SARM1 enzyme activity inhibitor and application thereof

Abstract

The present invention provides the use of an SARM1 enzyme activity inhibitor in the treatment of neurodegenerative or neurological diseases or disorders. The present invention particularly provides a compound of formula (I) as an SARM1 enzyme activity inhibitor and a pharmaceutical composition thereof. # imgabs0 #

Description

Technical Field

[0001] The present application relates to compounds that can be used to inhibit SARM1 enzyme activity, and / or the use of these compounds in treating and / or preventing neurodegenerative or neurological diseases or disorders associated with SARM1 enzyme activity. Background Art

[0002] Neurodegenerative diseases are a class of diseases that can seriously harm humans, which can cause devastating damage, such as progressive diseases of nerve cell death. As the primary neurodegenerative diseases, central nervous system diseases such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis (ALS), Huntington's disease, and peripheral nervous system diseases such as diabetes are already known. Most of them are related to aging, and in fact the onset of these diseases increases with age, but there are also cases where they occur in middle-aged people or even younger people.

[0003] As a result of research on brain structure and function, the effects of neurotransmitters and neurotrophic factors have been gradually clarified, but many local causes of neurodegeneration are still unclear. Only for Parkinson's disease, the relationship between the disease and a special neurotransmitter, i.e., dopamine, has been clarified, and the precursor of dopamine, L-dopa, has been used as a drug to alleviate neurological symptoms and restore neurological function. However, L-dopa cannot inhibit the development of neurodegeneration, and gradually loses its effect as the disease progresses, i.e., dopamine-based neuronal cells degenerate and become defective. Similarly, Alzheimer's disease is also caused by the degeneration and defect of various nerve cells, such as acetylcholine-based nerve cells, monoamine-based nerve cells, etc. As a drug for treating this disease, cholinesterase inhibitors have been put on the market or are being developed. However, L-dopa for treating Parkinson's disease is still limited to symptomatic treatment to temporarily improve neurological symptoms.

[0004] Therefore, there is a lack of effective therapeutic drugs for neurodegenerative diseases.

[0005] Studies have found that axonal damage occurs in a variety of neurodegenerative diseases, accidental injuries and other neurological diseases. Axonal degeneration can cause structural necrosis and functional disorders of the peripheral nervous system, ultimately leading to acquired or hereditary degenerative lesions of the central nervous system.

[0006] Although there is no very effective pharmacological method to accurately evaluate the weight of the morbidity caused by axonal degeneration, it has been found in histopathological studies that significant axonal damage degradation was observed in the early stages of various neuropathy such as Alzheimer's disease, Parkinson's disease, multiple sclerosis, amyotrophic lateral sclerosis, and peripheral neuropathy, indicating that axonal degeneration plays an important role in the development of neuropathy (Fischer et al., Neuro-degenerative Diseases, 2007, 4:431-442). Therefore, by weakening or even blocking axonal degeneration, maintaining the integrity of neuronal structure and function may be a therapeutic solution that benefits various nervous system diseases.

[0007] In the absence of effective therapeutic drugs for neurodegenerative diseases, the existing technology urgently needs to study and develop new compounds, especially small chemical molecules, including compounds that have effects on axonal degeneration. Summary of the invention

[0008] After long-term research, the present inventors unexpectedly discovered a class of compounds with significant SARM1 enzyme activity inhibitory effects, and found that the compounds can improve axonal degeneration and be used to treat or prevent neurodegenerative diseases and related disorders.

[0009] The SARM1 (Sterile alpha and TIR motif containing 1) protein is composed of three domains, namely the ARM (Armadillo / HEAT repeat) domain at the nitrogen terminus, two tandem SAM (Sterile alpha motif) domains and the TIR (Toll / Interleukin Receptor) domain at the carbon terminus. In addition, there is a mitochondrial localization signal peptide at the nitrogen terminus.

[0010] It is known that in wild-type neurons, axonal injury induces NAD + depletion and axonal degeneration; SARM1 knockout inhibits axonal degeneration, and NAD + Maintained at normal levels, indicating that SARM1 promotes NAD + consumption, exacerbating axonal degeneration.

[0011] The Milbrandt group at the University of Washington School of Medicine prepared the TIR domain of SARM1 (SARM1-TIR) and found that it has NAD + Through rigorous E. coli expression purification experiments and cell-free expression systems, high-purity SARM1-TIR was obtained, which ultimately proved that SARM1-TIR can catalyze NAD + Produce adenosine 5'-diphosphate ribose (ADPR) and cyclic adenosine 5'-diphosphate ribose (cADPR).

[0012] SARM1 is a multifunctional signaling enzyme that catalyzes the conversion of multiple substrates into NAD + , NADP + and NA to generate signaling molecules such as cADPR, ADPR, and NAADP. In a variety of neurodegenerative diseases, SARM1 is activated, leading to NAD + Depletion of SARM1 can inhibit axonal degeneration and disease progression, and is therefore considered a potential drug target for related neurological diseases, including TBI, AD, CIPN, ASL, etc.

[0013] In the present disclosure, the inventors prepared the full-length SARM1 for NAD enzyme activity experiments, and used it to screen and obtain the compound molecules of the present invention that have the ability to inhibit enzyme activity.

[0014] Therefore, based on the above findings, in a first aspect, the present invention provides the use of a SARM1 enzyme activity inhibitor in the preparation of a medicament for treating or preventing a neurodegenerative disease or a neurological disease or disorder.

[0015] In another aspect, the present invention provides a use of a SARM1 enzyme activity inhibitor in the preparation of a medicament for treating or preventing axonal degeneration-related diseases or disorders.

[0016] In particular, the present invention provides compounds of formula (I) that are useful as inhibitors of SARM1 enzyme activity:

[0017]

[0018] or its racemate, enantiomer, diastereomer, deuterated substance or pharmaceutically acceptable salt thereof, wherein,

[0019] X1, X2, X3, X4, X5 are each independently selected from CH or N;

[0020] Z represents -CH2-, -CH2(CH3)- or -O-;

[0021] represents a single bond or a double bond;

[0022] Y represents a carbon atom or a nitrogen atom;

[0023] R1 is independently selected from H, halogen, C1-C3 alkyl, cyano, trifluoromethyl, amino, hydroxyl, methoxy-C(O)NH2, preferably H, F, Cl, methyl, cyano and -C(O)NH2;

[0024] R2 is independently selected from H, halogen, C1-C3 alkyl, cyano, trifluoromethyl, amino, hydroxy, methoxy, C1-C3 alkyl-OC(O)-, C1-C3 alkyl-NHC(O)-, preferably H, cyano, Cl, methyl and methoxy;

[0025] M stands for O or S;

[0026] L is selected from -CH2-CH2-, -CH2-, -O- and -CO-, wherein one or two -CH2- may be optionally replaced by -O-, -S-, -CO- or -NH-; preferably, L is selected from -CH2-, -CH2-CH2-, -CH-O-, -O- and -CO-;

[0027]

[0028]

[0029] Wherein, X6, X7, X8 are each independently selected from CH or N;

[0030] R3 is independently selected from H, halogen, methyl, cyano, trifluoromethyl, nitro, preferably H, F, Cl, Br, cyano, trifluoromethyl, nitro;

[0031] R4 is independently selected from H, halogen, methyl, cyano, trifluoromethyl, and nitro, preferably H, F, Cl, Br, cyano, trifluoromethyl, and nitro.

[0032] In some preferred embodiments, E is selected from wherein X6, X7, X8, R3 and R4 have the same meanings as described above.

[0033] In some preferred embodiments, the compound of formula (I) has the following structure:

[0034]

[0035] wherein X1, X2, X3, X4, X5, L, Y, R1, R3 and R4 have the meanings as defined above.

[0036] In some preferred embodiments, the compound of the present invention is selected from the following compounds, or racemates, enantiomers, diastereomers, deuterated compounds or pharmaceutically acceptable salts thereof:

[0037]

[0038]

[0039]

[0040]

[0041] Herein, when referring to the compound of formula (I) or formula (II), it also includes the pharmaceutically acceptable salts of the compound of formula (I) or formula (II) or stereoisomers thereof.

[0042] The present invention also relates to a method for treating or preventing a neurodegenerative disease or a neurological disease or condition associated therewith, comprising administering a compound of the present invention as a SARM1 enzyme activity inhibitor to a subject in need thereof. In particular, the present invention relates to a method for treating or preventing a disease or condition associated with axonal degeneration, comprising administering a compound of the present invention as a SARM1 enzyme activity inhibitor to a subject in need thereof. More particularly, the present invention relates to a method for inhibiting SARM1 enzyme activity, comprising administering a compound of the present invention to a subject in need thereof; more particularly, the present invention relates to a method for inhibiting axonal degeneration, comprising administering a compound of the present invention to a subject in need thereof. The compound or composition of the present invention can be administered to a desired subject or patient in an effective amount.

[0043] Accordingly, the present invention also relates to the use of the compound of the present invention or its pharmaceutically acceptable salt or stereoisomer in the preparation of a method for treating or preventing a neurodegenerative disease or a neurological disease or condition. The present invention also relates to the use of the compound of the present invention or its pharmaceutically acceptable salt or stereoisomer in the preparation of a SARM1 enzyme activity inhibitor. The present invention also relates to the use of the compound of the present invention or its pharmaceutically acceptable salt or stereoisomer in the preparation of a method for treating or preventing axonal degeneration-related diseases or conditions. Preferably, the neurodegenerative disease or neurological disease or condition or axonal degeneration-related disease or condition is selected from Alzheimer's disease, Parkinson's disease, multiple sclerosis, amyotrophic lateral sclerosis, and peripheral neuropathy. DETAILED DESCRIPTION

[0044] the term

[0045]

[0046] Reference herein to a "compound" having a particular structural formula is generally also intended to encompass pharmaceutically acceptable salts, stereoisomers, diastereomers, enantiomers, racemic mixtures, and isotopic derivatives thereof.

[0046] The pharmaceutically acceptable salts of the present invention can be formed using, for example, the following inorganic or organic acids: "pharmaceutically acceptable salts" refer to salts that are suitable for contact with human and mammalian tissues, without undue toxicity, irritation, allergic reactions, etc., within the scope of reasonable medical judgment, and are considered to be a reasonable benefit / risk ratio. The salts can be prepared in situ during the final isolation and purification of the compounds of the present invention, or separately by reacting the free base or free acid with a suitable reagent. For example, the free base can be reacted with a suitable acid. Examples of pharmaceutically acceptable acid addition salts are salts formed by amino (amine) groups with inorganic acids (e.g., hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid) or organic acids (e.g., acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid), or by using other methods in the prior art such as ion exchange. Other pharmaceutically acceptable salts include sodium alginate, ascorbate, benzenesulfonate, adipate, camphorsulfonate, aspartate, benzoate, bisulfate, borate, butyrate, camphorate, citrate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, heptanoate, hexanoate, hydroiodide, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, bitter salt, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate and the like.

[0047] The pharmaceutically acceptable salts of the present invention can be prepared by conventional methods, for example, by dissolving the compound of the present invention in a water-miscible organic solvent (e.g., methanol, ethanol, acetone and acetonitrile), adding an excess of an organic acid or an aqueous inorganic acid solution thereto to precipitate the salt from the resulting mixture, removing the solvent and the remaining free acid therefrom, and then isolating the precipitated salt.

[0048] The "stereoisomerism" described in the present invention is divided into conformational isomerism and configurational isomerism. Configurational isomerism can also be divided into cis-trans isomerism and optical isomerism (i.e. optical isomerism). Conformational isomerism refers to a stereoisomerism phenomenon in which the atoms or atomic groups of an organic molecule with a certain configuration have different arrangements in space due to the rotation or distortion of carbon and carbon single bonds. Common examples include the structures of alkane and cycloalkane compounds, such as the chair conformation and boat conformation that appear in the structure of cyclohexane. "Stereoisomer" refers to when the compounds of the present invention contain one or more asymmetric centers, and thus can be used as racemates and racemic mixtures, single enantiomers, diastereomeric mixtures and single diastereoisomers. The compounds of the present invention have asymmetric centers, and each asymmetric center will produce two optical isomers. The scope of the present invention includes all possible optical isomers and diastereomeric mixtures and pure or partially pure compounds.

[0049] In some cases, the compounds of the present invention can exist in tautomeric forms, which have different hydrogen attachment points through one or more double bond displacements. For example, a ketone and its enol form are keto-enol tautomers. Acid amides and imines can also form tautomeric forms. Each tautomer and mixture thereof are included in the compounds of the present invention. Enantiomers, diastereomers, racemates, mesomorphs, cis-trans isomers, tautomers and mixtures thereof of all compounds are included in the scope of the present invention.

