A deuterated amide derivative and use thereof

Abstract

The application belongs to the field of medicine, and particularly relates to a deuterated amide derivative and application thereof, and particularly relates to a compound shown in the general formula I shown below or a pharmaceutically acceptable salt thereof, and a use thereof as a drug for treating neuropsychiatric diseases.

Description

[0001] This application claims priority to an earlier application filed on May 17, 2021, with patent application number CN202110532496.7, entitled "A Deuterated Amide Derivative and Its Application". The entire contents of the earlier application are incorporated herein by reference. Technical Field

[0002] This invention belongs to the field of medicine, specifically relating to a deuterated amide derivative and its applications. Background Technology

[0003] NMDAR (N-methyl-D-aspartate receptor) is a glutamate ionotropic receptor that primarily targets Ca2+. 2+ Ions are permeable and can be activated upon binding with glycine and glutamate, playing a crucial role in excitatory synaptic plasticity. Physiologically, they activate and trigger the opening of ion channels, generating an input current that only slowly inactivates. Under pathological conditions, they can lead to overactivation of NMDAR, a significant pathogenic mechanism of receptor excitotoxicity.

[0004] Physiological activity of NMDAR is essential for normal neurological function. Overactivation of NMDAR is associated with acute neurological diseases such as stroke or traumatic brain injury, and with chronic stress conditions such as neurodegenerative diseases. Many pathologies are thought to be associated with excessive NMDAR activity, and therefore NMDAR is potentially sensitive to NMDAR antagonists ([J]. Journal of Neurochemistry, 2006, 97(6): 1611-1626.).

[0005] Increasing evidence suggests the importance of NMDAR in inducing and maintaining central sensitization in pain states. Furthermore, NMDAR may also mediate peripheral sensitization and visceral pain ([J]. Nature, 2005, 438(7071):1162.). Extensive preclinical data support the potential of NMDAR antagonists to treat opioid-induced refractory pain, postoperative pain, and cancer pain. Other studies have shown that typical antidepressants alter the affinity of the NMDA receptor glycine site, and reduced NMDAR function contributes to antidepressant responses. In patients with treatment-resistant depression, intravenous administration of a single subanesthetic dose of ketamine significantly improved their condition, and the antidepressant effect lasted for one week ([J]. Archives of general psychiatry, 2006, 63(8):856-864.). Currently, S-ketamine nasal spray... It was approved for marketing in the United States in March 2019 for use as an adjunct therapy in the treatment of resistant depression.

[0006] Based on their sites of action, NMDAR antagonists can be broadly classified into three categories: non-competitive (or allosteric) antagonists (ATD sites), such as afenidil, RGH-896, and EVT101; competitive antagonists (LBD sites), such as GLYX-13 and NRX-1074; and non-competitive antagonists, channel pore blockers (TMD sites), including ketamine, dextromethorphan, and memantine. However, currently marketed NMDAR antagonists still commonly have various side effects, such as hallucinations, confusion, personality disorders, nightmares, agitation, attention deficit, mood changes, convulsions, and sedation ([J]. Biochemicalpharmacology, 2003, 66(6): 877-886.), thus limiting their use. The higher the affinity of the NMDAR channel pore antagonist, the slower its binding to NMDAR. The slower binding rate leads to Ca 2+ For sustained influx of NMDAR, very high drug concentrations are required to fully bind to the receptor, such as MK-801, which has a slow dissociation rate of NMDAR, resulting in significant psychotropic side effects.

[0007] Current research has confirmed that high-affinity, non-competitive NMDA receptor antagonists like MK-801 can prevent NMDAR activation and inhibit Ca2+ receptor activation. 2+ Intravenous influx, but its application is limited by significant psychomimetic adverse reactions. In contrast, low-affinity, non-competitive NMDAR antagonists (such as memantine) can reduce toxicity, thanks to the faster rate of NMDAR blockade and departure ([J]. European journal of pharmacology, 1996, 317(2-3): 377-381). Other studies have shown that the good clinical tolerability and symptomatic effect of memantine in the treatment of Alzheimer's disease are attributed to its moderate affinity for NMDA receptor channels and rapid dissociation from NMDAR ([J]. Neuropharmacology, 2009, 56(5): 866-875.); other studies have suggested that memantine has better inhibitory recovery kinetics than dizocilpine, which is considered to be the main determinant of the better clinical tolerability of memantine ([J]. ACS chemical neuroscience, 2018, 9(11): 2722-2730.). Therefore, the ability to rapidly dissociate from NMDAR is one of the key factors in the development of NMDAR antagonists.

[0008] CN106957285A discloses an aminocyclobutane derivative, an NMDAR antagonist, with the potential treatment of depression and chronic pain, and its structure is shown below:

[0009]

[0010] Although there are NMDAR inhibitors with channel pore blockers (TMD sites) on the market, they have not yet achieved the effect of rapidly dissociating from NMDAR and reducing psychogenic side effects. Therefore, NMDAR inhibitors remain a research hotspot in the field of neuropsychiatry. Summary of the Invention

[0011] This invention aims to provide a novel NMDAR inhibitor, belonging to the channel pore blocker (TMD site), which can inhibit channel opening caused by excessive NMDAR activation under pathological conditions, thereby preventing Ca2+. 2+ Excessive influx of NMDAR does not affect the normal function of NMDAR. Furthermore, the NMDAR antagonist described in this invention is a reversible NMDAR antagonist, which dissociates very rapidly after binding without affecting the normal function of the NMDA receptor.

[0012] In one aspect, the present invention relates to a compound of general formula I or a pharmaceutically acceptable salt, stereoisomer, or mixture thereof.

[0013]

[0014] Where n is 0 or 1; R1, R2, R3, R4, R5, R6, R7, R8, R9, R 10 R 11 R 12 R 13 R 14 Each is independently selected from H or D, provided that they are not both H; R 15 Selected from halogens.

[0015] Some specific embodiments of the present invention provide a compound of general formula I or a pharmaceutically acceptable salt, stereoisomer, or mixture thereof, wherein R1, R2, R3, R4, R5, R6, R7, R8, R9, R 10 At least one is D; R 15 Selected from fluorine, chlorine, bromine, and iodine.

[0016] In some specific embodiments of the present invention, the compound represented by general formula I or its pharmaceutically acceptable salt, stereoisomer, or mixture thereof, wherein at least one of R1, R2, R3, R7, and R8 is D; R 15 Selected from fluorine, chlorine, bromine, and iodine.

[0017] Some specific embodiments of the present invention, wherein the compound represented by general formula I or its pharmaceutically acceptable salt, stereoisomer, or mixture thereof, wherein R 11 R 12 R13 R 14 At least one is D; R 15 Selected from fluorine, chlorine, bromine, and iodine. In some specific embodiments of the present invention, the compound represented by general formula I, or its pharmaceutically acceptable salt, stereoisomer, or mixture thereof, wherein at least one of R1, R2, and R3 is D.

[0018] In some specific embodiments of the present invention, the compound represented by general formula I or a pharmaceutically acceptable salt, stereoisomer, or mixture thereof, wherein at least two of R1, R2, and R3 are D.

[0019] In some specific embodiments of the present invention, the compound represented by general formula I or its pharmaceutically acceptable salt, stereoisomer, or mixture thereof, wherein R1, R2, and R3 are all selected from D.

[0020] In some preferred embodiments of the present invention, a compound of general formula I or a pharmaceutically acceptable salt, stereoisomer, or mixture thereof is provided, wherein n is 0 or 1, R1, R2, R3 are D, and R4, R5, R6, R7, R8, R9, R 10 R 11 R 12 R 13 R 14 Each is independently selected from H or D; R 15 Selected from fluorine, chlorine, bromine, and iodine.

[0021] In some preferred embodiments of the present invention, a compound of general formula I or a pharmaceutically acceptable salt, stereoisomer, or mixture thereof is provided, wherein n is 0 or 1, R1, R2, R3, R7, and R8 are all D, and R4, R5, R6, R9, and R6 are D. 10 R 11 R 12 R 13 R 14 Each is independently selected from H or D; R 15 Selected from fluorine, chlorine, bromine, and iodine.

