WO2025011640A1 - Memantine derivative, pharmaceutical composition thereof, and use thereof - Google Patents

Abstract

Provided in the present invention are a memantine derivative or a stereoisomer, solvate or pharmaceutically acceptable salt thereof, a pharmaceutical composition thereof, and the use of same in preparing drugs for preventing and/or treating central nervous system diseases, especially Alzheimer's disease, Parkinson's disease or other neurodegenerative diseases. The compound of the present invention has low water solubility and thus can be prepared into suspension formulations well. The compound has a low dissolution rate in a living body, and simply by one time of administration, can achieve a drug efficacy lasting for several weeks, thus reducing the number of times of administration for patients, improving the compliance of patients while ensuring the curative effects, and having good prospects of application.

Description

Memantine derivatives, pharmaceutical compositions and uses thereof Technical Field

The present invention relates to the field of pharmaceutical chemistry, and in particular to memantine derivatives, stereoisomers, solvates, or pharmaceutically acceptable salts thereof, pharmaceutical compositions comprising the compounds, and use of the compounds or compositions in preparing drugs for preventing and/or treating central nervous system diseases.

Background Art

Alzheimer's disease (hereinafter referred to as AD) is a senile dementia, a chronic progressive neurodegenerative disease with an insidious onset. The factors that cause AD are very complex, including neurotransmitter factors, genetic factors, environment, age, and other diseases. Research data show that globally, a new dementia patient is diagnosed every 3 seconds. In 2018, about 50 million people in the world suffered from dementia. By 2050, this number will increase to 152 million, which will be three times as much as now. It is estimated that the global social dementia-related costs in 2018 were US$1 trillion, and by 2030, this figure will increase to US$2 trillion. In low-income and middle-income countries, less than 10% of dementia patients are diagnosed, and about 94% of dementia patients are cared for at home.

Currently, anti-dementia drugs on the market mainly include cholinesterase inhibitors (donepezil, galantamine, rivastigmine) and N-methyl-D-aspartate (N-methyl-D-aspartate, NMDA) receptor non-competitive antagonists (memantine).

Memantine is a non-competitive, moderate affinity, voltage-dependent NMDA receptor antagonist that does not interfere with glutamate activity in the normal brain. Memantine has potential neuroprotective effects on neurodegenerative diseases. Many degenerative diseases involve excessive intracellular calcium influx, which is considered a key early step in glutamate-induced excitotoxicity. Memantine can bind to the cyclohexidine binding site on the NMDA receptor, reduce calcium influx, and inhibit the cytotoxic effects induced by excitatory amino acids.

Memantine was developed by Merz, a German company. It was approved by the European Patent Medicines Committee in 2002 and entered the EU market in the same year. In 2003, memantine was approved by the US Food and Drug Administration for the treatment of moderate to severe Alzheimer's disease. In addition, memantine is also used in other types of dementia, such as vascular dementia, mixed dementia, Lewy body dementia, Parkinson's dementia, frontotemporal dementia, alcohol-related dementia, etc. (3-7).

Neurodegenerative diseases such as Alzheimer's disease mainly affect the elderly. The deterioration of their body functions makes it difficult for them to take care of themselves, and they need to be cared for, which brings a huge burden to their families and society. In addition, such diseases require long-term medication. Although memantine is the first choice for the treatment of Alzheimer's disease, it needs to be taken orally twice a day. Due to the physiological characteristics of patients, oral medication is prone to missed doses, resulting in unstable blood drug concentrations and thus affecting the therapeutic effect. Therefore, by synthesizing memantine derivatives through chemical means and combining them with modern preparation technology, a preparation with long-acting effect is prepared to provide a more convenient treatment approach for patients with Alzheimer's disease and neurodegenerative diseases, improve the compliance of patients to receive treatment, ensure the efficacy, reduce the burden on patients and their families, and bring economic benefits to society.

Summary of the invention

The present invention aims at the inconvenience that patients with central nervous system degeneration need to take memantine every day, and provides a memantine derivative with a long-acting effect. The compound of the present invention has low water solubility, can be well prepared into a suspension preparation, has a low dissolution rate in the body, forms a drug reservoir under the skin or in the muscle after a single subcutaneous or intramuscular injection, and the drug is slowly released from the reservoir, which can achieve the effect of drug efficacy lasting for several weeks, reduce the number of medication times for patients, improve the compliance of patients, and also ensure the efficacy, and has a good application prospect.

Another object of the present invention is to provide a pharmaceutical composition comprising the memantine derivative with long-lasting effect.

Another object of the present invention is to provide the use of the long-acting memantine derivative or its composition in the preparation of a drug for preventing and/or treating central nervous system diseases, especially Alzheimer's disease, Parkinson's disease or brain function recovery treatment of stroke sequelae, etc. In particular, the drug is a long-acting drug.

The above-mentioned object of the present invention is achieved through the following solutions:

A memantine derivative or a stereoisomer, solvate, or pharmaceutically acceptable salt thereof, wherein the memantine derivative has a structure represented by formula (I):

in,

^R1 and ^R2 are each independently H, D or _C1-4 alkyl;

Each X is independently a C _1-10 alkyl group or is absent, and each X may be the same or different;

Each Y is independently -C(=O)NH-, -NHC(=O)- or absent, and each Y may be the same or different;

W is selected from C _1-30 alkyl, C _1-30 heteroalkyl, C _2-30 alkenyl, C _2-30 alkynyl, C _3-10 cycloalkyl, C _3-10 cycloalkyl, C _1-10 aliphatic, C _2-10 heterocyclyl, C _2-10 heterocyclyl, C _1-10 aliphatic, aryl, aryl C _1-10 aliphatic, hetero Aryl or heteroaryl C _1-10 aliphatic.

In some embodiments, R ¹ and R ² are each independently H, D, methyl, or ethyl.

In some embodiments, W is selected from C _1-30 alkyl, C _2-30 alkenyl, C _3-10 cycloalkyl, C _3-10 cycloalkylC _1-6 aliphatic, C _2-7 heterocyclyl, C _2-7 heterocyclylC _1-6 aliphatic, C _6-10 aryl, C _6-10 arylC _1-6 aliphatic, C _5-9 heteroaryl, or C _5-9 heteroarylC _1-6 aliphatic.

In some embodiments, W is selected from C _1-22 alkyl, C _2-6 alkenyl, C _6-10 aryl, C _3-7 heterocyclylC _1-6 aliphatic, or C _6-10 arylC _1-6 aliphatic.

In some embodiments, W is selected from C _1-4 alkyl, C _1-6 alkyl, C _1-8 alkyl, C _1-10 alkyl, C _1-12 alkyl, C _1-16 alkyl, C _1-18 alkyl, C _1-20 alkyl, C _1-22 alkyl, C _2-6 alkenyl, phenylene, C _2-7 heterocyclylC _1-6 aliphatic or C _6-10 arylC _1-6 aliphatic.

In some embodiments, W is C _2-6 alkenyl.

In some embodiments, W is selected from C _2-4 alkyl, C _2-6 alkyl, C _2-8 alkyl, C _2-10 alkyl, C _2-12 alkyl, C _2-16 alkyl, C _2-18 alkyl, C _2-20 alkyl, C _2-22 alkyl.

In some embodiments, W is selected from C _2-4 alkyl, C _2-6 alkyl, C _4-8 alkyl, C _4-10 alkyl, C _4-12 alkyl, C _4-16 alkyl, C _4-18 alkyl, C _4-20 alkyl, C _4-22 alkyl.

In some embodiments, W is selected from C _2-4 alkyl, C _2-6 alkyl, C _6-8 alkyl, C _6-10 alkyl, C _6-12 alkyl, C _6-16 alkyl, C _6-18 alkyl, C _6-20 alkyl, C _6-22 alkyl.

In some embodiments, the memantine derivative has the structure shown in the following formula (I-1):

Wherein, n is an integer from 3 to 5; m is an integer from 2 to 20.

In some embodiments, n is 3.

In some embodiments, n is 4.

In some embodiments, n is 5.

In some embodiments, m is an integer from 2 to 18.

In some embodiments, m is an integer from 2 to 16.

In some embodiments, m is an integer from 4 to 20.

In some embodiments, m is an integer from 4 to 18.

In some embodiments, m is an integer from 4 to 16.

In some embodiments, m is an integer from 6 to 18.

In some embodiments, m is an integer from 6 to 16.

In some embodiments, m is an integer from 2 to 12.

In some embodiments, m is an integer from 2 to 10.

In some embodiments, m is an integer from 2 to 8.

In some embodiments, m is an integer from 4 to 12.

In some embodiments, m is an integer from 4 to 10.

In some embodiments, m is an integer from 4 to 8.

In some specific embodiments, when n is 3, m is 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20.

In some specific embodiments, when n is 3, m is 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12.

In some specific embodiments, when n is 3, m is 2, 3, 4, 5, 6, 7, 8, 9 or 10.

In some specific embodiments, when n is 3, m is 2, 3, 4, 5, 6, 7 or 8.

In some specific embodiments, when n is 3, m is 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20.

In some specific embodiments, when n is 3, m is 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17 or 18.

In some specific embodiments, when n is 3, m is 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 or 16.

In some specific embodiments, when n is 3, m is 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17 or 18.

In some specific embodiments, when n is 3, m is 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 or 16.

In some specific embodiments, when n is 3, m is 4, 6, 8, 10, 12, 14 or 16.

In some specific embodiments, when n is 3, m is 8, 10, 12, 14 or 16.

In some specific embodiments, when n is 3, m is 8, 10, 12 or 14.

