Tricyclic pyridine compound as SARM1 enzyme activity inhibitor and application thereof

Abstract

The invention provides application of an SARM1 enzyme activity inhibitor in treating neurodegenerative diseases or neurological diseases or symptoms. The invention particularly provides a compound as an SARM1 enzyme activity inhibitor and a pharmaceutical composition of the compound. # imgabs0 #

Description

Technical Field

[0001] The present application relates to compounds that can be used to inhibit SARM1 enzyme activity and 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 the first aspect, the present invention provides a compound of formula (I) which can be used as an inhibitor of SARM1 enzyme activity:

[0015]

[0016] or its racemate, enantiomer, diastereomer, deuterated substance or pharmaceutically acceptable salt thereof, wherein,

[0017] X1 is selected from -O-, -CH 2- , -OCH2-, -NR3CH2-, -CH2NR3-, -N=CH-, -CH=N-, excellent

[0018] Select -O-;

[0019] Wherein R3 is selected from H and C1-C3 alkyl;

[0020] X2, X3, X4 are each independently selected from CH or N;

[0021] 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;

[0022] 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;

[0023] M represents O, S or NH, preferably O;

[0024] L1 and L3 are each independently selected from -CH(R')-, -O-, -S- and -N(R')-, provided that at least one of L1 and L3 is -CH(R')-, wherein R' is hydrogen or C1-C3 alkyl;

[0025] L2 is selected from H, -CH3, -CH2-CH3, -CH2-CH2-CH3, -OR8, -NHR9;

[0026] Wherein, R8 and R9 are independently selected from H and C1-C3 alkyl;

[0027] A is selected from H, 5- to 10-membered aryl, 5- to 10-membered heteroaryl, 5- to 10-membered cycloalkyl, 5- to 10-membered heterocycloalkyl, 5- to 10-membered aryl and 3- to 6-membered cycloalkyl, 5- to 10-membered aryl and 3- to 6-membered heterocycloalkyl, wherein the heteroaryl or heterocycloalkyl may contain 1 or 2 heteroatoms selected from N, O and S, and the 5- to 10-membered aryl, 5- to 10-membered heteroaryl, 5- to 10-membered aryl and 3- to 6-membered cycloalkyl, 5- to 10-membered aryl and 3- to 6-membered heterocycloalkyl may be substituted by 1, 2 or 3 substituents selected from the following: halogen, C1-C3 alkyl, C1-C3 alkoxy, halo-C1-C3 alkyl, halo-C1-C3 alkoxy, cyano, nitro and (R a R a ')N-, where R a and R a 'are each independently selected from hydrogen and C1-C3 alkyl; preferably, the substituent is selected from methyl, methoxy, trifluoromethyl, trifluoromethoxy, F, Cl, Br;

[0028] L1 may be linked to L2 to form a 5-membered ring or a 6-membered ring, preferably a 5-membered ring.

[0029] In a preferred aspect, the compound of formula (I) of the present invention has the following structure:

[0030]

[0031] in,

[0032] X2, X3, X4, R1, R2, L3, A are as defined above;

[0033] X5 is selected from CH2, O, NH, preferably CH2.

[0034] In a preferred aspect, the compound of formula (I) of the present invention has the following structure:

[0035]

[0036] in,

[0037] R1, R2, M, L1, L2, L3, A are as defined above.

[0038] In a preferred aspect, the compound of formula (I) of the present invention has the following structure:

[0039]

[0040] in,

[0041] X2 and X3 are selected from CH and N, and X2 and X3 are not CH at the same time;

[0042] R1, R2, M, L1, L2, L3, A are as defined above.

[0043] In a preferred aspect, the compound of formula (II) of the present invention has the following structure:

[0044]

[0045] in,

[0046] R1, R2, X2, X3, and A are as defined above.

[0047] In a preferred aspect, the compound of formula (III) of the present invention has the following structure:

[0048]

[0049] in,

[0050] R1, R2, and A are as defined above.

[0051] In a preferred aspect, the compound of formula (IV) of the present invention has the following structure:

[0052]

[0053] in,

[0054] X2 and X3 are selected from CH and N, and X2 and X3 are not CH at the same time;

[0055] R1, R2, and A are as defined above.

[0056] 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:

[0057]

[0058]

[0059]

[0060]

[0061]

[0062]

[0063]

[0064]

[0065]

[0066]

[0067]

[0068] Herein, when referring to the compound of formula (I), it also includes the pharmaceutically acceptable salt of the compound of formula (I) or its stereoisomers (including enantiomers, diastereomers, racemates) or its tautomers or deuterated products.

[0069] In another aspect, the present invention provides use of the SARM1 enzyme activity inhibitor of the present invention in the preparation of a SARM1 enzyme activity inhibitor.

[0070] In another aspect, the present invention provides the use of the SARM1 enzyme activity inhibitor of the present invention in the preparation of a medicament for treating or preventing axonal degeneration-related diseases or disorders.

[0071] In another aspect, the present invention provides use of the SARM1 enzyme activity inhibitor of the present invention in the preparation of a medicament for treating or preventing a neurodegenerative disease or a neurological disease or condition.

[0072] Accordingly, 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 axonal degeneration-related diseases or conditions, 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.

[0073] 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

[0074] the term

[0075]

[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.

[0076] 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.

[0077] 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.

[0078] 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.

[0079] 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.

[0080] 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.

[0081] 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.

[0082] 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.

[0083] 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.

[0084] 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.

[0085] 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".

[0086] 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.

[0087] 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.

[0088] Unless otherwise defined, when a substituent is marked as "optionally substituted", the substituent is selected from, for example, substituents such as C1-C3 alkyl, C3-C6 cycloalkyl, C5-C 10Aryl, 3-10 membered heterocyclic group, halogen (including F, Cl, Br), hydroxyl, C1-C3 alkoxy, nitro, cyano, oxo (=O), C1-C3 alkyl acyl, C5-C 10 Aryloxy, C1-C3 alkylacyloxy, amino, C1-C3 alkylamino, C5-C 10 Arylamino, C1-C3 alkylthio, etc.

[0089] 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-.

[0090] 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)).

[0091] The term "aromatic ring" or "aryl" refers to an aromatic 5-10 membered ring structure. An aromatic carbocyclic ring refers to an aromatic carbocyclic ring structure whose ring members are all composed of carbon atoms. A non-aromatic carbocyclic ring refers to a non-aromatic carbocyclic ring structure whose ring members are all composed of carbon atoms.

[0092] The term "heteroaryl" as used herein refers to a 5-10 membered aromatic group containing 1, 2 or 3 heteroatoms selected from O, N, S.

[0093] "Halo" or "halogen" includes fluorine, chlorine, bromine and iodine; fluorine and chlorine are preferred.

[0094] 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, preferably 3-6 members, and containing at least one heteroatom selected from O, N, S, P (preferably containing 1, 2 or 3 heteroatoms selected from O, N and S). 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.

[0095] 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.

[0096] 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.

[0097] As used herein, the term "treat," ...

[0098] 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.

[0099] 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.

[0100] 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.

[0101] 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.

[0102] Route of administration

[0103] 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.

[0104] 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.

[0105] 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.

[0106] 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.

[0107] 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.

[0108] 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).

[0109] Kit / Product Packaging

[0110] 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.

[0111] 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.

[0112] 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.

[0113] 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.

[0114] 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.

[0115] 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.

[0116] 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.

[0117] 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.

[0118] 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).

[0119] 1 HNMR (400 MHz) spectra were recorded on a Bruker spectrometer at room temperature with TMS or residual solvent peak as internal standard. Chemical shift values ​​or peak shape multiples are given in (δ), and coupling constants (J) are given in absolute values ​​in Hertz (Hz). 1The multiplicity abbreviations in HNMR spectra are as follows: s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet), br or broad (broadened).

[0120] 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.

[0121] 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%).

[0122] Preparative TLC was performed on Whatman LK6F Silica Gel 60A plates of size 20x20 cm, thickness 500 μm.

[0123] The following examples are intended to illustrate embodiments of the present invention but are not intended to limit the same in any way.

[0124] Synthetic route of intermediate BB1

[0125]

[0126] Step 1: Intermediate BB1-C (5-bromo-2-(3-fluoropyridin-4-yl)phenyl)methanol

[0127]

[0128] PdCl2(dppf)·CH2Cl2(1.3g, 1.598mmol) and sodium carbonate (4.23g, 39.94mmol) were added to a solution of 1,4-dioxane (100mL) and water (10mL) containing intermediate BB1-A (5-bromo-2-iodophenyl)methanol (5.0g, 15.98mmol) and intermediate BB1-B 3-fluoropyridine-4-boronic acid pinacol ester (3.56g, 15.98mmol) at room temperature. The reaction system was replaced with nitrogen three times, heated to 80℃ and stirred for 12 hours. TLC monitored the reaction to be complete. The reaction solution was cooled to room temperature, filtered with celite, and concentrated under reduced pressure. The crude product was separated and purified by silica gel column chromatography (eluent: 50% ethyl acetate in petroleum ether) to obtain brown oily intermediate BB1-C (5-bromo-2-(3-fluoropyridin-4-yl)phenyl)methanol (1.71g).