[0022] In some preferred embodiments of the present invention, a compound of general formula I or a pharmaceutically acceptable salt, stereoisomer, or mixture thereof is provided, wherein n is 0 or 1, and R... 11 R 12 R 13 R 14 Selected from D; R1, R2, R3, R4, R5, R6, R7, R8, R9, R 10 Each is independently selected from H or D; R 15 Selected from fluorine, chlorine, bromine, and iodine.

[0023] In some preferred embodiments of the present invention, a compound of general formula I or a pharmaceutically acceptable salt, stereoisomer, or mixture thereof is provided, wherein n is 0 or 1, and R4, R5, R6, R9, R 10 Let D be the integers R1, R2, R3, R7, R8, and R. 11 R 12 R 13 R 14 Each is independently selected from H or D; R 15 Selected from fluorine, chlorine, bromine, and iodine.

[0024] In some preferred embodiments of the present invention, a compound of general formula I or a pharmaceutically acceptable salt, stereoisomer, or mixture thereof is provided, wherein n is 0 or 1, and R1, R2, R3, R4, R5, R6, R9, R 10 For D, R7, R8, R 11 R 12 R 13 R 14 Each is independently selected from H or D; R 15 Selected from fluorine, chlorine, bromine, and iodine.

[0025] Some specific embodiments of the present invention relate to a compound of general formula I or a pharmaceutically acceptable salt, stereoisomer, or mixture thereof, said compound being selected from one of the following structures:

[0026]

[0027] The present invention provides a pharmaceutical composition comprising a compound of general formula I or a pharmaceutically acceptable salt, stereoisomer, or mixture thereof, and one or more pharmaceutically acceptable carriers and / or excipients.

[0028] On the other hand, the present invention provides a method for preparing a compound as represented by general formula I or a pharmaceutically acceptable salt, stereoisomer, mixture thereof, or pharmaceutical composition thereof, comprising:

[0029]

[0030] The compound shown in general formula IV reacts with the compound shown in general formula SM-B in the presence of a Grignard reagent to prepare the compound shown in general formula III. The compound shown in general formula III undergoes methanesulfonyl protection and substitution reactions to prepare the compound shown in general formula II. The compound shown in general formula II undergoes deprotection reactions to prepare the compound shown in general formula I.

[0031] Where n can be 0 or 1; R1, R2, R3, R4, R5, R6, R7, R8, R9, R10 R 11 R 12 R 13 R 14 Each is independently selected from H or D, provided that they are not both H; R 15 Independently selected from halogens.

[0032] This invention provides an intermediate for preparing compounds of general formula I or pharmaceutically acceptable salts, stereoisomers, mixtures thereof, or pharmaceutical compositions thereof, as shown in general formula III:

[0033]

[0034] Where: n can be 0 or 1; R1, R2, R3, R4, R5, R6, R9, R 10 R 11 R 12 R 13 R 14 Each is independently selected from H or D, provided that they are not both H; R 15 Independently selected from halogens.

[0035] Further preferred are compounds represented by general formula III, wherein n is 0 or 1, R1, R2, R3 are D, and R4, R5, R6, R7, R8, R9, R 10 R 11 R 12 R 13 R 14 Each is independently selected from H or D; R 15 Selected from fluorine, chlorine, bromine, and iodine.

[0036] Further preferred are compounds represented by general formula III, wherein n is 0 or 1, R1, R2, R3, R7, and R8 are all D, and R4, R5, R6, R9, and R... 10 R 11 R 12 R 13 R 14 Each is independently selected from H or D; R 15 Selected from fluorine, chlorine, bromine, and iodine.

[0037] Further preferred are compounds represented by general formula III, wherein n is 0 or 1, and R 11 R 12 R 13 R 14 Selected from D; R1, R2, R3, R4, R5, R6, R7, R8, R9, R 10 Each is independently selected from H or D; R 15 Selected from fluorine, chlorine, bromine, and iodine.

[0038] Further preferred are compounds represented by general formula III, wherein n is 0 or 1, and R4, R5, R6, R9, R 10 Let D be the coordinates of R1, R2, R3, R7, R8, and R. 11 R 12 R 13 R 14 Each is independently selected from H or D; R 15 Selected from fluorine, chlorine, bromine, and iodine.

[0039] Further preferred are compounds represented by general formula III, wherein n is 0 or 1, and R1, R2, R3, R4, R5, R6, R9, R 10 For D, R7, R8, R 11 R 12 R 13 R 14 Each is independently selected from H or D; R 15 Selected from fluorine, chlorine, bromine, and iodine.

[0040] In a more preferred embodiment of the present invention, the compound represented by general formula III is selected from any of the following compounds:

[0041]

[0042] This invention provides the use of compounds of general formula I or pharmaceutically acceptable salts, stereoisomers, mixtures thereof, or pharmaceutical compositions thereof in the preparation of medicaments for treating neuropsychiatric disorders.

[0043] The present invention also provides a method for treating neuropsychiatric disorders using a compound of formula I or a pharmaceutically acceptable salt, stereoisomer, mixture thereof, or pharmaceutical composition thereof.

[0044] This invention provides the use of compounds of general formula I or pharmaceutically acceptable salts, stereoisomers, mixtures thereof, or pharmaceutical compositions thereof in the preparation of medicaments that modulate NMDAR receptors. The medicament optionally comprises one or more other active agents that modulate the mammalian nervous system or alleviate neuropsychiatric disorders. In preferred embodiments of the invention, the modulation includes, but is not limited to, inhibitory activity, antagonistic activity, partial agonistic activity, partial inhibitory activity, and inverse agonistic activity of the receptor.

[0045] In a preferred embodiment of the present invention, the compound of formula I or a pharmaceutically acceptable salt, stereoisomer or mixture thereof or a pharmaceutical composition thereof acts on the TMD site of the NMDA receptor.

[0046] In a preferred embodiment of the present invention, the neuropsychiatric diseases are selected from pain, schizophrenia, depression, anxiety, sleep disorders, neurodegenerative diseases, bipolar disorder, post-traumatic stress disorder, addictive diseases, withdrawal syndrome, or attention deficit.

[0047] In a preferred embodiment, the neuropsychiatric disorders are selected from pain, depression, anxiety, schizophrenia, sleep disorders, neurodegenerative diseases, or bipolar disorder.

[0048] In a more preferred embodiment, the neuropsychiatric disorders are selected from pain, depression, and neurodegenerative diseases.

[0049] In a preferred embodiment of the present invention, the pain is selected from acute pain and chronic pain, and the chronic pain includes, but is not limited to, headache, maxillofacial pain, nape of the neck and occipital region pain, neck and shoulder pain, upper limb pain, chest pain, abdominal pain, lower back and leg pain, reproductive tract pain, urinary tract pain, and dysmenorrhea.

[0050] In a further preferred embodiment of the present invention, the pain includes, but is not limited to, traumatic pain, inflammatory pain, ischemic pain, pain caused by metabolic diseases, neurogenic pain, pain caused by tissue and organ malformations, childbirth pain, and pain caused by malignant proliferative diseases.

[0051] In a further preferred embodiment of the present invention, the neurogenic pain includes, but is not limited to, phantom limb pain, stump pain, burning neuralgia, postherpetic neuralgia, sympathetic nerve-related pain, and peripheral nerve pain.

[0052] In a further preferred embodiment of the present invention, the pain caused by the metabolic disease includes, but is not limited to, pain caused by gout and pain caused by diabetes.

[0053] In a further preferred embodiment of the present invention, the pain caused by the malignant proliferative disease includes, but is not limited to, pain caused by tumors, such as leukemia, lymphoma, myeloma, breast cancer, lung cancer, esophageal cancer, stomach cancer, colorectal cancer, liver cancer, pancreatic cancer, head and neck cancer, kidney cancer, bladder cancer, prostate cancer, ovarian cancer, endometrial cancer, cervical cancer, osteosarcoma, soft tissue sarcoma, melanoma, and brain tumors.

[0054] In a further preferred embodiment of the present invention, the pain is selected from moderate to severe pain. Preferably, the moderate to severe pain includes, but is not limited to, traumatic pain, childbirth pain, tumor-related pain, and inflammatory pain.

[0055] In a preferred embodiment of the present invention, the neurodegenerative disease includes, but is not limited to, Alzheimer's disease, Parkinson's disease, Huntington's disease, and Lewy body dementia, with Alzheimer's disease being more preferred.