[0050] When the compound of the present invention can be used in combination with another SARM1 enzyme activity inhibitor for the treatment or prevention of neurodegenerative diseases or related neurological diseases or conditions, or can be used in combination with another active drug for the treatment or prevention of neurodegenerative diseases or related neurological diseases or conditions, it can be used to treat or prevent neurodegenerative diseases or related diseases or conditions.

[0051] In this article, the wavy line Indicates the position at which a group or substituent is attached to the parent compound.

[0052] The compound of the present invention or its mesomer, racemate, enantiomer, diastereomer or its pharmaceutically acceptable salt can be used as an active ingredient by oral or parenteral administration, and its effective amount ranges from 0.1 to 2000 mg / kg body weight / day, preferably 0.1 to 100 mg / kg body weight / day in mammals including humans (body weight about 70 kg), and is administered in single or divided doses every day, or with or without a predetermined time. The dosage of the active ingredient can be adjusted according to a number of relevant factors (e.g., the condition of the subject to be treated, the type and severity of the disease, the rate of administration and the doctor's opinion). In some cases, an amount less than the above dosage may be appropriate.

[0053] The compound of the present invention or its mesoform, racemate, enantiomer, diastereomer or pharmaceutically acceptable salt thereof can be formulated into a pharmaceutical composition. The pharmaceutical composition may comprise the compound of the present invention or its mesoform, racemate, enantiomer, diastereomer or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0054] The pharmaceutical composition of the present invention can be formulated into dosage forms for oral administration or parenteral administration (including intramuscular, intravenous and subcutaneous routes, intratumor injection) according to any of the conventional methods, such as tablets, granules, powders, capsules, syrups, emulsions, microemulsions, solutions or suspensions.

[0055] The pharmaceutical composition of the present invention for oral administration can be prepared by mixing the active ingredient with a pharmaceutically acceptable carrier such as cellulose, calcium silicate, magnesium stearate, calcium stearate, corn starch, lactose, sucrose, dextrose, calcium phosphate, stearic acid, surfactants, suspending agents, gelatin, talc, emulsifiers and diluents. Examples of carriers used in the injection composition of the present invention are water, glycerides, saline solutions, alcohols, glycols, glucose solutions, ethers (e.g., polyethylene glycol 400), oils, fatty acids, fatty acid esters, surfactants, suspending agents and emulsifiers.

[0056] If not stated otherwise, conventional methods of mass spectrometry, NMR, HPLC, protein chemistry, biochemistry, recombinant DNA technology and pharmacology are used. In this application, if not stated otherwise, "or" or "and" can be used to mean "and / or".

[0057] In the specification and claims, a given chemical formula or name shall encompass all stereo and optical isomers and racemates in which such isomers exist. Unless otherwise indicated, all chiral (enantiomers and diastereomers) and racemic forms are within the scope of the present invention. Many geometric isomers of C=C double bonds, C=N double bonds, ring systems, etc. may exist in the compounds, and all such stable isomers are encompassed by the present invention.

[0058] The compounds of the present invention may be isolated in optically active or racemic forms. All methods for preparing the compounds of the present invention and intermediates prepared therein are considered part of the present invention. When enantiomers or diastereoisomers are prepared, they may be separated by conventional methods (e.g., by chromatography or fractional crystallization). It should be understood that all isomeric forms that may exist are included in the present invention.

[0059] Unless otherwise defined, when a substituent is noted as "optionally substituted", the substituent is selected from, for example, substituents such as alkyl, cycloalkyl, aryl, heterocyclyl, halogen, hydroxy, alkoxy, nitro, cyano, oxo, alkanoyl, aryloxy, alkanoyloxy, amino, alkylamino, arylamino, alkylthio, and the like.

[0060] The term "alkyl" or "alkylene" as used herein is intended to include both branched and straight chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms. The alkyl group in the present invention is preferably C1-C 12 Alkyl, C1-C 10 C1-C8 alkyl, C1-C6 alkyl, more preferably C1-C4 alkyl, particularly preferably C1-C3 alkyl. For example, "C1-C6 alkyl" means an alkyl group having 1 to 6 carbon atoms. Examples of alkyl groups include, but are not limited to, methyl (Me), ethyl (Et), propyl (e.g., n-propyl and isopropyl), butyl (e.g., n-butyl, isobutyl, tert-butyl) and pentyl (e.g., n-pentyl, isopentyl, neopentyl). For the C1-C6 alkyl group in the present invention, 12 In the case of an alkyl group, 1 to 4 -CH2- units are optionally replaced by O atoms, S atoms or -NH-.

[0061] The term "carbonyl" refers to an organic functional group consisting of carbon and oxygen atoms connected by a double bond (C=O or C(O)).

[0062] The term "aromatic ring" refers to an aromatic ring structure. An aromatic carbocyclic ring refers to an aromatic carbocyclic ring structure in which all ring members are composed of carbon atoms. A non-aromatic carbocyclic ring refers to a non-aromatic carbocyclic ring structure in which all ring members are composed of carbon atoms.

[0063] "Halo" or "halogen" includes fluorine, chlorine, bromine and iodine; fluorine and chlorine are preferred.

[0064] The term "heterocycle" means a monocyclic heterocycloalkyl system or a bicyclic heterocycloalkyl system, and may also include spiro heterocycles or bridged heterocycloalkyls. A monocyclic heterocycloalkyl refers to a saturated or unsaturated but non-aromatic cyclic alkyl system having 3-8 members and containing at least one heteroatom selected from O, N, S, and P. A bicyclic heterocycloalkyl system refers to a heterocycloalkyl fused with a phenyl, or a cycloalkyl, or a cycloalkenyl, or a heterocycloalkyl, or a heteroaryl. An aromatic heterocycle refers to an aromatic heterocycle system, and a non-aromatic heterocycle refers to a non-aromatic heterocycle system.

[0065] When any variable occurs more than one time in any constituent or formula for a compound, its definition at each occurrence is independent of its definition at every other occurrence. Thus, for example, if a group is shown substituted with 0-3 R, then the group may be optionally substituted with up to three R groups, and at each occurrence R is independently selected from the definition of R. Furthermore, combinations of substituents and / or variables are permissible only if such combinations result in stable compounds.

[0066] The term "effective amount" as used herein means the amount of a drug or medicament (i.e., a compound of the present invention) that will cause a biological or medical response of a tissue, system, animal, or human being, such as that sought by a researcher or clinician. In addition, the term "therapeutically effective amount" means an amount that results in improved treatment, cure, prevention, or alleviation of a disease, condition, or side effect, or reduces the rate of progression of a disease or condition, compared to a corresponding subject that has not received the above amount. An effective amount can be given in one or more administrations, applications, or doses and is not intended to be limited by a specific formulation or route of administration. The term also includes an effective amount that enhances normal physiological function within its scope.

[0067] As used herein, the term "treat," ...

[0068] The term "pharmaceutically acceptable" is used herein to refer to those compounds, substances, compositions and / or dosage forms that are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and animals without excessive toxicity, irritation, allergic response and / or other problems or complications, and commensurate with a reasonable benefit / risk ratio.

[0069] As used herein, the phrase "pharmaceutically acceptable carrier" means a pharmaceutical substance, composition or vehicle, such as a liquid or solid filler, diluent, excipient, manufacturing aid (e.g., lubricant, talc, magnesium, calcium or zinc stearate or stearic acid) or solvent encapsulating substance, which is involved in carrying or transporting the subject compound from one organ or part of the body to another. Each carrier must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not injurious to the patient.

[0070] The term "pharmaceutical composition" means a composition comprising a compound of the present invention and at least one other pharmaceutical carrier. "Pharmaceutical carrier" refers to a medium generally accepted in the art for delivering biologically active agents to animals (particularly mammals), including (i.e.) adjuvants, excipients or vehicles, such as diluents, preservatives, fillers, flow regulators, disintegrants, wetting agents, emulsifiers, suspending agents, sweeteners, flavoring agents, aromatics, antibacterial agents, antifungal agents, lubricants and dispersants, depending on the nature of the mode of administration and dosage form.

[0071] The compounds or pharmaceutical compositions of the present invention can improve the disease, symptom or condition after administration, especially improve its severity, delay the onset, slow down the progression of the disease, or reduce the duration of the disease. Whether fixed or temporary administration, continuous administration or intermittent administration, it can be attributed to or related to the administration.

[0072] Route of administration

[0073] Suitable routes of administration of the compounds or pharmaceutical compositions of the present invention include, but are not limited to, oral, intravenous, rectal, aerosol, parenteral, ocular, pulmonary, transdermal, vaginal, auricular, nasal, and topical administration. In addition, parenteral administration, by way of example only, includes intramuscular, subcutaneous, intravenous, intramedullary, ventricular, intraperitoneal, intralymphatic, and intranasal injections.

[0074] In some embodiments, the administration mode of the compound in the present invention is topical administration. In other specific embodiments, the compound of the present invention can be administered by implantation (e.g., subcutaneous or intramuscular) or by intramuscular injection. In addition, in other specific embodiments, the compound of the present invention is administered by a targeted drug delivery system.

[0075] In the pharmaceutical compositions of the present invention, pharmaceutical carriers may be formulated based on a number of factors within the purview of those skilled in the art. These factors include, but are not limited to: the type and nature of the formulated active agent; the subject to whom the composition containing the active agent is to be administered; the intended route of administration of the composition; and the targeted therapeutic indication. Pharmaceutical carriers include aqueous and non-aqueous liquid media and various solid and semi-solid dosage forms.

[0076] Such carriers may include many different ingredients and additives in addition to the active agent, which are included in the formulation for various reasons known to those skilled in the art, such as stabilizing the active agent, binding agents, etc. Descriptions of suitable pharmaceutical carriers and factors involved in carrier selection can be found in a number of readily available sources, such as Allen LV Jr. et al. Remington: The Science and Practice of Pharmacy (2 Volumes), 22 nd Edition(2012),Pharmaceutical Press.

[0077] The compound is usually administered in a mixture with a suitable pharmaceutical diluent, excipient or carrier (collectively referred to herein as a pharmaceutical carrier) appropriately selected according to the intended administration form (eg, oral tablets, capsules, elixirs and syrups) and in accordance with conventional pharmaceutical practice.

[0078] While it is possible for a compound of the present invention to be administered alone, it is preferable to administer the compound as a pharmaceutical formulation (composition).

[0079] Kit / Product Packaging

[0080] Kits / product packages are also described herein for use in the treatment of the above-mentioned indications. These kits may consist of a conveyor, a medicine bag or a container box, which may be divided into multiple compartments to accommodate one or more containers, such as vials, test tubes and the like, each of which contains a single component of the method. Suitable containers include bottles, vials, syringes and test tubes. The container is made of acceptable materials such as glass or plastic.

[0081] For example, a container may contain one or more compounds described herein, which may be present as a pharmaceutical composition or in admixture with other ingredients described herein. The container may have a sterile outlet (e.g., the container may be an intravenous infusion bag or bottle, the stopper of which may be pierced by a hypodermic syringe needle). Such a kit may include a compound and instructions, labels, or operating instructions for use as described herein.

[0082] A typical kit may include one or more containers, each containing one or more materials (such as reagents, concentrated stock solutions, and / or instruments) to suit the needs of commercial promotion and user use of the compound. These materials include but are not limited to buffers, diluents, filters, needles, syringes, delivery devices, bags, containers, bottles and / or test tubes, with a list of contents and / or instructions for use, and the inner packaging also comes with instructions. The entire set of instructions must be included.

[0083] The above features mentioned in the present invention or the features mentioned in the embodiments can be combined in any way. All the features disclosed in the specification of this case can be used in any combination form, and each feature disclosed in the specification can be replaced by any alternative feature that can provide the same, equal or similar purpose. Therefore, unless otherwise specified, the disclosed features are only general examples of equal or similar features.

[0084] The present invention will be further described below in conjunction with specific examples. It should be understood that these examples are intended only to illustrate the present invention and are not intended to limit the scope of the present invention. The experimental methods in the following examples without specifying specific conditions are usually performed under normal conditions or according to the conditions recommended by the manufacturer. Unless otherwise stated, all percentages, ratios, proportions, or parts are by weight.

[0085] The units of weight volume percentage in the present invention are well known to those skilled in the art, for example, refer to the weight of solute in 100 ml of solution. Unless otherwise defined, all professional and scientific terms used in the text have the same meanings as those familiar to those skilled in the art. In addition, any methods and materials similar or equivalent to the described contents can be applied to the method of the present invention. The preferred implementation methods and materials described in the text are for demonstration purposes only.

