Thieno[2,3-c]pyridazine derivatives as positive allosteric modulators of cholinergic m4 receptors

Abstract

The present application relates to a kind of thieno [2, 3-c] pyridazine derivatives, and its isotope form, stereoisomer, tautomer, cis-trans isomer, pharmaceutically acceptable salt, pharmaceutically acceptable solvate, hydrate, prodrug and polymorph, these compounds can be used as cholinergic M4 receptor positive allosteric modulator, it has good application prospect in preparation for preventing and / or treating the drug for the disease related to abnormal muscarinic acetylcholine receptor.

Description

Technical Field

[0001] This invention relates to the field of biomedicine, specifically to a class of thieno[2,3-c]pyridazine derivatives that act as positive allosteric modulators of cholinergic M4 receptors. Background Technology

[0002] Cholinergic neurotransmission is a key physiological process mediated by the endogenous agonist acetylcholine (ACh) through its action on nicotinic acetylcholine receptors (nAChRs) or muscarinic acetylcholine receptors (mAChRs). In cognitive impairment diseases such as Alzheimer's, brain acetylcholine levels are significantly reduced, primarily due to the degeneration of cholinergic neurons in the basal forebrain. These neurons project extensively to brain regions crucial for learning and memory, such as the cerebral cortex and hippocampus. Furthermore, cholinergic dysfunction is also considered one of the important pathological mechanisms of cognitive deficits in patients with schizophrenia.

[0003] Currently, clinical strategies for increasing central acetylcholine levels mainly focus on two approaches: supplementing synthetic precursors (such as choline) and inhibiting acetylcholinesterase (AChE). Acetylcholinesterase inhibitors have been approved for palliative treatment of cognitive symptoms in Alzheimer's disease, but they cannot stop disease progression and often cause gastrointestinal adverse reactions (such as abdominal cramps, nausea, vomiting, and diarrhea) due to simultaneous activation of the peripheral cholinergic system, affecting approximately one-third of patients. Furthermore, some drugs (such as tacrine) pose a risk of hepatotoxicity, limiting their long-term use.

[0004] Given the aforementioned limitations, direct activation of central muscarinic acetylcholine receptors (mAChRs) is considered a promising alternative strategy. Studies have shown that certain muscarinic agonists (such as sambalin) have demonstrated antipsychotic activity in animal models without inducing rigidity; their ameliorative effects on psychotic symptoms in Alzheimer's patients have also been observed in clinical studies. However, these compounds have also limited widespread clinical application due to gastrointestinal and other side effects.

[0005] Muscarinic receptors comprise five subtypes, M1-M5, with the M4 subtype being highly expressed in the central nervous system (such as the striatum, hippocampus, and cerebral cortex) and considered to play a crucial role in regulating dopaminergic neurotransmission, cognitive function, and motor control. Selective targeting of the M4 receptor holds promise for improving cognitive and psychotic symptoms while avoiding adverse reactions caused by the widespread activation of other mAChR subtypes (especially those mediating peripheral side effects). Therefore, the development of highly efficient and selective M4 receptor agonists or modulators has become a research hotspot in this field.

[0006] Positive allosteric modulators (PAMs) represent an emerging drug discovery strategy. By binding to allosteric sites on receptors that differ from endogenous ligands, they enhance the receptor's response to acetylcholine, thereby providing higher subtype selectivity and spatiotemporal specificity. VU0467154 is a known M4 receptor PAM, providing a lead structure for developing M4-selective drugs. However, existing M4 PAMs still require optimization in terms of activity, selectivity, and pharmacokinetic properties (such as metabolic stability) to meet clinical therapeutic needs. Summary of the Invention

[0007] To address the aforementioned problems, this invention provides a class of thieno[2,3-c]pyridazine derivatives that serve as positive allosteric modulators of cholinergic M4 receptors.

[0008] Specifically, the present invention provides the following technical solutions: The first aspect of the present invention provides a thieno[2,3-c]pyridazine derivative of formula (I).

