Coronavirus papain-like protease inhibitor

Abstract

A coronavirus papain-like protease inhibitor represented by formula (Z), and use thereof.

Description

Coronavirus papain inhibitors

[0001] The present invention claims priority to Chinese patent application CN202311794503.6 filed on December 22, 2023, and Chinese patent application CN202311792162.9 filed on December 22, 2023, and incorporates their entire contents into this document by reference. Technical Field

[0002] The present invention belongs to the field of medicinal chemistry, and in particular relates to a coronavirus papain-like protease inhibitor represented by formula (Z) and uses thereof. Background Art

[0003] Coronaviruses, a class of pathogens that threaten human health, belong to the Coronaviridae family of the order Nidovirales and are enveloped, single-stranded, positive-strand RNA viruses classified 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 their genome contains 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, while the other 1 / 3 primarily encodes structural proteins, generally including the spike protein (S), the small envelope protein (E), the membrane protein (M), and the nucleocapsid protein (N). The E and M proteins are primarily involved in the viral assembly process, while 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.

[0004] 3C-like proteases (3CLpro or Mpro) and papain-like proteases (PLpro) play important roles in coronavirus replication. PLpro is a key regulatory protein molecule in the formation of the SARS-CoV-2 replicase complex (RC) and is crucial for viral genome transcription and replication. As a representative nonstructural protein, PLpro participates in counteracting the host's innate immune response and has important biological functions in regulating the replication and proliferation of the novel 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 be helpful in the treatment of novel coronavirus pneumonia.

[0005] Summary of the Invention

[0006] The present invention provides the following embodiments.

[0007] Embodiment 1. The compound represented by formula (Z), or its stereoisomer, or its tautomer, or its solvate, or its isotope-labeled compound, or its pharmaceutically acceptable salt,

[0008] in,

[0009] E1 and E2 are each independently selected from -C 1-4 Alkylene-, -C(=O)- and -N(R 19 )-;

[0010] R 19 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;

[0011] R 11 and R 12 Each independently selected from C 1-6 Alkyl and C 1-6 Haloalkyl, or R 11 and R 12 Together with the carbon atoms connected to form C 3-6 Cycloalkyl or 4-6 membered heterocycloalkyl;

[0012] R 13 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;

[0013] R 14 Selected from hydrogen, halogen, nitro, -CN, -OH, -COOH, -NH2, -OC 1-6 Alkyl, -NH-C1-6 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;

[0014] r is 0, 1, 2, or 3;

[0015] R 15 Selected from R 16 and

[0016] R 16 Selected from C 1-8 Alkyl, C 1-8 Haloalkyl and -NH-C 1-8 Alkyl, the C 1-8 Alkyl and C 1-8 The haloalkyl group is optionally substituted by one or more selected from hydrogen, -OH, -OC 1-4 Alkyl, -NH2, -NH-C 1-4 Alkyl and -N(C 1-4 Alkyl)2 group substitution;

[0017] Ring W 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;

[0018] R 17 Selected from hydrogen, oxo, halogen, nitro, -CN, -OH, -COOH, -NH2, C 1-6 Alkyl, -OC 1- 6-alkyl, -NH-C 1-6 Alkyl, -N-(C 1-6 alkyl)2, -S(=O)2NH2, -S(=O)2-C 1-6 Alkyl, -C(=O)-C 1-6 Alkyl, -C(=O)-NH-C 1-6 Alkyl, -NH-C(=O)-C 1-6 Alkyl, -C(=NH)NH2, -C(=NH)NHC(=NH)NH, 4-8 membered heterocyclic group and -NH-4-8 membered heterocyclic group, the C 1-6The alkyl and 4-8 membered heterocyclic groups are optionally substituted by one or more radicals selected from hydrogen, halogen, nitro, =O, -CN, -OH, -COOH, -NH2, -C 1- 6-alkyl, -OC 1-6 Alkyl, -NH-C 1-6 Alkyl, -N-(C 1-6 alkyl)2、-S(=O)2OH、-S(=O)2NH2、-S(=O)2-C 1-6 Alkyl, -C(=O)-C 1-6 Alkyl, -C(=O)-NH-C 1-6 Alkyl, -NH-C(=O)-C 1-6 Alkyl and morpholinyl radical substitution;

[0019] R 18 Selected from hydrogen, halogen, nitro, -CN, -OH, -COOH, -NH2, -OC 1-6 Alkyl, -NH-C 1-6 Alkyl, -N-(C 1-6 alkyl)2, -S(=O)2-C 1-6 Alkyl, -C(=O)-C 1-6 Alkyl, -C(=O)-NH-C 1-6 Alkyl, -NH-C(=O)-C 1-6 Alkyl, -S(=O)2NH2, C 1-6 Alkyl and C 1-6 Haloalkyl, or two R 18 Formation = O;

[0020] Or, R 17 With R 18 Connected to form a 4-6 membered heterocyclic group, the 4-6 membered heterocyclic group is optionally 1, 2 or 3 selected from OH and C 1-4 Alkyl radical substitution;

[0021] Or, two R 18 Form C with the connected atoms 3-6 Cycloalkyl and 4-7 membered heterocyclic groups, the C 3-6 Cycloalkyl and 4-7 membered heterocyclic groups are optionally substituted by 1, 2 or 3 groups selected from OH and C 1-4 Alkyl radical substitution;

[0022] s is 0, 1, 2, 3, 4, 5, 6, or 7.

[0023] Embodiment 2. The compound of Embodiment 1, or its stereoisomer, or its tautomer, or its solvate, or its isotope-labeled compound, or its pharmaceutically acceptable salt, wherein:

[0024] E1 and E2 are each independently selected from -CH2-, -CH2CH2-, -CH(CH3)-, -CH(CH2CH3)-, -C(=O)- and -N(R 19 )-,R 19 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;

[0025] Preferably, R 19 Selected from hydrogen, C 1-4 Alkyl and C 3-6 Cycloalkyl,

[0026] Preferably, R 19 is selected from hydrogen, methyl, ethyl, n-propyl, isopropyl, cyclobutyl, cyclopentyl and cyclobutyl,

[0027] Preferably, R 19 is selected from hydrogen, methyl, ethyl, isopropyl and cyclopropyl;

[0028] Preferably, E1 and E2 are each independently selected from -CH2-, -C(=O)- and -N(R 19 )-;

[0029] Preferably, E1 is selected from -CH2- and -C(=O)-;

[0030] Preferably, E2 is selected from -CH2- and -N(R 19 )-,R 19 As defined in this embodiment;

[0031] Preferably, -E1-E2- is selected from -CH2CH2- and -C(=O)-N(R 19 )-,R 19 As defined in this embodiment,

[0032] Preferably, -E1-E2-# is selected from -CH2CH2-#, -C(=O)-NH-#, -C(=O)-N(CH3)-#, -C(=O)-N(CH2CH3)-#, -C(=O)-N[CH(CH3)2]-# and -C(=O)-N(cyclopropyl)-#;

[0033] More preferably, R 19 Selected from hydrogen and C 1-4 alkyl,

[0034] More preferably, R 19 is selected from hydrogen, methyl, ethyl and isopropyl,

[0035] Further preferably, -E1-E2-# is selected from -CH2CH2-#, -C(=O)-NH-#, -C(=O)-N(CH3)-#, -C(=O)-N(CH2CH3)-# and -C(=O)-N[CH(CH3)2]-#.

[0036] Embodiment 3. The compound of embodiment 1 or 2, or its stereoisomer, or its tautomer, or its solvate, or its isotope-labeled compound, or its pharmaceutically acceptable salt, wherein:

[0037] R 11 and R 12 Each independently selected from C 1-4 Alkyl and C 1-4 Haloalkyl, or R 11 and R 12 Together with the carbon atoms connected to form C 3-5 Cycloalkyl or 4-5 membered heterocycloalkyl,

[0038] Preferably, R 11 and R 12 are each independently selected from methyl, ethyl and propyl, or R 11 and R 12 Together with the carbon atoms to which they are attached, they form a cyclopropyl, cyclobutyl, cyclopentyl, oxetanyl, azetidinyl, oxolanyl or azacyclopentyl group,

[0039] Preferably, R 11 and R 12 are each independently methyl, or R 11 and R 12 Together with the carbon atoms to which they are connected, they form a cyclopropyl or oxetane group,

[0040] More preferably, the structural unit for

[0041] Embodiment 4. The compound according to any one of Embodiments 1-3, or its stereoisomer, or its tautomer, or its solvate, or its isotope-labeled compound, or its pharmaceutically acceptable salt, wherein:

[0042] R 13 Selected from hydrogen, halogen, -CN, -OH, -COOH, -NH2, -OC 1-4 Alkyl, -NH-C 1-4 Alkyl, -N-(C 1-4 Alkyl)2, C 1-4 Alkyl and C 1-4 haloalkyl,

[0043] Preferably, R 13 is selected from the group consisting of hydrogen, fluorine, chlorine, -CN, -OH, -COOH, -NH2, -O-methyl, -NH-methyl, methyl, ethyl, halomethyl and haloethyl,

[0044] Preferably, R 13 selected from chloro, -O-methyl, methyl, ethyl and trifluoromethyl,

[0045] More preferably, R 13 selected from chlorine and methyl,

[0046] More preferably, R 13 It is a methyl group.

[0047] Embodiment 5. The compound according to any one of Embodiments 1 to 4, or its stereoisomer, or its tautomer, or its solvate, or its isotope-labeled compound, or its pharmaceutically acceptable salt, wherein:

[0048] R 14 Selected from hydrogen, halogen, -CN, -OH, -COOH, -NH2, -OC 1-4 Alkyl, -NH-C 1-4 Alkyl, -N-(C 1-4 Alkyl)2, C 1-6 Alkyl and C 1-6 haloalkyl,

[0049] Preferably, R 14 is selected from the group consisting of hydrogen, fluorine, chlorine, bromine, -CN, -OH, -COOH, -NH2, -O-methyl, -NH-methyl, methyl, ethyl, halomethyl and haloethyl,

[0050] Preferably, R 14 For hydrogen.

[0051] Embodiment 6. The compound according to any one of Embodiments 1 to 5, or its stereoisomer, or its tautomer, or its solvate, or its isotope-labeled compound, or its pharmaceutically acceptable salt, wherein:

[0052] R 16 Selected from C 1-6 Alkyl, C 1-6 Haloalkyl and -NH-C 1-6 Alkyl, the C 1-6 Alkyl and C 1-6 Haloalkyl is optionally substituted by 1, 2, 3, 4 or 5 groups selected from hydrogen, -NH2, -NH-C 1-4 Alkyl and -N(C 1-4 Alkyl)2 group substitution,

[0053] Preferably, R16 Selected from C 1-6 Alkyl and -NH-C 1-4 Alkyl, the C 1-6 Alkyl and C 1-4 The alkyl group is optionally substituted with 1, 2 or 3 groups selected from hydrogen, -NH2, -NH-methyl, -NH(methyl)2,

[0054] Preferably, R 16 Selected from

[0055] More preferably, R 16 Selected from

[0056] Ring W is selected from C 4-10 Cycloalkenyl, 4-10 membered heterocyclic group and C 6-10 Aryl,

[0057] Preferably, ring W is selected from C 4-10 Cycloalkenyl, 4-10 membered heterocyclic group and C 6-10 Aryl, the 4-10 membered heterocyclic group contains 1, 2 or 3 heteroatoms selected from N, O, S,

[0058] Preferably, ring W 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 and phenyl,

[0059] Preferably, ring W is selected from in represents the connection site between ring W and the phenyl group in formula (Z);

[0060] More preferably, ring W is selected from a 4-10 membered heterocyclic group,

[0061] Further preferably, ring W is selected from a 4-10 membered heterocyclic group, wherein the 4-10 membered heterocyclic group contains 1 or 2 N atoms, and optionally further contains 1 O atom,

[0062] More preferably, ring W is selected from in represents the connection site between ring W and the phenyl group in formula (Z);

[0063] R 17 Selected from hydrogen, oxo, halogen, nitro, -CN, -OH, -COOH, -NH2, C 1-4 Alkyl, -OC 1- 4-alkyl, -NH-C1-4 Alkyl, -N-(C 1-4 alkyl)2, -S(=O)2NH2, -S(=O)2-C 1-4 Alkyl, -C(=O)-C 1-4 Alkyl, -C(=O)-NH-C 1-4 Alkyl, -NH-C(=O)-C 1-4 Alkyl, -C(=NH)NH2, -C(=NH)NHC(=NH)NH, 4-6 membered heterocyclic group and -NH-4-6 membered heterocyclic group, the C 1-4 Alkyl and 4-6 membered heterocyclic groups are optionally substituted by 1, 2, 3, 4 or 5 groups selected from hydrogen, fluorine, chlorine, bromine, =O, -CN, -OH, -COOH, -NH2, -C 1-4 Alkyl, -OC 1-4 Alkyl, -NH-C 1-4 Alkyl, -N-(C 1-4 alkyl)2、-S(=O)2OH、-S(=O)2NH2、-S(=O)2-C 1-4 Alkyl and morpholinyl radicals,

[0064] Preferably, R 17 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-oxetanyl, -NH-tetrahydrofuranyl, -NH- wherein the methyl, ethyl, propyl, butyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, oxetanyl, tetrahydrofuranyl and tetrahydropyranyl are optionally substituted with 1, 2, 3, 4 or 5 groups selected from hydrogen, fluorine, chlorine, bromine, =O, -OH, -COOH, -NH2, methyl, ethyl, propyl, -O-methyl, -O-ethyl, -NH-methyl, -NH-ethyl, -NH-propyl, -NH-butyl, -N(methyl), -N(methyl)-ethyl, -N(ethyl), -S(=O)2OH, -S(=O)2NH2, -S(=O)2-methyl and morpholinyl,

[0065] Preferably, R 17 Selected from hydrogen, fluorine, -CN, -OH, -NH2, methyl, ethyl, propyl, butyl, The methyl, ethyl, propyl, butyl, optionally substituted by 1, 2 or 3 groups selected from hydrogen, fluorine, =O, -OH, -COOH, methyl, -N(CH3)2, -NHCH2CH2CH2CH3, -S(=O)2OH, -S(=O)2-methyl and morpholinyl,

[0066] Preferably, R 17 Selected from hydrogen, fluorine, -CN, -OH, -NH2, -CH3, -CH2CH3,

[0067] More preferably, R 17 Selected from hydrogen, -CN, -OH, -NH2, C 1-4 Alkyl, -NH-C 1-4 Alkyl, -N-(C 1- 4-membered alkyl)2, 4-6-membered heterocyclic group, -NH-4-6-membered heterocyclic group, -S(=O)2NH2, -S(=O)2-C 1-4 Alkyl, -C(=NH)NH2 and -C(=NH)NHC(=NH)NH, the C 1-4 The alkyl and 4-6 membered heterocyclic groups are optionally substituted by 1, 2 or 3 groups selected from hydrogen, halogen, =O, -CN, -OH, -COOH, -NH2, -N-(C 1-4 alkyl)2, -S(=O)2-methyl, C 1-4 Alkyl and morpholinyl radicals,

[0068] More preferably, R 17 Selected from hydrogen, -CN, -NH2, C 1-4 Alkyl, -NH-C 1-4 Alkyl, -N-(C 1-4 alkyl)2, 4-6 membered heterocyclic group, -NH-4-6 membered heterocyclic group, -S(=O)2NH2, -S(=O)2-C 1-4 Alkyl, -C(=NH)NH2 and -C(=NH)NHC(=NH)NH, 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 hydrogen, fluorine, =O, -OH, -COOH, -N(CH3)2, -S(=O)2-CH3, -CH3 and morpholinyl,

[0069] More preferably, R 17 Selected from hydrogen, -CN, -NH2, -CH3, -CH2CH3,

[0070] More preferably, R 17 Selected from hydrogen, -CN, -NH2, -CH3, -CH2CH3,

[0071] R 18 are each independently selected from hydrogen, halogen, nitro, -CN, -OH, -COOH, -NH2, -OC 1-4 Alkyl, -NH-C 1-4 Alkyl, -N-(C 1-4 alkyl)2, -C(=O)-C 1-4 Alkyl, -C(=O)-NH-C 1-4 Alkyl, -NH-C(=O)-C 1-4 Alkyl, C 1-6 Alkyl and C 1-4 haloalkyl,

[0072] Preferably, R 18 each independently selected from hydrogen, fluorine, chlorine, bromine, -CN, -OH, -COOH, -NH2, -O-methyl, -O-ethyl, -O-propyl, -NH-methyl, -NH-ethyl, -NH-propyl, -N(methyl)2, -N(methyl)-ethyl, -N(methyl)-propyl, -N(ethyl)2, methyl, ethyl, propyl, halomethyl, haloethyl and halopropyl,

[0073] Preferably, R 18 are each independently selected from hydrogen, fluorine, -OH, -NH2, -COOH and methyl;

[0074] More preferably, R 18 are each independently selected from hydrogen, fluorine, -OH, -COOH and methyl,

[0075] More preferably, R 18 are each independently selected from hydrogen, fluorine and methyl;

[0076] Or, two R 18 Formation =O.

[0077] Embodiment 7. The compound according to any one of Embodiments 1-6, or its stereoisomer, or its tautomer, or its solvate, or its isotope-labeled compound, or its pharmaceutically acceptable salt, wherein the compound is selected from the compound represented by formula (PI),

[0078] in,

[0079] 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;

[0080] 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;

[0081] R3 is selected from hydrogen, halogen, nitro, -CN, -OH, -COOH, -NH2, -OC 1-6 Alkyl, -NH-C 1-6 Alkyl, -N-(C 1-6 alkyl)2, -S(=O)2-C 1-6 Alkyl, -C(=O)-C 1-6 Alkyl, -C(=O)-NH-C 1-6 Alkyl, -NH-C(=O)-C 1-6 Alkyl, -S(=O)2NH2, C 1-6 Alkyl and C 1-6 alkyl halide;

[0082] m is 0, 1, 2, or 3;

[0083] R4 is selected from R5 and Preferably

[0084] 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 by one or more selected from hydrogen, -OH, -OC 1-4 Alkyl, -NH2, -NH-C 1-4 Alkyl and -N(C 1-4 Alkyl)2 group substitution;

[0085] 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;

[0086] R6 is selected from hydrogen, oxo, halogen, nitro, -CN, -OH, -COOH, -NH2, C 1-6 Alkyl, -OC 1-6 Alkyl, -NH-C 1-6 Alkyl, -N-(C 1-6 alkyl)2, -S(=O)2NH2, -S(=O)2-C 1-6 Alkyl, -C(=O)-C 1-6 Alkyl, -C(=O)-NH-C 1-6 Alkyl, -NH-C(=O)-C 1-6 Alkyl, -C(=NH)NH2, -C(=NH)NHC(=NH)NH, 4-8 membered heterocyclic group and -NH-4-8 membered heterocyclic group, the C 1-6 The alkyl and 4-8 membered heterocyclic groups are optionally substituted by one or more radicals selected from hydrogen, halogen, nitro, =O, -CN, -OH, -COOH, -NH2, -C 1-6 Alkyl, -OC 1-6 Alkyl, -NH-C 1-6 Alkyl, -N-(C 1-6 alkyl)2、-S(=O)2OH、-S(=O)2NH2、-S(=O)2-C 1-6 Alkyl, -C(=O)-C 1-6 Alkyl, -C(=O)-NH-C 1-6 Alkyl, -NH-C(=O)-C 1-6 Alkyl and morpholinyl radical substitution;

[0087] R7 is selected from hydrogen, halogen, nitro, -CN, -OH, -COOH, -NH2, -OC 1-6 Alkyl, -NH-C 1-6 Alkyl, -N-(C 1-6 alkyl)2, -S(=O)2-C 1-6 Alkyl, -C(=O)-C 1-6 Alkyl, -C(=O)-NH-C 1-6 Alkyl, -NH-C(=O)-C 1-6 Alkyl, -S(=O)2NH2, C 1-6 Alkyl and C 1-6 Haloalkyl, or two R7 form =O;

[0088] Alternatively, two R7 atoms form a C3-6 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;

[0089] Alternatively, R6 and R7 are linked to form a 4-6 membered heterocyclic group, wherein the 4-6 membered heterocyclic group is optionally substituted by 1, 2 or 3 groups selected from OH and C1-4 alkyl;

[0090] n is 0, 1, 2, 3, 4, 5, 6 or 7.

[0091] Embodiment 8. The compound according to any one of Embodiments 1 to 7, or its stereoisomer, or its tautomer, or its solvate, or its isotope-labeled compound, or its pharmaceutically acceptable salt, 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 Halogenated alkyl, C 3-6 Cycloalkyl and 4-6 membered heterocyclic groups,

[0092] Preferably, R1 is selected from hydrogen, C 1-4 Alkyl and C 3-6 Cycloalkyl,

[0093] Preferably, R1 is selected from hydrogen, methyl, ethyl, n-propyl, isopropyl, cyclobutyl, cyclopentyl and cyclobutyl,

[0094] Preferably, R1 is selected from hydrogen, methyl, ethyl, isopropyl and cyclopropyl;

[0095] Further preferably, R1 is selected from hydrogen and C1-4 alkyl,

[0096] More preferably, R1 is selected from hydrogen, methyl, ethyl and isopropyl.

[0097] Embodiment 9. The compound according to any one of Embodiments 1 to 8, or its stereoisomer, or its tautomer, or its solvate, or its isotope-labeled compound, or its pharmaceutically acceptable salt, 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,

[0098] Preferably, R2 is selected from hydrogen, fluorine, chlorine, -CN, -OH, -COOH, -NH2, -O-methyl, -NH-methyl, methyl, ethyl, halomethyl and haloethyl,

[0099] Preferably, R2 is methyl.

[0100] Embodiment 10. The compound according to any one of Embodiments 1 to 9, or its stereoisomer, or its tautomer, or its solvate, or its isotope-labeled compound, or its pharmaceutically acceptable salt, wherein R3 is selected from hydrogen, halogen, -CN, -OH, -COOH, -NH2, -OC 1-4 Alkyl, -NH-C 1-4 Alkyl, -N-(C 1-4 Alkyl)2, C 1-6 Alkyl and C 1-6 haloalkyl,

[0101] Preferably, R3 is selected from hydrogen, fluorine, chlorine, bromine, -CN, -OH, -COOH, -NH2, -O-methyl, -NH-methyl, methyl, ethyl, halomethyl and haloethyl,

[0102] Preferably, R3 is hydrogen.

[0103] Embodiment 11. The compound according to any one of Embodiments 1 to 10, or its stereoisomer, or its tautomer, or its solvate, or its isotope-labeled compound, or its pharmaceutically acceptable salt, wherein:

[0104] 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 hydrogen, -NH2, -NH-C 1-4 Alkyl and -N(C 1-4 Alkyl)2 group substitution,

[0105] 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 hydrogen, -NH2, -NH-methyl, -NH(methyl)2,

[0106] Preferably, R5 is selected from

[0107] Ring A is selected from C 4-10 Cycloalkenyl and 4-10 membered heterocyclic groups,

[0108] Preferably, ring A is selected from C 4-10Cycloalkenyl and 4-10 membered heterocyclic group, wherein the 4-10 membered heterocyclic group contains 1, 2 or 3 heteroatoms selected from N, O, S,

[0109] 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,

[0110] Preferably, ring A is selected from in represents the connection site between ring A and the phenyl group in formula (PI);

[0111] More preferably, ring A is selected from a 4-10 membered heterocyclic group,

[0112] Further preferably, ring A is selected from a 4-10 membered heterocyclic group containing 1 or 2 N atoms,

[0113] More preferably, ring A is selected from in represents the connection site between ring A and the phenyl group in formula (PI);

[0114] R6 is selected from hydrogen, oxo, halogen, nitro, -CN, -OH, -COOH, -NH2, C 1-4 Alkyl, -OC 1-4 Alkyl, -NH-C 1-4 Alkyl, -N-(C 1-4 alkyl)2, -S(=O)2NH2, -S(=O)2-C 1-4 Alkyl, -C(=O)-C 1-4 Alkyl, -C(=O)-NH-C 1-4 Alkyl, -NH-C(=O)-C 1-4 Alkyl, -C(=NH)NH2, -C(=NH)NHC(=NH)NH, 4-6 membered heterocyclic group and -NH-4-6 membered heterocyclic group, the C 1-4 Alkyl and 4-6 membered heterocyclic groups are optionally substituted by 1, 2, 3, 4 or 5 groups selected from hydrogen, fluorine, chlorine, bromine, =O, -CN, -OH, -COOH, -NH2, -C 1-4 Alkyl, -OC 1-4 Alkyl, -NH-C 1-4 Alkyl, -N-(C 1-4 alkyl)2、-S(=O)2OH、-S(=O)2NH2、-S(=O)2-C 1-4 Alkyl and morpholinyl radicals,

[0115] 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)2, -N(methyl)-ethyl, -N(methyl)-propyl, -N(ethyl)2, -N(ethyl)-propyl, -S(=O)2NH2, -S(=O)2-methyl, -S(=O)2-ethyl, -S(=O)2- propyl, -C(=NH)NH2, -C(=NH)NHC(=NH)NH2, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, -NH-oxetanyl, -NH-tetrahydrofuranyl and -NH-tetrahydropyranyl, the methyl, ethyl, propyl, butyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, oxetanyl, tetrahydrofuranyl and tetrahydropyranyl is optionally substituted by 1, 2, 3, 4 or 5 groups selected from hydrogen, fluorine, chlorine, bromine, =O, -OH, -COOH, -NH2, methyl, ethyl, propyl, -O-methyl, -O-ethyl, -NH-methyl, -NH-ethyl, -N(methyl), -N(methyl)-ethyl, -N(ethyl), -S(=O)2OH, -S(=O)2NH2, -S(=O)2-methyl and morpholinyl,

[0116] Preferably, R6 is selected from hydrogen, fluorine, -CN, -OH, -NH2, methyl, ethyl, propyl, butyl, The methyl, ethyl, propyl, butyl, optionally substituted by 1, 2 or 3 groups selected from hydrogen, fluorine, =O, -OH, -COOH, methyl, -N(CH3)2, -S(=O)2-methyl and morpholinyl,

[0117] Preferably, R6 is selected from hydrogen, fluorine, -CN, -OH, -NH2, -CH3, -CH2CH3,

[0118] More preferably, 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 The alkyl and 4-6 membered heterocyclic groups are optionally substituted by 1, 2 or 3 groups selected from hydrogen, halogen, =O, -CN, -OH, -COOH, -NH2, -N-(C 1-4 alkyl)2, -S(=O)2-methyl, C 1-4 Alkyl and morpholinyl radicals,

[0119] More preferably, R6 is selected from hydrogen, C 1-4 Alkyl, -N-(C 1-4 alkyl)2 and 4-6 membered heterocyclic group, said 4-6 membered heterocyclic group contains 1 or 2 heteroatoms selected from N, O, S, said C 1-4 Alkyl and 4-6 membered heterocyclyl are optionally substituted by 1, 2 or 3 groups selected from hydrogen, fluorine, =O, -OH, -N(CH3)2, -S(=O)2-CH3, -CH3 and morpholinyl,

[0120] More preferably, R6 is selected from hydrogen, -CH3, -CH2CH3,

[0121] R7 are each independently selected from hydrogen, halogen, nitro, -CN, -OH, -COOH, -NH2, -OC 1-4 Alkyl, -NH-C 1-4 Alkyl, -N-(C 1-4 alkyl)2, -C(=O)-C 1-4 Alkyl, -C(=O)-NH-C 1-4 Alkyl, -NH-C(=O)-C 1-4 Alkyl, C 1-6 Alkyl and C 1-4 haloalkyl,

[0122] Preferably, R7 is each independently selected from hydrogen, fluorine, chlorine, bromine, -CN, -OH, -COOH, -NH2, -O-methyl, -O-ethyl, -O-propyl, -NH-methyl, -NH-ethyl, -NH-propyl, -N(methyl)2, -N(methyl)-ethyl, -N(methyl)-propyl, -N(ethyl)2, methyl, ethyl, propyl, halomethyl, haloethyl and halopropyl,

[0123] Preferably, R7 are each independently selected from hydrogen, fluorine, -OH, -NH2, -COOH and methyl;

[0124] Further preferably, R7 are each independently selected from hydrogen, fluorine and methyl;

[0125] Alternatively, two R7 form =0.

