Naphthalimide-based coronavirus papain-like protease inhibitors

Abstract

The present invention relates to the field of pharmaceutical chemistry, and in particular to a naphthylimide-based coronavirus papain-like protease inhibitor as shown in formula (I) and its use, #imgabs0#

Description

Technical Field

[0001] The present invention belongs to the field of pharmaceutical chemistry, and in particular relates to a naphthalimide-based coronavirus papain-like protease inhibitor represented by formula (I) and uses thereof. Background Art

[0002] Coronavirus, as a type of pathogen that threatens human health, belongs to the Coronaviridae family of the Nidovirales order. It is an enveloped single-stranded, positive-strand RNA virus divided into three genera: α, β and γ. Coronavirus particles are spherical or irregular in shape, with an envelope and a size of 80-120nm. The 5' end of its genome has a cap structure, followed by 6-10 open reading frames (ORFs). The first reading frame, which occupies 2 / 3 of the genome, encodes the replicase, and the other 1 / 3 of the genome mainly encodes structural proteins, generally including spike protein (S), small envelope protein (E), membrane protein (M), and nucleocapsid (N). E protein and M protein are mainly involved in the assembly process of the virus, and N protein wraps the genome to form a nucleoprotein complex. Coronaviruses mainly mediate viral invasion and determine viral tissue or host tropism by binding to host cell receptors through the spike glycoprotein (S glycoprotein). They enter cells by recognizing the ACE2 protein of the human host. Amino acid variations in the S protein domain can lead to changes in the species tropism and infection characteristics of the virus.

[0003] 3C-like protease (3CLpro or Mpro) and papain-like protease (PLpro) play an important role in coronavirus replication. PLpro is an important regulatory protein molecule in the formation of the SARS-CoV-2 replicase complex (RC), which is essential for viral genome transcription and replication. As one of the representative proteins of non-structural proteins, PLpro participates in counteracting the host's natural immune response and has important biological functions in regulating the replication and proliferation of the new coronavirus and inhibiting the host's immune response. It is highly conserved in evolution and has a deubiquitination function. It is one of the ideal targets for the development of broad-spectrum anti-coronavirus drugs. Therefore, inhibiting the activity of the viral replication complex through small molecule inhibitors of PLpro protease may help treat pneumonia caused by new coronavirus infection. Summary of the invention

[0004] The first aspect of the present invention provides a compound represented by formula (I), or a stereoisomer thereof, or a tautomer thereof, or a solvate thereof, or an isotope-labeled compound thereof, or a pharmaceutically acceptable salt thereof,

[0005]

[0006] in,

[0007] R1 is selected from hydrogen, C 1-6 Alkyl, C 1-6 Haloalkyl, -C(=O)-C 1-6 Alkyl, -C(=O)-C 1-6 Haloalkyl, -C(=O)-NH-C 1-6 Alkyl, C 3-8 Cycloalkyl and 4-8 membered heterocyclic group;

[0008] R2 is selected from hydrogen, halogen, nitro, -CN, -OH, -COOH, -NH2, -OC 1-6 Alkyl, -NH-C 1-6 Alkyl, -N-(C 1-6 Alkyl)2, -S(=O)2-C 1-6 Alkyl, -C(=O)-C 1-6 Alkyl, -C(=O)-NH-C 1-6 Alkyl, -NH-C(=O)-C 1-6 Alkyl, -S(=O)2NH2, C 1-6 Alkyl and C 1-6 Haloalkyl;

[0009] R3 is selected from hydrogen, halogen, nitro, -CN, -OH, -COOH, -NH2, -OC 1-6 Alkyl, -NH-C 1-6 Alkyl, -N-(C 1-6 Alkyl)2, -S(=O)2-C 1-6 Alkyl, -C(=O)-C 1-6 Alkyl, -C(=O)-NH-C 1-6 Alkyl, -NH-C(=O)-C 1-6 Alkyl, -S(=O)2NH2, C 1-6 Alkyl and C 1-6 Haloalkyl;

[0010] m is 0, 1, 2 or 3;

[0011] R4 is selected from R5 and

[0012] R5 is selected from C 1-8 Alkyl and C 1-8 haloalkyl, the C 1-8 Alkyl and C 1-8 The haloalkyl group is optionally substituted with one or more selected from hydrogen, -OH, -OC 1-4 Alkyl, -NH2, -NH-C 1-4 Alkyl and -N(C 1-4Alkyl)2 group substitution;

[0013] Ring A is selected from C 3-12 Cycloalkyl, C 4-12 Cycloalkenyl, 4-12 membered heterocyclic group, C 6-12 Aryl and 5-12 membered heteroaryl;

[0014] R6 is selected from hydrogen, oxo, halogen, nitro, -CN, -OH, -COOH, -NH2, C 1-6 Alkyl, -OC 1-6 Alkyl, -NH-C 1-6 Alkyl, -N-(C 1-6 alkyl)2, -S(=O)2NH2, -S(=O)2-C 1-6 Alkyl, -C(=O)-C 1-6 Alkyl, -C(=O)-NH-C 1-6 Alkyl, -NH-C(=O)-C 1-6 alkyl, -C(=NH)NH2, -C(=NH)NHC(=NH)NH, 4-8 membered heterocyclic group and -NH-4-8 membered heterocyclic group, wherein the C 1-6 The alkyl and 4-8 membered heterocyclic groups are optionally substituted by one or more selected from hydrogen, halogen, nitro, =O, -CN, -OH, -COOH, -NH2, -C 1-6 Alkyl, -OC 1-6 Alkyl, -NH-C 1-6 Alkyl, -N-(C 1-6 alkyl)2, -S(=O)2OH, -S(=O)2NH2, -S(=O)2-C 1-6 Alkyl, -C(=O)-C 1-6 Alkyl, -C(=O)-NH-C 1-6 Alkyl, -NH-C(=O)-C 1-6 Alkyl and morpholinyl radical substitution;

[0015] R7 is selected from hydrogen, halogen, nitro, -CN, -OH, -COOH, -NH2, -OC 1-6 Alkyl, -NH-C 1-6 Alkyl, -N-(C 1-6 Alkyl)2, -S(=O)2-C 1-6 Alkyl, -C(=O)-C 1-6 Alkyl, -C(=O)-NH-C 1-6 Alkyl, -NH-C(=O)-C 1-6 Alkyl, -S(=O)2NH2, C 1-6 Alkyl and C 1-6 Haloalkyl, or two R7 form =O;

[0016] Alternatively, two R7 atoms form a C 3-6 Cycloalkyl, 4-7 membered heterocyclic group, the C 3-6 Cycloalkyl, 4-7 membered heterocyclic group optionally 1, 2 or 3 selected from OH and C 1-4 Alkyl radical substitution;

[0017] Alternatively, R6 and R7 are linked to form a 4-6 membered heterocyclic group, wherein the 4-6 membered heterocyclic group is optionally substituted by 1, 2 or 3 groups selected from OH and C 1-4 Alkyl radical substitution;

[0018] n is 0, 1, 2, 3, 4, 5, 6 or 7.

[0019] In some embodiments, R4 is

[0020] In some embodiments, R1 is selected from hydrogen, C 1-4 Alkyl, C 1-4 Haloalkyl, -C(=O)-C 1-4 Alkyl, -C(=O)-C 1-4 Haloalkyl, C 3-6 Cycloalkyl and 4-6 membered heterocyclic groups.

[0021] In some embodiments, R1 is selected from hydrogen, C 1-4 Alkyl and C 3-6 Cycloalkyl.

[0022] In some embodiments, the R1 is selected from hydrogen, methyl, ethyl, n-propyl, isopropyl, cyclobutyl, cyclopentyl, and cyclobutyl.

[0023] In some embodiments, the R1 is selected from hydrogen, methyl, ethyl, isopropyl, and cyclopropyl.

[0024] In some embodiments, R1 is selected from hydrogen and C 1-4 alkyl.

[0025] In some embodiments, the R1 is selected from hydrogen, methyl, ethyl, and isopropyl.

[0026] In some embodiments, R2 is selected from hydrogen, fluorine, chlorine, bromine, -CN, -OH, -COOH, -NH2, -OC 1-4 Alkyl, -NH-C 1-4 Alkyl, -N-(C 1-4 Alkyl)2, C 1-4 Alkyl and C 1-4 Halogenated alkyl.

[0027] In some embodiments, the R2 is selected from hydrogen, fluorine, chlorine, -CN, -OH, -COOH, -NH2, -O-methyl, -NH-methyl, methyl, ethyl, halomethyl and haloethyl.

[0028] In some embodiments, said R2 is methyl.

[0029] In some embodiments, R3 is selected from hydrogen, halogen, -CN, -OH, -COOH, -NH2, -OC 1-4 Alkyl, -NH-C 1-4 Alkyl, -N-(C 1-4 Alkyl)2, C 1-6 Alkyl and C 1-6 Halogenated alkyl.

[0030] In some embodiments, the R3 is selected from hydrogen, fluorine, chlorine, bromine, -CN, -OH, -COOH, -NH2, -O-methyl, -NH-methyl, methyl, ethyl, halomethyl and haloethyl.

[0031] In some embodiments, said R3 is hydrogen.

[0032] In some embodiments, R5 is selected from C 1-6 Alkyl and C 1-6 haloalkyl, the C 1-6 Alkyl and C 1-6 The haloalkyl group is optionally substituted by 1, 2, 3, 4 or 5 groups selected from hydrogen, -NH2, -NH-C 1-4 Alkyl and -N(C 1-4 alkyl)2 group substitution.

[0033] In some embodiments, R5 is selected from C 1-6 Alkyl, the C 1-6 The alkyl group is optionally substituted with 1, 2 or 3 groups selected from hydrogen, -NH2, -NH-methyl, -NH(methyl)2.

[0034] In some embodiments, the R5 is selected from

[0035] In some embodiments, the ring A is selected from C 4-10 Cycloalkenyl and 4-10 membered heterocyclic groups.

[0036] In some embodiments, the ring A is selected from C 4-10 Cycloalkenyl and 4-10 membered heterocyclic group, wherein the 4-10 membered heterocyclic group contains 1, 2 or 3 heteroatoms selected from N, O and S.

[0037] In some embodiments, the ring A is selected from C 4-8Cycloalkenyl, 4-7 membered nitrogen-containing monocyclic heterocyclic group, 7-10 membered nitrogen-containing bridged heterocyclic group, 7-10 membered nitrogen-containing cyclic heterocyclic group, 7-10 membered nitrogen-containing spirocyclic heterocyclic group.

[0038] In some embodiments, the ring A is selected from

[0039] in represents the connection point between ring A and the phenyl group in formula I.

[0040] In some embodiments, the ring A is selected from a 4-10 membered heterocyclyl.

[0041] In some embodiments, the ring A is selected from a 4-10 membered heterocyclyl group containing 1 or 2 N atoms.

[0042] In some embodiments, the ring A is selected from in represents the connection point between ring A and the phenyl group in formula I.

[0043] In some embodiments, R6 is selected from hydrogen, oxo, halogen, nitro, -CN, -OH, -COOH, -NH2, C 1-4 Alkyl, -OC 1-4 Alkyl, -NH-C 1-4 Alkyl, -N-(C 1-4 alkyl)2, -S(=O)2NH2, -S(=O)2-C 1-4 Alkyl, -C(=O)-C 1-4 Alkyl, -C(=O)-NH-C 1-4 Alkyl, -NH-C(=O)-C 1-4 alkyl, -C(=NH)NH2, -C(=NH)NHC(=NH)NH, 4-6 membered heterocyclic group and -NH-4-6 membered heterocyclic group, wherein the C 1-4 The alkyl and 4-6 membered heterocyclic groups are optionally substituted by 1, 2, 3, 4 or 5 groups selected from hydrogen, fluorine, chlorine, bromine, =O, -CN, -OH, -COOH, -NH2, -C 1-4 Alkyl, -OC 1-4 Alkyl, -NH-C 1-4 Alkyl, -N-(C 1-4 alkyl)2, -S(=O)2OH, -S(=O)2NH2, -S(=O)2-C 1-4 Alkyl and morpholinyl groups are substituted.

[0044] In some embodiments, R6 is selected from hydrogen, fluorine, chlorine, bromine, -CN, -OH, -NH2, methyl, ethyl, propyl, butyl, -NH-methyl, -NH-ethyl, -NH-propyl, -NH-butyl, -N(methyl)2, -N(methyl)-ethyl, -N(methyl)-propyl, -N(ethyl)2, -N(ethyl)-propyl, -S(=O)2NH2, -S(=O)2-methyl, -S(=O)2-ethyl, -S(=O)2-propyl, -C(=NH)NH2, -C(=NH)NHC(=NH)NH2, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, -NH- The methyl, ethyl, propyl, butyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, oxetanyl, tetrahydrofuranyl and tetrahydropyranyl groups are optionally substituted with 1, 2, 3, 4 or 5 groups selected from hydrogen, fluorine, chlorine, bromine, =O, -OH, -COOH, -NH2, methyl, ethyl, propyl, -O-methyl, -O-ethyl, -NH-methyl, -NH-ethyl, -N(methyl), -N(methyl)-ethyl, -N(ethyl), -S(=O)2OH, -S(=O)2NH2, -S(=O)2-methyl and morpholinyl.

[0045] In some embodiments, R6 is selected from hydrogen, fluorine, -CN, -OH, -NH2, methyl, ethyl, propyl, butyl, The methyl, ethyl, propyl, butyl, Optionally substituted with 1, 2 or 3 groups selected from hydrogen, fluorine, =O, -OH, -COOH, methyl, -N(CH3)2, -S(=O)2-methyl and morpholinyl.

[0046] In some embodiments, R6 is selected from hydrogen, fluorine, -CN, -OH, -NH2, -CH3, -CH2CH3,

[0047]

[0048] In some embodiments, R6 is selected from hydrogen, C 1-4 Alkyl, -N-(C 1-4 alkyl)2 and 4-6 membered heterocyclic group, the C 1-4 The alkyl and 4-6 membered heterocyclic groups are optionally substituted by 1, 2 or 3 groups selected from hydrogen, halogen, =O, -CN, -OH, -COOH, -NH2, -N-(C 1-4 alkyl)2, -S(=O)2-methyl, C 1-4 Alkyl and morpholinyl groups are substituted.

[0049] In some embodiments, R6 is selected from hydrogen, C 1-4 Alkyl, -N-(C 1-4 alkyl)2 and 4-6 membered heterocyclic group, the 4-6 membered heterocyclic group contains 1 or 2 heteroatoms selected from N, O, S, the C 1-4 The alkyl and 4-6 membered heterocyclyl groups are optionally substituted with 1, 2 or 3 groups selected from hydrogen, fluorine, =O, -OH, -N(CH3)2, -S(=O)2-CH3, -CH3 and morpholinyl.

[0050] In some embodiments, R6 is selected from hydrogen, -CH3, -CH2CH3,

[0051]

[0052] In some embodiments, each of the R7 groups is independently selected from hydrogen, halogen, nitro, -CN, -OH, -COOH, -NH2, -OC 1-4 Alkyl, -NH-C 1-4 Alkyl, -N-(C 1-4 Alkyl)2, -C(=O)-C 1-4 Alkyl, -C(=O)-NH-C 1-4 Alkyl, -NH-C(=O)-C 1-4 Alkyl, C 1-6 Alkyl and C 1-4 Halogenated alkyl.

[0053] In some embodiments, the R7 are each independently selected from hydrogen, fluorine, chlorine, bromine, -CN, -OH, -COOH, -NH2, -O-methyl, -O-ethyl, -O-propyl, -NH-methyl, -NH-ethyl, -NH-propyl, -N(methyl)2, -N(methyl)-ethyl, -N(methyl)-propyl, -N(ethyl)2, methyl, ethyl, propyl, halomethyl, haloethyl and halopropyl.

[0054] In some embodiments, the R7 are each independently selected from hydrogen, fluorine, -OH, -NH2, -COOH and methyl.

[0055] In some embodiments, the R7 are each independently selected from hydrogen, fluoro and methyl.

[0056] In some embodiments, two R7 form =0.

[0057] In some embodiments, the compound is selected from the compound represented by formula (I-1)

[0058]

[0059] wherein R1, R2, ring A, R6, R7 and n are as defined in any embodiment of the present invention.

[0060] In some embodiments, the compound is selected from the compound represented by formula (I-1A)

[0061]

[0062] Wherein, R1, R2, R6, R7 and n are defined as described in any embodiment of the present invention.

[0063] In some embodiments, the R1 is selected from methyl and ethyl.

[0064] In some embodiments, R6 is selected from -NH-C 1-4 Alkyl, -N-(C 1-4 alkyl)2, 4-6 membered heterocyclic group and -NH-4-6 membered heterocyclic group, the -NH-C 1-4 Alkyl, -N-(C 1-4 alkyl)2, 4-6 membered heterocyclyl and -NH-4-6 membered heterocyclyl are optionally substituted by 1, 2 or 3 groups selected from hydrogen, fluorine, chlorine, =O, -OH, -NH2, methyl and -N(CH3)2.

[0065] In some embodiments, the R6 is selected from -NH-methyl, -NH-ethyl, -NH-propyl, -NH-butyl, -N(methyl)2, -N(methyl)-ethyl, -N(methyl)-propyl, -N(ethyl)2, -N(ethyl)-propyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, -NH-oxetanyl, -NH-tetrahydrofuranyl and -NH-tetrahydropyranyl, and the methyl, ethyl, propyl, butyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, oxetanyl, tetrahydrofuranyl and tetrahydropyranyl are optionally substituted with 1, 2 or 3 groups selected from hydrogen, fluorine, chlorine, =O, -OH, -NH2 and methyl.

[0066] In some embodiments, the R6 is selected from

[0067] In some embodiments, the R7 are each independently selected from hydrogen.

[0068] In some embodiments, R6 and R7 are linked to form a pyrrolidinyl group, which is optionally substituted with 1 methyl group.

[0069] In some embodiments, n is 0, 1, 2 or 3.

[0070] In some embodiments, R6 is selected from 4-6 membered heterocyclyl, wherein the 4-6 membered heterocyclyl is optionally substituted by 1, 2 or 3 selected from hydrogen, halogen, =O, -OH and C 1-4 Alkyl radicals are substituted.

[0071] In some embodiments, R6 is selected from a 4-6 membered heterocyclyl, the 4-6 membered heterocyclyl is a monocyclic ring, the 4-6 membered heterocyclyl contains 1 or 2 heteroatoms selected from N, O, and S, and the 4-6 membered heterocyclyl is optionally substituted by 1, 2 or 3 groups selected from hydrogen, fluorine, =O, -OH and methyl.

[0072] In some embodiments, the R6 is selected from

[0073] In some embodiments, the compound is selected from the compound represented by formula (I-1A-1):

[0074]

[0075] in,

[0076] R1 and R2 are as defined in any embodiment of the present invention,

[0077] Ring B is selected from 4-6 membered heterocyclic groups,

[0078] R 61 is selected from hydrogen, halogen, =O, -CN, -OH, -COOH, -NH2, -C 1-4 Alkyl, -NH-C 1-4 Alkyl and -N-(C 1-4 Alkyl)2,

[0079] p is 0, 1, 2 or 3.

[0080] In some embodiments, the R1 is selected from methyl and ethyl.

[0081] In some embodiments, the ring B is selected from azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, and thiomorpholinyl.

[0082] In some embodiments, the R 61 Selected from hydrogen, fluorine, chlorine, bromine, =O, -CN, -OH, -COOH, -NH2, methyl, ethyl and propyl.

[0083] In some embodiments, the R 61 is selected from the group consisting of hydrogen, fluorine, =O, -OH and methyl.

[0084] In some embodiments, the compound is selected from the compound represented by formula (I-1A-2)

[0085]

[0086] in,

[0087] R1 and R2 are as defined in any embodiment of the present invention,

[0088] R 61 Selected from hydrogen, C 1-4 Alkyl and 4-6 membered heterocyclic group.

[0089] In some embodiments, said R1 is selected from methyl.

[0090] In some embodiments, the R 61 is selected from hydrogen, methyl, ethyl, propyl, butyl, oxetanyl, tetrahydrofuranyl and tetrahydropyranyl.

[0091] In some embodiments, the R 61 Selected from hydrogen, -CH2CH3 and

[0092] In some embodiments, the compound is selected from the compound represented by formula (I-1B)

[0093]

[0094] in,

[0095] T1 is C, CH or N, is a single bond or a double bond,

[0096] R1, R2, R6, R7 and n are as defined in any embodiment of the present invention.

[0097] In some embodiments, said T1 is N, For a single key.

[0098] In some embodiments, R6 is selected from hydrogen, -CN, -NH2, C 1-4 Alkyl, -C(=NH)NH2, -C(=NH)NHC(=NH)NH, -S(=O)2-C 1-4 Alkyl and -S(=O)2NH2, the C 1-4 The alkyl group is optionally substituted with 1, 2 or 3 groups selected from hydrogen, halogen, -OH, -COOH, methyl, -NH(CH3), -N(CH3)2, -N(CH3)(CH2CH3), -N(CH2CH3)2 and -S(=O)2-CH3.

[0099] In some embodiments, R6 is selected from hydrogen, -CN, -NH2, methyl, ethyl, propyl, butyl, -C(=NH)NH2, -C(=NH)NHC(=NH)NH, -S(=O)2-C 1-4 Alkyl and -S(=O)2NH2, the methyl, ethyl, propyl, butyl are optionally substituted by 1, 2 or 3 groups selected from hydrogen, fluorine, -OH, -COOH, methyl, -N(CH3)2 and -S(=O)2-CH3.

[0100] In some embodiments, R6 is selected from hydrogen, -CN, -NH2, -CH3, -CH2CH3,

[0101] In some embodiments, the R7 are each independently selected from hydrogen, -COOH and C 1-4 alkyl.

[0102] In some embodiments, the R7 are each independently selected from hydrogen, -COOH and methyl.

[0103] In some embodiments, two R7 form =0.

[0104] In some embodiments, R6 and R7 are linked to form a pyrrolidinyl group, which is optionally substituted with 1 OH group.

[0105] In some embodiments, n is 0, 1, 2, 3 or 4.

[0106] In some embodiments, R6 is selected from hydrogen and C 1-4 Alkyl, the C 1-4 The alkyl group is optionally substituted with 1, 2 or 3 groups selected from hydrogen, -OH, -NH(CH3), -N(CH3)2 and -S(=O)2-CH3.

[0107] In some embodiments, R6 is selected from hydrogen, -CH3, -CH2CH3,

[0108] In some embodiments, the R7 are each independently selected from hydrogen and C 1-4 alkyl.

[0109] In some embodiments, the R7 are each independently selected from hydrogen and methyl.

[0110] In some embodiments, two R7 and the atoms to which they are attached form cyclopropyl, azetidinyl, pyrrolidinyl, piperidinyl, or homopiperidinyl.

[0111] In some embodiments, R6 and R7 are linked to form a pyrrolidinyl group.

[0112] In some embodiments, n is 0, 1 or 2.

[0113] In some embodiments, the compound is selected from the compound represented by formula (I-1C)

[0114]

[0115] Wherein, R1, R2, R6, R7 and n are defined as described in any embodiment of the present invention.

[0116] In some embodiments, R6 is selected from hydrogen, C 1-4 Alkyl, -N-(C 1-4 alkyl)2 and 4-6 membered heterocyclic group, the C 1-4 The alkyl and 4-6 membered heterocyclyl groups are optionally substituted with 1, 2 or 3 groups selected from hydrogen, halogen, -OH, -COOH and methyl.

[0117] In some embodiments, R6 is selected from hydrogen, -CH3,

[0118] In some embodiments, said R7 is hydrogen.

[0119] In some embodiments, R6 and R7 are linked to form a 5-6 membered heterocyclic group, wherein the 5-6 membered heterocyclic group is optionally substituted with 1 OH or methyl group.

[0120] In some embodiments, R6 and R7 are linked to form a pyrrolidinyl or piperidinyl group, wherein the pyrrolidinyl or piperidinyl group is optionally substituted with 1 methyl group.

[0121] In some embodiments, n is 0, 1 or 2.

[0122] In some embodiments, the compound is selected from:

[0123]

[0124]

[0125]

[0126]

[0127]

[0128] The second aspect of the present invention provides a pharmaceutical composition comprising at least one compound described in the first aspect of the present invention, or a stereoisomer thereof, or a tautomer thereof, or a solvate thereof, or an isotope-labeled compound thereof, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers and / or excipients.

[0129] The third aspect of the present invention provides the use of the compound described in the first aspect of the present invention, or its stereoisomer, or its tautomer, or its solvate, or its isotope-labeled compound, or its pharmaceutically acceptable salt, or the pharmaceutical composition described in the second aspect of the present invention in the preparation of a medicament for treating and / or preventing a disease or condition or alleviating the severity of the disease or condition, wherein the disease or condition is caused by a coronavirus, and wherein the medicament includes human and veterinary drugs.

[0130] In some embodiments, the disease or disorder is selected from respiratory diseases (e.g., simple infections such as fever, cough, and sore throat, pneumonia, acute respiratory infections, severe acute respiratory infections (SARI), hypoxemic respiratory failure and acute respiratory distress syndrome, COVID-19, severe acute respiratory syndrome (SARS), Middle East respiratory syndrome (MERS)), sepsis, septic shock, and feline infectious peritonitis.

[0131] The fourth aspect of the present invention provides the compound described in the first aspect of the present invention, or its stereoisomer, or its tautomer, or its solvate, or its isotope-labeled compound, or its pharmaceutically acceptable salt, or the pharmaceutical composition described in the second aspect of the present invention, which is used to treat and / or prevent a disease or condition or alleviate the severity of the disease or condition, wherein the disease or condition is caused by a coronavirus, and wherein the drug includes human drugs and veterinary drugs.

[0132] In some embodiments, the disease or disorder is selected from respiratory diseases (e.g., simple infections such as fever, cough, and sore throat, pneumonia, acute respiratory infections, severe acute respiratory infections (SARI), hypoxemic respiratory failure and acute respiratory distress syndrome, COVID-19, severe acute respiratory syndrome (SARS), Middle East respiratory syndrome (MERS)), sepsis, septic shock, and feline infectious peritonitis.

[0133] The fifth aspect of the present invention provides a method for treating and / or preventing a disease or condition or reducing the severity of the disease or condition, which comprises administering to an individual in need an effective amount of the compound described in the first aspect of the present invention, or its stereoisomer, or its tautomer, or its solvate, or its isotope-labeled compound, or its pharmaceutically acceptable salt, or the pharmaceutical composition described in the second aspect of the present invention, wherein the disease or condition is caused by a coronavirus, and wherein the drug includes human drugs and veterinary drugs.

[0134] In some embodiments, the disease or disorder is selected from respiratory diseases (e.g., simple infections such as fever, cough, and sore throat, pneumonia, acute respiratory infections, severe acute respiratory infections (SARI), hypoxemic respiratory failure and acute respiratory distress syndrome, COVID-19, severe acute respiratory syndrome (SARS), Middle East respiratory syndrome (MERS)), sepsis, septic shock, and feline infectious peritonitis.

[0135] Definition of terms

[0136] In this application, unless otherwise specified, the scientific and technical terms used herein have the meanings commonly understood by those skilled in the art. At the same time, in order to better understand this application, the definitions and explanations of relevant terms are provided below.

[0137] When the name of the compound used in this application is inconsistent with the chemical structural formula, the chemical structural formula shall prevail.

[0138] As used herein, the term "stereoisomer" refers to an isomer formed by at least one asymmetric center. In compounds with one or more (e.g., 1, 2, 3, or 4) asymmetric centers, racemic mixtures, single enantiomers, diastereomeric mixtures, and individual diastereomers may be produced. Specific individual molecules may also exist as geometric isomers (cis / trans).

[0139] Similarly, the compound of the present application can exist with a mixture (commonly referred to as tautomer) of two or more structurally different forms in rapid equilibrium. Representative examples of tautomers include keto-enol tautomers, phenol-ketone tautomers, nitroso-oxime tautomers, imines-enamine tautomers, etc. It is to be understood that the scope of the present application encompasses all such isomers or mixtures thereof in any proportion (e.g., 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%).

[0140] Unless otherwise indicated, the compounds of the present application may exist in the form of stereoisomers (including cis and trans isomers, optical isomers (e.g., R and S enantiomers), diastereomers, geometric isomers, rotational isomers, conformational isomers, atropisomers, and mixtures thereof). The compounds of the present application may exhibit more than one type of isomerism and consist of mixtures thereof (e.g., racemic mixtures and diastereoisomer pairs).

[0141] The compounds of the present invention may exist in the form of solvates (such as hydrates), wherein the compounds of the present application contain a solvent as a structural element of the crystal lattice of the compound, such as water, methanol or ethanol. The amount of the solvent may exist in a stoichiometric ratio or a non-stoichiometric ratio.

[0142] As used herein, the term "isotopically labeled compound" refers to a compound in which one or more atoms are replaced with atoms of the same atomic number but with an atomic mass or mass number different from the atomic mass or mass number predominant in nature. Examples of isotopes suitable for inclusion in the compounds of the present invention include, but are not limited to, hydrogen isotopes such as 2 H, 3 H; carbon isotopes such as 11 C, 13 C and 14 C; chlorine isotopes such as 36 Cl; fluorine isotopes such as 18 F; iodine isotopes such as 123 I and 125 I; Nitrogen isotopes such as 13 N and 15 N; oxygen isotopes such as 15 Oh, 17 O and 18 O; and sulfur isotopes such as 35 S.

[0143] As used in this application, the term "pharmaceutically acceptable salt" refers to a salt of a compound of the present invention that is pharmaceutically acceptable and has the desired pharmacological activity of the parent compound. Such salts include: acid addition salts formed with inorganic acids or with organic acids, or coordination compounds formed by acidic protons present on the parent compound being substituted with metal ions or with organic bases.

[0144] Pharmaceutically acceptable salts of the compounds of the invention include those derived from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable non-toxic acid addition salts are salts of an amino group with inorganic acids (e.g., hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid) or with organic acids (e.g., acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid), or salts formed by using other methods used in the art (e.g., ion exchange). Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate and the like.

[0145] Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium and N + (C1-4 alkyl)4 salts. Representative alkali metal or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium and the like. Other pharmaceutically acceptable salts include non-toxic ammonium, quaternary ammonium and amine cations formed using counterions such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, lower alkyl sulfonates and aryl sulfonates, as appropriate.

[0146] Pharmaceutically acceptable salts are also intended to encompass hemi-salts, wherein the ratio of compound:acid is 2:1, respectively. Exemplary hemi-salts are those derived from acids comprising two carboxylic acid groups, such as malic acid, fumaric acid, maleic acid, succinic acid, tartaric acid, glutaric acid, oxalic acid, adipic acid, and citric acid. Other exemplary hemi-salts are those derived from diprotic mineral acids such as sulfuric acid. Preferred exemplary hemi-salts include, but are not limited to, hemimaleates, hemifumarates, and hemi-succinates.

[0147] As used in this application, the term "optionally substituted by" means that the group may be unsubstituted or substituted, for example, "C 1-6 "Alkyl is optionally substituted by halogen" means C 1-6 The alkyl group may be unsubstituted or substituted with halogen to give a haloalkyl group. 1-6Alkyl, -OC 1-6 Alkyl and -NH-C 1-6 Alkyl, the C 1-6 When the alkyl group is optionally substituted by halogen, it means C 1-6 Alkyl, -OC 1-6 Alkyl and -NH-C 1-6 C in the alkyl group 1-6 Alkyl groups are optionally substituted with halogen. 1-6 Alkyl)2 means that there are two C 1-6 The two alkyl groups may be the same or different.

[0148] As used in this application, unless explicitly stated otherwise, the description method "...are independently selected from" used throughout this article can mean that in different groups, the specific options expressed by the same or different symbols do not affect each other, and can also mean that in the same group, the specific options expressed by the same or different symbols do not affect each other.

[0149] As used herein, the term "halogen" refers to fluorine, chlorine, bromine, and iodine.

[0150] As used herein, the term "alkyl" refers to a straight or branched monovalent saturated hydrocarbon group, such as C 1-8 Alkyl refers to a group having 1 to 8 carbon atoms, such as 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms; 1-6 Alkyl refers to a group having 1 to 6 carbon atoms, such as 1, 2, 3, 4, 5 or 6 carbon atoms. 1-8 Alkyl groups include C 1-6 Alkyl, C 1-4 Alkyl, etc. Examples of the alkyl group include, but are not limited to, methyl, ethyl, propyl, butyl, etc., the propyl group includes n-propyl and isopropyl, the butyl group includes n-butyl, isobutyl and neobutyl.

[0151] As used herein, the term "halo" means that the group it modifies is substituted by one or more halogens, for example, 1, 2, 3, 4, 5 or 6 halogens. 1-6 "Haloalkyl" refers to a C 1-6 The alkyl group is substituted with one or more halogens, examples of which include but are not limited to CF3, CHF2 or CF2CF3 and the like.

