Heterocycloalkyl carboxylic acid derivative, intermediate and preparation method and application thereof

Abstract

The invention discloses a heterocyclic alkyl carboxylic acid derivative, an intermediate and a preparation method and application thereof, and relates to the technical field of medicinal chemistry. The heterocycloalkyl carboxylic acid derivative is a compound as shown in the following formula, and a stereoisomer, a geometric isomer, a tautomer, nitrogen oxide, hydrate, solvate, pharmaceutically acceptable salt or prodrug of the heterocycloalkyl carboxylic acid derivative, and in-vitro activity detection and animal behavioral experiments prove that the compound has good treatment effect on neurological diseases, neurological diseases, neurological diseases, neurological diseases, neurological diseases, neurological diseases, neurological diseases, neurological diseases, neurological diseases and neurological diseases. The traditional Chinese medicine composition has a good treatment effect on diseases such as depression, bidirectional affective disorder and the like, and metabolic diseases such as diabetes mellitus, metabolic disorder and the like.

Description

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, etc. Any abnormal change in any of the aspects or the incoordination between the mental activities and the environment can show mental activity disorders or mental abnormalities. Bipolar disorder is a neuropsychiatric disease with high morbidity, heritability and mortality, and seriously affects people's physical and mental health and social harmony. Bipolar disorder, also known as manic-depressive illness, is a serious mental illness with 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 characteristic of bipolar disorder, and its manifestations include low mood, loss of interest and reduced activity. However, the pathogenesis of bipolar disorder has been a long-standing scientific problem in the field of neuroscience and medicine. Among a large number of bipolar disorder and depression patients, 70% lack effective treatment. Traditional antidepressants and antipsychotics are mainly used for targeting based on monoamine hypothesis and for neurotransmitter receptors in the central nervous system, and have the disadvantages of slow onset, low efficiency, large side effects, poor effect of single drug, and high risk of suicide and self-injury. 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.

[0003] 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 sigma2 selective ligands:

[0004]

[0005] Patent CN101304973A discloses compounds and their pharmaceutically acceptable compositions for modulating the interaction of nerve growth factor and its precursors with neurotrophin receptors and treating disease conditions mediated by the interaction, such as pain, inflammatory diseases and neurological diseases, the treated neurological diseases 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]

[0007] 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 such as 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-C2A and C2B with repeated sequences. 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 studied in depth. The release of neurotransmitter between synapses is one of the most important biological phenomena for the nervous system to complete its physiological functions. The release of neurotransmitter is induced by Ca 2+ influx to induce exocytosis of synaptic vesicles containing neurotransmitters and presynaptic membrane fusion, Ca 2+ binding with intracellular Ca 2+ sensors 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.

[0008] 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 complexes, 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 zone of the synapse; this 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.

[0009] 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.

[0010] 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. 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 present 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]

[0015] wherein ring R is selected from the following structures:

[0016]

[0017] B is selected from C atom and N atom; when B is N atom, R2 is absent;

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

[0019] 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;

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

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

[0022] R8is selected from substituted or unsubstituted C1-C8alkyl, the substituted substituent is selected from carbonyl, hydroxyl, C1-C5alkyl, halogen, aryl;

[0023] R9is selected from substituted or unsubstituted C5-C30membered heterocyclyl, the substituted substituent is selected from carbonyl, hydroxyl, C1-C5alkyl, halogen, aryl;

[0024] R 10 is selected from substituted or unsubstituted C1-C6alkyl, the substituted substituent is selected from C5-C15heterocyclyl, carbonyl, hydroxyl, C1-C5alkyl, halogen, aryl;

[0025] 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;

[0026] R6, R7, R9, R 10 wherein the heteroatoms in the heterocycle or heterocyclyl are oxygen and / or nitrogen.

[0027] Preferably, B is selected from C atom, N atom; wherein R2is absent when B is N atom;

[0028] R0is n is selected from 1-8;

[0029] X is selected from substituted or unsubstituted C1-C5alkyl, amino, the substituted substituent is selected from carbonyl, hydroxyl;

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

[0031] 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;

[0032] R8is selected from substituted or unsubstituted C1-C8alkyl, the substituted substituent is selected from C3-C6cycloalkyl;

[0033] R9is selected from C5-C30heterocyclyl;

[0034] R 10 is selected from substituted or unsubstituted C1-C6alkyl, the substituted substituent is selected from C5-C15heterocyclyl;

[0035] 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;

[0036] R6, R7, R9, R 10 wherein the heteroatom in the heterocycle or heterocyclyl group is oxygen and / or nitrogen.

[0037] Preferably, B is selected from a C atom, a N atom; wherein R2is absent when B is a N atom;

[0038] R0is n is selected from 1-6;

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

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

[0041] 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;

[0042] R8is selected from C3-C5 cycloalkyl substituted C1-C5 alkyl;

[0043] R9is selected from C5-C30 heterocyclyl;

[0044] R 10 is selected from C5-C15 heterocycle substituted C1-C4 alkyl;

[0045] 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;

[0046] R6, R7, R9, R 10 wherein the heteroatom in the heterocycle or heterocyclyl group is oxygen and / or nitrogen.

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

[0048] Preferably, 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.

[0049] 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,

[0050] Preferably, halogen includes Cl, Br, I, F.

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

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

[0053] Preferably, R 10 is Preferably, the compound of formula I is selected from:

[0054]

[0055]

[0056]

[0057]

[0058]

[0059] More preferably, it is:

[0060] 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.

[0061] More preferably, the compound is:

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

[0063] More preferably, the compound is:

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

[0065] More preferably, the compound is:

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

[0067] In a second aspect, the present application provides a method for preparing the aforementioned heterocycloalkyl carboxylic acid derivatives, comprising the following reaction steps:

[0068] Compound 1 + X1-R0-X-Y' →

[0069] wherein compound 1 is selected from X1is selected from H, halogen, hydroxyl; Y' is Y or Y substituted with a protecting group.

[0070] Preferred protecting groups include, but are not limited to, protecting groups for hydroxyl, 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.

[0071] 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-butoxy carbamate (Boc), benzyloxy carbamate (Cbz), 9-fluorenylmethoxy carbamate (Fmoc).

[0072] 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-fluorenylmethoxycarbonyl (Fmoc).

[0073] Protecting groups for amine groups are preferably selected from the following protecting groups: 9-fluorenylmethyloxycarbonyl protecting group (Fmoc), carbobenzyloxy (Cbz), t-butoxycarbonyl (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.

[0074] In a third aspect, the present application provides a method for preparing the aforementioned heterocycloalkyl carboxylic acid derivatives, comprising the following reaction steps:

[0075] Compound 2

[0076] wherein compound 2 is selected from

[0077] X2, X3, X4 are 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, X3 or NO2 or hydrogenation to

[0078] the reaction of the corresponding groups.

[0079] In a fourth aspect, the present application provides a method for preparing the aforementioned heterocycloalkyl carboxylic acid derivatives, comprising the following reaction steps:

[0080]

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

[0082] In a fifth aspect, the present application provides a method for preparing the aforementioned heterocycloalkyl carboxylic acid derivatives, comprising the following reaction steps:

[0083]

[0084] wherein X is

[0085] In a sixth aspect, the present application provides a method for preparing the aforementioned heterocycloalkyl carboxylic acid derivatives, comprising the following reaction steps:

[0086]

[0087] wherein X is

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

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

[0090]

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

[0092] Preferably, it further comprises the step of hydrolyzing the ester group connected to the ring to a carboxyl group, and then cyclizing with the amide group on the ring.

[0093] In an eighth aspect, the present application provides a method for preparing the aforementioned heterocycloalkyl carboxylic acid derivatives, comprising the following reaction steps:

[0094]

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

[0096] Preferably, the method for preparing the aforementioned heterocyclic alkyl carboxylic acid derivative further comprises a deprotection step.

[0097] In a ninth aspect, the present application provides an intermediate for preparing the heterocyclic alkyl carboxylic acid derivative, which is a compound of formula II:

[0098]

[0099] wherein ring R is selected from the following structures:

[0100]

[0101] B is selected from C atom, N atom; when B is N atom, R2is absent;

[0102] R0is n is selected from 1-6;

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

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

[0105] 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 heterocyclic group.

[0106] 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 heterocyclic group.

[0107] 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.

[0108] 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.

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

[0110] Preferably, the intermediate is selected from:

[0111]

[0112]

[0113] In a tenth aspect, the present application provides use of the aforementioned heterocycloalkyl carboxylic acid derivative in the manufacture of a medicament for treating and / or preventing a neurological disease, a metabolic disease.

[0114] Syt7 has the biological activity of promoting vesicle release, and many hormones, such as insulin, are released through vesicles, so such heterocycloalkyl carboxylic acid derivatives can also be used for treating metabolic diseases by acting on Syt7.

[0115] 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.

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

[0117] The neurological disease is further preferably schizophrenia, bipolar disorder, depression.

[0118] The neurological disease is most preferably bipolar disorder.

[0119] In an eleventh aspect, the present application provides a pharmaceutical composition comprising the aforementioned heterocycloalkyl carboxylic acid derivative, and a pharmaceutically acceptable carrier or excipient.

[0120] 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 in mammals. Carriers include liquids, such as water, saline, and the like; and / or solids, such as starches, sugars, microcrystalline cellulose, powdered cellulose, gums, acacia, gelatin, magnesium stearate, talc, and the like; and / or combinations thereof. Examples of some suitable materials include lactose, dextrose, sucrose, sorbitol, mannitol, fructose, inositol, sodium chloride, and / or potassium chloride. Examples of suitable carriers include, but are not limited to, water, saline, dextrose, glycerol, ethanol, or the like and combinations thereof. The composition 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.

[0121] 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.

[0122] Suitable pharmaceutically acceptable carriers include, but are not limited to, water, salt solutions (e.g., NaCl), alcohols, acacia, vegetable oils, benzyl alcohol, polyethylene glycols, gelatin, sugars (e.g., lactose, amylose or starch), polyols (e.g., sorbitol, mannitol or glycerol), magnesium stearate, talc, silicic acid, viscous paraffin, perfume oil, fatty acid esters, hydroxymethylcellulose, polyethylene glycols, sodium carboxymethylcellulose, polyvinylpyrrolidone, etc. 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.