[0126] Embodiment 12. The compound according to any one of Embodiments 1-11, or its stereoisomer, or its tautomer, or its solvate, or its isotope-labeled compound, or its pharmaceutically acceptable salt, wherein the compound is selected from the compound represented by formula (PI-1)

[0127] wherein R1, R2, Ring A, R6, R7 and n are as defined in any one of Embodiments 1-11;

[0128] 1) Preferably, the compound is selected from the compound represented by formula (PI-1A)

[0129] wherein R1, R2, R6, R7 and n are as defined in any one of Embodiments 1-11;

[0130] Preferably, R1 is selected from methyl and ethyl;

[0131] 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 alkyl) 2, 4-6 membered heterocyclyl and -NH-4-6 membered heterocyclyl are optionally substituted by 1, 2 or 3 groups selected from hydrogen, fluorine, chlorine, =O, -OH, -NH2, methyl and -N(CH3)2;

[0132] 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, said methyl, ethyl, propyl, butyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, oxetanyl, tetrahydrofuranyl and tetrahydropyranyl being optionally substituted with 1, 2 or 3 groups selected from hydrogen, fluorine, chlorine, =O, -OH, -NH2 and methyl,

[0133] Preferably, R6 is selected from

[0134] Preferably, R7 are each independently selected from hydrogen;

[0135] Alternatively, R6 and R7 are linked to form a pyrrolidinyl group, and the pyrrolidinyl group is optionally substituted with 1 methyl group;

[0136] Preferably, n is 0, 1, 2 or 3;

[0137] 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 hydrogen, halogen, =O, -OH and C 1-4 Alkyl group substitution,

[0138] Further preferably, R6 is selected from a 4-6 membered heterocyclic group, wherein the 4-6 membered heterocyclic group is a monocyclic ring, the 4-6 membered heterocyclic group contains 1 or 2 heteroatoms selected from N, O, and S, and the 4-6 membered heterocyclic group is optionally substituted by 1, 2 or 3 groups selected from hydrogen, fluorine, =O, -OH and methyl.

[0139] Further preferably, R6 is selected from

[0140] Preferably, the compound is selected from the compound represented by formula (PI-1A-1)

[0141] in,

[0142] R1 and R2 are as defined in any one of Embodiments 1-11,

[0143] Ring B is selected from 4-6 membered heterocyclic groups,

[0144] R 61 Selected from hydrogen, halogen, =O, -CN, -OH, -COOH, -NH2, -C 1-4 Alkyl, -NH-C 1-4 Alkyl and -N-(C 1-4 Alkyl)2,

[0145] p is 0, 1, 2, or 3;

[0146] Preferably, R1 is selected from methyl and ethyl;

[0147] Preferably, ring B is selected from azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl and thiomorpholinyl;

[0148] Preferably, R 61 is selected from hydrogen, fluorine, chlorine, bromine, =O, -CN, -OH, -COOH, -NH2, methyl, ethyl and propyl, preferably, R 61 is selected from hydrogen, fluorine, =O, -OH and methyl;

[0149] Preferably, the compound is selected from the compound represented by formula (PI-1A-2)

[0150] in,

[0151] R1 and R2 are as defined in any one of Embodiments 1-11,

[0152] R 61 Selected from hydrogen, C 1-4 Alkyl and 4-6 membered heterocyclic group;

[0153] Preferably, R1 is selected from methyl;

[0154] Preferably, R 61 is selected from hydrogen, methyl, ethyl, propyl, butyl, oxetanyl, tetrahydrofuranyl and tetrahydropyranyl, preferably, R 61 Selected from hydrogen, -CH2CH3 and

[0155] 2) Or preferably, the compound is selected from the compound represented by formula (PI-1B)

[0156] in,

[0157] T1 is C, CH or N, is a single bond or a double bond,

[0158] R1, R2, R6, R7 and n are as defined in any one of Embodiments 1-11;

[0159] Preferably, T1 is N, is a single bond;

[0160] 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 Alkyl is optionally substituted by 1, 2 or 3 groups selected from hydrogen, halogen, -OH, -COOH, methyl, -NH(CH3), -N(CH3)2, -N(CH3)(CH2CH3), -N(CH2CH3)2 and -S(=O)2-CH3,

[0161] 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, the methyl, ethyl, propyl, butyl groups are optionally substituted by 1, 2 or 3 groups selected from hydrogen, fluorine, -OH, -COOH, methyl, -N(CH3)2 and -S(=O)2-CH3,

[0162] Preferably, R6 is selected from hydrogen, -CN, -NH2, -CH3, -CH2CH3,

[0163] Preferably, R7 are each independently selected from hydrogen, -COOH and C 1-4 alkyl,

[0164] Preferably, R7 are each independently selected from hydrogen, -COOH and methyl,

[0165] Alternatively, two R7 form =O,

[0166] Alternatively, two R7 and the atoms to which they are attached form a cyclopropyl, azetidinyl, pyrrolidinyl, piperidinyl or homopiperidinyl group,

[0167] Alternatively, R6 and R7 are linked to form a pyrrolidinyl group, and the pyrrolidinyl group is optionally substituted with 1 OH group;

[0168] Preferably, n is 0, 1, 2, 3 or 4;

[0169] 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 hydrogen, -OH, -NH(CH3), -N(CH3)2 and -S(=O)2-CH3,

[0170] More preferably, R6 is selected from hydrogen, -CH3, -CH2CH3,

[0171] Further preferably, R7 are each independently selected from hydrogen and C 1-4 alkyl,

[0172] Further preferably, R7 are each independently selected from hydrogen and methyl,

[0173] Alternatively, two R7 and the atoms to which they are attached form a cyclopropyl, azetidinyl, pyrrolidinyl, piperidinyl or homopiperidinyl group,

[0174] Alternatively, R6 and R7 are linked to form a pyrrolyl group;

[0175] Further preferably, n is 0, 1 or 2;

[0176] 3) Or preferably, the compound is selected from the compound represented by formula (PI-1C)

[0177] in,

[0178] R1, R2, R6, R7 and n are as defined in any one of Embodiments 1-11;

[0179] Preferably, 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 The alkyl and 4-6 membered heterocyclic groups are optionally substituted by 1, 2 or 3 groups selected from hydrogen, halogen, -OH, -COOH and methyl,

[0180] Preferably, R6 is selected from hydrogen, -CH3,

[0181] Preferably, R7 is hydrogen,

[0182] 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;

[0183] Preferably, n is 0, 1 or 2.

[0184] Embodiment 13. The compound according to any one of Embodiments 1-6, or its stereoisomer, or its tautomer, or its solvate, or its isotope-labeled compound, or its pharmaceutically acceptable salt, wherein the compound is selected from the compound represented by formula (QI),

[0185] in,

[0186] R1 and R2 are each independently selected from C 1-6 Alkyl and C 1-6 Haloalkyl, or R1 and R2 together with the carbon atom to which they are attached form a C 3-6 Cycloalkyl or 4-6 membered heterocycloalkyl;

[0187] R3 is selected from hydrogen, halogen, nitro, -OH, -CN, -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;

[0188] R4 is selected from hydrogen, halogen, nitro, -OH, -CN, -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)-C1-6 Alkyl, -S(=O)2NH2, C 1-6 Alkyl and C 1-6 alkyl halide;

[0189] L1 is selected from -C 1-6 Alkylene-, -NH-C 1-6 Alkylene-, 4-10 membered heterocycloalkylene, 4-10 membered heterocycloalkenylene, 6-12 membered arylene;

[0190] R5 is independently selected from hydrogen, halogen, nitro, -OH, -CN, -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 R5 form =O, or two R5 and the connected atom form C 3-8 Cycloalkyl or 4-10 membered heterocycloalkyl, the C 3-8 Cycloalkyl or 4-10 membered heterocycloalkyl is optionally substituted by one or more groups selected from halogen, nitro, -OH, -CN, -COOH, -NH2, -O-methyl, -NH-methyl, methyl or ethyl;

[0191] L2 is selected from a bond, -NH-, -O-, -S-, -C 1-6 Alkylene-, -NH-C 1-6 Alkylene-, -OC 1-6 Alkylene-, -SC 1-6 Alkylene- and 4-10 membered heterocycloalkylene;

[0192] R6 are each independently selected from hydrogen, halogen, nitro, -OH, -CN, -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 1-6Alkyl, -S(=O)2OH, -S(=O)2NH2, -C(=NH)NH2, -C(=NH)NHC(=NH)NH, C 1-6 Alkyl and 4-7 membered heterocycloalkyl;

[0193] Alternatively, R5 and -L2-(R6) p Connected to form a 4-6 membered heterocyclic group, the 4-6 membered heterocyclic group is optionally substituted by one or more selected from OH and C 1-4 Alkyl radical substitution;

[0194] m is 0, 1, 2, or 3;

[0195] n is 0, 1, 2, 3, 4, 5, 6, 7, 8 or 9;

[0196] p is 1, 2, 3, 4, 5, 6, 7, 8 or 9.

[0197] Embodiment 14. The compound according to any one of Embodiments 1-6 or 13, or its stereoisomer, or its tautomer, or its solvate, or its isotope-labeled compound, or its pharmaceutically acceptable salt, wherein R1 and R2 are each independently selected from C 1-4 Alkyl and C 1-4 Haloalkyl, or R1 and R2 together with the carbon atom to which they are attached form a C 3-5 Cycloalkyl or 4-5 membered heterocycloalkyl;

[0198] Preferably, R1 and R2 are each independently selected from methyl, ethyl and propyl, or R1 and R2 together with the carbon atom to which they are connected form a cyclopropyl, cyclobutyl, cyclopentyl, oxetanyl, azetidinyl, oxolanyl or azocyclopentyl group;

[0199] Preferably, R1 and R2 are each independently a methyl group, or R1 and R2 and the carbon atom to which they are connected together form a cyclopropyl group or an oxetane group;

[0200] Preferably, the structural unit for

[0201] Embodiment 15. The compound of any one of Embodiments 1-6, 13 or 14, or its stereoisomer, or its tautomer, or its solvate, or its isotopically labeled compound, or its pharmaceutically acceptable salt, wherein R3 is selected from hydrogen, halogen, -OH, -CN, -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 alkyl halide;

[0202] Preferably, R3 is selected from hydrogen, fluorine, chlorine, bromine, -OH, -CN, -COOH, -NH2, -O-methyl, -NH-methyl, methyl, ethyl, halomethyl and haloethyl;

[0203] Preferably, R3 is selected from chloro, -O-methyl, methyl, ethyl and trifluoromethyl;

[0204] Preferably, R3 is selected from chlorine and methyl;

[0205] Preferably, R3 is methyl.

[0206] Embodiment 16. The compound of any one of Embodiments 1-6, 13-15, or its stereoisomer, or its tautomer, or its solvate, or its isotope-labeled compound, or its pharmaceutically acceptable salt, wherein R4 is selected from hydrogen, halogen, -OH, -CN, -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 alkyl halide;

[0207] Preferably, R4 is selected from hydrogen, fluorine, chlorine, bromine, -OH, -CN, -COOH, -NH2, -O-methyl, -NH-methyl, methyl, ethyl, halomethyl and haloethyl;

[0208] Preferably, R4 is hydrogen.

[0209] Embodiment 17. The compound according to any one of Embodiments 1-6, 13-16, or its stereoisomer, or its tautomer, or its solvate, or its isotope-labeled compound, or its pharmaceutically acceptable salt, wherein:

[0210] L1 is selected from -C 1-4 Alkylene-, -NH-C 1-4 Alkylene-, 4-7 membered heterocycloalkylene, 4-7 membered heterocycloalkenylene, 6-10 membered arylene, preferably the 4-7 membered heterocycloalkylene or 4-7 membered heterocycloalkenylene contains 1 or 2 N atoms, preferably, L1 is selected from methylene, ethylene, propylene, -NH-methylene-, -NH-ethylene-, -NH-propylene-, azetidinyl, pyrrolidinylene, tetrahydroimidazolyl, piperidinylene, piperazinylene, hexahydropyrimidinylene, homopiperazinylene, morpholinylene, tetrahydropyridinylene and phenylene;

[0211] R5 is independently selected from hydrogen, halogen, nitro, -OH, -CN, -COOH, -NH2, -OC 1-4 Alkyl, -NH-C1-4 Alkyl, -N-(C 1-4 Alkyl)2, C 1-4 Alkyl and C 1-4 Haloalkyl, preferably, R5 is each independently selected from hydrogen, fluorine, chlorine, bromine, -OH, -CN, -COOH, -NH2, -O-methyl, -NH-methyl, -N(methyl)-methyl, methyl, ethyl, halomethyl and haloethyl, preferably, R5 is each independently selected from hydrogen, fluorine, -COOH, -NH2 and methyl;

[0212] Alternatively, two R5 form =O;

[0213] Alternatively, two R5 atoms form a C 3-6 Cycloalkyl or 4-7 membered heterocycloalkyl, the C 3-6 Cycloalkyl or 4-7 membered heterocycloalkyl is optionally substituted with 1, 2 or 3 groups selected from fluorine, chlorine, -OH, -CN, -COOH, -NH2 or methyl, preferably, two R5 and the atoms to which they are connected form a cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, tetrahydroimidazolyl, piperidinyl, piperazinyl, homopiperidinyl or homopiperazinyl, and the cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, tetrahydroimidazolyl, piperidinyl, piperazinyl, homopiperidinyl or homopiperazinyl is optionally substituted with 1, 2 or 3 groups selected from fluorine, chlorine, -OH, -CN, -COOH, -NH2 or methyl, preferably, two R5 and the atoms to which they are connected form a cyclopropyl, azetidinyl, pyrrolidinyl or piperidinyl, and the cyclopropyl, azetidinyl, pyrrolidinyl or piperidinyl is optionally substituted with 1 -OH or methyl;

[0214] Structural unit Selected from R5 is as defined in this embodiment, n is 0, 1, 2, 3 or 4,

[0215] Preferably, the structural unit Selected from Unless otherwise specified, the right side of the structural unit is connected to L2, and the * end indicates that it is connected to L2.

[0216] Embodiment 18. The compound of any one of Embodiments 1-6, 13-17, or its stereoisomer, or its tautomer, or its solvate, or its isotope-labeled compound, or its pharmaceutically acceptable salt, wherein L2 is selected from a bond, -C 1-4 Alkylene- and 4-7 membered heterocycloalkylene, preferably, L2 is selected from a bond, methylene, ethylene, propylene, azetidinyl, pyrrolidinyl and piperidinylene;

[0217] R6 are each independently selected from hydrogen, halogen, -OH, -CN, -COOH, -NH2, -NH-C 1-4 Alkyl, -N-(C 1- 4-alkyl)2, -S(=O)2-C 1-4 Alkyl, -S(=O)2OH, -S(=O)2NH2, -C(=NH)NH2, -C(=NH)NHC(=NH)NH, C 1-4 Alkyl and morpholinyl, preferably, R6 are each independently selected from hydrogen, fluorine, chlorine, bromine, -OH, -CN, -COOH, -NH2, -NH-methyl, -NH-ethyl, -NH-propyl, -NH-butyl, -N(methyl)-methyl, -N(methyl)-ethyl, -N(methyl)-propyl, -N(ethyl)-ethyl, -N(ethyl)-propyl, -S(=O)2-methyl, -S(=O)2-ethyl, -S(=O)2-propyl, -S(=O)2OH, -S(=O)2NH2, -C(=NH)NH2, - C(=NH)NHC(=NH)NH2, methyl, ethyl, propyl, butyl and morpholinyl, preferably, R6 are each independently selected from hydrogen, fluorine, -OH, -CN, -COOH, -CH3, -CH2CH3, -CH(CH3)2, -S(=O)2OH, -S(=O)2CH3, -S(=O)2NH2, -NH2, -NHCH3, -N(CH3)2, -NHCH2CH2CH2CH3,

[0218] Structural unit Selected from R6 is as defined in this embodiment, p is 1, 2, 3 or 4,

[0219] Preferably, the structural unit Selected from -CN,

[0220] Preferably, the structural unit Selected from

[0221] Embodiment 19. The compound of any one of Embodiments 1-6, 13-18, or its stereoisomer, or its tautomer, or its solvate, or its isotope-labeled compound, or its pharmaceutically acceptable salt, wherein the compound is selected from the compound represented by formula (QI-1)

[0222] in,

[0223] L1, L2, R3, R5, R6, n and p are as defined in any one of embodiments 1-6, 13-18;

[0224] 1) Preferably, the compound is selected from the compound represented by formula (QI-1-A)

[0225] in,

[0226] R3, R5, L2, R6, n and p are as defined in any one of embodiments 1-6, 13-18,

[0227] Preferably, said R3 is methyl,

[0228] Preferably, the R5 is hydrogen, or two R5s and the connected atom form a pyrrolidinyl group, and the pyrrolidinyl group is optionally substituted by a methyl group.

[0229] Preferably, said L2 is selected from a bond, an azetidinyl group, a pyrrolidinyl group and a piperidinyl group,

[0230] Preferably, the R6 are each independently selected from hydrogen, fluorine, -OH and methyl,

[0231] Preferably, R5 and -L2-(R6) p are connected to form a pyrrolidinyl group, wherein the pyrrolidinyl group is optionally substituted by a methyl group,

[0232] Preferably, n is 0, 1 or 2,

[0233] Preferably, p is 1, 2 or 3;

[0234] More preferably, the compound is selected from the compound represented by formula (QI-1-A1)

[0235] in,

[0236] R3, R6 and p are as defined in any one of embodiments 1-6, 13-18, and ring A is selected from 4-7 heterocycloalkyl,

[0237] Preferably, said R3 is methyl,

[0238] Preferably, the ring A is selected from azetidinyl, pyrrolidinyl and piperidinyl,

[0239] Preferably, the R6 are each independently selected from hydrogen, fluorine, -OH and methyl,

[0240] Preferably, p is 1 or 2;

[0241] 2) Or preferably, the compound is selected from the compound represented by formula (QI-1-B)

[0242] in,

[0243] T1 is C, CH or N, is a single bond or a double bond, and R3, R5, L2, R6, n and p are as defined in any one of Embodiments 1-6 and 13-18,

[0244] Preferably, said R3 is methyl,

[0245] Preferably, the R5 are each independently selected from hydrogen, -COOH and methyl, or two R5 form =0, or two R5 and the connected atom form a cyclopropyl, azetidinyl, pyrrolidinyl, piperidinyl or homopiperidinyl, and the azetidinyl, pyrrolidinyl, piperidinyl or homopiperidinyl is optionally substituted by 1 -OH,

[0246] Preferably, said L2 is selected from a bond, a methylene group, an ethylene group and a propylene group,

[0247] Preferably, the R6 are each independently selected from hydrogen, -OH, -COOH, -CN, -CH3, -CH(CH3)2, -S(=O)2OH, -S(=O)2CH3, -S(=O)2NH2, -NH2, -NHCH3, -N(CH3)2,

[0248] Preferably, R5 and -L2-(R6) p are connected to form a pyrrolidinyl group, wherein the pyrrolidinyl group is optionally substituted by one hydroxyl group,

[0249] Preferably, n is 0, 1 or 2,

[0250] Preferably, p is 1, 2 or 3;

[0251] Preferably, the compound is selected from the compound represented by formula (QI-1-B1)

[0252] in,

[0253] R3, R5, L2 and R6 are as defined in any one of embodiments 1-6, 13-18,

[0254] Preferably, said R3 is methyl,

[0255] Preferably, the R5 are each independently selected from -COOH and methyl,

[0256] Preferably, said L2 is selected from a bond, a methylene group, an ethylene group and a propylene group,

[0257] Preferably, the R6 are each independently selected from hydrogen, -OH, -COOH, -CN, -CH3, -CH(CH3)2, -S(=O)2OH, -S(=O)2CH3, -S(=O)2NH2, -NH2, -NHCH3, -N(CH3)2,

[0258] Preferably, p is 1 or 2;

[0259] Preferably, the compound is selected from the compound represented by formula (QI-1-B2)

[0260] in,

[0261] R3, L2, R6 and p are as defined in any one of embodiments 1-6, 13-18,

[0262] Preferably, said R3 is methyl,

[0263] Preferably, said L2 is selected from a bond and a methylene group,

[0264] Preferably, the R6 are each independently selected from hydrogen and methyl,

[0265] Preferably, p is 1 or 2;

[0266] Preferably, the compound is selected from the compound represented by formula (QI-1-B3)

[0267] in,

[0268] R3, L2, R6 and p are as defined in any one of embodiments 1-6, 13-18,

[0269] Preferably, said R3 is methyl,

[0270] Preferably, said L2 is selected from a bond and a methylene group,

[0271] Preferably, the R6 are each independently selected from hydrogen and methyl,

[0272] Preferably, p is 1 or 2;

[0273] Preferably, the compound is selected from the compound represented by formula (QI-1-B4)

[0274] in,

[0275] R3, L2, R6 and p are as defined in any one of embodiments 1-6, 13-18,

[0276] Preferably, said R3 is methyl,

[0277] Preferably, said L2 is selected from a bond and a methylene group,

[0278] Preferably, the R6 are each independently selected from hydrogen and methyl,

[0279] Preferably, p is 1 or 2;

[0280] 3) Or preferably, the compound is selected from the compound represented by formula (QI-1-C)

[0281] in,

[0282] R3, R5, L2, R6, n and p are as defined in any one of embodiments 1-6, 13-18,

[0283] Preferably, said R3 is methyl,

[0284] Preferably, the R5 is hydrogen, or two R5s and the connected atom form a pyrrolidinyl or piperidinyl group, and the pyrrolidinyl or piperidinyl group is optionally substituted by 1 methyl group,

[0285] Preferably, said L2 is selected from a bond, a pyrrolidinylene group and a piperidinylene group,

[0286] Preferably, the R6 are each independently selected from hydrogen, -NH2, -NHCH3, -N(CH3)2 and

[0287] Preferably, n is 0, 1 or 2,

[0288] Preferably, p is 1, 2 or 3;

[0289] 4) Or preferably, the compound is selected from the compound represented by formula (QI-1-D)

[0290] in,

[0291] R3, L2 and R6 are as defined in any one of embodiments 1-6, 13-18,

[0292] Preferably, said R3 is methyl,

[0293] Preferably, said L2 is a bond,

[0294] Preferably, R6 is methyl.

[0295] Embodiment 20. The compound of any one of Embodiments 1-19, or its stereoisomer, or its tautomer, or its solvate, or its isotopically labeled compound, or its pharmaceutically acceptable salt, wherein the compound is selected from:

[0296] Embodiment 21. A pharmaceutical composition comprising at least one compound according to any one of Embodiments 1 to 20, or a stereoisomer thereof, or a tautomer thereof, or a solvate thereof, or an isotopically labeled compound thereof, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers and / or excipients.

[0297] Embodiment 22. Use of the compound of any one of Embodiments 1 to 20, or its stereoisomer, or its tautomer, or its solvate, or its isotopically labeled compound, or its pharmaceutically acceptable salt, or the pharmaceutical composition of Embodiment 21 in the preparation of a medicament for treating and / or preventing a disease or condition or alleviating the severity of the disease or condition, wherein the disease or condition is caused by a coronavirus, and wherein the medicament includes human and veterinary drugs;

[0298] Preferably, the disease or condition is selected from respiratory diseases (e.g., 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.

[0299] Embodiment 23. The compound of any one of Embodiments 1 to 20, or its stereoisomer, or its tautomer, or its solvate, or its isotopically labeled compound, or its pharmaceutically acceptable salt, or the pharmaceutical composition of Embodiment 21, 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 drug includes human drugs and veterinary drugs;

[0300] Preferably, the disease or condition is selected from respiratory diseases (e.g., 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.

[0301] Embodiment 24. A method for treating and / or preventing a disease or condition or alleviating the severity of the disease or condition, comprising administering to a subject in need thereof an effective amount of a compound according to any one of Embodiments 1 to 20, or a stereoisomer thereof, or a tautomer thereof, or a solvate thereof, or an isotopically labeled compound thereof, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to Embodiment 21, wherein the disease or condition is caused by a coronavirus, wherein the drug includes human drugs and veterinary drugs;

[0302] Preferably, the disease or condition is selected from respiratory diseases (e.g., 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.

[0303] In addition, this application also provides the following implementation scheme:

[0304] Embodiment 1Q: The compound shown in Embodiment 13, or its stereoisomer, or its tautomer, or its solvate, or its isotope-labeled compound, or its pharmaceutically acceptable salt, wherein the compound is selected from the compound shown in formula (QI-2)

[0305] in,

[0306] R1 and R2 are each independently selected from C 1-4 Alkyl and C 1-4 Haloalkyl, or R1 and R2 together with the carbon atom to which they are attached form a C 3-5 Cycloalkyl or 4-5 membered heterocycloalkyl;

[0307] R3 is selected from hydrogen, halogen, -OH, -CN, -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 alkyl halide;

[0308] L1 is selected from C 1-4 Alkylene, -NH-C 1-4 Alkylene, 4-7 membered heterocycloalkylene, 4-7 membered heterocycloalkenylene, 6-10 membered arylene;

[0309] R5 is independently selected from hydrogen, halogen, nitro, -OH, -CN, -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, or two R5 form =O, or two R5 and the connected atom form C 3-6 Cycloalkyl or 4-7 membered heterocycloalkyl, the C 3-6 Cycloalkyl or 4-7 membered heterocycloalkyl is optionally substituted by 1, 2 or 3 groups selected from fluorine, chlorine, -OH, -CN, -COOH, -NH2 or methyl;

[0310] L2 is selected from a bond, -C 1-4 Alkylene- and 4-7 membered heterocycloalkylene;

[0311] R6 are each independently selected from hydrogen, halogen, nitro, -OH, -CN, -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)2OH, -S(=O)2NH2, -C(=NH)NH2, -C(=NH)NHC(=NH)NH, C 1-6 Alkyl and 4-7 membered heterocycloalkyl;

[0312] m is 0, 1, 2, or 3;

[0313] n is 0, 1, 2, 3 or 4;

[0314] p is 0, 1, 2, 3 or 4.

[0315] Embodiment 2Q: The compound of Embodiment 13 or 1Q, 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 and R2 are each independently selected from methyl, ethyl, and propyl, or R1 and R2, together with the carbon atom to which they are connected, form a cyclopropyl, cyclobutyl, cyclopentyl, oxetanyl, azetidinyl, oxolanyl, or azacyclopentyl group;

[0316] Preferably, R1 and R2 are each independently a methyl group, or R1 and R2 and the carbon atom to which they are connected together form a cyclopropyl group or an oxetane group;

[0317] Preferably, the structural unit for

[0318] Embodiment 3Q: The compound of Embodiment 13, 1Q or 2Q, or a stereoisomer, or a tautomer, or a solvate, or an isotopically labeled compound, or a pharmaceutically acceptable salt thereof, wherein R3 is selected from hydrogen, fluorine, chlorine, bromine, -OH, -CN, -COOH, -NH2, -O-methyl, -NH-methyl, methyl, ethyl, halomethyl and haloethyl;

[0319] Preferably, R3 is selected from chloro, -O-methyl, methyl, ethyl and trifluoromethyl;

[0320] Preferably, R3 is selected from chlorine and methyl;

[0321] Preferably, R3 is methyl.

