Heterocyclic alkyl carboxylic acid derivatives, intermediates and methods of preparation and use thereof

Abstract

The application discloses a heterocyclic alkyl carboxylic acid derivative, an intermediate, a preparation method and application thereof, and relates to the technical field of medicinal chemistry.The heterocyclic alkyl carboxylic acid derivative is a compound shown in the following formula, a stereoisomer, a geometric isomer, a tautomer, a nitrogen oxide, a hydrate, a solvate, a pharmaceutically acceptable salt or a prodrug thereof, and the compound has good therapeutic effect on neurological diseases, such as depression, bipolar disorder and the like, and metabolic diseases, such as diabetes, metabolic disorder and the like, through in-vitro activity detection and animal behavior experiment.

Description

Technical Field

[0001] This invention relates to the field of medicinal chemistry, and in particular to a heterocyclic alkyl carboxylic acid derivative, its preparation method, and its uses. Background Technology

[0002] Human mental activities include sensation, perception, memory, thinking, emotion, attention, will, intelligence, personality, and consciousness. Any abnormal change in any of these aspects, or a lack of coordination between mental activity and the environment, can manifest as a mental disorder, or mental abnormality. Bipolar disorder is a neuropsychiatric illness with a high incidence, heritability, and mortality rate, seriously affecting people's physical and mental health and social harmony. Also known as manic-depressive disorder, it is a severe mental illness characterized by alternating episodes of mania and depression. Manic episodes are a major hallmark of bipolar disorder, characterized by elevated mood, irritability, hyperactive thinking, and decreased sleep demand; depressive episodes are another major characteristic, characterized by depressed mood, loss of interest, and decreased activity. However, the pathogenesis of bipolar disorder remains a long-standing scientific challenge in neuroscience and medicine. Among patients with bipolar disorder and depression, 70% lack effective treatment options. Traditional antidepressants and antipsychotics mostly target monoamine-based hypotheses and neurotransmitter receptors in the central nervous system. They suffer from drawbacks such as slow onset of action, low efficacy, significant side effects, poor efficacy as a single drug, and a high risk of suicide and self-harm. The fundamental reason for this is that the mechanisms leading to mental illness are not yet fully understood, and there is a lack of new mechanisms and targets for drug development and treatment.

[0003] Patent CA2197172A1 discloses novel alkylamino derivatives, pharmaceutical compositions comprising such compounds, and the use of such compounds in the treatment of central nervous system disorders and several other conditions, including the use of the following compounds as novel alkylamino derivatives of σ2-selective ligands:

[0004]

[0005] Patent CN101304973A discloses compounds and pharmaceutically acceptable compositions thereof that regulate the interaction between nerve growth factor and its precursors with neurotrophic protein receptors and treat diseases mediated by this interaction, such as pain, inflammatory diseases, and neurological disorders. The neurological disorders treated are selected from schizophrenia, bipolar disorder, depression, Alzheimer's disease, epilepsy, multiple sclerosis, amyotrophic lateral sclerosis, stroke, cerebral ischemia, neuropathy, retinitis pigmentosa, glaucoma, arrhythmia, Huntington's disease, and Parkinson's disease, specifically as follows:

[0006]

[0007] Synaptotagmin (Syt) is a presynaptic vesicle protein and a key protein involved in neurotransmitter release and physiological functions such as learning and memory in the brain. Syt is a family of membrane transport proteins. They are characterized by containing two calcium-binding domains: C2A and C2B. They are also characterized by their N-terminus being located within the vesicle, their C-terminus within the cytoplasm, and only one transmembrane domain. The cytoplasmic region of Syt mainly consists of two calcium-binding domains with repetitive sequences. 2+ It is composed of the binding regions C2A and C2B. The region closer to the N-terminus is called C2A, and the region closer to the C-terminus is called C2B. To date, the role of Syt in neurotransmitter release has been extensively studied. The release of neurotransmitters between neural synapses is one of the most important biological phenomena for the nervous system to perform its physiological functions. Neurotransmitter release is caused by Ca2+. 2+ Influx is induced by exocytosis resulting from the fusion of neurotransmitter-containing synaptic vesicles with the presynaptic membrane, Ca 2+ Needs to interact with Ca inside the cell 2+ Receptor fusion to synergistically control vesicle exocytosis; Syt is a Ca2+ receptor fusion site on the vesicle membrane. 2+ Receptor proteins can interact with the SNARE complex, regulate the fusion of vesicle membranes with the plasma membrane, and play an important regulatory role in the secretory activities of nerve, endocrine cells and other cells.

[0008] Syt7, a member of the Syt family of 17, functions as a calcium sensor through two calcium structural domains (C2A / C2B), playing a crucial role in synaptic vesicle release and synaptic plasticity. Soluble N-ethylmaleimide-sensitive factor attachment protein receptors (SNAREs) are a small, conserved family of eukaryotic proteins that mediate membrane fusion between organelles and with the plasma membrane. Presynaptically, after a large influx of calcium ions induced by the action potential, Syt7 binds calcium ions via C2A / C2B, simultaneously interacting with the core protein of vesicle release, its SNARE complex, and the lipid bilayer of the plasma membrane, inducing slow-phase asynchronous release of synaptic vesicles (SVs). Furthermore, Syt7 deficiency leads to defects in SV pool replenishment during cross-stimulus induced release. On the other hand, studies have shown that NMDARs (glutamate receptors) play a significant role in depressive-like behavior in mice, and NMDARs activated by spontaneous glutamate release may play an important role in this process. Building upon these studies, further research revealed that Syt7, located at the edge of the presynaptic active zone (AZ), triggers spontaneous glutamate release that specifically activates GluN2B-NMDAR, also located at the synaptic edge. This small subset of SVs controlled by Syt7 cannot participate in the release during cascade stimulation, leading to insufficient SV replenishment. Furthermore, Syt7 deficiency results in postsynaptic homeostasis plasticity, thereby upregulating NMDAR expression levels. The study also indicates that Syt7 can act as a calcium receptor in GABAergic neurons, driving the slow-phase asynchronous release of GABA (γ-aminobutyric acid).

[0009] Patent WO2021147977A1 ​​discloses the following: Significant defects in Syt7 gene expression were observed in hippocampal neurons differentiated from induced pluripotent stem cells (iPSCs) of bipolar disorder patients; Syt7 gene-deficient mice exhibited spontaneous cycles of mania and depression characteristic of bipolar disorder; furthermore, the expression level of Syt7 mRNA in the plasma of BD patients was significantly reduced compared to healthy controls; the Syt7 mRNA level in blood cells was also reduced, consistent with plasma detection. Syt7 gene-related signaling pathways and their expression products play a crucial role in the emotional cycle of bipolar disorder. Targeting molecules in Syt7 gene-related signaling pathways can aid in the diagnosis and treatment of bipolar disorder. The invention also provides the use of the Syt7 gene and / or its expression products in the preparation of a drug for treating bipolar disorder and / or its complications. According to embodiments of the invention, the Syt7 gene expression product can be used as a protein drug. By administering an appropriate amount of the protein drug to patients with bipolar disorder or its complications, the in vivo content of the Syt7 gene expression product can be increased, thereby enabling its use in the treatment of bipolar disorder or its complications.

[0010] Currently, compounds that interact with Syt7 to treat mental illnesses such as depression and bipolar disorder are very rare. Therefore, this invention provides a heterocyclic alkyl carboxylic acid derivative with a novel structure based on this mechanism. Furthermore, in vitro activity assays and in vivo animal behavioral experiments have demonstrated its potential therapeutic applications for neurological disorders such as depression and bipolar disorder. In addition, Syt7 possesses the biological activity of promoting vesicle release, and since the metabolism of many hormones, such as insulin, is achieved through vesicle release, this type of heterocyclic alkyl carboxylic acid derivative can also be used to treat metabolic diseases by acting on Syt7. Summary of the Invention

[0011] The purpose of this invention is to provide a heterocyclic alkyl carboxylic acid derivative, an intermediate, a method for preparing the same, and its use in the preparation of drugs for treating neurological and metabolic diseases.

[0012] To achieve the above-mentioned objectives, the technical solution of this invention is as follows:

[0013] In a first aspect, the present invention provides a heterocyclic alkyl carboxylic acid derivative, which is a compound of Formula I, its stereoisomers, geometric isomers, tautomers, nitrides, hydrates, solvates, pharmaceutically acceptable salts or prodrugs;

[0014]

[0015] Among them, ring R is selected from the following structures:

[0016]

[0017] B is selected from C atoms and N atoms; when B is an N atom, R2 does not exist;

[0018] R0 is n is selected from 1-8;

[0019] X is selected from substituted or unsubstituted C1-C5 alkyl, amino, aryl, and C3-C10 cycloalkyl groups, wherein the substituted substituent is selected from carbonyl, hydroxyl, C1-C5 alkyl, halogen, and aryl.

[0020] Y is selected from -OH, -NH2, -NR6R7, -S-R8, R9, -CO-R 10 ;

[0021] R6 and R7 are each independently selected from H, substituted or unsubstituted C1-C8 alkyl, C1-C5 alkyl, C5-C15 heterocyclic, C4-C14 cycloalkyl, wherein the substituted substituent is selected from C5-C15 heterocyclic, aryl, carbonyl, hydroxyl, halogen;

[0022] R8 is selected from substituted or unsubstituted C1-C8 alkyl groups, wherein the substituents are selected from carbonyl, hydroxyl, C1-C5 alkyl, halogen, and aryl.

[0023] R9 is selected from substituted or unsubstituted C5-C30 membered heterocyclic groups, wherein the substituted group is selected from carbonyl, hydroxyl, C1-C5 alkyl, halogen, aryl;

[0024] R 10 Selected from substituted or unsubstituted C1-C6 alkyl groups, wherein the substituents are selected from C5-C15 heterocyclic groups, carbonyl groups, hydroxyl groups, C1-C5 alkyl groups, halogens, and aryl groups;

[0025] R1, R2, R3, R4, R5, R1', R2', R3', R4', R5', R1”, R2”, R3”, and R4” are each independently selected from H, amino, nitro, hydroxyl, cyano, halogen, aryl, C1-C8 alkoxy, substituted aryl, C1-C8 alkyl, C1-C8 haloalkyl, C1-C8 alkylamino, phenylamino, and C3-C10 heterocyclic groups;

[0026] R6, R7, R9, R 10 In this context, the heteroatom in the heterocycle or heterocyclic group is oxygen and / or nitrogen.

[0027] Preferably, B is selected from C atoms or N atoms; where B is an N atom, R2 is absent.

[0028] R0 is n is selected from 1-8;

[0029] X is selected from substituted or unsubstituted C1-C5 alkyl or amino groups, wherein the substituent is selected from carbonyl or hydroxyl groups;

[0030] Y is selected from -OH, -NH2, -NR6R7, -S-R8, R9, -CO-R 10 ;

[0031] R6 and R7 are each independently selected from H, substituted or unsubstituted C1-C8 alkyl, C1-C5 alkyl, C5-C15 heterocyclic, and C4-C14 cycloalkyl, wherein the substituted substituent is selected from C5-C15 heterocyclic and aryl.

[0032] R8 is selected from substituted or unsubstituted C1-C8 alkyl groups, wherein the substituents are selected from C3-C6 cycloalkyl groups;

[0033] R9 is selected from C5-C30 heterocyclic groups;

[0034] R 10 Selected from substituted or unsubstituted C1-C6 alkyl groups, wherein the substituents are selected from C5-C15 heterocyclic groups;

[0035] R1, R2, R3, R4, R5, R1', R2', R3', R4', R5', R1”, R2”, R3”, and R4” are each independently selected from H, amino, nitro, hydroxyl, cyano, halogen, aryl, C1-C8 alkoxy, substituted aryl, C1-C8 alkyl, C1-C8 haloalkyl, C1-C8 alkylamino, phenylamino, and C3-C10 heterocyclic groups;

[0036] R6, R7, R9, R 10 In this context, the heteroatom in the heterocycle or heterocyclic group is oxygen and / or nitrogen.

[0037] Preferably, B is selected from C atoms or N atoms; where B is an N atom, R2 is absent.

[0038] R0 is n is selected from 1-6;

[0039] X is selected from carbonyl, hydroxyl-substituted C1-C3 alkyl, and NH;

[0040] Y is selected from -OH, -NH2, -NR6R7, -S-R8, R9, -CO-R 10 ;

[0041] R6 and R7 are each independently selected from H, C1-C5 alkyl, C5-C15 heterocyclic substituted C1-C5 alkyl, aryl substituted C1-C5 alkyl, C5-C15 heterocyclic group, C4-C14 cycloalkyl, and substituted C4-C14 cycloalkyl.

[0042] R8 is selected from C1-C5 alkyl groups substituted with C3-C5 cycloalkyl groups;

[0043] R9 is selected from C5-C30 heterocyclic groups;

[0044] R 10 Selected from C1-C4 alkyl groups substituted with C5-C15 heterocycles;

[0045] R1, R2, R3, R4, R5, R1', R2', R3', R4', R5', R1”, R2”, R3”, and R4” are each independently selected from H, amino, nitro, hydroxyl, cyano, halogen, aryl, C1-C5 alkoxy, substituted aryl, C1-C5 alkyl, C1-C5 haloalkyl, C1-C5 alkylamino, phenylamino, and C3-C8 heterocyclic groups;

[0046] R6, R7, R9, R 10 In this context, the heteroatom in the heterocycle or heterocyclic group is oxygen and / or nitrogen.

[0047] Preferably, when R1, R2, R3, R4, and R5 are all H, R0 is not a C3 alkyl group, or X is not a carbonyl group, or Y is not a hydroxyl group.

[0048] Preferably, R1, R2, R3, R4, and R5 are all H or only one group is not H; R1', R2', R3', R4', and R5' are all H or only one group is not H; R1”, R2”, R3”, and R4” are all H or only one group is not H.

[0049] Preferably, R1, R2, R3, R4, R5, R1', R2', R3', R4', R5', R1”, R2”, R3”, and R4” are each independently selected from H, amino, nitro, hydroxyl, cyano, halogen, phenyl, methyl, ethyl, methoxy, halomethyl, etc.

[0050] Preferably, halogens include Cl, Br, I, and F.

[0051] Preferably, n = 1, 3, 4 or 5; the hydroxyl-substituted C1-C3 alkyl group is Preferably, R6 and R7 are each independently selected from H, methyl, isopropyl,

[0052] Preferably, R8 is Preferably, R9 is selected from

[0053] Preferred, R 10 for Preferably, the compound represented by Formula I is selected from:

[0054]

[0055]

[0056]

[0057]

[0058]

[0059] A further preferred option is:

[0060] LCT011000, LCT01L0001, LCT011009, LCT011016, LCT011024, LCT011047, LCT011028, LCT011030, L CT011035, LCT011062, LCT011063, LCT011064, LCT011065, LCT011071, LCT011068, LCT011078, LCT0 11079, LCT011083, LCT011084, LCT011091, LCT011097, LCT011098, LCT011099, LCT011101, LCT0111 02. LCT011103, LCT011108, LCT011105, LCT011109, LCT011100, LCT011117, LCT011121, LCT011133.

[0061] A further preferred option is:

[0062] LCT011016, LCT011024, LCT011028, LCT011062, LCT011063, LCT011064, LCT011065, LCT011068, LCT011078, LCT011079, LCT011097, LCT011098, LCT011103, LCT011105, LCT011108, LCT011100, LCT011117, LCT011133.

[0063] A further preferred option is:

[0064] LCT011016, LCT011078, LCT011062, LCT011063, LCT011064, LCT011065, LCT011097, LCT011108, LCT011117, LCT011133.

[0065] A further preferred option is:

[0066] LCT011016, LCT011078, LCT011097, LCT011108, LCT011117, LCT011133.

[0067] Secondly, the present invention provides a method for preparing the aforementioned heterocyclic alkyl carboxylic acid derivatives, comprising the following reaction steps:

[0068] Compound 1 + X1 - R0 - X - Y' →

[0069] Compound 1 is selected from X1 is selected from H, halogen, or hydroxyl; Y' is Y or Y substituted with a protecting group.

[0070] Preferred protecting groups include, but are not limited to: protecting groups for hydroxyl groups, protecting groups for amino or amine groups, protecting groups for carboxyl groups, protecting groups for aldehydes or ketones, protecting groups for thiol groups, and protecting groups for any combination of functional groups such as hydroxyl, amino or amine, carboxyl, aldehyde or ketone, and thiol.

[0071] The protecting group for the hydroxyl group is preferably selected from the following protecting groups: tetrahydropyranyl (THP), methyl (Me), benzyl (Bn), methoxymethyl (MOM), allyl (All), triphenylmethyl (Trt), acetyl (Ac), pivaloyl (Piv), tert-butyldimethylsilyl (TBDMS), tert-butyldimethylsilyl (TBDPS), trimethylsilyl (TMS), triethylsilyl (TES), phthalimide (Phth), tert-butyloxycarboxylate (Boc), benzyloxycarboxylate (Cbz), and 9-fluorenemethoxycarboxylate (Fmoc).

[0072] The carboxyl protecting group is preferably selected from the following protecting groups: tert-butyl ester (t-Bu), benzoyl ester (Bn), methyl ester (Me), ethyl ester (Et), allyl ester (All), isopropyl ester (i-Pr), isobutyl ester (i-Bu), triphenylmethyl ester (Trt), methoxymethyl (MOM), tert-butyldimethylsilane ester (TBDMS), and 9-fluorenylmethoxycarbonyl (Fmoc).

[0073] The protecting group for the amine group is preferably selected from the following protecting groups: 9-fluorenylmethoxycarbonyl (Fmoc), benzyloxycarbonyl (Cbz), tert-butoxycarbonyl (Boc), trichloroethoxycarbonyl (Troc), allyloxycarbonyl (Alloc), methoxycarbonyl (Moc), acetyl (Ac), trifluoroacetyl (TFA), 2,4-dimethoxybenzyl (DMB), benzyl (Bn), triphenylmethyl (Tr), benzyloxymethyl (Bom), p-toluenesulfonyl (Ts), 2,2,4,6,7-pentamethyldihydrobenzofuran-5-sulfonyl (Pbf), 4-methoxy-2,3,6-trimethylbenzenesulfonyl (Mtr), phthalimide (Phth), and benzylamine.

[0074] Thirdly, the present invention provides a method for preparing the aforementioned heterocyclic alkyl carboxylic acid derivatives, comprising the following reaction steps:

[0075] Compound 2

[0076] Compound 2 is selected from

[0077] X2, X3, and X4 are each independently selected from halogens; Y' is Y or Y substituted with a protecting group; the substitution, hydrogenation, or fluorination reaction is to substitute or hydrogenate H, X2, X3, or NO2 to...

[0078] The reaction of the corresponding group.

[0079] Fourthly, the present invention provides a method for preparing the aforementioned heterocyclic alkyl carboxylic acid derivatives, comprising the following reaction steps:

[0080]

[0081] Wherein, Y' is Y or Y substituted with a protecting group.

[0082] Fifthly, the present invention provides a method for preparing the aforementioned heterocyclic alkyl carboxylic acid derivatives, comprising the following reaction steps:

[0083]

[0084] Where X is

[0085] Sixthly, the present invention provides a method for preparing the aforementioned heterocyclic alkyl carboxylic acid derivatives, comprising the following reaction steps:

[0086]

[0087] Where X is

[0088] Preferably, the method further includes the step of oxidizing the hydroxyl group on X to a carbonyl group.

[0089] In a seventh aspect, the present invention provides a method for preparing the aforementioned heterocyclic alkyl carboxylic acid derivatives, comprising the following reaction steps:

[0090]

[0091] Wherein, X' is a carboxyl group or a halogen; Y' is Y or Y substituted with a protecting group; Y is selected from -NR6R7 or R9.

[0092] Preferably, the step involves hydrolyzing the ester group connected to the ring into a carboxyl group, and then forming a ring with the amide group on the ring.

[0093] Eighthly, the present invention provides a method for preparing the aforementioned heterocyclic alkyl carboxylic acid derivative, comprising the following reaction steps:

[0094]

[0095] Where Y' is Y or Y substituted with a protecting group; Y is R 10.

[0096] Preferably, the preparation method of the aforementioned heterocyclic alkyl carboxylic acid derivative further includes a deprotection step.

[0097] In a ninth aspect, the present invention provides an intermediate for a heterocyclic alkyl carboxylic acid derivative, which is a compound represented by Formula II;

[0098]

[0099] Among them, ring R is selected from the following structures:

[0100]

[0101] B is selected from C atoms and N atoms; when B is an N atom, R2 does not exist;

[0102] R0 is n is selected from 1-6;

[0103] M is selected from carbonyl, NH, vinyl, halogen, and epoxy groups;

[0104] A is selected from -OR 11 OH, H, halogen or absent; R 11 Selected from C1-C10 alkyl groups, more preferably tert-butyl;

[0105] R1, R2, R3, R4, R5, R1', R2', R3', R4', R5', R1”, R2”, R3”, and R4” are each independently selected from H, amino, nitro, hydroxyl, cyano, halogen, aryl, C1-C5 alkoxy, substituted aryl, C1-C5 alkyl, C1-C5 alkylamino, phenylamino, and C3-C8 heterocyclic groups.

[0106] Preferably, R1, R2, R3, R4, R5, R1', R2', R3', R4', R5', R1”, R2”, R3”, and R4” are each independently selected from H, amino, nitro, hydroxyl, cyano, halogen, aryl, C1-C5 alkoxy, substituted aryl, C1-C5 alkyl, C1-C5 alkylamino, phenylamino, and C3-C8 heterocyclic groups.

[0107] Preferably, R1, R2, R3, R4, and R5 are all H or only one group is not H; R1', R2', R3', R4', and R5' are all H or only one group is not H; R1”, R2”, R3”, and R4” are all H or only one group is not H.

[0108] Preferably, R1, R2, R3, R4, R5, R1', R2', R3', R4', R5', R1”, R2”, R3”, and R4” are each independently selected from H, amino, nitro, cyano, halogen, and phenyl.

[0109] Preferably, n = 1, 3, 4 or 5.

[0110] Preferably, the intermediate is selected from:

[0111]

[0112]

[0113] In a tenth aspect, the present invention provides the use of the aforementioned heterocyclic alkyl carboxylic acid derivatives in the preparation of drugs for treating and / or preventing neurological diseases and metabolic diseases.

[0114] Syt7 has the biological activity of promoting vesicle release, and many hormones, such as insulin, are metabolized through vesicle release. Therefore, such heterocyclic alkyl carboxylic acid derivatives can also be used to treat metabolic diseases by acting on Syt7.

[0115] Preferably, the neurological diseases include schizophrenia, bipolar disorder, depression, Alzheimer's disease, epilepsy, neurosis, chorea, and Parkinson's disease. The metabolic diseases include diabetes and metabolic disorders.

[0116] The neurological disease is further preferably schizophrenia, bipolar disorder, or depression.

[0117] The neurological disease is more preferably bipolar disorder or depression.

[0118] The preferred neurological disorder is bipolar disorder.

[0119] In one aspect, the present invention provides a pharmaceutical composition comprising the aforementioned heterocyclic alkyl carboxylic acid derivative and a pharmaceutically acceptable carrier or excipient.

[0120] The phrase "pharmaceutical-grade carrier" is well-known in the art and includes pharmaceutically acceptable materials, components, or carriers suitable for administration of the compounds of the present invention to mammals. Carriers include liquid or solid fillers, diluents, excipients, solvents, or encapsulating materials that participate in carrying or delivering the subject matter from one part of an organ or body to another. Each carrier must be "acceptable" in terms of compatibility with other components of the formulation or harmlessness to the subject. Some examples of materials that can serve as pharmaceutically-grade carriers include: sugars, such as lactose, glucose, and sucrose; starches, such as corn starch and potato starch; cellulose and its derivatives, such as sodium methylcellulose, ethylcellulose, and cellulose acetate; tannins, malt, gelatin, and talc; excipients, such as cocoa butter and suppository waxes; oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, and soybean oil; glycols, such as propylene glycol; and polyols, such as glycerol and sorbitol. Pear alcohol, mannitol, and polyethylene glycol, esters such as ethyl oleate and ethyl laurate, agar, buffers such as magnesium hydroxide and aluminum hydroxide, alginic acid, pyrogens, isotonic saline, ethanol, phosphate buffer and other non-toxic compatibility substances used in pharmaceutical formulations, wetting agents, emulsifiers and lubricants such as sodium dodecyl sulfate and stearate, as well as colorants, separating agents, coating agents, sweeteners, flavoring and aroma agents, preservatives and antioxidants may also be present in the composition.

[0121] Examples of pharmaceutically usable antioxidants include: water-soluble antioxidants such as ascorbic acid, cysteine ​​hydrochloride, sodium bisulfate, sodium metabisulfite, and sodium sulfite; oil-soluble antioxidants such as palmitic acid ascorbate, butylated benzoic acid (BHA), butylated hydroxytoluene (BHT), lecithin, propyl gallate, and α-tocopherol; and metal compounds such as citric acid, ethylenediaminetetraacetic acid (EDTA), sorbitol, tartaric acid, and phosphoric acid.

[0122] Suitable pharmaceutically acceptable carriers include, but are not limited to, water, salt solutions (e.g., NaCl), alcohols, gum arabic, vegetable oils, benzyl alcohol, polyethylene glycol, gelatin, sugars (e.g., lactose, amylose, or starch), polyethylene glycol, magnesium stearate, talc, silica, viscous paraffin, aromatic oils, fatty acid esters, methylcellulose, polyvinylpyrrolidone, etc. The pharmaceutical composition may be sterilized and, if desired, mixed with adjuvants such as lubricants, preservatives, stabilizers, humectants, emulsifiers, salt buffers affecting osmotic pressure, colorants, flavoring and / or aromatic substances, etc., which react harmlessly with the active compound.

[0123] The composition may also contain minor amounts of a wetting agent, emulsifier, or pH buffer. The composition may be a liquid solution, suspension, emulsion, tablet, pill, capsule, sustained-release formulation, or powder. The composition may be formulated into suppositories with conventional binders and carriers (such as triglycerides). Oral formulations may include standard carriers such as pharmaceutical-grade mannitol, lactose, magnesium stearate, polyvinylpyrrolidone, sodium saccharin, cellulose, magnesium carbonate, etc.

[0124] The composition can be formulated into a pharmaceutical composition suitable for intravenous administration to humans using conventional methods. Where necessary, the composition may also include stabilizers and local anesthetics to reduce pain at the injection site. Generally, the components are supplied individually or mixed together in unit dosage forms, such as in sealed containers like ampoules or small capsules indicating the amount of active agent as a dried, frozen powder or anhydrous concentrate. When the composition is to be administered by infusion, it can be dispersed in an infusion bottle containing pharmaceutical-grade sterile water, saline, or glucose solution. When the composition is to be administered by injection, an ampoule of sterile water or saline for injection may be provided, allowing the components to be mixed prior to administration.

[0125] The pharmaceutical compositions of the present invention may further include agents for controlling the release of the compounds of the present invention, thereby providing time-controlled or sustained-release compositions.

[0126] The pharmaceutical compositions of the present invention include compositions suitable for oral, rectal, topical, vaginal, and parenteral (including subcutaneous, intramuscular, and intravenous) administration, although the most suitable route in any particular case depends on the specific subject, the nature and severity of the disease to which the active ingredient is administered. The pharmaceutical compositions can be prepared by any method known in the field of pharmaceutical science.