[0123] The compositions can also contain minor amounts of wetting or emulsifying agents, or pH buffering agents. The composition can be a liquid solution, suspension, emulsion, tablet, pill, capsule, sustained release formulation, or powder. The composition can be formulated with a conventional binder and carrier such as glycerol, mannitol, lactose, magnesium stearate, polyvinylpyrrolidine, sodium saccharin, cellulose, magnesium carbonate etc. into a tablet or capsule. Oral formulations can include standard carriers such as pharmaceutical grades of mannitol, lactose, magnesium stearate, polyvinylpyrrolidine, sodium saccharin, cellulose, magnesium carbonate, etc.

[0124] The compositions can be formulated according to conventional pharmaceutical practice in a unit dosage form suitable for intravenous administration to humans. The compositions can also include stabilizers and local anesthetics, if desired, to lessen pain at the injection site. Typically, 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 indicated quantity in a foil packet. When the composition is to be administered by infusion, it can be dispensed by a infusion bottle containing sterile pharmaceutical grade water, saline or aqueous dextrose. When 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.

[0125] The pharmaceutical compositions of the present application can also include agents that control release of the compounds of the present application, thereby providing time- release or sustained release compositions.

[0126] 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 condition 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 preparation.

[0127] The active ingredients can be administered orally in solid dosage forms, such as capsules, tablets, troches, dragees, granules, and powders, or in liquid dosage forms, such as elixirs, syrups, emulsions, dispersions, and suspensions. The active ingredients can also be administered parenterally, in sterile liquid dosage forms, such as dispersions, suspensions, or solutions. Other dosage forms that can be used to administer the active ingredients include ointments, creams, drops, transdermal patches, or powders for topical administration; eye solutions or suspensions, i.e., eye drops, for ocular administration; 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 to provide slow or delayed release of the drug for example, by the use of gelatin capsules containing a slow-acting or delayed-release carrier, such as cross-linked sodium carboxymethyl cellulose, or by the use of a mixture of active ingredient and a slow-release agent, such as calcium lactate phosphate. Compressed tablets can be sugar- or film-coated, or can be enteric-coated, to mask any unpleasant taste and to protect the tablet from the atmosphere, or can be long-acting formulations. Liquid dosage forms for oral administration can contain coloring and flavoring to increase patient acceptance.

[0128] 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 in a powder form for inhalation, using a suitable powder inhaler device. The preferred delivery system for inhalation is a metered dose inhaler (MDI) aerosol which can be formulated as a suspension or solution of the compound of Formula I in a suitable propellant, such as a fluorocarbon or a hydrocarbon. For ocular administration, an ophthalmic preparation can be formulated using a suitable percentage by weight of the compound of Formula I in a suitable ophthalmic carrier, to maintain the compound in contact with the surface of the eye for a sufficient time to allow penetration of the compound into the cornea and interior regions of the eye.

[0129] 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.

[0130] When the compounds of the present application are administered as a pharmaceutical composition, the composition will contain about 0.1 % to about 99.99% by weight, preferably 5% to 75% of the active ingredient unless otherwise indicated. The compounds of the present application can be administered in a variety of unit dosage forms including injectable solutions, drug delivery systems and oral formulations. The actual dosage depends on the nature of the active ingredient, on the particular site of administration and on the age, weight and condition of the patient. The actual dosage for the compounds of the present application can be determined by one of ordinary skill in the art using conventional dosage determination tests.

[0131] Definitions:

[0132] The term "alkyl" as used herein, unless otherwise indicated, includes both branched and straight chain saturated aliphatic hydrocarbon groups having 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-, iso-, sec- and t-butyl, n- and iso-propyl, ethyl and methyl. The term "C 1-10 "alkyl" and the like have similar meanings.

[0133] The term "alkoxy" means straight and branched chain alkyl groups of the indicated number of carbon atoms attached through an oxygen bridge.

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

[0135] The term "aryl" means aromatic mono and polycarbocyclic ring systems wherein the individual carbocyclic rings are fused or linked by single bonds. Typical aryl groups include phenyl, naphthyl and biphenylene.

[0136] The term "heterocycle" means ring structures composed of carbon atoms and non-carbon atoms, such as nitrogen, oxygen and sulfur. Typical heterocyclic groups include pyridine, quinoline, tropane, phenothiazine, benzodiazepine, furan, pyrazolone and pyrimidine.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

[0155] Figure 11 NPY release results for some compounds.

[0156] wherein, in the present application, the compound numbered LCT011000 is also named "Drug 1", both designating the same compound of the following formula:

[0157] DETAILED DESCRIPTION

[0158] The following non-limiting examples can provide a more complete understanding of the application to a person of ordinary skill in the art, but do not limit the application in any way. The following merely illustrates the scope of the application claimed and those skilled in the art can make many changes and modifications to the application disclosed without departing from the scope of the application claimed.

[0159] The application will be further described in the following specific examples. The various chemical reagents used in the examples of the application were obtained from commercial suppliers unless otherwise stated. The amounts stated below are amounts by mass unless otherwise stated. It is to be understood that the processes described below are conducted at room temperature unless otherwise stated.

[0160] The compounds of the application having the formulae described herein can be prepared from commercially available starting materials or starting materials that can be prepared using literature procedures according to the processes illustrated in the following General Synthetic Schemes 1-7. The variables (e.g., R1, R2, and R3, etc.) in each of the General Synthetic Schemes 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.

[0161] General Synthetic Scheme 1

[0162] Compound 1 + X1-R0-X-Y' →

[0163] 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.

[0164] The above reaction can be carried out using K2CO3, KI as catalyst, DMF as solvent, at 50-70 °C for 1-20 h.

[0165] General Synthetic Scheme 2

[0166] Compound 2

[0167] 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 the 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.

[0168] The reaction conditions for Compound 2 with X4-R0-X-Y' are the same as in General Synthetic Scheme 1, which can be carried out using K2CO3, KI as catalyst, DMF as solvent, at 50-70 °C for 1-20 h.

[0169] 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.

[0170] The substitution reaction includes the substitution of halogen to phenyl, for example using As the reaction reagent, Pd(PPh3)4, K2CO3 is used as catalyst, dioxane / H2O is used as reaction solvent, and the reaction is carried out at 80-100 °C for 2-20 h.

[0171] The substitution reaction includes the substitution of halogen to -CN, for example using Zn(CN)2 as reaction reagent, Pd(PPh3)4 as catalyst, DMF as reaction solvent, and the reaction is carried out at 70-90 °C for 2-20 h.

[0172] The substitution reaction includes the substitution of halogen to , for example using as reaction reagent, Pd(dppf)Cl2, Cs3CO3 as catalyst, H2O as reaction solvent, and the reaction is carried out at 70-90 °C for 2-20 h.

[0173] The substitution reaction includes the substitution of halogen to methyl, for example using MeB(OH)2 as reaction reagent, Pd(OAc)2, K3PO4 as catalyst, and the reaction is carried out at 90-100 °C for 2-20 h.

[0174] General synthetic route 3

[0175]

[0176] 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.

[0177] The above reaction is carried out in AcOH at 90-110 °C for 1-10 h.

[0178] General synthetic route 4

[0179]

[0180] wherein X is

[0181] The above reaction can be carried out using K2CO3, iPrOH as catalyst at 70-90 °C.

[0182] General synthetic route 5

[0183]

[0184] wherein X is The reaction is carried out under basic conditions. The reaction scheme can further include the step of oxidizing the hydroxyl group on X to a carbonyl group, which is carried out at 0 °C to room temperature.

[0185] General synthetic scheme 6

[0186]

[0187] 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 reaction, which can be carried out according to conventional reaction conditions. The reaction scheme can further include the step of hydrolyzing the ester group on the non-ring to a carboxyl group, which is further reacted with an amino group to form a 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 the step of preparing the starting material containing the protecting group, and deprotecting the reaction product.

[0188] General synthetic scheme 7

[0189]

[0190] wherein Y' is Y or Y substituted with a protecting group; Y is R 10 The reaction is amidation reaction, 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 the step of preparing the starting material containing the protecting group, and deprotecting the reaction product.

[0191] Preparation of intermediates and compounds

[0192] Preparation of compound LCT011000, intermediate XI-1

[0193] Synthesis according to general synthetic scheme 1:

[0194]

[0195] Synthetic steps:

[0196] 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%).

[0197] 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] + .

[0198] 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%).

[0199] 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).

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

[0201] Synthesized according to general synthetic route 1:

[0202]

[0203] Synthesis steps:

[0204] 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 hours. 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.

[0205] Mass spectrum MS (ESI): the molecular formula is C 11 H 12 ClNO, the molecular weight is 209.06, the mass-to-charge ratio (m / z) is 209.95 [M+H] + .

[0206] Step 2: LCT011003-2 (4.00 g, 19.1 mmol), NBS (4.08 g, 22.9 mmol) and Pd(OAc)2(0.429 g, 1.91 mmol) were added to AcOH (20.0 mL), 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): the molecular formula is C 11 H 11BrClNO, molecular weight 288.97, mass to charge ratio (m / z) 289.85 [M+H] + .

[0207] Step 3: To a solution of LCT011003-3 (4.00 g, 13.9 mmol) in 1,4-dioxane (20.0 mL) was added 6 M 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] + .

[0208] 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] + .

[0209] Step 5: LCT011003-5 (1.80 g, 8.78 mmol) and DDQ (1.99 g, 8.78 mmol) were dissolved in DCM (20.0 mL) and stirred at 25 °C for 16 h. 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 11H6ClNO, molecular weight 203.01, mass-to-charge ratio (m / z) 203.95 [M+H] + .

[0210] 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] + .

[0211] 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). 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).

[0212] Method for preparing compound LCT011007 of Example 3

[0213] Synthesized according to general synthetic route 3:

[0214]

[0215] Synthesis steps:

[0216] 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. After completion of the reaction, the reaction was quenched by the addition of H2O. It 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).

[0217] 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).

[0218] Method of preparation of Example 4 compound LCT011009

[0219] Synthesized according to general synthetic scheme 3:

[0220]

[0221] Synthesis steps:

[0222] 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).

[0223] 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).

[0224] 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 in H2O containing 0.1% NH3H2O) to give LCT011009 as a yellow solid (34.4 mg, 18% yield).

[0225] Mass spectrum MS (ESI): The molecular formula is C 18 H 19 NO4, 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).