[0056] In a preferred embodiment of the present invention, the depression includes, but is not limited to, mild to severe depression, which generally meets the relevant diagnostic criteria of WHOICD-10 (International Classification of Diseases), DSM-5 (Diagnostic and Statistical Manual of Mental Disorders), and CCMD-3 (Chinese Classification and Diagnostic Criteria of Mental Disorders), and is preferably moderate to severe depression.

[0057] In a preferred embodiment of the present invention, the depression includes, but is not limited to, mild depressive episodes, moderate depressive episodes, severe depressive episodes, depression with or without other psychotic symptoms, and recurrent depressive episodes.

[0058] In one embodiment of the invention, the pharmaceutical composition can be formulated using one or more pharmaceutically acceptable carriers in a conventional manner. Therefore, the active compounds of the invention can be formulated into dosage forms for oral, sublingual, intranasal, parenteral (e.g., intravenous, intramuscular, or subcutaneous), or rectal administration, or suitable for inhalation or insufflation. The compounds of the invention or pharmaceutically acceptable salts thereof can also be formulated into sustained-release dosage forms.

[0059] The pharmaceutical compositions of the present invention can be administered in any manner, provided that they achieve the effect of preventing, alleviating, preventing, or curing symptoms in human or animal patients. For example, they can be formulated into various suitable dosage forms, especially injections, depending on the route of administration, such as lyophilized powder for injection, injection solution, or sterile powder for injection.

[0060] In one embodiment of the invention, an effective dose of the compound of the invention or a pharmaceutically acceptable salt thereof may be taken orally with an inert diluent or a carrier. According to some embodiments of the invention, the compound of the invention may be encapsulated in gelatin capsules or compressed into tablets. For oral therapeutic purposes, the compound of the invention may be used with excipients and in the form of tablets, lozenges, capsules, suspensions, syrups, etc. According to embodiments of the invention, the above-described formulations should contain at least 0.5% (w / w) of the active compound of the invention, but this may vary depending on the specific dosage form, wherein 4% to about 70% by weight is convenient. In such pharmaceutical compositions, the amount of the active compound should reach an appropriate dosage.

[0061] In one embodiment of the invention, regarding oral administration, the active compound of the invention can be formulated into tablets or capsules, for example, by conventional means with pharmaceutically acceptable excipients, such as binders, fillers, lubricants, disintegrants, or wetting agents. Tablets can be coated using methods well known in the art. Liquid formulations for oral administration can be solutions, syrups, or suspensions, or evaporated into a dried product, regenerated with water or other suitable carriers before use. Such liquid formulations can be prepared using pharmaceutically acceptable additives by conventional means, such as suspending agents, emulsifiers, non-aqueous carriers, and preservatives.

[0062] In one embodiment of the present invention, when the active compound of the present invention is used for parenteral administration, the compound provided by the present invention can be combined with sterile water or an organic medium to form an injectable solution or suspension.

[0063] In one embodiment of the present invention, the active compound of the present invention can be formulated into a rectal composition, such as a suppository or retention enema, for example containing a conventional suppository base, such as cocoa butter or other glycerides.

[0064] Unless otherwise stated, the terms used in the specification and claims have the following meanings.

[0065] The carbon or oxygen, or F, Cl, Br, I involved in the groups and compounds described in this invention include their isotopic forms. The carbon or oxygen involved in the groups and compounds described in this invention may optionally be further replaced by one or more of their corresponding isotopes, wherein the isotopes of carbon include... 12 C 13 C and 14 C, oxygen isotopes include 16 O、 17 O and 18 O, isotopes of fluorine include 17 F and 19 F, isotopes of chlorine include 35 Cl、 37 Cl, isotopes of bromine include 79 Br、 81 Br.

[0066] Additionally, it should be noted that, unless otherwise explicitly stated, the description used in this invention as “independently selected” should be interpreted broadly. It can mean that the specific options expressed by the same symbols in different groups do not affect each other, or that the specific options expressed by the same symbols in the same group do not affect each other.

[0067] The term "pharmaceutical acceptable" means that, within the bounds of normal medical judgment, contact with a patient's tissues will not cause undue toxicity, irritation, allergic reactions, etc., and that the benefits and risks are reasonable and that the product is effective for its intended use.

[0068] The compounds of this invention can exist in specific geometric or stereoisomeric forms. This invention contemplates all such compounds, including cis and trans isomers, (-)- and (+)- enantiomers, (R)- and (S)- enantiomers, diastereomers, (D)- isomers, (L)- isomers, and racemic mixtures thereof, as well as other mixtures, such as mixtures enriched with enantiomers or diastereomers, all of which are within the scope of this invention. Additional asymmetric carbon atoms may be present in substituents such as alkyl groups. All such isomers and mixtures thereof are included within the scope of this invention. In some embodiments, the preferred compounds are those isomers exhibiting superior biological activity. Purified or partially purified isomers and stereoisomers of the compounds of this invention, or racemic mixtures or diastereomer mixtures, are also included within the scope of this invention. Purification and separation of such substances can be achieved using standard techniques known in the art.

[0069] Optically pure enantiomers can be obtained by resolving racemic mixtures using conventional methods, such as by forming diastereomer salts using optically active acids or bases, or by forming covalent diastereomers. Mixtures of diastereomers can be separated into individual diastereomers based on their physical and / or chemical differences using methods known in the art (e.g., by chromatography or fractional crystallization). An optically active enantiomer base or acid is then released from the separated diastereomer salt. Another method for separating racemic enantiomers uses chiral chromatography (e.g., chiral HPLC columns), where the separated chiral isomers may be conventionally derivatized or not derivatized prior to separation, depending on which method allows for more efficient separation of the chiral isomers. Enzymatic methods can also be used to separate derivatized or underivatized chiral isomers.

[0070] Furthermore, the compounds of the present invention can exist in the form of tautomers. The present invention includes all possible tautomers of the compounds of the present invention, as well as single tautomers or any mixtures of said tautomers in any proportion.

[0071] The scope of this invention also includes metabolites of the compounds of this invention, i.e., substances formed in the body upon administration of the compounds of this invention. Metabolites of the compounds can be identified using techniques known in the art, and their activity can be characterized by experimental methods. Such products can be generated, for example, by oxidation, reduction, hydrolysis, amidation, deamidation, esterification, enzymatic hydrolysis, etc., of the administered compound. Therefore, this invention includes metabolites of the compounds of this invention, including compounds obtained by methods that expose the compounds of this invention to mammals for a time sufficient to produce their metabolites.

[0072] The term "pharmaceutically acceptable carrier" refers to substances that do not cause significant irritation to the organism and do not impair the biological activity and properties of the active compound. "Pharmaceutically acceptable carriers" include, but are not limited to, glidants, sweeteners, diluents, preservatives, dyes / colorants, flavoring agents, surfactants, wetting agents, dispersants, disintegrants, stabilizers, solvents, or emulsifiers.

[0073] The term "pharmaceutically acceptable salt" refers to any physiologically compatible salt (generally meaning non-toxic, and particularly because it contains ions with opposite charges) when used appropriately for treatment, application, or use, especially for humans and / or mammals. In this invention, especially for use in humans and / or mammals, these physiologically acceptable salts can also be formed from anions or acids. In the context of this invention, especially for use in humans and / or mammals, the aforementioned pharmaceutically acceptable salts should be understood as salts formed by at least one compound provided by this invention—generally protonated, such as in nitrogen—e.g., a cation, and at least one physiologically tolerant anion. In this invention, this definition explicitly includes salts formed by physiologically compatible acids, i.e., salts formed by a specific active compound and a physiologically compatible organic or inorganic acid.

[0074] "Pharmaceutical composition" means a mixture of one or more compounds described in this invention, their pharmaceutically acceptable salts, stereo compounds or mixtures thereof, and other chemical components, wherein "other chemical components" means pharmaceutically acceptable carriers, excipients and / or one or more other therapeutic agents.

[0075] "Excipients" are materials that do not cause significant irritation to organisms and do not eliminate the biological activity and properties of the compound they impart.