[0009] Or its isotopic forms, stereoisomers, tautomers, cis-trans isomers, pharmaceutically acceptable salts, pharmaceutically acceptable solvates, hydrates, prodrugs, and polymorphs, wherein, R1 and R2 are independently selected from H and C. 1-6 Alkyl, C 3-6 cycloalkyl, C 1-6 Haloalkyl, C 3-6 One of the halocycloalkyl groups; R3 is selected from H, halogens, and C. 1-6 Alkyl, C 3-6 cycloalkyl, C 1-6 Haloalkyl, C 3-6 One of the halocycloalkyl groups.

[0010] Furthermore, R1 is H.

[0011] Furthermore, R3 is H.

[0012] Furthermore, the thieno[2,3-c]pyridazine derivative is a compound represented by the following structural formulas 1 to 6, or a group consisting of compounds represented by the following structures: .

[0013] Further, the pharmaceutically acceptable salt is an inorganic salt or an organic salt; wherein the inorganic salt includes hydrochloride, hydrobromide, hydroiodide, sulfate, hydrogen sulfate, nitrate, phosphate, and acid phosphate; and the organic salt includes acetate, trifluoroacetate, propionate, pyruvate, glycolate, oxalate, malonate, fumarate, maleate, lactate, malate, citrate, tartrate, methanesulfonate, ethanesulfonate, benzenesulfonate, and salicylate.

[0014] A second aspect of the present invention provides a pharmaceutical composition comprising one or more of the following: a thieno[2,3-c]pyridazine derivative or isotopic form thereof, a stereoisomer, a tautomer, a cis-trans isomer, a pharmaceutically acceptable salt, a pharmaceutically acceptable solvate, a hydrate, a prodrug, and a polymorph, as well as at least one pharmaceutically acceptable carrier, excipient, or diluent.

[0015] Furthermore, the pharmaceutically acceptable carriers include microspheres, nanoparticles, and liposomes.

[0016] The third aspect of the present invention provides the use of a thieno[2,3-c]pyridazine derivative of formula (I) as described in the first aspect, or its isotopic form, stereoisomer, tautomer, cis-trans isomer, pharmaceutically acceptable salt, pharmaceutically acceptable solvate, hydrate, prodrug, polymorph, or pharmaceutical composition as described in the second aspect, in the preparation of a positive allosteric modulator of cholinergic muscarinic M4 receptor.

[0017] The fourth aspect of the present invention provides the use of a thieno[2,3-c]pyridazine derivative of formula (I) as described in the first aspect, or its isotopic form, stereoisomer, tautomer, cis-trans isomer, pharmaceutically acceptable salt, pharmaceutically acceptable solvate, hydrate, prodrug, polymorph, or pharmaceutical composition as described in the second aspect, in the preparation of a medicament for the prevention and / or treatment of cholinergic muscarinic M4 receptor-mediated diseases.

[0018] Furthermore, the condition is associated with decreased acetylcholine levels, for example, as a neuropsychiatric disorder related to abnormalities in muscarinic acetylcholine receptors.

[0019] Furthermore, the drug is used to activate the M4 subtype.

[0020] Furthermore, the neuropsychiatric disorders include psychosis, schizophrenia, behavioral disorders, disruptive behavioral disorders, bipolar disorder, psychotic episodes of anxiety disorders, anxiety associated with psychosis, psychotic mood disorders, mood disorders associated with mental disorders, acute mania, depression associated with bipolar disorder, mood disorders associated with schizophrenia, behavioral manifestations of intellectual disability, autism spectrum disorders, movement disorders, Tourette syndrome, akinesia-tonic syndrome, movement disorders associated with Parkinson's disease, tardive dyskinesia, drug-induced and neurodegenerative movement disorders, attention deficit hyperactivity disorder, cognitive impairment (e.g., Alzheimer's disease), dementia, and memory impairment.

[0021] Furthermore, the dosage forms of the drug include, but are not limited to, injection solutions, lyophilized powder for injection, suspensions, implants, embolic agents, capsules, tablets, pills, and oral solutions.