[0226] Method for preparing compound LCT011012, intermediate XII of Example 5

[0227] Synthesized according to general synthetic route 1:

[0228]

[0229] Synthesis steps:

[0230] 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] + .

[0231] 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] + .

[0232] 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.

[0233] 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).

[0234] Step 4: Compound LCT011012-4 (160 mg, 0.924 mmol), tert-butyl 4-bromobutyrate (206 mg, 0.924 mmol) and KI (613 mg, 3.69 mmol) were dissolved in DMF (2.0 mL), 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] + .

[0235] Step 5: Compound LCT011012-5 (100 mg, 0.317 mmol) was dissolved in TFA (1 mL) and stirred at room temperature for 1 h. The resulting mixture was concentrated 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] + .

[0236] 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).

[0237] Process for preparing compound LCT011013, intermediate XI-13 of example 6

[0238] Synthesis according to general synthetic route 1:

[0239]

[0240] Synthesis steps:

[0241] Step 1: Compound LCT011013-1 (2.00 g, 10.6 mmol) and NBS (2.28 g, 12.8 mmol) were dissolved in concentrated H2SO4(11 mL) and stirred at room temperature under 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] + .

[0242] Step 2: Compound LCT011013-2 (1.10 g, 4.13 mmol) and KOH (2.32 g, 41.3 mmol) were dissolved in MeOH / H2O = 1 / 1 (12 mL) and stirred at 70 °C under 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] + .

[0243] Step 3: Compound LCT011013-3 (900 mg, 3.57 mmol) and Cu (907 mg, 14.2 mmol) were dissolved in NH4OH (50 mL) and stirred at 80 °C under 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] + .

[0244] 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] + .

[0245] 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] + .

[0246] 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).

[0247] Example 7 Method of preparing compounds LCT011016, LCT011046, intermediates XI-3 to XI-6

[0248] Synthesized according to general synthetic route 2:

[0249]

[0250] Synthesis steps:

[0251] 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] + .

[0252] 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] + .

[0253] Step 3: LCT011046-3a, LCT011046-3b (1.00 g, 4.67 mmol), tert-butyl 4-bromobutyrate (2.1 g, 9.34 mmol), K2CO3 (2.58 g, 18.7 mmol) and KI (3.10 g, 18.7 mmol) were dissolved in DMF (10.0 mL), 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] + .

[0254] 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] + .

[0255] 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).

[0256] 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).

[0257] 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).

[0258] Method for preparing compound LCT011018 of Example 8

[0259] Synthesized according to general synthetic route 1:

[0260]

[0261] Synthesis procedure: Dissolve benzo[cd]indol-2(lH)-one (300 mg, 1.77 mmol), 4- chlorobutanamide (323 mg, 2.66 mmol) and Cs2C03(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 H20 (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).

[0262] Mass spectrum MS (ESI): The molecular formula is C 15 H 14 N2O2, the molecular weight is 254.11, m / z is 255.10 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) d 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).

[0263] Method for preparing compound LCT011022, intermediate XI-14 and intermediate XI-15 of example 9

[0264] Synthesized according to general synthesis route 5:

[0265]

[0266]

[0267] Synthesis procedure:

[0268] Step 1: Compound LCT011000-1 (1.00 g, 5.91 mmol), 3-bromoprop-1-ene (1.43 g, 11.8 mmol), K2CO3 (3.26 g, 23.6 mmol) and KI (3.92 g, 23.6% mmol) were dissolved in DMF (20 mL) and stirred at 60 °C under N2atmosphere for 16 h. The reaction was monitored by LCMS. After completion, the reaction mixture was quenched by the addition of water (200 mL). The mixture was then 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 resulting 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 C 14 H 11 NO2, molecular weight 225.08, m / z 226.15 [m+H] + .

[0269] Step 2: Compound LCT011022-2 (500 mg, 2.39 mmol) and m-CPBA (1.65 g, 9.55 mmol) were dissolved in DCM (10 mL) and stirred at room temperature under N2atmosphere for 16 h. 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 DCM (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 LCT011022-3 (i.e. intermediate XI-15, 200 mg, yield: 37%) as a yellow solid. Mass spectrum MS (ESI): molecular formula C 14 H 11 NO2, molecular weight 225.08, m / z 226.15 [m+H] + .

[0270] Step 3: Compound LCT011022-3 (200 mg, 0.888 mmol), methyl 1- (methylamino)cyclopentan-1 -carboxylate (167 mg, 1.06 mmol) and K2CO3 (368 mg, 2.66 mmol dissolved in iPrOH (4 mL) was stirred at 80 °C under N2atmosphere for 16 h. 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 in H2O containing 0.1% TFA) to give LCT011022 (9.45 mg, purity: 99.30%, yield: 2%) as a yellow solid. Mass MS (ESI): molecular formula C 21 H 24 N2O4, molecular weight 368.17, m / z 369.10 [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, 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).

[0271] Example 10 Process for preparing compounds LCT011024, LCT011047, intermediates XI-7 to XI-10

[0272] Synthesized according to general synthetic route 5:

[0273]

[0274] Synthesis steps:

[0275] Step 1 : Compound LCT011024-1 (500 mg, 1.80 mmol) and NH2OH HC1 (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 TcCl (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). 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 (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] + .

[0276] Step 2: Compound LCT011024-2 (500 mg, 1.12 mmol) and NaOH (134 mg, 3.36 mmol) were dissolved in EtOH / H2O = 1 / 1 (10 mL) and stirred at 80 °C under N2atmosphere for 1 h. The reaction was monitored by LCMS. Upon completion, the reaction mixture was quenched by the addition of 4N HC1 aqueous solution (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 (20 mL), dried over Na2S04, filtered and concentrated on a rotary evaporator to give 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] + .

[0277] Step 3: Compound LCT011024-3a, LCT011024-3b (250 mg, 1.00 mmol), tert-butyl 4-bromobutyrate (449 mg, 2.01 mmol), K2CO3(557 mg, 4.03 mmol), KI (669 mg, 4.03 mmol) were dispersed in DMF (50 mL) and stirred at 60 °C for 16 h under N2atmosphere. 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 allowed to separate. The aqueous layer was extracted with EtOAc (50 mL x 3). The combined organic layers were washed with brine (50 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 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] + .

[0278] 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 for 16 h under N2atmosphere. The reaction was monitored by LCMS. Upon completion, the reaction mixture was quenched by the addition of water (10 mL). The mixture was then poured into a separatory funnel and allowed to separate. 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 by SFC (column: Torus 2-PIC 20 x 250 mm, 5 μm; mobile phase: CO2 / MeOH (0.1% NH3) = 70 / 30) to provide 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] + .

[0279] Step 5: LCT011024-5a (100 mg, 0.258 mmol) was dissolved in TFA (2 mL) and stirred at room temperature for 2 h under N2atmosphere. The reaction was monitored by LCMS. Upon 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 Mass (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).

[0280] LCT011024-5b (90 mg, 0.232 mmol) was dissolved in TFA (2 mL) and stirred at room temperature for 2 h under N2atmosphere. The reaction was monitored by LCMS. Upon 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).

[0281] Process for the preparation of compound LCT011026 of example 11

[0282] Synthesized according to general synthetic route 5:

[0283]

[0284] Synthesis steps:

[0285] 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) with stirring. The resulting mixture was 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, 1:10) to give compound 2 (3.50 g, 78% yield) as a brown solid. Mass spectrum MS (ESI): molecular formula C 16 H 11 BrN2O, molecular weight 326.01, m / z 326.90 [m+H] + .

[0286] 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), NaI (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 N2 atmosphere. Upon completion, the resulting mixture was concentrated under vacuum. The residue was purified by silica gel column chromatography (PE / EtOAc, 1:10) to give compound 3 (360 mg, 29% yield) as a yellow oil. Mass spectrum MS (ESI): molecular formula C 20 H 17 BrN2O3, molecular weight 412.04, m / z 412.80 [m+H] + .

[0287] 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. Upon 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 Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE / EtOAc, 3:1) to give compound 4 (700 mg, 90% yield) as a yellow solid. Mass spectrum MS (ESI): molecular formula C 11 H6BrNO.

[0288] Step 4: To compound 4 (500 mg, 2.01 mmol) dissolved in DMF (10.0 mL), add tert-butyl 4-bromobutyrate (674 mg, 3.02 mmol), K2CO3 (835 mg, 6.04 mmol) and KI (334 mg, 2.0 mmol), stir at 50 °C for 2 h. Upon completion, dilute the resulting mixture with H2O (100 mL). Extract the aqueous layer with EtOAc (20.0 mL x 3). Dry the combined organic layers over anhydrous Na2SO4. After filtration, concentrate the filtrate under reduced pressure. Purify the residue by silica gel column chromatography (PE / EtOAc, 3:1 to 1:1) to give the product compound 5 (800 mg, 96% yield) as a yellow solid. Mass spectrum MS (ESI): molecular formula C 19 H 20 BrNO3, molecular weight 389.06, m / z 334.10 [m-t-Bu] + .

[0289] Step 5: Dissolve compound 5 (200 g, 0.512 mmol), ZnCN2 (78.2 mg, 0.666 mmol) and Pd(PPh3)4 (118 mg, 0.102 mmol) in DMF (4.00 mL), stir at 80 °C under N2for 2 h. Upon completion, dilute the resulting mixture with H2O (40 mL). Extract the aqueous layer with EtOAc (10.0 mL x 3). Dry the combined organic layers over anhydrous Na2SO4. After filtration, concentrate the filtrate under reduced pressure. Purify the residue 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] + .

[0290] Step 6: Dissolve compound 6 (240 mg, 0.713 mmol) in TFA (5 mL), stir at 25 °C for 1 h. Concentrate the combined organic phase under vacuum and purify 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] + .

[0291] 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).

[0292] Process for preparing compound LCT011027 of example 12

[0293] Synthesis according to general synthetic route 5:

[0294]

[0295] Synthesis steps:

[0296] Step 1 : Compound 1 (200 mg, 0.512 mmol), 3-(trifluoro-4-boranly)azetidine-1- carboxylate, 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 spectrum MS (ESI): molecular formula C 27 H 34 N2O5, molecular weight 466.25, m / z 467.45 [M+H] + .

[0297] Step 2: Compound 2 (200 mg, 0.427 mmol) was dissolved in TFA (4 mL) and stirred at room temperature for 2 hours under 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 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).

