,6-tetrahydropyridin-3-yl)-1,2,5-thiadiazole

[0062] The synthesis route is as follows:

[0063] Preparation of intermediate 2:

[0064] Sulfur monochloride (48 mL, 600 mmol) was dissolved in DMF (100 mL). α-Amino-α-(3-pyridyl)acetonitrile (34 g, 200 mmol) was slowly added to the solution, and the reaction mixture was stirred at room temperature for 18 hours. Water (400 mL) was added, and the aqueous phase was extracted with diethyl ether, followed by removal of the ether phase with α-amino-α-(3-pyridyl)acetonitrile. 50% potassium hydroxide solution was added to the aqueous phase until the pH reached 9–10. The aqueous phase was then extracted twice more with diethyl ether, and the ether phase was dried and concentrated under reduced pressure. Purification was achieved by rapid silica gel column chromatography, eluting with ethyl acetate-dichloromethane. The result was intermediate 2 (18.6 g).

[0065] Preparation of intermediate 3:

[0066] Intermediate 2 (4.9 g, 25 mmol) was dissolved in anhydrous tetrahydrofuran and added dropwise to a mixed solution of 5,5,5-trifluoropentane-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 achieved by rapid silica gel column chromatography, eluting with ethyl acetate-petroleum ether, to give intermediate 3 (5.9 g).

[0067] Preparation of intermediate 4:

[0068] Intermediate 3 (2.3 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 the solid precipitated from the solution. The solid was filtered and dried to obtain intermediate 4 (2.4 g).

[0069] Preparation of compound 1:

[0070] Intermediate 4 (2.7 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 hr, concentrated under reduced pressure, and water was added. The mixture was extracted with EA, and the organic phases were combined and concentrated under reduced pressure. The mixture was purified by rapid silica gel column chromatography with ethyl acetate-methanol gradient elution to give 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 / z322.1[M+1] + .

[0071] Example 2.

[0072] 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

[0073] The synthesis route is as follows:

[0074] Preparation of intermediate 5:

[0075] 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 hours. Water was added and the mixture was extracted with EA, dried, and concentrated under reduced pressure. Purification was achieved by rapid silica gel column chromatography, eluting with ethyl acetate-petroleum ether, to give intermediate 5 (5.2 g).

[0076] Preparation of intermediate 6:

[0077] Intermediate 5 (2.0 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 the solid precipitated from the solution. The solid was filtered and dried to obtain intermediate 6 (2.1 g).

[0078] Preparation of compound 2:

[0079] Intermediate 6 (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 hr, concentrated under reduced pressure, and extracted with water using EA. The organic phases were combined and concentrated under reduced pressure. Purification was achieved by rapid silica gel column chromatography with ethyl acetate-methanol gradient elution, yielding compound 2 (1.8 g). 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] + .

[0080] Example 3.

[0081] 3-((4,5,5,5-tetrafluoro-4-(trifluoromethyl)pentyl)oxy)-4-(1-methyl-1,2,5,6-tetrahydropyridin-3-yl)-1,2,5-thiadiazole

[0082] The synthesis route is as follows:

[0083] Preparation of intermediate 7:

[0084] 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)pentane-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 achieved by rapid silica gel column chromatography, eluting with ethyl acetate-petroleum ether, to give intermediate 7 (8.5 g).

[0085] Preparation of intermediate 8:

[0086] Intermediate 7 (2.9 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 the solid precipitated from the solution. The solid was filtered and dried to obtain intermediate 8 (2.2 g).

[0087] Preparation of compound 3:

[0088] Intermediate 8 (3.2 g, 6 mmol) was dissolved in anhydrous ethanol (65 mL), and sodium borohydride (0.45 g, 12 mmol) was added. The reaction mixture was stirred at 0 °C for 1 hr, concentrated under reduced pressure, and water was added. The mixture was extracted with EA, and the organic phases were combined and concentrated under reduced pressure. The mixture was purified by rapid silica gel column chromatography with ethyl acetate-methanol gradient elution to give 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] + .

[0089] Example 4.