[0127] The active ingredient can be administered orally in solid or liquid dosage forms, such as capsules, tablets, lozenges, sugar lozenges, granules, and powders, and in liquid forms such as elixirs, syrups, emulsions, dispersions, and suspensions. The active ingredient can also be administered parenterally in sterile liquid dosage forms such as dispersions, suspensions, or solutions. Other dosage forms that can be used to administer the active ingredient include ointments, creams, drops, transdermal patches, or powders for topical administration; ophthalmic solutions or suspensions for ocular administration, i.e., eye drops; sprays or powder compositions for inhalation or intranasal administration; or creams, ointments, sprays, or suppositories for rectal or vaginal administration. Gelatin capsules contain the active ingredient and a powdered carrier, such as lactose, starch, cellulose derivatives, magnesium stearate, stearic acid, etc. Similar diluents can be used to prepare compressed tablets. Both tablets and capsules can be formulated as sustained-release products to provide sustained release of the drug over several hours. Compressed tablets can be sugar-coated or film-coated to mask any unpleasant tastes and protect the tablet from air, or they can be enteric-coated for selective disintegration in the gastrointestinal tract. Liquid dosage forms for oral administration may contain colorants and flavoring agents to increase patient acceptability. Generally, water, suitable oils, saline, aqueous solutions of dextran (glucose), and related sugar solutions, as well as glycols such as propylene glycol or polyethylene glycol, are suitable carriers for parenteral solutions. Solutions for parenteral administration preferably contain water-soluble salts of the active ingredient, suitable stabilizers, and buffers as needed. Antioxidants such as sodium bisulfite, sodium sulfite, or ascorbic acid, alone or in combination, are suitable stabilizers. Citric acid and its salts, and sodium EDTA may also be used. In addition, parenteral solutions may contain preservatives such as benzalkonium chloride, methylparaben, or propylparaben, and chlorobutanol.

[0128] For inhalation administration, the compounds of the present invention can be conveniently delivered in aerosol form from pressurized packaging or nebulizers. The compounds can also be delivered in powder form, which can be inhaled with the aid of a powder inhaler device. A preferred delivery system for inhalation is a metered-dose inhaler (MDI) aerosol, which can be formulated as a suspension or solution of the compound of Formula I in a suitable propellant, such as a fluorocarbon or hydrocarbon. For ophthalmic administration, ophthalmic formulations can be formulated with a solution or suspension of the compound of Formula I in a suitable ophthalmic carrier at a suitable weight percentage, thereby maintaining sufficient contact time between the compound and the ocular surface to allow the compound to penetrate into the cornea and internal regions of the eye.

[0129] Useful pharmaceutical dosage forms for administering the compounds of the present invention include, but are not limited to, hard and soft gelatin capsules, tablets, parenteral injections, and oral suspensions.

[0130] When the compounds of the present invention are administered stepwise or in combination with other therapeutic agents, the same dosage forms as described above can be used. When the drugs are administered in physical combinations, the dosage form and route of administration should be selected based on the compatibility of the combined drugs. The compounds of the present invention can be administered as the sole active ingredient or in combination with a second active ingredient, which includes active ingredients known to be effective in treating neurological and metabolic diseases.

[0131] Terminology Explanation:

[0132] Unless otherwise stated, the term "alkyl" as used herein includes branched and straight-chain saturated aliphatic hydrocarbon groups having a specific number of carbon atoms, including all isomers. Common abbreviations for alkyl groups include methyl (e.g., "Me" or CH3), ethyl (e.g., "Et" or CH2CH3), propyl (e.g., "Pr" or CH2CH2CH3), butyl (e.g., "Bu" or CH2CH2CH2CH3," etc.). For example, "C..." 1-4 Alkyl (or "C1-C4 alkyl") refers to a straight-chain or branched alkyl group having a specific number of carbon atoms, including all isomers. 1-4 Alkyl groups include n-, iso-, secondary and tert-butyl, n- and isopropyl, ethyl and methyl. The term "C" is used in this context. 1-10 "Alkyl" and similar terms have similar meanings.

[0133] The term "alkoxy" refers to straight-chain and branched alkyl groups with a specified number of carbon atoms connected by oxygen bridges.

[0134] The term "halogen" (or "halogenated") refers to fluorine, chlorine, bromine, and iodine (or fluorinated (F), chlorinated (Cl), brominated (Br), and iodinated (I)).

[0135] The term "aryl" refers to aromatic monocyclic and polycyclic ring systems, in which the carbon rings are fused together or linked together by single bonds. Common aryl groups include phenyl, naphthyl, and biphenylene.

[0136] The term "heterocycle" refers to a ring structure composed of carbon atoms and non-carbon atoms. Examples of non-carbon atoms in the ring include nitrogen, oxygen, and sulfur. Common heterocyclic groups include pyridine, quinoline, tropane, phenothiazine, benzodiazepine, furan, pyrazolone, and pyrimidine.

[0137] The term "aromatic heterocycle" refers to a 5- or 6-membered monocyclic aromatic ring or a 7- to 12-membered bicyclic ring, which consists of a carbon atom and one or more heteroatoms selected from N, O, and S. Examples of aromatic heterocycles include pyridyl, pyrroloyl, pyrazinyl, pyrimidinyl, pyridazinyl, thiophene (or thiophenyl), thiazolyl, furanyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, azole, isozolyl, diazolyl, thiazolyl, isothiazolyl and thiadiazolyl, benzotriazolyl, indolyl, isoindolyl, indolyl, dihydroindolyl, isodihydroindolyl, quinoxalinyl, quinazolinyl, zolinyl, chromanyl, isochoryl, tetrahydroquinolinyl, quinolinyl, tetrahydroisoquinolinyl, isoquinolinyl, 2,3-dihydrobenzofuranyl, 2,3-dihydrobenzo-1,4-dienyl, imidazo(2,1-b)(1,3)thiazole and benzo-1,3-m-dioxanepentenyl.

[0138] The aryl group in the term "substituted aryl" is as defined above. When no substituent is specified for the substituted aryl group, the substituent may be selected from the following groups, including but not limited to: halogens, C1-C... 20 Alkyl, CF3, NH2, N(C1-C6 alkyl)2, NO2, oxo, CN, N3, -OH, -O(C1-C6 alkyl), C3-C 10 Cycloalkyl, C2-C6 alkenyl, C2-C6 ynyl, (C0-C6 alkyl)S(O) 0-2 -, Aryl-S(O) 0-2 -、(C0-C6 alkyl)S(O) 0-2 (C0-C6 alkyl)-, (C0-C6 alkyl)C(O)NH-, H2N-C(NH)-, -O(C1-C6 alkyl)CF3, (C0-C6 alkyl)C(O)-, (C0-C6 alkyl)OC(O)-, (C0-C6 alkyl)2NC(O)-(C0-C6 alkyl)O(C1-C6 alkyl)-, (C0-C6 alkyl)C(O) 1-2 (C0-C6 alkyl)-, (C0-C6 alkyl)OC(O)NH-, aryl, aralkyl, heteroaryl, heterocyclic alkyl, halogen-aryl, halogen-aralkyl, halogen-heterocyclic, halogen-heterocyclic alkyl, cyano-aryl, cyano-aralkyl, cyano-heterocyclic, and cyano-heterocyclic alkyl. The term "substituted phenyl" has a similar definition.

[0139] Unless otherwise stated, all ranges listed in this article are inclusive. For example, "n is an integer between 0 and 2" means that n can be 0, 1, or 2.

[0140] The term "pharmaceutically acceptable salt" refers to a salt prepared from a pharmaceutically acceptable, non-toxic alkali or acid. When the compounds of the present invention are acidic, their corresponding salts can be readily prepared from inorganic or organic bases. Salts derived from such inorganic bases include aluminum, ammonium, calcium, copper (copper and cuprous), iron, ferrous, lithium, magnesium, manganese (manganese and manganese), potassium, sodium, zinc, etc. Preferred are ammonium, calcium, magnesium, potassium, and sodium salts. Salts prepared from organic bases include primary, secondary, and tertiary amines derived from natural and synthetic sources. Pharmaceutically acceptable non-toxic organic bases that can form salts include arginine, betaine, caffeine, choline, N,N′-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucosamine, glucosamine, histidine, hydrabamine, isopropylamine, dicyclohexylamine, lysine, methylglucosamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine, etc. When the compounds of the present invention are basic, their corresponding salts can be readily prepared from inorganic or organic acids. Such acids include, for example, acetic acid, benzenesulfonic acid, benzoic acid, camphorsulfonic acid, citric acid, ethanesulfonic acid, fumaric acid, gluconic acid, glutamic acid, hydrobromic acid, hydrochloric acid, hydroxyethylsulfonic acid, lactic acid, maleic acid, malic acid, mandelic acid, methanesulfonic acid, viscous acid, nitric acid, pyric acid, pantothenic acid, phosphoric acid, succinic acid, sulfuric acid, tartaric acid, p-toluenesulfonic acid, etc.

[0141] The term "solvate" refers to a variable stoichiometric complex formed by a solute (i.e., a compound of formula I) or a pharmaceutically acceptable salt thereof and a solvent that does not interfere with the biological activity of the solute. Examples of solvents include, but are not limited to, water, ethanol, and acetic acid. When the solvent is water, the solvate is called a hydrate. Hydrates include, but are not limited to, hemihydrates, monohydrates, sesquihydrates, dihydrates, and trihydrates.

[0142] The term "prodrug" refers to a functional derivative of the compound of this invention that is readily converted into the desired compound in vivo.

[0143] The term "neurological disease" refers to damage, disease, and dysfunction of the nervous system, including the peripheral and central nervous systems. Neurological diseases include, but are not limited to, diseases and symptoms associated with stimulation of the syt7 target.

[0144] The beneficial effects of this invention are as follows: This invention provides a heterocyclic alkyl carboxylic acid derivative with a novel structure, which targets Syt7 to treat mental illnesses such as depression and bipolar disorder. At the same time, this invention provides a method for preparing the compound. Through in vitro activity testing and in vivo animal behavioral experiments, it has been demonstrated that the compound has good therapeutic effects on neurological diseases such as depression and bipolar disorder. Attached Figure Description

[0145] Figure 1 SPT and FST results for LCT011000, LCT011009, LCT011117 and LCT011133;

[0146] Figure 2 The SPT and SFT results for LCT011016;

[0147] Figure 3 The SPT and SFT results for LCT011060;

[0148] Figure 4 Comparison of NPY release results for some compounds;

[0149] Figure 5 Comparison of NPY release results for some compounds;

[0150] Figure 6 Comparison of NPY release results for some compounds;

[0151] Figure 7 Comparison of NPY release results for some compounds;

[0152] Figure 8 Comparison of NPY release results for some compounds;

[0153] Figure 9 Comparison of NPY release results for some compounds;

[0154] Figure 10 Comparison of NPY release results for some compounds;

[0155] Figure 11 This is a comparison chart showing the NPY release results of some compounds.

[0156] In this application, the compound designated LCT011000 is also named "Drug1", and both are the same compound with the following formula:

[0157] Detailed Implementation

[0158] The following non-limiting embodiments are intended to enable those skilled in the art to gain a more comprehensive understanding of the present invention, but do not limit the invention in any way. The following content is merely an exemplary description of the scope of protection claimed by the present invention, and those skilled in the art can make various changes and modifications to the invention based on the disclosed content, which should also fall within the scope of protection claimed in this application.

[0159] The present invention will be further described below by way of specific embodiments. Unless otherwise specified, all chemical reagents used in the embodiments of the present invention were obtained through conventional commercial means. Unless otherwise specified, all contents mentioned below are mass contents. Unless otherwise specified, it is understood that the process was carried out at room temperature.

[0160] The compounds of the present invention having the various forms described herein can be prepared from commercially available starting materials or starting materials that can be prepared using literature processes, according to the processes described in the following general synthetic routes 1-7. Variables (e.g., R1, R2, and R3, etc.) in each general synthetic route are as defined herein. Those skilled in the art will note that the order of certain steps in the reaction procedures and synthetic schemes described herein can be varied, such as the introduction and removal of protecting groups.

[0161] General Synthetic Route 1

[0162] Compound 1 + X1 - R0 - X - Y' →

[0163] Compound 1 is selected from X1 is selected from H, halogen, or hydroxyl; Y' is Y or Y substituted with a protecting group. R1, R2, R3, R4, R5, R1', R2', R3', R4', and R5' may contain protecting groups. When Y' or an alkyl group contains a protecting group, the process also includes the steps of preparing a raw material containing a protecting group and deprotecting the reaction product.

[0164] The above reaction can be carried out using K2CO3 or KI as catalysts and DMF as solvent, and the reaction can be carried out at 50-70℃ for 1-20h.

[0165] General Synthesis Route 2

[0166] Compound 2

[0167] Compound 2 is selected from X2, X3, and X4 are each independently selected from halogens; Y' is Y or Y substituted with a protecting group; the substitution, hydrogenation, or fluorination reaction is to substitute or hydrogenate H, X2, X3, or NO2 to... The reaction involves the application of a corresponding protecting group. When Y' contains a protecting group, the process also includes preparing a raw material containing a protecting group and deprotecting the reaction product.

[0168] The reaction conditions of compound 2 with X4-R0-X-Y' are the same as those of general synthetic route 1. K2CO3 and KI can be used as catalysts and DMF as solvent, and the reaction can be carried out at 50-70℃ for 1-20h.

[0169] The hydrogenation reaction involves hydrogenating -NO2 to -NH2, which can be carried out using Pd / C as a catalyst in THF or EtOH for 10-24 hours.

[0170] The substitution reaction includes a reaction that replaces a halogen with a phenyl group, for example using... Pd(PPh3)4 and K2CO3 were used as reaction reagents, and dioxane / H2O was used as reaction solvent. The reaction was carried out at 80-100℃ for 2-20 hours.

[0171] The substitution reaction includes the substitution of halogens with -CN, for example, using Zn(CN)2 as the reactant, Pd(PPh3)4 as the catalyst, and DMF as the reaction solvent, and reacting at 70-90°C for 2-20 h.

[0172] The substitution reaction includes replacing the halogen with... The reaction, for example, with Pd(dppf)Cl2 and Cs3CO3 were used as reaction reagents, and H2O was used as the reaction solvent. The reaction was carried out at 70-90℃ for 2-20 hours.

[0173] The substitution reaction includes the substitution of halogens with methyl groups, for example, using MeB(OH)2 as the reactant and Pd(OAc)2 and K3PO4 as catalysts, and reacting at 90-100℃ for 2-20h.

[0174] General Synthesis Route 3

[0175]

[0176] Wherein, Y' is Y or Y substituted with a protecting group. R1”, R2”, R3”, and R4” may contain protecting groups. When Y' or an alkyl group contains a protecting group, the process also includes the steps of preparing a raw material containing a protecting group and deprotecting the reaction product.

[0177] The above reaction was carried out in AcOH at 90-110℃ for 1-10 h.

[0178] General Synthesis Route 4

[0179]

[0180] Where X is

[0181] The above reaction can be carried out using K2CO3 or iPrOH as catalysts at 70-90℃.

[0182] General Synthesis Route 5

[0183]

[0184] Where X is The reaction is carried out under alkaline conditions. The reaction route may also include a step of oxidizing the hydroxyl group on X to a carbonyl group, with the oxidation reaction carried out at 0°C to room temperature.

[0185] General Synthesis Route 6

[0186]

[0187] Where X' is a carboxyl group or a halogen; Y' is Y or Y substituted with a protecting group; Y is selected from -NR6R7 and R9. This reaction is an amidation or substitution reaction and can be carried out under conventional reaction conditions. The reaction route may also include the step of hydrolyzing the non-cyclic ester group to a carboxyl group, followed by a further cyclization reaction of the carboxyl group with an amino group. For example, LiOH can be used as a catalyst, and MeOH or H2O as a solvent, and the reaction can be carried out at room temperature. When Y' or the alkyl group contains a protecting group, the reaction also includes steps for preparing a starting material containing a protecting group and for deprotecting the reaction product.

[0188] General Synthesis Route 7

[0189]

[0190] Where Y' is Y or Y substituted with a protecting group; Y is R 10 This reaction is an amidation reaction and can be carried out under conventional amidation reaction conditions. When Y' or the alkyl group contains a protecting group, the reaction also includes steps of preparing a starting material containing a protecting group and deprotecting the reaction product.

[0191] Preparation Examples of Intermediates and Compounds

[0192] Example 1: Preparation method of compound LCT011000 and intermediate XI-1

[0193] Synthesize according to general synthetic route 1:

[0194]

[0195] Synthesis steps:

[0196] Step 1: Add compound LCT011000-1 (benzo[cd]indole-2(1H)-one) (500 mg, 2.95 mmol), tert-butyl tetrabromobutyrate (1.31 g, 5.91 mmol), and potassium iodide (KI) (1.96 g, 11.8 mmol) to a three-necked flask. Dissolve the mixture in 10 mL of N,N-dimethylformamide (DMF). Heat the mixture to 60 °C under nitrogen protection and react for 12-24 h. The reaction was monitored by LC-MS to determine if it was complete. After the reaction was complete, the reaction mixture was purified by preparative liquid chromatography (purification conditions: column type: Biotage Isolera One C18 colμmn, mobile phase: elution with 30-50% MeCN / H2O containing 0.1% NH4OH), to obtain a yellow solid powder, namely compound LCT011000-2 (tert-butyl 4-(2-oxobenzo[cd]indole-1(2H)-yl)butyrate) (300 mg, yield: 32%).

[0197] Mass spectrometry (ESI): Molecular formula is C 19 H 21 NO3 has a molecular weight of 311.15 and a mass-to-charge ratio (m / z) of 312.25 [M+H]. + .

[0198] Step 2: Add compound LCT011000-2 (tert-butyl 4-(2-oxobenzo[cd]indole-1(2H)-yl)butyrate (200 mg, 0.642 mmol) to a three-necked flask, dissolved in 4 mL of trifluoroacetic acid (TAF). React the mixture at room temperature for 2 h under nitrogen protection. Monitor the reaction completion using LC-MS. After completion, concentrate the reaction mixture by vacuum distillation to remove the solvent trifluoroacetic acid (TAF). Purify the concentrated mixture using preparative liquid chromatography (prep-HPLC) (particle size: Gemini 5 μm C18 col μmn, 150 × 21.2 mm; mobile phase: 20-30% MeCN / H2O containing 0.1% NH4OH), yielding a yellow solid powder, namely compound LCT011000 (49.26 mg, purity: 99.67%, yield: 30%).

[0199] Mass spectrometry (ESI): Molecular formula is C 15 H 13 NO3 has a molecular weight of 255.09 and a mass-to-charge ratio (m / z) of 256.15 [M+H]. + 1H NMR spectrum 1 NMR): 1H NMR (400MHz, DMSO-d6) δ8.18(d,J=8.0Hz,1H),8.05(d,J=6.8Hz,1H),7.80(dd,J=8.0,7.2Hz,1H),7.63(d,J=8.4Hz,1H) ,7.55(dd,J=8.0,6.8Hz,1H),7.22(d,J=7.2Hz,1H),3.90(t,J=7.2Hz,2H),2.22(t,J=7.2Hz,2H),1.91(p,J=7.2Hz,2H).

[0200] Example 2: Preparation of compound LCT011003 and intermediate XI-2

[0201] Synthesize according to general synthetic route 1:

[0202]

[0203] Synthesis steps:

[0204] Step 1: Pyridine (3.30 g, 41.7 mmol) was added to a solution of compound LCT011003-1 (5.00 g, 27.8 mmol) and O-methylhydroxylamine hydrochloride (3.00 g, 36.1 mmol) in MeOH (10.0 mL). The mixture was stirred and stirred at 25 °C under a N2 atmosphere for 16 hours. After completion, the mixture was concentrated under vacuum. The residue was purified by silica gel column chromatography (PE / EtOAc, 1:0) to give product LCT011003-2 (4.00 g, 69% yield) as a yellow oil.

[0205] Mass spectrometry (ESI): Molecular formula is C 11 H 12 ClNO, with a molecular weight of 209.06 and a mass-to-charge ratio (m / z) of 209.95 [M+H] + .

[0206] Step 2: LCT011003-2 (4.00 g, 19.1 mmol), NBS (4.08 g, 22.9 mmol), and Pd(OAc)2 (0.429 g, 1.91 mmol) were added to AcOH (20.0 mL) and stirred at 80 °C under N2 atmosphere for 0.5 h. After completion, the resulting mixture was concentrated under vacuum. The residue was purified by silica gel column chromatography (PE / EtOAc, 1:0) to give the yellow solid product LCT011003-3 (4.00 g, 73% yield). Mass spectrometry (ESI): molecular formula C 11 H 11BrClNO, with a molecular weight of 288.97 and a mass-to-charge ratio (m / z) of 289.85 [M+H] + .

[0207] Step 3: Add 6M HCl (20.0 mL) to a solution of LCT011003-3 (4.00 g, 13.9 mmol) in 1,4-dioxane (20.0 mL). Stir the resulting mixture at 100 °C for 16 hours. After completion, alkalize the mixture to pH ~7 with 10% sodium hydroxide aqueous solution. Extract the aqueous layer with EtOAc. Wash the combined organic layers with brine and dry with anhydrous Na2SO4. Filter and concentrate the filtrate under reduced pressure. Purify the residue by silica gel column chromatography (PE / EtOAc, 10:1) to give the product LCT011003-4 (3.20 g, 89% yield) as a yellow solid. Mass spectrometry (MS) (ESI): Molecular formula C 10 H8BrClO, with a molecular weight of 259.94 and a mass-to-charge ratio (m / z) of 261.00 [M+H] + .

[0208] Step 4: CuCN (1.04 g, 11.6 mmol) was added to a solution of LCT011003-4 (3.00 g, 11.6 mmol) in DMF / H2O / t-BuOH (2:1:2, 25 mL). The resulting mixture was stirred at 110 °C under a N2 atmosphere for 48 hours. After stirring, the mixture was diluted with H2O (20.0 mL). The aqueous layer was extracted with EtOAc (20.0 mL × 3). The combined organic layers were washed with brine and dried over anhydrous Na2SO4. The filtrate was concentrated under reduced pressure after filtration. The residue was purified by silica gel column chromatography (PE / EtOAc, 3:1 to 1:1) to give the product LCT011003-5 (1.80 g, 76% yield) as a yellow solid. Mass spectrometry (ESI): molecular formula C 11 H8ClNO, with a molecular weight of 205.03 and a mass-to-charge ratio (m / z) of 205.95 [M+H] + .

[0209] Step 5: LCT011003-5 (1.80 g, 8.78 mmol) and DDQ (1.99 g, 8.78 mmol) were dissolved in DCM (20.0 mL) and stirred at 25 °C for 16 h. After completion, the resulting mixture was concentrated under vacuum. The residue was purified by silica gel column chromatography (PE / EtOAc, 3:1 to 1:1) to give the product LCT011003-6 (1.50 g, 84% yield) as a yellow solid. Mass spectrometry (ESI): Molecular formula C 11H6ClNO, with a molecular weight of 203.01 and a mass-to-charge ratio (m / z) of 203.95 [M+H] + .

[0210] Step 6: LCT011003-6 (1.0 g, 4.93 mmol), tert-butyl 4-bromobutyrate (2.19 g, 9.86 mmol), K₂CO₃ (2.72 g, 19.7 mmol), and KI (3.27 g, 19.7 mmol) were dissolved in DMF (20.0 mL) and stirred at 60 °C under N₂ atmosphere for 16 h. The resulting mixture was diluted with H₂O (20.0 mL). The aqueous layer was extracted with EtOAc (20.0 mL × 3). The combined organic layers were washed with brine and dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE / EtOAc, 100:1 to 50:1) to give the product LCT011003-7 (i.e., intermediate XI-2, 1.2 g, 71% yield) as a yellow solid. Mass spectrometry (ESI): molecular formula C 19 H 20 ClNO3, with a molecular weight of 345.11 and a mass-to-charge ratio (m / z) of 346.20 [M+H] + .

[0211] Step 7: Dissolve LCT011003-7 (200 mg, 0.578 mmol) in a solution of TFA (4.00 mL), stir the mixture at 25 °C for 1 hour, and concentrate under reduced pressure. Prepare the residue in MeCN / MeOH, filter, and dry under vacuum to obtain product LCT011003 (127 mg, 74% yield). Mass spectrometry (ESI): Molecular formula is C 15 H 12 ClNO3, with a molecular weight of 289.05 and a mass-to-charge ratio (m / z) of 290.15 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ12.10(s,1H),8.34-8.29(m,1H),8.07(s,1H),7.63-7.58(m,2H) ,7.26-7.20(m,1H),3.91(t,J=6.8Hz,2H),2.31(t,J=7.2Hz,2H),1.92(p,J=7.2Hz,2H).

[0212] Example 3: Preparation method of compound LCT011007

[0213] Synthesize according to general formula synthesis route 3:

[0214]

[0215] Synthesis steps:

[0216] Compound LCT011007-1 (100 mg, 0.550 mmol) and 4-aminobutyric acid (59.6 mg, 0.578 mmol) were dissolved in AcOH (2.00 mL) and the mixture was stirred at 100 °C for 3 hours. After the reaction was complete, the reaction was rapidly cooled by adding H2O. The solution was then alkalized to pH 6-8 with 0.1 M sodium hydroxide aqueous solution. The precipitated solid was collected by filtration and washed with H2O to give compound LCT011007 (68.44 mg, 47% yield) as a white solid.

[0217] Mass spectrometry (ESI): Molecular formula is C 12 H 10 ClNO4, with a molecular weight of 267.03 and a mass-to-charge ratio (m / z) of 268.00 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ12.04(s,1H),7.86-7.76(m,3H),3.60(t,J=6.8Hz,2H),2.28(t,J=7.2Hz,2H),1.82(p,J=7.2Hz,2H).

[0218] Example 4: Preparation method of compound LCT011009

[0219] Synthesize according to general formula synthesis route 3:

[0220]

[0221] Synthesis steps:

[0222] Step 1: Sodium hydride (60%) (60 mg, 1.5 mmol) was suspended in THF (1.00 mL), and diethyl oxalate (175 mg, 1.19 mmol) and ethyl 4-phenylbutyrate (LCT011009-1, 192 mg, 0.998 mmol) were added. The mixture was stirred for 1.5 hours in an external bath at 80 °C. The reaction mixture was concentrated under reduced pressure, and methanesulfonic acid (1.00 mL) was added. The mixture was stirred for 1.5 hours in an external bath at 80 °C. Then, the mixture was stirred for 1 hour in an external bath at 120 °C. After completion, the reaction mixture was cooled and the precipitated crystals were collected by filtration. The crystals were then washed twice with ethanol (1.00 mL) and twice with water (1.00 mL), and then dried under reduced pressure to give the product LCT011009-2 (130 mg, 64% yield) as a yellow solid.

[0223] 1H NMR (400MHz, DMSO-d6) δ7.91-7.84(m,1H),7.49-7.42(m,1H),7.42-7.34(m,2H),3.04(t,J=8.4Hz,2H),2.70(t,J=8.4Hz,2H).

[0224] Step 2: LCT011009-2 (116 mg, 0.579 mmol) and 6-aminohexanoic acid (76.0 mg, 0.579 mmol) were dissolved in AcOH (4.00 mL) and reacted with stirring at 100 °C for 3 h. After the reaction was complete, the resulting mixture was concentrated under vacuum. The residue was purified by preparative HPLC (Gemini 5 μm C18 column, 150 × 21.2 mm, eluted with 30%–90% MeCN / H2O containing 0.1% NH3H2O) to obtain a yellow solid LCT011009 (34.4 mg, 18% yield).

[0225] Mass spectrometry (ESI): Molecular formula is C 18 H 19 NO4 has a molecular weight of 313.13 and a mass-to-charge ratio (m / z) of 312.25 [M+H]. + . 1 H NMR(400MHz,DMSO-d6)δ11.98(s,1H),7.96(d,J=7.2Hz,1H),7.38-7.29(m,3H),3.44(t,J=7.2Hz,2H),2 .98(t,J=8.4Hz,2H),2.61(t,J=8.4Hz,2H),2.19(t,J=7.2Hz,2H),1.56-1.47(m,4H),1.32-1.21(m,2H).

[0226] Example 5: Preparation method of compound LCT011012 and intermediate XII

[0227] Synthesize according to general synthetic route 1:

[0228]

[0229] Synthesis steps:

[0230] Step 1: Compound LCT011012-1 (500 mg, 3.40 mmol) was dissolved in THF (10 mL), and Boc2O (889 mg, 4.08 mmol) was added. The mixture was stirred at 70 °C for 2 hours. The reaction mixture was concentrated under vacuum, and the residue was purified by silica gel column chromatography (elution buffer PE / EtOAc = 100:0 to 50:50) to give compound LCT011012-2 (800 mg, 95% yield) as a white solid. Mass spectrometry (MS) (ESI): Molecular formula C 15 H 21 NO2 has a molecular weight of 247.16 and a mass-to-charge ratio (m / z) of 233.00 [M+H]. + .