[0086] In the terms used in the present invention, "neurodegenerative disease" and "neurodegenerative disease" have the same meaning; "axonal degeneration" and "axonal degeneration" have the same meaning. Those skilled in the art will understand that the terms have commonly understood meanings.

[0087] The descriptions provided in the examples are included herein and are not intended to limit the scope of any claims. The following non-limiting examples are provided to further illustrate the present invention. Based on this disclosure, those skilled in the art will appreciate that many changes may be made to the disclosed specific embodiments and still achieve the same or similar results without departing from the spirit and scope of the present teachings.

[0088] Unless otherwise stated, all materials / reagents were obtained from commercial suppliers and used without further purification. Reactions were monitored by LC-MS and / or thin layer chromatography (TLC) on silica gel 60F254 (0.2 mm) pre-coated glass backing during the experiment and observed using UV light. The structures of the following example compounds were characterized by nuclear magnetic resonance (NMR) and / or mass spectrometry (MS).

[0089] 1 HNMR (400 MHz) spectra were recorded at room temperature on a Bruker spectrometer with TMS or residual solvent peaks as internal standards. Chemical shift values ​​or peak type multiples are given in (δ), and coupling constants (J) are given in absolute values ​​in Hertz (Hz). The multiplicity abbreviations in 1HNMR spectra are as follows: s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet), br or broad (broadened).

[0090] Preparative HPLC purification was performed on a Shimadzu LC-6AD. All purifications were performed using Shim-packPREP-DDS(H)KIT columns. The mobile phase was water (containing 0.1% HCO2H) and acetonitrile; all reagents used were HPLC grade. The flow rate was 10 ml / min.

[0091] LC-MS was performed on Agilent 1260infinityⅡ; mobile phase: A: water (0.1% trifluoroacetic acid), B: ACN; 3.5 min column run; column: YMC-Triart C18 50*3mm, 3um; flow rate: 1.8ml / min; oven temperature: 40°C; gradient: 5-100 (ACN%).

[0092] Preparative TLC was performed on Whatman LK6F Silica Gel 60A plates of size 20 x 20 cm, thickness 500 μm.

[0093] The following examples are intended to illustrate embodiments of the present invention but are not intended to limit the same in any way.

[0094] Synthetic route of intermediate BB1

[0095]

[0096] Step 1: Compound BB1-C tert-butyl 3-(4-chlorobenzyl)-2-oxopyrrolidine-1-carboxylate

[0097]

[0098] LiHMDS (21.6 ml, 21.6 mmol) was slowly added to a tetrahydrofuran (60 mL) solution containing compound BB1-A tert-butyl 2-oxopyrrolidine-1-carboxylate (4 g, 21.6 mmol) at -60°C under nitrogen protection.

[0099] After reacting at -60°C for 1 hour, a tetrahydrofuran solution (10 mL) containing compound BB1-B 4-chlorobenzyl bromide (4.44 g, 21.6 mmol) was slowly added dropwise, and the reaction solution was reacted at -60°C for 2 hours and then warmed to room temperature and continued to stir and react for 18 hours. TLC monitored the reaction to be complete. The reaction solution was added to a saturated ammonium chloride solution (50 mL) for quenching, extracted with ethyl acetate, the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was separated and purified by preparative thin layer chromatography (eluent: 10-15% ethyl acetate in petroleum ether solution) to obtain a colorless oily compound BB1-C 3-(4-chlorobenzyl)-2-oxopyrrolidine-1-carboxylic acid tert-butyl ester (1.7 g).

[0100] 1 H NMR (400MHz, CDCl3) δ7.30–7.27(m,2H),7.15(d,J=8.4Hz,2H),3.69(ddd,J=11.2,8.7,2.7Hz,1H),3.59–3.51(m,1H),3. 23(dd,J=13.6,3.9Hz,1H),2.83–2.74(m,1H),2.68(t,J=6.8Hz,1H),2.06–1.99(m,1H),1.71–1.65(m,1H),1.55(s,9H).

[0101] Step 2: Compound BB1 3-(4-chlorobenzyl)pyrrolidin-2-one

[0102]

[0103] Compound BB1-C tert-butyl 3-(4-chlorobenzyl)-2-oxopyrrolidine-1-carboxylate (1.7 g, 5.488 mmol) was added to a 4M hydrochloric acid-dioxane (20 mL) solution at room temperature and stirred for 1 hour. TLC monitored the reaction to be complete. Concentration under reduced pressure gave a white solid compound BB1 3-(4-chlorobenzyl)pyrrolidin-2-one (1.15 g). LC_MS: (ES + ):m / z210.06[M+H] +

[0104] Synthetic route of intermediate BB2

[0105]

[0106] Step 1: Compound BB2 1-(4-(pyridin-4-yl)phenyl)pyrrolidin-2-one

[0107]

[0108] Pd(PPh3)4 (1.2 g, 1.04 mmol) was added to a solution of acetonitrile (50 ml) and water (10 ml) containing compound BB2-A 1-(4-bromophenyl)pyrrolidin-2-one (2.5 g, 10.41 mmol), compound BB2-B pyridine-4-boric acid (1.92 g, 15.62 mmol), and sodium carbonate (2.76 g, 26.03 mmol). The reaction system was replaced with nitrogen three times and heated to 90°C for 18 hours. The reaction was complete when monitored by TLC. The reaction solution was cooled to room temperature, extracted with ethyl acetate and water, the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was separated and purified by silica gel column chromatography (eluent: 0%-0.047% methanol in dichloromethane) to obtain yellow solid compound BB2 1-(4-(pyridin-4-yl)phenyl)pyrrolidin-2-one (1.9 g).

[0109] LC_MS:(ES + ):m / z 239.05[M+H] + .

[0110] Synthetic route of intermediate BB3

[0111]

[0112] Step 1: Compound BB3-C tert-butyl 3-(4-chlorobenzyl)-2-oxopiperidin-1-carboxylate

[0113]

[0114] The synthesis of this step refers to the synthesis process of the first step of intermediate BB1.

[0115] LC_MS:(ES + ):m / z 324.13[M+H] + .

[0116] Step 2: Compound BB3 3-(4-chlorobenzyl)piperidin-2-one

[0117]

[0118] The synthesis of this step refers to the synthesis process of the second step of intermediate BB1.

[0119] LC_MS:(ES + ):m / z 224.10[M+H] + .

[0120] Example 1: Synthesis route of compound 1

[0121]

[0122] Step 1: Compound 1-C 1-(4-bromophenyl)-3-(4-chlorobenzyl)pyrrolidin-2-one

[0123]

[0124] Take compound 1-A 1-(4-bromophenyl)pyrrolidin-2-one (100mg, 0.42mmol) and dissolve it in anhydrous tetrahydrofuran (4mL). Cool the system to -65℃ under nitrogen protection, then add LDA (2M in THF, 0.46ml) dropwise at -65℃. The reaction temperature is slowly raised to -30℃ within half an hour, then lowered to -65℃, and a solution of compound 1-B 4-chlorobenzyl bromide (257mg, 1.25mmol) in THF (1mL) is added. The reaction is slowly returned to room temperature and the reaction is continued for 1 hour. The reaction was monitored by spot plate and completed. The mixture was quenched with saturated ammonium chloride solution (10 mL), extracted with ethyl acetate (10 mL x 2), the organic phases were combined, backwashed once with saturated brine (20 mL), dried and spin-dried, and the crude product was separated and purified by silica gel column chromatography (eluted with petroleum ether solution containing 6.7-16.7% ethyl acetate) to give white solid compound 1-C 1-(4-bromophenyl)-3-(4-chlorobenzyl)pyrrolidin-2-one (108 mg).

[0125] LC_MS:(ES + ):m / z 364.0[M+H] +

[0126] 1H NMR (400MHz, CDCl3): δ7.53-7.46(m,4H),7.28-7.26(m,2H),7.18-7.16(m,2H),3.76-3 .56(m,2H),3.25-3.21(m,1H),2.91-2.77(m,2H),2.22-2.15(m,1H),1.88-1.80(m,1H).

[0127] Step 2: Compound 1 3-(4-chlorobenzyl)-1-(4-(pyridin-4-yl)phenyl)pyrrolidin-2-one

[0128]

[0129] Take compound 1-C 1-(4-bromophenyl)-3-(4-chlorobenzyl)pyrrolidin-2-one (50mg, 0.137mmol), compound 1-D pyridine-4-boric acid (21mg, 0.164mmol), sodium carbonate (29mg, 0.27mmol) and tetrakistriphenylphosphine palladium (16mg, 0.014mmol) in a 10ml reaction bottle, then add dioxane (1mL) and H2O (0.5mL). Nitrogen is replaced three times in the system, and the reaction is carried out at 90℃ overnight. Cool to room temperature and monitor the reaction completion with a plate.

[0130] The reaction mixture was quenched with water and extracted with ethyl acetate (10 mL x 2). The organic phases were combined and backwashed once with saturated brine (20 mL), dried and spin-dried. The crude product was separated and purified by Pre-TLC (eluted with a dichloromethane solution containing 4% methanol) to give a white solid compound 13-(4-chlorobenzyl)-1-(4-(pyridin-4-yl)phenyl)pyrrolidin-2-one (30.4 mg).

[0131] LC_MS:(ES + ):m / z 363.5[M+H] +

[0132] 1 H NMR (400MHz, CDCl3): δ8.66(d,J=5.2Hz,2H),7.79-7.76(m,2H),7.69-7.67(m,2H),7.55(d,J=6.4Hz,2H),7.29-7.27(m,2H),7.2 0-7.18(m,2H),3.80-3.65(m,2H),3.29-3.24(m,1H),2.98-2.91(m,1H),2.86-2.81(m,1H),2.27-2.19(m,1H),1.92-1.82(m,1H).

[0133] Example 2: Synthesis route of compound 2

[0134]

[0135] Step 1: Compound 2-C 3-bromo-1-(4-(pyridin-4-yl)phenyl)pyrrolidin-2-one

[0136]

[0137] Compound 2-B 2,4-dibromobutyryl chloride (78 mg, 0.294 mmol) was added to a mixture of compound 2-A 4-(pyridin-4-yl)aniline (50 mg, 0.294 mmol) and K3PO4 (32 mg, 0.147 mmol) in acetonitrile (2 mL) under an ice bath. The ice bath was removed, the reaction solution was stirred at room temperature for 1 h, and then a 50% aqueous NaOH solution (0.6 mL) was added. The reaction solution was stirred overnight. The reaction solution was filtered, the filter cake was washed with acetonitrile, and the filtrate was evaporated to dryness. The crude product was separated and purified by silica gel column chromatography (eluted with a petroleum ether solution containing 20-30% ethyl acetate) to obtain a yellow solid compound 2-C 3-bromo-1-(4-(pyridin-4-yl)phenyl)pyrrolidin-2-one (20 mg).

[0138] LC_MS:(ES + ):m / z 317.00[M+H] + .

[0139] Step 2: Compound 2 3-(4-chlorophenoxy)-1-(4-(pyridin-4-yl)phenyl)pyrrolidin-2-one

[0140]

[0141] A solution of compound 2-C 3-bromo-1-(4-(pyridin-4-yl)phenyl)pyrrolidin-2-one (20 mg, 0.063 mmol), compound 2-D 4-chlorophenol (9 mg, 0.063 mmol) and Cs2CO3 (41 mg, 0.126 mmol) in acetonitrile (2 mL) was heated to 60°C and stirred for 5 h. After the reaction was complete, the reaction solution was evaporated to dryness, and 20 mL of a mixed solvent of CH2Cl2 / MeOH (V / V=20 / 1) was added. After sufficient dissolution, the filtrate was filtered and evaporated to dryness. The crude product was purified by Prep-TLC (eluent: CH2Cl2 / MeOH=20 / 1) to obtain a yellow solid compound 2 3-(4-chlorophenoxy)-1-(4-(pyridin-4-yl)phenyl)pyrrolidin-2-one (11 mg).

[0142] LC_MS:(ES + ):m / z 365.40[M+H] + .

[0143] Example 3: Synthesis route of compound 3

[0144]

[0145] Step 1: Compound 3-B N-(4-bromophenyl)hydroxylamine

[0146]

[0147] Rhodium carbon (100 mg) was added to a tetrahydrofuran (20 mL) solution containing compound 3-A 1-bromo-4-nitrobenzene (1.0 g, 4.95 mmol), the reaction solution was cooled to 0 ° C, hydrazine hydrate (309.77 mg, 4.95 mmol, 80% wt) was added in batches, and the dropwise addition temperature was kept below 25 ° C. The reaction solution was warmed to room temperature and stirred for 2 hours. TLC monitored the reaction to be complete. The reaction solution was filtered through diatomaceous earth and concentrated under reduced pressure to obtain a crude compound 3-B N-(4-bromophenyl)hydroxylamine (930.78 mg), which was used directly in the next step without further purification.