[0076] "Administration" or "giving" refers to methods that enable the delivery of a compound or composition to a desired biological site of action. These methods include, but are not limited to, oral or parenteral administration (including intraventricular, intravenous, subcutaneous, intraperitoneal, intramuscular, and intravascular injection or infusion), local administration, and rectal administration. In particular, injection or oral administration.

[0077] "Treatment" includes relieving, reducing, or improving a disease or symptom; preventing other symptoms; improving or preventing underlying metabolic factors of symptoms; inhibiting a disease or symptom, for example, preventing the development of a disease or symptom; reducing a disease or symptom; promoting the remission of a disease or symptom; or causing the cessation of symptoms of a disease or symptom; and extends to include prevention. "Treatment" also includes achieving therapeutic and / or preventive benefits. A therapeutic benefit refers to the eradication or improvement of the treated condition. Furthermore, a therapeutic benefit is achieved by eradicating or improving one or more physical symptoms associated with an underlying disease, whereby an improvement in the patient's condition can be observed even though the patient may still have the underlying disease. A preventive benefit refers to the patient's use of the composition to prevent the risk of a certain disease, or the patient's use when experiencing one or more physical symptoms of a disease, even though the disease has not yet been diagnosed.

[0078] "Active ingredient," "therapeutic agent," "active substance," or "active agent" refers to a chemical entity that can effectively treat or prevent a target disorder, disease, or symptom.

[0079] "Neurological and psychiatric disorders" is a general term for neurological and psychiatric disorders, including neurological and / or psychiatric disorders.

[0080] For the purposes of a drug, drug unit, or active ingredient, an "effective amount," "therapeutic effective amount," or "preventive effective amount" refers to a sufficient dosage of the drug or agent that provides acceptable side effects while achieving the desired therapeutic effect. The determination of an effective amount varies from person to person, depending on the individual's age and general condition, as well as the specific active substance. In a given case, the appropriate effective amount can be determined by a person skilled in the art based on routine testing.

[0081] "Individual" includes humans or non-human animals. Exemplary individuals include human individuals suffering from a disease (such as the disease described herein) (referred to as patients) or normal individuals. In this invention, "non-human animals" includes all vertebrates, such as non-mammals (e.g., birds, amphibians, reptiles) and mammals, such as non-human primates, livestock, and / or domesticated animals (e.g., sheep, dogs, cats, cows, pigs, etc.).

[0082] "Stereoisomers" refer to isomers that are produced by different spatial arrangements of atoms in a molecule, including cis-trans isomers, tautomers, enantiomers, diastereomers, meso-, racemic and conformational isomers.

[0083] The exemplary compounds provided by this invention are as follows:

[0084] Table 1 lists example compounds of general formula I.

[0085]

[0086]

[0087]

[0088] Implementation Plan

[0089] The following detailed description of the invention is intended to illustrate non-limiting embodiments, enabling other skilled in the art to more fully understand the technical solutions, principles, and practical applications of the invention, so that other skilled in the art can modify and implement the invention in many forms to best suit the requirements of a particular application.

[0090] Optically pure enantiomers can be obtained by resolving racemic mixtures using conventional methods, such as by forming diastereomer salts using optically active acids or bases, or by forming covalent diastereomers. Mixtures of diastereomers can be separated into individual diastereomers based on their physical and / or chemical differences using methods known in the art (e.g., by chromatography or fractional crystallization). An optically active enantiomer base or acid is then released from the separated diastereomer salt. Another method for separating racemic enantiomers uses chiral chromatography (e.g., chiral HPLC columns), where the separated chiral isomers may be conventionally derivatized or not derivatized prior to separation, depending on which method allows for more efficient separation of the chiral isomers. Enzymatic methods can also be used to separate derivatized or underivatized chiral isomers.

[0091] Beneficial effects

[0092] The compound provided by this invention is a reversible NMDAR antagonist with moderate affinity for NMDAR. It specifically targets TMD sites, inhibiting channel opening caused by excessive NMDAR activation under pathological conditions, thereby preventing Ca2+ channel opening. 2+ Excessive influx. Compared with commercially available NMDAR antagonists, the compound provided by this invention can rapidly dissociate after binding to NMDAR, thus not affecting the normal function of NMDAR.

[0093] In vitro studies showed that the compound provided by this invention has essentially the same activity as compound 1a1. However, the compound provided by this invention has a faster dissociation rate with NMDAR, which is significantly better than compound 1a1 and comparable to the dissociation rate of memantine and NMDAR. This suggests that the compound provided by this invention not only has significant analgesic and antidepressant activities, but also has a more prominent therapeutic advantage in reducing psychomimetic adverse reactions, and has great clinical value. Detailed Implementation

[0094] The embodiments of the present invention are described in detail below. The embodiments described below are exemplary and are only used to explain the present invention, and should not be construed as limiting the present invention. Unless otherwise specified, all proportions, percentages, etc., referred to herein are by weight.

[0095]

[0096] The compound shown in general formula IV reacts with the compound shown in general formula SM-B under the action of a base to prepare the compound shown in general formula III. The compound shown in general formula III is prepared into the compound shown in general formula II through methanesulfonyl protection and substitution reaction. The compound shown in general formula II is prepared into the compound shown in general formula I through deprotection reaction.

[0097] Where n can be 0 or 1; R1, R2, R3, R4, R5, R6, R7, R8, R9, R 10 R 11 R 12 R 13 R 14 Each is independently selected from H or D, provided that they are not both H; R 15 Selected from halogens.

[0098] Some specific embodiments of the present invention, wherein R1, R2, R3, R4, R5, R6, R7, R8, R9, R 10 Each is independently selected from H or D, provided that they are not both H; R 15 Selected from halogens.

[0099] In some specific embodiments of the present invention, at least one of R1, R2, R3, R7, and R8 is D; R 15 Selected from fluorine, chlorine, bromine, and iodine.

[0100] In some specific embodiments of the present invention, at least one of R1, R2, and R3 is D.

[0101] In some specific embodiments of the present invention, at least two of R1, R2, and R3 are D.

[0102] In some specific embodiments of the present invention, R1, R2, and R3 are all D.

[0103] In a preferred embodiment of the present invention, the compound of general formula IV is reacted with the compound of general formula SM-B in an organic solvent under the action of a Grignard reagent to prepare the compound of general formula III. For example, under nitrogen protection, at a temperature of -20 to 60°C, isopropyl magnesium chloride is added in portions to a suitable solvent such as THF to react the compound of general formula IV with the compound of general formula SM-B to obtain the compound of general formula III. The compound of general formula III is then reacted with methanesulfonyl chloride under organic base and organic solvent conditions to prepare the corresponding methanesulfonyl ester compound, which is then reacted with phthalimide and an inorganic base (or an inorganic alkali metal salt of phthalimide) in an organic solvent to prepare the compound of general formula II. Under nitrogen protection, at 0°C, the compound of general formula III, triethylamine, and methanesulfonyl chloride are added to a suitable solvent such as dichloromethane. The mixture is then heated to room temperature and reacted for 0.5–3 hours to give the corresponding methanesulfonyl ester compound. Optionally, the product is dissolved without separation in a suitable solvent such as dimethylformamide, and phthalimide, an inorganic base (such as potassium carbonate or cesium carbonate), or PhthNK / KI are added. The mixture is then heated to 70–140°C and reacted for 2–16 hours to give the compound of general formula II. The compound of general formula II is then reacted with a deprotecting agent, such as ethanolamine or hydrazine hydrate-d6, to prepare the compound of general formula I.

[0104] The present invention further provides a method for preparing a compound as shown in general formula IV, comprising:

[0105]

[0106] There are two methods for preparing the compound represented by formula IV.

[0107] Method 1: The compound of general formula V is prepared into the compound of general formula IV through a cyclization reaction;

[0108] or

[0109] Method 2: The compound shown in general formula VIII is reacted with the compound shown in general formula (SM-A) to prepare the compound shown in general formula VII. The compound shown in general formula VII is reacted with chloroacetyl chloride to prepare the compound shown in general formula VI. The compound shown in general formula VI is prepared by Friedel-Crafts reaction to prepare the compound shown in general formula IV.

[0110] Where n can be 0 or 1; R1, R2, R3, R4, R5, R6, R7, R8, R9, R 10 R 11 R 12 R 13 R 14 R 15 As defined above, X is a halogen.