[0152] As used herein, the term "cycloalkyl" refers to a saturated cyclic hydrocarbon group consisting of carbon atoms. 3-12 The cycloalkyl group has 3 to 12 carbon atoms, such as 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 carbon atoms. 3-12 Cycloalkyl groups include C 3-8 Cycloalkyl, C3-6 Cycloalkyl, C 6-12 Cycloalkyl, C 6-10 Cycloalkyl, C 6-8 Cycloalkyl, etc. The cycloalkyl includes monocyclic, bicyclic or polycyclic rings, including spirocyclic, fused or bridged rings. Examples include but are not limited to cyclohexyl, cycloheptyl, adamantyl, etc.

[0153] As used herein, the term "cycloalkenyl" refers to a partially unsaturated cyclic hydrocarbon group consisting of carbon atoms. 4-12 The cycloalkenyl group has 4 to 12 carbon atoms, such as 4, 5, 6, 7, 8, 9, 10, 11 or 12 carbon atoms. 4-12 Cycloalkenyl groups include C 4-8 Cycloalkenyl, C 6-12 Cycloalkenyl, C 6-10 Cycloalkenyl, C 6-8 Cycloalkenyl, etc. The cycloalkenyl includes monocyclic, bicyclic or polycyclic rings, including spirocyclic, fused or bridged rings. Examples include but are not limited to cyclohexenyl, hexahydronaphthyl, etc.

[0154] As used in this application, the term "heterocyclyl" refers to a saturated or partially unsaturated monovalent cyclic group consisting of ring atoms, wherein 1, 2, 3 or 4 ring atoms are heteroatoms and the rest are carbon atoms; preferably, the heteroatoms are selected from N, O or S, wherein the nitrogen atom is optionally quaternized, and the nitrogen and sulfur heteroatoms are optionally oxidized. For example, a 5-12 membered heterocyclyl refers to a 5-12 membered heterocyclyl consisting of 5-12 ring atoms, and the 5-12 membered heterocyclyl includes a 5-10 membered heterocyclyl, a 5-7 membered heterocyclyl, a 4-8 membered heterocyclyl, a 4-6 membered heterocyclyl, etc. The heterocyclyl includes a monocyclic, a bicyclic or a polycyclic ring, including a spirocyclic, a cyclic or a bridged ring. Examples include, but are not limited to, oxadiazine, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl or morpholinyl, etc. The term "nitrogen-containing monocyclic heterocyclic group" refers to a heterocyclic group in which at least one heteroatom is a nitrogen atom, and the heterocyclic group is a monocyclic ring, and examples include, but are not limited to, piperidinyl. The term "nitrogen-containing bridged heterocyclic group" means that at least one heteroatom in the heterocyclic group is a nitrogen atom, and the heterocyclic group is a bridged ring. Examples include but are not limited to The term "nitrogen-containing heterocyclic group" means that at least one heteroatom in the heterocyclic group is a nitrogen atom, and the heterocyclic group is a heterocyclic group. Examples include but are not limited to The term "nitrogen-containing spirocyclic heterocyclic group" means that at least one heteroatom in the heterocyclic group is a nitrogen atom, and the heterocyclic group is a cyclic ring, examples include but are not limited to wait.

[0155] As used herein, the term "partially unsaturated" refers to a ring system that is neither saturated (i.e., contains no double bonds) nor fully unsaturated (i.e., contains the maximum possible number of double bonds). In other words, a partially unsaturated ring system contains at least one double bond, but not the maximum possible number of double bonds.

[0156] As used in this application, the term "heteroaryl" refers to an unsaturated group with a conjugated π electron system composed of ring atoms, wherein 1, 2, 3 or 4 ring atoms are heteroatoms and the rest are carbon atoms; preferably, the heteroatoms are selected from N, O or S, wherein the nitrogen atom is optionally quaternized, and the nitrogen and sulfur heteroatoms may be optionally oxidized. For example, a 5-10 membered heteroaryl is composed of 5 to 10 (such as 5, 6, 7, 8, 9 or 10) ring atoms, including 5-9 membered, 9-10 membered, 5-6 membered heteroaryl, etc. The heteroaryl includes monocyclic and polycyclic rings, examples of which include, but are not limited to, imidazolyl, pyridyl, quinolyl or isoquinolyl, etc.

[0157] As used in this application, the term "pharmaceutical carrier and / or excipient" refers to a carrier and / or excipient that is pharmacologically and / or physiologically compatible with a subject and an active ingredient, which is well known in the art (see, for example, Remington's Pharmaceutical Sciences. Edited by Gennaro AR, 19th ed. Pennsylvania: Mack Publishing Company, 1995). Pharmaceutical carriers and / or excipients include, but are not limited to, pH regulators, surfactants, ionic strength enhancers, diluents, agents that maintain osmotic pressure, agents that delay absorption, preservatives, stabilizers. For example, pH regulators include, but are not limited to, phosphate buffers. Surfactants include, but are not limited to, cationic, anionic or nonionic surfactants, such as Tween-80. Ionic strength enhancers include, but are not limited to, sodium chloride. Preservatives include, but are not limited to, various antibacterial and antifungal agents, such as parabens, chlorobutanol, phenol, sorbic acid, and the like. Agents that maintain osmotic pressure include, but are not limited to, sugars, NaCl, and the like. Agents that delay absorption include, but are not limited to, monostearate and gelatin. Diluents include, but are not limited to, water, aqueous buffers (such as buffered saline), alcohols and polyols (such as glycerol), etc. Preservatives include, but are not limited to, various antibacterial and antifungal agents, such as thimerosal, 2-phenoxyethanol, parabens, chlorobutanol, phenol, sorbic acid, etc. Stabilizers have the meanings commonly understood by those skilled in the art, which can stabilize the desired activity of the active ingredient in the drug, including but not limited to sodium glutamate, gelatin, SPGA, sugars (such as sorbitol, mannitol, starch, sucrose, lactose, dextran, or glucose), amino acids (such as glutamic acid, glycine), proteins (such as dried whey, albumin or casein) or their degradation products (such as lactalbumin hydrolysate), etc.

[0158] As used herein, the term "effective amount" refers to that amount of a compound which, when administered, will relieve to some extent one or more of the symptoms of the condition being treated.

[0159] As used in this application, the term "treatment" is intended to alleviate, mitigate, improve or eliminate the disease state or condition being targeted. If a subject receives a therapeutic amount of the antibody-drug conjugate or its racemate, enantiomer, diastereomer, pharmaceutically acceptable salt, or a mixture of the foregoing forms according to the methods described herein, and one or more signs and symptoms of the subject show an observable and / or detectable reduction or improvement, the subject is successfully "treated". It should also be understood that the treatment of the disease state or condition includes not only complete treatment, but also failure to achieve complete treatment, but achieving some biological or medically relevant results.

[0160] As used in this application, the term "prevention" aims to avoid, reduce, prevent or delay the occurrence of a disease or disease-related symptoms, and such disease or disease-related symptoms have not yet appeared before the relevant drug is administered. "Prevention" does not require completely preventing the occurrence of a disease or disease-related symptoms. For example, after the relevant drug is administered, the risk of a subject developing a specific disease or disease-related symptom can be reduced, or the severity of the related symptoms that appear later can be reduced, which can be considered as "preventing" the occurrence or development of the disease. DETAILED DESCRIPTION

[0161] The embodiments of the present invention will be described in detail below in conjunction with the examples, but those skilled in the art will appreciate that the following examples are only used to illustrate the present invention and should not be considered to limit the scope of the present invention. If no specific conditions are specified in the examples, the conditions are carried out according to conventional conditions or conditions recommended by the manufacturer. If the manufacturer of the reagents or instruments used is not specified, they are all conventional products that can be obtained commercially, or can be prepared by methods known to those skilled in the art. The resulting compounds are as follows:

[0162] Embodiment 1

[0163] Compound P1: Preparation of 2-methyl-N-(1-(1-methyl-2-oxo-1,2-dihydrobenzo[cd]indol-6-yl)cyclopropyl)-5-(4-methylpiperazin-1-yl)benzamide

[0164]

[0165] (1) Preparation of Intermediate S2: 6-bromobenzo[cd]indol-2(1H)one

[0166]

[0167] S1 (2000 mg, 11.82 mmol) was placed in a single-mouth bottle, CH3CN (30 mL) was added, the temperature was lowered to 0°C, NBS (2746 mg, 15.42 mmol, added in three batches, 5 min interval between each batch) was added, and the reaction was stirred at this temperature for 3.0 h. The raw materials reacted completely and the reaction was stopped. After the reaction was completed, the reaction liquid was filtered, the filter cake was washed with water, and dried to obtain a yellow solid S2 (2613 mg, 89%). MS: m / z[M+1] + =249.56.

[0168] (2) Preparation of Intermediate S3: 6-bromo-1-methylbenz[cd]indol-2(1H)one

[0169]

[0170] Place S2 (2613 mg, 10.53 mmol) in a single-mouth bottle, add DMF (40 mL), cool to 0 ° C, add NaH (629 mg, 15.73 mmol), stir and react for 10 min, add CH3I (1771 mg, 12.48 mmol) dropwise, warm to room temperature, stir and react for 1.0 h, and stop the reaction until the raw materials react completely. After the reaction is completed, add water to the reaction solution to precipitate a yellow solid, and stir at room temperature for 20 min. Filter, wash the filter cake with water, then wash with PE, and drain to obtain a yellow solid S3 (2101 mg, 76%). MS: m / z[M+1] + =263.52.

[0171] (3) Intermediate S4: Preparation of 1-(1-methyl-2-oxo-1,2-dihydrobenzo[cd]indol-6-yl)cyclopropyl-1-carbonitrile

[0172]

[0173] Pd2(dba)3 (316 mg, 0.35 mmol) and NixantPhos (358 mg, 0.65 mmol) were placed in a three-necked flask, THF (20 mL) was added, nitrogen was bubbled for 30 s, and the mixture was stirred at room temperature for 5 min. Cyclopentyl methyl ether (20 mL), S3 (1628 mg, 6.56 mmol), and cyclopropylcarbonitrile (662 mg, 9.86 mmol) were added in sequence, and then LiHMDS (13 mL, 13.12 mmol, 1.0 M in THF) was added dropwise, and the mixture was heated to 60°C and stirred for 1.0 h. The raw materials reacted completely and the reaction was stopped. After the reaction was completed, the reaction solution was cooled to room temperature, saturated ammonium chloride solution (50 mL) was added, and the mixture was extracted three times with EA. The organic phases were combined, concentrated under reduced pressure, and purified by column chromatography (PE:EA=5:1-4:1-3:1) to obtain yellow solid S4 (788 mg, 51%). MS: m / z[M+1] + =249.36.

[0174] (4) Intermediate S5: Preparation of 1-(1-methyl-2-oxo-1,2-dihydrobenzo[cd]indol-6-yl)cyclopropyl-1-carboxamide

[0175]

[0176] S4 (788 mg, 3.18 mmol) was placed in a single-mouth bottle, i-PrOH (8 mL) and NaOH (382 mg, 9.54 mmol) were added, the temperature was raised to 90°C, and the reaction was stirred overnight. The raw materials reacted completely and the reaction was stopped. After the reaction was completed, the reaction solution was cooled to room temperature, water (10 mL) was added, and DCM was used for extraction three times. The organic phases were combined, concentrated under reduced pressure, and purified by column chromatography (PE: EA = 1: 1-DCM: MeOH = 20: 1) to obtain yellow solid S5 (113 mg, 13%). MS: m / z [M+1] + =267.43.

[0177] (5) Preparation of Intermediate S6: 6-(1-amino-cyclopropyl)-1-methylbenz[cd]indol-2(1H)-one

[0178]

[0179] S5 (94 mg, 0.35 mmol) was placed in a single-mouth bottle, t-BuOH (2 mL) was added, the temperature was lowered to 0°C, NaClO (0.41 mL, 0.98 mmol) solution and NaOH (3N, 0.33 mL, 0.98 mmol) solution were added, the temperature was raised to room temperature, and the reaction was stirred for 3 hours. The raw materials reacted completely and the reaction was stopped. After the reaction was completed, the reaction solution was concentrated under reduced pressure to remove the solvent, DCM was added to the resulting mixture to dissolve, the mixture was filtered, the filter cake was washed with DCM, the filtrate was taken, dried with anhydrous sodium sulfate, filtered, the filter cake was washed with DCM, the filtrate was taken, and the light yellow solid S6 (76 mg, 91%) was obtained after concentration under reduced pressure. MS: m / z[M+1] + =239.26.

[0180] (6) Preparation of Intermediate S9: 2-ethyl-5-(4-methylpiperazin-1-yl)benzoic acid methyl ester

[0181]

[0182] S7 (5000 mg, 21.83 mmol) and S8 (2420 mg, 24.10 mmol) were placed in a sealed tube, and toluene (100 mL), X-Phos (370 mg, 0.78 mmol), Cs2CO3 (13100 mg, 40.02 mmol) and Pd2(dba)3 (370 mg, 0.40 mmol) were added. N2 was bubbled for 30 s, and the temperature was raised to 110°C. The reaction was stirred overnight and the raw materials reacted completely, and the reaction was stopped. After the reaction was completed, the reaction solution was cooled to room temperature, filtered with diatomaceous earth, and the filter cake was washed with EA. The filtrate was concentrated under reduced pressure and purified by column chromatography (DCM: MeOH = 30: 1-20: 1) to obtain a reddish red oil S9 (5416 mg, 100%). MS: m / z [M+1] + =249.33.

[0183] (7) Intermediate S10: Preparation of 2-methyl-5-(4-methylpiperazin-1-yl)benzoic acid

[0184]

[0185] S9 (5416 mg, 21.83 mmol) was placed in a single-necked bottle, THF (25 mL) and EtOH (25 mL) were added, followed by a solution of NaOH (4366 mg, 109.15 mmol) in H2O (25 mL), the temperature was raised to 60°C, and the reaction was stirred for 2 h. The reaction was stopped after the raw materials were completely reacted. After the reaction, the reaction solution was concentrated under reduced pressure to remove THF and EtOH, and the pH was adjusted to 4-5 with dilute hydrochloric acid (2N), filtered, and the filter cake was washed with water. The filtrate was taken and extracted with EA (50 mL). The aqueous phase was taken and concentrated under reduced pressure to remove water. The obtained solid mixture was dissolved with a mixed solution of DCM and MeOH (DCM: MeOH = 10: 1, 500 mL), concentrated under reduced pressure, and then dissolved with a mixed solution of DCM and MeOH (DCM: MeOH = 20: 1, 500 mL), dried over anhydrous sodium sulfate, filtered, and the filter cake was washed with DCM. The obtained filtrate was concentrated under reduced pressure to obtain a light yellow solid S10 (5110 mg, 100%). MS: m / z [M+1] + =235.28.

[0186] (8) Preparation of P1: 2-methyl-N-(1-(1-methyl-2-oxo-1,2-dihydrobenzo[cd]indol-6-yl)cyclopropyl)-5-(4-methylpiperazin-1-yl)benzamide

[0187]

[0188] S6 (40 mg, 0.17 mmol) and S10 (47 mg, 0.20 mmol) were placed in a single-mouth bottle, and DMF (1.5 mL), DIPEA (71 mg, 0.55 mmol) and HATU (86 mg, 0.23 mmol) were added. The temperature was raised to 50°C, and the reaction was stirred for 1.0 h until the raw materials reacted completely, and the reaction was stopped. After the reaction was completed, the reaction solution was cooled to room temperature, water was added, and a yellow solid was precipitated. It was extracted three times with DCM, and the organic phases were combined, concentrated under reduced pressure, and purified by column chromatography (PE: EA = 1: 1-DCM: MeOH = 20: 1) to obtain a bright yellow solid P1 (62 mg, 20%). 1H NMR(600MHz,DMSO-d6)δ9.06(s,1H),8.81(d,J=8.2Hz,1H),8.04(d,J=6.9Hz,1H),7.83(dd ,J=8.3,7.0Hz,1H),7.73(d,J=7.3Hz,1H),7.08(d,J=7.3Hz,1H),6.96(d,J=8.4Hz,1H),6.8 4(dd,J=8.4,2.7Hz,1H),6.59(d,J=2.7Hz,1H),3.36(s,3H),3.03(t,J=5.0Hz,4H),2.27(s, 3H),1.93(s,3H),1.36-1.28(m,3H),1.24(d,J=9.3Hz,3H),1.20-1.17(m,2H).MS:m / z[M+1] + =454.37.

[0189] Embodiment 2

[0190] Compound P2: Preparation of 2-methyl-5-(4-methylpiperazin-1-yl)-N-(1-(2-oxo-1,2-dihydrobenzo[cd]indol-6-yl)cyclopropyl)benzamide

[0191]

[0192] (1) Intermediate S11: Preparation of 6-bromo-1-(4-methoxybenzyl)benzo[cd]indol-2(1H)one

[0193]

[0194] Place S2 (898 mg, 3.62 mmol) in a single-mouth bottle, add DMF (10 mL), cool to 0 ° C, add NaH (290 mg, 7.24 mmol), stir and react for 10 min, add p-methoxybenzyl chloride (850 mg, 5.43 mmol) dropwise, warm to room temperature, stir and react for 1.0 h, and stop the reaction until the raw materials react completely. After the reaction is completed, add water to the reaction solution to precipitate a yellow solid, and stir at room temperature for 20 min. Filter, wash the filter cake with water, then wash with PE, and dry to obtain a yellow solid S11 (905 mg, 68%). MS: m / z[M+1] + =369.27.

[0195] (2) Intermediate S12: Preparation of 1-(1-(4-methoxybenzyl)-2-oxo-1,2-dihydrobenzo[cd]indol-6-yl)cyclopropyl-1-carbonitrile

[0196]

[0197] Pd2(dba)3 (117 mg, 0.13 mmol) and NixantPhos (133 mg, 0.25 mmol) were placed in a three-necked flask, tetrahydrofuran (7 mL) was added, nitrogen was bubbled for 30 s, and the mixture was stirred at room temperature for 5 min. Cyclopentyl methyl ether (7 mL), S11 (905 mg, 2.46 mmol), and cyclopropylcarbonitrile (248 mg, 3.70 mmol) were added in sequence, and then LiHMDS (5 mL, 4.92 mmol, 1.0 M inTHF) was added dropwise, and the temperature was raised to 60°C. The reaction was stirred for 1.0 h, and the raw materials reacted completely, and the reaction was stopped. After the reaction was completed, the reaction solution was cooled to room temperature, saturated ammonium chloride solution (30 mL) was added, and the mixture was extracted three times with EA. The organic phases were combined, concentrated under reduced pressure, and purified by column chromatography (PE:EA=8:1-4:1-2:1) to obtain yellow solid S12 (386 mg, 44%). MS: m / z[M+1] + =355.36.

[0198] (3) Preparation of Intermediate S13: 1-(1-(4-methoxybenzyl)-2-oxo-1,2-dihydrobenzo[cd]indol-6-yl)cyclopropyl-1-carboxamide

[0199]

[0200] S12 (286 mg, 0.81 mmol) was placed in a single-mouth bottle, DMSO (3 mL) and K2CO3 (56 mg, 0.41) were added, the temperature was lowered to 0°C, H2O2 (0.14 mL, 1.22 mmol, 30% in water) was added dropwise, and the reaction was stirred for 2.5 h. The raw material reacted completely and the reaction was stopped. After the reaction was completed, water (6 mL) was added to the reaction solution to precipitate a yellow solid. Filter, wash the filter cake with water (2 mL), drain and purify by column chromatography (PE: EA = 1: 1-DCM: MeOH = 30: 1) to obtain a yellow solid S13 (62 mg, 21%). MS: m / z [M+1] + =373.43.

[0201] (4) Preparation of Intermediate S14: 6-(1-amino-cyclopropyl)-1-(4-methoxybenzyl)benzo[cd]indol-2(1H)-one

[0202]

[0203] S13 (62 mg, 0.17 mmol) was placed in a single-mouth bottle, t-BuOH (2 mL) was added, the temperature was lowered to 0°C, NaClO (0.2 mL, 0.48 mmol) solution and NaOH (3N, 0.16 mL, 0.48 mmol) solution were added, the temperature was raised to room temperature, and the reaction was stirred for 3 hours. The raw materials reacted completely and the reaction was stopped. After the reaction was completed, the reaction solution was concentrated under reduced pressure to remove the solvent, DCM (300 mL) was added to the obtained mixture, and the mixture was dried over anhydrous sodium sulfate, filtered, and the filter cake was washed with DCM. The obtained filtrate was concentrated under reduced pressure to obtain yellow solid S14 (37 mg, 64%). MS: m / z[M+1] + =345.29.

[0204] (5) Intermediate S15: Preparation of N-(1-(1-(4-methoxybenzyl)-2-oxo-1,2-dihydrobenzo[cd]indol-6-yl)cyclopropyl-2-methyl-5-(4-methylpiperazin-1-yl)benzamide

[0205]

[0206] S14 (37 mg, 0.11 mmol) and S10 (31 mg, 0.13 mmol) were placed in a single-mouth bottle, and DMF (1.5 mL), DIPEA (46 mg, 0.36 mmol) and HATU (57 mg, 0.15 mmol) were added. The temperature was raised to 50°C, and the reaction was stirred for 2 hours. The raw materials reacted completely and the reaction was stopped. After the reaction was completed, the reaction solution was cooled to room temperature, water was added, and a yellow solid was precipitated. The mixture was stirred at room temperature for 1.0 hour, filtered, and the filter cake was washed with water. The yellow solid S15 obtained by drying was directly used for the next step. MS: m / z[M+1] + =561.38.

[0207] (6) Preparation of P2: 2-methyl-N-(1-(1-methyl-2-oxo-1,2-dihydrobenzo[cd]indol-6-yl)cyclopropyl)-5-(4-methylpiperazin-1-yl)benzamide

[0208]

[0209] S15 (30 mg, 0.054 mmol) was placed in a single-mouth bottle, TFA (1.5 mL) was added, the temperature was raised to 60°C, and the reaction was stirred overnight. The raw materials reacted completely and the reaction was stopped. After the reaction was completed, TFA was removed by concentration under reduced pressure, and a saturated sodium bicarbonate solution (8 mL) was added to the resulting mixture, and extracted three times with DCM. The organic phase was concentrated under reduced pressure and purified by column chromatography (PE: EA = 1: 1-DCM: MeOH = 20: 1) to obtain a bright yellow solid P2 (14 mg, 55%). 1H NMR (600MHz, DMSO-d6) δ10.73(s,1H),9.05(s,1H),8.80(d,J=8.2Hz,1H),8.00(d,J =6.8Hz,1H),7.83(t,J=7.4Hz,1H),7.68(d,J=7.1Hz,1H),6.99(d,J=8.0Hz,1H),6.9 1(d,J=7.2Hz,1H),6.87(d,J=7.9Hz,1H),6.62(s,1H),3.12(s,3H),2.83(s,3H),1.9 5(s,3H),1.34(d,J=9.3Hz,1H),1.30(s,2H),1.23(s,4H),1.18(s,2H).MS:m / z[M+1] + =441.22.

[0210] Embodiment 3

[0211] Compound P3: Preparation of 2-methyl-N-(1-(1-methyl-2-oxo-1,2-dihydrobenzo[cd]indol-6-yl)cyclopropyl)-5-(1,2,3,6-tetrahydropiperidin-4-yl)benzamide

[0212]

[0213] (1) Preparation of Intermediate S4: 1-(1-methyl-2-oxo-1,2-dihydrobenzo[cd]indol-6-yl)cyclopropyl-1-carbonitrile

[0214]

[0215] Pd2(dba)3 (1102 mg, 1.20 mmol) and NixantPhos (1253 mg, 2.27 mmol) were placed in a three-necked flask, THF (70 mL) was added, nitrogen was bubbled for 30 seconds, and the mixture was stirred at room temperature for 5 min. Cyclopentyl methyl ether (70 mL), S3 (6000 mg, 22.89 mmol), and cyclopropylcarbonitrile (2307 mg, 34.39 mmol) were added in sequence, and then LiHMDS (46 mL, 45.78 mmol, 1.0 M in THF) was added dropwise. The temperature was raised to 60 ° C, and the reaction was stirred overnight. The raw materials were completely reacted and the reaction was stopped. After the reaction, the reaction solution was cooled to room temperature, saturated ammonium chloride solution (100 mL) was added, and EA was used for extraction three times. The organic phases were combined, concentrated under reduced pressure, and purified by column chromatography (PE:EA=5:1-4:1-3:1-2:1) to obtain yellow solid S4 (2424 mg, 43%). MS: m / z[M+1] + =249.26.

[0216] (2) Preparation of Intermediate S5: 1-(1-methyl-2-oxo-1,2-dihydrobenzo[cd]indol-6-yl)cyclopropyl-1-carboxamide

[0217]

[0218] S4 (2424 mg, 9.77 mmol) was placed in a single-mouth bottle, DMSO (8 mL) and K2CO3 (675 mg, 4.89 mmol) were added, the temperature was lowered to 0°C, H2O2 (4.8 mL, 44.16 mmol, 30% in water) was added dropwise, and then the temperature was raised to room temperature, and the reaction was stirred for 6 hours. The raw materials reacted completely and the reaction was stopped. After the reaction was completed, water (30 mL) was added to the reaction solution to precipitate a yellow solid, which was stirred at room temperature for 20 minutes, filtered, and the filter cake was washed with water. The filter cake was purified by column chromatography (PE: EA = 1: 1-DCM: MeOH = 30: 1) to obtain a yellow solid S5 (1124 mg, 43%). MS: m / z [M+1] + =267.43.

[0219] (3) Preparation of Intermediate S6: 6-(1-amino-cyclopropyl)-1-methylbenz[cd]indol-2(1H)-one

[0220]

[0221] S5 (1124 mg, 4.22 mmol) was placed in a single-mouth bottle, t-BuOH (15 mL) was added, the temperature was lowered to 0°C, NaClO (4.90 mL, 11.84 mmol) solution and NaOH (3N, 3.90 mL, 11.84 mmol) solution were added, the temperature was raised to room temperature, and the reaction was stirred for 3 hours. The raw materials reacted completely and the reaction was stopped. After the reaction was completed, the reaction solution was concentrated under reduced pressure to remove the solvent, and the obtained solid mixture was purified by column chromatography (PE: EA = 1: 1-DCM: MeOH = 30: 1) to obtain yellow solid S6 (590 mg, 60%). MS: m / z [M+1] + =239.26.

[0222] (4) Intermediate S17: Preparation of tert-butyl 4-(3-methoxycarbonyl)-4-methylphenyl)-3,6-dihydropiperidine-1(2H)-carboxylate

[0223]

[0224] S7 (500 mg, 2.18 mmol) and S16 (675 mg, 2.18 mmol) were placed in a sealed tube, 1,4-dioxane (10 mL), X-Phos (42 mg, 0.087 mmol), Cs2CO3 (1421 mg, 4.36 mmol) and Pd2(dba)3 (40 mg, 0.044 mmol) were added, N2 was bubbled for 30 s, the temperature was raised to 100 ° C, the reaction was stirred overnight, and the raw materials were completely reacted, and the reaction was stopped. After the reaction was completed, the reaction solution was cooled to room temperature, filtered with diatomaceous earth, and the filter cake was washed with EA. The filtrate was concentrated under reduced pressure and purified by column chromatography (PE: EA = 30: 1) to obtain a light yellow oil S17 (717 mg, 100%). MS: m / z [M+1] + =332.38.

[0225] (5) Preparation of Intermediate S18: 5-(1-(tert-butoxycarbonyl)-1,2,3,6-tetrahydropiperidin-4-yl)-2-methylbenzoic acid

[0226]

[0227] S17 (335 mg, 1.01 mmol) was placed in a single-mouth bottle, THF (2 mL) and EtOH (2 mL) were added, followed by a solution of NaOH (202 mg, 5.05 mmol) in H2O (2 mL), and the temperature was raised to 60°C. The reaction was stirred for 2 h, and the raw materials reacted completely and the reaction was stopped. After the reaction was completed, the reaction solution was concentrated under reduced pressure to remove THF and EtOH, and the pH was adjusted to 4-5 with a saturated citric acid solution to precipitate a white solid. Water (3 mL) was added and filtered. The filter cake was washed with a small amount of water, and the filter cake was dissolved in DCM, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a white solid S18 (319 mg, 100%). MS: m / z[M+1] + =318.28.

[0228] (6) Intermediate S19: Preparation of tert-butyl 4-(4-methyl-3-((1-(1-methyl-2-oxo-1,2-dihydrobenzo[cd]indol-6-yl)cyclopropyl)carbamoyl)phenyl)-3,6-dihydropiperidine-1(2H)-carboxylate

[0229]

[0230] S6 (35 mg, 0.15 mmol) and S18 (56 mg, 0.18 mmol) were placed in a single-mouth bottle, and DMF (1.5 mL), DIPEA (63 mg, 0.49 mmol) and HATU (78 mg, 0.20 mmol) were added. The temperature was raised to 50°C, and the reaction was stirred for 1.0 h. The raw materials reacted completely and the reaction was stopped. After the reaction was completed, the reaction solution was cooled to room temperature, water was added, and a yellow solid was precipitated. The mixture was stirred at room temperature for 0.5 h, filtered, and the filter cake was washed with water. The filter cake was purified by column chromatography (PE:EA=2:1) ​​to obtain a yellow solid S19 (64 mg, 80%). MS: m / z[M+1] + =538.38.

[0231] (7) Preparation of P3: 2-methyl-N-(1-(1-methyl-2-oxo-1,2-dihydrobenzo[cd]indol-6-yl)cyclopropyl)-5-(1,2,3,4-tetrahydropiperidin-4-yl)benzamide

[0232]

[0233] S19 (61 mg, 0.11 mmol) was placed in a single-mouth bottle, and DCM (2.0 mL) and hydrochloric acid (1.0 mL, 4.0 M in 1,4-dioxane) were added. The reaction was stirred at room temperature for 1.0 h. The raw material reacted completely and the reaction was stopped. After the reaction was completed, the solvent was removed by concentration under reduced pressure to obtain a yellow solid mixture. A saturated sodium bicarbonate solution (4 mL) was added to the obtained mixture, and the mixture was extracted three times with DCM. The organic phase was taken, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a bright yellow solid P3 (48 mg, 100%). 1 HNMR(600MHz,DMSO-d6)δ9.15(s,1H),8.80(d,J=8.3Hz,1H),8.04(d,J=6.9Hz,1 H),7.83(t,J=7.6Hz,1H),7.74(d,J=7.3Hz,1H),7.29(d,J=7.8Hz,1H),7.09(d, J=7.8Hz,3H),6.09(s,1H),3.36(s,3H),2.86(t,J=5.4Hz,2H),2.22(s,2H),2.0 3(s,3H),1.33(d,J=7.0Hz,2H),1.23(s,2H),1.20(d,J=5.4Hz,2H).MS:m / z[M+1] + =438.28.

[0234] Embodiment 4

[0235] Compound P4: Preparation of 2-methyl-N-(1-(1-methyl-2-oxo-1,2-dihydrobenzo[cd]indol-6-yl)cyclopropyl)-5-(piperidin-4-yl)benzamide

[0236]

[0237] (1) Preparation of Intermediate S20: tert-Butyl 4-(3-(methoxycarbonyl)-4-methylphenyl)piperidine-1-carboxylate

[0238]

[0239] S17 (382 mg, 1.15 mmol) was placed in a single-mouth bottle, ethanol (5.0 mL) and palladium carbon (191 mg, 10%) were added, and the reaction was stirred overnight under a hydrogen balloon at room temperature until the raw materials reacted completely and the reaction was stopped. After the reaction was completed, the reaction solution was filtered through diatomaceous earth, and the filter cake was washed with dichloromethane (20 mL). The filtrate was concentrated under reduced pressure and purified by column chromatography (PE:EA=6:1-4:1) to obtain a white solid S20 (360 mg, 94%). MS: m / z[M+1] + =334.36.

[0240] (2) Preparation of Intermediate S21: 5-(1-(tert-butoxycarbonyl)piperidin-4-yl)-2-methylbenzoic acid

[0241]

[0242] S20 (360 mg, 1.08 mmol) was placed in a single-mouth bottle, THF (2 mL) and EtOH (2 mL) were added, and then a solution of NaOH (216 mg, 5.40 mmol) in H2O (2 mL) was added, and the temperature was raised to 60°C, and the reaction was stirred for 2 h. The raw materials reacted completely and the reaction was stopped. After the reaction was completed, the reaction solution was concentrated under reduced pressure to remove THF and EtOH, and the pH was adjusted to 4-5 with a saturated citric acid solution. A white solid was precipitated, and water (3 mL) was added, and the filter cake was filtered. The filter cake was washed with a small amount of water, and the filter cake was dissolved in DCM, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a white solid S21 (325 mg, 94%). MS: m / z[M+1] + =320.26.