[0148] LC_MS:(ES + ):m / z 187.96[M+H] + .

[0149] Step 2: Compound 3-D 2-(4-bromophenyl)isoxazolin-3-one

[0150]

[0151] Potassium carbonate (684.46 mg, 4.95 mmol) and compound 3-C 3-chloropropionyl chloride (628.51 mg, 4.95 mmol) were added to a solution of N,N-dimethylformamide (10 mL) containing compound 3-B N-(4-bromophenyl)hydroxylamine N-(4-bromophenyl)hydroxylamine (930.78 mg, 4.95 mmol). The reaction solution was stirred at 25 ° C for 1 hour. LCMS monitored the reaction to be complete. The reaction solution was diluted with water (20 mL) and extracted with ethyl acetate (20 mLx2). The organic layers were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was separated and purified by silica gel column chromatography (eluent: 25% ethyl acetate in petroleum ether solution) to obtain a yellow solid compound 3-D 2-(4-bromophenyl)isoxazoline-3-one (680 mg).

[0152] LC_MS:(ES + ):m / z 241.97[M+H] + .

[0153] 1H NMR (400MHz, CDCl3) δ7.64–7.58(m,2H),7.53–7.47(m,2H),4.56(t,J=8.0Hz,2H),3.04(t,J=8.0Hz,2H).

[0154] Step 3: Compound 3-F 2-(4-(pyridin-4-yl)phenyl)isoxazolidin-3-one

[0155]

[0156] Pd(dppf)Cl2-CH2Cl2 (67.45 mg, 0.0826 mmol) was added to a solution of 1,4-dioxane (5 ml) and water (1 ml) containing compound 3-D 2-(4-bromophenyl)isoxazolin-3-one (200 mg, 0.826 mmol), compound 3-E pyridine-4-boronic acid (152.44 mg, 1.24 mmol), sodium carbonate (262.67 mg, 2.48 mmol), and the reaction system was replaced with nitrogen three times, heated to 85°C and reacted for 18 hours. The reaction was complete when monitored by TLC. The reaction solution was extracted with water (20 mL) and ethyl acetate (20 mL), and the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was separated and purified by silica gel column chromatography (eluent: 0%-0.047% methanol in dichloromethane) to give a yellow solid compound 3-F 2-(4-(pyridin-4-yl)phenyl)isoxazolidin-3-one (150 mg).

[0157] LC_MS:(ES + ):m / z 241.10[M+H] + .

[0158] Step 4: Compound 3 4-(4-chlorobenzyl)-2-(4-(pyridin-4-yl)phenyl)isoxazolidin-3-one

[0159]

[0160] Under nitrogen protection at -78°C, slowly add LDA (208ul, 0.416mmol) to a tetrahydrofuran (2.5ml) solution containing compound 3-F 2-(4-(pyridin-4-yl)phenyl)isoxazolidin-3-one (50mg, 0.208mmol), and react for 1 hour. Then add compound 3-G 4-chlorobenzyl bromide (42.74mg, 0.208mmol), and stir the reaction solution at -78°C for 2 hours. TLC monitors the reaction to be complete. The reaction solution is added to a saturated ammonium chloride solution (10ml) to quench, extracted with ethyl acetate, and the organic phases are combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product is separated and purified by preparative thin layer chromatography (eluent: 0.047% methanol in dichloromethane) to obtain a yellow solid compound 34-(4-chlorobenzyl)-2-(4-(pyridin-4-yl)phenyl)isoxazolidin-3-one (8mg).

[0161] LC_MS:(ES + ):m / z 365.50[M+H] + .

[0162] Example 4: Synthesis route of compound 4

[0163]

[0164] Step 1: Compound 4-C 1-(4-(pyridin-4-yl)phenyl)pyrrolidin-2-one

[0165]

[0166] Under nitrogen atmosphere, compound 4-A 4-(4-bromophenyl)pyridine (120 mg, 0.5 mmol), compound 4-B pyrrolidin-2-one (60 mg, 0.75 mmol), cuprous iodide (10 mg, 0.05 mmol), potassium phosphate (212 mg, 1 mmol) and (1R, 2R)-N, N'-dimethyl-1,2-cyclohexanediamine (14 mg, 0.1 mmol) were dispersed in 1,4-dioxane (1 mL). The reaction mixture was stirred at 100 ° C for 16 hours. LCMS detected that the raw material reacted completely and the target mass spectrum was detected. TLC detected that major points were generated. After the reaction solution was spin-dried, dichloromethane (20 mL) was added, and the reaction solution was washed with water (15 mL), saturated ammonium chloride solution (20 mL), and saturated brine (20 mL) in turn, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was separated and purified by preparative silica gel plate (DCM:MeOH=20:1) and dried in vacuo to obtain a white solid compound 4-C 1-(4-(pyridin-4-yl)phenyl)pyrrolidin-2-one (80 mg).

[0167] LC-MS: (ES+): m / z 239.11 [M+H]+.

[0168] Step 2: Compound 4 3-(1-(4-chlorophenyl)ethyl)-1-(4-(pyridin-4-yl)phenyl)pyrrolidin-2-one

[0169]

[0170] Compound 4-C 1-(4-(pyridin-4-yl)phenyl)pyrrolidin-2-one (26 mg, 0.1 mmol) was dissolved in 2 ml tetrahydrofuran at -78°C, and lithium diisopropylamide (0.1 ml, 2N) was added dropwise. Half an hour later, a tetrahydrofuran solution of compound 4-D 1-(1-bromoethyl)-4-chlorobenzene (26 mg, 0.12 mmol) was added dropwise. The reaction was continued to stir at low temperature for 1 hour. LCMS detected that the raw material reaction was complete, the target mass spectrum was detected, and TLC detected that major points were generated. The reaction was quenched by adding saturated ammonium chloride solution (10 mL), extracted with dichloromethane (10 mL x 3), washed with water (15 mL), saturated ammonium chloride solution (20 mL), and saturated brine (20 mL) in sequence, and the reaction solvent was removed by rotary evaporation. The crude product was purified by preparative silica gel plate (DCM: MeOH = 20: 1) and dried in vacuo to obtain yellow solid compound 4 3-(1-(4-chlorophenyl)ethyl)-1-(4-(pyridin-4-yl)phenyl)pyrrolidin-2-one (10 mg). LC-MS: (ES+): m / z 377.13 [M+H]+.

[0171] Example 5: Synthesis route of compound 5

[0172]

[0173] Step 1: Compound 5-C 3-(4-chlorophenyl)-N-(4-(pyridin-4-yl)phenyl)propionamide

[0174]

[0175] Under ice bath, a mixture of compound 5-A 3-(4-chlorophenyl)propionic acid (184 mg, 1 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (210 mg, 1.1 mmol) and N,N-diisopropylethylamine (387 mg, 3 mmol) was dissolved in 5 ml of dichloromethane. After stirring for 15 minutes, compound 5-B 4-(4-pyridine)aniline (170 mg, 1 mmol) was added. The reaction mixture was stirred at room temperature for 2 hours. LCMS detected that the raw material reacted completely and the target mass spectrum was detected. TLC detected that major points were generated. Dichloromethane (20 mL) was added to the reaction solution, and the reaction solution was washed with water (15 mL), saturated ammonium chloride solution (20 mL), and saturated brine (20 mL) in turn, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by column separation and dried in vacuo to obtain a white solid compound 5-C3-(4-chlorophenyl)-N-(4-(pyridin-4-yl)phenyl)propanamide (250 mg).

[0176] LC-MS: (ES+): m / z 337.1 [M+H]+.

[0177] Step 2: Compound 5 2-(4-chlorobenzyl)-3-hydroxy-N-(4-pyridine-4-phenyl)propionamide

[0178]

[0179] Compound 5-C 3-(4-chlorophenyl)-N-(4-(pyridin-4-yl)phenyl)propionamide (34 mg, 0.1 mmol) was dissolved in 1 ml of tetrahydrofuran under ice bath, sodium hydride (60% wt, 9 mg, 0.22 mmol) was carefully added, and after stirring for 0.5 hours, an excess of paraformaldehyde was added. The reaction mixture was allowed to warm to room temperature and continued to stir for 2 hours. The LCMS detection system showed product production. Saturated ammonium chloride solution (10 mL) was added to quench the reaction, and dichloromethane (10 mL x 3) was used for extraction. The reaction solution was washed with water (15 mL), saturated ammonium chloride solution (20 mL), and saturated brine (20 mL) in turn, and the reaction solvent was removed by rotary evaporation. The crude product was separated and purified by preparative HPLC to obtain yellow solid compound 5 2-(4-chlorobenzyl)-3-hydroxy-N-(4-pyridin-4-phenyl)propionamide (1 mg).

[0180] LC-MS: (ES+): m / z 349.05 [M+H]+.

[0181] Example 6: Synthesis route of compound 6

[0182]

[0183] Step 1: Compound 6-C 2-bromo-5-(pyridin-4-yl)pyridine

[0184]

[0185] Under nitrogen atmosphere at room temperature, [1,1-bis(diphenylphosphino)ferrocene]palladium dichloride (25.9 mg, 0.035 mmol) was added to a suspension of 1,4-dioxane (15 ml)-water (3 mL) containing compound 6-A 2-bromo-5-iodopyridine (1.0 g, 3.53 mmol), compound 6-B pyridine-4-boric acid (434 mg, 3.53 mmol) and potassium carbonate (976 mg, 7.06 mmol). The reaction mixture was replaced with nitrogen three times and stirred at 85°C for 12 hours. TLC showed that the reaction was complete. The reaction mixture was cooled to room temperature, distributed in water (20 mL), and extracted with ethyl acetate (10 mL x 3). The organic layers were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was separated and purified by preparative TLC (eluted with a dichloromethane solution containing 5% methanol) to give a white solid compound 6-C 2-bromo-5-(pyridin-4-yl)pyridine (490 mg).

[0186] LC_MS:(ES + ):m / z 234.95,236.95[M+H] + .

[0187] 1 H NMR (400MHz, DMSO) δ8.88–8.85(m,1H),8.70(dd,J=4.5,1.7Hz,2H),8.20(dd,J=8.3,2.7Hz,1H),7.85–7.82(m,1H),7.82–7.79(m,2H).

[0188] Step 2: Compound 6 1-([3,4'-bipyridyl]-6-yl)-3-(4-chlorobenzyl)pyrrolin-2-one

[0189]

[0190] Cuprous iodide (14 mg, 0.073 mmol) was added to a suspension of 1,4-dioxane (5 mL) containing compound 6-C 2-bromo-5-(pyridin-4-yl)pyridine (170 mg, 0.723 mmol), compound 6-D (BB1) 3-(4-chlorobenzyl)pyrrolin-2-one (150 mg, 0.723 mmol), (1R, 2R)-N, N'-dimethyl-1,2-cyclohexanediamine (21 mg, 0.145 mmol) and potassium phosphate (307 mg, 1.446 mmol) at room temperature under nitrogen atmosphere. The reaction mixture was replaced with nitrogen three times and stirred at 100°C for 12 hours. TLC showed that the reaction was complete. The reaction mixture was cooled to room temperature, distributed in water (20 mL), and extracted with ethyl acetate (10 mL x 3). The organic layers were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was separated and purified by preparative TLC (eluted with a dichloromethane solution containing 9% methanol) to give a white solid compound 6 1-([3,4'-bipyridyl]-6-yl)-3-(4-chlorobenzyl)pyrroline-2-one (209 mg).

[0191] LC_MS:(ES + ):m / z 364.10[M+H] + .

[0192] 1 H NMR (400MHz, CDCl3) δ8.87(d,J=2.5Hz,1H),8.75(m,2H),8.45(dd,J=8.7,2.7Hz,1H),8.01(d, J=4.4Hz,2H),7.89(d,J=8.8Hz,1H),7.30(t,J=5.4Hz,2H),7.21(d,J=8.4Hz,2H),3.83(dd,J=1 6.8,8.6Hz,1H),3.75(td,J=9.1,3.1Hz,1H),3.29(dd,J=13.7,4.2Hz,1H),2.99(qd,J=8.9,4. 2Hz,1H),2.87(dd,J=13.7,8.9Hz,1H),2.35–2.26(m,1H),1.95(ddd,J=18.0,12.8,8.8Hz,1H).

[0193] Example 7: Synthesis route of compound 7

[0194]

[0195] Step 1: Compound 7-C 5-bromo-2,4'-bipyridine

[0196]

[0197] The synthesis of this step uses compound 7-A 2,5-dibromopyridine as the raw material and refers to the synthesis process of the first step in Example 6.