[0111] In a preferred embodiment of the present invention, for example, in method one, the compound of general formula V is reacted with paraformaldehyde or deuterated paraformaldehyde in the presence of Eaton's reagent to prepare the compound of general formula IV. For instance, under nitrogen protection, the compound of general formula V and paraformaldehyde are reacted with Eaton's reagent as a solvent at a temperature of 60-80°C for 30 minutes to 2 hours to obtain the compound of general formula IV.

[0112] In a preferred embodiment of the present invention, for example, in method two, the compound of general formula VIII is reacted with the compound of general formula SM-A in an organic solvent to prepare the compound of general formula VII. For example, under nitrogen protection, at 0°C, in a suitable solvent, such as tetrahydrofuran (THF), a suitable base, such as triethylamine, is added to the compound of general formula VIII, followed by the addition of the compound of SM-A, and the mixture is heated under reflux for 1-2 hours to obtain the compound of general formula VII. The compound of general formula VII is reacted with chloroacetyl chloride in an organic solvent to prepare the compound of general formula VI. For example, at room temperature, in a suitable solvent, such as acetonitrile, the compound of general formula VII is reacted with the compound of general formula chloroacetyl chloride for 1-2 hours to obtain the compound of general formula VI. The compound of general formula VI is reacted with aluminum trichloride to prepare the compound of general formula IV. For example, at room temperature, the compound of general formula VI is heated to 140°C and reacted with aluminum trichloride for 4-6 hours to obtain the compound of general formula IV.

[0113] Synthesis Examples

[0114] Example 1: trans-3-amino-6'-chloro-2'-(methyl-d3)-1',2'-dihydro-3'H-spiro[cyclobutane-1,4'-isoquinoline]-3'-one (NH200102-A-D1)

[0115]

[0116] Step 1: 2-(3-chlorophenyl)-N-(methyl-d3)acetamide (NH200102-A-D1-int1)

[0117] 3-Chlorophenylacetic acid (2.9 g), deuterated methylamine hydrochloride (1 g), EDCI (4.07 g), HOBt (2.87 g), triethylamine (4.3 g), and DCM (20 mL) were added sequentially to a 100 mL single-necked flask, and the mixture was stirred overnight at room temperature. After the reaction was complete, 50 mL of water was added, and the aqueous phase was extracted three times with 60 mL of DCM until no product was found in the aqueous phase. The combined organic phases were washed with saturated sodium bicarbonate and then with saturated brine. The mixture was dried over anhydrous sodium sulfate, filtered, and concentrated to give 3.17 g of crude product, with a yield of 100%.

[0118] Step 2: 6-Chloro-2-(methyl-d3)-1,4-dihydroisoquinoline-3(2H)-one (NH200102-A-D1-int2)

[0119] In a 50 mL single-necked flask, NH200102-A-D1-int1 (3.17 g), paraformaldehyde (0.77 g), and 12 mL of Leaton's reagent were added. The mixture was stirred at 80 °C for 2 hours under nitrogen protection. After the reaction was complete, 70 mL of water and 25 mL of dichloromethane were added for extraction to obtain the organic phase. The organic phase was concentrated under reduced pressure to obtain the crude product, which was separated by column chromatography (petroleum ether: ethyl acetate = 2:1) to give 1.1 g of the yellow solid title compound, with a yield of 32.6%.

[0120] Step 3: 6'-Chloro-3-hydroxy-2'-(methyl-d3)-1',2'-dihydro-3'H-spiro[cyclobutane-1,4'-isoquinoline]-3'-one (NH200102-A-D1-int3)

[0121] In a 50 mL single-necked flask, 1.1 g of NH₂₀₁₀₂-A-D₁-int₂ was dissolved in 10 mL of tetrahydrofuran (THF). Under nitrogen protection, 6.1 mL of isopropyl magnesium chloride was added at -25 °C, and the mixture was stirred at 45 °C for 1 hour. At 0 °C, 5 mL of a THF solution containing 0.92 g of epichlorohydrin was added, and the reaction was carried out at room temperature for 1 hour. Then, 5.5 mL of isopropyl magnesium chloride was added, and the mixture was stirred at room temperature for 1 hour, followed by incubation at 60 °C overnight. After the reaction was complete, 60 mL of water and 100 mL of ethyl acetate were added for extraction to obtain the organic phase. The organic phase was concentrated under reduced pressure to obtain the crude product, which was separated by column chromatography (dichloromethane:methanol = 20:1) to obtain 1.4 g of the title compound as a yellow oil.

[0122] Step 4: 6'-chloro-2'-(methyl-d3)-3'-oxo-2',3'-dihydro-1'H-spiro[cyclobutane-1,4'-isoquinoline]-3-ylmethanesulfonate (NH200102-A-D1-int4)

[0123] In a 50 mL single-necked flask, 1.4 g of NH₂₀₁₀₂-A-D₁-int₃ dissolved in 20 mL of dichloromethane was added. Triethylamine (1.26 g) was added at 0 °C, followed by dropwise addition of methanesulfonyl chloride (1.67 g). The mixture was stirred at room temperature for 1 hour. After the reaction was complete, 50 mL of water was added to quench the reaction. The aqueous phase was extracted three times with 40 mL of dichloromethane. The organic phases were combined and concentrated under reduced pressure. The crude product was separated by column chromatography (PE:EA = 2:1-1:1) to give 740 mg of the title compound, with a yield of 40.5%.

[0124] Step 5: 2-trans-6'-chloro-2'-(methyl-d3)-3'-oxo-2',3'-dihydro-1'H-spiro[cyclobutane-1,4'-isoquinoline]-1,3-dione (NH200102-A-D1-int5)

[0125] In a 50 mL single-necked flask, NH₂₀₁₀₂-A-D₁-int 4 (740 mg), potassium phthalimide (1.23 g), potassium iodide (74 mg), and 10 mL of N,N-dimethylformamide were added, and the mixture was stirred at 140 °C for 6 hours. After the reaction was completed, 50 mL of water was added to quench the reaction, and the aqueous phase was extracted three times with 40 mL of ethyl acetate. The organic phases were combined, concentrated under reduced pressure, and the crude product was separated by column chromatography (PE:EA = 2:1-1:1) to give 230 mg of the title compound, with a yield of 27.0%.

[0126] Step 6: 3-Amino-6'-chloro-2'-(methyl-d3)-1',2'-dihydro-3'H-spiro[cyclobutane-1,4'-isoquinoline]-3'-one (NH200102-mix-D1)

[0127] In a 50 mL single-necked flask, 230 mg of NH₂₀₁₀₂-A-D₁-int 5 and 5 mL of ethanolamine were added, and the mixture was stirred at 70 °C for 4 hours. After the reaction was completed, 40 mL of water was added to quench the reaction, and the aqueous phase was extracted three times with 40 mL of dichloromethane. The organic phases were combined, and the organic phase was concentrated under reduced pressure to obtain a crude product. After separation by a pre-prepared plate (dichloromethane:methanol = 10:1), 100 mg of a yellow solid with a purity of 96.6% was obtained.

[0128] Step 7: trans-3-amino-6'-chloro-2'-(methyl-d3)-1',2'-dihydro-3'H-spiro[cyclobutane-1,4'-isoquinoline]-3'-one (NH200102-A-D1) and cis-3-amino-6'-chloro-2'-(methyl-d3)-1',2'-dihydro-3'H-spiro[cyclobutane-1,4'-isoquinoline]-3'-one (NH200102-B-D1)

[0129] NH200102-mix-D1 was prepared and separated by HPLC (Mobile Phase A: H2O (0.1% TFA, Mobile Phase B: CAN, Column: C18, 5um, 4.6x250mm, Flow rate: 15mL·min-1) to obtain NH200102-A-D1 and NH200102-B-D1 respectively.

[0130] NH200102-A-D1: 1[M+H] + 254.1;

[0131] NH200102-B-D1: 1 [M+H] + 254.1.

[0132] Example 2: trans-3-(amino-d2)-6'-chloro-2'-methyl-1',2'-dihydro-3'H-spiro[cyclobutane-1,4'-isoquinoline]-3'-one (NH200102-A-D2)

[0133]

[0134] The target compound was prepared by replacing the deuterated methylamine hydrochloride in step 1 of Example 1 with methylamine hydrochloride, and replacing the ethanolamine in step 6 of Example 1 with hydrazine hydrate-d6.

