Crystal form and salt of bicyclic heteroaryl amide compound, preparation method and application

Abstract

The invention provides a crystal form or salt of a bicyclic heteroaryl amide compound as well as a preparation method and application of the crystal form or salt. Specifically, the invention relates to a compound with a general formula (I) and a crystal form and a salt of a stereoisomer of the compound, a preparation method of the crystal form and the salt, and an application of the crystal form and the salt in treatment or prevention of neurodegenerative diseases characterized by protein aggregation.

Description

Crystal form and salt of bicyclic heteroarylamide compound, preparation method and use Technical Field

[0001] The present invention belongs to the field of biomedicine, and specifically relates to a crystalline form and salt of a bicyclic heteroarylamide compound, a preparation method, and its use in treating or preventing neurodegenerative diseases characterized by protein aggregation, such as Alzheimer's disease, Parkinson's disease, frontotemporal dementia, Lewy body disease, Parkinson's disease dementia, multiple system atrophy, amyotrophic lateral sclerosis, Huntington's disease, and cancer. Background Art

[0002] Neurodegenerative diseases, such as Alzheimer's disease, Parkinson's disease, and frontotemporal dementia, are a major cause of death in the elderly. A common feature among these neurodegenerative diseases is the long-term accumulation of proteins into neurotoxic aggregates.

[0003] The initial stage of protein aggregation involves mutation or post-translational modification (such as nitrosation, oxidation) of the target protein, which then generates an abnormal conformation and promotes interaction with similar misfolded proteins. The abnormal protein then aggregates to form dimers, trimers and higher-order polymers (also referred to as "soluble oligomers"), which may destroy synaptic function. In addition, the aggregates are then fixed in the cell membrane and form spherical oligomers (which in turn form holes in the membrane) and / or fibrils or filaments. These larger insoluble fibrils may serve as reservoirs for biologically active oligomers.

[0004] Research suggests that the progressive accumulation of protein aggregates is causally linked to the pathogenesis of neurodegenerative diseases. Several other proteins, including α-synuclein (SYN), Aβ, Tau, and TDP43, accumulate in the brains of patients with neurodegenerative diseases. Cognitive impairment in these patients is closely associated with synaptic loss in the neocortex and limbic system, and increased levels of protein aggregates may contribute to this synaptic loss. Numerous studies have focused on detailing the mechanisms by which the accumulation of α-synuclein and other amyloid precursor protein metabolites promotes synaptic damage and neurodegeneration. Furthermore, numerous studies support the hypothesis that the formation of small aggregates (also known as oligomers) plays a major role in neurotoxicity. These peptide oligomers can organize into higher-order aggregates such as dimers, trimers, tetramers, and pentamers. High levels of these oligomers predict dementia and synaptic loss in patients. Multiple lines of evidence suggest that oligomers, rather than smaller precursor fibrils, are the toxic agents. Therefore, compounds that specifically target these early aggregation processes could serve as potential new therapeutic approaches for the treatment or prevention of Alzheimer's disease, Parkinson's disease, and other related conditions.

[0005] Various neurodegenerative diseases are related to the accumulation of neurotoxic protein aggregates. In idiopathic Parkinson's disease, Lewy body dementia, Parkinson's disease dementia and multiple system atrophy, neurotoxic aggregates are composed of α-synuclein, which is a synaptic protein in the cell under normal conditions. In frontotemporal dementia and amyotrophic lateral sclerosis, neurotoxic aggregates are derived from other intracellular proteins (such as tau, TDP-43 or SOD1). For some diseases (such as Alzheimer's disease), α-synuclein and other major proteins (for example, Aβ protein) gather. In Huntington's disease, aggregates are formed by the cleavage products of Htt protein.

[0006] These protein accumulation processes involve two mechanisms. In the first mechanism, misfolded and / or aggregated proteins are fixed to various cell membrane structures. The binding of misfolded or aggregated molecules to the plasma membrane or organelle (such as mitochondria or lysosomes) membranes can interfere with protein transcription, autophagy, mitochondrial function and pore formation. For example, neurotoxic α-synuclein aggregates and interacts with lipids in the cell membrane through specific parts of the synuclein C-terminal region. Compounds that bind to this region can inhibit protein-protein or protein-lipid interactions and are therefore useful for blocking the neurotoxic oligomerization of α-synuclein or other proteins and their interactions with the membrane. In the second mechanism, aggregated proteins are released from fixed subunits and spread to neighboring cells. The spread of toxic protein aggregates from cell to cell may be the cause of further deterioration of neurodegenerative diseases. Therefore, small molecule drugs that interact with target proteins can limit their release and spread, thereby reducing the neurotoxic effects of aggregated proteins.

[0007] The compound of the present invention has the advantages of high inhibition rate of inhibiting α-synuclein aggregation, easier brain entry, long half-life, high bioavailability, low cardiac toxicity, low onset dose, and the like.

[0008] An international application (Application Number: PCT / CN2022 / 141820) discloses a series of compounds that inhibit protein aggregation. In subsequent research and development, in order to improve the solubility and stability of the drug and seek suitable crystals that are easy to store and have long-term product stability, the present inventors conducted a comprehensive study of the crystal forms and salts of the above-mentioned compounds.

[0009] Summary of the Invention

[0010] All contents involved in international application PCT / CN2022 / 141820 are added to the present invention by reference.

[0011] The present invention aims to provide a compound of formula (I) or a crystalline form and salt thereof, wherein the structure of formula (I) is as follows:

[0012] in:

[0013] X is selected from O, S and NR a ;

[0014] Y is selected from CR b and N;

[0015] Ring A is selected from a benzene ring and a pyridine ring;

[0016] Ring B is selected from a benzene ring, a pyridine ring, a pyridazine ring, a pyrimidine ring and a pyrazine ring;

[0017] The C ring is selected from

[0018] W is selected from O, NR c and CR d R e ;

[0019] R1 is absent or selected from fluorine, chlorine, bromine, iodine and C 1-6 alkyl;

[0020] R2 is selected from C 1-6 Alkyl, C 2-6 Alkenyl, -C 1-4 Alkylene-OC 1-4 Alkyl and -C 1-4 Alkylene-NR a R b ;

[0021] R3 represents absence or is selected from fluorine, chlorine, bromine, iodine, cyano and C 1-6 alkyl;

[0022] R a and R b Each independently selected from H and C 1-6 alkyl;

[0023] R c Selected from H, cyano, C 1-6 Alkyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, -SO2R f and 1-C 1-6 Alkyl-4-piperidinyl;

[0024] R d and R e Each independently selected from H, fluorine, chlorine, bromine, iodine, hydroxyl, cyano, -NR a R b 、C 1-6 Alkyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl and 1-C 1-6 Alkyl-4-piperidinyl;

[0025] Rf is selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.

[0026] It will be understood by those skilled in the art that in the compound of formula (I), the C ring is connected to the ring carbon atom of the B ring through its ring nitrogen atom;

[0027] In some embodiments, X is O and Y is CR b In some embodiments, X is S and Y is CR b In some embodiments, X is NR a , Y is CR b ; In some embodiments, X is S and Y is N;

[0028] In some embodiments, X is O and Y is CH; in some embodiments, X is S and Y is CH; in some embodiments, X is S and Y is CCH3; in some embodiments, X is S and Y is N; in some embodiments, X is NH and Y is CH; in some embodiments, X is NCH3 and Y is CH;

[0029] In some embodiments, Ring A is a benzene ring;

[0030] In some embodiments, Ring B is selected from a benzene ring and a pyridine ring; in some embodiments, Ring B is a benzene ring; in some embodiments, Ring B is a pyridine ring;

[0031] In some embodiments, the C ring is In some embodiments, the C ring is selected from In some embodiments, the C ring is

[0032] In some embodiments, the C ring is selected from

[0033] In some embodiments, the C ring is In some embodiments, the C ring is selected from In some embodiments, the C ring is

[0034] In some embodiments, the C ring is selected from

[0035] In some embodiments, the C ring is In some embodiments, the C ring is selected from In some embodiments, the C ring is

[0036] In some embodiments, the C ring is selected from

[0037] In some embodiments, the C ring is

[0038] In some embodiments, the C ring is

[0039] In some embodiments, the C ring is

[0040] In some embodiments, the C ring is

[0041] In some embodiments, R1 represents absence or is selected from fluorine, chlorine, bromine, iodine, methyl, ethyl, n-propyl and isopropyl; In some embodiments, R1 represents absence or is selected from fluorine, chlorine, methyl, ethyl, n-propyl and isopropyl; In some embodiments, R1 represents absence or is selected from fluorine, methyl;

[0042] In some embodiments, R2 is selected from C 4-6 Alkyl, C 4-6 Alkenyl, -C 1-3 Alkylene-OC 1-3 Alkyl and -C 1-3 Alkylene-NR a R b In some embodiments, R2 is selected from C 4-6 Alkyl and C 4-6 In some embodiments, R2 is C 4-6 alkyl;

[0043] In some embodiments, R2 is selected from n-butyl, isopentyl, -CH2CH2OCH3, -CH2OCH2CH3, -CH2CH2OCH2CH3, -CH2CH2N(CH3)2, -CH2CHCHCH3, -CHCHCH2CH3, and -CH2CHC(CH3)2;

[0044] In some embodiments, R3 represents absence or is selected from fluorine, chlorine, bromine, iodine, cyano, methyl, ethyl, n-propyl and isopropyl; In some embodiments, R3 represents absence or is selected from fluorine, chlorine, cyano, methyl, ethyl, n-propyl and isopropyl; In some embodiments, R3 represents absence or is selected from fluorine, methyl;

[0045] In some embodiments, Rc is selected from H, cyano, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, phenyl, -SO2R f and 1-C 1-3 Alkyl-4-piperidinyl; in some embodiments, Rc is selected from H, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, phenyl, methylsulfonyl, cyclopropylsulfonyl, and 1-methyl-4-piperidinyl; in some embodiments, R c It is a methyl group;

[0046] In some embodiments, R d and R e Each independently selected from H, fluorine, chlorine, hydroxyl, cyano, -NR a R b , methyl, ethyl, n-propyl, isopropyl, cyclopropyl, phenyl and 1-C 1-3 Alkyl-4-piperidinyl; in some embodiments, R d and R e are each independently selected from H, fluoro, -N(CH3)2, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, phenyl, and 1-methyl-4-piperidinyl; in some embodiments, R d and R e Each independently selected from H, fluorine, -N(CH3)2 and methyl;

[0047] In some embodiments, R f is selected from methyl, ethyl, n-propyl, isopropyl and cyclopropyl; in some embodiments, R f is selected from methyl and cyclopropyl;

[0048] In some embodiments, R a and R b are each independently selected from H, methyl, ethyl, n-propyl, and isopropyl; in some embodiments, R a and R b are each independently selected from H and methyl;

[0049] In some embodiments, for In some embodiments, Preferably

[0050] In some embodiments, for In some embodiments, Preferably

[0051] Wherein, the salt of the compound of general formula (I) or its stereoisomer is an acid salt, and the acid in the acid salt is an inorganic acid or an organic acid. Preferably, the inorganic acid is selected from hydrochloric acid, phosphoric acid, sulfuric acid, nitric acid or hydrobromic acid; the organic acid is selected from fumaric acid, 2,5-dihydroxybenzoic acid, 1-hydroxy-2-naphthoic acid, acetic acid, dichloroacetic acid, trichloroacetic acid, acetohydroxamic acid, adipic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, benzoic acid, 4-acetamidobenzoic acid, 4-aminobenzoic acid, capric acid, hexanoic acid, caprylic acid, cinnamic acid, citric acid, cyclohexanesulfamic acid, camphorsulfonic acid, aspartic acid, camphoric acid, gluconic acid, glucuronic acid, glutamic acid, isoascorbic acid, lactic acid, malic acid, mandelic acid, pyroglutamic acid, tartaric acid, dodecyl sulfuric acid, dibenzoyltartaric acid, ethane-1 , 2-disulfonic acid, ethanesulfonic acid, formic acid, galactosonic acid, gentisic acid, glutaric acid, 2-ketoglutaric acid, glycolic acid, hippuric acid, isethionic acid, lactobionic acid, ascorbic acid, aspartic acid, lauric acid, camphoric acid, maleic acid, malonic acid, methanesulfonic acid, 1,5-naphthalenedisulfonic acid, naphthalene-2-sulfonic acid, niacin, oleic acid, orotic acid, oxalic acid, palmitic acid, pamoic acid, propionic acid, salicylic acid, 4-aminosalicylic acid, sebacic acid, stearic acid, succinic acid, thiocyanic acid, pamoic acid, formic acid, undecylenic acid, trifluoroacetic acid, benzenesulfonic acid, p-toluenesulfonic acid, or L-malic acid;

[0052] In a further preferred embodiment of the present invention, the compound represented by general formula (I) or its stereoisomer is further represented by general formula (Ia) or general formula (Ib):

[0053] In a further preferred embodiment of the present invention, the compound represented by general formula (I) or its stereoisomer is further represented by general formula (II):

[0054] wherein R1, R2, R3 and W are as defined in formula (I);

[0055] In some embodiments, Selected from In some embodiments, the C ring is

[0056] In some embodiments, Selected from

[0057] In some embodiments, R1 represents absence or is selected from fluorine, chlorine, bromine, iodine, methyl, ethyl, n-propyl and isopropyl; in some embodiments, R1 represents absence or is selected from fluorine, chlorine, methyl, ethyl, n-propyl and isopropyl; in some embodiments, R1 represents absence or is selected from fluorine, methyl;

[0058] In some embodiments, R2 is selected from C 4-6 Alkyl, C 4-6 Alkenyl, -C 1-3 Alkylene-OC 1-3 Alkyl and -C 1-3 Alkylene-NR a R b In some embodiments, R2 is selected from C 4-6 Alkyl and C 4-6 In some embodiments, R2 is C 4-6 alkyl;

[0059] In some embodiments, R2 is selected from n-butyl, isopentyl, -CH2CH2OCH3, -CH2OCH2CH3, -CH2CH2OCH2CH3, -CH2CH2N(CH3)2, -CH2CHCHCH3, -CHCHCH2CH3, and -CH2CHC(CH3)2. In some embodiments, R2 is selected from n-butyl, -CH2CH2OCH3, and -CH2CHC(CH3)2;

[0060] In some embodiments, R3 represents absence or is selected from fluorine, chlorine, bromine, iodine, cyano, methyl, ethyl, n-propyl, isopropyl; In some embodiments, R3 represents absence or is selected from fluorine, chlorine, cyano, methyl, ethyl, n-propyl, isopropyl; In some embodiments, R3 represents absence or is selected from fluorine, methyl;

[0061] In some embodiments, R c Selected from H, cyano, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, phenyl, -SO2R f and 1-C 1-3 Alkyl-4-piperidinyl; in some embodiments, R c is selected from H, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, phenyl, methylsulfonyl, cyclopropylsulfonyl, and 1-methyl-4-piperidinyl; in some embodiments, R c It is a methyl group;

[0062] In some embodiments, R d and R e Each independently selected from H, fluorine, chlorine, hydroxyl, cyano, -NR a R b , methyl, ethyl, n-propyl, isopropyl, cyclopropyl, phenyl and 1-C 1-3 Alkyl-4-piperidinyl; in some embodiments, R d and R eare each independently selected from H, fluoro, -N(CH3)2, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, phenyl, and 1-methyl-4-piperidinyl; in some embodiments, R d and R e Each independently selected from H, fluorine, -N(CH3)2 and methyl;

[0063] In some embodiments, R f is selected from methyl, ethyl, n-propyl, isopropyl and cyclopropyl; in some embodiments, R f is selected from methyl and cyclopropyl;

[0064] In some embodiments, R a and R b are each independently selected from H, methyl, ethyl, n-propyl, and isopropyl; in some embodiments, R a and R b are each independently selected from H and methyl;

[0065] In a further preferred embodiment of the present invention, the compound represented by general formula (II) or its stereoisomer is further represented by general formula (IIa) or general formula (IIb):

[0066] In some embodiments of Formula (I) or Formula (II), the compound of the present invention is selected from:

[0067] In a further preferred embodiment of the present invention, the salts of the above general formula and specific compounds or their stereoisomers are acid salts selected from the group consisting of hydrochloride, phosphate, sulfate, nitrate, hydrobromide, fumarate, 2,5-dihydroxybenzoate, 1-hydroxy-2-naphthoate, acetate, dichloroacetate, trichloroacetate, acetohydroxamate, adipate, benzenesulfonate, 4-chlorobenzenesulfonate, benzoate, 4-acetamidobenzoate, 4-aminobenzoate, decanoate, hexanoate, octanoate, cinnamate, citrate, cyclohexanesulfamate, camphorsulfonate, aspartate, camphorate, gluconate, glucuronate, glutamate, isoascorbate, lactate, malate, mandelate, pyroglutamate salt, tartrate, lauryl sulfate, dibenzoyltartrate, ethane-1,2-disulfonate, ethanesulfonate, formate, galactonate, gentisate, glutarate, 2-ketoglutarate, glycolate, hippurate, isethionate, lactobionate, ascorbate, aspartate, laurate, camphorate, maleate, malonate, methanesulfonate, 1,5-naphthalenedisulfonate, naphthalene-2-sulfonate, nicotinate, oleate, orotate, oxalate, palmitate, pamoate, propionate, salicylate, 4-aminosalicylate, sebacate, stearate, succinate, thiocyanate, pamoate, formate, undecylenate, trifluoroacetate, benzenesulfonate, p-toluenesulfonate, or L-malate;

[0068] In a preferred embodiment of the present invention, the ratio of the basic portion of the compound of general formula I or its stereoisomer to the hydrogen proton ionized by the acid is 1:1; preferably, the ratio of the hydrogen proton to the monobasic acid radical is 1:1; the ratio of the hydrogen proton to the dibasic acid radical is 2:1; the ratio of the hydrogen proton to the tribasic acid radical is 3:1; the ratio of the hydrogen proton to the tetrabasic acid radical is 4:1;

[0069] In a preferred embodiment of the present invention, the ratio of the basic portion of the compound of formula II or its stereoisomer to the hydrogen proton ionized by the acid is 1:1; preferably, the ratio of the hydrogen proton to the monobasic acid radical is 1:1; the ratio of the hydrogen proton to the dibasic acid radical is 2:1; the ratio of the hydrogen proton to the tribasic acid radical is 3:1; the ratio of the hydrogen proton to the tetrabasic acid radical is 4:1;

[0070] In a preferred embodiment of the present invention, a compound 1 is provided: a crystalline form and salt of N-(1-(1H-indol-3-yl)hexane-2-yl)-6-(4-methylpiperazin-1-yl)benzo[b]thiophene-2-carboxamide, the structural formula of the compound is as follows:

[0071] In a preferred embodiment of the present invention, the X-ray powder diffraction pattern of the crystalline form α of compound 1 is 5.91±0.2°, 8.86±0.2°, 10.17±0.2°, 10.46±0.2°, 10.79±0.2°, 12.08±0.2°, 13.18±0.2°, 14.70±0.2°, 15.23±0.2° at 2θ. , 16.40±0.2°, 17.82±0.2°, 18.55±0.2°, 20.29±0.2°, 20.44±0.2°, 21.96±0.2°, 22.18±0.2°, 23.47±0.2°, 23.80±0.2°, 25.73±0.2°, 27.12±0.2°, 28.53 ...

[0072] Preferably, the X-ray powder diffraction pattern of Form α of Compound 1 has characteristic peaks at any 2-5 or more, or 3-5 or more, or 3-6 or more, or 3-8 or more, or 5-8 or more, or 6-8 or more, of 5.91±0.2°, 10.46±0.2°, 10.79±0.2°, 12.08±0.2°, 15.23±0.2°, 17.82±0.2°, 20.29±0.2°, 20.44±0.2°, 21.96±0.2°, 22.18±0.2°, 23.80±0.2°, and 25.73±0.2°, more preferably any 6, 7, 8 or 9 or more of them have characteristic peaks;

[0073] Optionally, the invention further comprises a characteristic peak at at least one of 2θ of 8.86±0.2°, 10.17±0.2°, 13.18±0.2°, 14.70±0.2°, 16.40±0.2°, 18.55±0.2°, 23.47±0.2°, 27.12±0.2°, and 28.53±0.2°, preferably comprising 2, 3, 4 or 5 or more characteristic peaks;

[0074] More preferably, the X-ray powder diffraction pattern of the crystalline form α of Compound 1 optionally has characteristic peaks at the following positions at 2θ:

[0075] 5.91±0.2°, 10.46±0.2°, 10.79±0.2°,

[0076] Or 12.08±0.2°, 15.23±0.2°, 17.82±0.2°,

[0077] Or 20.29±0.2°, 20.44±0.2°, 21.96±0.2°,

[0078] Or 22.18±0.2°, 23.80±0.2°, 25.73±0.2°,

[0079] Or 5.91±0.2°, 10.46±0.2°, 10.79±0.2°, 12.08±0.2°,

[0080] Or 10.46±0.2°, 12.08±0.2°, 15.23±0.2°, 17.82±0.2°,

[0081] Or 10.79±0.2°, 22.18±0.2°, 23.80±0.2°, 25.73±0.2°,

[0082] or 5.91±0.2°, 8.86±0.2°, 10.46±0.2°, 10.79±0.2°, 12.08±0.2°,

[0083] Or 10.17±0.2°, 10.46±0.2°, 12.08±0.2°, 15.23±0.2°, 17.82±0.2°,

[0084] Or 10.79±0.2°, 13.18±0.2°, 22.18±0.2°, 23.80±0.2°, 25.73±0.2°,

[0085] Or 18.86±0.2°, 21.96±0.2°, 22.18±0.2°, 23.80±0.2°, 25.73±0.2°,

[0086] or 5.91±0.2°, 8.86±0.2°, 10.46±0.2°, 10.79±0.2°, 12.08±0.2°, 15.23±0.2°,

[0087] Or at 13.18±0.2°, 15.23±0.2°, 17.82±0.2°, 20.29±0.2°, 20.44±0.2°, 21.96±0.2°,

[0088] or 8.86±0.2°, 20.44±0.2°, 21.96±0.2°, 22.18±0.2°, 23.80±0.2°, 25.73±0.2°,

[0089] or 10.17±0.2°, 20.29±0.2°, 20.44±0.2°, 21.96±0.2°, 22.18±0.2°, 23.80±0.2°, or 5.91±0.2°, 8.86±0.2°, 10.46±0.2°, 10.79±0.2°, 12.08±0.2°, 15.23±0.2°, 17.82±0.2°,

[0090] or 8.86±0.2°, 10.46±0.2°, 10.79±0.2°, 12.08±0.2°, 15.23±0.2°, 17.82±0.2°, 20.29±0.2°,

[0091] or 8.86±0.2°, 20.29±0.2°, 20.44±0.2°, 21.96±0.2°, 22.18±0.2°, 23.80±0.2°, 25.73±0.2°,

[0092] or 8.86±0.2°, 17.82±0.2°, 20.29±0.2°, 20.44±0.2°, 21.96±0.2°, 22.18±0.2°, 23.80±0.2°,

[0093] Or 13.18±0.2°, 15.23±0.2°, 17.82±0.2°, 20.29±0.2°, 20.44±0.2°, 21.96±0.2°, 22.18±0.2°,

[0094] or 5.91±0.2°, 10.46±0.2°, 10.79±0.2°, 12.08±0.2°, 15.23±0.2°, 17.82±0.2°, 20.29±0.2°, 20.44±0.2°,

[0095] or 10.79±0.2°, 12.08±0.2°, 15.23±0.2°, 17.82±0.2°, 20.29±0.2°, 20.44±0.2°, 21.96±0.2°, 22.18±0.2°,

[0096] or 8.86±0.2°, 12.08±0.2°, 15.23±0.2°, 17.82±0.2°, 20.29±0.2°, 20.44±0.2°, 21.96±0.2°, 22.18±0.2°,

[0097] or 5.91±0.2°, 10.46±0.2°, 10.79±0.2°, 12.08±0.2°, 15.23±0.2°, 17.82±0.2°, 22.18±0.2°, 23.80±0.2°, 25.73±0.2°,

[0098] or 5.91±0.2°, 10.46±0.2°, 10.79±0.2°, 12.08±0.2°, 15.23±0.2°, 20.29±0.2°, 22.18±0.2°, 23.80±0.2°, 25.73±0.2°,

[0099] or 5.91±0.2°, 10.46±0.2°, 10.79±0.2°, 12.08±0.2°, 15.23±0.2°, 20.29±0.2°, 20.44±0.2°, 23.80±0.2°, 25.73±0.2°,

[0100] or 8.86±0.2°, 10.17±0.2°, 17.82±0.2°, 20.29±0.2°, 20.44±0.2°, 21.96±0.2°, 22.18±0.2°, 23.80±0.2°, 25.73±0.2°,

[0101] or 5.91±0.2°, 10.46±0.2°, 10.79±0.2°, 12.08±0.2°, 15.23±0.2°, 17.82±0.2°, 20.29±0.2°, 20.44±0.2°, 21.96±0.2°, 22.18±0.2°,

[0102] or 10.46±0.2°, 10.79±0.2°, 12.08±0.2°, 15.23±0.2°, 17.82±0.2°, 20.29±0.2°, 20.44±0.2°, 21.96±0.2°, 22.18±0.2°, 23.80±0.2°,

[0103] or 10.79±0.2°, 12.08±0.2°, 15.23±0.2°, 17.82±0.2°, 20.29±0.2°, 20.44±0.2°, 21.96±0.2°, 22.18±0.2°, 23.80±0.2°, 25.73±0.2°,

[0104] or 5.91±0.2°, 8.86±0.2°, 10.46±0.2°, 10.79±0.2°, 12.08±0.2°, 15.23±0.2°, 17.82±0.2°, 20.29±0.2°, 20.44±0.2°, 21.96±0.2°,

[0105] or 5.91±0.2°, 10.46±0.2°, 10.79±0.2°, 12.08±0.2°, 15.23±0.2°, 17.82±0.2°, 20.29±0.2°, 20.44±0.2°, 21.96±0.2°, 22.18±0.2°, 23.80±0.2°,

[0106] or 10.46±0.2°, 10.79±0.2°, 12.08±0.2°, 15.23±0.2°, 17.82±0.2°, 20.29±0.2°, 20.44±0.2°, 21.96±0.2°, 22.18±0.2°, 23.80±0.2°, 25.73±0.2°,

[0107] or 8.86±0.2°, 10.79±0.2°, 12.08±0.2°, 15.23±0.2°, 17.82±0.2°, 20.29±0.2°, 20.44±0.2°, 21.96±0.2°, 22.18±0.2°, 23.80±0.2°, 25.73±0.2°,

[0108] or 8.86±0.2°, 10.17±0.2°, 10.79±0.2°, 12.08±0.2°, 15.23±0.2°, 17.82±0.2°, 20.29±0.2°, 20.44±0.2°, 21.96±0.2°, 22.18±0.2°, 23.80±0.2°,

[0109] or 8.86±0.2°, 15.91±0.2°, 10.46±0.2°, 10.79±0.2°, 12.08±0.2°, 15.23±0.2°, 17.82±0.2°, 20.29±0.2°, 20.44±0.2°, 21.96±0.2°, 22.18±0.2°, 23.80±0.2°, 25.73±0.2°,

[0110] or 8.86±0.2°, 15.91±0.2°, 10.46±0.2°, 10.79±0.2°, 12.08±0.2°, 15.23±0.2°, 17.82±0.2°, 20.29±0.2°, 20.44±0.2°, 21.96±0.2°, 22.18±0.2°, 23.80±0.2°, 25.73±0.2°, 28.53±0.2°,

[0111] In a further preferred embodiment of the present invention, the X-ray powder diffraction pattern of Form α of Compound 1 is substantially the same as the peak at the diffraction angle (2θ) shown in FIG1 , and the X-ray powder diffraction data of Form α of Compound 1 is shown in Table 1;

[0112] Table 1

[0113] In a further preferred embodiment of the present invention, the DSC curve of Form α of Compound 1 shows an endothermic peak with an onset temperature of 178.5°C and a peak value of approximately 183.3°C, which is the melting point of Form α; the TGA curve shows that there is almost no weight loss in the range of room temperature to 100°C, indicating that Form α of Compound 1 is an anhydrous crystal.

[0114] In a preferred embodiment of the present invention, a crystalline form and salt of compound 42: (S)-N-(1-(1H-indol-3-yl)hexane-2-yl)-6-(4-methylpiperazin-1-yl)benzo[b]thiophene-2-carboxamide are provided. The structural formula of the compound is as follows:

[0115] In a preferred embodiment of the present invention, compound 42 exists as an amorphous form, and its X-ray powder diffraction pattern has no characteristic peaks, and its X-ray powder diffraction pattern is shown in FIG2 ;

[0116] In a preferred embodiment of the present invention, the free base of compound 42 does not contain any solvent;

[0117] In a preferred embodiment of the present invention, the X-ray powder diffraction pattern of Form A of Compound 42 at 2θ is 5.12±0.2°, 6.66±0.2°, 7.58±0.2°, 9.18±0.2°, 10.28±0.2°, 13.32±0.2°, 15.20±0.2°, 15.60±0.2°, 17.16±0.2°, 17.44±0.2°, 18.42±0.2°, 18.74±0.2° , 19.74±0.2°, 20.74±0.2°, 21.36±0.2°, 21.72±0.2°, 22.92±0.2°, 26.28±0.2°, 27.46±0.2°, or more than 2-5 of them, or more than 3-5 of them, or more than 3-6 of them, or more than 3-8 of them, or more than 5-8 of them, or more than 6-8 of them have characteristic peaks, more preferably any 6, 7, 8 or 9 of them have characteristic peaks;

[0118] Preferably, the X-ray powder diffraction pattern of Form A of Compound 42 has characteristic peaks at any 2-5 or more, or 3-5 or more, or 3-6 or more, or 3-8 or more, or 5-8 or more, or 6-8 or more, of 5.12±0.2°, 6.66±0.2°, 7.58±0.2°, 13.32±0.2°, 15.20±0.2°, 15.60±0.2°, 17.16±0.2°, 18.42±0.2°, 19.74±0.2°, 20.74±0.2°, and 22.92±0.2°, more preferably any 6, 7, 8, or 9 or more of them have characteristic peaks;

[0119] Optionally, the invention further comprises a characteristic peak at at least one of 9.18±0.2°, 10.28±0.2°, 17.44±0.2°, 18.74±0.2°, 21.36±0.2°, 21.72±0.2°, 26.28±0.2°, and 27.46±0.2°, preferably comprising 2, 3, 4 or 5 or more characteristic peaks;

[0120] More preferably, the X-ray powder diffraction pattern of Form A of Compound 42 optionally has characteristic peaks at the following positions in 2θ:

[0121] 5.12±0.2°, 6.66±0.2°, 7.58±0.2°,

[0122] Or 13.32±0.2°, 15.20±0.2°, 15.60±0.2°,

[0123] Or 17.16±0.2°, 18.42±0.2°, 19.74±0.2°,

[0124] Or 19.74±0.2°, 20.74±0.2°, 22.92±0.2°,

[0125] Or 5.12±0.2°, 6.66±0.2°, 7.58±0.2°, 13.32±0.2°,

[0126] Or 15.20±0.2°, 15.60±0.2°, 17.16±0.2°, 18.42±0.2°,

[0127] Or 18.42±0.2°, 19.74±0.2°, 20.74±0.2°, 22.92±0.2°,

[0128] Or 6.66±0.2°, 7.58±0.2°, 13.32±0.2°, 15.20±0.2°,

[0129] Or 5.12±0.2°, 6.66±0.2°, 7.58±0.2°, 13.32±0.2°, 15.20±0.2°,

[0130] Or 7.58±0.2°, 13.32±0.2°, 15.20±0.2°, 15.60±0.2°, 17.16±0.2°,

[0131] Or 13.32±0.2°, 15.20±0.2°, 15.60±0.2°, 17.16±0.2°, 18.42±0.2°,

[0132] Or 17.16±0.2°, 18.42±0.2°, 19.74±0.2°, 20.74±0.2°, 22.92±0.2°,

[0133] Or 5.12±0.2°, 6.66±0.2°, 7.58±0.2°, 13.32±0.2°, 15.20±0.2°, 15.60±0.2°,

[0134] Or 6.66±0.2°, 7.58±0.2°, 13.32±0.2°, 15.20±0.2°, 15.60±0.2°, 17.16±0.2°,

[0135] Or 7.58±0.2°, 13.32±0.2°, 15.20±0.2°, 15.60±0.2°, 17.16±0.2°, 18.42±0.2°,

[0136] Or 15.60±0.2°, 17.16±0.2°, 18.42±0.2°, 19.74±0.2°, 20.74±0.2°, 22.92±0.2°,

[0137] Or 5.12±0.2°, 6.66±0.2°, 7.58±0.2°, 9.18±0.2°, 13.32±0.2°, 15.20±0.2°, 15.60±0.2°,

[0138] Or 6.66±0.2°, 7.58±0.2°, 9.18±0.2°, 10.28±0.2°, 13.32±0.2°, 15.20±0.2°, 15.60±0.2°,

[0139] Or 9.18±0.2°, 10.28±0.2°, 13.32±0.2°, 15.20±0.2°, 15.60±0.2°, 17.44±0.2°, 18.74±0.2°,

[0140] Or 5.12±0.2°, 6.66±0.2°, 7.58±0.2°, 13.32±0.2°, 15.20±0.2°, 15.60±0.2°, 17.16±0.2°, 18.42±0.2°,

[0141] Or 13.32±0.2°, 15.20±0.2°, 15.60±0.2°, 17.16±0.2°, 18.42±0.2°, 19.74±0.2°, 20.74±0.2°, 22.92±0.2°,

[0142] or 7.58±0.2°, 13.32±0.2°, 15.20±0.2°, 15.60±0.2°, 17.16±0.2°, 18.42±0.2°, 19.74±0.2°, 20.74±0.2°,

[0143] Or 5.12±0.2°, 6.66±0.2°, 7.58±0.2°, 9.18±0.2°, 13.32±0.2°, 15.20±0.2°, 15.60±0.2°, 17.16±0.2°,

[0144] or 5.12±0.2°, 6.66±0.2°, 7.58±0.2°, 13.32±0.2°, 15.20±0.2°, 15.60±0.2°, 17.16±0.2°, 18.42±0.2°, 19.74±0.2°,

[0145] or 6.66±0.2°, 7.58±0.2°, 13.32±0.2°, 15.20±0.2°, 15.60±0.2°, 17.16±0.2°, 18.42±0.2°, 19.74±0.2°, 20.74±0.2°,

[0146] Or 9.18±0.2°, 13.32±0.2°, 15.20±0.2°, 15.60±0.2°, 17.16±0.2°, 18.42±0.2°, 19.74±0.2°, 20.74±0.2°, 22.92±0.2°,

[0147] or 5.12±0.2°, 6.66±0.2°, 7.58±0.2°, 10.28±0.2°, 17.44±0.2°, 13.32±0.2°, 15.20±0.2°, 15.60±0.2°, 17.16±0.2°,

[0148] or 5.12±0.2°, 6.66±0.2°, 7.58±0.2°, 13.32±0.2°, 15.20±0.2°, 15.60±0.2°, 17.16±0.2°, 18.42±0.2°, 19.74±0.2°, 20.74±0.2°,

[0149] or 5.12±0.2°, 6.66±0.2°, 7.58±0.2°, 9.18±0.2°, 13.32±0.2°, 15.20±0.2°, 15.60±0.2°, 17.16±0.2°, 18.42±0.2°, 19.74±0.2°,

[0150] or 6.66±0.2°, 7.58±0.2°, 10.28±0.2°, 13.32±0.2°, 15.20±0.2°, 15.60±0.2°, 17.16±0.2°, 18.42±0.2°, 19.74±0.2°, 20.74±0.2°,

[0151] or 5.12±0.2°, 6.66±0.2°, 7.58±0.2°, 9.18±0.2°, 13.32±0.2°, 15.20±0.2°, 15.60±0.2°, 17.16±0.2°, 26.28±0.2°, 27.46±0.2°,

[0152] Or 6.66±0.2°, 7.58±0.2°, 10.28±0.2°, 13.32±0.2°, 15.20±0.2°, 15.60±0.2°, 17.44±0.2°, 18.74±0.2°, , 19.74±0.2°, 20.74±0.2°,

[0153] or 5.12±0.2°, 6.66±0.2°, 7.58±0.2°, 13.32±0.2°, 15.20±0.2°, 15.60±0.2°, 17.16±0.2°, 18.42±0.2°, 19.74±0.2°, 20.74±0.2°, 22.92±0.2°,

[0154] or 5.12±0.2°, 6.66±0.2°, 7.58±0.2°, 9.18±0.2°, 13.32±0.2°, 15.20±0.2°, 15.60±0.2°, 17.16±0.2°, 18.42±0.2°, 19.74±0.2°, 20.74±0.2°,

[0155] or 5.12±0.2°, 6.66±0.2°, 7.58±0.2°, 9.18±0.2°, 10.28±0.2°, 15.20±0.2°, 15.60±0.2°, 17.16±0.2°, 18.42±0.2°, 19.74±0.2°, 20.74±0.2°,

[0156] or 5.12±0.2°, 6.66±0.2°, 7.58±0.2°, 9.18±0.2°, 10.28±0.2°, 15.20±0.2°, 15.60±0.2°, 17.16±0.2°, 18.42±0.2°, 26.28±0.2°, 27.46±0.2°,

[0157] or 5.12±0.2°, 6.66±0.2°, 7.58±0.2°, 9.18±0.2°, 10.28±0.2°, 15.20±0.2°, 15.60±0.2°, 17.16±0.2°, 18.74±0.2°, 21.36±0.2°, 21.72±0.2°,

[0158] or 5.12±0.2°, 6.66±0.2°, 7.58±0.2°, 9.18±0.2°, 13.32±0.2°, 15.20±0.2°, 15.60±0.2°, 17.16±0.2°, 18.42±0.2°, 19.74±0.2°, 20.74±0.2°, 22.92±0.2°,

[0159] or 5.12±0.2°, 6.66±0.2°, 7.58±0.2°, 9.18±0.2°, 10.28±0.2°, 15.20±0.2°, 15.60±0.2°, 17.16±0.2°, 18.74±0.2°, 21.36±0.2°, 21.72±0.2°, 27.46±0.2°,

[0160] or 5.12±0.2°, 6.66±0.2°, 7.58±0.2°, 13.32±0.2°, 15.20±0.2°, 15.60±0.2°, 17.16±0.2°, 18.42±0.2°, 19.74±0.2°, 20.74±0.2°, 22.92±0.2°, 21.72±0.2°,

[0161] or 5.12±0.2°, 6.66±0.2°, 7.58±0.2°, 13.32±0.2°, 15.20±0.2°, 15.60±0.2°, 17.16±0.2°, 18.42±0.2°, 19.74±0.2°, 20.74±0.2°, 21.36±0.2°, 21.72±0.2°, 22.92±0.2°,

[0162] or 5.12±0.2°, 6.66±0.2°, 7.58±0.2°, 13.32±0.2°, 15.20±0.2°, 15.60±0.2°, 17.16±0.2°, 18.42±0.2°, 19.74±0.2°, 20.74±0.2°, 21.36±0.2°, 21.72±0.2°, 22.92±0.2°, 26.28±0.2°, 27.46±0.2°,

[0163] or 5.12±0.2°, 6.66±0.2°, 7.58±0.2°, 9.18±0.2°, 13.32±0.2°, 15.20±0.2°, 15.60±0.2°, 17.16±0.2°, 18.42±0.2°, 19.74±0.2°, 20.74±0.2°, 21.36±0.2°, 21.72±0.2°, 22.92±0.2°, 26.28±0.2°, 27.46±0.2°;

[0164] In a preferred embodiment of the present invention, the X-ray powder diffraction pattern of Form A of Compound 42 is substantially the same as the peak at the diffraction angle (2θ) shown in FIG3 . The X-ray powder diffraction data of Form A of Compound 42 are shown in Table 2 .

[0165] Table 2

[0166] In a preferred embodiment of the present invention, the DSC curve of Form A of Compound 42 shows an endothermic peak with an onset temperature of 158.9°C and a peak value of approximately 160.7°C, which is the melting point of Form A of Compound 42; its TGA curve shows that there is almost no weight loss in the range of room temperature to 100°C, and Form A of Compound 42 is an anhydrous crystal.

[0167] In a preferred embodiment of the present invention, the single crystal structure analysis of Form A of Compound 42 is shown in FIG9 , and its crystallographic parameters are as follows: α=101.197(4)°, β=95.939(4)°, γ=90.999(5)°, Z=2,Dx=1.255g / cm 3 ;

[0168] In a preferred embodiment of the present invention, the salt of compound 1 or compound 42 is an acid salt selected from hydrochloride, phosphate, sulfate, nitrate, hydrobromide, fumarate, 2,5-dihydroxybenzoate, 1-hydroxy-2-naphthoate, acetate, dichloroacetate, trichloroacetate, acetohydroxamate, adipate, benzenesulfonate, 4-chlorobenzenesulfonate, benzoate, 4-acetamidobenzoate, 4-aminobenzoate, decanoate, hexanoate, caprylate, cinnamate, citrate, cyclohexanesulfamate, camphorsulfonate, aspartate, camphorate, gluconate, glucuronate, glutamate, isoascorbate, lactate, malate, mandelate, pyroglutamate, tartaric acid salt, lauryl sulfate, dibenzoyl tartrate, ethane-1,2-disulfonate, ethanesulfonate, formate, galactonate, gentisate, glutarate, 2-ketoglutarate, glycolate, hippurate, isethionate, lactobionate, ascorbate, aspartate, laurate, camphorate, maleate, malonate, methanesulfonate, 1,5-naphthalenedisulfonate, naphthalene-2-sulfonate, nicotinate, oleate, orotate, oxalate, palmitate, pamoate, propionate, salicylate, 4-aminosalicylate, sebacate, stearate, succinate, thiocyanate, pamoate, formate, undecylenate, trifluoroacetate, benzenesulfonate, p-toluenesulfonate, or L-malate;

[0169] Preferably, the acid salt of compound 1 or compound 42 is selected from hydrochloride, phosphate, sulfate, nitrate, hydrobromide, fumarate, acetate, adipate, benzenesulfonate, benzoate, hexanoate, octanoate, cinnamate, citrate, aspartate, lactate, tartrate, aspartate, laurate, maleate, malonate, methanesulfonate, propionate, salicylate, formate, trifluoroacetate, benzenesulfonate;

[0170] More preferably, the acid salt of Compound 1 or Compound 42 is selected from hydrochloride, phosphate, sulfate, nitrate, hydrobromide, fumarate, benzenesulfonate, benzoate, citrate, lactate, tartrate, aspartate, laurate, maleate, malonate, methanesulfonate, benzenesulfonate;

[0171] In a further preferred embodiment of the present invention, the acid salt of Compound 1 or Compound 42 is a succinate;

[0172] In a further preferred embodiment of the present invention, the acid salt of Compound 1 or Compound 42 is a fumarate, and the salt ratio of Compound 1 or Compound 42 to fumaric acid is 1:1, 2:1 or 3:1;

[0173] In a further preferred embodiment of the present invention, the acid salt of Compound 1 or Compound 42 is a fumarate, and the stoichiometric ratio of Compound 1 or Compound 42 to fumaric acid is 2:1; in a further preferred embodiment of the present invention, the acid salt of Compound 1 or Compound 42 is a fumarate, and the stoichiometric ratio of Compound 1 or Compound 42 to fumaric acid is 1:1;

[0174] In a further preferred embodiment of the present invention, the crystalline form of the acid salt of Compound 1 or Compound 42 is an anhydrous crystalline form;

[0175] In a further preferred embodiment of the present invention, the crystalline form of the acid salt of Compound 1 or Compound 42 is a crystalline form containing water, wherein the water-containing form is a channel-containing water, wherein the channel-containing water may be a channel-saturated water or a portion of water may be contained in the channel;

[0176] In a preferred embodiment of the present invention, the X-ray powder diffraction pattern of the crystalline form I of the fumarate salt of compound 1 is 10.03±0.2°, 11.85±0.2°, 12.75±0.2°, 13.14±0.2°, 14.70±0.2°, 15.30±0.2°, 17.06±0.2°, 17.34±0.2°, 17.82±0.2°, 18.84±0.2°, 19.99±0.2°, 20.34±0.2°, 2 1.65±0.2°, 22.12±0.2°, 22.84±0.2°, 23.57±0.2°, 24.37±0.2°, 26.15±0.2°, 27.39±0.2°, 28.45±0.2°, at least 2-5 of any 1.65±0.2°, 22.12±0.2°, 22.84±0.2°, 23.57±0.2°, 24.37±0.2°, 26.15±0.2°, 27.39±0.2°, 28.45±0.2°, or at least 3 ...