In some specific embodiments, when n is 3, m is 5, 7, 9, 11, 13 or 15.

In some specific embodiments, when n is 3, m is 9, 11, 13 or 15.

In some specific embodiments, when n is 4, m is 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20.

In some specific embodiments, when n is 4, m is 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20.

In some specific embodiments, when n is 4, m is 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17 or 18.

In some specific embodiments, when n is 4, m is 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 or 16.

In some specific embodiments, when n is 4, m is 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17 or 18.

In some specific embodiments, when n is 4, m is 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 or 16.

In some specific embodiments, when n is 4, m is 4, 6, 8, 10, 12, 14 or 16.

In some specific embodiments, when n is 4, m is 8, 10, 12, 14 or 16.

In some specific embodiments, when n is 4, m is 8, 10, 12 or 14.

In some specific embodiments, when n is 4, m is 5, 7, 9, 11, 13 or 15.

In some specific embodiments, when n is 4, m is 9, 11, 13 or 15.

In some specific embodiments, when n is 5, m is 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20.

In some specific embodiments, when n is 5, m is 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20.

In some specific embodiments, when n is 5, m is 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17 or 18.

In some specific embodiments, when n is 5, m is 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 or 16.

In some specific embodiments, when n is 5, m is 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17 or 18.

In some specific embodiments, when n is 5, m is 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 or 16.

In some specific embodiments, when n is 5, m is 4, 6, 8, 10, 12, 14 or 16.

In some specific embodiments, when n is 5, m is 8, 10, 12, 14 or 16.

In some specific embodiments, when n is 5, m is 8, 10, 12 or 14.

In some specific embodiments, when n is 5, m is 5, 7, 9, 11, 13 or 15.

In some specific embodiments, when n is 5, m is 9, 11, 13 or 15.

In some embodiments, the memantine derivative is selected from one of the following structures:

Another object of the present invention is to provide a composition comprising the above-mentioned compound or its stereoisomer, solvate, or pharmaceutically acceptable salt, and a pharmaceutically acceptable excipient, carrier or diluent.

In some embodiments, the pharmaceutical compositions described herein further comprise an additional therapeutic agent.

The present invention also provides the use of the above compound or its stereoisomer, solvate, or pharmaceutically acceptable salt and the above pharmaceutical composition in the preparation of drugs for preventing and/or treating central nervous system diseases.

Wherein, the drug for preventing and/or treating central nervous system diseases is a long-acting drug.

Preferably, the central nervous system disease is Alzheimer's disease, Parkinson's disease or brain function damage caused by sequelae of stroke.

Another object of the present invention is to provide a method for preventing and/or treating central nervous system diseases, comprising administering the above-mentioned compound or its stereoisomer, solvate, or pharmaceutically acceptable salt and the above-mentioned pharmaceutical composition.

Preferably, the central nervous system disease is Alzheimer's disease, Parkinson's disease or brain function damage caused by sequelae of stroke.

The compound of the present invention has low water solubility, can be well prepared into a suspension preparation, has a low dissolution rate, and can achieve the effect of drug efficacy lasting for several weeks after a single administration.

Pharmaceutical compositions, preparations and uses

When used as a medicine, the compounds of this invention are usually used in the form of pharmaceutical compositions. The composition can be prepared in a manner well known in pharmaceutical technology and comprises at least one compound of the invention according to formula I or formula I-1. Usually, the compounds of this invention are used in a pharmaceutically effective amount. The amount of the compounds of this invention actually used will usually be determined by a physician according to the relevant circumstances, including the condition to be treated, the selected route of administration, the actual compound of the invention used, the age, body weight and response of individual patients, the severity of the patient's symptoms, etc.

The present invention provides a pharmaceutical composition comprising a compound of the present invention and a pharmaceutically acceptable carrier. The pharmaceutical composition can be prepared into a preparation suitable for a specific route of administration, such as oral administration, parenteral administration, rectal administration, subcutaneous or intramuscular injection, etc. In addition, the pharmaceutical composition of the present invention can be prepared into a solid form (including but not limited to capsules, tablets, pills, granules, powders or suppositories) or a liquid form (including but not limited to solutions, suspensions or emulsions). The pharmaceutical composition can be subjected to conventional pharmaceutical operations such as sterilization and/or can contain conventional inert diluents, lubricants or buffers and adjuvants, such as preservatives, stabilizers, wetting agents, emulsifiers and buffers, etc.

Compositions for parenteral administration can be emulsions or sterile solutions. In certain embodiments, propylene glycol, polyethylene glycol, vegetable oil, particularly olive oil or injectable organic esters can be used as solvents or carriers, and in some embodiments, ethyl oleate is used as solvents or carriers. These compositions can also include adjuvants, particularly wetting agents, isotonic agents, emulsifiers, dispersants and stabilizers. Sterilization can be carried out in several ways, and in certain embodiments, bacteriological filters are used, sterilized by radiation or by heating. They can also be prepared in the form of sterile solid compositions, which can be dissolved in sterile water or any other injectable sterile medium when used.

In certain embodiments, the composition provided by the invention is a pharmaceutical composition or a single unit dosage form. The pharmaceutical composition provided by the invention and the single unit dosage form include one or more preventive agents or therapeutic agents (for example, compounds or other preventive agents or therapeutic agents provided by the invention) of a preventive or therapeutically effective amount and one or more typical pharmaceutically acceptable carriers or excipients. In specific embodiments and the present invention, the term "pharmaceutically acceptable" refers to a drug for animals, particularly for humans, approved by a regulatory agency of a federal or state government, or listed in the U.S. Pharmacopoeia or other generally recognized pharmacopoeias. The term "carrier" includes a diluent, adjuvant (for example, Freund's adjuvant (complete and incomplete)), excipient or vehicle used together with a therapeutic agent. Such drug carriers can be sterile liquids, such as water and oils, including those of petroleum, animal oils, vegetable oils or synthetic sources, such as peanut oil, soybean oil, mineral oil, sesame oil, etc. When the pharmaceutical composition is administered intravenously, water can be used as a carrier. Saline solutions and aqueous glucose solutions and glycerol solutions can also be used as liquid carriers, particularly for injection solutions. Examples of suitable pharmaceutical carriers are described in Remington: The Science and Practice of Pharmacy; Pharmaceutical Press; 22nd edition (September 15, 2012).

Typical pharmaceutical compositions and dosage forms include one or more adjuvants. Suitable adjuvants are well known to those skilled in the art of pharmacy. In certain embodiments, suitable adjuvants include starch, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, sodium stearate, glycerol monostearate, talcum powder, sodium chloride, skim milk powder, glycerol, propylene, ethylene glycol, water, ethanol, etc. Whether a particular adjuvant is suitable for incorporation into a pharmaceutical composition or dosage form depends on various factors well known in the art, including but not limited to the manner in which the dosage form is applied to a subject and the specific active ingredient in the dosage form. If desired, the composition or single unit dosage form may also contain a small amount of a wetting agent or emulsifier, or a pH buffer.

For an individual of about 50-70 kg, the pharmaceutical composition or combination product of the present invention can be a unit dose of about 1-1000 mg of active ingredient, or about 1-500 mg, or about 1-250 mg, or about 1-150 mg, or about 0.5-100 mg, or about 1-50 mg of active ingredient. The therapeutically effective amount of the compound, pharmaceutical composition, or combination product thereof depends on the species, body weight, age, and individual health condition, the disorder or disease to be treated, or its severity. A physician, clinician, or veterinarian can easily determine the effective amount of each active ingredient necessary for preventing, treating, or inhibiting the progression of a disease or disorder.

The above dosage characteristics can be demonstrated by in vitro and in vivo tests using suitable mammals, such as mice, rats, dogs, monkeys or isolated organs, tissues and their products. The compounds of the present invention can be applied in vitro in the form of solutions, such as aqueous solutions; in vivo in the form of suspensions or aqueous solutions, for example, in the enteral, parenteral (preferably intravenous) application. The in vitro dosage range is between about 10-3 molar concentration and 10-9 molar concentration. The therapeutically effective amount is in the range of about 0.1-500 mg/kg or about 1-100 mg/kg, depending on the route of administration.

The compounds of the present invention may be administered simultaneously with one or more other therapeutic ingredients, or before or after them. The compounds of the present invention may be administered separately with another ingredient by the same or different routes of administration, or the two may be administered together in the same pharmaceutical composition.

On the other hand, the present invention provides a compound of the present invention or a pharmaceutical composition comprising the compound of the present invention, which is used in medicine. In a specific embodiment, the present invention provides a compound of the present invention or a pharmaceutical composition comprising the compound of the present invention, which is used to prevent and/or treat central nervous system diseases in mammals, especially brain function recovery treatment of Alzheimer's disease, Parkinson's disease or stroke sequelae, etc.

Compared with the prior art, the present invention has the following beneficial effects:

After entering the organism, the compound of the present invention can be decomposed into the active ingredient of memantine, and then exert its effect; and the compound of the present invention has low water solubility, can be well prepared into a suspension preparation, has a low dissolution rate in the organism, and after a single subcutaneous or intramuscular injection, a drug reservoir is formed in the subcutaneous or muscle area, and the drug is slowly released from the reservoir without obvious burst release phenomenon. At the same time, the blood drug concentration is maintained for a long time and is stable, and the effect of drug efficacy lasting for several weeks can be achieved, thereby reducing the number of medication times for patients, improving the compliance of patients, and ensuring the efficacy, and having good application prospects.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG1 is a time curve of the blood concentration of the original drug of the compound of the present invention after intramuscular injection into rats.