[0090] 3-((3-(1-fluorocyclopropyl)propoxy)-4-(1-methyl-1,2,5,6-tetrahydropyridin-3-yl)-1,2,5-thiadiazole

[0091] The synthesis route is as follows:

[0092] Preparation of intermediate 11:

[0093] Intermediate 2 (4.9 g, 25 mmol) was dissolved in anhydrous tetrahydrofuran and added dropwise to a mixed solution of 3-(1-fluorocyclopropyl)prop-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 achieved by rapid silica gel column chromatography, eluting with ethyl acetate-petroleum ether, to give intermediate 11 (4.8 g).

[0094] Preparation of intermediate 12:

[0095] Intermediate 11 (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 the solid precipitated from the solution. The solid was filtered and dried to obtain intermediate 12 (2.1 g).

[0096] Preparation of compound 4:

[0097] 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 hr, concentrated under reduced pressure, and water was added. The mixture was extracted with EA, and the organic phases were combined and concentrated under reduced pressure. The mixture was purified by rapid silica gel column chromatography with ethyl acetate-methanol gradient elution to give 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] + .

[0098] Example 5.

[0099] 3-((4-(cyclopropyl)butoxy)-4-(1-methyl-1,2,5,6-tetrahydropyridin-3-yl)-1,2,5-thiadiazole

[0100] The synthesis route is as follows:

[0101] Preparation of intermediate 18:

[0102] Intermediate 2 (4.9 g, 25 mmol) was dissolved in anhydrous tetrahydrofuran and added dropwise to a mixed solution of 4-(cyclopropyl)but-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 achieved by rapid silica gel column chromatography, eluting with ethyl acetate-petroleum ether, to give intermediate 18 (4.8 g).

[0103] Preparation of intermediate 19:

[0104] 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 the solid precipitated from the solution. The solid was filtered and dried to obtain intermediate 19 (2.3 g).

[0105] Preparation of compound 5:

[0106] Intermediate 19 (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 hr, concentrated under reduced pressure, and water was added. The mixture was extracted with EA, and the organic phases were combined and concentrated under reduced pressure. The mixture was purified by rapid silica gel column chromatography with ethyl acetate-methanol gradient elution to give 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] + .

[0107] Example 6.

[0108] 3-((4-(1-fluorocyclopropyl)butoxy)-4-(1-methyl-1,2,5,6-tetrahydropyridin-3-yl)-1,2,5-thiadiazole

[0109] The synthesis route is as follows:

[0110] Preparation of intermediate 20:

[0111] Intermediate 2 (4.9 g, 25 mmol) was dissolved in anhydrous tetrahydrofuran and added dropwise to a mixed solution of 4-(1-fluorocyclopropyl)but-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 achieved by rapid silica gel column chromatography, eluting with ethyl acetate-petroleum ether, to give intermediate 20 (5.1 g).

[0112] Preparation of intermediate 21:

[0113] 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 the solid precipitated from the solution. The solid was filtered and dried to obtain intermediate 21 (2.1 g).

[0114] Preparation of compound 6:

[0115] Intermediate 21 (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 hr, concentrated under reduced pressure, and water was added. The mixture was extracted with EA, and the organic phases were combined and concentrated under reduced pressure. The mixture was purified by rapid silica gel column chromatography with ethyl acetate-methanol gradient elution to give 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] + .

[0116] Example 7.

[0117] 3-((5,5,5-trifluoropentyl)oxy)-4-(1-(methyl-d3)-1,2,5,6-tetrahydropyridin-3-yl)-1,2,5-thiadiazole

[0118] The synthesis route is as follows:

[0119] Preparation of intermediate 13:

[0120] Intermediate 3 (2.3 g, 7.5 mmol) was dissolved in acetone (15 ml), and deuterated iodomethyl (1.5 ml, 30 mmol) was added dropwise to the reaction solution. The reaction mixture was stirred at room temperature for 18 hours, and the solid precipitated from the solution. The solid was filtered and dried to obtain intermediate 13 (2.5 g).

[0121] Preparation of compound 7:

[0122] Intermediate 13 (2.7 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 hr, concentrated under reduced pressure, and extracted with water using EA. The organic phases were combined and concentrated under reduced pressure. Purification was achieved by rapid silica gel column chromatography with an ethyl acetate-methanol gradient elution. 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] + .

[0123] Example 8.