[0243] (3) Intermediate S22: Preparation of tert-butyl 4-(4-methyl-3-((1-(1-methyl-2-oxo-1,2-dihydrobenzo[cd]indol-6-yl)cyclopropyl)carbamoyl)phenyl)piperidine-1-carboxylate

[0244]

[0245] S6 (35 mg, 0.15 mmol) and S21 (57 mg, 0.18 mmol) were placed in a single-mouth bottle, and DMF (1.5 mL), DIPEA (63 mg, 0.49 mmol) and HATU (78 mg, 0.20 mmol) were added. The temperature was raised to 50°C, and the reaction was stirred for 1.0 h. The raw materials reacted completely and the reaction was stopped. After the reaction was completed, the reaction solution was cooled to room temperature, water was added, and a yellow solid was precipitated. The mixture was stirred at room temperature for 0.5 h, filtered, and the filter cake was washed with water. The filter cake was purified by column chromatography (PE: EA = 2: 1) to obtain a yellow solid S22 (61 mg, 75%). MS: m / z [M+1] + =540.32.

[0246] (4) Preparation of P4: 2-methyl-N-(1-(1-methyl-2-oxo-1,2-dihydrobenzo[cd]indol-6-yl)cyclopropyl)-5-(piperidin-4-yl)benzamide

[0247]

[0248] S22 (61 mg, 0.11 mmol) was placed in a single-mouth bottle, and DCM (2.0 mL) and hydrochloric acid (1.0 mL, 4.0 M in 1,4-dioxane) were added. The reaction was stirred at room temperature for 1.0 h. The raw material reacted completely and the reaction was stopped. After the reaction was completed, the solvent was removed by concentration under reduced pressure to obtain a yellow solid mixture. A saturated sodium bicarbonate solution (4 mL) was added to the obtained mixture, and the mixture was extracted three times with DCM. The organic phase was taken, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a bright yellow solid P4 (48 mg, 100%). 1 HNMR(600MHz,DMSO-d6)δ9.10(s,1H),8.80(d,J=8.2Hz,1H),8.04(d,J=6.9Hz,1H),7.84(t,J= 7.6Hz,1H),7.75(d,J=7.3Hz,1H),7.10(t,J=6.7Hz,2H),7.05(d,J=7.8Hz,1H),6.90(s,1H),3 .36(s,3H),2.97(d,J=11.8Hz,2H),2.46(d,J=11.9Hz,1H),1.99(s,3H),1.58(d,J=11.9Hz,2H ),1.42-1.39(m,2H),1.33-1.31(m,2H),1.24-1.22(m,2H),1.20(d,J=5.5Hz,2H).MS:m / z[M+1] + =440.31.

[0249] Embodiment 5

[0250] Compound P5: Preparation of 5-(3,6-diazabicyclo[3.1.1]heptane-3-yl)-2-methyl-N-(1-(1-methyl-2-oxo-1,2-dihydrobenz[cd]indol-6-yl)cyclopropyl)benzamide

[0251]

[0252] (1) Preparation of Intermediate S24: tert-Butyl 3-(3-(methoxycarbonyl)-4-methylphenyl)-6-azabicyclo[3.1.1]heptane-6-carboxylate

[0253]

[0254] S7 (150 mg, 0.65 mmol) and S23 (154 mg, 0.78 mmol) were placed in a sealed tube, and toluene (3 mL), X-Phos (12 mg, 0.025 mmol), Cs2CO3 (423 mg, 1.30 mmol) and Pd2(dba)3 (12 mg, 0.013 mmol) were added. N2 was bubbled for 30 s, and the temperature was raised to 110 ° C. The reaction was stirred overnight. The raw materials reacted completely and the reaction was stopped. After the reaction was completed, the reaction solution was cooled to room temperature, concentrated under reduced pressure, and purified by column chromatography (PE: EA = 10: 1) to obtain a light yellow oil S24 (121 mg, 54%). MS: m / z [M+1] + =347.25.

[0255] (2) Preparation of Intermediate S25: 5-(6-(tert-butoxycarbonyl)-3,6-diazabicyclo[3.1.1]heptane-3-yl)-2-methylbenzoic acid

[0256]

[0257] S24 (121 mg, 0.35 mmol) was placed in a single-mouth bottle, THF (1 mL) and EtOH (1 mL) were added, and then a solution of NaOH (70 mg, 1.75 mmol) in H2O (1 mL) was added, and the temperature was raised to 60°C, and the reaction was stirred for 2 h. The raw materials reacted completely and the reaction was stopped. After the reaction was completed, the reaction solution was concentrated under reduced pressure to remove THF and EtOH, and the pH was adjusted to 4-5 with a saturated citric acid solution. A light yellow solid was precipitated, and water (3 mL) was added, and the mixture was filtered. The filter cake was washed with a small amount of water, and the filter cake was dissolved in DCM, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a light yellow solid S25 (116 mg, 100%). MS: m / z[M+1] + =333.23.

[0258] (3) Intermediate S26: Preparation of tert-butyl 3-(4-methyl-3-((1-(1-methyl-2-oxo-1,2-dihydrobenzo[cd]indol-6-yl)cyclopropyl)carbamoyl)phenyl)-3,6-diazabicyclo[3.1.1]heptane-6-carboxylate

[0259]

[0260] S6 (30 mg, 0.13 mmol) and S25 (50 mg, 0.15 mmol) were placed in a single-mouth bottle, and DMF (1.5 mL), DIPEA (55 mg, 0.42 mmol) and HATU (66 mg, 0.17 mmol) were added. The temperature was raised to 50°C, and the reaction was stirred for 1.0 h. The raw materials reacted completely and the reaction was stopped. After the reaction was completed, the reaction solution was cooled to room temperature, water was added, and a yellow solid was precipitated. The mixture was stirred at room temperature for 0.5 h, filtered, and the filter cake was washed with water. The filter cake was purified by column chromatography (PE: EA = 3: 1-1: 1-1: 2) to obtain a yellow solid S26 (57 mg, 79%). MS: m / z [M+1] + =553.25.

[0261] (4) Preparation of P5: 5-(3,6-diazabicyclo[3.1.1]heptane-3-yl)-2-methyl-N-(1-(1-methyl-2-oxo-1,2-dihydrobenz[cd]indol-6-yl)cyclopropyl)benzamide

[0262]

[0263] S26 (57 mg, 0.10 mmol) was placed in a single-mouth bottle, and DCM (2.0 mL) and hydrochloric acid (1.0 mL, 4.0 M in 1,4-dioxane) were added. The reaction was stirred at room temperature for 1.0 h. The raw materials reacted completely and the reaction was stopped. After the reaction was completed, the solvent was removed by concentration under reduced pressure to obtain a yellow solid mixture. A saturated sodium bicarbonate solution (4 mL) was added to the obtained mixture, and the mixture was extracted three times with DCM. The organic phase was concentrated under reduced pressure and purified by column chromatography (DCM: MeOH = 20: 1-10: 1-8: 1) to obtain a bright yellow solid P5 (37 mg, 82%). 1H NMR (600MHz, DMSO-d6) δ9.05(s,1H),8.82(d,J=8.2Hz,1H),8.04(d,J=6.9Hz,1H),7.83(dd,J=8.2,7. 0Hz,1H),7.73(d,J=7.3Hz,1H),7.09(d,J=7.3Hz,1H),6.98(d,J=8.5Hz,1H),6.62(dd,J=8.4,2.7Hz,1 H),6.39(d,J=2.7Hz,1H),3.99(d,J=5.4Hz,2H),3.49(d,J=11.0Hz,2H),3.36(s,3H),2.65-2.61(m,1H ),1.95(s,3H),1.57(d,J=9.1Hz,1H),1.32-1.30(m,2H),1.23(s,2H),1.21-1.19(m,2H).MS:m / z[M+1] + =453.39.

[0264] Embodiment 6

[0265] Compound P6: Preparation of 5-(3,8-diazabicyclo[3.2.1]octan-8-yl)-2-methyl-N-(1-(1-methyl-2-oxo-1,2-dihydrobenzo[cd]indol-6-yl)cyclopropyl)benzamide

[0266]

[0267] (1) Preparation of intermediate S28: tert-butyl 8-(3-(methoxycarbonyl)-4-methylphenyl)-3,8-diazabicyclo[3.2.1]octane-3-benzoate

[0268]

[0269] S7 (150 mg, 0.65 mmol) and S27 (166 mg, 0.78 mmol) were placed in a sealed tube, and toluene (3 mL), X-Phos (12 mg, 0.025 mmol), Cs2CO3 (423 mg, 1.30 mmol) and Pd2(dba)3 (12 mg, 0.013 mmol) were added. N2 was bubbled for 30 s, and the temperature was raised to 110 ° C. The reaction was stirred overnight. The raw materials reacted completely and the reaction was stopped. After the reaction was completed, the reaction solution was cooled to room temperature, concentrated under reduced pressure, and purified by column chromatography (PE: EA = 10: 1) to obtain a light yellow oil S28 (155 mg, 66%). MS: m / z [M+1] + =360.16.

[0270] (2) Preparation of Intermediate S29: 5-(3-(tert-butoxycarbonyl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-2-methylbenzoic acid

[0271]

[0272] S28 (121 mg, 0.35 mmol) was placed in a single-mouth bottle, THF (1 mL) and EtOH (1 mL) were added, and then a solution of NaOH (70 mg, 1.75 mmol) in H2O (1 mL) was added, and the temperature was raised to 60°C, and the reaction was stirred for 2 h. The raw materials reacted completely and the reaction was stopped. After the reaction was completed, the reaction solution was concentrated under reduced pressure to remove THF and EtOH, and the pH was adjusted to 4-5 with a saturated citric acid solution. A light yellow solid was precipitated, and water (3 mL) was added, and the mixture was filtered. The filter cake was washed with a small amount of water, and the filter cake was dissolved in DCM, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a light yellow solid S29 (149 mg, 100%). MS: m / z[M+1] + =347.23.

[0273] (3) Intermediate S30: Preparation of tert-butyl 8-(4-methyl-3-((1-(1-methyl-2-oxo-1,2-dihydrobenzo[cd]indol-6-yl)cyclopropyl)carbamoyl)phenyl)-3,8-diazabicyclo[3.2.1]octane-3-carboxylate

[0274]

[0275] S6 (30 mg, 0.13 mmol) and S29 (52 mg, 0.15 mmol) were placed in a single-mouth bottle, and DMF (1.5 mL), DIPEA (55 mg, 0.42 mmol) and HATU (66 mg, 0.17 mmol) were added. The temperature was raised to 50°C, and the reaction was stirred for 1.0 h. The raw materials reacted completely and the reaction was stopped. After the reaction was completed, the reaction solution was cooled to room temperature, water was added, and a yellow solid was precipitated. The mixture was stirred at room temperature for 0.5 h, filtered, and the filter cake was washed with water. The filter cake was purified by column chromatography (PE: EA = 3: 1-1: 1) to obtain a yellow solid S30 (61 mg, 82%). MS: m / z [M+1] + =567.23.

[0276] (4) Preparation of P6: 5-(3,8-diazabicyclo[3.2.1]octan-8-yl)-2-methyl-N-(1-(1-methyl-2-oxo-1,2-dihydrobenzo[cd]indol-6-yl)cyclopropyl)benzamide

[0277]

[0278] S30 (60 mg, 0.10 mmol) was placed in a single-mouth bottle, and DCM (2.0 mL) and hydrochloric acid (1.0 mL, 4.0 M in 1,4-dioxane) were added. The reaction was stirred at room temperature for 1.0 h. The raw material reacted completely and the reaction was stopped. After the reaction was completed, the solvent was removed by concentration under reduced pressure to obtain a yellow solid mixture. A saturated sodium bicarbonate solution (4 mL) was added to the obtained mixture, and the mixture was extracted three times with DCM. The organic phase was concentrated under reduced pressure and purified by column chromatography (DCM: MeOH = 20: 1-10: 1-8: 1) to obtain a bright yellow solid P6 (46 mg, 98%). 1 H NMR(600MHz,DMSO-d6)δ9.06(s,1H),8.80(d,J=8.2Hz,1H),8.04(d,J=6.9Hz,1H),7.83(dd,J=8 .2,7.0Hz,1H),7.73(d,J=7.3Hz,1H),7.08(d,J=7.3Hz,1H),6.94(d,J=8.5Hz,1H),6.73(dd,J= 8.4,2.6Hz,1H),6.47(d,J=2.5Hz,1H),4.06(s,2H),3.36(s,3H),2.89(d,J=11.9Hz,2H),2.56( d,J=12.2Hz,2H),1.91(s,3H),1.32-1.30(m,2H),1.23(s,4H),1.20-1.18(m,2H).MS:m / z[M+1] + =467.32.

[0279] Embodiment 7

[0280] Compound P7: Preparation of 2-methyl-5-(1-methyl-1,2,3,6-tetrahydropiperidin-4-yl)-N-(1-(1-methyl-2-oxo-1,2-dihydrobenzo[cd]indol-6-yl)cyclopropyl)benzamide

[0281]

[0282] (1) P7: Preparation of 2-methyl-5-(1-methyl-1,2,3,6-tetrahydropiperidin-4-yl)-N-(1-(1-methyl-2-oxo-1,2-dihydro[cd]indol-6-yl)cyclopropyl)benzamide

[0283]

[0284] P3 (20 mg, 0.046 mmol) was placed in a single-mouth bottle, MeOH (1.0 mL), formaldehyde aqueous solution (0.30 mL) and acetic acid (7 mg, 0.12 mmol) were added, and finally NaCNBH3 (4 mg, 0.069 mmol) was added, and the reaction was stirred at room temperature for 2 h. The raw materials reacted completely and the reaction was stopped. After the reaction was completed, a saturated sodium bicarbonate solution (5 mL) was added to the reaction solution, and DCM was used for extraction three times. The organic phases were combined and concentrated under reduced pressure to obtain a yellow solid, which was purified by column chromatography (PE: EA = 1: 1-DCM: MeOH = 30: 1-20: 1) to obtain a bright yellow solid P7 (12 mg, 57%). 1 H NMR(600MHz,DMSO-d6)δ9.16(s,1H),8.80(d,J=8.2Hz,1H),8.18(s,1H),8.04(d,J=6.9Hz,1 H),7.84(dd,J=8.2,7.0Hz,1H),7.74(d,J=7.3Hz,1H),7.31(dd,J=8.0,1.9Hz,1H),7.10(q,J =3.6,3.1Hz,2H),6.06(t,J=3.4Hz,1H),3.36(s,3H),3.02-3.01(m,2H),2.57(t,J=5.7Hz,2H ),2.39(s,2H),2.29(s,3H),2.03(s,3H),1.34-1.31(m,2H),1.21-1.19(m,2H).MS:m / z[M+1] + =452.35.

[0285] Embodiment 8

[0286] Compound P8: Preparation of 2-methyl-N-(1-(1-methyl-2-oxo-1,2-dihydrobenzo[cd]indol-6-yl)cyclopropyl)-3-methyl-3,8-diazabicyclo[3.2.1]octan-8-ylbenzamide

[0287]

[0288] (1) Preparation of P8: 2-methyl-N-(1-(1-methyl-2-oxo-1,2-dihydrobenzo[cd]indol-6-yl)cyclopropyl)-3-methyl-3,8-diazabicyclo[3.2.1]octan-8-ylbenzamide

[0289]

[0290] P6 (20 mg, 0.043 mmol) was placed in a single-mouth bottle, MeOH (1.0 mL), formaldehyde aqueous solution (0.30 mL) and acetic acid (7 mg, 0.11 mmol) were added, and finally NaCNBH3 (4 mg, 0.065 mmol) was added. The reaction was stirred at room temperature for 2 h. The raw materials reacted completely and the reaction was stopped. After the reaction was completed, a saturated sodium bicarbonate solution (5 mL) was added to the reaction solution, and DCM was used for extraction three times. The organic phases were combined and concentrated under reduced pressure to obtain a yellow solid. The yellow solid was purified by column chromatography (PE: EA = 1: 1-DCM: MeOH = 30: 1-20: 1) to obtain a bright yellow solid P8 (20 mg, 95%). MS: m / z [M+1] + =481.36.

[0291] Embodiment 9

[0292] Compound P9: Preparation of 5-(hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)-2-methyl-N-(1-(1-methyl-2-oxo-1,2-dihydrobenzo[cd]indol-6-yl)cyclopropyl)benzamide

[0293]

[0294] (1) Preparation of intermediate S32: tert-butyl 5-(3-(methoxycarbonyl)-4-methylphenyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate

[0295]

[0296] S7 (150 mg, 0.65 mmol) and S31 (165 mg, 0.78 mmol) were placed in a sealed tube, and toluene (3 mL), X-Phos (12 mg, 0.025 mmol), Cs2CO3 (423 mg, 1.30 mmol) and Pd2(dba)3 (12 mg, 0.013 mmol) were added. N2 was bubbled for 30 s, and the temperature was raised to 110 ° C. The reaction was stirred overnight. The raw materials reacted completely and the reaction was stopped. After the reaction was completed, the reaction solution was cooled to room temperature, concentrated under reduced pressure, and purified by column chromatography (PE: EA = 10: 1) to obtain a light yellow oil S32 (171 mg, 73%). MS: m / z [M+1] + =361.18.

[0297] (2) Preparation of Intermediate S33: 5-(5-(tert-butoxycarbonyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)-2-methylbenzoic acid

[0298]

[0299] S32 (171 mg, 0.47 mmol) was placed in a single-mouth bottle, THF (1.5 mL) and EtOH (1.5 mL) were added, followed by a solution of NaOH (94 mg, 2.35 mmol) in H2O (1.5 mL), and the temperature was raised to 60°C. The reaction was stirred for 2 h, and the raw materials reacted completely and the reaction was stopped. After the reaction was completed, the reaction solution was concentrated under reduced pressure to remove THF and EtOH, and the pH was adjusted to 4-5 with a saturated citric acid solution. A light yellow solid was precipitated, and water (3 mL) was added, filtered, and the filter cake was washed with a small amount of water. The filter cake was dissolved in DCM, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a yellow solid S33 (163 mg, 100%). MS: m / z[M+1] + =347.23.

[0300] (3) Intermediate S34: Preparation of tert-butyl 5-(4-methyl-3-((1-(1-methyl-2-oxo-1,2-dihydrobenzo[cd]indol-6-yl)cyclopropyl)carbamoyl)phenyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate

[0301]

[0302] S6 (30 mg, 0.13 mmol) and S33 (52 mg, 0.15 mmol) were placed in a single-mouth bottle, and DMF (1.5 mL), DIPEA (55 mg, 0.42 mmol) and HATU (66 mg, 0.17 mmol) were added. The temperature was raised to 50°C, and the reaction was stirred for 1.0 h. The raw materials reacted completely and the reaction was stopped. After the reaction was completed, the reaction solution was cooled to room temperature, water was added, and a yellow solid was precipitated. The mixture was stirred at room temperature for 0.5 h, filtered, and the filter cake was washed with water. The filter cake was purified by column chromatography (PE:EA=4:1-1:1) to obtain a light yellow solid S34 (58 mg, 78%). MS: m / z[M+1] + =567.23.

[0303] (4) Preparation of P9: 5-(hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)-2-methyl-N-(1-(1-methyl-2-oxo-1,2-dihydrobenzo[cd]indol-6-yl)cyclopropyl)benzamide

[0304]

[0305] S34 (58 mg, 0.10 mmol) was placed in a single-mouth bottle, and DCM (2.0 mL) and hydrochloric acid (1.0 mL, 4.0 M in 1,4-dioxane) were added. The reaction was stirred at room temperature for 1.0 h. The raw material reacted completely and the reaction was stopped. After the reaction was completed, the solvent was removed by concentration under reduced pressure to obtain a yellow solid mixture. A saturated sodium bicarbonate solution (5 mL) was added to the obtained mixture, and the mixture was extracted three times with DCM. The organic phase was concentrated under reduced pressure and purified by column chromatography (DCM: MeOH = 20: 1-10: 1-8: 1) to obtain a bright yellow solid P9 (42 mg, 89%). 1 H NMR(600MHz,DMSO-d6)δ9.03(s,1H),8.81(d,J=8.2Hz,1H),8.04(d,J=6.9Hz,1H),7.83(dd,J=8.2,7.0Hz, 1H),7.73(d,J=7.3Hz,1H),7.08(d,J=7.3Hz,1H),6.91(d,J=8.4Hz,1H),6.53(dd,J=8.3,2.6Hz,1H),6.30( d,J=2.6Hz,1H),3.36(s,3H),3.23-3.21(m,2H),2.97(dd,J=11.0,6.8Hz,2H),2.93(dd,J=9.6,3.1Hz,2H), 2.60(dd,J=11.2,3.3Hz,2H),1.91(s,3H),1.31-1.29(m,2H),1.23(s,3H),1.19-1.17(m,2H).MS:m / z[M+1] + =467.32.

[0306] Embodiment 10

[0307] Compound P10: Preparation of 2-methyl-N-(1-(1-methyl-2-oxo-1,2-dihydrobenzo[cd]indol-6-yl)cyclopropyl)-5-(2-methylpiperazin-1-yl)benzamide

[0308]

[0309] (1) Preparation of Intermediate S36: tert-Butyl 4-(3-(methoxycarbonyl)-4-methylphenyl)-3-methylpiperazine-1-carboxylate

[0310]

[0311] S7 (150 mg, 0.65 mmol) and S35 (156 mg, 0.78 mmol) were placed in a sealed tube, and toluene (3 mL), X-Phos (12 mg, 0.025 mmol), Cs2CO3 (423 mg, 1.30 mmol) and Pd2(dba)3 (12 mg, 0.013 mmol) were added. N2 was bubbled for 30 s, and the temperature was raised to 110 ° C. The reaction was stirred overnight and the raw materials were completely reacted. The reaction was stopped. After the reaction was completed, the reaction solution was cooled to room temperature, concentrated under reduced pressure, and purified by column chromatography (PE: EA = 10: 1) to obtain a light yellow oil S36 (110 mg, 49%). MS: m / z [M+1] + =349.36.

[0312] (2) Preparation of Intermediate S37: 5-(4-(tert-butoxycarbonyl)-2-methylpiperazin-1-yl)-2-methylbenzoic acid

[0313]

[0314] S36 (110 mg, 0.31 mmol) was placed in a single-mouth bottle, THF (1 mL) and EtOH (1 mL) were added, and then a solution of NaOH (63 mg, 1.58 mmol) in H2O (1 mL) was added, and the temperature was raised to 60°C, and the reaction was stirred for 2 h. The raw materials reacted completely and the reaction was stopped. After the reaction was completed, the reaction solution was concentrated under reduced pressure to remove THF and EtOH, and the pH was adjusted to 4-5 with a saturated citric acid solution. A light yellow solid was precipitated, and water (3 mL) was added, and the mixture was filtered. The filter cake was washed with a small amount of water, and the filter cake was dissolved in DCM, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a light yellow solid S37 (103 mg, 100%). MS: m / z[M+1] + =335.19.

[0315] (3) Intermediate S38: Preparation of tert-butyl 3-methyl-4-(4-methyl-3-((1-(1-methyl-2-oxo-1,2-dihydrobenzo[cd]indol-6-yl)cyclopropyl)carbamoyl)phenyl)piperazine-1-carboxylate

[0316]

[0317] S6 (30 mg, 0.13 mmol) and S37 (50 mg, 0.15 mmol) were placed in a single-mouth bottle, and DMF (1.5 mL), DIPEA (55 mg, 0.42 mmol) and HATU (66 mg, 0.17 mmol) were added. The temperature was raised to 50°C, and the reaction was stirred for 1.0 h. The raw materials reacted completely and the reaction was stopped. After the reaction was completed, the reaction solution was cooled to room temperature, water was added, and a yellow solid was precipitated. The mixture was stirred at room temperature for 0.5 h, filtered, and the filter cake was washed with water. The filter cake was purified by column chromatography (PE:EA=4:1-1:1) to obtain a light yellow solid S38 (58 mg, 81%). MS: m / z[M+1] + =555.25.

[0318] (4) P10: Preparation of 2-methyl-N-(1-(1-methyl-2-oxo-1,2-dihydrobenzo[cd]indol-6-yl)cyclopropyl)-5-(2-methylpiperazin-1-yl)benzamide

[0319]

[0320] S38 (58 mg, 0.10 mmol) was placed in a single-mouth bottle, and DCM (2.0 mL) and hydrochloric acid (1.0 mL, 4.0 M in 1,4-dioxane) were added. The reaction was stirred at room temperature for 1.0 h. The raw material reacted completely and the reaction was stopped. After the reaction was completed, the solvent was removed by concentration under reduced pressure to obtain a yellow solid mixture. A saturated sodium bicarbonate solution (5 mL) was added to the obtained mixture, and the mixture was extracted three times with DCM. The organic phase was concentrated under reduced pressure and purified by column chromatography (DCM: MeOH = 20: 1-10: 1-8: 1) to obtain a bright yellow solid P10 (45 mg, 100%). 1H NMR(600MHz,DMSO-d6)δ9.06(s,1H),8.81(d,J=8.2Hz,1H),8.04(d,J=6.9Hz,1H),7.83(dd,J=8.2,7.0Hz,1H),7. 73(d,J=7.3Hz,1H),7.09(d,J=7.3Hz,1H),6.98(d,J=8.5Hz,1H),6.82(dd,J=8.4,2.6Hz,1H),6.56(d,J=2.6Hz,1H ),3.36(s,3H),3.07(dt,J=11.1,2.8Hz,1H),3.02(d,J=11.8Hz,1H),2.98(dd,J=12.2,3.5Hz,1H),2.87-2.82(m, 2H),1.94(s,3H),1.32-1.30(m,2H),1.23(s,2H),1.19(dd,J=4.8,3.0Hz,2H),0.89(d,J=6.6Hz,3H).MS:m / z[M+1] + =455.27.

[0321] Embodiment 11

[0322] Compound P11: Preparation of 2-methyl-N-(1-(1-methyl-2-oxo-1,2-dihydrobenz[cd]indol-6-yl)cyclopropyl)-5-(6-methyl-3,6-diazabicyclo[3.1.1]heptane-3-yl)benzamide

[0323]

[0324] (1) P11: Preparation of 2-methyl-N-(1-(1-methyl-2-oxo-1,2-dihydrobenz[cd]indol-6-yl)cyclopropyl)-5-(6-methyl-3,6-diazabicyclo[3.1.1]heptane-3-yl)benzamide

[0325]

[0326] P5 (18 mg, 0.040 mmol) was placed in a single-mouth bottle, MeOH (1.0 mL), formaldehyde aqueous solution (0.30 mL) and acetic acid (6 mg, 0.10 mmol) were added, and finally NaCNBH3 (4 mg, 0.060 mmol) was added, and the reaction was stirred at room temperature for 2 h. The raw materials reacted completely and the reaction was stopped. After the reaction was completed, a saturated sodium bicarbonate solution (5 mL) was added to the reaction solution, and DCM was used for extraction three times. The organic phases were combined and concentrated under reduced pressure to obtain a yellow solid. The yellow solid was purified by column chromatography (DCM: MeOH = 10: 1-7: 1) to obtain a bright yellow solid P11 (14 mg, 77%). MS: m / z [M+1] + = 467.32.

[0327] Embodiment 12

[0328] Compound P12: Preparation of 2-methyl-N-(1-(1-methyl-2-oxo-1,2-dihydrobenzo[cd]indol-6-yl)cyclopropyl)-5-(4,7-diazaspiro[2,5]octan-7yl)benzamide

[0329]

[0330] (1) Preparation of intermediate S40: tert-butyl 7-(3-(methoxycarbonyl)-4-methylphenyl)-4,7-diazaspiro[2,5]octane-4-carboxylate

[0331]

[0332] S7 (42 mg, 0.18 mmol) and S39 (46 mg, 0.22 mmol) were placed in a sealed tube, and toluene (1 mL), X-Phos (3 mg, 0.0069 mmol), Cs2CO3 (117 mg, 0.36 mmol) and Pd2(dba)3 (3 mg, 0.0036 mmol) were added. N2 was bubbled for 30 s, and the temperature was raised to 110°C. The reaction was stirred overnight and the raw materials were completely reacted. The reaction was stopped. After the reaction was completed, the reaction solution was cooled to room temperature, concentrated under reduced pressure, and purified by column chromatography (PE:EA=20:1-10:1-8:1) to obtain a light yellow oil S40 (35 mg, 54%). MS: m / z[M+1] + =361.38.

[0333] (2) Preparation of Intermediate S41: 5-(4-(tert-butoxycarbonyl)-4,7-diazaspiro[2,5]octane)-7-yl)-2-methylbenzoic acid

[0334]

[0335] S40 (35 mg, 0.097 mmol) was placed in a single-mouth bottle, THF (0.5 mL) and EtOH (0.5 mL) were added, followed by a solution of NaOH (19 mg, 0.49 mmol) in H2O (0.5 mL), the temperature was raised to 60°C, and the reaction was stirred for 2 h. The raw materials reacted completely and the reaction was stopped. After the reaction was completed, the reaction solution was concentrated under reduced pressure to remove THF and EtOH, and the pH was adjusted to 4-5 with a saturated citric acid solution. A light yellow solid was precipitated, water (3 mL) was added, and the mixture was filtered. The filter cake was washed with a small amount of water, and the filter cake was dissolved in DCM, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a yellow solid S41 (33 mg, 100%). MS: m / z[M+1] + =347.15.

[0336] (3) Intermediate S42: Preparation of tert-butyl 7-(4-methyl-3-((1-(1-methyl-2-oxo-1,2-dihydrobenzo[cd]indol-6-yl)cyclopropyl)carbamoyl)phenyl)-4,7-diazaspiro[2,5]octane-4-carboxylate

[0337]

[0338] S6 (21 mg, 0.086 mmol) and S41 (33 mg, 0.095 mmol) were placed in a single-mouth bottle, and DMF (1.5 mL), DIPEA (36 mg, 0.28 mmol) and HATU (43 mg, 0.11 mmol) were added. The temperature was raised to 50°C, and the reaction was stirred for 1.0 h. The raw materials reacted completely and the reaction was stopped. After the reaction was completed, the reaction solution was cooled to room temperature, water was added, and a yellow solid was precipitated. The mixture was stirred at room temperature for 0.5 h, filtered, and the filter cake was washed with water. The filter cake was purified by column chromatography (PE:EA=4:1-2:1-1:1) to obtain a light yellow solid S42 (33 mg, 67%). MS: m / z[M+1] + =567.23.

[0339] (4) P12: Preparation of 2-methyl-N-(1-(1-methyl-2-oxo-1,2-dihydrobenzo[cd]indol-6-yl)cyclopropyl)-5-(4,7-diazaspiro[2,5]octan-7yl)benzamide

[0340]

[0341] S42 (33 mg, 0.058 mmol) was placed in a single-mouth bottle, and DCM (2.0 mL) and hydrochloric acid (1.0 mL, 4.0 M in 1,4-dioxane) were added. The reaction was stirred at room temperature for 1.0 h. The raw material reacted completely and the reaction was stopped. After the reaction was completed, the solvent was removed by concentration under reduced pressure to obtain a yellow solid mixture. Saturated sodium bicarbonate solution (5 mL) was added to the obtained mixture, and it was extracted three times with DCM. The organic phase was concentrated under reduced pressure and purified by column chromatography (DCM: MeOH = 10: 1) to obtain a bright yellow solid P12 (20 mg, 74%). MS: m / z [M+1] + =467.37.

[0342] Embodiment 13

[0343] Compound P13: Preparation of 5-(4-(dimethylamino)piperidin-1-yl)-2-methyl-N-(1-(1-methyl-2-oxo-1,2-dihydrobenzo[cd]indol-6-yl)cyclopropyl)benzamide

[0344]

[0345] (1) Preparation of intermediate S44: 5-(4-(dimethylamino)piperidin-1-yl)-2-methylbenzoic acid methyl ester

[0346]

[0347] S7 (150 mg, 0.65 mmol) and S43 (100 mg, 0.78 mmol) were placed in a sealed tube, and toluene (3 mL), X-Phos (12 mg, 0.025 mmol), Cs2CO3 (423 mg, 1.30 mmol) and Pd2(dba)3 (12 mg, 0.013 mmol) were added. N2 was bubbled for 30 s, and the temperature was raised to 110°C. The reaction was stirred overnight and the raw materials were completely reacted. The reaction was stopped. After the reaction was completed, the reaction solution was cooled to room temperature, concentrated under reduced pressure, and purified by column chromatography (DCM: MeOH = 20: 1-10: 1-8: 1) to obtain a light yellow oil S44 (70 mg, 39%). MS: m / z [M+1] + =277.38.

[0348] (2) Preparation of Intermediate 45: 5-(4-(dimethylamino)piperidin-1-yl)-2-methylbenzoic acid

[0349]

[0350] S44 (70 mg, 0.25 mmol) was placed in a single-mouth bottle, THF (1 mL) and EtOH (1 mL) were added, and then a solution of NaOH (51 mg, 1.26 mmol) in H2O (1 mL) was added, and the temperature was raised to 60°C. The reaction was stirred for 2 h, and the raw materials were completely reacted, and the reaction was stopped. After the reaction was completed, the reaction solution was concentrated under reduced pressure to remove THF and EtOH, and the pH was adjusted to 4-5 with dilute hydrochloric acid (2.0 M), and the solvent was removed by concentration under reduced pressure. The obtained solid was dissolved in DCM, dried over anhydrous sodium sulfate, filtered, and the filter cake was washed with DCM. The filtrate was taken, concentrated under reduced pressure to remove the solvent, and a light yellow solid S45 (65 mg, 100%) was obtained. MS: m / z[M+1] + =263.19.

