Memantine derivative, pharmaceutical composition thereof, and use thereof

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

[0001] 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

[0002] Alzheimer's disease (AD), also known as senile dementia, is a chronic, progressive neurodegenerative disease with an insidious onset. The factors that trigger AD are complex, including neurotransmitters, genetics, the environment, age, and other medical conditions. Research data shows that globally, a new case of dementia is diagnosed every three seconds. In 2018, approximately 50 million people worldwide were living with dementia, a number projected to triple to 152 million by 2050. It is estimated that the global cost of dementia to society was US$1 trillion in 2018, and this figure is projected to reach US$2 trillion by 2030. In low- and middle-income countries, less than 10% of people with dementia are diagnosed, and approximately 94% of those with dementia receive care at home.

[0003] Currently, anti-dementia drugs on the market mainly include cholinesterase inhibitors (donepezil, galantamine, rivastigmine) and N-methyl-D-aspartate (NMDA) receptor non-competitive antagonists (memantine).

[0004] Memantine is a noncompetitive, moderate-affinity, voltage-dependent NMDA receptor antagonist that does not interfere with glutamate activity in the normal brain. Memantine has potential neuroprotective effects in neurodegenerative diseases. Excessive intracellular calcium influx, a key early step in glutamate-induced excitotoxicity, is seen in many degenerative diseases. Memantine binds to the cyclohexidine binding site on the NMDA receptor, reducing calcium influx and potentially inhibiting the cytotoxic effects induced by excitatory amino acids.

[0005] Memantine, developed by Merz in Germany, received approval from the European Patent Medicines Committee in 2002 and entered the EU market that same year. In 2003, memantine was approved by the US Food and Drug Administration for the treatment of moderate to severe Alzheimer's disease. Memantine is also used in other types of dementia, such as vascular dementia, mixed dementia, dementia with Lewy bodies, Parkinson's disease, frontotemporal dementia, and alcohol-related dementia (3-7).

[0006] Neurodegenerative diseases such as Alzheimer's disease primarily affect the elderly. The deterioration of their physical functions makes it difficult for patients to care for themselves, requiring care and placing a significant burden on their families and society. Furthermore, these diseases require long-term medication. Although memantine is the preferred treatment for Alzheimer's disease, it requires oral administration twice daily. Due to the physiological characteristics of patients, oral administration is prone to missed doses, leading to unstable blood drug levels and thus compromising therapeutic efficacy. Therefore, the development of long-acting formulations using chemically synthesized memantine derivatives, combined with modern pharmaceutical technologies, offers a more convenient treatment option for patients with Alzheimer's disease and neurodegenerative diseases, improving patient compliance and ensuring efficacy. This can reduce the burden on patients and their families and bring economic benefits to society.

[0007] Summary of the Invention

[0008] The present invention addresses the inconvenience of patients with central nervous system degeneration requiring daily memantine administration and provides a memantine derivative with long-lasting effects. The compound has low water solubility and can be readily formulated into a suspension formulation. It exhibits a low dissolution rate in vivo. After a single subcutaneous or intramuscular injection, it forms a drug reservoir within the subcutaneous or intramuscular area, from which the drug is slowly released, resulting in a sustained effect lasting several weeks. This reduces the frequency of medication use, improves patient compliance, and maintains efficacy, thus promising promising applications.

[0009] Another object of the present invention is to provide a pharmaceutical composition comprising the memantine derivative with long-lasting effect.

[0010] Another object of the present invention is to provide the use of the long-acting memantine derivative or a composition thereof in the preparation of a medicament for preventing and / or treating central nervous system diseases, particularly Alzheimer's disease, Parkinson's disease, or brain function recovery treatment for stroke sequelae. In particular, the medicament is a long-acting medicament.

[0011] The above-mentioned object of the present invention is achieved through the following solutions:

[0012] A memantine derivative or a stereoisomer, solvate, or pharmaceutically acceptable salt thereof, wherein the memantine derivative has a structure represented by formula (I):

[0013] in,

[0014] R 1 and R 2 Each independently is H, D or C 1-4 alkyl;

[0015] Each X is independently C 1-10 The alkyl group is or is not present, each X may be the same or different;

[0016] Each Y is independently -C(=O)NH-, -NHC(=O)- or absent, and each Y may be the same or different;

[0017] 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 Heterocyclic group, C 2-10 Heterocyclyl C 1-10 Aliphatic, aryl, aryl C 1-10 Aliphatic, heteroaryl or heteroarylC 1-10 Fatty.

[0018] In some embodiments, R 1 and R 2 Each is independently H, D, methyl or ethyl.

[0019] In some embodiments, 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 Heterocyclic group, 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 Fatty.

[0020] In some embodiments, 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 Fatty.

[0021] 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, C1-20 Alkyl, C 1-22 Alkyl, C 2-6 Alkenyl, phenylene, C 2-7 Heterocyclyl C 1-6 Aliphatic or C 6-10 Aryl C 1-6 Fatty.

[0022] In some embodiments, W is C 2-6 Alkenyl.

[0023] 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.

[0024] 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.

[0025] 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.

[0026] In some embodiments, the memantine derivative has the structure shown in the following formula (I-1):

[0027] wherein n is an integer from 3 to 5; and m is an integer from 2 to 20.

[0028] In some embodiments, n is 3.

[0029] In some embodiments, n is 4.

[0030] In some embodiments, n is 5.

[0031] In some embodiments, m is an integer from 2 to 18.

[0032] In some embodiments, m is an integer from 2 to 16.

[0033] In some embodiments, m is an integer from 4 to 20.

[0034] In some embodiments, m is an integer from 4 to 18.

[0035] In some embodiments, m is an integer from 4 to 16.

[0036] In some embodiments, m is an integer from 6 to 18.

[0037] In some embodiments, m is an integer from 6 to 16.

[0038] In some embodiments, m is an integer from 2 to 12.

[0039] In some embodiments, m is an integer from 2 to 10.

[0040] In some embodiments, m is an integer from 2 to 8.

[0041] In some embodiments, m is an integer from 4 to 12.

