Heterocycloalkyl carboxylic acid derivative, intermediate, preparation method therefor and use thereof

Abstract

Disclosed are a heterocycloalkyl carboxylic acid derivative, an intermediate, a preparation method therefor, and a use thereof, relating to the technical field of pharmaceutical chemistry. The heterocycloalkyl carboxylic acid derivative of the present invention is a compound represented by formula (I) below, or a stereoisomer, geometric isomer, tautomer, N-oxide, hydrate, solvate, pharmaceutically acceptable salt or prodrug thereof. By means of in vitro activity detection and animal behavioral experiments, it has been proven that said compound has good therapeutic effects for neurological diseases such as depression and bipolar disorder, as well as metabolic diseases such as diabetes and metabolic disorders.

Description

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

[0001] The present application relates to the technical field of pharmaceutical chemistry, and particularly relates to a heterocyclic alkyl carboxylic acid derivative and a preparation method and use thereof. BACKGROUND

[0002] Human mental activities include sensation, perception, memory, thinking, emotion, attention, will, intelligence, personality, consciousness and the like. Any abnormal change in any aspect or mental activities and environment incoordination can show mental activity disorder or mental abnormality. Bipolar disorder is a neuropsychiatric disease with high incidence, high heritability and high mortality, which seriously affects people's physical and mental health and social harmony. Bipolar disorder, also known as manic depression, is a serious mental illness characterized by alternating episodes of mania and depression. Manic episode is a major characteristic of bipolar disorder, and its main manifestations include elevated mood, irritability, excessive thinking activity and reduced sleep demand; depressive episode is another major feature of bipolar disorder, and its manifestations include low mood, loss of interest and reduced activity.

[0003] However, the pathogenesis of bipolar disorder has been a long-standing scientific problem in the field of neuroscience and medicine. Among numerous bipolar disorder and depression patients, 70% lack effective treatment methods. Traditional antidepressants and antipsychotics are mainly used for targeting based on monoamine hypothesis and for central nervous system neurotransmitter receptors, and have the disadvantages of slow effect, low efficiency, large side effects, poor effect of single drug, risk of suicide and self-injury, and the like. The essential reason is that the mechanism of mental illness is not clear, and there is a lack of new mechanism and new target as a drug development direction and treatment method.

[0004] Patent CA2197172A1 discloses new alkylamino derivatives, pharmaceutical compositions comprising such compounds and the use of such compounds in the treatment of central nervous system disorders and several other disorders, including the use of the following compounds as new alkylamino derivatives of sigma 2 selective ligands:

[0005] Patent CN101304973A discloses compounds that modulate the interaction of nerve growth factor and its precursors with neurotrophin receptors and their pharmaceutically acceptable compositions, and the treatment of disease conditions mediated by this interaction, such as pain, inflammatory diseases and neurological diseases, the neurological diseases treated are selected from schizophrenia, bipolar disorder, depression, Alzheimer's disease, epilepsy, multiple sclerosis, amyotrophic lateral sclerosis, stroke, cerebral ischemia, neuropathy, retinal pigment degeneration, glaucoma, arrhythmia, Huntington's disease, and Parkinson's disease, and the specific compounds are as follows:

[0006] Synaptotagmin (Syt) is a presynaptic vesicle protein, and is one of the key proteins involved in the process of neurotransmitter release and physiological functions of brain learning and memory. Syt is a family of membrane transport proteins. They are characterized by containing two calcium binding regions: C2A and C2B. They are characterized by N-terminal located in the vesicle, C-terminal located in the cytoplasm, and only one transmembrane region. The cytoplasmic region of Syt is mainly composed of two Ca 2+ binding regions with repeated sequences-C2A and C2B. Close to the N-terminal is called C2A, and close to the C-terminal is called C2B. So far, the role of Syt in neurotransmitter release has been deeply studied. The release of neurotransmitter between synapses is one of the most important biological phenomena for the nervous system to complete its physiological functions. Neurotransmitter release is induced by Ca 2+ inflow to induce exocytosis of synaptic vesicles containing neurotransmitters and presynaptic membrane fusion, Ca 2+ binding in the cell interior needs to be combined with the Ca 2+ sensor in the cell to cooperatively control vesicle exocytosis release. Syt is a Ca 2+ sensor protein of vesicle membrane fusion, which can interact with SNARE complex to regulate the fusion of vesicle membrane and plasma membrane, and plays an important regulatory role in the secretion of nerve, endocrine cells and other cells.

[0007] Syt7 is a member of the Syt family of 17 members, which functions as a calcium sensor through two calcium-binding domains (C2A / C2B) and plays an important role in synaptic vesicle release and synaptic plasticity. The soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) is a small, conserved family of eukaryotic proteins that mediates membrane fusion between organelles and the plasma membrane. At the presynaptic terminal, Syt7 binds calcium ions through C2A / C2B after an action potential-induced massive influx of calcium ions, and interacts with the core proteins of vesicle release and their SNARE complex, and the lipid bilayer of the plasma membrane, to induce the slow-phase asynchronous release of synaptic vesicles (SVs). Moreover, Syt7 deficiency causes defects in SV pool replenishment in train-induced release. On the other hand, studies have shown that NMDAR (glutamate receptor) plays an important role in mouse depressive-like behavior, and NMDAR activated by spontaneous release of glutamate may play an important role in this process. Based on these studies, further studies have found that Syt7 is located in the marginal part of the presynaptic active zone (AZ), and the triggered spontaneous release of glutamate can specifically activate the GluN2B-NMDAR located in the marginal part of the synapse; the small part of SVs controlled by Syt7 cannot participate in the release in the train, thus leading to insufficient SV replenishment; and Syt7 deficiency can lead to the generation of postsynaptic homeostatic plasticity, thereby up-regulating the expression level of NMDAR. Studies have shown that Syt7 can act as a calcium sensor to drive the slow-phase asynchronous release of GABA (gamma-aminobutyric acid) in GABAergic neurons.

[0008] Patent WO2021147977A1 discloses that the expression of Syt7 gene in hippocampal neurons differentiated from induced pluripotent stem cells (iPSCs) of bidirectional mood disorder patients is significantly deficient; Syt7 gene knockout mice exhibit symptoms of spontaneous cycle of mania and depression of bidirectional mood disorder; and the expression level of Syt7 mRNA in the blood plasma of BD patients is significantly lower than that of healthy control group; the level of Syt7 mRNA in blood cells is also reduced, and the result is consistent with the detection in the blood plasma. The signal pathway related to the Syt7 gene and the expression product thereof play a key role in the mood cycle of bidirectional mood disorder, and the molecules targeting the signal pathway related to the Syt7 gene can provide help for the diagnosis and treatment of bidirectional mood disorder. The use of the Syt7 gene and / or the expression product thereof in the preparation of a drug for treating bidirectional mood disorder and / or its complications is provided. According to the embodiments of the present application, the expression product of the Syt7 gene can be used as a protein drug, and by administering an appropriate amount of protein drug to patients with bidirectional mood disorder or patients with complications, the content of the expression product of the Syt7 gene in the body can be increased, so that it can be used for treating bidirectional mood disorder or complications.

[0009] At present, there are few compounds for treating mental diseases such as depression and bipolar disorder by acting on Syt7, and therefore, the present application provides a heterocyclic alkyl carboxylic acid derivative with a new structure based on the mechanism, and through in vitro activity detection and in vivo animal behavior experiments, it is proved that the heterocyclic alkyl carboxylic acid derivative has good treatment effect on neurological diseases such as depression and bipolar disorder. In addition, Syt7 has the biological activity of promoting vesicle release, and the metabolism of many hormones, such as insulin, is released through vesicle release, so the heterocyclic alkyl carboxylic acid derivative can also be used for treating metabolic diseases by acting on Syt7.

[0010] SUMMARY

[0011] The purpose of the present application is to provide a heterocyclic alkyl carboxylic acid derivative, an intermediate and a preparation method thereof, and a use thereof in preparing a drug for treating neurological diseases and metabolic diseases.

[0012] To achieve the above-mentioned purpose of the application, the technical scheme of the present application is as follows:

[0013] In a first aspect, the present application provides a heterocyclic alkyl carboxylic acid derivative, which is a compound represented by formula I, a stereoisomer, a geometric isomer, a tautomer, a nitroxide, a hydrate, a solvate, a pharmaceutically acceptable salt or a prodrug thereof.

[0014] wherein ring R is selected from the following structures:

[0015] B is selected from C atom and N atom; when B is N atom, R2 is absent;

[0016] R0 is n is selected from 1-8;

[0017] X is selected from substituted or unsubstituted C1-C5 alkyl, amino, aryl, C3-C10 cycloalkyl, and the substituent of the substituted substituent is selected from carbonyl, hydroxyl, C1-C5 alkyl and halogen;

[0018] Y is selected from -OH, -NH2, -NR6R7, -S-R8, R9 and -CO-R 10 ;

[0019] R6 and R7 are each independently selected from H, substituted or unsubstituted C1-C8 alkyl, C1-C5 alkyl, C5-C15 heterocyclic group and C4-C14 cycloalkyl, and the substituent of the substituted substituent is selected from C5-C15 heterocyclic group, aryl, carbonyl, hydroxyl and halogen;

[0020] R8is selected from substituted or unsubstituted C1-C8alkyl, the substituted substituent is selected from carbonyl, hydroxyl, C1-C5alkyl, halogen, aryl;

[0021] R9is selected from substituted or unsubstituted C5-C30membered heterocyclyl, the substituted substituent is selected from carbonyl, hydroxyl, C1-C5alkyl, halogen, aryl;

[0022] R 10 is selected from substituted or unsubstituted C1-C6alkyl, the substituted substituent is selected from C5-C15heterocyclyl, carbonyl, hydroxyl, C1-C5alkyl, halogen, aryl;

[0023] R1, R2, R3, R4, R5, R1', R2', R3', R4', R5', R1", R2", R3", R4" are each independently selected from H, amino, nitro, hydroxyl, cyano, halogen, aryl, C1-C8alkoxy, substituted aryl, C1-C8alkyl, C1-C8haloalkyl, C1-C8alkylamino, phenylamino, C3-C10heterocyclyl;

[0024] R6, R7, R9, R 10 , wherein the heteroatom in the heterocycle or heterocyclyl is oxygen and / or nitrogen.

[0025] Preferably, B is selected from C atom, N atom; wherein R2is absent when B is N atom;

[0026] R0is n is selected from 1-8;

[0027] X is selected from substituted or unsubstituted C1-C5alkyl, amino, the substituted substituent is selected from carbonyl, hydroxyl;

[0028] Y is selected from -OH, -NH2, -NR6R7, -S-R8, R9, -CO-R 10 ;

[0029] R6, R7are each independently selected from H, substituted or unsubstituted C1-C8alkyl, C1-C5alkyl, C5-C15heterocyclyl, C4-C14cycloalkyl, the substituted substituent is selected from C5-C15heterocyclyl, aryl;

[0030] R8is selected from substituted or unsubstituted C1-C8alkyl, the substituted substituent is selected from C3-C6cycloalkyl;

[0031] R9is selected from C5-C30heterocyclyl;

[0032] R 10 is selected from substituted or unsubstituted C1-C6alkyl, the substituted substituent is selected from C5-C15heterocyclyl;

[0033] R1, R2, R3, R4, R5, R1', R2', R3', R4', R5', R1", R2", R3", R4" are each independently selected from the group consisting of H, amino, nitro, hydroxyl, cyano, halogen, aryl, C1-C8 alkoxy, substituted aryl, C1-C8 alkyl, C1-C8 haloalkyl, C1-C8 alkylamino, phenylamino, C3-C10 heterocyclyl;

[0034] R6, R7, R9, R 10 wherein the heteroatom in the heterocycle or heterocyclyl group is oxygen and / or nitrogen.

[0035] Preferably, B is selected from a C atom, a N atom; wherein R2is absent when B is a N atom;

[0036] R0is n is selected from 1-6;

[0037] X is selected from carbonyl, hydroxyl substituted C1-C3 alkyl, NH;

[0038] Y is selected from -OH, -NH2, -NR6R7, -S-R8, R9, -CO-R 10 ;

[0039] R6, R7are each independently selected from the group consisting of H, C1-C5 alkyl, C5-C15 heterocycle substituted C1-C5 alkyl, aryl substituted C1-C5 alkyl, C5-C15 heterocyclyl, C4-C14 cycloalkyl, substituted C4-C14 cycloalkyl;

[0040] R8is selected from C3-C5 cycloalkyl substituted C1-C5 alkyl;

[0041] R9is selected from C5-C30 heterocyclyl;

[0042] R 10 is selected from C5-C15 heterocycle substituted C1-C4 alkyl;

[0043] R1, R2, R3, R4, R5, R1', R2', R3', R4', R5', R1", R2", R3", R4" are each independently selected from the group consisting of H, amino, nitro, hydroxyl, cyano, halogen, aryl, C1-C5 alkoxy, substituted aryl, C1-C5 alkyl, C1-C5 haloalkyl, C1-C5 alkylamino, phenylamino, C3-C8 heterocyclyl;

[0044] R6, R7, R9, R 10 wherein the heteroatom in the heterocycle or heterocyclyl group is oxygen and / or nitrogen.

[0045] Preferably, when R1, R2, R3, R4, R5 are H simultaneously, R0 is not C3 alkyl, or X is not carbonyl, or Y is not hydroxyl.

[0046] Preferably, R1, R2, R3, R4, R5 are H simultaneously or only one group is not H; R1', R2', R3', R4', R5' are H simultaneously or only one group is not H; R1", R2", R3", R4" are H simultaneously or only one group is not H.

[0047] Preferably, R1, R2, R3, R4, R5, R1', R2', R3', R4', R5', R1", R2", R3", R4" are each independently selected from H, amino, nitro, hydroxyl, cyano, halogen, phenyl, methyl, ethyl, methoxy, halogenated methyl,

[0048] Preferably, halogen includes Cl, Br, I, F.

[0049] Preferably, n = 1, 3, 4 or 5; hydroxyl-substituted C1-C3 alkyl is

[0050] Preferably, R6, R7 are each independently selected from H, methyl, isopropyl,

[0051] Preferably, R8 is

[0052] Preferably, R9 is selected from

[0053] Preferably, R 10 is

[0054] Preferably, the compound shown in formula I is selected from:

[0055] More preferably, it is:

[0056] LCT011000, LCT01L0001, LCT011009, LCT011016, LCT011024, LCT011047, LCT011028, LCT011030, LCT011035, LCT011062, LCT011063, LCT011064, LCT011065, LCT011071, LCT011068, LCT011078, LCT011079, LCT011083, LCT011084, LCT011091, LCT011097, LCT011098, LCT011099, LCT011101, LCT011102, LCT011103, LCT011108, LCT011105, LCT011109, LCT011100, LCT011117, LCT011121, LCT011133.

[0057] More preferably, the compound is:

[0058] LCT011016, LCT011024, LCT011028, LCT011062, LCT011063, LCT011064, LCT011065, LCT011068, LCT011078, LCT011079, LCT011097, LCT011098, LCT011103, LCT011105, LCT011108, LCT011100, LCT011117, LCT011133.

[0059] More preferably, the compound is:

[0060] LCT011016, LCT011078, LCT011062, LCT011063, LCT011064, LCT011065, LCT011097, LCT011108, LCT011117, LCT011133.

[0061] More preferably, the compound is:

[0062] LCT011016, LCT011078, LCT011097, LCT011108, LCT011117, LCT011133.

[0063] In a second aspect, the present application provides a method for preparing the aforementioned heterocycloalkyl carboxylic acid derivatives, comprising the following reaction steps:

[0064] Compound 1 + X1-R0-X-Y' →

[0065] wherein compound 1 is selected from X1is selected from H, halogen, hydroxyl; Y' is Y or Y substituted with a protecting group.

[0066] Preferred protecting groups include, but are not limited to, protecting groups for hydroxyl, protecting groups for amino or amine groups, protecting groups for carboxyl, protecting groups for aldehyde or ketone, protecting groups for thiol, and protecting groups for any combination of hydroxyl, amino or amine groups, carboxyl, aldehyde or ketone, thiol, etc.

[0067] Protecting groups for hydroxyl are preferably selected from the following protecting groups: tetrahydropyranyl (THP), methyl (Me), benzyl (Bn), methoxymethyl (MOM), allyl (All), triphenylmethyl (Trt), acetyl (Ac), pivaloyl (Piv), t-butyldimethylsilyl (TBDMS), t-butyldimethylsilyl (TBDPS), trimethylsilyl (TMS), triethylsilyl (TES), phthalimide (Phth), t-butyloxy carbamate (Boc), benzyloxy carbamate (Cbz), 9-fluorenylmethyloxy carbamate (Fmoc).

[0068] Protecting groups for carboxyl are preferably selected from the following protecting groups: t-butyl ester (t-Bu), benzyl ester (Bn), methyl ester (Me), ethyl ester (Et), allyl ester (All), isopropyl ester (i-Pr), isobutyl ester (i-Bu), triphenylmethyl ester (Trt), methoxymethyl (MOM), t-butyldiylsilyl ester (TBDMS), 9-fluorenylmethyloxycarbonyl (Fmoc).

[0069] Protecting groups for amine groups are preferably selected from the following protecting groups: 9-fluorenylmethyloxycarbonyl protecting group (Fmoc), benzyloxycarbonyl (Cbz), t-butyloxycarbonyl (Boc), trichloroethoxycarbonyl (Troc), allyloxycarbonyl (Alloc), methoxycarbonyl (Moc), acetyl (Ac), trifluoroacetyl (TFA), 2,4-dimethoxybenzyl (DMB), benzyl (Bn), trityl (Tr), benzyloxymethyl (Bom), p-toluenesulfonyl (Ts), 2,2,4,6,7-pentamethyldihydrobenzofuran-5-sulfonyl (Pbf), 4-methoxy-2,3,6-trimethylbenzenesulfonyl (Mtr) phthalimide (Phth), benzhydryl amine.

[0070] In a third aspect, the present application provides a method for preparing the aforementioned heterocycloalkyl carboxylic acid derivatives, comprising the following reaction steps:

[0071] Compound 2

[0072] wherein compound 2 is selected from X2, X3, X4are each independently selected from halogen; Y' is Y or Y substituted with a protecting group; the substitution or hydrogenation or fluorination reaction is the substitution of H, X2, X3or NO2or hydrogenation to the reaction of the corresponding group.

[0073] In a fourth aspect, the present application provides a method for preparing the aforementioned heterocycloalkyl carboxylic acid derivative, comprising the following reaction steps:

[0074] wherein Y' is Y or Y substituted with a protecting group.

[0075] In a fifth aspect, the present application provides a method for preparing the aforementioned heterocycloalkyl carboxylic acid derivative, comprising the following reaction steps:

[0076] wherein X is

[0077] In a sixth aspect, the present application provides a method for preparing the aforementioned heterocycloalkyl carboxylic acid derivative, comprising the following reaction steps:

[0078] wherein X is

[0079] Preferably, the method further comprises the step of oxidizing the hydroxyl group on X to a carbonyl group.

[0080] In a seventh aspect, the present application provides a method for preparing the aforementioned heterocycloalkyl carboxylic acid derivative, comprising the following reaction steps:

[0081] wherein X' is a carboxyl group or halogen; Y' is Y or Y substituted with a protecting group; Y is selected from -NR6R7, R9.

[0082] Preferably, the method further comprises the step of hydrolyzing the ester group attached to the ring to a carboxyl group, and then cyclizing with the amide group on the ring.

[0083] In an eighth aspect, the present application provides a method for preparing the aforementioned heterocycloalkyl carboxylic acid derivative, comprising the following reaction steps:

[0084] wherein Y' is Y or Y substituted with a protecting group; Y is R 10 .

[0085] Preferably, the method for preparing the aforementioned heterocycloalkyl carboxylic acid derivative further comprises the step of deprotection.

[0086] In a ninth aspect, the present application provides an intermediate for preparing the aforementioned heterocycloalkyl carboxylic acid derivative, which is a compound of formula II:

[0087] wherein ring R is selected from the following structures:

[0088] B is selected from C atom, N atom; wherein B is N atom, R2 is absent;

[0089] R0 is n is selected from 1-6;

[0090] M is selected from carbonyl, NH, vinyl, halogen, epoxy;

[0091] A is selected from -OR 11 , OH, H, halogen or absent; R 11 is selected from C1-C10 alkyl, more preferably t-butyl;

[0092] R1, R2, R3, R4, R5, R1', R2', R3', R4', R5', R1", R2", R3", 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, C3-C8 heterocyclyl.

[0093] Preferably, R1, R2, R3, R4, R5, R1', R2', R3', R4', R5', R1", R2", R3", 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, C3-C8 heterocyclyl.

[0094] Preferably, R1, R2, R3, R4, R5 are all H or only one group is not H; R1', R2', R3', R4', R5' are all H or only one group is not H; R1", R2", R3", R4" are all H or only one group is not H.

[0095] Preferably, R1, R2, R3, R4, R5, R1', R2', R3', R4', R5', R1", R2", R3", R4" are each independently selected from H, amino, nitro, cyano, halogen, phenyl.

[0096] Preferably, n = 1, 3, 4 or 5.

[0097] Preferably, the intermediate is selected from:

[0098] In a tenth aspect, the present application provides use of the aforementioned heterocycloalkyl carboxylic acid derivative in the preparation of a medicament for treating and / or preventing neurological diseases, metabolic diseases.

[0099] Syt7 has a biological activity of promoting vesicle release, and the metabolism of many hormones, such as insulin, is released through vesicle release, so such heterocyclic alkyl carboxylic acid derivatives can also be used for the treatment of metabolic diseases by acting on Syt7.

[0100] Preferably, the neurological disease includes schizophrenia, bipolar disorder, depression, Alzheimer's disease, epilepsy, neuropathy, chorea, Parkinson's disease. The metabolic disease includes diabetes, metabolic disorder.

[0101] The neurological disease is further preferably schizophrenia, bipolar disorder, depression.

[0102] The neurological disease is more preferably bipolar disorder, depression.

[0103] The neurological disease is most preferably bipolar disorder.

[0104] In a eleventh aspect, the present application provides a pharmaceutical composition comprising the aforementioned heterocyclic alkyl carboxylic acid derivative, and a pharmaceutically acceptable carrier or excipient.

[0105] The phrase "pharmaceutically-acceptable carrier" is art-recognized and includes a pharmaceutically-acceptable material, composition or carrier, which is suitable for use with the compounds of the present application and not deleterious to the recipients thereof. Carriers include liquids or solids, diluents, excipients, solvents, or encapsulating materials, which are involved in carrying or transporting the subject agents from one organ, or portion of the body, to another organ, or portion of the body. Each carrier must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not injurious to the subject. Some examples of materials which can serve as pharmaceutically-acceptable carriers include: sugars, such as lactose, glucose and sucrose; starches, such as corn starch and potato starch; cellulose and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; magnesium stearate, talc, gelatin; 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; polyols, such as glycerin, sorbitol, mannitol, and polyethylene glycol; esters, such as ethyl oleate and ethyl laurate; agar; buffering agents, such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline; ethanol; phosphate buffer solutions; and other non-toxic compatible substances used in pharmaceutical formulations. Wetting agents, emulsifiers and lubricants such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents, release agents, coating agents, sweetening, flavoring and perfuming agents, preservatives and antioxidants can also be present in the compositions.

[0106] Examples of pharmaceutically acceptable antioxidants include: water soluble antioxidants, such as ascorbic acid, cysteine hydrochloride, sodium bisulfate, sodium metabisulfite, sodium sulfite, and the like; oil-soluble antioxidants, such as ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), lecithin, propyl gallate, alpha-tocopherol, and the like; and metal chelates, such as citric acid, ethylenediamine tetraacetic acid (EDTA), sorbitol, tartaric acid, phosphoric acid, and the like.

[0107] Suitable pharmaceutically acceptable carriers include, but are not limited to, water, salt solutions (e.g., NaCl), alcohols, gum arabic, vegetable oils, benzyl alcohol, polyethylene glycols, gelatin, sugars (e.g., lactose, amylose or starch), polyvinylpyrrolidone, magnesium stearate, talc, silicic acid, viscous paraffin, perfume oil, fatty acid, dimethyl malonate, glycofurol, and the like. The pharmaceutical compositions can be sterilized and, if desired, mixed with auxiliary agents such as lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts for influencing osmotic pressure, buffers, colorings, flavorings and / or aromatizers, and the like, which do not deleteriously react with the active compounds.

[0108] The compositions can also contain minor amounts of wetting or emulsifying agents, or pH buffering agents. The compositions can be a liquid solution, suspension, emulsion, tablet, pill, capsule, sustained release formulation, or powder. The compositions can be formulated with conventional binders and carriers such as glyceryl monostearate, which can be used to produce tablets, pills, or capsules. Oral formulations can include standard carriers such as pharmaceutical grades of mannitol, lactose, magnesium stearate, talc, sodium saccharine, cellulose, magnesium carbonate, etc.

[0109] The compositions can be formulated according to conventional methods into pharmaceutical compositions suitable for intravenous administration to humans. The compositions can also include stabilizers and local anesthetics, if desired, to lessen pain at the site of injection.

[0110] Generally, the ingredients are supplied either separately or mixed together in unit dosage form, for example, as a dry lyophilized powder or water free concentrate in a hermetically sealed container such as an ampule or articulated tube, which can show the quantity of active agent. Where the composition is to be administered by infusion, it can be dispensed with an infusion bottle containing sterile pharmaceutical grade water, saline or aqueous dextrose. Where the composition is to be administered by injection, an ampule of sterile water for injection or saline can be provided, so that the ingredients can be mixed prior to administration.

[0111] The pharmaceutical compositions of the present application can also include agents that control release of the compounds of the present application, to provide time- controlled or sustained release compositions.

[0112] The pharmaceutical compositions of the present application include compositions suitable for oral, rectal, topical, vaginal, and parenteral (including subcutaneous, intramuscular, and intravenous) administration, although the most suitable route in any given case will depend on the particular host, and nature and severity of the conditions for which the active ingredient is being administered. The pharmaceutical compositions can be manufactured by any of the methods well-known in the art of pharmaceutical science.

