Azetidine compounds, pharmaceutical compositions thereof, methods of preparation, and their use in treatment of CNS disorders

Abstract

The present disclosure relates to compounds of formula (I) wherein R1 to R9 are as defined in the claims, as well as stereoisomers and pharmaceutically acceptable salts thereof. Also disclosed are compounds of formula (I) for use in the treatment or prevention of drug addiction or CNS-related diseases or conditions. The invention also relates to pharmaceutical compositions, and processes for preparing the above compounds. # imgabs0 #

Description

Technical Field

[0001] The present invention relates to novel compounds derived from 3,3-disubstituted azetidines and pharmaceutical compositions comprising the compounds. In addition to methods for preparing the compounds, the present invention also relates to the use of the compounds in the treatment or prevention of drug addiction or CNS-related diseases or conditions. Background Art

[0002] Azetidine (azetidine) is a heterocyclic compound containing three carbon atoms and one nitrogen atom. Azetidine and its derivatives are relatively rare structural motifs in natural products. They are components of mugineic acid and penaresidin. A natural product containing azetidine is azetidine-2-carboxylic acid, which is a toxic mimetic of proline.

[0003] EA202092955A1 discloses certain 3,3-disubstituted azetidines as LPA1 receptor modulators for the treatment of fibrosis.

[0004] US2012232026A1 discloses certain 3,3-disubstituted azetidines as antiparasitic agents, which are spirocyclic isoxazoline derivatives.

[0005] WO2005049605A1 discloses antibacterial aminoquinazolidinedione derivatives, some of which contain a 3,3-disubstituted azetidin-1-yl group.

[0006] WO2016193241A1 discloses certain 3,3-disubstituted azetidines having muscarinic receptor antagonist and β2 adrenergic receptor agonist activities.

[0007] WO2016177849A1 discloses certain compounds containing a 3,3-disubstituted azetidin-1-yl group, wherein the compounds are both phosphodiesterase 4 (PDE4) enzyme inhibitors and muscarinic M3 receptor antagonists, and are used for preventing and / or treating asthma or COPD.

[0008] TAAR1 (trace amine-associated receptor 1) is a protein encoded by the TAAR1 gene in humans. TAAR1 plays a role in regulating neurotransmission in dopamine, norepinephrine, and serotonin neurons in the CNS and affects immune and neuroimmune system function through different mechanisms. Endogenous ligands for the human TAAR1 (hTAAR1) receptor include tyramine, β-phenylethylamine (PEA), dopamine, and octopamine. TAAR1 is a high-affinity receptor for amphetamine, methamphetamine, and trace amines, mediating some of the cellular effects of these amines in monoamine neurons within the CNS. Low concentrations of PEA in the brain are associated with major depressive disorder, while high concentrations of PEA are associated with schizophrenia. In addition, low PEA levels and insufficient TAAR1 activation appear to be associated with attention deficit hyperactivity disorder (ADHD). TAAR1-selective ligands have been proposed to have therapeutic potential for the treatment of psychostimulant addiction (e.g., cocaine, amphetamine, methamphetamine).

[0009] The dopamine transporter (DAT) is a transmembrane protein that pumps the neurotransmitter dopamine from the synaptic cleft back into the cytosol. As such, DAT is implicated in a variety of dopamine-related conditions, including ADHD, bipolar disorder, alcoholism, and substance use disorders (drug addiction, alcoholism). In addition, increased DAT activity has been associated with clinical depression.

[0010] Dopamine receptors are also involved in many neurological disorders, diseases and conditions, including ADHD, Parkinson's disease (PD), schizophrenia, neuroleptic malignant syndrome, drug addiction, alcoholism, social phobia and Tourette syndrome. Dopamine receptors bind dopamine; while psychostimulants are generally indirect agonists of dopamine receptors, dopamine receptor antagonists are often used as antipsychotics.

[0011] Like dopamine receptors, adrenergic receptors are also a class of G protein-coupled receptors (GPCRs). Adrenergic receptors are targets of catecholamines such as norepinephrine and epinephrine. FDA-approved drugs that bind to adrenergic receptors are used to treat, for example, hypertension and ADHD, while β2-adrenergic receptor agonists have been found to be effective in treating PD.

[0012] Serotonin receptors are also GPCRs and are ligand-gated ion channels activated by the endogenous neurotransmitter serotonin. Serotonin receptors are present in the central and peripheral nervous systems. The various biological and neural processes affected by serotonin receptors include, for example, aggressiveness, anxiety, appetite, cognition, learning, memory, mood, nausea, sleep, and temperature regulation. Therefore, serotonin receptors are targets for drugs such as antidepressants, antipsychotics, anorexia drugs, antiemetics, gastrokinetics, anti-migraine drugs, hallucinogens, and inducing agents.

[0013] The NMDA receptor (N-methyl-D-aspartate receptor) is a glutamate receptor and ion channel found in neurons. NMDA receptors may be important in controlling synaptic plasticity and mediating learning and memory functions. NMDA receptor inhibitors and antagonists are used to treat Alzheimer's disease and depression, and antagonists are used as anesthetics.

[0014] Cholinergic receptors are receptors and integral membrane proteins that are activated by the neurotransmitter acetylcholine. Cholinergic receptors include nicotinic acetylcholine (nAChR) receptors and muscarinic acetylcholine (mAChR) receptors.

[0015] Monoamine oxidase A (MAOA) is an enzyme that in humans is encoded by the MAOA gene. Diseases, disorders and conditions associated with MAOA include Alzheimer's disease (AD), aggression, panic disorder, bipolar disorder, depression, attention deficit hyperactivity disorder and antisocial behavior.

[0016] Catechol-O-methyltransferase (COMT) is one of several enzymes that inactivates catecholamines, such as the neurotransmitters dopamine, epinephrine, and norepinephrine, as well as catechol estrogens, by introducing a methyl group into the catechol structure. COMT inhibitors are used to treat PD.

[0017] Dopamine β-hydroxylase (DBH) is an enzyme that catalyzes the conversion of dopamine to norepinephrine. DBH is considered a target for drugs in diseases, disorders and conditions such as drug addiction, alcoholism, ADHD, schizophrenia and AD.

[0018] The μ-opioid receptor (MOR) is an inhibitory GPCP with high affinity for the endogenous peptides enkephalin and β-endorphin. MOR agonists are used to treat or prevent pain. Summary of the invention

[0019] This Summary is intended to introduce some concepts in a simplified form that are further described in the Detailed Description below. This Summary is not intended to identify key features or essential features of the claimed subject matter, nor is it intended to limit the scope of the claimed subject matter.

[0020] It is an object of the present invention to provide compounds that can be used in the treatment or prevention of drug addiction or CNS related diseases or conditions.

[0021] It has now surprisingly been found that compounds derived from 3,3-disubstituted azetidines show binding affinity for proteins associated with drug addiction or CNS related diseases or conditions.

[0022] Disclosed is a compound of formula (I)

[0023] in

[0024] R 1 , R 2 , R 3 , R 4 and R 5 are each independently selected from H, halogen, C 1-4 -alkyl, C 1-3 -(per)halogenated alkyl, C 1-3 -alkoxy, C 1-3 -(per)haloalkoxy and OH; or

[0025] R 1 , R 2 and R 5 are each independently selected from H, halogen, C 1-4 -alkyl, C 1-3 -(per)halogenated alkyl, C 1-3 -alkoxy, C 1-3 -(per)haloalkoxy and OH; and

[0026] R 3 and R 4 together form a group selected from OC(R')2O; or

[0027] R 1 , R 4 and R 5 are each independently selected from H, halogen, C 1-4 -alkyl, C 1-3 -(per)halogenated alkyl, C 1-3 -alkoxy, C 1-3 -(per)haloalkoxy and OH; and

[0028] R 2 and R 3 Together they form a group selected from OC(R')2O;

[0029] R 6 and R 7 Each independently selected from H, methyl and ethyl;

[0030] R 8 is selected from H, methyl, ethyl, CH2Ph(o-OMe), CH2Ph(o-OH), C(O)CH2NH2, C(O)CH(NH2)(CH2)4NH2, C(O)CH(NH2)(CH2)3N(H)C(NH)(NH2), 5-(1,2-dithiolan-3-yl)pentanoyl and 2-cyano-1-phenylethyl;

[0031] R 9 Selected from CO2R10 and COSR 10 ;

[0032] R 10 is selected from H, methyl and ethyl; and

[0033] Each R' is independently selected from H and F;

[0034] or a stereoisomer or a pharmaceutically acceptable salt thereof.

[0035] The present disclosure also provides a pharmaceutical composition comprising an effective amount of one or more compounds as defined in the present disclosure or a stereoisomer or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients.

[0036] The present disclosure also provides a compound of formula (I) or a stereoisomer or a pharmaceutically acceptable salt thereof for use as a medicament.

[0037] The present disclosure also provides a compound of formula (I) or a stereoisomer or a pharmaceutically acceptable salt thereof for use in the treatment or prevention of drug addiction or CNS-related diseases or conditions.

[0038] In addition, the present disclosure provides a compound of formula (I) or a stereoisomer or a pharmaceutically acceptable salt thereof for use in the treatment or prevention of drug addiction or CNS-related diseases or conditions, wherein the drug addiction or CNS-related diseases or conditions are selected from stimulant addiction, ADHD, ADD, cognitive tempo retardation, attention deficit disorder, motivational or reward system dysfunction, autism spectrum disorder, disruptive impulse control and conduct disorders, anxiety disorders, eating disorders, depression, dysthymic disorder, Alzheimer's disease, Parkinson's disease, ADHD, narcolepsy and alcoholism.

[0039] Furthermore, the present disclosure provides a process for preparing a compound of formula (I) or a pharmaceutically acceptable salt or stereoisomer thereof.

[0040] The objects of the invention are achieved by compounds and processes for their preparation as well as by said compounds for use as medicaments, said compounds being characterized as stated in the independent claims. Preferred embodiments of the invention are disclosed in the dependent claims. DETAILED DESCRIPTION

[0041] The compounds disclosed herein and below are derivatives of 3,3-disubstituted azetidines, which provide the inventive properties of the compounds of the present invention. The specific substitution pattern of the compounds favors binding affinity to proteins associated with drug addiction or CNS-related diseases or conditions.

[0042] "Including" or "comprising" means that the subsequently described features or actions may, but need not, include other features or actions. It should be further understood that reference to "an" item refers to one or more of those items.

[0043] "Optional" or "optionally" means that the subsequently described event or circumstance may but need not occur, and that the description includes instances where the event or circumstance occurs and instances where it does not.

[0044] The term "halogen" as used herein and hereinafter by itself or as part of another group refers to elements of Group VIIa including F, Cl, Br and I groups.

[0045] The term "alkyl" as used herein and hereinafter refers to an aliphatic straight-chain, branched-chain or cyclic hydrocarbon group having the specified number of carbon atoms, in particular a straight-chain or branched hydrocarbon group such as C 1-6 -alkyl has 1 to 6 carbon atoms in the alkyl portion, so that, for example, C 1-4 -alkyl includes methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, and C 1-6 -Alkyl also includes, but is not limited to, branched and straight chain pentyl and hexyl. Other examples of alkyl are benzyl (which may be a protecting group), 2-methoxybenzyl (CH2Ph(o-OMe)), 2-hydroxybenzyl (CH2Ph(o-OH)) and 2-cyano-1-phenylethyl.

[0046] The term “C 1-3 "-(Per)haloalkyl" refers to an alkyl group as above in which one or more hydrogen atoms are replaced by halogen, in particular I, Br, F or Cl. Examples of haloalkyl include, but are not limited to, chloromethyl, fluoromethyl and -CH2CF3. The term "perhaloalkyl" refers to an alkyl group in which all hydrogen atoms are replaced by halogen atoms. Examples of perhaloalkyl include, but are not limited to, trifluoromethyl (-CF3) and trichloromethyl (-CCl3).

[0047] The term “C 1-3 "-alkoxy" refers to -O-(C 1-3 -alkyl) group, wherein "C 1-3 "-alkyl" has the meaning defined above. Examples of alkoxy groups include, but are not limited to, methoxy, ethoxy and isopropoxy.

[0048] The term “C 1-3 "-(per)haloalkoxy" refers to -O-(C 1-3 -(per)haloalkyl) group, wherein C 1-3-(Per)haloalkyl has the meaning defined above. Examples of (per)haloalkoxy groups include, but are not limited to, trifluoromethoxy, 2,2,2-trichloromethoxy and 1,1,1,3,3,3-hexafluoroisopropoxy.

[0049] The term "stereoisomer" as used herein and hereinafter refers to a stereoisomer of a compound. Examples of stereoisomers include, but are not limited to, enantiomers, diastereomers, cis-trans isomers, and EZ isomers.

[0050] The term "pharmaceutically acceptable salts" as used herein and hereinafter refers to salts which are known to be non-toxic and commonly used in the pharmaceutical literature. Typically, these are acid addition salts or base addition salts of the compounds mentioned as disclosed herein and hereinafter.

[0051] The term "acid addition salt" includes any non-toxic organic and inorganic acid addition salts that the compounds of formula (I) can form. Exemplary inorganic acids that form suitable acid addition salts include, but are not limited to, hydrogen chloride, hydrogen bromide, sulfuric acid, and phosphoric acid. Exemplary organic acids that form suitable acid addition salts include, but are not limited to, acetic acid, lactic acid, malonic acid, succinic acid, glutaric acid, fumaric acid, malic acid, tartaric acid, citric acid, ascorbic acid, maleic acid, benzoic acid, phenylacetic acid, cinnamic acid, methanesulfonic acid, salicylic acid, and the like. The term "acid addition salt" as used herein also includes solvates that the compounds and their salts can form, such as hydrates, alcoholates, and the like. These salts also include salts that can be used for chiral resolution of racemates.

[0052] The term "base addition salt" includes any non-toxic base addition salt that the compound of formula (I) can form. Suitable base addition salts include, but are not limited to, those derived from inorganic bases, such as salts of aluminum, ammonium, calcium, copper, iron, lithium, magnesium, manganese, potassium, sodium and zinc, particularly sodium and ammonium salts. Further examples of organic base addition salts include salts of trialkylamines such as triethylamine and trimethylamine, salts of other organic amines such as methylamine, dimethylamine, trimethylamine, ethylamine, triethylamine, morpholine, etc., and choline salts. The term "base addition salt" used herein also includes solvates that the compound and its salts can form, such as hydrates, alcoholates, etc. These salts also include salts that can be used for chiral resolution of racemates.

[0053] The pharmaceutical composition of the present invention can be administered in an effective amount, and the dosage range of the effective amount is about 0.1 μg / kg to about 300 mg / kg, preferably 1.0 μg / kg to 10 mg / kg body weight. The compound of the present invention can be administered in a single daily dose, or the total daily dose can be administered in divided doses twice, three times, four times, five times or six times a day.

[0054] The term "effective amount" refers to the amount of a composition or pharmaceutical composition that produces a therapeutic effect on a subject. The therapeutic effect can be objective (i.e., it can be measured by certain tests or markers) or subjective (i.e., the subject gives an indication or feels the effect). This treatment does not necessarily completely improve the disease or condition. In addition, this treatment or prevention can be used in combination with other traditional treatment methods known to those skilled in the art for treating a disease or condition. The effective amount is usually determined by a doctor and depends on the disease or condition to be treated, the selected route of administration, the actual compound administered, the age, sex, weight and response of the individual patient, the severity of the patient's symptoms, etc.

[0055] The knowledge and skills in the art possessed by a skilled technician enable them to select suitable pharmaceutically acceptable excipients for the amount applicable to the present invention. In addition, there are many resources available for a skilled technician to use, which describe pharmaceutically acceptable excipients and can help select suitable pharmaceutically acceptable excipients.

[0056] Suitable pharmaceutically acceptable excipients include, but are not limited to, the following types of excipients: diluents (e.g., starch, mannitol), fillers (e.g., lactose, microcrystalline cellulose or calcium hydrogen phosphate), binders (e.g., pregelatinized corn starch, polyvinyl pyrrolidone or methylcellulose), additives (e.g., magnesium stearate, talc, silicon dioxide), disintegrants (e.g., potato starch), lubricants (e.g., sodium lauryl sulfate), glidants (e.g., fumed silica, talc, magnesium carbonate), granulating agents (e.g., water, ethanol), coating agents (e.g., hydroxypropyl methylcellulose, gelatin, wax, shellac, plastic, plant fiber), wetting agents (e.g., sorbitan monopalmitate, poloxamer 407), solvents (e.g., water), cosolvents (e.g., ethanol, propylene glycol), suspending agents (e.g., sorbitol, cellulose derivatives, edible hydrogenated fats), emulsifiers (e.g., lecithin or acacia), sweeteners (e.g., sucrose), flavoring agents (e.g., cherry, lime), masking agents (e.g., vanilla, citrus), coloring agents (e.g., titanium dioxide), anti-caking agents (e.g., silicon dioxide), humectants (e.g., glycerol, sorbitol), chelating agents (e.g., EDTA salts, histidine, aspartic acid), plasticizers (e.g., tributyl citrate, diethyl phthalate), viscosity increasing agents (e.g., methylcellulose), antioxidants (e.g., ascorbic acid, cysteine), preservatives (e.g., methyl or propyl paraben, sorbic acid or ascorbic acid), stabilizers (e.g., polysorbate 20 and 80, poloxamer 407), surfactants (e.g., polyethylene glycol, polysorbate 80), and buffers (e.g., sodium and potassium phosphates, citrates, acetates, carbonates, or glycine buffers, depending on the target pH range). Excipients and / or adjuvants can facilitate processing of the active agent into a pharmaceutically acceptable formulation. Those skilled in the art will appreciate that certain pharmaceutically acceptable excipients can serve multiple functions, and can serve alternative functions, depending on how much of the excipient is present in the pharmaceutical composition and which other ingredients are present in the pharmaceutical composition.