[0022] Further, the content of the thieno[2,3-c]pyridazine derivative or its isotopic form, stereoisomer, tautomer, cis-trans isomer, pharmaceutically acceptable salt, pharmaceutically acceptable solvate, hydrate, prodrug, or polymorph of the drug as represented by formula (I) is 0.01-1000 mg, for example 0.05-800 mg, 0.1-500 mg, 0.01-300 mg, 0.01-200 mg, 0.05-150 mg, 0.05-50 mg, etc.

[0023] Furthermore, when the drug is a solid dosage form for oral administration (e.g., capsules, tablets, pills, powders, granules, etc.), the thieno[2,3-c]pyridazine derivative or its isotopic form, stereoisomer, tautomer, cis-trans isomer, pharmaceutically acceptable salt, pharmaceutically acceptable solvate, hydrate, prodrug, and polymorph shown in formula (I) as the active ingredient may be mixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate; and / or, mixed with one or more of the following components: (1) filler or solubilizer, such as starch, lactose, sucrose, glucose (1) Glucose, mannitol and silicic acid, etc.; (2) Adhesives, such as hydroxymethyl cellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose, gum arabic, etc.; (3) Humectants, such as glycerin, etc.; (4) Disintegrants, such as agar, calcium carbonate, potato starch, cassava starch, alginic acid, silicates, sodium carbonate, etc.; (5) Slow solvents, such as paraffin, etc.; (6) Absorption accelerators, such as quaternary ammonium compounds, etc.; (7) Wetting agents, such as cetyl alcohol and glyceryl monostearate, etc.; (8) Adsorbents, such as kaolin, etc.; (9) Lubricants, such as talc, calcium stearate, solid polyethylene glycol, sodium dodecyl sulfate, etc.

[0024] Furthermore, the solid dosage form may be coated or microencapsulated using enteric coating materials and / or other materials known in the art. In such solid dosage forms, the release of the active ingredient can be delayed within a portion of the digestive tract.

[0025] Furthermore, when the drug is a liquid dosage form (e.g., emulsion, solution, suspension, syrup, tincture, etc.) for oral administration, in addition to the active ingredient (thieno[2,3-c]pyridazine derivatives or their isotopic forms, stereoisomers, tautomers, cis-trans isomers, pharmaceutically acceptable salts, pharmaceutically acceptable solvates, hydrates, prodrugs, and polymorphs as shown in formula (I), the liquid dosage form may also contain inert diluents conventionally used in the art, such as water, ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1,3-butanediol, dimethylformamide, and oils, particularly one or more of cottonseed oil, peanut oil, corn oil, olive oil, castor oil, and sesame oil. Besides these inert diluents, the liquid dosage form of the present invention may also include conventional adjuvants, such as pharmaceutically acceptable wetting agents, emulsifiers, suspending agents, sweeteners, flavoring agents, and fragrances.

[0026] Furthermore, the suspending agent includes one or more of ethoxylated octadecyl alcohol, polyoxyethylene sorbitol, dehydrated sorbitol, microcrystalline cellulose, and agar.

[0027] Furthermore, when the drug is a dosage form for parenteral injection, it includes, but is not limited to, sterile aqueous or anhydrous solutions, dispersions, suspensions, emulsions, sterile powders for reconstitution into sterile injectable solutions and dispersions, etc.

[0028] Furthermore, when the drug is a dosage form for topical administration, it includes, but is not limited to, ointments, powders, suppositories, drops, sprays, and inhalers. In addition to the active ingredient, the dosage form for topical administration may also contain pharmaceutically acceptable carriers, preservatives, buffers, and, if necessary, propellants.

[0029] As used herein, unless otherwise stated, the following definitions and terms shall apply.

[0030] "R" and "S" are terms used to describe isomers and are descriptors of the stereochemical configuration of asymmetrically substituted carbon atoms. Naming an asymmetrically substituted carbon atom "R" or "S" is accomplished by applying the Cahn-Ingold-Prelog priority rule, which is well known to those skilled in the art and described in Section E, Stereochemistry, of the International Union of Pure and Applied Chemistry (IUPAC) Rules of Nomenclature for Organic Chemistry.