[0351] (3) P13: Preparation of 5-(4-(dimethylamino)piperidin-1-yl)-2-methyl-N-(1-(1-methyl-2-oxo-1,2-dihydrobenzo[cd]indol-6-yl)cyclopropyl)benzamide

[0352]

[0353] S6 (20 mg, 0.084 mmol) and S45 (26 mg, 0.10 mmol) were placed in a single-mouth bottle, and DMF (1.5 mL), DIPEA (36 mg, 0.28 mmol) and HATU (43 mg, 0.11 mmol) were added. The temperature was raised to 50°C, and the reaction was stirred for 1.0 h. The raw materials reacted completely and the reaction was stopped. After the reaction was completed, the reaction solution was cooled to room temperature, water was added, and a yellow solid was precipitated. The mixture was stirred at room temperature for 0.5 h, filtered, and the filter cake was washed with water. The filter cake was purified by column chromatography (PE:EA=1:1-DCM:MeOH=20:1-10:1) to obtain a bright yellow solid P13 (23 mg, 57%). MS: m / z[M+1] + =483.32.

[0354] Embodiment 14

[0355] Compound P14: Preparation of (S)-5-(4-ethyl-3-methylpiperazin-1-yl)-2-methyl-N-(1-(1-methyl-2-oxo-1,2-dihydrobenzo[cd]indol-6-yl)cyclopropyl)benzamide

[0356]

[0357] (1) Intermediate S47: Preparation of (S)-methyl 5-(4-ethyl-3-methylpiperazin-1-yl)-2-methylbenzoate

[0358]

[0359] S7 (150 mg, 0.65 mmol) and S46 (100 mg, 0.78 mmol) were placed in a sealed tube, and toluene (3 mL), X-Phos (12 mg, 0.025 mmol), Cs2CO3 (423 mg, 1.30 mmol) and Pd2(dba)3 (12 mg, 0.013 mmol) were added. N2 was bubbled for 30 s, and the temperature was raised to 110°C. The reaction was stirred overnight and the raw materials were completely reacted. The reaction was stopped. After the reaction was completed, the reaction solution was cooled to room temperature, concentrated under reduced pressure, and purified by column chromatography (PE:EA=1:1-1:2) to obtain a colorless oil S47 (66 mg, 37%). MS: m / z[M+1] + =277.38.

[0360] (2) Preparation of Intermediate S48: (S)-5-(4-ethyl-3-methylpiperazin-1-yl)-2-methylbenzoic acid

[0361]

[0362] S47 (66 mg, 0.24 mmol) was placed in a single-mouth bottle, THF (1 mL) and EtOH (1 mL) were added, and then a solution of NaOH (48 mg, 1.20 mmol) in H2O (1 mL) was added, and the temperature was raised to 60°C. The reaction was stirred for 2 h, and the raw materials were completely reacted and the reaction was stopped. After the reaction was completed, the reaction solution was concentrated under reduced pressure to remove THF and EtOH, and the pH was adjusted to 4-5 with dilute hydrochloric acid (2.0 M). The solvent was removed by concentration under reduced pressure, and the obtained solid was dissolved in DCM, dried over anhydrous sodium sulfate, filtered, and the filter cake was washed with DCM. The filtrate was taken, concentrated under reduced pressure to remove the solvent, and a light yellow solid S48 (63 mg, 100%) was obtained. MS: m / z[M+1] + =263.19.

[0363] (3) P14: Preparation of (S)-5-(4-ethyl-3-methylpiperazin-1-yl)-2-methyl-N-(1-(1-methyl-2-oxo-1,2-dihydrobenzo[cd]indol-6-yl)cyclopropyl)benzamide

[0364]

[0365] S6 (20 mg, 0.084 mmol) and S48 (26 mg, 0.10 mmol) were placed in a single-mouth bottle, and DMF (1.5 mL), DIPEA (36 mg, 0.28 mmol) and HATU (43 mg, 0.11 mmol) were added. The temperature was raised to 50°C, and the reaction was stirred for 1.0 h. The raw materials reacted completely and the reaction was stopped. After the reaction was completed, the reaction solution was cooled to room temperature, water was added, and a yellow solid was precipitated. The mixture was stirred at room temperature for 0.5 h, filtered, and the filter cake was washed with water. The filter cake was purified by column chromatography (PE:EA=1:1-DCM:MeOH=20:1-10:1) to obtain a bright yellow solid P14 (18 mg, 45%). MS: m / z[M+1] + =483.32.

[0366] Embodiment 15

[0367] Compound P15: Preparation of 5-(3-(dimethylamino)pyrrol-1-yl)-2-methyl-N-(1-(1-methyl-2-oxo-1,2-dihydrobenzo[cd]indol-6-yl)cyclopropyl)benzamide

[0368]

[0369] (1) Preparation of intermediate S50: 5-(3-(dimethylamino)pyrrol-1-yl)-2-methylbenzoic acid methyl ester

[0370]

[0371] S7 (101 mg, 0.44 mmol) and S49 (100 mg, 0.53 mmol) were placed in a sealed tube, toluene (3 mL), X-Phos (8 mg, 0.017 mmol), Cs2CO3 (717 mg, 2.20 mmol) and Pd2(dba)3 (8 mg, 0.0088 mmol) were added, N2 was bubbled for 30 s, the temperature was raised to 110 ° C, the reaction was stirred overnight, and the raw materials were completely reacted, and the reaction was stopped. After the reaction was completed, the reaction solution was cooled to room temperature, filtered with diatomaceous earth, and the filter cake was washed with EA. The filtrate was concentrated under reduced pressure and purified by column chromatography (PE: EA = 1: 1-1: 2) to obtain a light yellow oil S50 (91 mg, 79%). MS: m / z [M+1] + =263.38.

[0372] (2) Preparation of Intermediate S51: 5-(3-(dimethylamino)pyrrol-1-yl)-2-methylbenzoic acid

[0373]

[0374] S50 (91 mg, 0.34 mmol) was placed in a single-mouth bottle, THF (1 mL) and EtOH (1 mL) were added, and then a solution of NaOH (68 mg, 1.70 mmol) in H2O (1 mL) was added, and the temperature was raised to 60°C. The reaction was stirred for 2 h, and the raw materials were completely reacted, and the reaction was stopped. After the reaction was completed, the reaction solution was concentrated under reduced pressure to remove THF and EtOH, and the pH was adjusted to 4-5 with dilute hydrochloric acid (2.0 M), and the solvent was removed by concentration under reduced pressure. The obtained solid was dissolved in DCM, dried over anhydrous sodium sulfate, filtered, and the filter cake was washed with DCM. The filtrate was taken, concentrated under reduced pressure to remove the solvent, and a light yellow solid S51 (84 mg, 100%) was obtained. MS: m / z[M+1] + =249.33.

[0375] (3) P15: Preparation of 5-(3-(dimethylamino)pyrrol-1-yl)-2-methyl-N-(1-(1-methyl-2-oxo-1,2-dihydrobenzo[cd]indol-6-yl)cyclopropyl)benzamide

[0376]

[0377] S6 (20 mg, 0.084 mmol) and S51 (25 mg, 0.10 mmol) were placed in a single-mouth bottle, and DMF (1.5 mL), DIPEA (36 mg, 0.28 mmol) and HATU (43 mg, 0.11 mmol) were added. The temperature was raised to 50°C, and the reaction was stirred for 1.0 h. The raw materials reacted completely and the reaction was stopped. After the reaction was completed, the reaction solution was cooled to room temperature, water was added, and a yellow solid was precipitated. The mixture was stirred at room temperature for 0.5 h, filtered, and the filter cake was washed with water. The filter cake was purified by column chromatography (PE:EA=1:1-DCM:MeOH=20:1-10:1) to obtain a bright yellow solid P15 (21 mg, 54%). MS: m / z[M+1] + =469.31.

[0378] Embodiment 16

[0379] Compound P16: Preparation of 5-(3,6-diazabicyclo[3.1.1]heptane-3-yl)-N-(1-(1-isopropyl-2-oxo-1,2-dihydrobenz[cd]indol-6-yl)cyclopropyl)benzamide

[0380]

[0381] (1) Preparation of Intermediate S52: 6-bromo-1-isopropylbenzo[cd]indol-2(1H)-one

[0382]

[0383] S2 (1000 mg, 4.03 mmol) was placed in a single-mouth bottle, DMF (15 mL) was added, the temperature was lowered to 0°C, NaH (242 mg, 6.05 mmol, 60% dispersed in mineral oil) was added, the reaction was stirred for 10 minutes, potassium iodide (792 mg, 4.77 mmol) and 2-bromopropane (1174 mg, 9.54 mmol) were added, the temperature was raised to 45°C, the reaction was stirred overnight, and the reaction was stopped. The reaction solution was cooled to room temperature, water (50 mL) was added, an orange solid was precipitated, the mixture was stirred at room temperature for 0.5 hours, filtered, the filter cake was washed with water, the filter cake was dried, and then purified by column chromatography (PE: EA = 30: 1) to obtain a yellow solid S52 (933 mg, 80%). MS: m / z [M+1] + =291.26.

[0384] (2) Intermediate S53: Preparation of 1-(1-isopropyl-2-oxo-1,2-dihydrobenzo[cd]indol-6-yl)cyclopropane-1-carbonitrile

[0385]

[0386] Pd2(dba)3 (157 mg, 0.17 mmol) and NixantPhos (176 mg, 0.32 mmol) were placed in a three-necked flask, THF (10 mL) was added, nitrogen was bubbled for 30 s, and the mixture was stirred at room temperature for 5 min. Cyclopentyl methyl ether (10 mL), S52 (933 mg, 3.22 mmol), and cyclopropylcarbonitrile (325 mg, 4.84 mmol) were added in sequence, and then LiHMDS (6 mL, 6.44 mmol, 1.0 M in THF) was added dropwise. The mixture was heated to 60°C and stirred for 1.0 h. The raw materials reacted completely and the reaction was stopped. After the reaction was completed, the reaction solution was cooled to room temperature, saturated ammonium chloride solution (20 mL) was added, and the mixture was extracted three times with EA. The organic phases were combined, concentrated under reduced pressure, and purified by column chromatography (PE:EA=20:1-10:1-5:1) to obtain yellow solid S53 (267 mg, 30%). MS: m / z[M+1] + =277.32.

[0387] (3) Preparation of Intermediate S54: 1-(1-isopropyl-2-oxo-1,2-dihydrobenzo[cd]indol-6-yl)cyclopropane-1-carboxamide

[0388]

[0389] S53 (267 mg, 0.97 mmol) was placed in a single-mouth bottle, DMSO (2 mL) and K2CO3 (67 mg, 0.48 mmol) were added, the temperature was lowered to 0°C, hydrogen peroxide (0.2 mL, 1.46 mmol, 30% in water) was added dropwise, the temperature was raised to room temperature, and the reaction was stirred for 2.0 hours. The raw materials reacted completely and the reaction was stopped. After the reaction was completed, water (20 mL) was added to precipitate a yellow solid, which was filtered, and the filter cake was washed with water, followed by column chromatography purification (PE: EA = 2: 1-1: 1) to obtain a yellow solid S54 (158 mg, 55%). MS: m / z [M+1] + =295.38.

[0390] (4) Preparation of Intermediate S55: 6-(1-aminocyclopropyl)-1-isopropylbenzo[cd]indol-2(1H)-one

[0391]

[0392] S54 (158 mg, 0.54 mmol) was placed in a single-mouth bottle, t-BuOH (2 mL) was added, the temperature was lowered to 0°C, NaClO (0.63 mL, 1.51 mmol) solution and NaOH (3N, 0.50 mL, 1.51 mmol) solution were added, the temperature was raised to room temperature, and the reaction was stirred for 2 h. The raw materials reacted completely and the reaction was stopped. After the reaction was completed, the reaction solution was concentrated under reduced pressure to remove the solvent and then purified by column chromatography (PE: EA = 2: 1-1: 1) to obtain yellow oil S55 (65 mg, 45%). MS: m / z [M+1] + = 267.36.

[0393] (5) Preparation of Intermediate S56: tert-butyl 3-(3-((1-(1-isopropyl-2-oxo-1,2-dihydrobenzo[cd]indol-6-yl)-cyclopropyl)carbamoyl)-4-methylphenyl)-3,6-diazabicyclo[3.1.1]heptane-6-carboxylate

[0394]

[0395] S55 (29 mg, 0.11 mmol) and S25 (41 mg, 0.12 mmol) were placed in a single-mouth bottle, and DMF (1.5 mL), DIPEA (47 mg, 0.37 mmol) and HATU (55 mg, 0.14 mmol) were added. The temperature was raised to 50°C, and the reaction was stirred for 1.0 h. The raw materials reacted completely and the reaction was stopped. After the reaction was completed, the reaction solution was cooled to room temperature, water was added, and a yellow solid was precipitated. The mixture was stirred at room temperature for 20 minutes, filtered, and the filter cake was washed with water. The filter cake was purified by column chromatography (PE:EA=3:1-1:1) to obtain a yellow solid S56 (53 mg, 83%). MS: m / z[M+1]+ =581.37.

[0396] (6) P16: Preparation of 5-(3,6-diazabicyclo[3.1.1]heptane-3-yl)-N-(1-(1-isopropyl-2-oxo-1,2-dihydrobenz[cd]indol-6-yl)cyclopropyl)benzamide

[0397]

[0398] S56 (53 mg, 0.091 mmol) was placed in a single-mouth bottle, and DCM (2.0 mL) and hydrochloric acid (2.0 mL, 4.0 M in 1,4-dioxane) were added. The reaction was stirred at room temperature for 5.5 h. The raw materials reacted completely and the reaction was stopped. After the reaction was completed, the solvent was removed by concentration under reduced pressure to obtain a yellow solid mixture. Saturated sodium bicarbonate solution (4 mL) was added to the obtained mixture, and extracted three times with DCM. The organic phase was concentrated under reduced pressure and purified by column chromatography (PE:EA=1:1-DCM:MeOH=20:1-10:1) to obtain a bright yellow solid P16 (32 mg, 73%). MS: m / z[M+1] + =481.28.

[0399] Embodiment 17

[0400] Compound P17: Preparation of 5-(3-(4-hydroxy-4-methylpiperidin-1-yl)azetidin-1-yl)-2-methyl-N-(1-(1-methyl-2-oxo-1,2-dihydrobenzo[cd]indol-6-yl)cyclopropyl)benzamide

[0401]

[0402] (1) Preparation of intermediate S58: methyl 5-(3-(4-hydroxy-4-methylpiperidin-1-yl)azetidin-1-yl)-2-methylbenzoate

[0403]

[0404] S7 (101 mg, 0.44 mmol) and S57 (129 mg, 0.53 mmol) were placed in a sealed tube, and toluene (3 mL), X-Phos (8 mg, 0.017 mmol), Cs2CO3 (717 mg, 2.20 mmol) and Pd2(dba)3 (8 mg, 0.0088 mmol) were added. N2 was bubbled for 30 s, and the temperature was raised to 110 ° C. The reaction was stirred overnight. The raw materials reacted completely and the reaction was stopped. After the reaction was completed, the reaction solution was cooled to room temperature, saturated ammonium chloride solution (6 mL) was added, and DCM was used for extraction three times. The organic phases were combined, concentrated under reduced pressure, and purified by column chromatography (PE: EA = 1: 1-1: 3) to obtain a light yellow oil S58 (92 mg, 66%). MS: m / z [M+1] + =319.27.

[0405] (2) Preparation of Intermediate S59: 5-(3-(4-hydroxy-4-methylpiperidin-1-yl)azetidin-1-yl)-2-methylbenzoic acid

[0406]

[0407] S58 (92 mg, 0.29 mmol) was placed in a single-mouth bottle, THF (1 mL) and EtOH (1 mL) were added, and then a solution of NaOH (58 mg, 1.45 mmol) in H2O (1 mL) was added, and the temperature was raised to 60°C. The reaction was stirred for 2 h, and the raw materials were completely reacted, and the reaction was stopped. After the reaction was completed, the reaction solution was concentrated under reduced pressure to remove THF and EtOH, and the pH was adjusted to 4-5 with dilute hydrochloric acid (2.0 M). The solvent was removed by concentration under reduced pressure, and the obtained solid was dissolved in DCM, dried over anhydrous sodium sulfate, filtered, and the filter cake was washed with DCM. The filtrate was taken and concentrated under reduced pressure to obtain a light yellow solid S59 (88 mg, 100%). MS: m / z[M+1] + =305.31.

[0408] (3) P17: Preparation of 5-(3-(4-hydroxy-4-methylpiperidin-1-yl)azetidin-1-yl)-2-methyl-N-(1-(1-methyl-2-oxo-1,2-dihydrobenzo[cd]indol-6-yl)cyclopropyl)benzamide

[0409]

[0410] S6 (20 mg, 0.084 mmol) and S59 (30 mg, 0.10 mmol) were placed in a single-mouth bottle, and DMF (1.5 mL), DIPEA (36 mg, 0.28 mmol) and HATU (43 mg, 0.11 mmol) were added. The temperature was raised to 50°C and stirred for 1.0 h. The raw materials reacted completely and the reaction was stopped. After the reaction was completed, the reaction solution was cooled to room temperature, water was added, and a yellow solid was precipitated. The mixture was stirred at room temperature for 20 minutes, filtered, and the filter cake was washed with water. The filter cake was purified by column chromatography (PE:EA=1:1-DCM:MeOH=20:1-10:1) to obtain a bright yellow solid P17 (27 mg, 61%). MS: m / z[M+1] + =525.25.

[0411] Embodiment 18

[0412] Compound P18: Preparation of 5-(3-(3,3-difluoropyrrol-1-yl)azetidin-1-yl)-2-methyl-N-(1-(1-methyl-2-oxo-1,2-dihydrobenzo[cd]indol-6-yl)cyclopropyl)benzamide

[0413]

[0414] (1) Preparation of intermediate S61: 5-(3-(3,3-difluoropyrrol-1-yl)azetidin-1-yl)-2-methylbenzoic acid methyl ester

[0415]

[0416] S7 (101 mg, 0.44 mmol) and S60 (125 mg, 0.53 mmol) were placed in a sealed tube, and toluene (3 mL), X-Phos (8 mg, 0.017 mmol), Cs2CO3 (717 mg, 2.20 mmol) and Pd2(dba)3 (8 mg, 0.0088 mmol) were added. N2 was bubbled for 30 s, and the temperature was raised to 110 ° C. The reaction was stirred overnight. The raw materials reacted completely and the reaction was stopped. After the reaction was completed, the reaction solution was cooled to room temperature, saturated ammonium chloride solution (6 mL) was added, and DCM was used for extraction three times. The organic phases were combined, concentrated under reduced pressure, and purified by column chromatography (PE: EA = 10: 1-7: 1) to obtain a light yellow oil S61 (115 mg, 85%). MS: m / z [M+1] + =311.26.

[0417] (2) Preparation of Intermediate S62: 5-(3-(3,3-difluoropyrrol-1-yl)azetidin-1-yl)-2-methylbenzoic acid

[0418]

[0419] S61 (115 mg, 0.37 mmol) was placed in a single-mouth bottle, THF (1 mL) and EtOH (1 mL) were added, and then a solution of NaOH (74 mg, 1.85 mmol) in H2O (1 mL) was added, and the temperature was raised to 60°C. The reaction was stirred for 2 h, and the raw materials were completely reacted, and the reaction was stopped. After the reaction was completed, the reaction solution was concentrated under reduced pressure to remove THF and EtOH, and the pH was adjusted to 4-5 with dilute hydrochloric acid (2.0 M). The solvent was removed by concentration under reduced pressure, and the obtained solid was dissolved in DCM, dried over anhydrous sodium sulfate, filtered, and the filter cake was washed with DCM. The filtrate was taken and concentrated under reduced pressure to obtain a light yellow solid S62 (109 mg, 100%). MS: m / z[M+1] + =297.31.

[0420] (3) P18: Preparation of 5-(3-(3,3-difluoropyrrol-1-yl)azetidin-1-yl)-2-methyl-N-(1-(1-methyl-2-oxo-1,2-dihydrobenzo[cd]indol-6-yl)cyclopropyl)benzamide

[0421]

[0422] S6 (20 mg, 0.084 mmol) and S62 (30 mg, 0.10 mmol) were placed in a single-mouth bottle, and DMF (1.5 mL), DIPEA (36 mg, 0.28 mmol) and HATU (43 mg, 0.11 mmol) were added. The temperature was raised to 50°C and stirred for 1.0 h. The raw materials reacted completely and the reaction was stopped. After the reaction was completed, the reaction solution was cooled to room temperature, water was added, and a yellow solid was precipitated. The mixture was stirred at room temperature for 20 minutes, filtered, and the filter cake was washed with water. The filter cake was purified by column chromatography (PE:EA=3:1-1:1) to obtain a bright yellow solid P18 (25 mg, 58%). MS: m / z[M+1] + =517.23.

[0423] Embodiment 19

[0424] Compound P19: Preparation of 2-methyl-N-(1-(1-methyl-2-oxo-1,2-dihydrobenzo[cd]indol-6-yl)cyclopropyl)-5-(6-methyl-2,6-diazaspiro[3,4]octan-2-ylbenzamide

[0425]

[0426] (1) Intermediate S64: Preparation of methyl 2-methyl-5-(6-methyl-2,6-diazaspiro[3,4]octan-2-yl)benzoate

[0427]

[0428] S7 (60 mg, 0.26 mmol) and S63 (111 mg, 0.31 mmol) were placed in a sealed tube, and toluene (2 mL), X-Phos (5 mg, 0.010 mmol), Cs2CO3 (424 mg, 1.30 mmol) and Pd2(dba)3 (5 mg, 0.0052 mmol) were added. N2 was bubbled for 30 s, and the temperature was raised to 110 ° C. The reaction was stirred overnight. The raw materials reacted completely and the reaction was stopped. After the reaction was completed, the reaction solution was cooled to room temperature, water (8 mL) was added, and DCM was used for extraction three times. The organic phases were combined, concentrated under reduced pressure, and purified by column chromatography (PE: EA = 1: 1-DCM: MeOH = 30: 1-20: 1-10: 1) to obtain a light yellow oil S64 (71 mg, 100%). MS: m / z [M+1] + =275.32.

[0429] (2) Preparation of intermediate S65: 2-methyl-5-(6-methyl-2,6-diazaspiro[3,4]octan-2-yl)benzoic acid

[0430]

[0431] S64 (70 mg, 0.26 mmol) was placed in a single-mouth bottle, THF (1 mL) and EtOH (1 mL) were added, and then a solution of NaOH (52 mg, 1.30 mmol) in H2O (1 mL) was added, and the temperature was raised to 60°C. The reaction was stirred for 2 h, and the raw materials were completely reacted, and the reaction was stopped. After the reaction was completed, the reaction solution was concentrated under reduced pressure to remove THF and EtOH, and the pH was adjusted to 4-5 with dilute hydrochloric acid (2.0 M). The solvent was removed by concentration under reduced pressure, and the obtained solid was dissolved in DCM, dried over anhydrous sodium sulfate, filtered, and the filter cake was washed with DCM. The filtrate was taken and concentrated under reduced pressure to obtain a light yellow solid S65 (68 mg, 100%). MS: m / z[M+1] + =261.31.

[0432] (3) P19: Preparation of 2-methyl-N-(1-(1-methyl-2-oxo-1,2-dihydrobenzo[cd]indol-6-yl)cyclopropyl)-5-(6-methyl-2,6-diazaspiro[3,4]octan-2-ylbenzamide

[0433]

[0434] S6 (20 mg, 0.084 mmol) and S65 (26 mg, 0.10 mmol) were placed in a single-mouth bottle, and DMF (1.5 mL), DIPEA (36 mg, 0.28 mmol) and HATU (43 mg, 0.11 mmol) were added. The temperature was raised to 50°C and stirred for 1.0 h. The raw materials reacted completely and the reaction was stopped. After the reaction was completed, the reaction solution was cooled to room temperature, water was added, and a yellow solid was precipitated. The mixture was stirred at room temperature for 20 minutes, filtered, and the filter cake was washed with water. The filter cake was purified by column chromatography (PE:EA=1:1-DCM:MeOH=20:1-10:1-8:1) to obtain a bright yellow solid P19 (27 mg, 67%). MS: m / z[M+1] + =481.23.

[0435] Embodiment 20

[0436] Compound P20: Preparation of 2-methyl-N-(1-(1-methyl-2-oxo-1,2-dihydrobenz[cd]indol-6-yl)cyclopropyl)-5-((1R,5S)-3-methyl-3,6-diazabicyclo[3.2.0]heptane-6-yl)benzamide

[0437]

[0438] (1) Intermediate S67: Preparation of methyl 2-methyl-5-((1S,5R)-3-methyl-3,6-diazabicyclo[3.2.0]heptane-6-yl)benzoate

[0439]

[0440] S7 (60 mg, 0.26 mmol) and S66 (105 mg, 0.31 mmol) were placed in a sealed tube, and toluene (2 mL), X-Phos (5 mg, 0.010 mmol), Cs2CO3 (424 mg, 1.30 mmol) and Pd2(dba)3 (5 mg, 0.0052 mmol) were added. N2 was bubbled for 30 s, and the temperature was raised to 110 ° C. The reaction was stirred overnight. The raw materials reacted completely and the reaction was stopped. After the reaction was completed, the reaction solution was cooled to room temperature, water (8 mL) was added, and DCM was used for extraction three times. The organic phases were combined, concentrated under reduced pressure, and purified by column chromatography (DCM: MeOH = 20: 1-10: 1) to obtain a light yellow oil S67 (67 mg, 99%). MS: m / z [M+1] + =261.32.

[0441] (2) Preparation of Intermediate S68: 2-methyl-5-((1S,5R)-3-methyl-3,6-diazabicyclo[3.2.0]heptane-6-yl)benzoic acid

[0442]

[0443] S67 (67 mg, 0.26 mmol) was placed in a single-mouth bottle, THF (1 mL) and EtOH (1 mL) were added, and then a solution of NaOH (52 mg, 1.30 mmol) in H2O (1 mL) was added, and the temperature was raised to 60°C. The reaction was stirred for 2 h, and the raw materials were completely reacted, and the reaction was stopped. After the reaction was completed, the reaction solution was concentrated under reduced pressure to remove THF and EtOH, and the pH was adjusted to 4-5 with dilute hydrochloric acid (2.0 M). The solvent was removed by concentration under reduced pressure, and the obtained solid was dissolved in DCM, dried over anhydrous sodium sulfate, filtered, and the filter cake was washed with DCM. The filtrate was taken and concentrated under reduced pressure to obtain a light yellow solid S68 (64 mg, 100%). MS: m / z[M+1] + =247.33.

[0444] (3) Preparation of P20: 2-methyl-N-(1-(1-methyl-2-oxo-1,2-dihydrobenz[cd]indol-6-yl)cyclopropyl)-5-((1R,5S)-3-methyl-3,6-diazabicyclo[3.2.0]heptane-6-yl)benzamide

[0445]

[0446] S6 (20 mg, 0.084 mmol) and S68 (25 mg, 0.10 mmol) were placed in a single-mouth bottle, and DMF (1.5 mL), DIPEA (36 mg, 0.28 mmol) and HATU (43 mg, 0.11 mmol) were added. The temperature was raised to 50°C, and the reaction was stirred for 1.0 h. The raw materials reacted completely and the reaction was stopped. After the reaction was completed, the reaction solution was cooled to room temperature, water was added, and a yellow solid was precipitated. The mixture was stirred at room temperature for 20 minutes, filtered, and the filter cake was washed with water. The filter cake was purified by column chromatography (PE: EA = 1: 1-DCM: MeOH = 20: 1-10: 1-8: 1) to obtain a bright yellow solid P20 (22 mg, 56%). MS: m / z [M+1] + =467.23.

[0447] Embodiment 21

[0448] Compound P21: Preparation of N-(1-(1-isopropyl-2-oxo-1,2-dihydrobenz[cd]indol-6-yl)cyclopropyl)-2-methyl-5-(6-methyl-3,6-diazabicyclo[3.1.1]heptane-3-yl)benzamide

[0449]

[0450] (1) P21: Preparation of N-(1-(1-isopropyl-2-oxo-1,2-dihydrobenz[cd]indol-6-yl)cyclopropyl)-2-methyl-5-(6-methyl-3,6-diazabicyclo[3.1.1]heptane-3-yl)benzamide

[0451]

[0452] P16 (20 mg, 0.042 mmol) was placed in a single-mouth bottle, MeOH (1.0 mL), formaldehyde aqueous solution (0.30 mL) and acetic acid (7 mg, 0.11 mmol) were added, and finally NaCNBH3 (4 mg, 0.063 mmol) was added. The reaction was stirred at room temperature for 2 h. The raw materials reacted completely and the reaction was stopped. After the reaction was completed, a saturated sodium bicarbonate solution (5 mL) was added to the reaction solution, and DCM was used for extraction three times. The organic phases were combined and concentrated under reduced pressure to obtain a yellow solid. The yellow solid was purified by column chromatography (PE: EA = 1: 1-DCM: MeOH = 30: 1-20: 1) to obtain a bright yellow solid P21 (14 mg, 69%). MS: m / z [M+1] + =495.35.

[0453] Embodiment 22

[0454] Compound P22: Preparation of 2-methyl-N-(1-(1-methyl-2-oxo-1,2-dihydrobenzo[cd]indol-6-yl)cyclopropyl)-5-(1-methylpiperidin-4-yl)benzamide

[0455]

[0456] (1) Preparation of P22: 2-methyl-N-(1-(1-methyl-2-oxo-1,2-dihydrobenzo[cd]indol-6-yl)cyclopropyl)-5-(1-methylpiperidin-4-yl)benzamide

[0457]

[0458] P4 (26 mg, 0.059 mmol) was placed in a single-mouth bottle, MeOH (1.0 mL), formaldehyde aqueous solution (0.50 mL) and acetic acid (9 mg, 0.15 mmol) were added, and finally NaCNBH3 (6 mg, 0.089 mmol) was added. The reaction was stirred at room temperature for 2 h. The raw materials reacted completely and the reaction was stopped. After the reaction was completed, a saturated sodium bicarbonate solution (5 mL) was added to the reaction solution, and DCM was used for extraction three times. The organic phases were combined and concentrated under reduced pressure to obtain a yellow solid. The yellow solid was purified by column chromatography (PE: EA = 1: 1-DCM: MeOH = 20: 1-10: 1) to obtain a bright yellow solid P22 (15 mg, 54%). MS: m / z [M+1] + =454.29.

[0459] Embodiment 23

[0460] Compound M23: Preparation of 2-methyl-N-(1-(1-methyl-2-oxo-1,2-dihydrobenzo[cd]indol-6-yl)cyclopropyl)-5-(3-(4-methylpiperazin-1-yl)azetidin-1-yl)benzamide

[0461]

[0462] (1) Intermediate S70: Preparation of methyl 2-methyl-5-(3-(4-methylpiperazin-1-yl)azetidin-1-yl)benzoate

[0463]

[0464] S7 (50 mg, 0.22 mmol) and S69 (60 mg, 0.26 mmol) were placed in a sealed tube, and toluene (2 mL), X-Phos (4 mg, 0.0085 mmol), Cs2CO3 (358 mg, 1.10 mmol) and Pd2(dba)3 (4 mg, 0.0044 mmol) were added. N2 was bubbled for 30 s, and the temperature was raised to 110 ° C. The reaction was stirred overnight. The raw materials reacted completely and the reaction was stopped. After the reaction was completed, the reaction solution was cooled to room temperature, water (6 mL) was added, and DCM was used for extraction three times. The organic phases were combined, concentrated under reduced pressure, and purified by column chromatography (PE: EA = 1: 1-DCM: MeOH = 20: 1) to obtain a white solid S70 (59 mg, 88%). MS: m / z [M+1] + =304.21.

[0465] (2) Preparation of Intermediate S71: 2-methyl-5-(3-(4-methylpiperazin-1-yl)azetidin-1-yl)benzoic acid

[0466]

[0467] S70 (59 mg, 0.19 mmol) was placed in a single-mouth bottle, THF (1.0 mL) and EtOH (1.0 mL) were added, followed by a solution of NaOH (39 mg, 0.97 mmol) in H2O (1.0 mL), and the temperature was raised to 60°C. The reaction was stirred for 2 h, and the raw materials reacted completely and the reaction was stopped. After the reaction was completed, the reaction solution was concentrated under reduced pressure to remove THF and EtOH, and the pH was adjusted to 4-5 with dilute hydrochloric acid (2N). The solvent was removed by concentration under reduced pressure, and the resulting solid mixture was dissolved in DCM, dried over anhydrous sodium sulfate, filtered, and the filter cake was washed with DCM. The filtrate was taken and concentrated under reduced pressure to obtain a white solid S71 (55 mg, 100%). MS: m / z[M+1] + =290.22.