[0322] Embodiment 4Q: The compound of any one of Embodiments 13, 1Q to 3Q, or its stereoisomer, or its tautomer, or its solvate, or its isotope-labeled compound, or its pharmaceutically acceptable salt, wherein:

[0323] L1 is selected from -NH-ethylene-, -NH-propylene-, azetidinyl, pyrrolidinyl, tetrahydroimidazolyl, piperidinyl, piperazinyl, hexahydropyrimidinyl, homopiperazinyl, morpholinyl and tetrahydropyridinyl;

[0324] R5 is each independently selected from hydrogen, fluorine, chlorine, bromine, -OH, -CN, -COOH, -NH2, -O-methyl, -NH-methyl, -N(methyl)-methyl, methyl, ethyl, halomethyl and haloethyl, preferably, R5 is each independently selected from hydrogen, fluorine, -COOH and methyl;

[0325] Alternatively, two R5 form =O;

[0326] Alternatively, two R5 and the atoms to which they are attached form a cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, tetrahydroimidazolyl, piperidinyl, piperazinyl, homopiperidinyl or homopiperazinyl group, wherein the cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, tetrahydroimidazolyl, piperidinyl, piperazinyl, homopiperidinyl or homopiperazinyl group is optionally substituted with 1, 2 or 3 groups selected from fluorine, chlorine, -OH, -CN, -COOH, -NH2 or methyl. Preferably, two R5 and the atoms to which they are attached form a cyclopropyl, azetidinyl, pyrrolidinyl or piperidinyl group, wherein the cyclopropyl, azetidinyl, pyrrolidinyl or piperidinyl group is optionally substituted with 1 -OH or methyl group.

[0327] Structural unit Selected from R5 is as defined in this embodiment, n is 0, 1 or 2,

[0328] Preferably, the structural unit Selected from

[0329] Preferably, the structural unit Selected from Unless otherwise specified, the right side of the structural unit is connected to L2, and the * end indicates that it is connected to L2.

[0330] Embodiment 5Q: The compound of any one of Embodiments 13, 1Q to 4Q, or a stereoisomer, or a tautomer, or a solvate, or an isotopically labeled compound, or a pharmaceutically acceptable salt thereof, wherein L2 is selected from a bond, a methylene group, an ethylene group, a propylene group, an azetidinyl group, a pyrrolidinyl group, and a piperidinyl group;

[0331] R6 are each independently selected from hydrogen, halogen, -OH, -CN, -COOH, -NH2, -NH-C 1-4 Alkyl, -N-(C 1- 4-alkyl)2, -S(=O)2-C 1-4 Alkyl, -S(=O)2OH, -S(=O)2NH2, -C(=NH)NH2, -C(=NH)NHC(=NH)NH, C 1-4alkyl and morpholinyl, preferably, R6 is each independently selected from hydrogen, fluorine, chlorine, bromine, -OH, -CN, -COOH, -NH2, -NH-methyl, -NH-ethyl, -NH-propyl, -NH-butyl, -N(methyl)-methyl, -N(methyl)-ethyl, -N(methyl)-propyl, -N(ethyl)-ethyl, -N(ethyl)-propyl, -S(=O)2-methyl, -S(=O)2-ethyl, -S(=O)2-propyl, S(=O)2OH, -S(=O)2NH2, -C(=NH)NH2, -C(=NH)NHC(=NH)NH2, methyl, ethyl, propyl, butyl and morpholinyl, preferably, R6 is each independently selected from hydrogen, fluorine, -OH, -CN, -COOH, -CH3, -S(=O)2CH3, -NH2, -NHCH3, -N(CH3)2,

[0332] Structural unit Selected from R6 is as defined in this embodiment, p is 1 or 2,

[0333] Preferably, the structural unit Selected from -CN,

[0334] Preferably, the structural unit Selected from

[0335] Definition of terms

[0336] 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.

[0337] When the compound name used in this application is inconsistent with the chemical structural formula, the chemical structural formula shall prevail.

[0338] Unless otherwise defined, a divalent group has no directional restrictions, for example, ALB, when L is -C(=O)-NH-, ALB is AC(=O)-NH-B or A-NH-C(=O)-B.

[0339] 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).

[0340] 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 in any proportion (e.g., 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%).

[0341] 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 consist of mixtures thereof (e.g., racemic mixtures and diastereomeric pairs).

[0342] The compounds of the present invention may exist in the form of solvates (e.g., hydrates), wherein the compounds of the present application contain a solvent, such as water, methanol, or ethanol, as a structural element of the crystal lattice of the compound. The amount of the solvent may be present in a stoichiometric or non-stoichiometric ratio.

[0343] 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 and18 O; and sulfur isotopes such as 35 S.

[0344] As used herein, the term "pharmaceutically acceptable salt" refers to a salt of a compound of the invention that is pharmaceutically acceptable and possesses the desired pharmacological activity of the parent compound. Such salts include acid addition salts formed with inorganic or organic acids, or coordination compounds formed by the substitution of an acidic proton present in the parent compound with a metal ion or an organic base.

[0345] Pharmaceutically acceptable salts of the compounds of the present invention include those derived from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable non-toxic acid addition salts are salts of an amino group formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid, or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid, or by using other methods used in the art, such as 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.

[0346] Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium and N + (C 1‐4 Representative alkali metal or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Other pharmaceutically acceptable salts include non-toxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, lower alkyl sulfonates, and aryl sulfonates, as appropriate.

[0347] Pharmaceutically acceptable salts are also intended to encompass hemi-salts, wherein the ratio of compound to acid is 2:1, respectively. 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.

[0348] As used in this application, the term "optionally substituted by..." means that the group may be unsubstituted or substituted, for example, "C 1-6 "Alkyl is optionally substituted by halogen" means C 1-6 Alkyl groups may be unsubstituted or substituted with halogen to give haloalkyl groups. It should be understood that when a group is composed of multiple parts, one of which may be substituted, then the part in the group may also be substituted. For example, the expression "R is selected from C 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 by halogen. For example, the expression "R is selected from methyl, -O-methyl, -NH-methyl, -S-methyl, -C(=O)-methyl and -C(=O)NH-methyl, wherein the methyl group is optionally substituted by one hydroxyl group" means that the methyl group and the methyl groups in -O-methyl, -NH-methyl, -S-methyl, -C(=O)-methyl and -C(=O)NH-methyl are optionally substituted by one hydroxyl group. 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.

[0349] 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.

[0350] As used herein, the term "halogen" refers to fluorine, chlorine, bromine, and iodine.

[0351] As used herein, the term "alkyl" refers to a linear or branched monovalent saturated hydrocarbon group, such as C 1-8Alkyl 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.

[0352] As used herein, the term "alkylene" refers to a straight or branched divalent saturated hydrocarbon group, such as C 1-4 Alkylene refers to a group having 1 to 4 carbon atoms, such as 1, 2, 3 or 4 carbon atoms. Examples of alkylene include, but are not limited to, methylene, ethylene, propylene, butylene, and the like.

[0353] As used herein, the term "halo" refers to a group that is substituted with one or more halogens, such as 1, 2, 3, 4, 5, or 6 halogens. For example, "C1-6 haloalkyl" refers to a C1-6 alkyl group as defined above that is substituted with one or more halogens, examples of which include but are not limited to CF3, CHF2, or CF2CF3.

[0354] As used herein, the term "cycloalkyl" refers to a saturated cyclic hydrocarbon group consisting of carbon atoms. 3- 12 The cycloalkyl group has 3 to 12 carbon atoms, such as 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 carbon atoms, 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.

[0355] As used herein, the term "cycloalkenyl" refers to a partially unsaturated cyclic hydrocarbon group consisting of carbon atoms. 4-12 The cycloalkenyl group has 4 to 12 carbon atoms, such as 4, 5, 6, 7, 8, 9, 10, 11 or 12 carbon atoms, wherein the C 4-12 Cycloalkenyl groups include C 4-8 Cycloalkenyl, C 6-12 Cycloalkenyl, C 6-10 Cycloalkenyl, C 6-8Cycloalkenyl, 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.

[0356] As used in this application, the term "heterocyclyl" refers to a saturated or partially unsaturated monovalent cyclic group consisting of ring atoms, wherein 1, 2, 3 or 4 ring atoms are heteroatoms and the rest are carbon atoms; preferably, the heteroatoms are selected from N, O or S, wherein the nitrogen atom is optionally quaternized, and the nitrogen and sulfur heteroatoms are optionally oxidized. For example, a 5-12 membered heterocyclyl refers to a 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.

[0357] 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.

[0358] As used herein, the term "heterocycloalkyl" refers to a saturated monovalent cyclic group consisting of ring atoms, wherein 1, 2, 3 or 4 of the 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 4-6 membered heterocycloalkyl group refers to a group consisting of 4-6 ring atoms, including 4-5 membered heterocycloalkyl groups. Examples include, but are not limited to, oxetanyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl or morpholinyl.

[0359] As used herein, the term "heterocycloalkylene" refers to a saturated divalent cyclic group consisting of ring atoms, wherein 1, 2, 3 or 4 of the 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 4-10 membered heterocycloalkylene group refers to a group consisting of 4-10 ring atoms, and the 4-10 membered heterocycloalkylene group includes a 4-7 membered heterocycloalkylene group, a 4-6 membered heterocycloalkylene group, a 5 membered heterocycloalkylene group, and the like. Examples include, but are not limited to, oxetanylene, azetidinylene, pyrrolidinylene, piperidinylene, piperazinylene, or morpholinylene.

[0360] As used herein, the term "heterocycloalkenylene" refers to a partially unsaturated divalent cyclic group consisting of ring atoms, 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 4-10 membered heterocycloalkenylene group is composed of 4-10 ring atoms, including 4-7 membered heterocycloalkenylene, 4-6 membered heterocycloalkenylene, 5 membered heterocycloalkenylene, and the like. Examples include, but are not limited to, tetrahydropyridylene, and the like.

[0361] As used herein, the term "heteroaryl" refers to an unsaturated group having a conjugated π electron system composed of ring atoms, wherein 1, 2, 3 or 4 of the 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 5-10 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.

[0362] As used herein, the term "aryl" refers to an unsaturated carbocyclic group having a conjugated π electron system, such as (C6-C 10 ) aryl consists of 6 to 10 (e.g., 6, 7, 8, 9 or 10) carbon atoms. Non-limiting examples include, but are not limited to, phenyl and the like.

[0363] As used herein, the term "arylene" refers to an unsaturated group composed of carbon atoms and having a conjugated π electron system. For example, a 6-12-membered arylene group is composed of 6 to 12 (e.g., 6, 7, 8, 9, or 10) ring atoms, including 6-10-membered arylene groups. Examples include, but are not limited to, phenylene, naphthylene, and the like.

[0364] 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.

[0365] As used herein, the term "effective amount" refers to an amount sufficient to achieve, or at least partially achieve, a desired effect. For example, a prophylactic effective amount is an amount sufficient to prevent, arrest, or delay the onset of a disease; a therapeutic effective amount is an amount sufficient to cure or at least partially arrest the disease and its complications in a patient already suffering from the disease. Determining such an effective amount is well within the capabilities of those skilled in the art. For example, an effective amount for therapeutic use will depend on the severity of the disease to be treated, the overall state of the patient's own immune system, the patient's general condition such as age, weight, and sex, the mode of administration of the drug, and other concurrently administered treatments.

[0366] As used herein, the term "treatment" is intended to alleviate, mitigate, improve, or eliminate the disease state or condition being treated. If a subject receives a therapeutic amount of the antibody-drug conjugate 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, the subject is successfully "treated." It should also be understood that the treatment of the disease state or condition includes not only complete treatment, but also achieving some biologically or medically relevant results despite not achieving complete treatment.

[0367] 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. Beneficial effects

[0368] The present invention provides a papain-like protease inhibitor with a novel structure. The inhibitor of the present invention has good antiviral activity, has an inhibitory effect on cells infected with the new coronavirus, and has good liver stability and oral pharmacokinetic properties. DETAILED DESCRIPTION

[0369] The embodiments of the present invention will be described in detail below with reference to the examples, but those skilled in the art will appreciate that the following examples are intended only to illustrate the present invention and should not be construed as limiting the scope of the present invention. Where specific conditions are not specified in the examples, the reactions were carried out under conventional conditions or the conditions recommended by the manufacturer. Where the manufacturer of the reagents or instruments used is not specified, they are all commercially available conventional products or can be prepared by methods known to those skilled in the art. The resulting compounds are as follows:

[0370] Preparation of P series compounds

[0371] Example 1

[0372] 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

[0373] (1) Preparation of Intermediate S2: 6-bromobenz[cd]indol-2(1H)one

[0374] S1 (2000 mg, 11.82 mmol) was placed in a single-necked flask, CH3CN (30 mL) was added, the temperature was lowered to 0°C, and NBS (2746 mg, 15.42 mmol, added in three batches, with 5 min intervals between each batch) was added. After addition, the mixture was stirred at this temperature for 3.0 h until the starting material was completely reacted, and the reaction was stopped. After the reaction was completed, the reaction solution 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.

[0375] (2) Preparation of Intermediate S3: 6-Bromo-1-methylbenz[cd]indol-2(1H)one

[0376] S2 (2613 mg, 10.53 mmol) was placed in a single-necked flask, and DMF (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. After the reaction was complete, the reaction was stopped. After the reaction was completed, 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 drain it to obtain S3 (2101 mg, 76%) as a yellow solid. MS: m / z [M+1] + =263.52.

[0377] (3) Preparation of Intermediate S4: 1-(1-methyl-2-oxo-1,2-dihydrobenzo[cd]indol-6-yl)cyclopropyl-1-carbonitrile

[0378] Pd2(dba)3 (316 mg, 0.35 mmol) and NixantPhos (358 mg, 0.65 mmol) were placed in a three-necked flask, THF (20 mL) was added, nitrogen was bubbled through the mixture for 30 s, and the mixture was stirred at room temperature for 5 min. Cyclopentyl methyl ether (20 mL), S3 (1628 mg, 6.56 mmol), and cyclopropylcarbonitrile (662 mg, 9.86 mmol) were then added sequentially. LiHMDS (13 mL, 13.12 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 reaction was complete, the reaction was stopped. After completion of the reaction, 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. The organic phases were combined, concentrated under reduced pressure, and purified by column chromatography (PE:EA = 5:1-4:1-3:1) to afford S4 (788 mg, 51%) as a yellow solid. MS:m / z[M+1] + =249.36.

[0379] (4) Preparation of Intermediate S5: 1-(1-methyl-2-oxo-1,2-dihydrobenz[cd]indol-6-yl)cyclopropyl-1-carboxamide

[0380] S4 (788 mg, 3.18 mmol) was placed in a single-necked flask, and i-PrOH (8 mL) and NaOH (382 mg, 9.54 mmol) were added. The temperature was raised to 90°C and the reaction was stirred overnight until the starting materials were completely reacted. The reaction was stopped. After the reaction was completed, the reaction solution was cooled to room temperature, water (10 mL) was added, and 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 obtain S5 (113 mg, 13%) as a yellow solid. MS: m / z [M+1] + =267.43.

[0381] (5) Preparation of Intermediate S6: 6-(1-amino-cyclopropyl)-1-methylbenz[cd]indol-2(1H)-one

[0382] S5 (94 mg, 0.35 mmol) was placed in a single-necked flask, t-BuOH (2 mL) was added, the temperature was lowered to 0°C, and 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. Once the starting material had reacted completely, the reaction was stopped. After the reaction was complete, the reaction solution was concentrated under reduced pressure to remove the solvent. DCM was added to the resulting mixture for dissolution, filtered, and the filter cake was washed with DCM. The filtrate was dried over anhydrous sodium sulfate, filtered, and the filter cake was washed with DCM. The filtrate was concentrated under reduced pressure to yield S6 (76 mg, 91%) as a pale yellow solid. MS: m / z [M+1] + =239.26.

[0383] (6) Preparation of Intermediate S9: 2-ethyl-5-(4-methylpiperazin-1-yl)benzoic acid methyl ester

[0384] 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 tube for 30 seconds, and the temperature was raised to 110°C. The reaction was stirred overnight until the starting materials were completely reacted, and the reaction was stopped. After the reaction was completed, 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 obtain S9 (5416 mg, 100%) as a burgundy oil. MS: m / z [M+1] + =249.33.

[0385] (7) Preparation of Intermediate S10: 2-methyl-5-(4-methylpiperazin-1-yl)benzoic acid

[0386] S9 (5416 mg, 21.83 mmol) was placed in a single-necked flask, and THF (25 mL) and EtOH (25 mL) were added, followed by a solution of NaOH (4366 mg, 109.15 mmol) in H2O (25 mL). The temperature was raised to 60°C and the reaction was stirred for 2 h. The reaction was stopped after the raw materials were completely reacted. After the reaction, the reaction mixture was concentrated under reduced pressure to remove THF and EtOH. The pH was adjusted to 4-5 with dilute hydrochloric acid (2N), filtered, and the filter cake was washed with water. The filtrate was extracted with EA (50 mL). The aqueous phase was concentrated under reduced pressure to remove water. The resulting solid mixture was dissolved in a mixed solution of DCM and MeOH (DCM:MeOH = 10:1, 500 mL), concentrated under reduced pressure, and then dissolved in a mixed solution of DCM and MeOH (DCM:MeOH = 20:1, 500 mL). The mixture was dried over anhydrous sodium sulfate, filtered, and the filter cake was washed with DCM. The resulting filtrate was concentrated under reduced pressure to obtain S10 (5110 mg, 100%) as a light yellow solid. MS: m / z [M+1] + =235.28.

[0387] (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

[0388] 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 (71 mg, 0.55 mmol), and HATU (86 mg, 0.23 mmol) were added. The temperature was raised to 50°C and stirred for 1.0 h until the starting materials reacted completely, at which point the reaction was stopped. After completion of the reaction, 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 combined organic phases were concentrated under reduced pressure and purified by column chromatography (PE:EA = 1:1 - DCM:MeOH = 20:1) to afford P1 (62 mg, 20%) 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=8.3,7.0Hz,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.

[0389] Example 2

[0390] Compound P2: Preparation of 2-methyl-5-(4-methylpiperazin-1-yl)-N-(1-(2-oxo-1,2-dihydrobenz[cd]indol-6-yl)cyclopropyl)benzamide

[0391] (1) Preparation of Intermediate S11: 6-Bromo-1-(4-methoxybenzyl)benzo[cd]indol-2(1H)one

[0392] 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. After the reaction was complete, the reaction was stopped. After the reaction was completed, 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.

[0393] (2) Preparation of Intermediate S12: 1-(1-(4-methoxybenzyl)-2-oxo-1,2-dihydrobenzo[cd]indol-6-yl)cyclopropyl-1-carbonitrile

[0394] 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 reaction was complete, the reaction was stopped. After completion of the reaction, 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 afford S12 (386 mg, 44%) as a yellow solid. MS:m / z[M+1] + =355.36.

[0395] (3) Preparation of Intermediate S13: 1-(1-(4-methoxybenzyl)-2-oxo-1,2-dihydrobenz[cd]indol-6-yl)cyclopropyl-1-carboxamide

[0396] S12 (286 mg, 0.81 mmol) was placed in a single-necked flask, DMSO (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 until the starting material was completely reacted, and the reaction was stopped. After the reaction was completed, 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.

[0397] (4) Preparation of Intermediate S14: 6-(1-amino-cyclopropyl)-1-(4-methoxybenzyl)benzo[cd]indol-2(1H)-one

[0398] 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, and NaClO (0.2 mL, 0.48 mmol) solution and NaOH (3N, 0.16 mL, 0.48 mmol) solution were added. The temperature was raised to room temperature and stirred for 3 h. Once the starting material had reacted completely, the reaction was stopped. After the reaction was complete, the reaction solution was concentrated under reduced pressure to remove the solvent. DCM (300 mL) was added to the resulting mixture, dried over anhydrous sodium sulfate, filtered, and the filter cake was washed with DCM. The filtrate was concentrated under reduced pressure to yield S14 (37 mg, 64%) as a yellow solid. MS: m / z [M+1] + =345.29.

[0399] (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

[0400] S14 (37 mg, 0.11 mmol) and S10 (31 mg, 0.13 mmol) were placed in a single-necked flask. 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. Once the starting materials had reacted completely, the reaction was stopped. After the reaction was complete, 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 1.0 h, filtered, and the filter cake was washed with water. The resulting yellow solid, S15, was dried and used directly in the next reaction. MS: m / z [M+1] + =561.38.

[0401] (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

[0402] S15 (30 mg, 0.054 mmol) was placed in a single-necked flask, TFA (1.5 mL) was added, and the temperature was raised to 60°C. The reaction was stirred overnight until the starting material reacted completely, and the reaction was stopped. After the reaction was completed, the TFA was removed by concentration under reduced pressure. The resulting mixture was added with saturated sodium bicarbonate solution (8 mL), and extracted three times with DCM. The organic phase was concentrated under reduced pressure and purified by column chromatography (PE:EA = 1:1 - DCM:MeOH = 20:1) to obtain P2 (14 mg, 55%) as a bright yellow solid. 1 H 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.

[0403] Example 3

[0404] 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

[0405] (1) Preparation of Intermediate S4: 1-(1-methyl-2-oxo-1,2-dihydrobenzo[cd]indol-6-yl)cyclopropyl-1-carbonitrile

[0406] Pd2(dba)3 (1102 mg, 1.20 mmol) and NixantPhos (1253 mg, 2.27 mmol) were placed in a three-necked flask, THF (70 mL) was added, nitrogen was bubbled for 30 seconds, and the mixture was stirred at room temperature for 5 min. Cyclopentyl methyl ether (70 mL), S3 (6000 mg, 22.89 mmol), and cyclopropylcarbonitrile (2307 mg, 34.39 mmol) were added in sequence, and then LiHMDS (46 mL, 45.78 mmol, 1.0 M in THF) was added dropwise. The temperature was raised to 60°C and the reaction was stirred overnight. The raw materials were completely reacted and the reaction was stopped. After the reaction, the reaction solution was cooled to room temperature, saturated ammonium chloride solution (100 mL) was added, and 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 obtain a yellow solid S4 (2424 mg, 43%). MS: m / z [M+1] + =249.26.

[0407] (2) Preparation of Intermediate S5: 1-(1-methyl-2-oxo-1,2-dihydrobenz[cd]indol-6-yl)cyclopropyl-1-carboxamide

[0408] 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 stirred for 6 h. Once the starting material had reacted completely, the reaction was stopped. After the reaction was complete, 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 afford S5 (1124 mg, 43%) as a yellow solid. MS: m / z [M+1] + =267.43.

[0409] (3) Preparation of Intermediate S6: 6-(1-amino-cyclopropyl)-1-methylbenz[cd]indol-2(1H)-one

[0410] 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 stirred for 3 h. Once the starting material was completely reacted, the reaction was stopped. After the reaction was completed, 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 afford S6 (590 mg, 60%) as a yellow solid. MS: m / z [M+1] + =239.26.

[0411] (4) Preparation of Intermediate S17: tert-Butyl 4-(3-methoxycarbonyl)-4-methylphenyl)-3,6-dihydropiperidine-1(2H)-carboxylate

[0412] S7 (500 mg, 2.18 mmol) and S16 (675 mg, 2.18 mmol) were placed in a sealed tube. 1,4-dioxane (10 mL), X-Phos (42 mg, 0.087 mmol), Cs2CO3 (1421 mg, 4.36 mmol), and Pd2(dba)3 (40 mg, 0.044 mmol) were added. N2 was bubbled through the solution for 30 seconds. The temperature was raised to 100°C and the reaction was stirred overnight until the starting materials were completely reacted. The reaction was then stopped. After the reaction, 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 afford S17 (717 mg, 100%) as a pale yellow oil. MS: m / z [M+1] + =332.38.

[0413] (5) Preparation of Intermediate S18: 5-(1-(tert-butoxycarbonyl)-1,2,3,6-tetrahydropiperidin-4-yl)-2-methylbenzoic acid

[0414] S17 (335 mg, 1.01 mmol) was placed in a single-necked flask, and THF (2 mL) and EtOH (2 mL) were added. A solution of NaOH (202 mg, 5.05 mmol) in H2O (2 mL) was then added. The temperature was raised to 60°C and stirred for 2 h. The reaction was stopped after the starting materials reacted completely. After the reaction, 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 yield S18 (319 mg, 100%) as a white solid. MS: m / z [M+1]+ =318.28.

[0415] (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

[0416] S6 (35 mg, 0.15 mmol) and S18 (56 mg, 0.18 mmol) were placed in a single-necked flask. 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 was stopped. After the reaction was completed, 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.

[0417] (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

[0418] 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, and the starting material was completely reacted, and the reaction was stopped. After the reaction was completed, the solvent was removed by concentration under reduced pressure to obtain a yellow solid mixture. Saturated sodium bicarbonate solution (4 mL) was added to the resulting mixture, and the mixture was extracted three times with DCM. The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain P3 (48 mg, 100%) as a bright yellow solid. 1H 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.

[0419] Example 4

[0420] 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

[0421] (1) Preparation of Intermediate S20: tert-Butyl 4-(3-(methoxycarbonyl)-4-methylphenyl)piperidine-1-carboxylate

[0422] S17 (382 mg, 1.15 mmol) was placed in a single-necked flask, ethanol (5.0 mL) and palladium on carbon (191 mg, 10%) were added, and the reaction was stirred under a hydrogen balloon at room temperature overnight. Once the starting material was completely reacted, the reaction was stopped. After completion of the reaction, 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.

[0423] (2) Preparation of Intermediate S21: 5-(1-(tert-butoxycarbonyl)piperidin-4-yl)-2-methylbenzoic acid

[0424] S20 (360 mg, 1.08 mmol) was placed in a single-necked flask, and THF (2 mL) and EtOH (2 mL) were added. A solution of NaOH (216 mg, 5.40 mmol) in H2O (2 mL) was then added. The temperature was raised to 60°C and stirred for 2 h. The reaction was stopped after the starting materials reacted completely. After the reaction, 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 yield S21 (325 mg, 94%) as a white solid. MS: m / z [M+1] + =320.26.

[0425] (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

[0426] S6 (35 mg, 0.15 mmol) and S21 (57 mg, 0.18 mmol) were placed in a single-necked flask. 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. Once the starting materials were completely reacted, the reaction was stopped. After the reaction was completed, 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.

[0427] (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

[0428] 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, and the starting material was completely reacted, and the reaction was stopped. After the reaction was completed, the solvent was removed by concentration under reduced pressure to obtain a yellow solid mixture. Saturated sodium bicarbonate solution (4 mL) was added to the resulting mixture, and the mixture was extracted three times with DCM. The organic phase was collected, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain P4 (48 mg, 100%) as a bright yellow solid. 1H 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.

[0429] Example 5

[0430] 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

[0431] (1) Preparation of Intermediate S24: tert-Butyl 3-(3-(methoxycarbonyl)-4-methylphenyl)-6-azabicyclo[3.1.1]heptane-6-carboxylate

[0432] S7 (150 mg, 0.65 mmol) and S23 (154 mg, 0.78 mmol) were placed in a sealed tube. 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 seconds. The temperature was raised to 110°C and the reaction was stirred overnight. After the starting materials were completely reacted, the reaction was stopped. After the reaction was completed, the reaction solution was cooled to room temperature, concentrated under reduced pressure, and purified by column chromatography (PE:EA = 10:1) to obtain S24 (121 mg, 54%) as a light yellow oil. MS: m / z [M+1] + =347.25.

[0433] (2) Preparation of Intermediate S25: 5-(6-(tert-butoxycarbonyl)-3,6-diazabicyclo[3.1.1]heptane-3-yl)-2-methylbenzoic acid

[0434] S24 (121 mg, 0.35 mmol) was placed in a single-necked flask, and THF (1 mL) and EtOH (1 mL) were added. A solution of NaOH (70 mg, 1.75 mmol) in H2O (1 mL) was then added. The temperature was raised to 60°C and stirred for 2 h. The reaction was stopped after the starting materials reacted completely. After the reaction, 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 yield S25 (116 mg, 100%) as a pale yellow solid. MS: m / z [M+1] + =333.23.