[0031] The term C used here i - jThis refers to the presence of ij carbon atoms in that part. For example, "C1-6 alkyl" means that the alkyl unit has any number of carbon atoms between 1 and 6.

[0032] As used herein, "alkyl" refers to a fully saturated straight-chain or branched alkane group. Example C 1-6 Non-limiting examples of alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, etc. Additionally, the term "cycloalkyl" refers to a monocyclic or bicyclic saturated carbon ring, such as cyclopentyl, cyclohexyl, etc.

[0033] Unless otherwise stated, the term "halogen" refers to a fluorine, chlorine, bromine, or iodine atom.

[0034] Additionally, in this article, "C" 1-6 "Halogenated alkyl" refers to C 1-6 At least one hydrogen atom in the alkyl group is substituted with a halogen atom, such as -CF3, etc. "C 1-6 "Halogenated cycloalkyl" refers to C 1-6 At least one hydrogen atom in a cycloalkyl group is replaced by a halogen atom.

[0035] In this invention, "pharmaceutically acceptable salt" refers to the acid salt of the compounds of this invention, which has the desired pharmacological activity and, within a reasonable medical judgment, is suitable for contact with human and lower animal tissues without excessive toxicity, irritation, allergic reactions, etc. The salt can be formed by a thieno[2,3-c]pyridazine derivative of formula (I) with an acid, including but not limited to hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, hydrogen sulfate, nitric acid, phosphoric acid, acidic phosphoric acid, acetic acid, trifluoroacetic acid, propionic acid, pyruvic acid, glycolic acid, oxalic acid, malonic acid, fumaric acid, maleic acid, lactic acid, malic acid, citric acid, tartaric acid, methanesulfonic acid, sulfonic acid, benzenesulfonic acid, salicylic acid, etc.

[0036] In this invention, the term "cholinergic muscarinic M4 receptor-mediated disease" refers to any disease or other harmful condition known to be associated with decreased cholinergic muscarinic M4 receptor activity.

[0037] By employing the above technical solution, the present invention has at least the following advantages: This invention provides a class of thieno[2,3-c]pyridazine derivatives that can serve as positive allosteric modulators of the cholinergic M4 receptor. Compared to the positive control (VU0467154), the activity and selectivity are significantly improved, making it suitable for the treatment and / or prevention of diseases mediated by the cholinergic M4 receptor. Furthermore, the compounds or their salts provided by this invention exhibit favorable pharmacokinetics and metabolism, showing promising applications in the preparation of agents for the prevention and / or treatment of cholinergic muscarinic M4 receptor-mediated diseases and as positive allosteric modulators of the cholinergic muscarinic M4 receptor. Detailed Implementation

[0038] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention pertains. The terminology used herein in the description of the invention is for the purpose of describing particular embodiments only and is not intended to be limiting of the invention. The term "and / or" as used herein includes any and all combinations of one or more of the associated listed items.

[0039] The present invention will be further described below with reference to specific embodiments, so that those skilled in the art can better understand and implement the present invention, but the embodiments are not intended to limit the present invention. Unless otherwise stated, the reagents used are purchased from commercial suppliers and used without further purification. The structures of the final products, intermediates and starting materials are confirmed by standard analytical methods, such as MS, NMR, etc. The abbreviations used are conventional abbreviations in the art.

[0040] The synthesis method of the reaction intermediate used in the following embodiments of this application is as follows: Intermediate a-2 was prepared according to the synthetic method shown in reaction route 1 below:

[0041] Reaction route 1 Specifically as follows: 1-Fluoro-4-[5'-(trifluoromethyl)sulfonylimino]benzene (a-1, 300 mg, 1.32 mmol) was dissolved in 20 mL of dimethyl sulfoxide, and potassium carbonate (230 mg, 1.66 mmol), potassium iodide (280 mg, 1.68 mmol), and potassium cyanide (260 mg, 4.0 mmol) were added. The mixture was heated and stirred overnight at 110 °C. After cooling to room temperature, about 10 mL of water was added to the mixture, and it was extracted with ethyl acetate (3 × 10 mL). After concentrating the organic phase, the residue was purified by silica gel chromatography. Intermediate a-2 (99 mg, 32%) of the target compound was obtained. MS-ESI (m / z): 235.07 [M+l] + .