[0057] The pharmaceutical composition of the present invention is most preferably used alone, or in combination, i.e., simultaneously, individually or sequentially with other active ingredients (e.g., pharmaceutically active compounds or biological products). The amount of the pharmaceutical composition of the present invention (particularly a pharmaceutical composition comprising a compound of formula (I) or its stereoisomer or a pharmaceutically acceptable salt and other active ingredients) and the relative time of application are selected to achieve the desired combined therapeutic effect. The pharmaceutical composition of the present invention can be applied by various routes, such as parenteral, subcutaneous, intravenous, intraarticular, intrathecal, intramuscular, intraperitoneal, local and intradermal injection, as well as by transdermal, rectal, buccal, oral mucosa, nasal cavity, ocular routes, as well as by inhalation and by implantation.

[0058] The pharmaceutical composition can be formulated into a suitable pharmaceutical preparation; suitable pharmaceutical preparations include, for example, solutions, dispersions, suspensions, sterile aqueous or non-aqueous solvents, emulsions, powders, capsules, tablets, pills, controlled release capsules, controlled release tablets and controlled release pills.

[0059] In addition to pharmaceutically acceptable excipients and / or other active ingredients or as an alternative, the pharmaceutical composition can also be combined with one or more pharmaceutically acceptable carriers. The term "pharmaceutically acceptable carrier" used herein and hereinafter refers to a matrix for drug delivery contained in the pharmaceutical composition, which is used to improve the selectivity, effectiveness and / or safety of drug administration. The example of a pharmaceutically acceptable carrier includes, but is not limited to, a pharmaceutically acceptable excipient, a liposome, (polymer) micelles, microspheres, nanoparticles and protein-drug conjugates.

[0060] The pharmaceutical compositions of the present invention are prepared using techniques and methods known to those skilled in the art.

[0061] Pharmaceutical formulations of the pharmaceutical compositions disclosed herein and hereinafter for parenteral or topical use may include, but are not limited to, sterile aqueous and / or non-aqueous solvents, suspensions, and emulsions.

[0062] Examples of non-aqueous solvents for pharmaceutical preparations are propylene glycol, polyethylene glycol, vegetable oils, fish oils, and injectable organic esters. Aqueous carriers include, but are not limited to, water, water-alcohol solutions, including saline and buffered parenteral vehicles, including sodium chloride solution, Ringer's dextrose solution, dextrose plus sodium chloride solution, Ringer's solution containing lactose, or fixed oils. Intravenous vehicles include, but are not limited to, liquid and nutritional supplements, electrolyte supplements, such as supplements based on Ringer's dextrose, etc. The aqueous pharmaceutical composition of the present invention may include suitable buffers, such as sodium and potassium phosphates, citrates, acetates, carbonates, or glycine buffers, depending on the target pH range. It is also useful to use sodium chloride as a tension regulator. The pharmaceutical composition may include other excipients, such as stabilizers or preservatives. Useful stabilizing excipients include surfactants (polysorbate 20 and 80, poloxamer 407), polymers (polyethylene glycol, povidone), carbohydrates (sucrose, mannitol, glucose, lactose), alcohols (sorbitol, glycerol propylene glycol, ethylene glycol), suitable proteins (albumin), suitable amino acids (glycine, glutamic acid), fatty acids (ethanolamine), antioxidants (ascorbic acid, cysteine, etc.), chelating agents (EDTA salts, histidine, aspartic acid) or metal ions (Ca, Ni, Mg, Mn). Useful preservatives include benzyl alcohol, chlorobutanol, benzalkonium chloride and possible parabens. The pharmaceutical composition of the present invention can be provided in concentrated form or powder form so that it can be reconstituted as needed. In this case, the formulation of the powder solution of the above-mentioned injection / infusion excipient can be used. In the case of lyophilization, certain cryoprotectants are preferred, including polymers (povidone, polyethylene glycol, dextran), sugars (sucrose, glucose, lactose), amino acids (glycine, arginine, glutamic acid) and albumin. If a solution for reconstitution is added to the package, it may consist of, for example, pure water for injection or sodium chloride solution or dextrose or glucose solution.

[0063] The terms "treating or preventing" as used herein and hereinafter include preventing or preventing the mentioned disease or condition as well as reducing the risk of an individual developing the mentioned disease or condition, or palliating, ameliorating, eliminating or curing an established said disease or condition.

[0064] The term "administering" to a subject or patient includes dispensing, delivering or applying a compound disclosed herein and below, or a stereoisomer or pharmaceutically acceptable salt thereof, or a pharmaceutical composition disclosed herein and below, to a subject or patient by any suitable route to deliver the composition or pharmaceutical composition to the desired site in the body.

[0065] The compounds of formula (I) disclosed herein can be used for treatment, in particular for the treatment or prevention of drug addiction or CNS-related diseases or conditions in animals (particularly mammals) and humans. Specifically, the compounds of formula (I) have pharmacological properties for the treatment and / or prevention of drug addiction or CNS-related diseases or conditions, including but not limited to stimulant addiction, ADHD, ADD, cognitive retardation, attention deficit disorder, motivational or reward system dysfunction, autism spectrum disorder, destructive impulse control and conduct disorder, anxiety, eating disorders, depression, dysthymia, Alzheimer's disease, Parkinson's disease, anxiety, hyperactivity, narcolepsy and alcoholism.

[0066] The compounds of formula (I) of the present invention may bind to one or more proteins associated with drug addiction or CNS-related diseases or conditions, wherein examples of proteins include, but are not limited to, trace amine receptors (trace amine-associated receptors (TAARs), such as TAAR1), dopamine and serotonin receptors, dopamine and serotonin transporters, acyl and methyltransferases, norepinephrine transporters, monoamino oxidases (such as MAO-A), catechin-O-methyltransferases (COMT), adrenergic receptors, tyrosine hydroxylases, histamine receptors (such as H1 histamine receptor), Orexin receptors, NMDA receptors, sigma-1 receptors, muscarinic and nicotinic acetylcholine receptors (such as M1, M2, M3 and M4 muscarinic acetylcholine receptors), opioid receptors (such as μ-opioid receptor (MOR)), neuropeptide receptors (such as neuropeptide Y2 receptor), melanocortin receptors (excluding MC3R), neurokinin receptors (such as NKR2 and NK3R), corticotropin-releasing factor receptor 1, acetylcholinesterase, 1B melatonin receptor, cholinergic receptors and dopamine β-hydroxylase (dopamine β-monooxygenase, DBH), etc.

[0067] The compounds of formula (I) disclosed herein and below can bind to and inhibit proteins including, but not limited to, HIV-1 reverse transcriptase, oxidosqualene cyclase, aldose reductase, and hepatitis C virus NS5B RNA-dependent RNA polymerase.

[0068] The term "protecting group" used herein and hereinafter refers to a chemical group covalently linked to an atom or functional group modified by a protecting group. The protecting group can make the reaction have chemical selectivity, and therefore, the protecting group can protect the atom or functional group from reacting at least partially in the reaction. It should be understood that the protecting group protects the atom or functional group completely or partially, that is, the atom or functional group protected by the protecting group may or may not react partially in the reaction. The knowledge and skills of the art possessed by a skilled technician enable them to select a suitable protecting group for the atom or functional group to be protected. In addition, a skilled technician can utilize many resources to describe the protecting group, which can be used to select a suitable protecting group for the atom or functional group to be protected. Regarding suitable protecting groups and methods for protecting compounds with suitable protecting groups, see, for example, Protective Groups in Organic Synthesis, 4th Edition, 2007, John Wiley & Sons, Inc., Hoboken, New Jersey. Examples of atoms and functional groups that may be protected with protecting groups include, but are not limited to, O, S, N, NH, NH2, OH, SH, carbonyls (such as aldehydes and ketones), ethers, esters, and amides. Examples of protecting groups include, but are not limited to, carbonylbenzyloxy (Cbz), p-methoxybenzylcarbonyl, BOC, Fmoc, acetyl, benzoyl, phenyl, benzyl, trityl, sulfonyl (e.g., phenylsulfonyl, toluenesulfonyl (Ts), methylsulfonyl, and trifluoromethylsulfonyl); toluenesulfonate, silyl ether, such as trimethylsilyl ether (TMS), tert-butyldimethylsilyl ether (TBDMS), triisopropylsilyloxymethyl ether (TOM), and triisopropylsilyl ether (TIPS); tetrahydropyranyl (THP), p-methoxyphenyl ether (PMP), p-methoxybenzyl ether (PMB), β-methoxyethoxymethyl ether (MEM), pivaloyl, thioether, acetal, ketal, dithiane, benzyl ester, tert-butyl ester, orthoester, and photolabile groups.

[0069] The term "activating group" as used herein and hereinafter refers to a functional group in a compound that promotes the reaction and / or has a positive effect on the overall reaction rate and / or directs the positional isomers of the formed product. The activating group may or may not be part of the formed product, i.e., it is understood that the activating group may be present in the product, or the activating group may be a leaving group, or a part of a leaving group, such as in S N 2. S N1 and addition-elimination reactions. The compounds disclosed herein may have one or more activating groups which may be the same or different. Examples of activating groups include, but are not limited to, sulfonyl groups such as benzenesulfonyl, toluenesulfonyl (Ts), mesyl and trifluoromethanesulfonyl; halogens such as Cl, Br, I and F; (substituted) amino groups such as 1-imidazolyl, intermediate ion pairs formed by PPh3 reactions, azodicarboxylates such as DEAD and DIAD, carboxylic acids, amides, esters such as DCC and O-acylisoureas of carboxylic acids, hydroxyl groups, alkoxy groups such as 1H-1,2,3-benzotriazole-1-ol esters, N-hydroxysuccinimide anions, acyloxy groups, benzyliodine (III) diacetate [PhI (OAc) 2, (PIDA)], metals and their complexes such as Ni, Ru, Os, Ir, Rh, Pd, Fe-PNP; thiols, alkyl groups, (per)halogenated alkoxy groups, (per)halogenated alkyl groups and photolabile groups.

[0070] The term "activating group reactant" as used herein and hereinafter refers to a compound comprising an activating group, wherein the compound reacts with another compound in a reaction to form a compound or intermediate comprising the activating group. It should be understood that there may be different activating group reactants comprising the same activating group. The reaction may include one or more activating group reactants which may be the same or different. Examples of activating group reactants include, but are not limited to, 1,1'-carbonyldiimidazole (CDI), diethyl azodicarboxylate (DEAD), diisopropyl azodicarboxylate (DIAD), N,N'-dicyclohexylcarbodiimide (DCC), triphenylphosphine (PPh3), benzene iodine (III) diacetate [PhI(OAc)2, (PIDA)], sulfinic acids such as benzenesulfinic acid and p-toluenesulfinic acid; methanesulfonyl halides such as methanesulfonyl chloride; trifluoroazide, trifluoromethanesulfonyl chloride, halogens such as Br2; metal halides such as NaI; trifluoroacetyl chloride and trifluoroacetic anhydride.

[0071] The term "activator" as used herein and hereinafter refers to a substance or compound added to a reaction to promote a chemical reaction. The activator may or may not be a catalyst. It should be understood that the activator may or may not be consumed in the reaction. Examples of activators include, but are not limited to, acids such as HCl and AcOH; bases such as NaOH and NaH; water, 4-dimethylaminopyridine (DMAP), triphenylphosphine (PPh3), metal halides such as NaI; Lewis acids such as TiCl4, boron trifluoride, and boron trifluoride etherate.

[0072] The term "carry out one or more reactions" used herein and hereinafter refers to one or more method steps, that is, the compound used for the method for preparing the compound of formula (I) reacts in the indicated reaction. It should be understood that if, for example, two reactions are carried out, a first reaction can be carried out to form one or more first reaction products, wherein at least one first reaction product can be used for subsequent reactions to form one or more second reaction products, which may or may not be compounds of formula (I). In addition, one or more (first, second, third, fourth and / or fifth) reaction products may be separated and / or purified after (first, second, third, fourth and / or fifth) reactions, or may not be separated and / or purified, that is, the reaction product may be directly used or not directly used for subsequent reactions. In addition, as long as the reaction conditions permit, one or more reactions may be carried out simultaneously.

[0073] The term "esterification" as used herein and hereinafter refers to the reaction disclosed herein and hereinafter to form an ester or thioester from a carboxylic acid.

[0074] The term "transesterification" as used herein and hereinafter refers to the reaction in which an alkoxy group of an ester or a thiol group of a thioester is converted into another alkoxy group or thiol group, i.e., an ester group or thioester group of a compound disclosed herein and hereinafter is converted into another ester group or thioester group. The knowledge and skills in the art possessed by skilled technicians enable them to select reactants and reagents suitable for transesterification. Examples of transesterification reactions include, but are not limited to, combining HCl, methanol or ethanol or methyl mercaptan or ethyl mercaptan with a compound of the method for preparing a compound of formula (I) to form a first composition, and optionally heating the formed first composition.

[0075] The term "amidation" used herein and below refers to the reaction of converting the ester group, carboxylic acid group and / or amine group of the compound of the method for preparing the compound of formula (I) into an amide group. That is, the carboxyl group, ester group and / or amine group of the compound of the method for preparing the compound of formula (I) react to form the amide group of the compound. Preferably, the amine group of the azetidine disclosed herein and below is converted into an amide group. Examples of amidation reactions include, but are not limited to, combining a carboxylic acid with a compound (preferably azetidine) of the method for preparing the compound of formula (I), optionally in the presence of one or more activating group reactants and / or one or more activators, forming a first composition, and optionally heating the formed first composition to form an amide.

[0076] The term "reductive alkylation" as used herein and hereinafter refers to a reductive amination in which the carbonyl group of a compound is converted to an amine via an intermediate imine. Examples of reductive alkylation reactions include, but are not limited to, the reaction of methanol or acetaldehyde with a compound containing a secondary amine group (i.e., for example, a compound of formula (I) wherein R 8 is H, and R 10 is methyl or ethyl), optionally in the presence of one or more water-removing compounds or means for removing water, to form an imine, which is combined with a reducing agent such as sodium borohydride to form a tertiary amine.

[0077] As used herein and hereinafter, the term "N-alkylation" refers to a reaction in which an amine group is alkylated. Examples of N-alkylation reactions include, but are not limited to, combining an alkyl halide (e.g., methyl bromide, ethyl bromide, methyl iodide, and ethyl iodide) with a compound containing a secondary amine group for use in the process for preparing a compound of formula (I), optionally in the presence of one or more activating group reactants and / or one or more activating agents (e.g., sodium iodide) to form an N-alkylated compound.

[0078] The term "reduction" as used herein and hereinafter refers to a reaction wherein a functional group of a compound is reduced, ie the oxidation state of a first functional group is reduced, thereby forming a second functional group having a lower oxidation state than the first functional group.

[0079] The term "hydrolysis" as used herein and hereinafter refers to a chemical reaction in which a water molecule breaks one or more chemical bonds. Typically, the hydrolysis is carried out on a carboxylic acid ester to form the corresponding carboxylic acid, or on an amide to form the corresponding carboxylic acid.

[0080] As used herein and hereinafter, the term "O-alkylation" refers to a reaction in which an OH group is alkylated. Examples of O-alkylation reactions include, but are not limited to, combining an alkyl halide (e.g., methyl bromide, ethyl bromide, methyl iodide, and ethyl iodide) with a hydroxyl-containing compound of the process for preparing a compound of formula (I), optionally in the presence of one or more bases, one or more activating group reactants, and / or one or more activators (e.g., sodium iodide) to form an O-alkylated compound.

[0081] The term "reductive trifluoromethylation" used herein and hereinafter refers to a chemical reaction in which one or more CF3 are introduced into the compound by reducing the oxidation state of the compound. Examples of reductive trifluoromethylation include, but are not limited to, converting the C(O)NHMe group of a compound into the CH(CF3)NHMe group of a compound, see, for example, Chen et al., Chemoselective direct reductive trifluoromethylation of amides: a flexible access to functionalized α-trifluoromethylamines, Org. Chem. Front., 2018, 5, 943-947. In particular, compounds with one or more CF3 groups have enhanced metabolic stability, lipophilicity, and bioavailability.

[0082] The term "fluorination" as used here and hereinafter refers to a chemical reaction which requires the introduction of one or more F groups into a compound.

[0083] The term "carry out one or more deprotection reactions" used herein and hereinafter refers to the reaction of carrying out one or more removal of protecting groups from a compound. The knowledge and skills of the skilled person in the art enable them to select the reactants or reagents suitable for deprotection reactions. In addition, the skilled person can use many resources to describe suitable reagents and reactants, which can help select reagents and reactants suitable for deprotection protecting groups. For suitable deprotection reactions, reactants and reagents, see, for example, Protective Groups in Organic Synthesis, 4th Edition, 2007, John Wiley & Sons, Inc., Hoboken, New Jersey. Examples of available reactants and reagents in deprotection reactions (in brackets, examples of protecting groups to be removed) include but are not limited to tetra-n-butylammonium fluoride (TMS), H2 (benzyl), bases such as NaOH (acetyl), acids such as pyridinium p-toluenesulfonate and EtOH (THP), and 2,3-dichloro-5,6-dicyano-p-benzoquinone (PMB).