[0435] (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

[0436] S6 (30 mg, 0.13 mmol) and S25 (50 mg, 0.15 mmol) were placed in a single-necked flask. 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. Once the starting materials were completely reacted, the reaction was stopped. After the reaction was completed, 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.

[0437] (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

[0438] 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, and the starting material was completely reacted, and the reaction was stopped. After the reaction was completed, the solvent was concentrated 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 a bright yellow solid P5 (37 mg, 82%). 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.

[0439] Example 6

[0440] 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

[0441] (1) Preparation of Intermediate S28: tert-Butyl 8-(3-(methoxycarbonyl)-4-methylphenyl)-3,8-diazabicyclo[3.2.1]octane-3-benzoate

[0442] S7 (150 mg, 0.65 mmol) and S27 (166 mg, 0.78 mmol) were placed in a sealed tube. 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 seconds. The temperature was raised to 110°C and the reaction was stirred overnight until the starting materials were completely reacted. The reaction was then stopped. After the reaction, the reaction solution was cooled to room temperature, concentrated under reduced pressure, and purified by column chromatography (PE:EA = 10:1) to afford S28 (155 mg, 66%) as a pale yellow oil. MS: m / z [M+1] + =360.16.

[0443] (2) Preparation of Intermediate S29: 5-(3-(tert-butoxycarbonyl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-2-methylbenzoic acid

[0444] S28 (121 mg, 0.35 mmol) was placed in a single-necked flask, and THF (1 mL) and EtOH (1 mL) were added. A solution of NaOH (70 mg, 1.75 mmol) in H2O (1 mL) was then added. The temperature was raised to 60°C and stirred for 2 h. The reaction was stopped after the starting materials reacted completely. After the reaction, 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 yield S29 (149 mg, 100%) as a pale yellow solid. MS: m / z [M+1] + =347.23.

[0445] (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

[0446] S6 (30 mg, 0.13 mmol) and S29 (52 mg, 0.15 mmol) were placed in a single-necked flask. 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. Once the starting materials were completely reacted, the reaction was stopped. After the reaction was completed, 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 to 1:1) to obtain S30 (61 mg, 82%) as a yellow solid. MS: m / z [M+1] + =567.23.

[0447] (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

[0448] 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, and the starting material was completely reacted, and the reaction was stopped. After the reaction was completed, the solvent was concentrated 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 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.

[0449] Example 7

[0450] 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

[0451] (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

[0452] P3 (20 mg, 0.046 mmol) was placed in a single-necked flask, and MeOH (1.0 mL), aqueous formaldehyde (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. Once the starting materials had reacted completely, the reaction was stopped. After completion of the 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 afford a yellow solid. The yellow solid was purified by column chromatography (PE:EA = 1:1 - DCM:MeOH = 30:1-20:1) to afford P7 (12 mg, 57%) as a bright yellow solid. 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.

[0453] Example 8

[0454] 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

[0455] (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

[0456] P6 (20 mg, 0.043 mmol) was placed in a single-necked flask, and MeOH (1.0 mL), aqueous formaldehyde (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. Once the starting materials had reacted completely, the reaction was stopped. After completion of the 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 afford a yellow solid. The yellow solid was purified by column chromatography (PE:EA = 1:1 - DCM:MeOH = 30:1-20:1) to afford P8 (20 mg, 95%) as a bright yellow solid. MS: m / z [M+1] + =481.36.

[0457] Embodiment 9

[0458] 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

[0459] (1) Preparation of Intermediate S32: tert-Butyl 5-(3-(methoxycarbonyl)-4-methylphenyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate

[0460] S7 (150 mg, 0.65 mmol) and S31 (165 mg, 0.78 mmol) were placed in a sealed tube. 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 seconds. The temperature was raised to 110°C and the reaction was stirred overnight until the starting materials were completely reacted. The reaction was then stopped. After the reaction was completed, the reaction solution was cooled to room temperature, concentrated under reduced pressure, and purified by column chromatography (PE:EA = 10:1) to obtain S32 (171 mg, 73%) as a light yellow oil. MS: m / z [M+1] + =361.18.

[0461] (2) Preparation of Intermediate S33: 5-(5-(tert-butoxycarbonyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)-2-methylbenzoic acid

[0462] 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 stirred for 2 h. The reaction was stopped after the starting materials reacted completely. After the reaction, 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. A pale yellow solid precipitated. 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 yield S33 (163 mg, 100%) as a yellow solid. MS: m / z [M+1] + =347.23.

[0463] (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

[0464] S6 (30 mg, 0.13 mmol) and S33 (52 mg, 0.15 mmol) were placed in a single-necked flask. 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. Once the starting materials were completely reacted, the reaction was stopped. After the reaction was completed, 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 to 1:1) to obtain S34 (58 mg, 78%) as a pale yellow solid. MS: m / z [M+1] + =567.23.

[0465] (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

[0466] 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, and the starting material was completely reacted, and the reaction was stopped. After the reaction, the solvent was removed 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 = 20:1-10:1-8:1) to obtain a bright yellow solid P9 (42 mg, 89%). 1 H NMR(600MHz,DMSO-d6)δ9.03(s,1H),8.81(d,J=8.2Hz,1H),8.04(d,J=6.9Hz,1H),7.83(dd,J=8.2,7.0Hz, 1H),7.73(d,J=7.3Hz,1H),7.08(d,J=7.3Hz,1H),6.91(d,J=8.4Hz,1H),6.53(dd,J=8.3,2.6Hz,1H),6.30( d,J=2.6Hz,1H),3.36(s,3H),3.23-3.21(m,2H),2.97(dd,J=11.0,6.8Hz,2H),2.93(dd,J=9.6,3.1Hz,2H), 2.60(dd,J=11.2,3.3Hz,2H),1.91(s,3H),1.31-1.29(m,2H),1.23(s,3H),1.19-1.17(m,2H).MS:m / z[M+1] + =467.32.

[0467] Example 10

[0468] Compound P10: Preparation of 2-methyl-N-(1-(1-methyl-2-oxo-1,2-dihydrobenzo[cd]indol-6-yl)cyclopropyl)-5-(2-methylpiperazin-1-yl)benzamide

[0469] (1) Preparation of Intermediate S36: tert-Butyl 4-(3-(methoxycarbonyl)-4-methylphenyl)-3-methylpiperazine-1-carboxylate

[0470] S7 (150 mg, 0.65 mmol) and S35 (156 mg, 0.78 mmol) were placed in a sealed tube. 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 seconds. The temperature was raised to 110°C and the reaction was stirred overnight until the starting materials were completely reacted. The reaction was then stopped. After the reaction was completed, the reaction solution was cooled to room temperature, concentrated under reduced pressure, and purified by column chromatography (PE:EA = 10:1) to afford S36 (110 mg, 49%) as a pale yellow oil. MS: m / z [M+1] + =349.36.

[0471] (2) Preparation of Intermediate S37: 5-(4-(tert-Butoxycarbonyl)-2-methylpiperazin-1-yl)-2-methylbenzoic acid

[0472] S36 (110 mg, 0.31 mmol) was placed in a single-necked flask, and THF (1 mL) and EtOH (1 mL) were added. A solution of NaOH (63 mg, 1.58 mmol) in H2O (1 mL) was then added. The temperature was raised to 60°C and stirred for 2 h. The reaction was stopped after the starting materials reacted completely. After the reaction, 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 yield S37 (103 mg, 100%) as a pale yellow solid. MS: m / z [M+1] + =335.19.

[0473] (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

[0474] S6 (30 mg, 0.13 mmol) and S37 (50 mg, 0.15 mmol) were placed in a single-necked flask. 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. Once the starting materials were completely reacted, the reaction was stopped. After the reaction was completed, 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 to 1:1) to obtain S38 (58 mg, 81%) as a pale yellow solid. MS: m / z [M+1] + =555.25.

[0475] (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

[0476] 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, and the starting material was completely reacted, and the reaction was stopped. After the reaction, the solvent was removed 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 = 20:1-10:1-8:1) to obtain a bright yellow solid P10 (45 mg, 100%). 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.

[0477] Example 11

[0478] 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

[0479] (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

[0480] 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 until the starting materials reacted completely, and the reaction was stopped. After the 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 obtain a yellow solid. The yellow solid was purified by column chromatography (DCM:MeOH = 10:1 to 7:1) to obtain P11 (14 mg, 77%) as a bright yellow solid. MS: m / z [M+1]+ = 467.32.

[0481] Example 12

[0482] 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

[0483] (1) Preparation of intermediate S40: tert-butyl 7-(3-(methoxycarbonyl)-4-methylphenyl)-4,7-diazaspiro[2,5]octane-4-carboxylate

[0484] S7 (42 mg, 0.18 mmol) and S39 (46 mg, 0.22 mmol) were placed in a sealed tube. 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 seconds. The temperature was raised to 110°C and the reaction was stirred overnight until the starting materials were completely reacted. The reaction was then stopped. After the reaction was completed, the reaction solution was cooled to room temperature, concentrated under reduced pressure, and purified by column chromatography (PE:EA = 20:1-10:1-8:1) to obtain S40 (35 mg, 54%) as a pale yellow oil. MS: m / z [M+1] + =361.38.

[0485] (2) Preparation of Intermediate S41: 5-(4-(tert-butoxycarbonyl)-4,7-diazaspiro[2,5]octane)-7-yl)-2-methylbenzoic acid

[0486] 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 stirred for 2 h. The reaction was stopped after the starting materials reacted completely. After the reaction, 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. A pale yellow solid precipitated. 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 yield S41 (33 mg, 100%) as a yellow solid. MS: m / z [M+1] + =347.15.

[0487] (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

[0488] S6 (21 mg, 0.086 mmol) and S41 (33 mg, 0.095 mmol) were placed in a single-necked flask. 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. Once the starting materials were completely reacted, the reaction was stopped. After the reaction was completed, 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 afford S42 (33 mg, 67%) as a pale yellow solid. MS: m / z [M+1] + =567.23.

[0489] (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

[0490] 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. Once the starting material had reacted completely, the reaction was stopped. After completion of the reaction, the solvent was removed by concentration under reduced pressure to yield 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 afford P12 (20 mg, 74%) as a bright yellow solid. MS: m / z [M+1] + =467.37.

[0491] Example 13

[0492] 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

[0493] (1) Preparation of Intermediate S44: 5-(4-(dimethylamino)piperidin-1-yl)-2-methylbenzoic acid methyl ester

[0494] S7 (150 mg, 0.65 mmol) and S43 (100 mg, 0.78 mmol) were placed in a sealed tube. 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 seconds. The temperature was raised to 110°C and the reaction was stirred overnight until the starting materials reacted completely. The reaction was stopped. After the reaction, 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 pale yellow oil. MS: m / z [M+1] + =277.38.

[0495] (2) Preparation of Intermediate 45: 5-(4-(dimethylamino)piperidin-1-yl)-2-methylbenzoic acid

[0496] 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 stirred for 2 h. The reaction was stopped after the starting materials reacted completely. After the reaction, 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 S45 (65 mg, 100%) as a pale yellow solid. MS: m / z [M+1] + =263.19.

[0497] (3) P13: Preparation of 5-(4-(dimethylamino)piperidin-1-yl)-2-methyl-N-(1-(1-methyl-2-oxo-1,2-dihydrobenzo[cd]indol-6-yl)cyclopropyl)benzamide

[0498] 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. Once the starting materials had reacted completely, the reaction was stopped. After the reaction was complete, 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 = 1:1 - DCM:MeOH = 20:1-10:1) to afford P13 (23 mg, 57%) as a bright yellow solid. MS: m / z [M+1] + =483.32.

[0499] Example 14

[0500] 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

[0501] (1) Preparation of Intermediate S47: (S)-5-(4-ethyl-3-methylpiperazin-1-yl)-2-methylbenzoic acid methyl ester

[0502] S7 (150 mg, 0.65 mmol) and S46 (100 mg, 0.78 mmol) were placed in a sealed tube. 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 seconds. The temperature was raised to 110°C and the reaction was stirred overnight until the starting materials reacted completely. The reaction was then stopped. After the reaction, 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.

[0503] (2) Preparation of Intermediate S48: (S)-5-(4-ethyl-3-methylpiperazin-1-yl)-2-methylbenzoic acid

[0504] S47 (66 mg, 0.24 mmol) was placed in a single-necked flask, and THF (1 mL) and EtOH (1 mL) were added. A solution of NaOH (48 mg, 1.20 mmol) in H2O (1 mL) was then added. The temperature was raised to 60°C and stirred for 2 h. The reaction was stopped after the starting materials reacted completely. After the reaction, 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 S48 (63 mg, 100%) as a pale yellow solid. MS: m / z [M+1] + =263.19.

[0505] (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

[0506] 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. Once the starting materials had reacted completely, the reaction was stopped. After completion of the reaction, 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 = 1:1 - DCM:MeOH = 20:1-10:1) to afford P14 (18 mg, 45%) as a bright yellow solid. MS: m / z [M+1] + =483.32.

[0507] Example 15

[0508] 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

[0509] (1) Preparation of Intermediate S50: 5-(3-(dimethylamino)pyrrol-1-yl)-2-methylbenzoic acid methyl ester

[0510] 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 solution for 30 seconds, and the temperature was raised to 110°C. The reaction was stirred overnight until the starting materials were completely reacted, and the reaction was stopped. After the reaction was completed, 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 = 1:1-1:2) to obtain S50 (91 mg, 79%) as a pale yellow oil. MS: m / z [M+1] + =263.38.

[0511] (2) Preparation of Intermediate S51: 5-(3-(dimethylamino)pyrrol-1-yl)-2-methylbenzoic acid

[0512] 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 stirred for 2 h. The reaction was stopped after the starting materials reacted completely. After the reaction, 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.

[0513] (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

[0514] S6 (20 mg, 0.084 mmol) and S51 (25 mg, 0.10 mmol) were placed in a single-necked flask. 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. Once the starting materials had reacted completely, the reaction was stopped. After completion of the reaction, 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 = 1:1 - DCM:MeOH = 20:1-10:1) to afford P15 (21 mg, 54%) as a bright yellow solid. MS: m / z [M+1] + =469.31.

[0515] Example 16

[0516] 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

[0517] (1) Preparation of Intermediate S52: 6-bromo-1-isopropylbenzo[cd]indol-2(1H)-one

[0518] S2 (1000 mg, 4.03 mmol) was placed in a single-necked flask, and DMF (15 mL) was added. The temperature was lowered 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 to terminate the reaction. 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. After drying, the filter cake was purified by column chromatography (PE:EA = 30:1) to afford S52 (933 mg, 80%) as a yellow solid. MS: m / z [M+1] + =291.26.

[0519] (2) Preparation of Intermediate S53: 1-(1-isopropyl-2-oxo-1,2-dihydrobenzo[cd]indol-6-yl)cyclopropane-1-carbonitrile

[0520] 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 then 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 reaction was complete, the reaction was stopped. After completion of the reaction, the reaction solution was cooled to room temperature and saturated ammonium chloride solution (20 mL) was added. The product 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 afford S53 (267 mg, 30%) as a yellow solid. MS:m / z[M+1] + =277.32.

[0521] (3) Preparation of Intermediate S54: 1-(1-isopropyl-2-oxo-1,2-dihydrobenz[cd]indol-6-yl)cyclopropane-1-carboxamide

[0522] 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 until the starting material was completely reacted. The reaction was stopped. After the reaction was completed, water (20 mL) was added to precipitate a yellow solid, which was filtered. The filter cake was washed with water and then purified by column chromatography (PE:EA = 2:1 to 1:1) to afford S54 (158 mg, 55%) as a yellow solid. MS: m / z [M+1] + =295.38.

[0523] (4) Preparation of Intermediate S55: 6-(1-aminocyclopropyl)-1-isopropylbenzo[cd]indol-2(1H)-one

[0524] 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) and NaOH (3N, 0.50 mL, 1.51 mmol) were added. The temperature was raised to room temperature and stirred for 2 h. Once the starting material had reacted completely, the reaction was stopped. After completion of the reaction, the reaction solution was concentrated under reduced pressure to remove the solvent and purified by column chromatography (PE:EA = 2:1 to 1:1) to afford S55 (65 mg, 45%) as a yellow oil. MS: m / z [M+1]+ = 267.36.

[0525] (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

[0526] S55 (29 mg, 0.11 mmol) and S25 (41 mg, 0.12 mmol) were placed in a single-necked flask. 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. Once the starting materials were completely reacted, the reaction was stopped. After the reaction was completed, 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 resulting filter cake was purified by column chromatography (PE:EA = 3:1 to 1:1) to afford S56 (53 mg, 83%) as a yellow solid. MS: m / z [M+1] + =581.37.

[0527] (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

[0528] 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 hours until the starting material reacted completely and the reaction was stopped. After the reaction, the solvent was removed 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.

[0529] Example 17

[0530] 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

[0531] (1) Preparation of Intermediate S58: 5-(3-(4-hydroxy-4-methylpiperidin-1-yl)azetidin-1-yl)-2-methylbenzoic acid methyl ester

[0532] 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 reacted completely, and the reaction was stopped. After the reaction, 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 = 1:1-1:3) to afford S58 (92 mg, 66%) as a pale yellow oil. MS: m / z [M+1] + =319.27.

[0533] (2) Preparation of Intermediate S59: 5-(3-(4-hydroxy-4-methylpiperidin-1-yl)azetidin-1-yl)-2-methylbenzoic acid

[0534] S58 (92 mg, 0.29 mmol) was placed in a single-necked flask, and THF (1 mL) and EtOH (1 mL) were added. A solution of NaOH (58 mg, 1.45 mmol) in H2O (1 mL) was then added. The temperature was raised to 60°C and stirred for 2 h. The reaction was stopped after the starting materials reacted completely. After the reaction, 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 yield S59 (88 mg, 100%) as a pale yellow solid. MS: m / z [M+1] + =305.31.

[0535] (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

[0536] 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. Once the starting materials were completely reacted, the reaction was stopped. After the reaction was completed, 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 afford P17 (27 mg, 61%) as a bright yellow solid. MS: m / z [M+1] + =525.25.

[0537] Embodiment 18

[0538] 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

[0539] (1) Preparation of Intermediate S61: 5-(3-(3,3-difluoropyrrol-1-yl)azetidin-1-yl)-2-methylbenzoic acid methyl ester

[0540] 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 seconds, and the temperature was raised to 110°C. The reaction was stirred overnight until the starting materials reacted completely, and the reaction was stopped. After the reaction, 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 = 10:1 to 7:1) to afford S61 (115 mg, 85%) as a pale yellow oil. MS: m / z [M+1] + =311.26.

[0541] (2) Preparation of Intermediate S62: 5-(3-(3,3-difluoropyrrol-1-yl)azetidin-1-yl)-2-methylbenzoic acid

[0542] 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 stirred for 2 h. The reaction was stopped after the starting materials reacted completely. After the reaction, 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 yield S62 (109 mg, 100%) as a pale yellow solid. MS: m / z [M+1] + =297.31.

[0543] (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

[0544] 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. Once the starting materials were completely reacted, the reaction was stopped. After the reaction was completed, 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 resulting filter cake was purified by column chromatography (PE:EA = 3:1 to 1:1) to yield P18 (25 mg, 58%) as a bright yellow solid. MS: m / z [M+1] + =517.23.

[0545] Example 19

[0546] 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

[0547] (1) Preparation of intermediate S64: methyl 2-methyl-5-(6-methyl-2,6-diazaspiro[3,4]octan-2-yl)benzoate

[0548] 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 reaction was stirred overnight until the starting materials were completely reacted, and the reaction was stopped. After the reaction, 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 (PE:EA = 1:1 - DCM:MeOH = 30:1 - 20:1 - 10:1) to afford S64 (71 mg, 100%) as a pale yellow oil. MS: m / z [M+1] + =275.32.

[0549] (2) Preparation of Intermediate S65: 2-Methyl-5-(6-methyl-2,6-diazaspiro[3,4]octan-2-yl)benzoic acid

[0550] S64 (70 mg, 0.26 mmol) was placed in a single-necked flask, and THF (1 mL) and EtOH (1 mL) were added. A solution of NaOH (52 mg, 1.30 mmol) in H2O (1 mL) was then added. The temperature was raised to 60°C and stirred for 2 h. The reaction was stopped after the starting materials reacted completely. After the reaction, 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 yield S65 (68 mg, 100%) as a pale yellow solid. MS: m / z [M+1] + =261.31.

[0551] (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

[0552] 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. Once the starting materials were completely reacted, the reaction was stopped. After the reaction was completed, 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 afford P19 (27 mg, 67%) as a bright yellow solid. MS: m / z [M+1] + =481.23.

[0553] Example 20

[0554] 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

[0555] (1) Intermediate S67: Preparation of methyl 2-methyl-5-((1S,5R)-3-methyl-3,6-diazabicyclo[3.2.0]heptane-6-yl)benzoate

[0556] 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, and the reaction was stopped. After the reaction, 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 to 10:1) to obtain S67 (67 mg, 99%) as a light yellow oil. MS: m / z [M+1] + =261.32.

[0557] (2) Preparation of Intermediate S68: 2-methyl-5-((1S,5R)-3-methyl-3,6-diazabicyclo[3.2.0]heptane-6-yl)benzoic acid

[0558] S67 (67 mg, 0.26 mmol) was placed in a single-necked flask, and THF (1 mL) and EtOH (1 mL) were added. A solution of NaOH (52 mg, 1.30 mmol) in H2O (1 mL) was then added. The temperature was raised to 60°C and stirred for 2 h. The reaction was stopped after the starting materials reacted completely. After the reaction, 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 yield S68 (64 mg, 100%) as a pale yellow solid. MS: m / z [M+1] + =247.33.

[0559] (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

[0560] 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 mixture was heated to 50°C and stirred for 1.0 h. Once the starting materials were fully reacted, the reaction was stopped. After completion of the reaction, 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 resulting filter cake was purified by column chromatography (PE:EA = 1:1 - DCM:MeOH = 20:1 - 10:1 - 8:1) to afford P20 (22 mg, 56%) as a bright yellow solid. MS: m / z [M+1] + =467.23.

[0561] Example 21

[0562] 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

[0563] (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

[0564] P16 (20 mg, 0.042 mmol) was placed in a single-necked flask, and MeOH (1.0 mL), aqueous formaldehyde (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. Once the starting materials had reacted completely, the reaction was stopped. After completion of the 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 afford a yellow solid. The yellow solid was purified by column chromatography (PE:EA = 1:1 - DCM:MeOH = 30:1-20:1) to afford P21 (14 mg, 69%) as a bright yellow solid. MS: m / z [M+1] + =495.35.

[0565] Example 22

[0566] 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

[0567] (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

[0568] P4 (26 mg, 0.059 mmol) was placed in a single-necked flask, and MeOH (1.0 mL), aqueous formaldehyde (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. Once the starting materials had reacted completely, the reaction was stopped. After completion of the 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 afford a yellow solid. The yellow solid was purified by column chromatography (PE:EA = 1:1 - DCM:MeOH = 20:1 - 10:1) to afford P22 (15 mg, 54%) as a bright yellow solid. MS: m / z [M+1] + =454.29.

[0569] Example 23

[0570] 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

[0571] (1) Intermediate S70: Preparation of methyl 2-methyl-5-(3-(4-methylpiperazin-1-yl)azetidin-1-yl)benzoate

[0572] 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, and the reaction was stopped. After the reaction, the reaction solution was cooled to room temperature, water (6 mL) was added, and 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 afford S70 (59 mg, 88%) as a white solid. MS: m / z [M+1] + =304.21.

[0573] (2) Preparation of Intermediate S71: 2-Methyl-5-(3-(4-methylpiperazin-1-yl)azetidin-1-yl)benzoic acid

[0574] 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. A solution of NaOH (39 mg, 0.97 mmol) in H2O (1.0 mL) was then added. The temperature was raised to 60°C and stirred for 2 h. The reaction was stopped after the starting materials reacted completely. After the reaction, 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 yield S71 (55 mg, 100%) as a white solid. MS: m / z [M+1] + =290.22.

[0575] (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

[0576] 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 was stopped. After the reaction was completed, 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 afford P23 (35 mg, 81%) as a bright yellow solid. MS: m / z [M+1] + =510.33.

[0577] Example 24

[0578] 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

[0579] (1) Preparation of Intermediate S73: 2-methyl-5-(3-(piperidin-1-yl)azetidin-1-yl)benzoic acid methyl ester

[0580] 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, and the reaction was stopped. After the reaction was completed, the reaction solution was cooled to room temperature, water (6 mL) was added, and the solution 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.

[0581] (2) Preparation of Intermediate S74: 2-methyl-5-(3-(piperidin-1-yl)azetidin-1-yl)benzoic acid

[0582] 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. A solution of NaOH (37 mg, 0.92 mmol) in H2O (1.0 mL) was then added. The temperature was raised to 60°C and stirred for 2 h. The reaction was stopped after the starting materials reacted completely. After the reaction, 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 yield S74 (49 mg, 100%) as a white solid. MS: m / z [M+1] + =275.26.

[0583] (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

[0584] 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 was stopped. After the reaction was completed, 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 afford P24 (28 mg, 67%) as a bright yellow solid. MS: m / z [M+1] + =495.32.

[0585] Example 25

[0586] 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

[0587] (1) Intermediate S76: Preparation of (S)-methyl 5-(hexahydropyrrolo[1,2-a]pyrazine-2(1H)-yl)-2-methylbenzoate

[0588] 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, and the reaction was stopped. After the reaction was completed, the reaction solution was cooled to room temperature, water (6 mL) was added, and the solution 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.

[0589] (2) Preparation of Intermediate S77: (S)-5-(hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl)-2-methylbenzoic acid

[0590] 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. 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 stirred for 2 h. The reaction was stopped after the starting materials reacted completely. After the reaction, 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 concentrating 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 yield S77 (62 mg, 100%) as a white solid. MS: m / z [M+1] + =261.26.

[0591] (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

[0592] 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 was stopped. After the reaction was completed, 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 afford P25 (16 mg, 40%) as a bright yellow solid. MS: m / z [M+1] + =481.32.

[0593] Example 26

[0594] 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

[0595] (1) Preparation of Intermediate S79: 5-(3-(4-fluoropiperidin-1-yl)azetidin-1-yl)-2-methylbenzoic acid methyl ester

[0596] 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 were completely reacted, and the reaction was stopped. After the reaction was completed, the reaction solution was cooled to room temperature, water (6 mL) was added, and the solution 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.

[0597] (2) Preparation of Intermediate S80: 5-(3-(4-fluoropiperidin-1-yl)azetidin-1-yl)-2-methylbenzoic acid

[0598] 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. A solution of NaOH (46 mg, 1.15 mmol) in H2O (1.0 mL) was then added. The temperature was raised to 60°C and stirred for 2 h. The reaction was stopped after the starting materials reacted completely. After the reaction, 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 then 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 yield S80 (67 mg, 100%) as a white solid. MS: m / z [M+1] + =293.26.

[0599] (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

[0600] 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 was stopped. After the reaction was completed, 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 afford P26 (27 mg, 63%) as a bright yellow solid. MS: m / z [M+1] + =513.32.

[0601] Example 27

[0602] 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

[0603] (1) Preparation of Intermediate S81: 6-bromo-1-ethylbenz[cd]indol-2(1H)-one

[0604] S2 (1000 mg, 4.02 mmol) was placed in a single-necked flask, 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 afford S81 (1000 mg, 90%) as a yellow solid. MS: m / z [M+1] + =277.21.

[0605] (2) Preparation of Intermediate S82: 1-(1-ethyl-2-oxo-1,2-dihydrobenzo[cd]indol-6-yl)cyclopropyl-1-carbonitrile

[0606] 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 temperature was raised to 60°C and stirred for 1 hour. The reaction was stopped after complete reaction of the starting materials. 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.

[0607] (3) Preparation of Intermediate S83: 1-(1-ethyl-2-oxo-1,2-dihydrobenz[cd]indol-6-yl)cyclopropyl-1-carboxamide

[0608] 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 until the starting material was completely reacted. The reaction was stopped. After the reaction was completed, water was added to the reaction solution to precipitate a yellow solid. The product was stirred at room temperature for 20 minutes. Filter the product, 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.