[0298] Process for preparing compound LCT011028 of example 13

[0299] Synthesized according to general synthetic route 5:

[0300]

[0301] Synthesis steps:

[0302] Step 1: Compound 1 (900 mg, 4.49 mmol) was dissolved in DCM (10 mL) and DMP (3.81 g, 8.99 mmol) was added. The reaction mixture was stirred at room temperature for 2 hours. The mixture was concentrated under vacuum and the residue was purified by silica gel column chromatography (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, 1H), 6.10 (dt, J = 10.4, 2.2 Hz, 1H), 4.18 (s, 2H), 4.01 (s, 2H), 1.42 (s, 9H).

[0303] Step 2: Compound 2 (880 mg, 4.44 mmol) and anthracene (1.19 g, 6.66 mmol) were dissolved in toluene (10 mL), and AlCl3(88.8 mg, 0.666 mmol) was added. The reaction mixture was stirred at 110 °C for 24 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 3 (100 mg, 6% yield) as a white solid. 1 H NMR (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).

[0304] 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 preparative HPLC (Gemini 5 pm C18 column, 150 x 21.2 mm, eluted with 50% - 80% MeCN / H2O with 0.1% FA) to give compound LCT011028 (68.1 mg, 34% yield) as a yellow solid.

[0305] Mass spectrum MS (ESI): The molecular formula is C 34 H 28 N2O3, the molecular weight is 512.21, m / z is 513.20 [M+H] + . 1H NMR (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).

[0306] Process for preparing compound LCT011029 of example 14

[0307] Synthesis according to general synthesis scheme 6:

[0308]

[0309] Synthesis steps:

[0310] Step 1 : Compound 1 (5.00 g, 28.06 mmol) was dissolved in EtOH (32.50 mL) and H2O (32.50 mL), 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] + .

[0311] 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 C18 H 22 N2O6, 362.15, m / z 363.15 [m+H] + .

[0312] 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 white solid compound 4 (1.60 g, yield 82.30 %). Mass spectrum MS (ESI): molecular formula C 14 H 14 N2O6, 306.09, m / z 307.09 [m+H] + .

[0313] 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 hour. The reaction was quenched with water (50 mL) and 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 yellow solid compound 5 (1.00 g, yield 99.39 %). Mass spectrum MS (ESI): molecular formula C 20 H 24 N2O3, 340.18, m / z 341.20 [m+H] + .

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

[0315] Step 6: To DCM (5.0 mL) was added compound 6 (304 mg, 0.99 mmol), l-(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 hours. The mixture was concentrated in vacuo and purified by preparative HPLC (Gemini 5 μm C18 column, 150 x 21.2 mm, eluted with 10% - 90% MeCN / H20 with 0.1% TFA to give compound LCT011029 (300.00 mg, 57.36% yield) 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] + .

[0316] 1 H 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).

[0317] Method for preparing compound LCT011030 of example 15

[0318] Synthesized according to general synthetic route 6:

[0319]

[0320] Synthesis steps:

[0321] 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 HC1 (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] + .

[0322] 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, 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] + .

[0323] 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.

[0324] Mass spectrum MS (ESI): molecular formula C 27 H 28 N2O2, molecular weight 412.22, m / z 413.20 [M+H] + . 1H 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).

[0325] Process for the preparation of compound LCT011045, intermediate XI-16 of example 16

[0326] Synthesis according to general synthesis scheme 6:

[0327]

[0328] Synthesis steps:

[0329] 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 hours. 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 spectrum MS (ESI): molecular formula C 12 H 21 NO4, molecular weight 243.15, m / z 188.1 [M- t Bu+H] + .

[0330] 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 warmed 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 spectrum MS (ESI): molecular formula C 13 H 23 NO4, molecular weight 257.16, m / z 279.95 [m+Na] + .

[0331] 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 spectrum MS (ESI): molecular formula C 15 NO2, molecular weight 157.11, m / z 157.90 [m+H] + .

[0332] Step 4: Compound 5 (1.00 g, 5.90 mmol) was dissolved in DMF (10 mL), and 1,3- dibromopropane (5.96 g, 29.5 mmol), K2CO3(1.22 g, 8.8 mmol), and KI (0.490 g, 2.95 mmol) were added. The mixture was heated at 50 °C for 16 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 yellow solid.

[0333] Mass spectrum MS (ESI): molecular formula C 14 H 12 BrNO, molecular weight 289.01, m / z 289.80 [m+H] + .

[0334] 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 yellow oil. Mass spectrum MS (ESI): molecular formula C 22 H 26 N2O3, 366.19, m / z 367.30 [M+H] + .

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

[0336] Mass spectrum MS (ESI): molecular formula C 21 H 24 N2O3, 352.18, m / z 353.25 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) d 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).

[0337] Example 17 Method of preparing compound LCT011055

[0338] Synthesized according to general synthetic route 2:

[0339]

[0340] Synthesis steps:

[0341] Step 1: Compound 1 (200 mg, 0.578 mmol), aniline (80.7 mg, 0.867 mmol), Pd2(dba)3 (52.9 mg, 0.0578 mmol), BINAP (72.0 mg, 0.115 mmol) and Cs2CO3 (565 mg, 1.73 mmol) were dissolved in 1,4-dioxane (4 mL) and stirred at 100 °C under N2atmosphere for 16 h. The reaction was monitored by LCMS. Upon completion, the reaction mixture was quenched by the addition of 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): molecular formula C 25 H 26 N2O3, molecular weight 402.19, m / z 403.30 [M+H] + .

[0342] Step 2: Compound 2 (200 mg, 0.496 mmol) was dissolved in TFA (4 mL) and stirred at room temperature under N2atmosphere for 2 h. 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 / H2O containing 0.1% TFA) to give compound LCT011055 as a yellow solid (109.42 mg, purity: 96.89%, yield: 61%).

[0343] Mass spectrum MS (ESI): molecular formula C 21 H 18 N2O3, molecular weight 346.13, m / z 347.10 [M+H] + . 1H 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).

[0344] Process for preparing compound LCT011057 of example 18

[0345] Synthesis according to general synthesis scheme 6:

[0346]

[0347] Synthesis steps:

[0348] 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 the reaction was stirred at 0 °C for 15 min. tert-Butyl (5-bromopentyl)carbamate (1.42 g, 5.33 mmol) was added. The reaction mixture was stirred at room temperature for 1 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 C 21 H 26 N2O3, molecular weight 354.45, m / z 355.45 [M+H] + .

[0349] 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 h. After completion of the reaction, 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): molecular formula C 16 H 19 C1N2O, molecular weight 290.79, m / z 255.33 [m-HC1+H] + .

[0350] 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 in vacuo, and 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 4 (500 mg, 83% yield) as a yellow solid. Mass spectrum MS (ESI): molecular formula C 26 H 28 N2O4, molecular weight 432.52, m / z 433.52 [M+H] + .

[0351] Step 4: Compound 4 (500 mg, 1.16 mmol) was dissolved in MeOH (5 mL) and H2O (3 mL), and LiOH was added. H2O (146 mg, 3.48 mmol) was added. The reaction mixture was stirred at room temperature for 2 hours. After the reaction was completed, the reaction was adjusted to pH = 2 with 1 N HCl and extracted with ethyl acetate (75 mL x 3) and water (100 mL), the combined organic layer was 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 LCT011057 (50 mg, 10% yield), yellow solid.

[0352] Mass spectrum MS (ESI): molecular formula C 25 H 24 N2O3, molecular weight 400.48, m / z 404.5 [M+H] + . 1H 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).

[0353] Method of preparing compound LCT011061 of Example 19

[0354] Synthesized according to general synthetic route 6:

[0355]

[0356] 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 μm 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] + .

[0357] 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).

[0358] Process for the preparation of compound LCT011062

[0359] Synthesis according to general synthetic route 6:

[0360]

[0361] Synthesis steps:

[0362] 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] + .

[0363] 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]+ .

[0364] 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] + .

[0365] Step 4: A mixture of compound LCT011062-5 and compound LCT011062-6 (5.4 g, 13.03 mmol) 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] + .

[0366] 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 1N 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 prep-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 C12 H 14 N2O3, 270.29, 271.30 [M+H] + .

[0367] 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).

[0368] Mass spectrum MS (ESI): molecular formula C 18 H 21 N3O2, 311.39, 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).

[0369] Example 21 Method of preparing compound LCT011063

[0370] Synthesized according to general synthetic route 6:

[0371]

[0372] 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.

[0373] Mass spectrum MS (ESI): The molecular formula of 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).

[0374] Method for preparing compound LCT011064 of example 22

[0375] Synthesized according to general synthesis route 6:

[0376]

[0377] 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 (containing 0.1% NH4HCO3) to give compound LCT011064 (17.5 mg, 57.8% yield) as a white solid.

[0378] Mass spectrum MS (ESI): The molecular formula of 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).

[0379] Method for preparing compound LCT011065 of example 23

[0380] Synthesized according to general synthesis route 6:

[0381]

[0382] 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 NH4OH (2 mL) was added to the residue 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.

[0383] Mass spectrum MS (ESI): Formula for C 15 H 15 N3O2, molecular weight 269.30, m / z 270.30 [M+H] + . 1 H 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).

[0384] Process for the preparation of compound LCT011068 of example 24

[0385] Synthesis according to general synthetic route 6:

[0386]

[0387] Synthesis step: 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 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 in H20 containing 0.1% ammonia) to get compound LCT011068 (56.34 mg, yield: 40%) as a yellow solid.

[0388] Mass spectrum MS (ESI): Formula for C 33 H 32 N2O2, molecular weight 488.25, m / z 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).

[0389] Process for preparing compound LCT011071 of example 25

[0390]

[0391] 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, 33% yield) as a yellow solid.

[0392] Mass spectrum MS (ESI): The molecular formula is C 20 H 23 N3O2, 337.18, m / z 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).

[0393] Process for preparing compound LCT011073 of example 26

[0394]

[0395] 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, then 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-HPLC (Gemini 5 pm C18 column, 150 x 21.2 mm, eluted with 30% to 95% MeCN in H20 with 0.1% FA) to give LCT011073 (92 mg, 57% yield) as a yellow solid.

[0396] Mass spectrum MS (ESI): The molecular formula is C 27 H 24 N2O2, 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).

[0397] Process for preparing compound LCT011101 of example 27

[0398]

[0399] Compound 3 was synthesized according to the procedure 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, yield 80%) 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] + .