[0113] The active ingredient can be administered in a solid dosage form, such as a capsule, tablet, lozenge, troche, granule, or powder, or in a liquid dosage form, such as an elixir, syrup, emulsion, dispersion, or suspension. The active ingredient can also be administered parenterally in a sterile liquid dosage form, such as a dispersion, suspension, or solution. Other dosage forms that can be used to administer the active ingredient include ointments, creams, drops, transdermal patches, or powders for topical administration; eye solutions or suspensions for ocular administration, i.e., eye drops; spray or powder compositions for inhalation or intranasal administration; or creams, ointments, sprays, or suppositories for rectal or vaginal administration. Gelatin capsules include the active ingredient and a powdered carrier, such as lactose, starch, cellulose derivatives, magnesium stearate, stearic acid, and the like. Similar diluents can be used to make compressed tablets. Both tablets and capsules can be manufactured as sustained release products to provide sustained release of the drug over a period of hours. Compressed tablets can be sugar coated or film coated to mask any unpleasant taste and to protect the tablet from the atmosphere, or they can be enteric coated for selective disintegration in the gastrointestinal tract. Liquid dosage forms for oral administration can include colorants and flavoring agents to increase patient acceptance. In general, water, suitable oils, saline, dextrose (glucose) in water, and related sugar solutions and glycols such as propylene glycol or polyethylene glycol are suitable carriers for parenteral solutions. Solutions for parenteral administration preferably include water soluble salts of the active ingredient, suitable stabilizing agents, and if necessary, buffer substances. Antioxidizing agents such as sodium bisulfite, sodium sulfite, or ascorbic acid, alone or in combination, are suitable stabilizing agents. Citric acid and its salts and EDTA sodium can also be used. In addition, parenteral solutions can contain preservatives, such as benzalkonium chloride, methyl- or propyl-paraben, and chlorobutanol.

[0114] For administration by inhalation, the compounds of the present application are conveniently delivered from a pressurized pack or a nebulizer. The compounds can also be delivered by means of a powder inhaler which is formulated to dispense a powder composition comprising the compound of Formula I. The preferred delivery system for inhalation is a metered dose inhaler (MDI) which can be formulated to dispense a suspension or solution of the compound of Formula I in a suitable propellant such as a fluorocarbon or a hydrocarbon. For administration to the eye, ophthalmic formulations can be prepared to dispense a solution or suspension of the compound of Formula I in a suitable weight percent in a suitable ophthalmic vehicle, to maintain contact of the compound with the surface of the eye for a sufficient time for the compound to penetrate the cornea and interior regions of the eye.

[0115] Useful pharmaceutical dosage forms for administration of the compounds of the present application include, but are not limited to, hard and soft gelatin capsules, tablets, parenteral injections and oral suspensions.

[0116] The same dosage forms as described above can be used when the compounds of the present application are administered stepwise or in combination with other therapeutic agents. When the drugs are administered in a physical combination, the dosage form and the route of administration should be selected according to the compatibility of the combined drugs. The compounds of the present application can be administered as the sole active ingredient or in combination with a second active ingredient, including those known to be useful in the treatment of neurological diseases, metabolic diseases.

[0117] Terminology:

[0118] The term "alkyl" as used herein, unless otherwise indicated, includes both branched and straight chain saturated aliphatic hydrocarbon groups with the indicated number of carbon atoms, including all isomers. Common abbreviations for alkyl groups are used, for example, methyl can be represented by "Me" or CH3, ethyl by "Et" or CH2CH3, propyl by "Pr" or CH2CH2CH3, butyl by "Bu" or CH2CH2CH2CH3, and the like. For example, "C 1-4 "alkyl" (or "C1-C4alkyl") means a straight or branched chain alkyl group having the indicated number of carbon atoms, including all isomers. C 1-4 "alkyl" includes n-, i-, s- and t-butyl, n- and i-propyl, ethyl and methyl. The term "C 1-10 "alkyl" and the like have similar meanings.

[0119] The term "alkoxy" means straight and branched chain alkyl groups of the indicated number of carbon atoms attached through an oxygen bridge.

[0120] The term "halogen" (or "halo") means fluorine, chlorine, bromine and iodine (or fluorinated (F), chlorinated (Cl), brominated (Br) and iodinated (I), respectively).

[0121] 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.

[0122] 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.

[0123] 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.

[0124] 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, heterocyclylalkyl, halo-aryl, halo-aralkyl, halo-heterocycle, halo-heterocyclylalkyl, cyano-aryl, cyano-aralkyl, cyano-heterocycle, and cyano-heterocyclylalkyl. The term "substituted phenyl" has a similar definition.

[0125] All ranges recited herein are inclusive of the endpoints. For example, "n is an integer between 0 and 2" means that n can be 0, 1, or 2.

[0126] The term "pharmaceutically acceptable salt" means a salt prepared from a pharmaceutically acceptable non-toxic base or acid. When the compound of the present application is acidic, its corresponding salt can be readily prepared from an inorganic or organic acid. Salts derived from inorganic bases include aluminum, ammonium, calcium, copper (copper and cuprous), ferric, ferrous, lithium, magnesium, manganic, manganous, potassium, sodium, zinc, and the like. Preferred are the ammonium, calcium, magnesium, potassium, and sodium salts. Salts prepared from organic bases include salts of primary, secondary, and tertiary amines, including those derived from natural and synthetic sources. Pharmaceutically acceptable organic non-toxic bases from which salts can be prepared include arginine, betaine, caffeine, choline, N,N'-dibenzylethylene-diamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, dicyclohexylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine, and the like. When the compound of the present application is basic, its corresponding salt can be readily prepared from an inorganic or organic acid. 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, isethionic acid, lactic acid, maleic acid, malic acid, mandelic acid, methanesulfonic acid, mucic acid, nitric acid, pamoic acid, pantothenic acid, phosphoric acid, succinic acid, sulfuric acid, tartaric acid, p-toluenesulfonic acid, and the like.

[0127] The term "solvate" means a complex of variable stoichiometry formed by a solute (i.e., a compound of Formula I or a pharmaceutically acceptable salt thereof) and a solvent, which can be a molecule of solvent, the solvent being involatile. Examples of solvents include, but are not limited to, water, ethanol, and acetic acid. When the solvent is water, the solvate is a hydrate. Hydrates include, but are not limited to, monohydrates, hemihydrates, monohemihydrates, dihydrates, and trihydrates. The term "prodrug" is a functional derivative of a compound of the present application that is readily convertible into the desired compound in vivo.

[0128] The term "neurological disease" means damage, disease, and malfunction of the nervous system, including the peripheral nervous system and the central nervous system. Neurological diseases include, but are not limited to, diseases and symptoms associated with agonizing the syt7 target.

[0129] The present application provides a heterocyclic alkyl carboxylic acid derivative with a new structure, which realizes the treatment of mental diseases such as depression, bipolar disorder and the like by targeting Syt7, and the present application also provides a preparation method of the compound, and the in vitro activity detection and in vivo animal behavior experiment prove that the compound has good treatment effect on neurological diseases such as depression, bipolar disorder and the like. BRIEF DESCRIPTION OF DRAWINGS

[0130] Figure 1 is the SPT and FST results of LCT011000, LCT011009, LCT011117 and LCT011133;

[0131] Figure 2 is the SPT and SFT results of LCT011016;

[0132] Figure 3 is the SPT and SFT results of LCT011060;

[0133] Figure 4 is a comparison chart of NPY release results of some compounds;

[0134] Figure 5 is a comparison chart of NPY release results of some compounds;

[0135] Figure 6 is a comparison chart of NPY release results of some compounds;

[0136] Figure 7 is a comparison chart of NPY release results of some compounds;

[0137] Figure 8 is a comparison chart of NPY release results of some compounds;

[0138] Figure 9 is a comparison chart of NPY release results of some compounds;

[0139] Figure 10 is a comparison chart of NPY release results of some compounds;

[0140] Figure 11 is a comparison chart of NPY release results of some compounds.

[0141] In the present application, the compound numbered LCT011000 is also named as "Drug1", and both are the same compound as shown in the following formula: DETAILED DESCRIPTION

[0142] The following non-limiting examples can make those skilled in the art more fully understand the present application, but do not limit the present application in any way. The following content is only an exemplary description of the scope of the present application, and those skilled in the art can make various changes and modifications to the present application according to the disclosed content, and it should also belong to the scope of the present application.

[0143] The application will be further described in the context of specific examples. The various chemical reagents used in the examples of the application were obtained from common commercial sources unless otherwise specified. The amounts recited in the following examples are by mass unless otherwise specified. Room temperature is understood to be 25°C unless otherwise specified.

[0144] The compounds of the application having the formulae described herein can be prepared from commercially available starting materials or starting materials prepared using literature procedures according to the procedures described in the following General Synthesis Routes 1-7. The variables (e.g., R1, R2, and R3, etc.) in each General Synthesis Route are as defined herein. It will be apparent to one of ordinary skill in the art that the order of certain steps can be varied in the reaction sequences and synthetic schemes described herein, such as the introduction and removal of protecting groups.

[0145] General Synthesis Route 1

[0146] Compound 1 + X1-R0-X-Y' →

[0147] wherein Compound 1 is selected from X1is selected from H, halogen, hydroxyl; Y' is Y or Y substituted with a protecting group. R1, R2, R3, R4, R5, R1', R2', R3', R4', R5' can contain protecting groups, and when Y' or alkyl contains a protecting group, steps to prepare the starting material containing the protecting group, and deprotection of the reaction product are also included.

[0148] The above reaction can be carried out using K2CO3, KI as catalyst, DMF as solvent, at 50-70°C for 1-20h.

[0149] General Synthesis Route 2

[0150] Compound 2

[0151] wherein Compound 2 is selected from X2, X3, X4are each independently selected from halogen; Y' is Y or Y substituted with a protecting group; the substitution, hydrogenation or fluorination reaction is substitution or hydrogenation of H, X2, X3or NO2to corresponding groups. When Y' contains a protecting group, steps to prepare the starting material containing the protecting group, and deprotection of the reaction product are also included.

[0152] The reaction conditions for Compound 2 with X4-R0-X-Y' are the same as General Synthesis Route 1, which can be carried out using K2CO3, KI as catalyst, DMF as solvent, at 50-70°C for 1-20h.

[0153] The hydrogenation reaction includes the hydrogenation of -NO2 to -NH2, which can be carried out using Pd / C as catalyst in THF or EtOH for 10-24 h.

[0154] The substitution reaction includes the substitution of halogen to phenyl, which can be carried out using Pd(PPh3)4, K2CO3 as catalyst, dioxane / H2O as reaction solvent at 80-100 °C for 2-20 h.

[0155] The substitution reaction includes the substitution of halogen to -CN, which can be carried out using Zn(CN)2 as reaction reagent, Pd(PPh3)4 as catalyst, DMF as reaction solvent at 70-90 °C for 2-20 h.

[0156] The substitution reaction includes the substitution of halogen to

[0157] The substitution reaction includes the substitution of halogen to methyl, which can be carried out using MeB(OH)2 as reaction reagent, Pd(OAc)2, K3PO4 as catalyst at 90-100 °C for 2-20 h.

[0158] General synthetic route 3

[0159] wherein Y' is Y or Y substituted with a protecting group. R1", R2", R3", R4" can contain protecting groups. When Y' or alkyl contains a protecting group, the steps for preparing the starting material containing the protecting group and deprotecting the reaction product are also included.

[0160] The above reaction can be carried out in AcOH at 90-110 °C for 1-10 h.

[0161] General synthetic route 4

[0162] wherein X is

[0163] The above reaction can be carried out using K2CO3, iPrOH as catalyst at 70-90 °C.

[0164] General synthetic route 5

[0165] wherein X is ​​​The reaction is carried out under basic conditions. The reaction scheme can also include a step of oxidizing the hydroxyl group on X to a carbonyl group, which is carried out at 0°C to room temperature.

[0166] General synthetic scheme 6

[0167] wherein X' is carboxyl or halogen; Y' is Y or Y substituted with a protecting group; Y is selected from -NR6R7, R9. The reaction is amidation or substitution, which can be carried out according to conventional reaction conditions. The reaction scheme can also include a step of hydrolyzing the ester group on the non-ring to a carboxyl group, which is further reacted with an amino group to close the ring, which can be carried out using LiOH as catalyst, MeOH, H2O as solvent at room temperature. When Y' or the alkyl group contains a protecting group, the reaction scheme also includes a step of preparing the starting material containing the protecting group, and a step of deprotecting the reaction product.

[0168] General synthetic scheme 7

[0169] wherein Y' is Y or Y substituted with a protecting group; Y is R 10 The reaction is amidation, which can be carried out according to conventional amidation reaction conditions. When Y' or the alkyl group contains a protecting group, the reaction scheme also includes a step of preparing the starting material containing the protecting group, and a step of deprotecting the reaction product.

[0170] Preparation of intermediates and compounds

[0171] Preparation of compound LCT011000, intermediate XI-1

[0172] Synthesis according to general synthetic scheme 1:

[0173] Synthetic procedure:

[0174] Step 1: Into a three-necked flask was placed compound of formula LCT011000-1 (benzo[cd]indol-2(lH)-one) (500 mg, 2.95 mmol), tert-butyl 4-bromobutyrate (1.31 g, 5.91 mmol) and potassium iodide (KI) (1.96 g, 11.8 mmol), the mixture was dissolved in 10 mL of N,N-dimethylformamide (DMF), the mixture was heated to 60 °C under nitrogen atmosphere for 12-24 h. The reaction was monitored by LC-MS, after the reaction was completed, the reaction mixture was purified by prep-HPLC (purification condition: Column type: Biotage Isolera One C18 colμmn, mobile phase: eluted with 30-50% MeCN / H2O with 0.1% NH4OH), to give yellow solid powder, compound of formula LCT011000-2 (tert-butyl 4-(2-oxobenzo[cd]indol-l(2H)-yl)butanoate) (300 mg, yield: 32%).

[0175] Mass spectrum MS (ESI): molecular formula C 19 H 21 NO3, molecular weight 311.15, mass to charge ratio (m / z) 312.25 [M+H] + .

[0176] Step 2: Into a three-necked flask was placed compound of formula LCT011000-2 (tert-butyl 4-(2-oxobenzo[cd]indol-l(2H)-yl)butanoate) (200 mg, 0.642 mmol), the mixture was dissolved in 4 mL of trifluoroacetic acid (TAF), the mixture was stirred at room temperature under nitrogen atmosphere for 2 h. The reaction was monitored by LC-MS, after the reaction was completed, the reaction mixture was concentrated under reduced pressure to remove the solvent trifluoroacetic acid (TAF), the concentrated mixture was purified by prep-HPLC (purification condition: Column type: Gemini 5 μm C18 colμmn, 150 x 21.2 mm, mobile phase: 20-30% MeCN / H2O with 0.1% NH4OH), to give yellow solid powder, compound LCT011000 (49.26 mg, purity: 99.67%, yield: 30%).

[0177] Mass spectrum MS (ESI): molecular formula C 15 H 13 NO3, molecular weight 255.09, mass to charge ratio (m / z) 256.15 [M+H] + . Nuclear magnetic hydrogen spectrum (H 1 NMR): 1H NMR (400 MHz, DMSO-d6) δ 8.18 (d, J = 8.0 Hz, 1H), 8.05 (d, J = 6.8 Hz, 1H), 7.80 (dd, J = 8.0, 7.2 Hz, 1H), 7.63 (d, J = 8.4 Hz, 1H), 7.55 (dd, J = 8.0, 6.8 Hz, 1H), 7.22 (d, J = 7.2 Hz, 1H), 3.90 (t, J = 7.2 Hz, 2H), 2.22 (t, J = 7.2 Hz, 2H), 1.91 (p, J = 7.2 Hz, 2H).

[0178] Preparation of Example 2 compound LCT011003, intermediate XI-2

[0179] Synthesized according to general synthetic route 1:

[0180] Synthesis steps:

[0181] Step 1: 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) was added pyridine (3.30 g, 41.7 mmol), stirred, the resulting mixture was stirred at 25 °C under N2atmosphere for 16 h. Upon completion, the resulting mixture was concentrated under vacuum. The residue was purified by silica gel column chromatography (PE / EtOAc, 1:0) to give the product LCT011003-2 (4.00 g, 69% yield) as a yellow oil.

[0182] Mass spectrum MS (ESI): molecular formula C 11 H 12 ClNO, molecular weight 209.06, mass (m / z) 209.95 [M+H] + .

[0183] 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), stirred at 80 °C under N2atmosphere for 0.5 h. Upon completion, the resulting mixture was concentrated under vacuum. The residue was purified by silica gel column chromatography (PE / EtOAc, 1:0) to give the product LCT011003-3 (4.00 g, 73% yield) as a yellow solid. Mass spectrum MS (ESI): molecular formula C 11 H 11 BrClNO, molecular weight 288.97, mass (m / z) 289.85 [M+H] + .

[0184] Step 3: To a solution of LCT011003-3 (4.00 g, 13.9 mmol) in 1,4-dioxane (20.0 mL) was added 6M HC1 (20.0 mL). The resulting mixture was stirred at 100 °C for 16 h. Upon completion, the mixture was basified to pH ~7 with 10% aqueous sodium hydroxide solution. The aqueous layer was extracted with EtOAc. The combined organic layers were washed with brine and dried over anhydrous Na2S04. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified 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 spectrum MS (ESI): molecular formula C 10 H8BrClO, molecular weight 259.94, mass-to-charge ratio (m / z) 261.00 [M+H] + .

[0185] Step 4: To a stirred solution of LCT011003-4 (3.00 g, 11.6 mmol) in DMF / H20 / t-BuOH (2:1:2, 25 mL) was added CuCN (1.04 g, 11.6 mmol). The resulting mixture was stirred at 110 °C under N2atmosphere for 48 h. Upon completion, the resulting mixture was diluted with H20 (20.0 mL). The aqueous layer was extracted with EtOAc (20.0 mL x 3). The combined organic layers were washed with brine and dried over anhydrous Na2S04. 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 LCT011003-5 (1.80 g, 76% yield) as a yellow solid. Mass spectrum MS (ESI): molecular formula C 11 H8ClNO, molecular weight 205.03, mass-to-charge ratio (m / z) 205.95 [M+H] + .

[0186] 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. Upon 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 spectrum MS (ESI): molecular formula C 11 H6ClNO, molecular weight 203.01, mass-to-charge ratio (m / z) 203.95 [M+H] + .

[0187] Step 6: LCT011003-6 (1.0 g, 4.93 mmol), 4-bromobutyric acid tert-butyl ester (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 x 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 spectrum MS (ESI): molecular formula C 19 H 20 ClNO3, molecular weight 345.11, mass-to-charge ratio (m / z) 346.20 [M+H] + .

[0188] Step 7: A solution of LCT011003-7 (200 mg, 0.578 mmol) in TFA (4.00 mL) was stirred at 25 °C for 1 h, and concentrated under reduced pressure. The residue was triturated in MeCN / MeOH, filtered, and dried under vacuum to give the product LCT011003 (127 mg, 74% yield).

[0189] Mass spectrum MS (ESI): molecular formula C 15 H 12 ClNO3, molecular weight 289.05, mass-to-charge ratio (m / z) 290.15 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 12.10 (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 = 6.8 Hz, 2H), 2.31 (t, J = 7.2 Hz, 2H), 1.92 (p, J = 7.2 Hz, 2H).

[0190] Method for preparing compound LCT011007 of Example 3

[0191] Synthesized according to general synthetic route 3:

[0192] Synthesis steps:

[0193] Compound LCT011007-1 (100 mg, 0.550 mmol), 4-aminobutyric acid (59.6 mg, 0.578 mmol) were dissolved in AcOH (2.00 mL) and the reaction was stirred at 100 °C for 3 hours. Upon completion of the reaction, the reaction was quenched by the addition of H2O. The reaction was then basified to pH 6-8 with 0.1 M aqueous sodium hydroxide solution. The precipitated solid was collected by filtration and washed with H2O to give compound LCT011007 as a white solid (68.44 mg, 47% yield).

[0194] Mass spectrum MS (ESI): The molecular formula is C 12 H 10 ClNO4, the molecular weight is 267.03, the mass-to-charge ratio (m / z) is 268.00 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 12.04 (s, 1H), 7.86-7.76 (m, 3H), 3.60 (t, J = 6.8 Hz, 2H), 2.28 (t, J = 7.2 Hz, 2H), 1.82 (p, J = 7.2 Hz, 2H).

[0195] Method of preparation of compound LCT011009 of example 4

[0196] Synthesized according to general synthesis route 3:

[0197] Synthesis steps:

[0198] Step 1 : Sodium hydride (60%) (60 mg, 1.5 mmol) was suspended in THF (1.00 mL), diethyl oxalate (175 mg, 1.19 mmol), ethyl 4-phenylbutanoate (LCT011009-1, 192 mg, 0.998 mmol) were added and the mixture was stirred in an external bath at 80 °C for 1.5 hours. The reaction mixture was concentrated under reduced pressure, methanesulfonic acid (1.00 mL) was added and the mixture was stirred in an external bath at 80 °C for 1.5 hours. Then, the mixture was stirred in an external bath at 120 °C for 1 hour. Upon completion, the reaction mixture was cooled and the precipitated crystals were collected by filtration. The product LCT011009-2 was then washed with ethanol (1.00 mL) twice and with water (1.00 mL) twice, and dried under reduced pressure to give a yellow solid (130 mg, 64% yield).

[0199] 1H NMR (400 MHz, DMSO-d6) δ 7.91 - 7.84 (m, 1H), 7.49 - 7.42 (m, 1H), 7.42 - 7.34 (m, 2H), 3.04 (t, J = 8.4 Hz, 2H), 2.70 (t, J = 8.4 Hz, 2H).

[0200] Step 2: LCT011009-2 (116 mg, 0.579 mmol), 6-aminohexanoic acid (76.0 mg, 0.579 mmol) were dissolved in AcOH (4.00 mL) and stirred at 100 °C for 3 h. After the reaction was completed, the resulting mixture was concentrated under vacuum. The residue was purified by preparative HPLC (Gemini 5 pm C18 column, 150 x 21.2 mm, eluted with 30-90% MeCN / H2O containing 0.1% NH3H2O) to give LCT011009 as a yellow solid (34.4 mg, 18% yield).

[0201] Mass spectrum MS (ESI): The molecular formula is C 18 H 19 N04, the molecular weight is 313.13, the mass-to-charge ratio (m / z) is 312.25 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 11.98 (s, 1H), 7.96 (d, J = 7.2 Hz, 1H), 7.38 - 7.29 (m, 3H), 3.44 (t, J = 7.2 Hz, 2H), 2.98 (t, J = 8.4 Hz, 2H), 2.61 (t, J = 8.4 Hz, 2H), 2.19 (t, J = 7.2 Hz, 2H), 1.56 - 1.47 (m, 4H), 1.32 - 1.21 (m, 2H).

[0202] Method for preparing compound LCT011012, intermediate XII of Example 5

[0203] Synthesized according to general synthetic route 1:

[0204] Synthesis steps:

[0205] Step 1 : To compound LCT011012-1 (500 mg, 3.40 mmol) dissolved in THF (10 mL), Boc20 (889 mg, 4.08 mmol) was added, and the mixture was stirred at 70 °C for 2 h. The reaction mixture was concentrated in vacuo, and the residue was purified by silica gel column chromatography (eluent PE / EtOAc = 100:0 to 50:50) to give compound LCT011012-2 (800 mg, 95% yield) as a white solid. Mass spectrum MS (ESI): molecular formula C 15 H 21 NO2, molecular weight 247.16, mass-to-charge ratio (m / z) 233.00 [M+H] + .

[0206] Step 2: Compound LCT011012-2 (700 mg, 2.29 mmol) was dissolved in THF (10 mL) under N2 atmosphere, and t-BuLi (1.3 m, 5.3 mL, 6.88 mmol) was added, and the mixture was stirred at -30 °C for 45 min, then CO2 was bubbled into the reaction system for 3 times and stirred at -30 °C for 45 min. The final mixture was quenched with H2O and washed with EtOAc for 3 times. The aqueous solution was adjusted to pH 5-6 with 2N HCl. The precipitate was collected by filtration and washed with water to give compound LCT011012-3 (400 mg, 46% yield) as an off-white solid. Mass spectrum MS (ESI): molecular formula C 16 H 21 NO4, molecular weight 291.15, mass-to-charge ratio (m / z) 290.05 [M+H] + .

[0207] Step 3: Compound LCT011012-3 (380 mg, 1.24 mmol) was dissolved in TFA / DCM (1 / 2, 5.0 mL) and stirred at 40 °C for 1 h, and concentrated under reduced pressure. To the resulting solid in DCM (5.0 mL) was added CDI (303 mg, 1.87 mmol). The reaction mixture was stirred at room temperature for 2 h. The mixture was concentrated in vacuo, 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.

[0208] 1H NMR (400 MHz, DMSO-d6) δ 10.11 (s, 1H), 7.05 (t, J = 7.6 Hz, 1H), 6.69 (d, J = 8.0 Hz, 1H), 6.57 (d, J = 7.6 Hz, 1H), 3.32-3.27 (m, 1H), 2.79 (dd, J = 17.2, 7.4 Hz, 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).

[0209] 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), K2CO3 (511 mg, 3.69 mmol) was added, and the mixture was stirred at 60 °C for 16 h. The resulting mixture was diluted with water (10 mL) and extracted with EtOAc (10 mL x 3). The combined organic phase was washed with brine, dried over sodium sulfate, concentrated, and purified by silica gel column chromatography (eluent PE / EtOAc = 100:0 to 50:50) to give compound LCT011012-5 (i.e. intermediate XII, 100 mg, 34.33% yield) as a yellow solid. Mass spectrum MS (ESI): molecular formula C 19 H 25 NO3, molecular weight 315.18, mass-to-charge ratio (m / z) 316.00 [M+H] + .

[0210] 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 under lyophilization and triturated with MTBE to give compound LCT011012 (20.73 mg, 25.20% yield) as a yellow solid. Mass spectrum MS (ESI): molecular formula C 15 H 17 NO3, molecular weight 259.12, mass-to-charge ratio (m / z) 259.95 [M+H] + .

[0211] 1H NMR (400 MHz, DMSO-d6) δ 10.12 (s, 1H), 7.06 (t, J = 7.6 Hz, 1H), 6.73 (d, J = 7.6 Hz, 1H), 6.61 (d, J = 7.6 Hz, 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).