[0231] Step 2: Under a nitrogen atmosphere, compound LCT011012-2 (700 mg, 2.29 mmol) was dissolved in THF (10 mL), and t-BμLi (1.3 mL, 5.3 mL, 6.88 mmol) was added. The mixture was stirred at -30 °C for 45 min, and then CO2 was introduced into the reaction system three times, followed by stirring at -30 °C for 45 min each time. The final mixture was quenched with H2O and washed three times with EtOAc. The pH of the aqueous solution was adjusted to 5-6 with 2N HCl. The precipitate was collected by filtration and washed with water to obtain compound LCT011012-3 (400 mg, 46% yield), a grayish-white solid. Mass spectrometry (ESI): Molecular formula C 16 H 21 NO4 has a molecular weight of 291.15 and a mass-to-charge ratio (m / z) of 290.05 [M+H]. + .

[0232] Step 3: Compound LCT011012-3 (380 mg, 1.24 mmol) was dissolved in TFA / DCM (1 / 2, 5.0 mL), stirred at 40 °C for 1 hour, and concentrated under reduced pressure. CDI (303 mg, 1.87 mmol) was added to the solution of the resulting solid in DCM (5.0 mL). The reaction mixture was stirred at room temperature for 2 hours. The mixture was concentrated under vacuum, and the residue was purified by silica gel column chromatography (eluent DCM / MeOH = 100:0 to 90:10) to give compound LCT011012-4 (180 mg, 83% yield) as a yellow solid.

[0233] 1H NMR (400MHz, DMSO-d6) δ10.11(s,1H),7.05(t,J=7.6Hz,1H),6.69(d,J=8.0Hz,1H),6.57(d,J=7.6Hz,1H),3.32-3.27(m,1H), 2.79(dd,J=17.2,7.4Hz,1H),2.61-2.52(m,1H),2.27-2.11(m,1H),2.06-1.94(m,1H),1.93-1.76(m,1H),1.23-1.14(m,1H).

[0234] Step 4: Compound LCT011012-4 (160 mg, 0.924 mmol), tert-butyl 4-bromobutyrate (206 mg, 0.924 mmol), and KI (613 mg, 3.69 mmol) were dissolved in DMF (2.0 mL), and K2CO3 (511 mg, 3.69 mmol) was added. The mixture was stirred at 60 °C for 16 hours. The resulting mixture was diluted with water (10 mL) and extracted with EtOAc (10 mL × 3). The combined organic phases were washed with brine, dried over sodium sulfate, concentrated, and purified by silica gel column chromatography (elution buffer PE / EtOAc = 100:0 to 50:50) to provide compound LCT011012-5 (i.e., intermediate XII, 100 mg, 34.33% yield) as a yellow solid. Mass spectrometry (MS) (ESI): Molecular formula C 19 H 25 NO3 has a molecular weight of 315.18 and a mass-to-charge ratio (m / z) of 316.00 [M+H]. + .

[0235] Step 5: Compound LCT011012-5 (100 mg, 0.317 mmol) was dissolved in TFA (1 mL) and stirred at room temperature for 1 h. The resulting mixture was concentrated by freeze-drying and prepared with MTBE to give compound LCT011012 (20.73 mg, 25.20% yield) as a yellow solid. Mass spectrometry (ESI): Molecular formula is C 15 H 17 NO3 has a molecular weight of 259.12 and a mass-to-charge ratio (m / z) of 259.95 [M+H]. + .

[0236] 1H NMR (400MHz, DMSO-d6) δ10.12(s,1H),7.06(t,J=7.6Hz,1H),6.73(d,J=7.6Hz,1H),6.61(d,J=7.6Hz,1H),2.83-2.73(m,1H),2.61-2.53(m ,1H),2.14-2.06(m,2H),2.06-1.98(m,1H),1.94-1.86(m,1H),1.77- 1.59(m,3H),1.44-1.32(m,1H),1.27-1.20(m,1H),1.19-1.06(m,2H).

[0237] Example 6: Preparation method of compound LCT011013 and intermediate XI-13

[0238] Synthesize according to general synthetic route 1:

[0239]

[0240] Synthesis steps:

[0241] Step 1: Compound LCT011013-1 (2.00 g, 10.6 mmol) and NBS (2.28 g, 12.8 mmol) were dissolved in concentrated H2SO4 (11 mL) and stirred at room temperature under N2 atmosphere for 16 hours. The reaction was monitored by LCMS. After completion, the reaction mixture was quenched by adding NaHCO3 aqueous solution (20 mL). The mixture was then poured into a separatory funnel and separated. The aqueous layer was extracted with EtOAc (20 mL × 3). The combined organic layers were washed with brine (20 mL), dried with Na2SO4, filtered, and concentrated on a rotary evaporator. The oily substance obtained by rapid column chromatography (PE / EtOAc = 2 / 1) gave compound LCT011013-2 (1.20 g, yield: 42%) as a yellow solid. Mass spectrometry (ESI): molecular formula C 11 H8BrNO2 has a molecular weight of 264.97 and a mass-to-charge ratio (m / z) of 266.05 [M+H]. + .

[0242] Step 2: Compound LCT011013-2 (1.10 g, 4.13 mmol) and KOH (2.32 g, 41.3 mmol) were dissolved in MeOH / H2O = 1 / 1 (12 mL), and stirred at 70 °C under N2 atmosphere for 3 hours. The reaction was monitored by LCMS. After completion, the reaction mixture was quenched by adding 4N HCl aqueous solution (10 mL). The mixture was then poured into a separatory funnel and separated. The aqueous layer was extracted with EtOAc (20 mL × 3). The combined organic layers were washed with brine (20 mL), dried with Na2SO4, filtered, and concentrated on a rotary evaporator to give compound LCT011013-3 (1.00 g, yield: 95%) as a yellow solid. Mass spectrometry (ESI): Molecular formula C 10 H6BrNO2, with a molecular weight of 250.96 and a mass-to-charge ratio (m / z) of 252.05 [M+H] + .

[0243] Step 3: Compound LCT011013-3 (900 mg, 3.57 mmol) and Cu (907 mg, 14.2 mmol) were dissolved in NH4OH (50 mL) and stirred at 80 °C under N2 atmosphere for 2 hours. Then, concentrated HCl (20 mL) was added to the reaction mixture, and the mixture was stirred at 90 °C under N2 atmosphere for 3 hours. The reaction was monitored by LCMS. After completion, the reaction mixture was purified on a Biotage Isolera One (C18 column, eluted with 30%-50% MeCN / H2O containing 0.1% NH4OH) to provide the product compound LCT011013-4 (400 mg, yield: 65%) as a yellow solid. Mass spectrometry (ESI): Molecular formula C 10 H6N2O, molecular weight 170.05, m / z 171.10 [m+H] + .

[0244] Step 4: Compound LCT011013-4 (350 mg, 2.05 mmol), tert-butyl 4-bromobutyrate (917 mg, 4.11 mmol), K₂CO₃ (1.13 g, 8.22 mmol), and KI (1.36 g, 8.22 mmol) were dissolved in DMF (10 mL) and stirred at 60 °C under N₂ atmosphere for 16 hours. The reaction was monitored by LCMS. After the reaction was complete, the reaction mixture was quenched by adding water (100 mL). The mixture was then poured into a separatory funnel and separated. The aqueous layer was extracted with EtOAc (100 mL × 3). The combined organic layers were washed with brine (100 mL), dried over Na₂SO₄, filtered, and concentrated on a rotary evaporator. The oily substance was purified by rapid column chromatography (PE / EtOAc = 5 / 1) to provide the compound LCT011013-5 (i.e., intermediate XI-13, 300 mg, yield: 46%) as a yellow solid. Mass spectrometry (ESI): molecular formula C 18 H 20 N₂O₃, with a molecular weight of 312.15 and an m / z of 313.25 [m+H] + .

[0245] Step 5: Under a nitrogen atmosphere, compound LCT011013-5 (200 mg, 0.640 mmol) was dissolved in TFA (4 mL) and stirred at room temperature for 2 hours. The reaction was monitored by LCMS. After completion, the reaction mixture was concentrated under vacuum. The residue was then purified to a yellow solid, product LCT011013 (100 mg, purity: 99.66%, yield: 60%), by preparative HPLC (Gemini 5 μm C18 column, 150 × 21.2 mm, eluted with 20%–30% MeCN / H2O containing 0.1% TFA). Mass spectrometry (ESI): Molecular formula is C 14 H 12 N₂O₃, with a molecular weight of 256.08 and an m / z of 257.05 [m+H] + .

[0246] 1 H NMR (400MHz, DMSO-d6) δ9.58(s,1H),9.12(s,1H),7.82(d,J=8.4Hz,1H),7.71(dd,J=8.4,7.2H z,1H),7.43(d,J=7.2Hz,1H),3.93(t,J=7.2Hz,2H),2.33(t,J=7.2Hz,2H),1.98-1.89(m,2H).

[0247] Example 7: Preparation method of compounds LCT011016, LCT011046, and intermediates XI-3 to XI-6

[0248] Synthesize according to general synthetic route 2:

[0249]

[0250] Synthesis steps:

[0251] Step 1: Compound LCT011046-1 (3.00 g, 12.3 mmol) and NH2OH HCl (0.849 g, 12.3 mol) were dissolved in pyridine (20.0 mL) and stirred at 116 °C for 1 h. The resulting mixture was then cooled to 80 °C, and TsCl (4.69 g, 24.6 mmol) was added in portions. The mixture was stirred at 116 °C for another 2 h. After completion, the mixture was poured into ice water. The precipitated solid was collected by filtration and washed with aqueous solutions of H2O and NaHCO3 to give the crude product LCT011046-2 (4.00 g, 79% yield) as a brown solid. Mass spectrometry (MS) (ESI): Molecular formula C 19 H 12 N₂O₇S, with a molecular weight of 412.04 and an m / z of 413.10 [m+H] + .

[0252] Step 2: While stirring, add NaOH (2.7 mL, 26.2 mmol, 9.70 mL) to an EtOH / H₂O (72 mL, 5:4) solution of LCT011046-2 (4.00 g, 9.71 mmol). The resulting mixture is stirred at 85 °C for 1 h. After stirring, the mixture is concentrated under vacuum to remove EtOH. The aqueous layer is heated to 75 °C and acidified with concentrated hydrochloric acid to pH = 1. The precipitated solid is collected by filtration and washed with H₂O to give crude products LCT011046-3a and LCT011046-3b (1.8 g, 87% yield) as yellow solids. The crude products are used directly in the next step without further purification. Mass spectrometry (ESI): Molecular formula C 11 H6N2O3, with a molecular weight of 214.04 and an m / z of 214.90 [m+H] + .

[0253] Step 3: LCT011046-3a, LCT011046-3b (1.00 g, 4.67 mmol), tert-butyl 4-bromobutyrate (2.1 g, 9.34 mmol), K₂CO₃ (2.58 g, 18.7 mmol), and KI (3.10 g, 18.7 mmol) were dissolved in DMF (10.0 mL), and the resulting mixture was diluted with H₂O (20.0 mL). The aqueous layer was extracted with EtOAc (20.0 mL × 3). The combined organic layers were washed with brine and dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure. The residues were purified by silica gel column chromatography (PE / EtOAc, 10:1 to 3:1) to give LCT011046-3a (i.e., intermediate XI-3) and LCT011046-3b (i.e., intermediate XI-4) as yellow solids. Mass spectrometry (ESI): Molecular formula is C 19 H 20 N₂O₅, with a molecular weight of 356.14 and an m / z of 301.00 [m+H] + .

[0254] Step 4: Under a H2 atmosphere, LCT011046-3a and LCT011046-3b (800 mg, 2.25 mmol), Pd / C (20 wt%, 160 mg), and EtOH / THF (1:1, 10.0 mL) were stirred for 16 h. After the reaction was complete, the mixture was filtered, and the filter cake was washed with THF. The filtrate was concentrated under reduced pressure to obtain crude products LCT011046-4a (intermediate XI-5) and LCT011046-4b (intermediate XI-6) as yellow solids. The crude products were used directly in the next step without further purification. Mass spectrometry (ESI): Molecular formula C 19 H 22 N₂O₃, with a molecular weight of 326.16 and an m / z of 327.00 [m+H] + .

[0255] Step 5: At 25°C, LCT011046-4a and LCT011046-4b (700 mg, 2.15 mmol) were dispersed in TFA (5.0 mL) and stirred for 2 h. After the reaction was complete, the resulting mixture was concentrated under reduced pressure. The crude product was purified by Prep SFC under the following conditions (Daicel Chiralpak IG SFC, 20 mm I.D. × 250 mL, 5 μm; CO2 / MeOH [0.1% NH3 (7 M MeOH solution), 60% / 40%, 48 mL / min), yielding peak 1 (LCT011046, 10.40 mg yellow solid) and peak 2 (LCT0110016, 40.05 mg).

[0256] LCT011046: Mass spectrometry (ESI): Molecular formula is C 15 H 14 N₂O₃, molecular weight 270.10, m / z 270.90 [M+H] + . 1 H NMR(400MHz, DMSO-d6)δ7.71(dd,J=6.8,1.6Hz,1H),7.58-7.50(m,2H),6.66(d,J=1.6Hz,1H),6.47 (d,J=1.6Hz,1H),5.73(s,2H),3.82(t,J=7.2Hz,3H),2.24(t,J=7.2Hz,2H),1.88(p,J=7.2Hz,2H).

[0257] LCT0110016: Mass spectrometry (ESI): Molecular formula is C 15 H 14 N₂O₃, molecular weight 270.10, m / z 270.95 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ7.39(d,J=1.6Hz,1H),7.36-7.29(m,1H),7.27(d,J=8.4Hz,1H),7.07(d,J=1.6Hz ,1H),6.83(d,J=6.8Hz,1H),5.79(s,2H),3.82(t,J=7.2Hz,2H),2.24(t,J=7.2Hz,2H),1.92-1.81(m,2H).

[0258] Example 8: Preparation method of compound LCT011018

[0259] Synthesize according to general synthetic route 1:

[0260]

[0261] Synthetic steps: Benzo[cd]indol-2(1H)-one (300 mg, 1.77 mmol), 4-chlorobutyramide (323 mg, 2.66 mmol), and Cs₂CO₃ (1.73 g, 5.32 mmol) were dissolved in DMF (10 mL) and stirred at 120 °C for 16 hours. The mixture was then cooled to room temperature. The resulting mixture was diluted with H₂O (20 mL). The aqueous layer was extracted with EtOAc (20 mL × 3). The combined organic layers were concentrated under reduced pressure. The residue was purified by preparative HPLC (ACN in water, containing 0.1% FA, with a gradient of 20%–70% over 9 min) to give LCT011018 (37.0 mg, 8.15% yield) as a yellow solid.

[0262] Mass spectrometry (ESI): Molecular formula is C 15 H 14 N₂O₂, molecular weight 254.11, m / z 255.10 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ8.19(d,J=8.0Hz,1H),8.05(d,J=6.8Hz,1H),7.85-7.77(m,1H),7.65(d,J=8.4Hz,1H),7.60-7.53( m,1H),7.27(s,1H),7.21(d,J=7.2Hz,1H),6.74(s,1H),3.90(t,J=7.2Hz,2H),2.14(t,J=7.2Hz,2H),1.92(p,J=7.2Hz,2H).

[0263] Example 9: Preparation method of compound LCT011022, intermediate XI-14, and intermediate XI-15

[0264] Synthesize according to general synthetic route 5:

[0265]

[0266]

[0267] Synthesis steps:

[0268] Step 1: Compound LCT011000-1 (1.00 g, 5.91 mmol), 3-bromoprop-1-ene (1.43 g, 11.8 mmol), K₂CO₃ (3.26 g, 23.6 mmol), and KI (3.92 g, 23.6 mmol) were dissolved in DMF (20 mL) and stirred at 60 °C under N₂ atmosphere for 16 h. The reaction was monitored by LCMS. After completion, the reaction mixture was quenched by adding water (200 mL). The mixture was then poured into a separatory funnel and separated. The aqueous layer was extracted with EtOAc (200 mL × 3). The combined organic layers were washed with brine (200 mL), dried over Na₂SO₄, filtered, and concentrated on a rotary evaporator. The oily substance obtained by rapid column chromatography (PE / EtOAc = 5 / 1) yielded compound LCT011022-2 (i.e., intermediate XI-14, 600 mg, yield: 48%), a yellow solid. Mass spectrometry (ESI) showed the molecular formula as C1. 14 H 11 NO, molecular weight 209.08, m / z 210.15 [m+H] + .

[0269] Step 2: Compound LCT011022-2 (500 mg, 2.39 mmol) and m-CPBA (1.65 g, 9.55 mmol) were dissolved in DCM (10 mL) and stirred at room temperature under N2 atmosphere for 16 hours. The reaction was monitored by LCMS. After completion, the reaction mixture was quenched by adding NaHCO3 aqueous solution (20 mL). The mixture was then poured into a separatory funnel and separated. The aqueous layer was extracted with DCM (20 mL × 3). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, filtered, and concentrated on a rotary evaporator. The oily compound LCT011022-3 (i.e., intermediate XI-15, 200 mg, yield: 37%) was purified by rapid column chromatography (PE / EtOAc = 2 / 1) as a yellow solid. Mass spectrometry (ESI): molecular formula C 14 H 11 NO2 has a molecular weight of 225.08 and an m / z of 226.15 [m+H]. + .

[0270] Step 3: Compound LCT011022-3 (200 mg, 0.888 mmol), methyl 1-(methylamino)cyclopentan-1-carboxylate (167 mg, 1.06 mmol), and K2CO3 (368 mg, 2.66 mmol) were dissolved in iPrOH (4 mL) and reacted at 80 °C for 16 h under a N2 atmosphere with stirring. The reaction was monitored by LCMS. After completion, the reaction mixture was concentrated under vacuum. The residue was then purified to LCT011022 (9.45 mg, purity: 99.30%, yield: 2%) as a yellow solid by preparative HPLC (Gemini 5 μm C18 column, 150 × 21.2 mm, eluted with 20%-30% MeCN / H2O containing 0.1% TFA) using MS (ESI). 21 H 24 N₂O₄, molecular weight 368.17, m / z 369.10 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ8.18(d,J=8.0Hz,1H),8.04(d,J=6.8Hz,1H),7.80(dd,J=8.0,6.8Hz,1H),7.63(d,J=8.4Hz,1H),7.55(dd,J=8.4,6.8Hz,1H), 7.18(d,J=6.8Hz,1H),4.04-3.93(m,3H),3.79-3.70(m,1H),2.68-2.55(m, 4H),2.34(s,2H),2.12-1.99(m,1H),1.71-1.59(m,4H),1.58-1.47(m,1H).

[0271] Example 10: Preparation method of compounds LCT011024, LCT011047, and intermediates XI-7 to XI-10

[0272] Synthesize according to general synthetic route 5:

[0273]

[0274] Synthesis steps:

[0275] Step 1: Compound LCT011024-1 (500 mg, 1.80 mmol) and NH2OH HCl (125 mg, 1.80 mmol) were dissolved in pyridine (5 mL) and stirred at 120 °C under N2 atmosphere for 1 hour. The reaction was then cooled to 80 °C and TcCl (688 mg, 3.61 mmol) was added. The reaction mixture was stirred at 80 °C under N2 atmosphere for 2 hours. The reaction was monitored by LCMS. After completion, the reaction mixture was quenched by adding H2O (20 mL). The mixture was then poured into a separatory funnel and separated. The aqueous layer was extracted with EtOAc (20 mL × 3). The combined organic layers were washed with brine (20 mL), dried with Na2SO4, filtered, and concentrated on a rotary evaporator to give compound LCT011024-2 (500 mg, yield: 62%) as a yellow solid. Mass spectrometry (ESI): Molecular formula C 19 H 12 BrNO5S, with a molecular weight of 444.96 and an m / z of 446.10 [m+H] + .

[0276] Step 2: Compound LCT011024-2 (500 mg, 1.12 mmol) and NaOH (134 mg, 3.36 mmol) were dissolved in EtOH / H2O = 1 / 1 (10 mL), and stirred at 80 °C under N2 atmosphere for 1 hour. The reaction was monitored by LCMS. After completion, the reaction mixture was quenched by adding 4N HCl aqueous solution (10 mL). The mixture was then poured into a separatory funnel and separated. The aqueous layer was extracted with EtOAc (20 mL × 3). The combined organic layers were washed with brine (20 mL), dried with Na2SO4, filtered, and concentrated on a rotary evaporator to provide compounds LCT011024-3a and LCT011024-3b (300 mg crude), as yellow solids. Mass spectrometry (ESI): Molecular formula C 11 H6BrNO, with a molecular weight of 246.96 and an m / z of 248.00 [m+H] + .

[0277] Step 3: Compounds LCT011024-3a, LCT011024-3b (250 mg, 1.00 mmol), tert-butyl 4-bromobutyrate (449 mg, 2.01 mmol), K₂CO₃ (557 mg, 4.03 mmol), and KI (669 mg, 4.03 mmol) were dispersed in DMF (50 mL) and stirred at 60 °C for 16 h under a N₂ atmosphere. The reaction was monitored by LCMS. After completion, the reaction mixture was quenched by adding water (50 mL). The mixture was then poured into a separatory funnel and separated. The aqueous layer was extracted with EtOAc (50 mL × 3). The combined organic layers were washed with brine (50 mL), dried over Na₂SO₄, filtered, and concentrated on a rotary evaporator. The oily substance obtained by rapid column chromatography (PE / EtOAc = 5 / 1) was used to provide compounds LCT011024-4a (i.e., intermediate XI-7) and LCT011024-4b (i.e., intermediate XI-8). Mass spectrometry (ESI): Molecular formula C 19 H 20 BrNO3, with a molecular weight of 389.06 and an m / z of 390.15 [m+H] + .

[0278] Step 4: Under a nitrogen atmosphere, compounds LCT011024-4a, LCT011024-4b (300 mg, 0.768 mmol), phenylboronic acid (140 mg, 0.15 mmol), Pd(PPh3)4 (88.8 mg, 0.0768 mmol), and K2CO3 (318 mg, 2.30 mmol) were dispersed in a 1,4-dioxane / H2O = 5 / 1 (6 mL) mixture and stirred at 90 °C for 16 h under a nitrogen atmosphere. The reaction was monitored by LCMS. After completion, the reaction mixture was quenched by adding water (10 mL). The mixture was then poured into a separatory funnel and separated. The aqueous layer was extracted with EtOAc (20 mL × 3). The combined organic layers were washed with brine (10 mL), dried over Na2SO4, filtered, and concentrated on a rotary evaporator. The obtained oil was purified by rapid column chromatography (PE / EtOAc = 2 / 1) and by SFC purification (column: Torus 2-PIC 20×250mm, 5μm; mobile phase: CO2 / MeOH (0.1% NH3) = 70 / 30) to provide compounds LCT011024-5a (i.e., intermediate XI-9, peak 2, 100mg) and LCT011024-5b (i.e., intermediate XI-10, peak 1, 90mg). Mass spectrometry (ESI): molecular formula C 25 H 25 NO3 has a molecular weight of 387.18 and an m / z of 388.35 [m+H]. + .

[0279] Step 5: Under a nitrogen atmosphere, LCT011024-5a (100 mg, 0.258 mmol) was dissolved in TFA (2 mL) and stirred at room temperature for 2 hours. The reaction was monitored by LCMS. After completion, the reaction mixture was concentrated under vacuum to give compound LCT011024 (63.62 mg, purity: 99.29%, yield: 73%) as a yellow solid. Mass spectrometry (ESI): Molecular formula is C 21 H 17 NO3 has a molecular weight of 331.12 and an m / z of 332.05 [m+H]. + . 1 H NMR(400MHz, DMSO-d6)δ12.12(s,1H),8.13(dd,J=10.8,7.6Hz,2H),7.84(t,J=7.6Hz,1H),7.62-7.51(m,5H), 7.50-7.44(m,1H),7.31(d,J=7.2Hz,1H),3.96(t,J=7.2Hz,2H),2.34(t,J=7.2Hz,1H),1.96(p,J=7.2Hz,2H).

[0280] LCT011024-5b (90 mg, 0.232 mmol) was dissolved in TFA (2 mL) and stirred at room temperature under N2 atmosphere for 2 h. The reaction was monitored by LCMS. After completion, the reaction mixture was concentrated under vacuum to provide compound LCT011047 (58.18 mg, purity: 99.17%, yield: 74%) as a yellow solid. Mass spectrometry (ESI): molecular formula C 21 H 17 NO3, molecular weight 331.12, m / z 332.10 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ12.11(s,1H),8.12(d,J=7.2Hz,1H),7.78(d,J=7.2Hz,1H),7.66-7.56(m,6H),7.5 6-7.51(m,1H),7.26(d,J=6.4Hz,1H),3.95(t,J=6.8Hz,2H),2.32(d,J=7.2Hz,1H),1.95(p,J=7.2Hz,2H).

[0281] Example 11 Preparation method of compound LCT011026

[0282] Synthesize according to general synthetic route 5:

[0283]

[0284] Synthesis steps:

[0285] Step 1: While stirring, 50% T4P (14.5 g, 20.2 mmol) and TEA (4.10 g, 40.5 mmol) were added to a DCM (60.0 mL) solution of compound 1 (3.00 g, 13.5 mmol) and pyridinecarboxylic acid (1.83 g, 14.8 mmol). The resulting mixture was stirred at 25 °C for 16 hours. After completion, the mixture was concentrated under vacuum. The residue was purified by silica gel column chromatography (PE / EtOAc, 1:10) to give compound 2 (3.50 g, 78% yield) as a brown solid. Mass spectrometry (ESI): Molecular formula C 16 H 11 BrN₂O, with a molecular weight of 326.01 and an m / z of 326.90 [m+H] + .

[0286] Step 2: Under a nitrogen atmosphere, compound 2 (1.00 g, 3.10 mmol), isopropyl carbonate (1.14 g, 9.30 mmol), NaOAc (0.510 g, 6.20 mmol), NaI (0.460 g, 3.10 mmol), and Pd(OAc)₂ (0.140 g, 0.620 mmol) were dissolved in toluene (20.0 mL) and stirred at 135 °C for 6 h. After completion, the resulting mixture was concentrated under vacuum. The residue was purified by silica gel column chromatography (PE / EtOAc, 1:10) to give compound 3 (360 mg, 29% yield) as a yellow oil. Mass spectrometry (MS / ESI): molecular formula C 20 H 17 BrN₂O₃, with a molecular weight of 412.04 and an m / z of 412.80 [m+H] + .

[0287] Step 3: Add NaOH (0.190 g, 4.65 mmol) to a solution of compound 3 (1.27 g, 3.10 mmol) in 25.0 mL of EtOH. Stir the resulting mixture at 80 °C for 1 hour. After completion, alkalize the mixture to pH 7 with a 10% aqueous HCl solution. Extract the aqueous layer with EtOAc. Wash the combined organic layers with brine and dry with anhydrous Na₂SO₄. Filter and concentrate the filtrate under reduced pressure. Purify the residue by silica gel column chromatography (PE / EtOAc, 3:1) to give compound 4 (700 mg, 90% yield) as a yellow solid. Mass spectrometry (ESI): Molecular formula C 11 H6BrNO.

[0288] Step 4: Compound 4 (500 mg, 2.01 mmol) was dissolved in DMF (10.0 mL), and tert-butyl 4-bromobutyrate (674 mg, 3.02 mmol), K₂CO₃ (835 mg, 6.04 mmol), and KI (334 mg, 2.0 mmol) were added. The mixture was stirred at 50 °C for 2 hours. After completion, the resulting mixture was diluted with H₂O (100 mL). The aqueous layer was extracted with EtOAc (20.0 mL × 3). The combined organic layers were washed with brine and dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE / EtOAc, 3:1 to 1:1) to give the product compound 5 (800 mg, 96% yield) as a yellow solid. Mass spectrometry (ESI): molecular formula C 19 H 20 BrNO3, with a molecular weight of 389.06 and an m / z of 334.10 [mt-Bu] + .

[0289] Step 5: Compound 5 (200 g, 0.512 mmol), ZnCN2 (78.2 mg, 0.666 mmol), and Pd(PPh3)4 (118 mg, 0.102 mmol) were dissolved in DMF (4.00 mL) and stirred at 80 °C under N2 for 2 h. After completion, the resulting mixture was diluted with H2O (40 mL). The aqueous layer was extracted with EtOAc (10.0 mL × 3). The combined organic layers were washed with brine and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE / EtOAc, 3:1 to 1:1) to give the product compound 6 (180 mg, 99% yield) as a yellow solid. Mass spectrometry (ESI): molecular formula C 20 H 20 N₂O₃, with a molecular weight of 336.15 and an m / z of 280.95 [mt-Bu] + .