[0609] (4) Preparation of Intermediate S84: 6-(1-aminocyclopropyl)-1-ethylbenz[cd]indol-2(1H)-one

[0610] 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 stirred for 3 h. Once the starting material had reacted completely, the reaction was stopped. After the reaction, 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 afford S84 (98 mg, 79%) as a yellow solid. MS: m / z [M+1] + =281.26.

[0611] (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

[0612] 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 was stopped. After the reaction was completed, 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 afford P27 (8 mg, 22%) as a bright yellow solid. MS: m / z [M+1] + =469.32.

[0613] Example 28

[0614] 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

[0615] (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

[0616] 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 was stopped. After the reaction was completed, 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 afford P28 (16 mg, 38%) as a bright yellow solid. MS: m / z [M+1] + =539.32.

[0617] Example 29

[0618] 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

[0619] (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

[0620] 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 was stopped. After the reaction was completed, 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 afford S85 (27 mg, 60%) as a yellow solid. MS: m / z [M+1] + =567.32.

[0621] (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

[0622] 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. Once the starting material had reacted completely, the reaction was stopped. After completion of the reaction, the solvent was removed by concentration under reduced pressure to afford 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 afford P29 (15 mg, 70%) as a bright yellow solid. MS: m / z [M+1] + =467.32.

[0623] Example 30

[0624] 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

[0625] (1) Preparation of Intermediate S87: 5-(3-(3-fluoropyrrolidin-1-yl)azetidin-1-yl)-2-methylbenzoic acid methyl ester

[0626] 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, and the reaction was stopped. After the reaction was completed, the reaction solution was cooled to room temperature, water (6 mL) was added, and the product 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.

[0627] (2) Preparation of Intermediate S88: 5-(3-(3-fluoropyrrolidin-1-yl)azetidin-1-yl)-2-methylbenzoic acid

[0628] 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 stirred for 2 h. The reaction was stopped after the starting materials reacted completely. After the reaction, 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 yield S88 (67 mg, 100%) as a white solid. MS: m / z [M+1] + =279.26.

[0629] (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

[0630] 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 was stopped. After the reaction was completed, 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 afford P30 (31 mg, 75%) as a bright yellow solid. MS: m / z [M+1] + =499.32.

[0631] Example 31

[0632] 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

[0633] (1) Preparation of intermediate S90: methyl 5-(3-(4,4-difluoropiperidin-1-yl)azetidin-1-yl)-2-methylbenzoate

[0634] 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 seconds, and the temperature was raised to 90°C. The reaction was stirred overnight until the starting materials were completely reacted, and the reaction was stopped. After the reaction was completed, the reaction solution was cooled to room temperature, water (6 mL) was added, and the solution 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.

[0635] (2) Preparation of Intermediate S91: 5-(3-(4,4-difluoropiperidin-1-yl)azetidin-1-yl)-2-methylbenzoic acid

[0636] 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 stirred for 2 h. The reaction was stopped after the starting materials reacted completely. After the reaction, 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 concentrating 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 yield S91 (56 mg, 100%) as a white solid. MS: m / z [M+1] + =311.26.

[0637] (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

[0638] 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 was stopped. After the reaction was completed, 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 afford P31 (22 mg, 55%) as a bright yellow solid. MS: m / z [M+1] + =531.32.

[0639] Example 32

[0640] 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

[0641] (1) Preparation of Intermediate S93: 5-(3-(4-hydroxypiperidin-1-yl)azetidin-1-yl)-2-methylbenzoate

[0642] S7 (50 mg, 0.22 mmol) and S92 (50 mg, 0.22 mmol) were placed in a sealed tube. 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 seconds. The temperature was raised to 90°C and the reaction was stirred overnight. The reaction was stopped after the starting materials were completely reacted. After the reaction, 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 to 1:1) to afford S93 (69 mg, 100%) as a colorless oil. MS: m / z [M+1] + =305.21.

[0643] (2) Preparation of Intermediate S94: 5-(3-(4-hydroxypiperidin-1-yl)azetidin-1-yl)-2-methylbenzoic acid

[0644] 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. A solution of NaOH (45 mg, 1.13 mmol) in H2O (1.0 mL) was then added. The temperature was raised to 60°C and stirred for 2 h. The reaction was stopped after the starting materials had reacted completely. After the reaction, 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 then 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 yield S94 (63 mg, 100%) as a pale yellow solid. MS: m / z [M+1] + =291.26.

[0645] (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

[0646] 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 was stopped. After the reaction was completed, 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 afford P32 (10 mg, 37%) as a bright yellow solid. MS: m / z [M+1] + =511.32.

[0647] Example 33

[0648] 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

[0649] (1) Preparation of intermediate S96: methyl 5-(3-(2,2-dimethylmorpholino)azetidin-1-yl)-2-methylbenzoate

[0650] S7 (29 mg, 0.13 mmol) and S95 (50 mg, 0.13 mmol) were placed in a sealed tube. 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 seconds. The temperature was raised to 90°C and the reaction was stirred overnight until the starting materials were completely reacted. The reaction was then stopped. After the reaction was completed, 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 to 1:1) to obtain S96 (35 mg, 87%) as a pale yellow oil. MS: m / z [M+1] + =319.21.

[0651] (2) Preparation of Intermediate S97: 5-(3-(2,2-dimethylmorpholino)azetidin-1-yl)-2-methylbenzoic acid

[0652] 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. A solution of NaOH (22 mg, 0.55 mmol) in H2O (1.0 mL) was then added. The temperature was raised to 60°C and stirred for 2 h. The reaction was stopped after the starting materials reacted completely. After the reaction, 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 then 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 yield S97 (30 mg, 89%) as a pale yellow solid. MS: m / z [M+1] + =305.26.

[0653] (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

[0654] 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 was stopped. After the reaction was completed, 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 afford P33 (16 mg, 37%) as a bright yellow solid. MS: m / z [M+1] + =525.32.

[0655] Example 34

[0656] 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

[0657] (1) Preparation of intermediate S99: methyl 2-methyl-5-(3-(2-methylpiperidin-1-yl)azetidin-1-yl)benzoate

[0658] S7 (74 mg, 0.32 mmol) and S98 (50 mg, 0.32 mmol) were placed in a sealed tube. 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 seconds. The temperature was raised to 90°C and the reaction was stirred overnight until the starting materials were completely reacted. The reaction was then stopped. After the reaction was completed, 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 afford S99 (96 mg, 97%) as a pale yellow oil. MS: m / z [M+1] + =303.21.

[0659] (2) Preparation of Intermediate S100: 2-methyl-5-(3-(2-methylpiperidin-1-yl)azetidin-1-yl)benzoic acid

[0660] 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. A solution of NaOH (63 mg, 1.58 mmol) in H2O (1.0 mL) was then added. The temperature was raised to 60°C and stirred for 2 h. The reaction was stopped after the starting materials reacted completely. After the reaction, 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 yield S100 (88 mg, 96%) as a pale yellow solid. MS: m / z [M+1] + =289.26.

[0661] (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

[0662] 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 was stopped. After the reaction was completed, 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 afford P34 (18 mg, 56%) as a bright yellow solid. MS: m / z [M+1] + =509.32.

[0663] Example 35

[0664] 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

[0665] (1) Preparation of intermediate S102: methyl 5-(3-(1,1-dioxothiomorpholino)azetidin-1-yl)-2-methylbenzoate

[0666] S7 (44 mg, 0.19 mmol) and S101 (50 mg, 0.19 mmol) were placed in a sealed tube. 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 seconds. The temperature was raised to 90°C and the reaction was stirred overnight until the starting materials were completely reacted. The reaction was then stopped. After the reaction, 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 afford S102 (60 mg, 93%) as a pale yellow solid. MS: m / z [M+1] + =339.21.

[0667] (2) Preparation of Intermediate S103: 5-(3-(1,1-dioxothiomorpholino)azetidin-1-yl)-2-methylbenzoic acid

[0668] 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. A solution of NaOH (35 mg, 0.89 mmol) in H2O (1.0 mL) was then added. The temperature was raised to 60°C and stirred for 2 h. The reaction was stopped after the starting materials reacted completely. After the reaction, 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 concentrating 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 yield S103 (41 mg, 71%) as a pale yellow solid. MS: m / z [M+1] + =325.26.

[0669] (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

[0670] 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 was stopped. After the reaction was completed, 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 afford P35 (7 mg, 20%) as a bright yellow solid. MS: m / z [M+1] + =545.32.

[0671] Example 36

[0672] 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

[0673] (1) Preparation of intermediate S105: (R)-methyl 5-(3-(3-(isopropyl(methyl)amino)pyrrolidin-1-yl)-2-methylbenzoate

[0674] S7 (53 mg, 0.23 mmol) and S104 (50 mg, 0.23 mmol) were placed in a sealed tube. 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 seconds. The temperature was raised to 90°C and the reaction was stirred overnight until the starting materials were completely reacted. The reaction was then stopped. After the reaction was completed, 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 afford S105 (51 mg, 76%) as a pale yellow oil. MS: m / z [M+1] + =291.21.

[0675] (2) Preparation of Intermediate S106: (R)-5-(3-(3-(isopropyl(methyl)amino)pyrrolidin-1-yl)-2-methylbenzoic acid

[0676] 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. A solution of NaOH (35 mg, 0.87 mmol) in H2O (1.0 mL) was then added. The temperature was raised to 60°C and stirred for 2 h. The reaction was stopped after the starting materials had reacted completely. After the reaction, 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 then 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 yield S106 (41 mg, 85%) as a pale yellow solid. MS: m / z [M+1] + =277.26.

[0677] (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

[0678] 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 was stopped. After the reaction was completed, 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 afford P36 (20 mg, 64%) as a bright yellow solid. MS: m / z [M+1] + =497.32.

[0679] Example 37

[0680] 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

[0681] (1) Preparation of intermediate S108: methyl 5-([1,3'-dipyrrolidino]-1'-yl)-2-methylbenzoate

[0682] S7 (54 mg, 0.23 mmol) and S107 (50 mg, 0.23 mmol) were placed in a sealed tube. 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 seconds. The temperature was raised to 90°C and the reaction was stirred overnight until the starting materials were completely reacted. The reaction was then stopped. After the reaction, 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 afford S108 (45 mg, 66%) as a pale yellow solid. MS: m / z [M+1] + =289.21.

[0683] (2) Preparation of Intermediate S109: 5-([1,3'-dipyrrolidino]-1'-yl)-2-methylbenzoic acid

[0684] 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. A solution of NaOH (31 mg, 0.78 mmol) in H2O (1.0 mL) was then added. The temperature was raised to 60°C and stirred for 2 h. The reaction was stopped after the starting materials reacted completely. After the reaction, 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 then 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 yield S109 (41 mg, 96%) as a pale yellow solid. MS: m / z [M+1] + =275.26.

[0685] (3) Preparation of P37: 5-([1,3'-dipyrrolidino]-1'-yl)-2-methyl-N-(1-(1-methyl-2-oxo-1,2-dihydrobenz[cd]indol-6-yl)cyclopropyl)benzamide

[0686] 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 was stopped. After the reaction was completed, 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 afford P37 (7 mg, 22%) as a bright yellow solid. MS: m / z [M+1] + =495.32.

[0687] Example 38

[0688] 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

[0689] (1) Preparation of intermediate S111: methyl 2-methyl-5-(4-(morpholinomethyl)piperidin-1-yl)benzoate

[0690] S7 (62 mg, 0.27 mmol) and S110 (50 mg, 0.27 mmol) were placed in a sealed tube. 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. The temperature was raised to 90°C and the reaction was stirred overnight until the starting materials were completely reacted. The reaction was stopped. After the reaction, 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 pale yellow solid. MS: m / z [M+1] + =333.21.

[0691] (2) Preparation of Intermediate S112: 2-Methyl-5-(4-(morpholinomethyl)piperidin-1-yl)benzoic acid

[0692] 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. 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 stirred for 2 h. The reaction was stopped after the starting materials reacted completely. After the reaction, 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 concentrating 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 yield S112 (80 mg, 97%) as a pale yellow solid. MS: m / z [M+1] + =319.26.

[0693] (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

[0694] 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 was stopped. After the reaction was completed, 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 afford P38 (10 mg, 29%) as a bright yellow solid. MS: m / z [M+1] + =539.32.

[0695] Example 39

[0696] 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

[0697] (1) Preparation of intermediate S114: methyl 2-methyl-5-(1-methyloctahydro-6H-pyrrolo[3,4-b]pyridin-6-yl)benzoate

[0698] S7 (82 mg, 0.36 mmol) and S113 (50 mg, 0.36 mmol) were placed in a sealed tube. 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 seconds. The temperature was raised to 90°C and the reaction was stirred overnight until the starting materials were completely reacted. The reaction was stopped. After the reaction, 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 afford S114 (70 mg, 68%) as a pale yellow solid. MS: m / z [M+1] + =289.21.

[0699] (2) Preparation of Intermediate S115: 2-Methyl-5-(1-methyloctahydro-6H-pyrrolo[3,4-b]pyridin-6-yl)benzoic acid

[0700] 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. A solution of NaOH (49 mg, 1.21 mmol) in H2O (1.0 mL) was then added. The temperature was raised to 60°C and stirred for 2 h. The reaction was stopped after the starting materials reacted completely. After the reaction, 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 yield S115 (60 mg, 90%) as a pale yellow solid. MS: m / z [M+1] + =275.26.

[0701] (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

[0702] 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 was stopped. After the reaction was completed, 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 afford P39 (14 mg, 45%) as a bright yellow solid. MS: m / z [M+1] + =495.32.

[0703] Example 40

[0704] 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

[0705] (1) Preparation of intermediate S117: methyl 2-methyl-5-((1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptane-2-yl)benzoate

[0706] S7 (42 mg, 0.18 mmol) and S116 (50 mg, 0.18 mmol) were placed in a sealed tube. 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. The temperature was raised to 90°C and the reaction was stirred overnight until the starting materials were completely reacted. The reaction was stopped. After the reaction, 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 afford S117 (42 mg, 88%) as a pale yellow oil. MS: m / z [M+1] + =261.21.

[0707] (2) Preparation of Intermediate S118: 2-methyl-5-((1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptane-2-yl)benzoic acid

[0708] S117 (42 mg, 0.16 mmol) was placed in a single-necked flask, and THF (1.0 mL) and EtOH (1.0 mL) were added. A solution of NaOH (32 mg, 0.80 mmol) in H2O (1.0 mL) was then added. The temperature was raised to 60°C and stirred for 2 h. The reaction was stopped after the starting materials reacted completely. After the reaction, 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 concentrating 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 yield S118 (35 mg, 90%) as a pale yellow solid. MS: m / z [M+1] + =247.26.

[0709] (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

[0710] 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 was stopped. After the reaction was completed, 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 afford P40 (9 mg, 31%) as a bright yellow solid. MS: m / z [M+1] + =467.32.

[0711] Example 41

[0712] 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

[0713] (1) Preparation of intermediate S120: methyl 5-(4-(2-hydroxypropyl)piperazin-1-yl)-2-methylbenzoate

[0714] S7 (79 mg, 0.35 mmol) and S119 (50 mg, 0.35 mmol) were placed in a sealed tube. 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 mixture for 30 s. The temperature was raised to 90°C and the reaction was stirred overnight until the starting materials were completely reacted. The reaction was then stopped. After completion of the reaction, 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 afford S120 (42 mg, 88%) as a pale yellow oil. MS: m / z [M+1] + =293.21.

[0715] (2) Preparation of Intermediate S121: 5-(4-(2-hydroxypropyl)piperazin-1-yl)-2-methylbenzoic acid

[0716] S120 (30 mg, 0.10 mmol) was placed in a single-necked flask, and THF (1.0 mL) and EtOH (1.0 mL) were added. A solution of NaOH (20 mg, 0.50 mmol) in H2O (1.0 mL) was then added. The temperature was raised to 60°C and stirred for 2 h. The reaction was stopped after the starting materials reacted completely. After the reaction, 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 then 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 yield S121 (24 mg, 86%) as a pale yellow solid. MS: m / z [M+1] + =279.26.

[0717] (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

[0718] 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 was stopped. After the reaction was completed, 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 afford P41 (9 mg, 37%) as a bright yellow solid. MS: m / z [M+1] + =499.32.

[0719] Example 42

[0720] 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

[0721] (1) Preparation of intermediate S123: methyl 5-([1,3'-diazetidine]-1'-yl)-2-methylbenzoate

[0722] 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 reaction was stirred overnight until the starting materials were completely reacted, and the reaction was stopped. After the reaction, 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 afford S123 (47 mg, 100%) as a pale yellow solid. MS: m / z [M+1] + =261.21.

[0723] (2) Preparation of Intermediate S124: 5-([1,3'-diazetidine]-1'-yl)-2-methylbenzoic acid

[0724] 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. 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 stirred for 2 h. The reaction was stopped after the starting materials reacted completely. After the reaction, 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 yield S124 (37 mg, 84%) as a pale yellow solid. MS: m / z [M+1] + =247.26.

[0725] (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

[0726] 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 was stopped. After the reaction was completed, 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 afford P42 (23 mg, 80%) as a bright yellow solid. MS: m / z [M+1] + =467.32.

[0727] Example 43

[0728] 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

[0729] (1) Preparation of intermediate S126: methyl 5-(3-(3-hydroxypyrrolidin-1-yl)azetidin-1-yl)-2-methylbenzoate

[0730] 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 reacted completely, and the reaction was stopped. After the reaction, 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 afford S126 (16 mg, 21%) as a colorless oil. MS: m / z [M+1] + =291.21.

[0731] (2) Preparation of Intermediate S127: 5-(3-(3-hydroxypyrrolidin-1-yl)azetidin-1-yl)-2-methylbenzoic acid

[0732] 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 stirred for 2 h. The reaction was stopped after the starting materials reacted completely. After the reaction, 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 then 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 yield S127 (15 mg, 100%) as a pale yellow solid. MS: m / z [M+1] + =247.26.

[0733] (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

[0734] 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 was stopped. After the reaction was completed, 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 afford P43 (9 mg, 41%) as a bright yellow solid. MS: m / z [M+1] + =497.32.

[0735] Example 44

[0736] 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

[0737] (1) Preparation of intermediate S129: methyl 2-methyl-5-(3-(4-methyl-3-oxopiperazin-1-yl)azetidin-1-yl)benzoate

[0738] S7 (60 mg, 0.26 mmol) and S128 (75 mg, 0.31 mmol) were placed in a sealed tube. 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 seconds. The temperature was raised to 110°C and the reaction was stirred overnight until the starting materials were completely reacted. The reaction was then stopped. After the reaction, 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 afford S129 (56 mg, 68%) as a pale yellow solid. MS: m / z [M+1] + =318.21.

[0739] (2) Preparation of Intermediate S130: 2-methyl-5-(3-(4-methyl-3-oxopiperazin-1-yl)azetidin-1-yl)benzoic acid

[0740] 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. A solution of NaOH (35 mg, 0.88 mmol) in H2O (1.0 mL) was then added. The temperature was raised to 60°C and stirred for 2 h. The reaction was stopped after the starting materials reacted completely. After the reaction, 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 concentrating 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 yield S130 (54 mg, 100%) as a pale yellow solid. MS: m / z [M+1] + =304.26.

[0741] (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

[0742] 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 was stopped. After the reaction was completed, 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 afford P44 (12 mg, 36%) as a bright yellow solid. MS: m / z [M+1] + =524.32.

[0743] Example 45

[0744] 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

[0745] (1) Preparation of Intermediate S132: methyl 2-methyl-5-(3-(pyrrolidin-1-yl)azetidin-1-yl)benzoate

[0746] 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 reaction was stirred overnight until the starting materials were completely reacted, and the reaction was stopped. After the reaction was completed, the reaction solution was cooled to room temperature, water (6 mL) was added, and 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 afford S132 (71 mg, 100%) as a pale yellow oil. MS: m / z [M+1] + =275.21.

[0747] (2) Preparation of Intermediate S133: 2-methyl-5-(3-(pyrrolidin-1-yl)azetidin-1-yl)benzoic acid

[0748] 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. 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 stirred for 2 h. The reaction was stopped after the starting materials reacted completely. After the reaction, 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 yield S133 (68 mg, 100%) as a pale yellow solid. MS: m / z [M+1] + =261.26.

[0749] (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

[0750] 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 was stopped. After the reaction was completed, 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 afford P45 (14 mg, 47%) as a bright yellow solid. MS: m / z [M+1] + =481.32.

[0751] Example 46

[0752] 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

[0753] (1) Preparation of intermediate S135: methyl 2-methyl-5-(3-morpholinoazetidin-1-yl)benzoate

[0754] 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 mixture for 30 s, and the temperature was raised to 110°C. The reaction was stirred overnight until the starting materials were completely reacted, and the reaction was stopped. After the reaction was completed, the reaction solution was cooled to room temperature, water (6 mL) was added, and 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 to 1:1) to obtain S135 (75 mg, 100%) as a white solid. MS: m / z [M+1] + =291.21.

[0755] (2) Preparation of Intermediate S136: 2-methyl-5-(3-morpholinoazetidin-1-yl)benzoic acid

[0756] 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 stirred for 2 h. The reaction was stopped after the starting materials reacted completely. After the reaction, 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 yield S136 (72 mg, 100%) as a white solid. MS: m / z [M+1] + =277.26.

[0757] (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

[0758] 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 was stopped. After the reaction was completed, 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 afford P46 (20 mg, 65%) as a bright yellow solid. MS: m / z [M+1] + =497.32.

[0759] Example 47

[0760] 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

[0761] (1) Preparation of intermediate S138: methyl 2-methyl-5-(3aR,6aR)-1-methylhexahydropyrrolo[3,4-b]pyrrol-5(1H)-yl)benzoate

[0762] 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 seconds, and the temperature was raised to 110°C. The reaction was stirred overnight until the starting materials were completely reacted, and the reaction was stopped. After the reaction was completed, the reaction solution was cooled to room temperature, water (6 mL) was added, and the solution 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 afford S138 (52 mg, 73%) as a pale yellow solid. MS: m / z [M+1] + =275.21.

[0763] (2) Preparation of intermediate S139: 2-methyl-5-(3aR,6aR)-1-methylhexahydropyrrolo[3,4-b]pyrrol-5(1H)-yl)benzoic acid

[0764] 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 stirred for 2 h. The reaction was stopped after the starting materials reacted completely. After the reaction, 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 then 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 yield S139 (49 mg, 100%) as a pale yellow solid. MS: m / z [M+1] + =261.26.

[0765] (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

[0766] 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 was stopped. After the reaction was completed, 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 afford P47 (17 mg, 57%) as a bright yellow solid. MS: m / z [M+1] + =481.32.

[0767] Example 48

[0768] 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

[0769] (1) Preparation of intermediate S141: methyl 5-(3,3-difluoro-4-(pyrrolidin-1-yl)piperidin-1-yl)-2-methylbenzoate

[0770] 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 seconds, and the temperature was raised to 110°C. The reaction was stirred overnight until the starting materials were completely reacted, and the reaction was stopped. After the reaction was completed, the reaction solution was cooled to room temperature, water (6 mL) was added, and the solution 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.

[0771] (2) Preparation of Intermediate S142: 5-(3,3-difluoro-4-(pyrrolidin-1-yl)piperidin-1-yl)-2-methylbenzoic acid

[0772] S141 (43 mg, 0.13 mmol) was placed in a single-necked flask, and THF (1.0 mL) and EtOH (1.0 mL) were added. A solution of NaOH (25 mg, 0.63 mmol) in H2O (1.0 mL) was then added. The temperature was raised to 60°C and stirred for 2 h. The reaction was stopped after the starting materials reacted completely. After the reaction, 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 then 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 yield S142 (34 mg, 81%) as a white solid. MS: m / z [M+1] + =325.26.

[0773] (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

[0774] 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 was stopped. After the reaction was completed, 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 to 1:1) to afford P48 (15 mg, 44%) as a bright yellow solid. MS: m / z [M+1] + =545.32.

[0775] Example 49

[0776] 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

[0777] (1) Preparation of intermediate S144: methyl 5-(4-(2-hydroxy-2-methylpropyl)piperazin-1-yl)-2-methylbenzoate

[0778] 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 were completely reacted, and the reaction was stopped. After the reaction was completed, the reaction solution was cooled to room temperature, saturated ammonium chloride solution (6 mL) was added, and 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.

[0779] (2) Preparation of Intermediate S145: 5-(4-(2-hydroxy-2-methylpropyl)piperazin-1-yl)-2-methylbenzoic acid

[0780] 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. A solution of NaOH (56 mg, 1.39 mmol) in H2O (1.0 mL) was then added. The temperature was raised to 60°C and stirred for 2 h. The reaction was stopped after the starting materials reacted completely. After the reaction, 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 yield S145 (41 mg, 50%) as a white solid. MS: m / z [M+1] + =293.26.

[0781] (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

[0782] 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 was stopped. After the reaction was completed, 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 afford P49 (21 mg, 66%) as a bright yellow solid. MS: m / z [M+1] + =513.32.

[0783] Embodiment 50

[0784] 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

[0785] (1) Preparation of intermediate S147: methyl 2-methyl-5-(3-(piperidin-1-yl)pyrrolidin-1-yl)benzoate

[0786] 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, and the reaction was stopped. After the reaction was completed, the reaction solution was cooled to room temperature, water (6 mL) was added, and 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 afford S147 (73 mg, 93%) as a pale yellow oil. MS: m / z [M+1] + =303.21.

[0787] (2) Preparation of Intermediate S148: 2-Methyl-5-(3-(piperidin-1-yl)pyrrolidin-1-yl)benzoic acid

[0788] 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 stirred for 2 h. The reaction was stopped after the starting materials reacted completely. After the reaction, 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 then 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 pale yellow oil. MS: m / z [M+1] + =289.26.

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

[0790] 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 was stopped. After the reaction was completed, 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 afford P50 (16 mg, 50%) as a bright yellow solid. MS: m / z [M+1] + =509.32.

[0791] Example 51

[0792] 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

[0793] (1) Preparation of intermediate S150: methyl 2-methyl-5-(4-(3-methylsulfonyl)propyl)piperazin-1-yl)benzoate

[0794] 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, and the reaction was stopped. After the reaction was completed, the reaction solution was cooled to room temperature, water (6 mL) was added, and the solution 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 pale yellow solid. MS: m / z [M+1] + =355.21.

[0795] (2) Preparation of Intermediate S151: 2-Methyl-5-(4-(3-methylsulfonyl)propyl)piperazin-1-yl)benzoic acid

[0796] 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. A solution of NaOH (14 mg, 0.34 mmol) in H2O (0.5 mL) was then added. The temperature was raised to 60°C and stirred for 2 h. The reaction was stopped after the starting materials reacted completely. After the reaction, 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 yield S151 (23 mg, 100%) as a pale yellow solid. MS: m / z [M+1] + =341.26.

[0797] (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

[0798] 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 was stopped. After the reaction was completed, 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 afford P51 (16 mg, 46%) as a bright yellow solid. MS: m / z [M+1] + =561.32.

[0799] Example 52

[0800] 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

[0801] (1) Preparation of intermediate S153: methyl 5-(4-(2-(dimethylamino)ethyl)piperazin-1-yl)-2-methylbenzoate

[0802] 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, and the reaction was stopped. After the reaction was completed, the reaction solution was cooled to room temperature, water (6 mL) was added, and the solution 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 pale yellow solid. MS: m / z [M+1] + =306.21.

[0803] (2) Preparation of Intermediate S154: 5-(4-(2-(dimethylamino)ethyl)piperazin-1-yl)-2-methylbenzoic acid

[0804] 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. A solution of NaOH (45 mg, 1.13 mmol) in H2O (1.0 mL) was then added. The temperature was raised to 60°C and stirred for 2 h. The reaction was stopped after the starting materials reacted completely. After the reaction, 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 yield S154 (67 mg, 100%) as a pale yellow solid. MS: m / z [M+1] + =292.26.