[0400] NaOH (18.6 mg, 0.46 mmol) was added in THF:H2O = 2:1 (10 mL) to give 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 the reaction was completed, the 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 give 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 give LCT011101 (30.75 mg, yield: 31%) as a yellow solid.

[0401] 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).

[0402] Preparation of compound LCT011102 of example 28

[0403]

[0404] Intermediate 5 was synthesized according to the procedure of LCT011073 using appropriate commercially available reagents to give intermediate 5 (100.0 mg, yield: 86%) as a yellow solid.

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

[0406] Intermediate 5 following the procedure for the preparation of LCT011101 gave LCT011102 (36.32 mg, yield 32%) as a yellow solid.

[0407] 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).

[0408] Preparation of compound LCT0110076 of example 29

[0409]

[0410] 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 NH4Cl 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 eluted with PE / EtOAc in the gradient of 100 / 00 to 98 / 02 to get compound 2 (610 mg, yield 61%) as a colorless oil.

[0411] To a solution of compound 2 (610 mg, 2.73 mmol) in ACN (12 mL) was added tributyl(l-ethoxy)stannane (987 mg, 2.73 mmol) and Pd AMPHOS (97 mg, 0.14 mmol). Stirring was carried out 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 and concentrated to give the product which was purified by flash chromatography (PE / EtOAc eluted from 100 / 00 to 95 / 5) to give compound 4 (440 mg, 86% yield) as a white oil.

[0412] Mass spectrum MS (ESI): molecular formula C 13 H 14 O, molecular weight 186.10, m / z 187.15 [M+H] + To a solution of compound 4 (440 mg, 2.36 mmol) in EtOH (9 mL) was added NH2OH-HCl (330 mg, 4.72 mmol) and NaOAc (774 mg, 9.44 mmol). Stirring was carried out 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 eluted from 100 / 00 to 75 / 25) to give compound 5 (420 mg, 84% yield) as a white solid.

[0413] Mass spectrum MS (ESI): molecular formula C 13 H 15 NO, molecular weight 201.12, m / z 202.15 [M+H] + To a solution of compound 5 (380 mg, 1.88 mmol) in MeOH (8 mL) was added Zn powder (617 mg, 9.44 mmol) and NH4CI (504 mg, 9.44 mmol) and stirring was carried out 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 eluted from 100 / 00 to 96 / 04) to give compound 6 (280 mg, 79% yield) as a white solid.

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

[0415] To a solution of compound 6 (160 mg, 0.85 mmol) in MeOH (16 mL) was added dry Pd / C (160 mg, 10% w.t). The mixture was stirred under H2at 25 °C for 12 h. The mixture was filtered and the filtrate was concentrated under vacuum to give the crude compound 7 (135 mg, yield 80%) which was used directly in the next step without further purification.

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

[0417] To a solution of compound LCT0110000 (87 mg, 0.34 mmol) in DCM (1.5 mL) was added DCC (106 mg, 0.51 mmol) and HOBT (69 mg, 0.51 mmol) at 0 °C under N2atmosphere, stirred at 0 °C for 15 min. Compound 7 (65 mg, 0.3434 mmol) was added and stirred at 25 °C for 3 h, water was added to the solution and extracted with DCM, the organic layer was concentrated to give the crude product which was purified by high performance liquid chromatography (column: Gemini 5 μm 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.

[0418] Mass spectrum MS (ESI): molecular formula C 28 H 30 N2O2, molecular weight 426.23, m / z 427.25 [M+H] + . 1H NMR (400 MHz, DMSO-d6) δ 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).

[0419] Process for the preparation of the compound of example 30 LCT011078

[0420]

[0421] Pd(OAc)2(14 mg, 0.066 mmol), K3PO4H2O (611 mg, 2.66 mmol), SPhos (54 mg, 0.13 mmol) and MeB(OH)2(159 mg, 2.66 mmol) were added to a solution of compound 1 (460 mg, 2.66 mmol) in Tol (15 mL). Stirring was performed 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 which was purified by chromatography (PE / EtOAc elution from 100 / 00 to 75 / 25 in 20 min) to give 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] + .

[0422] Compound 2 (370 mg, 1.11 mmol) was added to TFA (5 mL) and stirred at 25 °C for 1 h. The desired mass was 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%).

[0423] Mass spectrum MS (ESI): 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).

[0424] Process for the preparation of compound LCT0110079 of example 31

[0425]

[0426] 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) 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, which was purified by flash chromatography, eluted 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): formula C 22 H 28 N2O3, molecular weight 368.21, m / z 369.00 [M+H] + .

[0427] Compound 1 (72 mg, 0.19 mmol) was stirred in TFA (1.5 mL) for 1 h at 25 °C, the mixture was concentrated to 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-H20 (0.1% FA), gradient: 30-95, 13.00 min) to give LCT0110079 (20.5 mg, yield: 33%) as a yellow solid.

[0428] Mass spectrum MS (ESI): 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).

[0429] Process for preparing compound LCT011082 of example 32

[0430]

[0431] 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 obtain the crude product, which was purified by reverse phase column (eluted with 10-95% MeCN / H2O containing 0.05% ammonia water) to obtain compound 2 (200.0 mg, purity 80.0%, yield 63%) as a yellow solid.

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

[0433] Compound 2 (100.0 mg, 0.30 mmol) was dissolved in a 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 pm C18 column, 150 x 21.2 mm, eluted with 30%-95% MeCN / H2O containing 0.1% TFA) to obtain LCT011082 (51.09 mg, yield 60%) as an off-white solid.

[0434] Mass spectrum MS (ESI): molecular formula C15 H 13 NO4 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).

[0435] Preparation method of compound LCT011077 of Example 33

[0436] The preparation method of LCT011077 is the same as that of LCT011082, to obtain LCT011077 (21.7 mg, yield: 26%). Mass spectrum MS (ESI): molecular formula is C 15 H 13 NO4 271.08, m / z 272.05 [M+H] + . 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).

[0437] Preparation method of compound LCT011088 of Example 34

[0438]

[0439] To a 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 to the mixture was added prop-2-amine (17 mg, 0.29 mmol). The mixture was stirred at 25 °C for 3 h. Water was added to the solution and extracted with DCM, and the organic layer was concentrated to give a crude product, which was purified by HPLC (column: Gemini 5 pm C18 150 x 21.2 mm, mobile phase: acetonitrile-H20 (0.1% FA), gradient: 50-95, 12.50 min) to give LCT011088 (10.3 mg, yield: 22%) as a yellow solid. Mass spectrum MS (ESI): molecular formula C 19 H 22 N2O2, molecular weight 310.17, m / z 311.00 [M+H] + . 1 HNMR (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).

[0440] Example 35 Method of preparing compound LCT011083

[0441] Synthesized according to the method of preparing LCT011088 using appropriate commercially available reagents such as HOBt, DCC, and intermediates such as isopropylamine.

[0442]

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

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

[0445] 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).

[0446] Process for preparing compound LCT011084 of example 36

[0447] According to the process for preparing LCT011088, using appropriate commercial reagents such as HOBt, DCC, and intermediates such as ammonia in dichloromethane.

[0448]

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

[0450] Mass Mass MS (ESI): molecular formula C 21 H 18 N2O2, molecular weight 330.14, m / z 331.10 [M+H] + .

[0451] 1 1H 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).

[0452] Process for preparing compound LCT011087 of example 37

[0453] According to the process for preparing LCT011088, using appropriate commercial reagents and intermediates.

[0454]

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

[0456] Mass Mass MS (ESI): molecular formula C 16 H 16N2O2, with a molecular weight of 268.12 and m / z of 268.95 [M+H] + . 1 HNMR (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).

[0457] Example 38 Process for preparing compound LCT011097

[0458] Synthesized according to the process for preparing LCT011088, using appropriate commercially available reagents and intermediates.

[0459]

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

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

[0462] 1 HNMR (400 MHz, DMSO-d6) δ 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).

[0463] Example 39 Process for preparing compound LCT011089

[0464]

[0465] Compound 1 (90 mg, 0.19 mmol) was dissolved in a mixture of TFA / DCM = 1 :5 (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.

[0466] 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).

[0467] Process for preparing compounds LCT011092, LCT011090 of example 40

[0468]

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

[0470] Compound 1 (1.1 g, 2.8 mmol) was added to a mixture of DCM / TFA = 5 / 1 (5 mL) and stirred at 25 °C for 1 h. After the reaction was completed, the pH of the mixture was adjusted to 8 with NaHC03(aq.) and extracted with EtOAc. The organic layer was dried with Na2S04, filtered off and concentrated to give the desired product compound 8 (1.0 g, yield: 94%) as a yellow solid. Mass spectrum MS (ESI): molecular formula is C 15 H 12 BrNO3, molecular weight is 333.00, m / z is 333.95 [M+H] +.

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

[0472] 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 h, prop-2-amine (353.8 mg, 6.0 mmol) was added to the solution, the reaction was stirred at 25 °C for 16 h, the reaction was monitored by LCMS. After completion, the reaction mixture was quenched with H2O, extracted with DCM. 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) to get compound 9 (1.0 g, yield: 80%) as a yellow solid.

[0473] Mass Mass (ESI): Formula C 18 H 19 BrN2O2, 374.06, m / z 374.75 [M+H] + .

[0474] 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

[0475] To a solution of compound 9 (300 mg, 0.80 mmol) in 1.4-dioxane / H2O = 5 / 1 (6 mL) was added tert-butyl 4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H- pyridine-l-carboxylate (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 h under N2atmosphere. The reaction was monitored on LC-MS. Water was added to the solution, 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 get compound 10 (240 mg, yield: 58%) as a yellow solid. Mass Mass (ESI): Formula C 28 H 35 N3O 4， Molecular weight 477.26, m / z 478.25 [M+H] + .

[0476] Step 4: Preparation of 4-(l-(4-(isopentylamino)-4-oxobutyl)-2-oxo-l,2- dihydrobenzo[cd]indol-5-yl)piperidine-l-carboxylate

[0477] 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 a yellow solid. Mass spectrum MS (ESI): the molecular formula was C 28 H 37 N3O4, the molecular weight was 479.28, m / z was 480.25 [M+H] + .