[0212] Process for preparing compound LCT011013, intermediate XI-13 of example 6

[0213] Synthesis according to general synthetic route 1:

[0214] Synthesis steps:

[0215] 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 N2atmosphere for 16 hours. The reaction was monitored by LCMS. After completion, the reaction mixture was quenched by the addition of aqueous NaHCO3solution (20 mL). The mixture was then poured into a separatory funnel and separated. The aqueous layer was extracted with EtOAc (20 mL x 3). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, filtered and concentrated on a rotary evaporator. The resulting oil was purified by flash column chromatography (PE / EtOAc = 2 / 1) to give compound LCT011013-2 (1.20 g, yield: 42%) as a yellow solid. Mass spectrum MS (ESI): molecular formula C 11 H8BrNO2, molecular weight 264.97, mass-to-charge ratio (m / z) 266.05 [M+H] + .

[0216] 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 N2atmosphere for 3 h. The reaction was monitored by LCMS. Upon completion, the reaction mixture was quenched by the addition of 4 N aqueous HC1 (10 mL). The mixture was then poured into a separatory funnel and separated. The aqueous layer was extracted with EtOAc (20 mL x 3). The combined organic layers were washed with brine (20 mL), dried over Na2S04, filtered, and concentrated on a rotary evaporator to give compound LCT011013-3 (1.00 g, yield: 95%) as a yellow solid. Mass spectrum MS (ESI): molecular formula C 10 H6BrN02, molecular weight 250.96, m / z 252.05 [M+H] + .

[0217] 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 N2atmosphere for 2 h. The reaction was then added to concentrated HC1 (20 mL) and stirred at 90 °C under N2atmosphere for 3 h. The reaction was monitored by LCMS. Upon 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 spectrum MS (ESI): molecular formula C 10 H6N20, molecular weight 170.05, m / z 171.10 [m+H] + .

[0218] Step 4: Compound LCT011013-4 (350 mg, 2.05 mmol), 4-bromobutyric acid tert-butyl ester (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 N2atmosphere for 16 hours, the reaction was monitored by LCMS. After the reaction was completed, the reaction mixture was quenched by adding water (100 mL). Then the mixture was poured into a separatory funnel and separated. The aqueous layer was extracted with EtOAc (100 mL x 3). The combined organic layers were washed with brine (100 mL), dried over Na2SO4, filtered and concentrated on a rotary evaporator. The resulting oil was purified by flash column chromatography (PE / EtOAc = 5 / 1) to give compound LCT011013-5 (i.e. intermediate XI-13, 300 mg, yield: 46%) as a yellow solid. Mass spectrum MS (ESI): molecular formula C 18 H 20 N2O3, molecular weight 312.15, m / z 313.25 [m+H] + .

[0219] Step 5: Compound LCT011013-5 (200 mg, 0.640 mmol) was dissolved in TFA (4 mL) and stirred at room temperature for 2 hours under N2atmosphere, the reaction was monitored by LCMS. After completion, the reaction mixture was concentrated under vacuum. Then the residue was purified by preparative HPLC (Gemini 5 pm C18 column, 150 x 21.2 mm, eluted with 20-30% MeCN / H2O containing 0.1% TFA) to give the product LCT011013 (100 mg, purity: 99.66%, yield: 60%) as a yellow solid. Mass spectrum MS (ESI): molecular formula C 14 H 12 N2O3, molecular weight 256.08, m / z 257.05 [m+H] + .

[0220] 1 H NMR (400 MHz, DMSO-d6) δ 9.58 (s, 1H), 9.12 (s, 1H), 7.82 (d, J = 8.4 Hz, 1H), 7.71 (dd, J = 8.4, 7.2 Hz, 1H), 7.43 (d, J = 7.2 Hz, 1H), 3.93 (t, J = 7.2 Hz, 2H), 2.33 (t, J = 7.2 Hz, 2H), 1.98 - 1.89 (m, 2H).

[0221] Example 7 Method of preparing compounds LCT011016, LCT011046, intermediates XI-3 to XI-6

[0222] Synthesized according to general synthetic route 2:

[0223] Synthesis steps:

[0224] Step 1 : Compound LCT011046-1 (3.00 g, 12.3 mmol) and NH2OH HCI (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 TsCI (4.69 g, 24.6 mmol) was added portionwise. The resulting mixture was stirred at 116 °C for an additional 2 h. Upon completion, the resulting mixture was poured into ice water. The precipitated solid was collected by filtration and washed with H2O and aqueous NaHC03to give the crude product LCT011046-2 as a brown solid (4.00 g, 79% yield). Mass spectrum MS (ESI): molecular formula C 19 H 12 N2O7S, molecular weight 412.04, m / z 413.10 [m+H] + .

[0225] Step 2: To a solution of LCT011046-2 (4.00 g, 9.71 mmol) in EtOH / H2O (72 mL, 5:4) was added NaOH (2.7 m, 26.2 mmol, 9.70 mL) with stirring. The resulting mixture was stirred at 85 °C for 1 h. Upon completion, the resulting mixture was concentrated under vacuum to remove EtOH. The aqueous layer was heated to 75 °C and acidified with concentrated HCI to pH = 1. The precipitated solid was collected by filtration and washed with H2O to give the crude product LCT011046-3a and LCT011046-3b as yellow solids (1.8 g, 87% yield). The crude product was used directly in the next step without further purification. Mass spectrum MS (ESI): molecular formula C 11 H6N2O3, molecular weight 214.04, m / z 214.90 [m+H] + .

[0226] 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), the resulting mixture was diluted with H2O (20.0 mL). The aqueous layer was extracted with EtOAc (20.0 mL x 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, 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 spectrum MS (ESI): molecular formula C 19 H 20 N2O5, molecular weight 356.14, m / z 301.00 [m+H] + .

[0227] Step 4: LCT011046-3a and LCT011046-3b (800 mg, 2.25 mmol), Pd / C (20 wt%, 160 mg), EtOH / THF (1:1, 10.0 mL) were stirred at 25 °C under H2atmosphere for 16 h. After the reaction was completed, the resulting mixture was filtered, and the filter cake was washed with THF. The filtrate was concentrated under reduced pressure to give the crude product LCT011046-4a (i.e. intermediate XI-5) and LCT011046-4b (i.e. intermediate XI-6) as yellow solids. The crude product was used directly in the next step without further purification. Mass spectrum MS (ESI): molecular formula C 19 H 22 N2O3, molecular weight 326.16, m / z 327.00 [m+H] + .

[0228] Step 5: LCT011046-4a and LCT011046-4b (700 mg, 2.15 mmol) were dispersed in TFA (5.0 mL) and stirred at 25 °C for 2 h. After the reaction was completed, 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. x 250 mL, 5 μm; CO2 / MeOH [0.1% NH3(7 M in MeOH), 60% / 40%, 48 mL / min) to give peak 1 (LCT011046, 10.40 mg yellow solid) and peak 2 (LCT0110016, 40.05 mg).

[0229] LCT011046: Mass spectrum MS (ESI): Molecular formula is C 15 H 14 N2O3, molecular weight is 270.10, m / z is 270.90 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 7.71 (dd, J = 6.8, 1.6 Hz, 1H), 7.58 - 7.50 (m, 2H), 6.66 (d, J = 1.6 Hz, 1H), 6.47 (d, J = 1.6 Hz, 1H), 5.73 (s, 2H), 3.82 (t, J = 7.2 Hz, 3H), 2.24 (t, J = 7.2 Hz, 2H), 1.88 (p, J = 7.2 Hz, 2H).

[0230] LCT0110016: Mass spectrum MS (ESI): Molecular formula is C 15 H 14 N2O3, molecular weight is 270.10, m / z is 270.95 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 7.39 (d, J = 1.6 Hz, 1H), 7.36 - 7.29 (m, 1H), 7.27 (d, J = 8.4 Hz, 1H), 7.07 (d, J = 1.6 Hz, 1H), 6.83 (d, J = 6.8 Hz, 1H), 5.79 (s, 2H), 3.82 (t, J = 7.2 Hz, 2H), 2.24 (t, J = 7.2 Hz, 2H), 1.92 - 1.81 (m, 2H).

[0231] Method for preparing compound LCT011018 of Example 8

[0232] Synthesized according to general synthetic route 1:

[0233] Synthesis procedure: Dissolve benzo[cd]indol-2(lH)-one (300 mg, 1.77 mmol), 4- chlorobutanamide (323 mg, 2.66 mmol) and Cs2CO3(1.73 g, 5.32 mmol) in DMF (10 mL), stir at 120 °C for 16 h, cool the mixture to room temperature. Dilute the resulting mixture with H2O (20 mL). Extract the aqueous layer with EtOAc (20 mL x 3). Concentrate the combined organic layers under reduced pressure. Purify the residue by prep-HPLC (ACN in water with 0.1% FA, 20%-70% gradient over 9 min) to give LCT011018 as a yellow solid (37.0 mg, 8.15% yield).

[0234] Mass spectrum MS (ESI): molecular formula is C 15 H 14 N2O2, molecular weight is 254.11, m / z is 255.10 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 8.19 (d, J = 8.0 Hz, 1H), 8.05 (d, J = 6.8 Hz, 1H), 7.85-7.77 (m, 1H), 7.65 (d, J = 8.4 Hz, 1H), 7.60-7.53 (m, 1H), 7.27 (s, 1H), 7.21 (d, J = 7.2 Hz, 1H), 6.74 (s, 1H), 3.90 (t, J = 7.2 Hz, 2H), 2.14 (t, J = 7.2 Hz, 2H), 1.92 (p, J = 7.2 Hz, 2H).

[0235] Method for preparing compound LCT011022, intermediate XI-14 and intermediate XI-15 of example 9

[0236] Synthesized according to general synthesis route 5:

[0237] Synthesis steps:

[0238] 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 N2atmosphere for 16 h. The reaction was monitored by LCMS. After completion, the reaction mixture was quenched by adding water (200 mL). Then the mixture was poured into a separatory funnel and separated. The aqueous layer was extracted with EtOAc (200 mL x 3). The combined organic layers were washed with brine (200 mL), dried over Na2SO4, filtered and concentrated on a rotary evaporator. The obtained oil was purified by flash column chromatography (PE / EtOAc = 5 / 1) to give compound LCT011022-2 (i.e. intermediate XI-14, 600 mg, yield: 48%) as a yellow solid. Mass spectrum MS (ESI): molecular formula is C 14 H 11 NO, molecular weight is 209.08, m / z is 210.15 [m+H] + .

[0239] 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 for 16 h under N2atmosphere. The reaction was monitored by LCMS. Upon completion, the reaction mixture was quenched by the addition of aqueous NaHC03solution (20 mL). The mixture was then poured into a separatory funnel and separated. The aqueous layer was extracted with DCM (20 mL x 3). The combined organic layers were washed with brine (20 mL), dried over Na2S04, filtered and concentrated on a rotary evaporator. The resulting oily compound LCT011022-3 (i.e. intermediate XI-15, 200 mg, yield: 37%) was purified by flash column chromatography (PE / EtOAc = 2 / 1) as a yellow solid. Mass spectrum MS (ESI): molecular formula C 14 H 11 N02, molecular weight 225.08, m / z 226.15 [M+H] + .

[0240] Step 3: Compound LCT011022-3 (200 mg, 0.888 mmol), methyl 1- (methylamino)cyclopentan-1 -carboxylate (167 mg, 1.06 mmol) and K2C03(368 mg, 2.66 mmol) were dissolved in iPrOH (4 mL) and stirred at 80 °C for 16 h under N2atmosphere. The reaction was monitored by LCMS. Upon completion, the reaction mixture was concentrated under vacuum. The residue was then purified by preparative HPLC (Gemini 5 pm C18 column, 150 x 21.2 mm, eluted with 20-30% MeCN / H20 with 0.1% TFA) to give LCT011022 (9.45 mg, purity: 99.30%, yield: 2%) as a yellow solid. Mass spectrum MS (ESI): molecular formula C 21 H 24 N20, molecular weight 368.17, m / z 369.10 [M+H] + . 1H NMR (400 MHz, DMSO-d6) δ 8.18 (d, J = 8.0 Hz, 1H), 8.04 (d, J = 6.8 Hz, 1H), 7.80 (dd, J = 8.0, 6.8 Hz, 1H), 7.63 (d, J = 8.4 Hz, 1H), 7.55 (dd, J = 8.4, 6.8 Hz, 1H), 7.18 (d, J = 6.8 Hz, 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).

[0241] Process for the preparation of compounds LCT011024, LCT011047, intermediates XI-7 to XI-10 of example 10

[0242] Synthesis according to general synthesis scheme 5:

[0243] Synthesis steps:

[0244] Step 1 : Compound LCT011024-1 (500 mg, 1.80 mmol) and NH2OH HCI (125 mg, 1.80 mmol) were dissolved in pyridine (5 mL) and stirred at 120 °C under N2atmosphere for 1 h. Then the reaction was cooled to 80 °C and TcCI (688 mg, 3.61 mmol) was added. The reaction was stirred at 80 °C under N2atmosphere for 2 h. The reaction was monitored by LCMS. Upon completion, the reaction mixture was quenched by the addition of H2O (20 mL). The mixture was then poured into a separatory funnel and separated. The aqueous layer was extracted with EtOAc (20 mL x 3). The combined organic layers were washed with brine (20 mL), dried over Na2S04, filtered and concentrated on a rotary evaporator to give compound LCT011024-2 (500 mg, yield: 62%) as a yellow solid. Mass spectrum MS (ESI): molecular formula C 19 H 12 BrNO5S, molecular weight 444.96, m / z 446.10 [m+H] + .

[0245] 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 N2atmosphere for 1 h. The reaction was monitored by LCMS. Upon completion, the reaction mixture was quenched by the addition of 4N aqueous HC1 (10 mL). The mixture was then poured into a separatory funnel and separated. The aqueous layer was extracted with EtOAc (20 mL x 3). The combined organic layers were washed with brine (20 mL), dried over Na2S04, filtered and concentrated on a rotary evaporator to provide compound LCT011024-3a and LCT011024-3b (300 mg crude) as a yellow solid. Mass spectrum MS (ESI): molecular formula C 11 H6BrNO, molecular weight 246.96, m / z 248.00 [m+H] + .

[0246] Step 3: Compound LCT011024-3a, LCT011024-3b (250 mg, 1.00 mmol), 4-bromobutyric acid tert-butyl ester (449 mg, 2.01 mmol), K2C03(557 mg, 4.03 mmol), KI (669 mg, 4.03 mmol) were dispersed in DMF (50 mL) and stirred at 60 °C under N2atmosphere for 16 h. The reaction was monitored by LCMS. Upon completion, the reaction mixture was quenched by the addition of water (50 mL). The mixture was then poured into a separatory funnel and separated. The aqueous layer was extracted with EtOAc (50 mL x 3). The combined organic layers were washed with brine (50 mL), dried over Na2S04, filtered and concentrated on a rotary evaporator. The resulting oil was purified by flash column chromatography (PE / EtOAc = 5 / 1) to provide compound LCT011024-4a (i.e. intermediate XI-7) and LCT011024-4b (i.e. intermediate XI-8). Mass spectrum MS (ESI): molecular formula C 19 H 20 BrNO3, molecular weight 389.06, m / z 390.15 [m+H] + .

[0247] Step 4: Compound LCT011024-4a, LCT011024-4b (300 mg, 0.768 mmol), phenylboronic acid (140 mg, 01.15 mmol), Pd(PPh3)4 (88.8 mg, 0.0768 mmol), K2CO3 (318 mg, 2.30 mmol) were dispersed in 1,4-dioxane / H2O = 5 / 1 (6 mL) and stirred at 90 °C under N2atmosphere for 16 h. The reaction was monitored by LCMS. After completion, the reaction mixture was quenched by adding water (10 mL). Then the mixture was poured into a separatory funnel and separated. The aqueous layer was extracted with EtOAc (20 mL x 3). The combined organic layers were washed with brine (10 mL), dried over Na2SO4, filtered and concentrated on a rotary evaporator. The resulting oil was purified by flash column chromatography (PE / EtOAc = 2 / 1) and purified by SFC (column: Torus 2-PIC 20 x 250 mm, 5 pm; mobile phase: CO2 / MeOH (0.1% NH3) = 70 / 30) to afford compound LCT011024-5a (i.e. intermediate XI-9, peak 2, 100 mg) and LCT011024-5b (i.e. intermediate XI-10, peak 1, 90 mg). Mass spectrum MS (ESI): molecular formula C 25 H 25 NO3, molecular weight 387.18, m / z 388.35 [m+H] + .

[0248] Step 5: LCT011024-5a (100 mg, 0.258 mmol) was dissolved in TFA (2 mL) and stirred at room temperature for 2 hours under N2atmosphere. The reaction was monitored by LCMS. After completion, the reaction mixture was concentrated under vacuum to afford compound LCT011024 (63.62 mg, purity: 99.29%, yield: 73%) as a yellow solid. Mass spectrum MS (ESI): molecular formula C 21 H 17 NO3, molecular weight 331.12, m / z 332.05 [m+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 12.12 (s, 1H), 8.13 (dd, J = 10.8, 7.6 Hz, 2H), 7.84 (t, J = 7.6 Hz, 1H), 7.62 - 7.51 (m, 5H), 7.50 - 7.44 (m, 1H), 7.31 (d, J = 7.2 Hz, 1H), 3.96 (t, J = 7.2 Hz, 2H), 2.34 (t, J = 7.2 Hz, 1H), 1.96 (p, J = 7.2 Hz, 2H).

[0249] LCT011024-5b (90 mg, 0.232 mmol) was dissolved in TFA (2 mL) and stirred at room temperature under N2atmosphere for 2 h, the reaction was monitored by LCMS. After completion, the reaction mixture was concentrated under vacuum to afford compound LCT011047 (58.18 mg, purity: 99.17%, yield: 74%) as a yellow solid. Mass Mass (ESI): Molecular formula C 21 H 17 NO3, Molecular weight 331.12, m / z 332.10 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 12.11 (s, 1H), 8.12 (d, J = 7.2 Hz, 1H), 7.78 (d, J = 7.2 Hz, 1H), 7.66 - 7.56 (m, 6H), 7.56 - 7.51 (m, 1H), 7.26 (d, J = 6.4 Hz, 1H), 3.95 (t, J = 6.8 Hz, 2H), 2.32 (d, J = 7.2 Hz, 1H), 1.95 (p, J = 7.2 Hz, 2H).

[0250] Process for the preparation of compound LCT011026 of example 11

[0251] Synthesis according to general synthetic route 5:

[0252] Synthesis procedure:

[0253] Step 1 : To a solution of compound 1 (3.00 g, 13.5 mmol) and picolinic acid (1.83 g, 14.8 mmol) in DCM (60.0 mL) was added 50% T4P (14.5 g, 20.2 mmol) and TEA (4.10 g, 40.5 mmol) while stirring. The resulting mixture was 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, 1:10) to afford compound 2 (3.50 g, 78% yield) as a brown solid. Mass Mass (ESI): Molecular formula C 16 H 11 BrN2O, Molecular weight 326.01, m / z 326.90 [m+H] + .

[0254] Step 2: Compound 2 (1.00 g, 3.10 mmol), isopropyl chloroformate (1.14 g, 9.30 mmol), NaOAc (0.510 g, 6.20 mmol), Nal (0.460 g, 3.10 mmol), Pd(OAc)2(0.140 g, 0.620 mmol) were dissolved in toluene (20.0 mL) and stirred at 135 °C for 6 h under N2atmosphere. After completion, the resulting mixture was concentrated under vacuum. The residue was purified by silica gel column chromatography (PE / EtOAc, 1:10) to give the product as yellow oil. Compound 3 (360 mg, yield 29%). Mass spectrum MS (ESI): molecular formula C 20 H 17 BrN2O3, molecular weight 412.04, m / z 412.80 [m+H] + .

[0255] Step 3: To a solution of compound 3 (1.27 g, 3.10 mmol) in EtOH (25.0 mL) was added NaOH (0.190 g, 4.65 mmol) and the resulting mixture was stirred at 80 °C for 1 h. After completion, the mixture was basified to pH 7 with 10% aqueous HC1 solution. The aqueous layer was extracted with EtOAc. The combined organic layers were washed with brine and dried over anhydrous Na2S04. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE / EtOAc, 3:1) to give the product as yellow solid. Compound 4 (700 mg, 90% yield). Mass spectrum MS (ESI): molecular formula C 11 H6BrNO.

[0256] Step 4: To a solution of compound 4 (500 mg, 2.01 mmol) in DMF (10.0 mL) was added tert-butyl 4-bromobutanoate (674 mg, 3.02 mmol), K2C03(835 mg, 6.04 mmol) and Kl (334 mg, 2.0 mmol) and stirred at 50 °C for 2 h. After completion, the resulting mixture was diluted with H20 (100 mL). The aqueous layer was extracted with EtOAc (20.0 mL x 3). The combined organic layers were washed with brine and dried over anhydrous Na2S04. 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 as yellow solid. Compound 5 (800 mg, 96% yield). Mass spectrum MS (ESI): molecular formula C 19 H 20 BrNO3, molecular weight 389.06, m / z 334.10 [m-t-Bu] + .

[0257] 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 N2for 2 h. After completion, the resulting mixture was diluted with H2O (40 mL). The aqueous layer was extracted with EtOAc (10.0 mL x 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 spectrum MS (ESI): molecular formula C 20 H 20 N2O3, molecular weight 336.15, m / z 280.95 [m-t-Bu] + .

[0258] 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 phase was concentrated under vacuum and purified by preparative HPLC (Gemini 5 pm C18 column, 150 x 21.2 mm, eluted with 30%-90% MeCN / H2O containing 0.1% NH3H2O) to give the product LCT011026 (83.4 g, 41% yield) as a yellow solid. Mass spectrum MS (ESI): molecular formula C 16 H 12 N2O3, molecular weight 280.08, m / z 281.25 [m+H] + .

[0259] 1 H NMR (400 MHz, DMSO-d6) δ 8.37 (d, J = 7.2 Hz, 1H), 8.16 (d, J = 7.2 Hz, 1H), 7.82-7.72 (m, 1H), 7.65 (d, J = 8.8 Hz, 1H), 7.36 (d, J = 7.2 Hz, 1H), 3.90 (t, J = 7.2 Hz, 2H), 2.24 (t, J = 7.2 Hz, 2H), 1.96-1.84 (m, 2H).

[0260] Method for preparing compound LCT011027 of Example 12

[0261] Synthesized according to general synthesis route 5:

[0262] Synthesis steps:

[0263] Step 1 : Compound 1 (200 mg, 0.512 mmol), 3-(trifluoro-4-boranilyl)azetidine-1- carboxylic acid tert-butyl ester, potassium salt (203 mg, 0.768 mmol), Pd(dppf)Cl2(37.5 mg, 0.0512 mmol, Cs2CO3(501 mg, 1.53 mmol) were added to toluene / H2O = 5 / 1 (2.4 mL) and stirred at 80 °C for 16 h under N2atmosphere. The reaction was monitored by LCMS, after completion, the reaction mixture was quenched by adding water (10 mL). Then the mixture was poured into a separatory funnel and separated. The aqueous layer was extracted with EtOAc (20 mL x 3). The combined organic layers were washed with brine (10 mL), dried over Na2SO4, filtered and concentrated on a rotary evaporator. The resulting oily compound 2 (200 mg, yield: 83%) was purified by flash column chromatography (PE / EtOAc = 2 / 1) as a yellow solid. Mass MS (ESI): molecular formula C 27 H 34 N2O5, molecular weight 466.25, m / z 467.45 [m+H] + .

[0264] Step 2: Compound 2 (200 mg, 0.427 mmol) was dissolved in TFA (4 mL) and stirred at room temperature for 2 hours under N2atmosphere. The reaction was monitored by LCMS. After completion, the reaction mixture was concentrated under vacuum. Then the residue was purified by preparative HPLC (Gemini 5 pm C18 column, 150 x 21.2 mm, eluted with 20%-30% MeCN / H2O containing 0.1% TFA) to the product LCT011027 (77.25 mg, purity: 99.91%, yield: 58%) as a yellow solid. Mass MS (ESI): molecular formula C 18 H 18 N2O3, molecular weight 310.13, m / z 311.10 [m+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 12.13 (s, 1H), 8.11 (d, J = 7.2 Hz, 1H), 7.86 (d, J = 7.2 Hz, 1H), 7.62-7.53 (m, 2H), 7.25 (d, J = 6.8 Hz, 1H), 4.87 (p, J = 8.8 Hz, 1H), 4.53 (t, J = 10.0 Hz, 2H), 4.32 (t, J = 9.6 Hz, 2H), 3.91 (t, J = 7.2 Hz, 2H), 2.30 (t, J = 7.2 Hz, 2H), 1.92 (p, J = 7.2 Hz, 2H).

[0265] Method of preparation of compound LCT011028 of example 13

[0266] Synthesis according to general synthesis route 5:

[0267] Synthesis step:

[0268] Step 1 : Compound 1 (900 mg, 4.49 mmol) was dissolved in DCM (10 mL), 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, the residue was purified by column chromatography on silica gel (eluent PE / EtOAc = 100:0 to 50:50) to give compound 2 (880 mg, 98.77% yield) as a white solid. 1 H NMR (400 MHz, DMSO-d6) δ 7.23 (d, J = 7.6 Hz, 1 H), 6.10 (dt, J = 10.4, 2.2 Hz, 1 H), 4.18 (s, 2 H), 4.01 (s, 2 H), 1.42 (s, 9 H).

[0269] Step 2: Compound 2 (880 mg, 4.44 mmol) and anthracene (1.19 g, 6.66 mmol) were dissolved in toluene (10 mL), AICI3(88.8 mg, 0.666 mmol) was added. The reaction mixture was stirred at 1 10 °C for 24 hours. The mixture was concentrated under vacuum, the residue was purified by column chromatography on silica gel (eluent DCM / MeOH = 100:0 to 90:10) to give compound 3 (100 mg, 6% yield) as a white solid. 1 H NMR (400 MHz, DMSO-d6) δ 7.43 - 7.31 (m, 9 H), 7.28 - 7.23 (m, 1 H), 7.20 - 7.15 (m, 1 H), 7.13 - 7.08 (m, 2 H), 7.08 - 7.03 (m, 2 H), 4.76 (d, J = 2.4 Hz, 1 H), 4.27 (s, 1 H), 3.27 - 3.20 (m, 2 H), 2.73 - 2.64 (m, 1 H), 2.64 - 2.56 (m, 1 H), 2.43 - 2.39 (m, 1 H), 1.60 (t, J = 12.0 Hz, 1 H).