Definitions and general terms

Unless otherwise specified, all technical terms used in the present invention have the same meaning as commonly understood by those skilled in the art to which the present invention belongs. All patents and publications related to the present invention are incorporated herein by reference in their entirety.

Unless otherwise specified or there is a clear conflict in context, the articles "a", "an", and "the" as used herein are intended to include "at least one" or "one or more". Therefore, these articles as used herein refer to articles that refer to one or more than one (i.e., at least one) of the objects. For example, "a component" refers to one or more components, i.e., there may be more than one component contemplated for use or use in the implementation of the described embodiment.

"Stereoisomers" refer to compounds that have the same chemical constitution but differ in the way the atoms or groups are arranged in space. Stereoisomers include enantiomers, diastereomers, conformational isomers (rotamers), geometric isomers (cis/trans) isomers, atropisomers, and the like.

Any asymmetric atom (e.g., carbon, etc.) of the compounds disclosed in the present invention can be racemized or enantiomerically enriched. In some embodiments, each asymmetric atom has at least 50% enantiomeric excess, at least 60% enantiomeric excess, at least 70% enantiomeric excess, at least 80% enantiomeric excess, at least 90% enantiomeric excess, at least 95% enantiomeric excess, or at least 99% enantiomeric excess in the (R)- or (S)-configuration.

"Pharmaceutically acceptable" refers to compounds, materials, compositions and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with patient tissues without excessive toxicity, irritation, allergic response, or other problems and complications commensurate with a reasonable benefit/risk ratio, and are effective for their intended use.

In general, the term "substituted" means that one or more hydrogen atoms in a given structure are replaced by a specified substituent. Unless otherwise indicated, a substituted group may have a substituent at each substitutable position of the group. When more than one position in a given structure can be substituted by one or more substituents selected from a specified group, the substituents may be the same or different at each position.

The term "unsubstituted" means that the designated group bears no substituents.

The term "optionally substituted by..." can be used interchangeably with the term "unsubstituted or substituted by...", i.e., the structure is unsubstituted or substituted by one or more substituents described in the present invention, and the substituents described in the present invention include, but are not limited to H, D, F, Cl, Br, I, N ₃ , CN, NO ₂ , OH, SH, NH ₂ , haloalkyl, alkenyl, alkynyl, alkoxy, alkylamino, hydroxyalkyl, cyano-substituted alkyl, heterocyclyl, oxo (=O), thioxo (=S), -C(=O)NH-R ^4a , -NHC(=O)-R ^4a , -S(=O) _1-2 NH-R ^4b , -NHS(=O) _1-2 -R ^4b , C _1-6 alkyl, carbonyl, C _3-6 cycloalkyl, C _6-10 aryl or C _1-9 heteroaryl, etc., wherein R ^4a , and R ^4b have the definitions described in the present invention.

In addition, it should be noted that, unless explicitly stated otherwise, the description methods used in the present invention, "each... independently is" and "... each/respectively independently is" and "... independently is" can be interchanged and should be understood in a broad sense, which can mean that in different groups, the specific options expressed by the same symbols do not affect each other, or that in the same group, the specific options expressed by the same symbols do not affect each other.

In various parts of this specification, the substituents of the compounds disclosed in the present invention are disclosed according to group types or ranges. It is particularly pointed out that the present invention includes each independent secondary combination of the individual members of these group types and ranges. For example, the term "C _1-6 alkyl" specifically refers to the independently disclosed methyl, ethyl, C ₃ alkyl, C ₄ alkyl, C ₅ alkyl and C ₆ alkyl.

In various parts of this invention, linking substituents are described. When the structure clearly requires a linking group, the Markush variable listed for that group should be understood to be the linking group. For example, if the structure requires a linking group and the Markush group definition for that variable lists "alkyl" or "aryl", it should be understood that the "alkyl" or "aryl" represent a linked alkylene group or arylene group, respectively.

The term "alkyl" or "alkyl group" as used herein refers to a saturated straight or branched monovalent hydrocarbon group containing 1 to 30 carbon atoms, wherein the alkyl group may be optionally substituted with one or more substituents described herein. Unless otherwise specified, the alkyl group contains 1-30 carbon atoms. Unless otherwise specified, the alkyl group contains 1-22 carbon atoms. In one embodiment, the alkyl group contains 1-12 carbon atoms; in another embodiment, the alkyl group contains 1-6 carbon atoms; in yet another embodiment, the alkyl group contains 1-4 carbon atoms; in yet another embodiment, the alkyl group contains 1-3 carbon atoms. The alkyl group may be optionally substituted with one or more substituents described herein.

Examples of alkyl groups include, but are not limited to, methyl (Me, -CH ₃ ), ethyl (Et, -CH ₂ CH ₃ ), n-propyl (n-Pr, -CH ₂ CH ₂ CH ₃ ), isopropyl (i-Pr, -CH(CH ₃ ) ₂ ), n-butyl (n-Bu, -CH ₂ CH ₂ CH ₂ CH ₃ ), isobutyl (i-Bu, -CH2CH(CH ₃ ) ₂ ), sec-butyl (s-Bu, -CH(CH ₃ )CH ₂ CH ₃ ), tert-butyl (t-Bu, -C(CH ₃ ) ₃ ), n-pentyl (-CH ₂ CH ₂ CH ₂ CH ₂ CH ₃ ), 2-pentyl (-CH(CH ₃ )CH ₂ CH ₂ CH ₃ ), 3-pentyl (-CH(CH ₂ CH ₃ ) ₂ ), 2-methyl-2-butyl (-C(CH ₃ ) ₂ CH ₂ CH ₃ ), 3-methyl-2-butyl (-CH(CH ₃ )CH(CH ₃ ) ₂ ), 3-methyl-1-butyl (-CH ₂ CH ₂ CH(CH ₃ ) ₂ ), 2-methyl-1-butyl (-CH ₂ CH(CH ₃ )CH ₂ CH ₃ ), n-hexyl (-CH ₂ CH ₂ CH ₂ CH ₂ CH ₂ CH ₃ ), 2-hexyl (-CH(CH ₃ )CH ₂ CH ₂ CH ₂ CH ₃ ), 3-hexyl (-CH(CH ₂ CH ₃ )(CH ₂ CH ₂ CH ₃ )), 2-methyl-2-pentyl (-C(CH ₃ ) ₂ CH ₂ CH ₂ CH ₃ ), 3-methyl-2-pentyl (-CH(CH ₃ )CH(CH ₃ )CH ₂ CH ₃ ), 4-methyl-2-pentyl (-CH(CH ₃ )CH ₂ CH(CH ₃ ) ₂ ), 3-methyl-3-pentyl (-C(CH ₃ )(CH ₂ CH ₃ ) ₂ ), 2-methyl-3-pentyl (-CH(CH ₂ CH ₃ )CH(CH ₃ ) ₂ ), 2,3-dimethyl-2-butyl (-C(CH ₃ ) ₂ CH(CH ₃ ) ₂ ), 3,3-dimethyl-2-butyl (-CH(CH ₃ )C(CH ₃ ) ₃ ), n-heptyl, n-octyl, C ₁₂ alkyl, C ₁₄ alkyl, C ₁₆ alkyl, C ₁₈ alkyl, C ₂₀ alkyl, C ₂₂ alkyl and the like.

The term "alkenyl" refers to a straight or branched monovalent hydrocarbon group containing 2 to 30 carbon atoms, wherein there is at least one site of unsaturation, i.e., one carbon-carbon sp2 ^double bond, including "cis" and "trans" orientations, or "E" and "Z" orientations. In one embodiment, the alkenyl group contains 2 to 30 carbon atoms; in one embodiment, the alkenyl group contains 2 to 22 carbon atoms; in one embodiment, the alkenyl group contains 2 to 8 carbon atoms; in another embodiment, the alkenyl group contains 2 to 6 carbon atoms; in yet another embodiment, the alkenyl group contains 2 to 4 carbon atoms. Examples of alkenyl groups include, but are not limited to, vinyl (-CH= _CH2 ), allyl ( _-CH2CH = _CH2 ), and the like. The alkenyl group may be optionally substituted with one or more substituents described herein.

The term "alkynyl" refers to a straight or branched monovalent hydrocarbon radical containing 2 to 30 carbon atoms, wherein there is at least one site of unsaturation, i.e., one carbon-carbon sp triple bond. In one embodiment, the alkynyl group contains 2 to 30 carbon atoms; In one embodiment, the alkynyl group contains 2-22 carbon atoms; in one embodiment, the alkynyl group contains 2-8 carbon atoms; in another embodiment, the alkynyl group contains 2-6 carbon atoms; in yet another embodiment, the alkynyl group contains 2-4 carbon atoms. Examples of alkynyl groups include, but are not limited to, ethynyl (-C≡CH), propargyl (-CH ₂ C≡CH), 1-propynyl (-C≡C-CH ₃ ), and the like. The alkynyl group may be optionally substituted with one or more substituents described herein.

The term "aliphatic" or "aliphatic group" as used herein refers to a straight chain (i.e., unbranched) or branched, substituted or unsubstituted hydrocarbon chain that is fully saturated or contains one or more unsaturations. Unless otherwise specified, an aliphatic group contains 1-30 carbon atoms, in some embodiments, an aliphatic group contains 1-20 carbon atoms, in some embodiments, an aliphatic group contains 1-10 carbon atoms, in other embodiments, an aliphatic group contains 1-8 carbon atoms, in other embodiments, an aliphatic group contains 1-6 carbon atoms, in other embodiments, an aliphatic group contains 1-4 carbon atoms, and in other embodiments, an aliphatic group contains 1-3 carbon atoms. Suitable aliphatic groups include, but are not limited to, straight chain or branched, substituted or unsubstituted alkyl, alkenyl or alkynyl, such as methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, hexyl, isobutyl, sec-butyl, vinyl, ethynyl, and the like.