[0478] Step 5: Preparation of N-isopropyl-4-(2-oxo-5-(piperidin-4-yl)benzo[cd]indol-l(2H)- yl)butanamide:

[0479] Compound 11 was added (120.0 mg, 0.25 mmol) into a mixed solution of DCM / TFA = 5 / 1 (5 mL) and stirred for 1 hour, the reaction was detected on LC-MS. After the reaction was completed, the reaction mixture was evaporated to give the 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, 11.25 min) to give the product LCT011092 (33.37 mg, yield: 30%) as a yellow solid.

[0480] Mass spectrum MS (ESI): the molecular formula was C 23 H 29 N3O2, the molecular weight was 379.23, m / z was 380.15 [M+H] + . 1H 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).

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

[0482]

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

[0484] Mass spectrometry MS (ESI): molecular formula is C 22 H 27 N3O 2， Molecular weight 365.21, m / z 366.15 [M+H] + . 1 H NMR (400 MHz, 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).

[0485] Preparation method of compound LCT011091 in Example 41

[0486]

[0487] 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 hours. 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.

[0488] Mass spectrum MS (ESI): molecular formula is C 23 H 27 N3O2, molecular weight 377.21, m / z 378.60 [M+H] + . 1 H NMR (400 MHz, 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).

[0489] Method for preparing compound LCT011093 of example 42

[0490]

[0491] 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 hour. The reaction was detected on LC-MS. After completion, the reaction mixture was evaporated to give the crude product, which was purified by HPLC (Gemini 5 pm C18 column, 150 x 21.2 mm, eluted with 30% to 95% MeCN / H 2O O (0.1% TFA), 11.25 min) to give LCT011093 (TFA salt) (10.38 mg, yield: 30%) as a yellow solid. Mass spectrum MS (ESI): molecular formula is C 19 H 18 N2O3, molecular weight 322.13, m / z 323.10 [M+H] + .

[0492] 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).

[0493] Process for preparing compound LCT011094 of example 43

[0494]

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

[0496] To a solution of 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 the 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 MS (ESI): molecular formula C 28 H 34 N2O5, molecular weight 478.25, m / z 479.35 [M+H] + .

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

[0498] To a solution of compound 3 (160 mg, 0.33 mmol) in MeOH (10 mL) was added Pd / C (128 mg, 80% 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 MS (ESI): Molecular formula C 28 H 36 N2O5, Molecular weight 480.26, m / z 481.10 [M+H] + .

[0499] Step 3: Preparation of 4-(2-oxo-5-(pyrrolidin-3-yl)benzo[cd]indol-l(2H)-yl)butanoic acid (LCT011094)

[0500] A solution of compound 4 (50.0 mg, 0.1045 mmol) in DCM / TFA = 5: 1 (2 mL) was stirred at 25 °C for 1 h, the reaction was monitored by LCMS. After completion of the reaction, 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 O (0.1% TFA) in 10 min, to get the product LCT011094 (TFA salt) (80.0 mg, yield: 78%) as yellow solid.

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

[0502] 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).

[0503] Process for preparation of compound LCT011096 of example 44

[0504]

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

[0506] 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 (400MHz, DMSO-d6) δ 12.10 (brs, 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).

[0507] Preparation method of compound LCT011095 in Example 45

[0508]

[0509] Compound 1 (50.0 mg, 0.10 mmol) was added to a mixed solution of DCM:TFA = 5:1 (2 mL), stirred at 25°C for 1 hour, and the reaction was monitored by LC-MS. After the reaction was completed, the reaction mixture was evaporated to obtain a crude product, which was purified by HPLC (Gemini 5 μm C18 column, 150 x 21.2 mm, 30% to 95% MeCN / H 2O eluted with 0.1% TFA) to obtain the product LCT011095 (TFA salt) (10.88 mg, yield: 31%) as a yellow solid.

[0510] Mass spectrum MS (ESI): molecular formula is C 20 H 20 N2O3, molecular weight 336.15, m / z 337.15 [M+H] + . 1H 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).

[0511] Process for the preparation of compounds LCT011016 and LCT011098 of example 46

[0512]

[0513]

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

[0515] To a solution of 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 completion of the reaction, 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] - .

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

[0517] 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 and stirred at 25 °C for 72 h. After completion of the reaction, 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 phase 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 17N2O5, molecular weight 426.22, m / z 427.10 [M+H] + .

[0518] Step 3: Preparation of tert-butyl 4-(4-((tert-butoxycarbonyl)amino)-2-oxobenzo[cd]indol-1(2H)-yl)butanoate

[0519] 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 N2 atmosphere, stirred at 100 °C for 12 h. Upon completion, the reaction mixture was quenched by adding water (20 mL). The mixture was then separated into a separation funnel, 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 = 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] + .

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

[0521] Compound 5 (680 mg, 1.59 mmol) was added into a mixture solution of TFA / DCM = 1:5 (12 mL), the mixture was stirred at 25 °C for 3 h, upon completion, the mixture was concentrated, the residue was purified by reverse flash chromatography (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] + .

[0522] 1H 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).

[0523] Step 5: Preparation of 2,5-dioxopyrrolidin-1-yl 4-(4-amino-2-oxobenzo[cd]indol-1(2H)- yl)butanoate

[0524] 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 h, the reaction was monitored on LC-MS. 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 DCM (20 mL x 3). The combined organic layers were washed with brine (10 mL), dried over Na2S04, filtered and concentrated to give the crude compound 7 (110 mg, yield: 61%), which was used directly for the next step without further purification.

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

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

[0527] 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 spectrum MS (ESI): molecular formula C 33 H 29 N3O2, molecular weight 499.23, m / z 500.15 [M+H] + .

[0528] 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).

[0529] Process for preparing compound LCT011099 of example 47

[0530]

[0531] Step 1: Preparation of 2,5-dioxopyrrolidin-1-yl 4-(4-methyl-2-oxobenzo[cd]indol-1(2H)- yl)butanoate

[0532] 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, 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. Mass spectrum MS (ESI): molecular formula C 20 H 18 N2O5, molecular weight 366.12, m / z 367.05 [M+H] + .

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

[0534] 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), 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.

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

[0536] 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).

[0537] Method for preparing compound LCT011100 of Example 48

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

[0539]

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

[0541] Mass spectrum MS (ESI): the molecular formula of C 33 H 28 N2O3, molecular weight 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).

[0542] Example 49 Process for preparing compound LCT011103

[0543]

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

[0545] 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.

[0546] 1 H 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).

[0547] Step 2: Preparation of ((9S,10S)-9,10-dihydro-9,10-ethanooanthracen-l l- yl)methanamine 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 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.

[0548] Mass Mass (ESI): Formula for C 17 H 17 N, 235.14 and m / z 236.10 [M+H] + .

[0549] Step 3: Preparation of N-(((9S,10S)-9,10-dihydro-9,10-ethanooanthracen-l l- yl)methyl)-4-(4-methyl-2-oxobenzo[cd]indol-l(2H)-yl)butanamide

[0550] 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 stirred at 25 °C for 5 h. Then ((9s,10s)-9,10-dihydro-9,10-ethanooanthracen-l l- yl)methanamine (43.7 mg, 0.18 mmol) was added and stirred at 25 °C for 16 h. 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 30-95% MeCN in H2O with 0.1% FA) to get the product LCT011100 (30.55 mg, yield: 33%) as a yellow solid.

[0551] Mass Mass (ESI): Formula for C 33 H 30 N2O2, 486.23 and 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).

[0552] Process for preparing compound LCT011105 of example 50

[0553]

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

[0555] 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), stirred at 100 °C for 5 hours. The reaction was monitored 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, 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 yellow solid. Mass spectrum MS (ESI): molecular formula C 21 H 23 NO3, molecular weight 337.17, m / z 337.95 [M+H] + .

[0556] Step 2: tert-butyl 4-(4-ethyl-2-oxobenzo[cd]indol-l(2H)-yl)butanoate

[0557] 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), 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.

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

[0559] Step 3: Preparation of 4-(4-ethyl-2-oxobenzo[cd]indol-l(2H)-yl)butanoic acid

[0560] To a solution of compound 2 (100.0 mg, 0.29 mmol) in DCM:TFA = 5: 1 (5 mL) was stirred at 25 °C for 1 h, the reaction was monitored on LC-MS. After the reaction was completed, the reaction mixture was evaporated to give the crude product, which was purified by HPLC (Gemini 5 pm C18 column, 150 x 21.2 mm, eluted with 0.1% FA in 30% to 95% MeCN / H2O, 11.25 min) to give LCT011105 (54.01 mg, yield: 62%) as a yellow solid.

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

[0562] 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).

[0563] Method for preparing compound LCT011108 of Example 51

[0564]

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

[0566] 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 sodium sulfate, 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] + .

[0567] Step 2: Preparation of 4-(4-methoxy-2-oxobenzo[cd]indol-l(2H)-yl)butanoic acid

[0568] 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 sodium sulfate, 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] + .

[0569] 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).

[0570] Example 52 Process for preparation of compound LCT011109

[0571]

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

[0573] 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, the reaction was monitored by LC-MS. Water was added to the reaction solution, 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 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] - .

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

[0575] 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, the reaction was monitored by LC-MS. The reaction mixture was filtered and the solution was concentrated under vacuum. The crude compound 4 (1.1 g, yield: 100%) was used directly for the next step without further purification.

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

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

[0578] Compound 4 (500 mg, 1.57 mmol), 2M HC1 was added in Dioxane (5 mL), the mixture was stirred at 25 °C for 6 hours, the reaction was monitored by LC-MS. The reaction mixture was filtered, the filter cake was concentrated under vacuum to get the crude product, the obtained crude compound 5 (300 mg, yield: 88%) was used for the next step directly without further purification. Mass spectrum MS (ESI): molecular formula C 13 H 16 N2O, molecular weight 216.13, m / z 217.15 [M+H] + .

[0579] Step 4: Preparation of 4-methyl-l-(4-oxo-4-(4-(2-oxoindolin-3-yl)piperidin-l- yl)butyl)benzo[cd]indol-2(lH)-one

[0580] To the 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 hours, the reaction was monitored by LC-MS. The reaction mixture was concentrated under vacuum to get the 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: 30-95, 12.50 min) to get LCT011109 (69.01 mg, yield: 45.6%) yellow solid. Mass spectrum MS (ESI): molecular formula C 29 H 29 N3O3, molecular weight 467.22, m / z 468.20 [M+H] + .

[0581] 1HNMR (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).