[0468] (3) Preparation of P23: 2-methyl-N-(1-(1-methyl-2-oxo-1,2-dihydrobenzo[cd]indol-6-yl)cyclopropyl)-5-(3-(4-methylpiperazin-1-yl)azetidin-1-yl)benzamide

[0469]

[0470] S6 (20 mg, 0.084 mmol) and S71 (29 mg, 0.10 mmol) were placed in a single-mouth bottle, and DMF (1.5 mL), DIPEA (36 mg, 0.28 mmol) and HATU (43 mg, 0.11 mmol) were added. The temperature was raised to 50°C and stirred for 1.0 h. The raw materials reacted completely and the reaction was stopped. After the reaction was completed, the reaction solution was cooled to room temperature, water was added, and a yellow solid was precipitated. The mixture was extracted with DCM three times, and the organic phases were combined, concentrated under reduced pressure, and purified by column chromatography (PE:EA=1:1-DCM:MeOH=20:1-10:1) to obtain a bright yellow solid P23 (35 mg, 81%). MS: m / z[M+1] + =510.33.

[0471] Embodiment 24

[0472] Compound P24: Preparation of 2-methyl-N-(1-(1-methyl-2-oxo-1,2-dihydrobenzo[cd]indol-6-yl)cyclopropyl)-5-(3-(piperidin-1-yl)azetidin-1-yl)benzamide

[0473]

[0474] (1) Intermediate S73: Preparation of methyl 2-methyl-5-(3-(piperidin-1-yl)azetidin-1-yl)benzoate

[0475]

[0476] S7 (60 mg, 0.26 mmol) and S72 (66 mg, 0.31 mmol) were placed in a sealed tube, and toluene (2 mL), X-Phos (5 mg, 0.010 mmol), Cs2CO3 (424 mg, 1.30 mmol) and Pd2(dba)3 (5 mg, 0.0052 mmol) were added. N2 was bubbled for 30 s, and the temperature was raised to 110 ° C. The reaction was stirred overnight. The raw materials reacted completely and the reaction was stopped. After the reaction was completed, the reaction solution was cooled to room temperature, water (6 mL) was added, and DCM was extracted three times. The organic phases were combined, concentrated under reduced pressure and desolventized, and then purified by column chromatography (PE: EA = 4: 1-3: 1) to obtain a colorless oil S73 (53 mg, 71%). MS: m / z [M+1] + =289.21.

[0477] (2) Preparation of Intermediate S74: 2-methyl-5-(3-(piperidin-1-yl)azetidin-1-yl)benzoic acid

[0478]

[0479] S73 (53 mg, 0.18 mmol) was placed in a single-mouth bottle, THF (1.0 mL) and EtOH (1.0 mL) were added, followed by a solution of NaOH (37 mg, 0.92 mmol) in H2O (1.0 mL), and the temperature was raised to 60°C. The reaction was stirred for 2 h, and the raw materials reacted completely and the reaction was stopped. After the reaction was completed, the reaction solution was concentrated under reduced pressure to remove THF and EtOH, and the pH was adjusted to 4-5 with dilute hydrochloric acid (2N). The solvent was removed by concentration under reduced pressure, and the resulting solid mixture was dissolved in DCM, dried over anhydrous sodium sulfate, filtered, and the filter cake was washed with DCM. The filtrate was taken and concentrated under reduced pressure to obtain a white solid S74 (49 mg, 100%). MS: m / z[M+1] + =275.26.

[0480] (3) P24: Preparation of 2-methyl-N-(1-(1-methyl-2-oxo-1,2-dihydrobenzo[cd]indol-6-yl)cyclopropyl)-5-(3-(piperidin-1-yl)azetidin-1-yl)benzamide

[0481]

[0482] S6 (20 mg, 0.084 mmol) and S74 (27 mg, 0.10 mmol) were placed in a single-mouth bottle, and DMF (1.5 mL), DIPEA (36 mg, 0.28 mmol) and HATU (43 mg, 0.11 mmol) were added. The temperature was raised to 50°C and stirred for 1.0 h. The raw materials reacted completely and the reaction was stopped. After the reaction was completed, the reaction solution was cooled to room temperature, water was added, and a yellow solid was precipitated. The mixture was extracted with DCM three times, and the organic phases were combined, concentrated under reduced pressure, and purified by column chromatography (PE:EA=1:1-DCM:MeOH=20:1) to obtain a bright yellow solid P24 (28 mg, 67%). MS: m / z[M+1] + =495.32.

[0483] Embodiment 25

[0484] Compound P25: Preparation of (R)-5-(hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl)-2-methyl-N-(1-(1-methyl-2-oxo-1,2-dihydrobenzo[cd]indol-6-yl)cyclopropyl)benzamide

[0485]

[0486] (1) Intermediate S76: Preparation of (S)-methyl 5-(hexahydropyrrolo[1,2-a]pyrazine-2(1H)-yl)-2-methylbenzoate

[0487]

[0488] S7 (60 mg, 0.26 mmol) and S75 (62 mg, 0.31 mmol) were placed in a sealed tube, and toluene (2 mL), X-Phos (5 mg, 0.010 mmol), Cs2CO3 (424 mg, 1.30 mmol) and Pd2(dba)3 (5 mg, 0.0052 mmol) were added. N2 was bubbled for 30 s, and the temperature was raised to 110 ° C. The reaction was stirred overnight. The raw materials reacted completely and the reaction was stopped. After the reaction was completed, the reaction solution was cooled to room temperature, water (6 mL) was added, and DCM was extracted three times. The organic phases were combined, concentrated under reduced pressure, and then purified by column chromatography (PE: EA = 1: 1-1: 3) to obtain a white solid S76 (65 mg, 92%). MS: m / z [M+1] + =275.21.

[0489] (2) Intermediate S77: Preparation of (S)-5-(hexahydropyrrolo[1,2-a]pyrazine-2(1H)-yl)-2-methylbenzoic acid

[0490]

[0491] S76 (65 mg, 0.24 mmol) was placed in a single-mouth bottle, THF (1.0 mL) and EtOH (1.0 mL) were added, followed by a solution of NaOH (48 mg, 1.20 mmol) in H2O (1.0 mL), and the temperature was raised to 60°C. The reaction was stirred for 2 h, and the raw materials reacted completely and the reaction was stopped. After the reaction was completed, the reaction solution was concentrated under reduced pressure to remove THF and EtOH, and the pH was adjusted to 4-5 with dilute hydrochloric acid (2N). The solvent was removed by concentration under reduced pressure, and the resulting solid mixture was dissolved in DCM, dried over anhydrous sodium sulfate, filtered, and the filter cake was washed with DCM. The filtrate was taken and concentrated under reduced pressure to obtain a white solid S77 (62 mg, 100%). MS: m / z[M+1] + =261.26.

[0492] (3) P25: Preparation of (R)-5-(hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl)-2-methyl-N-(1-(1-methyl-2-oxo-1,2-dihydrobenzo[cd]indol-6-yl)cyclopropyl)benzamide

[0493]

[0494] S6 (20 mg, 0.084 mmol) and S77 (26 mg, 0.10 mmol) were placed in a single-mouth bottle, and DMF (1.5 mL), DIPEA (36 mg, 0.28 mmol) and HATU (43 mg, 0.11 mmol) were added. The temperature was raised to 50°C and stirred for 1.0 h. The raw materials reacted completely and the reaction was stopped. After the reaction was completed, the reaction solution was cooled to room temperature, water was added, and a yellow solid was precipitated. The mixture was extracted with DCM three times, and the organic phases were combined, concentrated under reduced pressure, and purified by column chromatography (PE:EA=1:1-DCM:MeOH=20:1) to obtain a bright yellow solid P25 (16 mg, 40%). MS: m / z[M+1] + =481.32.

[0495] Embodiment 26

[0496] Compound P26: Preparation of 5-(3-(4-fluoropiperidin-1-yl)azetidin-1-yl)-2-methyl-N-(1-(1-methyl-2-oxo-1,2-dihydrobenzo[cd]indol-6-yl)cyclopropyl)benzamide

[0497]

[0498] (1) Preparation of intermediate S79: methyl 5-(3-(4-fluoropiperidin-1-yl)azetidin-1-yl)-2-methylbenzoate

[0499]

[0500] S7 (60 mg, 0.26 mmol) and S78 (72 mg, 0.31 mmol) were placed in a sealed tube, toluene (2 mL), X-Phos (5 mg, 0.010 mmol), Cs2CO3 (424 mg, 1.30 mmol) and Pd2(dba)3 (5 mg, 0.0052 mmol) were added, N2 was bubbled for 30 s, the temperature was raised to 110 ° C, the reaction was stirred overnight, and the raw materials were completely reacted, and the reaction was stopped. After the reaction was completed, the reaction solution was cooled to room temperature, water (6 mL) was added, and DCM was extracted three times. The organic phases were combined, concentrated under reduced pressure and desolventized, and then purified by column chromatography (PE: EA = 5: 1-3: 1) to obtain a white solid S79 (72 mg, 90%). MS: m / z [M+1] + =307.21.

[0501] (2) Preparation of Intermediate S80: 5-(3-(4-fluoropiperidin-1-yl)azetidin-1-yl)-2-methylbenzoic acid

[0502]

[0503] S79 (72 mg, 0.23 mmol) was placed in a single-mouth bottle, THF (1.0 mL) and EtOH (1.0 mL) were added, followed by a solution of NaOH (46 mg, 1.15 mmol) in H2O (1.0 mL), and the temperature was raised to 60°C. The reaction was stirred for 2 h, and the raw materials reacted completely and the reaction was stopped. After the reaction was completed, the reaction solution was concentrated under reduced pressure to remove THF and EtOH, and the pH was adjusted to 4-5 with dilute hydrochloric acid (2N). The solvent was removed by concentration under reduced pressure, and the resulting solid mixture was dissolved in DCM, dried over anhydrous sodium sulfate, filtered, and the filter cake was washed with DCM. The filtrate was taken and concentrated under reduced pressure to obtain a white solid S80 (67 mg, 100%). MS: m / z[M+1] + =293.26.

[0504] (3) Preparation of P26: 5-(3-(4-fluoropiperidin-1-yl)azetidin-1-yl)-2-methyl-N-(1-(1-methyl-2-oxo-1,2-dihydrobenzo[cd]indol-6-yl)cyclopropyl)benzamide

[0505]

[0506] S6 (20 mg, 0.084 mmol) and S80 (29 mg, 0.10 mmol) were placed in a single-mouth bottle, and DMF (1.5 mL), DIPEA (36 mg, 0.28 mmol) and HATU (43 mg, 0.11 mmol) were added. The temperature was raised to 50°C and stirred for 1.0 h. The raw materials reacted completely and the reaction was stopped. After the reaction was completed, the reaction solution was cooled to room temperature, water was added, and a yellow solid was precipitated. The mixture was extracted three times with DCM, and the organic phases were combined, concentrated under reduced pressure, and purified by column chromatography (PE:EA=3:1-1:1-1:2) to obtain a bright yellow solid P26 (27 mg, 63%). MS: m / z[M+1] + =513.32.

[0507] Embodiment 27

[0508] Compound P27: Preparation of N-(1-(1-ethyl-2-oxo-1,2-dihydrobenzo[cd]indol-6-yl)cyclopropyl)-2-methyl-5-(4-methylpiperazin-1-yl)benzamide

[0509]

[0510] (1) Preparation of Intermediate S81: 6-bromo-1-ethylbenzo[cd]indol-2(1H)-one

[0511]

[0512] Place S2 (1000 mg, 4.02 mmol) in a single-mouth bottle, add DMF (10 mL), cool to 0 ° C, slowly add NaH (241 mg, 6.03 mmol, 60% dispersed in mineral oil), and stir to react for 0.5 h. Add EtI (753 mg, 4.82 mmol), heat to 60 ° C, and stir to react overnight. Add water (50 mL) to the reaction solution, extract with EA three times, combine the organic phases, concentrate under reduced pressure, and purify by column chromatography (PE: EA = 20: 1) to obtain a yellow solid S81 (1000 mg, 90%). MS: m / z [M+1] + =277.21.

[0513] (2) Intermediate S82: Preparation of 1-(1-ethyl-2-oxo-1,2-dihydrobenzo[cd]indol-6-yl)cyclopropyl-1-carbonitrile

[0514]

[0515] S81 (1000 mg, 3.60 mmol) and cyclopropylcarbonitrile (364 mg, 5.40 mmol) were placed in a three-necked flask, THF (15 mL), CPME (15 mL), Pd2(dba)3 (165 mg, 0.18 mmol) and Nixantphos (198 mg, 0.36 mmol) were added, nitrogen was bubbled for 30 s, stirred at room temperature for 0.5 h, and LiHMDS (7.2 mL, 7.20 mmol, 1 M in tetrahydrofuran) was added dropwise. After the addition, the temperature was raised to 60 ° C and stirred for 1 h. The raw material reacted completely and the reaction was stopped. The reaction was cooled to room temperature, saturated ammonium chloride solution (50 mL) was added, and EA was extracted three times. The organic phases were combined, concentrated under reduced pressure, and purified by column chromatography (PE:EA=5:1-3:1-2:1) to obtain orange-yellow solid S82 (360 mg, 38%). MS: m / z[M+1] + =263.26.

[0516] (3) Preparation of Intermediate S83: 1-(1-ethyl-2-oxo-1,2-dihydrobenzo[cd]indol-6-yl)cyclopropyl-1-carboxamide

[0517]

[0518] S82 (360 mg, 1.38 mmol) was placed in a single-mouth bottle, DMSO (4 mL) and K2CO3 (95 mg, 0.69 mmol) were added, the temperature was lowered to 0°C, H2O2 (170 μL, 2.07 mmol) was slowly added dropwise, the temperature was raised to room temperature and stirred for 1.5 h, the raw material was completely reacted, and the reaction was stopped. After the reaction was completed, water was added to the reaction solution to precipitate a yellow solid, and the mixture was stirred at room temperature for 20 min. Filter, wash the filter cake with water, and purify the filter cake by column chromatography (PE: EA = 1: 1-DCM: MeOH = 30: 1) to obtain a yellow solid S83 (137 mg, 35%). MS: m / z [M+1] + =281.26.

[0519] (4) Preparation of Intermediate S84: 6-(1-aminocyclopropyl)-1-ethylbenz[cd]indol-2(1H)-one

[0520]

[0521] S83 (137 mg, 0.49 mmol) was placed in a single-mouth bottle, t-BuOH (4 mL) was added, the temperature was lowered to 0°C, NaClO (0.83 mL, 1.37 mmol) and NaOH (3N, 0.45 mL, 1.37 mmol) solution were added, the temperature was raised to room temperature, and the reaction was stirred for 3 h. The raw materials reacted completely and the reaction was stopped. After the reaction was completed, the reaction solution was concentrated under reduced pressure to remove the solvent, and the obtained solid mixture was purified by column chromatography (PE: EA = 1: 1-DCM: MeOH = 30: 1) to obtain yellow solid S84 (98 mg, 79%). MS: m / z [M+1] + =281.26.

[0522] (5) P27: Preparation of N-(1-(1-ethyl-2-oxo-1,2-dihydrobenzo[cd]indol-6-yl)cyclopropyl)-2-methyl-5-(4-methylpiperazin-1-yl)benzamide

[0523]

[0524] S84 (20 mg, 0.079 mmol) and S10 (22 mg, 0.094 mmol) were placed in a single-mouth bottle, and DMF (1.5 mL), DIPEA (36 mg, 0.28 mmol) and HATU (43 mg, 0.11 mmol) were added. The temperature was raised to 50°C and stirred for 1.0 h. The raw materials reacted completely and the reaction was stopped. After the reaction was completed, the reaction solution was cooled to room temperature, water was added, and a yellow solid was precipitated. The mixture was extracted with DCM three times, and the organic phases were combined, concentrated under reduced pressure, and purified by column chromatography (PE:EA=1:1-DCM:MeOH=20:1-10:1) to obtain a bright yellow solid P27 (8 mg, 22%). MS: m / z[M+1] + =469.32.

[0525] Embodiment 28

[0526] Compound P28: Preparation of N-(1-(1-ethyl-2-oxo-1,2-dihydrobenzo[cd]indol-6-yl)cyclopropyl)-5-(3-(4-hydroxy-4-methylpiperidin-1-yl)azetidin-1-yl)-2-methyl-benzamide

[0527]

[0528] (1) P28: Preparation of N-(1-(1-ethyl-2-oxo-1,2-dihydrobenzo[cd]indol-6-yl)cyclopropyl)-5-(3-(4-hydroxy-4-methylpiperidin-1-yl)azetidin-1-yl)-2-methyl-benzamide

[0529]

[0530] S84 (20 mg, 0.079 mmol) and S59 (29 mg, 0.094 mmol) were placed in a single-mouth bottle, and DMF (1.5 mL), DIPEA (34 mg, 0.26 mmol) and HATU (39 mg, 0.10 mmol) were added. The temperature was raised to 50°C and stirred for 1.0 h. The raw materials reacted completely and the reaction was stopped. After the reaction was completed, the reaction solution was cooled to room temperature, water was added, and a yellow solid was precipitated. The mixture was extracted with DCM three times, and the organic phases were combined, concentrated under reduced pressure, and purified by column chromatography (PE:EA=1:1-DCM:MeOH=20:1-10:1) to obtain a bright yellow solid P28 (16 mg, 38%). MS: m / z[M+1] + =539.32.

[0531] Embodiment 29

[0532] Compound P29: Preparation of N-(1-(1-ethyl-2-oxo-1,2-dihydrobenzo[cd]indol-6-yl)cyclopropyl)-5-(3-(4-hydroxy-4-methylpiperidin-1-yl)azetidin-1-yl)-2-methyl-benzamide

[0533]

[0534] (1) Preparation of intermediate S85: tert-butyl 3-(3-((1-(1-ethyl-2-oxo-1,2-dihydrobenzo[cd]indol-6-yl)cyclopropyl)carbamoyl-4-methylphenyl)-3,6-diazabicyclo[3.1.1]heptane-6-carboxylate

[0535]

[0536] S84 (20 mg, 0.079 mmol) and S25 (32 mg, 0.095 mmol) were placed in a single-mouth bottle, and DMF (1.5 mL), DIPEA (34 mg, 0.26 mmol) and HATU (39 mg, 0.10 mmol) were added. The temperature was raised to 50°C and stirred for 1.0 h. The raw materials reacted completely and the reaction was stopped. After the reaction was completed, the reaction solution was cooled to room temperature, water was added, and a yellow solid was precipitated. The mixture was extracted three times with DCM, and the organic phases were combined, concentrated under reduced pressure, and purified by column chromatography (PE:EA=3:1-1:1-1:2) to obtain a yellow solid S85 (27 mg, 60%). MS: m / z[M+1] + =567.32.

[0537] (2) P29: Preparation of N-(1-(1-ethyl-2-oxo-1,2-dihydrobenzo[cd]indol-6-yl)cyclopropyl)-5-(3-(4-hydroxy-4-methylpiperidin-1-yl)azetidin-1-yl)-2-methyl-benzamide

[0538]

[0539] S85 (27 mg, 0.048 mmol) was placed in a single-mouth bottle, and DCM (2.0 mL) and hydrochloric acid (1.0 mL, 4.0 M in 1,4-dioxane) were added. The reaction was stirred at room temperature for 1.0 h. The raw material reacted completely and the reaction was stopped. After the reaction was completed, the solvent was removed by concentration under reduced pressure to obtain a yellow solid mixture. Saturated sodium bicarbonate solution (4 mL) was added to the obtained mixture, and extracted three times with DCM. The organic phase was concentrated under reduced pressure and purified by column chromatography (DCM: MeOH = 20: 1-10: 1-8: 1) to obtain a bright yellow solid P29 (15 mg, 70%). MS: m / z [M+1] + =467.32.

[0540] Embodiment 30

[0541] Compound P30: Preparation of 5-(3-(3-fluoropyrrolidin-1-yl)azetidin-1-yl)-2-methyl-N-(1-(1-methyl-2-oxo-1,2-dihydrobenzo[cd]indol-6-yl)cyclopropyl)benzamide

[0542]

[0543] (1) Preparation of intermediate S87: methyl 5-(3-(3-fluoropyrrolidin-1-yl)azetidin-1-yl)-2-methylbenzoate

[0544]

[0545] S7 (60 mg, 0.26 mmol) and S86 (67 mg, 0.31 mmol) were placed in a sealed tube, and toluene (2 mL), X-Phos (5 mg, 0.010 mmol), Cs2CO3 (424 mg, 1.30 mmol) and Pd2(dba)3 (5 mg, 0.0052 mmol) were added. N2 was bubbled for 30 s, and the temperature was raised to 110 ° C. The reaction was stirred overnight. The raw materials reacted completely and the reaction was stopped. After the reaction was completed, the reaction solution was cooled to room temperature, water (6 mL) was added, and DCM was extracted three times. The organic phases were combined, concentrated under reduced pressure, and then purified by column chromatography (PE: EA = 5: 1-3: 1) to obtain a white solid S87 (70 mg, 92%). MS: m / z [M+1] + =293.21.

[0546] (2) Preparation of Intermediate S88: 5-(3-(3-fluoropyrrolidin-1-yl)azetidin-1-yl)-2-methylbenzoic acid

[0547]

[0548] S87 (70 mg, 0.24 mmol) was placed in a single-mouth bottle, THF (1.0 mL) and EtOH (1.0 mL) were added, followed by a solution of NaOH (48 mg, 1.20 mmol) in H2O (1.0 mL), and the temperature was raised to 60°C. The reaction was stirred for 2 h, and the raw materials reacted completely and the reaction was stopped. After the reaction was completed, the reaction solution was concentrated under reduced pressure to remove THF and EtOH, and the pH was adjusted to 4-5 with dilute hydrochloric acid (2N). The solvent was removed by concentration under reduced pressure, and the resulting solid mixture was dissolved in DCM, dried over anhydrous sodium sulfate, filtered, and the filter cake was washed with DCM. The filtrate was taken and concentrated under reduced pressure to obtain a white solid S88 (67 mg, 100%). MS: m / z[M+1] + =279.26.

[0549] (3) Preparation of P30: 5-(3-(3-fluoropyrrolidin-1-yl)azetidin-1-yl)-2-methyl-N-(1-(1-methyl-2-oxo-1,2-dihydrobenzo[cd]indol-6-yl)cyclopropyl)benzamide

[0550]

[0551] S6 (20 mg, 0.084 mmol) and S88 (28 mg, 0.10 mmol) were placed in a single-mouth bottle, and DMF (1.5 mL), DIPEA (36 mg, 0.28 mmol) and HATU (43 mg, 0.11 mmol) were added. The temperature was raised to 50°C and stirred for 1.0 h. The raw materials reacted completely and the reaction was stopped. After the reaction was completed, the reaction solution was cooled to room temperature, water was added, and a yellow solid was precipitated. The mixture was extracted three times with DCM, and the organic phases were combined, concentrated under reduced pressure, and purified by column chromatography (PE:EA=3:1-1:1-1:2) to obtain a bright yellow solid P30 (31 mg, 75%). MS: m / z[M+1] + =499.32.

[0552] Embodiment 31

[0553] Compound P31: Preparation of 5-(3-(4,4-difluoropiperidin-1-yl)azetidin-1-yl)-2-methyl-N-(1-(1-methyl-2-oxo-1,2-dihydrobenzo[cd]indol-6-yl)cyclopropyl)benzamide

[0554]

[0555] (1) Preparation of intermediate S90: methyl 5-(3-(4,4-difluoropiperidin-1-yl)azetidin-1-yl)-2-methylbenzoate

[0556]

[0557] S7 (54 mg, 0.24 mmol) and S89 (50 mg, 0.24 mmol) were placed in a sealed tube, and dioxane (2 mL), X-Phos (4 mg, 0.0094 mmol), Cs2CO3 (383 mg, 1.17 mmol) and Pd2(dba)3 (4 mg, 0.0047 mmol) were added. N2 was bubbled for 30 s, and the temperature was raised to 90 ° C. The reaction was stirred overnight. The raw materials reacted completely and the reaction was stopped. After the reaction was completed, the reaction solution was cooled to room temperature, water (6 mL) was added, and DCM was extracted three times. The organic phases were combined, concentrated under reduced pressure and desolventized, and then purified by column chromatography (PE: EA = 5: 1-3: 1) to obtain a white solid S90 (58 mg, 76%). MS: m / z [M+1] + =325.21.

[0558] (2) Preparation of Intermediate S91: 5-(3-(4,4-difluoropiperidin-1-yl)azetidin-1-yl)-2-methylbenzoic acid

[0559]

[0560] S90 (58 mg, 0.18 mmol) was placed in a single-mouth bottle, THF (1.0 mL) and EtOH (1.0 mL) were added, followed by a solution of NaOH (36 mg, 0.90 mmol) in H2O (1.0 mL), and the temperature was raised to 60°C. The reaction was stirred for 2 h, and the raw materials reacted completely and the reaction was stopped. After the reaction was completed, the reaction solution was concentrated under reduced pressure to remove THF and EtOH, and the pH was adjusted to 4-5 with dilute hydrochloric acid (2N). The solvent was removed by concentration under reduced pressure, and the resulting solid mixture was dissolved in DCM, dried over anhydrous sodium sulfate, filtered, and the filter cake was washed with DCM. The filtrate was taken and concentrated under reduced pressure to obtain a white solid S91 (56 mg, 100%). MS: m / z[M+1] + =311.26.

[0561] (3) P31: Preparation of 5-(3-(4,4-difluoropiperidin-1-yl)azetidin-1-yl)-2-methyl-N-(1-(1-methyl-2-oxo-1,2-dihydrobenzo[cd]indol-6-yl)cyclopropyl)benzamide

[0562]

[0563] S6 (18 mg, 0.075 mmol) and S91 (28 mg, 0.090 mmol) were placed in a single-mouth bottle, and DMF (1.5 mL), DIPEA (32 mg, 0.25 mmol) and HATU (37 mg, 0.098 mmol) were added. The temperature was raised to 50°C and stirred for 1.0 h. The raw materials reacted completely and the reaction was stopped. After the reaction was completed, the reaction solution was cooled to room temperature, water was added, and a yellow solid was precipitated. The mixture was extracted three times with DCM, and the organic phases were combined, concentrated under reduced pressure, and purified by column chromatography (PE:EA=3:1-1:1-1:2) to obtain a bright yellow solid P31 (22 mg, 55%). MS: m / z[M+1] + =531.32.

[0564] Embodiment 32

[0565] Compound P32: Preparation of 5-(3-(4-hydroxypiperidin-1-yl)azetidin-1-yl)-2-methyl-N-(1-(1-methyl-2-oxo-1,2-dihydrobenzo[cd]indol-6-yl)cyclopropyl)benzamide

[0566]

[0567] (1) Preparation of intermediate S93: methyl 5-(3-(4-hydroxypiperidin-1-yl)azetidin-1-yl)-2-methylbenzoate

[0568]

[0569] S7 (50 mg, 0.22 mmol) and S92 (50 mg, 0.22 mmol) were placed in a sealed tube, and dioxane (2 mL), X-Phos (4 mg, 0.0088 mmol), Cs2CO3 (355 mg, 1.09 mmol) and Pd2(dba)3 (4 mg, 0.0044 mmol) were added. N2 was bubbled for 30 s, and the temperature was raised to 90 ° C. The reaction was stirred overnight. The raw materials reacted completely and the reaction was stopped. After the reaction was completed, the reaction solution was cooled to room temperature, saturated ammonium chloride solution (6 mL) was added, and DCM was used for extraction three times. The organic phases were combined, concentrated under reduced pressure, and then purified by column chromatography (PE: EA = 3: 1-1: 1) to obtain a colorless oil S93 (69 mg, 100%). MS: m / z [M+1] + =305.21.

[0570] (2) Preparation of Intermediate S94: 5-(3-(4-hydroxypiperidin-1-yl)azetidin-1-yl)-2-methylbenzoic acid

[0571]

[0572] S93 (69 mg, 0.22 mmol) was placed in a single-mouth bottle, THF (1.0 mL) and EtOH (1.0 mL) were added, followed by a solution of NaOH (45 mg, 1.13 mmol) in H2O (1.0 mL), and the temperature was raised to 60°C. The reaction was stirred for 2 h, and the raw materials reacted completely and the reaction was stopped. After the reaction was completed, the reaction solution was concentrated under reduced pressure to remove THF and EtOH, and the pH was adjusted to 4-5 with dilute hydrochloric acid (2N). The solvent was removed by concentration under reduced pressure, and the resulting solid mixture was dissolved in DCM, dried over anhydrous sodium sulfate, filtered, and the filter cake was washed with DCM. The filtrate was taken and concentrated under reduced pressure to obtain a light yellow solid S94 (63 mg, 100%). MS: m / z[M+1] + =291.26.

[0573] (3) P32: Preparation of 5-(3-(4-hydroxypiperidin-1-yl)azetidin-1-yl)-2-methyl-N-(1-(1-methyl-2-oxo-1,2-dihydrobenzo[cd]indol-6-yl)cyclopropyl)benzamide

[0574]

[0575] S6 (13 mg, 0.054 mmol) and S94 (19 mg, 0.065 mmol) were placed in a single-mouth bottle, and DMF (1.5 mL), DIPEA (23 mg, 0.18 mmol) and HATU (27 mg, 0.070 mmol) were added. The temperature was raised to 50°C and stirred for 1.0 h. The raw materials reacted completely and the reaction was stopped. After the reaction was completed, the reaction solution was cooled to room temperature, water was added, and a yellow solid was precipitated. The mixture was extracted with DCM three times, and the organic phases were combined, concentrated under reduced pressure, and purified by column chromatography (PE:EA=1:1-DCM:MeOH=20:1-10:1) to obtain a bright yellow solid P32 (10 mg, 37%). MS: m / z[M+1] + =511.32.

[0576] Embodiment 33

[0577] Compound P33: Preparation of 5-(3-(2,2-dimethylmorpholino)azetidin-1-yl)-2-methyl-N-(1-(1-methyl-2-oxo-1,2-dihydrobenz[cd]indol-6-yl)cyclopropyl)benzamide

[0578]

[0579] (1) Preparation of intermediate S96: methyl 5-(3-(2,2-dimethylmorpholino)azetidin-1-yl)-2-methylbenzoate

[0580]

[0581] S7 (29 mg, 0.13 mmol) and S95 (50 mg, 0.13 mmol) were placed in a sealed tube, and dioxane (2 mL), X-Phos (2 mg, 0.0050 mmol), Cs2CO3 (205 mg, 0.63 mmol) and Pd2(dba)3 (2 mg, 0.0025 mmol) were added. N2 was bubbled for 30 s, and the temperature was raised to 90 ° C. The reaction was stirred overnight. The raw materials reacted completely and the reaction was stopped. After the reaction was completed, the reaction solution was cooled to room temperature, water (6 mL) was added, and DCM was extracted three times. The organic phases were combined, concentrated under reduced pressure, and then purified by column chromatography (PE: EA = 3: 1-1: 1) to obtain a light yellow oil S96 (35 mg, 87%). MS: m / z [M+1] + =319.21.

[0582] (2) Preparation of Intermediate S97: 5-(3-(2,2-dimethylmorpholino)azetidin-1-yl)-2-methylbenzoic acid

[0583]

[0584] S96 (35 mg, 0.11 mmol) was placed in a single-mouth bottle, THF (1.0 mL) and EtOH (1.0 mL) were added, followed by a solution of NaOH (22 mg, 0.55 mmol) in H2O (1.0 mL), and the temperature was raised to 60°C. The reaction was stirred for 2 h, and the raw materials reacted completely and the reaction was stopped. After the reaction was completed, the reaction solution was concentrated under reduced pressure to remove THF and EtOH, and the pH was adjusted to 4-5 with dilute hydrochloric acid (2N). The solvent was removed by concentration under reduced pressure, and the resulting solid mixture was dissolved in DCM, dried over anhydrous sodium sulfate, filtered, and the filter cake was washed with DCM. The filtrate was taken and concentrated under reduced pressure to obtain a light yellow solid S97 (30 mg, 89%). MS: m / z[M+1] + =305.26.

[0585] (3) P33: Preparation of 5-(3-(2,2-dimethylmorpholino)azetidin-1-yl)-2-methyl-N-(1-(1-methyl-2-oxo-1,2-dihydrobenz[cd]indol-6-yl)cyclopropyl)benzamide

[0586]

[0587] S6 (20 mg, 0.082 mmol) and S97 (30 mg, 0.098 mmol) were placed in a single-mouth bottle, and DMF (1.5 mL), DIPEA (35 mg, 0.27 mmol) and HATU (41 mg, 0.11 mmol) were added. The temperature was raised to 50°C and stirred for 1.0 h. The raw materials reacted completely and the reaction was stopped. After the reaction was completed, the reaction solution was cooled to room temperature, water was added, and a yellow solid was precipitated. The mixture was extracted with DCM three times, and the organic phases were combined, concentrated under reduced pressure, and purified by column chromatography (PE:EA=1:1-DCM:MeOH=20:1-10:1) to obtain a bright yellow solid P33 (16 mg, 37%). MS: m / z[M+1] + =525.32.