[0124] 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

[0125] The synthesis route is as follows:

[0126] Preparation of intermediate 14

[0127] The preparation process of intermediate 14 is the same as that of intermediate 6, except that iodomethane is replaced with deuterated iodomethane to obtain intermediate 14 (2.2g).

[0128] Preparation of compound 8:

[0129] Intermediate 14 (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 hr, concentrated under reduced pressure, and extracted with water using EA. The organic phases were combined and concentrated under reduced pressure. The mixture was purified by rapid silica gel column chromatography with ethyl acetate-methanol gradient elution to give compound 8 (1.9 g).

[0130] Deuteration 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] + .

[0131] Example 9.

[0132] 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

[0133] The synthesis route is as follows:

[0134] Preparation of intermediate 15

[0135] The preparation process of intermediate 15 is the same as that of intermediate 8, except that iodomethane is replaced with deuterated iodomethane to obtain intermediate 15 (2.2g).

[0136] Preparation of compound 9:

[0137] Intermediate 15 (3.2 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 hr, concentrated under reduced pressure, and extracted with water using EA. The organic phases were combined and concentrated under reduced pressure. Purification was achieved by rapid silica gel column chromatography with an ethyl acetate-methanol gradient elution. 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] + .

[0138] Example 10.

[0139] 3-((3-(cyclopropyl)propoxy)-4-(1-(methyl-d3)-1,2,5,6-tetrahydropyridin-3-yl)-1,2,5-thiadiazole

[0140] The synthesis route is as follows:

[0141] Preparation of intermediate 9:

[0142] Intermediate 2 (4.9 g, 25 mmol) was dissolved in anhydrous tetrahydrofuran and added dropwise to a mixed solution of 3-(cyclopropyl)prop-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 achieved by rapid silica gel column chromatography, eluting with ethyl acetate-petroleum ether, to give intermediate 9 (4.7 g).

[0143] Preparation of intermediate 16:

[0144] Intermediate 9 (2.0 g, 7.5 mmol) was dissolved in acetone (15 ml), and deuterated iodomethyl (1.5 ml, 30 mmol) was added dropwise to the reaction solution. The reaction mixture was stirred at room temperature for 18 hours, and the solid precipitated from the solution. The solid was filtered and dried to obtain intermediate 16 (2.2 g).

[0145] Preparation of compound 10:

[0146] Intermediate 16 (2.4 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 hr, concentrated under reduced pressure, and extracted with water using EA. The organic phases were combined and concentrated under reduced pressure. Purification was achieved by rapid silica gel column chromatography with an ethyl acetate-methanol gradient elution, yielding compound 10 (1.6 g). 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 / z 283.2[M+1] + .

[0147] Example 11.

[0148] 3-((3-(1-fluorocyclopropyl)propoxy)-4-(1-(methyl-d3)-1,2,5,6-tetrahydropyridin-3-yl)-1,2,5-thiadiazole

[0149] The synthesis route is as follows:

[0150] Preparation of intermediate 17:

[0151] The preparation process of intermediate 17 is the same as that of intermediate 12, except that iodomethane is replaced with deuterated iodomethane to obtain intermediate 17 (2.0g).

[0152] Preparation of compound 11:

[0153] Intermediate 17 (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 hr, concentrated under reduced pressure, and extracted with water using EA. The organic phases were combined and concentrated under reduced pressure. Purification was achieved by rapid silica gel column chromatography with ethyl acetate-methanol gradient elution, yielding compound 11 (1.8 g). 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 / z 301.1[M+1] + .

[0154] Example 12.

[0155] 3-((4-(cyclopropyl)butoxy)-4-(1-(methyl-d3)-1,2,5,6-tetrahydropyridin-3-yl)-1,2,5-thiadiazole

[0156] The synthesis route is as follows:

[0157] Preparation of intermediate 22:

[0158] The preparation process of intermediate 22 is the same as that of intermediate 19, except that iodomethane is replaced with deuterated iodomethane to obtain intermediate 22 (2.4g).

[0159] Preparation of compound 12:

[0160] Intermediate 22 (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 hr, concentrated under reduced pressure, and extracted with water using EA. The organic phases were combined and concentrated under reduced pressure. Purification was achieved by rapid silica gel column chromatography with ethyl acetate-methanol gradient elution, yielding compound 12 (1.9 g). Deuteration rate: 99.1%. 1H 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 / z 297.2[M+1] + .