The term "cycloalkyl" used in the present invention, unless otherwise specified, refers to a monovalent saturated or partially unsaturated (but non-aromatic) monocyclic or polycyclic hydrocarbon. In some embodiments, the cycloalkyl group can be a bridged or non-bridged, spirocyclic or non-spirocyclic, and/or fused or non-fused bicyclic group. In some embodiments, the cycloalkyl group includes 3-10 carbon atoms, i.e., C ₃ to C ₁₀ cycloalkyl. In some embodiments, the cycloalkyl has 3-15 (C _3-15 ), 3-10 (C _3-10 ), 3-7 (C _3-7 ) carbon atoms, 3-6 (C _3-6 ) carbon atoms. In some embodiments, the cycloalkyl group is a monocyclic or bicyclic ring. In some embodiments, the cycloalkyl group is a monocyclic ring. In some embodiments, the cycloalkyl group is a bicyclic ring. In some embodiments, the cycloalkyl group is a tricyclic ring. In some embodiments, the cycloalkyl group is fully saturated. In some embodiments, the cycloalkyl group is partially saturated. In some embodiments, the cycloalkyl group is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, bicyclo[2.1.1]hexyl, bicyclo[2.2.1]heptyl, decahydronaphthyl, or adamantyl. When the cycloalkyl is substituted, it can be substituted independently with one or more substituents described herein on any ring, i.e., on any aromatic or non-aromatic ring contained by the cycloalkyl.

The terms "heterocyclyl" and "heterocycle" are used interchangeably in this application and, unless otherwise specified, refer to a monovalent monocyclic non-aromatic ring system and/or a polycyclic ring system comprising at least one non-aromatic ring; wherein one or more (in certain embodiments, 1, 2, 3 or 4) of the non-aromatic monocyclic atoms are independently selected from O, S(O) _0-2 and N heteroatoms. In some embodiments, the heterocyclic ring comprises 1 or 2 heteroatoms, and the heteroatoms are all nitrogen atoms. In some embodiments, the heterocyclic ring comprises 1 or 2 heteroatoms, and the remaining ring atoms are all carbon atoms; and wherein one or more (in some embodiments, 1, 2, 3 or 4) of the ring atoms of the polycyclic ring system are independently selected from O, S (O) _0-2 and N heteroatoms, and the remaining ring atoms are all carbon atoms. In some embodiments, the heterocyclic ring comprises 1 or 2 heteroatoms, and the heteroatoms are all nitrogen atoms. In some embodiments, the heterocyclic ring is polycyclic and comprises one heteroatom in a non-aromatic ring, or comprises one heteroatom in an aromatic ring, or comprises two heteroatoms in an aromatic ring, or comprises two heteroatoms, one of which is in an aromatic ring, and the other is in a non-aromatic ring. In some embodiments, the heterocyclic group has 3-20, 3-15, 3-10, 3-8, 4-7 or 5-6 ring atoms. In some embodiments, the heterocyclic group is a monocyclic, bicyclic, tricyclic or tetracyclic ring system. In some embodiments, the heterocyclyl group can be a bridged or non-bridged, spirocyclic or non-spirocyclic, and/or fused or non-fused bicyclic group. One or more nitrogen atoms and sulfur atoms can be optionally oxidized, one or more nitrogen atoms can be optionally quaternized, one or more carbon atoms can be optionally quaternized. Replacement. Some rings can be partially or completely saturated, or aromatic, provided that the heterocycle is non-completely aromatic. The monocyclic heterocycle and polycyclic heterocycle can be connected to the main structure on any heteroatom or carbon atom that leads to a stable compound. The polycyclic heterocyclic group can be connected to the main structure through any ring thereof, including any aromatic ring or non-aromatic ring, regardless of whether the ring contains a heteroatom. In some embodiments, the heterocyclic group is a "heterocycloalkyl", which is 1) a saturated or partially unsaturated (but non-aromatic) monovalent monocyclic group containing at least one ring heteroatom as described in the present invention, or 2) a saturated or partially unsaturated (but non-aromatic) monovalent bicyclic group or tricyclic group, wherein at least one ring contains at least one heteroatom as described in the present invention. When heterocyclic and heterocycloalkyl are substituted, they can be substituted on any ring, i.e., on any aromatic or non-aromatic ring contained by heterocyclic and heterocycloalkyl. In some embodiments, such heterocyclic groups include, but are not limited to, oxirane, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, 2-pyrrolinyl, 3-pyrrolinyl, pyrazolyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, 1,3-dioxolane, dithiolanyl, tetrahydropyranyl, dihydropyranyl, 2H-pyranyl, 4H-pyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, dioxanyl, dithianyl, thioxanyl, homopiperazinyl, homopiperidinyl, oxepanyl, thiepanyl, oxazepine Base, diazepine Base, thiazolin yl, benzodioxanyl, benzodioxolyl, benzofuranonyl, benzopyroneonyl, benzopyranyl, dihydrobenzofuranyl, benzotetrahydrothienyl, benzothiopyranyl, benzoxazinyl, β-carbolinyl, chromanyl, chromonyl, cinnolinyl, coumarinyl, decahydroquinolyl, decahydroisoquinolyl, dihydrobenzisothiazinyl, dihydrobenzisoxazinyl, dihydrofuranyl, dihydroisoindolyl, dihydropyranyl, dihydropyrazolyl, dihydropyrazinyl, dihydropyridinyl, dihydropyrimidinyl, dihydropyrrolyl, dioxolanyl, 1,4-dithiopyranyl, furanonyl, imidazolidinyl, 2,4-dioxo-imidazolidinyl, imidazolinyl, indolyl, 2-oxo-indolyl, isochromanyl, isochromanyl, isocoumarinyl, isoindolyl (isoindolyl), 1-oxo-isoindolyl, 1,3-dioxo-isoindolyl, isothiazolidinyl, isoxazolidinyl, 3-oxo-isoxazolidinyl, morpholinyl, 3,5- dioxo-morpholinyl, octahydroindolyl, octahydroisoindolyl, 1-oxo-octahydroisoindolyl, 1,3-dioxo-hexahydroisoindolyl, oxazolidinone, oxazolidinyl, oxiranyl, piperazinyl, 2,6-dioxo-piperazinyl, piperidinyl, 2,6-dioxo-piperidinyl, 4-piperidone, 2-oxopyrrolidinyl, 2,5-dioxopyrrolidinyl, quinuclidinyl, tetrahydroisoquinolinyl, 3,5-dioxo-thiomorpholinyl, thiazolidinyl, 2,4-dioxo-thiazolidinyl, tetrahydroquinolinyl, phenothiazinyl, phenoxazinyl, xanthenyl and 1,3,5-trithianyl. Examples of heterocyclic groups in which the -CH ₂ - group is replaced by -C(=O)- include, but are not limited to, 2-oxopyrrolidinyl, oxo-1,3-thiazolidinyl, 2-piperidinyl, 3,5-dioxopiperidinyl, and pyrimidinedione. Examples of heterocyclic groups in which the sulfur atom is oxidized include, but are not limited to, sulfolane and 1,1-dioxothiomorpholinyl. The heterocyclic group may be optionally substituted by one or more substituents described herein.

In one embodiment, the heterocyclic group is a 3-8-atom heterocyclic group, which refers to a saturated or partially unsaturated monocyclic ring containing 3-8 ring atoms, wherein at least one ring atom is selected from nitrogen, sulfur and oxygen atoms. Unless otherwise specified, the 3-8-atom heterocyclic group can be a carbon group or a nitrogen group, and the _-CH2- group can be optionally replaced by -C(=O)-. The sulfur atom of the ring can be optionally oxidized to S-oxide. The nitrogen atom of the ring can be optionally oxidized to N-oxide. Examples of heterocyclic groups of 3-8 atoms include, but are not limited to, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, 2-pyrrolinyl, 3-pyrrolinyl, pyrazolyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, 1,3-dioxolane, dithiolanyl, tetrahydropyranyl, dihydropyranyl, 2H-pyranyl, 4H-pyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, dioxanyl, dithianyl, thioxanyl, homopiperazinyl, homopiperidinyl, oxepanyl, thiepanyl, oxazepine Base, diazepine Base, thiazolin Examples of heterocyclic groups in which the -CH ₂ - group is replaced by -C(＝O)- include, but are not limited to, 2-oxopyrrolidinyl, oxo-1,3-thiazolidinyl, 2-piperidinyl, 3,5-dioxopiperidinyl, and pyrimidinedione. Examples of heterocyclic groups in which the sulfur atom is oxidized include, but are not limited to, sulfolane and 1,1-dioxothiomorpholinyl. The heterocyclic group consisting of 3 to 8 atoms may be optionally substituted by one or more substituents described herein.

In one embodiment, the heterocyclic group is a heterocyclic group consisting of 3-6 atoms, which refers to a saturated or partially unsaturated monocyclic ring containing 3-6 ring atoms, wherein at least one ring atom is selected from nitrogen, sulfur and oxygen atoms. Unless otherwise specified, The heterocyclic group of 3-6 atoms can be a carbon group or a nitrogen group, and the _-CH2- group can be optionally replaced by -C(=O)-. The sulfur atom of the ring can be optionally oxidized to S-oxide. The nitrogen atom of the ring can be optionally oxidized to N-oxide. The heterocyclic group of 3-6 atoms can be optionally substituted by one or more substituents described in the present invention.