[0042] 4-((trifluoromethyl)sulfonylimide)benzonitrile (a-2, 1 g, 4.3 mmol) and tetrahydrofuran (13 mL) were added to a flame-drying flask equipped with a magnetic stir bar. A 1 M borane-THF solution (8.5 mL, 8.5 mmol) was added to this solution. After attaching a condenser, the mixture was refluxed for approximately 18 hours. After cooling to room temperature, methanol was slowly added to decompose excess borane-THF. The volatiles were removed under reduced pressure, and the residue was redissolved in methanol and packed into an SCX column. The column was eluted with a methanol-ammonia solution, and the solvent was removed. Drying yielded the target compound intermediate a-3 (481 mg, 47%), which was used directly without further purification. MS-ESI (m / z): 239.05 [M+l] + .

[0043] Example 1 This embodiment relates to the preparation of a thieno[2,3-c]pyridazine derivative compound 1, which was prepared according to the synthetic method shown in reaction route 2 below:

[0044] Reaction route 2 5-Amino-3,4-dimethylthiopheno[2,3-c]pyridazine-6-carboxylic acid (I-1, 50 mg, 0.22 mmol) was dissolved in DMF (1 mL) to prepare a suspension. N,N-diisopropylethylamine (90 μL, 0.66 mmol) was added, followed by HATU (100 mg, 0.26 mmol). The mixture was stirred at room temperature, and then HATU (100 mg, 0.26 mmol) was added. After stirring at room temperature for about 45 minutes, (4-(aminomethyl)phenyl)(trifluoromethyl)sulfonylimide (a-3, 60 mg, 0.25 mmol) was added. After stirring for another 20 minutes, about 10 mL of water was added to the mixture, and it was extracted with ethyl acetate (3 × 10 mL). After concentrating the organic phase, the residue was purified by silica gel chromatography to give target compound 1 (50 mg, 51%). MS-ESI (m / z): 444.09 [M+l] + .

[0045] 1 H NMR (400 MHz, DMSO-d6): δ 8.85 (t, J = 5.6 Hz, 1H), 8.08 (d, J =8.4 Hz, 2H), 7.57 (d, J = 8.4 Hz, 2H), 6.96 (br. s, 2H), 4.55 (d, J = 5.8 Hz, 2H), 3.47 (br. s, 1H), 2.81 (s, 3H), 2.75 (s, 3H).

[0046] Test Example 1 The bioactivity of compound 1 synthesized in Example 1 was tested using compound VU0467154 ( As a control, the activity of different compounds on the muscarinic M4 receptor was determined. The specific procedures are as follows: CHO-K1 cells expressing the receptor were seeded at 15,000 cells / well in 384-well plates and cultured overnight at 37 °C. The following day, after washing, the cells were incubated with 2.3 µM Fluo-4 / AM dye for 50 minutes, followed by another wash. Test compounds were prepared at 11 concentration gradients (1:3 dilution, starting at 10 mM), and 2× test concentrations were obtained via Echo acoustic transfer and Combi dilution.

[0047] Detection of calcium flow signals using the FDSS system: (1) Add the test compound (20 µL, 2×); (2) Add EC at 144 seconds 20 Acetylcholine (10 µL, 5×); (3) Add EC at 230 seconds 80 Acetylcholine (12 µL, 5×).

[0048] Data analysis: Agonist activity: Compound-induced increase in calcium mobilization; Positive allosteric regulation: EC 20 Enhanced acetylcholine response; antagonist activity: EC 80 Inhibition of the acetylcholine response.

[0049] The concentration-response curve was fitted using a four-parameter logic equation, and the maximum agonist rate E was read. max value.