[0084] In one aspect, a compound of formula (I) is disclosed

[0085] in

[0086] R 1 , R 2 , R 3 , R 4 and R 5 are each independently selected from H, halogen, C1-4 -alkyl, C 1-3 -(per)halogenated alkyl, C 1-3 -alkoxy, C 1-3 -(per)haloalkoxy and OH; or

[0087] R 1 , R 2 and R 5 are each independently selected from H, halogen, C 1-4 -alkyl, C 1-3 -(per)halogenated alkyl, C 1-3 -alkoxy, C 1-3 -(per)haloalkoxy and OH; and

[0088] R 3 and R 4 together form a group selected from OC(R')2O; or

[0089] R 1 , R 4 and R 5 are each independently selected from H, halogen, C 1-4 -alkyl, C 1-3 -(per)halogenated alkyl, C 1-3 -alkoxy, C 1-3 -(per)haloalkoxy and OH; and

[0090] R 2 and R 3 Together they form a group selected from OC(R')2O;

[0091] R 6 and R 7 Each independently selected from H, methyl and ethyl;

[0092] R 8 is selected from H, methyl, ethyl, CH2Ph(o-OMe), CH2Ph(o-OH), C(O)CH2NH2, C(O)CH(NH2)(CH2)4NH2, C(O)CH(NH2)(CH2)3N(H)C(NH)(NH2), 5-(1,2-dithiolan-3-yl)pentanoyl and 2-cyano-1-phenylethyl;

[0093] R 9 Selected from CO2R 10 and COSR 10 ;

[0094] R 10 is selected from H, methyl and ethyl; and

[0095] Each R' is independently selected from H and F;

[0096] or a stereoisomer or a pharmaceutically acceptable salt thereof.

[0097] These compounds may have particularly strong binding affinity for one or more proteins associated with drug addiction or a CNS-related disease or condition.

[0098] Additionally or alternatively, in embodiments, R 9 Selected from CO2R 10 、COSR 10 、CH2OR 10 '、C(O)CH2R 10 ', CH(CF3)NHR 10 '、C(O)NFR 10 ' and C(O)N(R 10 ')2;

[0099] R 10 is selected from H, methyl and ethyl; and

[0100] Each R 10 ' is independently selected from H, methyl and ethyl;

[0101] or a stereoisomer or a pharmaceutically acceptable salt thereof.

[0102] Additionally or alternatively, in embodiments, R 9 Selected from CO2R 10 ; and R 10 As defined in the present disclosure; or a stereoisomer or pharmaceutically acceptable salt thereof. These compounds may have particularly strong binding affinity for proteins associated with drug addiction or CNS-related diseases or conditions.

[0103] Additionally or alternatively, in embodiments, R 1 , R 2 and R 5 It is H; R 3 and R 4 are each independently selected from H, halogen, C 1-4 -alkyl; R 9 It is CO2R 10 ; and R 10 As defined in the present disclosure; or a stereoisomer or pharmaceutically acceptable salt thereof. These compounds may have particularly strong binding affinity for proteins associated with drug addiction or CNS-related diseases or conditions.

[0104] Additionally or alternatively, in embodiments, R 6 , R 7 and R 8 At least one of is independently selected from methyl and ethyl, and R 6 , R7 and R 8 The other terms in are each independently selected from H, methyl and ethyl; or a stereoisomer or a pharmaceutically acceptable salt thereof. These compounds may have particularly strong binding affinity for proteins associated with drug addiction or CNS-related diseases or conditions.

[0105] Additionally or alternatively, in embodiments, R 1 , R 2 and R 5 is H; and R 3 and R 4 are halogen, preferably F; or R 3 and R 4 One of them is halogen or methyl, preferably F, and R 3 and R 4 The other term in is H, provided that R 8 is selected from methyl, ethyl, CH2Ph(o-OMe), CH2Ph(o-OH), C(O)CH2NH2, C(O)CH(NH2)(CH2)4NH2, C(O)CH(NH2)(CH2)3N(H)C(NH)(NH2), 5-(1,2-dithiolan-3-yl)pentanoyl and 2-cyano-1-phenylethyl, or with the condition that R 6 and R 7 At least one of each of which is independently selected from methyl and ethyl and R 6 and R 7 Another of the group consisting of H, methyl and ethyl; or a stereoisomer or a pharmaceutically acceptable salt thereof. These compounds may have particularly strong binding affinity for proteins associated with drug addiction or CNS-related diseases or conditions.

[0106] Additionally or alternatively, in embodiments, R 1 , R 2 and R 5 is H; and R 3 and R 4 are halogen, preferably F; or R 3 and R 4 One of them is halogen or methyl, preferably F, and R 3 and R 4 The other term in is H, provided that R 8Selected from methyl, ethyl, CH2Ph(o-OMe), CH2Ph(o-OH), C(O)CH2NH2, C(O)CH(NH2)(CH2)4NH2, C(O)CH(NH2)(CH2)3N(H)C(NH)(NH2), 5-(1,2-dithiolan-3-yl)pentanoyl and 2-cyano-1-phenylethyl, preferably selected from methyl and ethyl; or a stereoisomer or a pharmaceutically acceptable salt thereof. These compounds may have particularly strong binding affinity for proteins associated with drug addiction or CNS-related diseases or conditions.

[0107] Additionally or alternatively, in embodiments, R 1 , R 2 and R 5 is H; and R 3 and R 4 are halogen, preferably F; or R 3 and R 4 One of them is halogen or methyl, preferably F, and R 3 and R 4 The other term in is H, provided that R 6 and R 7 At least one of each of which is independently selected from methyl and ethyl and R 6 and R 7 Another of the group consisting of H, methyl and ethyl; or a stereoisomer or a pharmaceutically acceptable salt thereof. These compounds may have particularly strong binding affinity for proteins associated with drug addiction or CNS-related diseases or conditions.

[0108] Additionally or alternatively, in embodiments, R 1 , R 2 and R 5 is H; and R 8 Selected from methyl, ethyl, CH2Ph(o-OMe), CH2Ph(o-OH), C(O)CH2NH2, C(O)CH(NH2)(CH2)4NH2, C(O)CH(NH2)(CH2)3N(H)C(NH)(NH2), 5-(1,2-dithiolan-3-yl)pentanoyl and 2-cyano-1-phenylethyl; or a stereoisomer or a pharmaceutically acceptable salt thereof. These compounds may have particularly strong binding affinity for proteins associated with drug addiction or CNS-related diseases or conditions.

[0109] Additionally or alternatively, in embodiments, R 1 , R 2 and R 5 It is H; R 3 and R 4 At least one of each of which is independently selected from halogen, C 1-4-alkyl, C 1-3 -(per)halogenated alkyl, C 1-3 -alkoxy, C 1-3 -(per)haloalkoxy and OH, preferably selected from F, Cl, methyl and ethyl, and R 3 and R 4 The other of which is selected from H, halogen, C 1-4 -alkyl, C 1-3 -(per)halogenated alkyl, C 1-3 -alkoxy, C 1-3 -(per)haloalkoxy and OH, preferably selected from H, F, Cl, methyl and ethyl; and R 8 Selected from H, methyl, ethyl, CH2Ph(o-OMe), CH2Ph(o-OH), C(O)CH2NH2, C(O)CH(NH2)(CH2)4NH2, C(O)CH(NH2)(CH2)3N(H)C(NH)(NH2), 5-(1,2-dithiolan-3-yl)pentanoyl and 2-cyano-1-phenylethyl, preferably selected from H, methyl and ethyl; or a stereoisomer or a pharmaceutically acceptable salt thereof. These compounds may have particularly strong binding affinity for proteins associated with drug addiction or CNS-related diseases or conditions.

[0110] Additionally or alternatively, in embodiments, R 8 is selected from H, methyl, ethyl, CH2Ph(o-OMe), CH2Ph(o-OH), C(O)CH2NH2, C(O)CH(NH2)(CH2)4NH2, C(O)CH(NH2)(CH2)3N(H)C(NH)(NH2), 5-(1,2-dithiolan-3-yl)pentanoyl and 2-cyano-1-phenylethyl, provided that if R 8 is H, then R 6 and R 7 At least one of each of which is independently selected from methyl and ethyl and R 6 and R 7 Another of the methyl and ethyl groups is selected from the group consisting of methyl and ethyl groups; or a stereoisomer or a pharmaceutically acceptable salt thereof. These compounds may have particularly strong binding affinity for proteins associated with drug addiction or CNS-related diseases or conditions.

[0111] Additionally or alternatively, in embodiments, R 1 , R 2 and R 5 is H; and R 3 and R 4 are each independently selected from H, halogen, C 1-4 -alkyl, C 1-3 -(per)halogenated alkyl, C 1-3 -alkoxy, C1-3 -(per)haloalkoxy and OH, provided that if R 3 or R 4 If one of them is H, then R 6 and R 7 At least one of each of which is independently selected from methyl and ethyl and R 6 and R 7 The other of which is selected from H, methyl and ethyl, or R 6 and R 7 Both H and R 8 Selected from methyl, ethyl, CH2Ph(o-OMe), CH2Ph(o-OH), C(O)CH2NH2, C(O)CH(NH2)(CH2)4NH2, C(O)CH(NH2)(CH2)3N(H)C(NH)(NH2), 5-(1,2-dithiolan-3-yl)pentanoyl and 2-cyano-1-phenylethyl, preferably selected from methyl and ethyl; or a stereoisomer or a pharmaceutically acceptable salt thereof. These compounds may have particularly strong binding affinity for proteins associated with drug addiction or CNS-related diseases or conditions.

[0112] Additionally or alternatively, in embodiments, R 6 , R 7 and R 8 At least one of is independently selected from methyl and ethyl, and R 6 , R 7 and R 8 The other items in are each independently selected from H, methyl and ethyl; R 9 It is CO2R 10 ; and R 10is selected from methyl and ethyl; or a stereoisomer or a pharmaceutically acceptable salt thereof. These compounds may have particularly strong binding affinity for proteins associated with drug addiction or CNS-related diseases or conditions, such as trace amine receptor 1 (TAAR1), norepinephrine transporter (NET), 5-HT2A receptor, 5-HT2B receptor, OX1 orexin receptor, Mu-opioid receptor, neurokinin 1 receptor (NK1R), melanocortin 3 receptor (MC3R), dopamine transporter (DAT), phenylethanolamine N-methyltransferase (PNMT), dopamine 4 (D4) receptor, N-acetyl serotonin methyltransferase, 1A melatonin receptor, melanocortin 1 receptor (MSHR, MC1R), alpha-2A adrenergic receptor, prolactin receptor, dopamine 3 (D3) receptor, kappa-opioid receptor, serotonin transporter (SERT), 5-HT1A receptor, 5-HT1B receptor, beta1 adrenergic receptor, 5-HT2C receptor, alpha-1 B adrenergic receptor, alpha-2B adrenergic receptor, melanocortin 2 receptor (ACTHR, MC2R), melanocortin 4 receptor (MC4R), 5-HT3 receptor, COMT, alpha-1A adrenergic receptor, nociceptin / orphanin receptor, beta2 adrenergic receptor, phenylalanine hydroxylase, tyrosine hydroxylase, H1 histamine receptor, H3 histamine receptor, neurokinin 2 receptor (NK2R), OX2 orexin receptor, NMDA Receptor GluN1, NMDA receptor Glu2B, M2 muscarinic acetylcholine receptor, neuropeptide Y1 receptor, delta-opioid receptor, M1 muscarinic acetylcholine receptor, M3 muscarinic acetylcholine receptor, M4 muscarinic acetylcholine, acetylcholinesterase, melanocortin 5 receptor (MC5R), neuropeptide Y2 receptor, neurokinin 3 receptor (NK3R), oxytocin receptor (OXYR) and corticotropin releasing factor receptor 1 (CRF1R).

[0113] Additionally or alternatively, in embodiments, R 6 and R 7 are each independently selected from methyl and ethyl, or R 6 and R 7 One of them is selected from methyl and ethyl and R 6 and R 7 The other term in is H; R 8 is selected from H, methyl and ethyl; R 9 It is CO2R 10 ; and R 10 is selected from methyl and ethyl; or a stereoisomer or a pharmaceutically acceptable salt thereof.

[0114] Additionally or alternatively, in embodiments, R 6 and R 7 All are H; R 9 It is CO2R10 ; and R 10 is selected from methyl and ethyl; or a stereoisomer or a pharmaceutically acceptable salt thereof. These compounds may have particularly strong binding affinity for one or more proteins associated with drug addiction or CNS-related diseases or conditions, such as dopamine transporter (DAT), MAO-B, dopamine 2 (D2) receptor, MAO-A, α-2C adrenergic receptor, α4β2 nicotinic receptor, CHK1 kinase, serotonin transporter (SERT), serotonin N-acetyltransferase, H1 histamine receptor, neuropeptide Y2 receptor and oxytocin receptor (OXYR). Additionally, in an embodiment, R 3 is methyl or methoxy; R 1 , R 2 , R 3 , R 4 , R 5 and R 8 is H. The compounds may have particularly strong binding affinity for one or more of the dopamine 2 (D2) receptor, MAO-A, alpha-2C adrenergic receptor, alpha4beta2 nicotinic receptor, CHK1 kinase, and serotonin transporter (SERT).

[0115] Additionally or alternatively, in embodiments, R 1 , R 2 and R 5 It is H; R 3 and R 4 One of them is methoxy and R 3 and R 4 The other term in is H; R 9 It is CO2R 10 ; and R 10 is selected from methyl and ethyl; or a stereoisomer or a pharmaceutically acceptable salt thereof. These compounds may have particularly strong binding affinity for one or more of serotonin transporter (SERT), 5-HT1B receptor, β1 adrenergic receptor, phenylalanine hydroxylase and tyrosine hydroxylase. Additionally, in an embodiment, R 6 and R 7 At least one of is independently selected from methyl and ethyl, preferably methyl; and R 6 and R 7 The other of R is H, methyl or ethyl, preferably H or methyl; 8 is selected from methyl and ethyl, preferably ethyl; R 9 It is CO2R 10 ; and R 10Selected from methyl and ethyl, preferably methyl. These compounds may have particularly strong binding affinity to one or more of 5-HT1B receptor, β1 adrenergic receptor, phenylalanine hydroxylase and tyrosine hydroxylase.

[0116] Additionally or alternatively, in embodiments, R 1 and R 2 It is H; R 3 , R 4 and R 5 At least one of them is F, and R 3 , R 4 and R 5 The other terms in are H; R 6 and R 7 are each independently selected from H, methyl and ethyl; R 9 It is CO2R 10 ; and R 10 is selected from methyl and ethyl; or a stereoisomer or a pharmaceutically acceptable salt thereof. In an embodiment, R 1 and R 2 It is H; R 3 , R 4 and R 5 One of them is F, and R 3 , R 4 and R 5 The other terms in are H; R 6 and R 7 are each independently selected from H, methyl and ethyl; R 9 It is CO2R 10 ; and R 10 Selected from methyl and ethyl.

[0117] Additionally or alternatively, in embodiments, R 1 , R 2 and R 5 It is H; R 3 and R 4 one is selected from F, Cl, methyl and ethyl and R 3 and R 4 The other of which is selected from the group consisting of H, F, methyl and ethyl; R 9 It is CO2R 10 ; and R 10 is selected from methyl and ethyl; or a stereoisomer or a pharmaceutically acceptable salt thereof.

[0118] Additionally or alternatively, in embodiments, R 1 , R 2 and R 5 It is H; R 3 and R 4 All are F or R 3and R 4 One is F and R 3 and R 4 The other term in is H; R 6 and R 7 are each independently selected from H and methyl; R 9 It is CO2R 10 ; and R 10 or a stereoisomer or a pharmaceutically acceptable salt thereof. These compounds may have particularly strong binding affinity for one or more proteins associated with drug addiction or CNS-related diseases or conditions, such as trace amine receptor 1 (TAAR1), norepinephrine transporter (NET), 5-HT2A receptor, 5-HT2B receptor, OX1 orexin receptor, Mu-opioid receptor, neurokinin 1 receptor (NK1R), melanocortin 3 receptor (MC3R), dopamine transporter (DAT), MAO-B, phenylethanolamine N-methyltransferase (PNMT), N-acetyl serotonin methyltransferase (N-ACETYLSEROTOXIN) and serotonin transporter (SRT). transferase, 1A melatonin receptor, melanocortin 1 receptor (MSHR, MC1R), alpha-2A adrenergic receptor and prolactin receptor, dopamine 3 (D3) receptor, kappa-opioid receptor, 5-HT3 receptor, OX2 orexin receptor, NMDA receptor GluN1, NMDA receptor Glu2B, M2 muscarinic acetylcholine receptor, neuropeptide Y1 receptor, delta-opioid receptor, M1 muscarinic acetylcholine receptor, M3 muscarinic acetylcholine receptor, M4 muscarinic acetylcholine receptor and corticotropin-releasing factor receptor 1 (CRF1R).

[0119] Additionally or alternatively, in embodiments, R 1 , R 2 and R 5 It is H; R 3 and R 4 All are F; R 6 and R 7 are each independently selected from H and methyl; R 9 It is CO2R 10 ; and R 10is selected from methyl and ethyl; or a stereoisomer or a pharmaceutically acceptable salt thereof. These compounds may have particularly strong binding affinity for one or more proteins associated with drug addiction or CNS-related diseases or conditions, such as trace amine receptor 1 (TAAR1), norepinephrine transporter (NET), 5-HT2A receptor, 5-HT2B receptor, OX1 orexin receptor, Mu-opioid receptor, neurokinin 1 receptor (NK1R), melanocortin 3 receptor (MC3R), dopamine transporter (DAT), MAO-B, N-acetyl serotonin methyltransferase, 1A melatonin receptor, melanocortin 1 receptor (MSHR, MC1R), alpha-2A adrenergic receptor, prolactin receptor, serotonin transporter (SERT), 5-HT1A receptor, COMT, NMDA receptor GluN1, delta-opioid receptor, M1 muscarinic acetylcholine receptor, M3 muscarinic acetylcholine receptor, M4 muscarinic acetylcholine, acetylcholinesterase, and melanocortin 5 receptor (MC5R).

[0120] Additionally or alternatively, in embodiments, R 1 , R 2 and R 5 It is H; R 3 and R 4 one is selected from methyl and ethyl and R 3 and R 4 The other term in is H; R 9 It is CO2R 10 ; and R 10 is selected from methyl and ethyl; or a stereoisomer or a pharmaceutically acceptable salt thereof.