[0161] Example 13.

[0162] 3-((4-(1-fluorocyclopropyl)butoxy)-4-(1-(methyl-d3)-1,2,5,6-tetrahydropyridin-3-yl)-1,2,5-thiadiazole

[0163] The synthesis route is as follows:

[0164] Preparation of intermediate 23:

[0165] The preparation process of intermediate 23 is the same as that of intermediate 21, except that iodomethane is replaced with deuterated iodomethane to obtain intermediate 23 (2.3g).

[0166] Preparation of compound 13:

[0167] Intermediate 23 (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 hr, concentrated under reduced pressure, and extracted with water using EA. The organic phases were combined and concentrated under reduced pressure. Purification was achieved by rapid silica gel column chromatography with an ethyl acetate-methanol gradient elution, yielding compound 13 (1.8 g). Deuteration rate: 99.1%. 1 H 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] + .

[0168] Example 14.

[0169] 3-((5,5-difluoropentyl)oxy)-4-(1-methyl-1,2,5,6-tetrahydropyridin-3-yl)-1,2,5-thiadiazole

[0170] The synthesis route is as follows:

[0171] Preparation of intermediate 24:

[0172] Oxaloyl chloride (15.85 g, 124.84 mmol) was dissolved in 100 mL of DCM. Under N2 protection, the solution was cooled to -78 °C, and DMSO (14.63 g, 187.26 mmol) in DCM was added. The mixture was stirred for 15 min. Ethyl 5-hydroxyvalerate (9.1 g, 62.42 mmol) was dissolved in 50 mL of DCM and added dropwise to the above solution. The mixture was stirred for 10 min. Triethylamine (37.90 g, 374.51 mmol) was added dropwise. Under N2 protection, the mixture was stirred at -78 °C. The reaction was monitored by TLC until complete. Saturated ammonium chloride solution was added, and the mixture was extracted with ethyl acetate. The mixture was purified by rapid silica gel column chromatography with ethyl acetate-petroleum ether gradient elution to give intermediate 24 (6.2 g).

[0173] Preparation of intermediate 25:

[0174] Intermediate 24 (9 g, 61.32 mmol) was dissolved in 60 mL of DCM, cooled to -78 °C, and bis(2-methoxyethyl)aminosulfur trifluoride (16.28 g, 73.58 mmol) was added. The mixture was slowly heated to 50 °C and stirred for 16 hours. The reaction mixture was then extracted with ethyl acetate, purified by rapid silica gel column chromatography, and eluted with an ethyl acetate-petroleum ether gradient to obtain intermediate 25 (4.6 g).

[0175] Preparation of intermediate 26:

[0176] Intermediate 25 (4 g, 22.2 mmol) was dissolved in 30 mL of THF, cooled to 0 °C, protected with N2, and LiBH4 (1.5 g, 66.6 mmol) was added. The mixture was slowly heated to 15 °C and stirred for 30 h. The reaction solution was then added to a saturated ammonium chloride solution, extracted with ethyl acetate, purified by rapid silica gel column chromatography, and eluted with an ethyl acetate-petroleum ether gradient to obtain intermediate 26 (3.3 g). ESI-MS m / z 139.1 [M+1]+.

[0177] Preparation of intermediate 27:

[0178] 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 achieved by rapid silica gel column chromatography, eluting with ethyl acetate-petroleum ether, to give intermediate 27 (5.1 g).

[0179] Preparation of intermediate 28:

[0180] 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 the solid precipitated from the solution. The solid was filtered and dried to obtain intermediate 28 (2.1 g).

[0181] Preparation of compound 14:

[0182] 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 hr, concentrated under reduced pressure, and extracted with water using EA. The organic phases were combined and concentrated under reduced pressure. Purification was achieved by rapid silica gel column chromatography with ethyl acetate-methanol gradient elution. Compound 14 (1.5 g) was obtained. 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]+.

[0183] Example 15.