[0177] Preferably, the X-ray powder diffraction pattern of the fumarate salt form I of Compound 1 has characteristic peaks at any 2-5 or more, or 3-5 or more, or 3-6 or more, or 3-8 or more, or 5-8 or more, or 6-8 or more of 2θ of 11.85±0.2°, 14.70±0.2°, 15.30±0.2°, 17.06±0.2°, 17.34±0.2°, 17.82±0.2°, 18.84±0.2°, 19.99±0.2°, 22.12±0.2°, 23.57±0.2°, and 24.37±0.2°, more preferably any 6, 7, 8 or 9 or more of them have characteristic peaks;

[0178] Optionally, the invention further comprises a characteristic peak at at least one of 2θ of 10.03±0.2°, 12.75±0.2°, 13.14±0.2°, 20.34±0.2°, 21.65±0.2°, 22.84±0.2°, 26.15±0.2°, 27.39±0.2°, and 28.45±0.2°, preferably comprising 2, 3, 4 or 5 or more characteristic peaks;

[0179] More preferably, the X-ray powder diffraction pattern of the fumarate salt form I of Compound 1 optionally has characteristic peaks at the following positions at 2θ:

[0180] 11.85±0.2°, 14.70±0.2°, 15.30±0.2°,

[0181] Or 17.06±0.2°, 17.34±0.2°, 17.82±0.2°,

[0182] Or 18.84±0.2°, 19.99±0.2°, 22.12±0.2°,

[0183] Or 22.12±0.2°, 23.57±0.2°, 24.37±0.2°,

[0184] Or 11.85±0.2°, 14.70±0.2°, 15.30±0.2°, 17.06±0.2°,

[0185] Or 15.30±0.2°, 17.06±0.2°, 17.34±0.2°, 17.82±0.2°,

[0186] Or 17.34±0.2°, 17.82±0.2°, 18.84±0.2°, 19.99±0.2°,

[0187] Or 19.99±0.2°, 22.12±0.2°, 23.57±0.2°, 24.37±0.2°,

[0188] Or 11.85±0.2°, 14.70±0.2°, 15.30±0.2°, 17.06±0.2°, 17.34±0.2°,

[0189] Or 14.70±0.2°, 15.30±0.2°, 17.06±0.2°, 17.34±0.2°, 17.82±0.2°,

[0190] Or 18.84±0.2°, 19.99±0.2°, 22.12±0.2°, 23.57±0.2°, 24.37±0.2°,

[0191] Or 17.82±0.2°, 18.84±0.2°, 19.99±0.2°, 22.12±0.2°, 23.57±0.2°,

[0192] Or 17.06±0.2°, 17.34±0.2°, 17.82±0.2°, 23.57±0.2°, 24.37±0.2°,

[0193] Or 11.85±0.2°, 14.70±0.2°, 15.30±0.2°, 17.06±0.2°, 17.34±0.2°, 17.82±0.2°,

[0194] Or 15.30±0.2°, 17.06±0.2°, 17.34±0.2°, 10.03±0.2°, 12.75±0.2°, 13.14±0.2°,

[0195] Or 17.06±0.2°, 17.34±0.2°, 17.82±0.2°, 18.84±0.2°, 13.14±0.2°, 20.34±0.2°,

[0196] Or 17.82±0.2°, 18.84±0.2°, 19.99±0.2°, 13.14±0.2°, 20.34±0.2°, 21.65±0.2°,

[0197] Or 11.85±0.2°, 14.70±0.2°, 19.99±0.2°, 13.14±0.2°, 20.34±0.2°, 21.65±0.2°,

[0198] Or 11.85±0.2°, 14.70±0.2°, 15.30±0.2°, 17.06±0.2°, 17.34±0.2°, 17.82±0.2°, 18.84±0.2°,

[0199] Or 15.30±0.2°, 17.06±0.2°, 17.34±0.2°, 17.82±0.2°, 18.84±0.2°, 19.99±0.2°, 22.12±0.2°,

[0200] Or 10.03±0.2°, 12.75±0.2°, 17.34±0.2°, 17.82±0.2°, 18.84±0.2°, 19.99±0.2°, 22.12±0.2°,

[0201] Or 10.03±0.2°, 12.75±0.2°, 17.34±0.2°, 17.82±0.2°, 18.84±0.2°, 19.99±0.2°, 28.45±0.2°,

[0202] or 10.03±0.2°, 17.06±0.2°, 17.34±0.2°, 17.82±0.2°, 18.84±0.2°, 27.39±0.2°, 28.45±0.2°,

[0203] Or 10.03±0.2°, 11.85±0.2°, 12.75±0.2°, 13.14±0.2°, 14.70±0.2°, 15.30±0.2°, 17.06±0.2°, 17.34±0.2°,

[0204] Or 1.85±0.2°, 12.75±0.2°, 13.14±0.2°, 14.70±0.2°, 15.30±0.2°, 17.06±0.2°, 17.34±0.2°, 17.82±0.2°,

[0205] or 21.65±0.2°, 22.12±0.2°, 22.84±0.2°, 23.57±0.2°, 24.37±0.2°, 26.15±0.2°, 27.39±0.2°, 28.45±0.2,

[0206] or 11.85±0.2°, 14.70±0.2°, 15.30±0.2°, 22.84±0.2°, 23.57±0.2°, 24.37±0.2°, 26.15±0.2°, 27.39±0.2°, 28.45±0.2,

[0207] or 11.85±0.2°, 14.70±0.2°, 17.06±0.2°, 17.34±0.2°, 23.57±0.2°, 24.37±0.2°, 26.15±0.2°, 27.39±0.2°, 28.45±0.2,

[0208] or 17.34±0.2°, 17.82±0.2°, 18.84±0.2°, 19.99±0.2°, 20.34±0.2°, 21.65±0.2°, 22.12±0.2°, 22.84±0.2°, 24.37±0.2°,

[0209] or 10.03±0.2°, 11.85±0.2°, 12.75±0.2°, 13.14±0.2°, 14.70±0.2°, 15.30±0.2°, 17.06±0.2°, 17.34±0.2°, 17.82±0.2°, 18.84±0.2°,

[0210] or 11.85±0.2°, 12.75±0.2°, 13.14±0.2°, 14.70±0.2°, 15.30±0.2°, 17.06±0.2°, 17.34±0.2°, 17.82±0.2°, 18.84±0.2°, 19.99±0.2°,

[0211] or 17.06±0.2°, 17.34±0.2°, 17.82±0.2°, 18.84±0.2°, 19.99±0.2°, 20.34±0.2°, 21.65±0.2°, 22.12±0.2°, 22.84±0.2°, 23.57±0.2°,

[0212] Or 11.85±0.2°, 14.70±0.2°, 15.30±0.2°, 18.84±0.2°, 19.99±0.2°, 20.34±0.2°, 21.65±0.2°, 22.12±0.2°, 22.84±0.2°, 23.57±0.2°,

[0213] or 11.85±0.2°, 14.70±0.2°, 15.30±0.2°, 17.06±0.2°, 17.34±0.2°, 17.82±0.2°, 18.84±0.2°, 19.99±0.2°, 22.12±0.2°, 23.57±0.2°, 24.37±0.2°,

[0214] or 10.03±0.2°, 14.70±0.2°, 15.30±0.2°, 17.06±0.2°, 17.34±0.2°, 17.82±0.2°, 18.84±0.2°, 19.99±0.2°, 22.12±0.2°, 23.57±0.2°, 24.37±0.2°,

[0215] or 10.03±0.2°, 12.75±0.2°, 13.14±0.2°, 17.06±0.2°, 17.34±0.2°, 17.82±0.2°, 18.84±0.2°, 19.99±0.2°, 22.12±0.2°, 23.57±0.2°, 24.37±0.2°,

[0216] or 10.03±0.2°, 12.75±0.2°, 13.14±0.2°, 17.06±0.2°, 17.34±0.2°, 17.82±0.2°, 18.84±0.2°, 19.99±0.2°, 20.34±0.2°, 22.12±0.2°, 23.57±0.2°, 24.37±0.2°,

[0217] or 10.03±0.2°, 12.75±0.2°, 13.14±0.2°, 17.06±0.2°, 17.34±0.2°, 17.82±0.2°, 18.84±0.2°, 19.99±0.2°, 20.34±0.2°, 22.12±0.2°, 23.57±0.2°, 24.37±0.2°, 28.45±0.2°,

[0218] or 10.03±0.2°, 12.75±0.2°, 13.14±0.2°, 17.06±0.2°, 17.34±0.2°, 17.82±0.2°, 18.84±0.2°, 19.99±0.2°, 20.34±0.2°, 22.12±0.2°, 23.57±0.2°, 27.39±0.2°, 28.45±0.2°,

[0219] or 10.03±0.2°, 12.75±0.2°, 13.14±0.2°, 17.06±0.2°, 17.34±0.2°, 17.82±0.2°, 18.84±0.2°, 19.99±0.2°, 20.34±0.2°, 22.12±0.2°, 23.57±0.2°, 26.15±0.2°, 27.39±0.2°, 28.45±0.2°,

[0220] or 10.03±0.2°, 12.75±0.2°, 13.14±0.2°, 17.06±0.2°, 17.34±0.2°, 17.82±0.2°, 18.84±0.2°, 19.99±0.2°, 20.34±0.2°, 21.65±0.2°, 22.12±0.2°, 23.57±0.2°, 26.15±0.2°, 27.39±0.2°, 28.45±0.2°,

[0221] or 10.03±0.2°, 12.75±0.2°, 13.14±0.2°, 17.06±0.2°, 17.34±0.2°, 17.82±0.2°, 18.84±0.2°, 19.99±0.2°, 20.34±0.2°, 21.65±0.2°, 22.12±0.2°, 23.57±0.2°, 24.37±0.2°, 26.15±0.2°, 27.39±0.2°, 28.45±0.2°,

[0222] or 10.03±0.2°, 12.75±0.2°, 13.14±0.2°, 17.06±0.2°, 17.34±0.2°, 17.82±0.2°, 18.84±0.2°, 19.99±0.2°, 20.34±0.2°, 21.65±0.2°, 22.12±0.2°, 24.37±0.2°, 23.57±0.2°, 24.37±0.2°, 26.15±0.2°, 27.39±0.2°, 28.45±0.2°;

[0223] In a further preferred embodiment of the present invention, the X-ray powder diffraction pattern of the fumarate salt form I of Compound 1 is substantially the same as the peak at the diffraction angle (2θ) shown in Figure 4, and the X-ray powder diffraction data of the fumarate salt form I of Compound 1 is shown in Table 3;

[0224] Table 3

[0225] In a preferred embodiment of the present invention, the fumarate crystalline form I of compound 1 has a DSC curve showing an endothermic peak with an onset temperature of 204.0°C and a peak value of approximately 206.5°C, which is the melting point of the fumarate crystalline form I;

[0226] In a preferred embodiment of the present invention, the fumarate salt form I of compound 1 has a weight loss of 0.5-0.8% in the range of room temperature to 100°C in TGA analysis;

[0227] In a preferred embodiment of the present invention, the fumarate salt form I of compound 1 has a weight loss of 0.6-0.7% in the range of room temperature to 100°C in TGA analysis;

[0228] In a preferred embodiment of the present invention, the TGA curve of the fumarate salt form I of compound 1 shows that the weight loss is about 0.70% in the range of room temperature to 100°C, and the fumarate salt form I of compound 1 is a hydrated crystal form.

[0229] In a preferred embodiment of the present invention, the fumarate salt of compound 42 exists as an amorphous substance, and its X-ray powder diffraction pattern has no characteristic peaks, and its X-ray powder diffraction pattern is shown in FIG5 ;

[0230] In a preferred embodiment of the present invention, the X-ray powder diffraction pattern of the crystalline form I of the fumarate salt of compound 42 is 10.10±0.2°, 11.94±0.2°, 12.78±0.2°, 14.70±0.2°, 15.38±0.2°, 17.08±0.2°, 17.28±0.2°, 17.80±0.2°, 18.92±0.2°, 20.24±0.2°, 20.76±0.2°, 22.02±0.2°, 22.74±0.2°, 23.52±0.2°, 24.42±0.2°, 28.66±0.2°, at least 2-5, or at least 3-5, or at least 3-6, or at least 3-8, or at least 5-8, or at least 6-8 have characteristic peaks, more preferably at least 6, 7, 8 or 9 of them have characteristic peaks;

[0231] Preferably, the X-ray powder diffraction pattern of the fumarate salt form I of compound 42 has characteristic peaks at any 2-5 or more, or 3-5 or more, or 3-6 or more, or 3-8 or more, or 5-8 or more, or 6-8 or more of 2θ of 14.70±0.2°, 15.38±0.2°, 17.28±0.2°, 17.80±0.2°, 18.92±0.2°, 20.24±0.2°, 22.74±0.2°, 23.52±0.2°, and 24.42±0.2°, more preferably any 6, 7, 8 or 9 or more of them have characteristic peaks;

[0232] Optionally, the invention further comprises a characteristic peak at at least one of 2θ of 10.10±0.2°, 11.94±0.2°, 12.78±0.2°, 17.08±0.2°, 20.76±0.2°, 22.02±0.2°, and 28.66±0.2°, preferably comprising 2, 3, 4 or 5 or more characteristic peaks;

[0233] More preferably, the X-ray powder diffraction pattern of the fumarate salt form I of compound 42 optionally has characteristic peaks at the following positions in 2θ:

[0234] 14.70±0.2°, 15.38±0.2°, 17.28±0.2°,

[0235] Or 17.80±0.2°, 18.92±0.2°, 20.24±0.2°,

[0236] Or 22.74±0.2°, 23.52±0.2°, 24.42±0.2°,

[0237] Or 15.38±0.2°, 17.28±0.2°, 17.80±0.2°,

[0238] Or 14.70±0.2°, 15.38±0.2°, 17.28±0.2°, 17.80±0.2°,

[0239] Or 15.38±0.2°, 17.28±0.2°, 17.80±0.2°, 18.92±0.2°,

[0240] Or 20.24±0.2°, 22.74±0.2°, 23.52±0.2°, 24.42±0.2°,

[0241] Or 18.92±0.2°, 20.24±0.2°, 22.74±0.2°, 23.52±0.2°,

[0242] Or 14.70±0.2°, 15.38±0.2°, 17.28±0.2°, 17.80±0.2°, 18.92±0.2°,

[0243] Or 15.38±0.2°, 17.28±0.2°, 17.80±0.2°, 18.92±0.2°, 20.24±0.2°,

[0244] Or 17.28±0.2°, 17.80±0.2°, 18.92±0.2°, 20.24±0.2°, 22.74±0.2°,

[0245] Or 18.92±0.2°, 20.24±0.2°, 22.74±0.2°, 23.52±0.2°, 24.42±0.2°,

[0246] Or 14.70±0.2°, 15.38±0.2°, 17.28±0.2°, 17.80±0.2°, 18.92±0.2°, 20.24±0.2°,

[0247] Or 4.70±0.2°, 10.10±0.2°, 11.94±0.2°, 12.78±0.2°, 15.38±0.2°, 17.28±0.2°,

[0248] Or 15.38±0.2°, 17.28±0.2°, 17.80±0.2°, 18.92±0.2°, 20.76±0.2°, 22.02±0.2°,

[0249] Or 10.10±0.2°, 11.94±0.2°, 20.24±0.2°, 22.74±0.2°, 23.52±0.2°, 24.42±0.2°,

[0250] Or 14.70±0.2°, 15.38±0.2°, 17.28±0.2°, 17.80±0.2°, 18.92±0.2°, 20.24±0.2°, 22.74±0.2°,

[0251] Or 15.38±0.2°, 17.28±0.2°, 17.80±0.2°, 18.92±0.2°, 20.24±0.2°, 22.74±0.2°, 23.52±0.2°,

[0252] Or 10.10±0.2°, 11.94±0.2°, 14.70±0.2°, 15.38±0.2°, 17.28±0.2°, 17.80±0.2°, 18.92±0.2°,

[0253] Or 17.28±0.2°, 17.80±0.2°, 18.92±0.2°, 20.24±0.2°, 22.74±0.2°, 23.52±0.2°, 24.42±0.2°,

[0254] Or 10.10±0.2°, 11.94±0.2°, 12.78±0.2°, 17.28±0.2°, 17.80±0.2°, 18.92±0.2°, 20.24±0.2°,

[0255] Or 14.70±0.2°, 15.38±0.2°, 17.28±0.2°, 17.80±0.2°, 18.92±0.2°, 20.24±0.2°, 22.74±0.2°, 23.52±0.2°,

[0256] Or 10.10±0.2°, 11.94±0.2°, 14.70±0.2°, 15.38±0.2°, 17.28±0.2°, 17.80±0.2°, 18.92±0.2°, 20.24±0.2°, 22.74±0.2°,

[0257] Or 10.10±0.2°, 11.94±0.2°, 14.70±0.2°, 15.38±0.2°, 17.28±0.2°, 17.80±0.2°, 18.92±0.2°, 20.24±0.2°, 22.74±0.2°,

[0258] or 12.78±0.2°, 15.38±0.2°, 17.28±0.2°, 17.08±0.2°, 18.92±0.2°, 20.76±0.2°, 22.02±0.2°, 23.52±0.2°, 24.42±0.2°,

[0259] or 14.70±0.2°, 15.38±0.2°, 17.28±0.2°, 17.80±0.2°, 18.92±0.2°, 20.24±0.2°, 22.74±0.2°, 23.52±0.2°, 24.42±0.2°, 28.66±0.2°,

[0260] or 10.10±0.2°, 15.38±0.2°, 17.28±0.2°, 17.80±0.2°, 18.92±0.2°, 20.24±0.2°, 22.74±0.2°, 23.52±0.2°, 24.42±0.2°, 28.66±0.2°,

[0261] or 10.10±0.2°, 15.38±0.2°, 17.28±0.2°, 17.80±0.2°, 18.92±0.2°, 20.76±0.2°, 22.02±0.2°, 23.52±0.2°, 24.42±0.2°, 28.66±0.2°,

[0262] or 10.10±0.2°, 12.78±0.2°, 17.08±0.2°, 17.80±0.2°, 18.92±0.2°, 20.76±0.2°, 22.02±0.2°, 23.52±0.2°, 24.42±0.2°, 28.66±0.2°,

[0263] or 10.10±0.2°, 14.70±0.2°, 15.38±0.2°, 17.80±0.2°, 18.92±0.2°, 20.76±0.2°, 22.02±0.2°, 23.52±0.2°, 24.42±0.2°, 28.66±0.2°,

[0264] or 14.70±0.2°, 15.38±0.2°, 17.28±0.2°, 17.80±0.2°, 18.92±0.2°, 20.24±0.2°, 22.74±0.2°, 20.76±0.2°, 22.02±0.2°, 23.52±0.2°, 24.42±0.2°,

[0265] or 10.10±0.2°, 11.94±0.2°, 17.28±0.2°, 17.80±0.2°, 18.92±0.2°, 20.24±0.2°, 22.74±0.2°, 20.76±0.2°, 22.02±0.2°, 23.52±0.2°, 24.42±0.2°,

[0266] or 10.10±0.2°, 11.94±0.2°, 14.70±0.2°, 15.38±0.2°, 17.28±0.2°, 18.92±0.2°, 20.24±0.2°, 22.02±0.2°, 23.52±0.2°, 24.42±0.2°, 28.66±0.2°;

[0267] In a further preferred embodiment of the present invention, the X-ray powder diffraction pattern of the fumarate salt form I of compound 42 is substantially the same as the peak at the diffraction angle (2θ) shown in Figure 6 , and the X-ray powder diffraction data of the fumarate salt form I of compound 42 are shown in Table 4;

[0268] Table 4

[0269] In a preferred embodiment of the present invention, the fumarate salt form I of compound 42 has a DSC curve showing an endothermic peak with an onset temperature of 195.4°C and a peak value of approximately 197.4°C, which is the melting point of the fumarate salt form I of compound 42; and a TGA curve showing a weight loss of approximately 0.70% in the range of room temperature to 100°C, indicating that the fumarate salt form I of compound 42 is a hydrated crystalline form.

[0270] In a preferred embodiment of the present invention, the number of water atoms in the fumarate salt form I of compound 42 is 0 to 0.5; preferably 0.3, 0.38, 0.4 or 0.5, and more preferably 0.5; the water is channel water and has no substantial effect on the crystal form;

[0271] In a preferred embodiment of the present invention, the fumarate salt form I of compound 42 contains two compound cations, one fumarate anion and half a water molecule;

[0272] In a preferred embodiment of the present invention, the single crystal structure analysis diagram of compound 42 fumarate salt form I is shown in FIG10 , and the specific crystallographic parameters are as follows: α=90°, β=100.438(6)°, γ=90°, Z=2,Dx=1.305g / cm 3 ;

[0273] In another preferred embodiment of the present invention, the single crystal structure analysis diagram of compound 42 fumarate salt form I is shown in FIG11 , and the specific crystallographic parameters are as follows: α=90°, β=100.222(2)°, γ=90°, Z = 2;

[0274] In a preferred embodiment of the present invention, the X-ray powder diffraction pattern of the crystalline form II of the fumarate salt of compound 42 is 6.22±0.2°, 9.36±0.2°, 12.50±0.2°, 13.32±0.2°, 13.74±0.2°, 14.68±0.2°, 15.34±0.2°, 16.74±0.2°, 18.32±0.2°, 18.82±0.2°, 2 0.10±0.2°, 21.38±0.2°, 22.18±0.2°, 23.12±0.2°, 24.20±0.2°, 26.20±0.2°, at least 2-5, or at least 3-5, or at least 3-6, or at least 3-8, or at least 5-8, or at least 6-8 have characteristic peaks, more preferably at least 6, 7, 8 or 9 of them have characteristic peaks;

[0275] Preferably, the X-ray powder diffraction pattern of the fumarate crystalline form II of compound 42 has characteristic peaks at any 2-5 or more, or 3-5 or more, or 3-6 or more of 2θ of 6.22±0.2°, 9.36±0.2°, 13.74±0.2°, 18.82±0.2°, 20.10±0.2°, 21.38±0.2°, and 23.12±0.2°, more preferably any 3, 4, 5 or 6 or more of them have characteristic peaks;

[0276] Optionally, the invention further comprises a characteristic peak at at least one of 2θ of 12.50±0.2°, 13.32±0.2°, 14.68±0.2°, 15.34±0.2°, 16.74±0.2°, 18.32±0.2°, 22.18±0.2°, 24.20±0.2°, and 26.20±0.2°, preferably comprising 2, 3, 4 or 5 or more characteristic peaks;

[0277] More preferably, the X-ray powder diffraction pattern of the fumarate crystalline form II of compound 42 optionally has characteristic peaks at the following positions in 2θ:

[0278] 6.22±0.2°, 9.36±0.2°, 13.74±0.2°, 18.82±0.2°,

[0279] Or 9.36±0.2°, 13.74±0.2°, 18.82±0.2°, 20.10±0.2°,

[0280] Or 13.74±0.2°, 18.82±0.2°, 20.10±0.2°, 21.38±0.2°,

[0281] Or 18.82±0.2°, 20.10±0.2°, 21.38±0.2°, 23.12±0.2°,

[0282] Or 6.22±0.2°, 9.36±0.2°, 12.50±0.2°, 13.74±0.2°, 18.82±0.2°,

[0283] Or 9.36±0.2°, 13.32±0.2°, 13.74±0.2°, 18.82±0.2°, 20.10±0.2°,

[0284] Or 13.74±0.2°, 14.68±0.2°, 18.82±0.2°, 20.10±0.2°, 21.38±0.2°,

[0285] Or 13.32±0.2°, 14.68±0.2°, 18.82±0.2°, 20.10±0.2°, 21.38±0.2°, 23.12±0.2°,

[0286] Or 6.22±0.2°, 9.36±0.2°, 13.74±0.2°, 18.82±0.2°, 20.10±0.2°, 21.38±0.2°,

[0287] Or 9.36±0.2°, 13.74±0.2°, 18.82±0.2°, 20.10±0.2°, 21.38±0.2°, 23.12±0.2°,

[0288] Or 12.50±0.2°, 13.74±0.2°, 18.82±0.2°, 20.10±0.2°, 21.38±0.2°, 23.12±0.2°,

[0289] Or 6.22±0.2°, 9.36±0.2°, 12.50±-0.2°, 13.32±0.2°, 13.74±0.2°, 18.82±0.2°, 20.10±0.2°,

[0290] Or 6.22±0.2°, 9.36±0.2°, 12.50±0.2°, 13.32±0.2°, 13.74±0.2°, 18.82±0.2°, 24.20±0.2°,

[0291] Or 6.22±0.2°, 9.36±0.2°, 18.82±0.2°, 20.10±0.2°, 21.38±0.2°, 23.12±0.2°, 24.20±0.2°,

[0292] or 6.22±0.2°, 9.36±0.2°, 13.74±0.2°, 14.68±0.2°, 18.82±0.2°, 20.10±0.2°, 21.38±0.2°, 23.12±0.2°,

[0293] Or 12.50±0.2°, 9.36±0.2°, 13.74±0.2°, 14.68±0.2°, 18.82±0.2°, 20.10±0.2°, 21.38±0.2°, 23.12±0.2°,

[0294] Or 12.50±0.2°, 9.36±0.2°, 13.74±0.2°, 14.68±0.2°, 18.82±0.2°, 20.10±0.2°, 21.38±0.2°, 26.20±0.2°,

[0295] Or 12.50±0.2°, 9.36±0.2°, 13.74±0.2°, 14.68±0.2°, 18.82±0.2°, 20.10±0.2°, 24.20±0.2°, 26.20±0.2°,

[0296] or 6.22±0.2°, 9.36±0.2°, 12.50±0.2°, 13.32±0.2°, 13.74±0.2°, 18.82±0.2°, 20.10±0.2°, 21.38±0.2°, 23.12±0.2°,

[0297] or 6.22±0.2°, 9.36±0.2°, 13.74±0.2°, 15.34±0.2°, 16.74±0.2°, 18.82±0.2°, 20.10±0.2°, 21.38±0.2°, 23.12±0.2°,

[0298] Or 6.22±0.2°, 9.36±0.2°, 13.74±0.2°, 18.82±0.2°, 20.10±0.2°, 21.38±0.2°, 22.18±0.2°, , 23.12±0.2°, 24.20±0.2°,

[0299] or 6.22±0.2°, 9.36±0.2°, 13.74±0.2°, 18.82±0.2°, 18.32±0.2°, 20.10±0.2°, 22.18±0.2°, 21.38±0.2°, 23.12±0.2°,

[0300] or 6.22±0.2°, 9.36±0.2°, 12.50±0.2°, 13.32±0.2°, 13.74±0.2°, 14.68±0.2°, 18.82±0.2°, 20.10±0.2°, 21.38±0.2°, 23.12±0.2°,

[0301] or 6.22±0.2°, 9.36±0.2°, 12.50±0.2°, 13.74±0.2°, 18.82±0.2°, 20.10±0.2°, 21.38±0.2°, 23.12±0.2°, 24.20±0.2°, 26.20±0.2°,

[0302] or 6.22±0.2°, 9.36±0.2°, 13.74±0.2°, 14.68±0.2°, 15.34±0.2°, 16.74±0.2°, 18.82±0.2°, 20.10±0.2°, 21.38±0.2°, 23.12±0.2°,

[0303] or 6.22±0.2°, 9.36±0.2°, 13.74±0.2°, 18.82±0.2°, 20.10±0.2°, 21.38±0.2°, 22.18±0.2°, 23.12±0.2°, 24.20±0.2°, 26.20±0.2°,

[0304] or 6.22±0.2°, 9.36±0.2°, 12.50±0.2°, 13.32±0.2°, 13.74±0.2°, 14.68±0.2°, 15.34±0.2°, 18.82±0.2°, 20.10±0.2°, 21.38±0.2°, 23.12±0.2°,

[0305] or 6.22±0.2°, 9.36±0.2°, 13.32±0.2°, 13.74±0.2°, 14.68±0.2°, 15.34±0.2°, 16.74±0.2°, 18.82±0.2°, 20.10±0.2°, 21.38±0.2°, 23.12±0.2°,

[0306] or 6.22±0.2°, 9.36±0.2°, 13.74±0.2°, 16.74±0.2°, 18.32±0.2°, 18.82±0.2°, 20.10±0.2°, 21.38±0.2°, 22.18±0.2°, 23.12±0.2°, 24.20±0.2°,

[0307] or 6.22±0.2°, 9.36±0.2°, 12.50±0.2°, 13.32±0.2°, 13.74±0.2°, 14.68±0.2°, 15.34±0.2°, 16.74±0.2°, 18.82±0.2°, 20.10±0.2°, 21.38±0.2°, 23.12±0.2°,

[0308] or 6.22±0.2°, 9.36±0.2°, 13.32±0.2°, 13.74±0.2°, 14.68±0.2°, 15.34±0.2°, 16.74±0.2°, 18.32±0.2°, 18.82±0.2°, 20.10±0.2°, 21.38±0.2°, 23.12±0.2°,

[0309] or 6.22±0.2°, 9.36±0.2°, 13.74±0.2°, 14.68±0.2°, 15.34±0.2°, 16.74±0.2°, 18.32±0.2°, 18.82±0.2°, 20.10±0.2°, 21.38±0.2°, 22.18±0.2°, 23.12±0.2°,

[0310] or 6.22±0.2°, 9.36±0.2°, 13.74±0.2°, 15.34±0.2°, 16.74±0.2°, 18.32±0.2°, 18.82±0.2°, 20.10±0.2°, 21.38±0.2°, 22.18±0.2°, 23.12±0.2°, 24.20±0.2°,

[0311] or 6.22±0.2°, 9.36±0.2°, 13.74±0.2°, 18.82±0.2°, 20.10±0.2°, 21.38±0.2°, 23.12±0.2°, 12.50±0.2°, 13.32±0.2°, 14.68±0.2°, 15.34±0.2°, 16.74±0.2°, 18.32±0.2°, 22.18±0.2°, 24.20±0.2°, 26.20±0.2°;

[0312] In a further preferred embodiment of the present invention, the X-ray powder diffraction pattern of the fumarate crystalline form II of compound 42 is substantially the same as the peak at the diffraction angle (2θ) shown in FIG7 , and the X-ray powder diffraction data of the fumarate crystalline form II of compound 42 are shown in Table 5;

[0313] Table 5

[0314] In a preferred embodiment of the present invention, the fumarate form II of compound 42 has a DSC curve showing endothermic peaks with peak values ​​of approximately 131°C and 197.4°C, respectively; its TGA curve shows that the weight loss is approximately 1.5% in the range of room temperature to 120°C, and the fumarate form II of compound 42 is a hydrated form.

[0315] In a preferred embodiment of the present invention, the X-ray powder diffraction pattern of the crystalline form III of the fumarate salt of compound 42 at 2θ is 3.42±0.2°, 4.72±0.2°, 5.72±0.2°, 6.30±0.2°, 8.38±0.2°, 8.60±0.2°, 9.48±0.2°, 10.32±0.2°, 11.56±0.2°, 13.72±0.2°, 14.36±0.2°, 15.18±0.2°, 17.16±0.2°, 18. 02±0.2°, 18.66±0.2°, 19.56±0.2°, 20.06±0.2°, 20.80±0.2°, 21.62±0.2°, 22.04±0.2°, 22.56±0.2°, 25.76±0.2°, or more than 2-5 of any 0.02±0.2°, 18.66±0.2°, 19.56±0.2°, 20.06±0.2°, 20.80±0.2°, 21.62±0.2°, 22.04±0.2°, 22.56±0.2°, 25.76±0.2°, or more than 3 ...

[0316] Preferably, the X-ray powder diffraction pattern of the fumarate salt form III of compound 42 has characteristic peaks at any 2-5 or more, or 3-5 or more, or 3-6 or more, or 3-8 or more, or 5-8 or more, or 6-8 or more of 2θ of 4.72±0.2°, 6.30±0.2°, 9.48±0.2°, 10.32±0.2°, 13.72±0.2°, 14.36±0.2°, 17.16±0.2°, 19.56±0.2°, 20.06±0.2°, and 20.80±0.2°, more preferably any 6, 7, 8 or 9 or more of them have characteristic peaks;

[0317] Optionally, the invention further comprises at least one characteristic peak among 2θ of 3.42±0.2°, 5.72±0.2°, 8.38±0.2°, 8.60±0.2°, 11.56±0.2°, 15.18±0.2°, 18.02±0.2°, 18.66±0.2°, 21.62±0.2°, 22.04±0.2°, 22.56±0.2°, and 25.76±0.2°, preferably comprising 2, 3, 4 or 5 or more characteristic peaks;

[0318] More preferably, the X-ray powder diffraction pattern of the fumarate crystalline form III of compound 42 optionally has characteristic peaks at the following positions at 2θ:

[0319] 4.72±0.2°, 6.30±0.2°, 9.48±0.2°, 10.32±0.2°,

[0320] Or 13.72±0.2°, 14.36±0.2°, 17.16±0.2°, 19.56±0.2°,

[0321] Or 4.72±0.2°, 6.30±0.2°, 20.06±0.2°, 20.80±0.2°,

[0322] Or 9.48±0.2°, 10.32±0.2°, 14.36±0.2°, 19.56±0.2°,

[0323] Or 6.30±0.2°, 14.36±0.2°, 19.56±0.2°, 20.06±0.2°,

[0324] Or 4.72±0.2°, 6.30±0.2°, 9.48±0.2°, 10.32±0.2°, 13.72±0.2°,

[0325] Or 6.30±0.2°, 9.48±0.2°, 10.32±0.2°, 13.72±0.2°, 14.36±0.2°,

[0326] Or 14.36±0.2°, 17.16±0.2°, 19.56±0.2°, 20.06±0.2°, 20.80±0.2°,

[0327] Or 3.42±0.2°, 4.72±0.2°, 6.30±0.2°, 9.48±0.2°, 10.32±0.2°,

[0328] Or 13.72±0.2°, 14.36±0.2°, 17.16±0.2°, 18.66±0.2°, 21.62±0.2°,

[0329] Or 4.72±0.2°, 6.30±0.2°, 9.48±0.2°, 10.32±0.2°, 13.72±0.2°, 14.36±0.2°,

[0330] Or 6.30±0.2°, 9.48±0.2°, 10.32±0.2°, 13.72±0.2°, 14.36±0.2°, 17.16±0.2°,

[0331] or 9.48±0.2°, 10.32±0.2°, 13.72±0.2°, 14.36±0.2°, 17.16±0.2°, 19.56±0.2°, 20.06±0.2°,

[0332] Or 3.42±0.2°, 4.72±0.2°, 5.72±0.2°, 6.30±0.2°, 9.48±0.2°, 10.32±0.2°, 13.72±0.2°,

[0333] or 14.36±0.2°, 17.16±0.2°, 19.56±0.2°, 20.06±0.2°, 2, 22.04±0.2°, 22.56±0.2°, 25.76±0.2°,

[0334] Or 8.38±0.2°, 8.60±0.2°, 9.48±0.2°, 10.32±0.2°, 11.56±0.2°, 13.72±0.2°, 15.18±0.2°,

[0335] Or 8.38±0.2°, 8.60±0.2°, 13.72±0.2°, 14.36±0.2°, 17.16±0.2°, 19.56±0.2°, 20.06±0.2°, 20.80±0.2°,

[0336] or 4.72±0.2°, 6.30±0.2°, 9.48±0.2°, 10.32±0.2°, 13.72±0.2°, 14.36±0.2°, 17.16±0.2°, 19.56±0.2°,

[0337] or 6.30±0.2°, 9.48±0.2°, 10.32±0.2°, 13.72±0.2°, 14.36±0.2°, 17.16±0.2°, 19.56±0.2°, 20.06±0.2°,

[0338] or 9.48±0.2°, 10.32±0.2°, 13.72±0.2°, 14.36±0.2°, 17.16±0.2°, 19.56±0.2°, 20.06±0.2°, 20.80±0.2°,

[0339] Or 3.42±0.2°, 8.38±0.2°, 8.60±0.2°, 13.72±0.2°, 14.36±0.2°, 17.16±0.2°, 19.56±0.2°, 20.06±0.2°, 20.80±0.2°,

[0340] or 4.72±0.2°, 5.72±0.2°, 6.30±0.2°, 9.48±0.2°, 10.32±0.2°, 13.72±0.2°, 14.36±0.2°, 17.16±0.2°, 19.56±0.2°,

[0341] or 6.30±0.2°, 8.38±0.2°, 9.48±0.2°, 10.32±0.2°, 13.72±0.2°, 14.36±0.2°, 17.16±0.2°, 19.56±0.2°, 20.06±0.2°,

[0342] or 9.48±0.2°, 10.32±0.2°, 11.56±0.2°, 13.72±0.2°, 14.36±0.2°, 17.16±0.2°, 19.56±0.2°, 20.06±0.2°, 20.80±0.2°,

[0343] or 3.42±0.2°, 5.72±0.2°, 8.38±0.2°, 8.60±0.2°, 13.72±0.2°, 14.36±0.2°, 17.16±0.2°, 19.56±0.2°, 20.06±0.2°, 20.80±0.2°,

[0344] or 4.72±0.2°, 6.30±0.2°, 9.48±0.2°, 10.32±0.2°, 13.72±0.2°, 14.36±0.2°, 17.16±0.2°, 18.02±0.2°, 18.66±0.2°, 19.56±0.2°,

[0345] Or 6.30±0.2°, 8.38±0.2°, 8.60±0.2°, 9.48±0.2°, 10.32±0.2°, 13.72±0.2°, 14.36±0.2°, 17.16±0.2°, 19.56±0.2°, 20.06±0.2°,

[0346] or 3.42±0.2°, 5.72±0.2°, 8.38±0.2°, 9.48±0.2°, 10.32±0.2°, 13.72±0.2°, 14.36±0.2°, 17.16±0.2°, 19.56±0.2°, 20.06±0.2°, 20.80±0.2°, 22.56±0.2°, 25.76±0.2°,

[0347] or 8.38±0.2°, 8.60±0.2°, 13.72±0.2°, 14.36±0.2°, 17.16±0.2°, 19.56±0.2°, 20.06±0.2°, 20.80±0.2°, 21.62±0.2°, 22.04±0.2°, 22.56±0.2°, 25.76±0.2°,

[0348] or 4.72±0.2°, 6.30±0.2°, 8.60±0.2°, 9.48±0.2°, 10.32±0.2°, 11.56±0.2°, 13.72±0.2°, 14.36±0.2°, 15.18±0.2°, 17.16±0.2°, 19.56±0.2, 21.62±0.2°, 22.04±0.2°,

[0349] or 3.42±0.2°, 5.72±0.2°, 6.30±0.2°, 8.38±0.2°, 9.48±0.2°, 10.32±0.2°, 13.72±0.2°, 14.36±0.2°, 17.16±0.2°, 18.66±0.2°, 19.56±0.2°, 20.06±0.2°, 21.62±0.2°, 22.04±0.2°,

[0350] or 9.48±0.2°, 10.32±0.2°, 13.72±0.2°, 14.36±0.2°, 17.16±0.2°, 18.66±0.2°, 19.56±0.2°, 20.06±0.2°, 20.80±0.2°, 21.62±0.2°, 22.04±0.2°,

[0351] or 3.42±0.2°, 4.72±0.2°, 6.30±0.2°, 9.48±0.2°, 10.32±0.2°, 13.72±0.2°, 14.36±0.2°, 17.16±0.2°, 19.56±0.2°, 20.06±0.2°, 20.80±0.2°, 21.62±0.2°, 22.04±0.2°, 22.56±0.2°, 25.76±0.2°,

[0352] or 4.72±0.2°, 5.72±0.2°, 6.30±0.2°, 8.38±0.2°, 8.60±0.2°, 9.48±0.2°, 10.32±0.2°, 13.72±0.2°, 14.36±0.2°, 15.18±0.2°, 17.16±0.2°, 18.02±0.2°, 19.56±0.2°, 20.06±0.2°, 20.80±0.2°,

[0353] or 3.42±0.2°, 4.72±0.2°, 5.72±0.2°, 6.30±0.2°, 8.38±0.2°, 9.48±0.2°, 10.32±0.2°, 13.72±0.2°, 14.36±0.2°, 17.16±0.2°, 18.66±0.2°, 19.56±0.2°, 20.06±0.2°, 20.80±0.2°, 21.62±0.2°, 22.04±0.2°,

[0354] or 4.72±0.2°, 5.72±0.2°, 6.30±0.2°, 8.38±0.2°, 8.60±0.2°, 9.48±0.2°, 10.32±0.2°, 11.56±0.2°, 13.72±0.2°, 14.36±0.2°, 15.18±0.2°, 17.16±0.2°, 18.02±0.2°, 18.66±0.2°, 19.56±0.2°, 20.06±0.2°, 20.80±0.2°,

[0355] or 4.72±0.2°, 6.30±0.2°, 9.48±0.2°, 10.32±0.2°, 13.72±0.2°, 14.36±0.2°, 17.16±0.2°, 19.56±0.2°, 20.06±0.2°, 20.80±0.2°, 3.42±0.2°, 5.72±0.2°, 8.38±0.2°, 8.60±0.2°, 11.56±0.2°, 15.18±0.2°, 18.02±0.2°, 18.66±0.2°, 21.62±0.2°, 22.04±0.2°, 22.56±0.2°, 25.76±0.2°;

[0356] In a further preferred embodiment of the present invention, the X-ray powder diffraction pattern of the fumarate crystalline form III of compound 42 is substantially the same as the peak at the diffraction angle (2θ) shown in FIG8 , and the X-ray powder diffraction data of the fumarate crystalline form III of compound 42 are shown in Table 6;

[0357] Table 6

[0358] In a preferred embodiment of the present invention, the fumarate form III of compound 42 has a DSC curve showing an endothermic peak with a peak value of approximately 135°C, which is a melting endothermic peak; its TGA curve shows that the weight loss is approximately 3.0% in the range of room temperature to 120°C, and the fumarate form III of compound 42 is a hydrated form.

