Naphthalimide-based coronavirus papain-like protease inhibitor

Abstract

The present application relates to the field of pharmaceutical chemistry, and in particular to a naphthalimide-based coronavirus papain-like protease inhibitor as represented by formula (I) and a use thereof.

Description

Naphthalimide-based coronavirus papain-like protease inhibitors Technical Field

[0001] The present application belongs to the field of medicinal chemistry, and specifically relates to a naphthalene diimide-based coronavirus papain-like protease inhibitor represented by formula (I) and its use. Background Art

[0002] Coronaviruses, a class of pathogens that threaten human health, belong to the Coronaviridae family of the order Nidovirales. They are enveloped, single-stranded, positive-strand RNA viruses divided into three genera: α, β, and γ. Coronavirus particles are spherical or irregular in shape, have an envelope, and are 80-120 nm in size. 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 the spike protein (S), the small envelope protein (E), the membrane protein (M), and the nucleocapsid (N). The E and M proteins are mainly involved in the assembly process of the virus, and the N protein encapsulates 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 mutations in the S protein domain can lead to changes in the species tropism and infection characteristics of the virus.

[0003] 3C-like proteases (3CLpro or Mpro) and papain-like proteases (PLpro) play an important role in coronavirus replication. PLpro is a key regulatory protein molecule in the formation of the SARS-CoV-2 replicase complex (RC) and 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 innate immune response and has important biological functions in regulating the replication and proliferation of the new coronavirus and suppressing the host's immune response. It is highly conserved in evolution and has a deubiquitination function, making it an ideal target for the development of broad-spectrum anti-coronavirus drugs. Therefore, inhibiting the activity of this viral replication complex through small molecule inhibitors of PLpro protease may help treat novel coronavirus pneumonia. Summary of the Invention

[0004] The first aspect of the present application 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] in,

[0006] 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 groups;

[0007] 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 alkyl halide;

[0008] R3 is selected from 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 alkyl halide;

[0009] m is 0, 1, 2, or 3;

[0010] R4 is selected from R5 and

[0011] R5 is selected from C 1-8 Alkyl and C 1-8 Halogenated alkyl, the C 1-8 Alkyl and C 1-8 The haloalkyl group is optionally substituted with one or more selected from -OH, -OC 1-4 Alkyl, -NH2, -NH-C 1-4 Alkyl and -N(C 1-4Alkyl)2 group substitution;

[0012] 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;

[0013] R6 is selected from hydrogen, carbonyl, 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 heterocyclyl and -NH-(4-8 membered heterocyclyl), the C 1-6 The alkyl and 4-8 membered heterocyclic groups are optionally substituted by one or more selected from 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;

[0014] R7 is selected from 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;

[0015] 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;

[0016] 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;

[0017] n is 0, 1, 2, 3, 4, 5, 6 or 7.

[0018] In some embodiments, said R4 is

[0019] In some embodiments, the R1 is selected from hydrogen, C 1-4 Alkyl, C 1-4 Haloalkyl, -C(=O)-C 1-4 Alkyl, -C(=O)-C 1-4 Halogenated alkyl, C 3-6 cycloalkyl and 4-6 membered heterocyclic groups.

[0020] In some embodiments, the R1 is selected from hydrogen, C 1-4 Alkyl and C 3-6 Cycloalkyl.

[0021] In some embodiments, the R1 is selected from hydrogen, methyl, ethyl, n-propyl, isopropyl, cyclobutyl, cyclopentyl, and cyclobutyl.

[0022] In some embodiments, the R1 is selected from hydrogen, methyl, ethyl, isopropyl, and cyclopropyl.

[0023] In some embodiments, the R1 is selected from hydrogen and C 1-4 alkyl.

[0024] In some embodiments, the R1 is selected from hydrogen, methyl, ethyl, and isopropyl.

[0025] 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.

[0026] In some embodiments, the R2 is selected from hydrogen, fluorine, chlorine, -CN, -OH, -COOH, -NH2, -O-methyl, -NH-methyl, methyl, ethyl, halomethyl, and haloethyl.

[0027] In some embodiments, said R2 is methyl.

[0028] In some embodiments, the R3 is selected from 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.

[0029] In some embodiments, the R3 is selected from fluoro, chloro, bromo, -CN, -OH, -COOH, -NH2, -O-methyl, -NH-methyl, methyl, ethyl, halomethyl, and haloethyl.

[0030] In some embodiments, m is 0.

[0031] In some embodiments, the R5 is selected from C 1-6 Alkyl and C 1-6 Halogenated alkyl, the C 1-6 Alkyl and C 1-6 Haloalkyl is optionally substituted by 1, 2, 3, 4 or 5 groups selected from -NH2, -NH-C 1-4 Alkyl and -N(C 1-4 alkyl)2 group substitution.

[0032] In some embodiments, the 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 -NH2, -NH-methyl, -NH(methyl)2.

[0033] In some embodiments, the R5 is selected from

[0034] In some embodiments, the ring A is selected from C 4-10 cycloalkenyl and 4-10 membered heterocyclic groups.

[0035] 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.

[0036] 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.

[0037] In some embodiments, the ring A is selected from in represents the connection site between ring A and the phenyl group in formula I.

[0038] In some embodiments, the ring A is selected from a 4-10 membered heterocyclyl.

[0039] In some embodiments, the ring A is selected from a 4-10 membered heterocyclyl group containing 1 or 2 N atoms.

[0040] In some embodiments, the ring A is selected from in represents the connection site between ring A and the phenyl group in formula I.

[0041] In some embodiments, the R6 is selected from hydrogen, carbonyl, 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 heterocyclyl and -NH-(4-6 membered heterocyclyl), the C 1-4 Alkyl and 4-6 membered heterocyclic groups are optionally substituted by 1, 2, 3, 4 or 5 groups selected from 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.

[0042] 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, -N H-oxetanyl, -NH-tetrahydrofuranyl and -NH-tetrahydropyranyl, said methyl, ethyl, propyl, butyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, oxetanyl, tetrahydrofuranyl and tetrahydropyranyl being optionally substituted with 1, 2, 3, 4 or 5 groups selected from fluoro, chloro, bromo, =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.

[0043] In some embodiments, the 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 fluoro, =O, -OH, -COOH, methyl, -N(CH3)2, -S(=O)2-methyl and morpholinyl.

[0044] In some embodiments, the R6 is selected from hydrogen, fluorine, -CN, -OH, -NH2, -CH3, -CH2CH3,

[0045] In some embodiments, R6 is selected from hydrogen, C 1-4 Alkyl, -N-(C 1-4 alkyl) 2 and 4-6 membered heterocyclic group, said C 1-4 Alkyl and 4-6 membered heterocyclic groups are optionally substituted by 1, 2 or 3 groups selected from 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.

[0046] In some embodiments, R6 is selected from hydrogen, C 1-4 Alkyl, -N-(C 1-4 alkyl)2 and 4-6 membered heterocyclic group, wherein the 4-6 membered heterocyclic group contains 1 or 2 heteroatoms selected from N, O, S, and the C 1-4 The alkyl and 4-6 membered heterocyclyl groups are optionally substituted with 1, 2 or 3 groups selected from fluoro, =O, -OH, -N(CH3)2, -S(=O)2-CH3, -CH3 and morpholinyl.

[0047] In some embodiments, R6 is selected from hydrogen, -CH3, -CH2CH3,

[0048] In some embodiments, the R7 are each independently selected from 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.

[0049] In some embodiments, the R7 are each independently selected from 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.

[0050] In some embodiments, the R7 are each independently selected from fluoro, -OH, -NH2, -COOH and methyl.

[0051] In some embodiments, the R7 are each independently selected from fluoro and methyl.

[0052] In some embodiments, two R7 form =0.

[0053] In some embodiments, the compound is selected from the compound represented by formula (I-1),

[0054] Wherein, R1, R2, Ring A, R6, R7 and n are defined as described in any embodiment of the present application.

[0055] In some embodiments, the compound is selected from the compound represented by formula (I-1A),

[0056] Wherein, the definitions of R1, R2, R6, R7 and n are as described in any embodiment of the present application.

[0057] In some embodiments, the R1 is selected from methyl and ethyl.

[0058] In some embodiments, the 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 fluorine, chlorine, =O, -OH, -NH2, methyl and -N(CH3)2.

[0059] 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 fluoro, chloro, =O, -OH, -NH2 and methyl.

[0060] In some embodiments, the R6 is selected from

[0061] In some embodiments, R6 and R7 are linked to form a pyrrolidinyl group, which is optionally substituted with one methyl group.

[0062] In some embodiments, n is 0, 1, 2, or 3.

[0063] In some embodiments, the R6 is selected from 4-6 membered heterocyclyl, wherein the 4-6 membered heterocyclyl is optionally substituted by 1, 2 or 3 groups selected from halogen, =O, -OH and C 1-4 Alkyl groups are substituted.

[0064] In some embodiments, R6 is selected from a 4-6 membered heterocyclyl, wherein 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 fluorine, =O, -OH and methyl.

[0065] In some embodiments, the R6 is selected from

[0066] In some embodiments, the compound is selected from the compound represented by formula (I-1A-1),

[0067] in,

[0068] R1 and R2 are as defined in any embodiment of the present application;

[0069] Ring B is selected from 4-6 membered heterocyclic groups;

[0070] R 61 Selected from halogen, =O, -CN, -OH, -COOH, -NH2, -C 1-4 Alkyl, -NH-C 1-4 Alkyl and -N-(C 1-4 Alkyl)2;

[0071] p is 0, 1, 2 or 3.

[0072] In some embodiments, the R1 is selected from methyl and ethyl.

[0073] In some embodiments, the ring B is selected from azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, and thiomorpholinyl.

[0074] In some embodiments, the R 61 Selected from fluorine, chlorine, bromine, =O, -CN, -OH, -COOH, -NH2, methyl, ethyl and propyl.

[0075] In some embodiments, the R 61 is selected from fluorine, =O, -OH and methyl.

[0076] In some embodiments, the compound is selected from the compound represented by formula (I-1A-2),

[0077] in,

[0078] R1 and R2 are as defined in any embodiment of the present application;

[0079] R 61 Selected from hydrogen, C 1-4alkyl and 4-6 membered heterocyclic groups.

[0080] In some embodiments, said R1 is selected from methyl.

[0081] In some embodiments, the R 61 is selected from hydrogen, methyl, ethyl, propyl, butyl, oxetanyl, tetrahydrofuranyl and tetrahydropyranyl.

[0082] In some embodiments, the R 61 Selected from hydrogen, -CH2CH3 and

[0083] In some embodiments, the compound is selected from the compound represented by formula (I-1B),

[0084] in,

[0085] T1 is C, CH or N, is a single bond or a double bond;

[0086] The definitions of R1, R2, R6, R7 and n are as described in any embodiment of the present application.

[0087] In some embodiments, said T1 is N, For a single bond.

[0088] In some embodiments, the 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 halogen, -OH, -COOH, methyl, -NH(CH3), -N(CH3)2, -N(CH3)(CH2CH3), -N(CH2CH3)2 and -S(=O)2-CH3.

[0089] 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 groups are optionally substituted by 1, 2 or 3 groups selected from fluorine, -OH, -COOH, methyl, -N(CH3)2 and -S(=O)2-CH3.

[0090] In some embodiments, R6 is selected from hydrogen, -CN, -NH2, -CH3, -CH2CH3,

[0091] In some embodiments, the R7 are each independently selected from -COOH and C 1-4 alkyl.

[0092] In some embodiments, the R7 are each independently selected from -COOH and methyl.

[0093] In some embodiments, two R7 form =0.

[0094] In some embodiments, R6 and R7 are linked to form a pyrrolidinyl group, which is optionally substituted with 1 OH group.

[0095] In some embodiments, n is 0, 1, 2, 3, or 4.

[0096] In some embodiments, the 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 -OH, -NH(CH3), -N(CH3)2 and -S(=O)2-CH3.

[0097] In some embodiments, R6 is selected from hydrogen, -CH3, -CH2CH3,

[0098] In some embodiments, the R7 are each independently selected from C 1-4 alkyl.

[0099] In some embodiments, the R7 are each independently selected from methyl.

[0100] In some embodiments, two R7 together with the atoms to which they are attached form a cyclopropyl, azetidinyl, pyrrolidinyl, piperidinyl, or homopiperidinyl.

[0101] In some embodiments, R6 and R7 are linked to form a pyrrolidinyl group.

[0102] In some embodiments, n is 0, 1 or 2.

[0103] In some embodiments, the compound is selected from the compound represented by formula (I-1C),

[0104] Wherein, the definitions of R1, R2, R6, R7 and n are as described in any embodiment of the present application.

[0105] In some embodiments, R6 is selected from hydrogen, C 1-4 Alkyl, -N-(C 1-4alkyl) 2 and 4-6 membered heterocyclic group, said C 1-4 The alkyl and 4-6 membered heterocyclyl groups are optionally substituted with 1, 2 or 3 groups selected from halogen, -OH, -COOH and methyl.

[0106] In some embodiments, the R6 is selected from hydrogen, -CH3,

[0107] 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.

[0108] In some embodiments, R6 and R7 are linked to form a pyrrolidinyl or piperidinyl group, which is optionally substituted with one methyl group.

[0109] In some embodiments, n is 0, 1 or 2.

[0110] In some embodiments, the compound is selected from:

[0111] The second aspect of the present application provides a pharmaceutical composition comprising at least one compound of the general formula described in the first aspect of the present application, or its stereoisomer, or its tautomer, or its solvate, or its isotope-labeled compound, or its pharmaceutically acceptable salt, and one or more pharmaceutically acceptable carriers and / or excipients.

[0112] The third aspect of the present application provides the use of the compound described in the first aspect of the present application, or the pharmaceutical composition described in the second aspect of the present application 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 drugs and veterinary drugs.

[0113] In some embodiments, the disease or condition 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.

[0114] The fourth aspect of the present application provides the compound described in the first aspect of the present application, or the pharmaceutical composition described in the second aspect of the present application, 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.

[0115] In some embodiments, the disease or condition 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.

[0116] The fifth aspect of the present application provides a method for treating and / or preventing a disease or condition or alleviating the severity of the disease or condition, which comprises administering an effective amount of the compound described in the first aspect of the present application, or the pharmaceutical composition described in the second aspect of the present application to an individual in need, wherein the disease or condition is caused by a coronavirus, and the drug includes human drugs and veterinary drugs.

[0117] In some embodiments, the disease or condition 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.

[0118] Definition of terms

[0119] 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.

[0120] When the compound name used in this application is inconsistent with the chemical structural formula, the chemical structural formula shall prevail.

[0121] 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 occur. Specific individual molecules may also exist as geometric isomers (cis / trans).

[0122] Similarly, the compound of the present application can exist with two or more mixtures (commonly referred to as tautomers) of different forms of structures in rapid equilibrium. Representative examples of tautomers include keto-enol tautomers, phenol-ketone tautomers, nitroso-oxime tautomers, imines-enamine tautomers etc. It is understood that the scope of the present application encompasses all such isomers or mixtures thereof with any ratio (e.g., 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%).

[0123] Unless otherwise indicated, the compounds of the present invention may exist as 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 invention may exhibit more than one type of isomerism and may optionally consist of mixtures thereof (e.g., racemic mixtures and diastereomeric pairs).

[0124] The compounds of the present application 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 compound lattice, such as water, methanol or ethanol. The amount of the solvent may be present in a stoichiometric ratio or a non-stoichiometric ratio.

[0125] As used herein, the term "isotopically labeled compound" refers to a compound in which one or more atoms are replaced with atoms having the same atomic number but an atomic mass or mass number different from the atomic mass or mass number predominant in nature. Examples of suitable isotopes 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 O, 17 O and 18 O; and sulfur isotopes such as 35 S.

[0126] As used herein, the term "pharmaceutically acceptable salt" refers to a salt of a compound of the present invention that is pharmaceutically acceptable and possesses the pharmacological activity of the parent compound. Such salts include acid addition salts formed with inorganic or organic acids, salts in which an acidic proton present in the parent compound is replaced by a metal ion, or coordination compounds formed with organic bases.

[0127] Pharmaceutically acceptable salts of the compounds of the present invention include those derived from suitable inorganic and organic acids and inorganic or organic bases. Examples of pharmaceutically acceptable non-toxic acid addition salts are salts formed by amino groups 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 by 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.

[0128] Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium (eg, 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 ammonium cations formed using counterions such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, lower alkyl sulfonates, and aryl sulfonates, as appropriate.

[0129] Pharmaceutically acceptable salts are also intended to encompass hemi-salts, wherein the ratio of compound:acid is 2:1. Exemplary hemi-salts are those derived from acids containing 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, hemimaleate, hemifumarate, and hemisuccinate.

[0130] As used herein, the term "optionally substituted by..." means that the group may be unsubstituted or substituted by a substituent; for example, "C 1-6 "Alkyl is optionally substituted by halogen" means C 1-6 Alkyl groups may be unsubstituted or substituted with halogen to give haloalkyl groups. 1-6 Alkyl, -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. It should be understood that -N-(C 1-6 Alkyl)2 means that there are two C 1-6 The two alkyl groups may be the same or different.

[0131] As used in this application, unless otherwise explicitly stated, the description “…are independently selected from” used throughout this document may mean that in different groups, the specific options expressed by the same or different symbols do not affect each other, or that in the same group, the specific options expressed by the same or different symbols do not affect each other.

[0132] As used herein, the term "halogen" refers to fluorine, chlorine, bromine, and iodine.

[0133] As used herein, the term "alkyl" refers to a linear 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., wherein the propyl group includes n-propyl and isopropyl, and the butyl group includes n-butyl, isobutyl, and neobutyl.

[0134] 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. For example, "C 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.

[0135] As used herein, the term "cycloalkyl" refers to a saturated cyclic hydrocarbon group consisting of carbon and hydrogen 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, wherein the C 3-12 Cycloalkyl groups include C 3-8 Cycloalkyl, C 3-6 Cycloalkyl, C 6-12 Cycloalkyl, C 6-10 Cycloalkyl, C 6-8 Cycloalkyl, etc. The cycloalkyl group includes a monocyclic, bicyclic or polycyclic ring, including a spirocyclic, fused or bridged ring. Examples include but are not limited to cyclohexyl, cycloheptyl, adamantyl, etc.

[0136] As used herein, the term "cycloalkenyl" refers to a partially unsaturated cyclic hydrocarbon group consisting of carbon and hydrogen atoms and containing a carbon-carbon double bond. 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, wherein the C 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.

[0137] As used in this application, the term "heterocyclyl" refers to a saturated or partially unsaturated monovalent cyclic group containing heteroatoms, 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 group 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, bicyclic or polycyclic ring, including a spirocyclic, a cyclic or bridged ring. Examples include, but are not limited to, oxetanyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl or morpholinyl. The term "nitrogen-containing monocyclic heterocyclyl" refers to a heterocyclyl group in which at least one heteroatom is a nitrogen atom and the heterocyclyl is a monocyclic ring, and examples include, but are not limited to, piperidinyl. The term "nitrogen-containing bridged heterocyclic group" refers to a heterocyclic group in which at least one heteroatom 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" refers to a heterocyclic group in which at least one heteroatom is a nitrogen atom and the heterocyclic group is cyclic. Examples include but are not limited to The term "nitrogen-containing spirocyclic heterocyclic group" refers to a heterocyclic group in which at least one heteroatom is a nitrogen atom and the heterocyclic group is cyclic. Examples include but are not limited to wait.

[0138] 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.

[0139] As used herein, the term "heteroaryl" refers to an unsaturated cyclic group having a conjugated π electron system, wherein 1, 2, 3, or 4 of the ring atoms are heteroatoms, and the remainder 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 5-10 membered heteroaryl group is composed of 5 to 10 (e.g., 5, 6, 7, 8, 9, or 10) ring atoms, including 5-9 membered, 9-10 membered, 5-6 membered heteroaryl groups, etc. The heteroaryl group includes monocyclic and polycyclic rings, examples of which include, but are not limited to, imidazolyl, pyridyl, quinolyl, or isoquinolyl.

[0140] As used herein, the term "pharmaceutically acceptable carrier and / or excipient" refers to a carrier and / or excipient that is pharmacologically and / or physiologically compatible with the subject and the active ingredient, as is well known in the art (see, for example, Remington's Pharmaceutical Sciences. Edited by Gennaro AR, 19th ed. Pennsylvania: Mack Publishing Company, 1995). Pharmaceutically acceptable carriers and / or excipients include, but are not limited to, pH adjusters, surfactants, ionic strength enhancers, diluents, agents that maintain osmotic pressure, agents that delay absorption, preservatives, and stabilizers. For example, pH adjusters 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 their analogs. 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 generally understood by those skilled in the art, and are capable of stabilizing 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 degradation products thereof (such as lactalbumin hydrolysate), etc.