[0135] 1 H NMR(400MHz,CD3OD)δ7.65(d,J=4.0Hz,1H),7.31-7.23(m,2H),4.51(s,2H), 4.00-3.96(m,1H),3.03-2.97(m,2H),2.89(s,3H),2.45–2.39(m,2H);[M+H] + 253.1.

[0136] Example 3: trans-3-(amino-d2)-6'-chloro-2'-(methyl-d3)-1',2'-dihydro-3'H-spiro[cyclobutane-1,4'-isoquinoline]-3'-one

[0137]

[0138] The target compound was prepared by replacing the ethanolamine in step 6 of Example 1 with hydrazine hydrate-d6, and following the method described in the Example.

[0139] 1[M+H] + 256.2.

[0140] Example 4: trans-3-amino-6'-chloro-2'-methyl-1',2'-dihydro-3'H-spiro[cyclobutane-1,4'-isoquinoline]-3'-one-1',1'-d2

[0141]

[0142] LCMS: [M+H] + 253.2;

[0143] The target compound was prepared by replacing the deuterated methylamine hydrochloride in step 1 of Example 1 with methylamine hydrochloride and the paraformaldehyde in step 2 with deuterated paraformaldehyde, according to the method of Example 1.

[0144] Example 5: trans-3-amino-6'-chloro-2'-methyl-1',2'-dihydro-3'H-spiro[cyclobutane-1,4'-isoquinoline]-3'-one--2,2,3,4,4-d5

[0145]

[0146] LCMS: [M+H] + 256.1;

[0147] The target compound was prepared by replacing the deuterated methylamine hydrochloride in step 1 of Example 1 with methylamine hydrochloride and the epichlorohydrin in step 3 with deuterated epichlorohydrin, according to the method of Example 1.

[0148] Example 6: trans-3-amino-6'-chloro-2'-(methyl-d3)-1',2'-dihydro-3'H-spiro[cyclobutane-1,4'-isoquinoline]-3'-one-2,2,3,4,4-d5

[0149]

[0150] The epichlorohydrin in step 3 of Example 1 was replaced with deuterated epichlorohydrin, and the target compound was prepared according to the method of Example 1.

[0151] LCMS: [M+H] + 259.1.

[0152] Example 7: trans-3'-amino-6-chloro-3-(methyl-d3)-4,5-dihydrospiro[benzo[d]aza-1,1'-cyclobutane]-2(3H)-one (NH200168-A-D1)

[0153]

[0154] Step 1: 2-(2-chlorophenyl)-N-(methyl-d3)ethyl-1-amine (NH200168-A-int1)

[0155] In a 100 mL single-necked flask, triethylamine (2.76 g) was dissolved in 25 mL of tetrahydrofuran. Deuterated methylamine hydrochloride (1.93 g) was added in portions at 0 °C. After stirring at this temperature for 0.5 h, a tetrahydrofuran solution of 1-(2-bromoethyl)-2-chlorobenzene (18.22 mmol) (25 mL) was added. The flask was sealed and heated under reflux with stirring for 1.5 h. After the reaction was complete, the solution was directly evaporated to dryness and recrystallized from isopropanol to give 3.2 g of the title compound, with a yield of 95.5%.

[0156] Step 2: 2-Chloro-N-(2-Chlorophenyl)-N-(Methyl-d3)acetamide (NH200168-A-int 2)

[0157] In a 50 mL single-necked flask, 3.2 g of NH200168-A-int 1 (17.4 mmol) was dissolved in acetonitrile (10 mL). Triethylamine (2.3 g) and chloroacetyl chloride (2.36 g) were added at 0 °C, and the mixture was heated to room temperature and stirred for 1.5 hours. After the reaction was complete, 50 mL of water was added to quench the reaction. The mixture was extracted three times with 40 mL of ethyl acetate. The organic phases were combined and concentrated under reduced pressure to obtain the crude product. Separation by column chromatography (PE:EA = 10:1) yielded 1.87 g of the title compound, with a yield of 41.9%.

[0158] Step 3: 6-Chloro-3-(methyl-d3)-1,3,4,5-tetrahydro-2H-benzo[d]aza-2-one (NH200168-A-int 3)

[0159] In a 50 mL single-necked flask, 1.87 g of NH₂₀₁₆₈-A-int ₂ and 2.9 g of AlCl₃ were added. The mixture was heated to 140 °C and stirred for 5 hours under nitrogen protection. After the reaction was completed, 50 mL of water was added to quench the reaction. The mixture was extracted three times with 40 mL of ethyl acetate. The organic phases were combined and concentrated under reduced pressure to obtain the crude product. The crude product was separated by column chromatography (PE:EA = 3:1) to give 650 mg of the title compound, with a yield of 40.6%.

[0160] Step 4: trans-3'-amino-6-chloro-3-(methyl-d3)-4,5-dihydrospiro[benzo[d]aza-1,1'-cyclobutane]-2(3H)-one (NH200168-A-D1)

[0161] Replace NH200102-A-int 3 with NH200168-A-int 3, and prepare the target compound using a method similar to steps 4-7 of Example 1. LCMS: [M+H] + 268.1.

[0162] Example 8: trans-3'-(amino-d2)-6-chloro-3-methyl-4,5-dihydrospiro[benzo[d]aza-1,1'-cyclobutane]-2(3H)-one (NH200168-A-D2)

[0163]

[0164] The target compound was prepared by replacing the deuterated methylamine hydrochloride in step 1 of Example 7 with methylamine hydrochloride and the ethanolamine with hydrazine hydrate-d6, following a similar method to Example 7. LCMS: [M+H] + 267.1.

[0165] Example 9 trans-3'-(amino-d2)-6-chloro-3-(methyl-d3)-4,5-dihydrospiro[benzo[d]aza-1,1'-cyclobutane]-2(3H)-one

[0166]

[0167] The target compound was prepared by replacing ethanolamine with hydrazine hydrate-d6 in Example 7, following a similar method to Example 7. LCMS: [M+H] + 270.1.

[0168] Example 10: trans-3'-amino-6-chloro-3-methyl-4,5-dihydrospiro[benzo[d]aza-1,1'-cyclobutane]-2(3H)-one-4,4,5,5-d4

[0169]

[0170] The target compound was prepared by replacing the deuterated methylamine hydrochloride in step 1 of Example 7 with methylamine hydrochloride, and replacing 1-(2-bromoethyl)-2-chlorobenzene with 1-(2-bromoethyl-1,1,2,2-d4)-2-chlorobenzene, following a similar method to Example 7. LCMS: [M+H] + 269.1.

[0171] Example 11 trans-3'-amino-6-chloro-3-methyl-4,5-dihydrospiro[benzo[d]aza-1,1'-cyclobutane]-2(3H)-one-2', 2',3',4',4'-d5

[0172]

[0173] The target compound was prepared by replacing deuterated methylamine hydrochloride with methylamine hydrochloride and epichlorohydrin with deuterated epichlorohydrin in step 1 of Example 7, following a similar method to Example 7. LCMS: [M+H] + 270.0.

[0174] Example 12 trans-3'-amino-6-chloro-3-(methyl-d3)-4,5-dihydrospiro[benzo[d]aza-1,1'-cyclobutane]-2(3H)-one-2',2',3',4',4'-d5

[0175]

[0176] The target compound was prepared by replacing the epichlorohydrin in step 4 of Example 7 with deuterated epichlorohydrin, following a similar method to Example 7. LCMS: [M+H] + 273.2.

[0177] Test case

[0178] Test Example 1: NMDAR Inhibitory Activity

[0179] Test drug: Compound 1a1 was prepared according to the method in CN106957285A, and its structure is shown below:

[0180]

[0181] NH200102-A-D1 was prepared according to the above embodiments, and its structural formula is shown below:

[0182]

[0183] Negative control: Weigh an appropriate volume of DMSO as the storage solution.

[0184] Test compound: Weigh an appropriate mass of the compound (actual amount = theoretical concentration × volume × molecular weight / purity). Calculate the required volume of DMSO using the formula, and then convert this to the final required mass of DMSO. Next, dissolve the powder in the weighed DMSO using ultrasonication. Calculate the actual stock solution concentration based on the final amount of DMSO used. Generally, the actual stock solution concentration will slightly differ from the theoretical concentration. If there are solubility issues, adjust the stock solution concentration accordingly.