[0198] LC_MS:(ES + ):m / z 234.95,236.95[M+H] + .

[0199] 1 H NMR (400MHz, CDCl3) δ8.82(d,J=2.3Hz,1H),8.76(d,J=6.1Hz,2H),7.98(dd,J=8.4,2.4Hz,1H),7.91(dd,J=4.7,1.5Hz,2H),7.74(d,J=8.4Hz,1H).

[0200] Step 2: Compound 7 1-([2,4'-bipyridine]-5-)-3-(4-chlorobenzyl)pyrrolin-2-one

[0201]

[0202] The synthesis of this step refers to the synthesis process of the second step of Example 6.

[0203] LC_MS:(ES + ):m / z 364.10[M+H] + .

[0204] 1 H NMR (400MHz, CDCl3) δ8.74(m,2H),8.67(d,J=2.1Hz,1H),8.61(d,J=8.8Hz,1H),8.00(dd,J=8.8 ,2.5Hz,1H),7.56(m,2H),7.32–7.29(m,2H),7.21(d,J=8.4Hz,2H),4.13(ddd,J=11.4,8.8,2.8H z,1H),3.92(ddd,J=11.2,8.9,7.4Hz,1H),3.31(dd,J=13.8,4.3Hz,1H),3.02(ddd,J=18.3,9.3, 4.4Hz, 1H), 2.83 (dd, J=13.8, 9.2Hz, 1H), 2.23 (tdd, J=10.3, 7.5, 2.8Hz, 1H), 1.92–1.83 (m, 1H).

[0205] Example 8: Synthesis route of compound 8

[0206]

[0207] Step 1: Compound 8-C 3-bromo-6-(pyridin-4-yl)pyridazine

[0208]

[0209] The synthesis of this step uses compound 8-A 3,6-dibromopyridazine as raw material and refers to the synthesis process of the first step in Example 6.

[0210] LC_MS:(ES + ):m / z 235.90[M+H] + .

[0211] Step 2: Compound 8 3-(4-chlorobenzyl)-1-(6-(pyridin-4-yl)pyridazin-3-yl)pyrrolidin-2-one

[0212]

[0213] The synthesis of this step refers to the synthesis process of the second step of Example 6.

[0214] LC_MS:(ES + ):m / z 241.10[M+H] + .

[0215] 1 H NMR (400 MHz, CDCl3) δ8.87 (d, J = 9.4 Hz, 2H), 7.96 (d, J = 9.4 Hz, 2H), 7.32-7.29 (m, 2H), 7.23-7.18 (m, 4H), 4.32 (ddd, J = 11.6, 8.7, 2.9 Hz, 1H), 4.08 (ddd, J = 11.5, 9.0, 7.4 Hz, 1H), 3.30 (dd, J = 13.8, 4.5 Hz, 1H), 3.04 (qd, J = 9.1, 4.5 Hz, 1H), 2.84 (dd, J = 13.9, 9.1 Hz, 1H), 2.36-2.24 (m, 1H), 1.93 (dq, J = 12.8, 9.1 Hz, 1H). Example 9: Synthesis route of compound 9

[0216]

[0217] Step 1: Compound 9-B (E) -1-(4-bromophenyl)-3-(dimethylamino)-2-propen-1-one

[0218]

[0219] Weigh compound 9-A (1 g, 5.02 mmol) into a 25 mL reaction tube, add 2 mL DMF-DMA solvent, and heat to 80 ° C for 8 h. After the reaction is completed, cool to room temperature, pour the reaction solution into ice water, wait for solid precipitation, filter, take the filter cake, recrystallize with petroleum ether, filter, and dry the filter cake to obtain a yellow solid compound 9-B (E) -1- (4-bromophenyl) -3- (dimethylamino) -2-propene-1-one (1.0 g), which is directly used in the next step.

[0220] Step 2: Compound 9-C 4-(4-bromophenyl)pyrimidine

[0221]

[0222] Compound 9-B(E)-1-(4-bromophenyl)-3-(dimethylamino)-2-propene-1-one (100 mg, 393.50 umol) was placed in a 10 mL reaction tube. Formamidine acetate (49.2 mg, 472.20 umol), sodium methoxide (150 uL, 5.4 M methanol solution), and ethanol (1.5 mL) were added in sequence at room temperature, and heated to 70°C for overnight reaction. After the reaction was completed, the mixture was cooled to room temperature, an appropriate amount of water was added, a large amount of organic solvent was removed in vacuo, and the mixture was extracted with ethyl acetate (10 mL x 3), dried over anhydrous sodium sulfate, and spin-dried. The yellow compound 9-C 4-(4-bromophenyl)pyrimidine (50 mg) was separated and purified by preparative silica gel thin layer chromatography (eluted with a dichloromethane solution containing 5% methanol).

[0223] LC_MS:(ES + ):m / z 236.85[M+H] + .

[0224] Step 3: Compound 9 3-(4-chlorobenzyl)-1-(4-(pyrimidin-4-yl)phenyl)pyrrolidin-2-one

[0225]

[0226] The synthesis of this step refers to the synthesis process of the second step of Example 6.

[0227] LC_MS:(ES + ):m / z 364.10[M+H] + .

[0228] 1H NMR (400MHz, DMSO-d6) δ9.22(d,J=1.3Hz,1H),8.84(d,J=5.4Hz,1H),8.28-8.24(m,2H),8.09(dd,J=5.4,1.4Hz,1H),7.91-7.86(m,2H),7.3 9-7.30(m,4H),3.81-3.75(m,2H),3.16-3.11(m,1H),3.02-2.97(m,1H ),2.76(dd,J=13.6,9.3Hz,1H),2.12-2.06(m,1H),1.82-1.76(m,1H).

[0229] Example 10: Synthesis route of compound 10

[0230]

[0231] Step 1: Compound 10-C 1-(4-bromo-3-methylphenyl)pyrrolidin-2-one

[0232]

[0233] Compound 10-B 4-chlorobutyryl chloride (383 mg, 2.72 mmol) was added dropwise to a solution of compound 10-A 4-bromo-3-methylaniline (500 mg, 2.72 mmol) and triethylamine (554 mg, 5.54 mmol) in dichloromethane (10 mL) under ice bath conditions and stirred for 1 hour. After the reaction was completed, the reaction solution was washed with water (20 mL x 2). The organic layer was concentrated and dissolved in tetrahydrofuran (10 mL), and sodium hydrogen sulfide (163 mg, 4.08 mmol) was added under ice bath conditions. The mixture was stirred for 2 hours. After the reaction was completed, the reaction solution was poured into a saturated ammonium chloride solution (20 mL), extracted with ethyl acetate (15 mL x 2), the organic layers were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (eluted with a petroleum ether solution containing 25% ethyl acetate) to give a white solid compound 10-C 1-(4-bromo-3-methylphenyl)pyrrolidin-2-one (330 mg).

[0234] LC_MS:(ES + ):m / z 254.1[M+H] + .

[0235] Step 2: Compound 10-E 1-(4-bromo-3-methylphenyl)-3-(4-chlorobenzyl)pyrrolidin-2-one

[0236]

[0237] To a tetrahydrofuran (2 mL) solution of compound 10-C 1-(4-bromo-3-methylphenyl)pyrrolidin-2-one (100 mg, 0.418 mmol) was added lithium diisopropylamide (0.418 ml, 0.836 mmol) at -78°C. The reaction mixture was stirred at -78°C for 1 hour. A tetrahydrofuran solution of compound 10-D 4-chlorobenzyl bromide (86 mg, 0.418 mmol) was added dropwise, and the reaction was continued at -78°C for 2 hours. After the reaction, the reaction solution was poured into a saturated ammonium chloride (20 mL) solution, allowed to stand for separation, the organic phase was collected, and concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (eluted with a petroleum ether solution containing 25% ethyl acetate) to obtain a light yellow solid compound 10-E 1-(4-bromo-3-methylphenyl)-3-(4-chlorobenzyl)pyrrolidin-2-one (80 mg, 50%).

[0238] LC_MS:(ES + ):m / z 378.1[M+H] + .

[0239] Step 3: Compound 10 3-(4-chlorobenzyl)-1-(3-methyl-4-(pyridin-4-yl)phenyl)pyrrolidin-2-one

[0240]

[0241] A solution of compound 10-E 1-(4-bromo-3-methylphenyl)-3-(4-chlorobenzyl)pyrrolidin-2-one (80 mg, 0.212 mmol), compound 10-F pyridine-4-boric acid (52 mg, 0.424 mmol), tetrakistriphenylphosphine palladium (2.5 mg, 2 μmol), and potassium carbonate (50 mg, 0.424 mmol) in N,N-dimethylformamide (2 mL) was heated to 85°C and stirred under nitrogen for 16 hours. After the reaction was completed, water (20 mL) was added for dilution, and ethyl acetate (10 mL x 2) was used for extraction. The organic layers were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (eluted with a petroleum ether solution containing 25% ethyl acetate) to obtain a white solid compound 10 3-(4-chlorobenzyl)-1-(3-methyl-4-(pyridin-4-yl)phenyl)pyrrolidin-2-one (20 mg). LC_MS: (ES + ):m / z 377.1[M+H] + .

[0242] Example 11: Synthesis route of compound 11

[0243]

[0244] Step 1: Compound 11-C 1-(4-bromo-2-chlorophenyl)pyrrolidin-2-one

[0245]

[0246] The synthesis of this step uses compound 10-A 4-bromo-2-chloroaniline as raw material and refers to the synthesis process of the first step in Example 10.

[0247] LC_MS:(ES + ):m / z 274.02[M+H] + .

[0248] Step 2: Compound 11-E 1-(4-bromo-2-chlorophenyl)-3-(4-chlorobenzyl)pyrrolidin-2-one

[0249]

[0250] The synthesis of this step refers to the synthesis process of the second step in Example 10.

[0251] LC_MS:(ES + ):m / z 398.10[M+H] + .

[0252] Step 3: Compound 11 3-(4-chlorobenzyl)-1-(2-chloro-4-(pyridin-4-yl)phenyl)pyrrolidin-2-one

[0253]

[0254] The synthesis of this step refers to the synthesis process of the third step of Example 10

[0255] LC_MS:(ES + ):m / z 397.10[M+H] + .

[0256] 1H NMR (400MHz, DMSO-d6) δ8.71-8.66(m,2H),8.02(d,J=2.1Hz,1H),7.85(dd,J=8.2,2. 1Hz,1H),7.80-7.76(m,2H),7.53(d,J=8.2Hz,1H),7.44-7.31(m,4H),3.73-3.65(m, 1H),3.56(td,J=8.8,3.0Hz,1H),3.10(dd,J=13.7,4.4Hz,1H),2.92(qd,J=9.0,4.4H z,1H),2.76(dd,J=13.6,9.2Hz,1H),2.23-2.10(m,1H),1.86(dq,J=12.4,8.6Hz,1H).

[0257] Example 12: Synthesis route of compound 12

[0258]

[0259] Step 1: Compound 12 3-(4-chlorophenyl)-1-(4-(pyridin-4-yl)phenyl)pyrrolidine-2-thione

[0260]

[0261] To a toluene (2 mL) solution containing compound 1 3-(4-chlorophenyl)-1-(4-(pyridin-4-yl)phenyl)pyrrolidin-2-one (50 mg, 137.80 umol), Lawesson's reagent (167.2 mg, 413.39 umol) was added. The reaction solution was stirred at 100°C for 12 hours. TLC monitored the reaction to be complete. The reaction solution was concentrated, diluted with ethyl acetate, filtered, and the residue obtained by concentrating the mother liquor was separated and purified by preparative thin layer chromatography (eluent: 5% methanol in dichloromethane) to obtain compound 12 3-(4-chlorophenyl)-1-(4-(pyridin-4-yl)phenyl)pyrrolidine-2-thione (16.1 mg).

[0262] LC_MS:(ES + ):m / z 379.10[M+H] + .

[0263] Example 13: Synthesis route of compound 13

[0264]

[0265] Step 1: Compound 13-C 1-(2-chloroethyl)-3-(4-(pyridin-4-yl)phenyl)urea

[0266]

[0267] Compound 13-B chloroethyl isocyanate (308 mg, 2.94 mmol) was added dropwise to a solution of compound 13-A 4-(pyridin-4-yl)aniline (500 mg, 2.94 mmol) in dichloromethane (20 mL) under an ice bath. The reaction mixture was stirred under an ice bath for 1 hour. After the reaction was completed, the reaction solution was diluted with water (20 mL) and extracted with dichloromethane (20 mL x 2). The organic layers were combined and concentrated under reduced pressure. The residue was separated and purified by column chromatography (eluent: 50% ethyl acetate in petroleum ether) to obtain white solid compound 13-C 1-(2-chloroethyl)-3-(4-(pyridin-4-yl)phenyl)urea (360 mg).