[0141] 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.

[0142] As used herein, the term "treating" is intended to alleviate, mitigate, improve, or eliminate the disease state or condition being treated. If a subject receives a therapeutic amount of the papain inhibitor or its racemate, enantiomer, diastereomer, pharmaceutically acceptable salt, or mixture of the foregoing forms according to the methods described herein, and the subject exhibits an observable and / or detectable reduction or improvement in one or more signs and symptoms, then the subject is successfully "treated." It should also be understood that treatment of the disease state or condition includes not only complete treatment, but also achieving some biologically or medically relevant improvement results despite not achieving complete treatment.

[0143] As used herein, the term "prevention" is intended to avoid, reduce, prevent, or delay the onset of a disease or disease-related symptoms, provided that the disease or disease-related symptoms have not yet appeared before the administration of the relevant drug. "Prevention" does not necessarily require the complete prevention of the onset of a disease or disease-related symptoms. For example, if the administration of the relevant drug can reduce the risk of a subject developing a particular disease or disease-related symptom, or reduce the severity of related symptoms that later appear, it can be considered to have "prevented" the onset or development of the disease. DETAILED DESCRIPTION

[0144] The embodiments of the present application will be described in detail below with reference to the examples, but those skilled in the art will understand that the following examples are only used to illustrate the present application and should not be considered to limit the scope of the present application. Where specific conditions are not specified in the examples, they are carried out according to conventional conditions or conditions recommended by the manufacturer. Where 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:

[0145] Example 1

[0146] Compound P1: Preparation of 2-methyl-N-(1-(1-methyl-2-oxo-1,2-dihydrobenz[cd]indol-6-yl)cyclopropyl)-5-(4-methylpiperazin-1-yl)benzamide

[0147] (1) Preparation of Intermediate S2: 6-bromobenz[cd]indol-2(1H)one

[0148] S1 (2000 mg, 11.82 mmol) was placed in a single-necked flask, ACN (acetonitrile) (30 mL) was added, the temperature was lowered to 0°C, and NBS (N-bromosuccinimide) (2746 mg, 15.42 mmol, added in three batches with a 5-min interval between each batch) was added. After the addition was complete, the mixture was stirred at this temperature for 3.0 h. The reaction mixture was completely reacted. The reaction mixture was filtered, the filter cake was washed with water, and dried to obtain S2 (2613 mg, 89%) as a yellow solid. MS: m / z [M+1] + =249.56.

[0149] (2) Preparation of Intermediate S3: 6-Bromo-1-methylbenz[cd]indol-2(1H)one

[0150] S2 (2613 mg, 10.53 mmol) was placed in a single-necked flask, and DMF (dimethylformamide) (40 mL) was added. The temperature was lowered to 0°C, and NaH (629 mg, 15.73 mmol) was added. The mixture was stirred for 10 minutes. CHCl (1771 mg, 12.48 mmol) was added dropwise. The temperature was raised to room temperature, and the mixture was stirred for 1.0 hour. Once the starting material was completely reacted, water was added to the reaction mixture to precipitate a yellow solid. The mixture was stirred at room temperature for 20 minutes. Filter the filter cake, wash it with water, then with PE (petroleum ether), and drain to obtain S3 (2101 mg, 76%) as a yellow solid. MS: m / z [M+1] + =263.52.

[0151] (3) Preparation of Intermediate S4: 1-(1-methyl-2-oxo-1,2-dihydrobenzo[cd]indol-6-yl)cyclopropyl-1-carbonitrile

[0152] Pd2(dba)3 (tris(dibenzylideneacetone)dipalladium) (316 mg, 0.35 mmol) and NixantPhos (4,6-bis(diphenylphosphino)phenoxazine) (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), cyclopropylcarbonitrile (662 mg, 9.86 mmol) were added in sequence, and then the mixture was stirred for 10 min. LiHMDS (lithium hexamethyldisilazide) (13 mL, 13.12 mmol, 1.0 M (mol / L) in THF (tetrahydrofuran)) was added dropwise, the temperature was raised to 60°C, and the reaction was stirred for 1.0 h. After the starting material was completely reacted, the reaction solution was cooled to room temperature and saturated ammonium chloride solution (50 mL) was added. The mixture was extracted three times with EA (ethyl acetate). The organic phases were combined, concentrated under reduced pressure, and purified by column chromatography (PE:EA = 5:1, 4:1, 3:1) to give S4 (788 mg, 51%) as a yellow solid. MS: m / z [M+1] + =249.36.

[0153] (4) Preparation of Intermediate S5: 1-(1-methyl-2-oxo-1,2-dihydrobenz[cd]indol-6-yl)cyclopropyl-1-carboxamide

[0154] S4 (788 mg, 3.18 mmol) was placed in a single-necked flask, i-PrOH (isopropanol) (8 mL) and NaOH (382 mg, 9.54 mmol) were added, and the temperature was raised to 90°C. The reaction mixture was stirred and allowed to react overnight. After the reaction was complete, the reaction mixture was cooled to room temperature, water (10 mL) was added, and the mixture was extracted three times with DCM (dichloromethane). The organic phases were combined, concentrated under reduced pressure, and purified by column chromatography (PE:EA=1:1, DCM:MeOH=20:1) to obtain S5 (113 mg, 13%) as a yellow solid. MS: m / z[M+1] + =267.43.

[0155] (5) Preparation of Intermediate S6: 6-(1-amino-cyclopropyl)-1-methylbenz[cd]indol-2(1H)-one

[0156] S5 (94 mg, 0.35 mmol) was placed in a single-necked flask, t-BuOH (tert-butyl alcohol) (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 h. After the starting material was completely reacted, the reaction solution was concentrated under reduced pressure to remove the solvent. DCM was added to the resulting mixture to dissolve it, and the mixture was filtered. The filter cake was washed with DCM, the filtrate was dried over anhydrous sodium sulfate, filtered, the filter cake was washed with DCM, and the filtrate was concentrated under reduced pressure to give S6 (76 mg, 91%) as a light yellow solid. MS: m / z [M+1] + =239.26.

[0157] (6) Preparation of Intermediate S9: 2-ethyl-5-(4-methylpiperazin-1-yl)benzoic acid methyl ester

[0158] 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 through the mixture for 30 s, and the temperature was raised to 110°C. The mixture was stirred and reacted overnight until the starting materials were completely reacted. The reaction solution was cooled to room temperature and filtered through celite. 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 give S9 (5416 mg, 100%) as a jujube-red oil. MS: m / z [M+1] + =249.33.

[0159] (7) Preparation of Intermediate S10: 2-methyl-5-(4-methylpiperazin-1-yl)benzoic acid

[0160] S9 (5416 mg, 21.83 mmol) was placed in a single-necked bottle, THF (25 mL) and EtOH (25 mL) were added, and then a solution of NaOH (4366 mg, 109.15 mmol) in H2O (25 mL) was added. The temperature was raised to 60°C and stirred for 2 h. After the raw materials were completely reacted, 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 reaction mixture was filtered, the filter cake was washed with water, and the filtrate was washed with EA. The resulting solid mixture was dissolved in a mixture of DCM and MeOH (DCM:MeOH = 10:1, 500 mL) and concentrated under reduced pressure. The mixture was then dissolved in a mixture of DCM and MeOH (DCM:MeOH = 20:1, 500 mL) and dried over anhydrous sodium sulfate. The mixture was filtered and the filter cake was washed with DCM. The filtrate was concentrated under reduced pressure to give S10 (5110 mg, 100%) as a light yellow solid. MS: m / z [M+1] + =235.28.

[0161] (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

[0162] S6 (40 mg, 0.17 mmol) and S10 (47 mg, 0.20 mmol) were placed in a single-necked flask, and DMF (1.5 mL), DIPEA (N,N-diisopropylethylamine) (71 mg, 0.55 mmol) and HATU (2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate) (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 were completely reacted. The reaction solution was cooled to room temperature and water was added to precipitate a yellow solid. The product was extracted three times with DCM. The organic phases were combined, concentrated under reduced pressure, and purified by column chromatography (PE:EA=1:1, DCM:MeOH=20:1) to give P1 (62 mg, 20%) as a bright yellow solid. 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.

[0163] Example 2

[0164] Compound P2: Preparation of 2-methyl-5-(4-methylpiperazin-1-yl)-N-(1-(2-oxo-1,2-dihydrobenz[cd]indol-6-yl)cyclopropyl)benzamide

[0165] (1) Preparation of Intermediate S11: 6-Bromo-1-(4-methoxybenzyl)benzo[cd]indol-2(1H)one

[0166] S2 (898 mg, 3.62 mmol) was placed in a single-necked flask, and DMF (10 mL) was added. The temperature was lowered to 0°C, and NaH (290 mg, 7.24 mmol) was added. The mixture was stirred for 10 minutes. p-Methoxybenzyl chloride (850 mg, 5.43 mmol) was added dropwise. The temperature was raised to room temperature, and the mixture was stirred for 1.0 hour. Once the starting material was completely reacted, water was added to the reaction mixture to precipitate a yellow solid. The mixture was stirred at room temperature for 20 minutes. Filter the filter cake, wash it with water, then with PE, and dry it to obtain S11 (905 mg, 68%) as a yellow solid. MS: m / z [M+1] + =369.27.

[0167] (2) Preparation of Intermediate S12: 1-(1-(4-methoxybenzyl)-2-oxo-1,2-dihydrobenzo[cd]indol-6-yl)cyclopropyl-1-carbonitrile

[0168] 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 through the mixture 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 then added sequentially. LiHMDS (5 mL, 4.92 mmol, 1.0 M in THF) was then added dropwise. The temperature was raised to 60°C and the reaction was stirred for 1.0 h. After the starting materials were completely reacted, the reaction solution was cooled to room temperature and saturated ammonium chloride solution (30 mL) was added. 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 give S12 (386 mg, 44%) as a yellow solid. MS: m / z [M+1] + =355.36.

[0169] (3) Preparation of Intermediate S13: 1-(1-(4-methoxybenzyl)-2-oxo-1,2-dihydrobenz[cd]indol-6-yl)cyclopropyl-1-carboxamide

[0170] S12 (286 mg, 0.81 mmol) was placed in a single-necked flask, DMSO (dimethyl sulfoxide) (3 mL) and K2CO3 (56 mg, 0.41) were added, the temperature was lowered to 0°C, and H2O2 (0.14 mL, 1.22 mmol, 30% in water) was added dropwise. The reaction was stirred for 2.5 hours. After the starting material was completely reacted, water (6 mL) was added to the reaction solution to precipitate a yellow solid. The filter cake was filtered, washed with water (2 mL), and then dried by column chromatography (PE:EA = 1:1, DCM:MeOH = 30:1) to obtain S13 (62 mg, 21%) as a yellow solid. MS: m / z [M+1] + =373.43.

[0171] (4) Preparation of Intermediate S14: 6-(1-amino-cyclopropyl)-1-(4-methoxybenzyl)benzo[cd]indol-2(1H)-one

[0172] S13 (62 mg, 0.17 mmol) was placed in a single-necked flask, t-BuOH (2 mL) was added, the temperature was lowered to 0°C, a NaClO solution (0.2 mL, 0.48 mmol) and a NaOH solution (3N, 0.16 mL, 0.48 mmol) were added, the temperature was raised to room temperature, and the reaction was stirred for 3 h. The starting material was completely reacted. The reaction solution was concentrated under reduced pressure to remove the solvent. DCM (300 mL) was added to the resulting mixture, and the mixture was dried over anhydrous sodium sulfate and filtered. The filter cake was washed with DCM, and the resulting filtrate was concentrated under reduced pressure to obtain S14 (37 mg, 64%) as a yellow solid. MS: m / z [M+1] + =345.29.

[0173] (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

[0174] S14 (37 mg, 0.11 mmol) and S10 (31 mg, 0.13 mmol) were placed in a single-necked flask, 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 stirred for 2 h. After the starting materials reacted completely, the reaction solution was cooled to room temperature and water was added to precipitate a yellow solid. The solution was stirred at room temperature for 1.0 h, filtered, and the filter cake was washed with water and dried to obtain a yellow solid S15, which was used directly in the next reaction. MS: m / z [M+1] + =561.38.

[0175] (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

[0176] S15 (30 mg, 0.054 mmol) was placed in a single-necked flask, TFA (trifluoroacetic acid) (1.5 mL) was added, the temperature was raised to 60°C, and the reaction was stirred overnight. The raw material was completely reacted, and the TFA was removed by concentration under reduced pressure. A saturated sodium bicarbonate solution (8 mL) was added to the resulting mixture, and the mixture was 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 give P2 (14 mg, 55%) as a bright yellow solid. 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.

[0177] Example 3

[0178] 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

[0179] (1) Preparation of Intermediate S4: 1-(1-methyl-2-oxo-1,2-dihydrobenzo[cd]indol-6-yl)cyclopropyl-1-carbonitrile

[0180] 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. The reaction solution was cooled to room temperature and saturated ammonium chloride solution (100 mL) was added. 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, 2:1) to give S4 (2424 mg, 43%) as a yellow solid. MS:m / z[M+1] + =249.26.

[0181] (2) Preparation of Intermediate S5: 1-(1-methyl-2-oxo-1,2-dihydrobenz[cd]indol-6-yl)cyclopropyl-1-carboxamide

[0182] S4 (2424 mg, 9.77 mmol) was placed in a single-necked flask, DMSO (8 mL) and K2CO3 (675 mg, 4.89 mmol) were added, the temperature was lowered to 0°C, and H2O2 (4.8 mL, 44.16 mmol, 30% in water) was added dropwise. The temperature was then raised to room temperature and the reaction was stirred for 6 h. After the starting material was completely reacted, water (30 mL) was added to the reaction solution to precipitate a yellow solid. The mixture was stirred at room temperature for 20 min, 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 S5 (1124 mg, 43%) as a yellow solid. MS: m / z [M+1] + =267.43.

[0183] (3) Preparation of Intermediate S6: 6-(1-amino-cyclopropyl)-1-methylbenz[cd]indol-2(1H)-one

[0184] S5 (1124 mg, 4.22 mmol) was placed in a single-necked flask, t-BuOH (15 mL) was added, the temperature was lowered to 0°C, and 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 h. After the starting material was completely reacted, the reaction solution was concentrated under reduced pressure to remove the solvent. The resulting solid mixture was purified by column chromatography (PE:EA=1:1, DCM:MeOH=30:1) to obtain S6 (590 mg, 60%) as a yellow solid. MS: m / z[M+1] + =239.26.

[0185] (4) Preparation of Intermediate S17: tert-Butyl 4-(3-methoxycarbonyl)-4-methylphenyl)-3,6-dihydropiperidine-1(2H)-carboxylate

[0186] S7 (500 mg, 2.18 mmol) and S16 (675 mg, 2.18 mmol) were placed in a sealed tube, and 1,4-dioxane (10 mL), X-Phos (2-dicyclohexylphosphino-2,4,6-triisopropylbiphenyl) (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 through the tube for 30 s, and the temperature was raised to 100°C. The mixture was stirred and reacted overnight until the starting materials were completely reacted. The reaction solution was cooled to room temperature and filtered through celite. 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 S17 (717 mg, 100%) as a light yellow oil. MS: m / z [M+1] + =332.38.

[0187] (5) Preparation of Intermediate S18: 5-(1-(tert-butoxycarbonyl)-1,2,3,6-tetrahydropiperidin-4-yl)-2-methylbenzoic acid

[0188] S17 (335 mg, 1.01 mmol) was placed in a single-necked flask, THF (2 mL) and EtOH (2 mL) were added, followed by a solution of NaOH (202 mg, 5.05 mmol) in H2O (2 mL). The temperature was raised to 60°C and the reaction was stirred for 2 h. The starting material reacted completely. The reaction solution was concentrated under reduced pressure to remove THF and EtOH. The pH was adjusted to 4-5 with saturated citric acid solution to precipitate a white solid. Water (3 mL) was added and the mixture was filtered. The filter cake was washed with a small amount of water and dissolved in DCM, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give S18 (319 mg, 100%) as a white solid. MS: m / z [M+1] + =318.28.

[0189] (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

[0190] S6 (35 mg, 0.15 mmol) and S18 (56 mg, 0.18 mmol) were placed in a single-necked flask, 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. After the starting materials were completely reacted, the reaction solution was cooled to room temperature and water was added to precipitate a yellow solid. 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 S19 (64 mg, 80%) as a yellow solid. MS: m / z [M+1] + =538.38.

[0191] (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

[0192] S19 (61 mg, 0.11 mmol) was placed in a single-necked flask, 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 was completely reacted, and 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 resulting 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 H NMR(600MHz,DMSO-d6)δ9.15(s,1H),8.80(d,J=8.3Hz,1H),8.04(d,J=6.9Hz,1H ),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),2.03 (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.

[0193] Example 4

[0194] 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

[0195] (1) Preparation of Intermediate S20: tert-Butyl 4-(3-(methoxycarbonyl)-4-methylphenyl)piperidine-1-carboxylate

[0196] S17 (382 mg, 1.15 mmol) was placed in a single-necked flask, and ethanol (5.0 mL) and palladium on carbon (191 mg, 10%) were added. The reaction was stirred under a hydrogen balloon at room temperature overnight until the starting material was completely reacted. The reaction solution was filtered through celite, 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 S20 (360 mg, 94%) as a white solid. MS: m / z [M+1] + =334.36.

[0197] (2) Preparation of Intermediate S21: 5-(1-(tert-butoxycarbonyl)piperidin-4-yl)-2-methylbenzoic acid

[0198] S20 (360 mg, 1.08 mmol) was placed in a single-necked flask, THF (2 mL) and EtOH (2 mL) were added, followed by a solution of NaOH (216 mg, 5.40 mmol) in H2O (2 mL). The temperature was raised to 60°C and the reaction was stirred for 2 h. The starting material reacted completely. The reaction solution was concentrated under reduced pressure to remove THF and EtOH. The pH was adjusted to 4-5 with saturated citric acid solution to precipitate a white solid. Water (3 mL) was added and the mixture was filtered. The filter cake was washed with a small amount of water and dissolved in DCM. The filter cake was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain S21 (325 mg, 94%) as a white solid. MS: m / z [M+1] + =320.26.

[0199] (3) Preparation of Intermediate S22: tert-Butyl 4-(4-methyl-3-((1-(1-methyl-2-oxo-1,2-dihydrobenzo[cd]indol-6-yl)cyclopropyl)carbamoyl)phenyl)piperidine-1-carboxylate

[0200] S6 (35 mg, 0.15 mmol) and S21 (57 mg, 0.18 mmol) were placed in a single-necked flask, 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. After the starting materials were completely reacted, the reaction solution was cooled to room temperature and water was added to precipitate a yellow solid. 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 S22 (61 mg, 75%) as a yellow solid. MS: m / z [M+1] + =540.32.

[0201] (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

[0202] S22 (61 mg, 0.11 mmol) was placed in a single-necked flask, 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 was completely reacted, and 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 resulting 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 H NMR (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.

[0203] Example 5

[0204] Preparation of Compound 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

[0205] (1) Preparation of Intermediate S24: tert-Butyl 3-(3-(methoxycarbonyl)-4-methylphenyl)-6-azabicyclo[3.1.1]heptane-6-carboxylate

[0206] 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 through the tube for 30 s, and the temperature was raised to 110°C. The reaction was stirred overnight until the starting materials were completely reacted. The reaction solution was cooled to room temperature, concentrated under reduced pressure, and purified by column chromatography (PE:EA=10:1) to obtain S24 (121 mg, 54%) as a light yellow oil. MS: m / z[M+1] + =347.25.

[0207] (2) Preparation of Intermediate S25: 5-(6-(tert-butoxycarbonyl)-3,6-diazabicyclo[3.1.1]heptane-3-yl)-2-methylbenzoic acid

[0208] S24 (121 mg, 0.35 mmol) was placed in a single-necked flask, THF (1 mL) and EtOH (1 mL) were added, followed by a solution of NaOH (70 mg, 1.75 mmol) in H2O (1 mL). The temperature was raised to 60°C and the reaction was stirred for 2 h. The starting material reacted completely. The reaction solution was concentrated under reduced pressure to remove THF and EtOH. The pH was adjusted to 4-5 with saturated citric acid solution to precipitate a light yellow solid. Water (3 mL) was added and the mixture was filtered. The filter cake was washed with a small amount of water and dissolved in DCM, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to afford S25 (116 mg, 100%) as a light yellow solid. MS: m / z [M+1] + =333.23.