[0270] Step 3: Compound 3 (100 mg, 0.392 mmol), 4-(2-oxobenzo[cd]indol-l(2H)- yl)butanoic 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 h. The mixture was concentrated in vacuo, and the residue was purified by prep-HPLC (Gemini 5 pm C18 column, 150 x 21.2 mm, eluted with 50-80% MeCN / H20 with 0.1% FA) to give compound LCT011028 (68.1 mg, 34% yield) as a yellow solid.

[0271] Mass spectrum MS (ESI): The molecular formula of C 34 H 28 N2O3, the molecular weight is 512.21, m / z is 513.20 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) d 8.16 (t, J = 8.0 Hz, 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).

[0272] Method for preparing compound LCT011029 of example 14

[0273] Synthesized according to general synthetic route 6:

[0274] Synthesis steps:

[0275] Step 1: Compound 1 (5.00 g, 28.06 mmol) was dissolved in EtOH (32.50 mL) and H2O (32.50 mL), TMSCN (4.20 g, 42.33 mmol) and (NH4)2CO3(18.9 g, 196.96 mmol) were added, and the mixture was stirred at 60 °C overnight. After the reaction was cooled 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 spectrum MS (ESI): molecular formula C 12 H 12 N2O4, molecular weight 248.08, m / z 249.09 [M+H] + .

[0276] Step 2: To DMF (20 mL) was added 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) in 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 x 3), the combined organic layers were washed with brine, dried over MgSO4and concentrated under reduced pressure to give compound 3 (2.30 g, yield 78.76%) as a white solid. Mass spectrum MS (ESI): molecular formula C 18 H 22 N2O6, molecular weight 362.15, m / z 363.15 [m+H] + .

[0277] Step 3: To 4N HCl / dioxane (25 mL) was added compound 3 (2.30 g, 9.27 mmol). 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, yield 82.30%) as a white solid. Mass spectrum MS (ESI): molecular formula C 14 H 14 N2O6, molecular weight 306.09, m / z 307.09 [m+H] + .

[0278] Step 4: To a solution of compound 4 (500 mg, 2.96 mmol) in DMF (5.0 mL) was added 60% NaH (237 mg, 5.92 mmol) at 0 °C, the reaction mixture was stirred at 0 °C for 15 min. (4-Bromobutyl)carbamic acid tert-butyl ester (896 mg, 3.55 mmol) was added. The reaction mixture was stirred at room temperature for 1 h. The reaction was quenched with water (50 mL), extracted with ethyl acetate (50 mL x 3), the combined organic layers were washed with brine, dried over MgS04and concentrated under reduced pressure to give compound 5 (1.00 g, yield 99.39%) as a yellow solid. Mass spectrum MS (ESI): molecular formula C 20 H 24 N2O3, molecular weight 340.18, m / z 341.20 [m+H] + .

[0279] Step 5: To ethyl acetate (5 mL) was added compound 5 (1.00 g, 2.94 mmol), 4N HC1 / EA (5 mg). The reaction mixture was stirred at room temperature for 1 h. The mixture was filtered, the filtrate was concentrated under reduced pressure to give compound 6 (250.00 mg, yield 30.67%) as a yellow solid. Mass spectrum MS (ESI): molecular formula C 15 H 17 ClN2O mass spectrum MS (ESI): molecular formula 276.10, m / z 277.10 [m-HC1+H] + .

[0280] Step 6: To DCM (5.0 mL) was added compound 6 (304 mg, 0.99 mmol), 1-(4- aminobutyl)benzo[cd]indol-2(lH)-one hydrochloride (250 mg, 0.93 mmol), HOBt (134 mg, 0.99 mol), triethylamine (235 mg, 2.33 mmol), EDCI (190 mg, 0.99 mmol). The reaction mixture was stirred at room temperature for 3 h. The mixture was concentrated in vacuum, and purified by prep-HPLC (Gemini 5 pm C18 column, 150 x 21.2 mm, eluted with 10% - 90% MeCN / H20 (containing 0.1% TFA) to give compound LCT011029 (300.00 mg, yield 57.36%) as a yellow solid. Mass spectrum MS (ESI): molecular formula C 29 H 28 N4O6, molecular weight 528.20, m / z 529.20 [M+H] + .

[0281] 1H NMR (400 MHz, DMSO-d6) δ 8.81 (s, 1H), 8.20-8.28 (d, J = 8.0 Hz, 1H), 8.11-8.09 (m, 2H,), 7.83-7.80 (t, J = 7.6 Hz, 1H), 7.66-7.63 (t, J = 7.8 Hz, 1H), 7.57-7.53 (m, 1H), 7.23-7.21 (d, J = 7.2 Hz, 1H), 6.98-6.94 (m, 2H), 6.86-6.84 (d, J = 8.4 Hz, 1H), 4.23 (s, 4H), 3.94-3.89 (m, 4H), 3.13-3.09 (m, 2H), 1.75-1.63 (m, 2H), 1.63 (s, 3H), 1.50-1.43 (m, 2H).

[0282] Process for the preparation of compound LCT011030 of example 15

[0283] Synthesis according to general synthesis scheme 6:

[0284] Synthesis steps:

[0285] Step 1 : Compound 1 (560 mg, 3.21 mmol) was dissolved in EtOH (10 mL), 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 h. The final mixture was quenched with HCI (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 spectrum MS (ESI): molecular formula C 12 H 15 NO, molecular weight 189.12, m / z 190.20 [m+H] + .

[0286] Step 2: Compound 2 (600 mg, 3.17 mmol) was dissolved in MeOH (15 mL), NH4CI (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 h. The precipitate was filtered off, the solution was concentrated under reduced pressure and the residue was extracted with ethyl acetate and aqueous ammonia solution. The combined organic layers were dried over sodium sulfate and evaporated. The obtained crude product compound 3 (400 mg, 72.0% yield) as a light yellow oil was used without further purification. Mass spectrum MS (ESI): molecular formula C 12 H 17 N, molecular weight 175.14, m / z 159.15 [m-NH2]+ .

[0287] Step 3: To a solution of 4-(2-oxobenzo[cd]indol-l(2H)-yl)butanoic acid (150 mg, 0.587 mmol) in DCM (3 mL) was added HOBt (79.4 mg, 0.587 mmol) and DCC (133 mg, 0.646 mmol) at 0 °C under N2atmosphere, the mixture was stirred at the same temperature for 0.5 h while slowly warming 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 celite. The filtrate was concentrated and purified by silica gel column chromatography (eluted with PE / EtOAc = 2 / 1) to give the product LCT011030 (37.6 mg, 16% yield) as a yellow solid.

[0288] Mass spectrum MS (ESI): The molecular formula is C 27 H 28 N2O2, the molecular weight is 412.22, m / z is 413.20 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 8.24 - 8.13 (m, 2H), 8.05 (d, J = 7.2 Hz, 1H), 7.81 (dd, J = 8.0, 7.2 Hz, 1H), 7.64 (d, J = 8.4 Hz, 1H), 7.53 (dd, J = 8.4, 7.2 Hz, 1H), 7.14 (d, J = 7.2 Hz, 1H), 6.99 - 6.91 (m, 3H), 4.87 - 4.73 (m, 1H), 3.88 (t, J = 6.8 Hz, 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 = 6.8 Hz, 2H).

[0289] Method for preparing compound LCT011045, intermediate XI-16 of example 16

[0290] Synthesized according to general synthetic route 6:

[0291] Synthesis steps:

[0292] Step 1: To a solution of compound 1 (2.00 g, 13.9 mmol) in DCM (20.0 mL) was added Boc20 (3.64 g, 16.6 mmol), TEA (4.21 g, 41.7 mmol) and DMAP (169 mg, 1.39 mmol). The mixture was stirred at room temperature for 16 h. Upon completion, the resulting mixture was diluted with water (50 mL) and extracted with EtOAc (10 mL x 3). The combined organic phase was washed with brine, dried over sodium sulfate, concentrated and purified by silica gel column chromatography (eluted with EtOAc / PE, 0% - 50%) to give compound 2 (2.70 g, 79% yield) as colorless oil. Mass MS (ESI): molecular formula C 12 H 21 NO4, molecular weight 243.15, m / z 188.1 [M- t Bu+H] + .

[0293] Step 2: Compound 2 (2.51 g, 10.3 mmol) was dissolved in dry DMF (50.0 mL) at 0 °C under N2atmosphere, and 60% NaH (0.450 g, 11.3 mmol) was added. After addition, the solution was stirred at room temperature for 30 min. Then Mel (1.61 g, 11.3 mmol) was added dropwise. The resulting solution was slowly heated to room temperature and stirred for 1 h. Upon completion, the resulting mixture was diluted with water (50 mL) and extracted with EtOAc (50 mL x 3). The combined organic phase was washed with brine, dried over sodium sulfate, concentrated and purified by silica gel column chromatography (eluted with EtOAc / PE, 0% - 50%) to give compound 3 (2.3 g, 85% yield) as colorless oil. Mass MS (ESI): molecular formula C 13 H 23 NO4, molecular weight 257.16, m / z 279.95 [m+Na] + .

[0294] Step 3: Compound 3 (2.2 g, 8.50 mmol) was dissolved in HCl dioxane solution (4 m, 20.0 mL) and stirred at room temperature for 1 h. The mixture was concentrated under reduced pressure. The residue was triturated in hexane / DCM, filtered and dried under vacuum to give compound 4 (1.7 g, 97% yield). Mass MS (ESI): molecular formula C8H 15 NO2, molecular weight 157.11, m / z 157.90 [m+H] + .

[0295] Step 4: Compound 5 (1.00 g, 5.90 mmol) was dissolved in DMF (10 mL), 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 h. Upon completion, the resulting mixture was diluted with water (100 mL) and extracted with EtOAc (20 mL x 3). The combined organic phase was washed with brine, dried over sodium sulfate, concentrated and purified by silica gel column chromatography (eluted with EtOAc / PE, 0%-50%) to give compound 6 (i.e. intermediate XI-16, 600 mg, 35% yield) as a yellow solid.

[0296] Mass spectrum MS (ESI): The molecular formula of C 14 H 12 BrNO, the molecular weight is 289.01, m / z is 289.80 [m+H] + .

[0297] Step 5: To a solution of compound 6 (640 mg, 2.20 mmol) in DMF (13 mL) was added compound 4 (693 mg, 4.41 mmol), K2CO3(1.21 g, 8.82 mmol) and KI (1.46 g, 8.82 mmol). The mixture was heated at 50 °C for 16 h. Upon completion, the resulting mixture was diluted with water (130 mL) and extracted with EtOAc (20 mL x 3). The combined organic phase was washed with brine, dried over sodium sulfate, concentrated and purified by silica gel column chromatography (eluted with EtOAc / PE, 0%-50%) to give compound 7 (480 mg, 59% yield) as a yellow oil. Mass spectrum MS (ESI): The molecular formula of C 22 H 26 N2O3, the molecular weight is 366.19, m / z is 367.30 [m+H] + .

[0298] Step 6: Compound 7 (200 mg, 0.545 mmol) was dissolved in MeOH / H2O = 1 / 1 (4.00 mL), LiOH (52.4 mg, 2.18 mmol) was added. The resulting mixture was stirred at 70 °C for 16 h. Upon completion, the combined organic phase was washed with water and brine, dried over sodium sulfate, concentrated under vacuum and purified by preparative HPLC (Gemini 5 pm C18 column, 150 x 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.

[0299] Mass spectrum MS (ESI): Formula for C 21 H 24 N2O3, molecular weight 352.18, m / z 353.25 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 8.18 (d, J = 8.0 Hz, 1H), 8.04 (d, J = 6.8 Hz, 1H), 7.80 (dd, J = 8.0, 7.2 Hz, 1H), 7.63 (d, J = 8.4 Hz, 1H), 7.58 - 7.52 (m, 1H), 7.18 (d, J = 6.8 Hz, 1H), 3.90 - 3.83 (m, 2H), 2.58 - 2.53 (m, 2H), 2.20 (s, 3H), 2.15 - 2.04 (m, 2H), 1.82 - 1.73 (m, 2H), 1.53 - 1.43 (m, 4H), 1.40 - 1.31 (m, 2H).

[0300] Process for preparing compound LCT011055 of example 17

[0301] Synthesized according to general synthetic route 2:

[0302] Synthesis steps:

[0303] 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 under N2atmosphere for 16 h. 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 x 3). The combined organic layers were washed with brine (10 mL), dried over Na2SO4, filtered and concentrated on a rotary evaporator. The resulting oil was purified by flash column chromatography (PE / EtOAc = 2 / 1) to give compound 2 (200 mg, yield: 61 %). Mass spectrum MS (ESI): Formula for C 25 H 26 N2O3, molecular weight 352.18, m / z 353.25 [M+H] + .

[0304] Step 2: Compound 2 (200 mg, 0.496 mmol) was dissolved in TFA (4 mL) and stirred at room temperature for 2 H under N2atmosphere. 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 pm C18 column, 150 x 21.2 mm, eluted with 20-30% MeCN / H2O containing 0.1% TFA) to give compound LCT011055 as a yellow solid (109.42 mg, purity: 96.89%, yield: 61%).

[0305] Mass spectrum MS (ESI): molecular formula is C 21 H 18 N2O3, molecular weight is 346.13, m / z is 347.10 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 12.10 (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 = 6.8 Hz, 2H), 2.31 (t, J = 7.2 Hz, 2H), 1.92 (p, J = 7.2 Hz, 2H).

[0306] Process for preparing compound LCT011057 of example 18

[0307] Synthesized according to general synthetic route 6:

[0308] Synthesis steps:

[0309] Step 1: To a solution of compound 1 (750 mg, 4.44 mmol) in DMF (5 mL) was added 60% NaH (444 g, 11.1 mmol) at 0 °C and stirred the reaction for 15 min at 0 °C. tert-Butyl (5-bromopentyl)carbamate (1.42 g, 5.33 mmol) was added. The reaction mixture was stirred at room temperature for 1 h. The reaction was quenched with water (100 mL) and extracted with ethyl acetate (75 mL x 3), the combined organic layers were washed with brine, dried over MgS04and concentrated under reduced pressure to give compound 2 (1.4 g, yield 89%) as a yellow solid. Mass spectrum MS (ESI): molecular formula is C 21 H 26 N2O3, molecular weight is 354.45, m / z is 355.45 [M+H] + .

[0310] Step 2: To a solution of compound 2 (1.4 g, 03.95 mmol) in EA (5 mL) was added 4N HC1 / EA (10 mL). The reaction mixture was stirred at room temperature for 2 hours. After the reaction was completed, the mixture was filtered, and the filtrate was concentrated under reduced pressure to give compound 3 (400 mg, 40% yield) as a white solid. Mass spectrum MS (ESI): the molecular formula of C 16 H 19 ClN2O, the molecular weight was 290.79, m / z was 255.33 [m-HC1+H] + .

[0311] Step 3: Compound 3 (400 mg, 1.38 mmol), (1R,2R,3R,4S)-3-(methoxycarbonyl)bicyclo[2.2.1]hept-5-ene-2-carboxylic acid (270 mg, 1.38 mol), HOBt (205 mg, 1.52 mmol), 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 purified by preparative HPLC (Gemini 5 pm C18 column, 150 x 21.2 mm, eluted with 10% - 90% MeCN / H2O (containing 0.1% TFA) to give compound 4 (500 mg, yield 83%) as a yellow solid. Mass spectrum MS (ESI): the molecular formula of C 26 H 28 N2O4, the molecular weight was 432.52, m / z was 433.52 [m+H] + .

[0312] 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 completed, the reaction was adjusted to pH = 2 with 1N HC1, and extracted with ethyl acetate (75 mL x 3) and water (100 mL), the combined organic layer was washed with brine, dried over MgS04, concentrated under vacuum, and the residue was purified by preparative HPLC (Gemini 5 pm C18 column, 150 x 21.2 mm, eluted with 10% - 90% MeCN / H2O (containing 0.1% TFA) to give compound LCT011057 (50 mg, 10% yield), a yellow solid.

[0313] Mass spectrum MS (ESI): the molecular formula of C 25 H 24 N2O3, the molecular weight was 400.48, m / z was 404.5 [M+H]+ . 1 H NMR (400 MHz, CDC13) δ 8.07 - 8.01 (m, 2H), 7.73 - 7.69 (t, J = 7.6 Hz, 1H), 7.55 - 7.53 (d, J = 8.4 Hz, 1H), 7.50 - 7.46 (t, J = 7.6 Hz, 1H), 6.94 - 6.92 (d, J = 6.8 Hz, 1H), 6.04 (s, 2H), 3.93 - 3.89 (t, J = 7.6 Hz, 2H), 3.36 - 3.30 (m, 4H), 3.23 (s, 2H), 1.84 - 1.76 (m, 2H), 1.72 - 1.70 (d, J = 8.8 Hz, 1H), 1.53 - 1.26 (m, 5H).

[0314] Method of preparing compound LCT011061 of Example 19

[0315] Synthesized according to general synthetic route 6:

[0316] Synthesis procedure: Compound 1 (35 mg, 0.13 mmol), 1-(5,6,7,8-tetrahydronaphthalen-2-yl)ethan-1-amine (22.7 mg, 0.13 mmol), 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 in vacuo and the residue was purified by preparative HPLC (Gemini 5 pm C18 column, 150 x 21.2 mm, eluted with 10% - 90% MeCN / H20 with 0.1% NH4HCO3) to give compound LCT011061 (33 mg, 59% yield) as a white solid. Mass spectrum MS (ESI): molecular formula C 27 H 29 N3O2, molecular weight 427.55, m / z 428.5 [M+H] + .

[0317] 1H NMR (400 MHz, DMSO-d6) δ 8.19-8.17 (d, J = 8.0 Hz, 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 = 7.0 Hz, 2H), 2.67-2.65 (d, J = 5.6 Hz, 4H), 2.18-2.15 (t, J = 5.4 Hz, 2H), 1.92-1.85 (m, 2H), 1.70-1.69 (m, 4H), 11.28-1.26 (d, J = 7.2 Hz, 3H).

[0318] Process for the preparation of compound LCT011062

[0319] Synthesis according to general synthetic scheme 6:

[0320] Synthesis steps:

[0321] Step 1 : Compound LCT011062-1 (20 g, 0.08 mol) and hydroxylamine hydrochloride (142.9 mg, 0.08 mol) were heated to reflux for 2 hours, after which it was cooled to room temperature and poured into ice water (1 L) and stirred. The resulting precipitate was filtered and rinsed with additional cold water and saturated NaHC03to give compound LCT011062-2 as a white solid (45 g, excess yield). Mass spectrum MS (ESI): molecular formula C 19 H 12 N2O7S, molecular weight 412.37, m / z 413.37 [m+H] + .

[0322] Step 2: To a solution of compound LCT011062-2 (45 g, 0.08 mol) in ethanol (120 mL) and water (80 mL) was added aqueous sodium hydroxide (2.7 m, 120 mL) at room temperature. The resulting mixture was heated to reflux temperature for 1 hour while distilling the ethanol. When TLC showed the reaction was complete, the mixture was cooled to 75 °C and concentrated hydrochloric acid was added dropwise until a yellow precipitate formed. After cooling at room temperature, the precipitate was collected by filtration and washed with water to give a mixture of compound LCT011062-3 and compound LCT011062-4 as a yellow solid (13.7 g, 80% yield). Mass spectrum MS (ESI): molecular formula C 11 H6N2O3, molecular weight 214.18, m / z 215.10 [m+H] + .

[0323] Step 3: To a mixture of compound LCT011062-3 and compound LCT011062-4 (13.7 g, 0.06 mol) in methanol (300 mL) was added 10% Pd / C (1.4 g). The reaction mixture was stirred at room temperature for 12 h. The mixture was filtered, and the filtrate was concentrated under reduced pressure to give a mixture of compound LCT011062-5 and compound LCT011062-6 as a white solid (5.4 g, 49% yield). Mass spectrum MS (ESI): molecular formula C 23 H 27 NO4S, molecular weight 413.53, m / z 414.50 [m+H] + .

[0324] Step 4: A mixture of compound LCT011062-5 and compound LCT011062-6 (5.4 g, 13.03 mol) was dissolved in DMF (40 mL) at 0 °C, 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 h. The reaction was quenched with water (400 mL) and extracted with ethyl acetate (200 mL x 3), and the combined organic layers were washed with brine, dried over MgSO4, and concentrated under reduced pressure to give a mixture of compound LCT011062-7 and compound LCT011062-8 (3.1 g, 80% yield). Mass spectrum MS (ESI): molecular formula C 17 H 18 N2O3, molecular weight 298.34, m / z 299.34 [m+H] + .

[0325] Step 5: A mixture of compound LCT011062-7 and compound 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 h. The mixture was adjusted to pH = 3 with 1 N HCl, then extracted with ethyl acetate (200 mL x 3), and the combined organic layers were washed with brine, dried over MgSO4, concentrated in vacuo, and the residue was purified by preparative HPLC (Gemini 5 μm C18 column, 150 x 21.2 mm, eluted with 10% - 90% MeCN / H2O (containing 0.1% TFA) to give compound LCT011062-9 as a yellow solid (800 mg, 25.8% yield). Mass spectrum MS (ESI): molecular formula C 12 H 14N3O2, 311.39 g / mol, m / z 312.40 [M+H] + .

[0326] Step 6: Compound LCT011062-9 (50 mg, 0.185 mmol), propan-2-amine (13 mg, 0.22 mmol), 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 in vacuo, and the residue was purified by preparative HPLC (Gemini 5 pm C18 column, 150 x 21.2 mm, eluted with 10% - 90% MeCN / H2O (containing 0.1% NH4HCO3)) to give compound LCT011062 as a white solid (35 mg, 61% yield).

[0327] Mass spectrum MS (ESI): molecular formula C 18 H 21 N3O2, 311.39 g / mol, m / z 312.40 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 7.67 - 7.65 (d, J = 7.6 Hz, 1H), 7.40 - 7.39 (d, J = 1.2 Hz, 1H), 7.35 - 7.27 (m, 2H), 7.07 - 7.07 (d, J = 1.6 Hz, 1H), 6.82 - 6.80 (d, J = 6.8 Hz, 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 = 6.4 Hz, 6H).

[0328] Example 21 Method of preparing compound LCT011063

[0329] Synthesized according to general synthetic route 6:

[0330] Synthesis procedure: Compound LCT011062-9 (50 mg, 0.185 mmol), 1-phenylethan-1-amine (27 mg, 0.22 mmol), DIPEA (60 mg, 0.46 mmol) were dissolved in DCM (5.0 mL), HATU (105.5 mg, 0.28 mmol) was added. The reaction mixture was stirred at room temperature for 3 hours. The mixture was concentrated in vacuo and purified by preparative HPLC (Gemini 5 pm C18 column, 150 x 21.2 mm, eluted with 10-90% MeCN / H2O with 0.1% NH4HCO3) to give compound LCT011063 (40 mg, 57.8% yield) as a white solid.

[0331] Mass spectrum MS (ESI): The molecular formula is C 23 H 23 N3O2, the molecular weight is 373.46, m / z is 374.5 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 8.81 (s, 1H), 8.28-8.26 (d, J = 7.6 Hz, 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 = 6.4 Hz, 1H), 5.80 (s, 2H), 4.93-4.89 (m, 1H), 3.83-3.79 (t, J = 6.8 Hz, 2H), 2.21-2.17 (m, 2H), 1.91-1.87 (m, 2H), 1.32-1.30 (d, J = 7.2 Hz, 1H).

[0332] Example 22 Method of preparing compound LCT011064

[0333] Synthesized according to general synthetic scheme 6:

[0334] Synthesis procedure: Compound LCT011062-9 (50 mg, 0.185 mmol), methylamine hydrochloride (15 mg, 0.22 mmol), DIPEA (60 mg, 0.46 mmol) were dissolved in DCM (5.0 mL), HATU (105.5 mg, 0.28 mmol) was added. The mixture was stirred at room temperature for 3 hours. The mixture was concentrated in vacuo and the residue was purified by preparative HPLC (Gemini 5 pm C18 column, 150 x 21.2 mm, eluted with 10-90% MeCN / H2O with 0.1% NH4HCO3) to give compound LCT011064 (17.5 mg, 57.8% yield) as a white solid.

[0335] Mass spectrum MS (ESI): the molecular formula is C 16 H 17 N3O2, the molecular weight is 283.33, m / z is 284.33 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 7.73-7.72 (m, 1H), 7.40-7.39 (d, J = 1.6 Hz, 1H), 7.35-7.27 (m, 2H,), 7.07-7.07 (d, J = 1.6 Hz, 1H), 6.83-6.81 (d, J = 6.8 Hz, 1H), 5.80 (s, 2H), 3.82-3.79 (t, J = 7.2 Hz, 2H), 2.54-2.50 (m, 3H), 2.14-2.10 (t, J = 14.8 Hz, 2H), 1.90-1.87 (m, 2H).

[0336] Method of preparing compound LCT011065 of example 23

[0337] Synthesized according to general synthetic route 6:

[0338] Synthesis procedure: Compound LCT011062-9 (50 mg, 0.185 mmol) was added to a solution of SOCl2 (5.0 mL) and stirred at 85 °C for 1 hour. The mixture was concentrated in vacuo and to the residue was added NH4OH (2 mL) at room temperature for 1 hour. After the reaction was completed, the reaction solution was concentrated under reduced pressure. The residue was purified by preparative HPLC (Gemini 5 pm C18 column, 150 x 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.

[0339] Mass spectrum MS (ESI): the molecular formula is C 15 H 15 N3O2, the molecular weight is 269.30, m / z is 270.30 [M+H] + . 1H NMR (400 MHz, DMSO-d6) δ 7.39-7.39 (d, J = 1.2 Hz, 1H), 7.35-7.26 (m, 3H), 7.07-7.07 (d, J = 1.2 Hz, 1H), 6.82-6.81 (d, J = 6.4 Hz, 1H), 6.76 (s, 1H), 5.80 (s, 2H), 3.82-3.79 (t, J = 7.2 Hz, 2H), 2.13-2.09 (t, J = 14.8 Hz, 2H), 1.89-1.85 (m, 2H).

[0340] Process for the preparation of compound LCT011068 of example 24

[0341] Synthesis according to general synthetic route 6:

[0342] Synthesis procedure: To a solution of compound LCT011047 (94 mg, 0.28 mmol) in DCM (4 mL) was added HOBT (57 mg, 0.428 mmol) and DCC (88 mg, 0.43 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. Upon completion, the reaction mixture was quenched with water and extracted with EtOAc. The combined organic layers were dried over Na2S04and evaporated to give the crude product which was purified by preparative HPLC (Gemini 5 pm C18 column, 150 x 21.2 mm, eluted with 30-95% MeCN in H20 with 0.1% ammonia) to give compound LCT011068 (56.34 mg, yield: 40%) as a yellow solid.