[0184] 3-((5,5-difluoropentyl)oxy)-4-(1-(methyl-d3)-1,2,5,6-tetrahydropyridin-3-yl)-1,2,5-thiadiazole

[0185] Preparation of intermediate 29:

[0186] Intermediate 27 (2.1 g, 7.5 mmol) was dissolved in acetone (15 ml), and deuterated iodomethyl (1.5 ml, 30 mmol) was added dropwise to the reaction solution. The reaction mixture was stirred at room temperature for 18 hours, and the solid precipitated from the solution. The solid was filtered and dried to obtain intermediate 29 (2.6 g).

[0187] Preparation of compound 15:

[0188] Intermediate 29 (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 hr, concentrated under reduced pressure, and extracted with water using EA. The organic phases were combined and concentrated under reduced pressure. Purification was achieved by rapid silica gel column chromatography with an ethyl acetate-methanol gradient elution, yielding compound 15 (2.1 g). Deuteration rate: 99.1%. 1H NMR(400MHz,DMSO-d6)δ7.21(brs,1H),5.84(m,1H),4.45(m,2H),3.43(s,2H),2.5 8-2.53(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] + .

[0189] The control compound Xanomeline was prepared according to the above examples:

[0190] Example 1: In vitro radioligand binding assay

[0191] The test examples and control compounds showed positive effects on the Flp-In response of compounds stably expressing human M1-M5 (hM1-hM5) muscarinic acetylcholine receptor (mAChR). TM The agonistic ability of Chinese hamster ovarian (CHO) cells. (Flp-In) TM The cell line expressed the target protein using the Flp-In expression vector. TM Targeted integration of the expression vector ensured high-level expression of mAChR hM1-hM5.

[0192] Experimental steps:

[0193] 1. All test compounds and control compound Xanomeline were dissolved in dimethyl sulfoxide (DMSO) and the solution was stored at a concentration of 10 mM.

[0194] 2. The expression of mAChR in each CHO cell line was analyzed by combining [3H]-N-methylscopolamine ([3H]-NMS).

[0195] 3. pERK assays were performed using the example compounds and control compounds at different time points (2.5–60 minutes). Extracellular signal-associated kinases (ERK1 / 2 or p42 / 44) are kinases in the mitogen-activated protein kinase (MAPK) family. ERK phosphorylation (pERK) is used as a common endpoint measure of activation of signal transduction linked to various G protein-coupled receptors (GPCRs) and β-repressor proteins.

[0196] 4. Perform serum starvation on cells for 5 to 6 hours. Normalize the curves relative to the maximum response in fetal bovine serum (FBS) medium corresponding to a 5-minute stimulus. Select cells incubated with the test sample for 5 minutes for dose-response pERK assays (n=2).

[0197] 5. Perform pERK dose-response assays to test the agonist activity of the compounds of the examples in CHO cells stably expressing hM2, hM3, and hM5 (n=3). Repeat these pERK dose-response assays to test the agonist activity of the compounds of the examples in CHO cells stably expressing hM1 and hM4 (n=4). Compare EC 50 The EC value is used to evaluate differences in drug efficacy, and the maximum response (Emax) is used to analyze differences in compound efficacy. 50 The Emax values ​​are shown in Table 1.

[0198] Table 1: Agonistaltic effects of the compounds in the examples on human M1-M5 (hM1-hM5) stably expressed muscarinic acetylcholine receptor (mAChR).

[0199] Experimental results show that Xanomeline, as an M1 and M4 receptor agonist, exhibits good M1 agonist activity but moderate M4 agonist activity. All the example compounds showed superior M1 and M4 agonist activity compared to the control compound Xanomeline. In particular, compounds 5, 14, and 15 showed more than three times the M1 receptor agonist activity of Xanomeline. Compounds 5 and 14 had a maximum response Emax of 100% for M1 receptor agonist activity, higher than Xanomeline's 90%. Compounds 2 and 14 showed more than three times the M4 agonist activity of Xanomeline. Compounds 2 and 14 had maximum response Emax of 100% and 99% for M1 receptor agonist activity, respectively, higher than Xanomeline's 87%. Furthermore, all the example compounds showed superior selectivity for both M1 and M4 agonist activity compared to the control compound Xanomeline, indicating the clinical advantages of these compounds in clinical use, including lower dosage and fewer gastrointestinal side effects.