[0268] LC_MS:(ES + ):m / z 276.1[M+H] + .

[0269] Step 2: Compound 13-D 1-(4-(pyridin-4-yl)phenyl)imidazolin-2-one

[0270]

[0271] Sodium hydride (104 mg, 2.62 mmol) was added to a solution of compound 13-C 1-(2-chloroethyl)-3-(4-(pyridin-4-yl)phenyl)urea (360 mg, 1.31 mmol) in tetrahydrofuran (5 mL) under ice bath. The reaction mixture was stirred under ice bath for 3 hours. After the reaction was completed, the mixture was filtered, the filter cake was collected and dried to obtain a light yellow solid compound 13-D 1-(4-(pyridin-4-yl)phenyl)imidazoline-2-one (300 mg).

[0272] LC_MS:(ES + ):m / z 240.1[M+H] + .

[0273] Step 3: Compound 13 1-(4-chlorobenzyl)-3-(4-(pyridin-4-yl)phenyl)imidazolin-2-one

[0274]

[0275] Sodium hydride (17.5 mg, 314 μmol) was added to a solution of compound 13-D 1-(4-(pyridin-4-yl)phenyl)imidazoline-2-one (50 mg, 209 μmol) in N,N-dimethylformamide (1 mL) under ice bath conditions. After stirring for 30 minutes, compound 13-E 4-chlorobenzyl bromide (47 mg, 230 μmol) was added. The reaction mixture was stirred for 3 hours under ice bath. After the reaction was completed, the reaction solution was diluted with water (10 mL), filtered, and the filter cake was collected. Pulped with tetrahydrofuran (1 mL) for 2 hours, filtered, the filter cake was collected, and dried to obtain yellow solid compound 13 1-(4-chlorobenzyl)-3-(4-(pyridin-4-yl)phenyl)imidazoline-2-one (30 mg).

[0276] LC_MS:(ES + ):m / z 364.1[M+H] + .

[0277] 1 H NMR(400MHz,Chloroform-d)δ8.66–8.60(m,2H),7.75–7.69(m,2H),7.69–7.62(m,2H),7.55–7.49( m,2H),7.37–7.30(m,2H),7.28(d,J=2.3Hz,2H),4.47(s,2H),3.91–3.82(m,2H),3.44–3.36(m,2H).

[0278] Example 14: Synthesis route of compound 14

[0279]

[0280] Step 1: Compound 14 3-(4-chlorobenzyl)-1-(4-(3-methylpyridin-4-yl)phenyl)pyrrolidin-2-one

[0281]

[0282] The synthesis of this step uses compound 14-A 3-methylpyridine-4-boronic acid as the raw material and refers to the synthesis process of the second step of Example 1.

[0283] LC_MS: (ES+): m / z 377.15 [M+H]+.

[0284] 1H NMR(400MHz, CDCl3)δ8.52(s,1H),8.48(d,J=5.0Hz,1H),7.76–7.71(m,2H),7.40–7.35(m, 2H),7.33–7.29(m,2H),7.22(d,J=8.4Hz,2H),7.16(d,J=5.0Hz,1H),3.80(dd,J=16.8,8.5H z,1H),3.70(td,J=9.1,3.1Hz,1H),3.28(dd,J=13.7,4.1Hz,1H),2.96(ddd,J=17.6,8.9,4 .1Hz,1H),2.86(dd,J=13.7,8.9Hz,1H),2.32(s,3H),2.27–2.21(m,1H),1.93–1.85(m,1H).

[0285] Example 15: Synthesis route of compound 15

[0286]

[0287] Step 1: Compound 15 3-(4-fluorobenzyl)-1-(4-(pyridin-4-yl)phenyl)pyrrolidin-2-one

[0288]

[0289] The synthesis of this step uses compound 15-A 4-fluorobenzyl bromide as the raw material and refers to the synthesis process of the fourth step of Example 3. LC_MS: (ES + ):m / z 347.45[M+H] + .

[0290] 1 H NMR (400MHz, CDCl3) δ8.67(d,J=5.1Hz,2H),7.79(d,J=8.8Hz,2H),7.69(d,J=8.8Hz,2H),7 .54(d,J=6.0Hz,2H),7.23(dd,J=8.5,5.5Hz,2H),7.02(t,J=8.7Hz,2H),3.79(dt,J=15.9,8 .0Hz,1H),3.68(td,J=9.1,3.3Hz,1H),3.28(dd,J=13.6,4.0Hz,1H),2.96(ddd,J=17.5,8. 8,4.1Hz,1H),2.86(dd,J=13.6,8.9Hz,1H),2.30–2.19(m,1H),1.89(dd,J=8.7,4.1Hz,1H).

[0291] Example 16: Synthesis route of compound 16

[0292]

[0293] Step 1: Compound 16 3-(4-chloro-3-fluorobenzyl)-1-(4-(pyridin-4-yl)phenyl)pyrrolidin-2-one

[0294]

[0295] The synthesis of this step uses compound 16-A 3-fluoro-4-chlorobenzyl bromide as the raw material and refers to the synthesis process of the fourth step of Example 3.

[0296] LC_MS:(ES + ):m / z 381.05[M+H] + .

[0297] 1 H NMR (400MHz, CDCl3) δ8.67(d,J=5.7Hz,2H),7.79(d,J=8.7Hz,2H),7.69(d,J=8.7Hz,2H), 7.53(d,J=5.9Hz,2H),7.35(t,J=7.9Hz,1H),7.09(dd,J=9.9,1.5Hz,1H),7.01(d,J=8.2Hz ,1H),3.82(dd,J=16.7,8.9Hz,1H),3.74(td,J=9.1,2.7Hz,1H),3.29(dd,J=13.8,4.2Hz,1 H),3.01–2.92(m,1H),2.85(dd,J=13.8,9.0Hz,1H),2.31–2.23(m,1H),1.92–1.83(m,1H).

[0298] Example 17: Synthesis route of compound 17

[0299]

[0300] Step 1: Compound 17 3-(4-methylbenzyl)-1-(4-(pyridin-4-yl)phenyl)pyrrolidin-2-one

[0301]

[0302] The synthesis of this step uses compound 17-A 4-methylbenzyl bromide as the raw material and refers to the synthesis process of the fourth step of Example 3.

[0303] LC_MS:(ES + ):m / z 343.50[M+H] + .

[0304] 1 H NMR (400MHz, CDCl3) δ8.67(d,J=6.0Hz,2H),7.79(d,J=8.8Hz,2H),7.69(d,J=8.8Hz, 2H),7.54(dd,J=4.7,1.5Hz,2H),7.20–7.10(m,4H),3.77(dt,J=15.8,7.9Hz,1H),3.6 9(td,J=9.1,3.4Hz,1H),3.30(dd,J=13.7,4.1Hz,1H),2.96(ddd,J=17.8,9.0,4.1Hz, 1H), 2.81 (dd, J=13.7, 9.3Hz, 1H), 2.35 (s, 3H), 2.28–2.19 (m, 1H), 1.91–1.86 (m, 1H).

[0305] Example 18: Synthesis route of compound 18

[0306]

[0307] Step 1: Compound 18 3-(4-trifluoromethylbenzyl)-1-(4-(pyridin-4-yl)phenyl)pyrrolidin-2-one

[0308]

[0309] The synthesis of this step uses compound 18-A 4-trifluoromethylbenzyl bromide as the raw material and refers to the synthesis process of the fourth step of Example 3.

[0310] LC_MS:(ES + ):m / z 397.50[M+H] + .

[0311] Example 19: Synthesis route of compound 19

[0312]

[0313] Step 1: Compound 19 3-(4-cyanobenzyl)-1-(4-(pyridin-4-yl)phenyl)pyrrolidin-2-one

[0314]

[0315] The synthesis of this step uses compound 19-A 4-cyanobenzyl bromide as a raw material and refers to the synthesis process of the fourth step of Example 3.

[0316] LC_MS:(ES + ):m / z 354.20[M+H] + .

[0317] 1 H NMR (400MHz, CDCl3) δ8.68(d,J=5.1Hz,2H),7.79(d,J=8.6Hz,2H),7.70(d,J= 8.6Hz,2H),7.64(d,J=8.0Hz,2H),7.56(d,J=5.5Hz,2H),7.40(d,J=8.1Hz,2H) ,3.82(dd,J=16.7,8.8Hz,1H),3.73(td,J=9.1,2.6Hz,1H),3.38(dd,J=13.1,3 .7Hz,1H),3.06–2.90(m,2H),2.31–2.23(m,1H),1.91(dd,J=10.7,7.2Hz,1H).

[0318] Example 20: Synthesis route of compound 20

[0319]

[0320] Step 1: Compound 20-C 2-bromo-5-(pyridin-4-yl)pyrazine

[0321]

[0322] The synthesis of this step uses compound 20-A 2,5-dibromopyrazine as the raw material and refers to the synthesis process of the first step in Example 6.

[0323] LC_MS:(ES + ):m / z 235.95[M+H] + .

[0324] Step 2: Compound 20 3-(4-chlorobenzyl)-1-(5-(pyridin-4-yl)pyrazin-2-yl)pyrrolidin-2-one

[0325]

[0326] The synthesis of this step refers to the synthesis process of the second step of Example 6.

[0327] LC_MS:(ES + ):m / z 365.10[M+H] + .

[0328] 1H NMR (400MHz, CDCl3) δ9.88(s,1H),8.83(s,1H),7.94(s,2H),7.42–7.12(m,6H),4.13–4.01(m,1H),3.95–3.81(m,1H),3.31(dd, J=13.9,4.3Hz,1H),3.04(qd,J=9.3,4.1Hz,1H),2.85(dd,J=13.9,9.1Hz,1H),2.27(dt,J=14.8,6.0Hz,1H),1.96–1.88(m,1H).

[0329] Example 21: Synthesis route of compound 21

[0330]

[0331] Step 1: Compound 21-C 2-bromo-5-(pyridin-4-yl)benzonitrile

[0332]

[0333] The synthesis of this step uses compound 21-A 2-bromo-5-iodobenzonitrile as the raw material and refers to the synthesis process of the first step in Example 6.

[0334] LC_MS:(ES + ):m / z 259.02[M+H] + .

[0335] Step 2: Compound 21 2-(3-(4-chlorobenzyl)-2-pyrrolidinone-1-yl)-5-(pyridin-4-yl)benzonitrile

[0336]

[0337] The synthesis of this step refers to the synthesis process of the second step of Example 6.

[0338] LC_MS:(ES + ):m / z 388.20[M+H] + .

[0339] Example 22: Synthesis route of compound 22

[0340]

[0341] Step 1: Compound 22-B 3-(4-chlorobenzyl)-3-phenylselenyl-1-(4-(4-pyridin-4-yl)phenyl)pyrrolidin-2-one

[0342]

[0343] Under nitrogen atmosphere, compound 22-A 3-(4-chlorobenzyl)-1-(4-(pyridin-4-yl)phenyl)pyrrolidin-2-one (180 mg, 0.5 mmol) was dispersed in 2 mL of tetrahydrofuran, and lithium diisopropylamide (0.4 mL, 2N) was added dropwise at -50°C. After 0.5 hours, a tetrahydrofuran solution of phenylselenium bromide (140 mg, 0.6 mmol) was added dropwise. The reaction was stirred at low temperature for 1 hour, and the target mass spectrum was detected by LCMS, and major points were generated by TLC. Saturated ammonium chloride solution (20 mL) was added to quench the reaction, and the mixture was extracted with dichloromethane (10 mL x 3). The reaction solution was washed with water (15 mL), saturated ammonium chloride solution (20 mL), and saturated brine (20 mL) in sequence. The reaction solvent was removed by rotary evaporation, and the crude product was purified by preparative silica gel plate (DCM: MeOH = 20: 1) and dried in vacuo to obtain white solid compound 22-B 3-(4-chlorobenzyl)-3-phenylselenyl-1-(4-(4-pyridin-4-yl)phenyl)pyrrolidin-2-one (40 mg).

[0344] LC_MS:(ES + ):m / z 519.05[M+H] + .