[0042] In some embodiments, m is an integer from 4 to 10.

[0043] In some embodiments, m is an integer from 4 to 8.

[0044] 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.

[0045] In some specific embodiments, when n is 3, m is 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12.

[0046] In some specific embodiments, when n is 3, m is 2, 3, 4, 5, 6, 7, 8, 9 or 10.

[0047] In some specific embodiments, when n is 3, m is 2, 3, 4, 5, 6, 7 or 8.

[0048] 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.

[0049] 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.

[0050] In some specific embodiments, when n is 3, m is 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 or 16.

[0051] In some specific embodiments, when n is 3, m is 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17 or 18.

[0052] In some specific embodiments, when n is 3, m is 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 or 16.

[0053] In some specific embodiments, when n is 3, m is 4, 6, 8, 10, 12, 14 or 16.

[0054] In some specific embodiments, when n is 3, m is 8, 10, 12, 14 or 16.

[0055] In some specific embodiments, when n is 3, m is 8, 10, 12 or 14.

[0056] In some specific embodiments, when n is 3, m is 5, 7, 9, 11, 13 or 15.

[0057] In some specific embodiments, when n is 3, m is 9, 11, 13 or 15.

[0058] 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.

[0059] 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.

[0060] 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.

[0061] In some specific embodiments, when n is 4, m is 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 or 16.

[0062] In some specific embodiments, when n is 4, m is 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17 or 18.

[0063] In some specific embodiments, when n is 4, m is 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 or 16.

[0064] In some specific embodiments, when n is 4, m is 4, 6, 8, 10, 12, 14 or 16.

[0065] In some specific embodiments, when n is 4, m is 8, 10, 12, 14 or 16.

[0066] In some specific embodiments, when n is 4, m is 8, 10, 12 or 14.

[0067] In some specific embodiments, when n is 4, m is 5, 7, 9, 11, 13 or 15.

[0068] In some specific embodiments, when n is 4, m is 9, 11, 13 or 15.

[0069] 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.

[0070] 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.

[0071] 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.

[0072] In some specific embodiments, when n is 5, m is 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 or 16.

[0073] In some specific embodiments, when n is 5, m is 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17 or 18.

[0074] In some specific embodiments, when n is 5, m is 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 or 16.

[0075] In some specific embodiments, when n is 5, m is 4, 6, 8, 10, 12, 14 or 16.

[0076] In some specific embodiments, when n is 5, m is 8, 10, 12, 14 or 16.

[0077] In some specific embodiments, when n is 5, m is 8, 10, 12 or 14.

[0078] In some specific embodiments, when n is 5, m is 5, 7, 9, 11, 13 or 15.

[0079] In some specific embodiments, when n is 5, m is 9, 11, 13 or 15.

[0080] In some embodiments, the memantine derivative is selected from one of the following structures:

[0081] Another object of the present invention is to provide a composition comprising the above-mentioned compound or its stereoisomers, solvates, or pharmaceutically acceptable salts, and pharmaceutically acceptable excipients, carriers, or diluents.

[0082] In some embodiments, the pharmaceutical compositions described herein further comprise an additional therapeutic agent.

[0083] The present invention also provides use of the above-mentioned compound or its stereoisomer, solvate, or pharmaceutically acceptable salt, and the above-mentioned pharmaceutical composition in the preparation of drugs for preventing and / or treating central nervous system diseases.

[0084] Wherein, the drug for preventing and / or treating central nervous system diseases is a long-acting drug.

[0085] Preferably, the central nervous system disease is Alzheimer's disease, Parkinson's disease or brain function damage caused by sequelae of stroke.

[0086] 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 stereoisomers, solvates, or pharmaceutically acceptable salts and the above-mentioned pharmaceutical composition.

[0087] Preferably, the central nervous system disease is Alzheimer's disease, Parkinson's disease or brain function damage caused by sequelae of stroke.

[0088] The compound of the present invention has low water solubility and can be well prepared into a suspension preparation. It has a low dissolution rate and can achieve a drug effect lasting for several weeks after a single administration.

[0089] Pharmaceutical compositions, preparations and uses

[0090] When used as a medicine, the compounds of this invention are usually used in the form of a pharmaceutical composition. The composition can be prepared in a manner well known in pharmaceutical technology and comprises at least one compound of the present 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 present invention used, the age, weight and response of the individual patient, the severity of the patient's symptoms, etc.

[0091] 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 formulation 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.

[0092] The composition for parenteral administration can be an emulsion or a sterile solution. In certain embodiments, propylene glycol, polyethylene glycol, vegetable oil, particularly olive oil or injectable organic ester can be used as a solvent or carrier, and in some embodiments, ethyl oleate is used as a solvent or carrier. 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.

[0093] 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 provided by the invention or other preventive agents or therapeutic agents) and typical one or more pharmaceutically acceptable carriers or excipients of a preventive or therapeutically effective amount. In specific embodiments and the present invention, the term "pharmaceutically acceptable" refers to a drug approved by a regulatory agency of a federal or state government, or listed in the U.S. Pharmacopoeia or other generally recognized pharmacopoeias for animals, particularly for humans. The term "carrier" includes diluents, adjuvants (for example, Freund's adjuvant (complete and incomplete)), excipients or vehicles used together with the therapeutic agent. Such pharmaceutical carriers can be sterile liquids, such as water and oils, including those of petroleum, animal oils, vegetable oils or synthetic origins, 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).

[0094] Typical pharmaceutical compositions and dosage forms include one or more excipients. Suitable excipients are well known to those skilled in the art of pharmacy. In certain embodiments, suitable excipients include starch, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, sodium stearate, glycerol monostearate, talc, sodium chloride, skim milk powder, glycerol, propylene, ethylene glycol, water, ethanol, and the like. Whether a particular excipient 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 administered 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.

[0095] 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, weight, age, and individual health of the individual, the condition or disease to be treated, or its severity. A physician, clinician, or veterinarian can readily determine the effective amount of each active ingredient necessary to prevent, treat, or inhibit the progression of a disease or condition.