[0359] In a preferred embodiment of the present invention, the X-ray powder diffraction pattern of the crystalline form I of the succinate salt of compound 42 has characteristic peaks at any 2-5 or more, or 3-5 or more, or 3-6 or more, or 3-8 or more, or 5-8 or more, or 6-8 or more of 2θ of 14.66±0.2°, 15.40±0.2°, 17.06±0.2°, 17.20±0.2°, 17.78±0.2°, 19.00±0.2°, 20.16±0.2°, 23.52±0.2°, 24.38±0.2°, and 28.62±0.2°, more preferably any 6, 7, 8 or 9 or more of them have characteristic peaks;

[0360] Preferably, the X-ray powder diffraction pattern of the crystalline form I of the succinate salt of compound 42 has characteristic peaks at any 2-5 or more, or 3-5 or more, or 3-6 or more of 2θ of 11.92±0.2°, 12.72±0.2°, 21.14±0.2°, 21.92±0.2°, 22.72±0.2°, 27.64±0.2°, and 29.36±0.2°, more preferably any 3, 4, 5 or 6 or more of them;

[0361] Optionally, the invention further comprises a characteristic peak at at least one of 2θ of 10.07±0.2°, 20.68±0.2°, 21.40±0.2°, 25.10±0.2°, 26.34±0.2°, 28.34±0.2°, and 30.66±0.2°, preferably comprising 2, 3, 4 or 5 or more characteristic peaks;

[0362] More preferably, the X-ray powder diffraction pattern of the crystalline form I of the succinate salt of compound 42 optionally has characteristic peaks at the following positions at 2θ:

[0363] 14.66±0.2°, 17.78±0.2°, 19.00±0.2°, 23.52±0.2°,

[0364] Or 17.20±0.2°, 17.78±0.2°, 19.00±0.2°, 23.52±0.2°,

[0365] Or 14.66±0.2°, 15.40±0.2°, 17.20±0.2°, 19.00±0.2°,

[0366] Or 15.40±0.2°, 17.78±0.2°, 19.00±0.2°, 23.52±0.2°,

[0367] Or 14.66±0.2°, 19.00±0.2°, 20.16±0.2°, 23.52±0.2°,

[0368] Or 14.66±0.2°, 17.20±0.2°, 17.78±0.2°, 19.00±0.2°, 23.52±0.2°,

[0369] Or 15.40±0.2°, 17.20±0.2°, 17.78±0.2°, 19.00±0.2°, 23.52±0.2°,

[0370] Or 14.66±0.2°, 15.40±0.2°, 17.20±0.2°, 19.00±0.2°, 23.52±0.2°,

[0371] Or 15.40±0.2°, 17.78±0.2°, 19.00±0.2°, 20.16±0.2°, 23.52±0.2°,

[0372] Or 14.66±0.2°, 19.00±0.2°, 20.16±0.2°, 23.52±0.2°, 28.62±0.2°,

[0373] Or 14.66±0.2°, 17.20±0.2°, 17.78±0.2°, 19.00±0.2°, 23.52±0.2°, 24.38±0.2°,

[0374] Or 15.40±0.2°, 17.20±0.2°, 17.78±0.2°, 19.00±0.2°, 20.16±0.2°, 23.52±0.2°,

[0375] Or 14.66±0.2°, 15.40±0.2°, 17.20±0.2°, 19.00±0.2°, 23.52±0.2°, 28.62±0.2°,

[0376] Or 15.40±0.2°, 17.78±0.2°, 19.00±0.2°, 20.16±0.2°, 23.52±0.2°, 24.38±0.2°,

[0377] Or 11.92±0.2°, 12.72±0.2°, 17.78±0.2°, 19.00±0.2°, 23.52±0.2°, 24.38±0.2°,

[0378] Or 14.66±0.2°, 17.20±0.2°, 17.78±0.2°, 19.00±0.2°, 20.16±0.2°, 23.52±0.2°, 28.62±0.2°,

[0379] Or 14.66±0.2°, 17.20±0.2°, 17.78±0.2°, 19.00±0.2°12.72±0.2°, 21.14±0.2°, 21.92±0.2°,

[0380] Or 11.92±0.2°, 12.72±0.2°, 14.66±0.2°, 19.00±0.2°, 20.16±0.2°, 23.52±0.2°, 28.62±0.2°,

[0381] Or 12.72±0.2°, 15.40±0.2°, 17.20±0.2°, 17.78±0.2°, 19.00±0.2°, 21.14±0.2°, 23.52±0.2°,

[0382] Or 14.66±0.2°, 15.40±0.2°, 17.20±0.2°, 19.00±0.2°, 23.52±0.2°, 28.62±0.2°, 29.36±0.2°,

[0383] Or 14.66±0.2°, 17.20±0.2°, 17.78±0.2°, 19.00±0.2°, 20.16±0.2°, 23.52±0.2°, 28.62±0.2°,

[0384] or 10.07±0.2°, 14.66±0.2°, 17.20±0.2°, 17.78±0.2°, 19.00±0.2°, 20.16±0.2°, 23.52±0.2°, 28.62±0.2°,

[0385] Or 14.66±0.2°, 15.40±0.2°, 17.20±0.2°, 19.00±0.2°, 21.40±0.2°, 23.52±0.2°, 28.62±0.2°, 29.36±0.2°,

[0386] Or 14.66±0.2°, 17.20±0.2°, 17.78±0.2°, 19.00±0.2°12.72±0.2°, 21.14±0.2°, 21.92±0.2°, 30.66±0.2°,

[0387] or 14.66±0.2°, 17.20±0.2°, 17.78±0.2°, 19.00±0.2°12.72±0.2°, 21.14±0.2°, 21.92±0.2°, 25.10±0.2°,

[0388] or 14.66±0.2°, 17.20±0.2°, 17.78±0.2°, 19.00±0.2°, 20.16±0.2°, 23.52±0.2°, 25.10±0.2°, 26.34±0.2°, 28.62±0.2°,

[0389] Or 11.92±0.2°, 12.72±0.2°, 14.66±0.2°, 15.40±0.2°, 17.20±0.2°, 19.00±0.2°, 22.72±0.2°, 27.64±0.2°, 28.34±0.2°, 30.66±0.2°,

[0390] or 14.66±0.2°, 15.40±0.2°, 17.20±0.2°, 19.00±0.2°, 21.14±0.2°, 21.92±0.2°, 22.72±0.2°, 23.52±0.2°, 25.10±0.2°, 26.34±0.2°,

[0391] or 14.66±0.2°, 15.40±0.2°, 17.20±0.2°, 19.00±0.2°, 21.14±0.2°, 21.92±0.2°, 22.72±0.2°, 23.52±0.2°, 25.10±0.2°, 26.34±0.2°, 27.64±0.2°,

[0392] or 12.72±0.2°, 14.66±0.2°, 15.40±0.2°, 17.20±0.2°, 17.78±0.2°, 19.00±0.2°, 12.72±0.2°, 21.14±0.2°, 21.92±0.2°, 25.10±0.2°, 28.34±0.2°, 30.66±0.2°,

[0393] or 10.07±0.2°, 14.66±0.2°, 15.40±0.2°, 17.06±0.2°, 17.78±0.2°, 19.00±0.2°, 20.68±0.2°, 21.40±0.2°, 21.92±0.2°, 23.52±0.2°, 26.34±0.2°, 27.64±0.2°, 29.36±0.2°, 30.66±0.2°,

[0394] or 10.07±0.2°, 11.92±0.2°, 12.72±0.2°, 14.66±0.2°, 15.40±0.2°, 17.06±0.2°, 17.20±0.2°, 17.78±0.2°, 19.00±0.2°, 20.16±0.2°, 23.52±0.2°, 24.38±0.2°, 28.62±0.2°, 29.36±0.2°,

[0395] or 10.07±0.2°, 11.92±0.2°, 12.72±0.2°, 14.66±0.2°, 15.40±0.2°, 17.06±0.2°, 17.20±0.2°, 17.78±0.2°, 19.00±0.2°, 20.16±0.2°, 23.52±0.2°, 24.38±0.2°, 28.34±0.2°, 28.62±0.2°, 29.36±0.2°,

[0396] or 10.07±0.2°, 11.92±0.2°, 12.72±0.2°, 14.66±0.2°, 15.40±0.2°, 17.06±0.2°, 17.20±0.2°, 17.78±0.2°, 19.00±0.2°, 20.16±0.2°, 23.52±0.2°, 24.38±0.2°, 26.34±0.2°, 28.34±0.2°, 28.62±0.2°, 29.36±0.2°,

[0397] or 11.92±0.2°, 12.72±0.2°, 14.66±0.2°, 15.40±0.2°, 17.06±0.2°, 17.20±0.2°, 17.78±0.2°, 19.00±0.2°, 20.16±0.2°, 23.52±0.2°, 24.38±0.2°, 26.34±0.2°, 27.64±0.2°, 28.34±0.2°, 28.62±0.2°, 29.36±0.2°,

[0398] or 14.66±0.2°, 15.40±0.2°, 17.06±0.2°, 17.20±0.2°, 17.78±0.2°, 19.00±0.2°, 20.16±0.2°, 21.14±0.2°, 21.92±0.2°, 22.72±0.2°, 23.52±0.2°, 24.38±0.2°, 26.34±0.2°, 28.62±0.2°, 28.34±0.2°, 29.36±0.2°,

[0399] or 10.07±0.2°, 11.92±0.2°, 12.72±0.2°, 14.66±0.2°, 15.40±0.2°, 17.06±0.2°, 17.20±0.2°, 17.78±0.2°, 19.00±0.2°, 20.16±0.2°, 23.52±0.2°, 24.38±0.2°, 26.34±0.2°, 27.64±0.2°, 28.34±0.2°, 28.62±0.2°, 29.36±0.2°,

[0400] or 10.07±0.2°, 11.92±0.2°, 12.72±0.2°, 14.66±0.2°, 15.40±0.2°, 17.06±0.2°, 17.20±0.2°, 17.78±0.2°, 19.00±0.2°, 20.16±0.2°, 21.92±0.2°, 23.52±0.2°, 24.38±0.2°, 25.10±0.2°, 26.34±0.2°, 28.62±0.2°, 29.36±0.2°,

[0401] or 10.07±0.2°, 11.92±0.2°, 12.72±0.2°, 14.66±0.2°, 15.40±0.2°, 17.06±0.2°, 17.20±0.2°, 17.78±0.2°, 19.00±0.2°, 20.16±0.2°, 23.52±0.2°, 24.38±0.2°, 26.34±0.2°, 27.64±0.2°, 28.34±0.2°, 28.62±0.2°, 29.36±0.2°, 30.66±0.2°,

[0402] or 10.07±0.2°, 11.92±0.2°, 12.72±0.2°, 14.66±0.2°, 15.40±0.2°, 17.06±0.2°, 17.20±0.2°, 17.78±0.2°, 19.00±0.2°, 20.16±0.2°, 21.14±0.2°, 23.52±0.2°, 24.38±0.2°, 26.34±0.2°, 27.64±0.2°, 22.72±0.2°, 28.34±0.2°, 28.62±0.2°, 29.36±0.2°;

[0403] In a further preferred embodiment of the present invention, the X-ray powder diffraction pattern of Form I of the succinate salt of Compound 42 is substantially the same as the peak at the diffraction angle (2θ) shown in FIG12 , and the X-ray powder diffraction data of Form I of the succinate salt of Compound 42 are shown in Table 7;

[0404] Table 7

[0405] In a preferred embodiment of the present invention, the stoichiometric ratio of compound 42 and succinate anion is 2:1;

[0406] In a preferred embodiment of the present invention, the number of water atoms in the succinate salt form I of compound 42 is 0.1 to 0.5, preferably 0.2, 0.3, 0.4 or 0.5, more preferably 0.3; further preferably, the water is pipe water or crystal water or a combination of the two;

[0407] In a preferred embodiment of the present invention, the succinate salt crystal form I of compound 42 contains two compound cations, one succinate anion and 0.3 water molecules.

[0408] In a preferred embodiment of the present invention, the DSC curve of the succinate salt form I of compound 42 shows an endothermic peak with a peak value of approximately 155°C, which is the melting point of the succinate salt form I of compound 42; its TGA curve shows that the weight loss is approximately 0.83% in the range of room temperature to 100°C, and the succinate salt form I of compound 42 contains a certain amount of crystalline water or solvent.

[0409] In a preferred embodiment of the present invention, the single crystal structure analysis diagram of the succinate salt form I of compound 42 is shown in FIG13 , and the specific crystallographic parameters are as follows: β=99.883(2)°, Z = 2;

[0410] In a preferred embodiment of the present invention, the compounds represented by general formula (I) or (II) of the present invention may exist in more than one solid form, that is, they may exist in one crystalline form, an amorphous form, a polymorphic form, or optionally a mixture of two or more thereof;

[0411] In a preferred embodiment of the present invention, the compound of the present invention or a crystal form or salt thereof is prepared according to a general method for preparing a crystal form or salt;

[0412] In a preferred embodiment of the present invention, the acid salt crystals of the compound of the present invention may be solvates or anhydrates, i.e., wherein the solvent molecules form part of the crystal structure. The solvent forming the solvate may be water. In this case, the solvate is generally referred to as a hydrate. Furthermore, the water in the hydrate is pipe water or crystal water or a combination of the two. The solvate may be formed from one or more solvents selected from acetonitrile, methanol, ethanol, isopropanol, acetone, tetrahydrofuran, dichloromethane, ethyl acetate, toluene, dioxane, isopropyl ether, isopropyl acetate or methyl tert-butyl ether, preferably one or more selected from methanol, ethanol, isopropanol, acetonitrile, toluene, isopropyl ether, ethyl acetate or isopropyl acetate. The exact amount of the solvate generally depends on a variety of conditions.

[0413] The present invention also provides a pharmaceutical composition comprising one or more of the crystalline forms, salts or amorphous forms of the compound represented by the above-mentioned general formula (I) or (II) or its stereoisomers;

[0414] The present invention also provides a pharmaceutical composition comprising one or more of the crystalline forms, salts, or amorphous forms of Compound 1 or Compound 42 of the present invention;

[0415] The present invention also provides a method for treating or preventing neurodegenerative diseases characterized by protein aggregation, such as Alzheimer's disease, Parkinson's disease, frontotemporal dementia, Lewy body disease, Parkinson's disease dementia, multiple system atrophy, amyotrophic lateral sclerosis, Huntington's disease and cancer, comprising a crystalline form, salt or amorphous form of the compound represented by the above-mentioned general formula (I) or (II) of the present invention or its stereoisomer.

[0416] The present invention also provides a use of a crystalline form, salt or amorphous form of Compound 1 or Compound 42 of the present invention in treating or preventing neurodegenerative diseases characterized by protein aggregation, such as Alzheimer's disease, Parkinson's disease, frontotemporal dementia, Lewy body disease, Parkinson's disease dementia, multiple system atrophy, amyotrophic lateral sclerosis, Huntington's disease and cancer.

[0417] The compound represented by general formula (I) or (II) or its crystalline form, salt or amorphous form provided by the present invention has the advantages of high stability, high inhibition rate of inhibiting α-synuclein aggregation, low cardiac toxicity, etc., and can be better used in clinical practice. BRIEF DESCRIPTION OF THE DRAWINGS

[0418] Figure 1 is an X-ray powder diffraction pattern of Compound 1 Form α, wherein the abscissa is the angle 2θ (°) and the ordinate is the intensity (CPS);

[0419] Figure 2 is an X-ray powder diffraction pattern of an amorphous form of compound 42, wherein the abscissa is the angle 2θ (°) and the ordinate is the intensity (CPS);

[0420] Figure 3 is an X-ray powder diffraction pattern of Compound 42 Form A, wherein the abscissa is the angle 2θ (°) and the ordinate is the intensity (CPS);

[0421] Figure 4 is an X-ray powder diffraction pattern of the fumarate salt form I of Compound 1, wherein the abscissa is the angle 2θ (°) and the ordinate is the intensity (CPS);

[0422] FIG5 is an X-ray powder diffraction pattern of the amorphous fumarate of compound 42, wherein the abscissa is the angle 2θ (°) and the ordinate is the intensity (CPS);

[0423] Figure 6 is an X-ray powder diffraction pattern of the fumarate salt form I of compound 42, wherein the abscissa is the angle 2θ (°) and the ordinate is the intensity (CPS);

[0424] Figure 7 is an X-ray powder diffraction pattern of the fumarate salt form II of compound 42, wherein the abscissa is the angle 2θ (°) and the ordinate is the intensity (CPS);

[0425] FIG8 is an X-ray powder diffraction pattern of the fumarate salt form III of compound 42, wherein the abscissa is the angle 2θ (°) and the ordinate is the intensity (CPS);

[0426] FIG9 is an ORTEP (single crystal structure analysis) diagram of Compound 42 Form A;

[0427] FIG10 is an ORTEP (single crystal structure analysis) diagram of Form I of the fumarate salt of Compound 42 in Example 25;

[0428] FIG11 is an ORTEP (single crystal structure analysis) diagram of Form I of the fumarate salt of Compound 42 in Example 26;

[0429] Figure 12 is an X-ray powder diffraction pattern of the succinate salt form I of compound 42, wherein the abscissa is the angle 2θ (°) and the ordinate is the intensity (CPS);

[0430] FIG13 is an ORTEP (single crystal structure analysis) diagram of Form I of the succinate salt of Compound 42. DETAILED DESCRIPTION

[0431] The present invention is further illustrated by way of examples, but the invention is not limited to the scope of the examples. Experimental procedures in the following examples, where specific conditions are not specified, were performed according to conventional methods and conditions, or according to the commercial product specifications. Furthermore, those skilled in the art will recognize that the following synthetic reactions and schemes can be modified to obtain the compounds of the present invention by selecting appropriate starting materials and reagents.

[0432] The Examples and Biological Examples use the following abbreviations:

[0433] Xantphos:4,5-bis(diphenylphosphino)-9,9-dimethylxanthene

[0434] HATU:2-(7-Azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate

[0435] DIEA:N,N-diisopropylethylamine

[0436] DMF:N,N-dimethylformamide

[0437] MeOH: methanol

[0438] PE: Petroleum ether

[0439] EA: ethyl acetate

[0440] DCM: dichloromethane

[0441] LCMS: Liquid chromatography-mass spectrometry

[0442] DMSO: dimethyl sulfoxide

[0443] DMSO-d6: deuterated dimethyl sulfoxide

[0444] Chloroform-d: deuterated chloroform

[0445] Methanol-d4: deuterated methanol

[0446] SFC: Supercritical Fluid Chromatography

[0447] TLC: Thin layer chromatography

[0448] HPLC: high performance liquid chromatography.

[0449] In the preparative HPLC purification method of the embodiment, the chromatographic column is: Xbridge Prep C18 column OBD (10 μm, 19×250 mm); the mobile phase is: 0.1% ammonia solution / acetonitrile.

[0450] Before further describing the present invention, it should be understood that the present invention is not limited to the specific embodiments described, as these may, of course, vary. It should also be understood that the terminology used herein is for the purpose of describing specific embodiments only and is not intended to be limiting, as the scope of the present invention is limited only by the appended claims.

[0451] Unless otherwise indicated, all technical and scientific terms used herein have the same meanings as those generally understood by one of ordinary skill in the art to which this invention belongs. All patents, applications, published applications, and other publications cited herein are incorporated by reference in their entirety. To the extent that definitions in this section are contrary to or inconsistent with definitions listed in patents, applications, and other publications incorporated by reference herein, the definitions in this section shall prevail over the definitions incorporated by reference herein.

[0452] As used herein and in the appended claims, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise. It should also be noted that the claims may be drafted to exclude any optional elements. Likewise, this description should serve as a precondition for using such exclusive terminology, such as "only," "only," and the like, in connection with reciting claim elements, or for using a "negative" limitation.

[0453] As used herein, the terms "comprising," "including," and "including" are used in their open, non-limiting sense.

[0454] To provide a more concise description, the term "about" is not used before some quantitative expressions in this article. It should be understood that regardless of whether the term "about" is explicitly used, each content in this article represents an actual given numerical value, and it also represents an approximate value of a given numerical value that can be reasonably inferred based on ordinary skills in the art, including equivalents and approximate values ​​of such given numerical values ​​due to experimental and / or measurement conditions. Whenever the yield is expressed as a percentage, such yield represents the ratio of the mass of the entity used to calculate the yield to the maximum amount that can be obtained for the same entity under specific stoichiometric conditions. Concentrations in percentage form represent mass ratios unless otherwise stated.

[0455] Unless otherwise specified, all technical and scientific terms used herein have the same meanings as commonly understood by one of ordinary skill in the art to which this invention belongs. Although any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, preferred methods and materials are described below. All publications mentioned herein are incorporated by reference to disclose and describe the methods and / or materials in connection with the cited publications.

[0456] definition

[0457] As used herein, the term "alkyl" refers to a saturated monovalent hydrocarbon group having a straight or branched chain. For example, "C 1- "6-alkyl" refers to an alkyl group having 1 to 6 carbon atoms in the chain. Examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, and isohexyl.

[0458] As used herein, the term "alkylene" refers to a divalent group obtained by removing a hydrogen atom from an alkyl group as defined above. An alkylene group may be a straight chain or branched divalent alkyl group. For example, "C 1-4 "Alkylene" refers to an alkylene group having 1 to 4 carbon atoms. Examples of alkylene groups include, but are not limited to, methylene (i.e., -CH2-), ethylene (i.e., -CH2CH2- or -CH(CH3)-), and propylene (i.e., -CH2-CH2-CH2-, -CH(CH2CH3)- or -CH2CH(CH3)-).

[0459] As used herein, the term "alkenyl" refers to a straight or branched chain hydrocarbon group containing one or more double bonds, typically 2 to 20 carbon atoms in length. For example, "C 2-6 "Alkenyl" contains 2 to 6 carbon atoms. Examples of alkenyl include, but are not limited to, ethenyl, propenyl, butenyl, 2-methyl-2-buten-1-yl, and the like.

[0460] As used herein, the term "substituted" means that a specified group or moiety bears one or more substituents. The term "unsubstituted" means that a specified group bears no substituents. The term "optionally substituted" means that a specified group is unsubstituted or substituted with one or more substituents. When the term "substituted" is used to describe a structural system, substitutions can occur at any valency-allowed position on the system.

[0461] As used herein, the term "independently" means that when more than one substituent is selected from a number of possible substituents, the substituents may be the same or different. That is, each substituent is individually selected from the entire group of possible substituents recited.

[0462] When used herein for a class of substituents, the nomenclature "C i-j "(wherein j>i) represents an embodiment of the present invention that independently realizes each number of carbon atoms from i to j (including i and j). For example, the term C 1-3 independently represents an embodiment having one carbon atom (C1), an embodiment having two carbon atoms (C2), and an embodiment having three carbon atoms (C3).

[0463] As used herein, a wavy line Indicates the point of attachment of a group to the rest of the molecule.

[0464] As used herein, the term "pharmaceutically acceptable salts" refers to salts of free acids or bases of the compounds described herein that are non-toxic, biologically tolerable, or biologically suitable for administration to a subject.

[0465] As used herein, the terms "treatment" or "treating" include "prophylactic" and "therapeutic" treatment.

[0466] As used herein, the term "subject" refers to a mammalian patient, such as a human, in need of treatment.

[0467] One skilled in the art will recognize that the species listed or illustrated in the definitions provided herein are not exhaustive and that other species may be selected within the scope of these defined terms.

[0468] 1. Implementation

[0469] Example 1 N-(1-(1H-indol-3-yl)hexan-2-yl)-6-(4-methylpiperazin-1-yl)benzo[b]thiophene-2-carboxamide

[0470] Step 1: 1-(1H-indol-3-yl)hexan-2-one 1b

[0471] Compound 1a (40 g, 304.9 mmol) was dissolved in 1,2-dichloroethane (2000 mL). Aluminum chloride (81.3 g, 609.8 mmol) was added at 0°C. After stirring at room temperature for 0.5 hour, valeryl chloride (44.1 g, 365.9 mmol) was added. The reaction mixture was stirred at 15°C for 14 hours. Water (300 mL) was added to the reaction mixture to quench the reaction. The mixture was extracted with ethyl acetate (300 mL × 3). The combined organic phases were washed with saturated brine (300 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain crude product 1b (71 g), which was used directly in the next step.

[0472] Step 2: 1-(1H-indol-3-yl)hexane-2-amine 1c

[0473] Compound 1b (71 g, 329.7 mmol) was dissolved in methanol (1000 mL), and ammonium acetate (77.08 g, 1000 mmol) and sodium cyanoborohydride (31.08 g, 494.6 mmol) were added at room temperature. The reaction mixture was stirred at 70°C for 5 hours. After cooling, the reaction mixture was quenched with water (300 mL) and extracted with ethyl acetate (300 mL × 3). The combined organic phases were washed with saturated brine (300 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography (PE:EA = 1:1) to obtain compound 1c (31 g, 43.5% yield).

[0474] Step 3: Ethyl 6-bromobenzo[b]thiophene-2-carboxylate 1f

[0475] Compound 1d (2.0 g, 9.85 mmol) was dissolved in acetonitrile (10 mL). Potassium carbonate (2.04 g, 14.76 mmol) and compound 1e (1.42 g, 11.82 mmol) were added at room temperature. The reaction mixture was stirred at 80°C for 1 hour. The reaction mixture was filtered to remove the potassium carbonate, and the filtrate was concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography (PE:EA = 5:1) to obtain compound 1f (2.2 g, 78.3% yield).

[0476] Step 4: 6-(4-methylpiperazine-1-yl)-1-benzothiophene-2-carboxylic acid ethyl ester 1g

[0477] Compound 1f (0.5 g, 1.753 mmol) was dissolved in 1,4-dioxane (10 mL), and 1-methylpiperazine (0.264 g, 2.63 mmol), palladium acetate (0.02 g, 0.089 mmol), Xantphos (0.047 g, 0.081 mmol), and cesium carbonate (1.713 g, 5.26 mmol) were added at room temperature. The reaction mixture was stirred at 110°C for 2 hours. After cooling, the reaction mixture was quenched by the addition of water (100 mL) and extracted with ethyl acetate (30 mL × 3). The combined organic phases were washed with saturated brine (30 mL × 2), dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography (PE:EA = 1:1) to obtain compound 1g (0.41 g, 76.8% yield).

[0478] Step 5: 6-(4-methylpiperazin-1-yl)-1-benzothiophene-2-carboxylic acid 1h

[0479] Compound 1g (0.41 g, 1.347 mmol) was dissolved in tetrahydrofuran (10 mL) and water (10 mL). Sodium hydroxide (0.16 g, 4.00 mmol) was added at room temperature, and the reaction mixture was stirred at 70°C for 1 hour. The pH of the reaction mixture was adjusted to 3-4 with dilute hydrochloric acid, resulting in the precipitation of a large amount of solid. The mixture was filtered and the solid was collected to provide compound 1h (0.32 g, 86% yield).

[0480] Step 6: N-(1-(1H-indol-3-yl)hexane-2-yl)-6-(4-methylpiperazin-1-yl)benzo[b]thiophene-2-carboxamide 1

[0481] Compound 1c (1.0 g, 4.622 mmol) was dissolved in DMF (10 mL), and compound 1h (1.40 g, 5.07 mmol), triethylamine (2.34 g, 23.1 mmol), and 1-propylphosphoric acid cyclic anhydride (2.2 g, 6.91 mmol) were added at room temperature. The reaction mixture was stirred at room temperature for 1 hour, then quenched with water (50 mL). The mixture was extracted with ethyl acetate (30 mL × 3). The combined organic phases were washed with saturated brine (30 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography (PE:EA = 1:1) to obtain compound 1 (1200 mg, 54.7% yield).

[0482] 1H NMR (400MHz, Chloroform-d) δ8.10 (s, 1H), 7.64 (dd, J = 27.7, 8.4Hz, 2H), 7.47-7. 32(m,2H),7.25(d,J=11.6Hz,3H),7.12(ddd,J=8.1,7.0,1.0Hz,1H),7.09-7.03(m ,2H),5.85(d,J=8.8Hz,1H),4.56-4.38(m,1H),3.42-3.22(m,4H),3.16-3.01(m, 2H), 2.61 (t, J = 5.0Hz, 4H), 2.37 (s, 3H), 1.66-1.28 (m, 3H), 0.87 (t, J = 7.1Hz, 3H).

[0483] MS m / z(ESI):475.5[M+H]+.

[0484] Example 2 N-[1-(1H-indol-3-yl)hexyl-2-yl]-6-(4-methylpiperazin-1-yl)thienyl[2,3-b]pyridine-2-carboxamide

[0485] Step 1: Ethyl 2-[(6-chloro-3-formylpyridin-2-yl)thioacetate 2b

[0486] 2,6-Dichloropyridine-3-carboxaldehyde 2a (800 mg, 4.60 mmol) was dissolved in dichloromethane (20 mL). Triethylamine (0.7 mL, 4.60 mmol) was added, followed by compound 1e (600 mg, 4.60 mmol). The reaction mixture was stirred at room temperature for 2 hours, and the reaction was complete. The reaction mixture was purified by silica gel column chromatography (PE:EA = 2:1) to obtain compound 2b (120 mg, 9.24% yield).

[0487] MS m / z(ESI):260.0[M+H]+ .

[0488] Step 2: Ethyl 6-chlorothienyl[2,3-b]pyridine-2-carboxylate 2c

[0489] Ethyl 2-[(6-chloro-5-formylpyridin-2-yl)mercaptoacetate 2b (120 mg, 0.5 mmol) was dissolved in DMF (2.5 mL) and potassium carbonate (60 mg, 0.5 mmol) was added. The mixture was reacted at 70°C for 3 hours, and the reaction was complete. The reaction mixture was diluted with ethyl acetate (50 mL), and the organic phase was washed with saturated brine (30 mL × 2), dried over anhydrous sodium sulfate, and concentrated to obtain a crude product which was purified by silica gel column chromatography (PE:EA = 2:1) to obtain compound 2c (88 mg, 78.8% yield).

[0490] MS m / z(ESI):242.2[M+H] + .

[0491] Step 3: 6-Chlorothipheno[2,3-b]pyridine-2-carboxylic acid 2d

[0492] Ethyl 6-chlorothiophene[2,3-b]pyridine-2-carboxylate 2c (88 mg, 0.365 mmol) was dissolved in tetrahydrofuran (10 mL), and sodium hydroxide (80 mg, 2.19 mmol) was dissolved in water (5 mL) and added to the reaction mixture. The mixture was heated to 60°C for 3 hours. After the reaction was complete, the reaction mixture was concentrated to remove tetrahydrofuran and the pH was adjusted to 6 with 1M hydrochloric acid. The precipitated solid was filtered and dried to afford compound 2d (80 mg) in a 98.2% yield.

[0493] MS m / z(ESI):214.2[M+H] + .

[0494] Step 4: 6-chloro-N-[1-(1H-indol-3-yl)hexyl-2-yl]thienyl[2,3-b]pyridine-2-carboxamide 2e

[0495] 1-(1H-Indol-3-yl)hexyl-2-amine (96 mg, 0.376 mmol) and 6-chlorothienyl[2,3-b]pyridine-2-carboxylic acid (80 mg, 0.376 mmol) were mixed in DMF (2 mL). DIEA (0.13 mL) was added, followed by HATU (143 mg, 0.376 mmol). The mixture was stirred at room temperature for 3 hours. The reaction mixture was diluted with ethyl acetate (50 mL), and the organic phase was washed with saturated brine (30 mL × 2), dried, concentrated, and purified by silica gel column chromatography (PE:EA=1:1) to give compound 2e (140 mg, yield 91%).

[0496] MS m / z(ESI):413.1[M+H] + .

[0497] Step 5: N-[1-(1H-indol-3-yl)hexyl-2-yl]-6-(4-methylpiperazin-1-yl)thienyl[2,3-b]pyridine-2-carboxamide 2

[0498] 6-Chloro-N-[1-(1H-indol-3-yl)hexyl-2-yl]thiophene[2,3-b]pyridine-2-carboxamide 2e (70 mg, 0.170 mmol) was dissolved in 1,4-dioxane (2.5 mL). 1-Methylpiperazine (0.3 mL) was added and the mixture was placed in a microwave oven. The reaction mixture was heated at 150°C for 2 hours, and the reaction was complete. The reaction mixture was concentrated, diluted with ethyl acetate (50 mL), washed with water (30 mL x 2), dried, and concentrated. The mixture was then purified by silica gel column chromatography (PE:EA = 1:1) to afford compound 2 (45 mg, 55.7% yield).

[0499] 1 H NMR(400MHz,Chloroform-d)δ:8.09(s,1H),7.78-7.72(d,J=8Hz,1H),7.70-7.64(d, J=8Hz,1H),7.42-7.35(m,2H),7.24-7.17(m,1H),7.16-7.10(m,1H),7.09-7.05(m,1H ),6.75-6.69(m,1H),5.83-5.73(m,1H),4.52-4.42(m,1H),3.75-3.65(m,4H),3.13-3 .04(m,2H),2.59-2.50(m,4H),2.36(s,3H),1.54-1.29(m,6H),0.88(t,J=7.2Hz,3H).

[0500] MS m / z(ESI):476.3[M+H] + .

[0501] Example 3 N-(1-(1H-indol-3-yl)hexan-2-yl)-6-(4-cyclopropylpiperazin-1-yl)benzo[b]thiophene-2-carboxamide

[0502] Step 1: Ethyl 6-(4-cyclopropylpiperazin-1-yl)benzo[b]thiophene-2-carboxylate 3a

[0503] Compound 1f (1000 mg, 3.5 mmol), palladium acetate (40 mg, 0.2 mmol), Xantphos (202 mg, 0.35 mmol), and cesium carbonate (3.42 g, 10.5 mmol) were added to a reaction flask. 1-Cyclopropylpiperazine (674 mg, 5.3 mmol) was dissolved in 1,4-dioxane (10 mL). Under nitrogen, stirring was initiated and the reaction was carried out at 100°C for 3 hours. After completion, the reaction was quenched with water (50 mL) and extracted with ethyl acetate (50 mL x 3). The organic layers were combined, dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column chromatography (PE:EA = 5:1) to obtain compound 3a (450 mg, 41% yield).

[0504] MS m / z(ESI):331.2[M+H] + .

[0505] Step 2: 6-(4-cyclopropylpiperazin-1-yl)benzo[b]thiophene-2-carboxylic acid 3b

[0506] Compound 3a (450 mg, 2.0 mmol) was dissolved in 5 mL of tetrahydrofuran, followed by the addition of 5 mL of methanol. Sodium hydroxide was dissolved in 3 mL of water and added to the reaction flask. Stirring was initiated and the reaction was carried out at 70°C for 1 hour. After the reaction, the solvent was dried by rotary evaporation, the solid was dissolved in water, and the pH was adjusted to 5-6 with 1 M hydrochloric acid. The filter cake obtained by filtration was dissolved in methanol (50 mL), and the solvent was evaporated to afford compound 3b (380 mg, 92% yield).

[0507] MS m / z(ESI):303.2[M+H] + .

[0508] Step 3: N-(1-(1H-indol-3-yl)hexane-2-yl)-6-(4-cyclopropylpiperazin-1-yl)benzo[b]thiophene-2-carboxamide 3

[0509] Compound 3b (308 mg, 1.1 mmol) and compound 1c (200 mg, 0.9 mmol) were added to a reaction flask, dissolved in 5 mL of DMF, and then triethylamine (467 mg, 4.6 mmol) and 1-propylphosphoric acid cyclic anhydride (441 mg, 1.4 mmol) were added. Stirring was started and the mixture was reacted at room temperature for 1 hour. After the reaction was completed, water (50 mL) was added to quench the reaction, and the mixture was extracted with ethyl acetate (50 mL × 3). The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated. After purification and isolation by preparative HPLC, compound 3 (125 mg, yield 25%) was obtained.

[0510] MS m / z(ESI):503.3[M+H] + .

[0511] Example 4 N-(1-(1H-indol-3-yl)hexan-2-yl)-6-(4-methylpiperazin-1-yl)benzo[d]thiazole-2-carboxamide

[0512] Step 1: Ethyl 6-(4-methylpiperazin-1-yl)benzo[d]thiazole-2-carboxylate 4b

[0513] Compound 4a (200 mg, 3.5 mmol), palladium acetate (40 mg, 0.2 mmol), Xantphos (202 mg, 0.35 mmol), and cesium carbonate (3.42 g, 10.5 mmol) were added to a reaction flask. 1-Methylpiperazine (674 mg, 5.3 mmol) was dissolved in 1,4-dioxane (10 mL). Under nitrogen, stirring was initiated and the reaction was carried out at 100°C for 3 hours. After completion of the reaction, water (50 mL) was added to quench the reaction. The mixture was extracted with ethyl acetate (50 mL × 3). The organic layers were combined, dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column chromatography (PE:EA = 1:1) to obtain compound 4b (180 mg, 75% yield).

[0514] MS m / z(ESI):292.2[M+H] + .

[0515] Step 2: 6-(4-Methylpiperazin-1-yl)benzo[d]thiazole-2-carboxylic acid 4c

[0516] Compound 4b (180 mg, 1.5 mmol) was dissolved in 3 mL of tetrahydrofuran, followed by the addition of 3 mL of methanol. Sodium hydroxide was dissolved in 3 mL of water and added to the reaction flask. Stirring was initiated and the reaction was carried out at 70°C for 1 hour. After the reaction, the solvent was dried by rotary evaporation, and the solid was dissolved in water. The pH was adjusted to 5-6 with 1 M hydrochloric acid and filtered. The resulting filter cake was dissolved in methanol (20 mL), and the solvent was evaporated to afford compound 4c (120 mg, 75% yield).

[0517] MS m / z(ESI):278.2[M+H] + .

[0518] Step 3: N-(1-(1H-indol-3-yl)hexane-2-yl)-6-(4-methylpiperazin-1-yl)benzo[d]thiazole-2-carboxamide 4

[0519] Compound 4c (120 mg, 1.1 mmol) and compound 1c (95 mg, 0.89 mmol) were added to a reaction flask, dissolved in 5 mL of DMF, and then triethylamine (467 mg, 4.6 mmol) and 1-propylphosphoric acid cyclic anhydride (441 mg, 1.4 mmol) were added. Stirring was started and the mixture was reacted at room temperature for 1 hour. After the reaction was completed, water (50 mL) was added to quench the reaction, and the mixture was extracted with ethyl acetate (50 mL × 3). The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated to obtain a crude product. The crude product was purified by preparative HPLC to obtain compound 4 (42 mg, yield 35%).

[0520] 1 H NMR(400MHz,Chloroform-d)δ8.06(s,1H),7.85(d,J=9.3Hz,1H),7.69(d,J=7.9Hz,1H),7.41–7.31(m,3H),7.25–7.07(m,4H),4 .47(s,1H),3.33(d,J=5.6Hz,4H),3.18–3.00(m,2H),2.62(d,J=5.2Hz,4H),2.38(s,3H),1.48–1.22(m,6H),0.92–0.82(m,3H).

[0521] MS m / z(ESI):476.5[M+H] + .

[0522] Example 5 N-(1-(1H-indol-3-yl)hexan-2-yl)-5-fluoro-6-(4-methylpiperazin-1-yl)benzo[b]thiophene-2-carboxamide

[0523] Step 1: Ethyl 5-fluoro-6-(4-methylpiperazin-1-yl)benzo[b]thiophene-2-carboxylate 5b

[0524] Compound 5a (500 mg, 1.65 mmol), palladium acetate (40 mg, 0.2 mmol), Xantphos (202 mg, 0.35 mmol), and cesium carbonate (3.42 g, 10.5 mmol) were added to a reaction flask. 1-Methylpiperazine (674 mg, 5.3 mmol) was dissolved in 1,4-dioxane (10 mL). Under nitrogen protection, stirring was initiated and the reaction was carried out at 100°C for 3 hours. After completion of the reaction, water (50 mL) was added to quench the reaction. The mixture was extracted with ethyl acetate (50 mL × 3). The organic layers were combined, dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column chromatography (PE:EA = 1:1) to obtain compound 5b (460 mg, 89% yield).

[0525] MS m / z(ESI):323.4[M+H] + .

[0526] Step 2: 5-Fluoro-6-(4-methylpiperazin-1-yl)benzo[b]thiophene-2-carboxylic acid 5c

[0527] Compound 5b (200 mg, 0.62 mmol) was dissolved in tetrahydrofuran (2 mL), followed by the addition of 2 mL of methanol. Sodium hydroxide was dissolved in water (2 mL) and added to the reaction flask. Stirring was initiated and the reaction was carried out at 70°C for 1 hour. The reaction mixture was dried by rotary evaporation, the solid was dissolved in water, and the pH was adjusted to 5-6 with 1 M hydrochloric acid. The mixture was filtered, and the resulting filter cake was dissolved in methanol (20 mL). The solvent was then evaporated to afford compound 5c (130 mg, 78% yield).

[0528] MS m / z(ESI):295.3[M+H] + .

[0529] Step 3: N-(1-(1H-indol-3-yl)hexane-2-yl)-5-fluoro-6-(4-methylpiperazin-1-yl)benzo[b]thiophene-2-carboxamide 5

[0530] Compound 5c (130 mg, 0.44 mmol) and compound 1c (100 mg, 0.5 mmol) were added to a reaction flask, and DMF (5 mL) was added to dissolve the mixture. Triethylamine (467 mg, 4.6 mmol) and 1-propylphosphoric acid cyclic anhydride (351 mg, 1.0 mmol) were then added, stirred, and reacted at room temperature for 1 hour. After the reaction, water (50 mL) was added to quench the reaction, and the mixture was extracted with ethyl acetate (50 mL × 3). The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated to obtain a crude product, which was purified by silica gel column chromatography (PE:EA = 1:1) to obtain compound 5 (25 mg, yield 35%).

[0531] MS m / z(ESI):493.5[M+H] + .

[0532] Example 6 N-(1-(1H-indol-3-yl)hexan-2-yl)-4-fluoro-6-(4-methylpiperazin-1-yl)benzo[b]thiophene-2-carboxamide

[0533] Step 1: Ethyl 4-fluoro-6-(4-methylpiperazin-1-yl)benzo[b]thiophene-2-carboxylate 6b

[0534] Compound 6a (500 mg, 1.65 mmol), palladium acetate (40 mg, 0.2 mmol), Xantphos (202 mg, 0.35 mmol), and cesium carbonate (3.42 g, 10.5 mmol) were added to a reaction flask. 1-Methylpiperazine (674 mg, 5.3 mmol) was dissolved in 1,4-dioxane (10 mL). Under nitrogen, stirring was initiated and the reaction was carried out at 100°C for 3 hours. After completion of the reaction, water (50 mL) was added to quench the reaction. The mixture was extracted with ethyl acetate (50 mL × 3). The organic layers were combined, dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column chromatography (PE:EA = 5:1) to obtain compound 6b (420 mg, 84% yield).

[0535] MS m / z(ESI):323.4[M+H] + .

[0536] Step 2: 4-Fluoro-6-(4-methylpiperazin-1-yl)benzo[b]thiophene-2-carboxylic acid 6c

[0537] Compound 6b (200 mg, 0.62 mmol) was dissolved in 2 mL of tetrahydrofuran, followed by the addition of 2 mL of methanol. Sodium hydroxide was dissolved in water (2 mL) and added to the reaction flask. Stirring was initiated and the reaction was carried out at 70°C for 1 hour. The reaction mixture was dried by rotary evaporation, the solid was dissolved in water, and the pH was adjusted to 5-6 with 1 M hydrochloric acid. The mixture was filtered, and the resulting filter cake was dissolved in methanol (20 mL). The solvent was then evaporated to afford compound 6c (150 mg, 89% yield).

[0538] MS m / z(ESI):295.3[M+H] + .

[0539] Step 3: N-(1-(1H-indol-3-yl)hexane-2-yl)-4-fluoro-6-(4-methylpiperazin-1-yl)benzo[b]thiophene-2-carboxamide 6

[0540] Compound 6c (130 mg, 0.44 mmol) and compound 1c (100 mg, 0.5 mmol) were added to a reaction flask, dissolved in 5 mL of DMF, and then triethylamine (467 mg, 4.6 mmol) and 1-propylphosphoric acid cyclic anhydride (351 mg, 1.0 mmol) were added. Stirring was started and the mixture was reacted at room temperature for 1 hour. After the reaction, water (50 mL) was added to quench the reaction, and the mixture was extracted with ethyl acetate (50 mL × 3). The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated to obtain a crude product. The crude product was purified by silica gel column chromatography (PE:EA=1:1) to obtain compound 6 (35 mg, yield 38%).

[0541] MS m / z(ESI):493.5[M+H] +.

[0542] Example 7 N-(1-(1H-indol-3-yl)hexan-2-yl)-5-(4-methylpiperazin-1-yl)benzo[b]thiophene-2-carboxamide

[0543] Step 1: Ethyl 5-(4-methylpiperazin-1-yl)benzo[b]thiophene-2-carboxylate 7b

[0544] Compound 7a (500 mg, 1.65 mmol), palladium acetate (40 mg, 0.2 mmol), Xantphos (202 mg, 0.35 mmol), and cesium carbonate (3.42 g, 10.5 mmol) were added to a reaction flask. 1-Methylpiperazine (674 mg, 5.3 mmol) was dissolved in 1,4-dioxane (10 mL). Under nitrogen, stirring was initiated and the reaction was carried out at 100°C for 3 hours. After completion of the reaction, water (50 mL) was added to quench the reaction. The mixture was extracted with ethyl acetate (50 mL × 3). The organic layers were combined, dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column chromatography (PE:EA = 5:1) to obtain compound 7b (480 mg, 94% yield).

[0545] MS m / z(ESI):305.4[M+H] + .

[0546] Step 2: 5-(4-Methylpiperazin-1-yl)benzo[b]thiophene-2-carboxylic acid 7c

[0547] Compound 7b (200 mg, 0.62 mmol) was dissolved in 2 mL of tetrahydrofuran, followed by the addition of 2 mL of methanol. Sodium hydroxide was dissolved in 2 mL of water and added to the reaction flask. Stirring was initiated and the reaction was carried out at 70°C for 1 hour. After the reaction, the solvent was dried by rotary evaporation, and the solid was dissolved in water. The pH was adjusted to 5-6 with 1 M hydrochloric acid and filtered. The resulting filter cake was dissolved in methanol (20 mL), and the solvent was evaporated to afford compound 7c (110 mg, 89% yield).

[0548] MS m / z(ESI):277.3[M+H] + .

[0549] Step 3: N-(1-(1H-indol-3-yl)hexane-2-yl)-5-(4-methylpiperazin-1-yl)benzo[b]thiophene-2-carboxamide 7

[0550] Compound 7c (121.6 mg, 0.44 mmol) and compound 1c (100 mg, 0.5 mmol) were added to a reaction flask, dissolved in 5 mL of DMF, and then triethylamine (467 mg, 4.6 mmol) and 1-propylphosphoric acid cyclic anhydride (351 mg, 1.0 mmol) were added. Stirring was started and the reaction was allowed to react at room temperature for 1 hour. After completion of the reaction, water (50 mL) was added to quench the reaction, and the mixture was extracted with ethyl acetate (50 mL × 3). The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated to obtain a crude product. The crude product was purified by silica gel column chromatography (PE:EA = 1:1) to obtain compound 7 (35 mg, yield 38%).

[0551] MS m / z(ESI):475.5[M+H] + .

[0552] Example 8 N-(1-(1H-indol-3-yl)hexan-2-yl)-6-(4-methylpiperazin-1-yl)thieno[3,2-c]pyridine-2-carboxamide

[0553] Step 1: Ethyl 6-chlorothieno[3,2-c]pyridine-2-carboxylate 8b

[0554] Compound 8a (1.0 g, 5.682 mmol) was dissolved in DMF (5 mL), followed by the addition of potassium carbonate (1.18 g, 0.853 mmol) and compound 1e (0.75 g, 6.25 mmol) at room temperature. The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was quenched with water (50 mL) and extracted with ethyl acetate (50 mL × 3). The organic phase was washed with saturated brine (50 mL × 3), dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography (PE:EA = 5:1) to obtain compound 8b (0.95 g, 70% yield).

[0555] Step 2: 6-Chlorothieno[3,2-c]pyridine-2-carboxylic acid 8c

[0556] Compound 8b (0.9 g, 3.72 mmol) was dissolved in tetrahydrofuran (5 mL) and water (5 mL). Sodium hydroxide (0.74 g, 18.62 mmol) was then added at room temperature. The reaction mixture was stirred at 70°C for 1 hour. The pH of the reaction mixture was adjusted to 3-4 with dilute hydrochloric acid, resulting in the precipitation of a large amount of solid. The mixture was filtered and the solid was collected to provide compound 8c (0.65 g, 82% yield).

[0557] Step 3: N-(1-(1H-indol-3-yl)hexan-2-yl)-6-chlorothieno[3,2-c]pyridine-2-carboxamide 8d

[0558] Compound 1c (0.3 g, 1.387 mmol) was dissolved in DMF (5 mL), followed by the addition of compound 8c (0.33 g, 0.525 mmol), triethylamine (0.70 g, 6.934 mmol), and 1-propylphosphoric acid cyclic anhydride (0.66 g, 2.08 mmol) at room temperature. The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was quenched with water (30 mL) and extracted with ethyl acetate (50 mL × 3). The organic phase was washed with saturated brine (50 mL × 3), dried over anhydrous sodium sulfate, filtered, and concentrated. Compound 8d (0.33 g, 57.76% yield) was obtained by purification via silica gel column chromatography (PE:EA = 5:1).

[0559] Step 4: N-(1-(1H-indol-3-yl)hexane-2-yl)-6-(4-methylpiperazin-1-yl)thieno[3,2-c]pyridine-2-carboxamide 8

[0560] Compound 8d (0.24 g, 2.427 mmol) and 1-methylpiperazine (0.310 g, 3.09 mmol) were reacted in a microwave reactor at 170°C for 3 hours. The reaction mixture was quenched with water (30 mL) and extracted with ethyl acetate (50 mL × 3). The organic phase was washed with saturated brine (50 mL × 3), dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography (PE:EA = 5:1) to obtain compound 8 (35 mg, 15% yield).

[0561] MS m / z(ESI):477.5[M+H] + .

[0562] Example 9 N-(1-(1H-indol-3-yl)hexan-2-yl)-4-methyl-6-(4-methylpiperazin-1-yl)thieno[3,2-c]pyridine-2-carboxamide

[0563] Step 1: Ethyl 6-chloro-4-methylthieno[3,2-c]pyridine-2-carboxylate 9b

[0564] Compound 9a (0.25 g, 5.682 mmol) was dissolved in DMF (5 mL), followed by the addition of potassium carbonate (0.27 g, 1.973 mmol) and compound 1e (0.17 g, 1.447 mmol) at room temperature. The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was quenched with water (50 mL) and extracted with ethyl acetate (50 mL × 3). The organic phase was washed with saturated brine (50 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated. After purification, it was purified by silica gel column chromatography (PE:EA = 5:1) to obtain compound 9b (0.21 g, 62% yield).