[0121] Additionally or alternatively, in embodiments, R 1 , R 2 and R 5 It is H; R 3 and R 4 One of them is methyl and R 3 and R 4 The other term in is H; R 9 It is CO2R 10 ; and R 10or a stereoisomer or a pharmaceutically acceptable salt thereof. These compounds may have particularly strong binding affinity for one or more proteins associated with drug addiction or CNS-related diseases or conditions, such as dopamine 2 (D2) receptor, MAO-A, α-2C adrenergic receptor, α4β2 nicotinic receptor, CHK1 kinase, dopamine 4 (D4) receptor, dopamine 1 (D1) receptor, δ-1 receptor, 1B melatonin receptor, serotonin N-acetyltransferase, 5-HT1B receptor, β1 adrenergic receptor, 5-HT2C receptor, α-1B adrenergic receptor, adrenergic receptor, alpha-2B adrenergic receptor, melanocortin 2 receptor (ACTHR, MC2R), melanocortin 4 receptor (MC4R), COMT, alpha-1A adrenergic receptor, nociceptin / orphanin receptor, beta2 adrenergic receptor, tyrosine hydroxylase, H1 histamine receptor, NMDA receptor GluN1, acetylcholinesterase, melanocortin 5 receptor (MC5R), neuropeptide Y2 receptor, neuropeptide Y5 receptor, neurokinin 3 receptor (NK3R), and corticotropin releasing factor receptor 1 (CRF1R).

[0122] Additionally or alternatively, in embodiments, R 1 , R 2 and R 5 It is H; R 3 and R 4 All are F; R 8 is selected from methyl and ethyl; R 9 It is CO2R 10 ; and R 10 selected from methyl and ethyl; or a stereoisomer or a pharmaceutically acceptable salt thereof. These compounds may have particularly strong binding affinity for one or more proteins associated with drug addiction or CNS-related diseases or conditions, such as trace amine receptor 1 (TAAR1), norepinephrine transporter (NET), 5-HT2A receptor, 5-HT2B receptor, OX1 orexin receptor, Mu-opioid receptor, neurokinin 1 receptor (NK1R), melanocortin 3 receptor (MC3R), dopamine transporter (DAT), N-acetyl serotonin methyltransferase, 1A melatonin receptor, melanocortin 1 receptor (MSHR, MC1R), α-2A adrenergic receptor, prolactin receptor, OX2 orexin receptor, δ-opioid receptor, M1 muscarinic acetylcholine receptor, M3 muscarinic acetylcholine receptor and M4 muscarinic acetylcholine receptor.

[0123] Additionally or alternatively, in an embodiment, the compound is selected from:

[0124] Ethyl 3-(3,4-difluorophenyl)-1,2,4-trimethylazetidine-3-carboxylate (1);

[0125] Ethyl 3-(3,4-difluorophenyl)-1-ethylazetidine-3-carboxylate (2);

[0126] Ethyl 3-(3,4-difluorophenyl)-1-methylazetidine-3-carboxylate (3);

[0127] Ethyl 3-(3,4-difluorophenyl)azetidine-3-carboxylate (4);

[0128] Ethyl 3-(3-fluorophenyl)-2,4-dimethylazetidine-3-carboxylate (5);

[0129] Ethyl 3-(3-fluorophenyl)-2-methylazetidine-3-carboxylate (6);

[0130] Ethyl 3-(4-methylphenyl)azetidine-3-carboxylate (7);

[0131] 2-Methyl-3-(3-methylphenyl)azetidine-3-carboxylic acid methyl ester (8);

[0132] 3-(3,4-Difluorophenyl)-1-ethyl-2-methylazetidine-3-carboxylic acid methyl ester (9);

[0133] 3-(3,4-Difluorophenyl)-2-methylazetidine-3-carboxylic acid methyl ester (10);

[0134] 2-Methyl-3-(3-methylphenyl)azetidine-3-carboxylic acid ethyl ester (11);

[0135] 1-ethyl-3-(4-methylphenyl)azetidine-3-carboxylic acid ethyl ester (12);

[0136] Ethyl 3-(3,4-difluorophenyl)-2,4-dimethylazetidine-3-carboxylate (13);

[0137] 3-(3,4-Difluorophenyl)-1-ethyl-2,4-dimethylazetidine-3-carboxylic acid methyl ester (14);

[0138] 1-ethyl-2-methyl-3-(3-methylphenyl)azetidine-3-carboxylic acid methyl ester (15);

[0139] Ethyl 3-(3-methylphenyl)azetidine-3-carboxylate (16);

[0140] 3-(3-Fluorophenyl)-1,2,4-trimethylazetidine-3-carboxylic acid ethyl ester (17);

[0141] 1-Ethyl-2,4-dimethyl-3-(3-methylphenyl)azetidine-3-carboxylic acid ethyl ester (18);

[0142] Ethyl 3-(3,4-difluorophenyl)-2-methylazetidine-3-carboxylate (19);

[0143] Ethyl 3-(4-methoxyphenyl)azetidine-3-carboxylate (20);

[0144] 1-Ethyl-3-(3-methylphenyl)azetidine-3-carboxylate (21);

[0145] 1-ethyl-3-(3-methoxyphenyl)-2,4-dimethylazetidine-3-carboxylic acid methyl ester (22);

[0146] 1-Ethyl-2,4-dimethyl-3-(4-methylphenyl)azetidine-3-carboxylic acid ethyl ester (23);

[0147] 2,4-Dimethyl-3-(3-methylphenyl)azetidine-3-carboxylic acid ethyl ester (24);

[0148] 3-(3,4-difluorophenyl)-2,4-dimethylazetidine-3-carboxylic acid methyl ester (25);

[0149] 1,2-Dimethyl-3-(3-methylphenyl)azetidine-3-carboxylic acid ethyl ester (26);

[0150] 1-ethyl-2,4-dimethyl-3-(3-methylphenyl)azetidine-3-carboxylic acid methyl ester (27);

[0151] 1-ethyl-2-methyl-3-(4-methylphenyl)azetidine-3-carboxylic acid methyl ester (28);

[0152] 1-ethyl-3-(4-methoxyphenyl)-2,4-dimethylazetidine-3-carboxylic acid methyl ester (29);

[0153] 1-ethyl-3-(4-methoxyphenyl)-2-methylazetidine-3-carboxylic acid methyl ester (30);

[0154] 2,4-Dimethyl-3-(4-methylphenyl)azetidine-3-carboxylic acid methyl ester (31);

[0155] Ethyl 3-(3,4-difluorophenyl)-1-ethyl-2-methylazetidine-3-carboxylate (32);

[0156] 2-Methyl-3-(4-methylphenyl)azetidine-3-carboxylic acid methyl ester (33);

[0157] 3-(4-Methylphenyl)-1,2-dimethylazetidine-3-carboxylic acid methyl ester (34);

[0158] Ethyl 3-(3-fluorophenyl)azetidine-3-carboxylate (35);

[0159] 1,2-dimethyl-3-(4-methylphenyl)azetidine-3-carboxylic acid ethyl ester (36); and 1-ethyl-3-(3-fluorophenyl)-2,4-dimethylazetidine-3-carboxylic acid methyl ester (37);

[0160] or a stereoisomer or a pharmaceutically acceptable salt thereof.

[0161] Additionally or alternatively, the compound of formula (I) is dextrorotatory.

[0162] In one aspect, a pharmaceutical composition is disclosed, comprising an effective amount of one or more compounds as defined in the present disclosure or their stereoisomers or pharmaceutically acceptable salts, and one or more pharmaceutically acceptable excipients. It should be understood that one or more compounds as defined in the present disclosure or their stereoisomers or pharmaceutically acceptable salts refer to compounds of formula (I) as defined in the present disclosure or their stereoisomers or pharmaceutically acceptable salts.

[0163] Additionally or alternatively, in an embodiment, the pharmaceutical composition defined in the present disclosure is combined with one or more pharmaceutically acceptable carriers. Therefore, in an embodiment, the pharmaceutical composition comprises an effective amount of one or more compounds of formula (I) or its stereoisomer or pharmaceutically acceptable salt, and one or more pharmaceutically acceptable excipients and / or one or more pharmaceutically acceptable carriers, or any combination thereof. Preferably, the pharmaceutical composition comprises a compound of formula (I) or its stereoisomer or pharmaceutically acceptable salt, preferably a pharmaceutically acceptable salt thereof, combined with one or more pharmaceutically acceptable excipients and a pharmaceutically acceptable carrier.

[0164] Additionally or alternatively, in an embodiment, the pharmaceutical composition defined in the present disclosure is combined with one or more other active ingredients. Therefore, in addition to a pharmaceutically acceptable excipient and / or a pharmaceutically acceptable carrier or as an alternative, the pharmaceutical composition of the present disclosure may include an effective amount of one or more compounds of formula (I) or its stereoisomer or pharmaceutically acceptable salt, and one or more other active ingredients. Therefore, in an embodiment, the pharmaceutical composition includes an effective amount of one or more compounds of formula (I) or its stereoisomer or pharmaceutically acceptable salt, and one or more pharmaceutically acceptable excipients and / or one or more pharmaceutically acceptable carriers and / or one or more other active ingredients, or any combination thereof.

[0165] Additionally or alternatively, the pharmaceutical composition consists of an effective amount of one or more compounds of formula (I) or their stereoisomers or pharmaceutically acceptable salts (preferably pharmaceutically acceptable salts thereof) and one or more pharmaceutically acceptable excipients (preferably 1, 2 or 3 pharmaceutically acceptable excipients, more preferably 1 pharmaceutically acceptable excipient).

[0166] Additionally or alternatively, the pharmaceutical composition is composed of an effective amount of one or more compounds of formula (I) (preferably an effective amount of 1 or 2 compounds of formula (I), more preferably 1 compound of formula (I)) or a stereoisomer or a pharmaceutically acceptable salt thereof (preferably a pharmaceutically acceptable salt thereof), and one or more pharmaceutically acceptable excipients (preferably 1, 2 or 3 pharmaceutically acceptable excipients) and / or one or more pharmaceutically acceptable carriers (preferably 1, 2 or 3 pharmaceutically acceptable carriers, more preferably 1 pharmaceutically acceptable carrier).

[0167] Additionally or alternatively, the pharmaceutical composition is composed of an effective amount of one or more compounds of formula (I) (preferably an effective amount of 1 or 2 compounds of formula (I), more preferably 1 compound of formula (I)) or a stereoisomer or a pharmaceutically acceptable salt thereof (preferably a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients (preferably 1, 2 or 3 pharmaceutically acceptable excipients) and / or one or more pharmaceutically acceptable carriers (preferably 1, 2 or 3 pharmaceutically acceptable carriers, more preferably 1 pharmaceutically acceptable carrier) and / or one or more other active ingredients (preferably one other active ingredient).

[0168] In one aspect disclosed is a compound as defined in the present disclosure, or a stereoisomer or a pharmaceutically acceptable salt thereof, for use as a medicament.

[0169] In one aspect disclosed is a compound as defined in the present disclosure, or a stereoisomer or a pharmaceutically acceptable salt thereof, for use in the treatment or prevention of drug addiction or a CNS related disease or condition.

[0170] Additionally or alternatively, in an embodiment, the drug addiction or CNS-related disease or condition is selected from stimulant addiction, ADHD, ADD, cognitive retardation, attention deficit disorder, motivational or reward system dysfunction, autism spectrum disorder, disruptive impulse control and conduct disorders, anxiety disorders, eating disorders, depression, dysthymic disorder, Alzheimer's disease, Parkinson's disease, ADHD, narcolepsy and alcoholism.

[0171] Additionally or alternatively, the stimulant is selected from cocaine, amphetamines and methylphenidate.

[0172] Additionally or alternatively, the attention deficit hyperactivity disorder (ADHD) is selected from attention deficit hyperactivity disorder-inattentive type (ADHD-PI or ADHD-I), attention deficit hyperactivity disorder-hyperactive-impulsive type (ADHD-PH or ADHD-HI) and combined attention deficit hyperactivity disorder (ADHD-C).

[0173] Additionally or alternatively, the motivational or reward system dysfunction is selected from anhedonia, apathy, akinetic mutism, avolition, loss of will, psychomotor retardation, bradykinesia and weakness.

[0174] Additionally or alternatively, the disruptive impulse control and conduct disorder is selected from oppositional defiant disorder and obsessive compulsive disorder.

[0175] Additionally or alternatively, the anxiety disorder is selected from generalized anxiety disorder (GAD), phobias, panic disorder, agoraphobia, social anxiety disorder, post-traumatic stress disorder, separation anxiety disorder, obsessive-compulsive disorder, and selective mutism.

[0176] Additionally or alternatively, the eating disorder is selected from obesity, binge eating disorder, bulimia nervosa, other specific feeding or eating disorder (OSFED), anorexia nervosa, bulimia nervosa and the binge-purging subtype of anorexia nervosa.

[0177] In addition, the compounds disclosed herein and below, or stereoisomers or pharmaceutically acceptable salts thereof, may also be used to treat or prevent diseases or conditions associated with HIV-1 reverse transcriptase, oxidosqualene cyclase, aldose reductase or hepatitis C virus NS5B RNA-dependent RNA polymerase.

[0178] Additionally or alternatively, the disease or condition associated with HIV-1 reverse transcriptase, oxidosqualene cyclase, aldose reductase or hepatitis C virus NS5B RNA-dependent RNA polymerase is selected from acquired immunodeficiency syndrome (AIDS), hypercholesterolemia, Chagas disease, diabetes, hepatitis C.

[0179] In one aspect there is provided a compound of formula (I) or a stereoisomer or a pharmaceutically acceptable salt thereof as a nootropic compound.

[0180] At the metabolic attack position (mainly at the substituent R corresponding to the compound having formula (I) 2 , R 3 and R 4 Substitution, especially fluorination, can be used to change the pathway and rate of metabolic degradation. In addition, mainly at the position corresponding to the substituent R 2 , R 3 and / or R 4Substitution at the position of R, especially alkylation and / or halogenation, especially methylation and / or F-substitution, can change the protein binding affinity and / or lipophilicity, conformation, potential, dipole and pKa of the compound of formula (I). Substitution, especially fluorination and / or alkylation, can also change the tissue distribution, pharmacodynamics and toxicology of the compound. In summary, in the case of the substituent R 2 , R 3 and R 4 Substituting fluorine for hydrogen at the position of the receptor minimizes steric effects.

[0181] The compounds disclosed herein and below may be actively transported across the blood-brain barrier via organic cation transporters and may be concentrated in the brain. The compounds disclosed herein and below may not be oxidized to form epoxides, making them less susceptible to causing oxidative stress. The compounds disclosed herein and below may have neuroprotective and neuroregenerative properties, rather than neurotoxic or neurodegenerative properties.

[0182] The compounds disclosed herein and below can be used to treat or prevent general addiction in addition to diseases such as Alzheimer's disease and Parkinson's disease. Multiple positive pharmacological responses can be achieved simultaneously. While reducing the tendency to relapse and the likelihood of developing addiction, these compounds can act as general mood stabilizers and general neuroprotectants with significant anti-Parkinson's disease and anti-epileptic properties.

[0183] Without being bound by any particular theory or mechanism, it is believed that the mechanism of action of the disclosed compounds involves proteins in the mesocorticolimbic dopamine pathway and / or the locus coeruleus-noradrenergic system. The present invention is based on the recognition that the compounds of the present invention bind to and / or affect the activity of proteins associated with drug addiction or CNS-related diseases or conditions.

[0184] Also disclosed is a method of treating or preventing a disease or condition selected from drug addiction or a CNS-related disease or condition in a patient in need thereof, the disease or condition selected from stimulant addiction, ADHD, ADD, cognitive retardation, attention deficit disorder, motivational or reward system dysfunction, autism spectrum disorder, disruptive impulse control and conduct disorders, anxiety disorders, eating disorders, depression, dysthymic disorder, Alzheimer's disease, Parkinson's disease, ADHD, narcolepsy and alcoholism, the method comprising administering to the patient a compound disclosed herein and below, or a stereoisomer or pharmaceutically acceptable salt thereof.

[0185] Additionally or alternatively, the compounds disclosed herein and below, or stereoisomers or pharmaceutically acceptable salts thereof, are useful in the treatment or prevention of drug addiction or CNS-related diseases or conditions requiring inhibition or activation of at least one protein selected from the group consisting of trace amine receptors (trace amine-associated receptors (TAARs), such as TAAR1), dopamine and serotonin receptors, dopamine and serotonin transporters, acyl and methyltransferases, norepinephrine transporters, monoamino oxidases (such as MAO-A), catechin-O-methyltransferases (COMT), adrenergic receptors, tyrosine hydroxylases, histamine receptors, hydroxylase ... The receptors for nicotinic steroids are sigma-1, muscarinic and nicotinic acetylcholine receptors (e.g., H1 histamine receptors), orexin receptors, NMDA receptors, sigma-1 receptors, muscarinic and nicotinic acetylcholine receptors (e.g., M1, M2, M3, and M4 muscarinic acetylcholine receptors), opioid receptors (e.g., μ-opioid receptor (MOR)), neuropeptide receptors (e.g., neuropeptide Y2 receptor), melanocortin receptors (excluding MC3R), neurokinin receptors (e.g., NKR2 and NK3R), corticotropin-releasing factor receptor 1, acetylcholinesterase, 1B melatonin receptor, cholinergic receptors, and dopamine β-hydroxylase (dopamine β-monooxygenase, DBH).