[0129] LC_MS:(ES + ):m / z 281.95[M+H] + .

[0130] Step 2: Intermediate BB1 ​​8-bromo-6H-isochromeno[3,4-c]pyridine

[0131]

[0132] Sodium hydride (484.9 mg, 12.123 mmol, 60% purity) was added to a tetrahydrofuran (30 mL) solution containing the intermediate BB1-C (5-bromo-2-(3-fluoropyridin-4-yl)phenyl)methanol (1.71 g, 6.061 mmol) at 0°C. The reaction solution was stirred at room temperature for 12 hours. TLC monitored the reaction to be complete. The reaction solution was slowly poured into a saturated ammonium chloride (30 mL) solution and extracted with ethyl acetate (30 mL x 2). The organic layers were combined, washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was separated and purified by silica gel column chromatography (eluent: 33% to 50% ethyl acetate in petroleum ether) to obtain a yellow solid intermediate BB1 ​​8-bromo-6H-isochromano[3,4-c]pyridine (1.3 g).

[0133] LC_MS:(ES + ):m / z 261.94[M+H] + .

[0134] 1H NMR (400MHz, CDCl3) δ8.38 (s, 1H), 8.33 (d, J = 5.1Hz, 1H), 7.63 (d, J = 8.3Hz, 1H), 7.60-–7.52 (m, 2H), 7.38 (d, J = 1.4Hz, 1H), 5.19 (s, 2H).

[0135] Synthetic route of intermediate BB2

[0136]

[0137] Step 1: Intermediate BB2 1-(6H-isochromeno[3,4-c]pyridin-8-yl)pyrrolidin-2-one

[0138]

[0139] Pd2(dba)3 (225.4 mg, 0.246 mmol), Xant-Phos (142.3 mg, 0.246 mmol) and cesium carbonate (3.2 g, 9.844 mmol) were added to a solution of 1,4-dioxane (20 mL) containing intermediate BB1 ​​8-bromo-6H-isochromeno[3,4-c]pyridine (1.3 g, 4.922 mmol) and intermediate BB2-A pyrrolidin-2-one (418.9 mg, 4.922 mmol) at room temperature. The reaction system was replaced with nitrogen three times, heated to 100°C and stirred for 2 hours. The reaction was complete when monitored by TLC. The reaction solution was cooled to room temperature, filtered through celite, and concentrated under reduced pressure. The crude product was separated and purified by silica gel column chromatography (eluent: 7.2% methanol in dichloromethane) to give a yellow solid intermediate BB2 1-(6H-isochromeno[3,4-c]pyridin-8-yl)pyrrolidin-2-one (1.14 g).

[0140] LC_MS:(ES + ):m / z 267.10[M+H] + .

[0141] 1 H NMR (400MHz, CDCl3) δ8.35(s,1H),8.29(d,J=5.0Hz,1H),7.74(d,J=8.5Hz,1H),7.69(s,1H),7.58(d,J=8.4H z,1H),7.53(d,J=5.0Hz,1H),5.22(s,2H),3.92(t,J=7.0Hz,2H),2.67(t,J=8.1Hz,2H),2.27–-2.16(m,2H).

[0142] Synthetic route of intermediate BB3

[0143]

[0144] Step 1: Intermediate BB3-B 2-bromo-5-nitrobenzyl alcohol

[0145]

[0146] BH3-THF (40.64 mL, 40.64 mmol) was added to a tetrahydrofuran (50 mL) solution containing the intermediate BB3-A 2-bromo-5-nitrobenzoic acid (5 g, 20.32 mmol) at room temperature, and the reaction solution was reacted at 60°C for 4 hours. TLC monitored the reaction to be complete. The reaction solution was quenched with methanol (50 mL) and concentrated under reduced pressure. The crude product was separated and purified by silica gel column chromatography (eluent: 20% ethyl acetate in petroleum ether solution) to obtain a beige solid intermediate BB3-B 2-bromo-5-nitrobenzyl alcohol (4.2 g).

[0147] 1 H NMR (400MHz, CDCl3) δ8.45 (d, J = 2.7Hz, 1H), 8.04 (dd, J = 8.7, 2.7Hz, 1H), 7.74 (d, J = 8.7Hz, 1H), 4.85 (s, 2H).

[0148] Step 2: Intermediate BB3-D (2-(3-fluoropyridin-4-yl)-5-nitrophenyl)methanol

[0149]

[0150] Pd(dppf)Cl2-CH2Cl2 (1.48 g, 1.81 mmol) was added to 1,4-dioxane (60 mL) and water (10 mL) containing intermediate BB3-B 2-bromo-5-nitrobenzyl alcohol (4.2 g, 18.1 mmol), intermediate BB3-C 3-fluoropyridine-4-boronic acid pinacol ester (6.05 g, 27.15 mmol) and sodium carbonate (5.75 g, 54.3 mmol) at room temperature under nitrogen protection. 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 extracted with water (60 mL) and dichloromethane (120 mL), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was separated and purified by silica gel column chromatography (eluent: 40% ethyl acetate in petroleum ether solution) to give a brown solid intermediate BB3-D (2-(3-fluoropyridin-4-yl)-5-nitrophenyl)methanol (4.1 g).

[0151] LC_MS:(ES + ):m / z 249.05[M+H] + .

[0152] 1 H NMR (400MHz, CDCl3) δ8.56(dd,J=17.5,2.7Hz,3H),8.25(dd,J=8.4,2.1Hz,1H),7.45(d,J=8.4Hz,1H),7.31(s,1H),4.66(s,2H).

[0153] Step 3: Intermediate BB3-E 8-nitro-6H-isochromeno[3,4-c]pyridine

[0154]

[0155] At 0°C, sodium hydride (1.29 g, 32.23 mmol) was added to a tetrahydrofuran (50 mL) solution containing the intermediate BB3-D (2-(3-fluoropyridin-4-yl)-5-nitrophenyl) methanol (4 g, 16.11 mmol), and the reaction solution was heated to room temperature and stirred 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, and extracted with dichloromethane (20 mL x 2). The combined organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was separated and purified by silica gel column chromatography (eluent: 4.76% methanol in dichloromethane) to obtain a yellow solid intermediate BB3-E 8-nitro-6H-isochromano[3,4-c]pyridine (3.3 g).

[0156] LC_MS:(ES + ):m / z 229.05[M+H] + .

[0157] Step 4: Intermediate BB3 6H-isochromeno[3,4-c]pyridin-8-amine

[0158]

[0159] Zinc powder (4.59 g, 70.11 mmol) was added in batches to an ethanol (50 mL) / water (10 mL) solution containing the intermediate BB3-E 8-nitro-6H-isochromeno[3,4-c]pyridine (3.2 g, 14.02 mmol) and ammonium chloride (3.75 g, 70.11 mmol) at 80°C, and the reaction solution was stirred at 80°C for 18 hours. TLC monitored the reaction to be complete. The reaction solution was filtered, the filtrate was concentrated, and water (20 mL) and dichloromethane (30 mL x 3) were added for extraction. The combined organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was separated and purified by silica gel column chromatography (eluent: 4.76% methanol in dichloromethane) to obtain a brown solid intermediate BB3 6H-isochromeno[3,4-c]pyridine-8-amine (1.9 g).

[0160] LC_MS:(ES + ):m / z 199.0[M+H] + .

[0161] 1 H NMR (400MHz, DMSO) δ8.16-–8.10(m,2H),7.59(t,J=6.8Hz,2H),6.61(dd,J=8.4,2.3Hz,1H),6.41(d,J=2.2Hz,1H),5.71(s,2H),5.06(s,2H).

[0162] Synthetic route of intermediate BB4

[0163]

[0164] Step 1: Intermediate BB4-C tert-butyl 3-(4-chlorobenzyl)-2-oxopyrrolidine-1-carboxylate

[0165]

[0166] LiHMDS (21.6 ml, 21.6 mmol) was slowly added to a tetrahydrofuran (60 mL) solution containing the intermediate BB4-A 2-oxopyrrolidine-1-carboxylic acid tert-butyl ester (4 g, 21.6 mmol) at -60°C under nitrogen protection. After reacting at -60°C for 1 hour, a tetrahydrofuran solution (10 mL) containing the intermediate BB4-B 4-chlorobenzyl bromide (4.44 g, 21.6 mmol) was slowly added dropwise. The reaction solution was reacted at -60°C for 2 hours and then heated 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) to quench, extracted with ethyl acetate, and the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting crude product was separated and purified by silica gel column chromatography (eluent: 10-15% ethyl acetate in petroleum ether solution) to give a colorless oily intermediate BB4-C 3-(4-chlorobenzyl)-2-oxopyrrolidine-1-carboxylic acid tert-butyl ester (1.7 g).

[0167] 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).