[0209] (3) Preparation of Intermediate S26: 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

[0210] S6 (30 mg, 0.13 mmol) and S25 (50 mg, 0.15 mmol) were placed in a single-necked flask, 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. After the starting materials were completely reacted, the reaction solution was cooled to room temperature and water was added to precipitate a yellow solid. 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 S26 (57 mg, 79%) as a yellow solid. MS: m / z [M+1] + =553.25.

[0211] (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

[0212] S26 (57 mg, 0.10 mmol) was placed in a single-necked flask, 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 starting material was completely reacted, and the solvent was removed by concentration under reduced pressure to obtain a yellow solid mixture. To the resulting mixture was added saturated sodium bicarbonate solution (4 mL), 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 P5 (37 mg, 82%) as a bright yellow solid. 1 H 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.

[0213] Example 6

[0214] Compound P6: Preparation of 5-(3,8-diazabicyclo[3.2.1]octan-8-yl)-2-methyl-N-(1-(1-methyl-2-oxo-1,2-dihydrobenz[cd]indol-6-yl)cyclopropyl)benzamide

[0215] (1) Preparation of Intermediate S28: 8-(3-(methoxycarbonyl)-4-methylphenyl)-3,8-diazabicyclo[3.2.1]octane-3-benzoic acid tert-butyl ester

[0216] 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 through the tube for 30 s, and the temperature was raised to 110°C. The reaction was stirred overnight until the starting materials were completely reacted. The reaction solution was cooled to room temperature, concentrated under reduced pressure, and purified by column chromatography (PE:EA=10:1) to obtain S28 (155 mg, 66%) as a light yellow oil. MS: m / z[M+1] + =360.16.

[0217] (2) Preparation of Intermediate S29: 5-(3-(tert-butoxycarbonyl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-2-methylbenzoic acid

[0218] S28 (121 mg, 0.35 mmol) was placed in a single-necked flask, THF (1 mL) and EtOH (1 mL) were added, followed by a solution of NaOH (70 mg, 1.75 mmol) in H2O (1 mL). The temperature was raised to 60°C and the reaction was stirred for 2 h. The starting material reacted completely. The reaction solution was concentrated under reduced pressure to remove THF and EtOH. The pH was adjusted to 4-5 with saturated citric acid solution to precipitate a light yellow solid. Water (3 mL) was added and the mixture was filtered. The filter cake was washed with a small amount of water and dissolved in DCM, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to afford S29 (149 mg, 100%) as a light yellow solid. MS: m / z [M+1] + =347.23.

[0219] (3) Preparation of Intermediate S30: 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

[0220] S6 (30 mg, 0.13 mmol) and S29 (52 mg, 0.15 mmol) were placed in a single-necked flask, 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. After the starting materials were completely reacted, the reaction solution was cooled to room temperature and water was added to precipitate a yellow solid. The reaction solution 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 S30 (61 mg, 82%) as a yellow solid. MS: m / z [M+1] + =567.23.

[0221] (4) Preparation of P6: 5-(3,8-diazabicyclo[3.2.1]octan-8-yl)-2-methyl-N-(1-(1-methyl-2-oxo-1,2-dihydrobenz[cd]indol-6-yl)cyclopropyl)benzamide

[0222] S30 (60 mg, 0.10 mmol) was placed in a single-necked flask, 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 starting material was completely reacted, and the solvent was removed by concentration under reduced pressure to obtain a yellow solid mixture. To the resulting mixture was added saturated sodium bicarbonate solution (4 mL), 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.

[0223] Example 7

[0224] 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

[0225] (1) Preparation of P7: 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

[0226] P3 (20 mg, 0.046 mmol) was placed in a single-necked flask, and MeOH (1.0 mL), formaldehyde aqueous solution (0.30 mL) and acetic acid (7 mg, 0.12 mmol) were added. Finally, NaCNBH3 (4 mg, 0.069 mmol) was added. The reaction was stirred at room temperature for 2 h. The raw materials were completely reacted. Saturated sodium bicarbonate solution (5 mL) was added to the reaction solution, and the mixture was extracted three times with DCM. 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 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.

[0227] Example 8

[0228] Compound P8: Preparation of 2-methyl-N-(1-(1-methyl-2-oxo-1,2-dihydrobenz[cd]indol-6-yl)cyclopropyl)-3-methyl-3,8-diazabicyclo[3.2.1]octan-8-ylbenzamide

[0229] (1) Preparation of P8: 2-methyl-N-(1-(1-methyl-2-oxo-1,2-dihydrobenz[cd]indol-6-yl)cyclopropyl)-3-methyl-3,8-diazabicyclo[3.2.1]octan-8-ylbenzamide

[0230] P6 (20 mg, 0.043 mmol) was placed in a single-necked flask, and MeOH (1.0 mL), aqueous formaldehyde solution (0.30 mL), and acetic acid (7 mg, 0.11 mmol) were added. Finally, NaCNBH3 (4 mg, 0.065 mmol) was added. The reaction was stirred at room temperature for 2 h. After the starting materials were completely reacted, saturated sodium bicarbonate solution (5 mL) was added to the reaction solution, and the mixture was extracted three times with DCM. 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 P8 (20 mg, 95%) as a bright yellow solid. MS: m / z [M+1] + =481.36.

[0231] Embodiment 9

[0232] 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

[0233] (1) Preparation of Intermediate S32: tert-Butyl 5-(3-(methoxycarbonyl)-4-methylphenyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate

[0234] 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 through the tube for 30 s, and the temperature was raised to 110°C. The reaction was stirred overnight until the starting materials were completely reacted. The reaction solution was cooled to room temperature, concentrated under reduced pressure, and purified by column chromatography (PE:EA=10:1) to obtain S32 (171 mg, 73%) as a light yellow oil. MS: m / z[M+1] + =361.18.

[0235] (2) Preparation of Intermediate S33: 5-(5-(tert-butoxycarbonyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)-2-methylbenzoic acid

[0236] S32 (171 mg, 0.47 mmol) was placed in a single-necked flask, and THF (1.5 mL) and EtOH (1.5 mL) were added. A solution of NaOH (94 mg, 2.35 mmol) in H2O (1.5 mL) was then added. The temperature was raised to 60°C and the reaction was stirred for 2 h. The starting material reacted completely. The reaction solution was concentrated under reduced pressure to remove THF and EtOH. The pH was adjusted to 4-5 with saturated citric acid solution to precipitate a pale yellow solid. Water (3 mL) was added and the mixture was filtered. The filter cake was washed with a small amount of water and dissolved in DCM. The filter cake was dried over anhydrous sodium sulfate and concentrated under reduced pressure to afford S33 (163 mg, 100%) as a yellow solid. MS: m / z [M+1] + =347.23.

[0237] (3) Preparation of Intermediate S34: 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

[0238] S6 (30 mg, 0.13 mmol) and S33 (52 mg, 0.15 mmol) were placed in a single-necked flask, 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. After the starting materials were completely reacted, the reaction solution was cooled to room temperature and water was added to precipitate a yellow solid. 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 S34 (58 mg, 78%) as a light yellow solid. MS: m / z [M+1] + =567.23.

[0239] (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

[0240] S34 (58 mg, 0.10 mmol) was placed in a single-necked flask, 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 starting material was completely reacted, and the solvent was removed by concentration under reduced pressure to obtain a yellow solid mixture. To the resulting mixture was added saturated sodium bicarbonate solution (5 mL), 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 P9 (42 mg, 89%) as a bright yellow solid. 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.

[0241] Example 10

[0242] Compound P10: Preparation of 2-methyl-N-(1-(1-methyl-2-oxo-1,2-dihydrobenz[cd]indol-6-yl)cyclopropyl)-5-(2-methylpiperazin-1-yl)benzamide

[0243] (1) Preparation of Intermediate S36: tert-Butyl 4-(3-(methoxycarbonyl)-4-methylphenyl)-3-methylpiperazine-1-carboxylate

[0244] 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 through the tube for 30 s, and the temperature was raised to 110°C. The reaction was stirred overnight until the starting materials reacted completely. The reaction solution was cooled to room temperature, concentrated under reduced pressure, and purified by column chromatography (PE:EA=10:1) to obtain S36 (110 mg, 49%) as a light yellow oil. MS: m / z[M+1] + =349.36.

[0245] (2) Preparation of Intermediate S37: 5-(4-(tert-Butoxycarbonyl)-2-methylpiperazin-1-yl)-2-methylbenzoic acid

[0246] S36 (110 mg, 0.31 mmol) was placed in a single-necked flask, THF (1 mL) and EtOH (1 mL) were added, followed by a solution of NaOH (63 mg, 1.58 mmol) in H2O (1 mL). The temperature was raised to 60°C and the reaction was stirred for 2 h. The starting material reacted completely. The reaction solution was concentrated under reduced pressure to remove THF and EtOH. The pH was adjusted to 4-5 with saturated citric acid solution to precipitate a pale yellow solid. Water (3 mL) was added and the mixture was filtered. The filter cake was washed with a small amount of water and dissolved in DCM, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to afford S37 (103 mg, 100%) as a pale yellow solid. MS: m / z [M+1] + =335.19.

[0247] (3) Preparation of Intermediate S38: 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

[0248] S6 (30 mg, 0.13 mmol) and S37 (50 mg, 0.15 mmol) were placed in a single-necked flask, 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. After the starting materials were completely reacted, the reaction solution was cooled to room temperature and water was added to precipitate a yellow solid. 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 S38 (58 mg, 81%) as a light yellow solid. MS: m / z [M+1] + =555.25.

[0249] (4) Preparation of P10: 2-methyl-N-(1-(1-methyl-2-oxo-1,2-dihydrobenzo[cd]indol-6-yl)cyclopropyl)-5-(2-methylpiperazin-1-yl)benzamide

[0250] S38 (58 mg, 0.10 mmol) was placed in a single-necked flask, 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 starting material was completely reacted, and the solvent was removed by concentration under reduced pressure to obtain a yellow solid mixture. To the resulting mixture was added saturated sodium bicarbonate solution (5 mL), 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 P10 (45 mg, 100%) as a bright yellow solid. 1 H 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.

[0251] Example 11

[0252] 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

[0253] (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

[0254] P5 (18 mg, 0.040 mmol) was placed in a single-necked flask, and MeOH (1.0 mL), aqueous formaldehyde (0.30 mL), and acetic acid (6 mg, 0.10 mmol) were added. Finally, NaCNBH3 (4 mg, 0.060 mmol) was added. The reaction was stirred at room temperature for 2 h. After complete reaction, saturated sodium bicarbonate solution (5 mL) was added to the reaction solution, and the mixture was extracted three times with DCM. The organic phases were combined and concentrated under reduced pressure to give a yellow solid. The yellow solid was purified by column chromatography (DCM:MeOH = 10:1, 7:1) to give P11 (14 mg, 77%) as a bright yellow solid. MS: m / z [M+1]+ = 467.32.

[0255] Example 12

[0256] 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-7-yl)benzamide

[0257] (1) Preparation of intermediate S40: tert-butyl 7-(3-(methoxycarbonyl)-4-methylphenyl)-4,7-diazaspiro[2,5]octane-4-carboxylate

[0258] 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 through the tube for 30 s, and the temperature was raised to 110°C. The reaction was stirred overnight until the starting materials were completely reacted. 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 S40 (35 mg, 54%) as a light yellow oil. MS: m / z [M+1] + =361.38.

[0259] (2) Preparation of Intermediate S41: 5-(4-(tert-butoxycarbonyl)-4,7-diazaspiro[2,5]octane)-7-yl)-2-methylbenzoic acid

[0260] S40 (35 mg, 0.097 mmol) was placed in a single-necked flask, and THF (0.5 mL) and EtOH (0.5 mL) were added. A solution of NaOH (19 mg, 0.49 mmol) in H2O (0.5 mL) was then added. The temperature was raised to 60°C and the reaction was stirred for 2 h. The starting material reacted completely. The reaction solution was concentrated under reduced pressure to remove THF and EtOH. The pH was adjusted to 4-5 with saturated citric acid solution to precipitate a pale yellow solid. Water (3 mL) was added and the mixture was filtered. The filter cake was washed with a small amount of water and dissolved in DCM. The filter cake was dried over anhydrous sodium sulfate and concentrated under reduced pressure to afford S41 (33 mg, 100%) as a yellow solid. MS: m / z [M+1] + =347.15.

[0261] (3) Preparation of Intermediate S42: 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

[0262] S6 (21 mg, 0.086 mmol) and S41 (33 mg, 0.095 mmol) were placed in a single-necked flask, 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. After the starting materials were completely reacted, the reaction solution was cooled to room temperature and water was added to precipitate a yellow solid. 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 S42 (33 mg, 67%) as a light yellow solid. MS: m / z [M+1] + =567.23.

[0263] (4) Preparation of P12: 2-methyl-N-(1-(1-methyl-2-oxo-1,2-dihydrobenzo[cd]indol-6-yl)cyclopropyl)-5-(4,7-diazaspiro[2,5]octan-7-yl)benzamide

[0264] S42 (33 mg, 0.058 mmol) was placed in a single-necked flask, 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 starting material was completely reacted, and 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 resulting 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 = 10:1) to obtain a bright yellow solid P12 (20 mg, 74%). MS: m / z [M+1] + =467.37.

[0265] Example 13

[0266] Compound P13: Preparation of 5-(4-(dimethylamino)piperidin-1-yl)-2-methyl-N-(1-(1-methyl-2-oxo-1,2-dihydrobenz[cd]indol-6-yl)cyclopropyl)benzamide

[0267] (1) Preparation of Intermediate S44: 5-(4-(dimethylamino)piperidin-1-yl)-2-methylbenzoic acid methyl ester

[0268] 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 through the tube for 30 s, and the temperature was raised to 110°C. The reaction was stirred overnight until the starting materials were completely reacted. 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 S44 (70 mg, 39%) as a light yellow oil. MS: m / z [M+1] + =277.38.

[0269] (2) Preparation of Intermediate 45: 5-(4-(dimethylamino)piperidin-1-yl)-2-methylbenzoic acid

[0270] S44 (70 mg, 0.25 mmol) was placed in a single-necked flask, and THF (1 mL) and EtOH (1 mL) were added. A solution of NaOH (51 mg, 1.26 mmol) in H2O (1 mL) was then added. The temperature was raised to 60°C and the reaction was stirred for 2 h. The starting material reacted completely. The reaction solution was concentrated under reduced pressure to remove THF and EtOH. The pH was adjusted to 4-5 with dilute hydrochloric acid (2.0 M). The solvent was removed by concentration under reduced pressure. The resulting solid was dissolved in DCM, dried over anhydrous sodium sulfate, and filtered. The filter cake was washed with DCM. The filtrate was concentrated under reduced pressure to remove the solvent, giving S45 (65 mg, 100%) as a light yellow solid. MS: m / z [M+1] + =263.19.

[0271] (3) P13: Preparation of 5-(4-(dimethylamino)piperidin-1-yl)-2-methyl-N-(1-(1-methyl-2-oxo-1,2-dihydrobenz[cd]indol-6-yl)cyclopropyl)benzamide

[0272] S6 (20 mg, 0.084 mmol) and S45 (26 mg, 0.10 mmol) were placed in a single-necked flask, 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. After the starting materials were completely reacted, the reaction solution was cooled to room temperature and water was added to precipitate a yellow solid. The mixture was stirred at room temperature for 0.5 h and filtered. The filter cake was washed with water and purified by column chromatography (PE:EA=1:1, DCM:MeOH=20:1-10:1) to obtain P13 (23 mg, 57%) as a bright yellow solid. MS: m / z[M+1] + =483.32.

[0273] Example 14

[0274] Compound P14: Preparation of (S)-5-(4-ethyl-3-methylpiperazin-1-yl)-2-methyl-N-(1-(1-methyl-2-oxo-1,2-dihydrobenz[cd]indol-6-yl)cyclopropyl)benzamide

[0275] (1) Preparation of Intermediate S47: (S)-5-(4-ethyl-3-methylpiperazin-1-yl)-2-methylbenzoic acid methyl ester

[0276] 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 through the tube for 30 s, and the temperature was raised to 110°C. The mixture was stirred and reacted overnight until the starting materials were completely reacted. 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 S47 (66 mg, 37%) as a colorless oil. MS: m / z [M+1] + =277.38.

[0277] (2) Preparation of Intermediate S48: (S)-5-(4-ethyl-3-methylpiperazin-1-yl)-2-methylbenzoic acid

[0278] S47 (66 mg, 0.24 mmol) was placed in a single-necked flask, and THF (1 mL) and EtOH (1 mL) were added, followed by a solution of NaOH (48 mg, 1.20 mmol) in H2O (1 mL). The temperature was raised to 60°C and the reaction was stirred for 2 h. The starting material reacted completely. The reaction solution was concentrated under reduced pressure to remove THF and EtOH. The pH was adjusted to 4-5 with dilute hydrochloric acid (2.0 M). The solvent was removed by concentration under reduced pressure. The resulting solid was dissolved in DCM, dried over anhydrous sodium sulfate, and filtered. The filter cake was washed with DCM. The filtrate was concentrated under reduced pressure to remove the solvent, giving S48 (63 mg, 100%) as a light yellow solid. MS: m / z [M+1] + =263.19.

[0279] (3) P14: Preparation of (S)-5-(4-ethyl-3-methylpiperazin-1-yl)-2-methyl-N-(1-(1-methyl-2-oxo-1,2-dihydrobenz[cd]indol-6-yl)cyclopropyl)benzamide

[0280] S6 (20 mg, 0.084 mmol) and S48 (26 mg, 0.10 mmol) were placed in a single-necked flask, 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. After the starting materials were completely reacted, the reaction solution was cooled to room temperature and water was added to precipitate a yellow solid. The mixture was stirred at room temperature for 0.5 h and filtered. The filter cake was washed with water and purified by column chromatography (PE:EA=1:1, DCM:MeOH=20:1, 10:1) to obtain P14 (18 mg, 45%) as a bright yellow solid. MS: m / z[M+1] +=483.32.

[0281] Example 15

[0282] Compound P15: Preparation of 5-(3-(dimethylamino)pyrrol-1-yl)-2-methyl-N-(1-(1-methyl-2-oxo-1,2-dihydrobenz[cd]indol-6-yl)cyclopropyl)benzamide

[0283] (1) Preparation of Intermediate S50: 5-(3-(dimethylamino)pyrrol-1-yl)-2-methylbenzoic acid methyl ester

[0284] S7 (101 mg, 0.44 mmol) and S49 (100 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 through the mixture for 30 s, and the temperature was raised to 110°C. The mixture was stirred and reacted overnight until the starting materials were completely reacted. The reaction solution was cooled to room temperature and filtered through celite. The filter cake was washed with EA. The resulting filtrate was concentrated under reduced pressure and purified by column chromatography (PE:EA = 1:1, 1:2) to obtain S50 (91 mg, 79%) as a light yellow oil. MS: m / z [M+1] + =263.38.

[0285] (2) Preparation of Intermediate S51: 5-(3-(dimethylamino)pyrrol-1-yl)-2-methylbenzoic acid

[0286] S50 (91 mg, 0.34 mmol) was placed in a single-necked flask, and THF (1 mL) and EtOH (1 mL) were added. A solution of NaOH (68 mg, 1.70 mmol) in H2O (1 mL) was then added. The temperature was raised to 60°C and the reaction was stirred for 2 h. The starting material reacted completely. The reaction solution was concentrated under reduced pressure to remove THF and EtOH. The pH was adjusted to 4-5 with dilute hydrochloric acid (2.0 M). The solvent was removed by concentration under reduced pressure. The resulting solid was dissolved in DCM, dried over anhydrous sodium sulfate, and filtered. The filter cake was washed with DCM. The filtrate was concentrated under reduced pressure to remove the solvent, yielding S51 (84 mg, 100%) as a pale yellow solid. MS: m / z [M+1] + =249.33.