In another embodiment, the heterocyclic group is a 5-6 atom heterocyclic group, which refers to a saturated or partially unsaturated monocyclic ring containing 5-6 ring atoms, wherein at least one ring atom is selected from nitrogen, sulfur and oxygen atoms. Unless otherwise specified, the 5-6 atom heterocyclic group can be a carbon group or a nitrogen group, and the _-CH2- group can be optionally replaced by -C(=O)-. The sulfur atom of the ring can be optionally oxidized to S-oxide. The nitrogen atom of the ring can be optionally oxidized to N-oxide. Examples of 5-6 atom heterocyclic groups include, but are not limited to, pyrrolidinyl, 2-pyrrolinyl, 3-pyrrolinyl, pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, dihydrothienyl, 1,3-dioxolane, dithiolanyl, 2-oxopyrrolidinyl, oxo-1,3-thiazolidinyl, sulfolane, tetrahydropyranyl, dihydropyranyl, 2H-pyranyl, 4H-pyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, dioxanyl, dithianyl, thioxanyl, 2-piperidone, 3,5-dioxopiperidinyl and pyrimidinedione, 1,1-dioxothiomorpholinyl. The 5-6 atom heterocyclic group may be optionally substituted with one or more substituents described herein.

The term "aryl" as used herein, unless otherwise indicated, refers to a monovalent _C6 -C14 _carbocyclic ring system comprising at least one aromatic ring, wherein the aromatic ring system is monocyclic, bicyclic, or tricyclic. The aryl group may be attached to the main structure through any of its rings, i.e., any aromatic or non-aromatic ring. In some embodiments, the aryl group is phenyl, naphthyl, bicyclo[4.2.0]octa-1,3,5-trienyl, indanyl, fluorenyl, or tetrahydronaphthyl. When the aryl group is substituted, it may be substituted on any ring, i.e., on any aromatic or non-aromatic ring comprised by the aryl group. In some or any embodiments, the aryl group is phenyl, naphthyl, tetrahydronaphthyl, fluorenyl, or indanyl. The aryl group may be independently and optionally substituted by one or more substituents described herein.

The term "heteroaryl" as used herein, unless otherwise indicated, refers to a monovalent monocyclic or polycyclic aromatic group, wherein at least one (in certain embodiments, 1, 2, 3 or 4) ring atom is independently selected from the heteroatoms of O, S(O) _0-2 and N in the ring. The heteroaryl group is connected to the rest of the molecule through any atom in the ring system, where the valence rules permit. In some embodiments, each ring of the heteroaryl group may contain 1 or 2 O atoms, 1 or 2 S atoms, and/or 1 to 4 N atoms, or a combination thereof, provided that the total number of heteroatoms in each ring is 4 or less, and each ring contains at least 1 carbon atom. In some embodiments, the heteroaryl has 5-20, 5-15, or 5-10 ring atoms. When the heteroaryl is substituted, it may be on any ring. In certain embodiments, monocyclic heteroaryl groups include, but are not limited to, furanyl, imidazolyl, isothiazolyl, isoxazolyl, oxadiazolyl, oxazolyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridinyl, pyrimidinyl, pyrrolyl, thiadiazolyl, thiazolyl, thienyl, tetrazolyl, triazinyl and triazolyl. In certain embodiments, bicyclic heteroaryl groups include, but are not limited to, benzofuranyl, benzimidazolyl, benzisoxazolyl, benzopyranyl, benzothiadiazolyl, benzothiazolyl, benzothiophenyl, benzotriazolyl, benzoxazolyl, furopyridinyl, imidazopyridinyl, imidazothiazolyl, indolizinyl, indolyl, indazolyl, isobenzofuranyl, isobenzothiophenyl, isoindolyl, isoquinolyl, isothiazolyl, naphthyridinyl, oxazolopyridinyl, phthalazinyl, pteridinyl, purinyl, pyridopyridinyl, pyrrolopyridinyl, quinolyl, quinoxalinyl, quinazolinyl, thiadiazolopyrimidinyl, and thienopyridinyl. In certain embodiments, tricyclic heteroaryl groups include, but are not limited to, acridinyl, benzindolyl, carbazolyl, dibenzofuranyl, furidinyl, phenanthrolinyl, phenanthridinyl, and phenazinyl. In some or any embodiments, heteroaryl is phenylene, naphthylene, pyridinylene, pyrimidinylene, pyrazinylene, pyridazinylene, thiazolylene, benzothiazolyl, benzo[d]isothiazolyl, imidazo[1,2-a]pyridinyl, quinolinyl, 1H-indolyl, pyrrolo[1,2-b]pyridazinyl, benzofuranyl, benzo[b]thiophenyl, 1H-indazolyl, benzo[d]isoxazolyl, quinazolinyl, 1H-pyrrolo[3,2-c]pyridinyl, pyrazolo[1,5-a]pyrimidinyl, imidazo[1,2-b]pyridazinyl, or pyrazolo[1,5-a]pyridinyl; each of which is optionally substituted with 1, 2, 3, or 4 groups as defined throughout this specification.

As used herein, "pharmaceutically acceptable salts" refer to organic and inorganic salts of the compounds of the present invention. Pharmaceutically acceptable salts are well known in the art, as described in the literature: SM Berge et al., describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66: 1-19. Pharmaceutically acceptable salts formed by non-toxic acids include, but are not limited to, inorganic acid salts such as hydrochlorides, hydrobromides, phosphates, sulfates, perchlorates, and organic acid salts such as acetates, oxalates, maleates, tartrates, citrates, succinates, malonates, or other methods described in books and literature, such as ion exchange methods, to obtain these salts. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, cyclopentylpropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, picrate, pivalate, Propionate, stearate, thiocyanate, p-toluenesulfonate, undecanoate, valerate, and the like. Salts obtained by reaction with an appropriate base include alkali metal, alkaline earth metal, ammonium and N ⁺ (C ₁ -C ₄ alkyl) ₄ salts. The present invention also contemplates quaternary ammonium salts formed by compounds of any group containing N. Water-soluble or oil-soluble or dispersible products can be obtained by quaternization. Alkali metal or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Pharmaceutically acceptable salts further include appropriate, non-toxic ammonium, quaternary ammonium salts and amine cations formed by counter-balancing ions, such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, C _1-8 sulfonates and aromatic sulfonates.

The "solvate" of the present invention refers to an association formed by one or more solvent molecules and the compound of the present invention. Solvents that form solvates include, but are not limited to, water, isopropanol, ethanol, methanol, dimethyl sulfoxide, ethyl acetate, acetic acid and aminoethanol. The term "hydrate" refers to an association formed by the solvent molecule being water.

When the solvent is water, the term "hydrate" may be used. In some embodiments, one molecule of the compound of the present invention may be combined with one water molecule, such as a monohydrate; in other embodiments, one molecule of the compound of the present invention may be combined with more than one water molecule, such as a dihydrate, and in still other embodiments, one molecule of the compound of the present invention may be combined with less than one water molecule, such as a hemihydrate. It should be noted that the hydrates of the present invention retain the biological effectiveness of the non-hydrated form of the compound.

As used herein, the term "treating" any disease or condition, in some embodiments, refers to ameliorating the disease or condition (i.e., slowing or preventing or alleviating the development of the disease or at least one clinical symptom thereof). In other embodiments, "treating" refers to alleviating or improving at least one physical parameter, including physical parameters that may not be perceived by the patient. In other embodiments, "treating" refers to regulating the disease or condition physically (e.g., stabilizing perceptible symptoms) or physiologically (e.g., stabilizing physical parameters), or both. In other embodiments, "treating" refers to preventing or delaying the onset, occurrence, or worsening of a disease or condition.

DETAILED DESCRIPTION

The present invention is further described in detail below in conjunction with specific examples, which are only used to explain the present invention and are not used to limit the scope of the present invention. The test methods used in the following examples are conventional methods unless otherwise specified; the materials and reagents used are reagents and materials that can be obtained from commercial channels unless otherwise specified.

Generally, the compounds of the present invention can be prepared by the methods described herein, unless otherwise specified, wherein the substituents are defined as shown in Formula I, II or III. The following reaction schemes and examples are provided to further illustrate the present invention.

Those skilled in the art will recognize that the chemical reactions described herein can be used to suitably prepare many other compounds of the invention, and that other methods for preparing the compounds of the invention are considered to be within the scope of the invention. For example, the synthesis of the non-exemplified compounds of the invention can be successfully accomplished by those skilled in the art by modification methods, such as appropriate protection of interfering groups, by utilizing other known reagents in addition to those described herein, or by making some conventional modifications to the reaction conditions. In addition, the reactions disclosed herein or known reaction conditions are also recognized to be applicable to the preparation of other compounds of the invention.

In the examples described below, all temperatures are set forth in degrees Celsius unless otherwise indicated. Reagents were purchased from commercial suppliers such as Aldrich Chemical Company, Arco Chemical Company and Alfa Chemical Company and used without further purification unless otherwise indicated. Common reagents were purchased from Shantou Xilong Chemical Factory, Guangdong Guanghua Chemical Reagent Factory, Guangzhou Chemical Reagent Factory, Tianjin Haoyuyu Chemical Co., Ltd., Tianjin Fuchen Chemical Reagent Factory, Wuhan Xinhuayuan Technology Development Co., Ltd., Qingdao Tenglong Chemical Reagent Co., Ltd., and Qingdao Ocean Chemical Factory.