[0186] In one aspect, a method for preparing a compound of formula (I) as defined in the present disclosure or a stereoisomer or a pharmaceutically acceptable salt thereof is disclosed, comprising:

[0187] (i) providing a compound of formula (II)

[0188] in

[0189] R 1 , R 2 , R 3 , R 4 , R 5 , R 6 and R 7 As defined in this disclosure; and R 8 is methyl, ethyl, CH2Ph(o-OMe) or a protecting group;

[0190] (ii) reacting a compound of formula (II) with one or more compounds, each of which is independently selected from an acid, a base and water; or

[0191] reacting a compound of formula (II) with methanol or ethanol and a Lewis catalyst;

[0192] (iii) optionally esterified with a compound of formula (III)

[0193] R 11 -R”(III), where

[0194] R 11is methyl or ethyl; and

[0195] R" is selected from halogen, SR"', OR"' and a first activating group, wherein R"' is H or a second activating group, optionally in the presence of one or more activating group reactants and / or one or more activating agents;

[0196] (iv) optionally performing one or more first deprotection reactions;

[0197] (v) optionally transesterifying with a compound of formula (III), wherein R 11 is methyl or ethyl; and R" is selected from SH and OH, optionally in the presence of one or more activating group reactants and / or one or more activating agents;

[0198] (vi) optionally amidating with a compound of formula (IV)

[0199] R 12 -R 8’ (IV), where

[0200] R 12 It’s HO, R 13 O or R 13 , where R 13 is an activating group; and

[0201] R 8’ It is C(O)CH2NHR 14 、C(O)CH(NHR 14 )(CH2)4NHR 14 、C(O)CH(NHR 14 )(CH2)3N(R 14 )C(NR 14 )(NHR 14 ) or 5-(1,2-dithiolan-3-yl)pentanoyl, wherein each R 14 are independently selected from H and protecting groups, optionally in the presence of one or more activating group reactants and / or one or more activating agents;

[0202] (vii) optionally reductively alkylating with a compound of formula (V) and a reducing agent

[0203] R 8” -CHO(V), where

[0204] R 8” is H or CH3;

[0205] (viii) optionally N-alkylating with a compound of formula (VI)

[0206] R8”’ -R 15 (VI), where

[0207] R 8”’ is methyl, ethyl, (o-OMe)PhCH2 or (Ph)CH(CH2CN); and

[0208] R 15 Selected from halogen, SR 16 OR 16 , where R 16 is an activating group, optionally in the presence of one or more activating group reactants and / or one or more activating agents;

[0209] (ix) optionally performing one or more second deprotection reactions;

[0210] To obtain a compound of formula (I), wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 and R 10 As defined in this disclosure; and

[0211] (x) optionally converting the compound of formula (I) into a pharmaceutically acceptable salt thereof.

[0212] Additionally or alternatively, in (i), R 8 is methyl, ethyl, CH2Ph(o-OMe) or a protecting group, preferably, the protecting group is benzyl.

[0213] Additionally or alternatively, in (ii), the compound of formula (II) is reacted with one or more compounds independently selected from an acid, a base and water, preferably, the one or more compounds are HCl and water, preferably, the one or more compounds are two compounds, wherein the two compounds are HCl and water. A compound of formula (I) is formed, wherein R 9 is CO2H; R 8 is defined for a compound of formula (II) as defined in the present disclosure; and R 1 , R 2 , R 3 , R 4 , R 5 , R 6 and R 7 As defined in this disclosure.

[0214] Additionally or alternatively, in (ii), the compound of formula (II) is reacted with methanol or ethanol and a Lewis catalyst, preferably trimethylsilyl trifluoromethanesulfonate. A compound of formula (I) is formed, wherein R 9 It is CO2R 10 , R 10 is methyl or ethyl, R 8 is defined for a compound of formula (II) as defined in the present disclosure; and R 1 , R 2 , R 3 , R 4 , R 5 , R 6 and R 7 As defined in this disclosure.

[0215] Additionally or alternatively, the method comprises (iii) esterifying with a compound of formula (III),

[0216] R 11 -R”(III), where

[0217] R 11 is methyl or ethyl; and

[0218] R" is selected from the group consisting of halogen, SR", OR"' and a first activating group, wherein R"' is H or a second activating group, optionally in the presence of one or more activating group reactants and / or one or more activating agents, halogen is preferably Cl, Br or I; the first activating group is selected from sulfonate, preferably benzenesulfonate, toluenesulfonate, mesylate or triflate; halogen, preferably Cl, Br or I; amino group, preferably 1-imidazolyl; alkoxy, preferably 1H-1,2,3-benzotriazole-1-ol ester; R"' is H or a second activating group, the second activating group is preferably selected from sulfonyl, preferably toluenesulfonate (Ts), mesylate or triflate; and amino group, preferably benzotriazolyl, preferably in the presence of one activating group reactant and / or one or more activating agents, wherein the one activating group The activating group reactant is 1,1'-carbonyldiimidazole (CDI), diethyl azodicarboxylate (DEAD), diisopropyl azodicarboxylate (DIAD), N,N'-dicyclohexylcarbodiimide (DCC), triphenylphosphine (PPh3), sulfinic acid, preferably benzenesulfinic acid or p-toluenesulfinic acid; methanesulfonyl halide, preferably methanesulfonyl chloride; trifluoromethylsulfonyl chloride, trifluoromethanesulfonyl chloride, metal halide, preferably NaI; trifluoroacetyl chloride and trifluoroacetic anhydride; and the one or more activators are an activator, preferably selected from acid, preferably HCl, H2SO4 or AcOH; base, preferably NaOH or NaH; water, 4-dimethylaminopyridine (DMAP), triphenylphosphine (PPh3), metal halide, preferably NaI; Lewis acid, preferably TiCl4, boron trifluoride and boron trifluoride diethyl etherate. More preferably, the compound of formula (III) is methanol or ethanol, and HCl or H2SO4 is present. From the compound of formula (I) (wherein R 9 is CO2H; R 8 is defined for a compound of formula (II) as defined in the present disclosure; and R 1 , R 2 , R 3 , R 4 , R 5 , R 6 and R 7 As defined in the present disclosure) to form a compound of formula (I), wherein R 9 It is CO2R 10 or COSR 10 , preferably CO2R 10 ; R 10 is methyl or ethyl; R 8 is defined for a compound of formula (II) as defined in the present disclosure; and R 1 , R 2 , R 3 , R 4 , R 5 , R6 and R 7 As defined in this disclosure.

[0219] Additionally or alternatively, the method comprises (iv) performing one or more first deprotection reactions, preferably one first deprotection reaction, more preferably wherein the one or more first deprotection reactions are performed with reactants or reagents selected from tetra-n-butylammonium fluoride, BBr3, H2 (preferably H2 in the presence of Pd / C) and 2,3-dichloro-5,6-dicyano-p-benzoquinone. One or more protecting groups may be removed from a compound of formula (I), wherein R 9 It is CO2R 10 or COSR 10 , preferably CO2R 10 , R 10 is H, condition is R 9 It is CO2R 10 ; Methyl or ethyl; R 8 is CH2Ph(o-OMe) or a protecting group; and R 1 , R 2 , R 3 , R 4 , R 5 , R 6 and R 7 As defined in the present disclosure. It is understood that the one or more protecting groups that may be removed may be R 8 The group (i.e., R 8 The group is a protecting group) or R 8 One or more protecting groups of a group (e.g., one or more of methyl, TMS or benzyl), preferably, one or more protecting groups is a protecting group, one of which is benzyl or methyl, more preferably, one protecting group is R 8 The methyl group or a protecting group of CH2Ph(o-OMe) is R 8 , where R 8 is benzyl, and even more preferably, one protecting group is R 8 , where R 8 is benzyl. A compound of formula (I) is formed, wherein R 9 It is CO2R 10 or COSR 10 , R 10 is H, condition is R 9 It is CO2R 10 ; Methyl or ethyl; R 8 is H, methyl, ethyl or CH2Ph(o-OH); and R 1 , R 2 , R 3 , R 4 , R5 , R 6 and R 7 As defined in this disclosure.

[0220] Additionally or alternatively, the method comprises (v) transesterifying with a compound of formula (III) wherein R 11 is methyl or ethyl; and R" is selected from SH and OH, optionally in the presence of one or more activating group reactants and / or one or more activating agents, preferably in the presence of an activating agent, more preferably in the presence of an activating agent selected from an acid (preferably HCl, H2SO4 or AcOH), even more preferably the compound of formula (III) is methanol or ethanol, in the presence of HCl or H2SO4. 9 It is CO2R 10 or COSR 10 , preferably R 9 It is CO2R 10 ; R 10 is methyl or ethyl; R 8 is defined for a compound of formula (II) as defined in the present disclosure; and R 1 , R 2 , R 3 , R 4 , R 5 , R 6 and R 7 As defined in the present disclosure) to form a compound of formula (I), wherein R 9 It is CO2R 10 or COSR 10 , preferably R 9 It is CO 2 R 10 ; R 10 is methyl or ethyl; R 8 is defined for a compound of formula (II) as defined in the present disclosure; and R 1 , R 2 , R 3 , R 4 , R 5 , R 6 and R 7 As defined in this disclosure.

[0221] Additionally or alternatively, the method comprises (vi) amidating with a compound of formula (IV)

[0222] R 12 -R 8’ (IV), where

[0223] R 12 It’s HO, R 13 O or R13 , where R 13 is an activating group; and R 8’ It is C(O)CH2NHR 14 、C(O)CH(NHR 14 )(CH2)4NHR 14 、C(O)CH(NHR 14 )(CH2)3N(R 14 )C(NR 14 )(NHR 14 ) or 5-(1,2-dithiolan-3-yl)pentanoyl, wherein each R 14 independently selected from H and protecting groups, optionally in the presence of one or more activating group reactants and / or one or more activating agents, preferably, the activating group is selected from Cl, Br and I; (substituted) amino groups, preferably 1-imidazolyl; alkoxy groups, preferably 1H-1,2,3-benzotriazole-1-ol esters; each R 14 is independently a protecting group, each protecting group is independently selected from Fmoc and t-Boc; and there is an activating group reactant and / or an activating agent, more preferably there is an activating group reactant and an activating agent, even more preferably, the activating group reactant is selected from 1,1'-carbonyldiimidazole (CDI), diethyl azodicarboxylate (DEAD), diisopropyl azodicarboxylate (DIAD), N,N'-dicyclohexylcarbodiimide (DCC); and the activating agent is selected from 1-hydroxy-7-azabenzotriazole (HOAt), hydroxybenzotriazole (HOBt) and 4-dimethylaminopyridine (DMAP). From the compound of formula (I) (wherein R 9 It is CO2R 10 or COSR 10 , preferably R 9 It is CO2R 10 ; R 10 is methyl or ethyl; R 8 is H; and R 1 , R 2 , R 3 , R 4 , R 5 , R 6 and R 7 As defined herein) to form a compound of formula (I), wherein R 9 It is CO2R 10 or COSR 10 , preferably R 9 It is CO2R 10 ; R 10 is methyl or ethyl; R 8 It is C(O)CH2NHR 14 、C(O)CH(NHR14 )(CH2)4NHR 14 、C(O)CH(NHR 14 )(CH2)3N(R 14 )C(NR 14 )(NHR 14 ) or 5-(1,2-dithiolan-3-yl)pentanoyl; and R 1 , R 2 , R 3 , R 4 , R 5 , R 6 and R 7 As defined herein. It will be appreciated that in the preparation of compounds of formula (I) wherein R 9 is CO2H or COSH, preferably R 9 is CO2H; R 8 It is C(O)CH2NHR 14 、C(O)CH(NHR 14 )(CH2)4NHR 14 、C(O)CH(NHR 14 )(CH2)3N(R 14 )C(NR 14 )(NHR 14 ) or 5-(1,2-dithiolan-3-yl)pentanoyl; and R 1 , R 2 , R 3 , R 4 , R 5 , R 6 and R 7 In the methods as defined herein, R 9 (CO2R 10 or COSR 10 , preferably CO2R 10 ; R 10 Ester groups (eg, methyl or ethyl) can be hydrolyzed by methods known to those skilled in the art (eg, using KOH or LiOH).

[0224] Additionally or alternatively, the method comprises (vii) reductive alkylation with a compound of formula (V)

[0225] R 8” -CHO(V), where

[0226] R 8” is H or CH3; and a reducing agent. Preferably, the reducing agent is sodium borohydride. In an embodiment, the compound of formula (V) is first reacted with a compound of formula (I), wherein R 9 It is CO2R 10 or COSR10 , preferably R 9 It is CO2R 10 ; R 10 is methyl or ethyl; R 8 is H; and R 1 , R 2 , R 3 , R 4 , R 5 , R 6 and R 7 As defined herein, to form an intermediate compound which is then reduced with a reducing agent, preferably sodium borohydride. 9 It is CO2R 10 or COSR 10 , preferably R 9 It is CO2R 10 ; R 10 is methyl or ethyl; R 8 is H; and R 1 , R 2 , R 3 , R 4 , R 5 , R 6 and R 7 As defined herein) to form a compound of formula (I), wherein R 9 It is CO2R 10 or COSR 10 , preferably R 9 It is CO2R 10 ; R 10 is methyl or ethyl; R 8 is methyl or ethyl; and R 1 , R 2 , R 3 , R 4 , R 5 , R 6 and R 7 As defined herein. It will be appreciated that the compound formed can be further hydrolyzed using methods known to those skilled in the art (e.g., using KOH or LiOH) to form a compound of formula (I) wherein R 9 is CO2H or COSH, preferably R 9 It is CO2H.

[0227] Additionally or alternatively, the method comprises (viii) N-alkylating a compound of formula (VI)

[0228] R 8”’ -R 15 (VI), where

[0229] R 8”’is methyl, ethyl, (o-OMe)PhCH2 or (Ph)CH(CH2CN); and R 15 Selected from halogen, SR 16 OR 16 , where R 16 is an activating group, optionally in the presence of one or more activating group reactants and / or one or more activating agents. 15 It is Cl, Br, I, SR 16 OR 16 , where R 16 is an activating group; preferably, the activating group is selected from sulfonyl, preferably toluenesulfonyl (Ts), toluenesulfonyl or trifluoromethanesulfonyl. In an embodiment, (viii) comprises one or more activating group reactants and / or one or more activating agents, preferably one or more activating group reactants and / or one or more activating agents is an activating agent selected from metal halides, preferably NaI. From the compound of formula (I) (wherein R 9 It is CO2R 10 or COSR 10 , preferably R 9 It is CO2R 10 ; R 10 is methyl or ethyl; R 8 is H; and R 1 , R 2 , R 3 , R 4 , R 5 , R 6 and R 7 As defined herein) to form a compound of formula (I), wherein R 9 It is CO2R 10 or COSR 10 , preferably R 9 It is CO2R 10 ; R 10 is methyl or ethyl; R 8 is methyl, ethyl, (o-OMe)PhCH2 or (Ph)CH(CH2CN); and R 1 , R 2 , R 3 , R 4 , R 5 , R 6 and R 7 As defined herein. It will be appreciated that the compound formed can be further hydrolyzed using methods known to those skilled in the art (e.g., using KOH or LiOH) to form a compound of formula (I) wherein R 9 is CO2H or COSH, preferably R 9 It is CO2H.

[0230] Additionally or alternatively, the method comprises (iX) performing one or more second deprotection reactions, preferably one second deprotection reaction, more preferably wherein the one or more second deprotection reactions are performed with a reactant or reagent selected from a base (preferably NaOH or KOH), tetra-n-butylammonium fluoride, an acid (preferably trifluoroacetic acid or HCl), BBr3, H2 (preferably H2 in the presence of Pd / C) and 2,3-dichloro-5,6-dicyano-p-benzoquinone. A compound of formula (I) wherein R 9 It is CO2R 10 or COSR 10 , preferably CO2R 10 , R 10 The condition is H is R 9 It is CO2R 10 ; Methyl or ethyl; R 8 It is C(O)CH2NHR 14 、C(O)CH(NHR 14 )(CH2)4NHR 14 、C(O)CH(NHR 14 )(CH2)3N(R 14 )C(NR 14 )(NHR 14 ), CH2Ph(o-OMe) or a protecting group, wherein each R 14 are independently selected from H and protecting groups; and R 1 , R 2 , R 3 , R 4 , R 5 , R 6 and R 7 As defined herein, one or more protecting groups are removed to form a compound of formula (I) wherein R 9 It is CO2R 10 or COSR 10 , preferably CO2R 10 ; R 10 is H, methyl or ethyl; R 8 is H, CH2Ph(o-OH), C(O)CH2NH2, C(O)CH(NH2)(CH2)4NH2 or C(O)CH(NH2)(CH2)3N(H)C(NH)(NH2); and R 1 , R 2 , R 3 , R 4 , R 5 , R 6 and R 7 As defined herein. It is understood that any of the protecting groups which may be removed may be R8 The group, preferably R 8 is benzyl; or R 8 One or more protecting groups of a group, preferably R 8 A methyl group of CH2Ph(o-OMe); or R 8 R 14 One or more protecting groups, preferably R 14 It is t-Boc or Fmoc or a combination thereof.

[0231] Additionally or alternatively, the method comprises: (x) converting the compound of formula (I) into a pharmaceutically acceptable salt thereof.

[0232] Additionally or alternatively, in order to convert the compound of formula (I) into a pharmaceutically acceptable salt thereof, the method for preparing the compound of formula (I) or a pharmaceutically acceptable salt or stereoisomer thereof further comprises separating the isomers of the compound of formula (I), preferably separating the dextrorotatory isomer of the compound of formula (I), wherein said step is carried out before or after the step of optionally converting the compound of formula (I) into a pharmaceutically acceptable salt thereof, preferably before the step of optionally converting the compound of formula (I) into a pharmaceutically acceptable salt thereof.

[0233] Additionally or alternatively, in order to convert the compound of formula (I) into a pharmaceutically acceptable salt thereof, the method for preparing the compound of formula (I) or a pharmaceutically acceptable salt or stereoisomer thereof further comprises converting the compound of formula (I) into another stereoisomer thereof, wherein said step is carried out before or after the step of optionally converting the compound of formula (I) into a pharmaceutically acceptable salt thereof.

[0234] Additionally or alternatively, the process further comprises one or more steps of isolating and / or purifying one or more compounds of formula (I) and / or formula (II).