[0565] Step 2: 6-Chloro-4-methylthieno[3,2-c]pyridine-2-carboxylic acid 9c

[0566] Compound 9b (0.21 g, 0.821 mmol) was dissolved in tetrahydrofuran (5 mL) and water (5 mL), and sodium hydroxide (0.16 g, 4.106 mmol) was added at room temperature. The reaction mixture was stirred at 70°C for 1 hour. The pH of the reaction mixture was adjusted to 3-4 with dilute hydrochloric acid, resulting in the precipitation of a large amount of solid. The mixture was filtered and the solid was collected to obtain compound 9c (0.15 g, 80% yield).

[0567] Step 3: N-(1-(1H-indol-3-yl)hexan-2-yl)-6-chloro-4-methylthieno[3,2-c]pyridine-2-carboxamide 9d

[0568] Compound 1c (0.15 g, 1.387 mmol) was dissolved in DMF (5 mL), followed by the addition of compound 9c (0.33 g, 0.525 mmol), triethylamine (0.35 g, 3.467 mmol), and 1-propylphosphoric acid cyclic anhydride (0.33 g, 1.04 mmol) at room temperature. The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was quenched with water (30 mL) and extracted with ethyl acetate (30 mL × 3). The organic phase was washed with saturated brine (50 mL × 2), dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography (PE:EA = 5:1) to afford compound 9d (0.16 g, 54% yield).

[0569] Step 4: N-(1-(1H-indol-3-yl)hexane-2-yl)-4-methyl-6-(4-methylpiperazin-1-yl)thieno[3,2-c]pyridine-2-carboxamide 9

[0570] Compound 9d (0.16 g, 0.376 mmol) and 1-methylpiperazine (0.19 g, 1.878 mmol) were reacted in a microwave reactor at 180°C for 3 hours. The reaction mixture was quenched with water (30 mL) and extracted with ethyl acetate (30 mL × 3). The organic phase was washed with saturated brine (30 mL × 2), dried over anhydrous sodium sulfate, filtered, concentrated, and purified and isolated by preparative HPLC to obtain compound 9 (0.035 g, 15% yield).

[0571] MS m / z(ESI):490.5[M+H] + .

[0572] Example 10 N-(1-(1H-indol-3-yl)hexan-2-yl)-7-(4-methylpiperazin-1-yl)benzo[b]thiophene-2-carboxamide

[0573] Step 1: Ethyl 7-(4-methylpiperazin-1-yl)benzo[b]thiophene-2-carboxylate 10b

[0574] Compound 10a (500 mg, 1.65 mmol), palladium acetate (40 mg, 0.2 mmol), Xantphos (202 mg, 0.35 mmol), and cesium carbonate (3.42 g, 10.5 mmol) were added to a reaction flask. 1-Methylpiperazine (674 mg, 5.3 mmol) was dissolved in 1,4-dioxane (10 mL). Under nitrogen, stirring was initiated and the reaction was carried out at 100°C for 3 hours. The reaction mixture was quenched by adding water (50 mL) and extracted with ethyl acetate (30 mL × 3). The organic layers were combined, dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column chromatography (PE:EA = 5:1) to obtain compound 10b (380 mg, 68% yield).

[0575] MS m / z(ESI):305.4[M+H] + .

[0576] Step 2: 7-(4-Methylpiperazin-1-yl)benzo[b]thiophene-2-carboxylic acid 10c

[0577] Compound 10b (200 mg, 0.62 mmol) was dissolved in 2 mL of tetrahydrofuran, followed by the addition of 2 mL of methanol. Sodium hydroxide was dissolved in 2 mL of water and added to the reaction flask. Stirring was initiated and the reaction was carried out at 70°C for 1 hour. The reaction mixture was evaporated to dryness, and the solid was dissolved in 10 mL of water. The pH was adjusted to 5-6 with 1 M hydrochloric acid and filtered. The resulting filter cake was dissolved in 20 mL of methanol and the solvent was removed by rotary evaporation. This afforded compound 10c (110 mg, 89% yield).

[0578] MS m / z(ESI):277.3[M+H] + .

[0579] Step 3: N-(1-(1H-indol-3-yl)hexane-2-yl)-7-(4-methylpiperazin-1-yl)benzo[b]thiophene-2-carboxamide 10

[0580] Compound 10c (130 mg, 0.44 mmol) and compound 1c (100 mg, 0.5 mmol) were added to a reaction flask, dissolved in 5 mL of DMF, and then triethylamine (467 mg, 4.6 mmol) and 1-propylphosphoric acid cyclic anhydride (351 mg, 1.0 mmol) were added. Stirring was started and the mixture was reacted at room temperature for 1 hour. After the reaction was completed, water (50 mL) was added to quench the reaction, and the mixture was extracted with ethyl acetate (50 mL × 3). The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated to obtain a crude product. The crude product was purified by preparative HPLC to obtain compound 10 (35 mg, yield 38%).

[0581] MS m / z(ESI):475.5[M+H] + .

[0582] Example 11 N-(1-(1H-indol-3-yl)hexan-2-yl)-3-methyl-6-(4-methylpiperazin-1-yl)benzo[b]thiophene-2-carboxamide

[0583] Step 1: Ethyl 3-methyl-6-(4-methylpiperazin-1-yl)benzo[b]thiophene-2-carboxylate 11b

[0584] Compound 11a (0.25 g, 0.836 mmol) was dissolved in 1,4-dioxane (10 mL), followed by the addition of 1-methylpiperazine (0.167 g, 1.672 mmol), palladium acetate (9.38 mg, 0.042 mmol), Xantphos (48.35 mg, 0.084 mmol), and cesium carbonate (52.6 mmol, 17.1 mmol) at room temperature. The reaction mixture was stirred at 110°C for 3 hours under nitrogen. After cooling, the reaction mixture was quenched with water (50 mL) and extracted with ethyl acetate (50 mL × 3). The organic phase was washed with saturated brine (50 mL × 3), dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography (PE:EA = 5:1) to afford compound 11b (0.21 g, 78% yield).

[0585] Step 2: 3-Methyl-6-(4-methylpiperazin-1-yl)benzo[b]thiophene-2-carboxylic acid 11c

[0586] Compound 11b (0.21 g, 0.659 mmol) was dissolved in tetrahydrofuran (5 mL) and water (5 mL). Sodium hydroxide (0.08 g, 1.978 mmol) was then added at room temperature, and the reaction mixture was stirred at 70°C for 1 hour. The pH of the reaction mixture was adjusted to 3-4 with 1 M dilute hydrochloric acid, resulting in the precipitation of a large amount of solid. The mixture was filtered, and the solid was collected to provide compound 11c (0.17 g, 89% yield).

[0587] Step 3: N-(1-(1H-indol-3-yl)hexane-2-yl)-3-methyl-6-(4-methylpiperazin-1-yl)benzo[b]thiophene-2-carboxamide 11

[0588] Compound 1c (200 mg, 0.9 mmol) and compound 11c (295 mg, 1.0 mmol) were dissolved in 5 mL of DMF, followed by the addition of triethylamine (467 mg, 4.6 mmol) and finally 1-propylphosphoric acid cyclic anhydride (441 mg, 1.4 mmol). The mixture was stirred at room temperature for 1 hour. After completion of the reaction, 30 mL of water was added to quench the reaction, and the mixture was extracted with ethyl acetate (50 mL × 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered, concentrated, and purified by preparative HPLC to afford compound 11 (90 mg, 20% yield).

[0589] MS m / z(ESI):489.3[M+H] + .

[0590] Example 12 N-(1-(1H-indol-3-yl)hexan-2-yl)-3-methyl-6-(4-methylpiperazin-1-yl)benzo[b]thiophene-2-carboxamide

[0591] Step 1: Ethyl 6-(4-methylpiperidin-1-yl)benzo[b]thiophene-2-carboxylate 12a

[0592] Compound 1f (500 mg, 1.7 mmol) was added to a reaction flask, followed by palladium acetate (20 mg, 0.09 mmol), Xantphos (101 mg, 0.2 mmol), and cesium carbonate (1713 mg, 5.3 mmol). Finally, 4-methylpiperidine (260 mg, 2.6 mmol) and 1,4-dioxane (5 mL) were added. The temperature was raised to 100°C, and stirring was initiated under nitrogen for 3 hours. After completion, the reaction was quenched with water (50 mL), extracted with ethyl acetate (50 mL x 3), and the organic layers were combined, dried over anhydrous sodium sulfate, and concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography (PE:EA = 1:1) to obtain compound 12a (200 mg, 38% yield).

[0593] MS m / z(ESI):304.1[M+H] + .

[0594] Step 2: 6-(4-Methylpiperidin-1-yl)benzo[b]thiophene-2-carboxylic acid 12b

[0595] Compound 12a (164 mg, 0.5 mmol) was dissolved in tetrahydrofuran (3 mL), followed by methanol (3 mL). Sodium hydroxide (86 mg, 2.1 mmol) was dissolved in water (3 mL) and added to the reaction flask. Stirring was initiated and the reaction was carried out at 70°C for 1 hour. After the reaction, the solvent was dried by rotary evaporation, the solid was dissolved in water, and the pH was adjusted to a weakly acidic pH of 5-6 with 1 M hydrochloric acid. The mixture was filtered, and the filter cake was dissolved in methanol (20 mL). The solvent was then removed to afford compound 12b (140 mg, 94% yield).

[0596] MS m / z(ESI):276.3[M+H] + .

[0597] Step 3: N-(1-(1H-indol-3-yl)hexane-2-yl)-6-(4-methylpiperidin-1-yl)benzo[b]thiophene-2-carboxamide 12

[0598] Compound 1c (200 mg, 0.7 mmol) was dissolved in DMF (3 mL), followed by compound 12c (192 mg, 0.7 mmol), triethylamine (334 mg, 3.4 mmol) and 1-propylphosphoric acid cyclic anhydride (315 mg, 1.0 mmol), and the mixture was stirred and allowed to react for 1 hour. After completion of the reaction, 30 mL of water was added to quench the reaction, and the mixture was extracted with ethyl acetate (50 mL × 3). The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a crude product. The crude product was purified and isolated by preparative HPLC to obtain compound 12 (70 mg, 22% yield).

[0599] MS m / z(ESI):474.3[M+H] + .

[0600] Example 13 N-(1-(1H-indol-3-yl)hexan-2-yl)-6-(4-isopropylpiperazin-1-yl)benzo[b]thiophene-2-carboxamide

[0601] Step 1: Ethyl 6-(4-isopropylpiperazin-1-yl)benzo[b]thiophene-2-carboxylate 13a

[0602] Compound 1f (1000 mg, 3.5 mmol), palladium acetate (40 mg, 0.2 mmol), Xantphos (202 mg, 0.35 mmol), and cesium carbonate (3427 mg, 10.5 mmol) were added to a reaction flask, followed by 1-isopropylpiperazine (674 mg, 5.3 mmol) dissolved in 1,4-dioxane (10 mL). Under nitrogen protection, stirring was initiated and the reaction was carried out at 100°C for 3 hours. After completion of the reaction, water (50 mL) was added to quench the reaction, and the mixture was extracted with ethyl acetate (50 mL × 3). The organic layers were combined, dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column chromatography (PE:EA = 5:1) to obtain compound 13a (500 mg, 43% yield).

[0603] MS m / z(ESI):333.2[M+H] + .

[0604] Step 2: 6-(4-Isopropylpiperazin-1-yl)benzo[b]thiophene-2-carboxylic acid 13b

[0605] Compound 13a (650 mg, 2.0 mmol) was dissolved in tetrahydrofuran (3 mL), followed by methanol (3 mL). Sodium hydroxide was dissolved in 3 mL of water and added to the reaction flask, stirred, and reacted at 70°C for 1 hour. The reaction mixture was dried by rotary evaporation, the solid was dissolved in water (20 mL), and the pH was adjusted to 5-6 with 1 M hydrochloric acid. The mixture was filtered, and the resulting filter cake was dissolved in methanol (30 mL). The solvent was evaporated to give compound 13b (574 mg, 96% yield).

[0606] MS m / z(ESI):305.2[M+H] + .

[0607] Step 3: N-(1-(1H-indol-3-yl)hexane-2-yl)-6-(4-isopropylpiperazin-1-yl)benzo[b]thiophene-2-carboxamide 13

[0608] Compound 13b (308 mg, 1.0 mmol) and compound 1c (200 mg, 0.9 mmol) were added to a reaction flask, and DMF (5 mL) was added to dissolve the mixture. Triethylamine (467 mg, 4.6 mmol) and 1-propylphosphoric acid cyclic anhydride (441 mg, 1.4 mmol) were then added. Stirring was started and the mixture was reacted at room temperature for 1 hour. After the reaction, water (50 mL) was added to quench the reaction, and the mixture was extracted with ethyl acetate (50 mL × 3). The organic layers were combined, dried over anhydrous sodium sulfate, concentrated, and chromatographed to obtain compound 13 (110 mg, yield 23%).

[0609] MS m / z(ESI):503.3[M+H] + .

[0610] Example 14 N-(1-(1H-indol-3-yl)hexan-2-yl)-6-(4-phenylpiperazin-1-yl)benzo[b]thiophene-2-carboxamide

[0611] Step 1: Ethyl 6-(4-phenylpiperazin-1-yl)benzo[b]thiophene-2-carboxylate 14a

[0612] Compound 1f (1000 mg, 3.5 mmol), palladium acetate (40 mg, 0.2 mmol), Xantphos (202 mg, 0.3 mmol), and cesium carbonate (3427 mg, 10.5 mmol) were added to a reaction flask, followed by 1-phenylpiperazine (853 mg, 5.3 mmol). The mixture was dissolved in 1,4-dioxane (10 mL), and stirred under nitrogen atmosphere at 100°C for 3 hours. The reaction mixture was quenched with water (50 mL) and extracted with ethyl acetate (50 mL × 3). The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated to obtain a crude product, which was purified by silica gel column chromatography (PE:EA = 5:1) to obtain compound 14a (950 mg, 73.9% yield).

[0613] MS m / z(ESI):367.5[M+H] + .

[0614] Step 2: 6-(4-phenylpiperazin-1-yl)benzo[b]thiophene-2-carboxylic acid 14b

[0615] Compound 14a (950 mg, 2.6 mmol) was dissolved in tetrahydrofuran (3 mL), followed by the addition of 3 mL of methanol. Sodium hydroxide (51 g, 13.0 mmol) was dissolved in water (3 mL) and added to the reaction flask. Stirring was initiated and the reaction was carried out at 70°C for 1 hour. The reaction mixture was dried by rotary evaporation, and the solid was dissolved in water (10 mL). The pH was adjusted to 5-6 with 1 M hydrochloric acid, and the mixture was filtered. The resulting filter cake was dissolved in methanol (20 mL), and the solvent was removed by rotary evaporation to afford compound 14b (816 mg, 93% yield).

[0616] MS m / z(ESI):339.3[M+H] + .

[0617] Step 3: N-(1-(1H-indol-3-yl)hexane-2-yl)-6-(4-phenylpiperazin-1-yl)benzo[b]thiophene-2-carboxamide 14

[0618] Compound 14b (344 mg, 1.0 mmol) and compound 1c (200 mg, 0.9 mmol) were added to a reaction flask and dissolved in 5 mL of DMF. Triethylamine (467 mg, 4.6 mmol) and 1-propylphosphoric acid cyclic anhydride (441 mg, 1.4 mmol) were then added, stirred, and reacted at room temperature for 1 hour. The reaction mixture was quenched by adding 30 mL of water, extracted with ethyl acetate (50 mL × 3), separated, and the organic layers were combined, dried over anhydrous sodium sulfate, and concentrated to obtain a crude product. The crude product was purified and isolated by preparative HPLC to obtain compound 14 (128 mg, 26% yield).

[0619] MS m / z(ESI):536.3[M+H] + .

[0620] Example 15 N-(1-(1H-indol-3-yl)hexan-2-yl)-6-(4,4-difluoropiperidin-1-yl)benzo[b]thiophene-2-carboxamide

[0621] Step 1: Ethyl 6-(4,4-difluoropiperidin-1-yl)benzo[b]thiophene-2-carboxylate 15a

[0622] Compound 1f (392 mg, 1.37 mmol) and 4,4-difluoropiperidine (250 mg, 2.06 mmol) were added to a reaction flask, followed by palladium acetate (15 mg, 0.07 mmol), Xantphos (80 mg, 0.14 mmol), cesium carbonate (1345 mg, 4.13 mmol), and finally 1,4-dioxane (10 mL). Stirring was initiated under nitrogen and the reaction was carried out at 100°C for 3 hours. The reaction mixture was quenched with 30 mL of water and extracted with ethyl acetate (50 mL × 3). The layers were separated, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product, which was purified by silica gel column chromatography (PE:EA = 5:1) to obtain compound 15a (396 mg, 88% yield).

[0623] MS m / z(ESI):326[M+H] + .

[0624] Step 2: 6-(4,4-difluoropiperidin-1-yl)benzo[b]thiophene-2-carboxylic acid 15b

[0625] Compound 15a (396 mg, 1.2 mmol) was dissolved in tetrahydrofuran (3 mL) and methanol (3 mL). Sodium hydroxide (243 mg, 6.1 mmol) was dissolved in water and added to the reaction flask. Stirring was initiated and the mixture was heated to 70°C for 1 hour. The reaction mixture was rotary evaporated to remove the solvent, and the solid was dissolved in 10 mL of water. The pH was adjusted to 5-6 with 1 M hydrochloric acid, filtered, and dried to obtain compound 15b (349 mg, 96% yield).

[0626] MS m / z(ESI):298.1[M+H] + .

[0627] Step 3: N-(1-(1H-indol-3-yl)hexan-2-yl)-6-(4,4-difluoropiperidin-1-yl)benzo[b]thiophene-2-carboxamide 15

[0628] Compound 15b (227 mg, 0.76 mmol), compound 1c (150 mg, 0.69 mmol), and triethylamine (350 mg, 3.46 mmol) were added to a reaction flask and dissolved in DMF (5 mL). 1-Propylphosphonic acid cyclic anhydride (350 mg, 3.46 mmol) was then weighed and added to the reaction flask. Stirring was initiated and the reaction was allowed to proceed at room temperature for 1 hour. After the reaction, 50 mL of the organic phase was added and quenched with saturated sodium bicarbonate solution. The reaction was extracted with ethyl acetate (50 mL × 3). The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated to obtain a crude product. The crude product was purified and isolated by preparative HPLC to obtain compound 15 (124 mg, 36% yield).

[0629] MS m / z(ESI):496.3[M+H] + .

[0630] 1H NMR(400MHz,Chloroform-d)δ8.16(s,1H),7.67(d,J=7.9Hz,1H),7.61(d,J=8 .8Hz,1H),7.42(s,1H),7.37(d,J=8.0Hz,1H),7.27–7.16(m,1H),7.16–7.07( m,1H),7.10–7.01(m,2H),5.90(d,J=8.8Hz,1H),4.47(tdd,J=11.0,6.9,4.3H z,1H),3.46–3.38(m,4H),3.15–3.00(m,2H),2.19–2.05(m,4H),1.74–1.63(m, 1H),1.58–1.45(m,1H),1.45–1.38(m,1H),1.43–1.23(m,3H),0.87(t,J=7.1Hz,3H).

[0631] Example 16 N-(1-(1H-indol-3-yl)hexan-2-yl)-6-(4,4-dimethylpiperidin-1-yl)benzo[b]thiophene-2-carboxamide

[0632] Step 1: Ethyl 6-(4,4-dimethylpiperidin-1-yl)benzo[b]thiophene-2-carboxylate 16a

[0633] Compound 1f (500 mg, 1.84 mmol) and 4,4-dimethylpiperidine (313 mg, 2.76 mmol) were added to a reaction flask, followed by palladium acetate (20 mg, 0.09 mmol), Xantphos (107 mg, 0.18 mmol), cesium carbonate (1802 mg, 5.53 mmol), and finally 1,4-dioxane (10 mL). Stirring was initiated under nitrogen protection, and the temperature was raised to 100°C for 3 hours. After completion of the reaction, water (20 mL) was added to quench the reaction, and the mixture was extracted with ethyl acetate (50 mL × 3). The organic layers were combined, dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column chromatography (PE:EA = 5:1) to obtain compound 16a (479 mg, 82% yield).

[0634] MS m / z(ESI):318.1[M+H] + .

[0635] Step 2: 6-(4,4-dimethylpiperidin-1-yl)benzo[b]thiophene-2-carboxylic acid 16b

[0636] Compound 16a (479 mg, 1.5 mmol) was added to a reaction flask and dissolved in tetrahydrofuran (3 mL) and methanol (3 mL). Sodium hydroxide (301 mg, 7.05 mmol) was weighed and dissolved in water (3 mL) and then added to the reaction flask. Stirring was initiated and the mixture was reacted at 70°C for 1 hour. The reaction mixture was evaporated to remove the solvent, then dissolved in water (20 mL). The pH was adjusted to 5-6 with 1M hydrochloric acid and filtered. The filter cake was washed with water and dissolved in 20 mL of tetrahydrofuran. The solvent was evaporated to remove the solvent to provide compound 16b (424 mg, 97% yield).

[0637] MS m / z(ESI):290.2[M+H] + .

[0638] Step 3: N-(1-(1H-indol-3-yl)hexane-2-yl)-6-(4,4-dimethylpiperidin-1-yl)benzo[b]thiophene-2-carboxamide 16

[0639] Compound 16b (221 mg, 0.76 mmol) and compound 1c (150 mg, 0.69 mmol) were dissolved in DMF (10 mL). Triethylamine (350 mg, 3.47 mmol) was then added to the reaction flask. 1-Propylphosphonic acid cyclic anhydride (330 mg, 1.04 mmol) was added to the reaction flask, stirred, and reacted at room temperature for 1 hour. After the reaction, 30 mL of the organic phase was added and quenched with saturated sodium bicarbonate solution. The mixture was extracted with ethyl acetate (30 mL × 3). The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a crude product. The crude product was purified and separated by preparative HPLC to obtain compound 16 (110 mg, 33% yield).

[0640] MS m / z(ESI):488.3[M+H] + .

[0641] Example 17 7-Fluoro-N-[1-(1H-indol-3-yl)hexyl-2-yl]-6-(4-methylpiperazin-1-yl)-1-benzothiophene-2-carboxamide

[0642] Step 1: Ethyl 2-[(3-bromo-2-fluoro-6-formylphenyl)mercapto]acetate 17b

[0643] Compound 17a (806 mg, 3.65 mmol) was dissolved in dichloromethane (20 mL), and triethylamine (0.51 mL, 3.65 mmol) was added, followed by compound 1e (440 mg, 3.66 mmol). After reacting at room temperature for 3 hours, the reaction mixture was diluted with dichloromethane (50 mL), washed with water (30 mL × 3), and dried over anhydrous sodium sulfate. The crude product obtained after concentration was purified by silica gel column chromatography (PE:EA = 5:1) to obtain compound 17b (320 mg, yield 27.3%).

[0644] MS m / z(ESI):321.1[M+H] + .

[0645] Step 2: Ethyl 6-bromo-7-fluoro-1-benzothiophene-2-carboxylate 17c

[0646] Ethyl 2-[(3-bromo-2-fluoro-6-formaldehydephenyl)mercapto]acetate 17b (320 mg, 1 mmol) was dissolved in DMF (4 mL) and potassium carbonate (160 mg, 1.16 mmol) was added. The mixture was allowed to react at 70°C for 3 hours, and the reaction was complete. The reaction mixture was diluted with ethyl acetate (50 mL), and the organic phase was washed with saturated brine (30 mL x 2) and dried over anhydrous sodium sulfate to give a crude product. The crude product was purified by silica gel column chromatography (PE:EA = 5:1) to give compound 17c (223 mg, 73.8% yield).

[0647] Step 3: Ethyl 7-fluoro-6-(4-methylpiperazin-1-yl)-1-benzothiophene-2-carboxylate 17d

[0648] Ethyl 6-bromo-7-fluoro-1-benzothiophene-2-carboxylate 17c (223 mg, 0.736 mmol), 1-methylpiperazine (74 mg, 0.74 mmol), palladium acetate (20 mg, 0.09 mmol), Xantphos (90 mg, 0.155 mmol), and cesium carbonate (720 mg, 2.21 mmol) were mixed in 1,4-dioxane (10 mL). After nitrogen protection, the mixture was heated to 110°C for 4 hours, and the reaction was complete. The reaction mixture was concentrated and extracted with ethyl acetate (30 mL × 3). The organic phase was dried over anhydrous sodium sulfate, filtered, and spin-dried. The crude product was purified by silica gel column chromatography (PE:EA = 5:1) to obtain compound 17d (230 mg, 97% yield).

[0649] MS m / z(ESI):323.2[M+H] + .

[0650] Step 4: 7-Fluoro-6-(4-methylpiperazin-1-yl)-1-benzothiophene-2-carboxylic acid 17e

[0651] Ethyl 7-fluoro-6-(4-methylpiperazin-1-yl)-1-benzothiophene-2-carboxylate 17d (217 mg, 0.673 mmol) was dissolved in tetrahydrofuran (8 ml), and a solution of sodium hydroxide (160 mg, 4 mmol) in water (4 ml) was added to the reaction mixture. The reaction mixture was heated to 70°C for 2.5 hours, and the reaction was complete. After the reaction mixture was concentrated to remove the tetrahydrofuran, water (6 ml) was added, and the pH was adjusted to 6 with 1M hydrochloric acid. A solid precipitate was precipitated, filtered, and dried to give compound 17e (160 mg, 80.8% yield).

[0652] MS m / z(ESI):295.2[M+H] + .

[0653] Step 5: 7-Fluoro-N-[1-(1H-indol-3-yl)hexyl-2-yl]-6-(4-methylpiperazin-1-yl)-1-benzothiophene-2-carboxamide 17

[0654] Compound 1c (74 mg, 0.34 mmol) and compound 17e (100 mg, 0.34 mmol) were mixed in DMF (3 mL). DIEA (0.12 mL, 0.7 mmol) was added, followed by HATU (129 mg, 0.34 mmol). The reaction mixture was stirred at room temperature for 2 hours, and the reaction was complete. The reaction mixture was extracted with ethyl acetate (30 mL × 3), and the organic phase was washed with saturated brine (30 mL × 3), dried over anhydrous sodium sulfate, and concentrated to obtain a crude product which was purified by silica gel column chromatography (PE:EA = 5:1) to afford compound 17 (60 mg, 36% yield).

[0655] MS m / z(ESI):493.3[M+H] + .

[0656] Example 18 N-(1-(1H-indol-3-yl)hexan-2-yl)-6-(4-methylpiperidin-1-yl)thieno[3,2-c]pyridine-2-carboxamide

[0657] Compound 8d (125 mg, 0.3 mmol), 4-methylpiperidine (250 mg, 2.5 mmol), and DIEA (300 mg, 2.3 mmol) were dissolved in 1,4-dioxane (30 mL) and added to a microwave reactor. The mixture was reacted at 100°C for 3 hours. After completion of the reaction, 30 mL of water was added to quench the reaction. The mixture was extracted with ethyl acetate (30 mL x 3). The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product, which was purified and isolated by preparative HPLC to afford compound 18 (70 mg, 48% yield).

[0658] MS m / z(ESI):475.3[M+H] + .

[0659] Example 19 N-(1-(1H-indol-3-yl)hexan-2-yl)-6-(4-hydroxypiperidin-1-yl)benzo[b]thiophene-2-carboxamide 19

[0660] A similar synthesis method to Example 16 was used to replace 4,4-dimethylpiperidine with piperidin-4-ol to prepare Compound 19 in a yield of 17.40%.

[0661] MS m / z(ESI):476.2[M+H] + .

[0662] Example 20 N-[1-(1H-indol-3-yl)hexan-2-yl]-6-(2-oxa-7-azaspiro[3.5]nonan-7-yl)-1-benzothiophene-2-carboxamide

[0663] Step 1: Ethyl 6-(2-oxa-7-azaspiro[3.5]nonan-7-yl)-1-benzothiophene-2-carboxylate 20a

[0664] Compound 1f (0.224 g, 0.786 mmol), 2-oxa-7-azaspiro[3.5]nonane (0.100 g, 0.786 mmol), palladium acetate (0.018 g, 0.079 mmol), Xantphos (0.068 g, 0.118 mmol) and cesium carbonate (0.769 g, 2.359 mmol) were respectively weighed into a sealed tube, and 1,4-dioxane (6 mL) was added. The reaction was stirred at 100°C under nitrogen for 2 hours until completion. After filtration through celite, the filtrate was dried to give the crude product, which was purified by silica gel column chromatography (PE:EA=5:1) to give compound 20a (0.247 g, yield 90.18%).

[0665] MS m / z(ESI):332[M+H] + .

[0666] Step 2: 6-(2-oxa-7-azaspiro[3.5]nonan-7-yl)-1-benzothiophene-2-carboxylic acid 20b

[0667] Compound 20a (0.235 g, 0.709 mmol) was dissolved in a mixture of tetrahydrofuran (2 mL) and methanol (2 mL), followed by the addition of 1.0 mL of an aqueous solution of sodium hydroxide (0.085 g, 2.127 mmol). The reaction was allowed to proceed to completion at 70°C for 1 hour. The solvent was removed by distillation under reduced pressure, followed by the addition of 3 mL of water. The pH was then adjusted to 5-6 with 1 M dilute hydrochloric acid. The mixture was filtered and the filter cake dried to afford compound 20b (0.183 g, 85.05% yield).

[0668] MS m / z(ESI):304[M+H] + .

[0669] Step 3: N-[1-(1H-indol-3-yl)hexane-2-yl]-6-(2-oxa-7-azaspiro[3.5]nonane-7-yl)-1-benzothiophene-2-carboxamide 20

[0670] Compound 20b (0.092 g, 0.303 mmol) and compound 1c (0.066 g, 0.303 mmol) were dissolved in 3 mL of DMF. After dissolution, triethylamine (0.092 g, 0.910 mmol) and 1-propylphosphoric acid cyclic anhydride (0.288 g, 0.455 mmol) in tetrahydrofuran were added. The reaction was completed after stirring at room temperature for 1 hour. Ethyl acetate (50 mL) was directly added to the reaction solution, and the mixture was washed with water (20 mL × 3) and extracted with ethyl acetate (30 mL × 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, concentrated, and purified by preparative HPLC to obtain compound 20 (0.052 g, yield 34.18%).

[0671] 1H NMR(400MHz,Chloroform-d)δ8.24(s,1H),7.66(d,J=7.9Hz,1H),7.58(d,J=8.9Hz,1H),7.42(s,1H),7.37(d,J=8 .1Hz,1H),7.24–7.16(m,2H),7.11(t,J=7.5Hz,1H),7.08–7.02(m,2H),5.92(d,J=8.8Hz,1H),4.48(s,4H),3.20– 3.14(m,4H),3.07(t,J=5.7Hz,1H),2.06–1.98(m,4H),1.70–1.61(m,2H),1.55–1.23(m,6H),0.87(t,J=7.1Hz,3H).

[0672] MS m / z(ESI):502[M+H] + .

[0673] Example 21 N-[1-(1H-indol-2-yl)hexan-2-yl]-6-[2-(1-methylpiperidin-4-yl)-2,7-diazaspiro[3.5]nonan-7-yl]-1-benzothiophene-2-carboxamide

[0674] Step 1: tert-Butyl 7-[2-(ethoxycarbonyl)-1-benzothiophen-6-yl]-2,7-diazaspiro[3.5]nonane-2-carboxylate 21a

[0675] A similar synthesis method to compound 20a was used to replace 2-oxa-7-azaspiro[3.5]nonane with tert-butyl 2,7-diazaspiro[3.5]nonane-2-carboxylate to obtain compound 21a in a yield of 52.08%.

[0676] MS m / z(ESI):431[M+H] + .

[0677] Step 2: 6-(2-[(tert-Butoxy)carbonyl]-2,7-diazaspiro[3.5]nonan-7-yl)-1-benzothiophene-2-carboxylic acid 21b

[0678] A similar synthesis method to compound 20b was used to replace compound 20a with compound 21a to obtain compound 21b in a yield of 97.37%.

[0679] MS m / z(ESI):403[M+H] + .

[0680] Step 3: tert-Butyl 7-(2-([1-(1H-indol-2-yl)hexane-2-yl]carbamoyl)-1-benzothiophen-6-yl)-2,7-diazaspiro[3.5]nonane-2-carboxylate 21c

[0681] Compound 21b (0.974 g, 2.420 mmol) and compound 1c (0.520 g, 2.420 mmol) were dissolved in 25 mL of DMF. N-methylimidazole (0.990 g, 12.100 mmol) was then added. After stirring, N,N,N',N'-tetramethylchloroformamidine hexafluorophosphate (1.020 g, 3.630 mmol) was added. After stirring at room temperature for 2 hours, the reaction was complete. Ethyl acetate (50 mL) was added directly to the reaction solution, washed with water (30 mL × 3), and extracted with ethyl acetate (30 mL × 3). The organic phase was dried over anhydrous sodium sulfate and filtered. Compound 21c was purified by silica gel column chromatography (PE:EA = 1:1) to obtain compound 21c in a yield of 60.14%.

[0682] MS m / z(ESI):601[M+H] + .

[0683] Step 4: 6-(2,7-diazaspiro[3.5]nonan-7-yl)-N-[1-(1H-indol-2-yl)hexan-2-yl]-1-benzothiophene-2-carboxamide 21d

[0684] A similar synthesis method to compound 25d was used to replace compound 25c with compound 21c to prepare compound 21d in a yield of 104.50%.

[0685] MS m / z(ESI):501[M+H] + .

[0686] Step 5: N-[1-(1H-indol-2-yl)hexane-2-yl]-6-[2-(1-methylpiperidin-4-yl)-2,7-diazaspiro[3.5]nonan-7-yl]-1-benzothiophene-2-carboxamide 21

[0687] A synthetic method similar to that in the fifth step of Example 25 was used to prepare Compound 21 by replacing Compound 25d with Compound 21d and replacing paraformaldehyde with 4-methylpiperidone in a yield of 25.25%.

[0688] MS m / z(ESI):598[M+H] + .

[0689] 1H NMR (400MHz, DMSO-d6) δ10.77(d,J=2.4Hz,1H), δ8.33(d,J=8.5Hz,1H),7.94(s,1H),7.71(d,J=8.9Hz,1H),7. 62(d,J=7.8Hz,1H),7.44(d,J=2.2Hz,1H),7.32(d,J=8.0Hz,1H),7.19–7.11(m,2H),7.08–7.01(m,1H),6.96( t,J=7.4Hz,1H),4.18(td,J=8.2,5.4Hz,1H),3.98(s,4H),3.64–3.50(m,4H),3.25(s,3H),3.01–2.82(m,4H), 2.77(s,3H),2.13(d,J=12.9Hz,2H),1.89(s,4H),1.66–1.52(m,4H),1.39–1.18(m,4H),0.81(t,J=6.8Hz,3H).

[0690] Example 22 N-[1-(1H-indol-2-yl)hexan-2-yl]-6-(2-methyl-2,7-diazaspiro[3.5]nonan-7-yl)-1-benzothiophene-2-carboxamide

[0691] A synthetic method similar to that in the fifth step of Example 21 was used, except that 4-methylpiperidone was replaced with paraformaldehyde to obtain Compound 22 in a yield of 44.57%.

[0692] 1 H NMR (400MHz, DMSO-d6) δ10.65(d,J=2.4Hz,1H),8.20(d,J=8.5Hz,1H),7.83(s,1H),7.60(d,J=9.0Hz,1H),7.5 1(d,J=7.8Hz,1H),7.33(d,J=2.2Hz,1H),7.21(d,J=8.0Hz,1H),7.09–7.01(m,2H),6.94(ddd,J=8.1,6.9,1.2 Hz,1H),6.89–6.83(m,1H),4.07(q,J=7.8,6.4Hz,1H),3.79(s,4H),3.13(d,J=5.8Hz,4H),2.86(dd,J=14.3,6 .7Hz,2H),2.76(s,3H),1.84–1.75(m,4H),1.46(dd,J=9.4,4.8Hz,2H),1.30–1.04(m,4H),0.76–0.66(m,3H).

[0693] MS m / z(ESI):515[M+H] + .

[0694] Example 23 N-(1-(1H-indol-3-yl)hexan-2-yl)-6-morpholinobenzo[b]thiophene-2-carboxamide

[0695] Step 1: Ethyl 6-morpholinobenzo[b]thiophene-2-carboxylate 23a

[0696] Compound 1f (300 mg, 1.052 mmol), morpholine (137.5 mg, 1.578 mmol), palladium acetate (11.8 mg, 0.053 mmol), Xantphos (60.87 mg, 0.105 mmol), and cesium carbonate (1.028 g, 3.156 mmol) were placed in a single-necked flask. After nitrogen displacement, 1,4-dioxane (12 mL) was added. After a second nitrogen displacement, the reaction was continued at 100°C for 3 hours. The reaction solution was filtered, and the filtrate was concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography (PE:EA = 3:1) to obtain compound 23a (240 mg, 78.3% yield, as a yellow solid).

[0697] MS m / z(ESI):292.1[M+H] + .

[0698] Step 2: 6-Morpholinobenzo[b]thiophene-2-carboxylic acid 23b

[0699] Compound 23a (240 mg, 0.824 mmol) was dissolved in tetrahydrofuran (3 mL), and methanol and a solution of sodium hydroxide (164.8 mg, 4.120 mmol) in water (3 mL) were added. The mixture was reacted at 100°C for 1 hour. LCMS confirmed the reaction was complete, indicating product formation. The reaction solution was concentrated to remove tetrahydrofuran and methanol, and water (10 mL) was added. The pH was adjusted to 6-7 with 1M hydrochloric acid. A solid precipitated and was filtered. The filter cake was dried to yield compound 23b (190 mg, crude yellow solid).

[0700] MS m / z(ESI):264.1[M+H] + .

[0701] Step 3: N-(1-(1H-indol-3-yl)hexan-2-yl)-6-morpholinothieno[2,3-b]pyridine-2-carboxamide 23

[0702] Compound 23b (190 mg, 0.722 mmol) and compound 1c (156.1 mg, 0.722 mmol) were dissolved in DMF (10 mL). Triethylamine (365.1 mg, 3.608 mmol) and 1-propylphosphoric acid cyclic anhydride (919.0 mg, 1.443 mmol) were added and reacted at room temperature for 1 hour. LCMS analysis indicated the formation of the product. Water (100 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (40 mL × 3). The organic phase was washed with saturated brine (30 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography (PE:EA = 1:1) and dried to obtain compound 23 (120 mg, yellow solid, yield: 36.0%).

[0703] MS m / z(ESI):462.6[M+H] + .

[0704] Example 24 N-(1-(1H-indol-3-yl)hexan-2-yl)-6-(4-(dimethylamino)piperidin-1-yl)benzo[b]thiophene-2-carboxamide

[0705] Step 1: Ethyl 6-(4-(dimethylamino)piperidin-1-yl)benzo[b]thiophene-2-carboxylate 24a

[0706] Compound 1f (400 mg, 1.403 mmol), N,N-dimethylpiperidin-4-amine (269.8 mg, 2.104 mmol), palladium acetate (15.8 mg, 0.070 mmol), Xantphos (81.2 mg, 0.140 mmol), and cesium carbonate (1.371 g, 4.208 mmol) were placed in a single-necked flask. After purging the atmosphere with nitrogen, 1,4-dioxane (12 mL) was added. After a second purge of nitrogen, the mixture was reacted at 100°C for 3 hours. LCMS analysis confirmed the completion of the reaction and the formation of the product. The reaction solution was filtered, and the filtrate was concentrated and purified by silica gel column chromatography (DCM / MeOH = 10:1) to obtain compound 24a (300 mg, 64.3% yield).

[0707] MS m / z(ESI):333.5[M+H] + .

[0708] Step 2: 6-(4-(Dimethylamino)piperidin-1-yl)benzo[b]thiophene-2-carboxylic acid 24b

[0709] Compound 24a (300 mg, 0.902 mmol) was dissolved in tetrahydrofuran (4 mL), and methanol and a solution of sodium hydroxide (180.5 mg, 4.512 mmol) in water (4 mL) were added. The mixture was reacted at 70°C for 1 hour. LCMS confirmed the reaction was complete, indicating product formation. The reaction solution was concentrated to remove tetrahydrofuran and methanol, and water (10 mL) was added. The pH was adjusted to 6-7 with 1M hydrochloric acid. A solid precipitated and was filtered. The filter cake was dried to yield compound 24b (210 mg, crude gray solid).

[0710] MS m / z(ESI):305.1[M+H] + .

[0711] Step 3: N-(1-(1H-indol-3-yl)hexan-2-yl)-6-(4-(dimethylamino)piperidin-1-yl)benzo[b]thiophene-2-carboxamide 24

[0712] Compound 24b (110 mg, 0.361 mmol) and compound 1c (78.2 mg, 0.361 mmol) were dissolved in DMF (3 mL), and DIEA (140.1 mg, 1.084 mmol) and HATU (137.4 mg, 0.361 mmol) were added. The reaction was carried out at room temperature for 1 hour. LCMS showed that the reaction was complete. The reaction solution was diluted with ethyl acetate (100 mL), and the organic phase was separated and washed with water (50 mL×3). The organic phase was washed with saturated aqueous sodium carbonate solution (50 mL), dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column chromatography (MeOH / DCM, 1:30) to obtain compound 24 (12 mg, yellow solid, yield 6.6%).

[0713] MS m / z(ESI):503.3[M+H] + .

[0714] Example 25 N-(1-(1H-indol-3-yl)hexan-2-yl)-6-(6-methyl-2,6-diazaspiro[3.3]heptan-2-yl)benzo[b]thiophene-2-carboxamide

[0715] Step 1: tert-Butyl 6-(2-(ethoxycarbonyl)benzo[b]thiophen-6-yl)-2,6-diazaspiro[3.3]heptane-2-carboxylate 25a

[0716] Compound 1f (360 mg, 1.261 mmol), tert-butyl 2,6-diazaspiro[3.3]heptane-2-carboxylate (250 mg, 1.261 mmol), palladium acetate (14.2 mg, 0.063 mmol), Xantphos (73.0 mg, 0.126 mmol), and cesium carbonate (1.233 g, 3.783 mmol) were placed in a single-necked flask. After nitrogen displacement, 1,4-dioxane (12 mL) was added. After a second nitrogen displacement, the mixture was reacted at 100°C for 3 hours. LCMS analysis showed that the reaction was complete and the product was generated. The reaction solution was filtered and the filtrate was concentrated. Compound 25a (420 mg, yield 82.8%) was obtained by purification via silica gel column chromatography (PE:EA=3:1) to obtain a yellow solid.

[0717] MS m / z(ESI):403.2[M+H] + .

[0718] Step 2: 6-(6-(tert-Butoxycarbonyl)-2,6-diazaspiro[3.3]heptane-2-yl)benzo[b]thiophene-2-carboxylic acid 25b

[0719] Compound 25a (210 mg, 0.522 mmol) was dissolved in tetrahydrofuran (3 mL), and methanol (3 mL) and a solution of sodium hydroxide (104.3 mg, 2.609 mmol) in water (3 mL) were added. The mixture was reacted at 70°C for 1 hour. LCMS analysis confirmed the completion of the reaction and the formation of the product. The reaction solution was concentrated to remove tetrahydrofuran and methanol, and water (10 mL) was added. The pH was adjusted to 6-7 with 1 M hydrochloric acid, and the mixture was extracted with dichloromethane and dried over anhydrous sodium sulfate to obtain the product, compound 25b (190 mg, yellow solid, crude product).

[0720] MS m / z(ESI):375.1[M+H] + .

[0721] Step 3: tert-Butyl 6-(2-((1-(1H-indol-3-yl)hexan-2-yl)carbamoyl)benzo[b]thiophen-6-yl)-2,6-diazaspiro[3.3]heptane-2-carboxylate 25c

[0722] Compound 25b (190 mg, 0.507 mmol) and compound 1c (131.6 mg, 0.0.608 mmol) were dissolved in DMF (6 mL), and DIEA (196.6 mg, 1.521 mmol) and HATU (192.8 mg, 0.507 mmol) were added. The mixture was reacted at room temperature for 1 hour. LCMS showed the reaction was complete. The reaction solution was diluted with ethyl acetate (100 mL) and washed with water (30 mL × 2). The organic phase was washed with saturated sodium carbonate solution (50 mL), dried over anhydrous sodium sulfate, and concentrated. Compound 25c was purified by silica gel column chromatography (PE:EA = 1:1) to obtain compound 25c (290 mg, yellow colloid, yield 99.8%).

[0723] MS m / z(ESI):573.3[M+H] + .

[0724] Step 4: N-(1-(1H-indol-3-yl)hexan-2-yl)-6-(2,6-diazaspiro[3.3]heptan-2-yl)benzo[b]thiophene-2-carboxamide 25d

[0725] Compound 25c (290 mg, 0.506 mmol) was dissolved in dichloromethane (5 mL), and trifluoroacetic acid (576.9 mg, 5.06 mmol) was added. The mixture was allowed to react at room temperature for 2 hours until TLC indicated completion. The reaction solution was concentrated and dissolved in saturated aqueous sodium bicarbonate (50 mL). The mixture was then extracted with dichloromethane (50 mL x 3). The organic phase was separated and dried over anhydrous sodium sulfate. Concentration afforded crude compound 25d (220 mg, yellow solid).

[0726] MS m / z(ESI):473.3[M+H] + .