[0287] (3) P15: Preparation of 5-(3-(dimethylamino)pyrrol-1-yl)-2-methyl-N-(1-(1-methyl-2-oxo-1,2-dihydrobenz[cd]indol-6-yl)cyclopropyl)benzamide

[0288] S6 (20 mg, 0.084 mmol) and S51 (25 mg, 0.10 mmol) were placed in a single-necked flask, 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. After the starting materials were completely reacted, the reaction solution was cooled to room temperature and water was added to precipitate a yellow solid. The mixture was stirred at room temperature for 0.5 h and filtered. The filter cake was washed with water and purified by column chromatography (PE:EA=1:1, DCM:MeOH=20:1, 10:1) to obtain P15 (21 mg, 54%) as a bright yellow solid. MS: m / z[M+1] + =469.31.

[0289] Example 16

[0290] 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

[0291] (1) Preparation of Intermediate S52: 6-bromo-1-isopropylbenzo[cd]indol-2(1H)-one

[0292] S2 (1000 mg, 4.03 mmol) was placed in a single-necked flask, and DMF (15 mL) was added. The temperature was cooled to 0°C, and NaH (242 mg, 6.05 mmol, 60% dispersion 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, and the reaction was stirred overnight. The reaction solution was cooled to room temperature, and water (50 mL) was added to precipitate an orange solid. The solution was stirred at room temperature for 0.5 hours, filtered, and the filter cake was washed with water. The filter cake was dried and purified by column chromatography (PE:EA = 30:1) to obtain S52 (933 mg, 80%) as a yellow solid. MS: m / z [M+1] + =291.26.

[0293] (2) Preparation of Intermediate S53: 1-(1-isopropyl-2-oxo-1,2-dihydrobenzo[cd]indol-6-yl)cyclopropane-1-carbonitrile

[0294] 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 through the mixture 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 sequentially. LiHMDS (6 mL, 6.44 mmol, 1.0 M in THF) was then added dropwise. The temperature was raised to 60°C and the reaction was stirred for 1.0 h. After the starting materials were completely reacted, the reaction solution was cooled to room temperature and saturated ammonium chloride solution (20 mL) was added. 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 give S53 (267 mg, 30%) as a yellow solid. MS: m / z [M+1] + =277.32.

[0295] (3) Preparation of Intermediate S54: 1-(1-isopropyl-2-oxo-1,2-dihydrobenz[cd]indol-6-yl)cyclopropane-1-carboxamide

[0296] S53 (267 mg, 0.97 mmol) was placed in a single-necked flask, DMSO (2 mL) and K2CO3 (67 mg, 0.48 mmol) were added, the temperature was lowered to 0°C, and 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. After the starting material was completely reacted, water (20 mL) was added to precipitate a yellow solid. The solid was filtered, the filter cake was washed with water, and then purified by column chromatography (PE:EA = 2:1-1:1) to give S54 (158 mg, 55%) as a yellow solid. MS: m / z [M+1] + =295.38.

[0297] (4) Preparation of Intermediate S55: 6-(1-aminocyclopropyl)-1-isopropylbenzo[cd]indol-2(1H)-one

[0298] S54 (158 mg, 0.54 mmol) was placed in a single-necked flask, t-BuOH (2 mL) was added, the temperature was lowered to 0°C, and 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. After the starting material was completely reacted, the reaction solution was concentrated under reduced pressure to remove the solvent and purified by column chromatography (PE:EA = 2:1, 1:1) to obtain S55 (65 mg, 45%) as a yellow oil. MS: m / z [M+1]+ = 267.36.

[0299] (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

[0300] S55 (29 mg, 0.11 mmol) and S25 (41 mg, 0.12 mmol) were placed in a single-necked flask, 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. After the starting materials were completely reacted, the reaction solution was cooled to room temperature and water was added to precipitate a yellow solid. The reaction solution 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 S56 (53 mg, 83%) as a yellow solid. MS: m / z [M+1] + =581.37.

[0301] (6) Preparation of P16: 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

[0302] S56 (53 mg, 0.091 mmol) was placed in a single-necked flask, 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 starting material was completely reacted, and 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 resulting mixture, and the mixture was 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 P16 (32 mg, 73%) as a bright yellow solid. MS: m / z [M+1] + =481.28.

[0303] Example 17

[0304] 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-dihydrobenz[cd]indol-6-yl)cyclopropyl)benzamide

[0305] (1) Preparation of Intermediate S58: 5-(3-(4-hydroxy-4-methylpiperidin-1-yl)azetidin-1-yl)-2-methylbenzoic acid methyl ester

[0306] 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 through the tube for 30 s, and the temperature was raised to 110°C. The reaction was stirred overnight until the starting materials were completely reacted. The reaction solution was cooled to room temperature, and saturated ammonium chloride solution (6 mL) was added. The mixture was extracted three times with DCM. The organic phases were combined, concentrated under reduced pressure, and purified by column chromatography (PE:EA = 1:1-1:3) to afford S58 (92 mg, 66%) as a light yellow oil. MS: m / z [M+1] + =319.27.

[0307] (2) Preparation of Intermediate S59: 5-(3-(4-hydroxy-4-methylpiperidin-1-yl)azetidin-1-yl)-2-methylbenzoic acid

[0308] S58 (92 mg, 0.29 mmol) was placed in a single-necked flask, and THF (1 mL) and EtOH (1 mL) were added, followed by a solution of NaOH (58 mg, 1.45 mmol) in H2O (1 mL). The temperature was raised to 60°C and the reaction was stirred for 2 h. The starting material reacted completely. The reaction solution was concentrated under reduced pressure to remove THF and EtOH. The pH was adjusted to 4-5 with dilute hydrochloric acid (2.0 M). The solvent was removed by concentration under reduced pressure. The resulting solid was dissolved in DCM, dried over anhydrous sodium sulfate, and filtered. The filter cake was washed with DCM. The filtrate was concentrated under reduced pressure to give S59 (88 mg, 100%) as a pale yellow solid. MS: m / z [M+1] + =305.31.

[0309] (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-dihydrobenz[cd]indol-6-yl)cyclopropyl)benzamide

[0310] S6 (20 mg, 0.084 mmol) and S59 (30 mg, 0.10 mmol) were placed in a single-necked flask, 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. After the starting materials were completely reacted, the reaction solution was cooled to room temperature and water was added to precipitate a yellow solid. 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 P17 (27 mg, 61%) as a bright yellow solid. MS: m / z [M+1] + =525.25.

[0311] Embodiment 18

[0312] Compound P18: Preparation of 5-(3-(3,3-difluoropyrrol-1-yl)azetidin-1-yl)-2-methyl-N-(1-(1-methyl-2-oxo-1,2-dihydrobenz[cd]indol-6-yl)cyclopropyl)benzamide

[0313] (1) Preparation of Intermediate S61: 5-(3-(3,3-difluoropyrrol-1-yl)azetidin-1-yl)-2-methylbenzoic acid methyl ester

[0314] 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 through the tube for 30 s, and the temperature was raised to 110°C. The mixture was stirred and reacted overnight until the starting materials were completely reacted. The reaction mixture was cooled to room temperature, and saturated ammonium chloride solution (6 mL) was added. The mixture was extracted three times with DCM. The organic phases were combined, concentrated under reduced pressure, and purified by column chromatography (PE:EA = 10:1, 7:1) to obtain S61 (115 mg, 85%) as a light yellow oil. MS: m / z [M+1] + =311.26.

[0315] (2) Preparation of Intermediate S62: 5-(3-(3,3-difluoropyrrol-1-yl)azetidin-1-yl)-2-methylbenzoic acid

[0316] S61 (115 mg, 0.37 mmol) was placed in a single-necked flask, and THF (1 mL) and EtOH (1 mL) were added. A solution of NaOH (74 mg, 1.85 mmol) in H2O (1 mL) was then added. The temperature was raised to 60°C and the reaction was stirred for 2 h. The starting material reacted completely. The reaction solution was concentrated under reduced pressure to remove THF and EtOH. The pH was adjusted to 4-5 with dilute hydrochloric acid (2.0 M). The solvent was removed by concentration under reduced pressure. The resulting solid was dissolved in DCM, dried over anhydrous sodium sulfate, and filtered. The filter cake was washed with DCM. The filtrate was concentrated under reduced pressure to afford S62 (109 mg, 100%) as a pale yellow solid. MS: m / z [M+1] + =297.31.

[0317] (3) P18: Preparation of 5-(3-(3,3-difluoropyrrol-1-yl)azetidin-1-yl)-2-methyl-N-(1-(1-methyl-2-oxo-1,2-dihydrobenz[cd]indol-6-yl)cyclopropyl)benzamide

[0318] S6 (20 mg, 0.084 mmol) and S62 (30 mg, 0.10 mmol) were placed in a single-necked flask, 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. After the starting materials were completely reacted, the reaction solution was cooled to room temperature and water was added to precipitate a yellow solid. 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 P18 (25 mg, 58%) as a bright yellow solid. MS: m / z [M+1] + =517.23.

[0319] Example 19

[0320] Compound P19: Preparation of 2-methyl-N-(1-(1-methyl-2-oxo-1,2-dihydrobenz[cd]indol-6-yl)cyclopropyl)-5-(6-methyl-2,6-diazaspiro[3,4]octan-2-ylbenzamide

[0321] (1) Preparation of intermediate S64: methyl 2-methyl-5-(6-methyl-2,6-diazaspiro[3,4]octan-2-yl)benzoate

[0322] 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 through the mixture for 30 s, and the temperature was raised to 110°C. The mixture was stirred and reacted overnight until the starting materials were completely reacted. The reaction mixture was cooled to room temperature, water (8 mL) was added, and the mixture was extracted three times with DCM. 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 afford S64 (71 mg, 100%) as a light yellow oil. MS: m / z [M+1] + =275.32.

[0323] (2) Preparation of Intermediate S65: 2-Methyl-5-(6-methyl-2,6-diazaspiro[3,4]octan-2-yl)benzoic acid

[0324] S64 (70 mg, 0.26 mmol) was placed in a single-necked flask, and THF (1 mL) and EtOH (1 mL) were added, followed by a solution of NaOH (52 mg, 1.30 mmol) in H2O (1 mL). The temperature was raised to 60°C and the reaction was stirred for 2 h. The starting material reacted completely. The reaction solution was concentrated under reduced pressure to remove THF and EtOH. The pH was adjusted to 4-5 with dilute hydrochloric acid (2.0 M). The solvent was removed by concentration under reduced pressure. The resulting solid was dissolved in DCM, dried over anhydrous sodium sulfate, and filtered. The filter cake was washed with DCM. The filtrate was concentrated under reduced pressure to give S65 (68 mg, 100%) as a pale yellow solid. MS: m / z [M+1] + =261.31.

[0325] (3) P19: Preparation of 2-methyl-N-(1-(1-methyl-2-oxo-1,2-dihydrobenz[cd]indol-6-yl)cyclopropyl)-5-(6-methyl-2,6-diazaspiro[3,4]octan-2-ylbenzamide

[0326] S6 (20 mg, 0.084 mmol) and S65 (26 mg, 0.10 mmol) were placed in a single-necked flask, 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. After the starting materials were completely reacted, the reaction solution was cooled to room temperature and water was added to precipitate a yellow solid. 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 P19 (27 mg, 67%) as a bright yellow solid. MS: m / z [M+1] + =481.23.

[0327] Example 20

[0328] 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

[0329] (1) Intermediate S67: Preparation of methyl 2-methyl-5-((1S,5R)-3-methyl-3,6-diazabicyclo[3.2.0]heptane-6-yl)benzoate

[0330] 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 through the tube for 30 s, and the temperature was raised to 110°C. The reaction was stirred overnight until the starting materials were completely reacted. The reaction solution was cooled to room temperature, water (8 mL) was added, and the mixture was extracted three times with DCM. The organic phases were combined, concentrated under reduced pressure, and purified by column chromatography (DCM:MeOH = 20:1, 10:1) to obtain S67 (67 mg, 99%) as a light yellow oil. MS: m / z [M+1] + =261.32.

[0331] (2) Preparation of Intermediate S68: 2-methyl-5-((1S,5R)-3-methyl-3,6-diazabicyclo[3.2.0]heptane-6-yl)benzoic acid

[0332] S67 (67 mg, 0.26 mmol) was placed in a single-necked flask, and THF (1 mL) and EtOH (1 mL) were added, followed by a solution of NaOH (52 mg, 1.30 mmol) in H2O (1 mL). The temperature was raised to 60°C and the reaction was stirred for 2 h. The starting material reacted completely. The reaction solution was concentrated under reduced pressure to remove THF and EtOH. The pH was adjusted to 4-5 with dilute hydrochloric acid (2.0 M). The solvent was removed by concentration under reduced pressure. The resulting solid was dissolved in DCM, dried over anhydrous sodium sulfate, and filtered. The filter cake was washed with DCM. The filtrate was concentrated under reduced pressure to give S68 (64 mg, 100%) as a pale yellow solid. MS: m / z [M+1] + =247.33.

[0333] (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

[0334] S6 (20 mg, 0.084 mmol) and S68 (25 mg, 0.10 mmol) were placed in a single-necked flask, 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. After the starting materials were completely reacted, the reaction solution was cooled to room temperature and water was added to precipitate a yellow solid. 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 P20 (22 mg, 56%) as a bright yellow solid. MS: m / z [M+1] + =467.23.

[0335] Example 21

[0336] 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

[0337] (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

[0338] P16 (20 mg, 0.042 mmol) was placed in a single-necked flask, and MeOH (1.0 mL), aqueous formaldehyde solution (0.30 mL), and acetic acid (7 mg, 0.11 mmol) were added. Finally, NaCNBH3 (4 mg, 0.063 mmol) was added. The reaction was stirred at room temperature for 2 h. After the starting materials reacted completely, saturated sodium bicarbonate solution (5 mL) was added to the reaction solution, and the mixture was extracted three times with DCM. 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 P21 (14 mg, 69%) as a bright yellow solid. MS: m / z[M+1] + =495.35.

[0339] Example 22

[0340] Compound P22: Preparation of 2-methyl-N-(1-(1-methyl-2-oxo-1,2-dihydrobenz[cd]indol-6-yl)cyclopropyl)-5-(1-methylpiperidin-4-yl)benzamide

[0341] (1) Preparation of P22: 2-methyl-N-(1-(1-methyl-2-oxo-1,2-dihydrobenz[cd]indol-6-yl)cyclopropyl)-5-(1-methylpiperidin-4-yl)benzamide

[0342] P4 (26 mg, 0.059 mmol) was placed in a single-necked flask, and MeOH (1.0 mL), aqueous formaldehyde solution (0.50 mL), and acetic acid (9 mg, 0.15 mmol) were added. Finally, NaCNBH3 (6 mg, 0.089 mmol) was added. The reaction was stirred at room temperature for 2 h. After the starting materials reacted completely, saturated sodium bicarbonate solution (5 mL) was added to the reaction solution, and the mixture was extracted three times with DCM. The organic phases were combined and concentrated under reduced pressure to give a yellow solid. The yellow solid was purified by column chromatography (PE:EA=1:1; DCM:MeOH=20:1, 10:1) to give P22 (15 mg, 54%) as a bright yellow solid. MS: m / z[M+1] + =454.29.

[0343] Example 23

[0344] Compound M23: Preparation of 2-methyl-N-(1-(1-methyl-2-oxo-1,2-dihydrobenz[cd]indol-6-yl)cyclopropyl)-5-(3-(4-methylpiperazin-1-yl)azetidin-1-yl)benzamide

[0345] (1) Preparation of Intermediate S70: 2-methyl-5-(3-(4-methylpiperazin-1-yl)azetidin-1-yl)benzoate

[0346] 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 through the tube for 30 s, and the temperature was raised to 110°C. The reaction was stirred overnight until the starting materials were completely reacted. The reaction solution was cooled to room temperature, water (6 mL) was added, and the mixture was extracted three times with DCM. The organic phases were combined, concentrated under reduced pressure, and purified by column chromatography (PE:EA=1:1; DCM:MeOH=20:1) to give S70 (59 mg, 88%) as a white solid. MS: m / z[M+1] + =304.21.

[0347] (2) Preparation of Intermediate S71: 2-methyl-5-(3-(4-methylpiperazin-1-yl)azetidin-1-yl)benzoic acid

[0348] S70 (59 mg, 0.19 mmol) was placed in a single-necked flask, and 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). The temperature was raised to 60°C and the reaction was stirred for 2 h. Once the starting materials were completely reacted, the reaction solution was concentrated under reduced pressure to remove THF and EtOH. The pH was adjusted to 4-5 with dilute hydrochloric acid (2N), and the solvent was removed by concentration under reduced pressure. The resulting solid mixture was dissolved in DCM, dried over anhydrous sodium sulfate, and filtered. The filter cake was washed with DCM, and the filtrate was concentrated under reduced pressure to obtain S71 (55 mg, 100%) as a white solid. MS: m / z [M+1] + =290.22.

[0349] (3) P23: Preparation of 2-methyl-N-(1-(1-methyl-2-oxo-1,2-dihydrobenz[cd]indol-6-yl)cyclopropyl)-5-(3-(4-methylpiperazin-1-yl)azetidin-1-yl)benzamide

[0350] S6 (20 mg, 0.084 mmol) and S71 (29 mg, 0.10 mmol) were placed in a single-necked flask, 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. After the starting materials were completely reacted, the reaction solution was cooled to room temperature and water was added to precipitate a yellow solid. The solid was extracted three times with DCM. 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 P23 (35 mg, 81%) as a bright yellow solid. MS: m / z[M+1] + =510.33.

[0351] Example 24

[0352] Compound P24: Preparation of 2-methyl-N-(1-(1-methyl-2-oxo-1,2-dihydrobenz[cd]indol-6-yl)cyclopropyl)-5-(3-(piperidin-1-yl)azetidin-1-yl)benzamide

[0353] (1) Preparation of Intermediate S73: 2-methyl-5-(3-(piperidin-1-yl)azetidin-1-yl)benzoate

[0354] 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 through the tube for 30 s, and the temperature was raised to 110°C. The reaction was stirred overnight until the starting materials were completely reacted. The reaction solution was cooled to room temperature, water (6 mL) was added, and the mixture was extracted three times with DCM. The organic phases were combined, concentrated under reduced pressure, and purified by column chromatography (PE:EA = 4:1, 3:1) to obtain S73 (53 mg, 71%) as a colorless oil. MS: m / z [M+1] + =289.21.

[0355] (2) Preparation of Intermediate S74: 2-methyl-5-(3-(piperidin-1-yl)azetidin-1-yl)benzoic acid

[0356] S73 (53 mg, 0.18 mmol) was placed in a single-necked flask, and 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). The temperature was raised to 60°C and the reaction was stirred for 2 h. The starting material reacted completely. The reaction solution was concentrated under reduced pressure to remove THF and EtOH. The pH was adjusted to 4-5 with dilute hydrochloric acid (2N). The solvent was removed by concentration under reduced pressure. The resulting solid mixture was dissolved in DCM, dried over anhydrous sodium sulfate, and filtered. The filter cake was washed with DCM. The filtrate was concentrated under reduced pressure to give S74 (49 mg, 100%) as a white solid. MS: m / z [M+1] + =275.26.

[0357] (3) Preparation of P24: 2-methyl-N-(1-(1-methyl-2-oxo-1,2-dihydrobenz[cd]indol-6-yl)cyclopropyl)-5-(3-(piperidin-1-yl)azetidin-1-yl)benzamide

[0358] S6 (20 mg, 0.084 mmol) and S74 (27 mg, 0.10 mmol) were placed in a single-necked flask, 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. After the starting materials were completely reacted, the reaction solution was cooled to room temperature and water was added to precipitate a yellow solid. The solid was extracted three times with DCM. The organic phases were combined, concentrated under reduced pressure, and purified by column chromatography (PE:EA=1:1, DCM:MeOH=20:1) to obtain P24 (28 mg, 67%) as a bright yellow solid. MS: m / z[M+1] + =495.32.

[0359] Example 25

[0360] 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

[0361] (1) Intermediate S76: Preparation of (S)-methyl 5-(hexahydropyrrolo[1,2-a]pyrazine-2(1H)-yl)-2-methylbenzoate

[0362] 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 through the tube for 30 s, and the temperature was raised to 110°C. The reaction was stirred overnight until the starting materials were completely reacted. The reaction solution was cooled to room temperature, water (6 mL) was added, and the mixture was extracted three times with DCM. The organic phases were combined, concentrated under reduced pressure, and purified by column chromatography (PE:EA = 1:1, 1:3) to obtain S76 (65 mg, 92%) as a white solid. MS: m / z [M+1] + =275.21.