[0235] The compounds disclosed herein and below can be synthesized using well-documented reactions and commercially available starting materials. These novel compounds can be used to achieve the desired pharmacological response.

[0236] Furthermore, the compounds of formula (I) can be used as synthetic intermediates for the preparation of other compounds or other pharmaceutically active compositions which can be obtained from the compounds of formula (I), for example by introducing substituents or modifying functional moieties.

[0237] The compounds and pharmaceutical compositions defined in the present disclosure may also be used in medical devices and medical kits.

[0238] General preparation method

[0239] The compounds according to the present invention can be prepared by following methods known per se.

[0240] The following non-limiting examples illustrate the preparation of compounds of formula (I). Not all steps or features of the reactions are discussed in detail as many will be apparent to those skilled in the art.

[0241] General Procedure A for the Preparation of Compounds of Formula (I)

[0242] Step 1:

[0243]

[0244] In step 1, the turbo Grignard reagent is prepared as follows (Krasovskiy, A.; Knochel, P. Angew. Chem. Int. Ed. 2004, 43, 3333): i-PrMgCl·LiCl (1.05-1.2 equivalents) in THF is added to a dry flask equipped with a magnetic stirrer and a septum and flushed with argon, and kept below 15° C. Aryl halide (such as 4-chloro-1,2-difluorobenzene, 1 equivalent) is added dropwise to i-PrMgCl·LiCl at 0° C.-15° C., the resulting reaction mixture is stirred at a temperature below 15° C., and the halogen / Mg exchange is checked by TLC. The resulting crude Grignard reagent is used in the subsequent reaction step without purification;

[0245] Step 2:

[0246]

[0247] reflux a reaction mixture of optionally substituted 3-azetidinone (1 eq.), alkyl halide (such as methyl bromide or benzyl chloride) (1.05-1.2 eq.), KCO (1.05-1.3 eq.), and MeOH / isopropanol (10-20 mL / 10 mmol 3-azetidinone) to form a crude optionally substituted 1-alkyl-3-azetidinone (such as 1-benzyl-3-azetidinone or 1-methyl-3-azetidinone) which is used in the subsequent reaction step without purification;

[0248] Step 3:

[0249]

[0250] The Grignard reagent (in THF) formed in step 1 of general procedure A was cooled to -10 ° C, and the optionally substituted 1-alkyl-3-azetidinone (1.1-1.2 equivalents) formed in step 2 of general procedure A was added dropwise. The mixture was stirred in an ice bath for 1-2 hours (until the reaction was complete) and quenched with saturated aqueous NH4Cl solution. The aqueous phase was extracted with DCM, dried over Na2SO4, and concentrated in vacuo. The crude optionally substituted 1-alkyl-3-phenyl-3-azetidinol formed was used in subsequent reaction steps without purification;

[0251] Step 4:

[0252]

[0253] The optionally substituted 1-alkyl-3-phenyl-3-azetidinol (1 equivalent) in step 3 of general procedure A was stirred and dissolved in ether (20 mL per gram of optionally substituted 1-alkyl-3-phenyl-3-azetidinol). PBr3 (0.41 equivalent) was slowly added to the formed solution to maintain the temperature, and stirring was continued for 2 hours. The reaction mixture was poured into alkalized water (such as saturated NaHCO3 solution) (6.4 mL per gram of optionally substituted 1-alkyl-3-phenyl-3-azetidinol), the organic phase was separated, and the aqueous phase was extracted twice with ether (2 mL per gram of optionally substituted 1-alkyl-3-phenyl-3-azetidinol). The ether phases were combined, washed twice with water, dried with MgSO4, and concentrated in vacuo. The crude optionally substituted 3-bromo-1-alkyl-3-phenylazetidinol formed was used for subsequent reaction steps without further purification;

[0254] Step 5:

[0255]

[0256] The optionally substituted 3-bromo-1-alkyl-3-phenylazetidine (1 equivalent) in step 4 of general procedure A was dissolved in DMF (20 mL / gram) with stirring at 0°C, and then KCN (2.1 equivalents) was added to the solution and the ice bath was removed. After 1.5 hours, the mixture was poured into water (40 mL / gram of optionally substituted 3-bromo-1-alkyl-3-phenylazetidine) and extracted twice with hexane (2 mL / 1 gram of optionally substituted 3-bromo-1-alkyl-3-phenylazetidine). The organic phases were combined, washed twice with water (2 mL / 1 gram of optionally substituted 3-bromo-1-alkyl-3-phenylazetidine), dried with MgSO4 and concentrated in vacuo. The crude optionally substituted 1-alkyl-3-phenyl-3-azetidine carbonitrile formed was recrystallized with petroleum ether, or used in subsequent reaction steps without further purification;

[0257] Step 6 (Alternative 1a)

[0258]

[0259] Preparation of formula (I), wherein R 8 = alkyl (such as methyl, ethyl or a protecting group such as benzyl), and R 9 =CO2H product, otherwise jump to step 6 (alternative scheme 1b):

[0260] A suspension of the optionally substituted 1-alkyl-3-phenyl-3-azetidinecarbonitrile from step 5 of general procedure A in aqueous HCl (pH 4-5) and toluene is refluxed for 1-2 hours followed by azeotropic distillation to afford the optionally substituted 1-alkyl-3-phenyl-3-azetidinecarboxylic acid which is used in the subsequent reaction step without further purification or is optionally purified by flash chromatography; or

[0261] Step 6 (Alternative 1b):

[0262]

[0263] Preparation of products of formula (I), wherein R 8 =H, and R 9 =CO2H, otherwise jump to step 6 (alternative 2):

[0264] General Procedure A, Step 6 (Alternative Scheme 1a) was carried out using 1-alkyl-3-phenyl-3-azetidinecarbonitrile (alkyl = protecting group, such as benzyl) from General Procedure A, Step 5, and the crude residue was purified by flash chromatography or used in the subsequent reaction step without purification. The synthesis is carried out according to procedures well known in the art, such as catalytic hydrogenation using H2 and platinum (IV) oxide (PtO2), Raney nickel, palladium on carbon (Pd / C) and / or platinum on carbon (Pt / C), and the optional protecting group for nitrogen (i.e., R 8 = protecting group, such as benzyl) for deprotection. The crude residue is optionally purified by flash chromatography to give optionally substituted 3-phenyl-3-azetidinecarboxylic acid; or

[0265] Step 6 (Alternative 2):

[0266]

[0267] The products of formula (I) are prepared from the corresponding nitrile, wherein R 8 = alkyl (such as methyl, ethyl or 2-cyano-1-phenylethyl), and R 9 =CO2R 10 (R 10 = alkyl, such as methyl or ethyl), otherwise jump to optional step 7 (alternative scheme 1):

[0268] To a suspension of optionally substituted 1-alkyl-3-phenyl-3-azetidinecarbonitrile (3 eq., from step 5) and methanol or ethanol (1 eq.), and optionally nitrobenzene (1 eq.), a Lewis catalyst such as trimethylsilyl trifluoromethanesulfonate (TMSOTf, 2 eq.) is added, and the mixture is stirred at room temperature for 65 hours. H2O (25 mL) and brine (25 mL) are added, and the mixture is extracted with EtOAc (3×30 mL). The combined organic layers are dried (Na2SO4) and concentrated. The crude product is purified by flash column chromatography (silica gel) to give optionally substituted 1-alkyl-3-phenyl-3-azetidinecarboxylic acid alkyl esters (the alkyl groups can be the same or different alkyl groups). In R 8 Where a protecting group is present, it is removed according to procedures well known in the art, e.g., in the case of protecting group = TIPS, 2.2 molar equivalents of (TBAF) (1M solution in THF) are used. The crude product is purified by flash column chromatography (silica gel) to give the unprotected optionally substituted 1-alkyl-3-phenyl-3-azetidinecarboxylic acid alkyl ester (the alkyl groups can be the same or different alkyl groups).

[0269] Optional Step 7 (Alternative 1):

[0270]

[0271] Preparation of products of formula (I) from carboxylic acids, wherein R 8 = alkyl (such as methyl, ethyl or 2-cyano-1-phenylethyl), and R 9 =CO2R 10 (R 10 = alkyl, such as methyl or ethyl), otherwise jump to optional step 7 (alternative scheme 2):

[0272] The optionally substituted 1- alkyl-3-phenyl-3-azetidine carboxylic acid suspension, excess alcohol (methanol or ethanol) (10mL / 1g optionally substituted 1- alkyl-3-phenyl-3-azetidine carboxylic acid) and catalytic amount of H2SO4 are refluxed for 18 hours. EtOAc (2mL / 1g optionally substituted 1- alkyl-3-phenyl-3-azetidine carboxylic acid) and saturated NaHCO3 solution (1mL / 1g optionally substituted 1- alkyl-3-phenyl-3-azetidine carboxylic acid) are added, and the mixture is washed with saturated NaHCO3 solution (2×1mL / 1g optionally substituted 1- alkyl-3-phenyl-3-azetidine carboxylic acid). The organic layer is dried (Na2SO4) and concentrated. The crude product is purified by flash column chromatography (silica gel) to obtain optionally substituted 1- alkyl-3-phenyl-3-azetidine carboxylic acid alkyl esters (alkyl can be the same or different alkyl). In R 8Where there is a protecting group, it can be removed according to procedures well known in the art, for example, in the case of protecting group = TIPS, 2.2 molar equivalents of (TBAF) (1M solution in THF) are used. The crude product is purified by flash column chromatography (silica gel) to give unprotected optionally substituted 1-alkyl-3-phenyl-3-azetidinecarboxylic acid alkyl esters (the alkyl groups can be the same or different alkyl groups); or

[0273] Optional Step 7 (Alternative 2):

[0274]

[0275] Preparation of products of formula (I) from protected carboxylic acids, wherein R 8 =H, and R 9 =CO2R 10 (R 10 = alkyl, such as methyl or ethyl) (i.e., R 8 = protecting group), otherwise jump to optional step 7 (alternative scheme 3):

[0276] The optionally substituted 1- alkyl-3-phenyl-3-azetidine carboxylic acid suspension, excess alcohol (methanol or ethanol) (10mL / 1g optionally substituted 1- alkyl-3-phenyl-3-azetidine carboxylic acid) and catalytic amount of H2SO4 are refluxed for 18 hours. EtOAc (2mL / 1g optionally substituted 1- alkyl-3-phenyl-3-azetidine carboxylic acid) and saturated NaHCO3 solution (1mL / 1g optionally substituted 1- alkyl-3-phenyl-3-azetidine carboxylic acid) are added, and the mixture is washed with saturated NaHCO3 solution (2×1mL / 1g optionally substituted 1- alkyl-3-phenyl-3-azetidine carboxylic acid). The organic layer is dried (Na2SO4) and concentrated. The crude product is purified by flash column chromatography (silica gel) to obtain optionally substituted 1- alkyl-3-phenyl-3-azetidine carboxylic acid alkyl esters (alkyl can be the same or different alkyl). If present, protecting groups are removed according to procedures well known in the art, e.g., if R 8 Is a protecting group (which is benzyl), then H and platinum (IV) oxide (PtO), Raney nickel, palladium on carbon (Pd / C) and / or platinum on carbon (Pt / C) are used for catalytic hydrogenation. The crude product is optionally purified by flash column chromatography (silica gel) to obtain unprotected optionally substituted 3-phenyl-3-azetidine carboxylic acid alkyl esters; or

[0277] Optional Step 7 (Alternative 3):

[0278]

[0279] Preparation of products of formula (I) from protected carboxylic acid esters, wherein R 8 =H, and R 9 =CO2R 10 (R 10 = alkyl, such as methyl or ethyl) (i.e., R 8 = protecting group), otherwise jump to optional step 7 (alternative scheme 4):

[0280] Possible protecting groups (i.e., R) on the nitrogen of the optionally substituted 1-alkyl-3-phenyl-3-azetidinecarboxylic acid alkyl ester in step 6 (alternative 2) or optional step 7 (alternative 1) are prepared according to methods well known in the art, such as catalytic hydrogenation using H and platinum (IV) oxide (PtO), Raney nickel, palladium on carbon (Pd / C) and / or platinum on carbon (Pt / C). 8 = protecting group, such as benzyl, for example, benzyl of 1-benzyl-3-phenyl-3-azetidinecarboxylic acid methyl ester) for deprotection. The crude residue is optionally purified by flash chromatography to give an optionally substituted 3-phenyl-3-azetidinecarboxylic acid alkyl ester; or

[0281] Optional Step 7 (Alternative 4):

[0282]

[0283] The product of formula (I) is prepared from optionally substituted 3-phenyl-3-azetidinecarboxylic acid alkyl esters, wherein R 8 = methyl, ethyl, CH2Ph(o-OMe) or CH2Ph(o-OH), and R 9 =CO2R 10 (R 10 = alkyl, such as methyl or ethyl), otherwise jump to step 7 (alternative scheme 5):

[0284] The optionally substituted 3-phenyl-3-azetidine carboxylic acid alkyl ester from optional step 7 (alternative scheme 2 or 3) is subjected to reductive alkylation according to procedures well known in the art, for example, optionally in the presence of one or more water removing compounds or an apparatus arranged for removing water, by combining formaldehyde, acetaldehyde, o-[tri(isopropyl)silyloxy]benzaldehyde or 2-methoxybenzaldehyde with 3-phenyl-3-azetidine carboxylic acid alkyl ester from optional step 7 (alternative scheme 2 or 3) to form an imine. The formed imine is reduced with a reducing agent such as sodium borohydride. The crude residue is purified by flash chromatography to give an optionally substituted 1-alkyl-3-phenyl-3-azetidine carboxylic acid alkyl ester (the alkyl group may be the same or different alkyl groups). In R 8Where there is a protecting group, the protecting group is removed according to procedures well known in the art, for example, in the case of protecting group = TIPS, 2.2 molar equivalents of (TBAF) (1M solution in THF) are used. The crude product is purified by flash column chromatography (silica gel) to give unprotected optionally substituted 1-alkyl-3-phenyl-3-azetidinecarboxylic acid alkyl esters (the alkyl groups can be the same or different alkyl groups); or

[0285] The optionally substituted 3-phenyl-3-azetidine carboxylic acid alkyl ester from optional step 7 (alternative scheme 2 or 3) is N-alkylated according to methods well known in the art, for example, a halide such as methyl bromide, ethyl bromide, methyl iodide, ethyl iodide, [o-(bromomethyl)phenoxy]tri(isopropyl)silane or o-(bromomethyl)methoxybenzene is combined with the 3-phenyl-3-azetidine carboxylic acid alkyl ester from optional step 7 (alternative scheme 2 or 3) in the presence of one or more activating group reactants and / or one or more activating agents, such as sodium iodide. The crude residue is optionally purified by flash chromatography to give an optionally substituted 1-alkyl-3-phenyl-3-azetidine carboxylic acid alkyl ester (the alkyl group can be the same or different alkyl groups). For R 8 The protecting group at the position is removed according to methods well known in the art, for example, in the case of protecting group = TIPS, 2.2 molar equivalents of (TBAF) (1M solution in THF) are used. The crude product is optionally purified by flash column chromatography (silica gel) to give unprotected optionally substituted 1-alkyl-3-phenyl-3-azetidinecarboxylic acid alkyl esters (the alkyl groups can be the same or different alkyl groups); or

[0286] Optional Step 7 (Alternative 5):

[0287]

[0288] Preparation of products of formula (I) from carboxylic acid esters, wherein R 8 =C(O)CH2NH2, C(O)CH(NH2)(CH2)4NH2, C(O)CH(NH2)(CH2)3NHCNH(NH2) and R 9 =CO2R 10 (R 10 = alkyl, such as methyl or ethyl), otherwise jump to optional step 7 (alternative scheme 6):

[0289] The optionally substituted 3-phenyl-3-azetidinecarboxylic acid alkyl ester from optional step 7 (alternative scheme 2 or 3) is amidated according to procedures well known in the art, for example, an optionally protected amino acid (such as N-(tert-butoxycarbonyl)glycine) and the optionally substituted 3-phenyl-3-azetidinecarboxylic acid alkyl ester from optional step 7 (alternative scheme 2 or 3) are combined with an activating group reactant (such as a carbodiimide, such as diethyl azodicarboxylate (DEAD)), optionally in the presence of an activating agent (such as 1-hydroxy-7-azabenzotriazole (HOAt)). The crude residue formed is purified by flash chromatography or used in an optional subsequent reaction step without purification. In R 8 Where a protecting group is present, the protecting group is removed according to procedures well known in the art, for example, in the case of t-Boc protected compounds, by treatment with trifluoroacetic acid in dichloromethane, or with HCl in methanol. The crude product formed is purified by flash chromatography or used in an optional subsequent reaction step without purification; or

[0290] Optional Step 7 (Alternative 6):

[0291]

[0292] Preparation of products of formula (I) from carboxylic acid esters, R 8 = methyl, ethyl, CH2Ph(o-OMe), CH2Ph(o-OH), C(O)CH2NH2, C(O)CH(NH2)(CH2)4NH2, C(O)CH(NH2)(CH2)3N(H)C(NH)(NH2), 5-(1,2-dithiopentan-3-yl)pentanoyl and 2-cyano-1-phenylethyl and R 9 =CO2H:

[0293] The hydrolysis of the carboxylic acid ester in step 6 (alternative 2), optional step 7 (alternative 1, 4 or 5) is carried out according to procedures well known in the art, for example, by reacting the carboxylic acid ester with a solution comprising NaHCO and water or a solution comprising dilute aqueous NaOH at room temperature. The crude residue is acidified, extracted with EtOAc, dried over MgSO, concentrated in vacuo, and optionally purified by flash chromatography to give the optionally substituted carboxylic acid.