[0345] Step 2: Compound 22 3-(4-chlorobenzyl)-1-(4-pyridin-4-yl)phenyl)-1,5-dihydro-2H-pyrrol-2-one

[0346]

[0347] Compound 22-B 3-(4-chlorobenzyl)-3-phenylselenyl-1-(4-(4-pyridin-4-yl)phenyl)pyrrolidin-2-one (40 mg, 0.1 mmol) was dissolved in 2 mL of dichloromethane at -78°C, and hydrogen peroxide (0.1 ml, 30% wt) was added dropwise. After 0.5 hours, a drop of pyridine (15 mg, 0.2 mmol) was added dropwise. The reaction was continued to stir at low temperature for 0.5 hours, and then the temperature was raised to room temperature for stirring. The target mass spectrum was detected by LCMS detection. Saturated ammonium chloride solution (10 mL) was added to quench the reaction, and the mixture was extracted with dichloromethane (10 mL x 3). The reaction solution was washed with water (15 mL), saturated ammonium chloride solution (20 mL), and saturated brine (20 mL) in sequence. The reaction solvent was removed by rotary evaporation, and the crude product was purified by reverse phase preparative column and lyophilized to give white solid compound 22 (3-(4-chlorobenzyl)-1-(4-pyridin-4-yl)phenyl)-1,5-dihydro-2H-pyrrol-2-one) (5 mg).

[0348] LC_MS:(ES + ):m / z 361.50[M+H] + .

[0349] Example 23: Synthesis route of compound 23

[0350]

[0351] Step 1: Compound 23-C 1-(2-bromopyrimidin-5-yl)pyrrolidin-2-one

[0352]

[0353] The synthesis of this step uses compound 23-A 2-bromopyrimidin-5-amine as the raw material and refers to the synthesis process of the first step in Example 10.

[0354] LC_MS:(ES + ):m / z 241.90[M+H] + .

[0355] Step 2: Compound 23-E 1-(2-bromopyrimidin-5-yl)-3-(4-chlorobenzyl)pyrrolidin-2-one

[0356]

[0357] The synthesis of this step refers to the synthesis process of the second step in Example 10.

[0358] LC_MS:(ES + ):m / z 241.05[M+H] + .

[0359] Step 3: Compound 23 3-(4-chlorobenzyl)-1-(2-(pyridin-4-yl)pyrimidin-5-yl)pyrrolidin-2-one

[0360]

[0361] The synthesis of this step refers to the synthesis process of the third step in Example 10.

[0362] LC_MS:(ES + ):m / z 365.10[M+H] + .

[0363] Example 24: Synthesis route of compound 24

[0364]

[0365] Step 1: Compound 24 3-Benzyl-1-(4-(pyridin-4-yl)phenyl)pyrrolidin-2-one

[0366]

[0367] The synthesis of this step uses compound 24-A benzyl bromide as raw material and refers to the synthesis process of the fourth step of Example 3. LC_MS: (ES + ):m / z 329.20[M+H] + .

[0368] Example 25: Synthesis route of compound 25

[0369]

[0370] Step 1: Compound 25 3-((6-chloropyridin-3-yl)methyl)-1-(4-(pyridin-4-yl)phenyl)pyrrolidin-2-one

[0371]

[0372] The synthesis of this step uses compound 25-A 5-(bromomethyl)-2-chloropyridine as raw material and refers to the synthesis process of the fourth step of Example 3.

[0373] LC_MS:(ES + ):m / z 364.11[M+H] + .

[0374] Example 26: Synthesis route of compound 26

[0375]

[0376] Step 1: Compound 26 3-(3-chlorobenzyl)-1-(4-(pyridin-4-yl)phenyl)pyrrolidin-2-one

[0377]

[0378] The synthesis of this step uses compound 26-A 3-chlorobenzyl bromide as the raw material and refers to the synthesis process of the fourth step of Example 3. LC_MS: (ES + ):m / z 363.11[M+H] + .

[0379] Example 27: Synthesis route of compound 27

[0380]

[0381] Step 1: Compound 27 3-(4-chlorophenethyl)-1-(4-(pyridin-4-yl)phenyl)pyrrolidin-2-one

[0382]

[0383] The synthesis of this step uses compound 27-A 1-(2-bromoethyl)-4-chlorobenzene as raw material and refers to the synthesis process of the fourth step of Example 3.

[0384] LC_MS:(ES + ):m / z 377.13[M+H] + .

[0385] Example 28: Synthesis route of compound 28

[0386]

[0387] Step 1: Compound 28 3-((5-chloropyridin-2-yl)methyl)-1-(4-(pyridin-4-yl)phenyl)pyrrolidin-2-one

[0388]

[0389] The synthesis of this step uses compound 28-A 2-bromomethyl-5-chloropyridine as raw material and refers to the synthesis process of the fourth step of Example 3.

[0390] LC_MS:(ES + ):m / z 364.11[M+H] + .

[0391] Example 29: Synthesis route of compound 29

[0392]

[0393] Step 1: Compound 29 3-((5-chlorothien-2-yl)methyl)-1-(4-(pyridin-4-yl)phenyl)pyrrolidin-2-one

[0394]

[0395] The synthesis of this step uses compound 29-A 2-(bromomethyl)-5-chlorothiophene as raw material and refers to the synthesis process of the fourth step of Example 3.

[0396] LC_MS:(ES + ):m / z 369.10[M+H] + .

[0397] Example 30: Synthesis route of compound 30

[0398]

[0399] Step 1: Compound 30 3-(3,4-difluorobenzyl)-1-(4-(pyridin-4-yl)phenyl)pyrrolidin-2-one

[0400]

[0401] The synthesis of this step uses compound 30-A 3,4-difluorobenzyl bromide as the raw material and refers to the synthesis process of the fourth step of Example 3.

[0402] LC_MS:(ES + ):m / z 364.15[M+H] + .

[0403] Example 31: Synthesis route of compound 31

[0404]

[0405] Step 1: Compound 31 3-(4-bromobenzyl)-1-(4-(pyridin-4-yl)phenyl)pyrrolidin-2-one

[0406]

[0407] The synthesis of this step uses compound 31-A 4-bromobenzyl bromide as the raw material and refers to the synthesis process of the fourth step of Example 3. LC_MS: (ES + ):m / z 407.08[M+H] + .

[0408] Example 32: Synthesis route of compound 32

[0409]

[0410] Step 1: Compound 32 3-(4-nitrobenzyl)-1-(4-(pyridin-4-yl)phenyl)pyrrolidin-2-one

[0411]

[0412] The synthesis of this step uses compound 32-A 4-nitrobenzyl bromide as the raw material and refers to the synthesis process of the fourth step of Example 3.

[0413] LC_MS:(ES + ):m / z 374.15[M+H] + .

[0414] Example 33: Synthesis route of compound 33

[0415]

[0416] Step 1: Compound 33 3-(3,5-difluorobenzyl)-1-(4-(pyridin-4-yl)phenyl)pyrrolidin-2-one

[0417]

[0418] The synthesis of this step uses compound 33-A 3,5-difluorobenzyl bromide as the raw material and refers to the synthesis process of the fourth step of Example 3.

[0419] LC_MS:(ES + ):m / z 365.15[M+H] + .

[0420] Example 34: Synthesis route of compound 34

[0421]

[0422] Step 1: Compound 34 3-(4-chlorobenzyl)-1-(4-(3-chloropyridin-4-yl)phenyl)pyrrolidin-2-one

[0423]

[0424] The synthesis of this step uses compound 34-A 3-chloropyridine-4-boronic acid as the raw material and refers to the synthesis process of the second step of Example 1.

[0425] LC_MS: (ES+): m / z 397.12 [M+H]+.

[0426] Example 35: Synthesis route of compound 35

[0427]

[0428] Step 1: Compound 35 3-(4-chlorobenzyl)-1-(4-(3-fluoropyridin-4-yl)phenyl)pyrrolidin-2-one

[0429]

[0430] The synthesis of this step uses compound 35-A 3-fluoropyridine-4-boronic acid as the raw material and refers to the synthesis process of the second step of Example 1.

[0431] LC_MS: (ES+): m / z 381.11 [M+H]+.

[0432] Example 36: Synthesis route of compound 36

[0433]

[0434] Step 1: Compound 36 3-(4-chlorobenzyl)-1-(4-(3-cyanopyridin-4-yl)phenyl)pyrrolidin-2-one

[0435]

[0436] The synthesis of this step uses compound 36-A 3-cyanopyridine-4-boronic acid as the raw material and refers to the synthesis process of the second step of Example 1.

[0437] LC_MS: (ES+): m / z 388.11 [M+H]+.

[0438] Example 37: Synthesis route of compound 37

[0439]

[0440] Step 1: Compound 37 3-(4-chlorobenzyl)-1-(4-(nicotinamide pyridin-4-yl)phenyl)pyrrolidin-2-one

[0441]

[0442] Sodium carbonate (40.99 mg, 386.73 umol) was added to 1,4-dioxane (1 mL) / water (1 mL) containing compound 36 3-(4-chlorobenzyl)-1-(4-(3-cyanopyridin-4-yl)phenyl)pyrrolidin-2-one (50 mg, 128.91 umol), and the reaction solution was reacted at 80°C for 3 hours. LCMS monitored the completion of the reaction. The reaction solution was cooled to room temperature and concentrated under reduced pressure. The residue was separated and purified by preparative thin layer chromatography (eluent: 10% methanol in dichloromethane) to obtain yellow solid compound 37 3-(4-chlorobenzyl)-1-(4-(nicotinamide pyridin-4-yl)phenyl)pyrrolidin-2-one (20 mg).

[0443] LC_MS: (ES+): m / z 406.12 [M+H]+.

[0444] Example 38: Synthesis route of compound 38

[0445]

[0446] Step 1: Compound 38 3-(4-chlorobenzyl)-1-(4-(pyridin-4-yl)phenyl)piperidin-2-one

[0447]

[0448] Pd2(dba)3 (19.6 mg, 21.359 umol), Xant-Phos (12.4 mg, 21.359 umol) and cesium carbonate (208.77 mg, 640.76 umol) were added to a dioxane (3 mL) solution containing intermediate BB3 3-(4-chlorobenzyl)piperidin-2-one (47.78 mg, 213.59 umol) and compound 38-A4-(4-bromophenyl)pyridine (50 mg, 213.59 umol). The reaction solution was reacted at 100°C for 3 hours. The reaction was complete when monitored by LCMS. The reaction solution was cooled to room temperature, filtered, and concentrated under reduced pressure. The residue was separated and purified by preparative thin layer chromatography (eluent: 5% methanol in dichloromethane) to give yellow solid compound 38 3-(4-chlorobenzyl)-1-(4-(pyridin-4-yl)phenyl)piperidin-2-one (60 mg).

[0449] LC_MS: (ES+): m / z 377.12 [M+H]+.

[0450] Example 39: Synthesis route of compound 39

[0451]

[0452] Step 1: Compound 39-C 4-(4-bromo-3-methoxyphenyl)pyridine

[0453]

[0454] The synthesis of this step uses compound 39-A 1-bromo-4-iodo-2-methoxybenzene as raw material and refers to the synthesis process of the second step of Example 1.

[0455] LC_MS: (ES+): m / z 264.00 [M+H]+.

[0456] Step 2: Compound 39 3-(4-chlorobenzyl)-1-(2-methoxy-4-(pyridin-4-yl)phenyl)piperidin-2-one

[0457]

[0458] The synthesis of this step uses compound 39-C 4-(4-bromo-3-methoxyphenyl)pyridine as raw material and refers to the synthesis process of the first step of Example 38.

[0459] LC_MS: (ES+): m / z 407.14 [M+H]+.

[0460] Example 40: Synthesis route of compound 40

[0461]

[0462] Step 1: Compound 40-B 2-(4-bromophenyl)-1,2-oxazolidin-3-one

[0463]

[0464] The synthesis of this step uses compound 40-A 4-chlorobutyryl chloride as raw material and refers to the synthesis process of the second step of Example 3.

[0465] LC_MS: (ES+): m / z 256.02 [M+H]+.

[0466] Step 2: Compound 40-D 2-(4-(pyridin-4-yl)phenyl)-1,2-oxazolidin-3-one

[0467]

[0468] The synthesis of this step uses compound 40-B 2-(4-bromophenyl)-1,2-oxazolidin-3-one as raw material and refers to the synthesis process of the third step of Example 3.

[0469] LC_MS: (ES+): m / z 255.11 [M+H]+.

[0470] Step 3: Compound 40 4-(4-chlorobenzyl)-2-(4-(pyridin-4-yl)phenyl)-1,2-oxazol-3-one

[0471]

[0472] The synthesis of this step uses compound 40-D 2-(4-(pyridin-4-yl)phenyl)-1,2-oxazolidin-3-one as the raw material and refers to the synthesis process of the fourth step of Example 3.

[0473] LC_MS: (ES+): m / z 379.11 [M+H]+.