[0168] Step 2: Intermediate BB4 3-(4-chlorobenzyl)pyrrolidin-2-one

[0169]

[0170] The intermediate BB4-C 3-(4-chlorobenzyl)-2-oxopyrrolidine-1-carboxylic acid tert-butyl ester (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 the intermediate BB4 3-(4-chlorobenzyl)pyrrolidin-2-one (1.15 g) as a white solid. LC_MS: (ES + ):m / z210.06[M+H] +

[0171] Synthetic route of intermediate BB5

[0172]

[0173] Step 1: Intermediate BB5-C tert-butyl 3-(4-fluorobenzyl)-2-oxopyrrolidine-1-carboxylate

[0174]

[0175] The intermediate BB5-A tert-butyl 2-oxopyrrolidine-1-carboxylate (7404 mg, 40 mmol) was dissolved in THF (120 mL), cooled to -78 °C under nitrogen protection, and lithium bis(trimethylsilyl)amide (42 mmol, 42 mL) was added. The temperature was controlled to react for 1 hour. The intermediate BB5-B 1-(bromomethyl)-4-fluorobenzene (7518 mg, 40 mmol) was dissolved in tetrahydrofuran (40 mL), and the mixture was added to the reaction solution within 5 minutes. The temperature was controlled to react for 1 hour. Saturated ammonium chloride (30 mL) was added to quench the mixture, and the organic solvent was removed by concentration under reduced pressure. The aqueous phase was extracted with ethyl acetate (50 mL x 3), and the combined organic phase was washed with water (50 mL x 2) and saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to dryness. The residue was separated and purified by silica gel column chromatography (eluent: 27% ethyl acetate in n-hexane solution) to obtain the intermediate BB5-C tert-Butyl 3-(4-fluorobenzyl)-2-oxopyrrolidine-1-carboxylate (5240 mg, 18.22 mg), yield: 42.2%.

[0176] 1 H NMR (400MHz, Chloroform-d) δ7.21(dd,J=7.4,1.4Hz,1H),7.11(s,1H),7.06(d,J=7.5Hz,1H),4.67(s,3H),3.19(s,4H).

[0177] Step 2: Intermediate BB5 3-(4-fluorobenzyl)pyrrolidin-2-one

[0178]

[0179] The intermediate BB5-C tert-butyl 3-(4-fluorobenzyl)-2-oxopyrrolidine-1-carboxylate (5240 mg,

[0180] The mixture was stirred at room temperature for 1 hour and concentrated to dryness under reduced pressure. The residue was separated and purified by silica gel column chromatography (eluent: 7.6% methanol in dichloromethane) to obtain the intermediate BB5 3-(4-fluorobenzyl)pyrrolidin-2-one (2950 mg) in a yield of 84%.

[0181] LC_MS:(ES + ):m / z 194.07[M+H]+

[0182] Synthesis route of intermediate BB6

[0183]

[0184] Step 1: Intermediate BB6 2-(Bromomethyl)-5-chlorothiophene

[0185]

[0186] Phosphorus tribromide (136.6 mg, 0.505 mmol) was added to a dichloromethane (5 mL) solution containing the intermediate BB6-A 5-chloro-2-thiophene methanol (50 mg, 0.336 mmol) at 0°C, and the reaction solution was stirred from 0°C to room temperature for 4 hours. TLC monitored the reaction to be complete. Ice water was added to the reaction solution, and dichloromethane was extracted. The combined organic phase was dried over anhydrous sodium sulfate and concentrated. The crude product was separated and purified by preparative thin layer chromatography (eluent: 5% ethyl acetate in petroleum ether solution) to obtain a brown oily intermediate BB6 2-(bromomethyl)-5-chlorothiophene (90 mg).

[0187] Synthetic route of intermediate BB7

[0188]

[0189] Step 1: Intermediate BB7-B (5-chlorofuran-2-yl) methanol

[0190]

[0191] The intermediate BB7-A 5-chlorofuran-2-carboxaldehyde (100 mg, 0.77 mmol) was dissolved in anhydrous tetrahydrofuran (2 mL), placed in an ice bath, and then NaBH4 (30 mg, 0.79 mmol) was added. The reaction was allowed to react at room temperature for 2 h. After the reaction was completed, a saturated aqueous ammonium chloride solution (5 mL) was added dropwise, and ethyl acetate (5 mL) was extracted three times. The organic phases were combined, dried over anhydrous sodium sulfate, and filtered. The crude intermediate BB7-B (5-chlorofuran-2-yl) methanol (100 mg) was directly used in the next step.

[0192] Step 2: Intermediate BB7 2-(Bromomethyl)-5-chlorofuran

[0193]

[0194] Dissolve the intermediate BB7-B (5-chlorofuran-2-yl) methanol (100 mg, 0.77 mmol) in dichloromethane (2 mL), and add PBr3 (200 μL, 1.54 mmol) dropwise in an ice bath. After the addition is complete, place at room temperature to react for 2 hours. After the reaction is completed, spin dry directly, add dichloromethane (5 mL) to dilute, place in an ice bath, and add saturated sodium bicarbonate aqueous solution (5 mL). Extract once with dichloromethane (5 mL), dry with anhydrous sodium sulfate, filter, and the resulting crude intermediate BB7 2-(bromomethyl)-5-chlorofuran (110 mg) is directly used in the next step.

[0195] Synthetic route of intermediate BB8

[0196]

[0197] Step 1: Intermediate BB8-B Bicyclo[4.2.0]octane-1(6),2,4-trien-3-ylmethanol

[0198]

[0199] The synthesis of this step uses the intermediate BB8-A 4-formylbenzocyclobutene as the raw material and refers to the synthesis process of the first step of the intermediate BB7.

[0200] 1 H NMR (400MHz, Chloroform-d) δ7.21(dd,J=7.4,1.4Hz,1H),7.11(s,1H),7.06(d,J=7.5Hz,1H),4.67(s,3H),3.19(s,4H).

[0201] Step 2: Intermediate BB8 3-(Bromomethyl)bicyclo[4.2.0]octane-1(6),2,4-triene

[0202]

[0203] The synthesis of this step uses the intermediate BB8-B 4 bicyclo[4.2.0]octane-1(6),2,4-triene-3-ylmethanol as the raw material and refers to the synthesis process of the second step of intermediate BB7.

[0204] Synthetic route of intermediate BB9

[0205]

[0206] Step 1: Intermediate BB9 3-(5-chlorothiophene-2-yl)propanoic acid

[0207]

[0208] Triethylamine (834.2 mg, 8.186 mmol) was added to formic acid (941.8 mg, 20.465 mmol) at room temperature and stirred for 30 minutes. Intermediate BB9-A 5-chlorothiophene-2-carboxaldehyde (1.0 g, 6.822 mmol) and intermediate BB9-B2,2-dimethyl-1,3-dioxane-4,6-dione (983 mg, 6.822 mmol) were added respectively, the reaction solution was heated to 95°C and stirred for 20 hours. LCMS monitored the reaction to be complete. The reaction solution was diluted with water (15 mL) and extracted with ethyl acetate (15 mL x 2). The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was separated and purified by silica gel column chromatography (eluent: 5% methanol in dichloromethane solution) to obtain yellow oily intermediate BB9 3-(5-chlorothiophene-2-yl)propionic acid (940 mg).

[0209] LC_MS:(ES-):m / z 188.95[MH] - .

[0210] Synthetic route of intermediate BB10

[0211]

[0212] Step 1: Intermediate BB10 3-(4-cyano-3-fluorophenyl)propionic acid

[0213]

[0214] The synthesis of this step uses the intermediate BB10-A 2-fluoro-4-formylbenzonitrile as the raw material and refers to the synthesis process of the first step of the intermediate BB9.

[0215] LC_MS:(ES - ):m / z 385.10[2M-H]-.

[0216] Synthetic route of intermediate BB11

[0217]

[0218] Step 1: Intermediate BB11-C(E)-tert-butyl 3-(4-cyano-3,5-difluorophenyl)acrylate

[0219]

[0220] Under nitrogen protection, palladium acetate (156.3 mg, 0.7 mmol) was added to N,N-dimethylformamide (10 mL) containing intermediate BB11-A 4-bromo-2,6-difluorobenzonitrile (1 g, 4.6 mmol), intermediate BB11-B tert-butyl acrylate (882 mg, 6.9 mmol), DABCO (17 mg, 0.152 mmol) and potassium carbonate (565.83 mg, 4.1 mmol), and the reaction system was replaced with nitrogen three times, heated to 120°C for 2 hours, and the reaction was complete after TLC monitoring. The reaction solution was extracted with ethyl acetate (30 mL x 2) and water (30 mL), 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%-20% ethyl acetate in petroleum ether solution) to give a white solid intermediate BB11-C(E)-3-(4-cyano-3,5-difluorophenyl)acrylate tert-butyl ester (350 mg).

[0221] 1 H NMR (400MHz, CDCl3) δ7.47(d,J=15.9Hz,1H),7.18(d,J=8.2Hz,2H),6.47(d,J=15.9Hz,1H),1.56(s,9H).