[0096] The above-described dosage characteristics can be demonstrated by in vitro and in vivo studies using suitable mammals, such as mice, rats, dogs, monkeys, or isolated organs, tissues, and products thereof. The compounds of the present invention can be applied in vitro in the form of solutions, such as aqueous solutions, and in vivo in the form of suspensions or aqueous solutions, either enterally or parenterally (preferably intravenously). In vitro dosages range from about 10-3 to 10-9 molar concentrations. In vivo therapeutically effective amounts, depending on the route of administration, range from about 0.1 to 500 mg / kg or about 1 to 100 mg / kg.

[0097] 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 from another ingredient by the same or different routes of administration, or the two may be administered together in the same pharmaceutical composition.

[0098] In another aspect, the present invention provides a compound of the present invention or a pharmaceutical composition comprising the compound of the present invention for use 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 for use in preventing and / or treating central nervous system diseases in mammals, particularly brain function recovery treatment for Alzheimer's disease, Parkinson's disease, or stroke sequelae.

[0099] Compared with the prior art, the present invention has the following beneficial effects:

[0100] After entering the organism, the compound of the present invention can be decomposed into the active ingredient of memantine, thereby exerting its effect. In addition, the compound of the present invention has low water solubility and can be well prepared into a suspension preparation. It has a low dissolution rate in the organism. 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. At the same time, the blood drug concentration is maintained for a long time and is stable, and the drug effect can be achieved for several weeks, thereby reducing the number of medications for patients, improving patient compliance, and ensuring efficacy. The compound has good application prospects. BRIEF DESCRIPTION OF THE DRAWINGS

[0101] FIG1 is a time curve of the plasma concentration of the original drug after intramuscular injection of the compound of the present invention into rats.

[0102] Definitions and General Terms

[0103] 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.

[0104] Unless otherwise specified or clearly contradicted by context, the articles "a," "an," and "the" as used herein are intended to include "at least one" or "one or more." Thus, as used herein, these articles 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., more than one component may be contemplated for use or use in implementing the described embodiments.

[0105] "Stereoisomers" are compounds that have identical chemical constitutions but differ in the way the atoms or groups are arranged in space. Stereoisomers include enantiomers, diastereomers, conformers (rotamers), geometric (cis / trans) isomers, atropisomers, and the like.

[0106] Any asymmetric atom (e.g., carbon, etc.) of the compounds disclosed herein can exist in a racemic or enantiomerically enriched form, such as in the (R)-, (S)-, or (R, S)-configuration. In certain 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 terms of the (R)- or (S)-configuration.

[0107] "Pharmaceutically acceptable" refers to compounds, materials, compositions and / or dosage forms that are, within the scope of sound medical judgment, suitable for use in contact with the tissues of patients 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.

[0108] In general, the term "substituted" indicates that one or more hydrogen atoms in a given structure are replaced with 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 with one or more substituents selected from a specified group, the substituents may be the same or different at each position.

[0109] The term "unsubstituted" means that the designated group bears no substituents.

[0110] The term "optionally substituted with..." can be used interchangeably with the term "unsubstituted or substituted with...", i.e., the structure is unsubstituted or substituted with one or more substituents described herein, including, but not limited to, H, D, F, Cl, Br, I, N3, CN, NO2, OH, SH, NH2, 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 All have the definitions described in the present invention.

[0111] In addition, it should be noted that, unless otherwise explicitly stated, 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. They 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.

[0112] In various parts of this specification, substituents of compounds disclosed herein are disclosed in terms of group types or ranges. It is specifically noted that the present invention includes every independent subcombination of the individual members of these group types and ranges. For example, the term "C 1-6 "Alkyl" specifically refers to methyl, ethyl, C3 alkyl, C4 alkyl, C5 alkyl and C6 alkyl as disclosed independently.

[0113] In various parts of the present invention, linking substituents are described. When the structure clearly requires a linking group, the Markush variables listed for the group are understood to be linking groups. For example, if the structure requires a linking group and the Markush group definition for the variable lists "alkyl" or "aryl", it is understood that the "alkyl" or "aryl" represents the alkylene group or arylene group, respectively, of the linking.

[0114] The term "alkyl" or "alkyl group" as used herein refers to a saturated, linear 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, an alkyl group contains 1-30 carbon atoms. Unless otherwise specified, an alkyl group contains 1-22 carbon atoms. In one embodiment, an alkyl group contains 1-12 carbon atoms; in another embodiment, an alkyl group contains 1-6 carbon atoms; in yet another embodiment, an alkyl group contains 1-4 carbon atoms; and in yet another embodiment, an alkyl group contains 1-3 carbon atoms. The alkyl group may be optionally substituted with one or more substituents described herein.

[0115] Examples of alkyl groups include, but are not limited to, methyl (Me, -CH3), ethyl (Et, -CH2CH3), n-propyl (n-Pr, -CH2CH2CH3), isopropyl (i-Pr, -CH(CH3)2), n-butyl (n-Bu, -CH2CH2CH2CH3), isobutyl (i-Bu, -CH2CH(CH3)2), sec-butyl (s-Bu, -CH(CH3)CH2CH3), tert-butyl (t-Bu, -CH(CH3)CH2CH3), u, -C(CH3)3), n-pentyl (-CH2CH2CH2CH2CH3), 2-pentyl (-CH(CH3)CH2CH2CH3), 3-pentyl (-CH(CH2CH3)2), 2-methyl-2-butyl (-C(CH3)2CH2CH3), 3-methyl-2-butyl (-CH(CH3)CH(CH3)2), 3-methyl-1-butyl (-CH2CH2CH(CH3)2), 2-methyl- 1-Butyl (-CH2CH(CH3)CH2CH3), n-hexyl (-CH2CH2CH2CH2CH2CH3), 2-hexyl (-CH(CH3)CH2CH2CH2CH3), 3-hexyl (-CH(CH2CH3)(CH2CH2CH3)), 2-methyl-2-pentyl (-C(CH3)2CH2CH2CH3), 3-methyl-2-pentyl (-CH(CH3)CH(CH3)CH2C H3), 4-methyl-2-pentyl (-CH(CH3)CH2CH(CH3)2), 3-methyl-3-pentyl (-C(CH3)(CH2CH3)2), 2-methyl-3-pentyl (-CH(CH2CH3)CH(CH3)2), 2,3-dimethyl-2-butyl (-C(CH3)2CH(CH3)2), 3,3-dimethyl-2-butyl (-CH(CH3)C(CH3)3), n-heptyl, n-octyl, C 12 Alkyl, C 14 Alkyl, C 16 Alkyl, C 18 Alkyl, C20 Alkyl, C 22 Alkyl, etc.