[0343] Mass spectrum MS (ESI): The molecular formula of C 33 H 32 N2O2, the molecular weight is 488.25, m / z is 489.20 [M+H] + . 1H NMR (400 MHz, DMSO-d6) δ 8.17 (d, J = 8.0 Hz, 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 = 6.8 Hz, 2H), 2.65 (d, J = 6.0 Hz, 4H), 2.19 (t, J = 7.6 Hz, 2H), 1.99 - 1.86 (m, 2H), 1.79 - 1.59 (m, 4H), 1.26 (d, J = 7.2 Hz, 3H).

[0344] Process for preparing compound LCT011071 of example 25

[0345] To 4-(4-amino-2-oxobenzo[cd]indol-l(2H)-yl)butanoic acid (100 mg, 0.37 mmol) in DCM (5 mL) was added DCC (114 mg, 0.55 mmol) and HOBT (75 mg, 0.55 mmol), stirred at 0 °C for 0.5 h, piperidine (63 mg, 0.74 mmol) was added, stirred at 25 °C for 72 h, the reaction was monitored by LCMS. After the reaction was completed, the reaction mixture was quenched with water, extracted with ethyl acetate, the organic layer was dried over sodium sulfate, evaporated to give the crude product, which was purified by high performance liquid chromatography (Gemini 5 μm C18 column, 150 x 21.2 mm, eluted with 30-95% MeCN / H20 with 0.1% FA) to give the product LCT011071 (43.92 mg, yield 33%) as a yellow solid.

[0346] Mass spectrum MS (ESI): the molecular formula is C 20 H 23 N3O2, the molecular weight is 337.18, m / z is 338.20 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 7.41 - 7.18 (m, 3H), 7.07 (s, 1H), 6.83 (d, J = 6.8 Hz, 1H), 5.79 (s, 2H), 3.83 (t, J = 7.2 Hz, 2H), 3.43 - 3.35 (m, 2H), 3.3 - 3.27 (m, 2H), 2.34 (t, J = 7.2 Hz, 2H), 1.88 (t, J = 7.2 Hz, 2H), 1.63 - 1.51 (m, 2H), 1.44 - 1.33 (m, 4H).

[0347] Process for the preparation of compound LCT011073 of example 26

[0348] To LCT011000 (100 mg, 0.39 mmol) in DCM (5 mL) was added DCC (121 mg, 0.58 mmol) and HOBT (79 mg, 0.58 mmol) and stirred at 0 °C for 0.5 h, 1-(naphthalen-2-yl)ethane-1,2-diamine (67 mg, 0.39 mmol) was added and stirred at 25 °C for 1 h, the reaction was monitored by LCMS. After completion of the reaction, the reaction mixture was quenched with water and extracted with ethyl acetate. The organic layer was washed with brine (10 mL), dried over Na2S04, filtered and concentrated on a rotary evaporator. The resulting oil was purified by pre-high performance liquid chromatography (Gemini 5 pm C18 column, 150 x 21.2 mm, eluted with 30% to 95% MeCN / H20 with 0.1% FA) to give LCT011073 (92 mg, 57% yield) as a yellow solid.

[0349] Mass spectrum MS (ESI): molecular formula C 27 H 24 N2O2, molecular weight 408.18, m / z 409.10 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 8.37 (d, J = 8.0 Hz, 1H), 8.19 (d, J = 8.1 Hz, 1H), 8.06 (d, J = 6.8 Hz, 1H), 7.89 - 7.72 (m, 5H), 7.63 (d, J = 8.4 Hz, 1H), 7.53 - 7.40 (m, 4H), 7.13 (d, J = 6.8 Hz, 1H), 5.13 - 4.96 (m, 1H), 3.90 (t, J = 6.8 Hz, 2H), 2.23 (d, J = 7.6 Hz, 2H), 2.01 - 1.87 (m, 2H), 1.40 (d, J = 7.2 Hz, 3H).

[0350] Process for the preparation of compound LCT011101 of example 27

[0351] Compound 3 was synthesized according to the process for the preparation of LCT011073 using appropriate commercially available reagents to give compound 3 as methyl 4-(1-(4-(4-(4-methyl-2-oxobenzo[cd]indol-1(2H)-yl)butylamino)ethyl)benzoate (100.0 mg, 80% yield) as a yellow solid. Mass spectrum MS (ESI): molecular formula C 26 H 26 N2O4, molecular weight 430.19, m / z 431.25 [m+H]+ .

[0352] NaOH (18.6 mg, 0.46 mmol) was added in THF:H2O = 2:1 (10 mL) to get a solution of compound 3 (100.0 mg, 0.23 mmol). It was stirred at 50 °C for 10 h, the reaction was monitored by LCMS. After completion of the reaction, pH was adjusted to 5-6 with HC1 (1 N) and extracted with ethyl acetate. The organic layer was dried over sodium sulfate and evaporated to get the crude product which was purified by high-performance liquid chromatography (Gemini 5 pm C18 column, 150 x 21.2 mm, eluted with 30% to 95% MeCN / H2O (containing 0.1% FA)) to get LCT011101 (30.75 mg, yield: 31%) as a yellow solid.

[0353] Mass spectrum MS (ESI): molecular formula C 25 H 24 N2O4, molecular weight 416.17, m / z 417.05 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 12.77 (s, 1H), 8.35 (d, J = 8.0 Hz, 1H), 7.97 (s, 1H), 7.93-7.82 (m, 3H), 7.58-7.45 (m, 2H), 7.39 (d, J = 8.4 Hz, 2H), 7.07 (d, J = 6.8 Hz, 1H), 5.01-4.83 (m, 1H), 3.87 (t, J = 6.8 Hz, 2H), 2.61 (s, 3H), 2.21 (t, J = 7.6 Hz, 2H), 1.99-1.84 (m, 2H), 1.31 (d, J = 7.2 Hz, 3H).

[0354] Process for preparation of compound LCT011102 of example 28

[0355] Intermediate 5 was synthesized according to the process for preparation of LCT011073 using appropriate commercially available reagents to get intermediate 5 (100.0 mg, yield: 86%) as a yellow solid.

[0356] Mass spectrum MS (ESI): molecular formula C 31 H 28 N2O4, molecular weight 492.20, m / z 493.10 [M+H] + .

[0357] Intermediate 5 was synthesized according to the process for preparation of LCT011073 using appropriate commercially available reagents to get intermediate 5 (100.0 mg, yield: 86%) as a yellow solid.

[0358] Mass spectrum MS (ESI): molecular formula C 30 H 26 N2O4, molecular weight 478.19, m / z 479.10 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 12.77 (s, 1H), 8.36 (d, J = 8.0 Hz, 1H), 8.12 (d, J = 7.2 Hz, 1H), 7.87 (d, J = 8.4 Hz, 2H), 7.78 (d, J = 7.2 Hz, 1H), 7.66 - 7.57 (m, 4H), 7.57 - 7.49 (m, 3H), 7.39 (d, J = 8.4 Hz, 2H), 7.23 - 7.15 (m, 1H), 4.99 - 4.85 (m, 1H), 3.92 (t, J = 6.8 Hz, 2H), 2.23 (t, J = 7.2 Hz, 2H), 2.00 - 1.87 (m, 2H), 1.32 (d, J = 7.2 Hz, 3H).

[0359] Process for the preparation of compound LCT0110076 of example 29

[0360] A solution of methyltriphenylphosphonium iodide (2.13 g, 5.28 mmol) in THF (20 mL) was added KHMDS (1.0 M in THF, 6.6 mL, 6.6 mmol) and stirred at 0 °C under nitrogen for 0.5 h. Then 6-bromo-3,4-dihydro-2H-naphthalen-1-one (1 g, 4.4 mmol) was added and stirred at 25 °C for 12 h. The reaction was monitored by thin layer chromatography. After completion of the reaction, the reaction mixture was quenched with saturated NH4C1 solution and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered, concentrated to get the product which was purified by flash chromatography (PE / EtOAc eluting from 100 / 00 to 98 / 02) to get compound 2 (610 mg, yield 61 %) as colorless oil.

[0361] A solution of compound 2 (610 mg, 2.73 mmol) in ACN (12 mL) was added tributyl(1-ethoxy)stannane (987 mg, 2.73 mmol) and PdAMPHOS (97 mg, 0.14 mmol). It was stirred at 90 °C under nitrogen for 3 h. Water was added to the solution and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered, concentrated to get the product which was purified by flash chromatography (PE / EtOAc eluting from 100 / 00 to 95 / 5) to get compound 4 (440 mg, yield 86 %) as white oil.

[0362] Mass spectrum MS (ESI): molecular formula C 13 H14 O, 186.10, m / z 187.15 [M+H] + .

[0363] Compound 4 (440 mg, 2.36 mmol) was dissolved in EtOH (9 mL) and NH2OH-HCI (330 mg, 4.72 mmol) and NaOAc (774 mg, 9.44 mmol) were added. The solution was stirred at 80 °C under nitrogen for 3 h. Water was added to the solution and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated to give the product which was purified by flash chromatography (PE / EtOAc from 100 / 00 to 75 / 25) to give compound 5 (420 mg, 84% yield) as a white solid.

[0364] Mass spectrum MS (ESI): molecular formula C 13 H 15 NO, 201.12, m / z 202.15 [M+H] + .

[0365] Compound 5 (380 mg, 1.88 mmol) was dissolved in MeOH (8 mL) and Zn dust (617 mg, 9.44 mmol) and NH4CI (504 mg, 9.44 mmol) were added. The solution was stirred at 80 °C for 12 h. Water was added to the solution and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated to give the product which was purified by flash chromatography (DCM / MeOH from 100 / 00 to 96 / 04) to give compound 6 (280 mg, 79% yield) as a white solid.

[0366] Mass spectrum MS (ESI): molecular formula C 13 H 17 N, 187.14, m / z 171.15 [M+H-17] + .

[0367] Compound 6 (160 mg, 0.85 mmol) was dissolved in MeOH (16 mL) and dry Pd / C (160 mg, 10% w.t) was added. The mixture was stirred at 25 °C under H2for 12 h. The mixture was filtered and the filtrate was concentrated under vacuum to give the crude compound 7 (135 mg, 80% yield) which was used directly in the next step without further purification.

[0368] Mass spectrum MS (ESI): molecular formula C 13 H 19 N, 189.15, m / z 173.20 [M+H-17] + .

[0369] DCC (106 mg, 0.51 mmol) and HOBT (69 mg, 0.51 mmol) were added to a solution of compound LCT0110000 (87 mg, 0.34 mmol) in DCM (1.5 mL) at 0 °C under N2atmosphere, stirred at 0 °C for 15 min. Compound 7 (65 mg, 0.3434 mmol) was added, stirred at 25 °C for 3 h, water was added to the solution, extracted with DCM, the organic layer was concentrated to give the crude product, which was purified by high performance liquid chromatography (column: Gemini 5 pm C18 150 x 21.2 mm, mobile phase: ACN-H2O (0.1% FA), gradient: 50-95, 12.50 min) to give LCT0110076 (32.0 mg, yield: 21%) as a yellow solid.

[0370] Mass spectrum MS (ESI): molecular formula C 28 H 30 N2O2, molecular weight 426.23, m / z 427.25 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) d 8.22 - 8.14 (m, 2H), 8.05 (d, J = 6.8 Hz, 1H), 7.85 - 7.77 (m, 1H), 7.64 (d, J = 8.4 Hz, 1H), 7.53 (d, J = 7.2 Hz, 1H), 7.17 - 7.12 (m, 1H), 7.10 (d, J = 8.0 Hz, 1H), 7.03 - 6.97 (m, 1H), 6.93 (s, 1H), 4.86 - 4.75 (m, 1H), 3.88 (d, J = 6.8 Hz, 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 = 7.2 Hz, 3H), 1.22 - 1.16 (m, 3H).

[0371] Process for preparing compound LCT011078 of example 30

[0372] 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 solution of compound 1 (460 mg, 2.66 mmol) in Tol (15 mL). Stirring at 100 °C for 6 h. The desired mass was detected on LC-MS. Water was added to the solution, extracted with ethyl acetate, the organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated to give the product compound 2 (370 mg, yield 83%) as a yellow solid. Mass spectrum MS (ESI): molecular formula C 20 H 23 NO3, molecular weight 325.17, m / z 326.25 [M+H] + .

[0373] 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 detected on LC-MS. Water was added to the solution, 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, yield 94%).

[0374] Mass spectrum MS (ESI): molecular formula C 16 H 15 NO3, molecular weight 269.11, m / z 270.15 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 12.09 (s, 1H), 7.97 (s, 1H), 7.90 (s, 1H), 7.58-7.47 (m, 2H), 7.13 (d, J = 6.4 Hz, 1H), 3.90 (d, J = 6.8 Hz, 2H), 2.61 (s, 3H), 2.30 (d, J = 7.2 Hz, 2H), 1.96-1.87 (m, 2H).

[0375] Method for preparing compound LCT0110079 of example 31

[0376] To a solution of compound LCT0110003-7 (165 mg, 0.47 mmol) in 1.4-dioxane (3 mL) were added allyl-2-amine (42 mg, 0.71 mmol), Pd-PEPPSI-IPent (18 mg, 0.023 mmol) and Cs2C03(310 mg, 0.95 mmol) respectively under N2atmosphere, stirred at 100 °C for 12 h. Water was added to the solution, then extracted with ethyl acetate, the organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated to give the product, purified by flash chromatography eluting with PE / EtOAc (from 100 / 00 to 55 / 45), to give compound 1 (72 mg, yield 40%) as a yellow solid. Mass spectrum MS (ESI): molecular formula C 22 H 28 N2O3, molecular weight 368.21, m / z 369.00 [M+H] + .

[0377] 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 give the crude product, purified by high performance liquid chromatography (column: Gemini 5 pm C18 150 x 21.2 mm, mobile phase: ACN-H20 (0.1% FA), gradient: 30-95, 13.00 min) to give LCT0110079 (20.5 mg, yield: 33%) as a yellow solid.

[0378] Mass spectrum MS (ESI): molecular formula C 18 H 20 N2O3, molecular weight 312.15, m / z 313.15 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 12.06 (s, 1H), 7.42 (d, J = 1.6 Hz, 1H), 7.38 - 7.28 (m, 2H), 6.97 (d, J = 1.6 Hz, 1H), 6.85 - 6.78 (m, 1H), 6.16 (d, J = 7.6 Hz, 1H), 3.83 (d, J = 6.2 Hz, 2H), 3.78 - 3.65 (m, 1H), 2.28 (d, J = 7.2 Hz, 2H), 1.94 - 1.83 (m, 2H), 1.21 (d, J = 6.0 Hz, 6H).

[0379] Process for the preparation of compound LCT011082 of example 32

[0380] To 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), a reaction mixture was obtained. H2O2 (871.58 mg, 7.68 mmol) was dissolved in EtOH (2 mL) and added to the reaction mixture, which was stirred at 25 °C for 1 h, and the reaction was monitored by LCMS. After the reaction was completed, the reaction mixture was quenched with saturated Na2SO3(3 mL). The mixture was evaporated to get the crude product, which was purified by reverse phase column (eluted with 10-95% MeCN / H2O containing 0.05% ammonia water) to get compound 2 (200.0 mg, purity 80.0%, yield 63%) as a yellow solid.

[0381] Mass spectrum MS (ESI): molecular formula C 19 H 21 NO4, molecular weight 327.15, m / z 328.15 [M+H] + .

[0382] Compound 2 (100.0 mg, 0.30 mmol) was dissolved in a mixture of DCM:TFA = 5:1 (3 mL) and stirred at 25 °C for 1 h, and the reaction was monitored by LCMS. After the reaction was completed, the pH was adjusted to 7-8 with NH3, and the crude product was purified by high performance liquid chromatography (Gemini 5 μm C18 column, 150 x 21.2 mm, eluted with 30%-95% MeCN / H2O containing 0.1% TFA) to get LCT011082 (51.09 mg, yield 60%) as an off-white solid.

[0383] Mass spectrum MS (ESI): molecular formula C 15 H 13 NO4, molecular weight 271.08, m / z 272.05 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 12.08 (s, 1H), 11.32 (s, 1H), 7.87 (d, J = 7.6 Hz, 1H), 7.67 (d, J = 8.4 Hz, 1H), 7.49-7.39 (m, 1H), 7.15 (d, J = 7.2 Hz, 1H), 7.06 (d, J = 7.6 Hz, 1H), 3.87 (t, J = 6.8 Hz, 2H), 2.29 (t, J = 7.6 Hz, 2H), 1.95-1.82 (m, 2H).

[0384] Process for preparing compound LCT011077 of example 33

[0385] The preparation method of LCT011077 is the same with LCT011082, to get LCT011077 (21.7 mg, yield: 26%). Mass spectrum MS (ESI): molecular formula is C 15 H 13 NO4 271.08, m / z is 272.05 [M+H] + .

[0386] 1 H NMR (400 MHz, DMSO-d6) 12.04 (s, 1H), 10.26 (s, 1H), 7.50 (d, J = 1.6 Hz, 1H), 7.44 (d, J = 3.2 Hz, 2H), 7.40 (d, J = 1.6 Hz, 1H), 7.01 - 6.95 (m, 1H), 3.86 (t, J = 6.8 Hz, 2H), 2.30 (t, J = 7.2 Hz, 2H), 1.96 - 1.84 (m, 2H).

[0387] Preparation method of compound LCT011088 in Example 34

[0388] To the solution of LCT011078 (40 mg, 0.14 mmol) in DCM (1 mL) was added DCC (45 mg, 0.22 mmol) and HOBT (30 mg, 0.22 mmol) at 0 °C. The mixture was stirred at 0 °C for 15 min, and prop-2-amine (17 mg, 0.29 mmol) was added to the mixture. The mixture was stirred at 25 °C for 3 hours. Water was added to the solution and extracted with DCM, and the organic layer was concentrated to get the crude product, which was purified by HPLC (column: Gemini 5 pm C18 150 x 21.2 mm, mobile phase: acetonitrile-H2O (0.1% FA), gradient: 50-95, 12.50 min) to get LCT011088 (10.3 mg, yield: 22%) yellow solid. Mass spectrum MS (ESI): molecular formula is C 19 H 22 N2O2, molecular weight 310.17, m / z is 311.00 [M+H] + .

[0389] 1H NMR (400 MHz, DMSO-d6) δ 7.97 (s, 1H), 7.90 (s, 1H), 7.69 - 7.61 (m, 1H), 7.58 - 7.47 (m, 2H), 7.11 (d, J = 6.4 Hz, 1H), 3.87 (d, J = 7.2 Hz, 2H), 3.84 - 3.74 (m, 1H), 2.61 (s, 3H), 2.10 (d, J = 7.2 Hz, 2H), 1.96 - 1.84 (m, 2H), 0.99 (d, J = 6.4 Hz, 6H).

[0390] Process for the preparation of compound LCT011083 of example 35

[0391] According to the process for the preparation of LCT011088, using appropriate commercial reagents such as HOBt, DCC, and intermediates such as isopropylamine.

[0392] LCT011083 was obtained (33.9 mg, yield: 60%).

[0393] Mass Mass spectrum MS (ESI): molecular formula C 24 H 24 N2O2, molecular weight 372.18, m / z 373.15 [M+H] + .

[0394] 1H NMR (400 MHz, DMSO-d6) δ 8.12 (d, J = 7.2 Hz, 1H), 7.78 (d, J = 7.2 Hz, 1H), 7.70 - 7.49 (m, 8H), 7.25 (d, J = 6.4 Hz, 1H), 3.92 (t, J = 6.8 Hz, 2H), 3.86 - 3.73 (m, 1H), 2.12 (d, J = 7.6 Hz, 2H), 1.99 - 1.87 (m, 2H), 0.99 (d, J = 6.4 Hz, 6H).

[0395] Process for the preparation of compound LCT011084 of example 36

[0396] According to the process for the preparation of LCT011088, using appropriate commercial reagents such as HOBt, DCC, and intermediates such as ammonia in dichloromethane.

[0397] LCT011084 was obtained (32.3 mg, yield: 54%).

[0398] Mass Mass spectrum MS (ESI): molecular formula C 21 H 18N2O2, 330.14, m / z 331.10 [M+H] + .

[0399] 1 H NMR (400 MHz, DMSO-d6) δ 8.12 (d, J = 7.2 Hz, 1H), 7.78 (d, J = 7.2 Hz, 1H), 7.66 - 7.50 (m, 7H), 7.29 (s, 1H), 7.26 (d, J = 6.4 Hz, 1H), 6.77 (s, 1H), 3.92 (t, J = 6.8 Hz, 2H), 2.14 (d, J = 7.6 Hz, 2H), 1.99 - 1.87 (m, 2H).

[0400] Process for the preparation of compound LCT011087 of example 37

[0401] Synthesized according to the procedure for the preparation of LCT011088 using appropriate commercially available reagents and intermediates.

[0402] LCT011087 was obtained (8.5 mg, yield: 18%).

[0403] Mass spectrum MS (ESI): molecular formula C 16 H 16 N2O2, 268.12, m / z 268.95 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 7.98 (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 = 7.2 Hz, 2H), 2.61 (s, 3H), 2.12 (d, J = 7.2 Hz, 2H), 1.96 - 1.84 (m, 2H).

[0404] Process for the preparation of compound LCT011097 of example 38

[0405] Synthesized according to the procedure for the preparation of LCT011088 using appropriate commercially available reagents and intermediates.

[0406] LCT011097 was obtained (20.42 mg, yield: 17%).

[0407] Mass spectrum MS (ESI): molecular formula C 27 H 25 N3O2, 423.19, m / z 424.20 [M+H]]+ .

[0408] 1 H NMR (400 MHz, DMSO-d6) 8.37 (d, J = 8.4 Hz, 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 = 7.2 Hz, 2H), 2.21 (d, J = 6.0 Hz, 2H), 1.94-1.86 (m, 2H), 1.40 (d, J = 7.2 Hz, 3H).

[0409] Process for preparing compound LCT011089 of example 39

[0410] Compound 1 (90 mg, 0.19 mmol) was dissolved in TFA / DCM = 1:5 mixture (2 mL) and stirred at 25 °C for 3 h. The reaction mixture was concentrated to give the crude product, which was purified by preparative HPLC (column: Gemini 5 pm C18 150 x 21.2 mm, mobile phase: acetonitrile-H20 (0.1% FA), gradient: 5-95, 12.50 min) to give LCT011089 (31.32 mg, yield: 44%) as a yellow solid.

[0411] Mass spectrum MS (ESI): molecular formula is C 22 H 25 N3O2, molecular weight is 363.19, m / z is 364.25 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) 7.97 (d, J = 7.2 Hz, 1H), 7.82 (d, J = 8.8 Hz, 1H), 7.66 (d, J = 7.2 Hz, 1H), 7.61-7.52 (m, 1H), 7.43-7.33 (m, 1H), 7.17 (d, J = 7.2 Hz, 1H), 6.49-6.45 (m, 1H), 4.18-4.14 (m, 2H), 3.98-3.94 (m, 2H), 3.89 (d, J = 7.2 Hz, 2H), 3.87-3.76 (m, 1H), 2.14 (d, J = 7.6 Hz, 2H), 2.02-1.90 (m, 2H), 1.04 (d, J = 6.8 Hz, 6H).

[0412] Process for the preparation of compounds LCT011092, LCT011090 of example 40

[0413] Step 1 : Preparation of 4-(5-bromo-2-oxobenzo[cd]indol-l(2H)-yl)butanoic acid

[0414] Compound 1 (1.1 g, 2.8 mmol) was added to a mixture of DCM / TFA = 5 / 1 (5 mL) and the reaction was stirred at 25°C for 1 hour. After completion of the reaction, the pH of the mixture was adjusted to 8 with NaHC03(aq.) and extracted with EtOAc. The organic layer was dried over Na2S04, filtered off and concentrated to obtain the desired product, compound 8 (1.0 g, yield: 94%) as a yellow solid. Mass spectrum MS (ESI): molecular formula C 15 H 12 BrNO3, molecular weight 333.00, m / z 333.95 [M+H] + .

[0415] Step 2: Preparation of 4-(5-bromo-2-oxobenzo[cd]indol-l(2H)-yl)-N- isopropylbutanamide

[0416] To a solution of compound 8 (1.0 g, 2.99 mmol) in DCM (20 mL) was added HOBT (606 mg, 4.5 mmol) and DCC (926 mg, 4.5 mmol). The mixture was stirred at 0°C for 0.5 hour, prop-2-amine (353.8 mg, 6.0 mmol) was added to the solution and the reaction was stirred at 25°C for 16 hours, the reaction was monitored by LCMS. Upon completion, the reaction mixture was quenched with H20 and extracted with DCM. The organic layer was evaporated to obtain the crude product which was purified by flash chromatography (eluted with PE / EtOAc from 100 / 00 to 50 / 50) to obtain compound 9 (1.0 g, yield: 80%) as a yellow solid.

[0417] Mass spectrum MS (ESI): molecular formula C 18 H 19 BrN2O2, molecular weight 374.06, m / z 374.75 [M+H] + .

[0418] Step 3: Preparation of tert-butyl 4-(l-(4-(isopropylamino)-4-oxobutyl)-2-oxo- l,2-dihydrobenzo[cd]indol-5-yl)-3,6-dihydropyridine-l(2H)-carboxylate

[0419] To a solution of compound 9 (300 mg, 0.80 mmol) in 1.4-dioxane / H20 = 5 / 1 (6 mL) was added 4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-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), the mixture was stirred at 80 °C for 6 hours under N2atmosphere. The reaction was detected on LC-MS. Water was added to the solution and extracted with EtOAc, the organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated, purified by flash chromatography (eluted with PE / EtOAc from 100 / 00 to 60 / 40) to give compound 10 (240 mg, yield: 58%) as yellow solid. Mass spectrum MS (ESI): molecular formula C 28 H 35 N3O 4， Molecular weight 477.26, m / z 478.25 [M+H] + .