[0222] Step 2: Intermediate BB11-D tert-Butyl 3-(4-cyano-3,5-difluorophenyl)propionate

[0223]

[0224] Sodium borohydride (178.18 mg, 4.1 mmol) was slowly added to a methanol (5 mL) solution containing the intermediate BB11-C(E)-3-(4-cyano-3,5-difluorophenyl)acrylate (250 mg, 0.942 mmol) and cobalt chloride (25 mg, 0.192 mmol) at 0°C. The reaction solution was stirred at 0°C for 3 hours. TLC monitored the reaction to be complete. The reaction solution was quenched with saturated ammonium chloride (10 mL) solution, extracted with ethyl acetate (15 mL x 2) and water (10 mL), 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%-20% ethyl acetate in petroleum ether solution) to obtain a white solid intermediate BB11-D 3-(4-cyano-3,5-difluorophenyl)propionic acid tert-butyl ester (60 mg).

[0225] 1 H NMR (400MHz, CDCl3) δ6.93(d,J=8.3Hz,2H),2.98(t,J=7.3Hz,2H),2.58(td,J=7.4,2.2Hz,2H),1.44(s,9H).

[0226] Step 3: Intermediate BB11 3-(4-cyano-3,5-difluorophenyl)propionic acid

[0227]

[0228] Trifluoroacetic acid (200uL) was added to a dichloromethane (1mL) solution containing the intermediate BB11-D tert-butyl 3-(4-cyano-3,5-difluorophenyl) propionate (60mg, 0.224mmol), and the reaction solution was stirred at room temperature for 5 hours. TLC monitored the reaction to be complete. The reaction solution was concentrated to obtain the intermediate BB11 3-(4-cyano-3,5-difluorophenyl) propionic acid (55mg), which was directly used in the next step.

[0229] LC_MS:(ES-):m / z 210.1[MH]-.

[0230] Synthetic route of intermediate BB12

[0231]

[0232] Step 1: Intermediate BB12-C(E)-tert-butyl 3-(4-chloro-3,5-difluorophenyl)acrylate

[0233]

[0234] The synthesis of this step uses the intermediate BB12-A 5-bromo-2-chloro-1,3-difluorobenzene as the raw material.

[0235] The first step of the synthesis process.

[0236] 1 H NMR (400MHz, CDCl3) δ7.45 (d, J = 15.9 Hz, 1H), 7.17--7.10 (m, 2H), 6.36 (d, J = 15.9 Hz, 1H), 1.55 (s, 9H).

[0237] Step 2: Intermediate BB12-D tert-Butyl 3-(4-cyano-3,5-difluorophenyl)propionate

[0238]

[0239] Sodium borohydride (165.24 mg, 4.37 mmol) was slowly added to a methanol (10 mL) solution containing the intermediate BB12-C (E) -3- (4-chloro-3,5-difluorophenyl) tert-butyl acrylate (400 mg, 1.46 mmol) and nickel chloride (188.72 mg, 1.46 mmol) at 0°C. The reaction solution was stirred at 0°C for 3 hours. TLC monitored the reaction to be complete. The reaction solution was quenched with saturated ammonium chloride (10 mL) solution, extracted with ethyl acetate (10 mL x 2) and water (10 mL), 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%-20% ethyl acetate in petroleum ether solution) to obtain a white solid intermediate BB12-D 3- (4-cyano-3,5-difluorophenyl) propionic acid tert-butyl ester (380 mg).

[0240] 1 H NMR (400MHz, CDCl3) δ6.86 (d, J = 7.6 Hz, 2H), 2.89 (t, J = 7.5 Hz, 2H), 2.54 (dd, J = 8.6, 6.5 Hz, 2H), 1.44 (s, 9H).

[0241] Step 3: Intermediate BB12 3-(4-chloro-3,5-difluorophenyl)propionic acid

[0242]

[0243] The synthesis of this step uses the intermediate BB12-D tert-butyl 3-(4-cyano-3,5-difluorophenyl)propionate as the raw material and refers to the synthesis process of the third step of intermediate BB11.

[0244] LC_MS:(ES-):m / z 219.2[MH]-.

[0245] Synthetic route of intermediate BB13

[0246]

[0247] Step 1: Intermediate BB13-B (2-bromo-5-nitropyridin-3-yl)methanol

[0248]

[0249] The synthesis of this step uses the intermediate BB13-A 2-bromo-5-nitronicotinic acid as the raw material and refers to the synthesis process of the first step of the intermediate BB3.

[0250] LC_MS:(ES + ):m / z 232.9[M+H] + .

[0251] Step 2: Intermediate BB13-D (3'-fluoro-5-nitro-[2,4'-bipyridyl]-3-yl)methanol

[0252]

[0253] The synthesis of this step uses intermediate BB13-B (2-bromo-5-nitropyridine-3-yl)methanol and intermediate BB13-C3-fluoropyridine-4-boronic acid pinacol ester as raw materials, referring to the synthesis process of intermediate BB3 in the second step.

[0254] LC_MS:(ES + ):m / z 250.0[M+H] + .

[0255] Step 3: Intermediate BB13-E 3-nitro-5H-pyrano[4,5-b:2,3-c']bipyridine

[0256]

[0257] The synthesis of this step uses the intermediate BB13-D (3'-fluoro-5-nitro-[2,4'-bipyridine]-3-yl)methanol as the raw material and refers to the synthesis process of the third step of intermediate BB3.

[0258] LC_MS:(ES + ):m / z 230.0[M+H] + .

[0259] Step 4: Intermediate BB13 5H-pyrano[4,5-b:2,3-c']bipyridin-3-amine

[0260]

[0261] The synthesis of this step uses the intermediate BB13-E 3-nitro-5H-pyrano[4,5-b:2,3-c']bipyridine as the raw material and refers to the synthesis process of the fourth step of intermediate BB3.

[0262] LC_MS:(ES + ):m / z 200.1[M+H] + .

[0263] Synthetic route of intermediate BB14

[0264]

[0265] Step 1: Intermediate BB14-B (5-bromo-2-nitropyridin-4-yl)methanol

[0266]

[0267] The synthesis of this step uses the intermediate BB14-A 5-bromo-2-nitroisonicotinic acid as the raw material and refers to the synthesis process of the first step of the intermediate BB3.

[0268] LC_MS:(ES + ):m / z 232.9[M+H] + .

[0269] Step 2: Intermediate BB14-D (3'-fluoro-6-nitro-[3,4'-bipyridyl]-4-yl)methanol

[0270]

[0271] The synthesis of this step uses intermediate BB14-B (5-bromo-2-nitropyridine-4-yl)methanol and intermediate BB14-C3-fluoropyridine-4-boronic acid pinacol ester as raw materials, referring to the synthesis process of the second step of intermediate BB3.

[0272] LC_MS:(ES + ):m / z 250.0[M+H] + .

[0273] Step 3: Intermediate BB14-E 3-nitro-5H-pyrano[2,3-c:4,5-c']bipyridine

[0274]

[0275] The synthesis of this step uses the intermediate BB14-D (3'-fluoro-6-nitro-[3,4'-bipyridine]-4-yl)methanol as the raw material and refers to the synthesis process of the third step of intermediate BB3.

[0276] LC_MS:(ES + ):m / z 230.0[M+H] + .

[0277] Step 4: Intermediate BB14 5H-pyrano[2,3-c:4,5-c']bipyridin-3-amine

[0278]

[0279] The synthesis of this step uses the intermediate BB14-E 3-nitro-5H-pyrano[2,3-c:4,5-c']bipyridine as the raw material and refers to the synthesis process of the fourth step of intermediate BB3.

[0280] LC_MS:(ES + ):m / z 200.1[M+H] + .

[0281] Synthetic route of intermediate BB15

[0282]

[0283] Step 1: Intermediate BB15-B (2,5-dibromopyridin-3-yl)methanol

[0284]

[0285] The synthesis of this step uses the intermediate BB15-A 2,5-dibromonicotinic acid as the raw material and refers to the synthesis process of the first step of the intermediate BB3.

[0286] LC_MS:(ES + ):m / z 265.8[M+H] + .

[0287] Step 2: Intermediate BB15-D (5-bromo-3'-fluoro-[2,4'-bipyridyl]-3-yl)methanol

[0288]

[0289] The synthesis of this step uses intermediate BB15-B (2,5-dibromopyridin-3-yl)methanol and intermediate BB15-C 3-fluoropyridine-4-boronic acid pinacol ester as raw materials and refers to the synthesis process of intermediate BB1 ​​in the first step.

[0290] LC_MS:(ES + ):m / z 283.0[M+H] + .

[0291] Step 3: Intermediate BB15 3-bromo-5H-pyrano[4,5-b:2,3-c']bipyridine

[0292]

[0293] The synthesis of this step uses the intermediate BB15-D (5-bromo-3'-fluoro-[2,4'-bipyridine]-3-yl)methanol as the raw material and refers to the synthesis process of the second step of intermediate BB1.