Anhydrous tetrahydrofuran, dioxane, toluene, and ether were obtained by drying under reflux with sodium metal. Anhydrous dichloromethane and chloroform were obtained by drying under reflux with calcium hydride. Ethyl acetate, petroleum ether, n-hexane, N,N-dimethylacetamide, and N,N-dimethylformamide were dried over anhydrous sodium sulfate before use.

The following reactions were generally carried out under positive pressure of nitrogen or argon or with a drying tube over anhydrous solvents (unless otherwise indicated), reaction bottles were plugged with appropriate rubber stoppers, and substrates were injected via syringes. All glassware was dried.

The chromatographic column used was a silica gel column, and the silica gel (200-300 mesh) was purchased from Qingdao Ocean Chemical Plant.

¹ H NMR spectra were recorded using a Bruker 400 MHz or 500 MHz NMR spectrometer. ¹ H NMR spectra were recorded using CDCl ₃ , DMSO-d ₆ , CD ₃ OD or acetone-d ₆ as solvents (in ppm) and TMS (0 ppm) or chloroform (7.26 ppm) as reference standards. When multiple peaks are present, the following abbreviations are used: s (singlet), d (doublet), t (triplet), m (multiplet), br (broadened), dd (doublet of doublets), dt (doublet of triplets). Coupling constants are expressed in Hertz (Hz).

The low resolution mass spectrometry (MS) data were measured using Thermo LTQ (column model: Zorbax SB-C18, 2.1x30 mm, 3.5 microns, 6 min, flow rate 0.6 mL/min. Mobile phase: 5%-95% (CH ₃ CN containing 0.1% formic acid) in H ₂ O containing 0.1% formic acid), electrospray ionization (ESI), at 210 nm/254 nm, with UV detection.

Pure compounds were analyzed using Agilent 1260 pre-HPLC or Calesep pump 250 pre-HPLC (column type Model: NOVASEP 50/80mm DAC), detected by UV at 210nm/254nm.

The following abbreviations are used throughout this invention:

Typical synthetic procedures for preparing the compounds disclosed in the present invention are shown in the following synthetic schemes.

Example 1

Step 1) Preparation of Intermediate 1

Memantine (30.51 g, 170.15 mmol, 1 equivalent) and dichloromethane (300 mL) were added to a 500 mL single-mouth bottle, and p-anisaldehyde (24.32 g, 178.66 mmol, 1.05 equivalent) was added after dissolution, and acetic acid (10.21 g, 170.15 mmol, 1 equivalent) was added dropwise under stirring, and stirred at room temperature for 1 hour. Sodium triacetoxyborohydride (54.09 g, 255.23 mmol, 1.5 equivalent) was added, and stirring was continued at room temperature overnight. TLC showed that the reaction of A was basically completed. 400 mL of saturated sodium bicarbonate aqueous solution was added, and the mixture was separated after stirring for 10 minutes. The aqueous phase was extracted with dichloromethane (200 mL*1), and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and spin-dried. Methyl tert-butyl ether (500 mL) was added to dissolve it, and 16 mL of concentrated hydrochloric acid was added dropwise under stirring to precipitate a white solid. After stirring for 1 hour, the mixture was filtered, and the filter cake was washed with methyl tert-butyl ether and dried in vacuo to obtain intermediate 1 (Int1, 56.45 g, yield 98.8%) as a white solid.

Step 2) Preparation of Intermediate 2

Weigh N-(4-methoxybenzyl)-memantine hydrochloride (20 g, 59.53 mmol, 1 equivalent) into a 500 mL single-mouth bottle, add 150 mL of water and 200 mL of methyl tert-butyl ether, and the solid will not dissolve. Dissolve sodium hydroxide (3.57 g, 89.30 mmol, 1.5 equivalent) in 50 mL of water and add dropwise to the single-mouth bottle. The solid will gradually dissolve. After stirring for 30 minutes, Separate the liquid, extract the aqueous phase with methyl tert-butyl ether (100mL*1), combine the organic phases, and transfer to a 1L three-necked flask. Add 200mL of water and sodium bicarbonate (12.50g, 148.83mmol, 2.5 equivalents), dissolve, add chloromethyl chloroformate (11.51g, 89.30mmol, 1.5 equivalents) dropwise under stirring, control the internal temperature not to exceed 25°C, stir at room temperature for 1 hour after the addition is complete, TLC shows that the intermediate 1 has reacted completely, separate the liquid, extract the aqueous phase with methyl tert-butyl ether (100mL*1), combine the organic phases, dry over anhydrous sodium sulfate, filter, and spin dry to obtain an oily substance. Add 5mL of methyl tert-butyl ether to dissolve, add 100mL of n-heptane dropwise, precipitate a white solid, stir overnight and filter, wash the filter cake with n-heptane, and pump dry to obtain intermediate 2 (Int2, 18.50g, yield 79.3%), which is a white solid.

Step 3) Preparation of Intermediate 3

In a 250 mL single-mouth bottle, add intermediate 2 (3.0 g, 7.65 mmol, 1.0 equivalent), 2,2'-tetradecane diamide diacetic acid (1.43 g, 3.83 mmol, 0.5 equivalent), sodium bicarbonate (1.28 g, 15.30 mmol, 2.0 equivalent), add tetrahydrofuran (50 mL), triethylamine (1.06 mL, 7.65 mmol, 1.0 equivalent), stir and react at 60 ° C for more than 45 hours until TLC shows that the raw materials are basically reacted. The reaction solution is cooled to room temperature, filtered, the filter cake is washed with ethyl acetate (30 mL * 2), the filtrate is combined, concentrated, and then dissolved with dichloromethane (180 mL), washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, spin-dried, and pumped dry to obtain intermediate 3 (Int3, 4.02 g, yield 100%) as a white foam solid.

¹ H NMR (500MHz, CDCl ₃ )δ7.06 (d, J=8.5Hz, 4H), 6.84 (d, J=8.5Hz, 4H), 5.88 (t, J=5.0Hz, 2H), 5.79 (s, 4H), 4.55 (s, 4H), 4.0 3(d, J＝5.0Hz, 4H), 3.80(s, 6H), 2.22(t, J＝7.5Hz, 4H), 2.12(t, J＝3.0Hz, 2H), 1.94(s, 4H), 1.76(dd,J ₁ = 33.5Hz, J ₂ = 12.0Hz, 8H), 1.66-1.60 (m, 4H), 1.32-1.22 (m, 24H), 1.09 (dd, J ₁ =18.0Hz, J ₂ =12.5Hz, 4H), 0.81 (s, 12H).

Step 4) Preparation of target product

Intermediate 3 (4.0 g, 3.797 mmol) was placed in a 250 mL single-mouth bottle, and dichloromethane (75 mL) was added to dissolve it. Trifluoroacetic acid (7.5 mL) was added dropwise under an ice bath. After the addition was complete, the mixture was stirred under an ice-water bath for 15 min, and then stirred at room temperature for another 15 min. TLC showed that the raw material was basically reacted. The reaction solution was slowly added to an ice-cold saturated sodium bicarbonate aqueous solution and stirred vigorously for 10 minutes. 50 ml of dichloromethane was added, and the mixture was allowed to stand for separation. The organic phase was collected, dried over anhydrous sodium sulfate, filtered, and dried by spin drying. Purification was performed by silica gel column chromatography (dichloromethane-methanol gradient elution) to obtain 1.2 g of the product as a white foamy solid with a yield of 38.87%.

¹ H NMR (500MHz, CDCl ₃ )δ5.96 (t, J=5.0Hz, 2H), 5.72 (s, 4H), 4.78 (s, 2H), 4.09 (d, J=5.0Hz, 4H), 2.23 (t, J=7.5Hz, 4H), 2.16 -2.14(m, 2H), 1.76(s, 4H), 1.66-1.55(m, 12H), 1.37-1.22(m, 24H), 1.17-1.12(m, 4H), 0.85(s, 12H).

Example 2 Compound 1

Step 1) Preparation of Intermediate 1

Memantine (30.51 g, 170.15 mmol, 1 equivalent) and dichloromethane (300 mL) were added to a 500 mL single-mouth bottle, and p-anisaldehyde (24.32 g, 178.66 mmol, 1.05 equivalent) was added after dissolution, and acetic acid (10.21 g, 170.15 mmol, 1 equivalent) was added dropwise under stirring, and stirred at room temperature for 1 hour. Sodium triacetoxyborohydride (54.09 g, 255.23 mmol, 1.5 equivalent) was added, and stirring was continued at room temperature overnight. TLC showed that the reaction of A was basically completed. 400 mL of saturated sodium bicarbonate aqueous solution was added, and the mixture was separated after stirring for 10 minutes. The aqueous phase was extracted with dichloromethane (200 mL*1). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and spin-dried. Methyl tert-butyl ether (500 mL) was added to dissolve it. 16 mL of concentrated hydrochloric acid was added dropwise under stirring to precipitate a white solid. After stirring for 1 hour, the mixture was filtered, and the filter cake was washed with methyl tert-butyl ether and dried in vacuo to obtain intermediate 1 (56.45 g, yield 98.8%) as a white solid.