[0185] Preparation method of working solution for drug delivery formulation: Before channel current testing, dilute the negative control and test compound stock solution into an appropriate amount of extracellular fluid to prepare the working solution. See the table below for details:

[0186] Table 2. Administration methods and test concentrations

[0187]

[0188] Experimental protocol

[0189] Cell line selection

[0190] In this experiment, the HEK293 cell line stably expressing the rat NR1 / NR2B genes was used, with gene numbers NR1: NM_017010; NR2B: NM_012574.

[0191] Concentration selection criteria

[0192] In this experiment, the detection concentrations of the test compounds were 0.3 μM, 1 μM, 3 μM, 10 μM, and 30 μM. The negative control was 0.1% DMSO.

[0193] Preparation of the liquid for testing

[0194] Extracellular fluid: 140mM NaCl, 4mM KCl, 2mM CaCl2, 10mM HEPES, 5mM D-Glucose pH=7.4 (NaOH).

[0195] Intracellular fluid: 10mM NaCl, 135mM CsMes, 2mM MgCl2, 10mM HEPES, 10mM EGTA, 2mM Na2-ATP, 0.2mM Na2-GTP, pH=7.2 (CsOH).

[0196] After preparing the electrode internal solution, aliquot it into 1 mL tubes and store them at -20°C. Use freshly thawed electrode internal solution for each experiment. All electrode internal solutions should be used within one month. After one month, discard the old electrode internal solution and prepare fresh solution.

[0197] The patch clamp testing method is as follows:

[0198] A capillary glass tube (BF150-86-10, Sutter Instruments) was drawn into a recording electrode using a microelectrode drawing instrument (P97, Sutter Instruments). Under an inverted microscope (Olympus, IX71), the microelectrode manipulator (Sutter Instruments, MP285) was used to bring the recording electrode into contact with the cell, and negative pressure was applied to aspirate and form a GΩ seal. After forming the GΩ seal, rapid capacitance compensation was performed, and then negative pressure was continued to rupture the cell membrane, forming a whole-cell recording mode. Slow capacitance compensation was then performed, and membrane capacitance and series resistance were recorded. No leakage compensation was applied.

[0199] A coverslip containing cells was placed in the recording bath of an inverted microscope to form a whole-cell seal. Under normal extracellular fluid perfusion, NMDA and the test compound were sprayed onto the cell surface using a rapid jet drug delivery system, and the NMDA current was recorded. The test compound reaching the cell surface was rapidly carried away by the extracellular fluid. Multiple cells were independently and repeatedly tested. All electrophysiological experiments were performed at room temperature.

[0200] The voltage stimulation protocol for whole-cell patch-clamp recording of whole-cell NMDA currents is as follows: After whole-cell sealing is achieved, the cell membrane voltage is clamped at -70mV or -60mV. The drug administration sequence is as follows:

[0201] Step 1: Extracellular fluid (NMDA 100μM + glycine 10μM);

[0202] Step 2: Extracellular fluid (NMDA 100μM + glycine 10μM + test compound (0.3μM));

[0203] Step 3: Extracellular fluid (NMDA 100μM + glycine 10μM);

[0204] Step 4: Extracellular fluid (NMDA 100μM + glycine 10μM + test compound (1μM));

[0205] Step 5: Extracellular fluid (NMDA 100μM + glycine 10μM);

[0206] Step 6: Extracellular fluid (NMDA 100μM + glycine 10μM + test compound (3μM));

[0207] Step 7: Extracellular fluid (NMDA 100μM + glycine 10μM);

[0208] Step 8: Extracellular fluid (NMDA 100μM + glycine 10μM + test compound (10μM));

[0209] Step 9: Extracellular fluid (NMDA 100μM + glycine 10μM);

[0210] Step 10: Extracellular fluid (NMDA 100μM + glycine 10μM + test compound (30μM)).

[0211] Data Analysis

[0212] First, the current and blank control current after treatment with different concentrations of each analyte were standardized, and the corresponding inhibition rates were calculated. For each concentration, the mean and standard error were calculated, and the half-maximal inhibitory concentration (WMC) of each analyte was calculated using the following equation:

[0213] inhibition = 1 / [1+(IC) 50 / C) h ]

[0214] The dose-dependent effect was nonlinearly fitted using the above equation, where C represents the drug concentration, and IC50 is the concentration of the drug. 50 The half-inhibitory concentration (IC50) is represented by h, which represents the Hill coefficient. Curve fitting and IC50 are also mentioned. 50 The calculations were performed using the IGOR software.

[0215] Table 3 Results of NMDAR inhibitory activity test

[0216] Test compounds <![CDATA[IC 50 (μM)]]> Compound 1a1 0.99 NH200102-A-D1 2.2

[0217] in conclusion

[0218] The above results show that the compounds provided by this invention have good inhibitory activity against NMDAR. Most of the compounds provided by this invention are basically equivalent to or similar to compound 1a1, suggesting the potential for good clinical treatment of neuropsychiatric diseases.

[0219] Safety evaluation of target-selective action in Test Example 2

[0220] Off-target effects of test compounds on 44 selected targets (24 GPCR targets, 3 neurotransmitter transporters, 2 nuclear receptors, 7 enzymes, and 8 ion channel targets; targets refer to: Bowes J., et al. 2012. Reducing safety related drug attrition: the use of in vitro pharmacochemical profiling. Nat Rev Drug Discovery. 11(12):909-922.) were mainly evaluated using radioisotope binding methods, calcium flow detection methods, patch-clamp techniques, and enzymatic fluorescence or chemiluminescence techniques to assess the safety of test compounds on these targets.

[0221] The experimental protocol for the radioactive isotope binding method is as follows:

[0222] 1) Filtering method receptor binding experiment

[0223] Experimental buffer: 50mM Tris-HCl, pH 7.4; Wash buffer: 50mM Tris-HCl, pH 7.4; Incubation time / temperature: 1hr / RT.

[0224] Dilute cell membrane proteins to the specified concentration using experimental buffer; dilute radioactive isotope ligands to the specified concentration using experimental buffer. Positive compounds are serially diluted 4-fold at 8 spots, and test compounds are diluted to 2 mM. Transfer 1 μL of the diluted compound to the reaction plate according to the compound arrangement diagram. The final concentration of the test compound is 10 μM (or 100 μM). Transfer 1 μL of the prepared nonspecific binding compound and DMSO to the reaction plate, designated as nonspecific binding wells (low signal control: LC) and total binding wells (high signal control: HC), respectively. Add 100 μL of the specified concentration of cell membrane protein according to the reaction plate arrangement. Then add 100 μL of the specified concentration of radioactive isotope. After sealing the plate, incubate on a shaker at the specified temperature for the specified time. Immerse in 50 μL of 0.3% PEI solution at room temperature for at least half an hour. After the reaction is complete, collect the cell membranes onto a GF / C filter plate using CellHarvest and wash four times with cold wash buffer. The GF / C plate was dried in a 50°C oven for 1 hour. The bottom of the dried GF / C filter plate was sealed with a membrane, 50 μL of scintillation solution was added to each well, and the plate was sealed. Readings were performed using a MicroBeta2 reader.

[0225] Calculation formula: % Inhibition rate = 100 × [1 - (sample well reading - non-specific binding well reading) / (total binding well reading - non-specific binding well reading)].

[0226] The data was analyzed using the model "log(inhibitor) vs. response--Variableslope" in GraphPad Prism 5.0.