[0294] The pharmaceutically acceptable salts of the compounds of formula (I) can be prepared by conventional methods well known to those skilled in the art. For the preparation of pharmaceutical compositions and dosage forms and the carriers, diluents and adjuvants used in the preparation, see, for example, Remington's Pharmaceutical Sciences, 20th Edition, 2000, Mack Publishing Company, Easton, Pennsylvania.

[0295] The pharmacological activity of the compounds of the present invention can be verified by methods known in the art. For example, the reduction effect on alcohol seeking behavior can be verified using the method described in Heidbreder, CA, et al., Addict Biol. 2007 Mar; 12 (1): 35-50. For example, the Parkinson's disease prevention activity can be shown as described in Okuda, K., et al. Biol Pharm Bull. 2006 Jul; 29 (7): 1401-1403.

[0296] Reference will now be made in detail to some embodiments. The following specific non-limiting examples will further identify the compounds disclosed herein and below. Not all steps or features of the embodiments are discussed in detail, as many steps or features are apparent to those skilled in the art based on this specification.

[0297] Compound 1

[0298] Ethyl 3-(3,4-difluorophenyl)-1,2,4-trimethylazetidine-3-carboxylate

[0299]

[0300] Starting from 4-chloro-1,2-difluorobenzene, follow General Procedure A (step 1). Use 2,4-dimethyl-3-azetidinone and methyl iodide in step 2 of General Procedure A. Subsequently, follow steps 3-5, step 6 (Alternative 1a) and optional step 7 (Alternative 1, using ethanol) of General Procedure A. 1 H NMR(500MHz,DMSO-d6)δ7.34-7.16(m,3H),4.20(q,J=6.0Hz,2H),3.83(ddddd ,J=21.6,7.7,6.2,4.7,1.5Hz,2H),2.41(d,J=3.0Hz,3H),1.25-1.17(m,9H).

[0301] Compound 2

[0302] Ethyl 3-(3,4-difluorophenyl)-1-ethylazetidine-3-carboxylate

[0303]

[0304] Starting from 4-chloro-1,2-difluorobenzene, follow General Procedure A (step 1). Use 3-azetidinone and ethyl iodide in step 2 of General Procedure A. Subsequently, follow steps 3-5, step 6 (Alternative 1a) of General Procedure A, and optional step 7 (Alternative 1, using ethanol). 1 H NMR(500MHz,DMSO-d6)δ7.29-7.15(m,3H),4.24(q,J=6.0Hz,2H),3.94(d,J=11.5Hz ,2H),3.49(s,2H),2.64-2.58(m,2H),1.22(t,J=6.0Hz,3H),1.07(t,J=6.0Hz,3H).

[0305] Compound 3

[0306] Ethyl 3-(3,4-difluorophenyl)-1-methylazetidine-3-carboxylate

[0307]

[0308] Starting from 4-chloro-1,2-difluorobenzene, follow General Procedure A (step 1). Use 3-azetidinone and methyl iodide in step 2 of General Procedure A. Then follow steps 3-5, step 6 (Alternative 1a) and optional step 7 (Alternative 1, using ethanol) of General Procedure A. 1 H NMR(500MHz,DMSO-d6)δ7.29-7.14(m,3H),4.23(q,J=6.1Hz,2H),3.95(d,J=1 1.5Hz, 2H), 3.53 (dd, J = 11.5, 7.1Hz, 2H), 2.34 (s, 3H), 1.22 (t, J = 6.0Hz, 3H).

[0309] Compound 4

[0310] Ethyl 3-(3,4-difluorophenyl)azetidine-3-carboxylate

[0311]

[0312] Starting from p-chlorotoluene, follow General Procedure A (Step 1). Use 3-azetidinone and benzyl bromide in Step 2 of General Procedure A. Then follow General Procedure A, Steps 3-5, Step 6 (Alternative 1a), and Optional Step 7 (Alternative 2, using ethanol and removing the benzyl protecting group using H2 and Pd / C). 1 HNMR(500MHz,DMSO-d6)δ7.29-7.20(m,2H),7.20-7.13(m,1H),4.23(q,J=6.1Hz,2H),4.00(dd,J =13.1, 3.5Hz, 2H), 3.73 (dd, J = 13.0, 3.5Hz, 2H), 3.57 (pent, J = 3.5Hz, 1H), 1.22 (t, J = 6.0Hz, 3H).

[0313] Compound 5

[0314] Ethyl 3-(3-fluorophenyl)-2,4-dimethylazetidine-3-carboxylate

[0315]

[0316] Starting from m-chlorofluorobenzene, follow General Procedure A (step 1). Use 2,4-dimethyl-3-azetidinone and benzyl bromide in step 2 of General Procedure A. Subsequently, follow steps 3-5 of General Procedure A, step 6 (Alternative 1a), and optional step 7 (Alternative 2, using ethanol and removing the benzyl protecting group using H2 and Pd / C). 1 H NMR (500MHz, DMSO-d6) δ7.34(dddd,J=7.9,7.4,5.0,0.5Hz,1H),7.30-7.19(m,2H),7.10(dddd,J=10.1,7. 3, 2.2, 1.3Hz, 1H), 4.28-4.16 (m, 4H), 3.00 (t, J = 6.9Hz, 1H), 1.22 (t, J = 6.0Hz, 3H), 1.08 (d, J = 4.7Hz, 6H).

[0317] Compound 6

[0318] Ethyl 3-(3-fluorophenyl)-2-methylazetidine-3-carboxylate

[0319]

[0320] Starting from m-chlorofluorobenzene, follow General Procedure A (step 1). Use 2-methyl-3-azetidinone and benzyl bromide in step 2 of General Procedure A. Then follow steps 3-5 of General Procedure A, step 6 (Alternative 1a), and optional step 7 (Alternative 2, using ethanol and removing the benzyl protecting group using H2 and Pd / C). 1 H NMR (500MHz, DMSO-d6) δ7.36-7.18(m,3H),7.10(dddd,J=10.1,7.3,2.1,1.3Hz,1H),4.29-4.10(m,3H),3.97(dd,J=1 3.0, 3.6Hz, 1H), 3.74 (ddd, J = 13.0, 3.6, 1.0Hz, 1H), 3.24-3.18 (m, 1H), 1.22 (t, J = 6.0Hz, 3H), 1.09 (d, J = 4.8Hz, 3H).

[0321] Compound 7

[0322] Ethyl 3-(4-methylphenyl)azetidine-3-carboxylate

[0323]

[0324] Starting from p-chloromethylbenzene, follow General Procedure A (step 1). Use 3-azetidinone and benzyl bromide in step 2 of General Procedure A. Then follow steps 3-5 of General Procedure A, step 6 (Alternative 1a), and optional step 7 (Alternative 2, using ethanol and removing the benzyl protecting group using H2 and Pd / C). 1 H NMR (500MHz, DMSO-d6) δ7.33-7.27(m,2H),7.10(dp,J=8.3,0.6Hz,2H),4.23(q,J=6.0Hz,2H),3.97(dd,J=13 .0,3.5Hz,2H),3.66(dd,J=13.1,3.5Hz,2H),3.59-3.52(m,1H),2.30(d,J=1.3Hz,3H),1.22(t,J=6.0Hz,3H).

[0325] Compound 8

[0326] 2-Methyl-3-(3-methylphenyl)azetidine-3-carboxylic acid methyl ester

[0327]

[0328] Starting from m-chlorotoluene, follow General Procedure A (Step 1). Use 2-methyl-3-azetidinone and benzyl bromide in Step 2 of General Procedure A. Then follow Steps 3-5 of General Procedure A, Step 6 (Alternative 1a), and Optional Step 7 (Alternative 2, using ethanol and removing the benzyl protecting group using H2 and Pd / C). 1 H NMR (500MHz, DMSO-d6) δ7.30(ddd,J=7.7,2.2,1.3Hz,1H),7.26-7.19(m,2H),7.11(dddd,J=7.3,2.1,1.3,0.7Hz,1H),4.18(dqd,J=5.8,4.8,1.0H z,1H),3.98(dd,J=13.0,3.6Hz,1H),3.73(ddd,J=12.9,3.7,1.0Hz,4H),3.20(dt,J=5.9,3.6Hz,1H),2.31(d,J=1.2Hz,3H),1.10(d,J=4.8Hz,3H).

[0329] Compound 9

[0330] 3-(3,4-Difluorophenyl)-1-ethyl-2-methylazetidine-3-carboxylic acid methyl ester

[0331]

[0332] Starting from 4-chloro-1,2-difluorobenzene, follow General Procedure A (Step 1). Use 2-methyl-3-azetidinone and benzyl bromide in Step 2 of General Procedure A. Subsequently, follow General Procedure A, Steps 3-5, Step 6 (Alternative 1a), Alternative Step 7 (Alternative 2, using methanol and removing the benzyl protecting group), and Alternative Step 7 (Alternative 4, reductive alkylation using acetaldehyde and sodium borohydride). 1 H NMR(500MHz,DMSO-d6)δ7.35-7.27(m,1H),7.23(dddd,J=10.0,9.2,4.7,0.5Hz,1H),7.19-7.12(m,1H),3.73-3.65(m,2H),3.60(s,3H) ,3.53(dd,J=11.5,1.0Hz,1H),2.82(dq,J=11.8,5.9Hz,1H),2.64(dt,J=12.0,5.9Hz,1H),1.20(d,J=5.7Hz,3H),1.09(t,J=5.9Hz,3H).

[0333] Compound 10

[0334] Methyl 3-(3,4-difluorophenyl)-2-methylazetidine-3-carboxylate

[0335]

[0336] Starting from 4-chloro-1,2-difluorobenzene, follow General Procedure A (step 1). Use 2-methyl-3-azetidinone and benzyl bromide in step 2 of General Procedure A. Subsequently, follow steps 3-5 of General Procedure A, step 6 (Alternative 1a), and optional step 7 (Alternative 2, using ethanol and removing the benzyl protecting group using H2 and Pd / C). 1 H NMR(500MHz,DMSO-d6)δ7.30-7.19(m,2H),7.16(dddd,J=9.2,3.5,2.1,0.3Hz,1H),4.20(dqd,J=5.8,4.8,1.0Hz,1H) ,3.95(dd,J=13.0,3.6Hz,1H), 3.75(ddd,J=13.0,3.6,1.0Hz,4H), 3.21(dt,J=5.9,3.6Hz,1H), 1.10(d,J=4.8Hz,3H).

[0337] Experiments related to the binding affinity of the compounds of the invention

[0338] Binding affinities for compounds of the invention were calculated using Qvina2 for an explicit random seed using a value of 5061982. The exhaustiveness was 100. Methods for performing binding affinity calculations for compounds of the invention are well known in the art and have also been described in Alhossary A. et al. Fast,Accurate,and Reliable Molecular Docking withQuickVina 2Bioinformatics(2015)31(13)2214-2216;O.Trott,AJOlson,AutoDockVina:improving the speed and accuracy of docking with a new scoring function,efficient optimization and multithreading,Journal of Computational Chemistry31(2010)455-461;Feinstein WP,Brylinski M.Calculating an optimal box size forligand docking and virtual screening against experimental and predictedbinding pockets.J.Cheminform.(2015),7(1):18;Tetko,IVet al.Virtual computational chemistry laboratory-design and description,J.Comput.Aid.Mol.Des.,2005,19,453-63; VCCLAB,Virtual Computational ChemistryLaboratory, http: / / www.vcclab.org, 2005. The search space (X, Y, Z) coordinates of the center for calculating binding affinity can be obtained by methods well known in the art. For example, the search space (X, Y, Z) coordinates of PDB ID 1bp3 and protein homolog ClassA_5ht1a_human_Active_6G79_2018-07-10_GPCRDB are (13.730, 30.880, 13.170) and (91.84457623, 54.99481, 63.31365), respectively. The PDB ID and protein homolog codes of the proteins used in the calculation of the compounds of the present invention are listed in Table 1, and some of the calculation results are listed in Table 2.

[0339] Table 1. PDB IDs and protein homolog codes of proteins used in binding affinity calculations for compounds disclosed herein and below.

[0340]

[0341]

[0342] 1 The PDB structure was obtained from the Protein Data Bank: http: / / www.rcsb.org / . 2 Protein homologs were obtained from GPCRdb ( http: / / docs.gpcrdb.org / index.html ;Pándy-Szekeres G,Munk C,Tsonkov TM,Mordalski S, K,Hauser AS,Bojarski AJ,Gloriam DE.GPCRdb in 2018:addingGPCR structure models and ligands.2017,Nucleic Acids Res.,Nov 16. http: / / dx.doi.org / 10.1093 / nar / gkx1109 ).

[0343] Table 2. Results of binding affinity calculations of the compounds of the present invention for proteins, logP and logS values.

[0344]

[0345]

[0346]

[0347]

[0348] 1 The numbers of the docked proteins correspond to the item numbers visible in Table 1 .

[0349] The compound with the strongest binding affinity for trace amine receptor 1 (TAAR1), norepinephrine transporter (NET), 5-HT2A receptor, 5-HT2B receptor, OX1 orexin receptor, Mu-opioid receptor, neurokinin 1 receptor (NK1R), and melanocortin 3 receptor (MC3R) was ethyl 3-(3,4-difluorophenyl)-1,2,4-trimethylazetidine-3-carboxylate (1).

[0350] The compound with the strongest binding affinity to the dopamine transporter (DAT) is ethyl 3-(3,4-difluorophenyl)-1-methylazetidine-3-carboxylate (3).

[0351] The compound with the strongest binding affinity for the dopamine 1 (D1) receptor, the sigma-1 receptor, and the 1B melatonin receptor is 1-ethyl-2-methyl-3-(3-methylphenyl)azetidine-3-carboxylic acid methyl ester (15):

[0352]

[0353] The compound with the strongest binding affinity for dopamine 2 (D2) receptor, MAO-A, α-2C adrenergic receptor, α4β2 nicotinic receptor and CHK1 kinase is ethyl 3-(4-methylphenyl)azetidine-3-carboxylate (7).

[0354] The compound with the strongest binding affinity for both dopamine 3 (D3) receptors and kappa-opioid receptors is ethyl 3-(3,4-difluorophenyl)-2-methylazetidine-3-carboxylate (19):

[0355]

[0356] The compound with the strongest binding affinity for the dopamine 4 (D4) receptor is methyl 2-methyl-3-(3-methylphenyl)azetidine-3-carboxylate (8).

[0357] The compound with the strongest binding affinity to phenylethanolamine N-methyltransferase (PNMT) was ethyl 3-(3-fluorophenyl)-2,4-dimethylazetidine-3-carboxylate (5).

[0358] The compound with the strongest binding affinity to the serotonin transporter (SERT) is ethyl 3-(4-methoxyphenyl)azetidine-3-carboxylate (20):

[0359]

[0360] The compound with the strongest binding affinity for serotonin N-acetyltransferase is ethyl 1-ethyl-3-(3-methylphenyl)azetidine-3-carboxylate (21):

[0361]

[0362] The compound with the strongest binding affinity for N-acetylserotonin methyltransferase, 1A melatonin receptor and melanocortin 1 receptor (MSHR, MC1R) is methyl 3-(3,4-difluorophenyl)-1-ethyl-2-methylazetidine-3-carboxylate (9).

[0363] The compound with the strongest binding affinity for the 5-HT1A receptor is 1-ethyl-3-(3-methoxyphenyl)-2,4-dimethylazetidine-3-carboxylic acid methyl ester (22):

[0364]

[0365] The compound with the strongest binding affinity for 5-HT1B receptors and β1 adrenergic receptors is 1-ethyl-2,4-dimethyl-3-(4-methylphenyl)azetidine-3-carboxylic acid ethyl ester (23):

[0366]

[0367] The compound with the strongest binding affinity for 5-HT2C receptor, α-1B adrenergic receptor, α-2B adrenergic receptor, melanocortin 2 receptor (ACTHR, MC2R) and melanocortin 4 receptor (MC4R) is 2,4-dimethyl-3-(3-methylphenyl)azetidine-3-carboxylic acid ethyl ester (24):

[0368]

[0369] The compound with the strongest binding affinity for the 5-HT3 receptor is methyl 3-(3,4-difluorophenyl)-2,4-dimethylazetidine-3-carboxylate (25):

[0370]

[0371] The compound with the strongest binding affinity to MAO-B was ethyl 3-(3,4-difluorophenyl)azetidine-3-carboxylate (4).

[0372] The compound with the strongest binding affinity to COMT is 1,2-dimethyl-3-(3-methylphenyl)azetidine-3-carboxylic acid ethyl ester (26):

[0373]

[0374] The compound with the strongest binding affinity for the α-1A adrenergic receptor and the nociceptin / orphanin receptor is 1-ethyl-2,4-dimethyl-3-(3-methylphenyl)azetidine-3-carboxylic acid methyl ester (27):

[0375]

[0376] The compound with the strongest binding affinity for the α-2A adrenergic receptor and the prolactin receptor is methyl 3-(3,4-difluorophenyl)-2-methylazetidine-3-carboxylate (10).