[0363] (2) Preparation of Intermediate S77: (S)-5-(hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl)-2-methylbenzoic acid

[0364] S76 (65 mg, 0.24 mmol) was placed in a single-necked flask, and 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). The temperature was raised to 60°C and the reaction was stirred for 2 h. The starting material reacted completely. The reaction solution was concentrated under reduced pressure to remove THF and EtOH. The pH was adjusted to 4-5 with dilute hydrochloric acid (2N). The solvent was removed by concentration under reduced pressure. The resulting solid mixture was dissolved in DCM, dried over anhydrous sodium sulfate, and filtered. The filter cake was washed with DCM. The filtrate was concentrated under reduced pressure to give S77 (62 mg, 100%) as a white solid. MS: m / z [M+1] + =261.26.

[0365] (3) Preparation of P25: (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

[0366] S6 (20 mg, 0.084 mmol) and S77 (26 mg, 0.10 mmol) were placed in a single-necked flask, 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. After the starting materials were completely reacted, the reaction solution was cooled to room temperature and water was added to precipitate a yellow solid. The solid was extracted three times with DCM. The organic phases were combined, concentrated under reduced pressure, and purified by column chromatography (PE:EA=1:1, DCM:MeOH=20:1) to obtain P25 (16 mg, 40%) as a bright yellow solid. MS: m / z [M+1] + =481.32.

[0367] Example 26

[0368] Compound P26: Preparation of 5-(3-(4-fluoropiperidin-1-yl)azetidin-1-yl)-2-methyl-N-(1-(1-methyl-2-oxo-1,2-dihydrobenz[cd]indol-6-yl)cyclopropyl)benzamide

[0369] (1) Preparation of Intermediate S79: 5-(3-(4-fluoropiperidin-1-yl)azetidin-1-yl)-2-methylbenzoic acid methyl ester

[0370] S7 (60 mg, 0.26 mmol) and S78 (72 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 through the tube for 30 s, and the temperature was raised to 110°C. The reaction was stirred overnight until the starting materials reacted completely. The reaction solution was cooled to room temperature, water (6 mL) was added, and the mixture was extracted three times with DCM. The organic phases were combined, concentrated under reduced pressure, and purified by column chromatography (PE:EA = 5:1, 3:1) to obtain S79 (72 mg, 90%) as a white solid. MS: m / z [M+1] + =307.21.

[0371] (2) Preparation of Intermediate S80: 5-(3-(4-fluoropiperidin-1-yl)azetidin-1-yl)-2-methylbenzoic acid

[0372] S79 (72 mg, 0.23 mmol) was placed in a single-necked flask, and 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). The temperature was raised to 60°C and the reaction was stirred for 2 h. The starting material reacted completely. The reaction solution was concentrated under reduced pressure to remove THF and EtOH. The pH was adjusted to 4-5 with dilute hydrochloric acid (2N). The solvent was removed by concentration under reduced pressure. The resulting solid mixture was dissolved in DCM, dried over anhydrous sodium sulfate, and filtered. The filter cake was washed with DCM. The filtrate was concentrated under reduced pressure to give S80 (67 mg, 100%) as a white solid. MS: m / z [M+1] + =293.26.

[0373] (3) Preparation of P26: 5-(3-(4-fluoropiperidin-1-yl)azetidin-1-yl)-2-methyl-N-(1-(1-methyl-2-oxo-1,2-dihydrobenz[cd]indol-6-yl)cyclopropyl)benzamide

[0374] S6 (20 mg, 0.084 mmol) and S80 (29 mg, 0.10 mmol) were placed in a single-necked flask, 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. After the starting materials were completely reacted, the reaction solution was cooled to room temperature and water was added to precipitate a yellow solid. The solid was extracted three times with DCM. The organic phases were combined, concentrated under reduced pressure, and purified by column chromatography (PE:EA = 3:1, 1:1, 1:2) to obtain P26 (27 mg, 63%) as a bright yellow solid. MS: m / z [M+1] + =513.32.

[0375] Example 27

[0376] Compound P27: Preparation of N-(1-(1-ethyl-2-oxo-1,2-dihydrobenz[cd]indol-6-yl)cyclopropyl)-2-methyl-5-(4-methylpiperazin-1-yl)benzamide

[0377] (1) Preparation of Intermediate S81: 6-bromo-1-ethylbenz[cd]indol-2(1H)-one

[0378] S2 (1000 mg, 4.02 mmol) was placed in a single-necked flask, and DMF (10 mL) was added. The temperature was lowered to 0°C, and NaH (241 mg, 6.03 mmol, 60% dispersion in mineral oil) was slowly added. The reaction was stirred for 0.5 h. EtI (753 mg, 4.82 mmol) was added, the temperature was raised to 60°C, and the reaction was stirred overnight. Water (50 mL) was added to the reaction solution, 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) to obtain S81 (1000 mg, 90%) as a yellow solid. MS: m / z [M+1] + =277.21.

[0379] (2) Preparation of Intermediate S82: 1-(1-ethyl-2-oxo-1,2-dihydrobenzo[cd]indol-6-yl)cyclopropyl-1-carbonitrile

[0380] 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 through the flask for 30 seconds. The mixture was stirred at room temperature for 0.5 hours, and LiHMDS (7.2 mL, 7.20 mmol, 1 M in tetrahydrofuran) was added dropwise. After addition, the mixture was heated to 60°C and stirred for 1 hour until the starting materials were completely reacted. The reaction mixture was cooled to room temperature, and saturated ammonium chloride solution (50 mL) was added. 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, 3:1, 2:1) to afford S82 (360 mg, 38%) as an orange-yellow solid. MS: m / z [M+1] + =263.26.

[0381] (3) Preparation of Intermediate S83: 1-(1-ethyl-2-oxo-1,2-dihydrobenz[cd]indol-6-yl)cyclopropyl-1-carboxamide

[0382] S82 (360 mg, 1.38 mmol) was placed in a single-necked flask, DMSO (4 mL) and K2CO3 (95 mg, 0.69 mmol) were added, the temperature was lowered to 0°C, and H2O2 (170 μL, 2.07 mmol) was slowly added dropwise. The temperature was raised to room temperature and the reaction was stirred for 1.5 hours. Once the starting material was completely reacted, water was added to the reaction solution to precipitate a yellow solid. The mixture was stirred at room temperature for 20 minutes. Filter the mixture, wash the filter cake with water, and purify it by column chromatography (PE:EA = 1:1, DCM:MeOH = 30:1) to obtain S83 (137 mg, 35%) as a yellow solid. MS: m / z [M+1] + =281.26.

[0383] (4) Preparation of Intermediate S84: 6-(1-aminocyclopropyl)-1-ethylbenz[cd]indol-2(1H)-one

[0384] S83 (137 mg, 0.49 mmol) was placed in a single-necked flask and added to t-BuOH (4 mL). The temperature was lowered to 0°C, and NaClO (0.83 mL, 1.37 mmol) and NaOH (3N, 0.45 mL, 1.37 mmol) solutions were added. The temperature was raised to room temperature and the reaction was stirred for 3 h. After the starting material was completely reacted, the reaction solution was concentrated under reduced pressure to remove the solvent. The resulting solid mixture was purified by column chromatography (PE:EA=1:1, DCM:MeOH=30:1) to obtain S84 (98 mg, 79%) as a yellow solid. MS: m / z[M+1] + =281.26.

[0385] (5) P27: Preparation of N-(1-(1-ethyl-2-oxo-1,2-dihydrobenz[cd]indol-6-yl)cyclopropyl)-2-methyl-5-(4-methylpiperazin-1-yl)benzamide

[0386] S84 (20 mg, 0.079 mmol) and S10 (22 mg, 0.094 mmol) were placed in a single-necked flask, 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. After the starting materials were completely reacted, the reaction solution was cooled to room temperature and water was added to precipitate a yellow solid. The solid was extracted three times with DCM. 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 P27 (8 mg, 22%) as a bright yellow solid. MS: m / z[M+1] + =469.32.

[0387] Example 28

[0388] Compound P28: Preparation of N-(1-(1-ethyl-2-oxo-1,2-dihydrobenz[cd]indol-6-yl)cyclopropyl)-5-(3-(4-hydroxy-4-methylpiperidin-1-yl)azetidin-1-yl)-2-methyl-benzamide

[0389] (1) P28: Preparation of N-(1-(1-ethyl-2-oxo-1,2-dihydrobenz[cd]indol-6-yl)cyclopropyl)-5-(3-(4-hydroxy-4-methylpiperidin-1-yl)azetidin-1-yl)-2-methyl-benzamide

[0390] S84 (20 mg, 0.079 mmol) and S59 (29 mg, 0.094 mmol) were placed in a single-necked flask, 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 the reaction was stirred for 1.0 h. After the starting materials were completely reacted, the reaction solution was cooled to room temperature and water was added to precipitate a yellow solid. The solid was extracted three times with DCM. 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 P28 (16 mg, 38%) as a bright yellow solid. MS: m / z[M+1] + =539.32.

[0391] Example 29

[0392] Compound P29: Preparation of N-(1-(1-ethyl-2-oxo-1,2-dihydrobenz[cd]indol-6-yl)cyclopropyl)-5-(3-(4-hydroxy-4-methylpiperidin-1-yl)azetidin-1-yl)-2-methyl-benzamide

[0393] (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

[0394] S84 (20 mg, 0.079 mmol) and S25 (32 mg, 0.095 mmol) were placed in a single-necked flask, 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 the reaction was stirred for 1.0 h. After the starting materials were completely reacted, the reaction solution was cooled to room temperature and water was added to precipitate a yellow solid. The solid was extracted three times with DCM. The organic phases were combined, concentrated under reduced pressure, and purified by column chromatography (PE:EA = 3:1, 1:1, 1:2) to give S85 (27 mg, 60%) as a yellow solid. MS: m / z [M+1] + =567.32.

[0395] (2) P29: Preparation of N-(1-(1-ethyl-2-oxo-1,2-dihydrobenz[cd]indol-6-yl)cyclopropyl)-5-(3-(4-hydroxy-4-methylpiperidin-1-yl)azetidin-1-yl)-2-methyl-benzamide

[0396] S85 (27 mg, 0.048 mmol) was placed in a single-necked flask, 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 starting material was completely reacted, and 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 resulting 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 P29 (15 mg, 70%) as a bright yellow solid. MS: m / z [M+1] + =467.32.

[0397] Example 30

[0398] Compound P30: Preparation of 5-(3-(3-fluoropyrrolidin-1-yl)azetidin-1-yl)-2-methyl-N-(1-(1-methyl-2-oxo-1,2-dihydrobenz[cd]indol-6-yl)cyclopropyl)benzamide

[0399] (1) Preparation of Intermediate S87: 5-(3-(3-fluoropyrrolidin-1-yl)azetidin-1-yl)-2-methylbenzoic acid methyl ester

[0400] 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 through the tube for 30 s, and the temperature was raised to 110°C. The reaction was stirred overnight until the starting materials were completely reacted. The reaction solution was cooled to room temperature, water (6 mL) was added, and the mixture was extracted three times with DCM. The organic phases were combined, concentrated under reduced pressure, and purified by column chromatography (PE:EA = 5:1, 3:1) to obtain S87 (70 mg, 92%) as a white solid. MS: m / z [M+1] + =293.21.

[0401] (2) Preparation of Intermediate S88: 5-(3-(3-fluoropyrrolidin-1-yl)azetidin-1-yl)-2-methylbenzoic acid

[0402] S87 (70 mg, 0.24 mmol) was placed in a single-necked flask, and THF (1.0 mL) and EtOH (1.0 mL) were added. A solution of NaOH (48 mg, 1.20 mmol) in H2O (1.0 mL) was then added. The temperature was raised to 60°C and the reaction was stirred for 2 h. The starting material reacted completely. The reaction solution was concentrated under reduced pressure to remove THF and EtOH. The pH was adjusted to 4-5 with dilute hydrochloric acid (2N). The solvent was removed by concentration under reduced pressure. The resulting solid mixture was dissolved in DCM, dried over anhydrous sodium sulfate, and filtered. The filter cake was washed with DCM. The filtrate was concentrated under reduced pressure to afford S88 (67 mg, 100%) as a white solid. MS: m / z [M+1] + =279.26.

[0403] (3) Preparation of P30: 5-(3-(3-fluoropyrrolidin-1-yl)azetidin-1-yl)-2-methyl-N-(1-(1-methyl-2-oxo-1,2-dihydrobenz[cd]indol-6-yl)cyclopropyl)benzamide

[0404] S6 (20 mg, 0.084 mmol) and S88 (28 mg, 0.10 mmol) were placed in a single-necked flask, 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. After the starting materials were completely reacted, the reaction solution was cooled to room temperature and water was added to precipitate a yellow solid. The solid was extracted three times with DCM. The organic phases were combined, concentrated under reduced pressure, and purified by column chromatography (PE:EA = 3:1, 1:1, 1:2) to obtain P30 (31 mg, 75%) as a bright yellow solid. MS: m / z [M+1] + =499.32.

[0405] Example 31

[0406] Compound P31: Preparation of 5-(3-(4,4-difluoropiperidin-1-yl)azetidin-1-yl)-2-methyl-N-(1-(1-methyl-2-oxo-1,2-dihydrobenz[cd]indol-6-yl)cyclopropyl)benzamide

[0407] (1) Preparation of intermediate S90: methyl 5-(3-(4,4-difluoropiperidin-1-yl)azetidin-1-yl)-2-methylbenzoate

[0408] 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 through the tube for 30 s, and the temperature was raised to 90°C. The reaction was stirred overnight until the starting materials were completely reacted. The reaction solution was cooled to room temperature, water (6 mL) was added, and the mixture was extracted three times with DCM. The organic phases were combined, concentrated under reduced pressure, and purified by column chromatography (PE:EA = 5:1, 3:1) to obtain S90 (58 mg, 76%) as a white solid. MS: m / z [M+1] + =325.21.

[0409] (2) Preparation of Intermediate S91: 5-(3-(4,4-difluoropiperidin-1-yl)azetidin-1-yl)-2-methylbenzoic acid

[0410] S90 (58 mg, 0.18 mmol) was placed in a single-necked flask, and THF (1.0 mL) and EtOH (1.0 mL) were added. A solution of NaOH (36 mg, 0.90 mmol) in H2O (1.0 mL) was then added. The temperature was raised to 60°C and the reaction was stirred for 2 h. The starting materials reacted completely. The reaction solution was concentrated under reduced pressure to remove THF and EtOH. The pH was adjusted to 4-5 with dilute hydrochloric acid (2N). The solvent was removed by concentration under reduced pressure. The resulting solid mixture was dissolved in DCM, dried over anhydrous sodium sulfate, and filtered. The filter cake was washed with DCM. The filtrate was concentrated under reduced pressure to afford S91 (56 mg, 100%) as a white solid. MS: m / z [M+1] + =311.26.

[0411] (3) P31: Preparation of 5-(3-(4,4-difluoropiperidin-1-yl)azetidin-1-yl)-2-methyl-N-(1-(1-methyl-2-oxo-1,2-dihydrobenz[cd]indol-6-yl)cyclopropyl)benzamide

[0412] S6 (18 mg, 0.075 mmol) and S91 (28 mg, 0.090 mmol) were placed in a single-necked flask, 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 the reaction was stirred for 1.0 h. After the starting materials were completely reacted, the reaction solution was cooled to room temperature and water was added to precipitate a yellow solid. The solid was extracted three times with DCM. The organic phases were combined, concentrated under reduced pressure, and purified by column chromatography (PE:EA = 3:1, 1:1, 1:2) to obtain P31 (22 mg, 55%) as a bright yellow solid. MS: m / z [M+1] + =531.32.

[0413] Example 32

[0414] Compound P32: Preparation of 5-(3-(4-hydroxypiperidin-1-yl)azetidin-1-yl)-2-methyl-N-(1-(1-methyl-2-oxo-1,2-dihydrobenz[cd]indol-6-yl)cyclopropyl)benzamide

[0415] (1) Preparation of Intermediate S93: 5-(3-(4-hydroxypiperidin-1-yl)azetidin-1-yl)-2-methylbenzoate

[0416] 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 through the mixture for 30 s, and the temperature was raised to 90°C. The mixture was stirred and reacted overnight until the starting materials were completely reacted. The reaction solution was cooled to room temperature, and saturated ammonium chloride solution (6 mL) was added. The mixture was extracted three times with DCM. The organic phases were combined, concentrated under reduced pressure, and purified by column chromatography (PE:EA = 3:1, 1:1) to obtain S93 (69 mg, 100%) as a colorless oil. MS: m / z [M+1] + =305.21.

[0417] (2) Preparation of Intermediate S94: 5-(3-(4-hydroxypiperidin-1-yl)azetidin-1-yl)-2-methylbenzoic acid

[0418] S93 (69 mg, 0.22 mmol) was placed in a single-necked flask, and 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). The temperature was raised to 60°C and the reaction was stirred for 2 h. Once the starting materials were completely reacted, the reaction solution was concentrated under reduced pressure to remove THF and EtOH. The pH was adjusted to 4-5 with dilute hydrochloric acid (2N), and the solvent was removed by concentration under reduced pressure. The resulting solid mixture was dissolved in DCM, dried over anhydrous sodium sulfate, and filtered. The filter cake was washed with DCM, and the filtrate was concentrated under reduced pressure to give S94 (63 mg, 100%) as a pale yellow solid. MS: m / z [M+1] + =291.26.

[0419] (3) P32: Preparation of 5-(3-(4-hydroxypiperidin-1-yl)azetidin-1-yl)-2-methyl-N-(1-(1-methyl-2-oxo-1,2-dihydrobenz[cd]indol-6-yl)cyclopropyl)benzamide

[0420] S6 (13 mg, 0.054 mmol) and S94 (19 mg, 0.065 mmol) were placed in a single-necked flask, 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 the reaction was stirred for 1.0 h. After the starting materials were completely reacted, the reaction solution was cooled to room temperature and water was added to precipitate a yellow solid. The solid was extracted three times with DCM. 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 P32 (10 mg, 37%) as a bright yellow solid. MS: m / z[M+1] + =511.32.

[0421] Example 33

[0422] 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

[0423] (1) Preparation of intermediate S96: methyl 5-(3-(2,2-dimethylmorpholino)azetidin-1-yl)-2-methylbenzoate

[0424] 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 through the tube for 30 s, and the temperature was raised to 90°C. The reaction was stirred overnight until the starting materials were completely reacted. The reaction solution was cooled to room temperature, water (6 mL) was added, and the mixture was extracted three times with DCM. The organic phases were combined, concentrated under reduced pressure, and purified by column chromatography (PE:EA = 3:1, 1:1) to obtain S96 (35 mg, 87%) as a light yellow oil. MS: m / z [M+1] + =319.21.

[0425] (2) Preparation of Intermediate S97: 5-(3-(2,2-dimethylmorpholino)azetidin-1-yl)-2-methylbenzoic acid

[0426] S96 (35 mg, 0.11 mmol) was placed in a single-necked flask, and 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). The temperature was raised to 60°C and the reaction was stirred for 2 h. The starting material reacted completely. The reaction solution was concentrated under reduced pressure to remove THF and EtOH. The pH was adjusted to 4-5 with dilute hydrochloric acid (2N). The solvent was removed by concentration under reduced pressure. The resulting solid mixture was dissolved in DCM, dried over anhydrous sodium sulfate, and filtered. The filter cake was washed with DCM. The filtrate was concentrated under reduced pressure to give S97 (30 mg, 89%) as a pale yellow solid. MS: m / z [M+1] + =305.26.

[0427] (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

[0428] S6 (20 mg, 0.082 mmol) and S97 (30 mg, 0.098 mmol) were placed in a single-necked flask, 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 the reaction was stirred for 1.0 h. After the starting materials were completely reacted, the reaction solution was cooled to room temperature and water was added to precipitate a yellow solid. The solid was extracted three times with DCM. 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 P33 (16 mg, 37%) as a bright yellow solid. MS: m / z[M+1] + =525.32.

[0429] Example 34

[0430] 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

[0431] (1) Preparation of intermediate S99: methyl 2-methyl-5-(3-(2-methylpiperidin-1-yl)azetidin-1-yl)benzoate

[0432] 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 through the tube for 30 s, and the temperature was raised to 90°C. The reaction was stirred overnight until the starting materials were completely reacted. The reaction solution was cooled to room temperature, water (6 mL) was added, and the mixture was extracted three times with DCM. The organic phases were combined, concentrated under reduced pressure, and purified by column chromatography (PE:EA=1:1, DCM:MeOH=20:1) to obtain S99 (96 mg, 97%) as a light yellow oil. MS: m / z [M+1] + =303.21.