[0050] A second detection method was proposed: after adding a fixed concentration of the test compound, the baseline response was measured; 140 seconds later, an agonist was added, and the calcium response was measured. This was achieved via the agonist EC50. 50 The offset of the value indicates the activity of the compound: EC 50 Decrease (curve shift to the left): Positive allosteric adjustment, EC 50 Increase (curve shifts to the right): Antagonistic effect.

[0051] The experimental results are summarized in Table 1 below: Table 1 Activity evaluation results

[0052] As shown in Table 1, compound 1 prepared in Example 1 of the present invention has superior agonistic activity against muscarinic M4 receptors compared to reference compound VU0467154.

[0053] Test Example 2 The metabolic stability of compound 1 synthesized in Example 1 and control compound VU0467154 in human liver microsomes was tested as follows: (1) Experimental materials: human liver microsomes, purchased from Corning; NADPH, purchased from Bid Pharmaceuticals.

[0054] (2) Experimental method: Human liver microsomes (20 mg / mL) were stored in a -80 ℃ refrigerator, thawed in a 37 ℃ water bath before use, and then placed on ice for later use.

[0055] 10 μL of human liver microsomes (20 mg / mL, final concentration 0.5 mg / mL), 200 μL of phosphate buffer (200 mM, final concentration 100 mM), 40 μL of magnesium chloride (50 mM, final concentration 5 mM), and 106 μL of purified water were added to a 96-well plate. The system was pre-incubated in a 37 °C water bath for 10 minutes. 40 μL of NADPH solution (10 mM, final concentration 1 mM) was added to the reaction system; 40 μL of ultrapure water was used as a negative control instead of NADPH solution.

[0056] The reaction was initiated by adding 4 μL of 100 mM of the test compound and the control drug (Verapamil), with the final drug concentration being 1 μM.

[0057] At 1, 2, 3, and 6 h, 50 µL of the reaction sample was collected and quenched with 4 volumes of cold acetonitrile containing internal standards (3% formic acid, 100 nM alprazolam, 200 nM labetalol, 2 µM ketoprofen, and 200 nM caffeine). The sample was centrifuged at 3220 g for 45 min. After centrifugation, 100 µL of the supernatant was mixed with 100 µL of ultrapure water and used for LC-MS / MS analysis.

[0058] (3) Data Analysis: Peak areas were detected by extracting ion spectra. The in vitro half-life (t) of the parent drug was determined by linearly fitting the percentage disappearance of the parent drug with time. 1 / 2 ).

[0059] In vitro half-life (t 1 / 2 ) Calculated by slope: in vitro t 1 / 2 =0.693 / k, where k is the slope value.

[0060] The following formula is used to measure the in vitro t 1 / 2 Conversion to in vitro clearance rate (CL) int (µL / min / mg protein):

[0061] The incubation volume was 400 µL, and the protein amount was 0.2 mg. The results are shown in Table 2 below: Table 2. In vitro clearance rates of different compounds

[0062] As shown in Table 2, compared with VU0467154, compound 1 provided by the present invention has a lower in vitro clearance rate and better drug metabolism stability, which is beneficial to the potential to reduce drug dosage and extend the dosing interval.

[0063] The above-described embodiments are merely preferred embodiments provided to fully illustrate the present invention, and the scope of protection of the present invention is not limited thereto. Equivalent substitutions or modifications made by those skilled in the art based on the present invention are all within the scope of protection of the present invention. The scope of protection of the present invention is defined by the claims.

Claims

1. Thiophene[2,3-c]pyridazine derivatives represented by formula (I) ， Or its isotopic forms, stereoisomers, tautomers, cis-trans isomers, pharmaceutically acceptable salts, pharmaceutically acceptable solvates, hydrates, prodrugs, and polymorphs, wherein, R1 and R2 are independently selected from H and C. 1-6 Alkyl, C 3-6 cycloalkyl, C 1-6 Haloalkyl, C 3-6 One of the halocycloalkyl groups; R3 is selected from H, halogens, and C. 1-6 Alkyl, C 3-6 cycloalkyl, C 1-6 Haloalkyl, C 3-6 One of the halocycloalkyl groups.