[0727] Step 5: N-(1-(1H-indol-3-yl)hexan-2-yl)-6-(6-methyl-2,6-diazaspiro[3.3]heptan-2-yl)benzo[b]thiophene-2-carboxamide 25

[0728] Compound 25d (220 mg, 0.465 mmol) was dissolved in ethanol (6 mL), and paraformaldehyde (30 mg, 1.698 mmol), acetic acid (2.8 mg, 0.0465 mmol), and sodium cyanoborohydride (29.3 mg, 0.465 mmol) were added. The mixture was reacted at room temperature for 1 hour. LCMS showed that the reaction was complete. The reaction solution was poured into water (30 mL) and extracted with dichloromethane (50 mL×3). The organic phase was dried over anhydrous sodium sulfate and filtered to obtain a crude product. The crude product was purified by silica gel column chromatography (PE:EA=3:1) to obtain compound 25 (38.22 mg, white solid, yield 15.1%).

[0729] 1 H NMR (400MHz, DMSO-d6) δ10.77(d,J=2.2Hz,1H),8.29(d,J=8.5Hz,1H),7.93(s,1H),7.69(d,J=8.7Hz,1H ),7.62(d,J=7.9Hz,1H),7.32(d,J=8.1Hz,1H),7.14(d,J=2.3Hz,1H),7.06(t,J=7.5Hz,1H),7.01–6.90 (m,2H),6.60(dd,J=8.7,2.1Hz,1H),4.18(d,J=6.7Hz,1H),3.99(s,4H),3.56(s,4H),2.97(dd,J=14.4, 6.7Hz, 1H), 2.86 (dd, J = 14.4, 6.8Hz, 1H), 2.38 (s, 3H), 1.57 (s, 2H), 1.25 (s, 4H), 0.83 (t, J = 6.8Hz, 3H).

[0730] MS m / z(ESI):487.3[M+H] + .

[0731] Example 26 N-(1-(5-fluoro-1H-indol-3-yl)hexan-2-yl)-6-(4-methylpiperazin-1-yl)benzo[b]thiophene-2-carboxamide

[0732] Step 1: 1-(5-Fluoro-1H-indol-3-yl)hexan-2-one 26b

[0733] Compound 26a (1.0 g, 6.704 mmol) was dissolved in 1,2-dichloroethane (20 mL). Aluminum chloride (2.68 g, 20.1 mmol) was added at 0°C and stirred at room temperature for 30 minutes. The temperature was then lowered to 0°C and valeryl chloride (889 mg, 7.37 mmol) was added dropwise. The mixture was allowed to react at room temperature for 48 hours. LCMS indicated the reaction was complete. The reaction solution was slowly poured into ice water (50 mL) and extracted with dichloromethane (30 mL x 2). The organic phase was separated, dried over anhydrous sodium sulfate, and concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography (PE:EA = 1:1) to obtain compound 26b (140 mg, brown colloid, yield 8.95%).

[0734] MS m / z(ESI):234.2[M+H] + .

[0735] Step 2: 1-(5-Fluoro-1H-indol-3-yl)hexan-2-amine 26c

[0736] Compound 26b (140 mg, 0.6 mmol) was dissolved in methanol (5 mL), and ammonium acetate (92.5 mg, 1.2 mmol) and sodium cyanoborohydride (63.8 mg, 1.2 mmol) were added. The mixture was heated to 70°C for 18 hours. LCMS showed that the reaction was complete. The reaction solution was concentrated, and dichloromethane (30 mL) was added. The organic phase was washed with saturated brine (30 mL × 3), dried over anhydrous sodium sulfate, and concentrated to obtain compound 26c (80 mg, yellow colloid, crude product).

[0737] MS m / z(ESI):235.2[M+H] + .

[0738] Step 3: N-(1-(5-fluoro-1H-indol-3-yl)hexan-2-yl)-6-(4-methylpiperazin-1-yl)benzo[b]thiophene-2-carboxamide 26

[0739] Compound 26c (80 mg, 0.341 mmol) and compound 1h (94.35 mg, 0.341 mmol) were dissolved in DMF (3 mL), and DIEA (132.37 mg, 1.024 mmol) and HATU (129.82 mg, 0.341 mmol) were added. The reaction was carried out at room temperature for 1 hour. LCMS showed that the reaction was complete. The reaction solution was diluted with ethyl acetate (50 mL), and the organic phase was washed with saturated brine (30 mL×2), dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column chromatography (MeOH / DCM=1:10) to obtain compound 26 (5.23 mg, white solid, yield 3.11%).

[0740] 1 H NMR (400MHz, Methanol-d4) δ7.57 (d, J = 8.9 Hz, 1H), 7.48 (s, 1H), 7.24 (ddd, J = 9.0, 5. 9,3.6Hz,2H),7.14(d,J=2.2Hz,1H),7.10(s,1H),6.93–6.80(m,2H),4.34(t,J=7.2Hz ,1H),3.27–3.13(m,4H),3.07–2.88(m,2H),2.85(s,3H),2.19–1.92(m,1H),1.63(dt, J=13.7,7.7Hz,1H),1.30(dq,J=22.0,7.6Hz,2H),1.20(s,6H),0.83(t,J=7.1Hz,3H).

[0741] MS m / z(ESI):493.3[M+H] + .

[0742] Example 27 N-(1-(1H-indol-3-yl)hexan-2-yl)-6-(4-methylpiperazin-1-yl)benzofuran-2-carboxamide

[0743] Step 1: Ethyl 6-(4-methylpiperazin-1-yl)benzofuran-2-carboxylate 27b

[0744] Compound 27a (1000 mg, 3.6 mmol), palladium acetate (40 mg, 0.2 mmol), Xantphos (202 mg, 0.35 mmol), and cesium carbonate (3.42 g, 10.5 mmol) were added to a reaction flask, followed by 1-methylpiperazine (530 mg, 5.3 mmol) and 1,4-dioxane (10 mL). Under nitrogen, stirring was initiated and the mixture was reacted at 100°C for 3 hours. After completion, the reaction was quenched with water (50 mL) and extracted with ethyl acetate (40 mL × 3). The combined organic layers were dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column chromatography (PE:EA = 1:1) to afford compound 27b (650 mg, 78% yield).

[0745] MS m / z(ESI):288.2[M+H] + .

[0746] Step 2: 6-(4-Methylpiperazin-1-yl)benzofuran-2-carboxylic acid 27c

[0747] Compound 27b (450 mg, 2.0 mmol) was dissolved in tetrahydrofuran (5 mL), followed by methanol (5 mL). Sodium hydroxide was dissolved in water (3 mL) and added to the reaction flask. Stirring was initiated and the reaction was carried out at 70°C for 1 hour. After the reaction, the solvent was dried by rotary evaporation, and the solid was dissolved in water. The pH was adjusted to 5-6 with 1M hydrochloric acid and filtered. The resulting filter cake was dissolved in methanol (20 mL), and the solvent was evaporated to afford compound 27c (380 mg, 92% yield).

[0748] MS m / z(ESI):261.3[M+H] + .

[0749] Step 3: N-(1-(1H-indol-3-yl)hexane-2-yl)-6-(4-methylpiperazin-1-yl)benzofuran-2-carboxamide 27

[0750] Compound 27c (308 mg, 1.2 mmol) and compound 1c (200 mg, 0.9 mmol) were added to a reaction flask and dissolved in DMF (5 mL). Triethylamine (467 mg, 4.6 mmol) and 1-propylphosphoric acid cyclic anhydride (441 mg, 1.4 mmol) were then added, stirred, and reacted at room temperature for 1 hour. After completion of the reaction, water (50 mL) was added to quench the reaction, and the mixture was extracted with ethyl acetate (40 mL × 3). The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated. The resulting mixture was then purified and isolated by preparative HPLC to afford compound 27 (110 mg, 25% yield).

[0751] MS m / z(ESI):459.3[M+H] + .

[0752] Example 28 N-(1-(1H-indol-3-yl)hexan-2-yl)-6-(4-methylpiperazin-1-yl)-1H-indole-2-carboxamide

[0753] Step 1: Ethyl 6-(4-methylpiperazin-1-yl)-1H-indole-2-carboxylate 28b

[0754] Compound 28a (1000 mg, 3.9 mmol), palladium acetate (40 mg, 0.2 mmol), Xantphos (202 mg, 0.35 mmol), and cesium carbonate (3.42 g, 10.5 mmol) were added to a reaction flask, along with 1-methylpiperazine (530 mg, 5.3 mmol) and 1,4-dioxane (10 mL). Under nitrogen, stirring was initiated and the mixture was reacted at 70°C for 3 hours. After completion, the reaction was quenched with water (50 mL) and extracted with ethyl acetate (40 mL v 3). The combined organic layers were dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column chromatography (PE:EA = 1:1) to afford compound 28b (350 mg, 39% yield).

[0755] MS m / z(ESI):288.2[M+H] + .

[0756] Step 2: 6-(4-Methylpiperazin-1-yl)-1H-indole-2-carboxylic acid 28c

[0757] Compound 28b (350 mg, 2.0 mmol) was dissolved in 5 mL of tetrahydrofuran, followed by the addition of 5 mL of methanol. Sodium hydroxide was dissolved in 3 mL of water and added to the reaction flask. Stirring was initiated and the reaction was carried out at 70°C for 1 hour. After the reaction, the solvent was dried by rotary evaporation, and the solid was dissolved in water. The pH was adjusted to 5-6 with 1 M hydrochloric acid and filtered. The resulting filter cake was dissolved in methanol (30 mL), and the solvent was removed by rotary evaporation to afford compound 28c (210 mg, 77% yield).

[0758] MS m / z(ESI):260.3[M+H] + .

[0759] Step 3: N-(1-(1H-indol-3-yl)hexan-2-yl)-6-(4-methylpiperazin-1-yl)-1H-indole-2-carboxamide 28

[0760] Compound 28c (200 mg, 0.77 mmol) and compound 1c (0.15 mg, 0.77 mmol) were added to a reaction flask and dissolved in DMF (5 mL). Triethylamine (467 mg, 4.6 mmol) and 1-propylphosphoric acid cyclic anhydride (441 mg, 1.4 mmol) were then added, stirred, and reacted at room temperature for 1 hour. After completion of the reaction, water (50 mL) was added to quench the reaction, and the mixture was extracted with ethyl acetate (40 mL × 3). The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated. The mixture was then purified and isolated by preparative HPLC to afford compound 28 (90 mg, 25% yield).

[0761] 1H NMR (400MHz, DMSO-d6) δ10.8 (s, 1H), 10.65 (s, 1H), 7.85-7.70 (d, J = 8Hz 1H),7.52-7.15(m,6H),6.90-6.72(m,2H),6.42(m,1H),4.42–4.30(m,1H),3.26-3.12(m,4H),2.98-2. 74(m,2H),2.52-2.48(m,4H),2.28(s,3H),1.67-1.53(m,2H),1.34-1.20(m,4H),0.87(t,J=7.2Hz,3H).

[0762] MS m / z(ESI):458.2[M+H] + .

[0763] Example 29 N-(1-(1H-indol-3-yl)hexan-2-yl)-2-(4-methylpiperazin-1-yl)thieno[2,3-d]pyrimidine-6-carboxamide

[0764] Step 1: Ethyl 2-(methylthio)thieno[2,3-d]pyrimidine-6-carboxylate 29b

[0765] Compound 29a (1.0 g, 5.682 mmol) was dissolved in DMF (5 mL), followed by the addition of potassium carbonate (1.18 g, 0.853 mmol) and compound 1e (0.75 g, 6.25 mmol) at room temperature. The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was quenched with water (50 mL) and extracted with ethyl acetate (50 mL × 3). The organic phase was washed with saturated brine (50 mL × 3), dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography (PE:EA = 5:1) to afford compound 29b (0.75 g, 60% yield).

[0766] MS m / z(ESI):255.3[M+H] + .

[0767] Step 2: 2-(Methylthio)thieno[2,3-d]pyrimidine-6-carboxylic acid 29c

[0768] Compound 29b (750 mg, 2.0 mmol) was dissolved in 5 mL of tetrahydrofuran, followed by the addition of 5 mL of methanol. Sodium hydroxide was dissolved in 3 mL of water and added to the reaction flask. Stirring was initiated and the reaction was carried out at 70°C for 1 hour. After the reaction, the solvent was dried by rotary evaporation, and the solid was dissolved in water. The pH was adjusted to 5-6 with 1 M hydrochloric acid and filtered. The resulting filter cake was dissolved in methanol (20 mL), and the solvent was removed by rotary evaporation to afford compound 29c (650 mg, 91% yield).

[0769] MS m / z(ESI):227.4[M+H] + .

[0770] Step 3: N-(1-(1H-indol-3-yl)hexan-2-yl)-2-(methylthio)thieno[2,3-d]pyrimidine-6-carboxamide 29d

[0771] Compound 29c (200 mg, 0.77 mmol) and compound 1c (0.15 mg, 0.77 mmol) were added to a reaction flask, dissolved in 5 mL of DMF, and then triethylamine (467 mg, 4.6 mmol) and 1-propylphosphoric acid cyclic anhydride (441 mg, 1.4 mmol) were added. Stirring was started and the reaction was allowed to react at room temperature for 1 hour. After completion of the reaction, water (50 mL) was added to quench the reaction, and the mixture was extracted with ethyl acetate (50 mL × 3). The organic layers were combined, dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column chromatography (PE:EA = 5:1) to obtain compound 29d (190 mg, 65% yield).

[0772] MS m / z(ESI):458.3[M+H] + .

[0773] Step 4: N-(1-(1H-indol-3-yl)hexan-2-yl)-2-(4-methylpiperazin-1-yl)thieno[2,3-d]pyrimidine-6-carboxamide 29

[0774] Compound 29d (0.19 g, 2.427 mmol) and 1-methylpiperazine (0.310 g, 3.09 mmol) were placed in a microwave reactor and reacted at 180°C for 3 hours. The reaction mixture was quenched with water (30 mL) and extracted with ethyl acetate (50 mL × 3). The organic phase was washed with saturated brine (50 mL × 3), dried over anhydrous sodium sulfate, filtered, concentrated, and purified by preparative HPLC to obtain compound 29 (29 mg, 15% yield).

[0775] MS m / z(ESI):477.5[M+H] + .

[0776] Example 30 N-(1-(5-methyl-1H-indol-3-yl)hexan-2-yl)-6-(4-methylpiperazin-1-yl)benzo[b]thiophene-2-carboxamide

[0777] Step 1: 1-(5-Methyl-1H-indol-3-yl)hexan-2-one 30b

[0778] Compound 30a (1.0 g, 6.704 mmol) was dissolved in 1,2-dichloroethane (20 mL). Aluminum chloride (2.68 g, 20.1 mmol) was added at 0°C and stirred at room temperature for 30 minutes. The temperature was then lowered to 0°C and valeryl chloride (889 mg, 7.37 mmol) was added dropwise. The mixture was allowed to react at room temperature for 48 hours. LCMS indicated the reaction was complete. The reaction solution was slowly poured into ice water (50 mL) and extracted with dichloromethane (50 mL). The organic phase was dried over anhydrous sodium sulfate and concentrated to obtain the crude product, which was then purified by silica gel column chromatography (PE:EA = 1:1) to obtain compound 30b (210 mg, 12% yield).

[0779] MS m / z(ESI):231.2[M+H] + .

[0780] Step 2: 1-(5-Methyl-1H-indol-3-yl)hexan-2-amine 30c

[0781] Compound 30b (210 mg, 0.9 mmol) was dissolved in methanol (5 mL), and ammonium acetate (92.5 mg, 1.2 mmol) and sodium cyanoborohydride (63.8 mg, 1.2 mmol) were added. The mixture was heated to 70°C for 18 hours. LCMS indicated that the reaction was complete. The reaction solution was concentrated, and dichloromethane (30 mL) was added. The organic phase was washed with saturated brine (40 mL × 3), dried over anhydrous sodium sulfate, and concentrated to afford compound 30c (120 mg, yellow colloid, crude product).

[0782] MS m / z(ESI):232.3[M+H] + .

[0783] Step 3: N-(1-(5-methyl-1H-indol-3-yl)hexane-2-yl)-6-(4-methylpiperazin-1-yl)benzo[b]thiophene-2-carboxamide 30

[0784] Compound 30c (120 mg, 0.441 mmol) and compound 1h (100 mg, 0.441 mmol) were dissolved in DMF (3 mL), and DIEA (132.37 mg, 1.024 mmol) and HATU (129.82 mg, 0.341 mmol) were added. The reaction was carried out at room temperature for 1 hour. LCMS showed that the reaction was complete. The reaction solution was diluted with ethyl acetate (50 mL), and the organic phase was washed with saturated brine (50 mL×3), dried over anhydrous sodium sulfate, filtered, concentrated, and separated by preparative HPLC to obtain compound 30 (15 mg, white solid, yield 11%).

[0785] 1 H NMR(400MHz, Methanol-d4)δ7.68(d,J=8.9Hz,1H),7.44(s,1H),7.34(ddd,J=9.0,5.9,3 .6Hz,2H),7.14(d,J=2.2Hz,1H),7.10(s,1H),6.93–6.80(m,2H),4.34(t,J=7.2Hz,1H),3 .27–3.13(m,4H),3.07–2.88(m,2H),2.85(s,3H),2.44(s,3H),2.25–1.98(m,1H),1.66( dt,J=13.7,7.7Hz,1H),1.47(dq,J=22.0,7.6Hz,2H),1.30(s,6H),0.91(t,J=7.1Hz,3H).

[0786] MS m / z(ESI):489.3[M+H] + .

[0787] Example 31 N-(1-(1H-pyrrolo[3,2-c]pyridin-3-yl)hexan-2-yl)-6-(4-methylpiperazin-1-yl)benzo[b]thiophene-2-carboxamide

[0788] Step 1: 1-(1H-pyrrolo[3,2-c]pyridin-3-yl)hexan-2-one 31b

[0789] Compound 31a (1.0 g, 6.804 mmol) was dissolved in 1,2-dichloroethane (20 mL). Aluminum chloride (2.68 g, 20.1 mmol) was added at 0°C and stirred at room temperature for 30 minutes. The temperature was then lowered to 0°C and valeryl chloride (889 mg, 7.37 mmol) was added dropwise. The mixture was allowed to react at room temperature for 48 hours. LCMS indicated the reaction was complete. The reaction solution was slowly poured into ice water (50 mL), extracted with dichloromethane (30 mL × 3), dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column chromatography (PE:EA = 1:1) to afford compound 31b (250 mg, brown colloid, 14% yield).

[0790] MS m / z(ESI):217.3[M+H] + .

[0791] Step 2: 1-(1H-pyrrolo[3,2-c]pyridin-3-yl)hexan-2-amine 31c

[0792] Compound 31b (250 mg, 1.1 mmol) was dissolved in methanol (5 mL), and ammonium acetate (92.5 mg, 1.2 mmol) and sodium cyanoborohydride (63.8 mg, 1.2 mmol) were added. The mixture was heated to 70°C for 18 hours. LCMS indicated that the reaction was complete. The reaction solution was concentrated and extracted with dichloromethane (30 mL). The organic phase was washed with saturated brine (30 mL x 3), dried over anhydrous sodium sulfate, and concentrated to afford compound 31c (140 mg, yellow colloid, crude product).

[0793] MS m / z(ESI):218.2[M+H] + .

[0794] Step 3: N-(1-(1H-pyrrolo[3,2-c]pyridin-3-yl)hexan-2-yl)-6-(4-methylpiperazin-1-yl)benzo[b]thiophene-2-carboxamide 31

[0795] Compound 31c (98 mg, 0.451 mmol) and compound 1h (110 mg, 0.451 mmol) were dissolved in DMF (3 mL), and DIEA (132.37 mg, 1.024 mmol) and HATU (129.82 mg, 0.341 mmol) were added. The mixture was allowed to react at room temperature for 1 hour. LCMS indicated the reaction was complete. The reaction solution was diluted with ethyl acetate (50 mL), and the organic phase was washed with saturated brine (30 mL x 3), dried over anhydrous sodium sulfate, filtered, and concentrated. Compound 31 was then purified and isolated by preparative HPLC to afford 19 mg of a white solid in an 11% yield.

[0796] MS m / z(ESI):476.4[M+H] + .

[0797] Example 32 N-(1-(1H-indol-3-yl)-5-methylhex-4-en-2-yl)-6-(4-methylpiperazin-1-yl)benzo[b]thiophene-2-carboxamide

[0798] Step 1: 1-(1H-indol-3-yl)-5-methylhex-4-en-2-one 32a

[0799] Compound 1a (1.0 g, 7.63 mmol) was dissolved in 1,2-dichloroethane (10 mL). Aluminum chloride (2.68 g, 20.1 mmol) was added at 0°C and stirred at room temperature for 30 minutes. The temperature was then lowered to 0°C and 4-methylpent-3-enoyl chloride (889 mg, 9.50 mmol) was added dropwise. The mixture was allowed to react at room temperature for 48 hours. LCMS indicated the reaction was complete. The reaction solution was slowly poured into ice water (50 mL) and extracted with dichloromethane (30 mL × 3). The organic phase was dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column chromatography (PE:EA = 1:1) to afford compound 32a (150 mg, brown colloid, 6.8% yield).

[0800] MS m / z(ESI):228.4[M+H] + .

[0801] Step 2: 1-(1H-indol-3-yl)-5-methylhex-4-en-2-amine 32b

[0802] Compound 32a (150 mg, 0.72 mmol) was dissolved in methanol (5 mL), and ammonium acetate (92.5 mg, 1.2 mmol) and sodium cyanoborohydride (63.8 mg, 1.2 mmol) were added. The mixture was heated to 70°C for 18 hours. LCMS showed the reaction was complete. The reaction solution was concentrated, and dichloromethane (50 mL) was added. The organic phase was washed with saturated brine (30 mL × 3), dried over anhydrous sodium sulfate, and concentrated to obtain compound 32b (140 mg, yellow colloid, crude product).

[0803] MS m / z(ESI):229.2[M+H] + .

[0804] Step 3 N-(1-(1H-indol-3-yl)-5-methylhex-4-en-2-yl)-6-(4-methylpiperazin-1-yl)benzo[b]thiophene-2-carboxamide 32

[0805] Compound 32c (103 mg, 0.451 mmol) and compound 1h (110 mg, 0.451 mmol) were dissolved in DMF (3 mL), and DIEA (132.37 mg, 1.024 mmol) and HATU (145.8 mg, 0.451 mmol) were added. The reaction was carried out at room temperature for 1 hour. LCMS showed that the reaction was complete. The reaction solution was diluted with ethyl acetate (50 mL), and the organic phase was washed with saturated brine (30 mL×3), dried over anhydrous sodium sulfate, filtered, concentrated, and purified and separated by preparative HPLC to obtain compound 32 (11 mg, white solid, yield 9%).

[0806] MS m / z(ESI):487.4[M+H] + .

[0807] Example 33 N-(1-(1H-indol-3-yl)-5-methylhexan-2-yl)-6-(4-methylpiperazin-1-yl)benzo[b]thiophene-2-carboxamide

[0808] Step 1: 1-(1H-indol-3-yl)-5-methylhexan-2-one 33a

[0809] Compound 1a (1.0 g, 7.63 mmol) was dissolved in 1,2-dichloroethane (10 mL). Aluminum chloride (2.68 g, 20.1 mmol) was added at 0°C and stirred at room temperature for 30 minutes. The temperature was then lowered to 0°C and 4-methylvaleryl chloride (910 mg, 9.50 mmol) was added dropwise. The mixture was allowed to react at room temperature for 48 hours. LCMS indicated the reaction was complete. The reaction solution was slowly poured into ice water (50 mL) and extracted with dichloromethane (30 mL × 3). The organic phase was dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column chromatography (PE:EA = 1:1) to obtain compound 33a (220 mg, brown colloid, yield 11.5%).

[0810] MS m / z(ESI):230.2[M+H] + .

[0811] Step 2: 1-(1H-indol-3-yl)-5-methylhexane-2-amine 33b

[0812] Compound 33a (220 mg, 0.92 mmol) was dissolved in methanol (5 mL), and ammonium acetate (92.5 mg, 1.2 mmol) and sodium cyanoborohydride (63.8 mg, 1.2 mmol) were added. The mixture was heated to 70°C for 18 hours. LCMS showed the reaction was complete. The reaction solution was concentrated and extracted with dichloromethane (50 mL). The organic phase was washed with saturated brine (30 mL × 3), dried over anhydrous sodium sulfate, and concentrated to obtain compound 33b (160 mg, yellow colloid, crude product).

[0813] MS m / z(ESI):231.2[M+H] + .

[0814] Step 3: N-(1-(1H-indol-3-yl)-5-methylhexane-2-yl)-6-(4-methylpiperazin-1-yl)benzo[b]thiophene-2-carboxamide 33

[0815] Compound 33b (111 mg, 0.481 mmol) and compound 1h (110 mg, 0.481 mmol) were dissolved in DMF (3 mL), and DIEA (132.37 mg, 1.024 mmol) and HATU (145.8 mg, 0.481 mmol) were added. The reaction was allowed to react at room temperature for 1 hour. LCMS showed that the reaction was complete. The reaction mixture was diluted with ethyl acetate (50 mL), and the organic phase was washed with saturated brine (30 mL×3), dried over anhydrous sodium sulfate, filtered, concentrated, and purified and isolated by preparative HPLC to obtain compound 33 (21 mg, white solid, yield 16%).

[0816] MS m / z(ESI):489.3[M+H] + .

[0817] Example 34 N-[1-(1H-indol-3-yl)-4-methoxybutyl-2-yl]-6-(4-methylpiperazin-1-yl)-1-benzothiophene-2-carboxamide

[0818] Step 1: 1-Methoxy-3-nitropropane 34b

[0819] 1-Methoxy-3-iodopropane 34a (1 g, 5 mmol) and silver nitrite (1.54 g, 10 mmol) were mixed in water (15 mL) and heated to 70°C for 5 hours, resulting in the reaction being complete. The reaction mixture was filtered and extracted with dichloromethane (50 mL). The dichloromethane layer was concentrated at low temperature to afford compound 34b (480 mg, 80.6% yield).

[0820] Step 2: 3-[(4-methoxy-2-nitrobutyl-1-en-1-yl)-1H-indole 34c

[0821] 1H-Indole-3-carboxaldehyde (240 mg, 1.65 mmol), 1-methoxy-3-nitropropane 34b (480 mg, 4 mmol), and ammonium acetate (90 mg, 1.16 mmol) were mixed in a sealed tube and heated to 70°C for 3 hours, resulting in the reaction being complete. The reaction mixture was diluted with ethyl acetate (50 mL), and the organic phase was washed with saturated brine (30 mL × 3), concentrated, and purified by silica gel column chromatography (PE:EA = 3:1) to afford compound 34c (220 mg, 54% yield).

[0822] MS m / z(ESI):247.1[M+H] + .

[0823] Step 3: 1-(1H-indol-3-yl)-4-methoxybutyl-2-amine 34d

[0824] Compound 34c (220 mg, 0.89 mmol) was dissolved in anhydrous tetrahydrofuran (3 mL). 1 M lithium aluminum hydride solution (2.5 mL) was added at 70°C and stirred at room temperature overnight. The reaction was complete. 15% sodium hydroxide solution (3 mL) was added to the reaction mixture to quench the reaction. The mixture was then extracted with dichloromethane (50 mL). The organic phase was washed with saturated brine (30 mL × 3), concentrated, and purified by silica gel column chromatography (PE:EA = 3:1) to afford compound 34d (135 mg, 69.2% yield).

[0825] MS m / z(ESI):219.1[M+H] + .

[0826] Step 4: N-[1-(1H-indol-3-yl)-4-methoxybutyl-2-yl]-6-(4-methylpiperazin-1-yl)-1-benzothiophene-2-carboxamide 34

[0827] Compound 34d (135 mg, 0.62 mmol) and 6-(4-methylpiperazin-1-yl)-1-benzothiophene-2-carboxylic acid (171 mg, 0.62 mmol) were mixed in DMF (3 mL). DIEA (0.2 mL, 1.2 mmol) was added, followed by HATU (235 mg, 0.62 mmol). The reaction mixture was stirred at room temperature for 2 hours, and the reaction was complete. The reaction mixture was diluted with ethyl acetate (50 mL), and the organic phase was washed with saturated brine (30 mL × 3), dried over anhydrous sodium sulfate, and concentrated to obtain a crude product which was purified by silica gel column chromatography (PE:EA = 1:1) to afford compound 34 (143 mg, 48.4% yield).

[0828] MS m / z(ESI):477.2[M+H] + .

[0829] Example 35 (Z)-N-(1-(1H-indol-3-yl)hex-4-en-2-yl)-6-(4-methylpiperazin-1-yl)benzo[b]thiophene-2-carboxamide

[0830] Step 1: 5-Nitropent-2-ene 35b

[0831] Compound 35a (1 g, 5.1 mmol) and silver nitrite (1.54 g, 10 mmol) were mixed in water (15 mL) and heated to 70°C for 5 hours, resulting in completion of the reaction. The reaction mixture was filtered and extracted with dichloromethane (30 mL x 3). The dichloromethane layer was concentrated at low temperature to afford compound 35b (480 mg, 82.6% yield).

[0832] Step 2: 3-((1E,4Z)-2-Nitrohexa-1,4-dien-1-yl)-1H-indole 35c

[0833] 1H-Indole-3-carboxaldehyde (240 mg, 1.65 mmol) was mixed with compound 35b (480 mg, 4 mmol) and ammonium acetate (90 mg, 1.16 mmol). The mixture was sealed and heated to 70°C for 3 hours, resulting in completion. The reaction mixture was diluted with ethyl acetate (50 mL), and the organic phase was washed with saturated brine (30 mL × 3), concentrated, and purified by silica gel column chromatography (PE:EA = 3:1) to afford compound 35c (180 mg, 46% yield).

[0834] MS m / z(ESI):243.1[M+H] + .

[0835] Step 3: (Z)-1-(1H-indol-3-yl)hex-4-en-2-amine 35d

[0836] Compound 35c (180 mg, 0.74 mmol) was dissolved in anhydrous tetrahydrofuran (3 mL). 1 M lithium aluminum hydride solution (2.5 mL) was added at 70°C and stirred at room temperature overnight. The reaction was complete. The reaction mixture was quenched by the addition of 15% sodium hydroxide solution (3 mL) and extracted with dichloromethane (50 mL). The organic phase was washed with saturated brine (30 mL × 3), concentrated, and purified by silica gel column chromatography (PE:EA = 1:1) to afford compound 35d (95 mg, 59% yield).

[0837] MS m / z(ESI):215.1[M+H]+ .

[0838] Step 4: (Z)-N-(1-(1H-indol-3-yl)hex-4-en-2-yl)-6-(4-methylpiperazin-1-yl)benzo[b]thiophene-2-carboxamide 35

[0839] Compound 35d (95 mg, 0.44 mmol) and compound 1h (143 mg, 0.50 mmol) were mixed in DMF (3 mL). DIEA (0.2 mL, 1.2 mmol) was added, followed by HATU (235 mg, 0.62 mmol). The reaction mixture was stirred at room temperature for 2 hours, and the reaction was complete. The reaction mixture was diluted with ethyl acetate (50 mL), and the organic phase was washed with saturated brine (30 mL × 3), dried over anhydrous sodium sulfate, and concentrated to obtain a crude product which was purified by silica gel column chromatography (PE:EA = 1:1) to afford compound 35 (143 mg, 48.4% yield).

[0840] MS m / z(ESI):473.2[M+H] + .

[0841] Example 36 N-[1-(1H-indol-3-yl)hexyl-2-yl]-1-methyl-6-(4-methylpiperazin-1-yl)-1H-indole-2-carboxamide

[0842] Step 1: Ethyl 6-bromo-1-methyl-indole-2-carboxylate 36b

[0843] Compound 36a (400 mg, 1.5 mmol) was dissolved in anhydrous DMF (5 mL). Sodium hydride (72 mg, 1.8 mmol) was added and stirred for 10 minutes. Methyl iodide (0.123 mL, 2 mmol) was then added and the mixture was stirred for 2 hours. The reaction was completed by adding water (1 mL) to quench the reaction. The reaction mixture was diluted with ethyl acetate (50 mL), and the organic phase was washed with saturated brine (30 mL × 3), dried, and concentrated. The crude product was purified by silica gel column chromatography (PE:EA = 1:1) to obtain compound 36b (330 mg, 78% yield).

[0844] MS m / z(ESI):283.0[M+H] + .

[0845] Step 2: 1-Methyl-6-(4-methylpiperazin-1-yl)-indole-2-carboxylic acid ethyl ester 36c

[0846] Compound 36b (330 mg, 1.17 mmol), 1-methylpiperazine (117 mg, 1.17 mmol), palladium acetate (25 mg, 0.11 mmol), Xantphos (100 mg, 0.17 mmol), and cesium carbonate (1.14 g, 3.5 mmol) were mixed in 1,4-dioxane (10 mL). After nitrogen protection, the mixture was heated to 110°C for 4 hours, and the reaction was complete. The reaction mixture was concentrated, diluted with ethyl acetate (50 mL), washed with water (30 mL x 2), dried, and spin-dried. The crude product was purified by silica gel column chromatography (PE:EA = 2:1) to obtain compound 36c (280 mg, 79.5% yield).

[0847] MS m / z(ESI):302.1[M+H] + .

[0848] Step 3: 1-Methyl-6-(4-methylpiperazin-1-yl)-indole-2-carboxylic acid 36d

[0849] Compound 36c (280 mg, 0.93 mmol) was dissolved in tetrahydrofuran (10 mL), and sodium hydroxide (200 mg, 5 mmol) dissolved in water (5 mL) was added. The temperature was raised to 70°C and the reaction was allowed to react for 3 hours, resulting in completion. The reaction mixture was concentrated to remove tetrahydrofuran and adjusted to pH 6 with 1M hydrochloric acid. A solid precipitated and was filtered to afford compound 36d (210 mg, 82.7% yield).

[0850] MS m / z(ESI):274.2[M+H] + .

[0851] Step 4: N-[1-(1H-indol-3-yl)hexyl-2-yl]-1-methyl-6-(4-methylpiperazin-1-yl)-1H-indole-2-carboxamide 36

[0852] Compound 36d (136 mg, 0.5 mmol) and 1-(1H-indol-3-yl)hexyl-2-amine (108 mg, 0.5 mmol) were mixed in DMF (3 mL). DIEA (0.17 mL, 1 mmol) was added, followed by HATU (190 mg, 0.5 mmol). The reaction mixture was stirred at room temperature for 2 hours, and the reaction was complete. The reaction mixture was diluted with ethyl acetate (50 mL), and the organic phase was washed with saturated brine (30 mL × 3), dried over anhydrous sodium sulfate, and concentrated to obtain a crude product which was purified by silica gel column chromatography (PE:EA = 1:1) to afford compound 36 (95 mg, 40.4% yield).

[0853] 1H NMR (400MHz, DMSO-d6) δ10.8 (s, 1H), 7.80-7.64 (d, J = 8Hz 1H),7.50-7.12(m,6H),6.92-6.70(m,2H),6.48-6.40(m,1H),4.42-4.30(m,1H),3.45(s,1H),3.30-3.10(m,4H) ,2.96-2.72(m,2H),2.56-2.42(m,4H),2.28(s,3H),1.68-1.50(m,2H),1.36-1.20(m,4H),0.88(t,J=7.2Hz,3H).

[0854] MS m / z(ESI):472.2[M+H] + .

[0855] Example 37 (E)-N-(1-(1H-indol-3-yl)hex-3-en-2-yl)-6-(4-methylpiperazin-1-yl)benzo[b]thiophene-2-carboxamide

[0856] Step 1: (E)-1-Nitropent-2-ene 37b

[0857] Compound 37a (1 g, 5.1 mmol) and silver nitrite (1.54 g, 10 mmol) were mixed in water (15 mL) and heated to 70°C for 5 hours, resulting in completion of the reaction. The reaction mixture was filtered and extracted with dichloromethane (50 mL). The dichloromethane layer was then concentrated at low temperature to afford compound 37b (480 mg, 82.6% yield).

[0858] Step 2: 3-((1E,3E)-2-Nitrohexa-1,3-dien-1-yl)-1H-indole 37c

[0859] 1H-Indole-3-carboxaldehyde (240 mg, 1.65 mmol), compound 37b (480 mg, 4 mmol), and ammonium acetate (90 mg, 1.16 mmol) were mixed and heated to 70°C in a sealed tube for 3 hours, resulting in completion. The reaction mixture was diluted with ethyl acetate (50 mL), and the organic phase was washed with saturated brine (30 mL × 3), concentrated, and purified by silica gel column chromatography (PE:EA = 3:1) to afford compound 37c (210 mg, 51% yield).

[0860] MS m / z(ESI):243.1[M+H] + .

[0861] Step 3: (E)-1-(1H-indol-3-yl)hex-3-en-2-amine 37d

[0862] Compound 37c (210 mg, 0.81 mmol) was dissolved in anhydrous tetrahydrofuran (3 mL). 1 M lithium aluminum hydride solution (2.5 mL) was added at 70°C and stirred at room temperature overnight. The reaction was complete. The reaction mixture was quenched by the addition of 15% sodium hydroxide solution (3 mL) and extracted with dichloromethane (50 mL). The organic phase was washed with saturated brine (30 mL × 3), concentrated, and purified by silica gel column chromatography (PE:EA = 1:1) to afford compound 37d (105 mg, 61% yield).

[0863] MS m / z(ESI):215.1[M+H] + .

[0864] Step 4: (E)-N-(1-(1H-indol-3-yl)hex-3-en-2-yl)-6-(4-methylpiperazin-1-yl)benzo[b]thiophene-2-carboxamide 37

[0865] Compound 37d (105 mg, 0.49 mmol) and compound 1h (143 mg, 0.50 mmol) were mixed in DMF (3 mL). DIEA (0.2 mL, 1.2 mmol) was added, followed by HATU (235 mg, 0.62 mmol). The reaction mixture was stirred at room temperature for 2 hours, and the reaction was complete. The reaction mixture was diluted with ethyl acetate (50 mL), and the organic phase was washed with saturated brine (30 mL × 3), dried over anhydrous sodium sulfate, and concentrated to obtain a crude product which was purified by silica gel column chromatography (PE:EA = 1:1) to afford compound 37 (143 mg, 62% yield).

[0866] Example 38 (E)-N-(1-(1H-indol-3-yl)hex-3-en-2-yl)-6-(4-methylpiperazin-1-yl)benzo[b]thiophene-2-carboxamide

[0867] Step 1: N,N-dimethyl-3-nitropropane-1-amine 38b

[0868] Compound 38a (1 g, 4.7 mmol) and silver nitrite (1.54 g, 10 mmol) were mixed in water (15 mL) and heated to 70°C for 5 hours, resulting in completion of the reaction. The reaction mixture was filtered and extracted with dichloromethane (30 mL x 3). The dichloromethane layer was concentrated at low temperature to afford compound 38b (510 mg, 86.2% yield).

[0869] Step 2: (E)-4-(1H-indol-3-yl)-N,N-dimethyl-3-nitrobut-3-en-1-amine 38c

[0870] 1H-Indole-3-carboxaldehyde (240 mg, 1.65 mmol), compound 38b (510 mg, 4.1 mmol), and ammonium acetate (90 mg, 1.16 mmol) were mixed and heated to 70°C in a sealed tube for 3 hours, resulting in the reaction. The reaction mixture was diluted with ethyl acetate (50 mL), and the organic phase was washed with saturated brine (30 mL × 3), concentrated, and purified by silica gel column chromatography (PE:EA = 1:1) to afford compound 38c (210 mg, 51% yield).

[0871] MS m / z(ESI):260.1[M+H] + .

[0872] Step 3: 4-(1H-indol-3-yl)-N1,N1-dimethylbutane-1,3-diamine 38d

[0873] Compound 38c (210 mg, 0.81 mmol) was dissolved in anhydrous tetrahydrofuran (3 mL). 1 M lithium aluminum hydride solution (2.5 mL) was added at 70°C and stirred at room temperature overnight. The reaction was complete. The reaction mixture was quenched by the addition of 15% sodium hydroxide solution (3 mL) and extracted with dichloromethane (50 mL). The organic phase was washed with saturated sodium chloride (30 mL × 3) and then concentrated and purified by silica gel column chromatography (PE:EA = 1:1) to afford compound 38d (121 mg, 71% yield).

[0874] MS m / z(ESI):232.1[M+H] + .

[0875] Step 4: (E)-N-(1-(1H-indol-3-yl)hex-3-en-2-yl)-6-(4-methylpiperazin-1-yl)benzo[b]thiophene-2-carboxamide 38

[0876] Compound 38d (105 mg, 0.45 mmol) and compound 1h (143 mg, 0.50 mmol) were mixed in DMF (3 mL). DIEA (0.2 mL, 1.2 mmol) was added, followed by HATU (235 mg, 0.62 mmol). The reaction mixture was stirred at room temperature for 2 hours, and the reaction was complete. The reaction mixture was diluted with ethyl acetate (50 mL). The organic phase was washed with saturated brine (30 mL × 3), dried over anhydrous sodium sulfate, and concentrated. The crude product was purified by silica gel column chromatography (PE:EA = 1:1) to obtain compound 38 (143 mg, 66.7% yield).

[0877] MS m / z(ESI):473.2[M+H] + .

[0878] Example 39 N-(1-ethoxy-3-(1H-indol-3-yl)propan-2-yl)-6-(4-methylpiperazin-1-yl)benzo[b]thiophene-2-carboxamide

[0879] Step 1: 1-Ethoxy-2-nitroethane 39b

[0880] Compound 39a (1 g, 5.0 mmol) and silver nitrite (1.54 g, 10 mmol) were mixed in water (15 mL) and heated to 70°C for 5 hours, resulting in completion of the reaction. The reaction mixture was filtered and extracted with dichloromethane (30 mL x 3). The dichloromethane layer was concentrated at low temperature to afford compound 39b (580 mg, 92.2% yield).

[0881] Step 2: (E)-3-(3-Ethoxy-2-nitroprop-1-en-1-yl)-1H-indole 39c

[0882] 1H-Indole-3-carboxaldehyde (240 mg, 1.65 mmol), compound 39b (580 mg, 4.1 mmol), and ammonium acetate (90 mg, 1.16 mmol) were mixed and heated to 70°C in a sealed tube for 3 hours, resulting in the reaction being complete. The reaction mixture was diluted with ethyl acetate (50 mL), and the organic phase was washed with saturated brine (30 mL × 3), concentrated, and purified by silica gel column chromatography (PE:EA = 1:1) to afford compound 39c (260 mg, 51% yield).

[0883] MS m / z(ESI):247.2[M+H] + .

[0884] Step 3: 1-Ethoxy-3-(1H-indol-3-yl)propan-2-amine 39d

[0885] Compound 39c (260 mg, 1.06 mmol) was dissolved in anhydrous tetrahydrofuran (3 mL). 1 M lithium aluminum hydride solution (2.5 mL) was added at 70°C and stirred at room temperature overnight. The reaction was complete. 15% sodium hydroxide solution (3 mL) was added to the reaction mixture to quench the reaction. Dichloromethane (50 mL) was then added for extraction. The organic phase was washed with saturated brine (30 mL × 3), concentrated, and purified by silica gel column chromatography (PE:EA = 1:1) to afford compound 39d (121 mg, 52% yield).

[0886] MS m / z(ESI):219.1[M+H] + .

[0887] Step 4: N-(1-ethoxy-3-(1H-indol-3-yl)propan-2-yl)-6-(4-methylpiperazin-1-yl)benzo[b]thiophene-2-carboxamide 39

[0888] Compound 39d (120 mg, 0.55 mmol) and compound 1h (143 mg, 0.50 mmol) were mixed in DMF (3 mL). DIEA (0.2 mL, 1.2 mmol) was added, followed by HATU (235 mg, 0.62 mmol). The reaction mixture was stirred at room temperature for 2 hours, and the reaction was complete. The reaction mixture was diluted with ethyl acetate (50 mL). The organic phase was washed with saturated brine (30 mL × 3), dried over anhydrous sodium sulfate, and concentrated. The crude product was purified by silica gel column chromatography (PE:EA = 1:1) to obtain compound 39 (85 mg, 36% yield).

[0889] MS m / z(ESI):473.2[M+H] + .

[0890] Example 40 (E)-N-(1-(1H-indol-3-yl)-5-methylhex-3-en-2-yl)-6-(4-methylpiperazin-1-yl)benzo[b]thiophene-2-carboxamide

[0891] Step 1: (E)-1-(1H-indol-3-yl)-5-methylhex-3-en-2-one 40b

[0892] Compound 40a (1.0 g, 7.63 mmol) was dissolved in 1,2-dichloroethane (10 mL). Aluminum chloride (2.68 g, 20.1 mmol) was added at 0°C and stirred at room temperature for 30 minutes. The temperature was then lowered to 0°C and (E)-4-methylpent-2-enoyl chloride (889 mg, 9.50 mmol) was added dropwise. The mixture was allowed to react at room temperature for 48 hours. LCMS indicated the reaction was complete. The reaction solution was slowly poured into ice water, extracted with dichloromethane (50 mL × 3), dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column chromatography (PE:EA = 1:1) to afford compound 40b (240 mg, brown colloid, 14% yield).

[0893] MS m / z(ESI):228.4[M+H] + .

[0894] Step 2: (E)-1-(1H-indol-3-yl)-5-methylhex-3-en-2-amine 40c

[0895] Compound 40b (240 mg, 1.06 mmol) was dissolved in methanol (5 mL), and ammonium acetate (92.5 mg, 1.2 mmol) and sodium cyanoborohydride (63.8 mg, 1.2 mmol) were added. The mixture was heated to 70°C for 18 hours. LCMS indicated that the reaction was complete. The reaction solution was concentrated and extracted with dichloromethane (50 mL × 3). The organic phase was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, and concentrated to afford compound 40c (120 mg, yellow colloid, crude product).