[0116] The term "alkenyl" refers to a straight or branched chain monovalent hydrocarbon radical containing 2 to 30 carbon atoms, wherein there is at least one site of unsaturation, i.e., a carbon-carbon sp 2 Double bonds, including "cis" and "trans" orientations, or "E" and "Z" orientations. In one embodiment, the alkenyl group contains 2-30 carbon atoms; in one embodiment, the alkenyl group contains 2-22 carbon atoms; in one embodiment, the alkenyl group contains 2-8 carbon atoms; in another embodiment, the alkenyl group contains 2-6 carbon atoms; in yet another embodiment, the alkenyl group contains 2-4 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.

[0117] The term "alkynyl" refers to a straight or branched monovalent hydrocarbon radical containing 2-30 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 2-30 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 (-CH2C≡CH), 1-propynyl (-C≡C-CH3), and the like. The alkynyl group may be optionally substituted with one or more substituents described herein.

[0118] As used herein, the term "aliphatic" or "aliphatic group" refers to a straight (i.e., unbranched) or branched, substituted or unsubstituted hydrocarbon chain that is fully saturated or contains one or more degrees of unsaturation. Unless otherwise specified, an aliphatic group contains 1-30 carbon atoms, with some embodiments containing 1-20 carbon atoms, some embodiments containing 1-10 carbon atoms, other embodiments containing 1-8 carbon atoms, other embodiments containing 1-6 carbon atoms, other embodiments containing 1-4 carbon atoms, and other embodiments containing 1-3 carbon atoms. Suitable aliphatic groups include, but are not limited to, straight or branched, substituted or unsubstituted alkyl, alkenyl, or alkynyl groups, such as methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, hexyl, isobutyl, sec-butyl, vinyl, ethynyl, and the like.

[0119] The term "cycloalkyl" as used herein, unless otherwise indicated, 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., C3 to C 10 In some embodiments, the cycloalkyl group 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 a cycloalkyl group is substituted, it can be on any ring, that is, on any aromatic ring or non-aromatic ring contained by the cycloalkyl group, and can be independently substituted by one or more substituents described herein.

[0120] The terms "heterocyclyl" and "heterocycle" are used interchangeably herein and, unless otherwise indicated, refer to a monovalent monocyclic non-aromatic ring system and / or 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, and the remaining ring atoms are carbon atoms; and wherein one or more (in certain embodiments, 1, 2, 3 or 4) of the ring atoms of the polycyclic ring system are independently selected from O, S(O) 0-2and N heteroatoms, and the remaining ring atoms are all carbon atoms. In some embodiments, the heterocycle contains 1 or 2 heteroatoms, and the heteroatoms are all nitrogen atoms. In some embodiments, the heterocyclyl is polycyclic and contains one heteroatom in a non-aromatic ring, or contains one heteroatom in an aromatic ring, or contains two heteroatoms in an aromatic ring, or contains two heteroatoms one of which is in an aromatic ring and the other is in a non-aromatic ring. In some embodiments, the heterocyclyl group has 3-20, 3-15, 3-10, 3-8, 4-7, or 5-6 ring atoms. In some embodiments, the heterocyclyl 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 may be optionally oxidized, one or more nitrogen atoms may be optionally quaternized, and one or more carbon atoms may 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 radical 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 radical 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, oxiranyl, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, 2-pyrrolinyl, 3-pyrrolinyl, pyrazolinyl, 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 benzoxanyl, benzodioxanyl, benzodioxolyl, benzofuranonyl, benzopyronyl, benzopyranyl, dihydrobenzofuranyl, chromanthiophene, benzothiopyranyl, benzoxazinyl, β-carbolinyl, chromanyl, chromonyl, cinnolinyl, coumarinyl, decahydroquinolinyl, decahydroisoquinolinyl, dihydrobenzisothiazinyl, dihydrobenzisothiazinyl, 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, isochromanyl, isocoumarinyl, isoindolinyl (isoindolinyl), 1-oxo-isoindolinyl, 1,3-dioxo-isoindolinyl, 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, xanthanenyl and 1,3,5-trithianyl. Examples of heterocyclic groups in which the -CH2- group is replaced by -C(=O)- include, but are not limited to, 2-oxopyrrolidinyl, oxo-1,3-thiazolidinyl, 2-piperidonyl, 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 groups may be optionally substituted with one or more substituents described herein.

[0121] 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 indicated, the 3-8 atom heterocyclic group can be a carbon group or a nitrogen group, and the -CH2- group can optionally be replaced by -C(=O)-. The sulfur atom of the ring can optionally be oxidized to an S-oxide. The nitrogen atom of the ring can optionally be oxidized to an N-oxide. Examples of heterocyclic groups of 3-8 atoms include, but are not limited to, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, 2-pyrrolinyl, 3-pyrrolinyl, pyrazolinyl, 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, oxazepanyl, Base, diazepine Base, thiazolin Examples of heterocyclic groups in which the -CH2- group is replaced by -C(=O)- include, but are not limited to, 2-oxopyrrolidinyl, oxo-1,3-thiazolidinyl, 2-piperidonyl, 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 3-8 atom heterocyclic group may be optionally substituted with one or more substituents described herein.