[0294] LC_MS:(ES + ):m / z 263.0[M+H] + .

[0295] Synthetic route of intermediate BB16

[0296]

[0297] Step 1: Intermediate BB16-B (5-bromo-2-chloropyridin-4-yl)methanol

[0298]

[0299] The synthesis of this step uses the intermediate BB16-A 5-bromo-2-chloroisonicotinic acid as the raw material and refers to the synthesis process of the first step of the intermediate BB3.

[0300] LC_MS:(ES + ):m / z 221.9[M+H] + .

[0301] Step 2: Intermediate BB16-D (6-chloro-3'-fluoro-[3,4'-bipyridyl]-4-yl)methanol

[0302]

[0303] The synthesis of this step uses intermediate BB16-B (5-bromo-2-chloropyridin-4-yl)methanol and intermediate BB16-C 3-fluoropyridine-4-boronic acid pinacol ester as raw materials, referring to the synthesis process of intermediate BB1 ​​in the first step.

[0304] LC_MS:(ES + ):m / z 239.0[M+H] + .

[0305] Step 3: Intermediate BB16 3-chloro-5H-pyrano[2,3-c:4,5-c']bipyridine

[0306]

[0307] The synthesis of this step uses the intermediate BB16-D (6-chloro-3'-fluoro-[3,4'-bipyridine]-4-yl)methanol as the raw material and refers to the synthesis process of the second step of intermediate BB1.

[0308] LC_MS:(ES + ):m / z 219.0[M+H] + .

[0309] Synthetic route of intermediate BB17

[0310]

[0311] Step 1: Intermediate BB17-B (2-(3-fluoro-5-methylpyridin-4-yl)-5-nitrophenyl)methanol

[0312]

[0313] The synthesis of this step uses intermediate BB3-B (2-bromo-5-nitrophenyl) methanol and intermediate BB17-A (3-fluoro-5-methylpyridin-4-yl) boronic acid as raw materials and refers to the synthesis process of the second step of intermediate BB3.

[0314] LC_MS:(ES + ):m / z 263.1[M+H] + .

[0315] Step 2: Intermediate BB17-C 1-methyl-8-nitro-6H-isochromeno[3,4-c]pyridine

[0316]

[0317] The synthesis of this step uses the intermediate BB17-B (2-(3-fluoro-5-methylpyridin-4-yl)-5-nitrophenyl)methanol as the raw material and refers to the synthesis process of the third step of the intermediate BB3.

[0318] LC_MS:(ES + ):m / z 243.1[M+H] + .

[0319] Step 3: Intermediate BB17 1-methyl-6H-isochromeno[3,4-c]pyridin-8-amine

[0320]

[0321] The synthesis of this step uses the intermediate BB17-C 1-methyl-8-nitro-6H-isochromeno[3,4-c]pyridine as the raw material and refers to the synthesis process of the fourth step of intermediate BB3.

[0322] LC_MS:(ES + ):m / z 213.1[M+H] + .

[0323] Synthetic route of intermediate BB18

[0324]

[0325] Step 1: Intermediate BB18-B (6-bromo-2-methyl-3-nitrophenyl)methanol

[0326]

[0327] The synthesis of this step uses the intermediate BB18-A 6-bromo-2-methyl-3-nitrobenzoic acid methyl ester as the raw material and refers to the synthesis process of the first step of the intermediate BB3.

[0328] LC_MS:(ES +):m / z 246.0[M+H] + .

[0329] Step 2: Intermediate BB18-D (6-(3-fluoropyridin-4-yl)-2-methyl-3-nitrophenyl)methanol

[0330]

[0331] The synthesis of this step uses intermediate BB18-B (6-bromo-2-methyl-3-nitrophenyl)methanol and intermediate BB18-C 3-fluoropyridine-4-boronic acid pinacol ester as raw materials, referring to the synthesis process of intermediate BB3 in the second step. LC_MS: (ES + ):m / z 263.1[M+H] + .

[0332] Step 3: Intermediate BB18-E 7-methyl-8-nitro-6H-isochromeno[3,4-c]pyridine

[0333]

[0334] The synthesis of this step uses the intermediate BB18-D (6-(3-fluoropyridin-4-yl)-2-methyl-3-nitrophenyl)methanol as the raw material and refers to the synthesis process of the third step of the intermediate BB3.

[0335] LC_MS:(ES + ):m / z 243.1[M+H] + .

[0336] Step 4: Intermediate BB18 7-methyl-6H-isochromeno[3,4-c]pyridin-8-amine

[0337]

[0338] The synthesis of this step uses the intermediate BB18-E 7-methyl-8-nitro-6H-isochromeno[3,4-c]pyridine as the raw material and refers to the synthesis process of the fourth step of intermediate BB3.

[0339] LC_MS:(ES + ):m / z 213.1[M+H] + .

[0340] Example 1: Synthesis route of compound 1

[0341]

[0342] Step 1: Compound 42 3-(4-chlorobenzyl)-1-(6H-isochromeno[3,4-c]pyridin-8-yl)pyrrolidin-2-one

[0343]

[0344] Under nitrogen protection, Pd2(dba)3-CHCl3 (7.82 mg, 0.008 mmol) was added to 1,4-dioxane (3 mL) containing intermediate BB1 ​​8-bromo-6H-isochromeno[3,4-c]pyridine (40 mg, 0.153 mmol), intermediate BB4 3-(4-chlorobenzyl)pyrrolidin-2-one (35.2 mg, 0.168 mmol), Xant-Phos (9.72 mg, 0.0168 mmol) and cesium carbonate (149.5 mg, 0.459 mmol), the reaction system was replaced with nitrogen three times, heated to 100°C for 2 hours, and the reaction was complete after TLC monitoring. The reaction solution was extracted with ethyl acetate (5 mL x 2) and water (10 mL), 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: 4.76% methanol in dichloromethane) to give white solid compound 1 3-(4-chlorobenzyl)-1-(6H-isochromano[3,4-c]pyridin-8-yl)pyrrolidin-2-one (38 mg).

[0345] LC_MS:(ES + ):m / z 391.1[M+H] + .

[0346] 1 H NMR (400MHz, CDCl3) δ8.35 (s, 1H), 8.30 (d, J = 4.4Hz, 1H), 7.75 (d, J = 8.6Hz, 1H), 7.70 (d, J = 2. 0Hz,1H),7.61--7.55(m,2H),7.33--7.29(m,2H),7.20(d,J=8.4Hz,1H),5.23(s,2H),3.83-- 3.75(m,1H),3.68(td,J=9.1,3.1Hz,1H),3.27(dd,J=13.7,4.2Hz,1H),2.96(ddd,J=17.8,8. 9,4.2Hz,1H),2.84(dd,J=13.7,8.9Hz,1H),2.32--2.20(m,1H),1.90(dt,J=8.8,6.9Hz,1H).

[0347] Example 2: Synthesis route of compound 2

[0348]

[0349] Step 1: Compound 42 3-benzyl-1-(6H-isochromeno[3,4-c]pyridin-8-yl)pyrrolidin-2-one

[0350]

[0351] Take the intermediate BB2 1-(6H-isochromeno[3,4-c]pyridin-8-yl)pyrrolidin-2-one (50 mg, 0.188 mmol) and dissolve it in anhydrous tetrahydrofuran (5 mL). The system is cooled to -78 °C under nitrogen protection, and LDA (2M inTHF, 0.141 ml) is slowly added dropwise. After stirring for half an hour, a solution of compound 2-A benzyl bromide (32.1 mg, 0.188 mmol) in THF (5 mL) is injected along the wall of the reaction container with a syringe at once, and the reaction is continued at -78 °C for 1 hour. The reaction was completed as monitored by TLC and quenched with saturated ammonium chloride solution (10 mL). The product was extracted with ethyl acetate (10 mL x 2). The organic layers were combined and washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was separated and purified by Pre-TLC (eluted with dichloromethane solution containing 5% methanol) to give white solid compound 2 3-benzyl-1-(6H-isochromeno[3,4-c]pyridin-8-yl)pyrrolidin-2-one (18 mg).

[0352] LC_MS:(ES + ):m / z 357.50[M+H] +

[0353] 1 H NMR (400MHz, CDCl3) δ8.33 (s, 1H), 8.28 (d, J = 5.1Hz, 1H), 7.78--7.64 (m, 2H), 7.59--7. 46(m,2H),7.34--7.21(m,5H),5.2(s,2H),3.88--3.69(m,1H),3.64(td,J1=9.0Hz,J2=3 .4Hz,1H),3.31(dd,J1=13.7Hz,J2=4.2Hz,1H),2.96(qd,J1=8.9Hz,J2=4.1Hz,1H),2.82 (dd, J1=13.7Hz, J2=9.2Hz, 1H), 2.26-2.18(m, 1H), 1.90 (dq, J1=12.8Hz, J2=8.6Hz, 1H).