[0290] Step 6: Compound 6 (240 mg, 0.713 mmol) was dissolved in TFA (5 mL) and stirred at 25 °C for 1 h. The combined organic phases were concentrated under vacuum and purified by preparative HPLC (Gemini 5 μm C18 column, 150 × 21.2 mm, eluted with 30%–90% MeCN / H2O containing 0.1% NH3H2O) to give the product LCT011026 (83.4 g, yield 41%) as a yellow solid. Mass spectrometry (ESI): Molecular formula is C 16 H 12 N₂O₃, with a molecular weight of 280.08 and an m / z of 281.25 [m+H] + .

[0291] 1 H NMR (400MHz, DMSO-d6) δ8.37(d,J=7.2Hz,1H),8.16(d,J=7.2Hz,1H),7.82-7.72(m,1H),7.65(d,J= 8.8Hz,1H),7.36(d,J=7.2Hz,1H),3.90(t,J=7.2Hz,2H),2.24(t,J=7.2Hz,2H),1.96-1.84(m,2H).

[0292] Example 12 Preparation method of compound LCT011027

[0293] Synthesize according to general synthetic route 5:

[0294]

[0295] Synthesis steps:

[0296] Step 1: Compound 1 (200 mg, 0.512 mmol), tert-butyl 3-(trifluoro-4-boryl)azacyclobutane-1-carboxylic acid, potassium salt (203 mg, 0.768 mmol), Pd(dppf)Cl2 (37.5 mg, 0.0512 mmol), and Cs2CO3 (501 mg, 1.53 mmol) were added to a toluene / H2O = 5 / 1 (2.4 mL) mixture and stirred at 80 °C for 16 h under a N2 atmosphere. The reaction was monitored by LCMS. After completion, the reaction mixture was quenched by adding water (10 mL). The mixture was then poured into a separatory funnel and separated. The aqueous layer was extracted with EtOAc (20 mL × 3). The combined organic layers were washed with brine (10 mL), dried over Na2SO4, filtered, and concentrated on a rotary evaporator. The oily compound 2 (200 mg, yield: 83%) was purified by rapid column chromatography (PE / EtOAc = 2 / 1) as a yellow solid. Mass spectrometry (ESI): molecular formula C 27 H 34 N₂O₅, with a molecular weight of 466.25 and an m / z of 467.45 [m+H] + .

[0297] Step 2: Compound 2 (200 mg, 0.427 mmol) was dissolved in TFA (4 mL) and stirred at room temperature for 2 hours under N2 atmosphere. The reaction was monitored by LCMS. After completion, the reaction mixture was concentrated under vacuum. The residue was then purified to the product LCT011027 (77.25 mg, purity: 99.91%, yield: 58%) as a yellow solid by preparative HPLC (Gemini 5 μm C18 column, 150 × 21.2 mm, eluted with 20%–30% MeCN / H2O containing 0.1% TFA). Mass spectrometry (ESI): molecular formula C 18 H 18 N₂O₃, with a molecular weight of 310.13 and an m / z of 311.10 [m+H] + . 1 H NMR (400MHz, DMSO-d6) δ12.13(s,1H),8.11(d,J=7.2Hz,1H),7.86(d,J=7.2Hz,1H),7.62-7.53(m,2H),7.25(d,J=6.8Hz,1H),4.87( p,J=8.8Hz,1H),4.53(t,J=10.0Hz,2H),4.32(t,J=9.6Hz,2H),3.91(t,J=7.2Hz,2H),2.30(t,J=7.2Hz,2H),1.92(p,J=7.2Hz,2H).

[0298] Example 13 Preparation method of compound LCT011028

[0299] Synthesize according to general synthetic route 5:

[0300]

[0301] Synthesis steps:

[0302] Step 1: Compound 1 (900 mg, 4.49 mmol) was dissolved in DCM (10 mL), and DMP (3.81 g, 8.99 mmol) was added. The reaction mixture was stirred at room temperature for 2 hours. The mixture was concentrated under vacuum, and the residue was purified by silica gel column chromatography (elution buffer PE / EtOAc = 100:0 to 50:50) to give compound 2 (880 mg, 98.77% yield) as a white solid. 1 H NMR (400MHz, DMSO-d6) δ7.23(d,J=7.6Hz,1H),6.10(dt,J=10.4,2.2Hz,1H),4.18(s,2H),4.01(s,2H),1.42(s,9H).

[0303] Step 2: Compound 2 (880 mg, 4.44 mmol) and anthracene (1.19 g, 6.66 mmol) were dissolved in toluene (10 mL), and AlCl3 (88.8 mg, 0.666 mmol) was added. The reaction mixture was stirred at 110 °C for 24 hours. The mixture was concentrated under vacuum, and the residue was purified by silica gel column chromatography (eluent DCM / MeOH = 100:0 to 90:10) to give compound 3 (100 mg, 6% yield) as a white solid. 1 H NMR(400MHz,DMSO-d6)δ7.43-7.31(m,9H),7.28-7.23(m,1H),7.20-7.15(m,1H),7.13-7.08(m,2H),7.08-7.03(m,2H),4.76(d, J=2.4Hz,1H),4.27(s,1H),3.27-3.20(m,2H),2.73-2.64(m,1H),2.64-2.56(m,1H),2.43-2.39(m,1H),1.60(t,J=12.0Hz,1H).

[0304] Step 3: Compound 3 (100 mg, 0.392 mmol), 4-(2-oxobenzo[cd]indol-1(2H)-yl)butyric acid (108 mg, 0.392 mmol), and HOBt (52.9 mg, 0.392 mmol) were dissolved in DCM (2.0 mL), and DCC (88.9 mg, 0.431 mmol) was added. The reaction mixture was stirred at room temperature for 3 hours. The mixture was concentrated under vacuum, and the residue was purified by preparative HPLC (Gemini 5 μm C18 column, 150 × 21.2 mm, eluted with 50%–80% MeCN / H2O (containing 0.1% FA)) to give compound LCT011028 as a yellow solid (68.1 mg, 34% yield).

[0305] Mass spectrometry (ESI): Molecular formula is C 34 H 28 N₂O₃, molecular weight 512.21, m / z 513.20 [M+H] + . 1H NMR(400MHz, DMSO-d6)δ8.16(t,J=8.0Hz,1H),7.95-7.81(m,1H),7.81-7.70(m,1H),7. 61-7.53(m,1H),7.52-7.46(m,1H),7.43-7.37(m,1H),7.35-7.11(m,6H),7.07-7.01(m, 1H),7.00-6.90(m,1H),4.80-4.68(m,1H),4.45-4.31(m,1H),4.28-4.20(m,1H),4.14-3 .80(m,3H),2.96-2.80(m,1H),2.65-2.52(m,1H),2.45-2.37(m,2H),2.11-1.79(m,4H).

[0306] Example 14 Preparation method of compound LCT011029

[0307] Synthesize according to general formula synthesis route 6:

[0308]

[0309] Synthesis steps:

[0310] Step 1: Compound 1 (5.00 g, 28.06 mmol) was dissolved in EtOH (32.50 mL) and H2O (32.50 mL), and TMSCN (4.20 g, 42.33 mmol) and (NH4)2CO3 (18.9 g, 196.96 mmol) were added. The mixture was stirred overnight at 60 °C. After cooling the reaction mixture to room temperature, it was poured into water (300 mL). The mixture was stirred for another 2 hours and filtered. The filtrate was concentrated under reduced pressure to give compound 2 (5.70 g, 81.94% yield) as a white solid. Mass spectrometry (ESI): Molecular formula C 12 H 12 N₂O₄, with a molecular weight of 248.08 and an m / z of 249.09 [M+H] + .

[0311] Step 2: Compound 2 (2.00 g, 8.06 mmol), tert-butyl bromoacetate (1.80 g, 9.23 mmol), and K₂CO₃ (2.3 g, 16.64 mmol) were added to DMF (20 mL). The reaction mixture was stirred at room temperature for 3 hours. The reaction was quenched with water (200 mL), extracted with ethyl acetate (70 mL × 3), the combined organic layers were washed with brine, dried over MgSO₄, and concentrated under reduced pressure to give compound 3 (2.30 g, 78.76% yield) as a white solid. Mass spectrometry (MS) (ESI): Molecular formula C18 H 22 N₂O₆, with a molecular weight of 362.15 and an m / z of 363.15 [m+H] + .

[0312] Step 3: Compound 3 (2.30 g, 9.27 mmol) was added to 4N HCl / dioxane (25 mL). The reaction mixture was stirred at room temperature for 24 hours. The mixture was filtered, and the filtrate was concentrated under reduced pressure to give compound 4 (1.60 g, 82.30% yield), a white solid. Mass spectrometry (MS / ESI): Molecular formula C 14 H 14 N₂O₆, with a molecular weight of 306.09 and an m / z of 307.09 [m+H] + .

[0313] Step 4: 60% NaH (237 mg, 5.92 mmol) was added to a DMF (5.0 mL) solution of compound 4 (500 mg, 2.96 mmol) at 0 °C, and the reaction mixture was stirred at 0 °C for 15 min. Tert-butyl (4-bromobutyl)carbamate (896 mg, 3.55 mmol) was added. The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was quenched with water (50 mL), extracted with ethyl acetate (50 mL × 3), the combined organic layers were washed with brine, dried over MgSO4, and concentrated under reduced pressure to give compound 5 (1.00 g, 99.39% yield) as a yellow solid. Mass spectrometry (MS) (ESI): Molecular formula C 20 H 24 N₂O₃, with a molecular weight of 340.18 and an m / z of 341.20 [m+H] + .

[0314] Step 5: Compound 5 (1.00 g, 2.94 mmol) and 4N HCl / EA (5 mg) were added to ethyl acetate (5 mL). The reaction mixture was stirred at room temperature for 1 hour. The mixture was filtered, and the filtrate was concentrated under reduced pressure to give a yellow solid, compound 6 (250.00 mg, yield 30.67%). Mass spectrometry (ESI): Molecular formula C 15 H 17 ClN₂O mass spectrometry (ESI): Molecular formula 276.10, m / z 277.10 [m-HCl+H] + .

[0315] Step 6: Compound 6 (304 mg, 0.99 mmol), 1-(4-aminobutyl)benzo[cd]indole-2(1H)-one hydrochloride (250 mg, 0.93 mmol), HOBt (134 mg, 0.99 mol), triethylamine (235 mg, 2.33 mmol), and EDCI (190 mg, 0.99 mmol) were added to DCM (5.0 mL). The reaction mixture was stirred at room temperature for 3 hours. The mixture was concentrated under vacuum and eluted by preparative HPLC (Gemini 5 μm C18 column, 150 × 21.2 mm, eluting with 10%–90% MeCN / H2O (containing 0.1% TFA)) to give compound LCT011029 (300.00 mg, yield 57.36%) as a yellow solid. Mass spectrometry (ESI): molecular formula C 29 H 28 N4O6, molecular weight 528.20, m / z 529.20 [M+H] + .

[0316] 1 H NMR(400MHz, DMSO-d6)δ8.81(s,1H),8.20-8.28(d,J=8.0Hz,1H),8.11-8.09(m,2H,) ,7.83-7.80(t,J=7.6Hz,1H),7.66-7.63(t,J=7.8Hz,1H),7.57-7.53(m,1H),7.23-7. 21(d,J=7.2Hz,1H),6.98-6.94(m,2H),6.86-6.84(d,J=8.4Hz,1H),4.23(s,4H),3.9 4-3.89(m,4H),3.13-3.09(m,2H),1.75-1.63(m,2H),1.63(s,3H),1.50-1.43(m,2H).

[0317] Example 15: Preparation method of compound LCT011030

[0318] Synthesize according to general formula synthesis route 6:

[0319]

[0320] Synthesis steps:

[0321] Step 1: Compound 1 (560 mg, 3.21 mmol) was dissolved in EtOH (10 mL), and sodium acetate (2.64 g, 32.1 mmol) and hydroxylamine hydrochloride (1.12 g, 16.1 mmol) were added. The mixture was stirred at 40 °C for 16 hours. The final mixture was quenched with HCl (2 m, 6 mL) and extracted with EtOAc. The combined organic layers were dried over sodium sulfate and evaporated. The obtained compound 2 (600 mg, 98.6% yield) was used without further purification. Mass spectrometry (MS) (ESI): Molecular formula C 12 H 15 NO, molecular weight 189.12, m / z 190.20 [m+H] + .

[0322] Step 2: Compound 2 (600 mg, 3.17 mmol) was dissolved in MeOH (15 mL), and NH4Cl (848 mg, 15.8 mmol) and zinc powder (1.04 g, 15.8 mol) were added. The mixture was stirred at 60 °C for 16 hours. The precipitate was filtered off, and the solution was concentrated under reduced pressure. The residue was extracted with ethyl acetate and ammonia solution. The combined organic layers were dried over sodium sulfate and evaporated. The obtained pale yellow oily crude product, compound 3 (400 mg, 72.0% yield), was used without further purification. Mass spectrometry (MS) (ESI): Molecular formula C 12 H 17 N, with a molecular weight of 175.14 and an m / z of 159.15 [m-NH2] + .

[0323] Step 3: Under a N2 atmosphere and at 0 °C, HOBt (79.4 mg, 0.587 mmol) and DCC (133 mg, 0.646 mmol) were added to a DCM (3 mL) solution of 4-(2-oxobenzo[cd]indol-1(2H)-yl)butyric acid (150 mg, 0.587 mmol). The mixture was stirred at the same temperature for 0.5 h while slowly heating to room temperature. Compound 3 (103 mg, 0.587 mmol) was added to the solution and stirred at room temperature for 2 h. The mixture was filtered through diatomaceous earth. The filtrate was concentrated and purified by silica gel column chromatography (eluting with PE / EtOAc = 2 / 1) to give the yellow solid product LCT011030 (37.6 mg, 16% yield).

[0324] Mass spectrometry (ESI): Molecular formula is C 27 H 28 N₂O₂, molecular weight 412.22, m / z 413.20 [M+H] + . 1H NMR (400MHz, DMSO-d6) δ8.24-8.13(m,2H),8.05(d,J=7.2Hz,1H),7.81(dd,J=8.0 ,7.2Hz,1H),7.64(d,J=8.4Hz,1H),7.53(dd,J=8.4,7.2Hz,1H),7.14(d,J=7.2Hz, 1H),6.99-6.91(m,3H),4.87-4.73(m,1H),3.88(t,J=6.8Hz,1H),2.70-2.59(m,2H ),2.22-2.12(m,1H),1.97-1.85(m,1H),1.72-1.64(m,2H),1.26(d,J=6.8Hz,2H).

[0325] Example 16: Preparation method of compound LCT011045 and intermediate XI-16

[0326] Synthesize according to general formula synthesis route 6:

[0327]

[0328] Synthesis steps:

[0329] Step 1: Add Boc₂O (3.64 g, 16.6 mmol), TEA (4.21 g, 41.7 mmol), and DMAP (169 mg, 1.39 mmol) to a DCM (20.0 mL) solution of compound 1 (2.00 g, 13.9 mmol). Stir the mixture at room temperature for 16 hours. After completion, dilute the resulting mixture with water (50 mL) and extract with EtOAc (10 mL × 3). Wash the combined organic phases with brine, dry with sodium sulfate, concentrate, and purify by silica gel column chromatography (eluting with EtOAc / PE, 0%–50%) to give compound 2 (2.70 g, 79% yield) as a colorless oil. Mass spectrometry (ESI): Molecular formula C 12 H 21 NO4, with a molecular weight of 243.15 and an m / z of 188.1 [M- t Bu+H] + .

[0330] Step 2: Under a nitrogen atmosphere at 0°C, compound 2 (2.51 g, 10.3 mmol) was dissolved in dry DMF (50.0 mL), and 60% NaH (0.450 g, 11.3 mmol) was added. After addition, the solution was stirred at room temperature for 30 min. Then, MeI (1.61 g, 11.3 mmol) was added dropwise. The resulting solution was slowly heated to room temperature and stirred for 1 hour. After completion, the mixture was diluted with water (50 mL) and extracted with EtOAc (50 mL × 3). The combined organic phases were washed with brine, dried over sodium sulfate, concentrated, and purified by silica gel column chromatography (eluting with EtOAc / PE, 0%–50%) to give compound 3 (2.3 g, 85% yield) as a colorless oil. Mass spectrometry (ESI): molecular formula C 13 H 23 NO4 has a molecular weight of 257.16 and an m / z of 279.95 [m+Na]. + .

[0331] Step 3: Compound 3 (2.2 g, 8.50 mmol) was dissolved in a HCl dioxane solution (4 m, 20.0 mL) and stirred at room temperature for 1 hour. The mixture was concentrated under reduced pressure. The residue was prepared in hexane / DCM, filtered, and dried under vacuum to give compound 4 (1.7 g, 97% yield). Mass spectrometry (MS / ESI): Molecular formula C8H 15 NO2 has a molecular weight of 157.11 and an m / z of 157.90 [m+H]. + .

[0332] Step 4: Compound 5 (1.00 g, 5.90 mmol) was dissolved in DMF (10 mL), and 1,3-dibromopropane (5.96 g, 29.5 mmol), K₂CO₃ (1.22 g, 8.8 mmol), and KI (0.490 g, 2.95 mmol) were added. The mixture was heated at 50 °C for 16 hours. After completion, the resulting mixture was diluted with water (100 mL) and extracted with EtOAc (20 mL × 3). The combined organic phases were washed with brine, dried over sodium sulfate, concentrated, and purified by silica gel column chromatography (eluting with EtOAc / PE, 0%–50%) to give compound 6 (i.e., intermediate XI-16, 600 mg, yield 35%) as a yellow solid.

[0333] Mass spectrometry (ESI): Molecular formula is C 14 H 12 BrNO, with a molecular weight of 289.01 and an m / z of 289.80 [m+H] + .

[0334] Step 5: Compound 4 (693 mg, 4.41 mmol), K₂CO₃ (1.21 g, 8.82 mmol), and KI (1.46 g, 8.82 mmol) were added to a solution of compound 6 (640 mg, 2.20 mmol) in DMF (13 mL). The mixture was heated at 50 °C for 16 hours. After completion, the resulting mixture was diluted with water (130 mL) and extracted with EtOAc (20 mL × 3). The combined organic phases were washed with brine, dried over sodium sulfate, concentrated, and purified by silica gel column chromatography (eluting with EtOAc / PE, 0%–50%) to give compound 7 (480 mg, 59% yield) as a yellow oil. Mass spectrometry (ESI): molecular formula C 22 H 26 N₂O₃, with a molecular weight of 366.19 and an m / z of 367.30 [m+H] + .

[0335] Step 6: Compound 7 (200 mg, 0.545 mmol) was dissolved in MeOH / H2O = 1 / 1 (4.00 mL), and LiOH (52.4 mg, 2.18 mmol) was added. The resulting mixture was stirred at 70 °C for 16 hours. After completion, the combined organic phases were washed with water and brine, dried over sodium sulfate, concentrated under vacuum, and purified by preparative HPLC (Gemini 5 μm C18 column, 150 × 21.2 mm, eluted with 30%–90% MeCN / H2O containing 0.1% NH3H2O) to give the product compound LCT011045 (50.7 mg, 24% yield) as a yellow solid.

[0336] Mass spectrometry (ESI): Molecular formula is C 21 H 24 N₂O₃, molecular weight 352.18, m / z 353.25 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ8.18(d,J=8.0Hz,1H),8.04(d,J=6.8Hz,1H),7.80(dd,J=8.0,7.2Hz,1H),7.63(d,J=8.4Hz,1H),7.58-7.52(m,1H),7.18 (d,J=6.8Hz,1H),3.90-3.83(m,2H),2.58-2.53(m,2H),2.20(s,3H),2.1 5-2.04(m,2H),1.82-1.73(m,2H),1.53-1.43(m,4H),1.40-1.31(m,2H).

[0337] Example 17 Preparation method of compound LCT011055

[0338] Synthesize according to general synthetic route 2:

[0339]

[0340] Synthesis steps:

[0341] Step 1: Compound 1 (200 mg, 0.578 mmol), aniline (80.7 mg, 0.867 mmol), Pd2(dba)3 (52.9 mg, 0.0578 mmol), BINAP (72.0 mg, 0.115 mmol), and Cs2CO3 (565 mg, 1.73 mmol) were dissolved in 1,4-dioxane (4 mL) and stirred at 100 °C for 16 h under a N2 atmosphere. The reaction was monitored by LCMS. After completion, the reaction mixture was quenched by adding water (10 mL). The mixture was then poured into a separatory funnel and separated. The aqueous layer was extracted with EtOAc (20 mL × 3). The combined organic layers were washed with brine (10 mL), dried over Na2SO4, filtered, and concentrated on a rotary evaporator. The oily residue obtained by rapid column chromatography (PE / EtOAc = 2 / 1) gave compound 2 (200 mg, yield: 61%). Mass spectrometry (ESI): Molecular formula is C 25 H 26 N₂O₃, with a molecular weight of 402.19 and an m / z of 403.30 [m+H] + .

[0342] Step 2: Compound 2 (200 mg, 0.496 mmol) was dissolved in TFA (4 mL) and stirred at room temperature for 2 hours under N2 atmosphere. The reaction was monitored by LCMS. After completion, the reaction mixture was concentrated under vacuum. The residue was then purified by preparative HPLC (Gemini 5 μm C18 column, 150 × 21.2 mm, eluted with 20%–30% MeCN / H2O containing 0.1% TFA) to the yellow solid compound LCT011055 (109.42 mg, purity: 96.89%, yield: 61%).

[0343] Mass spectrometry (ESI): Molecular formula is C 21 H 18 N₂O₃, with a molecular weight of 346.13 and an m / z of 347.10 [M+H] + . 1H NMR(400MHz,DMSO-d6)δ12.10(s,1H),8.70(s,1H),7.73-7.65(m,2H),7.46-7.40(m,2H),7.37-7.30(m,2H) ,7.25-7.19(m,2H),6.99-6.93(m,2H),3.88(t,J=6.8Hz,2H),2.31(t,J=7.2Hz,2H),1.92(p,J=7.2Hz,2H).

[0344] Example 18: Preparation method of compound LCT011057

[0345] Synthesize according to general formula synthesis route 6:

[0346]

[0347] Synthesis steps:

[0348] Step 1: 60% NaH (444 g, 11.1 mmol) was added to a DMF (5 mL) solution of compound 1 (750 mg, 4.44 mmol) at 0 °C, and the mixture was stirred at 0 °C for 15 min. Tert-butyl (5-bromopentyl)carbamate (1.42 g, 5.33 mmol) was added. The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was quenched with water (100 mL), extracted with ethyl acetate (75 mL × 3), the combined organic layers were washed with brine, dried over MgSO4, and concentrated under reduced pressure to give compound 2 (1.4 g, 89% yield) as a yellow solid. Mass spectrometry (MS) (ESI): Molecular formula C 21 H 26 N₂O₃, molecular weight 354.45, m / z 355.45 [M+H] + .

[0349] Step 2: Add 4N HCl / EA (10 mL) to a solution of compound 2 (1.4 g, 0.395 mmol) in EA (5 mL). Stir the reaction mixture at room temperature for 2 hours. After the reaction is complete, filter the mixture, and concentrate the filtrate under reduced pressure to give compound 3 (400 mg, 40% yield) as a white solid. Mass spectrometry (MS) (ESI): Molecular formula is C 16 H 19 ClN₂O has a molecular weight of 290.79 and an m / z of 255.33 [m-HCl+H]. + .

[0350] Step 3: Compound 3 (400 mg, 1.38 mmol), (1R, 2R, 3R, 4S)-3-(methoxycarbonyl)bicyclo[2.2.1]hept-5-en-2-carboxylic acid (270 mg, 1.38 mol), HOBt (205 mg, 1.52 mmol), and triethylamine (342 mg, 3.38 mmol) were dissolved in DCM (5.0 mL), and EDCI (291 mg, 1.58 mmol) was added. The reaction mixture was stirred at room temperature for 3 hours. The mixture was concentrated under vacuum and eluted by preparative HPLC (Gemini 5 μm C18 column, 150 × 21.2 mm, eluting with 10%–90% MeCN / H2O (containing 0.1% TFA)) to give compound 4 (500 mg, 83% yield) as a yellow solid. Mass spectrometry (ESI): molecular formula C 26 H 28 N₂O₄, with a molecular weight of 432.52 and an m / z of 433.52 [m+H] + .

[0351] Step 4: Compound 4 (500 mg, 1.16 mmol) was dissolved in MeOH (5 mL) and H2O (3 mL), and LiOH was added. H2O (146 mg, 3.48 mmol) was added. The reaction mixture was stirred at room temperature for 2 hours. After the reaction was complete, the pH was adjusted to 2 with 1N HCl, and the mixture was extracted with ethyl acetate (75 mL × 3) and water (100 mL). The combined organic layers were washed with brine, dried over MgSO4, concentrated under vacuum, and the residue was subjected to preparative HPLC (Gemini 5 μm C18 column, 150 × 21.2 mm, eluted with 10%–90% MeCN / H2O (containing 0.1% TFA) to give compound LCT011057 (50 mg, 10% yield), a yellow solid.

[0352] Mass spectrometry (ESI): Molecular formula is C 25 H 24 N₂O₃, molecular weight 400.48, m / z 404.5 [M+H] + . 1H NMR (400MHz, CDCl3) δ8.07-8.01(m,2H),7.73-7.69(t,J=7.6Hz,1H),7.55-7.53(d,J=8.4Hz,1H),7.50-7.46(t,J=7.6Hz,1H),6.94-6.92(d,J=6.8H z,1H),6.04(s,2H),3.93-3.89(t,J=7.6Hz,2H),3.36-3.30(m,4H),3.23( s,2H),1.84-1.76(m,2H),1.72-1.70(d,J=8.8Hz,1H),1.53-1.26(m,5H).

[0353] Example 19 Preparation method of compound LCT011061

[0354] Synthesize according to general formula synthesis route 6:

[0355]

[0356] Synthetic steps: Compound 1 (35 mg, 0.13 mol), 1-(5,6,7,8-tetrahydronaphthyl-2-yl)ethane-1-amine (22.7 mg, 0.13 mmol), and triethylamine (33 mg, 0.33 mmol) were dissolved in DCM (5.0 mL), and HATU (74.1 mg, 0.20 mmol) was added. The reaction mixture was stirred at room temperature for 3 hours. The mixture was concentrated under vacuum and purified by preparative HPLC (Gemini 5 μm C18 column, 150 × 21.2 mm, eluted with 10%–90% MeCN / H2O (containing 0.1% NH4HCO3) to give a white solid of compound LCT011061 (33 mg, yield 59%). The residue was purified. Mass spectrometry (MS) (ESI): Molecular formula is C 27 H 29 N3O2, with a molecular weight of 427.55 and an m / z of 428.5 [m+H] + .

[0357] 1H NMR(400MHz,DMSO-d6)δ8.19-8.17(d,J=8.0Hz,1H),7.44(s,1H),7.35-7.30( m,2H,),7.16(s,1H),6.99-6.95(m,3H),6.80-6.78(m,1H),4.85-4.80(m,1H) ,3.82-3.79(t,J=7.0Hz,2H),2.67-2.65(d,J=5.6Hz,4H),2.18-2.15(t,J=5. 4Hz,2H),1.92-1.85(m,2H),1.70-1.69(m,4H),11.28-1.26(d,J=7.2Hz,3H).

[0358] Example 20: Preparation method of compound LCT011062

[0359] Synthesize according to general formula synthesis route 6:

[0360]

[0361] Synthesis steps:

[0362] Step 1: 5-Nitro-1H, compound LCT011062-1 (20 g, 0.08 mol), and hydroxylamine hydrochloride (142.9 mg, 0.08 mol) were heated under reflux for 2 hours. Afterward, the mixture was cooled to room temperature and poured into ice water (1 L) with stirring. The resulting precipitate was filtered and washed with additional cold water and saturated NaHCO3 to give a white solid, compound LCT011062-2 (45 g, excess yield). Mass spectrometry (MS) (ESI): Molecular formula C 19 H 12 N₂O₇S, with a molecular weight of 412.37 and an m / z of 413.37 [m+H] + .