[0805] (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

[0806] 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 was stopped. After the reaction was completed, 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 afford P52 (19 mg, 60%) as a bright yellow solid. MS: m / z [M+1] + =512.32.

[0807] Example 53

[0808] 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

[0809] (1) Preparation of intermediate S156: methyl 5-(4-(2-hydroxyethyl)piperazin-1-yl)-2-methylbenzoate

[0810] 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, and the reaction was stopped. After the reaction was completed, the reaction solution was cooled to room temperature, saturated ammonium chloride solution (6 mL) was added, and 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.

[0811] (2) Preparation of Intermediate S157: 5-(4-(2-hydroxyethyl)piperazin-1-yl)-2-methylbenzoic acid

[0812] 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. A solution of NaOH (6 mg, 0.14 mmol) in H2O (0.4 mL) was then added. The temperature was raised to 60°C and stirred for 2 h. The reaction was stopped after the starting materials reacted completely. After the reaction, 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.

[0813] (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

[0814] 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 was stopped. After the reaction was completed, 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 afford P53 (7 mg, 63%) as a bright yellow solid. MS: m / z [M+1] + =485.32.

[0815] Example 54

[0816] 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

[0817] (1) Preparation of intermediate S159: methyl 5-(3-fluoro-[1,3'-diazetidine]-1'-yl)-2-methylbenzoate

[0818] 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 seconds, and the temperature was raised to 110°C. The reaction was stirred overnight until the starting materials were completely reacted, and the reaction was stopped. After the reaction was completed, the reaction solution was cooled to room temperature, water (6 mL) was added, and the product was extracted three times with DCM. The organic phases were combined, concentrated under reduced pressure, and purified by column chromatography (PE:EA = 3:1 to 1:1) to obtain S159 (42 mg, 58%) as a colorless oil. MS: m / z [M+1] + =279.21.

[0819] (2) Preparation of intermediate S160: 5-(3-fluoro-[1,3'-diazetidine]-1'-yl)-2-methylbenzoic acid

[0820] 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 stirred for 2 h. The reaction was stopped after the starting materials reacted completely. After the reaction, 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 pale yellow oil. MS: m / z [M+1] + =265.26.

[0821] (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

[0822] 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 was stopped. After the reaction was completed, 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 afford P54 (22 mg, 72%) as a bright yellow solid. MS: m / z [M+1] + =485.32.

[0823] Preparation of Q series compounds:

[0824] Intermediate 4: Preparation of 5-bromo-N-(1-(1,2-dihydroacenaphthen-5-yl)cyclopropyl)-2-methylbenzamide. The synthetic route is as follows:

[0825] (1) Preparation of Intermediate 2: 1,2-Dihydroacenaphthene-5-carbonitrile

[0826] A 350 mL sealed tube was added with 5-bromoacenaphthene (23.3 g, 0.1 mol, 1 eq), CuCN (17.9 g, 0.2 mol, 2 eq), and NMP (100 mL). Stir at 170°C overnight. Cool and observe the disappearance of the starting material by TLC. Filter and wash the filter cake with NMP. Slowly add water to the filtrate to precipitate a solid, which was then filtered to obtain a light yellow solid (14.5 g, 81%). 1 H NMR(600MHz,Chloroform-d)δ7.87(d,J=8.2Hz,1H),7.84(d,J=7.2Hz,1H),7.65( dd,J=8.3,6.9Hz,1H),7.42(d,J=7.0Hz,1H),7.32(d,J=7.2Hz,1H),3.45(s,4H).

[0827] (2) Preparation of Intermediate 3: 1-(1,2-dihydroacenaphthen-5-yl)cyclopropane-1-amine

[0828] To a 500 mL single-necked flask, add 1,2-dihydroacenaphthene-5-carbonitrile (9 g, 50.22 mmol, 1 eq) and THF (90 mL). Add tetraisopropyl titanate (16.35 mL, 55.24 mmol, 1.1 eq). Cool to -78°C and add ethylmagnesium bromide (36.83 mL, 110.48 mmol, 2.2 eq) dropwise. Stir at ambient temperature for 2 h. Add boron trifluoride etherate (12.4 mL, 100.44 mmol, 2 eq). Stir at ambient temperature for 4 h. Monitor the disappearance of the starting material by TLC. 2N dilute hydrochloric acid was added to quench the reaction, and the pH was adjusted to 9 with NaOH solution. EtOAc (300 mL*3) / H2O (300 mL) was added for extraction at ambient temperature. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (DCM:MeOH=100:0-100:10) to obtain a dark brown oil (5 g, 47%). LC-MS (ESI, m / z): C 15 H 15 N,[M+H] + =209.90.

[0829] (3) Preparation of Intermediate 4: 5-Bromo-N-(1-(1,2-dihydroacenaphthen-5-yl)cyclopropyl)-2-methylbenzamide

[0830] To a 250 mL single-necked flask, add 1-(1,2-dihydroacenaphthen-5-yl)cyclopropane-1-amine (5 g, 23.89 mmol, 1 eq), 2-methyl-5-bromobenzoic acid (4.62 g, 21.5 mmol, 0.9 eq), DMF (50 mL), DIEA (8.32 mL, 47.78 mmol, 2 eq), and HATU (10.9 g, 28.67 mmol, 1.2 eq) and stir overnight at 50°C. TLC plate analysis indicated the disappearance of the starting material. Cool the mixture and slowly add H2O to precipitate the solid. Stir for 30 min and filter. Dissolve the filter cake in EtOAc, concentrate, and column chromatography (PE:EtOAc = 100:5-100:50) to obtain an off-white solid (3.6 g, 41%). LC-MS (ESI, m / z): C 15 H 15 N,[M+H] + =406.96.

[0831] Example 1 (Q1): Preparation of N-(1-(1,2-dihydroacenaphthen-5-yl)cyclopropyl)-2-methyl-5-(piperidin-4-yl)benzamide hydrochloride. The synthetic route is as follows:

[0832] (1) Intermediate 5: Preparation of tert-butyl 4-(3-((1-(1,2-dihydroacenaphthen-5-yl)cyclopropyl)carbamoyl)-4-methylphenyl)-3,6-dihydropyridine-1(2H)-carboxylate

[0833] A 25 mL sealed tube was added, and 5-bromo-N-(1-(1,2-dihydroacenaphthen-5-yl)cyclopropyl)-2-methylbenzamide (200 mg, 0.5 mmol, 1 eq), N-Boc-1,2,5,6-tetrahydropyridine-4-boronic acid pinacol ester (185 mg, 0.6 mmol, 1.2 eq), Cs2CO3 (488 mg, 1.5 mmol, 3 eq), X-phos (47 mg, 0.1 mmol, 0.2 eq), Pd2(dba)3 (12 mg, 0.05 mmol, 0.1 eq), and 1,4-dioxane (6 mL) were added. The mixture was stirred at 110°C overnight. The mixture was cooled and the disappearance of the starting material was detected by TLC. EtOAc (20 mL x 3) / H2O (20 mL) was added for extraction. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness. Column chromatography (PE:EtOAc=100:5-100:50) gave a light yellow oil 5 (220 mg, 87%).

[0834] (2) Intermediate 6: Preparation of N-(1-(1,2-dihydroacenaphthen-5-yl)cyclopropyl)-2-methyl-5-(1,2,3,6-tetrahydropyridin-4-yl)benzamide hydrochloride

[0835] To a 25 mL single-necked flask, add tert-butyl 4-(3-((1-(1,2-dihydroacenaphthen-5-yl)cyclopropyl)carbamoyl)-4-methylphenyl)-3,6-dihydropyridine-1(2H)-carboxylate (220 mg, 0.43 mmol), DCM (4 mL), and HCl / 1,4-dioxane (2 mL, 3 M). Stir at ambient temperature for 2 h. Dissolution of the starting material was monitored by TLC. The product was concentrated to dryness, and MTBE (5 mL) was added to precipitate a solid, which was filtered to afford a light yellow solid (120 mg, 70%).

[0836] (3) Preparation of Compound Q1: N-(1-(1,2-dihydroacenaphthen-5-yl)cyclopropyl)-2-methyl-5-(piperidin-4-yl)benzamide

[0837] To a 25 mL single-necked flask, add N-(1-(1,2-dihydroacenaphthen-5-yl)cyclopropyl)-2-methyl-5-(1,2,3,6-tetrahydropyridin-4-yl)benzamide hydrochloride (90 mg, 0.22 mmol), methanol (3 mL), and Pd / C (20 mg). Stir overnight at ambient temperature under a hydrogen atmosphere. Filter and concentrate to dryness. Add MTBE (4 mL) to precipitate a solid, which is filtered to obtain an off-white solid (20 mg, 22%). LC-MS (ESI, m / z): C 28 H 30 N2O,[M+H] + =410.96.

[0838] Example 4 (Q4): Preparation of 5-(3,6-diazabicyclo[3.1.1]heptane-3-yl)-N-(1-(1,2-dihydroacenaphthen-5-yl)cyclopropyl)-2-methylbenzamide. The synthetic route is as follows:

[0839] (1) Intermediate 5: Preparation of tert-butyl 3-(3-((1-(1,2-dihydroacenaphthen-5-yl)cyclopropyl)carbamoyl)-4-methylphenyl)-3,6-diazabicyclo[3.1.1]heptane-6-carboxylate

[0840] A 15 mL tube was sealed and added with 5-bromo-N-(1-(1,2-dihydroacenaphthen-5-yl)cyclopropyl)-2-methylbenzamide (100 mg, 0.25 mmol, 1 eq), 6-(tert-butyloxycarbonyl)-3,6-diazabicyclo[3.1.1]heptane (59 mg, 0.3 mmol, 1.2 eq), Cs2CO3 (244 mg, 0.75 mmol, 3 eq), Ru-phos (22 mg, 0.05 mmol, 0.2 eq), Pd(OAc)2 (6 mg, 0.025 mmol, 0.1 eq), and 1,4-dioxane (3 mL). The mixture was stirred at 110°C overnight. After cooling, TLC was performed to determine the disappearance of the starting material. The product was filtered and concentrated to dryness. Column chromatography (DCM:MeOH = 100:0 to 100:10) afforded a light yellow solid (78 mg, 60%). LC-MS (ESI, m / z): [M+H] + =523.96

[0841] (2) Preparation of Compound Q4: 5-(3,6-diazabicyclo[3.1.1]heptane-3-yl)-N-(1-(1,2-dihydroacenaphthen-5-yl)cyclopropyl)-2-methylbenzamide

[0842] To a 25 mL single-necked flask, tert-butyl 3-(3-((1-(1,2-dihydroacenaphthen-5-yl)cyclopropyl)carbamoyl)-4-methylphenyl)-3,6-diazabicyclo[3.1.1]heptane-6-carboxylate (78 mg, 0.15 mmol), DCM (4 mL), and HCl / 1,4-dioxane (2 mL, 3 M) were added. The mixture was stirred at ambient temperature for 2 h. The disappearance of the starting material was detected by TLC. The solution was concentrated to dryness, saturated NaHCO₃ solution was added, and the pH was adjusted to 9. The product was extracted with EtOAc (20 mL*3) / H₂O (20 mL). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (DCM:MeOH = 100:0-100:10) to give an off-white solid (9 mg). LC-MS (ESI, m / z): C28H29N3O, [M+H]+=423.90.

[0843] Example 30 (Q30): Preparation of N-(1-(1,2-dihydroacenaphthen-5-yl)cyclopropyl)-2-chloro-5-(4-methylpiperazin-1-yl)benzamide. The synthetic route is as follows:

[0844] (1) Preparation of Intermediate A3: 2-(1,2-dihydroacenaphthen-5-yl)benzeneacetonitrile

[0845] A1 (1000 mg, 4.30 mmol) and A2 (1008 mg, 5.18 mmol) were placed in a sealed tube. DMSO (30 mL) and H2O (12 mL) were added, followed by KF (750 mg, 12.90 mmol), and finally Pd(dppf)Cl2. N2 was bubbled through the mixture for 30 seconds, and the temperature was raised to 130°C. The mixture was stirred overnight to complete reaction. After completion of the reaction, the reaction solution was cooled to room temperature, EtOAc was added, and the mixture was filtered through Celite. The filter cake was washed with EtOAc. The filtrate was separated, and the aqueous phase was extracted twice with EtOAc. The organic phases were combined, concentrated under reduced pressure, and purified by column chromatography (PE:EtOAc = 50:1-30:1-15:1) to afford A3 (498 mg, 60%) as a yellow solid.

[0846] 1 H NMR (600MHz, Chloroform-d) δ7.60-7.54(m,2H),7.50(d,J=7.0Hz,1H),7.36(d,J=7.1Hz,1H),7.27(d,J=7.3Hz,1H),4.06(s,2H),3.45-3.38(m,4H).

[0847] (2) Preparation of Intermediate A4: 1-(1,2-dihydroacenaphthen-5-yl)phenylacetonitrile-cyclopropyl-1-carbonitrile

[0848] A3 (498 mg, 2.58 mmol) was placed in a single-necked flask, and DMF (6 mL) was added. The temperature was lowered to 0°C, and NaH (237 mg, 5.93 mmol, added in three portions, with a 5-min interval between each portion) was added portionwise. The reaction was stirred for 0.5 h, followed by the dropwise addition of 1,2-dibromoethane. The temperature was raised to room temperature, and the reaction was stirred overnight to complete reaction. After the reaction, water was added to the reaction solution, and the mixture was extracted three times with EtOAc. The organic phases were combined, concentrated under reduced pressure, and purified by column chromatography (PE:EtOAc = 50:1) to afford A4 (106 mg, 21%) as a yellow solid, which was used directly in the next step.

[0849] (3) Preparation of Intermediate A5: 1-(1,2-dihydroacenaphthen-5-yl)phenylacetonitrile cyclopropyl-1-carboxamide

[0850] A4 (106 mg, 0.48 mmol) was placed in a single-necked flask, and i-PrOH (2 mL) and NaOH (58 mg, 1.44 mmol) were added. The temperature was raised to 90°C and stirred for 7 h. The starting material reacted completely, a solid precipitated, and the reaction was stopped. After the reaction, the reaction solution was cooled to room temperature, and water was added to precipitate a solid. The solid 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 A5 (73 mg, 64%), which was used directly in the next reaction. LC-MS (ESI, m / z): [M+H]+ = 238.56.

[0851] (4) Preparation of Intermediate A6: 1-(1,2-dihydroacenaphthen-5-yl)phenylacetonitrile cyclopropyl-1-amine

[0852] A5 (73 mg, 0.31 mmol) was placed in a single-necked flask, t-BuOH (2 mL) was added, the temperature was lowered to 0°C, and NaClO (0.87 mmol, 0.36 mL) and NaOH (3N, 0.87 mmol, 0.29 mL) were added. The reaction was stirred overnight until the starting material reacted completely and the reaction was stopped. After the reaction was completed, water was added to the reaction solution and the mixture was extracted three times with DCM. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filter cake was washed with DCM. The filtrate was concentrated under reduced pressure to dryness to afford A6 (58 mg, 89%) as a yellow oil, which was used directly in the next step. LC-MS (ESI, m / z): [M+H]+ = 210.43.

[0853] (5) Preparation of Intermediate A9: Methyl 2-chloro-5-(4-methylpiperazin-1-yl)benzoate

[0854] A7 (500 mg, 2.01 mmol) and A8 (242 mg, 2.41 mmol) were placed in a sealed tube, and toluene (10 mL), X-Phos (37 mg, 0.078 mmol), Cs2CO3 (1310 mg, 4.02 mmol), and Pd2(dba)3 (37 mg, 0.040 mmol) were added. N2 was bubbled through the mixture for 30 seconds, and the temperature was raised to 110°C. The reaction was stirred overnight until the starting materials were completely reacted, and the reaction was stopped. After completion of the reaction, the reaction solution was cooled to room temperature, concentrated under reduced pressure to remove the solvent, and purified by column chromatography (PE:EtOAc = 10:1-2:1, then DCM:MeOH = 20:1) to afford A9 (433 mg, 80%) as a yellow oil. LC-MS (ESI, m / z): [M+H]+ = 269.25.

[0855] (6) Preparation of Intermediate A10: 2-chloro-5-(4-methylpiperazin-1-yl)benzoic acid

[0856] A9 (433 mg, 1.62 mmol) was placed in a single-necked flask, and THF (2 mL) and EtOH (2 mL) were added. A solution of NaOH (324 mg, 8.10 g) in H₂O (2 mL) was then added. The temperature was raised to 60°C and stirred for 2 h. The reaction was stopped after complete reaction. After completion of the reaction, 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. The solvent was then concentrated under reduced pressure. The resulting mixture was dissolved in DCM (300 mL), dried over anhydrous sodium sulfate, and filtered. The filter cake was washed with DCM (30 mL). The filtrate was concentrated under reduced pressure to yield A10 (412 mg, 100%) as a yellow solid. LC-MS (ESI, m / z): [M+H]⁺ = 255.38.

[0857] (7) Preparation of Compound Q30: N-(1-(1,2-dihydroacenaphthen-5-yl)cyclopropyl)-2-chloro-5-(4-methylpiperazin-1-yl)benzamide

[0858] A6 (33 mg, 0.16 mmol) and A10 (43 mg, 0.17 mmol) were placed in a single-necked flask. DMF (1.5 mL), DIPEA (68 mg, 0.52 mmol), and HATU (77 mg, 0.20 mmol) were added. The temperature was raised to 50°C and the reaction was stirred for 1.0 h until the starting materials reacted completely, at which point the reaction was stopped. After completion of the reaction, 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 combined organic phases were concentrated under reduced pressure and purified by column chromatography (DCM:MeOH = 20:1) to afford Q30 (8.4 mg) as a white solid. LC-MS (ESI, m / z): C27H28ClN3O, [M+H]+ = 446.29.

[0859] Example 31 (Q31): Preparation of N-(1-(1,2-dihydroacenaphthen-5-yl)cyclopropyl)-2-ethyl-5-(4-methylpiperazin-1-yl)benzamide. The synthetic route is as follows:

[0860] (1) Preparation of Intermediate A9: Methyl 2-ethyl-5-(4-methylpiperazin-1-yl)benzoate

[0861] A7 (1000 mg, 4.11 mmol) and A8 (618 mg, 6.17 mmol) were placed in a sealed tube. Toluene (20 mL), X-Phos (78 mg, 0.16 mmol), Cs2CO3 (2678 mg, 8.22 mmol), and Pd2(dba)3 (75 mg, 0.082 mmol) were added. N2 was bubbled through the mixture for 30 seconds. The temperature was raised to 110°C and the reaction was stirred overnight until the starting materials were completely reacted. The reaction was then stopped. After completion of the reaction, the reaction solution was cooled to room temperature, concentrated under reduced pressure, and purified by column chromatography (PE:EtOAc = 1:1) to afford A9 (1000 mg, 93%) as a yellow oil. LC-MS (ESI, m / z): [M+H]+ = 262.35.

[0862] (2) Preparation of Intermediate A10: 2-ethyl-5-(4-methylpiperazin-1-yl)benzoic acid

[0863] A9 (712 mg, 2.72 mmol) was placed in a single-necked flask, and THF (3 mL) and EtOH (3 mL) were added. A solution of NaOH (544 mg, 13.60 μg) in H₂O (3 mL) was then added. The temperature was raised to 60°C and stirred for 2 h. The reaction was stopped after complete reaction. After completion of the reaction, 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. The solvent was then concentrated under reduced pressure. The resulting mixture was dissolved in DCM (500 mL), dried over anhydrous sodium sulfate, and filtered. The filter cake was washed with DCM (50 mL). The filtrate was concentrated under reduced pressure to yield A10 (675 mg, 100%) as a yellow solid. LC-MS (ESI, m / z): [M+H]⁺ = 249.45.

[0864] (3) Preparation of Compound Q31: N-(1-(1,2-dihydroacenaphthen-5-yl)cyclopropyl)-2-ethyl-5-(4-methylpiperazin-1-yl)benzamide

[0865] A6 (24 mg, 0.11 mmol) and A10 (30 mg, 0.12 mmol) were placed in a single-necked flask, and DMF (1.5 mL), DIPEA (47 mg, 0.36 mmol), and HATU (54 mg, 0.14 mmol) were added. The temperature was raised to 50°C and stirred for 1.0 h until the starting materials reacted completely, at which point the reaction was stopped. After completion of the reaction, the reaction solution was cooled to room temperature and water was added to precipitate a yellow solid. This solid was extracted three times with DCM. The combined organic phases were concentrated under reduced pressure and purified by column chromatography (DCM:MeOH = 20:1) to afford Q31 (11.2 mg, 23%) as a white solid. LC-MS (ESI, m / z): C29H33N3O, [M+H]+ = 440.37.

[0866] Example 32 (Q32): Preparation of N-(1-(1,2-dihydroacenaphthen-5-yl)cyclopropyl)-2-methoxy-5-(4-methylpiperazin-1-yl)benzamide. The synthetic route is as follows:

[0867] (1) Preparation of Intermediate 2: 2-methoxy-5-(4-methylpiperazin-1-yl)benzoate

[0868] To a 100 mL single-necked flask, add methyl 5-bromo-2-methoxybenzoate (500 mg, 2.04 mmol, 1.0 eq.), 1-methylpiperazine (204 mg, 2.04 mmol, 1.0 eq.), Pd2(dba)3 (37 mg, 0.04 mmol, 0.02 eq.), X-phos (39 mg, 0.08 mmol, 0.04 eq.), Cs2CO3 (1.3 g, 4.08 mmol, 2.0 eq.), and 1,4-dioxane (10 mL). Stir at 110°C overnight under N2 protection. Cool and monitor TLC to confirm complete reaction. Dilute with water (20 mL) and EtOAc (20 mL), and separate the layers. Extract the aqueous phase with EtOAc (20 mL x 3). All organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to dryness. The crude product was purified by column chromatography to afford 2-methoxy-5-(4-methylpiperazin-1-yl)benzoate (530 mg, 98% yield). LC-MS (ESI, m / z): [M+H]+ = 265.48.

[0869] (2) Preparation of Intermediate 3: 2-Methoxy-5-(4-methylpiperazin-1-yl)benzoic acid

[0870] To a 100 mL single-necked flask, add 2-methoxy-5-(4-methylpiperazin-1-yl)benzoate (530 mg, 2.00 mmol, 1.0 eq.), NaOH (440 mg, 10.0 mmol, 5.0 eq.), MeOH (6 mL), THF (2 mL), and H₂O (2 mL). Stir at 50°C for 1 hour. Cool and analyze by TLC to determine complete reaction. Add water (10 mL) and adjust the pH to 6 with 1 M HCl. Solid precipitates. Filter, wash the filter cake with water and PE. Scrape off the filter cake and dry it under vacuum. This yields 2-methoxy-5-(4-methylpiperazin-1-yl)benzoic acid (351 mg, 70% yield). LC-MS (ESI, m / z): [M+H]⁺ = 251.18.

[0871] (3) Preparation of Compound Q32: N-(1-(1,2-dihydroacenaphthen-5-yl)cyclopropyl)-2-methoxy-5-(4-methylpiperazin-1-yl)benzamide

[0872] To a 100 mL single-necked flask, add 2-methoxy-5-(4-methylpiperazin-1-yl)benzoic acid (20 mg, 0.08 mmol, 1.0 eq.), 1-(1,2-dihydroacenaphthen-5-yl)cyclopropane-1-amine (17 mg, 0.08 mmol, 1.0 eq.), HATU (46 mg, 0.12 mmol, 1.5 eq.), DIPEA (21 mg, 0.16 mmol, 2.0 eq.), and DMF (3 mL). Stir at 50°C overnight. Cool and analyze by TLC to confirm complete reaction. Dilute with water (10 mL) and EtOAc (10 mL) and separate the layers. Extract the aqueous phase with EtOAc (15 mL x 3). Combine all organic phases, wash with saturated brine (10 mL x 2), dry over anhydrous sodium sulfate, filter, and concentrate to dryness. The crude product was separated by preparative HPLC to give N-(1-(1,2-dihydroacenaphthen-5-yl)cyclopropyl)-2-methoxy-5-(4-methylpiperazin-1-yl)benzamide (1.6 mg). LC-MS (ESI, m / z): [M+H]+=442.18.

[0873] Example 33 (Q33): Preparation of N-(3-(1,2-dihydroacenaphthene-5-yl)oxetane-3-yl)-5-(4-methylpiperazin-1-yl)-2-(trifluoromethyl)benzamide. The synthetic route is as follows:

[0874] (1) Intermediate 1: Preparation of N-(3-(1,2-dihydroacenaphthene-5-yl)oxetane-3-yl)-2-methylpropane-2-sulfonamide

[0875] 5-Bromoacenaphthene (500 mg, 2.14 mmol) was dissolved in anhydrous THF (30 mL), cooled to -78°C, and then 2.5 M n-butyllithium (1.7 mL, 4.28 mmol) was added. After addition, the mixture was allowed to react at this temperature for 30 minutes, followed by the addition of 2-methyl-N-(oxetane-3-ylidene)propane-2-sulfonamide (375 mg, 2.14 mmol) and the reaction continued for 5 hours. After completion, saturated ammonium chloride solution was added dropwise to quench the reaction. Water was added, and the mixture was extracted with ethyl acetate, dried over anhydrous sodium sulfate, and purified by column chromatography (DCM:MeOH = 30:1) to obtain Intermediate 1 (373 mg, 53%). LC-MS (ESI, m / z): C 19 H 23 NO2S, [M+H] + =330.23.

[0876] (2) Preparation of Intermediate 2: 3-(1,2-dihydroacenaphthen-5-yl)oxetane-3-amine hydrochloride

[0877] Intermediate 1 (373 mg, 1.13 mmol) was dissolved in DCM (10 mL), and HCl / 1,4-dioxane (5 mL) was added and reacted at room temperature for 2 hours. After the reaction was completed, the solvent was removed by concentration under reduced pressure to obtain Intermediate 2. LC-MS (ESI, m / z): C 15 H 15 NO, [M+H] + =226.48.

[0878] (3) Preparation of the intermediate 5-(4-methylpiperazin-1-yl)-2-(trifluoromethyl)benzoic acid methyl ester

[0879] Methyl 5-bromo-2-(trifluoromethyl)benzoate (300 mg, 1.06 mmol), 1-methylpiperazine (159 mg, 1.59 mmol), Pd2(dba)3 (97 mg, 0.11 mmol), X-Phos (50 mg, 0.11 mmol), and Cs2CO3 (1.04 g, 3.18 mmol) were dissolved in toluene (20 mL) and heated to 110°C under nitrogen for 12 hours. After completion of the reaction, the mixture was cooled to room temperature, concentrated under reduced pressure to remove the solvent, extracted with dichloromethane, washed three times with water, concentrated under reduced pressure, and purified by column chromatography (DCM:MeOH = 30:1) to obtain intermediate 3 (256 mg, 80%). LC-MS (ESI, m / z): C 14 H 17 F3N2O2, [M+H] + =303.17.

[0880] (4) Preparation of the intermediate 5-(4-methylpiperazin-1-yl)-2-(trifluoromethyl)benzoic acid

[0881] Intermediate 3 (256 mg, 0.85 mmol) was dissolved in a mixture of EtOH and H₂O (1:1, 10 mL). Sodium hydroxide (102 mg, 2.55 mmol) was added and the mixture was heated to 60°C for 1 hour. After completion of the reaction, the mixture was cooled to 0°C and 1N dilute hydrochloric acid was slowly added dropwise to adjust the pH to 5. The solvent was removed by concentration under reduced pressure, and a mixed solvent (DCM:MeOH = 10:1) was added to dissolve the mixture. The mixture was filtered and concentrated under reduced pressure again to obtain Intermediate 4 (240 mg, 98%). LC-MS (ESI, m / z): C 13 H 15 F3N2O2, [M+H] + =289.08.