[0354] Example 3: Synthesis route of compound 42

[0355]

[0356] Step 1: Compound 42 3-(4-chlorophenyl)-N-(6H-isochromeno[3,4-c]pyridin-8-yl)propanamide

[0357]

[0358] HATU (69.1 mg, 0.182 mmol) was added to a DMF (1 mL) solution containing the intermediate BB3 6H-isochromeno[3,4-c]pyridin-8-amine (30 mg, 0.151 mmol), compound 42-A (33.5 mg, 0.182 mmol), and N,N-diisopropylethylamine (58.7 mg, 0.454 mmol) at room temperature. The reaction solution was stirred at room temperature for 3 hours. LCMS monitored the reaction to be complete, diluted with water (5 mL), extracted with ethyl acetate (5 mL x 2), the organic layers were combined, washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was separated and purified by Pre-TLC (eluted with a dichloromethane solution containing 5% methanol) to obtain a white solid compound 42 3-(4-chlorophenyl)-N-(6H-isochromeno[3,4-c]pyridin-8-yl)propanamide (46 mg).

[0359] LC_MS:(ES + ):m / z 365.40[M+H] + .

[0360] 1 H NMR (400MHz, DMSO) δ10.18(s,1H),8.27–-8.20(m,2H),7.89(d,J=8.5Hz,1H),7.76(d,J=5.0Hz,1H),7.66-–7.5 3(m,2H),7.37-–7.33(m,2H),7.29(d,J=8.5Hz,2H),5.21(s,2H),2.92(t,J=7.5Hz,2H),2.66(t,J=7.6Hz,2H).

[0361] Example 4: Synthesis route of compound 10

[0362]

[0363] Step 1: Compound 10 3-(4-fluorobenzyl)-1-(6H-isochromeno[3,4-c]pyridin-8-yl)pyrrolidin-2-one

[0364]

[0365] The synthesis of this step uses the intermediate BB1 ​​8-bromo-6H-isochromeno[3,4-c]pyridine and the intermediate BB5 3-(4-fluorobenzyl)pyrrolidin-2-one as raw materials and refers to the synthesis process of the first step in Example 1.

[0366] LC_MS:(ES + ):m / z 375.2[M+H] + .

[0367] 1 H NMR (400MHz, DMSO-d6) δ8.33--8.21(m,2H),7.97(d,J=8.6Hz,1H),7.86--7.77(m,2H), 7.67(d,J=2.2Hz,1H),7.37--7.26(m,2H),7.18--7.07(m,2H),5.25(s,2H),3.74(dtd,J =18.3,9.5,6.9Hz,2H),3.12(dd,J=13.6,4.4Hz,1H),2.97(qd,J=9.2,4.4Hz,1H),2.74( dd,J=13.7,9.3Hz,1H),2.08(ddt,J=9.8,7.3,5.2Hz,1H),1.78(dq,J=12.1,8.8Hz,1H).

[0368] Example 5: Synthesis route of compound 45

[0369]

[0370] Step 1: Compound 45 1-(4-fluorobenzyl)-3-(6H-isochromano[3,4-c]pyridin-8-yl)urea

[0371]

[0372] CDI (24.5 mg, 0.151 mmol) and DIPEA (58.5 mg, 0.453 mmol) were added to a DMF (0.5 mL) solution containing the intermediate BB3 6H-isochromeno[3,4-c]pyridin-8-amine (30 mg, 0.151 mmol). After stirring at room temperature for 30 minutes, compound 45-A (4-fluorophenyl)methylamine (18.9 mg, 0.151 mmol) was added and stirred at room temperature for 16 hours. After the reaction was completed, ice water was added dropwise to dilute, and the precipitated solid was filtered and washed with water. The filter residue was dissolved in DCM / MeOH=10:1 (2 mL), and separated and purified by preparative thin layer chromatography (eluted with a dichloromethane solution containing 5% methanol) to obtain compound 45 1-(4-fluorobenzyl)-3-(6H-isochromeno[3,4-c]pyridin-8-yl)urea (18 mg).

[0373] LC_MS:(ES + ):m / z 350.1[M+H] + .

[0374] 1 H NMR(400MHz,Chloroform-d)δ8.32(s,1H),8.27(d,J=5.1Hz,1H),7.66(d,J=8.4Hz,1H),7.50(s,1H),7.43(d,J=2.2Hz,1H),7.33(dd,J=8.5,5 .4Hz,2H),7.24(dd,J=8.5,2.3Hz,1H),7.06(t,J=8.6Hz,2H),6.57(s,1H),5.17(s,2H),5.08(s,1H),4.46(d,J=5.7Hz,2H).MS:[M+H]+:350.1.

[0375] Example 6: Synthesis route of compound 49

[0376]

[0377] Step 1: Compound 49 3-(4-fluorophenyl)-N-(6H-isochromeno[3,4-c]pyridin-8-yl)-N-methylpropanamide

[0378]

[0379] Under ice bath, NaH (2.76 mg, 0.0689 mmol, 60% purity) was added to a DMF (1 mL) solution containing compound 29 3-(4-fluorophenyl)-N-(6H-isochromano[3,4-c]pyridin-8-yl)propanamide (20 mg, 0.0574 mmol). After stirring for half an hour, iodomethane (9.8 mg, 0.0689 mmol) was added, the temperature was raised to room temperature, and the reaction was stirred for 12 hours. LCMS monitored the reaction to be complete. The reaction solution was poured into a saturated ammonium chloride (5 mL) solution and extracted with ethyl acetate (5 mL x 2). The organic layers were combined, washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was separated and purified by Pre-TLC (eluted with a dichloromethane solution containing 5% methanol) to give a white solid compound 49 3-(4-fluorophenyl)-N-(6H-isochromeno[3,4-c]pyridin-8-yl)-N-methylpropanamide (15 mg).

[0380] LC_MS:(ES + ):m / z 363.12[M+H] + .

[0381] Example 7: Synthesis route of compound 52

[0382]

[0383] Step 1: Compound 52-B (tert-butyl 1-((6H-isochromano[3,4-c]pyridin-8-yl)amino)-3-(4-fluorophenyl)-1-oxopropan-2-yl)carbamate

[0384]

[0385] The synthesis of this step uses compound 52-A 2-((tert-butyloxycarbonyl)amino)-3-(4-fluorophenyl)propionic acid and intermediate BB3 6H-isochromano[3,4-c]pyridin-8-amine as raw materials, referring to the synthesis process of the first step in Example 3. LC_MS: (ES + ):m / z 464.2[M+H] + .

[0386] Step 2: Compound 52 2-amino-3-(4-fluorophenyl)-N-(6H-isochromeno[3,4-c]pyridin-8-yl)propanamide

[0387]

[0388] A solution of HCl / dioxane (1 mL, 4 M) containing compound 52-B (tert-butyl 1-((6H-isochromeno[3,4-c]pyridin-8-yl)amino)-3-(4-fluorophenyl)-1-oxopropan-2-yl)carbamate (25 mg, 0.0539 mmol) was stirred at room temperature for 1 hour. The reaction was complete as monitored by LCMS. The mixture was concentrated under reduced pressure to give a white solid hydrochloride salt of compound 52 2-amino-3-(4-fluorophenyl)-N-(6H-isochromeno[3,4-c]pyridin-8-yl)propanamide (18 mg). LC_MS: (ES + ):m / z 364.2[M+H] + .

[0389] 1 H NMR (400MHz, MeOH-d4): δ8.52(d,J=0.8Hz,1H),8.49–-8.37(m,2H),8.12(d,J=8.5Hz,1H),7.83-–7.69(m,2H),7.47–-7.3 3(m,2H),7.25--7.05(m,2H),5.49(s,2H),4.32(t,J=7.3Hz,1H),3.48--3.34(m,1H),3.20(dd,J1=14.0Hz,J2=7.9Hz,1H).

[0390] Example 8: Synthesis route of compound 53

[0391]

[0392] Step 1: Compound 53-B (4-bromopyridin-3-yl)methanol

[0393]

[0394] Add isobutyl chloroformate (3.24 g, 23.761 mmol) to a THF (50 mL) solution containing compound 53-A 4-bromonicotinic acid (4.8 g, 23.761 mmol) and N-methylmorpholine (2.90 g, 28.513 mmol) under ice bath. After stirring for half an hour, filter out the solid produced by the reaction, disperse the mother liquor in methanol (20 mL), add NaBH4 (1.35 g, 35.642 mmol), and stir at room temperature for 1 hour. LCMS monitors the reaction to be complete. The reaction solution is concentrated under reduced pressure, and water (30 mL) is added and extracted with ethyl acetate (30 mL x 2). The organic layers were combined, washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (eluted with petroleum ether containing 25% ethyl acetate) to give yellow solid compound 53-B (4-bromopyridin-3-yl)methanol (860 mg).

[0395] LC_MS:(ES + ):m / z 188.02[M+H] + .