[0363] Step 2: Add 2.7 mL of sodium hydroxide aqueous solution (120 mL) to a solution of compound LCT011062-2 (45 g, 0.08 mol) in ethanol (120 mL) and water (80 mL) at room temperature. Heat the resulting mixture to reflux temperature for 1 hour while distilling the ethanol. When TLC shows the reaction is complete, cool the mixture to 75 °C and add concentrated hydrochloric acid dropwise until a yellow precipitate forms. After cooling to room temperature, collect the precipitate by filtration and wash with water to obtain a mixture of compounds LCT011062-3 and LCT011062-4 as a yellow solid (13.7 g, 80% yield). Mass spectrometry (MS) (ESI): Molecular formula C 11 H6N2O3 has a molecular weight of 214.18 and an m / z of 215.10 [m+H].+ .

[0364] Step 3: Add 10% Pd / C (1.4 g) to a methanol (300 mL) solution of a mixture of compounds LCT011062-3 and LCT011062-4 (13.7 g, 0.06 mol). Stir the reaction mixture at room temperature for 12 hours. Filter the mixture and concentrate the filtrate under reduced pressure to give a mixture of compounds LCT011062-5 and LCT011062-6 (5.4 g, 49% yield) as a white solid. Mass spectrometry (MS) (ESI): Molecular formula C 23 H 27 NO4S has a molecular weight of 413.53 and an m / z of 414.50 [m+H]. + .

[0365] Step 4: At 0 °C, a mixture of compounds LCT011062-5 and LCT011062-6 (5.4 g, 13.03 mol) was dissolved in DMF (40 mL), and 60% NaH (1.3 g, 32.57 mmol) was added. The reaction mixture was stirred at 0 °C for 15 min. Ethyl 4-bromobutyrate (3.05 g, 15.64 mmol) was added. The reaction mixture was stirred at room temperature for 1 hour. The reaction was quenched with water (400 mL) and extracted with ethyl acetate (200 mL × 3). The combined organic layers were washed with brine, dried over MgSO4, and concentrated under reduced pressure to give a mixture of compounds LCT011062-7 and LCT011062-8 (3.1 g, 80% yield). Mass spectrometry (MS) (ESI): Molecular formula C 17 H 18 N₂O₃, with a molecular weight of 298.34 and an m / z of 299.34 [m+H] + .

[0366] Step 5: A mixture of compounds LCT011062-7 and LCT011062-8 (1.3 g, 31.17 mmol) was dissolved in MeOH (20 mL) and water (10 mL), and LiOH·H2O (1.3 g, 31.17 mmol) was added. The reaction mixture was stirred at room temperature for 3 hours. The mixture was adjusted to pH 3 with 1 N HCl, and then extracted with ethyl acetate (200 mL × 3). The combined organic layers were washed with brine, dried over MgSO4, concentrated under vacuum, and the residue was subjected to preparative HPLC (Gemini 5 μm C18 column, 150 × 21.2 mm, eluted with 10%–90% MeCN / H2O (containing 0.1% TFA)) to give compound LCT011062-9 (800 mg, 25.8% yield) as a yellow solid. Mass spectrometry (ESI): Molecular formula C12 H 14 N₂O₃, with a molecular weight of 270.29 and an m / z of 271.30 [m+H] + .

[0367] Step 6: Compound LCT011062-9 (50 mg, 0.185 mmol), propan-2-amine (13 mg, 0.22 mmol), and DIPEA (60 mg, 0.46 mmol) were dissolved in DCM (5.0 mL), and HATU (105.5 mg, 0.28 mmol) was added. The reaction mixture was stirred at room temperature for 3 hours. The mixture was concentrated under vacuum, and the residue was purified by preparative HPLC (Gemini 5 μm C18 column, 150 × 21.2 mm, eluted with 10%–90% MeCN / H2O (containing 0.1% NH4HCO3)) to give compound LCT011062 (35 mg, 61% yield) as a white solid.

[0368] Mass spectrometry (ESI): Molecular formula is C 18 H 21 N3O2, with a molecular weight of 311.39 and an m / z of 312.40 [M+H] + . 1 H NMR(400MHz, DMSO-d6)δ7.67-7.65(d,J=7.6Hz,1H),7.40-7.39(d,J=1.2Hz,1H),7.35-7.27(m,2H),7.07-7.07(d,J=1.6Hz,1H) ,6.82-6.80(d,J=6.8Hz,1H),5.80(s,2H),3.83-3.78(m,3H),2.11-2.07(m,2H),1.90-1.86(m,2H),1.02-1.00(d,J=6.4Hz,6H).

[0369] Example 21 Preparation method of compound LCT011063

[0370] Synthesize according to general formula synthesis route 6:

[0371]

[0372] Synthetic steps: Compound LCT011062-9 (50 mg, 0.185 mmol), 1-phenylethane-1-amine (27 mg, 0.22 mmol), and DIPEA (60 mg, 0.46 mmol) were dissolved in DCM (5.0 mL), and HATU (105.5 mg, 0.28 mmol) was added. The reaction mixture was stirred at room temperature for 3 hours. The mixture was concentrated under vacuum and eluted by preparative HPLC (Gemini 5 μm C18 column, 150 × 21.2 mm, eluting with 10%–90% MeCN / H2O (containing 0.1% NH4HCO3) to give compound LCT011063 (40 mg, 57.8% yield) as a white solid.

[0373] Mass spectrometry (ESI): Molecular formula is C 23 H 23 N3O2, with a molecular weight of 373.46 and an m / z of 374.5 [M+H] + . 1 H NMR(400MHz, DMSO-d6)δ8.81(s,1H),8.28-8.26(d,J=7.6Hz,1H),7.40(s,1H),7.33-7.27(m,6H),7.22-7.20(m,1H),7.07(s,1H),6.77-6.76(d ,J=6.4Hz,1H),5.80(s,2H),4.93-4.89(m,1H),3.83-3.79(t,J=6.8Hz, 2H),2.21-2.17(m,2H),1.91-1.87(m,2H),1.32-1.30(d,J=7.2Hz,1H).

[0374] Example 22 Preparation method of compound LCT011064

[0375] Synthesize according to general formula synthesis route 6:

[0376]

[0377] Synthetic steps: Compound LCT011062-9 (50 mg, 0.185 mmol), methylamine hydrochloride (15 mg, 0.22 mmol), and DIPEA (60 mg, 0.46 mmol) were dissolved in DCM (5.0 mL), and HATU (105.5 mg, 0.28 mmol) was added. The mixture was stirred at room temperature for 3 hours. The mixture was concentrated under vacuum, and the residue was purified by preparative HPLC (Gemini 5 μm C18 column, 150 × 21.2 mm, eluted with 10%–90% MeCN / H2O (containing 0.1% NH4HCO3)) to give compound LCT011064 (17.5 mg, 57.8% yield) as a white solid.

[0378] Mass spectrometry (ESI): Molecular formula is C 16 H 17 N3O2, with a molecular weight of 283.33 and an m / z of 284.33 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ7.73-7.72(m,1H),7.40-7.39(d,J=1.6Hz,1H),7.35-7.27(m,2H,),7.07-7.07(d,J=1.6Hz,1H),6.83-6. 81(d,J=6.8Hz,1H),5.80(s,2H),3.82-3.79(t,J=7.2Hz,2H),2.54-2.50(m,3H),2.14-2.10(t,J=14.8Hz,2H),1.90-1.87(m,2H).

[0379] Example 23 Preparation method of compound LCT011065

[0380] Synthesize according to general formula synthesis route 6:

[0381]

[0382] Synthetic steps: Compound LCT011062-9 (50 mg, 0.185 mmol) was added to a SOCl2 solution (5.0 mL), and the mixture was stirred at 85 °C for 1 hour. The mixture was concentrated under vacuum, and NH4OH (2 mL) was added to the residue at room temperature for 1 hour. After the reaction was complete, the reaction solution was concentrated under reduced pressure. The residue was eluent by preparative HPLC (Gemini 5 μm C18 column, 150 × 21.2 mm, eluted with 10%–90% MeCN / H2O (containing 0.1% NH4HCO3) to give compound LCT011065 (16.0 mg, 32% yield) as a white solid.

[0383] Mass spectrometry (ESI): Molecular formula is C 15 H 15 N3O2, with a molecular weight of 269.30 and an m / z of 270.30 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ7.39-7.39(d,J=1.2Hz,1H),7.35-7.26(m,3H),7.07-7.07(d,J=1.2Hz,1H),6.82-6.81(d,J =6.4Hz,1H),6.76(s,1H),5.80(s,2H),3.82-3.79(t,J=7.2Hz,2H),2.13-2.09(t,J=14.8Hz,2H),1.89-1.85(m,2H).

[0384] Example 24: Preparation method of compound LCT011068

[0385] Synthesize according to general formula synthesis route 6:

[0386]

[0387] Synthetic steps: HOBT (57 mg, 0.428 mmol) and DCC (88 mg, 0.43 mmol) were added to a DCM (4 mL) solution of compound LCT011047 (94 mg, 0.28 mmol), and the mixture was stirred at 0 °C for 0.5 h. Then, compound 1 (50 mg, 0.28 mmol) was added, and the reaction was stirred at 25 °C for 1 h. After completion, the reaction mixture was quenched with water and extracted with EtOAc. The combined organic layers were dried over Na2SO4 and evaporated to give a crude product, which was purified by preparative HPLC (Gemini 5 μm C18 column, 150 × 21.2 mm, eluted with 30%–95% MeCN / H2O containing 0.1% ammonia) to give compound LCT011068 (56.34 mg, yield: 40%) as a yellow solid.

[0388] Mass spectrometry (ESI): Molecular formula is C 33 H 32 N₂O₂, molecular weight 488.25, m / z 489.20 [M+H] + . 1H NMR(400MHz,DMSO-d6)δ8.17(d,J=8.0Hz,1H),8.13-8.08(m,1H),7.80-7.75 (m,1H),7.64-7.56(m,4H),7.56-7.50(m,3H),7.21-7.17(m,1H),6.99-6.92( m,3H),4.86-4.74(m,1H),3.91(t,J=6.8Hz,2H),2.65(d,J=6.0Hz,4H),2.19( t,J=7.6Hz,2H),1.99-1.86(m,2H),1.79-1.59(m,4H),1.26(d,J=7.2Hz,3H).

[0389] Example 25: Preparation method of compound LCT011071

[0390]

[0391] 4-(4-amino-2-oxobenzo[cd]indole-1(2H)-yl)butyric acid (100 mg, 0.37 mmol), DCC (114 mg, 0.55 mmol), and HOBT (75 mg, 0.55 mmol) were added to DCM (5 mL). The mixture was stirred at 0 °C for 0.5 h, and then piperidine (63 mg, 0.74 mmol) was added. The mixture was stirred at 25 °C for 72 h, and the reaction was monitored by LCMS. After the reaction was complete, the reaction mixture was quenched with water, extracted with ethyl acetate, and the organic layer was dried with sodium sulfate. The crude product was obtained by evaporation and purified by high performance liquid chromatography (Gemini 5 μm C18 column, 150 × 21.2 mm, eluted with 30-95% MeCN / H2O (containing 0.1% FA)) to obtain product LCT011071 (43.92 mg, yield 33%) as a yellow solid.

[0392] Mass spectrometry (ESI): Molecular formula is C 20 H 23 N3O2, molecular weight 337.18, m / z 338.20 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ7.41-7.18(m,3H),7.07(s,1H),6.83(d,J=6.8Hz,1H),5.79(s,2H),3.83(t,J=7.2Hz,2H),3.43-3.35(m,2H),3.3 -3.27(m,2H),2.34(t,J=7.2Hz,2H),1.88(t,J=7.2Hz,2H),1.63-1.51(m,2H),1.44-1.33(m,4H).

[0393] Example 26 Preparation method of compound LCT011073

[0394]

[0395] LCT011000 (100 mg, 0.39 mmol), DCC (121 mg, 0.58 mmol), and HOBT (79 mg, 0.58 mmol) were added to DCM (5 mL), and the mixture was stirred at 0 °C for 0.5 h. Then, 1-(naphthyl-2-yl)ethylenediamine (67 mg, 0.39 mmol) was added, and the mixture was stirred at 25 °C for 1 h. The reaction was monitored by LCMS. After the reaction was complete, the reaction mixture was quenched with water and extracted with ethyl acetate. The organic layer was washed with brine (10 mL), dried over Na2SO4, filtered, and concentrated on a rotary evaporator. The resulting oil phase was purified by pre-high performance liquid chromatography (Gemini 5 μm C18 column, 150 × 21.2 mm, eluted with 30%–95% MeCN / H2O (containing 0.1% FA)) to give LCT011073 (92 mg, yield 57%) as a yellow solid.

[0396] Mass spectrometry (ESI): Molecular formula is C 27 H 24 N₂O₂, molecular weight 408.18, m / z 409.10 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ8.37(d,J=8.0Hz,1H),8.19(d,J=8.1Hz,1H),8.06(d,J=6.8Hz,1H),7.89-7.72(m,5H),7.63(d,J=8.4Hz,1H),7.53-7 .40(m,4H),7.13(d,J=6.8Hz,1H),5.13-4.96(m,1H),3.90(t,J=6.8Hz,2H),2.23(d,J=7.6Hz,2H),2.01-1.87(m,2H),1.40(d,J=7.2Hz,3H).

[0397] Example 27 Preparation method of compound LCT011101

[0398]

[0399] Compound 3 was synthesized using suitable commercially available reagents according to the preparation method of LCT011073, yielding methyl 4-(1-(4-(4-(4-methyl-2-oxobenzo[cd]indol-1(2H)-yl)butylamine)ethyl)benzoate (100.0 mg, yield 80%) as a yellow solid. Mass spectrometry (MS (ESI)): Molecular formula C 26 H 26 N₂O₄, molecular weight 430.19, m / z 431.25 [m+H] + .

[0400] NaOH (18.6 mg, 0.46 mmol) was added to a THF:H₂O mixture of 2:1 (10 mL) to obtain a solution of compound 3 (100.0 mg, 0.23 mmol). The mixture was stirred at 50 °C for 10 h, and the reaction was monitored by LCMS. After the reaction was complete, the pH was adjusted to 5-6 with HCl (1N), and the mixture was extracted with ethyl acetate. The organic layer was dried over sodium sulfate, and the crude product was evaporated to obtain the crude product. The crude product was purified by high performance liquid chromatography (Gemini 5 μm C18 column, 150 × 21.2 mm, eluted with 30%–95% MeCN / H₂O (containing 0.1% FA)) to obtain LCT011101 (30.75 mg, yield: 31%) as a yellow solid.

[0401] Mass spectrometry (ESI): Molecular formula is C 25 H 24 N₂O₄, molecular weight 416.17, m / z 417.05 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ12.77(s,1H),8.35(d,J=8.0Hz,1H),7.97(s,1H),7.93-7.82(m,3H),7.58-7.45(m,2H),7.39(d,J=8.4Hz,2H),7.0 7(d,J=6.8Hz,1H),5.01-4.83(m,1H),3.87(t,J=6.8Hz,2H),2.61(s,3H),2.21(t,J=7.6Hz,2H),1.99-1.84(m,2H),1.31(d,J=7.2Hz,3H).

[0402] Example 28 Preparation method of compound LCT011102

[0403]

[0404] Intermediate 5 was synthesized using suitable commercially available reagents according to the preparation method of LCT011073, and intermediate 5 (100.0 mg, yield: 86%) was obtained as a yellow solid.

[0405] Mass spectrometry (ESI): Molecular formula is C 31 H 28 N₂O₄, molecular weight 492.20, m / z 493.10 [M+H] + .

[0406] Intermediate 5 was prepared as LCT011101 and LCT011102 (36.32 mg, yield 32%) was obtained as a yellow solid.

[0407] Mass spectrometry (ESI): Molecular formula is C 30 H 26 N₂O₄, molecular weight 478.19, m / z 479.10 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ12.77(s,1H),8.36(d,J=8.0Hz,1H),8.12(d,J=7.2Hz, 1H),7.87(d,J=8.4Hz,2H),7.78(d,J=7.2Hz,1H),7.66-7.57(m,4H),7.57-7.4 9(m,3H),7.39(d,J=8.4Hz,2H),7.23-7.15(m,1H),4.99-4.85(m,1H),3.92(t, J=6.8Hz,2H),2.23(t,J=7.2Hz,2H),2.00-1.87(m,2H),1.32(d,J=7.2Hz,3H).

[0408] Example 29: Preparation method of compound LCT0110076

[0409]

[0410] A 20 mL solution of methyltriphenylphosphine iodide (2.13 g, 5.28 mmol) in THF was added to KHMDS (6.6 mL, 6.6 mmol, 1.0 M THF solution), and the mixture was stirred at 0 °C under nitrogen for 0.5 h. Then, 1 g (4.4 mmol) of 6-bromo-3,4-dihydro-2h-naphthalene-1-1 was added, and the mixture was stirred at 25 °C for 12 h. The reaction was monitored by thin-layer chromatography. After the reaction was complete, the reaction mixture was quenched with saturated NH4Cl solution, extracted with ethyl acetate, the organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the product. The product was eluted with a PE / EtOAc gradient from 100 / 00 to 98 / 02 to give compound 2 (610 mg, 61% yield) as a colorless oil.

[0411] A solution of compound 2 (610 mg, 2.73 mmol) was added to 12 mL of ACN, followed by tributyl(1-ethoxy)stanane (987 mg, 2.73 mmol) and PdAMPHOS (97 mg, 0.14 mmol). The mixture was stirred at 90 °C under nitrogen for 3 h. Water was added to the solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The product was then purified by rapid chromatography (PE / EtOAc eluted from 100 / 00 to 95 / 5) to obtain compound 4 (440 mg, 86% yield) as a white oil.

[0412] Mass spectrometry (ESI): Molecular formula is C 13 H 14 O, molecular weight 186.10, m / z 187.15 [M+H] + Compound 4 (440 mg, 2.36 mmol) was added to EtOH (9 mL) solution with NH₂OH-HCl (330 mg, 4.72 mmol) and NaOAc (774 mg, 9.44 mmol). The mixture was stirred at 80 °C under nitrogen for 3 h. Water was added to the solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a rapidly purified product (PE / EtOAc eluted from 100 / 00 to 75 / 25), yielding compound 5 (420 mg, 84% yield) as a white solid.

[0413] Mass spectrometry (ESI): Molecular formula is C 13 H 15 NO, molecular weight 201.12, m / z 202.15 [M+H] + Zn powder (617 mg, 9.44 mmol) and NH4Cl (504 mg, 9.44 mmol) were added to a MeOH (8 mL) solution of compound 5 (380 mg, 1.88 mmol). The mixture was stirred at 80 °C for 12 h. Water was added to the solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the product. The product was purified by flash chromatography (eluting DCM / MeOH from 100 / 00 to 96 / 04) to obtain compound 6 (280 mg, 79% yield) as a white solid.

[0414] Mass spectrometry (ESI): Molecular formula is C 13 H 17 N, molecular weight 187.14, m / z 171.15 [M+H-17] + .

[0415] Dry Pd / C (160 mg, 10% wt) was added to a MeOH (16 mL) solution of compound 6 (160 mg, 0.85 mmol). The mixture was stirred at 25 °C under H2 for 12 h. The mixture was filtered, and the filtrate was concentrated under vacuum. The crude product compound 7 (135 mg, 80% yield) was used directly in the next step without further purification.

[0416] Mass spectrometry (ESI): Molecular formula is C 13 H 19 N, molecular weight 189.15, m / z 173.20 [M+H-17] + .

[0417] DCC (106 mg, 0.51 mmol) and HOBT (69 mg, 0.51 mmol) were added to a DCM (1.5 mL) solution of compound LCT0110000 (87 mg, 0.34 mmol) at 0 °C under a N2 atmosphere, and stirred at 0 °C for 15 min. Compound 7 (65 mg, 0.3434 mmol) was added, and the mixture was stirred at 25 °C for 3 h. Water was added to the solution, and the mixture was extracted with DCM. The organic layer was concentrated to obtain the crude product, which was purified by high performance liquid chromatography (column: Gemini 5 μm C18 150 × 21.2 mm, mobile phase: ACN-H2O (0.1% FA), gradient: 50–95, 12.50 min) to obtain a yellow solid, LCT0110076 (32.0 mg, yield: 21%).

[0418] Mass spectrometry (ESI): Molecular formula is C 28 H 30 N₂O₂, molecular weight 426.23, m / z 427.25 [M+H] + . 1H NMR (400MHz, DMSO-d6) δ8.22-8.14(m,2H),8.05(d,J=6.8Hz,1H),7.85-7.77(m,1H),7.64(d,J=8.4Hz,1H ),7.53(d,J=7.2Hz,1H),7.17-7.12(m,1H),7.10(d,J=8.0Hz,1H),7.03-6.97(m,1H),6.93(s,1H),4.86- 4.75(m,1H),3.88(d,J=6.8Hz,2H),2.84-2.75(m,1H),2.70-2.58(m,2H),2.22-2.14(m,2H),1.97-1.88( m,2H),1.86-1.72(m,2H),1.67-1.56(m,1H),1.48-1.37(m,1H),1.26(d,J=7.2Hz,3H),1.22-1.16(m,3H).

[0419] Example 30: Preparation method of compound LCT011078

[0420]

[0421] Pd(OAc)₂ (14 mg, 0.066 mmol), K₃PO₄H₂O (611 mg, 2.66 mmol), SPhos (54 mg, 0.13 mmol), and MeB(OH)₂ (159 mg, 2.66 mmol) were added to a Tol (15 mL) solution of compound 1 (460 mg, 2.66 mmol). The mixture was stirred at 100 °C for 6 h. The desired mass was determined by LC-MS. Water was added to the solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The product was purified by chromatography (PE / EtOAc elution, from 100 / 00 to 75 / 25, 20 min) to give compound 2 (370 mg, 83% yield) as a yellow solid. Mass spectrometry (ESI): Molecular formula C 20 H 23 NO3, molecular weight 325.17, m / z 326.25 [M+H] + .

[0422] Compound 2 (370 mg, 1.11 mmol) was added to TFA (5 mL) and stirred at 25 °C for 1 h. The desired mass was determined by LC-MS. Water was added to the solution, and the mixture was extracted with DCM. The organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated to give the crude product LCT011078 (290 mg, 94% yield).

[0423] Mass spectrometry (ESI): Molecular formula is C 16 H 15 NO3, with a molecular weight of 269.11 and an m / z of 270.15 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ12.09(s,1H),7.97(s,1H),7.90(s,1H),7.58-7.47(m,2H),7.13(d, J=6.4Hz,1H),3.90(d,J=6.8Hz,2H),2.61(s,3H),2.30(d,J=7.2Hz,2H),1.96-1.87(m,2H).

[0424] Example 31: Preparation method of compound LCT0110079

[0425]

[0426] Under a nitrogen atmosphere, propenyl-2-amine (42 mg, 0.71 mmol), Pd-PEPPSI-IPent (18 mg, 0.023 mmol), and Cs₂CO₃ (310 mg, 0.95 mmol) were added to a 3 mL solution of 1,4-dioxane containing compound LCT0110003-7 (165 mg, 0.47 mmol), and the mixture was stirred at 100 °C for 12 h. Water was added to the solution, followed by extraction with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by flash chromatography with PE / EtOAc elution (from 100 / 00 to 55 / 45) to give compound 1 (72 mg, 40% yield) as a yellow solid. Mass spectrometry (ESI): molecular formula C 22 H 28 N₂O₃, molecular weight 368.21, m / z 369.00 [M+H] + .

[0427] Compound 1 (72 mg, 0.19 mmol) was stirred in TFA (1.5 mL) for 1 h at 25 °C. The mixture was concentrated to obtain a crude product, which was purified by high performance liquid chromatography (column: Gemini 5 μm C18 150 × 21.2 mm, mobile phase: ACN-H2O (0.1% FA), gradient: 30-95, 13.00 min) to obtain LCT0110079 (20.5 mg, yield: 33%) as a yellow solid.

[0428] Mass spectrometry (ESI): Molecular formula is C 18 H 20 N₂O₃, molecular weight 312.15, m / z 313.15 [M+H]+ . 1 H NMR (400MHz, DMSO-d6) δ12.06(s,1H),7.42(d,J=1.6Hz,1H),7.38-7.28(m,2H),6.97(d,J=1.6Hz,1H),6.85-6.78(m,1H),6.1 6(d,J=7.6Hz,1H),3.83(d,J=6.2Hz,2H),3.78-3.65(m,1H),2.28(d,J=7.2Hz,2H),1.94-1.83(m,2H),1.21(d,J=6.0Hz,6H).

[0429] Example 32 Preparation method of compound LCT011082

[0430]

[0431] The reaction mixture was prepared by reacting compound 1 (300 mg, 0.77 mmol), B2Pin2 (390 mg, 1.54 mmol), AcOK (151 mg, 1.54 mmol), and Pd(dppf)Cl2 (56 mg, 0.077 mmol). H2O2 (871.58 mg, 7.68 mmol) was dissolved in EtOH (2 mL) and added to the reaction mixture. The mixture was stirred at 25 °C for 1 h, and the reaction was monitored by LCMS. After the reaction was complete, the reaction mixture was quenched with saturated Na2SO3 (3 mL). The mixture was evaporated to give a crude product, which was purified by reversed-phase chromatography (eluting with 10-95% MeCN / H2O containing 0.05% ammonia) to give compound 2 (200.0 mg, purity 80.0%, yield 63%) as a yellow solid.

[0432] Mass spectrometry (ESI): Molecular formula is C 19 H 21 NO4, molecular weight 327.15, m / z 328.15 [M+H] + .

[0433] Compound 2 (100.0 mg, 0.30 mmol) was dissolved in a 5:1 mixture of DCM and TFA (3 mL) and stirred at 25 °C for 1 h. The reaction was monitored by LCMS. After the reaction was complete, the pH was adjusted to 7-8 with NH3. The crude product was purified by high performance liquid chromatography (Gemini 5 μm C18 column, 150 × 21.2 mm, eluted with 30%-95% MeCN / H2O (containing 0.1% TFA)) to obtain LCT011082 (51.09 mg, 60% yield) as a grayish-white solid.

[0434] Mass spectrometry (ESI): Molecular formula is C15 H 13 NO4, molecular weight 271.08, m / z 272.05 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ12.08(s,1H),11.32(s,1H),7.87(d,J=7.6Hz,1H),7.67(d,J=8.4Hz,1H),7.49-7.39(m,1 H),7.15(d,J=7.2Hz,1H),7.06(d,J=7.6Hz,1H),3.87(t,J=6.8Hz,2H),2.29(t,J=7.6Hz,2H),1.95-1.82(m,2H).

[0435] Example 33 Preparation method of compound LCT011077

[0436] LCT011077 was prepared using the same method as LCT011082, yielding LCT011077 (21.7 mg, yield: 26%). Mass spectrometry (ESI): Molecular formula is C2. 15 H 13 NO4 271.08, m / z 272.05 [M+H] + . 1 H NMR (400MHz, DMSO-d6)12.04(s,1H),10.26(s,1H),7.50(d,J=1.6Hz,1H),7.44(d,J=3.2Hz,2H),7.40 (d,J=1.6Hz,1H),7.01-6.95(m,1H),3.86(t,J=6.8Hz,2H),2.30(t,J=7.2Hz,2H),1.96-1.84(m,2H).

[0437] Example 34 Preparation method of compound LCT011088

[0438]

[0439] DCC (45 mg, 0.22 mmol) and HOBT (30 mg, 0.22 mmol) were added to a DCM (1 mL) solution of LCT011078 (40 mg, 0.14 mmol) at 0 °C. The mixture was stirred at 0 °C for 15 min, and propan-2-amine (17 mg, 0.29 mmol) was added. The mixture was stirred at 25 °C for 3 h. Water was added to the solution and extracted with DCM. The organic layer was concentrated to obtain a crude product, which was purified by HPLC (column: Gemini 5 μm C18 150 × 21.2 mm, mobile phase: acetonitrile-H2O (0.1% FA), gradient: 50-95, 12.50 min) to obtain LCT011088 (10.3 mg, yield: 22%) as a yellow solid. Mass spectrometry (MS) (ESI): molecular formula C 19 H 22 N₂O₂, molecular weight 310.17, m / z 311.00 [M+H] + . 1 HNMR(400MHz,DMSO-d6)δ7.97(s,1H),7.90(s,1H),7.69-7.61(m,1H),7.58-7.47(m,2H),7.11(d,J=6.4Hz,1H),3.8 7(d,J=7.2Hz,2H),3.84-3.74(m,1H),2.61(s,3H),2.10(d,J=7.2Hz,2H),1.96-1.84(m,2H),0.99(d,J=6.4Hz,6H).