[0582] Process for the preparation of compound LCT011110 of example 53

[0583]

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

[0585] 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 the reaction was stirred at 25 °C for 6 h, monitored by TLC. 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 get the crude compound 2 (600 mg, yield: 81%), which was used directly in the next step without further purification.

[0586] Step 2: Preparation of tert-butyl (10,10-dioxo-9-oxo-9H-thioxanthren-3- yl)carbamate Under N2atmosphere, to a solution of compound 2 (600 mg, 1.85 mmol) in toluene was added K2CO3(513 mg, 3.71 mmol), BocNH2(1303 mg, 11.14 mmol), Pd2(dba)3(85 mg, 0.092 mmol) and t-BuXPhos (78 mg, 0.18 mmol). The reaction was stirred at 100 °C for 12 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, the product was purified by chromatography (eluted with PE / EtOAc from 100 / 00 to 60 / 40 in 20 min) to give compound 3 (420 mg, yield: 52%) as a white solid. Mass spectrum MS (ESI): molecular formula C 18 H 17 NO5S, molecular weight 359.08, m / z 358.05 [M-H] - .

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

[0588] Compound 3 (420 mg, 1.16 mmol), 2M HC1 was added into dioxane (5 mL), the reaction was stirred at 25 °C for 6 h, the reaction was monitored by LC-MS. The reaction mixture was filtered, the filter cake was concentrated under vacuum to give the crude product, the resulting crude compound 4 (210 mg, yield: 69%) was used directly for the next step without further purification. Mass spectrum MS (ESI): molecular formula C 13 H9NO3S, molecular weight 260.03, m / z 260.05 [M+H] + .

[0589] Step 4: Preparation of N-(10,10-dioxo-9-oxo-9H-thioxanthren-3-yl)-4-(4-methyl- 2-oxobenzo[cd]indol-l(2H)-yl)butanamide

[0590] 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.

[0591] 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).

[0592] Process of preparation of compound LCT011111 of example 54

[0593]

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

[0595] 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. 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] - .

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

[0597] 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] - .

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

[0599] Compound 4 (300.0 mg, 0.75 mmol), 1M HCl was added into EtOAc (5 mL), 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.

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

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

[0602] 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.

[0603] Mass spectrum MS (ESI): The molecular formula is C 29 H 32 N4O5S, 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).

[0604] Example 55 Method of preparing compound LCT011117

[0605]

[0606] Step 1 : Preparation of tert-butyl 4-(l-(4-((9S,10S)-9,10-dihydro-9,10- [3,4]cyclopentalphalen-13-yl)-4-oxobutyl)-2-oxo-l,2-dihydrobenzo[cd]indol-5-yl)- 3,6-dihydropyridine-l(2H)-carboxylate 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 was stirred at 50 °C for 1 h, monitoring the reaction by LC-MS. Upon completion of the reaction, water was added to the solution and the organic layer was extracted with EtOAc, washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated to give the product which was purified by flash chromatography (elution 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] + .

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

[0608] Compound 3 (100 mg, 0.15 mmol) was taken in TFA (2 mL) and the reaction was stirred at 25 °C for 1 h, monitoring the reaction by LC-MS. The reaction mixture was concentrated to give 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% TFA), gradient: 35-95, 12.50 min) to give LCT011117 (4.49 mg, yield: 2.6%) as a yellow solid. Mass spectrum MS (ESI): molecular formula C 38 H 35 N3O2, mass 565.27, m / z found 566.25 [M+H]+.

[0609] 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).

[0610] Example 56 Process for preparing compound LCT011118

[0611]

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

[0613] 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] + .

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

[0615] To a solution of compound 2 (400 mg, 1.10 mmol) in 1,4-dioxane / H2O ＝ 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) and stirred at 50 °C for 5 h, LCMS was used to monitor the reaction. After the reaction was completed, the pH was adjusted to 5-6 with aqueous HC1 (2N) and extracted with EtOAc, the organic layer was dried over Na2S04, filtered off and concentrated to give compound 4 (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] + .

[0616] 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

[0617] 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) and stirred at 50 °C for 5 h, LCMS was used to monitor the reaction. After the reaction was completed, the pH was adjusted to 5-6 with aqueous HC1 (2N) and extracted with EtOAc, the organic layer was dried over Na2S04, filtered off and concentrated to give 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] + .

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

[0619] 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] + .

[0620] 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) Compound 5 (100 mg, 0.15 mmol) was added to a mixture of TFA / DCM = 1 / 5 (5 mL), and stirred at 25 °C for 2 h, and the reaction was monitored by LC-MS. After the reaction was completed, the reaction mixture was evaporated to give the crude product, which was purified by HPLC (Gemini 5 μm C18 column, 150 x 21.2 mm, eluted with 30% to 95% MeCN / H2O containing 0.1% TFA in 11.25 min) to give the product LCT011118 (TFA salt) (27.1 mg, yield: 31%) as a yellow solid. Mass spectrum MS (ESI): molecular formula C 37 H 35 N3O2, 553.27, m / z 554.35 [M+H] + .

[0621] 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).

[0622] Process for preparing compound LCT011119 of example 57

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

[0624]

[0625] 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] + .

[0626] 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).

[0627] Process for preparing compound LCT011121 of example 58

[0628]

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

[0630] 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 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] + .

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

[0632] 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 the crude product 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] + .

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

[0634] A solution of compound 4 (550 mg, 1.80 mmol) in HCl-dioxane (5 mL, 2N) was stirred at 25 °C for 3 h. After the reaction was completed, the mixture was concentrated to remove most of the solvent, and 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): the molecular formula is C8H 12 N2O2S, 200.06 in molecular weight, 201.10 in m / z [M+H] + .

[0635] Step 5: Preparation of 4-(2-oxo-3-phenylbenzo[cd]indol-l(2H)-yl)-N-(l-(4- sulfosulfonylphenyl)ethyl)butanamide

[0636] 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 the reaction was completed, the mixture was concentrated to give the crude product, which was purified by preparative HPLC (Gemini 5 μm C18 column, 150 x 21.2 mm, eluted with 30-95% MeCN / H2O containing 0.05% ammonia) to give product LCT011121 (43.19 mg, yield: 58%) as a yellow solid. Mass spectrum MS (ESI): the molecular formula is C 29 H 27 N3O4S, 513.17 in molecular weight, 514.15 in m / z [M+H] + .

[0637] 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).

[0638] Method for preparing compound LCT011120 of Example 59

[0639] The method for preparing LCT011120 is the same as that for preparing LCT011121.

[0640]

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

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

[0643] Example 60: Preparation method of compound LCT011128

[0644]

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

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

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

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

[0649] 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 h. The mixture was concentrated in vacuo, 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.

[0650] 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).

[0651] 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

[0652] 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), the mixture was stirred at room temperature for 3 h, the reaction mixture was concentrated in vacuo, the residue was purified by HPLC (Gemini 5 pm C18 column, 150 x 21.2 mm, eluted with 50% to 80% MeCN / H20 (containing 0.1% FA) to give LCT011128 (68.1 mg, 34% yield) as a yellow solid. Mass MS (ESI): molecular formula C 34 H 28 N2O3, molecular weight 512.21, m / z 513.20 [M+H] + .

[0653] 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).

[0654] Process for the preparation of compounds LCT011056 and LCT011035 of example 61

[0655]

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

[0657] 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 layer was 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] + .

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

[0659] 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] + .

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

[0661] To a 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] + .

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

[0663] To a solution of compound 4 (1.0 g, 2.42 mmol) in methanol (5.0 mL) and water (2.5 mL) 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 1 N 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 H 22NO4S, 399.51, m / z 400.50 [M+H]+.

[0664] 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).

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

[0666] 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] + .

[0667] 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).

[0668] Example 62 Method of preparing compound LCT011133

[0669]

[0670] 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]+.

[0671] 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]+.

[0672] 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 14FNO3, molecular weight 287.10, m / z 288.05 [M+H]+.

[0673] 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).

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

[0675]

[0676]

[0677]

[0678]

[0679]

[0680] Pharmacodynamic experiment

[0681] 1. Cell experiment

[0682] Detection method: NPY (neuropeptide Y) vesicle release experiment method

[0683] (1) HEK293 cells stably transfected with syt7 and NPY-pHluorin were seeded into a six-well plate and cultured with DEME containing 5% FBS; when the cell number grew to 90%, the cells were digested and evenly seeded in a 96-well cell culture plate with a black bottom.

[0684] (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 into 1 L of ultrapure water to prepare a high potassium solution with PH 7.4.

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

[0686] (4) Add 4 μL of compound DMSO stock solution into 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.

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

[0688] Incubate the compounds at room temperature for 10 min, and then detect the emission intensity at 390 nm and 485 nm under 509 nm excitation light using a microplate reader, and calculate the ratio of the two.

[0689] Detection results:

[0690]

[0691]

[0692]

[0693]

[0694] 2. Animal experiments

[0695] Prepare male C57BL / 6J mice (6-8 weeks old) weighing 20-25 g, and adaptively feed them in a SPF level animal room for 5 days before use. Administer the drugs by intraperitoneal injection, with a dose ranging from 0.1 umol / kg to 36 umol / kg. Divide the mice into a blank group, a positive control group (dextro-escitalopram), a test compound group, and different dose groups for the same compound. Each group contains 6-12 mice.

[0696] 2.1. Sucrose preference test (SPT)

[0697] Detection method:

[0698] 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, with the metal tip of the drinking bottle inserted into the metal grid of the mouse cage at a 45° angle to the horizontal, and ensuring that the mice can easily drink from either bottle. Food is placed in the mouse cage for easy access.

[0699] (1) The first and second days are the stages of water adaptation for mice, that is, 40 mL of pure water is placed in each of the two 50 mL drinking water bottles.

[0700] (2) The third and fourth days are the stages of sugar adaptation for mice, that is, 40 mL of 2% sucrose water is placed in each of the two 50 mL drinking water bottles.

[0701] (3) On the fifth day, the drinking water bottles are removed, and the water deprivation stage is performed for 24 hours.

[0702] (4) On the sixth day, the sugar water preference test is performed, and two drinking water bottles are used, one of which is pure water and the other of which is 2% sucrose water. Before the test, the water on the surface of the water bottles is wiped off, and the initial weight of the water bottles is recorded. Then, the drinking water bottles are inserted into the metal grating of the mouse cage to start the test. After 1 hour, the positions of the two drinking water bottles are exchanged, and after another 1 hour, the test is completed. All drinking water bottles are removed from the metal grating and placed upright, and then weighed in order.