[0122] In one embodiment, the heterocyclyl group is a 3-6 atom heterocyclyl group, which refers to a saturated or partially unsaturated monocyclic ring containing 3-6 ring atoms, at least one of which is selected from nitrogen, sulfur, and oxygen atoms. Unless otherwise indicated, the 3-6 atom heterocyclyl group can be a carbon group or a nitrogen group, and the -CH2- group can optionally be replaced by -C(=O)-. The sulfur atom of the ring can optionally be oxidized to an S-oxide. The nitrogen atom of the ring can optionally be oxidized to an N-oxide. The 3-6 atom heterocyclyl group can optionally be substituted with one or more substituents described herein.

[0123] 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 indicated, 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 heterocyclyl groups include, but are not limited to, pyrrolidinyl, 2-pyrrolinyl, 3-pyrrolinyl, pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, 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-piperidonyl, 3,5-dioxopiperidinyl, pyrimidinedione, 1,1-dioxothiomorpholinyl. The 5-6 atom heterocyclyl groups may be optionally substituted with one or more substituents described herein.

[0124] The term "aryl" as used herein, unless otherwise specified, refers to a monovalent C6-C 14 Carbocyclic ring system, wherein the aromatic ring system is monocyclic, bicyclic or tricyclic. The aryl group can be connected to the main structure through any of its rings, i.e., any aromatic ring or non-aromatic ring. In some embodiments, the aryl group is phenyl, naphthyl, bicyclic [4.2.0] octa-1,3,5-trienyl, indanyl, fluorenyl or tetrahydronaphthyl. When the aryl group is substituted, it can be substituted on any ring, i.e., on any aromatic ring or non-aromatic ring contained by the aryl group. In some or any embodiment, the aryl group is phenyl, naphthyl, tetrahydronaphthyl, fluorenyl or indanyl. The aryl group can be independently and optionally substituted by one or more substituents described herein.

[0125] The term "heteroaryl" as used herein, unless otherwise specified, refers to a monovalent monocyclic or polycyclic aromatic group wherein at least one (in certain embodiments, 1, 2, 3, or 4) of the ring atoms are independently selected from O, S(O), 0-2and N heteroatoms. The heteroaryl group is connected to the rest of the molecule through any atom in the ring system, where its 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 group has 5-20, 5-15, or 5-10 ring atoms. When the heteroaryl group is substituted, it can be substituted on any ring. In certain embodiments, monocyclic heteroaryl groups include, but are not limited to, furyl, imidazolyl, isothiazolyl, isoxazolyl, oxadiazolyl, oxazolyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridyl, 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, isoquinolinyl, isothiazolyl, naphthyridinyl, oxazolopyridinyl, phthalazinyl, pteridinyl, purinyl, pyridopyridinyl, pyrrolopyridinyl, quinolinyl, 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.

[0126] 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 S.M. Berge et al., "Describe Pharmaceutically Acceptable Salts in Detail in J. Pharmaceutical Sciences, 1977, 66: 1-19." Pharmaceutically acceptable salts formed with non-toxic acids include, but are not limited to, inorganic acid salts such as hydrochlorides, hydrobromides, phosphates, sulfates, and perchlorates formed by reaction with amino groups, and organic acid salts such as acetates, oxalates, maleates, tartrates, citrates, succinates, and malonates, or salts obtained by other methods described in the literature, such as ion exchange. 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 + (C1-C4 alkyl) 4 salts. The present invention also contemplates quaternary ammonium salts formed by any compound containing a N group. 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 ions, such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, C 1-8 Sulfonates and aromatic sulfonates.

[0127] As used herein, a "solvate" refers to an association formed between one or more solvent molecules and a 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 when the solvent molecule is water.

[0128] 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 associated with one water molecule, such as a monohydrate; in other embodiments, one molecule of the compound of the present invention may be associated 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 associated 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.

[0129] As used herein, the term "treating" any disease or condition, in some embodiments, refers to ameliorating the disease or condition (i.e., slowing or arresting 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 a perceptible symptom) or physiologically (e.g., stabilizing a physical parameter), or both. In other embodiments, "treating" refers to preventing or delaying the onset, occurrence, or worsening of a disease or condition. DETAILED DESCRIPTION

[0130] The present invention is further described in detail below with reference to specific examples. The examples are intended only to illustrate the present invention and are not intended to limit the scope of the present invention. The experimental methods used in the following examples are conventional methods unless otherwise specified; the materials and reagents used are commercially available reagents and materials unless otherwise specified.

[0131] Generally, the compounds of the present invention can be prepared by the methods described herein, unless otherwise specified, wherein the substituents are as defined in Formula I, II or III. The following reaction schemes and examples are provided to further illustrate the present invention.

[0132] Those skilled in the art will recognize that the chemical reactions described herein can be used to appropriately prepare many other compounds of the present invention, and that other methods for preparing the compounds of the present invention are considered to be within the scope of the present invention. For example, the synthesis of non-exemplified compounds according to the present invention can be successfully accomplished by those skilled in the art through modifications, such as appropriate protection of interfering groups, by utilizing other known reagents in addition to those described herein, or by making conventional modifications to the reaction conditions. In addition, the reactions disclosed herein and known reaction conditions are also generally applicable to the preparation of other compounds of the present invention.

[0133] 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 Plant, Guangdong Guanghua Chemical Reagent Plant, Guangzhou Chemical Reagent Plant, Tianjin Haoyuyu Chemical Co., Ltd., Tianjin Fuchen Chemical Reagent Plant, Wuhan Xinhuayuan Technology Development Co., Ltd., Qingdao Tenglong Chemical Reagent Co., Ltd., and Qingdao Ocean Chemical Plant.

[0134] Anhydrous tetrahydrofuran, dioxane, toluene, and diethyl ether were dried over sodium reflux. Anhydrous dichloromethane and chloroform were dried over calcium hydride reflux. Ethyl acetate, petroleum ether, n-hexane, N,N-dimethylacetamide, and N,N-dimethylformamide were dried over anhydrous sodium sulfate before use.

[0135] The following reactions were generally carried out under a positive pressure of nitrogen or argon or with a drying tube over anhydrous solvents (unless otherwise indicated), reaction flasks were plugged with suitable rubber stoppers, and substrates were introduced via syringe. All glassware was dried.