[0440] Example 35 Preparation method of compound LCT011083

[0441] According to the preparation method of LCT011088, it is synthesized using appropriate commercially available reagents, such as HOBt, DCC, and intermediates such as isopropylamine.

[0442]

[0443] LCT011083 (33.9 mg, yield: 60%) was obtained.

[0444] Mass spectrometry (MS) (ESI): Molecular formula is C 24 H 24 N₂O₂, molecular weight 372.18, m / z 373.15 [M+H] + .

[0445] 1H NMR (400MHz, DMSO-d6) δ8.12(d,J=7.2Hz,1H),7.78(d,J=7.2Hz,1H),7.70-7.49(m,8H),7.25(d,J=6.4Hz,1H ),3.92(t,J=6.8Hz,2H),3.86-3.73(m,1H),2.12(d,J=7.6Hz,2H),1.99-1.87(m,2H),0.99(d,J=6.4Hz,6H).

[0446] Example 36: Preparation method of compound LCT011084

[0447] According to the preparation method of LCT011088, it is synthesized using appropriate commercially available reagents, such as HOBt, DCC, and intermediates such as ammonia in a dichloromethane solution.

[0448]

[0449] LCT011084 (32.3 mg, yield: 54%) was obtained.

[0450] Mass spectrometry (MS / ESI): Molecular formula is C 21 H 18 N₂O₂, with a molecular weight of 330.14 and an m / z of 331.10 [M+H] + .

[0451] 1 H NMR (400MHz, DMSO-d6) δ8.12(d,J=7.2Hz,1H),7.78(d,J=7.2Hz,1H),7.66-7.50(m,7H),7.29(s,1H) ,7.26(d,J=6.4Hz,1H),6.77(s,1H),3.92(t,J=6.8Hz,2H),2.14(d,J=7.6Hz,2H),1.99-1.87(m,2H).

[0452] Example 37 Preparation method of compound LCT011087

[0453] According to the preparation method of LCT011088, it was synthesized using appropriate commercially available reagents and intermediates.

[0454]

[0455] LCT011087 (8.5 mg, yield: 18%) was obtained.

[0456] Mass spectrometry (MS) (ESI): Molecular formula is C 16 H 16N₂O₂, with a molecular weight of 268.12 and an m / z of 268.95 [M+H] + . 1 HNMR(400MHz,DMSO-d6)δ7.98(s,1H),7.91(s,1H),7.58-7.47(m,2H),7.28(s,1H),7.13(d,J=6.4 Hz,1H),6.76(s,1H),3.87(d,J=7.2Hz,2H),2.61(s,3H),2.12(d,J=7.2Hz,2H),1.96-1.84(m,2H).

[0457] Example 38: Preparation method of compound LCT011097

[0458] According to the preparation method of LCT011088, it was synthesized using appropriate commercially available reagents and intermediates.

[0459]

[0460] LCT011097 (20.42 mg, yield: 17%) was obtained.

[0461] Mass spectrometry (MS) (ESI): Molecular formula is C 27 H 25 N3O2, with a molecular weight of 423.19 and an m / z of 424.20 [M+H] ]+ .

[0462] 1 H NMR(400MHz, DMSO-d6)8.37(d,J=8.4Hz,1H),7.89-7.82(m,3H),7.77(s,1H),7.53-7.42(m,3H),7.41-7.37(m,1H),7.29-7.23(m,2H),7.08-7.04 (m,1H),6.77-6.71(m,1H),5.78(s,2H),5.11-5.03(m,1H),3.81(d,J=7. 2Hz,2H),2.21(d,J=6.0Hz,2H),1.94-1.86(m,2H),1.40(d,J=7.2Hz,3H).

[0463] Example 39 Preparation method of compound LCT011089

[0464]

[0465] Compound 1 (90 mg, 0.19 mmol) was dissolved in a 1:5 mixture of TFA and DCM (2 mL) and stirred at 25 °C for 3 hours. The mixture was detected by LC-MS. The reaction mixture was concentrated to give a crude product, which was purified by preparative HPLC (column: Gemini 5 μm C18 150 × 21.2 mm, mobile phase: acetonitrile-H2O (0.1% FA), gradient: 5-95, 12.50 min) to obtain LCT011089 (31.32 mg, yield: 44%) as a yellow solid.

[0466] Mass spectrometry (MS) (ESI): Molecular formula is C 22 H 25 N3O2, with a molecular weight of 363.19 and an m / z of 364.25 [M+H] + . 1 H NMR(400MHz, DMSO-d6)7.97(d,J=7.2Hz,1H),7.82(d,J=8.8Hz,1H),7.66(d,J= 7.2Hz,1H),7.61-7.52(m,1H),7.43-7.33(m,1H),7.17(d,J=7.2Hz,1H),6.49- 6.45(m,1H),4.18-4.14(m,2H),3.98-3.94(m,2H),3.89(d,J=7.2Hz,2H),3.87 -3.76(m,1H),2.14(d,J=7.6Hz,2H),2.02-1.90(m,2H),1.04(d,J=6.8Hz,6H).

[0467] Example 40: Preparation method of compounds LCT011092 and LCT011090

[0468]

[0469] Step 1: Preparation of 4-(5-bromo-2-oxobenzo[cd]indole-1(2H)-yl)butyric acid

[0470] Compound 1 (1.1 g, 2.8 mmol) was added to a 5 mL mixture of DCM / TFA (5 / 1) and stirred at 25 °C for 1 hour. After the reaction was complete, the pH of the mixture was adjusted to 8 with NaHCO3 (aq.) and extracted with EtOAc. The organic layer was dried over Na2SO4, filtered, and concentrated to give the desired product, compound 8 (1.0 g, yield: 94%), as a yellow solid. Mass spectrometry (MS) (ESI): Molecular formula C 15 H 12 BrNO3, molecular weight 333.00, m / z 333.95 [M+H] +.

[0471] Step 2: Preparation of 4-(5-bromo-2-oxobenzo[cd]indol-1(2H)-yl)-N-isopropylbutyramide

[0472] HOBT (606 mg, 4.5 mmol) and DCC (926 mg, 4.5 mmol) were added to a DCM (20 mL) solution of compound 8 (1.0 g, 2.99 mmol). The mixture was stirred at 0 °C for 0.5 h. Propyl-2-amine (353.8 mg, 6.0 mmol) was added to the solution, and the reaction mixture was stirred at 25 °C for 16 h. The reaction was monitored by LCMS. After completion, the reaction mixture was quenched with H2O and extracted with DCM. The organic layer was evaporated to give a crude product, which was purified by rapid chromatography (eluting from 100 / 00 to 50 / 50 with PE / EtOAc) to give compound 9 (1.0 g, yield: 80%) as a yellow solid.

[0473] Mass spectrometry (MS) (ESI): Molecular formula is C 18 H 19 BrN₂O₂, molecular weight 374.06, m / z 374.75 [M+H] + .

[0474] Step 3: Preparation of tert-butyl 4-(1-(4-(isopropylamino)-4-oxobutyl)-2-oxo-1,2-dihydrobenzo[cd]indol-5-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid

[0475] To a solution of compound 9 (300 mg, 0.80 mmol) in 1,4-dioxane / H₂O = 5 / 1 (6 mL), 4-(4,4,5,5-tetramethyl-1,3,2-dioxoboronyl-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (370 mg, 1.2 mmol), Pd(dppf)Cl₂ (58 mg, 0.08 mmol), and K₂CO₃ (220 mg, 1.6 mmol) were added, and the mixture was stirred at 80 °C for 6 h under a N₂ atmosphere. The mixture was detected by LC-MS. Water was added to the solution, and the mixture was extracted with EtOAc. The organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by rapid chromatography (eluting with PE / EtOAc from 100 / 00 to 60 / 40) to give compound 10 (240 mg, yield: 58%) as a yellow solid. Mass spectrometry (MS) (ESI): Molecular formula is C 28 H 35 N3O 4， Molecular weight 477.26, m / z 478.25 [M+H] + .

[0476] Step 4: Preparation of 4-(1-(4-(isopentylamino)-4-oxobutyl)-2-oxo-1,2-dihydrobenzo[cd]indol-5-yl)piperidine-1-carboxylic acid ester

[0477] Pd / C (89.14 mg, 0.8376 mmol) was added to a MeOH (5 mL) solution of compound 10 (120.0 mg, 0.25 mmol). The mixture was stirred at 25 °C under a H2 atmosphere for 16 hours, and the reaction was detected by LC-MS. The reaction mixture was filtered and concentrated to give the desired product compound 11 (120 mg, purity: 80.0%, yield: 79%) as a yellow solid. Mass spectrometry (ESI): molecular formula C 28 H 37 N3O4, with a molecular weight of 479.28 and an m / z of 480.25 [M+H] + .

[0478] Step 5: Preparation of N-isopropyl-4-(2-oxo-5-(piperidin-4-yl)benzo[cd]indole-1(2H)-yl)butyramide:

[0479] Compound 11 was added (120.0 mg, 0.25 mmol) to a 5 mL mixture of DCM / TFA (5 / 1) and stirred for 1 hour. The reaction was detected by LC-MS. After the reaction was complete, the reaction mixture was evaporated to give the crude product, which was then analyzed by preparative HPLC (Gemini 5 μm C18 column, 150 × 21.2 mm, with 30% to 95% MeCN / H2O containing 0.1% TFA). 2O The product LCT011092 (33.37 mg, yield: 30%) was purified by elution (11.25 min) to obtain a yellow solid.

[0480] Mass spectrometry (MS) (ESI): Molecular formula is C 23 H 29 N3O2, molecular weight 379.23, m / z 380.15 [M+H] + . 1H NMR (400MHz, DMSO-d6) δ8.68-8.56(m,1H),8.48-8.32(m,2H),8.08(d,J=6.8Hz,1H) ,7.90-7.80(m,1H),7.66(d,J=7.2Hz,1H),7.35(d,J=7.6Hz,1H),7.17(d,J=7.6Hz, 1H),3.87(t,J=6.8Hz,2H),3.82-3.73(m,1H),3.69-3.60(m,1H),3.52-3.45(m,2H) ,3.23-3.12(m,2H),2.10(t,J=7.2Hz,2H),2.07-1.86(m,6H),0.99(d,J=6.4Hz,6H).

[0481] The preparation method of LCT011090 is the same as that of LCT011092.

[0482]

[0483] LCT011090 (TFA salt) (59.41 mg, purity: 99.44%, yield: 62.75%) was obtained as a yellow solid.

[0484] Mass spectrometry (MS) (ESI): Molecular formula is C 22 H 27 N3O 2， Molecular weight 365.21, m / z 366.15 [M+H] + . 1 H NMR(400MHz, DMSO-d6)δ9.07(s,2H),8.06(d,J=7.3Hz,1H),7.83-7.77(m,2H),7.69-7.56(m,2H),7.24(d,J=7.1Hz,1H),4.36-4.19(m,1H ),3.88(t,J=6.9Hz,2H),3.84-3.71(m,2H),3.50(s,2H),3.40-3.30(m,1H),2.18-2.06(m,3H),1.95-1.82(m,2H),1.00(d,J=6.6Hz,6H).

[0485] Example 41: Preparation method of compound LCT011091

[0486]

[0487] Compound 1 (120 mg, 0.25 mmol) was added to a 1:5 mixture of TFA and DCM (2 mL) and stirred at 25 °C for 3 hours. The reaction was detected by LC-MS. The reaction mixture was concentrated to give a crude product, which was purified by HPLC (column: Gemini 5 μm C18 150 × 21.2 mm, mobile phase: ACN-H2O (0.1% FA), gradient: 5-95, 12.50 min) to give LCT011091 (33.70 mg, yield: 35%) as a yellow solid.

[0488] Mass spectrometry (MS) (ESI): Molecular formula is C 23 H 27 N3O2, molecular weight 377.21, m / z 378.60 [M+H] + . 1 H NMR (400MHz, DMSO-d6)8.35-8.31(m,1H),8.02(d,J=6.8Hz,1H),7.74-7.61(m,3H),7.56(d,J=7.6Hz,1H),7.21(d,J=7.2Hz,1H),5.95(s,1H),3.88 (d,J=6.8Hz,2H),3.85-3.72(m,1H),3.66(s,2H),3.28-3.14(m,2H),2.5 9(s,2H),2.09(d,J=7.2Hz,2H),1.96-1.86(m,2H),0.99(d,J=6.8Hz,6H).

[0489] Example 42 Preparation method of compound LCT011093

[0490]

[0491] Compound 1 (50.0 mg, 0.10 mmol) was added to a 5 / 1 mixture of DCM and TFA (2 mL), and stirred at 25 °C for 1 hour. The reaction was detected by LC-MS. After completion, the reaction mixture was evaporated to obtain the crude product, which was then analyzed by HPLC (Gemini 5 μm C18 column, 150 × 21.2 mm, with 30% to 95% MeCN / H2O containing 0.1% TFA). 2O After elution (11.25 min), the solution was purified to a yellow solid, LCT011093 (TFA salt) (10.38 mg, yield: 30%). Mass spectrometry (ESI): molecular formula C 19 H 18 N₂O₃, molecular weight 322.13, m / z content 323.10 [M+H] + .

[0492] 1 H NMR (400MHz, DMSO-d6) δ11.90(brs,1H),9.43(brs,1H),8.08(d,J=7.2Hz,1H),7.88-7.73(m,2H),7.69-7.58(m,1H),7.28(d,J= 7.2Hz,1H),6.53(s,1H),4.59-4.49(m,2H),4.34-4.26(m,2H),3.93(t,J=6.8Hz,2H),2.31(t,J=7.6Hz,2H),1.98-1.85(m,2H).

[0493] Example 43: Preparation method of compound LCT011094

[0494]

[0495] Step 1: Preparation of tert-butyl 3-(1-(4-(tert-butoxy)-4-oxobutyl)-2-oxo-1,2-dihydrobenzo[cd]indol-5-yl)-2,5-dihydro-1H-pyrrole-1-carboxylic acid

[0496] Compound 1 (300 mg, 0.77 mmol) was reacted with 1,4-dioxane / H2O. ＝ Compound 2 (272 mg, 0.92 mmol), K₂CO₃ (212 mg, 1.5 mmol), and Pd(dppf)Cl₂ (56 mg, 0.077 mmol) were added to a 10:1 (10 mL) solution. The reaction was stirred at 100 °C for 5 hours, and the reaction was monitored by LCMS. After the reaction was complete, the reaction mixture was evaporated to give a crude product, which was purified by rapid chromatography (eluting with PE / EtOAc from 100 / 00 to 80 / 20) to give compound 3 (280.0 mg, yield: 68%) as a yellow solid. Mass spectrometry (ESI): molecular formula C 28 H 34 N₂O₅, molecular weight 478.25, m / z 479.35 [M+H] + .

[0497] Step 2: Preparation of tert-butyl 3-(1-(4-(tert-butoxy)-4-oxobutyl)-2-oxo-1,2-dihydrobenzo[cd]indol-5-yl)-2,5-dihydro-1H-pyrrole-1-carboxylic acid

[0498] Pd / C (128 mg, 80% by weight) was added to a MeOH (10 mL) solution of compound 3 (160 mg, 0.33 mmol). The mixture was stirred at 25 °C for 16 hours under a H2 atmosphere, and the reaction was monitored by LCMS. After the reaction was complete, the reaction mixture was filtered and evaporated to give the product compound 4 (150 mg, yield: 84%) as a yellow solid. Mass spectrometry (ESI): molecular formula C 28 H 36 N₂O₅, molecular weight 480.26, m / z 481.10 [M+H] + .

[0499] Step 3: Preparation of 4-(2-oxo-5-(pyrrolidone-3-yl)benzo[cd]indol-1(2H)-yl)butyric acid (LCT011094)

[0500] A solution of compound 4 (50.0 mg, 0.1045 mmol) in DCM / TFA = 5:1 (2 mL) was stirred at 25 °C for 1 hour, and the reaction was monitored by LCMS. After the reaction was complete, the reaction mixture was evaporated to give the crude product, which was then analyzed by preparative HPLC (Gemini 5 μm C18 column, 150 × 21.2 mm, with 30% to 95% MeCN / H2O containing 0.1% TFA). 2O The product LCT011094 (TFA salt) (80.0 mg, yield: 78%) was purified by elution and was given as a yellow solid.

[0501] Mass spectrometry (MS) (ESI): Molecular formula is C 19 H 20 N₂O₃, molecular weight 324.15, m / z 325.10 [M+H] + .

[0502] 1 H NMR(400MHz,DMSO-d6)δ10.01(brs,2H),8.05(d,J=7.2Hz,1H),7.86-7.75( m,2H),7.65-7.56(m,1H),7.24(d,J=6.8Hz,1H),4.35-4.16(m,1H),3.91(t, J=6.8Hz,2H),3.82-3.65(m,1H),3.51-3.37(m,1H),3.37-3.23(m,2H),2.4 8-2.43(m,1H),2.29(t,J=7.2Hz,2H),2.18-2.05(m,1H),1.97-1.84(m,2H).

[0503] Example 44 Preparation method of compound LCT011096

[0504]

[0505] The preparation method of LCT011096 is the same as that of LCT011094, and LCT011096 (TFA salt) (10.10 mg, purity: 99.244%, yield: 70.0%) is a yellow solid.

[0506] Mass spectrometry (MS) (ESI): Molecular formula is C 20 H 22 N₂O₃, molecular weight 338.16, m / z 339.15 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ12.10(brs,1H),8.88-8.74(m,1H),8.65-8.46(m,1H),8.05(d,J=7.7Hz,1H),7.90(d,J=8.8Hz,1H),7.66-7.55(m,2H), 7.23(d,J=7.2Hz,1H),3.91(t,J=6.8Hz,2H),3.82-3.70(m,1H),3.52-3 .39(m,2H),3.29-3.12(m,2H),2.31(t,J=7.2Hz,2H),2.09-1.84(m,6H).

[0507] Example 45: Preparation method of compound LCT011095

[0508]

[0509] Compound 1 (50.0 mg, 0.10 mmol) was added to a 5:1 mixture of DCM and TFA (2 mL), and stirred at 25 °C for 1 hour. The reaction was monitored by LC-MS. After the reaction was complete, the reaction mixture was evaporated to obtain the crude product, which was then passed by HPLC (Gemini 5 μm C18 column, 150 × 21.2 mm, 11.25 min) with 30% to 95% MeCN / H2O containing 0.1% TFA. 2O The product LCT011095 (TFA salt) (10.88 mg, yield: 31%) was purified by elution and given as a yellow solid.

[0510] Mass spectrometry (MS) (ESI): Molecular formula is C 20 H 20 N₂O₃, molecular weight 336.15, m / z 337.15 [M+H] + . 1H NMR (400MHz, DMSO-d6) δ12.08(brs,1H),8.92(s,2H),8.06(d,J=7.2Hz,1H),7.78-7.49(m,3H),7.25(d,J=7.2Hz,1 H),5.95(s,1H),3.97-3.83(m,4H),3.54-3.48(m,2H),2.78-2.69(m,2H),2.31(t,J=7.2Hz,2H),2.00-1.83(m,2H).

[0511] Example 46 Preparation method of compounds LCT011016 and LCT011098

[0512]

[0513]

[0514] Step 1: Preparation of (9s, 10s)-9,10-dihydro-9,10-[3,4]cyclopyrroloanthracene-12,14-dione

[0515] To a solution of anthracene (1.5 g, 8.4 mmol) in toluene (15 mL), 1H-pyrrole-2,5-dione (1.0 g, 10.9 mmol) was added, and the mixture was stirred at 80 °C for 48 hours. After the reaction was complete, the mixture was concentrated to remove most of the solvent, and the precipitate was collected by filtration. The precipitate was ground with EtOAc to give compound 3 (1.6 g, yield: 66%) as a white solid. Mass spectrometry (MS / ESI): molecular formula C 18 H 13 NO2, molecular weight 275.09, m / z 274.15 [MH] - .

[0516] Step 2: Preparation of (9s, 10s)-9,10-dihydro-9,10-[3,4]cyclopyrrole anthracene

[0517] A 32 mL solution of THF containing 1.6 g (5.8 mmol) of compound 3 was added to LiAlH4 (1.0 M THF solution, 28.9 mL, 28.9 mmol) at 0 °C, and stirred at 25 °C for 72 hours. After the reaction was complete, the mixture was quenched with Na2SO4·10H2O at 0 °C. The mixture was filtered, and the filtrate was concentrated under vacuum. The residue was purified by reversed-phase rapid chromatography (using H2O (0.1% FA·H2O) / MeCN from 90 / 10 to 75 / 25) to give compound 4 (270 mg, yield: 18%) as a white solid. Mass spectrometry (ESI): molecular formula C 18 H 17N, molecular weight 247.14, m / z 248.05 [M+H] + .

[0518] Step 3: Preparation of tert-butyl 4-(4-((tert-butyloxycarbonyl)amino)-2-oxobenzo[cd]indole-1(2H)-yl)butyrate

[0519] Under a nitrogen atmosphere, K₂CO₃ (639 mg, 4.62 mmol), BocNH₂ (1623 mg, 13.87 mmol), Pd₂(dba)₃ (105 mg, 0.11 mmol), and t-BuXPhos (98 mg, 0.23 mmol) were added to a Tol (16 mL) solution of compound LCT0110003-7 (800 mg, 2.31 mmol), and the mixture was stirred at 100 °C for 12 hours. After completion, the reaction mixture was quenched by adding water (20 mL). The mixture was then poured into a separating funnel for separation, the aqueous layer was extracted with EtOAc (20 mL × 3), the combined organic layers were washed with brine (20 mL), dried with Na₂SO₄, filtered, and concentrated on a rotary evaporator. The resulting oil phase was purified by rapid column chromatography (PE / EtOAc = 3 / 1) to give compound 5 (680 mg, yield: 68%), a yellow solid. Mass spectrometry (MS) (ESI): Molecular formula is C 24 H 30 N₂O₅, molecular weight 426.22, m / z 427.10 [M+H] + .

[0520] Step 4: Preparation of 4-(4-amino-2-oxobenzo[cd]indole-1(2H)-yl)butyric acid (LCT011016)

[0521] Compound 5 (680 mg, 1.59 mmol) was added to a 1:5 TFA / DCM mixture (12 mL). The mixture was stirred at 25 °C for 3 hours. After the reaction was complete, the mixture was concentrated, and the residue was purified by reversed-phase rapid chromatography (using H2O (0.1% FA·H2O) / MeCN from 90 / 10 to 65 / 35) to give LCT011016 (260 mg, yield: 60%) as a yellow solid. Mass spectrometry (ESI): molecular formula C 15 H 14 N₂O₃, molecular weight 270.10, m / z 271.10 [M+H] + .

[0522] 1H NMR(400MHz,DMSO-d6)12.07(s,1H),7.39(s,1H),7.37-7.24(m,2H),7.06(s,1H),6.82(d, J=6.4Hz,1H),5.80(s,2H),3.83(d,J=6.4Hz,2H),2.27(t,J=6.8Hz,2H),1.92-1.84(m,2H).

[0523] Step 5: Preparation of 2,5-dioxopyrrolidone-1-yl 4-(4-amino-2-oxobenzo[cd]indole-1(2H)-yl)butyrate

[0524] At 0 °C, DCC (117 mg, 0.56 mmol) and 1-hydroxypyrrolidine-2,5-dione (60 mg, 0.52 mmol) were added to a 2 mL solution of DCM containing LCT011016 (110 mg, 0.40 mmol). The mixture was stirred at 25 °C for 12 hours, and the reaction was monitored by LC-MS. After the reaction was complete, the reaction mixture was quenched by adding water (10 mL), and the mixture was then poured into a separating funnel and separated. The aqueous layer was extracted with DCM (20 mL × 3). The combined organic layers were washed with brine (10 mL), dried over Na2SO4, filtered, and concentrated to give crude compound 7 (110 mg, yield: 61%), which was used directly for the next step without further purification.

[0525] Mass spectrometry (MS) (ESI): Molecular formula is C 19 H 17 N3O5, molecular weight 367.12, m / z 368.10 [M+H] + .

[0526] Step 6: Preparation of 4-amino-1-(4-((9S,10S)-9,10-dihydro-9,10-[3,4]cyclopyrroloanth-13-yl)-4-oxobutyl)benzo[cd]indol-2(1H)-one (LCT011098)

[0527] Compound 4 (74 mg, 0.29 mmol) and TEA (60 mg, 0.59 mmol) were added to a solution of compound 7 (110 mg, 0.29 mmol) in acetonitrile (1 mL). The mixture was stirred at 25 °C for 3 hours. After stirring, the reaction mixture was quenched by adding water (10 mL), and then the mixture was poured into a separating funnel and separated. The aqueous layer was extracted with EtOAc (20 mL × 3). The combined organic layers were washed with brine (10 mL), dried with Na2SO4, filtered, and concentrated to give a crude product. The crude product was purified by prep-HPLC (column: Gemini 5 μm C18150 × 21.2 mm, mobile phase: ACN-H2O (0.1% FA), gradient: 40-95, 12.50 min) to give LCT011098 (29.3 mg, yield: 19%) as a yellow solid. Mass spectrometry (ESI): molecular formula C 33 H 29 N3O2, molecular weight 499.23, m / z 500.15 [M+H] + .

[0528] 1 H NMR (400MHz, DMSO-d6)7.42-7.37(m,1H),7.36-7.21(m,5H),7.15(d,J=7.2Hz,1H),7.12-7. 05(m,3H),6.97(d,J=7.2Hz,1H),6.86-6.74(m,2H),5.80(s,2H),4.29-4.23(m,2H),3.70-3 .60(m,2H),3.42-3.35(m,1H),3.27-3.17(m,1H),3.14-3.07(m,1H),2.96-2.89(m,1H),2.7 6-2.65(m,1H),2.65-2.55(m,1H),2.00-1.90(m,1H),1.78-1.68(m,1H),1.65-1.55(m,2H).

[0529] Example 47 Preparation method of compound LCT011099

[0530]

[0531] Step 1: Preparation of 2,5-dioxopyrrolidone-1-yl 4-(4-methyl-2-oxobenzo[cd]indole-1(2H)-yl)butyrate

[0532] At 0 °C, DCC (59 mg, 0.28 mmol) and 1-hydroxypyrrolidine-2,5-dione (30 mg, 0.26 mmol) were added to a DCM (2 mL) solution of compound LCT011078 (60 mg, 0.22 mmol). The mixture was stirred at 25 °C for 6 hours, and the reaction was monitored by LC-MS. After the reaction was complete, water was added to the solution and extracted with DCM. The organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated to give crude compound 5 (60 mg, yield: 73%), which was used directly in the next step without further purification. Mass spectrometry (ESI): Molecular formula C 20 H 18 N₂O₅, molecular weight 366.12, m / z 367.05 [M+H] + .

[0533] Step 2: Preparation of 1-(4-((9S,10S)-9,10-dihydro-9,10-[3,4]cyclopyrroloanth-13-yl)-4-oxobutyl)-4-methylbenzo[cd]indol-2(1H)-one

[0534] Compound 6 (40 mg, 0.16 mmol) and TEA (33 mg, 0.32 mmol) were added to a DCM (2 mL) solution of compound 5 (60 mg, 0.16 mmol). The mixture was stirred at 25 °C for 6 hours. Water was added to the solution and the mixture was extracted with DCM. The organic layer was concentrated to obtain a crude product, which was purified by prep-HPLC (column: Gemini 5 μm C18 150 × 21.2 mm, mobile phase: acetonitrile-H2O (0.1% FA), gradient: 55-95, 12.50 min) to obtain compound LCT011099 (34.35 mg, yield: 42%) as a yellow solid.

[0535] Mass spectrometry (MS) (ESI): Molecular formula is C 34 H 30 N₂O₂, molecular weight 498.23, m / z 499.20 [M+H] + .