[0433] (2) Preparation of Intermediate S100: 2-methyl-5-(3-(2-methylpiperidin-1-yl)azetidin-1-yl)benzoic acid

[0434] S99 (96 mg, 0.32 mmol) was placed in a single-necked flask, and 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). The temperature was raised to 60°C and the reaction was stirred for 2 h. The starting materials reacted completely. The reaction solution was concentrated under reduced pressure to remove THF and EtOH. The pH was adjusted to 4-5 with dilute hydrochloric acid (2N). The solvent was removed by concentration under reduced pressure. The resulting solid mixture was dissolved in DCM, dried over anhydrous sodium sulfate, and filtered. The filter cake was washed with DCM. The filtrate was concentrated under reduced pressure to obtain S100 (88 mg, 96%) as a pale yellow solid. MS: m / z [M+1] + =289.26.

[0435] (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

[0436] S6 (15 mg, 0.063 mmol) and S100 (22 mg, 0.075 mmol) were placed in a single-necked flask, 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 the reaction was stirred for 1.0 h. After the starting materials were completely reacted, the reaction solution was cooled to room temperature and water was added to precipitate a yellow solid. The solid was extracted three times with DCM. 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 P34 (18 mg, 56%) as a bright yellow solid. MS: m / z[M+1] + =509.32.

[0437] Example 35

[0438] 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

[0439] (1) Preparation of intermediate S102: methyl 5-(3-(1,1-dioxothiomorpholino)azetidin-1-yl)-2-methylbenzoate

[0440] 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 through the tube for 30 s, and the temperature was raised to 90°C. The reaction was stirred overnight until the starting materials were completely reacted. The reaction solution was cooled to room temperature, water (6 mL) was added, and the mixture was extracted three times with DCM. The organic phases were combined, concentrated under reduced pressure, and purified by column chromatography (PE:EA=1:1, DCM:MeOH=20:1) to obtain S102 (60 mg, 93%) as a light yellow solid. MS: m / z[M+1] + =339.21.

[0441] (2) Preparation of Intermediate S103: 5-(3-(1,1-dioxothiomorpholino)azetidin-1-yl)-2-methylbenzoic acid

[0442] S102 (60 mg, 0.18 mmol) was placed in a single-necked flask, and 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). The temperature was raised to 60°C and the reaction was stirred for 2 h. The starting material reacted completely. The reaction solution was concentrated under reduced pressure to remove THF and EtOH. The pH was adjusted to 4-5 with dilute hydrochloric acid (2N). The solvent was removed by concentration under reduced pressure. The resulting solid mixture was dissolved in DCM, dried over anhydrous sodium sulfate, and filtered. The filter cake was washed with DCM. The filtrate was concentrated under reduced pressure to give S103 (41 mg, 71%) as a light yellow solid. MS: m / z [M+1] + =325.26.

[0443] (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

[0444] S6 (15 mg, 0.063 mmol) and S103 (24 mg, 0.075 mmol) were placed in a single-necked flask, 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 the reaction was stirred for 1.0 h. After the starting materials were completely reacted, the reaction solution was cooled to room temperature and water was added to precipitate a yellow solid. The solid was extracted three times with DCM. 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 P35 (7 mg, 20%) as a bright yellow solid. MS: m / z[M+1] + =545.32.

[0445] Example 36

[0446] Compound P36: Preparation of (S)-5-(3-(3-(isopropyl(methyl)amino)pyrrolidin-1-yl)-2-methyl-N-(1-(1-methyl-2-oxo-1,2-dihydrobenz[cd]indol-6-yl)cyclopropyl)benzamide

[0447] (1) Preparation of intermediate S105: (R)-methyl 5-(3-(3-(isopropyl(methyl)amino)pyrrolidin-1-yl)-2-methylbenzoate

[0448] 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 through the tube for 30 s, and the temperature was raised to 90°C. The reaction was stirred overnight until the starting materials were completely reacted. The reaction solution was cooled to room temperature, water (6 mL) was added, and the mixture was extracted three times with DCM. The organic phases were combined, concentrated under reduced pressure, and purified by column chromatography (PE:EA=1:1, DCM:MeOH=20:1) to obtain S105 (51 mg, 76%) as a light yellow oil. MS: m / z [M+1] + =291.21.

[0449] (2) Preparation of Intermediate S106: (R)-5-(3-(3-(isopropyl(methyl)amino)pyrrolidin-1-yl)-2-methylbenzoic acid

[0450] S105 (51 mg, 0.17 mmol) was placed in a single-necked flask, and 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). The temperature was raised to 60°C and the reaction was stirred for 2 h. Once the starting materials were completely reacted, the reaction solution was concentrated under reduced pressure to remove THF and EtOH. The pH was adjusted to 4-5 with dilute hydrochloric acid (2N), and the solvent was removed by concentration under reduced pressure. The resulting solid mixture was dissolved in DCM, dried over anhydrous sodium sulfate, and filtered. The filter cake was washed with DCM, and the filtrate was concentrated under reduced pressure to obtain S106 (41 mg, 85%) as a light yellow solid. MS: m / z [M+1] + =277.26.

[0451] (3) P36: Preparation of (S)-5-(3-(3-(isopropyl(methyl)amino)pyrrolidin-1-yl)-2-methyl-N-(1-(1-methyl-2-oxo-1,2-dihydrobenz[cd]indol-6-yl)cyclopropyl)benzamide

[0452] S6 (15 mg, 0.063 mmol) and S106 (21 mg, 0.075 mmol) were placed in a single-necked flask, 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 the reaction was stirred for 1.0 h. After the starting materials were completely reacted, the reaction solution was cooled to room temperature and water was added to precipitate a yellow solid. The solid was extracted three times with DCM. 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 P36 (20 mg, 64%) as a bright yellow solid. MS: m / z[M+1] + =497.32.

[0453] Example 37

[0454] Compound P37: Preparation of 5-([1,3'-dipyrrolidino]-1'-yl)-2-methyl-N-(1-(1-methyl-2-oxo-1,2-dihydrobenz[cd]indol-6-yl)cyclopropyl)benzamide

[0455] (1) Preparation of intermediate S108: methyl 5-([1,3'-dipyrrolidino]-1'-yl)-2-methylbenzoate

[0456] 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 through the tube for 30 s, and the temperature was raised to 90°C. The reaction was stirred overnight until the starting materials were completely reacted. The reaction solution was cooled to room temperature, water (6 mL) was added, and the mixture was extracted three times with DCM. The organic phases were combined, concentrated under reduced pressure, and purified by column chromatography (PE:EA=1:1, DCM:MeOH=20:1) to obtain S108 (45 mg, 66%) as a light yellow solid. MS: m / z[M+1] + =289.21.

[0457] (2) Preparation of Intermediate S109: 5-([1,3'-dipyrrolidino]-1'-yl)-2-methylbenzoic acid

[0458] S108 (45 mg, 0.15 mmol) was placed in a single-necked flask, and 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). The temperature was raised to 60°C and the reaction was stirred for 2 h. The starting materials reacted completely. The reaction solution was concentrated under reduced pressure to remove THF and EtOH. The pH was adjusted to 4-5 with dilute hydrochloric acid (2N). The solvent was removed by concentration under reduced pressure. The resulting solid mixture was dissolved in DCM, dried over anhydrous sodium sulfate, and filtered. The filter cake was washed with DCM. The filtrate was concentrated under reduced pressure to give S109 (41 mg, 96%) as a pale yellow solid. MS: m / z [M+1] + =275.26.

[0459] (3) P37: Preparation of 5-([1,3'-dipyrrolidino]-1'-yl)-2-methyl-N-(1-(1-methyl-2-oxo-1,2-dihydrobenz[cd]indol-6-yl)cyclopropyl)benzamide

[0460] S6 (15 mg, 0.063 mmol) and S109 (20 mg, 0.075 mmol) were placed in a single-necked flask, 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 the reaction was stirred for 1.0 h. After the starting materials were completely reacted, the reaction solution was cooled to room temperature and water was added to precipitate a yellow solid. The solid was extracted three times with DCM. 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 P37 (7 mg, 22%) as a bright yellow solid. MS: m / z[M+1] + =495.32.

[0461] Example 38

[0462] 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

[0463] (1) Preparation of intermediate S111: methyl 2-methyl-5-(4-(morpholinomethyl)piperidin-1-yl)benzoate

[0464] 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 through the tube for 30 s, and the temperature was raised to 90°C. The reaction was stirred overnight until the starting materials were completely reacted. The reaction solution was cooled to room temperature, water (6 mL) was added, and the mixture was extracted three times with DCM. The organic phases were combined, concentrated under reduced pressure, and purified by column chromatography (PE:EA=1:1, DCM:MeOH=20:1) to obtain S111 (86 mg, 96%) as a light yellow solid. MS: m / z[M+1] + =333.21.

[0465] (2) Preparation of Intermediate S112: 2-Methyl-5-(4-(morpholinomethyl)piperidin-1-yl)benzoic acid

[0466] S111 (86 mg, 0.26 mmol) was placed in a single-necked flask, and 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). The temperature was raised to 60°C and the reaction was stirred for 2 h. The starting material reacted completely. The reaction solution was concentrated under reduced pressure to remove THF and EtOH. The pH was adjusted to 4-5 with dilute hydrochloric acid (2N). The solvent was removed by concentration under reduced pressure. The resulting solid mixture was dissolved in DCM, dried over anhydrous sodium sulfate, and filtered. The filter cake was washed with DCM. The filtrate was concentrated under reduced pressure to obtain S112 (80 mg, 97%) as a light yellow solid. MS: m / z [M+1] + =319.26.

[0467] (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

[0468] S6 (15 mg, 0.063 mmol) and S112 (24 mg, 0.075 mmol) were placed in a single-necked flask, 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 the reaction was stirred for 1.0 h. After the starting materials were completely reacted, the reaction solution was cooled to room temperature and water was added to precipitate a yellow solid. The solid was extracted three times with DCM. 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 P38 (10 mg, 29%) as a bright yellow solid. MS: m / z[M+1] + =539.32.

[0469] Example 39

[0470] 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

[0471] (1) Preparation of intermediate S114: methyl 2-methyl-5-(1-methyloctahydro-6H-pyrrolo[3,4-b]pyridin-6-yl)benzoate

[0472] 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 through the tube for 30 s, and the temperature was raised to 90°C. The reaction was stirred overnight until the starting materials were completely reacted. The reaction solution was cooled to room temperature, water (6 mL) was added, and the mixture was extracted three times with DCM. The organic phases were combined, concentrated under reduced pressure, and purified by column chromatography (PE:EA=1:1, DCM:MeOH=20:1) to obtain S114 (70 mg, 68%) as a light yellow solid. MS: m / z[M+1] + =289.21.

[0473] (2) Preparation of Intermediate S115: 2-Methyl-5-(1-methyloctahydro-6H-pyrrolo[3,4-b]pyridin-6-yl)benzoic acid

[0474] S114 (70 mg, 0.24 mmol) was placed in a single-necked flask, and 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). The temperature was raised to 60°C and the reaction was stirred for 2 h. The starting material reacted completely. The reaction solution was concentrated under reduced pressure to remove THF and EtOH. The pH was adjusted to 4-5 with dilute hydrochloric acid (2N). The solvent was removed by concentration under reduced pressure. The resulting solid mixture was dissolved in DCM, dried over anhydrous sodium sulfate, and filtered. The filter cake was washed with DCM. The filtrate was concentrated under reduced pressure to give S115 (60 mg, 90%) as a light yellow solid. MS: m / z [M+1] + =275.26.

[0475] (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

[0476] S6 (15 mg, 0.063 mmol) and S115 (21 mg, 0.075 mmol) were placed in a single-necked flask, 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 the reaction was stirred for 1.0 h. After the starting materials were completely reacted, the reaction solution was cooled to room temperature and water was added to precipitate a yellow solid. The solid was extracted three times with DCM. 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 P39 (14 mg, 45%) as a bright yellow solid. MS: m / z[M+1] + =495.32.

[0477] Example 40

[0478] 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

[0479] (1) Preparation of intermediate S117: methyl 2-methyl-5-((1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptane-2-yl)benzoate

[0480] 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 through the tube for 30 s, and the temperature was raised to 90°C. The reaction was stirred overnight until the starting materials were completely reacted. The reaction solution was cooled to room temperature, water (6 mL) was added, and the mixture was extracted three times with DCM. 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 S117 (42 mg, 88%) as a light yellow oil. MS: m / z [M+1] + =261.21.

[0481] (2) Preparation of Intermediate S118: 2-methyl-5-((1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptane-2-yl)benzoic acid

[0482] S117 (42 mg, 0.16 mmol) was placed in a single-necked flask, 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). The temperature was raised to 60°C and the reaction was stirred for 2 h. Once the starting material was completely reacted, the reaction solution was concentrated under reduced pressure to remove THF and EtOH. The pH was adjusted to 4-5 with dilute hydrochloric acid (2N), and the solvent was removed by concentration under reduced pressure. The resulting solid mixture was dissolved in DCM, dried over anhydrous sodium sulfate, and filtered. The filter cake was washed with DCM, and the filtrate was concentrated under reduced pressure to obtain S118 (35 mg, 90%) as a light yellow solid. MS: m / z [M+1] + =247.26.

[0483] (3) Preparation of P40: 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

[0484] S6 (15 mg, 0.063 mmol) and S118 (18 mg, 0.075 mmol) were placed in a single-necked flask, 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 the reaction was stirred for 1.0 h. After the starting materials were completely reacted, the reaction solution was cooled to room temperature and water was added to precipitate a yellow solid. The solid was extracted three times with DCM. 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 P40 (9 mg, 31%) as a bright yellow solid. MS: m / z[M+1] + =467.32.

[0485] Example 41

[0486] 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

[0487] (1) Preparation of intermediate S120: methyl 5-(4-(2-hydroxypropyl)piperazin-1-yl)-2-methylbenzoate

[0488] 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 through the system for 30 s, and the temperature was raised to 90°C. The reaction was stirred overnight until the starting materials were completely reacted. The reaction solution was cooled to room temperature, saturated ammonium chloride solution (6 mL) was added, and the mixture was extracted three times with DCM. 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 S120 (42 mg, 88%) as a light yellow oil. MS: m / z [M+1] + =293.21.

[0489] (2) Preparation of Intermediate S121: 5-(4-(2-hydroxypropyl)piperazin-1-yl)-2-methylbenzoic acid

[0490] S120 (30 mg, 0.10 mmol) was placed in a single-necked flask, 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). The temperature was raised to 60°C and the reaction was stirred for 2 h. Once the starting materials were completely reacted, the reaction solution was concentrated under reduced pressure to remove THF and EtOH. The pH was adjusted to 4-5 with dilute hydrochloric acid (2N), and the solvent was removed by concentration under reduced pressure. The resulting solid mixture was dissolved in DCM, dried over anhydrous sodium sulfate, and filtered. The filter cake was washed with DCM, and the filtrate was concentrated under reduced pressure to obtain S121 (24 mg, 86%) as a light yellow solid. MS: m / z [M+1] + =279.26.

[0491] (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

[0492] S6 (11 mg, 0.048 mmol) and S121 (16 mg, 0.057 mmol) were placed in a single-necked flask, 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 the reaction was stirred for 1.0 h. After the starting materials were completely reacted, the reaction solution was cooled to room temperature and water was added to precipitate a yellow solid. The solid was extracted three times with DCM. 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 P41 (9 mg, 37%) as a bright yellow solid. MS: m / z[M+1] + =499.32.

[0493] Example 42

[0494] Preparation of Compound P42: 5-([1,3'-diazetidine]-1'-yl)-2-methyl-N-(1-(1-methyl-2-oxo-1,2-dihydrobenz[cd]indol-6-yl)cyclopropyl)benzamide

[0495] (1) Preparation of intermediate S123: methyl 5-([1,3'-diazetidine]-1'-yl)-2-methylbenzoate

[0496] 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 through the mixture for 30 s, and the temperature was raised to 110°C. The mixture was stirred and reacted overnight until the starting materials were completely reacted. The reaction solution was cooled to room temperature, water (6 mL) was added, and the mixture was extracted three times with DCM. 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 S123 (47 mg, 100%) as a light yellow solid. MS: m / z [M+1] + =261.21.

[0497] (2) Preparation of intermediate S124: 5-([1,3'-diazetidine]-1'-yl)-2-methylbenzoic acid

[0498] S123 (47 mg, 0.18 mmol) was placed in a single-necked flask, and 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). The temperature was raised to 60°C and the reaction was stirred for 2 h. The starting material reacted completely. The reaction solution was concentrated under reduced pressure to remove THF and EtOH. The pH was adjusted to 4-5 with dilute hydrochloric acid (2N). The solvent was removed by concentration under reduced pressure. 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 concentrated under reduced pressure to give S124 (37 mg, 84%) as a light yellow solid. MS: m / z [M+1] + =247.26.

[0499] (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

[0500] S6 (15 mg, 0.063 mmol) and S124 (18 mg, 0.075 mmol) were placed in a single-necked flask, 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 the reaction was stirred for 1.0 h. After the starting materials were completely reacted, the reaction solution was cooled to room temperature and water was added to precipitate a yellow solid. The solid was extracted three times with DCM. 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 P42 (23 mg, 80%) as a bright yellow solid. MS: m / z[M+1] + =467.32.

[0501] Example 43

[0502] Compound P43: Preparation of 5-(3-(3-hydroxypyrrolidin-1-yl)azetidin-1-yl)-2-methyl-N-(1-(1-methyl-2-oxo-1,2-dihydrobenz[cd]indol-6-yl)cyclopropyl)benzamide

[0503] (1) Preparation of intermediate S126: methyl 5-(3-(3-hydroxypyrrolidin-1-yl)azetidin-1-yl)-2-methylbenzoate

[0504] 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 through the tube for 30 s, and the temperature was raised to 110°C. The reaction was stirred overnight until the starting materials were completely reacted. The reaction solution was cooled to room temperature, and saturated ammonium chloride solution (6 mL) was added. The mixture was extracted three times with DCM. 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 S126 (16 mg, 21%) as a colorless oil. MS: m / z [M+1] + =291.21.

[0505] (2) Preparation of Intermediate S127: 5-(3-(3-hydroxypyrrolidin-1-yl)azetidin-1-yl)-2-methylbenzoic acid

[0506] S126 (16 mg, 0.055 mmol) was placed in a single-necked flask, and THF (0.5 mL) and EtOH (0.5 mL) were added. A solution of NaOH (11 mg, 0.28 mmol) in H2O (0.5 mL) was then added. The temperature was raised to 60°C and the reaction was stirred for 2 h. The starting material reacted completely. The reaction solution was concentrated under reduced pressure to remove THF and EtOH. The pH was adjusted to 4-5 with dilute hydrochloric acid (2N). The solvent was removed by concentration under reduced pressure. The resulting solid mixture was dissolved in DCM, dried over anhydrous sodium sulfate, and filtered. The filter cake was washed with DCM. The filtrate was concentrated under reduced pressure to afford S127 (15 mg, 100%) as a pale yellow solid. MS: m / z [M+1] + =247.26.

[0507] (3) P43: Preparation of 5-(3-(3-hydroxypyrrolidin-1-yl)azetidin-1-yl)-2-methyl-N-(1-(1-methyl-2-oxo-1,2-dihydrobenz[cd]indol-6-yl)cyclopropyl)benzamide

[0508] S6 (11 mg, 0.045 mmol) and S127 (15 mg, 0.054 mmol) were placed in a single-necked flask, 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 the reaction was stirred for 1.0 h. After the starting materials were completely reacted, the reaction solution was cooled to room temperature and water was added to precipitate a yellow solid. The solid was extracted three times with DCM. 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 P43 (9 mg, 41%) as a bright yellow solid. MS: m / z[M+1] + =497.32.

[0509] Example 44

[0510] Compound P44: Preparation of 2-methyl-N-(1-(1-methyl-2-oxo-1,2-dihydrobenz[cd]indol-6-yl)cyclopropyl)-5-(3-(4-methyl-3-oxopiperazin-1-yl)azetidin-1-yl)benzamide

[0511] (1) Preparation of intermediate S129: methyl 2-methyl-5-(3-(4-methyl-3-oxopiperazin-1-yl)azetidin-1-yl)benzoate

[0512] 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 through the tube for 30 s, and the temperature was raised to 110°C. The reaction was stirred overnight until the starting materials were completely reacted. The reaction solution was cooled to room temperature, water (6 mL) was added, and the mixture was extracted three times with DCM. 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 S129 (56 mg, 68%) as a light yellow solid. MS: m / z[M+1] + =318.21.