[0588] Embodiment 34

[0589] Compound P34: Preparation of 2-methyl-N-(1-(1-methyl-2-oxo-1,2-dihydrobenz[cd]indol-6-yl)cyclopropyl)-5-(3-(2-methylpiperidin-1-yl)azetidin-1-yl)benzamide

[0590]

[0591] (1) Preparation of intermediate S99: methyl 2-methyl-5-(3-(2-methylpiperidin-1-yl)azetidin-1-yl)benzoate

[0592]

[0593] S7 (74 mg, 0.32 mmol) and S98 (50 mg, 0.32 mmol) were placed in a sealed tube, and dioxane (2 mL), X-Phos (6 mg, 0.013 mmol), Cs2CO3 (317 mg, 0.97 mmol) and Pd2(dba)3 (6 mg, 0.0065 mmol) were added. N2 was bubbled for 30 s, and the temperature was raised to 90 ° C. The reaction was stirred overnight. The raw materials reacted completely and the reaction was stopped. After the reaction was completed, the reaction solution was cooled to room temperature, water (6 mL) was added, and DCM was extracted three times. The organic phases were combined, concentrated under reduced pressure and desolventized, and then purified by column chromatography (PE: EA = 1: 1-DCM: MeOH = 20: 1) to obtain a light yellow oil S99 (96 mg, 97%). MS: m / z [M+1] + =303.21.

[0594] (2) Preparation of intermediate S100: 2-methyl-5-(3-(2-methylpiperidin-1-yl)azetidin-1-yl)benzoic acid

[0595]

[0596] S99 (96 mg, 0.32 mmol) was placed in a single-mouth bottle, THF (1.0 mL) and EtOH (1.0 mL) were added, followed by a solution of NaOH (63 mg, 1.58 mmol) in H2O (1.0 mL), and the temperature was raised to 60°C. The reaction was stirred for 2 h, and the raw materials reacted completely and the reaction was stopped. After the reaction was completed, the reaction solution was concentrated under reduced pressure to remove THF and EtOH, and the pH was adjusted to 4-5 with dilute hydrochloric acid (2N). The solvent was removed by concentration under reduced pressure, and the resulting solid mixture was dissolved in DCM, dried over anhydrous sodium sulfate, filtered, and the filter cake was washed with DCM. The filtrate was taken and concentrated under reduced pressure to obtain a light yellow solid S100 (88 mg, 96%). MS: m / z[M+1] + =289.26.

[0597] (3) P34: Preparation of 2-methyl-N-(1-(1-methyl-2-oxo-1,2-dihydrobenz[cd]indol-6-yl)cyclopropyl)-5-(3-(2-methylpiperidin-1-yl)azetidin-1-yl)benzamide

[0598]

[0599] S6 (15 mg, 0.063 mmol) and S100 (22 mg, 0.075 mmol) were placed in a single-mouth bottle, and DMF (1.5 mL), DIPEA (27 mg, 0.21 mmol) and HATU (31 mg, 0.082 mmol) were added. The temperature was raised to 50°C and stirred for 1.0 h. The raw materials reacted completely and the reaction was stopped. After the reaction was completed, the reaction solution was cooled to room temperature, water was added, and a yellow solid was precipitated. The mixture was extracted with DCM three times, and the organic phases were combined, concentrated under reduced pressure, and purified by column chromatography (PE:EA=1:1-DCM:MeOH=20:1-10:1) to obtain a bright yellow solid P34 (18 mg, 56%). MS: m / z[M+1] + =509.32.

[0600] Embodiment 35

[0601] Compound P35: Preparation of 5-(3-(1,1-dioxothiomorpholino)azetidin-1-yl)-2-methyl-N-(1-(1-methyl-2-oxo-1,2-dihydrobenz[cd]indol-6-yl)cyclopropyl)benzamide

[0602]

[0603] (1) Preparation of intermediate S102: 5-(3-(1,1-dioxothiomorpholino)azetidin-1-yl)-2-methylbenzoic acid methyl ester

[0604]

[0605] S7 (44 mg, 0.19 mmol) and S101 (50 mg, 0.19 mmol) were placed in a sealed tube, and dioxane (2 mL), X-Phos (4 mg, 0.0076 mmol), Cs2CO3 (310 mg, 0.95 mmol) and Pd2(dba)3 (3 mg, 0.0038 mmol) were added. N2 was bubbled for 30 s, and the temperature was raised to 90 ° C. The reaction was stirred overnight. The raw materials reacted completely and the reaction was stopped. After the reaction was completed, the reaction solution was cooled to room temperature, water (6 mL) was added, and DCM was extracted three times. The organic phases were combined, concentrated under reduced pressure, and then purified by column chromatography (PE: EA = 1: 1-DCM: MeOH = 20: 1) to obtain a light yellow solid S102 (60 mg, 93%). MS: m / z [M+1] + =339.21.

[0606] (2) Preparation of intermediate S103: 5-(3-(1,1-dioxothiomorpholino)azetidin-1-yl)-2-methylbenzoic acid

[0607]

[0608] S102 (60 mg, 0.18 mmol) was placed in a single-mouth bottle, THF (1.0 mL) and EtOH (1.0 mL) were added, followed by a solution of NaOH (35 mg, 0.89 mmol) in H2O (1.0 mL), and the temperature was raised to 60°C. The reaction was stirred for 2 h, and the raw materials reacted completely and the reaction was stopped. After the reaction was completed, the reaction solution was concentrated under reduced pressure to remove THF and EtOH, and the pH was adjusted to 4-5 with dilute hydrochloric acid (2N). The solvent was removed by concentration under reduced pressure, and the resulting solid mixture was dissolved in DCM, dried over anhydrous sodium sulfate, filtered, and the filter cake was washed with DCM. The filtrate was taken and concentrated under reduced pressure to obtain a light yellow solid S103 (41 mg, 71%). MS: m / z[M+1] + =325.26.

[0609] (3) P35: Preparation of 5-(3-(1,1-dioxothiomorpholino)azetidin-1-yl)-2-methyl-N-(1-(1-methyl-2-oxo-1,2-dihydrobenz[cd]indol-6-yl)cyclopropyl)benzamide

[0610]

[0611] S6 (15 mg, 0.063 mmol) and S103 (24 mg, 0.075 mmol) were placed in a single-mouth bottle, and DMF (1.5 mL), DIPEA (27 mg, 0.21 mmol) and HATU (31 mg, 0.082 mmol) were added. The temperature was raised to 50°C and stirred for 1.0 h. The raw materials reacted completely and the reaction was stopped. After the reaction was completed, the reaction solution was cooled to room temperature, water was added, and a yellow solid was precipitated. The mixture was extracted with DCM three times, and the organic phases were combined, concentrated under reduced pressure, and purified by column chromatography (PE:EA=1:1-DCM:MeOH=20:1-10:1) to obtain a bright yellow solid P35 (7 mg, 20%). MS: m / z[M+1] + =545.32.

[0612] Embodiment 36

[0613] Compound P36: Preparation of (S)-5-(3-(3-(isopropyl(methyl)amino)pyrrolidin-1-yl)-2-methyl-N-(1-(1-methyl-2-oxo-1,2-dihydrobenzo[cd]indol-6-yl)cyclopropyl)benzamide

[0614]

[0615] (1) Intermediate S105: Preparation of (R)-methyl 5-(3-(3-(isopropyl(methyl)amino)pyrrolidin-1-yl)-2-methylbenzoate

[0616]

[0617] S7 (53 mg, 0.23 mmol) and S104 (50 mg, 0.23 mmol) were placed in a sealed tube, and dioxane (2 mL), X-Phos (4 mg, 0.0092 mmol), Cs2CO3 (378 mg, 1.16 mmol) and Pd2(dba)3 (4 mg, 0.0046 mmol) were added. N2 was bubbled for 30 s, and the temperature was raised to 90 ° C. The reaction was stirred overnight. The raw materials reacted completely and the reaction was stopped. After the reaction was completed, the reaction solution was cooled to room temperature, water (6 mL) was added, and DCM was extracted three times. The organic phases were combined, concentrated under reduced pressure and desolventized, and then purified by column chromatography (PE: EA = 1: 1-DCM: MeOH = 20: 1) to obtain a light yellow oil S105 (51 mg, 76%). MS: m / z [M+1] + =291.21.

[0618] (2) Preparation of Intermediate S106: (R)-5-(3-(3-(isopropyl(methyl)amino)pyrrolidin-1-yl)-2-methylbenzoic acid

[0619]

[0620] S105 (51 mg, 0.17 mmol) was placed in a single-mouth bottle, THF (1.0 mL) and EtOH (1.0 mL) were added, followed by a solution of NaOH (35 mg, 0.87 mmol) in H2O (1.0 mL), and the temperature was raised to 60°C. The reaction was stirred for 2 h, and the raw materials reacted completely and the reaction was stopped. After the reaction was completed, the reaction solution was concentrated under reduced pressure to remove THF and EtOH, and the pH was adjusted to 4-5 with dilute hydrochloric acid (2N). The solvent was removed by concentration under reduced pressure, and the resulting solid mixture was dissolved in DCM, dried over anhydrous sodium sulfate, filtered, and the filter cake was washed with DCM. The filtrate was taken and concentrated under reduced pressure to obtain a light yellow solid S106 (41 mg, 85%). MS: m / z[M+1] + =277.26.

[0621] (3) P36: Preparation of (S)-5-(3-(3-(isopropyl(methyl)amino)pyrrolidin-1-yl)-2-methyl-N-(1-(1-methyl-2-oxo-1,2-dihydrobenzo[cd]indol-6-yl)cyclopropyl)benzamide

[0622]

[0623] S6 (15 mg, 0.063 mmol) and S106 (21 mg, 0.075 mmol) were placed in a single-mouth bottle, and DMF (1.5 mL), DIPEA (27 mg, 0.21 mmol) and HATU (31 mg, 0.082 mmol) were added. The temperature was raised to 50°C and stirred for 1.0 h. The raw materials reacted completely and the reaction was stopped. After the reaction was completed, the reaction solution was cooled to room temperature, water was added, and a yellow solid was precipitated. The mixture was extracted with DCM three times, and the organic phases were combined, concentrated under reduced pressure, and purified by column chromatography (PE:EA=1:1-DCM:MeOH=20:1-10:1) to obtain a bright yellow solid P36 (20 mg, 64%). MS: m / z[M+1] + =497.32.

[0624] Embodiment 37

[0625] Compound P37: Preparation of 5-([1,3'-dipyrrolidine]-1'-yl)-2-methyl-N-(1-(1-methyl-2-oxo-1,2-dihydrobenzo[cd]indol-6-yl)cyclopropyl)benzamide

[0626]

[0627] (1) Preparation of intermediate S108: methyl 5-([1,3'-dipyrrolidine]-1'-yl)-2-methylbenzoate

[0628]

[0629] S7 (54 mg, 0.23 mmol) and S107 (50 mg, 0.23 mmol) were placed in a sealed tube, and dioxane (2 mL), X-Phos (4 mg, 0.0094 mmol), Cs2CO3 (378 mg, 1.16 mmol) and Pd2(dba)3 (4 mg, 0.0047 mmol) were added. N2 was bubbled for 30 s, and the temperature was raised to 90 ° C. The reaction was stirred overnight. The raw materials reacted completely and the reaction was stopped. After the reaction was completed, the reaction solution was cooled to room temperature, water (6 mL) was added, and DCM was extracted three times. The organic phases were combined, concentrated under reduced pressure, and then purified by column chromatography (PE: EA = 1: 1-DCM: MeOH = 20: 1) to obtain a light yellow solid S108 (45 mg, 66%). MS: m / z [M+1] + =289.21.

[0630] (2) Preparation of Intermediate S109: 5-([1,3'-dipyrrolidine]-1'-yl)-2-methylbenzoic acid

[0631]

[0632] S108 (45 mg, 0.15 mmol) was placed in a single-mouth bottle, THF (1.0 mL) and EtOH (1.0 mL) were added, followed by a solution of NaOH (31 mg, 0.78 mmol) in H2O (1.0 mL), and the temperature was raised to 60°C. The reaction was stirred for 2 h, and the raw materials reacted completely and the reaction was stopped. After the reaction was completed, the reaction solution was concentrated under reduced pressure to remove THF and EtOH, and the pH was adjusted to 4-5 with dilute hydrochloric acid (2N). The solvent was removed by concentration under reduced pressure, and the resulting solid mixture was dissolved in DCM, dried over anhydrous sodium sulfate, filtered, and the filter cake was washed with DCM. The filtrate was taken and concentrated under reduced pressure to obtain a light yellow solid S109 (41 mg, 96%). MS: m / z[M+1] + =275.26.

[0633] (3) P37: Preparation of 5-([1,3'-dipyrrolidine]-1'-yl)-2-methyl-N-(1-(1-methyl-2-oxo-1,2-dihydrobenzo[cd]indol-6-yl)cyclopropyl)benzamide

[0634]

[0635] S6 (15 mg, 0.063 mmol) and S109 (20 mg, 0.075 mmol) were placed in a single-mouth bottle, and DMF (1.5 mL), DIPEA (27 mg, 0.21 mmol) and HATU (31 mg, 0.082 mmol) were added. The temperature was raised to 50°C and stirred for 1.0 h. The raw materials reacted completely and the reaction was stopped. After the reaction was completed, the reaction solution was cooled to room temperature, water was added, and a yellow solid was precipitated. The mixture was extracted three times with DCM, and the organic phases were combined, concentrated under reduced pressure, and purified by column chromatography (PE:EA=1:1-DCM:MeOH=20:1-10:1) to obtain a bright yellow solid P37 (7 mg, 22%). MS: m / z[M+1] + =495.32.

[0636] Embodiment 38

[0637] Compound P38: Preparation of 2-methyl-N-(1-(1-methyl-2-oxo-1,2-dihydrobenzo[cd]indol-6-yl)cyclopropyl)-5-(4-(morpholinomethyl)piperidin-1-yl)benzamide

[0638]

[0639] (1) Preparation of intermediate S111: methyl 2-methyl-5-(4-(morpholinomethyl)piperidin-1-yl)benzoate

[0640]

[0641] S7 (62 mg, 0.27 mmol) and S110 (50 mg, 0.27 mmol) were placed in a sealed tube, and dioxane (2 mL), X-Phos (5 mg, 0.011 mmol), Cs2CO3 (262 mg, 0.80 mmol) and Pd2(dba)3 (5 mg, 0.0054 mmol) were added. N2 was bubbled for 30 s, and the temperature was raised to 90 ° C. The reaction was stirred overnight. The raw materials reacted completely and the reaction was stopped. After the reaction was completed, the reaction solution was cooled to room temperature, water (6 mL) was added, and DCM was extracted three times. The organic phases were combined, concentrated under reduced pressure and desolventized, and then purified by column chromatography (PE: EA = 1: 1-DCM: MeOH = 20: 1) to obtain a light yellow solid S111 (86 mg, 96%). MS: m / z [M+1] + =333.21.

[0642] (2) Intermediate S112: Preparation of 2-methyl-5-(4-(morpholinomethyl)piperidin-1-yl)benzoic acid

[0643]

[0644] S111 (86 mg, 0.26 mmol) was placed in a single-mouth bottle, THF (1.0 mL) and EtOH (1.0 mL) were added, followed by a solution of NaOH (52 mg, 1.30 mmol) in H2O (1.0 mL), and the temperature was raised to 60°C. The reaction was stirred for 2 h, and the raw materials reacted completely and the reaction was stopped. After the reaction was completed, the reaction solution was concentrated under reduced pressure to remove THF and EtOH, and the pH was adjusted to 4-5 with dilute hydrochloric acid (2N). The solvent was removed by concentration under reduced pressure, and the resulting solid mixture was dissolved in DCM, dried over anhydrous sodium sulfate, filtered, and the filter cake was washed with DCM. The filtrate was taken and concentrated under reduced pressure to obtain a light yellow solid S112 (80 mg, 97%). MS: m / z[M+1] + =319.26.

[0645] (3) P38: Preparation of 2-methyl-N-(1-(1-methyl-2-oxo-1,2-dihydrobenzo[cd]indol-6-yl)cyclopropyl)-5-(4-(morpholinomethyl)piperidin-1-yl)benzamide

[0646]

[0647] S6 (15 mg, 0.063 mmol) and S112 (24 mg, 0.075 mmol) were placed in a single-mouth bottle, and DMF (1.5 mL), DIPEA (27 mg, 0.21 mmol) and HATU (31 mg, 0.082 mmol) were added. The temperature was raised to 50°C and stirred for 1.0 h. The raw materials reacted completely and the reaction was stopped. After the reaction was completed, the reaction solution was cooled to room temperature, water was added, and a yellow solid was precipitated. The mixture was extracted with DCM three times, and the organic phases were combined, concentrated under reduced pressure, and purified by column chromatography (PE:EA=1:1-DCM:MeOH=20:1-10:1) to obtain a bright yellow solid P38 (10 mg, 29%). MS: m / z[M+1] + =539.32.

[0648] Embodiment 39

[0649] Compound P39: Preparation of 2-methyl-N-(1-(1-methyl-2-oxo-1,2-dihydrobenzo[cd]indol-6-yl)cyclopropyl)-5-(1-methyloctahydro-6H-pyrrolo[3,4-b]pyridin-6-yl)benzamide

[0650]

[0651] (1) Preparation of intermediate S114: methyl 2-methyl-5-(1-methyloctahydro-6H-pyrrolo[3,4-b]pyridin-6-yl)benzoate

[0652]

[0653] S7 (82 mg, 0.36 mmol) and S113 (50 mg, 0.36 mmol) were placed in a sealed tube, and dioxane (2 mL), X-Phos (7 mg, 0.014 mmol), Cs2CO3 (349 mg, 1.07 mmol) and Pd2(dba)3 (7 mg, 0.0071 mmol) were added. N2 was bubbled for 30 s, and the temperature was raised to 90 ° C. The reaction was stirred overnight. The raw materials reacted completely and the reaction was stopped. After the reaction was completed, the reaction solution was cooled to room temperature, water (6 mL) was added, and DCM was extracted three times. The organic phases were combined, concentrated under reduced pressure and desolventized, and then purified by column chromatography (PE: EA = 1: 1-DCM: MeOH = 20: 1) to obtain a light yellow solid S114 (70 mg, 68%). MS: m / z [M+1] + =289.21.

[0654] (2) Intermediate S115: Preparation of 2-methyl-5-(1-methyloctahydro-6H-pyrrolo[3,4-b]pyridin-6-yl)benzoic acid

[0655]

[0656] S114 (70 mg, 0.24 mmol) was placed in a single-mouth bottle, THF (1.0 mL) and EtOH (1.0 mL) were added, followed by a solution of NaOH (49 mg, 1.21 mmol) in H2O (1.0 mL), and the temperature was raised to 60°C. The reaction was stirred for 2 h, and the raw materials reacted completely and the reaction was stopped. After the reaction was completed, the reaction solution was concentrated under reduced pressure to remove THF and EtOH, and the pH was adjusted to 4-5 with dilute hydrochloric acid (2N). The solvent was removed by concentration under reduced pressure, and the resulting solid mixture was dissolved in DCM, dried over anhydrous sodium sulfate, filtered, and the filter cake was washed with DCM. The filtrate was taken and concentrated under reduced pressure to obtain a light yellow solid S115 (60 mg, 90%). MS: m / z[M+1] + =275.26.

[0657] (3) P39: Preparation of 2-methyl-N-(1-(1-methyl-2-oxo-1,2-dihydrobenzo[cd]indol-6-yl)cyclopropyl)-5-(1-methyloctahydro-6H-pyrrolo[3,4-b]pyridin-6-yl)benzamide

[0658]

[0659] S6 (15 mg, 0.063 mmol) and S115 (21 mg, 0.075 mmol) were placed in a single-mouth bottle, and DMF (1.5 mL), DIPEA (27 mg, 0.21 mmol) and HATU (31 mg, 0.082 mmol) were added. The temperature was raised to 50°C and stirred for 1.0 h. The raw materials reacted completely and the reaction was stopped. After the reaction was completed, the reaction solution was cooled to room temperature, water was added, and a yellow solid was precipitated. The mixture was extracted with DCM three times, and the organic phases were combined, concentrated under reduced pressure, and purified by column chromatography (PE:EA=1:1-DCM:MeOH=20:1-10:1) to obtain a bright yellow solid P39 (14 mg, 45%). MS: m / z[M+1] + =495.32.

[0660] Embodiment 40

[0661] Compound P40: Preparation of 2-methyl-N-(1-(1-methyl-2-oxo-1,2-dihydrobenz[cd]indol-6-yl)cyclopropyl)-5-((1R,4R)-5-methyl-2,5-diazabicyclo[2.2.1]heptane-2-yl)benzamide

[0662]

[0663] (1) Preparation of intermediate S117: methyl 2-methyl-5-((1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptane-2-yl)benzoate

[0664]

[0665] S7 (42 mg, 0.18 mmol) and S116 (50 mg, 0.18 mmol) were placed in a sealed tube, and dioxane (2 mL), X-Phos (4 mg, 0.0070 mmol), Cs2CO3 (296 mg, 0.91 mmol) and Pd2(dba)3 (3 mg, 0.0036 mmol) were added. N2 was bubbled for 30 s, and the temperature was raised to 90 ° C. The reaction was stirred overnight. The raw materials reacted completely and the reaction was stopped. After the reaction was completed, the reaction solution was cooled to room temperature, water (6 mL) was added, and DCM was extracted three times. The organic phases were combined, concentrated under reduced pressure and desolventized, and then purified by column chromatography (PE: EA = 1: 1-DCM: MeOH = 20: 1-10: 1) to obtain a light yellow oil S117 (42 mg, 88%). MS: m / z [M+1] + =261.21.

[0666] (2) Intermediate S118: Preparation of 2-methyl-5-((1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptane-2-yl)benzoic acid

[0667]

[0668] S117 (42 mg, 0.16 mmol) was placed in a single-mouth bottle, THF (1.0 mL) and EtOH (1.0 mL) were added, followed by a solution of NaOH (32 mg, 0.80 mmol) in H2O (1.0 mL), and the temperature was raised to 60°C. The reaction was stirred for 2 h, and the raw materials reacted completely and the reaction was stopped. After the reaction was completed, the reaction solution was concentrated under reduced pressure to remove THF and EtOH, and the pH was adjusted to 4-5 with dilute hydrochloric acid (2N). The solvent was removed by concentration under reduced pressure, and the resulting solid mixture was dissolved in DCM, dried over anhydrous sodium sulfate, filtered, and the filter cake was washed with DCM. The filtrate was taken and concentrated under reduced pressure to obtain a light yellow solid S118 (35 mg, 90%). MS: m / z[M+1] + =247.26.

[0669] (3) Preparation of P40: 2-methyl-N-(1-(1-methyl-2-oxo-1,2-dihydrobenzo[cd]indol-6-yl)cyclopropyl)-5-((1R,4R)-5-methyl-2,5-diazabicyclo[2.2.1]heptane-2-yl)benzamide

[0670]

[0671] S6 (15 mg, 0.063 mmol) and S118 (18 mg, 0.075 mmol) were placed in a single-mouth bottle, and DMF (1.5 mL), DIPEA (27 mg, 0.21 mmol) and HATU (31 mg, 0.082 mmol) were added. The temperature was raised to 50°C and stirred for 1.0 h. The raw materials reacted completely and the reaction was stopped. After the reaction was completed, the reaction solution was cooled to room temperature, water was added, and a yellow solid was precipitated. The mixture was extracted with DCM three times, and the organic phases were combined, concentrated under reduced pressure, and purified by column chromatography (PE:EA=1:1-DCM:MeOH=20:1-10:1) to obtain a bright yellow solid P40 (9 mg, 31%). MS: m / z[M+1] + =467.32.

[0672] Embodiment 41

[0673] Compound P41: Preparation of 5-(4-(2-hydroxypropyl)piperazin-1-yl)-2-methyl-N-(1-(1-methyl-2-oxo-1,2-dihydrobenzo[cd]indol-6-yl)cyclopropyl)benzamide

[0674]

[0675] (1) Preparation of intermediate S120: 5-(4-(2-hydroxypropyl)piperazine-1-yl)-2-methylbenzoic acid methyl ester

[0676]

[0677] S7 (79 mg, 0.35 mmol) and S119 (50 mg, 0.35 mmol) were placed in a sealed tube, and dioxane (2 mL), X-Phos (7 mg, 0.014 mmol), Cs2CO3 (339 mg, 1.04 mmol) and Pd2(dba)3 (6 mg, 0.0069 mmol) were added. N2 was bubbled for 30 s, and the temperature was raised to 90 ° C. The reaction was stirred overnight. The raw materials reacted completely and the reaction was stopped. After the reaction was completed, the reaction solution was cooled to room temperature, saturated ammonium chloride solution (6 mL) was added, and DCM was used for extraction three times. The organic phases were combined, concentrated under reduced pressure, and then purified by column chromatography (PE: EA = 1: 1-DCM: MeOH = 20: 1-10: 1) to obtain a light yellow oil S120 (42 mg, 88%). MS: m / z [M+1] + =293.21.

[0678] (2) Preparation of Intermediate S121: 5-(4-(2-hydroxypropyl)piperazine-1-yl)-2-methylbenzoic acid

[0679]

[0680] S120 (30 mg, 0.10 mmol) was placed in a single-mouth bottle, THF (1.0 mL) and EtOH (1.0 mL) were added, followed by a solution of NaOH (20 mg, 0.50 mmol) in H2O (1.0 mL), and the temperature was raised to 60°C. The reaction was stirred for 2 h, and the raw materials reacted completely and the reaction was stopped. After the reaction was completed, the reaction solution was concentrated under reduced pressure to remove THF and EtOH, and the pH was adjusted to 4-5 with dilute hydrochloric acid (2N). The solvent was removed by concentration under reduced pressure, and the resulting solid mixture was dissolved in DCM, dried over anhydrous sodium sulfate, filtered, and the filter cake was washed with DCM. The filtrate was taken and concentrated under reduced pressure to obtain a light yellow solid S121 (24 mg, 86%). MS: m / z[M+1] + =279.26.

[0681] (3) P41: Preparation of 5-(4-(2-hydroxypropyl)piperazin-1-yl)-2-methyl-N-(1-(1-methyl-2-oxo-1,2-dihydrobenzo[cd]indol-6-yl)cyclopropyl)benzamide

[0682]

[0683] S6 (11 mg, 0.048 mmol) and S121 (16 mg, 0.057 mmol) were placed in a single-mouth bottle, and DMF (1.5 mL), DIPEA (20 mg, 0.16 mmol) and HATU (24 mg, 0.062 mmol) were added. The temperature was raised to 50°C and stirred for 1.0 h. The raw materials reacted completely and the reaction was stopped. After the reaction was completed, the reaction solution was cooled to room temperature, water was added, and a yellow solid was precipitated. The mixture was extracted with DCM three times, and the organic phases were combined, concentrated under reduced pressure, and purified by column chromatography (PE:EA=1:1-DCM:MeOH=20:1-10:1) to obtain a bright yellow solid P41 (9 mg, 37%). MS: m / z[M+1] + =499.32.

[0684] Embodiment 42

[0685] Compound P42: Preparation of 5-([1,3'-diazetidine]-1'-yl)-2-methyl-N-(1-(1-methyl-2-oxo-1,2-dihydrobenz[cd]indol-6-yl)cyclopropyl)benzamide

[0686]

[0687] (1) Preparation of intermediate S123: methyl 5-([1,3'-diazetidine]-1'-yl)-2-methylbenzoate

[0688]

[0689] S7 (42 mg, 0.18 mmol) and S122 (67 mg, 0.20 mmol) were placed in a sealed tube, and toluene (1.5 mL), X-Phos (3 mg, 0.069 mmol), Cs2CO3 (318 mg, 0.90 mmol) and Pd2(dba)3 (3 mg, 0.0036 mmol) were added. N2 was bubbled for 30 s, and the temperature was raised to 110 ° C. The reaction was stirred overnight. The raw materials reacted completely and the reaction was stopped. After the reaction was completed, the reaction solution was cooled to room temperature, water (6 mL) was added, and DCM was extracted three times. The organic phases were combined, concentrated under reduced pressure and desolventized, and then purified by column chromatography (PE: EA = 1: 1-DCM: MeOH = 20: 1-10: 1) to obtain a light yellow solid S123 (47 mg, 100%). MS: m / z [M+1] + =261.21.

[0690] (2) Preparation of intermediate S124: 5-([1,3'-diazetidine]-1'-yl)-2-methylbenzoic acid

[0691]

[0692] S123 (47 mg, 0.18 mmol) was placed in a single-mouth bottle, THF (1.0 mL) and EtOH (1.0 mL) were added, followed by a solution of NaOH (36 mg, 0.90 mmol) in H2O (1.0 mL), and the temperature was raised to 60°C. The reaction was stirred for 2 h, and the raw materials reacted completely and the reaction was stopped. After the reaction was completed, the reaction solution was concentrated under reduced pressure to remove THF and EtOH, and the pH was adjusted to 4-5 with dilute hydrochloric acid (2N). The solvent was removed by concentration under reduced pressure, and the resulting solid mixture was dissolved in DCM, dried over anhydrous sodium sulfate, filtered, and the filter cake was washed with DCM. The filtrate was taken and concentrated under reduced pressure to obtain a light yellow solid S124 (37 mg, 84%). MS: m / z[M+1] + =247.26.

[0693] (3) Preparation of P42: 5-([1,3'-diazetidine]-1'-yl)-2-methyl-N-(1-(1-methyl-2-oxo-1,2-dihydrobenz[cd]indol-6-yl)cyclopropyl)benzamide

[0694]

[0695] S6 (15 mg, 0.063 mmol) and S124 (18 mg, 0.075 mmol) were placed in a single-mouth bottle, and DMF (1.5 mL), DIPEA (27 mg, 0.21 mmol) and HATU (31 mg, 0.082 mmol) were added. The temperature was raised to 50°C and stirred for 1.0 h. The raw materials reacted completely and the reaction was stopped. After the reaction was completed, the reaction solution was cooled to room temperature, water was added, and a yellow solid was precipitated. The mixture was extracted with DCM three times, and the organic phases were combined, concentrated under reduced pressure, and purified by column chromatography (PE:EA=1:1-DCM:MeOH=20:1-10:1) to obtain a bright yellow solid P42 (23 mg, 80%). MS: m / z[M+1] + =467.32.

[0696] Embodiment 43

[0697] Compound P43: Preparation of 5-(3-(3-hydroxypyrrolidin-1-yl)azetidin-1-yl)-2-methyl-N-(1-(1-methyl-2-oxo-1,2-dihydrobenzo[cd]indol-6-yl)cyclopropyl)benzamide

[0698]

[0699] (1) Preparation of intermediate S126: methyl 5-(3-(3-hydroxypyrrolidin-1-yl)azetidin-1-yl)-2-methylbenzoate

[0700]

[0701] S7 (60 mg, 0.26 mmol) and S125 (67 mg, 0.31 mmol) were placed in a sealed tube, and toluene (2.0 mL), X-Phos (5 mg, 0.010 mmol), Cs2CO3 (424 mg, 1.30 mmol) and Pd2(dba)3 (5 mg, 0.0052 mmol) were added. N2 was bubbled for 30 s, and the temperature was raised to 110 ° C. The reaction was stirred overnight. The raw materials reacted completely and the reaction was stopped. After the reaction was completed, the reaction solution was cooled to room temperature, saturated ammonium chloride solution (6 mL) was added, and DCM was used for extraction three times. The organic phases were combined, concentrated under reduced pressure, and then purified by column chromatography (PE: EA = 1: 1-DCM: MeOH = 20: 1-10: 1) to obtain a colorless oil S126 (16 mg, 21%). MS: m / z [M+1] + =291.21.

[0702] (2) Preparation of Intermediate S127: 5-(3-(3-hydroxypyrrolidin-1-yl)azetidin-1-yl)-2-methylbenzoic acid

[0703]

[0704] S126 (16 mg, 0.055 mmol) was placed in a single-mouth bottle, THF (0.5 mL) and EtOH (0.5 mL) were added, followed by a solution of NaOH (11 mg, 0.28 mmol) in H2O (0.5 mL), and the temperature was raised to 60°C. The reaction was stirred for 2 h, and the raw materials reacted completely and the reaction was stopped. After the reaction was completed, the reaction solution was concentrated under reduced pressure to remove THF and EtOH, and the pH was adjusted to 4-5 with dilute hydrochloric acid (2N). The solvent was removed by concentration under reduced pressure, and the resulting solid mixture was dissolved in DCM, dried over anhydrous sodium sulfate, filtered, and the filter cake was washed with DCM. The filtrate was taken and concentrated under reduced pressure to obtain a light yellow solid S127 (15 mg, 100%). MS: m / z[M+1] + =247.26.