[0536] 1HNMR(400MHz,DMSO-d6)δ7.98(s,1H),7.92(s,1H),7.58-7.49(m,2H),7.33-7.27(m,2H),7.24(d,J=7 .2Hz,1H),7.15(d,J=7.2Hz,1H),7.12-7.05(m,3H),6.97(d,J=6.8Hz,1H),6.82(d,J=7.2Hz,1H),4.29 -4.24(m,2H),3.79-3.64(m,2H),3.43-3.33(m,1H),3.27-3.17(m,1H),3.14-3.06(m,1H),2.97-2.89( m,1H),2.76-2.67(m,1H),2.63-2.59(m,4H),2.02-1.92(m,1H),1.82-1.70(m,1H),1.69-1.58(m,2H).

[0537] Example 48: Preparation method of compound LCT011100

[0538] The preparation method of LCT011100 is the same as that of LCT011099.

[0539]

[0540] LCT011100 (31.87 mg, yield: 23%) was obtained.

[0541] Mass spectrometry (MS) (ESI): Molecular formula is C 33 H 28 N₂O₃, molecular weight 500.21, m / z 501.15 [M+H] + . 1H NMR (400MHz, DMSO-d6)10.27(s,1H),7.51(d,J=2.0Hz,1H),7.47-7.43(m,2H),7.41(d,J=2.0Hz,1H),7.32- 7.27(m,2H),7.24(d,J=7.2Hz,1H),7.15(d,J=7.2Hz,1H),7.11-7.05(m,2H),7.01-6.90(m,2H),6.85-6.77( m,1H),4.29-4.24(m,2H),3.73-3.61(m,2H),3.43-3.33(m,1H),3.26-3.17(m,1H),3.15-3.06(m,1H),2.97- 2.89(m,1H),2.76-2.67(m,1H),2.65-2.56(m,1H),2.01-1.91(m,1H),1.81-1.69(m,1H),1.66-1.56(m,2H).

[0542] Example 49 Preparation method of compound LCT011103

[0543]

[0544] Step 1: Preparation of (9S,10S)-9,10-dihydro-9,10-ethylanthracene-11-carboxynitrile

[0545] To a solution of anthracene (4.0 g, 22.4 mmol) in o-xylene (35 mL), propenylonitrile (5.94 g, 112.0 mmol) and BHT (50 mg, 0.022 mmol) were added, and the mixture was stirred at 150 °C for 24 h. The reaction mixture was cooled, unreacted anthracene was filtered off, and the solvent was removed under reduced pressure. The crude product was purified by rapid chromatography (eluting from 100 / 00 to 90 / 10 with PE / EtOAc within 20 min) to give compound 2 (2.8 g, yield: 51%) as a white solid. The product was confirmed by 1H NMR.

[0546] 1 HNMR(400MHz,DMSO-d6)δ7.46-7.41(m,1H),7.39-7.32(m,3H),7.21-7.17(m,2H),7.16-7.11(m,2H) ,4.71(d,J=2.4Hz,1H),4.55-4.44(m,1H),3.24-3.10(m,1H),2.23-2.11(m,1H),1.83-1.68(m,1H).

[0547] Step 2: Preparation of ((9S,10S)-9,10-dihydro-9,10-ethylanthracene-11-yl)methylamine. LiAlH4 (0.65 g, 17.2 mmol) was added to a THF (50 mL) solution of compound 2 (2.0 g, 8.6 mmol) at 0 °C and the mixture was stirred at 25 °C for 24 hours. The reaction was monitored by LCMS. After the reaction was complete, the reaction mixture was carefully quenched with ice water, extracted with EtOAc, and the organic layer was evaporated to obtain the crude product. The crude product was purified by reversed-phase chromatography (eluting with 10%-90% MeCN / H2O containing 0.1% FA) to give compound 3 (400.0 mg, yield: 18%) as a white solid.

[0548] Mass spectrometry (MS) (ESI): Molecular formula is C 17 H 17 N, molecular weight 235.14, m / z 236.10 [M+H] + .

[0549] Step 3: Preparation of N-(((9S,10S)-9,10-dihydro-9,10-ethylanthracene-11-yl)methyl)-4-(4-methyl-2-oxobenzo[cd]indol-1(2H)-yl)butyramide

[0550] DCC (57.5 mg, 0.28 mmol) and HOSu (32.1 mg, 0.28 mmol) were added to a DCM (5 mL) solution of compound 3 (50.0 mg, 0.18 mmol). The reaction was stirred at 25 °C for 5 h, followed by the addition of ((9S, 10S)-9,10-dihydro-9,10-ethylanthracene-11-yl)methylamine (43.7 mg, 0.18 mmol), and the reaction was stirred at 25 °C for 16 h. The reaction was monitored by LCMS. After the reaction was complete, the reaction mixture was quenched with H2O and extracted with DCM. The organic layer was evaporated to give the crude product, which was purified by HPLC (Gemini 5 μm C18 column, 150 × 21.2 mm, eluted with 30% to 95% MeCN / H2O containing 0.1% FA) to give product LCT011100 (30.55 mg, yield: 33%) as a yellow solid.

[0551] Mass spectrometry (MS) (ESI): Molecular formula is C 33 H 30 N₂O₂, molecular weight 486.23, m / z 487.15 [M+H] + . 1HNMR(400MHz, DMSO-d6)δ7.97(s,1H),7.90(s,1H),7.86(t,J=5.6Hz,1H),7.57-7.47(m,2H),7.31-7.24(m,4H),7.14-7.04(m,5H),4.33-4.23(m, 2H),3.89(t,J=6.8Hz,2H),2.67-2.59(m,4H),2.58-2.54(m,1H),2.16(t ,J=7.6Hz,2H),1.99-1.88(m,3H),1.86-1.76(m,1H),1.07-0.98(m,1H).

[0552] Example 50: Preparation method of compound LCT011105

[0553]

[0554] Step 1: Preparation of tert-butyl 4-(2-oxo-4-vinylbenzo[cd]indole-1(2H)-yl)butyrate

[0555] To a solution of compound LCT0110003-7 (400.0 mg, 1.16 mmol) in 1,4-dioxane:H₂O = 10:1 (15 mL), vinyl potassium trifluoroborate (309.88 mg, 2.31 mmol), K₂CO₃ (319.73 mg, 2.31 mmol), and Pd(dppf)Cl₂ (84.64 mg, 0.12 mmol) were added, and the mixture was stirred at 100 °C for 5 h. The reaction was monitored by LC-MS. Water was added to the solution, and the mixture was extracted with EtOAc. The organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The product was purified by rapid chromatography (eluting with PE / EtOAc from 100 / 00 to 90 / 10) to give compound 1 (250.0 mg, purity: 90.0%, yield: 57%) as a yellow solid. Mass spectrometry (ESI): molecular formula C 21 H 23 NO3, molecular weight 337.17, m / z 337.95 [M+H] + .

[0556] Step 2: tert-butyl 4-(4-ethyl-2-oxobenzo[cd]indole-1(2H)-yl)butyrate

[0557] Pd / C (10.0 mg, 10% wt) was added to a MeOH (15 mL) solution of compound 1 (100.0 mg, 0.30 mmol), and the mixture was stirred at 25 °C for 16 h. The reaction was monitored by LC-MS. After the reaction was complete, the reaction mixture was filtered and concentrated to give compound 2 (100 mg, yield: 89%) as a yellow solid.

[0558] Mass spectrometry (MS) (ESI): Molecular formula is C 21 H 25 NO3, molecular weight 339.18, m / z 340.30 [M+H] + .

[0559] Step 3: Preparation of 4-(4-ethyl-2-oxobenzo[cd]indole-1(2H)-yl)butyric acid

[0560] Compound 2 (100.0 mg, 0.29 mmol) was added to a mixed solution of DCM:TFA = 5:1 (5 mL), and the mixture was stirred at 25 °C for 1 hour. The reaction was monitored by LC-MS. After the reaction was complete, the reaction mixture was evaporated to give a crude product, which was purified by HPLC (Gemini 5 μm C18 column, 150 × 21.2 mm, eluted with 30% to 95% MeCN / H2O containing 0.1% FA, 11.25 min) to give LCT011105 (54.01 mg, yield: 62%) as a yellow solid.

[0561] Mass spectrometry (MS) (ESI): Molecular formula is C 17 H 17 NO3, molecular weight 283.12, m / z 283.80 [M+H] + .

[0562] 1 HNMR(400MHz,DMSO-d6)δ12.08(s,1H),8.00(s,1H),7.95(s,1H),7.60-7.47(m,2H),7.14(d,J=6.8Hz,1H) ,3.90(t,J=7.2Hz,2H),2.97-2.84(m,2H),2.30(t,J=7.2Hz,2H),1.99-1.86(m,2H),1.30(t,J=7.2Hz,3H).

[0563] Example 51: Preparation method of compound LCT011108

[0564]

[0565] Step 1: Preparation of tert-butyl 4-(4-methoxy-2-oxobenzo[cd]indole-1(2H)-yl)butyrate

[0566] NaH (7 mg, 0.29 mmol) was added to a DMF (2 mL) solution of compound 1 (80 mg, 0.24 mmol) at 0 °C. After reacting for 30 min at 0 °C, MeI (41 mg, 0.29 mmol) was added, and the reaction was stirred at 25 °C for 2 h. The reaction was monitored by LC-MS. Water was added to the solution, and the mixture was extracted with EtOAc. The organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The product was purified by rapid chromatography (eluting from 100 / 00 to 75 / 25 with PE / EtOAc within 30 min) to give compound 2 (65 mg, yield: 78%) as a yellow solid. Mass spectrometry (ESI): molecular formula C 20 H 23 NO4, molecular weight 341.16, m / z 341.95 [M+H] + .

[0567] Step 2: Preparation of 4-(4-methoxy-2-oxobenzo[cd]indole-1(2H)-yl)butyric acid

[0568] A TFA (1 mL) solution of compound 2 (65 mg, 0.19 mmol) was prepared. The reaction mixture was stirred at 25 °C for 1 hour, and the reaction was monitored by LC-MS. After the reaction was complete, the reaction mixture was concentrated, quenched with water, extracted with EtOAc, and the organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by prep-HPLC (column: Gemini 5 μm C18150 × 21.2 mm, mobile phase: acetonitrile-H2O (0.1% FA), gradient: 20-95, 12.50 min) to obtain LCT011108 (22.63 mg, yield: 41%) as a yellow solid. Mass spectrometry (ESI): molecular formula C 16 H 15 NO4, molecular weight 285.10, m / z 286.10 [M+H] + .

[0569] 1 HNMR(400MHz,DMSO-d6)12.10(s,1H),7.68-7.61(m,2H),7.57-7.46(m,2H),7.06(d,J=6 .4Hz,1H),3.95(s,3H),3.88(t,J=7.2Hz,2H),2.30(t,J=7.6Hz,2H),1.97-1.85(m,2H).

[0570] Example 52: Preparation method of compound LCT011109

[0571]

[0572] Step 1: Preparation of tert-butyl [4-(2-oxo-1H-indol-3-ylidene)piperidin-1-yl]formate

[0573] At 0 °C, NaH (0.79 g, 0.033 mol) was added to a THF (40 mL) solution of compound 1 (2 g, 0.015 mol). After 30 min, compound 2 (3 g, 0.015 mol) was added, and the reaction was stirred at 25 °C for 16 h. The reaction was monitored by LC-MS. Water was added to the reaction solution, and the mixture was extracted with EtOAc. The organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The product was purified by rapid chromatography (eluting with PE / EtOAc from 100 / 00 to 80 / 20, 30 min) to give compound 3 (1.6 g, yield: 34%) as a white solid. Mass spectrometry (ESI): molecular formula C 18 H 22 N₂O₃, molecular weight 314.16, m / z 313.10 [MH] - .

[0574] Step 2: Preparation of tert-butyl [4-(2-oxo-1,3-dihydroindol-3-yl)piperidin-1-yl]formate

[0575] Under a H2 atmosphere, Pd / C (330 mg, 10% wt) was added to a MeOH (50 mL) solution of compound 3 (1.1 g, 3.5 mmol), and the reaction was stirred at 25 °C for 12 h. The reaction mixture was monitored by LC-MS. The reaction mixture was filtered, and the solution was concentrated under vacuum. The resulting crude compound 4 (1.1 g, yield: 100%) was used directly in the next step without further purification.

[0576] Mass spectrometry (MS) (ESI): Molecular formula is C 18 H 24 N₂O₃, molecular weight 316.18, m / z 315.15 [MH] - .

[0577] Step 3: Preparation of 3-(piperidin-4-yl)-1,3-dihydroindole-2-one

[0578] Compound 4 (500 mg, 1.57 mmol) and 2 M HCl were added to dioxane (5 mL). The mixture was stirred at 25 °C for 6 hours, and the reaction was monitored by LC-MS. The reaction mixture was filtered, and the filter cake was concentrated under vacuum to obtain the crude product. The obtained crude compound 5 (300 mg, yield: 88%) was used directly in the next step without further purification. Mass spectrometry (ESI): Molecular formula C 13 H 16 N₂O, molecular weight 216.13, m / z 217.15 [M+H] + .

[0579] Step 4: Preparation of 4-methyl-1-(4-oxo-4-(4-(2-oxoindololin-3-yl)piperidin-1-yl)butyl)benzo[cd]indol-2(1H)-one

[0580] Compound 6 (118 mg, 0.32 mmol) and TEA (6.5 mg, 0.64 mmol) were added to a DCM (2 mL) solution of compound 5 (70 mg, 0.32 mmol). The reaction was stirred at 25 °C for 3 h, and the reaction was monitored by LC-MS. The reaction mixture was concentrated under vacuum to obtain a crude product, which was purified by prep-HPLC (column: Gemini 5 μm C18 150 × 21.2 mm, mobile phase: acetonitrile-H2O (0.1% FA), gradient: 30-95, 12.50 min) to obtain LCT011109 (69.01 mg, yield: 45.6%) as a yellow solid. Mass spectrometry (ESI): molecular formula C 29 H 29 N3O3, molecular weight 467.22, m / z 468.20 [M+H] + .

[0581] 1HNMR (400MHz, DMSO-d6)10.38(s,1H),7.96(s,1H),7.88(d,J=6.0Hz,1H),7.57-7.43(m,2H),7.23(d,J =7.6Hz,1H),7.17(d,J=7.6Hz,1H),7.11(d,J=6.8Hz,1H),6.93(d,J=7.2Hz,1H),6.81(d,J=7.6Hz,1H) ,4.52-4.35(m,1H),3.91-3.71(m,3H),3.44-3.40(m,1H),2.96-2.79(m,1H),2.60(s,3H),2.44-2.30( m,3H),2.27-2.14(m,1H),1.92-1.83(m,2H),1.65-1.50(m,1H),1.48-1.37(m,1H),1.36-1.18(m,2H).

[0582] Example 53: Preparation method of compound LCT011110

[0583]

[0584] Step 1: Preparation of 3-bromo-9H-thioxanthracene-9-one 10,10-dioxide

[0585] To a DCM (12 mL) solution of 3-bromothiaanthracene-9-one (600 mg, 2.06 mmol), m-CPBA (889 mg, 5.15 mmol) was added, and the mixture was stirred at 25 °C for 6 hours. The reaction was monitored by TLC. Water was added to the mixture, and the mixture was extracted with DCM. The organic layer was washed with saturated NaHCO3, dried over anhydrous sodium sulfate, filtered, and concentrated to give crude compound 2 (600 mg, yield: 81%), which could be used directly without further purification.

[0586] Step 2: Preparation of (10,10-dioxanthracene-3-yl)tert-butyl carbamate. Under a nitrogen atmosphere, K2CO3 (513 mg, 3.71 mmol), BocNH2 (1303 mg, 11.14 mmol), Pd2(dba)3 (85 mg, 0.092 mmol), and t-BuXPhos (78 mg, 0.18 mmol) were added to a toluene solution of compound 2 (600 mg, 1.85 mmol). The reaction was stirred at 100 °C for 12 h, and the reaction was monitored by LC-MS. Water was added to the solution, and the mixture was extracted with EtOAc. The organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The product was purified by chromatography (eluting from 100 / 00 to 60 / 40 with PE / EtOAc within 20 min) to give compound 3 (420 mg, yield: 52%) as a white solid. Mass spectrometry (MS) (ESI): Molecular formula is C 18 H 17 NO5S, molecular weight 359.08, m / z 358.05 [MH] - .

[0587] Step 3: Preparation of 10,10-dioxide of 3-amino-9H-thioxanthracene-9-one

[0588] Compound 3 (420 mg, 1.16 mmol) and 2 M HCl were added to dioxane (5 mL), and the mixture was stirred at 25 °C for 6 hours. The reaction was monitored by LC-MS. The reaction mixture was filtered, and the filter cake was concentrated under vacuum to obtain the crude product. The obtained crude product, compound 4 (210 mg, yield: 69%), was used directly in the next step without further purification. Mass spectrometry (ESI): Molecular formula C 13 H9NO3S, molecular weight 260.03, m / z 260.05 [M+H] + .

[0589] Step 4: Preparation of N-(10,10-dioxo-9-oxo-9H-thioxanthracene-3-yl)-4-(4-methyl-2-oxobenzo[cd]indole-1(2H)-yl)butyramide

[0590] To a pyridine (2 mL) solution of compound 4 (55 mg, 0.21 mmol), 4-(4-methyl-2-oxobenzo[cd]indol-1(2H)-yl)butyric acid (57 mg, 0.21 mmol) and T3P (337 mg, 1.06 mmol) were added, and the mixture was stirred at 50 °C for 1 h. The reaction was monitored by LC-MS. Water was added to the solution, and the mixture was extracted with EtOAc. The organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated to give the crude product. The crude product was ground with DMSO and acetonitrile to give LCT011110 (32.29 mg, yield: 29%) as a yellow solid.

[0591] Mass spectrometry (MS) (ESI): Molecular formula is C 29 H 22 N₂O₅S, molecular weight 510.12, m / z 511.05 [M+H] + . 1 H NMR(400MHz, DMSO-d6)10.82(s,1H),8.49(d,J=2.0Hz,1H),8.32-8.25(m,1H),8.25-8.17(m,2H),8.08-8.00(m,1H),7.99-7.95(m,1H), 7.95-7.91(m,1H),7.89-7.84(m,2H),7.55-7.47(m,2H),7.20-7.14(m,1H),3.98(d,J=6.8Hz,2H),2.58-2.52(m,5H),2.13-2.05(m,2H).

[0592] Example 54: Preparation method of compound LCT011111

[0593]

[0594] Step 1: Preparation of 2,4-dimethyl-5-aminosulfonylbenzoic acid

[0595] Under ice bath conditions, ammonia (5 mL) was added dropwise to a DCM (5 mL) suspension of compound 1 (400 mg, 1.6 mmol). The mixture was stirred at 25 °C for 1 hour, and the reaction was monitored by LCMS. After the reaction was complete, the mixture was concentrated under vacuum to remove DCm, and the pH was adjusted to 5-6 with 6 M HCl aqueous solution. The mixture was filtered, and the filter cake was collected and dried under vacuum to give compound 2 (350.0 mg, yield: 85%) as a white solid. Mass spectrometry (ESI): molecular formula C9H 11 NO4S, molecular weight 229.04, m / z 228.05 [MH] - .

[0596] Step 2: Preparation of 4-(2,4-dimethyl-5-aminosulfonylbenzoyl)piperazine-1-carboxylic acid tert-butyl ester

[0597] TCFH (642 mg, 2.3 mmol), NMI (626 mg, 7.6 mmol), and tert-butylpiperazine-1-carboxylate (385 mg, 1.5 mmol) were added to a DMF (10 mL) solution of compound 3 (350 mg, 1.5 mmol). The mixture was stirred at 25 °C for 1 h, and the reaction was monitored by LC-MS. After the reaction was complete, the reaction mixture was quenched with H₂O, extracted with EtOAc, and the organic layer was evaporated to give the crude product. The crude product was purified by rapid chromatography (eluting from 100 / 00 to 50 / 50 with PE / EtOAc within 20 min) to give compound 4 (600 mg, yield: 88%) as a white solid. Mass spectrometry (ESI): molecular formula C 18 H 27 N3O5S, molecular weight 397.17, m / z 396.10 [MH] - .

[0598] Step 3: Preparation of 2,4-dimethyl-5-(piperazine-1-carbonyl)benzenesulfonamide

[0599] Compound 4 (300.0 mg, 0.75 mmol) and 1 M HCl were added to EtOAc (5 mL), and the mixture was stirred at 25 °C for 2 hours. The reaction was monitored by LCMS. After the reaction was complete, the mixture was filtered to collect the filter cake, which was dried under vacuum to give a white solid compound 5 (HCl salt) (200.0 mg, yield: 80%).

[0600] Mass spectrometry (MS) (ESI): Molecular formula is C 13 H 19 N3O3S, molecular weight 297.11, m / z 298.10 [M+H] + .

[0601] Step 4: Preparation of 2,4-dimethyl-5-(4-(4-(4-methyl-2-oxobenzo[cd]indol-1(2H)-yl)butyryl)piperazine-1-carbonyl)benzenesulfonamide (LCT0111111)

[0602] Compound 5 (55 mg, 0.19 mmol) and a 50% T3P EtOAc solution (590 mg, 0.93 mmol) were added to a pyridine (4 mL) solution of 4-(4-methyl-2-oxobenzo[cd]indol-1(2H)-yl)butyric acid (50 mg, 0.19 mmol). The mixture was stirred at 60 °C for 1 h, and the reaction was monitored by LCMS. After the reaction was completed, the mixture was concentrated to give a crude product. The crude product was subjected to HPLC (Gemini 5 μm C18 column, 150 × 21.2 mm, eluted with 30-95% MeCN / H2O containing 0.05% ammonia) to give LCT0111111 (31.32 mg, yield: 30%) as a yellow solid.

[0603] Mass spectrometry (MS) (ESI): Molecular formula is C 29 H 32 N4O5S, molecular weight 548.21, m / z 549.15 [M+H] + . 1 HNMR(400MHz,DMSO-d6)δ7.99-7.93(m,1H),7.90(d,J=10.0Hz,1H),7.61(s,1 H),7.57-7.48(m,2H),7.41(s,2H),7.30(s,1H),7.17-7.09(m,1H),3.94-3.8 3(m,2H),3.73-3.56(m,2H),3.55-3.43(m,2H),3.44-3.32(m,2H),3.15-3.05 (m,2H),2.64-2.53(m,6H,2.45-2.32(m,2H),2.23(s,3H),2.00-1.84(m,2H).

[0604] Example 55 Preparation method of compound LCT011117

[0605]

[0606] Step 1: Preparation of 4-(1-(4-((9S,10S)-9,10-dihydro-9,10-[3,4]cyclopyrroloanth-13-yl)-4-oxobutyl)-2-oxo-1,2-dihydrobenzo[cd]indol-5-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester. Compound 2 (176 mg, 0.40 mmol) and T3P (643 mg, 2.02 mmol) were added to a pyridine (2 mL) solution of compound 1 (100 mg, 0.40 mmol). The reaction was stirred at 50 °C for 1 hour, and the reaction was monitored by LC-MS. After the reaction was complete, water was added to the solution, and the mixture was extracted with EtOAc. The organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the product. The product was purified by rapid chromatography (eluting from 100 / 00 to 95 / 05 with DCM / MeOH over 30 min) to give compound 3 (100 mg, yield: 37%) as a yellow solid. Mass spectrometry (ESI): Molecular formula C 43 H 43 N3O4, molecular weight 665.33, m / z 666.30 [M+H] + .

[0607] Step 2: Preparation of 1-(4-((9S,10S)-9,10-dihydro-9,10-[3,4]cyclopyrroloanth-13-yl)-4-oxobutyl)-5-(1,2,3,6-tetrahydropyridin-4-yl)benzo[cd]indol-2(1H)-one

[0608] Compound 3 (100 mg, 0.15 mmol) was added to TFA (2 mL), and the mixture was stirred at 25 °C for 1 hour. The reaction was monitored by LC-MS. The reaction mixture was concentrated to obtain a crude product, which was purified by prep-HPLC (column: Gemini 5 μm C18 150 × 21.2 mm, mobile phase: acetonitrile-H2O (0.1% TFA), gradient: 35-95, 12.50 min) to give LCT011117 (4.49 mg, yield: 2.6%) as a yellow solid. Mass spectrometry (ESI): molecular formula C 38 H 35 N3O2, molecular weight 565.27, m / z value found to be 566.25[M+H]+.

[0609] 1HNMR (400MHz, DMSO-d6)8.28(d,J=8.0Hz,1H),8.07(d,J=6.8Hz,1H),7.86-7.78(m,1H),7.40(d,J=7.2Hz,1H),7.31-7.27(m,2H ),7.24(d,J=7.2Hz,1H),7.16-7.11(m,2H),7.11-7.05(m,2H),6.97(t,J=6.8Hz,1H),6.80(t,J=7.2Hz,1H),5.87(s,1H),4.29- 4.23(m,2H),3.78-3.68(m,2H),3.48-3.43(m,2H),3.43-3.33(m,2H),3.26-3.16(m,1H),3.13-3.04(m,1H),3.04-2.97(m,1H), 2.96-2.88(m,1H),2.75-2.65(m,1H),2.64-2.57(m,1H),2.41(s,2H),2.03-1.93(m,1H),1.80-1.70(m,1H),1.70-1.59(m,2H).

[0610] Example 56 Preparation method of compound LCT011118

[0611]

[0612] Step 1: Preparation of ethyl 4-(5-bromo-2-oxobenzo[cd]indole-1(2H)-yl)butyrate

[0613] To a DMF (15 mL) solution of compound 1 (450 mg, 1.8 mmol), ethyl 4-bromobutyrate (2 mg, 7.3 mmol), KI (301 mg, 1.8 mmol), and K₂CO₃ (752 mg, 5.4 mmol) were added, and the mixture was stirred at 50 °C for 16 hours. After the reaction was complete, the reaction mixture was quenched with H₂O, extracted with EtOAc, and the organic layer was evaporated to give the crude product. This crude product was purified by rapid chromatography (eluting from 100 / 00 to 80 / 20 with PE / EtOAc within 20 min) to give compound 2 (400 mg, yield: 50%) as a yellow solid. Mass spectrometry (ESI): molecular formula C 17 H 16 BrNO3, molecular weight 361.03, m / z 362.05 [M+H] + .

[0614] Step 2: Preparation of tert-butyl 4-(1-(4-ethoxy-4-oxobutyl)-2-oxo-1,2-dihydrobenzo[cd]indol-5-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid

[0615] To compound 2 (400 mg, 1.10 mmol) 1,4-dioxane / H2O ＝ 4-(4,4,5,5-tetramethyl-1,3,2-dioxoboronyl-2-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester (409 mg, 1.32 mmol), K₂CO₃ (305 mg, 2.21 mmol), and Pd(dppf)Cl₂ (81 mg, 0.1104 mmol) were added to a 10 / 10 mL solution and stirred at 80 °C for 5 h. The reaction was monitored by LCMS. After the reaction was complete, water was added to the reaction solution and extracted with EtOAc. The organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The product was purified by rapid chromatography (eluting with PE / EtOAc from 100 / 00 to 80 / 20) to give compound 3 (400.0 mg, yield: 90%) as a yellow solid. Mass spectrometry (ESI): molecular formula C 27 H 32 N₂O₅, molecular weight 464.23, m / z 465.25 [M+H] + .

[0616] Step 3: Preparation of 4-(5-(1-(tert-butoxycarbonyl)-1,2,3,6-tetrahydropyridin-4-yl)-2-oxobenzo[cd]indole-1(2H)-yl)butyric acid

[0617] Compound 3 (400 mg, 0.86 mmol) was added to a THF / H₂O solution of 2:1 (1 mL) with NaOH (68 mg, 1.7 mmol). The mixture was stirred at 50 °C for 5 hours, and the reaction was monitored by LC-MS. After the reaction was complete, the pH was adjusted to 5-6 with aqueous HCl (2N), and the mixture was extracted with EtOAc. The organic layer was dried over Na₂SO₄, filtered, and concentrated to give compound 4 (330.0 mg, yield: 79%) as a yellow solid. Mass spectrometry (ESI): Molecular formula C 25 H 26 N₂O₅, molecular weight 436.20, m / z 437.05 [M+H] + .