[0896] MS m / z(ESI):229.2[M+H] + .

[0897] Step 3: (E)-N-(1-(1H-indol-3-yl)-5-methylhex-3-en-2-yl)-6-(4-methylpiperazin-1-yl)benzo[b]thiophene-2-carboxamide 40

[0898] Compound 40c (120 mg, 0.526 mmol) and compound 1h (110 mg, 0.451 mmol) were dissolved in DMF (3 mL), and DIEA (132.37 mg, 1.024 mmol) and HATU (145.8 mg, 0.451 mmol) were added. The reaction was carried out at room temperature for 1 hour. LCMS showed that the reaction was complete. The reaction solution was extracted with ethyl acetate (50 mL×3), and the organic phase was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and purified and separated by preparative HPLC to obtain compound 40 (12 mg, white solid, yield 5.5%).

[0899] MS m / z(ESI):487.4[M+H] + .

[0900] Example 41 N-(4-ethoxy-1-(1H-indol-3-yl)butan-2-yl)-6-(4-methylpiperazin-1-yl)benzo[b]thiophene-2-carboxamide

[0901] Step 1: 1-(2-nitroethoxy)propane 41b

[0902] Compound 41a (1 g, 4.7 mmol) and silver nitrite (1.54 g, 10 mmol) were mixed in water (15 mL) and heated to 70°C for 5 hours, resulting in completion of the reaction. The reaction mixture was filtered and extracted with dichloromethane (50 mL). The dichloromethane layer was concentrated at low temperature to afford compound 41b (460 mg, 86% yield).

[0903] Step 2: (E)-3-(3-Ethoxy-2-nitroprop-1-en-1-yl)-1H-indole 41c

[0904] 1H-Indole-3-carbaldehyde (240 mg, 1.65 mmol), compound 41b (460 mg, 3.8 mmol), and ammonium acetate (90 mg, 1.16 mmol) were mixed and heated to 70°C in a sealed tube for 3 hours, resulting in the reaction. The reaction mixture was diluted with ethyl acetate (50 mL), and the organic phase was washed with saturated brine (30 mL × 3), concentrated, and purified by silica gel column chromatography (PE:EA = 2:1) to afford compound 41c (260 mg, 51% yield).

[0905] MS m / z(ESI):261.2[M+H] + .

[0906] Step 3: 4-Ethoxy-1-(1H-indol-3-yl)butan-2-amine 41d

[0907] Compound 41c (260 mg, 1.00 mmol) was dissolved in anhydrous tetrahydrofuran (3 mL). 1 M lithium aluminum hydride solution (2.5 mL) was added at 70°C and stirred at room temperature overnight. The reaction was complete. 15% sodium hydroxide solution (3 mL) was added to the reaction mixture to quench the reaction. Dichloromethane (50 mL) was then added for extraction. The organic phase was washed with saturated brine (30 mL × 3), concentrated, and purified by silica gel column chromatography (PE:EA = 1:1) to afford compound 41d (121 mg, 52% yield).

[0908] MS m / z(ESI):233.1[M+H] + .

[0909] Step 4: N-(1-ethoxy-3-(1H-indol-3-yl)propan-2-yl)-6-(4-methylpiperazin-1-yl)benzo[b]thiophene-2-carboxamide 41

[0910] Compound 41d (120 mg, 0.52 mmol) and compound 1h (143 mg, 0.50 mmol) were mixed in DMF (3 mL). DIEA (0.2 mL, 1.2 mmol) was added, followed by HATU (235 mg, 0.62 mmol). The reaction mixture was stirred at room temperature for 2 hours, and the reaction was complete. The reaction mixture was diluted with ethyl acetate (50 mL), and the organic phase was washed with saturated brine (30 mL × 3), dried over anhydrous sodium sulfate, and concentrated to obtain a crude product which was purified by silica gel column chromatography (PE:EA = 1:1) to afford compound 41 (110 mg, 46.6% yield).

[0911] MS m / z(ESI):473.2[M+H] + .

[0912] Example 42 (S)-N-(1-(1H-indol-3-yl)hexan-2-yl)-6-(4-methylpiperazin-1-yl)benzo[b]thiophene-2-carboxamide

[0913] Example 43 (R)-N-(1-(1H-indol-3-yl)hexan-2-yl)-6-(4-methylpiperazin-1-yl)benzo[b]thiophene-2-carboxamide

[0914] The racemate compound 1 (500 mg, 1.053 mmol) was separated by chiral separation to give compound 42 (150 mg) and compound 43 (190 mg).

[0915] The enantiomers were separated using a Chiralpak AD-H column (250×30 mm) in a THAR 80 preparative SFC. The enantiomers were dissolved in methanol (100 mg / mL) and 100 mg of each enantiomer was loaded per injection. A mobile phase of 40% 2-propanol (additive: 0.05% NH 3 -H 2 O) in carbon dioxide at a flow rate of 70 g and a system back pressure of 100 bar were used to achieve the separation. The column temperature was maintained at 40° C. and the peak was detected at 220 nm. The total cycle time was 6 minutes.

[0916] Chiral purity test of compound 42 (OJ-H, 45% MeOH (0.05% NH3-H2O) peak RT: 1.95 (100%).

[0917] Chiral purity test of compound 43 (OJ-H, 45% MeOH (0.05% NH3-H2O) Peak 1 RT: 2.004 (1.16%) Peak 2 RT: 3.04 (98.54%).

[0918] Compound 42 MS m / z (ESI): 475.5 [M+H] + .

[0919] Compound 43 MS m / z (ESI): 475.5 [M+H] + .

[0920] Example 44 6-[4-(Cyclopropanesulfonyl)piperazin-1-yl]-N-[1-(1H-indol-3-yl)hexan-2-yl]-1-benzothiophene-2-carboxamide

[0921] Step 1: tert-Butyl 4-[2-(ethoxycarbonyl)-1-benzothiophen-6-yl]piperazine-1-carboxylate 44b

[0922] Ethyl 6-bromo-1-benzothiophene-2-carboxylate (2000 mg, 7 mmol), tert-butyl piperazine-1-carboxylate (1959 mg, 10.5 mmol), Xantphos (405 mg, 0.7 mmol), palladium acetate (79 mg, 0.4 mmol), and cesium carbonate (11.4 g, 35 mmol) were added to a reaction flask, followed by 20 mL of 1,4-dioxane. Stirring was started under nitrogen protection, and the temperature was raised to 100°C for 3 hours. After the reaction, 100 mL of water was added to quench the reaction, and the mixture was extracted with ethyl acetate (50 mL × 3). The organic layers were combined, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography (PE:EA = 5:1) to obtain compound 44b (2.3 g, yield 84%).

[0923] MS m / z(ESI):391.2[M+H] + .

[0924] Step 2: 6-(4-[(tert-Butoxy)carbonyl]piperazin-1-yl)-1-benzothiophene-2-carboxylic acid 44c

[0925] Compound 44b (1.2 g, 3.1 mmol) was added to a reaction flask and dissolved in 10 mL of methanol and 10 mL of tetrahydrofuran. Sodium hydroxide (0.61 g, 15.4 mmol) was dissolved in 10 mL of water and added to the flask. Stirring was initiated and the mixture was reacted at 70°C for 1 hour. After completion of the reaction, the solvent was removed by rotary evaporation, and the mixture was dissolved in water. The pH was adjusted to 5-6 with hydrochloric acid, filtered, and dried to obtain compound 44c (1.0 g, 90% yield).

[0926] MS m / z(ESI):363.1[M+H] + .

[0927] Step 3: tert-Butyl 4-(2-([1-(1H-indol-3-yl)hexan-2-yl]carbamoyl)-1-benzothiophen-6-yl)piperazine-1-carboxylate 44d

[0928] Compound 44c (500 mg, 1.38 mmol) and compound 1c (251 mg, 1.16 mmol) were dissolved in 5 mL of DMF, and 1-methylimidazole (476 mg, 5.8 mmol) and N,N,N',N'-tetramethylchloroformamidine hexafluorophosphate (488 mg, 1.7 mmol) were added. The mixture was stirred at room temperature for 1 hour. After completion of the reaction, 20 mL of water was added to quench the reaction, and the mixture was extracted with ethyl acetate (50 mL × 3). The organic layers were combined, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography (PE:EA = 2:1) to obtain compound 44d (560 mg, yield 86%).

[0929] MS m / z(ESI):561.3[M+H] + .

[0930] Step 4: N-[1-(1H-indol-3-yl)hexane-2-yl]-6-(piperazin-1-yl)-1-benzothiophene-2-carboxamide 44e

[0931] Compound 44d (560 mg, 1.0 mmol) was added to a solution of hydrogen chloride in ethyl acetate (10 mL, 4.0 M), stirred, and allowed to react at room temperature for 1 hour. After the reaction, the solvent was removed by rotary evaporation to obtain compound 44e (414 mg, 90% yield).

[0932] MS m / z(ESI):461.3[M+H] + .

[0933] Step 5: 6-[4-(cyclopropanesulfonyl)piperazin-1-yl]-N-[1-(1H-indol-3-yl)hexane-2-yl]-1-benzothiophene-2-carboxamide 44

[0934] Compound 44e (200 mg, 0.434 mmol) was dissolved in 3 mL of dichloromethane, and triethylamine (66 mg, 0.66 mmol) was added. The mixture was stirred under ice-cooling. Cyclopropylsulfonyl chloride (64 mg, 0.456 mmol) was diluted with 2 mL of dichloromethane and added dropwise to the reaction flask. After the addition was complete, the mixture was transferred to room temperature and allowed to react for 1 hour. After completion of the reaction, 20 mL of water was added to quench the reaction. The mixture was extracted with ethyl acetate (50 mL x 3). The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product, which was purified by silica gel column chromatography (PE:EA = 1:1) to afford compound 44 (70 mg, 29% yield).

[0935] MS m / z(ESI):565.2[M+H] + .

[0936] Example 45 N-[1-(1H-indol-3-yl)hexan-2-yl]-6-(4-methylsulfonylpiperazin-1-yl)-1-benzothiophene-2-carboxamide

[0937] Compound 44e (200 mg, 0.434 mmol) was dissolved in 3 mL of dichloromethane, and triethylamine (66 mg, 0.651 mmol) was added. The mixture was stirred under ice-cooling. Methanesulfonyl chloride (49 mg, 0.434 mmol) was diluted with 2 mL of dichloromethane and added dropwise to the reaction flask. After the addition was complete, the mixture was transferred to room temperature and allowed to react for 1 hour. After completion of the reaction, the reaction was quenched with 20 mL of water and extracted with ethyl acetate (50 mL x 3). The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product, which was purified and isolated by preparative HPLC to afford compound 45 (30 mg, 13% yield).

[0938] 1 H NMR(400MHz,Chloroform-d)δ8.16(s,1H),7.65(dd,J=15.3,8.4Hz,2H),7.43(s,1H),7 .38(d,J=8.1Hz,1H),7.20(ddd,J=8.2,6.9,1.2Hz,1H),7.15–7.01(m,3H),5.91(d,J=8. 8Hz, 1H), 4.47 (tdd, J=11.1, 7.0, 4.3Hz, 1H), 3.41 (dd, J=6.3, 3.1Hz, 4H), 3.33 (dd, J=6. 3, 3.2Hz, 4H), 3.15–3.01 (m, 2H), 2.83 (s, 3H), 1.74–1.23 (m, 7H), 0.88 (t, J = 7.1Hz, 3H).

[0939] MS m / z(ESI):539.2[M+H] + .

[0940] Example 46 N-[1-(1H-indol-3-yl)hexan-2-yl]-6-(4-methyl-3-oxopiperazin-1-yl)-1-benzothiophene-2-carboxamide

[0941] Step 1: Ethyl 6-(4-methyl-3-oxopiperazin-1-yl)-1-benzothiophene-2-carboxylate 46a

[0942] Compound 1f (500 mg, 1.753 mmol), 1-methylpiperazin-2-one (300 mg, 2.63 mmol), Xantphos (101 mg, 0.175 mmol), palladium acetate (20 mg, 0.088 mmol), and cesium carbonate (1713 mg, 5.26 mmol) were added to a reaction flask. 1,4-dioxane (10 mL) was then added. Stirring was initiated under nitrogen, and the temperature was raised to 100°C for 3 hours. After completion of the reaction, water (50 mL) was added to quench the reaction, and the mixture was extracted with ethyl acetate (50 mL × 3). The organic layers were combined, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (PE:EA = 1:1) to obtain compound 46a (460 mg, 83% yield).

[0943] MS m / z(ESI):319.1[M+H] + .

[0944] Step 2: 6-(4-Methyl-3-carbonylpiperazin-1-yl)benzo[b]thiophene-2-carboxylic acid 46b

[0945] Compound 46a (460 mg, 1.445 mmol) was added to a reaction flask and dissolved in 3 mL of methanol and 3 mL of tetrahydrofuran. Lithium hydroxide monohydrate (182 mg, 4.335 mmol) was dissolved in 3 mL of water and added to the reaction flask. Stirring was initiated and the mixture was allowed to react at room temperature for 1 hour. After the reaction, the solvent was removed by rotary evaporation, and the mixture was dissolved in water. The pH was adjusted to 5-6 with 1 M hydrochloric acid, filtered, and the filter cake was dried to obtain compound 46b (420 mg).

[0946] MS m / z(ESI):291.0[M+H] + .

[0947] Step 3: N-[1-(1H-indol-3-yl)hexan-2-yl]-6-(4-methyl-3-oxopiperazin-1-yl)-1-benzothiophene-2-carboxamide 46

[0948] Compound 46b (300 mg, 1.033 mmol) and compound 1c (203 mg, 0.939 mmol) were dissolved in 3 mL of DMF, and 1-methylimidazole (386 mg, 4.695 mmol) and N,N,N',N'-tetramethylchloroformamidine hexafluorophosphate (395 mg, 1.409 mmol) were added. The mixture was stirred at room temperature for 1 hour. After completion of the reaction, 20 mL of water was added to quench the reaction, and the mixture was extracted with ethyl acetate (50 mL x 3). The organic layers were combined, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by preparative HPLC to obtain compound 44 (100 mg, 22% yield).

[0949] MS m / z(ESI):489.3[M+H] + .

[0950] 1 H NMR (400MHz, DMSO-d6) δ10.77(d,J=2.3Hz,1H),8.34(d,J=8.5Hz,1H),7.97(s,1H),7.76(d,J= 8.9Hz,1H),7.63(d,J=7.9Hz,1H),7.46(d,J=2.3Hz,1H),7.33(d,J=8.0Hz,1H),7.21–7.12(m,2 H),7.10–7.02(m,1H),7.02–6.94(m,1H),3.88(s,2H),3.60(dd,J=6.5,4.3Hz,2H),3.47(dd,J= 6.5, 4.3Hz, 4H), 2.93 (s, 3H), 1.56 (d, J = 12.4Hz, 1H), 1.41–1.20 (m, 6H), 0.83 (t, J = 6.8Hz, 3H).

[0951] Example 47 N-[1-(1H-indol-3-yl)hexan-2-yl]-6-(4-methyl-2-oxopiperazin-1-yl)-1-benzothiophene-2-carboxamide

[0952] Step 1: Ethyl 6-(4-methyl-2-oxopiperazin-1-yl)-1-benzothiophene-2-carboxylate 47a

[0953] Compound 1f (300 mg, 1.052 mmol), 4-methylpiperazin-2-one (132 mg, 1.157 mmol), cuprous iodide (160 mg, 0.842 mmol), 1,10-phenanthroline (23 mg, 0.105 mmol), and potassium carbonate (695 mg, 2.104 mmol) were added to a reaction flask, followed by the addition of 2 mL of dimethyl sulfoxide. The mixture was microwaved at 130°C for 5 hours. After completion of the reaction, 20 mL of water was added to quench the reaction, and the mixture was extracted with ethyl acetate (50 mL × 3). The organic layers were combined, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography (PE:EA = 1:1) to afford compound 47a (220 mg, 66% yield).

[0954] MS m / z(ESI):319.1[M+H] + .

[0955] Step 2: 6-(4-methyl-2-oxopiperazin-1-yl)-1-benzothiophene-2-carboxylic acid 47b

[0956] Compound 47a (220 mg, 0.691 mmol) was dissolved in 3 mL of methanol, and sodium hydroxide (83 mg, 2.073 mmol) was dissolved in 3 mL of water. The mixture was added to a reaction flask, stirred, and allowed to react at room temperature for 1 hour. After completion of the reaction, the solvent was removed by rotary evaporation, and the mixture was dissolved in water. The pH was adjusted to 5-6 with 1 M hydrochloric acid, filtered, and the filter cake dried to afford compound 47b (160 mg, 80% yield).

[0957] MS m / z(ESI):291.1[M+H] + .

[0958] Step 3: N-[1-(1H-indol-3-yl)hexan-2-yl]-6-(4-methyl-2-oxopiperazin-1-yl)-1-benzothiophene-2-carboxamide 47

[0959] Compound 47b (160 mg, 0.551 mmol) and compound 1c (119 mg, 0.551 mmol) were dissolved in 5 mL of DMF, and 1-methylimidazole (226 mg, 2.755 mmol) and N,N,N',N'-tetramethylchloroformamidine hexafluorophosphate (232 mg, 0.827 mmol) were added. The mixture was stirred at room temperature for 1 hour. After completion of the reaction, 20 mL of water was added to quench the reaction, and the mixture was extracted with ethyl acetate (50 mL x 3). The organic layers were combined, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by preparative HPLC. The mixture was then freeze-dried to afford compound 47 (60 mg, 22% yield).

[0960] MS m / z(ESI):489.2[M+H] + .

[0961] 1 H NMR (400MHz, Chloroform-d) δ8.27 (s, 1H), 7.63 (dd, J=21.1, 8.2Hz, 2H), 7.36 (dd, J=7. 6,2.9Hz,3H),7.19(ddd,J=15.2,8.4,1.6Hz,2H),7.14–7.06(m,2H),6.24(d,J=9.4Hz,1 H),4.51(d,J=5.9Hz,1H),3.68(qt,J=11.5,5.3Hz,2H),3.32(s,2H),3.07(qd,J=15.0,5 .9Hz,2H),2.81(t,J=5.4Hz,2H),2.44(s,3H),1.83–1.22(m,6H),0.88(t,J=7.1Hz,3H).

[0962] Example 48 N-(1-(1H-indol-3-yl)hexan-2-yl)-6-(4-hydroxy-4-methylpiperidin-1-yl)benzo[b]thiophene-2-carboxamide 48

[0963] Step 1: Ethyl 6-(4-hydroxy-4-methylpiperidin-1-yl)benzo[b]thiophene-2-carboxylate 48a

[0964] Compound 1f (1000 mg, 3.5 mmol), palladium acetate (40 mg, 0.2 mmol), Xantphos (202 mg, 0.35 mmol), and cesium carbonate (3.42 g, 10.5 mmol) were added to a reaction flask. 4-Methylpiperidin-4-ol (674 mg, 5.3 mmol) was dissolved in 10 mL of 1,4-dioxane. Under nitrogen protection, stirring was initiated and the reaction was carried out at 100°C for 3 hours. After completion of the reaction, water (50 mL) was added to quench the reaction. The mixture was extracted with ethyl acetate (50 mL x 3). The organic layers were combined, dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column chromatography (PE:EA = 5:1) to obtain compound 48a (510 mg, 46% yield).

[0965] MS m / z(ESI):320.2[M+H] + .

[0966] Step 2: 6-(4-Hydroxy-4-methylpiperidin-1-yl)benzo[b]thiophene-2-carboxylic acid 48b

[0967] Compound 48a (0.24 g, 0.752 mmol) was dissolved in methanol (3 mL) and water (3 mL). Lithium hydroxide (0.05 g, 2.166 mmol) was then added at room temperature, and the reaction mixture was stirred at room temperature for 1 hour. TLC indicated completion of the reaction. The reaction mixture was adjusted to pH 3-4 with dilute hydrochloric acid (5 mL, 2.0 M), resulting in the precipitation of a white solid. The reaction mixture was filtered to obtain compound 48b (190 mg, 87% yield).

[0968] MS m / z(ESI):292.4[M+H] + .

[0969] Step 3: N-(1-(1H-indol-3-yl)hexan-2-yl)-6-(4-hydroxy-4-methylpiperidin-1-yl)benzo[b]thiophene-2-carboxamide 48

[0970] Compound 1c (160 mg, 0.720 mmol) and compound 48b (190 mg, 0.65 mmol) were added to a reaction flask and dissolved in 5 mL of DMF. 1-Methylimidazole (324 mg, 3.94 mmol) and N,N,N',N'-tetramethylchloroformamidine hexafluorophosphate (332 mg, 1.18 mg) were then added. Stirring was initiated at room temperature for 1 hour. After completion of the reaction, water (20 mL) was added to quench the reaction, and the mixture was extracted with ethyl acetate (50 mL × 3). The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated to obtain a crude product, which was purified and isolated using preparative HPLC to obtain compound 48 (35 mg, 11% yield).

[0971] MS m / z(ESI):490.3[M+H] + .

[0972] 1 H NMR(400MHz,Chloroform-d)δ8.45(s,1H),7.87–7.75(m,1H),7.54–7.48(m,1H),7.33–7.28(m,1H),7.18(s,1H),6.98–6.82(m,3H),5.40–5.34(m ,2H), 4.10–4.02(m,1H), 3.24-3.04(m,4H),2.86–2.61(m,2H), 2.25-2.1 1(m,4H),1.82-1.71(m,4H),1.52-1.47(m,4H),1.20(s,3H),0.88(t,3H).

[0973] Example 49 N-(1-(1H-indol-3-yl)hexan-2-yl)-6-(3-hydroxy-3-methylazetidin-1-yl)benzo[b]thiophene-2-carboxamide 49

[0974] Step 1: Ethyl 6-(3-hydroxy-3-methylazetidin-1-yl)benzo[b]thiophene-2-carboxylate 49a

[0975] Compound 1f (1000 mg, 3.5 mmol), palladium acetate (40 mg, 0.2 mmol), Xantphos (202 mg, 0.35 mmol), and cesium carbonate (3.42 g, 10.5 mmol) were added to a reaction flask. 3-Methylazetidin-3-ol (450 mg, 5.3 mmol) was dissolved in 10 mL of 1,4-dioxane. Under nitrogen protection, stirring was initiated and the reaction was carried out at 100°C for 3 hours. After completion of the reaction, water (50 mL) was added to quench the reaction. The mixture was extracted with ethyl acetate (50 mL × 3). The organic layers were combined, dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column chromatography (PE:EA = 5:1) to obtain compound 49a (650 mg, 64% yield).

[0976] MS m / z(ESI):292.2[M+H] + .

[0977] Step 2: 6-(3-Hydroxy-3-methylazetidin-1-yl)benzo[b]thiophene-2-carboxylic acid 49b

[0978] Compound 49a (0.65 g, 2.23 mmol) was dissolved in methanol (5 mL) and water (5 mL). Lithium hydroxide (0.281 g, 6.67 mmol) was then added at room temperature, and the reaction mixture was stirred at room temperature for 1 hour. TLC indicated completion of the reaction. The reaction mixture was adjusted to pH 3-4 with dilute hydrochloric acid (5 mL, 2.0 M), resulting in the precipitation of a white solid. The reaction mixture was filtered to obtain compound 49b (550 mg, 94% yield).

[0979] MS m / z(ESI):264.4[M+H] + .

[0980] Step 3: N-(1-(1H-indol-3-yl)hexan-2-yl)-6-(3-hydroxy-3-methylazetidin-1-yl)benzo[b]thiophene-2-carboxamide 49

[0981] Compound 1c (160 mg, 0.720 mmol) and compound 49b (170 mg, 0.65 mmol) were added to a reaction flask and dissolved in DMF (5 mL). 1-Methylimidazole (324 mg, 3.94 mmol) and N,N,N',N'-tetramethylchloroformamidine hexafluorophosphate (332 mg, 1.18 mg) were then added. Stirring was initiated at room temperature for 1 hour. After completion of the reaction, water (20 mL) was added to quench the reaction, and the mixture was extracted with ethyl acetate (50 mL × 3). The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated to obtain a crude product, which was purified and isolated using preparative HPLC to obtain compound 49 (45 mg, 15% yield).

[0982] MS m / z(ESI):462.3[M+H] + .

[0983] Example 50 N-(1-(1H-indol-3-yl)hexan-2-yl)-6-(6-hydroxy-6-methyl-2-azaspiro[3.3]heptan-2-yl)benzo[b]thiophene-2-carboxamide 50

[0984] Step 1: Ethyl 6-(6-hydroxy-6-methyl-2-azaspiro[3.3]heptane-2-yl)benzo[b]thiophene-2-carboxylate 50a

[0985] Compound 1f (1000 mg, 3.5 mmol), palladium acetate (40 mg, 0.2 mmol), Xantphos (202 mg, 0.35 mmol), and cesium carbonate (3.42 g, 10.5 mmol) were added to a reaction flask. 6-Methyl-2-azaspiro[3.3]heptan-6-ol (580 mg, 5.3 mmol) was dissolved in 10 mL of 1,4-dioxane. Under nitrogen protection, stirring was initiated and the reaction was carried out at 100°C for 3 hours. After completion of the reaction, water (50 mL) was added to quench the reaction. The mixture was extracted with ethyl acetate (50 mL × 3). The organic layers were combined, dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column chromatography (PE:EA = 5:1) to obtain compound 50a (720 mg, 62% yield).

[0986] MS m / z(ESI):332.2[M+H] + .

[0987] Step 2: 6-(6-Hydroxy-6-methyl-2-azaspiro[3.3]heptane-2-yl)benzo[b]thiophene-2-carboxylic acid 50b

[0988] Compound 50a (0.72 g, 2.10 mmol) was dissolved in methanol (5 mL) and water (5 mL). Lithium hydroxide (0.281 g, 6.60 mmol) was then added at room temperature. The reaction mixture was stirred at room temperature for 1 hour. TLC indicated completion of the reaction. The pH of the reaction mixture was adjusted to 3-4 with dilute hydrochloric acid (5 mL, 2.0 M). A white solid precipitated, which was collected by filtration to afford compound 50b (580 mg, 88% yield).

[0989] MS m / z(ESI):304.2[M+H] + .

[0990] Step 3: N-(1-(1H-indol-3-yl)hexan-2-yl)-6-(6-hydroxy-6-methyl-2-azaspiro[3.3]heptan-2-yl)benzo[b]thiophene-2-carboxamide 50

[0991] Compound 1c (160 mg, 0.720 mmol) and compound 50b (170 mg, 0.56 mmol) were added to a reaction flask and dissolved in 5 mL of DMF. 1-Methylimidazole (324 mg, 3.94 mmol) and N,N,N',N'-tetramethylchloroformamidine hexafluorophosphate (332 mg, 1.18 mg) were then added. Stirring was initiated at room temperature for 1 h. After completion of the reaction, water (20 mL) was added to quench the reaction, and the mixture was extracted with ethyl acetate (50 mL × 3). The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated to obtain a crude product, which was purified and isolated using preparative HPLC to obtain compound 50 (55 mg, 20% yield).

[0992] MS m / z(ESI):502.3[M+H] + .

[0993] Example 51 N-(1-(1H-indol-3-yl)hexan-2-yl)-6-(3-hydroxy-3-methylpyrrolidin-1-yl)benzo[b]thiophene-2-carboxamide 51

[0994] Step 1: Ethyl 6-(6-hydroxy-6-methyl-2-azaspiro[3.3]heptane-2-yl)benzo[b]thiophene-2-carboxylate 51a

[0995] Compound 1f (1000 mg, 3.5 mmol), palladium acetate (40 mg, 0.2 mmol), Xantphos (202 mg, 0.35 mmol), and cesium carbonate (3.42 g, 10.5 mmol) were added to a reaction flask. 3-Methylpyrrolidin-3-ol (510 mg, 5.5 mmol) was dissolved in 10 mL of 1,4-dioxane. Under nitrogen protection, stirring was initiated and the reaction was carried out at 100°C for 3 hours. After completion of the reaction, water (50 mL) was added to quench the reaction. The mixture was extracted with ethyl acetate (50 mL x 3). The organic layers were combined, dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column chromatography (PE:EA = 5:1) to obtain compound 51a (810 mg, 78% yield).

[0996] MS m / z(ESI):306.2[M+H] + .

[0997] Step 2: 6-(3-Hydroxy-3-methylpyrrolidin-1-yl)benzo[b]thiophene-2-carboxylic acid 51b

[0998] Compound 51a (0.810 g, 2.66 mmol) was dissolved in methanol (5 mL) and H₂O (5 mL). Lithium hydroxide (0.340 g, 8.10 mmol) was then added at room temperature. The reaction mixture was stirred at room temperature for 1 hour. TLC indicated completion of the reaction. The pH of the reaction mixture was adjusted to 3-4 with dilute hydrochloric acid (5 mL, 2.0 M). A white solid precipitated, which was collected by filtration to afford compound 51b (610 mg, 83% yield).

[0999] MS m / z(ESI):278.2[M+H] + .

[1000] Step 3: N-(1-(1H-indol-3-yl)hexan-2-yl)-6-(6-hydroxy-6-methyl-2-azaspiro[3.3]heptan-2-yl)benzo[b]thiophene-2-carboxamide 51

[1001] Compound 1c (160 mg, 0.720 mmol) and compound 51b (170 mg, 0.61 mmol) were added to a reaction flask and dissolved in DMF (5 mL). 1-Methylimidazole (324 mg, 3.94 mmol) and N,N,N',N'-tetramethylchloroformamidine hexafluorophosphate (332 mg, 1.18 mg) were then added. Stirring was initiated at room temperature for 1 hour. After completion of the reaction, water (20 mL) was added to quench the reaction, and the mixture was extracted with ethyl acetate (50 mL × 3). The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated to obtain a crude product, which was purified and isolated using preparative HPLC to obtain compound 51 (51 mg, 17% yield).

[1002] MS m / z(ESI):476.3[M+H] + .

[1003] 1 H NMR(400MHz,Chloroform-d)δ8.45(s,1H),7.87–7.75(m,1H),7.54–7.48(m,1H),7.33–7.28(m,1H),7.18(s,1H),6.98–6.82(m,3H),5.40–5.34(m ,2H), 4.10–4.02(m,1H), 3.92-3.72(m,1H), 3.11-3.02(m,4H), 2.86–2.6 1(m,2H),1.80-1.71(m,2H),1.47-1.32(m,6H),1.25(s,3H),0.88(t,3H).

[1004] Example 52 (S)-N-(1-(1H-indol-3-yl)hexan-2-yl)-6-(4-methylpiperazin-1-yl)thieno[3,2-c]pyridine-2-carboxamide

[1005] Example 53 (R)-N-(1-(1H-indol-3-yl)hexan-2-yl)-6-(4-methylpiperazin-1-yl)thieno[3,2-c]pyridine-2-carboxamide

[1006] The racemic compound 8 (1.6 g, 3.36 mmol) was separated by chiral separation to give the single compounds of compound 52 (0.48 g) and compound 53 (0.42 g).

[1007] Using DAICEL Enantiomers were separated using a THAR 80 preparative SFC system (250*40mm 10um). Compound 8 (1.6 g, 3.36 mmol) was dissolved in 80 mL of methanol and subjected to chiral separation using SFC. Mobile phase A consisted of supercritical fluid carbon dioxide and mobile phase B consisted of methanol in a ratio of A:B = 45:55. The mobile phase maintained an isocratic flow rate of 70 mL / min throughout the separation process. After separation, the mixture was dried at 40°C to afford compounds 52 (0.48 g) and 53 (0.42 g), respectively.

[1008] Chiral purity test of compound 52 (OJ, 40% MeOH (0.1% DEA)): Peak 1 RT: 2.527 (0.37%) Peak 2 RT: 4.470 (99.63%).

[1009] Chiral purity test of compound 53 (OJ, 40% MeOH (0.1% DEA)): Peak 1 RT: 2.470 (99.13%) Peak 2 RT: 4.522 (0.87%).

[1010] Compound 52 MS m / z (ESI): 477.5 [M+H] + .

[1011] Compound 53 MS m / z (ESI): 477.5 [M+H] + .

[1012] Comparative Example 1

[1013] Comparative compound 1 was prepared according to the synthesis method of Example 1 of WO2015116663A1.

[1014] 2. Biological Test Evaluation

[1015] Biological Example 1 HPLC detection of the ability of compounds to inhibit α-synuclein self-aggregation

[1016] The test compound (pre-dissolved in DMSO for poorly soluble compounds) was added to pure water along with fresh α-synuclein monomers (purchased from Sino Biological) to a final protein concentration of 250 μg / mL and a test compound concentration of 200 μg / mL. The cells were then incubated at 37°C for 9 days. The peak area of ​​α-synuclein multimers after incubation was measured by HPLC, and the inhibition rate was calculated. Analysis showed that the peak area of ​​α-synuclein multimers in the test compound group after incubation was significantly reduced compared to the model group (no test compound). Inhibition rate = (peak area of ​​model group - peak area of ​​example group) / peak area of ​​model group × 100%.

[1017] The inhibition rates of the compounds of the examples of the present invention on α-synuclein aggregation are shown in Table a below.

[1018] Table a

[1019] Table a shows that the compounds of the present invention can significantly inhibit the self-aggregation of α-synuclein.

[1020] Biological Example 2 Immunofluorescence Assay to Detect the Ability of Compounds to Inhibit α-Synuclein Self-Aggregation (Cell Experiment)

[1021] A lentiviral expression plasmid expressing a mutant α-synuclein was constructed, and the virus was packaged to infect SH-SY5Y cells. Stable cell lines were screened, and the effects of the compounds on α-synuclein aggregates were detected by immunofluorescence. An empty vector was also infected as a control. An antibody against phosphorylated α-synuclein was used to detect protein aggregation in cells. By immunoblotting, cells infected with the virus expressing α-synuclein showed high expression levels of α-synuclein monomers (14 kd) and oligomers (i.e., dimers, trimers, and tetramers) in both soluble and insoluble fractions compared to the model group (no test compound). After treatment with the test compound, the effect of the compound on α-synuclein multimers was detected. The higher the fluorescence intensity, the stronger the protein aggregation ability. Treatment with an inactive control compound did not affect the expression level of α-synuclein.

[1022] The experimental results show that the compounds of the present invention can significantly inhibit the self-aggregation of α-synuclein in cells. Biological Example 3 The effect of the compounds on the survival rate of transiently transduced cells was detected by MTT method.

[1023] The MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assay, also known as the MTT colorimetric assay, is a method for monitoring cell viability and growth. The assay works by reducing exogenous MTT to water-insoluble, blue-purple crystalline formazan by succinate dehydrogenase in the mitochondria of living cells, which then deposits within the cells. Dead cells, however, do not experience this reduction. Dimethyl sulfoxide (DMSO) dissolves the formazan in the cells, and the absorbance (OD) measured at 490 nm using an enzyme-linked immunosorbent assay (ELISA) indirectly reflects the number of viable cells. A higher OD value indicates a higher cell viability rate.

[1024] To examine the effects of test compounds on cell viability, the MTT assay was used to assess the effects of compounds on transiently transduced cell viability. The method is as follows: Cells are harvested from the logarithmic phase, the cell suspension concentration is adjusted, and 100 μL of MTT is added to each well. The cells are plated to a density of 10,000 cells per well (the edge wells are filled with sterile phosphate buffered saline). Incubate at 5% CO₂ and 37°C until the cell monolayer fills the bottom of the well (96-well flat-bottom plate). Once the cells have adhered, test compounds are added. Three replicates are set for each test compound. Incubate in a cell culture incubator for 48 hours and observe under an inverted microscope. Add 20 μL of MTT solution (5 mg / mL, i.e., 0.5% MTT) to each well and continue incubation for another 4 hours. If the drug reacts with MTT, centrifuge and discard the culture medium. Carefully rinse three times with phosphate buffered saline before adding the MTT-containing culture medium. Terminate the incubation and carefully aspirate the culture medium. Add 150 μL of dimethyl sulfoxide to each well and shake at low speed on a shaker for 10 minutes to dissolve any crystals. The absorbance of each well was measured at 490 nm using an enzyme-linked immunosorbent assay. The normal group consisted of cells that were not treated with any other methods, while the model group consisted of cells that had been transfected with α-synuclein.

[1025] The experimental results show that the compound of the present invention can improve the survival rate of cells.

[1026] Biological Example 4 Half-life determination in C57BL / 6 mice

[1027] C57BL / 6 mice (male) were selected and the compound of the present invention was intravenously administered at a dose of 2 mpk. About 0.03 mL of whole blood was collected from the mouse orbital venous plexus at 0 h before administration and 0.0833, 0.25, 0.5, 1, 2, 4, 6, 8, and 24 h after administration. The blood was placed in a centrifuge tube containing EDTA-K2 anticoagulant and placed on crushed ice. Within 0.5 h, the blood was centrifuged at 2000g and 40°C for 10 min. 10 μL of plasma was quantitatively divided and placed in another clean centrifuge tube, which was placed in a -20°C refrigerator. The blood drug concentration was determined by LC-MS / MS, and the half-life t was calculated. 1 / 2 As shown in Table b below.

[1028] Table b

[1029] The experimental results show that the compound of the present invention has a long half-life in vivo and can effectively prolong the drug's action time in the body.

[1030] Biological Example 5 Determination of Brain / Plasma Ratio

[1031] 1. Purpose of the Test

[1032] Male C57BL / 6 mice were used as research subjects. The pharmacokinetic characteristics of the compound of the present invention transported across the blood-brain barrier were investigated using cerebral perfusion technology. The drug concentrations in blood and brain tissue samples of the mice were measured 0.25 h, 1 h, 4 h and 8 h after administration, and the ratio of the average drug concentration in brain tissue to plasma was calculated.

[1033] 2. Materials and Methods

[1034] 1. Drug preparation

[1035] Oral administration solution of the compound of the present invention (1.000 mg·mL -1 ) Preparation:

[1036] Weigh 3.116 mg of the compound and place it in an EP tube. Then add 0.156 mL of DMSO, 0.312 mL of Solutol, and 2.648 mL of ultrapure water (volume ratio of 5:10:85, v:v:v). Vortex and sonicate to fully dissolve the compound. The final actual concentration is 1.000 mg mL -1 of a clear dosing solution.

[1037] 3.116mg×100%÷3.116mL=1.000mg·mL -1

[1038] 2. Experimental Animals

[1039] C57BL / 6 mice (male) were purchased from Sibeifu (Beijing) Biotechnology Co., Ltd., with the experimental animal production license number: SCXK (Beijing) 2019-0010.

[1040] Fasting: No food or water should be allowed overnight, and feed should be provided 4 hours after the drug is taken.

[1041] 3. Animal Experimental Protocol

[1042] Qualified healthy C57BL / 6 mice were selected, with 3 mice per group. After oral administration (10 mg / kg), approximately 150 μL of whole blood was collected from the orbital venous plexus of the mice at 0.25, 1, 4, and 8 hours post-dose and placed in centrifuge tubes containing EDTA-K2 anticoagulant. Approximately 1 minute before the scheduled time point, the mice were anesthetized and cerebral perfusion was performed at 0.25, 1, 4, and 8 hours post-dose. After perfusion, brain tissue samples were removed using ophthalmic scissors and forceps. Any excess blood on the tissue surface was immediately rinsed with ultrapure water within 5 minutes, dried, weighed, and homogenized with 4 volumes of acetonitrile-water solution (10:90, v:v). The homogenate was then placed in a -20°C refrigerator for testing. The collected samples were kept in an ice bath throughout the experimental operation.

[1043] 4. Whole blood sample collection

[1044] At the time points specified in the experimental protocol, approximately 150 μL of whole blood was collected from the orbital venous plexus of C57BL / 6 mice after administration and placed in a 1.5 mL centrifuge tube containing EDTA-K2. The collected whole blood was centrifuged at 2000g at 40°C for 10 minutes. The plasma was aliquoted and placed in a separate clean centrifuge tube. The tube was then stored at -20°C until assayed.

[1045] 5. Brain perfusion method

[1046] Adjust the peristaltic pump device to ensure that it is working properly, the liquid flows out steadily and smoothly, and there is no air in the flow path. Anesthetize the mice after administration with a mixed anesthetic of 70% CO2 and 30% O2. After the animal is fully anesthetized, quickly open the chest cavity with surgical scissors to expose the heart. Clamp the superior vena cava and inferior vena cava with hemostatic forceps, pierce the ventricle with a needle, and cut a small hole in the atrium. Turn on the peristaltic pump switch and perfuse for 2-5 minutes. The perfusion fluid is 100U / 1000mL sodium heparin saline. After the perfusion is completed, use ophthalmic scissors and ophthalmic forceps to dissect the mouse brain tissue sample, immediately rinse the remaining blood on the tissue surface with ultrapure water within 5 minutes, wipe dry, weigh, add 4 times the volume of acetonitrile-water solution (10:90, v:v) and homogenize, and then place the homogenate in a -20℃ refrigerator for testing.

[1047] The ratio of the average drug concentration in brain tissue to that in plasma, i.e., the brain / plasma ratio, was calculated. The 4-hour brain / plasma ratio is shown in Table C below:

[1048] Table c

[1049] The experimental results show that the compound of the present invention can easily penetrate the blood-brain barrier and enter the brain to exert its medicinal effect.

[1050] Biological Example 6 Behavioral and Histological Detection of MPTP-Induced Mouse PD Model

[1051] 1. Purpose of the Test

[1052] The Parkinson's disease (PD) animal model was induced by intraperitoneal injection of MPTP into C57BL / 6J mice for 20 consecutive days to reliably and reproducibly damage the dopaminergic pathways in the substantia nigra and striatum. The efficacy of the test compounds (including the compounds of the present invention and control compound 1) in treating PD was evaluated from the perspectives of behavior (rotarod and grip strength tests) and histology (TH immunofluorescence staining).

[1053] 2. Materials and Methods

[1054] 1. Experimental Animals

[1055] C57BL / 6J mice, 8 weeks old, male, 10 mice per group.

[1056] 2. Preparation of drug preparations

[1057] Solvent stock solution: DMSO, 15, ultrapure water, and the volume ratio of the three is 5:10:85.

[1058] Test compound: Prepare the compound to concentrations of 0.008, 0.024, 0.08, and 0.4 mg / mL. Weigh 0.0004, 0.0012, 0.0040, and 0.0200 g respectively into EP tubes, and add 2.5 mL of DMSO in sequence. 15 5mL, ultrapure water 42.5mL, vortex to dissolve.

[1059] 3. Dosage method

[1060] MPTP, Day 1-2 (10 mg / kg), Day 3-4 (15 mg / kg), Day 5-6 (20 mg / kg), Day 7-20 (25 mg / kg), intraperitoneal administration, once a day;

[1061] The test compound was administered orally on Day 7-20 (0.1, 0.3, 1, 5 mg / kg) once a day.

[1062] 3. Behavioral testing

[1063] 1. Rotarod test

[1064] Acclimatization: Animals were placed in the testing room to acclimate for 30-60 minutes before testing.

[1065] Adaptation training: Each experimental animal was placed on the rotarod fatigue apparatus for 5 minutes of adaptive training;

[1066] Formal testing: The parameters of the rotarod fatigue instrument were set to 20 rpm / min and the test time was 5 min. Mice were placed on the rotarod in batches for testing. After each round, feces and urine were removed and wiped dry with 75% alcohol.

[1067] Result analysis: The time each animal spent on the rod was counted.

[1068] 2. Grip test

[1069] The mouse was placed on the platform with both forelimbs placed on the gripping rods.

[1070] Grab the mouse by the tail and pull it in a straight line backward. Animals will instinctively grab anything they can to stop themselves from moving backwards, until the pull exceeds their grip strength.

[1071] After the animal loses its grip, the preamplifier automatically records the maximum value of the pulling force and displays it on the LCD screen. The amplifier can provide digital or analog output.

[1072] After the measurement is completed, the average of the maximum pulling force of each animal is calculated.

[1073] IV. Immunohistochemistry

[1074] After the behavioral study, three animals in each group were selected for cardiac perfusion; the samples were collected from the striatum (Str) and substantia nigra (SN).

[1075] 1. Perfusion - Fixation - Sugar Sedimentation - Sectioning

[1076] Mice were anesthetized with isoflurane breathing.

[1077] The abdominal and thoracic cavities were opened with straight scissors to expose the heart. The heart was first perfused with normal saline to flush out all blood, and then perfused with paraformaldehyde for initial fixation.

[1078] The head was cut off, the skull was carefully opened with forceps, the brain tissue was removed and fixed in paraformaldehyde solution for 24 h.

[1079] The next day, the cells were taken out and placed in 20% sucrose solution for 24 hours.

[1080] On the third day, the cells were taken out and placed in 30% sucrose solution for 24 hours.

[1081] On the fourth day, the cells were taken out and placed in 35% sucrose solution for 24 hours.

[1082] The brain tissue was removed, embedded in OCT embedding medium, and 16 μm brain slices were cut using a freezing microtome.

[1083] 2. Immunofluorescence staining (TH)

[1084] Rewarm the slices for 30 minutes;

[1085] Blocking: 10% serum + 0.3% TritonX-100 [about 50 μl per slide], room temperature for 1 h;

[1086] The slides were shaken and primary antibodies (diluted in PBS) were added at 4°C overnight;

[1087] Rewarm for 30 minutes;

[1088] Wash the primary antibody (PBS), 5 min × 3 times;

[1089] Secondary antibody (diluted in PBS) was added in backlight at room temperature for 2 h;

[1090] Wash the secondary antibody (PBS), 5 min × 3 times;

[1091] Add DAPI mounting medium.

[1092] The experimental results show that the compound of the present invention has a lower effective concentration.