[0200] Example 2: Pharmacokinetic Evaluation

[0201] 2.1 Determination of plasma concentration of compounds

[0202] Using SD rats as test animals, the plasma drug concentrations at different time points after gavage administration of the compound described in the examples to Sprague-Dawley (SD) rats were determined by LC / MS / MS. The pharmacokinetic behavior of the disclosed compound in Sprague-Dawley (SD) rats was investigated to evaluate its pharmacokinetic characteristics.

[0203] 1) Test drugs

[0204] Examples of compounds 1, 2, 6, 14, 15 and Xanomeline.

[0205] 2) Experimental animals

[0206] Thirty-six Sprague-Dawley (SD) rats were used, divided into groups of six (half male and half female). After fasting but not watering overnight, the rats were administered the drug by gavage.

[0207] 3) Drug preparation

[0208] Weigh out a certain amount of each compound from the examples and add the following medication solvent: citric acid + 5% DMSO + 10% Solutol + 85% physiological saline (pH 6.0) to prepare a homogeneous solution of 7.5 mg / mL.

[0209] 4) Administration

[0210] The dose administered by gavage was 75 mg / kg, and the volume of administration was 10.0 mL / kg.

[0211] 5) Operation

[0212] Blood samples of 0.2 mL were collected from the orbital cavity before administration and at 0.25, 0.5, 1.0, 2.0, 4.0, 6.0, 8.0, 12.0, and 24.0 hours after administration. The samples were placed in EDTA-K2 anticoagulant tubes and centrifuged at 10,000 rpm for 1 minute (4°C). Plasma was separated within 1 hour and stored at -20°C for analysis. The entire process, from blood collection to centrifugation, was performed under ice bath conditions. Patients ate 2 hours after administration.

[0213] Determination of the content of the analyte compound in the plasma of SD rats after administration of different drug concentrations: Plasma samples from SD rats at various time points after drug administration were diluted 10-fold with acetonitrile solution containing internal standard, vortexed, and centrifuged at 3700 rpm for 10 minutes. The supernatant was mixed with water at a 1:1 ratio, and 0.5 μL of the supernatant was analyzed by LC / MS / MS.

[0214] 6) The pharmacokinetic parameters are shown in Table 2.

[0215] Table 2: Pharmacokinetic parameters of the compounds in the examples in male and female SD rats.

[0216] Experimental results showed that the metabolic parameters of the control compound Xanomeline differed significantly between males and females, with the C0 of Xanomeline in female rats being significantly lower. max It was 5.6 times higher in males and the AUC concentration in female rats was [not specified]. 0-t It was 4.7 times that of males. The metabolic parameters of all compounds in the examples showed no significant sex difference, with differences within 2-fold. All tested compounds showed higher exposure levels than the control compound Xanomeline. Compound 15, in particular, showed higher exposure levels in male rats (C...). maxIt is 4.8 times that of Xanomeline, and its AUC in male rats is... 0-t It is 3.7 times that of Xanomeline. Experimental results show that the compounds in the examples have better metabolic parameters, with no gender difference in metabolic parameters, a wider range of clinical users, a broader drug safety window, and higher drug safety.

[0217] 2.2 Determination of Compound Concentration in Cerebrospinal Fluid

[0218] The purpose of this study was to evaluate the pharmacokinetic behavior of cerebrospinal fluid in male SD rats after a single oral administration of the compound by measuring the drug concentration in cerebrospinal fluid at different time points using LC / MS / MS.

[0219] 1) Test drugs

[0220] Example: Compound 1 and Xanomeline.

[0221] 2) Experimental animals

[0222] Eighteen male Sprague-Dawley (SD) rats were divided into 6 groups of 3 rats each. After fasting but not watering overnight, the drugs were administered by gavage.

[0223] 3) Drug preparation

[0224] Weigh a certain amount of L(+)-tartaric acid according to the weight ratio of test sample to L(+)-tartaric acid of 1:1.1, dissolve it in water and mix thoroughly. Transfer the test sample to the mixed solution and mix well (it should be a yellow / pale yellow transparent homogeneous liquid).

[0225] 4) Administration

[0226] The dose is 30 mg / kg administered via a single gavage, with a volume of 10.0 mL / kg.