[0618] Step 4: Preparation of tert-butyl 4-(1-(4-(9s, 10s)-9,10-dihydro-9,10-ethylanthracene-11-yl)methyl)amino)-4-oxobutyl)-2-oxo-1,2-dihydrobenzo[cd]indol-5-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid

[0619] To a pyridine (5 mL) solution of compound 4 (100 mg, 0.23 mmol), methylamine ((9S, 10S)-9,10-dihydro-9,10-ethylanthracene-11-yl)methylamine (53 mg, 0.23 mmol) and T3P (145 mg, 0.46 mmol) were added. The reaction was stirred at 60 °C for 16 h, and the reaction was monitored by LCMS. After the reaction was complete, the mixture was concentrated, and the concentrate was purified by rapid chromatography (eluting with PE / EtOAc from 100 / 00 to 50 / 50) to give compound 5 (100.0 mg, yield: 60%) as a yellow solid. Mass spectrometry (ESI): molecular formula C 42 H 43 N3O4, molecular weight 653.33, m / z 654.25 [M+H] + .

[0620] Step 5: Preparation of N-(((9S,10S)-9,10-dihydro-9,10-ethylanthracene-11-yl)methyl)-4-(2-oxo-5-(1,2,3,6-tetrahydropyridin-4-yl)benzo[cd]indol-1(2H)-yl)butyramide (LCT011118) Compound 5 (100 mg, 0.15 mmol) was added to a mixture of TFA / DCM = 1 / 5 (5 mL), and stirred at 25 °C for 2 hours. The reaction was monitored by LC-MS. After the reaction was complete, the reaction mixture was evaporated to obtain a crude product. This crude product was purified by HPLC (Gemini 5μm C18 column, 150×21.2mm, eluting with 30% to 95% MeCN / H2O containing 0.1% TFA over 11.25 min) to obtain product LCT011118 (TFA salt) (27.1 mg, yield: 31%), as a yellow solid. Mass spectrometry (MS) (ESI): Molecular formula C 37 H 35 N3O2, molecular weight 553.27, m / z 554.35 [M+H] + .

[0621] 1HNMR(400MHz,DMSO-d6)δ9.05-8.81(m,2H),8.31(d,J=8.4Hz,1H),8.09(d,J=6.8Hz,1H),7 .93-7.75(m,2H),7.44(d,J=7.6Hz,1H),7.31-7.17(m,5H),7.12-7.01(m,4H),5.88(s,1H) ,4.27(d,J=14.8Hz,2H),3.98-3.77(m,5H),3.50-3.30(m,2H),2.79-2.66(m,2H),2.66-2. 53(m,2H),2.17(t,J=7.2Hz,2H),1.98-1.88(m,3H),1.87-1.76(m,1H),1.07-0.99(m,1H).

[0622] Example 57 Preparation method of compound LCT011119

[0623] The preparation method of LCT 011119 is the same as that of LCT011118.

[0624]

[0625] LCT011119 (TFA salt) (14.06 mg, purity: 93.44%, yield: 17%) was obtained as a yellow solid. Mass spectrometry (ESI): molecular formula C 33 H 27 N3O5S, molecular weight 577.17, m / z 578.15 [M+H] + .

[0626] 1 H NMR (400MHz, DMSO-d6) δ10.78(s,1H),9.11-8.81(m,2H),8.50(d,J=2.0Hz,1H),8.29(d,J =8.4Hz,2H),8.24-8.17(m,2H),8.11-8.00(m,2H),7.96(t,J=7.2Hz,1H),7.90-7.78(m,2 H),7.46(d,J=7.2Hz,1H),7.27(d,J=7.2Hz,1H),5.86(s,1H),4.01(t,J=6.4Hz,2H),3.89 -3.79(m,2H),3.47-3.39(m,2H),2.74-2.68(m,2H),2.57-2.52(m,2H),2.18-2.01(m,2H).

[0627] Example 58 Preparation method of compound LCT011121

[0628]

[0629] Step 1: Preparation of (E)-4-(1-((tert-butylsulfinyl)imino)ethyl)benzenesulfonamide

[0630] Compound 2 (0.61 g, 5.0 mmol) and Ti(OEt)4 (2.2 g, 10 mmol) were added to a THF (20 mL) solution of compound 1 (1 g, 5.0 mmol). The mixture was stirred at 70 °C for 12 hours under a N2 atmosphere. After the reaction was complete, water (10 mL) was added to quench the reaction. The mixture was then poured into a separating funnel and separated. The aqueous layer was extracted with EtOAc (20 mL × 3). The combined organic layers were washed with brine (10 mL), dried with Na2SO4, filtered, and concentrated. The product was purified by rapid chromatography (PE / EtOAc = 3 / 2) to give compound 3 (0.61 g, yield: 40%) as a white solid. Mass spectrometry (ESI): molecular formula C 12 H 18 N₂O₃S₂, molecular weight 302.08, m / z found to be 303.05 [M+H] + .

[0631] Step 2: Preparation of 4-(1-((tert-butylsulfinyl)amino)ethyl)benzenesulfonamide

[0632] NaBH4 (152 mg, 4.03 mmol) was added to a THF (12 mL) solution of compound 3 (610 mg, 2.01 mmol) at 0 °C, and the mixture was stirred at 25 °C for 3 hours. After stirring, the reaction mixture was quenched by adding water (10 mL). The mixture was then poured into a separating funnel and separated. The aqueous layer was extracted with EtOAc (20 mL × 3). The combined organic layers were washed with brine (10 mL), dried over Na2SO4, filtered, and concentrated to give crude compound 4 (550 mg, yield: 70%), which was used directly in the next step without further purification. Mass spectrometry (MS) (ESI): Molecular formula C 12 H 20 N₂O₃S₂, molecular weight 304.09, m / z 305.15 [M+H] + .

[0633] Step 3: Preparation of 4-(1-aminoethyl)benzenesulfonamide

[0634] A solution of compound 4 (550 mg, 1.80 mmol) in HCl-dioxane (5 mL, 2N) was stirred at 25 °C for 3 hours. After the reaction was complete, the mixture was concentrated to remove most of the solvent. The precipitate was collected by filtration. Compound 5 (320 mg, yield: 88%) was used directly in the next step without further purification. Mass spectrometry (ESI): Molecular formula C8H 12 N₂O₂S, molecular weight 200.06, m / z 201.10 [M+H] + .

[0635] Step 5: Preparation of 4-(2-oxo-3-phenylbenzo[cd]indol-1(2H)-yl)-N-(1-(4-sulfonylphenyl)ethyl)butyramide

[0636] Compound 5 (55 mg, 0.275 mmol) and a 50% T3P EtOAc solution (873 mg, 1.375 mmol) were added to a solution of pyridine (4 mL) containing 91 mg (91 mg, 0.275 mmol) of 4-(2-oxo-3-phenylbenzo[cd]indol-1(2H)-yl)butyric acid. The mixture was stirred at 60 °C for 1 hour. After the reaction was complete, the mixture was concentrated to obtain a crude product, which was subjected to preparative HPLC (Gemini 5 μm C18 column, 150 × 21.2 mm, eluted with 30-95% MeCN / H2O containing 0.05% ammonia) to obtain product LCT011121 (43.19 mg, yield: 58%) as a yellow solid. Mass spectrometry (ESI): molecular formula C 29 H 27 N3O4S, molecular weight 513.17, m / z 514.15 [M+H] + .

[0637] 1 H NMR (400MHz, DMSO-d6) δ8.36(d,J=7.6Hz,1H),8.12(d,J=7.2Hz,1H),7.81-7.71(m,3H),7.65-7.50(m,7H),7.46(d,J=8.4Hz,2H) ,7.31-7.19(m,3H),4.93(t,J=7.2Hz,1H),3.93(t,J=6.8Hz,2H),2.23(t,J=7.2Hz,2H),2.01-1.88(m,2H),1.31(d,J=6.8Hz,3H).

[0638] Example 59 Preparation method of compound LCT011120

[0639] The preparation method of LCT011120 is the same as that of LCT011121.

[0640]

[0641] LCT011120 (53.54 mg, purity: 99.91%, yield: 58.79%) was obtained as a yellow solid. Mass spectrometry (MS / ESI): molecular formula C 24 H 25 N3O4S, molecular weight 451.16, m / z 452.10 [M+H]+.

[0642] 1 HNMR (400MHz, DMSO-d6) δ8.35(d,J=7.6Hz,1H),7.97(s,1H),7.91(s,1H),7.75(d,J=8.4Hz,2H),7.57-7.42(m,4H),7.27(s,2H),7.08(d, J=6.8Hz,1H),4.92(t,J=7.2Hz,1H),3.87(t,J=6.8Hz,2H),2.61(s,3H),2.21(t,J=7.6Hz,2H),1.96-1.85(m,2H),1.31(d,J=7.2Hz,3H).

[0643] Example 60: Preparation method of compound LCT011128

[0644]

[0645] Step 1: Preparation of tert-butyl 3-oxo-3,6-dihydropyridine-1(2H)-carboxylic acid

[0646] DMP (3.81 g, 8.99 mmol) was added to a DCM (10 mL) solution of compound 1 (900 mg, 4.49 mmol), the mixture was stirred at room temperature for 2 hours, the mixture was concentrated under vacuum, and the residue was purified by silica gel column chromatography (elution buffer PE / EtOAc = 100:0 to 50:50) to give compound 2 (880 mg, 98.77% yield) as a white solid.

[0647] 1 H NMR (400MHz, DMSO-d6) δ7.23(d,J=7.6Hz,1H),6.10(dt,J=10.4,2.2Hz,1H),4.18(s,2H),4.01(s,2H),1.42(s,9H).

[0648] Step 2: Preparation of (9S, 10S)-9,10-dihydro-9,10-[3,4]pyridylanthraphen-15-one

[0649] AlCl3 (88.8 mg, 0.666 mmol) was added to a toluene (10 mL) solution of compound 2 (880 mg, 4.44 mmol) and anthracene (1.19 g, 6.66 mmol), and the mixture was stirred at 110 °C for 24 h. The mixture was concentrated under vacuum, and the residue was purified by silica gel column chromatography (eluent DCM / MeOH = 100:0 to 90:10) to give compound 3 (100 mg, 6% yield) as a white solid.

[0650] 1 HNMR(400MHz,DMSO-d6)δ7.43-7.31(m,9H),7.28-7.23(m,1H),7.20-7.15(m,1H),7.13-7.08(m,2H),7.08-7.03(m,2H),4.76(d ,J=2.4Hz,1H),4.27(s,1H),3.27-3.20(m,2H),2.73-2.64(m,1H),2.64-2.56(m,1H),2.43-2.39(m,1H),1.60(t,J=12.0Hz,1H).

[0651] Step 3: Preparation of (9s, 10s)-13-(4-(2-oxobenzo[cd]indol-1(2H)-yl)butyryl)-9,10-dihydro-9,10-[3,4]pyridineanthraquinone-15-one

[0652] DCC (88.9 mg, 0.431 mmol) was added to a DCM (2.0 mL) solution of compound 3 (100 mg, 0.392 mmol), 4-(2-oxobenzo[cd]indol-1(2H)-yl)butyric acid (108 mg, 0.392 mmol), and HOBt (52.9 mg, 0.392 mmol). The mixture was stirred at room temperature for 3 hours. The reaction mixture was concentrated under vacuum, and the residue was purified by HPLC (Gemini 5 μm C18 column, 150 × 21.2 mm, eluted with 50% to 80% MeCN / H2O (containing 0.1% FA)) to give LCT011128 (68.1 mg, 34% yield) as a yellow solid. Mass spectrometry (ESI): molecular formula C 34 H 28 N₂O₃, molecular weight 512.21, m / z 513.20 [M+H] + .

[0653] 1HNMR(400MHz,DMSO-d6)δ8.16(t,J=8.0Hz,1H),7.95-7.81(m,1H),7.81-7.70(m,1H),7 .61-7.53(m,1H),7.52-7.46(m,1H),7.43-7.37(m,1H),7.35-7.11(m,6H),7.07-7.01(m ,1H),7.00-6.90(m,1H),4.80-4.68(m,1H),4.45-4.31(m,1H),4.28-4.20(m,1H),4.14- 3.80(m,3H),2.96-2.80(m,1H),2.65-2.52(m,1H),2.45-2.37(m,2H,2.11-1.79(m,4H).

[0654] Example 61: Preparation method of compounds LCT011056 and LCT011035

[0655]

[0656] Step 1: Preparation of 1-(pent-4-en-1-yl)benzo[cd]indole-2(1H)-one

[0657] To a DMF (40 mL) solution of compound 1 (4.20 g, 24.83 mmol), 60% NaH (2.48 g, 62.08 mmol) was added, and the mixture was stirred at 0 °C for 15 min. Then, 5-bromopent-1-ene (4.81 g, 32.28 mmol) was added, and the mixture was stirred at room temperature for 1 h. The reaction was quenched with water (400 mL), extracted with ethyl acetate (200 mL × 3), and the combined organic layers were washed with brine, dried over MgSO4, and concentrated under reduced pressure to give compound 2 (5.43 g, 92.19% yield) as a yellow solid. Mass spectrometry (MS) (ESI): Molecular formula C 16 H 15 NO, molecular weight 237.30, m / z 238.30 [M+H] + .

[0658] Step 2: Preparation of 1-(3-(ethylene oxide-2-yl)propyl)benzo[cd]indol-2(1H)-one

[0659] At 0 °C, 85% m-cPBA (6.53 g, 31.60 mmol) was added to a dichloromethane (50 mL) solution of compound 2 (5.0 g, 21.07 mmol). The mixture was stirred at room temperature for 24 hours. The mixture was filtered, the filtrate was quenched with water (200 mL), extracted with dichloromethane (100 mL × 3), and the combined organic layers were washed with brine, dried over MgSO4, and concentrated under reduced pressure to give compound 3 (4.2 g, 78.76% yield) as a yellow solid. Mass spectrometry (MS) (ESI): Molecular formula C 16 H 15 NO2, molecular weight 253.30, m / z 254.30 [M+H] + .

[0660] Step 3: Preparation of methyl 2-(1-(((2-hydroxy-5-(2-oxobenzo[cd]indol-1(2H)-yl)pentyl)thio)methyl)cyclopropyl)acetate

[0661] To a methanol solution (30 mL) of compound 3 (2.10 g, 8.29 mmol) and methyl 2-(1-(mercaptomethyl)cyclopropyl)acetate (1.46 g, 9.11 mmol), NaOH (829 mg, 20.73 mmol) was added, and the reaction mixture was stirred at room temperature for 3 hours. The reaction was quenched with water (150 mL), extracted with ethyl acetate (75 mL × 3), and the combined organic layers were washed with brine, dried over MgSO4, and concentrated under reduced pressure to give compound 4 (1.30 g, 37.90% yield) as a white solid. Mass spectrometry (MS / ESI): molecular formula C 23 H 27 NO4S, molecular weight 413.53, m / z 414.50 [M+H] + .

[0662] Step 4: Preparation of 2-(1-(((2-hydroxy-5-(2-oxobenzo[cd]indol-1(2H)-yl)pentyl)thio)methyl)cyclopropyl)acetic acid (LCT011056)

[0663] To a solution of compound 4 (1.0 g, 2.42 mmol) in methanol (5.0 mL) and water (2.5 mL), LiOH·H₂O (305 mg, 7.26 mmol) was added. The mixture was stirred at room temperature for 3 hours. The pH was adjusted to 3 with 1 N HCl. The mixture was extracted with ethyl acetate (50 mL × 3) and water (50 mL). The combined organic layers were washed with brine, dried over MgSO₄, and concentrated under reduced pressure to give LCT011056 (600 mg, 60% yield) as a yellow solid. Mass spectrometry (MS) (ESI): Molecular formula C 22 H 22NO4S has a molecular weight of 399.51 and an m / z of 400.50 [M+H]+.

[0664] 1 HNMR (400MHz, CDCl3) δ8.06-8.00(m,2H),7.71-7.68(m,1H),7.54-7.52(d,J=8.4Hz,1H),7.47-7.43(m,1H),6.96-6.94(d,J=6.8Hz,1H),3.98-3 .95(m,2H),3.78-3.72(m,1H),2.51-2.48(m,3H),2.46-2.43(m,3H),1.9 9-1.87(m,2H),1.63-1.57(m,2H),0.57-0.54(m,2H),0.51-0.48(m,2H).

[0665] Step 5: Preparation of 2-(1-(((2-oxo-5-(2-oxobenzo[cd]indol-1(2H)-yl)pentyl)thio)methyl)cyclopropyl)acetic acid (LCT011035)

[0666] At 0 °C, Dysmart oxidant (1.06 g, 2.5 mmol) was added to a DCM (5 mL) solution of LCT011056 (200 mg, 0.5 mmol). The mixture was stirred at 0 °C for 1 hour, filtered, and the filtrate was extracted with ethyl acetate (50 mL × 3) and water (75 mL). The combined organic layers were washed with brine, dried over MgSO4, and concentrated under reduced pressure to give compound LCT011035 (15 mg, 75% yield) as a white solid. Mass spectrometry (MS) (ESI): Molecular formula C 22 H 23 NO4S, molecular weight 397.49, m / z 398.49 [M+H] + .

[0667] 1 H NMR (400MHz, CDCl3) δ8.10-8.04(m,2H)7.76-7.72(m,1H),7.58-7.56(d,J=8.4,1H),7.52-7.48(m,1H),7.04-7.03(d,J=6.8Hz,1H),4 .00-3.96(t,J=6.8Hz,2H),3.30(s,2H),2.79-2.76(t,J=8.4Hz,2H),2.65(s,2H),2.47(s,2H),2.14-2.07(m,2H),0.60-0.56(m,4H).

[0668] Example 62 Preparation method of compound LCT011133

[0669]

[0670] Step 1: 1,4-Dioxane (40 mL), (tributyl)methanol (2.70 g, 8.4 mol), and XPhos Pd G2 (0.22 g, 0.28 mol) were added to a dry solution of LCT0110003-7 (1.95 g, 5.6 mmol). The mixture was stirred at 100 °C under N2 for 12 h. The desired mass was determined by LC-MS. Water was added to the solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the product. The product was purified by flash chromatography (PE / EtOAc elution, from 100 / 00 to 70 / 30, 30 min) to give LCT011133-1 (520 mg, yield 26.79%) as a yellow solid. Mass spectrometry (ESI): Molecular formula C 20 H 23 NO4, molecular weight 341.16, m / z 342.30 [M+H]+.

[0671] Step 2: DAST (491 mg, 3.04 mmol) was added to LCT011133-1 (520 mg, 1.52 mmol) DCM (10 mL) solution. The mixture was stirred at 25 °C under N2 for 3 h. The desired mass was determined by LC-MS. Water was added to the solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the product. The product was purified by flash chromatography (PE / EtOAc elution, from 100 / 00 to 80 / 20, 30 min) to obtain LCT011133-2 (350 mg, yield 66.92%) as a yellow solid. Mass spectrometry (ESI): Molecular formula C 20 H 22 FNO3 has a molecular weight of 343.16 and an m / z of 344.25 [M+H]+.

[0672] Step 3: LCT011133-2 (350 mg, 1.01 mmol), DCM / TFA = 5:1 (6 mL). Stir at 25 °C for 6 hours. The organic layer was concentrated to obtain the crude product, which was purified by pre-high performance liquid chromatography (column: Gemini 5 μm C18 150 × 21.2 mm, mobile phase: ACN-H2O (0.1% FA), gradient: 40-95, 12.50 min) to obtain LCT011133 (168.58 mg, yield: 57.57%) as a yellow solid. Mass spectrometry (ESI): molecular formula is C 16 H 14FNO3 has a molecular weight of 287.10 and an m / z of 288.05[M+H]+.

[0673] 1 H NMR(400MHz,DMSO-d6)12.11(s,1H),8.28-8.23(m,1H),8.09(s,1H),7.71-7.64(m,1H),7.63-7.55(m,1H),7 .23(d,J=7.2Hz,1H),5.71(d,J=43.2Hz,2H),3.92(d,J=7.2Hz,2H),2.31(d,J=7.6Hz,2H),1.98-1.87(m,2H).

[0674] The list of compounds prepared in the above embodiments is as follows:

[0675]

[0676]

[0677]

[0678]

[0679]

[0680] Pharmacological experiment

[0681] 1. Cell experiments

[0682] Detection method: NPY (Neuropeptide Y) vesicle release assay

[0683] (1) HEK293 cells that were simultaneously stable to syt7 and NPY-pHluorin were seeded into six-well plates and cultured in DEME containing 5% FBS. When the cell number grew to 90%, the cells were digested and seeded evenly in black 96-well cell culture plates.

[0684] (2) Prepare High-KCl buffer: Weigh 4.1749g of KCl, 5.5521g of NaCl, 0.2442g of CaCl2, 0.0476g of MgCl2, 1.0089g of glucose and 3.5745g of HEPES-KO and dissolve them in 1L of ultrapure water to prepare a high-potassium solution with pH 7.4.

[0685] (3) Prepare DMSO stock solutions of the test compound at concentrations of 40 mM, 20 mM, 10 mM, 2 mM, 1 mM, 0.2 mM, 0.1 mM, 0.04 mM and 0 mM.

[0686] (4) Add 4 μL of the compound DMSO stock solution to 396 μL of High-KCL buffer to prepare compound dilution solutions of the following concentrations: 400 μM, 200 μM, 100 μM, 20 μM, 10 μM, 2 μM, 1 μM, 0.4 μM and 0 μM.

[0687] (5) Add the prepared compound dilution to the 96-well plate. The volume ratio of culture medium to compound stock solution is 1:1. For example, add 100 μL of compound solution dilution to a well containing 100 μL of culture medium. Therefore, the final concentrations in the culture medium are 200 μM, 100 μM, 50 μM, 10 μM, 5 μM, 1 μM, 0.5 μM, 0.2 μM and 0 μM, respectively.

[0688] The compound was incubated at room temperature for 10 min. The emission intensity of each well at 390 nm and 485 nm under 509 excitation light was detected using a microplate reader, and the ratio of the two was calculated.

[0689] Test results:

[0690]

[0691]

[0692]

[0693]

[0694] 2. Animal experiments

[0695] Male C57BL / 6J mice (6-8 weeks old, weighing 20-25g) were prepared and acclimatized for 5 days in an SPF-grade animal facility. The drug was administered intraperitoneally at doses ranging from 0.1 μmol / kg to 36 μmol / kg. Mice were randomly assigned to a blank control group, a positive control group (dextralcitabine citalopram), and a test compound group. Different doses of the same compound could be further divided into different dose groups. Each group consisted of 6-12 mice.

[0696] 2.1 Sugar Water Preference Experiment (SPT)

[0697] Detection method:

[0698] The sucrose preference test (SPT) consists of four phases and takes six days to complete. Throughout the experiment, mice were housed individually in cages. Two 50mL centrifuge tubes were placed on one side of each cage, with the metal tips of the tubes inserted into the metal bars of the cages at a 45° angle to the horizontal, ensuring that the mice could easily drink from either tube. Food was placed inside the cages for easy access to food.

[0699] (1) Days 1 and 2 are the double water adaptation phase for mice, that is, each of the two 50mL water bottles is filled with 40mL of purified water.

[0700] (2) Days 3 and 4 are the disaccharide adaptation phase for mice, that is, 40 mL of 2% sucrose water is added to each of two 50 mL water bottles.

[0701] (3) On the 5th day, remove the water bottles and begin the water-free period, which lasts for 24 hours.

[0702] (4) On day 6, a sugar water preference test was conducted. Two water bottles were used, one containing purified water and the other containing 2% sucrose solution. Before the test, the water on the surface of the bottles was wiped dry, and the initial weight of the bottles was weighed and recorded. Then, the water bottles were inserted into the metal bars of the mouse cage to begin the test. After 1 hour, the positions of the two water bottles were switched. After another hour, the test ended. All the water bottles were removed from the metal bars and stood upright, and weighed one by one.

[0703] (5) Data statistical analysis, sucrose preference rate = amount of sucrose consumed / total amount of sucrose and water consumed.

[0704] 2.2 Results of the Forced Swimming Test (FST)

[0705] Detection method:

[0706] The bucket used for the Forced Swimming Test (FST) is 30cm high and 20cm in diameter. One hour before the test, fill the bucket with tap water to two-thirds full and test the water temperature to be 24±1℃. Position the GoPro directly in front of the bucket, ensuring there are no obstructions. Once everything is set up, you can begin recording the video.

[0707] (1) Gently place the mice that have been adapted for 1 hour into the bucket of water, with the mice's bodies parallel to the water surface as they enter the bucket, to prevent the mice from choking and drowning or affecting their subsequent behavior.

[0708] (2) After the mice swim freely in the bucket for 6 minutes, stop recording, take the mice out of the bucket, wipe the moisture off the mice with toilet paper, and put the mice back in the cage. You can put an appropriate amount of toilet paper in the cage to help keep the mice warm. After recording the relevant information of the video, you can proceed with the test of the next group of mice.

[0709] (3) After all mice were tested, they were returned to their original housing. FST data analysis was then performed, and the swimming time of the mice in the bucket was recorded. The final immobility time of the mice = total duration (300 seconds) - swimming time.

[0710] The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. Any modifications, equivalent substitutions, improvements, etc., made within the spirit and principles of the present invention should be included within the protection scope of the present invention.

Claims

1. A heterocyclic alkyl carboxylic acid derivative of Formula I, characterized in that, The compound represented by Formula I and its pharmaceutically acceptable salt; (I)； Among them, ring R is selected from the following structures: ； B is selected from C atoms; R0 is n is selected from 1-6; X is selected from substituted or unsubstituted C1-C5 alkylene groups or imine groups, wherein the substituted substituent is selected from carbonyl groups or hydroxyl groups; Y is selected from -OH, -NR6R7, -S-R8, R9, -CO-R 10 ; R6 and R7 are each independently selected from H, methyl, isopropyl, , , , , , , , , ; R8 is selected from ; R9 is selected from ; R 10 Selected from , , , , , ; R1, R2, R3, R4, and R5 are each independently selected from H, amino, hydroxyl, cyano, halogen, phenyl, phenylamino, methyl, ethyl, methoxy, and halomethyl. , , , , , ; When R1, R2, R3, R4, and R5 are all H, Y is neither a hydroxyl group nor -NR6R7; When R1, R2, R3, R4, or R5 is selected from halogens ， The compound represented by Formula I is: 。 2. The heterocyclic alkyl carboxylic acid derivative according to claim 1, characterized in that, R0 is n = 1, 3, 4 or 5.

3. The heterocyclic alkyl carboxylic acid derivative according to claim 1, characterized in that, R1, R2, R3, R4, and R5 are all H, or only one group is not H.

4. The heterocyclic alkyl carboxylic acid derivative according to claim 1, characterized in that, n = 1, 3, 4, or 5, where the hydroxyl-substituted C1-C3 alkyl group is... .

5. The heterocyclic alkyl carboxylic acid derivative according to any one of claims 1-4, characterized in that, The compound represented by Formula I is selected from one of the following:

6. An intermediate for a heterocyclic alkyl carboxylic acid derivative, characterized in that, The compound represented by Formula II; (II); Specifically selected from:

7. The use of the heterocyclic alkyl carboxylic acid derivatives as described in any one of claims 1-5, and their pharmaceutically acceptable salts, in the preparation of medicaments for the treatment and / or prevention of neurological and metabolic diseases.

8. The application as described in claim 7, characterized in that, The neurological diseases are selected from schizophrenia, bipolar disorder, depression, Alzheimer's disease, epilepsy, neurosis, chorea, and Parkinson's disease; the metabolic diseases are selected from diabetes and metabolic disorders.

9. The application as described in claim 8, characterized in that, The neurological diseases mentioned are selected from schizophrenia, bipolar disorder, and depression.

10. The application as described in claim 9, characterized in that, The neurological disorders mentioned are selected from bipolar disorder and depression.

11. The application as described in claim 10, characterized in that, The neurological disorder is depression.

12. A pharmaceutical composition, characterized in that, It is made from the heterocyclic alkyl carboxylic acid derivative as described in any one of claims 1-5, its pharmaceutically acceptable salt, and a pharmaceutically acceptable carrier or excipient.

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