[0136] The chromatographic column used was a silica gel column. Silica gel (200-300 mesh) was purchased from Qingdao Ocean Chemical Plant.

[0137] 1 H NMR spectra were recorded using a Bruker 400 MHz or 500 MHz nuclear magnetic resonance spectrometer. 1 H NMR spectra were obtained in CDCl₃, DMSO-d₆, CD₃OD, or acetone-d₆ as solvents (in ppm), using TMS (0 ppm) or chloroform (7.26 ppm) as the reference standard. When multiple peaks are present, the following abbreviations are used: s (singlet), d (doublet), t (triplet), m (multiplet), br (broadened), dd (doublet of doublets), and dt (doublet of triplets). Coupling constants are expressed in Hertz (Hz).

[0138] The measurement conditions of low-resolution mass spectrometry (MS) data are: Thermo LTQ (column model: Zorbax SB-C18, 2.1x30mm, 3.5 microns, 6 min, flow rate of 0.6 mL / min. Mobile phase: 5%-95% ((CH3CN containing 0.1% formic acid) in (H2O containing 0.1% formic acid) ratio), using electrospray ionization (ESI), at 210nm / 254nm, with UV detection.

[0139] Pure compounds were analyzed using Agilent 1260 pre-HPLC or Calesep pump 250 pre-HPLC (column model: NOVASEP 50 / 80 mm DAC) with UV detection at 210 nm / 254 nm.

[0140] The following abbreviations are used throughout this invention:

[0141] Typical synthetic steps for preparing the compounds disclosed in the present invention are shown in the following synthetic schemes.

[0142] Example 1

[0143] Step 1) Preparation of Intermediate 1

[0144] Memantine (30.51 g, 170.15 mmol, 1 equivalent) and dichloromethane (300 mL) were added to a 500 mL single-necked flask. After dissolution, p-anisaldehyde (24.32 g, 178.66 mmol, 1.05 equivalents) was added. Acetic acid (10.21 g, 170.15 mmol, 1 equivalent) was added dropwise with stirring, and the mixture was stirred at room temperature for 1 hour. Sodium triacetoxyborohydride (54.09 g, 255.23 mmol, 1.5 equivalents) was added, and stirring was continued at room temperature overnight. TLC showed that the basic reaction of A was completed, and 400 mL of saturated sodium bicarbonate aqueous solution was added. The mixture was stirred for 10 minutes and then separated. 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 with stirring to precipitate a white solid. After stirring for 1 hour, it 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.

[0145] Step 2) Preparation of Intermediate 2

[0146] Weigh N-(4-methoxybenzyl)-memantine hydrochloride (20 g, 59.53 mmol, 1 equivalent) into a 500 mL single-necked flask. Add 150 mL of water and 200 mL of methyl tert-butyl ether. Dissolve the remaining solid in 50 mL of water. Add sodium hydroxide (3.57 g, 89.30 mmol, 1.5 equivalents) dropwise to the single-necked flask. The solid gradually dissolves. Stir for 30 minutes, then separate the layers. Extract the aqueous phase with methyl tert-butyl ether (100 mL x 1). Combine the organic phases and transfer to a 1 L three-necked flask. 200 mL of water and sodium bicarbonate (12.50 g, 148.83 mmol, 2.5 equivalents) were added to dissolve the mixture. Chloromethyl chloroformate (11.51 g, 89.30 mmol, 1.5 equivalents) was added dropwise with stirring. The internal temperature was controlled not to exceed 25°C. After the addition was complete, the mixture was stirred at room temperature for 1 hour. TLC showed that the reaction of Intermediate 1 was complete. The liquid was separated, and the aqueous phase was extracted with methyl tert-butyl ether (100 mL*1). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and spin-dried to obtain an oil. 5 mL of methyl tert-butyl ether was added to dissolve the mixture, and 100 mL of n-heptane was added dropwise to precipitate a white solid. After stirring overnight, the mixture was filtered, and the filter cake was washed with n-heptane and pumped dry to obtain Intermediate 2 (Int2, 18.50 g, yield 79.3%) as a white solid.

[0147] Step 3) Preparation of Intermediate 3

[0148] To a 250 mL single-necked flask, intermediate 2 (3.0 g, 7.65 mmol, 1.0 equiv), 2,2'-tetradecanediamidinodiacetic acid (1.43 g, 3.83 mmol, 0.5 equiv), and sodium bicarbonate (1.28 g, 15.30 mmol, 2.0 equiv) were added. Tetrahydrofuran (50 mL) and triethylamine (1.06 mL, 7.65 mmol, 1.0 equiv) were then added. The mixture was stirred at 60°C for at least 45 hours, or until TLC indicated that the starting materials had substantially reacted. The reaction mixture was cooled to room temperature, filtered, and the filter cake was washed with ethyl acetate (30 mL x 2). The combined filtrates were concentrated, dissolved in dichloromethane (180 mL), washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and dried by rotary evaporation to afford intermediate 3 (Int3, 4.02 g, 100% yield) as a white foamy solid.

[0149] 1H NMR (500MHz, CDCl3) 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), 4.03 (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, J1=33.5Hz, J2=12.0Hz, 8H), 1.66- 1.60 (m, 4H), 1.32-1.22 (m, 24H), 1.09 (dd, J1=18.0Hz, J2=12.5Hz, 4H), 0.81 (s, 12H).

[0150] Step 4) Preparation of target product

[0151] Intermediate 3 (4.0 g, 3.797 mmol) was placed in a 250 mL single-necked flask and dissolved in dichloromethane (75 mL). Trifluoroacetic acid (7.5 mL) was added dropwise in an ice bath. After the addition was complete, the mixture was stirred in an ice-water bath for 15 minutes, then warmed to room temperature and stirred for an additional 15 minutes. TLC indicated that the reaction of the starting materials was substantially complete. The reaction solution was slowly added to an ice-cold saturated aqueous sodium bicarbonate 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. The mixture was purified by silica gel column chromatography (dichloromethane-methanol gradient elution) to obtain 1.2 g of the product as a white foamy solid in a yield of 38.87%.