[0227] 5) Sample collection and processing

[0228] Table 3. Sample Collection Schedule

[0229] Cerebrospinal fluid (CSF) collection:

[0230] 30 μL of CSF was collected from each animal after sacrifice and stored at -60°C or lower for LC-MS / MS analysis. Retention times of compounds and internal standards, chromatographic acquisition, and chromatographic integration were processed using Analyst (Applied Biosystems) software. Statistical analysis of the data was performed using Watson LIMS (Thermo Fisher Scientific) or Analyst (SCIEX) software.

[0231] 6) Drug concentrations were processed using a non-compartmental model from pharmacokinetic software, and pharmacokinetic parameters were calculated using the linear logarithmic trapezoidal method. The results of CSF pharmacokinetic parameters are shown in Table 4.

[0232] Table 4. Pharmacokinetic parameters of the compounds in the examples in the CSF of male SD rats.

[0233] *ND=Not determined (Parameters not determined due to inadequately defined terminal elimination phase)

[0234] Experimental results showed that, at the same dosage, all CSF metabolic parameters of Compound 1 in Example 1 were significantly better than those of the control compound Xanomelin. The CSF parameter C of Compound 1 in Example 1 was... max It is 11 times that of the control compound. Experimental results show that the compound in the example has a higher brain distribution, better clinical efficacy in treating schizophrenia and Alzheimer's disease, and fewer peripheral and pyramidal side effects common to psychiatric drugs.

[0235] Example 3: In vivo efficacy evaluation of the compound in treating schizophrenia

[0236] 1. Experimental Methods

[0237] Animals: CD-1 mice, housed in separate cages. They had free access to food and water, were fed standard rodent feed, and the room humidity was maintained at approximately 50%. The light-dark cycle was 12 hours. Experiments were conducted after one week of acclimatization feeding. All behavioral experiments were completed between 9:00 AM and 12:00 PM. All animal experiments strictly adhered to the ethical principles of animal use as outlined by international health research institutions.

[0238] Animal grouping: Seventy CD-1 mice were randomly divided into seven groups of ten mice each. These groups were: negative control group (blank control), model group, positive control group (Xanomeline), and groups containing compounds numbered 1, 2, 5, and 14, as shown in Table 5.

[0239] Table 5: Trial Groups and Dosing Regimens

[0240] Schizophrenia model preparation: The negative control group was injected with physiological saline (1 mL / kg) every morning for 7 days, while 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.

[0241] Drug administration: The dosage of experimental drugs was calculated based on the body surface area ratio. The gavage volume for each group was 10 mL / Kg, and the dosage was 20 mpk. BID was administered continuously for 10 days. See Table 5 for details.

[0242] Animal symptoms and cognitive function testing: Day 1 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 duration according to their groups.

[0243] 1) Open Field Experiment: This experiment consisted of four open gray observation boxes (50cm x 50cm x 40cm), a camera, and a Smart3.0 animal behavior video analysis system. During the experiment, four mice were placed in the observation boxes simultaneously. The Smart system automatically recorded the mice's movement trajectories and distances, allowing for 30 minutes of free movement. Each observation box was divided into nine 3×3 zones, designated as the peripheral and central zones. The exploratory behavior and spontaneous activities of the mice in different zones and at different time points were analyzed to study positive symptoms of schizophrenia. The movement distance in the central zone and the first 10 minutes (T1) represented the mice's exploratory behavior, while the movement distance in the peripheral zone and the remaining 20 minutes (10-20 minutes T2, and the remaining 10 minutes T3) represented the mice's spontaneous activities.

[0244] 2) Forced swimming test: Pour warm water into a glass beaker 40cm high and 25cm in diameter. During the experiment, each mouse is placed in the warm water and forced to swim for 5 minutes. The cumulative time that the mouse remains still (as indicated by being able to float in the water without struggling) is recorded, and the percentage of time that remains still is calculated. This is used to study the negative symptoms of schizophrenia.

[0245] 3) Adverse reaction record: On the first and third days, observe mice for diarrhea and vomiting 0.5-3 hours after the first administration. Record, analyze, and assess the overall severity of gastrointestinal adverse reactions in the animals: severe +++, moderate +, mild +, no effect -.

[0246] Statistical analysis: SPSS 18.0 software was used for statistical analysis. Data are expressed as mean ± standard deviation. The results indicate that, using factorial analysis of variance (SNK-q) and paired t-tests, P < 0.05 was considered statistically significant.