[1093] 3. Study on the Crystalline Form of the Compound and Its Salts

[1094] The instruments used in the present invention for detecting the properties of the crystal form of the compound and its salt are as follows:

[1095] Powder X-ray diffraction (PXRD) characterization: Instrument: Rigaku D / Max-2550 PC powder diffractometer, CuKα radiation, power 40 kV × 250 mA, scan range 3–50° 2θ, step width 0.02°, scan rate 5° / min. Data were analyzed and displayed using MDI-Jade version 7.5.1 software.

[1096] Single crystal X-ray diffraction (SXRD) characterization: Instrument: Bruker APEX-IICCD single crystal diffractometer, using MoKα The structures were solved and modified using ShelXL2015 and ShelXT2015. The structures were analyzed and displayed using Mercury software.

[1097] Differential Scanning Calorimetry (DSC) Characterization: Instrument: TA Instruments DSC Q100, purge gas: nitrogen 50 ml / min, heating rate: 10°C / min, temperature range: room temperature to 230°C. Plotted with the endothermic peak upward. Data were analyzed and displayed using a TA Universal Analyzer, with a tolerance of ±3°C.

[1098] Thermogravimetric analysis (TG) characterization: Instrument: TA Instruments SDT Q600, purge gas: nitrogen 120 mL / min, heating rate: 10°C / min, temperature range: room temperature to 400°C. Data were analyzed and presented using a TA Universal Analyzer.

[1099] The pH 4.5 medium involved in the present invention is used to determine the solubility of the compound crystal form. The specific preparation method of the pH 4.5 medium is as follows: 2.99 g of sodium acetate is mixed with 14.0 ml of acetic acid solution (2 mol / L), dissolved in water and diluted to 1000 ml, and shaken to obtain the solution.

[1100] Preparation of Crystal Form α of Compound 1 in Embodiment 1

[1101] Take 1200 mg of compound 1, add 25 mL of acetonitrile, stir, and heat to 80-85°C. The clear solution is naturally cooled to room temperature (20-25°C), then stirred at room temperature for 4 hours, and the resulting product is filtered. The filter cake is collected and vacuum-dried at 40°C for 12 hours to obtain Form α of compound 1.

[1102] The X-ray powder diffraction pattern of Form α of Compound 1 prepared in Implementation Example 1 is shown in FIG1 ; its DSC curve is shown in FIG9 , which includes an endothermic peak with an onset temperature of 178.5°C and a peak value of approximately 183.3°C, which is the melting point of Form α; its TGA curve is shown in FIG15 , which shows that there is almost no weight loss in the range of room temperature to 100°C, indicating that Form α of Compound 1 is an anhydrous crystalline form; after equilibration at a humidity of 25°C / RH80% for 48 hours, Form α does not absorb moisture and is non-hygroscopic.

[1103] Preparation of Fumarate Crystal Form I of Embodiment 2 Compound 1

[1104] Take 500 mg of compound 1, add 10 ml of acetone, stir, add 0.06 g of fumaric acid, stir at room temperature (20-25 ° C) until a white solid begins to precipitate, continue stirring for 4 hours, and filter the resulting product. Collect the filter cake and vacuum dry it at 40 ° C for 12 hours to obtain the fumarate salt form I of compound 1.

[1105] The X-ray powder diffraction pattern of Form I of the fumarate salt of Compound 1 prepared in Embodiment 2 is shown in Figure 4 . Its DSC curve shows an endothermic peak with an onset temperature of 204.0°C and a peak value of approximately 206.5°C, which is the melting point of Form I of the fumarate salt. Its TGA curve shows a weight loss of approximately 0.70% from room temperature to 100°C, indicating that Form I of the fumarate salt of Compound 1 is a hydrated crystalline form.

[1106] Preparation of the amorphous form of compound 42 in embodiment 3

[1107] The amorphous compound 42 can be obtained by chiral resolution of the racemic compound 1 in Example 42 of the above compound preparation. Its X-ray powder diffraction pattern is shown in Figure 2; after the amorphous compound 42 is equilibrated at 25°C / RH80% humidity for 48 hours, it absorbs approximately 0.9% water.

[1108] Regarding the amorphous form of Compound 42, the solubility in a medium at pH 4.5 was 7948.43 μg / ml.

[1109] Preparation of Compound 42 Crystalline Form A in Embodiment 4

[1110] Take 500 mg of the amorphous form of compound 42, add 5 ml of isopropanol, stir, and heat to 70°C to dissolve it. The clear solution is naturally cooled to room temperature (20-25°C) and stirred at room temperature for 4 hours. The resulting product is filtered, and the filter cake is collected and vacuum-dried at 40°C for 12 hours to obtain Form A of compound 42.

[1111] The X-ray powder diffraction pattern of Form A of Compound 42 prepared in Example 4 is shown in Figure 3 . Its DSC curve shows an endothermic peak with an onset temperature of 158.9°C and a peak value of approximately 160.7°C, which is the melting point of Form A of Compound 42. Its TGA curve shows little weight loss from room temperature to 100°C, indicating that Form A of Compound 42 is an anhydrous crystal. After equilibration for 48 hours at 25°C / RH 80%, Form A of Compound 42 did not absorb moisture and is non-hygroscopic.

[1112] Regarding Compound 42 Form A, the solubility in a medium at pH 4.5 was 22.52 μg / ml.

[1113] Preparation of Compound 42 Crystalline Form A in Embodiment 5

[1114] 500 mg of the amorphous form of compound 42 was added to 2 ml of acetone, stirred, and heated to 75°C to dissolve. 2 ml of methyl tert-butyl ether was added, and the mixture was stirred at room temperature (20-25°C) for 6 hours. The resulting product was filtered, and the filter cake was vacuum-dried at 40°C for 12 hours to obtain Form A of compound 42. Its X-ray powder diffraction pattern was substantially consistent with that of Figure 3 (Implementation Example 4).

[1115] Preparation of Compound 42 Crystalline Form A in Embodiment 6

[1116] 10.0 g of the amorphous form of compound 42 was added to 100 ml of acetonitrile, stirred, and heated to 75°C to dissolve the mixture. The clear solution was naturally cooled to room temperature (20-25°C) and stirred at room temperature for 4 hours. The resulting product was filtered, and the filter cake was collected and vacuum-dried at 40°C for 12 hours to obtain Form A of compound 42. Its X-ray powder diffraction pattern was substantially consistent with that of Figure 3 (Implementation Example 4).

[1117] Preparation of Compound 42 Crystalline Form A in Embodiment 7

[1118] 500 mg of the amorphous form of compound 42 was added to 8 ml of toluene, stirred, and heated to 75°C to dissolve the mixture. The clear solution was naturally cooled to room temperature (20-25°C) and stirred at room temperature for 4 hours. The resulting product was filtered, and the filter cake was collected and vacuum-dried at 40°C for 12 hours to obtain Form A of compound 42. Its X-ray powder diffraction pattern was substantially consistent with that of Figure 3 (Implementation Example 4).

[1119] Preparation of Compound 42 Crystalline Form A in Embodiment 8

[1120] 500 mg of the amorphous form of compound 42 was added to 18 ml of isopropyl acetate, stirred, and heated to 75°C to dissolve the mixture. The clear solution was naturally cooled to room temperature (20-25°C) and stirred at room temperature for 4 hours. The resulting product was filtered, and the filter cake was collected and vacuum-dried at 40°C for 12 hours to obtain Form A of compound 42. Its X-ray powder diffraction pattern was substantially consistent with that of Figure 3 (Embodiment 4).

[1121] Preparation of Compound 42 Crystalline Form A in Embodiment 9

[1122] 500 mg of the amorphous form of compound 42 was added to 4 ml of ethyl acetate, stirred, and heated to 75°C to dissolve the mixture. The clear solution was naturally cooled to room temperature (20-25°C) and stirred at room temperature for 4 hours. The resulting product was filtered, and the filter cake was collected and vacuum-dried at 40°C for 12 hours to obtain Form A of compound 42. Its X-ray powder diffraction pattern was substantially consistent with that of Figure 3 (Implementation Example 4).

[1123] Preparation of Compound 42 Crystalline Form A in Embodiment 10

[1124] 500 mg of the amorphous form of compound 42 was added to 4 ml of isopropanol, stirred, and heated to 75°C to dissolve the mixture. The clear solution was naturally cooled to room temperature (20-25°C) and stirred at room temperature for 4 hours. The resulting product was filtered, and the filter cake was collected and vacuum-dried at 40°C for 12 hours to obtain Form A of compound 42. Its X-ray powder diffraction pattern was substantially consistent with that of Figure 3 (Embodiment 4).

[1125] Embodiment 11 Fumarate Amorphous Compound 42

[1126] 500 mg of the fumarate salt of compound 42 was dissolved in 80% ethanol solution, and the solvent was removed by rotary evaporation at 40°C to obtain an amorphous fumarate salt of compound 42, the X-ray powder diffraction pattern of which is shown in Figure 5. After equilibration at 25°C / RH80% for 48 hours, the amorphous fumarate salt of compound 42 absorbed approximately 0.9% water.

[1127] The solubility of the amorphous fumarate of compound 42 in a medium with a pH of 4.5 was 5.10 μg / ml.

[1128] Take 500 mg of compound 42, add 10 ml of acetone, stir, add 0.06 g of fumaric acid, and stir at room temperature (20-25°C) until a white solid begins to precipitate. Continue stirring for 4 hours, and filter the resulting product. Collect the filter cake and vacuum dry it at 40°C for 12 hours to obtain compound 42 fumarate salt Form I.

[1129] The X-ray powder diffraction pattern of Compound 42 Fumarate Form I prepared in Example 12 is shown in Figure 6 . Its DSC curve shows an endothermic peak with an onset temperature of 195.4°C and a peak value of approximately 197.4°C, which is the melting point of Compound 42 Fumarate Form I. Its TGA curve shows a weight loss of approximately 0.70% from room temperature to 100°C, indicating that Compound 42 Fumarate Form I is a hydrated crystalline form. After equilibration for 48 hours at 25°C / RH 80%, Compound 42 Fumarate Form I absorbed approximately 0.3% water.

[1130] Regarding Compound 42 fumarate salt Form I, the solubility in a medium at pH 4.5 was 17.39 μg / ml.

[1131] Preparation of Fumarate Crystal Form I of Embodiment 13 Compound 42

[1132] To 500 mg of compound 42, 5 ml of acetone and 5 ml of toluene were added, respectively, and the mixture was stirred and heated to 60°C to dissolve. 0.06 g of fumaric acid was added, and a white solid began to precipitate under stirring. The mixture was naturally cooled to room temperature (20-25°C) and stirred at room temperature for 4 hours. The resulting product was filtered, and the filter cake was collected and vacuum-dried at 40°C for 12 hours to obtain Form I of the fumarate salt of compound 42. Its X-ray powder diffraction pattern was substantially consistent with that of Figure 6 (Embodiment 12), and its TGA curve showed a weight loss of approximately 0.72%.

[1133] Preparation of Fumarate Crystal Form I of Embodiment 14 Compound 42

[1134] 500 mg of compound 42 was added to 15 ml of ethyl acetate, stirred, and heated to 60°C to dissolve. 0.06 g of fumaric acid was added, and stirring began to precipitate a white solid. The mixture was naturally cooled to room temperature (20-25°C) and stirred at room temperature for 4 hours. The resulting product was filtered, and the filter cake was collected and vacuum-dried at 40°C for 12 hours to obtain Form I of the fumarate salt of compound 42. Its X-ray powder diffraction pattern was substantially consistent with that of Figure 6 (Embodiment 12), and its TGA curve showed a weight loss of approximately 0.75%.

[1135] Preparation of Fumarate Crystal Form I of Embodiment 15 Compound 42

[1136] 500 mg of compound 42 was added to 50 ml of ethanol, stirred, and heated to 60°C to dissolve. 0.06 g of fumaric acid was added, and stirring began to precipitate a white solid. The mixture was naturally cooled to room temperature (20-25°C) and stirred at room temperature for 4 hours. The resulting product was filtered, and the filter cake was collected and vacuum-dried at 40°C for 12 hours to obtain Form I of the fumarate salt of compound 42. Its X-ray powder diffraction pattern was substantially consistent with that of Figure 6 (Embodiment 12), and its TGA curve showed a weight loss of approximately 0.69%.

[1137] Preparation of Fumarate Crystal Form I of Compound 42 in Embodiment 16

[1138] 500 mg of compound 42 was added to 50 ml of acetone, stirred, and heated to 30°C to dissolve. 0.12 g of fumaric acid was added, and stirring began to precipitate a white solid. The mixture was naturally cooled to room temperature (20-25°C) and stirred at room temperature for 4 hours. The resulting product was filtered, and the filter cake was collected and vacuum-dried at 40°C for 12 hours to obtain Form I of the fumarate salt of compound 42. Its X-ray powder diffraction pattern was substantially consistent with that of Figure 6 (Embodiment 12), and its TGA curve showed a weight loss of approximately 0.67%.

[1139] Preparation of Fumarate Crystal Form I of Compound 42 in Embodiment 17

[1140] 500 mg of compound 42 was added to 10 ml of 95% acetone, stirred, and heated to 30°C to dissolve. 0.12 g of fumaric acid was added, and stirring began to precipitate a white solid. The mixture was naturally cooled to room temperature (20-25°C) and stirred at room temperature for 4 hours. The resulting product was filtered, and the filter cake was collected and vacuum-dried at 40°C for 12 hours to obtain Form I of the fumarate salt of compound 42. Its X-ray powder diffraction pattern was substantially consistent with that of Figure 6 (Embodiment 12), and its TGA curve showed a weight loss of approximately 0.61%.

[1141] Preparation of Fumarate Crystal Form II of Embodiment 18 Compound 42

[1142] To 500 mg of compound 42, 10 ml of tetrahydrofuran was added, and the mixture was stirred at 15-20°C. 0.06 g of fumaric acid was added, and a white solid began to precipitate during stirring. Stirring was continued for 4 hours, and the resulting product was filtered. The filter cake was collected and vacuum-dried at 40°C for 12 hours to obtain the fumarate salt form II of compound 42.

[1143] The X-ray powder diffraction pattern of Form II fumarate of Compound 42 prepared in Embodiment 18 is shown in Figure 7 . Its DSC curve shows endothermic peaks with peak values ​​of approximately 131°C and 197.4°C, respectively. Its TGA curve reveals a weight loss of approximately 1.5% between room temperature and 120°C, indicating that Form II fumarate of Compound 42 is a hydrated crystalline form. Form II fumarate of Compound 42 absorbed approximately 0.5% water after equilibration for 48 hours at 25°C / 80% humidity.

[1144] Preparation of Fumarate Crystal Form II of Compound 42 in Embodiment 19

[1145] 500 mg of compound 42 was added to 10 ml of dichloromethane and stirred at 15-20°C. 0.06 g of fumaric acid was added, and a white solid began to precipitate. Stirring was continued for 4 hours, and the resulting product was filtered. The filter cake was collected and vacuum-dried at 40°C for 12 hours to obtain Form II of the fumarate salt of compound 42. Its X-ray powder diffraction pattern was substantially consistent with that of Figure 7 (Embodiment 18).

[1146] Preparation of Fumarate Crystal Form III of Compound 42 in Embodiment 20

[1147] To 500 mg of compound 42, 10 ml of methyl tert-butyl ether was added, and the mixture was stirred at 15-20°C. 0.06 g of fumaric acid was added, and a white solid began to precipitate during stirring. Stirring was continued for 4 hours, and the resulting product was filtered. The filter cake was collected and vacuum-dried at 40°C for 12 hours to obtain the fumarate salt form III of compound 42.

[1148] The X-ray powder diffraction pattern of Form III fumarate of Compound 42 prepared in Embodiment 20 is shown in Figure 8 . Its DSC curve shows an endothermic peak with a peak value of approximately 135°C, which is a melting endothermic peak. Its TGA curve shows a weight loss of approximately 3.0% between room temperature and 120°C, indicating that Form III fumarate of Compound 42 is a hydrated crystalline form. After equilibration at 25°C / RH 80% for 48 hours, Form III fumarate of Compound 42 absorbed approximately 0.3% water.

[1149] Preparation of Fumarate Crystal Form III of Compound 42 in Embodiment 21

[1150] 500 mg of compound 42 was added to 10 ml of isopropyl ether and stirred at 15-20°C. 0.06 g of fumaric acid was added, and a white solid began to precipitate. Stirring was continued for 4 hours, and the resulting product was filtered. The filter cake was collected and vacuum-dried at 40°C for 12 hours to obtain Form III of the fumarate salt of compound 42. Its X-ray powder diffraction pattern was substantially consistent with that shown in Figure 8 (Embodiment 20).

[1151] Preparation of the Succinate Salt Form I of Compound 42 in Embodiment 22

[1152] 2.0 g of the free base of compound 42 was added to 40 ml of ethyl acetate, and the mixture was stirred at room temperature. 0.25 g of succinic acid was added, and the mixture was stirred for 24 hours. The solid was obtained by filtration, and the filter cake was collected and air-dried at 40°C overnight to obtain the succinate salt of compound 42, Form I.

[1153] The X-ray powder diffraction pattern of the succinate salt form I of compound 42 prepared in embodiment 22 is shown in Figure 12; its DSC curve shows an endothermic peak with a peak value of approximately 155°C, which is the melting point of the succinate salt form I of compound 42; its TGA curve shows a weight loss of approximately 0.83% in the range of room temperature to 100°C, indicating that the succinate salt form I of compound 42 contains a certain amount of crystalline water or solvent.

[1154] Preparation of the Succinate Salt Form I of Compound 42 in Embodiment 23

[1155] 2.0 g of the free base of compound 42 was added to 40 ml of acetone, stirred at room temperature, 0.25 g of succinic acid was added, and stirred for 24 hours. The solid was filtered off and the filter cake was air-dried at 40° C. overnight to obtain Form I of the succinate salt of compound 42; its X-ray powder diffraction pattern was substantially consistent with that of FIG12 (Implementation Example 22).

[1156] Embodiment 24 Preparation of Single Crystal of Compound 42 Form A

[1157] Crystal A of compound 42 obtained according to the preparation method of embodiment 4 was cultured to obtain a perfect crystal suitable for X-ray single crystal diffraction. The specific culture method of the single crystal is as follows:

[1158] 0.2 g of compound 42 was added to 2 ml of methanol and heated to 40-50°C to dissolve. After standing at room temperature for 1-3 days, perfect crystals suitable for X-ray single crystal diffraction were obtained and tested for single crystal form. Single crystal structural analysis of compound 42 Form A showed that compound 42 Form A belongs to the triclinic system, P1 space group, and contains two compound 42 molecules in the smallest asymmetric unit, connected by NH·…·N hydrogen bonds. Compound 42 Form A is an anhydrous form with the following crystallographic parameters: α=101.197(4)°, β=95.939(4)°, γ=90.999(5)°, Z=2,Dx=1.255g / cm 3 The single crystal structure analysis diagram is shown in Figure 9. The characteristic diffraction spectrum obtained by calculating the single crystal diffraction results is completely consistent with Figure 3.

[1159] Preparation of Single Crystal of Fumarate Form I of Compound 42 in Embodiment 25

[1160] The fumarate salt of compound 42 obtained according to the preparation method of embodiment 12 was cultured to obtain perfect crystals suitable for X-ray single crystal diffraction. The specific method for growing the single crystals is as follows:

[1161] Weigh 0.2 g of compound 42 fumarate, add 10 ml of acetone, heat to 55-60°C, then add about 0.4-0.8 ml of methanol dropwise until completely dissolved. After standing at room temperature for 1-3 days, perfect crystals suitable for X-ray single crystal diffraction are obtained. After the single crystals are left at room temperature for 3-5 days, the crystal form is tested.

[1162] Single crystal structure analysis of compound 42 fumarate form I shows that compound 42 fumarate form I belongs to the monoclinic crystal system (monoclinic), P21 space group, and contains two protonated compound 42 cations, one fumarate anion and 0.38 water molecules in the smallest asymmetric unit. The hydrogen ions of the two carboxyl groups on the fumaric acid molecule are transferred to the piperazine rings of two compound 42 molecules to form compound 42 cations, which are connected by NH·…·O charge hydrogen bonds. The water molecules are connected to the compound 42 molecules through OH·…·O hydrogen bonds. Compound 42 fumarate form I is a hydrated crystal form containing 0.38 water molecules. The specific crystallographic parameters are as follows: α=90°, β=100.438(6)°, γ=90°, Z=2,Dx=1.305g / cm 3 The single crystal structure analysis diagram is shown in Figure 10. The characteristic diffraction lines calculated from the single crystal diffraction results are completely consistent with those in Figure 6.

[1163] Embodiment 26 Preparation of Single Crystal of Compound 42 Fumarate Form I

[1164] The fumarate salt of compound 42 prepared according to Example 12 was cultured to obtain perfect crystals suitable for X-ray single crystal diffraction. The specific method for growing the single crystals is as follows:

[1165] Weigh 0.2 g of compound 42 fumarate, add 10 ml of acetone, heat to 55-60°C, then add about 0.4-0.8 ml of methanol dropwise until completely dissolved. After standing at room temperature for 1-3 days, perfect crystals suitable for X-ray single crystal diffraction are obtained, and single crystal detection is immediately performed.

[1166] Single crystal structure analysis of compound 42 fumarate salt form I shows that compound 42 fumarate salt form I belongs to the monoclinic system (monoclinic), P21 space group, and contains two free base cations, one fumarate anion and 0.5 water molecules in the smallest asymmetric unit. Compound 42 fumarate salt form I is a hydrate crystal form containing 0.5 water molecules. The specific crystallographic parameters are as follows: β=100.222(2)°, Z = 2; the single crystal structure analysis diagram is shown in Figure 11. The characteristic diffraction spectrum obtained by calculation of the single crystal diffraction results is completely consistent with Figure 6.

[1167] Preparation of Single Crystal of Compound 42 Succinate Salt Form I in Embodiment 27

[1168] The succinate salt of compound 42 obtained according to the preparation method of Example 22 was cultured to obtain perfect crystals suitable for X-ray single crystal diffraction. The specific method for growing the single crystals is as follows:

[1169] Weigh 0.2 g of succinate, add 10 ml of acetone, heat, and slowly add methanol dropwise until completely dissolved. After standing at room temperature for 1-3 days, obtain crystals suitable for X-ray single crystal diffraction and perform single crystal detection.

[1170] Single crystal structure analysis of the succinate salt form I of compound 42 shows that the succinate salt form I of compound 42 belongs to the monoclinic system (monoclinic), P21 space group, and the specific crystallographic parameters are as follows: β=99.883(2)°, Z = 2, and the single crystal structure analysis diagram is shown in Figure 13. Its smallest asymmetric unit contains two compound 42 cations, one succinate anion, and 0.3 water molecules, representing a hydrate of hemisuccinate. The characteristic diffraction spectrum calculated from the single crystal diffraction results is completely consistent with that in Figure 12.

Claims

1. A compound represented by general formula (I) or a crystalline form or salt thereof of a stereoisomer, in: X is selected from O, S and NR a ; Y is selected from CR b and N; Ring A is selected from a benzene ring and a pyridine ring; Ring B is selected from a benzene ring, a pyridine ring, a pyridazine ring, a pyrimidine ring and a pyrazine ring; The C ring is selected from W is selected from O, NR c and CR d R e ; R1 is absent or selected from fluorine, chlorine, bromine, iodine and C 1-6 alkyl; R2 is selected from C 1-6 Alkyl, C 2-6 Alkenyl, -C 1-4 Alkylene-OC 1-4 Alkyl and -C 1-4 Alkylene-NR a R b ; R3 represents absence or is selected from fluorine, chlorine, bromine, iodine, cyano and C 1-6 alkyl; R a and Rb are each independently selected from H and C 1-6 alkyl; R c Selected from H, cyano, C 1-6 Alkyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, -SO2R f and 1-C 1-6 Alkyl-4-piperidinyl; R d and R e are each independently selected from H, fluorine, chlorine, bromine, iodine, hydroxyl, cyano, -NR a R b , C 1-6 Alkyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl and 1-C 1-6 Alkyl-4-piperidinyl; R f is selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl; Wherein, the salt is an acid salt, and the acid in the acid salt is an inorganic acid or an organic acid. Preferably, the inorganic acid is selected from hydrochloric acid, phosphoric acid, sulfuric acid, nitric acid or hydrobromic acid; the organic acid is selected from fumaric acid, 2,5-dihydroxybenzoic acid, 1-hydroxy-2-naphthoic acid, acetic acid, dichloroacetic acid, trichloroacetic acid, acetohydroxamic acid, adipic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, benzoic acid, 4-acetylaminobenzoic acid, 4-aminobenzoic acid, capric acid, caproic acid, caprylic acid, cinnamic acid, citric acid, cyclohexanesulfamic acid, camphorsulfonic acid, aspartic acid, camphoric acid, gluconic acid, glucuronic acid, glutamic acid, isoascorbic acid, lactic acid, malic acid, mandelic acid, pyro Glutamic acid, tartaric acid, dodecyl sulfuric acid, dibenzoyltartaric acid, ethane-1,2-disulfonic acid, ethanesulfonic acid, formic acid, galactosonic acid, gentisic acid, glutaric acid, 2-ketoglutaric acid, glycolic acid, hippuric acid, isethionic acid, lactobionic acid, ascorbic acid, aspartic acid, lauric acid, camphoric acid, maleic acid, malonic acid, methanesulfonic acid, 1,5-naphthalene disulfonic acid, naphthalene-2-sulfonic acid, niacin, oleic acid, orotic acid, oxalic acid, palmitic acid, pamoic acid, propionic acid, salicylic acid, 4-aminosalicylic acid, sebacic acid, stearic acid, succinic acid, thiocyanic acid, pamoic acid, formic acid, undecylenic acid, trifluoroacetic acid, benzenesulfonic acid, p-toluenesulfonic acid, or L-malic acid.

2. The crystalline form or salt according to claim 1, characterized in that The general formula (I) is shown in the general formula (Ia) or the general formula (Ib):

3. The crystalline form or salt according to claim 1, characterized in that The general formula (I) is further shown in the general formula (II): Wherein, R1, R2, R3 and W are as defined in the general formula (I); Wherein, the salt is an acid salt, and the acid in the acid salt is an inorganic acid or an organic acid. Preferably, the inorganic acid is selected from hydrochloric acid, phosphoric acid, sulfuric acid, nitric acid or hydrobromic acid; the organic acid is selected from fumaric acid, 2,5-dihydroxybenzoic acid, 1-hydroxy-2-naphthoic acid, acetic acid, dichloroacetic acid, trichloroacetic acid, acetohydroxamic acid, adipic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, benzoic acid, 4-acetylaminobenzoic acid, 4-aminobenzoic acid, capric acid, caproic acid, caprylic acid, cinnamic acid, citric acid, cyclohexanesulfamic acid, camphorsulfonic acid, aspartic acid, camphoric acid, gluconic acid, glucuronic acid, glutamic acid, isoascorbic acid, lactic acid, malic acid, mandelic acid , pyroglutamic acid, tartaric acid, dodecyl sulfuric acid, dibenzoyltartaric acid, ethane-1,2-disulfonic acid, ethanesulfonic acid, formic acid, galactosonic acid, gentisic acid, glutaric acid, 2-ketoglutaric acid, glycolic acid, hippuric acid, isethionic acid, lactobionic acid, ascorbic acid, aspartic acid, lauric acid, camphoric acid, maleic acid, malonic acid, methanesulfonic acid, 1,5-naphthalene disulfonic acid, naphthalene-2-sulfonic acid, nicotinic acid, oleic acid, orotic acid, oxalic acid, palmitic acid, pamoic acid, propionic acid, salicylic acid, 4-aminosalicylic acid, sebacic acid, stearic acid, succinic acid, thiocyanic acid, pamoic acid, formic acid, undecylenic acid, trifluoroacetic acid, benzenesulfonic acid, p-toluenesulfonic acid, or L-malic acid.

4. The crystalline form or salt according to claim 3, characterized in that The general formula (II) is shown in the general formula (IIa) or the general formula (IIb):

5. The crystalline form or salt according to any one of claims 1 to 4, characterized in that The general formula (I) is selected from the following compounds:

6. The crystalline form or salt according to any one of claims 1 to 5, characterized in that The salt is an acid salt, and the acid salt is selected from hydrochloride, phosphate, sulfate, nitrate, hydrobromide, fumarate, 2,5-dihydroxybenzoate, 1-hydroxy-2-naphthoate, acetate, dichloroacetate, trichloroacetate, acetohydroxamate, adipate, benzenesulfonate, 4-chlorobenzenesulfonate, benzoate, 4-acetamidobenzoate, 4-aminobenzoate, decanoate, hexanoate, caprylate, cinnamate, citrate, cyclohexanesulfamic acid salt, camphorsulfonate, aspartate, camphorate, gluconate, glucuronate, glutamate, isoascorbate, lactate, malate, mandelate, pyroglutamate, tartrate, dodecyl sulfate, dibenzoyltartrate, ethane-1,2-disulfonate, ethanesulfonate, formate, galactonate, gentisate, glutarate, 2-ketoglutarate, glycolate, hippurate, isethionate, lactobionate, ascorbate, aspartate, laurate, camphorate, maleate, malonate, methanesulfonate, 1,5-naphthalene disulfonate, naphthalene-2-sulfonate, nicotinate, oleate, orotate, oxalate, palmitate, pamoate, propionate, salicylate, 4-aminosalicylate, sebacate, stearate, succinate, thiocyanate, pamoate, formate, undecylenate, trifluoroacetate, benzenesulfonate, p-toluenesulfonate, or L-malate.

7. The crystalline form or salt according to any one of claims 1 to 6, characterized in that It is a crystalline form or salt of compound 1: N-(1-(1H-indol-3-yl)hexane-2-yl)-6-(4-methylpiperazine-1-yl)benzo[b]thiophene-2-carboxamide, wherein the salt is an acid salt, and the acid salt is hydrochloride, phosphate, sulfate, nitrate, hydrobromide, fumarate, 2,5-dihydroxybenzoate, 1-hydroxy-2-naphthoate, acetate, dichloroacetate, trichloroacetate, acetohydroxamate, adipate, benzenesulfonate, 4-chlorobenzenesulfonate, benzoate, 4-acetamidobenzoate, 4-aminobenzoate, decanoate, hexanoate, caprylate, cinnamate, citrate, cyclohexanesulfamic acid salt, camphorsulfonate, aspartate, camphorate, gluconate, glucuronate, glutamate, isoascorbate, lactate, malate, mandelate, pyroglutamate, tartrate, dodecyl sulfate, dibenzoyltartrate, ethane-1,2-disulfonate, ethanesulfonate, formate, galactonate, gentisate, glutarate, 2-ketoglutarate, glycolate, hippurate, isethionate, lactobionate, ascorbate, aspartate, laurate, camphorate, maleate, malonate, methanesulfonate, 1,5-naphthalene disulfonate, naphthalene-2-sulfonate, nicotinate, oleate, orotate, oxalate, palmitate, pamoate, propionate, salicylate, 4-aminosalicylate, sebacate, stearate, succinate, thiocyanate, pamoate, formate, undecylenate, trifluoroacetate, benzenesulfonate, p-toluenesulfonate, or L-malate; Preferably, the acid salt is hydrochloride, phosphate, sulfate, nitrate, hydrobromide, fumarate, acetate, adipate, benzenesulfonate, benzoate, caproate, caprylate, cinnamate, citrate, aspartate, lactate, tartrate, aspartate, laurate, maleate, salt, malonate, methanesulfonate, propionate, salicylate, formate, trifluoroacetate, benzenesulfonate; More preferably, the acid salt is hydrochloride, phosphate, sulfate, nitrate, hydrobromide, fumarate, benzenesulfonate, benzoate, citrate, lactate, tartrate, aspartate, laurate, maleate, malonate, methanesulfonate, benzenesulfonate.

8. The crystalline form or salt according to claim 7, characterized in that It is a crystalline form or salt of compound 1, which is crystalline form α or crystalline form I of a fumarate salt, wherein: The X-ray powder diffraction pattern of Form α of Compound 1 at 2θ is 5.91±0.2°, 8.86±0.2°, 10.17±0.2°, 10.46±0.2°, 10.79±0.2°, 12.08±0.2°, 13.18±0.2°, 14.70±0.2°, 15.23±0.2°, 16.40±0.2°, 17.82±0.2°, 18.55±0.2°, 20.29±0.2°, 20.44 ±0.2°, 21.96±0.2°, 22.18±0.2°, 23.47±0.2°, 23.80±0.2°, 25.73±0.2°, 27.12±0.2°, 28.53±0.2°, or more than 2-5, or more than 3-5, or more than 3-6, or more than 3-8, or more than 5-8, or more than 6-8 have characteristic peaks, and more preferably any 6, 7, 8 or 9 of them have characteristic peaks; Preferably, the X-ray powder diffraction pattern of Form α of Compound 1 has characteristic peaks at any 2-5 or more, or 3-5 or more, or 3-6 or more, or 3-8 or more, or 5-8 or more, or 6-8 or more of 2θ of 5.91±0.2°, 10.46±0.2°, 10.79±0.2°, 12.08±0.2°, 15.23±0.2°, 17.82±0.2°, 20.29±0.2°, 20.44±0.2°, 21.96±0.2°, 22.18±0.2°, 23.80±0.2°, and 25.73±0.2°, more preferably any 6, 7, 8 or 9 or more of them have characteristic peaks; Optionally, the invention further comprises a characteristic peak at at least one of 2θ of 8.86±0.2°, 10.17±0.2°, 13.18±0.2°, 14.70±0.2°, 16.40±0.2°, 18.55±0.2°, 23.47±0.2°, 27.12±0.2°, and 28.53±0.2°, preferably 2, 3, 4 or 5 or more of them; More preferably, the X-ray powder diffraction pattern of the crystalline form α of Compound 1 optionally has characteristic peaks at the following positions at 2θ: 5.91±0.2°、10.46±0.2°、10.79±0.2°， Or 12.08±0.2°, 15.23±0.2°, 17.82±0.2°, Or 20.29±0.2°, 20.44±0.2°, 21.96±0.2°, Or 22.18±0.2°, 23.80±0.2°, 25.73±0.2°, Or 5.91±0.2°, 10.46±0.2°, 10.79±0.2°, 12.08±0.2°, Or 10.46±0.2°, 12.08±0.2°, 15.23±0.2°, 17.82±0.2°, Or 10.79±0.2°, 22.18±0.2°, 23.80±0.2°, 25.73±0.2°, Or 5.91±0.2°, 8.86±0.2°, 10.46±0.2°, 10.79±0.2°, 12.08±0.2°, Or 10.17±0.2°, 10.46±0.2°, 12.08±0.2°, 15.23±0.2°, 17.82±0.2°, Or 10.79±0.2°, 13.18±0.2°, 22.18±0.2°, 23.80±0.2°, 25.73±0.2°, Or 18.86±0.2°, 21.96±0.2°, 22.18±0.2°, 23.80±0.2°, 25.73±0.2°, Or 5.91±0.2°, 8.86±0.2°, 10.46±0.2°, 10.79±0.2°, 12.08±0.2°, 15.23±0.2°, Or at 13.18±0.2°, 15.23±0.2°, 17.82±0.2°, 20.29±0.2°, 20.44±0.2°, 21.96±0.2°, or 8.86±0.2°, 20.44±0.2°, 21.96±0.2°, 22.18±0.2°, 23.80±0.2°, 25.73±0.2°, Or 10.17±0.2°, 20.29±0.2°, 20.44±0.2°, 21.96±0.2°, 22.18±0.2°, 23.80±0.2°, Or 5.91±0.2°, 8.86±0.2°, 10.46±0.2°, 10.79±0.2°, 12.08±0.2°, 15.23±0.2°, 17.82±0.2°, Or 8.86±0.2°, 10.46±0.2°, 10.79±0.2°, 12.08±0.2°, 15.23±0.2°, 17.82±0.2°, 20.29±0.2°, or 8.86±0.2°, 20.29±0.2°, 20.44±0.2°, 21.96±0.2°, 22.18±0.2°, 23.80±0.2°, 25.73±0.2°, or 8.86±0.2°, 17.82±0.2°, 20.29±0.2°, 20.44±0.2°, 21.96±0.2°, 22.18±0.2°, 23.80±0.2°， Or 13.18±0.2°, 15.23±0.2°, 17.82±0.2°, 20.29±0.2°, 20.44±0.2°, 21.96±0.2°, 22.18±0.2°, or 5.91±0.2°, 10.46±0.2°, 10.79±0.2°, 12.08±0.2°, 15.23±0.2°, 17.82±0.2°, 20.29±0.2°, 20.44±0.2°, or 10.79±0.2°, 12.08±0.2°, 15.23±0.2°, 17.82±0.2°, 20.29±0.2°, 20.44±0.2°, 21.96±0.2°, 22.18±0.2°, or 8.86±0.2°, 12.08±0.2°, 15.23±0.2°, 17.82±0.2°, 20.29±0.2°, 20.44±0.2°, 21.96±0.2°, 22.18±0.2°, or 5.91±0.2°, 10.46±0.2°, 10.79±0.2°, 12.08±0.2°, 15.23±0.2°, 17.82±0.2°, 22.18±0.2°, 23.80±0.2°, 25.73±0.2°, or 5.91±0.2°, 10.46±0.2°, 10.79±0.2°, 12.08±0.2°, 15.23±0.2°, 20.29±0.2°, 22.18±0.2°, 23.80±0.2°, 25.73±0.2°, or 5.91±0.2°, 10.46±0.2°, 10.79±0.2°, 12.08±0.2°, 15.23±0.2°, 20.29±0.2°, 20.44±0.2°, 23.80±0.2°, 25.73±0.2°, or 8.86±0.2°, 10.17±0.2°, 17.82±0.2°, 20.29±0.2°, 20.44±0.2°, 21.96±0.2°, 22.18±0.2°, 23.80±0.2°, 25.73±0.2°, or 5.91±0.2°, 10.46±0.2°, 10.79±0.2°, 12.08±0.2°, 15.23±0.2°, 17.82±0.2°, 20.29±0.2°, 20.44±0.2°, 21.96±0.2°, 22.18±0.2°, or 10.46±0.2°, 10.79±0.2°, 12.08±0.2°, 15.23±0.2°, 17.82±0.2°, 20.29±0.2°, 、20.44±0.2°、21.96±0.2°、22.18±0.2°、23.80±0.2°， or 10.79±0.2°, 12.08±0.2°, 15.23±0.2°, 17.82±0.2°, 20.29±0.2°, 20.44±0.2°, 21.96±0.2°, 22.18±0.2°, 23.80±0.2°, 25.73±0.2°, or 5.91±0.2°, 8.86±0.2°, 10.46±0.2°, 10.79±0.2°, 12.08±0.2°, 15.23±0.2°, 17.82±0.2°, 20.29±0.2°, 20.44±0.2°, 21.96±0.2°, or 5.91±0.2°, 10.46±0.2°, 10.79±0.2°, 12.08±0.2°, 15.23±0.2°, 17.82±0.2°, 20.29±0.2°, 20.44±0.2°, 21.96±0.2°, 22.18±0.2°, 23.80±0.2°, or 10.46±0.2°, 10.79±0.2°, 12.08±0.2°, 15.23±0.2°, 17.82±0.2°, 20.29±0.2°, 20.44±0.2°, 21.96±0.2°, 22.18±0.2°, 23.80±0.2°, 25.73±0.2°, or 8.86±0.2°, 10.79±0.2°, 12.08±0.2°, 15.23±0.2°, 17.82±0.2°, 20.29±0.2°, 20.44±0.2°, 21.96±0.2°, 22.18±0.2°, 23.80±0.2°, 25.73±0.2°, or 8.86±0.2°, 10.17±0.2°, 10.79±0.2°, 12.08±0.2°, 15.23±0.2°, 17.82±0.2°, 20.29±0.2°, 20.44±0.2°, 21.96±0.2°, 22.18±0.2°, 23.80±0.2°, or 8.86±0.2°, 15.91±0.2°, 10.46±0.2°, 10.79±0.2°, 12.08±0.2°, 15.23±0.2°, 17.82±0.2°, 20.29±0.2°, 20.44±0.2°, 21.96±0.2°, 22.18±0.2°, 23.80±0.2°, 25.73±0.2°, or 8.86±0.2°, 15.91±0.2°, 10.46±0.2°, 10.79±0.2°, 12.08±0.2°, 15.23±0.2°, 17.82±0.2°, 20.29±0.2°, 20.44±0.2°, 21.96±0.2°, 22.18±0.2°, 23.80±0.2°, 25.73±0.2°, 28.53±0.2°, Wherein, the X-ray powder diffraction pattern of Form α of Compound 1 is shown in FIG1 ; Or the X-ray powder diffraction pattern of the fumarate salt form I of compound 1 at 2θ is 10.03±0.2°, 11.85±0.2°, 12.75±0.2°, 13.14±0.2°, 14.70±0.2°, 15.30±0.2°, 17.06±0.2°, 17.34±0.2°, 17.82±0.2°, 18.84±0.2°, 19.99±0.2°, 2 Any 2-5 or more, or 3-5 or more, or 3-6 or more, or 3-8 or more, or 5-8 or more, or 6-8 or more of any of 0.34±0.2°, 21.65±0.2°, 22.12±0.2°, 22.84±0.2°, 23.57±0.2°, 24.37±0.2°, 26.15±0.2°, 27.39±0.2°, 28.45±0.2° There are characteristic peaks at any 6, 7, 8 or 9 or more of them; Preferably, the X-ray powder diffraction pattern of the fumarate salt form I of Compound 1 has characteristic peaks at any 2-5 or more, or 3-5 or more, or 3-6 or more, or 3-8 or more, or 5-8 or more, or 6-8 or more of 2θ of 11.85±0.2°, 14.70±0.2°, 15.30±0.2°, 17.06±0.2°, 17.34±0.2°, 17.82±0.2°, 18.84±0.2°, 19.99±0.2°, 22.12±0.2°, 23.57±0.2°, and 24.37±0.2°, more preferably any 6, 7, 8 or 9 or more of them have characteristic peaks; Optionally, the invention further comprises a characteristic peak at at least one of 2θ of 10.03±0.2°, 12.75±0.2°, 13.14±0.2°, 20.34±0.2°, 21.65±0.2°, 22.84±0.2°, 26.15±0.2°, 27.39±0.2°, and 28.45±0.2°, preferably comprising 2, 3, 4 or 5 or more characteristic peaks; More preferably, the X-ray powder diffraction pattern of the fumarate salt form I of Compound 1 optionally has characteristic peaks at the following positions at 2θ: 11.85±0.2°、14.70±0.2°、15.30±0.2°， Or 17.06±0.2°, 17.34±0.2°, 17.82±0.2°, Or 18.84±0.2°, 19.99±0.2°, 22.12±0.2°, Or 22.12±0.2°, 23.57±0.2°, 24.37±0.2°, Or 11.85±0.2°, 14.70±0.2°, 15.30±0.2°, 17.06±0.2°, Or 15.30±0.2°, 17.06±0.2°, 17.34±0.2°, 17.82±0.2°, Or 17.34±0.2°, 17.82±0.2°, 18.84±0.2°, 19.99±0.2°, Or 19.99±0.2°, 22.12±0.2°, 23.57±0.2°, 24.37±0.2°, Or 11.85±0.2°, 14.70±0.2°, 15.30±0.2°, 17.06±0.2°, 17.34±0.2°, Or 14.70±0.2°, 15.30±0.2°, 17.06±0.2°, 17.34±0.2°, 17.82±0.2°, Or 18.84±0.2°, 19.99±0.2°, 22.12±0.2°, 23.57±0.2°, 24.37±0.2°, Or 17.82±0.2°, 18.84±0.2°, 19.99±0.2°, 22.12±0.2°, 23.57±0.2°, Or 17.06±0.2°, 17.34±0.2°, 17.82±0.2°, 23.57±0.2°, 24.37±0.2°, Or 11.85±0.2°, 14.70±0.2°, 15.30±0.2°, 17.06±0.2°, 17.34±0.2°, 17.82±0.2°, Or 15.30±0.2°, 17.06±0.2°, 17.34±0.2°, 10.03±0.2°, 12.75±0.2°, 13.14±0.2°, Or 17.06±0.2°, 17.34±0.2°, 17.82±0.2°, 18.84±0.2°, 13.14±0.2°, 20.34±0.2°, Or 17.82±0.2°, 18.84±0.2°, 19.99±0.2°, 13.14±0.2°, 20.34±0.2°, 21.65±0.2°, Or 11.85±0.2°, 14.70±0.2°, 19.99±0.2°, 13.14±0.2°, 20.34±0.2°, 21.65±0.2°, Or 11.85±0.2°, 14.70±0.2°, 15.30±0.2°, 17.06±0.2°, 17.34±0.2°, 17.82±0.2°, 18.84±0.2°, Or 15.30±0.2°, 17.06±0.2°, 17.34±0.2°, 17.82±0.2°, 18.84±0.2°, 19.99±0.2°, 22.12±0.2°, Or 10.03±0.2°, 12.75±0.2°, 17.34±0.2°, 17.82±0.2°, 18.84±0.2°, 19.99±0.2°, 22.12±0.2°, Or 10.03±0.2°, 12.75±0.2°, 17.34±0.2°, 17.82±0.2°, 18.84±0.2°, 19.99±0.2°, 28.45±0.2°, or 10.03±0.2°, 17.06±0.2°, 17.34±0.2°, 17.82±0.2°, 18.84±0.2°, 27.39±0.2°, 28.45±0.2°, Or 10.03±0.2°, 11.85±0.2°, 12.75±0.2°, 13.14±0.2°, 14.70±0.2°, 15.30±0.2°, 17.06±0.2°, 17.34±0.2°, Or 1.85±0.2°, 12.75±0.2°, 13.14±0.2°, 14.70±0.2°, 15.30±0.2°, 17.06±0.2°, 17.34±0.2°, 17.82±0.2°, or 21.65±0.2°, 22.12±0.2°, 22.84±0.2°, 23.57±0.2°, 24.37±0.2°, 26.15±0.2°, 27.39±0.2°、28.45±0.2， or 11.85±0.2°, 14.70±0.2°, 15.30±0.2°, 22.84±0.2°, 23.57±0.2°, 24.37±0.2°, 26.15±0.2°, 27.39±0.2°, 28.45±0.2, or 11.85±0.2°, 14.70±0.2°, 17.06±0.2°, 17.34±0.2°, 23.57±0.2°, 24.37±0.2°, 26.15±0.2°, 27.39±0.2°, 28.45±0.2, or 17.34±0.2°, 17.82±0.2°, 18.84±0.2°, 19.99±0.2°, 20.34±0.2°, 21.65±0.2°, 22.12±0.2°, 22.84±0.2°, 24.37±0.2°, or 10.03±0.2°, 11.85±0.2°, 12.75±0.2°, 13.14±0.2°, 14.70±0.2°, 15.30±0.2°, 17.06±0.2°, 17.34±0.2°, 17.82±0.2°, 18.84±0.2°, or 11.85±0.2°, 12.75±0.2°, 13.14±0.2°, 14.70±0.2°, 15.30±0.2°, 17.06±0.2°, 17.34±0.2°, 17.82±0.2°, 18.84±0.2°, 19.99±0.2°, or 17.06±0.2°, 17.34±0.2°, 17.82±0.2°, 18.84±0.2°, 19.99±0.2°, 20.34±0.2°, 21.65±0.2°, 22.12±0.2°, 22.84±0.2°, 23.57±0.2°, or 11.85±0.2°, 14.70±0.2°, 15.30±0.2°, 18.84±0.2°, 19.99±0.2°, 20.34±0.2°, 21.65±0.2°, 22.12±0.2°, 22.84±0.2°, 23.57±0.2°, or 11.85±0.2°, 14.70±0.2°, 15.30±0.2°, 17.06±0.2°, 17.34±0.2°, 17.82±0.2°, 18.84±0.2°, 19.99±0.2°, 22.12±0.2°, 23.57±0.2°, 24.37±0.2°, or 10.03±0.2°, 14.70±0.2°, 15.30±0.2°, 17.06±0.2°, 17.34±0.2°, 17.82±0.2°, 18.84±0.2°, 19.99±0.2°, 22.12±0.2°, 23.57±0.2°, 24.37±0.2°, or 10.03±0.2°, 12.75±0.2°, 13.14±0.2°, 17.06±0.2°, 17.34±0.2°, 17.82±0.2°, 18.84±0.2°, 19.99±0.2°, 22.12±0.2°, 23.57±0.2°, 24.37±0.2°, or 10.03±0.2°, 12.75±0.2°, 13.14±0.2°, 17.06±0.2°, 17.34±0.2°, 17.82±0.2°, 18.84±0.2°, 19.99±0.2°, 20.34±0.2°, 22.12±0.2°, 23.57±0.2°, 24.37±0.2°, or 10.03±0.2°, 12.75±0.2°, 13.14±0.2°, 17.06±0.2°, 17.34±0.2°, 17.82±0.2°, 18.84±0.2°, 19.99±0.2°, 20.34±0.2°, 22.12±0.2°, 23.57±0.2°, 24.37±0.2°, 28.45±0.2°, or 10.03±0.2°, 12.75±0.2°, 13.14±0.2°, 17.06±0.2°, 17.34±0.2°, 17.82±0.2°, 18.84±0.2°, 19.99±0.2°, 20.34±0.2°, 22.12±0.2°, 23.57±0.2°, 27.39±0.2°, 28.45±0.2°, or 10.03±0.2°, 12.75±0.2°, 13.14±0.2°, 17.06±0.2°, 17.34±0.2°, 17.82±0.2°, 18.84±0.2°, 19.99±0.2°, 20.34±0.2°, 22.12±0.2°, 23.57±0.2°, 26.15±0.2°, 27.39±0.2°, 28.45±0.2°, or 10.03±0.2°, 12.75±0.2°, 13.14±0.2°, 17.06±0.2°, 17.34±0.2°, 17.82±0.2°, 18.84±0.2°, 19.99±0.2°, 20.34±0.2°, 21.65±0.2°, 22.12±0.2°, 23.57±0.2°, 26.15±0.2°, 27.39±0.2°, 28.45±0.2°, or 10.03±0.2°, 12.75±0.2°, 13.14±0.2°, 17.06±0.2°, 17.34±0.2°, 17.82±0.2°, 18.84±0.2°, 19.99±0.2°, 20.34±0.2°, 21.65±0.2°, 22.12±0.2°, 23.57±0.2°, 24.37±0.2°, 26.15±0.2°, 27.39±0.2°, 28.45±0.2°, or 10.03±0.2°, 12.75±0.2°, 13.14±0.2°, 17.06±0.2°, 17.34±0.2°, 17.82±0.2°, 18.84±0.2°, 19.99±0.2°, 20.34±0.2°, 21.65±0.2°, 22.12±0.2°, 24.37±0.2°, 23.57±0.2°, 24.37±0.2°, 26.15±0.2°, 27.39±0.2°, 28.45±0.2°, Among them, the X-ray powder diffraction pattern of the fumarate salt form I of compound 1 is shown in Figure 4.