[0396] Step 2: Compound 53-C 4-bromo-3-(((tert-butyldimethylsilyl)oxy)methyl)pyridine

[0397]

[0398] TBSCl (1.378 g, 9.148 mmol) was added to a DCM (20 mL) solution containing compound 53-B (4-bromopyridin-3-yl)methanol (860 mg, 4.574 mmol) and imidazole (934.2 mg, 13.722 mmol). The reaction was stirred at room temperature for 12 hours. TLC monitored the reaction to be complete. Water (20 mL) was added to the reaction solution and extracted with DCM (15 mL x 2). The organic layers were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (eluted with a petroleum ether solution containing 2-4% ethyl acetate) to obtain a colorless oil compound 53-C 4-bromo-3-(((tert-butyldimethylsilyl)oxy)methyl)pyrrolidone (1.39 g). LC_MS: (ES + ):m / z 302.03[M+H] + .

[0399] Step 3: Compound 53-D 3-(((tert-butyldimethylsilyl)oxy)methyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine

[0400]

[0401] PdCl2(dppf)CH2Cl2 (348.5 mg, 0.4267 mmol) and potassium acetate (1.26 g, 12.802 mmol) were added to a solution of compound 53-C 4-bromo-3-(((tert-butyldimethylsilyl)oxy)methyl)pyridine (1.29 g, 4.267 mmol) and diboronic acid pinacol ester (2.17 g, 8.535 mmol) in 1,4-dioxane (20 mL). The reaction solution was stirred at 100°C under nitrogen atmosphere for 2 hours. The reaction was complete when monitored by LCMS. The reaction solution was filtered through celite and concentrated under reduced pressure to give a yellow oily compound 53-D 3-(((tert-butyldimethylsilyl)oxy)methyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (1.491 g). The crude product was used directly in the next reaction without further purification.

[0402] LC_MS:(ES + ):m / z 268.12[M-82+H] + .

[0403] Step 4: Compound 53-F (5-bromo-2-(3-(((tert-butyldimethylsilyl)oxy)methyl)pyridin-4-yl)phenyl)methanol

[0404]

[0405] PdCl2(dppf)CH2Cl2 (348.5 mg, 0.4267 mmol) and sodium carbonate (1.13 g, 10.668 mmol) were added to a solution of 1,4-dioxane (20 mL) and water (2 mL) containing compound 53-D 3-(((tert-butyldimethylsilyl)oxy)methyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (1.491 g, 4.267 mmol) and compound 53-E (5-bromo-2-iodophenyl)methanol (1.335 g, 4.267 mmol). The reaction solution was stirred at 80°C under nitrogen atmosphere for 12 hours. The reaction was complete when monitored by LCMS. The reaction solution was filtered through celite and concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (eluted with a petroleum ether solution containing 50% ethyl acetate) to give a crude yellow oily compound 53-F (5-bromo-2-(3-(((tert-butyldimethylsilyl)oxy)methyl)pyridin-4-yl)phenyl)methanol (500 mg).

[0406] LC_MS:(ES + ):m / z 408.10[M+H] + .

[0407] Step 5: Compound 53-G (5-bromo-2-(3-(hydroxymethyl)pyridin-4-yl)phenyl)methanol

[0408]

[0409] A solution of trifluoroacetic acid (10 mL) containing compound 53-F (5-bromo-2-(3-(((tert-butyldimethylsilyl)oxy)methyl)pyridin-4-yl)phenyl)methanol (450 mg, 1.1 mmol) was stirred at room temperature for 2 hours. LCMS monitored the reaction to be complete. The reaction solution was concentrated under reduced pressure to remove trifluoroacetic acid, and a saturated NHCO3 solution (20 mL) was added and extracted with ethyl acetate (15 mL x 2). The organic layers were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (eluted with a dichloromethane solution containing 5% methanol) and Prep-HPLC to obtain a yellow oil compound 53-G (5-bromo-2-(3-(hydroxymethyl)pyridin-4-yl)phenyl)methanol (60 mg).

[0410] LC_MS:(ES + ):m / z 294.00[M+H] + .

[0411] Step 6: Compound 53-H 9-bromo-5,7-dihydrobenzo[5,6]oxabinol[3,4-c]pyridine

[0412]

[0413] 48% hydrobromic acid (0.1 mL) was added to a solution of acetonitrile (2.5 mL) containing compound 53-G (5-bromo-2-(3-(hydroxymethyl)pyridin-4-yl)phenyl)methanol (50 mg, 169.98 umol). The reaction solution was stirred at 80°C for 1 hour. LCMS monitored the reaction to be complete. The reaction solution was adjusted to pH = 9 with saturated sodium bicarbonate solution and extracted with ethyl acetate (8 mL x 2). The organic layers were combined, washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was separated and purified by Pre-TLC (eluted with a dichloromethane solution containing 5% methanol) to obtain a yellow oil compound 53-H 9-bromo-5,7-dihydrobenzo[5,6]oxabino[3,4-c]pyridine (5 mg). LC_MS: (ES + ):m / z 276.10[M+H] + .

[0414] Step 7: Compound 53 1-(5,7-dihydrobenzo[5,6]oxirane[3,4-c]pyridin-9-yl)-3-(4-fluorobenzyl)pyrrolidin-2-one

[0415]

[0416] The synthesis of this step uses compound 53-H 9-bromo-5,7-dihydrobenzo[5,6]oxabinol[3,4-c]pyridine and intermediate BB5 3-(4-fluorobenzyl)pyrrolidin-2-one as raw materials and refers to the synthesis process of the first step in Example 1. LC_MS: (ES + ):m / z 389.18[M+H] + .

[0417] Example 9: Synthesis route of compound 91

[0418]

[0419] Step 1: Compound 91 3-(4-fluorophenyl)-N-(5H-pyrano[4,5-b:2,3-c']bipyridin-3-yl)propanamide

[0420]

[0421] The synthesis of this step uses the intermediate BB13 5H-pyrano[4,5-b:2,3-c']bipyridin-3-amine and compound 91-A3-(4-fluorophenyl)propionic acid as raw materials, and refers to the synthesis process of the first step in Example 3.

[0422] LC_MS:(ES + ):m / z 350.1[M+H] + .

[0423] Example 10: Synthesis route of compound 112

[0424]

[0425] Step 1: Compound 112 3-(4-fluorophenyl)-N-(5H-pyrano[2,3-c:4,5-c']bipyridin-3-yl)propanamide

[0426]

[0427] The synthesis of this step uses the intermediate BB14 5H-pyrano[2,3-c:4,5-c']bipyridin-3-amine and compound 112-A 3-(4-fluorophenyl)propionic acid as raw materials, and refers to the synthesis process of the first step in Example 3.

[0428] LC_MS:(ES + ):m / z 350.1[M+H] + .

[0429] Example 11: Synthesis route of compound 77

[0430]

[0431] Step 1: Compound 77 1-(4-fluorobenzyl)-3-(6H-isochromeno[3,4-c]pyridin-8-yl)thiourea

[0432]

[0433] Compound 77-A 4-fluorobenzyl thiocyanate (25.3 mg, 151.34 umol) was added to a DMF (1 mL) solution containing intermediate BB3 6H-isochromano[3,4-c]pyridin-8-amine (30 mg, 151.34 umol) and N,N-diisopropylethylamine (58.7 mg, 454.03 umol). The reaction solution was heated to 100°C and stirred for 12 hours. The reaction was complete when monitored by LCMS. The reaction solution was diluted with water (10 mL) and extracted with ethyl acetate (8 mL x 2). The organic layers were combined, washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was separated and purified by Pre-TLC (eluted with a dichloromethane solution containing 5% methanol) to give a yellow solid compound 771-(4-fluorobenzyl)-3-(6H-isochromano[3,4-c]pyridin-8-yl)thiourea (19.3 mg).

[0434] LC_MS:(ES + ):m / z 366.9[M+H] + .

[0435] 1 H NMR (400MHz, DMSO) δ9.87(s,1H),8.40(s,1H),8.27(s,1H),8.24(d,J=5.0Hz,1H),7.91(d,J=8.4Hz,1H),7.79(d,J=5.1Hz,1H), 7.53(dd,J=8.4,1.7Hz,1H),7.48(s,1H),7.40(dd,J=8.4,5.7Hz,2H),7.18(t,J=8.8Hz,2H),5.22(s,2H),4.74(d,J=4.6Hz,2H).

[0436] Example 12: Synthesis route of compound 101

[0437]

[0438] Step 1: Compound 101 1-(4-fluorobenzyl)-3-(5H-pyrano[4,5-b:2,3-c']bipyridin-3-yl)urea

[0439]

[0440] The synthesis of this step uses the intermediate BB13 5H-pyrano[4,5-b:2,3-c']bipyridin-3-amine and compound 101-A (4-fluorophenyl)methylamine as raw materials and refers to the synthesis process of the first step in Example 5.

[0441] LC_MS:(ES +):m / z 351.1[M+H] + .