Step 2) Preparation of Intermediate 2

Weigh N-(4-methoxybenzyl)-memantine hydrochloride (20g, 59.53mmol, 1 equivalent) and place it in a 500mL single-necked bottle, add 150mL water and 200mL methyl tert-butyl ether, and the insoluble solid. Dissolve sodium hydroxide (3.57g, 89.30mmol, 1.5 equivalent) in 50mL water and add it dropwise to the single-necked bottle. The solid gradually dissolves. After stirring for 30 minutes, separate the liquids, extract the aqueous phase with methyl tert-butyl ether (100mL*1), combine the organic phases, and transfer them to a 1L three-necked bottle. Add 200mL of water and sodium bicarbonate (12.50g, 148.83mmol, 2.5 equivalents) to dissolve, add chloromethyl chloroformate (11.51g, 89.30mmol, 1.5 equivalents) dropwise under stirring, control the internal temperature not to exceed 25°C, stir at room temperature for 1 hour after the addition is complete, TLC shows that the reaction of intermediate 1 is complete, separate the liquids, extract the aqueous phase with methyl tert-butyl ether (100mL*1), combine the organic phases, dry over anhydrous sodium sulfate, filter, and spin dry to obtain an oily substance. Add 5mL of methyl tert-butyl ether to dissolve, add 100mL of n-heptane dropwise, precipitate a white solid, stir overnight and filter, wash the filter cake with n-heptane, and pump dry to obtain intermediate 2 (18.50g, yield 79.3%) as a white solid.

Step 3) Preparation of intermediate 2-3

4,4′-(suberoylbis(azadiyl))dibutyric acid (1.3 g, 3.83 mmol, 0.5 equivalent), sodium bicarbonate (1.29 g, 15.30 mmol, 2.0 equivalent) were added to a 100 mL single-mouth bottle, tetrahydrofuran (50 mL), triethylamine (1.06 mL, 7.65 mmol, 1.0 equivalent), stirred at 60° C. for 10 minutes, then intermediate 2 (3.0 g, 7.65 mmol, 1.0 equivalent) was added, stirred and reacted for about 50 hours, until TLC showed that the reaction of memantine intermediate 2 was complete. The reaction solution was cooled to room temperature, filtered, the filter cake was washed with an appropriate amount of dichloromethane, the filtrate was combined, and dried, and the concentrate was purified by column chromatography (dichloromethane-methanol gradient elution) to obtain intermediate 2-3 (2.23 g, yield 55.2%) as a white solid.

₁ H NMR (500MHz, Chloroform-d) δ7.10 (d, J=8.5Hz, 4H), 6.86 (d, J=8.5Hz, 4H), 5.80 (t, J=6.0Hz, 2H), 5.77 (s, 4H), 4.58(s, 4H), 3.82(s, 6H), 3.27(m, 4H), 2.37(t, J=7.5Hz, 4H), 2.21-2.07(m, 6H), 1.96(s, 4H), 1.85-1.79(m , 8H), 1.64(m, 4H), 1.41-1.19(m, 12H), 1.18-1.04(m, 4H), 0.83(s, 12H).

Step 4) Preparation of Compound 1

Place intermediate 2-3 (2.23 g) in a 100 mL single-mouth bottle, add dichloromethane (30 mL) to dissolve, and stir in an ice-water bath. Add trifluoroacetic acid (3 mL) dropwise, and keep stirring in an ice-water bath after the addition is complete. After about 1 hour, TLC shows that the raw material reaction is complete. Slowly pour the reaction solution into 100 mL of saturated sodium bicarbonate aqueous solution and 100 mL of dichloromethane and stir for 5 minutes, stand and separate, collect the organic phase, dry over anhydrous sodium sulfate, filter, spin dry, and purify the concentrate by column chromatography (dichloromethane-methanol gradient elution) to obtain compound 1 (915 mg, yield 53.2%) as a white solid.

ESI-MS: 815.6 [M+H] ⁺ .

¹ H NMR (500MHz, Chloroform-d) δ5.84 (t, J=6.0Hz, 2H), 5.69 (s, 4H), 4.86 (s, 2H), 3.34-3.28 (m, 4H), 2.43 (t, J =7.5Hz, 4H), 2. 20-2.15(m, 6H), 1.90-1.84(m, 4H), 1.79(s, 4H), 1.67-1.57(m, 12H), 1.38-1.27(m, 12H), 1.20-1.13(m, 4H ), 0.85(s, 12H).

Example 3 Compound 3

According to the synthesis method of Example 2, 4,4′-(dodecanoylbis(azadiyl))dibutyric acid was used instead of 4,4′-(suberoylbis(azadiyl))dibutyric acid to prepare Compound 3 with a yield of 36.9% as a white solid.

ESI-MS: 871.6[M+H] ⁺ .

¹ H NMR (500MHz, Chloroform-d) δ5.74 (t, J=6.0Hz, 2H), 5.69 (s, 4H), 4.82 (s, 2H), 3.34-3.28 (m, 4H), 2.43 (t, J =7.5Hz, 4H), 2.20-2.14 (m, 6H), 1.87 (m, 4H), 1.76 (s, 4H), 1.65-1.56 (m, 12H), 1.39 (d, J=12.6Hz, 4H), 1.34-1.27 (m, 16H), 1.21-1.14(m,4H),0.85(s,12H).

Example 4 Compound 2

According to the synthesis method of Example 2, 4,4′-(sebanoylbis(azadiyl))dibutyric acid was used instead of 4,4′-(sebanoylbis(azadiyl))dibutyric acid to prepare Compound 2 with a yield of 41% as a white solid.

ESI-MS: 843.5[M+H] ⁺ .

¹ H NMR (500MHz, Chloroform-d) δ5.75 (t, J=6.0Hz, 2H), 5.67 (s, 4H), 4.82 (s, 2H), 3.31-3.26 (m, 4H), 2.41 (t, J =7.2Hz, 4H), 2. 18-2.10(m, 6H), 1.88-1.80(m, 4H), 1.76(s, 4H), 1.63-1.54(m, 12H), 1.38-1.23(m, 16H), 1.21-1.14(m, 4H ), 0.85(s, 12H).

Example 5 Compound 13

According to the synthesis method of Example 2, 4,4′-(adipoylbis(azadiyl))dibutyric acid was used instead of 4,4′-(suberoylbis(azadiyl))dibutyric acid to prepare Compound 13 with a yield of 81% as a white solid.

ESI-MS: 787.5[M+H] ⁺ .

¹ H NMR (500MHz, Chloroform-d) δ6.01 (t, J=6.0Hz, 2H), 5.67 (s, 4H), 4.86 (s, 2H), 3.32-3.27 (m, 4H), 2.41 (t, J =7.2Hz, 4H), 2.22-2.18(m, 4H), 2.16-2.13( m, 2H), 1.89-1.82 (m, 4H), 1.77 (s, 4H), 1.67-1.64 (m, 4H), 1.61-1.54 (m, 8H) , 1.58 (d, J=4.1Hz, 6H), 1.41-1.26 (m, 8H), 1.18-1.10 (m, 4H), 0.85 (s, 12H).

Example 6 Compound 4

According to the synthesis method of Example 2, 4,4′-(tetradecanoylbis(azadiyl))dibutyric acid was used instead of 4,4′-(suberoylbis(azadiyl))dibutyric acid to prepare compound 4 with a yield of 35% as a white solid.

ESI-MS: 899.7[M+H] ⁺ .

¹ H NMR (500MHz, Chloroform-d) δ5.74 (t, J=6.0Hz, 2H), 5.69 (s, 4H), 4.82 (s, 2H), 3.34-3.28 (m, 4H), 2.43 (t, J =7.5Hz, 4H) , 2.21-2.14(m, 6H), 1.87(m, 4H), 1.76(s, 4H), 1.65-1.55(m, 12H), 1.391.27(m, 24H), 1.21-1.14(m, 4H) ,0.85(s,12H).

Example 7 Compound 11

According to the synthesis method of Example 2, 4,4′-(succinylbis(azadiyl))dibutyric acid was used instead of 4,4′-(suberoylbis(azadiyl))dibutyric acid to prepare Compound 11 with a yield of 56% as a white solid.

ESI-MS: 759.4 [M+H] ⁺ .

¹ H NMR (500MHz, Chloroform-d) δ6.18 (t, J=6.0Hz, 2H), 5.69 (s, 4H), 4.94 (s, 2H), 3.33-3.28 (m, 4H), 2.52 (s, 4H) ), 2.42(t, J=7.2Hz , 4H), 2.19-2.15 (m, 2H), 1.90-1.84 (m, 4H), 1.80 (s, 4H), 1.61-1.54 (m, 8H), 1.41-1.29 (m, 8H), 1.21-1.40 (m, 4H), 0.85 (s, 12H).

Example 8 Compound 14

According to the synthesis method of Example 2, 5,5′-(adipoylbis(azadiyl))divaleric acid was used instead of 4,4′-(suberoylbis(azadiyl))dibutyric acid to prepare Compound 14 with a yield of 26% as a white solid.

ESI-MS: 815.6 [M+H] ⁺ .

Example 9 Compound 15

According to the synthesis method of Example 2, 5,5′-(suberoylbis(azadiyl))divaleric acid was used instead of 4,4′-(suberoylbis(azadiyl))dibutyric acid to prepare Compound 15 with a yield of 18% as a white solid.

ESI-MS: 843.5[M+H] ⁺ .

Example 10 Compound 16

According to the synthesis method of Example 2, 5,5′-(sebacylbis(azadiyl))divaleric acid was used instead of 4,4′-(suberylbis(azadiyl))dibutyric acid to prepare Compound 16 with a yield of 23% as a white solid.

ESI-MS: 871.7 [M+H] ⁺ .