[0474] Example 41: Synthesis route of compound 41

[0475]

[0476] Step 1: Compound 41 3-(2,4-difluorobenzyl)-1-(4-(pyridin-4-yl)phenyl)pyrrolidin-2-one

[0477]

[0478] The synthesis of this step uses compound 41-A 2,4-difluorobenzyl bromide as the raw material and refers to the synthesis process of the fourth step of Example 3.

[0479] LC_MS:(ES +):m / z 365.15[M+H] + .

[0480] Example 42: Synthesis route of compound 42

[0481]

[0482] Step 1: Compound 42 3-(4-chloro-2-fluorobenzyl)-1-(4-(pyridin-4-yl)phenyl)pyrrolidin-2-one

[0483]

[0484] The synthesis of this step uses compound 42-A 4-chloro-2-fluorobenzyl bromide as the raw material and refers to the synthesis process of the fourth step of Example 3.

[0485] LC_MS:(ES + ):m / z 365.15[M+H] + .

[0486] Example 43: Synthesis route of compound 43

[0487]

[0488] Step 1: Compound 43-C(E)-1-(4-bromophenyl)-3-(4-chlorobenzylidene)pyrrolidine-2,5-dione

[0489]

[0490] Weigh compound 43-A N-(4-bromophenyl)maleimide (250 mg, 0.99 mmol) and compound 43-B (154 mg, 1.10 mmol) and dissolve them in 10 mL of anhydrous ethanol. Add triphenylphosphine (274 mg, 1.05 mmol) at room temperature and react overnight at room temperature. After the reaction is completed, filter and wash with ethanol twice. Take the filter residue and dry it in vacuum to obtain compound 43-C(E)-1-(4-bromophenyl)-3-(4-chlorobenzylidene)pyrrolidine-2,5-dione (240 mg).

[0491] LC_MS:(ES + ):m / z 377.90[M+H]+.

[0492] Step 2: Compound 43-E (E)-3-(4-chlorobenzylidene)-1-(4-(pyridin-4-yl)phenyl)pyrrolidine-2,5-dione

[0493]

[0494] The synthesis of this step uses compound 43-C(E)-1-(4-bromophenyl)-3-(4-chlorobenzylidene)pyrrolidine-2,5-dione as raw material and refers to the synthesis process of the third step of Example 3.

[0495] LC_MS:(ES + ):m / z 375.15[M+H] + .

[0496] Step 3: Compound 43 3-(4-chlorobenzyl)-1-(4-(pyridin-4-yl)phenyl)pyrrolidin-2,5-one

[0497]

[0498] Weigh compound 43-E(E)-3-(4-chlorobenzylidene)-1-(4-(pyridin-4-yl)phenyl)pyrrolidine-2,5-dione (12 mg), add 2 mL of anhydrous ethanol, 2 mL of tetrahydrofuran, 2 mg of Pd / C, and replace with hydrogen three times. React at room temperature overnight, separate by preparative thin layer chromatography, and separate and purify by pre-HPLC to obtain compound 43 3-(4-chlorobenzyl)-1-(4-(pyridin-4-yl)phenyl)pyrrolidine-2,5-one (3 mg).

[0499] LC_MS:(ES + ):m / z 377.05[M+H] +

[0500] 1 H NMR(400MHz,Chloroform-d)δ8.71(d,J=5.1Hz,2H),7.77-7.72(m,2H),7.54-7.50(m,2H),7.36(dt,J=8.3,3.4Hz,4H),7.20(d,J=8.1Hz,2H),3. 37(dt,J=8.7,4.4Hz,1H), 3.26(dd,J=13.9,4.6Hz,1H), 3.11(dd,J=14.0,8.0Hz,1H), 2.96(dd,J=18.5,9.2Hz,1H), 2.66(dd,J=18.5,4.9Hz,1H).

[0501] Synthetic routes of compounds 44-52

[0502] The synthetic route of the following compounds is as follows, referring to the synthetic method of the fourth step of Example 3, using corresponding reagents for synthesis:

[0503]

[0504]

[0505]

[0506] Biological activity test example:

[0507] Biological Activity Example 1: Preparation of SARM1 enzyme

[0508] Preparation of test compounds:

[0509] Test compounds were prepared at stock concentrations of 200 uM or 10 mM (in DMSO) and further diluted to desired compound concentrations for in vitro SARM1 enzyme assays and inhibitor screening.

[0510] Expression and purification of SARM1 protein

[0511] (1) Plasmid construction

[0512] The gene sequence of SARM1 protein was amplified by PCR, and the PCR amplification product was constructed into pcDNA3.1-HIS-C plasmid. The above construction was completed by Youbao Bio (Hunan, China).

[0513] (2) Plasmid transfection

[0514] HEK293 cells were cultured in a 10 cm dish using DMEM, and the next day the cells were transfected with 15 μg of pcDNA3.1-SARM1-HIS-C expression plasmid.

[0515] (3) Cell collection and protein extraction

[0516] The cells were collected 48 hours after transfection, and the SARM1 protein expressed in the cells was obtained by diginotin cleavage for in vitro activity assay. The details are as follows:

[0517] Digest the cells with trypsin-EDTA, centrifuge at 1000rpm for 5 minutes, wash once with PBS, and then resuspend the cells with PBS containing 100μM diginotin, 0.6mL PBS / 10cm cells, and lyse for 5 minutes. Take the cells and add trypan blue to observe under a microscope. More than 90% of the cells have been lysed. Centrifuge at 5000rpm for 10 minutes and collect the supernatant of SARM1 protein.

[0518] Biological Activity Example 2: In vitro biochemical test for inhibition of SARM1 enzyme activity (IC 50 ):

[0519] First, 200 μM of the compound was added to a 50 mM Tris-HCl (pH 7.5) solution containing 0.05 μg / ml SARM1, and then half of it was added to an equal volume of 50 mM Tris-HCl (pH 7.5) solution containing 0.05 μg / ml SARM1 and mixed. The drug was diluted 6 times by analogy, and the final concentrations were 200, 100, 50, 25, 12.5, 6.25, 3.125 μM, or 200, 50, 12.5, 3.125, 0.78, 0.195, 0.049 μM, respectively. The control group was not added with inhibitors, and incubated at room temperature for 10 minutes.

[0520] Then, 50 μM NAD, 50 μM PC6 as substrates and 50 μM NMN as activator were added to the SARM1 protein after incubation with the inhibitor, and reacted at room temperature for 30 minutes. The concentration of each component is the final concentration in the reaction system.

[0521] During the reaction, the PC6 fluorescence spectrum dynamics were detected by an ELISA instrument, where the excitation wavelength and emission wavelength were 390 nm and 520 nm, respectively. The reaction rate was finally used to represent the activity of the protein and the half inhibition concentration was calculated. The higher the reaction rate, the stronger the protein activity and the lower the inhibition efficiency of the compound.

[0522] The dosage curve of compounds inhibiting SARM1 NAD enzyme activity was prepared using the above method.

[0523] The IC values ​​of these compounds in the assay are provided in Table 1 below. 50 Range:

[0524] ICs that inhibit SARM1 enzyme activity 50 Range: A<1μM; B:1-10μM; C:10-30μM

[0525] Table 1

[0526]

[0527]

[0528]

[0529] Biological Activity Example 3: Axon Degeneration Index

[0530] Mouse DRG explant culture

[0531] Dorsal root ganglia were dissected from two-month-old C57BL / 6 male mice and placed in a 35 mm culture dish containing pre-cooled HBSS buffer. Excess tissue of each dorsal root ganglion was removed using a scalpel and cut into 2-3 explants, which were planted in the wells of a 96-well plate coated with 100 ng / mL Matrigel (Corning), and 100 μL DRG culture medium (Neurobasal medium (Gibco) containing 2% B-27 (Gibco), 1% GlutaMax (Gibco) and 10 ng / mL NGF (MCE)) was added and placed in a 37 degree incubator for one week, the medium was changed once on the fourth day, and the experiment was performed on the eighth day.

[0532] Axonal Wallerian degeneration assay

[0533] The definition and measurement principle of axonal degeneration index can refer to the method reported in the prior art literature (Gerdts J, Sasaki Y, Vohra B, Marasa J, Milbrandt J. Image-based screening identifies novel roles for IkappaB kinase and glycogen synthase kinase 3 in axonal degeneration. J Biol Chem. 2011 Aug 12; 286(32): 28011-8). In the present invention, the specific determination method is as follows:

[0534] Take 0.1 μL of 10 mM test compound and dissolve it in 100 μL DRG culture medium to prepare a new culture medium containing 10 μM test compound. Pipette the culture medium in the 96-well plate and add the new culture medium containing the test compound, and incubate with the dorsal root ganglion explants in a 37-degree incubator for 2 hours for protection. After incubation, use a glass electrode to cut the axons in the area near the tissue block, and take bright field photos of the axons in the same area with a microscope (Olympus) at 20 times the scope at 0 hours and 24 hours. Use an internally developed script to evaluate axonal integrity. Among them, the results are listed in Table 2 below, classified by protection degree (A): >50% and (B): 20%-50%.

[0535] The results showed that the following compounds all exhibited potent neuroprotective effects in the explant axon Wallerian degeneration assay at a concentration of 10 μM.

[0536] Table 2

[0537] Compound No. Degree of protection of axons from Wallerian degeneration 1 A 3 B 6 A 7 A 8 A 15 B 17 A 20 B 21 B

Claims

1. Compound of formula (I): or its racemate, enantiomer, diastereomer, deuterated substance or pharmaceutically acceptable salt thereof, in, X1, X2, X3, X4, X5 are each independently selected from CH or N; Z represents -CH2-, -CH2(CH3)- or -O-; represents a single bond or a double bond; Y represents a carbon atom or a nitrogen atom; R1 is independently selected from H, halogen, C1-C3 alkyl, cyano, trifluoromethyl, amino, hydroxyl, methoxy-C(O)NH2, preferably H, F, Cl, methyl, cyano and -C(O)NH2; R2 is independently selected from H, halogen, C1-C3 alkyl, cyano, trifluoromethyl, amino, hydroxy, methoxy, C1-C3 alkyl-OC(O)-, C1-C3 alkyl-NHC(O)-, preferably H, cyano, Cl, methyl and methoxy; M stands for O or S; L is selected from -CH2-CH2-, -CH2-, -O-, -S-, -NH- and -CO-, wherein one -CH2- in the -CH2-CH2- can be optionally replaced by -O-, -S-, -CO- or -NH-; preferably, L is selected from -CH2-, -CH2-CH2-, -CH-O-, -O- and -CO-; E is selected from Wherein, X6, X7, X8 are each independently selected from CH or N; R3 is independently selected from H, halogen, methyl, cyano, trifluoromethyl, nitro, preferably H, F, Cl, Br, cyano, trifluoromethyl, nitro; R4 is independently selected from H, halogen, methyl, cyano, trifluoromethyl, and nitro, preferably H, F, Cl, Br, cyano, trifluoromethyl, and nitro.

2. The compound according to claim 1 or its racemate, enantiomer, diastereomer, deuterated substance or pharmaceutically acceptable salt thereof, wherein E is selected from wherein X6, X7, X8, R3 and R4 are as defined in claim 1.

3. The compound according to claim 1 or 2, or its racemate, enantiomer, diastereomer, deuterated substance or pharmaceutically acceptable salt thereof, wherein the compound of formula (I) has the following structure of formula (II): wherein X1, X2, X3, X4, X5, L, Y, R1, R3 and R4 are as defined in claim 1.

4. The compound according to any one of claims 1 to 3, or its racemate, enantiomer, diastereomer, deuterated substance or pharmaceutically acceptable salt thereof, wherein the compound is selected from the following compounds:

5. Use of a compound as claimed in any one of claims 1 to 4 or its racemate, enantiomer, diastereomer, deuterated substance or pharmaceutically acceptable salt thereof in the preparation of a medicament for treating or preventing a neurodegenerative disease or a neurological disease or condition.

6. Use of the compound according to any one of claims 1 to 5 or its racemate, enantiomer, diastereomer, deuterated substance or pharmaceutically acceptable salt thereof in the preparation of a SARM1 enzyme activity inhibitor.

7. Use of the compound according to any one of claims 1 to 6 or its racemate, enantiomer, diastereomer, deuterated substance or pharmaceutically acceptable salt thereof in the preparation of a medicament for treating or preventing axonal degeneration-related diseases or disorders.

8. The method according to any one of claims 5 to 7, wherein the neurodegenerative disease or neurological disease or disorder or axonal degeneration-related disease or disorder is selected from Alzheimer's disease, Parkinson's disease, multiple sclerosis, amyotrophic lateral sclerosis, peripheral neuropathy.

9. A pharmaceutical composition comprising the compound according to any one of claims 1 to 4 or its racemate, enantiomer, diastereomer, deuterated substance or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

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