[0420] Step 4: Preparation of 4-(l-(4-(isopentylamino)-4-oxobutyl)-2-oxo-l,2- dihydrobenzo[cd]indol-5-yl)piperidine-l-carboxylate

[0421] To a solution of compound 10 (120.0 mg, 0.25 mmol) in MeOH (5 mL) was added Pd / C (89.14 mg, 0.8376 mmol), the mixture was stirred at 25 °C under H2atmosphere for 16 hours, the reaction was detected on LC-MS. The reaction mixture was filtered and concentrated to give the desired product compound 11 (120 mg, purity: 80.0%, yield: 79%) as yellow solid. Mass spectrum MS (ESI): molecular formula C 28 H 37 N3O4, molecular weight 479.28, m / z 480.25 [M+H] + .

[0422] Step 5: Preparation of N-isopropyl-4-(2-oxo-5-(piperidin-4-yl)benzo[cd]indol-l(2H)- yl)butanamide:

[0423] Compound 11 was added (120.0 mg, 0.25 mmol) in a mixture of DCM / TFA = 5 / 1 (5 mL) and stirred for 1 hour, the reaction was monitored on LC-MS. After the reaction was completed, the reaction mixture was evaporated to get the crude product which was purified by preparative HPLC (Gemini 5 pm C18 column, 150 x 21.2 mm, 30% to 95% MeCN / H 2O elution, 11.25 min) to give the product LCT011092 (33.37 mg, yield: 30%) as a yellow solid.

[0424] Mass spectrum MS (ESI): molecular formula C 23 H 29 N3O2, molecular weight 379.23, m / z 380.15 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 8.68 - 8.56 (m, 1H), 8.48 - 8.32 (m, 2H), 8.08 (d, J = 6.8 Hz, 1H), 7.90 - 7.80 (m, 1H), 7.66 (d, J = 7.2 Hz, 1H), 7.35 (d, J = 7.6 Hz, 1H), 7.17 (d, J = 7.6 Hz, 1H), 3.87 (t, J = 6.8 Hz, 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 = 7.2 Hz, 2H), 2.07 - 1.86 (m, 6H), 0.99 (d, J = 6.4 Hz, 6H).

[0425] LCT011090 was prepared in the same way as LCT011092.

[0426] LCT011090 (TFA salt) was obtained (59.41 mg, purity: 99.44%, yield: 62.75%) as a yellow solid.

[0427] Mass spectrum MS (ESI): molecular formula C 22 H 27 N3O 2， molecular weight 365.21, m / z 366.15 [M+H] + . 1H NMR (400MHz, DMSO-d6) δ 9.07 (s, 2H), 8.06 (d, J = 7.3 Hz, 1H), 7.83-7.77 (m, 2H), 7.69-7.56 (m, 2H), 7.24 (d, J = 7.1 Hz, 1H), 4.36-4.19 (m, 1H), 3.88 (t, J = 6.9 Hz, 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 = 6.6 Hz, 6H).

[0428] Process for preparing compound LCT011091 of example 41

[0429] Compound 1 (120 mg, 0.25 mmol) was added to a mixture solution of TFA:DCM = 1:5 (2 mL) and stirred at 25 °C for 3 h. The reaction was detected on LC-MS. The reaction mixture was concentrated to give the crude product, which was purified by HPLC (column: Gemini 5 pm C18 150 x 21.2 mm, mobile phase: ACN-H20 (0.1% FA), gradient: 5-95, 12.50 min) to give LCT011091 (33.70 mg, yield: 35%) as a yellow solid.

[0430] Mass spectrum MS (ESI): molecular formula is C 23 H 27 N3O2, 377.21 of molecular weight, 378.60 of m / z [M+H] + . 1 H NMR (400MHz, DMSO-d6) 8.35-8.31 (m, 1H), 8.02 (d, J = 6.8 Hz, 1H), 7.74-7.61 (m, 3H), 7.56 (d, J = 7.6 Hz, 1H), 7.21 (d, J = 7.2 Hz, 1H), 5.95 (s, 1H), 3.88 (d, J = 6.8 Hz, 2H), 3.85-3.72 (m, 1H), 3.66 (s, 2H), 3.28-3.14 (m, 2H), 2.59 (s, 2H), 2.09 (d, J = 7.2 Hz, 2H), 1.96-1.86 (m, 2H), 0.99 (d, J = 6.8 Hz, 6H).

[0431] Process for preparing compound LCT011093 of example 42

[0432] Compound 1 (50.0 mg, 0.10 mmol) was added to a mixture solution of DCM / TFA = 5 / 1 (2 mL), stirred at 25 °C for 1 h, the reaction was monitored on LC-MS, after completion, the reaction mixture was evaporated to get the crude product, which was purified by HPLC (Gemini 5 pm C18 column, 150 x 21.2 mm, 30% to 95% MeCN / H 2O eluted, 11.25 min) to give LCT011093 (TFA salt) (10.38 mg, yield: 30%) as a yellow solid. Mass spectrum MS (ESI): molecular formula C 19 H 18 N2O3, molecular weight 322.13, m / z content 323.10 [M+H] + .

[0433] 1 H NMR (400 MHz, DMSO-d6) δ 11.90 (br s, 1H), 9.43 (br s, 1H), 8.08 (d, J = 7.2 Hz, 1H), 7.88 - 7.73 (m, 2H), 7.69 - 7.58 (m, 1H), 7.28 (d, J = 7.2 Hz, 1H), 6.53 (s, 1H), 4.59 - 4.49 (m, 2H), 4.34 - 4.26 (m, 2H), 3.93 (t, J = 6.8 Hz, 2H), 2.31 (t, J = 7.6 Hz, 2H), 1.98 - 1.85 (m, 2H).

[0434] Process for preparing compound LCT011094 of example 43

[0435] Step 1: Preparation of 3-(1-(4-(tert-butoxy)-4-oxobutyl)-2-oxo-1,2-dihydrobenzo[cd]indol-5-yl)- 2,5-dihydro-1H-pyrrole-1-carboxylic acid tert-butyl ester

[0436] To compound 1 (300 mg, 0.77 mmol) in 1,4-dioxane / H2O ＝10:1 (10 mL) was added compound 2 (272 mg, 0.92 mmol), K2CO3(212 mg, 1.5 mmol) and Pd(dppf)Cl2(56 mg, 0.077 mmol). The reaction was stirred at 100 °C for 5 h, the reaction was monitored by LCMS. After completion of the reaction, the reaction mixture was evaporated to get crude product which was purified by flash chromatography (eluted with PE / EtOAc from 100 / 00 to 80 / 20) to get compound 3 (280.0 mg, yield: 68%) as yellow solid. Mass spectrum MS (ESI): molecular formula C 28 H 34 N2O5, molecular weight 478.25, m / z 479.35 [M+H] + .

[0437] Step 2: Preparation of 3-(1-(4-(tert-butoxy)-4-oxobutyl)-2-oxo-1,2-dihydrobenzo[cd]indol-5-yl)- 2,5-dihydro-1H-pyrrole-1-carboxylic acid tert-butyl ester

[0438] To a solution of compound 3 (160 mg, 0.33 mmol) in MeOH (10 mL) was added Pd / C (128 mg, 80% by weight) and stirred at 25 °C for 16 h under H2atmosphere, the reaction was monitored by LCMS. After completion of the reaction, the reaction mixture was filtered and evaporated to get the product compound 4 (150 mg, yield: 84%) as yellow solid. Mass spectrum MS (ESI): molecular formula C 28 H 36 N2O5, molecular weight 480.26, m / z 481.10 [M+H] + .

[0439] Step 3: Preparation of 4-(2-oxo-5-(pyrrolidin-3-yl)benzo[cd]indol-1(2H)-yl)butanoic acid (LCT011094)

[0440] 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 h, the reaction was monitored by LCMS. After completion of the reaction, the reaction mixture was evaporated to get crude product which was purified by preparative HPLC (Gemini 5 pm C18 column, 150 x 21.2 mm, eluted with 0.1% TFA in 30% to 95% MeCN / H 2O O, 0.1% TFA) to get the product LCT011094 (TFA salt) (80.0 mg, yield: 78%) as yellow solid.

[0441] Mass spectrum MS (ESI): molecular formula C 19 H20 N2O3, molecular weight 324.15, m / z 325.10 [M+H] + .

[0442] 1 H NMR (400 MHz, DMSO-d6) δ 10.01 (br s, 2H), 8.05 (d, J = 7.2 Hz, 1H), 7.86-7.75 (m, 2H), 7.65-7.56 (m, 1H), 7.24 (d, J = 6.8 Hz, 1H), 4.35-4.16 (m, 1H), 3.91 (t, J = 6.8 Hz, 2H), 3.82-3.65 (m, 1H), 3.51-3.37 (m, 1H), 3.37-3.23 (m, 2H), 2.48-2.43 (m, 1H), 2.29 (t, J = 7.2 Hz, 2H), 2.18-2.05 (m, 1H), 1.97-1.84 (m, 2H).

[0443] Method for preparing compound LCT011096 of Example 44

[0444] The preparation method of LCT011096 is the same as that of LCT011094, to obtain LCT011096 (TFA salt) (10.10 mg, purity: 99.244%, yield: 70.0%) as a yellow solid.

[0445] Mass spectrum MS (ESI): molecular formula is C 20 H 22 N2O3, molecular weight 338.16, m / z 339.15 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 12.10 (br s, 1H), 8.88-8.74 (m, 1H), 8.65-8.46 (m, 1H), 8.05 (d, J = 7.7 Hz, 1H), 7.90 (d, J = 8.8 Hz, 1H), 7.66-7.55 (m, 2H), 7.23 (d, J = 7.2 Hz, 1H), 3.91 (t, J = 6.8 Hz, 2H), 3.82-3.70 (m, 1H), 3.52-3.39 (m, 2H), 3.29-3.12 (m, 2H), 2.31 (t, J = 7.2 Hz, 2H), 2.09-1.84 (m, 6H).

[0446] Method for preparing compound LCT011095 of Example 45

[0447] Compound 1 (50.0 mg, 0.10 mmol) was added to a mixture solution of DCM:TFA = 5:1 (2 mL) and stirred at 25 °C for 1 h, the reaction was monitored by LC-MS. After the reaction was completed, the reaction mixture was evaporated to get the crude product, which was purified by HPLC (Gemini 5 pm C18 column, 150 x 21.2 mm, 30% to 95% MeCN / H 2O O (11.25 min) with 0.1% TFA, to give the product LCT011095 (TFA salt) (10.88 mg, yield: 31%) as a yellow solid.

[0448] Mass spectrum MS (ESI): molecular formula C 20 H 20 N2O3, molecular weight 336.15, m / z 337.15 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 12.08 (br s, 1H), 8.92 (s, 2H), 8.06 (d, J = 7.2 Hz, 1H), 7.78 - 7.49 (m, 3H), 7.25 (d, J = 7.2 Hz, 1H), 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 = 7.2 Hz, 2H), 2.00 - 1.83 (m, 2H).

[0449] Example 46: Preparation of compounds LCT011016 and LCT011098

[0450] Step 1: Preparation of (9s,10s)-9,10-dihydro-9,10-[3,4]cyclopyrroloanthracene-12,14-dione

[0451] To a solution of p-anthracene (1.5 g, 8.4 mmol) in toluene (15 mL) was added 1H-pyrrole-2,5-dione (1.0 g, 10.9 mmol) and stirred at 80 °C for 48 h. After the reaction was completed, the mixture was concentrated to remove most of the solvent, the precipitate was collected by filtration and triturated with EtOAc to give compound 3 (1.6 g, yield: 66%) as a white solid. Mass spectrum MS (ESI): molecular formula C 18 H 13 NO2, molecular weight 275.09, m / z 274.15 [M-H] - .

[0452] Step 2: Preparation of (9s,10s)-9,10-dihydro-9,10-[3,4]cyclopyrroloanthracene

[0453] A solution of compound 3 (1.6 g, 5.8 mmol) in THF (32 mL) was added LiAlH4(1.0 M in THF, 28.9 mL, 28.9 mmol) at 0 °C, stirred at 25 °C for 72 h, after the reaction was completed, 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 reverse flash chromatography (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 spectrum MS (ESI): molecular formula C 18 H 17 N, molecular weight 247.14, m / z 248.05 [M+H] + .

[0454] Step 3: Preparation of tert-butyl 4-(4-((tert-butoxycarbonyl)amino)-2-oxobenzo[cd]indol-1(2H)-yl)butanoate

[0455] To a solution of compound LCT0110003-7 (800 mg, 2.31 mmol) in Tol (16 mL) was added 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) under N2atmosphere, stirred at 100 °C for 12 h. After completion, the reaction mixture was quenched by adding water (20 mL). Then the mixture was poured into a separation funnel to separate the aqueous layer, the combined organic layers were washed with brine (20 mL), dried over Na2SO4, filtered and concentrated on a rotary evaporator. The resulting oil phase was purified by flash column chromatography (PE / EtOAc = 3 / 1) to give compound 5 (680 mg, yield: 68%) as a yellow solid. Mass spectrum MS (ESI): molecular formula C 24 H 30 N2O5, molecular weight 426.22, m / z 427.10 [M+H] + .

[0456] Step 4: Preparation of 4-(4-amino-2-oxobenzo[cd]indol-1(2H)-yl)butanoic acid (LCT011016)

[0457] Compound 5 (680 mg, 1.59 mmol) was added to a mixture solution of TFA / DCM = 1:5 (12 mL), the mixture was stirred at 25 °C for 3 hours, after the reaction was completed, the mixture was concentrated, the residue was purified by reverse phase flash chromatography (with H2O (0.1% FA-H2O) / MeCN from 90 / 10 to 65 / 35) to give LCT011016 (260 mg, yield: 60%) as a yellow solid. Mass spectrum MS (ESI): molecular formula C 15 H 14 N2O3, molecular weight 270.10, m / z 271.10 [M+H] + .

[0458] 1 H NMR (400 MHz, DMSO-d6) 12.07 (s, 1H), 7.39 (s, 1H), 7.37-7.24 (m, 2H), 7.06 (s, 1H), 6.82 (d, J = 6.4 Hz, 1H), 5.80 (s, 2H), 3.83 (d, J = 6.4 Hz, 2H), 2.27 (t, J = 6.8 Hz, 2H), 1.92-1.84 (m, 2H).

[0459] Step 5: Preparation of 2,5-dioxopyrrolidin-1-yl 4-(4-amino-2-oxobenzo[cd]indol-1(2H)- yl)butanoate

[0460] To a solution of LCT011016 (110 mg, 0.40 mmol) in DCM (2 mL) was added DCC (117 mg, 0.56 mmol) and 1-hydroxypyrrolidine-2,5-dione (60 mg, 0.52 mmol) at 0 °C. The mixture was stirred at 25 °C for 12 hours, the reaction was monitored on LC-MS. After the reaction was completed, the reaction mixture was quenched by adding water (10 mL), then the mixture was poured into a separation funnel and separated, the aqueous layer was extracted with DCM (20 mL x 3). The combined organic layer was washed with brine (10 mL), dried over Na2SO4, filtered and concentrated to give the crude compound 7 (110 mg, yield: 61%) which was used directly for the next step without further purification.

[0461] Mass spectrum MS (ESI): molecular formula C 19 H 17 N3O5, molecular weight 367.12, m / z 368.10 [M+H] + .

[0462] Step 6: Preparation of 4-amino-l-(4-((9S,10S)-9,10-dihydro-9,10- [3,4]cyclopental[a]anthracen-13-yl)-4-oxobutyl)benzo[cd]indol-2(lH)-one (LCT011098)

[0463] To a solution of compound 7 (110 mg, 0.29 mmol) in acetonitrile (1 mL) was added compound 4 (74 mg, 0.29 mmol) and TEA (60 mg, 0.59 mmol), the mixture was stirred at 25 °C for 3 h, after completion, the reaction mixture was quenched by the addition of water (10 mL), then the mixture was poured into a separation funnel and separated. The aqueous layer was extracted with EtOAc (20 mL x 3). The combined organic layers were washed with brine (10 mL), dried over Na2S04, filtered and concentrated to give the crude product, which was purified by prep-HPLC (column: Gemini 5 pm C18 150 x 21.2 mm, mobile phase: ACN-H20 (0.1% FA), gradient: 40-95, 12.50 min) to give LCT011098 (29.3 mg, yield: 19%) as a yellow solid. Mass MS (ESI): molecular formula C 33 H 29 N3O2, molecular weight 499.23, m / z 500.15 [M+H] + .

[0464] 1 H NMR (400 MHz, DMSO-d6) 7.42-7.37 (m, 1H), 7.36-7.21 (m, 5H), 7.15 (d, J = 7.2 Hz, 1H), 7.12-7.05 (m, 3H), 6.97 (d, J = 7.2 Hz, 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), 2.76-2.65 (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).

[0465] Process for preparing compound LCT011099 of example 47

[0466] Step 1: Preparation of 2,5-dioxopyrrolidin-l-yl 4-(4-methyl-2-oxobenzo[cd]indol-l(2H)- yl)butanoate

[0467] To a solution of compound LCT011078 (60 mg, 0.22 mmol) in DCM (2 mL) was added DCC (59 mg, 0.28 mmol) and 1-hydroxypyrrolidine-2,5-dione (30 mg, 0.26 mmol) at 0 °C and the mixture was stirred at 25 °C for 6 h, the reaction was monitored on LC-MS. After completion of the reaction, 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 get the crude compound 5 (60 mg, yield: 73%) which was used directly for the next step without further purification.

[0468] Mass Mass (ESI): 498.23 (M+H) of C 20 H 18 N2O5, 366.12 (M+H) 367.05 + .

[0469] Step 2: Preparation of 1-(4-((9S,10S)-9,10-dihydro-9,10-[3,4]cyclopental[a] anthracen-13-yl)-4-oxobutyl)-4-methylbenzo[cd]indol-2(lH)-one

[0470] To a solution of compound 5 (60 mg, 0.16 mmol) in DCM (2 mL) was added compound 6 (40 mg, 0.16 mmol) and TEA (33 mg, 0.32 mmol) and the mixture was stirred at 25 °C for 6 h, water was added to the solution and extracted with DCM, the organic layer was concentrated to get the crude product which was purified by prep-HPLC (column: Gemini 5 pm C18 150 x 21.2 mm, mobile phase: acetonitrile-H20 (0.1% FA), gradient: 55-95, 12.50 min) to get compound LCT011099 (34.35 mg, yield: 42%) as a yellow solid.

[0471] Mass Mass (ESI): 498.23 (M+H) of C 34 H 30 N2O2, 498.23 (M+H) 499.20 + .

[0472] 1HNMR (400 MHz, DMSO-d6) δ 7.98 (s, 1H), 7.92 (s, 1H), 7.58-7.49 (m, 2H), 7.33-7.27 (m, 2H), 7.24 (d, J = 7.2 Hz, 1H), 7.15 (d, J = 7.2 Hz, 1H), 7.12-7.05 (m, 3H), 6.97 (d, J = 6.8 Hz, 1H), 6.82 (d, J = 7.2 Hz, 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).

[0473] Example 48 Preparation of compound LCT011100

[0474] The preparation of LCT011100 was the same as LCT011099.

[0475] LCT011100 (31.87 mg, yield: 23%) was obtained.

[0476] Mass spectrum MS (ESI): The molecular formula of C 33 H 28 N2O3, 500.21, m / z 501.15 [M+H] + . 1H NMR (400 MHz, DMSO-d6) 10.27 (s, 1H), 7.51 (d, J = 2.0 Hz, 1H), 7.47-7.43 (m, 2H), 7.41 (d, J = 2.0 Hz, 1H), 7.32-7.27 (m, 2H), 7.24 (d, J = 7.2 Hz, 1H), 7.15 (d, J = 7.2 Hz, 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).

[0477] Example 49 Process for the preparation of compound LCT011103

[0478] Step 1: Preparation of (9S,10S)-9,10-dihydro-9,10-ethylanthracen-l l-carbonitrile

[0479] To a solution of anthracene (4.0 g, 22.4 mmol) in o-xylene (35 mL) was added prop-2-enenitrile (5.94 g, 112.0 mmol) and BHT (50 mg, 0.022 mmol) and the reaction stirred at 150 °C for 24 h. The reaction mixture was cooled, filtered to remove unreacted anthracene and the solvent removed under reduced pressure. The crude product was purified by flash chromatography (eluting with PE / EtOAc from 100 / 00 to 90 / 10 over 20 min) to give compound 2 (2.8 g, yield: 51%) as a white solid. The product was confirmed by1H NMR.

[0480] 1 H NMR (400 MHz, DMSO-d6) δ 7.46-7.41 (m, 1H), 7.39-7.32 (m, 3H), 7.21-7.17 (m, 2H), 7.16-7.11 (m, 2H), 4.71 (d, J = 2.4 Hz, 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).

[0481] Step 2: Preparation of ((9S,10S)-9,10-dihydro-9,10-ethylanthracen-l l- yl)methanamine

[0482] To a solution of compound 2 (2.0 g, 8.6 mmol) in THF (50 mL) was added LiAlH4(0.65 g, 17.2 mmol) at 0 °C and stirred at 25 °C for 24 h. The reaction was monitored by LCMS. After completion of the reaction, the reaction mixture was carefully quenched with ice water and extracted with EtOAc. The organic layer was evaporated to get the crude product which was purified by reverse phase chromatography column (eluted with 10-90% MeCN in H2O with 0.1% FA to get the product compound 3 (400.0 mg, yield: 18%) as a white solid.

[0483] Mass spectrum MS (ESI): Molecular formula C 17 H 17 N, Molecular weight 235.14, m / z 236.10 [M+H] + .

[0484] Step 3: Preparation of N-(((9S,10S)-9,10-dihydro-9,10-ethylanthracen-l l- yl)methyl)-4-(4-methyl-2-oxobenzo[cd]indol-l(2H)-yl)butanamide

[0485] To a solution of compound 3 (50.0 mg, 0.18 mmol) in DCM (5 mL) was added DCC (57.5 mg, 0.28 mmol) and HOSu (32.1 mg, 0.28 mmol) and the reaction was stirred at 25 °C for 5 h. Then ((9s,10s)-9,10-dihydro-9,10-ethylanthracen-l l-yl)methanamine (43.7 mg, 0.18 mmol) was added and the reaction was stirred at 25 °C for 16 h and the reaction was monitored by LCMS. After completion of the reaction, the reaction mixture was quenched with H2O and extracted with DCM. The organic layer was evaporated to get the crude product which was purified by HPLC (Gemini 5 pm C18 column, 150 x 21.2 mm, eluted with 30% to 95% MeCN in H2O with 0.1% FA) to get the product LCT011100 (30.55 mg, yield: 33%) as a yellow solid.

[0486] Mass spectrum MS (ESI): Molecular formula C 33 H 30 N2O2, Molecular weight 486.23, m / z 487.15 [M+H] + . 1HNMR (400 MHz, DMSO-d6) δ 7.97 (s, 1H), 7.90 (s, 1H), 7.86 (t, J = 5.6 Hz, 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 = 6.8 Hz, 2H), 2.67-2.59 (m, 4H), 2.58-2.54 (m, 1H), 2.16 (t, J = 7.6 Hz, 2H), 1.99-1.88 (m, 3H), 1.86-1.76 (m, 1H), 1.07-0.98 (m, 1H).

[0487] Process for preparing compound LCT011105 of example 50

[0488] Step 1: Preparation of tert-butyl 4-(2-oxo-4-vinylbenzo[cd]indol-l(2H)-yl)butanoate

[0489] To a solution of compound LCT0110003-7 (400.0 mg, 1.16 mmol) in 1.4-dioxane: H20 = 10: 1 (15 mL) was added 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), and the reaction was stirred at 100 °C for 5 h. The reaction was monitored on LC-MS, water was added to the solution, and the solution was extracted with EtOAc, the organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated, the product was purified by flash chromatography (eluted 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 spectrum MS (ESI): molecular formula C 21 H 23 NO3, molecular weight 337.17, m / z 337.95 [M+H] + .

[0490] Step 2: tert-butyl 4-(4-ethyl-2-oxobenzo[cd]indol-l(2H)-yl)butanoate

[0491] To a solution of compound 1 (100.0 mg, 0.30 mmol) in MeOH (15 mL) was added Pd / C (10.0 mg, 10% wt), and the reaction was stirred at 25 °C for 16 h. The reaction was monitored on LC-MS. After the reaction was completed, the reaction mixture was filtered and concentrated to give compound 2 (100 mg, yield: 89%) as a yellow solid.

[0492] Mass mass MS (ESI): Formula for C 21 H 25 NO3, molecular weight 339.18, m / z 340.30 [M+H] + .

[0493] Step 3: Preparation of 4-(4-ethyl-2-oxobenzo[cd]indol-l(2H)-yl)butanoic acid

[0494] Compound 2 (100.0 mg, 0.29 mmol) was added to a mixture solution of DCM:TFA = 5: 1 (5 mL) and stirred at 25 °C for 1 h, the reaction was monitored by LC-MS. After the reaction was completed, the reaction mixture was evaporated to get the crude product, which was purified by HPLC (Gemini 5 pm C18 column, 150 x 21.2 mm, eluted with 30% to 95% MeCN in H2O containing 0.1% FA, 11.25 min) to give LCT011105 (54.01 mg, yield: 62%) as a yellow solid.

[0495] Mass mass MS (ESI): Formula for C 17 H 17 NO3, molecular weight 283.12, m / z 283.80 [M+H] + .

[0496] 1 HNMR (400 MHz, DMSO-d6) δ 12.08 (s, 1H), 8.00 (s, 1H), 7.95 (s, 1H), 7.60-7.47 (m, 2H), 7.14 (d, J = 6.8 Hz, 1H), 3.90 (t, J = 7.2 Hz, 2H), 2.97-2.84 (m, 2H), 2.30 (t, J = 7.2 Hz, 2H), 1.99-1.86 (m, 2H), 1.30 (t, J = 7.2 Hz, 3H).

[0497] Method for preparing Example 51 compound LCT011108

[0498] Step 1: Preparation of tert-butyl 4-(4-methoxy-2-oxobenzo[cd]indol-l(2H)- yl)butanoate

[0499] To a solution of compound 1 (80 mg, 0.24 mmol) in DMF (2 mL) was added NaH (7 mg, 0.29 mmol) at 0 °C. After 30 min at 0 °C, Mel (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 solution was extracted with EtOAc. The organic layer was washed with brine, dried over anhydrous Na2S04, filtered and concentrated. The product was purified by flash chromatography (eluted with PE / EtOAc from 100 / 00 to 75 / 25 in 30 min) to give compound 2 (65 mg, yield: 78%) as a yellow solid. Mass spectrum MS (ESI): molecular formula C 20 H 23 NO4, molecular weight 341.16, m / z 341.95 [M+H] + .