[0442] Example 13: Synthesis route of compound 122

[0443]

[0444] Step 1: Compound 122 1-(4-fluorobenzyl)-3-(5H-pyrano[2,3-c:4,5-c']bipyridin-3-yl)urea

[0445]

[0446] The synthesis of this step uses the intermediate BB14 5H-pyrano[2,3-c:4,5-c']bipyridin-3-amine and compound 122-A (4-fluorophenyl)methylamine as raw materials and refers to the synthesis process of the first step in Example 5.

[0447] LC_MS:(ES + ):m / z 351.1[M+H] + .

[0448] Example 14: Synthesis route of compound 130

[0449]

[0450] Step 1: Compound 130 3-(4-fluorophenyl)-N-(1-methyl-6H-isochromeno[3,4-c]pyridin-8-yl)propanamide

[0451]

[0452] The synthesis of this step uses the intermediate BB17 1-methyl-6H-isochromeno[3,4-c]pyridin-8-amine and compound 130-A 3-(4-fluorophenyl)propionic acid as raw materials, and refers to the synthesis process of the first step in Example 3.

[0453] LC_MS:(ES + ):m / z 363.1[M+H] + .

[0454] Example 15: Synthesis route of compound 131

[0455]

[0456] Step 1: Compound 131 3-(4-fluorophenyl)-N-(7-methyl-6H-isochromeno[3,4-c]pyridin-8-yl)propanamide

[0457]

[0458] The synthesis of this step uses the intermediate BB18 7-methyl-6H-isochromeno[3,4-c]pyridin-8-amine and compound 131-A 3-(4-fluorophenyl)propionic acid as raw materials, and refers to the synthesis process of the first step in Example 3.

[0459] LC_MS:(ES + ):m / z 363.1[M+H] + .

[0460] The synthetic route of the following compounds is as follows, referring to the synthetic method of the first step of Example 2, using corresponding reagents for synthesis:

[0461]

[0462]

[0463]

[0464]

[0465] The synthetic route of the following compounds is as follows, referring to the synthetic method of the first step of Example 3, using corresponding reagents for synthesis:

[0466]

[0467]

[0468]

[0469]

[0470]

[0471] The synthetic routes of the following compounds are as follows, referring to the synthetic method of the first step of Example 5, using corresponding reagents for synthesis:

[0472]

[0473]

[0474]

[0475] Biological activity test example:

[0476] Biological Activity Example 1: Preparation of SARM1 enzyme

[0477] Preparation of test compounds:

[0478] 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.

[0479] Expression and purification of SARM1 protein

[0480] (1) Plasmid construction

[0481] 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).

[0482] (2) Plasmid transfection

[0483] 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.

[0484] (3) Cell collection and protein extraction

[0485] 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:

[0486] 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.

[0487] Biological Activity Example 2: In vitro biochemical test for inhibition of SARM1 enzyme activity (IC 50 ):

[0488] 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.

[0489] 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.

[0490] 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.

[0491] The dosage curve of compounds inhibiting SARM1 NAD enzyme activity was prepared using the above method.

[0492] The IC values ​​of these compounds in the assay are provided in Table 1 below. 50 Range:

[0493] ICs that inhibit SARM1 enzyme activity 50 Range: A<0.1μM; B:0.1-1μM; C:1-10μM

[0494] Table 1

[0495]

[0496]

[0497]

[0498] Biological Activity Example 3: Axon Degeneration Index

[0499] For experimental methods, please refer to Gerdts J et al.

[0500] Mouse DRG explant culture

[0501] 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.

[0502] Axonal Wallerian degeneration assay

[0503] 0.1 μL of 10 mM test compound was dissolved in 100 μL DRG culture medium to prepare a new culture medium containing 10 μM test compound. The culture medium in the 96-well plate was aspirated and the new culture medium containing the test compound was added, and incubated with the dorsal root ganglion explants in a 37-degree incubator for 2 hours for protection. After incubation, axons were cut in the vicinity of the tissue block using a glass electrode, and bright field photos of axons in the same area were taken at 0 hours and 24 hours using a microscope (Olympus) with a 20x lens. Axonal integrity was assessed using an in-house developed script.

[0504] The compounds of the present invention showed neuroprotective effects in the explant axon Wallerian degeneration assay at a concentration of 10 μM, and were sorted according to the degree of protection: extreme protection (A)>50%, partial protection (B): 20%-50%. The results are listed in Table 2 below.

[0505] Table 2

[0506]

[0507]

Claims

1. Compound of formula (I): or its racemate, enantiomer, diastereomer, deuterated substance or pharmaceutically acceptable salt thereof, in, X1 is selected from -O-, -CH 2- , -OCH2-, -NR3CH2-, -CH2NR3-, -N=CH-, -CH=N-, excellent Select -O-; Wherein R3 is selected from H and C1-C3 alkyl; X2, X3, X4 are each independently selected from CH or N; R1 is independently selected from H, halogen, C1-C3 alkyl, cyano, trifluoromethyl, amino, hydroxy, 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 represents O, S or NH, preferably O; L1 and L3 are each independently selected from -CH(R')-, -O-, -S- and -N(R')-, provided that at least one of L1 and L3 is -CH(R')-, wherein R' is hydrogen or C1-C3 alkyl; L2 is selected from H, -CH3, -CH2-CH3, -CH2-CH2-CH3, -OR8, -NHR9; Wherein, R8 and R9 are independently selected from H and C1-C3 alkyl; A is selected from H, 5- to 10-membered aryl, 5- to 10-membered heteroaryl, 5- to 10-membered cycloalkyl, 5- to 10-membered heterocycloalkyl, 5- to 10-membered aryl and 3- to 6-membered cycloalkyl, 5- to 10-membered aryl and 3- to 6-membered heterocycloalkyl, wherein the heteroaryl or heterocycloalkyl may contain 1 or 2 heteroatoms selected from N, O and S, and the 5- to 10-membered aryl, 5- to 10-membered heteroaryl, 5- to 10-membered aryl and 3- to 6-membered cycloalkyl, 5- to 10-membered aryl and 3- to 6-membered heterocycloalkyl may be substituted by 1, 2 or 3 substituents selected from the following: halogen, C1-C3 alkyl, C1-C3 alkoxy, halo-C1-C3 alkyl, halo-C1-C3 alkoxy, cyano, nitro and (R a R a ')N-, where R a and R a 'are each independently selected from hydrogen and C1-C3 alkyl; preferably, the substituent is selected from methyl, methoxy, trifluoromethyl, trifluoromethoxy, F, Cl, Br; L1 may be linked to L2 to form a 5-membered ring or a 6-membered ring, preferably a 5-membered ring.

2. The compound of formula (I) according to claim 1, 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): in, X2, X3, X4, R1, R2, L3, A as defined in claim 1; X5 is selected from CH2, O, NH, preferably CH2.

3. The compound of formula (I) according to claim 1, or its racemate, enantiomer, diastereomer, deuterated substance or pharmaceutically acceptable salt thereof, wherein the compound of formula (I) has the following structure of formula (III): in, R1, R2, M, L1, L2, L3, A are as defined in claim 1.

4. The compound of formula (I) according to claim 1, or its racemate, enantiomer, diastereomer, deuterated substance or pharmaceutically acceptable salt thereof, wherein the compound of formula (I) has the following structure of formula (IV): in, X2 and X3 are selected from CH and N, and X2 and X3 are not CH at the same time; R1, R2, M, L1, L2, L3, A are as defined in claim 1.

5. The compound of formula (II) according to claim 2, or its racemate, enantiomer, diastereomer, deuterated substance or pharmaceutically acceptable salt thereof, wherein the compound of formula (II) has the following structure (V): in, R1, R2, X2, X3, A are as defined in claim 1.

6. The compound of formula (III) according to claim 3, or its racemate, enantiomer, diastereomer, deuterated substance or pharmaceutically acceptable salt thereof, wherein the compound of formula (III) has the following structure of formula (VI): in, R1, R2, and A are as defined in claim 1.

7. The compound of formula (IV) according to claim 4, or its racemate, enantiomer, diastereomer, deuterated substance or pharmaceutically acceptable salt thereof, wherein the compound of formula (IV) has the following structure of formula (VII): in, X2 and X3 are selected from CH and N, and X2 and X3 are not CH at the same time; R1, R2, and A are as defined in claim 1.

8. A compound, or a racemate, enantiomer, diastereomer, deuterated form or a pharmaceutically acceptable salt thereof, wherein the compound has a structure selected from the group consisting of:

9. Use of the compound according to any one of claims 1 to 8 or its racemate, enantiomer, diastereomer, deuterated substance or pharmaceutically acceptable salt thereof in the preparation of a SARM1 enzyme activity inhibitor.

10. Use of the compound according to any one of claims 1 to 8 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.

11. Use of the compound according to any one of claims 1 to 8 or its racemate, enantiomer, diastereomer, deuterated substance or pharmaceutically acceptable salt thereof in the preparation of a drug for treating or preventing a neurodegenerative disease or a neurological disease or condition.

12. Use according to claim 9 or 10 or 11, wherein 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.

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