[0882] (5) Preparation of Compound Q33: N-(3-(1,2-dihydroacenaphthene-5-yl)oxetane-3-yl)-5-(4-methylpiperazin-1-yl)-2-(trifluoromethyl)benzamide

[0883] Intermediate 2 (100 mg, 0.38 mmol) and Intermediate 4 (165 mg, 0.57 mmol) were dissolved in DMF (5 mL), and DIPEA (0.33 mL, 1.9 mmol) and HATU (216 mg, 0.57 mmol) were added. The reaction was heated to 50°C and allowed to react for 2 hours. After completion of the reaction, the mixture was cooled to room temperature and stirred vigorously after adding water. An off-white solid precipitated, which was filtered, dissolved, and purified by column chromatography (DCM:MeOH = 20:1) to give Compound Q33 (116 mg, 62%). LC-MS (ESI, m / z): C 28 H 28 F3N3O2, [M+H] + =495.81.

[0884] Example 34 (Q34): Preparation of N-(2-(1,2-dihydroacenaphthen-5-yl)propan-2-yl)-5-(4-methylpiperazin-1-yl)-2-(trifluoromethyl)benzamide. The synthetic route is as follows:

[0885] (1) Preparation of Intermediate 1: 2-(1,2-dihydroacenaphthen-5-yl)propan-2-amine

[0886] Anhydrous cerium trichloride (821 mg, 3.33 mmol) was added to 30 mL of dry tetrahydrofuran at 0°C and stirred at room temperature for 2 hours under argon. The reaction system was cooled to -78°C and 2.5 M methyl lithium (1.3 mL, 3.33 mmol) was slowly added. After stirring for 30 minutes, 1,2-dihydroacenaphthene-5-carbonitrile (200 mg, 1.11 mmol) was added. The reaction system was returned to room temperature and stirred for 2 hours. The temperature was again lowered to -78°C and an excess of aqueous ammonia was added dropwise. The mixture was extracted with ethyl acetate and the organic phase was collected and separated by column chromatography (DCM:MeOH = 20:1) to obtain Intermediate 1 (150 mg, 64%). LC-MS (ESI, m / z): C 15 H 17 N, [M+H] + =212.06.

[0887] (2) Preparation of Compound Q34: N-(2-(1,2-dihydroacenaphthen-5-yl)propan-2-yl)-5-(4-methylpiperazin-1-yl)-2-(trifluoromethyl)benzamide

[0888] Intermediate 1 (50 mg, 0.24 mmol) and 5-(4-methylpiperazin-1-yl)-2-(trifluoromethyl)benzoic acid (103 mg, 0.36 mmol) were dissolved in DMF (3 mL). DIPEA (0.13 mL, 0.72 mmol) and HATU (137 mg, 0.36 mmol) were added, and the mixture was heated to 50°C for 2 hours. After completion of the reaction, the mixture was cooled to room temperature, and water was added and stirred vigorously. An off-white solid precipitated. The solid was filtered, dissolved, and purified by column chromatography (DCM:MeOH = 20:1) to give compound Q34 (87 mg, 76%). LC-MS (ESI, m / z): C 28 H 30 F3N3O, [M+H] + =481.98.

[0889] Example 38 (Q38): N-(1-(1,2-dihydroacenaphthen-5-yl)cyclopropyl)-2-methyl-5-(1,7-diazaspiro[4.4]nonan-7-yl)benzamide, the synthesis route is as follows

[0890] (1) Preparation of Intermediate 5: 5-(1-benzyl-1,7-diazaspiro[4.4]nonan-7-yl)-N-(1-(1,2-dihydroacenaphthen-5-yl)cyclopropyl)-2-methylbenzamide

[0891] A 15 mL tube was sealed and added with 5-bromo-N-(1-(1,2-dihydroacenaphthen-5-yl)cyclopropyl)-2-methylbenzamide (100 mg, 0.25 mmol, 1 eq), 1-benzyl-1,7-diazaspiro[4.4]nonane (65 mg, 0.3 mmol, 1.2 eq), Cs2CO3 (244 mg, 0.75 mmol, 3 eq), Ru-phos (22 mg, 0.05 mmol, 0.2 eq), Pd(OAc)2 (6 mg, 0.025 mmol, 0.1 eq), and 1,4-dioxane (3 mL). The mixture was stirred at 110°C overnight. After cooling, TLC was performed to determine the disappearance of the starting material. The product was filtered and concentrated to dryness. Column chromatography (DCM:MeOH = 100:0 to 100:10) afforded an off-white solid (105 mg). LC-MS (ESI, m / z): C29H31N3O[M+H]+=542.12.

[0892] (2) Compound Q38: N-(1-(1,2-dihydroacenaphthen-5-yl)cyclopropyl)-2-methyl-5-(1,7-diazaspiro[4.4]nonan-7-yl)benzamide

[0893] To a 25 mL single-necked flask, add intermediate 5 (105 mg), MeOH (3 mL), and Pd(OH)2 (11 mg). Replace the mixture with hydrogen three times under hydrogen conditions and stir overnight at ambient temperature. TLC plate analysis indicated the disappearance of the starting material. Filter and concentrate to dryness. Column chromatography (DCM:MeOH = 100:0-100:10) afforded an off-white solid (25 mg). LC-MS (ESI, m / z): C30H33N3O [M+H]+ = 452.12.

[0894] Example 41 (Q41): 5-(piperazine-4-carboximide)-N-(1-(1,2-dihydroacenaphthen-5-yl)cyclopropyl)-2-methylbenzamide, the synthesis route is as follows:

[0895] (1) Intermediate 5: Preparation of tert-butyl 4-(3-((1-(1,2-dihydroacenaphthen-5-yl)cyclopropyl)carbamoyl)-4-methylphenyl)piperazine-1-carboxylate

[0896] A 250 mL sealed tube was added with 5-bromo-N-(1-(1,2-dihydroacenaphthen-5-yl)cyclopropyl)-2-methylbenzamide (1 g, 2.5 mmol, 1 eq), tert-butyl piperazine-1-carboxylate acetate (730 mg, 3 mmol, 1.2 eq), Cs2CO3 (2.44 g, 7.5 mmol, 3 eq), Ru-phos (220 mg, 0.5 mmol, 0.2 eq), Pd(OAc)2 (60 mg, 0.25 mmol, 0.1 eq), and 1,4-dioxane (30 mL). The mixture was stirred at 110°C overnight. After cooling, TLC was performed to determine the disappearance of the starting material. The product was filtered and concentrated to dryness. Column chromatography (DCM:MeOH = 100:0 to 100:10) afforded an off-white solid (820 mg, 65%). LC-MS (ESI, m / z): [M+H] + =511.96.

[0897] (2) Intermediate 6: Preparation of N-(1-(1,2-dihydroacenaphthen-5-yl)cyclopropyl)-2-methyl-5-(piperazin-1-yl)benzamide hydrochloride

[0898] To a 50 mL single-necked flask, add tert-butyl 4-(3-((1-(1,2-dihydroacenaphthen-5-yl)cyclopropyl)carbamoyl)-4-methylphenyl)piperazine-1-carboxylate (820 mg, 1.6 mmol), DCM (6 mL), and HCl / 1,4-dioxane (3 mL, 3 M). Stir at ambient temperature for 2 h. Monitor the disappearance of the starting material by TLC. Filter and concentrate to dryness to obtain a light yellow solid (900 mg).

[0899] Compound Q41: Preparation of 5-(piperazine-4-carboximide)-N-(1-(1,2-dihydroacenaphthen-5-yl)cyclopropyl)-2-methylbenzamide

[0900] To a 25 mL single-necked flask, add N-(1-(1,2-dihydroacenaphthen-5-yl)cyclopropyl)-2-methyl-5-(piperazin-1-yl)benzamide hydrochloride (134 mg, 0.3 mmol, 1 eq), 1H-pyrazole-1-carboximide hydrochloride (33 mg, 0.36 mmol, 1.2 eq), DIEA (193 mg, 1.5 mmol, 5 eq), and DMF (3 mL). Stir at 50°C overnight. Cool and observe the disappearance of the starting material by TLC. Filter and concentrate to dryness. Column chromatography (DCM:MeOH = 100:0-100:10) afforded an off-white solid (30 mg). LC-MS (ESI, m / z): C29H31N3O [M+H]+ = 454.12.

[0901] Example 42 (Q42): Preparation of 5-(4-(N-formimidoformimido)piperazin-1-yl)-N-(1-(1,2-dihydroacenaphthen-5-yl)cyclopropyl)-2-methylbenzamide. The synthetic route is as follows:

[0902] To a 25 mL single-necked flask, add Intermediate 6 (134 mg, 0.3 mmol, 1 eq), Intermediate 7 (30 mg, 0.36 mmol, 1.2 eq), trimethylsilyl chloride (98 mg, 0.9 mmol, 3 eq), 1,4-dioxane (1 mL), and acetonitrile (1 mL) and stir overnight at 50°C. Cool and observe the disappearance of the starting material using a TLC plate. Filter and concentrate to dryness. Column chromatography (DCM:MeOH = 100:0-100:10) afforded an off-white solid (35 mg). LC-MS (ESI, m / z): C29H31N3O [M+H]+ = 496.12.

[0903] The synthetic routes of other Q series compounds are as follows:

[0904] Referring to Examples 1, 4, 38, 41, and 42, the raw materials were replaced to obtain the corresponding products. Specifically, for example, in a 15 mL sealed tube, 5-bromo-N-(1-(1,2-dihydroacenaphthen-5-yl)cyclopropyl)-2-methylbenzamide (100 mg, 0.25 mmol, 1 eq), the raw material corresponding to R (containing N-heterocyclic hydrochloride) (1.2 eq), Cs2CO3 (244 mg, 0.75 mmol, 3 eq), Ru-phos (22 mg, 0.05 mmol, 0.2 eq), Pd(OAc)2 (6 mg, 0.025 mmol, 0.1 eq), and 1,4-dioxane (2 mL) were added and stirred at 110°C overnight. Cool and detect the disappearance of the raw material by TLC. Filter and concentrate to dryness. Column chromatography (eg, DCM:MeOH=100:0-100:10), followed by deprotection if any protecting group exists, yields the corresponding compound.

[0905] The raw material structures and sources of the R groups are shown in Table 1 below.

[0906] Table 1

[0907] The structures and identification results of the Q series embodiments are summarized in Table 2 below.

[0908] Table 2

[0909] Test Example 1. Protein level enzyme activity test

[0910] 1. Recombinantly express the SARS-CoV-2 PLpro catalytic domain to obtain the reactive protein.

[0911] 2. Substrate: Z-Arg-Leu-Arg-Gly-Gly-AMC (GLPBIO, Catalog No. GA23715).

[0912] 3. Buffer: 50 mM HEPES, 10 mM DTT, 0.1 mM EDTA, pH 7.2.

[0913] 4.384-well plate: Greiner, item number 784076.

[0914] 5. Inhibitor compounds.

[0915] 6. Prepare a single concentration or a concentration gradient of compound stock solution in DMSO.

[0916] 7. Incubate the protein mixture with the compound for 10 minutes.

[0917] 8. Add 15 μL of the protein and compound mixed solution to each well of a 384-well plate.

[0918] 9. Prepare 80 μM substrate working solution.

[0919] 10. Add 5 μL of 80 μM substrate working solution to each well and incubate for 10 minutes.

[0920] 11. Detection: BioTek synergy NEO2, Ex: 360nM / Em: 460nm.

[0921] 12. Data analysis: Use Prism to perform nonlinear regression fitting on the data and calculate IC 50 The results of the P series compounds are shown in Table 3, and the results of the Q series compounds are shown in Table 4.

[0922] Table 3 Inhibitory activity of P series compounds against papain

[0923] Note: +: 0.1 μM <IC50≤1μM;++:0.04μM<IC50≤0.1μM;+++:IC50≤0.04μM

[0924] Table 4. Q series papain inhibitory activity

[0925] Note: +: 0.5uM <IC50<=1μM;++:0.1μM<IC50≤0.5μM;+++:0.03μM<IC50≤0.1μM;++++:IC50<0.03μM

[0926] Test Example 2. Novel Coronavirus Infection Activity Inhibition Experiment of Vero E6 Cells

[0927] 1. Cell line: African green monkey kidney cells Vero E6 (ATCC, CRL-1586).

[0928] 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).

[0929] 3. Positive control: Ensitrelvir (Product No. HY-143216, MedChemExpress LLC).

[0930] 4. Infectious dose: MOI (multiplicity of infection) = 0.01.

[0931] 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 .

[0932] 6. Perform gradient dilution (1:3) with the highest concentration being 10 μM, and set up triplicate wells for each concentration.

[0933] 7. Add virus strain (MOI=0.01) to each well and infect cells for 48 hours.

[0934] 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 of the P series compounds are shown in Table 5, and the results of the Q series compounds are shown in Table 6.

[0935] Table 5 Inhibitory activity of P series compounds on VeroE6 cells infected with virus strains

[0936] Note: +: 0.1μM ≤ IC50 ≤ 1μM; ++: 0.04μM <IC50≤0.1μM;+++:IC50≤0.04μM

[0937] Table 6 Inhibitory activity of Q series compounds on VeroE6 cells infected with virus strains

[0938] Test Example 3. Liver microsome stability test

[0939] 1. Preheat PBS (pH 7.4).

[0940] 2. Preparation of Intermediate Solutions of Test and Positive Reference Compounds

[0941] 2.1 500 μM intermediate solution: Add 5 μL of 10 mM compound stock solution and positive reference compound to 95 μL DMSO;

[0942] 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.

[0943] 3. Prepare NADPH stock solution (6 mM, 5 mg / mL) by dissolving NADPH in PBS.

[0944] 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).

[0945] 5. Pre-incubate the plate at 37°C for 5 minutes.

[0946] 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).

[0947] 7. For other time points, add 15 μL of NADPH stock solution (6 mM) to the wells to start the reaction and timing.

[0948] 8. At 5, 15, 30, and 45 minutes, add 150 μL of the internal standard acetonitrile:methanol (1:1) stop solution to the corresponding wells of the plate to stop the reaction.

[0949] 9. After termination, shake the plate for 10 minutes (600 rpm) and then centrifuge at 4000 rpm for 15 minutes.

[0950] 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. The results are shown in Table 7.

[0951] Table 7 Liver microsome stability test results

[0952] Note: Rat means rat; Human means human; 1 / 2 represents: half-life; Clint represents: clearance rate; Eh represents: clearance ratio.

[0953] Test Example 4. Pharmacokinetic Test

[0954] Conventional PK test in rats:

[0955] 1. The experimental design is shown in Table 8 below:

[0956] Table 8

[0957] 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.

[0958] 2. Preparation of drug delivery preparations:

[0959] Solvent formulation: 10% DMSO, 5% ethanol, 5% Cremophor EL, and 80% deionized water. Weigh 6.68 mg of the test sample 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.

[0960] 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.

[0961] 3. Animal selection:

[0962] 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.

[0963] 4. Animal husbandry:

[0964] 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%.

[0965] 5. Route of administration:

[0966] The drug is administered by oral gavage, and the route of administration should be consistent with the intended clinical route of administration.

[0967] 6. Cage-side observation:

[0968] 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.

[0969] 7. Biological Sample Collection:

[0970] Oral sampling: 8 collection time points in total, 0.25, 0.5, 1, 2, 4, 6, 8 and 24 hours after administration.

[0971] 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.

[0972] 8. Biological Sample Analysis

[0973] 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).

[0974] 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.

[0975] 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.

[0976] 9. Final Disposition of Animals

[0977] All surviving experimental animals were euthanized after the experiment (using a dedicated euthanasia box for carbon dioxide euthanasia).

[0978] 10. Analytical methods

[0979] Analytical instrument: LC-MS / MS-12 (TQ5500, Triple quad);

[0980] Pipette: Eppendorf

[0981] Oscillator: 5810R, Eppendorf

[0982] Centrifuge: 420R, 220R, Eppendorf

[0983] (Other suppliers or models of equipment may be used if necessary)

[0984] Sample processing:

[0985] 1) Take 30 μL of the mixed standard curve sample, quality control sample, blank sample, zero concentration sample and test sample.

[0986] 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.

[0987] 3) Vortex mix for 1 minute

[0988] 4) Centrifuge at 4°C for 7 minutes (18,000 g)

[0989] 5) Take 200 μL of supernatant and add it to the corresponding 96-well sample plate

[0990] 6) 4 μL of the sample was injected and analyzed by LC-MS / MS. The results are shown in Table 9.

[0991] Table 9 In vivo oral pharmacokinetic data of compounds

[0992] Finally, it should be noted that the above embodiments are only used to illustrate the technical solutions of the present disclosure and not to limit it. Although the present disclosure 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 disclosure can still be modified or some technical features can be replaced by equivalents without departing from the spirit of the technical solutions of the present disclosure, which should all be included in the scope of the technical solutions requested for protection in the present disclosure.

Claims

1. A compound represented by formula (Z), 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, E1 and E2 are each independently selected from -C 1-4 Alkylene-, -C(=O)- and -N(R 19 )-; R 19 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; R 11 and R 12 Each independently selected from C 1-6 Alkyl and C 1-6 A haloalkyl group, or R 11 and R 12 Together with the carbon atoms connected together to form C 3-6 Cycloalkyl or 4-6 membered heterocycloalkyl; R 13 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; R 14 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; r is 0, 1, 2, or 3; R 15 Selected from R 16 and R 16 Selected from C 1-8 Alkyl, C 1-8 Haloalkyl and -NH-C 1-8 Alkyl, the C 1-8 Alkyl and C 1-8 The haloalkyl group is optionally substituted with one or more selected from hydrogen, -OH, -OC 1-4 Alkyl, -NH2, -NH-C 1-4 Alkyl and -N(C 1-4 Alkyl)2 group substitution; Ring W 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; R 17 Selected from hydrogen, oxo, halogen, nitro, -CN, -OH, -COOH, -NH2, C 1-6 Alkyl, -OC 1- 6-alkyl, -NH-C 1-6 Alkyl, -N-(C 1-6 alkyl)2, -S(=O)2NH2, -S(=O)2-C 1-6 Alkyl, -C(=O)-C 1-6 Alkyl, -C(=O)-NH-C 1-6 Alkyl, -NH-C(=O)-C 1-6 alkyl, -C(=NH)NH2, -C(=NH)NHC(=NH)NH, 4-8 membered heterocyclic group and -NH-4-8 membered heterocyclic group, wherein the C 1-6 Alkyl and 4-8 membered hetero The ring group is optionally substituted with one or more selected from hydrogen, halogen, nitro, =O, -CN, -OH, -COOH, -NH2, -C 1- 6-alkyl, -OC 1-6 Alkyl, -NH-C 1-6 Alkyl, -N-(C 1-6 alkyl)2, -S(=O)2OH, -S(=O)2NH2, -S(=O)2-C 1-6 Alkyl, -C(=O)-C 1-6 Alkyl, -C(=O)-NH-C 1-6 Alkyl, -NH-C(=O)-C 1-6 Alkyl and morpholinyl radical substitution; R 18 Selected from hydrogen, halogen, nitro, -CN, -OH, -COOH, -NH2, -OC 1-6 Alkyl, -NH-C 1-6 Alkyl, -N-(C 1-6 Alkyl)2, -S(=O)2-C 1-6 Alkyl, -C(=O)-C 1-6 Alkyl, -C(=O)-NH-C 1-6 Alkyl, -NH-C(=O)-C 1-6 Alkyl, -S(=O)2NH2, C 1-6 Alkyl and C 1-6 Haloalkyl, or two R 18 Formation = O; Or, R 17 With R 18 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; Or, two R 18 With the connected atom to form C 3-6 Cycloalkyl and 4-7 membered heterocyclic group, the C 3-6 The cycloalkyl and 4-7 membered heterocyclic groups are optionally substituted by 1, 2 or 3 groups selected from OH and C 1-4 Alkyl radical substitution; s is 0, 1, 2, 3, 4, 5, 6, or 7.

2. The compound according to claim 1, or its stereoisomer, or its tautomer, or its solvate, or its isotope-labeled compound, or its pharmaceutically acceptable salt, wherein: E1 and E2 are each independently selected from -CH2-, -CH2CH2-, -CH(CH3)-, -CH(CH2CH3)-, -C(=O)- and -N(R 19 )-,R 19 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, R 19 Selected from hydrogen, C 1-4 Alkyl and C 3-6 Cycloalkyl, Preferably, R 19 is selected from hydrogen, methyl, ethyl, n-propyl, isopropyl, cyclobutyl, cyclopentyl and cyclobutyl, Preferably, R 19 is selected from hydrogen, methyl, ethyl, isopropyl and cyclopropyl; Preferably, E1 and E2 are each independently selected from -CH2-, -C(=O)- and -N(R 19 )-; Preferably, E1 is selected from -CH2- and -C(=O)-; Preferably, E2 is selected from -CH2- and -N(R 19 )-,R 19 As defined in this claim; Preferably, -E1-E2- is selected from -CH2CH2- and -C(=O)-N(R 19 )-,R 19 As defined in this claim, Preferably, -E1-E2-# is selected from -CH2CH2-#, -C(=O)-NH-#, -C(=O)-N(CH3)-#, -C(=O)-N(CH2CH3)-#, -C(=O)-N[CH(CH3)2]-# and -C(=O)-N(cyclopropyl)-#; More preferably, R 19 Selected from hydrogen and C 1-4 alkyl, More preferably, R 19 is selected from hydrogen, methyl, ethyl and isopropyl, Further preferably, -E1-E2-# is selected from -CH2CH2-#, -C(=O)-NH-#, -C(=O)-N(CH3)-#, -C(=O)-N(CH2CH3)-# and -C(=O)-N[CH(CH3)2]-#.

3. The compound according to claim 1 or 2, or its stereoisomer, or its tautomer, or its solvate, or its isotope-labeled compound, or its pharmaceutically acceptable salt, wherein: R 11 and R 12 Each independently selected from C 1-4 Alkyl and C 1-4 A haloalkyl group, or R 11 and R 12 Together with the carbon atoms connected together to form C 3-5 Cycloalkyl or 4-5 membered heterocycloalkyl, Preferably, R 11 and R 12 are each independently selected from methyl, ethyl and propyl, or R 11 and R 12 Together with the carbon atoms to which they are attached, they form a cyclopropyl, cyclobutyl, cyclopentyl, oxetanyl, azetidinyl, oxolanyl or azolyl group, Preferably, R 11 and R 12 are each independently methyl, or R 11 and R 12 Together with the carbon atoms to which they are attached, they form a cyclopropyl or oxetanyl group, More preferably, the structural unit for 4. The compound according to any one of claims 1 to 3, or its stereoisomer, or its tautomer, or its solvate, or its isotope-labeled compound, or its pharmaceutically acceptable salt, wherein: R 13 Selected from hydrogen, halogen, -CN, -OH, -COOH, -NH2, -OC 1-4 Alkyl, -NH-C 1-4 alkyl,- N-(C 1-4 Alkyl)2, C 1-4 Alkyl and C 1-4 Haloalkyl, Preferably, R 13 is selected from the group consisting of hydrogen, fluorine, chlorine, -CN, -OH, -COOH, -NH2, -O-methyl, -NH-methyl, methyl, ethyl, halomethyl and haloethyl, Preferably, R 13 is selected from chloro, -O-methyl, methyl, ethyl and trifluoromethyl, More preferably, R 13 is selected from chlorine and methyl, More preferably, R 13 It is methyl.

5. The compound according to any one of claims 1 to 4, or its stereoisomer, or its tautomer, or its solvate, or its isotope-labeled compound, or its pharmaceutically acceptable salt, wherein: R 14 Selected from hydrogen, halogen, -CN, -OH, -COOH, -NH2, -OC 1-4 Alkyl, -NH-C 1-4 alkyl,- N-(C 1-4 Alkyl)2, C 1-6 Alkyl and C 1-6 Haloalkyl, Preferably, R 14 is selected from the group consisting of hydrogen, fluorine, chlorine, bromine, -CN, -OH, -COOH, -NH2, -O-methyl, -NH-methyl, methyl, ethyl, halomethyl and haloethyl, Preferably, R 14 For hydrogen.

6. The compound according to any one of claims 1 to 5, or its stereoisomer, or its tautomer, or its solvate, or its isotope-labeled compound, or its pharmaceutically acceptable salt, wherein: R 16 Selected from C 1-6 Alkyl, C 1-6 Haloalkyl and -NH-C 1-6 Alkyl, the C 1-6 Alkyl and C 1-6 The haloalkyl group is optionally substituted by 1, 2, 3, 4 or 5 groups selected from hydrogen, -NH2, -NH-C 1-4 Alkyl and -N(C 1-4 Alkyl)2 group substitution, Preferably, R 16 Selected from C 1-6 Alkyl and -NH-C 1-4 Alkyl, the C 1-6 Alkyl and C 1-4 The alkyl group is optionally substituted by 1, 2 or 3 groups selected from hydrogen, -NH2, -NH-methyl, -NH(methyl)2, Preferably, R 16 Selected from More preferably, R 16 Selected from Ring W is selected from C 4-10 Cycloalkenyl, 4-10 membered heterocyclic group and C 6-10 Aryl, Preferably, ring W is selected from C 4-10 Cycloalkenyl, 4-10 membered heterocyclic group and C 6-10 Aryl, the 4-10 membered heterocyclic group contains 1, 2 or 3 heteroatoms selected from N, O, S, Preferably, ring W 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 and phenyl, Preferably, ring W is selected from in represents the connection site between ring W and the phenyl group in formula (Z); More preferably, ring W is selected from a 4-10 membered heterocyclic group, Further preferably, ring W is selected from a 4-10 membered heterocyclic group, wherein the 4-10 membered heterocyclic group contains 1 or 2 N atoms, and optionally further contains 1 O atom, Further preferably, ring W is selected from in represents the connection site between ring W and the phenyl group in formula (Z); R 17 Selected from hydrogen, oxo, halogen, nitro, -CN, -OH, -COOH, -NH2, C 1-4 Alkyl, -OC 1- 4-alkyl, -NH-C 1-4 Alkyl, -N-(C 1-4 alkyl)2, -S(=O)2NH2, -S(=O)2-C 1-4 Alkyl, -C(=O)-C 1-4 Alkyl, -C(=O)-NH-C 1-4 Alkyl, -NH-C(=O)-C 1-4 alkyl, -C(=NH)NH2, -C(=NH)NHC(=NH)NH, 4-6 membered heterocyclic group and -NH-4-6 membered heterocyclic group, wherein the C 1-4 The alkyl and 4-6 membered heterocyclic groups are optionally substituted by 1, 2, 3, 4 or 5 groups selected from hydrogen, fluorine, chlorine, bromine, =O, -CN, -OH, -COOH, -NH2, -C 1-4 Alkyl, -OC 1-4 Alkyl, -NH-C 1-4 Alkyl, -N-(C 1-4 alkyl)2, -S(=O)2OH, -S(=O)2NH2, -S(=O)2-C 1-4 Alkyl and morpholinyl radicals, Preferably, R 17 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-oxetanyl, -NH-tetrahydrofuran wherein the methyl, ethyl, propyl, butyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, oxetanyl, tetrahydrofuranyl and tetrahydropyranyl are optionally substituted with 1, 2, 3, 4 or 5 groups selected from hydrogen, fluorine, chlorine, bromine, =O, -OH, -COOH, -NH2, methyl, ethyl, propyl, -O-methyl, -O-ethyl, -NH-methyl, -NH-ethyl, -NH-propyl, -NH-butyl, -N(methyl), -N(methyl)-ethyl, -N(ethyl), -S(=O)2OH, -S(=O)2NH2, -S(=O)2-methyl and morpholinyl, Preferably, R 17 Selected from hydrogen, fluorine, -CN, -OH, -NH2, methyl, ethyl, propyl, butyl, The methyl, ethyl, propyl, butyl, is optionally substituted by 1, 2 or 3 groups selected from hydrogen, fluorine, =O, -OH, -COOH, methyl, -N(CH3)2, -NHCH2CH2CH2CH3, -S(=O)2OH, -S(=O)2-methyl and morpholinyl, Preferably, R 17 Selected from hydrogen, fluorine, -CN, -OH, -NH2, -CH3, -CH2CH3, More preferably, R 17 Selected from hydrogen, -CN, -OH, -NH2, C 1-4 Alkyl, -NH-C 1-4 Alkyl, -N-(C 1- 4-membered alkyl)2, 4-6-membered heterocyclic group, -NH-4-6-membered heterocyclic group, -S(=O)2NH2, -S(=O)2-C 1-4 Alkyl, -C(=NH)NH2 and -C(=NH)NHC(=NH)NH, the C 1-4 The alkyl and 4-6 membered heterocyclic groups are optionally substituted by 1, 2 or 3 groups selected from hydrogen, halogen, =O, -CN, -OH, -COOH, -NH2, -N-(C 1-4 alkyl)2, -S(=O)2-methyl, C 1-4 Alkyl and morpholinyl radicals, More preferably, R 17 Selected from hydrogen, -CN, -NH2, C 1-4 Alkyl, -NH-C 1-4 Alkyl, -N-(C 1-4 alkyl)2, 4-6 membered heterocyclic group, -NH-4-6 membered heterocyclic group, -S(=O)2NH2, -S(=O)2-C 1-4 alkyl, -C(=NH)NH2 and -C(=NH)NHC(=NH)NH, the 4-6 membered heterocyclic group contains 1 or 2 heteroatoms selected from N, O, S, the C 1-4 The alkyl and 4-6 membered heterocyclyl groups are optionally substituted by 1, 2 or 3 groups selected from hydrogen, fluorine, =O, -OH, -COOH, -N(CH3)2, -S(=O)2-CH3, -CH3 and morpholinyl, More preferably, R 17 Selected from hydrogen, -CN, -NH2, -CH3, -CH2CH3, More preferably, R 17 Selected from hydrogen, -CN, -NH2, -CH3, -CH2CH3, R 18 are each independently selected from hydrogen, halogen, nitro, -CN, -OH, -COOH, -NH2, -OC 1-4 Alkyl, -NH-C 1-4 Alkyl, -N-(C 1-4 Alkyl)2, -C(=O)-C 1-4 Alkyl, -C(=O)-NH-C 1-4 Alkyl, -NH-C(=O)-C 1-4 Alkyl, C 1-6 Alkyl and C 1-4 Haloalkyl, Preferably, R 18 each independently selected from hydrogen, fluorine, chlorine, bromine, -CN, -OH, -COOH, -NH2, -O-methyl, -O-ethyl, -O-propyl, -NH-methyl, -NH-ethyl, -NH-propyl, -N(methyl), -N(methyl)-ethyl, -N(methyl)-propyl, -N(ethyl), methyl, ethyl, propyl, halomethyl, haloethyl and halopropyl, Preferably, R 18 Each independently selected from hydrogen, fluorine, -OH, -NH2, -COOH and methyl; More preferably, R 18 are each independently selected from hydrogen, fluorine, -OH, -COOH and methyl, More preferably, R 18 are each independently selected from hydrogen, fluorine and methyl; Or, two R 18 Formation =O.