[0500] Step 2: Preparation of 4-(4-methoxy-2-oxobenzo[cd]indol-l(2H)-yl)butanoic acid

[0501] A solution of compound 2 (65 mg, 0.19 mmol) in TFA (1 mL) was stirred at 25 °C for 1 h. The reaction was monitored by LC-MS. After the reaction was completed, the reaction mixture was concentrated, quenched with water and extracted with EtOAc. The organic layer was washed with brine, dried over anhydrous Na2S04, filtered and concentrated to give a crude product. The crude product was purified by prep-HPLC (column: Gemini 5 pm C18 150 x 21.2 mm, mobile phase: acetonitrile-H20 (0.1% FA), gradient: 20-95, 12.50 min) to give LCT011108 (22.63 mg, yield: 41%) as a yellow solid. Mass spectrum MS (ESI): molecular formula C 16 H 15 NO4, molecular weight 285.10, m / z 286.10 [M+H] + .

[0502] 1 HNMR (400 MHz, DMSO-d6) 12.10 (s, 1H), 7.68-7.61 (m, 2H), 7.57-7.46 (m, 2H), 7.06 (d, J = 6.4 Hz, 1H), 3.95 (s, 3H), 3.88 (t, J = 7.2 Hz, 2H), 2.30 (t, J = 7.6 Hz, 2H), 1.97-1.85 (m, 2H).

[0503] Process for preparing Example 52 compound LCT011109

[0504] Step 1: Preparation of tert-butyl [4-(2-oxo-lH-indol-3-ylidenyl)piperidin-l- yl]formate

[0505] To a solution of compound 1 (2 g, 0.015 mol) in THF (40 mL) was added NaH (0.79 g, 0.033 mol) at 0 °C, after 30 min, compound 2 (3 g, 0.015 mol) was added, the reaction was stirred at 25 °C for 16 h, LC-MS was used to monitor the reaction. Water was added to the reaction solution, the organic layer was extracted with EtOAc, washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated, the product was purified by flash chromatography (eluted with PE / EtOAc from 100 / 00 to 80 / 20, 30 mis) to give compound 3 (1.6 g, yield: 34%) as a white solid. Mass spectrum MS (ESI): molecular formula C 18 H 22 N2O3, molecular weight 314.16, m / z 313.10 [M-H] - .

[0506] Step 2: Preparation of tert-butyl [4-(2-oxo-l,3-dihydroindol-3-yl)piperidin-l- yl]formate

[0507] To a solution of compound 3 (1.1 g, 3.5 mmol) in MeOH (50 mL) was added Pd / C (330 mg, 10% w.t) under H2atmosphere, the reaction was stirred at 25 °C for 12 h, LC-MS was used to monitor the reaction. The reaction mixture was filtered and the solution was concentrated under vacuum. The obtained crude compound 4 (1.1 g, yield: 100%) was used directly in the next step without further purification.

[0508] Mass spectrum MS (ESI): molecular formula C 18 H 24 N2O3, molecular weight 316.18, m / z 315.15 [M-H] - .

[0509] Step 3: Preparation of 3-(piperidin-4-yl)-l,3-dihydroindol-2-one

[0510] Compound 4 (500 mg, 1.57 mmol), 2M HC1 was added into dioxane (5 mL), the mixture was stirred at 25 °C for 6 h, LC-MS was used to monitor the reaction. The reaction mixture was filtered and the filter cake was concentrated under vacuum to give the crude product, the obtained crude compound 5 (300 mg, yield: 88%) was used directly in the next step without further purification. Mass spectrum MS (ESI): molecular formula C 13 H 16 N2O, molecular weight 216.13, m / z 217.15 [M+H]+ .

[0511] Step 4: Preparation of 4-methyl-l-(4-oxo-4-(4-(2-oxoindolin-3-yl)piperidin-l- yl)butyl)benzo[cd]indol-2(lH)-one

[0512] To a solution of compound 5 (70 mg, 0.32 mmol) in DCM (2 mL) was added compound 6 (118 mg, 0.32 mmol) and TEA (6, 5 mg, 0.64 mmol), the reaction was stirred at 25 °C for 3 h, the reaction was monitored by LC-MS. The reaction mixture was concentrated under vacuum to get the crude product, which was purified by prep-HPLC (column: Gemini 5 pm C18 150 x 21.2 mm, mobile phase: acetonitrile-H20 (0.1% FA), gradient: 30-95, 12.50 min) to get LCT011109 (69.01 mg, yield: 45.6%) as yellow solid. Mass spectrum MS (ESI): molecular formula C 29 H 29 N3O3, molecular weight 467.22, m / z 468.20 [M+H] + .

[0513] 1 HNMR (400 MHz, DMSO-d6) 10.38 (s, 1H), 7.96 (s, 1H), 7.88 (d, J = 6.0 Hz, 1H), 7.57-7.43 (m, 2H), 7.23 (d, J = 7.6 Hz, 1H), 7.17 (d, J = 7.6 Hz, 1H), 7.11 (d, J = 6.8 Hz, 1H), 6.93 (d, J = 7.2 Hz, 1H), 6.81 (d, J = 7.6 Hz, 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).

[0514] Process for the preparation of compound LCT011110 of example 53

[0515] Step 1: Preparation of 3-bromo-9H-thioxanthene-9-one 10,10-dioxide

[0516] To a solution of 3-bromothioxanthene-9-one (600 mg, 2.06 mmol) in DCM (12 mL) was added m-CPBA (889 mg, 5.15 mmol) and stirred at 25 °C for 6 h, TLC monitored the reaction. Water was added to the mixture and extracted with DCM, the organic layer was washed with saturated NaHC03, then dried over anhydrous sodium sulfate, filtered off and concentrated to give the crude compound 2 (600 mg, yield: 81%), which was used directly in the next step without further purification.

[0517] Step 2: Preparation of tert-butyl (10,10-dioxo-9-oxo-9H-thioxanthen-3- yl)carbamate 18 H 17 NO5S, molecular weight 359.08, m / z 358.05 [M-H] - .

[0518] Step 3: Preparation of 3-amino-9H-thioxanthene-9-ketone 10,10-dioxide

[0519] Compound 3 (420 mg, 1.16 mmol), 2M HC1 was added in dioxane (5 mL) and stirred at 25 °C for 6 h, LC-MS monitored the reaction. The reaction mixture was filtered and the filter cake was concentrated under vacuum to give the crude, which was used directly in the next step without further purification. Compound 4 (210 mg, yield: 69%) was obtained. Mass spectrum MS (ESI): molecular formula C 13 H9NO3S, molecular weight 260.03, m / z 260.05 [M+H] + .

[0520] Step 4: Preparation of N-(10,10-dioxo-9-oxo-9H-thioxanthen-3-yl)-4-(4-methyl- 2-oxobenzo[cd]indol-l(2H)-yl)butanamide

[0521] To a solution of compound 4 (55 mg, 0.21 mmol) in pyridine (2 mL) was added 4-(4-methyl-2-oxobenzo[cd]indol-l(2H)-yl)butanoic acid (57 mg, 0.21 mmol) and T3P (337 mg, 1.06 mmol) and the reaction was stirred at 50 °C for 1 h, the reaction was monitored by LC-MS. Water was added to the solution and extracted with EtOAc, the organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated to get the crude. The crude was triturated with DMSO and acetonitrile to get LCT011110 (32.29 mg, yield: 29%) as a yellow solid.

[0522] Mass spectrum MS (ESI): molecular formula C 29 H 22 N2O5S, molecular weight 510.12, m / z 511.05 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) 10.82 (s, 1H), 8.49 (d, J = 2.0 Hz, 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 = 6.8 Hz, 2H), 2.58-2.52 (m, 5H), 2.13-2.05 (m, 2H).

[0523] Process for preparation of compound LCT011111 of example 54

[0524] Step 1: Preparation of 2,4-dimethyl-5-aminosulfonylbenzoic acid

[0525] To a suspension of compound 1 (400 mg, 1.6 mmol) in DCM (5 mL) was added dropwise aqueous ammonia (5 mL) under ice bath, the mixture was stirred at 25 °C for 1 h, the reaction was monitored by LCMS. After completion of the reaction, the mixture was concentrated under vacuum to remove DCM, and the pH was adjusted to 5-6 with 6 M aqueous HC1 solution. The mixture was filtered, the filter cake was collected and dried under vacuum to get compound 2 (350.0 mg, yield: 85%) as a white solid. Mass spectrum MS (ESI): molecular formula C9H 11 NO4S, molecular weight 229.04, m / z 228.05 [M-H] - .

[0526] Step 2: Preparation of tert-butyl 4-(2,4-dimethyl-5- aminosulfonylbenzoyl)piperazine-1-carboxylate

[0527] To a solution of compound 3 (350 mg, 1.5 mmol) in DMF (10 mL) was added TCFH (642 mg, 2.3 mmol), NMI (626 mg, 7.6 mmol) and tert-butyl piperazine-1-carboxylate (385 mg, 1.5 mmol), the reaction was stirred at 25 °C for 1 h, the reaction was monitored by LCMS. After the reaction was completed, the reaction mixture was quenched with H2O, extracted with EtOAc, the organic layer was evaporated to get the crude product, which was purified by flash chromatography (eluted with PE / EtOAc from 100 / 00 to 50 / 50 in 20 min) to give compound 4 (600 mg, yield: 88%) as a white solid. Mass spectrum MS (ESI): molecular formula C 18 H 27 N3O5S, 397.17, m / z 396.10 [M-H] - .

[0528] Step 3: Preparation of 2,4-dimethyl-5-(piperazine-1-carbonyl)benzenesulfonamide

[0529] To a solution of compound 4 (300.0 mg, 0.75 mmol) in EtOAc (5 mL) was added 1M HCl, the reaction was stirred at 25 °C for 2 h, the reaction was monitored by LCMS. After the reaction was completed, the mixture was filtered to collect the filter cake, which was dried under vacuum to give compound 5 (HCl salt) (200.0 mg, yield: 80%) as a white solid.

[0530] Mass spectrum MS (ESI): molecular formula C 13 H 19 N3O3S, 297.11, m / z 298.10 [M+H] + .

[0531] Step 4: Preparation of 2,4-dimethyl-5-(4-(4-(4-methyl-2-oxobenzo[cd]indol-1(2H)- yl)butanoyl)piperazine-1-carbonyl)benzenesulfonamide (LCT0111111)

[0532] To a solution of 4-(4-methyl-2-oxobenzo[cd]indol-l(2H)-yl)butanoic acid (50 mg, 0.19 mmol) in pyridine (4 mL) was added compound 5 (55 mg, 0.19 mmol) and 50% T3P in EtOAc (590 mg, 0.93 mmol), the reaction was stirred at 60 °C for 1 h, the reaction was monitored by LCMS. After the reaction was completed, the mixture was concentrated to give the crude product, which was purified by HPLC (Gemini 5 pm C18 column, 150 x 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.

[0533] Mass spectrum MS (ESI): The molecular formula is C 29 H 32 N4O5S, molecular weight 548.21, m / z 549.15 [M+H] + . 1 HNMR (400 MHz, DMSO-d6) δ 7.99 - 7.93 (m, 1H), 7.90 (d, J = 10.0 Hz, 1H), 7.61 (s, 1H), 7.57 - 7.48 (m, 2H), 7.41 (s, 2H), 7.30 (s, 1H), 7.17 - 7.09 (m, 1H), 3.94 - 3.83 (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).

[0534] Example 55 Method of preparing compound LCT011117

[0535] Step 1 : Preparation of 4-(l-(4-((9S,10S)-9,10-dihydro-9,10- [3,4]cyclopentalphthalen-l-yl)-4-oxobutyl)-2-oxo-l,2-dihydrobenzo[cd]indol-5-yl)-3,6- dihydropyridine-l(2H)-carboxylic acid tert-butyl ester To a solution of compound 1 (100 mg, 0.40 mmol) in pyridine (2 mL) was added compound 2 (176 mg, 0.40 mmol) and T3P (643 mg, 2.02 mmol) and the reaction stirred at 50 °C for 1 h, monitoring by LC-MS. Upon completion, water was added to the solution and extracted with EtOAc, the organic layer washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated to give the product which was purified by flash chromatography (eluting with DCM / MeOH from 100 / 00 to 95 / 05 in 30 min) to give compound 3 (100 mg, yield: 37%) as a yellow solid. Mass spectrum MS (ESI): molecular formula C 43 H 43 N3O4, mass 665.33, m / z found 666.30 [M+H] + .

[0536] Step 2: Preparation of l-(4-((9S,10S)-9,10-dihydro-9,10- [3,4]cyclopentalphthalen-l-yl)-4-oxobutyl)-5-(l,2,3,6-tetrahydropyridin-4-yl)benzo[cd]indol-2(lH)- one

[0537] Compound 3 (100 mg, 0.15 mmol) was added to TFA (2 mL) and the reaction stirred at 25 °C for 1 h, monitoring by LC-MS. The reaction mixture was concentrated to give the crude product which was purified by prep-HPLC (column: Gemini 5 μm C18 150 x 21.2 mm, mobile phase: acetonitrile-H20 (0.1% TFA), gradient: 35-95, 12.50 min) to give LCT011117 (4.49 mg, yield: 2.6%) as a yellow solid.

[0538] Mass spectrum MS (ESI): molecular formula C 38 H 35 N3O2, mass 565.27, m / z found 566.25 [M+H]+.

[0539] 1HNMR (400 MHz, DMSO-d6) 8.28 (d, J = 8.0 Hz, 1H), 8.07 (d, J = 6.8 Hz, 1H), 7.86-7.78 (m, 1H), 7.40 (d, J = 7.2 Hz, 1H), 7.31-7.27 (m, 2H), 7.24 (d, J = 7.2 Hz, 1H), 7.16-7.11 (m, 2H), 7.11-7.05 (m, 2H), 6.97 (t, J = 6.8 Hz, 1H), 6.80 (t, J = 7.2 Hz, 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).

[0540] Process for the preparation of compound LCT011118 of example 56

[0541] Step 1: Preparation of ethyl 4-(5-bromo-2-oxobenzo[cd]indol-l(2H)-yl)butanoate

[0542] To a solution of compound 1 (450 mg, 1.8 mmol) in DMF (15 mL) was added ethyl 4-bromobutanoate (2 mg, 7.3 mmol), KI (301 mg, 1.8 mmol) and K2CO3 (752 mg, 5.4 mmol) and the reaction was stirred at 50 °C for 16 h. After completion of the reaction, the reaction mixture was quenched with H2O and extracted with EtOAc and the organic layer was evaporated to get the crude product which was purified by flash chromatography (eluted with PE / EtOAc from 100 / 00 to 80 / 20 in 20 min) to get compound 2 (400 mg, yield: 50%) as a yellow solid. Mass MS (ESI): molecular formula C 17 H 16 BrNO3, molecular weight 361.03, m / z 362.05 [M+H] + .

[0543] Step 2: Preparation of tert-butyl 4-(l-(4-ethoxy-4-oxobutyl)-2-oxo-l,2-dihydrobenzo[cd]indol-5-yl)-3,6-dihydropyridine-l(2H)-carboxylate

[0544] To a solution of compound 2 (400 mg, 1.10 mmol) in 1,4-dioxane / H2O = 2:1 (5 mL) was added NaOH (68 mg, 1.7 mmol) at 50 °C and stirred for 5 h. The reaction was monitored by LCMS. After completion of the reaction, the pH was adjusted to 5-6 with aqueous HC1 (2 N) and extracted with EtOAc. The organic layer was dried over Na2S04, filtered off and concentrated to get compound 3 (330.0 mg, yield: 79%) as a yellow solid. Mass spectrum MS (ESI): molecular formula C ＝ To a solution of compound 2 (400 mg, 1.10 mmol) in 1,4-dioxane / H2O = 2:1 (5 mL) was added NaOH (68 mg, 1.7 mmol) at 50 °C and stirred for 5 h. The reaction was monitored by LCMS. After completion of the reaction, the pH was adjusted to 5-6 with aqueous HC1 (2 N) and extracted with EtOAc. The organic layer was dried over Na2S04, filtered off and concentrated to get compound 3 (330.0 mg, yield: 79%) as a yellow solid. Mass spectrum MS (ESI): molecular formula C 27 H 32 N2O5, molecular weight 464.23, m / z 465.25 [M+H] + .

[0545] Step 3: Preparation of 4-(5-(1-(tert-butoxycarbonyl)-1,2,3,6-tetrahydropyridin-4-yl)-2- oxobenzo[cd]indol-1(2H)-yl)butanoic acid

[0546] To a solution of compound 3 (400 mg, 0.86 mmol) in THF / H2O = 2:1 (1 mL) was added NaOH (68 mg, 1.7 mmol) at 50 °C and stirred for 5 h. The reaction was monitored by LCMS. After completion of the reaction, the pH was adjusted to 5-6 with aqueous HC1 (2 N) and extracted with EtOAc. The organic layer was dried over Na2S04, filtered off and concentrated to get compound 4 (330.0 mg, yield: 79%) as a yellow solid. Mass spectrum MS (ESI): molecular formula C 25 H 26 N2O5, molecular weight 436.20, m / z 437.05 [M+H] + .

[0547] Step 4: Preparation of tert-butyl 4-(1-(4-(9s,10s)-9,10-dihydro-9,10-ethylanthracen-11-yl)methyl)amino)- 4-oxobutyl)-2-oxo-1,2-dihydrobenzo[cd]indol-5-yl)-3,6-dihydropyridine-1(2H)-carboxylate

[0548] To a solution of compound 4 (100 mg, 0.23 mmol) in pyridine (5 mL) was added ((9s,10s)-9,10-dihydro-9,10-ethylanthracen-l l-yl)methanamine (53 mg, 0.23 mmol) and T3P (145 mg, 0.46 mmol). The reaction was stirred at 60 °C for 16 h, and the reaction was monitored by LCMS. After the reaction was completed, the mixture was concentrated, and the concentrate was purified by flash chromatography (eluted with PE / EtOAc from 100 / 00 to 50 / 50) to give compound 5 (100.0 mg, yield: 60%) as a yellow solid. Mass spectrum MS (ESI): molecular formula C 42 H 43 N3O4, 653.33, m / z 654.25 [M+H] + .

[0549] Step 5: Preparation of N-(((9S,10S)-9,10-dihydro-9,10-ethylanthracen-l l- yl)methyl)-4-(2-oxo-5-(l,2,3,6-tetrahydropyridin-4-yl)benzo[cd]indol-l(2H)-yl)butanamide (LCT011118) 37 H 35 N3O2, 553.27, m / z 554.35 [M+H] + .

[0550] 1H NMR (400 MHz, DMSO-d6) δ 9.05 - 8.81 (m, 2H), 8.31 (d, J = 8.4 Hz, 1H), 8.09 (d, J = 6.8 Hz, 1H), 7.93 - 7.75 (m, 2H), 7.44 (d, J = 7.6 Hz, 1H), 7.31 - 7.17 (m, 5H), 7.12 - 7.01 (m, 4H), 5.88 (s, 1H), 4.27 (d, J = 14.8 Hz, 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 = 7.2 Hz, 2H), 1.98 - 1.88 (m, 3H), 1.87 - 1.76 (m, 1H), 1.07 - 0.99 (m, 1H).

[0551] Process for preparing compound LCT011119 of example 57

[0552] The process for preparing LCT 011119 is the same as LCT011118.

[0553] LCT011119 (TFA salt) (14.06 mg, purity: 93.44%, yield: 17%) was obtained as a yellow solid. Mass spectrum MS (ESI): the molecular formula was C 33 H 27 N3O5S, molecular weight 577.17, m / z 578.15 [M+H] + .

[0554] 1 H NMR (400 MHz, DMSO-d6) δ 10.78 (s, 1H), 9.11 - 8.81 (m, 2H), 8.50 (d, J = 2.0 Hz, 1H), 8.29 (d, J = 8.4 Hz, 2H), 8.24 - 8.17 (m, 2H), 8.11 - 8.00 (m, 2H), 7.96 (t, J = 7.2 Hz, 1H), 7.90 - 7.78 (m, 2H), 7.46 (d, J = 7.2 Hz, 1H), 7.27 (d, J = 7.2 Hz, 1H), 5.86 (s, 1H), 4.01 (t, J = 6.4 Hz, 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).

[0555] Process for preparing compound LCT011121 of example 58

[0556] Step 1: Preparation of (E)-4-(1-((tert-butylsulfinyl)imino)ethyl)benzenesulfonamide

[0557] To a solution of compound 1 (1 g, 5.0 mmol) in THF (20 mL) was added compound 2 (0.61 g, 5.0 mmol) and Ti(OEt)4(2.2 g, 10 mmol), the mixture was stirred at 70 °C for 12 h under N2atmosphere. After the reaction was completed, the reaction mixture was quenched by the addition of water (10 mL), then the mixture was poured into a separation funnel and separated. The aqueous layer was extracted with EtOAc (20 mL x 3), the combined organic layers were washed with brine (10 mL), dried over Na2SO4, filtered and concentrated. The product was purified by flash chromatography (PE / EtOAc = 3 / 2) to give compound 3 (0.61 g, yield: 40%) as a white solid. Mass spectrum MS (ESI): molecular formula C 12 H 18 N2O3S2, molecular weight 302.08, m / z found 303.05 [M+H] + .

[0558] Step 2: Preparation of 4-(1-((tert-butylsulfinyl)amino)ethyl)benzenesulfonamide

[0559] To a solution of compound 3 (610 mg, 2.01 mmol) in THF (12 mL) was added NaBH4(152 mg, 4.03 mmol) at 0 °C, the mixture was stirred at 25 °C for 3 h. After completion, the reaction mixture was quenched by the addition of water (10 mL). Then the mixture was poured into a separation funnel and separated. The aqueous layer was extracted with EtOAc (20 mL x 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 spectrum MS (ESI): molecular formula C 12 H 20 N2O3S2, molecular weight 304.09, m / z 305.15 [M+H] + .

[0560] Step 3: Preparation of 4-(1-aminoethyl)benzenesulfonamide

[0561] A solution of compound 4 (550 mg, 1.80 mmol) in HCl-dioxane (5 mL, 2N) was stirred at 25 °C for 3 h. After completion, 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 spectrum MS (ESI): molecular formula C8H12 N2O2S, 200.06, m / z 201.10 [M+H] + .

[0562] Step 5: Preparation of 4-(2-oxo-3-phenylbenzo[cd]indol-l(2H)-yl)-N-(l-(4- sulfosulfonylphenyl)ethyl)butanamide

[0563] To a solution of 4-(2-oxo-3-phenylbenzo[cd]indol-l(2H)-yl)butanoic acid (91 mg, 0.275 mmol) in pyridine (4 mL) was added compound 5 (55 mg, 0.275 mmol) and 50% T3P in EtOAc (873 mg, 1.375 mmol), and the reaction was stirred at 60 °C for 1 h. After completion of the reaction, the mixture was concentrated to get the crude product, which was purified by preparative HPLC (Gemini 5 pm C18 column, 150 x 21.2 mm, eluted with 30-95% MeCN / H2O containing 0.05% ammonia) to get the product LCT011121 (43.19 mg, yield: 58%) as a yellow solid. Mass spectrum MS (ESI): molecular formula C 29 H 27 N3O4S, 513.17, m / z 514.15 [M+H] + .

[0564] 1 H NMR (400 MHz, DMSO-d6) δ 8.36 (d, J = 7.6 Hz, 1H), 8.12 (d, J = 7.2 Hz, 1H), 7.81 - 7.71 (m, 3H), 7.65 - 7.50 (m, 7H), 7.46 (d, J = 8.4 Hz, 2H), 7.31 - 7.19 (m, 3H), 4.93 (t, J = 7.2 Hz, 1H), 3.93 (t, J = 6.8 Hz, 2H), 2.23 (t, J = 7.2 Hz, 2H), 2.01 - 1.88 (m, 2H), 1.31 (d, J = 6.8 Hz, 3H).

[0565] Process for preparing compound LCT011120 of example 59

[0566] The process for preparing LCT011120 is the same as LCT011121.

[0567] LCT011120 (53.54 mg, purity: 99.91%, yield: 58.79%) was obtained as a yellow solid. Mass spectrum MS (ESI): molecular formula C 24 H 25N3O4S, 451.16, m / z 452.10 [M+H]+.

[0568] 1 HNMR (400 MHz, DMSO-d6) δ 8.35 (d, J = 7.6 Hz, 1H), 7.97 (s, 1H), 7.91 (s, 1H), 7.75 (d, J = 8.4 Hz, 2H), 7.57-7.42 (m, 4H), 7.27 (s, 2H), 7.08 (d, J = 6.8 Hz, 1H), 4.92 (t, J = 7.2 Hz, 1H), 3.87 (t, J = 6.8 Hz, 2H), 2.61 (s, 3H), 2.21 (t, J = 7.6 Hz, 2H), 1.96-1.85 (m, 2H), 1.31 (d, J = 7.2 Hz, 3H).

[0569] Method for preparing compound LCT011128 of example 60

[0570] Step 1: Preparation of tert-butyl 3-oxo-3,6-dihydropyridine-1(2H)-carboxylate

[0571] To a solution of compound 1 (900 mg, 4.49 mmol) in DCM (10 mL) was added DMP (3.81 g, 8.99 mmol), the mixture was stirred at room temperature for 2 hours, the mixture was concentrated in vacuum, the residue was purified by column chromatography on silica gel (eluent PE / EtOAc = 100:0 to 50:50) to give compound 2 (880 mg, 98.77% yield) as a white solid.

[0572] 1 H NMR (400 MHz, DMSO-d6) δ 7.23 (d, J = 7.6 Hz, 1H), 6.10 (dt, J = 10.4, 2.2 Hz, 1H), 4.18 (s, 2H), 4.01 (s, 2H), 1.42 (s, 9H).

[0573] Step 2: Preparation of (9S,10S)-9,10-dihydro-9,10-[3,4]pyridinylanthracen-15-one

[0574] To a solution of compound 2 (880 mg, 4.44 mmol) and anthracene (1.19 g, 6.66 mmol) in toluene (10 mL) was added AICI3(88.8 mg, 0.666 mmol), the mixture was stirred at 110 °C for 24 hours. The mixture was concentrated in vacuum, the residue was purified by column chromatography on silica gel (eluent DCM / MeOH = 100:0 to 90:10) to give compound 3 (100 mg, 6% yield) as a white solid.