[0227] 2) Nuclear acceptor binding experiment

[0228] Dilute the cytosolic solution to the specified concentration using experimental buffer. Dilute the radioisotope ligand to the specified concentration using experimental buffer. Perform 8-point, 4-fold serial dilutions for positive compounds, and dilute the test compound to 2 mM. Transfer 1 μL of the diluted compound to the reaction plate according to the compound arrangement diagram. The final concentration of the test compound is 10 μM (or 100 μM). Transfer 1 μL of the prepared nonspecific binding compound and DMSO to the reaction plate, designated as nonspecific binding wells (low signal control: LC) and total binding wells (high signal control: HC), respectively. Add 100 μL of the specified concentration of cytosolic solution according to the arrangement of the reaction plate. Then add 100 μL of the specified concentration of radioisotope. After sealing the plate, incubate it on a shaker at the specified temperature for the specified time. After the reaction was complete, 100 μL of buffer solution for absorbing the free isotopes (10 mM Tris-HCl, pH 7.4, 1.5 mM EDTA, 1 mM DTT, 0.25% charcoal, 0.0025% dextran) was added, and the mixture was incubated on a shaker at 4°C for 15 minutes. The reaction plate was then centrifuged at 4600 rpm for 30 minutes at 4°C. 100 μL of the supernatant was transferred to a scintillation tube, and 2 mL of scintillation solution was added. Liquid scintillation readings were performed using TriCarb.

[0229] Calculation formula: % Inhibition rate = 100 × [1 - (Sample well reading - Non-specific binding well reading) / (Total binding well reading - Non-specific binding well reading)]

[0230] The data was analyzed using the model "log(inhibitor) vs. response--Variableslope" in GraphPad Prism 5.0.

[0231] The effects of the tested compounds on 23 GPCRs (ADORA2A, Alpha1A, Alpha2A, β1, β2, CB1, CB2, CCKa, D1, D2, H1, H2, op-delta, op-kappa, op-mu, M1, M2, M3, 5HT1A, 5HT1B, 5HT2A, 5HT2B and V1A), 6 ion channels (nAChR-Alpha7, Ca2+-L, GABAA, hERG, NMDA and 5HT3), 3 neurotransmitter transporters (DAT, NET and 5HTT) and 2 nuclear receptors (AR and GR) targets were examined using radioisotope ligand binding assays.

[0232] Experimental results showed that when the test concentration of the tested compound was 10 μM, it had binding activity with Alpha1A, NMDA, H1 and D2 targets (inhibition rate ≥50%), but no significant binding activity with the other 30 targets (inhibition rate <50%). Among them, the relative inhibition rate of compound NH200102-A-D1 on the above targets was between 50% and 85%.

[0233] When the test concentration of the tested compound was 100 μM, it showed binding activity against the targets Alpha2A, NMDA, 5HT2A, H1, M1, M2, M3, Alpha1A, D2, H2, and 5HT1A (inhibition rate ≥ 50%), but no significant binding activity against the other 23 targets (inhibition rate < 50%). Among them, the test compound NH200102-A-D1, at a test concentration of 100 μM, showed relative inhibition rates of 50% to 99.8% against the targets Alpha2A, NMDA, 5HT2A, H1, M1, M2, M3, Alpha1A, D2, H2, and 5HT1A.

[0234] This demonstrates that the deuterated compounds of the present invention possess good target selectivity and safety, as well as moderate affinity for NMDA receptor channels.

[0235] Test Example 3: Dissociation Rate Detection

[0236] Taking compound NH200102-A-D1 as an example, and N-methyl-D-aspartic acid (NMDA) as a positive control, the dissociation rates of NH200102-A-D1, compound 1a1, ketamine, and memantine with NMDAR were detected using a patch-clamp assay. The experimental procedures were performed according to Test Example 2 in PCT / CN2020 / 129826. The experimental results showed that the dissociation rate of compound NH200102-A-D1 was significantly faster than that of other test drug compounds 1a1 and ketamine, comparable to that of memantine, suggesting that the compound of this invention can rapidly dissociate with NMDAR and has the potential for good clinical tolerability.

[0237] The above embodiments are only for illustrating the technical concept and features of the present invention, and are intended to enable those skilled in the art to understand the content of the present invention and implement it accordingly. They should not be construed as limiting the scope of protection of the present invention. All equivalent changes or modifications made in accordance with the spirit and essence of the present invention should be covered within the scope of protection of the present invention.

Claims

1. A compound of general formula I or a pharmaceutically acceptable salt, stereoisomer, or mixture thereof, in, n is 0; R1, R2, R3, R4, R5, R6, R7, R8, R9, R 10 R 11 R 12 R 13 R 14 Each is independently selected from H or D, provided that they are not both H; R 15 Selected from halogens.

2. The compound according to claim 1, or a pharmaceutically acceptable salt, stereoisomer, or mixture thereof, wherein R1, R2, R3, R4, R5, R6, R7, R8, R9, R 10 At least one is D; R 15 Selected from fluorine, chlorine, bromine, and iodine.

3. The compound according to claim 2, or a pharmaceutically acceptable salt, stereoisomer, or mixture thereof, wherein at least one of R1, R2, R3, R7, and R8 is D; R 15 Selected from fluorine, chlorine, bromine, and iodine.

4. The compound according to claim 1, or a pharmaceutically acceptable salt, stereoisomer, or mixture thereof, wherein R 11 R 12 R 13 R 14 At least one is D; R 15 Selected from fluorine, chlorine, bromine, and iodine.

5. The compound according to claim 1, or a pharmaceutically acceptable salt, stereoisomer, or mixture thereof, wherein R1, R2, and R3 are all selected from D; R 15 Selected from fluorine, chlorine, bromine, and iodine.

6. The compound according to any one of claims 1-5, or a pharmaceutically acceptable salt, stereoisomer, or mixture thereof, wherein the compound is selected from one of the following structures: 。 7. A pharmaceutical composition comprising the compound of any one of claims 1-6 or a pharmaceutically acceptable salt, stereoisomer, or mixture thereof, and one or more pharmaceutically acceptable carriers and / or excipients.

8. An intermediate for preparing the compound as described in any one of claims 1-6, or a pharmaceutically acceptable salt, stereoisomer, or mixture thereof, having the structure shown in general formula III: in: n is 0; R1, R2, R3, R4, R5, R6, R9, R 10 R 11 R 12 R 13 R 14 R 15 As defined in any one of claims 1 to 6.

9. Use of the compound of any one of claims 1-6, or a pharmaceutically acceptable salt, stereoisomer, or mixture thereof, or the pharmaceutical composition of claim 7, in the preparation of a medicament for treating neuropsychiatric disorders.

10. The use according to claim 9, wherein the neuropsychiatric disease is selected from: pain, schizophrenia, depression, anxiety, sleep disorders, neurodegenerative diseases, bipolar disorder, post-traumatic stress disorder, addictive diseases, withdrawal syndrome, or attention deficit.

11. Use of the compound of any one of claims 1-6, or a pharmaceutically acceptable salt, stereoisomer, or mixture thereof, or the pharmaceutical composition of claim 7, in the preparation of a medicament for regulating the NMDAR receptor; wherein, The drug may optionally also contain one or more other active agents that regulate the mammalian nervous system or alleviate neuropsychiatric disorders.

12. A method for preparing a compound of general formula I or a pharmaceutically acceptable salt, stereoisomer, or mixture thereof, comprising the following steps: ， The compound shown in general formula IV reacts with the compound shown in general formula SM-B under the action of Grignard reagent to prepare the compound shown in general formula III. The compound shown in general formula III reacts with methanesulfonyl chloride under organic base and organic solvent conditions to prepare a methanesulfonyl ester compound. Then, it reacts with phthalimide and an inorganic base in an organic solvent to obtain the compound shown in general formula II. The compound shown in general formula II is prepared into the compound shown in general formula I through a deprotection reaction. in: n is 0; R1, R2, R3, R4, R5, R6, R7, R8, R9, R 10 R 11 R 12 R 13 R 14 R 15 As defined in any one of claims 1 to 6.

13. The method according to claim 12, wherein, The compound represented by general formula IV is prepared by the following method: Method 1: The compound represented by general formula V is reacted with paraformaldehyde or deuterated paraformaldehyde in the presence of Eaton's reagent to prepare the compound represented by general formula IV; Alternatively, Method 2: The compound shown in general formula VIII is reacted with the compound shown in general formula SM-A to prepare the compound shown in general formula VII; the compound shown in general formula VII is reacted with chloroacetyl chloride to prepare the compound shown in general formula VI; and the compound shown in general formula VI is prepared by Friedel-Crafts reaction to prepare the compound shown in general formula IV. Where n is 0; R1, R2, R3, R4, R5, R6, R7, R8, R9, R 10 R 11 R 12 R 13 R 14 R 15 As defined in any one of claims 1 to 6, X is a halogen.

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