Example 11 Compound 21

According to the synthesis method of Example 2, 6,6′-(adipoylbis(azadiyl))dihexanoic acid was used instead of 4,4′-(suberoylbis(azadiyl))dibutyric acid to prepare Compound 21 with a yield of 41% as a white solid.

ESI-MS: 843.6[M+H] ⁺ .

Example 12 Compound 22

According to the synthesis method of Example 2, 6,6′-(suberoylbis(azadiyl))dihexanoic acid was used instead of 4,4′-(suberoylbis(azadiyl))dibutyric acid to prepare Compound 22 with a yield of 36% as a white solid.

ESI-MS: 871.7 [M+H] ⁺ .

Example 13 Compound 23

According to the synthesis method of Example 2, 6,6′-(sebacylbis(azadiyl))dihexanoic acid was used instead of 4,4′-(suberylbis(azadiyl))dibutyric acid to prepare Compound 23 with a yield of 28% as a white solid.

ESI-MS: 899.6[M+H] ⁺ .

Example 14 Compound 10

According to the synthesis method of Example 2, 4,4′-(glutarylbis(azadiyl))dibutyric acid was used instead of 4,4′-(suberoylbis(azadiyl))dibutyric acid to prepare compound 10 with a yield of 43% as a white solid.

ESI-MS: 773.5[M+H] ⁺ .

Example 15 Compound 12

According to the synthesis method of Example 1, 4,4′-(pimeloylbis(azadiyl))dibutyric acid was used instead of 4,4′-(suberoylbis(azadiyl))dibutyric acid to prepare Compound 12 with a yield of 65% as a white solid.

ESI-MS: 801.6[M+H] ⁺ .

Example 16 Compound 5

According to the synthesis method of Example 2, 4,4′-(hexadecandioylbis(azadiyl))dibutyric acid was used instead of 4,4′-(suberoylbis(azadiyl))dibutyric acid to prepare Compound 5 with a yield of 65% as a white solid.

ESI-MS: 928.7 [M+H] ⁺ .

Embodiment 17

Example 18 Stability Study of Samples

Take an appropriate amount of the sample of the present invention, and prepare a homogeneous solution with methanol, n-butanol and phosphate buffer with pH values of 6.0 and 7.4 in a ratio of 3:1:1, place at 25 and 37° C., take samples at different time points, and perform HPLC detection to examine the stability of the sample.

The measured results are shown in Table 1.

Table 1 Stability of compounds in solution

The results show that the patented compound has good stability, facilitates long-term storage of the preparation, and is more suitable for making long-acting drugs.

Example 19 Preparation of drug representative samples

An appropriate amount of the compound prepared in the present invention was accurately weighed and placed in a 10 mL vial, and a blank matrix solution and 20 g of zirconium oxide beads (0.6-0.8 mm) were added for vortex grinding. After grinding, the suspension sample was transferred, fixed to volume with a blank matrix solution, and dispensed into 5 mL vials to prepare a suspension of about 30 mg/mL. After the content was determined, it was used for rat pharmacokinetic experiments.

Pharmacokinetics of the compound in Example 20 in rats

The suspension prepared in Example 19 was used for animal experiments. Three animals were tested for each compound. SD rats were intramuscularly injected with whole blood at 1h, 2h, 4h, 8h, 24h, 48h, 72h, 96h, 120h, 168h, 216h, 264h, and 336h, respectively. 0.3mL/time point was added, _K2EDTA /heparin sodium was added for anticoagulation, and stabilizer BNPP was added. Plasma was collected by centrifugation within 30 minutes for testing, and the blood drug concentration and duration results were obtained after intramuscular injection in mice.

The measured results are shown in Table 2.

Table 2 Plasma concentrations of memantine at different time points after intramuscular injection of compound suspension in rats (ng/mL)

The test shows that the compound of the present invention has a low dissolution rate, and after a single administration, the drug effect can be sustained for several weeks. In addition, the compound of the present invention is released smoothly in the animal body, without obvious burst release, and the blood drug concentration is stable with a small fluctuation range. Over a long period of time, the blood drug concentration is persistent and stable, and it is suitable for development as a long-acting preparation.

In conclusion, the compound of the present invention has low water solubility and can be well prepared into a suspension preparation for subcutaneous or intramuscular injection. It has a short onset time and a long duration of drug efficacy and has a good prospect for clinical application.

All publications, patents and patent applications cited in this specification are incorporated herein by reference, just as each individual publication, patent or patent application is specifically and individually indicated to be incorporated by reference. Although the claimed subject matter has been described according to various embodiments/implementations, it will be appreciated by those skilled in the art that various modifications/modifications, substitutions, deletions and changes/variations may be made without departing from the spirit of the invention. Therefore, the scope of the claimed subject matter is intended to be limited only by the scope of the appended claims, including their equivalents.

Finally, it should be noted that the above embodiments are only used to illustrate the technical solutions of the present invention rather than to limit the protection scope of the present invention. For ordinary technicians in this field, other different forms of changes or modifications can be made based on the above descriptions and ideas. It is not necessary and impossible to list all the implementation methods here. Any modifications, equivalent substitutions and improvements made within the spirit and principles of the present invention should be included in the protection scope of the claims of the present invention.

Claims (14)

A memantine derivative or a stereoisomer, solvate, or pharmaceutically acceptable salt thereof, characterized in that the memantine derivative has a structure shown in formula (I):
in, ^R1 and ^R2 are each independently H, D or _C1-4 alkyl; Each X is independently a C _1-10 alkyl group or is absent, and each X may be the same or different; Each Y is independently -C(=O)NH-, -NHC(=O)- or absent, and each Y may be the same or different; W is selected from C _1-30 alkyl, C _1-30 heteroalkyl, C _2-30 alkenyl, C _2-30 alkynyl, C _3-10 cycloalkyl, C _3-10 cycloalkylC _1-10 aliphatic, C _2-10 heterocyclyl, C _2-10 heterocyclylC _1-10 aliphatic, aryl, arylC _1-10 aliphatic, heteroaryl or heteroarylC _1-10 aliphatic. The memantine derivative or its stereoisomer, solvate, or pharmaceutically acceptable salt according to claim 1, characterized in that R ¹ and R ² are each independently H, D, methyl or ethyl. The memantine derivative or its stereoisomer, solvate, or pharmaceutically acceptable salt according to claim 1, characterized in that W is selected from C _1-30 alkyl, C _2-30 alkenyl, C _3-10 cycloalkyl, C _3-10 cycloalkyl C _1-6 aliphatic, C _2-7 heterocyclyl, C _2-7 heterocyclyl C _1-6 aliphatic, C _6-10 aryl, C _6-10 aryl C _1-6 aliphatic, C _5-9 heteroaryl or C _5-9 heteroaryl C _1-6 aliphatic. The memantine derivative or its stereoisomer, solvate, or pharmaceutically acceptable salt according to claim 3, characterized in that W is selected from C _1-22 alkyl, C _2-6 alkenyl, C _6-10 aryl, C _3-7 heterocyclyl C _1-6 aliphatic or C _6-10 aryl C _1-6 aliphatic. The memantine derivative or its stereoisomer, solvate, or pharmaceutically acceptable salt according to claim 1, characterized in that the memantine derivative has a structure shown in the following formula (I-1):

Wherein, n is an integer from 3 to 5; m is an integer from 2 to 20. The memantine derivative or its stereoisomer, solvate, or pharmaceutically acceptable salt according to claim 5, characterized in that n is 3. The memantine derivative or its stereoisomer, solvate, or pharmaceutically acceptable salt according to claim 5, characterized in that n is 4. The memantine derivative or its stereoisomer, solvate, or pharmaceutically acceptable salt according to claim 5, characterized in that n is 5. The memantine derivative or its stereoisomer, solvate, or pharmaceutically acceptable salt according to any one of claims 5 to 8, characterized in that m is an integer from 4 to 20; Preferably, m is an integer from 2 to 18; Preferably, m is an integer from 2 to 16; Preferably, m is an integer from 4 to 18; Preferably, m is an integer from 4 to 16; Preferably, m is an integer from 6 to 18; Preferably, m is an integer from 6 to 16; Preferably, m is an integer from 2 to 12; Preferably, m is an integer from 2 to 10; Preferably, m is an integer from 2 to 8; Preferably, m is an integer from 4 to 12; Preferably, m is an integer from 4 to 10; Preferably, m is an integer from 4 to 8. The memantine derivative or its stereoisomer, solvate, or pharmaceutically acceptable salt according to any one of claims 1 to 9, characterized in that the memantine derivative is selected from one of the following structures:


A pharmaceutical composition, characterized in that the pharmaceutical composition comprises the compound according to any one of claims 1 to 10 or its stereoisomer, solvate, or pharmaceutically acceptable salt, and a pharmaceutically acceptable excipient, carrier, or diluent. Use of the compound according to any one of claims 1 to 10 or its stereoisomer, solvate, or pharmaceutically acceptable salt and the pharmaceutical composition according to claim 11 in the preparation of a medicament for preventing and/or treating a central nervous system disease; Preferably, the drug for preventing and/or treating central nervous system diseases is a long-acting drug; Preferably, the central nervous system disease is Alzheimer's disease, Parkinson's disease or brain function damage caused by sequelae of stroke. A method for preventing and/or treating central nervous system diseases, characterized in that it comprises administering the compound according to any one of claims 1 to 10 or its stereoisomer, solvate, or pharmaceutically acceptable salt and the pharmaceutical composition according to claim 11. The treatment method according to claim 13 is characterized in that the central nervous system disease is brain function damage caused by Alzheimer's disease, Parkinson's disease or sequelae of stroke.