[0703] (5) Data statistical analysis, sugar water preference rate (Sucrose preference) = sugar water consumption / total consumption of sugar water and water.

[0704] 2.2, Results of the forced swimming test (FST)

[0705] Detection method:

[0706] The water bucket used for the forced swimming test (FST) is 30 cm high and 20 cm in diameter. One hour before the experiment, 2 / 3 of the height of tap water is added to the water bucket, and the water temperature is tested to be 24+1℃; the Gopro is placed directly opposite the front of the water bucket without any angle of obstruction. After all the settings are complete, video recording can begin.

[0707] (1) The mouse that has been adapted for 1 hour is gently placed in the water bucket, with the mouse's body parallel to the water surface entering the water bucket to prevent the mouse from drowning or affecting the mouse's subsequent behavior.

[0708] (2) After 6 minutes of free swimming in the water bucket, stop recording, remove the mouse from the water bucket, wipe off the water on the mouse's body with toilet paper, and then place the mouse back in the cage. A suitable amount of toilet paper can be placed in the cage to help the mouse keep warm. Then, the corresponding information of the video is recorded, and the next group of mice can be tested.

[0709] (3) All mice were transported back to the home cage room at the end of the test, and then data analysis of the FST was performed. The time of the mice swimming in the bucket was counted. The final immobility time of the mice = total time (300 seconds) - mobility time.

[0710] The above description is merely preferred embodiments of the present application, and is not used to limit the present application. Any modification, equivalent replacement, improvement, etc. made within the spirit and principle of the present application shall fall within the protection scope of the present application.

Claims

1. A heterocyclic alkyl carboxylic acid derivative of Formula I, characterized in that, a compound of Formula I, a stereoisomer, a geometric isomer, a tautomer, a nitroso, a hydrate, a solvate, a pharmaceutically acceptable salt, or a prodrug thereof; wherein 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, R2 is absent; R0 is n is selected from 1-8; X is selected from substituted or unsubstituted C1-C5 alkyl, amino, aryl, C3-C10 cycloalkyl, the substituted substituent is selected from carbonyl, hydroxyl, C1-C5 alkyl, halogen, aryl; Y is selected from -OH, -NH2, -NR6R7, -S-R8, R9, -CO-R 10 ; R6, R7 are each independently selected from H, substituted or unsubstituted C1-C8 alkyl, C1-C5 alkyl, C5-C15 heterocyclyl, C4-C14 cycloalkyl, the substituted substituent is selected from C5-C15 heterocyclyl, aryl; R8 is selected from substituted or unsubstituted C1-C8 alkyl, the substituted substituent is selected from carbonyl, hydroxyl, C1-C5 alkyl, halogen, aryl; R9 is selected from substituted or unsubstituted C5-C30 membered heterocyclyl, the substituted substituent is selected from carbonyl, hydroxyl, C1-C5 alkyl, 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-C8 alkoxy, substituted aryl, C1-C8 alkyl, C1-C8 haloalkyl, C1-C8 alkylamino, phenylamino, C3-C10 heterocyclyl; R6, R7, R9, R 10 In the heterocycle or heterocyclyl group, the heteroatom is oxygen and / or nitrogen.

2. 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, R2 is absent; R0 is n is selected from 1-8; X is selected from substituted or unsubstituted C1-C5 alkyl, amino, the substituted substituent is selected from carbonyl, hydroxyl; Y is selected from -OH, -NH2, -NR6R7, -S-R8, R9, -CO-R 10 ; R6, R7 are each independently selected from H, substituted or unsubstituted C1-C8 alkyl, C1-C5 alkyl, C5-C15 heterocyclyl, C4-C14 cycloalkyl, the substituted substituent is selected from C5-C15 heterocyclyl, aryl; R8 is selected from substituted or unsubstituted C1-C8 alkyl, the substituted substituent is selected from C3-C6 cycloalkyl; R9 is selected from C5-C30 heterocyclyl; 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-C8 alkoxy, substituted aryl, C1-C8 alkyl, C1-C8 haloalkyl, C1-C8 alkylamino, phenylamino, C3-C10 heterocyclyl; R6, R7, R9, R 10 In the heterocycle or heterocyclyl group, the heteroatom is oxygen and / or nitrogen.

3. The heterocyclic alkyl carboxylic acid derivative according to claim 2, characterized in that, B is selected from a C atom, a N atom; wherein when B is a N atom, R2 is absent; R0 is n is selected from 1-6; X is selected from carbonyl, hydroxyl substituted C1-C3 alkyl, NH; Y is selected from -OH, -NH2, -NR6R7, -S-R8, R9, -CO-R 10 ; R6, R7 are each independently selected from H, C1-C5 alkyl, C5-C15 heterocyclic substituted C1-C5 alkyl, aryl substituted C1-C5 alkyl, C5-C15 heterocyclyl, C4-C14 cycloalkyl, substituted C4-C14 cycloalkyl; R8 is selected from C3-C5 cycloalkyl substituted C1-C5 alkyl; R9 is selected from C5-C30 heterocyclyl; R 10 selected from C5-C15 heterocyclic ring substituted C1-C4 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-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.

4. The heterocyclic alkyl carboxylic acid derivative according to claim 1, characterized in that, when R1, R2, R3, R4, R5 are simultaneously H, R0 is not C3 alkyl, or X is not carbonyl, or Y is not hydroxyl.

5. The heterocyclic alkyl carboxylic acid derivative according to claim 1, characterized in that, 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.

6. The heterocyclic alkyl carboxylic acid derivative according to claim 1, characterized in that, R1, R2, R3, R4, R5, R1', R2', R3', R4', R5', R1", R2", R3", R4" are each independently selected from H, amino, nitro, hydroxy, cyano, halogen, phenyl, methyl, ethyl, methoxy, halogenmethyl, 7. The heterocyclic alkyl carboxylic acid derivative according to claim 1, characterized in that, n = 1, 3, 4 or 5; hydroxy-substituted C1-C3alkyl is 8. The heterocyclic alkyl carboxylic acid derivative according to claim 1, characterized in that, R6, R7are each independently selected from the group consisting of H, methyl, isopropyl, 9. The heterocyclic alkyl carboxylic acid derivative according to claim 1, characterized in that, R8 is 10. The heterocyclic alkyl carboxylic acid derivative according to claim 1, characterized in that, R9 is selected from 11. The heterocyclic alkyl carboxylic acid derivative according to claim 1, wherein, R 10 To ​ 12. The heterocycloalkyl carboxylic acid derivative according to any one of claims 1 to 11, wherein the compound of formula I is selected from:

13. The heterocyclic alkyl carboxylic acid derivative according to claim 12, characterized in that, 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.

14. The heterocyclic alkyl carboxylic acid derivative according to claim 13, characterized in that, selected from: LCT011016, LCT011024, LCT011028, LCT011062, LCT011063, LCT011064, LCT011065, LCT011068, LCT011078, LCT011079, LCT011097, LCT011098, LCT011103, LCT011105, LCT011108, LCT011100, LCT1133.

15. The heterocyclic alkyl carboxylic acid derivative according to claim 14, characterized in that, selected from: LCT011016, LCT011078, LCT011062, LCT011063, LCT011064, LCT011097, LCT1108, LCT011117, LCT1133.

16. The heterocyclic alkyl carboxylic acid derivative according to claim 15, characterized in that, selected from: LCT011016, LCT011078, LCT011097, LCT011108, LCT011117, LCT1133.

17. 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 X1is selected from H, halogen, hydroxyl; Y' is Y or Y substituted with a protecting group.

18. 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 the substitution or hydrogenation of H, X2, X3or NO2to the corresponding group.

19. 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.

20. 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 21. 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 22. The method for preparing the heterocyclic alkyl carboxylic acid derivative as described in claim 21, characterized in that, comprising the following reaction steps:

23. 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.

24. The method for preparing the heterocyclic alkyl carboxylic acid derivative as described in claim 23, characterized in that, comprising the following reaction steps:

25. 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 .

26. The method for preparing a heterocycloalkyl carboxylic acid derivative according to any one of claims 17 to 25, wherein, ###00017### comprising the following reaction steps:

27. An intermediate for a heterocyclic alkyl carboxylic acid derivative, characterized in that, comprising the following reaction steps: comprising the following reaction steps: comprising the following reaction steps: R0 is n is selected from 1-6; comprising the following reaction steps: A is selected from -OR 11 , OH, H, halogen or null; R 11 is selected from C1-C10 alkyl; comprising the following reaction steps:

28. The intermediate of claim 27, wherein, 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-C5alkoxy, substituted aryl, C1-C5alkyl, C1-C5alkylamino, phenylamino, C3-C8heterocyclyl; R 11 is tert-butyl.

29. The intermediate of claim 27, wherein, comprising the following reaction steps:

30. The intermediate of claim 28, wherein, wherein ring R is selected from the following structures:

31. The intermediate of claim 27, wherein, B is selected from C atom, N atom; wherein when B is N atom, R2 is absent; 32. The intermediate of claim 27, wherein, M is selected from carbonyl, NH, vinyl, halogen, epoxy; 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.

34. The use of claim 33, wherein the compound is ###00021### 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.

35. The use of claim 34, wherein the compound is ###00021### 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.

36. The use of claim 35, wherein the compound is of formula (I) ###00019### (I) or a pharmaceutically acceptable salt thereof. n = 1, 3, 4 or 5.

37. The use of claim 36, wherein the compound is ###00022### 36 said intermediate is selected from:

38. A pharmaceutical composition comprising, 33. Use of a heterocycloalkyl carboxylic acid derivative according to any one of claims 1-16 for the preparation of a medicament for the treatment and / or prevention of a neurological disease, a metabolic disease. said neurological disease comprises schizophrenia, bipolar disorder, depression, Alzheimer's disease, epilepsy, neuropathy, chorea, Parkinson's disease; said metabolic disease comprises diabetes, metabolic disorder. said neurological disease is selected from schizophrenia, bipolar disorder, depression. said neurological disease is selected from bipolar disorder, depression. said neurological disease is depression. a heterocycloalkyl carboxylic acid derivative according to any one of claims 1-16, and a pharmaceutically acceptable carrier or excipient.

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