[0513] (2) Preparation of Intermediate S130: 2-methyl-5-(3-(4-methyl-3-oxopiperazin-1-yl)azetidin-1-yl)benzoic acid

[0514] S129 (56 mg, 0.18 mmol) was placed in a single-necked flask, and 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). The temperature was raised to 60°C and the reaction was stirred for 2 h. Once the starting material was completely reacted, the reaction solution was concentrated under reduced pressure to remove THF and EtOH. The pH was adjusted to 4-5 with dilute hydrochloric acid (2N), and the solvent was removed by concentration under reduced pressure. The resulting solid mixture was dissolved in DCM, dried over anhydrous sodium sulfate, and filtered. The filter cake was washed with DCM, and the filtrate was concentrated under reduced pressure to give S130 (54 mg, 100%) as a pale yellow solid. MS: m / z [M+1] + =304.26.

[0515] (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

[0516] S6 (15 mg, 0.063 mmol) and S130 (23 mg, 0.075 mmol) were placed in a single-necked flask, 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 the reaction was stirred for 1.0 h. After the starting materials were completely reacted, the reaction solution was cooled to room temperature and water was added to precipitate a yellow solid. The solid was extracted three times with DCM. 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 P44 (12 mg, 36%) as a bright yellow solid. MS: m / z[M+1] + =524.32.

[0517] Example 45

[0518] 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

[0519] (1) Preparation of Intermediate S132: methyl 2-methyl-5-(3-(pyrrolidin-1-yl)azetidin-1-yl)benzoate

[0520] 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 through the mixture for 30 s, and the temperature was raised to 110°C. The mixture was stirred and reacted overnight until the starting materials were completely reacted. The reaction solution was cooled to room temperature, water (6 mL) was added, and the mixture was extracted three times with DCM. 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 S132 (71 mg, 100%) as a light yellow oil. MS: m / z [M+1] + =275.21.

[0521] (2) Preparation of Intermediate S133: 2-methyl-5-(3-(pyrrolidin-1-yl)azetidin-1-yl)benzoic acid

[0522] S132 (71 mg, 0.26 mmol) was placed in a single-necked flask, and 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). The temperature was raised to 60°C and the reaction was stirred for 2 h. The starting material reacted completely. The reaction solution was concentrated under reduced pressure to remove THF and EtOH. The pH was adjusted to 4-5 with dilute hydrochloric acid (2N). The solvent was removed by concentration under reduced pressure. The resulting solid mixture was dissolved in DCM, dried over anhydrous sodium sulfate, and filtered. The filter cake was washed with DCM. The filtrate was concentrated under reduced pressure to give S133 (68 mg, 100%) as a light yellow solid. MS: m / z [M+1] + =261.26.

[0523] (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

[0524] S6 (15 mg, 0.063 mmol) and S133 (20 mg, 0.075 mmol) were placed in a single-necked flask, 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 the reaction was stirred for 1.0 h. After the starting materials were completely reacted, the reaction solution was cooled to room temperature and water was added to precipitate a yellow solid. The solid was extracted three times with DCM. 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 P45 (14 mg, 47%) as a bright yellow solid. MS: m / z[M+1] + =481.32.

[0525] Example 46

[0526] 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

[0527] (1) Preparation of intermediate S135: methyl 2-methyl-5-(3-morpholinoazetidin-1-yl)benzoate

[0528] 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 through the tube for 30 s, and the temperature was raised to 110°C. The reaction was stirred overnight until the starting materials were completely reacted. The reaction solution was cooled to room temperature, water (6 mL) was added, and the mixture was extracted three times with DCM. The organic phases were combined, concentrated under reduced pressure, and purified by column chromatography (PE:EA = 3:1, 1:1) to obtain S135 (75 mg, 100%) as a white solid. MS: m / z [M+1] + =291.21.

[0529] (2) Preparation of Intermediate S136: 2-methyl-5-(3-morpholinoazetidin-1-yl)benzoic acid

[0530] S135 (75 mg, 0.26 mmol) was placed in a single-necked flask, and THF (1.0 mL) and EtOH (1.0 mL) were added. A solution of NaOH (52 mg, 1.30 mmol) in H2O (1.0 mL) was then added. The temperature was raised to 60°C and the reaction was stirred for 2 h. The starting material reacted completely. The reaction solution was concentrated under reduced pressure to remove THF and EtOH. The pH was adjusted to 4-5 with dilute hydrochloric acid (2N). The solvent was removed by concentration under reduced pressure. The resulting solid mixture was dissolved in DCM, dried over anhydrous sodium sulfate, and filtered. The filter cake was washed with DCM. The filtrate was concentrated under reduced pressure to afford S136 (72 mg, 100%) as a white solid. MS: m / z [M+1] + =277.26.

[0531] (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

[0532] S6 (15 mg, 0.063 mmol) and S136 (21 mg, 0.075 mmol) were placed in a single-necked flask, 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 the reaction was stirred for 1.0 h. After the starting materials were completely reacted, the reaction solution was cooled to room temperature and water was added to precipitate a yellow solid. The solid was extracted three times with DCM. 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 P46 (20 mg, 65%) as a bright yellow solid. MS: m / z[M+1] + =497.32.

[0533] Example 47

[0534] 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

[0535] (1) Preparation of intermediate S138: methyl 2-methyl-5-(3aR,6aR)-1-methylhexahydropyrrolo[3,4-b]pyrrol-5(1H)-yl)benzoate

[0536] 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 through the tube for 30 s, and the temperature was raised to 110°C. The reaction was stirred overnight until the starting materials were completely reacted. The reaction solution was cooled to room temperature, water (6 mL) was added, and the mixture was extracted three times with DCM. The organic phases were combined, concentrated under reduced pressure, and purified by column chromatography (PE:EA=1:1, DCM:MeOH=20:1) to obtain S138 (52 mg, 73%) as a light yellow solid. MS: m / z [M+1] + =275.21.

[0537] (2) Preparation of intermediate S139: 2-methyl-5-(3aR,6aR)-1-methylhexahydropyrrolo[3,4-b]pyrrol-5(1H)-yl)benzoic acid

[0538] S138 (52 mg, 0.19 mmol) was placed in a single-necked flask, and THF (1.0 mL) and EtOH (1.0 mL) were added. A solution of NaOH (38 mg, 0.95 mmol) in H2O (1.0 mL) was then added. The temperature was raised to 60°C and the reaction was stirred for 2 h. The starting material reacted completely. The reaction solution was concentrated under reduced pressure to remove THF and EtOH. The pH was adjusted to 4-5 with dilute hydrochloric acid (2N). The solvent was removed by concentration under reduced pressure. The resulting solid mixture was dissolved in DCM, dried over anhydrous sodium sulfate, and filtered. The filter cake was washed with DCM. The filtrate was concentrated under reduced pressure to give S139 (49 mg, 100%) as a light yellow solid. MS: m / z [M+1] + =261.26.

[0539] (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

[0540] S6 (15 mg, 0.063 mmol) and S139 (20 mg, 0.075 mmol) were placed in a single-necked flask, 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 the reaction was stirred for 1.0 h. After the starting materials were completely reacted, the reaction solution was cooled to room temperature and water was added to precipitate a yellow solid. The solid was extracted three times with DCM. 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 P47 (17 mg, 57%) as a bright yellow solid. MS: m / z[M+1] + =481.32.

[0541] Example 48

[0542] 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

[0543] (1) Preparation of intermediate S141: methyl 5-(3,3-difluoro-4-(pyrrolidin-1-yl)piperidin-1-yl)-2-methylbenzoate

[0544] 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 through the tube for 30 s, and the temperature was raised to 110°C. The reaction was stirred overnight until the starting materials were completely reacted. The reaction solution was cooled to room temperature, water (6 mL) was added, and the mixture was extracted three times with DCM. The organic phases were combined, concentrated under reduced pressure, and purified by column chromatography (PE:EA = 3:1, 2:1) to obtain S141 (43 mg, 70%) as a white solid. MS: m / z [M+1] + =339.21.

[0545] (2) Preparation of Intermediate S142: 5-(3,3-difluoro-4-(pyrrolidin-1-yl)piperidin-1-yl)-2-methylbenzoic acid

[0546] S141 (43 mg, 0.13 mmol) was placed in a single-necked flask, 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). The temperature was raised to 60°C and the reaction was stirred for 2 h. Once the starting materials were completely reacted, the reaction solution was concentrated under reduced pressure to remove THF and EtOH. The pH was adjusted to 4-5 with dilute hydrochloric acid (2N), and the solvent was removed by concentration under reduced pressure. 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 concentrated under reduced pressure to obtain S142 (34 mg, 81%) as a white solid. MS: m / z [M+1] + =325.26.

[0547] (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

[0548] S6 (15 mg, 0.063 mmol) and S142 (24 mg, 0.075 mmol) were placed in a single-necked flask, 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 the reaction was stirred for 1.0 h. After the starting materials were completely reacted, the reaction solution was cooled to room temperature and water was added to precipitate a yellow solid. The solid 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) to obtain P48 (15 mg, 44%) as a bright yellow solid. MS: m / z [M+1] + =545.32.

[0549] Example 49

[0550] Compound P49: Preparation of 5-(4-(2-hydroxy-2-methylpropyl)piperazin-1-yl)-2-methyl-N-(1-(1-methyl-2-oxo-1,2-dihydrobenz[cd]indol-6-yl)cyclopropyl)benzamide

[0551] (1) Preparation of intermediate S144: methyl 5-(4-(2-hydroxy-2-methylpropyl)piperazin-1-yl)-2-methylbenzoate

[0552] 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 through the tube for 30 s, and the temperature was raised to 110°C. The reaction was stirred overnight until the starting materials reacted completely. The reaction solution was cooled to room temperature, saturated ammonium chloride solution (6 mL) was added, and the mixture was extracted three times with DCM. 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 S144 (69 mg, 87%) as a white solid. MS: m / z[M+1] + =307.21.

[0553] (2) Preparation of Intermediate S145: 5-(4-(2-hydroxy-2-methylpropyl)piperazin-1-yl)-2-methylbenzoic acid

[0554] S144 (69 mg, 0.28 mmol) was placed in a single-necked flask, and 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). The temperature was raised to 60°C and the reaction was stirred for 2 h. The starting material reacted completely. The reaction solution was concentrated under reduced pressure to remove THF and EtOH. The pH was adjusted to 4-5 with dilute hydrochloric acid (2N). The solvent was removed by concentration under reduced pressure. The resulting solid mixture was dissolved in DCM, dried over anhydrous sodium sulfate, and filtered. The filter cake was washed with DCM. The filtrate was concentrated under reduced pressure to give S145 (41 mg, 50%) as a white solid. MS: m / z [M+1] + =293.26.

[0555] (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

[0556] S6 (15 mg, 0.063 mmol) and S145 (22 mg, 0.075 mmol) were placed in a single-necked flask, 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 the reaction was stirred for 1.0 h. After the starting materials were completely reacted, the reaction solution was cooled to room temperature and water was added to precipitate a yellow solid. The solid was extracted three times with DCM. 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 P49 (21 mg, 66%) as a bright yellow solid. MS: m / z[M+1] + =513.32.

[0557] Embodiment 50

[0558] 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

[0559] (1) Preparation of intermediate S147: methyl 2-methyl-5-(3-(piperidin-1-yl)pyrrolidin-1-yl)benzoate

[0560] 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 through the tube for 30 s, and the temperature was raised to 110°C. The reaction was stirred overnight until the starting materials were completely reacted. The reaction solution was cooled to room temperature, water (6 mL) was added, and the mixture was extracted three times with DCM. The organic phases were combined, concentrated under reduced pressure, and purified by column chromatography (PE:EA=1:1, DCM:MeOH=20:1) to obtain S147 (73 mg, 93%) as a light yellow oil. MS: m / z [M+1] + =303.21.

[0561] (2) Preparation of Intermediate S148: 2-Methyl-5-(3-(piperidin-1-yl)pyrrolidin-1-yl)benzoic acid

[0562] S147 (73 mg, 0.24 mmol) was placed in a single-necked flask, and THF (1.0 mL) and EtOH (1.0 mL) were added. A solution of NaOH (48 mg, 1.20 mmol) in H2O (1.0 mL) was then added. The temperature was raised to 60°C and the reaction was stirred for 2 h. The starting material reacted completely. The reaction solution was concentrated under reduced pressure to remove THF and EtOH. The pH was adjusted to 4-5 with dilute hydrochloric acid (2N). The solvent was removed by concentration under reduced pressure. The resulting solid mixture was dissolved in DCM, dried over anhydrous sodium sulfate, and filtered. The filter cake was washed with DCM. The filtrate was concentrated under reduced pressure to afford S148 (69 mg, 100%) as a light yellow oil. MS: m / z [M+1] + =289.26.

[0563] (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

[0564] S6 (15 mg, 0.063 mmol) and S148 (22 mg, 0.075 mmol) were placed in a single-necked flask, 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 the reaction was stirred for 1.0 h. After the starting materials were completely reacted, the reaction solution was cooled to room temperature and water was added to precipitate a yellow solid. The solid was extracted three times with DCM. 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 P50 (16 mg, 50%) as a bright yellow solid. MS: m / z [M+1] + =509.32.

[0565] Example 51

[0566] 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

[0567] (1) Preparation of intermediate S150: methyl 2-methyl-5-(4-(3-methylsulfonyl)propyl)piperazin-1-yl)benzoate

[0568] 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 through the tube for 30 s, and the temperature was raised to 110°C. The reaction was stirred overnight until the starting materials were completely reacted. The reaction solution was cooled to room temperature, water (6 mL) was added, and the mixture was extracted three times with DCM. 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 S150 (24 mg, 26%) as a light yellow solid. MS: m / z [M+1] + =355.21.

[0569] (2) Preparation of Intermediate S151: 2-Methyl-5-(4-(3-methylsulfonyl)propyl)piperazin-1-yl)benzoic acid

[0570] S150 (24 mg, 0.068 mmol) was placed in a single-necked flask, and 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). The temperature was raised to 60°C and the reaction was stirred for 2 h. The starting material reacted completely. The reaction solution was concentrated under reduced pressure to remove THF and EtOH. The pH was adjusted to 4-5 with dilute hydrochloric acid (2N). The solvent was removed by concentration under reduced pressure. The resulting solid mixture was dissolved in DCM, dried over anhydrous sodium sulfate, and filtered. The filter cake was washed with DCM. The filtrate was concentrated under reduced pressure to afford S151 (23 mg, 100%) as a pale yellow solid. MS: m / z [M+1] + =341.26.

[0571] (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

[0572] S6 (15 mg, 0.063 mmol) and S151 (23 mg, 0.068 mmol) were placed in a single-necked flask, 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 the reaction was stirred for 1.0 h. After the starting materials were completely reacted, the reaction solution was cooled to room temperature and water was added to precipitate a yellow solid. The solid was extracted three times with DCM. 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 P51 (16 mg, 46%) as a bright yellow solid. MS: m / z[M+1] + =561.32.

[0573] Example 52

[0574] Compound P52: Preparation of 5-(4-(2-(dimethylamino)ethyl)piperazin-1-yl)-2-methyl-N-(1-(1-methyl-2-oxo-1,2-dihydrobenz[cd]indol-6-yl)cyclopropyl)benzamide

[0575] (1) Preparation of intermediate S153: methyl 5-(4-(2-(dimethylamino)ethyl)piperazin-1-yl)-2-methylbenzoate

[0576] 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 through the tube for 30 s, and the temperature was raised to 110°C. The reaction was stirred overnight until the starting materials were completely reacted. The reaction solution was cooled to room temperature, water (6 mL) was added, and the mixture was extracted three times with DCM. 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 S153 (69 mg, 87%) as a light yellow solid. MS: m / z[M+1] + =306.21.

[0577] (2) Preparation of Intermediate S154: 5-(4-(2-(dimethylamino)ethyl)piperazin-1-yl)-2-methylbenzoic acid

[0578] S153 (69 mg, 0.23 mmol) was placed in a single-necked flask, and 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). The temperature was raised to 60°C and the reaction was stirred for 2 h. The starting material reacted completely. The reaction solution was concentrated under reduced pressure to remove THF and EtOH. The pH was adjusted to 4-5 with dilute hydrochloric acid (2N). The solvent was removed by concentration under reduced pressure. The resulting solid mixture was dissolved in DCM, dried over anhydrous sodium sulfate, and filtered. The filter cake was washed with DCM. The filtrate was concentrated under reduced pressure to give S154 (67 mg, 100%) as a pale yellow solid. MS: m / z [M+1] + =292.26.

[0579] (3) P52: Preparation of 5-(4-(2-(dimethylamino)ethyl)piperazin-1-yl)-2-methyl-N-(1-(1-methyl-2-oxo-1,2-dihydrobenz[cd]indol-6-yl)cyclopropyl)benzamide

[0580] S6 (15 mg, 0.063 mmol) and S154 (22 mg, 0.075 mmol) were placed in a single-necked flask, 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 the reaction was stirred for 1.0 h. After the starting materials were completely reacted, the reaction solution was cooled to room temperature and water was added to precipitate a yellow solid. The solid was extracted three times with DCM. 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 P52 (19 mg, 60%) as a bright yellow solid. MS: m / z [M+1] + =512.32.

[0581] Example 53

[0582] 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

[0583] (1) Preparation of intermediate S156: methyl 5-(4-(2-hydroxyethyl)piperazin-1-yl)-2-methylbenzoate

[0584] 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 through the tube for 30 s, and the temperature was raised to 110°C. The reaction was stirred overnight until the starting materials were completely reacted. The reaction solution was cooled to room temperature, saturated ammonium chloride solution (6 mL) was added, and the mixture was extracted three times with DCM. The organic phases were combined, concentrated under reduced pressure, and purified by column chromatography (PE:EA=1:1, DCM:MeOH=20:1) to obtain S156 (8 mg, 11%) as a colorless oil. MS: m / z [M+1] + =279.21.

[0585] (2) Preparation of Intermediate S157: 5-(4-(2-hydroxyethyl)piperazin-1-yl)-2-methylbenzoic acid

[0586] S156 (8 mg, 0.028 mmol) was placed in a single-necked flask, and 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). The temperature was raised to 60°C and the reaction was stirred for 2 h. The starting material reacted completely. The reaction solution was concentrated under reduced pressure to remove THF and EtOH. The pH was adjusted to 4-5 with dilute hydrochloric acid (2N). The solvent was removed by concentration under reduced pressure. The resulting solid mixture was dissolved in DCM, dried over anhydrous sodium sulfate, and filtered. The filter cake was washed with DCM. The filtrate was concentrated under reduced pressure to afford S157 (7 mg, 100%) as a light yellow oil. MS: m / z [M+1] + =265.26.

[0587] (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

[0588] S6 (6 mg, 0.023 mmol) and S157 (7 mg, 0.028 mmol) were placed in a single-necked flask, 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 the reaction was stirred for 1.0 h. After the starting materials were completely reacted, the reaction solution was cooled to room temperature and water was added to precipitate a yellow solid. The solid was extracted three times with DCM. 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 P53 (7 mg, 63%) as a bright yellow solid. MS: m / z[M+1] + =485.32.

[0589] Example 54

[0590] 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

[0591] (1) Preparation of intermediate S159: methyl 5-(3-fluoro-[1,3'-diazetidine]-1'-yl)-2-methylbenzoate

[0592] 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 through the tube for 30 s, and the temperature was raised to 110°C. The reaction was stirred overnight until the starting materials were completely reacted. The reaction solution was cooled to room temperature, water (6 mL) was added, and the mixture was extracted three times with DCM. The organic phases were combined, concentrated under reduced pressure, and purified by column chromatography (PE:EA = 3:1, 1:1) to obtain S159 (42 mg, 58%) as a colorless oil. MS: m / z [M+1] + =279.21.