[0575] 1 HNMR (400 MHz, DMSO-d6) δ 7.43-7.31 (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 = 2.4 Hz, 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 = 12.0 Hz, 1H).

[0576] Step 3: Preparation of (9s,10s)-13-(4-(2-oxobenzo[cd]indol-l(2H)-yl)butanoyl)-9,10- dihydro-9,10-[3,4]pyranoanthracen-l5-one

[0577] To a solution of compound 3 (100 mg, 0.392 mmol), 4-(2-oxobenzo[cd]indol-l(2H)- yl)butanoic acid (108 mg, 0.392 mmol) and HOBt (52.9 mg, 0.392 mmol) in DCM (2.0 mL) was added DCC (88.9 mg, 0.431 mmol) and the mixture was stirred at room temperature for 3 hours. The reaction mixture was concentrated in vacuo and the residue was purified by HPLC (Gemini 5 μm C18 column, 150 x 21.2 mm, eluted with 50% to 80% MeCN in H20 with 0.1% FA) to give LCT011128 (68.1 mg, 34% yield) as a yellow solid. Mass spectrum MS (ESI): molecular formula C 34 H 28 N2O3, molecular weight 512.21, m / z 513.20 [M+H] + .

[0578] 1HNMR (400 MHz, DMSO-d6) δ 8.16 (t, J = 8.0 Hz, 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).

[0579] Process for the preparation of compounds LCT011056 and LCT011035 of example 61

[0580] Step 1: Preparation of 1-(pent-4-en-1-yl)benzo[cd]indol-2(1H)-one

[0581] To a solution of compound 1 (4.20 g, 24.83 mmol) in DMF (40 mL) was added 60% NaH (2.48 g, 62.08 mmol), stirred at 0 °C for 15 min, 5-bromopent-1-ene (4.81 g, 32.28 mmol) was added, stirred at room temperature for 1 h. The reaction was quenched with water (400 mL), extracted with ethyl acetate (200 mL x 3), the combined organic layers were washed with brine, dried over MgS04, concentrated under reduced pressure to give compound 2 (5.43 g, 92.19% yield) as a yellow solid. Mass spectrum MS (ESI): molecular formula C 16 H 15 NO, molecular weight 237.30, m / z 238.30 [M+H] + .

[0582] Step 2: Preparation of 1-(3-(oxetan-2-yl)propyl)benzo[cd]indol-2(1H)-one

[0583] To a solution of compound 2 (5.0 g, 21.07 mmol) in dichloromethane (50 mL) was added 85% m-cPBA (6.53 g, 31.60 mmol) at 0 °C, the mixture was stirred at room temperature for 24 h, the mixture was filtered, the filtrate was quenched with water (200 mL), extracted with dichloromethane (100 mL x 3), the combined organic layers were washed with brine, dried over MgS04, concentrated under reduced pressure to give compound 3 (4.2 g, 78.76% yield) as a yellow solid. Mass spectrum MS (ESI): the molecular formula was C 16 H 15 NO2, the molecular weight was 253.30, m / z was 254.30 [M+H] + .

[0584] Step 3: Preparation of methyl 2-(1-(((2-hydroxy-5-(2-oxobenzo[cd]indol-1(2H)- yl)pentyl)thio)methyl)cyclopropyl)acetate

[0585] To a solution of compound 3 (2.10 g, 8.29 mmol) and methyl 2-(1-(mercaptomethyl)cyclopropyl)acetate (1.46 g, 9.11 mmol) in methanol (30 mL) was added NaOH (829 mg, 20.73 mmol), the reaction mixture was stirred at room temperature for 3 h. The reaction was quenched with water (150 mL), extracted with ethyl acetate (75 mL x 3), the combined organic layers were washed with brine, dried over MgS04, concentrated under reduced pressure to give compound 4 (1.30 g, 37.90% yield) as a white solid. Mass spectrum MS (ESI): the molecular formula was C 23 H 27 NO4S, the molecular weight was 413.53, m / z was 414.50 [M+H] + .

[0586] Step 4: Preparation of 2-(1-(((2-hydroxy-5-(2-oxobenzo[cd]indol-1(2H)- yl)pentyl)thio)methyl)cyclopropyl)acetic acid (LCT011056)

[0587] To a solution of compound 4 (1.0 g, 2.42 mmol) in methanol (5.0 mL) and water (2.5 mL) was added a solution of LiOH.H20 (305 mg, 7.26 mmol), the mixture was stirred at room temperature for 3 h, adjusted to pH 3 with 1N HCl, extracted with ethyl acetate (50 mL x 3) and water (50 mL), the combined organic layers were washed with brine, dried over MgS04, concentrated under reduced pressure to give LCT011056 (600 mg, 60% yield) as a yellow solid. Mass spectrum MS (ESI): the molecular formula was C 22 H22 NO4S, 399.51, m / z 400.50 [M+H]+.

[0588] 1 HNMR (400 MHz, CDC13) δ 8.06-8.00 (m, 2H), 7.71-7.68 (m, 1H), 7.54-7.52 (d, J = 8.4 Hz, 1H), 7.47-7.43 (m, 1H), 6.96-6.94 (d, J = 6.8 Hz, 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), 1.99-1.87 (m, 2H), 1.63-1.57 (m, 2H), 0.57-0.54 (m, 2H), 0.51-0.48 (m, 2H).

[0589] Step 5: Preparation of 2-(l-(((2-oxo-5-(2-oxobenzo[cd]indol-l(2H)-yl)pentyl)thio)methyl)cyclopropyl)acetic acid (LCT011035)

[0590] To a solution of LCT011056 (200 mg, 0.5 mmol) in DCM (5 mL) was added Dess-Martin Oxidizing reagent (1.06 g, 2.5 mmol) at 0 °C. The mixture was stirred at 0 °C for 1 h, the mixture was filtered, the filtrate was extracted with ethyl acetate (50 mL x 3) and water (75 mL), the combined organic layer was washed with brine, dried over MgS04, concentrated under reduced pressure to give compound LCT011035 (15 mg, 75% yield) as a white solid. Mass spectrum MS (ESI): molecular formula C 22 H 23 NO4S, 397.49, m / z 398.49 [M+H]+. + .

[0591] 1 H NMR (400 MHz, CDC13) δ 8.10-8.04 (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 = 6.8 Hz, 1H), 4.00-3.96 (t, J = 6.8 Hz, 2H), 3.30 (s, 2H), 2.79-2.76 (t, J = 8.4 Hz, 2H), 2.65 (s, 2H), 2.47 (s, 2H), 2.14-2.07 (m, 2H), 0.60-0.56 (m, 4H).

[0592] Example 62 Method of preparing compound LCT011133

[0593] Step 1: LCT0110003-7 (1.95 g, 5.6 mmol) was added to dry solution of (tributyl) methanol (2.70 g, 8.4 mol) and XPhos Pd G2 (0.22 g, 0.28 mol) in 1.4-dioxane (40 mL). The mixture was stirred at 100 °C under N2for 12 h. The desired mass was detected on LC-MS. Water was added to the solution, extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated to give the product, which 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 spectrum MS (ESI): molecular formula C 20 H 23 NO4, molecular weight 341.16, m / z 342.30 [M+H]+.

[0594] Step 2: DAST (491 mg, 3.04 mmol) was added to a solution of LCT011133-1 (520 mg, 1.52 mmol) in DCM (10 mL). It was stirred at 25 °C under N2for 3 h. The desired mass was detected on LC-MS. Water was added to the solution, extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated to give the product, which was purified by flash chromatography (PE / EtOAc elution, from 100 / 00 to 80 / 20, 30 min) to give LCT011133-2 (350 mg, yield 66.92%) as a yellow solid. Mass spectrum MS (ESI): molecular formula C 20 H 22 FNO3, molecular weight 343.16, m / z 344.25 [M+H]+.

[0595] Step 3: LCT011133-2 (350 mg, 1.01 mmol), DCM / TFA = 5:1 (6 mL). It was stirred at 25 °C for 6 hours. The organic layer was concentrated to give the crude product, which was purified by pre-high performance liquid chromatography (column: Gemini 5um C18 150 x 21.2 mm, mobile phase: ACN-H2O (0.1% FA), gradient: 40-95, 12.50 min) to give LCT011133 (168.58 mg, yield: 57.57%) as a yellow solid. Mass spectrum MS (ESI): molecular formula C 16 H 14 FNO3, molecular weight 287.10, m / z 288.05 [M+H]+.

[0596] 1 H NMR (400 MHz, 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 = 7.2 Hz, 1H), 5.71 (d, J = 43.2 Hz, 2H), 3.92 (d, J = 7.2 Hz, 2H), 2.31 (d, J = 7.6 Hz, 2H), 1.98-1.87 (m, 2H).

[0597] The list of compounds prepared in the above examples is as follows:

[0598] Pharmacodynamic experiment

[0599] 1. Cell experiment

[0600] Detection method: NPY (neuropeptide Y) vesicle release experiment method

[0601] (1) Seed HEK293 cells stably transfected with syt7 and NPY-pHluorin into a six-well plate, and culture with DEME containing 5% FBS; when the cell number grows to 90%, digest the cells and evenly seed them in a 96-well cell culture plate with a black bottom.

[0602] (2) Prepare High-KCL buffer: weigh 4.1749 g of KCL, 5.5521 g of NaCL, 0.2442 g of CaCL2, 0.0476 g of MgCL2, 1.0089 g of glucose, and 3.5745 g of HEPES-KO, and dissolve them in 1 L of ultrapure water to prepare a high potassium solution with a pH of 7.4.

[0603] (3) Prepare 40 mM, 20 mM, 10 mM, 2 mM, 1 mM, 0.2 mM, 0.1 mM, 0.04 mM, and 0 mM DMSO stock solutions of the test compound.

[0604] (4) Add 4 μL of the compound DMSO stock solution to 396 μL of High-KCL buffer to prepare compound dilutions with the following concentrations: 400 μM, 200 μM, 100 μM, 20 μM, 10 μM, 2 μM, 1 μM, 0.4 μM, and 0 μM.

[0605] (5) The prepared compound dilution solution is added to the 96-well plate, and the volume ratio of the culture medium to the compound stock solution is 1:1, for example, 100 μL of the compound solution dilution solution is added to the well containing 100 μL of the culture medium. Thus, the final concentration in the culture solution is 200 μM, 100 μM, 50 μM, 10 μM, 5 μM, 1 μM, 0.5 μM, 0.2 μM and 0 μM, respectively.

[0606] The compound is incubated at room temperature for 10 min, and the emission intensity at 390 nm and 485 nm under 509 nm excitation light is detected using a microplate reader, and the ratio of the two is calculated.

[0607] Detection results:

[0608] 2. Animal experiment

[0609] Male C57BL / 6J mice (6-8 weeks old) weighing 20-25 g are prepared, and are used after being adaptively fed in a SPF level animal room for 5 days. The drug is administered by intraperitoneal injection, and the dose is in the range of 0.1 umol / kg to 36 umol / kg. The mice are divided into a blank group, a positive control group (dextrocelexoxetine), and a test compound group, and different doses of the same compound can be divided into different dose groups. Each group of mice contains 6-12 mice.

[0610] 2.1, Sucrose preference test (SPT)

[0611] Detection method:

[0612] The sucrose preference test (SPT) has 4 stages and takes 6 days to complete. During the entire experiment, the mice are singly housed, and 2 50 mL centrifuge tubes are placed on one side of the mouse cage to make drinking bottles, the metal fine head of the drinking bottle is inserted into the metal grid of the mouse cage at an angle of 45° with the horizontal, and it is ensured that the mouse can easily drink from any tube, and the food is placed in the mouse cage for the mouse to eat.

[0613] (1) Days 1 and 2 are the double water adaptation stage for the mice, i.e., 2 50 mL drinking bottles each containing 40 mL of pure water.

[0614] (2) Days 3 and 4 are the double sugar adaptation stage for the mice, i.e., 2 50 mL drinking bottles each containing 40 mL of 2% sucrose water.

[0615] (3) On day 5, the drinking bottles are removed, and the water deprivation stage is performed for 24 hours.

[0616] (4) On day 6, the sucrose preference test was performed. Two drinking bottles were used, one with pure water and the other with 2% sucrose solution. Before the test, the water on the surface of the bottles was wiped off, and the initial weight of the bottles was recorded. Then the bottles were inserted into the metal grid of the mouse cage to start the test. After 1 hour, the positions of the two bottles were exchanged. After another 1 hour, the test was over, and all the bottles were taken out of the grid and stood upright. They were weighed in turn.

[0617] (5) Data statistical analysis: Sucrose preference = sucrose drinking amount / total drinking amount of sucrose and water.

[0618] 2.2, Results of forced swimming test (FST)

[0619] Detection method:

[0620] The water bucket used for the forced swimming test (FST) was 30 cm high and 20 cm in diameter. One hour before the experiment, tap water was added to the bucket to a height of 2 / 3, and the water temperature was tested to be 24+1℃. The Gopro was placed directly in front of the bucket without any angle obstruction. After all the settings were complete, video recording could begin.

[0621] (1) The mouse that had been adapted for 1 hour was gently placed in the water bucket. It was appropriate for the mouse's body to be parallel to the water surface when entering the bucket to prevent the mouse from drowning or affecting its subsequent behavior.

[0622] (2) After the mouse freely swam in the bucket for 6 minutes, the recording was stopped, the mouse was taken out of the bucket, the water on the mouse's body was wiped off with toilet paper, and then the mouse was placed back in the cage. A certain amount of toilet paper was placed in the cage to help the mouse keep warm. Then the corresponding information of the video was recorded, and the next group of mice could be tested.

[0623] (3) After all the mice were tested, they were transferred back to the original housing room, and then the data of the FST were analyzed to calculate the swimming time of the mice in the bucket. The final immobility time of the mouse = total time (300 seconds) - mobility time.

[0624] The above only describes the preferred embodiments of the present application and is not intended to limit the present application. Any modification, equivalent replacement, improvement, etc. made within the spirit and principles of the present application shall be included in the protection scope of the present application.

Claims

A heterocyclic alkyl carboxylic acid derivative represented by the formula I, characterized in that, a compound of Formula I, a stereoisomer, geometric isomer, tautomer, nitroso, hydrate, solvate, pharmaceutically acceptable salt, or prodrug thereof; wherein the ring R is selected from the following structures: B is selected from a C atom, a N atom; wherein when B is a N atom, R2is absent; R0 is n is selected from 1-8; X is selected from substituted or unsubstituted C1-C5alkyl, amino, aryl, C3-C10cycloalkyl, the substituted substituent is selected from carbonyl, hydroxyl, C1-C5alkyl, halogen, aryl; Y is selected from -OH, -NH2, -NR6R7, -S-R8, R9, -CO-R 10 ; R6, R7are each independently selected from H, substituted or unsubstituted C1-C8alkyl, C1-C5alkyl, C5-C15heterocyclyl, C4-C14cycloalkyl, the substituted substituent is selected from C5-C15heterocyclyl, aryl; R8is selected from substituted or unsubstituted C1-C8alkyl, the substituted substituent is selected from carbonyl, hydroxyl, C1-C5alkyl, halogen, aryl; R9is selected from substituted or unsubstituted C5-C30membered heterocyclyl, the substituted substituent is selected from carbonyl, hydroxyl, C1-C5alkyl, halogen, aryl; R 10 selected from the group consisting of substituted or unsubstituted C1-C6alkyl, the substituent of which is selected from the group consisting of C5-C15heterocyclyl, carbonyl, hydroxyl, C1-C5alkyl, halogen, aryl; R1, R2, R3, R4, R5, R1', R2', R3', R4', R5', R1", R2", R3", R4"are each independently selected from H, amino, nitro, hydroxyl, cyano, halogen, aryl, C1-C8alkoxy, substituted aryl, C1-C8alkyl, C1-C8haloalkyl, C1-C8alkylamino, phenylamino, C3-C10heterocyclyl; R6, R7, R9, R 10 In the heterocycle or heterocyclyl group, the heteroatom is oxygen and / or nitrogen. The heterocyclic alkyl carboxylic acid derivative according to claim 1, wherein B is selected from a C atom, a N atom; wherein when B is a N atom, R2is absent; R0 is n is selected from 1-8; X is selected from substituted or unsubstituted C1-C5alkyl, amino, the substituted substituent is selected from carbonyl, hydroxyl; Y is selected from -OH, -NH2, -NR6R7, -S-R8, R9, -CO-R 10 ; R6, R7are each independently selected from H, substituted or unsubstituted C1-C8alkyl, C1-C5alkyl, C5-C15heterocyclyl, C4-C14cycloalkyl, the substituted substituent is selected from C5-C15heterocyclyl, aryl; R8is selected from substituted or unsubstituted C1-C8alkyl, the substituted substituent is selected from C3-C6cycloalkyl; R9is selected from C5-C30heterocyclyl; R 10 selected from substituted or unsubstituted C1-C6alkyl, the substituent of which is selected from C5-C15heterocyclyl; R1, R2, R3, R4, R5, R1', R2', R3', R4', R5', R1", R2", R3", R4"are each independently selected from H, amino, nitro, hydroxyl, cyano, halogen, aryl, C1-C8alkoxy, substituted aryl, C1-C8alkyl, C1-C8haloalkyl, C1-C8alkylamino, phenylamino, C3-C10heterocyclyl; R6, R7, R9, R 10 In the heterocycle or heterocyclyl group, the heteroatom is oxygen and / or nitrogen. The heterocyclic alkyl carboxylic acid derivative according to claim 2, wherein B is selected from a C atom, a N atom; wherein when B is a N atom, R2is absent; R0 is n is selected from 1-6; X is selected from carbonyl, hydroxyl substituted C1-C3alkyl, NH; Y is selected from -OH, -NH2, -NR6R7, -S-R8, R9, -CO-R 10 ; R6, R7are each independently selected from H, C1-C5alkyl, C5-C15heterocyclyl substituted C1-C5alkyl, aryl substituted C1-C5alkyl, C5-C15heterocyclyl, C4-C14cycloalkyl, substituted C4-C14cycloalkyl; R8is selected from C3-C5cycloalkyl substituted C1-C5alkyl; R9is selected from C5-C30heterocyclyl; R 10 selected from C5-C15 heterocyclic-substituted C1-C4 alkyl; R1, R2, R3, R4, R5, R1', R2', R3', R4', R5', R1", R2", R3", R4" are each independently selected from the group consisting of H, amino, nitro, hydroxy, cyano, halogen, aryl, C1-C5 alkoxy, substituted aryl, C1-C5 alkyl, C1-C5 haloalkyl, C1-C5 alkylamino, phenylamino, C3-C8 heterocyclyl; R6, R7, R9, R 10 In particular, the heteroatom in the heterocycle or heterocyclyl group is oxygen and / or nitrogen. The heterocyclic alkyl carboxylic acid derivative according to claim 1, wherein when R1, R2, R3, R4, R5 are simultaneously H, R0 is not C3 alkyl, or X is not carbonyl, or Y is not hydroxy. The heterocyclic alkyl carboxylic acid derivative according to claim 1, wherein R1, R2, R3, R4, R5 are simultaneously H or only one group is not H; R1', R2', R3', R4', R5' are simultaneously H or only one group is not H; R1", R2", R3", R4" are simultaneously H or only one group is not H. The heterocyclic alkyl carboxylic acid derivative according to claim 1, wherein R1, R2, R3, R4, R5, R1', R2', R3', R4', R5', R1", R2", R3", R4" are each independently selected from the group consisting of H, amino, nitro, hydroxy, cyano, halogen, phenyl, methyl, ethyl, methoxy, halogenmethyl, The heterocyclic alkyl carboxylic acid derivative according to claim 1, wherein n = 1, 3, 4 or 5; hydroxy-substituted C1-C3alkyl is The heterocyclic alkyl carboxylic acid derivative according to claim 1, wherein R6, R7are each independently selected from the group consisting of H, methyl, isopropyl, The heterocyclic alkyl carboxylic acid derivative according to claim 1, wherein R8 is The heterocyclic alkyl carboxylic acid derivative according to claim 1, wherein R9is selected from The heterocyclic alkyl carboxylic acid derivative according to claim 1, wherein R 10 For The heterocycloalkyl carboxylic acid derivative according to any one of claims 1 to 11, characterized in that, The compound of Formula I is selected from: The heterocyclic alkyl carboxylic acid derivative according to claim 12, wherein selected from the group consisting of: LCT011000, LCT01L0001, LCT011009, LCT011016, LCT011024, LCT011047, LCT011028, LCT011030, LCT011035, LCT011062, LCT011063, LCT011064, LCT011065, LCT011071, LCT011068, LCT011078, LCT011079, LCT011083, LCT011084, LCT011091, LCT011097, LCT011098, LCT011099, LCT011101, LCT011102, LCT011103, LCT011108, LCT011105, LCT011109, LCT011100, LCT011117, LCT011121, LCT011133. The heterocyclic alkyl carboxylic acid derivative according to claim 13, characterized by selected from the group consisting of: LCT011016, LCT011024, LCT011028, LCT011062, LCT011063, LCT011064, LCT011065, LCT011068, LCT011078, LCT011079, LCT011097, LCT011098, LCT011103, LCT011105, LCT011108, LCT011100, LCT1133. The heterocyclic alkyl carboxylic acid derivative according to claim 14, characterized by selected from the group consisting of: LCT011016, LCT011078, LCT011062, LCT011063, LCT011064, LCT011097, LCT1108, LCT011117, LCT1133. The heterocyclic alkyl carboxylic acid derivative according to claim 15, wherein selected from the group consisting of: LCT011016, LCT011078, LCT011097, LCT011108, LCT011117, LCT1133. The method of producing a heterocyclic alkyl carboxylic acid derivative according to any one of claims 1 to 16, wherein comprising the following reaction steps: wherein compound 1 is selected from X1 is selected from the group consisting of H, halogen, hydroxy; Y' is Y or Y substituted with a protecting group. The method of producing a heterocyclic alkyl carboxylic acid derivative according to any one of claims 1 to 16, wherein comprising the following reaction steps: wherein compound 2 is selected from X2, X3, X4are each independently selected from halogen; Y' is Y or Y substituted with a protecting group; the substitution or hydrogenation or fluorination reaction is a reaction of the corresponding group. H, X2, X3or NO2substituted or hydrogenated to wherein Y' is Y or Y substituted with a protecting group. The method of producing a heterocyclic alkyl carboxylic acid derivative according to any one of claims 1 to 16, wherein comprising the following reaction steps: wherein Y' is Y or Y substituted with a protecting group. The method of producing a heterocyclic alkyl carboxylic acid derivative according to any one of claims 1 to 16, wherein comprising the following reaction steps: wherein X is The method of producing a heterocyclic alkyl carboxylic acid derivative according to any one of claims 1 to 16, characterized by, comprising the following reaction steps: wherein X is The method for preparing heterocyclic alkyl carboxylic acid derivatives as described in claim 21 is characterized in that, Further comprising a step of oxidizing the hydroxyl on X to a carbonyl. The method of producing a heterocyclic alkyl carboxylic acid derivative according to any one of claims 1 to 16, wherein comprising the following reaction steps: wherein X' is carboxyl or halogen; Y' is Y or Y substituted with a protecting group; Y is selected from -NR6R7, R9. The method for preparing heterocyclic alkyl carboxylic acid derivatives as described in claim 23 is characterized in that, Further comprising a step of hydrolyzing the ester group attached to the ring to a carboxyl group, and then ring closing with the amide group on the ring. The method of producing a heterocyclic alkyl carboxylic acid derivative according to any one of claims 1 to 16, wherein comprising the following reaction steps: wherein Y' is Y or Y substituted with a protecting group; Y is R 10 . The method of producing a heterocyclic alkyl carboxylic acid derivative according to any one of claims 17 to 25, wherein Further comprising a step of deprotection. Intermediates of heterocyclic alkyl carboxylic acid derivatives, characterized in that for a compound of Formula II; wherein the ring R is selected from the following structures: B is selected from C atom, N atom; wherein when B is N atom, R2is absent; R0 is n is selected from 1-6; M is selected from carbonyl, NH, vinyl, halogen, epoxy; A is selected from -OR 11 , OH, H, halogen or null; R 11 is selected from C1-C10 alkyl; R1, R2, R3, R4, R5, R1', R2', R3', R4', R5', R1", R2", R3", 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, C3-C10 heterocyclyl. An intermediate as claimed in claim 27, characterised in that, R1, R2, R3, R4, R5, R1', R2', R3', R4', R5', R1", R2", R3", R4" are each independently selected from H, amino, nitro, hydroxyl, cyano, halogen, aryl, C1-C5 alkoxy, substituted aryl, C1-C5alkyl, C1-C5alkylamino, phenylamino, C3-C8heterocyclyl; R 11 is tert-butyl. An intermediate as claimed in claim 27, characterised in that, R1, R2, R3, R4, R5are simultaneously H or only one group is not H; R1', R2', R3', R4', R5' are simultaneously H or only one group is not H; R1", R2", R3", R4" are simultaneously H or only one group is not H. An intermediate as claimed in claim 28 characterised in that, R1, R2, R3, R4, R5, R1', R2', R3', R4', R5', R1", R2", R3", R4" are each independently selected from H, amino, nitro, cyano, halogen, phenyl. An intermediate as claimed in claim 27, characterised in that, n = 1, 3, 4 or 5. An intermediate as claimed in claim 27, characterised in that, the intermediate is selected from the group consisting of: Use of the heterocycloalkyl carboxylic acid derivative of any one of claims 1-16 in the manufacture of a medicament for the treatment and / or prevention of a neurological disease, a metabolic disease. The use as claimed in claim 33, characterized in that The neurological disease includes schizophrenia, bipolar disorder, depression, Alzheimer's disease, epilepsy, neuropathy, chorea, Parkinson's disease; the metabolic disease includes diabetes, metabolic disorder. The use as claimed in claim 34, characterized in that The neurological disease is selected from schizophrenia, bipolar disorder, depression. The use as claimed in claim 35, characterized in that The neurological disease is selected from bipolar disorder, depression. The use as claimed in claim 36, characterized in that The neurological disease is depression. A pharmaceutical composition, characterized in that, The heterocycloalkyl carboxylic acid derivative of any one of claims 1-16, and a pharmaceutically acceptable carrier or excipient.

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