[0247] 2. Results and Analysis

[0248] 1. Comparison of activity distances for each group

[0249] The differences in peripheral activity distance, total activity distance, and activity distance at T1, T2, and T3 were statistically significant among the mice in each group before drug intervention (P<0.01). Further comparisons showed that the peripheral activity distance, total activity distance, and activity distance at the three time points were significantly different between the model group, positive drug group, and mice in the six modeling groups (compounds in the examples) and the negative control group (P<0.05 or P<0.01), indicating that the model was successfully established.

[0250] After drug intervention, the peripheral activity distance and total activity distance of each group were significantly different from 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 compound of the example were significantly decreased (P<0.01). Paired t-test results before and after drug intervention showed that there was no statistically significant difference in data before and after drug administration in the model group (P>0.05), while the peripheral activity distance and total activity distance of the positive drug group and the compound of the example were significantly different from those before intervention (P<0.01). The reduction in peripheral activity distance and total activity distance after drug intervention in the compound of the example group was better than that in the positive control drug Xanomeline, as shown in Table 6.

[0251] Table 6: Comparison of activity distances in different regions of the open field test in rats of different groups before and after drug intervention. Note: Pairwise comparisons of SNK-q: 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.

[0252] 2. Comparison of forced swimming time among groups

[0253] Compared with the negative control group, the percentage of immobile swimming time in the six groups of rats (model group, positive drug group, and compound group of example) before drug intervention was significantly increased, indicating that the model was successfully established.

[0254] After 10 days of treatment with Xanomeline and the compound from the examples, compared with the model group, the positive control group showed a significant difference in the percentage reduction of forced swimming immobility time, and compared with the model group, the compound from the examples showed a significant difference in the percentage reduction of forced swimming immobility time (P<0.01). The percentage reduction of forced swimming immobility time in the compound from the examples was superior to that of Xanomeline. Xanomeline's gastrointestinal adverse reactions, such as diarrhea and vomiting, were severe, while the adverse reactions in the compound from the examples were mild or nonexistent. See Table 7.

[0255] Table 7: Comparison of forced swimming test and degree of gastrointestinal adverse reactions in rats after drug intervention. Note: Pairwise comparisons of SNK-q: **P<0.01 compared with the negative control group; #P<0.05 and ##P<0.01 compared with the model group.

[0256] The experimental results above demonstrate that the compounds in the examples can effectively alleviate the symptoms of schizophrenia in animal models of schizophrenia. The therapeutic effect of the compound group in treating schizophrenia is more significant, superior to the positive control compound Xanomeline. Drug-related gastrointestinal adverse reactions in the compound group are mild or non-existent, overcoming the clinical limitations of Xanomeline. Xanomeline was terminated during clinical trials due to severe gastrointestinal adverse reactions. The compounds in the examples of this invention exhibit superior in vivo and in vitro efficacy, high selectivity for M receptors, no gender difference in pharmacokinetic parameters, fewer gastrointestinal adverse reactions, a longer drug safety window, and higher drug safety.

[0257] For those skilled in the art, this 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 intended that all aspects be considered illustrative rather than restrictive, that references be made to the appended claims rather than the foregoing embodiments, that references be made only to the appended claims and not to the foregoing examples, and that all variations falling within the meaning and scope of claim equivalence are therefore intended to be included herein.

[0258] All patents, patent applications, and references listed in this specification are incorporated herein by reference in their entirety. In case of inconsistencies, this disclosure, including its definitions, will be considered more persuasive.

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 of claim 1 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.

3. Use of the pharmaceutical composition of claim 2 or the compound of 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 use according to claim 3, characterized in that, The relevant diseases are selected from pain or mental disorders.

5. The use according to claim 3, characterized in that, The relevant diseases are selected from intestinal pain, neuropathic pain, musculoskeletal pain, inflammatory pain, cancer pain, idiopathic pain, postoperative pain, or visceral pain.

6. The use according to claim 3, characterized in that, The relevant diseases are selected from schizophrenia, Alzheimer's disease, Huntington's disease, Parkinson's disease, Lewy body dementia, psychosis, or cognitive impairment.

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