[0377] The compound with the strongest binding affinity for the β2 adrenergic receptor is 1-ethyl-2-methyl-3-(4-methylphenyl)azetidine-3-carboxylic acid methyl ester (28):

[0378]

[0379] The compound with the strongest binding affinity for phenylalanine hydroxylase is 1-ethyl-3-(4-methoxyphenyl)-2,4-dimethylazetidine-3-carboxylic acid methyl ester (29):

[0380]

[0381] The compound with the strongest binding affinity for tyrosine hydroxylase is 1-ethyl-3-(4-methoxyphenyl)-2-methylazetidine-3-carboxylic acid methyl ester (30):

[0382]

[0383] and methyl 2,4-dimethyl-3-(4-methylphenyl)azetidine-3-carboxylate (31):

[0384]

[0385] The compound with the strongest binding affinity for the H1 histamine receptor is 1-ethyl-3-(4-methylphenyl)azetidine-3-carboxylic acid ethyl ester (12):

[0386]

[0387] The compound with the strongest binding affinity for H3 histamine receptors and neurokinin 2 receptor (NK2R) is ethyl 3-(3-fluorophenyl)-1,2,4-trimethylazetidine-3-carboxylate (17):

[0388]

[0389] The compound with the strongest binding affinity for the OX2 orexin receptor is ethyl 3-(3,4-difluorophenyl)-1-ethyl-2-methylazetidine-3-carboxylate (32):

[0390]

[0391] The compound with the strongest binding affinity to the NMDA receptor GluN1 is 2-methyl-3-(4-methylphenyl)azetidine-3-carboxylic acid methyl ester (33):

[0392]

[0393] The compound with the strongest binding affinity for the NMDA receptor Glu2B, the M2 muscarinic acetylcholine receptor, and the neuropeptide Y1 receptor is ethyl 3-(3,4-difluorophenyl)-2,4-dimethylazetidine-3-carboxylate (13):

[0394]

[0395] The compound with the strongest binding affinity for the delta-opioid receptor, M1 muscarinic acetylcholine receptor, M3 muscarinic acetylcholine receptor, and M4 muscarinic acetylcholine receptor is methyl 3-(3,4-difluorophenyl)-1-ethyl-2,4-dimethylazetidine-3-carboxylate (14):

[0396]

[0397] The compound with the strongest binding affinity for acetylcholinesterase and melanocortin 5 receptor (MC5R) is ethyl 2-methyl-3-(3-methylphenyl)azetidine-3-carboxylate (11):

[0398]

[0399] The compound with the strongest binding affinity for the neuropeptide Y2 receptor is ethyl 3-(3-methylphenyl)azetidine-3-carboxylate (16):

[0400]

[0401] The compound with the strongest binding affinity for the neuropeptide Y5 receptor is 3-(4-methylphenyl)-1,2-dimethylazetidine-3-carboxylic acid methyl ester (34):

[0402]

[0403] The compound with the strongest binding affinity for the neurokinin 3 receptor (NK3R) is 1-ethyl-2,4-dimethyl-3-(3-methylphenyl)azetidine-3-carboxylic acid ethyl ester (18):

[0404]

[0405] The compound with the strongest binding affinity for the oxytocin receptor (OXYR) is ethyl 3-(3-fluorophenyl)azetidine-3-carboxylate (35):

[0406]

[0407] The compound with the strongest binding affinity for corticotropin-releasing factor receptor 1 (CRF1R) is 1,2-dimethyl-3-(4-methylphenyl)azetidine-3-carboxylic acid ethyl ester (36):

[0408]

[0409] It is obvious to a person skilled in the art that, as technology advances, the inventive concept can be implemented in various ways.The invention and its embodiments are not limited to the examples described above but may vary within the scope of the claims.

[0410] The above embodiments can be used in any combination with each other. Several embodiments can be combined to form further embodiments. The products, systems, methods or uses disclosed herein may include at least one of the above embodiments. It should be understood that the above benefits and advantages may relate to one embodiment or to several embodiments. These embodiments are not limited to embodiments that solve any or all of the problems described, or embodiments that have any or all of the benefits and advantages described.

Claims

1. Compound of formula (I) in R 1 , R 2 , R 3 , R 4 and R 5 are each independently selected from H, halogen, C 1-4 -alkyl, C 1-3 -(per)halogenated alkyl, C 1-3 -alkoxy, C 1-3 -(per)haloalkoxy and OH; or R 1 , R 2 and R 5 are each independently selected from H, halogen, C 1-4 -alkyl, C 1-3 -(per)halogenated alkyl, C 1-3 -alkoxy, C 1-3 -(per)haloalkoxy and OH; and R 3 and R 4 together form a group selected from OC(R')2O; or R 1 , R 4 and R 5 are each independently selected from H, halogen, C 1-4 -alkyl, C 1-3 -(per)halogenated alkyl, C 1-3 -alkoxy, C 1-3 -(per)haloalkoxy and OH; and R 2 and R 3 Together they form a group selected from OC(R')2O; R 6 and R 7 Each independently selected from H, methyl and ethyl; R 8 is selected from H, methyl, ethyl, CH2Ph(o-OMe), CH2Ph(o-OH), C(O)CH2NH2, C(O)CH(NH2)(CH2)4NH2, C(O)CH(NH2)(CH2)3N(H)C(NH)(NH2), 5-(1,2-dithiolan-3-yl)pentanoyl and 2-cyano-1-phenylethyl; R 9 Selected from CO2R 10 and COSR 10 ; R 10 is selected from H, methyl and ethyl; and Each R' is independently selected from H and F; or a stereoisomer or a pharmaceutically acceptable salt thereof.

2. The compound of claim 1, wherein R 9 Selected from CO2R 10 ;and R 10 As defined in claim 1; or a stereoisomer or a pharmaceutically acceptable salt thereof.

3. A compound as claimed in any one of the preceding claims, wherein R 1 , R 2 and R 5 It is H; R 3 and R 4 are each independently selected from H, halogen, C 1-4 -alkyl; R 9 It is CO2R 10 ;and R 10 As defined in claim 1; or a stereoisomer or a pharmaceutically acceptable salt thereof.

4. A compound as claimed in any one of the preceding claims, wherein R 6 , R 7 and R 8 At least one of is independently selected from methyl and ethyl, and R 6 , R 7 and R 8 The other items in are each independently selected from H, methyl and ethyl; or a stereoisomer or a pharmaceutically acceptable salt thereof.

5. A compound as claimed in any one of the preceding claims, wherein R 6 , R 7 and R 8 At least one of is independently selected from methyl and ethyl, and R 6 , R 7 and R 8 The other items in are each independently selected from H, methyl and ethyl; R 9 It is CO2R 10 ;and R 10 is selected from methyl and ethyl; or a stereoisomer or a pharmaceutically acceptable salt thereof.

6. A compound as claimed in any one of the preceding claims, wherein R 6 and R 7 are each independently selected from methyl and ethyl, or R 6 and R 7 One of them is selected from methyl and ethyl and R 6 and R 7 The other term in is H; R 8 is selected from H, methyl and ethyl; R 9 It is CO2R 10 ;and R 10 is selected from methyl and ethyl; or a stereoisomer or a pharmaceutically acceptable salt thereof.

7. The compound according to any one of claims 1 to 5, wherein R 6 and R 7 All are H; R 9 It is CO2R 10 ;and R 10 is selected from methyl and ethyl; or a stereoisomer or a pharmaceutically acceptable salt thereof.

8. A compound as described in any one of claims 1-2 or 4-7, wherein R 1 , R 2 and R 5 It is H; R 3 and R 4 are each independently selected from H, halogen, C 1-4 -alkyl, C 1-3 -(per)halogenated alkyl, C 1-3 -alkoxy, C 1-3 -(per)haloalkoxy and OH, provided that if R 3 or R 4 If one of them is H, then R 6 and R 7 At least one of each of which is independently selected from methyl and ethyl and R 6 and R 7 The other of which is selected from H, methyl and ethyl, or R 6 and R 7 Both H and R 8 Selected from methyl, ethyl, CH2Ph(o-OMe), CH2Ph(o-OH), C(O)CH2NH2, C(O)CH(NH2)(CH2)4NH2, C(O)CH(NH2)(CH2)3N(H)C(NH)(NH2), 5-(1,2-dithiolan-3-yl)pentanoyl and 2-cyano-1-phenylethyl; or a stereoisomer or a pharmaceutically acceptable salt thereof.

9. A compound as claimed in any one of the preceding claims, wherein R 1 , R 2 and R 5 It is H; R 3 and R 4 is selected from F, Cl, methyl and ethyl, and R 3 and R 4 The other of which is selected from the group consisting of H, F, methyl and ethyl; R 9 It is CO2R 10 ;and R 10 is selected from methyl and ethyl; or a stereoisomer or a pharmaceutically acceptable salt thereof.

10. The compound according to any one of claims 1 to 8, wherein R 1 , R 2 and R 5 is H; and R 3 and R 4 are all halogens; or R 3 and R 4 one of them is halogen or methyl, and R 3 and R 4 The other term in is H, provided that R 8 is selected from methyl, ethyl, CH2Ph(o-OMe), CH2Ph(o-OH), C(O)CH2NH2, C(O)CH(NH2)(CH2)4NH2, C(O)CH(NH2)(CH2)3N(H)C(NH)(NH2), 5-(1,2-dithiolan-3-yl)pentanoyl and 2-cyano-1-phenylethyl, or with the condition that R 6 and R 7 At least one of each of which is independently selected from methyl and ethyl and R 6 and R 7 The other of which is selected from the group consisting of H, methyl and ethyl; or a stereoisomer or a pharmaceutically acceptable salt thereof.

11. The compound according to any one of claims 1 to 5 or 7 to 10, wherein R 1 , R 2 and R 5 It is H; R 3 and R 4 All F; or R 3 and R 4 One is F and R 3 and R 4 The other term in is H; R 6 and R 7 are each independently selected from H and methyl; R 9 It is CO2R 10 ;and R 10 is selected from methyl and ethyl; or a stereoisomer or a pharmaceutically acceptable salt thereof.

12. The compound of any one of claims 1-5 or 7-11, wherein R 1 , R 2 and R 5 It is H; R 3 and R 4 All are F; R 6 and R 7 are each independently selected from H and methyl; R 9 It is CO2R 10 ;and R 10 is selected from methyl and ethyl; or a stereoisomer or a pharmaceutically acceptable salt thereof.

13. The compound according to any one of claims 1 to 10, wherein R 1 , R 2 and R 5 It is H; R 3 and R 4 One of them is methyl and R 3 and R 4 The other term in is H; R 9 It is CO2R 10 ;and R 10 is selected from methyl and ethyl; or a stereoisomer or a pharmaceutically acceptable salt thereof.

14. The compound according to any one of claims 1 to 12, wherein R 1 , R 2 and R 5 It is H; R 3 and R 4 All are F; R 8 is selected from methyl and ethyl; R 9 It is CO2R 10 ;and R 10 is selected from methyl and ethyl; or a stereoisomer or a pharmaceutically acceptable salt thereof.

15. The compound according to any one of the preceding claims, wherein the compound is selected from: ethyl 3-(3,4-difluorophenyl)-1,2,4-trimethylazetidine-3-carboxylate (1); Ethyl 3-(3,4-difluorophenyl)-1-ethylazetidine-3-carboxylate (2); Ethyl 3-(3,4-difluorophenyl)-1-methylazetidine-3-carboxylate (3); Ethyl 3-(3,4-difluorophenyl)azetidine-3-carboxylate (4); Ethyl 3-(3-fluorophenyl)-2,4-dimethylazetidine-3-carboxylate (5); Ethyl 3-(3-fluorophenyl)-2-methylazetidine-3-carboxylate (6); Ethyl 3-(4-methylphenyl)azetidine-3-carboxylate (7); 2-Methyl-3-(3-methylphenyl)azetidine-3-carboxylic acid methyl ester (8); 3-(3,4-Difluorophenyl)-1-ethyl-2-methylazetidine-3-carboxylic acid methyl ester (9); 3-(3,4-Difluorophenyl)-2-methylazetidine-3-carboxylic acid methyl ester (10); 2-Methyl-3-(3-methylphenyl)azetidine-3-carboxylic acid ethyl ester (11); 1-ethyl-3-(4-methylphenyl)azetidine-3-carboxylic acid ethyl ester (12); Ethyl 3-(3,4-difluorophenyl)-2,4-dimethylazetidine-3-carboxylate (13); 3-(3,4-Difluorophenyl)-1-ethyl-2,4-dimethylazetidine-3-carboxylic acid methyl ester (14); 1-ethyl-2-methyl-3-(3-methylphenyl)azetidine-3-carboxylic acid methyl ester (15); Ethyl 3-(3-methylphenyl)azetidine-3-carboxylate (16); 3-(3-Fluorophenyl)-1,2,4-trimethylazetidine-3-carboxylic acid ethyl ester (17); 1-Ethyl-2,4-dimethyl-3-(3-methylphenyl)azetidine-3-carboxylic acid ethyl ester (18); Ethyl 3-(3,4-difluorophenyl)-2-methylazetidine-3-carboxylate (19); Ethyl 3-(4-methoxyphenyl)azetidine-3-carboxylate (20); 1-Ethyl-3-(3-methylphenyl)azetidine-3-carboxylate (21); 1-ethyl-3-(3-methoxyphenyl)-2,4-dimethylazetidine-3-carboxylic acid methyl ester (22); 1-Ethyl-2,4-dimethyl-3-(4-methylphenyl)azetidine-3-carboxylic acid ethyl ester (23); 2,4-Dimethyl-3-(3-methylphenyl)azetidine-3-carboxylic acid ethyl ester (24); 3-(3,4-difluorophenyl)-2,4-dimethylazetidine-3-carboxylic acid methyl ester (25); 1,2-Dimethyl-3-(3-methylphenyl)azetidine-3-carboxylic acid ethyl ester (26); 1-ethyl-2,4-dimethyl-3-(3-methylphenyl)azetidine-3-carboxylic acid methyl ester (27); 1-ethyl-2-methyl-3-(4-methylphenyl)azetidine-3-carboxylic acid methyl ester (28); 1-ethyl-3-(4-methoxyphenyl)-2,4-dimethylazetidine-3-carboxylic acid methyl ester (29); 1-ethyl-3-(4-methoxyphenyl)-2-methylazetidine-3-carboxylic acid methyl ester (30); 2,4-Dimethyl-3-(4-methylphenyl)azetidine-3-carboxylic acid methyl ester (31); Ethyl 3-(3,4-difluorophenyl)-1-ethyl-2-methylazetidine-3-carboxylate (32); 2-Methyl-3-(4-methylphenyl)azetidine-3-carboxylic acid methyl ester (33); 3-(4-Methylphenyl)-1,2-dimethylazetidine-3-carboxylic acid methyl ester (34); Ethyl 3-(3-fluorophenyl)azetidine-3-carboxylate (35); 1,2-dimethyl-3-(4-methylphenyl)azetidine-3-carboxylic acid ethyl ester (36); and 1-ethyl-3-(3-fluorophenyl)-2,4-dimethylazetidine-3-carboxylic acid methyl ester (37); or a stereoisomer or a pharmaceutically acceptable salt thereof.

16. A pharmaceutical composition comprising an effective amount of one or more compounds as defined in the preceding claims or stereoisomers or pharmaceutically acceptable salts thereof, and one or more pharmaceutically acceptable excipients.

17. The pharmaceutical composition of claim 16, in combination with one or more pharmaceutically acceptable carriers.

18. The pharmaceutical composition according to any one of claims 16-17, in combination with one or more other active ingredients.

19. A compound as defined in any one of claims 1 to 15, or a stereoisomer or a pharmaceutically acceptable salt thereof, for use as a medicament.

20. A compound as defined in any one of claims 1 to 15, or a stereoisomer or a pharmaceutically acceptable salt thereof, for use in the treatment or prevention of drug addiction or a CNS related disease or condition.

21. A compound as defined in any one of claims 1 to 15, or a stereoisomer or a pharmaceutically acceptable salt thereof, for use in the treatment or prevention of drug addiction or a CNS-related disease or condition as described in claim 17, wherein the drug addiction or the CNS-related disease or condition is selected from stimulant addiction, ADHD, ADD, cognitive retardation, attention deficit disorder, motivational or reward system dysfunction, autism spectrum disorder, disruptive impulse control and conduct disorders, anxiety disorders, eating disorders, depression, dysthymic disorder, Alzheimer's disease, Parkinson's disease, ADHD, narcolepsy and alcoholism.

22. A process for preparing a compound of formula (I) or a pharmaceutically acceptable salt or a stereoisomer thereof as defined in any one of claims 1 to 15, comprising: (i) providing a compound of formula (II) in R 1 , R 2 , R 3 , R 4 , R 5 , R 6 and R 7 As defined in claim 1; and R 8 is methyl, ethyl, CH2Ph(o-OMe) or a protecting group; (ii) reacting the compound of formula (II) with one or more compounds, wherein each of the compounds is independently selected from an acid, a base and water; or reacting the compound of formula (II) with methanol or ethanol and a Lewis catalyst; (iii) optionally esterified with a compound of formula (III) R 11 -R”(III), where R 11 is methyl or ethyl; and R" is selected from halogen, SR"', OR"' and a first activating group, wherein R"' is H or a second activating group, optionally in the presence of one or more activating group reactants and / or one or more activating agents; (iv) optionally performing one or more first deprotection reactions; (v) optionally transesterifying with a compound of formula (III), wherein R 11 is methyl or ethyl; and R" is selected from SH and OH, optionally in the presence of one or more activating group reactants and / or one or more activating agents; (vi) optionally amidating with a compound of formula (IV) R 12 -R 8’ (IV), where R 12 It’s HO, R 13 O or R 13 , where R 13 is an activating group; and R 8’ It is C(O)CH2NHR 14 、C(O)CH(NHR 14 )(CH2)4NHR 14 、C(O)CH(NHR 14 )(CH2)3N(R 14 )C(NR 14 )(NHR 14 ) or 5-(1,2-dithiolan-3-yl)pentanoyl, wherein each R 14 are independently selected from H and protecting groups, optionally in the presence of one or more activating group reactants and / or one or more activating agents; (vii) optionally reductively alkylating with a compound of formula (V) and a reducing agent R 8” -CHO(V), where R 8” is H or CH3; (viii) optionally N-alkylating with a compound of formula (VI) R 8”’ -R 15 (VI), where R 8”’ is methyl, ethyl, (o-OMe)PhCH2 or (Ph)CH(CH2CN); and R 15 Selected from halogen, SR 16 OR 16 , where R 16 is an activating group, optionally in the presence of one or more activating group reactants and / or one or more activating agents; (ix) optionally performing one or more second deprotection reactions; To obtain the compound of formula (I), wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 and R 10 As defined in claim 1; and (x) optionally converting the compound of formula (I) into a pharmaceutically acceptable salt thereof.

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