[0705] (3) P43: Preparation of 5-(3-(3-hydroxypyrrolidin-1-yl)azetidin-1-yl)-2-methyl-N-(1-(1-methyl-2-oxo-1,2-dihydrobenzo[cd]indol-6-yl)cyclopropyl)benzamide

[0706]

[0707] S6 (11 mg, 0.045 mmol) and S127 (15 mg, 0.054 mmol) were placed in a single-mouth bottle, and DMF (1.5 mL), DIPEA (19 mg, 0.15 mmol) and HATU (22 mg, 0.058 mmol) were added. The temperature was raised to 50°C and stirred for 1.0 h. The raw materials reacted completely and the reaction was stopped. After the reaction was completed, the reaction solution was cooled to room temperature, water was added, and a yellow solid was precipitated. The mixture was extracted with DCM three times, and the organic phases were combined, concentrated under reduced pressure, and purified by column chromatography (PE:EA=1:1-DCM:MeOH=20:1-10:1-8:1) to obtain a bright yellow solid P43 (9 mg, 41%). MS: m / z[M+1] + =497.32.

[0708] Embodiment 44

[0709] Compound P44: Preparation of 2-methyl-N-(1-(1-methyl-2-oxo-1,2-dihydrobenzo[cd]indol-6-yl)cyclopropyl)-5-(3-(4-methyl-3-oxopiperazin-1-yl)azetidin-1-yl)benzamide

[0710]

[0711] (1) Preparation of intermediate S129: methyl 2-methyl-5-(3-(4-methyl-3-oxopiperazin-1-yl)azetidin-1-yl)benzoate

[0712]

[0713] S7 (60 mg, 0.26 mmol) and S128 (75 mg, 0.31 mmol) were placed in a sealed tube, and toluene (2.0 mL), X-Phos (5 mg, 0.010 mmol), Cs2CO3 (424 mg, 1.30 mmol) and Pd2(dba)3 (5 mg, 0.0052 mmol) were added. N2 was bubbled for 30 s, and the temperature was raised to 110 ° C. The reaction was stirred overnight. The raw materials reacted completely and the reaction was stopped. After the reaction was completed, the reaction solution was cooled to room temperature, water (6 mL) was added, and DCM was extracted three times. The organic phases were combined, concentrated under reduced pressure and desolventized, and then purified by column chromatography (PE: EA = 1: 1-DCM: MeOH = 20: 1-10: 1) to obtain a light yellow solid S129 (56 mg, 68%). MS: m / z [M+1] + =318.21.

[0714] (2) Intermediate S130: Preparation of 2-methyl-5-(3-(4-methyl-3-oxopiperazin-1-yl)azetidin-1-yl)benzoic acid

[0715]

[0716] S129 (56 mg, 0.18 mmol) was placed in a single-mouth bottle, THF (1.0 mL) and EtOH (1.0 mL) were added, followed by a solution of NaOH (35 mg, 0.88 mmol) in H2O (1.0 mL), and the temperature was raised to 60°C. The reaction was stirred for 2 h, and the raw materials reacted completely and the reaction was stopped. After the reaction was completed, the reaction solution was concentrated under reduced pressure to remove THF and EtOH, and the pH was adjusted to 4-5 with dilute hydrochloric acid (2N). The solvent was removed by concentration under reduced pressure, and the resulting solid mixture was dissolved in DCM, dried over anhydrous sodium sulfate, filtered, and the filter cake was washed with DCM. The filtrate was taken and concentrated under reduced pressure to obtain a light yellow solid S130 (54 mg, 100%). MS: m / z[M+1] + =304.26.

[0717] (3) P44: Preparation of 2-methyl-N-(1-(1-methyl-2-oxo-1,2-dihydrobenzo[cd]indol-6-yl)cyclopropyl)-5-(3-(4-methyl-3-oxopiperazin-1-yl)azetidin-1-yl)benzamide

[0718]

[0719] S6 (15 mg, 0.063 mmol) and S130 (23 mg, 0.075 mmol) were placed in a single-mouth bottle, and DMF (1.5 mL), DIPEA (27 mg, 0.21 mmol) and HATU (31 mg, 0.082 mmol) were added. The temperature was raised to 50°C and stirred for 1.0 h. The raw materials reacted completely and the reaction was stopped. After the reaction was completed, the reaction solution was cooled to room temperature, water was added, and a yellow solid was precipitated. The mixture was extracted with DCM three times, and the organic phases were combined, concentrated under reduced pressure, and purified by column chromatography (PE:EA=1:1-DCM:MeOH=20:1-10:1-8:1) to obtain a bright yellow solid P44 (12 mg, 36%). MS: m / z[M+1] + =524.32.

[0720] Embodiment 45

[0721] Compound P45: Preparation of 2-methyl-N-(1-(1-methyl-2-oxo-1,2-dihydrobenzo[cd]indol-6-yl)cyclopropyl)-5-(3-(pyrrolidin-1-yl)azetidin-1-yl)benzamide

[0722]

[0723] (1) Preparation of intermediate S132: methyl 2-methyl-5-(3-(pyrrolidin-1-yl)azetidin-1-yl)benzoate

[0724]

[0725] S7 (60 mg, 0.26 mmol) and S131 (62 mg, 0.31 mmol) were placed in a sealed tube, and toluene (2.0 mL), X-Phos (5 mg, 0.010 mmol), Cs2CO3 (424 mg, 1.30 mmol) and Pd2(dba)3 (5 mg, 0.0052 mmol) were added. N2 was bubbled for 30 s, and the temperature was raised to 110 ° C. The reaction was stirred overnight. The raw materials reacted completely and the reaction was stopped. After the reaction was completed, the reaction solution was cooled to room temperature, water (6 mL) was added, and DCM was used for extraction three times. The organic phases were combined, concentrated under reduced pressure and desolventized, and then purified by column chromatography (PE: EA = 1: 1-DCM: MeOH = 20: 1-10: 1) to obtain a light yellow oil S132 (71 mg, 100%). MS: m / z [M+1] + =275.21.

[0726] (2) Intermediate S133: Preparation of 2-methyl-5-(3-(pyrrolidin-1-yl)azetidin-1-yl)benzoic acid

[0727]

[0728] S132 (71 mg, 0.26 mmol) was placed in a single-mouth bottle, THF (1.0 mL) and EtOH (1.0 mL) were added, followed by a solution of NaOH (52 mg, 1.30 mmol) in H2O (1.0 mL), and the temperature was raised to 60°C. The reaction was stirred for 2 h, and the raw materials reacted completely and the reaction was stopped. After the reaction was completed, the reaction solution was concentrated under reduced pressure to remove THF and EtOH, and the pH was adjusted to 4-5 with dilute hydrochloric acid (2N). The solvent was removed by concentration under reduced pressure, and the resulting solid mixture was dissolved in DCM, dried over anhydrous sodium sulfate, filtered, and the filter cake was washed with DCM. The filtrate was taken and concentrated under reduced pressure to obtain a light yellow solid S133 (68 mg, 100%). MS: m / z[M+1] + =261.26.

[0729] (3) P45: Preparation of 2-methyl-N-(1-(1-methyl-2-oxo-1,2-dihydrobenzo[cd]indol-6-yl)cyclopropyl)-5-(3-(pyrrolidin-1-yl)azetidin-1-yl)benzamide

[0730]

[0731] S6 (15 mg, 0.063 mmol) and S133 (20 mg, 0.075 mmol) were placed in a single-mouth bottle, and DMF (1.5 mL), DIPEA (27 mg, 0.21 mmol) and HATU (31 mg, 0.082 mmol) were added. The temperature was raised to 50°C and stirred for 1.0 h. The raw materials reacted completely and the reaction was stopped. After the reaction was completed, the reaction solution was cooled to room temperature, water was added, and a yellow solid was precipitated. The mixture was extracted three times with DCM, and the organic phases were combined, concentrated under reduced pressure, and purified by column chromatography (PE:EA=1:1-DCM:MeOH=20:1-10:1) to obtain a bright yellow solid P45 (14 mg, 47%). MS: m / z[M+1] + =481.32.

[0732] Embodiment 46

[0733] Compound P46: Preparation of 2-methyl-N-(1-(1-methyl-2-oxo-1,2-dihydrobenz[cd]indol-6-yl)cyclopropyl)-5-(3-morpholinoazetidin-1-yl)benzamide

[0734]

[0735] (1) Preparation of intermediate S135: methyl 2-methyl-5-(3-morpholinoazetidin-1-yl)benzoate

[0736]

[0737] S7 (60 mg, 0.26 mmol) and S134 (55 mg, 0.31 mmol) were placed in a sealed tube, and toluene (2.0 mL), X-Phos (5 mg, 0.010 mmol), Cs2CO3 (424 mg, 1.30 mmol) and Pd2(dba)3 (5 mg, 0.0052 mmol) were added. N2 was bubbled for 30 s, and the temperature was raised to 110 ° C. The reaction was stirred overnight. The raw materials reacted completely and the reaction was stopped. After the reaction was completed, the reaction solution was cooled to room temperature, water (6 mL) was added, and DCM was extracted three times. The organic phases were combined, concentrated under reduced pressure, and then purified by column chromatography (PE: EA = 3: 1-1: 1) to obtain a white solid S135 (75 mg, 100%). MS: m / z [M+1] + =291.21.

[0738] (2) Preparation of Intermediate S136: 2-methyl-5-(3-morpholinoazetidin-1-yl)benzoic acid

[0739]

[0740] S135 (75 mg, 0.26 mmol) was placed in a single-mouth bottle, THF (1.0 mL) and EtOH (1.0 mL) were added, followed by a solution of NaOH (52 mg, 1.30 mmol) in H2O (1.0 mL), and the temperature was raised to 60°C. The reaction was stirred for 2 h, and the raw materials reacted completely and the reaction was stopped. After the reaction was completed, the reaction solution was concentrated under reduced pressure to remove THF and EtOH, and the pH was adjusted to 4-5 with dilute hydrochloric acid (2N). The solvent was removed by concentration under reduced pressure, and the resulting solid mixture was dissolved in DCM, dried over anhydrous sodium sulfate, filtered, and the filter cake was washed with DCM. The filtrate was taken and concentrated under reduced pressure to obtain a white solid S136 (72 mg, 100%). MS: m / z[M+1] + =277.26.

[0741] (3) P46: Preparation of 2-methyl-N-(1-(1-methyl-2-oxo-1,2-dihydrobenz[cd]indol-6-yl)cyclopropyl)-5-(3-morpholinoazetidin-1-yl)benzamide

[0742]

[0743] S6 (15 mg, 0.063 mmol) and S136 (21 mg, 0.075 mmol) were placed in a single-mouth bottle, and DMF (1.5 mL), DIPEA (27 mg, 0.21 mmol) and HATU (31 mg, 0.082 mmol) were added. The temperature was raised to 50°C and stirred for 1.0 h. The raw materials reacted completely and the reaction was stopped. After the reaction was completed, the reaction solution was cooled to room temperature, water was added, and a yellow solid was precipitated. The mixture was extracted with DCM three times, and the organic phases were combined, concentrated under reduced pressure, and purified by column chromatography (PE:EA=1:1-DCM:MeOH=20:1-10:1) to obtain a bright yellow solid P46 (20 mg, 65%). MS: m / z[M+1] + =497.32.

[0744] Embodiment 47

[0745] Compound P47: Preparation of 2-methyl-N-(1-(1-methyl-2-oxo-1,2-dihydrobenzo[cd]indol-6-yl)cyclopropyl)-5-(3aR,6aR)-1-methylhexahydropyrrolo[3,4-b]pyrrol-5(1H)-yl)benzamide

[0746]

[0747] (1) Preparation of intermediate S138: methyl 2-methyl-5-(3aR,6aR)-1-methylhexahydropyrrolo[3,4-b]pyrrol-5(1H)-yl)benzoate

[0748]

[0749] S7 (60 mg, 0.26 mmol) and S137 (39 mg, 0.31 mmol) were placed in a sealed tube, and toluene (2.0 mL), X-Phos (5 mg, 0.010 mmol), Cs2CO3 (169 mg, 0.52 mmol) and Pd2(dba)3 (5 mg, 0.0052 mmol) were added. N2 was bubbled for 30 s, and the temperature was raised to 110 ° C. The reaction was stirred overnight. The raw materials reacted completely and the reaction was stopped. After the reaction was completed, the reaction solution was cooled to room temperature, water (6 mL) was added, and DCM was used for extraction three times. The organic phases were combined, concentrated under reduced pressure, and then purified by column chromatography (PE: EA = 1: 1-DCM: MeOH = 20: 1) to obtain a light yellow solid S138 (52 mg, 73%). MS: m / z [M+1] + =275.21.

[0750] (2) Intermediate S139: Preparation of 2-methyl-5-(3aR,6aR)-1-methylhexahydropyrrolo[3,4-b]pyrrol-5(1H)-yl)benzoic acid

[0751]

[0752] S138 (52 mg, 0.19 mmol) was placed in a single-mouth bottle, THF (1.0 mL) and EtOH (1.0 mL) were added, followed by a solution of NaOH (38 mg, 0.95 mmol) in H2O (1.0 mL), and the temperature was raised to 60°C. The reaction was stirred for 2 h, and the raw materials reacted completely and the reaction was stopped. After the reaction was completed, the reaction solution was concentrated under reduced pressure to remove THF and EtOH, and the pH was adjusted to 4-5 with dilute hydrochloric acid (2N). The solvent was removed by concentration under reduced pressure, and the resulting solid mixture was dissolved in DCM, dried over anhydrous sodium sulfate, filtered, and the filter cake was washed with DCM. The filtrate was taken and concentrated under reduced pressure to obtain a light yellow solid S139 (49 mg, 100%). MS: m / z[M+1] + =261.26.

[0753] (3) P47: Preparation of 2-methyl-N-(1-(1-methyl-2-oxo-1,2-dihydrobenzo[cd]indol-6-yl)cyclopropyl)-5-(3aR,6aR)-1-methylhexahydropyrrolo[3,4-b]pyrrol-5(1H)-yl)benzamide

[0754]

[0755] S6 (15 mg, 0.063 mmol) and S139 (20 mg, 0.075 mmol) were placed in a single-mouth bottle, and DMF (1.5 mL), DIPEA (27 mg, 0.21 mmol) and HATU (31 mg, 0.082 mmol) were added. The temperature was raised to 50°C and stirred for 1.0 h. The raw materials reacted completely and the reaction was stopped. After the reaction was completed, the reaction solution was cooled to room temperature, water was added, and a yellow solid was precipitated. The mixture was extracted with DCM three times, and the organic phases were combined, concentrated under reduced pressure, and purified by column chromatography (PE:EA=1:1-DCM:MeOH=20:1-10:1) to obtain a bright yellow solid P47 (17 mg, 57%). MS: m / z[M+1] + =481.32.

[0756] Embodiment 48

[0757] Compound P48: Preparation of 5-(3,3-difluoro-4-(pyrrolidin-1-yl)piperidin-1-yl)-2-methyl-N-(1-(1-methyl-2-oxo-1,2-dihydrobenzo[cd]indol-6-yl)cyclopropyl)benzamide

[0758]

[0759] (1) Preparation of intermediate S141: 5-(3,3-difluoro-4-(pyrrolidin-1-yl)piperidin-1-yl)-2-methylbenzoic acid methyl ester

[0760]

[0761] S7 (42 mg, 0.18 mmol) and S140 (53 mg, 0.20 mmol) were placed in a sealed tube, and toluene (1.5 mL), X-Phos (3 mg, 0.0069 mmol), Cs2CO3 (318 mg, 0.90 mmol) and Pd2(dba)3 (3 mg, 0.0036 mmol) were added. N2 was bubbled for 30 s, and the temperature was raised to 110 ° C. The reaction was stirred overnight. The raw materials reacted completely and the reaction was stopped. After the reaction was completed, the reaction solution was cooled to room temperature, water (6 mL) was added, and DCM was extracted three times. The organic phases were combined, concentrated under reduced pressure, and then purified by column chromatography (PE: EA = 3: 1-2: 1) to obtain a white solid S141 (43 mg, 70%). MS: m / z [M+1] + =339.21.

[0762] (2) Preparation of Intermediate S142: 5-(3,3-difluoro-4-(pyrrolidin-1-yl)piperidin-1-yl)-2-methylbenzoic acid

[0763]

[0764] S141 (43 mg, 0.13 mmol) was placed in a single-mouth bottle, THF (1.0 mL) and EtOH (1.0 mL) were added, followed by a solution of NaOH (25 mg, 0.63 mmol) in H2O (1.0 mL), and the temperature was raised to 60°C. The reaction was stirred for 2 h, and the raw materials reacted completely and the reaction was stopped. After the reaction was completed, the reaction solution was concentrated under reduced pressure to remove THF and EtOH, and the pH was adjusted to 4-5 with dilute hydrochloric acid (2N). The solvent was removed by concentration under reduced pressure, and the resulting solid mixture was dissolved in DCM, dried over anhydrous sodium sulfate, filtered, and the filter cake was washed with DCM. The filtrate was taken and concentrated under reduced pressure to obtain a white solid S142 (34 mg, 81%). MS: m / z[M+1] + =325.26.

[0765] (3) P48: Preparation of 5-(3,3-difluoro-4-(pyrrolidin-1-yl)piperidin-1-yl)-2-methyl-N-(1-(1-methyl-2-oxo-1,2-dihydrobenzo[cd]indol-6-yl)cyclopropyl)benzamide

[0766]

[0767] S6 (15 mg, 0.063 mmol) and S142 (24 mg, 0.075 mmol) were placed in a single-mouth bottle, and DMF (1.5 mL), DIPEA (27 mg, 0.21 mmol) and HATU (31 mg, 0.082 mmol) were added. The temperature was raised to 50°C and stirred for 1.0 h. The raw materials reacted completely and the reaction was stopped. After the reaction was completed, the reaction solution was cooled to room temperature, water was added, and a yellow solid was precipitated. The mixture was extracted with DCM three times, and the organic phases were combined, concentrated under reduced pressure, and purified by column chromatography (PE:EA=3:1-1:1) to obtain a bright yellow solid P48 (15 mg, 44%). MS: m / z[M+1] + =545.32.

[0768] Embodiment 49

[0769] Compound P49: Preparation of 5-(4-(2-hydroxy-2-methylpropyl)piperazin-1-yl)-2-methyl-N-(1-(1-methyl-2-oxo-1,2-dihydrobenzo[cd]indol-6-yl)cyclopropyl)benzamide

[0770]

[0771] (1) Preparation of intermediate S144: 5-(4-(2-hydroxy-2-methylpropyl)piperazine-1-yl)-2-methylbenzoic acid methyl ester

[0772]

[0773] S7 (60 mg, 0.26 mmol) and S143 (49 mg, 0.31 mmol) were placed in a sealed tube, and toluene (2.0 mL), X-Phos (5 mg, 0.010 mmol), Cs2CO3 (169 mg, 0.52 mmol) and Pd2(dba)3 (5 mg, 0.0052 mmol) were added. N2 was bubbled for 30 s, and the temperature was raised to 110 ° C. The reaction was stirred overnight. The raw materials reacted completely and the reaction was stopped. After the reaction was completed, the reaction solution was cooled to room temperature, saturated ammonium chloride solution (6 mL) was added, and DCM was used for extraction three times. The organic phases were combined, concentrated under reduced pressure, and then purified by column chromatography (PE: EA = 1: 1-DCM: MeOH = 20: 1-10: 1) to obtain a white solid S144 (69 mg, 87%). MS: m / z [M+1] + =307.21.

[0774] (2) Preparation of Intermediate S145: 5-(4-(2-hydroxy-2-methylpropyl)piperazine-1-yl)-2-methylbenzoic acid

[0775]

[0776] S144 (69 mg, 0.28 mmol) was placed in a single-mouth bottle, THF (1.0 mL) and EtOH (1.0 mL) were added, followed by a solution of NaOH (56 mg, 1.39 mmol) in H2O (1.0 mL), and the temperature was raised to 60°C. The reaction was stirred for 2 h, and the raw materials reacted completely and the reaction was stopped. After the reaction was completed, the reaction solution was concentrated under reduced pressure to remove THF and EtOH, and the pH was adjusted to 4-5 with dilute hydrochloric acid (2N). The solvent was removed by concentration under reduced pressure, and the resulting solid mixture was dissolved in DCM, dried over anhydrous sodium sulfate, filtered, and the filter cake was washed with DCM. The filtrate was taken and concentrated under reduced pressure to obtain a white solid S145 (41 mg, 50%). MS: m / z[M+1] + =293.26.

[0777] (3) P49: Preparation of 5-(4-(2-hydroxy-2-methylpropyl)piperazin-1-yl)-2-methyl-N-(1-(1-methyl-2-oxo-1,2-dihydrobenzo[cd]indol-6-yl)cyclopropyl)benzamide

[0778]

[0779] S6 (15 mg, 0.063 mmol) and S145 (22 mg, 0.075 mmol) were placed in a single-mouth bottle, and DMF (1.5 mL), DIPEA (27 mg, 0.21 mmol) and HATU (31 mg, 0.082 mmol) were added. The temperature was raised to 50°C and stirred for 1.0 h. The raw materials reacted completely and the reaction was stopped. After the reaction was completed, the reaction solution was cooled to room temperature, water was added, and a yellow solid was precipitated. The mixture was extracted with DCM three times, and the organic phases were combined, concentrated under reduced pressure, and purified by column chromatography (PE:EA=1:1-DCM:MeOH=20:1-10:1-8:1) to obtain a bright yellow solid P49 (21 mg, 66%). MS: m / z[M+1] + =513.32.

[0780] Embodiment 50

[0781] Compound P50: Preparation of 2-methyl-N-(1-(1-methyl-2-oxo-1,2-dihydrobenzo[cd]indol-6-yl)cyclopropyl)-5-(3-(piperidin-1-yl)pyrrolidin-1-yl)benzamide

[0782]

[0783] (1) Preparation of intermediate S147: methyl 2-methyl-5-(3-(piperidin-1-yl)pyrrolidin-1-yl)benzoate

[0784]

[0785] S7 (60 mg, 0.26 mmol) and S146 (70 mg, 0.31 mmol) were placed in a sealed tube, and toluene (2.0 mL), X-Phos (5 mg, 0.010 mmol), Cs2CO3 (424 mg, 1.30 mmol) and Pd2(dba)3 (5 mg, 0.0052 mmol) were added. N2 was bubbled for 30 s, and the temperature was raised to 110 ° C. The reaction was stirred overnight. The raw materials reacted completely and the reaction was stopped. After the reaction was completed, the reaction solution was cooled to room temperature, water (6 mL) was added, and DCM was used for extraction three times. The organic phases were combined, concentrated under reduced pressure, and then purified by column chromatography (PE: EA = 1: 1-DCM: MeOH = 20: 1) to obtain a light yellow oil S147 (73 mg, 93%). MS: m / z [M+1] + =303.21.

[0786] (2) Intermediate S148: Preparation of 2-methyl-5-(3-(piperidin-1-yl)pyrrolidin-1-yl)benzoic acid

[0787]

[0788] S147 (73 mg, 0.24 mmol) was placed in a single-mouth bottle, THF (1.0 mL) and EtOH (1.0 mL) were added, followed by a solution of NaOH (48 mg, 1.20 mmol) in H2O (1.0 mL), and the temperature was raised to 60°C. The reaction was stirred for 2 h, and the raw materials reacted completely and the reaction was stopped. After the reaction was completed, the reaction solution was concentrated under reduced pressure to remove THF and EtOH, and the pH was adjusted to 4-5 with dilute hydrochloric acid (2N). The solvent was removed by concentration under reduced pressure, and the resulting solid mixture was dissolved in DCM, dried over anhydrous sodium sulfate, filtered, and the filter cake was washed with DCM. The filtrate was taken and concentrated under reduced pressure to obtain a light yellow oil S148 (69 mg, 100%). MS: m / z[M+1] + =289.26.

[0789] (3) Preparation of P50: 2-methyl-N-(1-(1-methyl-2-oxo-1,2-dihydrobenzo[cd]indol-6-yl)cyclopropyl)-5-(3-(piperidin-1-yl)pyrrolidin-1-yl)benzamide

[0790]

[0791] S6 (15 mg, 0.063 mmol) and S148 (22 mg, 0.075 mmol) were placed in a single-mouth bottle, and DMF (1.5 mL), DIPEA (27 mg, 0.21 mmol) and HATU (31 mg, 0.082 mmol) were added. The temperature was raised to 50°C and stirred for 1.0 h. The raw materials reacted completely and the reaction was stopped. After the reaction was completed, the reaction solution was cooled to room temperature, water was added, and a yellow solid was precipitated. The mixture was extracted with DCM three times, and the organic phases were combined, concentrated under reduced pressure, and purified by column chromatography (PE:EA=1:1-DCM:MeOH=20:1-10:1-8:1) to obtain a bright yellow solid P50 (16 mg, 50%). MS: m / z[M+1] + =509.32.

[0792] Embodiment 51

[0793] Compound P51: Preparation of 2-methyl-N-(1-(1-methyl-2-oxo-1,2-dihydrobenz[cd]indol-6-yl)cyclopropyl)-5-(4-(3-methylsulfonyl)propyl)piperazin-1-yl)benzamide

[0794]

[0795] (1) Preparation of intermediate S150: methyl 2-methyl-5-(4-(3-methylsulfonyl)propyl)piperazin-1-yl)benzoate

[0796]

[0797] S7 (60 mg, 0.26 mmol) and S149 (86 mg, 0.31 mmol) were placed in a sealed tube, and toluene (2.0 mL), X-Phos (5 mg, 0.010 mmol), Cs2CO3 (424 mg, 1.30 mmol) and Pd2(dba)3 (5 mg, 0.0052 mmol) were added. N2 was bubbled for 30 s, and the temperature was raised to 110 ° C. The reaction was stirred overnight. The raw materials reacted completely and the reaction was stopped. After the reaction was completed, the reaction solution was cooled to room temperature, water (6 mL) was added, and DCM was used for extraction three times. The organic phases were combined, concentrated under reduced pressure and desolventized, and then purified by column chromatography (PE: EA = 1: 1-DCM: MeOH = 20: 1-10: 1) to obtain a light yellow solid S150 (24 mg, 26%). MS: m / z [M+1] + =355.21.

[0798] (2) Preparation of Intermediate S151: 2-Methyl-5-(4-(3-methylsulfonyl)propyl)piperazin-1-yl)benzoic acid

[0799]

[0800] S150 (24 mg, 0.068 mmol) was placed in a single-mouth bottle, THF (0.5 mL) and EtOH (0.5 mL) were added, followed by a solution of NaOH (14 mg, 0.34 mmol) in H2O (0.5 mL), and the temperature was raised to 60°C. The reaction was stirred for 2 h, and the raw materials reacted completely and the reaction was stopped. After the reaction was completed, the reaction solution was concentrated under reduced pressure to remove THF and EtOH, and the pH was adjusted to 4-5 with dilute hydrochloric acid (2N). The solvent was removed by concentration under reduced pressure, and the resulting solid mixture was dissolved in DCM, dried over anhydrous sodium sulfate, filtered, and the filter cake was washed with DCM. The filtrate was taken and concentrated under reduced pressure to obtain a light yellow solid S151 (23 mg, 100%). MS: m / z[M+1] + =341.26.

[0801] (3) P51: Preparation of 2-methyl-N-(1-(1-methyl-2-oxo-1,2-dihydrobenz[cd]indol-6-yl)cyclopropyl)-5-(4-(3-methylsulfonyl)propyl)piperazin-1-yl)benzamide

[0802]

[0803] S6 (15 mg, 0.063 mmol) and S151 (23 mg, 0.068 mmol) were placed in a single-mouth bottle, and DMF (1.5 mL), DIPEA (27 mg, 0.21 mmol) and HATU (31 mg, 0.082 mmol) were added. The temperature was raised to 50°C and stirred for 1.0 h. The raw materials reacted completely and the reaction was stopped. After the reaction was completed, the reaction solution was cooled to room temperature, water was added, and a yellow solid was precipitated. The mixture was extracted with DCM three times, and the organic phases were combined, concentrated under reduced pressure, and purified by column chromatography (PE:EA=1:1-DCM:MeOH=20:1-10:1-8:1) to obtain a bright yellow solid P51 (16 mg, 46%). MS: m / z[M+1] + =561.32.

[0804] Embodiment 52

[0805] Compound P52: Preparation of 5-(4-(2-(dimethylamino)ethyl)piperazin-1-yl)-2-methyl-N-(1-(1-methyl-2-oxo-1,2-dihydrobenzo[cd]indol-6-yl)cyclopropyl)benzamide

[0806]

[0807] (1) Preparation of intermediate S153: methyl 5-(4-(2-(dimethylamino)ethyl)piperazine-1-yl)-2-methylbenzoate

[0808]

[0809] S7 (60 mg, 0.26 mmol) and S152 (49 mg, 0.31 mmol) were placed in a sealed tube, and toluene (2.0 mL), X-Phos (5 mg, 0.010 mmol), Cs2CO3 (169 mg, 0.52 mmol) and Pd2(dba)3 (5 mg, 0.0052 mmol) were added. N2 was bubbled for 30 s, and the temperature was raised to 110 ° C. The reaction was stirred overnight. The raw materials reacted completely and the reaction was stopped. After the reaction was completed, the reaction solution was cooled to room temperature, water (6 mL) was added, and DCM was extracted three times. The organic phases were combined, concentrated under reduced pressure and desolventized, and then purified by column chromatography (PE: EA = 1: 1-DCM: MeOH = 20: 1-10: 1) to obtain a light yellow solid S153 (69 mg, 87%). MS: m / z [M+1] + =306.21.

[0810] (2) Preparation of Intermediate S154: 5-(4-(2-(dimethylamino)ethyl)piperazin-1-yl)-2-methylbenzoic acid

[0811]

[0812] S153 (69 mg, 0.23 mmol) was placed in a single-mouth bottle, THF (1.0 mL) and EtOH (1.0 mL) were added, followed by a solution of NaOH (45 mg, 1.13 mmol) in H2O (1.0 mL), and the temperature was raised to 60°C. The reaction was stirred for 2 h, and the raw materials reacted completely and the reaction was stopped. After the reaction was completed, the reaction solution was concentrated under reduced pressure to remove THF and EtOH, and the pH was adjusted to 4-5 with dilute hydrochloric acid (2N). The solvent was removed by concentration under reduced pressure, and the resulting solid mixture was dissolved in DCM, dried over anhydrous sodium sulfate, filtered, and the filter cake was washed with DCM. The filtrate was taken and concentrated under reduced pressure to obtain a light yellow solid S154 (67 mg, 100%). MS: m / z[M+1] + =292.26.

[0813] (3) P52: Preparation of 5-(4-(2-(dimethylamino)ethyl)piperazin-1-yl)-2-methyl-N-(1-(1-methyl-2-oxo-1,2-dihydrobenzo[cd]indol-6-yl)cyclopropyl)benzamide

[0814]

[0815] S6 (15 mg, 0.063 mmol) and S154 (22 mg, 0.075 mmol) were placed in a single-mouth bottle, and DMF (1.5 mL), DIPEA (27 mg, 0.21 mmol) and HATU (31 mg, 0.082 mmol) were added. The temperature was raised to 50°C and stirred for 1.0 h. The raw materials reacted completely and the reaction was stopped. After the reaction was completed, the reaction solution was cooled to room temperature, water was added, and a yellow solid was precipitated. The mixture was extracted with DCM three times, and the organic phases were combined, concentrated under reduced pressure, and purified by column chromatography (PE:EA=1:1-DCM:MeOH=20:1-10:1-8:1) to obtain a bright yellow solid P52 (19 mg, 60%). MS: m / z[M+1] + =512.32.

[0816] Embodiment 53

[0817] Compound P53: Preparation of 5-(4-(2-hydroxyethyl)piperazin-1-yl)-2-methyl-N-(1-(1-methyl-2-oxo-1,2-dihydrobenzo[cd]indol-6-yl)cyclopropyl)benzamide

[0818]

[0819] (1) Preparation of intermediate S156: methyl 5-(4-(2-hydroxyethyl)piperazine-1-yl)-2-methylbenzoate

[0820]

[0821] S7 (60 mg, 0.26 mmol) and S155 (40 mg, 0.31 mmol) were placed in a sealed tube, and toluene (2.0 mL), X-Phos (5 mg, 0.010 mmol), Cs2CO3 (169 mg, 0.52 mmol) and Pd2(dba)3 (5 mg, 0.0052 mmol) were added. N2 was bubbled for 30 s, and the temperature was raised to 110 ° C. The reaction was stirred overnight. The raw materials reacted completely and the reaction was stopped. After the reaction was completed, the reaction solution was cooled to room temperature, saturated ammonium chloride solution (6 mL) was added, and DCM was used for extraction three times. The organic phases were combined, concentrated under reduced pressure, and then purified by column chromatography (PE: EA = 1: 1-DCM: MeOH = 20: 1) to obtain a colorless oil S156 (8 mg, 11%). MS: m / z [M+1] + =279.21.