9. The crystalline form or salt according to any one of claims 1 to 6, characterized in that It is a crystalline form or salt of compound 42: (S)-N-(1-(1H-indol-3-yl)hexane-2-yl)-6-(4-methylpiperazine-1-yl)benzo[b]thiophene-2-carboxamide, wherein the salt is an acid salt, and the acid salt is hydrochloride, phosphate, sulfate, nitrate, hydrobromide, fumarate, 2,5-dihydroxybenzoate, 1-hydroxy-2-naphthoate, acetate, dichloroacetate, trichloroacetate, acetohydroxamate, adipate, benzenesulfonate, 4-chlorobenzenesulfonate, benzoate, 4-acetamidobenzoate, 4-aminobenzoate, decanoate, hexanoate, caprylate, cinnamate, citrate, cyclohexanesulfamate, camphorsulfonate, aspartate, camphorate, gluconate, glucuronate, glutamate, isoascorbic acid salt, lactate, malate, mandelate, pyroglutamate, tartrate, dodecyl sulfate, dibenzoyltartrate, ethane-1,2-disulfonate, ethanesulfonate, formate, galactonate, gentisate, glutarate, 2-ketoglutarate, glycolate, hippurate, isethionate, lactobionate, ascorbate, aspartate, laurate, camphorate, maleate, malonate, methanesulfonate, 1,5-naphthalene disulfonate, naphthalene-2-sulfonate, nicotinate, oleate, orotate, oxalate, palmitate, pamoate, propionate, salicylate, 4-aminosalicylate, sebacate, stearate, succinate, thiocyanate, pamoate, formate, undecylenate, trifluoroacetate, benzenesulfonate, p-toluenesulfonate, or L-malate; Preferably, the acid salt is hydrochloride, phosphate, sulfate, nitrate, hydrobromide, fumarate, acetate, adipate, benzenesulfonate, benzoate, caproate, caprylate, cinnamate, citrate, aspartate, lactate, tartrate, aspartate, laurate, maleate, malonate, methanesulfonate, propionate, salicylate, formate, trifluoroacetate, benzenesulfonate; More preferably, the acid salt is hydrochloride, phosphate, sulfate, nitrate, hydrobromide, fumarate, benzenesulfonate, benzoate, citrate, lactate, tartrate, aspartate, laurate, maleate, malonate, methanesulfonate, benzenesulfonate.

10. An amorphous compound of (S)-N-(1-(1H-indol-3-yl)hexane-2-yl)-6-(4-methylpiperazin-1-yl)benzo[b]thiophene-2-carboxamide, characterized in that: There are no characteristic peaks in its X-ray powder diffraction pattern.

11. The crystalline form or salt according to claim 9, characterized in that It is a crystalline form or salt of compound 42, wherein the crystalline form or salt is crystalline form A or an amorphous form of a fumarate, crystalline form I of a fumarate, crystalline form II of a fumarate, or crystalline form III of a fumarate, wherein: The X-ray powder diffraction pattern of Form A of Compound 42 at 2θ is 5.12±0.2°, 6.66±0.2°, 7.58±0.2°, 9.18±0.2°, 10.28±0.2°, 13.32±0.2°, 15.20±0.2°, 15.60±0.2°, 17.16±0.2°, 17.44±0.2°, 18.42±0.2°, 18.74±0.2°, 19.74 ±0.2°, 20.74±0.2°, 21.36±0.2°, 21.72±0.2°, 22.92±0.2°, 26.28±0.2°, 27.46±0.2°, any 2-5 or more, or 3-5 or more, or 3-6 or more, or 3-8 or more, or 5-8 or more, or 6-8 or more have characteristic peaks, more preferably any 6, 7, 8 or 9 or more of them have characteristic peaks; Preferably, the X-ray powder diffraction pattern of Form A of Compound 42 has characteristic peaks at any 2-5 or more, or 3-5 or more, or 3-6 or more, or 3-8 or more, or 5-8 or more, or 6-8 or more of 2θ of 5.12±0.2°, 6.66±0.2°, 7.58±0.2°, 13.32±0.2°, 15.20±0.2°, 15.60±0.2°, 17.16±0.2°, 18.42±0.2°, 19.74±0.2°, 20.74±0.2°, and 22.92±0.2°, more preferably any 6, 7, 8 or 9 or more of them have characteristic peaks; Optionally, the invention further comprises a characteristic peak at at least one of 2θ of 9.18±0.2°, 10.28±0.2°, 17.44±0.2°, 18.74±0.2°, 21.36±0.2°, 21.72±0.2°, 26.28±0.2°, and 27.46±0.2°, preferably 2, 3, 4 or 5 or more of them; More preferably, the X-ray powder diffraction pattern of Form A of Compound 42 optionally has characteristic peaks at the following positions at 2θ: 5.12±0.2°、6.66±0.2°、7.58±0.2°， Or 13.32±0.2°, 15.20±0.2°, 15.60±0.2°, Or 17.16±0.2°, 18.42±0.2°, 19.74±0.2°, Or 19.74±0.2°, 20.74±0.2°, 22.92±0.2°, Or 5.12±0.2°, 6.66±0.2°, 7.58±0.2°, 13.32±0.2°, Or 15.20±0.2°, 15.60±0.2°, 17.16±0.2°, 18.42±0.2°, Or 18.42±0.2°, 19.74±0.2°, 20.74±0.2°, 22.92±0.2°, Or 6.66±0.2°, 7.58±0.2°, 13.32±0.2°, 15.20±0.2°, Or 5.12±0.2°, 6.66±0.2°, 7.58±0.2°, 13.32±0.2°, 15.20±0.2°, Or 7.58±0.2°, 13.32±0.2°, 15.20±0.2°, 15.60±0.2°, 17.16±0.2°, Or 13.32±0.2°, 15.20±0.2°, 15.60±0.2°, 17.16±0.2°, 18.42±0.2°, Or 17.16±0.2°, 18.42±0.2°, 19.74±0.2°, 20.74±0.2°, 22.92±0.2°, Or 5.12±0.2°, 6.66±0.2°, 7.58±0.2°, 13.32±0.2°, 15.20±0.2°, 15.60±0.2°, Or 6.66±0.2°, 7.58±0.2°, 13.32±0.2°, 15.20±0.2°, 15.60±0.2°, 17.16±0.2°, Or 7.58±0.2°, 13.32±0.2°, 15.20±0.2°, 15.60±0.2°, 17.16±0.2°, 18.42±0.2°, Or 15.60±0.2°, 17.16±0.2°, 18.42±0.2°, 19.74±0.2°, 20.74±0.2°, 22.92±0.2°, Or 5.12±0.2°, 6.66±0.2°, 7.58±0.2°, 9.18±0.2°, 13.32±0.2°, 15.20±0.2°, 15.60±0.2°, Or 6.66±0.2°, 7.58±0.2°, 9.18±0.2°, 10.28±0.2°, 13.32±0.2°, 15.20±0.2°, 15.60±0.2°, Or 9.18±0.2°, 10.28±0.2°, 13.32±0.2°, 15.20±0.2°, 15.60±0.2°, 17.44±0.2°, 18.74±0.2°, Or 5.12±0.2°, 6.66±0.2°, 7.58±0.2°, 13.32±0.2°, 15.20±0.2°, 15.60±0.2°, 17.16±0.2°, 18.42±0.2°, Or 13.32±0.2°, 15.20±0.2°, 15.60±0.2°, 17.16±0.2°, 18.42±0.2°, 19.74±0.2°, 20.74±0.2°, 22.92±0.2°, or 7.58±0.2°, 13.32±0.2°, 15.20±0.2°, 15.60±0.2°, 17.16±0.2°, 18.42±0.2°, 19.74±0.2°, 20.74±0.2°, Or 5.12±0.2°, 6.66±0.2°, 7.58±0.2°, 9.18±0.2°, 13.32±0.2°, 15.20±0.2°, 15.60±0.2°, 17.16±0.2°, or 5.12±0.2°, 6.66±0.2°, 7.58±0.2°, 13.32±0.2°, 15.20±0.2°, 15.60±0.2°, 17.16±0.2°, 18.42±0.2°, 19.74±0.2°, Or 6.66±0.2°, 7.58±0.2°, 13.32±0.2°, 15.20±0.2°, 15.60±0.2°, 17.16±0.2°, 18.42±0.2°, 19.74±0.2°, 20.74±0.2°, Or 9.18±0.2°, 13.32±0.2°, 15.20±0.2°, 15.60±0.2°, 17.16±0.2°, 18.42±0.2°, 19.74±0.2°, 20.74±0.2°, 22.92±0.2°, Or 5.12±0.2°, 6.66±0.2°, 7.58±0.2°, 10.28±0.2°, 17.44±0.2°, 13.32±0.2°, 15.20±0.2°, 15.60±0.2°, 17.16±0.2°, or 5.12±0.2°, 6.66±0.2°, 7.58±0.2°, 13.32±0.2°, 15.20±0.2°, 15.60±0.2°, 17.16±0.2°, 18.42±0.2°, 19.74±0.2°, 20.74±0.2°, or 5.12±0.2°, 6.66±0.2°, 7.58±0.2°, 9.18±0.2°, 13.32±0.2°, 15.20±0.2°, 15.60±0.2°, 17.16±0.2°, 18.42±0.2°, 19.74±0.2°, or 6.66±0.2°, 7.58±0.2°, 10.28±0.2°, 13.32±0.2°, 15.20±0.2°, 15.60±0.2°, 17.16±0.2°, 18.42±0.2°, 19.74±0.2°, 20.74±0.2°, or 5.12±0.2°, 6.66±0.2°, 7.58±0.2°, 9.18±0.2°, 13.32±0.2°, 15.20±0.2°, 15.60±0.2°, 17.16±0.2°, 26.28±0.2°, 27.46±0.2°, Or 6.66±0.2°, 7.58±0.2°, 10.28±0.2°, 13.32±0.2°, 15.20±0.2°, 15.60±0.2°, 17.44±0.2°、18.74±0.2°、、19.74±0.2°、20.74±0.2°， or 5.12±0.2°, 6.66±0.2°, 7.58±0.2°, 13.32±0.2°, 15.20±0.2°, 15.60±0.2°, 17.16±0.2°, 18.42±0.2°, 19.74±0.2°, 20.74±0.2°, 22.92±0.2°, or 5.12±0.2°, 6.66±0.2°, 7.58±0.2°, 9.18±0.2°, 13.32±0.2°, 15.20±0.2°, 15.60±0.2°, 17.16±0.2°, 18.42±0.2°, 19.74±0.2°, 20.74±0.2°, or 5.12±0.2°, 6.66±0.2°, 7.58±0.2°, 9.18±0.2°, 10.28±0.2°, 15.20±0.2°, 15.60±0.2°, 17.16±0.2°, 18.42±0.2°, 19.74±0.2°, 20.74±0.2°, or 5.12±0.2°, 6.66±0.2°, 7.58±0.2°, 9.18±0.2°, 10.28±0.2°, 15.20±0.2°, 15.60±0.2°, 17.16±0.2°, 18.42±0.2°, 26.28±0.2°, 27.46±0.2°, or 5.12±0.2°, 6.66±0.2°, 7.58±0.2°, 9.18±0.2°, 10.28±0.2°, 15.20±0.2°, 15.60±0.2°, 17.16±0.2°, 18.74±0.2°, 21.36±0.2°, 21.72±0.2°, or 5.12±0.2°, 6.66±0.2°, 7.58±0.2°, 9.18±0.2°, 13.32±0.2°, 15.20±0.2°, 15.60±0.2°, 17.16±0.2°, 18.42±0.2°, 19.74±0.2°, 20.74±0.2°, 22.92±0.2°, or 5.12±0.2°, 6.66±0.2°, 7.58±0.2°, 9.18±0.2°, 10.28±0.2°, 15.20±0.2°, 15.60±0.2°, 17.16±0.2°, 18.74±0.2°, 21.36±0.2°, 21.72±0.2°, 27.46±0.2°, or 5.12±0.2°, 6.66±0.2°, 7.58±0.2°, 13.32±0.2°, 15.20±0.2°, 15.60±0.2°, 17.16±0.2°, 18.42±0.2°, 19.74±0.2°, 20.74±0.2°, 22.92±0.2°, 21.72±0.2°, or 5.12±0.2°, 6.66±0.2°, 7.58±0.2°, 13.32±0.2°, 15.20±0.2°, 15.60±0.2°, 17.16±0.2°, 18.42±0.2°, 19.74±0.2°, 20.74±0.2°, 21.36±0.2°, 21.72±0.2°, 22.92±0.2°, or 5.12±0.2°, 6.66±0.2°, 7.58±0.2°, 13.32±0.2°, 15.20±0.2°, 15.60±0.2°, 17.16±0.2°, 18.42±0.2°, 19.74±0.2°, 20.74±0.2°, 21.36±0.2°, 21.72±0.2°, 22.92±0.2°, 26.28±0.2°, 27.46±0.2°, or 5.12±0.2°, 6.66±0.2°, 7.58±0.2°, 9.18±0.2°, 13.32±0.2°, 15.20±0.2°, 15.60±0.2°, 17.16±0.2°, 18.42±0.2°, 19.74±0.2°, 20.74±0.2°, 21.36±0.2°, 21.72±0.2°, 22.92±0.2°, 26.28±0.2°, 27.46±0.2°, Among them, the X-ray powder diffraction pattern of Form A of Compound 42 is shown in Figure 3; Or the X-ray powder diffraction pattern of the crystalline form I of the fumarate salt of compound 42 at 2θ is 10.10±0.2°, 11.94±0.2°, 12.78±0.2°, 14.70±0.2°, 15.38±0.2°, 17.08±0.2°, 17.28±0.2°, 17.80±0.2°, 18.92±0.2°, 20.24±0.2°, 20.76±0.2°. 0.2°, 22.02±0.2°, 22.74±0.2°, 23.52±0.2°, 24.42±0.2°, 28.66±0.2°, any 2-5 or more, or 3-5 or more, or 3-6 or more, or 3-8 or more, or 5-8 or more, or 6-8 or more have characteristic peaks, more preferably any 6, 7, 8 or 9 or more of them have characteristic peaks; Preferably, the X-ray powder diffraction pattern of the fumarate crystalline form I of compound 42 has characteristic peaks at any 2-5 or more, or 3-5 or more, or 3-6 or more, or 3-8 or more, or 5-8 or more, or 6-8 or more of 2θ of 14.70±0.2°, 15.38±0.2°, 17.28±0.2°, 17.80±0.2°, 18.92±0.2°, 20.24±0.2°, 22.74±0.2°, 23.52±0.2°, and 24.42±0.2°, more preferably any 6, 7, 8 or 9 or more of them have characteristic peaks; Optionally, the invention further comprises a characteristic peak at at least one of 2θ of 10.10±0.2°, 11.94±0.2°, 12.78±0.2°, 17.08±0.2°, 20.76±0.2°, 22.02±0.2°, and 28.66±0.2°, preferably 2, 3, 4 or 5 or more of them; More preferably, the X-ray powder diffraction pattern of the fumarate salt form I of compound 42 optionally has characteristic peaks at the following positions at 2θ: 14.70±0.2°、15.38±0.2°、17.28±0.2°， Or 17.80±0.2°, 18.92±0.2°, 20.24±0.2°, Or 22.74±0.2°, 23.52±0.2°, 24.42±0.2°, Or 15.38±0.2°, 17.28±0.2°, 17.80±0.2°, Or 14.70±0.2°, 15.38±0.2°, 17.28±0.2°, 17.80±0.2°, Or 15.38±0.2°, 17.28±0.2°, 17.80±0.2°, 18.92±0.2°, Or 20.24±0.2°, 22.74±0.2°, 23.52±0.2°, 24.42±0.2°, Or 18.92±0.2°, 20.24±0.2°, 22.74±0.2°, 23.52±0.2°, Or 14.70±0.2°, 15.38±0.2°, 17.28±0.2°, 17.80±0.2°, 18.92±0.2°, Or 15.38±0.2°, 17.28±0.2°, 17.80±0.2°, 18.92±0.2°, 20.24±0.2°, Or 17.28±0.2°, 17.80±0.2°, 18.92±0.2°, 20.24±0.2°, 22.74±0.2°, Or 18.92±0.2°, 20.24±0.2°, 22.74±0.2°, 23.52±0.2°, 24.42±0.2°, Or 14.70±0.2°, 15.38±0.2°, 17.28±0.2°, 17.80±0.2°, 18.92±0.2°, 20.24±0.2°, Or 4.70±0.2°, 10.10±0.2°, 11.94±0.2°, 12.78±0.2°, 15.38±0.2°, 17.28±0.2°, Or 15.38±0.2°, 17.28±0.2°, 17.80±0.2°, 18.92±0.2°, 20.76±0.2°, 22.02±0.2°, Or 10.10±0.2°, 11.94±0.2°, 20.24±0.2°, 22.74±0.2°, 23.52±0.2°, 24.42±0.2°, Or 14.70±0.2°, 15.38±0.2°, 17.28±0.2°, 17.80±0.2°, 18.92±0.2°, 20.24±0.2°, 22.74±0.2°, Or 15.38±0.2°, 17.28±0.2°, 17.80±0.2°, 18.92±0.2°, 20.24±0.2°, 22.74±0.2°, 23.52±0.2°, Or 10.10±0.2°, 11.94±0.2°, 14.70±0.2°, 15.38±0.2°, 17.28±0.2°, 17.80±0.2°, 18.92±0.2°, Or 17.28±0.2°, 17.80±0.2°, 18.92±0.2°, 20.24±0.2°, 22.74±0.2°, 23.52±0.2°, 24.42±0.2°, Or 10.10±0.2°, 11.94±0.2°, 12.78±0.2°, 17.28±0.2°, 17.80±0.2°, 18.92±0.2°, 20.24±0.2°, Or 14.70±0.2°, 15.38±0.2°, 17.28±0.2°, 17.80±0.2°, 18.92±0.2°, 20.24±0.2°, 22.74±0.2°, 23.52±0.2°, Or 10.10±0.2°, 11.94±0.2°, 14.70±0.2°, 15.38±0.2°, 17.28±0.2°, 17.80±0.2°, 18.92±0.2°, 20.24±0.2°, 22.74±0.2°, Or 10.10±0.2°, 11.94±0.2°, 14.70±0.2°, 15.38±0.2°, 17.28±0.2°, 17.80±0.2°, 18.92±0.2°, 20.24±0.2°, 22.74±0.2°, or 12.78±0.2°, 15.38±0.2°, 17.28±0.2°, 17.08±0.2°, 18.92±0.2°, 20.76±0.2°, 22.02±0.2°, 23.52±0.2°, 24.42±0.2°, or 14.70±0.2°, 15.38±0.2°, 17.28±0.2°, 17.80±0.2°, 18.92±0.2°, 20.24±0.2°, 22.74±0.2°, 23.52±0.2°, 24.42±0.2°, 28.66±0.2°, or 10.10±0.2°, 15.38±0.2°, 17.28±0.2°, 17.80±0.2°, 18.92±0.2°, 20.24±0.2°, 22.74±0.2°, 23.52±0.2°, 24.42±0.2°, 28.66±0.2°, or 10.10±0.2°, 15.38±0.2°, 17.28±0.2°, 17.80±0.2°, 18.92±0.2°, 20.76±0.2°, 22.02±0.2°, 23.52±0.2°, 24.42±0.2°, 28.66±0.2°, or 10.10±0.2°, 12.78±0.2°, 17.08±0.2°, 17.80±0.2°, 18.92±0.2°, 20.76±0.2°, 22.02±0.2°, 23.52±0.2°, 24.42±0.2°, 28.66±0.2°, or 10.10±0.2°, 14.70±0.2°, 15.38±0.2°, 17.80±0.2°, 18.92±0.2°, 20.76±0.2°, 22.02±0.2°, 23.52±0.2°, 24.42±0.2°, 28.66±0.2°, or 14.70±0.2°, 15.38±0.2°, 17.28±0.2°, 17.80±0.2°, 18.92±0.2°, 20.24±0.2°, 22.74±0.2°, 20.76±0.2°, 22.02±0.2°, 23.52±0.2°, 24.42±0.2°, or 10.10±0.2°, 11.94±0.2°, 17.28±0.2°, 17.80±0.2°, 18.92±0.2°, 20.24±0.2°, 22.74±0.2°, 20.76±0.2°, 22.02±0.2°, 23.52±0.2°, 24.42±0.2°, or 10.10±0.2°, 11.94±0.2°, 14.70±0.2°, 15.38±0.2°, 17.28±0.2°, 18.92±0.2°, 20.24±0.2°, 22.02±0.2°, 23.52±0.2°, 24.42±0.2°, 28.66±0.2°, Among them, the X-ray powder diffraction pattern of Form I of the fumarate salt of Compound 42 is shown in Figure 6; Or the X-ray powder diffraction pattern of the crystalline form II of the fumarate salt of compound 42 at 2θ is 6.22±0.2°, 9.36±0.2°, 12.50±0.2°, 13.32±0.2°, 13.74±0.2°, 14.68±0.2°, 15.34±0.2°, 16.74±0.2°, 18.32±0.2°, 18.82±0.2°, 20.10±0.2°, 21.84±0.2°, 23.12±0.2°, 24.80±0.2°, 25.70±0.2°, 26.81±0.2°, 27.61±0.2°, 28.50±0.2°, 29.90±0.2°, 30. 0.2°, 21.38±0.2°, 22.18±0.2°, 23.12±0.2°, 24.20±0.2°, 26.20±0.2°, any 2-5 or more, or 3-5 or more, or 3-6 or more, or 3-8 or more, or 5-8 or more, or 6-8 or more have characteristic peaks, more preferably any 6, 7, 8 or 9 or more of them have characteristic peaks; Preferably, the X-ray powder diffraction pattern of the fumarate crystalline form II of compound 42 has characteristic peaks at any 2-5 or more, or 3-5 or more, or 3-6 or more, or 3-8 or more, or 5-8 or more, or 6-8 or more of 2θ of 6.22±0.2°, 9.36±0.2°, 13.74±0.2°, 18.82±0.2°, 20.10±0.2°, 21.38±0.2°, and 23.12±0.2°, more preferably any 6, 7, 8 or 9 or more of them have characteristic peaks; Optionally, the invention further comprises a characteristic peak at at least one of 2θ of 12.50±0.2°, 13.32±0.2°, 14.68±0.2°, 15.34±0.2°, 16.74±0.2°, 18.32±0.2°, 22.18±0.2°, 24.20±0.2°, and 26.20±0.2°, preferably comprising 2, 3, 4 or 5 or more characteristic peaks; More preferably, the X-ray powder diffraction pattern of the fumarate crystalline form II of compound 42 optionally has characteristic peaks at the following positions at 2θ: 6.22±0.2°、9.36±0.2°、13.74±0.2°、18.82±0.2°， Or 9.36±0.2°, 13.74±0.2°, 18.82±0.2°, 20.10±0.2°, Or 13.74±0.2°, 18.82±0.2°, 20.10±0.2°, 21.38±0.2°, Or 18.82±0.2°, 20.10±0.2°, 21.38±0.2°, 23.12±0.2°, Or 6.22±0.2°, 9.36±0.2°, 12.50±0.2°, 13.74±0.2°, 18.82±0.2°, Or 9.36±0.2°, 13.32±0.2°, 13.74±0.2°, 18.82±0.2°, 20.10±0.2°, Or 13.74±0.2°, 14.68±0.2°, 18.82±0.2°, 20.10±0.2°, 21.38±0.2°, Or 13.32±0.2°, 14.68±0.2°, 18.82±0.2°, 20.10±0.2°, 21.38±0.2°, 23.12±0.2°, Or 6.22±0.2°, 9.36±0.2°, 13.74±0.2°, 18.82±0.2°, 20.10±0.2°, 21.38±0.2°, Or 9.36±0.2°, 13.74±0.2°, 18.82±0.2°, 20.10±0.2°, 21.38±0.2°, 23.12±0.2°, Or 12.50±0.2°, 13.74±0.2°, 18.82±0.2°, 20.10±0.2°, 21.38±0.2°, 23.12±0.2°, Or 6.22±0.2°, 9.36±0.2°, 12.50±0.2°, 13.32±0.2°, 13.74±0.2°, 18.82±0.2°, 20.10±0.2°, Or 6.22±0.2°, 9.36±0.2°, 12.50±0.2°, 13.32±0.2°, 13.74±0.2°, 18.82±0.2°, 24.20±0.2°, Or 6.22±0.2°, 9.36±0.2°, 18.82±0.2°, 20.10±0.2°, 21.38±0.2°, 23.12±0.2°, 24.20±0.2°, or 6.22±0.2°, 9.36±0.2°, 13.74±0.2°, 14.68±0.2°, 18.82±0.2°, 20.10±0.2°, 21.38±0.2°, 23.12±0.2°, Or 12.50±0.2°, 9.36±0.2°, 13.74±0.2°, 14.68±0.2°, 18.82±0.2°, 20.10±0.2°, 21.38±0.2°, 23.12±0.2°, Or 12.50±0.2°, 9.36±0.2°, 13.74±0.2°, 14.68±0.2°, 18.82±0.2°, 20.10±0.2°, 21.38±0.2°, 26.20±0.2°, Or 12.50±0.2°, 9.36±0.2°, 13.74±0.2°, 14.68±0.2°, 18.82±0.2°, 20.10±0.2°, 24.20±0.2°, 26.20±0.2°, Or 6.22±0.2°, 9.36±0.2°, 12.50±0.2°, 13.32±0.2°, 13.74±0.2°, 18.82±0.2°, 20.10±0.2°, 21.38±0.2°, 23.12±0.2°, or 6.22±0.2°, 9.36±0.2°, 13.74±0.2°, 15.34±0.2°, 16.74±0.2°, 18.82±0.2°, 20.10±0.2°, 21.38±0.2°, 23.12±0.2°, Or 6.22±0.2°, 9.36±0.2°, 13.74±0.2°, 18.82±0.2°, 20.10±0.2°, 21.38±0.2°, 22.18±0.2°, 23.12±0.2°, 24.20±0.2°, or 6.22±0.2°, 9.36±0.2°, 13.74±0.2°, 18.82±0.2°, 18.32±0.2°, 20.10±0.2°, 22.18±0.2°, 21.38±0.2°, 23.12±0.2°, or 6.22±0.2°, 9.36±0.2°, 12.50±0.2°, 13.32±0.2°, 13.74±0.2°, 14.68±0.2°, 18.82±0.2°, 20.10±0.2°, 21.38±0.2°, 23.12±0.2°, Or 6.22±0.2°, 9.36±0.2°, 13.74±0.2°, 18.82±0.2°, 20.10±0.2°, 21.38±0.2°, 23.12±0.2°, or 6.22±0.2°, 9.36±0.2°, 13.74±0.2°, 14.68±0.2°, 15.34±0.2°, 16.74±0.2°, 18.82±0.2°, 20.10±0.2°, 21.38±0.2°, 23.12±0.2°, or 6.22±0.2°, 9.36±0.2°, 13.74±0.2°, 18.82±0.2°, 20.10±0.2°, 21.38±0.2°, 22.18±0.2°, 23.12±0.2°, 24.20±0.2°, 26.20±0.2°, or 6.22±0.2°, 9.36±0.2°, 12.50±0.2°, 13.32±0.2°, 13.74±0.2°, 14.68±0.2°, 15.34±0.2°, 18.82±0.2°, 20.10±0.2°, 21.38±0.2°, 23.12±0.2°, Or 6.22±0.2°, 9.36±0.2°, 13.74±0.2°, 18.82±0.2°, 20.10±0.2°, 21.38±0.2°, 23.12±0.2°, or 6.22±0.2°, 9.36±0.2°, 13.32±0.2°, 13.74±0.2°, 14.68±0.2°, 15.34±0.2°, 16.74±0.2°, 18.82±0.2°, 20.10±0.2°, 21.38±0.2°, 23.12±0.2°, or 6.22±0.2°, 9.36±0.2°, 13.74±0.2°, 16.74±0.2°, 18.32±0.2°, 18.82±0.2°, 20.10±0.2°, 21.38±0.2°, 22.18±0.2°, 23.12±0.2°, 24.20±0.2°, or 6.22±0.2°, 9.36±0.2°, 12.50±0.2°, 13.32±0.2°, 13.74±0.2°, 14.68±0.2°, 15.34±0.2°, 16.74±0.2°, 18.82±0.2°, 20.10±0.2°, 21.38±0.2°, 23.12±0.2°, or 6.22±0.2°, 9.36±0.2°, 13.32±0.2°, 13.74±0.2°, 14.68±0.2°, 15.34±0.2°, 16.74±0.2°, 18.32±0.2°, 18.82±0.2°, 20.10±0.2°, 21.38±0.2°, 23.12±0.2°, or 6.22±0.2°, 9.36±0.2°, 13.74±0.2°, 14.68±0.2°, 15.34±0.2°, 16.74±0.2°, 18.32±0.2°, 18.82±0.2°, 20.10±0.2°, 21.38±0.2°, 22.18±0.2°, 23.12±0.2°, or 6.22±0.2°, 9.36±0.2°, 13.74±0.2°, 15.34±0.2°, 16.74±0.2°, 18.32±0.2°, 18.82±0.2°, 20.10±0.2°, 21.38±0.2°, 22.18±0.2°, 23.12±0.2°, 24.20±0.2°, or 6.22±0.2°, 9.36±0.2°, 13.74±0.2°, 18.82±0.2°, 20.10±0.2°, 21.38±0.2°, 23.12±0.2°, 12.50±0.2°, 13.32±0.2°, 14.68±0.2°, 15.34±0.2°, 16.74±0.2°, 18.32±0.2°, 22.18±0.2°, 24.20±0.2°, 26.20±0.2°, Among them, the X-ray powder diffraction pattern of Form II of the fumarate salt of Compound 42 is shown in Figure 7; Or the X-ray powder diffraction pattern of the crystalline form III of the fumarate salt of compound 42 at 2θ is 3.42±0.2°, 4.72±0.2°, 5.72±0.2°, 6.30±0.2°, 8.38±0.2°, 8.60±0.2°, 9.48±0.2°, 10.32±0.2°, 11.56±0.2°, 13.72±0.2°, 14.36±0.2°, 15.18±0.2°, 17.16±0.2°, 18.02±0.2°, 19.70±0.2°, 20. 0.2°, 18.66±0.2°, 19.56±0.2°, 20.06±0.2°, 20.80±0.2°, 21.62±0.2°, 22.04±0.2°, 22.56±0.2°, 25.76±0.2°, any 2-5 or more, or 3-5 or more, or 3-6 or more, or 3-8 or more, or 5-8 or more, or 6-8 or more have characteristic peaks, more preferably any 6, 7, 8 or 9 or more thereof There are characteristic peaks; Preferably, the X-ray powder diffraction pattern of the fumarate crystalline form III of compound 42 has characteristic peaks at any 2-5 or more, or 3-5 or more, or 3-6 or more of 2θ of 4.72±0.2°, 6.30±0.2°, 9.48±0.2°, 10.32±0.2°, 13.72±0.2°, 14.36±0.2°, 17.16±0.2°, 19.56±0.2°, 20.06±0.2°, and 20.80±0.2°, more preferably any 3, 4, 5 or 6 or more of them have characteristic peaks; Optionally, the invention further comprises a characteristic peak at at least one of 2θ of 3.42±0.2°, 5.72±0.2°, 8.38±0.2°, 8.60±0.2°, 11.56±0.2°, 15.18±0.2°, 18.02±0.2°, 18.66±0.2°, 21.62±0.2°, 22.04±0.2°, 22.56±0.2°, and 25.76±0.2°, preferably comprising 2, 3, 4 or 5 or more characteristic peaks; More preferably, the X-ray powder diffraction pattern of the fumarate salt form III of compound 42 optionally has characteristic peaks at the following positions at 2θ: 4.72±0.2°、6.30±0.2°、9.48±0.2°、10.32±0.2°， Or 13.72±0.2°, 14.36±0.2°, 17.16±0.2°, 19.56±0.2°, Or 4.72±0.2°, 6.30±0.2°, 20.06±0.2°, 20.80±0.2°, Or 9.48±0.2°, 10.32±0.2°, 14.36±0.2°, 19.56±0.2°, Or 6.30±0.2°, 14.36±0.2°, 19.56±0.2°, 20.06±0.2°, Or 4.72±0.2°, 6.30±0.2°, 9.48±0.2°, 10.32±0.2°, 13.72±0.2°, Or 6.30±0.2°, 9.48±0.2°, 10.32±0.2°, 13.72±0.2°, 14.36±0.2°, Or 14.36±0.2°, 17.16±0.2°, 19.56±0.2°, 20.06±0.2°, 20.80±0.2°, Or 3.42±0.2°, 4.72±0.2°, 6.30±0.2°, 9.48±0.2°, 10.32±0.2°, Or 13.72±0.2°, 14.36±0.2°, 17.16±0.2°, 18.66±0.2°, 21.62±0.2°, Or 4.72±0.2°, 6.30±0.2°, 9.48±0.2°, 10.32±0.2°, 13.72±0.2°, 14.36±0.2°, Or 6.30±0.2°, 9.48±0.2°, 10.32±0.2°, 13.72±0.2°, 14.36±0.2°, 17.16±0.2°, Or 9.48±0.2°, 10.32±0.2°, 13.72±0.2°, 14.36±0.2°, 17.16±0.2°, 19.56±0.2°, 20.06±0.2°, Or 3.42±0.2°, 4.72±0.2°, 5.72±0.2°, 6.30±0.2°, 9.48±0.2°, 10.32±0.2°, 13.72±0.2°, or 14.36±0.2°, 17.16±0.2°, 19.56±0.2°, 20.06±0.2°, 2, 22.04±0.2°, 22.56±0.2°, 25.76±0.2°, Or 8.38±0.2°, 8.60±0.2°, 9.48±0.2°, 10.32±0.2°, 11.56±0.2°, 13.72±0.2°, 15.18±0.2°, Or 8.38±0.2°, 8.60±0.2°, 13.72±0.2°, 14.36±0.2°, 17.16±0.2°, 19.56±0.2°, 20.06±0.2°, 20.80±0.2°, Or 4.72±0.2°, 6.30±0.2°, 9.48±0.2°, 10.32±0.2°, 13.72±0.2°, 14.36±0.2°, 17.16±0.2°, 19.56±0.2°, Or 6.30±0.2°, 9.48±0.2°, 10.32±0.2°, 13.72±0.2°, 14.36±0.2°, 17.16±0.2°, 19.56±0.2°, 20.06±0.2°, Or 9.48±0.2°, 10.32±0.2°, 13.72±0.2°, 14.36±0.2°, 17.16±0.2°, 19.56±0.2°, 20.06±0.2°, 20.80±0.2°, Or 3.42±0.2°, 8.38±0.2°, 8.60±0.2°, 13.72±0.2°, 14.36±0.2°, 17.16±0.2°, 19.56±0.2°, 20.06±0.2°, 20.80±0.2°, Or 4.72±0.2°, 5.72±0.2°, 6.30±0.2°, 9.48±0.2°, 10.32±0.2°, 13.72±0.2°, 14.36±0.2°, 17.16±0.2°, 19.56±0.2°, Or 6.30±0.2°, 8.38±0.2°, 9.48±0.2°, 10.32±0.2°, 13.72±0.2°, 14.36±0.2°, 17.16±0.2°, 19.56±0.2°, 20.06±0.2°, or 9.48±0.2°, 10.32±0.2°, 11.56±0.2°, 13.72±0.2°, 14.36±0.2°, 17.16±0.2°, 19.56±0.2°, 20.06±0.2°, 20.80±0.2°, Or 3.42±0.2°, 5.72±0.2°, 8.38±0.2°, 8.60±0.2°, 13.72±0.2°, 14.36±0.2°, 17.16±0.2°, 19.56±0.2°, 20.06±0.2°, 20.80±0.2°, Or 4.72±0.2°, 6.30±0.2°, 9.48±0.2°, 10.32±0.2°, 13.72±0.2°, 14.36±0.2°, 17.16±0.2°, 18.02±0.2°, 18.66±0.2°, 19.56±0.2°, Or 6.30±0.2°, 8.38±0.2°, 8.60±0.2°, 9.48±0.2°, 10.32±0.2°, 13.72±0.2°, 14.36±0.2°, 17.16±0.2°, 19.56±0.2°, 20.06±0.2°, or 3.42±0.2°, 5.72±0.2°, 8.38±0.2°, 9.48±0.2°, 10.32±0.2°, 13.72±0.2°, 14.36±0.2°, 17.16±0.2°, 19.56±0.2°, 20.06±0.2°, 20.80±0.2°, 22.56±0.2°, 25.76±0.2°, or 8.38±0.2°, 8.60±0.2°, 13.72±0.2°, 14.36±0.2°, 17.16±0.2°, 19.56±0.2°, 20.06±0.2°, 20.80±0.2°, 21.62±0.2°, 22.04±0.2°, 22.56±0.2°, 25.76±0.2°, or 4.72±0.2°, 6.30±0.2°, 8.60±0.2°, 9.48±0.2°, 10.32±0.2°, 11.56±0.2°, 13.72±0.2°, 14.36±0.2°, 15.18±0.2°, 17.16±0.2°, 19.56±0.2°, 21.62±0.2°, 22.04±0.2°, or 3.42±0.2°, 5.72±0.2°, 6.30±0.2°, 8.38±0.2°, 9.48±0.2°, 10.32±0.2°, 13.72±0.2°, 14.36±0.2°, 17.16±0.2°, 18.66±0.2°, 19.56±0.2°, 20.06±0.2°, 21.62±0.2°, 22.04±0.2°, or 3.42±0.2°, 4.72±0.2°, 6.30±0.2°, 8.60±0.2°, 9.48±0.2°, 10.32±0.2°, 13.72±0.2°, 14.36±0.2°, 17.16±0.2°, 18.66±0.2°, 19.56±0.2°, 20.06±0.2°, 20.80±0.2°, 21.62±0.2°, or 3.42±0.2°, 4.72±0.2°, 6.30±0.2°, 9.48±0.2°, 10.32±0.2°, 13.72±0.2°, 14.36±0.2°, 17.16±0.2°, 19.56±0.2°, 20.06±0.2°, 20.80±0.2°, 21.62±0.2°, 22.04±0.2°, 22.56±0.2°, 25.76±0.2°, or 4.72±0.2°, 5.72±0.2°, 6.30±0.2°, 8.38±0.2°, 8.60±0.2°, 9.48±0.2°, 10.32±0.2°, 13.72±0.2°, 14.36±0.2°, 15.18±0.2°, 17.16±0.2°, 18.02±0.2°, 19.56±0.2°, 20.06±0.2°, 20.80±0.2°, or 3.42±0.2°, 4.72±0.2°, 5.72±0.2°, 6.30±0.2°, 8.38±0.2°, 9.48±0.2°, 10.32±0.2°, 13.72±0.2°, 14.36±0.2°, 17.16±0.2°, 18.66±0.2°, 19.56±0.2°, 20.06±0.2°, 20.80±0.2°, 21.62±0.2°, 22.04±0.2°, or 4.72±0.2°, 5.72±0.2°, 6.30±0.2°, 8.38±0.2°, 8.60±0.2°, 9.48±0.2°, 10.32±0.2°, 11.56±0.2°, 13.72±0.2°, 14.36±0.2°, 15.18±0.2°, 17.16±0.2°, 18.02±0.2°, 18.66±0.2°, 19.56±0.2°, 20.06±0.2°, 20.80±0.2°, or 4.72±0.2°, 6.30±0.2°, 9.48±0.2°, 10.32±0.2°, 13.72±0.2°, 14.36±0.2°, 17.16±0.2°, 19.56±0.2°, 20.06±0.2°, 20.80±0.2°, 3.42±0.2°, 5.72±0.2°, 8.38±0.2°, 8.60±0.2°, 11.56±0.2°, 15.18±0.2°, 18.02±0.2°, 18.66±0.2°, 21.62±0.2°, 22.04±0.2°, 22.56±0.2°, 25.76±0.2°, Among them, the X-ray powder diffraction pattern of the fumarate salt form III of compound 42 is shown in Figure 8.

12. A pharmaceutical composition comprising one or more of the crystalline forms, salts or amorphous forms of the compound according to any one of claims 1 to 11 or its stereoisomers.

13. Use of a crystalline form, salt or amorphous substance comprising a compound according to any one of claims 1 to 11 or a stereoisomer thereof in the treatment or prevention of a neurodegenerative disease characterized by protein aggregation, wherein the neurodegenerative disease is preferably Alzheimer's disease, Parkinson's disease, frontotemporal dementia, Lewy body disease, Parkinson's disease dementia, multiple system atrophy, amyotrophic lateral sclerosis, Huntington's disease and cancer.

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