[0152] 1 H NMR (500MHz, CDCl3) 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).

[0153] Example 2 Compound 1

[0154] Step 1) Preparation of Intermediate 1

[0155] Memantine (30.51 g, 170.15 mmol, 1 equivalent) and dichloromethane (300 mL) were added to a 500 mL single-necked flask. After dissolution, p-anisaldehyde (24.32 g, 178.66 mmol, 1.05 equivalents) was added. Acetic acid (10.21 g, 170.15 mmol, 1 equivalent) was added dropwise with stirring, and the mixture was stirred at room temperature for 1 hour. Sodium triacetoxyborohydride (54.09 g, 255.23 mmol, 1.5 equivalents) was added, and stirring was continued at room temperature overnight. TLC showed that the basic reaction of A was completed, and 400 mL of saturated sodium bicarbonate aqueous solution was added. The mixture was stirred for 10 minutes and then separated. 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 the mixture, and 16 mL of concentrated hydrochloric acid was added dropwise with 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.

[0156] Step 2) Preparation of Intermediate 2

[0157] Weigh N-(4-methoxybenzyl)-memantine hydrochloride (20 g, 59.53 mmol, 1 equivalent) into a 500 mL single-necked flask. Add 150 mL of water and 200 mL of methyl tert-butyl ether. The clear solution remains undissolved. Dissolve sodium hydroxide (3.57 g, 89.30 mmol, 1.5 equivalents) in 50 mL of water and add dropwise to the single-necked flask. The solid gradually dissolves. Stir for 30 minutes, then separate the layers. Extract the aqueous phase with methyl tert-butyl ether (100 mL x 1). Combine the organic phases and transfer to a 1 L three-necked flask. 200 mL of water and sodium bicarbonate (12.50 g, 148.83 mmol, 2.5 equivalents) were added to dissolve the mixture. Chloromethyl chloroformate (11.51 g, 89.30 mmol, 1.5 equivalents) was added dropwise with stirring. The internal temperature was controlled not to exceed 25°C. After the addition was complete, the mixture was stirred at room temperature for 1 hour. TLC showed that the reaction of Intermediate 1 was complete. The liquids were separated, and the aqueous phase was extracted with methyl tert-butyl ether (100 mL * 1). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and spin-dried to obtain an oil. 5 mL of methyl tert-butyl ether was added to dissolve the mixture, and 100 mL of n-heptane was added dropwise to precipitate a white solid. After stirring overnight, the mixture was filtered, the filter cake was washed with n-heptane, and pumped dry to obtain Intermediate 2 (18.50 g, yield 79.3%) as a white solid.

[0158] Step 3) Preparation of intermediate 2-3

[0159] To a 100 mL single-necked flask, 4,4′-(suberoylbis(azadiyl))dibutyric acid (1.3 g, 3.83 mmol, 0.5 eq) and sodium bicarbonate (1.29 g, 15.30 mmol, 2.0 eq) were added, followed by tetrahydrofuran (50 mL) and triethylamine (1.06 mL, 7.65 mmol, 1.0 eq). The mixture was stirred at 60°C for 10 minutes, followed by the addition of Intermediate 2 (3.0 g, 7.65 mmol, 1.0 eq). The reaction was stirred for approximately 50 hours, until TLC indicated complete reaction of memantine Intermediate 2. The reaction mixture was cooled to room temperature and filtered. The filter cake was washed with an appropriate amount of dichloromethane. The combined filtrates were dried and the concentrate was purified by column chromatography (dichloromethane-methanol gradient elution) to afford Intermediate 2-3 (2.23 g, 55.2% yield) as a white solid.

[0160] 1H 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).

[0161] Step 4) Preparation of Compound 1

[0162] Intermediate 2-3 (2.23 g) was placed in a 100 mL single-necked flask, and dichloromethane (30 mL) was added to dissolve the mixture. The mixture was stirred in an ice-water bath. Trifluoroacetic acid (3 mL) was added dropwise, and stirring was continued in an ice-water bath after the addition was complete. After about 1 hour, TLC showed that the reaction of the raw materials was complete. The reaction solution was slowly poured into 100 mL of saturated sodium bicarbonate aqueous solution and 100 mL of dichloromethane and stirred for 5 minutes. The mixture was allowed to stand for separation, and the organic phase was collected, dried over anhydrous sodium sulfate, filtered, and dried. The concentrate was purified by column chromatography (dichloromethane-methanol gradient elution) to obtain compound 1 (915 mg, yield 53.2%) as a white solid.

[0163] ESI-MS: 815.6[M+H] + .

[0164] 1H 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).

[0165] Example 3 Compound 3

[0166] 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.

[0167] ESI-MS: 871.6[M+H] + .

[0168] 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).

[0169] Example 4 Compound 2

[0170] According to the synthesis method of Example 2, 4,4′-(sebanoylbis(azadiyl))dibutyric acid was used instead of 4,4′-(suberoylbis(azadiyl))dibutyric acid to prepare Compound 2 with a yield of 41% as a white solid.

[0171] ESI-MS: 843.5[M+H] + .

[0172] 1H 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).

[0173] Example 5 Compound 13

[0174] 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.

[0175] ESI-MS: 787.5[M+H] + .

[0176] 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).

[0177] Example 6 Compound 4

[0178] According to the synthesis method of Example 2, 4,4′-(tetradecanedioylbis(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.

[0179] ESI-MS: 899.7[M+H] + .

[0180] 1H 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).

[0181] Example 7 Compound 11

[0182] 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.

[0183] ESI-MS: 759.4[M+H] + .

[0184] 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).

[0185] Example 8 Compound 14

[0186] 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 in a yield of 26% as a white solid.

[0187] ESI-MS: 815.6[M+H] + .

[0188] Example 9 Compound 15

[0189] 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.

[0190] ESI-MS: 843.5[M+H] + .

[0191] Example 10 Compound 16

[0192] According to the synthesis method of Example 2, 5,5′-(decaylbis(azadiyl))divaleric acid was used instead of 4,4′-(suberoylbis(azadiyl))dibutyric acid to prepare Compound 16 with a yield of 23% as a white solid.