2. The thieno[2,3-c]pyridazine derivative or its isotopic forms, stereoisomers, tautomers, cis-trans isomers, pharmaceutically acceptable salts, pharmaceutically acceptable solvates, hydrates, prodrugs, and polymorphs of formula (I) according to claim 1, characterized in that, R1 is H; and / or R3 is H.

3. The thieno[2,3-c]pyridazine derivative or its isotopic forms, stereoisomers, tautomers, cis-trans isomers, pharmaceutically acceptable salts, pharmaceutically acceptable solvates, hydrates, prodrugs, and polymorphs of formula (I) as described in claim 1 or 2, characterized in that, The thieno[2,3-c]pyridazine derivatives are selected from compounds with the following structures or the group consisting of compounds with the following structures: 。 4. The thieno[2,3-c]pyridazine derivative or its isotopic forms, stereoisomers, tautomers, cis-trans isomers, pharmaceutically acceptable salts, pharmaceutically acceptable solvates, hydrates, prodrugs, and polymorphs of formula (I) according to claim 1, characterized in that, The pharmaceutically acceptable salt is either an inorganic salt or an organic salt; among which... The inorganic salts include hydrochloride, hydrobromide, hydroiodide, sulfate, hydrogen sulfate, nitrate, phosphate, and acid phosphate; The organic salts include acetates, trifluoroacetates, propionates, pyruvates, glycolates, oxalates, malonates, fumarates, maleates, lactates, malates, citrates, tartrates, methanesulfonates, ethanesulfonates, benzenesulfonates, and salicylates.

5. A pharmaceutical composition, characterized in that, It comprises one or more of the following: a thieno[2,3-c]pyridazine derivative or its isotopic form, stereoisomer, tautomer, cis-trans isomer, pharmaceutically acceptable salt, pharmaceutically acceptable solvate, hydrate, prodrug, and polymorph as shown in formula (I) according to any one of claims 1-4, and at least one pharmaceutically acceptable carrier, excipient, or diluent.

6. The pharmaceutical composition according to claim 5, characterized in that, Pharmaceutically acceptable carriers include microspheres, nanoparticles, and liposomes.

7. The use of a thieno[2,3-c]pyridazine derivative of formula (I) as described in any one of claims 1-4, or its isotopic form, stereoisomer, tautomer, cis-trans isomer, pharmaceutically acceptable salt, pharmaceutically acceptable solvate, hydrate, prodrug, polymorph, or pharmaceutical composition as described in claim 5 or 6, in the preparation of a cholinergic muscarinic M4 receptor positive allosteric modulator.

8. The use of a thieno[2,3-c]pyridazine derivative of formula (I) as described in any one of claims 1-4, or its isotopic form, stereoisomer, tautomer, cis-trans isomer, pharmaceutically acceptable salt, pharmaceutically acceptable solvate, hydrate, prodrug, polymorph, or pharmaceutical composition as described in claim 5 or 6, in the preparation of a medicament for the prevention and / or treatment of cholinergic muscarinic M4 receptor-mediated diseases.

9. The application according to claim 8, characterized in that, The condition is a neuropsychiatric disorder associated with abnormal muscarinic acetylcholine receptors.

10. The application according to claim 9, characterized in that, The neuropsychiatric disorders include psychosis, schizophrenia, behavioral disorders, disruptive behavioral disorders, bipolar disorder, psychotic episodes of anxiety disorders, anxiety associated with psychosis, psychotic mood disorders, mood disorders associated with mental disorders, acute mania, depression associated with bipolar disorder, mood disorders associated with schizophrenia, behavioral manifestations of intellectual disability, autism spectrum disorders, movement disorders, Tourette syndrome, akinesia-tonic syndrome, movement disorders associated with Parkinson's disease, tardive dyskinesia, drug-induced and neurodegenerative movement disorders, attention deficit hyperactivity disorder, cognitive impairment, dementia, and memory impairment.

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