[0822] (2) Preparation of Intermediate S157: 5-(4-(2-hydroxyethyl)piperazine-1-yl)-2-methylbenzoic acid

[0823]

[0824] S156 (8 mg, 0.028 mmol) was placed in a single-mouth bottle, THF (0.4 mL) and EtOH (0.4 mL) were added, followed by a solution of NaOH (6 mg, 0.14 mmol) in H2O (0.4 mL), and the temperature was raised to 60°C. The reaction was stirred for 2 h, and the raw materials reacted completely and the reaction was stopped. After the reaction was completed, the reaction solution was concentrated under reduced pressure to remove THF and EtOH, and the pH was adjusted to 4-5 with dilute hydrochloric acid (2N). The solvent was removed by concentration under reduced pressure, and the resulting solid mixture was dissolved in DCM, dried over anhydrous sodium sulfate, filtered, and the filter cake was washed with DCM. The filtrate was taken and concentrated under reduced pressure to obtain a light yellow oil S157 (7 mg, 100%). MS: m / z[M+1] + =265.26.

[0825] (3) P53: Preparation of 5-(4-(2-hydroxyethyl)piperazin-1-yl)-2-methyl-N-(1-(1-methyl-2-oxo-1,2-dihydrobenzo[cd]indol-6-yl)cyclopropyl)benzamide

[0826]

[0827] S6 (6 mg, 0.023 mmol) and S157 (7 mg, 0.028 mmol) were placed in a single-mouth bottle, and DMF (1.5 mL), DIPEA (10 mg, 0.076 mmol) and HATU (11 mg, 0.030 mmol) were added. The temperature was raised to 50°C and stirred for 1.0 h. The raw materials reacted completely and the reaction was stopped. After the reaction was completed, the reaction solution was cooled to room temperature, water was added, and a yellow solid was precipitated. The mixture was extracted with DCM three times, and the organic phases were combined, concentrated under reduced pressure, and purified by column chromatography (PE:EA=1:1-DCM:MeOH=20:1-10:1-8:1) to obtain a bright yellow solid P53 (7 mg, 63%). MS: m / z[M+1] + =485.32.

[0828] Embodiment 54

[0829] Compound P54: Preparation of 5-(3-fluoro-[1,3'-diazetidine]-1'-yl)-2-methyl-N-(1-(1-methyl-2-oxo-1,2-dihydrobenz[cd]indol-6-yl)cyclopropyl)benzamide

[0830]

[0831] (1) Preparation of intermediate S159: 5-(3-fluoro-[1,3'-diazetidine]-1'-yl)-2-methylbenzoic acid methyl ester

[0832]

[0833] S7 (60 mg, 0.26 mmol) and S158 (68 mg, 0.31 mmol) were placed in a sealed tube, and toluene (2.0 mL), X-Phos (5 mg, 0.010 mmol), Cs2CO3 (339 mg, 1.04 mmol) and Pd2(dba)3 (5 mg, 0.0052 mmol) were added. N2 was bubbled for 30 s, and the temperature was raised to 110 ° C. The reaction was stirred overnight. The raw materials reacted completely and the reaction was stopped. After the reaction was completed, the reaction solution was cooled to room temperature, water (6 mL) was added, and DCM was extracted three times. The organic phases were combined, concentrated under reduced pressure, and then purified by column chromatography (PE: EA = 3: 1-1: 1) to obtain a colorless oil S159 (42 mg, 58%). MS: m / z [M+1] + =279.21.

[0834] (2) Preparation of intermediate S160: 5-(3-fluoro-[1,3'-diazetidine]-1'-yl)-2-methylbenzoic acid

[0835]

[0836] S159 (42 mg, 0.15 mmol) was placed in a single-mouth bottle, THF (1.0 mL) and EtOH (1.0 mL) were added, followed by a solution of NaOH (30 mg, 0.75 mmol) in H2O (1.0 mL), and the temperature was raised to 60°C. The reaction was stirred for 2 h, and the raw materials reacted completely and the reaction was stopped. After the reaction was completed, the reaction solution was concentrated under reduced pressure to remove THF and EtOH, and the pH was adjusted to 4-5 with dilute hydrochloric acid (2N). The solvent was removed by concentration under reduced pressure, and the obtained solid mixture was dissolved in DCM, dried over anhydrous sodium sulfate, filtered, and the filter cake was washed with DCM. The filtrate was taken and concentrated under reduced pressure to obtain a light yellow oil S160 (40 mg, 100%). MS: m / z[M+1] + =265.26.

[0837] (3) P54: Preparation of 5-(3-fluoro-[1,3'-diazetidine]-1'-yl)-2-methyl-N-(1-(1-methyl-2-oxo-1,2-dihydrobenz[cd]indol-6-yl)cyclopropyl)benzamide

[0838]

[0839] S6 (15 mg, 0.063 mmol) and S160 (20 mg, 0.075 mmol) were placed in a single-mouth bottle, and DMF (1.5 mL), DIPEA (27 mg, 0.021 mmol) and HATU (31 mg, 0.082 mmol) were added. The temperature was raised to 50°C and stirred for 1.0 h. The raw materials reacted completely and the reaction was stopped. After the reaction was completed, the reaction solution was cooled to room temperature, water was added, and a yellow solid was precipitated. The mixture was extracted with DCM three times, and the organic phases were combined, concentrated under reduced pressure, and purified by column chromatography (PE:EA=1:1-DCM:MeOH=20:1) to obtain a bright yellow solid P54 (22 mg, 72%). MS: m / z[M+1] + =485.32.

[0840] Test Example 1. Protein level enzyme activity test

[0841] 1. Recombinantly express the SARS-CoV-2PLpro catalytic domain to obtain the reactive protein.

[0842] 2. Substrate: Z-Arg-Leu-Arg-Gly-Gly-AMC (GLPBIO, Catalog No. GA23715).

[0843] 3. Buffer: 50 mM HEPES, 10 mM DTT, 0.1 mM EDTA, pH 7.2.

[0844] 4.384-well plate: Greiner, item number 784076.

[0845] 5. Inhibitor compounds.

[0846] 6. Prepare a single concentration or a certain concentration gradient of compound stock solution dissolved in DMSO.

[0847] 7. Incubate the protein and compound mixture for 10 minutes.

[0848] 8. Add 15 μL of the mixed solution of protein and compound to each well of a 384-well plate.

[0849] 9. Prepare 80 μM substrate working solution.

[0850] 10. Add 5 μL of 80 μM substrate working solution to each well and incubate for 10 minutes.

[0851] 11. Detection: BioTek synergy NEO2, Ex: 360nM / Em: 460nm.

[0852] 12. Data analysis: Use Prism to perform nonlinear regression fitting on the data and calculate IC 50 The results are shown in Table 1.

[0853] Table 1 Inhibitory activity of compounds against papain

[0854]

[0855]

[0856] Note: +: 0.1 μM <IC50≤1μM;++:0.04μM<IC50≤0.1μM;+++:IC50≤0.04μM

[0857] Test Example 2. Experiment on inhibition of activity of Vero E6 cells infected with novel coronavirus

[0858] 1. Cell line: African green monkey kidney cells Vero E6 (ATCC, CRL-1586).

[0859] 2. Virus strains: SARS-Cov-2 WT (WT-IQTC02-16#-P2-YQ), XBB.1 (XBB.1-P3-YQ), Omicron BA.5 (GDPCC-303-Omicron-BA.5-P3-YQ) (provided by Guangzhou Customs Technical Center).

[0860] 3. Positive control: Ensitrelvir (Product No. HY-143216, MedChemExpress LLC).

[0861] 4. Infection dose: MOI (multiplicity of infection) = 0.01.

[0862] 5. Add 250 μL of cells to each well of a 48-well plate the day before, so that the number of cells per well is about 5×10 4 .

[0863] 6. Perform gradient dilution (1:3) at a maximum concentration of 10 μM, with triplicate wells set up for each concentration.

[0864] 7. Add virus strain (MOI=0.01) to each well and infect cells for 48 hours.

[0865] 8. After 48 hours, the supernatant RNA was extracted using a kit (QIAamp Viral RNA Mini Kit, Qiagen), and the viral copy number was detected by qRT-PCR. The half-maximal effective concentration (EC) was calculated based on the absolute copy number. 50 ). The results are shown in Table 2.

[0866] Table 2 Inhibitory activity of VeroE6 cells infected by virus strains

[0867]

[0868] Note: +: 0.1μM ≤ EC50 ≤ 1μM; ++: 0.04μM <EC50≤0.1μM;+++:EC50≤0.04μM

[0869] Test Example 3. Liver microsome stability test

[0870] 1. Preheat PBS (pH 7.4).

[0871] 2. Preparation of intermediate solutions of test and positive reference compounds

[0872] 2.1 500 μM intermediate solution: add 5 μL of 10 mM compound stock solution and positive reference compound to 95 μL DMSO;

[0873] 2.2 1.5 μM intermediate solution in liver microsomes (0.75 mg / mL): Add 1.5 μL of 500 μM intermediate solution and 18.75 μL of 20 mg / mL liver microsomes to 479.75 μL PBS.

[0874] 3. Prepare NADPH stock solution (6 mM, 5 mg / mL) by dissolving NADPH in PBS.

[0875] 4. Dispense 30 μL of the 1.5 μM intermediate solution containing 0.75 mg / mL microsomal solution into the assay plates designated for different time points (0, 5, 15, 30, 45 minutes).

[0876] 5. Pre-incubate the plate at 37°C for 5 minutes.

[0877] 6. For 0 minutes, add 150 μL of stop solution of acetonitrile:methanol (1:1) containing internal standard to the wells before adding 15 μL of NADPH stock solution (6 mM).

[0878] 7. For other time points, add 15 μL of NADPH stock solution (6 mM) to the wells to start the reaction and timing.

[0879] 8. At 5, 15, 30, and 45 minutes, add 150 μL of the internal standard acetonitrile:methanol (1:1) stop solution to the corresponding wells of the plate to stop the reaction.

[0880] 9. After termination, shake the plate for 10 minutes (600 rpm) and then centrifuge at 4000 rpm for 15 minutes.

[0881] 10. Transfer 80 μL of supernatant from each well to a 96-well sample plate containing 140 μL of pure water for LC / MS analysis.

[0882] Table 3 Liver microsome stability test results

[0883]

[0884] Note: Rat means rat; Human means human; 1 / 2 represents: half-life; Clint represents: clearance rate; Eh represents: clearance ratio.

[0885] Test Example 4. Pharmacokinetic Test

[0886] Conventional PK test in rats:

[0887] 1. The experimental design is shown in the following table:

[0888]

[0889]

[0890] Note: **: Blood samples were collected from 3 rats at each time point. *: Animals in the oral administration group were fasted overnight (10-14 hours) before administration and fed 4 hours after administration.

[0891] 2. Preparation of drug delivery preparations:

[0892] Solvent formula: 10% DMSO, 5% ethanol, 5% Cremophor EL and 80% deionized water. Weigh 6.68 mg of the test sample into a suitable container, measure 1.316 mL of DMSO, vortex for 1 min, and sonicate for 10 min to obtain a 5 mg / mL clear DMSO stock solution.

[0893] Take 1 mL of 5 mg / mL DMSO stock solution, add 0.5 mL of ethanol, vortex for 1 min, add 0.5 mL of Cremophor EL, vortex for 1 min, and finally add 8 mL of deionized water, vortex for 1 min to obtain a clear drug delivery preparation with a concentration of 0.5 mg / mL. Prepare before use and store at room temperature after preparation.

[0894] 3. Animal selection:

[0895] Before the study begins, all animals suitable for the experiment are weighed, and after removing a certain number of animals with heavy and / or light weights, the weight of the animals used for the experiment is between ±20% of the average body weight.

[0896] 4. Animal husbandry:

[0897] The test animals will be housed in rat cages (2-5 rats / cage) and provided with approximately 12 hours / 12 hours of alternating light and dark lighting per day. The dark time can be interrupted intermittently due to the needs of research-related activities. The ambient temperature and relative humidity of the animal room are monitored daily and controlled within the range of 20-26°C and 40-70%.

[0898] 5. Administration route:

[0899] The drug is administered by oral gavage, and the route of administration is consistent with the intended clinical route of administration.

[0900] 6. Cage-side observation:

[0901] During the experiment, all animals were observed at least twice a day (sampling could be accompanied by observation), including morbidity, mortality, damage, and food and water supply. Animals in poor health should be marked and further observed, and euthanized if necessary.

[0902] 7. Biological Sample Collection:

[0903] Oral sampling: 8 collection time points in total, 0.25, 0.5, 1, 2, 4, 6, 8 and 24h after administration.

[0904] Plasma: After euthanasia, blood was collected by puncture. The samples were placed in tubes containing K2-EDTA and kept on ice until centrifugation. Blood samples were centrifuged at 6800g for 6 minutes at 2-8℃ within 1 hour after collection, and plasma samples were frozen at about -80℃.

[0905] 8. Biological Sample Analysis

[0906] The compounds were analyzed. The intra-day accuracy of the analytical batch was evaluated using quality control samples at the same time as the analytical samples. Acceptance criteria: At least 50% of the quality control samples at each quality control concentration level and all quality control concentration levels at least > 66.7% of the quality control samples should have an accuracy between 80-120% (75%-125% for the organization).

[0907] When calculating pharmacokinetic parameters, the BLQ concentration data before the peak time (Tmax) after administration of the oral group was calculated as "0", and the BLQ concentration data after Tmax was not included in the calculation.

[0908] Using Phoenix The non-compartmental statistical moment method of 7.0 software was used to calculate the following main pharmacokinetic parameters: Tmax, Cmax, AUC(0-t), T1 / 2, etc.

[0909] 9. Final Disposition of Animals

[0910] All surviving experimental animals were euthanized after the experiment (using a dedicated euthanasia box for carbon dioxide euthanasia).

[0911] 10. Analytical methods

[0912] Analytical instrument: LC-MS / MS-12 (TQ5500, Triple quad);

[0913] Pipette: Eppendorf

[0914] Oscillator: 5810R, Eppendorf

[0915] Centrifuge: 420R, 220R, Eppendorf

[0916] (Other suppliers or other models of equipment may be used if necessary)

[0917] Sample processing:

[0918] 1) Take 30 μL of the mixed standard curve sample, quality control sample, blank sample, zero concentration sample and test sample.

[0919] 2) For standard curve samples, quality control samples, zero concentration samples and test samples, add 300 μL of internal standard working solution (containing 100 ng / mL IS). For blank samples and ULOQ without IS samples (if necessary), add the same volume of acetonitrile.

[0920] 3) Vortex mix for 1 min

[0921] 4) Centrifuge at 4°C for 7 minutes (18,000 g)

[0922] 5) Take 200 μL of supernatant and add it to the corresponding 96-well injection plate

[0923] 6) Inject 4 μL and perform LC-MS / MS analysis.

[0924] Table 4 In vivo oral pharmacokinetic data of compounds

[0925]

[0926] Finally, it should be noted that the above embodiments are only used to illustrate the technical solution of the present invention rather than to limit it. Although the present invention has been described in detail with reference to the preferred embodiments, ordinary technicians in the field should understand that the specific implementation methods of the present invention can still be modified or some technical features can be replaced by equivalents without departing from the spirit of the technical solution of the present invention, which should be included in the scope of the technical solution for protection of the present invention.

Claims

1. A compound represented by formula (I), or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, in, R1 is selected from hydrogen, C 1-6 Alkyl, C 1-6 Haloalkyl and C 3-8 Cycloalkyl; R2 is selected from C 1-6 Alkyl and C 1-6 Haloalkyl; R3 is selected from hydrogen; m is 3; R4 is selected from Ring A is selected from 4-12 membered heterocyclic groups; R6 is selected from hydrogen, C 1-6 Alkyl, -OC 1-6 Alkyl, -NH-C 1-6 Alkyl, -N-(C 1-6 alkyl)2, 4-8 membered heterocyclic group and -NH-4-8 membered heterocyclic group, the C 1-6 The alkyl and 4-8 membered heterocyclic groups are optionally substituted by one or more selected from hydrogen, halogen, =O, -CN, -OH, -COOH, -NH2, -C 1-6 Alkyl, -OC 1-6 Alkyl, -NH-C 1-6 Alkyl, -N-(C 1-6 alkyl)2, -S(=O)2OH, -S(=O)2NH2, -S(=O)2-C 1-6 Alkyl, -C(=O)-C 1-6 Alkyl, -C(=O)-NH-C 1-6 Alkyl, -NH-C(=O)-C 1-6 Alkyl and morpholinyl radical substitution; R7 is selected from hydrogen, halogen, -CN, -OH, -COOH, -NH2, C 1-6 Alkyl and C 1-6 Haloalkyl, or two R7 form =O; Alternatively, two R7 atoms form a C 3-6 Cycloalkyl and 4-7 membered heterocyclic group, the C 3-6 Cycloalkyl, 4-7 membered heterocyclic group optionally 1, 2 or 3 selected from OH and C 1-4 Alkyl radical substitution; Alternatively, R6 and R7 are linked to form a 4-6 membered heterocyclic group, wherein the 4-6 membered heterocyclic group is optionally substituted by 1, 2 or 3 groups selected from OH and C1-4 alkyl; n is 0, 1, 2, 3, 4, 5, 6 or 7.

2. The compound according to claim 1, or its stereoisomer, or its pharmaceutically acceptable salt, wherein: R1 is selected from hydrogen, C 1-4 Alkyl, C 1-4 Haloalkyl and C 3-6 Cycloalkyl.

3. The compound according to claim 2, or its stereoisomer, or its pharmaceutically acceptable salt, wherein: R1 is selected from the group consisting of hydrogen, methyl, ethyl, n-propyl, isopropyl, cyclobutyl, cyclopentyl and cyclobutyl.

4. The compound according to claim 3, or its stereoisomer, or its pharmaceutically acceptable salt, wherein: R1 is selected from hydrogen, methyl, ethyl, isopropyl and cyclopropyl.

5. The compound according to claim 1, or its stereoisomer, or its pharmaceutically acceptable salt, wherein: R1 is selected from hydrogen and C 1-4 alkyl.

6. The compound according to claim 5, or its stereoisomer, or its pharmaceutically acceptable salt, wherein: R1 is selected from hydrogen, methyl, ethyl and isopropyl.

7. The compound according to claim 1, or its stereoisomer, or its pharmaceutically acceptable salt, wherein: R2 is selected from C 1-4 Alkyl and C 1-4 Halogenated alkyl.

8. The compound according to claim 7, or its stereoisomer, or its pharmaceutically acceptable salt, wherein: R2 is selected from the group consisting of methyl, ethyl, halomethyl and haloethyl.

9. The compound according to claim 8, or its stereoisomer, or its pharmaceutically acceptable salt, wherein: R2 is methyl.

10. The compound according to claim 1, or its stereoisomer, or its pharmaceutically acceptable salt, wherein: Ring A is selected from a 4- to 10-membered heterocyclic group.

11. The compound according to claim 10, or its stereoisomer, or its pharmaceutically acceptable salt, wherein: Ring A is selected from a 4- to 10-membered heterocyclic group containing 1, 2 or 3 heteroatoms selected from N, O and S.

12. The compound according to claim 10, or its stereoisomer, or its pharmaceutically acceptable salt, wherein: Ring A is selected from a 4-10 membered heterocyclic group containing 1 or 2 N atoms.

13. The compound according to claim 10, or its stereoisomer, or its pharmaceutically acceptable salt, wherein: Ring A is selected from a 4-7 membered nitrogen-containing monocyclic heterocyclic group, a 7-10 membered nitrogen-containing bridged heterocyclic group, a 7-10 membered nitrogen-containing bis-cyclic heterocyclic group, and a 7-10 membered nitrogen-containing spirocyclic heterocyclic group.

14. The compound according to claim 10, or its stereoisomer, or its pharmaceutically acceptable salt, wherein: Ring A is selected from in represents the connection site between ring A and the phenyl group in formula I.

15. The compound according to claim 10, or its stereoisomer, or its pharmaceutically acceptable salt, wherein: Ring A is selected from in represents the connection site between ring A and the phenyl group in formula I.

16. The compound according to claim 1, or its stereoisomer, or its pharmaceutically acceptable salt, wherein: R6 is selected from hydrogen, C 1-4 Alkyl, -OC 1-4 Alkyl, -NH-C 1-4 Alkyl, -N-(C 1-4 alkyl)2, 4-6 membered heterocyclic group and -NH-4-6 membered heterocyclic group, the C 1-4 The alkyl and 4-6 membered heterocyclic groups are optionally substituted by 1, 2, 3, 4 or 5 groups selected from hydrogen, fluorine, chlorine, bromine, =O, -CN, -OH, -COOH, -NH2, -C 1-4 Alkyl, -OC 1-4 Alkyl, -NH-C 1-4 Alkyl, -N-(C 1-4 alkyl)2, -S(=O)2OH, -S(=O)2NH2, -S(=O)2-C 1-4 Alkyl and morpholinyl groups are substituted.

17. The compound according to claim 16, or its stereoisomer, or its pharmaceutically acceptable salt, wherein: R6 is selected from hydrogen, methyl, ethyl, propyl, butyl, -NH-methyl, -NH-ethyl, -NH-propyl, -NH-butyl, -N(methyl), -N(methyl)-ethyl, -N(methyl)-propyl, -N(ethyl), -N(ethyl)-propyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, -NH-oxetanyl, -NH-tetrahydrofuranyl and -NH-tetrahydropyranyl, wherein the methyl, ethyl, propyl, butyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, -NH-oxetanyl, -NH-tetrahydrofuranyl and -NH-tetrahydropyranyl The pyridyl, piperazinyl, morpholinyl, thiomorpholinyl, oxetanyl, tetrahydrofuranyl and tetrahydropyranyl groups are optionally substituted with 1, 2, 3, 4 or 5 groups selected from hydrogen, fluorine, chlorine, bromine, =O, -OH, -COOH, -NH2, methyl, ethyl, propyl, -O-methyl, -O-ethyl, -NH-methyl, -NH-ethyl, -N(methyl)2, -N(methyl)-ethyl, -N(ethyl)2, -S(=O)2OH, -S(=O)2NH2, -S(=O)2-methyl and morpholinyl.

18. The compound according to claim 17, or its stereoisomer, or its pharmaceutically acceptable salt, wherein: R6 is selected from hydrogen, methyl, ethyl, propyl, butyl, The methyl, ethyl, propyl, butyl, Optionally substituted with 1, 2 or 3 groups selected from hydrogen, fluorine, =O, -OH, -COOH, methyl, -N(CH3)2, -S(=O)2-methyl and morpholinyl.

19. The compound according to claim 18, or its stereoisomer, or its pharmaceutically acceptable salt, wherein: R6 is selected from hydrogen, -CH3, -CH2CH3, 20. The compound according to claim 1, or its stereoisomer, or its pharmaceutically acceptable salt, wherein: R6 is selected from hydrogen, C 1-4 Alkyl, -N-(C 1-4 alkyl)2 and 4-6 membered heterocyclic group, the C 1-4 The alkyl and 4-6 membered heterocyclic groups are optionally substituted by 1, 2 or 3 groups selected from hydrogen, halogen, =O, -CN, -OH, -COOH, -NH2, -N-(C 1-4 alkyl)2, -S(=O)2-methyl, C 1-4 Alkyl and morpholinyl groups are substituted.

21. The compound according to claim 20, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein: R6 is selected from hydrogen, C 1-4 Alkyl, -N-(C 1-4 alkyl)2 and 4-6 membered heterocyclic group, the 4-6 membered heterocyclic group contains 1 or 2 heteroatoms selected from N, O, S, the C 1-4 The alkyl and 4-6 membered heterocyclyl groups are optionally substituted with 1, 2 or 3 groups selected from hydrogen, fluorine, =O, -OH, -N(CH3)2, -S(=O)2-CH3, -CH3 and morpholinyl.

22. The compound according to claim 21, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein: R6 is selected from hydrogen, -CH3, -CH2CH3, 23. The compound according to claim 1, or its stereoisomer, or its pharmaceutically acceptable salt, wherein: R7 are each independently selected from hydrogen, halogen, -CN, -OH, -COOH, -NH2, C 1-6 Alkyl and C 1-4 Halogenated alkyl.

24. The compound according to claim 23, or its stereoisomer, or its pharmaceutically acceptable salt, wherein: R7 is each independently selected from hydrogen, fluorine, chlorine, bromine, -CN, -OH, -COOH, -NH2, methyl, ethyl, propyl, halomethyl, haloethyl and halopropyl.

25. The compound according to claim 24, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein: R7 is each independently selected from hydrogen, fluorine, -OH, -NH2, -COOH and methyl.

26. The compound according to claim 25, or its stereoisomer, or its pharmaceutically acceptable salt, wherein: R7 are each independently selected from hydrogen, fluorine and methyl.

27. The compound according to any one of claims 1 to 26, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein: The compound is selected from the compound represented by formula (I-1A) in, R1 is defined as any one of claims 1 to 6; R2 is defined as any one of claims 1, 7-9; R6 is defined as in any one of claims 1, 16-22; R7 is defined as in any one of claims 1, 23-26; The definition of n is as described in claim 1.

28. The compound of claim 27, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, comprising one or more of the following: R1 is selected from methyl and ethyl; R7 are each independently selected from hydrogen; n is 0, 1, 2 or 3.

29. The compound according to claim 28, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein: R6 is selected from -NH-C 1-4 Alkyl, -N-(C 1-4 alkyl)2, 4-6 membered heterocyclic group and -NH-4-6 membered heterocyclic group, the -NH-C 1-4 Alkyl, -N-(C 1-4 alkyl)2, 4-6 membered heterocyclyl and -NH-4-6 membered heterocyclyl are optionally substituted by 1, 2 or 3 groups selected from hydrogen, fluorine, chlorine, =O, -OH, -NH2, methyl and -N(CH3)2.

30. The compound according to claim 29, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein: R6 is selected from -NH-methyl, -NH-ethyl, -NH-propyl, -NH-butyl, -N(methyl)2, -N(methyl)-ethyl, -N(methyl)-propyl, -N(ethyl)2, -N(ethyl)-propyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, -NH-oxetanyl, -NH-tetrahydrofuranyl and -NH-tetrahydropyranyl, and the methyl, ethyl, propyl, butyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, oxetanyl, tetrahydrofuranyl and tetrahydropyranyl are optionally substituted with 1, 2 or 3 groups selected from hydrogen, fluorine, chlorine, =O, -OH, -NH2 and methyl.

31. The compound according to claim 30, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein: R6 is selected from 32. The compound according to claim 27, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein: R6 and R7 are linked to form a pyrrolidinyl group, and the pyrrolidinyl group is optionally substituted with a methyl group.

33. The compound according to claim 28, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein: R6 is selected from 4-6 membered heterocyclic groups, wherein the 4-6 membered heterocyclic groups are optionally substituted by 1, 2 or 3 groups selected from hydrogen, halogen, =O, -OH and C 1-4 Alkyl radicals are substituted.

34. The compound according to claim 33, or its stereoisomer, or its pharmaceutically acceptable salt, wherein: R6 is selected from a 4-6 membered heterocyclic group, wherein the 4-6 membered heterocyclic group is a monocyclic ring, the 4-6 membered heterocyclic group contains 1 or 2 heteroatoms selected from N, O, S, and the 4-6 membered heterocyclic group is optionally substituted by 1, 2 or 3 groups selected from hydrogen, fluorine, =O, -OH and methyl.

35. The compound according to claim 34, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein: R6 is selected from 36. The compound according to any one of claims 1 to 26, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein: The compound is selected from the compound represented by formula (I-1A-1) in, R1 is defined as any one of claims 1 to 6 R2 is defined as any one of claims 1, 7-9, Ring B is selected from 4-6 membered heterocyclic groups, R 61 is selected from hydrogen, halogen, =O, -CN, -OH, -COOH, -NH2, -C 1-4 Alkyl, -NH-C 1-4 Alkyl and -N-(C 1-4 Alkyl)2, p is 0, 1, 2 or 3.

37. The compound according to claim 36, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein: R1 is selected from methyl and ethyl.

38. The compound according to claim 36, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein: Ring B is selected from azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl and thiomorpholinyl.

39. The compound according to claim 36, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein: R 61 Selected from hydrogen, fluorine, chlorine, bromine, =O, -CN, -OH, -COOH, -NH2, methyl, ethyl and propyl.

40. The compound according to claim 39, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein: R 61 is selected from the group consisting of hydrogen, fluorine, =O, -OH and methyl.

41. The compound according to any one of claims 1 to 26, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein: The compound is selected from the compound represented by formula (I-1B) in, T1 is C, is a single bond, R1 is defined as any one of claims 1 to 6; R2 is defined as any one of claims 1, 7-9; R6 is defined as in any one of claims 1, 16-22; R7 is defined as in any one of claims 1, 23-26; The definition of n is as described in claim 1.

42. The compound of claim 41, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, comprising one or more of the following: R6 is selected from hydrogen and C 1-4 Alkyl, the C 1-4 The alkyl group is optionally substituted with 1, 2 or 3 groups selected from hydrogen, halogen, -OH, -COOH, methyl, -NH(CH3), -N(CH3)2, -N(CH3)(CH2CH3), -N(CH2CH3)2 and -S(=O)2-CH3, R7 are each independently selected from hydrogen, -COOH and C 1-4 alkyl, Alternatively, two R7 form =O, Alternatively, two R7 and the atoms to which they are attached form a cyclopropyl, azetidinyl, pyrrolidinyl, piperidinyl or homopiperidinyl group, Alternatively, R6 and R7 are linked to form a pyrrolidinyl group, and the pyrrolidinyl group is optionally substituted with 1 OH group; n is 0, 1, 2, 3 or 4.

43. The compound according to claim 42, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein: R6 is selected from hydrogen, methyl, ethyl, propyl, butyl, and the methyl, ethyl, propyl, butyl are optionally substituted by 1, 2 or 3 groups selected from hydrogen, fluorine, -OH, -COOH, methyl, -N(CH3)2 and -S(=O)2-CH3.

44. The compound according to claim 43, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein: R6 is selected from hydrogen, -CH3, -CH2CH3, 45. The compound according to claim 42, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein: R6 is selected from hydrogen and C 1-4 Alkyl, the C 1-4 The alkyl group is optionally substituted with 1, 2 or 3 groups selected from hydrogen, -OH, -NH(CH3), -N(CH3)2 and -S(=O)2-CH3.

46. ​​The compound according to claim 45, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein: R6 is selected from hydrogen, -CH3, -CH2CH3, 47. The compound according to claim 41, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein: R7 are each independently selected from hydrogen, -COOH and methyl.

48. The compound of claim 41, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein: R7 are each independently selected from hydrogen and C 1-4 alkyl.

49. The compound according to claim 48, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein: R7 are each independently selected from hydrogen and methyl.

50. The compound of claim 41, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein: R6 and R7 are linked to form a pyrrolidyl group.

51. The compound of claim 41, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein: n is 0, 1 or 2.

52. The compound according to any one of claims 1 to 26, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein: The compound is selected from the compound represented by formula (I-1C) in, R1 is defined as any one of claims 1 to 6; R2 is defined as any one of claims 1, 7-9; R6 is defined as in any one of claims 1, 16-22; R7 is defined as in any one of claims 1, 23-26; The definition of n is as described in claim 1.

53. The compound according to claim 52, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein: R6 is selected from hydrogen, C 1-4 Alkyl, -N-(C 1-4 alkyl)2 and 4-6 membered heterocyclic group, the C 1-4 The alkyl and 4-6 membered heterocyclyl groups are optionally substituted with 1, 2 or 3 groups selected from hydrogen, halogen, -OH, -COOH and methyl.

54. The compound according to claim 53, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein: R6 is selected from hydrogen, -CH3, 55. The compound according to claim 52, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein: R7 is hydrogen.

56. The compound of claim 52, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein: R6 and R7 are linked to form a 5-6 membered heterocyclic group, and the 5-6 membered heterocyclic group is optionally substituted by one OH or methyl group.

57. The compound of claim 56, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein R6 and R7 are linked to form a pyrrolidinyl or piperidinyl group, and the pyrrolidinyl or piperidinyl group is optionally substituted with 1 methyl group.

58. The compound of claim 52, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein: n is 0, 1 or 2.

59. The compound according to any one of claims 1 to 26, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein: The compound is selected from:

60. A pharmaceutical composition comprising at least one compound according to any one of claims 1 to 59, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers and / or excipients.

61. A compound as described in any one of claims 1 to 59, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described in claim 60 for the preparation of a medicament for treating and / or preventing a disease or condition or alleviating the severity of the disease or condition, wherein the disease or condition is caused by a coronavirus, wherein the medicament comprises a human medicament and a veterinary medicament.

62. The use according to claim 61, wherein The disease or condition is selected from respiratory disease and feline infectious peritonitis.

63. The use according to claim 62, wherein the respiratory disease is a simple infection.

64. The use of claim 62, wherein the respiratory disease is pneumonia.

65. The use according to claim 62, wherein the respiratory disease is an acute respiratory tract infection.

66. The use of claim 62, wherein the respiratory disease is severe acute respiratory infection (SARI).

67. The use of claim 62, wherein the respiratory disease is selected from hypoxic respiratory failure and acute respiratory distress syndrome, COVID-19, severe acute respiratory syndrome (SARS) and Middle East respiratory syndrome (MERS).

68. The use of claim 63, wherein the simple infection is selected from the group consisting of fever, cough and sore throat.

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