[0193] ESI-MS: 871.7[M+H] + .

[0194] Example 11 Compound 21

[0195] 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.

[0196] ESI-MS: 843.6[M+H] + .

[0197] Example 12 Compound 22

[0198] 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.

[0199] ESI-MS: 871.7[M+H] + .

[0200] Example 13 Compound 23

[0201] According to the synthesis method of Example 2, 6,6′-(sebacedioylbis(azadiyl))dihexanoic acid was used instead of 4,4′-(suberoylbis(azadiyl))dibutyric acid to prepare Compound 23 with a yield of 28% as a white solid.

[0202] ESI-MS: 899.6[M+H] + .

[0203] Example 14 Compound 10

[0204] 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.

[0205] ESI-MS: 773.5[M+H] + .

[0206] Example 15 Compound 12

[0207] 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.

[0208] ESI-MS: 801.6[M+H] + .

[0209] Example 16 Compound 5

[0210] 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.

[0211] ESI-MS: 928.7[M+H] + .

[0212] Example 17

[0213] Example 18 Stability Study of Samples

[0214] An appropriate amount of the sample of the present invention was prepared into 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, respectively. The solution was placed at 25 and 37° C., and samples were taken at different time points. HPLC detection was performed to investigate the stability of the sample.

[0215] The measured results are shown in Table 1.

[0216] Table 1 Stability of compounds in solution

[0217] 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.

[0218] Example 19 Preparation of drug representative samples

[0219] An appropriate amount of the compound prepared in this invention was accurately weighed and placed in a 10 mL vial. A blank matrix solution and 20 g of zirconium oxide beads (0.6-0.8 mm) were added and vortex-milled. After milling, the suspension sample was transferred, adjusted to volume with blank matrix solution, and dispensed into 5 mL vials to prepare a suspension at approximately 30 mg / mL. After assay, the suspension was used in a pharmacokinetic study in rats.

[0220] Pharmacokinetics of the compound in Example 20 in rats

[0221] Animal experiments were conducted using the suspension prepared in Example 19. Three animals were tested for each compound, and SD rats were administered intramuscularly. Whole blood was collected at 1 hour, 2 hours, 4 hours, 8 hours, 24 hours, 48 ​​hours, 72 hours, 96 hours, 120 hours, 168 hours, 216 hours, 264 hours, and 336 hours. 0.3 mL of whole blood was collected at each time point. K2EDTA / heparin sodium was added for anticoagulation, and the stabilizer BNPP was added. Plasma was centrifuged within 30 minutes for analysis. The blood concentration and duration of drug administration in mice after intramuscular injection were obtained.

[0222] The measured results are shown in Table 2.

[0223] Table 2 Plasma concentrations of memantine at different time points after intramuscular injection of compound suspension in rats (ng / mL)

[0224] Tests have shown that the compounds of this invention have a low dissolution rate, resulting in sustained efficacy for several weeks after a single dose. Furthermore, the compounds of this invention exhibit a smooth release in animals, without a significant burst release, and maintain stable blood concentrations with minimal fluctuations. These concentrations remain persistent and stable over extended periods, making them suitable for development as long-acting formulations.

[0225] In summary, 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 efficacy, and has a good clinical application prospect.

[0226] All publications, patents, and patent applications cited in this specification are incorporated herein by reference, just as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference. Although the claimed subject matter has been described in terms of various embodiments / implementations, those skilled in the art will recognize that various modifications / alterations, 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.

[0227] Finally, it should be noted that the above embodiments are intended only to illustrate the technical solutions of the present invention and are not intended to limit the scope of protection of the present invention. Those skilled in the art will readily appreciate that other variations or modifications may be made based on the above descriptions and concepts. It is not necessary and impossible to provide an exhaustive list of all possible implementations. Any modifications, equivalent substitutions, and improvements made within the spirit and principles of the present invention shall be included within the scope of protection of the claims of the present invention.

Claims

1. 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, R 1 and R 2 Each independently is H, D or C 1-4 alkyl; Each X is independently C 1-10 The alkyl group may be 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 Heterocyclic group, C 2-10 Heterocyclyl C 1-10 Aliphatic, aryl, aryl C 1-10 Aliphatic, heteroaryl or heteroarylC 1-10 Fatty.

2. The memantine derivative or its stereoisomer, solvate, or pharmaceutically acceptable salt according to claim 1, characterized in that: The R 1 and R 2 Each is independently H, D, methyl or ethyl.

3. The memantine derivative or its stereoisomer, solvate, or pharmaceutically acceptable salt according to claim 1, characterized in that: The 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 Heterocyclic group, 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 Fatty.

4. The memantine derivative or its stereoisomer, solvate, or pharmaceutically acceptable salt according to claim 3, characterized in that: The 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 Fatty.

5. 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.

6. The memantine derivative or its stereoisomer, solvate, or pharmaceutically acceptable salt according to claim 5, characterized in that: The n is 3.

7. The memantine derivative or its stereoisomer, solvate, or pharmaceutically acceptable salt according to claim 5, characterized in that: The n is 4.

8. The memantine derivative or its stereoisomer, solvate, or pharmaceutically acceptable salt according to claim 5, characterized in that: The n is 5.

9. The memantine derivative or its stereoisomer, solvate, or pharmaceutically acceptable salt according to any one of claims 5 to 8, characterized in that: The 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.

10. 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:

11. A pharmaceutical composition, characterized in that The pharmaceutical composition comprises the compound according to any one of claims 1 to 10 or a stereoisomer, solvate, or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient, carrier, or diluent.

12. 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 central nervous system diseases; 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.

13. A method for preventing and / or treating central nervous system diseases, characterized in that: The method comprises administering the compound according to any one of claims 1 to 10 or a stereoisomer, solvate, or pharmaceutically acceptable salt thereof and the pharmaceutical composition according to claim 11.

14. The method of claim 13, characterized in that: The central nervous system disease is Alzheimer's disease, Parkinson's disease or brain function damage caused by sequelae of stroke.

Images