[0593] (2) Preparation of intermediate S160: 5-(3-fluoro-[1,3'-diazetidine]-1'-yl)-2-methylbenzoic acid

[0594] S159 (42 mg, 0.15 mmol) was placed in a single-necked flask, and THF (1.0 mL) and EtOH (1.0 mL) were added. A solution of NaOH (30 mg, 0.75 mmol) in H2O (1.0 mL) was then added. The temperature was raised to 60°C and the reaction was stirred for 2 h. The starting material reacted completely. The reaction solution was concentrated under reduced pressure to remove THF and EtOH. The pH was adjusted to 4-5 with dilute hydrochloric acid (2N). The solvent was removed by concentration under reduced pressure. The resulting solid mixture was dissolved in DCM, dried over anhydrous sodium sulfate, and filtered. The filter cake was washed with DCM. The filtrate was concentrated under reduced pressure to afford S160 (40 mg, 100%) as a light yellow oil. MS: m / z [M+1] + =265.26.

[0595] (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

[0596] S6 (15 mg, 0.063 mmol) and S160 (20 mg, 0.075 mmol) were placed in a single-necked flask, 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 the reaction was stirred for 1.0 h. After the starting materials were completely reacted, the reaction solution was cooled to room temperature and water was added to precipitate a yellow solid. The solid was extracted three times with DCM. The organic phases were combined, concentrated under reduced pressure, and purified by column chromatography (PE:EA=1:1, DCM:MeOH=20:1) to obtain P54 (22 mg, 72%) as a bright yellow solid. MS: m / z[M+1] + =485.32.

[0597] Test Example 1. Protein level enzyme activity test

[0598] Based on the fluorescence resonance energy transfer method, SARS-CoV-2PL was constructed using fluorescently labeled substrates. pro The enzyme activity detection system was used to determine the activity of the compound against SARS-CoV-2PL pro The specific steps are as follows:

[0599] 1. Construction of SARS-CoV-2 PL pro The recombinant expression plasmid of the catalytic domain (746-1060) was purified to obtain highly active recombinant expression of SARS-CoV-2PL pro Catalytic domain, used for enzyme activity testing.

[0600] 2. Substrate: Z-Arg-Leu-Arg-Gly-Gly-AMC (GLPBIO, Catalog No. GA23715).

[0601] 3. Buffer: 50 mM HEPES (4-hydroxyethylpiperazineethanesulfonic acid), 10 mM DTT (dithiothreitol), 0.1 mM EDTA (ethylenediaminetetraacetic acid), pH 7.2.

[0602] 4.384-well plate: Greiner, item number 784076.

[0603] 5. Inhibitor compounds to be tested.

[0604] 6. Prepare a single concentration or appropriate concentration gradient of compound stock solution in DMSO.

[0605] 7. SARS-CoV-2 PL pro The protein was pre-mixed with the test compound and incubated for 10 minutes.

[0606] 8. Add 15 μL of SARS-CoV-2 PL to each well of a 384-well plate. pro A mixed solution of protein and the compound to be tested.

[0607] 9. Prepare 80 μM substrate working solution using the above buffer.

[0608] 10. Add 5 μL of 80 μM substrate working solution to each well and incubate for 10 minutes.

[0609] 11. Detection: BioTek synergy NEO2, Ex: 360nm / Em: 460nm.

[0610] 12. Data analysis: Use Prism to perform nonlinear regression fitting on the data and calculate IC 50 The results are shown in Table 1.

[0611] Table 1 Inhibitory activity of compounds against papain Note: +: 0.1 μM <IC 50 ≤1μM;++:0.04μM <IC 50 ≤0.1μM;+++:IC 50 ≤0.04μM.

[0612] Test Example 2. Novel Coronavirus Infection Activity Inhibition Experiment of Vero E6 Cells

[0613] 1. Cell line: African green monkey kidney cells Vero E6 (ATCC, CRL-1586).

[0614] 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).

[0615] 3. Positive control: Ensitrelvir (Product No. HY-143216, MedChemExpress LLC).

[0616] 4. Infectious dose: MOI (multiplicity of infection) = 0.01.

[0617] 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 approximately 5×10 4 .

[0618] 6. Perform gradient dilution (1:3) with the highest concentration being 10 μM, and set up triplicate wells for each concentration.

[0619] 7. Add virus strain (MOI=0.01) to each well and infect cells for 48 hours.

[0620] 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.

[0621] Table 2 Inhibitory activity of VeroE6 cells infected by virus strains Note: +: 0.1μM ≤ IC 50 ≤1μM;++:0.04μM <IC 50 ≤0.1μM;+++:IC 50 ≤0.04μM.

[0622] Test Example 3. Liver microsome stability test

[0623] 1. Preheat PBS (pH 7.4).

[0624] 2. Preparation of Intermediate Solutions of Test and Positive Reference Compounds

[0625] 2.1 500 μM intermediate solution: Add 5 μL of 10 mM compound stock solution and positive reference compound dissolved in DMSO to 95 μL DMSO;

[0626] 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 of PBS.

[0627] 3. Prepare NADPH stock solution (6 mM) by dissolving NADPH in PBS.

[0628] 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).

[0629] 5. Pre-incubate the plate at 37°C for 5 minutes.

[0630] 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).

[0631] 7. For other time points, add 15 μL of NADPH stock solution (6 mM) to the wells to start the reaction and timing.

[0632] 8. At 5 minutes, 15 minutes, 30 minutes, and 45 minutes, add 150 μL of the internal standard acetonitrile:methanol (1:1) stop solution to the corresponding wells to stop the reaction.

[0633] 9. After termination, shake the plate for 10 minutes (600 rpm) and then centrifuge at 4000 rpm for 15 minutes.

[0634] 10. Transfer 80 μL of supernatant from each well to a 96-well sample plate containing 140 μL of purified water for LC / MS analysis.

[0635] Table 3 Liver microsome stability test results Note: Rat means rat; Human means human; 1 / 2 = represents half-life; Clint represents clearance rate; and Eh represents clearance ratio. Rat liver microsomes are extracted from rat livers, and human liver microsomes are extracted from human hepatocytes.

[0636] Test Example 4. Pharmacokinetic Test

[0637] Conventional PK test in rats:

[0638] 1. The experimental design is shown in the following table: 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.

[0639] 2. Preparation of drug delivery preparations:

[0640] Solvent formulation: 10% DMSO, 5% ethanol, 5% Cremophor EL, and 80% deionized water. Weigh 6.68 mg of the sample to be tested into a suitable container, add 1.316 mL of DMSO, vortex for 1 minute, and sonicate for 10 minutes to obtain a 5 mg / mL clear DMSO stock solution.

[0641] Take 1 mL of the 5 mg / mL DMSO stock solution, add 0.5 mL of ethanol, vortex for 1 minute, then add 0.5 mL of Cremophor EL, vortex for 1 minute, and finally add 8 mL of deionized water and vortex for 1 minute to obtain a clear drug formulation at a concentration of 0.5 mg / mL. Prepare immediately before use and store at room temperature.

[0642] 3. Animal selection:

[0643] Before the start of the study, all animals suitable for the experiment were weighed. After removing a certain number of heavy and / or light animals, the weight of the animals used for the experiment was within ±20% of the average body weight.

[0644] 4. Animal husbandry:

[0645] The animals were housed in rat cages (2-5 rats / cage) and provided with approximately 12-hour light / 12-hour dark alternating lighting daily. Dark periods could be interrupted intermittently as needed for study-related activities. The animal room temperature and relative humidity were monitored daily and maintained within the ranges of 20-26°C and 40-70%.

[0646] 5. Route of administration:

[0647] The drug is administered by oral gavage, and the route of administration should be consistent with the intended clinical route of administration.

[0648] 6. Cage-side observation:

[0649] During the experiment, all animals were observed at least twice a day at the cage side (which could be accompanied by sampling). Observations included morbidity, mortality, injuries, and food and water supply. Animals in poor health were marked and further observed, and euthanized if necessary.

[0650] 7. Biological Sample Collection:

[0651] Oral sampling: 8 collection time points in total, 0.25, 0.5, 1, 2, 4, 6, 8 and 24 hours after administration.

[0652] Plasma: Blood samples were collected by puncture after euthanasia. The samples were placed in tubes containing K2-EDTA and kept on ice until centrifugation. Within 1 hour of blood collection, the samples were centrifuged at 6800 g for 6 minutes at 2-8°C. Plasma samples were then collected and stored frozen at approximately -80°C.

[0653] 8. Biological Sample Analysis

[0654] The compounds were analyzed. Quality control samples were used simultaneously with the analytical samples to assess the intra-day accuracy of the analytical run. Acceptance criteria: at least 50% of the quality control samples at each quality control concentration level and at least 66.7% of all quality control samples should have an accuracy between 80% and 120% (75% to 125% for tissue).

[0655] 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.

[0656] Using Phoenix The following main pharmacokinetic parameters were calculated using the non-compartmental statistical moment method of 7.0 software: Tmax, Cmax, AUC(0-t), T1 / 2, etc.

[0657] 9. Final Disposition of Animals

[0658] All surviving experimental animals were euthanized after the experiment (using a dedicated euthanasia box for carbon dioxide euthanasia).

[0659] 10. Analytical methods

[0660] Analytical instrument: LC-MS / MS-12 (TQ5500, Triple quad);

[0661] Pipette: Eppendorf;

[0662] Oscillator: 5810R, Eppendorf;

[0663] Centrifuge: 420R, 220R, Eppendorf;

[0664] (Other suppliers or models of equipment may be used if necessary)

[0665] Sample processing:

[0666] 1) Take 30 μL of the mixed standard curve sample, quality control sample, blank sample, zero concentration sample and test sample;

[0667] 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.

[0668] 3) Vortex mix for 1 min;

[0669] 4) Centrifuge at 4°C for 7 minutes (18,000 g);

[0670] 5) Take 200 μL of supernatant and add it to the corresponding 96-well sample plate;

[0671] 6) Inject 4 μL of the sample and perform LC-MS / MS analysis.

[0672] Table 4 In vivo oral pharmacokinetic data of compounds

[0673] Finally, it should be noted that the above embodiments are only used to illustrate the technical solution of the present application and not to limit it. Although the present application has been described in detail with reference to the preferred embodiments, ordinary technicians in the relevant field should understand that the specific implementation methods of the present application 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 application. They should all be included in the scope of the technical solution for protection requested in this application.

Claims

1. 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, in, 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 groups; 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; R3 is selected from 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; m is 0, 1, 2 or 3; R4 is selected from R5 and Preferably 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 -OH, -OC 1-4 Alkyl, -NH2, -NH-C 1-4 Alkyl and -N(C 1-4 Alkyl)2 group substitution; 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; R6 is selected from hydrogen, carbonyl, 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 with one or more selected from 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; R7 is selected from 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; 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; 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; n is 0, 1, 2, 3, 4, 5, 6 or 7.

2. The compound according to claim 1, wherein 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; Preferably, R1 is selected from hydrogen, C 1-4 Alkyl and C 3-6 Cycloalkyl; Preferably, R1 is selected from hydrogen, methyl, ethyl, n-propyl, isopropyl, cyclobutyl, cyclopentyl and cyclobutyl; Preferably, R1 is selected from hydrogen, methyl, ethyl, isopropyl and cyclopropyl; More preferably, R1 is selected from hydrogen and C 1-4 alkyl; Further preferably, R1 is selected from hydrogen, methyl, ethyl and isopropyl.

3. The compound according to claim 1 or 2, wherein 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 Haloalkyl; Preferably, R2 is selected from hydrogen, fluorine, chlorine, -CN, -OH, -COOH, -NH2, -O-methyl, -NH-methyl, methyl, ethyl, halomethyl and haloethyl; Preferably, R2 is methyl.

4. The compound according to any one of claims 1 to 3, wherein R3 is selected from 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 Haloalkyl; Preferably, R3 is selected from fluorine, chlorine, bromine, -CN, -OH, -COOH, -NH2, -O-methyl, -NH-methyl, methyl, ethyl, halomethyl and haloethyl; Preferably, m is 0.

5. The compound according to any one of claims 1 to 4, wherein 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 -NH2, -NH- 1-4 Alkyl and -N(C 1-4 Alkyl)2 group substitution; Preferably, 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 -NH2, -NH-methyl, -NH(methyl)2; Preferably, R5 is selected from Ring A is selected from C 4-10 Cycloalkenyl and 4-10 membered heterocyclyl; preferably, the 4-10 membered heterocyclyl contains 1, 2 or 3 heteroatoms selected from N, O, S; Preferably, ring A is selected from C 4-8 Cycloalkenyl, 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; Preferably, ring A is selected from in, represents the connection site between ring A and the phenyl group in formula I; Further preferably, ring A is selected from a 4-10 membered heterocyclic group; Further preferably, the 4-10 membered heterocyclic group contains 1 or 2 N atoms; Further preferably, ring A is selected from in, represents the connection site between ring A and the phenyl group in formula I; R6 is selected from hydrogen, carbonyl, 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 heterocyclyl and -NH-(4-6 membered heterocyclyl), 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 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 radical substitution; Preferably, 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), -N(methyl)-ethyl, -N(methyl)-propyl, -N(ethyl), -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-oxacyclopentyl, -NH- cyclobutyl, -NH-tetrahydrofuranyl and -NH-tetrahydropyranyl, said methyl, ethyl, propyl, butyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, oxetanyl, tetrahydrofuranyl and tetrahydropyranyl being optionally substituted with 1, 2, 3, 4 or 5 groups selected from 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; Preferably, 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 fluorine, =O, -OH, -COOH, methyl, -N(CH3)2, -S(=O)2-methyl and morpholinyl; Preferably, R6 is selected from hydrogen, fluorine, -CN, -OH, -NH2, -CH3, -CH2CH3, More preferably, 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 halogen, =O, -CN, -OH, -COOH, -NH2, -N-(C 1-4 alkyl)2, -S(=O)2-methyl, C 1-4 Alkyl and morpholinyl radical substitution; More preferably, 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 Alkyl and 4-6 membered heterocyclyl are optionally substituted by 1, 2 or 3 groups selected from fluorine, =O, -OH, -N(CH3)2, -S(=O)2-CH3, -CH3 and morpholinyl; More preferably, R6 is selected from hydrogen, -CH3, -CH2CH3, R7 is independently selected from 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 Haloalkyl; Preferably, R7 is each independently selected from fluorine, chlorine, bromine, -CN, -OH, -COOH, -NH2, -O-methyl, -O-ethyl, -O-propyl, -NH-methyl, -NH-ethyl, -NH-propyl, -N(methyl), -N(methyl)-ethyl, -N(methyl)-propyl, -N(ethyl), methyl, ethyl, propyl, halomethyl, haloethyl and halopropyl; Preferably, R7 are each independently selected from fluorine, -OH, -NH2, -COOH and methyl; Further preferably, R7 are each independently selected from fluorine and methyl; Alternatively, two R7 form =0.

6. The compound according to any one of claims 1 to 5, wherein The compound is selected from the compound represented by formula (I-1), or its stereoisomer, or its tautomer, or its solvate, or its isotope-labeled compound, or its pharmaceutically acceptable salt, Wherein, R1, R2, Ring A, R6, R7 and n are defined as any one of claims 1-5; 1) Preferably, the compound is selected from the compound represented by formula (I-1A), or a stereoisomer thereof, or a tautomer thereof, or a solvate thereof, or an isotope-labeled compound thereof, or a pharmaceutically acceptable salt thereof, Wherein, R1, R2, R6, R7 and n are defined as any one of claims 1-5; Preferably, R1 is selected from methyl and ethyl; Preferably, 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 -(4-6 membered heterocyclyl) and -NH-(4-6 membered heterocyclyl) are optionally substituted by 1, 2 or 3 groups selected from fluorine, chlorine, =O, -OH, -NH2, methyl and -N(CH3)2; Preferably, R6 is selected from -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, oxetanyl, tetrahydrofuranyl and tetrahydropyranyl are optionally substituted with 1, 2 or 3 groups selected from fluorine, chlorine, =O, -OH, -NH2 and methyl; Preferably, R6 is selected from Alternatively, R6 and R7 are linked to form a pyrrolidinyl group, and the pyrrolidinyl group is optionally substituted with 1 methyl group; Preferably, n is 0, 1, 2 or 3; Further preferably, 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 halogen, =O, -OH and C 1-4 Alkyl radical substitution; Further preferably, R6 is selected from a 4-6 membered heterocyclic group, the 4-6 membered heterocyclic group is a monocyclic group, 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 fluorine, =O, -OH and methyl, More preferably, R6 is selected from Preferably, the compound is selected from the compound represented by formula (I-1A-1), or a stereoisomer thereof, or a tautomer thereof, or a solvate thereof, or an isotope-labeled compound thereof, or a pharmaceutically acceptable salt thereof, in, R1 and R2 are defined as in any one of claims 1 to 5; Ring B is selected from 4-6 membered heterocyclic groups; R 61 Selected from 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; Preferably, R1 is selected from methyl and ethyl; Preferably, Ring B is selected from azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl and thiomorpholinyl; Preferably, R 61 is selected from fluorine, chlorine, bromine, =O, -CN, -OH, -COOH, -NH2, methyl, ethyl and propyl, preferably, R 61 is selected from fluorine, =O, -OH and methyl; Preferably, the compound is selected from the compound represented by formula (I-1A-2), or a stereoisomer thereof, or a tautomer thereof, or a solvate thereof, or an isotope-labeled compound thereof, or a pharmaceutically acceptable salt thereof, in, R1 and R2 are defined as in any one of claims 1 to 5, R 61 Selected from hydrogen, C 1-4 Alkyl and 4-6 membered heterocyclic group; Preferably, R1 is selected from methyl; Preferably, R 61 is selected from hydrogen, methyl, ethyl, propyl, butyl, oxetanyl, tetrahydrofuranyl and tetrahydropyranyl, preferably, R 61 Selected from hydrogen, -CH2CH3 and 2) or preferably, the compound is selected from the compound represented by formula (I-1B), or its stereoisomer, or its tautomer, or its solvate, or its isotope-labeled compound, or its pharmaceutically acceptable salt, in, T1 is C, CH or N; is a single bond or a double bond; R1, R2, R6, R7 and n are defined as any one of claims 1 to 5; Preferably, T1 is N, is a single bond; Preferably, 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 halogen, -OH, -COOH, methyl, -NH(CH3), -N(CH3)2, -N(CH3)(CH2CH3), -N(CH2CH3)2 and -S(=O)2-CH3; Preferably, 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, wherein the methyl, ethyl, propyl, butyl groups are optionally substituted by 1, 2 or 3 groups selected from fluorine, -OH, -COOH, methyl, -N(CH3)2 and -S(=O)2-CH3; Preferably, R6 is selected from hydrogen, -CN, -NH2, -CH3, -CH2CH3, Preferably, R7 is each independently selected from -COOH and C 1-4 alkyl; Preferably, R7 are each independently selected from -COOH and methyl; 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; Preferably, n is 0, 1, 2, 3 or 4; More preferably, 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 -OH, -NH(CH3), -N(CH3)2 and -S(=O)2-CH3; More preferably, R6 is selected from hydrogen, -CH3, -CH2CH3, Further preferably, R7 are each independently selected from C 1-4 alkyl; Further preferably, R7 are each independently selected from methyl; 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 pyrrolidine group; Further preferably, n is 0, 1 or 2; 3) or preferably, the compound is selected from the compound represented by formula (I-1C), or its stereoisomer, or its tautomer, or its solvate, or its isotope-labeled compound, or its pharmaceutically acceptable salt, in, R1, R2, R6, R7 and n are defined as any one of claims 1 to 5; Preferably, 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 by 1, 2 or 3 groups selected from halogen, -OH, -COOH and methyl; Preferably, R6 is selected from hydrogen, -CH3, Alternatively, R6 and R7 are linked to form a 5-6 membered heterocyclic group, wherein the 5-6 membered heterocyclic group is optionally substituted with one OH or methyl group, preferably R6 and R7 are linked to form a pyrrolidinyl or piperidinyl group, wherein the pyrrolidinyl or piperidinyl group is optionally substituted with one methyl group; Preferably, n is 0, 1 or 2.

7. The compound according to any one of claims 1 to 6, wherein The compound is selected from:

8. A pharmaceutical composition comprising at least one compound according to any one of claims 1 to 7, and one or more pharmaceutically acceptable carriers and / or excipients.

9. The use of a compound as described in any one of claims 1 to 7 or a pharmaceutical composition as described in claim 8 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, wherein the medicament comprises a human medicament and a veterinary medicament.

10. The use according to claim 9, wherein The disease or condition is selected from respiratory diseases (including simple infections such as fever, cough and sore throat, pneumonia, acute respiratory tract infection, severe acute respiratory infection (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.

Images