7. The compound according to any one of claims 1 to 6, or its stereoisomer, or its tautomer, or its solvate, or its isotope-labeled compound, or its pharmaceutically acceptable salt, wherein: The compound is selected from the compound represented by formula (PI), 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 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; 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 hydrogen, -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, oxo, halogen, nitro, -CN, -OH, -COOH, -NH2, C 1-6 Alkyl, -OC 1-6 Alkyl, -NH-C 1-6 Alkyl, -N-(C 1-6 alkyl)2, -S(=O)2NH2, -S(=O)2-C 1-6 Alkyl, -C(=O)-C 1-6 Alkyl, -C(=O)-NH-C 1-6 Alkyl, -NH-C(=O)-C 1-6 alkyl, -C(=NH)NH2, -C(=NH)NHC(=NH)NH, 4-8 membered heterocyclic group and -NH-4-8 membered heterocyclic group, wherein the C 1-6 The alkyl and 4-8 membered heterocyclic groups are optionally substituted by one or more selected from hydrogen, halogen, nitro, =O, -CN, -OH, -COOH, -NH2, -C 1-6 Alkyl, -OC 1-6 Alkyl, -NH-C 1-6 Alkyl, -N-(C 1-6 alkyl)2, -S(=O)2OH, -S(=O)2NH2, -S(=O)2-C 1-6 Alkyl, -C(=O)-C 1-6 Alkyl, -C(=O)-NH-C 1-6 Alkyl, -NH-C(=O)-C 1-6 Alkyl and morpholinyl radical substitution; R7 is selected from hydrogen, halogen, nitro, -CN, -OH, -COOH, -NH2, -OC 1-6 Alkyl, -NH-C 1-6 Alkyl, -N-(C 1-6 Alkyl)2, -S(=O)2-C 1-6 Alkyl, -C(=O)-C 1-6 Alkyl, -C(=O)-NH-C 1-6 Alkyl, -NH-C(=O)-C 1-6 Alkyl, -S(=O)2NH2, C 1-6 Alkyl and C 1-6 Haloalkyl, or two R7 form =O; 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 C1-4 alkyl; n is 0, 1, 2, 3, 4, 5, 6 or 7.

8. The compound according to any one of claims 1 to 7, or its stereoisomer, or its tautomer, or its solvate, or its isotope-labeled compound, or its pharmaceutically acceptable salt, 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; Further preferably, R1 is selected from hydrogen and C1-4 alkyl, Further preferably, R1 is selected from hydrogen, methyl, ethyl and isopropyl.

9. The compound according to any one of claims 1 to 8, or its stereoisomer, or its tautomer, or its solvate, or its isotope-labeled compound, or its pharmaceutically acceptable salt, 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.

10. The compound according to any one of claims 1 to 9, or its stereoisomer, or its tautomer, or its solvate, or its isotope-labeled compound, or its pharmaceutically acceptable salt, wherein: R3 is selected from hydrogen, halogen, -CN, -OH, -COOH, -NH2, -OC 1-4 Alkyl, -NH-C 1-4 Alkyl, -N-(C 1-4 Alkyl)2, C 1-6 Alkyl and C 1-6 Haloalkyl, Preferably, R3 is selected from hydrogen, fluorine, chlorine, bromine, -CN, -OH, -COOH, -NH2, -O-methyl, -NH-methyl, methyl, ethyl, halomethyl and haloethyl, Preferably, R3 is hydrogen.

11. The compound according to any one of claims 1 to 10, or its stereoisomer, or its tautomer, or its solvate, or its isotope-labeled compound, or its pharmaceutically acceptable salt, 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 with 1, 2, 3, 4 or 5 selected from hydrogen, -NH2, -NH-C 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 by 1, 2 or 3 groups selected from hydrogen, -NH2, -NH-methyl, -NH(methyl)2, Preferably, R5 is selected from Ring A is selected from C 4-10 Cycloalkenyl and 4-10 membered heterocyclic group, Preferably, 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, 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 (PI); More preferably, ring A is selected from a 4-10 membered heterocyclic group, Further preferably, ring A is selected from a 4-10 membered heterocyclic group, wherein 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 (PI); R6 is selected from hydrogen, oxo, halogen, nitro, -CN, -OH, -COOH, -NH2, C 1-4 Alkyl, -OC 1-4 Alkyl, -NH-C 1-4 Alkyl, -N-(C 1-4 alkyl)2, -S(=O)2NH2, -S(=O)2-C 1-4 Alkyl, -C(=O)-C 1-4 Alkyl, -C(=O)-NH-C 1-4 Alkyl, -NH-C(=O)-C 1-4 alkyl, -C(=NH)NH2, -C(=NH)NHC(=NH)NH, 4-6 membered heterocyclic group and -NH-4-6 membered heterocyclic group, wherein the C 1-4 The alkyl and 4-6 membered heterocyclic groups are optionally substituted by 1, 2, 3, 4 or 5 groups selected from hydrogen, fluorine, chlorine, bromine, =O, -CN, -OH, -COOH, -NH2, -C 1-4 Alkyl, -OC 1-4 Alkyl, -NH-C 1-4 Alkyl, -N-(C 1-4 alkyl)2, -S(=O)2OH, -S(=O)2NH2, -S(=O)2-C 1-4 Alkyl and morpholinyl radicals, 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, wherein the methyl, ethyl, propyl, butyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, oxetanyl, tetrahydrofuranyl and tetrahydropyranyl are optionally substituted with 1, 2, 3, 4 or 5 groups selected from hydrogen, fluorine, chlorine, bromine, =O, -OH, -COOH, -NH2, methyl, ethyl, propyl, -O-methyl, -O-ethyl, -NH-methyl, -NH-ethyl, -N(methyl), -N(methyl)-ethyl, -N(ethyl), -S(=O)2OH, -S(=O)2NH2, -S(=O)2-methyl and morpholinyl, Preferably, R6 is selected from hydrogen, fluorine, -CN, -OH, -NH2, methyl, ethyl, propyl, butyl, The methyl, ethyl, propyl, butyl, optionally substituted by 1, 2 or 3 groups selected from hydrogen, 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 hydrogen, halogen, =O, -CN, -OH, -COOH, -NH2, -N-(C 1-4 alkyl)2, -S(=O)2-methyl, C 1-4 Alkyl and morpholinyl radicals, 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 The alkyl and 4-6 membered heterocyclyl groups are optionally substituted by 1, 2 or 3 groups selected from hydrogen, 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 hydrogen, halogen, nitro, -CN, -OH, -COOH, -NH2, -OC 1-4 Alkyl, -NH-C 1-4 Alkyl, -N-(C 1-4 Alkyl)2, -C(=O)-C 1-4 Alkyl, -C(=O)-NH-C 1-4 Alkyl, -NH-C(=O)-C 1-4 Alkyl, C 1-6 Alkyl and C 1-4 Haloalkyl, Preferably, R7 is each independently selected from hydrogen, fluorine, chlorine, bromine, -CN, -OH, -COOH, -NH2, -O-methyl, -O-ethyl, -O-propyl, -NH-methyl, -NH-ethyl, -NH-propyl, -N(methyl)2, -N(methyl)-ethyl, -N(methyl)-propyl, -N(ethyl)2, methyl, ethyl, propyl, halomethyl, haloethyl and halopropyl, Preferably, R7 are each independently selected from hydrogen, fluorine, -OH, -NH2, -COOH and methyl; Further preferably, R7 are each independently selected from hydrogen, fluorine and methyl; Alternatively, two R7 form =0.

12. The compound according to any one of claims 1 to 11, or its stereoisomer, or its tautomer, or its solvate, or its isotope-labeled compound, or its pharmaceutically acceptable salt, wherein: The compound is selected from the compound represented by formula (PI-1) Wherein, R1, R2, Ring A, R6, R7 and n are defined as any one of claims 1-11; 1) Preferably, the compound is selected from the compound represented by formula (PI-1A) Wherein, R1, R2, R6, R7 and n are defined as any one of claims 1-11; 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 alkyl)2, 4-6 membered heterocyclyl and -NH-4-6 membered heterocyclyl are optionally substituted by 1, 2 or 3 groups selected from hydrogen, fluorine, chlorine, =O, -OH, -NH2, methyl and -N(CH3)2; 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 hydrogen, fluorine, chlorine, =O, -OH, -NH2 and methyl, Preferably, R6 is selected from Preferably, R7 are each independently selected from hydrogen; 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 a 4-6 membered heterocyclic group, wherein the 4-6 membered heterocyclic group is optionally substituted by 1, 2 or 3 selected from hydrogen, 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 hydrogen, fluorine, =O, -OH and methyl, More preferably, R6 is selected from Preferably, the compound is selected from the compound represented by formula (PI-1A-1) in, R1 and R2 are defined as in any one of claims 1 to 11, Ring B is selected from 4-6 membered heterocyclic groups, R 61 is selected from hydrogen, halogen, =O, -CN, -OH, -COOH, -NH2, -C 1-4 Alkyl, -NH-C 1-4 Alkyl and -N-(C 1-4 Alkyl)2, p is 0, 1, 2 or 3; 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 hydrogen, fluorine, chlorine, bromine, =O, -CN, -OH, -COOH, -NH2, methyl, ethyl and propyl, preferably, R 61 is selected from hydrogen, fluorine, =O, -OH and methyl; Preferably, the compound is selected from the compound represented by formula (PI-1A-2) in, R1 and R2 are defined as in any one of claims 1 to 11, 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 (PI-1B) 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 11; 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 hydrogen, 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, the methyl, ethyl, propyl, butyl being optionally substituted by 1, 2 or 3 groups selected from hydrogen, 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 hydrogen, -COOH and C 1-4 alkyl, Preferably, R7 are each independently selected from hydrogen, -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 hydrogen, -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 hydrogen and C 1-4 alkyl, Further preferably, R7 are each independently selected from hydrogen and 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 (PI-1C) in, R1, R2, R6, R7 and n are defined as any one of claims 1 to 11; 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 hydrogen, halogen, -OH, -COOH and methyl, Preferably, R6 is selected from hydrogen, -CH3, Preferably, R7 is hydrogen, 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.

13. The compound according to any one of claims 1 to 6, or its stereoisomer, or its tautomer, or its solvate, or its isotope-labeled compound, or its pharmaceutically acceptable salt, wherein: The compound is selected from the compounds represented by formula (QI), in, R1 and R2 are each independently selected from C 1-6 Alkyl and C 1-6 Haloalkyl, or R1 and R2 together with the carbon atom to which they are attached form a C 3-6 Cycloalkyl or 4-6 membered heterocycloalkyl; R3 is selected from hydrogen, halogen, nitro, -OH, -CN, -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; R4 is selected from hydrogen, halogen, nitro, -OH, -CN, -COOH, -NH2, -OC 1-6 Alkyl, -NH-C 1-6 alkyl Base, -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; L1 is selected from -C 1-6 Alkylene-, -NH-C 1-6 Alkylene-, 4-10 membered heterocycloalkylene, 4-10 membered heterocycloalkenylene, 6-12 membered arylene; R5 is independently selected from hydrogen, halogen, nitro, -OH, -CN, -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 R5 form =O, or two R5 and the connected atom form C 3-8 Cycloalkyl or 4-10 membered heterocycloalkyl, the C 3-8 Cycloalkyl or 4-10 membered heterocycloalkyl is optionally substituted by one or more groups selected from halogen, nitro, -OH, -CN, -COOH, -NH2, -O-methyl, -NH-methyl, methyl or ethyl; L2 is selected from a bond, -NH-, -O-, -S-, -C 1-6 Alkylene-, -NH-C 1-6 Alkylene-, -OC 1-6 Alkylene-, -SC 1-6 Alkylene- and 4-10 membered heterocycloalkylene; R6 is independently selected from hydrogen, halogen, nitro, -OH, -CN, -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)2OH, -S(=O)2NH2, -C(=NH)NH2, -C(=NH)NHC(=NH)NH, C 1-6 Alkyl and 4-7 membered heterocycloalkyl; Or, R5 and -L2-(R6) p connected to form a 4-6 membered heterocyclic group, wherein the 4-6 membered heterocyclic group is optionally substituted by one or more selected from OH and C 1-4 Alkyl radical substitution; m is 0, 1, 2 or 3; n is 0, 1, 2, 3, 4, 5, 6, 7, 8 or 9; p is 1, 2, 3, 4, 5, 6, 7, 8 or 9.

14. The compound according to any one of claims 1 to 6 or 13, or its stereoisomer, or its tautomer, or its solvate, or its isotope-labeled compound, or its pharmaceutically acceptable salt, wherein: R1 and R2 are each independently selected from C 1-4 Alkyl and C 1-4 Haloalkyl, or R1 and R2 together with the carbon atom to which they are attached form a C 3-5 Cycloalkyl or 4-5 membered heterocycloalkyl; Preferably, R1 and R2 are each independently selected from methyl, ethyl and propyl, or R1 and R2 and the carbon atom to which they are connected together form a cyclopropyl, cyclobutyl, cyclopentyl, oxetanyl, azetidinyl, oxolyl or azocyclopentyl group; Preferably, R1 and R2 are each independently a methyl group, or R1 and R2 and the carbon atom to which they are connected together form a cyclopropyl group or an oxetane group; Preferably, the structural unit for 15. The compound according to any one of claims 1 to 6, 13 or 14, 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: R3 is selected from hydrogen, halogen, -OH, -CN, -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, R3 is selected from hydrogen, fluorine, chlorine, bromine, -OH, -CN, -COOH, -NH2, -O-methyl, -NH-methyl, methyl, ethyl, halomethyl and haloethyl; Preferably, R3 is selected from chloro, -O-methyl, methyl, ethyl and trifluoromethyl; Preferably, R3 is selected from chlorine and methyl; Preferably, R3 is methyl.

16. The compound according to any one of claims 1-6, 13-15, or its stereoisomer, or its tautomer, or its solvate, or its isotope-labeled compound, or its pharmaceutically acceptable salt, wherein: R4 is selected from hydrogen, halogen, -OH, -CN, -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, R4 is selected from hydrogen, fluorine, chlorine, bromine, -OH, -CN, -COOH, -NH2, -O-methyl, -NH-methyl, methyl, ethyl, halomethyl and haloethyl; Preferably, R4 is hydrogen.

17. The compound according to any one of claims 1 to 6, 13 to 16, 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: L1 is selected from -C 1-4 Alkylene-, -NH-C 1-4 Alkylene-, 4-7 membered heterocycloalkylene, 4-7 membered heterocycloalkenylene, 6-10 membered arylene, preferably the 4-7 membered heterocycloalkylene or 4-7 membered heterocycloalkenylene contains 1 or 2 N atoms, preferably, L1 is selected from methylene, ethylene, propylene, -NH-methylene-, -NH-ethylene-, -NH-propylene-, azetidinyl, pyrrolidinyl, tetrahydroimidazolyl, piperidinyl, piperazinyl, hexahydropyrimidinyl, homopiperazinyl, morpholinyl, tetrahydropyridinyl and phenylene; R5 is independently selected from hydrogen, halogen, nitro, -OH, -CN, -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 Preferably, R5 is each independently selected from hydrogen, fluorine, chlorine, bromine, -OH, -CN, -COOH, -NH2, -O-methyl, -NH-methyl, -N(methyl)-methyl, methyl, ethyl, halomethyl and haloethyl, preferably, R5 is each independently selected from hydrogen, fluorine, -COOH, -NH2, -O-methyl, -NH-methyl, -N(methyl)-methyl, methyl, ethyl, halomethyl and haloethyl. NH2 and methyl; Alternatively, two R5 form =O; Alternatively, two R5 atoms form a C 3-6 Cycloalkyl or 4-7 membered heterocycloalkyl, the C 3-6 Cycloalkyl or 4-7 membered heterocycloalkyl is optionally substituted by 1, 2 or 3 groups selected from fluorine, chlorine, -OH, -CN, -COOH, -NH2 or methyl. Preferably, two R5 and the atoms connected to it form a cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, tetrahydroimidazolyl, piperidinyl, piperazinyl, homopiperidinyl or homopiperazinyl, and the cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, tetrahydroimidazolyl, piperidinyl, piperazinyl, homopiperidinyl or homopiperazinyl is optionally substituted by 1, 2 or 3 groups selected from fluorine, chlorine, -OH, -CN, -COOH, -NH2 or methyl. Preferably, two R5 and the atoms connected to it form a cyclopropyl, azetidinyl, pyrrolidinyl or piperidinyl, and the cyclopropyl, azetidinyl, pyrrolidinyl or piperidinyl is optionally substituted by 1 -OH or methyl. Structural unit Selected from R5 is as defined in the claims, n is 0, 1, 2, 3 or 4, Preferably, the structural unit Selected from Unless otherwise specified, the right side of the structural unit is connected to L2, and the * end indicates that it is connected to L2.

18. The compound according to any one of claims 1 to 6, 13 to 17, or its stereoisomer, or its tautomer, or its solvate, or its isotope-labeled compound, or its pharmaceutically acceptable salt, wherein: L2 is selected from a bond, -C 1-4 Alkylene- and 4-7 membered heterocycloalkylene, preferably, L2 is selected from a bond, methylene, ethylene, propylene, azetidinyl, pyrrolidinyl and piperidinyl; R6 are each independently selected from hydrogen, halogen, -OH, -CN, -COOH, -NH2, -NH-C 1-4 Alkyl, -N-(C 1- 4-alkyl)2, -S(=O)2-C 1-4 Alkyl, -S(=O)2OH, -S(=O)2NH2, -C(=NH)NH2, -C(=NH)NHC(=NH)NH, C 1-4 Preferably, R6 is each independently selected from hydrogen, fluorine, chlorine, bromine, -OH, -CN, -COOH, -NH2, -NH-methyl, -NH-ethyl, -NH-propyl, -NH-butyl, -N(methyl)-methyl, -N(methyl)-ethyl, -N(methyl)-propyl, -N(ethyl)-ethyl, -N(ethyl)-propyl, -S(=O)2-methyl, -S(=O)2-ethyl, -S(=O)2-propyl, -S(=O)2OH, -S(=O) 2NH2, -C(=NH)NH2, -C(=NH)NHC(=NH)NH2, methyl, ethyl, propyl, butyl and morpholinyl, preferably, R6 are each independently selected from hydrogen, fluorine, -OH, -CN, -COOH, -CH3, -CH2CH3, -CH(CH3)2, -S(=O)2OH, -S(=O)2CH3, -S(=O)2NH2, -NH2, -NHCH3, -N(CH3)2, -NHCH2CH2CH2CH3, Structural unit Selected from R6 is as defined in the claims, p is 1, 2, 3 or 4, Preferably, the structural unit Selected from -CN, Preferably, the structural unit Selected from 19. The compound according to any one of claims 1-6, 13-18, or its stereoisomer, or its tautomer, or its solvate, or its isotope-labeled compound, or its pharmaceutically acceptable salt, wherein: The compound is selected from the compound represented by formula (QI-1) in, L1, L2, R3, R5, R6, n and p are defined as in any one of claims 1-6, 13-18; 1) Preferably, the compound is selected from the compound represented by formula (QI-1-A) in, R3, R5, L2, R6, n and p are defined as in any one of claims 1-6, 13-18, Preferably, said R3 is methyl, Preferably, the R5 is hydrogen, or two R5s and the connected atom form a pyrrolidinyl group, and the pyrrolidinyl group is optionally substituted by 1 methyl group. Preferably, L2 is selected from a bond, an azetidinyl group, a pyrrolidinyl group and a piperidinyl group, Preferably, the R6 are each independently selected from hydrogen, fluorine, -OH and methyl, Preferably, R5 and -L2-(R6) p are connected to form a pyrrolidinyl group, wherein the pyrrolidinyl group is optionally substituted with a methyl group, Preferably, n is 0, 1 or 2, Preferably, p is 1, 2 or 3; More preferably, the compound is selected from the compound represented by formula (QI-1-A1) in, The definitions of R3, R6 and p are as described in any one of claims 1-6, 13-18, and ring A is selected from 4-7 heterocycloalkyl, Preferably, said R3 is methyl, Preferably, the ring A is selected from azetidinyl, pyrrolidinyl and piperidinyl, Preferably, the R6 are each independently selected from hydrogen, fluorine, -OH and methyl, Preferably, p is 1 or 2; 2) Or preferably, the compound is selected from the compound represented by formula (QI-1-B) in, T1 is C, CH or N, is a single bond or a double bond, R3, R5, L2, R6, n and p are as defined in any one of claims 1-6, 13-18, Preferably, said R3 is methyl, Preferably, the R5 is independently selected from hydrogen, -COOH and methyl, or two R5 form =0, or two R5 and the connected atom form a cyclopropyl, azetidinyl, pyrrolidinyl, piperidinyl or homopiperidinyl, and the azetidinyl, pyrrolidinyl, piperidinyl or homopiperidinyl is optionally substituted by 1 -OH, Preferably, said L2 is selected from a bond, a methylene group, an ethylene group and a propylene group, Preferably, each of the R6 is independently selected from hydrogen, -OH, -COOH, -CN, -CH3, -CH(CH3)2, -S(=O)2OH, -S(=O)2CH3, -S(=O)2NH2, -NH2, -NHCH3, -N(CH3)2, Preferably, R5 and -L2-(R6) p are connected to form a pyrrolidinyl group, wherein the pyrrolidinyl group is optionally substituted by 1 hydroxyl group, Preferably, n is 0, 1 or 2, Preferably, p is 1, 2 or 3; Preferably, the compound is selected from the compound represented by formula (QI-1-B1) in, R3, R5, L2 and R6 are defined as in any one of claims 1-6, 13-18, Preferably, said R3 is methyl, Preferably, the R5 are each independently selected from -COOH and methyl, Preferably, said L2 is selected from a bond, a methylene group, an ethylene group and a propylene group, Preferably, each of the R6 is independently selected from hydrogen, -OH, -COOH, -CN, -CH3, -CH(CH3)2, -S(=O)2OH, -S(=O)2CH3, -S(=O)2NH2, -NH2, -NHCH3, -N(CH3)2, Preferably, p is 1 or 2; Preferably, the compound is selected from the compound represented by formula (QI-1-B2) in, R3, L2, R6 and p are defined as in any one of claims 1-6, 13-18, Preferably, said R3 is methyl, Preferably, said L2 is selected from a bond and a methylene group, Preferably, the R6 are each independently selected from hydrogen and methyl, Preferably, p is 1 or 2; Preferably, the compound is selected from the compound represented by formula (QI-1-B3) in, R3, L2, R6 and p are defined as in any one of claims 1-6, 13-18, Preferably, said R3 is methyl, Preferably, said L2 is selected from a bond and a methylene group, Preferably, the R6 are each independently selected from hydrogen and methyl, Preferably, p is 1 or 2; Preferably, the compound is selected from the compound represented by formula (QI-1-B4) in, R3, L2, R6 and p are defined as in any one of claims 1-6, 13-18, Preferably, said R3 is methyl, Preferably, said L2 is selected from a bond and a methylene group, Preferably, the R6 are each independently selected from hydrogen and methyl, Preferably, p is 1 or 2; 3) Or preferably, the compound is selected from the compound represented by formula (QI-1-C) in, R3, R5, L2, R6, n and p are defined as in any one of claims 1-6, 13-18, Preferably, said R3 is methyl, Preferably, the R5 is hydrogen, or two R5s and the atoms connected to them form a pyrrolidinyl or piperidinyl group, wherein the pyrrolidinyl or piperidinyl group is optionally substituted by 1 methyl group, Preferably, said L2 is selected from a bond, a pyrrolidinylene and a piperidinylene, Preferably, the R6 are each independently selected from hydrogen, -NH2, -NHCH3, -N(CH3)2 and Preferably, n is 0, 1 or 2, Preferably, p is 1, 2 or 3; 4) or preferably, the compound is selected from the compound represented by formula (QI-1-D) in, The definitions of R3, L2 and R6 are as described in any one of claims 1-6, 13-18, Preferably, said R3 is methyl, Preferably, said L2 is a bond, Preferably, R6 is methyl.

20. The compound according to any one of claims 1 to 19, or its stereoisomer, or its tautomer, or its solvate, or its isotope-labeled compound, or its pharmaceutically acceptable salt, wherein: The compound is selected from:

21. A pharmaceutical composition comprising at least one compound according to any one of claims 1 to 20, or a stereoisomer thereof, or a tautomer thereof, or a solvate thereof, or an isotope-labeled compound thereof, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers and / or excipients.

22. Use of a compound according to any one of claims 1 to 20, or a stereoisomer thereof, or a tautomer thereof, or a solvate thereof, or an isotope-labeled compound thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 21 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; Preferably, the disease or disorder is selected from respiratory diseases (e.g. 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.

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